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Hemorrhage of brain metastasis from non-small cell lung cancer post gefitinib therapy: two case reports and review of the literature
Yan, Dan-Fang
Yan, Sen-Xiang
Yang, Jing-Song
Wang, Yi-Xiang J
Sun, Xiao-Li
Liao, Xin-Biao
Liu, Jun-Qing
BMC Cancer
Gefitinib is one of the small molecule inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR TKIs). Clinical trials have demonstrated it is effective for treatment of a subset of patients with advanced non-small cell lung cancer (NSCLC). Gefitinib has been generally considered to be a relatively safe agent. Besides a small proportion of fatal interstitial pneumonia, the common adverse drug reactions of gefitinib include diarrhea and skin rash, which are generally mild and reversible. Herein, we report the first two cases of brain metastasis hemorrhage that might be involved with the use of gefitinib.
Case presentation
Two patients with brain metastasis from NSCLC developed brain hemorrhage after gefitinib therapy. The hemorrhage in one case occurred one month after gefitinib combined with whole brain radiation therapy (WBRT), and in the another case hemorrhage developed slowly within brain metastases eight months post gefitinib monotherapy for diffuse pulmonary metastasis from a lung cancer undergone surgical removal previously.
We speculate brain hemorrhage could be one of the adverse drug reactions of gefitinib treatment for NSCLC and suggest clinicians be aware of this possible rare entity. More data are needed to confirm our findings, especially when gefitinib is used in the settings of brain metastases from NSCLC or other origins.
Related Articles
Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer
Ontario Health Technology Assessment Series
Executive Summary
In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of the literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.
Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenetics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.
The following reports can be publicly accessed at the MAS website at: http://www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Gene Expression Profiling for Guiding Adjuvant Chemotherapy Decisions in Women with Early Breast Cancer: An Evidence-Based Analysis
Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: an Evidence-Based Analysis
K-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based Analysis
The Medical Advisory Secretariat undertook a systematic review of the evidence on the clinical effectiveness and cost-effectiveness of epidermal growth factor receptor (EGFR) mutation testing compared with no EGFR mutation testing to predict response to tyrosine kinase inhibitors (TKIs), gefitinib (Iressa®) or erlotinib (Tarceva®) in patients with advanced non-small cell lung cancer (NSCLC).
Clinical Need: Target Population and Condition
With an estimated 7,800 new cases and 7,000 deaths last year, lung cancer is the leading cause of cancer deaths in Ontario. Those with unresectable or advanced disease are commonly treated with concurrent chemoradiation or platinum-based combination chemotherapy. Although response rates to cytotoxic chemotherapy for advanced NSCLC are approximately 30 to 40%, all patients eventually develop resistance and have a median survival of only 8 to 10 months. Treatment for refractory or relapsed disease includes single-agent treatment with docetaxel, pemetrexed or EGFR-targeting TKIs (gefitinib, erlotinib). TKIs disrupt EGFR signaling by competing with adenosine triphosphate (ATP) for the binding sites at the tyrosine kinase (TK) domain, thus inhibiting the phosphorylation and activation of EGFRs and the downstream signaling network. Gefitinib and erlotinib have been shown to be either non-inferior or superior to chemotherapy in the first- or second-line setting (gefitinib), or superior to placebo in the second- or third-line setting (erlotinib).
Certain patient characteristics (adenocarcinoma, non-smoking history, Asian ethnicity, female gender) predict for better survival benefit and response to therapy with TKIs. In addition, the current body of evidence shows that somatic mutations in the EGFR gene are the most robust biomarkers for EGFR-targeting therapy selection. Drugs used in this therapy, however, can be costly, up to C$ 2000 to C$ 3000 per month, and they have only approximately a 10% chance of benefiting unselected patients. For these reasons, the predictive value of EGFR mutation testing for TKIs in patients with advanced NSCLC needs to be determined.
The Technology: EGFR mutation testing
The EGFR gene sequencing by polymerase chain reaction (PCR) assays is the most widely used method for EGFR mutation testing. PCR assays can be performed at pathology laboratories across Ontario. According to experts in the province, sequencing is not currently done in Ontario due to lack of adequate measurement sensitivity. A variety of new methods have been introduced to increase the measurement sensitivity of the mutation assay. Some technologies such as single-stranded conformational polymorphism, denaturing high-performance liquid chromatography, and high-resolution melting analysis have the advantage of facilitating rapid mutation screening of large numbers of samples with high measurement sensitivity but require direct sequencing to confirm the identity of the detected mutations. Other techniques have been developed for the simple, but highly sensitive detection of specific EGFR mutations, such as the amplification refractory mutations system (ARMS) and the peptide nucleic acid-locked PCR clamping. Others selectively digest wild-type DNA templates with restriction endonucleases to enrich mutant alleles by PCR. Experts in the province of Ontario have commented that currently PCR fragment analysis for deletion and point mutation conducts in Ontario, with measurement sensitivity of 1% to 5%.
Research Questions
In patients with locally-advanced or metastatic NSCLC, what is the clinical effectiveness of EGFR mutation testing for prediction of response to treatment with TKIs (gefitinib, erlotinib) in terms of progression-free survival (PFS), objective response rates (ORR), overall survival (OS), and quality of life (QoL)?
What is the impact of EGFR mutation testing on overall clinical decision-making for patients with advanced or metastatic NSCLC?
What is the cost-effectiveness of EGFR mutation testing in selecting patients with advanced NSCLC for treatment with gefitinib or erlotinib in the first-line setting?
What is the budget impact of EGFR mutation testing in selecting patients with advanced NSCLC for treatment with gefitinib or erlotinib in the second- or third-line setting?
A literature search was performed on March 9, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, CINAHL, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment for studies published from January 1, 2004 until February 28, 2010 using the following terms:
Non-Small-Cell Lung Carcinoma
Epidermal Growth Factor Receptor
An automatic literature update program also extracted all papers published from February 2010 until August 2010. Abstracts were reviewed by a single reviewer and for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, and then a group of epidemiologists, until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
The inclusion criteria were as follows:
Population: patients with locally advanced or metastatic NSCLC (stage IIIB or IV)
Procedure: EGFR mutation testing before treatment with gefitinib or erlotinib
Language: publication in English
Published health technology assessments, guidelines, and peer-reviewed literature (abstracts, full text, conference abstract)
Outcomes: progression-free survival (PFS), Objective response rate (ORR), overall survival (OS), quality of life (QoL).
The exclusion criteria were as follows:
Studies lacking outcomes specific to those of interest
Studies focused on erlotinib maintenance therapy
Studies focused on gefitinib or erlotinib use in combination with cytotoxic agents or any other drug
Grey literature, where relevant, was also reviewed.
Outcomes of Interest
ORR determined by means of the Response Evaluation Criteria in Solid Tumours (RECIST)
Quality of Evidence
The quality of the Phase II trials and observational studies was based on the method of subject recruitment and sampling, possibility of selection bias, and generalizability to the source population. The overall quality of evidence was assessed as high, moderate, low or very low according to the GRADE Working Group criteria.
Summary of Findings
Since the last published health technology assessment by Blue Cross Blue Shield Association in 2007 there have been a number of phase III trials which provide evidence of predictive value of EGFR mutation testing in patients who were treated with gefitinib compared to chemotherapy in the first- or second-line setting. The Iressa Pan Asian Study (IPASS) trial showed the superiority of gefitinib in terms of PFS in patients with EGFR mutations versus patients with wild-type EGFR (Hazard ratio [HR], 0.48, 95%CI; 0.36-0.64 versus HR, 2.85; 95%CI, 2.05-3.98). Moreover, there was a statistically significant increased ORR in patients who received gefitinib and had EGFR mutations compared to patients with wild-type EGFR (71% versus 1%). The First-SIGNAL trial in patients with similar clinical characteristics as IPASS as well as the NEJ002 and WJTOG3405 trials that included only patients with EGFR mutations, provide confirmation that gefitinib is superior to chemotherapy in terms of improved PFS or higher ORR in patients with EGFR mutations. The INTEREST trial further indicated that patients with EGFR mutations had prolonged PFS and higher ORR when treated with gefitinib compared with docetaxel.
In contrast, there is still a paucity of strong evidence regarding the predictive value of EGFR mutation testing for response to erlotinib in the second- or third-line setting. The BR.21 trial randomized 731 patients with NSCLC who were refractory or intolerant to prior first- or second-line chemotherapy to receive erlotinib or placebo. While the HR of 0.61 (95%CI, 0.51-0.74) favored erlotinib in the overall population, this was not a significant in the subsequent retrospective subgroup analysis. A retrospective evaluation of 116 of the BR.21 tumor samples demonstrated that patients with EGFR mutations had significantly higher ORRs when treated with erlotinib compared with placebo (27% versus 7%; P=0.03). However, erlotinib did not confer a significant survival benefit compared with placebo in patients with EGFR mutations (HR, 0.55; 95%CI, 0.25-1.19) versus wild-type (HR, 0.74; 95%CI, 0.52-1.05). The interaction between EGFR mutation status and erlotinib use was not significant (P=0.47). The lack of significance could be attributable to a type II error since there was a low sample size that was available for subgroup analysis.
A series of phase II studies have examined the clinical effectiveness of erlotinib in patients known to have EGFR mutations. Evidence from these studies has consistently shown that erlotinib yields a very high ORR (typically 70% vs. 4%) and a prolonged PFS (9 months vs. 2 months) in patients with EGFR mutations compared with patients with wild-type EGFR. Although having a prolonged PFS and higher respond in EGFR mutated patients might be due to a better prognostic profile regardless of the treatment received. In the absence of a comparative treatment or placebo control group, it is difficult to determine if the observed differences in survival benefit in patients with EGFR mutation is attributed to prognostic or predictive value of EGFR mutation status.
Based on moderate quality of evidence, patients with locally advanced or metastatic NSCLC with adenocarcinoma histology being treated with gefitinib in the first-line setting are highly likely to benefit from gefitinib if they have EGFR mutations compared to those with wild-type EGFR. This advantage is reflected in improved PFS, ORR and QoL in patients with EGFR mutation who are being treated with gefitinib relative to patients treated with chemotherapy.
Based on low quality of evidence, in patients with locally advanced or metastatic NSCLC who are being treated with erlotinib, the identification of EGFR mutation status selects those who are most likely to benefit from erlotinib relative to patients treated with placebo in the second or third-line setting.
