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1Department of Gastroenterology, University of Crete Medical School, Heraklion 71003, Greece.
2Department of Gastroenterology, University Hospital, Heraklion 71100, Greece.
3Department of Experimental Medicine, University of Crete Medical School, Heraklion 71003, Greece.
Correspondence Address: Dr. Elias Kouroumalis, Department of Gastroenterology, University of Crete Medical School, Heraklion 71003, Greece. E-mail: firstname.lastname@example.com
© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
The neuropeptide somatostatin has been shown to control the secretion of several hormones and growth factors, but also to inhibit the proliferation of several tumor cells. Hepatocellular carcinoma (HCC) is a leading cause of death all over the world due to very limited treatment modalities. Early reports showed that somatostatin may influence HCC growth, making somatostatin a potential therapeutic candidate. The introduction of somatostatin analogues with long half-lives has made this prospect feasible. In this review, experimental data regarding the presence of somatostatin receptors and their functional significance in HCC are presented. Potential mechanisms of direct anti-tumoral activity of somatostatin, including effects on tumor cell proliferation and apoptosis, inhibition of various trophic factors and angiogenesis are also reviewed, as well as indirect actions affecting liver fibrosis, inflammation and macrophage-associated innate immunity. Data on the use of somatostatin analogues for the treatment of induced HCC in experimental animals are presented and human studies of somatostatin treatment of advanced HCC are critically analyzed. Reasons and pitfalls for treatment failures are identified and indications for the proper use of somatostatin, either alone or as an adjunct to other modalities in future trials are proposed.
Somatostatin analogues, hepatocellular carcinoma, somatostatin receptors, action mechanisms, treatment
Hepatocellular carcinoma (HCC) is the fifth most common cancer among men and the seventh among women, with approximately 600,000 annual deaths worldwide. It is the third cause of cancer-associated death, after cancers of stomach and lung. HCC global incidence varies usually following the distribution of hepatitis B or C viruses. It is highest in China, eastern Asia and Africa (20-35 per 100,000 population) and low (< 5 per 100,000) in Northern Europe and the USA. Mediterranean and eastern European countries have an intermediate rate of 10-20 per 100,000 population[1-3].
In 1968, a hormone secretion inhibitory molecule was described, later cloned and named somatostatin[4]. The somatostatin (SST) protein has two active forms created by alternative cleavage of a single pre-protein: the 14 amino acids SST14 and the 28 amino acids SST28, different only in potency but not in function[5]. It soon became obvious that SST had many potential therapeutic implications but the natural molecules had the inherent drawback of a very short half-life (less than 3 min) that made in vitro and in vivo applications very difficult. Therefore somatostatin analogues (SSA), namely octreotide, vapreotide, lanreotide and pasireotide were later synthesized to overcome the difficulty[6-8].
Extensive research resulted in identification and cloning of five somatostatin receptor (SSTR) subtypes (SSTR1- SSTR5) with two splice variants (SSTR2A and SSTR2B) for SST2. They are a family of transmembrane G-protein-coupled receptors and are encoded by separate genes on different chromosomes. All five receptors bind natural SST14 and SST28 with a high affinity. The synthetic analogues bind to some but not all receptors with varying affinity. Octreotide and Lanreotide have a binding affinity only for SST2 and SST5 while pasireotide binds to all receptors with the exception of SST4[9,10].
Several intracellular pathways are activated after binding SST or its analogues to the receptors leading to down-stream signaling and modulation of adenylyl cyclase (AC) (SSTRs 1-5), phosphotyrosine phosphatases (PTPs) (SSTRs 1-3) and mitogen activated protein kinase (MAPK) (SSTR4), as well as calcium and potassium channels and the sodium-proton antiporter[6,9,11-13].
Research data have made clear that somatostatin has several antineoplastic actions and could be used in clinical applications in various human cancers[14], including HCC. An extensive review has been recently published[10]. The present report will therefore summarize both experimental and clinical data on the use of SST and SSA in HCC.
There are many reports providing strong evidence that somatostatin may have an effect on HCC. Research is focused on the variability of SSTRs present in isolated cells and liver tissue, but also on functional aspects of the activation of these receptors.
Hep G2 cells are the most widely used human hepatoma cell line in liver research. The presence of mRNA of only 2, 3 and 4 SSTR subtypes was demonstrated in these cells by Northern blotting[15] but inconsistent results have been reported.
Another report found that cultured HepG2 cells expressed all five SSTRs, at both the protein and mRNA levels, while HuH7 hepatoma cells lack SSTR3[16]. Using immunohistochemical staining, HepG2 cells were reported to display weak expression of SSTR2 and moderate levels of SSTR5. Hep3B cells showed weak expression of SSTR3 and strong SSTR2 and SSTR5 staining while HuH7 cells additionally stained positive also for SSTR1, but not SSTR3[17].
Our laboratory reported that HepG2 cells were found to express SSTR2, SSTR3 and SSTR5 receptors by RT-PCR. All these SSTRs were shown to have a mainly intracellular distribution with different individual distribution patterns. Membrane binding sites for SST were mainly of the SSTR3 and SSTR5 types, with a weak SSTR2 binding[18]. Later, we demonstrated the presence of SSTR2 and SSTR5 in another hepatoma cell line, the Hep3B cells[19]. Importantly we have also demonstrated that HepG2 cells express cortistatin and we attributed the SSTRs internalization to the endogenous production of cortistatin[18]. Cortistatin is a 17-aminoacid peptide with high affinity to all somatostatin receptor subtypes[20]. Internalization of SST2 receptors after octreotide administration has also been reported in neuroendocrine tumors[21].
Activated rat hepatic stellate cells were reported to express SSTR subtypes 1, 2, and 3[22], while another report found all five SSTRs in HSCs, at both the protein and mRNA level[16]. Using a different approach, the expression of SSTR2, SSTR3 and SSTR5, but not SSTR1 and SSTR4, was demonstrated by confocal microscopy in rat HSCs. The mRNA expression level of SSTR2 was much higher than the other subtypes[23].
We have recently shown that quiescent HSCs (day 0 or day 3) do not express SSTRs by immunocytochemistry or western blot. However at day 7, SSTRs 1, 2A, 2B, 3 and 4 started to appear in some cells activated by adherence to plastic but only after day 10, all cells were positive for SSTRs 1, 2A, 2B, 3 and 4. Therefore, whatever the effect of somatostatin might be on these cells, it is not evident from the beginning of any experiment[24].
In contrast to HSCs, quiescent rat Kupffer cells were shown to express mRNA of SSTR 1-4. However immunocytochemistry identified only the presence of internalized SSTR 3 and SSTR4 receptors. Western blotting on the other hand detected SSTR2 and SSTR2a. Thus it seems that in quiescent cells the detection of SSTRs depends on the method used. Moreover Kupffer cells were found to express both somatostatin and cortistatin, a finding that may explain the internalized receptors. Stimulation of the cells with lipopolysacharide activated the expression of SSTR2, SSTR3 and SST4[25,26].
Somatostatin receptors were identified in 41% of HCC in an earlier report on the presence of regulatory peptides receptors in HCC. These receptors showed high affinity for both natural somatostatin and octreotide[27]. This observation was verified and further extended. Cirrhotic livers and HCC expressed all five SSTRs both at the protein and mRNA levels, but normal livers were negative for all SSTRs[16]. Moreover, it seems that all HCCs do not display similar expression patterns for SSTRs. Expression rates as high as 75% for SSTR5 and as low as 41% for SSTR2 were demonstrated while SSTR4 was absent. There was no correlation between SSTR expression and tumor stage or underlying liver disease[28]. Higher overall rates of all SST receptors were reported in both HCC and cirrhosis in a report from China. In contrast with the previous study, high expression of SSTR4 was also identified. The protein levels of receptors were markedly higher in HCC than in cirrhosis. Moreover there was a strong correlation of all receptors with serum AFP levels[29]. A high 67% expression of SSTR2 was also shown but there was no correlation with tumor molecular characteristics including tumor suppressor genes[30]. Very high expressions of SSTR1 and SSTR5 were also reported in a recent study of 41 liver biopsies[31].
On the contrary, a recent report from Germany found very low overall rates (8%-15%) of weak SSTRs expression in the tissue of patients with either cirrhosis or HCC. It should be stressed however that all but two of their patients had alcohol-related disease. This is important when therapeutic implications are concerned[17].
Thus, the available literature indicates variable expression of SSTR subtypes in both hepatoma cell lines and liver tissue from cirrhotic and HCC patients. This may be due to different methodologies, different etiologies of cirrhosis and HCC or different molecular events leading to HCC. Nonetheless SSTRs are expressed in a significant proportion of HCC and may therefore be a potential therapeutic target. This is further supported by functional data.
Early preclinical studies have demonstrated that both natural SST and its synthetic analogues exert an anti-proliferative effect in hepatoma cell lines[32,33]. In addition to proliferation, SSAs were shown not only to decrease cells in the S-phase but most importantly to induce apoptosis in a dose-dependent manner in HepG2 cells[15]. These effects on proliferation and apoptosis were verified and correlated with the presence of SST receptors in HCC cell lines. Apoptosis was significantly lower in normal hepatocytes[34].
In contrast with these studies, no influence of SSAs on either proliferation or apoptosis could be identified in another study. However the migration of hepatoma cells (HepG2 and HuH7) was significantly reduced after incubation with a selective SSTR1 agonist in Boyden invasion chambers. These findings may indicate a reduced invasive capability of hepatoma cells attributable to the presence of SSTR1[16].
Negative results on proliferation and apoptosis were also verified using a different cell line. Short-term octreotide treatment of Bel-7402 cells did not affect cell proliferation and apoptosis. The SSTR2 protein level was significantly decreased after exposure to octreotide[35]. Different results were very recently obtained using the same Bel-7402 cells. All SSAs tested increased cellular apoptosis but had no effect on cellular proliferation while the effect on SSTRs expression was variable[36].
However in vivo experimental data have demonstrated that SST significantly inhibits tumor proliferation. The same investigators, have convincingly shown that long-term SSA treatment effectively inhibited the development and growth of HCC and improved survival rates, possibly through resensitization and upregulation of SSTR2 and SSTR5[35,36].
A very interesting observation was reported by Xie et al.[37]. While octreotide significantly enhanced apoptosis on HepG2, no such response was observed in HepG2 cells transfected with the HBV X gene. Moreover the expression of SSTR2 and SSTR5 was reduced in these cells. This may have therapeutic implications.
The role of HSCs/myofibroblasts in HCC has not been extensively investigated but early studies indicate that they favor tumor progression producing hepatocyte growth factor[38,39]. SST or its SSAs have been reported to influence hepatic stellate cells and indirectly the progress of HCC. Thus SST at nanomolar concentrations was found to decrease rat HSC proliferation and increase apoptosis[40].
SST caused a significant decrease of collagens I and III production by activated rat HSCs without reduction of cell proliferation thus implicating a direct action of somatostatin on HSC[41].
The effect of octreotide on cellular proliferation of isolated rat hepatic stellate cells was recently investigated in our lab. The drug had no effect on proliferation but strongly inhibited procollagen production from activated stellate cells. It also inhibited PDFG and TGFb1 dependent procollagen production probably through activation of phosphotyrosine phosphatase (PTP) and phosphoserine-phosphothreonine phosphatase (STP)[24].
Octreotide is effective in inhibiting growth of HCC in vivo and in vitro[42]. There are several potential mechanisms through which SST and SSAs might inhibit HCC progress.
Despite the negative results mentioned before it is accepted today that SST and SSAs have a direct antiproliferative effect on cancer cells via specific SSTRs. SSTRs 1, 4 and 5 modulate the MAP kinase pathway and induce G1 cell cycle arrest[43]. However, the cell cycle arrest mechanisms depend on the SSTR subtypes involved and are not similar to all cell types. SSTR1 acts through the stimulation of the tyrosine phosphatase SHP-2, activation of the MAP kinase ERK pathway and induction of the p21Waf1:Cip1[44], while the SSTR5 acts through inhibition of guanylate cyclase, and MAP kinase ERK[45]. The cytostatic role of the SSTR2 has been connected to the modulation of ERK1/2 signaling pathway[46] and the activation of the phosphotyrosine phosphatases (PTPs) SHP-1, SHP-2 and PTPη. SHP-1 induces proapoptoptic caspase-mediated signals and also causes apoptosis by activation of the NF-κB leading to the inhibition of the JNK anti-apoptotic effects. Activation of PTPη, dephosphorylates intracellular effectors such as the ERK and the PI3K/Akt pathways leading to upregulation of the cyclin kinase inhibitors p21cip1/waf1 and p27kip1. Cells are therefore accumulated in the G1 phase and cell proliferation is blocked[8,47]. pERK1/2 was inhibited in response to natural SST while receptor-specific agonist treatment caused a dual effect: inhibition at lower concentrations and activation at higher concentrations[48].
Earlier studies also pointed out that SSTR2, but not SSTR3, mediated induction of cyclin-dependent kinase inhibitors p21 and p27Kip1 leading to cell cycle arrest[49]. However, a recent report has shown that SSTR2 and SSTR3 co-expression strongly induced p21 and p27Kip1 expression and therefore had a cytostatic effect[48].
Inherent to the anti-proliferative effect of SST is the induction of apoptosis whether dependent or independent of p53[34,50,51]. Apoptosis induction is mediated by either the SSTR2 activation or the co-expression and heterodimerization of SSTR2 and SSTR3[48,52].
Caspase-mediated signaling pathways of octreotide antitumor activity in HepG2 cells were also reported from our lab. We have observed an interesting phenomenon that may have therapeutic implications. Measuring activities of various caspases and apoptosis in HepG2 cells we found that octreotide decreased proliferation only at concentrations of 10-8 mol/L, while lower concentrations increased proliferation, indicating that measurements of serum octreotide levels may be important, at least in clinical trials, to verify optimal therapeutic drug concentrations[53].
There are additional molecular pathways through which SST and SSAs increase apoptosis in a time and dose dependent manner in human hepatoma cells. Thus, they were found to increase expression rates of the Fas-Fas ligand system leading to apoptosis[54].
Another intriguing mechanism is the facilitation of apoptosis by endogenous opioids. We have demonstrated in HepG2 cells that opioids inhibit proliferation and induce apoptosis. Since functional opioid receptors were not found on HepG2 cells we demonstrated that opioids bind to somatostatin receptors activating a PTP signaling cascade[55]. Interestingly, a native functional endogenous opioid system was recently described. Opioid growth factor (OGF) and its receptor were identified in hepatoma cell lines and in specimens from HCC. OGF inhibited tumor cell replication by inhibition of DNA synthesis without interfering with apoptosis[56].
One of the most important systems involved in tumor progression is the growth hormone-insulin-like growth factor-somatostatin (GH-IGF-SST) system. Several components of this system have been shown to be regulators of hepatocarcinogenesis[57-59]. In particular over-expression of IGF1 receptor and decrease of IGF-binding proteins have been described in patients with HCC and hepatoma cell lines. Interestingly an increase of cathepsin D, an acid serum protease that cleaves IGF binding proteins, has also been described in HCC[60,61]. Many studies have evaluated the relation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its implication in angiogenesis, migration and, consequently, in tumor progression[62].
Pasireotide, a somatostatin analogue with high affinity for all SSTRs except SSTR4, is a more potent inhibitor of IGF1 than octreotide[63]. It is noteworthy that the GH-IGF system is connected with the important role of Raf/MEK/ERK, one of the signaling cascades stimulated by IGF1R in experimentally induced apoptosis of hepatoma cell lines and possibly explains why the Ras gene is activated in 30% of HCCs[64] while its substrate RAF kinase is over-expressed in many HCCs[65]. The same pathway is activated by other growth factors known to be over-expressed in HCC like PDGF, EGF and TGFa[66,67].
SST also inhibits the secretion of other hormones (gastrin, glucagon, insulin) which have been shown to be trophic factors for cancer cells but their significance in hepatocellular carcinoma evolution has not been elucidated[7,68].
Neo-angiogenesis is a vital process allowing tumors to grow and metastasize[69]. The SSA octreotide was able to inhibit angiogenesis induced by HCC in vivo[70]. In nude mice with an implanted hepatocellular carcinoma, octreotide showed a strong anti-angiogenic activity[71]. Available evidence suggests that SSAs inhibit angiogenesis either directly through somatostatin receptors on endothelial cells or indirectly through the inhibition of vascular endothelial growth factor (VEGF) or via inhibition of adenylyl cyclase[7,72,73]. Recently, a combination of celecoxib and octreotide was found to have a potent anti-angiogenetic activity by decreasing the phosphorylation of the integrated signaling pathways of p-ERK kinase-HIF-1a (hypoxia-inducible factor-1a)-VEGF[74]. This combination has been tried in hepatocellular carcinoma as analyzed in the relevant section.
