Risk factors for decreased bone mineral density in patients with metabolic dysfunction-associated steatotic liver disease: A cross-sectional study at a health examination center.

BACKGROUND & AIMS: Steatotic liver disease (SLD) is often detected in health examinations. However, although individuals with metabolic dysfunction-associated SLD (MASLD) may have decreased bone mineral density (BMD), the specific risk factors remain unclarified. The objective of this study was to identify the factors associated with decreased BMD in patients with MASLD. METHODS: Individuals who underwent abdominal ultrasonography and BMD measurements at our healthcare center were included. The BMD of the calcaneus was assessed using an AOS-10SA bone densitometer. Decreased BMD was defined as a T-score below -1.0 SD or the administration of osteoporosis treatment. SLD was diagnosed based on specific ultrasonographic criteria. RESULTS: A total of 1410 patients were diagnosed with MASLD. The median age was 52 years. Multivariate analysis using a logistic regression model revealed that the independent predictors of decreased BMD were a low body mass index (BMI) or a small waist circumference (odds ratio (OR): 0.48, 95% confidence interval (CI): 0.34-0.67), hypertriglyceridemia (OR: 1.29, 95% CI: 1.00-1.65), and a weak grip strength (OR: 0.98, 95% CI: 0.97-1.00). Subgroup analyses of individuals aged 50 years or older, men, and individuals with a FIB-4 index of 1.3 or greater revealed that the absence of a high BMI or a large waist circumference was associated with decreased BMD. The subgroup analysis of men revealed that a weaker grip strength was associated with decreased BMD. CONCLUSION: The present study suggested several potential risk factors for decreased BMD in patients with MASLD. Individuals with the abovementioned risk factors should be encouraged to undergo BMD measurement from the perspective of preventive medicine.

Outcomes of immune checkpoint inhibitor-induced liver toxicity managed by hepatologists in a multidisciplinary toxicity team.

AIM: To detect immune-related adverse events (irAEs) early and treat them appropriately, our institute established an irAE-focused multidisciplinary toxicity team in cooperation with various departments. This study aimed to evaluate a consultation system involving a team of hepatologists in terms of its utility for the management of severe immune checkpoint inhibitor (ICI)-induced liver toxicity. METHODS: To analyze the diagnosis and treatment of severe ICI-induced liver toxicity (Grade 2 requiring corticosteroid therapy and Grade 3 or higher), we examined patients' clinical courses before and after the hepatologist consultation system was established (pre-period, September 2014 to February 2019; post-period, March 2019 to March 2023). RESULTS: The median follow-up period was 392 days. Of the 1247 patients with advanced malignancies treated with ICIs, 66 developed severe ICI-induced liver toxicity (n = 22 and 44 in the pre- and post-periods, respectively). In the pre-period, hepatologist consultations were sought for 15/22 patients, whereas in the post-period, 42/44 patients were referred to and treated by hepatologists. The time from the onset of liver toxicity to the consultation was significantly shorter in the post-period than in the pre-period (mean 1.9 vs. 6.5 days, respectively; p = 0.012). The number of patients with a biopsy-confirmed diagnosis of ICI-induced liver toxicity was significantly higher in the post-period than in the pre-period (n = 22 vs. n = 3, respectively; p = 0.006). Finally, there were no cases of immune-related cholangitis in the pre-period, compared to five cases in the post-period. CONCLUSION: A hepatologist consultation system in an irAE-focused multidisciplinary toxicity team is useful for managing severe ICI-induced liver toxicity.

Pretreatment Proteinuria Predicts the Prognosis of Patients Receiving Systemic Therapy for Unresectable Hepatocellular Carcinoma.

