- Email: [email protected]
T1931 Vitamin D Levels in Cirrhosis and Hepatocellular Carcinoma
TNM stage (P=.025) and high CTP class (P=.022) were independently correlated to early mortality in HCC-CC group. When comparing only AJCC stage I of each disease, the TTR and the OS of patients with HCC-CC were significantly shorter than HCC (P<.001 and P= .015, respectively) or CC (P<.001 and P=.034, respectively). Conclusions: In this study, we found that male sex and high TNM stage were independent risk factors for early recurrence; and old age, high TNM stage and high CTP class were independent risk factors for early mortality in the HCC-CC group. Furthermore, HCC-CC showed poorer prognosis with earlier recurrence and shorter survival, which was significantly worse than HCC and CC, in the patients after curative resection in AJCC stage I of each disease. Close follow-up may be needed in the HCC-CC patients after curative resection with these risk factors, even in the early stage.
T1929 Alcohol Consumption and Not Metabolic Abnormalities Is Associated with Increased Hepatocellular Carcinoma Risk in Patients with END-Stage Liver Disease Tarek I. Abu-Rajab Tamimi, Ibrahim A. Hanouneh, Ribhi Hazin, Rocio Lopez, Nizar N. Zein Background: Hepatocellular carcinoma (HCC) is the most significant complication of liver cirrhosis and is associated with high mortality. Identifying factors associated with HCC, especially modifiable factors like obesity and diabetes mellitus enhances screening and preventive measures. Aim: To assess predictors of HCC in a large cohort of patients with End-Stage Liver Disease (ESLD). Methods: Retrospective, case-control study. All patients with ESLD referred for liver transplant (OLT) evaluation between January, 2003 and August, 2005 were identified (n= 894). All HCC patients at the time of initial presentation or at any time point during follow up were included in this analysis (n= 105). HCC patients were matched based on gender and age (1:1 ratio) to a control group of patients with ESLD without HCC. Univariable and multivariable conditional logistic regression analysis was used to assess associations between HCC and factors of interest. Results: In univariable analysis, history of cigarette smoking (P= 0.034), alcohol consumption whether mild or heavy consumption (P= 0.02) and underlying HCV cirrhosis (P= 0.01) were found to be significantly associated with HCC. Metabolic factors including hypertension, diabetes mellitus and body mass index were not associated with increased risk of HCC (all P> 0.05). By multivariate analysis, alcohol consumption remained independently associated with HCC risk. Compared to non-drinkers, those with heavy lifetime alcohol consumption (OR= 23.4, P= 0.002) and those with mild alcohol intake (OR= 8.5, P= 0.025) had increased HCC risk. Conclusions: 1) Alcohol consumption, a modifiable risk factor, appears to be the most significant factor associated with HCC risk in our patients with ESLD. 2) Metabolic abnormalities including diabetes mellitus were not associated with increased HCC risk in this population and warrants further studies.
T1927
AASLD Abstracts
Treatment Response Evaluated By Tumor Markers Can Predict Prognosis of Hepatocellular Carcinoma Independently of Radiological Evaluation Ryosuke Tateishi, Shuichiro Shiina, Hideo Yoshida, Tadashi Goto, Eriko Goto, Takahisa Sato, Takamasa Ohki, Ryota Masuzaki, Fumihiko Kanai, Keisuke Hamamura, Haruhiko Yoshida, Takao Kawabe, Masao Omata BACKGROUND: The assessment of treatment response in patients with hepatocellular carcinoma (HCC) primarily depends on radiological findings. We investigated in this study the impact of following 3 tumor makers before and after the treatment on the prognosis of patients with HCC: alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP) and lens culinaris agglutinin A-reactive fraction of alpha-fetoprotein (AFP-L3). PATIENTS AND METHODS: We enrolled 737 consecutive HCC patients (M/F = 488/249, median age 67 years, HCV/HBV/both/neither = 563/71/12/91, Child-Pugh A/B/C = 503/217/17) who received the initial treatment at the author's department with percutaneous ablation (N= 650), arterial embolization (N=81), or otherwise (N=6) from 1998 to 2004. Tumor marker concentrations were determined immediately before and after the treatment. Prognostic factors for HCC were assessed with Cox proportional hazard model using clinical data at entry included age, sex, the size and number of tumors, presence of extrahepatic metastasis and vascular invasion, viral markers, serum albumin, bilirubin, transaminases, prothrombin activity, platelet count, Child-Pugh score and tumor marker concentrations pre- and posttreatment. Multivariate analysis using step-wise variable selection was applied to select independent prognostic factors. We also performed a subgroup analysis in those with and without complete response evaluated by CT findings according to the criteria of Liver Cancer Study Group of Japan. RESULTS: The median (range) of the tumor size was 2.4 (1.0-15.0) cm. 388 patients had a solitary nodule, 259 had 2 or 3, and 90 had more than 3. Complete response evaluated by CT was achieved in 630 patients after the initial treatment. 312 patients died during the follow-up. Univariate analysis on the survival revealed that 400 ng/mL for AFP, 100 mAU/mL for DCP and 15% for AFP-L3 were the best cutoff points. Multivariate analysis indicated that post-treatment AFP > 400 ng/mL (hazard ratio [HR], 2.89; 95% confidence interval [CI], 1.69-4.95), pre- and post-treatment DCP > 100 mAU/ mL (HR, 1.72; 95%CI, 1.26-2.34 and HR,1.88; 95%CI, 1.23-2.87), and post-treatment AFP-L3 > 15% (HR, 1.80; 95%CI, 1.19-2.72) were significant predictors along with age, tumor size, number of tumor nodules, vascular invasion, extrahepatic metastasis and ChildPugh score. The subgroup analysis revealed that post-treatment values of AFP and DCP were significant predictors of prognosis independent of complete response evaluated by CT findings. CONCLUSION: Treatment response evaluated by tumor markers was an important prognostic factor for HCC as well as that by imaging modalities.
