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BACKGROUND AND AIMS: As practice patterns and hepatitis C virus (HCV) genotypes (GT) vary geographically, a global real-world study from both East and West covering all GTs can help inform practice policy toward the 2030 HCV elimination goal. This study aimed to assess the effectiveness and tolerability of DAA treatment in routine clinical practice in a multinational cohort for patients infected with all HCV GTs, focusing on GT3 and GT6. METHODS: We analyzed the sustained virological response (SVR12) of 15,849 chronic hepatitis C patients from 39 Real-World Evidence from the Asia Liver Consortium for HCV clinical sites in Asia Pacific, North America, and Europe between 07/01/2014-07/01/2021. RESULTS: The mean age was 62±13 years, with 49.6% male. The demographic breakdown was 91.1% Asian (52.9% Japanese, 25.7% Chinese/Taiwanese, 5.4% Korean, 3.3% Malaysian, and 2.9% Vietnamese), 6.4% White, 1.3% Hispanic/Latino, and 1% Black/African-American. Additionally, 34.8% had cirrhosis, 8.6% had hepatocellular carcinoma (HCC), and 24.9% were treatment-experienced (20.7% with interferon, 4.3% with direct-acting antivirals). The largest group was GT1 (10,246 [64.6%]), followed by GT2 (3,686 [23.2%]), GT3 (1,151 [7.2%]), GT6 (457 [2.8%]), GT4 (47 [0.3%]), GT5 (1 [0.006%]), and untyped GTs (261 [1.6%]). The overall SVR12 was 96.9%, with rates over 95% for GT1/2/3/6 but 91.5% for GT4. SVR12 for GT3 was 95.1% overall, 98.2% for GT3a, and 94.0% for GT3b. SVR12 was 98.3% overall for GT6, lower for patients with cirrhosis and treatment-experienced (TE) (93.8%) but ≥97.5% for treatment-naive patients regardless of cirrhosis status. On multivariable analysis, advanced age, prior treatment failure, cirrhosis, active HCC, and GT3/4 were independent predictors of lower SVR12, while being Asian was a significant predictor of achieving SVR12. CONCLUSIONS: In this diverse multinational real-world cohort of patients with various GTs, the overall cure rate was 96.9%, despite large numbers of patients with cirrhosis, HCC, TE, and GT3/6. SVR12 for GT3/6 with cirrhosis and TE was lower but still excellent (>91%).

DOI： 10.14218/JCTH.2024.00089

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To establish clinical prediction models of vessels encapsulating tumor clusters (VETC) pattern using preoperative contrast-enhanced ultrasound (CEUS) and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging (EOB-MRI) in patients with hepatocellular carcinoma (HCC). A total of 111 resected HCC lesions from 101 patients were included. Preoperative imaging features of CEUS and EOB-MRI, postoperative recurrence, and survival information were collected from medical records. The best subset regression and multivariable Cox regression were used to select variables to establish the prediction model. The VETC-positive group had a statistically lower survival rate than the VETC-negative group. The selected variables were peritumoral enhancement in the arterial phase (AP), hepatobiliary phase (HBP) on EOB-MRI, intratumoral branching enhancement in the AP of CEUS, intratumoral hypoenhancement in the portal phase of CEUS, incomplete capsule, and tumor size. A nomogram was developed. High and low nomogram scores with a cutoff value of 168 points showed different recurrence-free survival rates and overall survival rates. The area under the curve (AUC) and accuracy were 0.804 and 0.820, respectively, indicating good discrimination. Decision curve analysis showed a good clinical net benefit (threshold probability > 5%), while the Hosmer-Lemeshow test yielded excellent calibration (P = 0.6759). The AUC of the nomogram model combining EOB-MRI and CEUS was higher than that of the models with EOB-MRI factors only (0.767) and CEUS factors only (0.7). The nomogram verified by bootstrapping showed AUC and calibration curves similar to those of the nomogram model. The Prediction model based on CEUS and EOB-MRI is effective for preoperative noninvasive diagnosis of VETC.

DOI： 10.5582/bst.2024.01112

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BACKGROUND: This study aimed to clarify the morphological changes in esophageal varices after achieving sustained virological response (SVR) with direct-acting antivirals (DAAs) in patients with cirrhosis. METHODS: A total of 243 patients underwent esophagogastroduodenoscopy before DAA treatment and after achieving SVR. Morphological changes in esophageal varices were investigated using esophagogastroduodenoscopy. RESULTS: This study comprised 125 males and 118 females with a median age of 68 years. Esophageal varices at baseline were classified into no varix in 155 (63.8%), F1 in 59 (24.3%), F2 in 25 (10.3%) and F3 in 4 (1.6%) patients. The improvement, unchanged, and aggravation rates of esophageal varices after SVR were 11.9%, 73.3%, and 14.8%, respectively. High ALBI score at SVR12 was an independent factor associated with post-SVR esophageal varices aggravation (p = 0.045). Time-dependent receiver operating characteristic (ROC) curve analysis revealed a cut-off value of - 2.33 for ALBI score at SVR12 in predicting post-SVR esophageal varices aggravation. Of the 155 patients without esophageal varices at baseline, 17 developed de novo post-SVR esophageal varices. High ALBI score at SVR12 was a significant independent factor associated with de novo post-SVR esophageal varices (p = 0.046). ROC curve analysis revealed a cut-off value of - 2.65 for ALBI score at SVR12 in predicting de novo post-SVR esophageal varices. CONCLUSIONS: Patients with cirrhosis can experience esophageal varices aggravation or de novo esophageal varices, despite achieving SVR. In particular, patients with high ALBI score at SVR12 have a high likelihood of developing post-SVR esophageal varices aggravation or de novo post-SVR esophageal varices.

DOI： 10.1007/s00535-024-02109-8

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AIM: An association between hepatitis B core-related antigen (HBcrAg) kinetics and hepatocarcinogenesis during nucleoside (t)id analog (NA) treatment has recently been reported. HBcrAg kinetics and factors associated with HBcrAg response during tenofovir alafenamide (TAF) administration remain unclear. In this multicenter retrospective study, we aimed to clarify the efficacy and safety of TAF in treatment-naïve patients with chronic hepatitis B, focusing on the reduction in HBcrAg levels. METHODS: Patients were treated with TAF monotherapy for 96 weeks, and the kinetics of HBcrAg during treatment and the factors associated with HBcrAg response (defined as a change in HBcrAg of -1 log IU/mL from baseline) were evaluated. RESULTS: The study population comprised 241 patients, 36.9% of whom were HBeAg-positive. The median baseline HBcrAg level was 4.7 log IU/mL. The median change in HBcrAg from baseline was -1.1 log IU/mL at 96 weeks after treatment. The HBcrAg response rate at 96 weeks was 56.6% (43/76). Multivariate analysis revealed high alanine transaminase level as an independent baseline factor associated with HBcrAg response at 96 weeks of treatment (p = 4.53 × 10-6). No correlation was found between the HBcrAg and hepatitis B surface antigen kinetics in patients treated with TAF monotherapy. CONCLUSIONS: In TAF monotherapy for patients with chronic hepatitis B, HBcrAg levels were significantly decreased and baseline alanine transaminase level is an important factor associated with HBcrAg reduction. As no correlation was found between HBcrAg and reduced hepatitis B surface antigen levels in this study, HBcrAg kinetics in addition to hepatitis B surface antigen may need to be monitored during TAF treatment.

DOI： 10.1111/hepr.14052

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DOI： 10.22541/au.171189338.87013934/v1

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BACKGROUND AND AIM: The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)-related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear. METHODS: A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all-cause, liver-related, and non-liver-related mortality between patients receiving ETV and those receiving TDF. RESULTS: The annual incidence of all-cause mortality in the entire cohort was 1.0/100 person-years (follow-up, 15 757.5 person-years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e-antigen seropositivity than those who received ETV. The factors associated with all-cause mortality were fibrosis-4 index > 6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15-4.54, P < 0.001), age per year increase (HR/CI: 1.05/1.04-1.07, P < 0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996-0.999, P = 0.003), and γ-glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001-1.003, P < 0.001). No significant difference in all-cause mortality was observed between the ETV and TDF groups (log-rank test, P = 0.69). After propensity score matching, no significant differences in all-cause, liver-related, or non-liver-related mortality were observed between the two groups. CONCLUSIONS: Long-term outcomes of all-cause mortality and liver-related and non-liver-related mortality did not differ between patients treated with ETV and those receiving TDF.

DOI： 10.1111/jgh.16537

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Background and Aim

While several predictive models for the development of hepatocellular carcinoma (HCC) have been proposed, including those for patients with chronic hepatitis C virus (HCV) infection who have achieved sustained virologic response (SVR), the best model may differ between regions. We compared the ability of six reported models to stratify the risk of post‐SVR HCC in Japan, where rigorous surveillance and early detection of HCC is common.

Methods

A total of 6048 patients with no history of HCC who achieved SVR by oral direct‐acting antiviral drugs were enrolled in this nationwide study. Patients continued HCC surveillance every 6 months after SVR. The incidence of post‐SVR HCC was compared between risk groups using the aMAP score, FIB‐4 index, Tahata model, GAF4 criteria, GES score, and ADRES score.

Results

During the observation period with a median duration of 4.0 years after SVR, post‐SVR HCC developed in 332 patients (5.5%). All six models performed significantly at stratifying the incidence of HCC. However, Harrell's C‐index was below 0.8 for all models (range, 0.660–0.748), indicating insufficient stratification ability.

Conclusion

Although all six proposed models demonstrated a good ability to predict the development of post‐SVR HCC, their ability to stratify the risk of post‐SVRHCC was unsatisfactory. Further studies are necessary to identify the best model for assessing the risk of post‐SVR HCC in regions where early detection of HCC is common.

DOI： 10.1111/jgh.16494

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BACKGROUND & AIMS: Widespread use of direct-acting antivirals for hepatitis C virus infection has been paralleled with increased numbers of patients with hepatocellular carcinoma (HCC) after achieving sustained virologic response (post-SVR HCC) worldwide. Few data compare regional differences in the presentation and prognosis of patients with post-SVR HCC. METHODS: We identified patients with advanced fibrosis (F3/F4) who developed incident post-SVR HCC between March 2015 and October 2021 from 30 sites in Europe, North America, South America, the Middle East, South Asia, East Asia, and Southeast Asia. We compared patient demographics, liver dysfunction, and tumor burden by region. We compared overall survival by region using Kaplan-Meier analysis and identified factors associated with survival using multivariable Cox regression analysis. RESULTS: Among 8796 patients with advanced fibrosis or cirrhosis who achieved SVR, 583 (6.6%) developed incident HCC. There was marked regional variation in the proportion of patients detected by surveillance (range: 59.5%-100%), median maximum tumor diameter (range, 1.8-5.0 cm), and the proportion with multinodular HCC (range, 15.4%-60.8%). The prognosis of patients highly varied by region (hazard ratio range, 1.82-9.92), with the highest survival rates in East Asia, North America, and South America, and the lowest survival rates in the Middle East and South Asia. After adjusting for geographic region, HCC surveillance was associated with early stage detection (Barcelona Clinic Liver Cancer stage 0/A, 71.0% vs 21.3%; P < .0001) and lower mortality rates (adjusted hazard ratio, 0.29; 95% CI, 0.18-0.46). CONCLUSIONS: Clinical characteristics, including early stage detection, and prognosis of post-SVR HCC differed significantly across geographic regions. Surveillance utilization appears to be a high-yield intervention target to improve prognosis among patients with post-SVR HCC globally.

DOI： 10.1016/j.cgh.2023.06.026

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Elevated serum gamma-glutamyl transferase (GGT) levels are associated with chronic hepatitis B (CHB)-related hepatocellular carcinoma. However, their role in predicting mortality in patients with CHB treated with nucleotide/nucleoside analogs (NAs) remains elusive. Altogether, 2843 patients with CHB treated with NAs were recruited from a multinational cohort. Serum GGT levels before and 6 months (Month-6) after initiating NAs were measured to explore their association with all-cause, liver-related, and non-liver-related mortality. The annual incidence of all-cause mortality was 0.9/100 person-years over a follow-up period of 17,436.3 person-years. Compared with patients who survived, those who died had a significantly higher pretreatment (89.3 vs. 67.4 U/L, p = 0.002) and Month-6-GGT levels (62.1 vs. 38.4 U/L, p < 0.001). The factors associated with all-cause mortality included cirrhosis (hazard ratio [HR]/95% confidence interval [CI]: 2.66/1.92-3.70, p < 0.001), pretreatment GGT levels (HR/CI: 1.004/1.003-1.006, p < 0.001), alanine aminotransferase level (HR/CI: 0.996/0.994-0.998, p = 0.001), and age (HR/CI: 1.06/1.04-1.07, p < 0.001). Regarding liver-related mortality, the independent factors included cirrhosis (HR/CI: 4.36/2.79-6.89, p < 0.001), pretreatment GGT levels (HR/CI: 1.006/1.004-1.008, p < 0.001), alanine aminotransferase level (HR/CI: 0.993/0.990-0.997, p = 0.001), age (HR/CI: 1.03/1.01-1.05, p < 0.001), and fatty liver disease (HR/CI: 0.30/0.15-0.59, p = 0.001). Pretreatment GGT levels were also independently predictive of non-liver-related mortality (HR/CI: 1.003/1.000-1.005, p = 0.03). The results remained consistent after excluding the patients with a history of alcohol use. A dose-dependent manner of <25, 25-75, and >75 percentile of pretreatment GGT levels was observed with respect to the all-cause mortality (trend p < 0.001). Pretreatment serum GGT levels predicted all-cause, liver-related, and non-liver-related mortality in patients with CHB treated with NAs.

DOI： 10.1002/kjm2.12771

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BACKGROUND & AIMS: It is unclear if there may be sex differences in response to nucleos(t)ide analogs including viral suppression (VR), biochemical response (BR), complete response (CR), and hepatocellular carcinoma (HCC) incidence among hepatitis B patients. We compared nucleos(t)ide analog treatment outcomes by sex. METHODS: We performed a retrospective cohort study of 3388 treatment-naïve adult hepatitis B patients (1250 female, 2138 male) from the Real-World Evidence from the Global Alliance for the Study of Hepatitis B Virus consortium who initiated therapy with either entecavir or tenofovir from 22 sites (Argentina, Korea, Japan, Taiwan, and the United States). We used propensity-score matching to balance background characteristics of the male and female groups and competing-risks analysis to estimate the incidence and subdistribution hazard ratios (SHRs) of VR, BR, CR, and HCC. RESULTS: Females (vs males) were older (52.0 vs 48.6 y); less likely to be overweight/obese (49.3% vs 65.7%), diabetic (9.9% vs 13.1%), or cirrhotic (27.9% vs 33.0%); and had a lower HBV DNA level (5.9 vs 6.0 log10 IU/mL) and alanine aminotransferase level (91 vs 102 IU/L) (all P < .01). However, after propensity-score matching, relevant background characteristics were balanced between the 2 groups. Females (vs males) had similar 5-year cumulative VR (91.3% vs 90.3%; P = .40) and HCC incidence rates (5.1% vs 4.4%; P = .64), but lower BR (84.0% vs 90.9%; P < .001) and CR (78.8% vs 83.4%; P = .016). Males were more likely to achieve BR (SHR, 1.31; 95% CI, 1.17-1.46; P < .001) and CR (SHR, 1.16; 95% CI, 1.03-1.31; P = .016), but VR and HCC risks were similar. CONCLUSIONS: Sex differences exist for treatment outcomes among hepatitis B patients. Male sex was associated with a 16% higher likelihood of clinical remission and a 31% higher likelihood of biochemical response than females, while viral suppression and HCC incidence were similar between the 2 groups.

DOI： 10.1016/j.cgh.2023.09.002

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Language：English   Publisher：(一社)日本癌学会  

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12072-023-10547-4

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BACKGROUND: Tricuspid regurgitation pressure gradient (TRPG) measurement by echocardiography is recommended as the most objective examination to detect portopulmonary hypertension (PoPH). This study aimed to identify factors associated with a high TRPG in patients with cirrhosis and develop a scoring model for identifying patients who are most likely to benefit from echocardiography investigations. RESULTS: A total of 486 patients who underwent echocardiography were randomly allocated to the derivation and validation sets at a ratio of 2:1. Of the patients, 51 (10.5%) had TRPG ≥ 35 mmHg. The median brain natriuretic peptide (BNP) was 39.5 pg/mL. Shortness of breath (SOB) was reported by 91 (18.7%) patients. In the derivation set, multivariate analysis identified female gender, shortness of breath, and BNP ≥ 48.9 pg/mL as independent factors for TRPG ≥ 35 mmHg. The risk score for predicting TRPG ≥ 35 mmHg was calculated as follows: - 3.596 + 1.250 × gender (female: 1, male: 0) + 1.093 × SOB (presence: 1, absence: 0) + 0.953 × BNP (≥ 48.9 pg/mL: 1, < 48.9 pg/mL: 0). The risk score yielded sensitivity of 66.7%, specificity of 75.3%, positive predictive value of 25.5%, negative predict value of 94.3%, and predictive accuracy of 74.4% for predicting TRPG ≥ 35 mmHg. These results were almost similar in the validation set, indicating the reproducibility and validity of the risk score. CONCLUSIONS: This study clarified the characteristics of patients with suspected PoPH and developed a scoring model for identifying patients at high risk of PoPH, which may be used in selecting patients that may benefit from echocardiography.

DOI： 10.1007/s12072-022-10456-y

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DOI： 10.1111/jvh.13717

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

Lenvatinib is appropriate for reducing the production of nitric oxide (NO) and facilitating as block angiogenesis. However, to our knowledge, there are no data that support the correlation between NO and clinical response in patients who received lenvatinib therapy for HCC. Therefore, we investigated the correlation between the change rate of NO levels and clinical responses including adverse events (AEs) after lenvatinib therapy for unresectable hepatocellular carcinoma (HCC).

