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Adjuvant therapy for endometrial cancer
DeLeon, Maria C.; Ammakkanavar, Natraj R.
Endometrial cancer is a common gynecologic malignancy typically diagnosed at early stage and cured with surgery alone. Adjuvant therapy is tailored according to the risk of recurrence, estimated based on the International Federation of Gynecology and Obstetrics (FIGO) stage and other histological factors. The objective of this manuscript is to review the evidence guiding adjuvant therapy for early stage and locally advanced uterine cancer. For patients with early stage disease, minimizing toxicity, while preserving outstanding cure rates remains the major goal. For patients with locally advanced endometrial cancer optimal combined regimens are being defined. Risk stratification based on molecular traits is under development and may aid refine the current risk prediction model and permit personalized approaches for women with endometrial cancer. PMID:24761218
Adjuvant progestagens for endometrial cancer
Martin-Hirsch, Pierre PL; Bryant, Andrew; Keep, Sarah L; Kitchener, Henry C; Lilford, Richard
Background Endometrial cancer is the most common genital tract carcinoma among women in developed countries, with most women presenting with stage 1 disease. Adjuvant progestagen therapy has been advocated following primary surgery to reduce the risk of recurrence of disease. Objectives To evaluate the effectiveness and safety of adjuvant progestagen therapy for the treatment of endometrial cancer. Search methods We searched the Cochrane Gynaecological Cancer Group Trials Specilaised Register, Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2009. MEDLINE and EMBASE up to April 2009. Selection criteria Randomised controlled trials (RCTs) of progestagen therapy in women who have had surgery for endometrial cancer. Data collection and analysis Two review authors independently abstracted data and assessed risk of bias. Risk ratios (RRs) comparing survival in women who did and did not receive progestagen were pooled in random effects meta-analyses.. Main results Seven trials assessing 4556 women were identified. Three trials included women with stage one disease only, whereas four included women with more advanced disease. Meta-analysis of four trials showed that there was no significant difference in the risk of death at five years between adjuvant progestagen therapy and no further treatment (RR = 1.00, 95% CI 0.85 to 1.18). This conclusion is also robust to single trial analyses at 4 and 7 years and in one trial across all points in time using a hazard ratio (HR). There was also no significant difference between progestagen therapy and control in terms of the risk of death from endometrial cancer, cardiovascular disease and intercurrent disease. Relapse of disease appeared to be reduced by progestagen therapy in one trial (HR = 0.71, 95% CI 0.52 to 0.97 and 5 year RR = 0.74, 95% CI 0.58 to 0.96), but there was no evidence of a difference in disease recurrence in another trial at 7 years (RR = 1.34, 95% CI 0.79 to 2.27). Authors' conclusions There
Vaccine adjuvants as potential cancer immunotherapeutics.
Temizoz, Burcu; Kuroda, Etsushi; Ishii, Ken J
Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund's adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy. PMID:27006304
Vaccine adjuvants as potential cancer immunotherapeutics
Temizoz, Burcu; Kuroda, Etsushi
Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund's adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy. PMID:27006304
Extended Adjuvant Therapy for Breast Cancer
An NCI Cancer Currents blog on findings from a recent clinical trial which showed that extending adjuvant therapy with an aromatase inhibitor can have important benefits for some women with early-stage cancer.
Adjuvant Bisphosphonates for Postmenopausal Breast Cancer
A summary of a meta-analysis of randomized trials of bisphosphonates as adjuvant therapy for women with early-stage breast cancer that shows the drugs can reduce the rate of disease recurrence in bone.
Adjuvant high-dose chemotherapy with autologous hematopoietic stem cell support for high-risk primary breast cancer: results from the Italian national registry.
Pedrazzoli, Paolo; Martinelli, Giovanni; Gianni, Alessandro Massimo; Da Prada, Gian Antonio; Ballestrero, Alberto; Rosti, Giovanni; Frassineti, Giovanni Luca; Aieta, Michele; Secondino, Simona; Cinieri, Saverio; Fedele, Roberta; Bengala, Carmelo; Bregni, Marco; Grasso, Donatella; De Giorgi, Ugo; Lanza, Francesco; Castagna, Luca; Bruno, Barbara; Martino, Massimo
The efficacy of high-dose chemotherapy (HDC) and autologous hemopoietic progenitor cell transplantation (AHPCT) for breast cancer (BC) patients has been an area of intense controversy among the medical oncology community. The aim of this study was to assess toxicity and efficacy of this procedure in a large cohort of high-risk primary BC patients who underwent AHPCT in Italy. A total of 1183 patients receiving HDC for high-risk BC (HRBC) (>3 positive nodes) were identified in the Italian registry. The median age was 46 years, 62% of patients were premenopausal at treatment, 60.1% had endocrine-responsive tumors, and 20.7% had a human epidermal growth factor receptor 2 (HER2)-positive tumor. The median number of positive lymph nodes (LN) at surgery was 15, with 71.5% of patients having ≥ 10 positive nodes. Seventy-three percent received an alkylating agent-based HDC as a single procedure, whereas 27% received epirubicin or mitoxantrone-containing HDC, usually within a multitransplantation program. The source of stem cells was peripheral blood in the vast majority of patients. Transplantation-related mortality was .8%, whereas late cardiac and secondary tumor-related mortality were around 1%, overall. With a median follow-up of 79 months, median disease-free and overall survival (OS) in the entire population were 101 and 134 months, respectively. Subgroup analysis demonstrated that OS was significantly better in patients with endocrine-responsive tumors and in patients receiving multiple transplantation procedures. HER2 status did not affect survival probability. The size of the primary tumor and number of involved LN negatively affected OS. Adjuvant HDC with AHPCT has a low mortality rate and provides impressive long-term survival rates in patients with high-risk primary BC. Our results suggest that this treatment modality should be proposed in selected HRBC patients and further investigated in clinical trials.
Synthetic Self-Adjuvanting Glycopeptide Cancer Vaccines
NASA Astrophysics Data System (ADS)
Payne, Richard; McDonald, David; Byrne, Scott
Due to changes in glycosyltransferase expression during tumorigenesis, the glycoproteins of cancer cells often carry highly truncated carbohydrate chains compared to those on healthy cells. These glycans are known as tumor-associated carbohydrate antigens, and are prime targets for use in vaccines for the prevention and treatment of cancer. Herein, we review the state-of-the-art in targeting the immune system towards tumor-associated glycopeptide antigens via synthetic self adjuvanting vaccines, in which the antigenic and adjuvanting moieties of the vaccines are present in the same molecule. The majority of the self-adjuvanting glycopeptide cancer vaccines reported to date employ antigens from mucin 1, a protein which is highly over-expressed and aberrantly glycosylated in many forms of cancer. The adjuvants used in these vaccines predominantly include lipopeptide- or lipoamino acid-based TLR2 agonists, although studies investigating stimulation of TLR9 and TLR4 are also discussed. Most of these adjuvants are highly lipophilic, and, upon conjugation to antigenic peptides, provide amphiphilic vaccine molecules. The amphiphilic nature of these vaccine constructs can lead to the formation of higher-order structures by vaccines in solution, which are likely to be important for their efficacy in vivo.
Adjuvants for peptide-based cancer vaccines.
Khong, Hiep; Overwijk, Willem W
Cancer therapies based on T cells have shown impressive clinical benefit. In particular, immune checkpoint blockade therapies with anti-CTLA-4 and anti-PD-1/PD-L1 are causing dramatic tumor shrinkage and prolonged patient survival in a variety of cancers. However, many patients do not benefit, possibly due to insufficient spontaneous T cell reactivity against their tumors and/or lacking immune cell infiltration to tumor site. Such tumor-specific T cell responses could be induced through anti-cancer vaccination; but despite great success in animal models, only a few of many cancer vaccine trials have demonstrated robust clinical benefit. One reason for this difference may be the use of potent, effective vaccine adjuvants in animal models, vs. the use of safe, but very weak, vaccine adjuvants in clinical trials. As vaccine adjuvants dictate the type and magnitude of the T cell response after vaccination, it is critical to understand how they work to design safe, but also effective, cancer vaccines for clinical use. Here we discuss current insights into the mechanism of action and practical application of vaccine adjuvants, with a focus on peptide-based cancer vaccines. PMID:27660710
Adjuvant and neoadjuvant treatment in pancreatic cancer
Herreros-Villanueva, Marta; Hijona, Elizabeth; Cosme, Angel; Bujanda, Luis
Pancreatic adenocarcinoma is one of the most aggressive human malignancies, ranking 4th among causes for cancer-related death in the Western world including the United States. Surgical resection offers the only chance of cure, but only 15 to 20 percent of cases are potentially resectable at presentation. Different studies demonstrate and confirm that advanced pancreatic cancer is among the most complex cancers to treat and that these tumors are relatively resistant to chemotherapy and radiotherapy. Currently there is no consensus around the world on what constitutes "standard" adjuvant therapy for pancreatic cancer. This controversy derives from several studies, each fraught with its own limitations. Standards of care also vary somewhat with regard to geography and economy, for instance chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America while chemotherapy alone is the current standard in Europe. Regardless of the efforts in adjuvant and neoadjuvant improved therapy, the major goal to combat pancreatic cancer is to find diagnostic markers, identifying the disease in a pre-metastatic stage and making a curative treatment accessible to more patients. In this review, authors examined the different therapy options for advanced pancreatic patients in recent years and the future directions in adjuvant and neoadjuvant treatments for these patients. PMID:22529684
Adjuvant Chemotherapy in Rectal Cancer after Chemoradiotherapy.
Boustani, J; Caubet, M; Bosset, J-F
The aim of this overview was to investigate whether adjuvant chemotherapy has a favourable effect on the outcome of patients with rectal cancer who had preoperative (chemo)radiotherapy. A review of randomised clinical trials that allocated patients between fluorouracil-based and observation or between fluorouracil-based and oxaliplatin-based adjuvant chemotherapy after preoperative (chemo)radiotherapy was carried out, including their corresponding meta-analyses. None of the five randomised trials has shown a significant benefit of fluorouracil-based adjuvant chemotherapy for overall survival or disease-free survival. Also, the three corresponding meta-analyses failed to show a benefit of adjuvant treatment. Of three randomised trials - two phase III and one phase II with a 3-year disease-free survival end point - two showed a small benefit of adding oxaliplatin to fluorouracil, one failed. The corresponding meta-analyses showed that the pooled difference was not significant. In conclusion, the use of postoperative 5-fluorouracil-based chemotherapy with or without oxaliplatin in patients with rectal cancer after preoperative (chemo)radiotherapy is not scientifically proven.
[Adjuvant drug therapies for breast cancer].
Huovinen, Riikka; Auvinen, Päivi; Mattson, Johanna; Joensuu, Heikki
Most breast cancers are hormone receptor positive and exhibit a slow growth pattern. Based on biological properties, breast cancers are divided into four different biological subtypes. Furthermore, these subtypes are indicative of the risk of recurrence, which is also influenced by the size of the tumor and extension to lymph nodes. Postoperative adjuvant drug therapy is chosen on the basis of the biological type. Chemotherapy can be used in all subtypes. Hormonal therapies are used exclusively for the treatment of hormone receptor positive breast cancer. Trastuzumab antibody belongs to the treatment of the HER2 positive subtype. PMID:26245052
Outlining novel cellular adjuvant products for therapeutic vaccines against cancer.
Tefit, Josianne Nitcheu; Serra, Vincent
Despite the library of new adjuvants available for use in vaccines, we remain, at present, almost reliant on aluminum-based compounds for clinical use. The increasing use of recombinant subunit vaccines, however, makes the need for improved adjuvant of particular interest. Adjuvants are crucial components of all cancer vaccines whether they are composed of whole cells, proteins or peptides. For the purposes of this article, cellular adjuvant products are defined as adjuvants associated with cellular or T-cell immunity. Several pharmaceutical companies are developing new adjuvants or immune enhancers for the treatment of cancers such as melanoma and non-small-cell lung carcinoma. Several products are being developed and have entered clinical trials either alone or in combination. In this article, we discuss recent adjuvant development and novel cellular adjuvant products for therapeutic cancer vaccines.
Herbal Medicines as Adjuvants for Cancer Therapeutics
Wang, Chong-Zhi; Calway, Tyler; Yuan, Chun-Su
In the United States, many patients, including cancer patients, concurrently take prescription drugs and herbal supplements. Co-administration of prescription medicines and herbal supplements may have negative outcomes via pharmacodynamic and pharmacokinetic herb-drug interactions. However, multiple constituents in botanicals may also yield beneficial pharmacological activities. Botanicals could possess effective anticancer compounds that may be used as adjuvants to existing chemotherapy to improve efficacy and/or reduce drug-induced toxicity. Herbal medicines, such as ginseng, potentiated the effects of chemotherapeutic agents via synergistic activities, supported by cell cycle evaluations, apoptotic observations, and computer-based docking analysis. Since botanicals are nearly always administrated orally, the role of intestinal microbiota in metabolizing ginseng constituents is presented. Controlled clinical studies are warranted to verify the clinical utility of the botanicals in cancer chemoprevention. PMID:22809022
Adjuvant chemotherapy in head and neck cancer.
Stell, P. M.; Rawson, N. S.
An overview is presented of 23 trials of adjuvant chemotherapy in squamous cell carcinoma of the head and neck. These were reviewed from the point of view of design of the trial, analysis of survival, response rates, meta-analysis, site of failure, toxicity and cost. The minimal increase in survival that could be detected ranged from 11 to 51%, with a median of 25%. No trial was big enough to detect the likely increase of survival, which is 5%. Many trials excluded some eligible patients before randomisation, the proportion being 21% in those series with details. A further 9% of treated patients were excluded from analysis. A response rate in four induction studies of 47% equated with a 6% increase in cancer mortality. Meta-analysis showed an insignificant overall improvement in cancer mortality of 0.5%. Induction chemotherapy, synchronous chemotherapy and induction/maintenance chemotherapy did not affect cancer mortality whereas synchronous/maintenance therapy did. Cisplatinum, methotrexate, bleomycin, 5-FU and a variety of other regimens did not affect the death rate from cancer, but the combination of VBM significantly increased it. Neither single agent nor combination chemotherapy produced a significant reduction of cancer deaths. The rate of locoregional failure was significantly lower in the treated arms, whereas the metastatic rate was similar in both arms. Only three papers gave full details of toxicity with grading: these showed a high toxicity rate. The mortality rate from chemotherapy in nine series averaged 6.5%. PMID:2140045
Update on Adjuvant Chemotherapy for Early Breast Cancer
Rampurwala, Murtuza M; Rocque, Gabrielle B; Burkard, Mark E
Breast cancer is the second most common cancer in women worldwide. Although most women are diagnosed with early breast cancer, a substantial number recur due to persistent micro-metastatic disease. Systemic adjuvant chemotherapy improves outcomes and has advanced from first-generation regimens to modern dose-dense combinations. Although chemotherapy is the cornerstone of adjuvant therapy, new biomarkers are identifying patients who can forego such treatment. Neo-adjuvant therapy is a promising platform for drug development, but investigators should recognize the limitations of surrogate endpoints and clinical trials. Previous decades have focused on discovering, developing, and intensifying adjuvant chemotherapy. Future efforts should focus on customizing therapy and reducing chemotherapy for patients unlikely to benefit. In some cases, it may be possible to replace chemotherapy with treatments directed at specific genetic or molecular breast cancer subtypes. Yet, we anticipate that chemotherapy will remain a critical component of adjuvant therapy for years to come. PMID:25336961
Exercise as an Adjuvant Therapy for Hematopoietic Stem Cell Mobilization
Emmons, Russell; Niemiro, Grace M.; De Lisio, Michael
Hematopoietic stem cell transplant (HSCT) using mobilized peripheral blood hematopoietic stem cells (HSPCs) is the only curative strategy for many patients suffering from hematological malignancies. HSPC collection protocols rely on pharmacological agents to mobilize HSPCs to peripheral blood. Limitations including variable donor responses and long dosing protocols merit further investigations into adjuvant therapies to enhance the efficiency of HSPCs collection. Exercise, a safe and feasible intervention in patients undergoing HSCT, has been previously shown to robustly stimulate HSPC mobilization from the bone marrow. Exercise-induced HSPC mobilization is transient limiting its current clinical potential. Thus, a deeper investigation of the mechanisms responsible for exercise-induced HSPC mobilization and the factors responsible for removal of HSPCs from circulation following exercise is warranted. The present review will describe current research on exercise and HSPC mobilization, outline the potential mechanisms responsible for exercise-induced HSPC mobilization, and highlight potential sites for HSPC homing following exercise. We also outline current barriers to the implementation of exercise as an adjuvant therapy for HSPC mobilization and suggest potential strategies to overcome these barriers. PMID:27123008
Adjuvant chemotherapy for rectal cancer: Is it needed?
Milinis, Kristijonas; Thornton, Michael; Montazeri, Amir; Rooney, Paul S
Adjuvant chemotherapy has become a standard treatment of advanced rectal cancer in the West. The benefits of adjuvant chemotherapy after surgery alone have been well established. However, controversy surrounds the use adjuvant chemotherapy in patients who received preoperative chemoradiotherapy, despite it being recommended by a number of international guidelines. Results of recent multicentre randomised control trials showed no benefit of adjuvant chemotherapy in terms of survival and rates of distant metastases. However, concerns exist regarding the quality of the studies including inadequate staging modalities, out-dated chemotherapeutic regimens and surgical approaches and small sample sizes. It has become evident that not all the patients respond to adjuvant chemotherapy and more personalised approach should be employed when considering the benefits of adjuvant chemotherapy. The present review discusses the strengths and weaknesses of the current evidence-base and suggests improvements for future studies. PMID:26677436
Progress in adjuvant chemotherapy for breast cancer: an overview.
Anampa, Jesus; Makower, Della; Sparano, Joseph A
Breast cancer is the most common cause of cancer and cancer death worldwide. Although most patients present with localized breast cancer and may be rendered disease-free with local therapy, distant recurrence is common and is the primary cause of death from the disease. Adjuvant systemic therapies are effective in reducing the risk of distant and local recurrence, including endocrine therapy, anti-HER2 therapy, and chemotherapy, even in patients at low risk of recurrence. The widespread use of adjuvant systemic therapy has contributed to reduced breast cancer mortality rates. Adjuvant cytotoxic chemotherapy regimens have evolved from single alkylating agents to polychemotherapy regimens incorporating anthracyclines and/or taxanes. This review summarizes key milestones in the evolution of adjuvant systemic therapy in general, and adjuvant chemotherapy in particular. Although adjuvant treatments are routinely guided by predictive factors for endocrine therapy (hormone receptor expression) and anti-HER2 therapy (HER2 overexpression), predicting benefit from chemotherapy has been more challenging. Randomized studies are now in progress utilizing multiparameter gene expression assays that may more accurately select patients most likely to benefit from adjuvant chemotherapy.
Arvelo, Francisco; Cotte, Carlos; Sojo, Felipe
Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Cancer stem cells are a subpopulation of the cells that form the tumor. The discovery of these human cancer cells opens a perspective for understanding tumor recurrence, drug resistance and metastasis; and opens up new research directions on how cancer cells are capable of switching from dormancy to malignancy. Therapeutic alternatives emerge from a better understanding of the biology and the environment of tumor stem cells. The present paper aims to summarize the characteristics and properties of cancer stem cells, the ongoing research, as well as the best strategies for prevention and control of the mechanisms of tumor recurrence.
Chemotherapy targeting cancer stem cells.
Liu, Haiguang; Lv, Lin; Yang, Kai
Conventional chemotherapy is the main treatment for cancer and benefits patients in the form of decreased relapse and metastasis and longer overall survival. However, as the target therapy drugs and delivery systems are not wholly precise, it also results in quite a few side effects, and is less efficient in many cancers due to the spared cancer stem cells, which are considered the reason for chemotherapy resistance, relapse, and metastasis. Conventional chemotherapy limitations and the cancer stem cell hypothesis inspired our search for a novel chemotherapy targeting cancer stem cells. In this review, we summarize cancer stem cell enrichment methods, the search for new efficient drugs, and the delivery of drugs targeting cancer stem cells. We also discuss cancer stem cell hierarchy complexity and the corresponding combination therapy for both cancer stem and non-stem cells. Learning from cancer stem cells may reveal novel strategies for chemotherapy in the future.
Chemotherapy targeting cancer stem cells
Liu, Haiguang; Lv, Lin; Yang, Kai
Conventional chemotherapy is the main treatment for cancer and benefits patients in the form of decreased relapse and metastasis and longer overall survival. However, as the target therapy drugs and delivery systems are not wholly precise, it also results in quite a few side effects, and is less efficient in many cancers due to the spared cancer stem cells, which are considered the reason for chemotherapy resistance, relapse, and metastasis. Conventional chemotherapy limitations and the cancer stem cell hypothesis inspired our search for a novel chemotherapy targeting cancer stem cells. In this review, we summarize cancer stem cell enrichment methods, the search for new efficient drugs, and the delivery of drugs targeting cancer stem cells. We also discuss cancer stem cell hierarchy complexity and the corresponding combination therapy for both cancer stem and non-stem cells. Learning from cancer stem cells may reveal novel strategies for chemotherapy in the future. PMID:26045975
Adjuvant Endocrine Therapy in Premenopausal Women with Breast Cancer
Kadakia, Kunal C.; Henry, N. Lynn
Breast cancer remains the leading cause of cancer related mortality in premenopausal women. Multiple advances in local and systemic therapies have dramatically improved outcomes in women with HR+ early stage breast cancer. Despite these advances, early and late relapses occur. Therefore multiple adjuvant endocrine therapy trials have been conducted with the goal of decreasing breast cancer recurrence and mortality. Recently, large international trials evaluating extended endocrine therapy as well as ovarian suppression with and without tamoxifen or exemestane have been reported. These studies add to the large body of existing data related to adjuvant endocrine therapy in premenopausal women with breast cancer and provide additional therapeutic options in those at high risk of disease recurrence. This review will synthesize the most recent data and provide an evidenced based approach, highlighting quality-of-life concerns, when considering adjuvant endocrine therapies in premenopausal women. PMID:27058571
Role of Adjuvant Chemoradiotherapy for Resected Extrahepatic Biliary Tract Cancer
Kim, Tae Hyun; Han, Sung-Sik; Park, Sang-Jae Lee, Woo Jin; Woo, Sang Myung; Moon, Sung Ho; Yoo, Tae; Kim, Sang Soo; Kim, Seong Hoon; Hong, Eun Kyung; Kim, Dae Yong; Park, Joong-Won
Purpose: To evaluate the effect of adjuvant chemoradiotherapy (CRT) on locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) for patients with extrahepatic biliary tract cancer treated with curative resection. Methods and Materials: The study involved 168 patients with extrahepatic biliary tract cancer undergoing curative resection between August 2001 and April 2009. Of the 168 patients, 115 received adjuvant CRT (CRT group) and 53 did not (no-CRT group). Gender, age, tumor size, histologic differentiation, pre- and postoperative carbohydrate antigen 19-9 level, resection margin, vascular invasion, perineural invasion, T stage, N stage, overall stage, and the use of adjuvant CRT were analyzed to identify the prognostic factors associated with LRC, DFS, and OS. Results: For all patients, the 5-year LRC, DFS, and OS rate was 54.8%, 30.6%, and 33.9%, respectively. On univariate analysis, the 5-year LRC, DFS, and OS rates in the CRT group were significantly better than those in the no-CRT group (58.5% vs. 44.4%, p = .007; 32.1% vs. 26.1%, p = .041; 36.5% vs. 28.2%, p = .049, respectively). Multivariate analysis revealed that adjuvant CRT was a significant independent prognostic factor for LRC, DFS, and OS (p < .05). Conclusion: Our results have suggested that adjuvant CRT helps achieve LRC and, consequently, improves DFS and OS in patients with extrahepatic biliary tract cancer.
Adjuvant therapy in breast cancer and venous thromboembolism.
Mandalà, Mario; Tondini, Carlo
Breast cancer patients are considered to be at relatively low risk of developing a TEE. The highest incidence of VTE events occurs in metastatic breast cancer patients likely due to extension of disease, immobility for pathologic bone fractures, cancer cachexia and venous compression by the tumour mass. Although thrombosis is less common in patients with early stage cancer compared to those with more advanced disease, it does occur and is clinically challenging. The adjuvant setting is of particular interest in order to assess the specific thrombogenic potential of systemic chemotherapy, because of the low tumor burden with only microscopic tumor foci at the time of treatment administration. This review summarizes risk factors, incidence and strategies to avoid VTE in breast cancer patients receiving adjuvant therapy.
[Development of Nucleic Acid-Based Adjuvant for Cancer Immunotherapy].
Kobiyama, Kouji; Ishii, Ken J
Since the discovery of the human T cell-defined tumor antigen, the cancer immunotherapy field has rapidly progressed, with the research and development of cancer immunotherapy, including cancer vaccines, being conducted actively. However, the disadvantages of most cancer vaccines include relatively weak immunogenicity and immune escape or exhaustion. Adjuvants with innate immunostimulatory activities have been used to overcome these issues, and these agents have been shown to enhance the immunogenicity of cancer vaccines and to act as mono-therapeutic anti-tumor agents. CpG ODN, an agonist for TLR9, is one of the promising nucleic acid-based adjuvants, and it is a potent inducer of innate immune effector functions. CpG ODN suppresses tumor growth in the absence of tumor antigens and peptide administration. Therefore, CpG ODN is expected to be useful as a cancer vaccine adjuvant as well as a cancer immunotherapy agent. In this review, we discuss the potential therapeutic applications and mechanisms of CpG ODN for cancer immunotherapy.
[Development of Nucleic Acid-Based Adjuvant for Cancer Immunotherapy].
Kobiyama, Kouji; Ishii, Ken J
Since the discovery of the human T cell-defined tumor antigen, the cancer immunotherapy field has rapidly progressed, with the research and development of cancer immunotherapy, including cancer vaccines, being conducted actively. However, the disadvantages of most cancer vaccines include relatively weak immunogenicity and immune escape or exhaustion. Adjuvants with innate immunostimulatory activities have been used to overcome these issues, and these agents have been shown to enhance the immunogenicity of cancer vaccines and to act as mono-therapeutic anti-tumor agents. CpG ODN, an agonist for TLR9, is one of the promising nucleic acid-based adjuvants, and it is a potent inducer of innate immune effector functions. CpG ODN suppresses tumor growth in the absence of tumor antigens and peptide administration. Therefore, CpG ODN is expected to be useful as a cancer vaccine adjuvant as well as a cancer immunotherapy agent. In this review, we discuss the potential therapeutic applications and mechanisms of CpG ODN for cancer immunotherapy. PMID:26469159
Ovarian cancer stem cells enrichment.
Yang, Lijuan; Lai, Dongmei
The concept of cancer stem cells (CSCs) provides a new paradigm for understanding cancer biology. Cancer stem cells are defined as a minority of cancer cells with stem cell properties responsible for maintenance and growth of tumors. The targeting of CSCs is a potential therapeutic strategy to combat ovarian cancer. Ovarian epithelial cancer cells cultured in serum-free medium can form sphere cells. These sphere cells may be enriched for cancer stem cells (CSCs). The isolation of sphere cells from solid tumors is an important technique in studying cancer cell biology. Here we describe the isolation of sphere cells from primary ovarian cancer tissue, ascites fluid, and the cancer cell line SKOV3 with stem cell selection medium. PMID:23913228
Zhu, Ya-Yun; Yuan, Zhou
Studies are emerging in support of the cancer stem cells (CSCs) theory which considers that a tiny subset of cancer cells is exclusively responsible for the initiation and malignant behavior of a cancer. This cell population, also termed CSCs, possesses the capacity both to self-renew, producing progeny that have the identical tumorigenic potential, and to differentiate into the bulk of cancer cells, helping serve the formation of the tumor entities, which, altogether, build the hierarchically organized structure of a cancer. In this review, we try to articulate the complicated signaling pathways regulating the retention of the characteristics of pancreatic CSCs, and in the wake of which, we seek to offer insights into the CSCs-relevant targeted therapeutics which are, in the meantime, confronted with bigger challenges than ever. PMID:26045976
Postoperative adjuvant therapy of breast cancer. Oncology Overview
Not Available
Oncology Overviews are a service of the International Cancer Research Data Bank (ICRDB) Program of the National Cancer Institute, intended to facilitate and promote the exchange of information between cancer scientists by keeping them aware of literature related to their research being published by other laboratories throughout the world. Each Oncology Overview represents a survey of the literature associated with a selected area of cancer research. It contains abstracts of articles which have been selected and organized by researchers associated with the field. Contents: Postoperative chemotherapy; Postoperative radiotherapy; Postoperative hormone therapy; Postoperative immunotherapy and chemoimmunotherapy; Postoperative multimodal therapy; Prognostic factors in postoperative adjuvant therapy.
Carbohydrate-based vaccines with a glycolipid adjuvant for breast cancer.
Huang, Yen-Lin; Hung, Jung-Tung; Cheung, Sarah K C; Lee, Hsin-Yu; Chu, Kuo-Ching; Li, Shiou-Ting; Lin, Yu-Chen; Ren, Chien-Tai; Cheng, Ting-Jen R; Hsu, Tsui-Ling; Yu, Alice L; Wu, Chung-Yi; Wong, Chi-Huey
Globo H (GH) is a hexasaccharide specifically overexpressed on a variety of cancer cells and therefore, a good candidate for cancer vaccine development. To identify the optimal carrier and adjuvant combination, we chemically synthesized and linked GH to a carrier protein, including keyhole limpet hemocyanion, diphtheria toxoid cross-reactive material (CRM) 197 (DT), tetanus toxoid, and BSA, and combined with an adjuvant, and it was administered to mice for the study of immune response. Glycan microarray analysis of the antiserum obtained indicated that the combination of GH-DT adjuvanted with the α-galactosylceramide C34 has the highest enhancement of anti-GH IgG. Compared with the phase III clinical trial vaccine, GH-keyhole limpet hemocyanion/QS21, the GH-DT/C34 vaccine elicited more IgG antibodies, which are more selective for GH and the GH-related epitopes, stage-specific embryonic antigen 3 (SSEA3) and SSEA4, all of which were specifically overexpressed on breast cancer cells and breast cancer stem cells with SSEA4 at the highest level (>90%). We, therefore, further developed SSEA4-DT/C34 as a vaccine candidate, and after immunization, it was found that the elicited antibodies are also IgG-dominant and very specific for SSEA4.
Neoadjuvant and Adjuvant Chemotherapy of Cervical Cancer.
Mallmann, Peter; Mallmann, Christoph
Neoadjuvant chemotherapy is indicated in patients who can tolerate the side effects of a chemotherapy and with preoperative presentation of one of the following clinical risk situations: bulky disease with a maximal tumor diameter of > 4 cm, suspicious lymph nodes in magnetic resonance imaging (MRI), computed tomography (CT) scan or endosonography, histopathologically confirmed lymph node metastasis, or histopathologically documented risk factors such as G3 and L1V1. A neoadjuvant chemotherapy followed by surgery should be performed with cisplatin at a dosage of > 25 mg/m2 per week and an application interval of < 14 days. The previously published data suggests an improved rate of complete resection and reduced incidences of positive lymph nodes and parametric infiltration. Accordingly, the percentage of patients in need for adjuvant radiochemotherapy after operation can be significantly reduced. Some studies demonstrated a prolongation of progression-free and overall survival. Following the previously published studies, adjuvant chemotherapy after operation or after radiochemotherapy has no significant effect on the overall survival and, following the current guidelines, should be avoided. PMID:27614740
Role of Adjuvant Chemoradiotherapy for Ampulla of Vater Cancer
Kim, Kyubo; Chie, Eui Kyu Jang, Jin-Young; Kim, Sun Whe; Oh, Do-Youn; Im, Seock-Ah; Kim, Tae-You; Bang, Yung-Jue; Ha, Sung W.
Purpose: To evaluate the role of adjuvant chemoradiotherapy for ampulla of Vater cancer. Methods and Materials: Between January 1991 and December 2002, 118 patients with ampulla of Vater cancer underwent en bloc resection. Forty-one patients received adjuvant chemoradiotherapy [RT(+) group], and 77 did not [RT(-) group]. Postoperative radiotherapy was delivered to the tumor bed and regional lymph nodes, for a total dose of up to 40 Gy delivered in 2-Gy fractions, with a planned 2-week rest period halfway through the treatment period. Intravenous 5-fluorouracil (500 mg/m{sup 2}/day) was given on Days 1 to 3 of each split course. The median follow-up was 65 months. Results: The 5-year overall survival rate in the RT(-) and RT(+) groups was 66.9% and 52.8%, respectively (p = 0.2225). The 5-year locoregional relapse-free survival rate in the RT(-) and RT(+) groups was 79.9% and 80.2%, respectively (p = 0.9582). When age, type of operation, T stage, N stage, histologic differentiation, and the use of adjuvant chemoradiotherapy were incorporated into the Cox proportional hazard model, there was an improvement in the locoregional relapse-free survival rate (p = 0.0050) and a trend toward a longer overall survival (p = 0.0762) associated with the use of adjuvant chemoradiotherapy. Improved overall survival (p = 0.0235) and locoregional relapse-free survival (p = 0.0095) were also evident in patients with nodal metastasis. In contrast, enhanced locoregional control (p = 0.0319) did not result in longer survival in patients with locally advanced disease (p = 0.4544). Conclusions: Adjuvant chemoradiotherapy may enhance locoregional control and overall survival in patients with ampulla of Vater cancer after curative resection, especially in those with nodal involvement.
Evolution of endocrine adjuvant therapy for early breast cancer.
Lønning, Per Eystein
Endocrine treatment plays a pivotal role in the adjuvant therapy of patients harbouring oestrogen and/or progesterone receptor positive breast cancer. The objective of this paper is to critically review endocrine treatment options in early breast cancer focusing on ongoing development. Literature was collected through the ISI Web of Science and PubMed in January/February 2009 with subsequent update by December 2009, using the words breast cancer, endocrine therapy, oestrogen receptor and aromatase. Endocrine therapy improves outcome in early breast cancer. Yet several controversies remain. There has recently been a lack of general consensus regarding the limit of oestrogen receptor positivity. As for adjuvant therapy in general and use of aromatase inhibitors in particular, we need the results from ongoing studies to decide what may be the optimal duration of therapy and regimen (sequential treatment versus monotherapy; one drug compared with another). Further, there is a need to critically assess optimal use of endocrine therapy for metastatic disease among patients previously exposed to endocrine regimens in the adjuvant setting. While in general the mechanisms of resistance to endocrine therapy among ER positive tumours remains unknown, merging evidence suggest a role of different growth factor pathways, in particular HER-2 activation. Thus, particular attention is paid to the topic of HER-2 expression as a potential cause of endocrine resistance.
Compliance to adjuvant therapy in breast cancer patients.
Dittmer, C; Roeder, K; Hoellen, F; Salehin, D; Thill, M; Fischer, D
During recent years a continuous reduction of mortality from breast cancer has taken place in the Western countries. We wanted to verify whether the actual therapy for our own cases deviates from our recommendations, although the surgeon, radiotherapist and gynaecological oncologist are on the same premises. We sent out questionnaires to all newly diagnosed breast cancer patients in the last seven years regarding their adjuvant therapy. Comparing these answers to our own recommendation showed a very good compliance regarding chemotherapy and radiation therapy. Adjuvant endocrine therapy showed a very poor compliance with an adherence of 77%. Overall we can conclude that endocrine therapy causes many side-effects that seem to burden the patients. In combination with the duration of the therapy this causes a severe reduction in compliance and length of the therapy.
Mitomycin C as an adjuvant in resected gastric cancer.
Alcobendas, F; Milla, A; Estape, J; Curto, J; Pera, C
As a result of their previous experience with mitomycin C at high discontinuous doses in advanced gastric cancer, the authors studied its role as an adjuvant for locally advanced cases after surgical complete resection. Results from 70 evaluable patients are presented. Patients were allocated randomly to receive mitomycin C, 20 mg/m2 I.V. direct once every 6 weeks, four courses, or a placebo. After a follow-up period of 250 weeks, seven patients of treatment arm and 23 controls have already relapsed (p less than 0.001). Toxicity was moderate and controllable by symptomatic measures. The authors consider this investigation a positive contribution in the field of adjuvant therapy of gastric cancer. PMID:6407408
Chitin, Chitosan, and Glycated Chitosan Regulate Immune Responses: The Novel Adjuvants for Cancer Vaccine
Li, Xiaosong; Min, Min; Du, Nan; Gu, Ying; Hode, Tomas; Naylor, Mark; Chen, Dianjun; Nordquist, Robert E.; Chen, Wei R.
With the development of cancer immunotherapy, cancer vaccine has become a novel modality for cancer treatment, and the important role of adjuvant has been realized recently. Chitin, chitosan, and their derivatives have shown their advantages as adjuvants for cancer vaccine. In this paper, the adjuvant properties of chitin and chitosan were discussed, and some detailed information about glycated chitosan and chitosan nanoparticles was also presented to illustrate the trend for future development. PMID:23533454
Adjuvant Everolimus for Resected Kidney Cancer
In this clinical trial, patients with renal cell cancer who have undergone partial or complete nephrectomy will be randomly assigned to take everolimus tablets or matching placebo tablets daily for 54 weeks.
Optimizing Adjuvant Therapy for Resected Pancreatic Cancer
In this clinical trial, patients with resected pancreatic head cancer will be randomly assigned to receive either gemcitabine with or without erlotinib for 5 treatment cycles. Patients who do not experience disease progression or recurrence will then be r
Redefining Adjuvant Therapy for Colon Cancer
In this trial, patients with resected stage III colon cancer are being randomly assigned to receive FOLFOX chemotherapy for either 3 or 6 months and to take either a pill called celecoxib or a matching placebo pill for 3 years.
Adjuvant systemic therapy in older women with breast cancer.
Leone, Julieta; Leone, Bernardo Amadeo; Leone, José Pablo
Breast cancer in the elderly is an increasing clinical problem. In addition, ~60% of deaths from breast cancer occur in women aged 65 years and older. Despite this, older women with breast cancer have been underrepresented in clinical trials, and this has led to less than optimal evidence to guide their therapy. The management of elderly women with early breast cancer is a complex process that requires careful evaluation of life expectancy, comorbidities, patient values, and risks and benefits of available treatment options. This review will focus on current adjuvant systemic therapy options for older women with breast cancer, discuss the principles in the decision-making process, and define the role of endocrine therapy, chemotherapy, and targeted agents. PMID:27524919
Adjuvant systemic therapy in older women with breast cancer
Leone, Julieta; Leone, Bernardo Amadeo; Leone, José Pablo
Breast cancer in the elderly is an increasing clinical problem. In addition, ~60% of deaths from breast cancer occur in women aged 65 years and older. Despite this, older women with breast cancer have been underrepresented in clinical trials, and this has led to less than optimal evidence to guide their therapy. The management of elderly women with early breast cancer is a complex process that requires careful evaluation of life expectancy, comorbidities, patient values, and risks and benefits of available treatment options. This review will focus on current adjuvant systemic therapy options for older women with breast cancer, discuss the principles in the decision-making process, and define the role of endocrine therapy, chemotherapy, and targeted agents. PMID:27524919
[New insights in the adjuvant treatment of gastric cancer].
Jansen, E P M; Boot, H; Cats, A; van Coevorden, F; Zoetmulder, F A N; Verheij, M
The current standard treatment of patients with gastric cancer is partial or total stomach resection and dissection of the draining lymph nodes. This approach, however, results in a rather low survival rate, partly because the diagnosis is often established in an advanced stage. Various strategies, including adjuvant radiotherapy, chemotherapy or more extensive surgical procedures, have resulted mainly in increased morbidity without improving survival. In a recent randomised trial, concurrent postoperative radiotherapy and chemotherapy prolonged survival and reduced the chance of a local recurrence at an acceptable toxicity. Although several aspects of combined radiochemotherapy require further study, this new treatment concept appears to be a promising addition to the therapeutic arsenal for gastric cancer.
Adjuvant Treatment for Gastric Cancer: Chemotherapy Versus Radiation
Ashraf, Noman; Hoffe, Sarah
Gastric cancer is among the leading causes of cancer death worldwide. Surgery is the only curative modality, but mortality remains high because a significant number of patients have recurrence after complete surgical resection. Chemotherapy, radiation, and chemoradiotherapy have all been studied in an attempt to reduce the risk for relapse and improve survival. There is no globally accepted standard of care for resectable gastric cancer, and treatment strategies vary across the world. Postoperative chemoradiation with 5-fluorouracil/leucovorin is most commonly practiced in the United States; however, recent clinical trials from Asia have shown benefit of adjuvant chemotherapy alone and have questioned the role of radiation. In this review, we examine the current literature on adjuvant treatment of gastric cancer and discuss the roles of radiation and chemotherapy, particularly in light of these new data and their applicability to the Western population. We highlight some of the ongoing and planned clinical trials in resectable gastric cancer and identify future directions as well as areas where further research is needed. PMID:23966224
Bisphosphonates in the adjuvant treatment of breast cancer.
Winter, M C; Coleman, R E
Bisphosphonates, as potent inhibitors of osteoclast-mediated bone resorption, significantly reduce the risk of skeletal complications in metastatic bone disease and also prevent cancer treatment-induced bone loss (CTIBL). However, more recently, there has been increasing data indicating that bisphosphonates exhibit anti-tumour activity, possibly via both indirect and direct effects, and can potentially modify the metastatic disease process providing more than just supportive care. The evidence from previous studies of an anti-tumour effect of bisphosphonates was inconclusive, with conflicting evidence from adjuvant oral clodronate trials. However, more recent trials using zoledronic acid have shown benefits in terms of disease-free and overall survival outcomes in certain subgroups, most evidently in older premenopausal women with hormone-sensitive disease treated with ovarian suppression, and in women in established menopause at trial entry. In the adjuvant setting, the use of bisphosphonates has also been focused on the prevention and treatment of CTIBL and recent guidelines have defined treatment strategies for CTIBL. The role of bisphosphonates in CTIBL in early breast cancer is well defined. There have been mixed results from large adjuvant metastasis-prevention studies of bisphosphonates, but there are strong signals from large subgroups analyses of randomised phase III trials suggesting significant anti-tumour beneficial effects in specific patient populations.
Velasco-Velázquez, Marco A.; Homsi, Nora; De La Fuente, Marisol; Pestell, Richard G.
Breast cancer stem cells (BCSCs) constitute a subpopulation of tumor cells that express stem cell-associated markers and have a high capacity for tumor generation in vivo. Identification of BCSCs from tumor samples or breast cancer cell lines has been based mainly on CD44+/CD24−/low or ALDH+ phenotypes. BCSCs isolation has allowed the analysis of the molecular mechanisms involved in their origin, self-renewal, differentiation into tumor cells, resistance to radiation therapy and chemotherapy, and invasiveness and metastatic ability. Molecular genetic analysis using knockout animals and inducible transgenics have identified NF-κB, c-Jun, p21CIP1, and Forkhead-like-protein Dach1 in BCSC expansion and fate. Clinical analyses of BCSCs in breast tumors have found a correlation between the proportion of BCSCs and poor prognosis. Therefore, new therapies that specifically target BCSCs are an urgent need. We summarize recent evidence that partially explain the biological characteristics of BCSCs. PMID:22249027
Stem cells, colorectal cancer and cancer stem cell markers correlations.
Cherciu, Irina; Bărbălan, A; Pirici, D; Mărgăritescu, C; Săftoiu, A
: The idea of stem cells as being progenitors of cancer was initially controversial, but later supported by research in the field of leukemia and solid tumors. Afterwards, it was established that genetic abnormalities can affect the stem and progenitor cells, leading to uncontrolled replication and deregulated differentiation. These alterations will cause the changeover to cancerous stem cells (CSC) having two main characteristics: tumor initiation and maintenance. This review will focus on the colorectal cancer stem cell (CR-CSCs) theory which provides a better understanding of different tumor processes: initiation, aggressive growth, recurrence, treatment resistance and metastasis. A search in PubMed/Medline was performed using the following keywords: colorectal cancer stem cells (CR-CSCs), colorectal neoplasms stem cells, colorectal cancer stem cell (CR-CSCs) markers, etc. Electronic searches were supplemented by hand searching reference lists, abstracts and proceedings from meetings. Isolation of CR-CSCs can be achieved by targeting and selecting subpopulation of tumor cells based on expression of one or multiple cell surface markers associated with cancer self-renewal, markers as: CD133, CD166, CD44, CD24, beta1 integrin-CD29, Lgr5, EpCAM (ESA), ALDH-1, Msi-1, DCAMLK1 or EphB receptors. The identification and localization of CR-CSCs through different markers will hopefully lead to a better stratification of prognosis and treatment response, as well as the development of new effective strategies for cancer management.
The Adjuvant Nutritional Intervention in Cancer (ANICA) Trial.
Bjørklund, Geir
Adjuvant Nutritional Intervention in Cancer (ANICA) was a clinical study carried out in Denmark in the 1990s with 32 typical patients with breast cancer, aged 32-81 yr and classified high risk because of tumor spread to the lymph nodes. The patients received standard therapy for their breast cancer, but got from the start additionally an adjuvant therapy in form of a cocktail consisting of vitamin C (2,850 mg/day), vitamin E (2,500 IU/day), beta-carotene (32.5 IU/day), selenium (Se; 387 micrograms/day), various other vitamins and essential trace elements, essential fatty acids (1.2 g gamma-linolenic acid/day and 3.5 g omega-3 PUFAs/day), and coenzyme Q10 (CoQ10, 90 mg/day). The protocol was later changed, with reduction of the Se intake and more coenzyme Q10 than when the study was started. The average survival of high-risk breast patients in the study was 50% after 5 yr, whereas for low-risk breast cancer patients (without metastases in the axilla when treatment was started), the average survival was 90% after ten years. The main investigator died, and the final report from the ANICA study was therefore never written. However, the published preliminary results from the trial were very promising; it seems, therefore, important to follow-up this study. PMID:26473998
New approach to adjuvant radiotherapy in rectal cancer
Mohiuddin, M.; Dobelbower, R.R.; Kramer, S.
A sandwich technique of adjuvant radiotherapy was used to treat twenty-three patients with rectal cancer. In this technique, low dose preoperative irradiation (500 rad in one treatment) was given to all patients followed by immediate surgery (usually an A-P resection); on the basis of histopathological findings, patients with stage B/sub 2/ and C rectal cancer were selectively given 4500 rad post-operative irradiation in 5 weeks. Nine patients had early lesions (stage A and B/sub 1/) and did not receive postoperative irradiation. Thirteen patients had stage B/sub 2/ and C disease and hence received the full course of postoperative irradiation. One patient was found to have liver metastasis at the time of surgery, and hence received only palliative therapy. Follow-up of these twenty-three patients ranges from 10 months to 24 months with a median follow-up of 15 months. Treatment was well-tolerated with few side effects. Only two of the twenty-two patients who were treated for cure have failed to date. Both patients had stage C/sub 2/ disease; one patient developed an anterior abdominal wall recurrence in the surgical scar 3 months post-treatment and the second patient developed brain and bone metastases. No patients have failed in the pelvis. We feel this technique of adjuvant therapy is a logical approach to the treatment of rectal cancer and has potential for improving survival. The rationale for this approach to adjuvant radiotherapy is discussed together with implications for survival.
Adjuvant photodynamic therapy (PDT) of the superficial bladder cancer
NASA Astrophysics Data System (ADS)
Sokolov, V. V.; Russakov, I. G.; Teplov, A. A.; Filonenko, E. V.; Ul'yanov, R. V.; Bystrov, A. A.
Superficial transitional cell carcinoma represents 50 to 80% of newly diagnosed bladder cancer in various countries. Transurethral resection of the urinary bladder is the standard procedure for biopsy and treatment superficial bladder cancer. However recurrence tumors after transurethral resection alone is high enough (50-90%). Intravesical chemotherapy for prophylaxis after complete transurethral resection is reducing recurrence rate about 1 5%. Adjuvant intravesical Bacillus of Calmette and Guerin (BCG) is reducing recurrence rate about 30%, but frequency side effects of this therapy is very high. Purpose of this study is appreciate efficacy adjuvant PDT with photosensitizer Photogeme (Russia) of superficial bladder cancer for prophylaxis after complete transurethral resection. The follow up was from 3 to 63 months (27 months, on average). Sixty-five patients (75.6%) showed no recurrence. For the follow up period, the recurrence was revealed in 21 (24.4%) patient, in two of them it was progressing (one case of invasive growth and one case of remote metastases). Four cases of recurrence were revealed 4 months after the surgery. In other cases, the recurrence was diagnosed from 9 to 18 months.
Adjuvant platinum-based chemotherapy for early stage cervical cancer
Rosa, Daniela D; Medeiros, Lídia RF; Edelweiss, Maria I; Pohlmann, Paula R; Stein, Airton T
Background This is an updated version of the original Cochrane review published in The Cochrane Library 2009, Issue 3. Most women with early cervical cancer (stages I to IIA) are cured with surgery or radiotherapy, or both. We performed this review originally because it was unclear whether cisplatin-based chemotherapy after surgery, radiotherapy or both, in women with early stage disease with risk factors for recurrence, was associated with additional survival benefits or risks. Objectives To evaluate the effectiveness and safety of platinum-based chemotherapy after radical hysterectomy, radiotherapy, or both in the treatment of early stage cervical cancer. Search methods For the original 2009 review, we searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2009, Issue 1), MEDLINE, EMBASE, LILACS, BIOLOGICAL ABSTRACTS and CancerLit, the National Research Register and Clinical Trials register, with no language restriction. We handsearched abstracts of scientific meetings and other relevant publications. We extended the database searches to November 2011 for this update. Selection criteria Randomised controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy (after radical surgery, radiotherapy or both) with no adjuvant chemotherapy, in women with early stage cervical cancer (stage IA2-IIA) with at least one risk factor for recurrence. Data collection and analysis Two review authors extracted data independently. Meta-analysis was performed using a random-effects model, with death and disease progression as outcomes. Main results For this updated version, we identified three additional ongoing trials but no new studies for inclusion. Three trials including 368 evaluable women with early cervical cancer were included in the meta-analyses. The median follow-up period in these trials ranged from 29 to 42 months. All women had undergone surgery first. Two trials
Uncaria tomentosa—Adjuvant Treatment for Breast Cancer: Clinical Trial
Santos Araújo, Maria do Carmo; Farias, Iria Luiza; Gutierres, Jessie; Dalmora, Sergio L.; Flores, Nélia; Farias, Julia; de Cruz, Ivana; Chiesa, Juarez; Morsch, Vera Maria; Chitolina Schetinger, Maria Rosa
Breast cancer is the most frequent neoplasm affecting women worldwide. Some of the recommended treatments involve chemotherapy whose toxic effects include leukopenia and neutropenia. This study assessed the effectiveness of Uncaria tomentosa (Ut) in reducing the adverse effects of chemotherapy through a randomized clinical trial. Patients with Invasive Ductal Carcinoma—Stage II, who underwent a treatment regimen known as FAC (Fluorouracil, Doxorubicin, Cyclophosphamide), were divided into two groups: the UtCa received chemotherapy plus 300 mg dry Ut extract per day and the Ca group that only received chemotherapy and served as the control experiment. Blood samples were collected before each one of the six chemotherapy cycles and blood counts, immunological parameters, antioxidant enzymes, and oxidative stress were analyzed. Uncaria tomentosa reduced the neutropenia caused by chemotherapy and was also able to restore cellular DNA damage. We concluded that Ut is an effective adjuvant treatment for breast cancer. PMID:22811748
Uncaria tomentosa-Adjuvant Treatment for Breast Cancer: Clinical Trial.
Santos Araújo, Maria do Carmo; Farias, Iria Luiza; Gutierres, Jessie; Dalmora, Sergio L; Flores, Nélia; Farias, Julia; de Cruz, Ivana; Chiesa, Juarez; Morsch, Vera Maria; Chitolina Schetinger, Maria Rosa
Breast cancer is the most frequent neoplasm affecting women worldwide. Some of the recommended treatments involve chemotherapy whose toxic effects include leukopenia and neutropenia. This study assessed the effectiveness of Uncaria tomentosa (Ut) in reducing the adverse effects of chemotherapy through a randomized clinical trial. Patients with Invasive Ductal Carcinoma-Stage II, who underwent a treatment regimen known as FAC (Fluorouracil, Doxorubicin, Cyclophosphamide), were divided into two groups: the UtCa received chemotherapy plus 300 mg dry Ut extract per day and the Ca group that only received chemotherapy and served as the control experiment. Blood samples were collected before each one of the six chemotherapy cycles and blood counts, immunological parameters, antioxidant enzymes, and oxidative stress were analyzed. Uncaria tomentosa reduced the neutropenia caused by chemotherapy and was also able to restore cellular DNA damage. We concluded that Ut is an effective adjuvant treatment for breast cancer.
Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer
Sparano, Joseph A.; Wang, Molin; Martino, Silvana; Jones, Vicky; Perez, Edith A.; Saphner, Tom; Wolff, Antonio C.; Sledge, George W.; Wood, William C.; Davidson, Nancy E.
BACKGROUND We compared the efficacy of two different taxanes, docetaxel and paclitaxel, given either weekly or every 3 weeks, in the adjuvant treatment of breast cancer. METHODS We enrolled 4950 women with axillary lymph node–positive or high-risk, lymph node–negative breast cancer. After randomization, all patients first received 4 cycles of intravenous doxorubicin and cyclophosphamide at 3-week intervals and were then assigned to intravenous paclitaxel or docetaxel given at 3-week intervals for 4 cycles or at 1-week intervals for 12 cycles. The primary end point was disease-free survival. RESULTS As compared with patients receiving standard therapy (paclitaxel every 3 weeks), the hazard ratio for disease-free survival was 1.27 among those receiving weekly paclitaxel (P = 0.006), 1.23 among those receiving docetaxel every 3 weeks (P = 0.02), and 1.09 among those receiving weekly docetaxel (P = 0.29) (with a hazard ratio >1 favoring the groups receiving experimental therapy). As compared with standard therapy, weekly paclitaxel was also associated with improved survival (hazard ratio, 1.32; P = 0.01). An exploratory analysis of a subgroup of patients whose tumors expressed no human epidermal growth factor receptor type 2 protein found similar improvements in disease-free and overall survival with weekly paclitaxel treatment, regardless of hormone-receptor expression. Grade 2, 3, or 4 neuropathy was more frequent with weekly paclitaxel than with paclitaxel every 3 weeks (27% vs. 20%). CONCLUSIONS Weekly paclitaxel after standard adjuvant chemotherapy with doxorubicin and cyclophosphamide improves disease-free and overall survival in women with breast cancer. (ClinicalTrials.gov number, NCT00004125.) PMID:18420499
The role of adjuvant radiation in endometrial cancer.
Diavolitsis, Virginia; Boyle, John; Singh, Diljeet K; Small, William
Endometrial cancer treatment ideally begins with a staging procedure including abdominopelvic washing, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and lymph node evaluation. Recommendations for postoperative adjuvant radiotherapy are determined by recurrence risk. Patients who have undergone staging and have early stage I disease and an absence of high-risk features for recurrence generally are treated with surgery alone. Intermediate-risk patients--those with high-risk stage I disease and some stage II patients--may benefit from adjuvant radiation therapy. Several randomized trials show that radiation therapy improves locoregional control among intermediate-risk patients. The optimal type of radiation therapy, whether vaginal brachytherapy or whole-pelvic radiation therapy, remains undetermined, though treatment decision can be guided by risk factors not encompassed by the current staging system. Patients with high-risk stage II disease and stage III disease generally receive external-beam radiotherapy, often in combination with chemotherapy. Chemotherapy alone in advanced-stage patients is a consideration, given the results of the Gynecologic Oncology Group (GOG)-122 trial.
The role of adjuvant radiation in endometrial cancer.
Diavolitsis, Virginia; Boyle, John; Singh, Diljeet K; Small, William
Endometrial cancer treatment ideally begins with a staging procedure including abdominopelvic washing, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and lymph node evaluation. Recommendations for postoperative adjuvant radiotherapy are determined by recurrence risk. Patients who have undergone staging and have early stage I disease and an absence of high-risk features for recurrence generally are treated with surgery alone. Intermediate-risk patients--those with high-risk stage I disease and some stage II patients--may benefit from adjuvant radiation therapy. Several randomized trials show that radiation therapy improves locoregional control among intermediate-risk patients. The optimal type of radiation therapy, whether vaginal brachytherapy or whole-pelvic radiation therapy, remains undetermined, though treatment decision can be guided by risk factors not encompassed by the current staging system. Patients with high-risk stage II disease and stage III disease generally receive external-beam radiotherapy, often in combination with chemotherapy. Chemotherapy alone in advanced-stage patients is a consideration, given the results of the Gynecologic Oncology Group (GOG)-122 trial. PMID:19476264
Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments
Sundahl, Nora; Clarisse, Dorien; Bracke, Marc; Offner, Fritz; Berghe, Wim Vanden; Beck, Ilse M.
Although adverse effects and glucocorticoid resistance cripple their chronic use, glucocorticoids form the mainstay therapy for acute and chronic inflammatory disorders, and play an important role in treatment protocols of both lymphoid malignancies and as adjuvant to stimulate therapy tolerability in various solid tumors. Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance. In this context, selective GR agonists and modulators (SEGRAMs) with a more restricted GR activity profile have been developed, holding promise for further clinical development in anti-inflammatory and potentially in cancer therapies. Thus far, the research into the prospective benefits of selective GR modulators in cancer therapy limped behind. Our review discusses how selective GR agonists and modulators could improve the therapy regimens for lymphoid malignancies, prostate or breast cancer. We summarize our current knowledge and look forward to where the field should move to in the future. Altogether, our review clarifies novel therapeutic perspectives in cancer modulation via selective GR targeting. PMID:27713909
Adjuvant therapy use among Appalachian breast cancer survivors.
Tan, Xi; Marshall, Vincent D; Anderson, Roger T; Donohoe, Joseph; Camacho, Fabian; Balkrishnan, Rajesh
There is a paucity of literature systemically examining the effects of access to cancer care resources on adjuvant endocrine therapy (AET) use behaviors, especially in underserved regions such as the Appalachian region in the United States, where gaps in healthcare access are well documented. The objectives of this study were to explore AET adherence and persistence in Appalachia, delineate the effects of access to care cancer on adherence/persistence, and evaluate the influences of adherence and persistence on overall survival.A retrospective cohort study from 2006 to 2008 was conducted among female breast cancer survivors living in the Appalachian counties of 4 states (PA, OH, KY, and NC). We linked cancer registries to Medicare claims data and included patients with invasive, nonmetastatic, hormone-receptor-positive breast cancer who received guideline-recommended AET. Medication adherence was defined as corresponding to a Medication Possession Ratio (MPR) ≥0.8 and logistic regression was utilized to assess predictors of adherence. Medication nonpersistence was defined as the discontinuation of drugs after exceeding a 60-day medication gap, and multivariate adjusted estimates of nonpersistence were obtained using the Cox proportional hazards (PH) model.About 31% of the total 428 patients were not adherent to AET, and 30% were not persistent over an average follow-up period of 421 days. Tamoxifen, relative to aromatase inhibitors, was associated with higher odds of adherence (odds ratio = 2.82, P < 0.001) and a lower risk of nonpersistence (hazard ratio = 0.40, P < 0.001). Drug-related side effects like pain may be an important factor leading to nonadherence and early discontinuation. In addition, aromatase inhibitor (AI) adherence and persistence were significantly influenced by out-of-pocket drug costs, dual eligibility status, and coverage gaps. Nonadherence to and nonpersistence with AET were associated with higher risks of all-cause mortality.Our findings
K, Rycaj; D.G, Tang
Purpose Radiation therapy has made significant contributions to cancer therapy. However, despite continuous improvements, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be attributable to the presence of cancer stem cells (CSCs). Conclusions This review discusses CSC-specific mechanisms that confer radiation resistance with a focus on breast cancer and glioblastoma multiforme (GBM), thereby emphasizing the addition of these potential therapeutic targets in order to potentiate radiotherapy efficacy. PMID:24527669
Who Benefits From Adjuvant Radiation Therapy for Gastric Cancer? A Meta-Analysis
Ohri, Nitin; Garg, Madhur K.; Aparo, Santiago; Kaubisch, Andreas; Tome, Wolfgang; Kennedy, Timothy J.; Kalnicki, Shalom; Guha, Chandan
Purpose: Large randomized trials have demonstrated significant survival benefits with the use of adjuvant chemotherapy or chemoradiation therapy for gastric cancer. The importance of adjuvant radiation therapy (RT) remains unclear. We performed an up-to-date meta-analysis of randomized trials testing the use of RT for resectable gastric cancer. Methods and Materials: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized trials testing adjuvant (including neoadjuvant) RT for resectable gastric cancer. Hazard ratios describing the impact of adjuvant RT on overall survival (OS) and disease-free survival (DFS) were extracted directly from the original studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. Subgroup analyses were performed to determine whether the efficacy of RT varies with chemotherapy use, RT timing, geographic region, type of nodal dissection performed, or lymph node status. Results: Thirteen studies met all inclusion criteria and were used for this analysis. Adjuvant RT was associated with a significant improvement in both OS (HR = 0.78, 95% CI: 0.70-0.86, P<.001) and DFS (HR = 0.71, 95% CI: 0.63-0.80, P<.001). In the 5 studies that tested adjuvant chemoradiation therapy against adjuvant chemotherapy, similar effects were seen for OS (HR = 0.83, 95% CI: 0.67-1.03, P=.087) and DFS (HR = 0.77, 95% CI: 0.91-0.65, P=.002). Available data did not reveal any subgroup of patients that does not benefit from adjuvant RT. Conclusion: In randomized trials for resectable gastric cancer, adjuvant RT provides an approximately 20% improvement in both DFS and OS. Available data do not reveal a subgroup of patients that does not benefit from adjuvant RT. Further study is required to optimize the implementation of adjuvant RT for gastric cancer with regard to patient selection and integration with systemic therapy.
[A case of early gastric cancer completely responding to adjuvant chemotherapy for advanced colon cancer].
Tanaka, Ryo; Kameyama, Hitoshi; Nakano, Mae; Ichikawa, Hiroshi; Hanyu, Takaaki; Nakano, Masato; Ishikawa, Takashi; Shimada, Yoshifumi; Sakata, Jun; Kobayashi, Takashi; Kosugi, Shinichi; Minagawa, Masahiro; Koyama, Yu; Wakai, Toshifumi
A 70-year-old man was referred to our hospital with ascending colon cancer (cT3N1M0, Stage IIIa), which was found during examinations following a positive fecal occult blood test. The patient was also diagnosed with early gastric cancer (cT1a, N0, M0, Stage IA)during a preoperative gastroscopy examination. A laparoscopically assisted right colectomy and D3 lymphadenectomy was performed for the ascending colon cancer. The postoperative pathological diagnosis was Stage IIIb (pT3N2), he was administered in combination with capecitabine plus oxaliplatin (CapeOX) as adjuvant chemotherapy before the treatment for the colon cancer. After 6 months of adjuvant chemotherapy, we were unable to detect any gastric lesions at the same location using gastroscopy, and so diagnosed a clinical complete response. A follow-up gastroscopy 6 months later showed the same findings. The patient has had no recurrence of gastric cancer for 18 months after the initial operation. He will continue to be followed up closely using gastroscopy. In this case, CapeOX as adjuvant chemotherapy for advanced colon cancer was also effective for early gastric cancer.
Current adjuvant treatment modalities for gastric cancer: From history to the future
Kilic, Leyla; Ordu, Cetin; Yildiz, Ibrahim; Sen, Fatma; Keskin, Serkan; Ciftci, Rumeysa; Pilanci, Kezban Nur
The discrepancy between the surgical technique and the type of adjuvant chemotherapy used in clinical trials and patient outcomes in terms of overall survival rates has led to the generation of different adjuvant treatment protocols in distinct parts of the world. The adjuvant treatment recommendation is generally chemoradiotherapy in the United States, perioperative chemotherapy in the United Kingdom and parts of Europe, and chemotherapy in Asia. These options mainly rely on the United States Intergroup-0116, United Kingdom British Medical Research Council Adjuvant Gastric Infusional Chemotherapy, and the Asian Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer and Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer trials. However, the benefits were evident for only certain patients, which were not very homogeneous regarding the type of surgery, chemotherapy regimens, and stage of disease. Whether the dissimilarities in survival are attributable to surgical technique or intrinsic biological differences is a subject of debate. Regardless of the extent of surgery, multimodal therapy may offer modest survival advantage at least for diseases with lymph node involvement. Moreover, in the era of individualized treatment for most of the other cancer types, identification of special subgroups comprising those who will derive more or no benefit from adjuvant therapy merits further investigation. The aim of this review is to reveal the historical evolution and future reflections of adjuvant treatment modalities for resected gastric cancer patients. PMID:27190583
Adjuvant Trastuzumab in HER2-Positive Breast Cancer
Slamon, Dennis; Eiermann, Wolfgang; Robert, Nicholas; Pienkowski, Tadeusz; Martin, Miguel; Press, Michael; Mackey, John; Glaspy, John; Chan, Arlene; Pawlicki, Marek; Pinter, Tamas; Valero, Vicente; Liu, Mei-Ching; Sauter, Guido; von Minckwitz, Gunter; Visco, Frances; Bee, Valerie; Buyse, Marc; Bendahmane, Belguendouz; Tabah-Fisch, Isabelle; Lindsay, Mary-Ann; Riva, Alessandro; Crown, John
BACKGROUND Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. METHODS We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. RESULTS At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. CONCLUSIONS The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006
[Adjuvant chemotherapy for resectable non-small cell lung cancer (NSCLC)].
Nakajima, Eiji; Katou, H
A randomized clinical trial of adjuvant chemotherapy has been evaluated for non-small cell lung cancer (NSCLC) patients, because the prognosis of early NSCLC does not enough after surgery (stage I: 70-80%, stage II: 50% in overall 5-years survival). Japanese guide line for lung cancer treatment (2005 edition) recommends adjuvant chemotherapy after complete resection for pathological stage IB, II and IIIA. Previous studies have suggested that uracil-tegafur has benefit for stage IB NSCLC patients, and platinum-based adjuvant chemotherapy has benefit for stage IB, II and IIIA NSCLC patients. In 2007 ASCO Annual Meeting, Harpole D talked about molecular prognostic profiles in early resected NSCLC. The goal of this study design is to validate a molecular-based tumor model that identifies those patients at low risk for cancer recurrence who will not benefit from adjuvant chemotherapy. The remaining patients will be randomly assigned to observation (the present standard of care) or adjuvant chemotherapy to determine the efficacy of adjuvant in this population. Biomarker for response of chemotherapy will be available to know who has benefit from adjuvant chemotherapy. When each patient has appropriate adjuvant chemotherapy, the prognosis is improved by that.
Adjuvants and myeloid-derived suppressor cells: enemies or allies in therapeutic cancer vaccination.
Fernández, Audry; Oliver, Liliana; Alvarez, Rydell; Fernández, Luis E; Lee, Kelvin P; Mesa, Circe
Adjuvants are a critical but largely overlooked and poorly understood component included in vaccine formulations to stimulate and modulate the desired immune responses to an antigen. However, unlike in the protective infectious disease vaccines, adjuvants for cancer vaccines also need to overcome the effect of tumor-induced suppressive immune populations circulating in tumor-bearing individuals. Myeloid-derived suppressor cells (MDSC) are considered to be one of the key immunosuppressive populations that inhibit tumor-specific T cell responses in cancer patients. This review focuses on the different signals for the activation of the immune system induced by adjuvants, and the close relationship to the mechanisms of recruitment and activation of MDSC. This work explores the possibility that a cancer vaccine adjuvant may either strengthen or weaken the effect of tumor-induced MDSC, and the crucial need to address this in present and future cancer vaccines.
Cancer stem cell signaling pathways.
Matsui, William H
Tissue development and homeostasis are governed by the actions of stem cells. Multipotent cells are capable of self-renewal during the course of one's lifetime. The accurate and appropriate regulation of stem cell functions is absolutely critical for normal biological activity. Several key developmental or signaling pathways have been shown to play essential roles in this regulatory capacity. Specifically, the Janus-activated kinase/signal transducer and activator of transcription, Hedgehog, Wnt, Notch, phosphatidylinositol 3-kinase/phosphatase and tensin homolog, and nuclear factor-κB signaling pathways have all been shown experimentally to mediate various stem cell properties, such as self-renewal, cell fate decisions, survival, proliferation, and differentiation. Unsurprisingly, many of these crucial signaling pathways are dysregulated in cancer. Growing evidence suggests that overactive or abnormal signaling within and among these pathways may contribute to the survival of cancer stem cells (CSCs). CSCs are a relatively rare population of cancer cells capable of self-renewal, differentiation, and generation of serially transplantable heterogeneous tumors of several types of cancer. PMID:27611937
Margaritaria discoidea (Euphorbiaceae) stem bark extract attenuates allergy and Freund's adjuvant-induced arthritis in rodents
Obiri, David D.; Osafo, Newman; Oppong-Sarfo, Joshua; Prah, Jude K.
Background: Various parts of Margaritaria discoidea find use in traditional medicine in the treatment of pain and oedema. This study evaluated the anti-allergic, anti-inflammatory and anti-arthritic effects of a 70% (v/v) aqueous ethanol extract of the stem bark of Margaritaria discoidea, MDE in rodents. Materials and Methods: Systemic anaphylaxis was induced by the injection of compound 48/80 into mice and their survival rate was monitored to evaluate the anti-allergic action of the extract. The effect of MDE assessed on the maximal and total oedema responses in the mouse carrageenan-induced paw oedema was used to evaluate the anti-inflammatory action of the extract while the Freund's adjuvant-induced arthritis model was employed to study the anti-arthritic effects of MDE. Results: MDE dose-dependently increased the time for compound 48/80-induced mortality in mice. MDE suppressed the mean maximal swelling and the total paw swellings induced over 6 h in the carrageenan-induced paw oedema when administered either prophylactically or therapeutically. MDE caused a reduction in serum levels of TNFα and IL-6 and significantly suppressed Freund's adjuvant-induced arthritis. Conclusion: Margaritaria discoidea suppresses allergy and exhibits anti-inflammatory activity in mice. In addition it attenuates Freund's adjuvant-induced arthritis through a reduction in serum levels of TNFα and IL-6 in rats. PMID:24761122
Targeting Breast Cancer Stem Cells
McDermott, Sean P.; Wicha, Max S.
The cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self renewing cell populations that constitute the bulk of the tumor. Although, the CSC hypothesis does not directly address the cell of origin of cancer, it is postulated that tissue-resident stem or progenitors are the most common targets of transformation. Clinically, CSCs are predicted to mediate tumor recurrence after chemo- and radiation-therapy due to the relative inability of these modalities to effectively target CSCs. If this is the case, then CSC must be efficiently targeted to achieve a true cure. Similarities between normal and malignant stem cells, at the levels of cell-surface proteins, molecular pathways, cell cycle quiescence, and microRNA signaling present challenges in developing CSC-specific therapeutics. Approaches to targeting CSCs include the development of agents targeting known stem cell regulatory pathways as well as unbiased high-throughput siRNA or small-molecule screening. Based on studies of pathways present in normal stem cells, recent work has identified potential "Achilles heals" of CSC, whereas unbiased screening provides opportunities to identify new pathways utilized by CSC as well as develop potential therapeutic agents. Here, we review both approaches and their potential to effectively target breast CSC. PMID:20599450
Cancer Stem Cells Converted from Pluripotent Stem Cells and the Cancerous Niche
Kasai, T; Chen, L; Mizutani, AZ; Kudoh, T; Murakami, H; Fu, L; Seno, M
Nowadays, the cancer stem cells are considered to be significantly responsible for growth, metastasis, invasion and recurrence of all cancer. Cancer stem cells are typically characterized by continuous proliferation and self-renewal as well as by differentiation potential, while stem cells are considered to differentiate into tissue- specific phenotype of mature cells under the influence of micro-environment. Cancer stem cells should be traced to the stem cells under the influence of a micro-environment, which induces malignant tumors. In this review, we propose this micro-environment as a 'cancerous niche' and discuss its importance on the formation and maintenance of cancer stem cells with the recent experimental results to establish cancer stem cell models from induced pluripotent stem cells. These models of cancer stem cell will provide the great advantages in cancer research and its therapeutic applications in the future. PMID:25075155
Adjuvant therapy for pancreas cancer in an era of value based cancer care
Ahn, Daniel H.; Williams, Terence M.; Goldstein, Daniel A.; El-Rayes, Bassel; Bekaii-Saab, Tanios
In resected pancreas cancer, adjuvant therapy improves outcomes and is considered the standard of care for patients who recover sufficiently post operatively. Chemotherapy or combined chemotherapy and radiation therapy (chemoradiation; CRT) are strategies used in the adjuvant setting. However, there is a lack of evidence to suggest whether the addition of RT to chemotherapy translates to an improvement in clinical outcomes. This is true even when accounting for the subset of patients with a higher risk for recurrence, such as those with R1 and lymph node positive disease. When considering the direct and indirect costs, impact on quality of life and questionable added clinical benefit, the true "net health benefit" from added RT to chemotherapy becomes more uncertain. Future directions, including the utilization of modern RT, integration of novel therapies, and intensifying chemotherapy regimens may improve outcomes in resected pancreas cancer. PMID:26620819
Generation of "virtual" control groups for single arm prostate cancer adjuvant trials.
Jia, Zhenyu; Lilly, Michael B; Koziol, James A; Chen, Xin; Xia, Xiao-Qin; Wang, Yipeng; Skarecky, Douglas; Sutton, Manuel; Sawyers, Anne; Ruckle, Herbert; Carpenter, Philip M; Wang-Rodriguez, Jessica; Jiang, Jun; Deng, Mingsen; Pan, Cong; Zhu, Jian-Guo; McLaren, Christine E; Gurley, Michael J; Lee, Chung; McClelland, Michael; Ahlering, Thomas; Kattan, Michael W; Mercola, Dan
It is difficult to construct a control group for trials of adjuvant therapy (Rx) of prostate cancer after radical prostatectomy (RP) due to ethical issues and patient acceptance. We utilized 8 curve-fitting models to estimate the time to 60%, 65%, … 95% chance of progression free survival (PFS) based on the data derived from Kattan post-RP nomogram. The 8 models were systematically applied to a training set of 153 post-RP cases without adjuvant Rx to develop 8 subsets of cases (reference case sets) whose observed PFS times were most accurately predicted by each model. To prepare a virtual control group for a single-arm adjuvant Rx trial, we first select the optimal model for the trial cases based on the minimum weighted Euclidean distance between the trial case set and the reference case set in terms of clinical features, and then compare the virtual PFS times calculated by the optimum model with the observed PFSs of the trial cases by the logrank test. The method was validated using an independent dataset of 155 post-RP patients without adjuvant Rx. We then applied the method to patients on a Phase II trial of adjuvant chemo-hormonal Rx post RP, which indicated that the adjuvant Rx is highly effective in prolonging PFS after RP in patients at high risk for prostate cancer recurrence. The method can accurately generate control groups for single-arm, post-RP adjuvant Rx trials for prostate cancer, facilitating development of new therapeutic strategies.
