European Journal of Cancer - Articles in Press

The transcription factor Fra-2 promotes mammary tumour progression by changing the adhesive properties of breast cancer cells - Corrected Proof

2010-03-12

Abstract: The transcription factor Fra-2 (Fos-related antigen-2) has been implicated in invasion of breast cancer cells, but there is only sparse information about its role in clinical tumours. In the present study, we analysed Fra-2 mRNA expression in a cohort of 167 patients, and found significant correlations between high Fra-2 expression and nodal involvement or reduced disease-free survival. To get more information about the underlying mechanisms, we generated stably transfected MDA-MB231 breast cancer cells with increased Fra-2 expression. Compared with the controls, these clones did not differ in proliferation and motility, but had higher invasive potential. By global gene expression analysis and subsequent validation of selected genes, we identified a number of proteins involved in cell–cell or cell–matrix interactions that were up- or down-regulated in Fra-2 overexpressing cells, e.g. connexin 43, ICAM-1, L1-CAM, integrin beta 2, integrin beta 4, and integrin alpha 6. The association of Fra-2 overexpression and high ICAM-1 or L1-CAM levels could also be demonstrated in our clinical cohort of mammary tumours. In both MDA-MB231 and MCF7 cells, we found an increased attachment of Fra-2 transfectants to components of the extracellular matrix. In addition, we could show a striking increase in the number of rolling cells in flow-through assays using E-selectin coated capillaries, which might indicate a higher capacity of extravasation. In conclusion, our data obtained on breast cancer cell lines and clinical tissue samples suggest that overexpression of Fra-2 promotes breast cancer progression and metastasis by deregulation of genes involved in cell–cell and cell–ECM contacts.

The use of hsa-miR-21, hsa-miR-181b and hsa-miR-106a as prognostic indicators of astrocytoma - Corrected Proof

2010-03-11

Abstract: Background: The aberrant expression of microRNAs (miRNAs) is associated with a variety of diseases including cancers. In the present study, the miRNA expression profile was examined in astrocytoma, a malignant and prevalent intracranial tumour in adults.Methods: We screened the expression profile of 200 miRNAs in a training sample set consisting of 84 astrocytoma samples and 20 normal adjacent tissue (NAT) samples using the method of stem-loop quantitative RT-PCR. The significantly altered miRNAs were validated in another independent sample set consisting of 40 astrocytoma samples and 40 NAT samples. The correlation of the miRNA levels with survival in astrocytoma samples was estimated by performing Kaplan–Meier survival analysis and univariate/multivariate Cox proportional hazard regression analysis.Results: After a two-phase selection and validation process, seven miRNAs were found to have a significantly different expression profile in astrocytoma samples upon comparison to the NAT samples. Unsupervised clustering analysis further revealed the great potential of the 7-miRNA profile to differentiate between tumours and normal brain tissues. The down-regulation of hsa-miR-137 in astrocytomas was shown to be associated with advanced clinical stages of this disease. Using Kaplan–Meier survival analysis we showed that low expression of hsa-miR-181b or hsa-miR-106a, or high expression of hsa-miR-21 was significantly associated with poor patient survival. Moreover, Cox proportional hazard regression analysis revealed that this prognostic impact was independent of other clinicopathological factors.Conclusions: Our results suggest a great potential for the use of miRNA profiling as a powerful diagnostic and prognostic marker in defining the signature of astrocytomas and in predicting the post-surgical outcome.

Resveratrol attenuates the anticancer efficacy of paclitaxel in human breast cancer cells invitro and in vivo - Corrected Proof

Masayuki Fukui, Noriko Yamabe, Bao Ting Zhu — 2010-03-11

Abstract: It was reported recently that resveratrol could sensitise a number of cancer cell lines to the anticancer actions of several other cancer drugs, including paclitaxel. In the present study, we further investigated whether resveratrol could sensitise human breast cancer cells to paclitaxel-induced cell death. Unexpectedly, we found that resveratrol strongly diminished the susceptibility of MDA-MB-435s, MDA-MB-231 and SKBR-3 cells to paclitaxel-induced cell death in culture, although this effect was not observed in MCF-7 cells. Using MDA-MB-435s cells as a representative model, a similar observation was made in athymic nude mice. Mechanistically, the modulating effect of resveratrol was partially attributable to its inhibition of paclitaxel-induced G2/M cell cycle arrest, together with an accumulation of cells in the S-phase. In addition, resveratrol could suppress paclitaxel-induced accumulation of reactive oxygen species (ROS) and subsequently the inactivation of anti-apoptotic Bcl-2 family proteins. These observations suggest that the strategy of concomitant use of resveratrol with paclitaxel is detrimental in certain types of human cancers. Given the widespread use of resveratrol among cancer patients, this study calls for more preclinical and clinical testing of the potential benefits and harms of using resveratrol as a dietary adjuvant in cancer patients.

Mortality is persistently increased in Hodgkin’s lymphoma survivors - Corrected Proof

2010-03-11

Abstract: Background: Negative health outcomes of chronic fatigue (CF) in disease-free cancer survivors are mainly unexplored. Aims of this study were to examine mortality and causes of death in Hodgkin’s lymphoma survivors (HLSs) compared to controls from the general population, and to explore if CF was associated with increased mortality.Methods: HLSs (n=557) invited to participate in a survey on late effects in 1994 were divided into three groups: participants without CF (n=329), participants with CF (n=113), non-participants (n=98). Controls matched for gender and age were drawn from the general population (five per HLSs, n=2785). Observation time was calculated from 1st January 1994 until date of death or cut-off at 1st January 2007. Kaplan–Meier plots were used for univariate analyses and Cox models for multiple covariates.Results: Compared to controls HLSs had nearly five times higher mortality (HR=4.93; 95% confidence interval [CI]: 3.91–6.21) and the mortality rate of HLSs was higher than the rate of their controls for the entire observation period. Mortality was increased in all groups: participants with CF: HR=4.85 (95% CI: 3.02–7.77), participants without CF: HR=4.35 (95% CI: 3.16–6.00), non-participants: HR=9.45 (95% CI: 5.44–16.41).Compared to the controls HLSs had over six times increased mortality of cancer (HR: 6.6, 95% CI: 4.7–9.2) and almost five times increased mortality of cardiovascular diseases (HR: 4.9, 95% CI: 3.1–7.9).Conclusions: HLSs had almost five-time increased mortality compared to controls. CF was not associated with increased mortality rate. The high mortality among the non-participating HLSs indicates that serious health problems are underestimated in this group. This has implications for the interpretation of surveys in cancer survivors.

Trends in incidence, treatment and survival of gastric adenocarcinoma between 1990 and 2007: A population-based study in the Netherlands - Corrected Proof

2010-03-11

Abstract: Background: Survival of gastric cancer in the Western world remains poor. We conducted a retrospective population-based study to evaluate trends in incidence, treatment and outcome of gastric adenocarcinoma.Methods: All patients diagnosed with gastric adenocarcinoma during 1990–2007 in the Dutch Eindhoven Cancer Registry area were included (n=4797). Trend analyses were conducted for incidence, mortality, tumour and patient characteristics, treatment and crude overall survival, according to tumour location (cardia versus non-cardia). Temporal changes in the odds of undergoing surgery and the risk of death were analysed by means of multivariable regression methods.Results: Age-standardised incidence decreased among males (24–12 per 100,000 inhabitants) and females (10–6); mortality rates decreased at a similar pace. The proportion of cardia tumours remained stable. Stage distribution worsened over time among patients with cardia (stages I and II: 32% in 1990–1993 and 22% in 2006–2007, p=0.005) and non-cardia (stage IV: 33% in 1990–1993 and 40% in 2006–2007, p=0.0003) cancer. Chemotherapy rates increased in all settings. Five-year survival worsened over time for patients with non-cardia tumours. Age and stage had significant influence on survival after stratification for tumour localisation. After adjustments for relevant factors (i.e. stage), the risk of death decreased since the late 90s for patients with a cardia tumour (hazard ratio 0.8, p=0.01).Conclusion: The absence of improvement in survival rates indicates the need for earlier detection and prospective studies to evaluate new therapy regimens with standardised surgery and pathology.

