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This study aimed to evaluate the correlation between adverse events (AEs) and overall survival (OS) in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab (atezo/beva). This was a multicenter study in which 130 patients were enrolled. Hypertension and skin disorders had a significant correlation with longer survival (median survival time (MST): not reached vs. 14.3 months and not reached vs. 14.8 months, p = 0.001 and p = 0.047, respectively). In contrast, liver injuries were significantly correlated with shorter survival (MST: 14.7 months vs. not reached, p = 0.036), and the median development time was 21 days. In a logistic regression analysis, fatigue ≥ grade 2, liver injury ≥ grade 3, and modified albumin–bilirubin grade 2b were identified as independent factors for discontinuation due to AEs. The OS in the no discontinuation due to AE group was significantly longer than that in the discontinuation due to AEs group (MST not reached vs. 11.2 months, p = 0.001). We concluded that the development of liver injury was a negative factor for OS and that we should be vigilant in monitoring AE during atezo/beva treatments.

Background & Aims: Intermediate hepatocellular carcinoma (HCC) treatment has become complicated due to the development of various molecular-targeted agents (MTAs). We aimed to determine whether the administration of MTAs in patients with intermediate-stage HCC contributed to the prevention of progression to an advanced stage. Methods: We enrolled and retrospectively examined 289 patients with Child-Pugh class A who had been diagnosed with intermediate-stage HCC and underwent initial trans-arterial chemoembolization (TACE). Patients were classified into 2 groups: a group in which MTAs were administered to patients whose condition was refractory to TACE (n = 65) and a group in which MTAs were not administered (n = 65) at intermediate-stage HCC after propensity score matching (PSM). Time to stage progression (TTSP) and overall survival (OS) were calculated using the Kaplan-Meier method and analyzed using a log-rank test after PSM. Results: TTSP and OS of the group with MTA administration were significantly longer than those of the group without MTA administration (TTSP: 36.4 vs. 17.9 months, p < 0.001; median survival time [MST]: 44.6 vs. 26.6 months, p = 0.001). Within the up-to-seven criteria and administration of MTAs at the intermediate-stage HCC were identified as independent factors for TTSP and OS in the multivariate analysis. TTSP and OS in the era of the multi-MTA group were significantly longer than those in the era of the mono-MTA group (TTSP: 44.8 vs. 27.4 months, p = 0.01; MST: 53.4 vs. 33.3 months, p = 0.01). Conclusion: The administration of MTAs in patients with intermediate-stage HCC contributes to the prevention of stage progression and prolongs OS.

It remains unclear whether hepatocellular carcinoma (HCC) recurrence in hepatitis C virus (HCV)-infected patients can be suppressed by the elimination of the virus using direct-acting antivirals (DAAs) after radical HCC treatment. We evaluated the sustained inhibitory effect of DAAs on HCC recurrence after curative treatment. This multicenter retrospective study included 190 HCV-positive patients after radical treatment for early-stage HCC. Patients were classified into the DAA treatment group (n = 70) and the non-DAA treatment group (n = 120) after HCC treatment. After propensity score matching (PSM), 112 patients were assessed for first and second recurrences using the Kaplan–Meier method and analyzed using a log-rank test. The first recurrence rates at 1 and 3 years were 3.6% and 42.1% in the DAA treatment group and 21.7% and 61.9% in the non-DAA treatment group, respectively (p = 0.0026). Among 85 patients who received radical treatment, the second recurrence rate at 3 years was 2.2% in the DAA treatment group and 33.9% in the non-DAA treatment group (p = 0.0128). In HCV-positive patients with early-stage HCC, the first and second recurrences were suppressed by DAA therapy after radical treatment, suggesting that the inhibitory effect of DAA therapy on HCC recurrence was sustained.

The aim of the present study was to investigate whether the degree of contrast enhancement on contrast-enhanced (CE)-CT can predict the prognosis of patients with hepatocellular carcinoma (HCC) treated with lenvatinib (LEN). A total of 67 consecutive patients with LEN-treated HCC were retrospectively analysed. In the pretreatment CE-CT, the CT values were measured using a region of interest within the main nodule and the liver parenchyma in the arterial phase, and the macroscopic degree of contrast enhancement of the tumour area was quantified by calculating the enhancement ratio (ER) of the liver parenchyma. The associations of pretreatment ER with progression-free survival (PFS) and overall survival (OS) were then investigated. There were 20, 27 and 20 patients in the ER ≥1.5, 1.0≤ ER

Highlight • Sorafenib plus MC S-1 chemotherapy can be safely used in patients with advanced HCC. • Combination of the metronomic chemotherapy enhanced anti-angiogenic effects, leading a stronger tumor hypoxic environment. • Strong intra tumoral hypoxia increased tumor cell apoptosis and reduced tumor cells proliferation., Objective Although sorafenib, a molecular targeted agent, has survival benefits for advanced hepatocellular carcinoma (HCC) patients, its disease control rate remains limited. To explore the potential for augmenting its antitumor effect, we assessed the preclinical and clinical efficacy and tolerability of S-1 metronomic chemotherapy (MC) plus sorafenib. Methods Antitumor effects and toxicity of this combination were tested with HAK-1B xenograft and spontaneous HCC mouse models, and a prospective pilot study was performed to compare therapeutic effects and safety between sorafenib plus MC S-1 for 12 advanced HCC cases and the historical control of 363 sorafenib-treated advanced HCC patients at our hospital from July 2011 to June 2015. Results In mice, the combination chemotherapy enhanced anti-angiogenic effects, resulting in a stronger tumor hypoxic environment and increased tumor cell apoptosis. Clinically, the objective response rate of the combination chemotherapy was higher than that of sorafenib mono therapy (16.7%; 2/12 vs 5.2%; 19/363, p

Fontan-associated liver disease (FALD) caused by long-term systemic venous congestion following the Fontan procedure may eventually lead to hepatocellular carcinoma (HCC). Treatment strategies for HCC due to FALD (FALD-HCC) remain unclear. We herein report a 35-year-old man with FALD-HCC that was well controlled by 3 cycles of continuous infusion of 5-fluorouracil and low-dose cisplatin (low-dose FP therapy) combined with 60 Gy of radiation therapy. However, the patient ultimately died of extrahepatic metastases. A pathological autopsy revealed more than 90% necrosis in the primary HCC lesion. This case suggests that low-dose FP therapy might be effective in FALD-HCC.

Given that the outcome of hepatic arterial infusion chemotherapy (HAIC) with cisplatin for intrahepatic advanced hepatocellular carcinoma (HCC) is unclear, we aimed to compare prognostic factors for overall survival (OS) following HAIC with cisplatin versus sorafenib for intrahepatic advanced HCC using propensity score-matched analysis. We enrolled 331 patients with intrahepatic advanced HCC who received HAIC with cisplatin (n = 88) or sorafenib (n = 243) between June 2006 and March 2020. No significant difference was observed in OS between HAIC with cisplatin and sorafenib cohorts (median survival time [MST]: 14.0 vs. 12.3 months, p = 0.0721). To reduce confounding effects, 166 patients were selected using propensity score-matched analysis (n = 83 for each treatment). HAIC with cisplatin significantly prolonged OS compared with sorafenib (MST: 15.6 vs. 11.0 months, p = 0.0157). Following stratification according to the Child-Pugh classification, for patients with class A (MST: 24.0 vs. 15.0 months, p = 0.0145), HAIC with cisplatin rather than sorafenib significantly prolonged OS. Our findings suggest that HAIC with cisplatin demonstrates longer prognostic effects than sorafenib in intrahepatic advanced HCC.

Macroscopic vascular invasion (MVI) is a poor prognostic factor in hepatocellular carcinoma (HCC). Hepatic arterial infusion chemotherapy (HAIC) is a promising treatment in MVI-HCC. However, it is not clear which regimens are suitable for HAIC. In this study, we aimed to compare the therapeutic effects between New FP (a fine-powder cisplatin suspended with lipiodol plus 5-fluorouracil) and low dose FP (LFP/cisplatin plus 5-fluorouracil) in the treatment of MVI-HCC patients with Child–Pugh class A. New FP is a regimen that consists of a fine-powder cisplatin suspended with lipiodol and 5-fluorouracil. Fifty-one patients were treated with LFP, and 99 patients were New FP. We compared the therapeutic effects of LFP and New FP and assessed factors that associated with the therapeutic effects. The median survival and progression-free survival times of LFP and New FP were 16.1/24.7 and 5.4/8.8 months, respectively (p &lt, 0.05, p &lt, 0.05). The complete response (29％) and objective response rate (76%) of New FP were significantly higher than those of LFP (p &lt, 0.001, p &lt, 0.01). Factors associated with better therapeutic response were better ALBI-grade and New FP treatment choice. New FP is a more powerful regimen than LFP in HAIC for MVI-HCC. New FP represents a recommended HAIC regimen for the treatment of patients with MVI-HCC.

Background Invasion beyond inferior vena cava (IVC) to right atrium (RA) is a rare complication in patients with advanced hepatocellular carcinoma (HCC), and results in fatal oncologic emergencies, including pulmonary embolism and right heart failure. Aim As there is no gold standard treatment for unresectable HCC with tumor thrombi involving IVC and RA, we considered it valuable to assess safety and efficacy of a combination of hepatic arterial infusion chemoembolization (HAIC) therapy and external-beam radiation therapy (EBRT). Methods and results The "New FP" was chosen as the HAIC therapy, in which the enhanced permeation and retention effect was achieved using a cisplatin-Lipiodol suspension combined with continuous infusion of 5-fluorouracil (5-FU). Sixteen patients with HCC with tumor thrombi in IVC, RA, and pulmonary arteries were enrolled. modified response evaluation criteria in solid tumors-based evaluation of response to the combination treatment was as follows: complete response, 6.2% (1 patient); partial response, 81.3% (13 patients); stable disease, 12.5% (2 patients); progressive disease, 0%. The median overall survival time (MST) was 19.0 months. Notably, MST of patients receiving sequential sorafenib monotherapy (39.0 months) was significantly longer than that of the rest (15.3 months). Conclusion The combination of New FP and EBRT is an efficacious treatment option for unresectable HCC involving IVC and RA, complicated with pulmonary embolism. Sequential administration of molecular-targeted drugs may prolong survival in such patients.

