Neuroendocrine tumours (NET) of the gastroenteropancreatic system comprise a malignant entity with a low incidence. Only limited information is available on long-term clinical outcome and clinically applicable prognostic factors. We performed a retrospective analysis of a large, wellcharacterized centre-based patient cohort of 399 patients with histologically proven NET. Data were analysed according to epidemiological, clinical and histopathological characteristics. Detailed survival analyses using the Kaplan-Meier method were performed. Prognostic factors were tested by log-rank testing and independent risk factors were analysed using a Cox regression model. In the studied cohort, primary tumours originated in the fore-, mid-and hindgut in 46.1, 37.1 and 4.5% respectively. Extra-intestinal or unknown primary tumours were present in 8.4 and 10.5% respectively. Distant metastasis was present at initial diagnosis in 69.4%. Most frequent metastatic sites were liver (85%), peritoneal cavity (18%), bones (8%), other intraabdominal sites (6%) and lungs (4%). Overall, 5-and 10-year survival rates were 78 and 63% respectively. Time to progression after initial diagnosis was significantly shorter in pancreatic as compared with ileal NET. Survival analysis revealed significantly better clinical outcome for primary tumours smaller than 25 mm, absence of metastasis, absence of any clinical symptoms, positive immunohistochemical staining for chromogranin A and a lower Ki67 index. These results were confirmed as independent by multivariate analysis. Therefore, this large retrospective analysis of a well-documented cohort of patients with NET demonstrates several prognostic factors of clinical relevance and wide availability, which should be considered for risk stratification in the management of NET.

BACKGROUND. Neuroendocrine tumors (NETs) of the gastroenteropancreatic (GEP) system comprise a rare but challenging group of malignant neoplasms and occur at virtually any site of the GEP system. In 2006, a new TNM classification system was proposed for the staging and grading of upper GEP NETs. METHODS. The prognostic relevance of the TNM classification system was analyzed retrospectively in 202 patients from a referral center with histologically proven foregut NET. Patients were classified according to previous classification systems and the TNM classification. Survival data were acquired and statistical analyses were performed by using log‐rank and Cox regression testing. RESULTS. Primary tumors were gastric (n = 48), duodenal (n = 23), and pancreatic (n = 131). During the observation period, 21% of patients died. The overall 5‐ and 10‐year survival rates were 75% and 64%, respectively. Previous classification systems discriminated between low‐grade and high‐grade malignant NETs but did not allow further prognostic differentiation. In contrast, the proposed TNM classification was able to differentiate significantly between different tumor stages (stages I‐III vs stage IV; P < .01) and cellular proliferation rates according to Ki‐67 labeling (grade 1 vs grade 2, P = .04; grade 1 vs grade 3 and grade 2 vs grade 3, P < .01). Cox regression analysis confirmed an increased risk of reduced survival for patients with stage III or IV NET and grade 2 or 3 NET. CONCLUSIONS. The current results demonstrated the prognostic relevance of the newly proposed TNM classification system for foregut NETs with statistical significance for the subgroups of both the staging classification and the grading system. Thus, the new classification system provides a valid and powerful tool for prognostic stratification of GEP NETs in clinical practice and research. Cancer 2008. © 2008 American Cancer Society.

Somatostatin-producing neuroendocrine tumors (SOM-NETs) of the duodenum and pancreas appear to be heterogeneous. To determine their clinicopathological profiles, respective data were analyzed on a series of 82 duodenal and 541 pancreatic NETs. In addition, the clinical records of 821 patients with duodenal or pancreatic NETs were reviewed for evidence of a somatostatinoma syndrome. Predominant or exclusive expression of somatostatin was found in 21 (26%) duodenal and 21 (4%) pancreatic NETs. They were classified as sporadic (nZ31) or neurofibromatosis type 1 (NF1)-associated duodenal NETs (nZ3), gangliocytic paragangliomas (GCPGs; nZ6), or poorly differentiated neuroendocrine carcinomas (pdNECs; nZ2). In addition, five duodenal and four pancreatic SOM-NETs were found in five patients with multiple endocrine neoplasia type 1 (MEN1). Metastases occurred in 13 (43%) patients with sporadic or NF1-associated SOM-NETs, but in none of the duodenal or pancreatic MEN1-associated SOM-NETs or GCPGs. Sporadic advanced (stage IV) SOM-NETs were more commonly detected in the pancreas than in the duodenum. None of the patients (including the 821 patients for whom only the clinical records were reviewed) fulfilled the criteria of a somatostatinoma syndrome. Our data show that somatostatin expression is not only seen in sporadic NETs but may also occur in GCPGs, pdNECs, and hereditary NETs. Surgical treatment is effective in most duodenal and many pancreatic SOM-NETs. MEN1-associated SOM-NETs and GCPGs follow a benign course, while somatostatin-producing pdNECs are aggressive neoplasms. The occurrence of the so-called somatostatinoma syndrome appears to be extremely uncommon.