SST and SSAs may exert an anti-tumor activity through modulation of immune pathways. More data are required in this field[75-77]. Many studies have been focused on the effects of somatostatin on the innate component of immunity and in particular on inflammation and oxidative stress. Reduced secretion of reactive oxygen species by macrophages after incubation with SST has been reported[78]. More specifically for the liver, the amount of hydrogen peroxide released by Kupffer cells treated with SST was reduced compared to controls. Moreover SST also reduced production of nitric oxide and TNFa by Kupffer cells[79].
We have verified that octreotide reduces TNFa and NO production by Kupffer cells decreasing iNOS activity probably through an interference with phosphatidylinositol 3-kinase pathways. Like most, if not all cancers, HCC has an inflammatory component. SST may therefore inhibit the growth of HCC by reducing inflammation. In this respect we showed that rat Kupffer cells treated with octreotide produced reduced amounts of the pro-inflammatory cytokine IL-12 and increased amounts of the anti-inflammatory IL-13[80].
Macrophages are deeply involved in HCC pathogenesis through other mechanisms as well. Myeloid cells, including tumor-associated macrophages (TAMs) have been identified in large numbers in HCC microenvironment and are often associated with poor prognosis[81,82].
During induction of HCC, there is an increased production of IL-6 and TGFb1 by macrophages leading to activation of STAT3 and progression of the tumor[83]. At the same time, predominant activation of STAT3 leads to an M2 macrophage polarization[84]. M2 cells are involved in polarized Th2 responses and to tumor progression and immunoregulation[82]. TGFb1 production by Kupffer cells is reduced by octreotide in vitro, therefore the polarization of liver resident macrophages towards the M2 phenotype may be reduced as well[85]. We have also proposed that the antitumor effect of octreotide in HCC may in part be explained by its antiapoptotic effect on Kupffer cells. Using caspase3 mRNA as an index of apoptosis, we measured pro-and antiapoptotic molecules in Kupffer cells after incubation with octreotide. The increased apoptosis of cultured Kupffer cells was reversed by octreotide as a down-regulation of pro-apoptotic and an early increase of anti-apoptotic molecules were demonstrated[85].
Another important function of liver associated macrophages is mediated through the production of chemokines and their actions on their receptors. The co-operation of CCR2 bearing macrophages and T cells results in the clearance of senescent hepatocytes, thus preventing HCC development. In case of established HCC, however, recruitment of CCR2 positive macrophages leads to accumulation of suppressive TAMs resulting in tumor progression due to the inhibition of CD8 T lymphocytes and natural killer cells[86]. CCL2 is highly expressed and is a prognostic factor in HCC. Inhibition of CCL2/CCR2 signaling suppressed liver tumor in experimental animals through activation of T cell anti-tumor response as expected[87].
CC chemokines and particularly CCL2 (MCP-1) are also involved in the progression of liver fibrosis[88]. Kupffer cells were shown to secrete large amounts of CC chemokines (MCP-1, Rantes) and CXC chemokines (IL-8, MIP-2) after LPS stimulation. Octreotide inhibited only CC chemokines but not CXC chemokine secretion, an effect mediated by PI3-kinase. Therefore inhibition by octreotide of CC chemokines and specifically MCP-1 will lead to reduced HCC growth both directly inhibiting the accumulation of tumor suppressive macrophages and indirectly reducing fibrosis. Whether modifications of macrophage micro-environment influence HCC progression remains to be elucidated[89].
Strictly speaking, although hepatic stellate cells are not members of the innate immune system, they may participate in inflammation producing pro-inflammatory molecules[90,91]. Somatostatin inhibited the secretion of the pro-inflammatory cytokines IL-1beta and IL-8 from rat liver stellate cells[92].
Most HCCs are developed in a cirrhotic background. As mentioned before, SST has a profound effect on hepatic stellate cells reducing collagen I and III production and also procollagen production through activation of phosphotyrosine (PTP) and phosphoserine-phosphothreonine (STP) phosphatases without affecting stellate cell proliferation. A direct action of SST on stellate cells has been proposed[16,21].
Moreover SST may influence fibrosis through its action on Kupffer cells augmenting matrix degradation. Kupffer cells produce large amounts of MMP1 (the enzyme responsible for native collagen degradation), and lipopolysaccharide activation induces a significant early increased production of MMP1. Octreotide had a synergistic effect with lipopolysaccharide on MMP1 secretion. In addition lipopolysaccharide and octreotide, alone or in combination, induced a significant inhibition of the large amounts of TGF-b1 produced by unstimulated Kupffer cells. Inhibition of TGFb1 implied that SST may also indirectly influence stellate cells and liver fibrosis[93]. Some of the anti-tumoral actions of SST have been reviewed[94,95]. Figure 1 summarizes the cellular pathways of SST actions in HCC.
Figure 1. Anti-tumoral effect of somatostatin is achieved through various cellular pathways leading to inhibition of cell proliferation, inflammation, fibrosis and angiogenesis. Apoptosis is increased. It seems that a reduction of tumor associated macrophages (TAM) and a swift from M2 polarization in Kupffer cells may also help in the final effect
In an earlier report, HCCs were developed after implantation of Morris hepatoma cells in rats. Partial hepatectomy enhanced tumor progress, but treatment with octreotide inhibited the growth of the tumor[96]. Similarly octreotide was shown to inhibit liver regeneration after partial hepatectomy[97].
Subsequent studies from China have corroborated these results using the nude mice HCC xenograft model and octreotide administration. Tumor weights were significantly reduced, the growth was inhibited and secondary primaries and lung metastases were also decreased. More importantly, survival of the treated animals was significantly prolonged[98,99]. Recent studies reported on the effect of a combination of a COX 2 inhibitor with an SSA. They have demonstrated that the combination had an anti proliferative effect but most importantly it suppressed the metastasis of HCC in nude mice[100]. Moreover the same combination significantly prolonged the survival of rabbits with experimental liver cancer previously treated with tumor arterial embolization (TAE)[101]. Treatment with octreotide and celecoxib after TAE, synergistically inhibits hepatic allograft metastasis by promoting tumor encapsulation and inhibition of angiogenesis[102].
Lanreotide, a long acting SSA, was used as a cancer chemopreventive agent in a series of animal experiments. Thus, lanreotide was able to decrease the size of diethyl- nitrosamine induced liver preneoplastic foci by inhibiting cell proliferation and increasing apoptosis. This was associated with a decrease of cyclin D1 and an increase of p27kip1[103]. Lanreotide also reduced the number of chemically induced HCCs and significantly decreased fibrosis and the level of angiogenic factors[104,105]. In another animal model, albino mice developed HCC by injection with diethyl-nitrosamine. The administration of octreotide alone or in combination with a plant extract prevented malignant transformation. This effect was associated with a substantial reduction of oxidative stress observed in the control animals[106].
A rather intriguing finding was recently reported in rats with a high fat diet induced obesity. Octreotide increased hepatic glucogenesis associated with increased glucose synthase and decreased fasting blood glucose. More importantly, octreotide significantly reduced liver steatosis in obese rats. If confirmed, these results may justify the use of octreotide as a preventive measure of HCC in non alcoholic fatty liver disease[107].
These experimental preclinical data indicating anti-proliferative and anti-metastatic effects of SSAs in HCC, supported the initiation of clinical studies in patients with HCC.
For the first time octreotide was used for HCC treatment by our group in a randomized controlled trial of 58 mostly Okuda II and III patients. Subcutaneous octreotide almost doubled survival while treated patients clearly had a lower hazard of death (0.383), in the multivariate analysis.
We confirmed these results later in a non randomized trial with long-acting analogues where the relative risk of death of the untreated patients was 2.7 (95% CI: 1.4-5.3) compared to the treated patients. Approximately 40% of tumors either regressed (10%) or remained stable (30%), a figure similar to the overall reported expression of somatostatin receptors as mentioned before. Moreover patients retained their appetite, a satisfactory body weight and sense of well being even if tumors were radiologically progressing. The etiology of HCC in our group was related to viral hepatitis in over 90% of cases[108,109]. We have pointed out that somatostatin is not a rescue drug and the survival benefit is significant in the Kaplan-Meier survival curves only after 6 months of treatment. Moreover we observed that HCCs whose etiology was alcoholic cirrhosis were less responsive, particularly in patients who continued drinking[18].
