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Introduction:Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial. Methods:Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum (n= 68) were screened and classified according to their PD, 6 weeks after treatment initiation (early PD; n= 13). Of these, 4 patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort (n= 60) and evaluated in patients treated with lenvatinib. Results:No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (<333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs. 227 days; HR: 2.41, 95% CI: 1.22–4.80, p= 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without. Conclusion:Baseline low serum CXCL9 (<333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.

Background: The absence of high quality, large-scale data that indicates definitive mortality benefits does not allow for firm conclusions on the role of intravenous vasodilators in acute heart failure. We aimed to investigate the associations between intravenous vasodilators and clinical outcomes in acute heart failure patients, with a specific focus on patient profiles and type of vasodilators.Methods: Data of 26,212 consecutive patients urgently hospitalised for a primary diagnosis of acute heart failure between 2009 and 2015 were extracted from a government-funded multicentre data registration system. Propensity scores were calculated with multiple imputations and 1:1 matching performed between patients with and without vasodilator use. The primary endpoint was inhospital mortality.Results: On direct comparison of the vasodilator and non-vasodilator groups after propensity score matching, there were no significant differences in the inhospital mortality rates (7.5% vs. 8.8%, respectively; P=0.098) or length of intensive/cardiovascular care unit stay and hospital stay between the two groups. However, there was a substantial difference in baseline systolic blood pressure by vasodilator type; favourable impacts of vasodilator use on inhospital mortality were observed among patients who had higher systolic blood pressures and those who had no atrial fibrillation on admission. Furthermore, when compared to nitrates, the use of carperitide (natriuretic peptide agent) was significantly associated with worse outcomes, especially in patients with intermediate systolic blood pressures.Conclusions: In acute heart failure patients, vasodilator use was not universally associated with improved inhospital outcomes; rather, its effect depended on individual clinical presentation: patients with higher systolic blood pressure and no atrial fibrillation seemed to benefit maximally from vasodilators.Trial registration: UMIN-CTR identifier, UMIN000013128

Background We aimed to investigate the effects of ribavirin on hepatitis C virus (HCV). Immunological and virological effects were analysed in patients undergoing treatment with ribavirin monotherapy prior to the initiation of combination therapy with interferon-a.Methods A total of 25 patients with chronic HCV infection were enrolled in this study. All patients received ribavirin for 4 weeks during monotherapy; subsequently, interferon-a2b was additionally given as combined therapy. Patients were divided into two groups according to virological response. A rapid viral responder (RVR) was defined as a patient in whom HCV RNA became undetectable within 4 weeks after combination therapy. The changes of the T-helper (Th)1/Th2 subset of peripheral blood CD4+T-cells, serum cytokine levels and the alignment of the interferon sensitivity- determining region (ISDR) during ribavirin monotherapy were analysed by flow cytometry, ELISAs and sequencing methods.Results A total of 17 patients were classed as RVR. In the RVR group, the mean ±sd serum alanine aminotransferase levels significantly decreased (before treatment 103 ±92 IU/l and after treatment 57 ±46 IU/l; P<0.05) during ribavirin monotherapy. The mean ±sd Th1/Th2 ratio significantly increased (before treatment 13.9 ±5.1 and after treatment 16.7 ±6.2; P<0.05), but did not change in the non-RVR group. The levels of Th2 cytokines (interleukin-10 and soluble CD30) significantly decreased, especially in the RVR group. The mean ±sd mutation rates of ISDR at the nucleotide level increased in the RVR group (before treatment 2.6 ±0.9 sites/clone and after treatment 3.9 ±1.6 sites/clone; P<0.05), but did not change in the non-RVR group.Conclusions Ribavirin administration might increase the efficacy of interferon therapy for patients with chronic hepatitis C by stimulating the host immune system and promoting HCV gene mutation.

We examined the frequency and significance ofmutations in the core promoter and precore region in 103Japanese patients with chronic hepatitis B virus (HBV)infection. HBV DNAs from the patients' sera were amplified by polymerase chain reaction andwere directly sequenced. A double mutation(T1762A1764) in the core promoterwas frequently observed in the patients regardless ofHBeAg status except for asymptomatic carriers with HBeAg. Furthermore,a mutation at nucleotide 1753 from T to C or G wasfrequently found in anti-HBe positive patients and wasoften accompanied by the double mutation. TheA1896mutation was found in only about onefourth of the patients with anti-HBe. These data suggestthat the patients with chronic liver diseases frequentlyhad a double mutation regardless of HBeAg status and a mutation at nucleotide 1753 might beassociated with HBeAg-negative chronic hepatitis B virusinfection.

Background:Seasonal change of the incidents of the acute decompensation of heart failure (ADHF) has been reported, but few study has investigated the effect of meteorological factor on the incidents and manner of ADHF based on individual background.Method and result:Multicenter data registry (Tokyo CCU Network Database including 72 institutions in Tokyo metropolitan area in Japan) consisting of 8869 cases with ADHF from January 2015 to December 2016 was used to analyze relationship between the number of ADHF incidents per day and meteorological factors on the current day, previous three days and seven days (lag 3-day and lag 7-day) (Table 1). Mean number of incidence during the studied period was 12.8 +-4.9 per day. There was a negative correlation between temperature and the number of ADHF events, while diurnal temperature range (DTR) and atmospheric pressure showed positive correlation (p<0.001 for each) (Table 1). After multivariate analysis, average minimum temperature, DTR, atmospheric pressure on lag 7-day and holiday still remained as independent predictors of ADHF (Table1). We performed exploratory analysis to identify the subgroups which were strongly affected by meteorological factor. Significant interaction effects were observed in age, clinical scenario (CS) and ejection fraction (EF) with lag 7-day lowest temperature (p for interaction<0.001 for each) (Figure 1).Conclusion:Lag effect of the lowest temperature, DTR and atmospheric pressure were strong predictors of ADHF, and these effects were more apparent in groups of elderly, CS1 and EF over 50%. Prediction of ADHF in view of meteorological factor will be useful for effective prevention in high risk cases.