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Background: Gastrointestinal malrotation arises from intrauterine events that occur early in the first trimester of gestation, and can result in a midgut volvulus that classically presents in the neonatal period with bilious emesis. Gastrointestinal malrotation can present clinically with symptoms such as chronic abdominal pain or bowel obstruction, or remain completely asymptomatic only to be discovered as an incidental finding much later in life during surgical exploration for other diseases. We sought to identify the prevalence of gastrointestinal malrotation in patients undergoing surgical exploration for hepatopancreatobiliary (HPB) malignancy and describe the operative considerations of these cases.Case Presentation: We performed a retrospective review of our prospectively acquired HPB surgery database from January 1, 2006, to December 1, 2013. We identified three cases of gastrointestinal malrotation out of a total of 1220 HPB cases reviewed, which represents 0.2%. We found two cases of gastrointestinal malrotation in the setting of pancreatic ductal adenocarcinoma and one case in the setting of cholangiocarcinoma. All three patients underwent exploratory laparotomy with resection of their respective primary tumors. We searched the English literature for cases of HPB malignancy in the setting of gastrointestinal malrotation.Conclusion: Our case series and review of the literature underscore the rarity and complexity of these cases.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in adults. They frequently occur in the stomach. Gastric GISTs typically present as a gastrointestinal bleed but can sometimes cause obstructive symptoms such as nausea and vomiting. We present a patient with a gastric GIST and liver metastases who during treatment with iminitab therapy presented with an acute gastric outlet obstruction. A computed tomography scan revealed a gastroduodenal intussusception of the gastric GIST. The patient underwent a laparoscopic exploration and resection of the GIST. We reviewed the English language literature of GISTs that presented as a gastroduodenal intussusception and put our case in the context of the previously reported cases. We discuss the diagnostic and therapeutic challenges that arise when treating these patients.

A 4-month-old girl was presented to the Emergency Department by her parents after a fall. The father reported that he tripped and fell while holding the infant, causing her to hit her face on a wooden deck. Upon arrival she was in mild distress. Her primary survey was significant for a tachycardia to the 180s. The secondary survey revealed multiple bruises over her torso, extremities, and face, as well as bilateral dense cataracts. A chest X-ray study and bony radiographic studies showed an old healing clavicle fracture with evidence of multiple breaks, as well as healing rib fractures.

SESSION TITLE: Surgery Student/Resident Case Report Posters

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in adults. They frequently occur in the stomach. Gastric GISTs typically present as a gastrointestinal bleed but can sometimes cause obstructive symptoms such as nausea and vomiting. We present a patient with a gastric GIST and liver metastases who during treatment with iminitab therapy presented with an acute gastric outlet obstruction. A computed tomography scan revealed a gastroduodenal intussusception of the gastric GIST. The patient underwent a laparoscopic exploration and resection of the GIST. We reviewed the English language literature of GISTs that presented as a gastroduodenal intussusception and put our case in the context of the previously reported cases. We discuss the diagnostic and therapeutic challenges that arise when treating these patients.

Apoptosis is one of the core signaling pathways disrupted in pancreatic ductal adenocarcinoma (PDA). Death receptor 5 (DR5) is a member of the tumor necrosis factor (TNF)-receptor superfamily that is expressed in cancer cells. Binding of TNF-related apoptosis-inducing ligand (TRAIL) to DR5 is a potent trigger of the extrinsic apoptotic pathway, and numerous clinical trials are based on DR5-targeted therapies for cancer, including PDA. Human antigen R (HuR), an RNA-binding protein, regulates a select number of transcripts under stress conditions. Here we report that HuR translocates from the nucleus to the cytoplasm of PDA cells upon treatment with a DR5 agonist. High doses of DR5 agonist induce cleavage of both HuR and caspase 8. HuR binds to DR5 mRNA at the 5'-untranslated region (UTR) in PDA cells in response to different cancer-associated stressors and subsequently represses DR5 protein expression; silencing HuR augments DR5 protein production by enabling its translation and thus enhances apoptosis. In PDA specimens (n = 53), negative HuR cytoplasmic expression correlated with elevated DR5 expression (odds ratio 16.1, p < 0.0001). Together, these data demonstrate a feedback mechanism elicited by HuR-mediated repression of the key apoptotic membrane protein DR5.

BACKGROUND:We report a 53-year-old female who presented to the emergency department in distress with an acute abdomen after recreational use of cocaine.DISCUSSION:The patient's computed tomography scan revealed extensive portal venous air with small-bowel pneumatosis intestinalis resulting from intestinal ischemia. Air could be seen throughout the superior mesenteric vein, portal vein, and hepatic portal venous distribution. The patient underwent extensive resuscitation and resection of small bowel requiring three operative interventions. A pertinent review of the literature of cocaine-induced small-bowel ischemia is provided covering the pathophysiology, clinical findings, and epidemiology.CONCLUSION:Cocaine-induced mesenteric ischemia is a serious disease causing significant morbidity and mortality. Operative therapy is often required.