Background A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79–1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported. Methods The intent-to-treat population enrolled in Japan was analyzed. Results Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62–1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm. Conclusions The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC. Trial registration ID ClinicalTrials.gov. No. NCT01761266.

Background & Aims Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040. Methods CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018. Results There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations. Conclusion Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients. Lay summary The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878.

Background The antitumor effect of a drug is considered to be associated with a decrease in tumor blood flow. Aims We investigated whether the efficacy of lenvatinib (LEN) could be accurately assessed by measuring blood flow in hepatocellular carcinoma (HCC) during early treatment stages. Methods and results Blood flow changes and treatment results of 19 patients who underwent contrast-enhanced ultrasound (CEUS), before and after LEN administration, in Kurume University Hospital from July 2018 to June 2020 were examined. Blood flow was evaluated after the intravenous administration of perflubutane (0.015 ml/kg). The vascular phase was photographed and used as RAW data, and time-intensity curve analysis was used to obtain the region of interest (ROI) on the entire tumor nodule and quantify tumor blood flow. The evaluation was performed before and 1 and 4 weeks after LEN administration. Mean ± standard deviation (SD) values of the brightness of blood flow in the background liver before and 1 and 4 weeks after LEN administration were 2.84 × 10-4 ± 2.94 × 10-4 , 3.07 × 10-4 ± 3.79 × 10-4 , and 10.0 × 10-4 ± 20.8 × 10-4 dB, respectively. Blood flow in the background liver did not significantly decrease at 1 and 4 weeks compared with that before treatment. Mean ± SD values of the brightness of blood flow in HCC before and 1 and 4 weeks after administration were 3.49 × 10-3 ± 4.58 × 10-3 , 1.16 × 10-3 ± 1.57 × 10-3 , and 6.39 × 10-3 ± 22.8 × 10-3 dB, respectively. Blood flow in HCC after 1 week was significantly lower than that before administration (p = .0192). The therapeutic effects were significantly higher in the group with ≥50% blood flow reduction in HCC at 1 week after administration (p = .0038) and the group with reduced blood flow in HCC at 4 weeks after administration (p = .0051) than those before administration. Conclusion Early blood flow evaluation by CEUS may be useful in predicting the therapeutic effect of LEN for unresectable advanced HCC.

BACKROUND: Not all patients with hepatocellular carcinoma (HCC) benefit from treatment with molecular targeted agents such as sorafenib. We investigated whether New-FP (fine-powder cisplatin and 5-fluorouracil), a hepatic arterial infusion chemotherapy regimen, is more favorable than sorafenib as an initial treatment for locally progressed HCC. METHODS: To avoid selection bias, we corrected the data from different facilities that did or did not perform New-FP therapy. In total, 1709 consecutive patients with HCC initially treated with New-FP or sorafenib, 1624 (New-FP, n = 644, sorafenib n = 980) were assessed. After propensity score matching (PSM), overall survival (OS) and prognostic factors were assessed (n = 344 each). Additionally, the patients were categorized into four groups: cohort-1 [(without macrovascular invasion (MVI) and extrahepatic spread (EHS)], cohort-2 (with MVI), cohort-3 (with EHS), and cohort-4 (with MVI and EHS) to clarify the efficacy of each treatment. RESULTS: New-FP prolonged OS than sorafenib after PSM (New-FP, 12 months, sorafenib, 7.9 months, p &lt, 0.001). Sorafenib treatment, and severe MVI and EHS were poor prognostic factors. In the subgroup analyses, the OS was significantly longer the New-FP group in cohort-2. CONCLUSIONS: Local treatment using New-FP is a potentially superior initial treatment compared with sorafenib as a multidisciplinary treatment in locally progressed HCC without EHS.

