Vania Nose

Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia.

Aims/hypothesisPostprandial hypoglycaemia following gastric bypass for obesity is considered a late manifestation of the dumping syndrome and can usually be managed with dietary modification. We investigated three patients with severe postprandial hypoglycaemia and hyperinsulinaemia unresponsive to diet, octreotide and diazoxide with the aim of elucidating the pathological mechanisms involved.MethodsGlucose, insulin, and C-peptide were measured in the fasting and postprandial state, and insulin secretion was assessed following selective intra-arterial calcium injection. Pancreas histopathology was assessed in all three patients.ResultsAll three patients had evidence of severe postprandial hyperinsulinaemia and hypoglycaemia. In one patient, reversal of gastric bypass was ineffective in reversing hypoglycaemia. All three patients ultimately required partial pancreatectomy for control of neuroglycopenia; pancreas pathology of all patients revealed diffuse islet hyperplasia and expansion of beta cell mass.Conclusions/interpretationThese findings suggest that gastric bypass-induced weight loss may unmask an underlying beta cell defect or contribute to pathological islet hyperplasia, perhaps via glucagon-like peptide 1-mediated pathways.

Midline Carcinoma of Children and Young Adults With NUT Rearrangement

PURPOSE A balanced chromosomal translocation, t(15;19), resulting in the BRD4-NUT oncogene, has been identified in a lethal carcinoma of young people, a disease described primarily in case reports. We sought to amass a more definitive series of tumors with NUT and/or BRD4 gene rearrangements and to determine distinct clinicopathologic features. PATIENTS AND METHODS Carcinomas (N = 98) in young individuals (median age, 32.5 years) were screened for NUT and BRD4 rearrangements using dual-color fluorescence in situ hybridization. Four published carcinomas with BRD4 and NUT rearrangements were also evaluated. Immunophenotypic analyses were performed. RESULTS Eleven tumors had NUT gene rearrangements, including eight with BRD4-NUT fusions and three with novel rearrangements, which were designated as NUT variant. All NUT-rearranged carcinomas (NRCs) arose from midline epithelial structures, including the first example arising below the diaphragm. Patients were young (median age, 17.6 years). Squamous differentiation (seen in 82% of NRCs) was particularly striking in NUT-variant cases. In this first description of NUT-variant carcinomas, the average survival (96 weeks, n = 3) was longer than for BRD4-NUT carcinomas (28 weeks, n = 8). Strong CD34 expression was found in six of 11 NRCs but in zero of 45 NUT wild-type carcinomas. CONCLUSION NRCs arise from midline structures in young people, and NRCs with BRD4-NUT are highly lethal, despite intensive therapies. NUT-variant carcinomas might have a less fulminant clinical course than those with BRD4-NUT fusions. CD34 expression is characteristic in NRCs and, therefore, holds promise as a diagnostic test for this distinctive clinicopathologic entity.

Genetic and Biological Subgroups of Low-Stage Follicular Thyroid Cancer

Investigations of cancer-specific gene rearrangements have increased our understanding of human neoplasia and led to the use of the rearrangements in pathological diagnosis of blood cell and connective tissue malignancies. Here, we have investigated 3p25 rearrangements of the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene in follicular epithelial tumors of the human thyroid gland. Eleven of 42 (26%) low-stage follicular carcinomas, 0 of 40 follicular adenomas, 1 of 30 Hurthle cell carcinomas, 1 of 90 papillary carcinomas, and 0 of 10 nodular goiters had 3p25 rearrangements by interphase fluorescence in situ hybridization. All 11 follicular carcinomas with 3p25 rearrangement exhibited strong, diffuse nuclear immunoreactivity for PPAR gamma, consistent with expression of PPAR gamma fusion protein. Twelve of 42 (29%) low-stage follicular carcinomas had 3p25 aneusomy without PPAR gamma rearrangement (P = 0.01), suggesting that PPAR gamma rearrangement and aneuploidy are independent early events in follicular cancer. Eleven of 12 follicular carcinomas with 3p25 aneusomy exhibited no PPAR gamma immunoreactivity, supporting the existence of two independent pathways. Follicular carcinoma patients with PPAR gamma rearrangement more frequently had vascular invasion (P = 0.01), areas of solid/nested tumor histology (P < 0.001), and previous non-thyroid cancers (P < 0.01) compared with follicular carcinoma patients without PPAR gamma rearrangement. Our experiments identify genetic subgroups of low-stage follicular thyroid cancer and provide evidence that follicular carcinomas with PPAR gamma rearrangement are a distinct biological entity. The findings support a model in which separate genetic alterations initiate distinct pathways of oncogenesis in thyroid carcinoma subtypes.

Prevention of intra-abdominal adhesions using the antiangiogenic COX-2 inhibitor celecoxib.

