European Journal of Cancer

Editorial board

2010-09-01

EJC News

2010-09-01

Continuing medical education in Europe: Towards a harmonised system

2010-07-09

Abstract: One of the first reports on the state of medical education was published in 1910 in North America, with the support of the Carnegie Foundation, showing that the interest for this issue dates back at least a century. Doctors (and nurses) are among the few professionals who managed to avoid for a long time any sort of evaluation of their knowledge and competence after the achievement of their diploma. But concern has been rising in society about the fast obsolescence of medical knowledge, particularly in the last 50years when the development of research and technology in the field has been so fast. The concept of Continuing Medical Education gained growing interest after the Second World War as a necessity for health professionals, but also as a form of protection of patients, who have the right to be treated by competent and knowledgeable doctors and nurses. The United States (US)-based Josiah Macy Foundation recently sponsored a conference exploring the state of continuing education and the result is ‘a picture of a disorganised system of education with obvious foci of excellence (most in universities) but with most commercially supported events shading more towards product promotion and the welfare of doctors than prioritised dedication to enhancing the care of patients’.Despite the fact that there is a lot to be learned from the US experience, Europe has to find its own way. Considerable progress was made since 1995 when UEMS (Union Européenne des Médecins Spécialistes) started to structure CME activities in Europe at translational level. A workshop on the issue was jointly organised by the European School of Oncology (ESO) and the Accreditation Council of Oncology in Europe (ACOE) in Berlin in September 2009.

Quality indicators in breast cancer care

2010-08-02

Abstract: To define a set of quality indicators that should be routinely measured and evaluated to confirm that the clinical outcome reaches the requested standards, Eusoma has organised a workshop during which twenty four experts from different disciplines have reviewed the international literature and selected the main process and outcome indicators available for quality assurance of breast cancer care. A review of the literature for evidence-based recommendations have been performed by the steering committee.The experts have identified the quality indicators also taking into account the usability and feasibility. For each of them it has been reported: definition, minimum and target standard, motivation for selection and level of evidence (graded according to AHRO). In overall 17 main quality indicators have been identified, respectively, 7 on diagnosis, 4 on surgery and loco-regional treatment, 2 on systemic treatment and 4 on staging, counselling, follow-up and rehabilitation. Breast Units in Europe are invited to comply with these indicators and monitor them during their periodic audit meetings.

The emerging pathogenic and therapeutic importance of the anaplastic lymphoma kinase gene

Fergal C. Kelleher, Ray McDermott — 2010-05-07

Abstract: The anaplastic lymphoma kinase gene (ALK) is a gene on chromosome 2p23 that has expression restricted to the brain, testis and small intestine but is not expressed in normal lymphoid tissue. It has similarity to the insulin receptor subfamily of kinases and is emerging as having increased pathologic and potential therapeutic importance in malignant disease. This gene was originally established as being implicated in the pathogenesis of rare diseases including inflammatory myofibroblastic tumour (IMT) and ALK-positive anaplastic large cell lymphoma, which is a subtype of non-Hodgkin’s lymphoma. Recently the number of diseases in which ALK is implicated in their pathogenesis has increased. In 2007, an inversion of chromosome 2 involving ALK and a fusion partner gene in a subset of non-small cell lung cancer was discovered. In 2008, publications emerged implicating ALK in familial and sporadic cases of neuroblastoma, a childhood cancer of the sympatho-adrenal system.Chromosomal abnormalities involving ALK are translocations, amplifications or mutations. Chromosomal translocations are the longest recognised ALK genetic abnormality. When translocations occur a fusion gene is created between ALK and a gene partner. This has been described in ALK-positive anaplastic large cell lymphoma in which ALK is fused to NPM (nucleolar protein gene) and in non-small cell lung cancer where ALK is fused to EML4 (Echinoderm microtubule-associated protein 4). The most frequently described partner genes in inflammatory myofibroblastic tumour are tropomyosin 3/4 (TMP3/4), however in IMTs a diversity of ALK fusion partners have been found, with the ability to homodimerise a common characteristic. Point mutations and amplification of the ALK gene occur in the childhood cancer neuroblastoma. Therapeutic targeting of ALK fusion genes using tyrosine kinase inhibition, vaccination using an ALK specific antigen and treatment using viral vectors for RNAi are emerging potential therapeutic possibilities.