The aim of the present study was to evaluate the effects of switching to tenofovir alafenamide (TAF) in patients who had received a nucleos(t)ide analog (NA) for the treatment of chronic hepatitis B (CHB). The data from 33 Japanese patients with CHB who received TAF therapy after using NA [adefovir dipivoxil (ADV) and/or tenofovir disoproxil fumarate (TDF)] were retrospectively analyzed. Specifically, the biochemical and virological markers from the start of the TAF treatment to 6 months later were assessed. Comparative evaluation was performed by dividing patients into two groups: Long-term (n=19) and short-term administration groups (n=14), with a cutoff administration duration of 10 years. In all 33 patients, the levels of serum hepatitis B surface antigen (HBsAg; 1,126±1,724 to 1,001±1,591 IU/ml; P

Background/aim Assessment of the biological behavior of tumors is important for choosing an appropriate cancer therapy. In hepatocellular carcinoma (HCC), the biological behaviour can be assessed by tumor morphology and molecular biology. This study investigated the usefulness of tumor tissue biopsy for predicting the biological behavior of HCC. Patients and methods We studied 43 patients who underwent hepatectomy and preoperative liver tumor biopsy for HCC. We performed clinicopathological and immunohistochemical (IHC) analyses. The expression of the following molecules was examined: regulator of G-protein signaling 5 (RGS5), glypican-3 (GPC3), keratin 19 (K19), epithelial cell adhesion molecule (EpCAM), protein induced by vitamin K absence or antagonist-II (PIVKA-II), β-Catenin, and p53. Results There was an overall 83.7% agreement regarding tumor differentiation between the preoperative biopsy specimens and the resected specimens. The accuracy of IHC analysis was more than 70% for all molecules between the preoperative biopsy specimens and the resected specimens. The RGS5-positive biopsy cases had higher serum α-fetoprotein levels (p=0.04), a higher rate of moderately or poorly differentiated tumors (p=0.02) and portal vein invasion (p=0.0003) than the RGS5-negative biopsy cases. The GPC3-positive biopsy cases were younger (p=0.04), had higher serum PIVKA-II levels (p=0.01), and a higher rate of portal vein invasion (p=0.03) than the GPC3-negative biopsy cases. The PIVKA-II-positive biopsy cases had significantly higher serum PIVKA-II levels than the PIVKA-II-negative biopsy cases (p=0.02). The other molecular markers showed no significantly different clinical findings between the positive and negative cases. Conclusion In HCC, there was a high agreement rate of both the histopathological and IHC findings between preoperative biopsy specimens and resected specimens. In the biopsy specimens of HCC, RGS5 and GPC3 expression were useful molecular makers for predicting portal vein invasion. Liver tumor biopsy is useful for predicting the biological behavior of HCC through histopathological and immunohistochemical findings.

Background: Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model. Results: The incidence rates of any grade and grade &ge, 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival (p &lt, 0.001 and p &lt, 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs. Conclusion: Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs.

Background and Aims: Conventional transcatheter arterial chemoembolization (C-TACE) and drug-eluting bead (DEB)-based TACE are current treatments for hepatocellular carcinoma (HCC). We compared the therapeutic efficacies and adverse events of these methods in a single-center retrospective cohort study. Methods: We enrolled 174 patients treated between January 2010 and October 2016; 98 and 76 underwent C-TACE and DEB-TACE, respectively, with 76 and 22 of the former group and 49 and 27 of the latter group classified as Child-Pugh class A and B, respectively. Therapeutic outcomes, progression-free survival (PFS), and adverse events were evaluated. Results: The PFS rates in the C-TACE and DEB-TACE groups were 8.1 and 6.1 months, respectively (p = 0.79). The response and disease control rates were 64 and 71% in C-TACE patients and 69 and 78% in DEB-TACE patients, respectively (p = 0.25). Postprocedural pain, vomiting, and fever were more frequent following C-TACE than DEB-TACE (p < 0.001). In contrast, the incidences of bilomas and arterio-portal shunts were significantly higher following DEB-TACE (p < 0.001); the incident rates of arterio-portal shunt formation were 8.1 and 48.7% in patients undergoing C-TACE and DEB-TACE, respectively. Child-Pugh class A was significantly associated with arterio-portal shunt formation after DEB-TACE on multivariate analysis. Conclusions: There were no significant differences in the therapeutic efficacies of C-TACE and DEB-TACE. However, the frequency of arterio-portal shunt formation was significantly higher in HCC patients with Child-Pugh class A undergoing DEB-TACE. Our findings imply that C-TACE should be selected for HCC patients with Child-Pugh class A and DEB-TACE should be chosen for those with Child-Pugh class B.

We review 6 cases of diaphragmatic perforation, with and without herniation, treated in our institution. All patients with diaphragmatic perforation underwent radiofrequency ablation (RFA) treatments for hepatocellular carcinoma (HCC) performed at Kurume University Hospital and Tobata Kyoritsu Hospital. We investigated the clinical profiles of the 6 patients between January 2003 and December 2013. We further describe the clinical presentation, diagnosis, and treatment of diaphragmatic perforation. The change in the volume of liver and the change in the Child-Pugh score from just after the RFA to the onset of perforation was evaluated using a paired t-test. At the time of perforation, 4 patients had herniation of the viscera, while the other 2 patients had no herniation. The majority of ablated tumors were located adjacent to the diaphragm, in segments 4, 6, and 8. The average interval from RFA to the onset of perforation was 12.8 mo (range, 6-21 mo). The median Child-Pugh score at the onset of perforation (8.2) was significantly higher compared to the median Child-Pugh score just after RFA (6.5) (P = 0.031). All patients underwent laparotomy and direct suture of the diaphragm defect, with uneventful post-surgical recovery. Diaphragmatic perforation after RFA is not a matter that can be ignored. Clinicians should carefully address this complication by performing RFA for HCC adjacent to diaphragm.

