Faculty Bibliography

Our neoadjuvant clinical trial of a GM-CSF secreting allogeneic pancreas tumor vaccine (GVAX) revealed the development of tertiary lymphoid aggregates (TLAs) within the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment 2 weeks after GVAX treatment. Microarray studies revealed that multiple components of the TGF-β pathway were suppressed in TLAs from patients who survived greater than 3 years and who demonstrated vaccine-enhanced mesothelin-specific T cell responses. We tested the hypothesis that combining GVAX with TGF-β inhibitors will improve the anti-tumor immune response of vaccine therapy. In a metastatic murine model of pancreatic cancer, combination therapy with GVAX vaccine and a TGF-β blocking antibody improved the cure rate of PDA-bearing mice. TGF-β blockade in combination with GVAX significantly increased the infiltration of effector CD8+ T lymphocytes, specifically anti-tumor-specific IFN-g producing CD8+ T cells, when compared to monotherapy controls (all p < 0.05). TGF-β blockade alone did not deplete T regulatory cells (Tregs), but when give in combination with GVAX, GVAX induced intratumoral Tregs were depleted. Therefore, our PDA preclinical model demonstrates a survival advantage in mice treated with an anti-TGF-β antibody combined with GVAX therapy and provides strong rational for testing this combinational therapy in clinical trials.

The majority of patients with curative resection of pancreatic ductal adenocarcinoma recur within 5 years of resection. However, the prognosis associated with different patterns of recurrence has not been well studied. A retrospective review of patients who underwent curative surgical resection of pancreatic cancer was performed. Of the 209 patients, 174 patients developed recurrent disease. Of these 174, 28(16.1%) had recurrent disease limited to lung metastases, 20(11.5%) had recurrence in the lung plus one or more other sites excluding the liver, 73(42.0%) had liver metastasis alone or liver metastasis with any other site except lung, 28(16.1%) local recurrence only, and 25(14.3%) peritoneal recurrence alone or together with local recurrence. Patients with recurrence limited to lung had a 8.5 months(Mo) median survival from recurrence to death, which was significantly better than the survival associated with recurrence in the liver(5.1Mo), in the peritoneum(2.3Mo) or locally(5.1Mo) in multivariable analyses. Among all groups, the time from surgery to the diagnosis of recurrence in patients who recurred in only in the lung was also the longest. However, 75% of patients were found to have indeterminate lung nodules on their surveillance CT scans prior to the diagnosis of recurrence in lung. This delayed diagnosis of lung recurrence may have a negative impact on survival after recurrence. In conclusion, pancreatic cancer with lung recurrence has a significantly better prognosis than recurrence in other sites. Further studies are needed to investigate how different diagnostic and treatment modalities affect the survival of this unique subpopulation of pancreatic cancer patients.

OBJECTIVE:Although pancreatic ductal adenocarcinoma is considered a rapidly progressive disease, mathematical models estimate that it takes many years for an initiating pancreatic cancer cell to grow into an advanced stage cancer. In order to estimate the time it takes for a pancreatic cancer to progress through different tumor, node, metastasis (TNM) stages, we compared the mean age of patients with pancreatic cancers of different sizes and stages. DESIGN/METHODS:Patient age, tumour size, stage and demographic information were analysed for 13,131 patients with pancreatic ductal adenocarcinoma entered into the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database. Multiple linear regression models for age were generated, adjusting for patient ethnicity, gender, tumour location and neoplastic grades. RESULTS:African-American ethnicity and male gender were associated with an earlier age at diagnosis. Patients with stage I cancers (mean age 64.8 years) were on average 1.3 adjusted years younger at diagnosis than those with stage IV cancers (p=0.001). Among patients without distant metastases, those with T1 stage cancers were on average 1.06 and 1.19 adjusted years younger, respectively, than patients with T3 or T4 cancers (p=0.03 for both). Among patients with stage IIB cancers, those with T1/T2 cancers were 0.79 adjusted years younger than those with T3 cancers (p=0.06). There was no significant difference in the mean adjusted age of patients with stage IA versus stage IB cancers. CONCLUSIONS:These results are consistent with the hypothesis that once pancreatic ductal adenocarcinomas become detectable clinically progression from low-stage to advanced-stage disease is rapid.

BACKGROUND & AIMS/OBJECTIVE:The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. METHODS:We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. RESULTS:We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. CONCLUSIONS:We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

INTRODUCTION/BACKGROUND:The clinico-radiological characteristics and the natural history of postoperative omental infarct (OI) in patients who underwent distal pancreatectomy (DP) and splenectomy have not been defined. MATERIALS AND METHODS/METHODS:Twelve patients who underwent DP over a period of 2 years and were postoperatively diagnosed with OI based on computed tomography (CT) findings were identified. RESULTS:A total of 12 patients were diagnosed with an OI based on their postoperative imaging. Seven (58.3 %) patients had previously undergone laparoscopic DP, one (8.3 %) had undergone a robotic DP, and in one (8.3 %), a laparoscopic DP was converted to an open procedure. The remaining three (25.1 %) were treated with open DP. In five (41.6 %) patients, the diagnosis of OI was made during routine follow-up. One patient underwent surgical resection of OI, and two had drains placed in the mass. Nine patients were managed conservatively. During the study period, on review of CT imaging, the minimum prevalence of postoperative OI after DP was found to be 22.8 %. A review of literature identified nine articles that reported a total of 34 patients who were diagnosed with OI after abdominal surgery. CONCLUSION/CONCLUSIONS:The management of an asymptomatic postoperative OI should be conservative while an early invasive intervention should be performed in patients who are symptomatic or have infected OI.

BACKGROUND:Interest in laparoscopic liver resection (LLR) has grown since the International 'Louisville Statement' regarding laparoscopic liver surgery was published in 2009. However, limited population-based data on LLR utilization patterns and outcomes are available. METHODS:LLR data from the Nationwide Inpatient Sample (NIS, 2000-2012) and the National Surgical Quality Improvement Project (NSQIP, 2005-2012) were compared before and after the Louisville Statement in 2009. RESULTS:In total, 1131 and 642 LLR were identified from NIS and NSQIP, respectively. Three-quarters of patients underwent LLR for a malignant indication (NIS primary malignancy, 29.6% versus metastasis, 45.1%; NSQIP primary malignancy, 35.5% versus metastasis, 46.1%). The annual volume of LLR increased from 2000-2008 versus 2009-2012 (NIS: 63 versus 168, P < 0.001; NSQIP: 52 versus 127; both P = 0.001). The peri-operative mortality associated with LLR was 2.8% in NIS and 2.2% in NSQIP. The morbidity was 38.1% in NIS and 30.7% in NSQIP. Mortality and morbidity did not change over time (both P > 0.050). After 2009, LLR was associated with a shorter length of stay (LOS) (NIS: 5 versus 6 days, P = 0.007). CONCLUSION/CONCLUSIONS:Since the Louisville Statement in 2009, utilization of LLR has increased. LLR is associated with a modest decrease in LOS and appears to be safe with mortality and morbidity similar to open surgery.