Metformin: Taking away the candy for cancer?

2010-07-26

Abstract: Metformin is widely used in the treatment of diabetes mellitus type 2 where it reduces insulin resistance and diabetes-related morbidity and mortality. Population-based studies show that metformin treatment is associated with a dose-dependent reduction in cancer risk. The metformin treatment also increases complete pathological tumour response rates following neoadjuvant chemotherapy for breast cancer, suggesting a potential role as an anti-cancer drug. Diabetes mellitus type 2 is associated with insulin resistance, elevated insulin levels and an increased risk of cancer and cancer-related mortality. This increased risk may be explained by activation of the insulin- and insulin-like growth factor (IGF) signalling pathways and increased signalling through the oestrogen receptor. Reversal of these processes through reduction of insulin resistance by the oral anti-diabetic drug metformin is an attractive anti-cancer strategy. Metformin is an activator of AMP-activated protein kinase (AMPK) which inhibits protein synthesis and gluconeogenesis during cellular stress. The main downstream effect of AMPK activation is the inhibition of mammalian target of rapamycin (mTOR), a downstream effector of growth factor signalling. mTOR is frequently activated in malignant cells and is associated with resistance to anticancer drugs. Furthermore, metformin can induce cell cycle arrest and apoptosis and can reduce growth factor signalling. This review discusses the role of diabetes mellitus type 2 and insulin resistance in carcinogenesis, the preclinical rationale and potential mechanisms of metformin’s anti-cancer effect and the current and future clinical developments of metformin as a novel anti-cancer drug.

Patients report improvements in continuity of care when quality of life assessments are used routinely in oncology practice: Secondary outcomes of a randomised controlled trial

2010-05-31

Abstract: Introduction and aim: In a randomised trial investigating the effects of regular use of health-related quality of life (HRQOL) in oncology practice, we previously reported an improvement in communication (objective analysis of recorded encounters) and patient well-being. The secondary aims of the trial were to measure any impact on patient satisfaction and patients’ perspectives on continuity and coordination of their care.Methods: In a prospective trial involving 28 oncologists, 286 cancer patients were randomised to: (1) intervention arm: regular touch-screen completion of HRQOL with feedback to physicians; (2) attention-control arm: completion of HRQOL without feedback; and (3) control arm: no HRQOL assessment. Secondary outcomes were patients’ experience of continuity of care (Medical Care Questionnaire, MCQ) including ‘Communication’, ‘Coordination’ and ‘Preferences to see usual doctor’ subscales, patients’ satisfaction, and patients’ and physicians’ evaluation of the intervention. Analysis employed mixed-effects modelling, multiple regression and descriptive statistics.Results: Patients in the intervention arm rated their continuity of care as better than the control group for ‘Communication’ subscale (p=0.03). No significant effects were found for ‘Coordination’ or ‘Preferences to see usual doctor’. Patients’ evaluation of the intervention was positive. More patients in the intervention group rated the HRQOL assessment as useful compared to the attention-control group (86% versus 29%), and reported their doctors considered daily activities, emotions and quality of life.Conclusion: Regular use of HRQOL measures in oncology practice brought changes to doctor-patient communication of sufficient magnitude and importance to be reported by patients. HRQOL data may improve care through facilitating rapport and building inter-personal relationships.

