Impact of body composition on survival and morbidity after liver resection in hepatocellular carcinoma patients
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摘要
Background: Hepatocellular carcinoma is the most common innate liver tumor. Due to improved surgical techniques, even extended resections are feasible, and more patients can be treated with curative intent. As the liver is the central metabolic organ, preoperative metabolic assessment is crucial for risk stratification. Sarcopenia, obesity and sarcopenic obesity characterize body composition and metabolic status. Here we present the impact of body composition on survival after liver resection in patients with hepatocellular carcinoma. Methods: A retrospective database analysis of 70 patients who were assigned for liver resection due to hepatocellular carcinoma was conducted. For assessment of sarcopenia and obesity, skeletal muscle surface area was measured at lumbar vertebra 3 level(L3) in preoperative four-phase contrast enhanced abdominal CT scans, and L3 muscle index and body fat percentage were calculated. Results: Univariate analysis comparing the survival curves using the score test demonstrated superior postoperative overall survival for sarcopenic( P = 0.035) and sarcopenic obese( P = 0.048) patients as well as a trend favoring obese( P = 0.130) subjects. Whereas multivariate analysis could not identify significant difference in postoperative survival regarding sarcopenia, obesity or sarcopenic obesity. Only large tumor size, multifocal disease and male gender were risk factors for long-term survival. Conclusions: Sarcopenia, obesity and sarcopenic obesity are indeed no risk factors for poor postoperative survival in this study. Our data do not support the evaluation of sarcopenia, obesity and sarcopenic obesity before liver resection in hepatocellular carcinoma patients.
Background: Hepatocellular carcinoma is the most common innate liver tumor. Due to improved surgical techniques, even extended resections are feasible, and more patients can be treated with curative intent. As the liver is the central metabolic organ, preoperative metabolic assessment is crucial for risk stratification. Sarcopenia, obesity and sarcopenic obesity characterize body composition and metabolic status. Here we present the impact of body composition on survival after liver resection in patients with hepatocellular carcinoma. Methods: A retrospective database analysis of 70 patients who were assigned for liver resection due to hepatocellular carcinoma was conducted. For assessment of sarcopenia and obesity, skeletal muscle surface area was measured at lumbar vertebra 3 level(L3) in preoperative four-phase contrast enhanced abdominal CT scans, and L3 muscle index and body fat percentage were calculated. Results: Univariate analysis comparing the survival curves using the score test demonstrated superior postoperative overall survival for sarcopenic( P = 0.035) and sarcopenic obese( P = 0.048) patients as well as a trend favoring obese( P = 0.130) subjects. Whereas multivariate analysis could not identify significant difference in postoperative survival regarding sarcopenia, obesity or sarcopenic obesity. Only large tumor size, multifocal disease and male gender were risk factors for long-term survival. Conclusions: Sarcopenia, obesity and sarcopenic obesity are indeed no risk factors for poor postoperative survival in this study. Our data do not support the evaluation of sarcopenia, obesity and sarcopenic obesity before liver resection in hepatocellular carcinoma patients.
Background: Hepatocellular carcinoma is the most common innate liver tumor. Due to improved surgical techniques, even extended resections are feasible, and more patients can be treated with curative intent. As the liver is the central metabolic organ, preoperative metabolic assessment is crucial for risk stratification. Sarcopenia, obesity and sarcopenic obesity characterize body composition and metabolic status. Here we present the impact of body composition on survival after liver resection in patients with hepatocellular carcinoma. Methods: A retrospective database analysis of 70 patients who were assigned for liver resection due to hepatocellular carcinoma was conducted. For assessment of sarcopenia and obesity, skeletal muscle surface area was measured at lumbar vertebra 3 level(L3) in preoperative four-phase contrast enhanced abdominal CT scans, and L3 muscle index and body fat percentage were calculated. Results: Univariate analysis comparing the survival curves using the score test demonstrated superior postoperative overall survival for sarcopenic( P = 0.035) and sarcopenic obese( P = 0.048) patients as well as a trend favoring obese( P = 0.130) subjects. Whereas multivariate analysis could not identify significant difference in postoperative survival regarding sarcopenia, obesity or sarcopenic obesity. Only large tumor size, multifocal disease and male gender were risk factors for long-term survival. Conclusions: Sarcopenia, obesity and sarcopenic obesity are indeed no risk factors for poor postoperative survival in this study. Our data do not support the evaluation of sarcopenia, obesity and sarcopenic obesity before liver resection in hepatocellular carcinoma patients.
