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Introduction: Patients with hepatitis virus-related hepatocellular carcinoma (viral HCC) are decreasing as hepatitis control improves, but those with non-viral-related HCC (non-viral HCC) are increasing in Japan. No established surveillance system exists for patients with non-viral HCC, so they are often diagnosed at an advanced stage. To address this, we performed this study. Methods: We collected serum samples from 516 participants (154 healthy subjects, 93 chronic liver disease [CLD] patients without HCC, and 269 HCC patients). Participants were divided into a control group comprising healthy subjects and patients with CLD and an HCC group. We evaluated serum methylated HOXA1 (m-HOXA1) copy numbers using modified combined restriction digital PCR (CORD) assay (1-step CORD assay). We assessed diagnostic performance of m-HOXA1 compared to HCC tumor markers alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) and created a novel index to improve HCC prediction. Results: Serum m-HOXA1 level was significantly higher in each HCC stage group versus the control group. Its sensitivity was 69.1% and specificity was 78.5% for diagnosing HCC. The area under the curve (AUC) of m-HOXA1 was superior to that of AFP and equal to that of DCP. Multivariate logistic regression analysis revealed independent contributions of m-HOXA1, DCP, and AFP, in that order of strength, to diagnose HCC after adjustment for age and sex. We designated the predictive probability of HCC based on the regression model as the ASDAm-H1 (Age, Sex, DCP, AFP, and m-HOXA1) index. Its diagnostic accuracy was 0.96 by AUC with a sensitivity of 86.2% and specificity of 93.9%. Sensitivity was identical for viral and non-viral HCCs. When limited to early-stage HCC, sensitivity of the ASDAm-H1 index was 76.3%. Conclusions: We showed distinguished performance of the ASDAm-H1 index to detect viral and non-viral HCC, even at an early stage. This index might have potential as a non-viral HCC surveillance system. [ABSTRACT FROM AUTHOR]

Aim: Neoadjuvant transcatheter arterial chemoembolization (TACE) for large tumors is controversial, especially in the minimally invasive surgery era. The aim of this study was to compare features between groups treated with neoadjuvant TACE followed by surgery (TACE + surgery) or upfront surgery for hepatocellular carcinoma >5 cm. Methods: In this exploratory, multicenter, randomized phase I study, the primary measure was 2‐year disease‐free survival (DFS). Secondary measures were resection rate, necrosis rate by TACE, 2‐year overall survival, and site of recurrence. A total of 30 patients were randomly allocated to each arm. Results: The two arms did not differ in patient characteristics. The median time to surgery from randomization was 48 days for TACE + surgery and 29 for surgery only (p < 0.001). Postoperative morbidities did not differ between arms. The 2‐year DFS, overall survival, and resection rates were 56.7%, 80.0%, and 93.3%, respectively, in the TACE + surgery arm, and 56.1%, 89.9%, and 90.0% in the upfront surgery arm. Minimally invasive surgery was carried out in 35.7% in the TACE + surgery arm and in 29.6% in the upfront surgery arm. The median necrosis rate by TACE was 90.0%. In resected specimens, invasion to the hepatic vein was less with TACE + surgery (3.6% vs. 22.2%, p = 0.0380). In cases of 100% necrosis with TACE, 2‐year DFS was 100%. Site of recurrence did not differ between groups. Conclusion: Neoadjuvant TACE did not improve 2‐year DFS, and neoadjuvant TACE allowed delay of surgical treatment without increased morbidity and cancer progress. Clinical trial registration: UMIN: 000005241. [ABSTRACT FROM AUTHOR]

Introduction: The phase III REFLECT trial demonstrated that lenvatinib was superior to sorafenib in terms of progression-free survival (PFS), time to progression, and objective response rate (ORR) for patients with unresectable hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of preoperative lenvatinib therapy for patients with oncologically or technically unresectable HCC. Methods: In this multicenter single-arm phase II trial, patients with advanced HCC and factors suggestive of a poor prognosis (macroscopic vascular invasion, extrahepatic metastasis, or multinodular tumors) were enrolled. Patients with these factors, even with technically resectable HCC, were defined as oncologically unresectable because of the expected poor prognosis after surgery. After 8 weeks of lenvatinib therapy, the patients were assessed for resectability, and tumor resection was performed if the tumor was considered technically resectable. The primary endpoint was the surgical resection rate. The secondary endpoints were the macroscopic curative resection rate, overall survival (OS), ORR, PFS, and the change in the indocyanine green retention rate at 15 min as measured before and after lenvatinib therapy. The trial was registered with the Japan Registry of Clinical Trials (s031190057). Results: Between July 2019 and January 2021, 49 patients (42 oncologically unresectable patients and 7 technically unresectable patients) from 11 centers were enrolled. The ORR was 37.5% based on mRECIST and 12.5% based on RECIST version 1.1. Thirty-three patients underwent surgery (surgical resection rate: 67.3%) without perioperative mortality. The surgical resection rate was 76.2% for oncologically unresectable patients and 14.3% for technically unresectable patients. The 1-year OS rate and median PFS were 75.9% and 7.2 months, respectively, with a median follow-up period of 9.3 months. Conclusions: The relatively high surgical resection rate seen in this study suggests the safety and feasibility of lenvatinib therapy followed by surgical resection for patients with oncologically or technically unresectable HCC. [ABSTRACT FROM AUTHOR]

Background: Recent advancements in systemic therapy for hepatocellular carcinoma (HCC) necessitate the establishment of resectability criteria for advanced HCC. Methods: A questionnaire survey sought to clarify the perspectives of Japanese expert hepatobiliary surgeons regarding surgical indications for HCC. Thirty‐one questions were used to determine when surgery is strongly recommended (resectable: R) or not recommended (unresectable: UR). Results: A total of 351 responses were obtained. While 64.7% of the respondents considered solitary tumors as being R, irrespective of size, opinions diverged on the upper limit of the number of tumors/tumor size for R: (1) up to three nodules with no size limit (27.9%), (2) up to three nodules ≤5 cm in diameter each (21.4%) and (3) up to three nodules ≤3 cm in diameter each (19.4%). Vp1, Vp2, Vp3, and Vp4 were considered as being R by 90.9%, 70.7%, 39.0%, and 8.0% of respondents, respectively. Half of the respondents indicated they would consider resection even for cases with extrahepatic spread under limited conditions. Conclusions: The current views of Japanese expert surgeons on the resectability criteria for HCC were clarified for the first time. The findings could serve as a basis for preparing expert consensus statements on the resectability criteria for HCC. [ABSTRACT FROM AUTHOR]

Aim: Laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) located in the posterosuperior segments (PS) have generally been considered more difficult than those for HCC in anterolateral segments (AL), but may be safe and feasible for selected patients with accumulated experience. In the present study, we investigated the effectiveness of LLR for single nodular HCCs ≤3 cm located in PS. Methods: In total, 473 patients who underwent partial liver resection for single nodular HCCs ≤3 cm at the 18 institutions belonging to the Kyusyu Study Group of Liver Surgery from January 2010 to December 2018 were enrolled. The short‐term outcomes of laparoscopic partial liver resection and open liver resection (OLR) for HCCs ≤3 cm, with subgroup analysis of PS and AL, were compared using propensity score‐matching analysis. Furthermore, results were also compared between LLR‐PS and LLR‐AL. Results: The original cohort of patients with HCC ≤3 cm included 328 patients with LLR and 145 with OLR. After matching, 140 patients with LLR and 140 with OLR were analyzed. Significant differences were found between groups in terms of volume of blood loss (median, 55 vs. 287 ml, p < 0.001), postoperative complications (0.71 vs. 8.57%, p = 0.003), and postoperative hospital stay (median, 9 vs. 14 days, p < 0.001). The results of subgroup analysis of PS were similar. Short‐term outcomes did not differ significantly between LLR‐PS and LLR‐AL after matching. Conclusions: Laparoscopic partial resection could be the preferred option for single nodular HCCs ≤3 cm located in PS. [ABSTRACT FROM AUTHOR]

Background: A score derived from the concentrations of α‐fetoprotein (AFP) and des‐γ‐carboxy prothrombin (DCP) and tumor volume (TV), called ADV score, has been shown to be prognostic of hepatocellular carcinoma (HCC) recurrence following hepatic resection (HR) or liver transplantation. Methods: This multicenter, multinational validation study included 9200 patients who underwent HR from 2010 to 2017 at 10 Korean and 73 Japanese centers, and were followed up until 2020. Results: AFP, DCP, and TV showed weak correlations (ρ ≤.463, r ≤.189, p <.001). Disease‐free survival (DFS), overall survival (OS), and post‐recurrence survival rates were dependent on 1.0 log and 2.0 log intervals of ADV scores (p <.001). Receiver operating characteristic (ROC) curve analysis showed that ADV score cutoffs of 5.0 log for DFS and OS yielded the areas under the curve ≥.577, with both being significantly prognostic of tumor recurrence and patient mortality at 3 years. ADV score cutoffs of ADV 4.0 log and 8.0 log, derived through K‐adaptive partitioning method, showed higher prognostic contrasts in DFS and OS. ROC curve analysis showed that an ADV score cutoff of 4.2 log was suggestive of microvascular invasion, with both microvascular invasion and an ADV score cutoff of 4.2 log showing similar DFS rates. Conclusions: This international validation study demonstrated that ADV score is an integrated surrogate biomarker for post‐resection prognosis of HCC. Prognostic prediction using ADV score can provide reliable information that can assist in planning treatment of patients with different stages of HCC and guide individualized post‐resection follow‐up based on the relative risk of HCC recurrence. [ABSTRACT FROM AUTHOR]

The fifth version of the Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence‐based medicine and partly to the Grading of Recommendations Assessment, Development and Evaluation system, which was published in October 2021 in Japanese. In addition to surveillance–diagnostic and treatment algorithms, a new algorithm for systemic therapy has been created, as multiple drugs for hepatocellular carcinoma can be currently selected. Here, new or revised algorithms and evidence on which the recommendations are based are described. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aims to clarify the specific perioperative risk factors and short-term patient prognosis after central bisectionectomy (CB) for hepatocellular carcinoma (HCC). The specific operative risk factors for liver failure and increased blood loss in 142 HCC patients undergoing CB (H458) were tumor involvement in segment 1, tumor size exceeding 10 cm, and compression of the main vasculature. The three-year survival after CB was favorable and curable under precise preoperative simulations, elaborate techniques, and management. Large tumor size, surrounding tumor involvement, or compression to major vasculatures, and the related iBL were independent risk factors for severe morbidities in CB. These results showed the limits of up-front CB, which is useful information for deciding other novel non-operative treatments for conversion surgery. Background: This study aims to clarify the perioperative risk factors and short-term prognosis of central bisectionectomy (CB) for hepatocellular carcinoma (HCC). Methods: Surgical data from 142 selected patients out of 171 HCC patients who underwent anatomical CB (H458) between 2005 and 2020 were collected from 17 expert institutions in a single-arm retrospective study. Results: Morbidities recorded by the International Study Group of Liver Surgery (ISGLS) from grade BC post-hepatectomy liver failure (PHLF) and bile leakage (PHBL), or complications requiring intervention were observed in 37% of patients. A multivariate analysis showed that increased blood loss (iBL) > 1500 mL from PHLF (risk ratio [RR]: 2.79), albumin level < 4 g/dL for PHBL (RR, 2.99), involvement of segment 1, a large size > 6 cm, or compression of the hepatic venous confluence or cava by HCC for all severe complications (RR: 5.67, 3.75, 6.51, and 8.95, respectively) (p < 0.05) were significant parameters. Four patients (3%) died from PHLF. HCC recurred in 50% of 138 surviving patients. The three-year recurrence-free and overall survival rates were 48% and 81%, respectively. Conclusions: Large tumor size and surrounding tumor involvement, or compression of major vasculatures and the related iBL > 1500 mL were independent risk factors for severe morbidities in patients with HCC undergoing CB. [ABSTRACT FROM AUTHOR]

One of the most important areas of anatomical knowledge for liver surgery is the plate system in the hilar area. Four plates comprise the hilar area plate system: the hilar plate, cystic plate, umbilical plate, and Arantian plate. Based on the theory that the cystic plate is continuous with the hilar plate, isolation of the cystic plate can be applicable to various scenarios in liver surgery. We describe herein the procedure and usefulness of cystic plate isolation to approach the hilar plate, in both open and laparoscopic surgeries. This isolation can be applied in various manners. First, cystic plate traction can facilitate the Glissonian approach, drawing out the extrahepatic Glissonian pedicles and thus lengthening the pedicle, and facilitate isolation of these pedicles. Second, inflow control can be obtained by applying the cystic plate traction method to the Glissonian approach. This is suitable to control hepatic inflow when there is no need to divide vessels such as lymph node dissection or vascular resection and reconstruction. Third, the Glissonian approach can be used in surgery for hepatocellular carcinoma patients with portal thrombosis. The cystic plate traction method potentially avoids injury to the Glissonian pedicle that would cause unnecessary bleeding, and is thus particularly efficient for advanced cancers such as hepatocellular carcinoma patients with portal thrombosis and collateral vessels around the area of obstruction in the Glissonian sheath. In this article, we focused on our anatomical knowledge and technical tips for making use of cystic plate isolation in liver surgery. [ABSTRACT FROM AUTHOR]

Background: Cancer stem cells (CSCs) are thought to play important roles in carcinogenesis, recurrence, metastasis, and therapy-resistance. We have successfully induced cancer stem-like sphere cells (CSLCs) which possess enhanced chemoresistance and metastatic potential. To enable the development of targeted therapy against CSLCs, we identified a gene responsible for this phenotype in CSLC.Methods: Human hepatoma cell line SK-HEP-1 was used for CSLC induction with a unique sphere inducing medium, and HuH-7 cells were used as non-sphere forming cells in the same condition. RNA-sequencing was performed followed by validation with quantitative RT-PCR and western blotting. Knockdown experiments were done by using CRISPR-Cas9 genome-editing, and the rescue experiments were performed using the expressing plasmid vector. Chemoresistance and liver metastasis of the cells, was studied following the splenic injection of cells to severely immune deficient mice and evaluated using the MTS assay. Quantification of exosomes in the medium was done using ELISA.Results: RAB3B was identified as an up-regulated gene in both CSLCs and prognostically poor hepatocellular carcinoma (HCC) by RNA-sequencing. RAB3B-KD cells showed altered CSLC phenotypes such as sphere formation, chemoresistance, and metastatic potentials, and those were rescued by RAB3B complementation. Increased exosome secretion was observed in CSLCs, and it was not observed in the RAB3B-KD cells. In addition, the RAB3B expression correlated with the expression of ABCG2, APOE, LEPR, LXN, and TSPAN13.Conclusion: The up regulation of RAB3B may play an important role in the chemoresistance and metastatic potential of CSLCs. [ABSTRACT FROM AUTHOR]

