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Introduction: Systemic therapy is recommended for patients with Child-Pugh A in hepatocellular carcinoma (HCC). We analyzed the outcomes of a cohort of patients with HCC who received either sorafenib (Sor), lenvatinib (Len) or atezolizumab plus bevacizumab (Atezo + Bev) as first-line systemic therapy for HCC, with the aim of identifying prognostic factors for survival., Methods: A total of 825 patients with advanced HCC and Child-Pugh A or B received either Sor, Len or Atezo + Bev as first-line systemic therapy. Liver function was assessed according to the Child-Pugh score and the modified albumin-bilirubin (mALBI) grade., Results: Prognosis was analyzed according to liver function such as Child-Pugh classifications, scores, and mALBI grades that worsened with a decline in liver function (p <0.001 for all). A Child-Pugh score of 7 was a factor significantly associated with OS. In patients with a Child-Pugh score of 7, an mALBI grade of 3 was an independent predictor of OS. In Child-Pugh B patients with HCC, receiving Atezo + Bev was identified as a factor associated with PFS., Conclusion: Determining the hepatic reserve of patients with unresectable HCC might be useful for identifying patents suitable for systemic treatment for HCC. Atezo + Bev might prolong the PFS of patients with a Child-Pugh score of 7., (© 2023 S. Karger AG, Basel.)

Transarterial chemoembolization (TACE) has been the standard treatment for intermediate-stage, unresectable hepatocellular carcinoma (u-HCC). However, with recent advances in systemic therapy and the emergence of the concept of TACE-refractory or -unsuitable, the effectiveness of systemic therapy, as well as TACE, has been demonstrated for patients judged to be TACE-refractory or -unsuitable. In this study, the efficacy of lenvatinib and its combination with TACE after lenvatinib was investigated in 140 patients with intermediate-stage u-HCC treated with lenvatinib mainly because of being judged to be TACE-refractory or -unsuitable. Median overall survival (OS) and progression-free survival (PFS) were 24.4 and 9.0 months, respectively, indicating a good response rate. In multivariate analysis, modified albumin-bilirubin (mALBI) grade and up to seven criteria were identified as independent factors for OS, and mALBI grade and tumor morphology were identified as independent factors for PFS. While 95% of all patients were TACE-refractory or -unsuitable, the further prognosis was prolonged by the combination with TACE after lenvatinib initiation. These findings suggest that systemic therapy should be considered for intermediate-stage u-HCC, even in patients judged to be TACE-refractory or -unsuitable. The use of TACE after the start of systemic therapy may further improve prognosis.

The association between radiological response and overall survival (OS) was retrospectively evaluated in patients treated with lenvatinib as a first-line systemic treatment for unresectable hepatocellular carcinoma. A total of 182 patients with Child-Pugh class A liver function and an Eastern Cooperative Oncology Group performance status of zero or one were enrolled. Radiological evaluation was performed using Response Evaluation Criteria in Solid Tumors (RECIST) and modified Response Evaluation Criteria in Solid Tumors (mRECIST). Initial radiological evaluation confirmed significant stratification of OS by efficacy judgment with both RECIST and mRECIST, and that initial radiological response was an independent prognostic factor for OS on multivariate analysis. Furthermore, in patients with stable disease (SD) at initial evaluation, macrovascular invasion at the initial evaluation on RECIST and modified albumin-bilirubin grade at initial evaluation on mRECIST were independent predictors of OS on multivariate analysis. In conclusion, if objective response is obtained at the initial evaluation, continuation of treatment appears desirable because prolonged OS can be expected; but, if SD is obtained at the initial evaluation, one should determine whether to continue or switch to the next treatment, with careful consideration of factors related to the tumor and hepatic reserve at the initial evaluation.