Related Articles
BIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations
Costa, Daniel B
Halmos, Balázs
Kumar, Amit
Schumer, Susan T
Huberman, Mark S
Boggon, Titus J
Tenen, Daniel G
Kobayashi, Susumu
PLoS Medicine
Epidermal growth factor receptor (EGFR) mutations are present in the majority of patients with non-small cell lung cancer (NSCLC) responsive to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. These EGFR-dependent tumors eventually become TKI resistant, and the common secondary T790M mutation accounts for half the tumors with acquired resistance to gefitinib. However, the key proapoptotic proteins involved in TKI-induced cell death and other secondary mutations involved in resistance remain unclear. The objective of this study was to identify the mechanism of EGFR TKI-induced apoptosis and secondary resistant mutations that affect this process.
Methods and Findings
To study TKI-induced cell death and mechanisms of resistance, we used lung cancer cell lines (with or without EGFR mutations), Ba/F3 cells stably transfected with EGFR mutation constructs, and tumor samples from a gefitinib-resistant patient. Here we show that up-regulation of the BH3-only polypeptide BIM (also known as BCL2-like 11) correlated with gefitinib-induced apoptosis in gefitinib-sensitive EGFR-mutant lung cancer cells. The T790M mutation blocked gefitinib-induced up-regulation of BIM and apoptosis. This blockade was overcome by the irreversible TKI CL-387,785. Knockdown of BIM by small interfering RNA was able to attenuate apoptosis induced by EGFR TKIs. Furthermore, from a gefitinib-resistant patient carrying the activating L858R mutation, we identified a novel secondary resistant mutation, L747S in cis to the activating mutation, which attenuated the up-regulation of BIM and reduced apoptosis.
Our results provide evidence that BIM is involved in TKI-induced apoptosis in sensitive EGFR-mutant cells and that both attenuation of the up-regulation of BIM and resistance to gefitinib-induced apoptosis are seen in models that contain the common EGFR T790M and the novel L747S secondary resistance mutations. These findings also suggest that induction of BIM may have a role in the treatment of TKI-resistant tumors.
Susumu Kobayashi and colleagues provide evidence that the polypeptide BIM is involved in tyrosine kinase inhibitor (TKI)-induced apoptosis in sensitiveEGFR-mutant cells and suggest that induction of BIM may have a role in the treatment of TKI-resistant tumors.
Editors' Summary
Most cases of lung cancer—the leading cause of cancer deaths worldwide—are "non-small cell lung cancer" (NSCLC). Many patients with NSCLC die within a year of their diagnosis, but recently, "targeted" therapies have increased the life expectancy of some of them. Like all cancers, NSCLC occurs when cells begin to divide uncontrollably because of changes (mutations) in their genes. Targeted therapies specifically attack these changes and, unlike standard chemotherapy drugs, kill cancer cells without damaging normal cells. The targeted drugs used to treat NSCLC are gefitinib and erlotinib, two epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In normal cells, messenger proteins bind to EGFR and activate its tyrosine kinase, an enzyme that sticks phosphate groups on tyrosine (an amino acid) in other proteins. These "phosphorylated" proteins then tell the cell to divide. In some NSCLCs, EGFR drives uncontrolled cell division because its tyrosine kinase is mutated and the cancer becomes dependent on or "addicted" to EGFR signaling for its survival. TKI treatment can dramatically shrink this subset of NSCLCs, most of which lack a specific part of EGFR (the gene that encodes EGFR) or have the amino acid leucine instead of arginine at position 858 (an L858R mutation) of EGFR.
Why Was This Study Done?
TKI-sensitive NSCLCs eventually become resistant to TKIs because they acquire additional (secondary) mutations. In half of these TKI-resistant tumors, the additional mutation is replacement of threonine by methionine at position 790 (T790M) in EGFR. However, the mutations responsible for the remaining cases of TKI resistance are not known. In addition, little is known about how TKIs induce cell death other than that they induce a type of cell death called apoptosis. A better understanding of how TKIs kill tumor cells and how secondary mutations block their effects could reveal ways to enhance their action and improve the outcome for patients with NSCLC. In this study, the researchers have studied the mechanism of TKI-induced cell death and of resistance to TKIs.
What Did the Researchers Do and Find?
The researchers first measured the ability of gefitinib to cause apoptosis (genetically programmed cell death) in NSCLC cell lines (tumor cells adapted to grow indefinitely in dishes) that had the EGFR deletion, the L858R mutation, or normal EGFR. Gefitinib caused apoptosis only in cell lines with altered EGFR. Then they asked whether a proapoptotic protein called BIM (a member of the BCL2 family of pro- and antiapoptotic proteins) is involved in TKI-induced cell death—BIM is known to be involved in this process in leukemia (blood cancer) cells. Gefitinib treatment increased the expression of BIM in TKI-sensitive NSCLC cell lines and reduced the phosphorylation of BIM (which makes BIM more active). By contrast, blocking BIM expression using a technique called RNA interference reduced TKI-induced apoptosis in TKI-sensitive NSCLC cells. Furthermore, introduction of the T790M resistance mutation into these cells blocked gefitinib-induced up-regulation of BIM and apoptosis. Finally, the researchers identified a new TKI resistance mutation (L747S, substitution of serine for leucine at position 747) in a patient whose TKI-sensitive NSCLC had become resistant to gefitinib, and showed that this resistance mutation also reduced TKI-induced apoptosis in cells growing in dishes by interfering with BIM up-regulation.
What Do These Findings Mean?
These findings (and those reported by Gong et al. and Cragg et al.) show that BIM is required for TKI-induced apoptosis in EGFR mutant NSCLC cells. They also show that mutations that make TKI-sensitive cells resistant to these drugs reduce TKI-induced apoptosis by preventing the upregulation of BIM. These results were obtained by examining the behavior of established cell lines growing in dishes and need to be confirmed in cells freshly isolated from tumors and in tumors themselves. However, they suggest that the efficacy of TKIs could be increased by finding ways to increase BIM expression or to activate other proteins involved in apoptosis Such approaches might be particularly beneficial for patients with NSCLC whose initially TKI-sensitive tumors have acquired mutations that make them resistant to TKIs.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040315.
Ingo Mellinghoff discusses this paper and two related ones in a perspective article
US National Cancer Institute information for patients and professionals on lung cancer (in English and Spanish)
Information for patients from Cancer Research UK on lung cancer, including information on treatment with TKIs
CancerQuest information on all aspects of cancer from Emory University (in several languages)
Wikipedia pages on apoptosis, epidermal growth factor receptor, and BCL2 proteins (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Information for patients from Cancerbackup on erlotinib and gefitinib
Related Articles
Gefitinib-Induced Killing of NSCLC Cell Lines Expressing Mutant EGFR Requires BIM and Can Be Enhanced by BH3 Mimetics
Cragg, Mark S
Kuroda, Junya
Puthalakath, Hamsa
Huang, David C. S
Strasser, Andreas
PLoS Medicine
The epidermal growth factor receptor (EGFR) plays a critical role in the control of cellular proliferation, differentiation, and survival. Abnormalities in EGF-EGFR signaling, such as mutations that render the EGFR hyperactive or cause overexpression of the wild-type receptor, have been found in a broad range of cancers, including carcinomas of the lung, breast, and colon. EGFR inhibitors such as gefitinib have proven successful in the treatment of certain cancers, particularly non-small cell lung cancers (NSCLCs) harboring activating mutations within the EGFR gene, but the molecular mechanisms leading to tumor regression remain unknown. Therefore, we wished to delineate these mechanisms.
Methods and Findings
We performed biochemical and genetic studies to investigate the mechanisms by which inhibitors of EGFR tyrosine kinase activity, such as gefitinib, inhibit the growth of human NSCLCs. We found that gefitinib triggered intrinsic (also called "mitochondrial") apoptosis signaling, involving the activation of BAX and mitochondrial release of cytochrome c, ultimately unleashing the caspase cascade. Gefitinib caused a rapid increase in the level of the proapoptotic BH3-only protein BIM (also called BCL2-like 11) through both transcriptional and post-translational mechanisms. Experiments with pharmacological inhibitors indicated that blockade of MEK–ERK1/2 (mitogen-activated protein kinase kinase–extracellular signal-regulated protein kinase 1/2) signaling, but not blockade of PI3K (phosphatidylinositol 3-kinase), JNK (c-Jun N-terminal kinase or mitogen-activated protein kinase 8), or AKT (protein kinase B), was critical for BIM activation. Using RNA interference, we demonstrated that BIM is essential for gefitinib-induced killing of NSCLC cells. Moreover, we found that gefitinib-induced apoptosis is enhanced by addition of the BH3 mimetic ABT-737.
Inhibitors of the EGFR tyrosine kinase have proven useful in the therapy of certain cancers, in particular NSCLCs possessing activating mutations in the EGFR kinase domain, but the mechanisms of tumor cell killing are still unclear. In this paper, we demonstrate that activation of the proapoptotic BH3-only protein BIM is essential for tumor cell killing and that shutdown of the EGFR–MEK–ERK signaling cascade is critical for BIM activation. Moreover, we demonstrate that addition of a BH3 mimetic significantly enhances killing of NSCLC cells by the EGFR tyrosine kinase inhibitor gefitinib. It appears likely that this approach represents a paradigm shared by many, and perhaps all, oncogenic tyrosine kinases and suggests a powerful new strategy for cancer therapy.
Andreas Strasser and colleagues demonstrate that activation of the proapoptotic BH3-only protein BIM is essential for tumor cell killing and that shutdown of the EGFR−MEK−ERK signaling cascade is critical for BIM activation.
Editors' Summary
Normally, cell division (which produces new cells) and cell death are finely balanced to keep the human body in good working order. But sometimes cells acquire changes (mutations) in their genetic material that allow them to divide uncontrollably to form cancers—life-threatening, disorganized masses of cells. One protein with a critical role in cell division that is often mutated in tumors is the epidermal growth factor receptor (EGFR). In normal cells, protein messengers bind to EGFR and activate its tyrosine kinase. This enzyme then adds phosphate groups to tyrosine (an amino acid) in proteins that form part of signaling cascades (for example, the MEK–ERK signaling cascade) that tell the cell to divide. In cancers that have mutations in EGFR, signaling is overactive so the cancer cells divide much more than they should. Some non-small cell lung cancers (NSCLC, the commonest type of lung cancer), for example, have activating mutations within the EGFR tyrosine kinase. Treatment with EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib induces the cells in these tumors to stop growing and die. This cell death causes tumor shrinkage (regression) and increases the life expectancy of patients with this type of NSCLC.
