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Curative Intent Surgery in Borderline Resectable and Locally Advanced Unresectable Pancreatic Adenocarcinoma: A Seer Analysis
AGA Abstracts
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Su1264
SERUM LEVELS OF INSULIN-LIKE GROWTH FACTOR 1 (IGF-1) AND INSULIN LIKE GROWTH FACTOR BINDING PROTEIN 2 (IGFBP-2) IN PATIENTS WITH PANCREATIC ADENOCARCINOMA (PDAC) Barbara Wlodarczyk, Anna Borkowska, Anita Gasiorowska, Ewa I. Malecka-Panas
CHARACTERIZATION OF MIRNAS IN CHRONIC PANCREATITIS AND PANCREATIC CANCER USING NEXT GENERATION SEQUENCING Imteyaz A. Khan, Surabhi Gupta, Safoora Rashid, Mohd R. Hasan, Sumaira Rashid, Nidhi Singh, Deepak Gunjan, Anoop Saraya
Introduction: Pancreatic adenocarcinoma is a cancer with the worst 5-year survival rate (less than 5%). Given the increase in its incidence, a breakthrough for the early diagnosis raises great hopes in achieving better quality and length of life in these patients. IGF-1 and IGFBP2 are the part of IGF-axis which is involved in glucose and lipid metabolism and may also promote a cancer growth. A few studies support the fact that IGF-1 is enrolled in early carcinogenesis in animals and human. IGF-1 and IGFBP-2 serum estimation in PDAC may be a value in the early diagnosis of this disease. Aim of study: The aim of this study was to evaluate the serum concentrations of IGF-1 and IGFBP-2 in patients with newly diagnosed PDAC. Their values in diabetes (DM) in PDAC were also assessed. Materials and methods: The study included 69 patients with PDAC diagnosed within last 6 months and 20 patients as a control group. The concentrations of IGF-1 and IGFBP-2 were estimated with ELISA (Corgenix UK Ltd R&D Systems). PDAC was diagnosed with at least two imaging techniques and confirmed with a histopathology of surgical specimen or endoscopic ultrasonography with fine needle aspirate (EUS-FNA). Results: PDAC patients compared to controls have significantly lower mean serum IGF-1 level (45,83±30,03 ng/ml vs 70,66±60,57 ng/ml; p<0,0001). In contrast, in PDAC patients the mean IGFBP-2 level was significantly higher compared to the control group (225,06±86,37 ng/ml vs 51,92±29,40 ng/ml; p<0,0001). The sensitivity (α) and specificity (β) of the IGF-1/IGFBP-2 ratio as a diagnostic indicator of PDAC was tested and compared with the values obtained for the IGF-1 and IGFBP-2 taken separately. The results show that at the 0,01 sensitivity level (99% of PDAC-positive patients are correctly diagnosed), IGF-1/IGFBP-2 ratio lower than 0,85 points indicates PDAC presence. At this level of sensitivity the test has the specificity of 0,097, which translates into 9,7% of healthy controls misdiagnosed with cancer (α=0,01; β=0,097; IGF1/IGFBP-2 ≤ 0,85). Proposed index is nearly twice more efficient PDAC indicator than IGFBP-2 alone which, assuming the same specificity, would have correctly diagnosed 98% of PDAC-positive patients (α=0,01; β=0,152) and nearly twenty times more efficient than IGF-1 which would have diagnosed correctly only 77% of PDAC-positives (α=0,01; β= 0,996). The within-sample tests of proposed index showed that only one PDAC-diagnosed patient (1,49%) had the IGF-1/IGFBP-2 ratio higher than 0,85, whereas only for 2 healthy controls (10%) the values below 0,85 level were reported. Conclusions: Our results show that IGF-1 to IGFBP-2 ratio ≤ 0,85 may be the powerful PDAC indicator. Further studies in this area in larger patients group are necessary in order to confirm this findings.
