European Journal of Cancer - Articles in Press

Four and a half LIM protein 2 (FHL2) negatively regulates the transcription of E-cadherin through interaction with Snail1 - Corrected Proof

2010-09-01

Abstract: E-cadherin is a hallmark of epithelial–mesenchymal transition (EMT), which plays a crucial role in cancer metastasis. We previously demonstrated that four and a half LIM protein 2 (FHL2) inhibited E-cadherin expression and promoted invasive potential and EMT in colon cancer. Here, we aim to further define the mechanism underlying the inhibition of E-cadherin by FHL2 in colon cancer. The expression profiles of FHL2 and Snail1 were first observed by Western blot, immunofluorescence and immunohistochemistry. We found that both the protein level and the cellular localisation of Snail1 were quite similar to FHL2 in colon cancer; reciprocal co-immunoprecipitation assay showed that FHL2 was able to bind Snail1 and its intact structure was required. The expression of FHL2 was positively correlated to Snail1 while negatively to E-cadherin and phospho-Snail1. FHL2 over-expression induced the accumulation of Snail1 in the nucleus. Moreover, dual luciferase assay revealed that FHL2 over-expression decreased while FHL2 siRNA increased the transcriptional activities of two E-cadherin promoter constructs which contained E-box sites (Snail1-binding elements). Mutation of E-boxes increased the transcriptional activities and FHL2 expression was involved in the function of mutation. These results suggested that FHL2 negatively regulated E-cadherin transcriptional activity through interaction with Snail1. Our study established a novel regulatory function of FHL2 and revealed a potential mechanism on promoting the process of EMT.

Expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) by colorectal cancer cells and adjacent stroma cells – Associations with histopathology and patients outcome - Corrected Proof

2010-09-01

Abstract: Aim: To elucidate cellular features accountable for colorectal cancers’ (CRC) capability to invade normal tissue and to metastasize, we investigated the level of the collagenase matrix metalloproteinase 9 (MMP-9) and its physiological inhibitor tissue inhibitor of metalloproteinases 1 (TIMP-1) in cancer cells and supporting stroma cells of CRC.Methods: Immunoreactivity of MMP-9 and TIMP-1 by carcinoma cells, lymphocytes and fibroblasts in archival specimens of paraffin-embedded primary tumours were retrospectively associated with outcome in 340 consecutive patients completely resected for CRC stages II–IV and subsequently treated with adjuvant 5-fluorouracil.Results: Expression of MMP-9 by carcinoma cells was demonstrated in 9% of specimens without association to recurrence free survival (RFS) (HR=1.0; 95% CI: 0.6–1.8; P=0.9) or overall survival (OS) (HR=0.9; 95% CI: 0.5–1.6; P=0.6). TIMP-1 expression by carcinoma cells, which appeared in 64% of the specimens, was inversely related with RFS (HR=1.3; 95% CI: 0.9–1.8; P=0.08) and OS (HR=1.5; 95% CI: 1.1–2.1; P=0.02). Expression of TIMP-1 by fibroblasts at the invasive border was directly related to RFS (HR=0.7; 95% CI: 0.6–0.9; P=0.02) and OS (HR=0.7; 95% CI: 0.6–1.0; P=0.05). Expression of MMP-9 by lymphocytes correlated significantly with the degree of peritumoural inflammation (P=0.02) but not with RFS (HR=0.9; 95% CI: 0.7–1.1; P=0.2) or OS (HR=0.8; 95% CI: 0.7–1.0; P=0.07).Conclusion: TIMP-1 in cancer cells is associated with poor prognosis independent of its function as inhibitor of MMP-9. MMP-9 and TIMP-1 are important mediators of the host–cancer cell interaction in the tumour microenvironment with significant influence on the histopathology and on prognosis of CRC.

Downregulation of miR-21 modulates Ras expression to promote apoptosis and suppress invasion of Laryngeal squamous cell carcinoma - Corrected Proof

Jingyuan Ren, Dan Zhu, Ming Liu, Yanan Sun, Linli Tian — 2010-09-01

Abstract: MiRNAs are small, noncoding RNA molecules that emerge as important regulators of cancer-related processes. The miR-21 microRNA is overexpressed in a wide variety of cancers and has been causally related to cellular proliferation and apoptosis. In this study, we found that miR-21 is overexpressed in Laryngeal squamous cell carcinoma (LSCC) and correlated with advanced stage. Inhibition of miR-21 by antisense oligonucleotides (ASO) led to decreased protein level of Ras and profound suppression of cell proliferation and invasion. Hep-2 cells exposed to miR-21 ASO exhibited cell cycle arrest at G1 phase and increased apoptosis. Furthermore, growth of LSCC xenograft tumours was significantly suppressed by repeated injection of ASO-miR-21 lentivirus and the Ras protein expression in LSCC xenograft tumours was also downregulate by ASO-miR-21. Taken together, our data suggest that miR-21 may play an oncogenic role in the cellular processes of LSCC and represent a novel target for effective therapies.

Early cessation of the clinical development of LiPlaCis, a liposomal cisplatin formulation - Corrected Proof

2010-08-30

Abstract: Purpose: To evaluate the safety and tolerability of LiPlaCis, a liposomal formulated platinum compound, in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous (i.v.) LiPlaCis. and to assess plasma and urine pharmacokinetics and plasma biomarkers.Patients and methods: Patients with solid tumours without standard therapeutic options were enrolled to receive LiPlaCis administered as a 1h infusion without additional hydration every 3weeks until RECIST progression or unacceptable toxicity. Cohorts of 3–6 patients were treated at each dose level until MTD was reached.Results: Eighteen patients were enrolled and 64 cycles were delivered. At the first dose level 3 patients experienced an infusion reaction. Despite prophylactic pre-medication and prolongation of the infusion to 2h in further patients, three other patients had mild acute infusion reactions. Toxicity at the fifth dose level of 120mg consisted of grade 2 renal toxicity reversible after hydration in 2 patients and grade 4 thrombocytopaenia in one of these patients. Peak plasma concentrations and AUC were dose proportional. The interpatient variability in the clearance of total LiPlaCis-derived platinum was 41%. Platinum was excreted via the urine mainly during the first 24h after administration. Investigated plasma biomarkers sPLA2 and SC5b-9 were related to, but not predictive for, acute infusion reactions.Conclusion: The observed safety profile suggests no benefit over standard cisplatin formulations and LiPlaCis will require reformulation to enable further development.

Interleukin-1β regulates the migratory potential of MDAMB231 breast cancer cells through the hypoxia-inducible factor-1α - Corrected Proof

2010-08-30

Abstract: The casual relationship between inflammation and tumour progression has been widely accepted and the etiology of breast cancer has been associated with inflammatory processes. Interleukin (IL)-1β, besides its central role in inflammation, has also been recognised as a powerful player in tumour progression, angiogenesis and invasiveness. Recently, there has been considerable interest in understanding the non-hypoxic upregulation of the hypoxia-inducible factor (HIF)-1α by IL-1 in neoplastic cells since aberrant expression of HIF-1α correlates with tumour progression. Here, using the highly invasive human breast cancer cell line MDAMB231, we studied the effect of IL-1β on tumour cell migration along with HIF-1α accumulation. We observed that non-hypoxic induction of HIF-1α by IL-1β in MDAMB231 was associated with increased cell migration, paralleled by upregulation of p38 MAPK phosphorylation and CXCL8/CXCR1 expression. Inhibition of HIF-1α by siRNA resulted in a significant reduction of CXCR1 expression and IL-1β-induced cell migration in MDAMB231 cells, thus confirming a role of HIF-1α in the non-hypoxic-IL-1β-dependent induction of migratory potentials. Our observation that IL-1 induces HIF-1α accumulation in MDAMB231 cells was confirmed in tumour cells growing in vivo using an experimental approach, mimicking the endogenous release of IL-1 in mice bearing MDAMB231 xenografts. Our in vivo data, along with the fact that inhibition of HIF-1α resulted in the decrease of IL-1β-promoted cell migration, further support the link between inflammation and cancer. The overall results may have important implications in those therapeutic approaches aimed to inhibit IL-1-mediated activities in tumour cells, specifically in breast cancer.

First-line therapy with moderate dose capecitabine in metastatic breast cancer is safe and active: Results of the MONICA trial - Corrected Proof

2010-08-27

Abstract: Background: To determine activity and safety of capecitabine at a moderate dose of 2000mg/m2 as first-line therapy for metastatic breast cancer.Methods: In this prospective phase II trial, patients with HER2-negative metastatic breast cancer received first-line capecitabine 2000mg/m2 on days 1–14 every 3weeks. The primary aim was to exclude a time to progression (TTP) <6months. Secondary end-points were overall response rate, overall survival (OS), toxicity and quality of life.Results: Median age of the 161 included patients was 65years. Median TTP and OS were 7.3months [95% (confidence interval) CI: 6.2–8.4] and 17.1months (95% CI: 14.0–20.3), respectively. An overall response rate of 26.1%, including 13 complete remissions was observed. Patients developing grade I–III hand-foot syndrome had a significantly longer TTP and OS and patients >65years also achieved a significantly longer TTP. Haematological grade I–IV toxicities were leucopenia (64.0%), anaemia (50.9%) and thrombocytopenia (28.0%). Relevant non-haematological toxicities were hand-food-syndrome (37.3%), fatigue (34.2%), nausea (29.8%) and diarrhoea (20.5%). Quality of life assessment revealed an improved emotional function, but worsening of nausea and vomiting from cycle 1–10.Conclusions: Capecitabine at a dose of 2000mg/m2 is active and safe as first-line treatment of patients with metastatic breast cancer.