引文
[1]Ferlay J,Soerjomataram I,Dikshit R,Eser S,Mathers C,Rebelo M,et al.Cancer incidence and mortality worldwide:sources,methods and major patterns in GLOBOCAN 2012.Int J Cancer 2015;136:E359-E386.
[2]Caldwell SH,Oelsner DH,Iezzoni JC,Hespenheide EE,Battle EH,Driscoll CJ.Cryptogenic cirrhosis:clinical characterization and risk factors for underlying disease.Hepatology 1999;29:664-669.
[3]Rui L.Energy metabolism in the liver.Compr Physiol 2014;4:177-197.
[4]Mourtzakis M,Prado CM,Lieffers JR,Reiman T,Mc Cargar LJ,Baracos VE.Apractical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care.Appl Physiol Nutr Metab 20 08;33:997-10 06.
[5]Kudou K,Saeki H,Nakashima Y,Edahiro K,Korehisa S,Taniguchi D,et al.Prognostic significance of sarcopenia in patients with esophagogastric junction cancer or upper gastric cancer.Ann Surg Oncol 2017;24:1804-1810.
[6]Zheng ZF,Lu J,Zheng CH,Li P,Xie JW,Wang JB,et al.A novel prognostic scoring system based on preoperative sarcopenia predicts the long-term outcome for patients after r0 resection for gastric cancer:experiences of a high-volume center.Ann Surg Oncol 2017;24:1795-1803.
[7]Ninomiya G,Fujii T,Yamada S,Yabusaki N,Suzuki K,Iwata N,et al.Clinical impact of sarcopenia on prognosis in pancreatic ductal adenocarcinoma:a retrospective cohort study.Int J Surg 2017;39:45-51.
[8]Tan BH,Birdsell LA,Martin L,Baracos VE,Fearon KC.Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer.Clin Cancer Res 2009;15:6973-6979.
[9]Peng PD,van Vledder MG,Tsai S,de Jong MC,Makary M,Ng J,et al.Sarcopenia negatively impacts short-term outcomes in patients undergoing hepatic resection for colorectal liver metastasis.HPB(Oxford)2011;13:439-446.
[10]Harimoto N,Shirabe K,Yamashita YI,Ikegami T,Yoshizumi T,Soejima Y,et al.Sarcopenia as a predictor of prognosis in patients following hepatectomy for hepatocellular carcinoma.Br J Surg 2013;100:1523-1530.
[11]Lodewick TM,van Nijnatten TJ,van Dam RM,van Mierlo K,Dello SA,Neumann UP,et al.Are sarcopenia,obesity and sarcopenic obesity predictive of outcome in patients with colorectal liver metastases?HPB(Oxford)2015;17:438-446.
[12]Forner A,Llovet JM,Bruix J.Hepatocellular carcinoma.Lancet2012;379:1245-1255.
[13]Llovet JM,BrúC,Bruix J.Prognosis of hepatocellular carcinoma:the BCLC staging classification.Semin Liver Dis 1999;19:329-338.
[14]Stockmann M,Lock JF,Malinowski M,Niehues SM,Seehofer D,Neuhaus P.The LiMAx test:a new liver function test for predicting postoperative outcome in liver surgery.HPB(Oxford)2010;12:139-146.
[15]Jara M,Reese T,Malinowski M,Valle E,Seehofer D,Puhl G,et al.Reductions in post-hepatectomy liver failure and related mortality after implementation of the LiMAx algorithm in preoperative work-up:a single-centre analysis of1170 hepatectomies of one or more segments.HPB(Oxford)2015;17:651-658.
