Stabilization of b-catenin by inhibition of its phosphorylation is characteristic of an activation of the canonical Wnt/b-catenin signaling pathway and is associated with various human carcinomas. It contrasts to an as yet incompletely characterized action of an alternative noncanonical Wnt signaling pathway on neoplastic transformation. The aim of the present study was to test the effects of a member of the noncanonical Wnt signaling pathway, Wnt-5a, in primary thyroid carcinomas and in thyroid carcinoma cell lines. Compared to normal tissue Wnt-5a mRNA expression was clearly increased in thyroid carcinomas. Immunohistochemically, a bellshaped response was observed with low to undetectable levels in normal tissue and in anaplastic tumors whereas differentiated thyroid carcinomas showed strong positive immunostaining for Wnt-5a. Transfection of Wnt-5a in a thyroid tumor cell line FTC-133 was able to reduce proliferation, migration, invasiveness and clonogenicity in these cells. These effects of Wnt-5a are associated with membranous b-catenin translocation and c-myc oncogene suppression and are mediated through an increase in intracellular Ca 2 þ release, which via CaMKII pathways promotes b-catenin phosphorylation. Specific inhibition of b-catenin phosphorylation by W-7, a calmodulin inhibitor, or by KN-93, a CaMKII inhibitor, supports these findings whereas PKC inhibitors were without effect. This interaction occurs downstream of GSK-3b as no Wnt-5a effect was seen on the Ser 9 phosphorylation of GSK-3b. Our data are compatible with the hypothesis that Wnt-5a serves as an antagonist to the canonical Wnt-signaling pathway with tumor suppressor activity in differentiated thyroid carcinomas.

Resection of central bile duct carcinoma is feasible in many patients and a favorable outcome after resection is mainly determined by curative resection and the absence of lymph node metastases.

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The aim of this study was to evaluate the expression of E-cadherin as a potential marker for the prognosis of thyroid carcinomas. In normal thyroid (n = 8), the expression of E-cadherin messenger ribonucleic acid levels was uniformly high and seemed to be restricted to thyrocytes. Steady-state messenger ribonucleic acid levels and immunostaining were both completely lost in undifferentiated thyroid carcinomas (n = 7) and were variably reduced in differentiated thyroid carcinomas (n = 44). In a follow-up study during a mean of 4.5 +/- 1.4 yr, E-cadherin messenger ribonucleic acid and immunohistochemical expression were compared with the initial clinicopathological parameters and with locoregional recurrence and the development of nodal or distant metastases in differentiated thyroid carcinomas. Immunohistochemical expression of E-cadherin was greatly reduced with the progression to primary tumor stage 4 (pT4) tumors. In parallel, patients with pT4 tumors had a higher rate of locoregional tumor recurrence and distant metastasis than did the group of patients with pT1-3 tumors. In 5 of 29 patients with pT4 tumors, positive E-cadherin staining of more than 30% of the cells was detected. None of these patients showed signs of a regional recurrence or distant metastases during an observation period of 4.3 +/- 1.1 yr. In 13 patients with E-cadherin-positive tumors, none developed new distant metastases which was in contrast to 7 of the group of 31 patients with less than 30% E-cadherin-positive cells. Thus, E-cadherin expression seems to be associated with the dedifferentiation, progression, and metastatic spread of thyroid carcinomas and may be a useful marker for the prognosis of these tumors.

Summary. The aim of this study was to test and establish the accuracy and reliability of lymphoma classification in bone marrow trephines according to the new World Health Organization (WHO) classification by considering predominantly the morphology and immunophenotype. Therefore, we retrospectively compared lymphoma diagnoses, rendered exclusively on bone marrow trephines without knowledge of lymph node diagnosis in 124 patients, with the results of the reference centres that had reviewed lymph node (n ¼ 90) or extranodal biopsies (n ¼ 34). The overall concordance rate was higher than 85% and 91%, respectively, when patients with discordant malignancy grades were excluded. The concordance rate for low-grade B-cell lymphomas was 93% and for high-grade B-cell lymphomas 84%. The main reasons for discordant diagnoses were divergent immunophenotypes among low-grade B-cell lymphomas (6 out of 81, i.e. 7AE4%) and discrepant malignancy grades within high-grade B-cell lymphomas (6 out of 31, i.e. 19AE4%). No relationship between discordant diagnoses and chemotherapy given during the course of the disease with the site of biopsy (i.e. lymph nodes, extranodal sites) was noted. We conclude from our results that bone marrow trephines are a reliable tool, not only for establishing bone marrow infiltration, but also for the subtyping of lymphomas.

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Under moderate hypothermia, low flow perfusion seems to provide adequate protection for the lower body organs. Microcirculatory parameters during perfusion as well as lactate levels within normal ranges throughout the experiments further confirm the concept.

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