Background: Pancreatic cancer is a highly lethal cancer with a median survival of 6 months and 5-year survival rate of only 5%. Mostly by the time pancreatic cancer is diagnosed, it is already at an advanced stage where it cannot be resected. Hence there is an urgent need to find biomarkers for early detection. Since, chronic pancreatitis (CP) is a known risk factor for development of pancreatic cancer; it seems a promising idea to screen the CP patients for malignant transformation associated phenotypic changes. miRNAs are families of short, single-stranded and highly conserved non-coding RNAs which suppress gene expression at post-transcriptional level. miRNAs participate in the development and progression of cancer by acting as tumor suppressors or onco-miRs. Aberrant expression of miRNAs has been detected in a wide variety of cancers including breast, lungs, colorectal, hepatocellular and even pancreatic cancer. The aim of this study was to identify the miRNAs which are differentially expressed in CP and pancreatic cancer tissue. Methods: Total RNA enriched with miRNAs was isolated from the FFPE resected pancreatic tissues from patients with CP (n=5) and pancreatic cancer (n=5). Illumina single end reads (75*1 chemistry, Illumina NextSeq500) were generated and small RNA analysis was carried out. Processed reads were aligned against human genome and qualified reads were checked for small RNAs (rRNA, tRNA, snoRNA and miRNA). Differential Gene Expression (DGE) analysis was carried out between the two groups (CP and CA). Target and function prediction for all detected miRNAs (known and novel) was carried out against Homo sapiens reference. Srna-workbenchV3.0_ ALPHA, bowtie-1.1.1, miRbase-21, ncbi-blast-2.2.30+, Mireap_0.22, miRanda-3.3a, DESeq was used for bioinformatic data analysis. Results: Mean age of patients included in this study was 20.8±5.77 and 57±10.6 years for CP and pancreatic cancer patients respectively. On an average >500 known and >150 novel miRNAs were identified in all the samples. miRNA (hsa-miR-7704, hsa-miR-532-5p, hsa-miR-200c-3p, hsa-miR-215-5p, hsa-miR-320c and hsa-miR-196a-5p) were more than 50 fold up-regulated in pancreatic cancer tissue compared to CP tissue. miRNA ( hsa-miR-340-5p, hsa-miR-216a-5p, hsa-miR-19a-3p, hsamiR-217, hsa-miR-93-5p, hsa-miR-376c-3p and hsa-miR-382-5p) were more than 100 fold down-regulated in pancreatic cancer tissue compared to CP tissue. The targets for miRNAs over-expressed in pancreatic cancer include p53 pathway and EGF signaling pathway, both of which are known to play a crucial role in pancreatic cancer progression. Conclusion: This panel of differentially expressed miRNAs may be useful to identify CP patients who are at higher risk for developing pancreatic cancer. Alternatively, they may also be useful for therapeutic targeting.
Su1263 Su1265 AUTOPHAGY FAILS TO SUSTAIN PROLIFERATION OF PANCREATIC CANCER CELLS SUBJECTED TO AMINO ACID DEPLETION OR HYPOXIA Sandrina Maertin, Jason M. Elperin, Ethan Lotshaw, Matthias Sendler, Steven Speakman, Kazuki Takakura, Benjamin Reicher, Julia Mayerle, Markus M. Lerch, Anna Gukovskaya
CURATIVE INTENT SURGERY IN BORDERLINE RESECTABLE AND LOCALLY ADVANCED UNRESECTABLE PANCREATIC ADENOCARCINOMA: A SEER ANALYSIS Juan E. Corral, Omar Mousa, Pujan Kandel, John Stauffer, Horacio J. Asbun, Massimo Raimondo, Kabir Kabir, Yan Bi, Michael B. Wallace
Background and Aims: Pancreatic ductal adenocarcinoma displays extensive and poorly vascularized desmoplastic stromal reaction, and therefore pancreatic cancer (PaCa) cells are confronted with hypoxia and nutrient deprivation. Here, we investigate the roles of autophagy and metabolism in PaCa cell adaptation to environmental stresses. Methods: Human PaCa cell lines PANC-1, CAPAN-2 and BxPC3, as well as normal human pancreatic ductal HPDE cells and HPDE cells stably expressing oncogenic Kras, were cultured in normal conditions or subjected to hypoxia or amino acid (AA) depletion. We characterized signaling mechanisms mediating autophagy in PaCa cells by using siRNA knockdown and pharmacologic approaches. The role of autophagy in regulating oxidative and glycolytic cell metabolism was assayed with SeaHorse, and cell proliferation, with MTT assay. Results: PaCa cells exhibit strong basal autophagy mediated through non-canonical (Atg5-dependent but Beclin1/PI3K class III independent) pathway. They display mixed oxidative/glycolytic metabolism, with pronounced mitochondria contribution. We found that oncogenic Kras regulates mitochondrial metabolism as its expression in HPDE cells greatly stimulates oxidative phosphorylation but not glycolysis. Pharmacologic inhibition of mitochondrial ATP synthesis with oligomycin or the protonophore FCCP suppresses PaCa cell proliferation by 60-70%, indicating a key role of mitochondrial ATP production. We further find that in normal conditions autophagy is critical for maintaining oxidative phosphorylation and thus proliferation of PaCa cells. For example, blocking basal autophagy with lysosomal inhibitors suppresses both oxidative phosphorylation and proliferation of PANC-1 cells by >50%. In non-transformed cells, the environmental stresses markedly activate autophagy through inhibiting mTOR. Differently, in PaCa cells AA depletion and hypoxia fail to inhibit mTOR indicating defective mTOR nutrient sensing. As a result, the environmental stresses either do not activate autophagy in PaCa cells or activate it via mTOR-independent pathway. AA depletion greatly inhibits PaCa cell growth. This occurs even in cells where autophagy is activated by environmental stresses, indicating that autophagy fails to sustain proliferation of stressed PaCa cells. The inhibitory effect of AA depletion on proliferation is because the lack of AA supply inhibits oxidative phosphorylation necessary for PaCa cell growth. Conclusions: Autophagy is critical for maintaining PaCa cell proliferation in normal conditions but fails to sustain proliferation in conditions of environmental stress. AA depletion inhibits PaCa cell growth through suppressing oxidative phosphorylation. Thus, approaches aimed to limit AA supply, in addition to autophagy inhibition, could be beneficial in suppressing pancreatic tumorigenesis.
