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Mo1032 The Risk of Spontaneous Bacterial Peritonitis Associated With Proton Pump Inhibitor Use in Cirrhotic Patients With Ascites: Long-Term Outcome in the Propensity Score-Matched Cohort
to HCC pathobiology and clinical behavior are not well understood. We have shown that HCC cell survival can be modulated by extracellular non-coding RNA. Our aims were to investigate the involvement and functional roles of extracellular RNA (exRNA), and specifically extracellular lncRNAs in mediating responses to therapeutic agents used for HCC. Methods : Human HCC cells (HepG2, Hep3B, HepG2ST, Huh7, PLC-PRF5) and nonmalignant hepatocytes (HH) were used. exRNA preparations were obtained by ultracentrifugation of culture supernatants and analyzed using qPCR. Chemosensitivity was assessed by cell viability assays using MTS or trypan blue during incubation with 1-100 μM sorafenib, doxorubicin or campthothecin. siRNA was used to modulate lncRNA expression. Cell cycle was examined by flow cytometry, and protein expression by quantitative immunoblot analysis. Results : qPCR based expression profiling identified 8 lncRNAs that were increased by >2 log fold in exRNA released from two different HCC cell lines. Of these, lincRNA-VLDLR (linc-VLDLR) was up-regulated by 1.9 to 2.9-fold in HCC cell lines compared to HH. Incubation with chemotherapeutic agents increased linc-VLDLR expression in HCC cells by 1.3 to 3.7-fold as well as exRNA released from these cells by 3.0 to 4.5-fold after 24 hrs. Linc-VLDLR expression was increased and chemotherapy induced cell death was decreased in recipient HCC cells exposed to exRNA. siRNA to linc-VLDLR (60% reduction in lincVLDLR expression) increased sorafenib (10 μM, 72 hrs) induced cell death by 29% to 68% and abrogated cell cycle progression via G1/S arrest by 8%. Similarly, cell death was increased by 34% with 10 μM camptothecin and by 21-33% with 10 μM doxorubicin. Furthermore, siRNA to linc-VLDLR reduced expression of ATP-binding cassette half-transporter (ABCC1) by 0.61-fold and breast cancer resistance protein (BCRP) by 0.22 to 0.31-fold, whereas incubation with HCC cell derived exRNA increased ABCC1 expression by 1.19 to 1.44-fold and BCRP expression by 1.11 to 2.57-fold. Conclusions : These data provide mechanistic insights into resistance to chemotherapy in HCC by (a) showing intercellular signaling mediated by exRNA as a critical factor in resistance to therapy, (b) identifying linc-VLDLR as an extracellular enriched lncRNA that contributes to inter-cellular responses to therapeutic agents and (c) showing that linc-VLDLR could modulate expression of drug transporter genes that are involved in regulated transport of chemotherapeutic agents. These novel insights suggest several potential strategies to enhance responses to chemotherapy in HCC.
The Risk of Spontaneous Bacterial Peritonitis Associated With Proton Pump Inhibitor Use in Cirrhotic Patients With Ascites: Long-Term Outcome in the Propensity Score-Matched Cohort Kyung Suk Lim, Yang Won Min, Byung Hoon Min, Geum-Youn Gwak, Yong Han Paik, Jun Haeng Lee, Moon Seok Choi, Joon Hyoek Lee, Jae J Kim, Kwang Cheol Koh, Seung Woon Paik, Byung Chul Yoo, Poong-Lyul Rhee Background/Aims: Spontaneous bacterial peritonitis (SBP) is a frequent complication of cirrhosis, associated with a poor long-term prognosis. The risk of SBP associated with proton pump inhibitor (PPI) use has been raised in advanced cirrhotic patients. However, those studies are limited by small series and/or case-control study design. This study aimed to determine whether PPI use is associated with SBP in a cohort composed of cirrhotic patients with ascites. Methods: This retrospective cohort study included 1,965 cirrhotic patients with