Methods

This study was conducted using previously collected data from another study. We enrolled 70 patients who received lenvatinib for advanced or unresectable HCC. NO was measured by converting nitrate (NO₃⁻) to nitrite (NO₂⁻) with nitrate reductase, followed by quantitation of NO₂⁻ based on Griess reagent. To determine whether lenvatinib influences NO in unresectable HCC, we evaluated the influence of the change rate of NO from baseline after administration of lenvatinib on maximal therapeutic response and SAE.

Results

After lenvatinib administration, a change rate in the NO from 0.27 to 4.16 was observed. There was no difference between the clinical response to lenvatinib and the change rate of NO (p = 0.632). However, the change rate of NO was significantly lower in patients with AEs than in those without AEs (p = 0.030). When a reduction in NO rate of &lt; 0.8 was defined as a clinically significant reduction of NO (CSRN), the CSRN group had significantly worse progression-free survival (PFS) and overall survival (OS) than the non-CSRN group (p = 0.029 and p = 0.005, respectively).

Conclusion

Decreased NO levels were associated with the occurrence of AEs and worse prognosis after lenvatinib administration. Change rate in serum NO can be used as predictive markers in patients receiving lenvatinib therapy for HCC.

DOI： 10.1186/s12885-022-10002-x

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Despite reports of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection after achieving sustained virological response (SVR), only few studies have demonstrated the incidence of other (non-HCC) malignancies. This study aimed to clarify the incidence, survival probability, and factors associated with malignancy, especially non-HCC malignancies, in patients with chronic HCV infection after achieving SVR. In this retrospective study, records of 3580 patients with chronic HCV infection who achieved SVR following direct-acting antiviral (DAA) treatment were analyzed. The cumulative post-SVR incidence of non-HCC malignancies was 0.9%, 3.1%, and 6.8% at 1, 3, and 5 years, respectively. The survival probability for patients with non-HCC malignancies was 99.1%, 78.8%, and 60.2% at 1, 3, and 5 years, respectively, and the rate was significantly lower than that for patients with HCC. The Cox proportional hazards regression model identified Mac-2-binding protein glycan isomer (M2BPGi) cutoff index (COI) ≥ 1.90 at baseline and ≥ 1.50 at 12 weeks following DAA treatment as significant and independent factors associated with the post-SVR incidence of non-HCC malignancies. Furthermore, patients with either M2BPGi COI ≥ 1.90 at baseline or M2BPGi COI ≥ 1.50 at SVR12 had a significantly higher risk of post-SVR incidence of non-HCC malignancies than of HCC. Conclusion: M2BPGi measurements at baseline and SVR12 may help predict the post-SVR incidence of non-HCC malignancies in patients with chronic HCV infection who achieved SVR following DAA treatment. Early identification of these patients is critical to prolong patient survival.

DOI： 10.1002/hep4.1941

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BACKGROUND: In this study, we investigated the impact of simple measurement of psoas muscle index (PMI) on the tolerability of sorafenib treatment of switch from sorafenib to regorafenib. METHOD: This retrospective study enrolled 109 patients with Child-Pugh A hepatocellular carcinoma (HCC) treated with sorafenib. Pretreatment PMI was calculated by measuring and multiplying the greatest anterior/posterior and transverse diameters of the psoas muscles on axial computed tomography images at the L3 vertebral level, and normalizing the sum of bilateral psoas muscle areas by the square of the height in meters. We, then, statistically analyzed the association between PMI and adverse events (AEs) to treatment, tolerability of sorafenib, time to treatment failure (TTF), and prognosis in patients stratified according to PMI. RESULT: Patients were divided into high PMI (n = 41) and low PMI (n = 68) groups based on the cutoff PMI values (men: 7.04 cm2/m2; women: 4.40 cm2/m2) determined by receiver operating characteristic curve analysis to determine sorafenib tolerability. Frequencies of all types of severe AEs were higher in the low PMI group (50.0%) than in the high PMI group (29.3%; P = 0.045). The high PMI group (51.2%) had greater tolerance to sorafenib than the low PMI group (25.0%; P = 0.007). Moreover, in multivariable analysis, PMI was associated with sorafenib tolerability (odds ratio 0.26; P = 0.008) and was a prognostic factor affecting TTF (hazard ratio 1.77; P = 0.021). CONCLUSION: PMI might be a predictive marker of tolerance to treatment and TTF in HCC patients receiving sorafenib treatment.

DOI： 10.1097/MEG.0000000000002346

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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Lenvatinib is approved as a first-line treatment for unresectable HCC. The therapeutic duration of lenvatinib is limited by resistance, but the underlying mechanism is unclear. To establish lenvatinib-resistant cells, Hep3B cells were initially treated with 3 µM lenvatinib. The concentration was gradually increased by 1 µM or 0.5 µM per week and it reached to 7.5 µM 2 months after the initial exposure to lenvatinib. The biological characteristics of these cells were analyzed by ERK activation in the MAPK signaling pathway and a human phospho-receptor tyrosine kinase (RTK) antibody array. Factors possibly related to lenvatinib resistance were analyzed using inhibitors, and cell proliferation was analyzed. We established lenvatinib-resistant HCC cells (LR cells) by long-term exposure to lenvatinib. Lenvatinib reduced ERK activation in the parent cells, but not in the LR cells. RTK array analysis showed that the activities of EGFR and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) were significantly increased in LR cells, whereas the activities of other RTKs were unchanged. Erlotinib, a widely used EGFR inhibitor, downregulated ERK activation in LR cells. The proliferation of LR cells will also be affected when lenvatinib is combined with erlotinib to treat LR cells. In contrast, inhibition of IGFR/INSR did not affect ERK activation or cell proliferation. Scavenging of reactive oxygen species (ROS) ameliorated the enhanced EGFR activation in LR cells. Lenvatinib resistance was induced by enhanced EGFR activation, possibly via ROS accumulation, in lenvatinib- resistant cells. These findings may enable the development of lenvatinib combination therapies for HCC.

DOI： 10.1038/s41598-022-12076-w

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jiac.2022.04.024

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/hepr.13739

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Language：Japanese   Publisher：(一社)日本胃癌学会  

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.gastha.2022.02.018

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BACKGROUND: The present study aimed to evaluate the efficacy and safety of combined lenvatinib (first-line systemic therapy) and radiofrequency ablation (RFA) therapy in patients with intermediate-stage hepatocellular carcinoma with beyond up-to-seven criteria and Child-Pugh Class A liver function (CP A B2-HCC). METHODS: Twenty-two patients with CP A B2-HCC were enrolled in the study. The patients had no history of systemic treatment. For the initial lenvatinib administration in this study, all of the patients had an adequate course of treatment (no less than two weeks) and were administered the recommended dose. Of them, 13 were treated by means of lenvatinib monotherapy (monotherapy group), while the 9 patients with no contraindication to RFA operation and who had consented to RFA received initial lenvatinib plus subsequent RFA (combination group). The clinical outcomes that were considered to evaluate the treatments included tumor response, prognosis (recurrence and survivals), and possible adverse events (serum liver enzymes and clinically visible complications). RESULTS: The combination group exhibited a higher object response rate (9/9, 100%) as best tumor response than the monotherapy group (10/13, 76.9%). Longer progression-free survival (PFS) (12.5 months) and overall survival (OS) (21.3) were demonstrated in the combination group than in the monotherapy group (PFS: 5.5 months; OS:17.1 months). The combination group achieved a higher PFS rate (1-year: 74.1%) and OS rate (2-year: 80%) than the monotherapy group (1-year PFS rate: 0%; 2-year OS rate: 25.6%; for PFS, p<0.001; for OS, p=0.022). The treatment strategy was the independent factor for PFS (HR: 18.215 for monotherapy, p =0.010), which was determined by Cox regression analysis, suggesting that a combination strategy may reduce tumor progression when compared to the use of lenvatinib alone. There were no statistically significant intergroup differences that were observed in terms of adverse events, with the exception of ALT elevation (p=0.007) in the combination group. CONCLUSION: Our newly proposed combination therapy may potentially be effective and safe for CP A B2-HCC beyond up-to-seven criteria. A larger scale, multicenter, prospective study is warranted to confirm our findings.

DOI： 10.3389/fonc.2022.843680

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Hepatocellular carcinoma (HCC) can de novo develop in patients with chronic hepatitis C even after the achievement of sustained virologic response (SVR). We characterized de novo HCC after SVR, comparing it with HCC that developed in patients during persistent hepatitis C virus (HCV) infection. Characteristics, survival rates, and recurrence rates after curative treatment in 178 patients who developed initial HCC after SVR diagnosed between 2014 and 2020 were compared with those of 127 patients with initial HCC that developed during persistent HCV infection diagnosed between 2011 and 2015; HCC was detected under surveillance in both groups. HCC was less advanced and liver function worsened less in patients with SVR than in patients with persistent HCV. The survival rate after diagnosis was significantly higher for patients with SVR than for patients with persistent HCV (1-, 3-, and 5-year survival rates, 98.2%, 92.5%, and 86.8% versus 89.5%, 74.7%, and 60.8%, respectively; P < 0.001). By contrast, the recurrence rate after curative treatment was similar between groups (1-, 3-, and 5-year recurrence rates, 11.6%, 54.6%, and 60.4% versus 24.0%, 46.7%, and 50.4%, respectively; P = 0.7484). Liver function improved between initial HCC diagnosis and recurrence in patients with SVR (P = 0.0191), whereas it worsened in the control group (P < 0.001). In addition, patients with SVR could receive curative treatment for recurrence more frequently than patients with persistent HCV (80.4% versus 47.8%, respectively; P = 0.0008). Conclusion: Survival of patients with de novo HCC after SVR was significantly higher than that of patients in whom HCC developed during persistent HCV infection, despite similar rates of recurrence after curative treatment. A higher prevalence of curative treatment for recurrent HCC and improved liver function contributed to this result.

DOI： 10.1002/hep4.1716

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INTRODUCTION: Entecavir (ETV) and tenofovir alafenamide (TAF) are both first-line hepatitis B virus (HBV) therapies, but ETV-to-TAF switch outcome data are limited. We aimed to assess outcomes up to 96 weeks after ETV-to-TAF switch. METHODS: ETV-treated (≥12 months) chronic hepatitis B patients switched to TAF in routine practice at 15 centers (United States, Korea, Japan, and Taiwan) were included. Primary outcome was complete viral suppression (CVS) rate (HBV DNA <20 IU/mL). RESULTS: We analyzed 425 eligible patients (mean age 60.7 ± 13.2 years, 60% men, 90.8% Asian, 20.7% with diabetes, 27% with hypertension, 14.8% with cirrhosis, 8.3% with hepatocellular carcinoma, and mean ETV duration before switch 6.16 ± 3.17 years). The mean baseline estimated glomerular filtration rate (eGFR) was 89 ± 19 (chronic kidney disease [CKD] stages: 55.6% stage 1, 35.7% stage 2, and 8.8% stages 3-5). CVS rate increased from 91.90% at switch (from 90.46% 24 weeks before switch) to 95.57% and 97.21% at 48 and 96 weeks after (P = 0.03 and 0.02, respectively). Over the 96 weeks after switch, mean HBV DNA (P < 0.001) but not alanine aminotransferase or CKD stage decreased. Between switch and 96-week follow-up, 11% (26/235) of CKD stage 1 patients migrated to stage 2 and 8% (12/151) of stage 2 patients to stages 3-5, whereas 18% (27/151) from stage 2 to 1, and 19% (7/37) from stages 3-5 to 2. On multivariable generalized estimated equation analysis adjusted for age, sex, hypertension, diabetes, and cirrhosis, baseline eGFR, age (P < 0.001), and CKD stages 2 and 3-5 (vs 1) (both P < 0.001) were associated with lower follow-up eGFR. DISCUSSION: After an average of 6 years on ETV, CVS increased from 91.9% at TAF switch to 97.2% at 96 weeks later.

DOI： 10.14309/ajg.0000000000001157

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PURPOSE: To estimate the role of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced MRI (EOB-MRI) in predicting hypervascularization outcome of non-hypervascular hypointense hepatic lesions in high-risk patients for hepatocellular carcinoma (HCC). METHODS: Under the premise of non-hyperenhance in arterial phase (AP) and hypointensity in hepatobiliary phase (HBP) of EOB-MRI, 29 fresh lesions from 22 patients with chronic viral hepatitis (median (range) age: 69(57-82) years) were prospectively enrolled. During continuously followed-up by EOB-MRI, lesional vascularity in AP, the signal intensity (SI) ratios of lesions-to-parenchyma in HBP images (post-contrast ratio) and adjusted enhancement with reference of unenhanced images (EOB enhancement ratio) were examined. RESULTS: After 644 (220-2912) days of follow-up, 20 lesions changed into hyperenhancement in AP of EOB-MRI (hypervascularized group), while nine remained non-hyperenhanced (maintained non-hypervascular group). There is no statistical difference of post-contrast ratio at the initial detection. The post-contrast ratios in hypervascularized group were different between each follow-up time point when followed-up ≥ three (P < 0.01) and four (P < 0.05) times, and exposed a linear downward trend with time. Between the hypervascularized and maintained non-hypervascular groups, there were significant differences in the post-contrast ratio at endpoint for three-times' follow-up (P < 0.001); and at the second (P = 0.037), third follow-up time points (P = 0.005), endpoint (P = 0.005) for four-times' follow-up. EOB enhancement ratio showed inter-group difference only at endpoint for three-times' follow-up (P = 0.008). CONCLUSION: For non-hypervascular, HBP hypointense hepatic lesions, decreasing trend of SI in HBP may early predict unfavorable hypervascularized outcome.

DOI： 10.1007/s00261-020-02881-0

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BACKGROUND: This study aimed to compare the value of Sonazoid contrast-enhanced ultrasound (SCEUS) with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging (EOB-MRI) for histological grading diagnosis, especially for early hepatocellular carcinoma (eHCC). METHODS: A total of 163 histopathologically confirmed HCC lesions were retrospectively collected, including 71 eHCCs (27 hypervascular, 44 non-hypervascular) and 92 advanced HCCs (adHCC) (73 hypervascular, 19 non-hypervascular). We performed SCEUS to evaluate the lesions' vascularity during the portal phase (PP) and the echogenicity during the post-vascular phase (PVP). EOB-MRI was used to determine the signal intensity between lesions and the surrounding liver parenchyma on unenhanced T1-weighted images (pre-contrast ratio) in the hepatobiliary phase (HBP) (post-contrast ratio). RESULTS: For the PP and PVP of SCEUS (for all lesions), the pre-and post-contrast ratios of EOB-MRI (for all hypervascular lesions) showed statistical differences in the diagnosis of some (but not all) histological grades. For the diagnosis of eHCC, isoechogenicity in the PVP achieved the best diagnostic efficacy [area under the receiver operating characteristic curve (AUC) =0.892]. Whether used independently or in a combination of any form, all indicators failed to produce a higher diagnostic efficacy than PVP. Post- (≥0.610) and pre-contrast ratios (≥0.981) yielded acceptable diagnostic efficacy, with, respectively, accuracy levels of 69.3% and 75.5% and AUC values of 0.719 and 0.736. For eHCC diagnosis, the post-contrast ratio (≥0.625) and combined diagnosis using pre- (≥0.907) and post-contrast ratios (≥0.609) revealed the highest sensitivity (92.6%) for hypervascular lesions and perfect specificity (100%) for non-hypervascular lesions. CONCLUSIONS: Unenhanced T1-weighted images and the HBP of EOB-MRI [regardless of the vascularity in the arterial phase (AP)], and the PP and PVP of SCEUS showed their value in the histological grading diagnosis of HCC. In particular, isoechogenicity in the PVP may have promising diagnostic utility for eHCC.

DOI： 10.21037/qims-20-685

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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ABSTRACT: Oral direct-acting antiviral (DAA) treatment leads to >95% sustained virological response (SVR) and could be clinically useful in regression of liver fibrosis in chronic hepatitis C virus (HCV) infection. We evaluated if ledipasvir/sofosbuvir or sofosbuvir + ribavirin is associated with regression of fibrosis in HCV patients who achieved SVR.In this prospective cohort study performed at 3 sites in Japan, patients with genotype 1 and genotype 2 were given standard treatment of ledipasvir 90 mg/sofosbuvir 400 mg and sofosbuvir 400 mg + 200-1000 mg/day ribavirin, respectively, for 12 weeks. Liver fibrosis was assessed using Mac-2-binding protein glycosylation isomer (M2BPGi) and other fibrosis markers (platelet count, Fib-4 index, liver stiffness measurement [LSM]) in patients who achieved SVR.A total of 98.1% of (n = 101/103) patients in genotype 1 cohort and 100% (n = 16/16) in the genotype 2 cohort achieved SVR12. Based on per-protocol analysis, M2BPGi levels showed a significant decrease (-2.2  cut-off index [COI], P < .0001) at week 48 after treatment initiation. Forty-three patients showed a significant decrease in Fib-4 index (-1.2, P < .0001), and 44 patients showed improvement in LSM (-5.9 kPa, P < .0001).Achievement of SVR after antiviral therapy was associated with fibrosis regression. M2BPGi correlated well with LSM at week 48 after treatment initiation, supporting the sustainable benefit of HCV therapy.

DOI： 10.1097/MD.0000000000025110

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Baishideng Publishing Group Co  

BACKGROUND The oral nucleos(t)ide analogue, entecavir (ETV) was demonstrated to reduce the rate of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)- associated liver cirrhosis. However, the reduction of HCC differs in various regions of the world. AIM To investigate the reduction of HCC development due to ETV therapy by metaanalysis. METHODS We surveyed the differences in HCC development following ETV treatment based on published articles using PubMed (2004-2019). RESULTS The regions with the most marked reduction in HCC development due to ETV therapy were Spain (1.0%/year) and Canada (Southern part, 1.3%/year), and the most ineffective areas were South Korea (3.6%-3.8%/year), China (3.3%/year), Taiwan (2.4%-3.1%/year), and Hong Kong (2.8%/year). Following ETV administration, the incidence of HCC in genotype D regions (1.89% ± 0.28%/year, mean ± SE) was significantly lower than that in genotype C regions (2.91% ± 0.24%/year, P &lt
0.01). With regard to the initial HBV-DNA level, in genotype C patients (average: 5.61 Log10IU/mL) this was almost the same as that in genotype D patients (average: 5.46 Log10IU/mL). Moreover, there was no association between the prevalence ratio of HBV and the incidence of HCC on ETV treatment. CONCLUSION The effectiveness of ETV in preventing HCC development in HBV-associated liver cirrhosis is genotype-dependent.