AGA Abstracts
Background: Radical surgical resection is considered the only curative treatment of pancreatic cancer. Multiple studies have described the surgical trends and outcomes on localized pancreatic cancer (Stage I-II). There is limited evidence on the current practice and impact of curative intent surgery (CIS) in patients with borderline resectable and locally advanced unresectable pancreatic adenocarcinoma (T4 or Stage III). Objectives: Describe surgical trends in United States in Stage III pancreatic adenocarcinoma. Compare outcomes on surgically resected T3/4 cases with stage matched non-resected controls. Methods: Using the Surveillance Epidemiology and End Results (SEER) database, we examined the survival of patients receiving CIS between 2004 and 2013. Disease staging was based on the AJCC manual 6th Ed. All cases with Size T3 (tumor extends beyond the pancreas) and T4 (also involves the celiac axis or superior mesenteric artery) were included. Patients with and without lymph nodes were included (N0, N1, NX). Cases with metastasis (M1) were excluded. The definition of CIS in SEER is accurate and has been validated. Kaplan Meier curves were elaborated. Log rank test compare both groups (CIS vs. no-CIS). Analysis stratified for gender, age, ethnicity, residence (urban/rural), lymph node invasion, and use of radiotherapy. Results: Initially 198,739 cases of pancreatic adenocarcinoma were evaluated. 19,430 T3 and 7,476 T4 patients met inclusion criteria. 13,457 (50.01%) were female. Mean age was 68.77 ±11.68 years. The majority were 19,418 (72.17%) White, followed by Black 2,926 (10.87%), Hispanic 2,454 (9.12%) and Asian/Pacific Is. 1,939 (7.21%). We observed an increasing trend of CIS in T4 cases in United States over the 10 year period evaluated (Panel A). Survival was significantly higher for patients who underwent CIS in both groups (Logrank test for equality of survivor functions p<0.001)(Panel B). Specific analysis of patients with T4 disease, showed that patient with CIS had longer survival after adjusting for gender (p<0.001), age (0-39 years, 40-59 years or ≥60 years, p<0.001), ethnicity (White, Black or Hispanic, p<0.05), residency (urban or rural p<0.001), invasion of lymph nodes (p<0.001) or use of radiation (p<0.001). Limitations: SEER database did not allow to stratify between borderline resectable and locally advanced cases (< 50% or ≥50% arterial circumference involvement). SEER did not record comorbidities, patient performance status, medical center characteristics (i.e. surgical volume). Information on radiation timing was also inadequate (pre or post-op). Conclusion: We found an increasing trend in CIS on Stage III pancreatic adenocarcinoma (T4, borderline resectable or locally advanced unresectable). CIS increases survival in advanced pancreatic cancer after adjusting for demographics, lymph nodes invasion or radiation use.
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AGA Abstracts Figure 2: Receiver Operating Characteristic (ROC) curve demonstrating the accuracy of HPP in distinguishing patients with PDAC (n=99; 49 with new onset DM and 50 without DM) from patients with type 2 DM (n=49) and controls (n=50)(total n=99).