In an uncontrolled study of 21 patients, lanreotide caused a 43% response, similar to ours (one tumour regressed and 8 were stable, despite the fact that no patient had SSTRs on octreotide scintigraphy). Five patients (24%) had a decrease in serum-AFP levels by at least 30%[15]. A similar uncontrolled study of mostly viral HCC cases reported that octreotide improved survival time in non-cirrhotic patients. It should be noted however that 40% of the cirrhotics were Child Pugh C stage and that most of them died before 6 months[110].
Another Greek group also reported that octreotide doubled survival in a randomized trial of patients with HBV or HCV related HCC who had detectable SSTRs on 111Indium octreotide scintigraphy. By contrast SSTRs negative patients had no survival benefit. Again the Kaplan-Meier curve showed that the benefit was significant after approximately 6 months of treatment[111].
In a controlled trial from China, a combination of tamoxifen and octreotide was compared to conventional chemotherapy. In the octreotide arm, a complete response or partial response was found in 43% of patients and survival was also doubled compared to chemotherapy[112].
A controlled study from Pakistan in reported tumor regression in 45.4% of patients with HCV related HCC, while alpha fetoprotein reduction was noticed in 50%. Significant survival benefit and improvement of quality of life were also found[113]. A seemingly negative small observational study on patients with advanced HCC has been reported from the USA. The median survival was only 4.5 months. However, 6/22 patients (27%) survived for more than 10 months and most interestingly these were patients of Asian descent with a history of HBV infection[114].
In a retrospective controlled study of 95 patients on octreotide (57% viral etiology and 43% alcoholics), survival rates of patients with Barcelona classification stage B were significantly higher (22.4 months), compared to patients who received palliative care only (2.9 months). Patients with BCLC stage A had also higher survival (31.4 months) compared to palliative care (15.1 months) but this was not significant due to small number of patients in this group[115].
In addition to these data there have been two case reports of HCC patients of viral etiology who responded with complete regression of the tumor with either lanreotide or long-acting octreotide[116,117]. Recently a case of HBV-associated HCC with SSTR2 overexpression and metastases in the lung and mediastinal lymph nodes detected 17 months after left hepatectomy was described. Treatment with lanreotide 30 mg twice a month resulted in a significant size reduction of the mediastinal nodes and complete disappearance of the lung nodes. This objective response lasted for 42 months[118].
A randomized study of fairly advanced HCC compared treatment with either octreotide alone or in combination with rofecoxib. Survival in both groups was significantly associated with baseline serum VEGF and IGF1 levels[119].
Two large recent trials from China highlighted the significance of the presence of SSTR2 and SSTR5 for the response to SSAs. Importantly these were studies on early-stage HCC and treatment was administered after resection of the primary tumor. In the study by Li et al.[120], 76 patients with operable HBV-related HCC were divided into two groups according to SSTR2 and 5 expression profiles. The mean survival time was longer in the high SSTR2/5 expression group. Similar results were reported in another study of 99 HBV-related HCC. Recurrence rate and survival were significantly higher in patients with high expression of SSTR2[121]. Both studies concluded that the expression profile of SSTRs can be used as an independent prognostic factor.
There have been interesting results when SSAs were compared to transarterial chemoembolization (TACE) or radiofrequency ablation (RAF) or were given in combination with TACE or sorafenib.
In an earlier report of a prospective non-randomized study from Germany, 41 patients were treated with octreotide and compared for survival to another group of patients treated with TACE. A median survival of 571 days was found in the octreotide group, similar to the TACE group[122]. This was confirmed later in a larger randomized trial where, octreotide treatment had a similar outcome compared to patients who received TACE or multimodal therapy[115].
In an observational study, a combined approach of RAF followed by octreotide was adopted for treatment of viral-associated HCCs, mostly Child A and Child B (60% and 34% respectively). All patients had multiple liver HCC nodules; 14% had complete or partial tumor regression and a clinical benefit was evident in 80%. Mean survival was 31.4 months. Serum VEGF was significantly correlated with response[123].
In a different setting, 147 patients diagnosed with HCC suitable for TACE received 2-4 TACE procedures; 84 patients received an additional heparin plus octreotide combination and 63 patients were given only heparin and served as the controls without randomization. They reported a significant reduction in the incidence of tumor metastasis within a year of follow-up post-TACE, in the combination treatment[124].
In a recent randomized study from China, 71 patients with mostly viral associated HCC, BCLC stages B and C were assigned to either TACE (n = 35) or TACE plus celecoxib plus octreotide (n = 36) and were followed up for 3 years. The median overall survival of the TACE + C + L group of 15.0 months was twice as much compared to that of the TACE group (7.5 months) and the survival benefit was very significant for both BCLC stage B or C. Equally significant was the improvement in the quality of life in favor of octreotide. Post-embolization syndrome was also significantly lower in the octreotide group[125].
The results of the combination of octreotide plus sorafenib were reported in a prospective non controlled phase II study of advanced viral associated HCC (mostly HCV), Child-Pugh A or B; 10% of patients achieved partial response and 66% had stable disease with a median survival of 12 months. The combination was well tolerated[126].
Further work from the same group has shown that responders had a significant decrease of reactive oxygen species in the peripheral blood mononuclear cells and this reduction was enhanced when octreotide was added to sorafenib. A 50% pERK activity reduction was observed in responders compared to an 80% increase in non responders. Sorafenib induced a 40% increase in serum NO and this was further increased after octreotide[127]. Whether SSAs offer any advantage as an addition to sorafenib remains to be established.
A retrospective observational non controlled study found no evidence of survival benefit in 63 patients (40% alcoholics)[128]. The first negative randomized controlled study was reported by Yuen et al.[129]. It has been heavily criticized by us and many others, because the selected patients had a very short survival of 1.9 months in the control group (n = 35) vs. 2 months in the octreotide group (n = 35) indicating that most patients belonged to BCLC stage D. In fact 21/35 patients received either none or just one long-acting octreotide injection[130].
A non-randomized subsequent study found limited beneficial response after octreotide administration. However, 4 patients (6%) did not receive any octreotide because their disease progressed so rapidly they were unable to start treatment. These patients were included in the survival analysis; 5% received 1 dose, 19% 2 doses, 16% 3 doses and 16% 4 doses. Additionally, from the 30 patients surveyed, 6 were not enrolled due to intolerance to the test dose. The selection of patients also raises some questions. A significant number (50%) had vascular thrombosis (extent is not specified) and 13% had metastatic disease. It should be noted that among the 14 patients who received treatment of more than 3 months, 50% were judged to be stable, which is in accordance to virtually all previous results[131,132].
Another open-label study of 63 patients (22% alcoholics) reported little anti-cancer activity and a median survival of 8 months. However, the reason for stopping treatment was disease progression or toxicity and therefore assessment of survival was not really feasible[133].
A randomized controlled study compared the effect of tamoxifen (control group) with tamoxifen plus octreotide in 109 patients (52.4% alcoholics) and reported no survival benefit. Again the median survival of the treatment group was only 3 months and 44% of patients received only 1-3 injections. Moreover the median survival in Child-Pugh A patients was only 6 months[134].
The HECTOR study, a randomized double-blind placebo-controlled multicenter trial of 120 patients, showed no survival benefit for octreotide compared to placebo, with a median survival of 4.7 and 5.3 months respectively. Quality of life was also unaffected. However 52% of the treatment group had alcoholic cirrhosis and at 6 months the survival rate was only 40%[135].
Similarly negative were the results from another multicenter randomized placebo controlled study. But again 50% of the randomized patients had alcoholic cirrhosis[136]. A recent everolimus plus pasireotide open-label study of 26 patients (BCLC stage C 88%, and > 60% alcoholics) also gave negative results with a median survival of 6.7 months. However the reason for treatment discontinuation was disease progression and not death. Treatment was administered for only a median of two 28-day cycles. Yet, 10/22 evaluable patients had stable disease as best response[137].
A seemingly not favorable open label trial of twenty patients (all HBV or HCV) treated with pasireotide was recently reported. 90% had prior therapy, 75% had BCLC stage C, and 55% had metastatic disease. Despite this, a stable disease in 9 patients was demonstrated (45%), and the median survival was 9 months[138].