A phase 2 study of vatalanib in metastatic melanoma patients - Corrected Proof

2010-08-27

Abstract: Background: A phase 2 study of vatalanib (PTK787/ZK222584) an oral tyrosine kinase inhibitor of VEGFR 1, 2 and 3 was undertaken in patients with metastatic melanoma.Methods: Adults with pathologically confirmed metastatic melanoma, WHO Performance status 0–2, and adequate haematological, hepatic and renal function, were treated with vatalanib until disease progression. The trial used Fleming’s single stage design.Results: Tumour control rate (CR+PR+SD) was 35% at 16weeks, with objective response seen in only 1 patient. Median progression-free survival was 1.8months (95% CI 1.8–3.7months) and median overall survival was 6.5months (95% CI 3.9–10.2months).Conclusion: Vatalanib stabilised disease in a proportion of patients, although overall survival was disappointing.

An international multicentre validation study of a pain classification system for cancer patients - Corrected Proof

Stein Kaasa — 2010-08-27

Pain is a key symptom at all stages of cancer. It may be the first sign experienced by the patients, it may be a sign of relapse after curative treatment and many patients with metastatic disease may suffer for years due to suboptimal pain treatment. Cancer patients are reporting that pain is the symptom they mostly fear and that they hypothetically may consider to ask for euthanasia in a state of unbearable pain.

The tumour-targeting human L19-IL2 immunocytokine: Preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma - Corrected Proof

2010-08-27

Abstract: Background: L19-IL2, a tumour-targeting immunocytokine composed of the recombinant human antibody fragment L19 (specific to the alternatively-spliced EDB domain of fibronectin, a well characterised marker of tumour neo-vasculature) and of human IL2, has demonstrated strong therapeutic activity in animal cancer models. This phase I/II trial was performed to evaluate safety, tolerability, recommended phase II dose (RD) and early signs of activity of L19-IL2.Patients and methods: Five cohorts of patients with progressive solid tumours (n=21) received an intravenous infusion of L19-IL2 (from 5 to 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 3weeks. This treatment cycle was repeated up to six times. In the following expansion phase, patients with metastatic renal cell carcinoma (RCC) (n=12) were treated at the RD of L19-IL2. Clinical data and laboratory findings were analysed for safety, tolerability and activity.Results: Preclinical studies in rats and monkeys did not raise any safety concerns. The RD was defined to be 22.5 Mio IU IL2 equivalent. Pharmacokinetics of L19-IL2 was dose proportional over the tested range, with a terminal half-life of 2–3h. Toxicities were manageable and reversible with no treatment-related deaths. We observed stable disease in 17/33 patients (51%) and 15/18 with mRCC (83%) after two cycles. Median progression-free survival of RCC patients in the expansion phase of the study was 8months (1.5–30.5).Conclusions: L19-IL2 can be safely and repeatedly administered at the RD of 22.5 Mio IU IL2 equivalent in advanced solid tumours. Preliminary evaluation suggests clinical activity of L19-IL2 in patients with mRCC.

Psychological consequences of lymphoedema associated with breast cancer: A prospective cohort study - Corrected Proof

2010-08-27

Abstract: Background: The aim of this prospective cohort study of women attending a rehabilitation course at the Dallund Rehabilitation Centre was to explore the emotional and psychological aspects of living with lymphoedema, expressed as psychological distress, poorer quality of life and poorer self-reported health.Methods: Between November 2002 and January 2007 within the FOCARE study, self-completed questionnaires were collected 3weeks before and 6 and 12months after the rehabilitation course to elicit sociodemographic, physical and lifestyle information and responses to three psychometric tests. The population consisted of 633 women, 125 with and 508 without verified lymphoedema (time since surgery, 1month–5years). The population was reduced to 553 women at the first follow-up and 494 at the second.Results: Multivariate analysis showed that, in comparison with women without lymphoedema, those with lymphoedema had a 14% higher risk for scoring one level higher on the POMS-SF test, a 9% higher probability of scoring one point lower on the quality of life scale and a 29% higher likelihood of reporting poorer or bad health than women without lymphoedema. These findings were seen at all three measurement times.Conclusions: In this cohort of women with breast cancer, women with lymphoedema after surgery for breast cancer had significantly worse overall emotional well-being and adjustment to life compared to women without lymphoedema.

Toll-like receptor (TLR) 7 and TLR8 expression on CD133+ cells in colorectal cancer points to a specific role for inflammation-induced TLRs in tumourigenesis and tumour progression - Corrected Proof

2010-08-23

Abstract: Toll-like receptor (TLR) stimulation results in activation of NF-κB, a key modulator in driving inflammation to cancer and mitogen-activated protein kinases that have been shown to recruit mitotic and cyclooxygenase-2 (COX-2) induced pathways in carcinogenesis. Here we asked whether different TLR, COX-2 and stem cell marker expression profiles in colorectal cancer (CRC) provide further evidence for this hypothesis from a clinical perspective. We analysed gene and protein expression of TLR7-TLR10, COX-2 and CD133 as a marker for colon-initiating cells in CRC patients (n=65). Gene analysis demonstrated significantly upregulated TLR7–TLR10 and COX-2 expression in CRC tumour tissues. Analysis of isolated tumour cells from primary tumours showed co-expression of TLR7 and TLR8 with CD133 and gave evidence for a subpopulation of colon cancer-initiating cells. In multivariate analyses TLR8 expression was found to be an independent prognostic factor. Persistent TLR-specific activation of NF-κB in CRC and particularly in tumour-initiating cells may thus sustain further tumour growth and progression through perpetuated signalling known from inflammatory and tissue repair mechanisms with consecutive self-renewal in pluripotent tumour cells. Activation through self-ligands or viral RNA fragments may putatively maintain this inflammatory process, suggesting a key role in cancer progression.

Bevacizumab/docetaxel association is more efficient than docetaxel alone in reducing breast and prostate cancer cell growth: A new paradigm for understanding the therapeutic effect of combined treatment - Corrected Proof

2010-08-23

Abstract: Bevacizumab (Bvz), a Vascular Endothelial Growth Factor (VEGF)-targeted humanised monoclonal antibody, provides clinical benefit in combination with docetaxel (DXL), a microtubule-stabilising agent, in the treatment of metastatic breast and prostate cancers. Since VEGF and their receptors are expressed by tumour cells, we hypothesised that Bvz, in addition to its impact on neo-vascularisation, could have an impact on tumour cells and enhance the DXL activity. Hence, we studied the effect of DXL and Bvz on metastatic breast (MDA MB-231) and prostate (PC3) cancer cells lines. Bvz alone did not decrease cell proliferation but in combination with DXL, Bvz enhanced the anti-proliferative activity of DXL. Other anti-angiogenic factors Sunitinib, Sorafenib and Gefitinib enhanced the anti-proliferative effect of DXL. qPCR experiments showed that DXL significantly increased the VEGF and VEGF receptor 2 (VEGF-R2) mRNA levels. Activation of VEGF and VEGF-R2 promoters demonstrated that enhanced mRNA levels are partly due to transcriptional activation. ELISA assays showed that DXL induced accumulation of cytoplasmic VEGF but decreased extracellular levels by 39% (MDA) and 48% (PC3). Cell surface localisation of VEGF-R2 was increased by DXL alone, but decreased after combined treatment of DXL plus Bvz. Abnormal expression of VEGF-R2 was also shown on breast and prostate tumour samples reinforcing the results obtained on cellular models. In conclusion, DXL and Bvz in combination decreased extracellular VEGF and VEGF-R2 levels at the plasma membrane thereby blocking an important growth/survival loop. Thus, the combined therapeutic impact of Bvz and DXL observed in clinical trials is associated with enhanced anti-proliferative activity and inhibition of the vascular network.

Human glioblastoma tumours and neural cancer stem cells express the chemokine CX3CL1 and its receptor CX3CR1 - Corrected Proof

2010-08-23

Abstract: Human gliomas represent an unmet clinical challenge as nearly two-thirds of them are highly malignant lesions with fast progression, resistance to treatment and poor prognosis. The most severe form, the glioblastoma multiforme, is characterised by a marked and diffuse infiltration through the normal brain parenchyma. Given the multiple effects of chemokines on tumour progression, aim of this study was to analyse the expression of the chemokine CX3CL1 and of its specific receptor CX3CR1 in 36 human surgical glioma samples, with different degrees of histological malignancy and in glioblastoma-derived neurospheres. Herein we show that both ligand and receptor are expressed at the mRNA and protein levels in most specimens (31/36). While receptor expression was similarly detected in low or high grade tumours, the uppermost scores of CX3CL1 were found in grades III–IV tumours: oligodendrogliomas, anaplastic astrocytomas and glioblastomas. Accordingly, the expression of CX3CL1 was inversely correlated with patient overall survival (p=0.01). Glioblastoma-derived neurospheres, containing a mixed population of stem and progenitor cells, were positive for both CX3CR1 and for the membrane-bound chemokine, which was further up-regulated and secreted after TNF-IFNγ stimulation. Confocal microscopy of 3D neurospheres showed that the ligand was primarily expressed in the outer layer cells, with points of co-localisation with CX3CR1, indicating that this ligand–receptor pair may have important intercellular adhesive functions. The high expression of CXC3L1 in the most severe forms of gliomas suggests the involvement of this chemokine and its receptor in the malignantbehaviour of these tumours.

