European Journal of Cancer - Articles in Press

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.

Predictive biomarkers for personalised anti-cancer drug use: Discovery to clinical implementation - Corrected Proof

Nayef A. Alymani, Murray D. Smith, David J. Williams, Russell D. Petty — 2010-02-08

Abstract: A priority translational research objective in cancer medicine is the discovery of novel therapeutic targets for solid tumours. Ideally, co-discovery of predictive biomarkers occurs in parallel to facilitate clinical development of agents and ultimately personalise clinical use. However, the identification of clinically useful predictive biomarkers for solid tumours has proven challenging with many initially promising biomarkers failing to translate into clinically useful applications. In particular, the ‘failure’ of a predictive biomarker has often only become apparent at a relatively late stage in investigation. Recently, the field has recognised the need to develop a robust clinical biomarker development methodology to facilitate the process. This review discusses the recent progress in this area focusing on the key stages in the biomarker development process: discovery, validation, qualification and implementation. Concentrating on predictive biomarkers for selecting systemic therapies for individual patients in the clinic, the advances and progress in each of these stages in biomarker development are outlined and the key remaining challenges are discussed. Specific examples are discussed to illustrate the challenges identified and how they have been addressed. Overall, we find that significant progress has been made towards a formalised biomarker developmental process. This holds considerable promise for facilitating the translation of predictive biomarkers from discovery to clinical implementation. Further enhancements could eventually be found through alignment with regulatory processes.

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.

Future treatment of soft tissue sarcomas will be driven by histological subtype and molecular abberations - Corrected Proof

Jaap Verweij, Laurence H. Baker — 2010-02-08

Abstract: Soft tissue sarcomas, although sharing a mesenchymal origin, are a heterogeneous group of diseases. Nevertheless they are studied and frequently treated as if they were all the same. Recent developments suggest that a different approach may be more adequate. Genetic profiling studies have indicated that some soft tissue sarcoma subtypes, despite a distinct histo-pathological difference, may be closely related. Molecular biology research in addition has identified several subtype-specific oncogenes and their protein products that could serve as treatment targets. Since many of the new molecularly targeted agents do not induce tumour regression, but mainly result in growth inhibition, it is therefore necessary also to change the study end-point in screening studies in the search for active treatments. In view of all these it is proposed to consider using alternative end-points such as progression-free rates at pre-set times, or progression arrest at first evaluation. By using databases from large cooperative groups it should be possible to identify progression arrest rates for each specific subtype, and these could serve as reference for future trial design. Soft tissue sarcoma treatment and research will require a change of approach and necessitate global cooperation.

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.

Estimates of cancer incidence and mortality in Europe in 2008 - Corrected Proof

J. Ferlay, D.M. Parkin, E. Steliarova-Foucher — 2010-02-01

Abstract: Up-to-date statistics on cancer occurrence and outcome are essential for the planning and evaluation of programmes for cancer control. Since the relevant information for 2008 is not generally available as yet, we used statistical models to estimate incidence and mortality data for 25 cancers in 40 European countries (grouped and individually) in 2008. The calculations are based on published data. If not collected, national rates were estimated from national mortality data and incidence and mortality data provided by local cancer registries of the same or neighbouring country. The estimated 2008 rates were applied to the corresponding country population estimates for 2008 to obtain an estimate of the numbers of cancer cases and deaths in Europe in 2008.There were an estimated 3.2 million new cases of cancer and 1.7 million deaths from cancer in 2008. The most common cancers were colorectal cancers (436,000 cases, 13.6% of the total), breast cancer (421,000, 13.1%), lung cancer (391,000, 12.2%) and prostate cancer (382,000, 11.9%). The most common causes of death from cancer were lung cancer (342,000 deaths, 19.9% of the total), colorectal cancer (212,000 deaths, 12.3%), breast cancer (129,000, 7.5%) and stomach cancer (117,000, 6.8%).

Hypertension in long-term survivors of childhood cancer: A nested case-control study - Corrected Proof

2010-02-01

Abstract: Aim of the study: To examine risk factors for developing hypertension in childhood cancer survivors (CCS).Methods: We conducted a nested case-control study of risk for hypertension within a cohort of 1362 childhood cancer survivors treated between 1966 and 1996 in the Emma’s Children’s Hospital/Academic Medical Center in the Netherlands. Detailed information on treatment and several lifestyle factors was collected for 44 cases with hypertension and 123 matched controls. Odds ratios (ORs) for hypertension were calculated by conditional logistic regression analysis.Results: Body Mass Index (BMI) was the only significant risk factor associated with the occurrence of hypertension (OR 3.95; 95% confidence interval (CI) 1.7–9.1 for BMI⩾25kg/m2 compared to BMI<25kg/m2). However, cisplatin, cyclophosphamide and radiotherapy (RT) to the abdominal region were all associated with non-significant risk increases (ORs of 4.3, 2.1, and 1.8, respectively).Conclusion: Our results show that BMI is the most important risk factor for hypertension following treatment of childhood cancer, emphasising the need for CCS to maintain a normal weight.

Reduced risk of oestrogen receptor positive breast cancer among peri- and post-menopausal women in Scotland following a striking decrease in use of hormone replacement therapy - Corrected Proof

2010-02-01

Abstract: Many countries report a decline in breast cancer incidence among peri- and post-menopausal women following a decline in HRT prescribing. To investigate recent Scottish incidence trends, European age-standardised incidence rates from 1997 to 2005 were stratified by method of first detection, ER status and age group. We developed change point models of the annual age-specific cases for the peri- and post-menopausal age groups and ER status using Poisson regression.In Scotland all HRT categories together show a 32.4% increase in the number of items dispensed in 1993–2000 followed by a striking 61.8% decline by 2007.The incidence rates of screen-detected tumours increased gradually in the 50–64 and 65–74 age groups. For the older age group this increase accelerated after 2003 corresponding to an extension of the age range of screening.For ER positive tumours in the 50–64 age group, age-standardised rates increased 31.5% from 1997 to 2000, followed by a statistically significant decrease of 11.2% by 2005 (change in slope=−0.0943, P<0.0001). We conclude that an overall incidence in the 50–64 age group declined since 2000 reflecting the sudden fall in HRT dispensed items and is largely accounted for by the decrease in ER positive tumour incidence. A longer term decline in ER negative tumours for this age group was pre-existing and is unaffected by the collapse in HRT prescribing.

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.

Y-box binding protein-1 (YB-1) promotes cell cycle progression through CDC6-dependent pathway in human cancer cells - Corrected Proof

2010-01-15

Abstract: Y-box binding protein-1 (YB-1) plays pivotal roles in acquisition of global drug resistance and cell growth promotion through transcriptional activation of genes for both drug resistance and growth factor receptors. In this study, we investigated whether YB-1 is involved in regulation of the cell cycle and cell proliferation of human cancer cells. Treatment with YB-1 siRNA caused a marked suppression of cell proliferation and expression of a cell cycle related gene, CDC6 by cancer cells. Of cell cycle of cancer cells, S phase content was specifically reduced by knockdown of YB-1. The overexpression of CDC6 abrogated this inhibition of both cell proliferation and S phase entry. ChIP assay demonstrated that YB-1 binds to a Y-box located in the promoter region of the CDC6 gene. Expression of cyclin D1, CDK1 and CDK2 was also reduced with increased expression of p21Cip1 and p16INK4A when treated with YB-1 siRNA. Furthermore, the nuclear YB-1 expression was significantly associated with the level of CDC6 nuclear expression in patients with breast cancer. In conclusion, YB-1 plays an important role in cell cycle progression at G1/S of human cancer cells. YB-1 thus could be a potent biomarker for tumour growth and cell cycle in its close association with CDC6.

First-time-in-man and pharmacokinetic study of weekly oral perifosine in patients with solid tumours - Corrected Proof

2010-01-15

Abstract: Aim: To identify the maximum-tolerated dose (MTD) and pharmacokinetics of oral perifosine.Methods: Patients with solid tumours received perifosine at dosages ranging from 100–800mg/week. Eligibility criteria included life expectancy>12weeks, WHO performance status⩽2, normal blood, liver and renal functions and no recent anticancer treatment. Drug concentrations were analysed by HPLC–MS/MS.Results: Thirty six patients were recruited (75% males, mean age 54.7years, performance status 1 in 72.2%). Adverse events included nausea (69.4%), diarrhoea (55.6%), vomiting (52.8%) and abdominal pain (13.9%). Antiemetic regimens including glucocorticoids, dopamine antagonists and 5-HT3-antagonists were used as treatment and/or prophylaxis in 50% of the patients. Though MTD was formally not reached with 800mg/week, the treatment discontinuation due to diarrhoea and vomiting likely related to perifosine in two cases led to the decision to stop further dose escalation. Pharmacokinetics after a single dose were median tmax=8.0–24.2h, median t1/2=81.0–115.9h and meangeo CL/f=0.28–0.43mL/min/kg. Urinary excretion was below 1%. Perifosine slightly accumulated and steady state was nearly reached after 2–3weeks.Conclusion: Oral perifosine was tolerable up to 600mg/week in cancer patients when administered with meal and prophylactic antiemetics. Based on its half-life of about 4days, a weekly regimen may be appropriate.

Understanding the problem of inadequately staging early ovarian cancer - Corrected Proof

P.J. Timmers, A.H. Zwinderman, C. Coens, I. Vergote, J.B. Trimbos — 2010-01-14

Abstract: Background: Early ovarian cancer patients are often incompletely staged during initial surgery. This omission can have serious adverse consequences for the prognosis of patients as the completeness of surgical staging has been identified as an independent prognostic parameter for survival. The reasons for the problem of inadequate staging of early ovarian cancer are largely unknown. We have analysed the data of a large randomised trial in early ovarian cancer in which detailed information of the surgical staging procedure was monitored.Methods: Data of the EORTC Adjuvant ChemoTherapy In Ovarian Neoplasm (ACTION) Trial were used in which 448 early ovarian cancer patients were randomised between postoperative chemotherapy in one arm and observation following surgery in the other. In this trial strict criteria for surgical staging were advised but optimal, complete staging was performed in only 1/3 of patients. Staging characteristics of the incompletely staged patients were analysed and factors that could explain the failure to perform a complete staging were studied.Results: Sampling of para-aortic nodes was omitted in 78% of the incompletely staged patients, while 52% of these patients had no pelvic lymph node dissection. Taking blind biopsies from different peritoneal sites was not performed in more than 1/3 of the incompletely staged group. Omission of the staging steps ranged from 3% (infracolic omentectomy) to 55% (biopsy of the right hemi-diaphragm). A significant difference (p=0.04) between the fraction of completely staged patients was found when comparing institutes who entered less than 5 patients (21%) versus those who included more than 20 patients (37%) in the trial.Conclusions: Even in a randomised trial in which comprehensive surgical staging was strongly advised in the study protocol the majority of patients (66%) were incompletely staged. Factors relating to a lack of surgical skills attributed most to the number of incompletely staged patients, but insufficient knowledge of the tumour behaviour and routes of spread of ovarian cancer also contributed substantially to this problem. Multicentre trials recruiting patients from many institutes with small volume contribution to the study, run the risk of inadequate adherence to the study protocol.

WWOX tumour suppressor gene polymorphisms and ovarian cancer pathology and prognosis - Corrected Proof

2010-01-14

Abstract: WWOX is a bona fide tumour suppressor, with hypomorphic and knockout mouse models exhibiting increased tumour susceptibility. In ovarian cancer cells WWOX transfection abolishes tumourigenicity, suppresses tumour cell adhesion to extracellular matrix and induces apoptosis in non-adherent cells. One-third of ovarian tumours show loss of WWOX expression, and this loss significantly associates with clear cell and mucinous histology, advanced stage, low progesterone receptor expression and poor survival, suggesting that WWOX status affects ovarian cancer progression and prognosis. Genetic variation in other tumour suppressors (e.g. p53 and XPD) is reported to modify cancer progression/outcome, and single nucleotide polymorphisms (SNPs) within the WWOX gene are reported to associate with prostate cancer risk. We previously identified polymorphic variants within WWOX, some of which have potential to affect its expression. We therefore examined a cancer modifier role for these WWOX variants. Eight SNPs, based upon location, frequency and potential to affect WWOX expression, were genotyped in 554 ovarian cancer patients (CGP samples), and associations with pathological and survival data were examined. The CGP samples demonstrated significant associations after Bonferroni correction between Isnp1 and both tumour grade (pcorr=0.033) and histology (pcorr=0.046), Isnp8 and tumour grade (pcorr=0.032) and T1497G and progression-free survival (pcorr=0.037). None of these positive associations were confirmed in an independent ovarian cancer population (Scotroc1 samples, n=863). While these results may suggest that the associations are false positives, differences between the two populations cannot be excluded, and thus highlight the challenges in validation studies.

