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Background: Current risk models for renal cell carcinoma (RCC) based on clinicopathological factors are sub-optimal in accurately identifying high-risk patients. Here, we perform a head-to-head comparison of previously published DNA methylation markers and propose a potential prognostic model for clear cell RCC (ccRCC). Patients and methods: Promoter methylation of PCDH8, BNC1, SCUBE3, GREM1, LAD1, NEFH, RASSF1A, GATA5, SFRP1, CDO1, and NEURL was determined by nested methylation-specific PCR. To identify clinically relevant methylated regions, The Cancer Genome Atlas (TCGA) was used to guide primer design. Formalin-fixed paraffin-embedded (FFPE) tissue samples from 336 non-metastatic ccRCC patients from the prospective Netherlands Cohort Study (NLCS) were used to develop a Cox proportional hazards model using stepwise backward elimination and bootstrapping to correct for optimism. For validation purposes, FFPE ccRCC tissue of 64 patients from the University Hospitals Leuven and a series of 232 cases from The Cancer Genome Atlas (TCGA) were used. Results: Methylation of GREM1, GATA5, LAD1, NEFH, NEURL, and SFRP1 was associated with poor ccRCC-specific survival, independent of age, sex, tumor size, TNM stage or tumor grade. Moreover, the association between GREM1, NEFH, and NEURL methylation and outcome was shown to be dependent on the genomic region. A prognostic biomarker model containing GREM1, GATA5, LAD1, NEFH and NEURL methylation in combination with clinicopathological characteristics, performed better compared to the model with clinicopathological characteristics only (clinical model), in both the NLCS and the validation population with a c-statistic of 0.71 versus 0.65 and a c-statistic of 0.95 versus 0.86 consecutively. However, the biomarker model had limited added prognostic value in the TCGA series with a c-statistic of 0.76 versus 0.75 for the clinical model. Conclusion: In this study we performed a head-to-head comparison of potential prognostic methylation markers for ccRCC using a novel approach to guide primers design which utilizes the optimal location for measuring DNA methylation. Using this approach, we identified five methylation markers that potentially show prognostic value in addition to currently known clinicopathological factors. [ABSTRACT FROM AUTHOR]

Insulin-like growth factors (IGFs) have been associated with growth, body size, physical activity and colorectal cancer (CRC). We hypothesized that variants in IGF-related genes increase the CRC susceptibility associated with a larger body size and a lack of physical activity. We assessed this in The Netherlands Cohort Study. Participants (n = 120 852) completed a baseline questionnaire on diet and cancer. ~75% returned toenail clippings. Using a case-cohort approach and 16.3 years of follow-up, toenail DNA from 3768 subcohort members and 2580 CRC cases was genotyped. We aggregated unfavorable alleles (potentially increasing CRC risk) for 18 single nucleotide polymorphisms in 8 genes into a sum score. The sum score (in tertiles) and an IGF1 19-CA repeat polymorphism (19/19, 19/non-19 and non-19/non-19 repeats) in combination with body size (mostly in tertiles) and (non-)occupational physical activity (>12, 8-12 and <8 kJ/min in the job and >90, >60-90, >30-60 and =30 min/day) were analyzed by Cox regression. Increasingly higher hazard ratios (HRs) for CRC were observed for a larger adult body mass index, larger trouser size and tallness in the presence of more unfavorable alleles in men. HRs (95% confidence intervals) for joint effects were 1.55 (1.06-2.25), 1.78 (1.29-2.46) and 1.48 (1.01-2.17), respectively. In women, variant repeat alleles halved CRC risk irrespective of body size and physical activity. Almost no interactions tested significant. To conclude, a larger body size was a CRC risk factor in men in the presence of an accumulation of unfavorable alleles in IGF-related genes, but interactions were generally nonsignificant. [ABSTRACT FROM AUTHOR]

Background:As sodium, potassium and fluid intake are related to hypertension, an established risk factor for renal cell cancer (RCC), they may be independent risk factors for RCC.Methods:The Netherlands Cohort Study (NLCS) with case-cohort design included 120 852 participants aged 55-69 years. At baseline, diet and lifestyle were assessed with questionnaires. After 17.3 years of follow-up, 485 RCC cases and 4438 subcohort members were available for analyses.Results:Sodium intake increased RCC risk (P-trend=0.03), whereas fluid and potassium intake did not. For high sodium and low fluid intake, the RCC risk additionally increased (P-interaction=0.02).Conclusion:Sodium intake is a potential risk factor for RCC, particularly if fluid consumption is low. [ABSTRACT FROM AUTHOR]