Optimising methods for communicating survival data to patients undergoing cancer surgery - Corrected Proof

2010-08-23

Abstract: Background: Patients undergoing cancer surgery require outcome data to inform decisions, but communication of numerical risk is difficult. This study assessed patient understanding of survival data presented in different formats.Methods: Semi-structured interviews in which patients interpreted four presentation formats of survival data (three graphical and one narrative) were audio-recorded. The interviewer and a blinded observer (listening to the audio-recordings) scored patients’ understanding of each format. Logistic regression examined associations between understanding and clinical and socio-demographic details.Results: Seventy participants with colorectal cancer were interviewed and 67 [95.7%, 95% confidence intervals (CIs) 90.9–100%] correctly interpreted a simplified Kaplan–Meier survival curve. A high proportion accurately understood data presented as a bar chart or pictograph (94.3%, 95% CIs 88.7–99.9% and 92.9%, 95% CIs 86.7–99.0% respectively). Standard narrative alone was least well understood (n=53, 75.7%, 95% CIs 65.4–86.0%). Multivariable analyses demonstrated that older and female patients had poorer overall understanding (OR 0.93 per year, 95% CIs 0.87–0.98, p=0.01 and OR 0.24, 95% CIs 0.07–0.86, p=0.03).Conclusion: Patient understanding of survival data was higher when presented with graphs compared to narrative alone. Further work examining understanding in the clinical context and before surgery is recommended before this can be used routinely.

Amplification of thymidylate synthetase in metastatic colorectal cancer patients pretreated with 5-fluorouracil-based chemotherapy - Corrected Proof

2010-08-20

Abstract: Resistance to 5-fluorouracil (5-FU) represents a major contributor to cancer-related mortality in advanced colorectal cancer patients. Genetic variations and expression alterations in genes involved in 5-FU metabolism and effect have been shown to modulate 5-FU sensitivity in vitro, however these alterations do not fully explain clinical resistance to 5-FU-based chemotherapy. To determine if alterations of DNA copy number in genes involved in 5-FU metabolism-impacted clinical resistance to 5-FU-based chemotherapy, we assessed thymidylate synthetase (TYMS) and thymidine phosphorylase (TYMP) copy number in colorectal liver metastases. DNA copy number of TYMS and TYMP was evaluated using real time quantitative PCR in frozen colorectal liver metastases procured from 62 patients who were pretreated with 5-FU-based chemotherapy prior to surgical resection (5-FU exposed) and from 51 patients who received no pretreatment (unexposed). Gain of TYMS DNA copy number was observed in 18% of the 5-FU exposed metastases, while only 4% of the unexposed metastases exhibited TYMS copy gain (p=0.036). No significant differences were noted in TYMP copy number alterations between 5-FU-exposed and -unexposed metastases. Median survival time was similar in 5-FU-exposed patients with metastases containing TYMS amplification and those with no amplification. However, TYMS amplification was associated with shorter median survival in patients receiving post-resection chemotherapy (hazard ratio=2.7, 95% confidence interval=1.1–6.6; p=0.027). These results suggest amplification of TYMS amplification as a putative mechanism for clinical resistance to 5-FU-based chemotherapy and may have important ramifications for the post-resection chemotherapy choices for metastatic colorectal cancer.

C-reactive protein-associated genetic variants and cancer risk: Findings from FINRISK 1992, FINRISK 1997 and Health 2000 studies - Corrected Proof

2010-08-20

Abstract: Background: Evidence from prospective observational studies suggests that elevated circulating C-reactive protein (CRP) concentrations are associated with cancer risk, but it is unclear whether this association is causal. In order to examine this, we investigated whether genetic variants that are associated with circulating CRP concentrations are associated with cancer risk.Methods: We pooled data from three population-based prospective Finnish studies: FINRISK 1992 (n=5289), FINRISK 1997 (n=7160) and Health 2000 (n=6299). Cancer cases were identified from cancer registrations. Thirteen CRP-associated SNPs, identified from genome-wide association studies, were genotyped. We examined the associations of the SNPs and cancer risk using Cox, probit and instrumented probit regression models.Results: Compared to common allele homozygotes, individuals carrying one or two variant T alleles at rs1892534 had 1.05-fold (95% confidence interval (CI): 0.90, 1.23) and 1.2-fold (95% CI: 1.01, 1.42) increased overall cancer risk, respectively. Individuals with one or two variant A alleles at rs1169300 or rs2464196 had approximately 1.5- and 2-fold increased risk of lung cancer, respectively (p trend for both: 0.007). CRP SNPs were not associated with colorectal, prostate or breast cancer risk nor was CRP-associated with the probability of developing cancer in the instrumented probit analyses.Conclusions: We found some evidence for an association of a small number of CRP-associated SNPs with the overall cancer risk and lung cancer risk. Our instrumental variable analyses provided no clear evidence for a causal association of CRP and cancer. These findings suggest that circulating CRP concentrations are unlikely to have a causal role in cancer.

Consulting and prescribing behaviour for anxiety and depression in long-term survivors of cancer in the UK - Corrected Proof

Nada F. Khan, Alison M. Ward, Eila Watson, Peter W. Rose — 2010-08-20

Abstract: Introduction: Cancer survivors may experience long-term depression or anxiety, however, there is little previous research on the use of services in this area. We explored consultation and prescribing behaviour for depression and anxiety amongst cancer survivors in British primary health care.Methods: This study uses data on 26,213 survivors of breast, colorectal and prostate cancer at least 5 years post-diagnosis, matched to four controls without cancer, from the UK General Practice Research Database. We compared consultations for depression and anxiety, and prescribing for anti-depressants and anxiolytics between cancer survivors and controls.Results: Multivariate, matched regression models showed no difference in consulting for depression or anxiety between any cancer survivors and matched controls. However, breast cancer (odds ratio (OR) 1.16, 95% confidence interval (CI) 1.10–1.22) and prostate cancer survivors (OR 1.31, 95% CI 1.16–1.47) were more likely to receive a prescription for an antidepressant. Breast cancer survivors (IRR 2.49, 95% CI 1.82–3.42) and prostate cancer survivors (IRR 2.84, 95% CI 1.94–4.17) who died received significantly more antidepressants than controls who died. There were no differences in anxiolytic prescribing for colorectal and prostate cancer survivors compared to controls. However, breast cancer survivors nearing the end of life received a greater number of anxiolytic prescriptions compared to controls (IRR 1.84, 95% CI 1.36–2.49).Conclusions: In this cohort of cancer survivors, there were no differences in consultation behaviour for depression and anxiety compared to controls. However, breast and prostate cancer survivors access more antidepressants, and those nearing the end of life received the highest volume of prescriptions. Breast cancer survivors at the end of life also receive more anxiolytics.

The addition of pravastatin to chemotherapy in advanced gastric carcinoma: A randomised phase II trial - Corrected Proof

2010-08-20

Abstract: Purpose: Statins have for long been considered to play a potential role in anticancer treatment based upon their ability to inhibit the mevalonate synthesis pathway. This randomised phase II trial compared the efficacy and safety of pravastatin added to epirubicin, cisplatin and capecitabine (ECC versus ECC+P) in patients with advanced gastric carcinoma.Methods: Patients were randomised to receive up to six cycles of 3-weekly ECC with or without pravastatin (40mg, once daily from day 1 of the first cycle until day 21 of the last cycle). Primary end-point was progression-free rate at 6months (PFR6months). Secondary end-points were response rate (RR), progression-free survival (PFS), overall survival (OS) and safety. For early termination in case of futility, a two-stage design was applied (P0=50%; P1=70%; α=0.05; β=0.10).Results: Thirty patients were enrolled. PFR6months was 6/14 patients (42.8%) in the ECC+P arm, and 7/15 patients (46.7%) in the control arm, and therefore the study was terminated after the first stage. In the ECC and ECC+P arm, RR was 7/15 (46.7%) and 5/15 (33.3%), median PFS was 5 and 6months and median OS was 6 and 8months, respectively. Toxicity data showed no significant differences, although there was a trend towards more gastrointestinal side-effects such as diarrhoea and stomatitis in the ECC+P arm.Conclusion: In this randomised phase II trial the addition of pravastatin to ECC did not improve outcome in patients with advanced gastric cancer. Therefore, further testing of this combination in a randomised phase III trial cannot be recommended.

Elevated expression of HMGB1 in squamous-cell carcinoma of the head and neck and its clinical significance - Corrected Proof

2010-08-19

Abstract: Purpose: HMGB1 overexpression has been reported in a variety of human cancers. However, the role of HMGB1 in squamous-cell carcinoma of the head and neck (SCCHN) remains unclear. The aim of the present investigation was to analyse HMGB1 protein expression in both SCCHN tissue and cell levels and to assess its prognostic significance in SCCHN.Methods: HMGB1 protein expression in 103 primary SCCHN tissue specimens was analysed by immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Additionally, HMGB1 protein expression was evaluated in cell level by Western blotting.Results: By Western blotting analysis, all the 5 SCCHN cell lines overexpressed HMGB1 protein, whereas the non-transformed immortalised cell line NP-69 had relatively weak HMGB1 protein expression. Immunohistochemical staining revealed that HMGB1 protein was detected in 91 (91/103, 88.3%) primary tumour samples, but only in 7 (7/16, 43.75%) adjacent non-carcinoma samples (p<0.001); moreover, HMGB1 overexpression was significantly associated with T classification (p=0.001), clinical stage (p<0.001), recurrence (p<0.001) and lymph node metastasis (p<0.001). Survival analysis demonstrated that high HMGB1 expression was significantly associated with shorter disease-free and overall survival (both p<0.001), especially in late patients with SCCHN. When HMGB1 expression and lymph node status were combined, patients with HMGB1 overexpression/lymph node (+) had both poorer disease-free and overall survival than others (both p<0.001). Multivariate analysis further demonstrated that HMGB1 was an independent prognostic factor for patients with SCCHN.Conclusions: HMGB1 protein may contribute to the malignant progression of SCCHN, and present as a novel prognostic marker and a potential therapeutic target for patients with SCCHN.