Objective Lusutrombopag is a thrombopoietin receptor agonist that improves thrombocytopenia in patients with chronic liver disease scheduled to undergo invasive procedures. However, information on the efficacy of repeated lusutrombopag treatment and factors associated with the treatment is scarce. We analyzed the efficacy of repeated lusutrombopag treatment and the factors associated with a response to lusutrombopag. Methods Thirty-nine patients with chronic liver disease who received lusutrombopag treatment before undergoing invasive procedures were enrolled in this retrospective study. Of the 39 patients, 10 received lusutrombopag treatment multiple times for a total of 53 regimens of lusutrombopag treatment. Changes in platelet counts, the effects of repeated lusutrombopag treatment, and factors associated with response to lusutrombopag were analyzed. Results The median platelet count increased significantly from 4.5×10 4 /μL before lusutrombopag treatment to 7.2×10 4 /μL before the invasive procedure (p<0.01), and patients undergoing 49 of the 53 (92%) treatment regimens succeeded in undergoing invasive procedures without needing platelet transfusions. In patients who received lusutrombopag treatment repeatedly, the median platelet count significantly increased following the second administration of lusutrombopag, and the effects of lusutrombopag were similar between the first and second administration. A multivariate analysis identified the absence of diabetes mellitus (odds ratio, 5.56 for presence; p=0.04) as a significant and independent predictor of a response to lusutrombopag. Conclusion Lusutrombopag treatment significantly increased platelet counts in patients with chronic liver disease, making it possible to receive invasive procedures. The treatment produced identical effects when it was repeated. The efficacy of lusutrombopag might be decreased in patients with diabetes mellitus.

Introduction: We evaluated the efficacy and safety of lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for patients (n = 88) with intermediate-stage hepatocellular carcinoma (HCC)., Methods: Eighty-eight patients who obtained tumor control by LEN treatment were analyzed; 30 received LEN followed by TACE (LEN-TACE sequential therapy), and 58 received LEN monotherapy. Propensity score matching was performed, and the outcomes of 19 patients in the LEN-TACE group and 19 patients in the LEN-alone group were compared. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and change in albumin-bilirubin (ALBI) score were evaluated., Results: After matching, baseline characteristics were similar between the groups. The ORR was 63.2% with LEN-TACE group and 63.2% with the LEN-alone group. Multivariate analysis showed that addition of TACE during LEN treatment (hazard ratio [HR] 0.264, 95% confidence interval [CI] 0.087-0.802, p =  0.019) and Child-Pugh score 5 (HR 0.223, 95% CI 0.070-0.704, p = 0.011) were the significant factors for PFS. Median PFS was 11.6 months with LEN-TACE and 10.1 months with LEN-alone. The survival rate of the LEN-TACE group was significantly higher than that of the LEN-alone group (median survival time; not reached vs. 16.9 months, p = 0.007). The incidence of common LEN-associated AEs was similar between groups. Although elevated aspartate aminotransferase/alanine aminotransferase and fever were more frequent with LEN-TACE group, these events were manageable., Conclusion: For patients with intermediate-stage HCC, LEN-TACE sequential therapy may provide a deep response and favorable prognosis., (© 2021 S. Karger AG, Basel.)

Introduction: This study compared clinical outcomes of 2nd- and 3rd-line regorafenib in patients with unresectable hepatocellular carcinoma., Methods: In this retrospective cohort study, 48 patients were treated with regorafenib for unresectable hepatocellular carcinoma. Thirty-five and 13 patients were initiated on 2nd- and 3rd-line therapy, respectively. We assessed the responses to and safety of the therapy., Results: There were no statistically significant differences in clinical characteristics at the start of 2nd- or 3rd-line regorafenib therapy. The overall response rate of 2nd- and 3rd-line regorafenib was 20 and 8%, respectively. The disease control rate was 57 and 54%, respectively. Median overall survival (mOS) from the start of 2nd-line regorafenib was 17.5 months. mOS from the start of 3rd-line regorafenib was not obtained. Median progression-free survival of 2nd- and 3rd-line regorafenib was 4.9 and 2.3 months, respectively. mOS from 1st-line therapy with tyrosine kinase inhibitor plus sorafenib-regorafenib-lenvatinib was 29.5 months; that with lenvatinib-sorafenib-regorafenib was not obtained. Patients on 3rd-line therapy tended to have better Child-Pugh scores and tumor factors at the start of 1st-line therapy than other patients., Conclusion: Patients on 2nd- and 3rd-line regorafenib showed favorable responses. Good Child-Pugh scores and tumor factors may be associated with a better response rate and OS., (© 2021 S. Karger AG, Basel.)