Objectives. We aimed to compare quality of life (QoL) after surgical decompression of the thoracic outlet versus non-operative therapy in patients with neurogenic thoracic outlet syndrome (N-TOS). Design and methods. We retrospectively identified 46 patients, diagnosed with N-TOS between 1999 and 2008. Twenty-four operated and 22 conservatively treated patients were sent questionnaires on their current symptoms and QoL. A matched control group ( n = 24) of healthy individuals was selected for QoL comparison. Statistics were performed with linear and logistic regression analysis. Results. ANOVA revealed a significant QoL difference between the three groups ( p = 0.001). Separate analysis between groups demonstrated that all patients with N-TOS-like symptoms have a lower QoL than healthy controls ( p = 0.001 resp. p ≤ 0.000). No difference was found between conservatively and surgically treated patients ( p = 0.26). EQ-5D response rate was 83%. Of the 24 surgically treated patients, 15 would choose surgery again in a similar situation, although 4 did not benefit in terms of symptom reduction. Symptom relief and VAS pain scores in the conservatively and surgically treated patients did not show significant differences ( p = 0.95 resp. p = 0.40). Conclusions. All patients with N-TOS have a significantly decreased QoL compared with healthy individuals, regardless of the type of therapy they received. In this small study, surgical decompression fails to improve QoL in patients with N-TOS to the level measured in the healthy control group, despite symptom reduction consistent with previous reports. Variables significantly associated with outcome were duration of symptoms and localisation (variables included in the prediction model: age, sex, duration of symptoms, presence of paraesthesias, localisation, Adson's, Wright's and Roos' test, history of trauma, cervical arthrosis). In the perspective of QoL, the benefit of decompressive surgery is questionable. Improving patient selection seems imperative in order to achieve better results in our surgically treated patients. [ABSTRACT FROM AUTHOR]

Several studies described a role for the E2F/Rb pathway in ovarian serous carcinomas (SCAs). Since E2F/Rb pathway deregulation is a general hallmark of human cancer, it remains unclear whether this deregulation is of particular importance in SCAs or whether it reflects a common oncological feature. Here, we have clarified this issue by the examination of microarray expression profiles of SCAs and particularly by the comparison with another, less malignant, ovarian cancer type, serous borderline tumours (SBTs). Results were validated by quantitative RT-PCR, both on the microarray samples and on an independent panel, and TP53 mutation analysis was performed. This integrated analysis revealed a significant increase in the expression of the transcription factors E2F1 and E2F3 in SCAs, when compared to SBTs. This was associated with vast overexpression of E2F target genes in SCAs compared to SBTs. High-grade SCAs in particular exhibited a major deregulated E2F target expression pattern. Generally, overexpression of E2F targets in SCAs appeared to be well structured since those targets considered negative regulators of the cell cycle or promoters of apoptosis were usually not overexpressed in SCAs. Similar to E2F target deregulation, TP53 mutations were identified in SCA3s, to a lesser extent in SCA1s, and not in SBTs. These results suggest that a structured, generally up-regulated E2F transcription factor activity is associated with a global cell-cycle disturbance in high-grade SCAs and exceeds typical E2F/Rb pathway disruption in tumours, at least compared with SBTs. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter occurs in about 40% of breast tumours and has been correlated with reduced APC protein levels. To what extent epigenetic alterations of the APC gene may differ according to specific breast cancer phenotypes, remains to be elucidated. Our aim was to explore the role of APC methylation in the inflammatory breast cancer (IBC) phenotype. The status of APC gene promoter hypermethylation was investigated in DNA from normal breast tissues, IBC and non-IBC by both conventional and real-time quantitative methylation-specific PCR (MSP). APC methylation levels were compared with APC mRNA and protein levels. Hypermethylation of the APC gene promoter was present in 71% of IBC samples (n=21) and 43% of non-IBC samples (n=30) by conventional MSP (P=0.047). The APC gene also showed an increased frequency of high methylation levels in IBC (in 74% of cases, n=19) vs non-IBC (in 46% of cases, n=35) using a qMSP assay (P=0.048). We observed no significant association between APC methylation levels by qMSP and APC mRNA or protein expression levels. In conclusion, for the first time, we report the association of aberrant methylation of the APC gene promoter with the IBC phenotype, which might be of biological and clinical importance.British Journal of Cancer (2008) 99, 1735–1742. doi:10.1038/sj.bjc.6604705 www.bjcancer.com Published online 7 October 2008 [ABSTRACT FROM AUTHOR]