The situation is possibly clarified from a Chinese meta-analysis of approximately 800 patients from 9 trials. The 6- and 12-month survival rates in the octreotide group were significantly higher than those of the control group (6-month: RR 1.41, 95% CI: 1.12-1.77, P = 0.003; 12-month: RR 2.66, 95% CI: 1.30-5.44, P = 0.008) but this was not the case when only western studies were analyzed[139]. This meta-analysis vividly describes that there is a discrepancy in results between China (and in that regard Greece) and Western countries. This is also evident from the analysis presented in this review.
One possible explanation for the negative results is the tachyphylaxis through which SSTRs are internalized upon prolonged exposure of tumors to somatostatin analogues. However there is evidence that resensitization may occur[35]. In addition the expression profile of receptors is variable among tumors. Also production of endogenous cortistatin may further affect the expression and internalization of the receptors[95].
Serum levels of octreotide may also be a critical parameter in HCC response. As mentioned before octreotide decreased proliferation only at concentrations of 10-8 mol/L, while lower concentrations increased proliferation, making drug serum levels an important parameter at least in clinical trials[53]. However, these possible resistance mechanisms cannot explain the differences between the East (and Greece) and the West.
A critical evaluation of the reported studies offers potential explanations for the discrepancies. First, as we pointed out, the survival benefit is evident only in patients that live long enough to have a treatment period of more than 6 months. Somatostatin is not a magic bullet and the potential molecular pathways of its action require some time to produce measurable results. The second explanation is very important. Practically all negative western studies recruited a large number of alcoholic cirrhosis (between 25% and 60%) reflecting the etiological background of their population. In contrast, Chinese studies have almost exclusively recruited viral cirrhosis in accordance with cirrhosis etiology in their population. The same was true in the original Greek studies. It was our impression that our few alcoholics did not respond equally well to somatostatin particular those that do not abstain from alcohol. This critical point is not mentioned in any of the negative papers. As mentioned before, a very recent report from Germany found very low rates of weak expression of SSTRs in liver tissue from alcohol related HCC patients[17]. Only two of their patients had virus-related HCC.
Selection of patients is critical in any study of HCC treatment[18,130,132]. It seems that SST is suitable for patients with viral cirrhosis ideally after identification of the expression on the tumor of SSTR2 and 5, either with scintigraphy or even better by immunofluorescence after a liver biopsy. Eligible patients are those classified as BCLC stage B or C[140] which is the same indication with TACE and possibly sorafenib. Patients with alcoholic cirrhosis-related HCC may be treated as those in BCLC stage B, but the response will be limited. In that respect it is tempting to use SST as an adjunct to TACE.
Finally, it would be interesting in future to see if there are additional differences between viral and alcoholic related HCC like differential expression of receptors or production of trophic factors. In a recent study an increase of serum IGF2 level was reported to be associated with the occurrence of HCC metastasis after TACE and octreotide, as metastatic foci were found in 97% when IGF2 was increasing in contrast to only 13.6% of patients with an IGF2 decrease[141]. In the context of the previous discussion, it should be noted that the expression of IGF2 in HCC was strongly associated with HBV infection[142].
Devised the review, supervised the project and prepared the final draft: Kouroumalis E
Revised the clinical data and participated in the preliminary draft: Samonakis D
Revised experimental data and participated in the preliminary draft: Notas GAvailability of data and materials
Not applicable.Financial support and sponsorship
None.Conflicts of interest
All authors declare that there are no conflicts of interest.Ethical approval and consent to participate
Not applicable.Consent for publication
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© The Author(s) 2018.
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105. Borbath I, Stärkel P. Chemoprevention of hepatocellular carcinoma. Proof of concept in animal models. Acta Gastroenterol Belg 2011;74:34-44.PubMed
106. Abdel-Hamid NM, Mohafez OM, Nazmy MH, Farhan A, Thabet K. The effect of co-administration of Lawsonia inermis extract and octreotide on experimental hepatocellular carcinoma. Environ Health Prev Med 2015;20:195-203.DOIPubMedPMC
107. Wang XX, Ye T, Li M, Li X, Qiang O, Tang CW, Liu R. Effects of octreotide on hepatic glycogenesis in rats with high fat dietinduced obesity. Mol Med Rep 2017;16:109-18.DOIPubMedPMC
108. Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos ON. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut 1998;42:442-7.DOIPubMedPMC
109. Samonakis DN, Moschandreas J, Arnaoutis T, Skordilis P, Leontidis C, Vafiades I, Kouroumalis E. Treatment of hepatocellular carcinoma with long acting somatostatin analogues. Oncol Rep 2002;9:903-7.DOI
110. Patsanas T, Kapetanos D, Ilias A, Ch Gessiou, Tzarou V, Kokozidis G, Kitis G. Octreotide in the treatment of inoperable hepatocellular carcinoma. Ann Gastroenterol 2004;17:69-74.
111. Dimitroulopoulos D, Xinopoulos D, Tsamakidis K, Zisimopoulos A, Andriotis E, Panagiotakos D, Fotopoulou A, Chrysohoou C, Bazinis A, Daskalopoulou D, Paraskevas E. Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: randomized placebo-controlled trial. World J Gastroenterol 2007;13:3164-70.DOIPubMedPMC
112. Pan DY, Qiao JG, Chen JW, Huo YC, Zhou YK, Shi HA. Tamoxifen combined with octreotide or regular chemotherapeutic agents in treatment of primary liver cancer: a randomized controlled trial. Hepatobiliary Pancreat Dis Int 2003;2:211-5.PubMed
113. Gill ML, Atiq M, Sattar S, Khokhar N. Treatment outcomes with long acting octreotide in inoperable hepatocellular carcinoma: a local experience and review of literature. J Pak Med Assoc 2005;55:135-8.PubMed
114. Shah U, O'Neil B, Allen J, Goldberg RM, Bernard S, Moore D, Venook AP, Morse MM. A phase II study of long-acting octreotide in patients with advanced hepatocellular carcinoma and CLIP score of 3 or higher. Gastrointest Cancer Res 2009;3:45-8.PubMedPMC
115. Schöniger-Hekele M, Kettenbach J, Peck-Radosavljevic M, Müller C. Octreotide treatment of patients with hepatocellular carcinoma--a retrospective single centre controlled study. J Exp Clin Cancer Res 2009;28:142.DOIPubMedPMC
116. Raderer M, Hejna MH, Kurtaran A, Kornek GV, Valencak JB, Oberhuber G, Vorbeck F, Virgolini I, Scheithauer W. Successful treatment of an advanced hepatocellular carcinoma with the long-acting somatostatin analog lanreotide. Am J Gastroenterol 1999;94:278-9.DOIPubMed
117. Siveke J, Folwaczny C, Herberhold C. Complete regression of advanced HCC with long acting octreotide. Gut 2003;52:1531.DOIPubMedPMC
118. Borbath I, Lhommel R, Guiot Y, Coche E, Sempoux C. Lanreotide treatment of metastatic hepatocellular carcinoma resulting in partial regression and more than 3 years of progression-free survival. Acta Gastroenterologica Belgica 2012;75:270-3.PubMed
119. Treiber G, Wex T, Rocken C, Fostitsch P, Malfertheiner P. Impact of biomarkers on disease survival and progression in patients treated with octreotide for advanced hepatocellular carcinoma. J Cancer Res Clin Oncol 2006;132:699-708.DOIPubMed
120. Li S, Liu Y, Shen Z. Characterization of somatostatin receptor 2 and 5 expression in operable hepatocellular carcinomas. Hepatogastroenterology 2012;59:2054-8.DOI
121. Liu Y, Jiang L, Mu Y. Somatostatin receptor subtypes 2 and 5 are associated with better survival in operable hepatitis B-related hepatocellular carcinoma following octreotide long-acting release treatment. Oncology Lett 2013;6:821-8.DOIPubMedPMC