Aim: Combination therapy with sofosbuvir (SOF) plus velpatasvir (VEL) is approved for patients with hepatitis C virus (HCV)-related decompensated cirrhosis. We analyzed the real-world efficacy of SOF/VEL therapy., Methods: Thirty-three patients with HCV-related decompensated cirrhosis (25 and eight patients with Child B and C, respectively) were treated with SOF/VEL for 12 weeks. The HCV non-structural protein (NS)5A and NS5B drug resistance-associated substitutions (RASs) were determined by direct sequencing., Result: Thirty-two of 33 patients completed the treatment, but the remaining patient discontinued the therapy during third week of the treatment due to aggravation of hepatic encephalopathy. Serum HCV-RNA became negative during the treatment in all patients but relapsed after the end of therapy in five patients. In total, 28 out of 33 patients (85%) achieved sustained virological response 12 weeks following completion of treatment (SVR12). The SVR12 rate was 96% in patients with Child B, but significantly lower, at 50%, in patients with Child C (P < 0.05). In genotype 1b HCV-infected patients, all eight patients without baseline NS5A RASs, but only three of seven patients with RASs, achieved SVR12. Multivariate analysis identified Child B (odds ratio, 35.8 for Child C; P = 0.045) as an independent predictor of SVR12. Median serum albumin levels significantly increased only in patients who achieved SVR12. Child-Pugh scores improved in 16 of 28 patients (57%) following achievement of SVR12., Conclusion: The effect of SOF/VEL therapy is lower for patients with Child C. Improvement of hepatic function is expected after viral eradication with SOF/VEL therapy in patients with decompensated cirrhosis., (© 2020 The Japan Society of Hepatology.)

Background: Although a strong antitumor effect of lenvatinib (LEN) has been noted for patients with unresectable hepatocellular carcinoma (HCC), there are still no reports on the prognosis for patients with disease progression after first-line LEN therapy., Methods: Patients (n = 141) with unresectable HCC, Child-Pugh class A liver function, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1 who were treated with LEN from March 2018 to December 2019 were enrolled., Results: One hundred and five patients were treated with LEN as first-line therapy, 53 of whom had progressive disease (PD) at the radiological evaluation. Among the 53 patients with PD, there were 27 candidates for second-line therapy, who had Child-Pugh class A liver function and an ECOG-PS of 0 or 1 at progression. After progression on first-line LEN, 28 patients were treated with a molecular targeted agent (MTA) as second-line therapy (sorafenib: n = 26; ramucirumab: n = 2). Multivariate analysis identified modified albumin-bilirubin grade 1 or 2a at LEN initiation (odds ratio 5.18, 95% confidence interval [CI] 1.465-18.31, p = 0.011) as a significant and independent factor for candidates. The median post-progression survival after PD on first-line LEN was 8.3 months. Cox hazard multivariate analysis showed that a low alpha-fetoprotein level (<400 ng/mL; hazard ratio [HR] 0.297, 95% CI 0.099-0.886, p = 0.003), a relative tumor volume <50% at the time of progression (HR 0.204, 95% CI 0.07-0.592, p = 0.03), and switching to MTAs as second-line treatment after LEN (HR 0.299, 95% CI 0.12-0.746, p = 0.01) were significant prognostic factors., Conclusion: Among patients with PD on first-line LEN, good liver function at introduction of LEN was an important and favorable factor related to eligibility for second-line therapy. In addition, post-progression treatment with MTAs could improve the prognosis for patients who had been treated with first-line LEN., (© 2020 S. Karger AG, Basel.)