Ismail, E; Kornovski, Y
The cervical cancer is one of the most common malignancies. Worldwide 500,000 women a year become ill from cervical cancer. The aim of the study was to establish the role of adjuvant radiotherapy in patients with IB1 cervical cancer in terms of disease free survival. Between 2002-2012, 132 patients diagnosed as IB1 stage according to FIGO criteria were enrolled in the study. Depending on the administered therapy the patients were divided into two groups--Group 1-93 patients were treated surgically and with adjuvant radiotherapy and Group 2--39 patients were treated surgically without adjuvant radiotherapy Surgery was radical hysterectomy class III and pelvic or paraaortic lymph node dissection(in cases of bulky paraaortic nodes), and adjuvant RT-telegamma therapy(TGT) in dose 52 Gy. The frequency of recurrence in a Group I (surgery and TGT) is 9.7%. Tree and five years disease free survival (DFS) is 88%. The frequency of recurrence in a Group 2 (surgery without TGT) is 25.6%. Tree and five years DFS respectively are 70% and 65%. In an analysis of oncological results establish that adjuvant TGT after surgery significantly increases DFS. On the other hand the addition of adjuvant TGT increases the patients morbidity Therefore should determine which are the risk factors for the occurrence of relapses and select group of patients who would benefit from adjuvant TGT and the risk of complications in them would be justified.
Ismail, E; Kornovski, Y
The cervical cancer is one of the most common malignancies. Worldwide 500,000 women a year become ill from cervical cancer. The aim of the study was to establish the role of adjuvant radiotherapy in patients with IB1 cervical cancer in terms of disease free survival. Between 2002-2012, 132 patients diagnosed as IB1 stage according to FIGO criteria were enrolled in the study. Depending on the administered therapy the patients were divided into two groups--Group 1-93 patients were treated surgically and with adjuvant radiotherapy and Group 2--39 patients were treated surgically without adjuvant radiotherapy Surgery was radical hysterectomy class III and pelvic or paraaortic lymph node dissection(in cases of bulky paraaortic nodes), and adjuvant RT-telegamma therapy(TGT) in dose 52 Gy. The frequency of recurrence in a Group I (surgery and TGT) is 9.7%. Tree and five years disease free survival (DFS) is 88%. The frequency of recurrence in a Group 2 (surgery without TGT) is 25.6%. Tree and five years DFS respectively are 70% and 65%. In an analysis of oncological results establish that adjuvant TGT after surgery significantly increases DFS. On the other hand the addition of adjuvant TGT increases the patients morbidity Therefore should determine which are the risk factors for the occurrence of relapses and select group of patients who would benefit from adjuvant TGT and the risk of complications in them would be justified. PMID:26817258
Promise of cancer stem cell vaccine
Zhou, Li; Lu, Lin; Wicha, Max S; Chang, Alfred E; Xia, Jian-chuan; Ren, Xiubao; Li, Qiao
Dendritic cell (DC)-based vaccines designed to target cancer stem cells (CSC) can induce significant antitumor responses via conferring host anti-CSC immunity. Our recent studies have demonstrated that CSC-DC vaccine could inhibit metastasis of primary tumors and induce humoral immune responses against cancer stem cells. This approach highlights the promise of cancer stem cell vaccine in cancer immunotherapy. PMID:26337078
Learning about Cancer by Studying Stem Cells
... About Cancer by Studying Stem Cells Inside Life Science View All Articles | Inside Life Science Home Page Learning About Cancer by Studying Stem ... Once Upon a Stem Cell This Inside Life Science article also appears on LiveScience . Learn about related ...
Extinction models for cancer stem cell therapy
Sehl, Mary; Zhou, Hua; Sinsheimer, Janet S.; Lange, Kenneth L.
Cells with stem cell-like properties are now viewed as initiating and sustaining many cancers. This suggests that cancer can be cured by driving these cancer stem cells to extinction. The problem with this strategy is that ordinary stem cells are apt to be killed in the process. This paper sets bounds on the killing differential (difference between death rates of cancer stem cells and normal stem cells) that must exist for the survival of an adequate number of normal stem cells. Our main tools are birth–death Markov chains in continuous time. In this framework, we investigate the extinction times of cancer stem cells and normal stem cells. Application of extreme value theory from mathematical statistics yields an accurate asymptotic distribution and corresponding moments for both extinction times. We compare these distributions for the two cell populations as a function of the killing rates. Perhaps a more telling comparison involves the number of normal stem cells NH at the extinction time of the cancer stem cells. Conditioning on the asymptotic time to extinction of the cancer stem cells allows us to calculate the asymptotic mean and variance of NH. The full distribution of NH can be retrieved by the finite Fourier transform and, in some parameter regimes, by an eigenfunction expansion. Finally, we discuss the impact of quiescence (the resting state) on stem cell dynamics. Quiescence can act as a sanctuary for cancer stem cells and imperils the proposed therapy. We approach the complication of quiescence via multitype branching process models and stochastic simulation. Improvements to the τ-leaping method of stochastic simulation make it a versatile tool in this context. We conclude that the proposed therapy must target quiescent cancer stem cells as well as actively dividing cancer stem cells. The current cancer models demonstrate the virtue of attacking the same quantitative questions from a variety of modeling, mathematical, and computational perspectives
Cancer stem cells: impact, heterogeneity, and uncertainty
Magee, Jeffrey A.; Piskounova, Elena; Morrison, Sean J.
The differentiation of tumorigenic cancer stem cells into non-tumorigenic cancer cells confers heterogeneity to some cancers beyond that explained by clonal evolution or environmental differences. In such cancers, functional differences between tumorigenic and non-tumorigenic cells influence response to therapy and prognosis. However, it remains uncertain whether the model applies to many, or few, cancers due to questions about the robustness of cancer stem cell markers and the extent to which existing assays underestimate the frequency of tumorigenic cells. In cancers with rapid genetic change, reversible changes in cell states, or biological variability among patients the stem cell model may not be readily testable. PMID:22439924
Adjuvant therapy for gastric cancer: What have we learned since INT0116?
Jácome, Alexandre A; Sankarankutty, Ajith K; dos Santos, José Sebastião
Gastric cancer is one of the main cancer-related causes of death worldwide. The curative treatment of gastric cancer consists of tumor resection and lymphadenectomy. However, surgical treatment alone is associated with high recurrence rates. Adjuvant treatment strategies have been studied over the last decades, but there have been controversial results from the initial studies. The pivotal INT0116 study demonstrated that the use of adjuvant chemoradiotherapy with 5-fluorouracil increases relapse-free and overall survival, and it has been adopted across the Western world. The high toxicity of radiochemotherapy and suboptimal surgical treatment employed, with fewer than 10% of the patients submitted to D2 lymphadenectomy, were the main study limitations. Since its publication, other adjuvant treatment modalities have been studied, and radiochemotherapy is being refined to improve its efficacy and safety. A multimodal approach has been demonstrated to significantly increase relapse-free and overall survival, and it can be offered in the form of perioperative chemotherapy, adjuvant chemoradiotherapy or adjuvant chemotherapy, regardless of the extent of lymphadenectomy. The objective of the present review is to report the major advances obtained in the last decades in the adjuvant treatment of gastric cancer as well as the perspectives of treatment based on recent knowledge of the molecular biology of the disease. PMID:25852269
Cancer stem cells, cancer cell plasticity and radiation therapy.
Vlashi, Erina; Pajonk, Frank
Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be eliminated while the survival of differentiated progeny is less critical. In this review we discuss recent reports challenging the idea of a unidirectional differentiation of cancer cells. These reports provide evidence supporting the idea that non-stem cancer cells exhibit a remarkable degree of plasticity that allows them to re-acquire cancer stem cell traits, especially in the context of radiation therapy. We summarize conditions under which differentiation is reversed and discuss the current knowledge of the underlying mechanisms.
Cancer Stem Cells, Cancer Cell Plasticity and Radiation Therapy
Vlashi, Erina; Pajonk, Frank
Summary Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be eliminated while the survival of differentiated progeny is less critical. In this review we discuss recent reports challenging the idea of a unidirectional differentiation of cancer cells. These reports provide evidence supporting the idea that non-stem cancer cells exhibit a remarkable degree of plasticity that allows them to re-acquire cancer stem cell traits, especially in the context of radiation therapy. We summarize conditions under which differentiation is reversed and discuss the current knowledge of the underlying mechanisms. PMID:25025713
Sleep Aid Use During and Following Breast Cancer Adjuvant Chemotherapy
Moore, Tiffany A.; Berger, Ann M.; Dizona, Paul
Background Knowledge of sleep aid use is limited despite the high prevalence of insomnia among women before, during, and following breast cancer adjuvant chemotherapy treatments (CTX). This study's purpose was to 1) determine the frequency and characteristics of participants taking sleep aid(s); 2) identify the frequency and percent of sleep aid use by category (prescription sedative/hypnotics, prescription anti-depressants, prescription analgesics, prescription anti-emetics, over-the-counter (OTC) analgesics, OTC cold/flu/sinus, OTC sleep, alcohol, and herbal supplements); and 3) compare sleep aid use by category in the experimental and control groups within a randomized-controlled clinical trial RCT). Methods Longitudinal, descriptive, secondary RCT data analysis of women (n=219) receiving out-patient CTX, and at 30, 60, and 90 days following the last CTX and 1 year following CTX1. Participants recorded daily sleep aid use on a Sleep Diary. Analyses included descriptives, chi-square, and RM-ANOVA. Results Approximately 20% of participants took at least one sleep aid before CTX1; usage decreased over time (12-18%); a 2nd sleep aid was used infrequently. Prescription sedative/hypnotics (46%) and OTC analgesics (24%) were used most frequently. OTC sleep aids were most commonly used as a 2nd aid. Prescription sedative/hypnotics [F(7,211)=4.26, p=0.00] and OTC analgesics [F(7,211)=2.38, p=0.023] use decreased significantly over time. Conclusions Results reflect the natural course of CTX, recovery, and healing. Comprehensive screening for sleep-wake disturbances and sleep aid use may lead to a better understanding of the risks and benefits of pharmacologic and non-pharmacologic interventions, and ultimately lead to selection of the safest and most effective treatment. PMID:20878849
Cost-Effectiveness Analysis of Trastuzumab in the Adjuvant Treatment for Early Breast Cancer
Aboutorabi, Ali; Hadian, Mohammad; Ghaderi, Hossein; Salehi, Masoud; Ghiasipour, Maryam
Background: Evidence from randomized controlled trials (RCTs) has shown a significant survival advantage of trastuzumab. Although extant work in developed countries examined economic evaluation of trastuzumab in adjuvant treatment for early breast cancer based on the 1-year treatment, there is uncertainty about cost-effectiveness of trastuzumab in the Adjuvant Treatment of early breast cancer in developing countries. This study aimed to estimate cost-effectiveness of adjuvant trastuzumab therapy compared to AC-T regimen in early breast cancer in Iran. Methods: A cost-effectiveness analysis was performed using a Markov model to estimate outcomes and costs over a 20-year time period using a cohort of women with HER2 positive early breast cancer, treated with or without 12 months trastuzumab adjuvant chemotherapy. Transition probabilities were derived mainly from the BCIRG006 trial. Costs were estimated from the perspective of the Iranian health care system. Both costs and outcomes were discounted by 3%. One-way sensitivity analysis was undertaken to assess the associated uncertainties in the expected output measures. Results: On the basis of BCIRG006 trial, our model showed that adjuvant trastuzumab treatment in early breast cancer, yield 0.87 quality-adjusted life-years (QALY) compared with AC-T regimen. Adjuvant trastuzumab treatment yielded an incremental cost-effectiveness ratio (ICER) of US$ 51302 per QALY. Conclusion: By using threshold of 3 times GDP per capita, as per World Health Organization (WHO) recommendation, 12 months trastuzumab adjuvant chemotherapy is not a cost-effective therapy for patients with HER2-positive breast cancer in Iran. PMID:25560346
Common stemness regulators of embryonic and cancer stem cells.
Hadjimichael, Christiana; Chanoumidou, Konstantina; Papadopoulou, Natalia; Arampatzi, Panagiota; Papamatheakis, Joseph; Kretsovali, Androniki
Pluripotency of embryonic stem cells (ESCs) and induced pluripotent stem cells is regulated by a well characterized gene transcription circuitry. The circuitry is assembled by ESC specific transcription factors, signal transducing molecules and epigenetic regulators. Growing understanding of stem-like cells, albeit of more complex phenotypes, present in tumors (cancer stem cells), provides a common conceptual and research framework for basic and applied stem cell biology. In this review, we highlight current results on biomarkers, gene signatures, signaling pathways and epigenetic regulators that are common in embryonic and cancer stem cells. We discuss their role in determining the cell phenotype and finally, their potential use to design next generation biological and pharmaceutical approaches for regenerative medicine and cancer therapies.
Common stemness regulators of embryonic and cancer stem cells
Hadjimichael, Christiana; Chanoumidou, Konstantina; Papadopoulou, Natalia; Arampatzi, Panagiota; Papamatheakis, Joseph; Kretsovali, Androniki
Pluripotency of embryonic stem cells (ESCs) and induced pluripotent stem cells is regulated by a well characterized gene transcription circuitry. The circuitry is assembled by ESC specific transcription factors, signal transducing molecules and epigenetic regulators. Growing understanding of stem-like cells, albeit of more complex phenotypes, present in tumors (cancer stem cells), provides a common conceptual and research framework for basic and applied stem cell biology. In this review, we highlight current results on biomarkers, gene signatures, signaling pathways and epigenetic regulators that are common in embryonic and cancer stem cells. We discuss their role in determining the cell phenotype and finally, their potential use to design next generation biological and pharmaceutical approaches for regenerative medicine and cancer therapies. PMID:26516408
Prostate cancer stem cell biology
Yu, Chunyan; Yao, Zhi; Jiang, Yuan; Keller, Evan. T.
The cancer stem cell (CSC) model provides insights into pathophysiology of cancers and their therapeutic response. The CSC model has been both controversial, yet provides a foundation to explore cancer biology. In this review, we provide an overview of CSC concepts, biology and potential therapeutic avenues. We then focus on prostate CSC including (1) their purported origin as either basal-derived or luminal-derived cells; (2) markers used for prostate CSC identification; (3) alterations of signaling pathways in prostate CSCs (4) involvement of prostate CSCs in metastasis of PCa and (5) microRNA-mediated regulation of prostate CSCs. Although definitive evidence for the identification and characterization of prostate CSCs still remains unclear, future directions pursuing therapeutic targets of CSCs may provide novel insights for the treatment of PCa. PMID:22402315
Cancer stem cells and metastasis.
Sampieri, Katia; Fodde, Riccardo
Cancer stem cells (CSCs) represent a subpopulation of tumour cells endowed with self-renewal and multi-lineage differentiation capacity but also with an innate resistance to cytotoxic agents, a feature likely to pose major clinical challenges towards the complete eradication of minimal residual disease in cancer patients. Operationally, CSCs are defined by their tumour-propagating ability when serially transplanted into immune-compromised mice and by their capacity to fully recapitulate the original heterogeneity of cell types observed in the primary lesions they are derived from. CSCs were first identified in haematopoietic malignancies and later in a broad spectrum of solid tumours including those of the breast, colon and brain. Notably, several CSC characteristics are relevant to metastasis, such as motility, invasiveness and, as mentioned above, resistance to DNA damage-induced apoptosis. Here, we have reviewed the current literature on the relation between CSCs and metastasis formation. Preliminary studies on cancer cell lines and patient-derived material suggest a rate-limiting role for stem-like cells in the processes of tumour cell dissemination and metastasis formation. However, additional studies are needed to deliver formal proof of their identity as the cell of origin of recurrences at distant organ sites. Nevertheless, several studies have already provided pre-clinical evidence of the efficacy of novel therapies directed against disseminated CSCs.
[Menstrual abnormality in patients with breast cancer receiving adjuvant endocrine-chemotherapy].
Yasumura, T; Oka, T; Honjo, H; Okada, H
Menstrual status and ovarian function were studied in 24 premenopausal breast cancer patients receiving adjuvant therapy with chemotherapy and tamoxifen or chemotherapy alone. In 13 of 24 patients (54.1%), abnormal menses, including amenorrhea in 12 cases and oligomenorrhea in 1 case, developed during adjuvant therapy. In patients with abnormal menses, serum estradiol was significantly lower, and the levels of gonadotropins were significantly higher than in patients with normal menses. Among 13 patients with abnormal menses, 4 patients treated with cyclophosphamide revealed persistent amenorrhea during the whole period with adjuvant therapy, and the levels of serum estradiol and progesterone were extremely low. Furthermore, in these patients normal menses has not recovered and the levels of serum estradiol and progesterone remained low 4 to 5 months after cessation of cyclophosphamide administration. Thus, adjuvant chemotherapy caused depression of ovarian function, and cyclophosphamide induced ovarian failure, resulting in complete amenorrhea.
Wnt Signaling in Cancer Stem Cell Biology.
de Sousa E Melo, Felipe; Vermeulen, Louis
Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like tumor cells that are responsible for fueling tumor growth. As therapeutic targeting of these tumor stem cells is an intense area of investigation, a concise understanding on how Wnt activity relates to cancer stem cell traits is needed. This review attempts at summarizing the intricacies between Wnt signaling and cancer stem cell biology with a special emphasis on colorectal cancer.
Wnt Signaling in Cancer Stem Cell Biology
de Sousa e Melo, Felipe; Vermeulen, Louis
Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like tumor cells that are responsible for fueling tumor growth. As therapeutic targeting of these tumor stem cells is an intense area of investigation, a concise understanding on how Wnt activity relates to cancer stem cell traits is needed. This review attempts at summarizing the intricacies between Wnt signaling and cancer stem cell biology with a special emphasis on colorectal cancer. PMID:27355964
Practice patterns of adjuvant therapy for intermediate/high recurrence risk cervical cancer patients in Japan
Takeshima, Nobuhiro
Objective Although radiation therapy (RT) and concurrent chemoradiotherapy (CCRT) are the global standards for adjuvant therapy treatment in cervical cancer, many Japanese institutions choose chemotherapy (CT) because of the low frequency of irreversible adverse events. In this study, we aimed to clarify the trends of adjuvant therapy for intermediate/high-risk cervical cancer after radical surgery in Japan. Methods A questionnaire survey was conducted by the Japanese Gynecologic Oncology Group to 186 authorized institutions active in the treatment of gynecologic cancer. Results Responses were obtained from 129 facilities. Adjuvant RT/CCRT and intensity-modulated RT were performed in 98 (76%) and 23 (18%) institutions, respectively. On the other hand, CT was chosen as an alternative in 93 institutions (72%). The most common regimen of CT, which was used in 66 institutions (51%), was a combination of cisplatin/carboplatin with paclitaxel. CT was considered an appropriate alternative option to RT/CCRT in patients with risk factors such as bulky tumors, lymph node metastasis, lymphovascular invasion, parametrial invasion, and stromal invasion. The risk of severe adverse events was considered to be lower for CT than for RT/CCRT in 109 institutions (84%). Conclusion This survey revealed a variety of policies regarding adjuvant therapy among institutions. A clinical study to assess the efficacy or non-inferiority of adjuvant CT is warranted. PMID:27029750
Alternatives to chemotherapy and radiotherapy as adjuvant treatment for lung cancer.
Shepherd, F A
Because adjuvant chemotherapy has resulted in only modest prolongation of survival for patients with lung cancer, investigators have turned to the evaluation of alternative treatment strategies for this patient population. Immunotherapy with Bacillus Calmette Guerin, Corynebacterium parvum, and levamisole has been evaluated in several prospective randomized trials, and no study has shown a statistically significant difference in overall survival. Interferon has been evaluated in three trials of adjuvant therapy after response to chemotherapy for small cell lung cancer. Different interferon preparations were used, but none of the trials showed a significant prolongation of survival. The retinoids have been evaluated as adjuvant treatment after complete resection of stage IN-SCLC. One trial showed a reduction in second primary tumors, and in particular, tumors to tobacco smoking in patients treated with retinyl palmitate. A second trial using 13-cis retinoic acid is ongoing in North America. In the last decade, several inhibitors of angiogenesis have been identified, and they are now beginning to be evaluated in the clinical setting. The National Cancer Institute of Canada Clinical Trials Group and the European Organization for Research and Treatment of Cancer have initiated a study of adjuvant marimastat, a metalloproteinase inhibitor, for patients who have responded to induction chemotherapy for small cell lung cancer. This is the first adjuvant antiangiogenesis factor trial to be initiated for any tumor type. Other investigational agents which are currently undergoing Phase I and Phase II testing include monoclonal antibodies which may inhibit tumour cell growth by binding to growth factors, or which may be conjugated to toxins or chemotherapeutic agents which result in tumour cell death. In the last decade, we have witnessed an explosion in our knowledge and understanding of the regulation of normal and neoplastic cell growth at the molecular level. It remains
Cost–utility of adjuvant zoledronic acid in patients with breast cancer and low estrogen levels
Lamond, N.W.D.; Skedgel, C.; Rayson, D.; Younis, T.
Background Adjuvant zoledronic acid (za) appears to improve disease-free survival (dfs) in women with early-stage breast cancer and low levels of estrogen (lle) because of induced or natural menopause. Characterizing the cost–utility (cu) of this therapy could help to determine its role in clinical practice. Methods Using the perspective of the Canadian health care system, we examined the cu of adjuvant endocrine therapy with or without za in women with early-stage endocrine-sensitive breast cancer and lle. A Markov model was used to compute the cumulative costs in Canadian dollars and the quality-adjusted life-years (qalys) gained from each adjuvant strategy, discounted at a rate of 5% annually. The model incorporated the dfs and fracture benefits of adjuvant za. Probabilistic and one-way sensitivity analyses were conducted to examine key model parameters. Results Compared with a no-za strategy, adjuvant za in the induced and natural menopause groups was associated with, respectively, $7,825 and $7,789 in incremental costs and 0.46 and 0.34 in qaly gains for cu ratios of $17,007 and $23,093 per qaly gained. In one-way sensitivity analyses, the results were most sensitive to changes in the za dfs benefit. Probabilistic sensitivity analysis suggested a 100% probability of adjuvant za being a cost-effective strategy at a threshold of $100,000 per qaly gained. Conclusions Based on available data, adjuvant za appears to be a cost-effective strategy in women with endocrine-sensitive breast cancer and lle, having cu ratios well below accepted thresholds. PMID:26300674
Cancer stem cell targeted therapy: progress amid controversies
Wang, Tao; Shigdar, Sarah; Gantier, Michael P.; Hou, Yingchun; Wang, Li; Li, Yong; Shamaileh, Hadi Al; Yin, Wang; Zhou, Shu-Feng; Zhao, Xinhan; Duan, Wei
Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illustrated and via providing a panoramic view of cancer therapy, we addressed the recent controversies regarding the feasibility of cancer stem cells targeted anti-cancer therapy. PMID:26496035
Risk of Marrow Neoplasms After Adjuvant Breast Cancer Therapy: The National Comprehensive Cancer Network Experience
Wolff, Antonio C.; Blackford, Amanda L.; Visvanathan, Kala; Rugo, Hope S.; Moy, Beverly; Goldstein, Lori J.; Stockerl-Goldstein, Keith; Neumayer, Leigh; Langbaum, Terry S.; Theriault, Richard L.; Hughes, Melissa E.; Weeks, Jane C.; Karp, Judith E.
Purpose Outcomes for early-stage breast cancer have improved. First-generation adjuvant chemotherapy trials reported a 0.27% 8-year cumulative incidence of myelodysplastic syndrome/acute myelogenous leukemia. Incomplete ascertainment and follow-up may have underestimated subsequent risk of treatment-associated marrow neoplasm (MN). Patients and Methods We examined the MN frequency in 20,063 patients with stage I to III breast cancer treated at US academic centers between 1998 and 2007. Time-to-event analyses were censored at first date of new cancer event, last contact date, or death and considered competing risks. Cumulative incidence, hazard ratios (HRs), and comparisons with Surveillance, Epidemiology, and End Results estimates were obtained. Marrow cytogenetics data were reviewed. Results Fifty patients developed MN (myeloid, n = 42; lymphoid, n = 8) after breast cancer (median follow-up, 5.1 years). Patients who developed MN had similar breast cancer stage distribution, race, and chemotherapy exposure but were older compared with patients who did not develop MN (median age, 59.1 v 53.9 years, respectively; P = .03). Two thirds of patients had complex MN cytogenetics. Risk of MN was significantly increased after surgery plus chemotherapy (HR, 6.8; 95% CI, 1.3 to 36.1) or after all modalities (surgery, chemotherapy, and radiation; HR, 7.6; 95% CI, 1.6 to 35.8), compared with no treatment with chemotherapy. MN rates per 1,000 person-years were 0.16 (surgery), 0.43 (plus radiation), 0.46 (plus chemotherapy), and 0.54 (all three modalities). Cumulative incidence of MN doubled between years 5 and 10 (0.24% to 0.48%); 9% of patients were alive at 10 years. Conclusion In this large early-stage breast cancer cohort, MN risk after radiation and/or adjuvant chemotherapy was low but higher than previously described. Risk continued to increase beyond 5 years. Individual risk of MN must be balanced against the absolute survival benefit of adjuvant chemotherapy. PMID
Cancer stem cells in glioblastoma
Lathia, Justin D.; Mack, Stephen C.; Mulkearns-Hubert, Erin E.; Valentim, Claudia L.L.; Rich, Jeremy N.
Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial. PMID:26109046
Cancer stem cells of the digestive system.
Colvin, Hugh S; Nishida, Naohiro; Koseki, Jun; Konno, Masamitsu; Kawamoto, Koichi; Tsunekuni, Kenta; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi
Stem cells of the digestive system are ideal in many ways for research, given they are abundant, highly proliferative and have a uniform structural arrangement. This in turn has enormously aided the research of cancer stem cells of the digestive system, which is now shaping our understanding of cancer stem cells. In this review, the recent advances in the understanding of cancer stem cells of the digestive system have been summarized, including aspects such as their identification, origin, cell-cycle dormancy, relationship with epithelial-mesenchymal transition, cellular metabolism and the underlying molecular mechanisms. Newly acquired knowledge concerning cancer stem cells have led to the development of novel cancer therapeutics with provisional yet encouraging results.
The biology of cancer stem cells.
Lobo, Neethan A; Shimono, Yohei; Qian, Dalong; Clarke, Michael F
Cancers originally develop from normal cells that gain the ability to proliferate aberrantly and eventually turn malignant. These cancerous cells then grow clonally into tumors and eventually have the potential to metastasize. A central question in cancer biology is, which cells can be transformed to form tumors? Recent studies elucidated the presence of cancer stem cells that have the exclusive ability to regenerate tumors. These cancer stem cells share many characteristics with normal stem cells, including self-renewal and differentiation. With the growing evidence that cancer stem cells exist in a wide array of tumors, it is becoming increasingly important to understand the molecular mechanisms that regulate self-renewal and differentiation because corruption of genes involved in these pathways likely participates in tumor growth. This new paradigm of oncogenesis has been validated in a growing list of tumors. Studies of normal and cancer stem cells from the same tissue have shed light on the ontogeny of tumors. That signaling pathways such as Bmi1 and Wnt have similar effects in normal and cancer stem cell self-renewal suggests that common molecular pathways regulate both populations. Understanding the biology of cancer stem cells will contribute to the identification of molecular targets important for future therapies.
MYST3/CREBBP Rearranged Acute Myeloid Leukemia after Adjuvant Chemotherapy for Breast Cancer
Patnaik, Mrinal M.; Naina, Harris V.
Although rare, clinicians and patients must be aware that therapy related malignancies, specifically acute myeloid leukemia (AML), can occur as a complication of adjuvant chemotherapy for breast cancer. Vigilance for signs and symptoms is appropriate. AML with t (8;16) is a specific translocation leading to formation of a fusion protein (MYST3/CREBBP). The MYST3/CREBBP AML tends to develop within 2 years of adjuvant chemotherapy, especially for breast cancer, without preceding myelodysplasia. It usually presents with disseminated intravascular coagulation and osteolytic lesions and has a poor prognosis despite aggressive resuscitation and therapy. With the increasing use of adjuvant chemotherapy for breast cancer, we are seeing a definite increase in the incidence of therapy related myelodysplastic syndromes and AML. One must keep this complication in mind while counseling and following up breast cancer patients who have received adjuvant chemotherapy. New osteolytic bone lesions in a patient with history of breast cancer do not necessarily mean metastatic disease and should be fully evaluated. PMID:25548695
Racial variation in adjuvant chemotherapy initiation among breast cancer patients receiving oncotype DX testing.
Roberts, Megan C; Weinberger, Morris; Dusetzina, Stacie B; Dinan, Michaela A; Reeder-Hayes, Katherine E; Troester, Melissa A; Carey, Lisa A; Wheeler, Stephanie B
It is unknown whether racial differences exist in adjuvant chemotherapy initiation among women with similar oncotype DX (ODX) risk scores. We examined whether adjuvant chemotherapy initiation varied by race. Data come from the Phase III, Carolina Breast Cancer Study, a longitudinal, population-based study of North Carolina women diagnosed with breast cancer between 2008 and 2014. We used modified Poisson regression and report adjusted relative risk (aRR) and 95% confidence intervals (95%CI) to estimate the association between race and adjuvant chemotherapy initiation across ODX risk groups among women who received the test (n = 541). Among women who underwent ODX testing, 54.2, 37.5, and 8.3% of women had tumors classified as low-, intermediate-, and high-risk groups, respectively. We observed no racial variation in adjuvant chemotherapy initiation. Increasing ODX risk score (aRR = 1.39, 95%CI = 1.22, 1.58) and being married (aRR = 2.92, 95%CI = 1.12, 7.60) were independently associated with an increased likelihood of adjuvant chemotherapy in the low-risk group. Among women in the intermediate-risk group, ODX risk score (aRR = 1.15, 95%CI = 1.11, 1.20), younger age (aRR = 1.95, 95%CI = 1.35, 2.81), larger tumor size (aRR = 1.70, 95%CI = 1.22, 2.35), and higher income were independently associated with increased likelihood of adjuvant chemotherapy initiation. No racial differences were found in adjuvant chemotherapy initiation among women receiving ODX testing. As treatment decision-making becomes increasingly targeted with the use of genetic technologies, these results provide evidence that test results may drive treatment in a similar way across racial subgroups.
Long term side effects of adjuvant chemotherapy in patients with early breast cancer.
Tao, Jessica J; Visvanathan, Kala; Wolff, Antonio C
Adjuvant systemic therapy along with screening has been key to the observed improvements in disease-free and overall survival (DFS/OS) in breast cancer. Improvements in overall survival already take into account therapy related toxicities that can result in death. However, this measure alone does not adequately capture the impact on health-related quality of life. Therefore, it is important to examine the prevalence, frequency and short/long-term impact of therapy-related toxicities, identify patients who might be at greatest risk. Ultimately decisions regarding expected therapy benefits (relative and absolute percentage improvements in DFS/OS) must be made against a background of known potential harms. For many patients with early breast cancer (EBC), their risk of recurrence is not zero but is small. At the same time, for many therapies for early stage breast cancer, the risk of serious side effects is small but is not zero. As we better understand the long-term side effects of adjuvant chemotherapy and targeted therapy, it becomes critical to integrate our growing understanding of breast cancer biology with standard high-quality histopathologic measures to better identify the patients most likely to benefit from the various options for combined multimodality therapy. Hence, we must strive against the notion of recommending adjuvant systemic chemotherapy "just in case." This article focuses on the long-term side effects of adjuvant chemotherapy in patients with EBC.
In search of liver cancer stem cells.
Ma, Stephanie; Chan, Kwok Wah; Guan, Xin-Yuan
Recent research efforts in stem cell and cancer biology have put forth a "stem cell model of carcinogenesis" which stipulates that the capability to maintain tumor formation and growth specifically resides in a small population of cells called cancer stem cells. The stem cell-like characteristics of these cells, including their ability to self-renew and differentiate; and their limited number within the bulk of the tumor mass, are believed to account for their capability to escape conventional therapies. In the past few years, the hypothesis of stem cell-driven tumorigenesis in liver cancer has received substantial support from the recent ability to identify and isolate a subpopulation of liver cancer cells that is not only able to initiate tumor growth, but also serially establish themselves as tumor xenografts with high efficiency and consistency. In this review, stem cell biology that contributes to explain tumor development in the particular context of liver cancer will be discussed. We will begin by briefly considering the knowledge available on normal liver stem cells and their role in tissue renewal and regeneration. We will then summarize the current scientific knowledge of liver cancer stem cells, discuss their relevance to the diagnosis and treatment of the disease and consider the outstanding challenges and potential opportunities that lie ahead of us.
Breast cancer stem cells and radiation
NASA Astrophysics Data System (ADS)
Phillips, Tiffany Marie
The present studies explore the response of breast cancer stem cells (BCSC's) to radiation and the implications for clinical cancer treatment. Current cancer therapy eliminates bulky tumor mass but may fail to eradicate a critical tumor initiating cell population termed "cancer stem cells". These cells are potentially responsible for tumor formation, metastasis, and recurrence. Recently cancer stem cells have been prospectively identified in various malignancies, including breast cancer. The breast cancer stem cell has been identified by the surface markers CD44+/CD24 -(low). In vitro mammosphere cultures allow for the enrichment of the cancer stem cell population and were utilized in order to study differential characteristics of BCSC's. Initial studies found that BCSC's display increased radiation resistance as compared to other non-stem tumor cells. This resistance was accompanied by decreased H2AX phosphorylation, decreased reactive oxygen species formation, and increased phosphorylation of the checkpoint protein Chk1. These studies suggest differential DNA damage and repair within the BCSC population. Studies then examined the consequences of fractionated radiation on the BCSC population and found a two-fold increase in BCSC's following 5 x 3Gy. This observation begins to tie cancer stem cell self-renewal to the clinical stem cell phenomenon of accelerated repopulation. Accelerated repopulation is observed when treatment gaps increase between sequential fractions of radiotherapy and may be due to cancer stem cell symmetric self-renewal. The balance between asymmetric and symmetric stem cell division is vital for proper maintenance; deregulation is likely linked to cancer initiation and progression. The developmental Notch-1 pathway was found to regulate BCSC division. Over-expressing the constitutively active Notch-1-ICD in MCF7 cells produced an increase in the BCSC population. Additionally, radiation was observed to increase the expression of the Notch-1
Multiple Myeloma Cancer Stem Cells
Huff, Carol Ann; Matsui, William
Multiple myeloma is characterized by the clonal expansion of neoplastic plasma cells within the bone marrow, elevated serum immunoglobulin, and osteolytic bone disease. The disease is highly responsive to a wide variety of anticancer treatments including conventional cytotoxic chemotherapy, corticosteroids, radiation therapy, and a growing number of agents with novel mechanisms of action. However, few if any patients are cured with these modalities and relapse remains a critical issue. A better understanding of clonogenic multiple myleoma cells is essential to ultimately improving long-term outcomes, but the nature of the cells responsible for myeloma regrowth and disease relapse is unclear. We review evidence that functional heterogeneity exists in multiple myeloma and discuss potential strategies and clinical implications of the stem-cell model of cancer in this disease. PMID:18539970
Prostate Cancer Stem Cells: Research Advances
Jaworska, Dagmara; Król, Wojciech; Szliszka, Ewelina
Cancer stem cells have been defined as cells within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. Experimental evidence showed that these highly tumorigenic cells might be responsible for initiation and progression of cancer into invasive and metastatic disease. Eradicating prostate cancer stem cells, the root of the problem, has been considered as a promising target in prostate cancer treatment to improve the prognosis for patients with advanced stages of the disease. PMID:26593898
Prostate Cancer Stem Cells: Research Advances.
Jaworska, Dagmara; Król, Wojciech; Szliszka, Ewelina
Cancer stem cells have been defined as cells within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. Experimental evidence showed that these highly tumorigenic cells might be responsible for initiation and progression of cancer into invasive and metastatic disease. Eradicating prostate cancer stem cells, the root of the problem, has been considered as a promising target in prostate cancer treatment to improve the prognosis for patients with advanced stages of the disease.
Factor V Leiden Mutation and Thromboembolism Risk in Women Receiving Adjuvant Tamoxifen for Breast Cancer
Halabi, Susan; Tolaney, Sara M.; Kaplan, Ellen; Archer, Laura; Atkins, James N.; Edge, Stephen; Shapiro, Charles L.; Dressler, Lynn; Paskett, Electra M.; Kimmick, Gretchen; Orcutt, James; Scalzo, Anthony; Winer, Eric; Levine, Ellis; Shahab, Nasir; Berliner, Nancy
Background Tamoxifen use has been associated with increased risk of thromboembolic events (TEs) in women with breast cancer and women at high risk for the disease. Factor V Leiden (FVL) is the most common inherited clotting factor mutation and also confers increased thrombosis risk. We investigated whether FVL was associated with TE risk in women with early-stage breast cancer who took adjuvant tamoxifen. Methods A case–control study was conducted among 34 Cancer and Leukemia Group B (CALGB) institutions. We matched each of 124 women who had experienced a documented TE while taking adjuvant tamoxifen for breast cancer (but who were not necessarily on a CALGB treatment trial) to two control subjects (women who took adjuvant tamoxifen but did not experience TE) by age at diagnosis (±5 years). DNA from blood was analyzed for FVL mutations. Conditional logistic regression was used to estimate odds ratios (ORs) and to evaluate other potential factors associated with TE and tamoxifen use. All P values are based on two-sided tests. Results FVL mutations were identified in 23 (18.5%) case and 12 (4.8%) control subjects (OR = 4.66, 95% confidence interval = 2.14 to 10.14, P < .001). In the multivariable model, FVL mutation was associated with TE (OR = 4.73, 95% confidence interval = 2.10 to 10.68, P < .001). Other statistically significant factors associated with TE risk were personal history of TE and smoking. Conclusions Among women taking adjuvant tamoxifen for early-stage breast cancer, those who had a TE were nearly five times more likely to carry a FVL mutation than those who did not have a TE. Postmenopausal women should be evaluated for the FVL mutation before prescription of adjuvant tamoxifen if a positive test would alter therapeutic decision making. PMID:20554945
Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer.
Scheiermann, Julia; Klinman, Dennis M
Synthetic oligonucleotides (ODN) that express unmethylated "CpG motifs" trigger cells that express Toll-like receptor 9. In humans this includes plasmacytoid dendritic cells and B cells. CpG ODN induce an innate immune response characterized by the production of Th1 and pro-inflammatory cytokines. Their utility as vaccine adjuvants was evaluated in a number of clinical trials. Results indicate that CpG ODN improve antigen presentation and the generation of vaccine-specific cellular and humoral responses. This work provides an up-to-date overview of the utility of CpG ODN as adjuvants for vaccines targeting infectious agents and cancer. PMID:24975812
[Is there alternative to FOLFOX adjuvant chemotherapy for stage III colorectal cancer patients?].
Esch, Anouk; Coriat, Romain; Perkins, Géraldine; Brezault, Catherine; Chaussade, Stanislas
Being the second cancer for men and the third cancer for women in France, colorectal cancer represents a serious public health issue. Its incidence has increased these last years and despite new therapeutics being developed, it still has a bad prognostic. Thanks in part to Hemoccult national mass screening program, its diagnosis is made possible at an earlier stage, which makes a surgical curative resection and the carrying out of adjuvant chemotherapy possible. For stage III colic cancer that has been surgically removed, adjuvant chemotherapy by FOLFOX 4 has to be offered. Nevertheless, because of its toxicities, the patient's high age, important comorbidities or post-surgical complications, this chemotherapy occasionally cannot be done. What are the colorectal cancer prognostic factors which would guide the chemotherapy? TNM classification, number of examined lymph nodes, MSI status, and presence or not of a perforation or a perinervous, lymphatic or venous invasion is recognized prognostic factors. Also, what are the alternatives of FOLFOX 4 regimen as colorectal cancer adjuvant treatment?
Potential implications of adjuvant endocrine therapy for the oral health of postmenopausal women with breast cancer
Taichman, L. Susan; Havens, Aaron M.
Current adjuvant treatment modalities for breast cancer that express the estrogen receptor or progesterone receptor include adjuvant anti-estrogen therapies, and tamoxifen and aromatase inhibitors. Bone, including the jaw, is an endocrine-sensitive organ, as are other oral structures. This review examines the potential links between adjuvant anti-estrogen treatments in postmenopausal women with hormone receptor positive breast cancer and oral health. A search of PubMed, EMBASE, CENTRAL, and the Web of Knowledge was conducted using combinations of key terms "breast," "cancer," "neoplasm," "Tamoxifen," "Aromatase Inhibitor," "chemotherapy," "hormone therapy," "alveolar bone loss," "postmenopausal bone loss," "estrogen," "SERM," "hormone replacement therapy," and "quality of life." We selected articles published in peer-reviewed journals in the English. The authors found no studies reporting on periodontal diseases, alveolar bone loss, oral health, or oral health-related quality of life in association with anti-estrogen breast cancer treatments in postmenopausal women. Periodontal diseases, alveolar bone density, tooth loss, and conditions of the soft tissues of the mouth have all been associated with menopausal status supporting the hypothesis that the soft tissues and bone of the oral cavity could be negatively affected by anti-estrogen therapy. As a conclusion, the impact of adjuvant endocrine breast cancer therapy on the oral health of postmenopausal women is undefined. The structures of the oral cavity are influenced by estrogen; therefore, anti-estrogen therapies may carry the risk of oral toxicities. Oral health care for breast cancer patients is an important but understudied aspect of cancer survivorship. PMID:22986813
Body weight changes in breast cancer patients following adjuvant chemotherapy and contributing factors.
Wang, Jian-Sheng; Cai, Hui; Wang, Chang-Yan; Zhang, Jia; Zhang, Ming-Xin
Weight gain commonly occurs in breast cancer patients who receive adjuvant chemotherapy. Weight gain may cause psychosocial stress and is associated with patient prognosis and survival. Several factors contributing to weight gain have been identified in Western populations. However, there was lack of information associated with body weight changes following adjuvant chemotherapy in Chinese breast cancer patients. To the best of our knowledge, this is the first such study to be conducted in the Chinese population. A total of 98 patients who received adjuvant chemotherapy following a modified radical mastectomy were included in this study. Their weight was measured prior to the first and following the last cycle of chemotherapy. A weight gain, or loss, of >1 kg following adjuvant chemotherapy was considered to be significant. Cancer stage, treatment modalities, menopausal status and other clinical information were obtained through medical record review. The results revealed that the weight changes ranged from -11 to +9 kg, with a mean value of -0.4±4.4 kg. A total of 66.7% of the patients exhibited weight changes (34.6% gained >1 kg and 32.1% lost weight), whereas 33.3% of the patients maintained a stable weight (P<0.001). Patients aged ≤40 years [odds ratio (OR)=1.429, P=0.028], with a weight of ≥60 kg at diagnosis (OR=2.211, P=0.023), who received ≥4 cycles of chemotherapy (OR=1.591, P=0.039) and a total hormone dose of ≥200 mg (OR=2.75, P=0.013) exhibited a higher risk of weight gain. In conclusion, the body weight changes observed in Chinese breast cancer patient post-adjuvant chemotherapy were different from those observed among Western populations, represented predominantly by weight gain and were reflected by approximately equal percentages of weight gain, stable weight and weight loss. PMID:24649316
Adjuvant chemotherapy for non-small cell lung cancer: a New Zealand perspective.
Sasidharan, Rita; Gibbs, David; Sullivan, Richard; Simpson, Andrew; Perez, David; Christmas, Timothy; McKeage, Mark
This article reviews recent developments with the use of adjuvant chemotherapy for resected early-stage non-small cell lung cancer (NSCLC) and the implications of these developments for healthcare in New Zealand (NZ). Non-small cell lung cancer is a major cause of mortality and morbidity in NZ, and is greatly over-represented among Maori and socioeconomically deprived populations. Early-stage NSCLC is potentially curable by surgery, but long-term outcome after surgical resection is limited by disease recurrence locally or at sites distant from the primary disease. Three recent large randomised controlled phase III trials using modern platinum-based combination chemotherapy protocols have shown significant survival benefits for the use of postoperative adjuvant chemotherapy after resection of early-stage NSCLC. Cisplatin plus vinorelbine was used as the adjuvant chemotherapy regimen in two of these trials resulting in improvements in 5-year survival of 51.2% versus 42.6% (p=0.013) and 69% versus 54% (p=0.03), respectively. In NZ, adjuvant chemotherapy for NSCLC is expected to prevent up to 15 lung cancer deaths each year for relatively low drug expenditure and has the potential to benefit Maori and the economically-deprived disproportionately more than other populations. In conclusion, it is the opinion of this group of NZ lung cancer specialists that adjuvant chemotherapy with cisplatin plus vinorelbine should now be adopted as a standard of care for patients with resected stage II and III NSCLC. For this to occur, current PHARMAC policies preventing its use for these eligible patients will need to be revised.
Overcoming Multidrug Resistance in Cancer Stem Cells
Moitra, Karobi
The principle mechanism of protection of stem cells is through the expression of ATP-binding cassette (ABC) transporters. These transporters serve as the guardians of the stem cell population in the body. Unfortunately these very same ABC efflux pumps afford protection to cancer stem cells in tumors, shielding them from the adverse effects of chemotherapy. A number of strategies to circumvent the function of these transporters in cancer stem cells are currently under investigation. These strategies include the development of competitive and allosteric modulators, nanoparticle mediated delivery of inhibitors, targeted transcriptional regulation of ABC transporters, miRNA mediated inhibition, and targeting of signaling pathways that modulate ABC transporters. The role of ABC transporters in cancer stem cells will be explored in this paper and strategies aimed at overcoming drug resistance caused by these particular transporters will also be discussed. PMID:26649310
Adjuvant radiotherapy for pathological high-risk muscle invasive bladder cancer: time to reconsider?
Baumann, Brian C.; Eapen, Libni J.; Bahl, Amit; Murthy, Vedang; Roubaud, Guilhem; Orré, Mathieu; Efstathiou, Jason A.; Shariat, Shahrokh; Larré, Stephane; Richaud, Pierre; Christodouleas, John P.
Radical cystectomy with extended pelvic lymph-node dissection, associated with neo-adjuvant chemotherapy, remains the standard of care for advanced, non-metastatic muscle-invasive bladder cancer (MIBC). Loco-regional control is a key factor in the outcome of patients since it is related to overall survival (OS), disease-free survival (DFS) and cause-specific survival. The risk of loco-regional recurrence (LRR) is correlated to pathological factors as well as the extent of the lymphadenectomy. In addition, neither pre- nor post-operative chemotherapy have shown a clear impact on LRR-free survival. Several recent publications have led to the development of a nomogram predicting the risk of LRR, in order to identify patients most likely to benefit from adjuvant radiotherapy. Given the high risk of LRR for selected patients and improvements in radiation techniques that can reduce toxicity, there is a growing interest in adjuvant radiotherapy; international cooperative groups have come together to provide the rationale in favor of adjuvant radiotherapy. Clinical trials in order to reduce the risk of pelvic relapse are opened based on this optimizing patient selection. The aim of this critical literature review is to provide an overview of the rationale supporting the studies of adjuvant radiation for patients with pathologic high-risk MIBC. PMID:27785427
Adjuvant Cancer Biotherapy by Viscum Album Extract Isorel: Overview of Evidence Based Medicine Findings.
Sunjic, Suzana Borovic; Gasparovic, Ana Cipak; Vukovic, Tea; Weiss, Thomas; Weiss, Elisabeth Sussman; Soldo, Ivo; Djakovic, Nikola; Zarkovic, Tomislav; Zarkovic, Neven
Within the integrative medicine one of the most frequently used adjuvant cancer biotherapies is based on aqueous mistletoe (Viscum album) extracts. Tumor growth inhibition, stimulation of host immune response and improvement of the quality of life are the positive effects of mistletoe therapy described in several preclinical and clinical studies. However, cumulative results of the evidence based medicine findings on such treatments are rarely given. Therefore, this paper evaluates the evidence based findings describing effects of the Viscum album extract Isorel in cancer therapy with respect to the type of therapy, stage and type of illness. This study presents cumulated data for 74 patients with different types and stages of cancer treated by Viscum album extract as adjuvant treatment to different conventional therapies, mostly combined surgery and radiotherapy. The biotherapy effectiveness was evaluated according to the outcome as (1) no major therapeutic improvement (15% of patients), (2) prevention of tumor recurrence (47% of patients) and (3) regression of cancer (38% of patients). Notably, there was no obvious health worsening during the follow up period at all. Thus, the results obtained for conventional anticancer therapies combined with adjuvant biotherapy based on Viscum album extract seem to be beneficial for the majority of cancer patients (85%) without serious side effects.
Underuse of Breast Cancer Adjuvant Treatment: Patient Knowledge, Beliefs, and Medical Mistrust
Bickell, Nina A.; Weidmann, Jessica; Fei, Kezhen; Lin, Jenny J.; Leventhal, Howard
Purpose Little is known about why women with breast cancer who have surgery do not receive proven effective postsurgical adjuvant treatments. Methods We surveyed 258 women who recently underwent surgical treatment at six New York City hospitals for early-stage breast cancer about their care, knowledge, and beliefs about breast cancer and its treatment. As per national guidelines, all women should have received adjuvant treatment. Adjuvant treatment data were obtained from inpatient and outpatient charts. Factor analysis was used to create scales scored to 100 of treatment beliefs and knowledge, medical mistrust, and physician communication about treatment. Bivariate and multivariate analyses assessed differences between treated and untreated women. Results Compared with treated women, untreated women were less likely to know that adjuvant therapies increase survival (on a 100-point scale; 66 v 75; P < .0001), had greater mistrust (64 v 53; P = .001), and had less self-efficacy (92 v 97; P < .05); physician communication about treatment did not affect patient knowledge of treatment benefits (r = 0.8; P = .21). Multivariate analysis found that untreated women were more likely to be 70 years or older (adjusted relative risk [aRR], 1.11; 95% CI, 1.00 to 1.13), to have comorbidities (aRR, 1.10; 95% CI, 1.04 to 1.12), and to express mistrust in the medical delivery system (aRR, 1.003; 95% CI, 1.00 to 1.007), even though they were more likely to believe adjuvant treatments were beneficial (aRR, 0.99; 95% CI, 0.98 to 0.99; model c, 0.84; P ≤ .0001). Conclusion Patient knowledge and beliefs about treatment and medical mistrust are mutable factors associated with underuse of effective adjuvant therapies. Physicians may improve cancer care by ensuring that discussions about adjuvant therapy include a clear presentation of the benefits, not just the risks of treatment, and by addressing patient trust in and concerns about the medical system. PMID:19770368
Trastuzumab improves locoregional control in HER2-positive breast cancer patients following adjuvant radiotherapy
Cao, Lu; Cai, Gang; Xu, Fei; Yang, Zhao-Zhi; Yu, Xiao-Li; Ma, Jin-Li; Zhang, Qian; Wu, Jiong; Guo, Xiao-Mao; Chen, Jia-Yi
Abstract The benefit of adjuvant trastuzumab in disease-free and overall survival for human epidermal receptor 2–positive (HER2+) breast cancer patients is well established. However, the effect of trastuzumab on locoregional control remains unclear, particularly in patients treated with adjuvant radiotherapy (RT). In this study, we investigated the locoregional benefit of trastuzumab in patients with HER2+ breast cancer after adjuvant RT. Using a single institutional database, we identified 278 patients with stage II/III invasive HER2+ breast tumors receiving adjuvant RT between January 2008 and July 2011. We compared the locoregional outcomes of 134 patients who received trastuzumab to 144 patients without trastuzumab within the same period. Clinical and biological factors that might impact on the locoregional benefit of trastuzumab were also assessed. At the median follow-up of 45 months, trastuzumab significantly lowered the risk of locoregional recurrence (LRR) with a 3-year LRR rate of 2.4% versus 7.5% for the cohort with and without trastuzumab (P = 0.019). Trastuzumab was associated with a more significant locoregional benefit in the hormone receptor–positive (HR+)/HER2+ subgroup, with a 3-year LRR of 0% versus 6.7% in the cohort with and without trastuzumab (P = 0.027). For HR−/HER2+ breast tumor patients, the 3-year LRR rate was still lower for the cohort with trastuzumab (4.7% vs 8.6%). However, statistical significance was not found (P = 0.179). Both univariate and multivariate analyses confirmed that trastuzumab treatment was the only significant predictive factor for LRR (hazard ratio, 4.05; 95% confidence interval, 1.07–15.35; P = 0.039). Adjuvant trastuzumab in addition to RT is associated with significant reduced LRR risk in HER2+ breast cancer. PMID:27512838
How to search for specific markers of cancer stem cells.
Liu, Hai Guang; Zhang, Xiao Hua
According to the cancer stem cell hypothesis, cancer stem cells with unlimited self-renewal and multi-differentiation properties such as adult stem cells are the root cause of cancer initiation and progression, and targeted therapy to cancer stem cells is to become the most efficient therapy of cancer. However, specific markers should be discovered to define cancer stem cells accurately before targeted therapy. Therefore, we propose a model of specific markers of cancer stem cells and how to search for such markers.
Regulation of breast cancer stem cell features.
Czerwinska, Patrycja; Kaminska, Bozena
Cancer stem cells (CSCs) are rare, tumour-initiating cells that exhibit stem cell properties: capacity of self-renewal, pluripotency, highly tumorigenic potential, and resistance to therapy. Cancer stem cells have been characterised and isolated from many cancers, including breast cancer. Developmental pathways, such as the Wnt/β-catenin, Notch/γ-secretase/Jagged, Shh (sonic hedgehog), and BMP signalling pathways, which direct proliferation and differentiation of normal stem cells, have emerged as major signalling pathways that contribute to the self-renewal of stem and/or progenitor cells in a variety of organs and cancers. Deregulation of these signalling pathways is frequently linked to an epithelial-mesenchymal transition (EMT), and breast CSCs often possess properties of cells that have undergone the EMT process. Signalling networks mediated by microRNAs and EMT-inducing transcription factors tie the EMT process to regulatory networks that maintain "stemness". Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, which allows an assessment on how embryonic and normal tissue stem cells are deregulated during cancerogenesis to give rise to CSCs. Epigenetic-based mechanisms are reversible, and the possibility of "resetting" the abnormal cancer epigenome by applying pharmacological compounds targeting epigenetic enzymes is a promising new therapeutic strategy. Chemoresistance of CSCs is frequently driven by various mechanisms, including aberrant expression/activity of ABC transporters, aldehyde dehydrogenase and anti-oncogenic proteins (i.e. BCL2, B-cell lymphoma-2), enhanced DNA damage response, activation of pro-survival signalling pathways, and epigenetic deregulations. Despite controversy surrounding the CSC hypothesis, there is substantial evidence for their role in cancer, and a number of drugs intended to specifically target CSCs have entered clinical trials. PMID:25691826
Adjuvant Radiation Therapy Treatment Time Impacts Overall Survival in Gastric Cancer
McMillan, Matthew T.; Ojerholm, Eric; Roses, Robert E.; Plastaras, John P.; Metz, James M.; Mamtani, Ronac; Stripp, Diana; Ben-Josef, Edgar; Datta, Jashodeep
Purpose: Prolonged radiation therapy treatment time (RTT) is associated with worse survival in several tumor types. This study investigated whether delays during adjuvant radiation therapy impact overall survival (OS) in gastric cancer. Methods and Materials: The National Cancer Data Base was queried for patients with resected gastric cancer who received adjuvant radiation therapy with National Comprehensive Cancer Network–recommended doses (45 or 50.4 Gy) between 1998 and 2006. RTT was classified as standard (45 Gy: 33-36 days, 50.4 Gy: 38-41 days) or prolonged (45 Gy: >36 days, 50.4 Gy: >41 days). Cox proportional hazards models evaluated the association between the following factors and OS: RTT, interval from surgery to radiation therapy initiation, interval from surgery to radiation therapy completion, radiation therapy dose, demographic/pathologic and operative factors, and other elements of adjuvant multimodality therapy. Results: Of 1591 patients, RTT was delayed in 732 (46%). Factors associated with prolonged RTT were non-private health insurance (OR 1.3, P=.005) and treatment at non-academic facilities (OR 1.2, P=.045). Median OS and 5-year actuarial survival were significantly worse in patients with prolonged RTT compared with standard RTT (36 vs 51 months, P=.001; 39 vs 47%, P=.005); OS worsened with each cumulative week of delay (P<.0004). On multivariable analysis, prolonged RTT was associated with inferior OS (hazard ratio 1.2, P=.002); the intervals from surgery to radiation therapy initiation or completion were not. Prolonged RTT was particularly detrimental in patients with node positivity, inadequate nodal staging (<15 nodes examined), and those undergoing a cycle of chemotherapy before chemoradiation therapy. Conclusions: Delays during adjuvant radiation therapy appear to negatively impact survival in gastric cancer. Efforts to minimize cumulative interruptions to <7 days should be considered.
Antihormonal treatment associated musculoskeletal pain in women with breast cancer in the adjuvant setting
Seber, Selcuk; Solmaz, Dilek; Yetisyigit, Tarkan
Purpose Antihormonal treatment is an effective therapy in the adjuvant setting. However, musculoskeletal pain is a common adverse effect encountered in patients receiving this treatment. We aimed to evaluate the risk factors for the development of antihormonal treatment-associated musculoskeletal pain (AHAMP) and its impact on the health-related quality of life (HRQOL). Patients and methods A cross-sectional survey of 78 consecutive breast cancer patients receiving adjuvant antihormonal treatment for early-stage breast cancer in an academic medical oncology clinic was conducted. AHAMP was assessed by Health Assessment Questionnaire (HAQ) and 10 cm visual analog scale (VAS). HRQOL was assessed by self-administered short form 36 and Functional Assessment of Cancer Therapy-Breast subscale surveys. Results AHAMP was found to be present in 37 (47.7%) patients. In multivariate regression analysis, having a normal body mass index (<30 kg/m2), cigarette smoking, and low serum vitamin D level (20 ng/mL) were found to be independent risk factors. In HRQOL assessment, physical and mental scores were found to be significantly lower in patients with joint arthralgia. Conclusion AHAMP has an adverse effect on the quality of life of breast cancer patients receiving adjuvant antihormonal treatment, and assessment of predictive factors is important for identification of patient groups at risk of developing this condition. PMID:27563249
Redox Regulation in Cancer Stem Cells
Ding, Shijie; Li, Chunbao; Cheng, Ninghui; Cui, Xiaojiang; Xu, Xinglian; Zhou, Guanghong
Reactive oxygen species (ROS) and ROS-dependent (redox regulation) signaling pathways and transcriptional activities are thought to be critical in stem cell self-renewal and differentiation during growth and organogenesis. Aberrant ROS burst and dysregulation of those ROS-dependent cellular processes are strongly associated with human diseases including many cancers. ROS levels are elevated in cancer cells partially due to their higher metabolism rate. In the past 15 years, the concept of cancer stem cells (CSCs) has been gaining ground as the subpopulation of cancer cells with stem cell-like properties and characteristics have been identified in various cancers. CSCs possess low levels of ROS and are responsible for cancer recurrence after chemotherapy or radiotherapy. Unfortunately, how CSCs control ROS production and scavenging and how ROS-dependent signaling pathways contribute to CSCs function remain poorly understood. This review focuses on the role of redox balance, especially in ROS-dependent cellular processes in cancer stem cells (CSCs). We updated recent advances in our understanding of ROS generation and elimination in CSCs and their effects on CSC self-renewal and differentiation through modulating signaling pathways and transcriptional activities. The review concludes that targeting CSCs by manipulating ROS metabolism/dependent pathways may be an effective approach for improving cancer treatment. PMID:26273424
ALCHEMIST: Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials
ALCHEMIST represents three integrated, precision medicine trials that are designed to identify people with early-stage lung cancer who have tumors that harbor certain uncommon genetic changes and evaluate whether drug treatments targeted against those mol
Surgery and Adjuvant Chemotherapy Use Among Veterans With Colon Cancer: Insights From a California Study
Hynes, Denise M.; Tarlov, Elizabeth; Durazo-Arvizu, Ramon; Perrin, Ruth; Zhang, Qiuying; Weichle, Thomas; Ferreira, M. Rosario; Lee, Todd; Benson, Al B.; Bhoopalam, Nirmala; Bennett, Charles L.
Purpose US veterans have been shown to be a vulnerable population with high cancer rates, and cancer care quality in Veterans Affairs (VA) hospitals is the focus of a congressionally mandated review. We examined rates of surgery and chemotherapy use among veterans with colon cancer at VA and non-VA facilities in California to gain insight into factors associated with quality of cancer care. Methods A retrospective cohort of incident colon cancer patients from the California Cancer Registry, who were ≥ 66 years old and eligible to use VA and Medicare between 1999 and 2001, were observed for 6 months after diagnosis. Results Among 601 veterans with colon cancer, 72% were initially diagnosed and treated in non-VA facilities. Among veterans with stage I to III cancer, those diagnosed and initially treated in VA facilities experienced similar colectomy rates as those at non-VA facilities. Stage III patients diagnosed and initially treated in VA versus non-VA facilities had similar odds of receiving adjuvant chemotherapy. In both settings, older patients had lower odds of receiving chemotherapy than their younger counterparts even when race and comorbidity were considered (age 76 to 85 years: odds ratio [OR] = 0.18; 95% CI, 0.07 to 0.46; age ≥ 86 years: OR = 0.17; 95% CI, 0.04 to 0.73). Conclusion In California, older veterans with colon cancer used both VA and non-VA facilities for cancer treatment, and odds of receiving cancer-directed surgery and chemotherapy were similar in both systems. Among stage III patients, older age lowered odds of receiving adjuvant chemotherapy in both systems. Further studies should continue to explore potential health system effects on quality of colon cancer care across the United States. PMID:20406940
[Cancer stem cell research toward therapeutics].
Ito, Keisuke
The capacity of cancer stem cells, or cancer-initiating cells, to both provide mature tumor cells and perpetuate themselves through self-renewal is crucial to initiate and maintain tumorigenesis, and has become the focus of intense research interest as a promising source of new therapeutic strategies. However, many scientific challenges and technical barriers remain to be solved before recent findings can be translated into effective therapeutics. Here we highlight the latest advances in our knowledge of cancer stem cells, and provide a critical perspective on the clinical benefits promised by this developing area of research.
Regulation of breast cancer stem cell features
Kaminska, Bozena
Cancer stem cells (CSCs) are rare, tumour-initiating cells that exhibit stem cell properties: capacity of self-renewal, pluripotency, highly tumorigenic potential, and resistance to therapy. Cancer stem cells have been characterised and isolated from many cancers, including breast cancer. Developmental pathways, such as the Wnt/β-catenin, Notch/γ-secretase/Jagged, Shh (sonic hedgehog), and BMP signalling pathways, which direct proliferation and differentiation of normal stem cells, have emerged as major signalling pathways that contribute to the self-renewal of stem and/or progenitor cells in a variety of organs and cancers. Deregulation of these signalling pathways is frequently linked to an epithelial-mesenchymal transition (EMT), and breast CSCs often possess properties of cells that have undergone the EMT process. Signalling networks mediated by microRNAs and EMT-inducing transcription factors tie the EMT process to regulatory networks that maintain "stemness". Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, which allows an assessment on how embryonic and normal tissue stem cells are deregulated during cancerogenesis to give rise to CSCs. Epigenetic-based mechanisms are reversible, and the possibility of "resetting" the abnormal cancer epigenome by applying pharmacological compounds targeting epigenetic enzymes is a promising new therapeutic strategy. Chemoresistance of CSCs is frequently driven by various mechanisms, including aberrant expression/activity of ABC transporters, aldehyde dehydrogenase and anti-oncogenic proteins (i.e. BCL2, B-cell lymphoma-2), enhanced DNA damage response, activation of pro-survival signalling pathways, and epigenetic deregulations. Despite controversy surrounding the CSC hypothesis, there is substantial evidence for their role in cancer, and a number of drugs intended to specifically target CSCs have entered clinical trials. PMID:25691826
Neurotrophin signaling in cancer stem cells.
Chopin, Valérie; Lagadec, Chann; Toillon, Robert-Alain; Le Bourhis, Xuefen
Cancer stem cells (CSCs), are thought to be at the origin of tumor development and resistance to therapies. Thus, a better understanding of the molecular mechanisms involved in the control of CSC stemness is essential to the design of more effective therapies for cancer patients. Cancer cell stemness and the subsequent expansion of CSCs are regulated by micro-environmental signals including neurotrophins. Over the years, the roles of neurotrophins in tumor development have been well established and regularly reviewed. Especially, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are reported to stimulate tumor cell proliferation, survival, migration and/or invasion, and favors tumor angiogenesis. More recently, neurotrophins have been reported to regulate CSCs. This review briefly presents neurotrophins and their receptors, summarizes their roles in different cancers, and discusses the emerging evidence of neurotrophins-induced enrichment of CSCs as well as the involved signaling pathways.
Cancer Stem Cell Hierarchy in Glioblastoma Multiforme
Bradshaw, Amy; Wickremsekera, Agadha; Tan, Swee T.; Peng, Lifeng; Davis, Paul F.; Itinteang, Tinte
Glioblastoma multiforme (GBM), an aggressive tumor that typically exhibits treatment failure with high mortality rates, is associated with the presence of cancer stem cells (CSCs) within the tumor. CSCs possess the ability for perpetual self-renewal and proliferation, producing downstream progenitor cells that drive tumor growth. Studies of many cancer types have identified CSCs using specific markers, but it is still unclear as to where in the stem cell hierarchy these markers fall. This is compounded further by the presence of multiple GBM and glioblastoma cancer stem cell subtypes, making investigation and establishment of a universal treatment difficult. This review examines the current knowledge on the CSC markers SALL4, OCT-4, SOX2, STAT3, NANOG, c-Myc, KLF4, CD133, CD44, nestin, and glial fibrillary acidic protein, specifically focusing on their use and validity in GBM research and how they may be utilized for investigations into GBM's cancer biology. PMID:27148537
Outpatient management without initial assessment for febrile patients undergoing adjuvant chemotherapy for breast cancer
Kimura, Kosei; Tanaka, Satoru; Iwamoto, Mitsuhiko; Fujioka, Hiroya; Sato, Nayuko; Terasawa, Risa; Kawaguchi, Kanako; Matsuda, Junna; Umezaki, Nodoka; Uchiyama, Kazuhisa
The purpose of this study was to retrospectively analyze the feasibility of outpatient management without initial assessment for febrile patients undergoing adjuvant chemotherapy for breast cancer. A total of 131 consecutive patients with breast cancer treated with adjuvant or neoadjuvant chemotherapy from 2011 to 2013 at Osaka Medical College Hospital (Osaka, Japan) were retrospectively reviewed. In the case of developing a fever (body temperature, ≥38°C), the outpatients had been instructed to take previously prescribed oral antibiotics for 3 days without any initial assessment, and if no improvement had occurred by then, they were required to visit the hospital for examination and to undergo treatment based on the results of a risk assessment for complications. The primary aim of the present study was to assess the outcome of febrile episodes, while the secondary aim was to assess the incidence of febrile episodes, hospitalizations, and the type of chemotherapy. The 131 patients received 840 chemotherapy administrations. Fifty-five patients (42.0%) had a total of 75 febrile episodes after 840 chemotherapy administrations (8.9%). Treatment failure occurred in 12 of the 75 episodes (16.0%) in 11 of the 55 patients (20.0%). Only four episodes required hospitalization. Treatment success was achieved in 63 episodes (84.0%). In conclusion, the feasibility of outpatient management without initial assessment was evaluated in the present study for febrile patients undergoing adjuvant chemotherapy for breast cancer, and the outpatient strategy regimen may be safe and convenient for these patients. PMID:27699031
Outpatient management without initial assessment for febrile patients undergoing adjuvant chemotherapy for breast cancer
Kimura, Kosei; Tanaka, Satoru; Iwamoto, Mitsuhiko; Fujioka, Hiroya; Sato, Nayuko; Terasawa, Risa; Kawaguchi, Kanako; Matsuda, Junna; Umezaki, Nodoka; Uchiyama, Kazuhisa
The purpose of this study was to retrospectively analyze the feasibility of outpatient management without initial assessment for febrile patients undergoing adjuvant chemotherapy for breast cancer. A total of 131 consecutive patients with breast cancer treated with adjuvant or neoadjuvant chemotherapy from 2011 to 2013 at Osaka Medical College Hospital (Osaka, Japan) were retrospectively reviewed. In the case of developing a fever (body temperature, ≥38°C), the outpatients had been instructed to take previously prescribed oral antibiotics for 3 days without any initial assessment, and if no improvement had occurred by then, they were required to visit the hospital for examination and to undergo treatment based on the results of a risk assessment for complications. The primary aim of the present study was to assess the outcome of febrile episodes, while the secondary aim was to assess the incidence of febrile episodes, hospitalizations, and the type of chemotherapy. The 131 patients received 840 chemotherapy administrations. Fifty-five patients (42.0%) had a total of 75 febrile episodes after 840 chemotherapy administrations (8.9%). Treatment failure occurred in 12 of the 75 episodes (16.0%) in 11 of the 55 patients (20.0%). Only four episodes required hospitalization. Treatment success was achieved in 63 episodes (84.0%). In conclusion, the feasibility of outpatient management without initial assessment was evaluated in the present study for febrile patients undergoing adjuvant chemotherapy for breast cancer, and the outpatient strategy regimen may be safe and convenient for these patients.
Surgical adjuvant treatment of locally advanced breast cancer.
Townsend, C M; Abston, S; Fish, J C
The reported incidence of local recurrence after mastectomy for locally advanced breast cancer (TNM Stage III and IV) is between 30% and 50%. The purpose of this study was to evaluate the effect of radiation therapy (XRT) followed by total mastectomy on the incidence of local recurrence in patients with locally advanced breast cancer. Fifty-three patients who presented with locally advanced breast cancer, without distant metastases, were treated with XRT (4500-5000 R) to the breast, chest wall, and regional lymph nodes. Five weeks after completion of XRT, total mastectomy was performed. There were no operative deaths. The complications that occurred in 22 patients after surgery were flap necrosis, wound infection, and seroma. Patients have been followed from 3 to 134 months. Twenty-five patients are alive (3-134 months), 12 free of disease; 28 patients have died with distant metastases (6-67 months). Isolated local recurrence occurred in only two patients. Four patients had local and distant recurrence (total local recurrence is 6/53). The remaining patients all developed distant metastases. We have devised a treatment strategy which significantly decreases the incidence of local recurrence in patients with locally advanced breast cancer. However, the rapid appearance of distant metastases emphasizes the need for systemically active therapy in patients with locally advanced breast cancer. PMID:3994434
Emerging Adjuvant Therapy for Cancer: Propolis and its Constituents.
Patel, Seema
Propolis is a bee-metabolized resinous substance (bee glue) from plant sap and gums. It has been in usage as a healing agent since antiquity, yet has not garnered global popularity as a health promoter. Its biological effects, which range from antimicrobial, antioxidant, anti-inflammatory, antidiabetic, dermatoprotective, anti-allergic, laxative and immunomodulatory to anticancer, have been validated. Propolis has shown efficacy against brain, head and neck, skin, breast, liver, pancreas, kidney, bladder, prostate, colon and blood cancers. The inhibition of matrix metalloproteinases, anti-angiogenesis, prevention of metastasis, cell-cycle arrest, induction of apoptosis and moderation of the chemotherapy-induced deleterious side effects have been deduced as the key mechanisms of cancer manipulation. The components conferring antitumor potentials have been identified as caffeic acid phenethyl ester, chrysin, artepillin C, nemorosone, galangin, cardanol, etc. These compounds target various genetic and biochemical pathways of cancer progression. Depending on the botanical sources and the geographical origin, biological activities of propolis vary. Despite phenomenal development in cancer research, conventional therapy falls short in complete malignancy management. The findings obtained so far build hope that propolis as a complementary medicine may address the lacunae. This review documents the recent advances and scope of amendement in cancer remediation with adequate emphasis on the mechanistic aspect of propolis.
Neoplastic human embryonic stem cells as a model of radiation resistance of human cancer stem cells
Dingwall, Steve; Lee, Jung Bok; Guezguez, Borhane; Fiebig, Aline; McNicol, Jamie; Boreham, Douglas; Collins, Tony J.; Bhatia, Mick
Studies have implicated that a small sub-population of cells within a tumour, termed cancer stem cells (CSCs), have an enhanced capacity for tumour formation in multiple cancers and may be responsible for recurrence of the disease after treatment, including radiation. Although comparisons have been made between CSCs and bulk-tumour, the more important comparison with respect to therapy is between tumour-sustaining CSC versus normal stem cells that maintain the healthy tissue. However, the absence of normal known counterparts for many CSCs has made it difficult to compare the radiation responses of CSCs with the normal stem cells required for post-radiotherapy tissue regeneration and the maintenance of tissue homeostasis. Here we demonstrate that transformed human embryonic stem cells (t-hESCs), showing features of neoplastic progression produce tumours resistant to radiation relative to their normal counterpart upon injection into immune compromised mice. We reveal that t-hESCs have a reduced capacity for radiation induced cell death via apoptosis and exhibit altered cell cycle arrest relative to hESCs in vitro. t-hESCs have an increased expression of BclXL in comparison to their normal counterparts and re-sensitization of t-hESCs to radiation upon addition of BH3-only mimetic ABT737, suggesting that overexpression of BclXL underpins t-hESC radiation insensitivity. Using this novel discovery platform to investigate radiation resistance in human CSCs, our study indicates that chemotherapy targeting Bcl2-family members may prove to be an adjuvant to radiotherapy capable of targeting CSCs. PMID:26082437
Neoplastic human embryonic stem cells as a model of radiation resistance of human cancer stem cells.