Time until definitive quality of life score deterioration as a means of longitudinal analysis for treatment trials in patients with metastatic pancreatic adenocarcinoma - Corrected Proof

2010-08-19

Abstract: Background: The Fédération Francophone de Cancérologie Digestive phase III trial in patients with metastatic pancreatic adenocarcinoma comparing 5FU, folinic acid and cisplatin combination followed by gemcitabine (Arm A) versus the opposite sequence (Arm B) failed to demonstrate a benefit in overall survival. To longitudinally compare the quality of life (QoL) we explored different definitions of time until definitive deterioration (TUDD) of QoL scores according to minimal clinically important difference (MCID) cut-offs.Methods: QoL was evaluated using the EORTC QLQ-C30 every 8 weeks until death. The following scores were analysed: global health, emotional functioning, physical functioning, fatigue and pain. TUDD was defined as the time interval between randomisation and the first occurrence of a decrease in QLQ-C30 score ⩾5 points without any further improvement in QoL score ⩾5 points or any further available QoL data. Analyses were repeated using a 10 point MCID and/or including death as event.Results: From 08/2003 to 05/2006, 102 patients in Arm A and 100 in Arm B were included. Using a 5 and a 10 point MCID, TUDD curves of the 5 scores did not differ according to treatment arm., The median TUDD of global health was 5.2 months (4.3–6.2) in Arm A and 6.1 months (5.1–8.5) in Arm B (log-rank p=0.50) including death as an event for a 5 point MCID. Multivariate Cox model showed that tumour localisation and progression were independently associated with TUDD (p<0.05).Conclusions: The strategy of chemotherapy did not influence the deterioration of QoL. The TUDD approach seems to provide meaningful clinical results that are adapted to metastatic pancreatic adenocarcinoma trials.

Differential expression and prognostic value of HMGA1 in pancreatic head and periampullary cancer - Corrected Proof

2010-08-19

Abstract: The high mortality rate and minimal progress made in the treatment of pancreatic cancer over the last few decades, warrant an alternative approach. Treatment protocols should be individualised to the patient guided by prognostic markers. A particularly interesting target would be the architectural transcription factor high mobility group A1 (HMGA1), that is low or undetectable in normal tissue, induced during neoplastic transformation and consequently often exceptionally high in cancer. The aim of the current study was therefore to determine the differential expression of HMGA1 in pancreatic head and periampullary cancer and investigate its relation with outcome.HMGA1 expression was determined by immunohistochemistry on original paraffin embedded tissue from 99 pancreatic head- and 112 periampullary cancers (with R0). Expression was investigated for associations with recurrence free (RFS), cancer specific (CSS) and overall survival (OS) and conventional prognostic factors.HMGA1 was expressed in 47% and 26% of pancreatic head- and periampullary cancer, respectively and associated with poor RFS, CSS and OS in periampullary cancer. CSS 5years following surgery was 25% and 44% for patients with tumours which were positive or negative for HMGA1 protein, respectively. HMGA1 expression was not associated with survival in pancreatic head cancer.In conclusion HMGA1 was identified as an independent prognostic marker predicting poor outcome in periampullary cancer. Although expressed to a higher extent as compared to periampullary cancer, HMGA1 was not associated with survival in pancreatic head cancer.

A lethal combination for cancer cells: Synthetic lethality screenings for drug discovery - Corrected Proof

Elisa Ferrari, Chiara Lucca, Marco Foiani — 2010-08-19

Abstract: In recent years, cancer drug discovery has faced the challenging task of integrating the huge amount of information coming from the genomic studies with the need of developing highly selective target-based strategies within the context of tumour cells that experience massive genome instability.The combination between genetic and genomic technologies has been extremely useful and has contributed to efficiently transfer certain approaches typical of basic science to drug discover projects. An example comes from the synthetic lethal approaches, very powerful procedures that employ the rational used by geneticists working on model organisms. Applying the synthetic lethality (SL) screenings to anticancer therapy allows exploiting the typical features of tumour cells, such as genome instability, without changing them, as opposed to the conventional anticancer strategies that aim at counteracting the oncogenic signalling pathways.Recent and very encouraging clinical studies clearly show that certain promising anticancer compounds work through a synthetic lethal mechanism by targeting pathways that are specifically essential for the viability of cancer cells but not of normal cells.Herein we describe the rationale of the synthetic lethality approaches and the potential applications for anticancer therapy.

Nuclear S100A4 is a novel prognostic marker in colorectal cancer - Corrected Proof

2010-08-18

Abstract: Current staging classifications in colorectal cancer are not able to accurately predict patient outcome, and the need for novel prognostic markers is evident. S100A4 is a Ca2+-binding protein which promotes metastasis in several tumour types, and the aim of the present study was to investigate the prognostic impact of S100A4 expression in colorectal cancer. Two hundred and forty two patients with curatively resected adenocarcinoma of the colon or rectum were prospectively included in the study at the time of surgery. S100A4 expression was analysed by immunohistochemistry, and associations with clinicopathological variables and patient outcome were investigated. Nuclear expression of S100A4 was observed in 29% and cytoplasmic expression was observed in 64% of the tumours. In univariate analysis, nuclear S100A4 was a negative predictor of metastasis-free (P=0.006) and overall survival (P=0.01), whereas cytoplasmic S100A4 was not associated with patient outcome. In multivariate analysis, nuclear localisation was inversely associated with metastasis-free (P=0.03) and overall survival (P=0.02). Interestingly, the prognostic impact was largely confined to TNM stage II, and stage II patients with tumours expressing nuclear S100A4 had a similar prognosis as stage III patients. In conclusion, nuclear expression of S100A4 is a novel prognostic marker in colorectal cancer, and the prognostic value in TNM stage II suggests that nuclear S100A4 could be used in the stratification of stage II patients for adjuvant treatment.

Detection of extra-axillary lymph node involvement with FDG PET/CT in patients with stage II–III breast cancer - Corrected Proof

2010-08-18

Abstract: Purpose: The aim of this prospective study was to assess the incidence of extra-axillary lymph node involvement on baseline FDG PET/CT in patients with stage II–III breast cancer scheduled for neo-adjuvant chemotherapy.Methods: Patients with invasive breast cancer of >3cm and/or proven axillary lymph node metastasis were included for before neo-adjuvant chemotherapy. Baseline ultrasound of the infra- and supraclavicular regions was performed with fine-needle biopsy as needed. Subsequently FDG PET/CT was performed. All visually FDG-positive nodes were regarded as metastatic based on the previously reported high specificity of the technique.Results: Sixty patients were included. In 17 patients (28%) extra-axillary lymph nodes were detected by FDG PET/CT, localised in an intra-mammary node (1 lymph node in 1 patient), mediastinal (2 lymph nodes in 2 patients), internal mammary chain (9 lymph nodes in 8 patients), intra- and interpectoral (6 lymph nodes in 4 patients), infraclavicular (5 lymph nodes in 4 patients) and in the contralateral axilla (3 lymph nodes in 2 patients). Ultrasound-guided cytology had detected extra-axillary lymph node involvement in seven of these patients, but was unable to detect extra-axillary nodes in the other 10 patients with positive extra-axillary lymph nodes on FDG PET/CT. Radiotherapy treatment was altered in 7 patients with extra-axillary involvement (12% of the total group).Conclusions: FDG PET/CT detected extra-axillary lymph node involvement in almost one-third of the patients with stage II–III breast cancer, including regions not evaluable with ultrasound. FDG PET/CT may be useful as an additional imaging tool to assess extra-axillary lymph node metastasis, with an impact on the adjuvant radiotherapy management.

Elevated LDH predicts poor outcome of recurrent germ cell tumours treated with dose dense chemotherapy - Corrected Proof

Marco Gerlinger, Peter Wilson, Thomas Powles, Jonathan Shamash — 2010-08-16

Abstract: Aims of the study: Prognostic factors for recurrent germ cell tumours (GCTs) treated with dose dense salvage chemotherapy have not been identified. This study determines whether lactate dehydrogenase (LDH) or established prognostic models can predict the outcome of recurrent GCTs treated with dose dense cisplatin-based chemotherapy.Patients and methods: Retrospective analysis of 117 consecutive male patients with a first recurrence of a GCT treated with dose dense chemotherapy at a single cancer centre. Characteristics associated with progression-free survival (PFS) and overall survival (OS) were identified by univariate and multivariate analyses. Prognostic criteria published by the Medical Research Council (MRC) and the Memorial Sloan Kettering Cancer Centre (MSK) were also applied in an attempt to validate them and to compare their performance to that of LDH.Results: Raised LDH was significantly associated with poor PFS (hazard ratio (HR)=3.7; p<0.001) and OS (HR=3.4; p=0.001). Further factors associated with poor PFS and OS, respectively, were failure to achieve a complete response or marker negative partial response for at least 6months (HR=2.1; p=0.033) and seminoma histology (HR=3.4; p=0.003). The MRC prognostic model, but not the MSK model, identified groups of patients with statistically significant differences in PFS and OS but raised LDH predicted OS and PFS with a higher HR.Conclusions: Raised LDH is associated with a poor prognosis in recurrent GCTs and outperforms established prognostic models in this setting. LDH as a prognostic factor should be validated prospectively and should also be assessed in patients receiving conventional dose chemotherapy regimens.

