Clinical implication of immune checkpoint inhibitor on the chronic hepatitis B virus infection.

AIM: The risk of hepatitis B virus (HBV) reactivation with immune checkpoint inhibitors (ICIs) is an important issue that has not yet been fully investigated. ICI is also expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect. We herein investigated the risk of HBV reactivation and the antiviral effect of ICI administration. METHODS: This study included 892 patients on ICIs between September 2014 and May 2021 at our hospital. The frequency of HBV reactivation and antiviral effects were investigated. RESULTS: Among the 892 patients who underwent ICI, 27 were hepatitis B surface antigen (HBsAg) positive. HBV reactivation was evaluated in 24 cases, among which 4.1% (1/24) had HBV reactivation. Nucleic acid analog prophylaxis was not administered to patients with reactivation. In a study of 15 cases, the amount of HBsAg decreased from baseline; 2.18 ± 0.77 log to 48 weeks later; 1.61 ± 1.38 log (p = 0.17). Forty-eight weeks after the start of ICI, disappearance of HBsAg was observed in two out of 15 cases (13.3%), and one case each with and without nucleic acid analog. CONCLUSION: In rare cases, HBsAg-positive patients may be reactivated by ICI administration. On the other hand, when ICI is administered, it is expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect, and future drug development is expected.

Outcome of Combination Therapy with Sofosbuvir and Ledipasvir for Chronic Type C Liver Disease.

INTRODUCTION: Recently, the treatment of chronic hepatitis C has markedly advanced. A phase III clinical study of combination therapy with sofosbuvir (SOF) and ledipasvir (LDV) was conducted in Japan, and the additive therapeutic effects were reported. In this study, we report the results of treatment in our hospital. METHODS: Of 147 patients with chronic type C liver disease who had consulted our hospital since September 2015 and received SOF/LDV therapy, in 91 subjects a sustained virological response of 12 weeks (SVR12) could be evaluated. RESULTS: In all 91 patients, end treatment response was achieved. Subsequently, recrudescence was noted in 1 before the completion of treatment (week 12); an SVR12 was achieved in 90 patients (99%). The following adverse reactions were observed in 3 patients (3.3%): bradycardia, paroxysmal atrial fibrillation, and heart failure with QT prolongation, which were associated with heart disease. CONCLUSION: A favorable SVR was achieved by SOF/LDV therapy even in elderly patients, those with liver cirrhosis, or those having undergone radical treatment of liver cancer. Furthermore, a high tolerance was demonstrated, but adverse reactions associated with the heart may appear in patients with heart disease as an underlying disease; strict management during treatment is necessary.

Contrast-Enhanced Tissue Harmonic Imaging versus Phase Inversion Harmonic Sonographic Imaging for the Delineation of Hepatocellular Carcinomas.

OBJECTIVE: To compare contrast tissue harmonic imaging (THI) with low mechanical index (MI) and conventional contrast harmonic imaging (CHI) with respect to lesion visibility of hepatocellular carcinoma (HCC). METHODS: One hundred and twenty-five patients (84 men and 41 women, age range 39-94 years, mean age 74 years) with 100 naïve HCCs and 30 lesions after radiofrequency ablation (RFA) for HCC were evaluated. One hundred and four patients had liver cirrhosis of Child-Pugh class A, and the remaining 21 had Child-Pugh class B cirrhosis. The lesion conspicuity and intratumoral echogenicity during the postvascular phase were compared using conventional CHI and contrast THI with low MI. RESULTS: The MI values ranged from 0.20 to 0.30 on conventional CHI and from 0.30 to 0.35 on contrast THI. Regarding HCC lesion conspicuity, contrast THI with low MI was clearer in 79 lesions (60.8%), equal in 34 lesions (26.2%), and less clear in 17 lesions (13.1%) when compared with conventional CHI. The lesion conspicuity with contrast THI was significantly better than that with conventional CHI (p < 0.01). All of the postablative lesions were well delineated in patients who received RFA. CONCLUSION: Low-MI contrast THI was superior to conventional CHI with respect to lesion visibility of HCCs and might offer good imaging for the guiding of RFA.

Malignant Transformation of Hepatocellular Adenoma.