DOI： 10.4254/wjh.v13.i1.144

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

Oral direct-acting antivirals (DAAs) are the main therapy for hepatitis C virus (HCV)-associated liver disease in Japan. Moreover, many DAAs include an indication for compensated liver cirrhosis. However, patients with decompensated HCV-associated cirrhosis have hitherto not been indicated for therapy with DAAs. Recently, a new DAA, sofosbuvir/velpatasvir (SOF/VEL), was indicated for decompensated HCV-associated cirrhotic patients. Actually, it has been shown to eradicate HCV in many cases. However, it is not clear whether hepatic encephalopathy, ascites, and pleural effusion in patients with decompensated HCV-associated cirrhosis disappear by SOF/VEL treatment. Recently, we encountered a decompensated HCV-associated cirrhosis patient who showed the disappearance of hepatic encephalopathy, ascites, and pleural effusion with marked improvement of serum ammonia level, albumin level, prothrombin time, and platelet count after the eradication of HCV by the administration of SOF/VEL. Her consciousness was cloudy and it took many hours for the preparation of each meal just before SOF/VEL treatment, but after the disappearance of HCV-RNA by the therapy, her consciousness became clear and she could prepare meals in a short time. This case suggests the possibility of improvement from decompensated HCV-associated liver cirrhosis to compensated liver cirrhosis with disappearance of hepatic encephalopathy, ascites, and pleural effusion by SOF/VEL therapy.

DOI： 10.1159/000511749

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DOI： 10.1002/jgh3.12443

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Evaluating liver fibrosis is crucial for disease severity assessment, treatment decisions, and hepatocarcinogenic risk prediction among patients with chronic hepatitis C. In this retrospective multicenter study, we aimed to construct a novel model formula to predict cirrhosis. A total of 749 patients were randomly allocated to training and validation sets at a ratio of 2:1. Liver stiffness measurement (LSM) was made via transient elastography using FibroScan. Patients with LSM ≥12.5 kPa were regarded as having cirrhosis. The best model formula for predicting cirrhosis was constructed based on factors significantly and independently associated with LSM (≥12.5 kPa) using multivariate regression analysis. Among the 749 patients, 198 (26.4%) had LSM ≥12.5 kPa. In the training set, multivariate analysis identified logarithm natural (ln) type IV collagen 7S, ln hyaluronic acid, and ln Wisteria floribunda agglutinin positive Mac-2-binding protein (WFA+-Mac-2 BP) as the factors that were significantly and independently associated with LSM ≥12.5 kPa. Thus, the formula was constructed as follows: score = -6.154 + 1.166 × ln type IV collagen 7S + 0.526 × ln hyaluronic acid + 1.069 × WFA+-Mac-2 BP. The novel formula yielded the highest area under the curve (0.882; optimal cutoff, -0.381), specificity (81.5%), positive predictive values (62.6%), and predictive accuracy (81.6%) for predicting LSM ≥12.5 kPa among fibrosis markers and indices. These results were almost similar to those in the validated set, indicating the reproducibility and validity of the novel formula. The novel formula scores were significantly, strongly, and positively correlated with LSM values in both the training and validation data sets (correlation coefficient, 0.721 and 0.762; p = 2.67 × 10-81 and 1.88 × 10-48, respectively). In conclusion, the novel formula was highly capable of diagnosing cirrhosis in patients with chronic hepatitis C and exhibited better diagnostic performance compared to conventional fibrosis markers and indices.

DOI： 10.1371/journal.pone.0257166

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Baishideng Publishing Group Co  

BACKGROUND In hepatocellular carcinoma (HCC), detection and treatment prior to growth beyond 2 cm are important as a larger tumor size is more frequently associated with microvascular invasion and/or satellites. In the surveillance of very small HCC nodules (&lt
2 cm in maximum diameter, Barcelona clinical stage 0), we demonstrated that the tumor markers alpha-fetoprotein and PIVKA-II are not so useful. Therefore, we must survey with imaging modalities. The superiority of magnetic resonance imaging (MRI) over ultrasound (US) to detect HCC was confirmed in many studies. Although enhanced MRI is now performed to accurately diagnose HCC, in conventional clinical practice for HCC surveillance in liver diseases, unenhanced MRI is widely performed throughout the world. While, MRI has made marked improvements in recent years. AIM To make a comparison of unenhanced MRI and US in detecting very small HCC that was examined in the last ten years in patients in whom MRI and US examinations were performed nearly simultaneously. METHODS In 394 patients with very small HCC nodules, those who underwent MRI and US at nearly the same time (on the same day whenever possible or at least within 14 days of one another) at the first diagnosis of HCC were selected. The detection rate of HCC with unenhanced MRI was investigated and compared with that of unenhanced US. RESULTS The sensitivity of unenhanced MRI for detecting very small HCC was 95.1% (97/102, 95% confidence interval: 90.9-99.3) and that of unenhanced US was 69.6% (71/102, 95% confidence interval: 60.7-78.5). The sensitivity of unenhanced MRI for detecting very small HCC was significantly higher than that of unenhanced US (P &lt
0.001). Regarding the location of HCC in the liver in patients in whom detection by US was unsuccessful, S7-8 was identified in 51.7%. CONCLUSION Currently, unenhanced MRI is a very useful tool for the surveillance of very small HCC in conventional clinical follow-up practice.

DOI： 10.4254/wjh.v13.i6.699

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BACKGROUND: In hepatocellular carcinoma (HCC), detection and treatment prior to growth beyond 2 cm are relevant as a larger tumor size is more frequently associated with microvascular invasion and/or satellites. AIM: To examine the impact of the tumor marker alpha-fetoprotein (AFP) or PIVKA-II in detecting very small HCC nodules (≤ 2 cm in maximum diameter, Barcelona stage 0) in the large number of very small HCC. The difference in the behavior of these tumor markers in HCC development was also examined. METHODS: A total of 933 patients with single-nodule HCC were examined. They were subdivided into 394 patients with HCC nodules ≤ 2 cm in maximum diameter and 539 patients whose nodules were > 2 cm. The rates of patients whose AFP and PIVKA-II showed normal values were examined. RESULTS: The positive ratio of the marker PIVKA-II was significantly different (P < 0.0001) between patients with nodules ≤ 2 cm in diameter and those with nodules > 2 cm, but there was no significant difference in AFP (P = 0.4254). In the patients whose tumor was ≤ 2 cm, 50.5% showed normal levels in AFP and 68.8% showed normal levels in PIVKA-II. In 36.4% of those patients, both AFP and PIVKA-II showed normal levels. The PIVKA-II-positive ratio was markedly increased with an increase in the tumor size. In contrast, the positivity in AFP was increased gradually and slowly. CONCLUSION: In the surveillance of very small HCC nodules (≤ 2 cm in diameter, Barcelona clinical stage 0) the tumor markers AFP and PIVKA-II are not so useful.

DOI： 10.4254/wjh.v12.i11.1046

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER LONDON LTD  

Introduction Clinical trials of direct-acting antivirals for patients with decompensated cirrhosis have been conducted, but there is limited information on the medicinal applications in clinical settings. We aimed to evaluate the safety and efficacy of sofosbuvir/velpatasvir for decompensated cirrhotic patients with genotypes 1 and 2 in real-world clinical practice. Methods A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted for patients with decompensated cirrhosis at 33 institutions. Results The cohort included 71 patients (52 genotype 1, 19 genotype 2): 7 with Child-Pugh class A, 47 with class B, and 17 with class C (median score 8; range 5-13). The albumin-bilirubin (ALBI) score ranged from - 3.01 to - 0.45 (median - 1.58). Sixty-nine patients (97.2%) completed treatment as scheduled. The overall rate of sustained virologic response at 12 weeks post-treatment (SVR12) was 94.4% (67/71). SVR12 rates in the patients with Child-Pugh classes A, B, and C were 85.7%, 97.9%, and 88.2%, respectively. Among 22 patients with a history of hepatocellular carcinoma treatment, 20 (90.9%) achieved SVR12. The Child-Pugh score and ALBI grade significantly improved after achieving SVR12 (p = 7.19 x 10(-4)and 2.42 x 10(-4), respectively). Notably, the use of diuretics and branched-chain amino acid preparations significantly reduced after achieving SVR12. Adverse events were observed in 19.7% of the patients, leading to treatment discontinuation in two patients with cholecystitis and esophageal varices rupture, respectively. Conclusion Twelve weeks of sofosbuvir/velpatasvir in real-world clinical practice yielded high SVR rates and acceptable safety profiles in decompensated cirrhotic patients with genotypes 1 and 2. Achievement of SVR not only restored the liver functional reserve but also reduced or spared the administration of drugs for related complications.

DOI： 10.1007/s40121-020-00329-y

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BACKGROUND AND AIM: The presence of cirrhosis is an important factor for the management of patients with hepatitis C virus (HCV) infection and it determines the duration of treatment for HCV with the direct-acting antiviral (DAA) regimen of glecaprevir (GLE) and pibrentasvir (PIB), that is, 8 or 12 weeks, if patients do not have a history of DAA failure. However, in real-world settings, determination of cirrhosis depends on the discretion of the attending hepatologists, and it is unclear whether compensated cirrhosis was homogenously diagnosed or not. In this study, we investigated the real-world diagnosis of cirrhosis by characterizing DAA-naïve patients who underwent a 12-week GLE/PIB regimen in whom cirrhosis was diagnosed, comparing their characteristics with those of patients who underwent an 8-week regimen in whom cirrhosis was absent. METHODS: In a large, multicenter cohort study, we compared background characteristics and treatment outcomes among DAA-naïve patients who underwent an 8-week versus a 12-week GLE/PIB regimen. RESULTS: Among 977 patients enrolled, 296 (30.3%) were determined to have cirrhosis and underwent a 12-week regimen. Some patient characteristics largely overlapped between the two groups, including liver fibrosis indices. Sustained viral response rates were similar between groups after adjusting liver fibrosis index with propensity score matching. CONCLUSION: Although adequately diagnosed, the determination of cirrhosis varied widely among institutions or by hepatologists in real-world settings, and the severity of liver fibrosis overlapped significantly between patients in whom compensated cirrhosis was determined to be present and patients in whom cirrhosis was absent. Virologic efficacy was similar after adjusting for the degree of liver fibrosis.

DOI： 10.1111/jgh.14982

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

BACKGROUND AND AIM: The prognosis of cirrhotic patients with hepatic edema is poor. Although several short-term predictors of tolvaptan (novel diuretic agent) treatment for such patients have been reported, the factors related to long-term survival are still unclear. METHODS: Among 459 patients with hepatic edema enrolled in a retrospective, multicenter collaborative study, we analyzed 407 patients who received tolvaptan. RESULTS: Patients consisted of 266 men and 141 women, with the median age of 68 years (range, 28-93 years). The frequency of short-term responders to tolvaptan was 59.7% (243/407). In the Cox regression analysis, short-term response to tolvaptan, low average dosages of furosemide and spironolactone during tolvaptan treatment, Child-Pugh classification A and B, and absence of hepatocellular carcinoma were independent factors contributed to 1-year survival. The 1-year and long-term cumulative survival rates in short-term responders were significantly higher than those in non-responders (P = 0.011 and 0.010, respectively). Using a receiver operating characteristic curve analysis, the optimal cut-off values of average daily dosages of furosemide and spironolactone for predicting 1-year survival were 19 and 23 mg/day, respectively. The long-term cumulative survival rates in patients who received a mean dosage of spironolactone < 23 mg/day during tolvaptan treatment were significantly higher than those receiving a mean dosage of ≥ 23 mg/day (P = 0.001). CONCLUSIONS: The present study suggests that the short-term response to tolvaptan and low dosages of conventional diuretics during tolvaptan treatment might improve the 1-year and long-term survival rates in cirrhotic patients with hepatic edema.

DOI： 10.1111/jgh.14965

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Language：Japanese   Publisher：(一社)日本膵臓学会  

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DOI： 10.1007/s00535-020-01672-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

We attempted to establish an ultrasound (US) imaging-diagnostic system for histopathological grades of differentiation of hepatocellular carcinoma (HCC). We conducted a retrospective study of histopathologically confirmed 200 HCCs, classified as early (45 lesions), well- (31 lesions), moderately (68 lesions) or poorly differentiated (diff.) (56 lesions) HCCs. We performed grayscale US to estimate the presence/absence of halo and mosaic signs, Sonazoid contrast-enhanced US (CEUS) to determine vascularity (hypo/iso/hyper) of lesion in arterial and portal phase (PP), and echogenicity of lesion in post-vascular phase (PVP). All findings were of significance for the diagnosis of some (but not all) histological grades (p &lt; 0.001–0.05). Combined findings with a relatively high diagnostic efficacy for early, poorly and moderately diff. HCC were a combination of absence of halo sign and isoechogenicity in PVP of CEUS (accuracy: 93.0%, AUC: 0.908), hypovascularity in PP (accuracy: 78.0%, area under the curve (AUC): 0.750), and a combination of isovascularity in PP and hypoechogenicity in PVP (accuracy: 75.0%, AUC: 0.739), respectively. On the other hand, neither any individual finding nor any combination of findings yielded an AUC of over 0.657 for the diagnosis of well-diff. HCC. Our study provides encouraging data on Sonazoid CEUS in the histological differential diagnosis of HCC, especially in early HCC, and the effectiveness of this imaging method should be further proved by prospective, large sample, multicenter studies.

DOI： 10.3390/diagnostics10050321

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Background In clinical trials, a pangenotype direct-acting antiviral (DAA) regimen consisting of glecaprevir (GLE) and pibrentasvir (PIB) exhibited high virologic efficacy and tolerability in patients with hepatitis C virus (HCV) infection. This study sought to confirm these findings in real-world settings, focusing on patients with cirrhosis, history of DAA failure, or HCV genotype 3 who were treated with a 12-week regimen in a large multicenter study from Japan. Methods In a nationwide multicenter prospective cohort study, we analyzed background characteristics, tolerability, and treatment outcome of patients who underwent a 12-week GLE/PIB regimen. Results Of 1190 patients, 509 (42.8%) underwent the 12-week regimen, and the remaining patients underwent an 8-week regimen. The rate of sustained virologic response (SVR) of patients treated with the 12-week regimen was 99.0%, comparable with that of patients treated with the 8-week regimen. The adverse events were observed in 29.1% of patients. The main adverse event was pruritus, which was observed in 14.7%. Ten patients (2.0%) discontinued therapy during treatment period. Conclusion The 12-week GLE/PIB regimen was well-tolerated with high virologic efficacy in patients with cirrhosis, experience of DAA, or HCV genotype 3; tolerability and SVR rate were comparable with those of DAA-naive, non-cirrhotic, non-genotype 3 patients who underwent 8-week regimen.

DOI： 10.1111/jgh.14874

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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BACKGROUND: Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment. METHODS: In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed. RESULTS: Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naïve patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10-5; genotype 2 vs. 3, p = 3.28 × 10-5) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1-3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4-5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512-148.550), p value (p = 4.06 × 10-5)] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153-13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4-5 (41.6% [79/190]) than CKD stage 1-3 (26.1% [319/1220]) patients (p = 2.00 × 10-5). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10-18) patients. CONCLUSIONS: G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.

DOI： 10.1007/s12072-020-10019-z

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DOI： 10.1007/s12072-020-10019-z

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Other Link： http://link.springer.com/article/10.1007/s12072-020-10019-z/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Predictive biomarkers of the response of hepatocellular carcinoma (HCC) to Lenvatinib therapy have not yet been clarified. The aim of this study was to identify clinically significant biomarkers of response to Lenvatinib therapy, to target strategies against HCC. Levels of circulating angiogenic factors (CAFs) were analyzed in blood samples collected at baseline and after introducing lenvatinib, from 74 Child-Pugh class A HCC patients who received lenvatinib. As CAF biomarkers, serum vascular endothelial growth factor (VEGF), fibroblast growth factor 19 (FGF19), FGF23, and angiopoietin-2 (Ang-2) were measured using enzyme-linked immunosorbent assays. Results: Significantly increased FGF19 (FGF19-i) levels and decreased Ang-2 (Ang-2-d) levels were seen in Lenvatinib responders as compared to non-responders (ratio of FGF19 level at 4 weeks/baseline in responders vs. non-responders: 2.09 vs. 1.32, respectively, p = 0.0004; ratio of Ang-2 level at four weeks/baseline: 0.584 vs. 0.810, respectively, p = 0.0002). Changes in FGF23 and VEGF levels at four weeks versus baseline, however, were not significantly different in responders versus non-responders. In multivariate analysis, the combination of serum FGF19-i and Ang-2-d was the most independent predictive factor for Lenvatinib response (Odds ratio, 9.143; p = 0.0012). Furthermore, this combination biomarker showed the greatest independent association with progression-free survival (Hazard ratio, 0.171; p = 0.0240). Early changes in circulating FGF19 and Ang-2 levels might be useful for predicting clinical response and progression-free survival in HCC patients on Lenvatinib therapy.

DOI： 10.3390/cancers12020293

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According to cancer genome sequences, more than 90% of cases of pancreatic ductal adenocarcinoma (PDAC) harbor active KRAS mutations. Digital PCR (dPCR) enables accurate detection and quantification of rare mutations. We assessed the dynamics of circulating tumor DNA (ct-DNA) in patients with advanced PDAC undergoing chemotherapy using dPCR. KRAS G12/13 mutation was assayed by dPCR in 47 paired tissue- and ct-DNA samples. The 21 patients were subjected to quantitative ct-DNA monitoring at 4 to 8-week intervals during chemotherapy. KRAS mutation was detected in 45 of those 47 patients using tissue DNA. In the KRAS mutation-negative cases, next-generation sequencing revealed KRAS Q61K and NRAS Q61R mutations. KRAS mutation was detected in 23/45 cases using ct-DNA (liver or lung metastasis, 18/19; mutation allele frequency [MAF], 0.1%-31.7%; peritoneal metastasis, 3/9 [0.1%], locally advanced, 2/17 [0.1%-0.2%]). In the ct-DNA monitoring, the MAF value changed in concordance with the disease state. In the 6 locally advanced cases, KRAS mutation appeared concurrently with liver metastasis. Among the 6 cases with liver metastasis, KRAS mutation disappeared during the duration of stable disease or a partial response, and reappeared at the time of progressive disease. The median progression-free survival was longer in cases in which KRAS mutation disappeared after an initial course of chemotherapy than in those in which it was continuously detected (248.5 vs 50 days, P < .001). Therefore, ct-DNA monitoring enables continuous assessment of disease state and could have prognostic utility during chemotherapy.