A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas - Corrected Proof

2010-08-16

Abstract: Purpose: To estimate the maximum-tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ⩽21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification and expression in STMG.Patients and methods: Three strata were identified: stratum 1A – BSG; stratum IB – incompletely resected STMG not receiving enzyme-inducing anticonvulsant drugs (EIACD); and stratum II – incompletely resected STMG receiving EIACD. Dose escalation using a modified 3+3 cohort design was performed in strata IA and II. The initial gefitinib dosage was 100mg/m2/d commencing with radiation therapy and the dose-finding period extended until 2weeks post-radiation. Pharmacokinetics (PK) and biology studies were performed in consenting patients.Results: Of the 23 eligible patients, 20 were evaluable for dose-finding. MTDs for strata IA and II were not established as accrual was halted due to four patients experiencing symptomatic intratumoral haemorrhage (ITH); two during and two post dose-finding. ITH was observed in 0 of 11 patients treated at 100mg/m2/d, 1 of 10 at 250mg/m2/d and 3 of 12 at 375mg/m2/d. Subsequently a second patient at 250mg/m2/d experienced ITH. PK analysis showed that the median gefitinib systemic exposure increased with dosage (p=0.04). EGFR was over-expressed in 5 of 11 STMG and amplified in 4 (36%) samples.Conclusion: This trial provides clear evidence of EGFR amplification in a significant proportion of paediatric STMG and 250mg/m2/d was selected for the phase II trial.

Molecular targets of apigenin in colorectal cancer cells: Involvement of p21, NAG-1 and p53 - Corrected Proof

2010-08-16

Abstract: Persuasive epidemiological and experimental evidence suggests that dietary flavonoids have anti-cancer activity. Since conventional therapeutic and surgical approaches have not been able to fully control the incidence and outcome of most cancer types, including colorectal neoplasia, there is an urgent need to develop alternative approaches for the management of cancer. We sought to develop the best flavonoids for the inhibition of cell growth, and apigenin (flavone) proved to be the most promising compound in colorectal cancer cell growth arrest. Subsequently, we found that pro-apoptotic proteins (NAG-1 and p53) and cell cycle inhibitor (p21) were induced in the presence of apigenin, and kinase pathways, including PKCδ and ataxia telangiectasia mutated (ATM), play an important role in activating these proteins. The data generated by in vitro experiments were confirmed in an animal study using APCMIN+ mice. Apigenin is able to reduce polyp numbers, accompanied by increasing p53 activation through phosphorylation in animal models. Our data suggest apparent beneficial effects of apigenin on colon cancer.

STAT3 activation induced by Epstein-Barr virus latent membrane protein1 causes vascular endothelial growth factor expression and cellular invasiveness via JAK3 And ERK signaling - Corrected Proof

2010-08-16

Abstract: The principal Epstein–Barr virus (EBV) oncoprotein, latent membrane protein 1 (LMP1), has been suggested to contribute to the highly invasive nature of nasopharyngeal carcinoma (NPC). Signal transducer and activator of transcription 3 (STAT3) is a master transcriptional regulator in proliferation and apoptosis and is newly implicated in angiogenesis and invasiveness, which, in turn, are likely to contribute to the highly invasive character of NPC. The fundamental molecular mechanisms of LMP1-regulated STAT3 activation in NPC cell invasion have not been completely explored. Here, we showed that LMP1 signals the Janus kinase 3 (JAK3) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways upon the activation of STAT3 as well as STAT transactivation activity. LMP1 induces vascular endothelial growth factor (VEGF) expression via the JAK/STAT and mitogen-activated protein kinase (MAPK)/ERK signalling pathways. Induction of STAT3 by the human viral oncoprotein LMP1 may contribute to the invasion of NPC.

The relationship between new-onset diabetes mellitus and pancreatic cancer risk: A case–control study - Corrected Proof

2010-08-16

Abstract: Diabetes mellitus (DM) is widely considered to be associated with pancreatic cancer, however, whether DM is a cause or consequence of pancreatic cancer is controversial. In the present study, 1458 patients with pancreatic ductal adenocarcinoma (PDAC) and 1528 age-, sex- and sociodemographic variables-matched controls were recruited in two university-affiliated hospitals from 1st January 2000 to 31st December 2009. DM was defined as fasting blood glucose (FBG) level of 7.0mmol/L or greater. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs) and 95% confidence interval (CI). Compared with controls, a moderate increased risk of PDAC was observed among cases with long-standing diabetes (⩾2-year duration), with an AOR (95% CI) of 2.11 (1.51–2.94). Interestingly, a significant higher risk was observed among cases with new-onset DM (<2-year duration), with an AOR of 4.43 (3.44–5.72) compared to controls without DM. In addition, we found a synergistic interaction between cigarette smoking and DM on modifying the risk of pancreatic cancer development (AOR=6.17, 95% CI 3.82–9.94). Similarly, a synergistic interaction between new-onset DM and family history of pancreatic cancer was found for pancreatic cancer risk, with an AOR (95% CI) of 11.04 (2.51–48.53). This study suggested that DM could be both an early manifestation of pancreatic cancer and an aetiologic factor. Possible effect modification on DM by family history of pancreatic cancer and smoking status should be further explored in future aetiologic studies.

Phase II study of NGR-hTNF, a selective vascular targeting agent, in patients with metastatic colorectal cancer after failure of standard therapy - Corrected Proof

2010-08-16

Abstract: Background: NGR-hTNF consists of human tumour necrosis factor (hTNF) fused with the tumour-homing peptide Asp-Gly-Arg (NGR), which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. Preclinical antitumour activity was observed even at low doses. We evaluated the activity and safety of low-dose NGR-hTNF in colorectal cancer (CRC) patients failing standard therapies.Patients and methods: Thirty-three patients with progressive disease at study entry received NGR-hTNF 0.8μg/m2 given intravenously every 3weeks. The median number of prior treatment regimens was three (range, 2–5). One-quarter of patients had previously received four or more regimens and two-thirds targeted agents. Progression-free survival (PFS) was the primary study objective.Results: NGR-hTNF was well tolerated. No treatment-related grade 3 to 4 toxicities were detected, most common grade 1 to 2 adverse events being short-lived, infusion-time related chills (50.0%). One partial response and 12 stable diseases were observed, yielding a disease control rate of 39.4% (95% CI, 22.9–57.8%). Median PFS and overall survival were 2.5months (95% CI, 2.1–2.8) and 13.1months (95% CI, 8.9–17.3), respectively; whereas in patients who achieved disease control the median PFS and overall survival were 3.8 and 15.4months, respectively. In an additional cohort of 13 patients treated at same dose with a weekly schedule, there was no increased toxicity and 2 patients experienced PFS longer than 10months.Conclusion: Based on tolerability and preliminary evidence of disease control in heavily pretreated CRC patients, NGR-hTNF deserves further evaluation in combination with standard chemotherapy.

Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients - Corrected Proof

2010-08-16

Abstract: Aim: The hypoxia inducible factor (HIF) pathway plays an important role in sporadic clear cell renal cell carcinoma (ccRCC) by stimulating processes of angiogenesis, cell proliferation, cell survival and metastases formation. Herein, we evaluate the significance of upstream proteins directly regulating the HIF pathway; the prolyl hydroxylases domain proteins (PHD)1, 2 and 3 and factor-inhibiting HIF (FIH), as prognostic markers for ccRCC.Methods: Immunohistochemical marker expression was examined on a tissue microarray containing tumour tissue derived from 100 patients who underwent nephrectomy for ccRCC. Expression levels of HIF, FIH and PHD1, 2 and 3 were correlated with overall survival (OS) and clinicopathological prognostic factors.Results: HIF-1α was positively correlated with HIF-2α (p<0.0001), PHD1 (p=0.024), PHD2 (p<0.0001), PHD3 (p=0.004), FIH (p<0.0001) and VHL (p=0.031). HIF-2α levels were significantly associated with FIH (p<0.0001) and PHD2 (p=0.0155). Mutations in the VHL gene, expression variations of HIF-1α, HIF-2α and PHD1, 2, 3 did not show a correlation to OS or clinicopathological prognostic factors. Tumour stage, grade, diameter, metastastic disease and intensity of nuclear FIH were significantly correlated to OS in univariable analysis (p=0.023). Low nuclear FIH levels remained a strong independent prognostic factor in multivariable analysis (p=0.009).Conclusion: These results show that low nuclear expression of FIH is a strong independent prognostic factor for a poor overall survival in ccRCC.