BACKGROUND: Proteinuria is a common adverse event in systemic therapy for hepatocellular carcinoma (HCC). However, whether the presence of pretreatment proteinuria affects the clinical course is still unclear. METHOD: From 2011 to 2022, 321 patients with unresectable HCC who were treated with systemic therapy as first-line treatment were enrolled in this study. We retrospectively analyzed the presence of pretreatment proteinuria and the treatment course of systemic therapy. RESULTS: In the cohort, 190 patients were tested for proteinuria qualitatively within 3 months before systemic therapy; 75 were treated with sorafenib, 72 were treated with lenvatinib, and 43 were treated with atezolizumab plus bevacizumab. Overall survival tended to be longer for patients treated with lenvatinib and significantly longer with atezolizumab plus bevacizumab in patients without pretreatment proteinuria but not for those treated with sorafenib. Further analysis was performed in 111 patients treated with lenvatinib or atezolizumab plus bevacizumab who had proteinuria measured quantitatively. Multivariate analysis including proteinuria, liver function, and HCC stage revealed that the severity of proteinuria was an independent predictor of prognosis. CONCLUSION: Pretreatment proteinuria predicts a poorer prognosis in patients with unresectable HCC treated with lenvatinib or atezolizumab plus bevacizumab but not in those treated with sorafenib.

Abdominal pain accompanied by elevated serum inflammatory markers and biliary enzymes for diagnosing immune checkpoint inhibitor-induced sclerosing cholangitis.

Immune-related sclerosing cholangitis (irSC) is relatively rare and its clinical characteristics are not well known. In this study, we aimed to summarize the clinical features of irSC. Clinical data were collected retrospectively from 1,393 patients with advanced malignancy treated with immune-checkpoint inhibitors (ICIs) between August 2014 and October 2021. We analyzed patients with immune-related adverse events of liver injury (liver-irAEs) and compared irSC and non-irSC groups. Sixty-seven patients (4.8%) had a liver-irAE (≥ grade 3) during the follow-up period (median, 262 days). Among these, irSC was observed in eight patients (11.9%). All patients in the irSC group were treated with anti-PD-1/PD-L1 antibodies. Compared with the non-irSC group, the irSC group showed mainly non-hepatocellular liver injury (87.5 % vs 50.8 %, P = 0.065), and had elevated serum inflammatory markers (e.g., CRP and NLR) and biliary enzymes (e.g., GGTP and ALP) at the onset of liver-irAEs. Furthermore, most patients with irSC had abdominal pain. In the non-irSC group, the liver injury of 23 patients improved only with the discontinuation of ICIs, and 22 patients improved with medication including prednisolone (PSL). Conversely, almost all patients (n=7) in the irSC group were treated with PSL, but only two patients experienced an improvement in liver injury. We found that irSC is characterized by a non-hepatocellular type of liver injury with abdominal pain and a high inflammatory response and is refractory to treatment. Further examination by imaging is recommended to detect intractable irSC in cases with these characteristics.

Serum osteopontin predicts the response to atezolizumab plus bevacizumab in patients with hepatocellular carcinoma.

BACKGROUND: Combination therapy with anti-programmed death-ligand 1 and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for un-resectable hepatocellular carcinoma (uHCC). We aimed to identify predictive circulating biomarkers for the outcome/response of the combination therapy in uHCC patients. METHODS: This prospective multicenter study enrolled 70 patients with uHCC who received atezolizumab and bevacizumab (Atez/Bev). We evaluated 47 circulating proteins in sera before and after 1 and 6 weeks of Atez/Bev therapy by multiplex bead-based immunoassay and ELISA. As controls, we analyzed the sera from 62 uHCC patients before treatment of lenvatinib (LEN) and healthy volunteers (HVs). RESULTS: The disease control rate was 77.1%. Median progression-free survival (PFS) was 5.7 months (95% confidence interval [CI] = 3.8-9.5). The pretreatment levels of osteopontin (OPN), angiopoietin-2, VEGF, S100-calcium-binding protein A8/S100-calcium-binding protein A9, soluble programmed cell death-1, soluble CD163, and 14 cytokines/chemokines were higher in patients with uHCC than in HVs. Among these, pretreatment OPN levels were higher in PD group than in non-PD group for Atez/Bev. The PD rate was higher in high OPN group than in low OPN group. Multivariate analysis identified high pretreatment OPN and high α-fetoprotein levels as independent predictors of PD. In the sub-analysis of Child-Pugh class A patients, PFS was also shorter in the high OPN group than in the low OPN group. Pretreatment OPN level was not associated with treatment response for LEN. CONCLUSION: High serum OPN levels were associated with poor response to Atez/Bev in patients with uHCC.