Cisplatin-induced apoptosis involves a Fas-ROCK-ezrin-dependent actin remodelling in human colon cancer cells - Corrected Proof

2010-03-08

Abstract: In human colon cancer cells, cisplatin-induced apoptosis involves the Fas death receptor pathway independent of Fas ligand. The present study explores the role of ezrin and actin cytoskeleton in relation with Fas receptor in this cell death pathway. In response to cisplatin treatment, a rapid and transient actin reorganisation is observed at the cell membrane by fluorescence microscopy after Phalloidin-FITC staining. This event is dependent on the membrane fluidification studied by electron paramagnetic resonance and necessary for apoptosis induction. Moreover, early after the onset of cisplatin treatment, ezrin co-localised with Fas at the cell membrane was visualised by membrane microscopy and was redistributed with Fas, FADD and procaspase-8 into membrane lipid rafts as shown on Western blots. In fact, cisplatin exposure results in an early small GTPase RhoA activation demonstrated by RhoA–GTP pull down, Rho kinase (ROCK)-dependent ezrin phosphorylation and actin microfilaments remodelling. Pretreatment with latrunculin A, an inhibitor of actin polymerisation, or specific extinction of ezrin or ROCK by RNA interference prevents both cisplatin-induced actin reorganisation and apoptosis. Interestingly, specific extinction of Fas receptor by RNA interference abrogates cisplatin-induced ROCK-dependent ezrin phosphorylation, actin reorganisation and apoptosis suggesting that Fas is a key regulator of cisplatin-induced actin remodelling and is indispensable for apoptosis. Thus, these findings show for the first time that phosphorylation of ezrin by ROCK via Fas receptor is involved in the early steps of cisplatin-induced apoptosis.

A phase I clinical and pharmacokinetic study of paclitaxel liposome infused in non-small cell lung cancer patients with malignant pleural effusions - Corrected Proof

2010-03-08

Abstract: Purpose: To investigate the feasibility, pharmacokinetics, efficacy and toxicity of intrapleural paclitaxel liposome injection in non-small cell lung cancer (NSCLC) patients with malignant pleural effusions.Patients and methods: Twelve of 15 NSCLC patients with malignant pleural effusions were treated with paclitaxel liposome and three were treated with free paclitaxel. Adequate pleural fluid, blood and urine were collected for pharmacokinetic study. The clinical efficacy and toxicity were synthetically evaluated according to the correlative criteria.Results: The overall toxicity of paclitaxel liposome was lower than that of free paclitaxel. In the patients treated with paclitaxel liposome, there were minimal local chest pain, anaphylaxis, anaemia, neutropaenia and hepatotoxicity. The complete response rates of pleural effusion at the first, second, third and sixth month were, respectively, 27.3%, 18.2%, 9.1% and 9.1%, and overall response rates were 90.9%, 72.7%, 63.6% and 54.5%, respectively. Pharmacokinetic study showed that mean Cmax,IP, T1/2 and AUC0→96,IP in pleural fluid were, respectively, about 2-fold, 2-fold and 2.5-fold than those of free paclitaxel, and AUC0→96,Pla in plasma was also much higher than that of free paclitaxel, however, excretory rate in 24h from urine was lower than that of free paclitaxel.Conclusions: This study demonstrated that paclitaxel liposome was a more useful agent than free paclitaxel for the treatment of malignant pleural effusions because of its relatively low toxicity and distinct pharmacokinetic characteristics. The phase II study of a large number of patients was recommended to confirm this finding.

Hepatitis B virus-associated intrahepatic cholangiocarcinoma and hepatocellular carcinoma may hold common disease process for carcinogenesis - Corrected Proof

2010-03-08

Abstract: Aims: To evaluate potential risk factors for intrahepatic cholangiocarcinoma (ICC) and analyse clinicopathologic characteristics of ICC patients with seropositive hepatitis B surface antigen (HBsAg).Methods: A retrospective case–control study was conducted. Cases were 317 ICC patients referred to the Eastern Hepatobiliary Surgery Hospital in China between 2003 and 2006. Controls were 634 healthy individuals. Adjusted odds ratios (ORs) were calculated in logistic regression analysis. Among 317 consecutively enrolled ICC patients, 154 patients were seropositive HBsAg (48.6%). We compared clinicopathologic characteristics of these patients (group I) with ICC patients seronegative for HBsAg (group II; n=163) and compared the age and sex distributions of patients in group I with randomly selected hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) (group III; n=1140).Results: Compared with the controls, ICC patients had a high prevalence of seropositive HBsAg, cirrhosis, hepatolithiasis and hepatic schistosomiasis. Compared with seronegative-HBsAg ICC patients, seropositive-HBsAg ICC patients were younger, more frequently male and had a higher proportion of abnormal aminotransferase and serum alpha-fetoprotein (AFP) level, histological inflammation and cirrhosis, right-lobe focus, poor tumour differentiation, tumour encapsulation and microvascular invasion; had a lower proportion of abnormal serum carbohydrate antigen 19-9 (CA19-9) level and lymphatic metastasis. The age and sex distribution profiles were nearly identical between seropositive-HBsAg ICC patients and HBV-associated HCC patients.Conclusions: The HBV infection, cirrhosis, hepatolithiasis and hepatic schistosomiasis may be potential risk factors for ICC. HBV-associated ICC shares many clinicopathological similarities with HBV-associated HCC. The result indicated HBV-associated ICC and HBV-associated HCC may hold common disease process for carcinogenesis.

Oxidative stress-induced antioxidant enzyme expression is an early phenomenon in ovarian carcinogenesis - Corrected Proof

Marjo Pylväs, Ulla Puistola, Saila Kauppila, Ylermi Soini, Peeter Karihtala — 2010-03-08

Abstract: Oxidative stress and antioxidant enzymes have been widely investigated in various carcinomas. However, there is only some information about their role in ovarian carcinogenesis or in ovarian carcinomas in vivo. We studied immunohistochemical nuclear and/or cytoplasmic expression of oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine, as well as major antioxidative enzymes peroxiredoxins (PRDX) I–VI and thioredoxin (TXN) in ovarian tumours. The material consisted of 20 benign (10 serous, 10 mucinous) and 51 borderline (33 serous, 18 mucinous) epithelial ovarian tumours. The markers of oxidative stress, 8-OHdG and nitrotyrosine, were seen already in benign tumours (in 20% and 45% of the tumours, respectively) and their expression patterns were similar in benign and borderline tumours. The levels of PRDX II, III, IV, V and VI were significantly higher in borderline than in benign tumours (p<0.02 for all). Specifically for PRDX II (for both nuclear and cytoplasmic expression, p<0.00005) and PRDX VI (for cytoplasmic expression, p=0.0003 and for nuclear expression, p=0.0005) the difference between benign and borderline tumours was remarkable. In general, serous benign and borderline tumours expressed higher antioxidant enzyme levels than mucinous ones. Nuclear TXN was expressed more strongly in benign than in borderline tumours (p=0.003). Oxidative stress occurs already in benign ovarian tumours and the levels are comparable to borderline tumours. However, some of the antioxidant enzymes, especially PRDX II and VI, are more profoundly induced in borderline ovarian tumours, reflecting their possible role as cancer preventers. This difference could also offer a potential tool for differential diagnosis between benign and borderline epithelial ovarian tumours.