DOI： 10.1111/cas.14245

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BACKGROUND & AIMS: To explore the ability of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging (EOB-MRI)/ultrasound (US) fusion imaging (FI) to improve the prognosis of radiofrequency ablation (RFA) by ablating the characteristic findings of hepatocellular carcinoma (HCC) in hepatobiliary phase (HBP) imaging. METHODS: We retrospectively recruited 115 solitary HCC lesions with size of (15.9 ± 4.6) mm. They were all treated by RFA and preoperative EOB-MRI. According to the modalities guiding RFA performance, the lesions were grouped into contrast enhanced US (CEUS)/US guidance group and EOB-MRI/US FI guidance group. For the latter group, the ablation scope was set to cover the HBP findings (peritumoral hypointensity and irregular protruding margin). The presence of HBP findings, the modalities guided RFA, the recurrence rate were observed. RESULTS: After an average follow-up of 377 days, local tumor progression (LTP) and intrahepatic distant recurrence (IDR) were 14.8% and 38.4%, respectively. The lesions having HBP findings exhibited a higher recurrence rate (73.7%) than the lesions without HBP findings (42.9%) (p = 0.002) and a low overall recurrence-free curve using the Kaplan-Meier method (p = 0.038). Using EOB-MRI/US FI as guidance, there was no difference in the recurrence rate between the groups with and without HBP findings (p = 0.799). In lesions with HBP findings, RFA guided by EOB-MRI/US FI (53.8%) produced a lower recurrence rate than CEUS/US (84.0%) (p = 0.045). CONCLUSIONS: The intraprocedurally application of EOB-MRI/US FI to determine ablation scope according to HBP findings is feasible and beneficial for prognosis of RFA.

DOI： 10.1080/02656736.2020.1825837

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© 2020, The Author(s). Introduction: Clinical trials of direct-acting antivirals for patients with decompensated cirrhosis have been conducted, but there is limited information on the medicinal applications in clinical settings. We aimed to evaluate the safety and efficacy of sofosbuvir/velpatasvir for decompensated cirrhotic patients with genotypes 1 and 2 in real-world clinical practice. Methods: A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted for patients with decompensated cirrhosis at 33 institutions. Results: The cohort included 71 patients (52 genotype 1, 19 genotype 2): 7 with Child–Pugh class A, 47 with class B, and 17 with class C (median score 8; range 5–13). The albumin–bilirubin (ALBI) score ranged from − 3.01 to − 0.45 (median − 1.58). Sixty-nine patients (97.2%) completed treatment as scheduled. The overall rate of sustained virologic response at 12 weeks post-treatment (SVR12) was 94.4% (67/71). SVR12 rates in the patients with Child–Pugh classes A, B, and C were 85.7%, 97.9%, and 88.2%, respectively. Among 22 patients with a history of hepatocellular carcinoma treatment, 20 (90.9%) achieved SVR12. The Child–Pugh score and ALBI grade significantly improved after achieving SVR12 (p = 7.19 × 10−4 and 2.42 × 10−4, respectively). Notably, the use of diuretics and branched-chain amino acid preparations significantly reduced after achieving SVR12. Adverse events were observed in 19.7% of the patients, leading to treatment discontinuation in two patients with cholecystitis and esophageal varices rupture, respectively. Conclusion: Twelve weeks of sofosbuvir/velpatasvir in real-world clinical practice yielded high SVR rates and acceptable safety profiles in decompensated cirrhotic patients with genotypes 1 and 2. Achievement of SVR not only restored the liver functional reserve but also reduced or spared the administration of drugs for related complications. Trial Registration: UMIN registration no, 000038587.

DOI： 10.1007/s40121-020-00329-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Based on high efficacy and safety demonstrated in clinical trials, treatment with glecaprevir/pibrentasvir (G/P) for 8 weeks is recommended for hepatitis C virus (HCV)-infected patients who are direct-acting antiviral (DAA) naïve, genotype 1 or 2, and noncirrhotic. The aim of this study was to validate real-world experience with 8-week G/P treatment in Japan. We conducted a prospective observational cohort study in 554 patients who underwent 8-week treatment from among 1,022 patients who initiated G/P therapy. The majority (54.5%) were male, with a median age of 66 years, and HCV genotype distribution was genotype 1, 43.8%; genotype 2, 55.3%; and mixed subtype, 0.9%. Overall, the sustained virologic response rate at 12 weeks (SVR12) was 92.8% (530/571) in the intention-to-treat population and 99.3% (526/530) in the per-protocol population. The SVR12 rates by subgroups were as follows: subtype 1a, 100% (6/6); 1b, 100% (189/189); 2a, 99.3% (150/151); 2b, 99.0% (103/104); and mixed subtype, 50% (2/4). Among four patients with virologic failure following 8-week treatment with G/P, none had baseline polymorphisms or treatment-emergent amino acid substitutions in NS3. However, 2 of 4 patients with virologic failure had treatment-emergent amino acid substitutions in NS5A. Adverse events (AEs) were reported in 21.5% of patients and 1.2% of patients discontinued due to drug-related AEs. In conclusion, G/P treatment for 8 weeks was safe and effective for DAA-naïve noncirrhotic genotype 1 or 2 patients in a real-world clinical setting in Japan.

DOI： 10.1111/jvh.13170

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/jvh.13170

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

OBJECTIVES: We evaluated the detection rates for perfusion defects in hypervascular hepatocellular carcinomas comparing the low mechanical index (MI) and high MI contrast modes during the post-vascular phase (PVP) of contrast-enhanced ultrasonography. METHODS: Seventy-eight patients with 84 hypervascular hepatocellular carcinomas (mean diameter, 23.4 ± 11.2 mm) were selected for this retrospective study. All the patients underwent whole-liver scanning using conventional ultrasonography before injection of a perflubutane-based contrast agent (Sonazoid), and all the detected nodules were classified as either hypoechoic or hyperechoic nodules. Next, hypoechoic and hyperechoic nodules were evaluated using contrast-enhanced ultrasonography, and the presence of a perfusion defect was assessed for each nodule using both the low MI (0.2-0.3) and the high MI (0.7-1.2) contrast modes during the PVP (10 minutes after injection). The data were analyzed using the McNemar test. RESULTS: Forty-four nodules were classified as hypoechoic nodules, and the remaining 40 nodules were classified as hyperechoic nodules using conventional ultrasonography. The detection rate for perfusion defects determined using the high MI contrast mode was higher than that determined using the low MI contrast mode in hyperechoic nodules during the PVP (low MI, 58% [23 of 40]; high MI, 90% [36 of 40]; P < .0001). However, no significant difference was observed between the low MI and the high MI contrast modes in hypoechoic nodules (low MI, 80% [35 of 44]; high MI, 89% [39 of 44]; P = .125). CONCLUSION: Compared with the low MI contrast mode, the high MI contrast mode was more sensitive for detecting perfusion defects in hypervascular hepatocellular carcinomas in patients with hyperechoic nodules during the PVP.

DOI： 10.1002/jum.14926

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Language：English   Publisher：(一社)日本癌学会  

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AIMS: Early tumor recurrence (ETR) after hepatic resection is a crucial predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify clinically significant serum microRNAs (miRNAs) involved in the ETR of HCC. METHODS: We compared expression profiles of circulating miRNAs from serum samples between five HCC patients with ETR (recurrence within 12 months after hepatectomy) and five HCC patients without recurrence using microarray analysis of miRNA. The identified miRNA associated with ETR was further verified in 121 HCC patients, 73 liver disease patients, and 15 health controls by real-time quantitative reverse transcription-polymerase chain reaction (PCR). RESULTS: Of the approximately 2000 miRNAs analyzed, we identified 15 miRNAs for which expression levels correlated significantly with ETR. Of these miRNAs, we further investigated expression of miRNA-1246 (miR-1246). Quantitative PCR confirmed that miR-1246 was upregulated in HCC with ETR, compared to the level in HCC without ETR (P < 0.001). Serum miR-1246 showed a receiver operating characteristic curve area of 0.762, with 77.4% specificity and 54.1% sensitivity in discriminating HCC patients with ETR from HCC patients without ETR. Altered expression of miR-1246 was associated with aggressive tumor characteristics, including tumor-node-metastasis classification (P = 0.0413), tumor differentiation (P = 0.0419), and portal vein invasion (P = 0.0394). Moreover, multivariate Cox regression analysis identified serum miR-1246 level as an independent risk factor for overall survival (hazard ratio, 2.784; 95% confidence interval, 1.528-5.071; P = 0.0008). CONCLUSION: Circulating miR-1246 in serum has strong potential as a novel ETR and prognostic biomarker for HCC.

DOI： 10.1111/hepr.13338

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/hepr.13338

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

BACKGROUND: Patients with chronic hepatitis C are often complicated by chronic kidney disease (CKD). AIM: To evaluate the efficacy, safety and pharmacokinetics of glecaprevir/pibrentasvir in patients with severe renal impairment. METHODS: In a prospective, multicentre study involving 35 medical institutions, 832 genotype 1-3 patients were treated with glecaprevir/pibrentasvir. The efficacy and safety of glecaprevir/pibrentasvir were analysed for patients with CKD stage 4 or 5. Multivariate analysis was performed to identify the factors associated with the most frequently observed adverse event. In patients undergoing haemodialysis, a pharmacokinetic study was conducted to investigate the dialysability of the drugs: plasma samples were obtained from the arterial and venous sides of a dialyser to serially measure drug concentrations. RESULTS: The subjects comprised 141 patients (32 with CKD stage 4 and 109 with CKD stage 5), of whom 100 were undergoing haemodialysis. All but one stage 5 CKD patients undergoing haemodialysis achieved sustained virologic response (99.3%). Adverse events were observed in 39.7% of subjects: pruritus was the most frequent (30.5%), and was significantly associated with haemodialysis. In the pharmacokinetic study, no arterial-venous differences in the plasma concentrations of glecaprevir/pibrentasvir were detected during the haemodialysis sessions. CONCLUSIONS: Glecaprevir/pibrentasvir was highly effective and safe in chronic hepatitis C patients with severe renal impairment. Haemodialysis was associated with increased incidence of pruritus, which was the most frequent adverse event, but had little or no influence on the drug concentrations, which indicated that their dialysability is very low and that no dose modification is required in patients undergoing haemodialysis. (UMIN registration no. 000032073).

DOI： 10.1111/apt.15218

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Background: We investigated changes in patient characteristics, rate of sustained virologic response (SVR), and factors associated with SVR after anti-hepatitis C virus (HCV) therapy with direct-acting antiviral (DAA) regimens in real-world practice in Japan, where patients with HCV are characterized by older age and high prevalence of cirrhosis and hepatocellular carcinoma (HCC). Methods: Changes in patient characteristics and SVR rates were evaluated from medical records among 10 688 patients who started interferon (IFN)-free DAA therapy between September 2014 and June 2018 in a nationwide, multicenter study. Factors associated with failure of SVR were analyzed. In particular, effects of cirrhosis or history of HCC on SVR were assessed by exact matching. Results: Patient age was becoming younger and baseline liver fibrosis was becoming milder over time. Overall SVR rate was 95.4%. The SVR rates increased over time in patients without a history of IFN-free DAA therapy. Multivariate analysis revealed that cirrhosis was unfavorably associated with achievement of SVR in both patients with genotype 1 (odds ratio, 1.68; 95% confidence interval [CI], 1.27-2.21) and genotype 2 (odds ratio, 1.69; 95% CI, 1.01-2.78). Comparisons after exact matching showed that the SVR rate was significantly lower in patients with cirrhosis than without it, whereas patients with and without a history of HCC had similar SVR rates. Conclusions: Background characteristics of patients who undergo IFN-free DAA therapy are changing in Japan. Patients without a history of IFN-free DAA therapy have high SVR rates. Exact matching confirmed that cirrhosis significantly influences the achievement of SVR in real-world settings.

DOI： 10.1093/ofid/ofz185

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Other Link： http://academic.oup.com/ofid/article-pdf/6/5/ofz185/28668643/ofz185.pdf

Language：Japanese   Publisher：(一財)日本消化器病学会  

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/cam4.1998

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：(一社)日本膵臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Verlag  

Purpose: Radiofrequency ablation for liver tumors (liver RFA) is widely performed under ultrasound guidance. However, discriminating between the tumor and the needle is often difficult because of cavitation caused by RFA-induced coagulation. An unclear ultrasound image can lead to complications and tumor residue. Therefore, image-guided navigation systems based on fiducial registration have been developed. Fiducial points are usually set on a patient’s skin. But the use of internal fiducial points can improve the accuracy of navigation. In this study, a new device is introduced to use internal fiducial points using 2D US. Methods: 3D Slicer as the navigation software, Polaris Vicra as the position sensor, and two target tumors in a 3D abdominal phantom as puncture targets were used. Also, a new device that makes it possible to obtain tracking coordinates in the body was invented. First, two-dimensional reslice images from the CT images using 3D Slicer were built. A virtual needle was displayed on the two-dimensional reslice image, reflecting the movement of the actual needle after fiducial registration. A phantom experiment using three sets of fiducial point configurations: one conventional case using only surface points, and two cases in which the center of the target tumor was selected as a fiducial point was performed. For each configuration, one surgeon punctured each target tumor ten times under guidance from the 3D Slicer display. Finally, a statistical analysis examining the puncture error was performed. Results: The puncture error for each target tumor decreased significantly when the center of the target tumor was included as one of the fiducial points, compared with when only surface points were used. Conclusion: This study introduces a new device to use internal fiducial points and suggests that the accuracy of image-guided navigation systems for liver RFA can be improved by using the new device.

DOI： 10.1007/s11548-017-1647-9

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Aim: The aim of this study was to compare vascularity observed using contrast-enhanced 3D ultrasonography and pathological changes in human hepatocellular carcinoma (HCC) and surrounding non-tumorous areas after sorafenib treatment. Materials and methods: Twelve patients with HCC were enrolled in this clinical study. The maximum tumor diameter as measured using sonography ranged from 15 to 33 mm (mean, 24.0 mm; SD, 5.7 mm). Assessments using contrast-enhanced (0.2 mL of Sonazoid suspension; Daiichi Sankyo, Tokyo, Japan) 3D ultrasonography (LOGIQ 7; GE Healthcare, Milwaukee) were performed in all the patients before and 1 week after sorafenib treatment. The microvessel density (MVD) of the HCC and surrounding non-tumorous area was evaluated based on the immunohistochemical staining of microvessels using an antigen for CD34. Results: Blood flow in the tumor was decreased in all 12 cases after sorafenib treatment. The MVD of the tumorous area at 1 week after sorafenib administration (38.8 ± 5.2) was significantly lower than that observed before sorafenib administration (72.4 ± 13.0) (P < 0.01). Blood flow in the non-tumorous area had decreased in 6 cases at 1 week after sorafenib treatment and had not changed in the 6 other cases. In the reduced blood flow group, the MVD of the non-tumorous area at 1 week after sorafenib administration had decreased significantly, compared with the MVD of the non-tumorous area before sorafenib administration. However, in the group with no change in blood flow, the MVD of the non-tumorous area at 1 week after sorafenib treatment had not changed, compared with the MVD of the non-tumorous area before sorafenib treatment. Conclusion: Contrast-enhanced 3D ultrasonography studies showed a correlation between vascularity and pathological changes in human HCC and the surrounding non-tumorous area after sorafenib treatment.

DOI： 10.7150/jca.24236

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Language：Japanese   Publisher：The Japan Society of Hepatology  

<p>In this prospective multicenter study, we evaluate the efficacy and safety of glecaprevir/pibrentasvir (GLE/PIB) combination therapy for genotype 1b chronic hepatitis C patients undergoing hemodialysis. Of 17 patients who received GLE/PIB for 8 or 12 weeks, 11 completed the treatment and the 12-week follow-up care that followed. All 11 patients (100%) achieved sustained virologic response 12 (SVR12). Adverse events were observed in 41.2% of all patients and the most frequent adverse event was pruritus. This study suggests that GLE/PIB combination therapy is highly effective and safe even in genotype 1b chronic hepatitis C patients undergoing hemodialysis.</p>

DOI： 10.2957/kanzo.59.578

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Other Link： http://search.jamas.or.jp/link/ui/2019021699

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Baishideng Publishing Group Co  

AIM To survey the efficacy and safety of dual therapy with daclatasvir and asunaprevir in the elderly hepatitis C virus (HCV) patients multicentricity. METHODS Interferon-ineligible/intolerant patients and non-responders to previous pegylated-interferon/ribavirin therapy with chronic HCV genotype 1b infection were enrolled. Child B, C cirrhotic patients were excluded.Patients received oral direct acting antiviral treatment consisting of 60 mg daclatasvir once daily plus 200 mg asunaprevir twice daily for 24 wk. We divided the patients into two groups of 56 elderly patients (≥ 75 years-old) and 141 non-elderly patients (&lt
75 years old) and compared the efficacy and safety. RESULTS Ninety-one point one percent of elderly patients and 90.1% of non-elderly patients achieved sustained virological response at 24 wk (SVR24). In the former, 1.8% experienced viral breakthrough, as compared with 3.5% in the latter (not significant). Adverse events occurred in 55.4% of the former and 56.0% of the latter. In the former, 7 cases (12.5%) were discontinued due to adverse events, and in the latter 9 cases were discontinued (6.4%, not significant). CONCLUSION Dual therapy with daclatasvir and asunaprevir achieved the same high rates of SVR24 in HCV elderly patients without more adverse events than in the non-elderly patients.