The optimal treatment for hepatocellular carcinoma (HCC) should be selected based on tumor conditions, liver functional reserve, and performance status. Surgical treatment, such as liver resection and liver transplantation, is the most favorable treatment method; however, its indication criteria differ according to each country's guidelines. In Western countries, liver resection is indicated only for early-stage HCC patients with Barcelona-Clinic Liver Cancer staging classification (BCLC) 0/A. While in Asian countries, liver resection is one of the treatment options for advanced HCC, such as BCLC B/C. Recently, the treatment of HCC is about to enter a drastic transitional period. It started with the widespread use of minimally invasive surgery for HCC, followed by a high rate of hepatitis C virus eradication with the advent of direct acting antivirals and developing a multidisciplinary treatment for highly advanced HCC. As a result, the importance of liver resection for HCC is increasing, and it is time to reconsider the criteria for selecting treatment methods for HCC patients. This article outlines current topics in the surgical treatment of HCC. [ABSTRACT FROM AUTHOR]

Aim: The impact of sustained virologic response (SVR) on surgical outcomes for patients with hepatitis C virus (HCV)‐related hepatocellular carcinoma (HCC) remains controversial. This study aimed to evaluate the influence of SVR on long‐term surgical outcomes after hepatectomy. Methods: This multicenter study included 504 patients who underwent curative resection for HCV‐related HCC. Patients with a history of HCC treatment, HBV infection, poor liver function, and tumor with major vascular invasion were excluded. Long‐term surgical outcomes (overall survival [OS] and recurrence‐free survival [RFS]) among patients who achieved SVR before hepatectomy (Pre‐SVR group: 58 patients), after hepatectomy (Post‐SVR group: 54 patients), and without SVR (Non‐SVR group: 186 patients) were compared after adjusting for 13 confounding factors. Using the surgically resected specimens, comparison of the pathological changes in liver fibrosis between the first and second hepatectomy were analyzed. Results: Patients with SVR were younger, had better liver function, and less liver fibrosis compared to patients without SVR. Propensity score‐matched OS and RFS were significantly better in Pre‐SVR group than Non‐SVR group (P =.029 and P =.009, respectively). Inverse probability‐weighted OS and RFS were also significantly better in the Post‐SVR group (P =.001 and P =.021, respectively) than in the Non‐SVR group. Histopathological evaluation revealed that only the patients with SVR had regression of liver fibrosis (P <.05). Conclusion: Achievement of SVR before or after hepatectomy is essential for improving long‐term surgical outcomes in patients with HCV‐related HCC. [ABSTRACT FROM AUTHOR]

The optimal type of surgery (e.g., anatomic or non-anatomic resection) or radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is still under debate despite numerous comparative studies based on overall survival. This debate continues not only because these endpoints are influenced by non-surgical factors, such as liver function, but because the definition of non-anatomic resection for HCC has remained unclear. The optimal surgery could be logically determined based on the mechanism of local intrahepatic metastasis, that is, the drainage of tumour blood flow (TBF), because HCC spreads locally through tumour blood flowing to the peri-tumourous liver parenchyma. Since TBF is clearly demonstrated by CT scan under hepatic arteriography, the surgical margin can be determined individually based on the drainage of TBF without deteriorating local curability. Controversy regarding RFA and surgery does not result from the curability of treatment itself but from the lack of scientific evidence on safety margins. Based on proper concepts and self-evident truths, an algorithm of loco-regional treatment for HCC is proposed. [ABSTRACT FROM AUTHOR]

Our previous study reported the effectiveness of the product of tumor number and size (NxS factor) as a predictor of the prognosis of patients with hepatocellular carcinoma (HCC) following hepatectomy. The aim of the present study was to validate the prognostic value of scoring systems based on the NxS factor for HCC. The records of 940 patients who underwent hepatectomy for HCC at Osaka University Graduate School of Medicine and Osaka International Cancer Institute were analyzed. The discriminatory abilities of the mathematical integrated model for tumor staging (MITS) score, which combines the NxS factor with liver function, and known prognostic systems, including the Japan Integrated Staging system, the Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program and the Tokyo system, were compared. Firstly, the present study demonstrated that a higher NxS factor was associated with decreased disease-free survival (DFS) and overall survival (OS) in patients with HCC (P<0.05). Subsequently, univariate analysis of DFS and OS curves revealed significant differences among all NxS factor and liver damage combinations (MITS-LD score; score 0 vs. score 1; score 1 vs. score 2; score 2 vs. score 3; all P<0.05) and all NxS factor and albumin-bilirubin (ALBI) score combinations (MITS-ALBI score; score 0 vs. score 1; score 1 vs. score 2; score 2 vs. score 3; all P<0.05). Furthermore, multivariate Cox proportional hazards model analysis demonstrated that there were significant differences in DFS [Hazard Ratio (HR); score 0 vs. score 1 (1.48); score 1 vs. score 2 (1.27); score 2 vs. score 3 (1.64); all P<0.05] and OS [HR; score 0 vs. score 1 (1.34); score 1 vs. score 2 (1.29); score 2 vs. score 3 (1.64); all P<0.05] among patients with different MITS-LD scores, and there were significant differences in DFS [HR; score 0 vs. score 1 (1.38); score 1 vs. score 2 (1.43); score 2 vs. score 3 (1.60); all P<0.05] among patients with different MITS-ALBI scores. The NxS factor may be a comprehensive measure of tumor burden for predicting the prognosis of patients with HCC following liver resection, and MITS scores could be an improved scoring system for predicting the prognosis of patients with HCC after hepatectomy. [ABSTRACT FROM AUTHOR]