Trends in G-CSF use in 990 patients after EORTC and ASCO guidelines

C. Falandry, M. Campone, G. Cartron, D. Guerin, G. Freyer — 2010-06-07

Abstract: Background: Although international guidelines have standardised conditions for G-CSF administration, real practice seems to vary.Patients and methods: A large survey was undertaken in France following a three-step method. Data concerning 990 patients in seven main indications were collected prospectively and analysed for their compliance with international guidelines.Results: G-CSF prescription rate varied from 81% in non-Hodgkin lymphoma (NHL), 55% in ovarian, 44% in breast and 21% in colorectal cancer. The main criteria for G-CSF administration were a chemotherapy regimen with a high risk of neutropaenia (65%) and associated risk factors (51%). Public hospital practitioners prescribed G-CSF more frequently as primary prophylaxis, whereas prescriptions of recently graduated practitioners (⩽5years) and former ones (⩾16years) were often proposed as secondary prophylaxis or as G-CSF therapy, i.e. during ongoing neutropaenia. In prophylactic settings, administration schedules were highly variable depending on molecules, with a first day of administration between days 1 and 3 after chemotherapy in 66%, but before the end of the chemotherapy infusion in 13% of the cases. Concerning lenograstim (38% of prescriptions) and filgrastim (20%), the mean treatment duration was 5.5days, significantly shorter than in 1999 (7.8days).Conclusion: G-CSF prescription was mainly in compliance with international guidelines. However, some too early administrations during chemotherapy are at risk of increased myelosuppression and should be more clearly disadvised in next international guidelines.

Lobular invasive carcinoma of the breast is a molecular entity distinct from luminal invasive ductal carcinoma

2010-06-23

Abstract: In order to get insight into the molecular alterations of invasive lobular carcinoma (ILC), comparative genomic hybridisation array and transcriptomic analyses of a series of 62 oestrogens-positive (ER) invasive tumours [21 ILC and 41 invasive ductal carcinomas (IDC)] were performed. ILC and IDC shared highly recurrent regions of gains (1q12–q44+ in more than 60% of the cases, 16pter–p11.2+ in 45% and 63% of ILC and IDC, respectively) and losses (16q11.2–q24.2– in 84% of ILC and 67.5% of IDC and 17pter–p12– in 50% of ILC and IDC). However, ILC genomic signature was characterised by significantly more frequent losses of 13q21.33–q31.3 region (46.5%) and 22q11.23–q12.1 region (50%) whereas IDC showed significantly more frequent losses of 11q23.1–q23.2 region (in 44% of IDC). Nine different regions of high level amplifications were found in 38% of ILC (8/21 cases). Localised on chromosome 11 (11q13.2 region), the most frequent region of amplification encompassing the CCND1 and FGF3 genes was observed in five different ILC. Unsupervised hierarchical clustering of transcriptomic data showed that ILC and IDC clustered apart. Genes involved in cell adhesion, cell communication and trafficking, extra cellular matrix-interaction pathways or cell mobility contributed to this clustering. Despite these differences, the overall clinical outcome of ILC was identical to that of IDC. This molecular study highlights that lobular and oestrogens-positive ductal invasive carcinomas share common genomic alterations but that ILC present some specific molecular alterations. These molecular specificities should help with the identification of new therapeutic targets for ILC patients.

The unclear zone in phase II clinical trials

Sabrina Allegro, Gregory R. Pond, Sébastien J. Hotte — 2010-06-28

Abstract: Objective: There appears to be considerable confusion about the interpretation of phase II clinical trial conclusions as contrasted with the alternative (HA) and null (H0) hypotheses. This study was conducted to evaluate whether there is congruence with numerical results of phase II trials and their overall verbal conclusions.Methods: A literature search of 2006 and 2007 phase II clinical trials was conducted. The alternative and null hypotheses were noted as were point estimates with confidence intervals (CIs). These were compared with the final conclusions and concordance and discordance rates were calculated.Results: A total of 152 eligible analyses were reviewed. The point estimates were below H0 in 42 (27.6%) trials, above HA in 60 (39.4%) trials and between H0 and HA (i.e. the grey zone) in 50 (32.9%) trials. Thirty-three (21.7%) trials reported negative conclusions, 111 (73.0%) reported positive conclusions and 8 (5.3%) were ambiguous. All 60 trials in which the point estimate was greater than HA reported positive conclusions, as did 40/50 (80.0%) of trials with point estimates in the grey zone.Conclusions: There exist inconsistencies and ambiguities in the conclusions drawn from phase II trials, particularly when results are in the grey zone (greater than H0 but less than HA). This may make the integration of phase II trials in phase III trial development strategies difficult and better understanding of the statistical properties of phase II clinical trials is required.