Why Was This Study Done?
Unfortunately, treatment with TKIs rarely cures NSCLC, so it would be useful to find a way to augment the effect that TKIs have on cancer cells. To do this, the molecular mechanisms that cause cancer-cell death and tumor regression in response to these drugs need to be fully understood. In this study, the researchers have used a combination of biochemical and genetic approaches to investigate how gefitinib kills NSCLC cells with mutated EGFR.
What Did the Researchers Do and Find?
The researchers first measured the sensitivity of NSCLC cell lines (tumor cells that grow indefinitely in dishes) to gefitinib-induced apoptosis. Gefitinib caused extensive apoptosis in two cell lines expressing mutant EGFR but not in one expressing normal EGFR. Next, they investigated the mechanism of gefitinib-induced apoptosis in the most sensitive cell line (H3255). Apoptosis is activated via two major pathways. Hallmarks of the "intrinsic" pathway include activation of a protein called BAX and cytochrome c release from subcellular compartments known as mitochondria. Gefitinib treatment induced both these events in H3255 cells. BAX (a proapoptotic member of the BCL-2 family of proteins) is activated when proapoptotic BH3-only BCL-2 proteins (for example, BIM; "BH3-only" describes the structure of these proteins) bind to antiapoptotic BCL2 proteins. Gefitinib treatment rapidly increased BIM activity in H3255 and HCC827 cells (but not in gefitinib-resistant cells) by increasing the production of BIM protein and the removal of phosphate groups from it, which increases BIM activity. Pharmacological blockade of the MEK–ERK signaling cascade, but not of other EGFR signaling cascades, also caused the accumulation of BIM. By contrast, blocking BIM expression using a technique called RNA interference reduced gefitinib-induced apoptosis. Finally, a combination of gefitinib and a BH3-mimicking compound called ABT-737 (which, like BIM, binds to antiapoptotic BCL-2 proteins) caused more apoptosis than gefitinib alone.
What Do These Findings Mean?
These findings (and those reported by Gong et al. and Costa et al.) indicate that activation of the proapoptotic BH3-only protein BIM is essential for gefitinib-induced killing of NSCLC cells that carry EGFR tyrosine kinase mutations. They also show that inhibition of the EGFR–MEK–ERK signaling cascade by gefitinib is essential for BIM activation. Because these findings come from studies on NSCLC cell lines, they need confirming in freshly isolated tumor cells and in tumors growing in people. However, the demonstration that a compound that mimics BH3 action enhances gefitinib-induced killing of NSCLC cells suggests that combinations of TKIs and drugs that affect the intrinsic pathway of apoptosis activation might provide a powerful strategy for treating cancers in which tyrosine kinase mutations drive tumor growth.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040316.
A perspective by Ingo Mellinghoff discusses this article and two related research articles
Wikipedia pages on epidermal growth factor receptor, apoptosis, and BCL2 proteins (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
CancerQuest provides information on all aspects of cancer from Emory University (in several languages)
US National Cancer Institute information for patients and professionals on lung cancer (in English and Spanish)
Information for patients from Cancer Research UK on lung cancer including information on treatment with TKIs
Information for patients from Cancerbackup on erlotinib and gefitinib
Related Articles
Rechallenge with gefitinib following severe drug-induced hepatotoxicity in a patient with advanced non-small cell lung cancer: A case report and literature review
Oncology Letters
Gefitinib has come to be the most widely used epidermal growth factor receptor-tyrosine kinase inhibitor in the treatment of advanced non-small cell lung cancer (NSCLC) in Asian patients. Common side effects include mild to moderate skin rash and diarrhea, however, drug-induced liver injury of varying severity is overlooked in long-term gefitinib administration and rarely reported. The current case report presents a female Chinese NSCLC patient who developed severe gefitinib-induced hepatotoxicity and was rechallenged with gefitinib following a 3-month break. The patient achieved partial clinical remission but developed drug-induced grade 4 hepatotoxicity following gefitinib administration for 14 months. As an alternative, 4 cycles of chemotherapy were administered to control tumor progression. Following restoration of the patient's liver function, gefitinib was rechallenged together with active hepatoprotective therapy. The patient presented good disease control and maintained normal liver function for >6 months. Thus, sequential chemotherapy and gefitinib rechallenge with hepatoprotective therapy may be a potential new treatment strategy for gefitinib-induced hepatotoxicity.
hepatotoxicity; epidermal growth factor; tyrosine kinase inhibitor; adverse drug reactions
Related Articles
Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis
Watanabe, Satoshi
Tanaka, Junta
Ota, Takeshi
Kondo, Rie
Tanaka, Hiroshi
Kagamu, Hiroshi
Ichikawa, Kosuke
Koshio, Jun
Baba, Junko
Miyabayashi, Takao
Narita, Ichiei
Yoshizawa, Hirohisa
BMC Cancer
Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2nd EGFR-TKI administration.
We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.
Three patients (27%) were treated with gefitinib as the 2nd EGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2nd EGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2nd EGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2nd EGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.
Our results indicate that a 2nd EGFR-TKI treatment can be an effective treatment option for gefitinib responders.
Related Articles
Phase I study of irinotecan and gefitinib in patients with gefitinib treatment failure for non-small cell lung cancer
Horiike, A
Kudo, K
Miyauchi, E
Ohyanagi, F
Kasahara, K
Horai, T
Nishio, M
British Journal of Cancer
Currently, no effective treatments exist for non-small cell lung cancer (NSCLC) after failure of gefitinib therapy. Pre-clinical studies have demonstrated that gefitinib-resistant NSCLC cells are more sensitive to irinotecan than parental cells, and that combined administration of irinotecan and gefitinib has a synergistic additive effect. We conducted a phase I study to evaluate the combination of irinotecan and gefitinib as a therapeutic option for NSCLC patients with progressive disease (PD) after initial gefitinib treatment.
Eligibility criteria included histologically confirmed NSCLC, age range of 20–74 years, refractory to or relapsed after gefitinib treatment, one or more previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0–2, adequate organ function, and informed consent. Patients were treated with irinotecan on days 1 and 15, and treated daily with gefitinib from day 2 every 4 weeks. The treatment was continued until disease progression. The gefitinib dose was fixed at 250 mg. Irinotecan dosing started at 50 mg m−2 and was escalated in patients by 25 mg m−2 increments up to a maximum dose of 150 mg m−2.
Twenty-seven patients were enrolled: male/female=14/13; median age=60 (45–75); histology, adenocarcinoma/non-adenocarcinoma=25/2; performance status 0–1/2=19/8; previous response to gefitinib, partial response/stable disease/PD=21/2/4. Dose-limiting toxicities were observed in 2 patients at level 3. Maximum tolerated dose was not determined, and the full dose of irinotecan could be combined with the full dose of gefitinib. The disease control rate (DCR) and response rate (RR) were 69.2 and 26.9%, respectively. For 12 patients at level 5 (the recommended phase II dose), the DCR and RR were 75.0% and 41.7%, respectively. The median treatment cycles were 4; median time to treatment failure, 57 days (95% confidence interval (CI), 32–82 days); median overall survival, 244 days (95% CI, 185–303 days); and 1-year survival rate, 32.6%.
The combination of irinotecan and gefitinib was well tolerated and potentially beneficial for NSCLC patients failing initial gefitinib monotherapy.
gefitinib; resistance; irinotecan; non-small cell lung cancer
Related Articles
Subsequent chemotherapy reverses acquired tyrosine kinase inhibitor resistance and restores response to tyrosine kinase inhibitor in advanced non-small-cell lung cancer
Guo, Renhua
Chen, Xiaofen
Wang, Tongshan
Zhang, Zhiyuan
Sun, Jin
Shu, Yongqian
BMC Cancer
Patients with advanced or metastatic non-small cell lung cancer (NSCLC) can develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Here, we report the successful treatment with alternating chemotherapy and TKIs of two cases of advanced NSCLC who developed resistance to TKI.
Case presentation
Two patients with advanced or metastatic NSCLC were treated with palliative chemotherapy followed by erlotinib/gefitinib. When TKI therapy failed, two cycles of chemotherapy were provided, which were followed by re-challenge with erlotinib or gefitinib.
NSCLC patients with acquired TKI resistance should be managed aggressively whenever possible. Subsequent chemotherapy and target treatment is one of the reasonable choices for those with an initial dramatic clinical response with erlotinib/gefitinib treatment. Further studies are warranted to substantiate the association of erlotinib /gefitinib treatment with the efficacy of NSCLC patients with acquired TKI failure.
Related Articles
Mig-6 overcomes gefitinib resistance by inhibiting EGFR/ERK pathway in non-small cell lung cancer cell lines
Li, Zi-Xuan
Qu, Lian-Yue
Wen, Hi
Zhong, Hong-Shan
Xu, Ke
Qiu, Xue-Shan
Wang, En-Hua
International Journal of Clinical and Experimental Pathology
Non small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and is the most common cause of lung cancer death. Currently, the epidermal growth factor receptor inhibitor gefitinib is widely used for patients with advanced NSCLC. However, drug resistance is a major obstacle. Mig-6 is a feedback inhibitor of EGFR and its down-stream pathway; it has been shown to play a role in gefitinib sensitivity. There is neither systematical research on the relationship between Mig-6 expression and gefitinib sensitivity, nor has the contribution of up-regulated Mig-6 on the gefitinib-resistant cell lines. In the present work, four NSCLC cell lines (H1299, A549, PC-9, and PC-9/AB11) with different sensitivities to gefitinib were subjected to analysis of the expression of Mig-6. We found that Mig-6 is over-expressed in gefitinib-sensitive NSCLC cell lines, but is low in gefitinib-resistant NSCLC cell lines. Further analysis revealed that over-expression of Mig-6 increased cell apoptosis and inhibited proliferation of gefitinib-resistant NSCLC cells treated with gefitinib, whereas lowering the expression of Mig-6 decreased cell apoptosis and promoted cell proliferation after treatment with gefitinib in gefitinib-sensitive NSCLC cell lines. These results suggest that Mig-6 is involved in mediating the response to gefitinib in NSCLC cell lines. Additionally we demonstrated that Mig-6 could reverse gefitinib resistance through inhibition of EGFR/ERK pathway in NSCLC cells. Our work uncovered that Mig-6 may be an effective therapeutic target in gefitinib-resistant lung cancer patients.
