Faculty Bibliography

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.

BACKGROUND:In 2005, the International Study Group of Pancreatic Fistula developed a definition and grading of postoperative pancreatic fistula that has been accepted universally. Eleven years later, because postoperative pancreatic fistula remains one of the most relevant and harmful complications of pancreatic operation, the International Study Group of Pancreatic Fistula classification has become the gold standard in defining postoperative pancreatic fistula in clinical practice. The aim of the present report is to verify the value of the International Study Group of Pancreatic Fistula definition and grading of postoperative pancreatic fistula and to update the International Study Group of Pancreatic Fistula classification in light of recent evidence that has emerged, as well as to address the lingering controversies about the original definition and grading of postoperative pancreatic fistula. METHODS:The International Study Group of Pancreatic Fistula reconvened as the International Study Group in Pancreatic Surgery in order to perform a review of the recent literature and consequently to update and revise the grading system of postoperative pancreatic fistula. RESULTS:Based on the literature since 2005 investigating the validity and clinical use of the original International Study Group of Pancreatic Fistula classification, a clinically relevant postoperative pancreatic fistula is now redefined as a drain output of any measurable volume of fluid with an amylase level >3 times the upper limit of institutional normal serum amylase activity, associated with a clinically relevant development/condition related directly to the postoperative pancreatic fistula. Consequently, the former "grade A postoperative pancreatic fistula" is now redefined and called a "biochemical leak," because it has no clinical importance and is no longer referred to a true pancreatic fistula. Postoperative pancreatic fistula grades B and C are confirmed but defined more strictly. In particular, grade B requires a change in the postoperative management; drains are either left in place >3 weeks or repositioned through endoscopic or percutaneous procedures. Grade C postoperative pancreatic fistula refers to those postoperative pancreatic fistula that require reoperation or lead to single or multiple organ failure and/or mortality attributable to the pancreatic fistula. CONCLUSION:This new definition and grading system of postoperative pancreatic fistula should lead to a more universally consistent evaluation of operative outcomes after pancreatic operation and will allow for a better comparison of techniques used to mitigate the rate and clinical impact of a pancreatic fistula. Use of this updated classification will also allow for more precise comparisons of surgical quality between surgeons and units who perform pancreatic surgery.

BACKGROUND:Recent literature suggests that chyle leak may complicate up to 10% of pancreatic resections. Treatment depends on its severity, which may include chylous ascites. No international consensus definition or grading system of chyle leak currently is available. METHODS:The International Study Group on Pancreatic Surgery, an international panel of pancreatic surgeons working in well-known, high-volume centers, reviewed the literature and worked together to establish a consensus on the definition and classification of chyle leak after pancreatic operation. RESULTS:Chyle leak was defined as output of milky-colored fluid from a drain, drain site, or wound on or after postoperative day 3, with a triglyceride content ≥110 mg/dL (≥1.2 mmol/L). Three different grades of severity were defined according to the management needed: grade A, no specific intervention other than oral dietary restrictions; grade B, prolongation of hospital stay, nasoenteral nutrition with dietary restriction, total parenteral nutrition, octreotide, maintenance of surgical drains, or placement of new percutaneous drains; and grade C, need for other more invasive in-hospital treatment, intensive care unit admission, or mortality. CONCLUSION:This classification and grading system for chyle leak after pancreatic resection allows for comparison of outcomes between series. As with the other the International Study Group on Pancreatic Surgery consensus statements, this classification should facilitate communication and evaluation of different approaches to the prevention and treatment of this complication.

BACKGROUND:The majority of patients who have undergone a pancreatic resection for pancreatic cancer develop disease recurrence within two years. In around 30% of these patients, isolated local recurrence (ILR) is found. The aim of this study was to systematically review treatment options for this subgroup of patients. METHODS:A systematic search was performed in PubMed, Embase and the Cochrane Library. Studies reporting on the treatment of ILR after initial curative-intent resection of primary pancreatic cancer were included. Primary endpoints were morbidity, mortality and survival after ILR treatment. RESULTS:After screening 1152 studies, 18 studies reporting on 313 patients undergoing treatment for ILR were included. Treatment options for ILR included surgical re-resection (8 studies, 100 patients), chemoradiotherapy (7 studies, 153 patients) and stereotactic body radiation therapy (SBRT) (4 studies, 60 patients). Morbidity and mortality were reported for re-resection (29% and 1%, respectively), chemoradiotherapy (54% and 0%) and SBRT (3% and 1%). Most patients had a prolonged disease-free interval before recurrence. Median survival after treatment of ILR of up to 32, 19 and 16 months was reported for re-resection, chemoradiotherapy and SBRT, respectively. CONCLUSION:In selected patients, treatment of ILR following pancreatic resection for pancreatic cancer seems safe, feasible and associated with relatively good survival.

Purpose The European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC) staging classifications are two widely used systems in managing pancreatic neuroendocrine tumors. However, there is no universally accepted system. Methods An analysis was performed to evaluate the application of the ENETS and AJCC staging classifications using the SEER registry (N = 2,529 patients) and a multicentric series (N = 1,143 patients). A modified system was proposed based on analysis of the two existing classifications. The modified system was then validated. Results The proportion of patients with AJCC stage III disease was extremely low for both the SEER series (2.2%) and the multicentric series (2.1%). For the ENETS staging system, patients with stage I disease had a similar prognosis to patients with stage IIA disease, and patients with stage IIIB disease had a lower hazard ratio for death than did patients with stage IIIA disease. We modified the ENETS staging classification by maintaining the ENETS T, N, and M definitions and adopting the AJCC staging definitions. The proportion of patients with stage III disease using the modified ENETS (mENETS) system was higher than that of the AJCC system in both the SEER series (8.9% v 2.2%) and the multicentric series (11.6% v 2.1%). In addition, the hazard ratio of death for patients with stage III disease was higher than that for patients with stage IIB disease. Moreover, statistical significance and proportional distribution were observed in the mENETS staging classification. Conclusion An mENETS staging classification is more suitable for pancreatic neuroendocrine tumors than either the AJCC or ENETS systems and can be adopted in clinical practice.