As incidence data on gastroenteropancreatic neuroendocrine tumours (GEP-NETs) have so far only been retrospectively obtained and based on inhomogeneous material, we conducted a prospective study in Austria collecting all newly diagnosed GEP-NETs during 1 year. Using the current WHO classification, the tumor, nodes, metastases (TNM) staging and Ki67 grading and the standard diagnostic procedure proposed by the European Neuroendocrine Tumor Society (ENETS), GEP-NETs from 285 patients (male: 148; female: 137) were recorded. The annual incidence rates were 2.51 per 100 000 inhabitants for men, 2.36 per 100 000 for women. The stomach (23%) was the main site, followed by appendix (21%), small intestine (15%) and rectum (14%). Patients with appendiceal tumours were significantly younger than patients with tumours in any other site. About 46.0% were classified as benign, 15.4% as uncertain, 31.9% as well differentiated malignant and 6.7% as poorly differentiated malignant. Patients with benign or uncertain tumours were significantly younger than patients with malignant tumours. Among the malignant tumours of the digestive tract, 1.49% arose from neuroendocrine cells. For malignant gastrointestinal NETs, the incidence was 0.80 per 100 000: 40.9% were ENETS stage I, 23.8% stage II, 11.6% stage III and 23.8% stage IV. The majority (59.7%) were grade 1, 31.2% grade 2 and 9.1% grade 3. NETs of the digestive tract are more common than previously reported; the majority show benign behaviour, are located in the stomach and are well differentiated. G3 tumours are very rare.

We have cloned a novel pancreatic beta cell and neuroendocrine cell-specific calcium-binding protein termed secretagogin. The cDNA obtained by immunoscreening a human pancreatic cDNA library using the recently described murine monoclonal antibody D24 contains an open reading frame of 828 base pairs. This codes for a cytoplasmic protein with six putative EF finger hand calcium-binding motifs. The gene could be localized to chromosome 6 by alignment with GenBank genomic sequence data. Northern blot analysis demonstrated abundant expression of this protein in the pancreas and to a lesser extent in the thyroid, adrenal medulla, and cortex. In addition it was expressed in scant quantity in the gastrointestinal tract (stomach, small intestine, and colon). Thyroid tissue expression of secretagogin was restricted to C-cells. Using a sandwich capture enzyme-linked immunosorbent assay with a detection limit of 6.5 pg/ml, considerable amounts of constitutively secreted protein could be measured in tissue culture supernatants of stably transfected RIN-5F and dog insulinoma (INS-H1) cell clones; however, in stably transfected Jurkat cells, the protein was only secreted upon CD3 stimulation. Functional analysis of transfected cell lines expressing secretagogin revealed an influence on calcium flux and cell proliferation. In RIN-5F cells, the antiproliferative effect is possibly due to secretagogin-triggered down-regulation of substance P transcription.

In individuals with mammary carcinoma, the most relevant prognostic predictor of distant organ metastasis and clinical outcome is the status of axillary lymph node metastasis. Metastases form initially in axillary sentinel lymph nodes and progress via connecting lymphatic vessels into postsentinel lymph nodes. However, the mechanisms of consecutive lymph node colonization are unknown. Through the analysis of human mammary carcinomas and their matching axillary lymph nodes, we show here that intrametastatic lymphatic vessels and bulk tumor cell invasion into these vessels highly correlate with formation of postsentinel metastasis. In an in vitro model of tumor bulk invasion, human mammary carcinoma cells caused circular defects in lymphatic endothelial monolayers. These circular defects were highly reminiscent of defects of the lymphovascular walls at sites of tumor invasion in vivo and were primarily generated by the tumor-derived arachidonic acid metabolite 12S-HETE following 15-lipoxygenase-1 (ALOX15) catalysis. Accordingly, pharmacological inhibition and shRNA knockdown of ALOX15 each repressed formation of circular defects in vitro. Importantly, ALOX15 knockdown antagonized formation of lymph node metastasis in xenografted tumors. Furthermore, expression of lipoxygenase in human sentinel lymph node metastases correlated inversely with metastasis-free survival. These results provide evidence that lipoxygenase serves as a mediator of tumor cell invasion into lymphatic vessels and formation of lymph node metastasis in ductal mammary carcinomas.