EORTC Melanoma Group sentinel node protocol identifies high rate of submicrometastases according to Rotterdam Criteria

2010-07-12

Abstract: Sentinel node (SN) status is the most important prognostic factor for disease-free survival (DFS) and overall survival (OS) in stages I–II melanoma. We evaluated the positive sentinel node identification rate of the EORTC Melanoma Group (MG) protocol as well as its capacity to identify minimal tumour burden, according to the Rotterdam Criteria in 421 consecutive patients. Correlations between primary tumour characteristics and SN tumour burden were investigated. The same 2 pathologists worked up all SNs according to the EORTC MG protocol and tumour burden was scored according to the Rotterdam Criteria (<0.1mm, 0.1–1.0mm and >1.0mm for the largest diameter of the largest metastasis in the SN).The positive SN detection rate was 28.7% with a false negative rate of 10.4% at a median Breslow thickness of 2.1mm. The high positive identification rate of about 30% of the EORTC MG protocol has been confirmed in this study. The protocol is sensitive and identifies submicrometastases (<0.1mm) in a high percentage (18%). The variables SN tumour load, non-SN (NSN) status and ulceration of the primary were independent prognostic factors for DFS and OS in the multivariate analysis. At a median follow-up time of 4.3years patients with minimal tumour burden (<0.1mm) had a 5year OS rate of 91%, virtually identical to 90% for SN-negative patients. The NSN positivity rate of 0% in these patients indicates that they may be spared a completion lymph node dissection (CLND) and its morbidity.

Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer–Results from two randomised studies

2010-07-09

Abstract: Introduction: Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled.Methods: Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I–III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy.Results: In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41–0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44–0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46–1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35–0.88; P=0.01).Conclusion: Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.

Long-term safety of sorafenib in advanced renal cell carcinoma: Follow-up of patients from phase III TARGET

2010-07-26

Abstract: Background: The phase III Treatment Approaches in Renal cancer Global Evaluation Trial (TARGET) indicated that sorafenib is effective and well tolerated in advanced renal cell carcinoma patients. However, few data have been published on the safety of long-term sorafenib treatment. A retrospective subgroup analysis was performed to evaluate the efficacy and safety of sorafenib in patients in TARGET who received treatment for >1year.Methods: The present subgroup analysis (based on the September 2006 database with updated safety analysis) evaluated the efficacy and safety of sorafenib in all patients in the sorafenib arm of TARGET who were treated for >1 year. The assessments included the overall survival, progression-free survival (PFS), disease control rate (DCR), and safety. The patients remained on therapy post-progression at the discretion of the investigator.Results: In TARGET, 169 patients received treatment with sorafenib for >1year. The median PFS of patients in this subpopulation was 10.9months from the date of randomisation, with a DCR of 92%. The most commonly reported treatment-related adverse events of any grade were diarrhoea (74%), rash/desquamation (51%), hand–foot skin reaction (49%), alopecia (39%), and fatigue (38%). Adverse events were mild to moderate, and presented early in the course of the treatment; there were no unexpected toxicities associated with the long-term administration of sorafenib.Conclusions: Results of this subgroup analysis of patients enrolled in TARGET who received treatment for >1year indicate that long-term treatment with sorafenib is associated with continued efficacy and a well-tolerated safety profile.

Hospitalisations 1998–2000 in a British Columbia population-based cohort of young cancer survivors: Report of the Childhood/Adolescent/Young Adult Cancer Survivors (CAYACS) Research Program

2010-06-07

Abstract: Background and objectives: Because of late effects among survivors of cancer in young people, increased hospitalisations would be expected. This study determined the occurrence, frequency and days in hospital (DIH) of hospital admissions among 5-year survivors of childhood and adolescent cancer diagnosed in British Columbia (BC), compared hospitalisation risk with the general population and examined the impact of sociodemographic, health care system and clinical factors.Design: This population-based study frequency matched 1157 survivors of cancer diagnosed before 20years of age from 1970 to 1992 from the BC Cancer Registry with 11,570 randomly selected individuals from BC’s health insurance plan Client Registry. Administrative hospitalisation records from 1998 to 2000 were linked to study cohorts, and regression and trend analyses were carried out.Results: From 1998 to 2000, 240 (21%) of survivors and 614 (5.3%) of the population sample were admitted to hospital at least once [adjusted OR=4.36 (95% CI 3.68–5.16)]. Hospitalised survivors had a higher average number of admissions (2.0 versus 1.5 admissions, respectively) and longer mean DIH (10.9 versus 7.8d, respectively) than hospitalised population controls. Female gender and older age increased the risk of hospitalisation, as did the presence of a relapse or second cancer by 5years post-diagnosis.Conclusion: Our cohort of child and adolescent cancer survivors had higher odds of hospitalisation, more admissions among those hospitalised and longer stay in hospital compared to the population sample. This has implications for health care system resources and appropriate management of late effects of survivors.