Su1267 Su1266 THE BURDEN OF PANCREATIC CANCER IN THE UNITED STATES POPULATION Aynur Unalp-Arida, Constance E. Ruhl
FASTING HUMAN PANCREATIC POLYPEPTIDE (HPP) LEVEL IS NOT A RELIABLE MARKER OF PANCREATIC CANCER, CHRONIC PANCREATITIS OR TYPE 3C (PANCREATOGENIC) DIABETES MELLITUS (DM) Sajan Jiv Singh Nagpal, Amrit K. Kamboj, Raghuwansh P. Sah, William R. Bamlet, Suresh T. Chari
Pancreatic cancer has the poorest survival of any major cancer. Among digestive system malignancies, it is second only to colorectal cancer as a cause of mortality and is projected to surpass colorectal cancer in number of deaths annually beyond 2020. We used national databases to investigate current trends in the pancreatic cancer burden in the United States. Methods: The Surveillance Epidemiology and End Results Program, National Ambulatory and Hospital Ambulatory Medical Care Surveys, Nationwide Inpatient Sample, and Vital Statistics of the U.S. databases were used to estimate incidence, 5-year survival, medical care, and mortality with a primary diagnosis of pancreatic cancer. Rates were age-adjusted and shown per 100,000 population for the most recent year of national data available. Results: Pancreatic cancer accounted for 42,000 incident cases, 419,000 ambulatory visits, 35,000 hospital discharges, and 40,000 deaths. Age at diagnosis was higher than for many other digestive system malignancies, with a median of 70 years. Incidence rates were higher among men compared with women (14.2 vs. 11.0), African Americans compared with whites (15.0 vs. 12.4) and non-Hispanics compared with Hispanics (12.7 vs. 10.9). The number of new cases increased from 25,000 in 1993 to 31,000 in 2003 to 42,000 in 2013. The age-adjusted incidence rate rose overall by 12% (11.1 to 12.5) during the past 2 decades and among gender and racial-ethnic groups, except for a decline among African Americans (Figure 1). Albeit doubling from 2.8% among persons diagnosed in 1993 to 5.7% among persons diagnosed in 2008, 5-year survival remained low. Similar to incidence, ambulatory visit rates were higher among men, African Americans, and non-Hispanics. The ambulatory visit rate more than doubled over the past 2 decades (53 to 114). Hospital discharge rates were also higher among men compared with women (11 vs. 9) and African Americans compared with whites (13 vs. 9) and slightly higher among non-Hispanics compared with Hispanics (10 vs. 9). In contrast to ambulatory visits, the hospital discharge rate declined by 17% (12 to 10). Because of low survival, the mortality rate reflected the burden of new cases annually and was similar to the incidence rate. Mortality rates were higher among men compared with women (12.6 vs. 9.5), African Americans compared with whites (13.2 vs. 10.9) and non-Hispanics compared with Hispanics (11.3 vs. 7.3). Because 5-year survival increased more than incidence, mortality rates remained flat overall from 1993 to 2014 and among gender and racial-ethnic groups, except for a decline among African Americans (Figure 2). Conclusions: With a steady rise in number of new cases annually over the past 2 decades and poor survival rates, the pancreatic cancer burden in the United States remains substantial, particularly among men and African Americans.
Background and Aims HPP is a hormone predominantly secreted by islets in the ventral pancreas in response to fasting, insulin administration, ingestion of a mixed meal, and cholecystokinin administration. While postprandial HPP levels have been studied in patients with chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), there is a paucity of literature on fasting HPP in these diseases. Also, there are no data on whether fasting HPP in patients distinguish type 3c (pancreatogenic) from type 2 DM. Patients and Methods Fasting HPP levels were measured in 248 patients belonging to one of the following groups (n): CP with DM (16), CP without DM (34), PDAC with new-onset DM (50), PDAC without DM (49), new-onset type 2 DM (50), and controls without DM (49). All subjects were enrolled in the database of the Mayo Clinic Specialized Program of Research Excellence (SPORE) in pancreas cancer. PDAC was histologically confirmed in 94%. In this cohort there were 66 subjects with type 3c DM (CP-DM 16 and PDAC-DM 50) and 50 with type 2 DM. Non-parametric tests were used for the comparison of means between the subgroups. Results The mean age (mean years ± S.D) of patients in the groups were as follows: CP with no DM 54.55 ± 15.26, CP with DM: 64.69 ± 15.26, PaC with DM 66.2 ± 9.41, PaC without DM 65.92 ± 9.81 , type 2 DM 65.28 ± 7.70 and Controls 65.52 ±9.82 (p=0.013*). There was no significant difference in the gender distribution between the groups. Median (IQR) fasting HPP levels (pg/mL) were similar among the groups: PDAC with DM: 242.31(32.38-797.12), PDAC without DM: 253.23 (136.52-1342.05), CP with DM: 303.78 (142.63-2295.75), CP without DM: 235.04 (94.58-816.77), new onset type 2 DM: 288.32 (80.12-1072.06) and controls without DM: 493.26 (193.90-2129.44) (p=0.73) (Figure 1). A receiver operating characteristic (ROC) curve showed poor accuracy of HPP in distinguishing patients with PDAC (n=99; 49 with new onset DM, and 50 without DM) from patients with new onset type-2 DM (n=50) and controls (n=49) (total n=99), with an area under the curve (AUC) of 0.44 (Figure 2). There was also no significant difference in HPP levels in patients with type 2 DM (n = 50): 288.32 (80.12-1072.06) and type 3c DM (n = 66):242.31(64.92890.92) (p = 0.71). Conclusions Fasting levels of HPP cannot distinguish patients with CP or PDAC from controls, with or without concurrent DM. Fasting levels of HPP are also not useful in distinguishing type 3c from type 2 DM.
