Does Liver Regeneration Increase the Postoperative HCC Recurrence after Curative Resection ? Jin-Ho Lee, MD. Department of Surgery, Yonsei University College of Medicine Division of Hepato-Biliary-Pancreas Cancer Clinic, Institute of Gastroenterology, Severance Hospital, Seoul, Korea

Background

P =0.029 P =0.187 In conclusion, Despite standard radiological selection criteria based on number and size, patients who underwent LDLT for HCC had more recurrence because of selection bias for other clinical characteristics.

Background

In conclusion, significant activation of cell signaling pathways leading to tumor invasion and migration in small-for-size liver grafts promotes tumor growth and metastasis after liver transplantation.

Background

In conclusion, LDLT showed poorer outcome than DDLT In conclusion, LDLT showed poorer outcome than DDLT. This should be considered to select optimal strategy for HCC.

Study design Duration: 2006. 01. 01~2009. 12. 31 Liver volumetry Mevisys company VoxelPlus® 2 Pre-Operative CT image POD #7day CT image POD #90day CT image

Flow diagram of Study Total patients: 420 Tumor Operation extent Number ≤3개 Tumor size ≤5cm Operation extent Anatomical resection Over Sectionectomy Total patients: 107 Liver cirrhosis ?? Non-cirrhotic liver: 54 Cirrhotic liver: 53

Results Table 1. Baseline characteristics of the study population Variable n=107 Age 55 (27-77) Sex (male/female) 84 (78.5%) / 23 (21.5%) BMI (Kg/m2) 23.53 (17.85-32.89) White blood cell count (103/uL) 5700 (1920-13710) Hemoglobin (g/dL) 14.1 (9.3-18.1) Platelet count (109/L) 163 (23-359) Total protein (g/dL) 7.4 (3.7-8.6) Albumin (g/dL) 4.5 (3.1-5.2) AST (IU/L) 31 (12-149) ALT (IU/L) 34 (8-158) Total bilirubin (mg/L) 0.7 (0.3-1.4) Prothrombin time (%) Partial thromboplastin time (sec) 32.2 (20.4-47.0) Alpha-feto protein (ng/mL) 28.7 (0.89-56475.8) PIVKA-II* (mAU/mL) 52 (10-2000) ICG-R15 (%) 8.9 (0.5-32.9) Child-Pugh score A (100%) *Prothrombin induced by vitamin K absence-II

Results Table 2. Perioperative and tumor characteristics of the study population Variable n=107 Operation extent Rt. hemi 51 (47.7%) Lt. hemi 27 (25.2%) Sectionectomy 23 (21.5%) Extended hepatecctomy 6 (5.6%) Operation time (min) 260 (120-600) Transfusion (yes/no, %) 26 (19.6%) / 81 (80.4%) Resected liver volume (ml) 410.5 (90.6-1100.9) Remnent liver volume (ml) 575.5 (185-1235.5) Postoperative 90th day liver volume (ml) 851.6 (336.9-1392.8) Postoperative 90th day liver regeneration rate 1.384 (1.00-4.40) Edmonsion-Steiner grade(I/II/III/IV/없음, %)* 4 (3.7%)/63 (58.9%)/26(24.2%)/-/14(13.2%) Underline liver cirrhosis (yes/no, %) 53 (49.5%) / 54 (50.5%) Tumor size (cm) 3 (1-5) Tumor number 1 (1-3) GVI (negative/positive, %)** 94 (87.8%) / 12 (12.2%) MVI (negative/Positive, %)*** 55 (51.4%) / 51 (48.6%) Satellite nodule (negative/Positive, %) 98 (91.5%) / 8 (7.5%) Intrahepatic metastasis (negative/Positive, %) 100 (93.5%) / 7 (6.5%) Multicentric occurrence (negative/Positive, %) 98(91.5%) /9 (8.5%) Surgical margin (negative/Positive, %) 106 (99.1%) / 1 (0.9%) Postoperative mortality 0 (0%) * Worst score was selected in Edmonson-Steiner grade, ** Gross vascular invasion, *** Microvascular invasion

Non-cirrhotic Liver

Clinicopathologic Outcomes Regeneration ratio Total P-value ≤1.5 >1.5 (N=26) (N=28) (N=54) Age (year) 53.5 (29-77) 52 (32-70) 0.386 Gender Male 21 24 45 0.626 Female 5 4 9 AFP (ng/mL) 13.89 (1.5-4044.91) 21.68 (1.71-10165.79) 18.02 (1.5-10165.79) 0.206 PIVKAII (mAU/mL) 56 (17-2000) 56.5 (16-2000) 0.389 PLT (103/μL) 202.5 (126-359) 205 (117-304) 203.5 (117-359) 0.357 INR 0.995 (0.9-2.43) (0.89-1.20) (0.89-2.43) Albumin (g/dL) 4.7 (3.9-5.2) 4.6 (4.0-5.2) 0.918 OT (IU/L) 29 (12-58) 25.5 (15-73) (12-73) 0.343 PT (IU/L) 32 (9-87) 27.5 (8-101) 31 0.914 Bilirubin (mg/dL) 0.6 (0.4-1.2) 0.7 (0.3-1.1) (0.3-1.2) 0.708 ICG-R15 (%) 6.20% (2.7-32.9) 8.4 (3.8-17.2) 7.95 0.919 OP time (min) 263.5 (120-420) 263 (140-600) (120-600) 0.789

