A.J. Moser

The Role of Pancreatic Cyst Fluid Molecular Analysis in Predicting Cyst Pathology

BACKGROUND & AIMS Current methods to detect malignancy in mucinous cystic neoplasms of the pancreas remain inadequate. The role of detailed molecular analysis in this context was investigated. METHODS Endoscopic ultrasound-guided pancreatic cyst aspirates were prospectively collected during a period of 19 months and studied for cytology, carcinoembryonic antigen level, and molecular analysis. Molecular evaluation incorporated DNA quantification (amount and quality), k-ras point mutation, and broad panel tumor suppressor linked microsatellite marker allelic loss analysis by using fluorescent capillary electrophoresis. The sequence of mutation acquisition was also calculated on the basis of a clonal expansion model, and comparison was made to the final pathology. RESULTS Thirty-six cysts with confirmed histology were analyzed. There were 11 malignant, 15 premalignant, and 10 benign cysts. Malignant cysts could be differentiated from premalignant cysts on the basis of fluid carcinoembryonic antigen level (P=.034), DNA quality (P=.009), number of mutations (P=.002), and on the sequence of mutations acquired (P<.001). Early k-ras mutation followed by allelic loss was the most predictive of a malignant cyst (sensitivity, 91%; specificity, 93%). CONCLUSIONS Malignant cyst fluid contains adequate DNA to allow mutational analysis. A first hit k-ras mutation followed by allelic loss is most predictive of the presence of malignancy in a pancreatic cyst. This approach should serve as an ancillary tool to the conventional work-up of pancreatic cysts. Cumulative amount and timing of detectable mutational damage can assist in diagnosis and clinical management.

Stereotactic body radiotherapy in the treatment of advanced adenocarcinoma of the pancreas.

Objectives: The aim of the study was to assess the feasibility and safety of stereotactic body radiotherapy (SBRT) in patients with advanced pancreatic adenocarcinoma. Methods: We reviewed outcomes of 71 patients treated with SBRT for pancreatic cancer between July 2004 and January 2009. Forty patients (56%) had locally unresectable disease, 11 patients (16%) had local recurrence following surgical resection, 8 patients (11%) had metastatic disease, and 12 patients (17%) received adjuvant SBRT for positive margins. The median dose was 24 Gy (18–25 Gy), given in a single-fraction SBRT (n = 67) or fractionated SBRT (n = 4). Kaplan-Meyer survival analyses were used to estimate freedom from local progression (FFLP) and overall survival (OS) rates. Results: The median follow-up among surviving patients was 12.7 months (4–26 months). The median tumor volume was 17 mL (5.1–249 mL). The overall FFLP rates at 6 months/1 year were 71.7%/48.5%, respectively. Among those with macroscopic disease, FFLP was achieved in 77.3% of patients with tumor size <15 mL (n = 22), and 59.5% for ≥15 mL (n = 37) (P = 0.02). FFLP was achieved in 73% following 24 to 25 Gy, and 45% with 18 to 22 Gy (P = 0.004). The median OS was 10.3 months, with 6 month/1 year OS rates of 65.3%/41%, respectively. Grade 1–2 acute and late GI toxicity were seen in 39.5% of patients. Three patients experienced acute grade 3 toxicities. Conclusions: SBRT is feasible, with minimal grade ≥3 toxicity. The overall FFLP rate for all patients was 64.8%, comparable to rates with external beam radiotherapy. This shorter treatment course can be delivered without delay in adjuvant systemic therapy.

Assessment of Quality Outcomes for Robotic Pancreaticoduodenectomy: Identification of the Learning Curve