Figure 1: Box-Whisker plot comparing the values of fasting HPP (pg/mL) between groups (p=0.73). Horizontal bars represent the median
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AGA Abstracts
Su1262
Su1264
SERUM LEVELS OF INSULIN-LIKE GROWTH FACTOR 1 (IGF-1) AND INSULIN LIKE GROWTH FACTOR BINDING PROTEIN 2 (IGFBP-2) IN PATIENTS WITH PANCREATIC ADENOCARCINOMA (PDAC) Barbara Wlodarczyk, Anna Borkowska, Anita Gasiorowska, Ewa I. Malecka-Panas
CHARACTERIZATION OF MIRNAS IN CHRONIC PANCREATITIS AND PANCREATIC CANCER USING NEXT GENERATION SEQUENCING Imteyaz A. Khan, Surabhi Gupta, Safoora Rashid, Mohd R. Hasan, Sumaira Rashid, Nidhi Singh, Deepak Gunjan, Anoop Saraya
Introduction: Pancreatic adenocarcinoma is a cancer with the worst 5-year survival rate (less than 5%). Given the increase in its incidence, a breakthrough for the early diagnosis raises great hopes in achieving better quality and length of life in these patients. IGF-1 and IGFBP2 are the part of IGF-axis which is involved in glucose and lipid metabolism and may also promote a cancer growth. A few studies support the fact that IGF-1 is enrolled in early carcinogenesis in animals and human. IGF-1 and IGFBP-2 serum estimation in PDAC may be a value in the early diagnosis of this disease. Aim of study: The aim of this study was to evaluate the serum concentrations of IGF-1 and IGFBP-2 in patients with newly diagnosed PDAC. Their values in diabetes (DM) in PDAC were also assessed. Materials and methods: The study included 69 patients with PDAC diagnosed within last 6 months and 20 patients as a control group. The concentrations of IGF-1 and IGFBP-2 were estimated with ELISA (Corgenix UK Ltd R&D Systems). PDAC was diagnosed with at least two imaging techniques and confirmed with a histopathology of surgical specimen or endoscopic ultrasonography with fine needle aspirate (EUS-FNA). Results: PDAC patients compared to controls have significantly lower mean serum IGF-1 level (45,83±30,03 ng/ml vs 70,66±60,57 ng/ml; p<0,0001). In contrast, in PDAC patients the mean IGFBP-2 level was significantly higher compared to the control group (225,06±86,37 ng/ml vs 51,92±29,40 ng/ml; p<0,0001). The sensitivity (α) and specificity (β) of the IGF-1/IGFBP-2 ratio as a diagnostic indicator of PDAC was tested and compared with the values obtained for the IGF-1 and IGFBP-2 taken separately. The results show that at the 0,01 sensitivity level (99% of PDAC-positive patients are correctly diagnosed), IGF-1/IGFBP-2 ratio lower than 0,85 points indicates PDAC presence. At this level of sensitivity the test has the specificity of 0,097, which translates into 9,7% of healthy controls misdiagnosed with cancer (α=0,01; β=0,097; IGF1/IGFBP-2 ≤ 0,85). Proposed index is nearly twice more efficient PDAC indicator than IGFBP-2 alone which, assuming the same specificity, would have correctly diagnosed 98% of PDAC-positive patients (α=0,01; β=0,152) and nearly twenty times more efficient than IGF-1 which would have diagnosed correctly only 77% of PDAC-positives (α=0,01; β= 0,996). The within-sample tests of proposed index showed that only one PDAC-diagnosed patient (1,49%) had the IGF-1/IGFBP-2 ratio higher than 0,85, whereas only for 2 healthy controls (10%) the values below 0,85 level were reported. Conclusions: Our results show that IGF-1 to IGFBP-2 ratio ≤ 0,85 may be the powerful PDAC indicator. Further studies in this area in larger patients group are necessary in order to confirm this findings.