[16]Strasberg SM.Nomenclature of hepatic anatomy and resections:a review of the Brisbane 20 0 0 system.J Hepatobiliary Pancreat Surg 2005;12:351-355.
[17]Meza-Junco J,Montano-Loza AJ,Baracos VE,Prado CM,Bain VG,Beaumont C,et al.Sarcopenia as a prognostic index of nutritional status in concurrent cirrhosis and hepatocellular carcinoma.J Clin Gastroenterol 2013;47:861-870.
[18]Prado CM,Lieffers JR,Mc Cargar LJ,Reiman T,Sawyer MB,Martin L,et al.Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts:a population-based study.Lancet Oncol 2008;9:629-635.
[19]Lodewick TM,Roeth AA,Olde Damink SW,Alizai PH,van Dam RM,Gassler N,et al.Sarcopenia,obesity and sarcopenic obesity:effects on liver function and volume in patients scheduled for major liver resection.J Cachexia Sarcopenia Muscle 2015;6:155-163.
[20]Martin L,Birdsell L,Macdonald N,Reiman T,Clandinin MT,Mc Cargar LJ,et al.Cancer cachexia in the age of obesity:skeletal muscle depletion is a powerful prognostic factor,independent of body mass index.J Clin Oncol2013;31:1539-1547.
[21]Baumgartner RN,Wayne SJ,Waters DL,Janssen I,Gallagher D,Morley JE.Sarcopenic obesity predicts instrumental activities of daily living disability in the elderly.Obes Res 20 04;12:1995-20 04.
[22]Davison KK,Ford ES,Cogswell ME,Dietz WH.Percentage of body fat and body mass index are associated with mobility limitations in people aged 70 and older from NHANES III.J Am Geriatr Soc 2002;50:1802-1809.
[23]Prado CM,Wells JC,Smith SR,Stephan BC,Siervo M.Sarcopenic obesity:a critical appraisal of the current evidence.Clin Nutr 2012;31:583-601.
[24]Stenholm S,Harris TB,Rantanen T,Visser M,Kritchevsky SB,Ferrucci L.Sarcopenic obesity:definition,cause and consequences.Curr Opin Clin Nutr Metab Care 20 08;11:693-70 0.
[25]van den Broek MA,van Dam RM,van Breukelen GJ,Bemelmans MH,Oussoultzoglou E,Pessaux P,et al.Development of a composite endpoint for randomized controlled trials in liver surgery.Br J Surg 2011;98:1138-1145.
[26]Dindo D,Demartines N,Clavien PA.Classification of surgical complications:a new proposal with evaluation in a cohort of 6336 patients and results of a survey.Ann Surg 2004;240:205-213.
[27]Venables WN,Ripley BD.Modern applied statistics with S.New York:Springer;2002.
[28]Harrell FE.Regression modeling strategies with applications to linear models,logistic regression,and survival analysis.Springer series in statistics.Bickel P,editor ed..New York:Springer;2015.
[29]El-Serag HB,Kanwal F.Epidemiology of hepatocellular carcinoma in the United States:where are we?Where do we go?Hepatology 2014;60:1767-1775.
[30]Begini P,Gigante E,Antonelli G,Carbonetti F,Iannicelli E,Anania G,et al.Sarcopenia predicts reduced survival in patients with hepatocellular carcinoma at first diagnosis.Ann Hepatol 2017;16:107-114.
[31]Iritani S,Imai K,Takai K,Hanai T,Ideta T,Miyazaki T,et al.Skeletal muscle depletion is an independent prognostic factor for hepatocellular carcinoma.JGastroenterol 2015;50:323-332.
[32]van Vledder MG,Levolger S,Ayez N,Verhoef C,Tran TC,Ijzermans JN.Body composition and outcome in patients undergoing resection of colorectal liver metastases.Br J Surg 2012;99:550-557.