Introduction: Muscle cramps are common comorbidities in chronic liver disease (CLD). Although the prevalence of these has been reported in patients with liver cirrhosis (LC), that of CLD is unknown. In this study, we aimed to clarify the prevalence and characteristics of muscle cramps in individual CLD., Patients and Methods: A total of 432 patients with CLD who visited our hospital were enrolled. The existence of muscle cramps, frequency, time zone, duration, and the degree of pain were investigated using a medical interview questionnaire., Results: The median age of the patients was 65 years and 48.6% of the patients were women. The prevalence of muscle cramps was 25.9%. Age, female sex, lower BMI, existence of comorbid diseases, and liver fibrosis were associated significantly with muscle cramps. In LC, muscle cramps were significantly frequent, and the severity and duration of these were significantly stronger and longer compared with chronic hepatitis. Female sex [odds ratio (OR): 2.26; P=0.014], diabetes (OR: 29.4; P<0.001), chronic kidney disease (OR: 8.33; P=0.004), and lower BMI (OR: 0.853; P<0.001) were independent factors associated with muscle cramps in CLD. Muscle mass indices were significantly lower among nonalcoholic fatty liver disease patients with muscle cramps, female patients, elderly patients, and patients with advanced fibrosis., Conclusion: The prevalence of muscle cramps was relatively high in CLD. Female sex, comorbid diabetes, and chronic kidney disease are associated with muscle cramps in CLD. Furthermore, reduced muscle mass is related to muscle cramps in nonalcoholic fatty liver disease.

Background and Aim: Sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and HCC refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). Also, hepatic arterial infusion chemotherapy (HAIC) has been used for advanced HCC in Southeast and East Asian countries. However, clearer information is needed for choosing appropriately between these therapies., Methods: The subjects were 391 HAIC and 431 sorafenibs administered at our hospital and related hospitals. In this case, cases that satisfy the following three conditions were targeted: (i) no extrahepatic metastasis, (ii) Child-Pugh A, and (ii) not having received treatment of both HAIC and sorafenib during the course. As a result, 150 cases of HAIC and 134 cases of sorafenib were analyzed this time., Results: Univariate and multivariate analyses were performed for the HAIC and sorafenib groups. TACE refractory status and MVI were factors contributing to overall survival (OS). Therefore, this study divided all cases according to those variables. The median survival time of MVI-positive and non-TACE refractory cases was significantly better with HAIC (13 months) versus sorafenib (6 months). However, in MVI-negative and TACE refractory cases, the median survival time of HAIC (8 months) was significantly poorer than for sorafenib (20 months)., Conclusion: Transcatheter arterial chemoembolization refractory status with HAIC and MVI with sorafenib were factors for poor prognosis. In particular, HAIC was significantly better than sorafenib as primary treatment in MVI and non-TACE refractory cases. It is necessary to consider these factors in treatment selection., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

An 83-year-old woman was admitted to our hospital because of a space-occupying lesion (SOL) in the liver. Enhanced computed tomography (CT) showed a nodule measuring 20mm in size in the posterosuperior segment of the right hepatic lobe (S7) and another nodule measuring 14mm in size in the anterosuperior segment of the right hepatic lobe (S8). The margins of these nodules showed faint enhancement in the arterial phase and presented as low-density areas in the equilibrium phase. The S8 SOL could not be easily identified using ultrasonography (US). However, the S7 SOL could be clearly identified as a nodule accompanying the marginal enhancement in the early vascular phase and a defect in the late vascular phase using contrast-enhanced US. On gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, both nodules were described as low-intensity lesions in the T1 phase, high-intensity lesions in the T2 phase, faint high-intensity diffusion-weighted images, and clear low-intensity lesions in the hepatobiliary phase. On positron-emission CT, there was no uptake of 18F-fluorodeoxyglucose in these nodules. Hepatectomy was performed because we were unable to rule out a malignant tumor. Histopathologically, these lesions demonstrated collapsed vascular spaces against a background of rich paucicellular fibrous stroma and were diagnosed as sclerosed hemangiomas. The occurrence of multiple sclerosed hemangiomas is rare and often difficult to diagnose because of variable findings on imaging studies. We report a case of multiple hepatic sclerosed hemangiomas, which was difficult to diagnose preoperatively. Moreover, we have reviewed the literature, particularly with respect to the relevant imaging findings.