The patient was a 20-year-old male in whom a hepatic hypervascular mass accompanied by intratumoral hemorrhage was detected on examination for epigastric pain. Based on the enlargement of the mass and diagnostic imaging, hepatocellular adenoma (HCA) was suspected and hepatectomy was performed. The lesion was diagnosed as malignant transformation of ß-catenin-activated HCA. There are only few reports of cases with malignant transformation of HCA in Japan; it is necessary to accumulate cases to investigate it.

Hepatocarcinogenesis Is Associated with Serum Albumin Levels after Sustained Virological Responses with Interferon-Based Therapy in Patients with Hepatitis C.

OBJECTIVE: It is a generally accepted fact that eradication of hepatitis virus C inhibits the subsequent development of hepatocellular carcinoma (HCC). On the contrary, a significant population of patients developed HCC despite sustained virological responses (SVRs) to interferon (IFN) therapy. METHODS: A total of 415 patients with chronic hepatitis C, who were treated at our hospital between 2004 and 2014, were enrolled for this study. We examined the risk factors for HCC development after IFN therapy. RESULTS: After analyzing various clinical parameters, it was concluded that a serum albumin (ALB) level <4.0 g/dL and the presence or absence of SVR achievement were risk factors for the development of HCC. When analyzing pre- and posttreatment factors, only a serum ALB level <4.0 g/dL was considered a significant risk factor. The presence or absence of liver fibrosis progression was not identified as a risk factor. CONCLUSIONS: In patients with a serum ALB level <4.0 g/dL before IFN therapy, hepatic carcinogenesis after SVR achievement need to be considered. Furthermore, the serum ALB level may be more useful than the degree of fibrosis for the prediction of HCC after SVR in chronic hepatitis C.

Hepatocellular Carcinoma after Achievement of Sustained Viral Response with Daclatasvir and Asunaprevir in Patients with Chronic Hepatitis C Virus Infection.

BACKGROUND: Interferon-based antiviral therapies against hepatitis C virus (HCV) infection have been shown to reduce the incidence of hepatocellular carcinoma (HCC) in patients with sustained viral response (SVR). Recently, direct-acting antivirals (DAAs) have been proven to be much more effective in achieving SVR than interferon-based therapies. However, whether DAAs can efficiently prevent the occurrence of HCC after SVR remains controversial. To clarify this issue, we analyzed the clinical features of patients in whom HCC developed after achievement of SVR with DAAs for chronic HCV infection. SUMMARY: Among patients who achieved SVR with daclatasvir and asunaprevir (n = 100), HCC developed in 17 patients (HCC group; n = 17) and did not develop in 83 patients (non-HCC group; n = 83) during a mean observation period of 15 months. A multivariate Cox proportional hazards analysis identified past history of HCC and male sex as significant risk factors for the emergence of HCC after DAAs. Sixteen cases with HCC after DAAs were in the very early or early stage (16/17, 94.1%), and one case was in the advanced stage (1/17, 5.9%) with portal venous tumor thrombus. Radiofrequency ablation and/or transarterial chemoembolization were performed in most cases as curative therapy (16/17, 94.1%). Key Messages: SVR by DAAs did not completely prevent the occurrence of HCC. However, even if HCC did develop after SVR, curative anticancer therapy was applicable in most cases.

Unique Characteristics Associated with Sustained Liver Damage in Chronic Hepatitis C Patients Treated with Direct Acting Antivirals.

BACKGROUND AND AIMS: Direct-acting antivirals (DAAs) dramatically improve the sustained virological response (SVR) of chronic hepatitis C (CHC) patients. However, continuous liver damage after SVR may be a risk of hepatocellular carcinoma (HCC). We clarified pretreatment characteristics related to sustained liver damage after SVR. METHODS: A total of 286 CHC patients were treated with an interferon-free DAA regimen. Among them, 250 patients achieved SVR for 12 weeks after the end of treatment (SVR12); these individuals were classified based on α-fetoprotein (AFP) and alanine transaminase (ALT) levels posttreatment. Baseline characteristics significantly associated with AFP >5 ng/mL and ALT level ≥20 IU/L after SVR were clarified using multivariate analyses. RESULTS: Among the pretreatment factors examined, serum AFP values and the presence of fatty liver (FL) were significantly associated with abnormal AFP (p < 0.0001) and ALT levels 12 weeks after SVR12 (SVR24; p = 0.0109). For 126 patients who showed an increase in baseline AFP level, FL, fibrosis-4 (FIB-4) index, and albumin levels before treatment were related to abnormal AFP at SVR24 (p = 0.0005, 0.0232, and 0.0400 for FL, FIB-4 index, and albumin, respectively). Similarly, for 150 patients with abnormal baseline ALT levels, FL was associated with an ALT level ≥ 30 IU/L after SVR (p = 0.0430). CONCLUSIONS: High FIB-4 index, low albumin level, and FL before DAA treatment were associated with a risk of sustained liver damage with AFP and ALT elevation after SVR; patients with these factors should be carefully monitored for emergence of HCC.