[33]Dahlberg SE,Schiller JH,Bonomi PB,Sandler AB,Brahmer JR,Ramalingam SS,et al.Body mass index and its association with clinical outcomes for advanced non-small-cell lung cancer patients enrolled on eastern cooperative oncology Group clinical trials.J Thorac Oncol 2013;8:1121-1127.
[34]Rogde AJ,Gudbrandsdottir G,Hjelle KM,Sand KE,Bostad L,Beisland C.Obesity is associated with an improved cancer-specific survival,but an increased rate of postoperative complications after surgery for renal cell carcinoma.Scand JUrol Nephrol 2012;46:348-357.
[35]Valentijn TM,Galal W,Tjeertes EK,Hoeks SE,Verhagen HJ,Stolker RJ.The obesity paradox in the surgical population.Surgeon 2013;11:169-176.
[36]Chapman IM.Obesity paradox during aging.Interdiscip Top Gerontol2010;37:20-36.
[37]Siriwardana RC,Niriella MA,Dassanayake AS,Liyanage C,Gunathilaka B,Jayathunge S,et al.Clinical characteristics and outcome of hepatocellular carcinoma in alcohol related and cryptogenic cirrhosis:a prospective study.Hepatobiliary Pancreat Dis Int 2015;14:401-405.
[38]Costentin CE,Mourad A,Lahmek P,Causse X,Pariente A,Hagège H,et al.Hepatocellular carcinoma is diagnosed at a later stage in alcoholic patients:results of a prospective,nationwide study.Cancer 2018;124:1964-1972.
[39]Farinati F,Sergio A,Giacomin A,Di Nolfo MA,Del Poggio P,BenvegnùL,et al.Is female sex a significant favorable prognostic factor in hepatocellular carcinoma?Eur J Gastroenterol Hepatol 2009;21:1212-1218.
[40]Dohmen K,Shigematsu H,Irie K,Ishibashi H.Longer survival in female than male with hepatocellular carcinoma.J Gastroenterol Hepatol 2003;18:267-272.
[41]Yang D,Hanna DL,Usher J,Lo Coco J,Chaudhari P,Lenz HJ,et al.Impact of sex on the survival of patients with hepatocellular carcinoma:a surveillance,epidemiology,and end results analysis.Cancer 2014;120:3707-3716.
[42]Nakatani T,Roy G,Fujimoto N,Asahara T,Ito A.Sex hormone dependency of diethylnitrosamine-induced liver tumors in mice and chemoprevention by leuprorelin.Jpn J Cancer Res 2001;92:249-256.
[43]Prieto J.Inflammation,HCC and sex:IL-6 in the centre of the triangle.J Hepatol 2008;48:380-381.
[44]Ladenheim MR,Kim NG,Nguyen P,Le A,Stefanick ML,Garcia G,et al.Sex differences in disease presentation,treatment and clinical outcomes of patients with hepatocellular carcinoma:a single-centre cohort study.BMJ Open Gastroenterol 2016;3:e0 0 0107.
[45]Huang WJ,Jeng YM,Lai HS,Sheu FY,Lai PL,Yuan RH.Tumor size is a major determinant of prognosis of resected stage I hepatocellular carcinoma.Langenbecks Arch Surg 2015;400:725-734.
[46]Goh BK,Teo JY,Chan CY,Lee SY,Jeyaraj P,Cheow PC,et al.Importance of tumor size as a prognostic factor after partial liver resection for solitary hepatocellular carcinoma:Implications on the current AJCC staging system.J Surg Oncol 2016;113:89-93.
[47]Wang X,Wang Z,Wu L.Combined measurements of tumor number and size helps estimate the outcome of resection of Barcelona clinic liver cancer stage B hepatocellular carcinoma.BMC Surg 2016;16:22.
[48]Torzilli G,Belghiti J,Kokudo N,Takayama T,Capussotti L,Nuzzo G,et al.Asnapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers:is it adherent to the EASL/AASLD recommendations?:an observational study of the HCC East-West study group.Ann Surg 2013;257:929-937.
