Regenerating islet-derived family, member 4 (Reg IV) is a candidate marker for cancer and inflammatory bowel disease. In the present study, immunohistochemical analysis of Reg IV was performed in various human neoplastic (n = 289) and non-neoplastic tissues. In the stomach, foveolar epithelium was negative for Reg IV, whereas goblet cells of intestinal metaplasia and neuroendocrine cells at the base of intestinal metaplasia expressed Reg IV. Neuroendocrine cells of the small intestine and colon showed strong expression of Reg IV, whereas goblet cells of the small intestine and colon showed weak or no expression of Reg IV. Insulin-producing beta cells of the endocrine pancreas were positive for Reg IV. Among 143 gastric adenocarcinomas, Reg IV expression was detected in 42 (29.4%) and was associated with both the intestinal mucin phenotype and neuroendocrine differentiation. No association was found between Reg IV expression and clinical characteristics such as tumour stage and patient prognosis. Of 36 colorectal adenocarcinomas, 13 (36.1%) were positive for Reg IV, which was associated with tumour stage (p = 0.0379, Fisher's exact test). Expression of Reg IV was detected in 14 (93.3%) of 15 colorectal carcinoid tumours. Reg IV expression was also detected in 5 (21.7%) of 23 ductal adenocarcinomas of the pancreas. In contrast, lung cancers (n = 30) and breast cancers (n = 30) did not express Reg IV. This is the first immunohistochemical analysis of the expression and distribution of Reg IV protein in human tumours. These data suggest that Reg IV is expressed by gastrointestinal and pancreatic tumours, including adenocarcinomas and carcinoid tumours, and that Reg IV is associated with intestinal and neuroendocrine differentiation of the stomach and gastric carcinoma.

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OBJECTIVEPeople with type 2 diabetes are at increased risk of age-related cognitive decline and dementia. Hypoglycemia is a candidate risk factor, but the direction of association between episodes of severe hypoglycemia and cognitive decline in type 2 diabetes remains uncertain. RESEARCH DESIGN AND METHODSIn the Edinburgh Type 2 Diabetes Study, cognitive function was assessed in 831 adults with type 2 diabetes (aged 60-75 years) at baseline and after 4 years. Scores on seven neuropsychological tests were combined into a standardized general ability factor g. Self-reported history of severe hypoglycemia at baseline (history of hypoglycemia) and at follow-up (incident hypoglycemia) was recorded. RESULTSA history of hypoglycemia was reported by 9.3% of subjects, and 10.2% reported incident hypoglycemia. Incident hypoglycemia was associated with poorer cognitive ability at baseline (age-and sex-adjusted odds ratio for lowest tertile of g 2.04 [95% CI 1.25-3.31], P = 0.004). Both history of hypoglycemia and incident hypoglycemia were also associated with greater cognitive decline during followup (mean follow-up g adjusted for age, sex, and baseline g 20. CONCLUSIONSThe relationship between cognitive impairment and hypoglycemia appeared complex, with severe hypoglycemia associated with both poorer initial cognitive ability and accelerated cognitive decline. Diabetes Care 2014;37:507-515 | DOI: 10.233737:507-515 | DOI: 10. /dc13-1384 Type 2 diabetes is associated with an increased risk of cognitive impairment, agerelated cognitive decline, and dementia (1). Given the increasing numbers of elderly people with type 2 diabetes in the general population, the identification of potentially modifiable risk factors and the prevention of cognitive decline during older age in this group are of major importance to public health. Although the