GSTM1, GSTT1, GSTP1, GSTA1 and colorectal cancer risk: A comprehensive meta-analysis - Corrected Proof

Konstantinos P. Economopoulos, Theodoros N. Sergentanis — 2010-03-08

Abstract: Glutathione S-transferases (GSTs) catalyse reactions between glutathione and lipophilic compounds with electrophilic centres, leading to neutralisation of toxic compounds, xenobiotics and products of oxidative stress. Controversy exists about whether GST polymorphisms (GSTM1 null/present genotype, GSTT1 null/present genotype, GSTP1 Ile105Val and GSTA1∗A/∗B) represent risk factors for colorectal cancer. This meta-analysis aims to examine the associations between the above-mentioned polymorphisms and colorectal cancer risk. Forty-four studies were eligible for GSTM1 (11,998 colorectal cancer cases, 17,552 controls), 34 studies for GSTT1 (8596 cases, 13,589 controls), 19 studies for GSTP1 (5421 cases, 7671 controls) and four studies for GSTA1 polymorphism (1648 cases, 2039 controls). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. Separate analyses were conducted on Caucasian and Chinese populations. Where appropriate, sensitivity analysis concerning the deviation of genotype frequencies in controls from the Hardy–Weinberg equilibrium was performed. GSTM1 null allele carriers exhibited increased colorectal cancer risk in Caucasian populations (pooled OR=1.150, 95% confidence interval (CI): 1.060–1.248, random effects); no significant association was detected for Chinese subjects (pooled OR=1.025, 95% CI: 0.903–1.163, fixed effects). Similarly, GSTT1 null allele carriers exhibited increased colorectal cancer risk in Caucasian populations (pooled OR=1.312, 95% CI: 1.119–1.538, random effects); the association in Chinese subjects was not significant (pooled OR=1.068, 95% CI: 0.788–1.449, random effects). Concerning GSTP1 Ile105Val no significant associations were demonstrated in either race. GSTA1∗A/∗B polymorphism was not associated with colorectal cancer risk. GSTM1 and GSTT1 null genotypes confer additional risk for colorectal cancer in Caucasian populations.

Phase II study of oral masitinib mesilate in imatinib-naïve patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST) - Corrected Proof

2010-03-08

Abstract: Background: Masitinib is a tyrosine kinase inhibitor with greater in vitro activity and selectivity for the wild-type c-Kit receptor and its juxtamembrane mutation than imatinib, without inhibiting kinases of known toxicities. This phase II study evaluated masitinib as a first-line treatment of advanced GIST.Patients and methods: Imatinib-naïve patients with advanced GIST received oral masitinib at 7.5mg/kg/d. Efficacy end-points included response rate (RR) at 2months, best response according to RECIST, metabolic response rate, disease control rate (DCR), progression-free survival (PFS) and overall survival rate (OS).Results: Thirty patients were enrolled with a median follow-up of 34months. The most frequent grade 3–4 toxicities were rash (10%) and neutropaenia (7%). Two patients withdrew due to treatment-related adverse events. At 2months, RR was 20% according to response evaluation criteria in solid tumours (RECIST) and 86% according to FDG-PET response criteria. Best responses were a complete response in 1/30 patient (3.3%), partial response in 15/30 patients (50%), stable disease in 13/30 patients (43.3%) and progressive disease in 1/30 patient (3.3%); (DCR: 96.7%). Median time-to-response was 5.6months (0.8–23.8months). Estimated median PFS was 41.3months with PFS rate of 59.7% [37.9; 76.0] and 55.4 [33.9; 72.5] at 2 and 3years, respectively. The OS at 2 and 3years was stable at 89.9% [71.8; 96.6].Conclusions: Masitinib appears to be effective as a first-line treatment of advanced GIST with comparable results to imatinib in terms of safety and response. PFS and in particular OS data show promise that masitinib may provide sustainable benefits. There is sufficient compelling evidence to warrant a phase III clinical trial.

Serum biomarkers of cell death for monitoring therapy response of gastrointestinal carcinomas - Corrected Proof

2010-03-04

Abstract: Purpose: Antitumour treatments are thought to exert their therapeutic efficacy mainly by induction of apoptosis in tumour cells. In epithelial cells, caspases, the key enzymes of apoptosis, cleave the intermediate filament protein cytokeratin (CK)-18 into specific fragments that are released into circulating blood and can be detected by a specific ELISA.Experimental design: To investigate the use of CK-18 fragments as a potential biomarker for the treatment response, we examined the association of serum CK-18 levels and clinical response in 35 patients with gastrointestinal cancers.Results: While both cleaved and total CK-18 levels were intrinsically elevated in tumour patients, they were further increased during 5-fluorouracil (5-FU)-based therapy. Importantly, the increased levels of CK-18 could discriminate between patients with different clinical response. Cancer patients with a partial response or stable disease revealed a significantly higher increase of cleaved CK-18 during chemotherapy as compared to patients with progressive disease.Conclusions: Our results suggest that detection of circulating caspase-cleaved CK-18 might be a useful serum biomarker for monitoring treatment response and should merit further evaluation in larger patient groups.

Loss of expression of TIMP3 in clear cell renal cell carcinoma - Corrected Proof

2010-03-02

Abstract: Aims: In clear cell renal cell carcinoma (CCRCC), vascular endothelial growth factor (VEGF) represents the central positive mediator of tumour angiogenesis while VEGF receptor (VEGFR) is the primary target of anti-angiogenic therapies. TIMP3 is a physiological VEGFR-2 antagonist and thus could be considered as an anti-angiogenic factor. We therefore determined the status of this physiological inhibitor in CCRCC.Patients and methods: Archival tumour from 105 patients was studied. TIMP3 expression was analysed using immuno-histochemistry and real-time RT-PCR. Results were correlated with clinicopathological variables. To analyse the mechanisms of gene silencing involved, we performed Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-specific MLPA (MS-MLPA). At last, we evaluated the main upstream pathway described implicating TGFβRII, which induces TIMP3 expression.Results: A down-expression of TIMP3, determined by immunohistochemistry, affected 100/105 renal cancers (95.2%). TIMP3 mRNA levels were significantly lower in high-grade tumours. Loss of heterozygosity of the TIMP3 gene was observed in 8 tumours (7.6%) and the 5′CpG island of the TIMP3 promoter was found to be methylated in 25 tumours (23.8%). A down-expression of TGFβRII was found in 85/105 CCRCCs (80.9%). A significant correlation was found between TIMP3 expression and TGFβRII expression.Conclusions: This is the first demonstration that the loss of TIMP3 expression is observed in almost all CCRCCs. This loss of expression is a common molecular event in CCRCC. It may be an important initiation step for tumour development in a complex process implicating loss of heterozygosity on chromosome 22q, promoter hyper-methylation and inactivation of the TGFβRII pathway.

Aspects of quality of life, anxiety, and depression among persons diagnosed with cancer during adolescence: A long-term follow-up study - Corrected Proof

Gunnel Larsson, Elisabet Mattsson, Louise von Essen — 2010-03-02

Abstract: Aim: Quality of life, anxiety, and depression among persons diagnosed with cancer during adolescence up to 4years after diagnosis, and in comparison with a reference group were investigated.Methods: The cancer group (N=61) completed the SF-36 mental health and vitality and the HADS anxiety and depression subscales shortly after and at 6, 12, 18, 24, 36 and 48months after diagnosis. A reference group (N=300) randomly drawn by Statistics Sweden from their civil register of the Swedish population completed the same instruments at one assessment. Data were collected by telephone interviews.Results: Up to 6months after diagnosis the cancer group reports lower levels of mental health and vitality and a higher level of depression than the reference group. At 18months after diagnosis a reverse situation occurs and at 48months after diagnosis the cancer group reports a higher level of vitality and lower levels of anxiety and depression than the reference group.Conclusion: The findings suggest that a positive psychological change may develop in the aftermath of cancer during adolescence. However, efforts should be made to enable clinicians and nursing staff to identify and to provide psychological support to individuals who experience low quality of life and high emotional distress. If these problems remain undetected and appropriate support is not provided the distress may become a barrier to physical recovery, resulting in a vicious cycle of physical and mental disability.