Various factors are associated with the prognosis of patients with non-viral hepatocellular carcinoma (HCC). The present study aimed to investigate the prognosis of patients with non-viral HCC compared with that of patients with hepatitis C virus-related (HCV)-HCC and the features associated with prognosis of patients with non-viral HCC using data mining analyses. Patients with non-viral HCC (n=182, age 70.4±8.9 years) and HCV-HCC (n=612, age 70±8.4 years) were enrolled and the overall survival was compared between the non-viral HCC and HCV-HCC groups. The present study performed random forest and decision tree analyses to identify features that distinguish prognosis between the non-viral HCC and HCV-HCC groups. The median survival of the non-viral HCC group was significantly shorter than the HCV-HCC group (1,553 vs. 2,304 days, PI, the survival period in the non-viral HCC group was significantly shorter than the HCV-HCC group (HR 1.39, 95% CI 1.07–1.81, P=0.0132). The prognosis of patients with non-viral HCC was poorer than patients with HCV-HCC. In addition, data mining analysis revealed that tumor-related variables had the highest importance for survival in patients with non-viral HCC.

The prognosis of hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE) is still poor. We aimed to evaluate the impact of TACE combined with radiofrequency ablation (TACE+RFA) on the prognosis of HCC patients using decision-tree analysis after propensity score matching.This was a retrospective study. We enrolled 420 patients with HCC treated with TACE alone (n = 311) or TACE+RFA (n = 109) between 1998 and 2016 (median age, 72 years; male / female, 272/148; Barcelona Clinic Liver Cancer (BCLC) stage A / B, 215/205). The prognosis of patients who underwent TACE+RFA was compared to patients who underwent TACE alone after propensity score matching. Decision-tree analysis was used to investigate the profile for prognosis of the patients.After propensity score matching, there was no significant difference in age, sex, BCLC stage, or albumin-bilirubin (ALBI) score between both groups. The survival rate of the TACE+RFA group was significantly higher than the TACE alone group (median survival time [MST] 57.9 months vs. 33.1 months, P 0.001). In a stratification analysis according to BCLC stage, the overall survival rate of the TACE+RFA group was significantly higher than the TACE alone group in BCLC stage A and B (MST 57.9 and 50.7 months vs. 39.8 and 24.5 months [P = 0.007 and 0.001], respectively). Decision-tree analysis showed that TACE+RFA was the third distinguishable factor for survival in patients with α-fetoprotein level 7 ng/mL and ALBI-2.08.Decision-tree analysis after propensity score matching showed that TACE+RFA could prolong the survival of HCC patients compared to TACE alone.

Background The immunological inflammatory biomarkers for advanced hepatocellular carcinoma are unclear. We aimed to investigate the association of immunity and inflammatory status with treatment outcomes in patients with advanced hepatocellular carcinoma who received molecular-targeted agents as primary treatment. Patients and methods We enrolled 728 consecutive patients with advanced hepatocellular carcinoma who received sorafenib (n = 554) or lenvatinib (n = 174) as primary treatment in Japan between May 2009 and June 2020. Changes in the neutrophil-to-lymphocyte ratio before and 1 month after treatment and their impact on survival were evaluated. The cut-off values of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for predicting overall and progression-free survival were calculated using receiver operating characteristic curves. Results The neutrophil-to-lymphocyte ratio, but not the platelet-to-lymphocyte ratio, was an independent prognostic factor. Patients with decreased neutrophil-to-lymphocyte ratio survived significantly longer than patients with increased neutrophil-to-lymphocyte ratio (median overall survival: 14.7 versus 10.4 months, P = 0.0110). Among patients with a low pre-treatment neutrophil-to-lymphocyte ratio, the overall survival did not differ significantly between those with decreased and those with increased neutrophil-to-lymphocyte ratio after 1 month (median: 19.0 versus 14.8 months, P = 0.1498). However, among patients with high pre-treatment neutrophil-to-lymphocyte ratio, those whose neutrophil-to-lymphocyte ratio decreased after 1 month showed significantly longer survival than those whose neutrophil-to-lymphocyte ratio increased (median: 12.7 versus 5.5 months, P < 0.0001). The therapeutic effect was not correlated with pre-treatment neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio. Conclusions The neutrophil-to-lymphocyte ratio is a prognostic factor, along with liver function and tumor markers, in patients with advanced hepatocellular carcinoma who received molecular-targeted agents as primary treatment. Thus, the neutrophil-to-lymphocyte ratio could be a prognostic biomarker for advanced hepatocellular carcinoma primarily treated with immunotherapy., Highlights • NLR was an independent prognostic factor with advanced HCC, along with liver function and tumor markers. • Patients with decreased NLR 1 month after treatment survived significantly longer than patients with increased NLR. • The therapeutic effect was not correlated with pre-treatment NLR or PLR. • NLR is a prognostic factor in patients with advanced HCC who received molecular-targeted agents as primary treatment. • Thus, NLR could be a prognostic biomarker for advanced HCC treated with immunotherapy.

