Kathryn M. Ziegler

Pancreatic Enucleation: Improved Outcomes Compared to Resection

IntroductionPancreatic enucleation is associated with a low operative mortality and preserved pancreatic parenchyma. However, enucleation is an uncommon operation, and good comparative data with resection are lacking. Therefore, the aim of this analysis was to compare the outcomes of pancreatic enucleation and resection.Material and MethodsFrom 1998 through 2010, 45 consecutive patients with small (mean, 2.3 cm) pancreatic lesions underwent enucleation. These patients were matched with 90 patients undergoing pancreatoduodenectomy (n = 38) or distal pancreatectomy (n = 52). Serious morbidity was defined in accordance with the American College of Surgeons–National Surgical Quality Improvement Program. Outcomes were compared with standard statistical analyses.ResultsOperative time was shorter (183 vs. 271 min, p < 0.01), and operative blood loss was significantly lower (160 vs. 691 ml, p < 0.01) with enucleation. Fewer patients undergoing enucleation required monitoring in an intensive care unit (20% vs. 41%, p < 0.02). Serious morbidity was less common among patients who underwent enucleation compared to those who had a resection (13% vs. 29%, p = 0.05). Pancreatic endocrine (4% vs. 17%, p = 0.05) and exocrine (2% vs. 17%, p < 0.05) insufficiency were less common with enucleation. Ten-year survival was no different between enucleation and resection.ConclusionCompared to resection, pancreatic enucleation is associated with improved operative as well as short- and long-term postoperative outcomes. For small benign and premalignant pancreatic lesions, enucleation should be considered the procedure of choice when technically appropriate.

Pancreatic surgery: Evolution at a high-volume center

BACKGROUND Advances in imaging, minimally invasive techniques, and regionalization have changed pancreatic surgery. Therefore, the aims of this report are to determine whether the pancreatic operations or the spectrum of disease have evolved at a high-volume center. METHODS From 1996 through 2009, 2,004 pancreatic operations were performed at Indiana University Hospital. The operations, pathology, and outcomes for 1996-2003 were compared with 2004-2009. RESULTS In 2004-2009, more operations/year were performed (215 vs 89; P < .01) and patients were older (58.8 years vs 55.8 years; P < .01). In recent years, more pancreatoduodenectomies (55.0% vs 50.4%) and fewer pancreatojejunostomies (6.2% vs 12.6%) and Beger/Frey procedures (2.6% vs 4.8%) were performed (P < .05). In 2004-2009, pylorus preservation (81.1% vs 64.4%), laparoscopic distal pancreatectomy (33.9% vs 0%), and splenic preservation (25.3% vs 2.2%) were carried out more frequently (P < .001). Pathology review revealed more tumors (68.8% vs 60.4%) and less pancreatitis (29.2% vs 34.4%; P < .01). Thirty-day mortality improved from 2.5% to 1.8%. CONCLUSION At a high-volume pancreatic surgery center, the number and age of the patients, the percentage of pancreatic resections, preservation of the pylorus and spleen as well as laparoscopic procedures, and the percentage of patients with tumors all have increased, whereas the outcomes continued to improve.

Choledochoceles: are they choledochal cysts?

Objective:The aim of this analysis was to report a multidisciplinary series comparing choledochoceles to Todani Types I, II, IV, and V choledochal cysts. Summary Background Data:Choledochoceles have been classified as Todani Type III choledochal cysts. However, most surgical series of choledochal cysts have reported few choledochoceles because they are managed primarily by endoscopists. Methods:Surgical, endoscopic, and radiologic records were reviewed at the Riley Childrens Hospital and the Indiana University Hospitals to identify patients with choledochal cysts. Patient demographics, presenting symptoms, radiologic studies, associated abnormalities, surgical and endoscopic procedures as well as outcomes were reviewed. Results:A total of 146 patients with “choledochal cysts” including 45 children (31%) and 28 with choledochoceles (18%) were identified, which represents the largest Western series. Patients with choledochoceles were older (50.7 vs. 29.0 years, P < 0.05) and more likely to be male (43% vs. 19%, P < 0.05), to present with pancreatitis (48% vs. 24%, P < 0.05) rather than jaundice (11% vs. 30%, P < 0.05) or cholangitis (0% vs. 21%, P < 0.05), to have pancreas divisum (38% vs. 10%, P < 0.01), and to be managed with endoscopic therapy (79% vs. 17%, P < 0.01). Two patients with choledochoceles (7%) had pancreatic neoplasms. Conclusions:Patients with choledochoceles differ from patients with choledochal cysts with respect to age, gender, presentation, pancreatic ductal anatomy, and their management. The association between choledochoceles and pancreas divisum is a new observation. Therefore, we conclude that classifications of choledochal cysts should not include choledochoceles.

Adipocytes enhance murine pancreatic cancer growth via a hepatocyte growth factor (HGF)-mediated mechanism

INTRODUCTION Obesity accelerates the development and progression of pancreatic cancer, though the mechanisms underlying this association are unclear. Adipocytes are biologically active, producing factors such as hepatocyte growth factor (HGF) that may influence tumor progression. We therefore sought to test the hypothesis that adipocyte-secreted factors including HGF accelerate pancreatic cancer cell proliferation. MATERIAL AND METHODS Murine pancreatic cancer cells (Pan02 and TGP-47) were grown in a) conditioned medium (CM) from murine F442A preadipocytes, b) HGF-knockdown preadipocyte CM, c) recombinant murine HGF at increasing doses, and d) CM plus HGF-receptor (c-met) inhibitor. Cell proliferation was measured using the MTT assay. ANOVA and t-test were applied; p < 0.05 considered significant. RESULTS Wild-type preadipocyte CM accelerated Pan02 and TGP-47 cell proliferation relative to control (59 ± 12% and 34 ± 12%, p < 0.01, respectively). Knockdown of preadipocyte HGF resulted in attenuated proliferation vs. wild type CM in Pan02 cells (35 ± 5% vs. 68 ± 14% greater than control; p < 0.05), but proliferation in TGP-47 cells remained unchanged. Recombinant HGF dose-dependently increased Pan02, but not TGP-47, proliferation (p < 0.05). Inhibition of HGF receptor, c-met, resulted in attenuated proliferation versus control in Pan02 cells, but not TGP-47 cells. CONCLUSIONS These experiments demonstrate that adipocyte-derived factors accelerate murine pancreatic cancer proliferation. In the case of Pan02 cells, HGF is responsible, in part, for this proliferation.

Laparoscopic Transgastric Gastroplasty: A Novel Technique for a Large Esophagogastric Fistula

Esophagogastric fistula is a rare complication related to severe inflammation at the gastroesophageal junction. Most causes are related to severe gastroesophageal reflux disease, previous surgery, or malignancy. This is the case of a 72-year-old man who had a laparoscopic Nissen fundoplication. He developed an esophageal obstruction from an intraesophageal pledget. It was removed laparoscopically, and the esophagotomy was buttressed with a Nissen fundoplication. Two months later he developed severe dysphagia, and an esophagogastric fistula was diagnosed. This was a large fistula measuring 20 mm in diameter. A novel hybrid technique was used to divide the fundoplication. Under endoscopic guidance, a 12-mm balloon-tipped trocar was inserted transgastrically. A linear-cutting surgical stapler was used to divide the fundoplication and reopen the gastroesophageal junction. The patient had no further dysphagia or gastroesophageal reflux.

Periampullary choledochal diverticula are not choledochal cysts.

BACKGROUND Choledochal cysts (CC) are rare, congenital anomalies of the biliary tree, associated with the development of biliary malignancies. Small periampullary choledochal diverticula (PCD) are a previously unreported type of biliary anomaly found primarily at ERCP. OBJECTIVE The aim of this study was to assess whether PCD are congenital or acquired lesions by comparing the clinical presentation, management, and risk of malignancy between patients with PCD and CC. DESIGN Retrospective analysis of a medical center database. SETTING Academic tertiary referral center. PATIENTS Over the study period, data regarding 16 patients with PCD were identified and compared with that of 118 patients with CC. INTERVENTION Retrospective review of ERCP, surgical pathology, billings, and a diagnostic imaging database from our institution from 1985 to 2009 was done. MAIN OUTCOME MEASUREMENTS Clinical presentation, investigations, management strategies, complication rates, and long-term outcomes were compared in patients with classic CC and PCD over the same time period. RESULTS Patients with PCD were less likely to be female (50% vs 81%), older aged (mean 68 vs 28 years), to complain of abdominal pain (88% vs 68%), and were less likely to present with jaundice (0% vs 32%) (P<.05 for all pairs). Patients with PCD also were noted to have lower frequency of anomalous pancreatobiliary junction (0% vs 83%) and biliary neoplasia (0% vs 5%) and more likely to have sphincter of Oddi dysfunction (63% vs 1%). Management of PCD was done with ERCP in 87% of cases and with surgery in 0% of cases, whereas management of CC was done with ERCP in 20% of cases and surgery in 80% of cases (P<.001). Long-term complications at a mean follow-up of 3.7 years after therapy were more common in CC (40% vs 6%, P=.02). LIMITATIONS Retrospective study. Lack of structured follow up. CONCLUSION Small, periampullary, choledochal diverticula are a newly reported, likely acquired anomaly of the biliary tract that are frequently associated with sphincter of Oddi dysfunction and may be secondary to biliary hypertension. These acquired lesions should not be classified as CC.

Abstract 510: Do adipocytes in the tumor microenvironment influence the growth of pancreatic cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Introduction: Pancreatic cancer develops more frequently and progresses more rapidly in obesity. The mechanisms influencing this association are incompletely understood. Using our murine model of pancreatic cancer in diet-induced obesity, we hypothesized that changes in the immune profile and tumor microenvironment may contribute to accelerated pancreatic cancer growth in obesity. Methods: Thirty male C57BL/6J mice were studied. At 5 weeks of age, 20 mice were fed high fat diet (60% fat; HFD) and 10 were fed low fat (10% fat) diet. At 19 weeks of age all mice were inoculated in the flank with 2.5 x105 Pan02 murine pancreatic cancer cells. After 5 weeks of tumor growth, spleens and tumors were collected, splenic flow cytometry evaluated lymphocyte population, proliferation was determined by PCNA staining, and tumor infiltrating lymphocytes (TIL), both B and T, were scored by immunohistochemistry. Intratumoral adipocyte volume was assessed by H&E staining. Studentss t-test and Pearsons correlation were applied where appropriate. P value <0.05 was accepted as statistically significant. Results: Mice were segregated into overweight (OW – heavier than the mean body weight of the HFD mice – 35.5g, n=15) and lean (<35.5g, n=14). OW mice were significantly heavier (37.3±0.2g vs. 33.9±0.3g, p<0.001). Tumors were twice as large in OW mice as in lean mice (1.23±0.2g vs. 0.6±0.1g; p=0.001). The peripheral lymphocyte profile was similar in both OW and lean animals (T cells: 51.2±2.5% vs. 49.2±2.3%, p=0.59; B cells: 32.9±1.0% vs. 32.0±1.9%, p=0.73). TIL were observed in similar numbers in both OW and lean groups (T cell: 1.31±0.18 vs. 1.54±0.16, p=0.35; B cell: 0.63±0.08 vs. 0.91±0.15, p=0.33). Tumor proliferation as measured by PCNA was similar in both groups (139±18 OW vs. 143±14 lean, p=0.85). Interestingly, adipocyte volume was significantly greater in the OW tumor microenvironment than in the lean tumors (3.7%±0.7 vs. 2.2%±0.3, p<0.05). Conclusions: These results demonstrate that: 1) tumor weight was significantly greater in OW mice; 2) peripheral and tumor infiltrating lymphocyte profile was similar in OW and lean animals; and 3) adipocyte volume was significantly greater in the tumor microenvironment of OW mice. We conclude that obesity accelerates the growth of pancreatic cancer, and adipocytes in the tumor microenvironment may directly influence tumor growth. 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 510. doi:10.1158/1538-7445.AM2011-510