MC1R variants increase melanoma risk in families with CDKN2A mutations: A meta-analysis - Corrected Proof

2010-03-02

Abstract: Aim of the study: We performed a meta-analysis to assess whether MC1R variants increase the risk of melanoma in CDKN2A mutation carriers of melanoma-prone families.Methods: Data from 96 CDKN2A-positive melanoma-prone families from seven independent populations of Europe, United States and Australia were included in the analysis. Summary risk estimates were calculated by random-effect models. We explored between-study heterogeneity and publication bias. Association between MC1R variants and age at diagnosis was assessed by the non-parametric Wilcoxon test.Results: CDKN2A mutation carriers with ⩾1 MC1R variant showed a double melanoma risk as compared to CDKN2A mutation carriers without MC1R variants (Summary OR; 95%CI: 2.2; 1.1–4.5). MC1R heterozygous subjects had no significantly higher melanoma risk than wild-type subjects (1.6; 0.5–5.4) while carriers of multiple MC1R variants had a more than four-times higher melanoma risk (4.6; 1.3–16.4). Carriers of red hair colour (RHC) variants showed an increased melanoma risk with a Summary OR of 3.5 (95%CI: 1.3–9.9). CDKN2A mutation carriers with MC1R variants had a statistically significant lower median age at melanoma diagnosis than CDKN2A mutation carriers with no MC1R variants (37years versus 47years, p-value<0.0001).Conclusion: MC1R variants significantly increase penetrance of CDKN2A mutations in melanoma-prone families, especially with respect to multiple MC1R variants and to RHC variants. A significant anticipation of melanoma diagnosis is observed in CDKN2A mutation carriers with MC1R variants.

TLE1 is a robust diagnostic biomarker for synovial sarcomas and correlates with t(X;18): Analysis of 319 cases - Corrected Proof

2010-03-02

Abstract: Introduction: Genomewide expression profiling has identified a number of genes expressed at higher levels in synovial sarcoma than in other sarcomas. Our objectives in this study were (1) to test whether the differentially expressed gene, Transducin-Like Enhancer of split (TLE1) belonging to the groucho/TLE family, is also distinct on the protein level; (2) to evaluate this biomarker in a series of well-characterised synovial sarcomas on standard, full-sized tissue sections and (3) to correlate the expression of TLE1 with t(X;18) and other established biomarkers.Methods: Three-hundred and eighty four spindle cell sarcomas from the German consultation and reference centre of soft tissue tumours initially suspected for synovial sarcoma were revisited. Three-hundred and nineteen of these specimens were analysed immunohistochemically using a monoclonal antibody TLE1 and standard, full-sized tissue sections. The nuclear staining was scored semiquantitatively as −, negative; +, weak; ++, moderate and +++, strong positive. Furthermore, 118 specimens among these were further analysed using FISH and/or PCR to detect t(X;18). We correlated the TLE1 expression with the t(X;18) translocation and other established biomarkers (EMA, PanCK, CK7, CD34 and BCL2).Results: TLE1 expression was observed in 96% of the synovial sarcomas (score⩾+, 249/259) and discriminates them from other soft tissue tumours (p<0.001). Multivariate analysis showed that positive TLE1 staining was a statistically independent diagnostic marker. Furthermore molecular analysis showed that t(X;18) was clearly correlated with TLE1 protein expression (p<0.001).Conclusions: Expression of TLE1 is significantly correlated with t(X;18) and may serve as a new robust diagnostic biomarker in synovial sarcomas and potential therapeutic target.

Are reported increases in incidence of primary CNS tumours real? An analysis of longitudinal trends in England, 1979–2003 - Corrected Proof

2010-03-02

Abstract: Reported increases in the incidence of CNS tumours in the developed world in the 1970s to 1990s have been a cause for concern and debate. It still remains to be adequately answered whether these increases are true or an artefact of changes in diagnostic and registration practices. Using high-quality national cancer registration data, we have analysed incidence trends for each major histological subgroup of CNS tumour (2000 World Health Organisation (WHO) classification) registered in those aged 0–84years for the whole of England during the period 1979 through 2003. 134,509 primary CNS tumours of malignant, benign and uncertain behaviour located in the brain, meninges, spinal cord, cranial nerves, other parts of the central nervous system and in the pituitary and pineal glands were registered. In summary, we present the single largest nationwide study on the longitudinal incidence trends of CNS tumours. The increase in incidence observed in the 1970s and 1980s was mainly in the young and the elderly and has now plateaued and may even be decreasing. There is however variation in trends by histology. The incidence of some histological sub-groups has continued to increase until the most recent period of analysis. Much of the initial increase can be attributed to the emergence of much more widely available neuroimaging, while the most recent incidence changes for specific sub-groups of CNS tumours appear to be due to greater diagnostic specificity leading to a shift in registered categories. However, the trends for high-grade astrocytomas and other gliomas need further observation and investigation.

Sex differences in the incidence of gastrointestinal adenocarcinoma in Sweden 1970–2006 - Corrected Proof

Martin Rutegård, Richard Shore, Yunxia Lu, Pernilla Lagergren, Mats Lindblad — 2010-02-26

Abstract: Background: Oesophageal and gastric adenocarcinoma share a male predominance not seen for other adenocarcinomas of the gastrointestinal tract. These sex differences are not explained by known risk factors. An endogenous factor, such as premenopausal oestrogen exposure, may act protectively in favour of women and might be detected by scrutinising sex ratios and incidence rates stratified by age.Methods: The Swedish Cancer Register was used to collect primary oesophageal, gastric cardia, non-cardia gastric, colonic and pancreatic adenocarcinoma cases aged 25–84, during the study period of 1970–2006. Cases were divided into five-year age groups and crude incidence rates and male: female ratios were calculated. Evaluating potential time period effect, the corresponding results from 1970–1986 and 1987–2006 were also derived.Results: The sex ratio for oesophageal adenocarcinoma ranged from approximately 10:1 to 4:1, presenting a seemingly consistent decline with age. The sex ratio for non-cardia gastric adenocarcinoma, however, increased with age to reach 2:1 at a point one to two decades after menopause, where the ratio levelled off and eventually declined. There was no discernible time period effect concerning any type of adenocarcinoma. The ratios for gastric cardia, colonic and pancreatic adenocarcinoma were stable with age.Conclusion: This study indicates separate patterns of age-dependency of the sex difference in oesophageal and non-cardia gastric adenocarcinoma incidence. The non-cardia gastric adenocarcinoma pattern might be due to a protective effect during premenopausal years for the female population, while the seemingly steady decline in sex ratio in oesophageal adenocarcinoma indicates a mechanism independent of menopause.

Alpha-fetoprotein-producing non-germ cell tumours of the female genital tract - Corrected Proof

M. El-Bahrawy — 2010-02-25

Abstract: Elevated levels of alpha-fetoprotein (AFP), a foetal serum protein, occur mainly on the development of hepatocellular carcinoma (HCC) or germ cell tumours, including yolk sac tumour (YST) and embryonal carcinoma of the ovary. Rarely, other tumours of the female genital tract produce AFP. This article reviews the AFP-producing non-germ cell tumours reported in different parts of the female genital tract to date. These include different types of carcinomas and carcinosarcomas of the uterus, ovary and cervix and sex cord stromal tumours of the ovary. It is important for both pathologists and oncologists to be aware of such cases and the clinicopathological distinction from germ cell tumours, as the diagnosis would affect the management plan for the patient. The reviewed cases suggest that regardless of the patient’s age when no lesion is detected in the liver and stomach of a woman whose serum AFP level is abnormally high, the female reproductive system should be examined as a possible site of AFP-producing tumour. Biochemical, physiological and pathological features of AFP are briefly presented.