We aimed to evaluate the impact of alternating lenvatinib (LEN) and trans-arterial therapy (AT) in patients with intermediate-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 113 patients with intermediate-stage HCC treated LEN. Patients were classified into the AT (n = 41) or non-AT group (n = 72) according to the post LEN treatment. Overall survival (OS) was calculated using the Kaplan&ndash, Meier method and analyzed using a log-rank test after PSM. Factors associated with AT were evaluated using a decision tree analysis. After PSM, there were no significant differences in age, sex, etiology, or albumin-bilirubin (ALBI) score/grade between groups. The survival rate of the AT group was significantly higher than that of the non-AT group (median survival time, not reached vs. 16.3 months, P = 0.01). Independent factors associated with OS were AT and ALBI grade 1 in the Cox regression analysis. In the decision tree analysis, age and ALBI were the first and second splitting variables for AT. In this study, we show that AT may improve prognosis in patients with intermediate-stage HCC. Moreover, alternating LEN and trans-arterial therapy may be recommended for patients below 70 years of age with ALBI grade 1.

Background Poor differentiation and microvascular invasion are indicators of poor outcome after hepatectomy for patients with small hepatocellular carcinoma (HCC). Aims We investigated whether gadoxetic acid-enhanced and diffusion-weighted magnetic resonance imaging (MRI) could predict these factors before hepatectomy. Methods Between July 2008 and April 2012, 75 patients who underwent hepatectomy for small HCCs (diameter: ≤3 cm, tumor number: ≤3) were consecutively enrolled. In gadoxetic acid-enhanced MRI, the signal intensity in the tumor was corrected to that in the paraspinous muscles, and the relative enhancement was calculated. In diffusion-weighted imaging, we measured the apparent diffusion coefficient (ADC). We then investigated the correlations between relative enhancement or ADC and histological grade, microvascular invasion and recurrence-free survival. Results Poorly differentiated HCCs showed significantly lower ADC than well-differentiated and moderately differentiated HCCs. There was no significant difference in the hepatobiliary phase. Only ADC was an independent predictor of microvascular invasion, and the best cut-off point of its prediction was 1.175 × 10−3 mm2/s. Additionally, the recurrence-free survival was significantly shorter in low-ADC group than in high-ADC group. Conclusion ADC is useful for predicting poorly differentiated HCCs and microvascular invasion, and low ADC is associated with increased recurrence risk for small HCCs after hepatectomy.

Sorafenib is an oral multikinase inhibitor that has been approved to treat advanced hepatocellular carcinoma (HCC), though it is unclear how much benefit advanced HCC patients with progressive disease (PD) derive from sorafenib treatment. This study aimed to assess survival risk factors and evaluate therapeutic strategies for advanced HCC patients with PD after sorafenib treatment. We analyzed the clinical data and treatment outcomes for 315 consecutive advanced HCC patients treated with sorafenib. Univariate analyses of overall survival identified therapeutic effect as an independent risk factor in all patients. Among all patients, 141 developed PD. Of those, 58 (41%) were treated with sorafenib monotherapy, 70 (50%) with agents other than sorafenib, and 13 (9%) were not treated at all. The median survival time was 6.1 months for PD patients with sorafenib monotherapy and 12.2 months for those administered alternative treatments (p < 0.0001). Our results indicated that sorafenib treatment may have negative long-term therapeutic effects in advanced HCC patients with PD, and that alternative treatments should be considered for these patients after sorafenib administration.

Aims Sarcopenia and physical disability assessed by a 6-min walking test (6MWT) are associated with poor prognosis of patients with chronic liver disease (CLD). However, CLD patients with hepatocellular carcinoma (HCC) mostly rest in bed during hospitalization. We aimed to investigate the effects of therapeutic exercise on liver function, 6MWT, and skeletal muscle mass during HCC treatment in patients with CLD. Methods We enrolled 54 CLD patients with HCC (median age, 76 years). During hospitalization, patients performed a combination of stretching, strength training, balance practice, and endurance training (2.5–4 metabolic equivalents/20 min/day). Primary outcomes were changes from admission to discharge in Child–Pugh class, 6MWT, and skeletal muscle mass. Furthermore, factors associated with skeletal muscle atrophy were analyzed by a decision-tree analysis. Results Exercise did not worsen the Child–Pugh class. On discharge, the 6MWT ambulation distance was maintained, and heart rate variability during the 6MWT was significantly improved compared to that on admission (area under the curve 50.3 vs. 39.0 arbitrary units; P = 0.0027). Although skeletal muscle mass was significantly reduced (20.6 kg vs. 20.0 kg, P = 0.0301), branched-chain amino acid (BCAA) treatment was identified as the most distinguishable factor for minimizing muscle mass atrophy (−1.1 kg vs. −0.5 kg/hospitalization). Conclusions Therapeutic exercise improved physical ability without worsening liver function during hospitalization for HCC treatment in CLD patients. Although exercise did not completely prevent skeletal muscle atrophy, BCAA treatment minimized the skeletal muscle atrophy. Thus, exercise with BCAA treatment may be important for the management of CLD patients with HCC.