Sorting of eukaryotic membrane and secretory proteins depends on recognition of ribosome-bound nascent chain signal sequences by the signal recognition particle (SRP). The current model suggests that the SRP cycle is initiated when a signal sequence emerges from the ribosomal tunnel and binds to SRP. Then elongation is slowed until the SRP-bound ribosome-nascent chain complex (RNC) is targeted to the SRP receptor in the endoplasmic reticulum (ER) membrane. The RNC is then transferred to the translocon, SRP is released, and translation resumes. Because RNCs do not target to the translocon efficiently if nascent chains become too long, the window for SRP to identify its substrates is short. We now show that a transmembrane signal-anchor sequence (SA) significantly enhances binding of SRP to RNCs even before the SA emerges from the ribosomal tunnel. In this mode, SRP does not contact the SA directly but is in close proximity to the portion of the nascent polypeptide that has already left the ribosomal tunnel. Early recruitment of SRP provides a mechanism to expand the window for substrate identification. We suggest that the dynamics of the SRP-ribosome interaction is affected not only by the direct binding of SRP to an exposed signal sequence but also by properties of the translating ribosome that are triggered from within the tunnel.chaperones ͉ site-specific cross-linking ͉ yeast ͉ nascent polypeptide-associated complex ͉ Ssb1/2

Galectin-4 is a carbohydrate-binding protein belonging to the galectin family. Here we provide novel evidence that galectin-4 is selectively expressed and secreted by intestinal epithelial cells and binds potently to activated peripheral and mucosal lamina propria T-cells at the CD3 epitope. The carbohydrate-dependent binding of galectin-4 at the CD3 epitope is fully functional and inhibited T cell activation, cycling and expansion. Galectin-4 induced apoptosis of activated peripheral and mucosal lamina propria T cells via calpain-, but not caspase-dependent, pathways. Providing further evidence for its important role in regulating T cell function, galectin-4 blockade by antisense oligonucleotides reduced TNF-alpha inhibitor induced T cell death. Furthermore, in T cells, galectin-4 reduced pro-inflammatory cytokine secretion including IL-17. In a model of experimental colitis, galectin-4 ameliorated mucosal inflammation, induced apoptosis of mucosal T-cells and decreased the secretion of pro-inflammatory cytokines. Our results show that galectin-4 plays a unique role in the intestine and assign a novel role of this protein in controlling intestinal inflammation by a selective induction of T cell apoptosis and cell cycle restriction. Conclusively, after defining its biological role, we propose Galectin-4 is a novel anti-inflammatory agent that could be therapeutically effective in diseases with a disturbed T cell expansion and apoptosis such as inflammatory bowel disease.

Neuroendocrine tumors (NETs) are rare neoplasms. Approximately 75% of all cases manifest in the gastroenteropancreatic (GEP) system. Because of the low incidence of NETs, limited data about the clinical outcome and prognostic variables are available. In an attempt to identify prognostic parameters, we investigated the distribution of primary tumors, pattern of metastasis formation, clinical presentation, histological classification, and outcome of therapeutic interventions in a large patient cohort cared for in a German referral center. In 254 patients with GEP-NETs, the primary tumor was of foregut, midgut, or hindgut origin in 44.1% (28.7% pancreas), 43.7% (34.7% jejunoileum), and 4.3%, respectively. No primary tumor was found in 7.9%. Metastases occurred preferentially in lymph nodes and the liver. The overall 5-year survival rate was 57.1%. In the absence or presence of metastases at initial diagnosis the 5-year survival rate was 80.0% and 51.7%, respectively. The 5-year survival rate was related to the localization of the primary and was 75.0% and 42.9% for jejunoileal and pancreatic tumors, respectively. The size of the primary tumor (<2 cm) and histological grading as low-grade malignant were both associated with a significantly longer survival. Surgery with curative intent was attempted in 141 patients. However, an R(0) resection was achieved in only 66.0% of these patients. Five-year survival rate in the latter group was significantly higher (77.3%) as compared with all surgical patients (55.4%). Long-term tumor-free survival was obtained in only 53.7% of successfully resected patients. Palliative medical treatment, either with chemotherapy (i.e., especially for foregut NETs) or biotherapy (especially for midgut NETs), was only moderately effective for both therapeutic regimens.

Galectins have recently emerged as central regulators of the immune system. We have previously demonstrated that carbohydrate-dependent binding of galectin-2 induces apoptosis in activated T cells. Here, we investigate the potential therapeutic effect of galectin-2 in experimental colitis. Galectin-2 expression and its binding profile were determined by immunohistochemistry. Acute and chronic colitis was induced by dextran sodium sulfate administration and in a T-cell transfer colitis model. Apoptosis was assessed by TdT-mediated dUTP-biotin nick-end labeling, and cytokine secretion was determined by cytometric bead array. We show that galectin-2 was constitutively expressed mainly in the epithelial compartment of the mouse intestine and bind to lamina propria mononuclear cells. During colitis, galectin-2 expression was reduced, but could be restored to normal levels by immunosuppressive treatment. Galectin-2 treatment induced apoptosis of mucosal T cells and thus ameliorated acute and chronic dextran-sodium-sulfate-induced colitis and in a T-helper-cell 1-driven model of antigen-specific transfer colitis. Furthermore, the pro-inflammatory cytokine release was inhibited by galectin-2 treatment. In preliminary toxicity studies, galectin-2 was well tolerated. Our study provides evidence that galectin-2 induces apoptosis in vivo and ameliorates acute and chronic murine colitis. Furthermore, galectin-2 has no significant toxicity over a broad dose range, suggesting that it may serve as a new therapeutic agent in the treatment of inflammatory bowel disease.

NAC acts as a modulator of SRP function. It can bind to signal sequences directly. SRP initially displaces NAC from RNCs; however, when the signal sequence emerges, trimeric NAC·RNC·SRP complexes form. Upon docking NAC·RNC·SRP complexes to the ER, NAC remains bound, allowing NAC to shield cytosolically exposed nascent chain domains.