Objective:To determine the effects of COX-2 specific inhibitors on postoperative adhesion formation. Summary and Background Data:Intra-abdominal adhesions are the major cause of intestinal obstruction and secondary infertility after surgical procedures. Because adhesion synthesis requires angiogenesis, and cyclooxygenase-2 enzyme (COX-2) inhibitors have antiendothelial activity, we tested COX-2 inhibitors in a murine model of intra-abdominal adhesion formation. Methods:A silicone patch was secured to the lateral abdominal wall of groups of C57BL/6 mice, followed by cecal abrasion to promote adhesion formation. Beginning on the day of surgery, mice were treated with the selective COX-2 agents, celecoxib or rofecoxib, and the nonspecific COX inhibitors, aspirin, naproxen, ibuprofen, or indomethacin. Animals were treated for 10 days and killed. A second group (celecoxib, rofecoxib, aspirin) was treated for 10 days and observed for an additional 25 days. After treatment, intra-abdominal adhesions were scored using a standard method. The patch was subjected to immunohistochemistry with the endothelial-specific marker, CD31. Results:Animals treated with selective and nonselective COX-2 inhibitors, except aspirin, had significantly fewer adhesions than control animals. Celecoxib produced a maximal reduction in adhesion formation compared with rofecoxib and the nonselective COX-2 inhibitors at 10 days. After 25 days, celecoxib and rofecoxib, but not aspirin, had fewer adhesions than control mice. Adhesions from mice treated with celecoxib had reduced microvessel density compared with rofecoxib, the nonselective COX inhibitors, and control animals. Conclusions:Selective COX-2 inhibitors, in particular celecoxib, provide durable inhibition of intra-abdominal adhesions through an antiangiogenic mechanism.

Omega-3 Fatty Acids Improve Hepatic Steatosis in a Murine Model: Potential Implications for the Marginal Steatotic Liver Donor

The presence of nonalcoholic fatty liver disease often precludes potential organs from being used for transplantation. To date, there is no adequate treatment for hepatic steatosis, and it is expected that, because of increased obesity in Western society, the incidence of this disorder will increase. We investigated the effect of omega-3 polyunsaturated fatty acid supplementation on the treatment of hepatic steatosis in C57/Bl6 mice fed a high-carbohydrate, fat-free diet and in B6.V-Lep(ob) obese mice. Omega-3 fatty acid supplementation reversed hepatic steatosis in C57/Bl6 mice fed a high-carbohydrate, fat-free diet and converted macrovesicular to microvesicular steatosis in B6.V-Lep(ob) obese mice as determined by histology, magnetic resonance spectroscopy, and liver biochemistry We therefore conclude that omega-3 fatty acid supplementation improves hepatic steatosis in mice and may be used to increase the pool of potential live liver donors that are currently excluded because of the presence of macrovesicular steatosis.

Distinct chromosomal rearrangements in subungual (Dupuytren) exostosis and bizarre parosteal osteochondromatous proliferation (Nora lesion)

Background:Proliferative lesions of the bone surface, such as subungual (Dupuytren) exostosis and bizarre parosteal osteochondromatous proliferation (BPOP, Nora lesion) are currently classified as reactive, proliferative processes that mimic primary neoplasms of bone. Methods:Cytogenetic analysis was performed on 3 subungual exostoses of the great toe and 2 BPOP lesions of the radius and ulna. Results:A balanced translocation t(X;6) was identified in all cases of subungual exostoses. The chromosomal rearrangements observed in 1 case of BPOP differed from those seen in subungual exostosis. Conclusions:The presence of chromosomal abnormalities in subungual exostosis and BPOP suggests that these lesions are neoplastic, with a different molecular pathogenesis, and that each is a distinct clinicopathologic entity.

Comparison of 5 intravenous lipid emulsions and their effects on hepatic steatosis in a murine model

BACKGROUND Plant-based intravenous lipid emulsions have been shown to contribute to parenteral nutrition-associated liver disease (PNALD). There is mounting evidence that fish oil-based emulsions may prevent this liver injury. This study compares 5 emulsions with different fat compositions and their effect on hepatic steatosis, one of the first hits in PNALD. METHODS C57BL/6J mice were placed on a fat-free diet and randomized into 5 equal groups. Each group received one of the commercially available intravenous lipid emulsions (Intralipid [Baxter/Fresenius Kabi, Deerfield, Ill], Liposyn II [Hospira Inc, Lake Forest, Ill], ClinOleic [Baxter/Clintec Parenteral SA, Cedex, France], SMOFlipid [Fresenius Kabi, Bad Homburg, Germany], or Omegaven [Fresenius Kabi Deutschland GmbH]) or normal saline. Liver enzymes, degree of steatosis, and fatty acid compositions were analyzed after 19 days. RESULTS Intralipid, Liposyn II, ClinOleic, and SMOFlipid groups all demonstrated moderate steatosis with hepatic fat contents of 17.4%, 21.9%, 22.5%, and 12.6%, respectively. Omegaven mice, however, had normal livers. Saline control mice developed biochemical evidence of essential fatty acid deficiency (EFAD). Lipid supplementation with Intralipid, Liposyn II, and Omegaven prevented the onset of biochemical EFAD, whereas administration of ClinOleic and SMOFlipid did not. CONCLUSION The fish oil-based lipid emulsion Omegaven prevented hepatic steatosis and EFAD in this murine model. ω-3 fatty acids may be efficacious in preventing PNALD and should be explored in the development of novel lipid emulsions.