The fourth version of Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence‐based medicine and partly to the Grading of Recommendations Assessment, Development, and Evaluation system, which was published in October 2017 in Japanese. New or revised recommendations were described, herein, with a special reference to the surveillance, diagnostic, and treatment algorithms. [ABSTRACT FROM AUTHOR]

Management of multinodular hepatocellular carcinoma (HCC) in the intermediate Barcelona Clinic Liver Cancer (BCLC)-B stage is controversial. The aim of the present study as to identify the subgroup of patients with BCLC-B HCC who could benefit from liver resection. The present study retrospectively analyzed the outcomes of 65 patients (training cohort) who underwent liver resection for multinodular BCLC-B HCC. Cox's regression analysis was conducted to identify the independent prognostic factors for overall survival and to develop the prognostic score. As some authors have reported that maximum tumor size (cm) plus tumor number (N+S) is a prognostic factor in patients with BCLC-B HCC who undergo chemoembolization, the usefulness of this factor in patients who underwent liver resection was also evaluated. Subsequently, the validity of the prognostic score was assessed in an independent validation cohort (n=132). Multivariate analysis revealed that positivity for hepatitis C virus antibody (HCV-ab), platelet count ≤1010/l, N+S >8, and des-γ-carboxy prothrombin (DCP) >400 mAU/ml were independent prognostic factors for overall survival. The prognostic score differentiated two groups (≤2, ≥3) with distinct outcomes (median survival time 68.3 months vs. 29.1 months; P<0.0001). This result was confirmed in an external validation cohort. Therefore, surgery can promote long-term survival in patients with multinodular HCC although the indications for surgery are limited. HCV-Ab status, preoperative platelet count, DCP level and N+S may be useful for patient selection. [ABSTRACT FROM AUTHOR]

Aim: No effective therapies for extrahepatic metastases from hepatocellular carcinoma (HCC) have yet been identified. Previous studies suggested a potentially promising antitumor effect of combination therapy of S‐1, a novel oral dihydropyrimidine dehydrogenase inhibitor, and interferon (IFN)‐α. The present study aimed to investigate the clinical efficacy of single agent S‐1 and S‐1/IFN‐α for HCC patients with extrahepatic metastases in a randomized, open‐label, multicenter trial. Methods: A total of 103 patients with HCC with extrahepatic metastases were randomly assigned to the S‐1/IFN‐α group, receiving the combination of S‐1 and IFN‐α, or the S‐1 group, receiving the single agent of S‐1. Clinical efficacy and adverse events were compared between the two groups. Results: A total of 49 patients in the S‐1/IFN‐α group and 51 patients in the S‐1 group were included in the efficacy analysis. The response rate was 22.4% (11/49) in the S‐1/IFN‐α group and 13.7% (7/51) in the S‐1 group; there was no significant difference. Overall and progression‐free survival in the two groups were also not significantly different (1‐year overall survival 50.8% vs. 72.4%, median progression‐free survival 127 days vs. 157 days). The incidence of grade ≥3 adverse events in the S‐1/IFN‐α group was 62.7% (32/51), which tended to be higher than in the S‐1 group (43.1% [22/51]). Conclusions: Oncological outcomes in both treatment groups were favorable compared with previous reports, though there was no significant beneficial effect of adding IFN‐α to S‐1 for the treatment of HCC patients with extrahepatic metastases. [ABSTRACT FROM AUTHOR]

We previously reported the effectiveness of the product of tumor number and size (NxS factor) for the prognosis of hepatocellular carcinoma (HCC) in patients following hepatectomy. The present study aimed to propose a new score based on the NxS factor to predict HCC recurrence following hepatectomy. A total of 406 patients who underwent hepatectomy for HCC at Osaka University Graduate School of Medicine were retrospectively analyzed to develop the new score. Among clinicopathological factors, including the NxS factor, the marker subset that achieved the best performance for prediction of early recurrence was assessed, and a prognostic model for HCC recurrence after curative hepatectomy (REACH) was developed. As the validation set, 425 patients who underwent hepatectomy for HCC at Yamaguchi University Graduate School of Medicine and Shimonoseki Medical Center were analyzed, and the prognostic ability of the REACH score was compared with that of well-known staging systems. Following analysis, the REACH score was constructed using six covariates (NxS factor, microscopic hepatic vein invasion, differentiation, serum albumin, platelet count and indocyanine green retention rate at 15 min). In the validation set, the REACH score predicted early recurrence in 73 of 81 samples, with a sensitivity of 89% and a specificity of 58%. The area under the curve (AUC) of the receiver operating characteristic curve of the REACH score was 0.78 and 0.74, respectively, for 1- and 2-year recurrence after hepatectomy; each AUC was higher than that of any of the other staging systems. Survival analysis indicated the REACH score had the best predictive value in disease-free and overall survival. The present findings demonstrated that the REACH score may be used to classify patients with HCC into high- and low-risk of recurrence, and to predict subsequent survival following hepatic resection. [ABSTRACT FROM AUTHOR]