[49]Lin CT,Hsu KF,Chen TW,Yu JC,Chan DC,Yu CY,et al.Comparing hepatic resection and transarterial chemoembolization for Barcelona Clinic Liver Cancer(BCLC)stage B hepatocellular carcinoma:change for treatment of choice?World J Surg 2010;34:2155-2161.
[2]Caldwell SH,Oelsner DH,Iezzoni JC,Hespenheide EE,Battle EH,Driscoll CJ.Cryptogenic cirrhosis:clinical characterization and risk factors for underlying disease.Hepatology 1999;29:664-669.
[3]Rui L.Energy metabolism in the liver.Compr Physiol 2014;4:177-197.
[4]Mourtzakis M,Prado CM,Lieffers JR,Reiman T,Mc Cargar LJ,Baracos VE.Apractical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care.Appl Physiol Nutr Metab 20 08;33:997-10 06.
[5]Kudou K,Saeki H,Nakashima Y,Edahiro K,Korehisa S,Taniguchi D,et al.Prognostic significance of sarcopenia in patients with esophagogastric junction cancer or upper gastric cancer.Ann Surg Oncol 2017;24:1804-1810.
[6]Zheng ZF,Lu J,Zheng CH,Li P,Xie JW,Wang JB,et al.A novel prognostic scoring system based on preoperative sarcopenia predicts the long-term outcome for patients after r0 resection for gastric cancer:experiences of a high-volume center.Ann Surg Oncol 2017;24:1795-1803.
[7]Ninomiya G,Fujii T,Yamada S,Yabusaki N,Suzuki K,Iwata N,et al.Clinical impact of sarcopenia on prognosis in pancreatic ductal adenocarcinoma:a retrospective cohort study.Int J Surg 2017;39:45-51.
[8]Tan BH,Birdsell LA,Martin L,Baracos VE,Fearon KC.Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer.Clin Cancer Res 2009;15:6973-6979.
[9]Peng PD,van Vledder MG,Tsai S,de Jong MC,Makary M,Ng J,et al.Sarcopenia negatively impacts short-term outcomes in patients undergoing hepatic resection for colorectal liver metastasis.HPB(Oxford)2011;13:439-446.
[10]Harimoto N,Shirabe K,Yamashita YI,Ikegami T,Yoshizumi T,Soejima Y,et al.Sarcopenia as a predictor of prognosis in patients following hepatectomy for hepatocellular carcinoma.Br J Surg 2013;100:1523-1530.
[11]Lodewick TM,van Nijnatten TJ,van Dam RM,van Mierlo K,Dello SA,Neumann UP,et al.Are sarcopenia,obesity and sarcopenic obesity predictive of outcome in patients with colorectal liver metastases?HPB(Oxford)2015;17:438-446.
[12]Forner A,Llovet JM,Bruix J.Hepatocellular carcinoma.Lancet2012;379:1245-1255.
[13]Llovet JM,BrúC,Bruix J.Prognosis of hepatocellular carcinoma:the BCLC staging classification.Semin Liver Dis 1999;19:329-338.
[14]Stockmann M,Lock JF,Malinowski M,Niehues SM,Seehofer D,Neuhaus P.The LiMAx test:a new liver function test for predicting postoperative outcome in liver surgery.HPB(Oxford)2010;12:139-146.
[15]Jara M,Reese T,Malinowski M,Valle E,Seehofer D,Puhl G,et al.Reductions in post-hepatectomy liver failure and related mortality after implementation of the LiMAx algorithm in preoperative work-up:a single-centre analysis of1170 hepatectomies of one or more segments.HPB(Oxford)2015;17:651-658.
[16]Strasberg SM.Nomenclature of hepatic anatomy and resections:a review of the Brisbane 20 0 0 system.J Hepatobiliary Pancreat Surg 2005;12:351-355.