DOI： 10.4254/wjh.v9.i11.544

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI LTD  

Background. Sorafenib is a first-line treatment option for advanced hepatocellular carcinoma (HCC) patients; however, survival predictors upon progression have not been well characterized. In the present study, we aimed to show the efficacy of multidisciplinary therapy for patients who had failed to respond to sorafenib treatment. Methods. Among 146 BCLC stage B or C HCC patients treated with sorafenib monotherapy between July 2009 and August 2014, the first radiological progression according to the modified RECIST was identified in 71 patients; factors predicting overall survival (OS) and survival postprogression (SPP) were analyzed in these patients. Results. The median OS and SPP for patients who failed to respond to sorafenib treatment were 10.5 and 6.2 months, respectively, and the SPP was strongly correlated with the OS (r = 0 982, P &lt; 0 01, and R-2 = 0 965). The independent predictors of OS and SPP were identical. The predictors of SPP were des-gammacarboxy prothrombin, progression of portal vein thrombosis, and subsequent second-line or additional treatment. Conclusions. SPP is closely associated with OS and might be notable in patients who have failed to respond to initial sorafenib treatment. Furthermore, interventions consisting of other treatment options upon the appearance of progression might prolong OS.

DOI： 10.1155/2017/5728946

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Patients receiving methotrexate (MTX) for the treatment of autoimmune disease are at a high risk of developing lymphoproliferative disorders (LPD), the so-called methotrexate-associated lymphoproliferative disorders (MTX-LPD). We recently performed abdominal ultrasonography (US) in a patient with rheumatoid arthritis (RA) who had developed hepatic dysfunction during the course of MTX therapy; the examination revealed multiple well-demarcated hepatic tumors with slightly irregular borders, the largest one measuring 9 cm in diameter. In view of the finding of portal and hepatic veins perforating the tumor, we suspected a diagnosis of malignant lymphoma and performed a hepatic tumor biopsy. Histopathological examination of the biopsy specimens revealed a diagnosis of diffuse large B-cell lymphoma, and we made a final diagnosis of MTX-LPD. MTX treatment was discontinued, which resulted in rapid resolution of the lesions. Resolution of MTX-LPD can be obtained just by discontinuation of MTX treatment. In patients receiving MTX therapy who are found to have hepatic tumors perforated by the portal vein and/or hepatic vein on abdominal US, it is advisable to perform hepatic tumor biopsy to facilitate differential diagnosis of MTX-LPD and enable a definite diagnosis.

DOI： 10.1007/s10396-016-0740-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

Background and Aims: The prevalence of sexually transmitted acute infections of the genotype A hepatitis B virus (HBV) has been increasing in Japan. Genotype A HBV is associated with an increased risk of HBV progression to chronic infection after acute hepatitis B (AHB) in adults. A nationwide survey was conducted to evaluate the geographic distribution, clinical, and virologic characteristics of genotype A AHB and chronic hepatitis B (CHB) in Japan. Methods: Five hundred seventy AHB patients were recruited between 2005 and 2010, and 3682 CHB patients were recruited between 2010 and 2011. HBV genotypes were determined for 552 and 3619 AHB and CHB patients, respectively. Clinical characteristics were compared among different genotypes in AHB and CHB patients. Genomic characteristics of HBV genotype A were examined by molecular evolutionary analysis. Results: Hepatitis B virus genotype A was the predominant genotype for AHB between 2005 and 2010. Phylogenetic analysis showed that all strains in the AHB patients with genotype A were classified into subtype Ae. Among CHB patients, the occurrence of genotype A was 4.1%, and genotype A was spreading in young adults. In genotype A CHB patients, early stage liver diseases were predominant, although liver diseases progressed to cirrhosis or hepatocellular carcinoma in some patients. Conclusions: The distribution of HBV genotypes is quite different between AHB and CHB in Japanese patients. Genotype A infection is spreading in young adults of Japanese CHB patients. Sequences derived from Japanese AHB patients were identical to or closely resembled the sequences derived from other Japanese AHB patients.

DOI： 10.1111/jgh.13030

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Language：Japanese   Publisher：The Japan Society of Hepatology  

<p>The aim of this study was to reveal the real-life effectiveness of sofosbuvir (SOF) with ribavirin (RBV) in Japanese patients with genotype 2 hepatitis C virus infection. A total of 153 patients were enrolled. The rates of SVR at 12 weeks after end of treatment were 94.1%. Of all 9 patients with treatment-failure were relapsers, and no breakthrough cases were observed. The starting RBV doses were reduced in 44 patients. However, RBV dose reduction has no impact on treatment outcome. Male and low-platelet counts were significantly higher in relapsed group than SVR12 group. Factors, which affect the outcome should be farther investigated. SOF plus RBV was found to be well-tolerated with high SVR rate in Japanese "real-life" cohort.</p>

DOI： 10.2957/kanzo.57.561

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: We evaluated the use of tumor vessel patterns observed during arterial-phase contrast-enhanced ultrasonography (US) to differentiate regenerative nodules (RN) from early hepatocellular carcinoma (HCC) or high-grade dysplastic nodules (HGDN) in patients with chronic liver disease. SUBJECTS AND METHODS: Pathologically confirmed lesions (83 early HCC, 6 HGDN, and 13 RN with mean maximal diameters of 15.4, 15.3, and 16.2 mm, respectively) were enrolled in this retrospective study. We performed contrast-enhanced US using a perflubutane-based contrast agent. We then classified the tumor vessels observed during the arterial phase of contrast-enhanced US into two patterns: peripheral vessels (centripetal pattern) and central vessels (centrifugal pattern). RESULTS: Eighty-one (97.6%) of the 83 early HCC exhibited various enhancement patterns (hypovascular, 44.6%; isovascular, 25.3%; and hypervascular, 27.7%) and a peripheral vessel pattern, while the remaining 2 lesions (2.4%) exhibited hypovascular enhancement and a central vessel pattern. All 6 HGDN lesions were hypovascular with a peripheral vessel pattern. Twelve (92.3%) of the 13 RN were hypovascular with a central vessel pattern, and the remaining one (7.7%) was hypervascular with a central vessel pattern. When lesions exhibiting a central vessel pattern during arterial-phase contrast-enhanced US were diagnosed as RN, the sensitivity, specificity, and accuracy of these diagnoses were 100%, 97.8%, and 98.0%, respectively. CONCLUSION: The tumor vessel patterns observed during arterial-phase contrast-enhanced US may be useful for differentiating RN from early HCC or HGDN in patients with chronic liver disease.

DOI： 10.1007/s00261-015-0489-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Reducing blood flow in the liver during radiofrequency ablation causes enlargement of the ablation area. In this animal study, we evaluated the extended effects of radiofrequency ablation combined with transarterial embolization using various embolic agents.
We treated 38 radiofrequency ablation lesions after embolization in 13 pigs using the following embolic agents: gelatin sponge (Group A); iodized oil followed by gelatin sponge (Group B); 700-900 A mu m calibrated microspheres (Group C); and 100-300 A mu m calibrated microspheres (Group D). Lesion size and pathological evaluations of these ablation lesions were compared with those receiving radiofrequency ablation alone (control).
Both the long- and short-axis diameters of the ablation lesions for Groups A, B, C, and D were significantly longer than those of controls (long axis/short axis for Groups A, B, C, D, and controls were 27.2/23.2, 30.2/26.0, 28.2/22.2, 32.0/24.4, and 23.2 mm/18.5 mm, respectively) (P &lt; 0.05). The long-axis of the ablation lesion for Group D was significantly longer than those for both Groups A and C (P &lt; 0.05). At pathological examination, the central ablation lesions showed coagulative necrosis with a surrounding hemorrhagic rim, and the microspheres were fitted to occlude the small arteries in peripheral liver parenchyma in Groups C and D.
The extended effects of embolization with small microspheres may be stronger than those with large microspheres and were equal to those with iodized oil followed by gelatin sponge.

DOI： 10.1007/s00261-014-0332-5

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Language：English   Publishing type：Research paper (international conference proceedings)  

DOI： 10.1186/2050-5736-3-S1-P47

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OBJECTIVE: We aimed to evaluate the efficacy and tolerability of hepatic arterial infusion chemotherapy (HAIC) using cisplatin as an alternative to sorafenib for the treatment of hepatocellular carcinoma (HCC) patients who had not responded to transarterial chemoembolization (TACE). METHODS: Medical records of 127 consecutive HCC patients without extrahepatic metastasis (cisplatin, n = 44; sorafenib, n = 83) who had not responded to prior TACE at four institutions were retrospectively reviewed. An inverse probability of treatment weighting using propensity scoring was used to adjust for the selection bias. RESULTS: Severe adverse events accounting for treatment discontinuation occurred in 2.3% of the patients in the cisplatin group and 32.5% of those in the sorafenib group. The median overall survival (OS) period was 11.2 months (95% CI 4.8-17.7) in the cisplatin group and 10.2 months (95% CI 8.8-11.5) in the sorafenib group, respectively. After an inverse probability of treatment weighting adjustment, the survival outcome of the HAIC treatment group was not inferior to that of the sorafenib treatment group (hazard ratio 0.758; 95% CI 0.471-1.219, P = 0.253). CONCLUSION: HAIC with cisplatin can be an alternative treatment for the selection of HCC patients who have not responded to prior TACE and cannot tolerate sorafenib.

DOI： 10.1111/1751-2980.12221

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Background and Objectives
Sushi repeat-containing protein X-linked 2 (SRPX2) was first described as a downstream target gene for E2A-HLA, which causes pro-B acute leukemia. SRPX2 is considered to promote cellular migration and adhesion in cancers. Our objective was to evaluate the relative expression of the SRPX2 gene and to determine whether such expression correlates with outcomes in patients with gastric cancer.
Methods
Surgical specimens of cancer tissue and adjacent normal mucosa obtained from 227 patients with previously untreated gastric cancer were examined. SRPX2 mRNA expression levels of cancer tissue and adjacent normal mucosa were measured by quantitative real-time polymerase chain reaction. We evaluated the clinicopathological significance of the relative expression of SRPX2 in patients with gastric cancer.
Results
SRPX2 expression was higher in cancer tissue than in adjacent normal mucosa (P &lt; 0.001). On analysis of the relations between gene expression and clinicopathological factors, SRPX2 expression correlated with tumor size and distant metastasis. Overall survival was significantly lower in patients whose tumors had high SRPX2 expression than in those who had low SRPX2 expression (P = 0.003). Multivariate analysis showed that high SRPX2 expression was an independent predictor of survival (HR = 2.028, 95% CI = 1.265-3.251).
Conclusions
SRPX2 expression was significantly higher in gastric cancer tissue than in adjacent normal mucosa, and overexpression of the SRPX2 gene is considered a useful independent predictor of outcomes in patients with gastric cancer. J. Surg. Oncol. 2014 109:836-840. (c) 2014 Wiley Periodicals, Inc.

DOI： 10.1002/jso.23602

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Inhibin-beta A (INHBA), a ligand belonging to the transforming growth factor-beta superfamily, is associated with cell proliferation in cancer. We studied the relations of INHBA gene expression to clinicopathological factors and outcomes in 168 patients with gastric cancer who underwent curative surgery. Relative INHBA gene expression was measured in surgical specimens of cancer tissue and adjacent normal mucosa by quantitative real-time, reverse-transcription polymerase chain reaction. INHBA expression levels were significantly higher in cancer tissue than in adjacent normal mucosa and were related to TNM stage and venous invasion. High INHBA gene expression was associated with significantly poorer 5-year overall survival than was low expression. On multivariate analysis, INHBA gene expression was an independent prognostic factor. Overexpression of the INHBA gene is considered a useful independent predictor of outcomes in patients with gastric cancer after curative surgery.

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Objective: We evaluated the contrast-enhanced ultrasonography (US) imaging features of early hepatocellular carcinomas (HCCs) and compared these findings with those obtained using contrast-enhanced computed tomography ( CT).
Subjects and methods: Forty-three patients with 52 early HCCs with a mean maximal diameter of 15.6 mm were enrolled in this retrospective study. After confirming the location of the target lesion using fusion imaging combining conventional US and hepatobiliary phase of contrast-enhanced magnetic resonance (MR) imaging with gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid, we evaluated findings of contrast-enhanced US using a perflubutane-based contrast agent. The contrast-enhanced US detection rates for hyper-vascularity in early HCCs were compared with those obtained for contrast-enhanced CT.
Results: Transient hypo-vascularity subsequent to iso-vascularity during arterial phase and iso-vascularity during portal and post-vascular phases were the predominant contrast-enhanced US findings seen for 25(48.1%) of the 52 early HCCs. Nine (17.3%) showed iso-vascularity during all three phases, while 1(1.9%) showed hypo-vascularity during all three phases. The remaining 17 (32.7%) showed partial or whole hyper-vascularity during arterial phase, iso-vascularity during portal phase, and iso- or hypo-vascularity during post-vascular phase. The detection rate for the hyper-vascularity of early HCCs using contrast-enhanced US (32.7%, 17/52) was significantly higher than that obtained using contrast-enhanced CT (21.2%, 111/52) (P&lt;0.05 by McNemar test).
Conclusion: Hypo-vascularity, iso-vascularity, and hyper-vascularity were observed during the arterial phase of contrast-enhanced US in 50.0%, 17.3%, and 32.7% of the early HCCs, respectively. Contrastenhanced US was more sensitive than contrast-enhanced CT for the detection of hyper-vascularity in early HCCs. Of note, early HCCs might not exhibit the early arterial enhancement that is generally considered to be a typical finding for HCCs. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ejrad.2013.09.025

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Purpose: We evaluated the usefulness of color Doppler flow imaging to compensate for the inadequate resolution of the ultrasound (US) monitoring during high-intensity focused ultrasound (HIFU) for the treatment of hepatocellular carcinoma (HCC).
Materials and methods: US-guided HIFU ablation assisted using color Doppler flow imaging was performed in 11 patients with small HCC (&lt;3 lesions, &lt;3 cm in diameter). The HIFU system (Chongqing Haifu Tech) was used under US guidance. Color Doppler sonographic studies were performed using an HIFU 6150S US imaging unit system and a 2.7-MHz electronic convex probe.
Results: The color Doppler images were used because of the influence of multi-reflections and the emergence of hyperecho. In 1 of the 11 patients, multi-reflections were responsible for the poor visualization of the tumor. In 10 cases, the tumor was poorly visualized because of the emergence of a hyperecho. In these cases, the ability to identify the original tumor location on the monitor by referencing the color Doppler images of the portal vein and the hepatic vein was very useful. HIFU treatments were successfully performed in all 11 patients with the assistance of color Doppler imaging.
Conclusion: Color Doppler imaging is useful for the treatment of HCC using HIFU, compensating for the occasionally poor visualization provided by B-mode conventional US imaging.

DOI： 10.1007/s00261-013-0010-z

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A 23-year-old nulliparous woman, a hepatitis B virus (HBV) carrier with stable liver functions, presented with exacerbation of viral replication (HBV DNA level &gt;9.0log copies/mL) in gestational week 26. During the subsequent follow up without antiviral therapy, she was hospitalized with progression to hepatic failure in gestational week 35. Following initiation of antiviral therapy with lamivudine, emergent cesarean delivery was conducted for fetal safety. Liver atrophy and persistent hepatic encephalopathy (stage 2) necessitated artificial liver support (ALS) involving online hemodiafiltration (HDF) and plasma exchange. She regained full consciousness after the sixth online HDF session. ALS was terminated after the seventh online HDF session. On day 33 of hospitalization, she was discharged home without sequelae. Genetic analysis of the HBV strain isolated from her serum showed that this strain had genotype C. Direct full-length sequencing identified no known mutations associated with fulminant hepatitis B. HBV-related hepatic failure observed in the present case might have been related to perinatal changes in the host immune response.

DOI： 10.1111/hepr.12090

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A 23-year-old woman developed acute severe hepatitis and jaundice on day 183 after bone marrow transplantation from HLA-B antigen mismatched-related donor. The administration of prednisolone and cessation of the prescribed drugs resolved the liver injury. Drug lymphocyte stimulation test was positive for acyclovir, and liver biopsy indicated the characteristics of drug-induced liver injury (DILI) rather than graft-versus-host disease. Physicians should keep DILI in mind when considering differential diagnosis for liver complications after allogeneic cell transplantation.

DOI： 10.1007/s12185-013-1434-5

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OBJECTIVE: We evaluated the efficacy of contrast-enhanced ultrasonography (US), compared with contrast-enhanced computed tomography (CT), for early assessments after transarterial chemoembolization (TACE) for the treatment of hypervascular hepatocellular carcinoma (HCC) lesions. SUBJECTS AND METHODS: Thirty-two patients with 59 HCC lesions who were scheduled to receive TACE were enrolled in this prospective study. TACE was performed by injecting a mixture of iodized oil and miriplatin hydrate, followed by a gelatin sponge. Digital subtraction angiography (DSA) and/or contrast-enhanced CT were performed 2-6 months after TACE and were used as the reference standard for residual HCC; the detection rates for residual viable HCC using contrast-enhanced US with a perflubutane-based contrast agent and a high mechanical index (MI) mode performed one day after TACE were also compared with those obtained using contrast-enhanced CT performed one month after TACE. The comparisons were made using the McNemar test. RESULTS: Forty-seven (79.7%) of the 59 HCC lesions were diagnosed as having residual viability based on DSA and contrast-enhanced CT findings obtained 2-6 months after TACE. Eight (17.0%) of the 47 HCC lesions that were diagnosed as having residual viability using one-day contrast-enhanced US were not detected using one-month contrast-enhanced CT because of artifacts produced by the high attenuation of the iodized oil. The detection rate for residual HCC lesions using one-day contrast-enhanced US (95.7%, 45/47) was significantly higher than that using one-month contrast-enhanced CT (78.7%, 37/47) (P<0.05). CONCLUSION: Contrast-enhanced US performed one day after TACE is more sensitive than contrast-enhanced CT performed one month after TACE for detecting residual viable HCC.