Objective: To compare the outcome of hepatic arterial infusion chemotherapy combined with radiotherapy (HAIC + RT) versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombosis (PVTT)., Methods: This retrospective study included 108 HCC patients with PVTT of the main trunk or first branch and Child-Pugh ≤7. Sixty-eight received HAIC + RT and 40 received sorafenib. Patients were then assigned to the HAIC + RT group (n = 36) and the sorafenib group (n = 36) through case-control matching. The decision to treat with HAIC + RT or sorafenib was left to the attending physician., Results: The median overall, progression-free, and postprogression survival were significantly longer in the HAIC + RT group than in the sorafenib group (9.9 vs. 5.3, p = 0.002; 3.9 vs. 2.1, p = 0.048; and 3.7 vs. 1.9 months, p = 0.02, respectively). Multivariate analysis identified HAIC + RT (hazard ratio = 2.02; 95% confidence interval, 1.14-3.57; p = 0.01) as a significant and independent determinant of overall survival., Conclusions: In patients with advanced HCC and major PVTT, survival was significantly longer in those treated with HAIC + RT than with sorafenib., (© 2018 S. Karger AG, Basel.)

According to WHO, about 10 million new cases of thrombotic disorders are diagnosed worldwide every year. Thrombotic disorders, including atherothrombosis (the leading cause of death in the US and Europe), are induced by occlusion of blood vessels, due to the formation of blood clots in which aggregated platelets play an important role. The presence of aggregated platelets in blood may be related to atherothrombosis (especially acute myocardial infarction) and is, hence, useful as a potential biomarker for the disease. However, conventional high-throughput blood analysers fail to accurately identify aggregated platelets in blood. Here we present an in vitro on-chip assay for label-free, single-cell image-based detection of aggregated platelets in human blood. This assay builds on a combination of optofluidic time-stretch microscopy on a microfluidic chip operating at a high throughput of 10 000 blood cells per second with machine learning, enabling morphology-based identification and enumeration of aggregated platelets in a short period of time. By performing cell classification with machine learning, we differentiate aggregated platelets from single platelets and white blood cells with a high specificity and sensitivity of 96.6% for both. Our results indicate that the assay is potentially promising as predictive diagnosis and therapeutic monitoring of thrombotic disorders in clinical settings.

Motivation: Considerable attention has been given to the quantification of environmental effects on organisms. In natural conditions, environmental factors are continuously changing in a complex manner. To reveal the effects of such environmental variations on organisms, transcriptome data in field environments have been collected and analyzed. Nagano et al. proposed a model that describes the relationship between transcriptomic variation and environmental conditions and demonstrated the capability to predict transcriptome variation in rice plants. However, the computational cost of parameter optimization has prevented its wide application., Results: : We propose a new statistical model and efficient parameter optimization based on the previous study. We developed and released FIT, an R package that offers functions for parameter optimization and transcriptome prediction. The proposed method achieves comparable or better prediction performance within a shorter computational time than the previous method. The package will facilitate the study of the environmental effects on transcriptomic variation in field conditions., Availability and Implementation: Freely available from CRAN ( https://cran.r-project.org/web/packages/FIT/ )., Contact: : anagano@agr.ryukoku.ac.jp., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2017. Published by Oxford University Press.)