[17]Meza-Junco J,Montano-Loza AJ,Baracos VE,Prado CM,Bain VG,Beaumont C,et al.Sarcopenia as a prognostic index of nutritional status in concurrent cirrhosis and hepatocellular carcinoma.J Clin Gastroenterol 2013;47:861-870.
[18]Prado CM,Lieffers JR,Mc Cargar LJ,Reiman T,Sawyer MB,Martin L,et al.Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts:a population-based study.Lancet Oncol 2008;9:629-635.
[19]Lodewick TM,Roeth AA,Olde Damink SW,Alizai PH,van Dam RM,Gassler N,et al.Sarcopenia,obesity and sarcopenic obesity:effects on liver function and volume in patients scheduled for major liver resection.J Cachexia Sarcopenia Muscle 2015;6:155-163.
[20]Martin L,Birdsell L,Macdonald N,Reiman T,Clandinin MT,Mc Cargar LJ,et al.Cancer cachexia in the age of obesity:skeletal muscle depletion is a powerful prognostic factor,independent of body mass index.J Clin Oncol2013;31:1539-1547.
[21]Baumgartner RN,Wayne SJ,Waters DL,Janssen I,Gallagher D,Morley JE.Sarcopenic obesity predicts instrumental activities of daily living disability in the elderly.Obes Res 20 04;12:1995-20 04.
[22]Davison KK,Ford ES,Cogswell ME,Dietz WH.Percentage of body fat and body mass index are associated with mobility limitations in people aged 70 and older from NHANES III.J Am Geriatr Soc 2002;50:1802-1809.
[23]Prado CM,Wells JC,Smith SR,Stephan BC,Siervo M.Sarcopenic obesity:a critical appraisal of the current evidence.Clin Nutr 2012;31:583-601.
[24]Stenholm S,Harris TB,Rantanen T,Visser M,Kritchevsky SB,Ferrucci L.Sarcopenic obesity:definition,cause and consequences.Curr Opin Clin Nutr Metab Care 20 08;11:693-70 0.
[25]van den Broek MA,van Dam RM,van Breukelen GJ,Bemelmans MH,Oussoultzoglou E,Pessaux P,et al.Development of a composite endpoint for randomized controlled trials in liver surgery.Br J Surg 2011;98:1138-1145.
[26]Dindo D,Demartines N,Clavien PA.Classification of surgical complications:a new proposal with evaluation in a cohort of 6336 patients and results of a survey.Ann Surg 2004;240:205-213.
[27]Venables WN,Ripley BD.Modern applied statistics with S.New York:Springer;2002.
[28]Harrell FE.Regression modeling strategies with applications to linear models,logistic regression,and survival analysis.Springer series in statistics.Bickel P,editor ed..New York:Springer;2015.
[29]El-Serag HB,Kanwal F.Epidemiology of hepatocellular carcinoma in the United States:where are we?Where do we go?Hepatology 2014;60:1767-1775.
[30]Begini P,Gigante E,Antonelli G,Carbonetti F,Iannicelli E,Anania G,et al.Sarcopenia predicts reduced survival in patients with hepatocellular carcinoma at first diagnosis.Ann Hepatol 2017;16:107-114.
[31]Iritani S,Imai K,Takai K,Hanai T,Ideta T,Miyazaki T,et al.Skeletal muscle depletion is an independent prognostic factor for hepatocellular carcinoma.JGastroenterol 2015;50:323-332.
[32]van Vledder MG,Levolger S,Ayez N,Verhoef C,Tran TC,Ijzermans JN.Body composition and outcome in patients undergoing resection of colorectal liver metastases.Br J Surg 2012;99:550-557.
[33]Dahlberg SE,Schiller JH,Bonomi PB,Sandler AB,Brahmer JR,Ramalingam SS,et al.Body mass index and its association with clinical outcomes for advanced non-small-cell lung cancer patients enrolled on eastern cooperative oncology Group clinical trials.J Thorac Oncol 2013;8:1121-1127.