Clinicopathologic Outcomes Regeneration ratio Total P-value ≤1.5 >1.5 (N=26) (N=28) (N=54) OP method <0.001 Rt. hemi 2 23 25 Lt. hemi 16 18 Sectionectomy 6 1 7 Extended hepatectomy 4 Transfusion Yes 9 0.847 No 17 19 36 Tumor No. (1-2) 0.340 Tumor size (cm) 3 (1.5-5.0) (1.0-5.0) 0.480 Satellite nodule Absent 26 24 50 0.080 Present Micro vascular invasion 14 15 29 0.859 11 13 Portal vein invasion 47 0.112 5 Intrahepatic meta 51 0.597 Multicentric occurrence 28 54 Resection margin R0 27 53 0.331 R1

Disease-free Survival: Non-cirrhotic liver P =0.019 ≤ 1.5배 > 1.5배

Multivariate analysis Factor Univariate analysis Multivariate analysis Patients (n) p-value Exp(B) 95% CI Gender 0.228 Male 45 Female 9 Age 0.366 ≤60 34 >60 20 Grade 0.169 I 2 II 28 III 18 Regeneration rate 0.019 0.047 5.252 1.200-26.993 ≤1.50 26 >1.50 Satellite nodule 0.012 0.469 2.268 0.248-20.756 No 50 Yes 3 Portal vein invasion 0.602 47 6

Multivariate analysis Factor Univariate analysis Multivariate analysis Patients (n) p-value Exp(B) 95% CI Microvascular invasion 0.032 0.325 2.102 0.497-9.228 No 29 Yes 24 Intraheaptic metastasis 0.010 0.097 7.078 0.700-71.624 51 3 AST (IU/L) 0.132 ≤50 >50 ALT (IU/L) 0.024 42 12 Albumin 0.339 ≤4.0 2 >4.0 52 Resection Margin 0.033 0.950 1.090 0.073-16.273 53 1 Transfusion 0.972 18 36

Cirrhotic liver

Clinicopathologic Outcomes Regeneration ratio Total P-value ≤1.5 >1.5 (N=34) (N=19) (N=53) Age (year) 55.0 (27-72) 55 (32-71) 56 0.914 Gender Male 25 14 39 0.990 Female 9 5 AFP (ng/mL) 56.65 (0.8-56475,84) 31.04 (2.09-18205.26) 48.52 (0.89-56475.84) 0.511 PIVKAII (mAU/mL) (10-2000) 59.5 (16-2000) 47 0.656 PLT (103/μL) 134 (23-255) 147 (93-278) 141 (23-278) 0.150 INR 1.035 (0.92-1.23) 1.06 (0.89-1.16) 1.05 (0.89-1.23) 0.898 Albumin (g/dL) 4.15 (3.1-5.0) 4.5 (3.4-5.1) 4.3 (3.1-5.1) 0.035 OT (IU/L) 37 (21-136) 30 (23-149) 35 (21-149) 0.584 PT (IU/L) 38 (12-99) (13-158) (12-158) 0.379 Bilirubin (mg/dL) 0.65 (0.3-1.4) 0.7 (0.4-1.1) 0.437 ICG-R15 (%) 11.10% (0.5-29.9) 8.95 (3.9-20.0) 9.90 0.218 OP time (min) 274.0 (148-600) 235 (169-310) 254 0.074

Clinicopathologic Outcomes Regeneration ratio Total P-value ≤1.5 >1.5 (N=34) (N=19) (N=53) OP method <0.001 Rt. hemi 8 18 26 Lt. hemi 1 9 Sectionectomy 16 Extended hepatectomy 2 Transfusion Yes 7 0.135 No 27 45 Tumor No. (1-2) (1-3) 0.414 Tumor size (cm) 3 (1.0-5.0) 0.568 Satellite nodule Absent 32 48 0.237 Present 5 Micro vascular invasion 15 11 0.336 19 Portal vein invasion 31 47 0.443 6 Intrahepatic meta 33 49 0.089 4 Multicentric occurrence 29 44 0.555 Resection margin R0 34 53 0.331 R1

Disease-free Survival: Cirrhotic liver P =0.040 ≤ 1.5배 > 1.5배

Multivariate analysis Factor Univariate analysis Multivariate analysis Patients (n) p-value Exp(B) 95% CI Gender 0.639 Male 39 Female 14 Age 0.717 ≤60 34 >60 19 Grade 0.141 I 2 II 35 III 8 Regeneration rate 0.037 0.040 0.048 0.016-0.434 ≤1.50 >1.50 Satellite nodule 0.860 No 48 Yes 5 Portal vein invasion 0.060 0.001 17.378 4.129-73.132 47 6

Multivariate analysis Factor Univariate analysis Multivariate analysis Patients (n) p-value Exp(B) 95% CI Microvascular invasion 0.053 0.809 0.865 0.267-2.803 No 26 Yes 27 Intraheaptic metastasis 0.414 49 4 AST (IU/L) 0.007 0.005 5.464 1.679-17.781 ≤50 42 >50 11 ALT (IU/L) 0.109 43 10 Albumin 0.238 ≤4.0 14 >4.0 39 Resection Margin 53 Transfusion 0.020 0.137 2.055 0.795-5.312 45 8 In conclusion, among the HBV infected HCC patients with curative resection, postoperative recurrences occurred more as there were more liver regeneration in non-cirrhotic liver. However, patients with cirrhotic liver showed the opposite result. We think this is probably because tumor recurrence will be activated more by a serial signaling pathway as there was more liver regeneration.

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