DOI： 10.1016/j.ejrad.2013.04.045

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Aim: Interleukin (IL)-28B gene polymorphism is closely linked with treatment response to peginterferon plus ribavirin combination therapy for hepatitis C virus genotype 1. However, few studies have reported its effects on therapy for genotype 2. We aimed to examine the effects of IL-28B gene polymorphism on treatment response in hepatitis C virus genotype 2 patients.
Methods: In a retrospective study of 101 patients infected with either genotype 2a (n=65) or 2b (n=36) and treated with peginterferon plus ribavirin, we investigated predictive factors for a sustained virological response (SVR), including genetic variations near the IL-28B gene (rs8099917, rs11881222 and rs8103142) and clinical variables such as age, sex, body mass index, stage of fibrosis and drug adherence.
Results: Ultra-rapid virological response, rapid virological response (RVR), end-of-treatment response, SVR and relapse rates were 22.2%, 61.4%, 95.0%, 87.1% and 7.9%, respectively. In univariate analysis, RVR and IL-28B single nucleotide polymorphisms (SNP) (rs8099917, rs11881222 and rs8103142) were significantly associated with SVR. In subgroup analysis, IL-28BSNP were significantly associated with SVR in genotype 2a patients but not in genotype 2b patients. In multiple logistic regression analysis, RVR and IL-28BSNP (rs8099917) were independently associated with SVR. Furthermore, IL-28BSNP was significantly associated with relapse but RVR was not.
Conclusion: In genotype 2 patients treated with peginterferon plus ribavirin combination therapy, IL-28B gene polymorphism was a significant independent predictor of SVR as well as RVR. IL-28B major allele may favor reduced relapse rates in patients with genotype 2 chronic hepatitis C.

DOI： 10.1111/hepr.12037

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Aim: This study aimed to evaluate the fucosylated fraction of alpha-fetoprotein (AFP-L3) as a marker of early hepatocellular carcinoma (HCC). Patients and Methods: We diagnosed early HCC in 15 patients (15 tumors) by gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid-enhanced magnetic resonance imaging and confirmed the diagnoses using new criteria of the International Consensus Group for Hepatocellular Neoplasia. We measured the AFP-L3%, simultaneously, using a liquid-phase binding assay electrokinetic analyte transport assay. We compared the AFP-L3% levels between patients with early HCC and a control cohort with benign liver disease. Results: The AFP-L3% levels were higher in patients with early HCC than in the controls (4.1%+/- 4.0% vs. 2.0%+/- 3.5%, p=0.024). The sensitivity and specificity with AFP-L3% were 33.3% and 78.7% at a cut-off value of 5%, and 20.0% and 88.0% at a cut-off value of 7%, respectively. Conclusion: AFP-L3% is a suitable serological marker for evaluating early HCC.

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Objective: We evaluated the efficacy of fusion imaging, which fuses contrast-enhanced ultrasonography images with arterial-phase, contrast-enhanced CT images as a reference on a single screen in real time, for the evaluation of the effectiveness of radiofrequency ablation for treatment of hypervascular hepatocellular carcinoma.
Materials and methods: Eighty hepatocellular carcinoma lesions with a maximum diameter of between 1 and 3 cm that were scheduled for treatment with radiofrequency ablation were enrolled in this prospective study. After bolus injection of perflubutane-based contrast agent, fusion imaging combining contrast-enhanced ultrasonography images and arterial-phase, contrast-enhanced CT images was performed one day after radiofrequency ablation. We used two functions, which were subsets of the fusion imaging, to confirm the location of the hepatocellular carcinoma lesions in the ablated areas and to evaluate the presence or absence of an adequate safety margin. Contrast-enhanced CT was performed one month after the ablation. Two blinded observers reviewed the images obtained using both modalities to evaluate the effect of ablation.
Results: When the one-month contrast-enhanced CT images were used as the reference standard, the sensitivity, specificity, and accuracy of the one-day fusion imaging for the diagnosis of adequate ablation were 97%, 83%, and 96%, respectively; the kappa value for the agreement between the findings obtained using the two modalities was 0.75.
Conclusion: Fusion imaging combining contrast-enhanced ultrasonography images and arterial-phase, contrast-enhanced CT images as a reference appears to be a useful method for the early evaluation of the efficacy of radiofrequency ablation for the treatment of hypervascular hepatocellular carcinoma. (c) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ejrad.2011.11.052

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Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) is a specific marker used to detect hepatocellular carcinoma (HCC). However, its clinical utility is not sufficient in patients with low total AFP concentrations because of limitations in instrument sensitivity. Recent advances have led to the introduction of a highly sensitive AFP-L3% assay (sensitive AFP-L3%), provided by a novel on-chip, liquid-phase binding assay. This cross-sectional study was conducted to evaluate the clinical significance of the sensitive AFP-L3% in determining HCC recurrence in patients with low total AFP concentrations.
A total of 370 consecutive patients with HCC were screened within 1-3 months of locoregional treatment, and 215 of the 370 patients showed serum AFP &lt; 20 ng/ml. Total AFP, sensitive AFP-L3%, and des-gamma-carboxy prothrombin (DCP) were measured in those 215 patients and HCC recurrence was evaluated by radiological findings. Optimal cutoff values of the markers for detecting HCC recurrence were obtained on the basis of receiver operating characteristic (ROC) curve.
The area under the ROC curve of the total AFP, sensitive AFP-L3%, and DCP in HCC patients with serum AFP &lt; 20 ng/ml were 0.638, 0.724, and 0.779, respectively. The diagnostic accuracies of the total AFP, sensitive AFP-L3%, and DCP were 60.9% (cutoff value 5 ng/ml), 67.7% (cutoff value 7%), and 64.6% (cutoff value 40 ng/ml), respectively.
The new sensitive AFP-L3% assay provides great utility in determining HCC recurrence in patients with low AFP concentrations. Further studies focusing on the combinatorial use of the markers (total AFP, sensitive AFP-L3%, and DCP) are required.

DOI： 10.1007/s10147-011-0306-3

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Immunosuppressive therapy can induce viral reactivation in patients with chronic hepatitis B virus (HBV) infection and, more rarely, in patients with resolved HBV infection. We report the case of a 57-year-old Japanese woman with rheumatoid arthritis (RA) who developed de-novo hepatitis B virus-related hepatitis after methotrexate (MTX) therapy. Entecavir and oral prednisolone following steroid pulse therapy were administered and her liver function recovered. MTX is widely used for RA for its efficiency and safety. But some cases of HBV reactivation caused by MTX, including de-novo hepatitis, have been reported. Considering these conditions, more attention should be paid when using MTX in patients with RA. And more studies are needed to determine who needs screening of HBV, monitoring of HBV-DNA, and prophylaxis with chemotherapy or immunosuppressive therapy.

DOI： 10.1007/s10165-011-0521-9

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Purpose: We evaluated the efficacy of high-intensity focused ultrasound (HIFU) ablation for hepatocellular carcinoma (HCC), and a long-term study by follow-up multidetector-row computed tomography (CT) was conducted to evaluate the changes occurring in the treatment area following the HIFU ablation.
Materials and methods: HIFU ablation was carried out in 14 patients with small HCCs (&lt;= 3 lesions, &lt;= 3 cm in diameter). The HIFU system (Chongqing Haifu Tech) was used under ultrasound guidance. The evaluations were performed by follow-up CT at 1 week, 1, 3, 6 and 12 months after the HIFU ablation.
Results: HIFU ablation was carried out successfully in 11 of the 14 patients. At 1 week after the HIFU, a peripheral rim enhancement was found in all cases (100%). This finding was persistent in 6 of the 11 cases (54.5%) at 1 month, and in 1 of the 11 (9%) cases at 3 months after HIFU ablation. In all cases, the rim enhancement disappeared by 6 or 12 months after the HIFU ablation. At the 12 months follow-up, a decrease in the diameter of the ablated lesions was found. The enhancement around the treated area was found to be persistent at the 12 months follow-up in the one case of recurrence of the treated site in which the safety margin was not sufficiently wide. During the follow-up period, there were 2 cases with residual of HCC tumors. We performed radiofrequency ablation (RFA) for these residual tumors after the HIFU ablation.
Conclusion: To ascertain the cause of the peripheral enhancement on follow-up CT images after the HIFU ablation, in particular, to determine whether it might be caused by residual tumor or recurrence at the treated site, careful follow-up is important, especially in cases where the safety margin of the ablated area was not sufficiently wide. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ejrad.2011.01.101

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Background: No reliable prognostic predictor is known for patients undergoing sorafenib treatment for advanced hepatocellular carcinoma (HCC). Patients and Methods: In 81 patients receiving sorafenib treatment for advanced HCC, we evaluated the prognostic significance of an inflammation-based prognostic score, the Glasgow prognostic score [evidenced by an elevated C-reactive protein level (&gt;1.0 mg/dl) and hypoalbuminemia (&lt;3.5 g/dl)] and compared it with Child-Pugh grade, Barcelona Clinic Liver Cancer staging system, Japan Integrated Staging (JIS) score, and the performance status by Cox-proportional analysis. Results: Median overall survival after sorafenib administration was 11.3 months. On multivariate analysis, Glasgow prognostic score (0 vs. 1 and 2; p&lt;0.001), JIS score (1 and 2 vs. 3 and 4; p=0.001), and performance status (0 vs. 1; p=0.001) were found to be independently associated with survival. Conclusion: The Glasgow prognostic score has significant prognostic value in patients undergoing sorafenib treatment for advanced HCC.

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High-intensity focused ultrasound (HIFU) is a noninvasive method that can cause complete coagulation necrosis without requiring the insertion of any instruments. The hyperechoic grayscale change (hyperechoic region) is used as a sign that the treated lesion has been completely coagulated. The purpose of this study was to evaluate the first hyperechoic region during treatment using HIFU ablation according to various conditions, such as the sonication power, the depth of the tumor from the surface of the skin, and the shield rate. HIFU treatment was performed in 20 patients. The HIFU system (Chongqing Haifu Tech, Chongqing, China) was used under ultrasound guidance. Complete coagulation was achieved in 17 cases. Hyperechoic region were detected after HIFU ablation in 17 patients. The size of the hyperechoic region at a depth of &gt;50 mm was significantly smaller than that at a depth of &lt;= 50 mm. The number and power of the sonications for areas at a depth of &gt;50 mm were significantly larger than those for areas at a depth of &lt;= 50 mm. The number and power in cases with a shield rate of 31-60% were significantly larger than those in cases with a shield rate of 0-30%. When the shield rate was 0%, a hyperechoic region occurred, even when a maximum sonication power was not used. In all three cases with tumors located at a depth of greater than 70 mm and a shield rate of larger than 60%, a hyperechoic region was not seen. In conclusion, hyperechoic regions are easy to visualize in cases with tumors located at a depth of &lt;= 50 mm or shield rates of 0-30%. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ejrad.2011.09.001

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Purpose: We evaluated the safety and usefulness of high-intensity focused ultrasound (HIFU) assisted by ultrasound-computed tomography three-dimensional (US-CT 3D) dual imaging for the treatment of hepatocellular carcinoma (HCC).
Materials and methods: HIFU ablation was performed in 13 patients with small HCC (&lt;= 3 lesions, &lt;= 3 cm in diameter). The HIFU system (Chongqing Haifu Tech) was used under ultrasound guidance. By transferring the sagittal or axial plane of the 3D US and the CT volume data into the ZioM900, multiplanar reconstruction images were displayed in a manner resembling conventional monitor US to assist the HIFU treatment.
Results: Overall, 69% (9/13) of the patients in whom good visualization using B-mode sonography could not be obtained because of the influence of multi-reflections, rib shadows, and unclear tumor margins were successfully treated under the guidance of US-CT 3D dual imaging. In 5 of the 13 patients, multireflections were responsible for the poor visualization. In 2 cases, the tumor was poorly visualized because of a rib shadow. In one case, the margin of the tumor was too unclear to be detected using ultrasography. The 3D US images obtained as part of the US-CT 3D dual imaging had a high resolution and were useful for examining the area of HCC invasion and for determining the extent of the ablation area. The CT images, which are not influenced by bone shadows or multi-reflections, were useful for detecting the tumors and for visualizing the presence of the intestines in the sonication zone. HIFU treatments were successfully performed in all the patients with the assistance of US-CT 3D dual imaging.
Conclusion: US-CT 3D dual imaging is useful for HIFU treatment for HCC, compensating for the occasionally poor visualization provided by US monitor. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ejrad.2010.12.073

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Circadian rhythms are daily oscillations in various biological processes, generated by the feedback loops of eight core circadian genes: Period1. (Per1), Period2 (Per2), Period3 (Per3), Cryptochrome1 (Cry1), Cryptochrome2 (Cry2), Clock, Bmall and Casein Kinase 1 epsilon (CKI epsilon). Recent studies have suggested that circadian genes participate in the growth and development of various cancers. This study examined the relations of circadian gene expression to clinicopathological factors and outcomes in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 202 patients with untreated colorectal cancer. The relative expression levels of the circadian genes in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. Expression of the Clock gene and the CKI epsilon gene in cancer tissue were significantly higher compared to that in adjacent normal mucosa. Expression of the Per1 and Per3 genes in cancer tissue was significantly lower compared to that in adjacent normal mucosa. Analysis of the relations between clinicopathological features and expression of the eight circadian genes in cancer tissue showed that high expression of the Bmall gene and low expression of the Per1 gene correlated with liver metastasis. On analysis of the relations between outcomes and gene expression, high expression of the Per2 gene was associated with significantly better outcomes than low expression of the Per2 gene. Overexpression of the Bmall gene and reduced expression of the Per1 gene may thus be useful predictors of liver metastasis. Moreover, reduced expression of the Per2 gene may be a predictor of outcomes in patients with colorectal cancer.

DOI： 10.3892/or.2011.1207

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We retrospectively evaluated the antitumor effect, survival and toxicities of hepatic arterial infusion therapy using a fine powder formulation of cisplatin (cisplatin powder) in hepatocellular carcinoma patients with portal vein tumor thrombosis.
Twenty-four patients classified as Child-Pugh class A or B underwent a single session of hepatic arterial infusion therapy using cisplatin powder. The treatment was repeated every 4-6 weeks in patients with no evidence of tumor progression or unacceptable toxicity. The treatment response was evaluated using contrast-enhanced computed tomography performed 1 month after each treatment. The survival rate was evaluated using the Kaplan-Meier method, and predictors of a better outcome were identified using univariate analysis.
The mean follow-up period was 11.2 months (range, 1.3-44.2 months). A total of 57 sessions of intra-arterial infusion (1-6 sessions per patient; mean, 2.4 sessions) with cisplatin powder were performed. A complete response and a partial response were obtained in one and four patients, respectively (objective response rate = 20.8%). The median survival time for all the patients was 7.0 months; the median survival times for the 5 responders and 19 non-responders were 37.3 and 5.6 months, respectively. The 1- and 2-year survival rates were 38% and 16%, respectively. Significant prognostic factors related to survival were the therapeutic effect, patient age and serum alanine aminotransferase level. Severe adverse reactions resulting in treatment discontinuation were not observed, and all the toxicities were successfully managed using conservative treatment.
Hepatic arterial infusion therapy with a fine powder formulation of cisplatin was safe, well-tolerated and might help to prolong the life span of advanced hepatocellular carcinoma patients with portal vein tumor thrombosis.

DOI： 10.1093/jjco/hyq145

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DOI： 10.2957/kanzo.52.429

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BACKGROUND: To improve the efficacy of radiofrequency ablation (RFA) for the treatment of intermediate-sized hepatocellular carcinomas (HCCs), the authors compared PEA combined with transcatheter arterial chemoembolization (TACE) to RFA alone. METHODS: The authors randomly assigned 37 patients with solitary HCCs (diameter, 3.1-5.0 cm in the greatest dimension) to 2 groups: the TACE-RFA group, in which the patients received TACE followed by RFA on the same day, and the RFA group, in which the patients received only PEA. RESULTS: Technical success was achieved after 1.4 +/- 0.5 RFA sessions in the RFA group and after 1.1 +/- 0.2 RFA sessions in the TACE-RFA group (P &lt; .01). The mean diameters of the longer and shorter axes of the RFA-induced ablated areas were 50 +/- 8.0 mm and 41 +/- 7.1 mm, respectively, in the RFA group and 58 +/- 13.2 mm and 50 +/- 11.3 mm, respectively, in the TACE-RFA group; the mean diameters of the shorter axes were significantly different (P = .012). The rates of local tumor progression at the end of the third year in the RFA and TACE-RFA groups were 39% and 6%, respectively (P = .012). The 3-year survival rates of the patients in the RFA and TACE-RFA groups were 80% and 93%, respectively (P = .369). CONCLUSIONS: In patients with intermediate-sized HCCs, RFA combined with TACE is more effective than RFA alone for extending the ablated area in fewer treatment sessions and for decreasing the local tumor progression rate. Cancer 2010;116:5452-60 (C) 2010 American Cancer Society.