Soft tissue sarcomas in the first year of life

2010-06-10

Abstract: Background: Soft tissue sarcomas (STS) occurring in the first year of life represent a rare entity. Challenges in delivering optimal therapy may affect the outcome in this very young population.Methods: We searched the SEER database for records of infants less than 1year of age, with a reported diagnosis of STS who were diagnosed from 1973 to 2006. We analysed their clinical features and survival. These patients were also compared to older patients (1–18years old) in order to understand the differences between the two groups.Results: The incidence rate of STS in the first year of life was 16.0 per million. As an entity, they represented 7.3% of malignancies reported in the first year of life. One fifth of these tumours (20.9%) were reported to be metastatic at diagnosis. The most common histologies were rhabdomyosarcoma (n=99, 32.8%), fibrosarcoma (n=74, 24.5%), malignant rhabdoid tumours (n=43, 14.2%) and haemangiopericytoma (n=12, 4.0%); except for rhabdomyosarcoma, the other 3 entities were very rare in older children. The 5-year survival of STS in children less than 1year of age (62±3.0%) was significantly worse than that of older children (71±0.9%, P=0.0002). In a multivariate model, histologic types other than fibrosarcoma and haemangiopericytoma (HR, 5.7; 95% CI, 2.28–14.20) as well as advanced stage (HR, 5.15; 95% CI, 3.28–8.10) were found to be significant adverse prognostic factors. Significantly less use of radiation was reported in infants when compared to older children (P<0.0001).Conclusion: As a group, infantile STS are associated with worse survival than STS in older children. Outcome, however, is significantly associated with histologic subtype, with infantile fibrosarcoma and infantile haemangiopericytoma having better outcomes. Avoidance of radiotherapy in this young age may contribute to worse outcomes.

Polymorphisms in the adenomatous polyposis coli (APC) gene and advanced colorectal adenoma risk

2010-06-01

Abstract: While germline mutations in the adenomatous polyposis coli (APC) gene cause the hereditary colon cancer syndrome (familial adenomatous polyposis (FAP)), the role of common germline APC variants in sporadic adenomatous polyposis remains unclear. We studied the association of eight APC single nucleotide polymorphisms (SNPs), possibly associated with functional consequences, and previously identified gene–environment (dietary fat intake and hormone replacement therapy (HRT) use) interactions, in relation to advanced colorectal adenoma in 758 cases and 767 sex- and race-matched controls, randomly selected from the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Cases had at least one verified advanced adenoma of the distal colon; controls, a negative sigmoidoscopy. We did not observe an association between genotypes for any of the eight APC SNPs and advanced distal adenoma risk (Pglobal gene-based=0.92). Frequencies of identified common haplotypes did not differ between cases and controls (Pglobal haplotype test=0.97). However, the risk for advanced distal adenoma was threefold higher for one rare haplotype (cases: 2.7%; controls: 1.6%) (odds ratio (OR)=3.27; 95% confidence interval (CI)=1.08–9.88). The genetic association between D1822V and advanced distal adenoma was confined to persons consuming a high-fat diet (Pinteraction=0.03). Similar interactions were not observed with HRT use. In our large, nested case-control study of advanced distal adenoma and clinically verified adenoma-free controls, we observed no association between specific APC SNPs and advanced adenoma. Fat intake modified the APC D1822V-adenoma association, but further studies are warranted.