Papillary (PTC) and follicular thyroid carcinoma (FTC) are known as differentiated thyroid carcinoma (DTC). Nevertheless, according to the UICC/AJCC (TNM) classification PTC and FTC are frequently analyzed as one cancer. The aim of this study is to show differences in outcome and specific prognostic factors in an iodine-replete endemic goiter region.Six hundred and three patients with DTC treated within a 35-year-period were retrospectively analyzed with respect to carcinoma-specific survival. Prognostic factors were tested for their significance using univariate and multivariate analysis.The histological type (PTC versus FTC) was found to be a highly significant factor -carcinomaspecific survival both in univariate ðP < 0:001Þ and multivariate analyses ðP ¼ 0:003Þ was significantly different. Univariate analysis revealed patients' age, extra-thyroid tumor spread, lymph node and distant metastases, increasing tumor size, and the tall cell variant to be significant prognostic factors for PTC patients. Age !45 years, positive lymph nodes and increasing tumor size were confirmed as independent prognostic factors. Univariate analysis of FTC patients revealed age at presentation, gender, extrathyroidal tumor spread, lymph node and distant metastases, increasing tumor size, multifocality, widely invasive tumor growth and oxyphilic variant to be factors bearing prognostic significance. The presence of distant metastases and increasing tumor size could be identified as independent prognostic factors for FTC patients.This study shows distinctive differences in prognostic factors of PTC and FTC: independent factors predicting poor prognosis are age !45 years, positive lymph nodes and increasing tumor size for PTC, and distant metastases and increasing tumor size for FTC. PTC and FTC patients should be analyzed and reported separately.

The clinical behavior of the follicular variant of papillary thyroid carcinoma (FVPTC) is similar to pure papillary thyroid carcinoma (PPTC) and completely different from follicular thyroid carcinoma (FTC).Design: Retrospective analysis of prospectively documented data.Setting: Referral center of a university hospital.Patients: Two hundred thirty-seven consecutive patients with follicular cell-derived thyroid carcinomas were operated on in our institution during a 15-year period, from January 1, 1980, to December 31, 1994. Of the 154 PTC patients, 37 (24%) had FVPTC. The mean follow-up was 128.2 months (10.7 years).Main Outcome Measures: Demographic features, tumor characteristics, local and distant spread, persistence or recurrence of disease, and carcinoma-related mortality were compared between the groups with FVPTC, PPTC, and non-Hü rthle cell FTC (NHFTC).Results: The frequency of multicentricity was significantly higher in the FVPTC group than in the PPTC group (P =.03) or in the NHFTC group (P =.01) (12 [32%] of 37 patients vs 17 [15%] of 117 patients vs 6 [10%] of 58 patients, respectively). The incidence of cervical lymph node metastases was lower in the FVPTC group than in the PPTC group (P = .30) and higher than in NHFTC group (P =.004) (12 [32%] of 37 patients vs 53 [45%] of 117 patients vs 6 [10%] of 58 patients, respectively). At diagnosis, no patient with FVPTC showed distant metastases, compared with 5 patients (4%) with PPTC (P=.34) and 19 (33%) with NHFTC (PϽ.001). There was no carcinoma-related death in the FVPTC group. The strikingly poorer prognosis for the NHFTC group was statistically significant (PϽ.001), whereas the difference in carcinoma-specific survival between the PPTC and the FVPTC groups did show a trend toward better survival in the FVPTC group. Conclusion:The clinical behavior of the FVPTC group did not differ significantly from that of the PPTC group, whereas compared with the NHFTC group, the FVPTC group showed statistically significant differences for most of the analyzed variables.

Indeterminate or suspicious findings on fine-needle aspiration (FNA) of nodular thyroid disease (i.e., findings that neither give immediate indication for surgery nor lead to clear-cut conservative management) have been the key diagnostic problem in thyroid cytology for which the inability to differentiate cytologically benign from malignant follicular growth has been one reason. The aim of this cohort study of 120 consecutive (103 females, 17 males) patients with palpable nodular thyroid disease diagnosed as follicular neoplasia (FN) by FNA (defined by the triad of high numbers of follicular cells, microfollicular arrangement, and scanty or absent colloid) was to identify patients at high risk for malignancy based on the prospective evaluation of clinical features and to characterize the histologic entities of FN. Based on a 100% surgery rate we found an 18% malignancy rate (12 papillary carcinomas, 9 follicular carcinomas). Previously suggested factors with elevated risk for malignancy such as extremes of age, male gender, and large nodule size were not associated with increased risk as were cold nodules by 99mTc-scintigraphy (relative risk: 1.2, 95% confidence interval [CI] 0.4-3.3). However, hard lesions to palpation (relative risk 2.6, 95% CI: 1.2-5.6), solitary (relative risk: 2.6, 95% CI: 1.7-4.0), and hypoechoic FNs (relative risk: 3.4, 95% CI: 2.0-5.7) by ultrasound showed elevated risks of malignancy. In summary, suspicious palpation or ultrasound results may help to define a subgroup of patients with elevated risk of malignancy when FNA indicates the diagnosis of follicular neoplasm of the thyroid.

These findings indicate that in patients without additional extraskeletal distant metastases, the radical surgical extirpation of bone metastases from differentiated thyroid carcinoma might be associated with improved survival.

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