122. Plentz RR, Tillmann HL, Kubicka S, Bleck JS, Gebel M, Manns MP, Rudolph KL. Hepatocellular carcinoma and octreotide: treatment results in prospectively assigned patients with advanced tumor and cirrhosis stage. J Gastroenterol Hepatol 2005;20:1422-8.DOIPubMed
123. Montella L, Addeo R, Caraglia M, Faiola V, Guarrasi R, Vincenzi B, Palmeri A, Capasso E, Nocera V, Tarantino L, Ariete M, Martorelli A, Del Prete S. Vascular endothelial growth factor monitoring in advanced hepatocellular carcinoma patients treated with radiofrequency ablation plus octreotide: a single center experience. Oncol Rep 2008;20:385-90.PubMed
124. Jia W, Feng K, Fan P, Fan G, Yang S, Zhang T, Wei Q, Qian L. Post-TACE combination therapy of heparin and octreotide results in decreased tumor metastasis in extrahepatic tumorigenesis. Cell Biochem Biophys 2012;62:35-40.DOIPubMed
125. Tong H, Wei B, Chen S, Xie YM, Zhang MG, Zhang LH, Huang ZH, Tang CW. Adjuvant celecoxib and lanreotide following transarterial chemoembolisation for unresectable hepatocellular carcinoma: a randomized pilot study. Oncotarget 2017;8:48303-12.DOIPubMedPMC
126. Prete SD, Montella L, Caraglia M, Maiorino L, Cennamo G, Montesarchio V, Piai G, Febbraro A, Tarantino L, Capasso E, Palmieri G, Guarrasi R, Bianco M, Mamone R, Savastano C, Pisano A, Vincenzi B, Sabia A, D'Agostino A, Faiola V, Addeo R. Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR study. Cancer Chemother Pharmacol 2010;66:837-44.DOIPubMed
127. Caraglia M, Giuberti G, Marra M, Addeo R, Montella L, Murolo M, Sperlongano P, Vincenzi B, Naviglio B, Del Prete S, Abbruzzese A, Stiuso P. Oxidative stress and ERK1/2 phosphorylation as predictors of outcome in hepatocellular carcinoma patients treated with sorafenib plus octreotide LAR. Cell Death Dis 2011;2:e150.DOIPubMedPMC
128. Rabe C, Pilz T, Allgaier HP, Halm U, Strasser C, Wettstein M, Sauerbruch T, Caselmann WH. Clinical outcome of a cohort of 63 patients with hepatocellular carcinoma treated with octreotide. Z Gastroenterol 2002;40:395-400.DOIPubMed
129. Yuen MF, Poon RT, Lai CL, Fan ST, Lo CM, Wong KW, Wong WM, Wong BC. A randomized placebo-controlled study of long-acting octreotide for treatment of advanced hepatocellular carcinoma. Hepatology 2002;36:687-91.DOIPubMed
130. Kouroumalis E, Samonakis D, Sordilis P. Octreotide treatment of hepatocellular carcinoma. Hepatology 2003;37:477.DOIPubMed
131. Slijkhuis WA, Stadheim L, Hassoun ZM, Nzeako UC, Kremers WK, Talwalkar JA, Gores GJ. Octreotide therapy for advanced hepatocellular carcinoma. J Clin Gastroenterol 2005;39:333-8.DOIPubMed
132. Samonakis DN, Christodoulakis N, Kouroumalis EA. Octreotide for unresectable hepatocellular carcinoma: beyond the first sight. J Clin Gastroenterol 2006;40:86-7.DOIPubMed
133. Cebon J, Findlay M, Hargreaves C, Stockler M, Thompson P, Boyer M, Roberts S, Poon A, Scott AM, Kalff V, Garas G, Dowling A, Crawford D, Ring J, Basser R, Strickland A, Macdonald G, Green M, Nowak A, Dickman B, Dhillon H, Gebski V, Australasian Gastro-intestinal Trials group (AGITG) and Ag0001H Investigators. Somatostatin receptor expression, tumour response, and quality of life in patients with advanced hepatocellular carcinoma treated with long-acting octreotide. Br J Cancer 2006;95:853-61.DOIPubMedPMC
134. Verset G, Verslype C, Reynaert H, Borbath I, Langlet P, Vandebroek A, Peeters M, Houbiers G, Francque S, Arvanitakis Van Laethem JL. Efficacy of the combination of long-acting release octreotide and tamoxifen in patients with advanced hepatocellular carcinoma: a randomised multicentre phase III study. Br J Cancer 2007;97:582-8.DOIPubMedPMC
135. Becker G, Allgaier HP, Olschewski M, Zahringer A, Blum HE, HECTOR Study Group. Long-acting octreotide versus placebo for treatment of advanced HCC: a randomized controlled double-blind study. Hepatology 2007;45:9-15.DOIPubMed
136. Barbare JC, Bouché O, Bonnetain F, Dahan L, Lombard-Bohas C, Faroux R, Raoul JL, Cattan S, Lemoine A, Blanc JF, Bronowicki JP, Zarski JP, Cazorla S, Gargot D, Thevenot T, Diaz E, Bastie A, Aparicio T, Bedenne L. Treatment of advanced hepatocellular carcinoma with long-acting octreotide: a phase III multicentre, randomised, double blind placebo-controlled study. Eur J Cancer 2009;45:1788-97.DOIPubMed
137. Sanoff HK, Kim R, Ivanova A, Alistar A, McRee AJ, O'Neil BH. Everolimus and pasireotide for advanced and metastatic hepatocellular carcinoma. Invest New Drugs 2015;33:505-9.DOIPubMedPMC
138. Feun LG, Wangpaichitr M, Li YY, Kwon D, Richman SP, Hosein PJ, Savaraj N. Phase II trial of SOM230 (pasireotide LAR) in patients with unresectable hepatocellular carcinoma. J Hepatocell Carcinoma 2018;5:9-15.DOIPubMedPMC
139. Ji XQ, Ruan XJ, Chen H, Chen G, Li SH, Yu B. Somatostatin analogues in advanced hepatocellular carcinoma: an updated systematic review and meta-analysis of randomized controlled trials. Med Sci Monit 2011;17:RA169-76.DOIPubMedPMC
140. Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020-2.DOIPubMedPMC
141. Xiong ZP, Huang F, Lu MH. Association between insulin-like growth factor-2 expression and prognosis after transcatheter arterial chemoembolization and octreotide in patients with hepatocellar carcinoma. Asian Pacific J Cancer Prev 2012;13:3191-4.DOI
142. Qian J, Yao D, Dong Z, Wu W, Qiu L, Yao N, Li S, Bian Y, Wang Z, Shi G. Characteristics of hepatic IGF-II expression and monitored levels of circulating IGF-II mRNA in metastasis of hepatocellular carcinoma. Am J Clin Pathol 2010;134:799-806.DOIPubMed
Kouroumalis E, Samonakis D, Notas G. Somatostatin in hepatocellular carcinoma: experimental and therapeutic implications. Hepatoma Res 2018;4:34. http://dx.doi.org/10.20517/2394-5079.2018.33
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text:
Water is one of seventeen global priorities agreed by world leaders, captured within the Sustainable Development Goals (SDGs); the SDG 6 demands to halve the amount of untreated wastewater and provide universal access to adequate sanitation by 2030.
To address the high standards and targets set under this goal, the sector needs to attract and support the development of new talents. It needs those people who will bring research to practice, pilot and catalyse new thinking, and implement best practices.
According to recent national human resource assessments, water sector human resources are in short supply. Beyond shortages, the sector loses professionals every day to more competitive sectors. We can counter this trend by driving existing professionals from other sectors, but also students and young professionals to enter the water sector.
As an industry young professional, Matteo Viccardi, ISOIL's Export Manager, gives an advice for other smart water young professionals interested in pursuing this field:
"Having joined the water industry only a couple of years ago, I can definitely say that the possibility of contributing to the global challenge of water management is both exciting and rewarding. The water sector definitely needs motivated young professionals with different skills and backgrounds to integrate new technology and break down challenges in to smaller localised concepts and solutions. The water industry can hardly compete with some other industries in terms of salaries and compensations packages, but it can surely offer the great chance to work on one of the most important, complex and underestimated issues of our times, with objective of leaving a better world to future generations".

subset: commoncrawl


text:
See more Cabinet Doors
IT Kitchens Brookfield Textured Ivory Style Shaker Standard Cabinet door (W)300mm
Our stores do not stock this product
Product details
Product information
This stylish white Standard door will spruce up any kitchen, giving it a contemporary feel.
- 300mm base and wall cabinets - or 925mm base corner cabinets and 625mm wall corner cabinets (2 packs required)
- Easy to clean, just wipe down with a damp cloth and buff dry immediately - Do not use detergents, alcohol or abrasives to clean
- 10 years Guarantee
Features and benefits
Create a decadent feel with our Brookfield Textured Ivory Style Shaker kitchen. With traditional shaker panelling and a pale ivory finish, it's a timeless look that never gets old.