Constitutive HIF-1 activity in malignant melanoma - Corrected Proof

Silke Kuphal, Andreas Winklmeier, Christina Warnecke, Anja-Katrin Bosserhoff — 2010-02-25

Abstract: The hypoxia-inducible factor-1 (HIF-1), which consists of the constitutive HIF-1β and the oxygen-responsive HIF-1α subunit, is the master activator of the cellular transcriptional response to hypoxia coordinating gene expression during reduced oxygen tension.Overexpression of HIF-1 and increased transcriptional activity induced by hypoxia are linked to progression of many tumour types such as head and neck cancer, cervical carcinoma, leukaemia and renal cell carcinoma.In this study, we demonstrate that HIF activity is increased in malignant melanoma cells already under normoxic conditions in contrast to other tumour types. HIF-1α and -2α knockdown by siRNA transfection revealed that this effect is due to constitutive HIF-1α expression. Furthermore, the inhibition or activation of reactive oxygen species (ROS) decreased or activated, respectively, HIF-1 activity and HIF-1α protein expression. Interestingly, the inhibition of the NFkappaB pathway also reduced the accumulation of HIF-1α assuming a context between ROS and NFkappaB, and suggesting that ROS and NFkappaB activity contribute to HIF-1α accumulation. In summary, we identified an increased HIF-1α protein expression and activity in melanoma under normoxia mediated by ROS and the NFkappaB pathway.

Loss of the CBX7 protein expression correlates with a more aggressive phenotype in pancreatic cancer - Corrected Proof

2010-02-25

Abstract: Polycomb group (PcG) proteins function as multiprotein complexes and are part of a gene regulatory mechanism that determines cell fate during normal and pathogenic development. Several studies have implicated the deregulation of different PcG proteins in neoplastic progression.Pancreatic ductal adenocarcinoma is an aggressive neoplasm that follows a multistep model of progression through precursor lesions called pancreatic intraepithelial neoplasia (PanIN).Aim of this study was to investigate the role of PcG protein CBX7 in pancreatic carcinogenesis and to evaluate its possible diagnostic and prognostic significance.We analysed by immunohistochemistry the expression of CBX7 in 210 ductal pancreatic adenocarcinomas from resection specimens, combined on a tissue microarray (TMA) including additional 40 PanIN cases and 40 normal controls. The results were evaluated by using receiver operating characteristic (ROC) curve analysis for the selection of cut-off scores and correlated to the clinicopathological parameters of the tumours and the outcome of the patients. Expression of E-cadherin, a protein positively regulated by CBX7, was also assessed.A significantly differential, and progressively decreasing CBX7 protein expression was found between normal pancreatic tissue, PanINs and invasive ductal adenocarcinoma. Loss of CBX7 expression was associated with increasing malignancy grade in pancreatic adenocarcinoma, whereas the maintenance of CBX7 expression showed a trend toward a longer survival. Moreover, loss of E-cadherin expression was associated with loss of CBX7 and with a trend towards worse patient survival.These results suggest that CBX7 plays a role in pancreatic carcinogenesis and that its loss of expression correlates to a more aggressive phenotype.

PRISMA: A pan-European co-ordinating action to advance the science in end-of-life cancer care - Corrected Proof

Richard Harding, Irene J. Higginson, On behalf of PRISMA — 2010-02-25

Abstract: Introduction: The epidemiology of progressive cancer and associated mortality in Europe underlines the essential need for high quality palliative and end-of-life care for its citizens. Currently, care of patients at the end-of-life is under-researched and under-funded. This is due to a lack of prioritisation, challenges in defining end-of-life, lack of a common research strategy for Europe that identifies and implements best practice and highest scientific principles, and the need for common use of appropriate well-validated tools to measure and improve the end-of-life cancer experience in Europe.Methods: PRISMA is a pan-European co-ordinating action funded under Framework Programme 7 of the European Commission. With 12 partners in 9 countries, it is delivering a series of 8 Work Packages with the common aim of promoting best practice in the measurement of end-of-life care, setting an agenda and guidance that reflects European cultural diversity, and is informed by both public and clinical priorities. Guidance in the selection, adaptation and use of core tools is informed by experts in public health and clinical research.Discussion: PRISMA is currently producing a series of outputs to be accessible to the wider community of researchers, policy makers, funders and clinicians. We encourage new partnerships to build on the work of PRISMA and to lead high quality work informed by our deliverables. PRISMA, we hope, is redressing the current lack of co-ordination of cancer end-of-life research across Europe, and will catalyse the conduct of evidence-based care that reflects European populations and priorities.

An international validation study of the EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-related quality of life and symptoms in brain cancer patients - Corrected Proof

2010-02-24

Abstract: Aims: The psychometric properties of the EORTC QLQ-BN20, a brain cancer-specific HRQOL questionnaire, have been previously determined in an English-speaking sample of patients. This study examined the validity and reliability of the questionnaire in a multi-national, multi-lingual study.Methods: QLQ-BN20 data were selected from two completed phase III EORTC/NCIC clinical trials in brain cancer (N=891), including 12 languages. Experimental treatments were surgery followed by radiotherapy (RT) and adjuvant PCV chemotherapy or surgery followed by concomitant RT plus temozolomide (TMZ) chemotherapy and adjuvant TMZ chemotherapy. Standard treatment consisted of surgery and postoperative RT alone. The psychometrics of the QLQ-BN20 were examined by means of multi-trait scaling analyses, reliability estimation, known groups validity testing, and responsiveness analysis.Results: All QLQ-BN20 items correlated more strongly with their own scale (r>0.70) than with other QLQ-BN20 scales. Internal consistency reliability coefficients were high (all α⩾0.70). Known-groups comparisons yielded positive results, with the QLQ-BN20 distinguishing between patients with differing levels of performance status and mental functioning. Responsiveness of the questionnaire to changes over time was acceptable.Conclusion: The QLQ-BN20 demonstrates adequate psychometric properties and can be recommended for use in conjunction with the QLQ-C30 in assessing the HRQOL of brain cancer patients in international studies.

Operating characteristics of two independent sample design in phase I trials in paediatric oncology - Corrected Proof

Mathilde Raphaël, Marie-Cécile le Deley, Gilles Vassal, Xavier Paoletti — 2010-02-22

Abstract: Purpose: The European medicines agency (EMEA) has stated that the degree of pre-treatment could modify the patient’s tolerance to new treatments in paediatric oncology. It is current practice to divide a phase I trial into two groups to identify the maximum tolerated dose (MTD) in each group separately. The aim of this study was to investigate the relevance of this approach.Methods: We reanalysed a large phase I trial of Irinotecan that included 80 children (32 heavily pretreated patients and 48 less heavily pretreated). An extended simulation study was performed to investigate the robustness of the conclusions in the context of small sample sizes. Dose recommendations were studied according to scenarios with group differences, as measured by odds ratio (OR), ranging from 1 (no difference) to 10 (large difference) and sample sizes increasing from 20×2 to 60×2 patients.Results: This study shows a high risk of misidentification of the MTD in each of the two groups, regardless of the group difference. With a group difference corresponding to OR=8 and balanced sample sizes (20×2 patients), the same MTD was identified in 11% of the simulations. Even with larger sample sizes (40×2 patients), this figure reached 24% for OR=3. There is also a very high risk of identifying two different MTD (52% for 40×2 patients) although the risk is similar in both groups.Conclusions: Two independent sample designs in paediatric phase I trials should be avoided or reserved to limited situations when there is a strong rationale possibly based on adult data.

