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. ß-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.

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.

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.

Congenital Variants of Gastrointestinal Rotation Found at Resection of Hepatopancreatobiliary Tumors: A Case Series with Review of the Literature.

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.

Acute Small-Bowel Obstruction From Intestinal Anisakiasis After the Ingestion of Raw Clams; Documenting a New Method of Marine-to-Human Parasitic Transmission.

Enteric anisakiasis is a known parasitic infection. To date, human infection has been reported as resulting from the inadvertent ingestion of the anisakis larvae when eating raw/undercooked fish, squid, or eel. We present a first reported case of intestinal obstruction caused by anisakiasis, after the ingestion of raw clams.

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.

Massive portal venous air and pneumatosis intestinalis associated with cocaine-induced mesenteric ischemia.

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.

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.

Subject review: pancreatic ductal adenocarcinoma in the setting of mutations in the cystic fibrosis transmembrane conductance regulator gene: case report and review of the literature.

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.

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.

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.

pp32 (ANP32A) expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs.

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.