A 46-year-old man with schizoaffective disorder suffered carotid thrombosis, subdural hemorrhage, and stroke resulting in death following autoenucleation of the left globe. This is the first reported case of carotid thrombosis as a result of autoenucleation.

Background Cystic fibrosis (CF) is the most commonly inherited lethal autosomal recessive genetic disease amongst Caucasians. CF results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Patients with homozygous or compound heterozygous CFTR mutations have a risk of pancreatitis, but typically do not live long enough to develop pancreatic ductal adenocarcinoma (PDA), a disease that has an average age at diagnosis of 65 years. Little is known about the risk of the development of PDA in people who are heterozygous for mutations in the CFTR gene.Patients and Methods We report a case of a patient with PDA who underwent resection, who is a carrier for the W1282X nonsense mutation in the CFTR gene. The patient is of Ashkenazi Jewish ethnicity and has a family history of CF, but no family history of PDA. We reviewed the English language literature for the prevalence of PDA in CF patients (and CFTR mutations in the setting of PDA) and their significance in terms of screening, and the use of this mutation as a biomarker for an increased risk of the development of PDA.Conclusion We conclude that patients with CFTR mutations, who also have other risks for the development of PDA such as a family history of the disease, should undergo screening and be educated about their risks.

Abstract Apoptosis has been identified as a core signaling pathway disrupted in pancreatic ductal adenocarcinoma (PDA) tumorigenesis. Death Receptor 5 (DR5, TRAIL-R2) is a membrane bound protein that initiates the extrinsic apoptotic pathway upon ligand exposure and is currently being explored as a ‘druggable’ target in multiple cancers including PDA. Identifying a mechanism that regulates DR5 in the tumor microenvironment (e.g. hypoxia, chemotherapeutic exposure) is critical for optimizing DR5 based-therapies. Human antigen R (HuR), an RNA binding protein, controls post-transcriptional gene expression by binding to specific regions of 3’and 5’ UTRs of mRNA target genes. Previously, HuR, a pro-survival molecule, has been shown to play an important role in the intrinsic apoptotic pathway. We identified DR5 mRNA as a HuR target in PDA cells and explored the significance of HuR's role in functionally regulating the extrinsic apoptotic pathway in PDA cells. We also explored HuR as a modulator of DR5-targeted therapy for the treatment of PDA. Ribonucleoprotein immunoprecipitation (RNP-IP) assays were performed on PDA cells using HuR antibody (Ab) compared to a control (IgG Ab) under stress conditions, 3 hours with 1μM of the standard of care drug for PDA, gemcitabine; and 75 μM of a PARP inhibitor (PARPi). mRNA was converted to cDNA using RT-PCR, and then analyzed by qPCR. DR5 mRNA was validated as a HuR target with a 6-fold greater binding to HuR compared to the control. Strikingly, this binding increases 12- and 24-fold upon treatment with gemcitabine and the PARPi respectively. Silencing HuR expression, through siRNA transfections, leads to an increase of DR5 protein expression at 24 and 48 hours in multiple PDA cell lines. Additionally, silencing of HuR significantly enhances the action of a DR5-specific monoclonal Ab (0.8 mg/mL) against PDA cells within 36 hours (a 20% detected increase in cell death compared to control cells), most likely due to an enhanced availability of the DR5 receptor. Finally, in a training set of PDA clinical specimens, we found a significant inverse correlation between high/low HuR cytoplasmic expression and low/high DR5 levels (p value=0.03). In over 80% (26 of 31) of the specimens HuR cytoplasmic levels inversely correlated with DR5 expression levels, providing further evidence that elevated cytoplasmic HuR is repressing DR5 protein levels in patient tumor cells. In sum, we have shown that ‘activated HuR’ represses DR5 protein expression in PDA cells. Therefore, we conclude that low cytoplasmic HuR levels allow for greater availability of the target DR5, and will thus accordingly enhance the efficacy of DR5-targeted therapy. Thus, manipulating and/or utilizing HuR expression levels may serve as a clinically informative tool for optimizing DR5-targeted therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4100. doi:10.1158/1538-7445.AM2011-4100

significantly lower than Control Group (p<0.05).A significant reduction on liver MDA content and on mitochondrial dysfunction were observed in Diazoxide Group compared to Control Group (p<0.05).No differences in pulmonary vascular permeability and MPO activity were observed between groups.Twenty four hours after reperfusion Diazoxide Group showed a reduction of AST and ALT serum levels when compared to Control group (p<0.05).Conclusion: Diazoxide attenuates liver ischemia/reperfusion injury probably by a mechanism related to mitochondrial function preservation during liver ischemia.