Carbonic anhydrase 9 in clear cell renal cell carcinoma: A marker for diagnosis, prognosis and treatment - Corrected Proof

Jacques Tostain, Guorong Li, Anne Gentil-Perret, Marc Gigante — 2010-08-16

Abstract: Carbonic anhydrase 9 (CA9) is a transmembrane member of the carbonic anhydrase family. It catalyses the reversible hydration of carbon dioxide into bicarbonate and a proton, thus enabling tumour cells to maintain a neutral pH despite an acidic microenvironment. CA9 is not expressed in healthy renal tissue but is expressed in most clear cell renal cell carcinomas (CCRCC) through HIF-1α accumulation driven by hypoxia and inactivation of the VHL gene. CA9 expression can be detected in the tumour by immunohistochemistry (IHC), in blood and tissue by ELISA assay and RT-PCR. It has a 100% diagnostic specificity in solid renal tumours, while ELISA assays on aspiration fluids may help in atypical cysts. Blood-based assays, ELISA for CA9 antigen and RT-PCR for CA9 mRNA are promising for the prognosis and follow-up of localised CCRCC. In metastatic disease, high CA9 expression by IHC was reported to be a powerful prognostic marker with better survival and sensitivity to IL-2, but this is still debated. Almost no data are currently available on the association of CA9 expression and outcome to targeted drugs. The prognostic value of CA9 in CCRCC could be explained by the frequent VHL gene inactivation driving an early activation of the HIF pathway. The poorer prognosis associated with low CA9 expressing tumours could be due to the simultaneous overexpression of EGFR contributing to the activation of AkT and mTOR pathways. Targeting CA9 by inhibitors, radioimmunotherapy, monoclonal antibodies or vaccination is promising and offers new avenues for clinical research.

Receptor tyrosine kinase and downstream signalling analysis in diffuse malignant peritoneal mesothelioma - Corrected Proof

2010-08-09

Abstract: Our aim was to assess the activation profile of EGFR, PDGFRB and PDGFRA receptor tyrosine kinases (RTK) and their downstream effectors in a series of cryopreserved diffuse malignant peritoneal mesothelioma (DMPM) surgical specimens to discover the targets for drug inhibition. We also made a complementary analysis of the cytotoxic effects of some kinase inhibitors on the proliferation of the human peritoneal mesothelioma STO cell line.We found the expression/phosphorylation of EGFR and PDGFRB in most of the tumours, and PDGFRA activation in half. The expression of the cognate ligands TGF-α, PDGFB and PDGFA in the absence of RTK mutation and amplification suggested the presence of an autocrine/paracrine loop. There was also evidence of EGFR and PDGFRB co-activation. RTK downstream signalling analysis demonstrated the activation/expression of ERK1/2, AKT and mTOR, together with S6 and 4EBP1, in almost all the DMPMs. No KRAS/BRAF mutations, PI3KCA mutations/amplifications or PTEN inactivation were observed. Real-time polymerase chain reaction revealed the decreased expression of TSC1 c-DNA in half of the tumours. In vitro cytotoxicity studies showed the STO cell line to be resistant to gefitinib and sensitive to sequential treatment with RAD001 and sorafenib; these findings were consistent with the presence of the KRAS mutation G12D in these cells although it was not detectable in the original tumour.Our results highlight the ligand-dependent activation and co-activation of EGFR and PDGFRB, as well as a connection between these activated RTKs and the downstream mTOR pathway, thus supporting the role of combined treatment with RTK and mTOR inhibitors in DMPM.

Dose-escalation models for combination phase I trials in oncology - Corrected Proof

Paul Hamberg, Mark J. Ratain, Emmanuel Lesaffre, Jaap Verweij — 2010-08-06

Abstract: Designing combination drug phase I trials has become increasingly complex, due to the increasing diversity in classes of agents, mechanisms of action, safety profiles and drug-administration schedules. With approximately 850 agents currently in development for cancer treatment, it is evident that combination development must be prioritised, as based on a specific hypothesis, as well as a projected development path for the involved combination.In this manuscript the most relevant issues and pitfalls for combination drug phase I trial design are discussed. Several phase I study designs that incorporate controls to circumvent bias due to imbalances in observed background toxicity are discussed.

Association between Epstein–Barr virus infection and risk for development of pregnancy-associated breast cancer: Joint effect with vitamin D? - Corrected Proof

2010-08-06

Abstract: Background: Few studies have evaluated the role of the ubiquitous Epstein–Barr virus (EBV) infection, together with levels of the immunomodulator, vitamin D, in different breast cancer entities. We studied, prospectively, the association of EBV and vitamin D status with the risk of pregnancy-associated breast cancer (PABC), breast cancer diagnosed during pregnancy or 1year post-partum, using a nested case–control study.Methods: Serum vitamin D and antibodies to EBV were measured for 108 PABC cases of the Finnish Maternity Cohort, and 208 controls matched for date of birth, date of sampling and parity. The joint effect of vitamin D and EBV on the risk of PABC was evaluated.Results: EBV seropositivity was generally not associated with the risk of PABC. Among individuals with sufficient (⩾75nmol/l) levels of vitamin D, we, however, found similar increased risk estimates for PABC associated with serum immunoglobulin G (IgG) antibodies to EBV early antigens [odds ratio (OR)=7.7, 95% (confidence interval) CI 1.4–42.3] and the viral reactivator protein, ZEBRA (OR=7.8, 95% CI 1.1–61.2).Conclusion: Immunological markers of EBV reactivation status among individuals with sufficient vitamin D levels were consistently associated with increased risk of the disease. This suggests that EBV reactivation may be an indicator of the progression of breast cancer occurring soon after pregnancy, while the virus probably is not the aetiological agent.

An international validation study of the EORTC QLQ-INFO25 questionnaire: An instrument to assess the information given to cancer patients - Corrected Proof

2010-08-02

Abstract: Aim: The EORTC Quality of Life (QOL) Group has developed an instrument to evaluate the information received by cancer patients. This study assessed the psychometric characteristics of the EORTC INFO module in a large international/multi-cultural sample of cancer patients.Methods: The provisional 26-item information module (EORTC INFO26) was administered with the EORTC QLQ-C30 and the information scales of the inpatient satisfaction module EORTC IN-PATSAT32 on two occasions during the patients’ treatment and follow-up period. Questionnaire-hypothesised scale structure, reliability, validity and responsiveness to changes were evaluated through standard psychometric analyses. Patient acceptability was assessed with a debriefing questionnaire.Results: The study comprised 509 patients from 8 countries (7 European countries and Taiwan) with different cancers and disease stages. Multi-trait scaling analysis led to the deletion of one item but confirmed the hypothesised 4 multi-item scales (information about disease, medical tests, treatment and other services) and eight single items. Internal consistency for all scales was good (α>0.70), as was test–retest reliability (intraclass correlations>0.70). All items can be combined to generate a single score (α>0.90). Convergent validity was supported by significant correlations with related areas of IN-PATSAT32 (r>0.40). Low correlations with EORTC QLQ-C30 scales confirmed divergent validity (r<0.30) The EORTC INFO-25 module discriminated among groups based on gender, age, education, levels of anxiety and depression, information wishes and satisfaction. Only one scale captured changes over time.Conclusions: The EORTC QLQ-INFO 25 is a reliable and valid self-reported instrument. The module can be used in cross-cultural observational and intervention studies.

Interconversion of three measures of performance status: An empirical analysis - Corrected Proof

2010-08-02

Abstract: Purpose: To construct empirically a conversion table to convert performance status scores among the Eastern Cooperative Oncology Group (ECOG), Karnofsky Performance Status (KPS) and Palliative Performance Scale (PPS) measures, using a large sample of patients with advanced cancer.Methods: Seven physicians completed assessments on 1385 consecutive patients attending an oncology palliative care clinic, or admitted to an acute cancer palliative care unit. The three measures were distributed as a questionnaire package; the order in which they were presented was randomly assigned for each week. Scales were compared using the hit rate and the weighted kappa coefficient (κw). The KPS and PPS were compared directly; for comparisons of either scale with the ECOG, all 70 possible categorisations of KPS and PPS were computed. An ‘ideal’ categorisation was selected based on maximisation of both statistical methods.Results: The KPS and PPS matched in 1209 out of 1385 assessments (hit rate 87%; κw 0.97). For both the KPS and the PPS, the categorisation of 100 (ECOG 0), 80–90 (1), 60–70 (2), 40–50 (3), 10–30 (4) had the highest hit rate (75%), and the second highest κw (0.84, p<0.0001). One other combination had a slightly higher κw (0.85 for both KPS and PPS), but a lower hit rate (73% for KPS, 72% for PPS).Conclusions: We have derived empirically a conversion scale among the ECOG, KPS and PPS scales. The proposed scale provides a means of translating amongst these measures, which may improve accuracy of communication about performance status amongst oncology clinicians and researchers.

Predictors of outcome and methodological issues in children with acute lymphoblastic leukaemia in El Salvador - Corrected Proof

2010-08-02

Abstract: Background: Most children with cancer live in low-income countries (LICs) where risk factors in paediatric acute lymphoblastic leukaemia (ALL) developed in high-income countries may not apply.Methods: We describe predictors of survival for children in El Salvador with ALL. We included patients <16years diagnosed with ALL between January 2001 and July 2007 treated with the El Salvador–Guatemala–Honduras II protocol. Demographic, disease-related, socioeconomic and nutritional variables were examined as potential predictors of event-free survival (EFS) and overall survival (OS).Results: 260/443 patients (58.7%) were classified as standard risk. Standard- and high-risk 5-year EFS were 56.3±4.5% and 48.6±5.5%; 5-year OS were 77.7±3.8% and 61.9±5.8%, respectively. Among standard-risk children, socioeconomic variables such as higher monthly income (hazard ratio [HR] per $100=0.84 [95% confidence interval (CI) 0.70–0.99; P=0.04]) and parental secondary education (HR=0.49, 95% CI 0.29–0.84; P=0.01) were associated with better EFS. Among high-risk children, higher initial white blood cell (HR per 10×109/L=1.03, 95% CI 1.02–1.05; P<0.001) predicted worse EFS; socioeconomic variables were not predictive. The difference in EFS and OS appeared related to overestimating OS secondary to poor follow-up after abandonment/relapse.Conclusion: Socioeconomic variables predicted worse EFS in standard-risk children while disease-related variables were predictive in high-risk patients. Further studies should delineate pathways through which socioeconomic status affects EFS in order to design effective interventions. EFS should be the primary outcome in LIC studies.

