Pancreatic Ductal Adenocarcinoma: Long-Term Survival Does Not Equal Cure

Background: Pancreatic ductal adenocarcinoma represents 90% of pancreatic cancers and is an important cause of cancer death in the United States. Operative resection remains as the only treatment providing prolonged survival, but even after a curative resection, 5-year survival rates are low. Our aim was to identify the prognostic factors for long-term survival after resection of pancreatic ductal adenocarcinoma related to patients, treatments, and tumor biology. Methods: Retrospective review identified 959 patients who underwent resection of their pancreatic adenocarcinoma between February 1985 and December 2010, of whom 499 were resected before November 2006 and represent the cohort we describe in this study. Patient, tumor, and treatment-related variables were assessed for their associations with 5- and 10-year overall survival. Results: Of the 499 patients, 49% were female and median age was 65 years. The majority of patients had stage IIb disease (60%). Actual 5-year survival after resection of pancreatic adenocarcinoma was 19% (95/499), and actual 10-year survival was 10% (33/329). Significant clinicopathologic factors predicting 5- and 10-year survival were negative margins and negative nodal status. Interestingly, 41% (39/95) of long-term survivors had positive nodes and 24% (23/95) had positive margins. Conclusion: Pancreatic ductal adenocarcinoma demonstrates a very heterogeneous biology, but patients with negative resection margins and node negative cancers are more likely to survive 5 years after resection. However, our series demonstrates that the biology of the cancer rather than simple pathologic factors determine a patient's prognosis

Endothelial cells promote migration and proliferation of enteric neural crest cells via β1 integrin signaling

AbstractEnteric neural crest-derived cells (ENCCs) migrate along the intestine to form a highly organized network of ganglia that comprises the enteric nervous system (ENS). The signals driving the migration and patterning of these cells are largely unknown. Examining the spatiotemporal development of the intestinal neurovasculature in avian embryos, we find endothelial cells (ECs) present in the gut prior to the arrival of migrating ENCCs. These ECs are patterned in concentric rings that are predictive of the positioning of later arriving crest-derived cells, leading us to hypothesize that blood vessels may serve as a substrate to guide ENCC migration. Immunohistochemistry at multiple stages during ENS development reveals that ENCCs are positioned adjacent to vessels as they colonize the gut. A similar close anatomic relationship between vessels and enteric neurons was observed in zebrafish larvae. When EC development is inhibited in cultured avian intestine, ENCC migration is arrested and distal aganglionosis results, suggesting that ENCCs require the presence of vessels to colonize the gut. Neural tube and avian midgut were explanted onto a variety of substrates, including components of the extracellular matrix and various cell types, such as fibroblasts, smooth muscle cells, and endothelial cells. We find that crest-derived cells from both the neural tube and the midgut migrate avidly onto cultured endothelial cells. This EC-induced migration is inhibited by the presence of CSAT antibody, which blocks binding to β1 integrins expressed on the surface of crest-derived cells. These results demonstrate that ECs provide a substrate for the migration of ENCCs via an interaction between β1 integrins on the ENCC surface and extracellular matrix proteins expressed by the intestinal vasculature. These interactions may play an important role in guiding migration and patterning in the developing ENS

Meiosis I Arrest Abnormalities Lead to Severe Oligozoospermia in Meiosis 1 Arresting Protein (M1ap)-Deficient Mice

Meiosis 1 arresting protein (M1ap) is a novel vertebrate gene expressed exclusively in germ cells of the embryonic ovary and the adult testis. In male mice, M1ap expression, which is present from spermatogonia to secondary spermatocytes, is evolutionarily conserved and has a specific spatial and temporal pattern suggestive of a role during germ cell development. To test its function, mice deficient in M1ap were created. Whereas females had histologically normal ovaries, males exhibited reduced testicular size and a myriad of tubular defects, which led to severe oligozoospermia and infertility. Although some germ cells arrested at the zygotene/pachytene stages, most cells advanced to metaphase I before arresting and entering apoptosis. Cells that reached metaphase I were unable to properly align their chromosomes at the metaphase plate due to abnormal chromosome synapses and failure to form crossover foci. Depending on the state of tubular degeneration, all germ cells, with the exemption of spermatogonia, disappeared; with further deterioration, tubules displaying only Sertoli cells reminiscent of Sertoli cell-only syndrome in humans were observed. Our results uncovered an essential role for M1ap as a novel germ cell gene not previously implicated in male germ cell development and suggest that mutations in M1AP could account for some cases of nonobstructive oligozoospermia in men

c-Jun N-terminal Kinase Inhibitor II (SP600125) Activates Müllerian Inhibiting Substance Type II Receptor-Mediated Signal Transduction