Red wine polyphenols cause growth inhibition and apoptosis in acute lymphoblastic leukaemia cells by inducing a redox-sensitive up-regulation of p73 and down-regulation of UHRF1 - Corrected Proof

2010-01-14

Abstract: Several epidemiological studies suggest that a diet rich in fruits and vegetables, which contain high levels of polyphenols, is associated with a reduced risk of cancer. The aim of the present study was to determine whether a red wine polyphenolic extract (RWPs, a rich source of polyphenols; 2.9g/L) affects the proliferation of human lymphoblastic leukaemia cells (Jurkat cells) and, if so, to determine the underlying mechanism. Cell proliferation and viability were determined by the MTS and trypan blue exclusion assays, respectively. Cell cycle analysis, apoptosis activity and oxidative stress levels were assessed by flow cytometry, and the expression of p73, UHRF1 and active caspase-3 by Western blot analysis. RWPs inhibited the proliferation of Jurkat cells and induced G0/G1 cell cycle arrest in a concentration-dependent manner. Moreover, RWPs triggered apoptosis, which is associated with an increased expression level of the pro-apoptotic protein p73 and the active caspase-3. RWPs induced apoptosis confirmed by DNA fragmentation analysis, and this effect was associated with down-regulation of the antiapoptotic protein UHRF1. Furthermore RWPs significantly increased the formation of reactive oxygen species (ROS). Intracellular scavengers of superoxide anions (MnTMPyP, MnTBAP, PEG-SOD) prevented the RWPs-induced formation of ROS and apoptosis, while native extracellular superoxide dismutase (SOD) was without effect. In addition, the effect of RWPs on the expression levels of p73, active caspase-3 and UHRF1 was also prevented by MnTMPyP. Thus, these findings indicate that RWPs induce apoptosis in Jurkat cells by a redox-sensitive mechanism involving the intracellular formation of superoxide anions and consequently the up-regulation of p73 and down-regulation of UHRF1.

The multikinase inhibitor Sorafenib induces apoptosis and sensitises endometrial cancer cells to TRAIL by different mechanisms - Corrected Proof

2010-01-13

Abstract: Sorafenib induces apoptosis and enhances Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-induced cell killing of tumoural cells. We have investigated the effects of the multikinase inhibitor Sorafenib alone or in combination with TRAIL and agonistic Fas antibodies on endometrial carcinoma cells. We have also focused on the search of the differential molecular mechanisms by which Sorafenib induces cell death and the ones involved in sensitisation to TRAIL. In the present study, we show that Sorafenib induces apoptosis of both endometrial cancer cell lines and human primary cultures and sensitises these cells to TRAIL and agonistic Fas antibodies (aFas)-induced apoptosis. However, Raf/MEK/ERK inhibition by Sorafenib was not responsible for Sorafenib cell death or TRAIL sensitisation of endometrial cancer cells. Sorafenib treatment correlated with a downregulation of both FLICE-Inhibitory Protein (FLIP) and myeloid cell leukaemia-1 (Mcl-1), caused by a proteasomal degradation of both proteins. We evaluated the contribution of FLIP and Mcl-1 downregulation in apoptosis triggered by Sorafenib alone or Sorafenib plus TRAIL. Interestingly, cell death caused by Sorafenib was mediated by downregulation of Mcl-1, but not by FLIP. In contrast, we found that Sorafenib sensitisation of endometrial carcinoma cells to TRAIL- and Fas-induced apoptosis was dependent on FLIP but not on Mcl-1 downregulation. Altogether, we discern the dual mechanisms by which Sorafenib causes cell death from those involved in death receptor sensitisation.

17ß-Hydroxysteroid dehydrogenase type 1 as predictor of tamoxifen response in premenopausal breast cancer - Corrected Proof

2010-01-11

Abstract: 17ß-Hydroxysteroid dehydrogenases (17HSDs) are involved in the local regulation of sex steroids. 17HSD1 converts oestrone (E1) to the more potent oestradiol (E2) and 17HSD2 catalyses the reverse reaction. The aim of this study was to investigate the expression of these enzymes in premenopausal breast cancers and to analyse if they have any prognostic or tamoxifen predictive value. Premenopausal patients with invasive breast cancer, stage II (UICC), were randomised to either 2years of adjuvant tamoxifen (n=276) or no tamoxifen (n=288). The median follow-up was 13.9years (range 10.5–17.5). The expression of 17HSD1 and 17HSD2 was analysed with immunohistochemistry using tissue microarrays. The enzyme expression level (–/+/++/+++) was successfully determined in 396 and 373 tumours, respectively. Women with hormone-receptor positive tumours, with low levels (–/+/++) of 17HSD1, had a 43% reduced risk of recurrence, when treated with tamoxifen (Hazard Ratio (HR)=0.57; 95% confidence interval (CI), 0.37–0.86; p=0.0086). On the other hand high expression (+++) of 17HSD1 was associated with no significant difference between the two treatment arms (HR=0.91; 95% CI, 0.43–1.95; p=0.82). The interaction between 17HSD1 and tamoxifen was significant during the first 5 years of follow-up (p=0.023). In the cohort of systemically untreated patients no prognostic importance was observed for 17HSD1. We found no predictive or prognostic value for 17HSD2. This is the first report of 17HSD1 in a cohort of premenopausal women with breast cancer randomised to tamoxifen. Our data suggest that 17HSD1 might be a predictive factor in this group of patients.

Hepatocellular carcinoma surveillance and appropriate treatment options improve survival for patients with liver cirrhosis - Corrected Proof

2010-01-11

Abstract: Objective/aim: Hepatocellular carcinoma (HCC) surveillance is a common practice for patients with liver cirrhosis. The aims of the study were to assess impacts of surveillance and therapeutic options on survival of patients with HCC.Methods: A total of 1436 cirrhotic patients with newly diagnosed HCC were enrolled between January 2002 and December 2004. Patients with HCC detected within periodic surveillance were the surveillance group (n=318, 22.1%). The other patients with HCC incidentally detected were the non-surveillance group (n=1118, 77.95%). Initial treatment options were recorded and overall survival was analysed.Results: Compared with patients in the non-surveillance group, larger proportions of patients in the surveillance group possessed small tumours, at an early stage without vascular invasion or metastases, and afforded more curative treatment options including surgical resection, radiofrequency ablation and percutaneous ethanol injection. The overall survival was better for patients in surveillance (3-year survival rate: 59.1% versus 29.3%, p<0.001), early stages by Barcelona Clinic Liver Cancer (BCLC) staging or curative treatment options. Multivariate analysis demonstrated surveillance, hepatitis aetiology, alpha-fetoprotein, tumour gross type, tumour stage and treatment options were associated factors for patients’ survival. Moreover, surveillance patients in curative BCLC stage following the treatment guideline for HCC proposed by the American association for the study of liver disease (AASLD) had a significantly better 3-year survival rate (77.1% versus 55.2%, p<0.001).Conclusions: HCC surveillance for cirrhotic patients could detect HCC at early and curative stages. However, appropriate treatment options following AASLD guideline further improve the survival for patients in early stage.