T1930 Managing Hemorrhagic Complications After Radiofrequency Ablation Therapy for Liver Tumors Eriko Goto, Ryosuke Tateishi, Shuichiro Shiina, Takahisa Sato, Takamasa Ohki, Ryota Masuzaki, Jun Imamura, Tadashi Goto, Hideo Yoshida, Fumihiko Kanai, Keisuke Hamamura, Haruhiko Yoshida, Masao Omata Background: Radiofrequency ablation (RFA) is progressively spreading as a percutaneous treatment for liver neoplasms, considered as minimally invasive. However there are some serious complications related to RFA resulting in 0.1 to 0.5% of mortality. In this study, we focused on hemorrhagic complications including hemoperitoneum, hemothorax and hemobilia in which urgent diagnosis and treatment are crucial. Methods: From February 1999 to December 2006, 3229 patients with liver tumors were treated with percutaneous RFA under ultrasound guidance. All patients were treated on inpatient basis and subsequently observed intensively by checking vital signs every 4 hours and blood tests were performed on the next day. Hemoperitoneum and hemothorax were diagnosed as fluid collection in the peritoneal or pleural cavity with declined hemoglobin by > 2g/dL. Hemobilia was diagnosed by imaging modalities. A total of 42 cases presented a hemorrhagic complication and we assessed them by evaluating the following items on medical records: symptoms or changes in vital signs first noticed, interval between the procedure and detection of the complication, changes in laboratory test data, location of target nodule and treatments for complications including blood transfusion and drainage. Results: There were 19, 5 and 18 cases of hemoperitoneum, hemothorax and hemobilia, respectively. The characteristic symptoms were abdominal pain for hemoperitoneum (5) and hemobilia (5) and chest pain (2) for hemothorax. Hypovolemic shock, as defined by tachycardia > 100 beat per minute and/or blood pressure < 100 mmHg, was observed only in 7 patients with hemoperitoneum. The complications were noticed within 8 hours in 12, 3 and 13 patients with hemoperitoneum, hemothorax and hemobilia, respectively. Ten patients with hemobilia were diagnosed during the procedure by “hemobilia sign.” (Obi et al. Eur J Gastroenterol Hepatol 2000) Blood transfusion was required in 10, 2 and 1 patients with hemoperitoneum, hemothorax and hemobilia, respectively. Endoscopic drainage was performed in 3 patients with hemobilia due to obstructive jaundice with increased bilirubin > 8 mg/dL. Bleeding was self-limiting in all patients who received blood transfusion except for 2 who encountered re-bleeding and died of multi organ failure. As for high risk locations, tumors were located deep in all patients with hemoperitoneum; adjacent to the diaphragm in all patients with hemothorax. Conclusions: Bleeding complications can be detected by careful post procedural observation and immediate treatment will save most patients from fatal course. And recognition of the risk of bleeding complication might be preventive.
T1928 Safety Results of a Phase I/II Study with Oncolytic Herpes Simplex Virus, Nv1020, Administered Repeatedly Via Hepatic Artery Infusion Prior to 2ndLine Chemotherapy, in Patients with Colorectal Adenocarcinoma Metastatic to the Liver John J. Nemunaitis, David A. Geller, Matthias Karrasch, Anette E. Knoll, Axel Mescheder, Neil Senzer, Kenneth K. Tanabe, Tony Reid Introduction: For patients suffering from metastatic colorectal cancer (mCRC), tumor response rates and survival are modest once conventional approaches have been exhausted. NV1020 is an oncolytic herpes simplex virus offering a new potential strategy for tumors refractory to conventional chemotherapy. Single doses of NV1020 were found to be well tolerated and appeared to improve tumor response to subsequent chemotherapy in a previous study. Study Design: A total of 32 HSV-1 seropositive subjects who had failed first-line chemotherapy (up to 5 agents, all FDA-approved for mCRC) and showed tumor progression with liver-dominant metastases were enrolled in this open-label Phase 1/2 study comprising a dose-escalation stage (Stage 1; n=3/group), followed by expansion of one selected ‘optimal' dose cohort (Stage 2; n=18). Four weekly NV1020 infusions were administered into the hepatic artery. NV1020 was followed by a minimum of two cycles of additional conventional chemotherapy. Follow-up was performed every 3 months and then by phone for survival and safety issues. Maximum tolerated dose (MTD) was monitored clinically and with routine lab testing. NCI CTC criteria were used for dose-limiting toxicity (DLT): All data were reviewed periodically by an independent Data Safety Monitoring Board. Results: Most frequent NV1020-related adverse events were transient pyrexia (74%), chills (48%), nausea (45%), abdominal pain (35%), headache (29%), fatigue (29 %), vomiting (26%), anaemia (19%), neutropenia (16%) diarrhea (16%), back pain (16%). Three (10%) patients discontinued NV1020 prematurely due to rapid tumor progression. Dose-dependent perturbations after NV1020 infusion were observed for measured cytokines (IL-6, TNFα, IFNγ), ANC, platelet count, lymphocyte count, D-dimers, fibrinogen and CRP. No dose-related trends in liver function abnormalities, no shedding (mucosa, saliva, serum) of NV1020 was detected at any time. Conclusions: Repeated intrahepatic infusions of NV1020 were well tolerated by all patients. Principal clinical toxicity was a transient, cytokine-mediated, viral syndrome. No interaction was reported with follow-up chemotherapeutic agents. MTD was not reached. DLT was subclinical coagulation perturbation. Optimal biologic NV1020 dose selected for Stage 2 was the highest dose evaluated (1X108 pfu). Possible antitumor signals were detected, based on unblinded analysis of CT scans and overall survival.
