Mortality from pancreatic ductal adenocarcinoma cancer (PDAC) is among the highest of any cancer and frontline therapy has changed little in years. Activation of endothelial nitric oxide synthase (eNOS or NOS III) has been implicated recently in the pathogenesis of PDAC. In this study, we used genetically engineered mouse and human xenograft models to evaluate the consequences of targeting eNOS in PDAC. Genetic deficiency in eNOS limited the development of pre-invasive pancreatic lesions and trended towards an extended lifespan in mice with advanced pancreatic cancer. These effects were also observed upon oral administration of the clinically evaluated NOS small molecule inhibitor L-NAME. Similarly, other transgenic models of oncogenic KRas-driven tumors responded to L-NAME treatment. Finally, these results were recapitulated in xenograft models of human pancreatic cancer, in which L-NAME was found to broadly inhibit tumorigenic growth. Taken together, our findings offer preclinical proof-of-principle to repurpose L-NAME for clinical investigations in treatment of PDAC and possibly other KRas-driven human cancers.

Objective. To describe the usefulness of intraoperative frozen section in the diagnosis and treatment of thyroid nodules where fine needle aspirate biopsies have evidence of follicular neoplasm. Study Design. Retrospective case series. Methods. All patients have a fine needle aspirate biopsy, an intraoperative frozen section, and final pathology performed on a thyroid nodule after initiation of the Bethesda System for Reporting Thyroid Cytopathology in 2009 at a single tertiary referral center. Sensitivity, specificity, positive predictive value, and negative predictive value are calculated in order to determine added benefit of frozen section to original fine needle aspirate data. Results. The sensitivity and specificity of the frozen section were 76.9% and 67.9%, respectively, while for the fine needle aspirate were 53.8% and 74.1%, respectively. The positive and negative predictive values for the fine needle aspirates were 25% and 90.9%, respectively, while for the frozen sections were 27.8% and 94.8%, respectively. There were no changes in the operative course as a consequence of the frozen sections. Conclusion. Our data does not support the clinical usefulness of intraoperative frozen section when the fine needle aspirate yields a Bethesda Criteria diagnosis of follicular neoplasm, suspicious for follicular neoplasm, or suspicious for malignancy at our institution.

Gastrointestinal (GI) complications including graft-versus-host disease (GVHD) are a major cause of morbidity and mortality in allogenic stem transplant recipients. Although several studies have previously looked into the acute GI complications, fewer smaller studies have reported late complications. In this large study we focus on the late (100 days post-transplant) GI complications in allogenic stem transplant recipients. In this single-center, retrospective study of all adult allogenic stem cell transplant recipients who had their transplant at Duke University over a 6-year period, 479 patients underwent allogenic stem cell transplant, of whom 392 recipients survived for at least 100 days post-transplant. Late GI symptoms were noted in 71 patients, prompting endoscopic evaluation. The primary endpoint of our study was the diagnosis of GI-GVHD based on endoscopic findings, whereas overall survival and nonrelapse mortality were the secondary endpoints. Of the 71 patients who underwent endoscopy, 45 (63%) had GI-GVHD. Of these 45 patients, 39 (87%) had late acute GVHD, 1 (2%) had chronic GVHD, and 5 patients (11%) had overlap disease. Of the patients who did not have GVHD, the symptoms were mostly related to infectious and inflammatory causes. Less common causes included drug toxicity, food intolerance, disease relapse, and motility issues. In a multivariate analysis the factors most indicative of GI-GVHD were histologic findings of apoptosis on the tissue specimen (odds ratio, 2.35; 95% confidence interval, 1.18 to 4.70; P = .015) and clinical findings of diarrhea (odds ratio, 5.43; 95% confidence interval, 1.25 to 23.54; P = .024). The median survival time from the first endoscopy was 8.5 months. The incidence of nonrelapse mortality at 6 months was 31% in patients with GI-GVHD and 19% in patients without GI-GVHD (P = .42). All patients with GI-GVHD were on steroid therapy, and 31% of them received total parenteral nutrition. In our population close to one-fifth of allogenic transplant recipients experienced late GI complications, warranting endoscopic evaluation. Most of these patients were found to have GI-GVHD that had a high incidence of nonrelapse mortality at 6 months and close to one-third of these patients needed total parenteral nutrition.

Background Graft-versus-host disease (GVHD) complicates half of hematopoietic stem cell transplants (HCT), and the gastrointestinal tract is commonly affected. Endoscopic biopsies have a key role in the diagnosis. The optimal procedure(s) to perform and site(s) to biopsy remain unclear. Methods We retrospectively analyzed the charts of all adult patients who underwent allogeneic HCT at Duke University Medical Center between 1/1/05 and 1/1/11 and extracted data from those who underwent endoscopic biopsy for suspected GVHD. All histology was re-evaluated by blinded pathologists using 2006 NIH diagnostic criteria and then compared to the original clinical diagnosis of GVHD. Results A total of 169 adult patients underwent 250 endoscopic procedures to evaluate GVHD. The sensitivity of biopsies for clinical GVHD was 76 and 72 % for upper and lower tract sites, respectively. In the presence of nausea, upper tract biopsies were positive for GVHD in 65 %, 70 % while lower tract biopsies were positive in 61–70 %. In the presence of diarrhea, lower tract biopsies were positive in 65 %, while upper tract sites were positive in 64–69 %. Twenty six (40 %) of the sixty-five endoscopies that simultaneously sampled upper and lower tract sites had discordant results. All were histologically positive for GVHD, yet 15 % of upper tract biopsies and 25 % of lower tract biopsies were negative. Conclusions In this large review, the overall sensitivity of biopsies taken during EGD and Flex-Sig was 76 and 72 %, respectively. A symptom-driven biopsy approach was not clearly supported as upper tract and lower tract biopsies were similarly diagnostic for GVHD regardless of symptoms.

