439 To Capture Complication-Related Readmission After Pancreatectomy “90-Days From Surgery” Is Superior to “30-Days From Discharge”

examine the relationship between pre-treatment CEA and pCR in a large validated, population-based cohort. Methods: Patients with clinical stage II and III rectal cancer who underwent neoadjuvant chemoradiation and surgical resection with curative intent were selected from the 2006-2011 National Cancer Data Base. CEA was defined as normal, borderline and elevated based on the standards of each facility laboratory. Bivariate analysis was used to examine pCR rates across patient, tumor, and facility characteristics. Separate logistic regression models were used to estimate the odds of pCR, pathological tumor regression and tumor downsizing associated with normal, borderline, and elevated CEA levels after controlling for pertinent covariates. Results: Of 11,029 patients meeting inclusion criteria, 44% had elevated CEA and 12% experienced pCR. On bivariate analysis, elevated CEA was associated with decreased odds of pCR (OR=0.47, 95%CI=0.42-0.54, p<0.001). After adjusting for covariates, patients with an elevated CEA had a 50% decrease in the odds of pCR as compared to those with normal CEA (OR=0.50, 95%CI=0.44-0.58, p<0.001). Additionally, elevated CEA was associated with reduced pathological tumor regression (OR= 0.63, 95%CI=0.54-0.73, p<0.001) and reduced tumor downsizing (OR=0.55, 95%CI=0.510.60, p<0.001). There was no observed effect of borderline CEA on pCR (Table 1), tumor regression or tumor downsizing. Conclusion: Rectal cancer patients with an elevated pretreatment CEA are less likely to experience pCR, pathological tumor regression and tumor downsizing after neoadjuvant treatment. This may reflect unfavorable tumor biology or decreased responsiveness to treatment. These patients are very unlikely to achieve a significant tumor response following neoadjuvant therapy and are probably not suitable for a watch and wait strategy. These patients would most likely benefit from prompt surgical resection and expeditious delivery of adjuvant therapy rather than an extended duration between completion of neoadjuvant treatment and surgery as the likelihood of a significant tumor response is quite low.

438 When Should We Propose Liver Transplantation After Liver Resection for Hepatocellular Carcinoma? Ecoline Tribillon, Louise Barbier, Olivier Scatton, Claire Goumard, Sabine Irtan, Fabiano Perdigao-Cotta, Francois Durand, Valerie Paradis, Jacques Belghiti, Olivier Soubrane

437

SSAT Abstracts

A Novel Immunocompetent Orthotopic Mouse Model of Pancreatic Cancer With Robust Stroma: A Unique Tool for Evaluation of Therapies Kaustav Majumder, Shrey Modi, Nivedita Arora, Rohit Chugh, Alice Nomura, Patricia Dauer, Sulagna Banerjee, Rajinder Dawra, Ashok Saluja, Vikas Dudeja

Introduction: Liver resection (LR) can be used as a selection tool for the management of early hepatocellular carcinoma (HCC). The best timing to propose liver transplantation (LT) after initial LR is still debated. The aim of this study was to compare survival outcomes in patients listed for LT before or at HCC recurrence. Methods: All patients who underwent LT following LR for HCC in 2 French centers from January 1998 to June 2013 were included and compared according to their status at the time of listing for LT: before or at recurrence of HCC. Primary end-point was survival since LT. Results: One hundred and six patients underwent LT following LR for HCC. Forty patients were listed at recurrence, and 66 patients before recurrence, among whom 20 had HCC recurrence while on the waiting list. Regarding initial HCC resection, preoperative α-fetoprotein levels were not different between groups. Pathological characteristics of the resected specimen were not different regarding number of tumors, total diameter of the tumors, differentiation, presence of a capsule, satellite nodules, vascular invasion, R1 resections, and Milan criteria. However, the mean diameter of the largest tumor was higher in the group listed at recurrence (48 ± 38 versus 32 ± 18 mm, p=0.024). Regarding LT, pathological examination of the explant found HCC nodules in 30 (46%) patients listed before recurrence and 32 (80%) listed at recurrence (p<0.001). After a mean follow-up of 68 ± 52 months since LT, the 5-year disease-free survival rate was significantly higher in the group listed before recurrence compared to the group listed at recurrence (respectively 80% versus 60%, p=0.008). Furthermore, 5-year overall survival rate since LT was also significantly increased in the group listed before recurrence compared to the group listed at recurrence (respectively 86% versus 63%, p=0.003). In a multivariate analysis, the only independent prognostic factor for recurrence-free survival since LT was the listing for LT before recurrence of HCC (p=0.038, OR=2.5 [1.1-5.8]). Conclusion: This study suggests that patients who had resection of HCC should be listed for LT before recurrence. This strategy was associated with greater overall and disease-free survivals.