Paclitaxel/carboplatin versus topotecan/paclitaxel/carboplatin in patients with FIGO suboptimally resected stage III–IV epithelial ovarian cancer a multicenter, randomized study - Corrected Proof

2010-07-30

Abstract: Objective: The objective of this prospective randomized phase III trial was to compare paclitaxel plus carboplatin (PC) versus topotecan plus carboplatin and paclitaxel (TPC) in women with suboptimal stage III (residual tumour >1cm) or stage IV ovarian cancer to evaluate the survival rate and toxicities.Methods: Eligible for the study were patients aged at least 18 years old with histological/cytological diagnosis of FIGO stages III (residual tumour ⩾1cm after primary surgery) – IV epithelial ovarian cancer. Patients were randomized to iv PC on day 1, every 21 days or iv topotecan daily for three days and PC on day 3, every 21 days.Results: The intention to treat population was made of 326 patients in total, 170 in the PC group and 156 in the TPC group. The life table estimates of survival probabilities at one, three and five years were, respectively, 0.94 (95% CI: 0.88–0.97), 0.53 (95% CI: 0.44–0.62) and 0.32 (95%CI: 0.23–0.42) in the PC group, and 0.92 (95% CI: 0.86–0.95), 0.52 (95% CI: 0.42–0.61), and 0.32(95%CI: 0.22–0.43) in the TPC group (log-rank test at 5 years: ns). The results of the survival analysis based on Cox regression model showed no statistically significant differences between groups (p-value: ns). The number of subjects with at least one event with possible relationship to study medication was 151 (88.8%) in the PC group and 139 (89.1%) in the TPC group (p=ns).In the PC group, 79 patients (23.6%) experienced at least one Adverse Event (AE) graded as severe and 16 patients (4.8%) at least one life-threatening AE, whilst in the TPC group, the number of patients who presented at least one severe or life-threatening AE was 86 (24%) and 37 (10.3%), respectively.Conclusion: The results of the present study show that the addition of topotecan to a standard paclitaxel/carboplatin regimen in the treatment of advanced epithelial ovarian cancer did not result in significant advantages in terms of survival rate. A slightly worse toxicity profile for TPC was observed.

A study of the pattern of hospital admissions in a specialist Phase I oncology trials unit: Unplanned admissions as an early indicator of patient attrition - Corrected Proof

2010-07-28

Abstract: Background: Unplanned hospital admissions (UHAs) in the context of oncology Phase I trials are important, yet rarely reported.Methods: All patients admitted to the Royal Marsden Hospital Phase I clinical trials unit during February and March of 2005–2007 were included. The patient-, admission- and trial-related variables were collected. Correlations were sought between the occurrence of UHAs and the baseline patient/trial-related characteristics.Results: Of the 308 admissions involving 177 patients, UHAs constituted 21% of all the admissions and 38% of the total bed occupancy. The majority of UHAs were cancer related (78%) and their occurrence was associated with a significant early patient attrition. Using multivariate analysis, the factors significantly associated with UHAs included age >60years (RR 2.32, confidence interval (CI)-95% 1.12–4.81), ⩾3 metastatic sites (RR 3.26, CI-95% 1.54–6.90) and LDH>ULN (RR 2.18, CI-95% 1.06–4.46), with albumin <35g/dL trending to significance (p=0.052). The trials that contained cytotoxic chemotherapy incurred disproportionately higher rates of admissions (69.5%) than the trials that did not.Conclusions: UHAs constitute a substantial workload and impact on the speed and cost of, as well as resource allocation in Phase I oncology trials. The majority of UHAs are cancer rather than treatment related. The risk stratification to guide patient selection may help reduce the incidence of UHAs.

A multi-centre Canadian pilot study of metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem glioma - Corrected Proof

2010-07-26

Abstract: Purpose: Survival rates for paediatric diffuse intrinsic brainstem glioma (DIBSG) are dismal. Metronomic dosing of temozolomide (TMZ) combined with standard radiotherapy may improve survival by increasing the therapeutic index and anti-angiogenic effect of TMZ. This study aimed to evaluate the safety and efficacy of this regimen in paediatric DIBSG patients.Methods: Children aged 18years or younger with newly diagnosed DIBSG were treated with standard radiotherapy and concomitant metronomic TMZ at 85mg/m2/day for 6weeks, followed by metronomic TMZ monotherapy at the same dose. Treatment was continued until tumour progression or unacceptable toxicity occurred. Primary endpoints included overall survival and toxicities. For patients who consented, plasma and urine samples were collected at diagnosis, post-induction and prior to each course of maintenance therapy for the quantification of angiogenesis markers.Results: Fifteen eligible patients were enrolled, with a median age of 6.4years. The most common toxicities were myelosuppression, most notably prolonged lymphopaenia and thrombocytopaenia. The only dose-limiting toxicity was thrombocytopaenia. Intratumoural haemorrhage was confirmed in one patient. Median time to progression was 5.13months (95% CI=6.4, 10.8) and median overall survival (OS) was 9.8months (95% CI=6.4, 10.8). Six-months OS was 80%±10.3%, with a 1-year OS of 20%±10.3%. Serum levels of both VEGF and endoglin tended to decrease during the first two cycles of therapy.Conclusion: Chemoradiotherapy with metronomic dosing of TMZ showed similar toxicity to previous TMZ regimens, and does not appear to improve survival in paediatric DIBSG.

Novel mechanism of reducing tumourigenesis: Upregulation of the DNA repair enzyme OGG1 by rapamycin-mediated AMPK activation and mTOR inhibition - Corrected Proof

2010-07-26

Abstract: Inhibition of mTOR by rapamycin is an important approach in cancer therapy. In early clinical trials, tuberous sclerosis complex (TSC)-related kidney tumours were found to regress following rapamycin treatment. Since loss of function of the DNA repair OGG1 enzyme has a major role in multistep carcinogenesis of the kidney and other organs, we investigated the effect of rapamycin on OGG1 regulation. Treatment of HK2 cells, mouse Tsc-deficient cells and human VHL-deficient cells (786-O) with rapamycin resulted in decrease in p70S6K phosphorylation at Thr389, and increase in the expression of NF-YA and OGG1 proteins. In addition, rapamycin increased OGG1 promoter activity in cells transfected with OGG1 promoter construct. Furthermore, rapamycin increased the phosphorylation at Thr172 of the energy sensor AMPK. Downregulation of AMPK phosphorylation by high glucose (HG) increases the phosphorylation of p70S6K and decreases the protein expression of NF-YA and OGG1. Pretreatment of the cells with rapamycin before exposure to HG reversed the effects of HG. However, downregulation of AMPK by dominant negative (DN)-AMPK in Tsc2+/− cells abolished AMPK and decreased OGG1 expression. In contrast, transfection of Tsc2+/− cells with DN-S6K abolished p70S6K phosphorylation and increased OGG1 expression, a response enhanced by rapamycin. Treatment of Tsc2+/− mice with rapamycin resulted in activation of AMPK, downregulation of phospho-p70S6K and enhanced OGG1 expression. Our data show that inhibition of mTOR can activate AMPK and lead to upregulation of DNA repair enzyme OGG1. These data comprise the first report to provide one mechanism whereby rapamycin might prevent or inhibit the formation and progression of certain cancers.

Health economics in drug development: Efficient research to inform healthcare funding decisions - Corrected Proof

Peter S. Hall, Christopher McCabe, Julia M. Brown, David A. Cameron — 2010-07-26

Abstract: In order to decide whether a new treatment should be used in patients, a robust estimate of efficacy and toxicity is no longer sufficient. As a result of increasing healthcare costs across the globe healthcare payers and providers now seek estimates of cost-effectiveness as well. Most trials currently being designed still only consider the need for prospective efficacy and toxicity data during the development life-cycle of a new intervention. Hence the cost-effectiveness estimates are inevitably less precise than the clinical data on which they are based. Methods based on decision theory are being developed by health economists that can contribute to the design of clinical trials in such a way that they can more effectively lead to better informed drug funding decisions on the basis of cost-effectiveness in addition to clinical outcomes. There is an opportunity to apply these techniques prospectively in the design of future clinical trials. This article describes the problems encountered by those responsible for drug reimbursement decisions as a consequence of the current drug development pathway. The potential for decision theoretic methods to help overcome these problems is introduced and potential obstacles in implementation are highlighted.

Clustering of concordant and discordant cancer types in Swedish couples is rare - Corrected Proof

Marianne Weires, Justo Lorenzo Bermejo, Jan Sundquist, Kari Hemminki — 2010-07-26

Abstract: Background: Spouses are exposed to common environmental cancer risk factors during adulthood. Investigating the aggregation of cancer in couples might provide valuable insights into cancer development.Methods: The 2008 update of the Swedish Family-Cancer Database includes over 2million couples with at least one child in common with one single partner. We quantified the contribution of shared adulthood environment by standardised incidence ratios (SIRs) and population attributable fractions (PAFs). Estimated SIRs were used to build an etiological map reflecting the similarity of cancers by adult environmental exposures.Results: Increased risks of concordant types amongst spouses were found for lung, upper aerodigestive tract and skin cancers (SIRs from 1.24 to 1.97),which are probably related to shared exposure to smoking and UV radiation. PAFs were low with the highest value of 1.46% for uterus cancer in wives of men affected by prostate cancer. Further analysis, based on all non-sex-specific concordant and discordant types, revealed a clustering of lung, stomach, pancreas and bladder cancers sharing smoking as a risk factor. This aggregation was used as a cut-point to identify further “novel” clusters.Conclusion: Shared lifestyles including smoking and drinking habits as well as human papilloma virus infection (HPV) might be associated with an excess of cancer incidence amongst spouses. We observed significantly an increased risk for smoking-related cancers such as lung, upper aerodigestive tract and oesophageal cancers. The present population-based study confirms that the lifestyle shared by spouses plays a minor role in cancer causation. Only strong environmental risk factors such as smoking seem to influence cancer development in adulthood. The proposed etiological map based on 24 cancer types identifies novel clusters – for example, non-Hodgkin lymphoma and leukaemia, bone cancer and myeloma – that are not completely explained by established risk factors. Some of the identified clusters relied on reproduced associations between cancer risks amongst husband and wives; however, the role of chance cannot be excluded.