Impact of Tumor Factors on Survival in Patients with Hepatocellular Carcinoma Classified Based on Kinki Criteria Stage B2.

BACKGROUND: Tumors classified based on the Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) are heterogeneous in nature. Previously, the Kinki criterion was proposed for a more precise subclassification of tumors in BCLC-stage B. However, tumors in sub-stage B2 include various size and number of HCCs even with the Kinki criteria, which could lead to heterogeneity for overall survival (OS). In this study, we assessed how the size and number of tumors affect the OS and time to progression (TTP) in patients with Kinki criteria stage B2 tumors and treated with transarterial chemoembolization (TACE). METHODS: Of 906 HCC patients treated with TACE at Kindai University Hospital, 236 patients with HCC considered as Kinki criteria stage B2 were examined. They were classified into the following 4 groups according to the maximum tumor diameter and number of tumors: B2a group, tumor size ≤6 cm and total number of tumors ≤6; B2b group, size ≤6 cm and number >6; B2c group, size >6 cm and number ≤6; and B2d group, size >6 cm and number >6. The OS and TTP of patients in each group were compared. RESULTS: There were 131 patients (55.5%) in the B2a group, 58 (24.6%) in the B2b group, 41 (17.4%) in the B2c group, and 6 (0.03%) in the B2d group. Comparison of the survivals revealed that the median OS was 2.8 years (95% CI 2.0-3.5) in the B2a group, 2.8 years (95% CI 2.0-3.3) in the B2b group, 1.9 years (95% CI 0.8-4.0) in the B2c group, and 2.3 years (95% CI 1.2-ND [no data]) in the B2d group, respectively (p = 0.896). The median TTP in B2a, B2b, B2c, and B2d sub-substage HCC were13.2, 12.1, 13.8, and 11.5 months, respectively (p = 0.047). The median TTP in B2a + B2c sub-substage patients was longer than that in B2b + B2d sub-substage HCC patients (14.0 months and 10.4 months; p = 0.002). CONCLUSION: No significant differences were observed in the OS among HCC patients subclassified based on the maximum tumor diameter and tumor number in Kinki criteria stage B2. Consequently, Kinki criteria stage B2 HCC is a homogeneous subgroup in terms of OS prediction. However, shorter TTP in B2b+B2c sub-substage HCC patients than that in B2a + B2c sub-substage HCC patients suggests that different treatment strategy, such as systemic therapy with targeted agents instead of TACE, may be suitable to preserve the liver function.

Time to Transcatheter Arterial Chemoembolization Refractoriness in Patients with Hepatocellular Carcinoma in Kinki Criteria Stages B1 and B2.

BACKGROUND: Transarterial chemoembolization (TACE) is recommended for patients with hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) stage B. However, because of the heterogeneity of HCC in BCLC stage B; various subclassification systems have been proposed to predict the prognosis of patients. Previously, we proposed the Kinki criteria for precise classification of HCC cases in BCLC stage B. In this study, we compared the time to TACE refractoriness in HCC patients with Kinki criteria substages B1 and B2-HCC. SUMMARY: Between January 2006 and December 2013, 592 HCC patients (substage B1, n = 118; substage B2, n = 170) underwent TACE. Time to progression under TACE treatment was defined as the time to untreatable progression (TTUP). TTUP and changes in liver function were analyzed in patients with substages B1 and B2-HCC. The median TTUP was 25.7 months (95% CI 19.3-37.3) and 16.4 months (95% CI 13.1-20.2) in patients with substage B1-HCC and substage B2-HCC, respectively (p = 0.0050). In patients with substage B2-HCC, median Child-Pugh scores after the first TACE session was significantly different from those after third and fifth TACE sessions (first-third, p = 0.0020; first-fifth, p = 0.0008). Key Message: TACE refractoriness occurred earlier in patients with substage B2-HCC than those with substage B1-HCC; deterioration of liver function with repeated TACE was more obvious in HCC cases with stage-B1 tumor. Shorter TTUP and impaired liver function due to repeated TACE could be responsible for the shorter survival in patients with substage B2-HCC.