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A B S T R A C T PurposePlasma levels of lysophospholipids were evaluated as potential biomarkers for colorectal cancer (CRC), where a highly reliable and minimally invasive blood test is lacking. Patients and MethodsPatients with CRC (n ϭ 133) and control subjects (n ϭ 125) were recruited through the Cleveland Clinic. Preoperative plasma samples were analyzed for lysophospholipid levels using liquid chromatography mass spectrometry in a blinded fashion. Participants were randomly divided in a 2:1 ratio into a "training set" (TS) and a "validation set" (VS). Logistic regression models were used in the TS to identify markers that best discriminated between CRC and controls. A cutoff point for the final discriminating model was developed using the receiver operating characteristic curve to achieve 95% specificity. All analyses were then independently validated in the VS. ResultsPlasma levels of several lysophosphatidylcholines (LPCs), including 18:1-and 18:2-LPC, were significantly decreased in CRC patients compared with controls (P Ͻ .001). A model based on total saturated LPC and the difference between the proportional amounts of 18:2-LPC and 18:1-LPC in the unsaturated LPC fraction was derived from the TS. This model achieved a sensitivity and specificity of 82% and 93%, respectively, in the VS. Overall, 118 (94%) of 125 control subjects and 113 (85%) of 133 CRC cases were correctly identified, including eight (89%) of nine CRC cases with stage T1 disease. ConclusionPercentage of 18:1-LPC or 18:2-LPC plasma levels compared with total saturated LPC levels, either individually or in combination, may represent potential biomarkers for CRC.

Mutated in colorectal cancer (MCC ) was originally identified as a candidate gene for familial adenomatous polyposis (FAP) but further study identified adenomatous polyposis coli (APC) as responsible for FAP and the physiologic/pathologic roles of MCC remained poorly understood. Recently, MCC promoter methylation was discovered as a frequent early event in a distinct subset of precursor lesions and colorectal cancer (CRC) associated with the serrated CRC pathway. Here we provide the first evidence of the biological significance of MCC loss in CRC and the molecular pathways involved. We show MCC expression is dramatically decreased in many CRC cell lines and the distinct subset of sporadic CRC characterized by the CpG island methylator phenotype and BRAF V600E mutation due to promoter methylation as reported previously. Importantly, we find MCC interacts with b-catenin and that reexpression of MCC in CRC cells specifically inhibits Wnt signaling, b-catenin/T-cell factor/lymphoid-enhancer factor-dependent transcription and cellular proliferation even in the presence of oncogenic mutant APC. We also show that MCC is localized in the nucleus and identify two functional nuclear localization signals. Taken together, MCC is a nuclear, b-catenininteracting protein that can act as a potential tumor suppressor in the serrated CRC pathway by inhibiting Wnt/b-catenin signal transduction.

Monoclonal antibodies against the immune checkpoint programmed cell death receptor 1 (PD-1) improve the hosts' antitumor immune response and have showed tremendous promise in the treatment of advanced solid tumors and hematologic malignancies. Reports of serious autoimmune dermatologic toxicities from immune checkpoint blockade therapy, however, are emerging. We report our experience with five patients who presented with pruritic vesicles and blisters on the skin while treated with anti-PD-1 antibody immunotherapy with either nivolumab or pembrolizumab. Four of the patients' skin biopsies revealed subepidermal bullae with immunohistochemical study for type IV collagen labeling the floor of the blister cavity and direct immunofluorescence studies (in three of the four patients tested) decorated linear IgG and C3 immune deposits on the blister roof, diagnostic of bullous pemphigoid. One patient developed bullous erythema multiforme. All patients had partial or complete resolution of skin lesions following treatment with systemic corticosteroid and cessation of checkpoint blockade. Recognition and treatment of rare immune-related bullous dermatologic toxicities will become increasingly important as more patients are treated with effective and newer immune checkpoint blockade therapy.

Cutaneous angiosarcoma (cAS) is a rare malignant neoplasm with variable clinical presentation. Although a distinct vascular tumour, cAS shares many overlapping histopathological features with other vasoformative and epithelioid tumours or 'mimickers'. cAS shows aggressive behaviour and carries a grave prognosis, thus early diagnosis is of paramount importance to achieve the best possible outcomes. Recently, several genetic studies were conducted leading to the identification of novel molecular targets in the treatment of cAS. Herein, we present a comprehensive review of cAS with discussion of its clinical, histopathological and molecular aspects, the differential diagnosis, as well as current therapies including ongoing clinical trials.