Dingwall, Steve; Lee, Jung Bok; Guezguez, Borhane; Fiebig, Aline; McNicol, Jamie; Boreham, Douglas; Collins, Tony J; Bhatia, Mick
Studies have implicated that a small sub-population of cells within a tumour, termed cancer stem cells (CSCs), have an enhanced capacity for tumour formation in multiple cancers and may be responsible for recurrence of the disease after treatment, including radiation. Although comparisons have been made between CSCs and bulk-tumour, the more important comparison with respect to therapy is between tumour-sustaining CSC versus normal stem cells that maintain the healthy tissue. However, the absence of normal known counterparts for many CSCs has made it difficult to compare the radiation responses of CSCs with the normal stem cells required for post-radiotherapy tissue regeneration and the maintenance of tissue homeostasis. Here we demonstrate that transformed human embryonic stem cells (t-hESCs), showing features of neoplastic progression produce tumours resistant to radiation relative to their normal counterpart upon injection into immune compromised mice. We reveal that t-hESCs have a reduced capacity for radiation induced cell death via apoptosis and exhibit altered cell cycle arrest relative to hESCs in vitro. t-hESCs have an increased expression of BclXL in comparison to their normal counterparts and re-sensitization of t-hESCs to radiation upon addition of BH3-only mimetic ABT737, suggesting that overexpression of BclXL underpins t-hESC radiation insensitivity. Using this novel discovery platform to investigate radiation resistance in human CSCs, our study indicates that chemotherapy targeting Bcl2-family members may prove to be an adjuvant to radiotherapy capable of targeting CSCs.
Multiple myeloma cancer stem cells
Gao, Minjie; Kong, Yuanyuan; Yang, Guang; Gao, Lu; Shi, Jumei
Multiple myeloma (MM) remains incurable despite much progress that has been made in the treatment of the disease. MM cancer stem cell (MMSC), a rare subpopulation of MM cells with the capacity for self-renewal and drug resistance, is considered to lead to disease relapse. Several markers such as side population (SP) and ALDH1+ have been used to identify MMSCs. However, ideally and more precisely, the identification of the MMSCs should rely on MMSCs phenotype. Unfortunately the MMSC phenotype has not been properly defined yet. Drug resistance is the most important property of MMSCs and contributes to disease relapse, but the mechanisms of drug resistance have not been fully understood. The major signaling pathways involved in the regulation of self-renewal and differentiation of MMSCs include Hedgehog (Hh), Wingless (Wnt), Notch and PI3K/Akt/mTOR. However, the precise role of these signaling pathways needs to be clarified. It has been reported that the microRNA profile of MMSCs is remarkably different than that of non-MMSCs. Therefore, the search for targeting MMSCs has also been focused on microRNAs. Complex and mutual interactions between the MMSC and the surrounding bone marrow (BM) microenvironment sustain self-renewal and survival of MMSC. However, the required molecules for the interaction of the MMSC and the surrounding BM microenvironment need to be further identified. In this review, we summarize the current state of knowledge of MMSCs regarding their phenotype, mechanisms of drug resistance, signaling pathways that regulate MMSCs self-renewal and differentiation, abnormal microRNAs expression, and their interactions with the BM microenvironment. PMID:27007154
Cancer stem cell plasticity and tumor hierarchy
Cabrera, Marina Carla; Hollingsworth, Robert E; Hurt, Elaine M
The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and cancer stem cell (CSC) models have been proposed as drivers of this heterogeneity. However, the concept of cancer stem cell plasticity and bidirectional conversion between stem and non-stem cells has added additional complexity to these highly studied paradigms and may help explain the tumor heterogeneity observed in solid tumors. The process of cancer stem cell plasticity in which cancer cells harbor the dynamic ability of shifting from a non-CSC state to a CSC state and vice versa may be modulated by specific microenvironmental signals and cellular interactions arising in the tumor niche. In addition to promoting CSC plasticity, these interactions may contribute to the cellular transformation of tumor cells and affect response to chemotherapeutic and radiation treatments by providing CSCs protection from these agents. Herein, we review the literature in support of this dynamic CSC state, discuss the effectors of plasticity, and examine their role in the development and treatment of cancer. PMID:25621103
Cancer stem cell plasticity and tumor hierarchy.
Cabrera, Marina Carla; Hollingsworth, Robert E; Hurt, Elaine M
The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and cancer stem cell (CSC) models have been proposed as drivers of this heterogeneity. However, the concept of cancer stem cell plasticity and bidirectional conversion between stem and non-stem cells has added additional complexity to these highly studied paradigms and may help explain the tumor heterogeneity observed in solid tumors. The process of cancer stem cell plasticity in which cancer cells harbor the dynamic ability of shifting from a non-CSC state to a CSC state and vice versa may be modulated by specific microenvironmental signals and cellular interactions arising in the tumor niche. In addition to promoting CSC plasticity, these interactions may contribute to the cellular transformation of tumor cells and affect response to chemotherapeutic and radiation treatments by providing CSCs protection from these agents. Herein, we review the literature in support of this dynamic CSC state, discuss the effectors of plasticity, and examine their role in the development and treatment of cancer.
Adjuvant therapy sparing in rectal cancer achieving complete response after chemoradiation
García-Albéniz, Xabier; Gallego, Rosa; Hofheinz, Ralf Dieter; Fernández-Esparrach, Gloria; Ayuso-Colella, Juan Ramón; Bombí, Josep Antoni; Conill, Carles; Cuatrecasas, Miriam; Delgado, Salvadora; Ginés, Angels; Miquel, Rosa; Pagés, Mario; Pineda, Estela; Pereira, Verónica; Sosa, Aarón; Reig, Oscar; Victoria, Iván; Feliz, Luis; María de Lacy, Antonio; Castells, Antoni; Burkholder, Iris; Hochhaus, Andreas; Maurel, Joan
AIM: To evaluate the long-term results of conventional chemoradiotherapy and laparoscopic mesorectal excision in rectal adenocarcinoma patients without adjuvant therapy. METHODS: Patients with biopsy-proven adenocarcinoma of the rectum staged cT3-T4 by endoscopic ultrasound or magnetic resonance imaging received neoadjuvant continuous infusion of 5-fluorouracil for five weeks and concomitant radiotherapy. Laparoscopic surgery was planned after 5-8 wk. Patients diagnosed with ypT0N0 stage cancer were not treated with adjuvant therapy according to the protocol. Patients with ypT1-2N0 or ypT3-4 or N+ were offered 5-fluorouracil-based adjuvant treatment on an individual basis. An external cohort was used as a reference for the findings. RESULTS: One hundred and seventy six patients were treated with induction chemoradiotherapy and 170 underwent total mesorectal excision. Cancer staging of ypT0N0 was achieved in 26/170 (15.3%) patients. After a median follow-up of 58.3 mo, patients with ypT0N0 had five-year disease-free and overall survival rates of 96% (95%CI: 77-99) and 100%, respectively. We provide evidence about the natural history of patients with localized rectal cancer achieving a complete response after preoperative chemoradiation. The inherent good prognosis of these patients will have implications for clinical trial design and care of patients. CONCLUSION: Withholding adjuvant chemotherapy after complete response following standard neoadjuvant chemoradiotherapy and laparoscopic mesorectal excision might be safe within an experienced multidisciplinary team. PMID:25400468
Molecular Markers Predict Distant Metastases After Adjuvant Chemoradiation for Rectal Cancer
Kim, Jun Won; Kim, Yong Bae; Choi, Jun Jeong; Koom, Woong Sub; Kim, Hoguen; Kim, Nam-Kyu; Ahn, Joong Bae; Lee, Ikjae; Cho, Jae Ho; Keum, Ki Chang
Purpose: The outcomes of adjuvant chemoradiation for locally advanced rectal cancer are nonuniform among patients with matching prognostic factors. We explored the role of molecular markers for predicting the outcome of adjuvant chemoradiation for rectal cancer patients. Methods and Materials: The study included 68 patients with stages II to III rectal adenocarcinoma who were treated with total mesorectal excision and adjuvant chemoradiation. Chemotherapy based on 5-fluorouracil and leucovorin was intravenously administered each month for 6-12 cycles. Radiation therapy consisted of 54 Gy delivered in 30 fractions. Immunostaining of surgical specimens for COX-2, EGFR, VEGF, thymidine synthase (TS), and Raf kinase inhibitor protein (RKIP) was performed. Results: The median follow-up was 65 months. Eight locoregional (11.8%) and 13 distant (19.1%) recurrences occurred. Five-year locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates for all patients were 83.9%, 78.7%, 66.7%, and 73.8%, respectively. LRFFS was not correlated with TNM stage, surgical margin, or any of the molecular markers. VEGF overexpression was significantly correlated with decreased DMFS (P=.045), while RKIP-positive results were correlated with increased DMFS (P=.025). In multivariate analyses, positive findings for COX-2 (COX-2+) and VEGF (VEGF+) and negative findings for RKIP (RKIP-) were independent prognostic factors for DMFS, DFS, and OS (P=.035, .014, and .007 for DMFS; .021, .010, and <.0001 for DFS; and .004, .012, and .001 for OS). The combination of both COX-2+ and VEGF+ (COX-2+/VEGF+) showed a strong correlation with decreased DFS (P=.007), and the combinations of RKIP+/COX-2- and RKIP+/VEGF- showed strong correlations with improved DFS compared with the rest of the patients (P=.001 and <.0001, respectively). Conclusions: Molecular markers can be valuable in predicting treatment outcome of adjuvant
Bisphosphonates in the adjuvant treatment of cancer: experimental evidence and first clinical results
Diel, I J; Mundy, G R
Several animal models, as well as a number of cell culture experiments, indicate a prophylactic effect of bisphosphonates in respect of subsequent bone metastasis. Moreover, in preliminary clinical trials involving patients with advanced breast cancer and local or remote metastases, biophosphonates produced a reduction in new skeletal metastases. This overview summarizes and discusses the results of the latest investigations. It opens with a section on the pathophysiology of bone metastasis, which is followed by a report on animal models and first studies of bisphosphonate treatment as a new approach in systemic adjuvant therapy. © 2000 Cancer Research Campaign PMID:10780514
Stem cell plasticity in development and cancer: epigenetic origin of cancer stem cells.
Shah, Mansi; Allegrucci, Cinzia
Stem cells are unique cells that can self-renew and differentiate into many cell types. Plasticity is a fundamental characteristic of stem cells and it is regulated by reversible epigenetic modifications. Although gene-restriction programs are established during embryonic development when cell lineages are formed, stem cells retain a degree of flexibility that is essential for tissue regeneration. For instance, quiescent adult stem cells can be induced to proliferate and trans-differentiate in response to injury. The same degree of plasticity is observed in cancer, where cancer cells with stem cell characteristics (or cancer stem cells) are formed by transformation of normal stem cells or de-differentiation of somatic cells. Reprogramming experiments with normal somatic cells and cancer cells show that epigenetic landscapes are more plastic than originally thought and that their manipulation can induce changes in cell fate. Our knowledge of stem cell function is still limited and only by understanding the mechanisms regulating developmental potential together with the definition of epigenetic maps of normal and diseased tissues we can reveal the true extent of their plasticity. In return, the control of plastic epigenetic programs in stem cells will allow us to develop effective treatments for degenerative diseases and cancer. PMID:23150267
Cancer Stem Cells: Plasticity Works against Therapy
Vinogradova, T. V.; Chernov, I. P.; Monastyrskaya, G. S.; Kondratyeva, L. G.; Sverdlov, E. D.
Great successes in identification and deciphering of mechanisms of the adult stem cells regulation have given rise to the idea that stem cells can also function in tumors as central elements of their development, starting from the initial stage and continuing until metastasis. Such cells were called cancer stem cells (CSCs). Over the course of intense discussion, the CSCs hypothesis gradually began to be perceived as an obvious fact. Recently, the existence of CSCs has been indeed confirmed in a number of works. However, when are CSCs universal prerequisites of tumors and to what extent their role is essential for tumor evolution remains an issue far from resolved. Likewise, the problem of potential use of CSCs as therapeutic targets remains unsolved. The present review attempts to analyze the issue of cancer stem cells and the potential of targeting them in tumor therapy. PMID:26798491
Adjuvant chemotherapy in breast cancer: To use or not to use, the anthracyclines
Crozier, Jennifer A; Swaika, Abhisek; Moreno-Aspitia, Alvaro
Breast cancer continues to be one of the leading causes of cancer mortality in the world. The treatment generally involves multiple modalities including surgery, radiation and/or chemotherapy. Anthracyclines, one of the first chemotherapeutic agents introduced in the 1960s, has been the backbone for the last 30 years and has been used extensively so far. However, the cardiac toxicity and the concern for secondary hematological malignancy has always been a challenge. A better understanding of the tumor biology, role of Her2 expression and the discovery of trastuzumab and other anti-Her 2 agents along with other effective novel therapeutic options, have revolutionized the treatment for breast cancer. The role of anthracyclines has come under close scrutiny, especially in the adjuvant setting for patients with early stage breast cancer and those with low or intermediate risk of disease recurrence. Recent studies have highlighted such a shift in the use of anthracyclines in both the academic and community clinical practice. However, in patients with a high risk of relapse, anthracyclines still hold promise. Ongoing clinical trials are underway to further define the role of anthracyclines in such a patient population. This review highlights the development, clinical utility, limitations and potential future use of anthracyclines in the adjuvant setting for patients with breast cancer. We consulted PubMed, Scopus, MEDLINE, ASCO annual symposium abstracts, and http://clinicaltrials.gov/ for the purpose of this review. PMID:25114866
Herbal Medicine and Acupuncture for Breast Cancer Palliative Care and Adjuvant Therapy
Liao, Guo-Shiou; Shyur, Lie-Fen
Breast cancer is a life-threatening disease among women worldwide with annual rates of reported incidence and death increasing alarmingly. Chemotherapy is a recommended and effective treatment option for breast cancer; however, the narrow therapeutic indices and varied side effects of currently approved drugs present major hurdles in increasing its effectiveness. An increasing number of literature evidence indicate that complementary and alternative medicine (CAM) used in treatment-related symptom control and alleviation of side effects plays an important role in increasing survival rate and quality of life in breast cancer patients. This review focuses on the use of herbal medicines and acupuncture in palliative care and as adjuvants in the treatment of breast cancer. Herbal medicinal treatments, the correlation of clinical use with demonstrated in vitro and in vivo mechanisms of action, and the use of certain acupoints in acupuncture are summarized. The aim of this review is to facilitate an understanding of the current practice and usefulness of herbal medicine and acupuncture as adjuvants in breast cancer therapy. PMID:23840256
GRP78 as potential predictor for breast cancer response to adjuvant taxane therapy
Lee, Eunjung; Nichols, Peter; Groshen, Susan; Spicer, Darcy; Lee, Amy S.
Few predictive markers exist for response to adjuvant chemotherapy in breast cancer. The 78-kD glucose-regulated protein (GRP78) is a potent anti-apoptotic factor, conferring drug resistance. Recently, we reported that high GRP78 expression in breast cancer specimens predict a shorter recurrence-free survival in patients who received doxorubicin-based adjuvant chemotherapy. Interestingly, the opposite effect was observed in 25 patients who additionally received a taxane. To confirm this potentially paradigm shifting finding, we investigated whether GRP78 is associated with recurrence-free survival in an independent cohort of taxane-treated breast cancer patients. Immunohistochemical staining of GRP78 was performed on archival paraffin-embedded formalin-fixed tumor specimens obtained from 48 female breast cancer patients before chemotherapy treatment. These patients received doxorubicin and cyclophosphamide, followed by paclitaxel or docetaxel on a clinical trial. GRP78 expression level was evaluated by a pathologist, masked to all clinical and outcome data. Association between GRP78 expression and recurrence-free survival was evaluated. GRP78 positivity predicts a better recurrence-free survival, independent of other prognostic factors [hazard ratio (HR) for moderate positivity: 0.40 (95% confidence interval (CI): 0.087–1.83); HR for strong positivity: 0.16 (95% CI: 0.018–1.50); Ptrend=0.053]. In a pooled analysis with the previous 25 patients, almost identical HRs were obtained with Ptrend=0.024. This provides further evidence that GRP78 is a potential independent predictor for response to taxane-based adjuvant chemotherapy in breast cancer. PMID:20473863
Flagellin is a strong vaginal adjuvant of a therapeutic vaccine for genital cancer
Lee, Shee Eun; Hong, Seol Hee; Verma, Vivek; Lee, Youn Suhk; Duong, Tra-My Nu; Jeong, Kwangjoon; Uthaman, Saji; Sung, Young Chul; Lee, Jae-Tae; Park, In-Kyu; Min, Jung-Joon; Rhee, Joon Haeng
ABSTRACT Cervical cancer is a high-incidence female cancer most commonly caused by human papilloma virus (HPV) infection of the genital mucosa. Immunotherapy targeting HPV-derived tumor antigens (TAs) has been widely studied in animal models and in patients. Because the female genital tract is a portal for the entry of HPV and a highly compartmentalized system, the development of topical vaginal immunotherapy in an orthotopic cancer model would provide an ideal therapeutic. Thus, we examined whether flagellin, a potent mucosal immunomodulator, could be used as an adjuvant for a topical therapeutic vaccine for female genital cancer. Intravaginal (IVAG) co-administration of the E6/E7 peptides with flagellin resulted in tumor suppression and long-term survival of tumor-bearing mice. In contrast to IVAG vaccination, intranasal (IN) or subcutaneous (SC) immunization did not induce significant tumor suppression in the same model. The vaginal adjuvant effect of the flagellin was completely abolished in Toll-like receptor-5 (TLR5) knock-out mice. IVAG immunization with the E6/E7 peptides plus flagellin induced the accumulation of CD4+ and CD8+ cells and the expression of T cell activation-related genes in the draining genital lymph nodes (gLNs). The co-administered flagellin elicited antigen-specific IFNγ production in the gLNs and spleen. The intravaginally administered flagellin was found in association with CD11c+ cells in the gLNs. Moreover, after immunization with a flagellin and the E6/E7 peptides, the TLR5 expression in gLN cells was significantly upregulated. These results suggest that flagellin serves as a potent vaginal adjuvant for a therapeutic peptide cancer vaccine through the activation of TLR5 signaling. PMID:27057462
[A questionnaire survey on QOL and toxicity in colorectal cancer survivors who received adjuvant chemotherapy].
Taniguchi, Hiroya; Narita, Yukiya; Komori, Koji; Kimura, Kenya; Kinoshita, Takashi; Komori, Azusa; Uegaki, Shiori; Nomura, Motoo; Nitta, Souhei; Yamaguchi, Kazuhisa; Kadowaki, Shigenori; Takahari, Daisuke; Ura, Takashi; Andoh, Masashi; Muro, Kei
The relative risk of cancer recurrence with postoperative adjuvant FOLFOX/CapeOX therapy(Ox)for stage III colorectal cancer is reduced by approximately 20%when compared to that with fluorouracil plus Leucovorin. We performed a questionnaire survey to evaluate the quality of life(QOL)and extent of side effects in patients who received adjuvant chemotherapy. In order to evaluate the risks and benefits of oxaliplatin administration, we also examined the differences in awareness of oxaliplatin side effects between patients and medical staff. Responses were obtained from 147 patients, 54 doctors, and 84 nurses. Analysis of the patient responses showed higher current QOL scores regardless of the chemotherapy regimen, although patients in the Ox group had a high rate of residual sensory peripheral neuropathy. In the Ox group, 81% of patients responded that the side effects were moderate. In contrast, 40% of medical staff identified the side effects of oxaliplatin as severe, which differed from that reported by the patients. Considering that Ox adjuvant chemotherapy may reduce the risk of recurrence by approximately 20%, the risk/benefit balance is acceptable.
Adjuvant chemo- and hormonal therapy in locally advanced breast cancer: a randomized clinical study
Schaake-Koning, C.; van der Linden, E.H.; Hart, G.; Engelsman, E.
Between 1977 and 1980, 118 breast cancer patients with locally advanced disease, T3B-4, any N, M0 or T1-3, tumor positive axillary apex biopsy, were randomized to one of three arms: I: radiotherapy (RT) to the breast and adjacent lymph node areas; II: RT followed by 12 cycles of cyclophosphamide, methotrexate, 5 fluorouracil (CMF) and tamoxifen during the chemotherapy period; III: 2 cycles of adriamycin and vincristine (AV), alternated with 2 cycles of CMF, then RT, followed by another 4 cycles of AV, alternated with 4 CMF; tamoxifen during the entire treatment period. The median follow-up period was 5 1/2 years. The adjuvant chemo- and hormonal therapy did not improve the overall survival; the 5-year survival was 37% for all three treatment arms. There was no statistically significant difference in RFS between the three modalities, nor when arm I was compared to arm II and III together. LR was not statistically different over the three treatment arms. In 18 of the 24 patients with LR, distant metastases appeared within a few months from the local recurrence. The menopausal status did not influence the treatment results. Dose reduction in more than 4 cycles of chemotherapy was accompanied by better results. In conclusion: adjuvant chemo- and hormonal therapy did not improve RFS and overall survival. These findings do not support the routine use of adjuvant chemo- and endocrine therapy for inoperable breast cancer.
Nonlinear Growth Kinetics of Breast Cancer Stem Cells: Implications for Cancer Stem Cell Targeted Therapy
NASA Astrophysics Data System (ADS)
Liu, Xinfeng; Johnson, Sara; Liu, Shou; Kanojia, Deepak; Yue, Wei; Singn, Udai; Wang, Qian; Wang, Qi; Nie, Qing; Chen, Hexin
Cancer stem cells (CSCs) have been identified in primary breast cancer tissues and cell lines. The CSC population varies widely among cancerous tissues and cell lines, and is often associated with aggressive breast cancers. Despite of intensive research, how the CSC population is regulated within a tumor is still not well understood so far. In this paper, we present a mathematical model to explore the growth kinetics of CSC population both in vitro and in vivo. Our mathematical models and supporting experiments suggest that there exist non-linear growth kinetics of CSCs and negative feedback mechanisms to control the balance between the population of CSCs and that of non-stem cancer cells. The model predictions can help us explain a few long-standing questions in the field of cancer stem cell research, and can be potentially used to predict the efficicacy of anti-cancer therapy.
Cancer stem cells niche: a target for novel cancer therapeutics.
Yi, Shan-Yong; Hao, Yi-Bin; Nan, Ke-Jun; Fan, Tian-Li
Nowadays, cancer has been a frequent disease, and the first or second most common cause of death worldwide. Despite a better understanding of the biology of cancer cells, the therapy of most cancers has not significantly changed for the past four decades. It is because conventional chemotherapies and/or radiation therapies are usually designed to eradicate highly proliferative cells. Mounting evidence has implicated that cancer is a disease of stem cells. Cancer stem cells (CSC) are often relatively quiescent, and therefore may not be affected by therapies targeting rapidly dividing cells. Like normal stem cells (NSC) residing in a "stem cell niche" that maintains them in a stem-like state, CSC also require a special microenvironment to control their self-renewal and undifferentiated state. The "CSC niche" is likely to be the most crucial target in the treatment of cancer. In this article, we summarize the current knowledge regarding CSC and their niche microenvironments. Understanding of CSC's origin, molecular profile, and interaction with their microenvironments, this could be a paradigm shift in the treatment of cancer, away from targeting the blast cells and towards the targeting of the CSC, thus improving therapeutic outcome.
Influence of Adjuvant Therapy in Cancer Survivors on Endothelial Function and Skeletal Muscle Deoxygenation.
Ederer, Austin K; Didier, Kaylin D; Reiter, Landon K; Brown, Michael; Hardy, Rachel; Caldwell, Jacob; Black, Christopher D; Larson, Rebecca D; Ade, Carl J
The cardiotoxic effects of adjuvant cancer treatments (i.e., chemotherapy and radiation treatment) have been well documented, but the effects on peripheral cardiovascular function are still unclear. We hypothesized that cancer survivors i) would have decreased resting endothelial function; and ii) altered muscle deoxygenation response during moderate intensity cycling exercise compared to cancer-free controls. A total of 8 cancer survivors (~70 months post-treatment) and 9 healthy controls completed a brachial artery FMD test, an index of endothelial-dependent dilation, followed by an incremental exercise test up to the ventilatory threshold (VT) on a cycle ergometer during which pulmonary V̇O2 and changes in near-infrared spectroscopy (NIRS)-derived microvascular tissue oxygenation (TOI), total hemoglobin concentration ([Hb]total), and muscle deoxygenation ([HHb] ≈ fractional O2 extraction) were measured. There were no significant differences in age, height, weight, and resting blood pressure between cancer survivors and control participants. Brachial artery FMD was similar between groups (P = 0.98). During exercise at the VT, TOI was similar between groups, but [Hb]total and [HHb] were significantly decreased in cancer survivors compared to controls (P < 0.01) The rate of change for TOI (ΔTOIΔ/V̇O2) and [HHb] (Δ[HHb]/ΔV̇O2) relative to ΔV̇O2 were decreased in cancer survivors compared to controls (P = 0.02 and P = 0.03 respectively). In cancer survivors, a decreased skeletal muscle microvascular function was observed during moderate intensity cycling exercise. These data suggest that adjuvant cancer therapies have an effect on the integrated relationship between O2 extraction, V̇O2 and O2 delivery during exercise.
Influence of Adjuvant Therapy in Cancer Survivors on Endothelial Function and Skeletal Muscle Deoxygenation.
Ederer, Austin K; Didier, Kaylin D; Reiter, Landon K; Brown, Michael; Hardy, Rachel; Caldwell, Jacob; Black, Christopher D; Larson, Rebecca D; Ade, Carl J
The cardiotoxic effects of adjuvant cancer treatments (i.e., chemotherapy and radiation treatment) have been well documented, but the effects on peripheral cardiovascular function are still unclear. We hypothesized that cancer survivors i) would have decreased resting endothelial function; and ii) altered muscle deoxygenation response during moderate intensity cycling exercise compared to cancer-free controls. A total of 8 cancer survivors (~70 months post-treatment) and 9 healthy controls completed a brachial artery FMD test, an index of endothelial-dependent dilation, followed by an incremental exercise test up to the ventilatory threshold (VT) on a cycle ergometer during which pulmonary V̇O2 and changes in near-infrared spectroscopy (NIRS)-derived microvascular tissue oxygenation (TOI), total hemoglobin concentration ([Hb]total), and muscle deoxygenation ([HHb] ≈ fractional O2 extraction) were measured. There were no significant differences in age, height, weight, and resting blood pressure between cancer survivors and control participants. Brachial artery FMD was similar between groups (P = 0.98). During exercise at the VT, TOI was similar between groups, but [Hb]total and [HHb] were significantly decreased in cancer survivors compared to controls (P < 0.01) The rate of change for TOI (ΔTOIΔ/V̇O2) and [HHb] (Δ[HHb]/ΔV̇O2) relative to ΔV̇O2 were decreased in cancer survivors compared to controls (P = 0.02 and P = 0.03 respectively). In cancer survivors, a decreased skeletal muscle microvascular function was observed during moderate intensity cycling exercise. These data suggest that adjuvant cancer therapies have an effect on the integrated relationship between O2 extraction, V̇O2 and O2 delivery during exercise. PMID:26807572
Adjuvant chemotherapy is not associated with improved survival for all high-risk factors in stage II colon cancer.
Verhoeff, S R; van Erning, F N; Lemmens, V E P P; de Wilt, J H W; Pruijt, J F M
Adjuvant chemotherapy can be considered in high-risk stage II colon cancer comprising pT4, poor/undifferentiated grade, vascular invasion, emergency surgery and/or <10 evaluated lymph nodes (LNs). Adjuvant chemotherapy administration and its effect on survival was evaluated for each known risk factor. All patients with high-risk stage II colon cancer who underwent resection and were diagnosed in the Netherlands between 2008 and 2012 were included. After stratification by risk factor(s) (vascular invasion could not be included), Cox regression was used to discriminate the independent association of adjuvant chemotherapy with the probability of death. Relative survival was used to estimate disease-specific survival. A total of 4,940 of 10,935 patients with stage II colon cancer were identified as high risk, of whom 790 (16%) patients received adjuvant chemotherapy. Patients with a pT4 received adjuvant chemotherapy more often (37%). Probability of death in pT4 patients receiving chemotherapy was lower compared to non-recipients (3-year overall survival 91% vs. 73%, HR 0.43, 95% CI 0.28-0.66). The relative excess risk (RER) of dying was also lower for pT4 patients receiving chemotherapy compared to non-recipients (3-year relative survival 94% vs. 85%, RER 0.36, 95% CI 0.17-0.74). For patients with only poor/undifferentiated grade, emergency surgery or <10 LNs evaluated, no association between receipt of adjuvant chemotherapy and survival was observed. In high-risk stage II colon cancer, adjuvant chemotherapy was associated with higher survival in pT4 only. To prevent unnecessary chemotherapy-induced toxicity, further refinement of patient subgroups within stage II colon cancer who could benefit from adjuvant chemotherapy seems indicated.
Epithelial to mesenchymal transition and the cancer stem cell phenotype: Insights from cancer biology with therapeutic implications for colorectal cancer
Findlay, Victoria J.; Wang, Cindy; Watson, Dennis K.; Camp, E. Ramsay
Although mortality from colorectal cancer (CRC) is decreasing, colorectal cancer is still the second highest cause of cancer related deaths in America. Chemotherapy and radiation therapy now play central roles in our strategies to fight cancer, although we continue to lack novel strategies overcoming therapeutic resistance. Molecular mechanisms of therapeutic resistance in CRC continue to be under intense investigation. In this review, we highlight the recent evidence linking epithelial-to-mesenchymal transition (EMT) with aggressive tumor biology as well as with the cancer stem cells (CSC) across multiple organ systems including colon cancer. Furthermore, in the era of neo-adjuvant treatment, the clinical implications are concerning that our treatments may have the potential to induce more aggressive cancer cells through EMT, perhaps even generating CSCs more capable of metastasis and further resistant to treatment. This concern and potential reality highlights the critical need for further understanding the impact of clinical therapy on the pathobiology of cancer and further supports the need to therapeutically target the CSC. Besides serving as potential biomarkers for aggressive tumor biology and therapeutic resistance, EMT and CSC molecular pathways may highlight novel therapeutic targets as strategies for improving the response to conventional anti-neoplastic agents translating into improved oncologic outcomes. PMID:24787239
Adjuvant endocrine therapy for premenopausal women with hormone-responsive breast cancer.
Mathew, Aju; Davidson, Nancy E
Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed and results have been presented over the last two years. These include tamoxifen for 5-10 years (ATLAS and aTTom), tamoxifen for 5 years followed by aromatase inhibitor (AI) for 5 years for women who have become postmenopausal (MA-17); ovarian ablation (OA) by surgery (EBCTCG overview); ovarian function suppression (OFS) by LHRH agonist (LHRH agonist meta-analysis); or combinations of approaches including OFS plus tamoxifen or AI (SOFT, TEXT, ABCSG 12 and E3193). Many of these trials have taken place in the backdrop of (neo)adjuvant chemotherapy which can confound interpretation because such therapy can suppress ovarian function either transiently or permanently. Nonetheless these trials suggest in aggregate that 10 years of tamoxifen are better than 5 years and that a program of extended adjuvant therapy of tamoxifen for 5 years followed by aromatase inhibitor for 5 years is effective for suitable candidates. The SOFT and E3193 trials do not show a major advantage for use of OFS + tamoxifen compared to tamoxifen alone. The joint SOFT/TEXT analysis and ABCGS12 trials both suggest that outcomes can be excellent with the use of combined endocrine therapy alone in properly selected patients but give conflicting results with regard to potential benefits for OFS + AI compared with OFS + tamoxifen. Further work will be needed to ascertain long-term outcomes, identify factors that predict who will benefit from extended adjuvant endocrine therapy, and assess role of OFS by medical or surgical means. It is clear, however, that endocrine therapy is a critical part of the adjuvant regimen for most premenopausal women with hormone-responsive breast cancer, and a subset of these women with luminal A-type tumors can be safely treated with endocrine therapy alone.
Signaling in colon cancer stem cells.
Roy, Sanchita; Majumdar, Adhip Pn
: Colorectal cancer is the fourth most common form of cancer worldwide and ranks third among the cancer-related deaths in the US and other Western countries. It occurs with equal frequency in men and women, constituting 10% of new cancer cases in men and 11% in women. Despite recent advancement in therapeutics, the survival rates from metastatic are less than 5%. Growing evidence supports the contention that epithelial cancers including colorectal cancer, the incidence of which increases with aging, are diseases driven by the pluripotent, self-renewing cancer stem cells (CSCs). Dysregulation of Wnt, Notch, Hedgehog and/or TGF-β signaling pathways that are involved in proliferation and maintenance of CSCs leads to the development of CRC. This review focuses on the signaling pathways relevant for CRC to understand the mechanisms leading to tumor progression and therapy resistance, which may help in the development of therapeutic strategies for CRC. PMID:22866952
Mutated Pathways as a Guide to Adjuvant Therapy Treatments for Breast Cancer.
Liu, Yang; Hu, Zhenjun; DeLisi, Charles
Adjuvant therapy following breast cancer surgery generally consists of either a course of chemotherapy, if the cancer lacks hormone receptors, or a course of hormonal therapy, otherwise. Here, we report a correlation between adjuvant strategy and mutated pathway patterns. In particular, we find that for breast cancer patients, pathways enriched in nonsynonymous mutations in the chemotherapy group are distinct from those of the hormonal therapy group. We apply a recently developed method that identifies collaborative pathway groups for hormone and chemotherapy patients. A collaborative group of pathways is one in which each member is altered in the same-generally large-number of samples. In particular, we find the following: (i) a chemotherapy group consisting of three pathways and a hormone therapy group consisting of 20, the members of the two groups being mutually exclusive; (ii) each group is highly enriched in breast cancer drivers; and (iii) the pathway groups are correlates of subtype-based therapeutic recommendations. These results suggest that patient profiling using these pathway groups can potentially enable the development of personalized treatment plans that may be more accurate and specific than those currently available.
Tamoxifen as the First Targeted Long Term Adjuvant Therapy for Breast Cancer
Jordan, V. Craig
Tamoxifen is an unlikely pioneering medicine in medical oncology. Nevertheless, the medicine has continued to surprise us, perform and save lives for the past 40 years. Unlike any other medicine in oncology, it is used to treat all stages of breast cancer, ductal carcinoma in situ, male breast cancer, pioneered the use of chemoprevention by reducing the incidence of breast cancer in women at high risk and induces ovulation in subfertile women! The impact of tamoxifen is ubiquitous. However, the power to save lives from this unlikely success story came from the first laboratory studies which defined that "longer was going to be better" when tamoxifen was being considered as an adjuvant therapy (Jordan 1978 Use of the DMBA-induced rat mammary carcinoma system for the evaluation of tamoxifen as a potential adjuvant therapy Reviews in Endocrine Related Cancer. October Supplement: 49–55.). This is that success story, with a focus on the interdependent components of: excellence in drug discovery, investment in self-selecting young investigators, a conversation with Nature, a conversation between the laboratory and the clinic, and the creation of the Oxford Overview Analysis. Each of these factors was essential to propel the progress of tamoxifen to evolve as an essential part of the fabric of society. "Science is adventure, discovery, new horizons, insight into our world, a means of predicting the future and enormous power to help others"(Hoagland 1990).- Mahlon Hoagland, MD. Director, Worcester Foundation for Experimental Biology (1970–85) PMID:24659478
Tocotrienol-Adjuvanted Dendritic Cells Inhibit Tumor Growth and Metastasis: A Murine Model of Breast Cancer
Abdul Hafid, Sitti Rahma; Chakravarthi, Srikumar; Nesaretnam, Kalanithi; Radhakrishnan, Ammu Kutty
Tocotrienol-rich fraction (TRF) from palm oil is reported to possess anti-cancer and immune-enhancing effects. In this study, TRF supplementation was used as an adjuvant to enhance the anti-cancer effects of dendritic cells (DC)-based cancer vaccine in a syngeneic mouse model of breast cancer. Female BALB/c mice were inoculated with 4T1 cells in mammary pad to induce tumor. When the tumor was palpable, the mice in the experimental groups were injected subcutaneously with DC-pulsed with tumor lysate (TL) from 4T1 cells (DC+TL) once a week for three weeks and fed daily with 1 mg TRF or vehicle. Control mice received unpulsed DC and were fed with vehicle. The combined therapy of using DC+TL injections and TRF supplementation (DC+TL+TRF) inhibited (p<0.05) tumor growth and metastasis. Splenocytes from the DC+TL+TRF group cultured with mitomycin-C (MMC)-treated 4T1 cells produced higher (p<0.05) levels of IFN-γ and IL-12. The cytotoxic T-lymphocyte (CTL) assay also showed enhanced tumor-specific killing (p<0.05) by CD8+ T-lymphocytes isolated from mice in the DC+TL+TRF group. This study shows that TRF has the potential to be used as an adjuvant to enhance effectiveness of DC-based vaccines. PMID:24069344
Association between adjuvant regional radiotherapy and cognitive function in breast cancer patients treated with conservation therapy
Shibayama, Osamu; Yoshiuchi, Kazuhiro; Inagaki, Masatoshi; Matsuoka, Yutaka; Yoshikawa, Eisho; Sugawara, Yuriko; Akechi, Tatsuo; Wada, Noriaki; Imoto, Shigeru; Murakami, Koji; Ogawa, Asao; Akabayashi, Akira; Uchitomi, Yosuke
Although protracted cognitive impairment has been reported to occur after radiotherapy even when such therapy is not directed to brain areas, the mechanism remains unclear. This study investigated whether breast cancer patients exposed to local radiotherapy showed lower cognitive function mediated by higher plasma interleukin (IL)-6 levels than those unexposed. We performed the Wechsler Memory Scale-Revised (WMS-R) and measured plasma IL-6 levels for 105 breast cancer surgical patients within 1 year after the initial therapy. The group differences in each of the indices of WMS-R were investigated between cancer patients exposed to adjuvant regional radiotherapy (n = 51) and those unexposed (n = 54) using analysis of covariance. We further investigated a mediation effect by plasma IL-6 levels on the relationship between radiotherapy and the indices of WMS-R using the bootstrapping method. The radiotherapy group showed significantly lower Immediate Verbal Memory Index and Delayed Recall Index (P = 0.001, P = 0.008, respectively). Radiotherapy exerted an indirect effect on the lower Delayed Recall Index of WMS-R through elevation of plasma IL-6 levels (bootstrap 95% confidence interval = −2.6626 to −0.0402). This study showed that breast cancer patients exposed to adjuvant regional radiotherapy in conservation therapy might have cognitive impairment even several months after their treatment. The relationship between the therapy and the cognitive impairment could be partially mediated by elevation of plasma IL-6 levels. PMID:24756915
Oncometabolic Nuclear Reprogramming of Cancer Stemness
Menendez, Javier A.; Corominas-Faja, Bruna; Cuyàs, Elisabet; García, María G.; Fernández-Arroyo, Salvador; Fernández, Agustín F.; Joven, Jorge; Fraga, Mario F.; Alarcón, Tomás
Summary By impairing histone demethylation and locking cells into a reprogramming-prone state, oncometabolites can partially mimic the process of induced pluripotent stem cell generation. Using a systems biology approach, combining mathematical modeling, computation, and proof-of-concept studies with live cells, we found that an oncometabolite-driven pathological version of nuclear reprogramming increases the speed and efficiency of dedifferentiating committed epithelial cells into stem-like states with only a minimal core of stemness transcription factors. Our biomathematical model, which introduces nucleosome modification and epigenetic regulation of cell differentiation genes to account for the direct effects of oncometabolites on nuclear reprogramming, demonstrates that oncometabolites markedly lower the "energy barriers" separating non-stem and stem cell attractors, diminishes the average time of nuclear reprogramming, and increases the size of the basin of attraction of the macrostate occupied by stem cells. These findings establish the concept of oncometabolic nuclear reprogramming of stemness as a bona fide metabolo-epigenetic mechanism for generation of cancer stem-like cells. PMID:26876667
Embryonic stem cell factors and pancreatic cancer
Herreros-Villanueva, Marta; Bujanda, Luis; Billadeau, Daniel D; Zhang, Jin-San
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic tumor, is a highly aggressive human cancer with the lowest five-year survival rate of any human maligancy primarily due to its early- metastasis and lack of response to chemotherapy and radiation. Recent research suggests that PDAC cells comprise a hierarchy of tumor cells that develop around a population of cancer stem cells (CSCs), a small and distinct population of cancer cells that mediates tumoregenesis, metastasis and resistance to standard treatments. Thus, CSCs could be a target for more effective treatment options. Interestingly, pancreatic CSCs are subject to regulation by some of key embryonic stem cell (ESC) transctiption factors abberently expressed in PDAC, such as SOX2, OCT4 and NANOG. ESC transcription factors are important DNA-binding proteins present in both embryonic and adult somatic cells. The critical role of these factors in reprogramming processes makes them essential not only for embryonic development but also tumorigenesis. Here we provide an overview of stem cell transcription factors, particularly SOX2, OCT4, and NANOG, on their expression and function in pancreatic cancer. In contrast to embryonic stem cells, in which OCT4 and SOX2 are tightly regulated and physically interact to regulate a wide spectrum of target genes, de novo SOX2 expression alone in pancreatic cancer cells is sufficient to promote self-renewal, de-differentiation and imparting stemness characteristics via impacting specific cell cycle regulatory genes and epithelial-mesnechymal transtion driver genes. Thus, targeting ESC factors, particularly SOX2, could be a worthy strategy for pancreatic cancer therapy. PMID:24605024
Embryonic stem cell factors and pancreatic cancer.
Herreros-Villanueva, Marta; Bujanda, Luis; Billadeau, Daniel D; Zhang, Jin-San
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic tumor, is a highly aggressive human cancer with the lowest five-year survival rate of any human maligancy primarily due to its early- metastasis and lack of response to chemotherapy and radiation. Recent research suggests that PDAC cells comprise a hierarchy of tumor cells that develop around a population of cancer stem cells (CSCs), a small and distinct population of cancer cells that mediates tumoregenesis, metastasis and resistance to standard treatments. Thus, CSCs could be a target for more effective treatment options. Interestingly, pancreatic CSCs are subject to regulation by some of key embryonic stem cell (ESC) transctiption factors abberently expressed in PDAC, such as SOX2, OCT4 and NANOG. ESC transcription factors are important DNA-binding proteins present in both embryonic and adult somatic cells. The critical role of these factors in reprogramming processes makes them essential not only for embryonic development but also tumorigenesis. Here we provide an overview of stem cell transcription factors, particularly SOX2, OCT4, and NANOG, on their expression and function in pancreatic cancer. In contrast to embryonic stem cells, in which OCT4 and SOX2 are tightly regulated and physically interact to regulate a wide spectrum of target genes, de novo SOX2 expression alone in pancreatic cancer cells is sufficient to promote self-renewal, de-differentiation and imparting stemness characteristics via impacting specific cell cycle regulatory genes and epithelial-mesnechymal transtion driver genes. Thus, targeting ESC factors, particularly SOX2, could be a worthy strategy for pancreatic cancer therapy.
Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel.
Hadji, P; Coleman, R E; Wilson, C; Powles, T J; Clézardin, P; Aapro, M; Costa, L; Body, J-J; Markopoulos, C; Santini, D; Diel, I; Di Leo, A; Cameron, D; Dodwell, D; Smith, I; Gnant, M; Gray, R; Harbeck, N; Thurlimann, B; Untch, M; Cortes, J; Martin, M; Albert, U-S; Conte, P-F; Ejlertsen, B; Bergh, J; Kaufmann, M; Holen, I
Bisphosphonates have been studied in randomised trials in early breast cancer to investigate their ability to prevent cancer treatment-induced bone loss (CTIBL) and reduce the risk of disease recurrence and metastasis. Treatment benefits have been reported but bisphosphonates do not currently have regulatory approval for either of these potential indications. This consensus paper provides a review of the evidence and offers guidance to breast cancer clinicians on the use of bisphosphonates in early breast cancer. Using the nominal group methodology for consensus, a systematic review of the literature was augmented by a workshop held in October 2014 for breast cancer and bone specialists to present and debate the available pre-clinical and clinical evidence for the use of adjuvant bisphosphonates. This was followed by a questionnaire to all members of the writing committee to identify areas of consensus. The panel recommended that bisphosphonates should be considered as part of routine clinical practice for the prevention of CTIBL in all patients with a T score of <-2.0 or ≥2 clinical risk factors for fracture. Compelling evidence from a meta-analysis of trial data of >18,000 patients supports clinically significant benefits of bisphosphonates on the development of bone metastases and breast cancer mortality in post-menopausal women or those receiving ovarian suppression therapy. Therefore, the panel recommends that bisphosphonates (either intravenous zoledronic acid or oral clodronate) are considered as part of the adjuvant breast cancer treatment in this population and the potential benefits and risks discussed with relevant patients. PMID:26681681
Stem cells: tissue regeneration and cancer.
Tataria, Monika; Perryman, Scott V; Sylvester, Karl G
Regenerative medicine is the promised paradigm of replacement and repair of damaged or senescent tissues. As the building blocks for organ development and tissue repair, stem cells have unique and wide-ranging capabilities, thus delineating their potential application to regenerative medicine. The recognition that consistent patterns of molecular mechanisms drive organ development and postnatal tissue regeneration has significant implications for a variety of pediatric diseases beyond replacement biology. The observation that organ-specific stem cells derive all of the differentiated cells within a given tissue has led to the acceptance of a stem cell hierarchy model for tissue development, maintenance, and repair. Extending the tissue stem cell hierarchical model to tissue carcinogenesis may revolutionize the manner in which we conceptualize cancer therapeutics. In this review, the clinical promise of these technologies and the emerging concept of "cancer stem cells" are examined. A basic understanding of stem cell biology is paramount to stay informed of this emerging technology and the accompanying research in this area with the potential for clinical application. PMID:17055959
Cancer stem cells: progress and challenges in lung cancer.
Templeton, Amanda K; Miyamoto, Shinya; Babu, Anish; Munshi, Anupama; Ramesh, Rajagopal
The identification of a subpopulation of tumor cells with stem cell-like characteristics first in hematological malignancies and later in solid tumors has emerged into a novel field of cancer research. It has been proposed that this aberrant population of cells now called "cancer stem cells" (CSCs) drives tumor initiation, progression, metastasis, recurrence, and drug resistance. CSCs have been shown to have the capacity of self-renewal and multipotency. Adopting strategies from the field of stem cell research has aided in identification, localization, and targeting of CSCs in many tumors. Despite the huge progress in other solid tumors such as brain, breast, and colon cancers no substantial advancements have been made in lung cancer. This is most likely due to the current rudimentary understanding of lung stem cell hierarchy and heterogeneous nature of lung disease. In this review, we will discuss the most recent findings related to identification of normal lung stem cells and CSCs, pathways involved in regulating the development of CSCs, and the importance of the stem cell niche in development and maintenance of CSCs. Additionally, we will examine the development and feasibility of novel CSC-targeted therapeutic strategies aimed at eradicating lung CSCs. PMID:27358855
Cancer stem cells: progress and challenges in lung cancer
Templeton, Amanda K.; Miyamoto, Shinya; Babu, Anish; Munshi, Anupama
The identification of a subpopulation of tumor cells with stem cell-like characteristics first in hematological malignancies and later in solid tumors has emerged into a novel field of cancer research. It has been proposed that this aberrant population of cells now called "cancer stem cells" (CSCs) drives tumor initiation, progression, metastasis, recurrence, and drug resistance. CSCs have been shown to have the capacity of self-renewal and multipotency. Adopting strategies from the field of stem cell research has aided in identification, localization, and targeting of CSCs in many tumors. Despite the huge progress in other solid tumors such as brain, breast, and colon cancers no substantial advancements have been made in lung cancer. This is most likely due to the current rudimentary understanding of lung stem cell hierarchy and heterogeneous nature of lung disease. In this review, we will discuss the most recent findings related to identification of normal lung stem cells and CSCs, pathways involved in regulating the development of CSCs, and the importance of the stem cell niche in development and maintenance of CSCs. Additionally, we will examine the development and feasibility of novel CSC-targeted therapeutic strategies aimed at eradicating lung CSCs. PMID:27358855
[Advances in Lung Stem Cells and Lung Cancer Stem Cells].
Yin, Huijing; Deng, Jiong
Cancer stem cells (CSCs) are emerging as a hot topic for cancer research. Lung CSCs share many characteristics with normal lung stem cells (SCs), including self-renewal and multi-potency for differentiation. Many molecular markers expressed in various types of CSCs were also found in lung CSCs, such as CD133, CD44, aldehyde dehydrogenase (ALDH) and ATP-binding cassette sub-family G member 2 (ABCG2). Similarly, proliferation and expansion of lung CSCs are regulated not only by signal transduction pathways functioning in normal lung SCs, such as Notch, Hedgehog and Wnt pathways, but also by those acting in tumor cells, such as epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositol 3 kinase (PI3K) pathways. As CSC plays an critical role in tumor recurrence, metastasis and drug-resistance, understanding the difference between lung CSCs and normal lung SCs, identifying and targeting CSC markers or related signaling pathways may increase the efficacy of therapy on lung cancer and improved survival of lung cancer patients.
Predicting the response of localised oesophageal cancer to neo-adjuvant chemoradiation
Gillham, Charles M; Reynolds, John; Hollywood, Donal
Background A complete pathological response to neo-adjuvant chemo-radiation for oesophageal cancer is associated with favourable survival. However, such a benefit is seen in the minority. If one could identify, at diagnosis, those patients who were unlikely to respond unnecessary toxicity could be avoided and alternative treatment can be considered. The aim of this review was to highlight predictive markers currently assessed and evaluate their clinical utility. Methods A systematic search of Pubmed and Google Scholar was performed using the following keywords; "neo-adjuvant", "oesophageal", "trimodality", "chemotherapy", "radiotherapy", "chemoradiation" and "predict". The original manuscripts were sourced for further articles of relevance. Results Conventional indices including tumour stage and grade seem unable to predict histological response. Immuno-histochemical markers have been extensively studied, but none has made its way into routine clinical practice. Global gene expression from fresh pre-treatment tissue using cDNA microarray has only recently been assessed, but shows considerable promise. Molecular imaging using FDG-PET seems to be able to predict response after neo-adjuvant chemoradiation has finished, but there is a paucity of data when such imaging is performed earlier. Conclusion Currently there are no clinically useful predictors of response based on standard pathological assessment and immunohistochemistry. Genomics, proteomics and molecular imaging may hold promise. PMID:17716369
Is Adjuvant Chemoradiotherapy Overtreatment in Cervical Cancer Patients With Intermediate Risk Factors?
Ryu, Sang-Young; Park, Sang-Il; Nam, Byung-Ho; Cho, Chul-Koo; Kim, Kidong; Kim, Beob-Jong; Kim, Moon-Hong; Choi, Seok-Cheol; Lee, Eui-Don; Lee, Kyoung-Hee
Purpose: To determine whether adjuvant chemoradiotherapy (CRT) improves the outcome of cervical cancer patients with intermediate risk factors. Methods and Materials: Between January 2000 and June 2006, the medical records of 735 patients who had undergone radical surgery for Stage IB-IIA cervical cancer were reviewed retrospectively. Of the 735 patients, 172 with two or more intermediate risk factors (i.e., lymphovascular space involvement, deep stromal invasion, and tumor size {>=}2 cm) were grouped as follows according to the adjuvant treatment received: 34 patients, no further treatment; 49 patients, RT; and 89 patients, CRT. The significance of the clinical parameters and recurrence-free survival of each group were analyzed. Results: Of the 172 patients with any of the intermediate risk factors, 137 (79.6%) had two or more intermediate risk factors. Of the 172 patients, 12 developed recurrences (6.4%)->(7.0%), with 6 in the pelvis and 6 in distant sites. All 12 recurrences occurred in those who had two or more intermediate risk factors (sensitivity, 100%); however, only six recurrences were detected in patients who met the Gynecologic Oncology Group criteria for the intermediate-risk group (sensitivity, 50%; Z test, p < .05). A statistically significant difference was found in the 3-year recurrence-free survival rate among the no further treatment, RT, and CRT groups (67.5%, 90.5%, and 97.5%, respectively; p < .05). The incidence of Grade 3-4 hematologic and gastrointestinal toxicities was not significantly different statistically between the RT and CRT groups (6.1% and 13.4%, respectively; p > .05). Conclusion: Postoperative adjuvant CRT can improve the outcome of cervical cancer patients with intermediate risk factors, with low increase in toxicity.
Adjuvant paclitaxel and carboplatin chemotherapy with involved field radiation in advanced endometrial cancer: A sequential approach
Lupe, Krystine; Kwon, Janice . E-mail: firstname.lastname@example.com; D'Souza, David; Gawlik, Christine; Stitt, Larry; Whiston, Frances; Nascu, Patricia; Wong, Eugene; Carey, Mark S.
Purpose: To determine the feasibility of adjuvant paclitaxel and carboplatin chemotherapy interposed with involved field radiotherapy for women with advanced endometrial cancer. Methods and Materials: This was a prospective cohort study of women with Stage III and IV endometrial cancer. Adjuvant therapy consisted of 4 cycles of paclitaxel (175 mg/m{sup 2}) and carboplatin (350 mg/m{sup 2}) every 3 weeks, followed sequentially by external beam radiotherapy (RT) to the pelvis (45 Gy), followed by an additional two cycles of chemotherapy. Para-aortic RT and/or HDR vault brachytherapy (BT) were added at the discretion of the treating physician. Results: Thirty-three patients (median age, 63 years) received treatment between April 2002 and June 2005. Median follow-up was 21 months. Stage distribution was as follows: IIIA (21%), IIIC (70%), IVB (9%). Combination chemotherapy was successfully administered to 30 patients (91%) and 25 patients (76%), before and after RT respectively. Nine patients (27%) experienced acute Grade 3 or 4 chemotherapy toxicities. All patients completed pelvic RT; 19 (58%) received standard 4-field RT and 14 (42%) received intensity-modulated radiotherapy. Ten (30%) received extended field radiation. Four patients (12%) experienced acute Grade 3 or 4 RT toxicities. Six (18%) patients developed chronic RT toxicity. There were no treatment-related deaths. Two-year disease-free and overall survival rates were both 55%. There was only one pelvic relapse (3%). Conclusions: Adjuvant treatment with combination chemotherapy interposed with involved field radiation in advanced endometrial cancer was well tolerated. This protocol may be suitable for further evaluation in a clinical trial.
Use of Adjuvant 5-Fluorouracil and Radiation Therapy After Gastric Cancer Resection Among the Elderly and Impact on Survival
Strauss, Joshua; Hershman, Dawn L.; Buono, Donna; McBride, Russell; Clark-Garvey, Sean; Woodhouse, Shermian A.; Abrams, Julian A.
Purpose: In randomized trials patients with resected nonmetastatic gastric cancer who received adjuvant chemotherapy and radiotherapy (chemoRT) had better survival than those who did not. We investigated the effectiveness of adjuvant chemoRT after gastric cancer resection in an elderly general population and its effects by stage. Methods and Materials: We identified individuals in the Surveillance, Epidemiology, and End Results-Medicare database aged 65 years or older with Stage IB through Stage IV (M0) gastric cancer, from 1991 to 2002, who underwent gastric resection, using multivariate modeling to analyze predictors of chemoRT use and survival. Results: Among 1,993 patients who received combined chemoRT or no adjuvant therapy after resection, having a later year of diagnosis, having a more advanced stage, being younger, being white, being married, and having fewer comorbidities were associated with combined treatment. Among 1,476 patients aged less than 85 years who survived more than 4 months, the 313 who received combined treatment had a lower mortality rate (hazard ratio, 0.83; 95% confidence interval, 0.71-0.98) than the 1,163 who received surgery alone. Adjuvant therapy significantly reduced the mortality rate for Stages III and IV (M0), trended toward improved survival for Stage II, and showed no benefit for Stage IB. We observed trends toward improved survival in all age categories except 80 to 85 years. Conclusions: The association of combined adjuvant chemoRT with improved survival in an overall analysis of Stage IB through Stage IV (M0) resected gastric cancer is consistent with clinical trial results and suggests that, in an elderly population, adjuvant chemoradiotherapy is effective. However, our observational data suggest that adjuvant treatment may not be effective for Stage IB cancer, is possibly appropriate for Stage II, and shows significant survival benefits for Stages III and IV (M0) for those aged less than 80 years.
Dual HER2 blockade in the neoadjuvant and adjuvant treatment of HER2-positive breast cancer
Advani, Pooja; Cornell, Lauren; Chumsri, Saranya; Moreno-Aspitia, Alvaro
Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase transmembrane receptor that is overexpressed on the surface of 15%–20% of breast tumors and has been associated with poor prognosis. Consistently improved pathologic response and survival rates have been demonstrated with use of trastuzumab in combination with standard chemotherapy in both early and advanced breast cancer. However, resistance to trastuzumab may pose a major problem in the effective treatment of HER2-positive breast cancer. Dual HER2 blockade, using agents that work in a complimentary fashion to trastuzumab, has more recently been explored to evade resistance in both the preoperative (neoadjuvant) and adjuvant settings. Increased effectiveness of dual anti-HER2 agents over single blockade has been recently reported in clinical studies. Pertuzumab in combination with trastuzumab and taxane is currently approved in the metastatic and neoadjuvant treatment of HER2-positive breast cancer. Various biomarkers have also been investigated to identify subsets of patients with HER2-positive tumors who would likely respond best to these targeted therapy combinations. In this article, available trial data regarding efficacy and toxicity of treatment with combination HER2 agents in the neoadjuvant and adjuvant setting have been reviewed, and relevant correlative biomarker data from these trials have been discussed. PMID:26451122
Stem vs non-stem cell origin of colorectal cancer
Huels, D J; Sansom, O J
Colorectal cancer (CRC) is one of the most common cancers in the western world and is characterised by deregulation of the Wnt signalling pathway. Mutation of the adenomatous polyposis coli (APC) tumour suppressor gene, which encodes a protein that negatively regulates this pathway, occurs in almost 80% of CRC cases. The progression of this cancer from an early adenoma to carcinoma is accompanied by a well-characterised set of mutations including KRAS, SMAD4 and TP53. Using elegant genetic models the current paradigm is that the intestinal stem cell is the origin of CRC. However, human histology and recent studies, showing marked plasticity within the intestinal epithelium, may point to other cells of origin. Here we will review these latest studies and place these in context to provide an up-to-date view of the cell of origin of CRC. PMID:26110974
Southwest Oncology Group experience: adjuvant therapy for Stage IB and II non-seminomatous testicular cancer
Stephens, R.L.; Eltringham, J.R.; Coltman, C.A. Jr.; Neidhart, J.; Mullins, J.; Frank, J.
During a two year period, 65 patients with Stage II non-seminomatous testis cancer were randomized to receive adjuvant chemotherapy and radiation. Of the 52 evaluable patients, 23 received radiation followed by chemotherapy (sequential), and 29 received the same chemotherapy as initial treatment, but had drug treatment temporarily interrupted for radiation (sandwich). The combined treatment was well tolerated, but did not eliminate recurrence. With regard to duration of survival and disease-free survival, no statistically significant difference could be found between the sequential and sandwich approaches.
Tuberculosis axillary lymph node coexistent breast cancer in adjuvant treatment: case report
Bromberg, Silvio Eduardo; do Amaral, Paulo Gustavo Tenório
Coexistence of breast cancer and tuberculosis is rare. In most cases, involvement by tuberculosis occurs in axillary lymph nodes. We report a case of a 43-years-old patient who had undergone adenomastectomy and left sentinel lymph node biopsy due to a triple negative ductal carcinoma. At the end of adjuvant treatment, the patient had an atypical lymph node in the left axilla. Lymph node was excised, and after laboratory analysis, the diagnosis was ganglion tuberculosis. The patient underwent treatment for primary tuberculosis. The development of these two pathologies can lead to problems in diagnosis and treatment. An accurate diagnosis is important to avoid unnecessary surgical procedures. PMID:26018148
Integration of targeted agents in the neo-adjuvant treatment of gastro-esophageal cancers.
Power, D G; Ilson, D H
Pre- and peri-operative strategies are becoming standard for the management of localized gastro-esophageal cancer. For localized gastric/gastro-esophageal junction (GEJ) cancer there are conflicting data that a peri-operative approach with cisplatin-based chemotherapy improves survival, with the benefits seen in esophageal cancer likely less than a 5-10% incremental improvement. Further trends toward improvement in local control and survival, when combined chemotherapy and radiation therapy are given pre-operatively, are suggested by recent phase III trials. In fit patients, a significant survival benefit with pre-operative chemoradiation is seen in those patients who achieve a pathologic complete response. In esophageal/GEJ cancer, definitive chemoradiation is now considered in medically inoperable patients. In squamous cell carcinoma of the esophagus, surgery after primary chemoradiation is not clearly associated with an improved overall survival, however, local control may be better. In localized gastric/GEJ cancer, the integration of bevacizumab with pre-operative chemotherapy is being explored in large randomized studies, and with chemoradiotherapy in pilot trials. The addition of anti-epidermal growth factor receptor and anti-human epidermal growth factor receptor-2 antibody treatment to pre-operative chemoradiation continues to be explored. Early results show the integration of targeted therapy is feasible. Metabolic imaging can predict early response to pre-operative chemotherapy and biomarkers may further predict response to pre-operative chemo-targeted therapy. A multimodality approach to localized gastro-esophageal cancer has resulted in better outcomes. For T3 or node-positive disease, surgery alone is no longer considered appropriate and neo-adjuvant therapy is recommended. The future of neo-adjuvant strategies in this disease will involve the individualization of therapy with the integration of molecular signatures, targeted therapy, metabolic imaging
Neoadjuvant or adjuvant therapy for resectable gastric cancer? A practice guideline
Earle, Craig C.; Maroun, Jean; Zuraw, Lisa
Objective To make recommendations on the use of neoadjuvant or adjuvant therapy in addition to surgery in patients with resectable gastric cancer (T1–4, N1–2, M0). Options Neoadjuvant or adjuvant treatments compared with "curative" surgery alone. Outcomes Overall survival, disease-free survival, and adverse effects. Evidence The MEDLINE, CANCERLIT and Cochrane Library databases and relevant conference proceedings were searched to identify randomized trials. Values Evidence was selected and reviewed by one member of the Cancer Care Ontario Practice Guidelines Initiative (CCOPGI) Gastrointestinal Cancer Disease Site Group and methodologists. A systematic review of the published literature was combined with a consensus process around the interpretation of the evidence in the context of conventional practice, to develop an evidence-based practice guideline. This report has been reviewed and approved by the Gastrointestinal Cancer Disease Site Group, comprising medical oncologists, radiation oncologists, surgeons, a pathologist and 2 community representatives. Benefits, harms and costs When compared with surgery alone, at 3 years adjuvant chemoradiotherapy has been shown to increase overall survival by 9% (50% v. 41%, p = 0.005) and to improve relapse-free survival from 31% to 48% (p = 0.001). At 5 years, it has been shown to increase overall survival by 11.6% (40% v. 28.4%) and to improve relapse-free survival from 25% to 38% (p < 0.001). Treatment has been associated with toxic deaths in 1% of patients. The most frequent adverse effects (> grade 3 [Southwest Oncology Group toxicity scale] are hematologic (54%), gastrointestinal (33%), influenza-like (9%), infectious (6%) and neurologic (4%). The radiation fields used can possibly damage the left kidney, resulting in hypertension and other renal problems. Furthermore, this therapy could increase the demand on radiation resources. Physicians and patients should understand the tradeoffs between survival benefit
Curcumin: a promising agent targeting cancer stem cells.
Zang, Shufei; Liu, Tao; Shi, Junping; Qiao, Liang
Cancer stem cells are a subset of cells that are responsible for cancer initiation and relapse. They are generally resistant to the current anticancer agents. Successful anticancer therapy must consist of approaches that can target not only the differentiated cancer cells, but also cancer stem cells. Emerging evidence suggested that the dietary agent curcumin exerted its anti-cancer activities via targeting cancer stem cells of various origins such as those of colorectal cancer, pancreatic cancer, breast cancer, brain cancer, and head and neck cancer. In order to enhance the therapeutic potential of curcumin, this agent has been modified or used in combination with other agents in the experimental therapy for many cancers. In this mini-review, we discussed the effect of curcumin and its derivatives in eliminating cancer stem cells and the possible underlying mechanisms.
Hallmarks of cancer stem cell metabolism
Sancho, Patricia; Barneda, David; Heeschen, Christopher
Cancer cells adapt cellular metabolism to cope with their high proliferation rate. Instead of primarily using oxidative phosphorylation (OXPHOS), cancer cells use less efficient glycolysis for the production of ATP and building blocks (Warburg effect). However, tumours are not uniform, but rather functionally heterogeneous and harbour a subset of cancer cells with stemness features. Such cancer cells have the ability to repopulate the entire tumour and thus have been termed cancer stem cells (CSCs) or tumour-initiating cells (TICs). As opposed to differentiated bulk tumour cells relying on glycolysis, CSCs show a distinct metabolic phenotype that, depending on the cancer type, can be highly glycolytic or OXPHOS dependent. In either case, mitochondrial function is critical and takes centre stage in CSC functionality. Remaining controversies in this young and emerging research field may be related to CSC isolation techniques and/or the use of less suitable model systems. Still, the apparent dependence of CSCs on mitochondrial function, regardless of their primary metabolic phenotype, represents a previously unrecognised Achilles heel amendable for therapeutic intervention. Elimination of highly chemoresistant CSCs as the root of many cancers via inhibition of mitochondrial function bears the potential to prevent relapse from disease and thus improve patients' long-term outcome. PMID:27219018
Hallmarks of cancer stem cell metabolism.
Sancho, Patricia; Barneda, David; Heeschen, Christopher
Cancer cells adapt cellular metabolism to cope with their high proliferation rate. Instead of primarily using oxidative phosphorylation (OXPHOS), cancer cells use less efficient glycolysis for the production of ATP and building blocks (Warburg effect). However, tumours are not uniform, but rather functionally heterogeneous and harbour a subset of cancer cells with stemness features. Such cancer cells have the ability to repopulate the entire tumour and thus have been termed cancer stem cells (CSCs) or tumour-initiating cells (TICs). As opposed to differentiated bulk tumour cells relying on glycolysis, CSCs show a distinct metabolic phenotype that, depending on the cancer type, can be highly glycolytic or OXPHOS dependent. In either case, mitochondrial function is critical and takes centre stage in CSC functionality. Remaining controversies in this young and emerging research field may be related to CSC isolation techniques and/or the use of less suitable model systems. Still, the apparent dependence of CSCs on mitochondrial function, regardless of their primary metabolic phenotype, represents a previously unrecognised Achilles heel amendable for therapeutic intervention. Elimination of highly chemoresistant CSCs as the root of many cancers via inhibition of mitochondrial function bears the potential to prevent relapse from disease and thus improve patients' long-term outcome. PMID:27219018
Targeting Lung Cancer Stem Cells with Antipsychological Drug Thioridazine
Yue, Haiying; Huang, Dongning; Qin, Li; Zheng, Zhiyong; Hua, Li; Wang, Guodong; Huang, Jian
Lung cancer stem cells are a subpopulation of cells critical for lung cancer progression, metastasis, and drug resistance. Thioridazine, a classical neurological drug, has been reported with anticancer ability. However, whether thioridazine could inhibit lung cancer stem cells has never been studied. In our current work, we used different dosage of thioridazine to test its effect on lung cancer stem cells sphere formation. The response of lung cancer stem cells to chemotherapy drug with thioridazine treatment was measured. The cell cycle distribution of lung cancer stem cells after thioridazine treatment was detected. The in vivo inhibitory effect of thioridazine was also measured. We found that thioridazine could dramatically inhibit sphere formation of lung cancer stem cells. It sensitized the LCSCs to chemotherapeutic drugs 5-FU and cisplatin. Thioridazine altered the cell cycle distribution of LCSCs and decreased the proportion of G0 phase cells in lung cancer stem cells. Thioridazine inhibited lung cancer stem cells initiated tumors growth in vivo. This study showed that thioridazine could inhibit lung cancer stem cells in vitro and in vivo. It provides a potential drug for lung cancer therapy through targeting lung cancer stem cells. PMID:27556038
Cancer stem cells targeting agents--a review.
Shi, A-M; Tao, Z-Q; Li, H; Wang, Y-Q; Zhao, J
Major current cancer strategies like surgery, radiotherapy, and chemotherapy are compromised due to major problem of recurrence, which usually lead to mortality. The widely accepted reason for this is resistance offered by cancer cells towards cancer drugs or inability of a therapeutic procedure to target real culprits viz. cancer-initiating cells (cancer stem cells). So, there is a current need of development of new agents targeting these cancer stem cells in order to overcome resistance to therapeutic procedures. The present review article is focused on new cancer cell targeting agents like salinomycin, apopotin etc and their mechanisms to target cancer stems cells will be discussed.
Cost-effectiveness of adjuvant chemotherapy with uracil–tegafur for curatively resected stage III rectal cancer
Hisashige, A; Yoshida, S; Kodaira, S
Recently, the National Surgical Adjuvant Study of Colorectal Cancer in Japan, a randomised controlled trial of oral uracil–tegafur (UFT) adjuvant therapy for stage III rectal cancer, showed remarkable survival gains, compared with surgery alone. To evaluate value for money of adjuvant UFT therapy, cost-effective analysis was carried out. Cost-effectiveness analysis of adjuvant UFT therapy was carried out from a payer's perspective, compared with surgery alone. Overall survival and relapse-free survival were estimated by Kaplan–Meier method, up to 5.6 years from randomisation. Costs were estimated from trial data during observation. Quality-adjusted life-years (QALYs) were calculated using utility score from literature. Beyond observation period, they were simulated by the Boag model combined with the competing risk model. For 5.6-year observation, 10-year follow-up and over lifetime, adjuvant UFT therapy gained 0.50, 0.96 and 2.28 QALYs, and reduced costs by $2457, $1771 and $1843 per person compared with surgery alone, respectively (3% discount rate for both effect and costs). Cost-effectiveness acceptability and net monetary benefit analyses showed the robustness of these results. Economic evaluation of adjuvant UFT therapy showed that this therapy is cost saving and can be considered as a cost-effective treatment universally accepted for wide use in Japan. PMID:18797469
Cancer Stem Cells in the Thyroid
Nagayama, Yuji; Shimamura, Mika; Mitsutake, Norisato
The cancer stem cell (CSC) model posits that CSCs are a small, biologically distinct subpopulation of cancer cells in each tumor that have self-renewal and multi-lineage potential, and are critical for cancer initiation, metastasis, recurrence, and therapy-resistance. Numerous studies have linked CSCs to thyroid biology, but the candidate markers and signal transduction pathways that drive thyroid CSC growth are controversial, the origin(s) of thyroid CSCs remain elusive, and it is unclear whether thyroid CSC biology is consistent with the original hierarchical CSC model or the more recent dynamic CSC model. Here, we critically review the thyroid CSC literature with an emphasis on research that confirmed the presence of thyroid CSCs by in vitro sphere formation or in vivo tumor formation assays with dispersed cells from thyroid cancer tissues or bona fide thyroid cancer cell lines. Future perspectives of thyroid CSC research are also discussed. PMID:26973599
Cancer Stem Cells in the Thyroid.
Nagayama, Yuji; Shimamura, Mika; Mitsutake, Norisato
The cancer stem cell (CSC) model posits that CSCs are a small, biologically distinct subpopulation of cancer cells in each tumor that have self-renewal and multi-lineage potential, and are critical for cancer initiation, metastasis, recurrence, and therapy-resistance. Numerous studies have linked CSCs to thyroid biology, but the candidate markers and signal transduction pathways that drive thyroid CSC growth are controversial, the origin(s) of thyroid CSCs remain elusive, and it is unclear whether thyroid CSC biology is consistent with the original hierarchical CSC model or the more recent dynamic CSC model. Here, we critically review the thyroid CSC literature with an emphasis on research that confirmed the presence of thyroid CSCs by in vitro sphere formation or in vivo tumor formation assays with dispersed cells from thyroid cancer tissues or bona fide thyroid cancer cell lines. Future perspectives of thyroid CSC research are also discussed. PMID:26973599
Targeting prostate cancer stem cells for cancer therapy
Wang, Guocan; Wang, Zhiwei; Sarkar, Fazlul H.; Wei, Wenyi
Prostate cancer (PCa) is the most common malignant neoplasm in men and the second most frequent cause of cancer death for males in the United States. Recently, emerging evidence suggests that prostate cancer stem cells (CSCs) may play a critical role in the development and progression of PCa. Therefore, targeting prostate CSCs for the prevention of tumor progression and treatment of PCa could become a novel strategy for better treatment of patients diagnosed with PCa. In this review article, we will summarize the most recent advances in the prostate CSCs field, with particular emphasis on targeting prostate CSCs to treat prostate cancer. PMID:22369972
Stacking the DEK: from chromatin topology to cancer stem cells.
Privette Vinnedge, Lisa M; Kappes, Ferdinand; Nassar, Nicolas; Wells, Susanne I
Stem cells are essential for development and tissue maintenance and display molecular markers and functions distinct from those of differentiated cell types in a given tissue. Malignant cells that exhibit stem cell-like activities have been detected in many types of cancers and have been implicated in cancer recurrence and drug resistance. Normal stem cells and cancer stem cells have striking commonalities, including shared cell surface markers and signal transduction pathways responsible for regulating quiescence vs. proliferation, self-renewal, pluripotency and differentiation. As the search continues for markers that distinguish between stem cells, progenitor cells and cancer stem cells, growing evidence suggests that a unique chromatin-associated protein called DEK may confer stem cell-like qualities. Here, we briefly describe current knowledge regarding stem and progenitor cells. We then focus on new findings that implicate DEK as a regulator of stem and progenitor cell qualities, potentially through its unusual functions in the regulation of local or global chromatin organization.