- These kitchen doors are easy to clean, with no need for detergents, alcohol or abrasives. Simply wipe down with a damp cloth and buff dry. Great for messy chefs.
- Our kitchen doors are designed and manufactured in Italy by experienced craftsmen and each kitchen is personally inspected and hand finished by experts. That's why we guarantee them for 10 years.
- Everything you need to complete your kitchen is available at B&Q, from our range of handles to our soft close hinges.
Health and safety
Please note that this item has additional safety or regulatory datasheets available. The product may have possible health and safety hazards covered in these documents. Refer to the container for full information and always follow the instructions.
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Stylish doors
Hill top - 3 years ago
After having a glossy kitchen for the last 12 years,I opted for this ivory textured look which is completely different. My kitchen has been transformed! The doors are well made and look clean and stylish. Good service from B&Q.
eddo22 - 4 years ago
having only found this item in the kitchen book and not on display I was surprised to find that this product to be very good once delivered and able to inspect most fully I consider that this item should be displayed in store if only a single panel door as this would allow for product evaluation to be undertaken
Anonymous - 4 years ago
These are good quality and look great in my new kitchen. One of the doors was slightly warped but B&Q replaced without any problems.


text:
English Majors - Office-Based Teacher in Quezon Ci
at J-P English Corporation (Metro Manila)
For office-based teachers:
§ Unbooked slots will be paid if you teach from 4 AM to 7 AM and 7 PM to 12MN if you avail the free accommodation, or 6 AM to 9AM and 6 PM to 11 PM.
§ Get a chance to meet and teach your students offline
§ Take advantage of the free company accommodation located just beside the office building.
§ After 6 months, Office-based teachers can choose if they want to stay as a freelance teacher or be a regular employee.
ü SSS, Phil health, PAGIBIG (Mandatory benefits) – 13th month pay – Fixed salary (based on the number of classes from previous month before regularization)
· With or without teaching experience (any course)
· FRESH GRADUATES are encouraged to apply, UNDERGRADUATES are also welcome!
· Can communicate in English (conversational to advanced)
· Proficiency in the Japanese language (with or without JLPT certificate) is an advantage but not required.
· Willing to work in Quezon City (for Office-based and avail of free accommodation)
· Willing to work for at least 8 hours a day for 5-7 days a week including weekends (Full time home-based and office-based) or 4-5 hours a day and 5-7 days a week including weekends (Part time)
For our home-based teachers, you must have:
· Either your own laptop/desktop computer
· Own wired internet connection (LAN) with a speed of at least 3mbps (Unlimited; for with Data capacity, minimum of 100gb)
· A clear webcam and a headset with an external microphone (mobile earphones are not allowed)
· A good working environment conducive to online classes (no background noises, good lighting, etc.)
Applicants using any wireless connection (broadband sticks, pocket Wi-Fi, etc.) won't be entertained.
· Provide 25 – 125 minute English lessons to Japanese students via Skype/Zoom (depending on the account assigned).
· Report to the office at least 30 minutes before the work shift (For office-based teachers) or go online 30 minutes before first class (For home-based teachers).
· Maintain good attendance and performance record.
· Post lesson memos and submit sound files on time for every class conducted (for evaluation of students' performance, provide appropriate recommendations and monitor their progress)
· Attend training/coaching as needed.
Apply Now
Recent jobs at J-P English Corporation
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text:
Question about Computers & Internet
Posted by sallynaknoo on
when i right click on the icon i want it doesnt say anything about saving it too disk n where can i download an icon editin tool i havent got a clue how to use da laptop yet i only got it a couple of weeks ago its a dell inspiron 1525
no still dont work just comes up as the e icon for internet
you were right about the view not being set to classic but it still didnt work
hi i figured out what was wrong the text size was changed to larger so i changed it too smaller n all is good now so thanks very much
I had the same issue on a Vista Home Basic system. I dragged th icon to the desktop and I got the e-icon instead os a Bebo icon, but when I changed the Desktop icon size to Classic it worked fine. Unless you use Classic it will not work at all.
Thats all I can suggest.
Posted on Aug 12, 2008
If you drag the icon from the address bar in IE to the desktop, it should change the icon when it is copied to the desktop.
otherwise -
go to the website and right-click on the icon you want to use and save the icon to disk. Download an icon editing tool and load the icon and save it as a .ico file. Then right-click - properties on the shortcut and then change icon and browse to the icon you just saved.
Posted on Aug 08, 2008
I di this
1. type www.bebo.com into internet explorer and click on arrow - IE loads BEBO page
2. Left-click on the icon in the address bar (icon just before www.bebo.com text
3. Drag icon to Desktop and release mouse button
4. Viola - a bebo icon is now on Desktop
Does this not work for you?
I think your problem is you do not have Desktop Icon size set to Classic.
Right-click on Desktop
Thats it!
Tips for a great answer:
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text:
Come to our event!
Let's Create a Vision
IN THE LOOP Program of Success
The mission of IN THE LOOP Program of Success is to empower young people to reach their full potential by providing resources that allow them opportunities to gain exposure and explore positive options.
The IN THE LOOP provides support and resources related to self-development/personal awareness, scholarships, post-secondary college options, career development and conflict management. In addition, IN THE LOOP also conducts empowerment workshops and develops production opportunities.


text:
After releasing the Wilmington College Top 30 in segments of five, the Wilmington College Athletic Communications department has started releasing the Top 10 individually.
More than 100 people took time to vote in the poll, and here are the results.
#6 Erika Good (Women's Soccer)
After missing the 2014 season, Good returned to action in 2015 and made an immediate impact as the women's soccer team returned to the Ohio Athletic Conference tournament.
For her efforts, she was named All-OAC, All-Ohio and first team Academic All-Ohio after scoring five goals with one assist.
"Erika is a fifth-year senior that had a tremendous year for us last year," said Wilmington head coach Steve Spirk. "We are excited to have her for one more season. Not only is she a talented and strong player, but she is a tremendous leader."
Good was also selected as the Wilmington College Comeback Player of the Year.
The countdown
7. Junior Devon Maki (Men's Lacrosse)
8. Senior Reid Delaney (Men's Lacrosse)
9. Senior Brittaney Jefferson (Women's Basketball)
10. Junior Christian Jones (Men's Basketball)
11. Senior Antone Truss (Men's Track and Field)
12. Senior Taylor Scott (Women's Soccer)
13. Junior Chris Hein (Men's Lacrosse)
14. Senior Erik Spraul (Men's Swimming)
15. Senior David Spraul (Men's Swimming)
16. Junior Jhordan Lang (Men's Lacrosse)
17. Sophomore Niklas Martennson (Men's Soccer)
18. Junior Courtney Mackey (Softball)
19. Junior D.J. Iles (Men's Basketball)
20. Sophomore Benny Spirk (Men's Soccer)
21. Samantha Glish (Women's Swimming)
22. Senior Mary Moyer (Women's Basketball)
23. Junior Nils Asteberg (Men's Soccer)
24. Sophomore Jake Hyatt (Baseball)
25. Senior Elyse Spraul (Women's Swimming)
26. Junior Hunter Stith (Cross Country)
27. Junior Griffin Stith (Cross Country)
28. Junior Kennedy Harshaw (Volleyball)
29. Senior Ashley Andracki (Women's Basketball)
30. Junior Becca Petra (Women's Lacrosse)
The rest of the releases
July 28 - #5
August 2 - #4
August 4 - #3
August 9 - #2
August 11 - #1


text:
retinal vasculopathy with cerebral leukodystrophy
Also found in: Dictionary, Thesaurus, Legal, Financial, Encyclopedia.
retinal vasculopathy with cerebral leukodystrophyA microvascular endotheliopathy of the retina (OMIM:192315) of middle-age onset characterised by telangiectasias, microaneurysms and retinal capillary obliteration beginning in the macula, and microinfarcts of cerebral white matter that often coalesce to form pseudotumours.
Molecular pathology
Caused by defects of TREX1, which encodes a nuclear protein with 3' exonuclease activity.


text:
Linux sucks
I'm so tired of struggling to get Linux running. It's my own fault but you know, it's too frustrating.