- Use of the NIH histology consensus guidelines results in a high sensitivity and specificity, thereby decreasing false-negatives. Additionally, use of the NIH guidelines aids in creating uniformity and diagnostic clarity. Correlation with clinical and laboratory findings is critical in evaluating the differential diagnosis and to avoid false-positives. As expected, increased apoptosis with decreased inflammation was associated with a pathologic diagnosis of graft-versus-host disease and supports the NIH guidelines.

mg/kg/day on days-3 and-2) and TBI (2 Gy on day-1). GVHD prophylaxis consisted of Cy (50 mg/kg/day on days 3 and 4), tacrolimus (days 5 to 180), and mycophenolate mofetil (days 5 to 60). Our primary endpoint was the incidence of nonrelapse mortality (NRM) at day 100. Secondary endpoints included overall survival (OS), disease-free survival (DFS), the incidence of engraftment, acute GVHD, and relapse. Results: Median age was 48 (range 21-65) with 22 male and 9 female. Diagnosis of the patients included AML (n¼17), ALL/LBL (n¼8), MDS/MPN (n¼4), and lymphoma (n¼2). The majority (61.3%) of patients were not in remission and 13 patients (41.9%) had a history of prior allogeneic stem cell transplantation (allo-SCT). Twenty-seven patients (87.1%) engrafted with median neutrophil engraftment on 19 days (range 15-27). The cumulative incidence of grades II-IV and III-IV acute GVHD at day 100 was 22.6% (95% CI, 9.8-38.6%) and 3.2% (95% CI, 0.2-14.4%), respectively. NRM at day 100 was 19.4% (95% CI, 7.7-34.9%). Cumulative incidence of relapse at day 100 was 19.4% (95% CI, 7.7-35.0%). With a median follow-up of 171 days, OS and DFS was 74.2% (95% CI, 55.0-86.2%) and 61.3% (95% CI, 42.0-75.8%), respectively, at day 100. Subgroup analysis showed that patients who had a history of prior allo-SCT had higher NRM (30.8% vs. 11.1%, p¼0.07) and less lower OS (53.8% vs. 83.9%, p¼0.03) than those in patients without a history of prior allo-SCT. Conclusions: Our results suggest that posttransplant Cy based HLA-haploidentical PBSCT after busulfan containing reduced-intensity conditioning achieves stable donor engraftment and low incidence of GVHD. NRM was acceptable in the setting of the first allo-SCT. Given the promising results of GVHD and NRM, phase II study in much larger scale are now under investigation.

Introduction: Hirschsprung Disease (HD) is the congenital absence of ganglionic cells in the rectum and often thought of as a disease of childhood. However, this disease may persist into adulthood and symptoms such as chronic constipation can negatively affect quality of life. Patients often require a multidisciplinary approach between geneticists, colorectal surgeons, endoscopists and gastrointestinal pathologists during initial evaluation. Confirming the diagnosis has historically required a suction or open rectal biopsy, which is considered the gold standard for diagnosis. This is an invasive procedure that is prone to complications. Potential biopsy modalities include open, punch, suction and endoscopic. Interestingly, endoscopic biopsy using an endoscopic full-thickness resection (EFTR) device is rarely reported. Case Description/Methods: Here we present a case of a 42-year-old female with a history of Hirschsprung disease diagnosed as a child. The patient had an extensive surgical history including colostomy, colostomy reversal, and closed loop obstruction. The patient had also been recently diagnosed with an enterocutaneous fistula. The patient was evaluated by a general surgeon who referred her to gastroenterology motility clinic. Gastrografin enema confirmed extensive stool burden without strictures. The patient underwent anorectal manometry, which found abnormal push, high sphincter pressure at rest, and absence in rectal inhibitory reflex, findings concerning for HD. A flexible sigmoidoscopy was performed to determine the extent of the disease. Full thickness endoscopic biopsy of the rectum using an EFTR device showed an absence of ganglionic cells. The patient underwent a takedown of enterocutaneous fistula as well with improvement in symptoms. (Figure ) Discussion: Endoscopic biopsy of the rectum is a minimally invasive technique that can provide adequate tissue samples to confirm a diagnosis. There is a paucity of data regarding the comparison between endoscopic versus traditional techniques. Based on our experience, we suggest that endoscopic rectal biopsy may be a safe and effective method to diagnose Hirschsprung Disease in the adult population. EFTR devices are potentially able to resect the entire wall of the gastrointestinal tract. This technique could greatly simplify the diagnostic process in that it is safe and effective, and less invasive than surgical techniques. However, further studies are needed to better characterize the utility of this technique in this specific patient population.[2819] Figure 1. A) H&E showing absence of myenteric ganglion cells B) Successful endoscopic full-thickness resection of tissue with Ovesco clip in place.

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