Several indices have been proposed to evaluate the systemic inflammatory response (SIR), which has been reported to be a useful prognostic factor in various types of cancer. We investigated the usefulness of the Glasgow Prognostic Score (GPS), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic factors in patients with advanced hepatocellular carcinoma (HCC) with extrahepatic metastasis (stage IVB). Between April, 1997 and March, 2013, a total of 434 HCC patients who developed extrahepatic metastasis were enrolled in the present study. The GPS was defined on the basis of pretreatment C-reactive protein (CRP) and albumin (Alb) levels, and the subjects were grouped according to GPS 0–2. The NLR was calculated as the neutrophil count/lymphocyte count, and the PLR was calculated as the platelet count/lymphocyte count. A comparative examination was performed using a survival analysis with approximate median values to determine the cut-off value for both ratios. The median survival time (MST) of the 434 patients overall was 7.3 months, with cumulative survival rates of 31.8, 14.5 and 7.7% at 1, 2 and 3 years, respectively. The patient backround was as follows: The male:female ratio was 363:71, with a median age of 67.0 years (range, 15.0–92.0 years). Hepatitis B virus patients:hepatitis C virus patients:non-B, non-C hepatitis patients = 75:303:56. Child-Pugh class A:B:C = 218:153:63. As regards T stage, ≤T2:T3:T4 = 60:190:181. The median white blood cell count was 4,650/l (range, 1,400-20,500/l); the platelet count was 11.1×104/µl (range, 3.1×104-45.5×104/µl); the aspartate aminotransferase level was 40.0 U/l (range, 7.0–338.0 U/l) and the alanine aminotransferase level 64.5 U/l (range, 16.0–407.0 U/l); the α-fetoprotein level was 622.1 ng/ml (range, 1.5–3,311,794.0 ng/ml); and the des-gamma-carboxyprothrombin level was 1,285.0 mAU/ml (range, 8.0->75,000 mAU/ml). The principal sites of metastasis included the lungs (53.9%), bone (38.9%), lymph nodes (21.4%) and adrenal glands (10.1%). The survival analysis revealed that hepatic functional reserve [Child-Pugh class B+C; hazard ratio (HR)=2.055; 95% confidence interval (CI): 1.592–2.651, P

Portal vein tumor thrombosis is a critical complication in patients with hepatocellular carcinoma (HCC). This prospective multicenter trial assessed the efficacy of hepatic arterial infusion chemoembolization therapy with cisplatin suspended in lipiodol combined with 5-fluorouracil for HCC patients with portal vein tumor thrombosis. We enrolled 52 HCC patients with portal vein tumor thrombosis. They received hepatic arterial infusion chemoembolization therapy with cisplatin suspension in lipiodol and 5-fluorouracil. The primary efficacy endpoint was progression-free survival (PFS), while the secondary endpoints were overall survival (OS), tumor response rate, safety, and tolerability. Independent factors for survival were also evaluated. The median PFS and OS were 8.6 and 27.0 months, respectively. Ten patients showed complete response, while 29 had partial response (response rate, 75.0 %). The median survival time of 10 patients with complete response and 29 with partial response was 32 months, while that of 15 patients with partial response who later showed disappearance of HCC following additional therapies was 50 months. Multivariate analysis identified response to treatment and disappearance of viable HCC as independent predictors of survival. The treatment was well tolerated, and the only encountered Grade 3 toxicities were thrombocytopenia and hyperbilirubinemia. Hepatic arterial infusion chemoembolization therapy with cisplatin suspension in lipiodol combined with 5-fluorouracil is effective treatment for unresectable HCC with portal vein tumor thrombosis.