BACKGROUND: The development of novel therapeutics for pancreatic cancer has been hindered by a lack of relevant preclinical models. A valid tumor model has to recapitulate the tumorigenic properties as well as immune and stromal microenvironment which is absent in immunodeficient mice models (SCID, Athymic nude). While these components are present in the KPC (Pdx-Cre KrasG12D/+ p53-/-) model, this genetic model has an immense variability in time to invasive disease (47-355 days of life) which makes it unsuitable for the evaluation of novel therapies. In this study we have developed a novel orthotopic tumor model with tumors from KPC mice implanted in C57Black6 mice to address the shortcomings of previous models. Using this novel model we have evaluated the efficacy of Minnelide, a water soluble analog of triptolide, which was developed in our laboratory and is currently in Phase I clinical trials. METHODS: Pancreatic tumors were extracted from 6 month KPC and cut into ~3mm3 pieces. Laparotomy was performed on C57BL/6 mice and a tumor piece was sewn into a pocket of pancreas using a figure-of-8 stitch of 7-0 prolene. After 4-8 weeks, animals were euthanized and tumors collected. Stromal components and immune cell infiltration were studied by IHC and flow cytometry. In a separate model, the effect of Minnelide (0.42mg/kg/day) on tumor growth and microenvironment was evaluated. RESULTS: Tumor take rate was 90%. Consistent tumor growth was observed with time [Tumor volume (mm3, Mean ± SD); 4 wk: 1101±347, 8 wk: 1958±590]. At 8 weeks, 30% of mice had died due to tumor burden suggesting that this model can be used to evaluate the impact of novel therapies on disease specific survival. Staining for stromal components (collagen and αSMA) and immune markers (CD45) showed intense desmoplasia as well as infiltration of tumor and surrounding pancreas with leukocytes respectively (Figure1). Flow cytometric analysis of tumor cellular composition showed infiltration with macrophages, myeloid derived suppressor cells and regulatory T cells. As shown in Figure 2, Minnelide treatment resulted in a significant decrease in the tumor volumes and weight [Tumor volume (mm3, mean ± SD). 4 wk: Minnelide 62± 19 vs Control 1101± 347 mm3, 8 wk: Minnelide 368± 180 vs Control 1985 ± 590 mm3, p<0.05]. Furthermore, Minnelide treatment significantly decreased the stromal collagen content (Figure 2) and CD4 infiltrate [24± 3% vs 36±4%, Minnelide vs Control, p<0.05]. CONCLUSIONS: Our orthotopic model demonstrates consistent growth rate, tumor associated mortality and recapitulates the tumor microenvironment of human pancreatic ductal adenocarcinoma in terms of stroma components and immune infiltration. It also circumvents the variability seen in previous mouse models. This clinically relevant model can be a valuable tool to evaluate novel therapies in pancreatic cancer.

SSAT Abstracts

439 To Capture Complication-Related Readmission After Pancreatectomy "90-Days From Surgery" Is Superior to "30-Days From Discharge" Yoshihiro Mise, Matthew H. Katz, Ryan W. Day, Kristoffer W. Brudvik, Lilian Schwarz, Claudius Conrad, Jean-Nicolas Vauthey, Jeffrey E. Lee, Jason B. Fleming, Thomas Aloia Background: Although hospital readmission after pancreatectomy is an important measure of the quality of surgical treatment, it can be difficult to isolate readmissions related to surgical complications from those related to medical, oncologic or other issues. Previous studies have defined the readmission interval as either "30-Days from Discharge" or "90Days from Surgery". The objective of this study was to determine which of these definitions best captures readmissions that occur as a direct result of surgical complications after pancreatectomy. Methods: A prospectively maintained database at a high volume HPB surgery center was queried to identify individuals who underwent pancreatectomy between 2000

S-1106

and 2012. All cases of readmission in the 365 days following the initial operation were identified, indexed by cause, and stratified according to a standard grading scale. Unplanned disease-related readmissions were defined as those caused by symptoms of radiologically or pathologically confirmed disease progression. All other unplanned readmissions were defined as complication-related readmissions and categorized. The data was analyzed at 30-days after discharge and 90-days after operation in order to compare the capture rates of complication-related readmissions. Multivariable analysis assessed risk-factors for readmission at each time point. Results: During the study period, 1,123 patients were discharged from hospitalization after pancreatectomy. Complication-related readmissions occurred in 248 (22%) individuals while readmissions related to disease progression occurred in 25 (2%) individuals. For patients with a complication-related readmission, 93 (37.5%) readmissions were associated with a major adverse event requiring intervention or ICU admission. The "30-Days from Discharge" definition encompassed 184 complication-related readmissions and 1 disease-related readmission (sensitivity: 0.74, specificity: 0.96). In contrast, the "90Days from Surgery" definition captured 215 complication-related readmissions and 1 diseaserelated readmission (sensitivity 0.87, specificity 0.96). The "30-Days from Discharge" definition captured only 66 (sensitivity 0.71) major surgical complications, while the "90-Days from Surgery" definition captured 84 major surgical complications (sensitivity 0.90). For the subset of readmissions uniquely captured by the "90-Days from Surgery" definition, major complication was the only independent risk factor for readmission (p=0.02, HR: 3.94, 95% CI 1.44-12.22). Conclusions: The "90-Days from Pancreatectomy" readmission definition more precisely captures readmissions directly related to surgical morbidity, particularly those associated with major complications. These data indicate that this readmission definition should routinely be used after pancreatectomy. Clinicopathological features of pancreatectomy readmissions

440 Operative vs. Non-Operative Management of Nonfunctioning Pancreatic Neuroendocrine Tumors Irene Y. Zhang, Carlos Fernandez-del Castillo, Jing Zhao, Shadi Razmdjou, Andrew L. Warshaw, Keith D. Lillemoe, Cristina R. Ferrone Background: Surgical resection is the only curative treatment for pancreatic neuroendocrine tumors (PNETs), but pancreatic operations are high risk, with up to a 40% complication rate. There are currently no guidelines for surgery vs. surveillance when small, asymptomatic nonfunctioning PNETs are identified. We therefore investigated when resection of nonfunctioning PNETs offers therapeutic benefit. Methods: A retrospective review of all patients with nonfunctioning PNETs presenting between 1998-2014 was performed. Non-operative patients had at least one follow-up imaging study. Kaplan-Meier survival analysis was conducted, and clinicopathologic and treatment-related variables were tested for association with overall and disease-specific survival. Results: A total of 251 patients with nonfunctioning PNETs were analyzed, including 195 operative and 56 non-operative cases. Median age was 56 years and 48% were female. Operative patients had a significantly longer overall survival than non-operative patients (p=0.0013). In multivariate models, metastasis was the only significant predictor of overall survival in each cohort (non-operative, p=0.0044; operative, p<0.0001). Surgery was a significant positive prognostic factor for overall survival (p= 0.0016), after controlling for metastasis, tumor size, and age-adjusted Charlson Comorbidity Index (CCI), and for disease-specific survival (p=0.0007), after controlling for tumor size and CCI (all disease-specific deaths were associated with metastasis). In patients with small PNETs (≤3cm) and no metastasis at presentation, the population for which resection is debated, there was a significant statistical interaction between an operation and tumor size. In a systematic exploratory analysis, the hazard ratio associated with an operation decreased monotonically with increased tumor size, and an operation became a significant prognostic factor for overall survival for tumors over 1.5cm (p=0.029 or less for larger tumors) but was not significant for tumors under 1.5cm (p=0.657 or more for smaller tumors). Conclusion: For small nonfunctioning PNETs, tumor size should be a key consideration in management decisions. Resection of nonfunctioning PNETs over 1.5cm is significantly associated with a longer survival; however, the benefit of resection for tumors under 1.5cm is unclear. 441

Background. Pancreatic ductal adenocarcinoma has a dismal prognosis. Although pancreatic cancer care has become more concentrated at high-volume centres and increasingly standardized there are still considerable differences in care between centres. The role of adjuvant radiation in the treatment of resectable pancreatic cancer is controversial. It is the standard of care in most high-volume the United States (US) centres, but is not generally utilized in Europe (EU). This study compares treatment characteristics and survival outcomes between two representative high-volume pancreatic cancer centres in the US and EU. Methods. Medical records of patients with pancreatic ductal adenocarcinoma (PDAC) who underwent surgical resection from January 2003 through December 2013 at ternary centres in Boston (US) and Leiden (EU) were reviewed for clinical pathological characteristics, operative techniques, postoperative outcomes, adjuvant treatment and overall survival. Patient and treatment characteristics were compared by chi-square. Survival curves for both treatment groups were compared using the log-rank test. Multivariate Cox regression was performed to identify independent predictors for overall survival in resected PDAC patients. Results. 410 total patients were identified, 233 (54%) and 187 (46%) were treated in the US and EU respectively. The majority of patients had stage II disease at presentation (83%), which was similar (p = 0.842) in both treatment groups. Negative resection margins were comparable (57% US vs. 66% EU; p = 0.102). 82% of the patients in this US population proceeded to adjuvant treatment after surgery compared to 51% of the patients in EU (p < 0.001). 65% of the US patients received adjuvant radiation therapy while EU patients were solely treated with adjuvant chemotherapy. The perioperative morbidity was comparable (1.4% US vs. 2.7% EU; p = 0.345), but unadjusted median overall survival was significantly (p = 0.011) lower in the EU (16 months vs. 22 months). However, after adjustment for factors including adjuvant treatment, centre location was no longer predictive for overall survival. Predictive factors for overall survival were resection margin status (p = 0.019), pT stage (p = 0.012), adjuvant chemotherapy (p = 0.039) and adjuvant radiation (p = 0.030). Conclusion. The academic high-volume pancreatic cancer centres in the US and EU investigated in this study offer comparable standards of pancreatic cancer care, with the notable lack of adjuvant radiation treatment in the EU population. This study, while nonrandomized, suggest that adjuvant radiation may be associated with a survival benefit for resectable pancreatic cancer patients. Adjuvant treatment, including consideration of radiation therapy, should be of paramount importance in the care of early-stage pancreatic adenocarcinoma.

ASA= American Society of Anesthesiologists, PD = Pancreaticoduodenectomy DP = Distal Pancreatectomy, EBL = Estimated Blood Loss, IH = Index hospitalization, LOS = Length of Stay, *=Fisher's Exact Test, **=Mann-Whitney U Test, All others Chi-Squared

442 Trends in Receipt and Timing of Multimodality Therapy in Early Stage Pancreatic Cancer Francesca Dimou, Helmneh Sineshaw, Abhishek Parmar, Nina Tamirisa, Daniel Jupiter, Ahmedin Jemal, Taylor S. Riall INTRODUCTION: For patients with locoregional pancreatic cancer multimodality therapy (MMT) with surgical resection and chemotherapy is the standard of care. The objective of this study was to evaluate contemporary treatment patterns and time trends in receipt of multimodality therapy and timing of chemotherapy relative to surgery in patients undergoing MMT for locoregional pancreatic cancer. METHODS: We used the National Cancer Data Base (NCDB) to identify patients >18 years of age with stage I and II pancreatic adenocarcinoma (excluding T3 tumors). Treatment groups were defined as no treatment, surgical resection only, chemotherapy only, or MMT with chemotherapy (neoadjuvant or adjuvant) and surgery.

S-1107

SSAT Abstracts

SSAT Abstracts

A Tale of Two Cities: Reconsidering Adjuvant Radiation in Pancreatic Cancer Care Susanna W. deGeus, Lindsay A. Bliss, Mariam F. Eskander, Alexander Vahrmeijer, Tara S. Kent, A. James Moser, Mark P. Callery, Bert A. Bonsing, Jennifer F. Tseng