Marked improvements in survival of patients with rectal cancer in the Netherlands following changes in therapy, 1989–2006 - Corrected Proof

2010-02-22

Abstract: Background: Since the 1990s, treatment of patients with rectal cancer has changed in the Netherlands. Aim of this study was to describe these changes in treatment over time and to evaluate their effects on survival.Methods: All patients in the Netherlands Cancer Registry with invasive primary rectal cancer diagnosed during the period 1989–2006 were selected. The Cochran–Armitage trend test was used to analyse trends in treatment over time. Multivariate relative survival analyses were performed to estimate relative excess risk (RER) of dying.Results: In total, 40,888 patients were diagnosed with rectal cancer during the period 1989–2006. The proportion of patients with stages II and III disease receiving preoperative radiotherapy increased from 1% in the period 1989–1992 to 68% in the period 2004–2006 for younger patients (<75years) and from 1% to 51% for older patients (⩾75years), whereas the use of postoperative radiotherapy decreased. Administration of chemotherapy to patients with stage IV disease increased over time from 21% to 66% for patients younger than 75years. Both males and females exhibited an increase in five-year relative survival from 53% to 60%. The highest increase in survival was found for patients with stage III disease. In the multivariate analyses survival improved over time for patients with stages II–IV disease. After adjustment for treatment variables, this improvement remained significant for patients with stages III and IV disease.Conclusions: The changes in therapy for rectal cancer have led to a markedly increased survival. Patients with stage III disease experienced the greatest improvement in survival.

Expression profiles of viral responsive genes in oral and oropharyngeal cancers - Corrected Proof

2010-02-22

Abstract: The association between Human Papillomavirus (HPV) DNA and oropharyngeal squamous cell carcinoma (SCC) has been supported by numerous studies strongly implicating HPV infection as a factor in the development of this cancer. In contrast, squamous cell carcinoma of the oral cavity has not been associated with HPV DNA, suggesting alternate aetiologic factors. The possibility that viral agents other than HPV could contribute to the development of oral cavity SCC should be given consideration, especially given the association of Epstein-Barr virus (EBV) with nasopharyngeal cancer. We used quantitative polymerase chain reaction (qPCR) studies to compare the expression levels of genes that may act as indicators of persistent stimulation by viral antigen in both oral cavity and oropharyngeal squamous cell cancers. Our results demonstrate that HPV-positive oropharyngeal tumours displayed gene expression patterns indicative of a viral signature and that HPV-negative oropharyngeal tumours do not display similar expression patterns. In contrast, we saw no evidence of either a viral or bacterial signature in the oral tumours examined. This would suggest that either an as of yet unidentified virus present in the oral tumour samples is not eliciting a typical immune response, or that there are no novel viral sequences or viruses present in the oral tumours examined.

MicroRNA-130b regulates the tumour suppressor RUNX3 in gastric cancer - Corrected Proof

2010-02-22

Abstract: Aim: Accumulating evidence indicates that RUNX3 is an important tumour suppressor that is inactivated in many cancer types. This study aimed to assess the role of microRNA (miRNA) in the regulation of RUNX3.Methods: Four bioinformatic algorithms were used to predict miRNA binding to RUNX3. The correlation between candidate miRNAs and RUNX3 expression in cell lines was determined by real-time reverse transcriptase quantitative PCR (RT-qPCR) and Western blot. Candidate miRNAs were tested for functional effects through transfection of miRNA precursors and inhibitors, and monitoring cell viability, apoptosis and Bim expression. miRNA and RUNX3 expression, RUNX3 methylation and RUNX3 protein levels were assessed in gastric tissue by RT-qPCR, Methylight analysis and immunohistochemistry, respectively.Results: Bioinformatics, gene and protein expression analysis in eight gastric cell lines identified miR-130b as the top candidate miRNA for RUNX3 binding. Overexpression of miR-130b increased cell viability, reduced cell death and decreased expression of Bim in TGF-β mediated apoptosis, subsequent to the downregulation of RUNX3 protein expression. In 15 gastric tumours, miR-130b expression was significantly higher compared to matched normal tissue, and was inversely associated with RUNX3 hypermethylation.Conclusion: Attenuation of RUNX3 protein levels by miRNA may reduce the growth suppressive potential of RUNX3 and contribute to tumourigenesis.

Multikinase inhibitors in thyroid cancer - Corrected Proof

Lisa Licitra, Laura D. Locati, Angela Greco, Roberta Granata, P. Bossi — 2010-02-19

Abstract: Biological agents are rapidly developing for the treatment of metastatic RAI resistant thyroid cancer. The most promising results were shown by agents that target BRAF and VEGFR rather than RET. BRAF V600E mutation seems to be positively associated with tumour response by using BRAF targeting agents.With these agents impressive clinical responses and prolonged disease stabilisation were observed. This activity compares favourably with that of chemotherapy with less prominent toxicity, although typically associated drug side-effects should be promptly recognised and managed. To date no drug has proved to prolong survival, as such none of these agents has been approved.

Comparison of self-reported late effects with medical records among survivors of childhood cancer - Corrected Proof

2010-02-19

Abstract: Background: Survival rates following childhood cancer have increased, but survivors experience significant late effects. Long-term follow-up is recommended but imposes an increasing burden on health services. We report prevalence of morbidity in a cohort of survivors from South Yorkshire based on: (i) case-note analysis and (ii) self-reported late effects (parent-reported for under-16s).Methods: Treatment information was taken from case-notes. Comparisons were made between late effects described in notes and reported by 108 survivors aged >16 years, and 45 parents of survivors (12–15 years).Findings: Of 892 patients diagnosed with childhood cancer and some benign conditions registered on hospital databases from January 1990 to December 2005, 337 (37.8%) met eligibility criteria. Ninety-one survivors (⩾16) (84.3%, confidence interval [CI]: 76.0–90.6) reported one or more late effects (mean=3.5; CI: 3.0–4.1), significantly higher than the number of late effects documented in medical notes (mean=0.7; CI: 0.5–0.9; t=−11.26, p<0.001). Thirty-five parents (77.8%, CI: 65.1–90.4) reported late effects for their children (mean=2.7; CI: 2.0–3.4), again higher than medical notes (mean=0.7; CI: 0.4–1.1; t=7.18, p<0.001). More than 30 specialties were involved in survivor care (mean=1.5; CI: 1.4–1.6; range 0–6). Those with more late effects saw more specialties (r=0.51, p<0.001).Interpretation: We confirm the wide range of late effects experienced by survivors of child cancer, significantly greater than those recorded in medical notes, and requiring care from a range of specialties. Decisions about follow-up need to take account of patient-reported morbidity and concerns.

What reasons lie behind long-term survival differences for gastric cancer within Europe? - Corrected Proof

2010-02-17

Abstract: Background: Wide geographic variations in survival for gastric cancer in Europe have been reported. The aim of this study was to analyse the effect of stage at diagnosis, treatment and cancer characteristics on long-term survival for gastric cancer in populations covered by cancer registries.Methods: We analysed survival in 4620 cases of gastric cancer from 17 European population-based cancer registries from 8 countries. Univariate and multivariate regression of relative survival were performed.Results: Five-year relative survival varied between 10.6% and 24.0%, while 10-year survival ranged from 7.7% to 23.0%. After adjustment for age and sex, the regional excess hazard ratio (EHR) of death was significantly higher in Ragusa, Granada, Yorkshire, Slovakia, Slovenia and Poland than in France, Northern Italy, The Netherlands and the Basque Country. After further adjustment for surgical resection versus no resection (a proxy of stage), the EHR of death remained significantly higher only in Granada and Yorkshire than in the reference country (France). After adjustment for stage, the EHR was significantly higher only in Yorkshire (EHR: 1.51; 95% confidence interval (CI): 1.29–1.77). The EHR in this area was limited to the first year following diagnosis.Conclusion: Differences across Europe in gastric cancer survival depend to a large extent on differences in stage at diagnosis. However they do not explain all variations. Quality of management and treatment can explain some differences.