DOI： 10.1002/cncr.25314

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PURPOSE To assess the extended effects of transcatheter arterial embolization with iodized oil and gelatin sponge on liver histopathologic changes in radiofrequency (RF)-ablated zones and the surrounding liver parenchyma in a pig model
MATERIALS AND METHODS Eighteen consecutive pigs subjected to 36 RF applications performed immediately after segmental embolization with iodized oil and gelatin sponge to the left lobe of the liver (embolization/RF ablation) were euthanized immediately after the procedure or 1 or 4 weeks later The right lobes were used as controls for RF applications without embolization The ablated zones and the surrounding liver parenchyma were measured and examined histopathologically
RESULTS The average maximum ablated zone was significantly larger in the embolization/RF ablation specimens than in the RF ablation-alone specimens at all three follow-up time points Ten of the 12 specimens obtained immediately after embolization/RF ablation showed wide hemorrhagic areas spreading to the periphery of the liver and microscopically showed marked intralobular congestion with sinusoidal dilation This hemorrhagic change had disappeared in all the specimens obtained 1 week after embolization/RF ablation, but 10 of the 12 specimens showed wedge-shaped areas of segmental degenerative parenchyma beginning at the ablated zone and extending to the periphery of the liver, these were microscopically revealed to be areas of coagulative necrosis, indicating hepatic infarction The sizes of these necrotic zones had decreased at 4 weeks after embolization/RF ablation
CONCLUSIONS RF ablation performed immediately after embolization in normal pig liver induced large ablated zones accompanied by wedge-shaped areas of segmental infarction

DOI： 10.1016/j.jvir.2010.06.020

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Objective: We performed contrast-enhanced three-dimensional sonography (CE 3D US) with a perflubutane-based contrast agent to immediately evaluate the completeness of ablation of small hepatocellular carcinoma (HCC) lesions by extracorporeal high-intensity focused ultrasound (HIFU).
Subjects and methods: Twenty-one HCC lesions were treated by a single ultrasound-guided HIFU ablation session, and CE 3D US was performed before, immediately after, and 1 week, and 1 month after HIFU, and contrast-enhanced CT (CE CT) or contrast-enhanced MRI (CE MRI) was performed before HIFU, 1 week and 1 month after HIFU, and during the follow-up period.
Results: Immediately and 1 month after HIFU, 17 lesions were evaluated as adequately ablated by CE 3D US, and the other 4 lesions as residual tumors. One month after HIFU, 18 were evaluated as adequately ablated by CE CT or CE MRI, and the other 3 as residual tumors. The evaluation by CE 3D US immediately after HIFU and by CE CT or CE MRI 1 month after HIFU was concordant with 20 lesions. The kappa value for agreement between the findings of CE 3D US and other modalities by two blinded observers was 0.83. When the 1-month CE CT or CE MRI findings were used as the reference standard, the sensitivity, specificity, and accuracy of CE 3D US immediately after HIFU for the diagnosis of the adequate ablation were 100%, 75%, and 95%, respectively.
Conclusion: CE 3D US appears to be a useful method for immediate evaluation of therapeutic efficacy of HIFU ablation of HCC lesions. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ejrad.2009.11.022

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ROENTGEN RAY SOC  

OBJECTIVE. We describe our experience with the application of a novel technology in which fluoroscopy and 3D imaging from C-arm cone beam CT systems are combined with integrated navigation software.
CONCLUSION. We applied this technology to five cases in which radiofrequency ablation was performed for hepatocellular carcinoma. Technical success was achieved without treatment-related complications in all cases. We conclude that this novel technology is potentially useful for targeting hepatic lesions.

DOI： 10.2214/AJR.09.3514

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BAISHIDENG PUBL GRP CO LTD  

AIM: To differentiate focal liver lesions based on enhancement patterns using three-dimensional ultrasonography (3D US) with perflubutane-based contrast agent.
METHODS: Two hundred and eighty two patients with focal liver lesions, including 168 hepatocellular carcinomas (HCCs), 63 metastases, 40 hemangiomas and 11 focal nodular hyperplasias (FNHs), were examined by 3D US with perflubutane-based contrast agent. Tomographic ultrasound images and sonographic angiograms were reconstructed. Among 282 lesions, enhancement patterns of 163 lesions between January 2007 and October 2007 were analyzed retrospectively. Then from November 2007 to May 2008, compared with contrast-enhanced (CE) 2D US, CE 3D US was performed on 119 lesions for prospective differential diagnosis. Sensitivity, specificity, area under receiver operating characteristic curve (Az) and inter-reader agreement were assessed.
RESULTS: With the tridimensional view, dominant enhancement patterns were revealed as diffuse enhancement or peripheral ring-like enhancement, followed with washout change for HCCs or metastases, respectively, and peripheral nodular enhancement or diffuse enhancement with spoke-wheel arteries, followed by persistent enhancement for hemangiomas or FNHs, respectively. At CE 3D US, the prospective differentiation of lesions showed sensitivity 92% (mean for two readers), specificity 91% and Az value 0.95 for HCCs, 84%, 97%, and 0.95 for metastases, 91%, 98%, and 0.98 for hemangiomas and 80%, 99%, and 0.99 for FNHs, respectively, while good to excellent inter-reader agreement was achieved. No significant difference exists between prospective diagnosis accuracy at CE 3D US and that at CE 2D US.
CONCLUSION: CE 3D US provides a spatial perspective for liver tumor enhancement, and could help in differentiating focal liver lesions. (C) 2010 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v16.i17.2109

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER WIEN  

Hepatitis C virus (HCV) is the main causative agent of chronic liver disease, which may develop into liver cirrhosis and hepatocellular carcinoma. By using a recently developed reporter assay system in which genome-length HCV RNA replicates efficiently, we found that hydroxyurea (HU), a DNA synthesis inhibitor, inhibited HCV RNA replication. Moreover, we demonstrated that the anti-HCV activity of the combination of IFN-alpha and HU was higher than that of IFN-alpha alone. These results suggest that HU may be an effective anti-HCV reagent that can be used not only singly but also in combination with IFN-alpha to treat chronic hepatitis C.

DOI： 10.1007/s00705-010-0624-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT MEDICAL PRESS LTD  

Background: HCV is the main causative agent of chronic liver disease, which could progress to liver cirrhosis and hepatocellular carcinoma. By using a recently developed genome-length HCV RNA replication reporter assay system, we found that hydroxyurea (HU), an inhibitor of DNA synthesis, inhibited HCV RNA replication.
Methods: To test the hypothesis that HU suppresses HCV replication in humans, we conducted a Phase I trial involving Japanese patients with chronic hepatitis C (CHC) and investigated the safety and effectiveness of a 4-week course of oral HU.
Results: A total of nine patients were treated with an HU dose level of 500 mg three times daily. Dose-limiting toxicity was not observed at this dose level. Of the nine patients, eight exhibited a moderate decrease in serum HCV RNA levels during the trial. A decrease in HCV RNA levels to nadir levels was achieved for the eight patients (median -0.27 log(10) IU/ml [range -0.08--0.44]) at various times during the 4 weeks after therapy initiation.
Conclusions: The results of this Phase 1 trial suggest that HU has potential as an anti-HCV agent that could be effective for the treatment of CHC patients.

DOI： 10.3851/IMP1668

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Language：Japanese   Publishing type：Research paper (scientific journal)  

We compared with the adverse events of half-dose (400 mg per day, n = 13) administration and standard-dose (800 mg per day, n = 12) administration of sorafenib as initial-dose treatment for advanced hepatocellular carcinoma. Baseline characteristics such as sex, age, Child Pugh's classification, and presence or absence of portal vein thrombosis and extrahepatic metastasis did not differ significantly between the two initial-dose groups. The dose of sorafenib was reduced because of adverse events in 75% of the standard-dose cases and in 38% the half-dose cases The difference between the two groups in time to radiographic progression was not significant. A randomized, double-blind, study may be necessary to find the optimal dose of sorafenib for treatment of Japanese patients with advanced hepatocellular carcinoma lesions. © 2010 The Japan Society of Hepatology.

DOI： 10.2957/kanzo.51.400

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Objectives: We investigated clinical utility of contrast-enhanced three-dimensional ultrasound (CE 3D US) imaging with contrast medium Sonazoid for demonstrating characteristic enhancement of hepatocellular carcinoma (HCC).
Methods: Among 115 focal liver tumors undergoing CE 3D US imaging, 70 HCCs confirmed with contrast-enhanced multi-detector computed tomography, contrast-enhanced magnetic resonance imaging or histopathologic examination were retrospectively analyzed. CE 3D US imaging was performed using Autosweep 3D scan functionality in the early, middle and late phase, after bolus injection of 0.2 ml Sonazoid. The CE 3D tomographic images reconstructed in parallel slices and sonographic angiogram images were independently reviewed by two reviewers. Kappa values were used to assess inter-reviewers&apos; agreement.
Results: TUI images showed most of HCCs were detected with intratumoral vessels and early tumor enhancement in the early phase. expressed homogenous or heterogeneous tumor enhancement in the middle phase, and became hypoechoic or isoechoic in the late phase. The kappa values in the early, middle and late phase for inter-reviewer agreements regarding the characteristic enhancement of tumors were 0.817, 0.774, and 0.785. In addition, TUI images demonstrated satellite foci and tortuous tumor vessels in three orthogonal planes. Sonographic angiogram reconstructed by different rendering modes showed the vessels and tumor stain in spatial view. The spatial configuration of anatomic structures was revealed on basis of both TUI and sonographic angiogram images.
Conclusion: CE 3D US imaging, with spatial visualization, is clinically useful to exhibit the characteristic enhancement of HCC tumors objectively. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ejrad.2008.09.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER INST ULTRASOUND MEDICINE  

Objective. The purpose of this study was to evaluate the enhancement patterns of focal liver tumors in the late phase of Sonazoid-enhanced ultrasonography by intermittent imaging with a high mechanical index (MI). Methods. A total of 142 patients with 208 lesions, including 109 hepatocellular carcinomas (HCCs), 61 metastases, 30 hemangiomas, and 8 focal nodular hyperplasias (FNHs), were enrolled in this prospective study. Contrast-enhanced ultrasonography with intermittent scanning at 2 frames per second (MI, 0.7-12) was conducted in the late phase (&gt;5 minutes after bolus intravenous injection of the perflubutane-based contrast agent Sonazoid; Daiichi Sankyo, Tokyo, Japan). Two blinded readers classified the enhancement patterns of the lesions. The sensitivity, specificity and positive predictive value (PPV) of the dominant enhancement patterns and inter-reader agreement were assessed. Results. A combination of diffuse enhancement with intratumoral vessels and intratumoral vessels alone yielded sensitivity of 85% (average of both readers), specificity of 88%, and a PPV of 88% for HCC. For metastasis, a combination of peripheral ringlike enhancement with peritumoral vessels and peripheral ringlike enhancement with intratumoral vessels yielded sensitivity of 79%, specificity of 95%, and a PPV of 85%. For hemangiomas, a combination of peripheral nodular enhancement with peritumoral vessels and peripheral nodular enhancement without peritumoral vessels yielded sensitivity of 75%, specificity of 99%, and a PPV of 92%. Diff use enhancement with spoked wheel arteries yielded sensitivity of 82%, specificity of 100%, and a PPV of 87% for FNHs. Good inter-reader agreement was achieved. Conclusions. Sonazoid-enhanced ultrasonography using intermittent imaging with a high MI can potentially be used for evaluating the enhancement patterns of focal liver tumors in the late phase.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

The aims of this study were to identify prognostic factors in patients who received a non-surgical second treatment for the development of recurrent hepatocellular carcinoma (HCC) after an initial percutaneous ablation therapy.
We retrospectively studied 147 patients with HCC who had received an initially successful percutaneous ablation therapy. The patients were followed up using computed tomography and/or ultrasound every 3 months and a second treatment was performed for subsequent recurrent tumours.
The 3- and 5-year survival rates of the 147 patients were 90 and 65% respectively. During a mean follow-up period of 33 months, local or distant tumour recurrences developed in 77 of the 147 patients, and the 3- and 5-year survival rates after a second treatment in these 77 patients were 73 and 44% respectively. Forty-six of the 77 patients with up to three recurrent tumours received percutaneous ablation therapy for the second treatment, and the remaining 31 patients with more than three (multiple) recurrent tumours received transcatheter arterial chemoembolization for their second treatment. A multivariate analysis revealed the serum alpha-fetoprotein level at the time of the appearance of the recurrent HCC (&lt; 100 ng/ml vs &gt;= 100 ng/ml, P=0.009) and the number of recurrent tumours (up to three vs more than three, P=0.009) to be independent prognostic factors after the second treatment.
The serum alpha-fetoprotein level and recurrent tumour number were prognostic factors following the second treatment in patients with recurrent HCC who had received an initially successful ablation therapy.

DOI： 10.1111/j.1478-3231.2008.01890.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ROENTGEN RAY SOC  

OBJECTIVE. We investigated visualization methods of 3D sonography with a perflubutane-based contrast agent in the imaging evaluation of vascular patterns of focal liver tumors.
MATERIALS AND METHODS. Eighty-four patients with focal liver tumors underwent automatic scanning with 3D sonography 20-60 seconds after administration of a perflubutane contrast agent. The confirmed final diagnoses were 50 hepatocellular carcinomas, 20 metastatic lesions, nine hemangiomas, and five cases of focal nodular hyperplasia. Tomographic sonographic images reconstructed in 3D parallel slices and rendered sonographic images resembling angiograms were reviewed by two readers.
RESULTS. Sonographic angiograms rendered by maximum intensity of gray values in surface smooth mode showed tumor vessels and early tumor enhancement. The average intensity of gray values with surface texture mode showed unenhanced areas within tumors. Interobserver agreement for classifying enhancement patterns with both tomographic sonography and sonographic angiography was excellent (kappa = 0.84). The main pattern, intratumoral vessels with early homogeneous or heterogeneous tumor enhancement, had a sensitivity of 97% (average of both readers), specificity of 94%, and positive predictive value (PPV) of 96% for hepatocellular carcinomas. The presence of tumor vessels with early peripheral ringlike tumor enhancement had a sensitivity of 90%, specificity of 95%, and PPV of 86% for metastatic lesions. Peripheral nodular enhancement had a sensitivity of 84%, specificity of 99%, and PPV of 89% for hemangioma. The presence of spoke-wheel arteries with early tumor enhancement had a sensitivity of 80%, specificity of 100%, and PPV of 100% for focal nodular hyperplasia.
CONCLUSION. Three-dimensional sonography with a perflubutane-based contrast agent is useful in the evaluation of vascular patterns of focal liver tumors.

DOI： 10.2214/AJR.08.1107

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Language：Japanese   Publisher：Study Group of Microwave Surgery  

We previously reported that radiofrequency (RF) ablation combined with transcatheter arterial embolization (TAE) using iodized oil and gelatin sponge created wedge-shaped necrotic area starting from the ablation zone to the periphery of the liver in animal model. In this study, we evaluated the extended effects of the combination therapy to 17 patients with hepatocellular carcinoma (HCC) located periphery of the liver. Immediately after segmental TAE, RF expandable electrode was inserted to proximal portion of HCC. In 16 of 17 patients, wedge-shaped segmental necrotic area including HCC was confirmed by CT, and no local tumor recurrences were observed during 24-48 months of follow-up periods. Three adverse events (pleural effusion) were related to the treatment. We conclude that this combination therapy makes it possible to induce the wedge-shaped segmental necrosis including HCC.

DOI： 10.3380/jmicrowavesurg.27.55

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CENTER ACADEMIC PUBL JAPAN  

Previously, we found that bovine and human lactoferrin (LF) specifically inhibited hepatitis C virus (HCV) infection in cultured non-neoplastic human hepatocyte-derived PH5CH8 cells, and we identified 33 amino acid residues (termed C-s3-33; amino acid 600-632) from human LF that were primarily responsible for the binding activity to the HCV E2 envelope protein and for the inhibiting activity against HCV infection. Since the anti-HCV activity of C-s3-33 was weaker than that of human LF, we speculated that an increase of E2 protein-binding activity might contribute to the enhancement of anti-HCV activity. To test this possibility, we made two repeats [(C-0-33)(2)] and three repeats [(C-s3-33)(3)] of C-s3-33 and characterized them. Far-Western blot analysis revealed that the E2 protein-binding activities of (C-s3-33), and (C-ws3-33)(3) became stronger than that of the C-0-33, and that the binding activity of (C-s3-33)(3) was stronger than that of (C-s3-33)(3). Using an HCV infection system in PH5CH8 cells, we demonstrated that the anti-HCV activities of (C-s3-33)2 and (C-s3-33)(3) became stronger than that of the C-0-33. Furthermore, using a recently developed infection system with a VSV pseudotype harboring the green fluorescent protein gene and the native E1 and E2 genes, we demonstrated that the antiviral activities of (C-s3-33)(2) and (C-s3-33)(3) were stronger than that of C-s3-33. These results suggest that tandem repeats of LF-derived anti-HCV peptide are useful as anti-HCV reagents.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC GENERAL MICROBIOLOGY  

Hepatitis C virus (HCV) genomic sequences are known to vary widely among HCV strains, but to date there have been few reports on the genetic variations and dynamics of HCV in an experimental system of HCV replication. In this study, a genetic analysis of HCV replicons obtained in long-term culture of two HCV replicon cells (50-1 and 1B-2R1), which were established from two HCV strains, 1B-1 and 1B-2, respectively, was performed. One person cultured 50-1 cells for 18 months, and two people independently cultured 50-1 cells for 12 months. 1B-2R1 cells were also cultured for 12 months. The whole nucleotide sequences of the three independent replicon RNA clones obtained at several time points were determined. It was observed that genetic mutations in both replicons accumulated in a time-dependent manner, and that the mutation rates of both replicons were approximately 3.0 x 10(-3) base substitutions/site/year. The genetic diversity of both replicons was also enlarged in a time-dependent manner. The colony formation assay by transfection of total RNAs isolated from both replicon cells at different time points into naive HuH-7 cells revealed that the genetic mutations accumulating with time in both replicons apparently improved colony formation efficiency. Taken together, these results suggest that the HCV replicon system is useful for the analysis of evolutionary dynamics and variations of HCV. Using this replicon cell culture system, it was demonstrated further that neither ribavirin nor its derivative mizoribine accelerated the mutation rate or the increase in the genetic diversity of HCV replicon.