Safety, Tolerability, and Efficacy of Sofosbuvir Plus Ribavirin in Elderly Patients Infected with Hepatitis C Virus Genotype 2.

BACKGROUND: An interferon-free regimen including sofosbuvir and ribavirin (RBV) for patients with hepatitis C virus (HCV) genotype 2 (G2) infection leads to a drastic improvement of sustained virological response (SVR). However, the safety, tolerability, and efficacy in patients aged 75 or older have not been completely understood. SUMMARY: Fifty-six patients with HCV G2 infection who were treated with sofosbuvir and weight-based dose of RBV were enrolled. Thirty-seven patients aged ≥75 and 19 patients aged ≤74 were classified as the aged and non-aged groups, respectively. The aged group was characterized by significantly more number of women, history of hepatocellular carcinoma, low serum albumin (ALB) level, low hemoglobin (Hb) concentration, low estimated glomerular filtration rate (eGFR), and high fibrosis-4 index (p = 0.0029). Forty-one patients were evaluated for SVR at 12 weeks after the end of therapy (SVR12); of them, all but one completed the treatment scheduled for 12 weeks. The aged group showed lower SVR12 rate than the non-aged group (81.3% for aged and 96.0% for non-aged groups). Although the Hb concentration and eGFR are significantly lower in the aged group throughout the clinical course, all patients in the aged group completed the 12-week treatment with a gradual increase of serum ALB level. Key Messages: The combination of sofosbuvir plus RBV is tolerable and beneficial in patients aged >75. However, intensive management of anemia by dose reduction of RBV is necessary, which could lead to a low SVR12 rate compared to that observed in patients younger than 75 years.

US-US Fusion Imaging in Radiofrequency Ablation for Liver Metastases.

OBJECTIVE: Radiofrequency ablation (RFA) induces gas bubbles in ablation zones, and the ablative margin cannot be evaluated accurately on ultrasound (US) during and immediately after RFA. This study assessed the usefulness of US-US fusion imaging to visualize the ablative margin of RFA for liver metastasis. METHODS: RFA guided by US-US fusion imaging was performed on 12 targeted tumors in 10 patients. Secondary hepatic malignancies included patients with colorectal cancer (n = 4), breast cancer (n = 2), lung cancer (n = 1), gastrointestinal stromal tumor (n = 1), pancreatic neuroendocrine tumor (n = 1), and adrenocortical carcinoma (n = 1). The maximal diameter of the tumors ranged from 0.8 to 4.0 cm (mean ± SD 1.6 ± 0.9 cm). RESULTS: The mean number of electrode insertions was 1.6 per session (range 1-3). Technically, effective ablation was achieved in a single session in all patients, and safety ablative margins were confirmed on contrast-enhanced CT for early assessment of tumor response. There were no serious adverse events or procedure-related complications. During the follow-up period (median 220 days, range 31-417 days), none of the patients showed local tumor progression. CONCLUSION: US-US fusion imaging could show the tumor images before ablation and the ablative area on US in real time. The image overlay of US-US fusion imaging made it possible to evaluate the ablative margin three dimensionally according to the US probe action. Therefore, US-US fusion imaging can contribute to RFA therapy with a safety margin, that is, the so-called precise RFA.

Outcome of Asunaprevir/Daclatasvir Combination Therapy for Chronic Liver Disease Type C.

OBJECTIVE: Treatment for chronic hepatitis C has recently developed in a very rapid manner. In Japan, in September 2014, IFN-free asunaprevir (ASV) and daclatasvir (DCV) became available for combination therapy. We report the treatment outcomes achieved at our hospital using this combination therapy. METHODS: Sustained virological response (SVR) 24 could be evaluated in 120 of 125 patients with chronic liver disease type C who visited our hospital and were treated with ASV/DCV after September 2014, and these patients were analyzed. RESULTS: SVR24 was achieved in 106 patients (88%). End-of-treatment response was not achieved in 10 patients (8.3%). Five of them carried multiple-resistant NS3/4A or NS5A region, and administration was discontinued early in 4 patients due to adverse effects. After ASV/DCV treatment, hepatocellular carcinoma (HCC) developed in 2 patients (1.7%) and recurred in 5 (4.2%). CONCLUSIONS: ASV/DCV treatment achieved favorable SVR in elderly and hepatic cirrhosis patients and patients in whom HCC was cured. However, an increase in the incidence of HCC development in patients who markedly respond to direct-acting antivirals treatment is expected and surveillance of HCC becomes more important.

