Association between family history and mismatch repair in colorectal cancer

BACKGROUND AND AIMS: Germline mutations in mismatch repair (MMR) genes cause a greatly increased risk of cancer of the gastrointestinal and female reproductive tracts (hereditary non-polyposis colorectal cancer (HNPCC)). Loss of MMR expression is common in colorectal cancer (CRC) overall. Such loss is assumed to be acquired predominantly, although a population of CRC cases will include individuals with unrecognised MMR mutations. This study examines the association between MMR gene expression and family history of cancer among the CRC population. METHODS: Individuals with CRC were identified from two well characterised populations: (1) consecutive hospital patients (n = 644) and (2) a population based cases series (n = 249). CRC was examined for expression of hMLH1 and hMSH2 using immunohistochemistry, and expression was related to family history using logistic regression. RESULTS: hMLH1 and hMSH2 expression was assessed in 732 CRCs with 8% showing loss of expression. No association was seen overall for hMLH1 or hMSH2 expression and family history of CRC. Loss of hMSH2 was predicted by family history of extracolonic cancer (odds ratio (OR) 5.78 (95% confidence interval (CI) 0.95–35.18)) and family history suggestive of HNPCC (OR 27.84 (95% CI 4.37–177.56)). Loss of hMLH1 was not predicted by family history of extracolonic cancer or a family history suggestive of HNPCC but was for a family history of at least two affected relatives (OR 4.88 (95% CI 1.25–19.03)). CONCLUSIONS: Individuals with hMSH2 deficient CRC in the general population exhibit a family history and other characteristics suggestive of HNPCC, and may carry germline MMR mutations. Loss of hMLH1 is only associated with a strong family history of extracolonic cancer at older ages, suggesting a novel mechanism of susceptibility

Time to Surgery Following Short-Course Radiotherapy in Rectal Cancer and its Impact on Postoperative Outcomes. A Population-Based Study Across the English National Health Service, 2009–2014

Aims Preoperative short-course radiotherapy (SCRT) is an important treatment option for rectal cancer. The length of time between completing SCRT and surgery may influence postoperative outcomes, but the evidence available to determine the optimal interval is limited and often conflicting. Materials and methods Information was extracted from a colorectal cancer data repository (CORECT-R) on all surgically treated rectal cancer patients who received SCRT in the English National Health Service between April 2009 and December 2014. The time from radiotherapy to surgery was described across the population. Thirty-day postoperative mortality, returns to theatre, length of stay and 1-year survival were investigated in relation to the interval between radiotherapy and surgery. Results Within the cohort of 3469 patients, the time to surgery was 0–7 days for 76% of patients, 8–14 days for 19% of patients and 15–27 days for 5% of patients. There was a clear variation in relation to different patient characteristics. There was, however, no evidence of differences in postoperative outcomes in relation to interval length. Conclusions This study suggests that the time interval between SCRT and surgery does not influence postoperative outcomes up to a year after surgery. The study provides population-level, real-world evidence to complement that from clinical trials

Wide Variation in the Use of Radiotherapy in the Management of Surgically Treated Rectal Cancer Across the English National Health Service

Aims: Radiotherapy is an important treatment modality in the multidisciplinary management of rectal cancer. It is delivered both in the neoadjuvant setting and postoperatively, but, although it reduces local recurrence, it does not influence overall survival and increases the risk of long-term complications. This has led to a variety of international practice patterns. These variations can have a significant effect on commissioning, but also future clinical research. This study explores its use within the large English National Health Service (NHS). Materials and methods: Information on all individuals diagnosed with a surgically treated rectal cancer between April 2009 and December 2010 were extracted from the Radiotherapy Dataset linked to the National Cancer Data Repository. Individuals were grouped into those receiving no radiotherapy, short-course radiotherapy with immediate surgery (SCRT-I), short-course radiotherapy with delayed surgery (SCRT-D), long-course chemoradiotherapy (LCCRT), other radiotherapy (ORT) and postoperative radiotherapy (PORT). Patterns of use were then investigated. Results: The study consisted of 9201 individuals; 4585 (49.3%) received some form of radiotherapy. SCRT-I was used in 12.1%, SCRT-D in 1.2%, LCCRT in 29.5%, ORT in 4.7% and PORT in 2.3%. Radiotherapy was used more commonly in men and in those receiving an abdominoperineal excision and less commonly in the elderly and those with comorbidity. Significant and substantial variations were also seen in its use across all the multidisciplinary teams managing this disease. Conclusion: Despite the same evidence base, wide variation exists in both the use of and type of radiotherapy delivered in the management of rectal cancer across the English NHS. Prospective population-based collection of local recurrence and patient-reported early and late toxicity information is required to further improve patient selection for preoperative radiotherapy

Optimization of peptide-based polyagonists for treatment of diabetes and obesity.

Transport properties of the kesterite-like single crystals of Cu2ZnSnS4, Cu(2)ZnSnxGe(1) Se-x(4) and Cu2ZnGeS4 are investigated in pulsed magnetic fields up to B = 20 T. The Mott variable-range hopping (VRH) conduction is established by investigations of the resistivity, q (T), in all the materials mentioned above within broad temperature intervals of Delta T-v4 similar to 50-150 K, 50-250 K and 100-200 K, respectively. In addition, the Shklovskii-Efros VRH conductivity below T-v2 similar to 3-4 K, the nearest-neighbour hopping (NNH) charge transfer between T similar to 250-320 K and the conductivity by activation of holes on the mobility threshold at temperatures outside DTv4, respectively, are observed in these materials. In Cu2ZnSnS4, magnetoresistance (MR) contains only a positive contribution, connected mainly to a shrinkage of impurity wave functions by the magnetic field. At the same time, a negative contribution to MR, attributable to interference effects in VRH, is observed in Cu(2)ZnSnxGe(1) Se-x(4) and, especially, in Cu2ZnGeS4. The joint analysis of the MR and q (T) data has yielded important electronic parameters of the materials. This includes widths of the acceptor band W and of the Coulomb gap D, the NNH activation energy En, the localization radius a, the acceptor concentration NA and the density of the localized states at the Fermi level, g (l). A dramatic increase of a in Cu2ZnSnS4 with decreasing T is observed, whereas in Cu(2)ZnSnxGe(1) Se-x(4) all the parameter W, En, g (l), a and NA are non-monotonic functions of x. Finally, in Cu2ZnGeS4 the Hall coefficient RH (T) is negative (despite of the p-type conduction), exhibiting the dependence close to that of q (T) in the Mott VRH interval. (C) 2017 Elsevier B.V. All rights reserved

Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates.

The continued global growth in the prevalence of obesity coupled with the limited number of efficacious and safe treatment options elevates the importance of innovative pharmaceutical approaches. Combinatorial strategies that harness the metabolic benefits of multiple hormonal mechanisms have emerged at the preclinical and more recently clinical stages of drug development. A priority has been anti-obesity unimolecular peptides that function as balanced, high potency poly-agonists at two or all the cellular receptors for the endocrine hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon. This report reviews recent progress in this area, with emphasis on what the initial clinical results demonstrate and what remains to be addressed

Evolution of Training Guidelines for Echocardiography Performed by the Neonatologist: Toward Hemodynamic Consultation

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