Reevaluation of Makuuchi's criteria for resecting hepatocellular carcinoma: A Japanese nationwide survey.

AIM: Although Makuuchi's criteria are widely used to determine the cut-off for safe liver resection, there have been few reports of concrete data supporting their validity. Here, we verified the utility of Makuuchi's criteria by comparing the operative mortality rates associated with liver resection between hepatocellular carcinoma (HCC) patients meeting or exceeding the criteria. METHODS: A database was built using data from 15 597 patients treated between 2000 and 2007 for whom values for all three variables included in Makuuchi's criteria for liver resection (clinical ascites, serum bilirubin, and indocyanine green clearance) were available. The patients were divided into those fulfilling (n = 12 175) or exceeding (n = 3422) the criteria. The postoperative mortality (death for any reason within 30 days) and long-term survival were compared between the two groups. RESULTS: The operative mortality rate was significantly lower in patients meeting the criteria than in those exceeding the criteria (1.07% vs. 2.01%, respectively; p < 0.001). On multivariate analysis, exceeded the criteria was significantly associated with the risk for operative mortality (relative risk 2.08; 95% confidence interval (CI), 1.23-3.52; p = 0.007). Surgical indication meeting or exceeding the criteria was an independent factor for overall survival (hazard ratio 1.27; 95% CI, 1.18-1.36; p < 0.001). CONCLUSION: Makuuchi's criteria are suitable for determining the indication for resection of HCC due to the reduction in risk of operative mortality.

Objective Definition and Optimized Strategy for "Biologically Borderline Resectable" Colorectal Liver Metastases.

BACKGROUND: The prognostic benefit of preoperative chemotherapy leading to conversion surgery for unresectable colorectal liver metastases (CRLM) is well recognized, while that of neoadjuvant chemotherapy (NAC) compared with upfront surgery (UFS) for resectable CRLM is negligible. This study aims to assess the prognostic benefit and search for optimal indication of NAC for resectable advanced CRLM by establishing an objective definition of biologically borderline resectable (bBR) CRLM. METHODS: A bicentric retrospective analysis of patients with CRLM undergoing curative-intent initial liver resection between 2007 and 2021 was performed. An original classification matrix was established, which reassessed technical resectability using virtual hepatectomy and oncological favorability using Beppu's nomogram. Patients with technically resectable but biologically unfavorable CRLM were classified into the bBR group. The propensity score matching analysis using preoperatively available factors was performed to assess long-term outcomes of the bBR-UFS and bBR-NAC groups. RESULTS: Of 831 patients reviewed, 240 were categorized into the bBR group: bBR -UFS (n = 139) and bBR-NAC (n = 101). Ten (10%) in the bBR-NAC group (n = 101) experienced biological status change from unfavorable to favorable after NAC (Biological Conversion) and showed significantly longer overall survival (hazard ratio 5.63, 95% confidence interval 1.37-23.1; P = 0.016) than the bBR-UFS group. However, after propensity score matching, no significant difference between the UFS and NAC groups (n = 67 for each) was found in long-term outcomes. CONCLUSIONS: NAC for bBR-CRLM did not enhance the prognostic impact of the following liver resection, except for a limited number of optimal candidates experiencing the Biological Conversion.

Phase I/II study of streptozocin monotherapy in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: This phase I/II study was conducted to evaluate the efficacy, safety and pharmacokinetics of streptozocin (STZ) in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors. METHODS: Twenty-two patients received up to 4 cycles of intravenous STZ at either 500 mg/m2 once daily for 5 consecutive days every 6 weeks (daily regimen) or at 1000-1500 mg/m2 once weekly for 6 weeks (weekly regimen). Tumor response was evaluated using the modified RECIST criteria ver. 1.1, and adverse events were assessed by grade according to the National Cancer Institute CTCAE (ver. 4.0). RESULTS: Fourteen (63.6%) patients completed the study protocol. No patients had complete response; partial response in 2 (9.1%), stable disease in 17 (77.3%), non-complete response/non-progressive disease in 2 (9.1%) and only 1 (4.5%) had non-evaluable disease. Excluding the latter, the response rate in the daily and weekly regimens was 6.7% (1/15) and 16.7% (1/6), respectively, with an overall response rate of 9.5% (2/21). However, the best overall response in each patient showed that the disease control rate was 100%.Adverse events occurred in all 22 patients, including 17 grade 3 adverse events in 11 patients; however, no grade 4 or 5 adverse events were reported. Prophylactic hydration and antiemetic treatment reduced the severity and incidence of nephrotoxicity, nausea and vomiting. Plasma STZ concentrations decreased rapidly after termination of infusion, with a half-life of 32-40 min. Neither repeated administration nor dose increases affected pharmacokinetic parameters. CONCLUSIONS: STZ may be a useful option for Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

Algorithm for Resecting Hepatocellular Carcinoma in the Caudate Lobe.

