A MicroRNA Panel in Pancreatic Cyst Fluid for the Risk Stratification of Pancreatic Cysts in a Prospective Cohort.

A subset of pancreatic cystic neoplasms are regarded as precursor lesions of pancreatic cancer, but only a minority of all pancreatic cystic neoplasms will undergo malignant transformation. MicroRNAs are increasingly recognized as molecular targets in carcinogenesis. Previously, a 9-microRNA (miR) signature was suggested to discriminate between high risk and low risk pancreatic cystic neoplasm. In this study, we aimed to validate this 9-miR panel in a prospective cohort. Total miR was isolated from pancreatic cyst fluid and expression of miR18a, miR24, miR30a-3p, miR92a, miR99b, miR106b, miR142-3p, miR342-3p, and miR532-3p was analyzed by singleplex Taqman MicroRNA Assay. A total of 62 patient samples were analyzed. During follow-up, 24 (38.7%) patients underwent resection, of which 6 (9.7%) patients showed at least high grade dysplasia. A logistic regression model presented a "predicted risk" score which significantly differed between low and high risk cysts, either including all patients or only those with histological confirmation of diagnosis. Using a set cut-off of 50%, the sensitivity of the model for the total cohort was 10.0%, specificity 100.0%, positive predicted value 100.0%, negative predicted value 85.2%, and diagnostic accuracy of 85.5%. Thus, while observing a significant difference between low and high risk cysts, clinical implementation of this biomarker panel is as yet unlikely to be beneficial in the management of pancreatic cysts.

Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies.

Traditional chemotherapeutics have largely failed to date to produce significant improvements in pancreatic cancer survival. One of the reasons for the resilience of pancreatic cancer towards intensive treatment is that the cancer is capable of high jacking the immune system: during disease progression the immune system is converted from a system that attacks tumor cells into a support structure for the cancer, exerting trophic actions on the cancer cells. This turn-around of immune system action is achieved through mobilization and activation of regulatory T cells, myeloid derived suppressor cells, tumor-associated macrophages and fibroblasts, all of which suppress CD8 T cells and NK cells. This immune suppression occurs both through the expression of tolerance-inducing cell surface molecules, such as PD-L1, as well as through the production of "tolerogenic" cytokines, such as IL-10 and TGF-ß. Based on the accumulating insight into the importance of the immune system for the outcome of pancreatic cancer patients multiple new immunotherapeutic approaches against pancreatic cancer are being currently tested in clinical trials. In this review we give an overview of both the immune escaping mechanisms of pancreatic cancer as well as the new immune related therapeutic strategies currently being tested in pancreatic cancer clinical trials.

Monocytes and their pathophysiological role in Crohn's disease.

Our immune system shows a stringent dichotomy, on the one hand displaying tolerance towards commensal bacteria, but on the other hand vigorously combating pathogens. Under normal conditions the balance between flora tolerance and active immunity is maintained via a plethora of dynamic feedback mechanisms. If, however, the balancing act goes faulty, an inappropriate immune reaction towards an otherwise harmless intestinal flora causes disease, Crohn's disease for example. Recent developments in the immunology and genetics of mucosal diseases suggest that monocytes and their derivative cells play an important role in the pathophysiology of Crohn's disease. In our review, we summarize the recent studies to discuss the dual function of monocytes - on the one hand the impaired monocyte function initiating Crohn's disease, and on the other hand the overactivation of monocytes and adaptive immunity maintaining the disease. With a view to developing new therapies, both aspects of monocyte functions need to be taken into account.

Antibiotics with a selective aerobic or anaerobic spectrum have different therapeutic activities in various regions of the colon in interleukin 10 gene deficient mice.

BACKGROUND AND AIMS: Multiple rodent models implicate resident intestinal bacteria in the pathogenesis of chronic immune mediated intestinal inflammation. Specific pathogen free (SPF) interleukin 10 gene deficient (IL-10(-/-)) mice develop colitis, which does not occur in the germ free (GF) state. We investigated whether broad or narrow spectrum antibiotics affect onset and progression of disease in various regions of IL-10(-/-) mice. METHODS: Metronidazole, ciprofloxacin, vancomycin-imipenem (50 mg/kg/day), or water (control) was administered orally before (prevention) or two weeks after (treatment) colonisation of GF IL-10(-/-) mice with SPF bacteria. After four weeks, colonic histology scores and cytokine production by colonic explants were determined. Caecal and colonic contents were collected for quantitative bacterial analysis. RESULTS: In the prevention study, all antibiotics decreased inflammation in the caecum and colon. However, in the treatment study, ciprofloxacin and vancomycin-imipenem decreased caecal inflammation, and reduced Escherichia coli and Enterococcus faecalis concentrations, whereas only vancomycin-imipenem lowered direct microscopic bacterial counts. In contrast, metronidazole and vancomycin-imipenem reduced colonic injury and eliminated anaerobic bacteria, including Bacteroides spp. CONCLUSIONS: Both narrow and broad spectrum antibiotics can prevent disease but treatment of established colitis is more selective. Ciprofloxacin is most effective in the treatment of caecal inflammation, metronidazole preferentially treats the colon, whereas vancomycin-imipenem definitively treats both regions. These results suggest that subsets of aerobic or anaerobic bacteria show regional differences in their capacity to mediate experimental colitis in IL-10(-/-) mice.

Fever induced by labetalol.

Fever caused by beta-adrenoceptor blocking agents is rare. We describe fever in two patients who had been treated with labetalol. In both patients, two challenge periods were rapidly followed by a relapse, whereas on each occasion there was normalization of temperature after discontinuation of the drug therapy. This reaction is rare and unpredictable. Because there was a clear sensitization period of three to four weeks, dose independency, and an accelerated reaction to rechallenge, this adverse effect seems to be caused by an immunoallergic reaction.