Trop-2 overexpression as an independent marker for poor overall survival in ovarian carcinoma patients - Corrected Proof

2010-01-11

Abstract: Background: Prognostic factors currently available are insufficient to predict the clinical course of epithelial ovarian cancer (EOC). In a previous microarray study we identified the human trophoblast cell surface antigen Trop-2 as one of the top differentially expressed genes in serous papillary EOCs compared to normal human ovarian surface epithelial (HOSE) short-term cultures. The aim of the present investigation was to analyse Trop-2 expression at mRNA and protein level and to assess its prognostic significance in EOC.Methods: Using quantitative real-time PCR we tested a total of 104 fresh-frozen EOC tissues and 24 HOSE for Trop-2 mRNA expression. Trop-2 protein expression was then examined by immunohistochemistry in matched formalin-fixed paraffin-embedded EOC samples and in 13 normal ovaries. Finally, we correlated Trop-2 expression to EOC conventional clinicopathological features and patient outcomes.Results: We found a significant Trop-2 mRNA and protein upregulation in EOCs compared to normal controls (p<0.001). Trop-2 protein overexpression was significantly associated with the presence of ascites (p=0.04) and lymph node metastases (p=0.04). By univariate survival analysis, Trop-2 protein overexpression was significantly associated with decreased progression-free (p=0.02) and overall survival (p=0.01). Importantly, Trop-2 protein overexpression was an independent prognostic marker for shortened survival time in multivariate Cox regression analysis (p=0.04, HR=2.35, CI95%=1.03–5.34).Conclusions: Our results indicate, for the first time, that Trop-2 protein overexpression correlates with an aggressive malignant phenotype and may constitute a novel prognostic factor for EOC. The targeting of Trop-2 overexpression by immunotherapeutic strategies may represent an attractive and potentially effective approach in patients harbouring EOC.

Understanding the impact of public policy on cancer research: A bibliometric approach - Corrected Proof

Grant Lewison, Arnie Purushotham, Malcolm Mason, Gordon McVie, Richard Sullivan — 2010-01-11

Abstract: With global spend on cancer research from the public sector now in excess of 14 billion euro, as well as the increasing burden of disease in market economies and low-middle income countries through changing demographics (ageing and population growth) cancer is now one of the most complex and global public policy issues. Using novel bibliometrics we have sought to investigate changes in research activity (total output), relative commitment and collaborations between countries/regions with similar healthcare and population and development parameters – United Kingdom, France, Germany, Canada and Sweden – to assess the utility of this policy research approach by analysing two different cohorts (1995–1999 and 2000–2004) to study the impact of changes on research publications as a surrogate for overall research activity.

Low expression of CysLT1R and high expression of CysLT2R mediate good prognosis in colorectal cancer - Corrected Proof

2010-01-11

Abstract: Colorectal cancer is the third most common cancer type in the Western world. In search of new treatment possibilities, the inflammation mediators, know as cysteinyl leukotrienes (CysLTs), have been shown to regulate intestinal epithelial cell survival and proliferation via the CysLT1R, and cell differentiation via the CysLT2R. These results prompted us to investigate the significance of CysLT1R and CysLT2R expression in colorectal cancer tissue for patient survival. The CysLT1R, CysLT2R, β-catenin and Bcl-xL protein expression levels were evaluated by immunohistochemistry in a tissue microarray of 329 colorectal patients. We found that high nuclear expression of CysLT1R is associated with a poor prognosis, whereas high nuclear expression of CysLT2R is associated with a good prognosis. We also observed that patients with colorectal tumours characterised by high CysLT1R but low CysLT2R nuclear expression had the lowest survival expectancy, whereas patients with colorectal tumours characterised by low CysLT1R but high CysLT2R nuclear expression had the best survival expectancy. Interestingly, β-catenin as a single prognostic marker did not exhibit any prognostic value. However, in patients with tumours characterised by a high CysLT1R nuclear expression, an elevated β-catenin nuclear expression had a significantly prognostic value.In conclusion these data indicate that nuclear expressions of CysLTRs are potential prognostic indicators of colorectal cancer.

Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours - Corrected Proof

2010-01-11

Abstract: Aim: Cediranib is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. Preclinical and clinical data suggest that inhibition of the VEGFR and epidermal growth factor receptor (EGFR) pathways may be synergistic. Combination treatment with cediranib and gefitinib, an EGFR signalling inhibitor, was evaluated in patients with advanced solid tumours.Patients and methods: Ninety patients received treatment in this four-part, open-label study (NCT00502060). The patients received once-daily oral doses of cediranib (20–45mg) and gefitinib 250mg (part A1; n=16) or 500mg (part B1; n=44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30mg with gefitinib 250mg (part A2; n=15) or 500mg (part B2; n=15). The primary objective was to assess the safety and tolerability of cediranib with gefitinib. Secondary assessments included pharmacokinetics, efficacy and pharmacodynamics.Results: Combination treatment was generally well tolerated; the protocol-defined maximum-tolerated dose of cediranib was 30mg/day with gefitinib 250mg/day (part A1) and cediranib 45mg/day was the maximum dose investigated with gefitinib 500mg/day (part B1). The most common adverse events were diarrhoea (84 [93%]), anorexia (63 [70%]) and fatigue (60 [67%]). Cediranib pharmacokinetic parameters were not substantially different when given alone or in combination with gefitinib. Gefitinib pharmacokinetic parameters were similar to those seen previously with gefitinib monotherapy. Efficacy results included eight (9%) confirmed partial responses (6 renal; 1 lung; 1 osteosarcoma) and 38 (42%) patients with stable disease. Pharmacodynamic assessments demonstrated changes in levels of VEGF and soluble VEGFR-2 following treatment.Conclusions: Combination treatment was generally well tolerated and showed encouraging antitumour activity in patients with advanced solid tumours. These results merit further exploration.