IMPORTANCE Quality assessment is an important instrument to ensure optimal surgical outcomes, particularly during the adoption of new surgical technology. The use of the robotic platform for complex pancreatic resections, such as the pancreaticoduodenectomy, requires close monitoring of outcomes during its implementation phase to ensure patient safety is maintained and the learning curve identified. OBJECTIVE To report the results of a quality analysis and learning curve during the implementation of robotic pancreaticoduodenectomy (RPD). DESIGN, SETTING, AND PARTICIPANTS A retrospective review of a prospectively maintained database of 200 consecutive patients who underwent RPD in a large academic center from October 3, 2008, through March 1, 2014, was evaluated for important metrics of quality. Patients were analyzed in groups of 20 to minimize demographic differences and optimize the ability to detect statistically meaningful changes in performance. EXPOSURES Robotic pancreaticoduodenectomy. MAIN OUTCOMES AND MEASURES Optimization of perioperative outcome parameters. RESULTS No statistical differences in mortality rates or major morbidity were noted during the study. Statistical improvements in estimated blood loss and conversions to open surgery occurred after 20 cases (600 mL vs 250 mL [P = .002] and 35.0% vs 3.3% [P < .001], respectively), incidence of pancreatic fistula after 40 cases (27.5% vs 14.4%; P = .04), and operative time after 80 cases (581 minutes vs 417 minutes [P < .001]). Complication rates, lengths of stay, and readmission rates showed continuous improvement that did not reach statistical significance. Outcomes for the last 120 cases (representing optimized metrics beyond the learning curve) included a mean operative time of 417 minutes, median estimated blood loss of 250 mL, a conversion rate of 3.3%, 90-day mortality of 3.3%, a clinically significant (grade B/C) pancreatic fistula rate of 6.9%, and a median length of stay of 9 days. CONCLUSIONS AND RELEVANCE Continuous assessment of quality metrics allows for safe implementation of RPD. We identified several inflexion points corresponding to optimization of performance metrics for RPD that can be used as benchmarks for surgeons who are adopting this technology.

EUS-guided fiducial placement for stereotactic body radiotherapy in locally advanced and recurrent pancreatic cancer

BACKGROUND Stereotactic body radiotherapy (SBRT) has been approved for the treatment of locally advanced pancreatic cancer. Placement of gold fiducials is required for real-time tracking and delivery of a high-dose therapeutic beam of radiation to the tumor. Traditionally, fiducials have been placed either intraoperatively or percutaneously. Recently, EUS-guided fiducial placement has been reported, but the safety and feasibility of this approach is not well defined. OBJECTIVE The aim of this study was to determine the safety, feasibility, and limitations of EUS-guided placement of 0.8 x 5.0 mm fiducials via a 19-gauge needle for locally advanced and recurrent pancreatic cancer. DESIGN Prospective study of patients with either locally advanced or recurrent pancreatic cancer referred for EUS-guided fiducial placement for SBRT at our institution over a 3-year period. SETTING Tertiary referral center conducting >1800 EUS procedures annually. MAIN OUTCOME MEASUREMENTS Primary outcome measurements included success, complications, and technical limitations of EUS-guided fiducial placement in pancreatic cancer. In addition, the percentage of patients successfully completing SBRT after EUS-guided fiducial placement was determined. RESULTS A total of 51 patients (mean age 73 years; 57% male) with locally advanced (n = 36) and recurrent (n = 15) pancreatic cancer were referred for EUS-guided fiducial placement. Fiducials were successfully placed in 46 patients (90%), with technical failures occurring in 4 patients (8%) with recurrent cancer after pancreaticoduodenectomy. In 3 patients (7%), the fiducials spontaneously migrated from the original site of injection, thereby requiring a second EUS procedure for placement of additional fiducials. Of the 46 patients with fiducials placed under EUS guidance, 42 patients (91%) successfully completed SBRT. Two patients experienced disease progression before SBRT, 1 patient was lost to follow-up, and 1 patient experienced a complication at ERCP that precluded further therapy. Only 1 complication (2%), of mild pancreatitis, occurred in a patient undergoing simultaneous placement of fiducials and celiac plexus neurolysis for intractable abdominal pain. LIMITATIONS Single-center experience and lack of a formal follow-up protocol to assess for complications. CONCLUSION EUS-guided fiducial placement for SBRT in locally advanced and recurrent pancreatic cancer is safe and feasible. Successful placement was achieved in 90% of patients, with a low complication rate (2%). Furthermore, 91% of patients successfully completed SBRT after EUS-guided fiducial delivery. Although fiducials can spontaneously migrate from the initial injection site, the rate of migration is relatively low (7%), and no migration-related complications occurred over the course of this study. Limitations to EUS-guided fiducial placement may include surgically altered anatomy (pancreaticoduodenectomy) in patients with recurrent pancreatic cancer.