Clinical Factors Predicting the Effect of Tolvaptan for Refractory Ascites in Patients with Decompensated Liver Cirrhosis.

OBJECTIVE: Refractory ascites reduces the quality of life of liver cirrhosis patients. Albumin preparation and diuretics, such as furosemide, have been used to treat refractory ascites, but the effect was poor in many patients. In this study, we analyzed patients treated with tolvaptan (TLV) at our hospital and investigated predictors of the effect. METHODS: The subjects were 70 patients for whom TLV was introduced to treat refractory ascites who could be analyzed between November 2013 and March 2015 at our hospital. Patient background before initiation of oral TLV treatment, the dose of diuretics, and each item of biochemical tests of blood and urine were investigated, and factors correlated with the treatment effect were analyzed. An increase of ≥1,000 ml in the daily urine volume from the day before oral treatment or a decrease of ≥1 kg in the body weight within 7 days as an early effect was observed in 33 patients and not observed in 37 patients. TLV treatment was continued for 60 days or longer in 12 of the 37 patients in whom no early effect was observed, and the presence or absence of a delayed effect and predictors of the effect were investigated. A decrease in ascites on abdominal CT with improvement of subjective symptoms at 60 days was defined as a delayed effect. RESULTS: When early predictors of the effect were investigated by univariate analysis, serum blood urea nitrogen (BUN) and serum creatinine (Cr) were significantly higher in the non-responder group (BUN: p = 0.03, Cr: p = 0.04), but no factor independently associated with the treatment effect was extracted on multivariate analysis. The delayed effect was noted in 4 (33.3%) of the 12 patients, but no predictor of the effect before treatment was identified. However, reactions, such as an increase in serum Na and reduction of urinary osmotic pressure, were observed early after TLV administration in some patients in whom the delayed effect was observed. CONCLUSIONS: The diuretic effect of TLV may decrease in renal hypofunction patients. Since the delayed effect was noted in a specific ratio of patients, continuation of TLV administration is an option even though the early treatment effect is poor unless ascites aggravates or adverse effects develop.

Validation of Kinki Criteria, a Modified Substaging System, in Patients with Intermediate Stage Hepatocellular Carcinoma.

BACKGROUND: The standard treatment option that is available for patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) is transarterial chemoembolization (TACE). However, the condition of the patients with BCLC stage B disease is heterogeneous showing different tumor statuses and Child-Pugh scores; treatment strategies other than TACE are frequently employed for the patients in this stage. Based on the subclassification system proposed by Bolondi et al. [Semin Liver Dis 2012;32:348-359], we developed the Kinki criteria focusing on a substaging for BCLC stage B disease, which is simpler and should be more suitable in actual clinical setting in Japan. In this study, we evaluated the performance of Kinki criteria. SUMMARY: This study included 1,633 HCC patients who received first-line treatment at the Kindai University Hospital. Patients were classified into subgroups based on the Kinki criteria and the survival time was estimated for each group. There were 156 (33.3%) patients in subclass B1, 278 (59.3%) in B2, and 35 (7.4%) in B3. The median overall survival times and 95% CI for BCLC B subclasses B1, B2, and B3 were 4.3 years (3.7-4.9), 2.9 years (2.2-3.4), and 1.1 years (0.5-1.8), respectively (p < 0.001). Key Messages: Classification of HCC patients in BCLC stage B based on the Kinki criteria showed statistically significant differences in survival, indicating the performance of Kinki criteria, which takes Child-Pugh score and tumor status into account for determining treatment options for HCC in BCLC stage B.

Evaluation of ART Scores for Repeated Transarterial Chemoembolization in Japanese Patients with Hepatocellular Carcinoma.

