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Cheng-Cheng Zhang1 ,* Cheng-Wu Zhang2 ,* Hao Xing3 ,* Yu Wang4 ,* Lei Liang2,5 ,* Yong-Kang Diao2,5 ,* Ting-Hao Chen,6 Wan Yee Lau,3,7 Ping Bie,8 Zhi-Yu Chen,1 Tian Yang1,3 1Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; 2Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, China; 3Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China; 4Department of Hepatobiliary Surgery, Chongqing University Cancer Hospital, Chongqing, China; 5Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, China; 6Department of General Surgery, Ziyang First People’s Hospital, Sichuan, China; 7Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; 8Department of Hepatobiliary, The Third Affiliated Hospital, Chongqing Medical University, Chongqing, China*These authors contributed equally to this workCorrespondence: Zhi-Yu ChenDepartment of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), No. 30, Gaotanyan Street, Chongqing 400038, ChinaEmail chenzhiyu_umn@163.comTian YangDepartment of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), No. 225, Changhai Road, Shanghai 200438, ChinaEmail yangtian6666@hotmail.comBackground: A normal albumin-to-globulin ratio (NAGR) in serum is greater than 1. Inversed albumin-to-globulin ratio (IAGR < 1) indicates poor synthetic liver function or malnutrition. The aim of this study is to evaluate whether preoperative IAGR was associated with worse oncologic survival after hepatectomy for hepatocellular carcinoma (HCC).Patients and Methods: Patients who underwent curative hepatectomy for HCC between 2009 and 2016 in four centers were divided into the IAGR and NAGR groups based on their preoperative levels, and their clinical characteristics and long-term survival outcomes were compared. Univariable and multivariable Cox regression analyses were performed to identify risk factors of overall survival (OS) and recurrence-free survival (RFS).Results: Of 693 enrolled patients, 136 (19.6%) were in the IAGR group. Their 5-year OS and RFS rates were 31.6% and 21.3%, respectively, which were significantly worse than the NAGR group (43.4% and 28.7%, both P < 0.001). The area under the receiver operating characteristic curves in predicting 5-year OS and RFS using the albumin-to-globulin ratio were 0.68 and 0.67, respectively, which were significantly higher than albumin (0.60 and 0.59), globulin (0.56 and 0.57), Child-Pugh grading (0.61 and 0.60), Model for End-Stage Liver Disease Score (0.59 and 0.58), and Albumin-Bilirubin grading (0.64 and 0.63). Multivariable analyses identified that preoperative IAGR was independently associated with worse OS (HR: 1.444, 95% confidence interval (CI): 1.125– 1.854, P = 0.004) and RFS (HR: 1.463, 95% CI: 1.159– 1.848, P = 0.001).Conclusion: Preoperative IAGR was useful in predicting worse OS and RFS in patients who underwent curative hepatectomy for HCC.Keywords: hepatocellular carcinoma, hepatectomy, albumin, globulin, survival, recurrence

Zheng-Liang Chen,1,* Cheng-Wu Zhang,2,* Lei Liang,2,* Han Wu,3,* Wan-Guang Zhang,4 Yong-Yi Zeng,5 Wei-Min Gu,6 Ting-Hao Chen,7 Jie Li,8 Yao-Ming Zhang,9 Hong Wang,10 Ya-Hao Zhou,11 Chao Li,2 Yong-Kang Diao,2 Wan Yee Lau,3,12 Meng-Chao Wu,3 Feng Shen,3 Tian Yang,3 Ying-Jian Liang1 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, People’s Republic of China; 2Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, People’s Republic of China; 3Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital (Navy Medical University), Second Military Medical University, Shanghai, People’s Republic of China; 4Department of Hepatic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 5Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fujian, People’s Republic of China; 6The First Department of General Surgery, The Fourth Hospital of Harbin, Heilongjiang, People’s Republic of China; 7Department of General Surgery, Ziyang First People’s Hospital, Sichuan, People’s Republic of China; 8Department of Hepatobiliary Surgery, Fuyang People’s Hospital, Anhui, People’s Republic of China; 9The 2nd Department of Hepatobiliary Surgery, Meizhou People’s Hospital, Guangdong, People’s Republic of China; 10Department of General Surgery, Liuyang People’s Hospital, Hunan, People’s Republic of China; 11Department of Hepatobiliary Surgery, Pu’er People’s Hospital, Yunnan, People’s Republic of China; 12Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ying-Jian LiangDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Road, Heilongjiang 150006, People’s Republic of ChinaEmail genomeliang@hotmail.comTian YangDepartment of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), No. 225, Changhai Road, Shanghai 200438, People’s Republic of ChinaEmail yangtiandfgd@hotmail.comBackground: With an increase in life expectancy and improvement of surgical safety, more elderly patients with hepatocellular carcinoma (HCC), even with large tumors, are now considered for hepatectomy. This study aimed to clarify the impact of age on short- and long-term outcomes after major hepatectomy (≥ 3 segments) for large HCC (≥ 5 cm).Patients and Methods: Using a multicenter database, patients who underwent curative-intent major hepatectomy for large HCC between 2006 and 2016 were identified. Postoperative morbidity and mortality, overall survival (OS) and recurrence-free survival (RFS) were compared between the elderly (≥ 65 years) and younger (< 65 years) patients. Univariable and multivariable Cox-regression analyses were performed to identify the risk factors of OS and RFS in the entire and elderly cohorts, respectively.Results: Of 830 patients, 92 (11.1%) and 738 (88.9%) were elderly and younger patients, respectively. There were no significant differences in postoperative 30-day mortality and morbidity between the two groups (5.4% vs 2.6% and 43.5% vs 38.3%, both P> 0.05). The 5-year OS and RFS rates in elderly patients were also comparable to younger patients (35.0% vs 33.2% and 20.0% vs 20.8%, both P> 0.05). In the entire cohort, multivariable Cox-regression analyses identified that old age was not independently associated with OS and RFS. However, in the elderly cohort, preoperative alpha-fetoprotein level > 400 μg/L, multiple tumors, macrovascular invasion and microvascular invasion were independently associated with decreased OS and RFS.Conclusion: Carefully selected elderly patients benefited from major hepatectomy for large HCC as much as younger patients, and their long-term prognosis was determined by preoperative alpha-fetoprotein level, tumor number and presence of macro- or micro-vascular invasion.Keywords: hepatocellular carcinoma, hepatectomy, survival, recurrence, elderly