Treating triple-negative breast cancer by a combination of rapamycin and cyclophosphamide: An in vivo bioluminescence imaging study - Corrected Proof

2010-02-16

Abstract: Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to inhibit the growth of oestrogen positive breast cancer. However, triple-negative (TN) breast cancer is resistant to rapamycin treatment in vitro. We set to test a combination treatment of rapamycin with DNA-damage agent, cyclophosphamide, in a TN breast cancer model. By binding to and disrupting cellular DNA, cyclophosphamide kills cells via interfering with their normal functions. We assessed the responses of nude mice bearing tumour xenografts of TN MDA-MB-231 cells to the combination of rapamycin and cyclophosphamide in both orthotopic mammary and lung-metastasis models. We tracked tumour growth and metastasis by bioluminescent imaging and examined the expression of Ki67, CD34 and HIF-1α in tumour tissues by immunohistochemistry and apoptosis index with TUNEL assay, and found that MDA-MB-231 cells are sensitive to rapamycin therapy in orthotopic mammary, but not in lung with metastasis. Rapamycin when combined with cyclophosphamide is found to have a more significant effect in reducing tumour volume and metastasis with a much improved survival rate. Our data also show that the sensitivity of TN tumours to rapamycin is associated with the microenvironment of the tumour cells. The data indicate that in a relatively hypoxic environment HIF-1α may play a role in mediating the anti-cancer effect of rapamycin and cyclophosphamide may prevent the feedback activation of Akt by rapamycin. Overall our results show that rapamycin plus cyclophosphamide can achieve an improved efficacy in suppressing tumour growth and metastasis, suggesting that the combination therapy can be a promising treatment option for TN cancer.

MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function - Corrected Proof

2010-02-16

Abstract: Small molecule inhibitors (SMIs) of murine double minute 2 (MDM2) are known to restore the apoptotic and cell cycle regulatory functions of p53 by disrupting the MDM2–p53 interaction. In principle, these SMIs are not effective against tumours with mutation in the tumour suppressor p53 (mut-p53), which is known to be present in approximately 50% of all cancers. In this study we are reporting, for the first time, that MI-319 in combination with cisplatin induced cell growth inhibition and apoptosis in pancreatic cancer (PC) cells irrespective of their p53 mutational status. MI-319–cisplatin combination synergistically suppressed cell growth (MTT Combination Index [CI]<1) and colony formation (clonogenic assay) and induced apoptosis. Western blot analysis and siRNA silencing studies in mutant as well as p53 null cells highlighted a mechanism involving p73 which is also known to be under the regulation of MDM2, and unlike p53, it is rarely mutated in PC. Down-regulating MDM2 using siRNA enhanced p73 reactivation and increased cell death. Further, the combination effectively reduced tumour growth in both wt-p53 and mut-p53 tumour xenograft models (50% Capan-2 animals were tumour free). Consistent with our in vitro results, remnant tumour tissue analysis showed up-regulation of p73 and the cell cycle regulator p21. In conclusion, this study highlights a new role of MDM2 inhibitors in combination with cisplatin, and thus warrants further clinical investigation in human pancreatic tumours containing both wt-p53 and mut-p53.

Frameless single-session robotic radiosurgery of liver metastases in colorectal cancer patients - Corrected Proof

S. Stintzing, R.T. Hoffmann, V. Heinemann, M. Kufeld, A. Muacevic — 2010-02-15

Abstract: Introduction: Due to advanced chemotherapy regimens, patients presenting with residual liver metastases of colorectal cancer (CRC) has increased. Surgery of residual metastases enhances overall survival, but surgical resection is often limited. Less invasive techniques have been invented to enhance local disease control. We investigated in a selected patient cohort local control of liver metastasis from CRC using robotic radiosurgery.Methods and materials: In this study patients with colorectal liver metastases were prospectively followed after having been treated with single-session radiosurgery using a robotic image-guided device and real-time tumour tracking. The primary end-point was local control (LC); secondary end-points were toxicity, progression-free survival (PFS) and overall survival (OS). Extrahepatic metastases were excluded using a whole body (PET-CT: positron emission tomography computed tomography). Follow up was done by liver MRI every 3 months post-treatment.Results: Fourteen patients (median age 65years), with a total of 19 colorectal liver metastases were treated with 24Gy in one fraction. Median follow up was 16.8months. A one-year LC rate of 87% and a median PFS of 9.2months were reached.Discussion: Frameless robotic image-guided radiosurgery with real-time tumour tracking as an effective treatment for patients with colorectal liver metastases. This technique enhances the possibilities of multidisciplinary oncological concepts.

Common variants in human CRC genes as low-risk alleles - Corrected Proof

2010-02-10

Abstract: The genetic susceptibility to colorectal cancer (CRC) has been estimated to be around 35% and yet high-penetrance germline mutations found so far explain less than 5% of all cases. Much of the remaining variations could be due to the co-inheritance of multiple low penetrant variants. The identification of all the susceptibility alleles could have public health relevance in the near future. To test the hypothesis that what are considered polymorphisms in human CRC genes could constitute low-risk alleles, we selected eight common SNPs for a pilot association study in 1785 cases and 1722 controls. One SNP, rs3219489:G>C (MUTYH Q324H) seemed to confer an increased risk of rectal cancer in homozygous status (OR=1.52; CI=1.06–2.17). When the analysis was restricted to our ‘super-controls’, healthy individuals with no family history for cancer, also rs1799977:A>G (MLH1 I219V) was associated with an increased risk in both colon and rectum patients with an odds ratio of 1.28 (CI=1.02–1.60) and 1.34 (CI=1.05–1.72), respectively (under the dominant model); while 2 SNPs, rs1800932:A>G (MSH6 P92P) and rs459552:T>A (APC D1822V) seemed to confer a protective effect. The latter, in particular showed an odds ratio of 0.76 (CI=0.60–0.97) among colon patients and 0.73 (CI=0.56–0.95) among rectal patients. In conclusion, our study suggests that common variants in human CRC genes could constitute low-risk alleles.

Prognostic significance and clinical relevance of the expression of the HER family of type I receptor tyrosine kinases in human laryngeal squamous cell carcinoma - Corrected Proof

2010-02-10

Abstract: Introduction: The full clinical relevance of the expression pattern of HER family of type I receptor tyrosine kinases in laryngeal squamous cell carcinoma remains to be elucidated. We evaluated the clinical relevance of such parameter in our population.Patients and methods: This study examined the expression pattern of HER family receptor members by quantitative immunohistochemistry and the amount of the EGF binding sites by a radioligand binding assay, in the same group of 67 LSCC patients, analysing the correlation between the expression of the four HER receptors and the clinical and prognostic parameters.Results: HER1 levels inversely correlated with that of HER2–4, while HER2–4 directly correlated among them. Cox univariate analysis using HER1–4 values as continuous covariates indicated that HER1 expression was directly associated with the risk of death and relapse while that of HER2–4 was inversely associated with the risk of death. Among the patients with high HER1 expressing tumours, those with tumours co-expressing HER2–4 showed a lower risk of death and relapse (in particular regional relapse) than those with tumours displaying a negative HER2–4 status.Conclusions: The evaluation of HER2–4 status adds more power to the prognostic role of HER1 detection. In the era of molecularly targeted therapy, the expression of HER family of receptor tyrosine kinases in LSCC may hold relevant clinical significance and turn out to be a key factor in prognostic assessment and in treatment planning.