AASLD Abstracts
T1931 Vitamin D Levels in Cirrhosis and Hepatocellular Carcinoma Zahid Azam, Zaigham Abbas, Uzma Saleem, Wasim Jafri BACKGROUND/OBJECTIVES: Vitamin D has inverse relation with advancing stage of cirrhosis. Our aim was to evaluate the Vitamin D level in patients with HCC and cirrhosis. Further if the hypothesis that low level is associated with HCC is proved, then it may generate future therapeutic replacement hypothesis/ studies. METHODS: HCC was diagnosed by 2 out of 3 criteria i.e. tumor blush on biphasis CT, AFP>400 IU/ml or biopsy. Sixty-five HCC (Cases/ group I) and 35 cirrhotic (Controls/ group II) were taken & Vitamin D was measured by RIA method. (Normal level: 40-100 ng/ml). The minimum detection limit of this assay was 1.5 ng/ml. Bilirubin, ALT, Albimin, Prothrombin Time (PT), Alfafeto protein (AFP) were checked and after history & examination Child's score were calculated. The two groups were matched according to Child's score. RESULTS: The mean Vitamin D levels were 16.46±9.58 and 28.97±17.51 in HCC & Cirrhosis (p-value<0.005). There was no statistical difference in Gender, PT, Bilirubin, albumin & Child's score in the two groups. No difference in Albumin in the two groups indirectly suggests that there was no significant difference in
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their nutritional status. When stratified on the basis of Child's A, B & C, each stratum maintained the significant low Vitamin D level in HCC group as compared to Cirrhosis (pvalue<0.05), suggesting that as the cirrhosis advances, the Vitamin D level drops proportionately but significant difference is observed when they develop HCC. CONCLUSIONS: Vitamin D level is significantly reduced in HCC as compared to cirrhotic patients. Deficiency of Vitamin D may have a role in triggering the mechanisms leading to HCC in cirrhotic patients. Our data suggests that therapeutic value of vitamin D replacement therapy in cirrhosis to prevent HCC needs to be explored.
diagnosed between 1997 and 2006. Alcoholic liver disease was defined as more than 60g of daily ethanol consumption, liver dysfunction without HBs antigen and HCV antibody. In addition, alcoholic liver cirrhosis (LC) without hepatocellular carcinoma was used as the disease control group. (Results) 1. Groups A and B consisted of 49 and 77 patients, respectively. The percentage of alcoholic liver disease patients among those with HCC was significantly higher in group B than in group A. Percentages of obesity (BMI>25) and DM tended to be higher in group B, but the differences were not significant. In group B, the rates of HT (45.3%) and HL (28%) were significantly higher than in group A (26.1%, 12.8%). Serum albumin level and percentage of prothrombin time in group B were significantly higher than those of group A. Regarding the Child-Pugh classification, Child A was also more frequent in group B, indicating that liver function was retained in the more recent HCC group. 2. We compared all HCC patients (group A + group B) with LC patients without HCC. The frequencies of obesity and DM in HCC were significantly higher than those of LC. Serum albumin level and percentage of prothrombin time in LC were significantly higher than those of HCC. Child A was also more frequent in HCC, indicating that liver function was retained in HCC, compared with alcoholic LC without HCC. (Conclusion) Recently, HCC with alcoholic liver disease has been increasing in Japan. This might be associated with increases in lifestyle-related diseases, and HCC might be occurring at an early stage of alcoholic liver disease. It is important to control the lifestyle-related diseases when we care for alcoholic liver disease.
T1932 Expanded Criteria for Liver Transplantation in Cirrhotic Patients with Hepatocellular Carcinoma Maurício Silva, Angel Moya, Marina Berenguer, Martin Prieto, Fernando Sanjuan, Rafael Lopez-Andujar, Rodrigo Torres-Quevedo, Victoria Aguilera, Angelo Mattos, Jose Mir Background: Selection criteria for patients with hepatocellular carcinoma (HCC) suitable for ortothopic liver transplantation (OLT) is a matter of debate. The international transplantation community has largely adopted an approach to OLT for HCC based on the Milan criteria. The main aim of this study was to evaluate the survival rates and recurrence probabilities of a new proposal of expanded criteria (up to 3 tumors, each no larger than 5 cm). Methods: All patients included in waiting list time (WLT) from 1991 to 2006 were evaluated. Outcomes were compared in patients within and beyond the Milan criteria (single tumor up to 5 cm or up to 3 tumors, each no larger than 3 cm). The survival analysis was based on the intention-to-treat principle - considering all patients included in WLT - and among transplanted patients. Results: A total of 281 patients were included in WLT for OLT. Twentyfour cases did not achieve the procedure (dropout rate of 8.5%), all but 1 presented tumours within the Milan criteria. Among 257 transplanted patients, 26 had tumors beyond the Milan criteria in the pre-OLT evaluation. Based on the intention-to-treat principle, the 5-years survival was 66% versus 56% in tumors beyond and within the Milan criteria, respectively (p = 0.487). Considering only transplanted patients, the 5-years survival was 69% versus 62% in tumors beyond and within the Milan criteria, respectively (p = 0.734). Multivariate analysis showed that microvascular invasion (p = 0.004) predicted poor survival. Recurrence occurred in 33 cases (13%). The recurrence probabilities at 1, 3, and 5 years were 12% versus 7%, 21% versus 13%, and 28% versus 14% in tumors beyond and within the Milan criteria, respectively (p = 0.063). Multivariate analysis showed that poor differentiation degree (p < 0.001) and microvascular invasion independently increased the risk of recurrence (p < 0.001). Conclusion: The expansion to up to 3 nodules, each up to 5 cm did not result in a reduction of survival when compared with patients within the Milan criteria.