OBJECTIVE: To propose an algorithm for resecting hepatocellular carcinoma (HCC) in the caudate lobe. BACKGROUND: Owing to a deep location, resection of HCC originating in the caudate lobe is challenging, but a plausible guideline enabling safe, curable resection remains unknown. METHODS: We developed an algorithm based on sublocation or size of the tumor and liver function to guide the optimal procedure for resecting HCC in the caudate lobe, consisting of 3 portions (Spiegel, process, and caval). Partial resection was prioritized to remove Spiegel or process HCC, while total resection was aimed to remove caval HCC depending on liver function. RESULTS: According to the algorithm, we performed total (n = 43) or partial (n = 158) resections of the caudate lobe for HCC in 174 of 201 patients (compliance rate, 86.6%), with a median blood loss of 400 (10-4530) mL. Postoperative morbidity (Clavien grade ≥III b) and mortality rates were 3.0% and 0%, respectively. After a median follow-up of 2.6 years (range, 0.5-14.3), the 5-year overall and recurrence-free survival rates were 57.3% and 15.3%, respectively. Total and partial resection showed no significant difference in overall survival (71.2% vs 54.0% at 5 yr; P = 0.213), but a significant factor in survival was surgical margin (58.0% vs 45.6%, P = 0.034). The major determinant for survival was vascular invasion (hazard ratio 1.7, 95% CI 1.0-3.1, P = 0.026). CONCLUSIONS: Our algorithm-oriented strategy is appropriate for the resection of HCC originating in the caudate lobe because of the acceptable surgical safety and curability.

Is portal vein embolization safe and effective for patients with impaired liver function?

BACKGROUND AND OBJECTIVES: Portal vein embolization (PVE) is a safe and effective procedure used to increase the safety of extensive hepatectomy for selected patients. However, it is unknown whether PVE is safe for patients with impaired liver functional reserve. METHODS: Patients who underwent PVE from April 2007 to September 2016 in our hospital were retrospectively assessed. According to indocyanine green retention rate at 15 min (ICG-R15), we divided patients into Group A (≤10%), Group B (10%-20%), and Group C (>20%). We described and compared the treatment course and the outcome among the three groups. RESULTS: A total of 106 patients were assessed and divided into groups A (n = 46), B (n = 49), and C (n = 11). The morbidity and mortality after PVE showed no significant differences among the three groups (A:B:C = 37%:53%:64%, p = .16; A:B:C = 0%:0%:0%, p = 1.00, respectively). The morbidity and mortality after successive hepatectomy also showed no significant differences among the three groups (A:B:C = 55%:71%:78%, p = .19; A:B:C = 0%:2%:0%, p = 1.00, respectively). CONCLUSION: A patient with impaired liver functional reserve (ICG-R15 > 20%) can be a candidate for PVE and successive hepatectomy, as safely as a patient with normal and slightly impaired liver functional reserve (ICG-R15 ≤ 20%).

Living donor liver transplantation: looking back at my 30 years of experience.

Since I moved from the National Cancer Center to Shinshu University, I have been performing living donor liver transplantation (LDLT), which is the only way to save the life of patients with end-stage liver disease. In June 1990, we performed the first LDLT that case was the first successful case in Japan. The patient remains healthy and is enjoying a normal life still 28 years after the transplant. In 1993, we successfully performed adult-to-adult LDLT, which was the first successful case in the world. The patient enjoyed a normal life for 17 years until she died at 70 years of age. For small children, the left liver of adult donors is too large to close the abdomen. However, in adolescents or adults, even when the whole right liver is used, the volume of the graft is too small. The concept of the standard liver volume (SLV) has proven very important for this procedure and is calculated as follows: 706.2 × body surface area + 2.4. We proposed a method for evaluating the congestion of the liver by Doppler ultrasound. In addition, we devised the right lateral sector graft. Over the years, we have contributed to LDLT in many ways and published many papers. We feel that our findings are quite useful not only for LDLT but also for other hepatectomy procedures.

Hepatopancreaticoduodenectomy for Biliary Cancer: Strategies for Near-zero Operative Mortality and Acceptable Long-term Outcome.

OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of hepatopancreaticoduodenectomy (HPD) for patients with biliary cancer. BACKGROUND: HPD is thought to be the only curative treatment for widespread bile duct cancer and for some advanced cases of gallbladder cancer; however, HPD has not yet been accepted as a standard operative procedure because of concerns over morbidity and mortality. METHODS: Fifty-two patients undergoing HPD were retrospectively reviewed. The patient and tumor characteristics, preoperative treatments, operative results, and survival outcomes were investigated. RESULTS: Preoperative biliary drainage and portal vein embolization were applied for all patients undergoing right-sided HPD or a left trisectionectomy. A major hepatectomy was performed in 42 patients, and a 2-stage pancreaticojejunostomy was selected in all the cases. The 90-day mortality was 0; however, 1 patient died because of a liver abscess 230 days after surgery. Postoperative significant complications (grade III or greater) and liver insufficiency were observed in 19 (37%) and 2 (3.8%) patients, respectively, and no abdominal bleeding events after the formation of a pancreatic fistula were encountered. The 5-year overall survival rate was 44.5%, and a significant difference was not observed between patients with bile duct cancer and those with gallbladder cancer. The operative procedure was switched to an HPD in 13 patients based on intraoperative findings, and the recurrence-free survival rate for these patients was poorer than that for patients who did not require a switch in operative procedure (P = 0.004). CONCLUSIONS: HPD can be safely performed using the presently reported surgical strategies with acceptable short and long-term outcomes. A precise assessment of the extent of tumor spread might improve patient outcome.

Feasibility of Intraoperative Navigation for Liver Resection Using Real-time Virtual Sonography With Novel Automatic Registration System.

BACKGROUND: The clinical feasibility and usability of intraoperative ultrasonography (IOUS) tracked by computed tomography (CT) images have been proposed; however, it requires technically demanding manual registration procedure. STUDY DESIGN: A prospective study using real-time virtual sonography (RVS) with novel automatic registration system was conducted in four high-volume centers of liver resection from 2015 to 2016. The requiring time for registration of IOUS and CT images and positional error of confluence of middle hepatic venous tributaries (V8-MHV, V5-MHV) were measured in patients undergoing laparotomy. RESULTS: Automatic registration was successful in 43 of 52 enrolled patients (83%), with error ranges of 11.4 (3.1-69.4) mm for V8-MHV and 16.2 (4.3-66.8) mm for V5-MHV. Time required for total registration process was 36 (27-74) s. CONCLUSIONS: The RVS with novel automatic registration system can provide quick and easy registration and acceptable accuracy, which can promote the usage of IOUS.

Surgical Site Infection after Hepatectomy for Hepatocellular Carcinoma.

AIMS: To clarify the clinical impact, risk factors, and preventive methods for surgical site infection (SSI) after hepatectomy for hepatocellular carcinoma (HCC). METHODS: We included 879 consecutive patients who underwent hepatectomy for HCC between 2002 and 2011. Univariate and multivariate analyses were conducted to identify the risk factors for incisional and organ/space SSIs. ORs and 95% CIs are reported. RESULTS: The incidences of incisional and organ/space SSIs were 24 (2.7%) and 73 (8.3%), respectively. High body mass index, multiple resections, and organ/space SSI were associated with incisional SSIs, while repeat hepatectomy (OR 2.14, 95% CI 1.27-3.60), ascites (OR 2.97, 95% CI 1.55-5.48), and bile leakage (OR 4.77, 95% CI 2.77-8.11) were independent risk factors for organ/space SSI. Among the cases with bile leakage, lower rates of organ/space SSIs tended to be observed in patients with cystic duct tubes than in patients without such tubes (13.2 vs. 26.5%, p = 0.157). Retrograde drain infections increased when drain placement was prolonged for more than 4 postoperative days. CONCLUSION: Bile leakage was associated with the greatest risk of organ/space SSI after hepatectomy for HCC. Cystic duct tubes might be useful for preventing bile leakage and subsequent organ/space SSI after procedures that extensively expose Glissonean pedicles.

Prospective evaluation of the International Study Group for Liver Surgery definition of post hepatectomy liver failure after liver resection: an international multicentre study.