Background: Pancreatic cancer is a highly lethal cancer with a median survival of 6 months and 5-year survival rate of only 5%. Mostly by the time pancreatic cancer is diagnosed, it is already at an advanced stage where it cannot be resected. Hence there is an urgent need to find biomarkers for early detection. Since, chronic pancreatitis (CP) is a known risk factor for development of pancreatic cancer; it seems a promising idea to screen the CP patients for malignant transformation associated phenotypic changes. miRNAs are families of short, single-stranded and highly conserved non-coding RNAs which suppress gene expression at post-transcriptional level. miRNAs participate in the development and progression of cancer by acting as tumor suppressors or onco-miRs. Aberrant expression of miRNAs has been detected in a wide variety of cancers including breast, lungs, colorectal, hepatocellular and even pancreatic cancer. The aim of this study was to identify the miRNAs which are differentially expressed in CP and pancreatic cancer tissue. Methods: Total RNA enriched with miRNAs was isolated from the FFPE resected pancreatic tissues from patients with CP (n=5) and pancreatic cancer (n=5). Illumina single end reads (75*1 chemistry, Illumina NextSeq500) were generated and small RNA analysis was carried out. Processed reads were aligned against human genome and qualified reads were checked for small RNAs (rRNA, tRNA, snoRNA and miRNA). Differential Gene Expression (DGE) analysis was carried out between the two groups (CP and CA). Target and function prediction for all detected miRNAs (known and novel) was carried out against Homo sapiens reference. Srna-workbenchV3.0_ ALPHA, bowtie-1.1.1, miRbase-21, ncbi-blast-2.2.30+, Mireap_0.22, miRanda-3.3a, DESeq was used for bioinformatic data analysis. Results: Mean age of patients included in this study was 20.8±5.77 and 57±10.6 years for CP and pancreatic cancer patients respectively. On an average >500 known and >150 novel miRNAs were identified in all the samples. miRNA (hsa-miR-7704, hsa-miR-532-5p, hsa-miR-200c-3p, hsa-miR-215-5p, hsa-miR-320c and hsa-miR-196a-5p) were more than 50 fold up-regulated in pancreatic cancer tissue compared to CP tissue. miRNA ( hsa-miR-340-5p, hsa-miR-216a-5p, hsa-miR-19a-3p, hsamiR-217, hsa-miR-93-5p, hsa-miR-376c-3p and hsa-miR-382-5p) were more than 100 fold down-regulated in pancreatic cancer tissue compared to CP tissue. The targets for miRNAs over-expressed in pancreatic cancer include p53 pathway and EGF signaling pathway, both of which are known to play a crucial role in pancreatic cancer progression. Conclusion: This panel of differentially expressed miRNAs may be useful to identify CP patients who are at higher risk for developing pancreatic cancer. Alternatively, they may also be useful for therapeutic targeting.
Su1263 Su1265 AUTOPHAGY FAILS TO SUSTAIN PROLIFERATION OF PANCREATIC CANCER CELLS SUBJECTED TO AMINO ACID DEPLETION OR HYPOXIA Sandrina Maertin, Jason M. Elperin, Ethan Lotshaw, Matthias Sendler, Steven Speakman, Kazuki Takakura, Benjamin Reicher, Julia Mayerle, Markus M. Lerch, Anna Gukovskaya
CURATIVE INTENT SURGERY IN BORDERLINE RESECTABLE AND LOCALLY ADVANCED UNRESECTABLE PANCREATIC ADENOCARCINOMA: A SEER ANALYSIS Juan E. Corral, Omar Mousa, Pujan Kandel, John Stauffer, Horacio J. Asbun, Massimo Raimondo, Kabir Kabir, Yan Bi, Michael B. Wallace
Background and Aims: Pancreatic ductal adenocarcinoma displays extensive and poorly vascularized desmoplastic stromal reaction, and therefore pancreatic cancer (PaCa) cells are confronted with hypoxia and nutrient deprivation. Here, we investigate the roles of autophagy and metabolism in PaCa cell adaptation to environmental stresses. Methods: Human PaCa cell lines PANC-1, CAPAN-2 and BxPC3, as well as normal human pancreatic ductal HPDE cells and HPDE cells stably expressing oncogenic Kras, were cultured in normal conditions or subjected to hypoxia or amino acid (AA) depletion. We characterized signaling mechanisms mediating autophagy in PaCa cells by using siRNA knockdown and pharmacologic approaches. The role of autophagy in regulating oxidative and glycolytic cell metabolism was assayed with SeaHorse, and cell proliferation, with MTT assay. Results: PaCa cells exhibit strong basal autophagy mediated through non-canonical (Atg5-dependent but Beclin1/PI3K class III independent) pathway. They display mixed oxidative/glycolytic metabolism, with pronounced mitochondria contribution. We found that oncogenic Kras regulates mitochondrial metabolism as its expression in HPDE cells greatly stimulates oxidative phosphorylation but not glycolysis. Pharmacologic inhibition of mitochondrial ATP synthesis with oligomycin or the protonophore FCCP suppresses PaCa cell proliferation by 60-70%, indicating a key role of mitochondrial ATP production. We further find that in normal conditions autophagy is critical for maintaining oxidative phosphorylation and thus proliferation of PaCa cells. For example, blocking basal autophagy with lysosomal inhibitors suppresses both oxidative phosphorylation and proliferation of PANC-1 cells by >50%. In non-transformed cells, the environmental stresses markedly activate autophagy through inhibiting mTOR. Differently, in PaCa cells AA depletion and hypoxia fail to inhibit mTOR indicating defective mTOR nutrient sensing. As a result, the environmental stresses either do not activate autophagy in PaCa cells or activate it via mTOR-independent pathway. AA depletion greatly inhibits PaCa cell growth. This occurs even in cells where autophagy is activated by environmental stresses, indicating that autophagy fails to sustain proliferation of stressed PaCa cells. The inhibitory effect of AA depletion on proliferation is because the lack of AA supply inhibits oxidative phosphorylation necessary for PaCa cell growth. Conclusions: Autophagy is critical for maintaining PaCa cell proliferation in normal conditions but fails to sustain proliferation in conditions of environmental stress. AA depletion inhibits PaCa cell growth through suppressing oxidative phosphorylation. Thus, approaches aimed to limit AA supply, in addition to autophagy inhibition, could be beneficial in suppressing pancreatic tumorigenesis.