High-ceiling diuretics are associated with an increased risk of basal cell carcinoma in a population-based follow-up study

2010-06-04

Abstract: Introduction: In Caucasians, basal cell carcinoma (BCC) is among the most frequently diagnosed cancers and its incidence is increasing. Known risk factors for the development of BCC are age, sun exposure, and certain skin characteristics. Despite photosensitizing abilities of diuretic agents, little is known about a possible association with BCC.Methods: Data were obtained from the Rotterdam Study; a large prospective population-based follow-up study with coverage of prescription-only drugs from pharmacies. The diagnoses of BCC were obtained through general practitioners, and by linkage with a registry of histo- and cytopathology. Cumulative use of diuretics at the date of diagnosis was categorized into quartiles for users of high-ceiling diuretics, potassium sparing agents and thiazides. The association between these drugs and BCC was assessed by Cox proportional hazard modeling with adjustment for age, gender and potential confounders. Effect modification was tested with interaction terms.Results: Use of high-ceiling diuretics in the highest quartile (>3.7years cumulative exposure) was associated with an increased hazard of BCC of 62% compared to no use (HR 1.6; 95% CI 1.1–2.4). Patients who used high-ceiling diuretics and had a high tendency of getting sunburned had a higher risk of diagnosis than non-users who do not easily get sunburned. Neither the use of potassium sparing agents, nor the use of thiazides was associated with BCC.Conclusion: In our study, cumulative use of high-ceiling diuretics was associated with an increased risk of diagnosis of BCC. This effect is stronger in patients who easily get sunburned.

Male predominance of upper gastrointestinal adenocarcinoma cannot be explained by differences in tobacco smoking in men versus women

2010-06-04

Abstract: Background: Adenocarcinomas of the upper gastrointestinal tract (UGI) show remarkable male predominance. As smoking is a well-established risk factor, we investigated the role of tobacco smoking in the male predominance of UGI adenocarcinomas in the United States NIH-AARP Diet and Health Study.Method: A questionnaire was completed by 281,422 men and 186,133 women in 1995–1996 who were followed until 31st December 2003. Incident UGI adenocarcinomas were identified by linkage to state cancer registries. We present age-standardised cancer incidence rates per 100,000-person years and male/female ratios (M/F) calculated from age-adjusted Cox proportional hazards models, both with 95% confidence intervals (CI).Results: After 2013,142-person years follow-up, 338 adenocarcinomas of the oesophagus, 261 of gastric cardia and 222 of gastric non-cardia occurred in men. In women, 23 tumours of oesophagus, 36 of gastric cardia and 88 of gastric non-cardia occurred in 1351,958-person years follow-up. The age-standardised incidence rate of all adenocarcinoma sites was 40.5 (37.8–43.3) and 11.0 (9.2–12.8) in men and women, respectively. Among smokers, the M/F of all UGI adenocarcinomas was 3.4 (2.7–4.1), with a M/F of 7.3 (4.6–11.7) for tumours in oesophagus, 3.7 (2.5–5.4) for gastric cardia and 1.7 (1.2–2.3) for gastric non-cardia. In non-smokers, M/F ratios were 14.2 (5.1–39.5) for oesophagus, 6.1 (2.6–14.7) for gastric cardia and 1.3 (0.8–2.0) for gastric non-cardia. The overall M/F ratio was 3.0 (2.2–4.3).Conclusion: The male predominance was similar in smokers and non-smokers for these cancer sites. These results suggest that the male predominance of upper GI adenocarcinomas cannot be explained by differences in smoking histories.