T1935
Introduction: Prognosis of Hepatocellular Cancer (HCC) depends on many factors, most of them incorporated in current staging systems such as BCLC; there are scarce data about an influence of iron status upon prognosis in patients with NAFLD, chronic viral hepatitis, and liver cirrhosis. Methods: To determine the impact of iron status on the prognosis of patients with advanced hepatocellular cancer, treated with octreotide (alone or in combination with other drugs), we analysed HCC outcome from 2 previous prospective trials (one published fully in ZGastro2007, the second as an abstract in ASCO GI Cancer 2007) with identical entry criteria in terms of tumor progression and overall survival depending on baseline (BL) serum ferritin +/- serum iron. Results: A total of 102 patients could be analysed and clinical data were comparable in both studies: OS was 154 vs 266 days, and TTP was 94 vs 90 days. BL serum ferritin correlated with OS: combined r=-0,455 (95%-CI:-0.624 to -0.244,p<0.0001); and TTP: combined r=-0,380 (95%-CI:-0.575 to -0.145, p=0,0016. The distribution of BL serum ferritin followed a one phase exponential decay (r-squared 0.994) with a median of 446 ng/ml for survival and 336 ng/ml for progression. BL serum iron was measured only in one study and correlated with survival: r=-0,404 (95%-CI:-0.659 to -0.0662, p=0,0177); but not with progression: r=-0,263 (95%-CI:-0.567 to 0.106, p=>0,147). Serum ferritin further correlated significantly (p<0.01 each) with the presence of portal vein infiltration or any metastasis, serum alkaline phosphatase and albumin, as well as CLIP score. Conclusions: In our patient population, serum ferritin was highly predictive for TTP and overall survival. At this time, we cannot differentiate between a surrogate marker function and a causal association. However, data from In Vitro studies point towards an independent trophic factor for HCC tumor growth.
T1933 Significance of Inflammatory Mediators in Hepatocellular Carcinoma Yuji Ishii, Ryusuke Ito, Taro Sakamoto, Shigeki Wakiyama, Hiroaki Shiba, Takeyuki Misawa, Yuichi Ishida, Katsuhiko Yanaga Aim and Purpose: Persistent inflammation seems to be an important factor for the development of hepatocellular carcinoma (HCC) in chronic liver diseases. Endogenous cannabinoids (CBs) have been confirmed to play a role as early mediators, while high mobility group box-1 (HMGB-1) is known to be a late mediator in inflammatory response with inducing various physiologic actions.. The aim of this study is to clarify a relationship between various inflammatory mediators including cytokines for the development and progression of HCC. Patients and Methods: For patients with hepatocellular carcinoma (HCC, n=9), liver cirrhosis (LC, n=7) or chronic hepatitis (CH, n=5) as well as in healthy volunteers (n=10), the serum levels of CBs, 2-arachidonoylglycerol (2-AG) and anandamide (AEA) were measured by high performance liquid chromatography combined mass spectrometry (LC/MS). The serum levels of HMGB-1 and 6 inflammatory cytokines (IL-1β, 6, 8 & 10, TNF-α, IFN-γ) were measured by an enzyme-linked immunosorbent assay. The expression of receptors for CBs, CB1R and CB2R as well as receptor for advanced glycation end product (RAGE) were examined by immunohistochemical analyses using the resected samples of HCC (n=23). Results: In patients with HCC, the mean level of 2-AG was 11.5±6.14 ng/ml, which was significantly higher than those of the other groups (p<0.01). On the other hand, no such differences were defined in AEA. The serum level of IL-8 was significantly higher in the advanced HCC group (p<0.01). Furthermore, serum level of IFN-γ was less than 1.0 pg/ml in all patients with HCC. The characteristic findings of the other inflammatory cytokines were not observed in HCC group. The mean level of HMGB-1 in HCC group was 5.62±3.24 ng/ml, which was significantly higher than those of the other groups (p<0.01). There existed a significant correlation between 2-AG and HMGB-1 (r=0.872, p<0.001). In the immunohistochemical analysis of HCC, the expressions of CB1R and RAGE correlated with dedifferentiation of HCC. Conclusions: 2-AG, CB1R, IL-8 and HMGB-1 seem to be associated with the development and progression of HCC.Blockage of such mediators may have potential for prevention and treatment of HCC.
T1936 Intratumoral Pressure and Local Ablative Therapies for Hepatocellular Carcinoma Chiaki Kawamoto, Atsushi Yamauchi, Yoko Baba, Koji Yakabi [Background] Sporadic cases of unexpected recurrence, such as intrahepatic dissemination and peritoneal dissemination, have been described following radiofrequency ablation (RFA). Some of these recurrences may be caused by increased intratumoral pressure. Therefore, we performed basic and clinical studies to examine the relationships between RFA and intrahepatic pressure, as well as between percutaneous ethanol injection (PEI) and intrahepatic pressure. [Subjects and Methods] A. Basic study: Under general anesthesia, laparotomy was performed on 19 pigs. A 20-mm LeVeen needle electrode or a 21-G PEI needle was inserted into the liver for ablation. Intrahepatic pressure was monitored by placing a PEI needle near the first needle and using an invasive blood pressure monitor. 1) RFA. RFA was performed as follows: a) Single-step method: After fully deploying the electrode, the power was initially applied at 30 W, then increased in increments of 10 W/min until power roll-off. b) Multi-step method: The array was gradually deployed in 8 steps. At each step, the power was fixed at 30 W until power roll-off. 2) PEI. Ethanol (2 ml) was injected, and intrahepatic pressure was monitored. B. Clinical study: 1) RFA. 41 HCC patients with a mean tumor size of 15.3±5.4 mm were studied. Under local anesthesia, after inserting a
T1934 Recent Clinical Features in Japanese Hepatocellular Carcinoma with Alcoholic Liver Disease Ayae Kabutake, Katsutoshi Tokushige, Etsuko Hashimoto, Haruka Noto, Maki Tobari, Satoru Yatsuji, Makiko Taniai, Keiko Shiratori (Aim) In Japan, hepatocellular carcinoma (HCC) with alcoholic liver disease is relatively rare, but alcohol consumption has recently been increasing. Life style-related diseases such as diabetes (DM), hypertension (HT) and hyperlipidemia (HL) are increasing, and these diseases have been reported as risk factors of hepatocellular carcinoma. In this study, we investigated recent trends in HCC with alcoholic liver disease in Japan and the relationship between HCC and lifestyle-related diseases. (Patients and Methods) We studied HCC with alcoholic liver disease in our hospital from 1987 to 2006. The patients were classified into two groups: group A, patients diagnosed between 1987 and 1996, and group B, patients
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AASLD Abstracts
AASLD Abstracts
An Increased Iron Status Is Associated with a Poor Prognosis in Patients with Hepatocellular Cancer Gerhard Treiber
T1929 Alcohol Consumption and Not Metabolic Abnormalities Is Associated with Increased Hepatocellular Carcinoma Risk in Patients with END-Stage Liver Disease Tarek I. Abu-Rajab Tamimi, Ibrahim A. Hanouneh, Ribhi Hazin, Rocio Lopez, Nizar N. Zein Background: Hepatocellular carcinoma (HCC) is the most significant complication of liver cirrhosis and is associated with high mortality. Identifying factors associated with HCC, especially modifiable factors like obesity and diabetes mellitus enhances screening and preventive measures. Aim: To assess predictors of HCC in a large cohort of patients with End-Stage Liver Disease (ESLD). Methods: Retrospective, case-control study. All patients with ESLD referred for liver transplant (OLT) evaluation between January, 2003 and August, 2005 were identified (n= 894). All HCC patients at the time of initial presentation or at any time point during follow up were included in this analysis (n= 105). HCC patients were matched based on gender and age (1:1 ratio) to a control group of patients with ESLD without HCC. Univariable and multivariable conditional logistic regression analysis was used to assess associations between HCC and factors of interest. Results: In univariable analysis, history of cigarette smoking (P= 0.034), alcohol consumption whether mild or heavy consumption (P= 0.02) and underlying HCV cirrhosis (P= 0.01) were found to be significantly associated with HCC. Metabolic factors including hypertension, diabetes mellitus and body mass index were not associated with increased risk of HCC (all P> 0.05). By multivariate analysis, alcohol consumption remained independently associated with HCC risk. Compared to non-drinkers, those with heavy lifetime alcohol consumption (OR= 23.4, P= 0.002) and those with mild alcohol intake (OR= 8.5, P= 0.025) had increased HCC risk. Conclusions: 1) Alcohol consumption, a modifiable risk factor, appears to be the most significant factor associated with HCC risk in our patients with ESLD. 2) Metabolic abnormalities including diabetes mellitus were not associated with increased HCC risk in this population and warrants further studies.
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AASLD Abstracts
Treatment Response Evaluated By Tumor Markers Can Predict Prognosis of Hepatocellular Carcinoma Independently of Radiological Evaluation Ryosuke Tateishi, Shuichiro Shiina, Hideo Yoshida, Tadashi Goto, Eriko Goto, Takahisa Sato, Takamasa Ohki, Ryota Masuzaki, Fumihiko Kanai, Keisuke Hamamura, Haruhiko Yoshida, Takao Kawabe, Masao Omata BACKGROUND: The assessment of treatment response in patients with hepatocellular carcinoma (HCC) primarily depends on radiological findings. We investigated in this study the impact of following 3 tumor makers before and after the treatment on the prognosis of patients with HCC: alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP) and lens culinaris agglutinin A-reactive fraction of alpha-fetoprotein (AFP-L3). PATIENTS AND METHODS: We enrolled 737 consecutive HCC patients (M/F = 488/249, median age 67 years, HCV/HBV/both/neither = 563/71/12/91, Child-Pugh A/B/C = 503/217/17) who received the initial treatment at the author's department with percutaneous ablation (N= 650), arterial embolization (N=81), or otherwise (N=6) from 1998 to 2004. Tumor marker concentrations were determined immediately before and after the treatment. Prognostic factors for HCC were assessed with Cox proportional hazard model using clinical data at entry included age, sex, the size and number of tumors, presence of extrahepatic metastasis and vascular invasion, viral markers, serum albumin, bilirubin, transaminases, prothrombin activity, platelet count, Child-Pugh score and tumor marker concentrations pre- and posttreatment. Multivariate analysis using step-wise variable selection was applied to select independent prognostic factors. We also performed a subgroup analysis in those with and without complete response evaluated by CT findings according to the criteria of Liver Cancer Study Group of Japan. RESULTS: The median (range) of the tumor size was 2.4 (1.0-15.0) cm. 388 patients had a solitary nodule, 259 had 2 or 3, and 90 had more than 3. Complete response evaluated by CT was achieved in 630 patients after the initial treatment. 312 patients died during the follow-up. Univariate analysis on the survival revealed that 400 ng/mL for AFP, 100 mAU/mL for DCP and 15% for AFP-L3 were the best cutoff points. Multivariate analysis indicated that post-treatment AFP > 400 ng/mL (hazard ratio [HR], 2.89; 95% confidence interval [CI], 1.69-4.95), pre- and post-treatment DCP > 100 mAU/ mL (HR, 1.72; 95%CI, 1.26-2.34 and HR,1.88; 95%CI, 1.23-2.87), and post-treatment AFP-L3 > 15% (HR, 1.80; 95%CI, 1.19-2.72) were significant predictors along with age, tumor size, number of tumor nodules, vascular invasion, extrahepatic metastasis and ChildPugh score. The subgroup analysis revealed that post-treatment values of AFP and DCP were significant predictors of prognosis independent of complete response evaluated by CT findings. CONCLUSION: Treatment response evaluated by tumor markers was an important prognostic factor for HCC as well as that by imaging modalities.