OBJECTIVE: Transarterial chemoembolization (TACE) is recommended as a first-line therapy for hepatocellular carcinoma (HCC) patients ineligible for curative therapy and without portal invasion. The Assessment for Retreatment with TACE (ART) scoring system was recently proposed for identifying patients who would not show sufficient survival benefit from repeated TACE. We reevaluated the performance of ART in HCC patients treated in Japan, where selective TACE is commonly used. METHODS: Between 2000 and 2013, 988 patients with HCC underwent TACE at Kinki University Hospital, and 627 received ≥2 sessions of TACE. Seventy-six patients who underwent ≥2 TACE sessions within 90 days were investigated for their performance of the ART score in the context of overall survival (OS). RESULTS: Only 12% (76/627) of patients underwent ≥2 TACE sessions within 90 days. Of those, 52 patients showed a low ART score (0-1.5), and 24 had a high ART score (≥2.5); the median OS was 20.2 and 37.6 months, respectively (p = 0.8207). CONCLUSION: The ART scoring system did not demonstrate a sufficiently predictive impact on OS among the patients who underwent ≥2 TACE sessions within 90 days. Application of the ART score should be carefully considered because differences in TACE procedures and post-TACE treatment can affect the results while evaluating OS.

Balloon-Occluded Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: A Single-Center Experience.

OBJECTIVE: To investigate whether balloon-occluded transcatheter arterial chemoembolization (b-TACE) can produce a more dense accumulation of iodized oil in various stages of hepatocellular carcinoma (HCC), from single to uncountable, to overcome inferior local control. MATERIALS AND METHODS: We studied 27 patients with HCC, including single to uncountable multiple lesions, who underwent b-TACE between August 2013 and April 2015. Dynamic CT was performed at baseline and 1-3 months after b-TACE. The treatment effect (TE) after b-TACE was evaluated using the Response Evaluation Criteria in Cancer of the Liver (RECICL) proposed by the Liver Cancer Study Group of Japan. RESULTS: In the countable HCC group, contrast-enhanced CT demonstrated RECICL TE4 in 43.8% (14/32), TE3 in 12.5% (4/32), TE2 in 37.5% (12/32), and TE1 in 6.3% (2/32) of patients. For the TACE-naïve cohort, the objective response rate was 52.9%. The objective response rate was 60% for the previously TACE-treated cohort. In the uncountable multiple HCC group, the objective response rate was 0% (0/10), with progressive disease in 90% (9/10) of patients. CONCLUSION: Our observations suggested that b-TACE did not reduce the efficacy of retreatment for HCC with an insufficient outcome from conventional TACE, but it could not improve the efficacy of treatment for uncountable multiple HCCs.

Validation of a Modified Substaging System (Kinki Criteria) for Patients with Intermediate-Stage Hepatocellular Carcinoma.

INTRODUCTION: Barcelona Clinic Liver Cancer (BCLC) stage B, an intermediate stage, includes various conditions of hepatocellular carcinoma (HCC). This heterogeneity of the patients with intermediate-stage HCC makes it difficult to predict their survival rates. In the present study, we examined the validity of the modified Bolondi classification (Kinki criteria) as a subclassification of patients with BCLC stage B HCC. METHODS: Of 906 patients who underwent conventional transarterial chemoembolization at Kinki University Hospital, 753, who met the inclusion criteria, were examined. Of these 753 patients, 425 (56.4%) with BCLC stage B were subclassified using the Kinki criteria to examine the survival rate. RESULTS: According to the Kinki criteria, 158 (37.2%) were subclassified into subclass B1, 236 (55.5%) into B2, and 31 (7.3%) into B3. The comparison of the survival rates showed that the median overall survival was 3.9 years (95% CI, 3.2-4.6) in the BCLC subclass B1 group, 2.5 years (95% CI, 2.2-3.1) in the B2 group, and 1.1 years (95% CI, 0.6-1.5) in the B3 group (p < 0.001). CONCLUSION: When the BCLC stage B patients were subclassified according to the Kinki criteria, survival curves were stratified with significant differences, suggesting that the Kinki criteria were suitable for the subclassification of the intermediate-stage HCC patients.

Early Viral Response Predicts the Efficacy of Antiviral Triple Therapy with Simeprevir, Peg-Interferon and Ribavirin in Patients Infected with Hepatitis C Virus Genotype 1.

