Explore the vast range of titles available.

Over the past 5 years, a number of notable research advances have been made in the field of neuroendocrine cancer, specifically with regard to neuroendocrine cancer of the gastrointestinal tract. The aim of this Review is to provide an update on current knowledge that has proven effective for the clinical management of patients with these tumours. For example, for the first time in the tubular gastrointestinal tract, well-differentiated high-grade (grade 3) tumours and mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) are defined in the WHO classification. This novel classification enables efficient identification of the most aggressive well-differentiated neuroendocrine tumours and helps in defining the degree of aggressiveness of MiNENs. The Review also discusses updates to epidemiology, cell biology (including vesicle-specific components) and the as-yet-unresolved complex genetic background that varies according to site and differentiation status. The Review summarizes novel diagnostic instruments, including molecules associated with the secretory machinery, novel radiological approaches (including pattern recognition techniques), novel PET tracers and liquid biopsy combined with DNA or RNA assays. Surgery remains the treatment mainstay; however, peptide receptor radionuclide therapy with novel radioligands and new emerging medical therapies (including vaccination and immunotherapy) are evolving and being tested in clinical trials, which are summarized and critically reviewed here.During the past 5 years, a number of notable research advances have been reported for neuroendocrine cancers of the gastrointestinal tract. This Review provides an up-to-date summary of the research advances that have improved the clinical management of these cancers.

Background There have been few epidemiological studies on gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Japan. Methods We examined the epidemiology of GEP-NETs [pancreatic endocrine tumors (PETs) and gastrointestinal neuroendocrine tumors (GI-NETs)] in Japan in 2005 using a nationwide stratified random sampling method. Results A total of 2,845 individuals received treatment for PETs. Prevalence was estimated as 2.23/100,000 with an annual onset incidence of 1.01/100,000. Non-functioning tumor (NF)-PET constituted 47.4%, followed by insulinoma (38.2%) and gastrinoma (7.9%). Distant metastases were reported in 21% patients with NF-PETs and occurred more frequently as tumor size increased (>2 cm). Multiple endocrine neoplasia type 1 (MEN-1) was detected in 10% of PETs but only in 6.1% of NF-PETs. NF-PETs were detected incidentally by physical examination in 24% patients. In 2005, an estimated 4,406 patients received treatment for GI-NETs. Prevalence was estimated as 3.45/100,000, with an annual onset incidence of 2.10/100,000. The locations of GI-NETs varied: foregut, 30.4%; midgut, 9.6%; and hindgut, 60.0%. Distant metastases were observed in 6%. Lymph node metastases occurred more frequently as tumor size increased (>1 cm). The frequency of MEN-1 complications was 1%. Physical examination revealed GI-NETs in 44% patients. The frequency of symptomatic GI-NETs was 3.4%. Interestingly, 77.1% of patients with foregut GI-NETs had type A gastritis. Conclusion Our results show there are large differences in GEP-NETs between Japan and Western nations, primarily due to differences in the presence of MEN-1 in NF-PETs and the location, symptomatic status, and prevalence of malignancy in GI-NETs.

Myofibroblast-derived R-spondin 3 orchestrates regeneration of antral stomach epithelium via Wnt signalling in Axin2 + stem cells. Sustaining stomach tissue Regeneration of the stomach epithelium is thought to be driven by long-lived stem cells residing in a niche that is yet to be defined and which can be activated in response to gastric pathogens, such as Helicobacter pylori , through an unknown mechanism. Thomas Meyer and colleagues now show that Wnt target gene expression is constrained to a restricted region of the stomach encompassing Lgr5 + stem cells. The myofibroblasts adjacent to this region provide R-spondin 3 to the stem cell compartment. R-spondin 3 is able to convert Lgr5 − cells to Lgr5 + cells. The authors also find that Helicobacter pylori infection stimulates the expression of R-spondin 3 in myofibroblasts. This control of epithelial stem cell dynamics by stromal niche cells illustrates the sophisticated mechanism behind epithelial regeneration. The constant regeneration of stomach epithelium is driven by long-lived stem cells 1 , 2 , 3 , but the mechanism that regulates their turnover is not well understood. We have recently found that the gastric pathogen Helicobacter pylori can activate gastric stem cells and increase epithelial turnover 4 , while Wnt signalling is known to be important for stem cell identity and epithelial regeneration in several tissues 5 . Here we find that antral Wnt signalling, marked by the classic Wnt target gene Axin2 , is limited to the base and lower isthmus of gastric glands, where the stem cells reside. Axin2 is expressed by Lgr5 + cells, as well as adjacent, highly proliferative Lgr5 − cells that are able to repopulate entire glands, including the base, upon depletion of the Lgr5 + population. Expression of both Axin2 and Lgr5 requires stroma-derived R-spondin 3 produced by gastric myofibroblasts proximal to the stem cell compartment. Exogenous R-spondin administration expands and accelerates proliferation of Axin2 + /Lgr5 − but not Lgr5 + cells. Consistent with these observations, H. pylori infection increases stromal R-spondin 3 expression and expands the Axin2 + cell pool to cause hyperproliferation and gland hyperplasia. The ability of stromal niche cells to control and adapt epithelial stem cell dynamics constitutes a sophisticated mechanism that orchestrates epithelial regeneration and maintenance of tissue integrity.