ERCC2 Lys751Gln polymorphism is associated with lung cancer among Caucasians

Jian Zhang, Shi-Yang Gu, Ping Zhang, Zhen Jia, Jian-Hua Chang — 2010-06-04

Abstract: To derive a more precise estimation of the relationship between the excision repair cross-complementing rodent repair deficiency, group 2 (ERCC2) Lys751Gln polymorphism and lung cancer risk, a meta-analysis was performed. A total of 23 studies including 8137 cases and 9824 controls were involved in this meta-analysis. Overall, significantly elevated lung cancer risk was associated with ERCC2 Gln allele when all studies were pooled into the meta-analysis (Lys/Gln versus Lys/Lys: odds ratio (OR)=1.10, 95% confidence interval (CI)=1.03–1.19; Gln/Gln versus Lys/Lys: OR=1.20, 95% CI=1.06–1.35; dominant model: OR=1.13, 95% CI=1.05–1.20; and recessive model: OR=1.15, 95% CI=1.03–1.29). In the subgroup analysis by ethnicity, significantly increased risk was only found for Caucasians (Gln/Gln versus Lys/Lys: OR=1.25, 95% CI=1.08–1.45; dominant model: OR=1.10, 95% CI=1.00–1.22; and recessive model: OR=1.22, 95% CI=1.06–1.40). When stratified by study design, statistically significantly elevated risks were found in hospital-based studies (Lys/Gln versus Lys/Lys: OR=1.12, 95% CI=1.03–1.22; Gln/Gln versus Lys/Lys: OR=1.24, 95% CI=1.06–1.44; dominant model: OR=1.15, 95% CI=1.06–1.24; and recessive model: OR=1.19, 95% CI=1.03–1.37) and population-based studies (Gln/Gln versus Lys/Lys: OR=1.57, 95% CI=1.12–2.20 and recessive model: OR=1.50, 95% CI=1.08–2.07). In the subgroup analysis whether or not the studies were matched on smoking, significantly increased risk was found not in those matched studies but in the unmatched studies (Lys/Gln versus Lys/Lys: OR=1.11, 95% CI=1.03–1.19; Gln/Gln versus Lys/Lys: OR=1.22, 95% CI=1.07–1.40; dominant model: OR=1.13, 95% CI=1.05–1.22; and recessive model: OR=1.18, 95% CI=1.04–1.33). In conclusion, this meta-analysis suggests that the ERCC2 Lys751Gln polymorphism may contribute to lung cancer susceptibility among Caucasians.

Inhibin-alpha, -betaA and -betaB subunits in uterine non-endometrioid carcinomas: Prognostic significance and clinical implications

Ioannis Mylonas — 2010-07-05

Abstract: Inhibins, dimeric peptide hormones composed of an alpha-subunit and one of two possible beta-subunits (betaA or betaB), exhibit substantial roles in human reproduction and in endocrine-responsive tumours. However, the prognostic significance and clinical implications of the inhibin-alpha, -betaA and -betaB subunits in uterine non-endometrioid cancers are still quite unclear. A series of 41 uterine non-endometrioid carcinomas were immunohistochemically analysed with monoclonal antibodies against inhibin-subunits. The staining reactions were correlated with several clinicopathological characteristics and clinical outcome. The inhibin-alpha subunit showed a significant association with age although the loss of this subunit did not affect the survival of patients with non-endometrioid carcinomas and did not constitute an independent prognostic parameter. The inhibin-betaA expression was not associated with any of the analysed clinicopathological parameters and did not affect patients’ survival. In contrast, a low betaB-subunit demonstrated a significant better cause-specific survival. Moreover, inhibin-βB did constitute an independent prognostic parameter in uterine non-endometrioid cancer patients. In contrast to inhibin-alpha and -betaA subunits, the inhibin-betaB subunit seems to have a substantial role in the carcinogenesis and pathology of uterine non-endometrioid carcinomas and might be used as a marker to identify high-risk patients and may aid in the selection of patients for a more aggressive adjuvant therapy.