Recombinant kringle 5 from plasminogen antagonises hepatocyte growth factor-mediated signalling - Corrected Proof

2010-01-11

Abstract: The blood protein plasminogen is proteolytically cleaved to produce angiostatin and kringle 5 (K5), both of which are known angiogenesis inhibitors. A common structural element between K5, angiostatin and other endogenous angiogenesis inhibitors is the presence of the kringle protein-interacting domain. Another kringle domain-containing protein, hepatocyte growth factor (HGF), promotes angiogenesis by binding to and stimulating the tyrosine kinase receptor Met. HGF binding to Met is dependent on the kringle domains of HGF. Because both K5 and HGF contain kringle motifs and because these proteins have opposite effects on angiogenesis, we hypothesised that K5 can antagonise HGF-mediated signalling in a Met-dependent manner. We determined that K5 binding to H1299 cells is competed by HGF suggesting that these two proteins bind to the same protein. Purified K5 immunoprecipitates with Met and this interaction is abolished by increasing doses of HGF. Using proliferation, phosphorylation of Met and Akt as markers of HGF activity, we determined that K5 inhibits HGF-mediated signalling. Taken together, these data support a model by which K5 binds to Met and functions as a competitive antagonist of HGF signalling and presents a novel mechanism of action of K5.

VEGF-A promotes lymphoma tumour growth by activation of STAT proteins and inhibition of p27KIP1 via paracrine mechanisms - Corrected Proof

2010-01-11

Abstract: Increased levels of circulating VEGF-A have been demonstrated in patients with non-Hodgkin lymphoma (NHL) and are associated with progressive disease and poor clinical outcome. We investigated the role of VEGF-A in lymphoma tumour growth on a molecular level in order to identify the mechanism of VEGF-A-promoted tumour growth and to identify the potential targets for therapy. We used a model in which Daudi (human Burkitt lymphoma) tumour cells were transduced with VEGF-A165 or an empty vector (negative control) and subcutaneously injected in NOD/SCID mice. The weight of tumours overexpressing VEGF-A was increased 4-fold compared to that of control tumours (p<0.0001), whereas no in vitro growth advantage was demonstrated upon VEGF-A overexpression. VEGF-A-tumours were associated with increased microvessel densities (p=0.004) and increased tumour cell proliferation (Ki67; p<0.001) compared to control tumours. VEGF-A-tumours were characterised by upregulation of phosphorylated STAT-4 and STAT-6 and downregulation of phospho-p27KIP1, a crucial cell cycle inhibitor (p<0.05). This was accompanied by increased levels of phosphorylated receptor tyrosine kinases, including EGFR (ErbB-2 and ErbB-4, p<0.05), an upstream regulator of STAT proteins. We demonstrated that various mouse-derived cytokines produced by mouse-derived tumour stromal cells are upregulated in VEGF-A-tumours compared to control tumours (p<0.05). These results indicate an important role for the tumour microenvironment in paracrine promotion of lymphoma tumour growth in response to tumour-derived VEGF-A. In conclusion, lymphoma-derived VEGF-A promoted lymphoma tumour growth in a paracrine loop by activation of tumour stromal cells. Our study reveals VEGF-A and STAT proteins as potential additional targets in the treatment of lymphoma.

Plasma 25-hydroxyvitamin D and prostate cancer risk: The Multiethnic Cohort - Corrected Proof

2010-01-11

Abstract: The purpose of this study was to examine the relationship of plasma 25-hydroxyvitamin D (25(OH)D) concentrations to prostate cancer within a large multiethnic cohort in Hawaii and California using a nested case-control design. The study included 329 incidents of prostate cancer of African American, Native Hawaiian, Japanese, Latino and White ancestry, and 656 controls matched on age, race/ethnicity, date/time of blood collection and fasting status. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). No association with prostate cancer risk was found in an analysis based on quartiles of 25(OH)D. When clinically defined cutpoints were used, there was no increased risk for the lowest 25(OH)D concentration (OR for <20 versus 30–<50ng/ml=1.10, 95% CI=0.68–1.78), while there was a suggestive increased risk for higher concentrations (OR for ⩾50ng/ml=1.52, 95% CI=0.92–2.51). The findings from this prospective study of men in the Multiethnic Cohort do not support the hypothesis that vitamin D lowers the risk of prostate cancer. Further follow-up is warranted to determine whether the findings are consistent across ethnic groups.

Liver and gallbladder cancer in immigrants to Sweden - Corrected Proof

Kari Hemminki, Seyed Mohsen Mousavi, Andreas Brandt, Jianguang Ji, Jan Sundquist — 2010-01-11

Abstract: Background: The changes of cancer incidence upon immigration can be used as an estimator of environmental influence on cancer risk. We studied site-specific liver and biliary cancers in first-generation immigrants to Sweden with an aim to search for aetiological clues and to find evidence for indigenous incidence rates.Material and methods: We used the nation-wide Swedish Family-Cancer Database to calculate standardised incidence ratios (SIRs) in immigrants compared to native Swedes.Results: A total of 1428 cancers were identified in immigrants whose median ages (years) at immigration were 27 for men and 26 for women and whose median diagnostic ages were 64 and 66, respectively. The highest SIRs of 6.7 for primary liver cancer were observed for men from East Asia and sub-Saharan Africa. Increased SIRs were recorded for male immigrants from previous Yugoslavia (1.78), Southern Europe (2.91), Turkey (2.15) and Asian Arab countries (2.89). For gallbladder cancer, only women from the Indian subcontinent (3.84) and Chile (2.34) had increased risk while some Northern European immigrants showed decreased risks.Conclusions: Primary liver cancer was increased in immigrants from endemic regions of hepatitis B virus infection but also from large regions lacking cancer incidence data, North Africa, Asian Arab countries, Turkey and previous Yugoslavia; these are probably intermediary risk regions for this infection. The consideration of these regions as risk areas would justify active diagnostic and vaccination programs. The increase in gallbladder cancer in Chileans and Indians suggests that some persistent damage was inflicted before emigration, characterisation of which will be a challenge for aetiological studies.