In this trial, daily oral sunitinib was associated with a median progression-free survival of 11.4 months, as compared with 5.5 months for placebo (hazard ratio, 0.42; 95% confidence interval, 0.26 to 0.67; P<0.001), in patients with advanced pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors are uncommon tumors arising from endocrine cells of the pancreas. 1 Surgery is the mainstay of treatment for resectable disease, 2 and therapy directed to the liver may have some palliative benefit for metastases that occur predominantly in the liver. 3 , 4 Somatostatin analogues relieve symptoms resulting from hormone hypersecretion in functioning tumors and may delay disease progression in selected patients. 5 – 7 Streptozocin alone or in combination with doxorubicin remains the only chemotherapeutic agent approved for the treatment of advanced pancreatic neuroendocrine tumors, 8 – 11 though the magnitude of benefit has been challenged. 12 , 13 Vascular endothelial growth factor (VEGF) is a . . .

BackgroundA recently developed haemostatic peptide gel for endoscopic application has been introduced to improve the management of gastrointestinal bleeding. The aim of this pilot study was to evaluate the feasibility, safety, efficacy and indication profiles of PuraStat in a clinical setting.MethodsIn this prospective observational multicentre pilot study, patients with acute non-variceal gastrointestinal bleeding (upper and lower) were included. Primary and secondary application of PuraStat was evaluated. Haemoglobin, prothrombin time, platelets and transfusion behaviour were documented before and after haemostasis. The efficacy of PuraStat was assessed during the procedure, at 3 days and 1 week after application.Results111 patients with acute gastrointestinal bleeding were recruited into the study. 70 percent (78/111) of the patients had upper gastrointestinal bleeding and 30% (33/111) had lower gastrointestinal bleeding. After primary application of PuraStat, initial haemostatic success was achieved in 94% of patients (74/79, 95% CI 88–99%), and in 75% of the patients when used as a secondary haemostatic product, following failure of established techniques (24/32, 95% CI 59–91%). The therapeutic success rates (absence of rebleeding) after 3 and 7 days were 91% and 87% after primary use, and 87% and 81% in all study patients. Overall rebleeding rate at 30 day follow-up was 16% (18/111). In the 5 patients who finally required surgery (4.5%), PuraStat allowed temporary haemostasis and stabilisation.ConclusionsPuraStat expanded the therapeutic toolbox available for an effective treatment of gastrointestinal bleeding sources. It could be safely applied and administered without complications as a primary or secondary therapy. PuraStat may additionally serve as a bridge to surgery in order to achieve temporary haemostasis in case of refractory severe bleeding, possibly playing a role in preventing immediate emergency surgery.

Mucosal antibody responses play a major role in mediating homeostasis with the intestinal flora. It has been suggested that imbalance in the IgA+ and IgG+ intestinal B cell repertoire may be associated with the development of diseases such as inflammatory bowel disease. Despite this, little is known about the antibody specificity of human intestinal plasmablasts. Here, we have determined the reactivity profile of single isolated IgA+ and IgG+ plasmablasts from human terminal ileum using antibody cloning and in vitro expression. We found that approximately 25% of intestinal IgA and IgG plasmablast antibodies were polyreactive; the majority were antigen-specific. Antigen specificity was not only directed against enteropathogenic microbes but also against commensal microbes and self antigens. Regardless of their reactivity, all intestinal antibodies were somatically mutated and showed signs of antigen-mediated selection, suggesting that they developed from antigen-specific B cell responses. Together, our data indicate that antigen-specific immune responses to intestinal microbes are largely responsible for the maintenance of intestinal homeostasis and thus provide a basis for understanding the deregulated immune responses observed in patients with inflammatory bowel disease.