Aven blocks DNA damage-induced apoptosis by stabilising Bcl-xL

Ozgur Kutuk, Sehime Gulsun Temel, Sahsine Tolunay, Huveyda Basaga — 2010-07-09

Abstract: Induction of apoptosis by DNA-damaging agents involves the activation of mitochondrial apoptotic pathway. Aven has been identified as an antiapoptotic protein and has been shown to activate ATM in response to DNA damage. In this study, we demonstrated that enforced expression of Aven blocks UV-irradiation-, SN-38- or cisplatin-induced apoptosis upstream of mitochondria by stabilising Bcl-xL protein levels in breast cancer cells. Aven silencing by RNA interference markedly enhanced apoptotic response following treatment with DNA-damaging agents. Aven is complexed with Bcl-xL in untreated breast cancer cells and treatment with DNA-damaging agents led to decreased Aven/Bcl-xL interaction. Importantly, Bcl-xL was necessary for the prosurvival activity of Aven and depletion of Bcl-xL abrogated Aven-mediated protection against DNA damage-induced apoptosis. Analysis of breast cancer tissue microarrays revealed decreased Aven nuclear expression in breast cancer tissues compared with non-neoplastic breast tissues. In particular, we detected reduced nuclear expression of Aven in infiltrating ductal carcinoma and papillary carcinoma breast cancer subtypes compared with non-neoplastic breast tissues and infiltrating lobular breast cancer tissues. Our results suggest that Aven is an important mediator in DNA damage-induced apoptotic signalling in breast cancer cells and its nuclear expression is altered in breast cancer tissues, which may contribute to genomic instability in breast cancer tumours.

Prognostic impact of CD31-positive microvessel density in follicular lymphoma patients treated with immunochemotherapy

2010-07-14

Abstract: Background: Tumour-infiltrating mast cells (MCs) can remodel tumour microenvironment and growth by suppressing immune responses and potentiating angiogenesis. Furthermore, accumulation of MCs in follicular lymphoma (FL) correlates with unfavourable prognosis after immunochemotherapy. Here we investigated whether tumour vascularity is associated with MC content and outcome in FL patients treated with immunochemotherapy.Patients and methods: Microvessel density (MVD) and MC content were determined immunohistochemically from pretreatment samples of 95 FL patients using CD31, CD34 and mast cell tryptase antibodies. Gene expression data from a separate set of 24 FL patients were analysed for comparison. All patients were treated with the combination of rituximab (R) and cyclophoshamide-doxorubicin–vincristine–prednisone (CHOP) chemotherapy.Results: Increased CD31+ MVD correlated positively with the number of tumour infiltrating MCs and CD34+ vessels, and negatively with the outcome. Overall survival and progression-free survival were significantly better among patients with low CD31+ MVDs. In multivariate analyses, CD31+ MVD had prognostic value independently of Follicular Lymphoma Prognostic Index but not of MC content. Consistent with the immunohistochemical data, high CD31/PECAM1 mRNA levels were associated with adverse outcome. Conversely, a positive prognostic impact of VEGF mRNA expression on the outcome was found.Conclusion: Vascularity is associated with MC content and outcome in R-CHOP-treated FL patients.

Therapeutic effects and prognostic factors in high-intensity focused ultrasound combined with chemoembolisation for larger hepatocellular carcinoma

Chuanxing Li, Weidong Zhang, Rong Zhang, Liang Zhang, Peihong Wu, Fujun Zhang — 2010-07-21

Abstract: The purpose of this study is to evaluate high-intensity focused ultrasound (HIFU) ablation combined with transcatheter arterial chemoembolisation (TACE) in the treatment of larger hepatocellular carcinoma (HCC). Eighty-nine (89) patients with unrespectable larger HCC were randomised into a TACE group (n=45) and a TACE plus HIFU group (n=44). Therapeutic effects were assessed at follow-up with physical examination, level of serum α-fetoprotein and computed tomography or magnetic resonance imaging. All patients were followed up to observe long-term therapeutic effects and evaluated prognostic factors for survival. No severe complication was observed. Follow-up images showed that total effective rate in tumour response accounted for 72.8% in the TACE–HIFU group, which were significantly higher than that of TACE group (44.5%, P<0.05). The 1-, 2-, 3- and 5-year overall survival rates for the TACE–HIFU group were 72.7%, 50.0%, 31.8% and 11.4%, respectively; correspondingly, for the TACE group were 47.2%, 16.7%, 2.8% and 0%, respectively (P<0.01). The 1-, 2-, 3- and 5-year disease-free survival rates for the TACE–HIFU group were 34.1%, 18.2%, 9.1% and 0%, respectively; correspondingly, for the TACE group were 13.9%, 5.6%, 0% and 0%, respectively (P<0.01). TNM stage, portal vein tumour thrombosis and Child-Pugh classification each had a significant effect on the survival. HIFU ablation combined with TACE is safe, effective and a promising approach for the treatment of larger HCC.

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2010-09-01