A randomised phase II study of combination chemotherapy with epirubicin, cisplatin and capecitabine (ECX) or cisplatin and capecitabine (CX) in advanced gastric cancer - Corrected Proof

2010-01-08

Abstract: Background: Both cisplatin/capecitabine (CX) and epirubicin plus CX (ECX) have clearly demonstrated efficacy against advanced gastric cancer (AGC).Methods: Chemotherapy-naïve patients with histologically confirmed, measurable AGC were randomised to receive CX (cisplatin 75mg/m2 iv on day 1 and capecitabine 1000mg/m2 bid po on days 1–14) or ECX (epirubicin 50mg/m2 plus CX) every 3weeks. The primary endpoint was progression-free survival (PFS).Results: Of the 91 registered patients, 45 patients were treated with CX and 44 with ECX. A total of 241 CX (median, 6; range, 1–12) and 201 ECX (median, 5; range, 1–11) cycles were delivered. Treatment duration was similar for both arms (4.4 for CX versus 4.2months for ECX). There was no relevant difference in the occurrence of overall grade 3 or 4 toxicities between the CX and ECX arms (80% versus 78%, respectively; P=0.516). However, none in the CX and 12% in the ECX arm discontinued treatment because of toxicity. There were no significant differences in therapeutic efficacy between CX and ECX with respect to the response rate (38% versus 37%, respectively) and PFS (6.4 versus 6.5months).Conclusion: Both CX and ECX appear to be active as first-line chemotherapy for AGC, and the safety profiles are acceptable. Given the comparable efficacy results, CX could be a reasonable standard chemotherapy for untreated AGC patients.

Anthocyanin-rich red grape extract impedes adenoma development in the ApcMin mouse: Pharmacodynamic changes and anthocyanin levels in the murine biophase - Corrected Proof

2010-01-08

Abstract: Purpose: Red grape pomace extract (oenocyanin) is a cheap and rich source of anthocyanins, the agents suggested to possess cancer chemopreventive properties. Here the hypothesis was tested that oenocyanin added to the diet can interfere with intestinal adenoma development in the ApcMin mouse, a model of intestinal carcinogenesis linked to an Apc mutation.Methods: Mice received oenocyanin (0.3%) in their diet until week 16, when adenoma number and burden were recorded. Expression of Akt and ERK proteins was studied by Western blot in adenomas to discover effects of anthocyanins on cellular signalling via the PI3 and MAP kinase pathways. Levels of anthocyanins were measured by HPLC with visible spectroscopic or mass spectrometric detection.Results: In mice which had consumed oenocyanin, overall adenoma burden was halved and adenoma number was marginally reduced when compared with mice on control diet. The proliferation index in colonic adenomatous crypts, as reflected by Ki-67 staining, was significantly decreased from 88.14% in control mice to 75.6±4% in mice on oenocyanin (P=0.014). Expression of Akt in small intestinal adenomas from ApcMin mice on oenocyanin was reduced by 54% (P=0.003), when compared to controls. Oenocyanin anthocyanins and glucuronide metabolites were found in the urine and intestine but not in plasma.Conclusions: The results suggest that oenocyanin may be a viable and economical alternative to anthocyanin-rich berry extracts for chemopreventive intervention. Akt and pErk might be suitable biomarkers of anthocyanin target organ efficacy.

Expression and prognostic significance of the inhibitor of apoptosis protein (IAP) family and its antagonists in chronic lymphocytic leukaemia - Corrected Proof

Olga Grzybowska-Izydorczyk, Barbara Cebula, Tadeusz Robak, Piotr Smolewski — 2010-01-04

Abstract: Impaired apoptosis is still considered to be an important event in the development and progression of chronic lymphocytic leukaemia (CLL). However, mechanisms of this defect have not been fully elucidated. In this study, expression of inhibitor of apoptosis proteins, IAPs (cIAP1, cIAP2, XIAP and survivin), and their antagonists (Smac/DIABLO and HtrA2/Omi) was comprehensively analysed in 100 untreated CLL patients, using flow cytometry and Western blot techniques.Expression of anti-apoptotic cIAP1 and cIAP2 in leukaemic cells was significantly higher than in non-tumour lymphocytes (p=0.000001 and p=0.014, respectively), whereas the IAP-antagonist, Smac/DIABLO, was decreased in CLL (p=0.010). Higher expression of all analysed IAPs (cIAP1, p=0.002; cIAP2, p=0.026; XIAP, p=0.002; survivin, p=0.00006) and lower levels of Smac/DIABLO (p=0.006) were found in patients with progressive disease, compared to those with stable CLL. High baseline expression of cIAP1 and survivin correlated with worse response to treatment. Co-expression of these proteins was associated with shorter overall survival of CLL patients (p=0.005).In conclusion, CLL cells show the apoptosis-resistant profile of IAPs/IAP-antagonist expression. Upregulation of IAPs is associated with a progressive course of the disease. Co-expression of cIAP1 and survivin seems to be an unfavourable prognostic factor in CLL patients. Further studies with longer follow up are warranted to confirm and expand these findings.

Clinical assessment of patients with advanced non-small-cell lung cancer eligible for second-line chemotherapy: A prognostic score from individual data of nine randomised trials - Corrected Proof

2010-01-04

Abstract: Purpose: Knowledge of prognostic factors for advanced non-small-cell lung cancer (NSCLC) patients eligible for second-line treatment is scarce. The aim of this study was to assess the prognostic role of a number of routinely collected clinical variables and to provide a summary index to discriminate patients according to probability of survival.Methods: Individual data from nine randomised trials of second-line treatment in advanced NSCLC were analysed. Primary end-point was overall survival (OS). Cox model, stratified by trial, was used for multivariate analyses, and a prognostic index was provided and validated according to an internal/external procedure.Results: Out of 1239 patients, 1197 patients (97%) had complete information. Median OS was 7.4months. At multivariate analysis, prognosis was significantly influenced by gender (worse in males), performance status (PS), tumour histology (worse in squamous and other histology versus adenocarcinoma), stage (worse in IV versus IIIB), type of previous treatment (worse for patients pretreated with platinum) and response to first-line (worse for patients not obtaining objective response). Prognostic score values range from 0 to 14. When three categories were derived, median overall survival values were equal to 11.6, 7.5 and 3.0months for best (<5), intermediate (5-9) and worst (>9) categories, respectively.Conclusion: Prognosis of patients eligible for second-line treatment of advanced NSCLC is significantly conditioned by gender, PS, histology, stage, previous use of platinum and response to first-line. A prognostic score was derived that discriminates well subjects with a relatively more favourable prognosis and those with very short life expectancy.