Mig-6; gefitinib resistance; NSCLC; EGFR signaling
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Metabolism of the EGFR tyrosin kinase inhibitor gefitinib by cytochrome P450 1A1 enzyme in EGFR-wild type non small cell lung cancer cell lines
Alfieri, Roberta R
Galetti, Maricla
Tramonti, Stefano
Andreoli, Roberta
Mozzoni, Paola
Cavazzoni, Andrea
Bonelli, Mara
Fumarola, Claudia
La Monica, Silvia
Galvani, Elena
De Palma, Giuseppe
Mutti, Antonio
Mor, Marco
Tiseo, Marcello
Mari, Ettore
Ardizzoni, Andrea
Petronini, Pier Giorgio
Molecular Cancer
Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) especially effective in tumors with activating EGFR gene mutations while EGFR wild-type non small cell lung cancer (NSCLC) patients at present do not benefit from this treatment.
The primary site of gefitinib metabolism is the liver, nevertheless tumor cell metabolism can significantly affect treatment effectiveness.
In this study, we investigated the intracellular metabolism of gefitinib in a panel of EGFR wild-type gefitinib-sensitive and -resistant NSCLC cell lines, assessing the role of cytochrome P450 1A1 (CYP1A1) inhibition on gefitinib efficacy. Our results indicate that there is a significant difference in drug metabolism between gefitinib-sensitive and -resistant cell lines. Unexpectedly, only sensitive cells metabolized gefitinib, producing metabolites which were detected both inside and outside the cells. As a consequence of gefitinib metabolism, the intracellular level of gefitinib was markedly reduced after 12-24 h of treatment. Consistent with this observation, RT-PCR analysis and EROD assay showed that mRNA and activity of CYP1A1 were present at significant levels and were induced by gefitinib only in sensitive cells. Gefitinib metabolism was elevated in crowded cells, stimulated by exposure to cigarette smoke extract and prevented by hypoxic condition. It is worth noting that the metabolism of gefitinib in the sensitive cells is a consequence and not the cause of drug responsiveness, indeed treatment with a CYP1A1 inhibitor increased the efficacy of the drug because it prevented the fall in intracellular gefitinib level and significantly enhanced the inhibition of EGFR autophosphorylation, MAPK and PI3K/AKT/mTOR signalling pathways and cell proliferation.
Our findings suggest that gefitinib metabolism in lung cancer cells, elicited by CYP1A1 activity, might represent an early assessment of gefitinib responsiveness in NSCLC cells lacking activating mutations. On the other hand, in metabolizing cells, the inhibition of CYP1A1 might lead to increased local exposure to the active drug and thus increase gefitinib potency.
Lung cancer; EGFR; gefitinib; metabolism; CYP1A1
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Clinical benefit of readministration of gefitinib for initial gefitinib-responders with non-small cell lung cancer
Yokouchi, Hiroshi
Yamazaki, Koichi
Kinoshita, Ichiro
Konishi, Jun
Asahina, Hajime
Sukoh, Noriaki
Harada, Masao
Akie, Kenji
Ogura, Shigeaki
Ishida, Takashi
Munakata, Mitsuru
Dosaka-Akita, Hirotoshi
Isobe, Hiroshi
Nishimura, Masaharu
BMC Cancer
Gefitinib, an oral agent of epidermal growth factor receptor tyrosine kinase inhibitor, has a certain efficacy against non-small cell lung cancer (NSCLC). Several predictive factors of gefitinib sensitivity have been well described. However, few studies have investigated the clinical features of gefitinib-responders. In the present study, we analyzed the response and disease progression of primary and metastatic lesions to gefitinib in responders and the results of gefitinib readministration following temporary cessation of gefitinib upon progression of initial gefitinib treatment and other treatments.
We retrospectively evaluated the clinical courses of 27 NSCLC patients who received gefitinib and achieved either a complete or partial response.
The best-response rate and disease-control rate against the initial chemotherapy for the gefitinib-responders were 27.3% and 77.3%, respectively. Favorable efficacy was observed in the primary lesion and metastases to the lung, liver and brain, while there was no obvious effect on bone metastasis. The primary lesion and intrapulmonary metastasis were the sites of major recurrence. Median progression-free survival was 13.8 months, median duration of gefitinib treatment was 17.0 months and median overall survival was 29.2 months. Some of the patients who experienced disease progression after responding to gefitinib were again sensitive to readministration of gefitinib following temporary cessation of gefitinib and other treatments.
Patients may still be expected to have prolonged survival if they once responded to gefitinib and then underwent various subsequent treatments followed by readministration of gefitinib. These findings might provide valuable information for the management of gefitinib-responders.
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Curcumin Induces EGFR Degradation in Lung Adenocarcinoma and Modulates p38 Activation in Intestine: The Versatile Adjuvant for Gefitinib Therapy
Lee, Jen-Yi
Lee, Yee-Ming
Chang, Gee-Chen
Yu, Sung-Liang
Hsieh, Wan-Yu
Chen, Jeremy J. W.
Chen, Huei-Wen
Yang, Pan-Chyr
PLoS ONE
Non-small cell lung cancer (NSCLC) patients with L858R or exon 19 deletion mutations in epidermal growth factor receptor (EGFR) have good responses to the tyrosine kinase inhibitor (TKI), gefitinib. However, patients with wild-type EGFR and acquired mutation in EGFR T790M are resistant to gefitinib treatment. Here, we showed that curcumin can improve the efficiency of gefitinib in the resistant NSCLC cells both in vitro and in vivo models.
Methods/Principal Findings
After screening 598 herbal and natural compounds, we found curcumin could inhibit cell proliferation in different gefitinib-resistant NSCLC cell lines; concentration-dependently down-regulate EGFR phosphorylation through promoting EGFR degradation in NSCLC cell lines with wild-type EGFR or T790M EGFR. In addition, the anti-tumor activity of gefitinib was potentiated via curcumin through blocking EGFR activation and inducing apoptosis in gefitinib-resistant NSCLC cell lines; also the combined treatment with curcumin and gefitinib exhibited significant inhibition in the CL1-5, A549 and H1975 xenografts tumor growth in SCID mice through reducing EGFR, c-MET, cyclin D1 expression, and inducing apoptosis activation through caspases-8, 9 and PARP. Interestingly, we observed that the combined treatment group represented better survival rate and less intestinal mucosal damage compare to gefitinib-alone therapy. We showed that curcumin attenuated the gefitinib-induced cell proliferation inhibition and apoptosis through altering p38 mitogen-activated protein kinase (MAPK) activation in intestinal epithelia cell.
Curcumin potentiates antitumor activity of gefitinib in cell lines and xenograft mice model of NSCLC through inhibition of proliferation, EGFR phosphorylation, and induction EGFR ubiquitination and apoptosis. In addition, curcumin attenuates gefitinib-induced gastrointestinal adverse effects via altering p38 activation. These findings provide a novel treatment strategy that curcumin as an adjuvant to increase the spectrum of the usage of gefitinib and overcome the gefitinib inefficiency in NSCLC patients.
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Emerging role of gefitinib in the treatment of non-small-cell lung cancer (NSCLC)
Tiseo, M
Bartolotti, M
Gelsomino, F
Bordi, P
Drug design, development and therapy
Most patients with non-small-cell lung cancer (NSCLC) present with advanced disease and their long-term prognosis remains poor. Epidermal growth factor receptor (EGFR)-targeted therapies, such as gefitinib, have been subjected to comprehensive clinical development. Several phase II and III trials evaluated the clinical efficacy of gefitinib as monotherapy in pretreated patients with advanced NSCLC, as well as both monotherapy and combined with chemotherapy in chemotherapy-naive patients. A phase III trial (ISEL) in heavily pretreated advanced NSCLC patients demonstrated some improvement in survival with gefitinib compared with placebo; however, the difference was not statistically significant within the overall population. A large phase III trial in pretreated patients (INTEREST) demonstrated the non-inferiority of gefitinib in comparison with docetaxel for overall survival, together with an improved quality of life and tolerability profiles. In a large phase III trial (IPASS) in Asian chemotherapy-naive, never or former light-smoker patients with adenocarcinoma, gefitinib was more effective than carboplatin–paclitaxel in prolonging progression-free survival, particularly in patients harboring EGFR gene mutations. Gefitinib was a generally well tolerated treatment, with skin rash and diarrhea being the most common treatment adverse events. As a result, gefitinib is expected to have a large impact on the management of patients with advanced NSCLC, in particular in EGFR mutated patients.
non-small-cell lung cancer; gefitinib; EGFR
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Enhancement of gefitinib-induced growth inhibition by Marsdenia tenacissima extract in non-small cell lung cancer cells expressing wild or mutant EGFR
Han, Shu-Yan
Ding, Hui-Rong
Zhao, Wei
Teng, Fei
Li, Ping-Ping
BMC Complementary and Alternative Medicine
Non-small cell lung cancer (NSCLC) expressed high levels of epidermal growth factor receptor (EGFR). Gefitinib (Iressa) has demonstrated clinical efficacy in NSCLC patients harboring EGFR mutations or refractory to chemotherapy. However, most of NSCLC patients are with wild type EGFR, and showed limited response to gefitinib. Therefore, to develop new effective therapeutic interventions for NSCLC is still required. Our previous study showed Marsdenia tenacissima extract (MTE) restored gefitinib efficacy in the resistant NSCLC cells, but whether MTE acts in the gefitinib-sensitive NSCLC cells is the same as it in the resistant one is unknown.
Dose response curves for gefitinib and MTE were generated for two sensitive NSCLC cell lines with mutant or wild type EGFR status. Three different sequential combinations of MTE and gefitinib on cell growth were evaluated using IC50 and Combination Index approaches. The flow cytometric method was used to detect cell apoptosis and cell cycle profile. The impact of MTE combined with gefitinib on cell molecular network response was studied by Western blotting.
Unlike in the resistant NSCLC cells, our results revealed that low cytotoxic dose of MTE (8 mg/ml) combined gefitinib with three different schedules synergistically or additively enhanced the growth inhibition of gefitinib. Among which, MTE → MTE + gefitinib treatment was the most effective one. MTE markedly prompted cell cycle arrest and apoptosis caused by gefitinib both in EGFR mutant (HCC827) and wild type of NSCLC cells (H292). The Western blotting results showed that MTE → MTE + gefitinib treatment further enhanced the suppression of gefitinib on cell growth and apoptosis pathway such as ERK1/2 and PI3K/Akt/mTOR. This combination also blocked the activation of EGFR and c-Met which have cross-talk with each other. Unlike in gefitinib-resistant NSCLC cells, MTE alone also demonstrated certain unexpected modulation on EGFR related cell signal pathways in the sensitive cells.
Our results suggest that MTE is a promising herbal medicine to improve gefitinib efficacy in NSCLC regardless of EGFR status. However, why MTE acted differently between gefitinib-sensitive and -resistant NSCLC cells needs a further research.
Marsdenia tenacissima extract (MTE); Gefitinib; Non-small cell lung cancer (NSCLC); Combination; EGFR related pathway
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Phase II study of erlotinib as a salvage treatment for non-small-cell lung cancer patients after failure of gefitinib treatment
Lee, D. H.
Kim, S.-W.
Suh, C.
Yoon, D. H.
Yi, E. J.
Lee, J.-S.
Annals of Oncology
Background: Both gefitinib and erlotinib are reversible epidermal growth factor receptor tyrosine kinase inhibitors, but they have somewhat different pharmacological properties. We conducted a phase II study of erlotinib after failure of gefitinib treatment in patients with non-small-cell lung cancer (NSCLC).
Patients and methods: Patients with advanced/metastatic NSCLC who had shown disease progression on gefitinib treatment were treated with erlotinib 150 mg/day until disease progression or intolerable toxicity.
Results: Between September 2006 and January 2008, a total of 23 patients were enrolled and all were assessable for response and toxicity. All patients were never smokers and all but one had adenocarcinoma. Of these 23 patients, one had a partial response and one stable disease, resulting in an objective response rate of 4.3% and a disease control rate of 8.7%. These two patients benefited from erlotinib for 6.2 months and 7.8 months, respectively; both had also benefited from prior gefitinib therapy. The most common toxic effects were skin rash and diarrhea.
Conclusion: Erlotinib should not be given routinely after failure of gefitinib treatment, but can be an option for more highly selected subsets, especially those who had benefited from prior gefitinib treatment. Identification of molecular markers in tumors is important to understand and overcome acquired resistance to gefitinib.
erlotinib; gefitinib; non-small cell lung cancer
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Economic Outcomes of Maintenance Gefitinib for Locally Advanced/Metastatic Non-Small-Cell Lung Cancer with Unknown EGFR Mutations: A Semi-Markov Model Analysis
Zeng, Xiaohui
Li, Jianhe
Peng, Liubao
Wang, Yunhua
Tan, Chongqing
Chen, Gannong
Wan, Xiaomin
Lu, Qiong
Yi, Lidan
PLoS ONE
Maintenance gefitinib significantly prolonged progression-free survival (PFS) compared with placebo in patients from eastern Asian with locally advanced/metastatic non-small-cell lung cancer (NSCLC) after four chemotherapeutic cycles (21 days per cycle) of first-line platinum-based combination chemotherapy without disease progression. The objective of the current study was to evaluate the cost-effectiveness of maintenance gefitinib therapy after four chemotherapeutic cycle's stand first-line platinum-based chemotherapy for patients with locally advanced or metastatic NSCLC with unknown EGFR mutations, from a Chinese health care system perspective.
Methods and Findings
A semi-Markov model was designed to evaluate cost-effectiveness of the maintenance gefitinib treatment. Two-parametric Weibull and Log-logistic distribution were fitted to PFS and overall survival curves independently. One-way and probabilistic sensitivity analyses were conducted to assess the stability of the model designed. The model base-case analysis suggested that maintenance gefitinib would increase benefits in a 1, 3, 6 or 10-year time horizon, with incremental $184,829, $19,214, $19,328, and $21,308 per quality-adjusted life-year (QALY) gained, respectively. The most sensitive influential variable in the cost-effectiveness analysis was utility of PFS plus rash, followed by utility of PFS plus diarrhoea, utility of progressed disease, price of gefitinib, cost of follow-up treatment in progressed survival state, and utility of PFS on oral therapy. The price of gefitinib is the most significant parameter that could reduce the incremental cost per QALY. Probabilistic sensitivity analysis indicated that the cost-effective probability of maintenance gefitinib was zero under the willingness-to-pay (WTP) threshold of $16,349 (3×per-capita gross domestic product of China). The sensitivity analyses all suggested that the model was robust.
Maintenance gefitinib following first-line platinum-based chemotherapy for patients with locally advanced/metastatic NSCLC with unknown EGFR mutations is not cost-effective. Decreasing the price of gefitinib may be a preferential choice for meeting widely treatment demands in China.
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Gefitinib-induced interstitial pneumonia: A case report and review of the literature
Experimental and Therapeutic Medicine
The aim of this study was to explore the clinical characteristics of and treatment strategies for interstitial pneumonia induced by gefitinib in patients with advanced non-small cell lung cancer (NSCLC). The detailed clinical data of one patient with NSCLC and gefitinib-induced interstitial pneumonia were compiled and a review of relevant previous studies was performed. Based on this case report and the review, the clinical characteristics, mechanisms and treatment strategies of this rare disease were analyzed. The analyses showed that older, male patients with a long smoking history, high smoking index and adenocarcinoma (particularly bronchoalveolar carcinoma) were more likely to suffer from interstitial pneumonia while taking gefitinib. The onset time of interstitial pneumonia was 1–2 months subsequent to gefitinib administration. The clinical manifestations included chest tightness, shortness of breath, progressive dyspnea, severe hypoxemia and respiratory failure. Diffuse infiltration and alveolar interstitial shadows were observed on the chest tomography scan. In such circumstances, a timely judgment is required, in addition to the withdrawal of gefitinib treatment and the administration of high-dose glucocorticoids, as well as oxygen inhalation and anti-infective therapies, in order to relieve the symptoms. In conclusion, following the onset of gefitinib-induced interstitial pneumonia, the discontinuation of gefitinib is likely to alleviate the suffering of the majority of patients. Early interstitial pneumonia is not an absolute index for the permanent discontinuation of gefitinib treatment. It is necessary to comprehensively consider the benefits and hazards of gefitinib for the patients.
gefitinib; interstitial pneumonia; glucocorticoid
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Establishment of patient-derived non-small cell lung cancer xenograft models with genetic aberrations within EGFR, KRAS and FGFR1: useful tools for preclinical studies of targeted therapies
Zhang, Xu-chao
Zhang, Jingchuan
Li, Ming
Huang, Xiao-sui
Yang, Xue-ning
Zhong, Wen-zhao
Xie, Liang
Zhang, Lin
Zhou, Minhua
Gavine, Paul
Su, Xinying
Zheng, Li
Zhu, Guanshan
Zhan, Ping
Ji, Qunsheng
Wu, Yi-long
Journal of Translational Medicine
Patient-derived tumor xenograft models have been established and increasingly used for preclinical studies of targeted therapies in recent years. However, patient-derived non-small cell lung cancer (NSCLC) xenograft mouse models are relatively few in number and are limited in their degree of genetic characterization and validation. In this study, we aimed to establish a variety of patient-derived NSCLC models and characterize these for common genetic aberrations to provide more informative models for preclinical drug efficacy testing.
NSCLC tissues from thirty-one patients were collected and implanted into immunodeficient mice. Established xenograft models were characterized for common genetic aberrations, including detection of gene mutations within EGFR and KRAS, and genetic amplification of FGFR1 and cMET. Finally, gefitinib anti-tumor efficacy was tested in these patient-derived NSCLC xenograft models.
Ten passable patient-derived NSCLC xenograft models were established by implantation of NSCLC specimens of thirty-one patients into immunodeficient mice. Genetic aberrations were detected in six of the models, including one model with an EGFR activating mutation (Exon19 Del), one model with KRAS mutation, one model with both KRAS mutation and cMET gene amplification, and three models with FGFR1 amplification. Anti-tumor efficacy studies using gefitinib demonstrated that the EGFR activating mutation model had superior sensitivity and that the KRAS mutation models were resistant to gefitinib. The range of gefitinib responses in the patient-derived NSCLC xenograft models were consistent with the results reported from clinical trials. Furthermore, we observed that patient-derived NSCLC models with FGFR1 gene amplification were insensitive to gefitinib treatment.
Ten patient-derived NSCLC xenograft models were established containing a variety of genetic aberrations including EGFR activating mutation, KRAS mutation, and FGFR1 and cMET amplification. Gefitinib anti-tumor efficacy in these patient-derived NSCLC xenografts containing EGFR and KRAS mutation was consistent with the reported results from previous clinical trials. Thus, data from our panel of patient-derived NSCLC xenograft models confirms the utility of these models in furthering our understanding of this disease and aiding the development of personalized therapies for NSCLC patients.
NSCLC; Patient-derived NSCLC xenograft; EGFR/KRAS mutations; FGFR1 amplification
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Gene-guided Gefitinib switch maintenance therapy for patients with advanced EGFR mutation-positive Non-small cell lung cancer: an economic analysis
Zhu, Jun
Li, Te
Wang, Xiaohui
Ye, Ming
Cai, Jian
Xu, Yuejuan
Wu, Bin
BMC Cancer
Maintenance therapy with gefitinib notably improves survival in patients with advanced non-small cell lung cancer (NSCLC) and EGFR mutation-positive tumors, but the economic impact of this practice is unclear.
A decision-analytic model was developed to simulate 21-day patient transitions in a 10-year time horizon. The clinical data were primarily obtained from the results of a pivotal phase III trial that assessed gefitinib maintenance treatment in patients with advanced NSCLC. The cost data were derived from the perspective of the Chinese health care system. The primary outcome was the incremental cost-effectiveness ratio (ICER) at a willingness-to-pay (WTP) threshold of 3 times the per capita GDP of China. Sensitivity analyses were used to explore the impact of uncertainty regarding the results. The impact of the gefitinib patient assistance program (GPAP) was evaluated.