Introduction: African American (AA) men have an increased death rate compared to Caucasian men (15.4 per 100,000 persons versus 12.1 per 100,000 persons respectively) after gemcitabine-based standard of care therapy for pancreatic ductal adenocarcinoma (PDA). HuR, an mRNA binding protein, creates a favorable ‘therapeutic window’ for gemcitabine efficacy against cancer cells (while sparing normal cells) by regulating its metabolic enzyme, deoxycytidine kinase (dCK) mRNA (Cancer Research 2009;69:4567-72). Computational analysis identified a single nucleotide polymorphism (SNP) residing in the regulatory binding site of the dCK gene. This germline SNP has a prevalence of ∼65% in the AA population, in contrast to only 5% in Caucasians. We hypothesized that the presence of this SNP may significantly affect gemcitabine metabolism and contribute to the survival disparity that is seen in the AA patient population. Methods: We designed a 33 base pair probe that encompassed the dCK-SNP to test whether this region of dCK mRNA could bind to HuR. We cloned the wild type (T) and the SNP (C) sequences into luciferase reporter constructs in order to quantitate any effect the single nucleotide change had on protein expression in an unbiased manner. We also developed a facile genotyping assay to determine dCK-SNP genotypes in a group of 47 patients with resected PDA and correlated the genotypes with clinical outcome. Results: We identified the short sequence motif in which HuR regulates dCK. HuR preferentially and robustly binds to the dCK mRNA sequence (33bps) that harbors the SNP. A single nucleotide change (T to C) in this binding region induced a 2.7-fold increase in protein expression. One hundred percent of our AA patient population (n=13) had the presence of the SNP in at least one allele (39% homozygous for the SNP) while only 11% of Caucasian patients (n=37) had one SNP allele (none of these patients were homozygous for the SNP) (p=0.0001). Of the patients treated with gemcitabine, patients with a wild type dCK-genotype (n=27, all Caucasian) had a median survival of 20.7 months, compared to 10.4 months in patients (n=11, all AA patients) that harbored at least one SNP allele (hazard ratio 2.5, p=0.058 by Gehan-Breslow-Wilcoxon test). Conclusion: Taken together, our data show that: 1) the dCK-SNP is frequently detected in the AA population; 2) the dCK-SNP functionally affects protein translation; and 3) the presence of the SNP is associated with poor clinical outcome after gemcitabine therapy. We hypothesize that patients who harbor the germline dCK-SNP improperly metabolize gemcitabine in normal cells, and thus negate the favorable ‘gemcitabine-therapeutic window’ that preferentially destroys tumor cells. Detection of the dCK-SNP genotype in addition to other validated biomarkers such as HuR status will help guide adjuvant treatment options and ultimately enhance outcomes in the AA, PDA patient population.

Introduction Dorsal agenesis of the pancreas (DAP) is a rare congenital anomaly, with only 44 cases having been reported in the English literature since 1966. Materials and Methods A retrospective review of our IRB-approved pancreatic surgery database was performed from November 2005 to November 2010 searching for cases of DAP. Discussion Disorders in the retinoic acid ( Raldh ) and hedgehog ( Hh ) signaling pathways, which appear to play a role in the development of DAP, have been implicated in other diseases of the pancreas such as pancreatic ductal adenocarcinoma (PDA) and nonalcoholic chronic calcific pancreatitis (NCCP). Conclusion In this report, we describe three cases of DAP in the setting of PDA, two of which include the third component of NCCP. We provide a discussion of the clinical features of this novel triad and address the molecular pathways that relate to these respective diseases.

The expression of protein phosphatase 32 (PP32, ANP32A) is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1), a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C), but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, including gemcitabine. pp32 overexpression reduced the association of HuR with the mRNA encoding the gemcitabine-metabolizing enzyme deoxycytidine kinase (dCK), causing a significant reduction in dCK protein levels. Similarly, ectopic pp32 expression caused a reduction in HuR binding of mRNAs encoding tumor-promoting proteins (e.g., VEGF and HuR), while silencing pp32 dramatically enhanced the binding of these mRNA targets. Low pp32 nuclear expression correlated with high-grade tumors and the presence of lymph node metastasis, as compared to patients' tumors with high nuclear pp32 expression. Although pp32 expression levels did not enhance the predictive power of cytoplasmic HuR status, nuclear pp32 levels and cytoplasmic HuR levels associated significantly in patient samples. Thus, we provide novel evidence that the tumor suppressor function of pp32 can be attributed to its ability to disrupt HuR binding to target mRNAs encoding key proteins for cancer cell survival and drug efficacy.