Stromal expression of hypoxia inducible factor 2 alpha (HIF-2 alpha) and carbonic anhydrase 9 (CA9) are associated with a poorer prognosis in colorectal cancer (CRC). Tumour cell death, regulated by a hypoxic stromal microenvironment, could be of importance in this respect. Therefore, we correlated apoptosis, TP53 mutational status and BNIP3 promoter hypermethylation of CRC cells with HIF-2 alpha- and CA9-related poor outcome. In a series of 195 CRCs, TP53 mutations in exons 5-8 were analysed by direct sequencing, and promoter hypermethylation of BNIP3 was determined by methylation-specific PCR. Expressions of HIF-2 alpha, CA9, p53, BNIP3 and M30 were analysed immunohistochemically. Poorer survival of HIF-2 alpha and CA9 stromal-positive CRCs was associated with wild-type TP53 (P=0.001 and P=0.0391), but not with BNIP3 methylation. Furthermore, apoptotic levels were independent of the TP53 status, but lower in unmethylated BNIP3 CRCs (P=0.004). It appears that wild-type TP53 in CRC cells favours the progression of tumours expressing markers for hypoxia in their stroma, rather than in the epithelial compartment. Preserved BNIP3 function in CRC cells lowers apoptosis, and may thus be involved in alternative cell death pathways, such as autophagic cell death. However, BNIP3 silencing in tumour cells does not impact on hypoxia-driven poorer prognosis. These results suggest that the biology of CRC cells can be modified by alterations in the tumour microenvironment under conditions of tumour hypoxia. [ABSTRACT FROM AUTHOR]

Presents an abstract of the article '‘Components Separation Technique’: A Useful Method for Repair of (Contaminated) Abdominal Wall Defects,' by T.S. de Vries Reilingh, M.I.A. van Engeland, H. van Goor, C. Rosman. M.H.A. Bemelmans, D. de Jong and R.P.I. Bleichrodt presented to the joint meeting of the Surgical Infection Society of Europe and the European Shock Society on May 2000 in Nijmegen, Netherlands.

A letter to the editor is presented discussing the potential of defects in DNA mismatch to signify an early-onset basal cell carcinoma.

Introduction: Lung carcinoids comprise a heterogeneous group of neuroendocrine tumors. Only few parameters have been identified that correlated with poor disease outcome, including 11q22-q25 deletions. New biomarkers are required to further improve diagnosis and prediction of prognosis. Aim(s): To identify differentially expressed genes between carcinoids with a favorable and poor outcome using high resolution gene-expression profiling, and to test their value as prognostic markers. Materials and methods: mRNA of five tumors with a favorable (>5yr survival) and five with a poor (distant metastasis / deceased) disease outcome was labeled and hybridized to 4x44k Agilent arrays, with a human pool expressing 70-80% of genes as a control. Results were validated by qRT-PCR and immunohistochemistry on an independent series of lung carcinoids. Results: Expression profiling revealed amongst others overexpression of the RET oncogene and repression of the homeobox gene OTP and CD44 in the poor prognosis group. In 54 frozen cases, low CD44 (p<0.0001) and OTP (p=0.0013), and high RET (p=0.0035) expression were significantly associated with decreased 15-year survival, outperforming WHO classification. Downregulation of CD44 and OTP expression was confirmed in tumors with a poor prognosis by immunohistochemistry. Conclusion: High resolution expression profiling unmasked new lung carcinoid candidate genes, of which CD44, OTP, and RET efficiently predict poor outcome. [ABSTRACT FROM AUTHOR]