DOI： 10.1099/vir.0.80479-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Lactoferrin (LF), a milk protein belonging to the iron transporter transferrin family, is known as a primary defense protein against pathogenic microorganisms. Previously, we found that bovine and human LFs prevented hepatitis C virus infection in cultured human hepatocytes by a direct interaction with the virus. Since LF is proposed to have transcriptional regulatory activity in addition to its antimicrobial function, we sought to identify the target genes that these two types of LF have in common. To this end, we were the first to perform microarray analysis (9970 genes) using human hepatocytes that expressed bovine or human LF by retrovirus-mediated gene transfer. In the results, LF could give a variety of expression profiles in the human hepatocytes, and showed that 9 and 19 genes were commonly upregulated (more than 2.0-fold) and down-regulated (less than 0.50-fold), respectively, in both bovine and human LF-expressing cells compared with control cells. Among these genes, we found that gamma-aminobutyric acid (GABA)-B receptor 2 was transcriptionally down-regulated by bovine and human Us, but not by human transferrin. Furthermore, we obtained the suggestive result that LF may modulate the level of intracellular cAMP. This modulation is one of the cellular responses that the GABA-B receptor modifies. This is the first report of microarray analysis applied to search inclusively for the target genes of LF. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.bbagen.2004.10.003

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To clarify the mechanism underlying resistance to interferon (IFN) by the hepatitis C virus (HCV) in patients with chronic hepatitis, we attempted to develop an IFN-resistant HCV replicon from the IFN-sensitive 50-1 replicon established previously. By treating 50-1 replicon cells with a prolonged low-dose treatment of IFN-α and then transfecting the total RNA derived from the IFN-α-treated replicon cells, we successfully obtained four clones (named 1, 3, 4, and 5) of HCV replicon cells that survived against IFN-α (200 IU/ml). These cloned cells were further treated with IFN-α or IFN-β (increased gradually to 2000 or 1000 IU/ml, respectively). This led to four replicon cell lines (αR series) possessing the IFN-α-resistant phenotype and four replicon cell lines (βR series) possessing the IFN-β-resistant phenotype. Furthermore, we obtained an additional replicon cell line (αRmix) possessing the IFN-β-resistant phenotype by two rounds of prolonged treatment with IFN-α and RNA transfection as mentioned above. Characterization of these obtained HCV replicon cell lines revealed that the αR series were highly resistant to both IFN-α and IFN-β, although the αR series containing αRmix were only partially resistant to both IFN-α and IFN-β. Genetic analysis of these HCV replicons found one common amino acid substitution in the NS4B and several additional amino acid substitutions in the NS5A of the βR series, suggesting that these genetic alterations are involved in the IFN resistance of these HCV replicons. These newly established HCV replicon cell lines possessing IFN-resistant phenotypes are the first useful tools for understanding the mechanisms by which HCV acquires IFN resistance in vivo. © 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2004.08.091

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Hepatitis C virus proteins exert an effect on a variety of cellular functions, including gene expression, signal transduction, and apoptosis, and because they possess oncogenic potentials, they have also been suggested to play an important role in hepatocarcinogenesis. Although the mechanisms of hepatocarcinogenesis remain poorly understood, we hypothesized that the disease may arise because of a disturbance of the DNA repair system by hepatitis C virus proteins. To test this hypothesis, we developed a reproducible microsatellite instability assay system for mismatch-repair using human-cultured cells transducted with pCXpur retrovirus expression vector, in which the puromycin resistance gene was rendered out-of-frame by insertion of a (CA)(17) dinucleotide repeat tract immediately following the ATG start codon. Using several human cancer cell lines known to be replication error positive or negative, we demonstrated that this assay system was useful for monitoring the propensity for mismatch-repair in the cells. This assay system was applicable to nonneoplastic human PH5CH8 hepatocytes, which could support hepatitis C virus replication. Using PH5CH8 cells, in which hepatitis C virus proteins were stably expressed by the retrovirus-mediated gene transfer, we found that the core protein promoted microsatellite instability in PH5CH8 cells. Interestingly, such promotion by the core protein only occurred in cells having the core protein belonging to genotype 1b or 2a and did not occur in cells having the core protein belonging to genotype 1a, 2b, or 3a. This is the first report to demonstrate that the core protein may disturb the DNA repair system.

DOI： 10.1158/0008-5472.CAN-03-2992

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier  

We previously found that hepatitis C virus (HCV) core protein, which possesses the consensus sequence of genotype 1b, transcriptionally activates the interferon (IFN)-inducible 2′-5′-oligoadenylate synthetase (2′-5′-OAS) gene in human hepatocyte cells. To clarify the mechanism of this activation, we further characterized the core protein as an activator of the 2′-5′-OAS gene. We demonstrated that the activation of the 2′-5′-OAS gene by the core protein is a general phenomenon, regardless of HCV genotype and strain. We showed that the 20 N-terminal amino acids (aa) of the core protein were important to the activation of the 2′-5′-OAS gene, although this N-terminal region did not have any effect on the subcellular localization of the core protein. We demonstrated that the core protein was able to activate all promoters possessing the IFN-stimulated response element (ISRE) examined. However, we found that the level of activation of the 2′-5′-OAS gene promoter possessing a particular variant type of ISRE was significantly higher than that of other IFN-inducible gene promoters. This phenomenon was confirmed using synthetic promoters possessing five repeats of the consensus or a 2′-5′-OAS-type ISRE. In addition, we showed that gene activation induced by the core protein is mediated by the ISRE. These results imply that the core protein prefers a subclass of IFN-inducible genes, the promoters of which possess the 2′-5′-OAS-type ISRE. Accordingly, we found that the IFN-inducible double-stranded RNA-specific adenosine deaminase gene promoter, possessing a 2′-5′-OAS-type ISRE sequence, was also efficiently activated by the core protein. The exact mechanism by which the core protein enhances gene expression was not determined, but we could find no effects of core protein on gene expression and phosphorylation status of the components of the JAK-STAT signaling transduction pathway. © 2003 Elsevier B.V. All rights reserved.

DOI： 10.1016/S0168-1702(03)00218-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The hepatitis C virus (HCV) replicon system is a potent tool for understanding the mechanisms of HCV replication and proliferation, and for the development of treatments for patients with HCV. Recently, we established an HCV subgenomic replicon (501) using HCV genome RNA obtained from the cultured human T cell line MT-2C infected with HCV (isolate 1B-1) in vitro. In order to further obtain other HCV replicons without difficulty, we generated a replicon RNA library derived from human non-neoplastic hepatocytes infected with HCV (isolate 1B-2) in vitro. Upon transfection of the generated RNA library to "cured cells," from which the 50-1 subgenomic replicon was eliminated by prolonged treatment with interferon-alpha, we successfully established a new HCV subgenomic replicon, 1B-2R1. We characterized 1B-2R1 replicon in terms of efficiency of replication, HCV sequence, and sensitivity to interferons. The results revealed that the replication level of the 1B-2R1 replicon was comparable to that of the 50-1 replicon. We also found that the 1B-2R1 replicon possessed an HCV sequence distinct from those of other replicons established to date, and that the 1B-2R1 replicon was sensitive to interferon-a, interferon-P, and interferon-gamma. Taken together, present results indicate that the replicon RNA library generated using an in vitro HCV infection system is useful for the establishment of an HCV subgenomic replicon. (C) 2003 Elsevier Science (USA). All rights reserved.

DOI： 10.1016/S0006-291X(03)01047-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Bovine and human lactoferrins (LF) prevent hepatitis C virus (HCV) infection in cultured human hepatocytes; the preventive mechanism is thought to be the direct interaction between LF and HCV. To clarify this hypothesis, we have characterized the binding activity of LF to HCV E2 envelope protein and have endeavored to determine which region(s) of LF are important for this binding activity. Several regions of human LF have been expressed and purified as thioredoxin-fused proteins in Escherichia coli. Far-Western blot analysis using these LF fragments and the E2 protein, expressed in Chinese hamster ovary cells, revealed that the 93 carboxyl amino acids of LF specifically bound to the E2 protein. The 93 carboxyl amino acids of LFs derived from bovine and horse cells also possessed similar binding activity to the E2 protein. In addition, the amino acid sequences of these carboxyl regions appeared to show partial homology to CD81, a candidate receptor for HCV I, and the binding activity of these carboxyl regions was also comparable with that of CD81. Further deletion analysis identified 33 amino acid residues as the minimum binding site in the carboxyl region of LF, and the binding specificity of these 33 amino acids was also confirmed by using 33 maltose-binding protein-fused amino acids. Furthermore, we demonstrated that the 33 maltose-binding protein-fused amino acids prevented HCV infection in cultured human hepatocytes. In addition, the site-directed mutagenesis to an Ala residue in both terminal residues of the 33 amino acids revealed that Cys at amino acid 628 was determined to be critical for binding to the E2 protein. These results led us to consider the development of an effective anti-HCV peptide. This is the first identification of a natural protein-derived peptide that specifically binds to HCV E2 protein and prevents HCV infection.

DOI： 10.1074/jbc.M207879200

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

We have shown that highly proofreading DNA polymerase is required for the polymerase chain reaction in the genetic analysis of hepatitis C virus (HCV). To clarify the status of HCV quasispecies in hepatic tissue using proofreading DNA polymerase, we performed a genetic analysis of the HCV core protein-encoding region in cancerous and noncancerous lesions derived from 4 patients with hepatocellular carcinoma. In contrast to the previously published data, we observed neither deletions nor stop codons in the analyzed region and no significant difference in the complexity of HCV quasispecies between cancerous and noncancerous lesions. This result suggests that the HCV core gene is never structurally defective in hepatic tissues, including cancerous lesions. However, in 3 of the patients, the consensus HCV species differed between cancerous and noncancerous lesions, suggesting that the predominant replicating HCV species differs between these 2 types of lesions. Moreover, during the course of the study, we obtained several interesting variants possessing a substitution at codon 9 of the core gene, whose substitution has been shown to induce the production of the F protein synthesized by a -2/+1 ribosomal frameshift.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Based on recent LightCycler techniques developed for the quantitation of serum HCV RNA, we have developed a quantitative method for the intracellular hepatitis C virus (HCV) RNA using LightCycler PCR. A simple real-time PCR assay, based on the SYBR Green I dye and LightCycler fluorimeter and with no probe requirement, is described. In the presence of 0.5 mug of cellular RNA, it was demonstrated that as few as 25 copies of HCV RNA could be specifically detected with a set of primers that amplify a 144-base pair sequence unique to the 5'-noncoding region of HCV RNA. We demonstrated that this method was useful for the evaluation of antiviral reagents using HCV-infected human cultured cells.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

We have developed a reliable internally controlled RT-nested PCR method for the detection of hepatitis C virus (HCV) RNA using in vitro synthesized Renilla luciferase (Rluc) RNA as an internal control. Using this method, the 5'-noncoding region of HCV RNA (144 nucleotides) and Rluc RNA (276 nucleotides) were efficiently amplified in a single tube, and the sensitivity and specificity of this method were comparable to standard RT-nested PCR. This method was successfully performed on RNA specimens obtained from in vitro HCV-infected human hepatocyte PH5CH8 cells, which support HCV replication. in addition, we demonstrated that this method was useful for the evaluation of antiviral reagents by confirming the anti-HCV activity of bovine lactoferrin, which we previously found to be a new inhibitor of HCV infection. Therefore, this method may be useful for the studies of not only HCV but also of other viruses.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We recently found that bovine lactoferrin (bLF), a milk glycoprotein belonging to the iron transporter family, prevented hepatitis C virus (HCV) infection in human hepatocyte PH5CH8 cells, that are susceptible to HCV infection, and demonstrated that the anti-HCV activity of bLF was due to the interaction of bLF and HCV. In this study we further characterized the anti-HCV activity of bLF and the mechanism by which bLF prevents HCV infection. We found that bLF inhibited viral entry to the cells by interacting directly with HCV immediately after mixing of bLF and HCV inoculum. The anti-HCV activity of bLF was lost by heating at 65 degrees C, and other milk proteins (mucin, beta-lactoglobulin and casein) did not prevent HCV infection, indicating that bLF prevented HCV infection in a rather specific manner. Furthermore, we found that bovine lactoferricin, a basic N-terminal loop of bLF that is an important region for antibacterial activity, did not exhibit any anti-HCV activity, suggesting that some other region is involved in anti-HCV activity. We confirmed that prevention of HCV infection by bLF was a general phenomenon, because bLF inhibited HCV infection with all five inocula examined, and bLF inhibited HCV infection in human MT-2C T-cells, that were susceptible to HCV infection. In addition, infection with hepatitis G virus, which is distantly related to HCV, was prevented also by bLF. In conclusion, lactoferrin is a natural glycoprotein which effectively protects against HCV infection in hepatocytes and lymphocytes by neutralizing the virus. (C) 2000 Elsevier Science B.V. All rights reserved.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Microbiology  

The effects of hepatitis C virus (HCV) proteins on several signal transduction pathways in human nonneoplastic hepatocyte PH5CH8 cells were investigated using expression vectors encoding HCV proteins derived from HCV-infected human nonneoplastic cultured T-lymphocyte and hepatocyte cells (MT-2C and PH5CH7), which could support HCV replication. The amino acid sequences of HCV proteins obtained from HCV-infected human cells were identical or very close to the consensus sequences of the proteins derived from the original inoculum used for HCV infection. During the course of the study, we found that HCV core protein specifically activated the 40/46-kDa 2'-5'-oligoadenylate synthetase (2'-5'-OAS) gene promoter in a dose-dependent manner in different human hepatocyte cell lines (PH5CH8, HepG2, and PLC/PRF/5). We also found that the activation by core protein was further enhanced in the cells treated with alpha interferon. The expression of E1 or E2 envelope protein or nonstructural NS5A protein did not activate the 2'-5'-OAS gene promoter. We demonstrated that the activation by core protein in the hepatocyte cells was suppressed by antisense RNA complementary to core-encoding RNA. Deletion mutant analysis of core protein and deletion analysis of the 2'-5'-OAS gene promoter have been performed. Finally, we demonstrated that the activation of the 2'-5'-OAS gene occurred at the transcriptional level and furthermore demonstrated that the endogenous 2'-5'-OAS gene was also activated by core protein. This is the first report to show that a viral protein activated the 2'-5'-OAS gene.

DOI： 10.1128/JVI.74.18.8744-8750.2000

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：ELSEVIER SCIENCE BV  

We reported that bovine lactoferrin (bLF), a milk glycoprotein belonging to the iron transporter family prevented hepatitis C virus (HCV) infection in human hepatocyte PH5CH8 cells that are susceptible to HCV infection, and demonstrated that the anti-HCV activity of bLF was due to the interaction of bLF and HCV. We further characterized the anti-HCV activity of bLF and the mechanism by which bLF prevents HCV infection. We found that bLF effectively inhibited viral adsorption to both hepatocyte (PH5CH8) and lymphocyte (MT-2C) cells, regardless of HCV strain used. We obtained the results that the interaction of bLF and HCV occurred faster than HCV adsorption to the cells. Mucin, beta-lactoglobulin, casein and transferrin had no anti-HCV activity, indicating that bLF prevented HCV infection in a rather specific manner. Bovine lactoferricin, a basic N-terminal loop of bLF that is an important region for antibacterial activity, did not exhibit any anti-HCV activity, suggesting that some other region is involved in anti-HCV activity. In addition, infection with hepatitis G virus was also inhibited by bLF with the same mechanism as HCV.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Cancer Association  

Hepatitis C virus (HCV) is associated with the development of cirrhosis and hepatocellular carcinoma. We recently found that bovine lactoferrin, a milk protein belonging to the iron transporter family, effectively prevented HCV infection in cultured human hepatocytes (PH5CH8). We tested the hypothesis that lactoferrin inhibits HCV viremia in patients with chronic hepatitis C. Eleven patients with chronic hepatitis C received an 8-week course of bovine lactoferrin (1.8 or 3.6 g/day). At the end of lactoferrin treatment, a decrease in serum alanine transaminase and HCV RNA concentrations was apparent in 3 (75%) of 4 patients with low pretreatment serum concentrations of HCV RNA. However, 7 patients with high pretreatment concentrations showed no significant changes in these indices. This pilot study suggests that lactoferrin is one potential candidate as an anti-HCV reagent that may be effective for the treatment of patients with chronic hepatitis.

DOI： 10.1111/j.1349-7006.1999.tb00756.x

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

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Language：English   Publisher：WILEY-BLACKWELL  

The proportion of patients who progress to chronicity following acute hepatitis B (AHB) varies widely worldwide. Moreover, the association between viral persistence after AHB and hepatitis B virus (HBV) genotypes in adults remains unclear. A nationwide multicenter study was conducted throughout Japan to evaluate the influence of clinical and virological factors on chronic outcomes in patients with AHB. For comparing factors between AHB patients with viral persistence and those with self-limited infection, 212 AHB patients without human immunodeficiency virus (HIV) coinfection were observed in 38 liver centers until serum hepatitis B surface antigen (HBsAg) disappeared or a minimum of 6 months in cases where HBsAg persisted. The time to disappearance of HBsAg was significantly longer for genotype A patients than that of patients infected with non-A genotypes. When chronicity was defined as the persistence of HBsAg positivity for more than 6 or 12 months, the rate of progression to chronicity was higher in patients with genotype A, although many cases caused by genotype A were prolonged cases of AHB, rather than chronic infection. Multivariate logistic regression analysis revealed only genotype A was independently associated with viral persistence following AHB. A higher peak level of HBV DNA and a lower peak of alanine aminotransferase (ALT) levels were characteristics of AHB caused by genotype A. Treatment with nucleotide analogs (NAs) did not prevent progression to chronic infection following AHB overall. Subanalysis suggested early NA initiation may enhance the viral clearance. Conclusion: Genotype A was an independent risk factor for progression to chronic infection following AHB. Our data will be useful in elucidating the association between viral persistence after AHB, host genetic factors, and treatment with NAs in future studies. (Hepatology 2014;58:89-97)

DOI： 10.1002/hep.26635

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Language：English   Publisher：CENTER ACADEMIC PUBL JAPAN  

Hepatitis C virus (HCV) non-structural protein 5B (NS5B) is an RNA replicase, We expressed full-length NS5B (591 amino acid residues) in Escherichia coli as a fusion protein with maltose binding protein (MBP-NS5B). MBP-NS5B was recovered in the soluble fraction after centrifugation at 40,000 x g and affinity-purified with amylose resin, The purified MBP-NS5B had a high-level of poly (A), oligo (U)-dependent UMP incorporation with a Km of 2 mu M for UTP. Surprisingly, the enzymatically active MBP-NS5B was sedimented by ultracentrifugation at 160,000 x g, The pellet contained 16S and 23S ribosomal RNAs, suggesting that ribosomes were associated with MBP-NS5B. Ribosomes and MBP-NS5B were subsequently co-purified on amylose resin, Deletion study revealed that either the N-terminal (amino acid residues 1-107) or the C-terminal (amino acid residues 498-591) region of NS5B were sufficient for this association with ribosomes, We further found that NS5B also bound with human ribosomes, Our results implicate a novel mechanism of coupling between replication and translation of the viral genome in the life cycle of HCV.

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