MicroRNA-193b regulates proliferation, migration and invasion in human hepatocellular carcinoma cells - Corrected Proof

2010-07-26

Abstract: Background and Aims: Recently, some miRNAs have been reported to be connected closely with the development of human hepatocellular carcinoma. However, the functions of these miRNAs in HCC remain largely undefined.Methods: The expression profiles of miR-193b were compared between HCC tissues and adjacent normal liver tissues using qRT-PCR method. This method was also be used to screen the potential target genes of miR-193b. A luciferase reporter assay was conducted to confirm target association. Finally, the functional effect of miR-193b in hepatoma cells was examined further.Results: miR-193b was significantly down-regulated in most of the HCC tissues compared to the matching non-tumoural liver tissues. Furthermore, ectopic expression of miR-193b dramatically suppressed the ability of hepatoma cells to form colonies in vitro and to develop tumours in nude mice. CCND1 and ETS1 were revealed to be regulated by miR-193b directly. By regulating the expressions of these oncogenes, miR-193b induced cell cycle arrest and inhibited the invasion and migration of hepatoma cells.Conclusions: miR-193b may function as a tumour suppressor in the development of HCC by acting on multiple tumourigenic pathways.

Protein kinase A-mediated phosphorylation of the RASSF1A tumour suppressor at Serine 203 and regulation of RASSF1A function - Corrected Proof

2010-07-26

Abstract: Epigenetic inactivation of the Ras-Association Domain Family 1A (RASSF1A) gene is one of the most frequent alterations detected in cancer. The tumour suppressor function of RASSF1A contributes to cell cycle progression, microtubule stabilisation and apoptotic signalling. Here we investigated the putative phosphorylation sites of RASSF1A and the functional consequences. RASSF1A is mainly phosphorylated at Serine 203 within its Ras association domain. Phosphorylation at this site is accomplished by protein kinase A (PKA) and is reduced and elevated by PKA-specific inhibitors and activators, respectively. Functionally, an alanine substitution of Serine 203 (S203A) slightly affected the microtubule stability mediated by RASSF1A (p<0.05). Interestingly, the inhibition of PKA and the S203A substitution of RASSF1A resulted in a reduced rate of apoptotic cells induced by RASSF1A. Moreover, RASSF1A-mediated upregulation of p21 and BAX was observed. This induction was reduced when the S203A substitution was present or when PKA activity was inhibited. In summary our data show that RASSF1A is phosphorylated by PKA and this phosphorylation may affect apoptotic signalling of RASSF1A. Thus epigenetic silencing of RASSF1A may counteract its proapoptotic function in cancer.

Promoter polymorphisms in matrix metallopeptidase 1 and risk of cutaneous melanoma - Corrected Proof

2010-07-26

Abstract: Matrix metallopeptidase 1 (MMP1) is one of the interstitial collagens in the extracellular matrix metalloproteinase family and involved in tumour behaviours. However, there is no report on the role of genetic variation in MMP1 in risk of cutaneous melanoma (CM). We investigated the association between genotypes and haplotypes of seven reported MMP1 promoter polymorphisms [–1607G ins/del (2G/1G), –839G>A, –755T>G, –519A>G, –422A>T, –340A>G and –320T>C, genotyped by the TaqMan assay] and CM risk in 872 patients and 873 cancer-free controls. These seven polymorphisms were not in linkage disequilibrium among each other (r2<0.63). Compared to their common homozygous genotypes, the variant –519GG was associated with significantly decreased CM risk [adjusted odds ratio (OR)=0.71, 95% confidence interval (CI)=0.52–0.99], whereas variants –422TT and –320CC were associated with significantly increased CM risk (OR=1.50, 95% CI=1.11–2.03 and OR=1.72, 95% CI=1.05–2.81, respectively) after adjustment for age, sex, family history and sun-exposure-related risk factors. The number of risk alleles of these three polymorphisms was associated with CM risk in a dose–response manner (Ptrend=0.0002). In the stratification analysis, we found that the associations of these polymorphisms with CM risk were modified by some of the risk factors. Furthermore, the haplotypes Gdel–A–G–A–T–G–T and G–G–G–A–T–A–T were associated with significantly increased CM risk (ORs=1.56 and 2.13, 95% CIs=1.02–2.38 and 1.22–3.70, respectively). These findings suggest that MMP1 promoter polymorphisms may individually or jointly play roles in the development of CM.

Corrigendum to “Preclinical evidence for a beneficial impact of valproate on the response of small cell lung cancer to first-line chemotherapy” [Eur. J. Cancer 46(9) (2010) 1724-1734] - Corrected Proof

2010-07-21

The authors would like to draw your attention to the fact that the third author’s name should be listed as M. Cecilia Crisanti as stated above.

Cost-effectiveness of human papillomavirus vaccination and screening in Spain - Corrected Proof

2010-07-20

Abstract: Background: In Spain, prophylactic vaccination against human papillomavirus (HPV) types 16 and 18 is being offered free-of-charge to one birth cohort of girls aged 11–14. Screening is opportunistic (annual/biannual) contributing to social and geographical disparities.Methods: A multi-HPV-type microsimulation model was calibrated to epidemiologic data from Spain utilising likelihood-based methods to assess the health and economic impact of adding HPV vaccination to cervical cancer screening. Strategies included (1) screening alone of women over age 25, varying frequency (every 1–5years) and test (cytology, HPV DNA testing); (2) HPV vaccination of 11-year-old girls combined with screening. Outcomes included lifetime cancer risk, life expectancy, lifetime costs, number of clinical procedures and incremental cost-effectiveness ratios.Results: After the introduction of HPV vaccination, screening will need to continue, and strategies that incorporated HPV testing are more effective and cost-effective than those with cytology alone. For vaccinated girls, 5-year organised cytology with HPV testing as triage from ages 30 to 65 costs 24,350€ per year of life saved (YLS), assuming life-long vaccine immunity against HPV-16/18 by 3 doses with 90% coverage. Unvaccinated girls would benefit from organised cytology screening with HPV testing as triage; 5-year screening from ages 30 to 65 costs 16,060€/YLS and 4-year screening from ages 30 to 85 costs 38,250€/YLS. Interventions would be cost-effective depending on the cost-effectiveness threshold and the vaccine price.Conclusions: In Spain, inequitable coverage and overuse of cytology make screening programmes inefficient. If high vaccination coverage among pre-adolescent girls is achieved, organised cytology screening with HPV triage starting at ages 30 to at least 65 every 4–5years represents the best balance between costs and benefits.

FGFR4 transmembrane domain polymorphism and cancer risk: A meta-analysis including 8555 subjects - Corrected Proof

2010-07-20

Abstract: Fibroblast growth factor receptor 4 (FGFR4), belonging to the receptor tyrosine kinase family, is involved in cancer initiation and progression. The FGFR4 Gly388Arg polymorphism in the transmembrane domain of the receptor was shown to contribute to genetic susceptibility to cancer but the results were inconsistent. We performed a meta-analysis using 12 eligible case-control studies with a total of 4892 patients and 3663 controls to summarise the data on the association between the FGFR4 Gly388Arg polymorphism and cancer risks. The overall odds ratio (OR) with a 95% confidence interval (CI) showed statistical association between the FGFR4 Gly388Arg polymorphism and cancer risks under homozygote comparison, allele contrast and the recessive genetic model. In the subgroup analysis by ethnicity, statistically significantly increased cancer risks were found among Asians for homozygote comparison (OR=1.43, 95% CI=1.13–1.80, Pheterogeneity=0.24), allele contrast (OR=1.16, 95% CI=1.04–1.29, Pheterogeneity=0.25) and the recessive genetic model (OR=1.47, 95% CI=1.19–1.81, Pheterogeneity=0.15). In the subgroup analysis for different tumour types, Arg388 allele had an effect of increasing the risks of breast (homozygote comparison OR=1.57, 95% CI=1.04–2.37, Pheterogeneity=0.83 and the recessive model OR=1.51, 95% CI=1.02–2.24, Pheterogeneity=0.80) and prostate cancer (Gly/Arg versus Gly/Gly: OR=1.16, 95% CI=1.02–1.32, Pheterogeneity=0.74; Arg versus Gly: OR=1.17, 95% CI=1.07–1.29, Pheterogeneity=0.18 and the dominant model: OR=1.20, 95% CI=1.06–1.35, Pheterogeneity=0.89). Our meta-analysis suggests that the FGFR4 Gly388Arg polymorphism most likely contributes to susceptibility to cancer, especially in Asians. Besides, the Arg388 allele might be associated with increased risks of breast and prostate cancer.