After EGFR genotyping, gefitinib maintenance treatment for advanced NSCLC with EGFR mutations increased the life expectancy by 0.74 years and 0.46 QALYs compared with routine follow-up at an additional cost of $26,149.90 USD ($7,178.20 with the GPAP). The ICER for gefitinib maintenance was $57,066.40 and $15,664.80 per QALY gained (at a 3% discount rate) without and with the GPAP, respectively. The utility of progression free survival, the hazard ratio of progression-free survival for gefitinib treatment and the cost of gefitinib per dose were the three factors that had the greatest influence on the results.
These results indicate that gene-guided maintenance therapy with gefitinib with the GPAP might be a cost-effective treatment option.
Gefitinib maintenance treatment; EGFR mutation; Cost-effectiveness; Non-small cell lung cancer
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High efficacy of gefitinib in the treatment of EGFR mutation-positive advanced non-small cell lung adenocarcinoma: A case report
Oncology Letters
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, are known to play a significant role in EGFR mutation-positive non-small cell lung cancer. When an EGFR mutation is found, gefitinib and erlotinib have been shown to have significant roles in the treatment of untreated advanced NSCLC. This study reports an EGFR mutation in NSCLC treated with gefitinib and is notable due to the patient's marked improvement following a shorter than average duration of treatment with gefitinib. The present study reports the case of a 58-year-old male smoker with a dry cough. Computed tomography revealed a mass in the left inferior lobe of the lung. The patient was subsequently diagnosed with advanced lung adenocarcinoma, and an EGFR mutation (in-frame deletions of E746-A750 in exon 19) was found. The patient received multiple rounds of chemotherapy, followed by gefitinib maintenance therapy for 3 months. Later on, a grade 1 acne-like rash developed on the face and back that lasted throughout the treatment. Currently, the patient is stable, with no evidence of disease progression. The present study describes the disease and the treatment using gefitinib.
gefitinib; epidermal growth factor receptor; tyrosine kinase inhibitors; non-small cell lung cancer
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First-line single agent treatment with gefitinib in patients with advanced non-small-cell lung cancer
Yin, Yong-Mei
Geng, Yi-Ting
Shao, Yong-Feng
Hu, Xiao-Li
Li, Wei
Shu, Yong-Qian
Wang, Zhao-Xia
Journal of Experimental & Clinical Cancer Research : CR
Lung cancer is a malignant carcinoma which has the highest morbidity and mortality in Chinese population. Gefitinib, a tyrosine kinase (TK) inhibitor of epidermal growth factor receptor (EGFR), displays anti-tumor activity. The present data regarding first-line treatment with single agent gefitinib against non-small-cell lung cancer (NSCLC) in Chinese population are not sufficient.
To assess the efficacy and toxicity of gefitinib in Chinese patients with advanced non-small-cell lung cancer (NSCLC), a study of single agent treatment with gefitinib in Chinese patients was conducted.
45 patients with advanced NSCLC were treated with gefitinib (250 mg daily) until the disease progression or intolerable toxicity.
Among the 45 patients, 15 patients achieved partial response (PR), 17 patients experienced stable disease (SD), and 13 patients developed progression disease (PD). None of the patients achieved complete response (CR). The tumor response rate and disease control rate was 33% and 71.1%, respectively. Symptom remission rate was 72.5%, and median remission time was 8 days. Median overall survival and median progression-free survival was 15.3 months and 6.0 months, respectively. The main induced toxicities by gefitinib were skin rash and diarrhea (53.3% and 33.3%, respectively). The minor induced toxicities included dehydration and pruritus of skin (26.7% and 22.2%, respectively). In addition, hepatic toxicity and oral ulceration occurred in few patients (6.7% and 4.4%2, respectively).
Single agent treatment with gefitinib is effective and well tolerated in Chinese patients with advanced NSCLC.
Related Articles
FoxM1 mediated resistance to gefitinib in non-smallcell lung cancer cells
Xu, Nuo
Zhang, Xin
Wang, Xun
Ge, Hai-yan
Wang, Xiao-ying
Garfield, David
Yang, Ping
Song, Yuan-lin
Bai, Chun-xue
Acta Pharmacologica Sinica
Gefitinib is effective in only approximately 20% of patients with non-small-cell lung cancer (NSCLC), and the underlying mechanism remains unclear. FoxM1 is upregulated in NSCLC and associated with a poor prognosis in NSCLC patients. In this study, we examined the possible role of FoxM1 in gefitinib resistance and the related mechanisms.
Gefitinib resistant human lung adenocarcinoma cell line SPC-A-1 and gefitinib-sensitive human lung mucoepidermoid carcinoma cell line NCI-H292 were used. mRNA and protein expression of FoxM1 and other factors were tested with quantitative RT PCR and Western blot analysis. RNA interference was performed to suppress FoxM1 expression in SPC-A-1 cells, and lentiviral infection was used to overexpress FoxM1 in H292 cells. MTT assay and flow cytometry were used to examine the proliferation and apoptosis of the cells.
Treatment of SPC-A-1 cells with gefitinib (1 and 10 μmol/L) upregulated the expression of FoxM1 in time- and concentration-dependent manners, while gefitinib (1 μmol/L) downregulated in H292 cells. In SPC-A-1 cells treated with gefitinib (1 μmol/L), the expression of several downstream targets of FoxM1, including survivin, cyclin B1, SKP2, PLK1, Aurora B kinase and CDC25B, were significantly upregulated. Overexpression of FoxM1 increased the resistance in H292 cells, while attenuated FoxM1 expression restored the sensitivity to gefitinib in SPC-A-1 cells by inhibiting proliferation and inducing apoptosis.
The results suggest that FoxM1 plays an important role in the resistance of NSCLC cells to gefitinib in vitro. FoxM1 could be used as a therapeutic target to overcome the resistance to gefitinib.
FoxM1; non-small-cell lung cancer; gefitinib; drug resistance; RNA interference; human lung adenocarcinoma cell; human lung mucoepidermoid carcinoma cell
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Gefitinib treatment affects androgen levels in non-small-cell lung cancer patients
Nishio, M
Ohyanagi, F
Horiike, A
Ishikawa, Y
Satoh, Y
Okumura, S
Nakagawa, K
Nishio, K
Horai, T
British Journal of Cancer
Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR, HER1/ErbB1) tyrosine kinase, has been shown to have clinical activity against non-small-cell lung cancers (NSCLCs), especially in women nonsmokers with adenocarcinomas. The aim of the present study was to clarify the relationship between androgen levels and gefitinib treatment in patients with advanced NSCLCs. Sera from 67 cases (36 men and 31 women) were obtained pretreatment and during treatment with gefitinib monotherapy (days 14–18) for examination of testosterone, dehydroepiandrosterone sulphate (DHEA), and dehydroepiandrosterone sulphate (DHEAS) levels. Testosterone and DHEA during treatment were significantly lower than the pretreatment values in both women and men, and the DHEAS levels during treatment were also significantly lowered in women. Gefitinib treatment significantly suppressed androgen levels, especially in women who had no smoking history. In addition, hormone levels in women responding to gefitinib were significantly lower during the treatment than in women who did not respond. Gefitinib-associated decrease in serum androgen levels may play a role in its clinical efficacy.
sex hormone; epidermal growth factor receptor; tyrosine kinase inhibitor
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Efficacy of chemotherapy plus gefitinib treatment in advanced non-small-cell lung cancer patients following acquired resistance to gefitinib
Molecular and Clinical Oncology
Non-small-cell lung cancer (NSCLC) may exhibit oncogene addiction in patients who benefited from prior treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Preclinical data suggested that EGFR addiction persists after the development of TKI resistance, leading many clinicians to continue TKI treatment along with chemotherapy. However, this strategy has not been adequately evaluated in clinical practice. Patients who benefited from gefitinib followed by acquired resistance to this drug were reviewed in the Zhejiang Cancer Hospital. Patients were included if they received chemotherapy and gefitinib following failure of prior gefitinib treatment. A total of 26 patients were included in the present study. Six patients (23.1%) exhibited a partial response (PR), 13 (50%) achieved stable disease (SD) and 7 (26.9%) had progressive disease (PD) during the chemotherapy and gefitinib treatment. The disease control rate (DCR) was 73.1% and the median progression-free survival (PFS) was 4.6 months [95% confidence interval (CI): 3.8–5.4]. The toxicities associated with gefitinib and chemotherapy were generally acceptable. In conclusion, continued concurrent gefitinib and chemotherapy may be a valuable strategy, with acceptable and well-tolerated toxicity. However, this treatment requires further investigation.
non-small-cell lung cancer; gefitinib; combination; efficacy
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Adenosquamous cell lung cancer successfully treated with gefitinib: A case report
Molecular and Clinical Oncology
Although adenosquamous cell lung cancer (ASCLC) is included in the non-small-cell lung cancers (NSCLCs), the number of currently available studies on the response of this type of cancer to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is limited. This is the case report of a 66-year-old female who was referred to the Mito Medical Center (Mito, Japan) with hemoptysis and the chest computed tomography (CT) scan revealed a large cavitary mass in the lower lobe of the left lung. The patient underwent surgical resection of the lesion and the final pathological diagnosis was ASCLC staged as pT2bN2M0. Notably, an EGFR exon 19 deletion was identified in the adenocarcinomatous as well as the squamous cell carcinomatous components of the tumor. Despite adjuvant chemotherapy, the patient developed small cavitary metastases in the lungs bilaterally. Therefore, treatment with gefitinib was initiated. The chest CT scan revealed substantial regression of the metastatic cavitary tumors in both lungs, with thinning of the walls. The patient remains alive and recurrence-free 19 months following the initiation of gefitinib therapy. This case demonstrated an optimal clinical response to gefitinib treatment for EGFR mutation-positive ASCLC, suggesting that gefitinib is a therapeutic option for such a subset of patients with ASCLC.
adenosquamous cell lung cancer; gefitinib; cavitary formation; non-small cell lung cancer
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Hi there,
Is there a way to have the bg colour transparant?
I want to use the plugin on my site but the color of the bg does not match and i want to just use transparant.
I am thinking i might need to add some CSS into the aitwitter.css file somewhere?
great plugin by the way, works really well


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On Second Thought is a one-hour, daily news talk show that airs at 9 a.m. ET weekdays.