BACKGROUND: The International Study Group for Liver Surgery (ISGLS) definition of post hepatectomy liver failure (PHLF) was developed to be consistent, widely applicable, and to include severity stratification. This international multicentre collaborative study aimed to prospectively validate the ISGLS definition of PHLF. METHODS: 11 HPB centres from 7 countries developed a standardised reporting form. Prospectively acquired anonymised data on liver resections performed between 01 July 2010 and 30 June 2011 was collected. A multivariate analysis was undertaken of clinically important variables. RESULTS: Of the 949 patients included, 86 (9%) met PHLF requirements. On multivariate analyses, age ≥70 years, pre-operative chemotherapy, steatosis, resection of >3 segments, vascular reconstruction and intraoperative blood loss >300 ml significantly increased the risk of PHLF. Receiver operator curve (ROC) analysis of INR and serum bilirubin relationship with PHLF demonstrated post-operative day 3 and 5 INR performed equally in predicting PHLF, and day 5 bilirubin was the strongest predictor of PHLF. Combining ISGLS grades B and C groups resulted in a high sensitivity for predicting mortality compared to the 50-50 rule and Peak bilirubin >7 mg/dl. CONCLUSIONS: The ISGLS definition performed well in this prospective validation study, and may be the optimal definition for PHLF in future research to allow for comparability of data.

Nomogram predicting long-term survival after the diagnosis of intrahepatic recurrence of hepatocellular carcinoma following an initial liver resection.

BACKGROUND: The aim of this study was to construct and validate a nomogram for predicting survival after the intrahepatic recurrence of hepatocellular carcinoma (HCC) following an initial hepatectomy. METHODS: A primary cohort of 268 patients who underwent curative hepatectomy for HCC at Shinshu University Hospital between 1990 and 2010 was retrospectively studied. A nomogram was constructed based on independent prognostic factors for overall survival after recurrence. The predictive performance was evaluated using the concordance index (c-index) and a calibration curve. The nomogram was then externally validated in a cohort of patients from Tokyo University Hospital (n = 296). RESULTS: In multivariate analysis, the following 5 variables were identified as independent predictors of overall survival and incorporated into the nomogram-Japan Integrated Stage score at initial liver resection, platelet count at initial liver resection, time until intrahepatic recurrence, vascular invasion at recurrence, and type of treatment used for intrahepatic recurrence. The nomogram had a c-index of 0.75 (95% confidence interval 0.60-0.85) for the Shinshu cohort and 0.71 (0.57-0.81) for the Tokyo cohort. The predicted 3- and 5-year survival probabilities corresponded well with the actual outcomes. CONCLUSIONS: The established nomogram might be useful for estimating survival after the intrahepatic recurrence of HCC.

Left hepatectomy after right paramedian sectoriectomy.

Repeat hepatectomy is beneficial for selected patients with recurrence of liver malignancies. However, the operative procedure becomes technically demanding when the previous hepatectomy was complex, with hepatic veins and stump of portal pedicles exposed on the liver transection surface. We performed left hepatectomy after right paramedian sectoriectomy (RPMS) for three patients. Here, we describe our surgical technique and the postoperative outcomes achieved. This procedure allowed for safe adhesiolysis between the middle and right hepatic veins by following a fibrous plane. The mean operative time was 8.7 h, including 4.9 h of adhesiolysis. The mean remnant liver volume (right lateral sector and the caudate lobe) was calculated as 704 ml, being 62% of total liver volume. There was no postoperative liver failure or mortality. In conclusion, left hepatectomy after RPMS is a feasible procedure for patients with sufficient remnant liver volume, even though the middle and right hepatic veins run side by side after liver regeneration.

Complete removal of the tumor-bearing portal territory decreases local tumor recurrence and improves disease-specific survival of patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Anatomic resection (AR) of the tumor-bearing portal territory has been reported to be associated with a decreased recurrence of hepatocellular carcinoma (HCC). However, because of the heterogeneity of the study populations, its oncologic advantage remains controversial. The objective of the present study was to determine the clinical advantage of AR for primary HCC, based on the data from a large prospective cohort treated under a constant surgical policy. METHODS: In 209 Child-Pugh class A patients with primary, solitary HCC measuring ⩽5.0cm in diameter, which was resectable either by AR or limited resection (non-AR), the overall survival (OS) and disease-free survival (DFS) were compared with patients in whom complete AR was achieved and those who eventually ended up with non-AR after adjustment for the propensity scores to select AR. Advantages of AR in disease-specific survival and local recurrence were also evaluated by competing-risks regression to clarify the true oncologic impact of AR. RESULTS: The AR group showed better DFS than the non-AR group (HR, 0.67; 95% CI, 0.45-0.99; p=0.046), while no significant difference was observed in OS (hazard ratio [HR], 0.82; 95% CI, 0.46-1.48; p=0.511). Competing-risks regression revealed that AR significantly decreases local recurrence (HR, 0.12; 95% CI, 0.05-0.30; p<0.001) and improves disease-specific survival (HR, 0.50; 95% CI, 0.28-0.90; p=0.020), while the other cause of death was highly influenced by patient age (>65years) (HR, 7.51; 95% CI, 2.16-26.04; p=0.002) and not associated with AR. CONCLUSION: Complete removal of tumor-bearing portal territory decreases the risk of local recurrence and death from HCC.