Purpose: The influence of allogenic blood transfusion on the postoperative outcomes of hepatocellular carcinoma (HCC) surgery remains controversial. This study aims to clarify the clinical impacts of perioperative allogenic blood transfusion on liver resection outcome in HCC patients. Methods: We analyzed data collected over 5 years for 642 patients who underwent hepatectomy for HCC at one of the five university hospitals. We investigated the impact of allogenic blood transfusion on postoperative outcome after surgery in all patients and in 74 matched pairs, using a propensity score. Results: Of the 642 patients, 198 (30.8%) received perioperative allogenic blood transfusion (AT group) and 444 (69.2%) did not (non-AT group). Overall survival was lower in the AT group than in the non-AT group in univariate ( P < 0.001) and multivariate analyses (risk ratio 1.521, P = 0.011). After matching the different distributions using propensity scores, perioperative blood transfusion was found to be a poor prognostic factor for HCC patients. Conclusions: In this multi-center study, perioperative blood transfusion was an independent factor for poor prognosis after curative surgery for primary HCC in the patient group and in pairs matched by propensity scores. [ABSTRACT FROM AUTHOR]

Aim Forkhead Box M1 (FoxM1) is a proliferation-specific transcription factor. In this study, we aimed to elucidate the clinicopathological and prognostic values of FoxM1 expression in human hepatocellular carcinoma (HCC) and correlate FoxM1 expression with various etiologies of liver diseases. We also investigated its therapeutic value in HCC. Methods We investigated the expression of FoxM1 in tumor tissues and adjacent non-tumor tissues of 79 Japanese HCC patients by quantitative real-time reverse transcription-polymerase chain reaction analysis. Depletion by siRNA or specific inhibition by siomycin A were also used to investigate the effect of FoxM1 inhibition on stem-like features of human HCC cells. Results Quantitative real-time reverse transcription-polymerase chain reaction analysis showed that tumor tissues displayed an approximately 14-fold increase in FoxM1 expression compared with adjacent non-tumor tissues. Interestingly, the expression levels of FoxM1in tumor tissues did not depend on the etiology of liver disease. The expression of FoxM1 in tumor tissues was associated with serum α-fetoprotein level, maximum tumor size, histological grade, TNM staging, and portal involvement. Kaplan-Meier analysis indicated that the high FoxM1 expression (≥median) group had a poor prognosis compared with the low FoxM1 expression (

The Barcelona Clinic Liver Cancer staging system recommends a tyrosine kinase inhibitor (sorafenib) as standard therapy in advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT). Sorafenib has been shown to prolong median overall survival (OS) by approximately 3 months in advanced HCC patients with PVTT (8.1 vs. 4.9 months). However, its clinical effectiveness is still controversial and standard treatment with sorafenib is not established in Japan. Surgical resection is considered a potentially curative treatment and provides an acceptable outcome for carefully selected patients. The surgical mortality rate in patients with PVTT who receive surgical resection ranges from 0% to 10%. The median survival time and 1-year OS rate in HCC patients with PVTT who undergo surgical resection have been found to range from 8 to 22 months and 21.7% to 69.6%, respectively. But improvement in therapeutic outcome is difficult with surgical treatment alone. Combination treatment in conjunction with such methods as transarterial chemoembolization, hepatic artery infusion chemotherapy, and radiotherapy has been found to improve the prognosis (median survival time, 11.5-37 months; 1-year OS rate, 46.8-100%). Yet, many problems remain, such as surgical indications and surgical techniques. After resolving these points, a multidisciplinary strategy based on surgical treatment should be established for advanced HCC with PVTT. [ABSTRACT FROM AUTHOR]

Background: In the present study, we conducted a multicenter nationwide survey to investigate the effects of preoperative fluorine‐18‐fluorodeoxyglucose (FDG) positron emission tomography (PET) on the prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). Methods: From 16 Japanese LT centers, data were collected on 182 recipients with HCC who underwent living donor liver transplantation (LDLT) between February 2005 and November 2013. PET‐positive status was defined as increased uptake of FDG in the tumor compared to the surrounding non‐tumor liver tissue. The median follow‐up after LDLT was 54.5 months (range 1–125 months). Results: Postoperative HCC recurrence occurred in 23 patients. Multivariate analysis revealed that exceeding the Milan criteria (MC), alpha‐fetoprotein (AFP) level ≥115 ng/ml, and PET‐positive status were significant and independent risk factors for recurrence. In the over‐MC group, a subgroup of patients with AFP level <115 ng/ml and PET‐negative status (n = 22) had a significantly lower 5‐year recurrence rate than the other patients (n = 27, 19% vs. 53%, P = 0.019). Conclusions: These results suggest that preoperative FDG‐PET status offers additional information on HCC recurrence risk after LT. Over‐MC patients with PET‐negative status and lower AFP level may achieve successful outcome comparable to that of within‐MC patients. Highlight To elucidate the efficacy of preoperative FDG‐PET in predicting HCC recurrence after living donor liver transplantation, Takada and colleagues investigated data of 182 recipients from 16 centers. Patients exceeding the Milan criteria with PET‐negative status and lower AFP levels achieved favorable outcomes comparable with those of patients within the Milan criteria. [ABSTRACT FROM AUTHOR]