Aim: To compare the outcome of 5-fluorouracil (FU)-based hepatic arterial infusion chemotherapy (HAIC) with sorafenib monotherapy in patients with hepatocellular carcinoma (HCC) refractory to transcatheter arterial chemoembolization (TACE)., Patients and Methods: In this retrospective cohort study, 123 patients with HCC refractory to TACE, with Child-Pugh A and free of extrahepatic metastasis, were divided into two groups: 65 received HAIC and 58 received sorafenib. Since the size of main tumor and portal vein invasion were significantly different between the HAIC and sorafenib groups, we selected 48 patients from the 65 patients of the HAIC group and 48 from the 58 patients of the sorafenib group. The model used one-to-one matching between the two groups using the case-control method matching method. The clinical characteristics of patients of the case-control HAIC (n=48) and sorafenib groups (n=48) were similar. Overall survival, time to progression and time to treatment failure (TTTF) were compared between the two groups., Results: The median survival time and TTTF were significantly longer in the sorafenib group than in the HAIC group (15 and 12.2 months versus 8 and 4.4 months, respectively; p=0.021 and p=0.002, respectively). Multivariate analysis identified male gender (p=0.008), relative tumor size <50% (p=0.012), α-fetoprotein <400 ng/ml (p=0.005), and treatment with sorafenib (p=0.001) as significant and independent determinants of better overall survival., Conclusion: In patients with HCC refractory to TACE, overall survival was favorable in those treated with sorafenib rather than HAIC., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background and Aim: Chronic hepatitis C genotype 2 patients show high susceptibility to pegylated interferon plus ribavirin therapy (PEG/RBV). However, the differences in response to therapy between genotypes 2a and 2b, and the efficacy of prolonged therapy for refractory patients have not been evaluated. We investigated the differences in response to PEG/RBV between each genotype and examined the efficacy of prolonged therapy., Methods: A total of 343 chronic hepatitis patients infected with hepatitis C virus (HCV) genotype 2 (2a: n = 195; 2b: n = 148) were enrolled in this study. All patients received PEG/RBV for 24 (24 week group, n = 242) or more weeks (prolonged group, n = 101). We analyzed the differences in virological response between genotypes 2a and 2b. Clinical and virological factors of patients in the 24-week group and the prolonged treatment group were matched using propensity score analysis, and the efficacy of prolonged therapy established by comparing time of serum HCV disappearance for each genotype., Results: Virological response tended to be higher for genotype 2a compared with genotype 2b; however, there was no significant difference in sustained virological response rates between genotypes (2a: 78.3%; 2b: 70.2%; P = 0.19). After propensity score matching, the adjusted P-value for sustained virological response rate was significantly different for genotype 2b patients with undetectable HCV-RNA between weeks 5 and 8, and for genotype 2a patients with detectable HCV-RNA at week 8., Conclusion: Prolonged therapy with PEG/RBV may be effective when serum HCV-RNA is detectable at week 4 and week 8 for genotype 2b and 2a patients, respectively., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

A Japanese woman was treated with injectable methylprednisolone and oral prednisolone for dermatomyositis. On admission, her serum was positive for anti-hepatitis C virus (HCV) antibodies, although HCV RNA was undetectable on polymerase chain reaction. Glucocorticoid therapy improved the dermatomyositis; however, the serum alanine aminotransferase levels rapidly increased, with positive serum HCV RNA and a high viral titer. Both parameters decreased in association with prednisolone tapering, whereas dermatomyositis subsequently recurred and the administration of glucocorticoid therapy was repeated. The serum alanine aminotransferase and HCV RNA levels subsequently increased in a similar manner to that observed after the first course of therapy. Liver enzymes and the viral load should be monitored in anti-HCV-positive patients receiving immunosuppressives, even if serum HCV RNA is negative.

Background/aims: Interferon (IFN) improves the prognosis of HCV-related hepatocellular carcinoma (HCC) in patients. However, the effects of IFN therapy for second hepatectomy (Hx) for recurrent HCC have not been established., Methodology: Subjects included 96 patients who underwent a second Hx for recurrence of HCV-related HCC. Forty-four patients received IFN therapy past or postoperatively of the first Hx. Twenty of those patients attained a sustained viral response (SVR). The other 24 were non-responders (NR) and 52 patients who had not received IFN therapy (non-IFN) were classified as the NR/non-IFN group., Results: Overall survival (SVR group vs. NR/non-IFN group: 5-yr, 91.7 vs. 51.0%; p = 0.012) and disease-free survival (SVR group vs. NR/non-IFN group: 3-yr, 64.7 vs. 25.9%; p = 0.006) rates were significantly different in both groups. By multivariate analysis, NR/non-IFN therapy, was the independent risk factor for overall survival (p = 0.025) and disease-free survival (p = 0.006) after second Hx., Conclusions: SVR achieved past or postoperatively of the first Hx of HCV-related HCC significantly inhibits recurrence and consequently improves patient survival after second Hx for recurrent HCC. Patients with SVR to IFN therapy would be good candidates for second Hx for recurrent HCC.