T1930 Managing Hemorrhagic Complications After Radiofrequency Ablation Therapy for Liver Tumors Eriko Goto, Ryosuke Tateishi, Shuichiro Shiina, Takahisa Sato, Takamasa Ohki, Ryota Masuzaki, Jun Imamura, Tadashi Goto, Hideo Yoshida, Fumihiko Kanai, Keisuke Hamamura, Haruhiko Yoshida, Masao Omata Background: Radiofrequency ablation (RFA) is progressively spreading as a percutaneous treatment for liver neoplasms, considered as minimally invasive. However there are some serious complications related to RFA resulting in 0.1 to 0.5% of mortality. In this study, we focused on hemorrhagic complications including hemoperitoneum, hemothorax and hemobilia in which urgent diagnosis and treatment are crucial. Methods: From February 1999 to December 2006, 3229 patients with liver tumors were treated with percutaneous RFA under ultrasound guidance. All patients were treated on inpatient basis and subsequently observed intensively by checking vital signs every 4 hours and blood tests were performed on the next day. Hemoperitoneum and hemothorax were diagnosed as fluid collection in the peritoneal or pleural cavity with declined hemoglobin by > 2g/dL. Hemobilia was diagnosed by imaging modalities. A total of 42 cases presented a hemorrhagic complication and we assessed them by evaluating the following items on medical records: symptoms or changes in vital signs first noticed, interval between the procedure and detection of the complication, changes in laboratory test data, location of target nodule and treatments for complications including blood transfusion and drainage. Results: There were 19, 5 and 18 cases of hemoperitoneum, hemothorax and hemobilia, respectively. The characteristic symptoms were abdominal pain for hemoperitoneum (5) and hemobilia (5) and chest pain (2) for hemothorax. Hypovolemic shock, as defined by tachycardia > 100 beat per minute and/or blood pressure < 100 mmHg, was observed only in 7 patients with hemoperitoneum. The complications were noticed within 8 hours in 12, 3 and 13 patients with hemoperitoneum, hemothorax and hemobilia, respectively. Ten patients with hemobilia were diagnosed during the procedure by “hemobilia sign.” (Obi et al. Eur J Gastroenterol Hepatol 2000) Blood transfusion was required in 10, 2 and 1 patients with hemoperitoneum, hemothorax and hemobilia, respectively. Endoscopic drainage was performed in 3 patients with hemobilia due to obstructive jaundice with increased bilirubin > 8 mg/dL. Bleeding was self-limiting in all patients who received blood transfusion except for 2 who encountered re-bleeding and died of multi organ failure. As for high risk locations, tumors were located deep in all patients with hemoperitoneum; adjacent to the diaphragm in all patients with hemothorax. Conclusions: Bleeding complications can be detected by careful post procedural observation and immediate treatment will save most patients from fatal course. And recognition of the risk of bleeding complication might be preventive.
T1928 Safety Results of a Phase I/II Study with Oncolytic Herpes Simplex Virus, Nv1020, Administered Repeatedly Via Hepatic Artery Infusion Prior to 2ndLine Chemotherapy, in Patients with Colorectal Adenocarcinoma Metastatic to the Liver John J. Nemunaitis, David A. Geller, Matthias Karrasch, Anette E. Knoll, Axel Mescheder, Neil Senzer, Kenneth K. Tanabe, Tony Reid Introduction: For patients suffering from metastatic colorectal cancer (mCRC), tumor response rates and survival are modest once conventional approaches have been exhausted. NV1020 is an oncolytic herpes simplex virus offering a new potential strategy for tumors refractory to conventional chemotherapy. Single doses of NV1020 were found to be well tolerated and appeared to improve tumor response to subsequent chemotherapy in a previous study. Study Design: A total of 32 HSV-1 seropositive subjects who had failed first-line chemotherapy (up to 5 agents, all FDA-approved for mCRC) and showed tumor progression with liver-dominant metastases were enrolled in this open-label Phase 1/2 study comprising a dose-escalation stage (Stage 1; n=3/group), followed by expansion of one selected ‘optimal' dose cohort (Stage 2; n=18). Four weekly NV1020 infusions were administered into the hepatic artery. NV1020 was followed by a minimum of two cycles of additional conventional chemotherapy. Follow-up was performed every 3 months and then by phone for survival and safety issues. Maximum tolerated dose (MTD) was monitored clinically and with routine lab testing. NCI CTC criteria were used for dose-limiting toxicity (DLT): All data were reviewed periodically by an independent Data Safety Monitoring Board. Results: Most frequent NV1020-related adverse events were transient pyrexia (74%), chills (48%), nausea (45%), abdominal pain (35%), headache (29%), fatigue (29 %), vomiting (26%), anaemia (19%), neutropenia (16%) diarrhea (16%), back pain (16%). Three (10%) patients discontinued NV1020 prematurely due to rapid tumor progression. Dose-dependent perturbations after NV1020 infusion were observed for measured cytokines (IL-6, TNFα, IFNγ), ANC, platelet count, lymphocyte count, D-dimers, fibrinogen and CRP. No dose-related trends in liver function abnormalities, no shedding (mucosa, saliva, serum) of NV1020 was detected at any time. Conclusions: Repeated intrahepatic infusions of NV1020 were well tolerated by all patients. Principal clinical toxicity was a transient, cytokine-mediated, viral syndrome. No interaction was reported with follow-up chemotherapeutic agents. MTD was not reached. DLT was subclinical coagulation perturbation. Optimal biologic NV1020 dose selected for Stage 2 was the highest dose evaluated (1X108 pfu). Possible antitumor signals were detected, based on unblinded analysis of CT scans and overall survival.