Background: Transcatheter arterial chemoembolization (TACE) is a standard therapy used in the treatment of intermediate hepatocellular carcinoma (HCC). Recently, balloon-occluded TACE (B-TACE) has been developed. Purpose: This study aimed to clarify the effects of B-TACE in patients with HCC, with a focus on which drug is suitable to suspend in Lipiodol for B-TACE. Methods: We retrospectively evaluated 35 patients with HCC treated with B-TACE. Factors associated with enhanced time to progression (TTP) after B-TACE were evaluated using univariate and multivariate analyses. Results: A total of 35 patients with HCC (40 nodules) were treated with B-TACE between June 2013 and August 2016. Epirubicin was used in 25 nodules and miriplatin was used in 15 nodules. Epirubicin (15.1 months) was significantly better than miriplatin (3.2 months) in prolonging the local TTP after B-TACE (p = 0.0293). Epirubicin showed a positive tendency in TE4 (100% tumor necrosis) rate when compared with miriplatin (p = 0.058). Achievement of TE4 was the only significant factor associated with better TTP after B-TACE. Epirubicin- and TACE-naïve statuses were significant factors in achieving TE4 with B-TACE. Conclusion: To enhance the TTP with B-TACE, TE4 should be achieved. Epirubicin is a more optimal anticancer drug (as a Lipiodol suspension) than miriplatin for achieving TE4 with B-TACE.

Sorafenib, an oral multikinase inhibitor, is approved for advanced hepatocellular carcinoma (HCC) treatment. However, its therapeutic effect in advanced HCC patients with extrahepatic metastasis remains uncertain. This study aimed to prospectively assess the efficacy, safety, and survival risk factors and evaluate the prognostic impact of sorafenib treatment in advanced HCC patients with or without extrahepatic metastasis. Between May 2009 and March 2014, 312 consecutive advanced HCC patients who received sorafenib were enrolled in this study. We evaluated their characteristics and compared the clinical outcomes of those with and without extrahepatic metastasis. Of the enrolled patients, 245 (81%) received sorafenib treatment for more than 1 month, with a median duration of 3.6 months. Eighteen patients demonstrated partial response to sorafenib therapy, 127 had stable disease, and 134 had progressive disease at the first radiologic assessment. The median survival time (MST) and progression‐free survival (PFS) were 10.3 and 3.6 months, respectively. Multivariate analysis identified gender, Child‐Pugh class, baseline serum des‐gamma‐carboxy prothrombin level, and treatment duration as independent risk factors for survival. Extrahepatic metastasis was detected in 178 patients. However, the MST, PFS, and therapeutic effect were comparable between patients with and without extrahepatic metastasis. The independent risk factors for decreased overall survival in patients with extrahepatic metastasis were similar to those affecting all patients. Our results indicated that sorafenib could be administered for hepatic reserve and as long‐term treatment for advanced HCC patients regardless of their extrahepatic metastasis status.

Although sorafenib and hepatic arterial infusion chemotherapy (HAIC) have been proven to improve prognosis in hepatocellular carcinoma (HCC) patients with macroscopic vascular invasion (MVI), the most appropriate approach remains unclear. The present multicenter, non-randomized, prospective cohort study aimed to compare the efficacy and safety of HAIC and sorafenib in patients with advanced HCC and MVI, without extra-hepatic spread (EHS) and Child-Pugh class A disease. The present study was performed between April 2008 and March 2014, and 64 HCC patients with MVI, without EHS and Child-Pugh class A disease were registered. Of these patients, 44 were treated with HAIC and 20 with sorafenib. HAIC involved cisplatin (50 mg fine powder in 5-10 ml lipiodol) and a continuous infusion of 5-fluorouracil (FU) (1,500 mg/5 days), which is referred to as new 5-FU and cisplatin therapy (NFP). The primary outcome was progression-free survival, and the secondary outcome was overall survival (OS). Clinical factors influencing OS and the therapeutic effect were identified using univariate and multivariate analyses. There were no differences in clinical factors between the two groups. The median progression-free survival was 5.1 and 9.5 months in the sorafenib and NFP groups, respectively (P=0.001). The complete response (CR) or partial response (PR) rates were 10 and 71% in the sorafenib and NFP groups, respectively (P

We report on a 62-year-old man with chronic hepatitis C who developed rapidly growing hepatocellular carcinoma (HCC) after achieving sustained virological response at post-treatment week 24 (SVR 24) by direct-acting antiviral (DAA) treatment. In 2008, he failed interferon therapy at 56 years of age. He received daclatasvir plus asunaprevir for 24 weeks after confirmation of no liver tumor by abdominal ultrasonography. He had no advanced liver fibrosis. Three months after initiation of DAA treatment, a liver tumor measuring 6 mm in diameter was detected by ultrasonography and confirmed with magnetic resonance imaging. After achieving SVR 24, the tumor increased in size to 16 mm. Two months later, a tumor biopsy was performed, and histology revealed moderately to poorly differentiated HCC. The patient’s alpha-fetoprotein (AFP) level was within the normal range, but the Lens culinaris agglutinin-reactive fraction of AFP level was elevated. The diameter of the tumor increased to 32 mm at 2 months after diagnosis. Lymph node metastasis in porta hepatis was found by positron emission tomography at 4 months after diagnosis. The patient received hepatic arterial infusion chemotherapy and radiation therapy, but died later. Careful monitoring is required during and after DAA treatment because HCC can grow fast even in patients with normal AFP and no advanced liver fibrosis.