Prognostic nutritional index before adjuvant chemotherapy predicts chemotherapy compliance and survival among patients with non-small-cell lung cancer
Shimizu, Katsuhiko; Okita, Riki; Saisho, Shinsuke; Yukawa, Takuro; Maeda, Ai; Nojima, Yuji; Nakata, Masao
Background Adjuvant chemotherapy after the complete resection of non-small-cell lung cancer (NSCLC) is now the standard of care. To improve survival, it is important to identify risk factors for the continuation of adjuvant chemotherapy. In this study, we analyzed chemotherapy compliance and magnitude of the prognostic impact of the prognostic nutritional index (PNI) before adjuvant chemotherapy. Methods We conducted a retrospective review of data from 106 patients who had received adjuvant chemotherapy. The adjuvant chemotherapy consisted of an oral tegafur agent (OT) or platinum-based chemotherapy (PB). The correlations between the PNI values and recurrence-free survival (RFS) were then evaluated. Results In the PB group, the percentage of patients who completed the four planned cycles of chemotherapy was not correlated with the PNI. In the OT group, however, a significant difference was observed in the percentage of patients who completed the planned chemotherapy according to the PNI before adjuvant chemotherapy. The RFS of patients with a PNI <50 before adjuvant chemotherapy was significantly poorer than that of the patients with a PNI ≥50. A multivariate analysis showed that nodal metastasis and PNI before chemotherapy were independent predictors of the RFS. However, PNI before surgery was not a predictor of the RFS. In the subgroup analysis, PNI before chemotherapy was independent predictor of the RFS in the OT group (P=0.019), but not in the PB group (P=0.095). Conclusion The PNI before adjuvant chemotherapy influenced the treatment compliance with the planned chemotherapy in the OT group, but not the PB group. In addition, a low PNI before adjuvant chemotherapy was associated with a poor RFS in a multivariate analysis, especially in the OT group. PMID:26504397
Cancer stem cells: a metastasizing menace!
Bandhavkar, Saurabh
Cancer is one of the leading causes of death worldwide, and is estimated to be a reason of death of more than 18 billion people in the coming 5 years. Progress has been made in diagnosis and treatment of cancer; however, a sound understanding of the underlying cell biology still remains an unsolved mystery. Current treatments include a combination of radiation, surgery, and/or chemotherapy. However, these treatments are not a complete cure, aimed simply at shrinking the tumor and in majority of cases, there is a relapse of tumor. Several evidences suggest the presence of cancer stem cells (CSCs) or tumor-initiating stem-like cells, a small population of cells present in the tumor, capable of self-renewal and generation of differentiated progeny. The presence of these CSCs can be attributed to the failure of cancer treatments as these cells are believed to exhibit therapy resistance. As a result, increasing attention has been given to CSC research to resolve the therapeutic problems related to cancer. Progress in this field of research has led to the development of novel strategies to treat several malignancies and has become a hot topic of discussion. In this review, we will briefly focus on the main characteristics, therapeutic implications, and perspectives of CSCs in cancer therapy. PMID:26773710
Subsequent endometrial carcinoma with adjuvant tamoxifen treatment in Japanese breast cancer patients.
Nishimura, N; Hachisuga, T; Saito, T; Kawarabayashi, T
This study aimed to detail the clinicopathologic features of endometrial carcinomas that developed in Japanese patients receiving adjuvant tamoxifen treatment for breast cancer patients. Ten endometrial carcinomas in tamoxifen-treated breast cancer patients were collected from two medical centers. The endometrial carcinomas included two stage Ia, four stage Ib, two stage Ic and two stage IIIc. Three tumors were Grade 1, six were Grade 2, and one was Grade 3. The tumor was limited to the endometrium in two cases. Myometrial invasion was limited to the inner half of the myometrium in five cases and involved the outer half in three. A mild degree of lymphovascular space invasion was identified in five cases. Deep cervical invasion was recognized in one case. The cell types comprised nine endometrioid adenocarcinomas and one serous carcinoma. Five of eight postmenopausal endometrial carcinomas were associated with polypoid endometrial lesions composed of cystically dilated atrophic and proliferative glands widely separated by fibrotic stroma. Two patients with retroperitoneal lymph node metastases died of endometrial cancer. One patient developed a contralateral breast cancer during tamoxifen treatment. No patient died of breast cancer. We did not demonstrate a higher frequency of either high-grade tumors or unfavorable histologic subtypes in tamoxifen-treated Japanese breast cancer patients.
Zingiber officinale Roscoe (ginger) as an adjuvant in cancer treatment: a review.
Pereira, M M; Haniadka, R; Chacko, P P; Palatty, P L; Baliga, M S
Despite acquiring a strong understanding of the molecular basis and advances in treatment, cancer is the second major cause of death in the world. In clinics, the stagedependent treatment strategies may include surgery, radiotherapy and systemic treatments like hormonotherapy and chemotherapy, which are associated with side effects. The use of traditional herbal medicine in cancer patients is on a rise, as it is believed that these medications are non toxic and alleviate the symptoms of cancer, boost the immune system, or may tackle the cancer itself. Since antiquity the rhizome of Zingiber officinale Roscoe commonly known as ginger (family Zingiberaceae) have widely been used as a spice and condiment in different societies. Additionally, ginger also has a long history of medicinal use in various cultures for treating common colds, fever, to aid digestion, treat stomach upset, diarrhoea, nausea, rheumatic disorders, gastrointestinal complications and dizziness. Preclinical studies have also shown that ginger possesses chemopreventive and antineoplastic properties. It is also reported to be effective in ameliorating the side effects of γ-radiation and of doxorubicin and cisplatin; to inhibit the efflux of anticancer drugs by P-glycoprotein (P-gp) and to possess chemosensitizing effects in certain neoplastic cells in vitro and in vivo. The objective of this review is to address observations on the role of ginger as adjuvant to treatment modalities of cancer. Emphasis is also placed on the drawbacks and on future directions for research that will have a consequential effect on cancer treatment and cure. PMID:22006742
Antitumor and Adjuvant Activity of λ-carrageenan by Stimulating Immune Response in Cancer Immunotherapy
Luo, Min; Shao, Bin; Nie, Wen; Wei, Xia-Wei; Li, Yu-Li; Wang, Bi-Lan; He, Zhi-Yao; Liang, Xiao; Ye, Ting-Hong
λ-Carrageenan is a seaweed polysaccharide which has been generally used as proinflammatory agent in the basic research, however, how the immunomodulating activity of λ-carrageenan affects tumor microenvironment remains unknown. In this study, we found that intratumoral injection of λ-carrageenan could inhibit tumor growth in B16-F10 and 4T1 bearing mice and enhance tumor immune response by increasing the number of tumor-infiltrating M1 macrophages, DCs and more activated CD4+CD8+ T lymphocytes in spleen. In addition, λ-carrageenan could enhance the secretion of IL17A in spleen and significantly increase the level of TNF-α in tumor, most of which was secreted by infiltrating macrophages. Moreover, λ-carrageenan exhibited an efficient adjuvant effect in OVA-based preventative and therapeutic vaccine for cancer treatment, which significantly enhanced the production of anti-OVA antibody. The toxicity analysis suggested that λ-carrageenan was with a good safety profile. Thus, λ-carrageenan might be used both as a potent antitumor agent and an efficient adjuvant in cancer immunotherapy. PMID:26098663
Pilot study of bone mineral density in breast cancer patients treated with adjuvant chemotherapy
NASA Technical Reports Server (NTRS)
Headley, J. A.; Theriault, R. L.; LeBlanc, A. D.; Vassilopoulou-Sellin, R.; Hortobagyi, G. N.
The objective of this cross-sectional study was to determine lumbar spine bone mineral density (BMD) in breast cancer patients previously treated with adjuvant chemotherapy. Sixteen of 27 patients who received adjuvant chemotherapy became permanently amenorrheic as a result of chemotherapy. BMD was measured at the lumbar spine using dual energy X-ray absorptiometry (DEXA). Chemotherapy drugs and dosages along with a history of risk factors for reduced bone density including activity level, tobacco and/or alcohol use, metabolic bone disease, family history, and hormone exposure were identified. Results showed that women who became permanently amenorrheic as a result of chemotherapy had BMD 14% lower than women who maintained menses after chemotherapy. Chemotherapy-treated women who maintained ovarian function had normal BMD. This study suggests that women who have premature menopause as a result of chemotherapy for breast cancer are at increased risk of bone loss and may be at risk for early development of osteoporosis. Women who maintain menses do not appear to be at risk for accelerated trabecular bone loss.
Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy
Findlay, John M.; Castro-Giner, Francesc; Makino, Seiko; Rayner, Emily; Kartsonaki, Christiana; Cross, William; Kovac, Michal; Ulahannan, Danny; Palles, Claire; Gillies, Richard S.; MacGregor, Thomas P.; Church, David; Maynard, Nicholas D.; Buffa, Francesca; Cazier, Jean-Baptiste; Graham, Trevor A.; Wang, Lai-Mun; Sharma, Ricky A.; Middleton, Mark; Tomlinson, Ian
How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor responders pass through bottlenecks, but re-grow by the time of surgical resection, suggesting a missed therapeutic opportunity. Cancers often show major changes in driver mutation presence or frequency after treatment, owing to outgrowth persistence or loss of sub-clones, copy number changes, polyclonality and/or spatial genetic heterogeneity. Post-therapy mutation spectrum shifts are also common, particularly C>A and TT>CT changes in good responders or bottleneckers. Post-treatment samples may also acquire mutations in known cancer driver genes (for example, SF3B1, TAF1 and CCND2) that are absent from the paired pre-treatment sample. Neo-adjuvant chemotherapy can rapidly and profoundly affect the oesophageal adenocarcinoma genome. Monitoring molecular changes during treatment may be clinically useful. PMID:27045317
Future Prospects in Breast Cancer Research – Cancer Stem Cells
Franke, Henk R.; Klaase, Joost M.; Brinkhuis, Mariël; van den Berg, Albert; Vermes, István
Breast cancer is one of the leading causes of cancer deaths among women. Although significant advances in the prevention, diagnosis and management are made, still every year half a million women die of breast cancer. Personalised treatment has the potential to increase treatment efficacy, and hence decrease mortality rates. Moreover, understanding cancer biology and translating this knowledge to the clinic, will improve the breast cancer therapy regime tremendously. Recently, it has been proposed that cancer stem cells (CSC) play an important role in tumour biology. CSC have the ability for self-renewal and are pivotal in setting the heterogeneous character of a tumour. Additionally, CSC possess several characteristics that make them resistant and more aggressive to the conventional chemo- and radiotherapy. Nowadays, breast cancer therapy is focused on killing the differentiated tumour cells, leaving the CSC unharmed, potentially causing recurrence of the disease and metastasis. Specific targeting of the CSC will improve the disease-free survival of breast cancer patients. In this article, two methods are described, aiming at specifically attacking the differentiated tumour cells ('Apoptosis chip') and the cancer stem cell. For this, microfluidics is used.
Stem cells in normal mammary gland and breast cancer.
Luo, Jie; Yin, Xin; Ma, Tao; Lu, Jun
The mammary gland is a structurally dynamic organ that undergoes dramatic alterations with age, menstrual cycle, and reproductive status. Mammary gland stem cells, the minor cell population within the mature organ, are thought to have multiple functions in regulating mammary gland development, tissue maintenance, major growth, and structural remodeling. In addition, accumulative evidence suggests that breast cancers are initiated and maintained by a subpopulation of tumor cells with stem cell features (called cancer stem cells). A variety of methods have been developed to identify and characterize mammary stem cells, and several signal transduction pathways have been identified to be essential for the self-renewal and differentiation of mammary gland stem cells. Understanding the origin of breast cancer stem cells, their relationship to breast cancer development, and the differences between normal and cancer stem cells may lead to novel approaches to breast cancer diagnosis, prevention, and treatment.
Cancer stem cells in head and neck cancer.
Allegra, Eugenia; Trapasso, Serena
Cancer stem cells (CSCs), also called "cells that start the tumor," represent in themselves one of the most topical and controversial issues in the field of cancer research. Tumor stem cells are able to self-propagate in vitro (self-renewal), giving rise both to other tumor stem cells and most advanced cells in the line of differentiation (asymmetric division). A final characteristic is tumorigenicity, a fundamental property, which outlines the tumor stem cell as the only cell able to initiate the formation of a tumor when implanted in immune-deficient mice. The hypothesis of a hierarchical organization of tumor cells dates back more than 40 years, but only in 1997, thanks to the work of John Dick and Dominique Bonnet, was there the formal proof of such an organization in acute myeloid leukemia. Following this, many other research groups were able to isolate CSCs, by appropriate selection markers, in various malignancies, such as breast, brain, colon, pancreas, and liver cancers and in melanoma. To date, however, it is not possible to isolate stem cells from all types of neoplasia, particularly in solid tumors. From a therapeutic point of view, the concept of tumor stem cells implies a complete revision of conventional antineoplastic treatment. Conventional cytotoxic agents are designed to target actively proliferating cells. In the majority of cases, this is not sufficient to eliminate the CSCs, which thanks to their reduced proliferative activity and/or the presence of proteins capable of extruding chemotherapeutics from the cell are not targeted. Therefore, the theory of cancer stem cells can pose new paradigms in terms of cancer treatment. Potential approaches, even in the very early experimental stages, relate to the selective inhibition of pathways connected with self-renewal, or more specifically based on the presence of specific surface markers for selective cytotoxic agent vehicles. Finally, some research groups are trying to induce these cells to
ACR Appropriateness Criteria® Adjuvant Management of Early-Stage Endometrial Cancer.
Wahl, Andrew O; Gaffney, David K; Jhingran, Anuja; Yashar, Catheryn M; Biagioli, Matthew; Elshaikh, Mohamed A; Jolly, Shruti; Kidd, Elizabeth; Lee, Larissa J; Li, Linna; Moore, David H; Rao, Gautam G; Williams, Ned L; Small, William
These consensus guidelines on adjuvant radiotherapy for early-stage endometrial cancer were developed from an expert panel convened by the American College of Radiology. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method; and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. After a review of the published literature, the panel voted on three variants to establish best practices for the utilization of imaging, radiotherapy, and chemotherapy after primary surgery for early-stage endometrial cancer. PMID:27633412
An overview of randomised controlled trials of adjuvant chemotherapy in head and neck cancer.
Munro, A. J.
Meta-analysis of the published results from 54 randomised controlled trials of adjuvant chemotherapy in head and neck cancer suggests that chemotherapy might increase absolute survival by 6.5% (95% confidence interval 3.1-9.9%). The odds ratio in favour of chemotherapy is 1.37 (95% confidence interval 1.24-1.5). Single-agent chemotherapy given synchronously with radiotherapy increased survival by 12.1% (95% confidence interval 5-19%). The benefit from neoadjuvant chemotherapy was less: a rate difference of 3.7% (95% confidence interval 0.9-6.5%). The results suggest that the investigation of optimal agents and scheduling for synchronous radiotherapy and chemotherapy might still be important in clinical trials in head and neck cancer. PMID:7819055
Longitudinal Assessments of Quality of Life in Endometrial Cancer Patients: Effect of Surgical Approach and Adjuvant Radiotherapy
Le, Tien; Menard, Chantal; Samant, Rajiv; Choan, E.; Hopkins, Laura; Faught, Wylam; Fung-Kee-Fung, Michael
Purpose: Adjuvant radiotherapy (RT) is often considered for endometrial cancer. We studied the effect of RT and surgical treatment on patients' quality of life (QOL). Methods and Materials: All patients referred to the gynecologic oncology clinics with biopsy findings showing endometrial cancer were recruited. QOL assessments were performed using the European Organization for Research and Treatment of Cancer QOL questionnaire-C30, version 3. Assessments were obtained at study entry and at regular 3-month intervals for a maximum of 2 years. Open-ended telephone interviews were done every 6 months. Linear mixed regression models were built using QOL domain scores as dependent variables, with the predictors of surgical treatment and adjuvant RT type. Results: A total of 40 patients were recruited; 80% of the surgeries were performed by laparotomy. Significant improvements were seen in most QOL domains with increased time from treatment. Adjuvant RT resulted in significantly more severe bowel symptoms and improvement in insomnia compared with conservative follow-up. No significant adverse effect from adjuvant RT was seen on the overall QOL. Bowel symptoms were significantly increased in patients treated with laparotomy compared with laparoscopy in the patients treated with whole pelvic RT. Qualitatively, about one-half of the patients noted improvements in their overall QOL during follow-up, with easy fatigability the most prevalent. Conclusion: No significant adverse effect was seen on patients' overall QOL with adjuvant pelvic RT after the recovery period. The acute adverse effects on patients' QOL significantly improved with an increasing interval from diagnosis.
Ovarian hyperstimulation in premenopausal women during adjuvant tamoxifen treatment for endocrine-dependent breast cancer: A report of two cases
Adjuvant endocrine therapy is an integral component of care for endocrine-dependent breast cancer. The aim of this type of therapy is to counteract the production and the action of estrogens. The ovary is the primary site of estrogen production in premenopausal women, whereas, in postmenopausal women, the main source of estrogens is adipose tissue. Therefore, ovarian function suppression is an effective adjuvant strategy in premenopausal estrogen-dependent breast cancer. Similarly, the inhibition of estrogen action at the receptor site by tamoxifen has proven to be effective. To date, international consensus statements recommend tamoxifen (20 mg/day) for five years as the standard adjuvant endocrine therapy for premenopausal women. It should be noted that tamoxifen is a potent inducer of ovarian function and consequent hyperestrogenism in premenopausal women. In the present study, we report two cases of ovarian cyst formation with very high estrogen levels and endometrial hyperplasia during the administration of tamoxifen alone as adjuvant treatment for estrogen receptor-positive breast cancer in premenopausal women. These cases suggest that in young premenopausal patients with estrogen-dependent breast cancer, ovarian suppression is an essential prerequisite for an adjuvant endocrine therapy with tamoxifen. In this context, luteinizing hormone-releasing hormone agonist treatment by suppressing effective ovarian function may lead to a hypoestrogenic status that may positively impact breast cancer prognosis and prevent the effects of tamoxifen at the gynecological level. It is important to reconsider the action of tamoxifen on ovarian function and include these specific effects of tamoxifen in the informed consent of premenopausal patients who are candidates for tamoxifen alone as adjuvant endocrine treatment. PMID:25120706
Adjuvant Therapy for HER2+ Breast Cancer: Practice, Perception and Toxicity
Rocque, Gabrielle; Onitilo, Adedayo; Engel, Jessica; Pettke, Erica; Boshoven, Alice; Kim, KyungMann; Rishi, Shailly; Waack, Bonnie; Wisinski, Kari B.; Tevaarwerk, Amye; Burkard, Mark E.
Multiple adjuvant regimens are used for HER2+ breast cancer, but experience in routine practice is not reported. We evaluated whether oncologists' perceptions of these regimens matches clinical experience. We surveyed Wisconsin medical oncologists throughout the state regarding factors impacting selection of TCH (docetaxel, carboplatin, trastuzumab) or anthracycline-based therapy. We also reviewed 200 cases of HER2+ breast cancer treated at the University of Wisconsin and the Marshfield Clinic and collected data on patient and tumor characteristics, chemotherapy regimen, and toxicities. Two-thirds of surveyed oncologists prefer anthracycline-based therapy, particularly for node-positive cancers. However, TCH was preferred for early stage (T1a-bN0) tumors. Half of oncologists use prophylactic G-CSF with TCH. In the 200 cases reviewed at our centers, acute toxicity occurred more frequently with TCH. There were fewer dose modifications or delays for AC-TH (doxorubicin, cyclophosphamide, paclitaxel, trastuzumab) than TCH (31% vs. 47%, p=0.07), possibly due to higher use of prophylactic G-CSF with AC-TH (77% vs. 34% with TCH, p<0.001). Fifteen patients received prophylactic G-CSF during TCH; none developed neutropenic fever. In contrast, 25% developed neutropenic fever during TCH without G-CSF. There were modest declines in median left ventricular ejection fraction reaching 9% with AC-TH and 3% with TCH at 12 months, but early cessation of trastuzumab was similar for both regimens. We conclude that TCH and AC-TH are common adjuvant regimens used for HER2+ breast cancer. The preference of TCH for early-stage disease and anthracycline-based therapy for node-positive disease suggests that many oncologists perceive that TCH is safer and AC-TH more effective. Myelosuppression from TCH is greater than AC-TH, but can be mitigated with routine G-CSF. PMID:22065290
[Cancer stemness and circulating tumor cells].
Saito, Tomoko; Mimori, Koshi
The principle concept of cancer stem cells (CSCs) giving rise to the carcinogenesis, relapse or metastasis of malignancy is broadly recognized. On the other hand, circulating tumor cells (CTCs) also plays important roles in relapse or metastasis of malignancy, and there has been much focused on the association between CSCs and CTCs in cancer cases. The technical innovations for detection of CTCs enabled us to unveil the nature of CTCs. We now realize that CTCs isolated by cell surface antibodies, such as DCLK1, LGR5 indicated CSC properties, and CTCs with epitherial-mesenchymal transition(EMT) phenotype showed characteristics of CSCs. PMID:25985635
Metastatic cancer stem cells: new molecular targets for cancer therapy.
Leirós, G J; Balañá, M E
The cancer stem cell (CSC) hypothesis, predicts that a small subpopulation of cancer cells that possess "stem-like" characteristics, are responsible for initiating and maintaining cancer growth. According to the CSC model the many cell populations found in a tumour might represent diverse stages of differentiation. From the cellular point of view metastasis is considered a highly inefficient process and only a subset of tumour cells is capable of successfully traversing the entire metastatic cascade and eventually re-initiates tumour growth at distant sites. Some similar features of both normal and malignant stem cells suggest that CSCs are not only responsible for tumorigenesis, but also for metastases. The CSC theory proposes that the ability of a tumour to metastasize is an inherent property of a subset of CSCs. The similar biological characteristics shared by normal stem cells (NSCs) and CSCs mainly implicate self-renewal and differentiation potential, survival ability, niche-specific microenvironment requirements and specific homing to metastatic sites and may have important implications in terms of new approaches to cancer therapy in the metastatic setting. There are several agents targeting many of these CSC features that have shown to be effective both in vitro and in vivo. Although clinical trials results are still preliminary and continue under investigation, these new therapies are very promising. The identification of new therapeutic targets and drugs based on CSC model constitutes a great challenge. PMID:21470128
Metastatic cancer stem cells: new molecular targets for cancer therapy.
Leirós, G J; Balañá, M E
The cancer stem cell (CSC) hypothesis, predicts that a small subpopulation of cancer cells that possess "stem-like" characteristics, are responsible for initiating and maintaining cancer growth. According to the CSC model the many cell populations found in a tumour might represent diverse stages of differentiation. From the cellular point of view metastasis is considered a highly inefficient process and only a subset of tumour cells is capable of successfully traversing the entire metastatic cascade and eventually re-initiates tumour growth at distant sites. Some similar features of both normal and malignant stem cells suggest that CSCs are not only responsible for tumorigenesis, but also for metastases. The CSC theory proposes that the ability of a tumour to metastasize is an inherent property of a subset of CSCs. The similar biological characteristics shared by normal stem cells (NSCs) and CSCs mainly implicate self-renewal and differentiation potential, survival ability, niche-specific microenvironment requirements and specific homing to metastatic sites and may have important implications in terms of new approaches to cancer therapy in the metastatic setting. There are several agents targeting many of these CSC features that have shown to be effective both in vitro and in vivo. Although clinical trials results are still preliminary and continue under investigation, these new therapies are very promising. The identification of new therapeutic targets and drugs based on CSC model constitutes a great challenge.
Infection, Stem Cells and Cancer Signals
Sell, S.
The association of cancer with preceding parasitic infections has been observed for over 200 years. Some such cancers arise from infection of tissue stem cells by viruses with insertion of viral oncogenes into the host DNA (mouse polyoma virus, mouse mammary tumor virus). In other cases the virus does not insert its DNA into the host cells, but rather commandeers the metabolism of the infected cells, so that the cells continue to proliferate and do not differentiate (human papilloma virus and cervical cancer). Cytoplasmic Epstein Barr virus infection is associated with a specific gene translocation (Ig/c-myc) that activates proliferation of affected cells (Burkitt lymphoma). In chronic osteomyelitis an inflammatory reaction to the infection appears to act through production of inflammatory cytokines and oxygen radical formation to induce epithelial cancers. Infection with Helicobacter pylori leads to epigenetic changes in methylation and infection by a parasite. Clonorchis sinensis also acts as a promoter of cancer of the bile ducts of the liver (cholaniocarcinoma). The common thread among these diverse pathways is that the infections act to alter tissue stem cell signaling with continued proliferation of tumor transit amplifying cells. PMID:21044009
Safety, compliance, and predictive parameters for dosage modification in adjuvant S-1 chemotherapy for gastric cancer.
Kim, Su-Jung; Kim, Yu Jung; Kim, Jee Hyun; Park, Do Joong; Kim, Hyung-Ho; Lee, Jong Seok; Lee, Keun-Wook
This study was performed to investigate the compliance, safety, dosage modifications (dose reduction and/or schedule change [including permanent S-1 withdrawal]), and clinical parameters that predict S-1 dosage modification in gastric cancer patients receiving adjuvant S-1 chemotherapy. One hundred and forty-nine patients who underwent curative D2 surgery and received adjuvant S-1 chemotherapy were enrolled. S-1 was administered orally (40 mg/m(2) twice daily on days 1-28 every 6 weeks) for 1 year. For patients unable to tolerate S-1, the dosage was reduced or the schedule was changed to a 3-weekly schedule of 2 weeks on treatment followed by 1 week off treatment. The planned 1-year treatment was completed in 73.8% of patients; 69 patients required dosage modification because of toxicity. The most frequent cause of dosage modification was enterocolitis (37 patients; defined as ≥ grade 2 abdominal pain and/or ≥ grade 2 diarrhea). Most dosage modification occurred during the early cycles of treatment (within the first 3 months). Severe toxicities (≥ grade 3) included neutropenia (13.4%), abdominal pain (8.1%) and diarrhea (8.1%). In multivariate analyses, decreased relative dose intensity was related to poor disease-free survival independent of stage, and only low creatinine clearance predicted S-1 dosage modification. In conclusion, although adjuvant S-1 therapy has a high compliance rate, meticulous monitoring of adverse events is required in the early period of treatment. Decreased creatinine clearance was the only factor that predicted dosage modification. In patients with creatinine clearance <50 mL/min, dosage reduction should be considered from the initiation of S-1 treatment.
Impact of body mass index on compliance and persistence to adjuvant breast cancer therapy.
Schmid, Seraina Margaretha; Eichholzer, Monika; Bovey, Florence; Myrick, Mary Elizabeth; Schötzau, Andreas; Güth, Uwe
Several authors found that the prognosis of overweight and obese breast cancer (BC) patients was lower than that of normal weight patients. We present the first study which evaluates the impact of body mass index (BMI) on compliance (i.e. to start a recommended therapy) and persistence to adjuvant BC therapy. An unselected cohort of 766 patients (≤75 years) diagnosed from 1997 to 2009 was analyzed in relevance to the four adjuvant therapy modalities: (A) radiation, (B) chemotherapy, (C) therapy with trastuzumab, and (D) endocrine therapy. With respect to compliance, multivariate analyses calculated Odds ratios (ORs) >1 for increased BMI in all four therapy modalities, i.e. increased BMI had a positive influence on compliance. The results were significant for radiotherapy (OR,2.37;95%CI,1.45-3.88;p < 0.001) and endocrine therapy (OR,1.92;95%CI,1.21-3.04;p = 0.002) and showed a trend in chemotherapy (OR,1.42;95%CI,0.97-2.08;p = 0.063). Analyzing persistence, increasing BMI had ORs <1 for chemotherapy and therapy with trastuzumab, both not reaching statistical significance. For endocrine therapy, increasing BMI was a significant predictor for persistence (OR,1.35;95%CI,1.08-1.80;p = 0.042). Failure of compliance and persistence to adjuvant therapy does not pose a contributing factor for the observed unfavorable prognosis in overweight/obese BC patients. In most therapy modes, patients with increasing BMI demonstrated a higher motivation and perseverance to the recommended treatment.
Adjuvant sorafenib after heptectomy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma patients
Xia, Feng; Wu, Li-Li; Lau, Wan-Yee; Huan, Hong-Bo; Wen, Xu-Dong; Ma, Kuan-Sheng; Li, Xiao-Wu; Bie, Ping
AIM: To investigate the efficacy and safety of adjuvant sorafenib after curative resection for patients with Barcelona Clinic Liver Cancer (BCLC)-stage C hepatocellular carcinoma (HCC). METHODS: Thirty-four HCC patients, classified as BCLC-stage C, received adjuvant sorafenib for high-risk of tumor recurrence after curative hepatectomy at a tertiary care university hospital. The study group was compared with a case-matched control group of 68 patients who received curative hepatectomy for HCC during the study period in a 1:2 ratio. RESULTS: The tumor recurrence rate was markedly lower in the sorafenib group (15/34, 44.1%) than in the control group (51/68, 75%, P = 0.002). The median disease-free survival was 12 mo in the study group and 10 mo in the control group. Tumor number more than 3, macrovascular invasion, hilar lymph nodes metastasis, and treatment with sorafenib were significant factors of disease-free survival by univariate analysis. Tumor number more than 3 and treatment with sorafenib were significant risk factors of disease-free survival by multivariate analysis in the Cox proportional hazards model. The disease-free survival and cumulative overall survival in the study group were significantly better than in the control group (P = 0.034 and 0.016, respectively). CONCLUSION: Our study verifies the potential benefit and safety of adjuvant sorafenib for both decreasing HCC recurrence and extending disease-free and overall survival rates for patients with BCLC-stage C HCC after curative resection. PMID:27340354
Cisplatin induces stemness in ovarian cancer.
Wiechert, Andrew; Saygin, Caner; Thiagarajan, Praveena S; Rao, Vinay S; Hale, James S; Gupta, Nikhil; Hitomi, Masahiro; Nagaraj, Anil Belur; DiFeo, Analisa; Lathia, Justin D; Reizes, Ofer
The mainstay of treatment for ovarian cancer is platinum-based cytotoxic chemotherapy. However, therapeutic resistance and recurrence is a common eventuality for nearly all ovarian cancer patients, resulting in poor median survival. Recurrence is postulated to be driven by a population of self-renewing, therapeutically resistant cancer stem cells (CSCs). A current limitation in CSC studies is the inability to interrogate their dynamic changes in real time. Here we utilized a GFP reporter driven by the NANOG-promoter to enrich and track ovarian CSCs. Using this approach, we identified a population of cells with CSC properties including enhanced expression of stem cell transcription factors, self-renewal, and tumor initiation. We also observed elevations in CSC properties in cisplatin-resistant ovarian cancer cells as compared to cisplatin-naïve ovarian cancer cells. CD49f, a marker for CSCs in other solid tumors, enriched CSCs in cisplatin-resistant and -naïve cells. NANOG-GFP enriched CSCs (GFP+ cells) were more resistant to cisplatin as compared to GFP-negative cells. Moreover, upon cisplatin treatment, the GFP signal intensity and NANOG expression increased in GFP-negative cells, indicating that cisplatin was able to induce the CSC state. Taken together, we describe a reporter-based strategy that allows for determination of the CSC state in real time and can be used to detect the induction of the CSC state upon cisplatin treatment. As cisplatin may provide an inductive stress for the stem cell state, future efforts should focus on combining cytotoxic chemotherapy with a CSC targeted therapy for greater clinical utility. PMID:27105520
Synthesis and evaluation of monophosphoryl lipid A derivatives as fully synthetic self-adjuvanting glycoconjugate cancer vaccine carriers.
Zhou, Zhifang; Mondal, Mohabul; Liao, Guochao; Guo, Zhongwu
A fully synthetic carbohydrate-based cancer vaccine is an attractive concept, but an important topic in the area is to develop proper vaccine carriers that can improve the immunogenicity and other immunological properties of tumor-associated carbohydrate antigens (TACAs). In this context, four monophosphoryl derivatives of Neisseria meningitidis lipid A were synthesized via a highly convergent and effective strategy and evaluated as vaccine carriers and adjuvants. The conjugates of these monophosphoryl lipid A (MPLA) derivatives with a modified form of the sTn antigen were found to elicit high titers of antigen-specific IgG antibodies, indicating a T cell-dependent immune response, in the absence of an external adjuvant. It was concluded that MPLAs could be utilized as potent vaccine carriers and built-in adjuvants to create fully synthetic self-adjuvanting carbohydrate-based cancer vaccines. The lipid composition and structure of MPLA were shown to have a significant influence on its immunological activity, and among the MPLAs examined, natural N. meningitidis MPLA exhibited the most promising properties. Moreover, Titermax Gold, a conventional vaccine adjuvant, was shown to inhibit, rather than promote, the immunological activity of MPLA conjugates, maybe via interacting with MPLA.
Endocrine therapy as adjuvant or neoadjuvant therapy for breast cancer: selecting the best agents, the timing and duration of treatment.
Li, Jun-Jie; Shao, Zhi-Min
Hormone receptor (HR) positive breast cancers represent the vast majority of breast cancers. Adjuvant and/or neoadjuvant endocrine therapy is highly effective and appropriate for nearly all women with HR positive tumors. Adjuvant tamoxifen (TAM) is a major endocrine treatment option, which has been found to be effective in both premenopausal and postmenopausal patients. Considerable evidence has been accrued of a benefit for ovarian ablation or suppression (OA/S) in premenopausal patients, for aromatase inhibitors (AIS) in postmenopausal patients, for the longer duration of adjuvant endocrine therapy and for the clinical utility of neoadjuvant endocrine therapy. Clinical practice guidelines should keep changing with developing evidence-based practice guidelines pertaining to breast cancer care. The present publication conducted a comprehensive systematic review of the literature addressing the use of endocrine therapy as adjuvant or neoadjuvant therapy for HR positive breast cancer, focusing on selecting the best agents for both premenopausal and postmenopausal patients, as well as the optimal duration of such treatment.
The impact of adjuvant chemotherapy in older breast cancer patients on clinical and biological aging parameters
Brouwers, Barbara; Hatse, Sigrid; Lago, Lissandra Dal; Neven, Patrick; Vuylsteke, Peter; Dalmasso, Bruna; Debrock, Guy; Van Den Bulck, Heidi; Smeets, Ann; Bechter, Oliver; Bailur, Jithendra Kini; Kenis, Cindy; Laenen, Annouschka; Schöffski, Patrick; Pawelec, Graham; Journe, Fabrice; Ghanem, Ghanem-Elias; Wildiers, Hans
Purpose This prospective observational study aimed to evaluate the impact of adjuvant chemotherapy on biological and clinical markers of aging and frailty. Methods Women ≥ 70 years old with early breast cancer were enrolled after surgery and assigned to a chemotherapy (Docetaxel and Cyclophosphamide) group (CTG, n=57) or control group (CG, n=52) depending on their planned adjuvant treatment. Full geriatric assessment (GA) and Quality of Life (QoL) were evaluated at inclusion (T0), after 3 months (T1) and at 1 year (T2). Blood samples were collected to measure leukocyte telomere length (LTL), levels of interleukin-6 (IL-6) and other circulating markers potentially informative for aging and frailty: Interleukin-10 (IL-10), Tumor Necrosis Factor Alpha (TNF-α), Insulin-like Growth Factor 1 (IGF-1), Monocyte Chemotactic Protein 1 (MCP-1) and Regulated on Activation, Normal T cell Expressed and Secreted (RANTES). Results LTL decreased significantly but comparably in both groups, whereas IL-6 was unchanged at T2. However, IL-10, TNF-α, IGF-1 and MCP-1 suggested a minor biological aging effect of chemotherapy. Clinical frailty and QoL decreased at T1 in the CTG, but recovered at T2, while remaining stable in the CG. Conclusion Chemotherapy (TC) is unlikely to amplify clinical aging or induce frailty at 1 year. Accordingly, there is no impact on the most established aging biomarkers (LTL, IL-6). PMID:27102154
Adjuvant chemotherapy for breast cancer: side effects and quality of life.
Palmer, B V; Walsh, G A; McKinna, J A; Greening, W P
In a trial of postoperative adjuvant chemotherapy women with primary breast cancer and spread to one or more axillary nodes were randomised to receive a six-month course of either the single agent chlorambucil or the five-drug combination of chlorambucil, methotrexate, fluorouracil, vincristine, and adriamycin. On completing the treatment 47 patients were asked to fill in questionnaires at home on the side effects of treatment and its influence on the quality of their life. Side effects including nausea, vomiting, malaise, and alopecia had been severe enough to interfere with their lifestyle in 9 (42%) of the patients who had received the single agent and 19 (79%) of those who had received multiple-drug treatment. Various other side effects were reported by a few patients. Seven (29%) of the patients who had received the multiple-drug schedule voluntarily added that the treatment had been "unbearable" or "could never be gone though again." The proportion of patients who had experienced severe side effects while receiving the treatment was considerable; hence such adjuvant chemotherapy is justifiable only if it will substantially improve a patient's prognosis. PMID:7004560
Zn- and Mg- Containing Tricalcium Phosphates-Based Adjuvants for Cancer Immunotherapy
NASA Astrophysics Data System (ADS)
Wang, Xiupeng; Li, Xia; Onuma, Kazuo; Sogo, Yu; Ohno, Tadao; Ito, Atsuo
Zn-, and Mg-containing tricalcium phosphates (TCPs) loaded with a hydrothermal extract of a human tubercle bacillus (HTB) were prepared by immersing Zn-TCP and Mg-TCP in HTB-containing supersaturated calcium phosphate solutions. The in vitro and in vivo immunogenic activities of the HTB-loaded Zn-, and Mg-TCPs (Zn-Ap-HTB and Mg-Ap-HTB, respectively) were evaluated as potential immunopotentiating adjuvants for cancer immunotherapy. The Zn-Ap-HTB and Mg-Ap-HTB adjuvants showed no obvious cytotoxicity and more effectively stimulated granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion by macrophage-like cells than unprocessed HTB or HTB-loaded TCP (T-Ap-HTB) in vitro. Zn-Ap-HTB and Mg-Ap-HTB mixed with liquid-nitrogen-treated tumor tissue markedly inhibited the in vivo development of rechallenged Lewis lung carcinoma (LLC) cells compared with T-Ap-HTB and the unprocessed HTB mixed liquid-nitrogen-treated tumor tissue. Zn-Ap-HTB and Mg-Ap-HTB contributed to eliciting potent systemic antitumor immunity in vivo.
Helicobacter pylori and gastrointestinal symptoms in diagnostics and adjuvant chemotherapy of colorectal cancer.
Soveri, Leena-Maija; Osterlund, Pia; Ruotsalainen, Tarja; Poussa, Tuija; Rautelin, Hilpi; Bono, Petri
5-Fluorouracil (5-FU)-based chemotherapy is the mainstay of adjuvant treatment for colorectal cancer (CRC). Few studies have explored Helicobacter pylori (H. pylori)-associated gastrointestinal symptoms in the diagnosis of CRC, and the association between H. pylori infection and gastrointestinal toxicity during adjuvant chemotherapy in CRC. Seventy-nine CRC patients were randomised in a prospective clinical trial to receive 5-FU and leucovorin administered as bolus injection (Mayo regimen) or continuous infusion (simplified de Gramont regimen). H. pylori antibodies were analysed at baseline, twice monthly during treatment and after treatment up to 12 months. Thirty-seven patients (47%) were H. pylori-seronegative at baseline. There was no significant association between baseline H. pylori seropositivity (n=42; 53%) and oro-gastrointestinal toxicity during chemotherapy. The median time from symptom onset of CRC to surgery was significantly longer in patients with H. pylori infection (median time, 6 vs. 5 months; P=0.012). Functional dyspeptic symptoms at presentation significantly delayed diagnosis (median time, 7.5 vs. 5 months; P=0.035), whereas anaemia, bowel symptoms, occlusion, blood in the stool, infection and hypolactasia did not. We conclude that there is no association between H. pylori status and gastrointestinal toxicity in CRC patients during chemotherapy. Dyspeptic symptoms and presence of H. pylori may delay the diagnosis of CRC. (www.controlled-trials.com/ISRCTN98405441).
Immune adjuvants as critical guides directing immunity triggered by therapeutic cancer vaccines.
Schijns, Virgil; Tartour, Eric; Michalek, Jaroslav; Stathopoulos, Apostolos; Dobrovolskienė, Neringa T; Strioga, Marius M
Tumor growth is controlled by natural antitumor immune responses alone or by augmented immune reactivity resulting from different forms of immunotherapy, which has demonstrated clinical benefit in numerous studies, although the overall percentage of patients with durable clinical responses remains limited. This is attributed to the heterogeneity of the disease, the inclusion of late-stage patients with no other treatment options and advanced tumor-associated immunosuppression, which may be consolidated by certain types of chemotherapy. Despite variable responsiveness to distinct types of immunotherapy, therapeutic cancer vaccination has shown meaningful efficacy for a variety of cancers. A key step during cancer vaccination involves the appropriate modeling of the functional state of dendritic cells (DCs) capable of co-delivering four critical signals for proper instruction of tumor antigen-specific T cells. However, the education of DCs, either directly in situ, or ex vivo by various complex procedures, lacks standardization. Also, it is questioned whether ex vivo-prepared DC vaccines are superior to in situ-administered adjuvant-guided vaccines, although both approaches have shown success. Evaluation of these variables is further complicated by a lack of consensus in evaluating vaccination clinical study end points. We discuss the role of signals needed for the preparation of classic in situ and modern ex vivo DC vaccines capable of proper reprogramming of antitumor immune responses in patients with cancer.
Efficacy and Interaction of Antioxidant Supplements as Adjuvant Therapy in Cancer Treatment: A Systematic Review.
Yasueda, Asuka; Urushima, Hayato; Ito, Toshinori
Oxidative stress is a key component in carcinogenesis. Although radiation produces reactive oxygen species, some anticancer agents such as alkylating agents, platinum and antitumor antibiotics exert cytotoxicity by generating free radicals. Nonenzymatic exogenous antioxidants such as vitamins, minerals, and polyphenols can quench ROS activity. However, whether antioxidants alter antitumor effects during radiotherapy and some types of chemotherapy remains unclear. In the present study, we reviewed antioxidants as an adjuvant therapy for cancer patients during chemotherapy or radiotherapy. Electronic literature searches were performed to select all randomized controlled clinical trials (RCTs) in which antioxidants were administered to cancer patients along with chemotherapy or radiotherapy. Articles or abstracts written in English were included. In total, 399 reports received primary screening. Duplicated articles and those meeting the exclusion criteria (not RCT, not human, and no oral administration) were excluded. Finally, 49 reports matching the inclusion criteria were included. It was difficult to determine whether antioxidants affect treatment outcomes or whether antioxidants ameliorate adverse effects induced by chemotherapy and radiotherapy. It is desirable to use an evidence-based method to select supplements best suited to cancer patients. Although there are many opinions about risks or benefits of antioxidant supplementation, we could mostly conclude that the harm caused by antioxidant supplementation remains unclear for patients during cancer therapy, except for smokers undergoing radiotherapy. PMID:26503419
Positive esophageal proximal resection margin: an important prognostic factor for esophageal cancer that warrants adjuvant therapy
Wang, Yun-Cang; Deng, Han-Yu; Wang, Wen-Ping; He, Du; Ni, Peng-Zhi; Hu, Wei-Peng; Wang, Zhi-Qiang
Background Positive esophageal proximal resection margin (ERM+) following esophagectomy was considered as incomplete or R1 resection. The clinicopathological data and long-term prognosis of esophageal cancer (EC) patients with ERM+ after esophagectomy were still unknown. Therefore, the aim of this study was to assess the clinical significance of ERM+ and its therapeutic option. Methods From November 2008 to December 2014, 3,594 patients with histologically confirmed EC underwent radical resection in our department. Among them there were 37 patients (1.03%) who had ERM+. ERM+ was defined as carcinoma or atypical hyperplasia (severe or moderate) at the residual esophageal margin in our study. For comparison, another 74 patients with negative esophageal proximal resection margin (ERM−) were propensity-matched at a ratio of 1:2 as control group according to sex, age, tumor location and TNM staging. The relevant prognostic factors were investigated by univariate and multivariate regression analysis. Results In this large cohort of patients, the rate of ERM+ was 1.03%. The median survival time was 35.000 months in patients with ERM+, significantly worse than 68.000 months in those with ERM− (Chi-square =4.064, P=0.044). Survival in patients with esophageal residual atypical hyperplasia (severe or moderate) was similar to those with esophageal residual carcinoma. Survival rate in stage I–II was higher than that in stage III–IV (Chi-square =27.598, P=0.000) in ERM−; But there was no difference between the two subgroups of patients in ERM+. Furthermore, in those patients with ERM+, survival was better in those who having adjuvant therapy, compared to those without adjuvant therapy (Chi-square =5.480, P=0.019). And the average survival time which was improved to a well situation for ERM+ patients who have adjuvant therapy was 68.556 months which is comparable to average survival time (65.815 months) of ERM− for those patients who are at earlier stages
Adverse prognostic value of peritumoral vascular invasion: is it abrogated by adequate endocrine adjuvant therapy? Results from two International Breast Cancer Study Group randomized trials of chemoendocrine adjuvant therapy for early breast cancer
Viale, G.; Giobbie-Hurder, A.; Gusterson, B. A.; Maiorano, E.; Mastropasqua, M. G.; Sonzogni, A.; Mallon, E.; Colleoni, M.; Castiglione-Gertsch, M.; Regan, M. M.; Brown, R. W.; Golouh, R.; Crivellari, D.; Karlsson, P.; Öhlschlegel, C.; Gelber, R. D.; Goldhirsch, A.; Coates, A. S.
Background: Peritumoral vascular invasion (PVI) may assist in assigning optimal adjuvant systemic therapy for women with early breast cancer. Patients and methods: Patients participated in two International Breast Cancer Study Group randomized trials testing chemoendocrine adjuvant therapies in premenopausal (trial VIII) or postmenopausal (trial IX) node-negative breast cancer. PVI was assessed by institutional pathologists and/or central review on hematoxylin–eosin-stained slides in 99% of patients (analysis cohort 2754 patients, median follow-up >9 years). Results: PVI, present in 23% of the tumors, was associated with higher grade tumors and larger tumor size (trial IX only). Presence of PVI increased locoregional and distant recurrence and was significantly associated with poorer disease-free survival. The adverse prognostic impact of PVI in trial VIII was limited to premenopausal patients with endocrine-responsive tumors randomized to therapies not containing goserelin, and conversely the beneficial effect of goserelin was limited to patients whose tumors showed PVI. In trial IX, all patients received tamoxifen: the adverse prognostic impact of PVI was limited to patients with receptor-negative tumors regardless of chemotherapy. Conclusion: Adequate endocrine adjuvant therapy appears to abrogate the adverse impact of PVI in node-negative disease, while PVI may identify patients who will benefit particularly from adjuvant therapy. PMID:19633051
The metabolic landscape of cancer stem cells.
Dando, Ilaria; Dalla Pozza, Elisa; Biondani, Giulia; Cordani, Marco; Palmieri, Marta; Donadelli, Massimo
Cancer stem cells (CSCs) are a sub-population of quiescent cells endowed with self-renewal properties that can sustain the malignant behavior of the tumor mass giving rise to more differentiated cancer cells. For this reason, the specific killing of CSCs represents one of the most important challenges of the modern molecular oncology. However, their particular resistance to traditional chemotherapy and radiotherapy imposes a thorough understanding of their biological and biochemical features. The metabolic peculiarities of CSCs may be a therapeutic and diagnostic opportunity in cancer research. In this review, we summarize the most significant discoveries on the metabolism of CSCs describing and critically analyzing the studies supporting either glycolysis or mitochondrial oxidative phosphorylation as a primary source of energy for CSCs.
A Meta-Analysis of Cognitive Impairment and Decline Associated with Adjuvant Chemotherapy in Women with Breast Cancer
Ono, Miyuki; Ogilvie, James M.; Wilson, Jennifer S.; Green, Heather J.; Chambers, Suzanne K.; Ownsworth, Tamara; Shum, David H. K.
A meta-analysis was performed to quantify the magnitude and nature of the association between adjuvant chemotherapy and performance on a range of cognitive domains among breast cancer patients. A total of 27 studies (14 cross-sectional, 8 both cross-sectional and prospective, and 5 prospective) were included in the analyses, involving 1562 breast cancer patients who had undergone adjuvant chemotherapy and 2799 controls that included breast cancer patients who did not receive adjuvant chemotherapy. A total of 737 effect sizes (Cohen's d) were calculated for cross-sectional and prospective longitudinal studies separately and classified into eight cognitive domains. The mean effect sizes varied across cross-sectional and prospective longitudinal studies (ranging from −1.12 to 0.62 and −0.29 to 1.12, respectively). Each cognitive domain produced small effect sizes for cross-sectional and prospective longitudinal studies (ranging from −0.25 to 0.41). Results from cross-sectional studies indicated a significant association between adjuvant chemotherapy and cognitive impairment that held across studies with varied methodological approaches. For prospective studies, results generally indicated that cognitive functioning improved over time after receiving adjuvant chemotherapy. Greater cognitive impairment was reported in cross-sectional studies comparing chemotherapy groups with healthy control groups. Results suggested that cognitive impairment is present among breast cancer patients irrespective of a history of chemotherapy. Prospective longitudinal research is warranted to examine the degree and persisting nature of cognitive impairment present both before and after chemotherapy, with comparisons made to participants' cognitive function prior to diagnosis. Accurate understanding of the effects of chemotherapy is essential to enable informed decisions regarding treatment and to improve quality of life among breast cancer patients. PMID:25806355
Adjuvant systemic treatment for individual patients with triple negative breast cancer.
Oakman, Catherine; Moretti, Erica; Galardi, Francesca; Biagioni, Chiara; Santarpia, Libero; Biganzoli, Laura; Di Leo, Angelo
Chemotherapy is the only evidence based adjuvant systemic treatment option in triple negative breast cancer (TNBC). Despite emerging results for targeted biological therapies for this subpopulation, lack of robust results does not currently support their use beyond the confines of a clinical trial. Conventional systemic chemotherapy remains the standard of care and is curative in a minority of patients. There is no defined standard chemotherapy and there is currently no robust, prospective, randomized data to advise different use of specific chemotherapy agents in TNBC as compared to non-TNBC. Data suggest high sensitivity to chemotherapy, however it is yet to be determined whether this increased sensitivity is agent/regimen specific or whether it reflects general chemosensitivity. This review will focus on systemic chemotherapy in early TNBC, particularly anthracyclines and platinums, and potential predictive tools to guide chemotherapy use. PMID:22015281
Influence of definitive radiation therapy for primary breast cancer on ability to deliver adjuvant chemotherapy
Lippman, M.E.; Edwards, B.K.; Findlay, P.; Danforth, D.W. Jr.; MacDonald, H.; D'Angelo, T.; Gorrell, C.
Primary radiotherapy as a means of managing stage I and II breast cancer is receiving increasing attention. In a prospectively randomized trial comparing modified radical mastectomy to lumpectomy followed by definitive radiotherapy, we evaluated whether radiotherapy has a deleterious effect on the ability to administer adjuvant doxorubicin and cyclophosphamide to patients with histologically positive axillary lymph nodes. All patients were treated with an identical regimen, and doses were escalated to the same degree until myelosuppression occurred. There were no significant differences in the amount of chemotherapy administered to either treatment group. Patients in both groups received approximately 100% of the predicted dose of doxorubicin and approximately 117% of the predicted dose of cyclophosphamide. At present, we have no evidence that there are differences in recurrence rates as a function of the quantity of drug received, although longer follow-up is required.
Cost-Effectiveness of Aspirin Adjuvant Therapy in Early Stage Colorectal Cancer in Older Patients
Soon, Swee Sung; Chia, Whay-Kuang; Chan, Mun-ling Sarah; Ho, Gwo Fuang; Jian, Xiao; Deng, Yan Hong; Tan, Chuen-Seng; Sharma, Atul; Segelov, Eva; Mehta, Shaesta; Ali, Raghib; Toh, Han-Chong; Wee, Hwee-Lin
Background & Aims Recent observational studies showed that post-operative aspirin use reduces cancer relapse and death in the earliest stages of colorectal cancer. We sought to evaluate the cost-effectiveness of aspirin as an adjuvant therapy in Stage I and II colorectal cancer patients aged 65 years and older. Methods Two five-state Markov models were constructed separately for Stage I and II colorectal cancer using TreeAge Pro 2014. Two hypothetical cohorts of 10,000 individuals at a starting age of 65 years and with colorectal cancer in remission were put through the models separately. Cost-effectiveness of aspirin was evaluated against no treatment (Stage I and II) and capecitabine (Stage II) over a 20-year period from the United States societal perspective. Extensive one-way sensitivity analyses and multivariable Probabilistic Sensitivity Analyses (PSA) were performed. Results In the base case analyses, aspirin was cheaper and more effective compared to other comparators in both stages. Sensitivity analyses showed that no treatment and capecitabine (Stage II only) can be cost-effective alternatives if the utility of taking aspirin is below 0.909, aspirin's annual fatal adverse event probability exceeds 0.57%, aspirin's relative risk of disease progression is 0.997 or more, or when capecitabine's relative risk of disease progression is less than 0.228. Probabilistic Sensitivity Analyses (PSA) further showed that aspirin could be cost-effective 50% to 80% of the time when the willingness-to-pay threshold was varied from USD20,000 to USD100,000. Conclusion Even with a modest treatment benefit, aspirin is likely to be cost-effective in Stage I and II colorectal cancer, thus suggesting a potential unique role in secondary prevention in this group of patients. PMID:25250815
No increased venous thromboembolism risk in Asian breast cancer patients receiving adjuvant tamoxifen.
Chen, Tom Wei-Wu; Chen, Ho-Min; Lin, Ching-Hung; Huang, Chiun-Sheng; Cheng, Ann-Lii; Lai, Mei-Shu; Lu, Yen-Shen
Tamoxifen is an effective endocrine treatment for early breast cancer (EBC) but increases the risk of venous thromboembolism. Whether Asian EBC patients (pts) bear the same risk when treated with adjuvant tamoxifen is uncertain. EBC pts diagnosed between 2004 and 2009 were selected from a population database in Taiwan. The pts were followed up from the index date to December 31, 2011 to collect events of deep vein thrombosis (DVT) and pulmonary embolism (PE). Cumulative incidence rates and hazard ratios (HRs) were used to compare the risk between pts treated with and without tamoxifen. In addition, comorbidities were included in an adjusted model of the risk of DVT and PE. A total of 28,029 EBC pts, including 17,843 (63.8 %) in the tamoxifen group and 10,155 (36.2 %) in the nontamoxifen group, were analyzed. The 7-year cumulative incidence rates for DVT and PE were 2.58 and 0.32 % in the tamoxifen group and 2.51 and 0.32 % in the nontamoxifen group (P = 0.92 for DVT, P = 0. 65 for PE), respectively. The HR for the nonadjusted and adjusted models showed no differences in DVT and PE risks between the tamoxifen and nontamoxifen groups. The uterine cancer risk was significantly increased in the pts receiving tamoxifen (adjusted HR = 2.79, P < 0.001), suggesting tamoxifen compliance. The risks of developing DVT and PE are not increased in Asian EBC pts receiving adjuvant tamoxifen. Ethnicity differences should be considered when discussing optimal endocrine treatments with EBC pts.
[Hypofractionated adjuvant radiotherapy for breast cancer: no signs of increased risk of cardiotoxicity].
Aleman, Berthe M P; van Leeuwen, Floor E
Adjuvant radiotherapy is frequently used in women with breast cancer to improve both local control of the tumour and overall survival. Hypofractionated regimens are increasingly being used as they involve fewer treatment sessions and, in terms of tumour control, the effects of conventionally fractionated and hypofractionated radiotherapy seem to be comparable. However, there is concern regarding increased cardiotoxicity following hypofractionated radiotherapy treatment to the left side. In order to determine if cardiac mortality increases with hypofractionation relative to conventional fractionation, a Canadian research group performed a retrospective analysis in 5334 women with breast cancer treated between 1990-1998 with postoperative radiotherapy to the breast/chest wall only. At 15-year follow-up the authors concluded that cardiac mortality was not statistically different among patients with left-sided breast cancer whether treated with hypofractionated or conventionally fractionated whole breast/chest wall irradiation. This commentary discusses the data presented in the paper, puts them into perspective and describes the clinical implications.
MicroRNAs targeting prostate cancer stem cells
Fang, Yu-Xiang; Chang, Yun-Li
Prostate cancer is a frequently diagnosed cancer in males with high mortality in the world. As a heterogeneous tissue, the tumor mass contains a subpopulation that is called as cancer stem cells and displays stem-like properties such as self-renewal, epithelial–mesenchymal transition, metastasis, and drug resistance. Cancer stem cells have been identified in variant tumors and shown to be regulated by various molecules including microRNAs. MicroRNAs are a class of small non-coding RNAs, which can influence tumorigenesis via different mechanisms. In this review, we focus on the functions of microRNAs on regulating the stemness of prostate cancer stem cells with different mechanisms and propose the potential roles of microRNAs in prostate cancer therapy. PMID:25966983
Stem cells and lung cancer: future therapeutic targets?
Alison, Malcolm R; Lebrenne, Arielle C; Islam, Shahriar
In both the UK and USA more people die of lung cancer than any other type of cancer. Lung cancer's high mortality rate is also reflected on a global scale, with lung cancer accounting for more than 1 million deaths per year. In tissues with ordered structure such a lung epithelia, it is likely that the cancers have their origins in normal adult stem cells, and then the tumours themselves are maintained by a population of malignant stem cells - so-called cancer stem cells. This review examines both these postulates in animal models and in the clinical setting, noting that stem cell niches appear to foster tumour development, and that drug resistance can often be attributed to malignant cells with stem cell properties. PMID:19653862
Improved biochemical outcome with adjuvant radiotherapy after radical prostatectomy for prostate cancer with poor pathologic features
Vargas, Carlos; Kestin, Larry L. . E-mail: email@example.com; Weed, Dan W.; Krauss, Daniel; Vicini, Frank A.; Martinez, Alvaro A.
Purpose: The indications for adjuvant external beam radiotherapy (EBRT) after radical prostatectomy (RP) are poorly defined. We performed a retrospective comparison of our institution's experience treating prostate cancer with RP vs. RP followed by adjuvant EBRT. Methods and materials: Between 1987 and 1998, 617 patients with clinical Stage T1-T2N0M0 prostate cancer underwent RP. Patients who underwent preoperative androgen deprivation and those with positive lymph nodes were excluded. Of the 617 patients, 34 (5.5%) with an undetectable postoperative prostate-specific antigen (PSA) level underwent adjuvant prostatic fossa RT at a median of 0.25 year (range, 0.1-0.6) postoperatively because of poor pathologic features. The median total dose was 59.4 Gy (range, 50.4-66.6 Gy) in 1.8-2.0-Gy fractions. These 34 RP+RT patients were compared with the remaining 583 RP patients. Biochemical failure was defined as any postoperative PSA level {>=}0.1 ng/mL and any postoperative PSA level {>=}0.3 ng/mL (at least 30 days after surgery). Administration of androgen deprivation was also scored as biochemical failure when applying either definition. The median clinical follow-up was 8.2 years (range, 0.1-11.2 years) for RP and 8.4 years (range, 0.3-13.8 years) for RP+RT. Results: Radical prostatectomy + radiation therapy patients had a greater pathologic Gleason score (mean, 7.3 vs. 6.5; p < 0.01) and pathologic T stage (median, T3a vs. T2c; p < 0.01). Age (median, 65.7 years) and pretreatment PSA level (median, 7.9 ng/mL) were similar between the treatment groups. Extracapsular extension was present in 72% of RP+RT patients vs. 27% of RP patients (p < 0.01). The RP+RT patients were more likely to have seminal vesicle invasion (29% vs. 9%, p < 0.01) and positive margins (73% vs. 36%, p < 0.01). Despite these poor pathologic features, the 5-year biochemical control (BC) rate (PSA < 0.1 ng/mL) was 57% for RP+RT and 47% for RP (p = 0.28). For patients with extracapsular extension, the
New Findings on Breast Cancer Stem Cells: A Review.
Bozorgi, Azam; Khazaei, Mozafar; Khazaei, Mohammad Rasool
Since the introduction of the "cancer stem cell" theory, significant developments have been made in the understanding of cancer and the heterogenic structure of tumors. In 2003, with the isolation of cancer stem cells from the first solid tumor, breast cancer, and recognition of the tumorigenicity of these cells, this theory suggested that the main reason for therapy failure might be the presence of cancer stem cells. This review article describes breast cancer stem cell origin, the related cellular and molecular characteristics, signaling pathways, and therapy resistance mechanisms. The databases PubMed, SCOPUS, and Embase were explored, and articles published on these topics between 1992 and 2015 were investigated. It appears that this small subpopulation of cells, with the capacity for self-renewal and a high proliferation rate, originate from normal stem cells, are identified by specific markers such as CD44(+)/CD24(-/low), and enhance a tumor's capacity for metastasis, invasion, and therapy resistance. Cancer stem cell characteristics depend on their interactions with their microenvironment as well as on the inducing factors and elements. Although uncertainties about breast cancer stem cells exist, many of researchers believe that cancer stem cells should be considered as possible therapeutic targets.
New Findings on Breast Cancer Stem Cells: A Review
Bozorgi, Azam; Khazaei, Mohammad Rasool
Since the introduction of the "cancer stem cell" theory, significant developments have been made in the understanding of cancer and the heterogenic structure of tumors. In 2003, with the isolation of cancer stem cells from the first solid tumor, breast cancer, and recognition of the tumorigenicity of these cells, this theory suggested that the main reason for therapy failure might be the presence of cancer stem cells. This review article describes breast cancer stem cell origin, the related cellular and molecular characteristics, signaling pathways, and therapy resistance mechanisms. The databases PubMed, SCOPUS, and Embase were explored, and articles published on these topics between 1992 and 2015 were investigated. It appears that this small subpopulation of cells, with the capacity for self-renewal and a high proliferation rate, originate from normal stem cells, are identified by specific markers such as CD44+/CD24-/low, and enhance a tumor's capacity for metastasis, invasion, and therapy resistance. Cancer stem cell characteristics depend on their interactions with their microenvironment as well as on the inducing factors and elements. Although uncertainties about breast cancer stem cells exist, many of researchers believe that cancer stem cells should be considered as possible therapeutic targets. PMID:26770236
The Nature and Severity of Cognitive Impairment Associated with Adjuvant Chemotherapy in Women with Breast Cancer: A Meta-Analysis of the Current Literature
ERIC Educational Resources Information Center
Falleti, Marina G.; Sanfilippo, Antonietta; Maruff, Paul; Weih, LeAnn; Phillips, Kelly-Anne
Objective: Several studies have identified that adjuvant chemotherapy for breast cancer is associated with cognitive impairment; however, the magnitude of this impairment is unclear. This study assessed the severity and nature of cognitive impairment associated with adjuvant chemotherapy by conducting a meta-analysis of the published literature to…
Morbidity of ischemic heart disease in early breast cancer 15-20 years after adjuvant radiotherapy
Gyenes, G.; Rutqvist, L.E. ); Fornander, T.; Carlens, P.
The purpose of this study was to assess the cardiac side effects, primarily the occurrence of ischemic heart disease, in symptom-free patients with early breast cancer treated with radiotherapy. Thirty-seven survivors of a former randomized study of early breast cancer were examined. Twenty patients irradiated pre- or postoperatively for left sided disease (study group patients) were compared with 17 controls who were either treated for right sided disease, or were nonirradiated patients. Radiotherapy was randomized in the original study; either tangential field [sup 60]Co, or electron-therapy was delivered. Echocardiography and bicycle ergometry stress test with [sup 99m]Tc SestaMIBI myocardial perfusion scintigraphy were carried out and the patients' major risk factors for ischemic heart disease were also listed. Our results showed a significant difference between the scintigraphic findings of the two groups. Five of the 20 study group patients (25%), while none of the 17 controls exhibited some kind of significant defects on scintigraphy, indicating ischemic heart disease (p < 0.05). No deterioration in left ventricular systolic and/or diastolic function could be detected by echocardiography. Radiotherapy for left sided breast cancer with the mentioned treatment technique may present as an independent risk factor in the long-term development of ischemic heart disease, while left ventricular dysfunction could not be related to the previous irradiation. The authors emphasize the need to optimize adjuvant radiotherapy for early breast cancer by considering the dose both to the heart as well as the cancer. 39 refs., 4 tabs.
Time to use a dose of Chloroquine as an adjuvant to anti-cancer chemotherapies.
Pascolo, Steve
Chloroquine, a drug used for over 80 years to treat and prevent malaria and, more recently, to treat autoimmune diseases, is very safe but has a plethora of dose-dependent effects. By increasing pH in acidic compartments it inhibits for example lysosomal enzymes. In the context of cancer, Chloroquine was found to have direct effects on different types of malignancies that could potentiate chemotherapies. For example, the anti-malaria drug may inhibit both the multidrug-resistance pump and autophagy (mechanisms that tumor cells may use to resist chemotherapies), intercalate in DNA and enhance the penetration of chemotherapeutic drugs in cells or solid cancer tissues. However, these activities were mostly demonstrated at high doses of Chloroquine (higher than 10mg/kg or 10mg/l i.e. ca. 31μM). Nevertheless, it was reported that daily uptake of clinically acceptable doses (less than 10mg/kg) of Chloroquine in addition to chemo-radio-therapy increases the survival of glioblastoma patients (Sotelo et al., 2006; Briceno et al., 2007). However, the optimal dose and schedule of this multi-active drug with respect to chemotherapy has never been experimentally determined. The present article reviews the several known direct and indirect effects of different doses of Chloroquine on cancer and how those effects may indicate that a fine tuning of the dose/schedule of Chloroquine administration versus chemotherapy may be critical to obtain an adjuvant effect of Chloroquine in anti-cancer treatments. We anticipate that the appropriate (time and dose) addition of Chloroquine to the standard of care may greatly and safely potentiate current anti-cancer treatments. PMID:26687632
Economic comparison of capecitabine + oxaliplatin and 5-fluorouracil + oxaliplatin in the adjuvant treatment of colon cancer
Aitini, Enrico; Rossi, Anna; Morselli, Patrizia; Vivorio, Beatrice; Bruschi, Alessandra; Bottura, Chiara; Colombo, Giorgio L
Background Colorectal cancer is one of the most frequent and lethal cancers. The aim of this study was to analyze the costs relating to treatment of colorectal cancer between Xelox and Folfox-4 at a regional level according to the clinical experience at an Italian hospital in Lombardy. Methods A cost analysis was carried out regarding resource consumption by patients suffering from colorectal cancer based on data collected over a 12-month period between 2010 and 2011. The analysis involved 40 patients who attended the Department of Medical Oncology and Hematology at Carlo Poma Hospital to undergo adjuvant therapy for colorectal cancer. A chart was created for each patient containing their medical history, their pharmacological therapy indicating the number and duration of chemotherapy cycles, dose in mg administered for each cycle, number of day hospital visits for each cycle, number of days spent in hospital to position the central vein catheter, type of infusion pump used, any subsequent supportive therapy, and any side effects and outpatient visits connected with side effects. Results The cost analysis shows the savings involved in using Xelox for a single cycle of treatment, ie, approximately €1414.00 per patient (53% compared with Folfox-4). For each single cycle of treatment, the savings generated by using capecitabine compared with 5-FU can be attributed mostly to the fact that oral administration of chemotherapy requires fewer resources and does not require use of a central vein catheter (approximately 70% of overall cost) which amply compensates for the higher cost of capecitabine compared with 5-FU-LV. Sensibility analysis confirms the results of the base-case scenario. Conclusion The results of our study indicate that infusion via a central vein catheter represents a significant cost, and that substitution with an oral therapy, even when associated with drugs administered intravenously, represents a consistent saving of hospital resources. PMID
Apoptotic Death of Cancer Stem Cells for Cancer Therapy
He, Ying-Chun; Zhou, Fang-Liang; Shen, Yi; Liao, Duan-Fang; Cao, Deliang
Cancer stem cells (CSCs) play crucial roles in tumor progression, chemo- and radiotherapy resistance, and recurrence. Recent studies on CSCs have advanced understanding of molecular oncology and development of novel therapeutic strategies. This review article updates the hypothesis and paradigm of CSCs with a focus on major signaling pathways and effectors that regulate CSC apoptosis. Selective CSC apoptotic inducers are introduced and their therapeutic potentials are discussed. These include synthetic and natural compounds, antibodies and recombinant proteins, and oligonucleotides. PMID:24823879
Predictive Factors for Late Genitourinary and Gastrointestinal Toxicity in Patients With Prostate Cancer Treated With Adjuvant or Salvage Radiotherapy
Feng, Mary; Hanlon, Alexandra L.; Pisansky, Thomas M.; Kuban, Deborah; Catton, Charles N.; Michalski, Jeff M.; Zelefsky, Michael J.; Kupelian, Patrick A.; Pollack, Alan; Kestin, Larry L.; Valicenti, Richard K.; De Weese, Theodore L.; Sandler, Howard M. . E-mail: email@example.com
Purpose: To determine the rate and magnitude of late genitourinary (GU) and gastrointestinal (GI) toxicities after salvage or adjuvant radiotherapy (RT) for prostate cancer, and to determine predictive factors for these toxicities. Methods and Materials: A large multi-institutional database that included 959 men who received postoperative RT after radical prostatectomy (RP) was analyzed: 19% received adjuvant RT, 81% received salvage RT, 78% were treated to the prostate bed only, and 22% received radiation to the pelvis. Results: The median follow-up time was 55 months. At 5 years, 10% of patients had Grade 2 late GU toxicity and 1% had Grade 3 late GU toxicity, while 4% of patients had Grade 2 late GI toxicity and 0.4% had Grade 3 late GI toxicity. Multivariate analysis demonstrated that adjuvant RT (p = 0.03), androgen deprivation (p < 0.0001), and prostate bed-only RT (p = 0.007) predicted for Grade 2 or higher late GU toxicity. For GI toxicity, although adjuvant RT was significant in the univariate analysis, no significant factors were found in the multivariate analysis. Conclusions: Overall, the number of high-grade toxicities for postoperative RT was low. Therefore, adjuvant and salvage RT can safely be used in the appropriate settings.
Is There a Role for Adjuvant Therapy in R0 Resected Gallbladder Cancer?: A Propensity Score-Matched Analysis
Go, Se-Il; Kim, Young Saing; Hwang, In Gyu; Kim, Eun Young; Oh, Sung Yong; Ji, Jun Ho; Song, Haa-Na; Park, Se Hoon; Park, Joon Oh; Kang, Jung Hun
Purpose The purpose of this study is to assess the role of adjuvant therapy in stage I-III gallbladder cancer (GBC) patients who have undergone R0 resection. Materials and Methods Clinical data were collected on 441 consecutive patients who underwent R0 resection for stage I-III GBC. Eligible patients were classified into adjuvant therapy and surveillance only groups. Propensity score matching (PSM) between the two groups was performed, adjusting clinical factors. Results In total, 84 and 279 patients treated with adjuvant therapy and followed up with surveillance only, respectively, were included in the analysis. Before PSM, the 5-year relapse-free survival (RFS) rate was lower in the adjuvant therapy group than in the surveillance only group (50.8% vs. 74.8%, p < 0.001), although there was no statistically significant difference in the 5-year overall survival (OS) rate (66.2% vs. 79.5%, p=0.089). After the PSM, baseline characteristics became comparable and there were no differences in the 5-year RFS (50.8% vs. 64.8%, p=0.319) and OS (66.2% vs. 70.4%, p=0.703) rates between the two groups. Conclusion The results suggest that fluoropyrimidine-based adjuvant therapy is not indicated in stage I-III GBC patients who have undergone R0 resection. PMID:26875193
Health-related quality of life, psychological distress, and adverse events in postmenopausal women with breast cancer who receive tamoxifen, exemestane, or anastrozole as adjuvant endocrine therapy: National Surgical Adjuvant Study of Breast Cancer 04 (N-SAS BC 04).
Takei, Hiroyuki; Ohsumi, Shozo; Shimozuma, Kojiro; Takehara, Megumi; Suemasu, Kimito; Ohashi, Yasuo; Hozumi, Yasuo
Health-related quality of life (HRQOL), symptoms of depression, and adverse events (AEs) were compared between Japanese postmenopausal patients with hormone-sensitive breast cancer (BC) who received adjuvant tamoxifen, exemestane, or anastrozole in an open-labeled, randomized, multicenter trial designated as the National Surgical Adjuvant Study of Breast Cancer (N-SAS BC) 04 substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. During the first year of treatment, HRQOL and symptoms of depression were analyzed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and its Endocrine Symptom Subscale (ES), and the Center for Epidemiologic Studies Depression Scale (CES-D), respectively. In addition, predefined AEs were analyzed. A total of 166 eligible patients were randomly assigned to receive adjuvant tamoxifen, exemestane, or anastrozole. FACT-B scores increased after treatment began and remained significantly higher in the tamoxifen group than in the exemestane group or anastrozole group during the first year (P = 0.045). FACT-B scores were similar in the exemestane group and anastrozole group. ES scores and CES-D scores were similar in all treatment groups. Arthralgia and fatigue were less frequent, but vaginal discharge was more frequent in the tamoxifen group than in the exemestane group or anastrozole group. HRQOL was better in Japanese postmenopausal women treated with tamoxifen than those treated with exemestane or anastrozole. HRQOL and AEs were similar with exemestane and anastrozole. Given the results of the TEAM trial, upfront use of tamoxifen followed by an aromatase inhibitor (AI) may be an important option for adjuvant endocrine therapy in Japanese postmenopausal women.
Cancer stem cells in small cell lung cancer.
Codony-Servat, Jordi; Verlicchi, Alberto; Rosell, Rafael
Small cell lung cancer (SCLC) is one of the most aggressive lung tumors, with poor survival rates. Although patients may initially respond to treatment, this is followed by rapid development of drug resistance and disease progression. SCLC patients often present with metastasis at time of diagnosis, ruling out surgery as a treatment option. Currently, treatment options for this disease remain limited and platinum-based chemotherapy is the treatment of choice. A better understanding of the biology of SCLC could allow us to identify new therapeutic targets. Cancer stem cell (CSC) theory is currently crucial in cancer research and could provide a viable explanation for the heterogeneity, drug resistance, recurrence and metastasis of several types of tumors. Some characteristics of SCLC, such as aggressiveness, suggest that this kind of tumor could be enriched in CSCs, and drug resistance in SCLC could be attributable to the existence of a CSC subpopulation in SCLC. Herein we summarize current understanding of CSC in SCLC, including the evidence for CSC markers and signaling pathways involved in stemness. We also discuss potential ongoing strategies and areas of active research in SCLC, such as immunotherapy, that focus on inhibition of signaling pathways and targeting molecules driving stemness. Understanding of signaling pathways and the discovery of new therapeutic markers specific to CSCs will lead to new advances in therapy and improvements in prognosis of SCLC patients. Therefore, evaluation of these CSC-specific molecules and pathways may become a routine part of SCLC diagnosis and therapy.