Aim CD26 is a membrane glycoprotein that has multiple functions, including dipeptidyl peptidase IV activity. CD26 expression varies in different tumor types, and its role in tumor growth in hepatocellular carcinoma ( HCC) remains unclear. Methods CD26 expression levels were examined in resected HCC and surrounding non-cancerous lesions. The effect of CD26 knockdown on the cellular proliferation of HepG2 or Huh7 cells, both of which highly express CD26, was studied in vitro. Results CD26 mRNA expression levels were significantly increased in HCC compared with their surrounding non-cancerous lesions. We confirmed that various HCC cell lines, especially HepG2 and Huh7 cells, showed high expression levels of CD26. siRNA-mediated knockdown of CD26 suppressed hepatoma cell growth in vitro. CD26 knockdown induced cell cycle arrest through the upregulation of Cip/Kip family proteins, p21 in HepG2 cells and p27 in Huh7 cells. CD26 knockdown did not affect apoptosis, but it increased expressions of the pro-apoptotic proteins Bim and Bak and the anti-apoptotic protein Bcl-xL, suggesting an addiction of CD26 knockdown cells to Bcl-xL for survival. We thus treated CD26 knockdown cells with ABT-737, a Bcl-xL/-2/-w inhibitor, and observed that the synthetic lethal interaction of combined Bcl-xL and CD26 inhibition induced significant apoptosis and impaired cellular viability. Conclusion CD26 mRNA was overexpressed in HCC, and its inhibition suppressed cellular proliferation through cell cycle arrest. The combined use of CD26 knockdown with a Bcl-xL inhibitor further elicited substantial apoptosis and therefore may serve as a powerful anticancer combination therapy against HCC. [ABSTRACT FROM AUTHOR]

The significance of disseminated tumor cells (DTCs) in bone marrow (BM) on tumor recurrence has not been investigated in patients with hepatocellular carcinoma (HCC). The aim of the present study was to clarify the molecular characteristics of DTCs that affect postoperative recurrence based on microRNA (miRNA) expression profiles in clinical HCC patients undergoing curative resection. DTCs were prospectively collected from the BM of preoperative HCC patients using immunomagnetic beads and subjected to miRNA microarray analysis. Microarray analysis of nine HCC patients (n=5 patients with postoperative HCC recurrence, n=4 patients without HCC recurrence) demonstrated that miR-615-3p is significantly upregulated in the DTCs of patients with recurrence compared to the DTCs from patients without recurrence. In vitro experiments demonstrated that the miR-615-3p expression level is significantly correlated with malignant characteristics in HCC cells. These data suggest that miR-615-3p in DTCs may play an important role in postoperative HCC recurrence, which suggests that miR-615-3p is a potential target molecule for regulating postoperative HCC recurrence. [ABSTRACT FROM AUTHOR]

The incidence of advanced hepatocellular carcinoma (HCC) is increasing worldwide, and its prognosis is extremely poor. Interferon-alpha (IFN-α)/5-fluorouracil (5-FU) therapy is reportedly effective in some HCC patients. In the present study, to improve HCC prognosis, we identified the genes that are sensitizing to these agents. The screening strategy was dependent on the concentration of ribozymes that rendered HepG2 cells resistant to 5-FU by the repeated transfection of ribozymes into the cells. After 10 cycles of transfection, which was initiated by 5,902,875 sequences of a ribozyme library, three genes including protein kinase, adenosine monophosphate (AMP)-activated, gamma 2 non-catalytic subunit (PRKAG2); transforming growth factor-beta receptor II (TGFBR2); and exostosin 1 (EXT1) were identified as 5-FU-sensitizing genes. Adenovirus-mediated transfer of TGFBR2 and EXT1 enhanced IFN-α/5-FU-induced cytotoxicity as well as 5-FU, although the overexpression of these genes in the absence of IFN-α/5-FU did not induce cell death. This effect was also observed in a tumor xenograft model. The mechanisms of TGFBR2 and EXT1 include activation of the TGF-β signal and induction of endoplasmic reticulum stress, resulting in apoptosis. In HCC patients treated with IFN-α/5-FU therapy, the PRKAG2 mRNA level in HCC tissues was positively correlated with survival period, suggesting that PRKAG2 enhances the effect of IFN-α/5-FU and serves as a prognostic marker for IFN-α/5-FU therapy. In conclusion, we identified three genes that chemosensitize the effects of 5-FU and IFN-α/5-FU on HCC cells and demonstrated that PRKAG2 mRNA can serve as a prognostic marker for IFN-α/5-FU therapy. [ABSTRACT FROM AUTHOR]

