Liver resection is associated with good outcomes for hepatocellular carcinoma patients beyond the Barcelona Clinic Liver Cancer criteria: A multicenter study with the Hiroshima Surgical study group of Clinical Oncology.

BACKGROUND: Liver resection for hepatocellular carcinoma beyond the Barcelona Clinic Liver Cancer criteria remains controversial. Strict candidate selection is crucial to achieve optimal results in this population. This study explored postoperative outcomes and developed a preoperative predictive formula to identify patients most likely to benefit from liver resection. METHODS: In total, 382 patients who underwent liver resection for hepatocellular carcinoma beyond the Barcelona Clinic Liver Cancer resection criteria between 2000 and 2017 were identified from a multicenter database with the Hiroshima Surgical study group of Clinical Oncology. An overall survival prediction model was developed, and patients were classified by risk status. RESULTS: The 5-year overall survival after curative resection was 50.0%. Overall survival multivariate analysis identified that a high a-fetoprotein level, macrovascular invasion, and high total tumor burden were independent prognostic risk factors; these factors were used to formulate risk scores. Patients were divided into low-, moderate-, and high-risk groups; the 5-year overall survival was 65.7%, 49.5%, and 17.0% (P < .001), and the 5-year recurrence-free survival was 31.3%, 26.2%, and 0%, respectively (P < .001). The model performance was good (C-index, 0.76). Both the early and extrahepatic recurrence increased with higher risk score. CONCLUSION: The prognosis of patients with hepatocellular carcinoma beyond the Barcelona Clinic Liver Cancer resection criteria depended on a high a-fetoprotein level, macrovascular invasion, and high total tumor burden, and risk scores based on these factors stratified the prognoses. Liver resection should be considered in patients with hepatocellular carcinoma beyond the Barcelona Clinic Liver Cancer criteria with a low or moderate-risk score.

A multicenter randomized controlled trial comparing administration of antithrombin III after liver resection (HiSCO-05 trial).

BACKGROUND: Posthepatectomy liver failure is a poor prognostic factor after hepatectomy. Various preventive treatments have been tried; however, there are no clinical trials that use posthepatectomy liver failure as the primary endpoint, and the clinical effects of posthepatectomy liver failure have not been fully verified. The aim of this study was to investigate whether administration of antithrombin III can prevent posthepatectomy liver failure in patients with coagulopathy after hepatectomy. This study also evaluated the safety of AT-III administration after hepatectomy. METHODS: The current study enrolled 141 patients diagnosed with coagulopathy after hepatectomy between October 2015 and September 2018 at 7 hospitals in Hiroshima, Japan (HiSCO group). Patients were randomized to undergo either administration of antithrombin III (n = 64) or non-administration (n = 77). The primary endpoint was the incidence of posthepatectomy liver failure. This randomized controlled trial was registered with the University Medical Information Network Clinical Trial Registry (UMIN000018852). RESULTS: Treatment for postoperative coagulopathy was performed safely without adverse events. The incidence of posthepatectomy liver failure was similar in both treatment groups (nonadministration of antithrombin III group, 28.5%, versus administration of antithrombin III group, 28.1%; P = .953) The rate of morbidity was higher in the administration group than the non-administrated group (17.2% vs 11.7%, P = .351). Following the multivariate analysis of the whole study group, body mass index ≥25, total bilirubin ≥1.5 mg/dL, and the disseminated intravascular coagulation score ≥5 postoperatively were the independent risk factors for posthepatectomy liver failure. CONCLUSION: This study showed that the administration of antithrombin III resulted in no significant difference in preventing posthepatectomy liver failure, possibly through suppressing coagulopathy.

A novel model for predicting posthepatectomy liver failure based on liver function and degree of liver resection in patients with hepatocellular carcinoma.

BACKGROUND: The permissible liver resection rate for preventing posthepatectomy liver failure (PHLF) remains unclear. We aimed to develop a novel PHLF-predicting model and to strategize hepatectomy for hepatocellular carcinoma (HCC). METHODS: This retrospective study included 335 HCC patients who underwent anatomical hepatectomy at eight institutions between 2013 and 2017. Risk factors, including volume-associated liver-estimating parameters, for PHLF grade B-C were analyzed in a training set (n = 122) via multivariate analysis, and a PHLF prediction model was developed. The utility of the model was evaluated in a validation set (n = 213). RESULTS: Our model was based on the three independent risk factors for PHLF identified in the training set: volume-associated indocyanine green retention rate at 15 min, platelet count, and prothrombin time index (the VIPP score). The areas under the receiver operating characteristic curve of the VIPP scores for severe PHLF in the training and validation sets were 0.864 and 0.794, respectively. In both sets, the VIPP score stratified patients at risk for severe PHLF, with a score of 3 (specificity, 0.92) indicating higher risk. CONCLUSION: Our model facilitates the selection of the appropriate hepatectomy procedure by providing permissible liver resection rates based on VIPP scores.

Laparoscopic versus open limited liver resection for hepatocellular carcinoma with liver cirrhosis: a propensity score matching study with the Hiroshima Surgical study group of Clinical Oncology (HiSCO).