Adjuvant chemotherapy for early colon cancer: What survival benefits make it worthwhile? - Corrected Proof

2010-02-08

Abstract: Background: We sought to determine the minimum survival benefits that patients judged sufficient to make adjuvant chemotherapy for early colon cancer worthwhile, factors associated with these judgments; and, to compare a self-administered questionnaire with a validated, scripted interview.Patients and methods: One twenty three subjects who completed adjuvant chemotherapy for early colon cancer 3–60months earlier completed a questionnaire; 97 were randomised to complete an interview before or after the questionnaire. Preferences were elicited by the time trade-off method in 4 hypothetical scenarios. Concordance between the interview and questionnaire was assessed with the intraclass correlation coefficient (ICC).Results: Median age was 65years (range 19–86), 52% were female and 74% had involved lymph nodes. Over 60% of patients judged an additional 1month beyond life expectancies of 5years or 15years, and an additional 1–2% beyond 5-year survival rates of 85% or 65%, sufficient to make chemotherapy worthwhile. Subjects with tertiary education (p=0.003) or aged 75years or less (p=0.02) judged larger benefits necessary to make chemotherapy worthwhile. Concordance between the interview and questionnaire was high (ICCs 0.71–0.82).Conclusions: Most subjects judged small survival benefits sufficient to make adjuvant chemotherapy worthwhile. A self-administered questionnaire was a valid and acceptable way of eliciting preferences.

Questionnaires and instruments for a multidimensional assessment of the older cancer patient: What clinicians need to know? - Corrected Proof

A.G. Pallis, U. Wedding, D. Lacombe, P. Soubeyran, H. Wildiers — 2010-02-08

Abstract: Due to the ageing of the population in the Western world, a significant increase in the number of older patients diagnosed with neoplastic diseases is observed. Hence, there is an emerging need for tools to efficiently evaluate older patients’ functional and global status. These tools can allow treating oncologists to better select patients, to propose treatment modifications, implement supportive measures and develop interventions to decrease the risk of toxicity and in general better tailor the treatment plan on an individual level. Currently significant uncertainty exists about the optimal tools and strategy for geriatric assessment, but on the other hand there is more than enough evidence that (some form of) geriatric assessment detects many previously unrecognised problems, and allows directed intervention which can improve outcome and compliance of proposed treatments. In the present paper, we discuss the most commonly used and studied tools for the assessment of functional status of older cancer patients.

Does delaying adjuvant chemotherapy after curative surgery for colorectal cancer impair survival? A meta-analysis - Corrected Proof

2010-02-08

Abstract: Background: In stage III colorectal cancer (CRC), adjuvant chemotherapy (CT) is usually prescribed within two months after curative surgery. Whether or not delaying initiation of CT affects survival is still debated.Material and methods: We performed a meta-analysis (MA) of all published studies (full papers or abstracts) comparing delayed CT with standard care. Studies were obtained from a PubMed query (keywords: CRC, adjuvant treatment, delay of CT), a review (Chau et al., 2006), cross-checking references and abstracts from the proceedings of ASCO, ASCO GI and WCGI annual meetings. We chose a cutoff delay of 8 weeks. Risk Ratios (RRs) were calculated from the recorded events (deaths, relapses). We used EasyMA software (fixed-effect model).Results: Fourteen studies (including four abstracts) were identified (17,645 patients; 5952 males, 5151 females, mean age 70 years). Of these, three could not be statistically analysed and three used another cutoff (4, 5 or 6 weeks), leaving 8 studies for main MA (13,158 patients; 3932 males, 3644 females, 5942 missing data; 5576 colon cancers, 6677 rectal, 1265 missing data). Delaying CT more than 8 weeks was associated to worse Overall Survival (OS) (RR: 1.20; 95% Confidence Interval (CI) 1.15–1.26). In the MA including all studies whatever their cutoff, longer delay was similarly associated to a worse OS but not a worse Relapse-Free Survival (RFS) (five studies).Conclusion: Adjuvant chemotherapy should be started within 8 weeks after surgery. Delaying the initiation of adjuvant CT for more than 8 weeks after surgery significantly decreased OS but not RFS. This discrepancy might be due to factors not directly related to cancer (post-operative complications, social status) or to a more accurate appraisal of death.

Inhibition profiles of phosphatidylinositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39 - Corrected Proof

Dexin Kong, Shingo Dan, Kanami Yamazaki, Takao Yamori — 2010-02-03

Abstract: As accumulating evidences suggest close involvement of phosphatidylinositol 3-kinase (PI3K) in various diseases particularly cancer, considerable competition occurs in development of PI3K inhibitors. Consequently, novel PI3K inhibitors such as ZSTK474, GDC-0941 and NVP-BEZ235 have been developed. Even though all these inhibitors were reported to inhibit class I PI3K but not dozens of protein kinases, whether they have different molecular targets remained unknown. To investigate such molecular target specificity, we have determined the inhibitory effects of these novel inhibitors together with classical PI3K inhibitor LY294002 on PI3K superfamily (including classes I, II, and III PI3Ks, PI4K and PI3K-related kinases) by using several novel non-radioactive biochemical assays. As a result, ZSTK474 and GDC-0941 indicated highly similar inhibition profiles for PI3K superfamily, with class I PI3K specificity much higher than NVP-BEZ235 and LY294002. We further investigated their growth inhibition effects on JFCR39, a human cancer cell line panel which we established for molecular target identification, and analysed their cell growth inhibition profiles (fingerprints) by using COMPARE analysis programme. Interestingly, we found ZSTK474 exhibited a highly similar fingerprint with GDC-0941 (r=0.863), more similar than with that of either NVP-BEZ235 or LY294002, suggesting that ZSTK474 shares more in molecular targets with GDC-0941 than with either of the other two PI3K inhibitors, consistent with the biochemical assay result. The biological implication of the difference in molecular target specificity of these PI3K inhibitors is under investigation.

Dietary carotenoids and risk of hormone receptor-defined breast cancer in a prospective cohort of Swedish women - Corrected Proof

Susanna C. Larsson, Leif Bergkvist, Alicja Wolk — 2010-01-29

Abstract: Carotenoids have antioxidant and antiproliferative properties and may reduce the risk of breast cancer. We examined the association between dietary carotenoids and risk of invasive breast cancer in the Swedish Mammography Cohort, a population-based cohort of 36,664 women who completed a questionnaire in 1997. During a mean follow-up of 9.4years, 1008 women were diagnosed with incident breast cancer. Dietary carotenoids were not significantly associated with the risk of breast cancer overall or with any subtype defined by oestrogen receptor (ER) and progesterone receptor (PR) status. However, dietary α-carotene and β-carotene were inversely associated with the risk of ER–PR-breast cancer among ever smokers. Among ever smokers, the multivariable relative risks of ER–PR-breast cancer comparing the highest with the lowest quintile of intake were 0.32 (95% confidence interval (CI): 0.11–0.94; Ptrend=0.01) for α-carotene and 0.35 (95% CI: 0.12–0.99; Ptrend=0.03) for β-carotene. The risk of breast cancer also decreased with increasing intakes of α-carotene (Ptrend = 0.02) and β-carotene (Ptrend=0.01) among women who did not use dietary supplements. These findings suggest that dietary α-carotene and β-carotene are inversely associated with the risk of breast cancer among smokers and among women who do not use dietary supplements.

WITHDRAWN: Enhancement of docetaxel efficacy in head and neck cancer treatment by G0 cell stimulation - Corrected Proof

2008-08-11

This article has been withdrawn consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause.

WITHDRAWN: Papillary thyroid carcinoma: Monoinstitutional 40-year experience on 2500 patients - Corrected Proof

Domenico Rubello, Maria Rosa Pelizzo — 2008-08-11

This article has been withdrawn consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause.