A Multicenter, Open-Label, Randomized Controlled Trial of Pancreatic Enzyme Replacement Therapy in Unresectable Pancreatic Cancer

at diagnosis and at least 1 year prior for 216 PC and 143 CoC patients. Precursor adipocytes (Ad) isolated from VAT and SAT of healthy renal transplant donors were differentiated in presence of exosomes (from 4 PC and 2 CoC cell lines). Results: The time line of change in weight and fasting glucose levels are depicted in figure 1 and figure 2 respectively. These data demonstrate that PC patients start losing weight as early as 18 months prior to the diagnosis of PC which weight loss immediately preceding diagnosis and after diagnosis was seen in CoC. Similar trend was seen for fasting glucose levels which begins to rise about 18 months prior to the diagnosis of PC. No significant change in fasting glucose levels were seen in CoC. CT data showed 8% greater loss of SAT than VAT in PC compared to 5% greater loss of VAT than SAT in CoC (P=0.008). PC (but not CoC) exosomes induced 220% increase in lipid content of VAT Ad vs no exosome (p=0.01). In contrast, PC and CC exosomes, respectively, reduced lipid content in SAT Ad by 40% and 30% vs no exosome (p<0.01 each). RNA sequencing (confirmed by qPCR) revealed differentially regulated pathways in VAT and SAT Ad differentiated with PC exosomes, with adipogenesis upregulated in VAT and lipolysis, browning and inflammation upregulated in SAT. Conclusion: Weight loss and rise in fasting glucose begins as early as 1.5 year prior to diagnosis of PC. In contrast to type 2 diabetes where fasting glucose improves with weight loss, a paradoxical rise in fasting glucose occurs with weight loss in PC. This paradoxical phenomenon could be explained by differential effects of PC on visceral and subcutaneous adipose tissues, with relative preservation of the metabolically active VAT (leading to worsening glycemia) with preferential loss of SAT (leading to weight loss).

Figure 1 Time line of weight loss in pancreatic cancer and colon cancer prior to the diagnosis of cancer (second order regression line shown)

Figure 1 Time line of rise in fasting glucose levels in pancreatic cancer and colon cancer prior to the diagnosis of cancer (second order regression line shown)

Su1256 A MULTICENTER, OPEN-LABEL, RANDOMIZED CONTROLLED TRIAL OF PANCREATIC ENZYME REPLACEMENT THERAPY IN UNRESECTABLE PANCREATIC CANCER Tomotaka Saito, Hiroyuki Isayama, Yousuke Nakai, Kenji Hirano, Ryunosuke Hakuta, Yukiko Ito, Dai Mohri, Dai Akiyama, Natsuyo Yamamoto, Hiroshi Yagioka, Osamu Togawa, Kazunaga Ishigaki, Tsuyoshi Takeda, Kei Saito, Gyotane Umefune, Takeo Watanabe, Kaoru Takagi, Tsuyoshi Hamada, Naminatsu Takahara, Rie Uchino, Suguru Mizuno, Hirofumi Kogure, Saburo Matsubara, Minoru Tada, Kazuhiko Koike Objective: Although pancreatic cancer (PC) patients are potentially prone to exocrine pancreatic insufficiency (EPI), there are few evidences about pancreatic enzyme replacement therapy (PERT) in PC patients, especially those receiving chemotherapy. Our previous prospective cohort study of PERT in patients with advanced PC suggested administration of pancrelipase during systemic chemotherapy might improve nutritional status (Pancreas 2016, in press. UMIN-CTR:000011378). Therefore, we conducted this randomized controlled trial to evaluate the role of PERT in patients with unresectable PC receiving systemic chemotherapy (UMIN-CTR:000016542). Methods: This is a multicenter, open-label, randomized controlled trial in seven Japanese hospitals. Inclusion criteria were patients receiving 1st line systemic chemotherapy for unresectable PC with pathological confirmation, ≥20 years of age, and adequate organ function. Exclusion criteria were prior history of PERT and prior therapy for PC including surgical resection, and poor oral intake. Eligible patients were randomly assigned in 1:1 ratio to pancrelipase group or non-pancrelipase group. Patients in the pancrelipase group took oral pancrelipase of 48,000-lipase units per meal at the time of introduction of chemotherapy. To evaluate the prevalence of EPI in PC patients, NBT-PABA test was performed at baseline on both groups. The primary endpoint was change in the nutritional status at 8 weeks (Body mass index [BMI]), serum albumin and serum total cholesterol). The secondary endpoints were change in other nutritional status at 8 and 16 weeks and overall survival. The change in the nutritional marker was evaluated as one at 8 weeks divided by that at baseline. Results: Between May 2014 and May 2016, a total

Su1255 PARANEOPLASTIC WEIGHT LOSS AND RISE IN BLOOD GLUCOSE PRECEDING SYMPTOMS OF PANCREATIC CANCER (PC): OPPORTUNITY FOR EARLY DETECTION Raghuwansh P. Sah, Sajan Jiv Singh Nagpal, Anil Sharma, Amrit K. Kamboj, Naoki Takahashi, Debabrata Mukhopadhyay, Suresh T. Chari Background: Prognosis and survival of patients with pancreatic cancer (PC) continues to remain dismal. Lack of effective therapy and late presentation are recognized as major limitations. More than 80% patients are unresectable at presentation. We have previously described paraneoplastic diabetes in PC. Weight loss occurring in PC patients has also been observed. We believe that better characterization of paraneoplastic metabolic effects of diabetes and weight loss seen in PC and understanding of their mechanisms will enable development of strategies for early detection of PC. Here we aim to characterize the timeline of weight loss and rise in blood glucose prior to the diagnosis of PC and explore the mechanisms of the paradoxical worsening glycemia paralleling weight loss. Methods: Weight and fasting glucose levels at various 6 monthly time points from the diagnosis of cancer were extracted from electronic databases of patients with PC and colon cancer (CoC). Visceral (VAT) and Subcutaneous Adipose Tissue (SAT) were measured at L3-L4 in abdominal CTs

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AGA Abstracts

Distribution and intensity of Claudin 4 protein were significantly reduced in intracellular junction (ICJ) of villous duodenal biopsy (p <0.03 and p <0.01), similar changes were reported in crypts ICJ for claudin-4 (P <0.01 and p <0.01). However, claudin-2 distribution and intensity were significantly over-expressed in ICJ of crypt only (p<0.01 and p<0.01), no such changes could be reported in villi. RT-PCR revealed significantly increased relative expression of Claudin-2 in patients of AP compare to control (p<0.01). On differentiating AP into mild -moderate and severe category, there was significant over-expressed relative expression of claudin-2 in severe cases compare to mild-moderate (p<0.01). During functional studies, intestinal permeability (LM ratio) was significantly higher in acute pancreatitis patients compare to controls (0.98 ± 0.4 vs. 0.18 ± 0.14, p < 0.03) and lactulose concentration was also higher in AP patients compare to control (p<0.01). Pentalaminar structure of TJ was dilated in 7(43.7% ) and dilatation was also more prevalent in severe AP compare to mild-moderate AP (p=0.02). Other than TJ, few changes were also noted in intestinal mucosa i.e. increase in inter-villous width, shortening of villi, desmosomes multiplication, and mitochondrial de-compensation in AP. There was an association between Claudin-2 relative expression and TJ dilation in patients with organ failure (p=0.01 and <0.01 and p <0.01 & p=0.01). Conclusion: Changes in claudin -2 and claudin-4 expression and dilated TJ were more prevalent and persistent in patients who developed severe disease. So, altered TJ protein and dilated TJ could be associated with increased IP which initiate cascade of events responsible for severe disease. Baseline comparision of clinical and experimental parameters of AP cases and controls included in study

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of 88 patients were randomly assigned to pancrelipase group (n=44) and non-pancrelipase group (n=44). Five patients were excluded from analysis(1 in pancrelipase group, 4 in nonpancrelipase group) because they discontinued chemotherapy due to disease progression within 8 weeks after the introduction of chemotherapy. NBT-PABA test was lower than the normal range in 90% (56/62). Baseline characteristics were comparable between two groups other than performance status (P=0.044). As for the primary endpoint, there were no significant differences in changes in nutritional markers at 8 weeks in the pancrelipase group and non-pancrelipase group: 0.978 vs. 0.976 in serum albumin (P=0.561), 0.975 vs. 0.980 in BMI (P=0.780) and 0.960 vs. 1.011 in serum total cholesterol (P=0.934). Those at 16 weeks were also comparable between two groups. The median overall survival was 21.0 months in pancrelipase group as compared with 14.5 months in non-pancrelipase group (P=0.078). Conclusions: Despite the promising results in our previous study, our RCT failed to demonstrate the effects of PERT on nutritional markers at 8 weeks. Patients' baseline characteristics