Clustering using unsupervised machine learning to stratify the risk of immune-related liver injury.

BACKGROUND AND AIM: Immune-related liver injury (liver-irAE) is a clinical problem with a potentially poor prognosis. METHODS: We retrospectively collected clinical data from patients treated with immune checkpoint inhibitors between September 2014 and December 2021 at the Nagoya University Hospital. Using an unsupervised machine learning method, the Gaussian mixture model, to divide the cohort into clusters based on inflammatory markers, we investigated the cumulative incidence of liver-irAEs in these clusters. RESULTS: This study included a total of 702 patients. Among them, 492 (70.1%) patients were male, and the mean age was 66.6 years. During the mean follow-up period of 423 days, severe liver-irAEs (Common Terminology Criteria for Adverse Events grade ≥ 3) occurred in 43 patients. Patients were divided into five clusters (a, b, c, d, and e). The cumulative incidence of liver-irAE was higher in cluster c than in cluster a (hazard ratio [HR]: 13.59, 95% confidence interval [CI]: 1.70-108.76, P = 0.014), and overall survival was worse in clusters c and d than in cluster a (HR: 2.83, 95% CI: 1.77-4.50, P < 0.001; HR: 2.87, 95% CI: 1.47-5.60, P = 0.002, respectively). Clusters c and d were characterized by high temperature, C-reactive protein, platelets, and low albumin. However, there were differences in the prevalence of neutrophil count, neutrophil-to-lymphocyte ratio, and liver metastases between both clusters. CONCLUSIONS: The combined assessment of multiple markers and body temperature may help stratify high-risk groups for developing liver-irAE.

Immune-related Liver Injury is a Poor Prognostic Factor in Patients with Nonsmall Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

It remains unclear whether severe liver immune-related adverse events (liver-irAEs) can affect the prognosis in nonsmall cell lung carcinoma (NSCLC) patients. Of the 365 NSCLC patients treated with immune checkpoint inhibitors (ICIs), 19 suffered from severe liver-irAEs (grade ≥3). The median time-to-onset of liver-irAEs was 53 days postinjection of the first ICI. The progression-free survival and overall survival of the liver-irAEs group (median 69 and 262 days, respectively) were significantly worse than the nonliver-irAEs group (128 and 722 days; P = 0.010 and P = 0.007; respectively). In conclusion, liver-irAEs were associated with poor prognosis in NSCLC patients.

Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies.

BACKGROUND: The clinical course of liver injury induced by immune checkpoint inhibitors (ICIs) varies among individuals, and there were few reports on the therapeutic effects of corticosteroids based on the patterns of liver injury. METHODS: We evaluated the characteristics and clinical course of immune-related liver injury in 1214 patients treated with ICIs for advanced malignancies except for hepatocellular carcinoma between August 2014 and May 2021. RESULTS: During the follow-up period (median, 252 days), 58 patients (4.8%) had an immune-related liver injury (≥ Grade 3). The liver-injury patterns were hepatocellular (n = 26, 44.8%), mixed (n = 11, 19.0%), or cholestatic (n = 21, 36.2%), and the median time to onset of liver injury was 39, 81, and 53 days, respectively; the hepatocellular pattern occurred earlier than the other types (p = 0.047). Corticosteroids were administered to 30 (51.7%) patients; while liver injury was improved in almost all patients with the hepatocellular pattern (n = 13/14, 92.9%), that failed to show improvement in over half of the patients with the non-hepatocellular patterns, and three patients with mixed patterns needed secondary immunosuppression with mycophenolate mofetil. Liver biopsies performed in 13 patients mainly showed lobular injury, endothelialitis, and spotty necrosis with infiltration of T cells positive for CD3 and CD8, but not CD4 or CD20. CONCLUSION: The incidence pattern and therapeutic response to corticosteroids in immune-related liver injury differ according to the injury type. Although corticosteroids were effective for the hepatocellular pattern, an additional strategy for refractory non-hepatocellular patterns is needed.