Müllerian inhibiting substance (MIS), the hormone required for Müllerian duct regression in fetal males, is also expressed in both adult males and females, but its physiological role in these settings is not clear. The expression of the MIS type II receptor (MISRII) in ovarian cancer cells and the ability of MIS to inhibit proliferation of these cells suggest that MIS might be a promising therapeutic for recurrent ovarian cancer. Using an MISRII-dependent activity assay in a small-molecule screen for MIS-mimetic compounds, we have identified the c-Jun N-terminal kinase inhibitor SP600125 as an activator of the MIS signal transduction pathway. SP600125 increased the activity of a bone morphogenetic protein-responsive reporter gene in a dose-dependent manner and exerted a synergistic effect when used in combination with MIS. This effect was specific for the MISRII and was not seen with other receptors of the TGFβ family. Moreover, treatment of mouse ovarian cancer cells with a combination of SP600125 and paclitaxel, an established chemotherapeutic agent used in the treatment of ovarian cancer, or with MIS enabled inhibition of cell proliferation at a lower dose than with each treatment alone. These results offer a strong rationale for testing the therapeutic potential of SP600125, alone or in combination with already established drugs, in the treatment of recurrent ovarian cancer with a much-needed decrease in the toxic side effects of currently employed therapeutic agents

Hospital readmission after distal pancreatectomy is predicted by specific intra- and post-operative factors

Background: Distal pancreatectomy (DP) continues to carry a significant risk of morbidity resulting in hospital readmissions and increased costs. Prognostic factors predicting 30-day readmission after DP were evaluated. Methods: Data were collected from 946 patients undergoing DP at the University of Verona Hospital Trust and the Massachusetts General Hospital between 2004 and 2014. Patients were divided into a derivation and a validation cohort. Results: The 30-day readmission rate was 13.9%. Predictors of readmission were age over 60 years (OR 1.8), intraoperative transfusions (OR 2.02), CR-POPF (OR 2.4), abdominal abscesses (OR 3.9), and urinary tract infections (OR 5.9). The score generated by the derivation cohort was validated identifying three different categories with a progressively increased risk for readmission. Conclusion: One out of seven patients undergoing DP will be readmitted within 30 days of discharge. Comorbidities seems not to affect the risk. A 10-point score predicts the risk of 30-days readmission

Clinical clearance of the cervical spine in blunt trauma patients younger than 3 years: A multi-center study of the American association for the surgery of trauma

Background: Cervical spine clearance in the very young child is challenging. Radiographic imaging to diagnose cervical spine injuries (CSI) even in the absence of clinical findings is common, raising concerns about radiation exposure and imaging-related complications. We examined whether simple clinical criteria can be used to safely rule out CSI in patients younger than 3 years.Methods: The trauma registries from 22 level I or II trauma centers were reviewed for the 10-year period (January 1995 to January 2005). Blunt trauma patients younger than 3 years were identified. The measured outcome was CSI. Independent predictors of CSI were identified by univariate and multivariate analysis. A weighted score was calculated by assigning 1, 2, or 3 points to each independent predictor according to its magnitude of effect. The score was established on two thirds of the population and validated using the remaining one third.Results: Of 12,537 patients younger than 3 years, CSI was identified in 83 patients (0.66%), eight had spinal cord injury. Four independent predictors of CSI were identified: Glasgow Coma Score \u3c14, GCSEYE = 1, motor vehicle crash, and age 2 years or older. A score of \u3c2 had a negative predictive value of 99.93% in ruling out CSI. A total of 8,707 patients (69.5% of all patients) had a score of \u3c2 and were eligible for cervical spine clearance without imaging. There were no missed CSI in this study.Conclusions: CSI in patients younger than 3 years is uncommon. Four simple clinical predictors can be used in conjunction to the physical examination to substantially reduce the use of radiographic imaging in this patient population