validated scoring system. In phase 2, EUS-FNA slides were randomly assigned to 11 experienced CyPs (median yrs of independent practice 5.8) at 5 tertiary care centers. CyPs evaluated slides using the standardized scoring system that included: a) quantity measures: number of nucleated and diagnostic cells, b) quality measures: blood, GI contaminant, and preparation/ staining and c) diagnostic measures: insufficient, benign, atypical, suspicious and malignant for individual passes and final cytologic diagnosis (Table 1). Clinical presentation and EUS findings were shared with all CyPs. IOA was calculated using multi-rater kappa (κ) statistics with 95% CI (weighted using Cicchetti-Allison weights). Sensitivity analysis included IOA using a combined endpoint of suspicious+malignant diagnosis and impact of an individual CyP on the overall results. Assuming an overall κ of 0.8 and prevalence of malignancy of 0.6, in order to estimate κ with a lower limit of 95% CI ≥ 0.6 with 11 CyPs and 90% power, a sample size of at least 46 cases was required. RESULTS: 46 patients were included [50% males; mean age 64.9 yrs]. On EUS, the median lesion size was 27 mm, median number of 3 EUS-FNA passes (range 1-4) with majority of lesions in the head/neck (59%) of the pancreas. Final cytologic diagnosis was malignancy in 60% of cases, atypical 15%, and benign 24%. The κ value for the overall final cytologic diagnosis was 0.54 (95% CI: 0.40-0.69) with no improvement for the combined endpoint of suspicious+malignant diagnosis (κ=0.5, 95 % CI: 0.34-0.66). A sensitivity analysis using a jackknife approach showed no change in κ values after excluding individual CyPs. Overall κ value with 95% CI and strength of agreement for each category and each individual pass are provided in Table 2. CONCLUSIONS: This validation study confirms the suboptimal IOA among CyPs for pancreatic EUS-FNA specimens (moderate for the final cytologic diagnosis and slightmoderate for individual quality and quantity parameters). These results stress the importance of consensus diagnosis among CyPs in clinical practice. There is a need for refining cytologic criteria and techniques to improve diagnostic reproducibility. Table 1: Standardized scoring tool to assess individual EUS-FNA passes* and final cytologic diagnosis based on predefined quantity and quality measures

Numbers are shown in either n (%) or median (range). ECOG PS, Eastern Cooperative Oncology Group performance status: GSL, gemcitabine+S-1+leucovorin: FOLFIRINOX, oxaliplatin+irinotecan+leucovorin+fluorouracil: GEM+nabPTX, gemcitabine+nab-paclitaxel: CEA, carcinoembryonic antigen: CA19-9, carbohydrate antigen 19-9: BMI, body mass index: HbA1c, hemoglobin A1c: NBT-PABA, N-benzoyl-tryrosyl para-aminobenzoic acid Comparison of changes in nutritional markers

*Typically, one alcohol-fixed Papanicolaou stained slide and one air-dried modified Giemsa stained slide were made for each pass Table 2: Interobserver agreement with strength of agreement among cytopathologists - for individual quantity and quality measures and cytologic diagnosis for each pass

All numbers are expressed as median (range). BMI, body mass index:HbA1c, Hemoglobin A1c.

Su1257 SUBOPTIMAL INTEROBSERVER AGREEMENT (IOA) AMONGT CYTOPATHOLOGISTS (CYPS) FOR PANCREATIC ENDOSCOPIC ULTRASOUND FINE NEEDLE ASPIRATION (EUS-FNA) CYTOLOGY SPECIMENS: A MULTICENTER VALIDATION STUDY Sachin B. Wani, Rawad Mounzer, Matt Hall, Violette C. Simon, Barbara A. Centeno, Katie Dennis, Jasreman Dhillon, Fang Fan, Laila Khazai, Jason B. Klapman, Sri Komanduri, Xiaoqi Lin, David Lu, Sanjana Mehrotra, V. Raman Muthusamy, Ritu Nayar, Ajit Paintal, Jianyu Rao, Sharon Sams, Janak N. Shah, Timothy M. Tynan, Rabindra R. Watson, Amit Rastogi, Carrie B. Marshall

Based on Landis and Koch definitions, strength of rater agreement was categorized as: 00.2, slight; 0.21-0.4, fair; 0.41-0.6, moderate; 0.61-0.8, substantial; 0.81-1, almost perfect

Su1258 QUANTITATIVE DETECTION OF SPARC GENE PROMOTER METHYLATION IN PANCREATIC CANCER Nidhi Singh, Sumaira Rashid, Safoora Rashid, Surabhi Gupta, Anoop Saraya

BACKGROUND: Although standardized nomenclature for reporting final cytologic diagnosis of pancreaticobiliary FNA samples has been established, data from our pilot study suggests that the level of IOA among CyPs for pancreatic EUS-FNA specimens is moderate for the final cytologic diagnosis. AIM: The aim of this multicenter study was to assess IOA among CyPs for pancreatic EUS-FNA cytology specimens using a standardized scoring system. METHODS: Patients who underwent EUS-FNA of solid pancreatic masses at a tertiary care center were included. In the first phase of the study, three experienced CyPs, in a consensus meeting, established criteria for the assessment of pancreatic EUS-FNA specimens using a

AGA Abstracts

Background: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive cancer and its molecular pathogenesis involves interplay of many genes which may get upregulated or downregulated. Epigenetic events like promoter methylation have an important role in regulating expression of these genes. SPARC (Serine Protein Acidic and Rich in Cysteine) is a tumor suppressor protein involved in matrix remodelling. It has been found to be downregulated due to promoter methylation in pancreatic cancer cell lines and tissues.

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