Controversies Concerning Pathophysiology and Management of Acalculous Biliary-Type Abdominal Pain

Acalculous biliary-type abdominal pain is a commonly encountered clinical problem whose pathophysiology is unclear and evaluation and management are controversial. Cholecystokinin cholescintigraphy to measure the gallbladder ejection fraction (GEF) has been advocated as a criterion for cholecystectomy. However, there is no consensus regarding the dose and rate of infusion of cholecystokinin, both of which can alter the GEF, and the definition of an abnormal ejection fraction varies among studies. Many but not all studies have concluded that a low GEF predicts good outcomes after cholecystectomy, but most studies suffer from poor methodology and there is only one prospective randomized controlled trial. Also, some patients with a normal GEF have responded to cholecystectomy. Another controversial area has been the role of sphincter of Oddi dysfunction (SOD) in patients with biliary-type pain and gallbladder in situ. Some reports suggest an overlap between SOD and low GEF, although a causal relationship has not been established. Yet another subject of interest is the role of visceral hyperalgesia in patients with acalculous biliary-type pain. We have reviewed the relevant literature relating to these issues and have highlighted the controversial aspects. In the absence of high-quality studies, an evidence-based treatment algorithm is difficult to design but will be proposed. More prospective controlled trials are warranted to better define the appropriate evaluation and management of patients with this syndrome.

A phase 1B study of a MUC1 pulsed autologous dendritic cell (DC) vaccine as adjuvant therapy in patients (Pts) with resected pancreatic or biliary tumors

2578 Background: MUC1 is a transmembrane hypoglycosylated protein overexpressed on adenocarcinomas and a target of specific immune responses. Pts with cancer do not spontaneously generate MUC1-specific T helper cells and as a result make only IgM antibodies against MUC1. In preclinical studies, MUC1 peptide pulsed DC vaccine in MUC1 transgenic (Tg) mice elicited strong immunity, tumor rejection and induction of MUC1 specific CD4+ and CD8+ T cells (J Immunol. 2001;166:6555-63) Methods: The objectives are to evaluate induction of MUC1-specific immunity and to evaluate toxicity of the vaccine, in pts following potentially curative surgery. 90 ml of peripheral blood is withdrawn for DC generation in IL-4 and GMCSF. Immature DCs are pulsed with 100 μg of MUC1-100mer peptide to process and present in MHC class II molecules to T helper cells, then matured and injected subcutaneously or intradermally in the upper arm once every 3 weeks for a total of 3 doses. A booster dose is given 6 months later. For immune assays, peripheral blood lymphocytes are obtained pre-vaccination, prior to each vaccine dose and 7 days post vaccination and 4 weeks after the third vaccination. Development of MUC1-specific T helper cells is evaluated in ELISA assays by the ability of vaccinated patients to switch their anti-MUC1 serum antibodies from IgM to IgG isotypes. The target accrual is 12 patients Results: 8 patients are enrolled and 27 vaccine doses have been given without any toxicity. DC generation from peripheral blood has been successful with 0.5 x106-3.2 x106 cells generated for each vaccine dose, with the target being 1.0 x106 DCs per vaccine dose. ELISA assays have been performed on serum samples obtained from seven patients. Two patients have shown isotype switching after the second injection, suggesting activation of helper T cells. This is now being confirmed by ELISPOT assays. CONCLUSIONS Vaccine administration in the first 8 patients has been extremely safe, with preliminary evidence of immune activity. Supported by grants: Lustgarten foundation (LF01-055), NCI - PO1 CA073743, NIH/NCCR/GCRC #5M01 RR 00056. No significant financial relationships to disclose.

Primary duodenal carcinoma showing divergent growth patterns as determined by microdissection-based mutational genotyping

Primary duodenal adenocarcinoma accounts for less than 0.5% of all gastrointestinal cancers. We report a case of duodenal adenocarcinoma with highly divergent growth patterns consisting of poorly differentiated adenocarcinoma and neuroendocrine carcinoma proven to arise as a single neoplasm of monoclonal origin, as demonstrated by microdissection-based mutational profiling. Multicomponent growth patterns, as seen in this case, can occasionally be encountered in gastrointestinal malignancies and have led to speculation about the pathogenesis. The methods used to clearly establish monoclonal origin based on the unique profiling of mutational damage can address fundamental issues related to tumor development and progression, while providing cogent clinical information. Our findings confirm the great potential for intestinal epithelial cells to differentiate along different histogenetic lines during tumor progression.