Background Despite strong recommendations for colorectal cancer (CRC) screening, participation rates are low. Understanding factors that affect screening choices is essential to developing future screening strategies. Therefore, this study assessed patient willingness to use non-invasive stool or blood based screening tests after refusing colonoscopy. Methods Participants were recruited during regular consultations. Demographic, health, psychological and socioeconomic factors were recorded. All subjects were advised to undergo screening by colonoscopy. Subjects who refused colonoscopy were offered a choice of non-invasive tests. Subjects who selected stool testing received a collection kit and instructions; subjects who selected plasma testing had a blood draw during the office visit. Stool samples were tested with the Hb/Hp Complex Elisa test, and blood samples were tested with the Epi proColon® 2.0 test. Patients who were positive for either were advised to have a diagnostic colonoscopy. Results 63 of 172 subjects were compliant to screening colonoscopy (37%). 106 of the 109 subjects who refused colonoscopy accepted an alternative non-invasive method (97%). 90 selected the Septin9 blood test (83%), 16 selected a stool test (15%) and 3 refused any test (3%). Reasons for blood test preference included convenience of an office draw, overall convenience and less time consuming procedure. Conclusions 97% of subjects refusing colonoscopy accepted a non-invasive screening test of which 83% chose the Septin9 blood test. The observation that participation can be increased by offering non-invasive tests, and that a blood test is the preferred option should be validated in a prospective trial in the screening setting.

BackgroundWhile platinum-based chemotherapy represents the standard treatment for advanced grade 3 (G3) neuroendocrine neoplasms (NENs) according to the European Neuroendocrine Tumor Society guidelines, the role of radical-intended surgery in these patients, as well as the use of adjuvant chemotherapy, are still controversial. The aim of the present work is to describe, in a retrospective series of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) G3, the overall survival (OS) rate and risk factors for death after radical surgery. Secondary aims are the description of median recurrence-free survival (RFS) and of the role of adjuvant chemotherapy.Patients and MethodsMulticenter analysis of a series of stage I–III GEP-NEN G3 patients receiving radical surgery (R0/R1) with/without adjuvant chemotherapy was performed.ResultsSixty patients from eight neuroendocrine tumor (NET) referral centers, with median follow-up of 23 months (5–187 months) were evaluated. While 28.6% of cases had NET G3, 71.4% had neuroendocrine carcinoma G3 (NEC G3). The 2-year OS rate after radical surgery was 64.5%, with a statistically significant difference in terms of Ki67 threshold (cut-off 55%, P = 0.03) and tumor differentiation (NEC G3 vs. NET G3, P = 0.03). Median RFS after radical surgery was 14 months, and 2-year RFS rate was 44.9%. Use of adjuvant chemotherapy provided no benefit in terms of either OS or RFS in this series.ConclusionsSurgery with radical intent might represent a valid option for GEP-NEN G3 patients with locoregional disease, especially with Ki67 value ≤ 55%.

Wnt signalling stimulated by binding of R-spondin (Rspo) to Lgr-family members is crucial for gastrointestinal stem cell renewal. Infection of the stomach with Helicobacter pylori stimulates increased secretion of Rspo by myofibroblasts, leading to an increase in proliferation of Wnt-responsive Axin2 + Lgr5 − stem cells in the isthmus of the gastric gland and finally gastric gland hyperplasia. Basal Lgr5 + cells are also exposed to Rspo3, but their response remains unclear. Here, we demonstrate that—in contrast to its known mitogenic activity—Rspo3 induces differentiation of basal Lgr5 + cells into secretory cells that express and secrete antimicrobial factors, such as intelectin-1, into the lumen. The depletion of Lgr5 + cells or the knockout of Rspo3 in myofibroblasts leads to hypercolonization of the gastric glands with H. pylori , including the stem cell compartment. By contrast, systemic administration or overexpression of Rspo3 in the stroma clears H. pylori from the gastric glands. Thus, the Rspo3–Lgr5 axis simultaneously regulates both antimicrobial defence and mucosal regeneration. Sigal et al. report that Rspo3 regulates Lgr5 cells in the gastric gland base, induces their differentiation into secretory cells and stimulates epithelial antimicrobial defence against H. pylori infection.