The stromal part of adenocarcinomas of the oesophagus: Does it conceal targets for therapy? - Corrected Proof

2009-12-31

Abstract: Objective: To evaluate the prognostic value of the tumour stroma ratio (TSR) in resected adenocarcinoma of the oesophagus.Background: In the literature, a refinement of oesophageal cancer staging has been proposed. Recently, TSR has been identified as a histological characteristic of the tumour itself that proved to be a strong predictor for survival in colorectal cancer.Methods: In our cancer registry database, we identified 93 consecutive patients who underwent resection for oesophageal adenocarcinoma between 1990 and 2004 in two hospitals in our region. Using a predefined histopathological protocol, TSR was determined on the original haematoxylin–eosin (H&E) tissue sections of oesophagectomy specimens by two independent investigators.Results: With a cut-off value of 50% tumour/stroma, patients were classified as TSR high (n=60) or TSR low (n=33). There were no significant differences in patient, tumour and treatment characteristics between the two groups, except for M status (M1a) and radicality of resection. The (disease-free) survival in the TSR high group was significantly better than in the TSR low group. By multivariate analysis, TSR was identified as a highly significant prognostic factor for overall survival (HR 2.0; P=0.010), independent of depth of tumour invasion, nodal status, lymph node ratio, extracapsular involvement, TNM stage, histological grade and radicality of resection.Conclusion: TSR is a new and practicable prognostic tumour characteristic for oesophageal adenocarcinoma that can discriminate patients with a poor outcome from those with a better outcome.

The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer-staging system: A North American validation - Corrected Proof

2009-12-31

Abstract: Background: A reclassification of the International Union Against Cancer (UICC) staging system for adrenocortical carcinoma (ACC) patients has recently been proposed by the European Network for the Study of Adrenal Tumors (ENSAT) to better discriminate between cancer-specific mortality (CSM) risk strata. We formally tested the validity of the modified staging system in a large North American population-based cohort.Methods: Kaplan–Meier survival curves depicted CSM rates in the overall population and after stratification according to the 2004 UICC or the 2008 ENSAT-staging system. Cox regression models addressing CSM tested the prognostic value of respectively the UICC or the ENSAT-staging system. Harrell’s concordance index quantified the accuracy of the standard versus the modified staging system.Results: In the overall population (n=573), the CSM-free survival rates at 1, 3, and 5 years were, respectively, 62.9%, 47.0%, and 38.1%. No statistically significant differences in survival were recorded between 2004 UICC stages II and III patients (p=0.1). Conversely, a statistically significant difference was observed between 2008 ENSAT stage II and stage III patients (p<0.001). The 2008 ENSAT-staging system showed higher accuracy (83.0%) in predicting 3-year CSM rates, relative to the 2004 UICC-staging system (79.5%) (p<0.001).Conclusion: Our study corroborates the superior accuracy of the ENSAT-staging system for ACC relative to the 2004 UICC-staging system. In consequence, the 2008 ENSAT-staging system may warrant consideration in the next update of staging manuals.

Active and passive cigarette smoking and the risk of endometrial cancer in Poland - Corrected Proof

2009-12-28

Abstract: Background: Epidemiological studies have consistently reported that active cigarette smoking is inversely associated with endometrial cancer risk. However, dose-response relationships with quantitative measures of active smoking or passive smoking remain less clear.Methods: Data on lifetime active and passive smoking were collected for 551 endometrial cancer cases and 1925 controls in a population-based case-control study conducted during 2001–2003 in Poland (Warsaw and Łódz).Results: Compared with never active smokers, active current (Odds Ratio (OR)=0.51, 95% Confidence Interval (CI): 0.39, 0.68) and former smokers (OR=0.60, 95% CI: 0.45, 0.80) were at a statistically significantly decreased risk. We did not observe statistically significant inverse dose-response relationships with increasing exposure with duration and cumulative measures. However, there was some indication that the highest category of number of years (OR=0.35, 95% CI: 0.23–0.55), intensity (OR=0.41, 95% CI: 0.24–0.69), and dose (OR=0.38, 95% CI: 0.24–0.60) of smoking among current smokers had the greatest inverse association compared to never smokers. Our data did not support the presence of an inverse association with passive smoking among never active smokers (OR=0.92; 95% CI: 0.65, 1.29).Conclusion: Our results support that long-term and heavy smoking among current smokers strongly influence endometrial cancer risk.

From cancer patients to cancer survivors: The issue of Cardioncology – A biological perspective - Corrected Proof

Alberto Zambelli, Matteo Della Porta, Vittorio Rosti — 2009-12-28

Abstract: Long-term survival of cancer patients can be worsened by cardiovascular morbidity and mortality due to anticancer treatments based on cardiotoxic or antiangiogenic regimens. Growing scientific evidences support a role for circulating endothelial progenitor cells (EPCs) both in cancer pathogenesis and in cardiovascular diseases. High frequency of circulating EPCs seems to play a role in cancer growth and dissemination by favouring tumor angiogenesis and estabilishment of sites of metastasis. On the other hand, high level of circulating EPCs seems to be associated with a lower risk of developing cardiovascular diseases and with improved vascular regeneration after cardiovascular damage. Here, the possibile opposing roles of circulating EPCs in cancer patients suffering from therapy related-cardiovascular diseases are discussed, under the light of the potential modulation of their levels for therapeutic purposes. This can become a relevant issue in the field of cardioncology, the discipline that deals with the managing and treatment of cancer patients suffering from concomitant cardiovascular diseases or who are exposed to an increased risk to develop therapy related-cardiovascular complications.

Estimation of an optimal chemotherapy utilisation rate for breast cancer: Setting an evidence-based benchmark for the best-quality cancer care - Corrected Proof

Weng Ng, Geoff P. Delaney, Susannah Jacob, Michael B. Barton — 2009-12-25

Abstract: Background: The proportion of breast cancer patients that received chemotherapy varies widely in high-income countries. An evidence-based estimate of the optimal chemotherapy utilisation rate for a breast cancer population may serve as a useful benchmark for measuring and improving the quality of care.Methods: An optimal chemotherapy utilisation model was constructed using indications for chemotherapy identified from evidence-based guidelines. Data on the proportion of patient (age, performance status and preference) and tumour (stage, size, grade, nodal status, hormone receptor and HER2 status) attributes were obtained and merged with the treatment indications to calculate an optimal utilisation rate. This model was peer-reviewed by a panel of independent experts.Results: Chemotherapy was indicated in 17 of the 24 possible clinical scenarios depicted in the optimal utilisation model. The estimated optimal proportion of breast cancer patients who should received chemotherapy at least once was 68%. Sensitivity analyses showed that the range of optimal rate was 60–69%. The optimal rate appears to be substantially higher than the reported actual rates (29–49%).Conclusion: It is possible to generate an optimal chemotherapy utilisation rate in breast cancer to serve as an evidence-based benchmark. The optimal chemotherapy utilisation rate in breast cancer has remained largely unchanged over the past 15years. The reported actual utilisation rates of chemotherapy in breast cancer populations appear to have remained below the estimated optimal rate, suggesting that potential opportunities for improvement in the compliance to guideline recommended care exist.