ascites who was first diagnosed at Samsung Medical Hospital between Jan 2005 and Dec 2009. Propensity score matching generated a matched cohort composed of 886 patients. According to the PPI use (PPI group vs. non-PPI group), the SBP incidence was calculated in the each total study population and in the propensity score matched-cohort. Results: Of the 1,965 patients, 512 (32.9%) were included in PPI group. At baseline, PPI group showed lower platelet count (91.3 ± 54.2 x 103/mm3 vs. 103.4 ± 62.7 x 103/mm3; P<0.001), more prolonged prothrombin time (1.41 ± 0.43 INR vs. 1.35 ± 0.31 INR; P=0.001), and higher Child-Pugh score (8.0 ± 1.8 vs. 7.8 ± 1.6; P=0.041) than non-PPI group. PPI group showed higher SBP incidence rate than non-PPI group (10.3%/year vs. 5.9%/year; P=0.002). In the propensity score-matched cohort, baseline characteristics did not differ between the two groups. After matching, SBP incidence rate did not differ between the two groups (PPI group vs. non-PPI group, P=0.124) during a mean follow-up of 22.8 ± 24.5 months (range: 095.3 months). Conclusion: On the contrary to the current knowledge, our data suggest that PPI use is not a significant risk factor for SBP in cirrhotic patients with ascites. Mo1033
Mo1035
Tumor Antigen Expression Differs in Hepatocellular Carcinoma (HCC) Between Viral Hepatitis and Non-Viral Hepatitis Patients Kostandinos Sideras, Steven Bots, Wojciech G. Polak, Jan N. Ijzermans, Dave Sprengers, Stefan Sleijfer, Katharina Biermann, Marco J. Bruno, Jaap Kwekkeboom
Surveillance and Outcomes in Non-Alcoholic Fatty Liver Disease Related Hepatocellular Carcinoma in Veteran Affairs (VA) Population Sahil Mittal, Yvonne Sada, Hashem El-Serag, Zhigang Duan, Sarah Temple, Sarah B. May, Jennifer R. Kramer, Peter Richardson, Jessica A. Davila
Background: Identification of proper tumor antigens is of the outmost importance for the development of effective therapeutic vaccination strategies in HCC. Studies from highendemic areas, where hepatitis B-induced cirrhosis is the main cause of HCC, have suggested possible candidates. However, since the etiology of HCC substantially differs in low-endemic, western areas, there is a need to investigate the prevalence of tumor antigens in non-viral hepatitis and non-cirrhotic HCC patients. Methods: HCC tissue samples were obtained from 144 HCC patients who underwent surgical resection in our center between 2004 and 2013. Tissue microarrays were constructed containing three 0.6 cm cores from tumor tissue and 2 cores from non-tumorous liver tissue per patient. Immunohistochemistry was performed using standard techniques. Scoring was performed by 2 investigators and expression on more than 5% of tumor cells was considered positive. Medical histories were independently examined to establish the presence, or not, of viral hepatitis and cirrhosis. Results: Ninetyseven patients (67%) did not have viral hepatitis and 75 patients (52%) did not have cirrhosis. The following antigen panel was first examined in a cohort of 42 pts: MAGE-A1, MAGE-A3/4, MAGE-A10, MAGE-C1, MAGE-C2, NY-ESO-1, SSX-2, Annexin A2, Survivin, WT-1, AFP, MUC-1, Glypican-3 (GPC-3) and SALL-4. From these, 4 antigens that were expressed most commonly, and at the same time lacked expression in non-tumorous liver tissue, were chosen for further study. In the full cohort (n=144) MAGE-C1 was expressed in 17%, MAGE-C2 in 19%, SALL-4 in 25%, and GPC-3 in 38% of patients. Sixty percent of patients expressed at least one of these 4 antigens. Seventy-four present of HCC-patients with viral hepatitis but only 53% with non-viral hepatitis expressed at least one of these 4 antigens (p= .012, see table). The expression of the testis-type antigens MAGE-C1 and MAGE-C2 (p< .001), as well as the expression of the oncofetal