Bioinformatics and Functional Analyses Implicate Potential Roles for EOGT and L-fringe in Pancreatic Cancers.

Notch signaling receptors, ligands, and their downstream target genes are dysregulated in pancreatic ductal adenocarcinoma (PDAC), suggesting a role of Notch signaling in pancreatic tumor development and progression. However, dysregulation of Notch signaling by post-translational modification of Notch receptors remains poorly understood. Here, we analyzed the Notch-modifying glycosyltransferase involved in the regulation of the ligand-dependent Notch signaling pathway. Bioinformatic analysis revealed that the expression of epidermal growth factor (EGF) domain-specific O-linked N-acetylglucosamine (EOGT) and Lunatic fringe (LFNG) positively correlates with a subset of Notch signaling genes in PDAC. The lack of EOGT or LFNG expression inhibited the proliferation and migration of Panc-1 cells, as observed by the inhibition of Notch activation. EOGT expression is significantly increased in the basal subtype, and low expression of both EOGT and LFNG predicts better overall survival in PDAC patients. These results imply potential roles for EOGT- and LFNG-dependent Notch signaling in PDAC.

Real world data of liver injury induced by immune checkpoint inhibitors in Japanese patients with advanced malignancies.

BACKGROUND: Liver injury induced by immune checkpoint inhibitors (ICIs) is an immune-related adverse event (irAE) whose incidence has increased with the broader use of ICIs in clinical practice. However, the incidental risk factors of immune-related liver injury are unknown. We investigated the clinical characteristics of immune-related liver injury. METHODS: A total of 546 patients treated with ICIs for advanced malignancies between September 2014 and February 2019 were included retrospectively. Factors associated with immune-related liver injury were determined. RESULTS: Immune-related liver injury (≥ Grade 3) occurred in 29 (5.3%) patients (Grade 3, n = 20; Grade 4, n = 8; Grade 5, n = 1) during the follow-up period (median 153 days). The patterns of liver injuries were hepatocellular, n = 6 (20.7%); cholestatic, n = 17 (58.6%); and mixed, n = 6 (20.7%). The median period between the initial administration of ICIs and the incidence of irAEs was 52 days. Of 29 patients with immune-related liver injury (≥ Grade 3), four showed immune-related cholangitis with non-obstructive dilation of the bile ducts. Factors that were significantly associated with the incidence of immune-related liver injury in multivariate analysis were use of ipilimumab, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agent [hazard ratio [HR] 4.22, 95% confidence interval (CI) 1.65-10.80, P = 0.003], and fever over 38 °C within 24 h of initial ICI administration (HR 6.21, 95% CI 2.68-14.40, P < 0.001). CONCLUSIONS: We found that the use of ipilimumab and the presence of fever within 24 h of initial ICI administration were predictive factors for immune-related liver injury.

Dynamic Evaluation of Liver Fibrosis to Assess the Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis C Who Achieved Sustained Virologic Response.

BACKGROUND: Liver fibrosis is an important risk factor for the development of hepatocellular carcinoma (HCC) after sustained virologic response (SVR) in patients with persistent hepatitis C virus (HCV) infection. However, as the degree of liver fibrosis changes following the eradication of HCV after SVR, it is unclear whether the prediction of HCC development based on liver fibrosis at baseline remains valid. METHODS: In 522 patients who achieved SVR by interferon-based anti-HCV therapy, the Fibrosis-4 Index for Liver Fibrosis (FIB-4 index) was updated annually by recalculation based on laboratory values after SVR. The incidence of HCC was reassessed annually based on the updated FIB-4 index. RESULTS: The percentage of patients with mild liver fibrosis (FIB-4 index <1.45) increased annually after SVR, whereas the percentage of patients with advanced liver fibrosis (FIB-4 index ≥3.25) decreased. The incidences of HCC based on the FIB-4 index remained constant between the time of SVR and subsequent annual updates. No patients developed HCC after SVR if the FIB-4 index decreased to <1.45. CONCLUSIONS: The FIB-4 index retained its predictive ability for the risk of HCC when recalculated after SVR, despite the decrease in patients with high FIB-4 index values. Dynamic assessment of the FIB-4 index can be useful in the surveillance of HCC after SVR. Patients with a FIB-4 index <1.45 did not develop HCC even by the regression from advanced fibrosis after SVR. Further studies will be necessary to confirm these findings, which may result in a decrease in the number of patients in whom surveillance is required.