OBJECTIVES: Triple therapy using peg-interferon, ribavirin and simeprevir (PEG-IFN/RBV/SMV) has reportedly resulted in high-sustained virological response (SVR) rates in patients with chronic hepatitis C (CHC), especially in naïve cases and relapsers to prior PEG-IFN/RBV therapy. Here, we retrospectively analyzed the antiviral response associated with a triple regimen, in the context of early reduction of viral load during treatment. METHODS: Forty-six CHC patients with HCV genotype 1b were treated with PEG-IFN/RBV/SMV triple therapy: 20 were naïve cases, 12 were relapsers and 14 were non-responders to prior PEG-IFN/RBV therapy. We evaluated rapid virological response (RVR), complete early virological response (EVR), viral clearance at the end of the treatment (EOT) and at 12 weeks after the EOT (SVR12). In addition, we quantified the serum HCV-RNA on the 1st day and the 7th day after initiating treatment. RESULTS: Multivariate analysis revealed that response to prior treatment was identified as an independent factor for achieving SVR12 after triple therapy (p = 0.0005). The achievement of serum HCV-RNA <2 log(10) IU/ml on day 7, RVR, EVR and EOT were associated with SVR12 (p = 0.0050, p = 0.0002, p = 0.0009 and p = 0.0002, respectively). CONCLUSIONS: Rapid decline of HCV is a predictive factor for the achievement of SVR12, even in antiviral triple therapy with PEG-IFN/RBV/SMV. An extended treatment period should be applied for patients who show detectable serum HCV-RNA at week 4.

Real-Life Clinical Practice with Sorafenib in Advanced Hepatocellular Carcinoma: A Single-Center Experience Second Analysis.

OBJECTIVES: Sorafenib has become a standard therapy for advanced hepatocellular carcinoma following the demonstration of significant increase in progression-free survival as well as overall survival (OS) in the 2-phase III trials. We examined efficacy and adverse events (AEs) in patients treated with sorafenib over a 6-year period since approval in Japan. METHODS: Two hundred and forty-one patients treated with sorafenib at the Kinki University Hospital were retrospectively analyzed clinically for the factors related to survival periods, tumor response evaluated by the Response Evaluation Criteria In Cancer of the Liver (RECICL) and AEs. RESULTS: OS was 14.3 months. According to the RECICL, the objective response and disease control rates were 18.6% (43 of 241) and 61.1% (137 of 241), respectively. AEs were seen in 77.3% (187 of 241), with Grade 3 or higher in 23.6% (57 of 241). The most frequent AE was hand-foot skin reaction in 109 patients (45.0%), and 28 patients (11.8%) showed Grade 3 or higher. Significant factors contributing to the OS were treatment duration (p = 0.0204), up-to-7 criteria (p = 0.0400), increase of Child-Pugh score (p = 0.0008) and tumor response determined by the RECICL (p = 0.0007). CONCLUSION: Based on the analysis, using many cases at a single center, we concluded that continuation of treatment with sorafenib for ≥90 days without decrease of liver function was critical if tumor response was determined as stable disease or higher.

Hepatic DNA Methylation Is Affected by Hepatocellular Carcinoma Risk in Patients with and without Hepatitis Virus.

OBJECTIVES: Several studies revealed that the proportion of hepatocellular carcinoma (HCC) without hepatitis virus infection (NBNC-HCC) is increasing. On the other hand, epigenetic alterations are reportedly responsible for HCC development. Here, we identified HCC risk factors that are associated with DNA methylation in the background liver tissue of NBNC-HCC patients. METHODS: We performed methylation analysis in 37 pairs of virus-positive and 22 pairs of NBNC-HCC and non-cancerous livers using a HumanMethylation450 BeadChip array. After the selection of differentially methylated CpGs (DM-CpGs) in cancerous and non-cancerous livers, we analyzed DNA methylation of DM-CpGs within the adjacent non-cancerous liver tissue that is affected by specific HCC risk factors. RESULTS: A total of 38,331 CpGs were selected as DM-CpGs using the following criteria: difference of ß-value between HCC and non-cancerous liver ≥0.15 and false discovery rate (FDR) q < 1.0E-12. We subsequently selected the DM-CpGs that had methylation differences with the background liver tissue (that has FDR q < 0.35). Among the virus-positive patients, the type of hepatitis virus was mostly associated with differences in methylation within the background liver tissues. However, we found that background methylation patterns were most significantly associated with aging in NBNC patients. Interestingly, age-related methylation differences in DM-CpGs were also observed in NBNC-HCC tissues. CONCLUSIONS: Hepatitis viruses affect the methylation profiles within background liver tissues. However, difference in background methylation was mostly associated with age in NCBC-HCC patients; some age-related methylation events could contribute to emergence of NBNC-HCC in elderly individuals.