Aim:   To examine the impact of ribavirin dose reduction on the efficacy of pegylated interferon (PEG IFN) plus ribavirin combination therapy for elderly patients infected with genotype 1b and high viral loads., Methods:   A total of 72 patients, over 65 years old, were recruited for this study. Patients were divided into groups receiving either 600-800 mg of ribavirin according to bodyweight (Group 1, n = 36) or 400 mg of ribavirin (Group 2, n = 36) plus 1.5 µg/kg (range: 1.3-2.0 µg/kg) of PEG IFN-α-2b for 48 weeks., Results:   Total ribavirin doses were administrated at 9.80 ± 2.39 mg/kg per day (3.29 ± 0.80 g/kg) for Group 1 and 5.87 ± 1.82 mg/kg per day (1.97 ± 0.61 g/kg) for Group 2 (P < 0.001). According to the total clearance (CL/F) of ribavirin, 34 of 36 patients in Group 1 received over-doses of ribavirin. In contrast, numbers of those receiving equivalent doses of ribavirin were two of 36 patients in Group 1 and 36 of 36 patients in Group 2, respectively (P < 0.001). End-of-treatment response (ETR) rates were observed in 23 of 36 patients (63.9%) in the standard ribavirin dose protocol and in 23 of 36 patients (63.9%) in the reduction ribavirin dose protocol (NS). Sustained virological response (SVR) rates were observed in 11 of 36 patients (30.6%) in the standard ribavirin dose protocol, and in 13 of 36 patients (36.1%) in the reduced ribavirin dose protocol (NS)., Conclusion:   Reduction of ribavirin doses for elderly patients did not affect the outcome for the 48-week combination therapy., (© 2011 The Japan Society of Hepatology.)

Aim: We estimated viral dynamics after serum hepatitis C virus (HCV) RNA became negative and assessed the relation between the estimated viral load at the end of treatment (EVE) index and the response to the combination therapy with peginterferon alpha-2b plus ribavirin., Methods: Patients with chronic HCV, genotype 1b, and a high viral load were treated with this combination therapy for 48 weeks, and serum HCV RNA was measured frequently during the treatment period. In the patients showing an end-of-treatment response (ETR), the viral load profile from the start of treatment until serum HCV RNA became negative was expressed by an approximate curve. Then the EVE index was calculated by using the expression obtained from the curve, and differences between the sustained virologic response (SVR) and relapse groups were investigated., Results: The SVR rate increased as the EVE index became lower, and the EVE index was significantly lower in the SVR group than in the relapse group. The SVR rate was higher for those in whom the EVE index was below the cut-off point., Conclusion: Prediction of SVR and relapse from the EVE index is more useful than prediction from viral dynamics at the time when HCV RNA becomes negative or when HCV RNA shows a decrease of 2-log or more.

Washed human erythrocytes were incubated with titanium dioxide (TiO2) particles at 37 degrees C for 1 hr and hemolysis was determined by the percentage of hemoglobin released (optical density at 540 nm; OD540) from the cells. Effects of TiO2 on OD540 were corrected and dose-response curves were analyzed by the Hill plot. Judging from the estimated dose to cause 50% hemolysis, the anatase form of micron-scale (<5000 nm) particles was 73 and 11 times more potent than the amorphous (<50 nm) and rutile (<5000 nm) forms, respectively, whereas it was 1.3 times more potent than the nano-scale (<25 nm) anatase particles. Plasma abolished the hemolysis due to anatase and rutile forms. Thus, hemolytic effects of TiO2 can be greatly different depending on the polymorph but not on the primary size (nano- or micron-scale) of particles. TiO2-induced hemolysis is unlikely to occur in vivo because of the presence of plasma.

Lamivudine (LAM) is a nucleoside analogue widely used for the treatment of chronic hepatitis B virus (HBV) infection. Emergence of resistant strains with amino acid substitutions in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of reverse transcriptase is a serious problem in patients on LAM therapy. The amount of covalently closed circular DNA in the serum is reported to be higher in patients who develop YMDD mutants than in those without mutants. However, there is no useful serum marker that can predict early emergence of mutants during LAM therapy. Analysis of patients who were treated with entecavir (n=7) and LAM (n=36) showed some patients had high serum levels of HBV RNA. Median serum levels of HBV RNA were significantly higher in patients in whom the YMDD mutant had emerged within 1 year (n=6, 1.688 log copies/ml) than in those in whom the YMDD mutant emerged more than 1 year after treatment (n=12, 0.456 log copies/ml, P=0.0125) or in whom the YMDD mutant never emerged (n=18, 0.688 log copies/ml, P=0.039). Our results suggest that HBV RNA is a valuable predictor of early occurrence of viral mutation during LAM therapy.