Circulating Exosomal miRNA Profiles Predict the Occurrence and Recurrence of Hepatocellular Carcinoma in Patients with Direct-Acting Antiviral-Induced Sustained Viral Response.

Direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection patients (CH) results in a sustained viral response (SVR) in over 95% of patients. However, hepatocellular carcinoma (HCC) occurs in 1-5% of patients who achieved an SVR after treatment with interferon. We attempted to develop a minimally invasive and highly reliable method of predicting the occurrence and recurrence of HCC in patients who achieved an SVR with DAA therapy. The exosomal miRNA expression patterns of 69 CH patients who underwent HCC curative treatment and 70 CH patients were assessed using microarray analysis. We identified a miRNA expression pattern characteristic of SVR-HCC by using machine learning. Twenty-five of 69 patients had HCC recurrence. The expression of four exosomal miRNAs predicted HCC recurrence with 85.3% accuracy. Fifteen of 70 patients had HCC occurrence. The expression of four exosomal miRNAs predicted the onset of HCC with 85.5% accuracy. The expression patterns of miR-4718, 642a-5p, 6826-3p, and 762 in exosomes were positively correlated with those in the liver, and downregulation of these miRNAs induced cell proliferation and prevented apoptosis in vitro. Aberrant expression of four miRNAs, which was used for prediction, was associated with HCC onset after HCV eradication. Expression patterns of exosomal miRNAs are a promising tool to predict SVR-HCC.

The emergence of non-hypervascular hypointense nodules on Gd-EOB-DTPA-enhanced MRI in patients with chronic hepatitis C.

BACKGROUND: Intrahepatic non-hypervascular hypointense nodules (NHHNs) detected during the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have the potential to transition into typical hypervascular hepatocellular carcinoma (HCC). However, the incidence and risk factors for the emergence of these nodules in patients with chronic hepatitis C virus (HCV) infection are unknown. AIM: To investigate the incidence and risk factors for NHHNs in patients with chronic HCV infection in a longitudinal follow-up study METHODS: EOB-MRI was performed in 608 patients with chronic HCV infection and no history of HCC. The characteristics of patients with and without NHHNs were compared. In patients without NHHNs at baseline, the incidence of NHHN emergence and associated risk factors were analysed. RESULTS: NHHNs were detected at baseline in 93 of 608 patients (15.3%). Among 515 patients without NHHNs at baseline, the 1-year, 3-year and 5-year incidence of NHHN emergence was 1.8%, 9.8% and 16.4%, respectively. Only FIB-4 index was independently associated with the emergence of NHHNs in multivariate analyses. Whereas NHHNs emerged in 24.1% of patients with FIB-4 index ≥ 3.25 at 5 years, none emerged in patients with FIB-4 index < 1.45. CONCLUSION: In patients with chronic HCV infection, advanced liver fibrosis is an important risk factor for the presence or emergence of NHHNs.

The course of elderly patients with persistent hepatitis C virus infection without hepatocellular carcinoma.