AASLD Abstracts
T1931 Vitamin D Levels in Cirrhosis and Hepatocellular Carcinoma Zahid Azam, Zaigham Abbas, Uzma Saleem, Wasim Jafri BACKGROUND/OBJECTIVES: Vitamin D has inverse relation with advancing stage of cirrhosis. Our aim was to evaluate the Vitamin D level in patients with HCC and cirrhosis. Further if the hypothesis that low level is associated with HCC is proved, then it may generate future therapeutic replacement hypothesis/ studies. METHODS: HCC was diagnosed by 2 out of 3 criteria i.e. tumor blush on biphasis CT, AFP>400 IU/ml or biopsy. Sixty-five HCC (Cases/ group I) and 35 cirrhotic (Controls/ group II) were taken & Vitamin D was measured by RIA method. (Normal level: 40-100 ng/ml). The minimum detection limit of this assay was 1.5 ng/ml. Bilirubin, ALT, Albimin, Prothrombin Time (PT), Alfafeto protein (AFP) were checked and after history & examination Child's score were calculated. The two groups were matched according to Child's score. RESULTS: The mean Vitamin D levels were 16.46±9.58 and 28.97±17.51 in HCC & Cirrhosis (p-value<0.005). There was no statistical difference in Gender, PT, Bilirubin, albumin & Child's score in the two groups. No difference in Albumin in the two groups indirectly suggests that there was no significant difference in
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their nutritional status. When stratified on the basis of Child's A, B & C, each stratum maintained the significant low Vitamin D level in HCC group as compared to Cirrhosis (pvalue<0.05), suggesting that as the cirrhosis advances, the Vitamin D level drops proportionately but significant difference is observed when they develop HCC. CONCLUSIONS: Vitamin D level is significantly reduced in HCC as compared to cirrhotic patients. Deficiency of Vitamin D may have a role in triggering the mechanisms leading to HCC in cirrhotic patients. Our data suggests that therapeutic value of vitamin D replacement therapy in cirrhosis to prevent HCC needs to be explored.
diagnosed between 1997 and 2006. Alcoholic liver disease was defined as more than 60g of daily ethanol consumption, liver dysfunction without HBs antigen and HCV antibody. In addition, alcoholic liver cirrhosis (LC) without hepatocellular carcinoma was used as the disease control group. (Results) 1. Groups A and B consisted of 49 and 77 patients, respectively. The percentage of alcoholic liver disease patients among those with HCC was significantly higher in group B than in group A. Percentages of obesity (BMI>25) and DM tended to be higher in group B, but the differences were not significant. In group B, the rates of HT (45.3%) and HL (28%) were significantly higher than in group A (26.1%, 12.8%). Serum albumin level and percentage of prothrombin time in group B were significantly higher than those of group A. Regarding the Child-Pugh classification, Child A was also more frequent in group B, indicating that liver function was retained in the more recent HCC group. 2. We compared all HCC patients (group A + group B) with LC patients without HCC. The frequencies of obesity and DM in HCC were significantly higher than those of LC. Serum albumin level and percentage of prothrombin time in LC were significantly higher than those of HCC. Child A was also more frequent in HCC, indicating that liver function was retained in HCC, compared with alcoholic LC without HCC. (Conclusion) Recently, HCC with alcoholic liver disease has been increasing in Japan. This might be associated with increases in lifestyle-related diseases, and HCC might be occurring at an early stage of alcoholic liver disease. It is important to control the lifestyle-related diseases when we care for alcoholic liver disease.
T1932 Expanded Criteria for Liver Transplantation in Cirrhotic Patients with Hepatocellular Carcinoma Maurício Silva, Angel Moya, Marina Berenguer, Martin Prieto, Fernando Sanjuan, Rafael Lopez-Andujar, Rodrigo Torres-Quevedo, Victoria Aguilera, Angelo Mattos, Jose Mir Background: Selection criteria for patients with hepatocellular carcinoma (HCC) suitable for ortothopic liver transplantation (OLT) is a matter of debate. The international transplantation community has largely adopted an approach to OLT for HCC based on the Milan criteria. The main aim of this study was to evaluate the survival rates and recurrence probabilities of a new proposal of expanded criteria (up to 3 tumors, each no larger than 5 cm). Methods: All patients included in waiting list time (WLT) from 1991 to 2006 were evaluated. Outcomes were compared in patients within and beyond the Milan criteria (single tumor up to 5 cm or up to 3 tumors, each no larger than 3 cm). The survival analysis was based on the intention-to-treat principle - considering all patients included in WLT - and among transplanted patients. Results: A total of 281 patients were included in WLT for OLT. Twentyfour cases did not achieve the procedure (dropout rate of 8.5%), all but 1 presented tumours within the Milan criteria. Among 257 transplanted patients, 26 had tumors beyond the Milan criteria in the pre-OLT evaluation. Based on the intention-to-treat principle, the 5-years survival was 66% versus 56% in tumors beyond and within the Milan criteria, respectively (p = 0.487). Considering only transplanted patients, the 5-years survival was 69% versus 62% in tumors beyond and within the Milan criteria, respectively (p = 0.734). Multivariate analysis showed that microvascular invasion (p = 0.004) predicted poor survival. Recurrence occurred in 33 cases (13%). The recurrence probabilities at 1, 3, and 5 years were 12% versus 7%, 21% versus 13%, and 28% versus 14% in tumors beyond and within the Milan criteria, respectively (p = 0.063). Multivariate analysis showed that poor differentiation degree (p < 0.001) and microvascular invasion independently increased the risk of recurrence (p < 0.001). Conclusion: The expansion to up to 3 nodules, each up to 5 cm did not result in a reduction of survival when compared with patients within the Milan criteria.
T1935
Introduction: Prognosis of Hepatocellular Cancer (HCC) depends on many factors, most of them incorporated in current staging systems such as BCLC; there are scarce data about an influence of iron status upon prognosis in patients with NAFLD, chronic viral hepatitis, and liver cirrhosis. Methods: To determine the impact of iron status on the prognosis of patients with advanced hepatocellular cancer, treated with octreotide (alone or in combination with other drugs), we analysed HCC outcome from 2 previous prospective trials (one published fully in ZGastro2007, the second as an abstract in ASCO GI Cancer 2007) with identical entry criteria in terms of tumor progression and overall survival depending on baseline (BL) serum ferritin +/- serum iron. Results: A total of 102 patients could be analysed and clinical data were comparable in both studies: OS was 154 vs 266 days, and TTP was 94 vs 90 days. BL serum ferritin correlated with OS: combined r=-0,455 (95%-CI:-0.624 to -0.244,p<0.0001); and TTP: combined r=-0,380 (95%-CI:-0.575 to -0.145, p=0,0016. The distribution of BL serum ferritin followed a one phase exponential decay (r-squared 0.994) with a median of 446 ng/ml for survival and 336 ng/ml for progression. BL serum iron was measured only in one study and correlated with survival: r=-0,404 (95%-CI:-0.659 to -0.0662, p=0,0177); but not with progression: r=-0,263 (95%-CI:-0.567 to 0.106, p=>0,147). Serum ferritin further correlated significantly (p<0.01 each) with the presence of portal vein infiltration or any metastasis, serum alkaline phosphatase and albumin, as well as CLIP score. Conclusions: In our patient population, serum ferritin was highly predictive for TTP and overall survival. At this time, we cannot differentiate between a surrogate marker function and a causal association. However, data from In Vitro studies point towards an independent trophic factor for HCC tumor growth.
