Congenital hypertrophy of the retinal pigment epithelium (CHRPE) in familial colorectal cancer

B ackground and aim: Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a pigmented fundus lesion associated with familial adenomatous polyposis (FAP). CHRPE prevalence has been reported to be increased in subjects with familial or sporadic non-polyposis colorectal cancer (CRC), suggesting that some individuals with non-polyposis CRC have an attenuated form of FAP. Other studies have not confirmed these clinical observations and have failed to identify mutations in the gene responsible for FAP, but the reason for the discrepancy in relation to CHRPE prevalence has not been resolved. We determined the prevalence of CHRPE in subjects without CRC (negative control cohort), subjects with FAP (positive control cohort), and subjects with familial non-polyposis CRC (test cohort). Method: A cohort study consisting of 37 negative control subjects, 9 positive control subjects with documented APC gene mutations, and 36 test subjects with familial non-polyposis CRC but no identified pathogenic APC gene mutation. The diagnosis of hereditary non-polyposis colon cancer was excluded in the test cohort by testing for microsatellite instability in tumour tissue. Results: None of the 37 people in the negative control group had CHRPE. Five of nine (56%) patients with FAP had multiple CHRPE lesions. None of the 36 subjects in the test cohort had CHRPE lesions. Conclusions: Ophthalmoscopy may contribute to risk assessment in families with FAP but not in familial non-polyposis CRC. Care must be exercised when interpreting pigmented fundus lesions because 8–13% of subjects in each of the cohorts had pigmented retinal lesions that were not CHRPE. Bilateral lesions and lesions with a depigmented halo␣were the hallmarks of CHRPE associated with FAP.Celia S. Chen, Kerry D. Phillips, Scott Grist, Graeme Bennet, Jamie E. Craig, James S. Muecke, Graeme K. Suther

Improving the Accuracy of TNM Staging in Esophageal Cancer: A Pathological Review of Resected Specimens

The original publication can be found at www.springerlink.comBackground Controversy exists over the Sixth Edition of the International Union Against Cancer (UICC) TNM staging system for esophageal cancer. Inclusion of additional information such as the number of metastatic lymph nodes and extracapsular lymph node invasion may improve the current staging system and lead to optimization of patient treatment. Methods All patients in Adelaide who underwent resection for esophageal cancer between 1997 and 2007 were identified from a prospective database. Two independent observers then reexamined all pathology slides from the original resection. Univariate and multivariate analysis was performed to identify significant prognostic factors. The goodness of fit and accuracy of additional prognostic factors were assessed, and the staging system was modified according to this information. Results There were 240 patients (mean age, 62 years) who met the inclusion criteria. The 5-year overall survival rate was 36% (median, 24 months). Only histological grade and a refined pN stage were found to be independent prognostic factors that could then be used to improve current TNM staging. Subdivision of pN stage into three groups (0, 1–2, and >2 positive nodes) showed significant differences in 5-year survival between all three groups: 53% vs 27% vs 6%, respectively (P < .01). The optimal staging model was the same for patients who received neoadjuvant therapy and surgery (n = 116), and those who underwent surgery alone (n = 124). Conclusion A staging model that incorporates a refined pN stage and histological grade appears to be more accurate than the current UICC-TNM staging system. This staging model is still applicable in patients who receive neoadjuvant therapy.Sarah K. Thompson, Andrew R. Ruszkiewicz, Glyn G. Jamieson, Adrian Esterman, David I. Watson, Bas P. L. Wijnhoven, Peter J. Lamb and Peter G. Devit

Environmental Risk Assessment of Sunscreens

22 pagesThe sunscreens are complex products for protecting the skin of UV radiation. These products contain active ingredients organic and inorganic UV filters. The release of some of these components can provoke negative effects to aquatic ecosystems. The UV filters have shown to be present in environmental compartments (freshwater, wastewater, groundwater, seawater, sediment, and sand) and to be ubiquitous, motivated by the use in other applications. To assess the environmental risk of these products implies to know exposure conditions and toxic effects in order to establish the risk quotient. This is calculated as the ratio between predicted environmental concentration (PEC) or measured environmental concentration (MEC) and predicted no-effect concentration (PNEC). The organic compounds that presented higher risk were benzophenone-3, ethylhexyl methoxycinnamate, and 4-methylbenzylidene camphor. Nevertheless, this risk is depending on the location and environmental compartment. The lack of a database concentration of inorganic nanoparticles (TiO2 and ZnO) makes difficult to carry out a realistic assessment of environmental risk, although using modeled data an approach was carried out. The results evidenced that certain risk can be related to the release of these nanomaterials from sunscreens, although a refinement will be necessary to reduce the uncertainties. Finally, some gaps of information have been identified in order to get a more realistic environmental risk assessment. Thus, the toxicity of the mixture of sunscreens compounds under realistic conditions and the improvement of the knowledge of their mode of actions could be the next stepsWe would like to thank to the projects CTM2016-75908-R funding by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and FEDER funds and the Junta de Andalucía PAIDI, Excellence Research Group RNM306 for their supportPeer reviewe

The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations(1-4) in addition to numerous lower frequency genetic events of uncertain significance(5). Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis(6,7) in a mouse model of pancreatic ductal preneoplasia(8) to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia(9), we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA