Sean J. Mulvihill

Phenotype and Genotype of Pancreatic Cancer Cell Lines

Abstract The dismal prognosis of pancreatic adenocarcinoma is due in part to a lack of molecular information regarding disease development. Established cell lines remain a useful tool for investigating these molecular events. Here we present a review of available information on commonly used pancreatic adenocarcinoma cell lines as a resource to help investigators select the cell lines most appropriate for their particular research needs. Information on clinical history; in vitro and in vivo growth characteristics; phenotypic characteristics, such as adhesion, invasion, migration, and tumorigenesis; and genotypic status of commonly altered genes (KRAS, p53, p16, and SMAD4) was evaluated. Identification of both consensus and discrepant information in the literature suggests careful evaluation before selection of cell lines and attention be given to cell line authentication.

Stat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and Progression

Chronic pancreatitis is a well-known risk factor for pancreatic ductal adenocarcinoma (PDA) development in humans, and inflammation promotes PDA initiation and progression in mouse models of the disease. However, the mechanistic link between inflammatory damage and PDA initiation is unclear. Using a Kras-driven mouse model of PDA, we establish that the inflammatory mediator Stat3 is a critical component of spontaneous and pancreatitis-accelerated PDA precursor formation and supports cell proliferation, metaplasia-associated inflammation, and MMP7 expression during neoplastic development. Furthermore, we show that Stat3 signaling enforces MMP7 expression in PDA cells and that MMP7 deletion limits tumor size and metastasis in mice. Finally, we demonstrate that serum MMP7 level in human patients with PDA correlated with metastatic disease and survival.

Safety and feasibility of injection with an E1B-55 kDa gene-deleted, replication-selective adenovirus (ONYX-015) into primary carcinomas of the pancreas: a phase I trial.

Novel therapies are needed for locally advanced pancreatic carcinoma. ONYX-015 (dl1520) is an E1B-55 kDa region-deleted adenovirus that selectively replicates in and lyses tumor cells with abnormalities in p53 function (eg gene mutation). We carried out a phase I dose escalation study of ONYX-015 in patients with unresectable pancreatic cancer. ONYX-015 was administered via CT-guided injection (n = 22 patients) or intraoperative injection (n = 1) into pancreatic primary tumors every 4 weeks until tumor progression. Interpatient dose escalation was carried out with at least three patients per dose level from 108 p.f.u. up to the 1011 p.f.u. dose level (two patients treated at this dose). The majority of patients had abnormally low cellular immunity (CD4 counts and hypersensitivity skin testing). Injection of ONYX-015 into pancreatic carcinomas was well-tolerated. Mild, transient pancreatitis was noted in only one patient. Dose-escalation proceeded to the highest dose level. Neutralizing antibodies rose post-treatment in all patients. After injection, ONYX-015 was detectable in the blood 15 min later, but not between 1 and 15 days later. Viral replication was not documented, however, in contrast to trials in other tumor types. No objective responses were demonstrated. Intratumoral injection of an E1B-55 kDa region-deleted adenovirus into primary pancreatic tumors was feasible and well-tolerated at doses up to 1011 p.f.u. (2 × 1012particles), but viral replication was not detectable.

Changing management of gallstone disease during pregnancy

AbstractBackground: Symptomatic gallstones may be problematic during pregnancy. The advisability of laparoscopic cholecystectomy (LC) is uncertain. The objective of this study is to define the natural history of gallstone disease during pregnancy and evaluate the safety of LC during pregnancy. Methods: Review of medical records of all pregnant patients with gallstone disease at the University of California, San Francisco, from 1980 to 1996. Results: Of approximately 29,750 deliveries, 47 (0.16%) patients were treated for gallstone disease, including biliary colic in 33, acute cholecystitis in 12, and pancreatitis in two. Conservative treatment was attempted in all patients but failed in 17 (36%) cases. Two patients required combined preterm Cesarean-section cholecystectomy and 10 required surgery in the early postpartum period for persistent symptoms. Seventeen patients required cholecystectomy during pregnancy for biliary colic (10), acute cholecystitis (six), and pancreatitis (one). Three patients were treated with open cholecystectomy. Fourteen patients underwent LC at a mean gestational age of 18.6 weeks, mean OR time of 74 min, and mean length of stay of 1.2 days. Hasson cannulation was utilized in 11 patients. Reduced-pressure pneumoperitoneum (6–10 mmHg) was used in seven patients. Prophylactic tocolytics were used in seven patients, with transient postoperative preterm labor observed in one. There were no open conversions, preterm deliveries, fetal loss, teratogenicity, or maternal morbidity. Conclusions: In past years, symptomatic gallstones during pregnancy were managed conservatively or with open cholecystectomy. LC is a feasible and safe method for treating severely symptomatic patients.