[34]Rogde AJ,Gudbrandsdottir G,Hjelle KM,Sand KE,Bostad L,Beisland C.Obesity is associated with an improved cancer-specific survival,but an increased rate of postoperative complications after surgery for renal cell carcinoma.Scand JUrol Nephrol 2012;46:348-357.
[35]Valentijn TM,Galal W,Tjeertes EK,Hoeks SE,Verhagen HJ,Stolker RJ.The obesity paradox in the surgical population.Surgeon 2013;11:169-176.
[36]Chapman IM.Obesity paradox during aging.Interdiscip Top Gerontol2010;37:20-36.
[37]Siriwardana RC,Niriella MA,Dassanayake AS,Liyanage C,Gunathilaka B,Jayathunge S,et al.Clinical characteristics and outcome of hepatocellular carcinoma in alcohol related and cryptogenic cirrhosis:a prospective study.Hepatobiliary Pancreat Dis Int 2015;14:401-405.
[38]Costentin CE,Mourad A,Lahmek P,Causse X,Pariente A,Hagège H,et al.Hepatocellular carcinoma is diagnosed at a later stage in alcoholic patients:results of a prospective,nationwide study.Cancer 2018;124:1964-1972.
[39]Farinati F,Sergio A,Giacomin A,Di Nolfo MA,Del Poggio P,BenvegnùL,et al.Is female sex a significant favorable prognostic factor in hepatocellular carcinoma?Eur J Gastroenterol Hepatol 2009;21:1212-1218.
[40]Dohmen K,Shigematsu H,Irie K,Ishibashi H.Longer survival in female than male with hepatocellular carcinoma.J Gastroenterol Hepatol 2003;18:267-272.
[41]Yang D,Hanna DL,Usher J,Lo Coco J,Chaudhari P,Lenz HJ,et al.Impact of sex on the survival of patients with hepatocellular carcinoma:a surveillance,epidemiology,and end results analysis.Cancer 2014;120:3707-3716.
[42]Nakatani T,Roy G,Fujimoto N,Asahara T,Ito A.Sex hormone dependency of diethylnitrosamine-induced liver tumors in mice and chemoprevention by leuprorelin.Jpn J Cancer Res 2001;92:249-256.
[43]Prieto J.Inflammation,HCC and sex:IL-6 in the centre of the triangle.J Hepatol 2008;48:380-381.
[44]Ladenheim MR,Kim NG,Nguyen P,Le A,Stefanick ML,Garcia G,et al.Sex differences in disease presentation,treatment and clinical outcomes of patients with hepatocellular carcinoma:a single-centre cohort study.BMJ Open Gastroenterol 2016;3:e0 0 0107.
[45]Huang WJ,Jeng YM,Lai HS,Sheu FY,Lai PL,Yuan RH.Tumor size is a major determinant of prognosis of resected stage I hepatocellular carcinoma.Langenbecks Arch Surg 2015;400:725-734.
[46]Goh BK,Teo JY,Chan CY,Lee SY,Jeyaraj P,Cheow PC,et al.Importance of tumor size as a prognostic factor after partial liver resection for solitary hepatocellular carcinoma:Implications on the current AJCC staging system.J Surg Oncol 2016;113:89-93.
[47]Wang X,Wang Z,Wu L.Combined measurements of tumor number and size helps estimate the outcome of resection of Barcelona clinic liver cancer stage B hepatocellular carcinoma.BMC Surg 2016;16:22.
[48]Torzilli G,Belghiti J,Kokudo N,Takayama T,Capussotti L,Nuzzo G,et al.Asnapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers:is it adherent to the EASL/AASLD recommendations?:an observational study of the HCC East-West study group.Ann Surg 2013;257:929-937.
[49]Lin CT,Hsu KF,Chen TW,Yu JC,Chan DC,Yu CY,et al.Comparing hepatic resection and transarterial chemoembolization for Barcelona Clinic Liver Cancer(BCLC)stage B hepatocellular carcinoma:change for treatment of choice?World J Surg 2010;34:2155-2161.