Objective: We examined whether a sustained negative HCV-RNA status for 48 weeks affects the outcome in patients with genotype 1b and super-high viral load, and also investigated whether the outcome is affected by the induction therapy of twice-daily pre-administrated interferon (IFN)-beta., Methods: 78 eligible patients were divided into four groups. 40 were patients assigned to the short treatment protocol. 13 patients received 3 MU IFN-beta twice daily for 2 weeks followed by IFN-alpha2b+ribavirin for 22 weeks (beta-induction group: group 1). 27 patients received IFN-alpha2b+ribavirin for 24 weeks (standard combination group: group 2). 38 patients were assigned to the maintenance treatment protocol. All of the 13 in the beta-induction group (group 3) and 21 of 25 patients in the standard combination group (group 4) who were negative HCV-RNA PCR at week 24 had IFN monotherapy to maintain a negative HCV-RNA result for 48 weeks., Results: An HCV-RNA-negative status at week 24 was observed in 96% (25/26) of groups 1 and 3 versus in 79% (41/52) of groups 2 and 4 (p<0.01). The sustained virological response (SVR) was 38% (5/13) in group 1 and 11% (3/27) in group 2 (p<0.05). In the maintenance treatment, SVR was observed in 46% (6/13) of group 3 and 32% (8/25) of group 4 (NS)., Conclusions: A sustained negative HCV-RNA status for 48 weeks might be associated with viral elimination in patients with genotype 1 and super-high viral load., (Copyright (c) 2006 S. Karger AG, Basel.)

A 53-year-old housewife was the donor when living-related donor liver transplantation (LRLT) was performed in her younger sister (49-year-old) with terminal primary biliary cirrhosis (PBC). The donor's liver histology was diagnostic and compatible with PBC, although she was negative for antimitochondrial antibody (AMA: a specific marker of PBC) by immunofluorescence and had normal liver function tests as well as no symptoms of liver disease. In this patient with latent PBC, AMA was eventually detected by immunoblotting, although it was not detected by ELISA. These findings indicate that a family history of PBC is a risk factor for the development of this disease. Our patient was diagnosed before the advent of any clinical or biochemical indicators and before or at the onset of AMA positivity, so her liver histology revealed the earliest stage of PBC.

We have previously reported the induction of immune-mediated cholangiohepatitis following injection of a hybrid recombinant proteins containing the E2 of the pyruvate dehydrogenase (PDC-E2) and the branched-chain keto-acid dehydrogenase (BCOADC-E2) to neonatally thymectomized (Tx) A/J mice. Further, we demonstrated that intrahepatic infiltrating mononuclear cells could transfer pathology to other Tx mice. To further our observations, we examined intrahepatic infiltrating mononuclear cells by flow cytometry and used cell transfer experiments to identify the phenotype involved. Interestingly, following immunization of neonatally Tx A/J mice and immunization with the bihybrid molecule, the number of CD3+infiltrating mononuclear cells were significantly higher (77.8%) compared with the control group. There was a small although not significant increase among intrahepatic infiltrating mononuclear cells and splenic cells of Vbeta 5.1,5.2+, Vbeta7+and Vbeta17+. In addition, Vbeta14+cells accounted for 20.4% of the infiltrating T-cells (P<0.01 vs. the control group). In further experiments, CD3+, CD4+or CD8+cells were isolated and removed from intrahepatic infiltrating mononuclear cells and subpopulations of mononuclear cells transferred to Tx mice. Both CD3+CD4+cells and CD3+CD8+cells are required for development of the lesion, and the damage is mediated by CD3+Vbeta14+cells., (Copyright 2000 Academic Press.)