Elevated Biliary Calmodulin During Gallstone Formation (The Role of Bile Acids)

Hepatic bile synthesis is altered duringexperimental gallstone formation. In response tocholesterol, there is a hydrophobic shift in hepaticbile acid synthesis and hypersecretion of phospholipids.These changes decrease the vesicular capacity forcholesterol and favor crystallization. The mechanism forthese changes in hepatic bile formation is unknown.Calmodulin (CaM), a Ca2+ receptor proteininvolved in cellular secretion, regulates gallbladdertransport and may play an important role in alterationsof hepatic bile formation during cholelithiasis. Wehypothesized that biliary CaM activity is altered during gallstone formation and may beassociated with changes in bile acid and phospholipidsynthesis. Prairie dogs were fed either control (N = 22)or 1.2% cholesterol-enriched ( N 26) diets for one to six weeks. Cholecystectomy was performed; thecommon bile duct was cannulated, and hourly bile sampleswere collected. CaM was measured in bile and gallbladdertissues by radioimmunoassay. Bile samples were analyzed for cholesterol, phospholipids,total bile acids, total protein, calcium, and individualbile acid composition. Compared to controls, gallstoneanimals had elevated hepatic bile levels of CaM, phospholipids, and cholesterol.Hydrophobic bile acid synthesis was also stimulated,with increased levels of taurochenodeoxycholic acid(TCDCA) and decreased taurocholic acid (TCA).Gallbladder bile demonstrated similar changes. Althoughgallbladder bile CaM levels were increased, tissuelevels were unchanged, suggesting that increased CaMconcentration is a hepatic phenomenon. Hepatic bile CaMactivity correlated linearly with TCDCA concentration (r= 0.64, P < 0.004) and phospholipid hypersecretion (r= 0.53, P < 0.03). The relationship between biliaryCaM and increased concentrations of TCDCA andphospholipids suggests a role for CaM in alterations ofhepatocyte secretion that may promote gallstoneformation.

Utilization of laparoscopy for resections of stomach and esophagus cancers: Is hospital the deciding factor?

86 Background: Foregut surgery is technically complex. Outcomes for such high-stakes operations receive increasing scrutiny and the use of minimally invasive approaches has been further adopted. This study aims to determine national trends in laparoscopy utilization and patient outcomes for potentially curative cancer resections of the esophagus and stomach. Methods: Retrospective review of all esophageal and gastric cancer resections in the Nationwide Inpatient Sample during 1998 to 2011. Univariate analyses of sex, race, admission status, Elixhauser comorbidity score, year, insurance, hospital characteristics, procedure, and center volume were performed by chi-square. Cochran-Armitage test was used for trends. Logistic regressions were used to model inpatient mortality, complications and laparoscopy. Results: From 1998 to 2011, 120,527 and 25,540 patients (nationally-weighted records) underwent gastrectomies and esophagectomies for cancer. From early (1998-2002) to late (2008-2011) study years, inpatien...

Conference report for APA postgraduate course: clinical controversies in pancreatobiliary diseases.

The Annual Meeting of the American Pancreatic Association (APA) draws basic scientists and clinical experts in pancreatic diseases from multiple disciplines and multiple countries to Chicago on a yearly basis. This event provides a unique opportunity for the presentation of a continuing medical education (CME) course from a multidisciplinary approach with an outstanding international faculty. With this in mind a postgraduate CME course, jointly sponsored by the University of Pittsburgh School of Medicine and the Northwestern University Feinberg School of Medicine in collaboration with the APA and the National Pancreas Foundation, was presented. These organizations conducted a 1-day course entitled ‘‘Clinical Controversies in Pancreatobiliary Diseases,’’ which occurred immediately after the annual APA meeting. The course was designed to address some of the new and controversial areas of research and clinical practice, especially related to cystic lesions of the pancreas and pancreatic cancer.