Watch an entire episode devoted to the Victorian age, an era that gave birth to modern baking. Friday, July 29 at 9 PM
National Signing Day is over and the reigning AAAAAA Champions, the Colquitt County Packers, had 25 players sign letters of intent on National Signing Day. I had a chance to go one-on-one with Head... MORE
Make your secure online donation at GPB.org.
Okay, we all know that there's no real end and beginning to the football season here in Georgia. In honor of the four seasons--Football, Spring Football, Recruiting, and National Signing Day--we're...


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In Immigration Battle, a special two-hour feature film presentation from FRONTLINE and INDEPENDENT LENS, acclaimed independent filmmakers Shari Robertson and Michael Camerini take viewers behind closed doors in Washington's corridors of power to explore the political realities surrounding one of the country's most pressing and divisive issues.
Domestic cats are derived from an wild African species that moved in with humans some 10,000 years ago. Although they no longer have to hunt their own food, even as kittens, they display a number of traits that make them effective killers. From the award-winning team that brought us EARTHflight and Penguins: Spy in the ...Continue Reading
Ride along with Phil as he steps out of his comfort zone in this Pacific metropolis and gateway to Asia. He tries hot pot and a classic dish of century-old eggs, and even seeks medical aid in the form of unusual tea. Join Phil Rosenthal as he continues his global travels in search of new ...Continue Reading
See a new preview of the final season of Downton Abbey. Come home to Downton Abbey and experience the love and friendship one last time. Downton Abbey premieres Sunday, January 3, 2016 on MASTERPIECE on PBS. Get involved with KCPT The Man Behind the Manners: Meet Alastair Bruce with KCPT Join KCPT for this exclusive opportunity ...Continue Reading
Part One: "Family Engagement — Starts Day 1″ On Oct. 8, KCPT offered a group of early childhood providers fun and educational hands-on activities as part of the Raising Readers Early Childhood workshops. Program speaker, Phyllis Harris, President at Pathfinders Professional Development, LLC and Consultant to Webster University, offered great ideas and best practices for teachers to take back to ...Continue Reading
If you watched local TV news this week, you might not even have seen a break for a weather update, it was wall-to-wall Royals coverage. A 7- 2 win over the Houston Astros send Kansas City to the American League Championship Series for the second straight year. The Pitch newspaper in their new Best of Kansas City ...Continue Reading


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linkAges TimeBank Gets Cooking with Community Outreach Event
They may not be TV celebrity chefs, but linkAges TimeBank members were willing to share their cooking skills and knowledge at an International Cafe Cooking Class on June 25th. An enthusiastic group of 48 prospective and current linkAges TimeBank members, ages 10-80, gathered at Mountain View's historic Adobe Building to learn about a variety of dishes crossing cultural lines.
The seven amateur cooks who led the sessions shared recipes and techniques for dishes that included pasta, stir-fries, sushi, kimchi, veggie smoothies, cole slaw and smores. To make it more interesting, participants helped with the preparation under the direction of the "chefs." And of course, everyone got to taste everything made that evening.
"The reason we organized this event was to draw attention to how the linkAges TimeBank can connect diverse members of the community in a fun way through shared interests," said Dr. Paul Tang, who directs PAMF's David Druker Center for Health Systems Innovation. "We also used the event to acquaint Mountain View residents with both the broader linkAges program and to recruit them to sign up for the TimeBank."
The linkAges TimeBank is one component of the emerging linkAges system and is being used as a mechanism to connect neighbors and community members across all ages. Members of the linkAges TimeBank, including seniors and family caregivers, can address personal needs through exchanges with other members that focus on their interests and skills and explore new possibilities for meaningful engagement in their communities. In the TimeBank, everyone's time and services are valued equally.
You can find out more about how to participate in the linkAges Bay Area TimeBank here: http://timebank.linkages.org/
linkAges Launches First Silicon Valley TimeBank at Community Planning Event
Residents and community leaders from across Silicon Valley and the greater Bay gathered at the Druker Center for Health Systems Innovation on May 8, 2012 to learn about the linkAges Bay Area TimeBank, a service exchange network where members exchange neighborly services with each other in exchange for time. Participants at the May 8 event learned about how TimeBanking works, brainstormed service exchange ideas, and identified a wide range of community outreach opportunities aimed at raising awareness and building broad community participation in linkAges Bay Area TimeBank, Silicon Valley's first TimeBank.
Participants of the May 8th event included residents from The Sequoias, a LifeCare Community located in Portola Valley, several members of the Mountain View Co‐housing Community (MVCC), and community leaders from Peninsula Circle of Care and San Mateo County Health System.
During the event, attendees participated in a fun service exchange activity where each participant listed 3 services that they would be interested in offering to other individuals in the community through the linkAges TimeBank. Participants were encouraged to think of services that they would enjoy providing (vs. services that they would be 'willing' to provide) and to consider services that reflected their unique skills or expertise or personal interests and hobbies.
Participants were then asked to list 3 services they would like to receive from other members. Participants were encouraged to identify service requests related to their personal interests or goals (e.g. learning a new language) as well as things in their everyday lives that they would be more likely to tackle or enjoy more if they could do those things with other people (e.g. gardening, cleaning out a garage, sorting through photos, etc.)
By the end of the activity, participants had generated more than 40 service offers and nearly an equal number of service requests. Service offers were diverse, ranging from personal bargain hunting, reviewing legal documents and fine jewelry repair, to care planning, lawn mowing and post‐ party cleanup. Service requests were equally diverse, ranging from help with photo organizing, garden work and recycling runs, to learning Sudoku, receiving short lessons in European history, and learning calligraphy.
Service offers and requests generated by attendees at the May 8 Community Planning Event have been catalogued in the linkAges Bay Area TimeBank's online database in preparation for official Go Live of the linkAges TimeBank website in early August.
Once the linkAges TimeBank website goes live, any TimeBank members who has attended an orientation session and successfully completed the linkAges TimeBank membership process will be able to access the site to post service ads, respond to service requests, and record service exchanges with other members.
How TimeBanking works
TimeBanking is a service exchange network where members provide and receive services from other members in exchange for time (see How does TimeBanking work?). In a TimeBank, members earn time dollars (TD$) when they provide services to other members, and use TD$ to 'buy' services from other members. Every hour of service equals one (1) TD$ regardless of the service, and everyone's time is valued equally.
Learn More
Are you part of a neighborhood, community group or local business that would be interested in learning more about how TimeBanking works? Are you interested in participating in a grassroots movement to rebuild community in Silicon Valley and the greater Bay Area where people know each other, help each other, and watch out for each other? If so, TimeBanking may be just the thing for you! Email firstname.lastname@example.com, or call (650) 691‐6267 to learn more and to schedule a local TimeBank orientation session for your neighborhood, community group or business.
PAMF Innovation
The David Druker Center for Health Systems Innovation
|The David Druker Center for Health Systems Innovation (Innovation Center) invents and deploys breakthrough innovations to advance the health and well-being of communities. We apply human-centered design and leverage technology to create scalable solutions that address the pressing health challenges of our time.
|linkAges™ is a modular community-based program that creates a social support network for all ages and across generations by using resources already in place in communities.linkAges strengthens community connections to reduce social isolation and loneliness and improves the quality of life for all participants while improving the health and well-being of older adults and family caregivers.
|linkAges TimeBank™ is a neighborhood service-exchange network that matches you with the unique skills, talents and needs of those who live nearby. Members earn hours by providing servicesm and use those hours to receive services in return. linkAges TimeBank members develop meaningful social connections through giving and receiving help, learning new skills and sharing hobbies and interests.
The Innovation Center Team
Our diverse team represents expertise in medicine, ethnography, software development, data, design, social entrepreneurship, public health and business.
Andrew Bordner, Ph.D.
Senior Data Scientist
Andrew joined the Innovation Center in February 2014 from the Mayo Clinic where he led multidiscplinary research projects in the fields of bioinformatics and clinical informatics. His recent work there involved developing new machine learning approaches to predict patient outcomes in liver transplantation surgery and to identify key mutations from cancer genome sequencing data. In his role at the Innovation Center, Andrew will support the team by developing data analysis tools and predictive models for both the linkAges and EMPOWER-H programs.
Andrew earned his Ph.D. degree in Physics from the University of Wisconsin – Madison. After completing postdoctoral work in computational biology at the University of California – San Diego he worked as a researcher at The Scripps Research Institute and Oak Ridge National Laboratory.
Chris Waugh
Chief Innovation Officer
Chris Waugh is Sutter Health's first chief innovation officer, using his extensive experience in human-centered design to guide our enterprise innovation strategy. In this role, he is developing and managing our innovation portfolio and enhancing Sutter Health's reputation as a market leader, while he refines and expands our innovation processes.
Recognized for inspiring audiences and bringing together people from many multi-disciplinary teams, Chris brings unique and inventive approaches to benefit patients across our network. He and his team serve as the entry point for external innovators to connect with Sutter Health, providing an avenue for them to present ideas that can improve our health delivery processes.
Chris has a decade of entrepreneurial leadership experience at IDEO, the Bay Area design and innovation consulting firm. He also served as vice president of design at San Francisco's One Medical Group, where he helped create a culture of innovation. He is a graduate of Fort Lewis College in Colorado with degrees in international business and French.
Christina Araiza
Community Engagement Manager
Christina is responsible for developing community partnerships to expand the linkAges program and promoting community engagement through outreach activities and events. Christina has ten years of experience in nonprofit program development and management. Prior to PAMF, she worked with U.S.-based and international NGOs to develop and implement community-based health programs addressing lifestyle-related health factors and infectious diseases, for diverse populations. Christina holds a Master's degree in Pubic Health from Loma Linda University.
Erica Gibson, Ph.D.
Medical Ethnographer
Erica joined the Innovation Center team in January of 2015 with a background in medical anthropology. As the team Medical Ethnographer she is working with community members to better understand the experiences of older adults and the challenges that they face affecting their health and well-being. Medical ethnography allows deeper insight into the context and behaviors that impact people's lives, which helps the team to design innovations that enhance health at the individual and community levels.