antigens SALL-4 and GPC3 (p< .001), were strongly correlated. In addition, the expression of SALL-4 and GPC-3 was correlated with vascular invasion (p= .09 and p= .001 respectively) and poor differentiation (p= .02 and p= .002 respectively). Conclusion: Etiologic differences result in differences in tumor antigen expression in HCC. A therapeutic vaccine containing MAGE-C1, MAGEC2, SALL-4 and GPC-3 would cover only 60% of HCC-patients in low-endemic, western, areas. Thus, for non-viral hepatitis patients, novel tumor antigen identification is needed. While the co-expression of MAGE-C1 and MAGE-C2 was expected, the co-expression of the oncofetal antigens SALL-4 and GPC-3 is a novel finding. Given that SALL-4 and GPC3 are strongly related to vascular invasion and poor differentiation, targeting these oncofetal antigens may be beneficial to HCC patients with more aggressive tumors. Tumor antigen expression in relation to viral hepatitis status
Background: Recent epidemiologic evidence suggests NAFLD as a risk factor for HCC. Periodic surveillance is recommended for patients with recognizable risk factors for HCC. Due to the absence of serologic disease markers, NAFLD may be more difficult to recognize in the general population than other causes of HCC. There are no population level studies from United States looking at pre diagnosis testing patterns or outcomes in HCC attributable to NAFLD. Methods: We identified a national sample of patients who developed HCC during fiscal years 2005-2011 from Veterans Administration (VA) hospitals in the United States. HCC cases were initially identified using ICD-9 code 155.0 in the absence of 155.1, and subsequently had their full VA medical record manually reviewed for confirmation of HCC and data abstraction. NAFLD was diagnosed on the basis of histologic evidence of fatty liver infiltration or presence of metabolic syndrome in the absence of other risk factors. HCV and HBV were identified based on laboratory tests and alcohol based on history of alcohol use (> 3 drinks per day), documented alcoholism, alcoholic hepatitis or enrollment in alcohol abuse program. We compared receipt of HCC surveillance (AFP/liver ultrasound), stage at diagnosis, treatment received and survival among the three main risk factor categories (NAFLD, alcohol abuse, HCV). Results: We identified 1,500 patients diagnosed with HCC. NAFLD was the only underlying risk factor in 120 (8%), HCV in 1013 (68%) and alcohol abuse in 286 (19%). Patients with NAFLD-HCC were significantly less likely to receive HCC surveillance within 2 years prior to HCC diagnosis as compared with HCC related to HCV or alcohol abuse (Table 1). At the time of HCC diagnosis, only 6% of NAFLD-HCC cases were classified as early stage HCC (BCLC Stage A) compared to 6% and 16% with HCV and alcohol, respectively. A significantly higher proportion of NAFLD-HCC were well differentiated compared with HCV or alcohol tumors. The proportion of patients not receiving any HCC specific treatment was significantly higher in NAFLD-HCC compared with HCC patients with HCV (Table 1). Among those who received HCC specific treatment, NAFLDHCC patients were significantly less likely to receive potentially curative treatment (transplantation, resection or ablation) as compared to patients with HCV or alcohol (11% vs. 22% vs. 13%, P<0.01). The 1-year survival following diagnosis was 47% in NAFLD-HCC, 44.7% in alcohol, and 50% in HCV and was not statistically different (p-value=0.09). Conclusion: Patients with HCC in setting of NAFLD received less medical attention compared to HCV or alcohol as evidenced by lower rates of HCC surveillance. They were also less likely to receive curative treatment. Despite this, overall survival was similar in the three risk categories.
Mo1034 Extracellular Long Non-Coding RNA Lincrna-Vldlr Modulates Hepatocellular Cancer Responses to Chemotherapy Kenji Takahashi, Irene Yan, Hiroaki Haga, Joseph D. Wood, Tushar Patel Background : Innate and acquired resistance to therapeutic agents is a major limitation to the successful treatment of Hepatocellular cancer (HCC). Although long non-coding RNAs (lncRNAs) are being implicated in the pathogenesis of several diseases, their contributions
S-991
AASLD Abstracts
AASLD Abstracts
Mo1032
The Risk of Spontaneous Bacterial Peritonitis Associated With Proton Pump Inhibitor Use in Cirrhotic Patients With Ascites: Long-Term Outcome in the Propensity Score-Matched Cohort Kyung Suk Lim, Yang Won Min, Byung Hoon Min, Geum-Youn Gwak, Yong Han Paik, Jun Haeng Lee, Moon Seok Choi, Joon Hyoek Lee, Jae J Kim, Kwang Cheol Koh, Seung Woon Paik, Byung Chul Yoo, Poong-Lyul Rhee Background/Aims: Spontaneous bacterial peritonitis (SBP) is a frequent complication of cirrhosis, associated with a poor long-term prognosis. The risk of SBP associated with proton pump inhibitor (PPI) use has been raised in advanced cirrhotic patients. However, those studies are limited by small series and/or case-control study design. This study aimed to determine whether PPI use is associated with SBP in a cohort composed of cirrhotic patients with ascites. Methods: This retrospective cohort study included 1,965 cirrhotic patients with ascites who was first diagnosed at Samsung Medical Hospital between Jan 2005 and Dec 2009. Propensity score matching generated a matched cohort composed of 886 patients. According to the PPI use (PPI group vs. non-PPI group), the SBP incidence was calculated in the each total study population and in the propensity score matched-cohort. Results: Of the 1,965 patients, 512 (32.9%) were included in PPI group. At baseline, PPI group showed lower platelet count (91.3 ± 54.2 x 103/mm3 vs. 103.4 ± 62.7 x 103/mm3; P<0.001), more prolonged prothrombin time (1.41 ± 0.43 INR vs. 1.35 ± 0.31 INR; P=0.001), and higher Child-Pugh score (8.0 ± 1.8 vs. 7.8 ± 1.6; P=0.041) than non-PPI group. PPI group showed higher SBP incidence rate than non-PPI group (10.3%/year vs. 5.9%/year; P=0.002). In the propensity score-matched cohort, baseline characteristics did not differ between the two groups. After matching, SBP incidence rate did not differ between the two groups (PPI group vs. non-PPI group, P=0.124) during a mean follow-up of 22.8 ± 24.5 months (range: 095.3 months). Conclusion: On the contrary to the current knowledge, our data suggest that PPI use is not a significant risk factor for SBP in cirrhotic patients with ascites. Mo1033
Mo1035
Tumor Antigen Expression Differs in Hepatocellular Carcinoma (HCC) Between Viral Hepatitis and Non-Viral Hepatitis Patients Kostandinos Sideras, Steven Bots, Wojciech G. Polak, Jan N. Ijzermans, Dave Sprengers, Stefan Sleijfer, Katharina Biermann, Marco J. Bruno, Jaap Kwekkeboom
Surveillance and Outcomes in Non-Alcoholic Fatty Liver Disease Related Hepatocellular Carcinoma in Veteran Affairs (VA) Population Sahil Mittal, Yvonne Sada, Hashem El-Serag, Zhigang Duan, Sarah Temple, Sarah B. May, Jennifer R. Kramer, Peter Richardson, Jessica A. Davila
Background: Identification of proper tumor antigens is of the outmost importance for the development of effective therapeutic vaccination strategies in HCC. Studies from highendemic areas, where hepatitis B-induced cirrhosis is the main cause of HCC, have suggested possible candidates. However, since the etiology of HCC substantially differs in low-endemic, western areas, there is a need to investigate the prevalence of tumor antigens in non-viral hepatitis and non-cirrhotic HCC patients. Methods: HCC tissue samples were obtained from 144 HCC patients who underwent surgical resection in our center between 2004 and 2013. Tissue microarrays were constructed containing three 0.6 cm cores from tumor tissue and 2 cores from non-tumorous liver tissue per patient. Immunohistochemistry was performed using standard techniques. Scoring was performed by 2 investigators and expression on more than 5% of tumor cells was considered positive. Medical histories were independently examined to establish the presence, or not, of viral hepatitis and cirrhosis. Results: Ninetyseven patients (67%) did not have viral hepatitis and 75 patients (52%) did not have cirrhosis. The following antigen panel was first examined in a cohort of 42 pts: MAGE-A1, MAGE-A3/4, MAGE-A10, MAGE-C1, MAGE-C2, NY-ESO-1, SSX-2, Annexin A2, Survivin, WT-1, AFP, MUC-1, Glypican-3 (GPC-3) and SALL-4. From these, 4 antigens that were expressed most commonly, and at the same time lacked expression in non-tumorous liver tissue, were chosen for further study. In