BACKGROUND: Little is known about the course of elderly patients with persistent hepatitis C virus (HCV) infection. We investigated the course of HCV infection in this patient population. METHODS: Among 9,126 HCV antibody-positive patients who visited our hospital between 1995 and 2015, there were 453 patients with continuous follow-up who survived to age 80. They were included in the study following the inclusion criteria: confirmed persistent detection of HCV RNA, no HCV eradication if anti-HCV therapy occurred before enrollment, and no development of hepatocellular carcinoma (HCC) before enrollment. For all study patients, baseline was defined as the date when they turned 80. Mortality rates after the age of 80 years and cause of death were analyzed. RESULTS: During the study period, 155 patients (34.2%) died. Median survival time (MST) after age 80 was 8.8 years, which was comparable to that of the general population (10.1 years). Among 155 deceased patients, the majority (115 patients, 74.2%) died due to non-liver-related disease, followed by HCC (28 patients, 18.1%) and liver-related disease other than HCC (12 patients, 7.7%). Patients with advanced liver fibrosis (FIB-4 index > 3.25, n = 245) had shorter MST than patients with mild liver fibrosis (FIB-4 index ≤ 3.25, n = 208) (7.1 vs. 10.2 years; p = 0.020) due to a higher mortality rate from liver-related complications, including HCC. CONCLUSION: Most elderly HCV patients die from non-liver-related disease, especially those with less advanced liver fibrosis.

Influence of renal dysfunction on dose reduction and virologic efficacy of regimens combining ribavirin and all-oral direct acting antivirals in patients with chronic hepatitis C virus infection.

AIM: Several interferon (IFN)-free, all-oral regimens with direct acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection also include ribavirin (RBV). We investigated the influence of renal dysfunction on virologic efficacy and adverse effects in 189 patients with HCV genotype 2 infection who received combination RBV-DAA regimens. METHODS: The incidence of RBV-induced anemia, RBV dose reduction, and virologic efficacy were compared according to baseline renal function as defined by the estimated glomerular filtration rate (eGFR). RESULTS: Patients with renal dysfunction (eGFR = 30-59 mL/min/1.73 m2 ) had higher rate of RBV dose reduction and more marked decreases in hemoglobin levels. These findings were more pronounced in patients with the ITPA CC genotype, who are more sensitive to RBV-induced anemia. Although there were no statistically significant differences in sustained virologic response (SVR) rates according to renal function overall (P = 0.1650), the SVR rate was significantly lower in patients who required RBV dose reduction than in those who did not (P < 0.0001). CONCLUSIONS: Baseline renal dysfunction could unfavorably affect the outcomes of RBV-DAA in patients with chronic HCV infection due to the increased risk of RBV dose reduction, even in the era of IFN-free DAA regimens.

The impact of HCV eradication by direct-acting antivirals on the transition of precancerous hepatic nodules to HCC: A prospective observational study.

BACKGROUND & AIMS: It remains controversial whether the eradication of hepatitis C virus (HCV) by interferon (IFN)-free anti-HCV therapy using direct-acting antivirals (DAAs) suppresses or promotes hepatocellular carcinoma (HCC) development. We investigated the influence of HCV eradication by DAA therapy on HCC development, by observing changes of non-hypervascular hypointense nodules (NHHNs) by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI). METHODS: A total of 401 patients treated with DAA therapy who did not have a history of HCC were enrolled in this prospective cohort study. All patients underwent EOB-MRI prior to the start of DAA therapy and were followed up periodically after therapy. The progression of NHHNs detected at baseline to typical HCC, as indicated by hypervascularization and the incidence of newly emergent NHHNs, was analyzed. RESULTS: In comparison of patients who achieved sustained virologic response (SVR) with propensity score-matched patients with persistent HCV infection, there was no difference in the incidence of hypervascularization of NHHNs to typical HCC among patients who had NHHNs at baseline. Among patients who did not have NHHNs at baseline, the incidence of the new emergence of NHHNs did not differ between study patients and propensity score-matched patients with persistent HCV infection. CONCLUSIONS: During a 2-year observation period after SVR, the eradication of HCV by IFN-free DAA therapy did not suppress or enhance HCC development. (UMIN000017020).