I read a story last week about the 'death' of desktop linux and I think it's true. Linux on the desktop is a pipe dream.
I've long been a fan of RedHat Linux and the Fedora desktop suite. But some time ago they started screwing it up with virtually every release. I guess starting about the time they went from Fedora Core to just Fedora. Maybe even Fedora Core 6 was fucked up, I dunno.
I have a Dell GX280 which is a hypertheaded Pentium IV 3.2ghz system (socket 775). The motherboard uses DDR2 RAM and has onboard video and audio. Everything worked fine with Fedora 9 and Fedora 10 but neither Fedora 11 or 12 would install properly. It just failed with error after error.
Posts on fedora specific forums didn't get any help so I gave up and stayed with 10.
Then I wanted to add more storage and when I was prompted with warning about my software being out-of-date I tried to upgrade to Fedora 13. It actually worked fine, well, I mean it installed fine but it wouldn't boot because it didn't like my add in PCI SATA card.
Nothing I did would make it work. So, I did the next best thing. I replaced the motherboard with a more modern board that had 6 onboard SATA controllers. Fine.
Only now the install process hangs because suddenly it doesn't like the PCIe card I am using. It worked fine in the Dell but not on the new board.
There are alternate install options so I chose to use a more compatible video setting. That seemed to help but it hung a little further into the install process.
Fine, I looked for a fix for that but I couldn't find one. I saw bug reports that mentioned the problem but no fix.
Fuck it. I've got another copy of Win7 Pro so I'm just going to use that. Why not? It installed fine in about 20 minutes and it's already up and working fine.
All hardware detected and working perfectly (so far).
Everyone talks shit about Windows (well, not everyone) and talks up how great Linux is, but every time I've tried to install it in the last 4 years I've struggled with it and fought with it and had to come up with some compromise to make it work.
I know, I could try some other flavor of Linux like Mint or FreeBSD or the ubiquitous Ubuntu. Well, I HAVE tried some of them and they didn't solve my problems.
Sorry to raise such a stink here. It ain't like anyone will read it. I just needed to vent.
Farking Fedora. WTF.
Your friend,
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text:
two of the culprits
boy, howdy. i was in for it. last night, i experienced a real fight. like, a real face-punching, wrestling-to-the-ground and into furniture, feet-kicking fight.
it all started by play wrestling. surprise surprise. we have somewhat of a circle that connects our dining room, living room, family room, and kitchen and triston and jackson were chasing each other around and around and of course i was busy doing something domestic and sometimes i just kind of check out. when i came too, and they were running in circles, i interceded and told them we don't do that. so they took it in the family room and started wrestling around. someone got hurt and the fight was on.
usually when someone gets hurt, the afflicted comes running to me and i give them the bit "that is why we shouldn't play like that" and "if you want to wrestle you've got to be more careful", but this time no one came. all i heard was grunts and yelps and "thuds" which is making my stomach hurt as i type this.
i ran into the family room and broke it up. they were screaming about who did what and who started it and i being the wise mother that i am didn't ask for details and didn't take sides but instead reminded them that we are a loving family who doesn't fight, unless we are going after liberals, and even then violence is not the answer. ha ha, just joking (or am i?)(i totally did not say that to the kids). i made them hug, which elicited lots of complaining, but mothers know how to make their kids do it anyway (by issuing threats, of course). i came back to the kitchen to finish up cleaning and it started all over again, except the little-er one was chasing after the bigger one right up the stairs into dark territory, which doesn't happen around here because like their mother, they are afraid of the dark. but it happened anyway and i knew this was some serious shiz taking place.
i followed up the stairs and broke it up again only after seeing jackson throw a right into triston's chin and triston kick-slamming j right into the wall (aunt danielle, style). i made the guys apologize to each other and hug-it-out once more and to even throw an "i love you" in there, too. the weirdest thing about it all was that jackson had on this stupid electronic spider-man glove (just on one hand) during the whole fight, and every time he moved there was this whole array of noises like "huh!" "pow" "scat!" and the like. it was kind of surreal.
there were no tears, only breathless anger and above all: my threats of house-hold peace were being ignored. i grabbed jackson and took him to the bathroom for teeth-brushing (and a good talking to) and triston busted through the door with wild eyes, not unlike a crazed meth addict. only, he is seven and is most definitely NOT a crazy meth addict. jackson bolts off the counter and gets in some ridiculous stance and then this is where i got pissed. after throwing triston out of the bathroom and locking the door, i started yelling about how "triston is supposed to be your best friend" "who are you going to sit with on the school bus the very first day?" "he will always have your back, and here you are fighting with him" "he is your brother!" blah blah blah. although mostly very sweet, jackson has a tendency to look right though you and completely not care what you are saying. it's the second biggest reason why i got rid of the wii. anyway, i sent jackson off and yelled for triston to come into the bathroom pretty much for me to do and say the same things to him. except i added the part about "you are older, you set the example".
triston, god bless him, he is a reason-er. he'll think about things and over think them and if he feels his very core has been wronged, will give 250 bazillion reasons why he did what he did and he just can't let it go. and that is exactly what he started doing...which ultimately lead me to offer him a candy bar of his choice if he would just go apologize and see what happens.
also like his mother, he can't resist candy bars, so he did it and the contention that was palpable just minutes before suddenly vanished and jackson, without hesitation and a simple shoulder shrug, said "me, too" and it was all over.
20 seconds later (literally 20 seconds later) they were talking about a couple of army guys triston had and jackson asked if he could borrow it. triston said, "sure, but i have two of the same and we could just play with them both - together- if you want". and then they went to bed with no further problems.
if you are like me, you are thinking "wth" only i was thinking more like "wtf", except i am a christian and don't use words like that.
honestly, i was sad to see these two fighting. and you better believe i broke out the "jesus doesn't like it" speech. if all of that failed, and they do it again, i have a really great scary "mean mommy voice" in my arsenal that i only pull out on special occasions. we'll see what happens.
but, the most important thing everyone should pick up on, though, is that peace was instilled in our home by a candy bar. a freaking candy bar was all it took. the power of chocolate is quite persuasive and i'm thinking all the president needs to do for a bi-partisan vote on this debt debacle up on capitol hill is start passing around the chocolate. dark for me, please. seriously...contention vanished just. like. that.
let's pray for peace....all around.
PS my baby has two little "toofers" trying to pop through and last time i checked he is just 3 months old. what is going on, here?
PPS did you know that e.t. still scares the crap out of little kids? it does. and elliott also says "penis-breath" to his brother and my kids thought it was hilarious. awesome.


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Handcrafted Four Poster Bed
Artisanal Marvel
Handcrafted creations hold a unique connect, which in this world of mass-produced goods, is to be deeply treasured. Each tells a story of inspiration and painstaking efforts and comes with its own unique touch that can never be replicated. A four-poster bed is a fitting example of a handmade product that anyone who appreciates art would yearn for. It brings in magnificence to space, celebrates nature and its beauty and is worthy of all the praise.
Now unleash your creative urges and how. Here are six easy to follow steps that will help you choose the right four-poster bed:
1.An Elegant Design Theme: The theme should be considered according to room interiors. Many theme options are available such as vintage style, royal British style, and contemporary style.
- Decide the Dimension: Next major concern is to determine the size of your bed that includes the bed frame, width, height, and depth of poster bed.
- Perfectly Shaped: To plan the perfect shape of your bed, you can have the four posters carved, or you can leave them flat. And then pick a variety of designs as an option.
- Material Matters: Choosing the right material can make your buying experience wonderful. So, go for hardwood which is more sturdy, durable, easy to maintain, and comfortable.
- Using Admirable Drapery: Use drapery along the sides in your four-poster bed to free the head area. Use mesh panels along the rails and incorporate the drapery along the way.
- Choose Complementary Colour and Finish: Go for the color which complements your bedroom's theme. Prefer bright natural wooden finish for natural look otherwise go for mahogany or honey finish.
The old furnishes were crafted with a purpose and quality- that was made to last a lifetime. That is the ethos RA Lifestyles like to apply to furniture-making, where we try to work with the best materials available to create products with old-world quality.
Our process, from design to the last steps of manufacturing a four-poster bed, is designed to obtain signature finish. There is human touch at every step of the way. Visit our Classic Furniture Store in Pune, and experience the royal grandeur of a four-poster bed. Hope it coaxes you to buy this pure artisanal marvel.