Laparoscopic Repair of Paraesophageal Hiatal Hernias

BACKGROUND Regardless of symptoms, paraesophageal hiatal hernias should be repaired in order to prevent complications. This study reports the University of California San Francisco experience with laparoscopic repair of paraesophageal hiatal hernias, emphasizing the technical steps essential for good results. PATIENTS AND METHODS From May 1993 to September 1997, 55 patients, 27 women and 28 men, with a mean age of 67 years (range, 35-102 years) underwent laparoscopic repair of paraesophageal hernias at the University of California San Francisco. Symptoms, which had been present an average of 85 months before surgery, consisted mainly of pain (55%), heartburn (52%), dysphagia (45%), and regurgitation (41%). Of the four patients who presented with acute illness, two had gastric obstruction, one had severe dyspnea, and one had gastric bleeding. Endoscopy demonstrated esophagitis in 25 (69%) of 36 patients, and 24-hour pH-monitoring demonstrated acid reflux in 22 (67%) of 33 patients. Manometry detected severely impaired distal esophageal peristalsis in 17 (52%) of 33 patients. The preferred operation consisted of reduction of the hernia, excision of the sack and the gastric fat pad, closure of the enlarged hiatus without mesh, and construction of a fundoplication anchored by sutures within the abdomen. RESULTS Of the 55 patients, the operations of 49 were completed laparoscopically using the following reconstructions: Guarner (270-degree) fundoplication (30 patients); Nissen fundoplication (10 patients); and gastropexy (9 patients). Five (9%) operations were converted to laparotomies. The average operating time was 219 minutes; the average blood loss was less than 25 mL; resumption of an unrestricted diet, 27 hours; and mean hospital stay, 58 hours. Intraoperative technical complications occurred in five (9%) patients. One patient died during surgery from a sudden pulmonary embolus. Two (4%) patients required a second operation for recurrent paraesophageal hernias. CONCLUSIONS Laparoscopic repair of paraesophageal hiatal hernias is safe and effective, but the operation is difficult and good results hinge on details of the operative technique and the surgeons experience. In this series, the crus could always be closed securely without using mesh. We realized early that a fundoplication should be a routine step, because it corrects reflux and is the best method to secure the gastroesophageal junction in the abdomen.

Safety and Timing of Nonobstetric Abdominal Surgery in Pregnancy

Background/Aims: Abdominal disorders occurring during pregnancy pose special difficulties in diagnosis and management to the obstetrician and surgeon. The advisability of nonobstetric abdominal surgery during pregnancy is uncertain. Our objective was to evaluate the safety and timing of abdominal surgery during pregnancy. Methods: We retrospectively reviewed 77 consecutive gravid patients undergoing nonobstetric abdominal surgery from 1989 to 1996 at an urban academic medical center and a large affiliated community teaching hospital. Medical records were evaluated for clinical presentation, perioperative management, preterm labor, and maternal and fetal morbidity and mortality. Results: The rate of nonobstetric abdominal surgery during pregnancy was 1 in every 527 births. Among the 77 patients, the indications for surgery were adnexal mass (42%), acute appendicitis (21%), gallstone disease (17%) and other (21%). There was no maternal or fetal loss or identifiable neonatal birth defect. Preterm labor occurred in 26% of the second-trimester patients and 82% of the third-trimester patients. Preterm labor was most common in patients with appendicitis and after adnexal surgery. Preterm delivery occurred in 16% of the patients, but appeared to be directly related to the abdominal surgery in only 5%. Conclusion: Surgery during the first or second trimester is not associated with significant preterm labor, fetal loss or risk of teratogenicity. Surgery during the third trimester is associated with preterm labor, but not fetal loss.

The role of amniotic fluid in fetal nutrition.

The contribution of amniotic fluid to fetal growth and gastrointestinal tract development was studied in a rabbit model. In the fetal rabbit, at 23 days gestation, 3 conditions were surgically produced: (1) prevention of swallowing of amniotic fluid by esophageal ligation (n = 8); (2) esophageal ligation but insertion of an esophageal cannula distally to allow continuous infusion into the stomach of bovine amniotic fluid to mimic fetal swallowing (n = 7); and (3) sham operation (n = 7). Fetuses were delivered by Caesarean section at 28 days gestation. Esophageal ligation resulted in significant reductions of birth weight and crown-rump length and a trend to decreased liver weight when compared to sham operated controls. Additionally, marked reductions in gastric and intestinal tissue weight and gastric acidity were found following esophageal ligation. These reductions in both somatic and gastrointestinal tract growth and gastric function were reversed by infusion of amniotic fluid intragastrically. We conclude that amniotic fluid provides 10% to 14% of the nutritional requirements of the normal fetus, and that amniotic fluid contains a potent and as yet undefined gastrointestinal tract trophic factor.

Laparoscopic splenectomy : The emerging standard

AbstractBackground: The purpose of this study was to evaluate the outcome of patients undergoing laparoscopic splenectomy (LS) at the University of California, San Francisco. Methods: The medical records of the initial 52 unselected patients undergoing LS were reviewed and compared to 28 concurrently treated open splenectomy patients (OS). Results: Patients did not differ with regard to age, gender, body, or splenic weights. The operative time was longer in the LS patients (mean 196 vs 156 min), but the length of stay and duration of ileus were shorter in the LS group. For adult patients admitted exclusively for splenectomy, operative times did not differ between LS and OS and total hospital cost was less in the LS group (mean

Early Detection of Sporadic Pancreatic Cancer: Summative Review

8,939 vs

Screening for Pancreatic Cancer: Why, How, and Who?

14,022). Six patients required conversion to OS, four occurring in the first 11 patients treated (overall conversion rate of 11%). Three patients died from complications related to their underlying disease. Two other major complications occurred. Complication rates and transfusion requirements did not differ between OS and LS patients. Conclusions: Laparoscopic splenectomy is a safe and effective alternative to open splenectomy for treatment of hematologic diseases in patients of all ages.