the full cohort (n=144) MAGE-C1 was expressed in 17%, MAGE-C2 in 19%, SALL-4 in 25%, and GPC-3 in 38% of patients. Sixty percent of patients expressed at least one of these 4 antigens. Seventy-four present of HCC-patients with viral hepatitis but only 53% with non-viral hepatitis expressed at least one of these 4 antigens (p= .012, see table). The expression of the testis-type antigens MAGE-C1 and MAGE-C2 (p< .001), as well as the expression of the oncofetal antigens SALL-4 and GPC3 (p< .001), were strongly correlated. In addition, the expression of SALL-4 and GPC-3 was correlated with vascular invasion (p= .09 and p= .001 respectively) and poor differentiation (p= .02 and p= .002 respectively). Conclusion: Etiologic differences result in differences in tumor antigen expression in HCC. A therapeutic vaccine containing MAGE-C1, MAGEC2, SALL-4 and GPC-3 would cover only 60% of HCC-patients in low-endemic, western, areas. Thus, for non-viral hepatitis patients, novel tumor antigen identification is needed. While the co-expression of MAGE-C1 and MAGE-C2 was expected, the co-expression of the oncofetal antigens SALL-4 and GPC-3 is a novel finding. Given that SALL-4 and GPC3 are strongly related to vascular invasion and poor differentiation, targeting these oncofetal antigens may be beneficial to HCC patients with more aggressive tumors. Tumor antigen expression in relation to viral hepatitis status
Background: Recent epidemiologic evidence suggests NAFLD as a risk factor for HCC. Periodic surveillance is recommended for patients with recognizable risk factors for HCC. Due to the absence of serologic disease markers, NAFLD may be more difficult to recognize in the general population than other causes of HCC. There are no population level studies from United States looking at pre diagnosis testing patterns or outcomes in HCC attributable to NAFLD. Methods: We identified a national sample of patients who developed HCC during fiscal years 2005-2011 from Veterans Administration (VA) hospitals in the United States. HCC cases were initially identified using ICD-9 code 155.0 in the absence of 155.1, and subsequently had their full VA medical record manually reviewed for confirmation of HCC and data abstraction. NAFLD was diagnosed on the basis of histologic evidence of fatty liver infiltration or presence of metabolic syndrome in the absence of other risk factors. HCV and HBV were identified based on laboratory tests and alcohol based on history of alcohol use (> 3 drinks per day), documented alcoholism, alcoholic hepatitis or enrollment in alcohol abuse program. We compared receipt of HCC surveillance (AFP/liver ultrasound), stage at diagnosis, treatment received and survival among the three main risk factor categories (NAFLD, alcohol abuse, HCV). Results: We identified 1,500 patients diagnosed with HCC. NAFLD was the only underlying risk factor in 120 (8%), HCV in 1013 (68%) and alcohol abuse in 286 (19%). Patients with NAFLD-HCC were significantly less likely to receive HCC surveillance within 2 years prior to HCC diagnosis as compared with HCC related to HCV or alcohol abuse (Table 1). At the time of HCC diagnosis, only 6% of NAFLD-HCC cases were classified as early stage HCC (BCLC Stage A) compared to 6% and 16% with HCV and alcohol, respectively. A significantly higher proportion of NAFLD-HCC were well differentiated compared with HCV or alcohol tumors. The proportion of patients not receiving any HCC specific treatment was significantly higher in NAFLD-HCC compared with HCC patients with HCV (Table 1). Among those who received HCC specific treatment, NAFLDHCC patients were significantly less likely to receive potentially curative treatment (transplantation, resection or ablation) as compared to patients with HCV or alcohol (11% vs. 22% vs. 13%, P<0.01). The 1-year survival following diagnosis was 47% in NAFLD-HCC, 44.7% in alcohol, and 50% in HCV and was not statistically different (p-value=0.09). Conclusion: Patients with HCC in setting of NAFLD received less medical attention compared to HCV or alcohol as evidenced by lower rates of HCC surveillance. They were also less likely to receive curative treatment. Despite this, overall survival was similar in the three risk categories.
Mo1034 Extracellular Long Non-Coding RNA Lincrna-Vldlr Modulates Hepatocellular Cancer Responses to Chemotherapy Kenji Takahashi, Irene Yan, Hiroaki Haga, Joseph D. Wood, Tushar Patel Background : Innate and acquired resistance to therapeutic agents is a major limitation to the successful treatment of Hepatocellular cancer (HCC). Although long non-coding RNAs (lncRNAs) are being implicated in the pathogenesis of several diseases, their contributions
S-991
AASLD Abstracts
AASLD Abstracts
Mo1032