Risk factors for acute liver allograft rejection and their influences on treatment outcomes of rescue therapy in living donor liver transplantation.

BACKGROUND: Several clinical factors are reportedly correlated with acute cellular rejection (ACR) after liver transplantation. However, the factors that determine the response to rescue therapies remain unclear. METHODS: A prospective database of 413 consecutive adult patients who underwent living donor liver transplantation (LDLT) was reviewed. RESULTS: Ninety-nine (24%) patients developed ACR after LDLT. A multivariate analysis revealed that a positive T-lymphocytotoxic test (odds ratio [OR], 3.85; P=.017), HLA-DR mismatch (OR, 2.99; P=.013), autoimmune disease (OR, 2.61; P=.001), and a younger recipient age (OR, 0.60 for +10 years; P<.001) were independent risk factors for ACR. Among these, autoimmune disease was significantly correlated with refractoriness to the standard rescue therapy (53% vs 30%, P=.02) and relapse of cellular rejection (34% vs 16%, P=.04). After rescue therapy, 98 of the 99 (99%) patients eventually recovered from ACR and graft loss was observed in only one patient. None of the risk factors for ACR impaired both graft survival and overall survival after LDLT. CONCLUSIONS: Autoimmune liver disease is associated with refractoriness to rescue therapy for ACR and the relapse of rejection. However, ACR does not affect the long-term outcomes of LDLT if it is well controlled.

Dynamic assessment of carcinoembryonic antigen in the first month after liver resection for colorectal liver metastases as a rapid-recurrence predictor.

BACKGROUND: Carcinoembryonic antigen (CEA) is a tumor marker used widely for detecting the recurrence and predicting the prognosis of colorectal cancer. This study investigates the possibility of serial measurement of serum CEA in several weeks after liver resection for colorectal liver metastases (CRLM) in detecting earlier detection of recurrence. METHODS: From 2007 to 2014, CEA levels were assessed at 1 week and at 2-3 weeks after curative-intent liver resection among a total of 240 patients with CRLM. The CEA half-life was calculated and patients were divided into two groups: those with a CEA half-life ≤10 days or normalized (Group S), and those with a CEA half-life >10 days or rising (Group L). RESULTS: The 1-, 3-, and 5-year overall survival rates in Group S versus Group L were 91.3% versus 83.3%, 64.0% versus 41.3%, and 44.2% versus 29.3%, respectively (P = 0.0079). Multivariate analysis revealed that resection of extrahepatic lesions, four or more lesions of liver metastases, and categorization in Group L were independent factors of rapid recurrence within 100 days. CONCLUSION: A CEA half-life >10 days or rising 1 month after curative-intent liver resection was associated with rapid recurrence of CRLM within 100 days. J. Surg. Oncol. 2016;113:463-468. © 2016 Wiley Periodicals, Inc.

No Need of Immediate Treatment for Hypovascular Tumors Associated with Hepatocellular Carcinoma.

BACKGROUND: Hypovascular tumors associated with hepatocellular carcinoma (HCC) can be diagnosed, but it remains unknown whether such lesions should be treated immediately. This study aimed to clarify the clinical significance of treating hypovascular liver nodules. METHODS: After diagnosis of hypovascular tumors smaller than 3 cm, 104 patients underwent liver resection immediately (Group 1), while 93 patients were placed under observation (Group 2). In Group 1, 98 patients were diagnosed as having HCC (Group 1'), while 80 patients in Group 2 underwent liver resection after vascularization or appearance of other hypervascular HCC (Group 2'), eight patients had been observed, and five patients could not undergo operation due to appearance of other multiple HCCs. To avoid lead time bias for tumor vascularization, survival rates of patients after diagnosis of hypovascular tumors as well as those after operation in the two groups were compared. RESULTS: After a median follow-up of 3.3 years (range 0.6-11.2), the 5-year overall survival rates after liver resection of Group 1' (74.8 %; 95 % CI 64.3-86.1) was significantly higher than that of Group 2' (59.2 %; 46.4-75.6; P = 0.027). However, the 5-year overall survival rates after diagnosis of hypovascular liver nodules of Group 1' (74.7 %; 66.1-85.0) was not significantly different from that of Group 2' (77.1 %; 67.0-88.6; P = 0.761). Consequently, the 5-year overall survival rate after diagnosis of Group 2 (75.6 %; 64.7-83.1) was not significantly different from that of Group 1 (73.2 %; 67.5-86.1; P = 0.591) by intention-to-treat analysis. CONCLUSIONS: It is not necessary to treat hypovascular liver tumors immediately after diagnosis.

Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation. METHODS: We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov, number NCT00692770. FINDINGS: We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12·5 months (IQR 2·6-35·8) and 577 mg per day (SD 212·8) for sorafenib, compared with 22·2 months (8·1-38·8) and 778·0 mg per day (79·8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8·5 months (IQR 2·9-19·5) in the sorafenib group and 8·4 months (2·9-19·8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33·3 months in the sorafenib group vs 33·7 months in the placebo group; hazard ratio [HR] 0·940; 95% CI 0·780-1·134; one-sided p=0·26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 [28%] of 559 patients in the sorafenib group vs four [<1%] of 548 patients in the placebo group) and diarrhoea (36 [6%] vs five [<1%] in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten [2%]), abnormal hepatic function (four [<1%]), and fatigue (three [<1%]). There were four (<1%) drug-related deaths in the sorafenib group and two (<1%) in the placebo group. INTERPRETATION: Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation.

The Feasibility of Third or More Repeat Hepatectomy for Recurrent Hepatocellular Carcinoma.

OBJECTIVES: To investigate the feasibility and prognostic benefits of third or more hepatectomy (third or more Hx) for recurrent hepatocellular carcinoma. BACKGROUND: Second hepatectomy (second Hx) has been accepted as an effective treatment of recurrent hepatocellular carcinoma after first hepatectomy (first Hx). However, the feasibility and efficacy of third or more Hx have not been adequately assessed. METHODS: Data were reviewed from 1340 patients with hepatocellular carcinoma who underwent curative hepatectomy. Among them, 941, 289, and 110 underwent first Hx, second Hx, and third or more Hx, respectively. Surgical outcomes and long-term survival were compared among the groups. RESULTS: Surgical duration was significantly longer in third or more Hx (median, 6.4 hours) than in second Hx (median, 5.9 hours). Postoperative bile leakage and wound infection were more frequently observed in third or more Hx versus second Hx (12.5% vs 6.2%, [P = 0.04] and 2.9% vs 0.4% [P = 0.03], respectively). Three and 5-year disease-free survival rates were 36.8% and 27.1% in first Hx, 24.4% and 17.9 % in second Hx, and 26.1% and 12.8% in third or more Hx, respectively (P < 0.01 [first Hx vs third Hx], P = 0.95 [second Hx vs third or more Hx]). The 5-year overall survival rates from each resection were similar among the groups (65.3%, 60.5%, 68.2%, respectively). The 5- and 10-year overall survival rates from initial hepatectomy in patients who received third or more Hx were 91.4% and 75.5%, respectively. CONCLUSIONS: Third or more Hx is technically demanding in terms of surgical duration and morbidity compared with second Hx. However, aggressive repeat resection offers a survival similar to second Hx, leading to cumulative long-term survival from initial resection.

Living donor liver transplantation using a graft with periportal fibrosis.

A 57-year-old woman with familial amyloid polyneuropathy (FAP) was scheduled to undergo living donor liver transplantation (LDLT), but the operation was cancelled because the only potential donor had chronic alcohol-related liver disease. One year later, FAP-related neurological symptoms progressed rapidly, and emergency LDLT was planned. The donor's hepatic function had returned to normal range after 1 year of abstinence. The left liver graft volume was equivalent to 37.7% of the standard liver volume (SLV) of the recipient. However, a liver biopsy revealed mild fibrosis (score, F1). LDLT was successfully performed without any complications. The recipient's neurological findings returned to normal. One year after LDLT, the liver graft volume was equivalent to approximately 90% of the SLV, and the fibrosis had improved. LDLT using a graft with a fibrosis score of up to F1 may be an acceptable alternative for recipients with normal hepatic function.

Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines).

The 3rd version of Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine, which was published in October 2013 in Japanese. Here, we briefly describe new or changed recommendations with a special reference to the two algorithms for surveillance, diagnosis, and treatment.