Survival or disease-free survival is not considered an appropriate surrogate outcome for the locoregional curability (i.e. surgical margin) of hepatectomy for hepatocellular carcinoma because these are greatly influenced by non-metastatic factors like multicentric carcinogenesis ( MC) or liver function. Hepatocellular carcinoma metastasizes by hematogenous seeding; therefore, the tumor blood flow ( TBF) drainage area is a high-risk area for intrahepatic metastasis, and can be identified by computed tomography under hepatic arteriography and completely resected as part of the surgical margin. The TBF pattern is classified into marginal, portal vein or hypovascular types. Partial hepatectomies were mostly performed in patients with marginal or hypovascular type, whereas anatomical surgery was frequently performed in those with portal vein type. Pathologically, nodules inside the TBF drainage area were moderately or poorly differentiated carcinomas, suggesting intrahepatic metastasis. In contrast, those outside the drainage area were frequently solitary and contained well-differentiated carcinoma, which is consistent with MC. The pattern of tumor recurrences after TBF-based hepatectomy is divided into two distinct groups - 'a few nodules' and 'many nodules in multiple segments or extrahepatic' - indicating that intrahepatic recurrences develop from MC and from circulating tumor cells in peripheral blood, respectively. Anatomical resection has not shown a survival benefit over that of TBF-based partial hepatectomy. TBF-based hepatectomy enables us to preserve liver function without compromising locoregional curability. [ABSTRACT FROM AUTHOR]

Background/Aim: We previously reported the beneficial effects of a combination therapy of interferon (IFN)-α/5-fluorouracil (FU) for advanced hepatocellular carcinoma (HCC) with tumor thrombi in the major portal branches. This report describes the results of longer follow-up and includes more than twice the number of patients relative to the previous report; it also evaluates the clinical predictor on the response to the combination therapy and long-term survival. Methods: The study subjects were 102 patients with advanced HCC and tumor thrombi in the major branches of the portal vein (Vp3 or 4). They were treated with at least 2 courses of IFN-α/5-FU. Results: No major treatment-related complications were noted. In the 102 patients, 40 (39.2%) showed objective response [11 (10.8%) showed complete response, 29 (28.4%) partial response], 8 (7.9%) showed no response and 54 (52.9%) showed progressive disease. Conclusion: IFN-α/5-FU combination therapy is a promising modality for advanced HCC with tumor thrombi in the major portal branches. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Minimally invasive approaches for small liver tumors are desirable. We describe a single-incision laparoscopic hepatectomy (SILH) using total laparoscopic surgery (TLS) technique. SILH was performed to remove a solitary 2-cm hepatocellular carcinoma located at segment 3. The technique included a one-inch skin incision with three ports (one 12 mm and two of 5 mm each). The liver was sealed and dissected by three different devices: Harmonic scalpel, TissueLink sealing dissector, and Endoclip. Operation time was 70 minutes and blood loss was trivial. The patient required no analgesia postoperatively and walked unaided the next day. Various aspects of the procedure were not different from TLS. SILH is a safe procedure with several advantages. The procedure is promising as minimally invasive liver surgery. [ABSTRACT FROM AUTHOR]

Aim: Metastasis to gallbladder (GB) from hepatocellular carcinoma (HCC) is rare, and it is difficult to determine indications for surgery. We report eight cases of synchronous isolated GB metastasis, and analyze their features retrospectively. Methods: Among 439 HCC patients who underwent hepatectomy from 1998 to 2008 at our institution, 393 (89.5%) underwent concurrent cholecystectomy. Results: Among them, eight (1.8%) had GB metastasis without other distant metastases. None of these cases showed evidence of direct invasion. All cases had advanced portal vein thrombus (PVTT) and their main tumor located near the GB bed. Five cases had apparent tumor mass in the GB wall, and the other three cases had only tumor thrombus in the GB veins. Six cases were treated postoperatively with local infusion therapy with interferon, and three of them showed long-term survival. Conclusion: Our eight cases of GB metastasis from HCC were closely related to PVTT. Surgical resection and multimodal treatment would be necessary for long-term survival in cases with isolated GB metastasis. [ABSTRACT FROM AUTHOR]

Because of the difficulties of low sensitivity for anticancer agents and giving a sufficient dose because of chronic liver dysfunction, chemotherapy may not play a central role in the treatment of hepatocellular carcinoma (HCC), especially those with liver cirrhosis. However, chemotherapy must be one of the important possibilities of multimodal treatment for advanced HCC, for which hepatic resection, percutaneous ablation, transcatheter arterial embolization and other general therapies would not be effective or even possible. Also, intraarterial perfusion chemotherapy is a common therapy for HCC and it is not difficult to maintain; but the effective rate is not sufficient. Recently, the combination therapy of subcutaneous interferon (IFN)-α and intraarterial 5-fluorouracil (5-FU) showed an outstanding response rate for intractable HCC (with portal vein thrombosis). In addition, recent preclinical and clinical studies have revealed that the mechanism of combination therapy may concern direct antitumor effects (through cell-cycle arrest and induction of apoptosis) and indirect actions (through immunocompetent cells and antiangiogenic effect). For the further advance of HCC treatment and prognosis, this therapy might be a promising treatment modality and is expected to develop. In this review, we summarize recent clinical and preclinical data regarding IFN-α and 5-FU combination therapy and discuss the further prospects of this therapy. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article details a study which examined the efficacy of interferon (IFN)-α/5-fluorouracil (5-FU) combination therapy in patients diagnosed with advanced hepatocellular carcinoma (HCC). The study included 30 patients with advanced HCC, tumor thrombi in the main trunk of portal vein and multiple nodules in the liver. It concluded that adjunct IFN/5 FU treatment regiment is effective for patients with advanced HCC, tumor thrombi in the main trunk of portal vein and multiple nodules in the liver.