BACKGROUND: Laparoscopic liver resection (LLR) has evolved as a safe and effective alternative to conventional open liver resection (OLR) for malignant lesions. However, LLR in cirrhotic patients remains challenging. This study analyzed the perioperative and oncological outcomes of LLR for hepatocellular carcinoma (HCC) with cirrhosis compared with OLR using propensity score matching. METHODS: A multicenter retrospective analysis of records of patients who underwent limited liver resection for HCC and were histologically diagnosed with liver cirrhosis between January 2009 and December 2017 in the eight institutions belonging to the Hiroshima Surgical study group of Clinical Oncology was performed. The patients were divided into two groups: the LLR and OLR groups. After propensity score matching, we compared clinicopathological features and outcomes. RESULTS: In total 256 patients with histological liver cirrhosis who underwent limited liver resection for HCC were included in this study; 58 patients had undergone LLR, and the remaining 198 patients OLR. The number of tumors was higher, tumor size was larger, and difficulty score was significantly higher in the OLR group before propensity matching. After the matching, the data of the well-matched 58 patients in each group were evaluated; the intraoperative blood loss was lower in the LLR group (p = 0.004), and incidence of the postoperative complications was significantly higher in the OLR group (p = 0.019). The duration of the postoperative hospital stay was significantly shorter in the LLR group (p < 0.001). There were no differences between two groups in overall survival and recurrent-free survival. CONCLUSIONS: LLR decreased the incidences of postoperative complications, shortened the duration of postoperative hospital stay. Thus, LLR is a safe and feasible procedure even in patients with cirrhosis.

Comparison of new prognostic systems for patients with resectable hepatocellular carcinoma: Albumin-Bilirubin grade and Albumin-Indocyanine Green Evaluation grade.

AIM: We aimed to compare the prognostic abilities of two novel liver function-estimating models, Albumin-Bilirubin (ALBI) and Albumin-Indocyanine Green Evaluation (ALICE) grades, in patients with hepatocellular carcinoma. METHODS: Data of 1270 patients who underwent initial hepatectomy for hepatocellular carcinoma between 1986 and 2016 were retrospectively collected from a multi-institutional database. The prognostic impact of each system was analyzed according to the results of the area under the receiver operating characteristic curve, the Cox regression model and the linear trend χ2 -test. RESULTS: The ALBI and ALICE scores, which were obtained before grading status, were significantly correlated (correlation coefficient 0.930; P < 0.001). Both ALBI and ALICE grades stratified well in terms of overall survival, and were found to be independent prognostic factors on multivariate analysis (P < 0.05). The area under the receiver operating characteristic curves for 5-year survival in both groups were equivalent (0.602 vs. 0.614, P = 0.402); however, homogeneity, discriminatory ability, and the Akaike information criterion were superior for the ALICE grade than for the ALBI grade (73.8 vs. 65.7, 43.4 vs. 34.9, and 7204.1 vs. 7212.2, respectively). CONCLUSIONS: Both grading systems could estimate the liver function of patients with hepatocellular carcinoma. Regarding hepatectomy patients, the ALICE grade was a more suitable model than the ALBI grade.

Therapeutic potential of propagated hepatocyte transplantation in liver failure.

BACKGROUND: This study aimed to evaluate the therapeutic potential of intrasplenic transplantation of culture-propagated homologous hepatocytes in rats suffering from acute liver failure (ALF). METHODS: ALF was induced in dipeptidyl peptidase IV-negative (DPPIV(-)) Fischer 344 rats by totally removing the two anterior liver lobes (68% of the liver) and ligating the pedicle of the right lobe (24% of the liver). Hepatocytes isolated from DPPIV(+) Fischer 344 rats were cultured for 11 d to propagate 3-fold, and the resulting hepatocytes were dubbed "culture-propagated hepatocytes (CPHEPs)". A total of 1.5 × 10(7) cells of CPHEPs were transplanted intrasplenically before ALF induction (CPHEP group). Similarly, freshly isolated hepatocytes (FIHEPs) were transplanted as a positive control (FIHEP group), and culture medium (CM) was injected into rats as a negative control (CM group). RESULTS: The survival of the CPHEP group was comparable to that of the FIHEP group and longer than that of the CM group (P < 0.01). Both CPHEP and FIHEP transplantation improved blood parameters such as ammonia, total bilirubin, glutamic pyruvic transaminase, and glutamic oxaloacetic transaminase; transplantation also affected liver tissue parameters such as apoptosis rate and bromodeoxyuridine-labeling index. CONCLUSIONS: Transplantation of culture-propagated homologous hepatocytes has a remarkable therapeutic potential for ALF in rats.

Efficient in vivo xenogeneic retroviral vector-mediated gene transduction into human hepatocytes.

We developed a method for efficient retroviral vector-mediated gene transfer into human hepatocytes, using a human hepatocyte-bearing mouse model. Normal human hepatocytes were transplanted into the livers of immunodeficient and liver-damaged mice. Donor hepatocytes multiplied and replaced the host hepatocytes, which yielded human hepatocyte-bearing mice (human hepatocyte-chimeric mice). As control cells, rat hepatocytes were similarly transplanted. The replacement level reached 86% at 8 weeks and 100% at 5 weeks posttransplantation of human and rat hepatocytes, respectively. Human and rat hepatocytes in the host liver showed a high bromodeoxyuridine-labeling index during the first 2 weeks posttransplantation. Human- and rat-chimeric mice were injected 7 and 10 days posttransplantation, respectively, with retroviral vectors carrying the beta-galactosidase gene and were thereafter injected daily for 20 and 10 days, respectively. The level of beta-galactosidase-positive hepatocytes in the human- and rat-chimeric mice reached 7.1 +/- 1.8% at 8 weeks and 5.3 +/- 0.9% at 5 weeks after transplantation, respectively. The human hepatocyte-chimeric mouse will be useful for testing the ability of vectors to transduce human cells.