Erica earned her Ph.D in Anthropology from the University of Alabama in 2007. Prior to her work at the Innovation Center, she conducted cross-cultural research on pregnancy and birth experiences of women in the US, Italy, and Mexico while she was a professor of anthropology and women's and gender studies.
Linette Fung, MBA, MS
Program Director
Linette joined the Innovation Center from McKinsey & Company, where she worked as a management consultant in their health care practice. At McKinsey, her work with health and hospital systems focused on achieving growth through innovative approaches to partnering, service line optimization and provision of care for seniors and patients with chronic disease.
Linette holds a master's degree in Molecular and Cellular Physiology from Stanford University, a master's in business administration from the UCLA Anderson School of Management, and a bachelor's degree in Molecular and Cellular Biology from Harvard University.
Liz Silva
Executive Project Specialist
Prior to joining the Innovation Center team, Liz worked as a project coordinator for PAMF's Personalized Health Care Program and as an implementation coordinator for the Electronic Health Record (EHR) Team. Liz earned a bachelor's degree in Health Sciences from California State University, East Bay.
Nadia Safaeinili
Program Development Specialist, Deployment
Nadia joined the Innovation Center team in September 2015. She brings a background in public health and a passion for community-centered work, spanning local and federal levels. At the U.S. Department of Health and Human Services in Washington D.C., Nadia focused on community engagement, linking hospitals with community based organizations, and translated complex health information into clear language for the public. Her work in southern California and New York City involved community empowerment, as well as increasing access to health care and health information in community-based settings. Past research experiences at UC Berkeley and NYU included understanding the impacts of racism and stress on the cardiovascular health of African American women, and evaluating how food environments impact consumer choice and diet. At the Innovation Center, Nadia supports program development and deployment for the linkAges program.
Nadia holds a master's degree in Public Health from Columbia University, with a specialization in Health Promotion, Research and Practice, and a bachelor's degree in Public Health from the University of California, Berkeley.
Tiffany Dao
Program Development Specialist
Tiffany joined the Innovation Center team in January 2013 with a background in health and public policy. Her previous work focused on multiple topics, ranging from health education in the Office of the Surgeon General to health care policy and reform at the National Opinion Research Center and in the Office of Senator Dianne Feinstein. Aside from policy work, Tiffany also focused on social and private sector approaches to health and environmental issues through programs at the Stanford Graduate School of Business and the Stanford Earth Systems Program.
In her role at the Innovation Center and with linkAges, Tiffany works on a team to drive and support linkAges program development and provides operational support to the linkAges TimeBank.
Tiffany holds a master's degree in Earth Systems, focusing on Environmental and Food Policy, and bachelor's degree in Human Biology, concentrating on Health and Environmental Policy, from Stanford University
Vandana Pant
Senior Director Strategic Initiatives
Vandana specializes in creating and implementing scalable models for social impact and organizational growth. In her current engagement with the Druker Center, Vandana leads strategy, program deployment, operations and external relations to support upstream community health interventions. Prior to this she led strategic development at The Health Trust, a Silicon Valley-based operating foundation advancing solutions for health equity and wellness. Vandana also led strategy and development at Montalvo Arts Center, an international artists residency and multicultural arts organization. As a consultant, Vandana has led capacity building for diverse San Francisco Bay Area organizations. She currently serves on the Board of Art with Impact, a nationally growing nonprofit venture that promotes mental wellness by creating space for young people to learn and connect through art and media. She was previously on the Board of ORAM International, an advocacy organization focusing exclusively on refugees fleeing sexual and gender-based violence worldwide.
Vandana has a graduate degree in Mass Communications from the Mass Communications Research Center in New Delhi and an undergraduate degree in Psychology from Delhi University.
Zehui Zhang
Zehui has been with Palo Alto Medical Foundation since early 2002. She has worked on MyChart and EpicCare Ambulatory applications for over 10 years and is currently part of Innovation Center team. Prior to joining PAMF, she worked in software development and medical research. She also volunteered at Peninsula Healthcare Connection. Zehui holds a master's in Computer Science, and is ECFMG certified.


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Submitted by Jenny
Share More
Becca Ross:
September 18, 2012 at 7:12 am
It gives a new meaning to swiping your card through the slot.
Sarah-Jayne Oxborrow:
May 13, 2013 at 4:59 pm
Omg spitting with slaughter.
May 13, 2013 at 5:00 pm
I mean laughter lmao
"Best of" Lists


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No results found.
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Pam Grier
Kit Porter
Leisha Hailey
Alice Pieszecki
Erin Daniels
Dana Fairbanks
Mia Kirshner
Jenny Schecter
Laurel Holloman
Tina Kennard
Jennifer Beals
Bette Porter
Julian Sands
Nick Barashkov
Guest Star
Audra Ricketts
Guest Star
Camille Sullivan
Guest Star
Holland Taylor
Peggy Peabody
Recurring Role
Anne Archer
Lenore Pieszecki
Recurring Role
Devon Gummersall
Recurring Role
Opening Teaser:
Greenwich Village -- Present Day: A woman named Helen comes to the door of her friend, Tess, worrying about her missing girlfriend, Stacey, who is asleep in Tess' bed. Helen is also carrying a small statue of Abraxas.
The Connection: Later, Jenny writes a story about Abraxas, the demon of lies and deceit.
Alice: We wouldn't have been late if you hadn't spent 15 minutes in the bathroom.
Lenore: Do I look okay? Huh?
Alice: (nodding) You look good, you look great. You do. You really do.
Lenore: You could take a little more time with your face, you know. You might have a girlfriend by now.
Dana: Wait, wait, wait. What's happening? Why's everybody congratulating you guys?
Marina: Tina's having a baby. They're pregnant!
Dana: Oh, my god. Congratulations! (Tina and Dana hug) Wow! Why am I always the last to know these things?
Bette: It's okay, Dana. I was second-to-last.
Kit: (about Tina's pregnancy) You're gonna have to be so good. You can't have any more fun, uh-uh!
Tina: I know. No red meat, no additives, no Margaritas, wine, beer... and no Xanax! No matter how stressed-out I get.
Alice: No more smack, no more crack, and no more blow.
Tina: Are you sure you want to go back to men?
Alice: I'm positive. I've had enough drama and mind-fucks, and women are fucking crazy.
Tina: Yeah, men are boring.
Alice: Yeah, well bring it on, because I could use a little nice, uncomplicated, boring, boy-girl sex masquerading as love. It's fine with me.
Jenny: (to Marina at The Planet) Bonjour.
Marina: Oh, bonjour!
Jenny: (whispering) Do you have a minute for me?
Marina: But of course!
Jenny: Trés bien.
Alice: What's with Mopey Pants? What is it, Dana, are you having embarrassing multiple orgasms now?
Dana: No. Just, Lara hasn't called me. And it's been, like... (checks Alice's watch) It's been 21 hours.
Alice: Well, how'd you leave it?
Dana: I left without saying anything.
Alice: From your own apartment?
Dana: I was really embarrassed, Alice!
Lisa: (re: Alice's broken heart) That's no reason to swear off being a lesbian.
Shane: I agree.
Lisa: Maybe I can change her mind.
Dana: Wait. I'm sorry, I don't think... I don't know if you've noticed, but you're a guy. (laughs)
Shane: Lisa's a lesbian.
Lisa: I'm a lesbian-identified man.
Alice: Something happen with you and Lara?
Dana: No. I'm just never having sex again, that's all.
Shane: Easy, Dana, come on.
Dana: I've never been more humiliated or embarrassed or ashamed of anything in my entire life.
Alice: What, did she tie you up and leave you?
Tina: (about the pregnancy test box) Oh my God, I would have so much more respect for that box if it had some more honest pictures. Like some sobbing infertile woman with a negative test stick in her hand.
Alice: Yeah. And on the other side it could have a teenage girl with a positive one, about to hang herself.
Tina: Yeah.
Alice: (Tina is taking a pregnancy test) How do you not pee on your hand?
Tina: You just aim below the clit.
Alice: Oh, really?
Tina: Where did you think pee came out of?
Alice: I don't know, there's a lot going on down there.
International Episode Titles:
Czech Republic: Lži, samé lži (Lies, All Lies)
Original International Air Dates:
Czech Republic: September 2, 2011 on Prima LOVE
Music Featured in This Episode:
- Lady Love by Joystick
- Pacific Theme by Broken Social Scene
- Husband and Wife by Patric Caird
- Organic by FNDMNTL
- Last Night by Paloma
- Microphone by Transientworld
- I'm Gonna Be the One by Sattalites
- Clouds on Ground by Hellenkeller
- In My Secret Life by Leonard Cohen
S 6 : Ep 8
Aired 3/8/09 (1:05:00)
S 6 : Ep 7
Aired 3/1/09 (52:00)
S 6 : Ep 6
Aired 2/22/09 (59:00)
S 6 : Ep 5
Aired 2/15/09 (55:00)
User Score: 329
User Score: 3675
User Score: 467
User Score: 397
User Score: 358
User Score: 100
User Score: 73
User Score: 72
User Score: 66
User Score: 47
User Score: 44
User Score: 30
User Score: 30
User Score: 24
User Score: 21
User Score: 20
User Score: 16
User Score: 16
User Score: 14
User Score: 14


text: Page Content 1Newsletter The newsletter highlights the latest campus news, events, and other important announcements. To receive either version of the Babson Alumni newsletter, update your contact preferences in the Alumni Directory or email email@example.com. View the June 2016 Newsletter to learn about Alumni Weekend 2016, the Global Entrepreneur In Residence program, the fiscal-year-end Countdown, and more!


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SXSW 2007 Panel: Why Does Today's Music Sound Like Shit? Page 5
Ludwig: Of all the projects I've done, I've never gotten more compliments in my life than on my remasters of the Rolling Stones' ABKCO catalog for stereo SACD [read review]. People come up to me and say, "You know, I'm listening to music again for the first time in years." And that's really nice to hear.
But since Sony stopped supporting SACD, my workload on that format has gone to zero. The same is pretty much true for DVD-Audio. Telarc still puts out hybrid SACDs. The format certainly isn't dead in Europe, where almost all of the indie classical labels put out records on hybrid discs. And the thing that's exciting is that, if you listen to BBC Radio 3, which is their classical station, they'll play something and the announcer will rave about it and actually say over the air, "And if you think that was good in stereo, you should hear it on multichannel SACD in surround!"
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