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Background/Objectives: Loss of expression of mismatch repair (MMR) proteins is frequently observed in sebaceous skin lesions and can be a herald for Lynch syndrome. The aim of this study was to identify clinico‐pathological predictors of MMR deficiency in sebaceous neoplasia that could aid dermatologists and pathologists in determining which sebaceous lesions should undergo MMR immunohistochemistry (IHC). Methods: An audit of sebaceous skin lesions (excluding hyperplasia) where pathologist‐initiated MMR IHC was performed between January 2009 to December 2016 was undertaken from a single pathology practice identifying 928 lesions from 882 individuals. Lesions were further analysed for differences in gender, age at diagnosis, lesion type and anatomic location, stratified by MMR status. Results: The 882 individuals (67.7% male) had a mean (SD) age of diagnosis of 68.4 ± 13.3 years. Nearly two‐thirds of the lesions were sebaceous adenomas, with 82.6% of all lesions occurring on the head and neck. MMR deficiency, observed in 282 of the 919 lesions (30.7%), was most common in sebaceous adenomas (210/282; 74.5%). MMR‐deficient lesions occurred predominantly on the trunk or limbs (64.7%), compared with 23.2% in head or neck (P < 0.001). Loss of MSH2 and MSH6 protein expression was most frequent pattern of loss (187/281; 66.5%). The highest AUC for discriminating MMR‐deficient sebaceous lesions from MMR‐proficient lesions was observed for the ROC curve based on subgroups defined by type and anatomic location of the sebaceous lesion (AUC = 0.68). Conclusion: The best combination of measured clinico‐pathological features achieved only modest positive predictive values, sensitivity and specificity for identifying MMR‐deficient sebaceous skin lesions. [ABSTRACT FROM AUTHOR]

In colorectal cancers (CRCs) with tumour mismatch repair (MMR) deficiency, genes involved in the host immune response that contain microsatellites in their coding regions, including beta-2-microglobulin ( B2M), can acquire mutations that may alter the immune response, tumour progression and prognosis. We screened the coding microsatellites within B2M for somatic mutations in MMR-deficient CRCs and adenomas to determine associations with tumour subtypes, clinicopathological features and survival. Incident MMR-deficient CRCs from Australasian Colorectal Cancer Family Registry (ACCFR) and the Melbourne Collaborative Cohort Study participants (n = 144) and 63 adenomas from 41 MMR gene mutation carriers from the ACCFR were screened for somatic mutations within five coding microsatellites of B2M. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival by B2M mutation status were estimated using Cox regression, adjusting for age at CRC diagnosis, sex, AJCC stage and grade. B2M mutations occurred in 30 (20.8%) of the 144 MMR-deficient CRCs (29% of the MLH1-methylated, 17% of the Lynch syndrome and 9% of the suspected Lynch CRCs). No B2M mutations were identified in the 63 adenomas tested. B2M mutations differed by site, stage, grade and lymphocytic infiltration although none reached statistical significance (p > 0.05). The HR for overall survival for B2M mutated CRC was 0.65 (95% CI 0.29-1.48) compared with B2M wild-type. We observed differences in B2M mutation status in MMR-deficient CRC by tumour subtypes, site, stage, grade, immune infiltrate and for overall survival that warrant further investigation in larger studies before B2M mutation status can be considered to have clinical utility. [ABSTRACT FROM AUTHOR]

We previously found high carotenoid levels in Karat and other Micronesian bananas, indicating potential importance for alleviating vitamin A deficiency and other nutritionally related health problems in the Federated States of Micronesia. Past work focused on carotenoid and mineral analyses, whereas here we investigated 16 cultivars (most not previously analysed) for a broader micronutrient profile, including seven vitamins. Karat carotenoid levels were higher than in previous analyses, confirming Karat as exceptionally carotenoid-rich. We identified an additional 10 carotenoid-rich cultivars, expanding the range having potential for alleviating vitamin A deficiency. A striking finding is the high riboflavin level in Karat, including high levels of uncharacterized flavonoids. Niacin and α-tocopherol are at levels that may contribute importantly to dietary intake within normal patterns of consumption. These data present a more complete basis for promoting the nutritional benefits of these banana cultivars where they are consumed in the Pacific, and potential benefits for promoting elsewhere. [ABSTRACT FROM AUTHOR]

The range of therapeutic modalities to treat type 2 diabetes mellitus has broadened in recent years. Biguanides and thiazolidinediones are the two currently available classes of anti-hyperglycemic agents with insulin-sensitizing properties. Thiazolidinediones, in particular, have received much attention, not only for the well documented hepatotoxicity of troglitazone that led to its removal from the market in 2000, but also for the emerging data that support the beneficial effects of the thiazolidinedione class of drugs on β-cell rejuvenation and cardiovascular risk reduction. In the US, thiazolidinediones are indicated either as monotherapy or in combination with a sulfonylurea, metformin, or insulin in cases where diet, exercise, and a single drug fail. In contrast, the UK National Institute for Clinical Excellence included in its re-appraisal of ‘glitazones’ in August 2003 the continued exclusion from licensed use in the UK of combination therapy with thiazolidinediones and insulin. When added to insulin therapy, thiazolidinediones appear to effectively lower glucose levels and reduce insulin dosage in clinical trials involving individuals with poorly controlled type 2 diabetes. However, weight gain, hypoglycemia, and fluid retention pose problems in certain patients. The fluid retention may exacerbate or even precipitate congestive heart failure, which usually necessitates discontinuation of the drug. Risk stratification and careful management of patients at risk for heart failure, including those taking insulin concomitantly, allow healthcare providers to safely administer combination therapy with thiazolidinediones in patients with type 2 diabetes. Hepatic toxicity with currently available thiazolidinediones has been found to be minimal overall. [ABSTRACT FROM AUTHOR]