Impact of previously cured hepatocellular carcinoma (HCC) on new development of HCC after eradication of hepatitis C infection with non-interferon-based treatments.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) in patients with a history of curatively-treated HCC is higher than in patients with no history of HCC even after sustained virologic response (SVR). AIM: To investigate differences in the patterns of HCC development after SVR in patients with a history of curatively-treated HCC and those with no history of HCC, based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) findings. METHODS: EOB-MRI was performed in 164 patients with HCV cirrhosis who achieved SVR by interferon-free direct-acting antiviral (DAA) therapy just before the start of therapy. Changes in EOB-MRI findings after SVR were compared prospectively between patients with (n = 62) and without (n = 102) a history of HCC. RESULTS: The incidence of HCC after SVR was higher in patients with a history of HCC (P < 0.0001). The prevalence of nonhypervascular hypointense nodules (NHHNs) by EOB-MRI was significantly higher in patients with a history of HCC at baseline (P = 0.05). Although there was no difference in the incidence of the hypervascularisation of baseline NHHNs to typical hypervascular HCC between patients with and without a history of HCC, the incidence of direct emergence of hypervascular HCC despite the absence of NHHNs at baseline was significantly higher in patients with a history of HCC (P < 0.0001). CONCLUSION: Direct emergence of hypervascular HCC and a higher prevalence of NHHNs before DD therapy contributed to the higher incidence of HCC after SVR. (UMIN000017020).

Impact of hepatocellular carcinoma aetiology and liver function on the benefit of surveillance: A novel approach for the adjustment of lead-time bias.

BACKGROUND & AIMS: Surveillance reportedly has benefit on survival in patients with hepatocellular carcinoma (HCC), even after adjustment for lead-time bias. However, previous adjustment for lead-time bias using tumour volume doubling time (TVDT) had inherent problem in accuracy. We evaluated survival benefit of HCC surveillance with newly developed approach for adjusting lead-time bias. In addition, survival benefit was evaluated according to HCC aetiology and liver function. METHODS: A total of 3899 patients were studied. TVDT was calculated in 255 study patients with ≥2 tumour size measurements before the diagnosis of HCC. Adjusted survival time was calculated based on TVDT, as the time from when HCC was assumed to be 5 mm to death or last follow-up. Survival rates based on this adjusted survival time were compared between the surveillance and nonsurveillance groups and categorized by HCC aetiology and liver function. RESULTS: Calculated TVDT varied widely by study patients (median 141.9, IQR, 73.1-261.7 days). Survival rates based on adjusted survival time were higher in the surveillance group overall and by patients HCC aetiology. Whereas adjusted survival rates were higher in the surveillance group in Child-Pugh class A patients, the survival benefit was smaller in Child-Pugh class B patients and not statistically significant in Child-Pugh class C patients. CONCLUSIONS: The survival benefit of surveillance for patients with HCC was demonstrated after adjustment for lead-time bias with novel, more accurate methodology. However, the benefits differed based on liver function and may vary largely by patients because of wide variation in TVDT.

Significance of day-1 viral response of hepatitis C virus in patients with chronic hepatitis C receiving direct-acting antiviral therapy.

BACKGROUND AND AIM: On-treatment response of serum hepatitis C virus (HCV) is reportedly less useful to predict the outcome of anti-HCV therapy with interferon (IFN)-free regimen with direct-acting antivirals than with IFN-based regimens in clinical trials. We evaluated the significance of very early viral response after the start of therapy, which indicates direct HCV response to the drugs, on therapeutic outcome. METHODS: Reductions in serum HCV-RNA levels were measured at 1 day after the start of therapy in 544 patients who underwent IFN-free direct-acting antiviral regimens. The association between these reductions and the achievement or failure of sustained virologic response (SVR) was evaluated. RESULTS: Patient characteristics did not influence 1-day reduction in serum HCV-RNA except for liver fibrosis. There was no difference in 1-day HCV reduction between SVR and non-SVR patients treated with a 24-week regimen. In contrast, in patients treated with a 12-week regimen, 1-day reduction was significantly greater in SVR than in non-SVR patients (P = 0.0013) and was predictive of SVR versus non-SVR (area under the receiver-operating characteristics curve: 0.80). CONCLUSIONS: Whereas the reduction in serum HCV-RNA levels at 1 day after the start of therapy was not associated with treatment outcomes in patients who underwent a 24-week regimen of IFN-free therapy, there was an association in patients receiving a 12-week regimen, and this reduction was predictive of SVR, thus potentially serving as a factor to identify patients at risk of treatment failure.