A Neuroendocrine Carcinoma of Undetermined Origin in a Dog

In this report, we describe a case of neuroendocrine carcinoma of undetermined origin in a dog. Necropsy revealed scattered small neoplastic nodules in the bilateral lungs and a small nodule in the parapancreatic lymph node. Histopathologically, both pulmonary and lymph nodal nodules showed a similar histologic pattern, with neoplastic cells being arranged in diffusely proliferating sheet-like cellular nests separated by variable amounts of fibrous septa, sometimes forming rosettes and duct-like structures. Scattered small necrotic foci and invasion to fibrous septa were typically observed. Neoplastic cells showed round to oval-shaped nuclei with prominent nucleoli and abundant eosinophilic cytoplasm that were positive for Grimelius’ silver impregnation staining and immunostaining with cytokeratin, synaptophysin, vasoactive intestinal peptide and chromogranin A, indicative of the development of a neuroendocrine carcinoma. However, judging from the distribution of tumors lacking the portion suggestive of the primary site in any organ examined, as well as no further indication of differentiation potential of neoplastic cells, this tumor has so far been diagnosed as neuroendocrine carcinoma of undetermined origin

The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer

available in PMC 2011 February 3.MCL-1 has emerged as a major oncogenic and chemoresistance factor. A screen of stapled peptide helices identified the MCL-1 BH3 domain as selectively inhibiting MCL-1 among the related anti-apoptotic Bcl-2 family members, providing insights into the molecular determinants of binding specificity and a new approach for sensitizing cancer cells to apoptosis.National Institutes of Health (U.S.) (NIH award 5RO1GM084181)National Institutes of Health (U.S.) (NIH grant 5P01CA92625)National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F31CA144566)Burroughs Wellcome Fund (Career Award

Family Income Gradients in the Health and Health Care Access of US Children

This study sought to examine the shape and magnitude of family income gradients in US children’s health, access to care, and use of services. We analyzed cross-sectional data from the 2003 National Survey of Children’s Health, a telephone survey of 102,353 parents of children aged 0–17 years. Associations between family income [Below 100% Federal Poverty Level (FPL), 100–199% FPL, 200–299% FPL, 300–399% FPL, 400% FPL or Greater] and a set of 32 health and health care indicators were examined using linear polynomial testing and multivariate logistic regression. The percentage of children in better health increased with family income for 15 health outcomes. In multivariate logistic regression models that controlled for health insurance coverage and socio-demographic confounders, odds ratios >2 comparing the lowest to the highest income groups were noted for health conditions across both physical and developmental domains (diabetes, headaches, ear infections, learning disabilities, behavior/conduct problems, speech problems). Parent-reported global child health status, activity limitation, and oral health status showed steeper gradients than specific chronic and acute conditions. Ten measures of health care access and utilization were associated with family income in multivariate logistic regression models. Income gradients are pervasive across many health indicators at an early age. Social and health policy interventions are needed to address the multitude of factors that can affect children’s health and initiate disparities in development

Hedgehog Inhibition Promotes a Switch from Type II to Type I Cell Death Receptor Signaling in Cancer Cells

TRAIL is a promising therapeutic agent for human malignancies. TRAIL often requires mitochondrial dysfunction, referred to as the Type II death receptor pathway, to promote cytotoxicity. However, numerous malignant cells are TRAIL resistant due to inhibition of this mitochondrial pathway. Using cholangiocarcinoma cells as a model of TRAIL resistance, we found that Hedgehog signaling blockade sensitized these cancer cells to TRAIL cytotoxicity independent of mitochondrial dysfunction, referred to as Type I death receptor signaling. This switch in TRAIL requirement from Type II to Type I death receptor signaling was demonstrated by the lack of functional dependence on Bid/Bim and Bax/Bak, proapoptotic components of the mitochondrial pathway. Hedgehog signaling modulated expression of X-linked inhibitor of apoptosis (XIAP), which serves to repress the Type I death receptor pathway. siRNA targeted knockdown of XIAP mimics sensitization to mitochondria-independent TRAIL killing achieved by Hedgehog inhibition. Regulation of XIAP expression by Hedgehog signaling is mediated by the glioma-associated oncogene 2 (GLI2), a downstream transcription factor of Hedgehog. In conclusion, these data provide additional mechanisms modulating cell death by TRAIL and suggest Hedgehog inhibition as a therapeutic approach for TRAIL-resistant neoplasms

Feasibility, safety and pharmacokinetic study of hepatic administration of drug-eluting beads loaded with irinotecan (DEBIRI) followed by intravenous administration of irinotecan in a porcine model

Irinotecan eluting embolization beads (DEBIRI) are currently being evaluated in the clinic for the treatment of colorectal cancer metastases to the liver. The aim of this study was to determine the safety and pharmacokinetics associated with two cycles of hepatic embolization using DEBIRI followed by intravenous administration of irinotecan. Pigs were embolized with DEBIRI (100–300 μm, 100 mg dose, n = 6) and blood samples taken over 24 h to determine plasma levels of irinotecan and SN-38 metabolite and for haematology and biochemistry. At 24 h an IV infusion of 250 mg/m2 of irinotecan was administered and the plasma levels taken again. This cycle was repeated 3 weeks later. A single animal was subjected to a more aggressive regimen of embolization with 200 mg bead dose and IV of 350 mg/m2 for two cycles. Three animals were sacrificed at 6 weeks and the remaining four (n = 3 standard dose, n = 1 high dose) animals at 12 weeks and detailed histopathology performed. All animals tolerated the treatments well, with only minor changes in haematological and biochemical parameters. There was no overlap in drug plasma levels observed from the bead and IV treatments when given 24 h apart and no difference between the pharmacokinetic profiles of the two cycles separated by 3 weeks. Irinotecan plasma AUC values were similar in both the embolization and IV arms of the study. Cmax values obtained during the IV arms of the study are approximately double that of the embolization arms whilst Tmax times are shorter in the IV arms, supporting extended release of drug from the beads. Bioavailability for bead-based delivery was double that for IV administration, which was attributed to reduced clearance of the drug when delivered by this route. No additive toxicity was observed as a consequence of the combined treatments. The combination of irinotecan delivery via drug eluting bead and IV was well-tolerated with no significant clinical effects. Pharmacokinetic analyses suggest the bioavailability from bead-based delivery of drug is double that of IV infusion, attributable to reduced drug clearance for the former.Andrew L. Lewis, Rachel R. Holden, S. Ting Chung, Peter Czuczman, Timothy Kuchel, John Finnie, Susan Porter, David Foste

Expert consensus document:Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted