Faculty Bibliography

Purpose: Circulating tumor cells (CTCs) have been identified in the blood of patients with pancreatic adenocarcinoma (PDAC), but little is known about the exact phenotype of these cells. We assessed expression of aldehyde dehydrogenase (ALDH), CD133, and CD44 as markers of CTCs with a tumor-initiating cell (TIC) phenotype in patients with PDAC and the relationship of this expression to patient outcomes.Experimental Design: Peripheral blood from 60 consecutive patients with PDAC undergoing surgical resection was obtained and processed using the Isolation by Size of Epithelial Tumor (ISET) method. Immunofluorescence was used to identify CTCs expressing cytokeratin, CD133, CD44, and ALDH.Results: Forty-seven patients (78%) had epithelial CTCs staining positive for pan-cytokeratin and at least one TIC marker. Forty-six patients (77%) had epithelial CTCs that labeled with antibodies to cytokeratin and ALDH. By separate analysis, 34 (57%) had cytokeratin-positive, CD133-positive, and CD44-positive (triple-positive) CTCs, whereas 40 (67%) had cytokeratin-positive, CD133-positive, CD44-negative CTCs. The remaining 13 patients did not have CTCs, as defined by cytokeratin expression. ALDH-positive CTCs and triple-positive CTCs were significantly associated with worse survival by univariate analysis, even when accounting for other significant prognostic factors (all, P ≤ 0.01). ALDH-positive CTCs, triple-positive CTCs, and dual cytokeratin- and CD133-positive CTCs were independent predictors of tumor recurrence by logistic regression analysis and associated with decreased disease-free survival (all, P ≤ 0.03).Conclusions: CTCs labeling with one or more markers of TICs are found in a majority of patients with PDAC and are independently predictive of decreased disease-free and overall survival. Clin Cancer Res; 23(11); 2681-90. ©2016 AACR.

BACKGROUND:Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently referred to tertiary centers after unsuccessful attempted resections at other institutions. The outcome of these patients who are ultimately resected is not well understood. METHODS:We performed a retrospective review of patients with PDAC who underwent re-exploration between 1995 and 2013 at a single high volume tertiary care institution. We aimed to evaluate the association of neoadjuvant therapy prior to re-exploration on pathologic findings and clinical outcome in previously explored patients with PDAC. RESULTS:10 months, P<0.001). CONCLUSIONS:Patients with PDAC deemed unresectable may warrant re-exploration. Treatment with neoadjuvant therapy between operations is associated with improved pathological stage and survival. In this highly selected group of patients, successful resection is associated with improved survival compared to R2 resections.

High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions. CDKN2A alterations occurred in six HG-PanIN lesions, and RNF43 alterations in five. Mutations in TP53, GNAS, ARID1A, PIK3CA, and TGFBR2 were limited to one or two HG-PanINs. No non-synonymous mutations in SMAD4 were detected. Immunohistochemistry for p53 and SMAD4 proteins in 18 HG-PanINs confirmed the paucity of alterations in these genes, with aberrant p53 labelling noted only in three lesions, two of which were found to be wild type in sequencing analyses. Sixteen adjacent LG-PanIN lesions from ten patients were also sequenced using targeted sequencing. LG-PanIN harboured KRAS mutations in 94% of the lesions; mutations in CDKN2A, TP53, and SMAD4 were not identified. These results suggest that inactivation of TP53 and SMAD4 are late genetic alterations, predominantly occurring in invasive PDAC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BACKGROUND/OBJECTIVES/OBJECTIVE:Mucinous cystic neoplasms (MCNs) are rare pancreas tumors distinguished from intraductal papillary mucinous neoplasms (IPMNs) by the presence of ovarian-type stroma. Historical outcomes for MCNs vary due to previously ambiguous diagnostic criteria resulting in confusion with IPMNs. This study seeks to characterize and clarify the clinical features and long-term outcomes of MCNs versus IPMNs in the largest single-institution series of pathology-confirmed MCNs to date. METHODS:We compared 142 MCNs and 746 IPMNs resected at a single institution. MCNs were reviewed for confirmation of ovarian-type stroma and reclassified according to current WHO guidelines. RESULTS:MCNs presented almost exclusively in middle-aged women (median 47.5 years, 96.5% female) as solitary (100%), macrocystic (94.2%) lesions in the distal pancreas (92.1%). IPMNs were distributed equally by sex in an older population (median 69.0 years, 49.6% female) and favored the proximal pancreas (67.6%). Compared with IPMNs, MCNs were larger (4.2 cm vs 2.5 cm) and more often low-grade (71.1% vs 13.8%). Associated invasive carcinoma was less common in MCNs than in IPMNs (9.9% vs 32.4%). Surgical resection was curative for 100% of noninvasive MCNs. Patients with an MCN-associated invasive carcinoma had a much better prognosis than did patients with an IPMN-associated invasive carcinoma with 10-year disease-specific survival of 79.6% versus 27.2%, respectively. CONCLUSION/CONCLUSIONS:MCNs have a stereotypical clinical profile that is readily distinguishable from IPMNs based on demographic features, imaging, and pathology. Most MCNs are noninvasive and curable with surgical resection. Prognosis remains excellent even for invasive disease with 10-year survival approaching 80% following resection.

OBJECTIVE:This multicenter study sought to evaluate the accuracy of the American College of Surgeons National Surgical Quality Improvement Program's (ACS-NSQIP) surgical risk calculator for predicting outcomes after pancreatoduodenectomy (PD) and to determine whether incorporating other factors improves its predictive capacity. BACKGROUND:The ACS-NSQIP surgical risk calculator has been proposed as a decision-support tool to predict complication risk after various operations. Although it considers 21 preoperative factors, it does not include procedure-specific variables, which have demonstrated a strong predictive capacity for the most common and morbid complication after PD - clinically relevant pancreatic fistula (CR-POPF). The validated Fistula Risk Score (FRS) intraoperatively predicts the occurrence of CR-POPF and serious complications after PD. METHODS:This study of 1480 PDs involved 47 surgeons at 17 high-volume institutions. Patient complication risk was calculated using both the universal calculator and a procedure-specific model that incorporated the FRS and surgeon/institutional factors. The performance of each model was compared using the c-statistic and Brier score. RESULTS:The FRS was significantly associated with 30-day mortality, 90-day mortality, serious complications, and reoperation (all P < 0.0001). The procedure-specific model outperformed the universal calculator for 30-day mortality (c-statistic: 0.79 vs 0.68; Brier score: 0.020 vs 0.021), 90-day mortality, serious complications, and reoperation. Neither surgeon experience nor institutional volume significantly predicted mortality; however, surgeons with a career PD volume >450 were less likely to have serious complications (P < 0.001) or perform reoperations (P < 0.001). CONCLUSIONS:Procedure-specific complication risk influences outcomes after pancreatoduodenectomy; therefore, risk adjustment for performance assessment and comparative research should consider these preoperative and intraoperative factors along with conventional ACS-NSQIP preoperative variables.

BACKGROUND:Pancreatic cancer has become the third leading cause of cancer death with minimal improvements in outcome for over 40 years. Recent trials of therapies that target-defective DNA maintenance using poly (ADP-ribose) polymerase (PARP) inhibitors are showing promising results, yet invariably patients recur and succumb to disease. Mechanisms of resistance to platinum-based and PARP inhibitor therapy in other cancer types include secondary mutations, which restore the integrity of DNA repair through an increasing number of different mechanisms. METHODS:Here we present a case of a 63-year-old female patient with a germ line pathogenic BRCA2 mutation (6714 deletion) who developed pancreatic cancer and had an exceptional response to platinum and PARP inhibitor therapy. Through next-generation sequencing and clinical follow-up, we correlated tumour response and resistance to the BRCA2 mutational status in the tumour. RESULTS:Initially, the patient had an exceptional response to platinum and PARP inhibitor therapy, most likely due to the BRCA2 mutation. However, the primary lesion recurred while on PARP inhibitor therapy and contained a secondary mutation in BRCA2, which mostly likely restored BRCA2 function in PARP inhibitor-resistant tumour cells. CONCLUSIONS:To our knowledge, this is the first report of a BRCA2 reversion mutation that conferred resistance to PARP inhibitor-based therapy in a pancreatic ductal adenocarcinoma patient. Future studies are needed to understand this important mechanism of resistance and how it may impact the choice of therapy for patients with pancreatic cancer.

BACKGROUND:Underutilization of potential curative surgical treatment remains a problem in the management of hepatocellular carcinoma (HCC). Demographic and socioeconomic disparities continue to be important factors impacting utilization patterns, and exact mechanisms underlying these disparities remain largely unclarified. Focusing on these mechanisms provides us with a potential approach to improve survival of HCC patients. METHODS:We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results Database to assess patients with early stage HCC diagnosed between January 2004 and December 2012. Demographic and socioeconomic factors were analyzed to assess associations with utilization of treatment, stage of presentation, and disease-specific survival by means of multinominal and Cox regression. RESULTS:A total of 13,694 patients were included in the analysis of which only 6239 (45.6%) underwent surgical treatment for early stage HCC. Surgical treatment options consisted of 1445 liver resections (10.6%), 2121 liver transplantations (15.5%), and 2673 liver ablations (19.5%). The rate of surgical treatment fell from 56.1% in 2004 to 37.8% in 2012. Compared with no surgical therapy, African Americans were less likely to undergo liver transplantation (relative risk ratio [RRR] = 0.54; 95% confidence interval [CI], 0.36-0.79) than Caucasian patients and more likely to undergo surgical resection (RRR = 1.67; 95% CI, 1.13-2.48). Patients from the Pacific West were less likely to be transplanted versus patients from the Southeast (RRR = 0.68; 95% CI, 0.50-0.93). Also, patients who were married (RRR = 2.44; 95% CI, 1.96-3.04) or had health insurance (RRR = 4.74; 95% CI, 1.66-13.6) were more likely to receive liver transplantation. Young age (hazard ratio = 1.02; 95% CI, 1.00-1.03; P = 0.025) and positive marital status (hazard ratio = 0.71; 95% CI, 0.55-0.92; P = 0.010) both were independently associated with increased disease-specific survival. CONCLUSIONS:An increasing proportion of patients with early stage HCC did not undergo surgical therapy between 2004 and 2012. Demographic and socioeconomic factors were associated with different treatment modality utilization after controlling for available confounders. Of these factors, age and marital status were independently associated with increased disease-specific survival.

PURPOSE/OBJECTIVE:The goal of this study was to assess the outcomes and characteristics of patients who underwent pancreatectomy for metastatic disease to the pancreas. METHODS:Patients who underwent surgical resection of metastatic disease to the pancreas from 1988 to 2016 were identified using a prospectively maintained database. Data on clinicopathological features and outcomes of these patients were analyzed. Cox proportional hazard models were employed to identify patient-specific risk factors that influence survival. RESULTS:Ninety-seven patients underwent 98 pancreatic metastasectomies from July 1988 through March 2016 for metastatic disease from 13 different primary cancers. Pancreaticoduodenectomy, distal pancreatectomy, and total pancreatectomy were performed in 49 (50 %), 37 (38 %), and 12 (12 %) patients, respectively. Postoperative complications occurred in 55 (56 %) patients, while 3 (3 %) perioperative deaths occurred. Median follow-up was 2.0 years, with a median survival of 3.2 years. Multivariate analysis revealed that older patients [hazard ratio (HR) 1.04/year; p = 0.006], non-renal cell carcinomas (HR 5.07; p < 0.001), vascular invasion (HR 3.53; p < 0.001), and positive resection margins (HR 2.62; p = 0.008) were independently associated with an increased risk of mortality. CONCLUSIONS:Pancreatic metastasectomy is safe and feasible in well-selected patients and is associated with acceptable long-term survival.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Previous literature has suggested that small intestine GISTs are more aggressive than gastric GISTs. Our primary objective was to compare the outcomes of gastric and small intestine GISTs in the decade after approval of imatinib for treatment. METHODS:The SEER database was queried for cases of gastric and small intestine GIST between the years 2002 and 2012, using the ICD-O-3 histology code 8936. Survival analysis was performed using generalized gamma models for time to cause-specific mortality (CSM). RESULTS:CSM was 14.0% for the 3,759 gastric GIST patients and 14.3% for the 1,848 small intestine GIST patients. Five-year survival was 82.2% and 83.3% for gastric and small intestine patients, respectively. The number of diagnosed cases of GIST increased over the course of this study, especially for tumors <5 cm in size and in patients over age 50 years. CONCLUSIONS:In this large nation-wide study, we found that patients with gastric and small intestine GISTs had similar outcomes, in contrast to previous reports. The diagnosis of GIST has significantly increased in the last decade, which may reflect the increased recognition of this entity and frequent use of imaging. J. Surg. Oncol. 2017;115:351-357. © 2016 Wiley Periodicals, Inc.