T1933 Significance of Inflammatory Mediators in Hepatocellular Carcinoma Yuji Ishii, Ryusuke Ito, Taro Sakamoto, Shigeki Wakiyama, Hiroaki Shiba, Takeyuki Misawa, Yuichi Ishida, Katsuhiko Yanaga Aim and Purpose: Persistent inflammation seems to be an important factor for the development of hepatocellular carcinoma (HCC) in chronic liver diseases. Endogenous cannabinoids (CBs) have been confirmed to play a role as early mediators, while high mobility group box-1 (HMGB-1) is known to be a late mediator in inflammatory response with inducing various physiologic actions.. The aim of this study is to clarify a relationship between various inflammatory mediators including cytokines for the development and progression of HCC. Patients and Methods: For patients with hepatocellular carcinoma (HCC, n=9), liver cirrhosis (LC, n=7) or chronic hepatitis (CH, n=5) as well as in healthy volunteers (n=10), the serum levels of CBs, 2-arachidonoylglycerol (2-AG) and anandamide (AEA) were measured by high performance liquid chromatography combined mass spectrometry (LC/MS). The serum levels of HMGB-1 and 6 inflammatory cytokines (IL-1β, 6, 8 & 10, TNF-α, IFN-γ) were measured by an enzyme-linked immunosorbent assay. The expression of receptors for CBs, CB1R and CB2R as well as receptor for advanced glycation end product (RAGE) were examined by immunohistochemical analyses using the resected samples of HCC (n=23). Results: In patients with HCC, the mean level of 2-AG was 11.5±6.14 ng/ml, which was significantly higher than those of the other groups (p<0.01). On the other hand, no such differences were defined in AEA. The serum level of IL-8 was significantly higher in the advanced HCC group (p<0.01). Furthermore, serum level of IFN-γ was less than 1.0 pg/ml in all patients with HCC. The characteristic findings of the other inflammatory cytokines were not observed in HCC group. The mean level of HMGB-1 in HCC group was 5.62±3.24 ng/ml, which was significantly higher than those of the other groups (p<0.01). There existed a significant correlation between 2-AG and HMGB-1 (r=0.872, p<0.001). In the immunohistochemical analysis of HCC, the expressions of CB1R and RAGE correlated with dedifferentiation of HCC. Conclusions: 2-AG, CB1R, IL-8 and HMGB-1 seem to be associated with the development and progression of HCC.Blockage of such mediators may have potential for prevention and treatment of HCC.
T1936 Intratumoral Pressure and Local Ablative Therapies for Hepatocellular Carcinoma Chiaki Kawamoto, Atsushi Yamauchi, Yoko Baba, Koji Yakabi [Background] Sporadic cases of unexpected recurrence, such as intrahepatic dissemination and peritoneal dissemination, have been described following radiofrequency ablation (RFA). Some of these recurrences may be caused by increased intratumoral pressure. Therefore, we performed basic and clinical studies to examine the relationships between RFA and intrahepatic pressure, as well as between percutaneous ethanol injection (PEI) and intrahepatic pressure. [Subjects and Methods] A. Basic study: Under general anesthesia, laparotomy was performed on 19 pigs. A 20-mm LeVeen needle electrode or a 21-G PEI needle was inserted into the liver for ablation. Intrahepatic pressure was monitored by placing a PEI needle near the first needle and using an invasive blood pressure monitor. 1) RFA. RFA was performed as follows: a) Single-step method: After fully deploying the electrode, the power was initially applied at 30 W, then increased in increments of 10 W/min until power roll-off. b) Multi-step method: The array was gradually deployed in 8 steps. At each step, the power was fixed at 30 W until power roll-off. 2) PEI. Ethanol (2 ml) was injected, and intrahepatic pressure was monitored. B. Clinical study: 1) RFA. 41 HCC patients with a mean tumor size of 15.3±5.4 mm were studied. Under local anesthesia, after inserting a
T1934 Recent Clinical Features in Japanese Hepatocellular Carcinoma with Alcoholic Liver Disease Ayae Kabutake, Katsutoshi Tokushige, Etsuko Hashimoto, Haruka Noto, Maki Tobari, Satoru Yatsuji, Makiko Taniai, Keiko Shiratori (Aim) In Japan, hepatocellular carcinoma (HCC) with alcoholic liver disease is relatively rare, but alcohol consumption has recently been increasing. Life style-related diseases such as diabetes (DM), hypertension (HT) and hyperlipidemia (HL) are increasing, and these diseases have been reported as risk factors of hepatocellular carcinoma. In this study, we investigated recent trends in HCC with alcoholic liver disease in Japan and the relationship between HCC and lifestyle-related diseases. (Patients and Methods) We studied HCC with alcoholic liver disease in our hospital from 1987 to 2006. The patients were classified into two groups: group A, patients diagnosed between 1987 and 1996, and group B, patients
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AASLD Abstracts
AASLD Abstracts
An Increased Iron Status Is Associated with a Poor Prognosis in Patients with Hepatocellular Cancer Gerhard Treiber