AGA Abstracts
Background: Radical surgical resection is considered the only curative treatment of pancreatic cancer. Multiple studies have described the surgical trends and outcomes on localized pancreatic cancer (Stage I-II). There is limited evidence on the current practice and impact of curative intent surgery (CIS) in patients with borderline resectable and locally advanced unresectable pancreatic adenocarcinoma (T4 or Stage III). Objectives: Describe surgical trends in United States in Stage III pancreatic adenocarcinoma. Compare outcomes on surgically resected T3/4 cases with stage matched non-resected controls. Methods: Using the Surveillance Epidemiology and End Results (SEER) database, we examined the survival of patients receiving CIS between 2004 and 2013. Disease staging was based on the AJCC manual 6th Ed. All cases with Size T3 (tumor extends beyond the pancreas) and T4 (also involves the celiac axis or superior mesenteric artery) were included. Patients with and without lymph nodes were included (N0, N1, NX). Cases with metastasis (M1) were excluded. The definition of CIS in SEER is accurate and has been validated. Kaplan Meier curves were elaborated. Log rank test compare both groups (CIS vs. no-CIS). Analysis stratified for gender, age, ethnicity, residence (urban/rural), lymph node invasion, and use of radiotherapy. Results: Initially 198,739 cases of pancreatic adenocarcinoma were evaluated. 19,430 T3 and 7,476 T4 patients met inclusion criteria. 13,457 (50.01%) were female. Mean age was 68.77 ±11.68 years. The majority were 19,418 (72.17%) White, followed by Black 2,926 (10.87%), Hispanic 2,454 (9.12%) and Asian/Pacific Is. 1,939 (7.21%). We observed an increasing trend of CIS in T4 cases in United States over the 10 year period evaluated (Panel A). Survival was significantly higher for patients who underwent CIS in both groups (Logrank test for equality of survivor functions p<0.001)(Panel B). Specific analysis of patients with T4 disease, showed that patient with CIS had longer survival after adjusting for gender (p<0.001), age (0-39 years, 40-59 years or ≥60 years, p<0.001), ethnicity (White, Black or Hispanic, p<0.05), residency (urban or rural p<0.001), invasion of lymph nodes (p<0.001) or use of radiation (p<0.001). Limitations: SEER database did not allow to stratify between borderline resectable and locally advanced cases (< 50% or ≥50% arterial circumference involvement). SEER did not record comorbidities, patient performance status, medical center characteristics (i.e. surgical volume). Information on radiation timing was also inadequate (pre or post-op). Conclusion: We found an increasing trend in CIS on Stage III pancreatic adenocarcinoma (T4, borderline resectable or locally advanced unresectable). CIS increases survival in advanced pancreatic cancer after adjusting for demographics, lymph nodes invasion or radiation use.
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AGA Abstracts Figure 2: Receiver Operating Characteristic (ROC) curve demonstrating the accuracy of HPP in distinguishing patients with PDAC (n=99; 49 with new onset DM and 50 without DM) from patients with type 2 DM (n=49) and controls (n=50)(total n=99).
