David W. Rittenhouse

HuR status is a powerful marker for prognosis and response to gemcitabine-based chemotherapy for resected pancreatic ductal adenocarcinoma patients.

Background:Pancreatic ductal adenocarcinoma (PDA) is a devastating disease that killed nearly 38,000 people in the United States this past year. Objective:Treatment of PDA typically includes surgery and/or chemotherapy with gemcitabine. No reliable biomarker exists for prognosis or response to chemotherapy. Two previously proposed prognostic markers, cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), are regulated by Hu protein antigen R (HuR), an mRNA binding protein that we have previously demonstrated to be a promising predictive marker of gemcitabine response. This study was designed to evaluate the clinical utility of HuR, COX-2, and VEGF as potential prognostic and predictive biomarkers for PDA. Methods:A tissue microarray of 53 PDA specimens from patients who underwent potentially curative pancreatic resection was analyzed. HuR, COX-2, and VEGF status were correlated with clinicopathologic and survival data. We also performed ribonucleoprotein immunoprecipitation assays using an HuR antibody to assess VEGF and COX-2 mRNA binding to HuR in pancreatic cancer cells. Results:Roughly 50% (27/53) of patients had high cytoplasmic HuR expression. These patients had worse pathologic features as assessed by T staging (P = 0.005). Only cytoplasmic HuR status correlated with tumor T staging, whereas VEGF (P = 1.0) and COX-2 (P = 0.39) expression did not correlate with T staging. Additionally, HuR status was an unprecedented positive predictive marker for overall survival in patients treated with gemcitabine, pushing median survival over 45 months in the high cytoplasmic HuR expressing patient population compared with less than 23 months in the low cytoplasmic HuR expressing patient group (P = 0.033 for log-rank test and P = 0.04 in a Cox regression model) for the low versus high cytoplasmic HuR expressing group. We also validated that mRNA transcripts for both VEGF and the gemcitabine metabolizing enzyme, deoxycytidine kinase, are specifically bound by HuR in pancreatic cancer cells. Conclusions:HuR is a useful prognostic biomarker for PDA patients as indicated by its association with higher tumor T stage. Additionally, HuR status is a robust predictor of outcome for patients with resected PDA in the setting of adjuvant gemcitabine therapy. Finally, HuR binds to VEGF mRNA implying that HuR, in part, regulates VEGF expression in PDA. This study supports the notion that HuR status should be used by clinicians for the individualized treatment of PDA in the future.

HuR’s post-transcriptional regulation of death receptor 5 in pancreatic cancer cells

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.

The Novel Triad of Dorsal Agenesis of the Pancreas with Concurrent Pancreatic Ductal Adenocarcinoma and Nonalcoholic Chronic Calcific Pancreatitis: A Case Series and Review of the Literature

IntroductionDorsal 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 MethodsA retrospective review of our IRB-approved pancreatic surgery database was performed from November 2005 to November 2010 searching for cases of DAP.DiscussionDisorders 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).ConclusionIn 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.

Gastroduodenal intussusception of a gastrointestinal stromal tumor (GIST): case report and review of the literature.

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 retrospective study of the factors associated with hypercoagulability in the pediatric patients at a tertiary care children's hospital.

Objective: The objective of this study was to determine the risk factors of hypercoagulability in children. We explored the interaction of multiple risk factors with the incidence of thrombosis. Our hypothesis was that as the number of risk factors for thrombosis increased the actual incidence of thrombosis would also increase. Design: Retrospective review from 2003 through 2006 based on a search using two electronic medical record databases. Setting: Pediatric Tertiary Care Children’s Hospital. Patients: Two hundred twenty-six patients were identified and analyzed. Measurements: Search terms included factor V Leiden polymerase chain reaction, prothrombin gene 20210A mutation, methylene tetrahydrofolate reductase mutation, antithrombin III, and protein C and S levels. Clinical data were compiled for regression analysis. Main Results: The presence of one risk factor was not significant. Two risk factors increased the risk of thrombosis (p = 0.005; OR 3.128). Three or more risk factors further increased the risk of thrombosis (p = 0.003; OR 4.861). Older age (>11 yrs) was protective against thrombosis (p = 0.007; OR 0.995), and the presence of a central venous catheter when analyzed against accumulating risk factors showed a higher risk than that found during the regression analysis (p = 0.001; OR 3.638). Conclusions: The population at our institution is reflective of the previously reported standards for the genetic predispositions toward thrombosis. Although older age is associated with a lower incidence of thrombosis, the presence of a central venous access device is detrimental. Accumulation of factors results in an increased risk of thrombosis. This article suggests that when inserting a central venous access device, consideration of a hypercoagulation workup should occur. Those with any two or more risk factors, genetic or acquired, and the comorbidity of a CVL may warrant consideration for the institution of anticoagulation with an agent like low molecular weight heparin.

Autoenucleation resulting in carotid thrombosis, subdural hemorrhage, stroke, and death.

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.

Infantile choriocarcinoma in a neonate with massive liver involvement cured with chemotherapy and liver transplant.

A 6-week-old boy presented with fever, pallor, and hepatomegaly. Ultrasound showed a huge midline abdominal mass. &bgr;-human chorionic gonadotropin was markedly elevated, suggesting a diagnosis of infantile choriocarcinoma of the liver. A biopsy confirmed the diagnosis. The patient received 6 cycles of bleomycin, cisplatin, and etoposide with significant decrease in tumor size. However, the tumor remained unresectable. A donor liver became available, and the infant underwent successful liver transplantation. He received 2 posttransplant cycles of moderate dose of methotrexate. This case shows the use of liver transplantation in cases of infantile choriocarcinoma of the liver where the tumor remains unresectable despite chemotherapy.

Massive Portal Venous Air and Pneumatosis Intestinalis Associated with Cocaine-Induced Mesenteric Ischemia

BackgroundWe report a 53-year-old female who presented to the emergency department in distress with an acute abdomen after recreational use of cocaine.DiscussionThe 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.ConclusionCocaine-induced mesenteric ischemia is a serious disease causing significant morbidity and mortality. Operative therapy is often required.

Surgical care of the elderly

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Critical Care in Older Adults

Geriatric patients constitute a substantial proportion of those utilizing critical care services in acute care hospital settings. This chapter reviews clinical indications for critical care services in this population. Specific treatments are reviewed in the context of overall care, including care at the end of life. Critical care medicine plays an important role in the management of elderly urologic patients with complex care requirements.