Evaluation of the safety of C-1311 (SYMADEX) administered in a phase 1 dose escalation trial as a weekly infusion for 3 consecutive weeks in patients with advanced solid tumours - Corrected Proof

2009-12-25

Abstract: Purpose: C-1311 is a member of the novel imidazoacridinone family of anticancer agents. This phase 1 trial was designed to investigate the safety, tolerability and preliminary anti-tumour activity of C-1311.Patients and methods: This was a phase 1, inter-subject dose escalating and pharmacokinetic study of intravenous (IV) C-1311, administered weekly during 3consecutive weeks followed by 1week rest (constituting 1 cycle) in subjects with advanced solid tumours.Results: Twenty-two (22) patients were treated with C-1311, the highest dose given was 640mg/m2. All subjects experienced one or more treatment-related adverse events (AEs). The most frequently observed treatment-related AEs were neutropaenia and nausea (50% each), followed by vomiting (27%), anaemia (23%), asthenia (23%) and diarrhoea (18%). Most treatment-related AEs were of Common Terminology Criteria for Adverse Events (CTCAE) grades 1–2, except for the blood and lymphatic system disorders, which were primarily of grades 3–4. The recommended dose (RD) of C-1311 administered as once weekly IV infusions for 3weeks every 4weeks is 480mg/m2, with the dose limiting toxicity (DLT) being grade 4 neutropaenia lasting more than 7days. Treatment at this dose offers a predictable safety profile and excellent tolerability.Conclusion: The safety profile and preliminary anti-tumour efficacy of C-1311, observed in this broad-phase dose-finding study, warrants further evaluation of the compound.

Association between CYP2E1 genetic polymorphisms and lung cancer risk: A meta-analysis - Corrected Proof

Yadong Wang, Haiyan Yang, Li Li, Haiyu Wang, Congke Zhang, Gongju Yin, Baoyu Zhu — 2009-12-23

Abstract: Genetic variations in metabolic genes are thought to modify the metabolic process of carcinogens and are suggested to be related to cancer risk. However, epidemiological results are not always consistent. In this meta-analysis, we assessed reported studies of associations between polymorphisms of CYP2E1 RsaI/PstI and DraI, and the risk of lung cancer. We found decreased lung cancer risk among subjects carrying CYP2E1 RsaI/PstI c1/c2 and c1/c2+c2/c2 genotype [odds ratio (OR)=0.80, 95% confidence interval (CI): 0.72–0.89 and OR=0.82, 95% CI: 0.72–0.93, respectively], using 4436 cases and 6385 controls from 26 studies. We also observed a decreased lung cancer risk among subjects carrying c1/c2 and c1/c2+c2/c2 genotypes in the Asian population and on the basis of population control in stratified analysis. We found a protective effect of the CYP2E1 DraI CC and CD+CC polymorphisms for lung cancer (OR=0.58, 95% CI: 0.41–0.81 and OR=0.84, 95% CI: 0.73–0.96, respectively). The meta-analysis suggests that CYP2E1 RsaI/PstI and DraI polymorphisms may affect the susceptibility of lung cancer, and a study with a larger sample size is needed to further evaluate gene–environment interaction on CYP2E1 polymorphisms and lung cancer risk.

Familial risks of breast and prostate cancers: Does the definition of the at risk period matter? - Corrected Proof

Andreas Brandt, Justo Lorenzo Bermejo, Jan Sundquist, Kari Hemminki — 2009-12-18

Abstract: Aim: ‘Being at familial risk’ may have different connotations in studies on familial risk of cancer. The register-based definition of a family history considers individuals with an affected relative at familial risk independently of the family member’s diagnostic time. Alternatively, the individuals are classified to be at familial risk only after the diagnosis date of their relative, relevant to clinical counselling and screening situations. The aim of this study was to compare familial breast and prostate cancer risks according to the two definitions.Patients and methods: The nationwide Swedish Family-Cancer Database with information on cancers from 1958 to 2006 was used to calculate the hazard ratio of breast and prostate cancers according to family history using Cox regression. Family history was defined considering the number and type of affected relatives and the relative’s diagnostic age, respectively. Individuals were considered at familial risk from their entry to the study or, alternatively, from the diagnostic time of the relative.Results: Hazard ratios were equal whether individuals were considered at risk independent of the relative’s diagnostic date or only after the relative’s diagnostic date.Conclusion: These results indicate that studies on familial breast or prostate cancer risk which do not take the relative’s diagnosis date into account are applicable to screening and clinical counselling situations. The estimates according to the register-based definition are based on larger numbers of patients, which may be crucial for analysis of small groups such as families of multiple cases.

HMGB1 attenuates anti-metastatic defence of the liver in colorectal cancer - Corrected Proof

2009-12-17

Abstract: High mobility group box (HMGB) 1 induces apoptosis of monocyte-lineage cells. We examined the effect of HMGB1 on Kupffer cells (KCs). In 50 Dukes C and 12 liver-metastasised Dukes D colorectal cancers (CRCs), higher HMGB1 concentration in the primary tumours and metastatic foci, and fewer KCs were found in Dukes D cases than in Dukes C cases. The portal blood HMGB1 concentration was higher in Dukes D cases than in Dukes C cases. HMGB1 induced growth inhibition and apoptosis in mouse KCs in a dose-dependent manner, which was associated with the phosphorylation of c-Jun N-terminal kinase (JNK). JNK inhibition and knockdown of HMGB1 receptor abrogated growth inhibition and apoptosis. In a nude mouse liver metastasis model, the caecal administration of HMGB1 decreased the number of KCs and increased the embedment of Colo320 CRC cells in a dose-dependent manner. HMGB1 transfection increased the liver metastasis of Colo320 cells, and the metastasis was inhibited by anti-HMGB1 antibody administration. These results suggest that HMGB1 secreted from primary tumours decreases the number of KCs and attenuates the anti-metastatic defence of the liver in patients with CRCs.

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.