Su1267 Su1266 THE BURDEN OF PANCREATIC CANCER IN THE UNITED STATES POPULATION Aynur Unalp-Arida, Constance E. Ruhl
FASTING HUMAN PANCREATIC POLYPEPTIDE (HPP) LEVEL IS NOT A RELIABLE MARKER OF PANCREATIC CANCER, CHRONIC PANCREATITIS OR TYPE 3C (PANCREATOGENIC) DIABETES MELLITUS (DM) Sajan Jiv Singh Nagpal, Amrit K. Kamboj, Raghuwansh P. Sah, William R. Bamlet, Suresh T. Chari
Pancreatic cancer has the poorest survival of any major cancer. Among digestive system malignancies, it is second only to colorectal cancer as a cause of mortality and is projected to surpass colorectal cancer in number of deaths annually beyond 2020. We used national databases to investigate current trends in the pancreatic cancer burden in the United States. Methods: The Surveillance Epidemiology and End Results Program, National Ambulatory and Hospital Ambulatory Medical Care Surveys, Nationwide Inpatient Sample, and Vital Statistics of the U.S. databases were used to estimate incidence, 5-year survival, medical care, and mortality with a primary diagnosis of pancreatic cancer. Rates were age-adjusted and shown per 100,000 population for the most recent year of national data available. Results: Pancreatic cancer accounted for 42,000 incident cases, 419,000 ambulatory visits, 35,000 hospital discharges, and 40,000 deaths. Age at diagnosis was higher than for many other digestive system malignancies, with a median of 70 years. Incidence rates were higher among men compared with women (14.2 vs. 11.0), African Americans compared with whites (15.0 vs. 12.4) and non-Hispanics compared with Hispanics (12.7 vs. 10.9). The number of new cases increased from 25,000 in 1993 to 31,000 in 2003 to 42,000 in 2013. The age-adjusted incidence rate rose overall by 12% (11.1 to 12.5) during the past 2 decades and among gender and racial-ethnic groups, except for a decline among African Americans (Figure 1). Albeit doubling from 2.8% among persons diagnosed in 1993 to 5.7% among persons diagnosed in 2008, 5-year survival remained low. Similar to incidence, ambulatory visit rates were higher among men, African Americans, and non-Hispanics. The ambulatory visit rate more than doubled over the past 2 decades (53 to 114). Hospital discharge rates were also higher among men compared with women (11 vs. 9) and African Americans compared with whites (13 vs. 9) and slightly higher among non-Hispanics compared with Hispanics (10 vs. 9). In contrast to ambulatory visits, the hospital discharge rate declined by 17% (12 to 10). Because of low survival, the mortality rate reflected the burden of new cases annually and was similar to the incidence rate. Mortality rates were higher among men compared with women (12.6 vs. 9.5), African Americans compared with whites (13.2 vs. 10.9) and non-Hispanics compared with Hispanics (11.3 vs. 7.3). Because 5-year survival increased more than incidence, mortality rates remained flat overall from 1993 to 2014 and among gender and racial-ethnic groups, except for a decline among African Americans (Figure 2). Conclusions: With a steady rise in number of new cases annually over the past 2 decades and poor survival rates, the pancreatic cancer burden in the United States remains substantial, particularly among men and African Americans.
Background and Aims HPP is a hormone predominantly secreted by islets in the ventral pancreas in response to fasting, insulin administration, ingestion of a mixed meal, and cholecystokinin administration. While postprandial HPP levels have been studied in patients with chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), there is a paucity of literature on fasting HPP in these diseases. Also, there are no data on whether fasting HPP in patients distinguish type 3c (pancreatogenic) from type 2 DM. Patients and Methods Fasting HPP levels were measured in 248 patients belonging to one of the following groups (n): CP with DM (16), CP without DM (34), PDAC with new-onset DM (50), PDAC without DM (49), new-onset type 2 DM (50), and controls without DM (49). All subjects were enrolled in the database of the Mayo Clinic Specialized Program of Research Excellence (SPORE) in pancreas cancer. PDAC was histologically confirmed in 94%. In this cohort there were 66 subjects with type 3c DM (CP-DM 16 and PDAC-DM 50) and 50 with type 2 DM. Non-parametric tests were used for the comparison of means between the subgroups. Results The mean age (mean years ± S.D) of patients in the groups were as follows: CP with no DM 54.55 ± 15.26, CP with DM: 64.69 ± 15.26, PaC with DM 66.2 ± 9.41, PaC without DM 65.92 ± 9.81 , type 2 DM 65.28 ± 7.70 and Controls 65.52 ±9.82 (p=0.013*). There was no significant difference in the gender distribution between the groups. Median (IQR) fasting HPP levels (pg/mL) were similar among the groups: PDAC with DM: 242.31(32.38-797.12), PDAC without DM: 253.23 (136.52-1342.05), CP with DM: 303.78 (142.63-2295.75), CP without DM: 235.04 (94.58-816.77), new onset type 2 DM: 288.32 (80.12-1072.06) and controls without DM: 493.26 (193.90-2129.44) (p=0.73) (Figure 1). A receiver operating characteristic (ROC) curve showed poor accuracy of HPP in distinguishing patients with PDAC (n=99; 49 with new onset DM, and 50 without DM) from patients with new onset type-2 DM (n=50) and controls (n=49) (total n=99), with an area under the curve (AUC) of 0.44 (Figure 2). There was also no significant difference in HPP levels in patients with type 2 DM (n = 50): 288.32 (80.12-1072.06) and type 3c DM (n = 66):242.31(64.92890.92) (p = 0.71). Conclusions Fasting levels of HPP cannot distinguish patients with CP or PDAC from controls, with or without concurrent DM. Fasting levels of HPP are also not useful in distinguishing type 3c from type 2 DM.
Figure 1: Box-Whisker plot comparing the values of fasting HPP (pg/mL) between groups (p=0.73). Horizontal bars represent the median
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AGA Abstracts