Cancer stem cells in small cell lung cancer
Verlicchi, Alberto; Rosell, Rafael
Small cell lung cancer (SCLC) is one of the most aggressive lung tumors, with poor survival rates. Although patients may initially respond to treatment, this is followed by rapid development of drug resistance and disease progression. SCLC patients often present with metastasis at time of diagnosis, ruling out surgery as a treatment option. Currently, treatment options for this disease remain limited and platinum-based chemotherapy is the treatment of choice. A better understanding of the biology of SCLC could allow us to identify new therapeutic targets. Cancer stem cell (CSC) theory is currently crucial in cancer research and could provide a viable explanation for the heterogeneity, drug resistance, recurrence and metastasis of several types of tumors. Some characteristics of SCLC, such as aggressiveness, suggest that this kind of tumor could be enriched in CSCs, and drug resistance in SCLC could be attributable to the existence of a CSC subpopulation in SCLC. Herein we summarize current understanding of CSC in SCLC, including the evidence for CSC markers and signaling pathways involved in stemness. We also discuss potential ongoing strategies and areas of active research in SCLC, such as immunotherapy, that focus on inhibition of signaling pathways and targeting molecules driving stemness. Understanding of signaling pathways and the discovery of new therapeutic markers specific to CSCs will lead to new advances in therapy and improvements in prognosis of SCLC patients. Therefore, evaluation of these CSC-specific molecules and pathways may become a routine part of SCLC diagnosis and therapy. PMID:26958490
Noninitiation of Adjuvant Chemotherapy in Women With Localized Breast Cancer: The Breast Cancer Quality of Care Study
Neugut, Alfred I.; Hillyer, Grace Clarke; Kushi, Lawrence H.; Lamerato, Lois; Leoce, Nicole; Nathanson, S. David; Ambrosone, Christine B.; Bovbjerg, Dana H.; Mandelblatt, Jeanne S.; Magai, Carol; Tsai, Wei Yann; Jacobson, Judith S.; Hershman, Dawn L.
Purpose For some women, adjuvant chemotherapy for nonmetastatic breast cancer decreases recurrences and increases survival; however, patient-physician decisions regarding chemotherapy receipt can be influenced by medical and nonmedical factors. Patients and Methods We used a prospective cohort design and multivariate modeling to investigate factors related to noninitiation of chemotherapy among women with newly diagnosed breast cancer recruited from three US sites. We interviewed patients at baseline and during treatment on sociodemographic, tumor, and treatment decision-making factors. Patients were categorized according to National Comprehensive Cancer Network guidelines as those for whom chemotherapy was definitely indicated, clinically discretionary, or discretionary based on age greater than 70 years. Results Of 1,145 patients recruited, chemotherapy was clinically indicated for 392 patients, clinically discretionary for 459 patients, discretionary because of age for 169 patients, and not indicated for 93 patients; data were insufficient for 32 patients. Chemotherapy rates were 90% for those in whom chemotherapy was clinically indicated, 36% for those in whom it was discretionary because of clinical factors, and 19% for those in whom it was discretionary based on age greater than 70 years. Nonreceipt of chemotherapy was associated with older age, more negative beliefs about treatment efficacy, less positive beliefs about chemotherapy, and more concern about adverse effects. In the two discretionary groups, clinical predictors of worse outcome (greater tumor size, positive nodes, worse grade, and estrogen receptor– and progesterone receptor–negative status) were associated with increased chemotherapy initiation. Conclusion Utilization of adjuvant chemotherapy was most common among patients who, based on clinical criteria, would most likely benefit from it, patients with more positive than negative beliefs regarding treatment efficacy, and patients with few
Cancer metabolism, stemness and tumor recurrence
Curry, Joseph M.; Tuluc, Madalina; Whitaker-Menezes, Diana; Ames, Julie A.; Anantharaman, Archana; Butera, Aileen; Leiby, Benjamin; Cognetti, David M.; Sotgia, Federica; Lisanti, Michael P.; Martinez-Outschoorn, Ubaldo E.
tumor can actually determine clinical outcome, likely by providing high-energy mitochondrial "fuels" for proliferative cancer cells to burn. Finally, we also show that in normal mucosal tissue, the basal epithelial "stem cell" layer is hyper-proliferative (Ki-67+), mitochondrial-rich (TOMM20+/COX+) and is metabolically programmed to use mitochondrial fuels (MCT1+), such as ketone bodies and L-lactate. Thus, oxidative mitochondrial metabolism (OXPHOS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCT1 and MCT4 inhibitors, to target "metabolic symbiosis." PMID:23574725
Adjuvant Oral Uracil-Tegafur with Leucovorin for Colorectal Cancer Liver Metastases: A Randomized Controlled Trial
Takayama, Tadatoshi; Miyagawa, Shinichi; Yamamoto, Junji; Ijichi, Masayoshi; Teruya, Masanori; Yoshimi, Fuyo; Kawasaki, Seiji; Koyama, Hiroto; Oba, Masaru; Takahashi, Michiro; Mizunuma, Nobuyuki; Watanabe, Toshiaki
Background The high recurrence rate after surgery for colorectal cancer liver metastasis (CLM) remains a crucial problem. The aim of this trial was to evaluate the efficacy of adjuvant therapy with uracil-tegafur and leucovorin (UFT/LV). Methods In the multicenter, open-label, phase III trial, patients undergoing curative resection of CLM were randomly assigned in a 1:1 ratio to either the UFT/LV group or surgery alone group. The UFT/LV group orally received 5 cycles of adjuvant UFT/LV (UFT 300mg/m2 and LV 75mg/day for 28 days followed by a 7-day rest per cycle). The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included overall survival (OS). Results Between February 2004 and December 2010, 180 patients (90 in each group) were enrolled into the study. Of these, 3 patients (2 in the UFT/LV group and 1 in the surgery alone group) were excluded from the efficacy analysis. Median follow-up was 4.76 (range, 0.15–9.84) years. The RFS rate at 3 years was higher in the UFT/LV group (38.6%, n = 88) than in the surgery alone group (32.3%, n = 89). The median RFS in the UFT/LV and surgery alone groups were 1.45 years and 0.70 years, respectively. UFT/LV significantly prolonged the RFS compared with surgery alone with the hazard ratio of 0.56 (95% confidence interval, 0.38–0.83; P = 0.003). The hazard ratio for death of the UFT/LV group against the surgery alone group was not significant (0.80; 95% confidence interval, 0.48–1.35; P = 0.409). Conclusion Adjuvant therapy with UFT/LV effectively prolongs RFS after hepatic resection for CLM and can be recommended as an alternative choice. Trial Registration UMIN Clinical Trials Registry C000000013 PMID:27588959
Adjuvant Chemotherapy for the Completely Resected Stage IB Nonsmall Cell Lung Cancer
He, Jiaxi; Shen, Jianfei; Yang, Chenglin; Jiang, Long; Liang, Wenhua; Shi, Xiaoshun; Xu, Xin; He, Jianxing
Abstract Adjuvant chemotherapy is recommended for postoperative stage II-IIIB nonsmall cell lung cancer patients. However, its effect remains controversial in stage IB patients. We, therefore, performed a meta-analysis to compare the efficacy of adjuvant chemotherapy versus surgery alone in stage IB patients. Six electronic databases were searched for relevant articles. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS). The time-to-event outcomes were compared by hazard ratio using log-rank test. Sixteen eligible trials were identified. A total of 4656 patients were included and divided into 2 groups: 2338 in the chemotherapy group and 2318 in the control group (surgery only). Patients received platinum-based therapy, uracil-tegafur, or a combination of them. Our results demonstrated that patients can benefit from the adjuvant chemotherapy in terms of OS (HR 0.74 95% CI 0.63–0.88) and DFS (HR 0.64 95% CI 0.46–0.89). Patients who received 6-cycle platinum-based therapy (HR 0.45 95% CI 0.29–0.69), uracil-tegafur (HR 0.71 95% CI 0.56–0.90), or a combination of them (HR 0.51 95% CI 0.36–0.74) had better OS, but patients who received 4 or fewer cycles platinum-based therapy (HR 0.97 95% CI 0.85–1.11) did not. Moreover, 6-cycle platinum-based therapy (HR 0.29 95% CI 0.13–0.63) alone or in combination with uracil-tegafur (HR 0.44 95% CI 0.30–0.66) had advantages in DFS. However, 4 or fewer cycles of platinum-based therapy (HR 0.89 95% CI 0.76–1.04) or uracil-tegafur alone (HR 1.19 95% CI 0.79–1.80) were not beneficial. Six-cycle platinum-based chemotherapy can improve OS and DFS in stage IB NSCLC patients. Uracil-tegafur alone or in combination with platinum-based therapy is beneficial to the patients in terms of OS, but uracil-tegafur seems to have no advantage in prolonging DFS, unless it is administered with platinum-based therapy. PMID:26039122
GALNT14 Genotype Predicts Postoperative Outcome of Stage III Colorectal Cancer With Oxaliplatin as Adjuvant Chemotherapy
Lin, Wey-Ran; Chiang, Jy-Ming; Liang, Kung-Hao; Lim, Siew-Na; Lai, Ming-Wei; Tsou, Yung-Kuan; Hsieh, Tzu-Yun; Hsu, Chih-Kai; Yeh, Chau-Ting
Abstract Adjuvant oxaliplatin-based chemotherapy is widely used for stage III colorectal cancer (CRC) after curative surgery. CRC is a molecularly heterogeneous disease, and our current knowledge of therapeutic response-related genetic factors remains limited. N-acetylgalactosaminyltransferase 14 (GALNT14)-rs9679162 genotype is a prognostic predictor for chemotherapy response in advanced hepatocellular carcinoma. Here, we investigated whether this genotype was related to the therapeutic outcome of stage III CRC. A cohort of 300 stage III CRC patients receiving curative resection followed by oxaliplatin-based chemotherapy was retrospectively recruited. GALNT14 genotypes and the clinicopathological factors were correlated with posttherapeutic prognosis. Of these patients, 18% patients had GALNT14-rs9679162 "TT" and 82% had the "GT" + "GG" genotypes. The analysis showed that the "TT" genotype was associated with unfavorable overall survival (OS, P = 0.009) but not with recurrence-free survival (RFS, P = 0.700). The subgroup analysis showed that the "TT" genotype was associated with unfavorable OS in the following subgroups: age ≤65 years, men, left side CRC, N2 stage, carcinoembryonic antigen >5 ng/mL, and mucinous histology (P = 0.012, 0.011, 0.009, 0.025, 0.013, and 0.007, respectively). Within the latter 2 subgroups, the "TT" genotype was the only independent predictor for OS. Finally, the "TT" genotype was associated with the T4 tumor stage (P = 0.017) and in patients with T4 tumors, the "TT" genotype was the only independent predictor for unfavorable RFS (P = 0.007). GALNT14 "TT" genotype was associated with unfavorable OS in stage III CRC patients receiving curative surgery and adjuvant oxaliplatin-based chemotherapy. PMID:27124048
A Prospective Cohort Study on Cardiotoxicity of Adjuvant Trastuzumab Therapy in Breast Cancer Patients
Matos, Erika; Jug, Borut; Blagus, Rok; Zakotnik, Branko
Background Cardiotoxicity is an important side effect of trastuzumab therapy and cardiac surveillance is recommended. Objectives The aim of our study was to prospectively assess baseline patients' characteristics, level of N-terminal pro-brain natriuretic peptide (NT-proBNP) and echocardiographic parameters as possible predictors of trastuzumab-related cardiac dysfunction. Methods In a prospective cohort study, clinical, echocardiographic and neurohumoral assessment was performed at baseline, after 4, 8 and 12 months in breast cancer patients undergoing post-anthracycline (3-4 cycles) adjuvant therapy with trastuzumab. Trastuzumab-related cardiac dysfunction was defined as a decline of ≥ 10% in left ventricular ejection fraction (LVEF). Results 92 patients (mean age, 53.6 ± 9.0 years) were included. Patients who developed trastuzumab-related LVEF decline ≥ 10% (20.6%) during treatment had significantly higher baseline LVEF (70.7 ± 4.4%) than those without (64.8 ± 5.5%) (p = 0.0035). All other measured baseline parameters (age, body mass index, arterial hypertension, level of NT-proBNP and other echocardiographic parameters) were not identified as significant. Conclusions Our findings suggest that baseline patient' characteristics, level of NT-proBNP and echocardiographic parameters, as long as they are within normal range, are not a reliable tool to predict early trastuzumab-related cardiac dysfunction in patients undergoing post-low dose anthracycline adjuvant trastuzumab therapy. A LVEF decline in patients with high-normal baseline level although statistically significant is not clinically relevant. PMID:27305108
Management of sexual dysfunction in postmenopausal breast cancer patients taking adjuvant aromatase inhibitor therapy
Derzko, C.; Elliott, S.; Lam, W.
Treatment with aromatase inhibitors for postmenopausal women with breast cancer has been shown to reduce or obviate invasive procedures such as hysteroscopy or curettage associated with tamoxifen-induced endometrial abnormalities. The side effect of upfront aromatase inhibitors, diminished estrogen synthesis, is similar to that seen with the natural events of aging. The consequences often include vasomotor symptoms (hot flushes) and vaginal dryness and atrophy, which in turn may result in cystitis and vaginitis. Not surprisingly, painful intercourse (dyspareunia) and loss of sexual interest (decreased libido) frequently occur as well. Various interventions, both non-hormonal and hormonal, are currently available to manage these problems. The purpose of the present review is to provide the practitioner with a wide array of management options to assist in treating the sexual consequences of aromatase inhibitors. The suggestions in this review are based on recent literature and on the recommendations set forth both by the North American Menopause Association and in the clinical practice guidelines of the Society of Gynaecologists and Obstetricians of Canada. The complexity of female sexual dysfunction necessitates a biopsychosocial approach to assessment and management alike, with interventions ranging from education and lifestyle changes to sexual counselling, pelvic floor therapies, sexual aids, medications, and dietary supplements—all of which have been reported to have a variable, but often successful, effect on symptom amelioration. Although the use of specific hormone replacement—most commonly local estrogen, and less commonly, systemic estrogen with or without an androgen, progesterone, or the additional of an androgen in an estrogenized woman (or a combination)—may be highly effective, the concern remains that in patients with estrogen-dependent breast cancer, including those receiving anti-estrogenic adjuvant therapies, the use of these hormones may be
TNIK inhibition abrogates colorectal cancer stemness
Masuda, Mari; Uno, Yuko; Ohbayashi, Naomi; Ohata, Hirokazu; Mimata, Ayako; Kukimoto-Niino, Mutsuko; Moriyama, Hideki; Kashimoto, Shigeki; Inoue, Tomoko; Goto, Naoko; Okamoto, Koji; Shirouzu, Mikako; Sawa, Masaaki; Yamada, Tesshi
Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik−/−/Apcmin/+ mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/+ mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach. PMID:27562646
TNIK inhibition abrogates colorectal cancer stemness.
Masuda, Mari; Uno, Yuko; Ohbayashi, Naomi; Ohata, Hirokazu; Mimata, Ayako; Kukimoto-Niino, Mutsuko; Moriyama, Hideki; Kashimoto, Shigeki; Inoue, Tomoko; Goto, Naoko; Okamoto, Koji; Shirouzu, Mikako; Sawa, Masaaki; Yamada, Tesshi
Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik(-/-)/Apc(min/+) mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apc(min/+) mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach. PMID:27562646
Psychoneuroimmunology-Based Stress Management during Adjuvant Chemotherapy for Early Breast Cancer.
Robins, Jo Lynne W; McCain, Nancy L; Elswick, R K; Walter, Jeanne M; Gray, D Patricia; Tuck, Inez
Objective. In a randomized trial of women with early stage breast cancer undergoing adjuvant chemotherapy, two stress management interventions, tai chi training and spiritual growth groups, were compared to a usual care control group, to evaluate psychosocial functioning, quality of life (QOL), and biological markers thought to reflect cancer- and treatment-specific mechanisms. Method. The sample consisted of 145 women aged 27-75 years; 75% were Caucasian and 25% African American. A total of 109 participants completed the study, yielding a 75% retention rate. Grounded in a psychoneuroimmunology framework, the overarching hypothesis was that both interventions would reduce perceived stress, enhance QOL and psychosocial functioning, normalize levels of stress-related neuroendocrine mediators, and attenuate immunosuppression. Results. While interesting patterns were seen across the sample and over time, the interventions had no appreciable effects when delivered during the period of chemotherapy. Conclusions. Findings highlight the complex nature of biobehavioral interventions in relation to treatment trajectories and potential outcomes. Psychosocial interventions like these may lack sufficient power to overcome the psychosocial or physiological stress experienced during the chemotherapy treatment period. It may be that interventions requiring less activity and/or group attendance would have enhanced therapeutic effects, and more active interventions need to be tested prior to and following recovery from chemotherapy.
Bicalutamide Activated Oncolytic Adenovirus for the Adjuvant Therapy of High Risk Prostate Cancer
Johnson, Tamara Jane; Hoti, Naser Uddin; Liu, Chunyan; Chowdhury, Wasim H.; Li, Ying; Zhang, Yonggang; Lupold, Shawn E.; DeWeese, Theodore; Rodriguez, Ronald
Conditionally replicating adenoviruses (CRAds) utilize tissue specific promoters to control the expression of the early genes, E1A and E1B, to preferentially replicate and lyse tumor cells (oncolysis). Previous CRAds used in prostate cancer gene therapy require androgens to activate prostate specific promoters and induce viral replication. Unfortunately, these CRAds have reduced activity in patients on androgen suppressive therapy. We describe a novel prostate specific CRAd generated by fusing the E1A gene to the androgen receptor (AR) cDNA with a point mutation in codon 685 (C685Y). The E1A-AR fusion neutralizes the previously described mutual inhibition of E1A & AR, and the C685Y point mutation alters specificity of steroid ligand binding to the AR, such that both androgens and non-steroidal anti-androgens can activate viral replication. We demonstrate that the mutated E1A-AR retained the ability to function in regulating AR responsive genes and E1A responsive viral genes. In combination therapy of virus, bicalutamide (anti-androgen) and radiation, a profound impact on cell death by viral oncolysis was seen both in vitro and tumor xenografts. To our knowledge, this is the first gene therapy engineered to be enhanced by anti-androgens, and a particularly attractive adjuvant strategy for intensity modulated radiation therapy (IMRT) of high-risk prostate cancers. PMID:23764901
Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling.
Balic, Anamaria; Sørensen, Morten Dræby; Trabulo, Sara Maria; Sainz, Bruno; Cioffi, Michele; Vieira, Catarina R; Miranda-Lorenzo, Irene; Hidalgo, Manuel; Kleeff, Joerg; Erkan, Mert; Heeschen, Christopher
Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent inhibition of hedgehog signaling by decreasing the production of Smoothened, translating into a significant reduction in sonic hedgehog-induced chemotaxis and downregulation of downstream targets in CSCs and the surrounding stroma. Our study demonstrates that via to date unreported effects, chloroquine is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer. PMID:24785258
Assessing the Real-World Cost-Effectiveness of Adjuvant Trastuzumab in HER-2/neu Positive Breast Cancer
Hedden, Lindsay; O'Reilly, Susan; Lohrisch, Caroline; Chia, Stephen; Speers, Caroline; Kovacic, Laurel; Taylor, Suzanne
Background. Among women with surgically removed, high-risk HER-2/neu-positive breast cancer, trastuzumab has demonstrated significant improvements in disease-free and overall survival. The objective of this study is to evaluate the cost-effectiveness of the currently recommended 12-month adjuvant protocol of trastuzumab using a Markov modeling approach and real-world cost data. Methods. A 10-health-state Markov model tracked patients' quarterly transitions between health states in the local and advanced states of breast cancer. Clinical data were obtained from the joint analysis of the National Surgical Adjuvant Breast and Bowel Project and North Central Cancer Treatment Group, as well as from the metastatic study conducted by Norum et al. Clinical outcomes were adjusted for quality of life using utility estimates published in a systematic review. Real cost data were obtained from the British Columbia Cancer Agency and were evaluated from a payer perspective. Costs and utilities were discounted at 5% per year, respectively, for a 28-year time horizon. Results. In the base case analysis, treatment with a 12-month adjuvant trastuzumab regimen resulted in a gain of 1.38 quality-adjusted life years or 1.17 life years gained at a cost of $18,133 per patient. Thus, the cost per QALY gained for the base case is $13,095. Cost per LYG is $15,492. Conclusions. Over the long term, treatment of HER-2/neu mutation positive breast cancer with a 12-month protocol of trastuzumab in the adjuvant setting is predicted to be cost-effective in a Canadian context. PMID:22302231
Adjuvant chemotherapy for ypT0N0M0 rectal cancer following chemoradiotherapy and total mesorectal excision.
Kainthla, Radhika; Huerta, Sergio
The management of adenocarcinoma of the rectum is a dynamic field in oncology. The multidisciplinary approach to the management of this disease continues to evolve in each segment of its trimodality treatment. New scheduling regimens and radiosensitizing agents continue to emerge. Although total mesorectal excision continues to be the operation of choice for rectal cancers, what is done before and after surgery continues to evolve to maximize an ideal oncologic outcome with minimal morbidity. The achievement of a pathological complete response [pCR (i.e. ypT0N0)] in a fraction of patients undergoing neoadjuvant chemoradiation poses an interesting management dilemma. The cohort of patients who can achieve a pCR have superior oncologic outcomes compared to nonresponders. The present review addresses the need for adjuvant therapy in patients with a pCR. We discuss the evolution of the role of adjuvant therapy in patients with rectal cancer and the studies addressing the elimination of this strategy in all patients with rectal cancer with a goal of determining the current evidence that might result in the omission of adjuvant therapy for patients with ypT0N0 rectal cancer after chemoradiation and total mesorectal excision. PMID:27387144
Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer
Andersson, M.; Storm, H.H.; Mouridsen, H.T. )
The incidence of new primary cancers was evaluated in 3538 postmenopausal patients who had received surgical treatment for primary breast cancer. Of these patients, 1828 with a low risk of recurrence received no further treatment. High-risk patients were randomly assigned to one of two groups. The first group (n = 846) received postoperative radiotherapy, while the second group (n = 864) received radiotherapy plus tamoxifen at a dose of 30 mg given daily for 48 weeks. The median observation time was 7.9 years. In comparison with the number of new cancers in the general population, the number of new cancers in the three groups was elevated mostly due to a high number of cancers of the contralateral breast and of colorectal cancers in the high-risk groups. The cumulative risk of nonlymphatic leukemia was increased among patients who received postoperative radiotherapy (P = .04). Cancer incidence in the high-risk tamoxifen-treated group relative to that in the high-risk group not treated with tamoxifen was not significant (1.3). No protective effect of tamoxifen on the opposite breast was seen (rate ratio for breast cancer = 1.1), but a tendency to an elevated risk of endometrial cancer was observed (rate ratio = 3.3; 95% confidence interval = 0.6-32.4). Continued and careful follow-up of women treated with tamoxifen is necessary to clarify the potential cancer-suppressive or cancer-promoting effects of this drug.
Cost effectiveness of personalized treatment in women with early breast cancer: the application of OncotypeDX and Adjuvant! Online to guide adjuvant chemotherapy in Austria.
Jahn, B; Rochau, U; Kurzthaler, C; Hubalek, M; Miksad, R; Sroczynski, G; Paulden, M; Kluibenschädl, M; Krahn, M; Siebert, U
A Breast Cancer Outcomes model was developed at the ONCOTYROL research center to evaluate personalized test-treatment strategies in Austria. The goal was to evaluate the cost-effectiveness of a new 21-gene assay (ODX) when used in conjunction with the Adjuvant! Online (AO) decision aid to support personalized decisions about use of adjuvant chemotherapy in early-stage breast cancer patients in Austria. We applied a validated discrete-event-simulation model to a hypothetical cohort of 50 years old women over a lifetime horizon. The test-treatment strategies of interest were defined using three-letter acronyms. The first (second, third) letter indicates whether patients with a low (intermediate, high) risk according to AO were tested using ODX (Y yes, N no). The main outcomes were life-years gained, quality-adjusted life-years (QALYs), costs and cost effectiveness. Robustness of the results was tested in sensitivity analyses. Results were compared to a Canadian analysis conducted by the Toronto Health Economics and Technology Assessment Collaborative (THETA). Five of eight strategies were dominated (i.e., more costly and less effective: NNY, NYN, YNN, YNY, YYN). The base-case analysis shows that YYY (ODX provided to all patients) is the most effective strategy and is cost effective with an incremental cost-effectiveness ratio of 15,700 EUR per QALY gained. These results are sensitive to changes in the probabilities of distant recurrence, age and costs of chemotherapy. The results of the base-case analysis were comparable to the THETA results. Based on our analyses, using ODX in addition to AO is effective and cost effective in all women in Austria. The development of future genetic tests may require alternative or additional test-treatment strategies to be evaluated.
Anti-inflammatory and anti-oxidant properties of Sida rhombifolia stems and roots in adjuvant induced arthritic rats.
Narendhirakannan, R T; Limmy, T P
Free radical stress leads to tissue injury and progression of disease conditions such as arthritis, hemorrhagic shock, atherosclerosis, diabetes, hepatic injury, aging and ischemia, reperfusion injury of many tissues, gastritis, tumor promotion, neurodegenerative diseases and carcinogenesis. Safer anti-oxidants suitable for long term use are needed to prevent or stop the progression of free radical mediated disorders. Herbal medicine provides a foundation for various traditional medicine systems worldwide. The Sida species is one of the most important families of medicinal plants in India. Hence, the present study was aimed to investigate the possible anti-oxidant potential of Sida rhombifolia extracts for 30 days on adjuvant induced arthritis in experimental rats. The altered levels of hematological parameters were reverted to near normal levels, especially the elevated rate of erythrocyte sedimentation was significantly reduced by S. rhombifolia extracts in experimental rats. Oral administration of root and stem of S. rhombifolia extracts significantly increased the levels of thiobarbituric acid reactive substances and activities of catalase and glutathione peroxidase and decreased the levels of reduced glutathione and superoxide dismutase activity in arthritis induced rats. The free radical scavenging activity of the plant was further evidenced by histological and transmission electron microscopy observations made on the hind limb tissue.
The stem cell patent landscape as relevant to cancer vaccines.
Wang, Shyh-Jen
Cancer vaccine targeting cancer stem cells is proposed to serve as a potent immunotherapy. Thus, it would be useful to examine the main trends in stem cell patenting activity as a guide for those seeking to develop such cancer vaccines. We found that a substantial number of stem cell patents were granted up to the end of 2010, including ~2000 issued in the US. Many of these have been filed since 2001, including 7,551 applications in the US. Stem cell development, as evidenced by the numbers of PubMed articles, has matured steadily in recent years. However, the other metrics, such as the number of patent applications, the technology-science linkage and the number of patent assignees, have been stagnant. Moreover, the ownership of stem cell patents is still quiet fragmented across multiple organizations, and the number of stem cell patent assignees from the business sector has not increased significantly. Academic and nonprofit institutions not only account for a large share of stem cell patents but also apply for patents continually. Based on this analysis, the strength of stem cell resources seems to remain stagnant in recent years due to the ban on government funding of embryonic stem cell research. Furthermore, the patent prosecution or technical barriers in the field of stem cells would be another main reason that the number of US-issued stem cell patents for each application have been in gradual decline since 2000. Therefore, we consider stem cell technology to still be under development.
Can Nanomedicines Kill Cancer Stem Cells?
Zhao, Yi; Alakhova, Daria Y.; Kabanov, Alexander V.
Most tumors are heterogeneous and many cancers contain small population of highly tumorigenic and intrinsically drug resistant cancer stem cells (CSCs). Like normal stem cell, CSCs have ability to self-renew and differentiate to other tumor cell types. They are believed to be a source for drug resistance, tumor recurrence and metastasis. CSCs often overexpress drug efflux transporters, spend most of their time in non-dividing G0 cell cycle state, and therefore, can escape the conventional chemotherapies. Thus, targeting CSCs is essential for developing novel therapies to prevent cancer relapse and emerging of drug resistance. Nanocarrier-based therapeutic agents (nanomedicines) have been used to achieve longer circulation times, better stability and bioavailability over current therapeutics. Recently, some groups have successfully applied nanomedicines to target CSCs to eliminate the tumor and prevent its recurrence. These approaches include 1) delivery of therapeutic agents (small molecules, siRNA, antibodies) that affect embryonic signaling pathways implicated in self-renewal and differentiation in CSCs, 2) inhibiting drug efflux transporters in an attempt to sensitize CSCs to therapy, 3) targeting metabolism in CSCs through nanoformulated chemicals and field-responsive magnetic nanoparticles and carbon nanotubes, and 4) disruption of multiple pathways in drug resistant cells using combination of chemotherapeutic drugs with amphiphilic Pluronic block copolymers. Despite clear progress of these studies the challenges of targeting CSCs by nanomedicines still exist and leave plenty of room for improvement and development. This review summarizes biological processes that are related to CSCs, overviews the current state of anti-CSCs therapies, and discusses state-of-the-art nanomedicine approaches developed to kill CSCs. PMID:24120657
Response to adjuvant chemotherapy in primary breast cancer: no correlation with expression of glutathione S-transferases.
Peters, W. H.; Roelofs, H. M.; van Putten, W. L.; Jansen, J. B.; Klijn, J. G.; Foekens, J. A.
Of 139 node-positive breast cancer patients treated with adjuvant chemotherapy, the pre-treatment levels of glutathione S-transferase (GST) classes alpha, mu and pi, were determined by immuno-quantification on Western blots in cytosols of the primary tumours. Their expression was studied with respect to cytosolic oestrogen-receptor, progesterone-receptor and cathepsin D levels, and to the length of disease-free survival. GST class pi was negatively correlated with oestrogen receptor and progesterone receptor, and positively correlated with cathepsin D. There was no correlation between GST isoenzymes and the length of disease-free survival. These data suggest that glutathione S-transferases are not useful as markers to predict the response to adjuvant chemotherapy in human breast cancer. Images Figure 1 PMID:8318426
Factors affecting baseline quality of life in two international adjuvant breast cancer trials. International Breast Cancer Study Group (IBCSG).
Bernhard, J.; Hürny, C.; Coates, A. S.; Peterson, H. F.; Castiglione-Gertsch, M.; Gelber, R. D.; Galligioni, E.; Marini, G.; Thürlimann, B.; Forbes, J. F.; Goldhirsch, A.; Senn, H. J.; Rudenstam, C. M.
Quality of life (QL) is used to assess treatments in clinical trials but may be influenced by other factors. We analysed the impact of biomedical, sociodemographic and cultural factors on baseline QL indicators in two International Breast Cancer Study Group trials. Patients with stage II breast cancer were randomized within 6 weeks of primary surgery to various adjuvant treatments. They were asked to assess five indicators of QL at baseline. QL forms were available for 1231 (83%) of the 1475 premenopausal and 989 (82%) of the 1212 post-menopausal patients, who were from nine countries and spoke seven languages. Culture (defined as language/country groups) had a statistically significant impact on baseline QL measures. Premenopausal patients with poor prognostic factors showed a tendency to report worse QL, with oestrogen receptor status as an independent predictor for mood (P = 0.0005). Older post-menopausal patients reported better emotional wellbeing (P = 0.002), mood (P = 0.002), and less effort to cope (P = 0.0009) compared with younger post-menopausal patients. Co-morbidity, type of surgery, treatment assignment and sociodemographic factors showed a statistically significant impact in post-menopausal patients only. Cultural and biomedical factors influenced baseline QL and should be considered when evaluating the impact of treatment on QL in international breast cancer clinical trials. PMID:9744512
Health-related Quality of Life in Metastatic and Adjuvant Breast Cancer Patients
Wallwiener, M.; Simoes, E.; Sokolov, A. N.; Brucker, S. Y.; Fasching, P. A.; Graf, J.
Introduction: When cancer patients have advanced disease and a primary cure is no longer possible, the focus is on maintaining the patient's quality of life. Recent therapeutic advances in breast cancer treatment mean that even patients with metastatic disease can remain stable for long periods of time. The aim of this study was to look at the health-related quality of life (HRQL) of these patients and compare it with data for the general population and to show the differences in outcomes for different survey instruments used to measure quality of life. Material and Methods: A total of 96 breast cancer patients with metastatic disesae or receiving adjuvant therapy were questioned about their quality of life. Patients were investigated using the established survey instruments EORTC QLQ-C30, EORTC QLQ-BR23, EQ-5D-5L and EQ VAS. All patients filled out questionnaires. Statistical analysis was done using MS Excel and SPSS. Results: Although the questionnaires were completed at the same time, the different questionnaires showed significant differences with regard to the level of stress experienced by the patient. When the EQ VAS questionnaire was used, the patient's current state of health was assessed as significantly better than with the EORTC QLQ-C30. Overall, all aspects of patients' quality of life were found to be in need of optimization and HRQL of patients was significantly poorer in all areas compared to the reference population. Conclusion: To improve the quality of life of patients with metastatic disease, it is necessary to continuously monitor the success of therapy. The choice of survey tools is highly relevant as assessments differ considerably depending on the choice of questionnaire. PMID:27761027
Understanding the Challenges of Adjuvant Treatment Measurement and Reporting in Breast Cancer
Bickell, Nina A.; McAlearney, Ann Scheck; Wellner, Jill; Fei, Kezhen; Franco, Rebeca
Background Healthcare accrediting organizations and insurers increasingly require reporting of clinical data, and cancer treatment is one area of enhanced scrutiny. Objectives To compare rates of received versus reported adjuvant breast cancer treatments, and to assess barriers to measuring and reporting treatments to the tumor registry (TR) of a high-volume medical center with both hospital-based and community-based oncologists. Research Design We calculated rates of received treatments using data collected using chart abstraction (N = 115) and compared these with rates of reported treatments from the TR (N = 535). We conducted 31 indepth interviews with clinical and administrative informants. Asking about perceptions of the TR, current reporting methods, and reporting barriers. Interviews were recorded, transcribed, and analyzed using deductive and inductive methods. Results Rates of reported versus received treatments were radiation therapy after breast-conserving surgery 22% versus 84% (P < 0.0001); chemotherapy for stage 2 or 3: 17% versus 79% (P < 0.0001); hormonal therapy for stage 2 or 3: 1% versus 91% (P < 0.0001). Comparing community-based versus hospital-based oncologists' rates reported to the TR, we found the following differences: radiation therapy post-breast conserving surgery 12% versus 32% (< 0.0001); chemotherapy 8% versus 29% (< 0.0001); and hormonal therapy 0% versus 3% (0.09).We found 4 key barriers to measuring and reporting poor understanding about the TR, limited information technology capabilities, poor communication, and mistrust. Conclusions Efforts to improve cancer care quality by improved treatment reporting must overcome key barriers, especially those involving information exchange and mistrust. Communications between the TR and oncology practices must improve to facilitate better treatment measurement and reporting. PMID:22214980
Alterations in Hormone Levels After Adjuvant Chemoradiation in Male Rectal Cancer Patients
Yoon, Frederick H.; Perera, Francisco Fisher, Barbara; Stitt, Larry
Purpose: To evaluate follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels after postoperative chemoradiation in men with rectal cancer. Methods and Materials: Forty-three men with rectal cancer had baseline and postchemoradiation FSH, LH, and testosterone measured. Adjuvant chemoradiation consisted of two 5-day cycles of bolus 5-fluorouracil (5-FU) every 4 weeks at a dose of 500 mg/m{sup 2}/d followed by concurrent chemoradiation followed by two additional 5-day cycles of 5-FU at a dose of 450 mg/m{sup 2}/d. Continuous-infusion 5-FU at 225 mg/m{sup 2}/d was given during radiation. Pelvic radiation consisted of a three- or four-field technique with a median dose of 54.0 Gy in 30 fractions. Results: Median follow-up was 6.1 years. Mean baseline FSH levels increased from 5.3 to a peak of 23.9 IU/L (p < 0.001) 13-24 months after chemoradiation. Mean baseline LH levels increased from 4.3 to a peak of 8.5 IU/L (p < 0.001) within 6 months after chemoradiation. Mean testosterone levels decreased from 15.4 nmol/L at baseline to 8.0 nmol/L more than 4 years after chemoradiation. Mean testosterone to mean LH ratio decreased from 4.4 at baseline to 1.1 after 48 months posttreatment, suggesting a continued decrease in Leydig cell function with time. Testicular dose was measured in 5 patients. Median dose was 4 Gy (range, 1.5-8.9 Gy). Conclusions: Chemoradiation in men with rectal cancer causes persistent increases in FSH and LH levels and decreases in testosterone levels.
How much survival benefit is necessary for breast cancer patients to opt for adjuvant chemotherapy? Results from a Chilean survey
Acevedo, Francisco; Sanchez, Cesar; Jans, Jaime; Rivera, Solange; Camus, Mauricio; Besa, Pelayo
Background: Breast cancer (BC) is the leading cause of cancer death in Chilean women. Adjuvant chemotherapy decreases recurrence and death from BC. The recommendation to indicate chemotherapy is complex. Adjuvant! Online is a valuable computational tool to predict survival benefit obtained with adjuvant systemic therapy. Previous studies in Caucasian patients with BC showed that they are willing to receive chemotherapy for a small benefit. No studies, to our knowledge, have been done in the Hispanic or Latino populations. Methods: We interviewed females with BC who had previously received adjuvant chemotherapy. Age, stage at presentation, time since last chemotherapy, type of chemotherapy, marital status, number of children, and level of education were recorded. We used the graphic representation from Adjuvant! Online to question each patient on how much survival benefit she required to accept chemotherapy. Results: There were 101 women surveyed. The average age was 55.9 (±10.2), 54.5% had involved lymph nodes, 59.4% were married, and 15.8% did not have parity; 62.3% of females accepted chemotherapy for an absolute survival benefit of 1% or less. In a multivariate analysis, younger (p = 0.02) and less-educated patients (p = 0.018) were associated with lower survival benefit required to opt for chemotherapy. Conclusion: In our study, the acceptance of chemotherapy by the Hispanic population requires minimal survival benefit and is in agreement with the Caucasian population reported elsewhere. To our knowledge, our report is the first study that evaluates the perception of Latino patients regarding the benefit of chemotherapy in early BC. PMID:24678346
Efficacy of Adjuvant 5-Fluorouracil Therapy for Patients with EMAST-Positive Stage II/III Colorectal Cancer
Hamaya, Yasushi; Guarinos, Carla; Tseng-Rogenski, Stephanie S.; Iwaizumi, Moriya; Das, Ritabrata; Jover, Rodrigo; Castells, Antoni; Llor, Xavier; Andreu, Montserrat; Carethers, John M.
Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) is a genetic signature found in up to 60% of colorectal cancers (CRCs) that is caused by somatic dysfunction of the DNA mismatch repair (MMR) protein hMSH3. We have previously shown in vitro that recognition of 5-fluorouracil (5-FU) within DNA and subsequent cytotoxicity was most effective when both hMutSα (hMSH2-hMSH6 heterodimer) and hMutSβ (hMSH2-hMSH3 heterodimer) MMR complexes were present, compared to hMutSα > hMutSβ alone. We tested if patients with EMAST CRCs (hMutSβ defective) had diminished response to adjuvant 5-FU chemotherapy, paralleling in vitro findings. We analyzed 230 patients with stage II/III sporadic colorectal cancers for which we had 5-FU treatment and survival data. Archival DNA was analyzed for EMAST (>2 of 5 markers mutated among UT5037, D8S321, D9S242, D20S82, D20S85 tetranucleotide loci). Kaplan-Meier survival curves were generated and multivariate analysis was used to determine contribution to risk. We identified 102 (44%) EMAST cancers. Ninety-four patients (41%) received adjuvant 5-FU chemotherapy, and median follow-up for all patients was 51 months. Patients with EMAST CRCs demonstrated improved survival with adjuvant 5FU to the same extent as patients with non-EMAST CRCs (P<0.05). We observed no difference in survival between patients with stage II/III EMAST and non-EMAST cancers (P = 0.36). There is improved survival for stage II/III CRC patients after adjuvant 5-FU-based chemotherapy regardless of EMAST status. The loss of contribution of hMSH3 for 5-FU cytotoxicity may not adversely affect patient outcome, contrasting patients whose tumors completely lack DNA MMR function (MSI-H). PMID:25996601
Disease-Free Survival as a Surrogate for Overall Survival in Adjuvant Trials of Gastric Cancer: A Meta-Analysis
Paoletti, Xavier; Alberts, Steven; Bang, Yung-Jue; Benedetti, Jacqueline; Bleiberg, Harry; Catalano, Paul; Lordick, Florian; Michiels, Stefan; Morita, Satoshi; Ohashi, Yasuo; Pignon, Jean-pierre; Rougier, Philippe; Sasako, Mitsuru; Sakamoto, Junichi; Sargent, Daniel; Shitara, Kohei; Cutsem, Eric Van; Buyse, Marc; Burzykowski, Tomasz
Background In investigations of the effectiveness of surgery and adjuvant chemotherapy for gastric cancers, overall survival (OS) is considered the gold standard endpoint. However, the disadvantage of using OS as the endpoint is that it requires an extended follow-up period. We sought to investigate whether disease-free survival (DFS) is a valid surrogate for OS in trials of adjuvant chemotherapy for gastric cancer. Methods The GASTRIC group initiated a meta-analysis of individual patient data collected in randomized clinical trials comparing adjuvant chemotherapy vs surgery alone for patients with curatively resected gastric cancer. Surrogacy of DFS was assessed through the correlation between the endpoints as well as through the correlation between the treatment effects on the endpoints. External validation of the prediction based on DFS was also evaluated. Results Individual patient data from 14 randomized clinical trials that included a total of 3288 patients were analyzed. The rank correlation coefficient between DFS and OS was 0.974 (95% confidence interval [CI] = 0.971 to 0.976). The coefficient of determination between the treatment effects on DFS and on OS was as high as 0.964 (95% CI = 0.926 to 1.000), and the surrogate threshold effect based on adjusted regression analysis was 0.92. In external validation, the six hazard ratios for OS predicted according to DFS were in very good agreement with those actually observed for OS. Conclusions DFS is an acceptable surrogate for OS in trials of cytotoxic agents for gastric cancer in the adjuvant setting. PMID:24108812
Adjuvant Brachytherapy Removes Survival Disadvantage of Local Disease Extension in Stage IIIC Endometrial Cancer: A SEER Registry Analysis
Rossi, Peter J. Jani, Ashesh B.; Horowitz, Ira R.; Johnstone, Peter A.S.
Purpose: To assess the role of radiotherapy (RT) in women with Stage IIIC endometrial cancer. Methods and Materials: The 17-registry Survival, Epidemiology, and End Results (SEER) database was searched for patients with lymph node-positive non-Stage IV epithelial endometrial cancer diagnosed and treated between 1988 and 1998. Two subgroups were identified: those with organ-confined Stage IIIC endometrial cancer and those with Stage IIIC endometrial cancer with direct extension of the primary tumor. RT was coded as external beam RT (EBRT) or brachytherapy (BT). Observed survival (OS) was reported with a minimum of 5 years of follow-up; the survival curves were compared using the log-rank test. Results: The therapy data revealed 611 women with Stage IIIC endometrial cancer during this period. Of these women, 51% were treated with adjuvant EBRT, 21% with EBRT and BT, and 28% with no additional RT (NAT). Of the 611 patients, 293 had organ-confined Stage IIIC endometrial cancer and 318 patients had Stage IIIC endometrial cancer with direct extension of the primary tumor. The 5-year OS rate for all patients was 40% with NAT, 56% after EBRT, and 64% after EBRT/BT. Adjuvant RT improved survival compared with NAT (p <0.001). In patients with organ-confined Stage IIIC endometrial cancer, the 5-year OS rate was 50% for NAT, 64% for EBRT, and 67% for EBRT/BT. Again, adjuvant RT contributed to improved survival compared with NAT (p = 0.02). In patients with Stage IIIC endometrial cancer and direct tumor extension, the 5-year OS rate was 34% for NAT, 47% for EBRT, and 63% for EBRT/BT. RT improved OS compared with NAT (p <0.001). Also, in this high-risk subgroup, adding BT to EBRT was superior to EBRT alone (p = 0.002). Conclusion: Women with Stage IIIC endometrial cancer receiving adjuvant EBRT and EBRT/BT had improved OS compared with patients receiving NAT. When direct extension of the primary tumor was present, the addition of BT to EBRT was even more beneficial.
Oncolytic viral therapy: targeting cancer stem cells
Smith, Tyrel T; Roth, Justin C; Friedman, Gregory K; Gillespie, G Yancey
Cancer stem cells (CSCs) are defined as rare populations of tumor-initiating cancer cells that are capable of both self-renewal and differentiation. Extensive research is currently underway to develop therapeutics that target CSCs for cancer therapy, due to their critical role in tumorigenesis, as well as their resistance to chemotherapy and radiotherapy. To this end, oncolytic viruses targeting unique CSC markers, signaling pathways, or the pro-tumor CSC niche offer promising potential as CSCs-destroying agents/therapeutics. We provide a summary of existing knowledge on the biology of CSCs, including their markers and their niche thought to comprise the tumor microenvironment, and then we provide a critical analysis of the potential for targeting CSCs with oncolytic viruses, including herpes simplex virus-1, adenovirus, measles virus, reovirus, and vaccinia virus. Specifically, we review current literature regarding first-generation oncolytic viruses with their innate ability to replicate in CSCs, as well as second-generation viruses engineered to enhance the oncolytic effect and CSC-targeting through transgene expression. PMID:24834430
Wnt signaling in cancer stem cells and colon cancer metastasis
Ben-Ze'ev, Avri
Overactivation of Wnt signaling is a hallmark of colorectal cancer (CRC). The Wnt pathway is a key regulator of both the early and the later, more invasive, stages of CRC development. In the normal intestine and colon, Wnt signaling controls the homeostasis of intestinal stem cells (ISCs) that fuel, via proliferation, upward movement of progeny cells from the crypt bottom toward the villus and differentiation into all cell types that constitute the intestine. Studies in recent years suggested that cancer stem cells (CSCs), similar to ISCs of the crypts, consist of a small subpopulation of the tumor and are responsible for the initiation and progression of the disease. Although various ISC signature genes were also identified as CRC markers and some of these genes were even demonstrated to have a direct functional role in CRC development, the origin of CSCs and their contribution to cancer progression is still debated. Here, we describe studies supporting a relationship between Wnt-regulated CSCs and the progression of CRC. PMID:27134739
Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone +/- thalidomide for systemic light-chain amyloidosis: results of a phase II trial.
Cohen, Adam D; Zhou, Ping; Chou, Joanne; Teruya-Feldstein, Julie; Reich, Lilian; Hassoun, Hani; Levine, Beth; Filippa, Daniel A; Riedel, Elyn; Kewalramani, Tarun; Stubblefield, Michael D; Fleisher, Martin; Nimer, Stephen; Comenzo, Raymond L
High-dose melphalan (MEL) with autologous stem cell transplant (SCT) is an effective therapy for systemic AL amyloidosis (AL), but treatment-related mortality (TRM) has historically been high. We performed a phase II trial of risk-adapted SCT followed by adjuvant dexamethasone (dex) and thalidomide (thal) in an attempt to reduce TRM and improve response rates. Patients (n = 45) with newly diagnosed AL involving < or =2 organ systems were assigned to MEL 100, 140, or 200 mg/m(2) with SCT, based on age, renal function and cardiac involvement. Patients with persistent clonal plasma cell disease 3 months post-SCT received 9 months of adjuvant thal/dex (or dex if there was a history of deep vein thrombosis or neuropathy). Organ involvement was kidney (67%), heart (24%), liver/GI (22%) and peripheral nervous system (18%), with 31% having two organs involved. TRM was 4.4%. Thirty-one patients began adjuvant therapy, with 16 (52%) completing 9 months of treatment and 13 (42%) achieving an improvement in haematological response. By intention-to-treat, overall haematological response rate was 71% (36% complete response), with 44% having organ responses. With a median follow-up of 31 months, 2-year survival was 84% (95% confidence interval: 73%, 94%). Risk-adapted SCT with adjuvant thal/dex is feasible and results in low TRM and high haematological and organ response rates in AL patients. PMID:17897298
Neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer: The likelihood of initiation and completion
Eldefrawy, Ahmed; Soloway, Mark S.; Katkoori, Devendar; Singal, Rakesh; Pan, David; Manoharan, Murugesan
Introduction: Chemotherapy was shown to improve survival in patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). The initiation and completion rates for perioperative chemotherapy are variable. Our aim is to compare the likelihood of initiating and completing neoadjuvant (NAC) and adjuvant chemotherapy (AC) in patients who underwent of RC for MIBC. Materials and Methods: We performed a retrospective analysis of patients who underwent RC between 1992 and 2011. NAC was advised for patients with clinical stage ≥T2, hydronephrosis, extensive lymphovascular invasion (LVI), or prostatic stromal invasion. Patients with ≥pT3 or lymph node metastases were considered for AC. Results: A total of 363 patients were considered for perioperative chemotherapy. Among the 141 patients who were offered NAC, 125 (88.6%) initiated NAC. A total of 222 were considered for AC, and 151 (68.0%) initiated AC (P < 0.001). In the NAC group, 118 (83.5%) completed planned number of cycles of chemotherapy and 7 (5.6%) did not complete the planned chemotherapy. In the AC group, 79 (35.5%) completed at least four cycles and 72 (47.3%) could not complete the planned cycles (P < 0.001). Conclusions: Patients with MIBC are more likely to initiate and complete NAC than AC. PMID:23449818
[Administration Order of FEC-DOC in Breast Cancer Adjuvant Chemotherapy Has an Effect on Toxicity].
Miyaki, Toshiko; Tsujimura, Hideki; Nakamura, Rikiya; Okubo, Yoshiyuki; Kumagai, Kyoya; Yamamoto, Naohito
Sequential administration of anthracycline - and taxane-based regimens has been established as standard adjuvant chemotherapy for breast cancer. In our hospital, FEC(5-FU/EPI/CPA) followed by docetaxel therapy has been used for this indication. Recently, we changed the sequence of FEC and docetaxel to reduce skin toxicities during the docetaxel phase. Since the effect of the administration order on efficacy and toxicity is not clear, we retrospectively compared the toxicities and relative dose intensity (RDI) of the administration orders. From January to December of 2012, 46 patients received FEC followed by docetaxel (AT group), while 42 patients underwent docetaxel followed by FEC during the same period in 2013(TA group). The incidence of severe hematological and major non-hematological toxicities was similar in the two groups. There was no significant difference in RDI between groups. However, grade 2 or higher hand-foot syndrome(HFS)during the docetaxel phase, which can be a reason for dose reduction or treatment termination, was more frequently observed in the AT group than in the TA group(54% vs 33%, p<0.05). Our data shows that the risk of HFS was reduced when the taxane was administered first. Interestingly, HFS significantly increased in the winter, regardless of the administration order(p<0.01).
Nanomedicine-mediated cancer stem cell therapy.
Shen, Song; Xia, Jin-Xing; Wang, Jun
Circumstantial evidence suggests that most tumours are heterogeneous and contain a small population of cancer stem cells (CSCs) that exhibit distinctive self-renewal, proliferation and differentiation capabilities, which are believed to play a crucial role in tumour progression, drug resistance, recurrence and metastasis in multiple malignancies. Given that the existence of CSCs is a primary obstacle to cancer therapy, a tremendous amount of effort has been put into the development of anti-CSC strategies, and several potential approaches to kill therapeutically-resistant CSCs have been explored, including inhibiting ATP-binding cassette transporters, blocking essential signalling pathways involved in self-renewal and survival of CSCs, targeting CSCs surface markers and destroying the tumour microenvironment. Meanwhile, an increasing number of therapeutic agents (e.g. small molecule drugs, nucleic acids and antibodies) to selectively target CSCs have been screened or proposed in recent years. Drug delivery technology-based approaches hold great potential for tackling the limitations impeding clinical applications of CSC-specific agents, such as poor water solubility, short circulation time and inconsistent stability. Properly designed nanocarrier-based therapeutic agents (or nanomedicines) offer new possibilities of penetrating CSC niches and significantly increasing therapeutic drug accumulation in CSCs, which are difficult for free drug counterparts. In addition, intelligent nanomedicine holds great promise to overcome pump-mediated multidrug resistance which is driven by ATP and to decrease detrimental effects on normal somatic stem cells. In this review, we summarise the distinctive biological processes related to CSCs to highlight strategies against inherently drug-resistant CSCs. We then focus on some representative examples that give a glimpse into state-of-the-art nanomedicine approaches developed for CSCs elimination. A perspective on innovative therapeutic
Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial
Paterson, Alexander H G; Anderson, Stewart J; Lembersky, Barry C; Fehrenbacher, Louis; Falkson, Carla I; King, Karen M; Weir, Lorna M; Brufsky, Adam M; Dakhil, Shaker; Lad, Thomas; Baez-Diaz, Luis; Gralow, Julie R; Robidoux, André; Perez, Edith A; Zheng, Ping; Geyer, Charles E; Swain, Sandra M; Costantino, Joseph P; Mamounas, Eleftherios P; Wolmark, Norman
Summary Background Bisphosphonates are thought to act through the osteoclast by changing bone microenvironment. Previous findings of adjuvant clodronate trials in different populations with operable breast cancer have been mixed. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-34 aims to ascertain whether oral clodronate can improve outcomes in women with primary breast cancer. Methods NSABP B-34 is a multicentre, randomised, double-blind, placebo-controlled study in 3323 women with stage 1–3 breast cancer. After surgery to remove the tumour, patients were stratified by age, axillary nodes, and oestrogen and progesterone receptor status and randomly assigned in a 1:1 ratio to either oral clodronate 1600 mg daily for 3 years (n=1662) or placebo (1661). The primary endpoint was disease-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00009945. Findings Median follow-up was 90·7 months (IQR 82·7–100·0) and 3311 patients had data for this period. Disease-free survival did not differ between groups (286 events in the clodronate group vs 312 in the placebo group; hazard ratio 0·91, 95% CI 0·78–1·07; p=0·27). Moreover, no differences were recorded for overall survival (0·84, 0·67–1·05; p=0·13), recurrence-free interval (0·83, 0·67–1·04; p=0·10), or bone metastasis-free interval (0·77, 0·55–1·07; p=0·12). Non-bone metastasis-free interval was slightly increased with clodronate (0·74, 0·55–1·00; p=0·047). Analyses in women age 50 years or older on study entry showed benefits of clodronate for recurrence-free interval (0·75, 0·57–0·99; p=0·045), bone metastasis-free interval (0·62, 0·40–0·95; p=0·027), and non-bone metastasis-free interval (0·63, 0·43–0·91; p=0·014), but not for overall survival (0·80, 0·61–1·04, p=0·094). Adherence to treatment at 3 years was 56% for the clodronate group and 60% for the placebo group. Grade 3 or
Counting the costs of treatment: the reproductive and gynaecological consequences of adjuvant therapy in young women with breast cancer.
Friedlander, M; Thewes, B
As the mortality rate from breast cancer decreases, the issues facing breast cancer survivors are becoming increasingly important. Survivors of all ages may face physical and psychosocial consequences of their diagnosis and treatments. However, the long-term fertility and menopause-related side-effects of adjuvant therapy uniquely affect younger premenopausal breast cancer survivors. This article provides an evidence-based overview of the reproductive and gynaecological impact of breast cancer therapy for premenopausal women diagnosed with breast cancer. The physical and psychosocial implications of premature menopause are presented. Strategies for preserving fertility in selected patients are also discussed. Recent clinical trials strongly indicate that premenopausal women with oestrogen receptor positive tumours should receive endocrine therapy. The increased use of endocrine therapies in younger women raises important questions regarding patient information needs and treatment decision-making.
Cancer Stem Cell Biomarker Discovery Using Antibody Array Technology.
Burgess, Rob; Huang, Ruo-Pan
Cancer is a complex disease involving hundreds of pathways and numerous levels of disease progression. In addition, there is a growing body of evidence that the origins and growth rates of specific types of cancer may involve "cancer stem cells," which are defined as "cells within a tumor that possess the capacity to self-renew and to cause the development of heterogeneous lineages of cancer cells that comprise the tumor.(1)" Many types of cancer are now thought to harbor cancer stem cells. These cells themselves are thought to be unique in comparison to other cells types present within the tumor and to exhibit characteristics that allow for the promotion of tumorigenesis and in some cases metastasis. In addition, it is speculated that each type of cancer stem cell exhibits a unique set of molecular and biochemical markers. These markers, alone or in combination, may act as a signature for defining not only the type of cancer but also the progressive state. These biomarkers may also double as signaling entities which act autonomously or upon neighboring cancer stem cells or other cells within the local microenvironment to promote tumorigenesis. This review describes the heterogeneic properties of cancer stem cells and outlines the identification and application of biomarkers and signaling molecules defining these cells as they relate to different forms of cancer. Other examples of biomarkers and signaling molecules expressed by neighboring cells in the local tumor microenvironment are also discussed. In addition, biochemical signatures for cancer stem cell autocrine/paracrine signaling, local site recruitment, tumorigenic potential, and conversion to a stem-like phenotype are described.
Epirubicin-Adsorbed Nanodiamonds Kill Chemoresistant Hepatic Cancer Stem Cells
Chemoresistance is a primary cause of treatment failure in cancer and a common property of tumor-initiating cancer stem cells. Overcoming mechanisms of chemoresistance, particularly in cancer stem cells, can markedly enhance cancer therapy and prevent recurrence and metastasis. This study demonstrates that the delivery of Epirubicin by nanodiamonds is a highly effective nanomedicine-based approach to overcoming chemoresistance in hepatic cancer stem cells. The potent physical adsorption of Epirubicin to nanodiamonds creates a rapidly synthesized and stable nanodiamond–drug complex that promotes endocytic uptake and enhanced tumor cell retention. These attributes mediate the effective killing of both cancer stem cells and noncancer stem cells in vitro and in vivo. Enhanced treatment of both tumor cell populations results in an improved impairment of secondary tumor formation in vivo compared with treatment by unmodified chemotherapeutics. On the basis of these results, nanodiamond-mediated drug delivery may serve as a powerful method for overcoming chemoresistance in cancer stem cells and markedly improving overall treatment against hepatic cancers. PMID:25437772
Therapeutic Effectiveness of Anticancer Phytochemicals on Cancer Stem Cells
Oh, Jisun; Hlatky, Lynn; Jeong, Yong-Seob; Kim, Dohoon
Understanding how to target cancer stem cells (CSCs) may provide helpful insights for the development of therapeutic or preventive strategies against cancers. Dietary phytochemicals with anticancer properties are promising candidates and have selective impact on CSCs. This review summarizes the influence of phytochemicals on heterogeneous cancer cell populations as well as on specific targeting of CSCs. PMID:27376325
Limited Advantages of Intensity-Modulated Radiotherapy Over 3D Conformal Radiation Therapy in the Adjuvant Management of Gastric Cancer
Alani, Shlomo; Soyfer, Viacheslav; Strauss, Natan; Schifter, Dan; Corn, Benjamin W.
Purpose: Although chemoradiotherapy was considered the standard adjuvant treatment for gastric cancer, a recent Phase III trial (Medical Research Council Adjuvant Gastric Infusional Chemotherapy [MAGIC]) did not include radiotherapy in the randomization scheme because it was considered expendable. Given radiotherapy's potential, efforts needed to be made to optimize its use for treating gastric cancer. We assessed whether intensity-modulated radiotherapy (IMRT) could improve upon our published results in patients treated with three-dimensional (3D) conformal therapy. Methods and Materials: Fourteen patients with adenocarcinoma of the stomach were treated with adjuvant chemoradiotherapy using a noncoplanar four-field arrangement. Subsequently, a nine-field IMRT plan was designed using a CMS Xio IMRT version 4.3.3 module. Two IMRT beam arrangements were evaluated: beam arrangement 1 consisted of gantry angles of 0 deg., 53 deg., 107 deg., 158 deg., 204 deg., 255 deg., and 306 deg.. Beam arrangement 2 consisted of gantry angles of 30 deg., 90 deg., 315 deg., and 345 deg.; a gantry angle of 320 deg./couch, 30 deg.; and a gantry angle of 35{sup o}/couch, 312{sup o}. Both the target volume coverage and the dose deposition in adjacent critical organs were assessed in the plans. Dose-volume histograms were generated for the clinical target volume, kidneys, spine, and liver. Results: Comparison of the clinical target volumes revealed satisfactory coverage by the 95% isodose envelope using either IMRT or 3D conformal therapy. However, IMRT was only marginally better than 3D conformal therapy at protecting the spine and kidneys from radiation. Conclusions: IMRT confers only a marginal benefit in the adjuvant treatment of gastric cancer and should be used only in the small subset of patients with risk factors for kidney disease or those with a preexisting nephropathy.
Combined Adjuvant Radiochemotherapy With IMRT/XELOX Improves Outcome With Low Renal Toxicity in Gastric Cancer
Boda-Heggemann, Judit; Hofheinz, Ralf-Dieter; Weiss, Christel; Mennemeyer, Philipp; Mai, Sabine K.; Hermes, Petra; Wertz, Hansjoerg; Post, Stefan; Massner, Bernd; Hieber, Udo; Hochhaus, Andreas; Wenz, Frederik; Lohr, Frank
Objectives: Adjuvant radiochemotherapy improves survival of patients with advanced gastric cancer. We assessed in two sequential cohorts whether improved radiotherapy technique (IMRT) together with intensified chemotherapy improves outcome vs. conventional three-dimensional conformal radiotherapy (3D-CRT) and standard chemotherapy in these patients while maintaining or reducing renal toxicity. Materials and Methods: Sixty consecutive patients treated for gastric cancer either with 3D-CRT (n = 27) and IMRT (n = 33) were evaluated. More than 70% had undergone D2 resection. Although there was a slight imbalance in R0 status between cohorts, N+ status was balanced. Chemotherapy consisted predominantly of 5-fluorouracil/folinic acid (n = 36) in the earlier cohort and mostly of oxaliplatin/capecitabine (XELOX, n = 24) in the later cohort. Primary end points were overall survival (OS), disease-free survival (DFS), and renal toxicity based on creatinine levels. Results: Median follow-up (FU) of all patients in the 3D-CRT group was 18 months and in the IMRT group 22 months (median FU of surviving patients 67 months in the 3D-CRT group and 25 months in the IMRT group). Overall median survival (and DFS) were 18 (13) months in the 3D-CRT group and both not reached in the IMRT group (p = 0.0492 and 0.0216). Actuarial 2-year survival was 37% and 67% in the 3D-CRT and IMRT groups, respectively. No late renal toxicity >Grade 2 (LENT-SOMA scale) was observed in either cohort. Conclusion: When comparing sequentially treated patient cohorts with similar characteristics, OS and DFS improved with the use of IMRT and intensified chemotherapy without signs of increased renal toxicity.
Identification of distinct fatigue trajectories in patients with breast cancer undergoing adjuvant chemotherapy
Junghaenel, Doerte U.; Cohen, Jules; Schneider, Stefan; Neerukonda, Anu R.; Broderick, Joan E.
Purpose The goal of this study was to characterize changes in daily fatigue in women undergoing chemotherapy for breast cancer. We examined whether there are subgroups of patients with distinct fatigue trajectories and explored potential psychosocial and biomedical predictors of these subgroups. Methods Participants were 77 women with breast cancer receiving adjuvant chemotherapy with AC-T (2-week cycle) and TC or TCH (3-week cycle) regimens. They completed 28 daily ratings online using an adapted version of the Patient-Reported Outcomes Measurement Information System (PROMIS®) fatigue instrument. Results Both regimens followed an "inverted-U shaped" fatigue pattern over approximately 2 weeks. Growth mixture modeling identified three patient subgroups with distinct trajectories. Fatigue scores in the "low fatigue" group (23%) increased following the infusion and quickly abated. The "transient fatigue" (27%) group had a very pronounced increase. Patients in the "high fatigue" (50%) group reported consistently elevated fatigue with a relatively small increase. Demographic and medical variables were not associated with fatigue trajectory. Patients in the "high fatigue" group reported significantly poorer physical, emotional, and social functioning, poorer general health, and more depressed mood than patients in the "low fatigue" group. The "transient fatigue" group reported significantly better physical and social functioning than the "high fatigue" group, but emotional distress and depression similar to the "high fatigue" group. Conclusions The identification of patient subgroups with distinct fatigue trajectories during chemotherapy is an essential step for developing preventative strategies and tailored interventions. Our results suggest that different trajectories are associated with patients' psychosocial and general health. PMID:25876159
Phase II study of neo-adjuvant chemotherapy for locally advanced gastric cancer
Chang, Alex Yuang-Chi; Foo, Kian Fong; Koo, Wen-Hsin; Ong, Simon; So, Jimmy; Tan, Daniel; Lim, Khong Hee
Background Neoadjuvant chemotherapy improves survival of locally advanced gastric cancer patients. However, benefit is limited and the best regimen remains controversial. Objectives Our primary objective of this prospective, multicenter phase 2 study was to evaluate the pathological complete response rate (PCR) with 2 cycles of docetaxel and capecitabine. Methods To be eligible, patients had to have histologically documented gastric cancer, a ECOG performance status 0 or 1, T3or4 Nany M0 staging after oesophagogastroduodenoscopy (OGD), endoscopic ultrasound (EUS), CT scan of thorax and abdomen, and negative laparoscopic examination and peritoneal washing. Eligible patients received two cycles of intravenous docetaxel 60 mg/m2 on day 1 and oral capecitabine 900 mg/m2 two times per day from day 1 to day 14 every 3 weeks. We evaluated the response by CT scan and EUS. The patients underwent curative resection with D2 lymphadenectomy subsequently. Results 18 patients were enrolled in the study: 66% were male and the median age was 60 years. 17 patients had T3 disease at diagnosis. There was no pCR noted. 4 patients had a partial response of 22% (95% CI: 7–42%), 8 patients had stable disease and 3 patients had disease progression. The median survival was 17.1 months with 3 long-term survivors after at least 3 years of follow-up. The treatment was well tolerated with neutropenia being the most common toxicity. We observed 22% grade III and 33% grade IV neutropenia, but no neutropenic fever or death was observed from chemotherapy. Conclusion Neo-adjuvant chemotherapy with docetaxel and capecitabine has limited activity against GC. More effective treatment regimens are needed urgently. Trial registration number NCT00414271.
Phase II study of neo-adjuvant chemotherapy for locally advanced gastric cancer
Chang, Alex Yuang-Chi; Foo, Kian Fong; Koo, Wen-Hsin; Ong, Simon; So, Jimmy; Tan, Daniel; Lim, Khong Hee
Background Neoadjuvant chemotherapy improves survival of locally advanced gastric cancer patients. However, benefit is limited and the best regimen remains controversial. Objectives Our primary objective of this prospective, multicenter phase 2 study was to evaluate the pathological complete response rate (PCR) with 2 cycles of docetaxel and capecitabine. Methods To be eligible, patients had to have histologically documented gastric cancer, a ECOG performance status 0 or 1, T3or4 Nany M0 staging after oesophagogastroduodenoscopy (OGD), endoscopic ultrasound (EUS), CT scan of thorax and abdomen, and negative laparoscopic examination and peritoneal washing. Eligible patients received two cycles of intravenous docetaxel 60 mg/m2 on day 1 and oral capecitabine 900 mg/m2 two times per day from day 1 to day 14 every 3 weeks. We evaluated the response by CT scan and EUS. The patients underwent curative resection with D2 lymphadenectomy subsequently. Results 18 patients were enrolled in the study: 66% were male and the median age was 60 years. 17 patients had T3 disease at diagnosis. There was no pCR noted. 4 patients had a partial response of 22% (95% CI: 7–42%), 8 patients had stable disease and 3 patients had disease progression. The median survival was 17.1 months with 3 long-term survivors after at least 3 years of follow-up. The treatment was well tolerated with neutropenia being the most common toxicity. We observed 22% grade III and 33% grade IV neutropenia, but no neutropenic fever or death was observed from chemotherapy. Conclusion Neo-adjuvant chemotherapy with docetaxel and capecitabine has limited activity against GC. More effective treatment regimens are needed urgently. Trial registration number NCT00414271. PMID:27648294
Stacking the DEK: From chromatin topology to cancer stem cells
Privette Vinnedge, Lisa M.; Kappes, Ferdinand; Nassar, Nicolas; Wells, Susanne I.
Stem cells are essential for development and tissue maintenance and display molecular markers and functions distinct from those of differentiated cell types in a given tissue. Malignant cells that exhibit stem cell-like activities have been detected in many types of cancers and have been implicated in cancer recurrence and drug resistance. Normal stem cells and cancer stem cells have striking commonalities, including shared cell surface markers and signal transduction pathways responsible for regulating quiescence vs. proliferation, self-renewal, pluripotency and differentiation. As the search continues for markers that distinguish between stem cells, progenitor cells and cancer stem cells, growing evidence suggests that a unique chromatin-associated protein called DEK may confer stem cell-like qualities. Here, we briefly describe current knowledge regarding stem and progenitor cells. We then focus on new findings that implicate DEK as a regulator of stem and progenitor cell qualities, potentially through its unusual functions in the regulation of local or global chromatin organization. PMID:23255114
Breast cancer follow-up strategies in randomized phase III adjuvant clinical trials: a systematic review
The effectiveness of different breast cancer follow-up procedures to decrease breast cancer mortality are still an object of debate, even if intensive follow-up by imaging modalities is not recommended by international guidelines since 1997. We conducted a systematic review of surveillance procedures utilized, in the last ten years, in phase III randomized trials (RCTs) of adjuvant treatments in early stage breast cancer with disease free survival as primary endpoint of the study, in order to verify if a similar variance exists in the scientific world. Follow-up modalities were reported in 66 RCTs, and among them, minimal and intensive approaches were equally represented, each being followed by 33 (50%) trials. The minimal surveillance regimen is preferred by international and North American RCTs (P = 0.001) and by trials involving more than one country (P = 0.004), with no relationship with the number of participating centers (P = 0.173), with pharmaceutical industry sponsorship (P = 0.80) and with trials enrolling > 1000 patients (P = 0.14). At multivariate regression analysis, only geographic location of the trial was predictive for a distinct follow-up methodology (P = 0.008): Western European (P = 0.004) and East Asian studies (P = 0.010) use intensive follow-up procedures with a significantly higher frequency than international RCTs, while no differences have been detected between North American and international RCTs. Stratifying the studies according to the date of beginning of patients enrollment, before or after 1998, in more recent RCTs the minimal approach is more frequently followed by international and North American RCTs (P = 0.01), by trials involving more than one country (P = 0.01) and with more than 50 participating centers (P = 0.02). It would be highly desirable that in the near future breast cancer follow-up procedures will be homogeneous in RCTs and everyday clinical settings. PMID:24438135
Stem Cell Based Gene Therapy in Prostate Cancer
Lee, Hong Jun; Song, Yun Seob
Current prostate cancer treatment, especially hormone refractory cancer, may create profound iatrogenic outcomes because of the adverse effects of cytotoxic agents. Suicide gene therapy has been investigated for the substitute modality for current chemotherapy because it enables the treatment targeting the cancer cells. However the classic suicide gene therapy has several profound side effects, including immune-compromised due to viral vector. Recently, stem cells have been regarded as a new upgraded cellular vehicle or vector because of its homing effects. Suicide gene therapy using genetically engineered mesenchymal stem cells or neural stem cells has the advantage of being safe, because prodrug administration not only eliminates tumor cells but consequently kills the more resistant therapeutic stem cells as well. The attractiveness of prodrug cancer gene therapy by stem cells targeted to tumors lies in activating the prodrug directly within the tumor mass, thus avoiding systemic toxicity. Therapeutic achievements using stem cells in prostate cancer include the cytosine deaminase/5-fluorocytosine prodrug system, herpes simplex virus thymidine kinase/ganciclovir, carboxyl esterase/CPT11, and interferon-beta. The aim of this study is to review the stem cell therapy in prostate cancer including its proven mechanisms and also limitations. PMID:25121103
Cancer stem cell: fundamental experimental pathological concepts and updates.
Islam, Farhadul; Qiao, Bin; Smith, Robert A; Gopalan, Vinod; Lam, Alfred K-Y
Cancer stem cells (CSCs) are a subset of cancer cells which play a key role in predicting the biological aggressiveness of cancer due to its ability of self-renewal and multi-lineage differentiation (stemness). The CSC model is a dynamic one with a functional subpopulation of cancer cells rather than a stable cell population responsible for tumour regeneration. Hypotheses regarding the origins of CSCs include (1) malignant transformation of normal stem cells; (2) mature cancer cell de-differentiation with epithelial-mesenchymal transition and (3) induced pluripotent cancer cells. Surprisingly, the cancer stem cell hypothesis originated in the late nineteenth century and the existence of haematopoietic stem cells was demonstrated a century later, demonstrating that the concept was possible. In the last decade, CSCs have been identified and isolated in different cancers. The hallmark traits of CSCs include their heterogeneity, interaction with microenvironments and plasticity. Understanding these basic concepts of CSCs is important for translational applications using CSCs in the management of patients with cancer. PMID:25659759
Isolation of Cancer Stem Cells From Human Prostate Cancer Samples
Vidal, Samuel J.; Quinn, S. Aidan; de la Iglesia-Vicente, Janis; Bonal, Dennis M.; Rodriguez-Bravo, Veronica; Firpo-Betancourt, Adolfo; Cordon-Cardo, Carlos; Domingo-Domenech, Josep
The cancer stem cell (CSC) model has been considerably revisited over the last two decades. During this time CSCs have been identified and directly isolated from human tissues and serially propagated in immunodeficient mice, typically through antibody labeling of subpopulations of cells and fractionation by flow cytometry. However, the unique clinical features of prostate cancer have considerably limited the study of prostate CSCs from fresh human tumor samples. We recently reported the isolation of prostate CSCs directly from human tissues by virtue of their HLA class I (HLAI)-negative phenotype. Prostate cancer cells are harvested from surgical specimens and mechanically dissociated. A cell suspension is generated and labeled with fluorescently conjugated HLAI and stromal antibodies. Subpopulations of HLAI-negative cells are finally isolated using a flow cytometer. The principal limitation of this protocol is the frequently microscopic and multifocal nature of primary cancer in prostatectomy specimens. Nonetheless, isolated live prostate CSCs are suitable for molecular characterization and functional validation by transplantation in immunodeficient mice. PMID:24686446
Phase 2 Study of Erlotinib Combined With Adjuvant Chemoradiation and Chemotherapy in Patients With Resectable Pancreatic Cancer
Herman, Joseph M.; Fan, Katherine Y.; Wild, Aaron T.; Hacker-Prietz, Amy; Wood, Laura D.; Blackford, Amanda L.; Ellsworth, Susannah; Zheng, Lei; Le, Dung T.; De Jesus-Acosta, Ana; Hidalgo, Manuel; Donehower, Ross C.; Schulick, Richard D.; Edil, Barish H.; Choti, Michael A.; Hruban, Ralph H.; and others
Purpose: Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine-erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of erlotinib in combination with adjuvant chemoradiation and chemotherapy for resected PDAC. Methods and Materials: Forty-eight patients with resected PDAC received adjuvant erlotinib (100 mg daily) and capecitabine (800 mg/m{sup 2} twice daily Monday-Friday) concurrently with intensity modulated radiation therapy (IMRT), 50.4 Gy over 28 fractions followed by 4 cycles of gemcitabine (1000 mg/m{sup 2} on days 1, 8, and 15 every 28 days) and erlotinib (100 mg daily). The primary endpoint was recurrence-free survival (RFS). Results: The median follow-up time was 18.2 months (interquartile range, 13.8-27.1). Lymph nodes were positive in 85% of patients, and margins were positive in 17%. The median RFS was 15.6 months (95% confidence interval [CI], 13.4-17.9), and the median overall survival (OS) was 24.4 months (95% CI, 18.9-29.7). Multivariate analysis with adjustment for known prognostic factors showed that tumor diameter >3 cm was predictive for inferior RFS (hazard ratio, 4.01; P=.001) and OS (HR, 4.98; P=.02), and the development of dermatitis was associated with improved RFS (HR, 0.27; P=.009). During CRT and post-CRT chemotherapy, the rates of grade 3/4 toxicity were 31%/2% and 35%/8%, respectively. Conclusion: Erlotinib can be safely administered with adjuvant IMRT-based CRT and chemotherapy. The efficacy of this regimen appears comparable to that of existing adjuvant regimens. Radiation Therapy Oncology Group 0848 will ultimately determine whether erlotinib produces a survival benefit in patients with resected pancreatic cancer.
Factors Influencing Clinicians' Choice of Adjuvant S-1 versus Capecitabine plus Oxaliplatin after Curative Gastrectomy in Patients with Gastric Cancer
Lee, Ha Yeon; Hwang, In Gyu; Park, Song-Ee; Kim, Moon Jin; Park, Se Hoon; Kang, Jung Hun; Kim, Young Saing; Oh, Sung Yong; Won, Young-Woong; Lee, Soon Il; Ji, Jun Ho; Chi, Kyong-Choun
Purpose: Two recent randomized, phase III trials in Asia (ACTS-GC and CLASSIC) documented the survival benefit of postoperative chemotherapy after D2 lymph node dissection in patients with gastric cancer. We sought to determine what factors influenced clinicians' choices of either S-1 or capecitabine plus oxaliplatin (CAPOX) as adjuvant therapy after curative D2 gastrectomy. Materials and Methods: We retrospectively reviewed the clinicopathologic factors and adjuvant treatments for 435 patients from nine centers in Korea who were treated with either S-1 or CAPOX adjuvant chemotherapy after undergoing curative D2 gastrectomy between January 2013 and July 2014. Results: Of the 435 patients, 204 (46.9%) were treated with S-1 and 231 (53.1%) were treated with CAPOX. The median age at diagnosis was 61 years (range, 30-88). CAPOX was prescribed more often for patients who were 65 years of age or younger than for patients who were age 65 or older (77.1% vs. 22.9%, P<0.0001). Of the patients in stage II, 121 (60.8%) were treated with S-1 and 78 (39.2%) were given CAPOX; however, of those in stage III, 83 (35.2%) received S-1 and 153 (64.8%) were treated with CAPOX (P<0.0001). Conclusions: Clinicians only preferred CAPOX for younger patients with stage III gastric cancer after curative D2 gastrectomy. However, for elderly patients, clinicians more chose S-1 regardless of the stage.
Use of Cancer Stem Cells to Investigate the Pathogenesis of Colitis-associated Cancer
Davies, Julie M.; Santaolalla, Rebeca
Abstract: Colitis-associated cancer (CAC) can develop in patients with inflammatory bowel disease with long-term uncontrolled inflammation. The mutational history and tumor microenvironment observed in CAC patients is distinct from that observed in sporadic colon cancer and suggests a different etiology. Recently, much attention has been focused on understanding the cellular origin of cancer and the cancer stem cells, which is key to growth and progression. Cancer stem cells are often chemo-resistant making them attractive targets for improving patient outcomes. New techniques have rapidly been evolving allowing for a better understanding of the normal intestinal stem cell function and behavior in the niche. Use of these new technologies will be crucial to understanding cancer stem cells in both sporadic and CAC. In this review, we will explore emerging methods related to the study of normal and cancer stem cells in the intestine, and examine potential avenues of investigation and application to understanding the pathogenesis of CAC. PMID:26963566
Effects of physical exercise during adjuvant breast cancer treatment on physical and psychosocial dimensions of cancer-related fatigue: A meta-analysis.
van Vulpen, Jonna K; Peeters, Petra H M; Velthuis, Miranda J; van der Wall, Elsken; May, Anne M
Cancer-related fatigue has a multidimensional nature and complaints typically increase during adjuvant treatment for breast cancer. Physical exercise might prevent or reduce cancer-related fatigue. So far, no meta-analysis has investigated the effects of physical exercise on different dimensions of fatigue. The aim of the present meta-analysis was to investigate the effects of physical exercise during adjuvant breast cancer treatment on physical and psychosocial dimensions of fatigue. We performed a systematic literature search in PubMed, Embase and the Cochrane Library in June 2015. Randomised controlled trials reporting the effects of physical exercise during adjuvant breast cancer treatment on different dimensions of fatigue were included. Pooled effects of 6 exercise programmes (including 784 patients) showed significant beneficial exercise effects on general fatigue (ES: -0.22, 95% CI -0.38; -0.05) and physical fatigue (ES: -0.35, 95% CI -0.49; -0.21). Effects on fatigue subscales 'reduced activity' (ES: -0.22, 95% CI -0.38; -0.05) and 'reduced motivation' (ES: -0.18, 95% CI -0.35; -0.01) were also in favour of physical exercise. No effects were found on cognitive and affective fatigue. Including only the supervised exercise programmes (n=4 studies), slightly larger pooled effect estimates were found on general fatigue (ES: -0.25, 95% CI -0.47; -0.04) and physical fatigue (-0.39, 95% CI -0.56; -0.23). In conclusion, physical exercise during adjuvant breast cancer treatment has beneficial effects on general fatigue, physical fatigue, 'reduced activity' and 'reduced motivation', but did not show effects on cognitive and affective fatigue. Largest effect sizes are found for physical fatigue, suggesting that this is the fatigue dimension most sensitive to physical exercise.
Modeling head and neck cancer stem cell-mediated tumorigenesis.
Pearson, Alexander T; Jackson, Trachette L; Nör, Jacques E
A large body of literature has emerged supporting the importance of cancer stem cells (CSCs) in the pathogenesis of head and neck cancers. CSCs are a subpopulation of cells within a tumor that share the properties of self-renewal and multipotency with stem cells from normal tissue. Their functional relevance to the pathobiology of cancer arises from the unique properties of tumorigenicity, chemotherapy resistance, and their ability to metastasize and invade distant tissues. Several molecular profiles have been used to discriminate a stem cell from a non-stem cell. CSCs can be grown for study and further enriched using a number of in vitro techniques. An evolving option for translational research is the use of mathematical and computational models to describe the role of CSCs in complex tumor environments. This review is focused discussing the evidence emerging from modeling approaches that have clarified the impact of CSCs to the biology of cancer. PMID:27151511
Liver cancer stem cell markers: Progression and therapeutic implications.
Sun, Jing-Hui; Luo, Qing; Liu, Ling-Ling; Song, Guan-Bin
Cancer stem cells (CSCs) are a small subpopulation in cancer, have been proposed to be cancer-initiating cells, and have been shown to be responsible for chemotherapy resistance and cancer recurrence. The identification of CSC subpopulations inside a tumor presents a new understanding of cancer development because it implies that tumors can only be eradicated by targeting CSCs. Although advances in liver cancer detection and treatment have increased the possibility of curing the disease at early stages, unfortunately, most patients will relapse and succumb to their disease. Strategies aimed at efficiently targeting liver CSCs are becoming important for monitoring the progress of liver cancer therapy and for evaluating new therapeutic approaches. Herein, we provide a critical discussion of biological markers described in the literature regarding liver cancer stem cells and the potential of these markers to serve as therapeutic targets. PMID:27053846
Liver cancer stem cell markers: Progression and therapeutic implications
Sun, Jing-Hui; Luo, Qing; Liu, Ling-Ling; Song, Guan-Bin
Cancer stem cells (CSCs) are a small subpopulation in cancer, have been proposed to be cancer-initiating cells, and have been shown to be responsible for chemotherapy resistance and cancer recurrence. The identification of CSC subpopulations inside a tumor presents a new understanding of cancer development because it implies that tumors can only be eradicated by targeting CSCs. Although advances in liver cancer detection and treatment have increased the possibility of curing the disease at early stages, unfortunately, most patients will relapse and succumb to their disease. Strategies aimed at efficiently targeting liver CSCs are becoming important for monitoring the progress of liver cancer therapy and for evaluating new therapeutic approaches. Herein, we provide a critical discussion of biological markers described in the literature regarding liver cancer stem cells and the potential of these markers to serve as therapeutic targets. PMID:27053846
The Development of a Mindfulness-Based Music Therapy (MBMT) Program for Women Receiving Adjuvant Chemotherapy for Breast Cancer.
Lesiuk, Teresa
Problems with attention and symptom distress are common clinical features reported by women who receive adjuvant chemotherapy for breast cancer. Mindfulness practice significantly improves attention and mindfulness programs significantly reduce symptom distress in patients with cancer, and, more specifically, in women with breast cancer. Recently, a pilot investigation of a music therapy program, built on core attitudes of mindfulness practice, reported significant benefits of enhanced attention and decreased negative mood and fatigue in women with breast cancer. This paper delineates the design and development of the mindfulness-based music therapy (MBMT) program implemented in that pilot study and includes clients' narrative journal responses. Conclusions and recommendations, including recommendation for further exploration of the function of music in mindfulness practice are provided. PMID:27517966
The Development of a Mindfulness-Based Music Therapy (MBMT) Program for Women Receiving Adjuvant Chemotherapy for Breast Cancer
Lesiuk, Teresa
Problems with attention and symptom distress are common clinical features reported by women who receive adjuvant chemotherapy for breast cancer. Mindfulness practice significantly improves attention and mindfulness programs significantly reduce symptom distress in patients with cancer, and, more specifically, in women with breast cancer. Recently, a pilot investigation of a music therapy program, built on core attitudes of mindfulness practice, reported significant benefits of enhanced attention and decreased negative mood and fatigue in women with breast cancer. This paper delineates the design and development of the mindfulness-based music therapy (MBMT) program implemented in that pilot study and includes clients' narrative journal responses. Conclusions and recommendations, including recommendation for further exploration of the function of music in mindfulness practice are provided. PMID:27517966
Regulating cancer stem cells the miR way.
Peter, Marcus E
A recent study in Nature Cell Biology, Wellner et al. (2009) identifies ZEB1, a known promoter of tumor invasion, as a negative regulator of miRNA clusters that target stem cell factors. These findings provide new insight into the network of transcription factors and miRNAs that regulate cancer stem cells.
Translational potential of cancer stem cells: A review of the detection of cancer stem cells and their roles in cancer recurrence and cancer treatment.
Islam, Farhadul; Gopalan, Vinod; Smith, Robert A; Lam, Alfred K-Y
Cancer stem cells (CSCs) are a subpopulation of cancer cells with many clinical implications in most cancer types. One important clinical implication of CSCs is their role in cancer metastases, as reflected by their ability to initiate and drive micro and macro-metastases. The other important contributing factor for CSCs in cancer management is their function in causing treatment resistance and recurrence in cancer via their activation of different signalling pathways such as Notch, Wnt/β-catenin, TGF-β, Hedgehog, PI3K/Akt/mTOR and JAK/STAT pathways. Thus, many different therapeutic approaches are being tested for prevention and treatment of cancer recurrence. These may include treatment strategies targeting altered genetic signalling pathways by blocking specific cell surface molecules, altering the cancer microenvironments that nurture cancer stem cells, inducing differentiation of CSCs, immunotherapy based on CSCs associated antigens, exploiting metabolites to kill CSCs, and designing small interfering RNA/DNA molecules that especially target CSCs. Because of the huge potential of these approaches to improve cancer management, it is important to identify and isolate cancer stem cells for precise study and application of prior the research on their role in cancer. Commonly used methodologies for detection and isolation of CSCs include functional, image-based, molecular, cytological sorting and filtration approaches, the use of different surface markers and xenotransplantation. Overall, given their significance in cancer biology, refining the isolation and targeting of CSCs will play an important role in future management of cancer.
Race and Insurance Differences in the Receipt of Adjuvant Chemotherapy Among Patients With Stage III Colon Cancer
Murphy, Caitlin C.; Harlan, Linda C.; Warren, Joan L.; Geiger, Ann M.
Purpose Although the incidence and mortality of colon cancer in the United States has declined over the past two decades, blacks have worse outcomes than whites. Variations in treatment may contribute to mortality differentials. Methods Patients diagnosed with stage III colon cancer were randomly sampled from the SEER program from the years 1990, 1991, 1995, 2000, 2005, and 2010. Patients were categorized as non-Hispanic white (n = 835) or black (n = 384). Treatment data were obtained from a review of the medical records, and these data were verified through contact with the original treating physicians. Log-binomial regression models were used to estimate the association between race and receipt of adjuvant chemotherapy. Effect modification by insurance was assessed with use of single referent models. Results Receipt of adjuvant chemotherapy among both white and black patients increased from the period encompassing the years 1990 and 1991 (white, 58%; black, 45%) to the year 2005 (white, 72%; black, 71%) and then decreased in the year 2010 (white, 66%; black, 57%). There were marked racial disparities in the time period of 1990 to 1991 and again in 2010, with black patients less likely to receive adjuvant chemotherapy as compared with white patients (risk ratio [RR], .82; 95% CI, .72 to .93). For black patients, receipt of adjuvant chemotherapy did not differ across insurance categories (RR for private insurance, .80; 95% CI, .69 to .93; RR for Medicare, .84; 95% CI, .69 to 1.02; and RR for Medicaid, .84; 95% CI, .69 to 1.02), although a larger proportion had Medicaid in all years of the study as compared with white patients. Conclusion The chemotherapy differential narrowed after the time period of 1990 to 1991, but our findings suggest that the disparity reemerged in 2010. Recent decreases in chemotherapy use may be due, in part, to the economic downturn and an increase in Medicaid coverage. PMID:26150445
A hard pill to swallow: a qualitative study of women's experiences of adjuvant endocrine therapy for breast cancer
Harrow, Alison; Dryden, Ruth; McCowan, Colin; Radley, Andrew; Parsons, Mark; Thompson, Alastair M; Wells, Mary
Objective To explore women's experiences of taking adjuvant endocrine therapy as a treatment for breast cancer and how their beliefs about the purpose of the medication, side effects experienced and interactions with health professionals might influence adherence. Design Qualitative study using semistructured, one-to-one interviews. Setting 2 hospitals from a single health board in Scotland. Participants 30 women who had been prescribed tamoxifen or aromatase inhibitors (anastrozole or letrozole) and had been taking this medication for 1–5 years. Results Women clearly wished to take their adjuvant endocrine therapy medication as prescribed, believing that it offered them protection against breast cancer recurrence. However, some women missed tablets and did not recognise that this could reduce the efficacy of the treatment. Women did not perceive that healthcare professionals were routinely or systematically monitoring their adherence. Side effects were common and impacted greatly on the women's quality of life but did not always cause women to stop taking their medication, or to seek advice about reducing the side effects they experienced. Few were offered the opportunity to discuss the impact of side effects or the potential options available. Conclusions Although most women in this study took adjuvant endocrine therapy as prescribed, many endured a range of side effects, often without seeking help. Advice, support and monitoring for adherence are not routinely offered in conventional follow-up settings. Women deserve more opportunity to discuss the pros, cons and impact of long-term adjuvant endocrine therapy. New service models are needed to support adherence, enhance quality of life and ultimately improve survival. These should ideally be community based, in order to promote self-management in the longer term. PMID:24928595
Gemcitabine-Based Combination Chemotherapy Followed by Radiation With Capecitabine as Adjuvant Therapy for Resected Pancreas Cancer
Desai, Sameer; Ben-Josef, Edgar; Griffith, Kent A.; Simeone, Diane; Greenson, Joel K.; Francis, Isaac R.; Hampton, Janet; Colletti, Lisa; Chang, Alfred E.; Lawrence, Theodore S.; Zalupski, Mark M.
Purpose: To report outcomes for patients with resected pancreas cancer treated with an adjuvant regimen consisting of gemcitabine-based combination chemotherapy followed by capecitabine and radiation. Patients and Methods: We performed a retrospective review of a series of patients treated at a single institution with a common postoperative adjuvant program. Between January 2002 and August 2006, 43 resected pancreas cancer patients were offered treatment consisting of 4, 21-day cycles of gemcitabine 1 g/m{sup 2} intravenously over 30 min on Days 1 and 8, with either cisplatin 35 mg/m{sup 2} intravenously on Days 1 and 8 or capecitabine 1500 mg/m{sup 2} orally in divided doses on Days 1-14. After completion of combination chemotherapy, patients received a course of radiotherapy (54 Gy) with concurrent capecitabine (1330 mg/m{sup 2} orally in divided doses) day 1 to treatment completion. Results: Forty-one patients were treated. Median progression-free survival for the entire group was 21.7 months (95% confidence interval 13.9-34.5 months), and median overall survival was 45.9 months. In multivariate analysis a postoperative CA 19-9 level of >=180 U/mL predicted relapse and death. Toxicity was mild, with only two hospitalizations during adjuvant therapy. Conclusions: A postoperative adjuvant program using combination chemotherapy with gemcitabine and either cisplatin or capecitabine followed by radiotherapy with capecitabine is tolerable and efficacious and should be considered for Phase III testing in this group of patients.
Is Duodenal Invasion a Relevant Prognosticator in Patients Undergoing Adjuvant Chemoradiotherapy for Distal Common Bile Duct Cancer?
Kim, Kyubo; Chie, Eui Kyu; Jang, Jin-Young; Kim, Sun Whe
Purpose: To analyze the outcome of adjuvant chemoradiotherapy for patients with distal common bile duct (CBD) cancer who underwent curative surgery, and to identify the prognostic factors for these patients. Methods and Materials: Between January 1991 and December 2002, 38 patients with adenocarcinoma of the distal CBD underwent curative resection followed by adjuvant chemoradiotherapy. There were 27 men and 11 women, and the median age was 60 years (range, 34-73). Adjuvant radiotherapy was delivered to the tumor bed and regional lymph nodes up to 40 Gy at 2 Gy/fraction with a 2-week planned rest. Intravenous 5-fluorouracil (500mg/m{sup 2}/day) was given on day 1 to day 3 of each split course. The median follow-up period was 39 months. Results: The 5-year overall survival rate of all patients was 49.1%. On univariate analysis, only histologic differentiation (p = 0.0005) was associated with overall survival. Tumor size ({<=}2cm vs. >2cm) had a marginally significant impact on the treatment outcome (p = 0.0624). However, there was no difference in overall survival rates between T3 and T4 tumors (p = 0.6189), for which the main determinants were pancreatic and duodenal invasion, respectively. On multivariate analysis, histologic differentiation (p = 0.0092) and tumor size (p = 0.0046) were independent risk factors for overall survival. Conclusions: Long-term survival can be expected in patients with distal CBD cancer undergoing curative surgery and adjuvant chemoradiotherapy. Histologic differentiation and tumor size were significant prognostic factors predicting overall survival, whereas duodenal invasion was not. This finding suggests the need for further refinement in tumor staging.
Retreating recurrent breast cancer with the same CMF-containing regimen used as adjuvant therapy. The International Breast Cancer Study Group.
Castiglione-Gertsch, M; Tattersall, M; Hacking, A; Goldhirsch, A; Gudgeon, A; Gelber, R D; Lindtner, J; Coates, A; Collins, J; Isley, M; Senn, H J; Rudenstam, C M
Breast cancer metastases appearing soon after adjuvant chemotherapy (within 12 months of its completion) are usually resistant to retreatment with the same cytotoxic agents, while relapses occurring later (beyond 12 months) regress when rechallenged with the same agents, showing similar response rates observed in non-pretreated patients with advanced disease. The International Breast Cancer Study Group (IBCSG) prospectively explored the efficacy of retreatment for patients upon relapse using the same therapy administered during the adjuvant programme. 87 patients previously treated with an adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil) combination chemotherapy (with or without the addition of low-dose prednisone and tamoxifen), who had measurable first breast cancer relapse, usually after at least 6 months of completion of the adjuvant treatment, were treated with CMF. Pretreatment consisted of 1-3 CMF courses in 27 patients and 4 or more courses in 60 patients. 17 patients were retreated with additional tamoxifen or had tamoxifen stopped at relapse. The data of these patients are shown separately. 47 of the 86 fully evaluable patients (55%) had an objective response, which was complete in 25 (29%). The dominant metastatic type and the number of involved sites were the most important factors influencing response to retreatment. Patients with soft tissue metastases had a high response rate (36/52, 69%) compared with those who had visceral involvement (9/24, 38%) or those with bony disease (2/10, 20%) (P = 0.002). In conclusion, response rates to retreatment with CMF were similar to those expected in a non-pretreated population. The patterns of relapse and the number of metastatic sites were the most important factors predicting response to retreatment, while treatment-free interval (usually longer than 6 months due to the study design) did not influence response rates. This study supports the hypothetic effectiveness of late reintroduction of adjuvant
Is distance to chemotherapy an obstacle to adjuvant care among the N.C. Medicaid—enrolled colon cancer patients?
Song, Eunyoung; Klepin, Heidi D.; Foley, Kristie L.
Background Adjuvant chemotherapy for colon cancer has been linked to patient and provider characteristics but little is known about whether distance to chemotherapy providers constitutes an obstacle to chemotherapy. Methods A total of 1,184 Medicaid patients diagnosed with colon cancer in North Carolina in 1999–2002 comprised the sample. Data from the N.C. Central Cancer Registry, N.C. Medicaid Claims, American Hospital Directory and US Census were merged. Logistic regression models were used to estimate the association between chemotherapy receipt and the distance to nearest chemotherapy provider. Results Compared to the referent group of SEER-staged II (local) cancer patients living less than 2 miles from the nearest chemotherapy provider, the odds of receiving chemotherapy fell as the distance to the nearest provider increased. The odds ratio (OR) for those living ≥5 to <15 miles away was 0.13 [95% confidence intervals (CI), 0.04–0.39], and OR for those living ≥15 miles away was 0.06 (95% CI, 0.01–0.52). Patients diagnosed with regional, SEER-staged III (regional) cancer were less likely to receive chemotherapy if they lived in rural areas more than 20 miles away from the nearest provider (OR =0.08; 95% CI, 0.01–0.72). However, we found no evidence of association between chemotherapy receipt and distance to the nearest provider for regional cancer patients living in urban areas and those living in rural areas within 20 miles from the nearest chemotherapy provider. Conclusions Distance to provider may be an obstacle to chemotherapy for some groups of low-income colon cancer patients. Relieving travel burdens of rural patients living far from providers may help Medicaid increase guideline-consistent adjuvant care for regional cancer patients. PMID:27284464
An update on the biology of cancer stem cells in breast cancer.
García Bueno, José María; Ocaña, Alberto; Castro-García, Paola; Gil Gas, Carmen; Sánchez-Sánchez, Francisco; Poblet, Enrique; Serrano, Rosario; Calero, Raúl; Ramírez-Castillejo, Carmen
Breast cancer stem cells are defined as cancer cells with self-renewal capacity. These cells represent a small subpopulation endowed with the ability to form new tumours when injected in nude mice. Markers of differentiation have been used to identify these cancer cells. In the case of breast cancer, CD44+/CD24- select a population with stem cell properties. The fact that these cells have self-renewal ability has suggested that this population could be responsible for new tumour formation and cancer relapse. These cells have been shown to be more resistant to chemotherapy and radiotherapy than normal cancer cells. The identification of the molecular druggable alterations responsible for the initiation and maintenance of cancer stem cells is an important goal. In this article we will review all these points with special emphasis on the possible role of new drugs designed to interact with molecular pathways of cancer stem cells.
[Postoperative Adjuvant Chemotherapy for Stage III Colon Cancer--Drug Selection, Tolerability, and Safety in Clinical Practice].
Okada, Kazutake; Sadahiro, Sotaro; Saito, Gota; Tanaka, Akira; Suzuki, Toshiyuki
In the National Comprehensive Cancer Network (NCCN) guidelines, oxaliplatin (L-OHP)-based chemotherapeutic regimens, including 5-fluorouracil, Leucovorin (LV), and L-OHP (FOLFOX); capecitabine and L-OHP (CapeOX); and 5-fluorouracil, folinic acid, and L-OHP (FLOX) are designated as category 1 recommendations for postoperative adjuvant chemotherapy in Stage III colon cancer, followed by capecitabine and 5-fluorouracil plus LV as category 2A recommendations. We studied the selection of drugs for adjuvant chemotherapy and assessed the tolerability and safety of CapeOX and tegafur-uracil (UFT) plus LV (UFT/LV) in patients with Stage III colon cancer. The study group included 104 consecutive patients with Stage III colon cancer who underwent curative surgery. One patient changed hospitals immediately after surgery. Among the remaining 103 patients, 82 (80%) received adjuvant chemotherapy and 21 (20%) did not. CapeOX was administered to 32 patients (31%), UFT/LV to 49 patients (48%), and capecitabine to 1 patient (1%). In 59 patients, the treatment choice was determined according to the patient's preference; 32 patients (54%) selected CapeOX, 26 (44%) selected UFT/LV, and 1 (2%) selected no chemotherapy. The treatment completion rate was 80% for CapeOX and 84% for UFT/LV. Among patients who completed chemotherapy, dose reduction and drug withdrawal were not required in 22% of patients who received CapeOX and 80% of those who received UFT/LV. Neither CapeOX nor UFT/LV was associated with any serious adverse events. The tolerability and safety of CapeOX and UFT/LV were acceptable. However, CapeOX dose had to be carefully adjusted according to each patient's condition.
Neoadjuvant vs. adjuvant treatment of Siewert type II gastroesophageal junction cancer: an analysis of data from the surveillance, epidemiology, and end results (SEER) registry
Miccio, Joseph A.; Oladeru, Oluwadamilola T.; Yang, Jie; Xue, Yaqi; Choi, Minsig; Zhang, Yue; Yoon, Hannah; Ryu, Samuel
Background Cancer of the gastroesophageal junction (GEJ) has been rising in incidence in recent years. The role of radiation therapy (RT) in the treatment of GEJ cancer remains unclear, as the largest prospective trials advocating for either adjuvant or neoadjuvant chemoradiotherapy (CRT) combine GEJ cancer with either gastric or esophageal cancer. The aim of the present study is to examine the association of neoadjuvant versus adjuvant treatment with overall and disease-specific survival (DSS) for patients with surgically resected cancer of the true GEJ (Siewert type II). Methods The surveillance, epidemiology, and end results (SEER) registry database (2001–2011) was queried for cases of surgically resected Siewert type II GEJ cancer. A total of 1,497 patients with resectable GEJ cancer were identified, with 746 receiving adjuvant RT and 751 receiving neoadjuvant RT. Retrospective analysis was performed with the endpoints of overall and DSS. Results Using cox regression and controlling for independent covariates (age, sex, race, stage, grade, histology, and year of diagnosis), we showed that adjuvant RT was associated with a significantly lower death risk [hazard ratio (HR), 0.84; 95% confidence interval 0.73–0.97; P value=0.0168] and significantly lower disease-specific death risk (HR, 0.84; 95% confidence interval, 0.72–0.97; P value=0.0211) as compared to neoadjuvant RT. Conclusions This analysis of SEER data showed that adjuvant RT was associated with a survival benefit as compared to neoadjuvant RT for the treatment of Siewert type II GEJ cancer. We suggest future prospective studies to compare outcomes of adjuvant versus neoadjuvant treatment for true GEJ cancer. PMID:27284473
Neo-adjuvant Therapy With Anastrozole Plus Pazopanib in Stage II and III ER+ Breast Cancer
Estrogen Receptor-positive Breast Cancer; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Male Breast Cancer; Recurrent Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer
The significance of circulating tumor cells in prostate cancer patients undergoing adjuvant or salvage radiation therapy
Lowes, L E; Lock, M; Rodrigues, G; D'Souza, D; Bauman, G; Ahmad, B; Venkatesan, V; Allan, A L; Sexton, T
Background: Following radical prostatectomy, success of adjuvant and salvage radiation therapy (RT) is dependent on the absence of micrometastatic disease. However, reliable prognostic/predictive factors for determining this are lacking. Therefore, novel biomarkers are needed to assist with clinical decision-making in this setting. Enumeration of circulating tumor cells (CTCs) using the regulatory-approved CellSearch System (CSS) is prognostic in metastatic prostate cancer. We hypothesize that CTCs may also be prognostic in the post-prostatectomy setting. Methods: Patient blood samples (n=55) were processed on the CSS to enumerate CTCs at 0, 6, 12 and 24 months after completion of RT. CTC values were correlated with predictive/prognostic factors and progression-free survival. Results: CTC status (presence/absence) correlated significantly with positive margins (increased likelihood of CTCneg disease; P=0.032), and trended toward significance with the presence of seminal vesicle invasion (CTCpos; P=0.113) and extracapsular extension (CTCneg; P=0.116). Although there was a trend toward a decreased time to biochemical failure (BCF) in baseline CTC-positive patients (n=9), this trend was not significant (hazard ratio (HR)=0.3505; P=0.166). However, CTC-positive status at any point (n=16) predicted for time to BCF (HR=0.2868; P=0.0437). Conclusions: One caveat of this study is the small sample size utilized (n=55) and the low number of patients with CTC-positive disease (n=16). However, our results suggest that CTCs may be indicative of disseminated disease and assessment of CTCs during RT may be helpful in clinical decision-making to determine, which patients may benefit from RT versus those who may benefit more from systemic treatments. PMID:26238233
Biological characterization and selection criteria of adjuvant chemotherapy for early breast cancer: experience from the Italian observational NEMESI study
Background International treatment guidelines recommend administration of adjuvant chemotherapy in early breast cancer based on clinical, prognostic and predictive parameters. Methods An observational study (NEMESI) was conducted in 63 Italian oncology centres in patients with early breast cancer. Age, performance status, concomitant disease, menopausal status, histology, tumor dimension (pT), axillary lymph node status (pN), grading (G), estrogen and progesterone receptor (ER and PgR), proliferative index (ki67 or MIB-1), human epidermal growth factor receptor 2 (HER2) and type of adjuvant treatment were recorded. The primary objective of the study was to define parameters influencing the decision to prescribe adjuvant chemotherapy and the type of chemotherapy. Results Data for 1894 patients were available. 69.0% postmenopausal, 67.0% pT1, 22.3% pTmic/pT1a/pT1b, 61.0% pN0, 48.7% luminal A, 18.1% luminal B, 16.1% HER2 positive, 8.7% triple negative, 8.4% unknown. 57.8% received adjuvant chemotherapy: 38.1% of luminal A, 67.3% luminal B, 88.2% HER2-positive, 97.6% triple negative. Regimens administered: 9.1% CMF-like, 48.8% anthracyclines, 38.4% anthracyclines plus taxanes, 3.7% taxanes alone. Increasing pT/pN and, marginally, HER2-positive were associated with the prescription of anthracyclines plus taxanes. Suboptimal schedules (CMF-like or AC/EC or FEC-75) were prescribed in 37.3% receiving chemotherapy, even in HER2-positive and triple negative disease (36.5% and 34.0%, respectively). Conclusions This study showed an overprescription of adjuvant chemotherapy for early breast cancer, particularly referred to luminal A. pT, pN and, marginally, HER2 were the principal determinants for the choice of chemotherapy type. Suboptimal chemotherapy regimens were adopted in at least one third of HER2-positve and triple negative. PMID:22672524
Harnessing the apoptotic programs in cancer stem-like cells
Wang, Ying-Hua; Scadden, David T
Elimination of malignant cells is an unmet challenge for most human cancer types even with therapies targeting specific driver mutations. Therefore, a multi-pronged strategy to alter cancer cell biology on multiple levels is increasingly recognized as essential for cancer cure. One such aspect of cancer cell biology is the relative apoptosis resistance of tumor-initiating cells. Here, we provide an overview of the mechanisms affecting the apoptotic process in tumor cells emphasizing the differences in the tumor-initiating or stem-like cells of cancer. Further, we summarize efforts to exploit these differences to design therapies targeting that important cancer cell population. PMID:26253117
Second non-breast primary cancer following adjuvant therapy for early breast cancer: A report from the International Breast Cancer Study Group
Gianni, Lorenzo; Gelber, Shari; Ravaioli, Alberto; Price, Karen N.; Panzini, Ilaria; Fantini, Manuela; Castiglione-Gertsch, Monica; Pagani, Olivia; Simoncini, Edda; Gelber, Richard D.; Coates, Alan S.; Goldhirsch, Aron
The incidence of second non-breast primary cancer following adjuvant treatment was evaluated using data from patients enrolled from 1978 to 1999 in four International Breast Cancer Study Group (IBCSG) trials. The occurrence of these tumours as sites of first failure was assessed separately for two treatment comparisons: toremifene versus tamoxifen for five years in 1035 patients in IBCSG Trials 12-93 and 14-93 with a median follow-up of eight years and endocrine therapy (toremifene or tamoxifen) versus chemoendocrine therapy (CMF or AC plus toremifene or tamoxifen) in 1731 patients from IBCSG Trials III, VII and 12-93, with a combined median follow-up of 14 years. No significant differences in second non-breast primary tumours were observed in either comparison. In particular the incidences of second primary uterine tumours with toremifene and tamoxifen were similar and no significant increase of secondary leukaemias was observed with chemoendocrine therapy compared with endocrine therapy. PMID:19062268
Cancer Stem Cell Plasticity Drives Therapeutic Resistance.
Doherty, Mary R; Smigiel, Jacob M; Junk, Damian J; Jackson, Mark W
The connection between epithelial-mesenchymal (E-M) plasticity and cancer stem cell (CSC) properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy-resistant CSCs remain poorly understood. The enrichment of cells with a mesenchymal/CSC phenotype following therapy has been interpreted in two different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, evidence is emerging that suggests non-CSCs can be induced into a transient, drug-tolerant, CSC-like state by chemotherapy. The ability to transition between distinct cell states may be as critical for the survival of tumor cells following therapy as it is for metastatic progression. Therefore, inhibition of the pathways that promote E-M and CSC plasticity may suppress tumor recurrence following chemotherapy. Here, we review the emerging appreciation for how plasticity confers therapeutic resistance and tumor recurrence. PMID:26742077
Cancer Stem Cell Plasticity Drives Therapeutic Resistance
Doherty, Mary R.; Smigiel, Jacob M.; Junk, Damian J.; Jackson, Mark W.
The connection between epithelial-mesenchymal (E-M) plasticity and cancer stem cell (CSC) properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy-resistant CSCs remain poorly understood. The enrichment of cells with a mesenchymal/CSC phenotype following therapy has been interpreted in two different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, evidence is emerging that suggests non-CSCs can be induced into a transient, drug-tolerant, CSC-like state by chemotherapy. The ability to transition between distinct cell states may be as critical for the survival of tumor cells following therapy as it is for metastatic progression. Therefore, inhibition of the pathways that promote E-M and CSC plasticity may suppress tumor recurrence following chemotherapy. Here, we review the emerging appreciation for how plasticity confers therapeutic resistance and tumor recurrence. PMID:26742077
A prospective cohort study of early discontinuation of adjuvant chemotherapy in women with breast cancer: the breast cancer quality of care study (BQUAL).
Neugut, Alfred I; Hillyer, Grace Clarke; Kushi, Lawrence H; Lamerato, Lois; Buono, Donna L; Nathanson, S David; Bovbjerg, Dana H; Mandelblatt, Jeanne S; Tsai, Wei-Yann; Jacobson, Judith S; Hershman, Dawn L
For many women with non-metastatic breast cancer, adjuvant chemotherapy prevents recurrence and extends survival. Women who discontinue chemotherapy early may reduce those benefits, but little is known about what predicts early discontinuation. We sought to determine prospectively the rate and reasons for early discontinuation of adjuvant chemotherapy in women with breast cancer. We conducted a prospective cohort study among three U.S. health care organizations. Of 1158 women with newly diagnosed non-metastatic breast cancer, 2006-2010, we analyzed 445 (38.4 %) patients who initiated standard adjuvant chemotherapy as defined by accepted guidelines. We interviewed patients at baseline and twice during treatment regarding sociodemographic/psychosocial factors and treatment decision-making and collected clinical data. They were categorized according to the number of cycles required by the chemotherapy regimen they had initiated. The outcome was early discontinuation (<80 % of planned cycles). Of patients analyzed, 392 (88.1 %) completed the prescribed therapy. The strongest predictor was receipt of a regimen entailing >4 cycles of therapy (18.1 % for longer regimens, 7.4 % for 4 cycles) (odds ratio [OR] 2.59, 95 % CI 1.32-5.08), controlling for race, age, stage, hormone receptor status, social support, optimism, spirituality, stress, and physical symptoms. Higher levels of psychological symptoms on the Memorial symptom assessment scale also increased the odds of early discontinuation (OR 1.92, 95 % CI 0.998-3.68). The large majority of patients who initiated adjuvant chemotherapy for breast cancer completed their prescribed regimens, but early discontinuation was associated with lengthier regimens and, with borderline statistical significance, for those with psychological side effects. PMID:27287779
Splenomegaly and Its Associations with Genetic Polymorphisms and Treatment Outcome in Colorectal Cancer Patients Treated with Adjuvant FOLFOX
Kim, Mi-Jung; Han, Sae-Won; Lee, Dae-Won; Cha, Yongjun; Lee, Kyung-Hun; Kim, Tae-Yong; Oh, Do-Youn; Kim, Se Hyung; Im, Seock-Ah; Bang, Yung-Jue; Kim, Tae-You
Purpose Splenomegaly is a clinical surrogate of oxaliplatin-induced sinusoidal obstruction syndrome (SOS). We investigated development of splenomegaly and its association with treatment outcome and genetic polymorphisms following adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in colorectal cancer (CRC) patients. Materials and Methods Splenomegaly was determined by spleen volumetry using computed tomography images obtained before initiation of chemotherapy and after completion of adjuvant FOLFOX in CRC patients. Ten genetic polymorphisms in 4 SOS-related genes (VEGFA, MMP9, NOS3, and GSTP1) were analyzed using DNA from peripheral blood mononuclear cells. Results Of 124 patients included, increase in spleen size was observed in 109 (87.9%). Median change was 31% (range, –42% to 168%). Patients with splenomegaly had more severe thrombocytopenia compared to patients without splenomegaly during the chemotherapy period (p < 0.0001). The cumulative dose of oxaliplatin and the lowest platelet count during the chemotherapy period were clinical factors associated with splenomegaly. However, no significant associations were found between genetic polymorphisms and development of splenomegaly. Disease-free survival was similar regardless of the development of splenomegaly. Conclusion Splenomegaly was frequently observed in patients receiving adjuvant FOLFOX and resulted in more severe thrombocytopenia but did not influence treatment outcome. Examined genetic polymorphisms did not predict development of splenomegaly. PMID:26790967
Single Nucleotide Polymorphisms as Prognostic and Predictive Factors of Adjuvant Chemotherapy in Colorectal Cancer of Stages I and II
Horvat, Matej; Potočnik, Uroš; Repnik, Katja; Kavalar, Rajko; Štabuc, Borut
Colorectal cancer (CRC) is a highly heterogeneous disease regarding the stage at time of diagnosis and there is special attention regarding adjuvant chemotherapy in unselected patients with stage I and stage II. The clinicohistologically based TNM staging system with emphasis on histological evaluation of primary tumor and resected regional lymph nodes remains the standard of staging, but it has restricted sensitivity resulting in false downward stage migration. Molecular characteristics might predispose tumors to a worse prognosis and identification of those enables identifying patients with high risk of disease recurrence. Suitable predictive markers also enable choosing the most appropriate therapy. The current challenge facing adjuvant chemotherapy in stages I and II CRC is choosing patients with the highest risk of disease recurrence who are going to derive most benefit without facing unnecessary adverse effects. Single nucleotide polymorphisms (SNPs) are one of the potential molecular markers that might help us identify patients with unfavorable prognostic factors regarding disease initiation and recurrence and could determine selection of an appropriate chemotherapy regimen in the adjuvant and metastatic setting. In this paper, we discuss SNPs of genes involved in the multistep processes of cancerogenesis, metastasis, and the metabolism of chemotherapy that might prove clinically significant. PMID:26884752
Prospective cohort study of febrile neutropenia in breast cancer patients with neoadjuvant and adjuvant chemotherapy: CSPOR-BC FN study.
Ishikawa, Takashi; Sakamaki, Kentaro; Narui, Kazutaka; Kaise, Hiroshi; Tsugawa, Koichiro; Ichikawa, Yasushi; Mukai, Hirofumi
With the increasing use of adjuvant chemotherapy for treating early breast cancer, febrile neutropenia management has become crucial. Guidelines for febrile neutropenia management are mostly based on a Caucasian population survey although ethnic differences are reported in terms of adverse events. We survey the current status of febrile neutropenia and risk factors in Japanese female breast cancer patients receiving neoadjuvant and adjuvant chemotherapy regimens potential for febrile neutropenia. Subsequently, we plan to conduct a multicenter prospective cohort study involving 1000 patients with operable breast cancer. With the current state of oral antibiotics being routinely prescribed without hematology tests, we survey febrile neutropenia based on two different definitions, namely, true febrile neutropenia: ≥37.5°C and Grade 4 neutropenia, and surrogate febrile neutropenia: ≥37.5°C and oral antibiotic and antipyretic intake. The comparison of true febrile neutropenia and surrogate febrile neutropenia incidences is anticipated to provide information on the safety and feasibility of chemotherapy management without performing blood tests.
Spinal infarction related to the adjuvant chemotherapy for surgically resected non-small cell lung cancer: report of a case.
Matsutani, Noriyuki; Kawamura, Masafumi
We report the development of spinal infarction during adjuvant chemotherapy with tegafur, gimeracil and oteracil (TS-1) after surgery for lung adenocarcinoma. A 69-year-old female had a left upper lobectomy for pulmonary adenocarcinoma, T2aN0M0. Six weeks after the surgery, tegafur, gimeracil and oteracil were administered orally as adjuvant chemotherapy for 1 year. After 10 months of adjuvant chemotherapy, the patient suddenly showed signs of numbness and weakness in both lower limbs. The patient did not have a previous medical history, and was receiving only tegafur, gimeracil and oteracil with the stomach medication. Neurological findings showed muscle weakness, numbness and a loss of tendon reflex in both lower limbs, as well as bladder and rectal disturbance. Blood tests, brain magnetic resonance imaging and chest computed tomography showed no signs of abnormalities or metastasis. Magnetic resonance imaging of the spine showed a hyperintense lesion between the Th12 and L1 spinal levels by T2-weighted image. A spinal fluid test indicated no abnormalities, and cytological diagnosis was class II. Anti-aquaporin 4, anti-ganglioside and anti-neuronal autoantibodies were all negative. These results indicated that the patient had a spinal infarction, rather than myelitis or paraneoplastic neurological syndrome. The patient was treated with heparin and steroid pulse treatment followed by rehabilitation, and recovered sufficiently to be able to walk using a cane after 2 months. The development of spinal infarction during anti-cancer chemotherapy has not been previously reported. In this case, an association of spinal infarction with the use of adjuvant chemotherapy was strongly indicated due to the lack of abnormalities in coagulability, atherosclerotic lesions and aortic disease.
Role of Adjuvant Chemotherapy in ypT0-2N0 Patients Treated with Preoperative Chemoradiation Therapy and Radical Resection for Rectal Cancer
Park, In Ja; Kim, Dae Yong; Kim, Hee Cheol; Kim, Nam Kyu; Kim, Hyeong-Rok; Kang, Sung-Bum; Choi, Gyu-Seog; Lee, Kang Young; Kim, Seon-Hahn; Oh, Seung Taek; Lim, Seok-Byung; Kim, Jin Cheon; Oh, Jae Hwan; Kim, Sun Young; Lee, Woo Yong; Lee, Jung Bok; Yu, Chang Sik
Objective: To explore the role of adjuvant chemotherapy for patients with ypT0-2N0 rectal cancer treated by preoperative chemoradiation therapy (PCRT) and radical resection. Patients and Methods: A national consortium of 10 institutions was formed, and patients with ypT0-2N0 mid- and low-rectal cancer after PCRT and radical resection from 2004 to 2009 were included. Patients were categorized into 2 groups according to receipt of additional adjuvant chemotherapy: Adj CTx (+) versus Adj CTx (−). Propensity scores were calculated and used to perform matched and adjusted analyses comparing relapse-free survival (RFS) between treatment groups while controlling for potential confounding. Results: A total of 1016 patients, who met the selection criteria, were evaluated. Of these, 106 (10.4%) did not receive adjuvant chemotherapy. There was no overall improvement in 5-year RFS as a result of adjuvant chemotherapy [91.6% for Adj CTx (+) vs 87.5% for Adj CTx (−), P=.18]. There were no differences in 5-year local recurrence and distant metastasis rate between the 2 groups. In patients who show moderate, minimal, or no regression in tumor regression grade, however, possible association of adjuvant chemotherapy with RFS would be considered (hazard ratio 0.35; 95% confidence interval 0.14-0.88; P=.03). Cox regression analysis after propensity score matching failed to show that addition of adjuvant chemotherapy was associated with improved RFS (hazard ratio 0.81; 95% confidence interval 0.39-1.70; P=.58). Conclusions: Adjuvant chemotherapy seemed to not influence the RFS of patients with ypT0-2N0 rectal cancer after PCRT followed by radical resection. Thus, the addition of adjuvant chemotherapy needs to be weighed against its oncologic benefits.
The NF-κB Pathway and Cancer Stem Cells.
Rinkenbaugh, Amanda L; Baldwin, Albert S
The NF-κB transcription factor pathway is a crucial regulator of inflammation and immune responses. Additionally, aberrant NF-κB signaling has been identified in many types of cancer. Downstream of key oncogenic pathways, such as RAS, BCR-ABL, and Her2, NF-κB regulates transcription of target genes that promote cell survival and proliferation, inhibit apoptosis, and mediate invasion and metastasis. The cancer stem cell model posits that a subset of tumor cells (cancer stem cells) drive tumor initiation, exhibit resistance to treatment, and promote recurrence and metastasis. This review examines the evidence for a role for NF-κB signaling in cancer stem cell biology.
The NF-κB Pathway and Cancer Stem Cells
Rinkenbaugh, Amanda L.; Baldwin, Albert S.
The NF-κB transcription factor pathway is a crucial regulator of inflammation and immune responses. Additionally, aberrant NF-κB signaling has been identified in many types of cancer. Downstream of key oncogenic pathways, such as RAS, BCR-ABL, and Her2, NF-κB regulates transcription of target genes that promote cell survival and proliferation, inhibit apoptosis, and mediate invasion and metastasis. The cancer stem cell model posits that a subset of tumor cells (cancer stem cells) drive tumor initiation, exhibit resistance to treatment, and promote recurrence and metastasis. This review examines the evidence for a role for NF-κB signaling in cancer stem cell biology. PMID:27058560
Nanomedicine-Mediated Therapies to Target Breast Cancer Stem Cells.
He, Lili; Gu, Jian; Lim, Lee Y; Yuan, Zhi-Xiang; Mo, Jingxin
Accumulating evidences have suggested the existence of breast cancer stem cells (BCSCs), which possess the potential of both self-renewal and differentiation. The origin of BCSCs might have relationship to the development of normal mammary stem cells. BCSCs are believed to play a key role in the initiation, recurrence and chemo-/radiotherapy resistances of breast cancer. Therefore, elimination of BCSCs is crucial for breast cancer therapy. However, conventional chemo and radiation therapies cannot eradicate BCSCs effectively. Fortunately, nanotechnology holds great potential for specific and efficient anti-BCSCs treatment. "Smart" nanocarriers can distinguish BCSCs from the other breast cancer cells and selectively deliver therapeutic agents to the BCSCs. Emerging findings suggest that BCSCs in breast cancer could be successfully inhibited and even eradicated by functionalized nanomedicines. In this review, we focus on origin of BCSCs, strategies used to target BCSCs, and summarize the nanotechnology-based delivery systems that have been applied for eliminating BCSCs in breast cancer. PMID:27679576
Nanomedicine-Mediated Therapies to Target Breast Cancer Stem Cells.
He, Lili; Gu, Jian; Lim, Lee Y; Yuan, Zhi-Xiang; Mo, Jingxin
Accumulating evidences have suggested the existence of breast cancer stem cells (BCSCs), which possess the potential of both self-renewal and differentiation. The origin of BCSCs might have relationship to the development of normal mammary stem cells. BCSCs are believed to play a key role in the initiation, recurrence and chemo-/radiotherapy resistances of breast cancer. Therefore, elimination of BCSCs is crucial for breast cancer therapy. However, conventional chemo and radiation therapies cannot eradicate BCSCs effectively. Fortunately, nanotechnology holds great potential for specific and efficient anti-BCSCs treatment. "Smart" nanocarriers can distinguish BCSCs from the other breast cancer cells and selectively deliver therapeutic agents to the BCSCs. Emerging findings suggest that BCSCs in breast cancer could be successfully inhibited and even eradicated by functionalized nanomedicines. In this review, we focus on origin of BCSCs, strategies used to target BCSCs, and summarize the nanotechnology-based delivery systems that have been applied for eliminating BCSCs in breast cancer.
Nanomedicine-Mediated Therapies to Target Breast Cancer Stem Cells
He, Lili; Gu, Jian; Lim, Lee Y.; Yuan, Zhi-xiang; Mo, Jingxin
Accumulating evidences have suggested the existence of breast cancer stem cells (BCSCs), which possess the potential of both self-renewal and differentiation. The origin of BCSCs might have relationship to the development of normal mammary stem cells. BCSCs are believed to play a key role in the initiation, recurrence and chemo-/radiotherapy resistances of breast cancer. Therefore, elimination of BCSCs is crucial for breast cancer therapy. However, conventional chemo and radiation therapies cannot eradicate BCSCs effectively. Fortunately, nanotechnology holds great potential for specific and efficient anti-BCSCs treatment. "Smart" nanocarriers can distinguish BCSCs from the other breast cancer cells and selectively deliver therapeutic agents to the BCSCs. Emerging findings suggest that BCSCs in breast cancer could be successfully inhibited and even eradicated by functionalized nanomedicines. In this review, we focus on origin of BCSCs, strategies used to target BCSCs, and summarize the nanotechnology-based delivery systems that have been applied for eliminating BCSCs in breast cancer.
Evolution and Phenotypic Selection of Cancer Stem Cells
Poleszczuk, Jan; Hahnfeldt, Philip; Enderling, Heiko
Cells of different organs at different ages have an intrinsic set of kinetics that dictates their behavior. Transformation into cancer cells will inherit these kinetics that determine initial cell and tumor population progression dynamics. Subject to genetic mutation and epigenetic alterations, cancer cell kinetics can change, and favorable alterations that increase cellular fitness will manifest themselves and accelerate tumor progression. We set out to investigate the emerging intratumoral heterogeneity and to determine the evolutionary trajectories of the combination of cell-intrinsic kinetics that yield aggressive tumor growth. We develop a cellular automaton model that tracks the temporal evolution of the malignant subpopulation of so-called cancer stem cells(CSC), as these cells are exclusively able to initiate and sustain tumors. We explore orthogonal cell traits, including cell migration to facilitate invasion, spontaneous cell death due to genetic drift after accumulation of irreversible deleterious mutations, symmetric cancer stem cell division that increases the cancer stem cell pool, and telomere length and erosion as a mitotic counter for inherited non-stem cancer cell proliferation potential. Our study suggests that cell proliferation potential is the strongest modulator of tumor growth. Early increase in proliferation potential yields larger populations of non-stem cancer cells(CC) that compete with CSC and thus inhibit CSC division while a reduction in proliferation potential loosens such inhibition and facilitates frequent CSC division. The sub-population of cancer stem cells in itself becomes highly heterogeneous dictating population level dynamics that vary from long-term dormancy to aggressive progression. Our study suggests that the clonal diversity that is captured in single tumor biopsy samples represents only a small proportion of the total number of phenotypes. PMID:25742563
Paracrine effects of stem cells in wound healing and cancer progression (Review).
Dittmer, Jürgen; Leyh, Benjamin
Stem cells play an important role in tissue repair and cancer development. The capacity to self-renew and to differentiate to specialized cells allows tissue-specific stem cells to rebuild damaged tissue and cancer stem cells to initiate and promote cancer. Mesenchymal stem cells, attracted to wounds and cancer, facilitate wound healing and support cancer progression primarily by secreting bioactive factors. There is now growing evidence that, like mesenchymal stem cells, also tissue-specific and cancer stem cells manipulate their environment by paracrine actions. Soluble factors and microvesicles released by these stem cells have been shown to protect recipient cells from apoptosis and to stimulate neovascularization. These paracrine mechanisms may allow stem cells to orchestrate wound healing and cancer progression. Hence, understanding these stem cell-driven paracrine effects may help to improve tissue regeneration and cancer treatment.
Stem cell biology in thyroid cancer: Insights for novel therapies
Bhatia, Parisha; Tsumagari, Koji; Abd Elmageed, Zakaria Y; Friedlander, Paul; Buell, Joseph F; Kandil, Emad
Currently, thyroid cancer is one of the most common endocrine cancer in the United States. A recent involvement of sub-population of stem cells, cancer stem cells, has been proposed in different histological types of thyroid cancer. Because of their ability of self-renewal and differentiation into various specialized cells in the body, these putative cells drive tumor genesis, metastatic activity and are responsible to provide chemo- and radioresistant nature to the cancer cells in the thyroid gland. Our Review was conducted from previously published literature to provide latest apprises to investigate the role of embryonic, somatic and cancer stem cells, and discusses the hypothesis of epithelial-mesenchymal transition. Different methods for their identification and isolation through stemness markers using various in vivo and in vitro methods such as flow cytometry, thyrosphere formation assay, aldehyde dehydrogenase activity and ATP-binding cassette sub-family G member 2 efflux-pump mediated Hoechst 33342 dye exclusion have been discussed. The review also outlines various setbacks that still remain to target these tumor initiating cells. Future perspectives of therapeutic strategies and their potential to treat advanced stages of thyroid cancer are also disclosed in this review. PMID:25426258
The Colon Cancer Stem Cell Microenvironment Holds Keys to Future Cancer Therapy
Huang, Emina H.
Background Colorectal cancer remains the most common gastrointestinal cancer. While screening combined with effective surgical treatment has reduced its mortality, we still do not have effective means to prevent recurrence nor to treat metastatic disease. What we know about cancer biology has gone through revolutionary changes in recent decades. The advent of the cancer stem cell theory has accelerated our understanding of the cancer cell. However, there is increasing evidence that cancer cells are influenced by their surrounding microenvironment. Purpose This review divides the tumor microenvironment into four functional components—the stem cell niche, cancer stroma, immune cells, and vascular endothelia—and examines their individual and collective influence on the growth and metastasis of the colon cancer stem cell. The discussion will highlight the need to fully exploit the tumor microenvironment when designing future prognostic tools and therapies. PMID:24643495
Luteinizing hormone-releasing hormone analogues--the rationale for adjuvant use in premenopausal women with early breast cancer.
Jonat, W
Current standard adjuvant therapies for early breast cancer include tamoxifen and chemotherapy, depending on the disease prognosis and menopausal status. Luteinizing hormone-releasing hormone (LHRH) analogues offer a different approach to the management of early breast cancer in pre- and perimenopausal women. The most widely studied LHRH analogue is goserelin. It acts on the hypothalamic-pituitary axis to suppress ovarian function, decreasing luteinizing hormone and oestradiol levels to post-menopausal values. Pooled data from 228 premenopausal and perimenopausal patients with advanced breast cancer enrolled in 29 studies worldwide demonstrated an objective response rate for goserelin, 3.6 mg, of 36.4%, with a median duration of response of 44 weeks. These results fall well within the ranges of reported response rates for ovarian ablation and for tamoxifen in similar patient populations. By virtue of its mode of action, goserelin does not stimulate the ovaries and is unlikely to have detrimental effects on the endometrium. In addition, given that goserelin has no oestrogen agonist-like effects, unlike tamoxifen, there is no potential for tumour stimulation in those patients becoming resistant to treatment. Goserelin is generally well tolerated, and the main side-effects are related to ovarian suppression, which is potentially reversible. Preliminary results in premenopausal women with early breast cancer indicate that endocrine treatment with goserelin plus tamoxifen may be as effective as standard combination chemotherapy (cyclophosphamide-methotrexate-5-fluorouracil), but has significantly less acute toxicity. A number of large, randomized trials are now in progress to assess the potential role of goserelin as adjuvant therapy for early breast cancer.
Adequacy of the National Quality Forum's Colon Cancer Adjuvant Chemotherapy Quality Metric: Is 4 Months Soon Enough?
Massarweh, Nader N; Haynes, Alex B; Chiang, Yi-Ju; Chang, George J; You, Y. Nancy; Feig, Barry W.; Cormier, Janice N
Objective To ascertain whether the National Quality Forum (NQF)-endorsed time interval for adjuvant chemotherapy (AC) initiation optimizes patient outcome. Background Delayed AC initiation for stage III colon cancer is associated with worse survival and the focus of an NQF quality metric (<4 months among patients aged <80 years). Methods Observational cohort study of stage III colon cancer patients aged <80 years within the National Cancer Data Base (2003-2010). The primary outcome was 5-year overall survival evaluated using multivariate Cox regression. Aggregate survival estimates for historical surgery-only controls from pooled National Surgical Adjuvant Breast and Bowel Project trial data were also used. Results Among 51,331 patients (60.8±11.6 years, 50.2% male, and 77.3% white), 76.3% received standard (≤2 months) and 21.6% delayed (>2 and <4 months) AC. Earlier AC was associated with better five-year overall survival (standard, 69.8%; delayed, 62.0%; late [4-6 months], 51.4%; log-rank, p<0.001). Survival after late AC was similar to surgery alone (51.1%; Wilcoxon-rank sum, p=0.10). Compared with late AC, standard (Hazard Ratio [HR] 0.62; 95% CI 0.54-0.72) and delayed (HR 0.77; 95% CI 0.66-0.89) significantly decreased risk of death. Risk of death was also lower for standard AC compared to delayed (HR 0.81; 95% CI 0.77-0.86). Conclusions One in five stage III colon cancer patients initiates AC within the NQF-endorsed interval, but does not derive the full benefit. These data support strengthening current quality improvement initiatives and colon cancer treatment guidelines to encourage AC initiation within 2 months of resection when possible, but not beyond 4 months. PMID:25185467
Circulating cancer stem cells: the importance to select
Yang, Ming-Hsin; Imrali, Ahmet
It has been demonstrated that even localized tumors without clinically apparent metastasis give rise to circulating tumor cells (CTCs). A growing number of technically diverse platforms are being developed for detecting/isolating CTCs in the circulating blood. Despite the technical challenges of isolating rare CTCs from blood, recent studies have already shown the predictive value of CTCs enumeration. Thus, it is becoming increasingly accepted that CTC numbers are linked to patients' outcome and may also be used to monitor treatment response and disease relapse, respectively. Further CTCs provide a non-invasive source for tumor material, 'liquid biopsy', which is particularly important for patients, where no biopsy material can be obtained or where serial biopsies of the tumor, e.g., following treatment, are practically impossible. On the other hand the molecular and biological characterization of CTCs has still remained at a rather experimental stage. Future studies are necessary to define CTC heterogeneity to establish the crucial role of circulating cancer stem cells for driving metastasis, which represent a distinct subpopulation of CTCs that bear metastasis-initiating capabilities based on their stemness properties and invasiveness and thus are critical for the patients' clinical outcome. As compared to non-tumorigenic/metastatic bulk CTCs, circulating cancer stem cells may not only be capable of evading from the primary tumor, but also escape from immune surveillance, survive in the circulating blood and subsequently form metastases in distant organs. Thus, circulating cancer stem cells represent a subset of exclusively tumorigenic cancer stem cells characterized by their invasive characteristics and are potential therapeutic targets for preventing disease progression. To date, only a few original reports and reviews have been published focusing on circulating cancer stem cells. This review discusses the potential importance of isolating and
Cancer Genes Hypermethylated in Human Embryonic Stem Cells
Calvanese, Vincenzo; Horrillo, Angelica; Hmadcha, Abdelkrim; Suarez-Álvarez, Beatriz; Fernandez, Agustín F.; Lara, Ester; Casado, Sara; Menendez, Pablo; Bueno, Clara; Garcia-Castro, Javier; Rubio, Ruth; Lapunzina, Pablo; Alaminos, Miguel; Borghese, Lodovica; Terstegge, Stefanie; Harrison, Neil J.; Moore, Harry D.; Brüstle, Oliver; Lopez-Larrea, Carlos; Andrews, Peter W.; Soria, Bernat; Esteller, Manel; Fraga, Mario F.
Developmental genes are silenced in embryonic stem cells by a bivalent histone-based chromatin mark. It has been proposed that this mark also confers a predisposition to aberrant DNA promoter hypermethylation of tumor suppressor genes (TSGs) in cancer. We report here that silencing of a significant proportion of these TSGs in human embryonic and adult stem cells is associated with promoter DNA hypermethylation. Our results indicate a role for DNA methylation in the control of gene expression in human stem cells and suggest that, for genes repressed by promoter hypermethylation in stem cells in vivo, the aberrant process in cancer could be understood as a defect in establishing an unmethylated promoter during differentiation, rather than as an anomalous process of de novo hypermethylation. PMID:18820729
mTOR plays critical roles in pancreatic cancer stem cells through specific and stemness-related functions
NASA Astrophysics Data System (ADS)
Matsubara, Shyuichiro; Ding, Qiang; Miyazaki, Yumi; Kuwahata, Taisaku; Tsukasa, Koichiro; Takao, Sonshin
Pancreatic cancer is characterized by near-universal mutations in KRAS. The mammalian target of rapamycin (mTOR), which functions downstream of RAS, has divergent effects on stem cells. In the present study, we investigated the significance of the mTOR pathway in maintaining the properties of pancreatic cancer stem cells. The mTOR inhibitor, rapamycin, reduced the viability of CD133+ pancreatic cancer cells and sphere formation which is an index of self-renewal of stem-like cells, indicating that the mTOR pathway functions to maintain cancer stem-like cells. Further, rapamycin had different effects on CD133+ cells compared to cyclopamine which is an inhibitor of the Hedgehog pathway. Thus, the mTOR pathway has a distinct role although both pathways maintain pancreatic cancer stem cells. Therefore, mTOR might be a promising target to eliminate pancreatic cancer stem cells.
Lung Cancer Stem Cell Lose Their Stemness Default State after Exposure to Microgravity
Pisanu, Maria Elena; Noto, Alessia; De Vitis, Claudia; Masiello, Maria Grazia; Coluccia, Pierpaolo; Proietti, Sara; Giovagnoli, Maria Rosaria; Ricci, Alberto; Giarnieri, Enrico; Cucina, Alessandra; Ciliberto, Gennaro; Bizzarri, Mariano; Mancini, Rita
Microgravity influences cell differentiation by modifying the morphogenetic field in which stem cells are embedded. Preliminary data showed indeed that stem cells are committed to selective differentiation when exposed to real or simulated microgravity. Our study provides evidence that a similar event occurs when cancer stem cells (CSCs) are cultured in microgravity. In the same time, a significant increase in apoptosis was recorded: those data point out that microgravity rescues CSCs from their relative quiescent state, inducing CSCs to lose their stemness features, as documented by the decrease in ALDH and the downregulation of both Nanog and Oct-4 genes. Those traits were stably acquired and preserved by CSCs when cells were placed again on a 1 g field. Studies conducted in microgravity on CSCs may improve our understanding of the fundamental role exerted by biophysical forces in cancer cell growth and function. PMID:25276790
Lung cancer stem cell lose their stemness default state after exposure to microgravity.
Pisanu, Maria Elena; Noto, Alessia; De Vitis, Claudia; Masiello, Maria Grazia; Coluccia, Pierpaolo; Proietti, Sara; Giovagnoli, Maria Rosaria; Ricci, Alberto; Giarnieri, Enrico; Cucina, Alessandra; Ciliberto, Gennaro; Bizzarri, Mariano; Mancini, Rita
Microgravity influences cell differentiation by modifying the morphogenetic field in which stem cells are embedded. Preliminary data showed indeed that stem cells are committed to selective differentiation when exposed to real or simulated microgravity. Our study provides evidence that a similar event occurs when cancer stem cells (CSCs) are cultured in microgravity. In the same time, a significant increase in apoptosis was recorded: those data point out that microgravity rescues CSCs from their relative quiescent state, inducing CSCs to lose their stemness features, as documented by the decrease in ALDH and the downregulation of both Nanog and Oct-4 genes. Those traits were stably acquired and preserved by CSCs when cells were placed again on a 1 g field. Studies conducted in microgravity on CSCs may improve our understanding of the fundamental role exerted by biophysical forces in cancer cell growth and function.
Thoughts about cancer stem cells in solid tumors.
La Porta, Caterina Am
Cancer chemotherapy efficacy is frequently impaired by either intrinsic or acquired tumor resistance. A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells. In recent years, the cancer stem cell (CSC) theory has changed the classical view of tumor growth and therefore the therapeutic perspective. Overcoming intrinsic and acquired resistance of cancer stem/progenitor cells to current clinical treatments represents a major challenge in treating and curing the most aggressive and metastatic cancers. On the other hand, the identification of CSCs in vivo and in vitro relies on specific surface markers that should allow the sorting cancer cells into phenotypically distinct subpopulations. In the present review, recent papers published on CSCs in solid tumors (breast, prostate, brain and melanoma) are discussed, highlighting critical points such as the choice of markers to sort CSCs and mouse models to demonstrate that CSCs are able to replicate the original tumor. A discussion of the possible role of aldehyde dehydrogenase and CXCR6 biomarkers as signaling molecules in CSCs and normal stem cells is also discussed. The author believes that efforts have to be made to investigate the functional and biological properties of putative CSCs in cancer. Developing diagnostic/prognostic tools to follow cancer development is also a challenge. In this connection it would be useful to develop a multidisciplinary approach combining mathematics, physics and biology which merges experimental approaches and theory. Biological models alone are probably unable to resolve the problem completely.
Comparison of adjuvant chemotherapy and radiation in patients with intermediate risk factors after radical surgery in FIGO stage IB-IIA cervical cancer.
Lee, K-B; Lee, J-M; Ki, K-D; Lee, S-K; Park, C-Y; Ha, S-Y
The aim of this study was to compare the outcome of chemotherapy or radiation as adjuvant therapy for patients with FIGO stage IB-IIA cervical cancer and surgically confirmed intermediate risk factors. Data were collected from patients with uterine cervical cancer FIGO stage IB-IIA who had adjuvant chemotherapy following radical hysterectomy with pelvic lymph node dissection (RHLND, cases) or adjuvant radiotherapy following RHLND (controls). The study groups consisted of 38 cases and 42 controls. Adjuvant treatment was given to the patients with a combination of intermediate risk factors including deep stromal invasion (>50%), lymphvascular space invasion, large tumor size (3-6 cm), or close vaginal resection margin (<1 cm). Comparison of the cases with the controls revealed no significant differences in variables studied including median age (P = 0.18), stage distribution (P = 0.30), histologic subtype (P = 0.93), pathologic tumor size (P = 0.46), depth of the stromal invasion (P = 0.29), lymphvascular space invasion (P = 0.50), and close vaginal resection margin (P = 0.62). The difference in disease-free survival rates was not significant (P = 0.68). However, the overall survival analysis was incomplete due to the limited number of events available at the end of the study period. The findings of this study suggest that adjuvant chemotherapy in patients with FIGO stage IB-IIA uterine cervical cancer and surgically confirmed intermediate risk factors may be effective.
Do cancer cells undergo phenotypic switching? The case for imperfect cancer stem cell markers
Zapperi, Stefano; La Porta, Caterina A. M.
The identification of cancer stem cells in vivo and in vitro relies on specific surface markers that should allow to sort cancer cells in phenotypically distinct subpopulations. Experiments report that sorted cancer cell populations after some time tend to express again all the original markers, leading to the hypothesis of phenotypic switching, according to which cancer cells can transform stochastically into cancer stem cells. Here we explore an alternative explanation based on the hypothesis that markers are not perfect and are thus unable to identify all cancer stem cells. Our analysis is based on a mathematical model for cancer cell proliferation that takes into account phenotypic switching, imperfect markers and error in the sorting process. Our conclusion is that the observation of reversible expression of surface markers after sorting does not provide sufficient evidence in support of phenotypic switching. PMID:22679555
Tumoral stem cell reprogramming as a driver of cancer: Theory, biological models, implications in cancer therapy.
Vicente-Dueñas, Carolina; Hauer, Julia; Ruiz-Roca, Lucía; Ingenhag, Deborah; Rodríguez-Meira, Alba; Auer, Franziska; Borkhardt, Arndt; Sánchez-García, Isidro
Cancer is a clonal malignant disease originated in a single cell and characterized by the accumulation of partially differentiated cells that are phenotypically reminiscent of normal stages of differentiation. According to current models, therapeutic strategies that block oncogene activity are likely to selectively target tumor cells. However, recent evidences have revealed that cancer stem cells could arise through a tumor stem cell reprogramming mechanism, suggesting that genetic lesions that initiate the cancer process might be dispensable for tumor progression and maintenance. This review addresses the impact of these results toward a better understanding of cancer development and proposes new approaches to treat cancer in the future.
High-throughput screening identifies artesunate as selective inhibitor of cancer stemness: Involvement of mitochondrial metabolism.
Subedi, Amit; Futamura, Yushi; Nishi, Mayuko; Ryo, Akihide; Watanabe, Nobumoto; Osada, Hiroyuki
Cancer stem cells (CSCs) have robust systems to maintain cancer stemness and drug resistance. Thus, targeting such robust systems instead of focusing on individual signaling pathways should be the approach allowing the identification of selective CSC inhibitors. Here, we used the alkaline phosphatase (ALP) assay to identify inhibitors for cancer stemness in induced cancer stem-like (iCSCL) cells. We screened several compounds from natural product chemical library and evaluated hit compounds for their efficacy on cancer stemness in iCSCL tumorspheres. We identified artesunate, an antimalarial drug, as a selective inhibitor of cancer stemness. Artesunate induced mitochondrial dysfunction that selectively inhibited cancer stemness of iCSCL cells, indicating an essential role of mitochondrial metabolism in cancer stemness.
Postoperative Radiotherapy for Pathologic N2 Non–Small-Cell Lung Cancer Treated With Adjuvant Chemotherapy: A Review of the National Cancer Data Base
Robinson, Cliff G.; Patel, Aalok P.; Bradley, Jeffrey D.; DeWees, Todd; Waqar, Saiama N.; Morgensztern, Daniel; Baggstrom, Maria Q.; Govindan, Ramaswamy; Bell, Jennifer M.; Guthrie, Tracey J.; Colditz, Graham A.; Crabtree, Traves D.; Kreisel, Daniel; Krupnick, Alexander S.; Patterson, G. Alexander; Meyers, Bryan F.; Puri, Varun
Purpose To investigate the impact of modern postoperative radiotherapy (PORT) on overall survival (OS) for patients with N2 non–small-cell lung cancer (NSCLC) treated nationally with surgery and adjuvant chemotherapy. Patients and Methods Patients with pathologic N2 NSCLC who underwent complete resection and adjuvant chemotherapy from 2006 to 2010 were identified from the National Cancer Data Base and stratified by use of PORT (≥ 45 Gy). A total of 4,483 patients were identified (PORT, n = 1,850; no PORT, n = 2,633). The impact of patient and treatment variables on OS was explored using Cox regression. Results Median follow-up time was 22 months. On univariable analysis, improved OS correlated with younger age, treatment at an academic facility, female sex, urban population, higher income, lower Charlson comorbidity score, smaller tumor size, multiagent chemotherapy, resection with at least a lobectomy, and PORT. On multivariable analysis, improved OS remained independently predicted by younger age, female sex, urban population, lower Charlson score, smaller tumor size, multiagent chemotherapy, resection with at least a lobectomy, and PORT (hazard ratio, 0.886; 95% CI, 0.798 to 0.988). Use of PORT was associated with an increase in median and 5-year OS compared with no PORT (median OS, 45.2 v 40.7 months, respectively; 5-year OS, 39.3% [95% CI, 35.4% to 43.5%] v 34.8% [95% CI, 31.6% to 38.3%], respectively; P = .014). Conclusion For patients with N2 NSCLC after complete resection and adjuvant chemotherapy, modern PORT seems to confer an additional OS advantage beyond that achieved with adjuvant chemotherapy alone. PMID:25667283
A Study on Dosimetric Outcomes and Acute Toxicity of Post Mastectomy Adjuvant Hypofractionated Radiotherapy for Breast Cancer
Deshmukh, Shivaprasad; Fernandes, Donald Jerard; Srinivasa, Vidyasagar Mamidipudi; Yathiraj, Prahlad Hiremagalur; Singh, Anshul; Reddy, Anusha
Introduction Hypofractionated External Beam Radiotherapy (HFRT) is a relatively new adjuvant Radiotherapy (RT) schedule for breast cancers following breast conservation surgery and less commonly, following mastectomy. Here we report our experience on normal tissue exposure and acute toxicity of HFRT after mastectomy. Aim To assess the dosimetric outcomes and acute toxicity profile of adjuvant HFRT following mastectomy for breast cancer. Materials and Materials This prospective observational study considered consecutive patients planned for adjuvant HFRT (42.5 Gy in 16 sessions delivered over 3 weeks) to the chest wall with/without regional nodes between October 2014 and June 2015. The dosimetric parameters including dose homogeneity to the target volume and exposure to heart and lung were analyzed. Acute haematological and dermatological toxicity was recorded until upto three months after completion of RT. Results Among the 56 patients treated with HFRT, the mean age was 49 years (range: 28-69 years). Pathologically positive nodes and ≥pT3 primary was observed in 44 (78.6%) and 12 (21.4%) patients, respectively. Majority (87.5%) received prior adjunct chemotherapy. RT to the supraclavicular fossa was delivered for 39 (69.6%) patients. The mean V90 and V95 to the Planning Target Volume (PTV) were 95% (± 3.3%) and 93% (± 4%), respectively. The maximum dose received was on average 47.7 Gy (112%; range: 46.2-48.5 Gy). The mean lung dose was 10.2 Gy (± 3.5 Gy) and V20 was 20.9% (± 6%). The mean V25 to heart was 6.6% (± 4.8%) for left sided and 0% for right sided tumours (p=0.001). Acute skin toxicity peaked at completion of RT and was tolerable (grade 0, I, II and III reactions were 75%, 16% and 1.8%, respectively). No patient had ≥ grade III haematological toxicity, and treatment was not interrupted for any patient. Conclusion Adjuvant HFRT could be planned while meeting the dose constraints to normal tissues in all patients and was well tolerated, with mild
Cancer Stem Cells Protect Non-Stem Cells From Anoikis: Bystander Effects.
Kim, Seog-Young; Hong, Se-Hoon; Basse, Per H; Wu, Chuanyue; Bartlett, David L; Kwon, Yong Tae; Lee, Yong J
Cancer stem cells (CSCs) are capable of initiation and metastasis of tumors. Therefore, understanding the biology of CSCs and the interaction between CSCs and their counterpart non-stem cells is crucial for developing a novel cancer therapy. We used CSC-like and non-stem breast cancer MDA-MB-231 and MDA-MB-453 cells to investigate mammosphere formation. We investigated the role of the epithelial cadherin (E-cadherin)-extracellular signal-regulated kinase (Erk) axis in anoikis. Data from E-cadherin small hairpin RNA assay and mitogen-activated protein kinase kinase (MEK) inhibitor study show that activation of Erk, but not modulation of E-cadherin level, may play an important role in anoikis resistance. Next, the two cell subtypes were mixed and the interaction between them during mammosphere culture and xenograft tumor formation was investigated. Unlike CSC-like cells, increased secretion of interleukin-6 (IL-6) and growth-related oncogene (Gro) chemokines was detected during mammosphere culture in non-stem cells. Similar results were observed in mixed cells. Interestingly, CSC-like cells protected non-stem cells from anoikis and promoted tumor growth. Our results suggest bystander effects between CSC-like cells and non-stem cells. J. Cell. Biochem. 117: 2289-2301, 2016. © 2016 Wiley Periodicals, Inc. PMID:26918647
Stem cell research: paths to cancer therapies and regenerative medicine.
Weissman, Irving
Most tissues in complex metazoans contain a rare subset of cells that, at the single-cell level, can self-renew and also give rise to mature daughter cells. Such stem cells likely in development build tissues and are retained in adult life to regenerate them. Cancers and leukemias are apparently not an exception: rare leukemia stem cells and cancer stem cells have been isolated that contain all of the tumorigenicity of the whole tumor, and it is their properties that will guide future therapies. None of this was apparent just 20 years ago, yet this kind of stem cell thinking already provides new perspectives in medical science and could usher in new therapies. Today, political, religious, and ethical issues surround embryonic stem cell and patient-specific pluripotent stem cell research and are center stage in the attempts by governments to ban these fields for discovery and potential therapies. These interventions require physicians and physician-scientists to determine for themselves whether patient welfare or personal ethics will dominate in their practices, and whether all aspects of stem cell research can be pursued in a safe and regulated fashion.
Tyrosine kinase inhibitors target cancer stem cells in renal cell cancer.
Czarnecka, Anna M; Solarek, Wojciech; Kornakiewicz, Anna; Szczylik, Cezary
This study was designed to analyze the impact of multi-targeted tyrosine kinase inhibitors on the cancer stem cell subpopulation in renal cell cancer. The second objective was to evaluate the effect of tumor growth inhibition related to a tumor niche factor - oxygen deprivation - as hypoxia develops along with the anti-angiogenic activity of tyrosine kinase inhibitors in renal tumors. Cells were treated with tyrosine kinase inhibitors, sunitinib, sorafenib and axitinib, in 2D and 3D culture conditions. Cell proliferation along with drug toxicity were evaluated. It was shown that the proliferation rate of cancer stem cells was decreased by the tyrosine kinase inhibitors. The efficacy of the growth inhibition was limited by hypoxic conditions and 3D intratumoral cell-cell interactions. We conclude that understanding the complex molecular interaction feedback loops between differentiated cancer cells, cancer stem cells and the tumor microenvironment in 3D culture should aid the identification of novel treatment targets and to evalute the efficacy of renal cancer therapies. Cell-cell interaction may represent a critical microenvironmental factor regulating cancer stem cell self-renewal potential, enhancing the stem cell phenotype and limiting drug toxicity. At the same time the role of hypoxia in renal cancer stem cell biology is also significant.
Cell Line Derived 5-FU and Irinotecan Drug-Sensitivity Profiles Evaluated in Adjuvant Colon Cancer Trial Data
Delorenzi, Mauro; Jensen, Thomas; Jensen, Peter Buhl; Bosman, Fred; Tejpar, Sabine; Roth, Arnaud; Brunner, Nils; Hansen, Anker; Knudsen, Steen
Purpose This study evaluates whether gene signatures for chemosensitivity for irinotecan and 5-fluorouracil (5-FU) derived from in vitro grown cancer cell lines can predict clinical sensitivity to these drugs. Methods To test if an irinotecan signature and a SN-38 signature could identify patients who benefitted from the addition of irinotecan to 5-FU, we used gene expression profiles based on cell lines and clinical tumor material. These profiles were applied to expression data obtained from pretreatment formalin fixed paraffin embedded (FFPE) tumor tissue from 636 stage III colon cancer patients enrolled in the PETACC-3 prospective randomized clinical trial. A 5-FU profile developed similarly was assessed by comparing the PETACC-3 cohort with a cohort of 359 stage II colon cancer patients who underwent surgery but received no adjuvant therapy. Results There was no statistically significant association between the irinotecan or SN-38 profiles and benefit from irinotecan. The 5-FU sensitivity profile showed a statistically significant association with relapse free survival (RFS) (hazard ratio (HR) = 0.54 (0.41–0.71), p<1e-05) and overall survival (HR = 0.47 (0.34–0.63), p<1e-06) in the PETACC-3 subpopulation. The effect of the 5-FU profile remained significant in a multivariable Cox Proportional Hazards model, adjusting for several relevant clinicopathological parameters. No statistically significant effect of the 5-FU profile was observed in the untreated cohort of 359 patients (relapse free survival, p = 0.671). Conclusion The irinotecan predictor had no predictive value. The 5-FU predictor was prognostic in stage III patients in PETACC-3 but not in stage II patients with no adjuvant therapy. This suggests a potential predictive ability of the 5-FU sensitivity profile to identify colon cancer patients who may benefit from 5-FU, however, any biomarker predicting benefit for adjuvant 5-FU must be rigorously evaluated in independent cohorts. Given differences
Inactivation of the MAL gene in breast cancer is a common event that predicts benefit from adjuvant chemotherapy
Horne, Hisani N.; Lee, Paula S.; Murphy, Susan K.; Alonso, Miguel A.; Olson, John A.; Marks, Jeffrey R.
Dis-regulation of MAL (myelin and lymphocyte protein) has been implicated in several malignancies including esophageal, ovarian, and cervical cancers. The MAL protein functions in apical transport in polarized-epithelial cells, therefore its disruption may lead to loss of organized polarity characteristic of most solid malignancies. Bisulfite sequencing of the MAL promoter CpG island revealed hypermethylation in breast cancer cell lines and 69% of primary tumors analyzed compared to normal breast epithelial cells. Differential methylation between normal and cancer DNA was confined to the proximal promoter region. In a subset of breast cancer cell lines including T47D and MCF7 cells, promoter methylation correlated with transcriptional silencing that was reversible with the methylation inhibitor 5-Aza-2'-deoxycytidine. In addition, expression of MAL reduced motility and resulted in a redistribution of lipid raft components in MCF10A cells. MAL protein expression measured by immunohistochemistry revealed no significant correlation with clinico-pathologic features. However, in patients who did not receive adjuvant chemotherapy, reduced MAL expression was a significant predictive factor for disease-free survival. These data implicate MAL as a commonly altered gene in breast cancer with implications for response to chemotherapy. PMID:19208741
Self-adjuvanted nanovaccine for cancer immunotherapy: Role of lysosomal rupture-induced ROS in MHC class I antigen presentation.
Wang, Ce; Li, Ping; Liu, Lanlan; Pan, Hong; Li, Hongchang; Cai, Lintao; Ma, Yifan
MHC class I (MHC I) antigen presentation of exogenous antigens (so called "cross presentation") is a central mechanism of CD8(+) cytotoxic T lymphocyte (CTL) responses essential for successful vaccine-based cancer immunotherapy. The present study constructed amphiphilic pH-sensitive galactosyl dextran-retinal (GDR) nanogels for cancer vaccine delivery, in which dextran was conjugated with all-trans retinal (a metabolite of vitamin A) through a pH-sensitive hydrazone bond, followed by galactosylation to acquire dendritic cell (DC)-targeting ability. Our results showed that pH-sensitive GDR nanogel was a self-adjuvanted vaccine carrier that not only promoted DC maturation through activating retinoic acid receptor (RAR) signaling, but also facilitated antigen uptake and cytosolic antigen release in DCs. Furthermore, pH-sensitive GDR nanogel effectively augmented MHC I antigen presentation and evoked potent anti-cancer immune responses in vivo. More importantly, we first reported that nanoparticle-triggered lysosome rupture could directly induce ROS production in DCs, which was found to be essential for augmenting proteasome activity and downstream MHC I antigen presentation. Hence, DC-targeted pH-sensitive GDR nanogels could be a potent delivery system for cancer vaccine development. Triggering lyososomal rupture in DCs with pH-sensitive nanoparticles might be a plausible strategy to elevate intracellular ROS production for promoting antigen cross presentation, thereby improving cancer vaccine efficacy. PMID:26702587
[Administration of S-1 Monotherapy as Adjuvant Chemotherapy in a Patient with Advanced Gastric Cancer with HIV Infection].
Amaki, Misato; Yajima, Kazuhito; Iwasaki, Yoshiaki; Ken, Yuu; Oohinata, Ryouki; Imamura, Akifumi
A 64-year-old man with advanced gastric cancer presented with chief complaints of chest pain. His preoperative blood examination revealed positive results for serum HIV-antibody. His HIV-RNA level was 1.0×10 / 5 copies/mL, and his CD4lymphocyte count was 491 cell/mL; the patient was diagnosed with advanced gastric cancer and HIV infection. Distal gastrectomy with D2 lymphadenectomy and Roux-en-Y reconstruction were performed for treatment of the gastric cancer. Pathological examination revealed T3(SS)N3aM0, Stage III C cancer. After surgery, the patient was administered S-1 monotherapy as adjuvant treatment with antiretroviral therapy including tenofovir/emtricitabine and raltegravir. He completed 8 courses of S- 1 chemotherapy with no adverse events, such as a decrease in the CD4lymphocyte count or an increase in the HIV-RNA level. This patient with gastric cancer and HIV infection was safely treated using both antiretroviral therapy and chemotherapy owing to treatment intervention by chemotherapy and infectious diseases specialists. PMID:27539043
Self-adjuvanted nanovaccine for cancer immunotherapy: Role of lysosomal rupture-induced ROS in MHC class I antigen presentation.
Wang, Ce; Li, Ping; Liu, Lanlan; Pan, Hong; Li, Hongchang; Cai, Lintao; Ma, Yifan
MHC class I (MHC I) antigen presentation of exogenous antigens (so called "cross presentation") is a central mechanism of CD8(+) cytotoxic T lymphocyte (CTL) responses essential for successful vaccine-based cancer immunotherapy. The present study constructed amphiphilic pH-sensitive galactosyl dextran-retinal (GDR) nanogels for cancer vaccine delivery, in which dextran was conjugated with all-trans retinal (a metabolite of vitamin A) through a pH-sensitive hydrazone bond, followed by galactosylation to acquire dendritic cell (DC)-targeting ability. Our results showed that pH-sensitive GDR nanogel was a self-adjuvanted vaccine carrier that not only promoted DC maturation through activating retinoic acid receptor (RAR) signaling, but also facilitated antigen uptake and cytosolic antigen release in DCs. Furthermore, pH-sensitive GDR nanogel effectively augmented MHC I antigen presentation and evoked potent anti-cancer immune responses in vivo. More importantly, we first reported that nanoparticle-triggered lysosome rupture could directly induce ROS production in DCs, which was found to be essential for augmenting proteasome activity and downstream MHC I antigen presentation. Hence, DC-targeted pH-sensitive GDR nanogels could be a potent delivery system for cancer vaccine development. Triggering lyososomal rupture in DCs with pH-sensitive nanoparticles might be a plausible strategy to elevate intracellular ROS production for promoting antigen cross presentation, thereby improving cancer vaccine efficacy.
The Hippo signaling pathway in stem cell biology and cancer.
Mo, Jung-Soon; Park, Hyun Woo; Guan, Kun-Liang
The Hippo signaling pathway, consisting of a highly conserved kinase cascade (MST and Lats) and downstream transcription coactivators (YAP and TAZ), plays a key role in tissue homeostasis and organ size control by regulating tissue-specific stem cells. Moreover, this pathway plays a prominent role in tissue repair and regeneration. Dysregulation of the Hippo pathway is associated with cancer development. Recent studies have revealed a complex network of upstream inputs, including cell density, mechanical sensation, and G-protein-coupled receptor (GPCR) signaling, that modulate Hippo pathway activity. This review focuses on the role of the Hippo pathway in stem cell biology and its potential implications in tissue homeostasis and cancer.
Telomeres, stem cells, senescence, and cancer
Sharpless, Norman E.; DePinho, Ronald A.
Mammalian aging occurs in part because of a decline in the restorative capacity of tissue stem cells. These self-renewing cells are rendered malignant by a small number of oncogenic mutations, and overlapping tumor suppressor mechanisms (e.g., p16INK4a-Rb, ARF-p53, and the telomere) have evolved to ward against this possibility. These beneficial antitumor pathways, however, appear also to limit the stem cell life span, thereby contributing to aging. PMID:14722605
Sell, Stewart
Identification of the cells in the liver that produce alpha-fetoprotein (AFP) during development, in response to liver injury, and during the early stages of chemical hepatocarcinogenesis led to the conclusion that maturation arrest of liver-determined tissue stem cells was the cellular process that gives rise to hepatocellular carcinomas (HCC). When the cellular changes in these processes were compared that of the formation of teratocarcinomas, the hypothesis arose that all cancers arise from maturation arrest of tissue determined stem cells. This was essentially a reinterpretation of the embryonal rest theory of cancer whereby tissue stem cells take the role of embryonal rests. A corollary of the stem cell theory of the origin of cancer is that cancers contain the same functional cell populations as do normal tissues: stem cells, transit-amplifying cells, and mature cells. Cancer stem cells retain the essential feature of normal stem cells: the ability to self-renew. Growth of cancers is due to continued proliferation of cancer transit-amplifying cells that do not differentiate to mature cells (maturation arrest). On the other hand, cancer stem cells generally divide very rarely and contribute little to tumor growth. However, the presence of cancer stem cells in tumors is believed to be responsible for the properties of immortalization, transplantability and resistance to therapy characteristic of cancers. Current therapies for cancer (chemotherapy, radiotherapy, anti-angiogenesis and differentiation therapy) are directed against the cancer transit amplifying cells. When these therapies are discontinued, the cancer re-forms from the cancer stem cells. Therapy directed toward interruption of the cell-signaling pathways that maintain cancer stem cells could lead to new modalities to the prevention of re-growth of the cancer. PMID:18612221
Characteristics of liver cancer stem cells and clinical correlations.
Cheng, Zhuo; Li, Xiaofeng; Ding, Jin
Liver cancer is an aggressive malignant disease with a poor prognosis. Patients with liver cancer are usually diagnosed at an advanced stage and thus miss the opportunity for surgical resection. Chemotherapy and radiofrequency ablation, which target tumor bulk, have exhibited limited therapeutic efficacy to date. Liver cancer stem cells (CSCs) are a small subset of undifferentiated cells existed in liver cancer, which are considered to be responsible for liver cancer initiation, metastasis, relapse and chemoresistance. Elucidating liver CSC characteristics and disclosing their regulatory mechanism might not only deepen our understanding of the pathogenesis of liver cancer but also facilitate the development of diagnostic, prognostic and therapeutic approaches to improve the clinical management of liver cancer. In this review, we will summarize the recent advances in liver CSC research in terms of the origin, identification, regulation and clinical correlation.
Early cardiac toxicity following adjuvant radiotherapy of left-sided breast cancer with or without concurrent trastuzumab
Cao, Lu; Cai, Gang; Chang, Cai; Yang, Zhao-Zhi; Feng, Yan; Yu, Xiao-Li; Ma, Jin-Li; Wu, Jiong; Guo, Xiao-Mao; Chen, Jia-Yi
Purpose To evaluate the influence of concurrent trastuzumab on the cardiotoxicity in patients receiving left-sided adjuvant radiotherapy. Materials and Methods Medical records of stage I-III left-sided breast cancer patients, including 64 receiving concurrent trastuzumab with radiotherapy and 73 receiving radiotherapy alone were retrospectively reviewed. All of the patients had normal LVEF after adjuvant chemotherapy. Information of doses volume to cardiac structures was collected. Cardiac events were assessed according to CTC 2.0. Results Median follow-up of LVEF and clinical assessment of cardiac function from the initiation of radiotherapy was 6.7 months (range 3–60.9) and 26 months (range 6.4–60.9), respectively. Grade 1 LVEF dysfunction occurred in 5 (7.8%) and 3 (4.1%) patients of the concurrent-trastuzumab and radiotherapy alone cohort, respectively. Trastuzumab was the only significant factor influencing absolute LVEF decrease in univariate analysis. In multivariate analysis of concurrent-trastuzumab cohort, IMC radiotherapy and start trastuzumab during radiotherapy were independent risk factors. For concurrent cohort, mean heart dose, as well as D10-D30, D50-D55, V5-V20 of the heart and D30-D45, D65-D75, V6-V15 of the LV were significantly higher in patients developing LVEF dysfunction. Conclusions Concurrent trastuzumab and left-sided radiotherapy is well tolerated in terms of cardiotoxicity in patients with normal baseline cardiac function after adjuvant chemotherapy. However, increases in mean dose and low–dose volume of cardiac structures are associated with a higher risk of acute LVEF dysfunction. PMID:26460956
Myelodysplastic syndrome and acute myeloid leukemia following adjuvant chemotherapy with and without granulocyte colony-stimulating factors for breast cancer.
Calip, Gregory S; Malmgren, Judith A; Lee, Wan-Ju; Schwartz, Stephen M; Kaplan, Henry G
Risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) post-breast cancer treatment with adjuvant chemotherapy and granulocyte colony-stimulating factors (G-CSF) is not fully characterized. Our objective was to estimate MDS/AML risk associated with specific breast cancer treatments. We conducted a retrospective cohort study of women aged ≥66 years with stage I-III breast cancer between 2001 and 2009 using the Surveillance, Epidemiology, and End Results-Medicare database. Women were classified as receiving treatment with radiation, chemotherapy, and/or G-CSF. We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios (HR) and 95 % confidence intervals (CI) for MDS/AML risk. Among 56,251 breast cancer cases, 1.2 % developed MDS/AML during median follow-up of 3.2 years. 47.1 % of women received radiation and 14.3 % received chemotherapy. Compared to breast cancer cases treated with surgery alone, those treated with chemotherapy (HR = 1.38, 95 %-CI 0.98-1.93) and chemotherapy/radiation (HR = 1.77, 95 %-CI 1.25-2.51) had increased risk of MDS/AML, but not radiation alone (HR = 1.08, 95 % CI 0.86-1.36). Among chemotherapy regimens and G-CSF, MDS/AML risk was differentially associated with anthracycline/cyclophosphamide-containing regimens (HR = 1.86, 95 %-CI 1.33-2.61) and filgrastim (HR = 1.47, 95 %-CI 1.05-2.06), but not pegfilgrastim (HR = 1.10, 95 %-CI 0.73-1.66). We observed increased MDS/AML risk among older breast cancer survivors treated with anthracycline/cyclophosphamide chemotherapy that was enhanced by G-CSF. Although small, this risk warrants consideration when determining adjuvant chemotherapy and neutropenia prophylaxis for breast cancer patients.
Cellular origin of cancer: dedifferentiation or stem cell maturation arrest?
Sell, S
Given the fundamental principle that cancer must arise from a cell that has the potential to divide, two major nonexclusive hypotheses of the cellular origin of cancer are that malignancy arises a) from stem cells due to maturation arrest or b) from dedifferentiation of mature cells that retain the ability to proliferate. The role of stem cells in carcinogenesis is clearly demonstrated in teratocarcinomas. The malignant stem cells of teratocarcinomas are derived from normal multipotent stem cells and have the potential to differentiate into normal benign mature tissue. A widely studied model supporting dedifferentiation has been the putative origin of hepatocarcinomas from "premalignant" foci and nodules induced in the rat liver by chemicals. However, the dedifferentiation concept for hepatocarcinogenesis is challenged by more recent interpretations indicating that hepatocellular carcinoma arises from maturation arrest caused by aberrant differentiation of determined stem cells. Either hypothesis is supported by the cellular changes that occur in the rodent liver after different hepatocarcinogenic regimens. The formation of foci and nodules from altered hepatocytes supports dedifferentiation; the proliferation of small oval cells with the potential to differentiate into either biliary ducts or hepatocytes supports arrested maturation of determined stem cells. It is now postulated that foci and nodular change reflect adaptive changes to the toxic effects of carcinogens and not "preneoplastic" stages to cancer. The stem cell model predicts that genotoxic chemicals induce mutations in the determined stem cell which may be expressed in its progeny. Proliferation of initiated cells is induced by promoting events which also allow additional mutations to occur. PMID:7516873
Epigenetic and metabolic regulation of breast cancer stem cells*
Liu, Hui-xin; Li, Xiao-li; Dong, Chen-fang
Breast cancer has a relatively high mortality rate in women due to recurrence and metastasis. Increasing evidence has identified a rare population of cells with stem cell-like properties in breast cancer. These cells, termed cancer stem cells (CSCs), which have the capacity for self-renewal and differentiation, contribute significantly to tumor progression, recurrence, drug resistance and metastasis. Clarifying the mechanisms regulating breast CSCs has important implications for our understanding of breast cancer progression and therapeutics. A strong connection has been found between breast CSCs and epithelial mesenchymal transition (EMT). In addition, recent studies suggest that the maintenance of the breast CSC phenotype is associated with epigenetic and metabolic regulation. In this review, we focus on recent discoveries about the connection between EMT and CSC, and advances made in understanding the roles and mechanisms of epigenetic and metabolic reprogramming in controlling breast CSC properties. PMID:25559951
Concise Review: Breast Cancer Stem Cells: Regulatory Networks, Stem Cell Niches, and Disease Relevance
Accumulating evidence has shown that cancer stem cells (CSCs), the cancer cells that have long-term proliferative potential and the ability to regenerate tumors with phenotypically heterogeneous cell types, are important mediators of tumor metastasis and cancer relapse. In breast cancer, these cells often possess attributes of cells that have undergone an epithelial-mesenchymal transition (EMT). Signaling networks mediated by microRNAs and EMT-inducing transcription factors connect the EMT program with the core stem cell regulatory machineries. These signaling networks are also regulated by extrinsic niche signals that induce and maintain CSCs, contributing to metastatic colonization and promoting the reactivation of dormant tumor cells. Targeting these CSC pathways is likely to improve the efficacy of conventional chemo- and radiotherapies. PMID:24904174
Lung cancer stem cells and implications for future therapeutics.
Wang, Jing; Li, Ze-hong; White, James; Zhang, Lin-bo
Lung cancer is the most dreaded of all cancers because of the higher mortality rates associated with it worldwide. The various subtypes of lung cancer respond differently to a particular treatment regime, which makes the therapeutic interventions all the more complicated. The concept of cancer stem cells (CSCs) is based primarily on the clinical and experimental observations that indicate the existence of a subpopulation of cells with the capacity to self-renew and differentiate as well as show increased resistance to radiation and chemotherapy. They are considered as the factors responsible for the cases of tumor relapse. The CSCs may have significant role in the development of lung tumorigenesis based on the identification of the CSCs which respond during injury. The properties of multi-potency and self-renewal are shared in common by the lung CSCs with the normal pluripotent stem cells which can be isolated using the similar markers. This review deals with the origin and characteristics of the lung cancer stem cells. The role of different markers used to isolate lung CSCs like CD44, ALDH (aldehyde dehydrogenase), CD133 and ABCG2 (ATP binding cassette sub family G member 2) have been discussed in detail. Analysis of the developmental signaling pathways such as Wnt/β-catenin, Notch, hedgehog in the regulation and maintenance of the lung CSCs have been done. Finally, before targeting the lung CSC biomarkers for potential therapeutics, challenges faced in lung cancer stem cell research need to be taken into account. With the accepted notion that the CSCs are to blame for cancer relapse and drug resistance, targeting them can be an important aspect of lung cancer therapy in the future.
Multi-institutional Pooled Analysis on Adjuvant Chemoradiation in Pancreatic Cancer
Morganti, Alessio G.; Falconi, Massimo; Stiphout, Ruud G.P.M. van; Mattiucci, Gian-Carlo; Alfieri, Sergio; Calvo, Felipe A.; Dubois, Jean-Bernard; Fastner, Gerd; Herman, Joseph M.; Maidment, Bert W.; Miller, Robert C.; Regine, William F.; Reni, Michele; Sharma, Navesh K.; Ippolito, Edy; and others
Purpose: To determine the impact of chemoradiation therapy (CRT) on overall survival (OS) after resection of pancreatic adenocarcinoma. Methods and Materials: A multicenter retrospective review of 955 consecutive patients who underwent complete resection with macroscopically negative margins (R0-1) for invasive carcinoma (T1-4; N0-1; M0) of the pancreas was performed. Exclusion criteria included metastatic or unresectable disease at surgery, macroscopic residual disease (R2), treatment with intraoperative radiation therapy (IORT), and a histological diagnosis of no ductal carcinoma, or postoperative death (within 60 days of surgery). In all, 623 patients received postoperative radiation therapy (RT), 575 patients received concurrent chemotherapy (CT), and 462 patients received adjuvant CT. Results: Median follow-up was 21.0 months. Median OS after adjuvant CRT was 39.9 versus 24.8 months after no adjuvant CRT (P<.001) and 27.8 months after CT alone (P<.001). Five-year OS was 41.2% versus 24.8% with and without postoperative CRT, respectively. The positive impact of CRT was confirmed by multivariate analysis (hazard ratio [HR] = 0.72; confidence interval [CI], 0.60-0.87; P=.001). Adverse prognostic factors identified by multivariate analysis included the following: R1 resection (HR = 1.17; CI = 1.07-1.28; P<.001), higher pT stage (HR = 1.23; CI = 1.11-1.37; P<.001), positive lymph nodes (HR = 1.27; CI = 1.15-1.41; P<.001), and tumor diameter >20 mm (HR = 1.14; CI = 1.05-1.23; P=.002). Multivariate analysis also showed a better prognosis in patients treated in centers with >10 pancreatic resections per year (HR = 0.87; CI = 0.78-0.97; P=.014) Conclusion: This study represents the largest comparative study on adjuvant therapy in patients after resection of carcinoma of the pancreas. Overall survival was better in patients who received adjuvant CRT.
Cancer Stem Cells: Potential Target for Bioactive Food Components
Kim, Young S.; Farrar, William; Colburn, Nancy H.; Milner, John A.
Cancer stem cells often have phenotypic and functional characteristics similar to normal stem cells including the properties of self-renewal and differentiation. Recent findings suggest that uncontrolled self-renewal may explain cancer relapses and may represent a critical target for cancer prevention. It is conceivable that the loss of regulatory molecules resulting from inappropriate consumption of specific foods and their constituents may foster the aberrant self-renewal of cancer stem cells. In fact, increasing evidence points to the network delivering signals for self-renewal from extracellular compartments to the nucleus including changes in stem cell environments, inducible expression of microRNAs, hyperplastic nuclear chromatin structures, and the on/off of differentiation process as possible sites of action for bioactive food components. Diverse dietary constituents such as vitamins A and D, genistein, (−)-epigallocatechin-3-gallate (EGCG), sulforaphane, curcumin, piperine, theanine, and choline have been shown to modify self-renewal properties of cancer stem cells. The ability of these bioactive food components to influence the balance between proliferative and quiescent cells by regulating critical feedback molecules in the network including dickkopf 1 (DKK-1), secreted frizzled-related protein 2 (sFRP2), B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1), and cyclin-dependent kinase 6 (CDK6) may account for their biological response. Overall, the response to food components does not appear to be tissue or organ specific, suggesting there may be common cellular mechanisms. Unquestionably, additional studies are needed to clarify the physiological role of these dietary components in preventing the resistance of tumor cells to traditional drugs and cancer recurrence. PMID:22704055
PrPC from stem cells to cancer
Martin-Lannerée, Séverine; Hirsch, Théo Z.; Hernandez-Rapp, Julia; Halliez, Sophie; Vilotte, Jean-Luc; Launay, Jean-Marie; Mouillet-Richard, Sophie
The cellular prion protein PrPC was initially discovered as the normal counterpart of the pathological scrapie prion protein PrPSc, the main component of the infectious agent of Transmissible Spongiform Encephalopathies. While clues as to the physiological function of this ubiquitous protein were greatly anticipated from the development of knockout animals, PrP-null mice turned out to be viable and to develop without major phenotypic abnormalities. Notwithstanding, the discovery that hematopoietic stem cells from PrP-null mice have impaired long-term repopulating potential has set the stage for investigating into the role of PrPC in stem cell biology. A wealth of data have now exemplified that PrPC is expressed in distinct types of stem cells and regulates their self-renewal as well as their differentiation potential. A role for PrPC in the fate restriction of embryonic stem cells has further been proposed. Paralleling these observations, an overexpression of PrPC has been documented in various types of tumors. In line with the contribution of PrPC to stemness and to the proliferation of cancer cells, PrPC was recently found to be enriched in subpopulations of tumor-initiating cells. In the present review, we summarize the current knowledge of the role played by PrPC in stem cell biology and discuss how the subversion of its function may contribute to cancer progression. PMID:25364760
Adjuvant photodynamic therapy (PDT) with photosensitizer photosens for superficial bladder cancer: experimental investigations to treat prostate cancer by PDT with photosens
NASA Astrophysics Data System (ADS)
Apolikhin, Oleg I.; Chernishov, Igor V.; Sivkov, Andrey V.; Altunin, Denis V.; Kuzmin, Sergey G.; Vorozhtsov, Georgy N.
14 patients with transional-cell bladder cancer in stage T1N0M0G2 after transurethral bladder resection were offered adjuvant treatment with PDT. Adjuvant PDT was performed 1-1.5 months after transurethral bladder resection for superficial bladder cancer. Prior to PDT conventional and fluorescent cystoscopy were performed. In the absence of inflammation and after full epitalisation of postoperative wound a session of therapy was performed. 24 hours prior to PDT-session photosensitizer Photosens was injected intravenously in the dose of 0.8 mg per kg of body weight. Prior to PDT local anesthesia of urethra with lidocain-gel was performed. Cystoscopy was carried out. PDT was performed with diode laser "Biospec" (675 nm). During the session the place of standing diffuser and the volume of a bladder were controlled. After 7 months of observation no tumor recidivists were observed. Registered side effects were not life-threatened. 5 patients had pain or discomfort in suprapubic area, ceasing spontaneously or requiring administration of analgetics. No systemic side-effects or allergic reactions were observed. The method can be used in out-patient practice. Absence of early recidivists shows efficiency of PDT in the treatment of superficial bladder cancer. Further study is necessary to estimate optimal regimen of PDT. The further controlling of condition on the patients in this group is required. At the laboratory animals' experiment, we conducted the explorations devoted to the influence of the photodynamic effect at the prostate's tissues.
Concise reviews: cancer stem cells: from concept to cure.
Matchett, K B; Lappin, T R
In 1953, noting a remarkable consistency between the agents causing mutations and those associated with cancer, Carl Nordling, a Finnish-born architect, proposed that cancer results from an accumulation of genetic mutations. It is now generally accepted that inherited mutations and environmental carcinogens can lead to the development of premalignant clones. After further mutations, one cell reaches a critical state which confers a survival or growth advantage over normal cells. Such cells have the ability to initiate a malignant tumour. They share many of the features of normal stem cells, including the capacity for self-renewal and differentiation, and are widely termed cancer stem cells (CSCs). Although CSCs have been well characterized in hematological malignancies, their existence in some other tissues has been questioned. Here, we review recent work in which stem cells and stem cell-like cells have been used to investigate the pathogenesis of cancer and potential anticancer treatment strategies, in the context of both hematological and somatic tissue disease.
Nuclear receptors as regulators of stem cell and cancer stem cell metabolism.
Simandi, Zoltan; Cuaranta-Monroy, Ixchelt; Nagy, Laszlo
Cellular metabolism is underpinning physiological processes in all cells. These include housekeeping functions as well as specific activities unique to a particular cell type. A growing number of studies in various experimental models indicate that metabolism is tightly connected to embryonic development as well. It is also emerging that metabolic processes have regulatory roles and by changing metabolism, cellular processes and even fates can be influenced. Nuclear receptors (NRs) are transcription factors, responding to changes in metabolites and are implicated in diverse biological processes such as embryonic development, differentiation, metabolism and cancer. Therefore, NRs are key links between metabolism and cell fate decisions. In this review, we introduce ESRRβ, DAX-1 and LRH-1 as putative regulators of metabolism in pluripotent embryonic stem cells. We also discuss the role of TR4, NGF1β, LXRβ and RARs in stemness. In addition, we summarize our current understanding of the potential roles of NRs in cancer stem cells. PMID:24184382
Adjuvant for vaccine immunotherapy of cancer--focusing on Toll-like receptor 2 and 3 agonists for safely enhancing antitumor immunity.
Seya, Tsukasa; Shime, Hiroaki; Takeda, Yohei; Tatematsu, Megumi; Takashima, Ken; Matsumoto, Misako
Immune-enhancing adjuvants usually targets antigen (Ag)-presenting cells to tune up cellular and humoral immunity. CD141(+) dendritic cells (DC) represent the professional Ag-presenting cells in humans. In response to microbial pattern molecules, these DCs upgrade the maturation stage sufficient to improve cross-presentation of exogenous Ag, and upregulation of MHC and costimulators, allowing CD4/CD8 T cells to proliferate and liberating cytokines/chemokines that support lymphocyte attraction and survival. These DCs also facilitate natural killer-mediated cell damage. Toll-like receptors (TLRs) and their signaling pathways in DCs play a pivotal role in DC maturation. Therefore, providing adjuvants in addition to Ag is indispensable for successful vaccine immunotherapy for cancer, which has been approved in comparison with antimicrobial vaccines. Mouse CD8α(+) DCs express TLR7 and TLR9 in addition to the TLR2 family (TLR1, 2, and 6) and TLR3, whereas human CD141(+) DCs exclusively express the TLR2 family and TLR3. Although human and mouse plasmacytoid DCs commonly express TLR7/9 to respond to their agonists, the results on mouse adjuvant studies using TLR7/9 agonists cannot be simply extrapolated to human adjuvant immunotherapy. In contrast, TLR2 and TLR3 are similarly expressed in both human and mouse Ag-presenting DCs. Bacillus Calmette-Guerin peptidoglycan and polyinosinic-polycytidylic acid are representative agonists for TLR2 and TLR3, respectively, although they additionally stimulate cytoplasmic sensors: their functional specificities may not be limited to the relevant TLRs. These adjuvants have been posted up to a certain achievement in immunotherapy in some cancers. We herein summarize the history and perspectives of TLR2 and TLR3 agonists in vaccine-adjuvant immunotherapy for cancer.
Non-coding RNAs Functioning in Colorectal Cancer Stem Cells.
Fanale, Daniele; Barraco, Nadia; Listì, Angela; Bazan, Viviana; Russo, Antonio
In recent years, the hypothesis of the presence of tumor-initiating cancer stem cells (CSCs) has received a considerable support. This model suggested the existence of CSCs which, thanks to their self-renewal properties, are able to drive the expansion and the maintenance of malignant cell populations with invasive and metastatic potential in cancer. Increasing evidence showed the ability of such cells to acquire self-renewal, multipotency, angiogenic potential, immune evasion, symmetrical and asymmetrical divisions which, along with the presence of several DNA repair mechanisms, further enhance their oncogenic potential making them highly resistant to common anticancer treatments. The main signaling pathways involved in the homeostasis of colorectal (CRC) stem cells are the Wnt, Notch, Sonic Hedgehog, and Bone Morfogenic Protein (BMP) pathways, which are mostly responsible for all the features that have been widely referred to stem cells. The same pathways have been identified in colorectal cancer stem cells (CRCSCs), conferring a more aggressive phenotype compared to non-stem CRC cells. Recently, several evidences suggested that non-coding RNAs (ncRNAs) may play a crucial role in the regulation of different biological mechanisms in CRC, by modulating the expression of critical stem cell transcription factors that have been found active in CSCs. In this chapter, we will discuss the involvement of ncRNAs, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in stemness acquisition and maintenance by CRCSCs, through the regulation of pathways modulating the CSC phenotype and growth, carcinogenesis, differentiation, and epithelial to mesenchymal transition (EMT). PMID:27573896
Non-coding RNAs Functioning in Colorectal Cancer Stem Cells.
Fanale, Daniele; Barraco, Nadia; Listì, Angela; Bazan, Viviana; Russo, Antonio
In recent years, the hypothesis of the presence of tumor-initiating cancer stem cells (CSCs) has received a considerable support. This model suggested the existence of CSCs which, thanks to their self-renewal properties, are able to drive the expansion and the maintenance of malignant cell populations with invasive and metastatic potential in cancer. Increasing evidence showed the ability of such cells to acquire self-renewal, multipotency, angiogenic potential, immune evasion, symmetrical and asymmetrical divisions which, along with the presence of several DNA repair mechanisms, further enhance their oncogenic potential making them highly resistant to common anticancer treatments. The main signaling pathways involved in the homeostasis of colorectal (CRC) stem cells are the Wnt, Notch, Sonic Hedgehog, and Bone Morfogenic Protein (BMP) pathways, which are mostly responsible for all the features that have been widely referred to stem cells. The same pathways have been identified in colorectal cancer stem cells (CRCSCs), conferring a more aggressive phenotype compared to non-stem CRC cells. Recently, several evidences suggested that non-coding RNAs (ncRNAs) may play a crucial role in the regulation of different biological mechanisms in CRC, by modulating the expression of critical stem cell transcription factors that have been found active in CSCs. In this chapter, we will discuss the involvement of ncRNAs, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in stemness acquisition and maintenance by CRCSCs, through the regulation of pathways modulating the CSC phenotype and growth, carcinogenesis, differentiation, and epithelial to mesenchymal transition (EMT).
The Anti-Cancer Effect of Polyphenols against Breast Cancer and Cancer Stem Cells: Molecular Mechanisms
Abdal Dayem, Ahmed; Choi, Hye Yeon; Yang, Gwang-Mo; Kim, Kyeongseok; Saha, Subbroto Kumar; Cho, Ssang-Goo
The high incidence of breast cancer in developed and developing countries, and its correlation to cancer-related deaths, has prompted concerned scientists to discover novel alternatives to deal with this challenge. In this review, we will provide a brief overview of polyphenol structures and classifications, as well as on the carcinogenic process. The biology of breast cancer cells will also be discussed. The molecular mechanisms involved in the anti-cancer activities of numerous polyphenols, against a wide range of breast cancer cells, in vitro and in vivo, will be explained in detail. The interplay between autophagy and apoptosis in the anti-cancer activity of polyphenols will also be highlighted. In addition, the potential of polyphenols to target cancer stem cells (CSCs) via various mechanisms will be explained. Recently, the use of natural products as chemotherapeutics and chemopreventive drugs to overcome the side effects and resistance that arise from using chemical-based agents has garnered the attention of the scientific community. Polyphenol research is considered a promising field in the treatment and prevention of breast cancer. PMID:27657126
Tumours with cancer stem cells: A PDE model.
Fasano, A; Mancini, A; Primicerio, M
The role of cancer stem cells (CSC) in tumour growth has received increasing attention in the recent literature. Here we stem from an integro-differential system describing the evolution of a population of CSC and of ordinary (non-stem) tumour cells formulated and studied in a previous paper, and we investigate an approximation in which the system reduces to a pair of nonlinear coupled parabolic equation. We prove that the new system is well posed and we examine some general properties. Numerical simulations show more on the qualitative behaviour of the solutions, concerning in particular the so-called tumour paradox, according to which an increase of the mortality rate of ordinary (non-stem) tumour cells results asymptotically in a faster growth.
Cutaneous adverse effects of hormonal adjuvant therapy for breast cancer: a case of localised urticarial vasculitis following anastrozole therapy and a review of the literature.
Bock, Vanessa L; Friedlander, Michael; Waring, Dale; Kossard, Steven; Wood, Glenda K
Hormonal therapy with either tamoxifen or aromatase inhibitors is commonly used to treat women with breast cancer in both the adjuvant and recurrent disease setting. Cutaneous adverse reactions to these drugs have been rarely reported in the literature. We report an unusual case of urticarial vasculitis following the aromatase inhibitor anastrozole that localised to the unilateral trunk and mastectomy scar, and review the literature on the cutaneous adverse effects of hormonal therapy for breast cancer.
Neoadjuvant and adjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy for lung cancer
Zhai, Haoran; Zhong, Wenzhao; Yang, Xuening
The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis and the meta-analysis of individual participant data reported by non-small cell lung cancer (NSCLC) Meta-analysis Collaborative Group in neo-adjuvant setting validated respectively that adjuvant and neoadjuvant chemotherapy would significantly improve overall survival (OS) and recurrence-free survival for resectable NSCLC. However, chemotherapy has reached a therapeutic plateau. It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeting therapy provides a dramatic response to patients with advanced EGFR-mutation positive NSCLC. Researchers have paid more attention to exploring applications of TKIs to early resectable NSCLCs. Several studies on adjuvant TKI treatment concluded its safety and feasibility. But there existed certain limitations of these studies as inference factors to interpret data accurately: the BR19 study recruited patients among which almost 52% had stage IB and only 15 (3.0%, 15/503) had been confirmed with EGFR-mutant type; retrospective studies performed at Memorial Sloan Kettering Cancer Center (MSKCC) selected EGFR mutant-type NSCLC patients but couldn't avoid inherent defects inside retrospective researches; the RADIANT study revised endpoints from targeting at EGFR immunohistochemistry (IHC)+ and/or fluorescence in situ hybridization (FISH)+ mutation to only EGFR IHC+ mutation, leading to selective bias; despite that the SELECT study validated efficacy of adjuvant TKI and second round of TKI after resistance occurred, a single-arm clinical trial is not that persuasive in the absence of comparison with chemotherapy. Taking all these limitations into account, CTONG1104 in China and IMPACT in Japan have been conducted and recruiting patients to offer higher level of evidences to explore efficacy of preoperative TKI therapy for early resectable EGFR mutation positive NSCLC patients (confirmed by pathological results of tumor tissue or
Redox regulation in cancer stem cells
Technology Transfer Automated Retrieval System (TEKTRAN)
Reactive oxygen species (ROS) and ROS-dependent (redox regulation) signaling pathways and transcriptional activities are thought to be critical in stem cell self-renewal and differentiation during growth and organogenesis. Aberrant ROS burst and dysregulation of those ROS-dependent cellular processe...
Challenges in the Delivery of Quality Breast Cancer Care: Initiation of Adjuvant Hormone Therapy at an Urban Safety Net Hospital
Crowley, Meaghan M.; McCoy, Molly E.; Bak, Sharon M.; Caron, Sarah E.; Ko, Naomi Y.; Kachnic, Lisa A.; Alvis, Faber; Battaglia, Tracy A.
Purpose: Breast cancer treatment disparities in racial/ethnic minority and low-income populations are well documented; however, underlying reasons remain poorly understood. This study sought to identify barriers to the delivery of quality breast cancer treatment, addressing compliance with the National Quality Forum (NQF) quality metric for adjuvant hormone therapy (HT; administration of HT within 365 days of diagnosis in eligible patients) at an urban safety net hospital. Methods: This retrospective, observational study included women diagnosed with nonmetastatic, T1c or greater, estrogen and/or progesterone receptor–positive breast cancer from 2006 to 2008. Data sources included the hospital cancer registry and electronic medical record. Compliance with the NQF quality metric was defined as HT prescription within 365 days of diagnosis. Bivariate analysis compared compliant with noncompliant patients. Qualitative analysis assessed reasons for delayed compliance (HT at > 365 days) and never compliance (no HT at 4 years). Results: Of 113 eligible patients, the majority were racial/ethnic minority (56%), stage II (54%), unmarried (60%), and had public or no insurance (72%). Sixty-four percent were compliant, and 36% were noncompliant. Of the noncompliant, 78% had delayed compliance, and 22% were never compliant. Noncompliant patients were significantly more likely to be Black, Hispanic, foreign-born, and stage III at diagnosis. Ten reasons for delayed compliance were identified, including patient- and system-level barriers. Most patients (56%) had more than one reason contributing to delay. Conclusion: Urgently needed interventions to reduce disparities in breast cancer treatment should take into account obstacles inherent among immigrant and indigent populations and complexities of multidisciplinary cancer care. PMID:24345397
Cancer stem cells: an insight and future perspective.
Kaur, Sandeep; Singh, Gurdeep; Kaur, Kirandeep
The cancer stem cell (CSC) concept derives from the fact that cancers are dysregulated tissue clones whose continued propagation is vested in a biologically distinct subset of cells that are typically rare. Rare CSCs have been isolated from a number of human tumors, including hematopoietic, brain, colon, and breast cancer. With the growing evidence that CSCs exist in a wide array of tumors, it is becoming increasingly important to understand the molecular mechanisms that regulate self-renewal and differentiation because corruption of genes involved in these pathways likely participates in tumor growth. Understanding the biology of CSCs will contribute to the identification of molecular targets important for future therapies.
[Prostate cancer stem cells: advances in current research].
Wu, Gang; Wu, Deng-long
Prostate cancer is one of the most common malignancies threatening men's health, and the mechanisms underlying its initiation and progression are poorly understood. Last decade has witnessed encouraging progress in the studies of prostate cancer stem cells (PCSCs), which are considered to play important roles in tumor initiation, recurrence and metastasis, castration resistance, and drug resistance. Therefore, a deeper insight into PCSCs is of great significance for the successful management of prostate cancer. This article presents an overview on the location, origin, and markers of PCSCs as well as their potential correlation with tumor metastasis and castration resistance.
Isolation and Culturing of Glioma Cancer Stem Cells
Kim, Sang-Soo; Pirollo, Kathleen F.; Chang, Esther H.
In many human cancers including malignant glioblastoma multiforme (GBM), cancer stem cells (CSCs) are thought to be responsible for tumor initiation, metastasis and resistance to conventional anti-cancer therapies. Therefore, a CSC-targeted drug delivery strategy to eliminate CSCs is a desirable approach for developing a more effective therapeutic. Moreover, isolated CSCs will provide an invaluable tool for studying the underlying cellular mechanisms of tumor development and provide insight into therapeutic options for successful eradication of CSCs. This unit describes a method for the isolation and culture of CSCs from human GBM tumor tissue. PMID:26061242
Current and Emerging Systemic Therapy in Gastro-Esophageal Cancer "The Old and New Therapy for Metastatic Disease, The Role of Adjuvant and Neoadjuvant Therapy for Localized Disease".
Lim, Bora; Jiang, Yixing
Cancers of esophagus and stomach are common malignant diseases worldwide, and they are associated with serious morbidity and high mortality rates. When diagnosed at an early stage, gastro-esophageal cancers are potentially curable. Neo-adjuvant or adjuvant therapies using both chemotherapy and radiation therapy have been shown to reduce the risk of local recurrence and distant metastasis. For advanced or metastatic tumors, systemic chemotherapy offers symptomatic palliation and moderate benefits in survival. With recent advances in anti-cancer therapeutics, progress has been made to improve treatment response and life expectancy in patients with advanced gastro-esophageal cancers. Furthermore, the clinical use of molecularly targeted agents in combination with cytotoxic chemotherapeutics is being evaluated in a number of ongoing clinical trials. In this article, we review currently used standard systemic therapies including recently evolving targeted therapies for metastatic gastro-esophageal cancers, as well as the proven role and the regimens that are used as neoadjuvant and adjuvant treatment in localized gastro-esophageal cancers.
Combination of Cancer Stem Cell Markers CD44 and CD24 Is Superior to ALDH1 as a Prognostic Indicator in Breast Cancer Patients with Distant Metastases
Horimoto, Yoshiya; Arakawa, Atsushi; Sasahara, Noriko; Tanabe, Masahiko; Sai, Sei; Himuro, Takanori; Saito, Mitsue
The combination of CD44 and CD24, or aldehyde dehydrogenase 1 (ALDH1) alone, is a widely used cancer stem cell marker in breast cancer. However, no conclusion has yet been reached as to which marker is the best for characterizing cancer stemness. Immunohistochemical evaluation using cancer stem cell markers is clearly less common clinically than in basic experiments and how the expressions of these markers relate to patient outcomes remains controversial. To investigate whether combining these markers might improve the prediction of patient outcomes, we immunohistochemically examined clinical samples. Primary invasive breast cancer samples from 61 patients who eventually developed distant metastases after curative surgery were immunohistochemically examined. All patients were free of metastatic disease at the time of surgery and received standard adjuvant systemic treatments. CD44+/24- and ALDH1-positive rates in primary tumors differed according to intrinsic subtype. ER-positive patients with CD44+/24- tumors had significantly longer disease-free-survival than all other ER-positive patients (p = 0.0047). On the other hand, CD44+/24- tumors were associated with poor outcomes of ER-negative patients (p = 0.038). Finally, expression patterns of CD44 and ALDH1 in single tumors were strikingly different and there were virtually no individual double-stained cells. Thus, this combination does not allow evaluation of relationships with patient outcomes. Our results raise the possibility of CD44+/24- being a good prognostic marker, one which would allow treatment effects and outcomes to be predicted in patients with recurrent breast cancer. PMID:27768764
Breast cancer stem cells: current advances and clinical implications.
Luo, Ming; Clouthier, Shawn G; Deol, Yadwinder; Liu, Suling; Nagrath, Sunitha; Azizi, Ebrahim; Wicha, Max S
There is substantial evidence that many cancers, including breast cancer, are driven by a population of cells that display stem cell properties. These cells, termed cancer stem cells (CSCs) or tumor initiating cells, not only drive tumor initiation and growth but also mediate tumor metastasis and therapeutic resistance. In this chapter, we summarize current advances in CSC research with a major focus on breast CSCs (BCSCs). We review the prevailing methods to isolate and characterize BCSCs and recent evidence documenting their cellular origins and phenotypic plasticity that enables them to transition between mesenchymal and epithelial-like states. We describe in vitro and clinical evidence that these cells mediate metastasis and treatment resistance in breast cancer, the development of novel strategies to isolate circulating tumor cells (CTCs) that contain CSCs and the use of patient-derived xenograft (PDX) models in preclinical breast cancer research. Lastly, we highlight several signaling pathways that regulate BCSC self-renewal and describe clinical implications of targeting these cells for breast cancer treatment. The development of strategies to effectively target BCSCs has the potential to significantly improve the outcomes for patients with breast cancer.
Prior Adjuvant Tamoxifen Treatment in Breast Cancer Is Linked to Increased AIB1 and HER2 Expression in Metachronous Contralateral Breast Cancer
Alkner, Sara; Bendahl, Pär-Ola; Ehinger, Anna; Lövgren, Kristina; Rydén, Lisa; Fernö, Mårten
Aim The estrogen receptor coactivator Amplified in Breast Cancer 1 (AIB1) has been associated with an improved response to adjuvant tamoxifen in breast cancer, but also with endocrine treatment resistance. We hereby use metachronous contralateral breast cancer (CBC) developed despite prior adjuvant tamoxifen for the first tumor as an "in vivo"-model for tamoxifen resistance. AIB1-expression in the presumable resistant (CBC after prior tamoxifen) and naïve setting (CBC without prior tamoxifen) is compared and correlated to prognosis after CBC. Methods From a well-defined population-based cohort of CBC-patients we have constructed a unique tissue-microarray including >700 patients. Results CBC developed after adjuvant tamoxifen more often had a HER2-positive/triple negative-subtype and a high AIB1-expression (37% vs. 23%, p = 0.009), than if no prior endocrine treatment had been administered. In patients with an estrogen receptor (ER) positive CBC, a high AIB1-expression correlated to an inferior prognosis. However, these patients seemed to respond to tamoxifen, but only if endocrine therapy had not been administered for BC1. Conclusions Metachronous CBC developed after prior endocrine treatment has a decreased ER-expression and an increased HER2-expression. This is consistent with endocrine treatment escape mechanisms previously suggested, and indicates metachronous CBC to be a putative model for studies of treatment resistance "in vivo". The increased AIB1-expression in CBC developed after prior tamoxifen suggests a role of AIB1 in endocrine treatment resistance. In addition, we found indications that the response to tamoxifen in CBC with a high AIB1-expression seem to differ depending on previous exposure to this drug. A different function for AIB1 in the tamoxifen treatment naïve vs. resistant setting is suggested, and may explain previously conflicting results where a high AIB1-expression has been correlated to both a good response to adjuvant
High-dose consolidation therapy with autologous stem cell rescue in stage IV breast cancer.
Williams, S F; Mick, R; Desser, R; Golick, J; Beschorner, J; Bitran, J D
We designed a phase II study to determine whether induction chemotherapy (CT) consisting of leucovorin, vincristine, methotrexate, doxorubicin, and cyclophosphamide (LOMAC) followed by high-dose intensification chemotherapy (ICT) with cyclophosphamide, thiotepa, and autologous stem cell rescue (ASCR) could increase the complete response (CR) rate and survival in women with stage IV breast cancer. Twenty-nine women were enrolled on study; 16 patients had received prior adjuvant chemotherapy and no patient had received chemotherapy for stage IV disease. Two patients were found to be ineligible and excluded from further analysis. Of the 27 patients treated, four (15%) obtained a CR and 15 (56%) a partial response (PR) after LOMAC induction, for an overall response rate of 70%. Of the 22 patients treated with ICT, 12 patients had a CR, and nine were in PR after induction and converted to CR after ICT. The toxicities included nausea/vomiting, mucositis, diarrhea, dermatitis, alopecia, and infections secondary to neutropenia. The 1-year survival is 60%; the median has not yet been reached. The time to treatment failure for patients on study is 10 months. The treatment approach of ICT and ASCR following induction chemotherapy can lead to an improved CR rate in stage IV breast cancer. How this increased CR rate leads to a prolonged disease-free survival requires further follow-up.
Preferential targeting of cancer stem cells in the radiosensitizing effect of ABT-737 on HNSCC
Gilormini, Marion; Malesys, Céline; Armandy, Emma; Manas, Patrick; Guy, Jean-Baptiste; Magné, Nicolas; Rodriguez-Lafrasse, Claire; Ardail, Dominique
Head and neck squamous cell carcinomas (HNSCC) are common human malignancies with poor clinical outcomes. The 5-year survival rates for patients with advanced stage HNSCC have not changed appreciably in the past few decades, underscoring a dire need for improved therapeutic options. HNSCC is frequently characterized by overexpression of anti-apoptotic Bcl-2 family members. Increased levels of these anti-apoptotic proteins have been associated with radio- and chemoresistance and poor clinical outcome. The aim of this study was to evaluate combined effects of radiation and ABT-737, a BH3-mimetic molecule, in HNSCC. Although ABT-737, as a single agent, was largely ineffective at promoting HNSCC cell death, we found that combining ABT-737 and radiation induced strong synergistic apoptosis in HNSCC cell lines and delayed tumoral growth in vivo. Moreover, we demonstrated for the first time that ABT-737, alone or in combination with radiation, can efficiently eliminate cancer stem cells (CSCs). Altogether, our results indicate that therapy targeting anti-apoptotic Bcl-2 family members could be a highly effective potential adjuvant to radiotherapy capable of targeting CSCs in HNSCC and therefore overcoming cancer recurrence and metastasis. PMID:26934442
Neo-adjuvant chemotherapy plus surgery versus surgery alone for cervical cancer: Meta-analysis of randomized controlled trials.
Peng, Yun-Hua; Wang, Xin-Xiu; Zhu, Jing-Song; Gao, Li
The aim of this study was to evaluate the efficacy and safety of neo-adjuvant chemotherapy (NACT) versus radical surgery (RS) for patients with cervical cancer. A meta-analysis of randomized controlled trials (RCT) of NACT + RS versus RS alone for patients with cervical cancer was performed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The following electronic databases were searched from their inception to April 2015: PUBMED, EMBASE and Cochrane Library. Statistical analysis was done using REVIEW MANAGER 5.3. Five RCT involving 739 patients were studied. There were significant differences between the NACT + RS and the RS-alone groups for positive lymph nodes (OR, 0.45; 95%CI: 0.29-0.70) and parametrial infiltration (OR, 0.48; 95% CI: 0.25-0.92), while treatment efficacy did not differ significantly for 5-year overall survival rate (OR, 1.17; 95% CI: 0.85-1.61), 5-year disease-free survival rate (OR, 1.09; 95% CI: 0.77-1.56) or recurrence rate (OR, 1.17; 95% CI: 0.85-1.61). The results also indicated that chemotherapy-related toxicity was well tolerated. For patients with cervical cancer, NACT could significantly reduce the number of positive lymph nodes and the level of parametrial infiltration compared with RS alone, and be well tolerated.
[Innovation in adjuvant radiotherapy for breast cancer: new biologic parameters, a perspective for treatment tailoring].
Belkacémi, Y
In the adjuvant setting, whole breast radiation therapy (RT) delivering 50 Gy in 5 weeks with or without a boost to the tumor bed remains the standard of care. RT indications and volume definition are generally dependant on existing prognostic factors. Except in particular cases, RT technique does not vary according to the patient or tumor biology profiles in terms of total dose, dose per fraction, fractionation, and RT duration. The challenge is to define new parameters or tumor biology profiles that will allow patient selection for more tailored RT than the 5 to 7 week standard schedules. The future issue is to define biological markers able to screen patients and tumors according to their high metastatic potential (in which the primary therapeutic challenge may not be locoregional control) and those patients that have a particular radiosensitivity to ionizing radiation for higher benefit/risk ratio. Thus, it is probable that patient profiles, tumor biology markers and gene expression profiling could provide in future an added value to conventional markers to predict patients at high-risk of local and distant recurrences who need tailored treatment or a particular sequence of adjuvant therapy.
Macrophage-directed immunotherapy as adjuvant to photodynamic therapy of cancer.
Korbelik, M.; Naraparaju, V. R.; Yamamoto, N.
The effect of Photofrin-based photodynamic therapy (PDT) and adjuvant treatment with serum vitamin D3-binding protein-derived macrophage-activating factor (DBPMAF) was examined using a mouse SCCVII tumour model (squamous cell carcinoma). The results show that DBPMAF can markedly enhance the curative effect of PDT. The most effective DBPMAF therapy consisted of a combination of intraperitoneal and peritumoral injections (50 and 0.5 ng kg-1 respectively) administered on days 0, 4, 8 and 12 after PDT. Used with a PDT treatment curative to 25% of the treated tumours, this DBPMAF regimen boosted the cures to 100%. The DBPMAF therapy alone showed no notable effect on the growth of SCCVII tumour. The PDT-induced immunosuppression, assessed by the evaluation of delayed-type contact hypersensitivity response in treated mice, was greatly reduced with the combined DBPMAF treatment. These observations suggest that the activation of macrophages in PDT-treated mice by adjuvant immunotherapy has a synergistic effect on tumour cures. As PDT not only reduces tumour burden but also induces inflammation, it is proposed that recruitment of the activated macrophages to the inflamed tumour lesions is the major factor for the complete eradication of tumours. PMID:9010027
Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy
Chen, Qian; Xu, Ligeng; Liang, Chao; Wang, Chao; Peng, Rui; Liu, Zhuang
A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours. PMID:27767031
Ascophyllan functions as an adjuvant to promote anti-cancer effect by dendritic cell activation
Zhang, Wei; Okimura, Takasi; Xu, Li; Zhang, Lijun; Oda, Tatsuya; Kwak, Minseok; Yu, Qing; Jin, Jun-O
Our previous study demonstrated that ascophyllan, a sulfated polysaccharide purified from brown alga, has immune-activating effects. In this study, we evaluated ascophyllan as an adjuvant for its therapeutic and preventive effect on tumor in a mouse melanoma model. Ascophyllan induced migration of DCs to spleen and tumor-draining lymph node (drLN) in a mouse B16 melanoma model. Moreover, ascophyllan induced activation of dendritic cells (DCs), and promoted IFN-γ- and TNF-α-producing Th1 immune responses in tumor-bearing mice. In addition, treatment with a combination of ascophyllan and ovalbumin (OVA) in the tumor-bearing mice promoted proliferation of OVA-specific CD4 and CD8 T cells and migration of those cells into the tumor, consequently inhibiting the tumor growth. Immunization with the combination of ascophyllan and OVA caused enhanced OVA-specific antibody production and memory T cell responses compared to OVA immunization alone, and almost completely prevented B16-OVA tumor growth upon subsequent tumor challenge. Finally, the combination of ascophyllan and OVA prevented B16-OVA tumor invasion and metastasis into the liver. Thus, these results demonstrate that ascophyllan can function as an adjuvant to induce DC activation, antigen specific CTL activation, Th1 immune response and antibody production, and hence may be useful as a therapeutic and preventive tumor vaccine. PMID:27008707
Adjuvant chemotherapy for resected non-small-cell lung cancer: future perspectives for clinical research
Adjuvant chemotherapy for non-small-cell lung carcinoma (NSCLC) is a debated issue in clinical oncology. Although it is considered a standard for resected stage II-IIIA patients according to the available guidelines, many questions are still open. Among them, it should be acknowledged that the treatment for stage IB disease has shown so far a limited (if sizable) efficacy, the role of modern radiotherapies requires to be evaluated in large prospective randomized trials and the relative impact of age and comorbidities should be weighted to assess the reliability of the trials' evidences in the context of the everyday-practice. In addition, a conclusive evidence of the best partner for cisplatin is currently awaited as well as a deeper investigation of the fading effect of chemotherapy over time. The limited survival benefit since first studies were published and the lack of reliable prognostic and predictive factors beyond pathological stage, strongly call for the identification of bio-molecular markers and classifiers to identify which patients should be treated and which drugs should be used. Given the disappointing results of targeted therapy in this setting have obscured the initial promising perspectives, a biomarker-selection approach may represent the basis of future trials exploring adjuvant treatment for resected NSCLC. PMID:22206620
Chemopreventive drugs: mechanisms via inhibition of cancer stem cells in colorectal cancer.
Kim, Tae Il
Recent epidemiological studies, basic research and clinical trials on colorectal cancer (CRC) prevention have helped identify candidates for effective chemopreventive drugs. However, because of the conflicting results of clinical trials or side effects, the effective use of chemopreventive drugs has not been generalized, except for patients with a high-risk for developing hereditary CRC. Advances in genetic and molecular technologies have highlighted the greater complexity of carcinogenesis, especially the heterogeneity of tumors. We need to target cells and processes that are critical to carcinogenesis for chemoprevention and treatment of advanced cancer. Recent research has shown that intestinal stem cells may serve an important role in tumor initiation and formation of cancer stem cells. Moreover, studies have shown that the tumor microenvironment may play additional roles in dedifferentiation, to enable tumor cells to take on stem cell features and promote the formation of tumorigenic stem cells. Therefore, early tumorigenic changes of stem cells and signals for dedifferentiation may be good targets for chemoprevention. In this review, I focus on cancer stem cells in colorectal carcinogenesis and the effect of major chemopreventive drugs on stem cell-related pathways.
Role of Axillary Clearance After a Tumor-Positive Sentinel Node in the Administration of Adjuvant Therapy in Early Breast Cancer
Straver, Marieke E.; Meijnen, Philip; van Tienhoven, Geertjan; van de Velde, Cornelis J.H.; Mansel, Robert E.; Bogaerts, Jan; Demonty, Gaston; Duez, Nicole; Cataliotti, Luigi; Klinkenbijl, Jean; Westenberg, Helen A.; van der Mijle, Huub; Hurkmans, Coen; Rutgers, Emiel J.T.
Purpose The After Mapping of the Axilla: Radiotherapy or Surgery? (AMAROS) phase III study compares axillary lymph node dissection (ALND) and axillary radiation therapy (ART) in early breast cancer patients with tumor-positive sentinel nodes. In the ART arm, the extent of nodal involvement remains unknown, which could have implications on the administration of adjuvant therapy. In this preliminary analysis, we studied the influence of random assignment to ALND or ART on the choice for adjuvant treatment. Patients and Methods In the first 2,000 patients enrolled in the AMAROS trial, we analyzed the administration of adjuvant systemic therapy. Multivariate analysis was used to assess variables affecting the administration of adjuvant chemotherapy. Adjuvant therapy was applied according to institutional guidelines. Results Of 2,000 patients, 566 patients had a positive sentinel node and were treated per random assignment. There was no significant difference in the administration of adjuvant systemic therapy. In the ALND and ART arms, 58% (175 of 300) and 61% (162 of 266) of the patients, respectively, received chemotherapy. Endocrine therapy was administered in 78% (235 of 300) of the patients in the ALND arm and in 76% (203 of 266) of the patients in the ART arm. Treatment arm was not a significant factor in the decision, and no interactions between treatment arm and other factors were observed. Multivariate analysis showed that age, tumor grade, multifocality, and size of the sentinel node metastasis significantly affected the administration of chemotherapy. Within the ALND arm, the extent of nodal involvement remained not significant in a sensitivity multivariate analysis. Conclusion Absence of knowledge regarding the extent of nodal involvement in the ART arm appears to have no major impact on the administration of adjuvant therapy. PMID:20038733
Treating cancer stem cells and cancer metastasis using glucose-coated gold nanoparticles.
Hu, Chenxia; Niestroj, Martin; Yuan, Daniel; Chang, Steven; Chen, Jie
Cancer ranks among the leading causes of human mortality. Cancer becomes intractable when it spreads from the primary tumor site to various organs (such as bone, lung, liver, and then brain). Unlike solid tumor cells, cancer stem cells and metastatic cancer cells grow in a non-attached (suspension) form when moving from their source to other locations in the body. Due to the non-attached growth nature, metastasis is often first detected in the circulatory systems, for instance in a lymph node near the primary tumor. Cancer research over the past several decades has primarily focused on treating solid tumors, but targeted therapy to treat cancer stem cells and cancer metastasis has yet to be developed. Because cancers undergo faster metabolism and consume more glucose than normal cells, glucose was chosen in this study as a reagent to target cancer cells. In particular, by covalently binding gold nanoparticles (GNPs) with thio-PEG (polyethylene glycol) and thio-glucose, the resulting functionalized GNPs (Glu-GNPs) were created for targeted treatment of cancer metastasis and cancer stem cells. Suspension cancer cell THP-1 (human monocytic cell line derived from acute monocytic leukemia patients) was selected because it has properties similar to cancer stem cells and has been used as a metastatic cancer cell model for in vitro studies. To take advantage of cancer cells' elevated glucose consumption over normal cells, different starvation periods were screened in order to achieve optimal treatment effects. Cancer cells were then fed using Glu-GNPs followed by X-ray irradiation treatment. For comparison, solid tumor MCF-7 cells (breast cancer cell line) were studied as well. Our irradiation experimental results show that Glu-GNPs are better irradiation sensitizers to treat THP-1 cells than MCF-7 cells, or Glu-GNPs enhance the cancer killing of THP-1 cells 20% more than X-ray irradiation alone and GNP treatment alone. This finding can help oncologists to design
Metformin and prostate cancer stem cells: a novel therapeutic target.
Mayer, M J; Klotz, L H; Venkateswaran, V
Prostate cancer is the second most frequently diagnosed cancer in the world. Localized disease can be effectively treated with radiation therapy or radical prostatectomy. However, advanced prostate cancer is more difficult to treat and if metastatic, is incurable. There is a need for more effective therapy for advanced prostate cancer. One potential target is the cancer stem cell (CSC). CSCs have been described in several solid tumors, including prostate cancer, and contribute to therapeutic resistance and tumor recurrence. Metformin, a common oral biguanide used to treat type 2 diabetes, has been demonstrated to have anti-neoplastic effects. Specifically, metformin targets CSCs in breast cancer, pancreatic cancer, glioblastoma and colon cancer. Metformin acts directly on the mitochondria to inhibit oxidative phosphorylation and reduce mitochondrial ATP production. This forces tumor cells to compensate by increasing the rate of glycolysis. CSCs rely heavily on mitochondrial oxidative phosphorylation for energy production. The glycolytic switch results in an energy crisis in these cells. Metformin could be used to exploit this metabolic weakness in CSCs. This would increase CSC sensitivity to conventional cancer therapies, circumventing treatment resistance and enhancing treatment efficacy. This review will explore the characteristics of prostate CSCs, their role in tumor propagation and therapeutic resistance and the role of metformin as a potential prostate CSC sensitizer to current anticancer therapies. PMID:26215782
Metformin and prostate cancer stem cells: a novel therapeutic target.
Mayer, M J; Klotz, L H; Venkateswaran, V
Prostate cancer is the second most frequently diagnosed cancer in the world. Localized disease can be effectively treated with radiation therapy or radical prostatectomy. However, advanced prostate cancer is more difficult to treat and if metastatic, is incurable. There is a need for more effective therapy for advanced prostate cancer. One potential target is the cancer stem cell (CSC). CSCs have been described in several solid tumors, including prostate cancer, and contribute to therapeutic resistance and tumor recurrence. Metformin, a common oral biguanide used to treat type 2 diabetes, has been demonstrated to have anti-neoplastic effects. Specifically, metformin targets CSCs in breast cancer, pancreatic cancer, glioblastoma and colon cancer. Metformin acts directly on the mitochondria to inhibit oxidative phosphorylation and reduce mitochondrial ATP production. This forces tumor cells to compensate by increasing the rate of glycolysis. CSCs rely heavily on mitochondrial oxidative phosphorylation for energy production. The glycolytic switch results in an energy crisis in these cells. Metformin could be used to exploit this metabolic weakness in CSCs. This would increase CSC sensitivity to conventional cancer therapies, circumventing treatment resistance and enhancing treatment efficacy. This review will explore the characteristics of prostate CSCs, their role in tumor propagation and therapeutic resistance and the role of metformin as a potential prostate CSC sensitizer to current anticancer therapies.
Would cancer stem cells affect the future investment in stem cell therapy.
Rameshwar, Pranela
The common goal within the overwhelming interests in stem cell research is to safely translate the science to patients. Although there are various methods by which this goal can be reached, this editorial emphasizes the safety of mesenchymal stem cell (MSC) transplant and possible confounds by the growing information on cancer stem cells (CSCs). There are several ongoing clinical trials with MSCs and their interactions with CSCs need to be examined. The rapid knowledge on MSCs and CSCs has now collided with regards to the safe treatment of MSCs. The information discussed on MSCs can be extrapolated to other stem cells with similar phenotype and functions such as placenta stem cells. MSCs are attractive for cell therapy, mainly due to reduced ethical concerns, ease in expansion and reduced ability to be transformed. Also, MSCs can exert both immune suppressor and tissue regeneration simultaneously. It is expected that any clinical trial with MSCs will take precaution to ensure that the cells are not transformed. However, going forward, the different centers should be aware that MSCs might undergo oncogenic events, especially as undifferentiated cells or early differentiated cells. Another major concern for MSC therapy is their ability to promote tumor growth and perhaps, to protect CSCs by altered immune responses. These issues are discussed in light of a large number of undiagnosed cancers.
Cancer stem cells and signaling pathways in radioresistance
Chang, Lei; Graham, Peter; Hao, Jingli; Ni, Jie; Deng, Junli; Bucci, Joseph; Malouf, David; Gillatt, David; Li, Yong
Radiation therapy (RT) is one of the most important strategies in cancer treatment. Radioresistance (the failure to RT) results in locoregional recurrence and metastasis. Therefore, it is critically important to investigate the mechanisms leading to cancer radioresistance to overcome this problem and increase patients' survival. Currently, the majority of the radioresistance-associated researches have focused on preclinical studies. Although the exact mechanisms of cancer radioresistance have not been fully uncovered, accumulating evidence supports that cancer stem cells (CSCs) and different signaling pathways play important roles in regulating radiation response and radioresistance. Therefore, targeting CSCs or signaling pathway proteins may hold promise for developing novel combination modalities and overcoming radioresistance. The present review focuses on the key evidence of CSC markers and several important signaling pathways in cancer radioresistance and explores innovative approaches for future radiation treatment. PMID:26716904
p27Kip1 in Stage III Colon Cancer: Implications for Outcome Following Adjuvant Chemotherapy in CALGB 89803
Bertagnolli, Monica M.; Warren, Robert S.; Niedzwiecki, Donna; Mueller, Elke; Compton, Carolyn C.; Redston, Mark; Hall, Margaret; Hahn, Hejin P.; Jewell, Scott D.; Mayer, Robert J.; Goldberg, Richard M.; Saltz, Leonard B.; Loda, Massimo
Background In retrospective studies, loss of p27Kip1 (p27), a cyclin dependent kinase inhibitor, has been associated with poor prognosis following colorectal cancer treatment. In a prospective study, we validated this relationship in patients enrolled on a trial of adjuvant chemotherapy for Stage III colon cancer. Methods Cancer and Leukemia Group B (CALGB) protocol 89803 randomized 1264 stage III colon cancer patients to receive weekly bolus fluorouracil/leucovorin (5FU/LV) or weekly bolus irinotecan, fluorouracil, and leucovorin (IFL). The primary endpoint was overall survival (OS); disease-free survival (DFS) was a secondary endpoint. Expression of p27 and DNA mismatch repair (MMR) proteins were determined by immunohistochemistry (IHC) in primary tumor and normal tissue from paraffin blocks. Data were analyzed using logrank test. Results Of 601 tumors analyzed, 207 (34.4%) demonstrated p27 loss, 377 (62.8%) retained p27, and 17 (2.8%) were indeterminate. Patients with p27 negative tumors showed reduced OS (5-year 66%; 95%CI 0.59-0.72 vs. 75%; 95%CI 0.70-0.79, logrank p=0.021). This relationship was not influenced by treatment arm. Combination of p27 status with MMR status, however, identified a small subset of patients that may benefit from IFL (n=36; 5-year DFS 81%; 95%CI 0.64-0.98 vs. 47%; 95%CI 0.21-0.72, logrank p=0.042; 5-year OS 81%; 95%CI 0.64-0.98 vs. 60%; 95%CI 0.35-0.85; logrank p=0.128). Conclusions Loss of p27 is associated with reduced survival in stage III colon cancer, but by itself does not indicate a significant difference in outcome between patients treated IFL or 5FU-LV. PMID:19276255
An individual patient data meta-analysis of adjuvant therapy with uracil–tegafur (UFT) in patients with curatively resected rectal cancer
Sakamoto, J; Hamada, C; Yoshida, S; Kodaira, S; Yasutomi, M; Kato, T; Oba, K; Nakazato, H; Saji, S; Ohashi, Y
Uracil–Tegafur (UFT), an oral fluorinated pyrimidine chemotherapeutic agent, has been used for adjuvant chemotherapy in curatively resected colorectal cancer patients. Past trials and meta-analyses indicate that it is somewhat effective in extending survival of patients with rectal cancer. The objective of this study was to perform a reappraisal of randomised clinical trials conducted in this field. We designed an individual patient-based meta-analysis of relevant clinical trials to examine the benefit of UFT for curatively resected rectal cancer in terms of overall survival (OS), disease-free survival (DFS), and local relapse-free survival (LRFS). We analysed individual patient data of five adjuvant therapy randomised clinical trials for rectal cancer, which met the predetermined inclusion criteria. These five trials had a combined total of 2091 patients, UFT as adjuvant chemotherapy compared to surgery-alone, 5-year follow-up, intention-to-treat-based analytic strategy, and similar endpoints (OS and DFS). In a pooled analysis, UFT had significant advantage over surgery-alone in terms of both OS (hazard ratio, 0.82; 95% confidence interval (CI), 0.70–0.97; P=0.02) and DFS (hazard ratio, 0.73; 95%CI, 0.63–0.84; P<0.0001). This individual patient-based meta-analysis demonstrated that oral UFT significantly improves both OS and DFS in patients with curatively resected rectal cancer. PMID:17375049
Wnt signaling in adult intestinal stem cells and cancer.
Krausova, Michaela; Korinek, Vladimir
Signaling initiated by secreted glycoproteins of the Wnt family regulates many aspects of embryonic development and it is involved in homeostasis of adult tissues. In the gastrointestinal (GI) tract the Wnt pathway maintains the self-renewal capacity of epithelial stem cells. The stem cell attributes are conferred by mutual interactions of the stem cell with its local microenvironment, the stem cell niche. The niche ensures that the threshold of Wnt signaling in the stem cell is kept in physiological range. In addition, the Wnt pathway involves various feedback loops that balance the opposing processes of cell proliferation and differentiation. Today, we have compelling evidence that mutations causing aberrant activation of the Wnt pathway promote expansion of undifferentiated progenitors and lead to cancer. The review summarizes recent advances in characterization of adult epithelial stem cells in the gut. We mainly focus on discoveries related to molecular mechanisms regulating the output of the Wnt pathway. Moreover, we present novel experimental approaches utilized to investigate the epithelial cell signaling circuitry in vivo and in vitro. Pivotal aspects of tissue homeostasis are often deduced from studies of tumor cells; therefore, we also discuss some latest results gleaned from the deep genome sequencing studies of human carcinomas of the colon and rectum. PMID:24308963
Radiation-Induced Notch Signaling in Breast Cancer Stem Cells
Lagadec, Chann; Vlashi, Erina; Alhiyari, Yazeed; Phillips, Tiffany M.; Bochkur Dratver, Milana; Pajonk, Frank
Purpose: To explore patterns of Notch receptor and ligand expression in response to radiation that could be crucial in defining optimal dosing schemes for γ-secretase inhibitors if combined with radiation. Methods and Materials: Using MCF-7 and T47D breast cancer cell lines, we used real-time reverse transcription–polymerase chain reaction to study the Notch pathway in response to radiation. Results: We show that Notch receptor and ligand expression during the first 48 hours after irradiation followed a complex radiation dose–dependent pattern and was most pronounced in mammospheres, enriched for breast cancer stem cells. Additionally, radiation activated the Notch pathway. Treatment with a γ-secretase inhibitor prevented radiation-induced Notch family gene expression and led to a significant reduction in the size of the breast cancer stem cell pool. Conclusions: Our results indicate that, if combined with radiation, γ-secretase inhibitors may prevent up-regulation of Notch receptor and ligand family members and thus reduce the number of surviving breast cancer stem cells.
Nanomedicine-Mediated Therapies to Target Breast Cancer Stem Cells
He, Lili; Gu, Jian; Lim, Lee Y.; Yuan, Zhi-xiang; Mo, Jingxin
Accumulating evidences have suggested the existence of breast cancer stem cells (BCSCs), which possess the potential of both self-renewal and differentiation. The origin of BCSCs might have relationship to the development of normal mammary stem cells. BCSCs are believed to play a key role in the initiation, recurrence and chemo-/radiotherapy resistances of breast cancer. Therefore, elimination of BCSCs is crucial for breast cancer therapy. However, conventional chemo and radiation therapies cannot eradicate BCSCs effectively. Fortunately, nanotechnology holds great potential for specific and efficient anti-BCSCs treatment. "Smart" nanocarriers can distinguish BCSCs from the other breast cancer cells and selectively deliver therapeutic agents to the BCSCs. Emerging findings suggest that BCSCs in breast cancer could be successfully inhibited and even eradicated by functionalized nanomedicines. In this review, we focus on origin of BCSCs, strategies used to target BCSCs, and summarize the nanotechnology-based delivery systems that have been applied for eliminating BCSCs in breast cancer. PMID:27679576
A perspective on new immune adjuvant principles: Reprogramming inflammatory states to permit clearance of cancer cells and other age-associated cellular pathologies.
Prendergast, George C; Metz, Richard
Aging entails the accumulation of neoantigens comprised of aggregated, oxidized, mutated and misfolded biomolecules, including advanced-glycation end projects (AGEs). There is evidence that the immune system can recognize and clear cells fouled by these molecular debris, which contribute to the emergence of cancer and other major age-associated diseases such as atherogenic and neurodegenerative disorders. However, this process may become increasingly inefficient with aging, perhaps in part because of an insufficiency of adjuvant signals normally associated with infection that can program productive inflammatory states and properly orient the immune system toward regenerative healing. Here we propose conceptual foundations for exploring a small set of infection-associated molecules as potential immune adjuvants to reprogram non-productive inflammatory states in aging tissues, and to improve the clearance of cellular pathologies that engender age-associated disease. The proposed adjuvant classes include a subset of D-amino acids used by bacteria to disrupt biofilms; nucleoside derivatives of N6-methyladenine, which functions at the core of bacterial dam restriction systems; and derivatives of the galactosyl trisaccharide α-Gal, which invokes the hyperacute response in primates. These foreign amino acids, nucleosides and sugar molecules are generally rare or absent in humans, except in association with infections by bacteria, protists or nematodes. A rationale for exploration of these candidate adjuvant principles and their chemical derivatives is discussed in terms of their use in generalized strategies to improve the prevention or treatment of cancer and other age-associated diseases, as negative modifiers of aging.
Retrospective Study of Adjuvant Chemotherapy Effects on Survival Rate after Three-Field Lymph Node Dissection for Stage IIA Esophageal Cancer.
Chen, Hua-Xia; Wang, Zhou
To determine the efficacy of postoperative adjuvant chemotherapy with paclitaxel plus cisplatin (Taxol+DDP, TP therapy) for stage IIA esophageal squamous cell carcinoma (ESCC) and to investigate the expression of RUNX3 in lymph node metastasis-negative esophageal cancer and its relationship with medical prognosis, a retrospective summary of clinical treatment of 143 cases of stage IIA esophageal squamous cell carcinoma patients was made. The patients were divided into two groups, a surgery alone control group (52 patients) and a chemotherapy group that received postoperative TP therapy (91 patients). The disease-free and 5 year survival rates were compared between the groups and a multivariate analysis of prognostic factors was performed. The same analysis was performed for cases classified as RUNX3 positive and negative, with post-operative specimens assessed by immunohistochemistry. Although the disease-free and 5 year survival rates in control and chemotherapy groups did not significantly differ and there was no significance in RUNX3 negative cases, postoperative adjuvant chemotherapy in the chemotherapy group was shown to improve disease-free and 5 year survival rate compared to the control group in RUNX3 positive cases. On Cox regression multivariate analysis, postoperative adjuvant chemotherapy (P<0.01) was an independent prognostic factor for RUNX3 positive cases, suggesting that postoperative TP may be effective as adjuvant chemotherapy for stage IIA esophageal cancer patients with RUNX3 positive lesions. PMID:26225648
Adjuvant Chemotherapy With or Without Pelvic Radiotherapy After Simultaneous Surgical Resection of Rectal Cancer With Liver Metastases: Analysis of Prognosis and Patterns of Recurrence
An, Ho Jung; Yu, Chang Sik; Yun, Sung-Cheol; Kang, Byung Woog; Hong, Yong Sang; Lee, Jae-Lyun; Ryu, Min-Hee; Chang, Heung Moon; Park, Jin Hong; Kim, Jong Hoon; Kang, Yoon-Koo; Kim, Jin Cheon; Kim, Tae Won
Purpose: To investigate the outcomes of adjuvant chemotherapy (CT) or chemoradiotherapy (CRT) after simultaneous surgical resection in rectal cancer patients with liver metastases (LM). Materials and Methods: One hundred and eight patients receiving total mesorectal excision for rectal cancer and surgical resection for LM were reviewed. Forty-eight patients received adjuvant CRT, and 60 were administered CT alone. Recurrence patterns and prognosis were analyzed. Disease-free survival (DFS) and overall survival (OS) rates were compared between the CRT and CT groups. The inverse probability of the treatment-weighted (IPTW) method based on the propensity score was used to adjust for selection bias between the two groups. Results: At a median follow-up period of 47.7 months, 77 (71.3%) patients had developed recurrences. The majority of recurrences (68.8%) occurred in distant organs. By contrast, the local recurrence rate was only 4.7%. Median DFS and OS were not significantly different between the CRT and CT groups. After applying the IPTW method, we observed no significant differences in terms of DFS (hazard ratio [HR], 1.347; 95% confidence interval [CI], 0.759-2.392; p = 0.309) and OS (HR, 1.413; CI, 0.752-2.653; p = 0.282). Multivariate analyses showed that unilobar distribution of LM and normal preoperative carcinoembryonic antigen level (<6 mg/mL) were significantly associated with longer DFS and OS. Conclusions: The local recurrence rate after simultaneous resection of rectal cancer with LM was relatively low. DFS and OS rates were not different between the adjuvant CRT and CT groups. Adjuvant CRT may have a limited role in this setting. Further prospective randomized studies are required to evaluate optimal adjuvant treatment in these patients.
Longitudinal Assessment of Cognitive Changes Associated with Adjuvant Treatment for Breast Cancer: The Impact of APOE and Smoking
Ahles, Tim A.; Li, Yuelin; McDonald, Brenna C.; Schwartz, Gary N.; Kaufman, Peter A.; Tsongalis, Gregory J.; Moore, Jason H.; Saykin, Andrew J.
Purpose This study examined the association of post-treatment changes in cognitive performance, APOE and smoking in breast cancer patients treated with adjuvant therapy. Participants and Methods Breast cancer patients treated with chemotherapy (N=55, age=51.9+/−7.1, education=15.7+/−2.6) were evaluated with a battery of neuropsychological tests prior to chemotherapy and at 1, 6, and 18 months post-chemotherapy. Matched groups of breast cancer patients not exposed to chemotherapy (N=68, age=56.8+/−8.3, education=14.8+/−2.2) and healthy controls (N=43, age=53.0+/−10.1, education=15.2+/−2.6) were evaluated at similar intervals. APOE epsilon 4 carrier status (APOE4+) and smoking history were also evaluated. Results The detrimental effect of APOE4+ genotype on post-treatment cognitive functioning was moderated by smoking history, i.e., patients without a smoking history had significantly lower performance on measures of processing speed and working memory compared to those with a smoking history and healthy controls. Exploratory analyses revealed that APOE4+ patients without a smoking history who were exposed to chemotherapy showed a decline in performance in processing speed, compared to patients with a smoking history. A similar, but less pronounced pattern was seen in the no chemotherapy group (primarily endocrine treatment). For working memory, the APOE4+ by smoking interaction was observed in the no chemotherapy group only. Conclusions The association between APOE status, breast cancer treatment, and cognitive functioning was moderated by smoking history suggesting that both chemotherapy and endocrine therapy interact with APOE status and smoking to influence cognition. A putative mechanism is that smoking corrects a deficit in nicotinic receptor functioning and dopamine levels in APOE4+ individuals. PMID:24789331
Detection of cancer cells in peripheral blood stem cells of women with breast cancer by RT-PCR and cell culture.
Krüger, W H; Stockschläder, M; Hennings, S; Aschenbrenner, M; Gruber, M; Gutensohn, K; Löliger, C; Gieseking, F; Jonat, W; Zander, A R
The benefit of high-dose therapy and blood stem cell reinfusion for women with high-risk breast cancer is currently under investigation. Contaminations of autologous blood stem cells with cancer cells have been described. Cancer micrometastases may be detected by immunocytochemistry, culture techniques and cytokeratin-19 mRNA reverse transcriptase PCR. Women with breast cancer received adjuvant HD-CTM with peripheral blood stem cell (PBSC) support after surgical therapy and 4 cycles conventional chemotherapy. Peripheral blood stem cells were mobilised by G-CsF and harvested after the third or fourth cycle of standard therapy. Aliquots of PBSC-collections (10(7)-2*10(7) cells) were subjected to CK19-mRNA reverse transcriptase PCR. RNA was extracted by standard methods and reverse transcription was performed with MMV-RT. Integrity of RNA was checked by coamplification of housekeeping sequences. Aliquots of the RT-mix were subjected to PCR-amplification with outer and inner primer pairs, subsequently. A second aliquot of 2*10(7) cells was cultured over 42 days in liquid culture. Cytospins were prepared weekly from cultured cells and evaluated by light microscopy with or without prior immunocytochemistry. Ten leukaphereses from 6 women were available for PCR-analysis and cell culture. Six leukaphereses were negative for CK19-mRNA and for detection of cancer cells by culture technique, two samples were positive for CK19-mRNA and culturally enriched cells and two samples were positive for CK19-mRNA and negative for cultured cancer cells. No sample was positive for cultured cells and negative for CK19-mRNA. Overall, the results corresponded in 80%. Two sensitive techniques for the detection of cancer micrometastases were applied to aliquots from 10 leukaphereses of six breast cancer patients with corresponding results in 80%. PCR-mediated detection of cancer cells was confirmed by culture technique and light microscopy, however, further comparison of CK19-PCR with
The intersection of cancer, cancer stem cells, and the immune system: therapeutic opportunities.
Silver, Daniel J; Sinyuk, Maksim; Vogelbaum, Michael A; Ahluwalia, Manmeet S; Lathia, Justin D
During brain neoplasia, malignant cells subjugate the immune system to provide an environment that favors tumor growth. These mechanisms capitalize on tumor-promoting functions of various immune cell types and typically result in suppression of tumor immune rejection. Immunotherapy efforts are underway to disrupt these mechanisms and turn the immune system against developing tumors. While many of these therapies are already in early-stage clinical trials, understanding how these therapies impact various tumor cell populations, including self-renewing cancer stem cells, may help to predict their efficacy and clarify their mechanisms of action. Moreover, interrogating the biology of glioma cell, cancer stem cell, and immune cell interactions may provide additional therapeutic targets to leverage against disease progression. In this review, we begin by highlighting a series of investigations into immune cell-mediated tumor promotion that do not parse the tumor into stem and non-stem components. We then take a closer look at the immune-suppressive mechanisms derived specifically from cancer stem cell interactions with the immune system and end with an update on immunotherapy and cancer stem cell-directed clinical trials in glioblastoma.
Current Stem Cell Biomarkers and Their Functional Mechanisms in Prostate Cancer
Zhang, Kaile; Zhou, Shukui; Wang, Leilei; Wang, Jianlong; Zou, Qingsong; Zhao, Weixin; Fu, Qiang; Fang, Xiaolan
Currently there is little effective treatment available for castration resistant prostate cancer, which is responsible for the majority of prostate cancer related deaths. Emerging evidence suggested that cancer stem cells might play an important role in resistance to traditional cancer therapies, and the studies of cancer stem cells (including specific isolation and targeting on those cells) might benefit the discovery of novel treatment of prostate cancer, especially castration resistant disease. In this review, we summarized major biomarkers for prostate cancer stem cells, as well as their functional mechanisms and potential application in clinical diagnosis and treatment of patients. PMID:27447616
Tumor-biological factors uPA and PAI-1 as stratification criteria of a multicenter adjuvant chemotherapy trial in node-negative breast cancer.
Prechtl, A; Harbeck, N; Thomssen, C; Meisner, C; Braun, M; Untch, M; Wieland, M; Lisboa, B; Cufer, T; Graeff, H; Selbmann, K; Schmitt, M; Jänicke, F
In axillary node-negative primary breast cancer, 70% of the patients will be cured by locoregional treatment alone. Therefore, adjuvant systemic therapy is only needed for those 30% of node-negative patients who will relapse after primary therapy and eventually die of metastases. Traditional histomorphological and clinical factors do not provide sufficient information to allow accurate risk group assessment in order to identify node-negative patients who might benefit from adjuvant systemic therapy. In the last decade various groups have reported a strong and statistically independent prognostic impact of the serine protease uPA (urokinase-type plasminogen activator) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1) in node-negative breast cancer patients. Based on these data, a prospective multicenter therapy trial in node-negative breast cancer patients was started in Germany in June 1993, supported by the German Research Association (DFG). Axillary node-negative breast cancer patients with high levels of either or both proteolytic factors in the tumor tissue were randomized to adjuvant CMF chemotherapy versus observation only. Recruitment was continued until the end of 1998, by which time 684 patients had been enrolled. Since then, patients have been followed up in order to assess the value of uPA and PAI-1 determination as an adequate selection criterion for adjuvant chemotherapy in node-negative breast cancer patients. This paper reports on the rationale and design of this prospective multicenter clinical trial, which may have an impact on future policies in prognosis-oriented treatment strategies.
Outcome of patients with HER2-positive breast cancer treated with or without adjuvant trastuzumab in the Finland Capecitabine Trial (FinXX)
Background. Little information is available about survival outcomes of patients with HER2-positive early breast cancer treated with adjuvant capecitabine-containing chemotherapy with or without trastuzumab. Patients and methods. One thousand and five hundred patients with early breast cancer were entered to the Finland Capecitabine trial (FinXX) between January 2004 and May 2007, and were randomly assigned to receive either three cycles of adjuvant TX (docetaxel, capecitabine) followed by three cycles of CEX (cyclophosphamide, epirubicin, capecitabine; TX-CEX) or three cycles of docetaxel followed by three cycles of CEF (cyclophosphamide, epirubicin, fluorouracil; T-CEF). The primary endpoint was recurrence-free survival (RFS). The study protocol was amended in May 2005 while study accrual was ongoing to allow adjuvant trastuzumab for patients with HER2-positive cancer. Of the 284 patients with HER2-positive cancer accrued to FinXX, 176 (62.0%) received trastuzumab after amending the study protocol, 131 for 12 months and 45 for nine weeks. The median follow-up time was 6.7 years. Results. Patients with HER2-positive cancer who received trastuzumab had better RFS than those who did not (five-year RFS 89.2% vs. 75.9%; HR 0.41, 95% CI 0.23–0.72; p = 0.001). Patients treated with trastuzumab for 12 months or nine weeks had similar RFS. There was no significant interaction between trastuzumab administration and the type of chemotherapy. Four (2.3%) patients treated with trastuzumab had heart failure or left ventricular dysfunction, three of these received capecitabine. Conclusion. Adjuvant trastuzumab improves RFS of patients treated with TX-CEX or T-CEF. Few patients had cardiac failure. PMID:23957715
Hedgehog Signaling in the Maintenance of Cancer Stem Cells
Cochrane, Catherine R.; Szczepny, Anette; Watkins, D. Neil; Cain, Jason E.
Cancer stem cells (CSCs) represent a rare population of cells with the capacity to self-renew and give rise to heterogeneous cell lineages within a tumour. Whilst the mechanisms underlying the regulation of CSCs are poorly defined, key developmental signaling pathways required for normal stem and progenitor functions have been strongly implicated. Hedgehog (Hh) signaling is an evolutionarily-conserved pathway essential for self-renewal and cell fate determination. Aberrant Hh signaling is associated with the development and progression of various types of cancer and is implicated in multiple aspects of tumourigenesis, including the maintenance of CSCs. Here, we discuss the mounting evidence suggestive of Hh-driven CSCs in the context of haematological malignancies and solid tumours and the novel strategies that hold the potential to block many aspects of the transformation attributed to the CSC phenotype, including chemotherapeutic resistance, relapse and metastasis. PMID:26270676
Breast cancer stem cells programs: enter the (non)-code.
Salvador, Marion A; Birnbaum, Daniel; Charafe-Jauffret, Emmanuelle; Ginestier, Christophe
Breast tumors exhibit a hierarchical cellular organization driven by several subpopulations of cancer stem cells (CSCs). These breast CSC subpopulations are able to infinitely self-renew and to differentiate, giving rise to tumor heterogeneity. Accumulating evidence show that breast CSCs resist conventional therapies and i`nitiate tumor relapse. The development of anti-CSCs therapies may therefore greatly improve patient survival. A better elucidation of molecular circuitries involved in stemness would offer new relevant targets. Noncoding RNAs, especially microRNAs and long noncoding RNAs, are regulators of cell identity and are notably found deregulated in breast CSCs. This review will focus on noncoding RNAs involved in CSCs biology during breast cancer initiation, maintenance, therapeutic resistance and metastatic progression. Potential clinical applications using noncoding RNAs as biomarkers or therapies will be discussed.
Targeting cancer stem cells by using the nanoparticles
Hong, In-Sun; Jang, Gyu-Beom; Lee, Hwa-Yong; Nam, Jeong-Seok
Cancer stem cells (CSCs) have been shown to be markedly resistant to conventional cancer treatments such as chemotherapy and radiation therapy. Therefore, therapeutic strategies that selectively target CSCs will ultimately lead to better cancer treatments. Currently, accessible conventional therapeutic agents mainly eliminate the bulk tumor but do not eliminate CSCs. Therefore, the discovery and improvement of CSC-targeting therapeutic agents are necessary. Nanoparticles effectively inhibit multiple types of CSCs by targeting specific signaling pathways (Wnt/β-catenin, Notch, transforming growth factor-β, and hedgehog signaling) and/or specific markers (aldehyde dehydrogenases, CD44, CD90, and CD133) critically involved in CSC function and maintenance. In this review article, we summarized a number of findings to provide current information about their therapeutic potential of nanoparticles in various cancer cell types and CSCs. PMID:26425092
Cancer microenvironment, inflammation and cancer stem cells: A hypothesis for a paradigm change and new targets in cancer control
Blaylock, Russell L.
Since President Nixon officially declared a war on cancer with the National Cancer Act, billions of dollars have been spent on research in hopes of finding a cure for cancer. Recent reviews have pointed out that over the ensuing 42 years, cancer death rates have barely changed for the major cancers. Recently, several researchers have questioned the prevailing cancer paradigm based on recent discoveries concerning the mechanism of carcinogenesis and the origins of cancer. Over the past decade we have learned a great deal concerning both of these central issues. Cell signaling has taken center stage, particularly as regards the links between chronic inflammation and cancer development. It is now evident that the common factor among a great number of carcinogenic agents is activation of genes controlling inflammation cell-signaling pathways and that these signals control all aspects of the cancer process. Of these pathways, the most important and common to all cancers is the NFκB and STAT3 pathways. The second discovery of critical importance is that mutated stem cells appear to be in charge of the cancer process. Most chemotherapy agents and radiotherapy kill daughter cells of the cancer stem cell, many of which are not tumorigenic themselves. Most cancer stem cells are completely resistant to conventional treatments, which explain dormancy and the poor cure rate with metastatic tumors. A growing number of studies are finding that several polyphenol extracts can kill cancer stem cells as well as daughter cells and can enhance the effectiveness and safety of conventional treatments. These new discoveries provide the clinician with a whole new set of targets for cancer control and cure. PMID:26097771
Monitoring cancer stem cells: insights into clinical oncology
Lin, ShuChen; Xu, YingChun; Gan, ZhiHua; Han, Kun; Hu, HaiYan; Yao, Yang; Huang, MingZhu; Min, DaLiu
Cancer stem cells (CSCs) are a small, characteristically distinctive subset of tumor cells responsible for tumor initiation and progression. Several treatment modalities, such as surgery, glycolytic inhibition, driving CSC proliferation, immunotherapy, and hypofractionated radiotherapy, may have the potential to eradicate CSCs. We propose that monitoring CSCs is important in clinical oncology as CSC populations may reflect true treatment response and assist with managing treatment strategies, such as defining optimal chemotherapy cycles, permitting pretreatment cancer surveillance, conducting a comprehensive treatment plan, modifying radiation treatment, and deploying rechallenge chemotherapy. Then, we describe methods for monitoring CSCs. PMID:26929644
Metabostemness: Metaboloepigenetic reprogramming of cancer stem-cell functions
Menendez, Javier A.; Corominas-Faja, Bruna; Cuyàs, Elisabet; Alarcón, Tomás
Cancer researchers are currently embarking on one of their field's biggest challenges, namely the understanding of how cellular metabolism or certain classes of elite metabolites (e.g., oncometabolites) can directly influence chromatin structure and the functioning of epi-transcriptional circuits to causally drive tumour formation. We here propose that refining the inherent cell attractor nature of nuclear reprogramming phenomena by adding the under-appreciated capacity of metabolism to naturally reshape the Waddingtonian landscape's topography provides a new integrative metabolo-epigenetic model of the cancer stem cell (CSC) theory. PMID:25621295
Aldehyde dehydrogenase 1A1 in stem cells and cancer
Tomita, Hiroyuki; Tanaka, Kaori; Tanaka, Takuji; Hara, Akira
The human genome contains 19 putatively functional aldehyde dehydrogenase (ALDH) genes, which encode enzymes critical for detoxification of endogenous and exogenous aldehyde substrates through NAD(P)+-dependent oxidation. ALDH1 has three main isotypes, ALDH1A1, ALDH1A2, and ALDH1A3, and is a marker of normal tissue stem cells (SC) and cancer stem cells (CSC), where it is involved in self-renewal, differentiation and self-protection. Experiments with murine and human cells indicate that ALDH1 activity, predominantly attributed to isotype ALDH1A1, is tissue- and cancer-specific. High ALDH1 activity and ALDH1A1 overexpression are associated with poor cancer prognosis, though high ALDH1 and ALDH1A1 levels do not always correlate with highly malignant phenotypes and poor clinical outcome. In cancer therapy, ALDH1A1 provides a useful therapeutic CSC target in tissue types that normally do not express high levels of ALDH1A1, including breast, lung, esophagus, colon and stomach. Here we review the functions and mechanisms of ALDH1A1, the key ALDH isozyme linked to SC populations and an important contributor to CSC function in cancers, and we outline its potential in future anticancer strategies. PMID:26783961
The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells?
Plaks, Vicki; Kong, Niwen; Werb, Zena
Cancer stem cells (CSCs) are tumor cells that have the principal properties of self-renewal, clonal tumor initiation capacity, and clonal long-term repopulation potential. CSCs reside in niches, which are anatomically distinct regions within the tumor microenvironment. These niches maintain the principle properties of CSCs, preserve their phenotypic plasticity, protect them from the immune system, and facilitate their metastatic potential. In this perspective, we focus on the CSC niche and discuss its contribution to tumor initiation and progression. Since CSCs survive many commonly employed cancer therapies, we examine the prospects of targeting the niche components as preferable therapeutic targets. PMID:25748930
The Cancer Stem Cell Niche: How Essential is the Niche in Regulating Stemness of Tumor Cells?
Plaks, Vicki; Kong, Niwen; Werb, Zena
Cancer stem cells (CSCs) are tumor cells that have the principal properties of self-renewal, clonal tumor initiation capacity and clonal long-term repopulation potential. CSCs reside in niches, which are anatomically distinct regions within the tumor microenvironment. These niches maintain the principle properties of CSCs, preserve their phenotypic plasticity, protect them from the immune system and facilitate their metastatic potential. In this perspective, we focus on the CSC niche and discuss its contribution to tumor initiation and progression. Since CSCs survive many commonly employed cancer therapies, we examine the prospects of targeting the niche components as preferable therapeutic targets. PMID:25748930
Epigenetic Gene Regulation in Stem Cells and Correlation to Cancer
Mathews, Lesley A.; Crea, Francesco; Farrar, W. L.
Through the classic study of genetics, much has been learned about the regulation and progression of human disease. Specifically, cancer has been defined as a disease driven by genetic alterations, including mutations in tumor-suppressor genes and oncogenes, as well as chromosomal abnormalities. However, the study of normal human development has identified that in addition to classical genetics, regulation of gene expression is also modified by 'epigenetic' alterations including chromatin remodeling and histone variants, DNA methylation, the regulation of polycomb group proteins and the epigenetic function of non-coding RNA. These changes are modifications inherited both during meiosis and mitosis, yet they do not result in alterations of the actual DNA sequence. A number of biological questions are directly influenced by epigenetics, such as how does a cell know when to divide, differentiate or remain quiescent, and more importantly, what happens when these pathways become altered? Do these alterations lead to the development and/or progression of cancer? This review will focus on summarizing the limited current literature involving epigenetic alterations in the context of human cancer stems cells (CSCs). The extent to which epigenetic changes define cell fate, identity, and phenotype are still under intense investigation, and many questions remain largely unanswered. Before discussing epigenetic gene silencing in CSCs, the different classifications of stem cells and their properties will be introduced. This will be followed by an introduction to the different epigenetic mechanisms Finally, there will be a discussion of the current knowledge of epigenetic modifications in stem cells, specifically what is known from rodent systems and established cancer cell lines, and how they are leading us to understand human stem cells. PMID:19443100
Head and Neck Cancer Stem Cells: From Identification to Tumor Immune Network.
Dionne, L K; Driver, E R; Wang, X J
Head and neck squamous cell carcinoma (HNSCC) is the most common form of head and neck cancer. Annually, more than half a million individuals are diagnosed with this devastating disease, with increasing incidence in Europe and Southeast Asia. The diagnosis of HNSCC often occurs in late stages of the disease and is characterized by manifestation of a high-grade primary tumor and/or lymph node metastasis, precluding timely management of this deadly cancer. Recently, HNSCC cancer stem cells have emerged as an important factor for cancer initiation and maintenance of tumor bulk. Like normal stem cells, cancer stem cells can undergo self-renewal and differentiation. This unique trait allows for maintenance of the cancer stem cell pool and facilitates differentiation into heterogeneous neoplastic progeny when necessary. Recent studies have suggested coexistence of different cancer stem cell populations within a tumor mass, where the tumor initiation and metastasis properties of these cancer stem cells can be uncoupled. Cancer stem cells also possess resistant phenotypes that evade standard chemotherapy and radiotherapy, resulting in tumor relapse. Therefore, understanding distinctive pathways relating to cancer stem cells will provide insight into early diagnosis and treatment of HNSCC. In this review, we highlight current advances in identifying cancer stem cells, detail the interactions of these cells with the immune system within the tumor niche, and discuss the potential use of immunotherapy in managing HNSCC.
Culture and characterization of mammary cancer stem cells in mammospheres.
Piscitelli, Eleonora; Cocola, Cinzia; Thaden, Frank Rüdiger; Pelucchi, Paride; Gray, Brian; Bertalot, Giovanni; Albertini, Alberto; Reinbold, Rolland; Zucchi, Ileana
Mammospheres (MMs) are a model for culturing and maintaining mammary gland stem cells (SCs) or cancer stem cells (CSCs) ex situ. As MMs recapitulate the micro-niche of the mammary gland or a tumor, MMs are a model for studying the properties of SCs or CSCs, and for mapping, isolating, and characterizing the SC/CSC generated lineages. Cancer stem cells share with normal SCs the properties of self-renewal and the capacity to generate all cell types and organ structures of the mammary gland. Analysis of human tumor samples suggests that CSCs are heterogeneous in terms of proliferation and differentiation potential. Mammospheres from CSCs likewise display heterogeneity. This heterogeneity makes analysis of CSC generated MMs challenging. To identify the unique and diverse properties of MM derived CSCs, comparative analysis with MMs obtained from normal SCs is required. Here we present protocols for identifying and enriching cells with SC features from a cancer cell line using the LA7CSCs as a model. A comprehensive and comparative approach for identifying, isolating, and characterizing MMs from SCs and CSCs from human breast is also introduced. In addition, we describe detailed procedures for identifying, isolating, and characterizing mammary gland specific cell types, generated during MM formation.
Cancer stem cells and cell size: A causal link?
Li, Qiuhui; Rycaj, Kiera; Chen, Xin; Tang, Dean G
The majority of normal animal cells are 10-20 μm in diameter. Many signaling mechanisms, notably PI3K/Akt/mTOR, Myc, and Hippo pathways, tightly control and coordinate cell growth, cell size, cell division, and cell number during homeostasis. These regulatory mechanisms are frequently deregulated during tumorigenesis resulting in wide variations in cell sizes and increased proliferation in cancer cells. Here, we first review the evidence that primitive stem cells in adult tissues are quiescent and generally smaller than their differentiated progeny, suggesting a correlation between small cell sizes with the stemness. Conversely, increased cell size positively correlates with differentiation phenotypes. We then discuss cancer stem cells (CSCs) and present some evidence that correlates cell sizes with CSC activity. Overall, a causal link between CSCs and cell size is relatively weak and remains to be rigorously assessed. In the future, optimizing methods for isolating cells based on size should help elucidate the connection between cancer cell size and CSC characteristics.
Randomized controlled trial to evaluate the effects of progressive resistance training compared to progressive muscle relaxation in breast cancer patients undergoing adjuvant radiotherapy: the BEST study
Background Cancer-related fatigue (CRF) is one of the most common and distressing side effects of cancer and its treatment. During and after radiotherapy breast cancer patients often suffer from CRF which frequently impairs quality of life (QoL). Despite the high prevalence of CRF in breast cancer patients and the severe impact on the physical and emotional well-being, effective treatment methods are scarce. Physical activity for breast cancer patients has been reported to decrease fatigue, to improve emotional well-being and to increase physical strength. The pathophysiological and molecular mechanisms of CRF and the molecular-biologic changes induced by exercise, however, are poorly understood. In the BEST trial we aim to assess the effects of resistance training on fatigue, QoL and physical fitness as well as on molecular, immunological and inflammatory changes in breast cancer patients during adjuvant radiotherapy. Methods/design The BEST study is a prospective randomized, controlled intervention trial investigating the effects of a 12-week supervised progressive resistance training compared to a 12-week supervised muscle relaxation training in 160 patients with breast cancer undergoing adjuvant radiotherapy. To determine the effect of exercise itself beyond potential psychosocial group effects, patients in the control group perform a group-based progressive muscle relaxation training. Main inclusion criterion is histologically confirmed breast cancer stage I-III after lumpectomy or mastectomy with indication for adjuvant radiotherapy. Main exclusion criteria are acute infectious diseases, severe neurological, musculosceletal or cardiorespiratory disorders. The primary endpoint is cancer-related fatigue; secondary endpoints include immunological and inflammatory parameters analyzed in peripheral blood, saliva and urine. In addition, QoL, depression, physical performance and cognitive capacity will be assessed. Discussion The BEST study is the first randomized
Bladder Cancer Patterns of Pelvic Failure: Implications for Adjuvant Radiation Therapy
Baumann, Brian C.; Guzzo, Thomas J.; He Jiwei; Vaughn, David J.; Keefe, Stephen M.; Vapiwala, Neha; Deville, Curtiland; Bekelman, Justin E.; Tucker, Kai; Hwang, Wei-Ting; Malkowicz, S. Bruce; Christodouleas, John P.
Purpose: Local-regional failures (LFs) after cystectomy with or without chemotherapy are common in locally advanced disease. Adjuvant radiation therapy (RT) could reduce LFs, but toxicity has discouraged its use. Modern RT techniques with improved normal tissue sparing have rekindled interest but require knowledge of pelvic failure patterns to design treatment volumes. Methods and Materials: Five-year LF rates after radical cystectomy plus pelvic node dissection with or without chemotherapy were determined for 8 pelvic sites among 442 urothelial bladder carcinoma patients. The impact of pathologic stage, margin status, nodal involvement, and extent of node dissection on failure patterns was assessed using competing risk analysis. We calculated the percentage of patients whose sites of LF would have been completely encompassed within various hypothetical clinical target volumes (CTVs) for postoperative radiation. Results: Compared with stage {<=}pT2, stage {>=}pT3 patients had higher 5-year LF rates in virtually all pelvic sites. Among stage {>=}pT3 patients, margin status significantly altered the failure pattern whereas extent of node dissection and nodal positivity did not. In stage {>=}pT3 patients with negative margins, failure occurred predominantly in the iliac/obturator nodes and uncommonly in the cystectomy bed and/or presacral nodes. Of these patients in whom failure subsequently occurred, 76% would have had all LF sites encompassed within CTVs covering only the iliac/obturator nodes. In stage {>=}pT3 with positive margins, cystectomy bed and/or presacral nodal failures increased significantly. Only 57% of such patients had all LF sites within CTVs limited to the iliac/obturator nodes, but including the cystectomy bed and presacral nodes in the CTV when margins were positive increased the percentage of LFs encompassed to 91%. Conclusions: Patterns of failure within the pelvis are summarized to facilitate design of adjuvant RT protocols. These data suggest
Sequential cancer mutations in cultured human intestinal stem cells.
Drost, Jarno; van Jaarsveld, Richard H; Ponsioen, Bas; Zimberlin, Cheryl; van Boxtel, Ruben; Buijs, Arjan; Sachs, Norman; Overmeer, René M; Offerhaus, G Johan; Begthel, Harry; Korving, Jeroen; van de Wetering, Marc; Schwank, Gerald; Logtenberg, Meike; Cuppen, Edwin; Snippert, Hugo J; Medema, Jan Paul; Kops, Geert J P L; Clevers, Hans
Crypt stem cells represent the cells of origin for intestinal neoplasia. Both mouse and human intestinal stem cells can be cultured in medium containing the stem-cell-niche factors WNT, R-spondin, epidermal growth factor (EGF) and noggin over long time periods as epithelial organoids that remain genetically and phenotypically stable. Here we utilize CRISPR/Cas9 technology for targeted gene modification of four of the most commonly mutated colorectal cancer genes (APC, P53 (also known as TP53), KRAS and SMAD4) in cultured human intestinal stem cells. Mutant organoids can be selected by removing individual growth factors from the culture medium. Quadruple mutants grow independently of all stem-cell-niche factors and tolerate the presence of the P53 stabilizer nutlin-3. Upon xenotransplantation into mice, quadruple mutants grow as tumours with features of invasive carcinoma. Finally, combined loss of APC and P53 is sufficient for the appearance of extensive aneuploidy, a hallmark of tumour progression.
Biomolecular markers as determinants of patients selection for adjuvant chemotherapy of sporadic colorectal cancers.
Sudoyo, Aru W
Colorectal cancer (CRC) is a disease classified and based on genetic alteration resulting from interaction of environmental factors, individual cancer susceptibility and accumulated somatic changes of the colorectal epithelium. Advanced knowledge in genetics and epigenetics of colorectal cancer develops a hypothesis that various clinical manifestations of colorectal cancer are caused by different carcinogenesis pathways. Different carcinogenesis pathways and types of colorectal cancer appear to bring effects on different response against chemotherapy and prognosis. Chemotherapy is mainly provided for patients with stage III CRC which are also the largest proportion of CRC patients in Indonesia. However, it is also provided for some patients with high risk stage II CRC. Classically, clinical factors have been generally accepted as prognostic factors including depth of tumor invasion, regional nodal metastasis, vascular invasion, poor differentiation, and serologic tumor marker such as carcinoembryonic antigen (CEA). However, clinical and histopathological factors themselves do not provide accurate prediction for colorectal cancer prognosis and treatment. A biomolecular marker is necessary to provide such prediction. Numerous studies have been conducted to evaluate the molecular biological markers in order to determine either the possibility of successful treatment for colorectal cancer (predictive factor) or life-expectancy (prognostic factor). Results of several studies demonstrate different status of some molecular markers to determine successful treatment between stage II and stage III colorectal cancer. Certainly, such finding should be followed up but it shall be accepted that there will be a shift of paradigm of CRC treatment. Therefore, the success of colorectal cancer, excluding the patient's socioeconomic factors and the surgeon's skill, will depend extremely on molecular parameter and not only the stage.
Breast cancer stem cells, EMT and therapeutic targets
Kotiyal, Srishti; Bhattacharya, Susinjan
Highlights: • Therapeutic targeting or inhibition of the key molecules of signaling pathways can control growth of breast cancer stem cells (BCSCs). • Development of BCSCs also involves miRNA interactions. • Therapeutic achievement can be done by targeting identified targets in the BCSC pathways. - Abstract: A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo "epithelial to mesenchymal transition" (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they are also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements.
Adjuvant Anti-Angiogenesis Drugs Are No Benefit in Kidney Cancer
Results from a recent clinical trial show that post-surgical therapy with two anti-angiogenesis drugs does not improve progression-free survival for patients with kidney cancer and may cause serious side effects.
Multimodal MRI and cognitive function in patients with breast cancer prior to adjuvant treatment — The role of fatigue
Menning, Sanne; de Ruiter, Michiel B.; Veltman, Dick J.; Koppelmans, V.; Kirschbaum, Clemens; Boogerd, Willem; Reneman, Liesbeth; Schagen, Sanne B.
An increasing body of literature indicates that chemotherapy (ChT) for breast cancer (BC) is associated with adverse effects on the brain. Recent research suggests that cognitive and brain function in patients with BC may already be compromised before the start of chemotherapy. This is the first study combining neuropsychological testing, patient-reported outcomes, and multimodal magnetic resonance imaging (MRI) to examine pretreatment cognition and various aspects of brain function and structure in a large sample. Thirty-two patients with BC scheduled to receive ChT (pre-ChT+), 33 patients with BC not indicated to undergo ChT (pre-ChT−), and 38 no-cancer controls (NCs) were included. The examination consisted of a neuropsychological test battery, self-reported aspects of psychosocial functioning, and multimodal MRI. Patients with BC reported worse scores on several aspects of quality of life, such as higher levels of fatigue and stress. However, cortisol levels were not elevated in the patient groups compared to the control group. Overall cognitive performance was lower in the pre-ChT+ and the pre-ChT− groups compared to NC. Further, patients demonstrated prefrontal hyperactivation with increasing task difficulty on a planning task compared to NC, but not during a memory task. White matter integrity was lower in both patient groups. No differences in regional brain volume and brain metabolites were found. The cognitive and imaging data converged to show that symptoms of fatigue were associated with the observed abnormalities; the observed differences were no longer significant when fatigue was accounted for. This study suggests that cancer-related psychological or biological processes may adversely impact cognitive functioning and associated aspects of brain structure and function before the start of adjuvant treatment. Our findings stress the importance to further explore the processes underlying the expression of fatigue and to study whether it has a
The probiotic Propionibacterium freudenreichii as a new adjuvant for TRAIL-based therapy in colorectal cancer
Théret, Nathalie; Brenner, Catherine; Jouan, Elodie; Le Moigne-Muller, Gwénaëlle; Dimanche-Boitrel, Marie-Thérèse
TNF-Related Apoptosis-Inducing Ligand (TRAIL) is a well-known apoptosis inducer, which activates the extrinsic death pathway. TRAIL is pro-apoptotic on colon cancer cells, while not cytotoxic towards normal healthy cells. However, its clinical use is limited by cell resistance to cell death which occurs in approximately 50% of cancer cells. Short Chain Fatty Acids (SCFA) are also known to specifically induce apoptosis of cancer cells. In accordance, we have shown that food grade dairy propionibacteria induce intrinsic apoptosis of colon cancer cells, via the production and release of SCFA (propionate and acetate) acting on mitochondria. Here, we investigated possible synergistic effect between Propionibacterium freudenreichii and TRAIL. Indeed, we hypothesized that acting on both extrinsic and intrinsic death pathways may exert a synergistic pro-apoptotic effect. Whole transcriptomic analysis demonstrated that propionibacterial supernatant or propionibacterial metabolites (propionate and acetate), in combination with TRAIL, increased pro-apoptotic gene expression (TRAIL-R2/DR5) and decreased anti-apoptotic gene expression (FLIP, XIAP) in HT29 human colon cancer cells. The revealed synergistic pro-apoptotic effect, depending on both death receptors (TRAIL-R1/DR4, TRAIL-R2/DR5) and caspases (caspase-8, -9 and -3) activation, was lethal on cancer cells but not on normal human intestinal epithelial cells (HIEC), and was inhibited by Bcl-2 expression. Finally, milk fermented by P. freudenreichii induced HT29 cells apoptosis and enhanced TRAIL cytotoxic activity, as did P. freudenreichii DMEM culture supernatants or its SCFA metabolites. These results open new perspectives for food grade P. freudenreichii-containing products in order to potentiate TRAIL-based cancer therapy in colorectal cancer. PMID:26771233
The probiotic Propionibacterium freudenreichii as a new adjuvant for TRAIL-based therapy in colorectal cancer.
Cousin, Fabien J; Jouan-Lanhouet, Sandrine; Théret, Nathalie; Brenner, Catherine; Jouan, Elodie; Le Moigne-Muller, Gwénaëlle; Dimanche-Boitrel, Marie-Thérèse; Jan, Gwénaël
TNF-Related Apoptosis-Inducing Ligand (TRAIL) is a well-known apoptosis inducer, which activates the extrinsic death pathway. TRAIL is pro-apoptotic on colon cancer cells, while not cytotoxic towards normal healthy cells. However, its clinical use is limited by cell resistance to cell death which occurs in approximately 50% of cancer cells. Short Chain Fatty Acids (SCFA) are also known to specifically induce apoptosis of cancer cells. In accordance, we have shown that food grade dairy propionibacteria induce intrinsic apoptosis of colon cancer cells, via the production and release of SCFA (propionate and acetate) acting on mitochondria. Here, we investigated possible synergistic effect between Propionibacterium freudenreichii and TRAIL. Indeed, we hypothesized that acting on both extrinsic and intrinsic death pathways may exert a synergistic pro-apoptotic effect. Whole transcriptomic analysis demonstrated that propionibacterial supernatant or propionibacterial metabolites (propionate and acetate), in combination with TRAIL, increased pro-apoptotic gene expression (TRAIL-R2/DR5) and decreased anti-apoptotic gene expression (FLIP, XIAP) in HT29 human colon cancer cells. The revealed synergistic pro-apoptotic effect, depending on both death receptors (TRAIL-R1/DR4, TRAIL-R2/DR5) and caspases (caspase-8, -9 and -3) activation, was lethal on cancer cells but not on normal human intestinal epithelial cells (HIEC), and was inhibited by Bcl-2 expression. Finally, milk fermented by P. freudenreichii induced HT29 cells apoptosis and enhanced TRAIL cytotoxic activity, as did P. freudenreichii DMEM culture supernatants or its SCFA metabolites. These results open new perspectives for food grade P. freudenreichii-containing products in order to potentiate TRAIL-based cancer therapy in colorectal cancer.
An In silico Chimeric Vaccine Targeting Breast Cancer Containing Inherent Adjuvant
Imani Fooladi, Abbas Ali; Mahmoodzadeh Hosseini, Hamideh; Amani, Jafar
Background: Today, Lack of efficient therapeutic strategy for breast cancer (the most common cause of death in women) is one of the momentous problematic topics for all health care committees. Designing new specific vaccine, based on antigens located on the surface of cancer cells can be useful. Over expression of ROR1, lacked of HER2/neu, and hormone receptors on cell surface in the breast cancer, introduce this protein as an appropriate candidate for designing cancer vaccine. Objectives: We hypothesized the extracellular domain of receptor tyrosine kinase like orphan receptor 1 (ROR-1) along with a super antigen such as staphylococcal enterotoxin B could be a potent vaccine for drug resistant breast cancer. Materials and Methods: Here, we assessed the findings of bioinformatics analysis to identify the antitumor immune properties of this chimeric construct. In addition, the stability, physic-chemical properties and allergic potency of designed fusion protein were investigated by valid bioinformatics software. Results: Our result suggested that chimeric model is capable to be a stimulant of both T-cell and B- cell mediated immune responses with an acceptable accessibility and solubility but without any allergenicity. Conclusions: The ROR-1 with an enterotoxin B could be a potent vaccine for breast cancer. PMID:26413246
Pharmacogenetic predictors of outcome in patients with stage II and III colon cancer treated with oxaliplatin and fluoropyrimidine-based adjuvant chemotherapy.
Custodio, Ana; Moreno-Rubio, Juan; Aparicio, Jorge; Gallego-Plazas, Javier; Yaya, Ricardo; Maurel, Joan; Rodríguez-Salas, Nuria; Burgos, Emilio; Ramos, David; Calatrava, Ana; Andrada, Encarna; Díaz-López, Esther; Sánchez, Antonio; Madero, Rosario; Cejas, Paloma; Feliu, Jaime
Identifying molecular markers for tumor recurrence is critical in successfully selecting patients with colon cancer who are more likely to benefit from adjuvant chemotherapy. We investigated the effect of single-nucleotide polymorphisms (SNP) within genes involved in oxaliplatin and fluoropyrimidines metabolism, DNA repair mechanisms, drug transport, or angiogenesis pathways on outcome for patients with stage II and III colon cancer treated with adjuvant chemotherapy. Genomic DNA was extracted from formalin-fixed paraffin-embedded samples of 202 patients with stage II and III colon cancer receiving oxaliplatin-based adjuvant chemotherapy from January 2004 to December 2009. Genotyping was performed for 67 SNPs in 32 genes using the MassARRAY (SEQUENOM) technology. Our results were validated in an independent cohort of 177 patients treated with the same chemotherapy regimens. The combination of the selectin E (SELE) rs3917412 G>A G/G and the methylentetrahydrofolate reductase (MTHFR) rs1801133 T/T genotypes was associated with a significantly increased risk for recurrence in both the training [RR = 4.103; 95% confidence interval (CI), 1.803-9.334; P = 0.001] and the validation cohorts (RR = 3.567; 95% CI, 1.253-10.151; P = 0.017) in the multiple regression analysis considering the stage, lymphovascular invasion, and bowel perforation as covariates. The combined analysis of these polymorphisms was also significantly associated with overall survival in both cohorts (RR = 3.388; 95% CI, 0.988-11.623; P = 0.052, and RR = 3.929; 95% CI, 1.144-13.485; P = 0.020, respectively). Our findings suggest that the SELE rs3917412 and MTHFR rs1801133 SNPs could serve as pharmacogenetic predictors of tumor recurrence in patients with early-stage colon cancer treated with oxaliplatin-based adjuvant chemotherapy, thus allowing personalized selection of treatment to optimize clinical outcomes.
Therapies targeting cancer stem cells: Current trends and future challenges
Dragu, Denisa L; Necula, Laura G; Bleotu, Coralia; Diaconu, Carmen C; Chivu-Economescu, Mihaela
Traditional therapies against cancer, chemo- and radiotherapy, have multiple limitations that lead to treatment failure and cancer recurrence. These limitations are related to systemic and local toxicity, while treatment failure and cancer relapse are due to drug resistance and self-renewal, properties of a small population of tumor cells called cancer stem cells (CSCs). These cells are involved in cancer initiation, maintenance, metastasis and recurrence. Therefore, in order to develop efficient treatments that can induce a long-lasting clinical response preventing tumor relapse it is important to develop drugs that can specifically target and eliminate CSCs. Recent identification of surface markers and understanding of molecular feature associated with CSC phenotype helped with the design of effective treatments. In this review we discuss targeting surface biomarkers, signaling pathways that regulate CSCs self-renewal and differentiation, drug-efflux pumps involved in apoptosis resistance, microenvironmental signals that sustain CSCs growth, manipulation of miRNA expression, and induction of CSCs apoptosis and differentiation, with specific aim to hamper CSCs regeneration and cancer relapse. Some of these agents are under evaluation in preclinical and clinical studies, most of them for using in combination with traditional therapies. The combined therapy using conventional anticancer drugs with CSCs-targeting agents, may offer a promising strategy for management and eradication of different types of cancers. PMID:26516409
PIM1 kinase as a promise of targeted therapy in prostate cancer stem cells
Since the last decade, the PIM family serine/threonine kinases have become a focus in cancer research. Numerous clinical data supports that overexpression of PIM1 is associated with tumor formation in various tissues. However, little is known regarding the function of PIM1 in cancer stem cells. In cancer cells, PIM1 has essential roles in the regulation of the cell cycle, cell proliferation, cell survival and multiple drug resistance. In stem cells, PIM1 kinase exhibits a significant function in stem cell proliferation, self-renewal and expansion. Thus, PIM1 shows a great promise in cancer therapy by targeting stem cells. Furthermore, it is imperative to investigate Pim-1 targeting in cancer stem cells by applicable inhibitors for improving future outcomes. The present review investigated the potential of PIM1 as a therapy target in prostate cancer stem cells. PMID:26835011
Cancer Stem Cell Quiescence and Plasticity as Major Challenges in Cancer Therapy
Chen, Wanyin; Dong, Jihu; Haiech, Jacques; Kilhoffer, Marie-Claude
Cells with stem-like properties, tumorigenic potential, and treatment-resistant phenotypes have been identified in many human malignancies. Based on the properties they share with nonneoplastic stem cells or their ability to initiate and propagate tumors in vivo, such cells were designated as cancer stem (stem-like) or tumor initiating/propagating cells. Owing to their implication in treatment resistance, cancer stem cells (CSCs) have been the subject of intense investigation in past years. Comprehension of CSCs' intrinsic properties and mechanisms they develop to survive and even enhance their aggressive phenotype within the hostile conditions of the tumor microenvironment has reoriented therapeutic strategies to fight cancer. This report provides selected examples of malignancies in which the presence of CSCs has been evidenced and briefly discusses methods to identify, isolate, and functionally characterize the CSC subpopulation of cancer cells. Relevant biological targets in CSCs, their link to treatment resistance, proposed targeting strategies, and limitations of these approaches are presented. Two major aspects of CSC physiopathology, namely, relative in vivo quiescence and plasticity in response to microenvironmental cues or treatment, are highlighted. Implications of these findings in the context of the development of new therapies are discussed. PMID:27418931
The influence of number of high risk factors on clinical outcomes in patients with early-stage cervical cancer after radical hysterectomy and adjuvant chemoradiation
Lim, Soyi; Lee, Seok-Ho; Park, Chan-Yong
Objective The purpose of this study was to evaluate the prognosis according to the number of high risk factors in patients with high risk factors after radical hysterectomy and adjuvant chemoradiation therapy for early stage cervical cancer. Methods Clinicopathological variables and clinical outcomes of patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB1 to IIA cervical cancer who had one or more high risk factors after radical hysterectomy and adjuvant chemoradiation therapy were retrospectively analyzed. Patients were divided into two groups according to the number of high risk factors (group 1, single high risk factor; group 2, two or more high risk factors). Results A total of 93 patients were enrolled in the present study. Forty nine out of 93 (52.7%) patients had a single high risk factor, and 44 (47.3%) had two or more high risk factors. Statistically significant differences in stage and stromal invasion were observed between group 1 and group 2. However, age, histology, tumor size, and lymphovascular space invasion did not differ significantly between the groups. Distant recurrence occurred more frequently in group 2, and the probability of recurrence and death was higher in group 2. Conclusion Patients with two or more high risk factors had worse prognosis in early stage cervical cancer. For these patients, consideration of new strategies to improve survival may be worthwhile. Conduct of further clinical trials is warranted for development of adjuvant treatment strategies individualized to each risk group. PMID:27200308
A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC)
Oki, E.; Murata, A.; Yoshida, K.; Maeda, K.; Ikejiri, K.; Munemoto, Y.; Sasaki, K.; Matsuda, C.; Kotake, M.; Suenaga, T.; Matsuda, H.; Emi, Y.; Kakeji, Y.; Baba, H.; Hamada, C.; Saji, S.; Maehara, Y.
Backgrounds Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur–uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. Patients and methods The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20–80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500–600 mg/day on days 1–5, followed by 2 days rest) or S-1 (80–120 mg/day on days 1–28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. Results In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63–0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. Conclusion One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection. PMID:27056996
Decreasing the ratio of matriptase/HAI-1 by downregulation of matriptase as a potential adjuvant therapy in ovarian cancer
Sun, Pengming; Jiang, Zhongqing; Chen, Xiaofang; Xue, Lifang; Mao, Xiaodan; Ruan, Guanyu; Song, Yiyi; Mustea, Alexander
Tumor invasion and metastasis are complex biological processes. Matriptase and its endogenous inhibitor, hepatocyte growth factor activator inhibitor-1 (HAI-1) are involved in invasion and metastasis. To evaluate the ratio of matriptase/HAI-1 and their potential therapeutic value in ovarian cancer, HO-8910 human ovarian cancer cells and the homologous high-metastatic HO-8910PM cells were used as in vitro cellular models ovarian cancer. The invasive and metastatic abilities, and the expression of matriptase and HAI-1 in these cells were detected using scratch assays, Transwell chamber assays, reverse transcription-quantitative polymerase chain reaction, western blotting and fluorescent immunocytochemistry. Following infection with lentivirus-mediated matriptase-targeting small interfering RNA (siRNA), cell cycle progression and apoptosis were also analyzed. The migration distance and number of invading HO-8910PM cells were significantly increased compared with HO-8910 cells. HO-8910PM cells exhibited a significantly higher ratio of matriptase/HAI-1 mRNA levels compared with HO-8910 cells (0.51 vs. 0.24, ~2.2 fold increase). Compared with HO-8910 cells, the matriptase mRNA level was increased by ~3.6 fold in HO-8910PM cells, whereas the HAI-1 mRNA level was increased by ~1.7 fold. Similar increases in protein expression levels were also observed in HO-8910PM cells compared with HO-8910 cells. Migration and invasiveness were positively correlated with matriptase expression level (r=0.994, P<0.01) and the ratio of matriptase/HAI-1 (r=0.929, P<0.01). Downregulation of matriptase using siRNA resulted in inhibition of the invasive and metastatic abilities of HO-8910PM cells, cell cycle arrest in the G0/G1 phase and increased apoptosis. The present study demonstrated that ovarian cancer cell metastasis and invasion were more dependent on upregulation of matriptase levels than downregulation of HAI-1. Matriptase may be a potential adjuvant therapeutic target for inhibiting
Decreasing the ratio of matriptase/HAI‑1 by downregulation of matriptase as a potential adjuvant therapy in ovarian cancer.
Sun, Pengming; Jiang, Zhongqing; Chen, Xiaofang; Xue, Lifang; Mao, Xiaodan; Ruan, Guanyu; Song, Yiyi; Mustea, Alexander
potential adjuvant therapeutic target for inhibiting ovarian cancer invasion and metastasis. PMID:27356668
Targeting self-renewal pathways in cancer stem cells: clinical implications for cancer therapy
Borah, A; Raveendran, S; Rochani, A; Maekawa, T; Kumar, D S
Extensive cancer research in the past few decades has identified the existence of a rare subpopulation of stem cells in the grove of cancer cells. These cells are known as the cancer stem cells marked by the presence of surface biomarkers, multi-drug resistance pumps and deregulated self-renewal pathways (SRPs). They have a crucial role in provoking cancer cells leading to tumorigenesis and its progressive metastasis. Cancer stem cells (CSCs) are much alike to normal stem cells in their self-renewal mechanisms. However, deregulations in the SRPs are seen in CSCs, making them resistant to conventional chemotherapeutic agents resulting in the tumor recurrence. Current treatment strategies in cancer fail to detect and differentiate the CSCs from their non-tumorigenic progenies owing to absence of specific biomarkers. Now, it has become imperative to understand complex functional biology of CSCs, especially the signaling pathways to design improved treatment strategies to target them. It is hopeful that the SRPs in CSCs offer a promising target to alter their survival strategies and impede their tumorigenic potential. However, there are many perils associated with the direct targeting method by conventional therapeutic agents such as off targets, poor bioavailability and poor cellular distribution. Recent evidences have shown an increased use of small molecule antagonists directly to target these SRPs may lead to severe side-effects. An alternative to solve these issues could be an appropriate nanoformulation. Nanoformulations of these molecules could provide an added advantage for the selective targeting of the pathways especially Hedgehog, Wnt, Notch and B-cell-specific moloney murine leukemia virus integration site 1 in the CSCs while sparing the normal stem cells. Hence, to achieve this goal a complete understanding of the molecular pathways corroborate with the use of holistic nanosystem (nanomaterial inhibition molecule) could possibly be an encouraging direction
Oncolytic viruses against cancer stem cells: A promising approach for gastrointestinal cancer
Huang, Fang; Wang, Bin-Rong; Wu, Ye-Qing; Wang, Fan-Chao; Zhang, Jian; Wang, Yi-Gang
Gastrointestinal cancer has been one of the five most commonly diagnosed and leading causes of cancer mortality over the past few decades. Great progress in traditional therapies has been made, which prolonged survival in patients with early cancer, yet tumor relapse and drug resistance still occurred, which is explained by the cancer stem cell (CSC) theory. Oncolytic virotherapy has attracted increasing interest in cancer because of its ability to infect and lyse CSCs. This paper reviews the basic knowledge, CSC markers and therapeutics of gastrointestinal cancer (liver, gastric, colon and pancreatic cancer), as well as research advances and possible molecular mechanisms of various oncolytic viruses against gastrointestinal CSCs. This paper also summarizes the existing obstacles to oncolytic virotherapy and proposes several alternative suggestions to overcome the therapeutic limitations. PMID:27672294
Oncolytic viruses against cancer stem cells: A promising approach for gastrointestinal cancer
Huang, Fang; Wang, Bin-Rong; Wu, Ye-Qing; Wang, Fan-Chao; Zhang, Jian; Wang, Yi-Gang
Gastrointestinal cancer has been one of the five most commonly diagnosed and leading causes of cancer mortality over the past few decades. Great progress in traditional therapies has been made, which prolonged survival in patients with early cancer, yet tumor relapse and drug resistance still occurred, which is explained by the cancer stem cell (CSC) theory. Oncolytic virotherapy has attracted increasing interest in cancer because of its ability to infect and lyse CSCs. This paper reviews the basic knowledge, CSC markers and therapeutics of gastrointestinal cancer (liver, gastric, colon and pancreatic cancer), as well as research advances and possible molecular mechanisms of various oncolytic viruses against gastrointestinal CSCs. This paper also summarizes the existing obstacles to oncolytic virotherapy and proposes several alternative suggestions to overcome the therapeutic limitations.
Oncolytic viruses against cancer stem cells: A promising approach for gastrointestinal cancer.
Huang, Fang; Wang, Bin-Rong; Wu, Ye-Qing; Wang, Fan-Chao; Zhang, Jian; Wang, Yi-Gang
Gastrointestinal cancer has been one of the five most commonly diagnosed and leading causes of cancer mortality over the past few decades. Great progress in traditional therapies has been made, which prolonged survival in patients with early cancer, yet tumor relapse and drug resistance still occurred, which is explained by the cancer stem cell (CSC) theory. Oncolytic virotherapy has attracted increasing interest in cancer because of its ability to infect and lyse CSCs. This paper reviews the basic knowledge, CSC markers and therapeutics of gastrointestinal cancer (liver, gastric, colon and pancreatic cancer), as well as research advances and possible molecular mechanisms of various oncolytic viruses against gastrointestinal CSCs. This paper also summarizes the existing obstacles to oncolytic virotherapy and proposes several alternative suggestions to overcome the therapeutic limitations. PMID:27672294
Mesenchymal stem cell: a new horizon in cancer gene therapy.
Mohammadi, M; Jaafari, M R; Mirzaei, H R; Mirzaei, H
Cancer is one of the main problems in public health worldwide. Despite rapid advances in the diagnosis and treatment of cancer, the efficacy of current treatment strategies is still limited. There are promising new results in animal models whereby mesenchymal stem cells (MSCs) can be used as vehicles for targeted therapies. The use of MSCs as therapeutic biological vehicles in cell therapy has several advantages, including immune-silence, tumor tropism, easy and rapid isolation, ex vivo expansion, multilineage differentiation and the capacity to deliver a number of therapeutic agents. Some studies have shown that the microenvironment of the tumor provides a preferential niche for homing and survival of MSCs. Here, we have highlighted various applications of MSCs in cancer gene therapy. PMID:27650780
Adjuvant endocrine therapy for early breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline
Freedman, O.C.; Fletcher, G.G.; Gandhi, S.; Mates, M.; Dent, S.F.; Trudeau, M.E.; Eisen, A.
Background Cancer Care Ontario's Program in Evidence-Based Care (pebc) recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question "What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?" The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and her2 (human epidermal growth factor receptor 2)–targeted therapy. Methods For the systematic review, the literature in the medline and embase databases was searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were "breast cancer" and "systemic therapy" (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (rcts), guidelines, systematic reviews, and meta-analyses. Results Several hundred documents that met the inclusion criteria were retrieved. Meta-analyses from the Early Breast Cancer Trialists' Collaborative Group encompassed many of the rcts found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. Summary The results of the systematic review constitute a comprehensive compilation of high-level evidence, which was the basis for the 2014 pebc guideline on systemic therapy for early breast cancer. The review of the evidence for systemic endocrine therapy (adjuvant tamoxifen, aromatase inhibitors, and ovarian ablation and suppression) is presented here; the evidence for chemotherapy and her2-targeted treatment—and the final clinical practice recommendations—are presented separately in this supplement. PMID:25848344
Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199
Adams, Sylvia; Gray, Robert J.; Demaria, Sandra; Goldstein, Lori; Perez, Edith A.; Shulman, Lawrence N.; Martino, Silvana; Wang, Molin; Jones, Vicky E.; Saphner, Thomas J.; Wolff, Antonio C.; Wood, William C.; Davidson, Nancy E.; Sledge, George W.; Sparano, Joseph A.; Badve, Sunil S.
Purpose Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Patients and Methods Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. Results The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. Conclusion In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter. PMID:25071121
Real-Life Use and Effectiveness of Adjuvant Trastuzumab in Early Breast Cancer Patients: A Study of the Southeast Netherlands Breast Cancer Consortium
Seferina, Shanly C.; Lobbezoo, Dorien J.A.; de Boer, Maaike; Dercksen, M. Wouter; van den Berkmortel, Franchette; van Kampen, Roel J.W.; van de Wouw, Agnès J.; de Vries, Bart; Joore, Manuela A.; Peer, Petronella G.M.; Voogd, Adri C.
Background. The impact of drug prescriptions in real life as opposed to strict clinical trial prescription is only rarely assessed, although it is well recognized that incorrect use may harm patients and may have a significant impact on health care resources. We investigated the use and effectiveness of adjuvant trastuzumab in daily practice compared with the effectiveness in clinical trials. Methods. We included all patients with stage I–III invasive breast cancer, irrespective of human epidermal growth factor receptor 2 (HER2) status, diagnosed in five hospitals in the southeast of The Netherlands in 2005–2007. We aimed to assess the actual use of adjuvant trastuzumab in early HER2-positive breast and its efficacy in daily practice. Results. Of 2,684 patients included, 476 (17.7%) had a HER2-positive tumor. Of these, 251 (52.7%) patients had an indication for trastuzumab treatment of which 196 (78.1%) patients actually received it. Of the 225 patients without an indication, 34 (15.1%) received trastuzumab. Five-year disease-free survival was 80.7% for (n = 230) patients treated with versus 68.2% for (n = 246) patients not treated with trastuzumab (p = .0023), and 5-year overall survival rates were 90.7% and 77.4%, respectively (p = .0002). The hazard ratio for disease recurrence was 0.63 (95% confidence interval, 0.37–1.06) for trastuzumab when adjusting for potential confounders. Conclusion. This study shows that in real life, patients treated with trastuzumab in early-stage HER2-positive breast cancer had a 5-year disease-free and overall survival comparable to prior randomized trials. For informative decision making, real-life data are of additional value, providing insight on outcome of patients considered ineligible for treatment. PMID:26099745
Stem Cells Antigen-1 Enriches for a Cancer Stem Cell-Like Subpopulation in Mouse Gastric Cancer.
Park, Jun Won; Park, Jung Min; Park, Dong Min; Kim, Dae-Yong; Kim, Hark Kyun
There is a strong need to identify markers to enrich gastric cancer stem cells (CSCs). However, CSC enrichment markers for mouse gastric cancers have not yet been determined. In our previous study, we generated primary mouse gastric cancer cell line NCC-S1 (S1) established from a Villin-cre;Smad4(F/F) ;Trp53(F/F) ;Cdh1(F/wt) mouse and its metastatic variant cell line NCC-S1M (S1M). Interestingly, S1M cells exhibited CSC-like features, such as increased tumorigenic potential and chemoresistance. By comparing gene expression profiles between S1 and S1M cells, we identified Stem Cells Antigen-1 (Sca-1) as a cell surface marker, which was mostly upregulated in S1M. Sca-1 was upregulated in tumorspheres from S1 cells or after cisplatin treatment in S1 cells. Immunofluorescence (IF) analysis showed that approximately 7% of cancer cells exhibited positivity for Sca-1 in primary mouse gastric cancer tissues. An in vivo-limiting dilution assay showed that Sca-1(high) mouse gastric cancer cells demonstrated increased tumorigenicity compared with Sca-1(negative) cells. The Sca-1 expression was downregulated by TGF-β pathway activation and Wnt pathway inhibition in mouse gastric cancer cells. Sca-1(high) cells showed relatively low TGF-β reporter activity and high TCF/LEF1 reporter activity compared with Sca-1(negative) cells. A chromatin immunoprecipitation analysis demonstrated that Sca-1 was a β-catenin/LEF1 target gene. Sca-1(high) allografts were more resistant to cisplatin/fluorouracil chemotherapy than Sca-1(negative) allografts, and overexpressed Bcl-xL. Eighty-five mouse genes overexpressed in Sca-1(high) S1 cells compared with Sca-1(negative) cells clustered 123 pretreatment gastric cancer patient samples according to survival following chemotherapy. Taken together, Sca-1 is a novel CSC enrichment marker that mediates TGF-β and Wnt/β-catenin signaling in mouse gastric cancer. Stem Cells 2016;34:1177-1187. PMID:26869189
To Treat or Not to Treat: The Role of Adjuvant Radioiodine Therapy in Thyroid Cancer Patients
Carballo, Marilee; Quiros, Roderick M.
Radioactive iodine (RAI) is used in treatment of patients with differentiated papillary and follicular thyroid cancer. It is typically used after thyroidectomy, both as a means of imaging to detect residual thyroid tissue or metastatic disease, as well as a means of treatment by ablation if such tissue is found. In this paper, we discuss the indications for and the mechanisms of RAI in the treatment of patients with thyroid cancer. We discuss the attendant risks and benefits that come with its use, as well as techniques used to optimize its effectiveness as an imaging tool and a therapeutic modality. PMID:23193402
[Effects and costs of adjuvant chemotherapy for operable lymph node positive breast cancer with HER2/neu overexpression].
Vos, E J; Linn, S C; Rodenhuis, S
Newer forms ofadjuvant chemotherapy can considerably improve the prognosis for breast cancer. The benefits that can be achieved are particularly high for young women (< 50 years) with an unfavourable risk profile (tumour-positive axilliary nodes). The recent application of taxans and trastuzumab has sharply increased the costs of an adjuvant treatment for high-risk mammary breast carcinoma. The cost increase can especially be attributed to trastuzumab. The additional costs of cytostatics (10,079 Euro per life-year gained) appear to be justified if the following is taken into account: women under the age of 50 years still have a life expectancy of approximately 33 years, many have socially relevant positions, and that cure also prevents such things as absence through illness and inability to work as well as expensive palliative care. The pharmaceutical industry spends approximately the same amount on research and innovation as it does on advertising. By reducing marketing costs, there will be more room to lessen the costs of new and socially relevant medications. Ultimately, the pressing question remains on why the Dutch government does not fully compensate hospitals in the Netherlands for the introduction of new, potentially life-saving medications. At present, a substantial percentage of the costs has to be paid by the hospitals themselves out of the regular hospital budget, which is not meant for this. This is happening at the expense of other care to an increasing extent.
A novel adjuvant Ling Zhi-8 enhances the efficacy of DNA cancer vaccine by activating dendritic cells.
Lin, Chi-Chen;