Galectin-3 Targeted Therapy with a Small Molecule Inhibitor Activates Apoptosis and Enhances Both Chemosensitivity and Radiosensitivity in Papillary Thyroid Cancer

Although most patients with papillary thyroid cancer (PTC) have favorable outcomes, some have advanced PTC that is refractory to external beam radiation and systemic chemotherapy. Galectin-3 (Gal-3) is a β-galactoside–binding protein with antiapoptotic activity that is consistently overexpressed in PTC. The purpose of this study is to determine if Gal-3 inhibition promotes apoptosis, chemosensitivity, and radiosensitivity in PTC. PTC cell lines (8505-C and TPC-1) and human ex vivo PTC were treated with a highly specific small molecule inhibitor of Gal-3 (Td131_1). Apoptotic activity was determined by flow cytometric analysis as well as caspase-3 and PARP cleavage. The minimum inhibitory concentrations of Td131_1 and doxorubicin were determined, and their combined effects were measured to test for synergistic activity. The effects of Td131_1 on radiosensitivity were determined by a clonogenic assay. Td131_1 promoted apoptosis, improved radiosensitivity, and synergistically enhanced chemosensitivity to doxorubicin in PTC cell lines. In PTC ex vivo, Td131_1 treatment alone induced the cleavage of caspase-3 and PARP. Td131_1 and doxorubicin together activated apoptosis in PTC ex vivo to a greater degree than their combined individual effects. Td131_1 activated apoptosis and had synergistic activity with doxorubicin in PTC. We conclude that Gal-3 targeted therapy is a promising therapeutic strategy for advanced PTC that is refractory to surgery and radioactive iodine therapy. (Mol Cancer Res 2009;7(10):1655–62)

SCF β-TRCP suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2

The E3 ubiquitin ligase β-TRCP, acting in concert with casein kinase I, drives ubiquitination and degradation of VEGFR2, and renders human papillary thyroid cancer cells resistant to the VEGFR2 inhibitor sorafenib.

Searching for mammary analog secretory carcinoma of salivary gland among its mimics

Mammary analog secretory carcinoma of salivary gland is a recently described entity with unique morphologic, clinical, and genetic characteristics, including the characteristic t(12;15)(p13;q25) with ETV6-NTRK3 translocation found in secretory carcinomas of the breast. Before their initial description, these salivary gland tumors were generally diagnosed as acinic cell carcinoma or adenocarcinoma. For the purpose of this study, all cases of salivary gland acinic cell carcinoma, cribriform cystadenocarcinoma, and adenocarcinoma, not otherwise specified (NOS), diagnosed over a 10-year period were retrieved from our surgical pathology files. There were a total of 11 cases diagnosed as acinic cell carcinoma, 10 cases of adenocarcinoma, NOS, and 6 cases of cribriform cystadenocarcinoma. All slides were reviewed by two pathologists (AP, CGF) and tumors that show morphologic features of mammary analog secretory carcinoma according to the recent literature were selected. This process narrowed down the initial number to six cases originally diagnosed as acinic cell carcinoma, three cases originally diagnosed as adenocarcinoma, NOS, and one case originally diagnosed as cribriform cystadenocarcinoma. The 10 cases were subjected to immunohistochemistry for S-100, mammaglobin, and ANO1, as well as fluorescence in situ hybridization analysis for t(12;15)(p13;q25) with ETV6-NTRK3 fusion rearrangement. The ETV6-NTRK3 gene rearrangement was detected in three tumors. These three tumors, initially diagnosed as acinic cell carcinomas, stained positive for S-100 and mammaglobin, and negative for ANO1 by immunohistochemistry. Two of the three patients were male (2/3). In summary, mammary analog secretory carcinoma is a newly described diagnostic entity that should be in the differential diagnosis of salivary gland tumors that morphologically mimic other neoplasms, mainly acinic cell carcinomas. They differ from conventional acinic cell tumors immunohistochemically and molecularly. Positivity for mammaglobin and S-100, and negativity for ANO1 are useful screening tools before confirmatory molecular studies.