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Purpose Previous reports suggest that contrast-enhanced ultrasonography (CEUS) is useful for predicting the efficacy of sorafenib and lenvatinib treatment. However, there are no reports on the utility of CEUS for predicting the efficacy of atezolizumab plus bevacizumab combination therapy (Atezo + Bev). This study aimed to identify CEUS parameters for predicting the efficacy of Atezo + Bev. Methods A total of 30 patients with hepatocellular carcinoma (HCC) treated with Atezo + Bev who underwent CEUS before and 5 weeks after treatment initiation were included. Results Post area under the curve (post AUC) was identified as a predictive factor for early progressive disease (PD). The optimal cut-off value of post AUC for predicting progression-free survival (PFS) was 61.3. Conclusion The results of this study suggest that CEUS at 5 weeks after initiation of Atezo + Bev may predict PFS in HCC patients. Changes to the treatment plan may need to be considered in patients with post AUC > 61.3.

BackgroundThis study investigated time-course changes in skeletal muscle volume per year with tolvaptan in patients with refractory ascites that was unresponsive to loop diuretics and aldosterone antagonists.MethodsThis retrospective study included 42 patients who received tolvaptan for refractory ascites and/or hepatic edema and underwent computed tomography (CT) before and ≥ 3 months after initiating tolvaptan. The time-course changes in skeletal muscle index per year [ΔSMI (%)] was calculated as follows: ΔSMI (%) = (SMI at final CT scan − SMI at initial CT scan)/SMI at initial CT scan × 100/years between CT scans.ResultsEligible patients were 23 men and 19 women of median age of 71 years (range 21–94 years). The median follow-up period was 22.7 (range 3.5–54.6) months. ΔSMI (%) was significantly higher in the responders group than in the nonresponder group. Multivariate analysis showed the response to tolvaptan was an independent and significant factor associated with an increase in muscle mass [odds ratio (OR) 20.364; 95% CI 2.327–178.97; P = 0.006]. Overall survival with tolvaptan was significantly higher in the responder group than in the nonresponder group. Multivariate analysis showed that the response to tolvaptan treatment was a significant contributor to good prognosis (OR 3.884; 95% CI 1.264–11.931; P = 0.018). A significant negative correlation was observed between the dosage of furosemide and ΔSMI (%) (P = 0.014).ConclusionsTreatment of refractory ascites with tolvaptan may attenuate the progression of sarcopenia and improve the prognosis in patients with decompensated cirrhosis.

Purpose Transient elastography (TE) and the controlled attenuation parameter (CAP) have been used for diagnosis of liver fibrosis and steatosis. Obesity is a limiting factor to the accuracy of elastography; however, an XL probe was validated for use in obese patients. Two-dimensional shear wave elastography (2D-SWE) and attenuation imaging (ATI) have also been developed. It is unknown if obesity affects 2D-SWE/ATI values for evaluation of liver fibrosis and steatosis. We assessed the reliability of the measurement rate and the diagnostic performance of TE/CAP versus SWE/ATI. Methods The patients ( n  = 85) underwent TE/CAP, 2D-SWE/ATI, and liver biopsy on the same day. They were diagnosed with chronic hepatitis based on liver biopsy. The patients were divided into three groups by skin–liver capsule distance (SCD). Results The reliability of the measurement rate for the M probe was lower than that for the XL probe in the group with SCD over 22.5 mm. The rate achieved with 2D-SWE was high in all groups regardless of the SCD. In the assessment of the diagnostic performance, there was no difference between the area under the receiver-operating curve (AUROC) of TE compared to 2D-SWE to stratify the fibrosis stage. There was no difference in the AUROC for the stratification of the steatosis grades between CAP and ATI. The diagnostic accuracy of TE for F ≥ 3 fibrosis evaluated with the M probe and 2D-SWE was lower than that of TE evaluated with the XL probe in the group with SCD over 22.5 mm. Conclusion The ability of 2D-SWE to stratify fibrosis stage and steatosis grade was as good as FibroScan. However, 2D-SWE had a high reliability in the measurement rate regardless of the SCD with one probe. And the XL probe showed high diagnostic accuracy for severe fibrosis in the group with SCD over 22.5 mm.

Background and aimsThe clinical course and responsiveness to antiviral treatments differs among hepatitis B virus (HBV) genotypes. However, the cause of these differences is unclear. In the present study, we compared mRNA expression profiles in human hepatocyte chimeric mice infected with HBV genotypes A and C.MethodsFifteen chimeric mice were prepared and divided into the following three groups: uninfected control mice, HBV genotype A-infected mice, and HBV genotype C-infected mice. Human hepatocytes were collected from these mouse livers and gene expression analyses were performed using next-generation RNA sequencing.ResultsAlthough similar pathways were influenced by HBV infection, including inflammation mediated by chemokine and cytokine signaling, p53, and integrin signaling pathways, expression levels of up-regulated genes by HBV genotype A or C infection were quite different. In HBV genotype A-infected hepatocytes, 172 genes, including KRT23 and C10orf54, were significantly more highly expressed than in HBV genotype C-infected cells, whereas 10 genes, including SPX and IER3, were expressed at significantly lower levels. Genes associated with the p53 pathway and the inflammation mediated by chemokine and cytokine signaling pathway were more highly expressed in cells with HBV genotype A infection, whereas genes associated with CCKR signaling map and oxidative stress response were more highly expressed in cells with HBV genotype C infection.ConclusionSeveral differences in gene expression with respect to HBV genotype A and C infection were detected in human hepatocytes. These differences might be associated with genotypic difference in the clinical course or responsiveness to treatment.

Background: Although lenvatinib was recently approved for treatment of advanced unresectable hepatocellular carcinoma (HCC) based on the phase III REFLECT trial, no biomarkers for management of lenvatinib treatment have been established. The aim of this study is to identify predictive biomarkers for the management of lenvatinib treatment in advanced HCC patients. Methods: A total of 41 patients with advanced HCC were enrolled in this retrospective study. Serum levels of 22 circulating cytokines and angiogenic factors (CAFs) were measured by multiplex Luminex assay. Profiles of CAFs, clinical chemistry/hematology parameters, and clinical background were evaluated to explore biomarkers associated with clinical outcomes. Results: Relative dose intensity (RDI) decreased significantly between weeks 1–2 and 3–4 (p < 0.001), and RDI during weeks 3–4 was a prominent indicator of progression-free survival (PFS). A signature based on baseline serum levels of nine CAFs associated with low RDI was identified. In a multivariate Cox regression analysis, patients with a favorable 9-CAFs signature [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.18–0.96, p = 0.040] had lower risk, and Child-Pugh grade B (HR 1.6, 95% CI 1.1–8.3, p = 0.026) and presence of macrovascular invasion (MVI; HR 2.9, 95% CI 1.0–8.3, p = 0.045) had higher risk of shorter PFS. Conclusion: This study demonstrates that RDI is an important predictive factor for longer PFS during lenvatinib treatment. In this hypothesis-generating exploratory analysis, we report that a CAF-signature associated with adverse events and RDI could predict PFS, which might contribute to improved management of lenvatinib treatment in HCC patients.

Background While immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (irAEs) in various organs, the prevalence of irAEs and potential risk factors have not been clarified. We identified irAE predictive factors and examined the relationship between the effect of ICIs and irAEs for patients with malignancies. Methods A total of 533 cases treated with ICIs, including programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), for various malignancies were included retrospectively. We recorded irAEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 5. Prevalence and predictive factors associated with immune-related liver injury and the relationship between irAE and treatment response were analyzed. Results During a median of 10 (1–103) cycles with a median follow-up after several ICI initiations of 384 (21–1715) days, irAEs with all grades and with grade ≥ 3 developed in 144 (27.0%) and 57 (10.7%) cases. Cumulative irAE development rates were 21.9, 33.5, and 43.0% in all grades and 8.8, 14.9, and 20.7% in grade ≥ 3 at 5, 10, and 20 cycles, respectively. Patients who received anti-CTLA4 therapy were more likely to develop irAEs compared to those who received anti-PD-1 or anti-PD-L1 monotherapy. Liver injury was the most common irAE. Multivariate analysis identified the combination of PD-1 and anti-CTL-4 antibodies (hazard ratio [HR], 17.04; P  < 0.0001) and baseline eosinophil count ≥130/μL (HR, 3.01 for < 130; P  = 0.012) as independent risk factors for the incidence of immune-related liver injury with grade ≥ 2. Patients who developed irAEs had a higher disease control rate ( P  < 0.0001) and an increased overall survival rate compared to those without irAEs ( P  < 0.0001). Conclusion Combination therapy with anti-PD-1 and anti-CTL-4 antibodies resulted in higher a frequency of irAEs. Baseline absolute eosinophil count was found to be a predictive factor for immune-related liver injury. Occurrence of irAEs may be associated with higher efficacy of ICI treatment and longer survival among patients who receive ICI therapy.

Background There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). Method We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. Results In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAF mean ) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAF mean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. Conclusion Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice.

Background We previously reported on the trends in the etiologies of hepatocellular carcinoma (HCC) diagnosed in patients between 1995 and 2009. The aims of our updated study were to evaluate the incidence, nonhepatitis B and nonhepatitis C viral (NBNC) etiologies, and clinical characteristics of HCCs occurring in patients between 1992 and 2018. Methods The study enrolled 2171 consecutive patients with HCC between 1992 and 2018. Their medical records were reviewed. The patients were divided into two groups, patients with early diagnoses from 1992 to 2009 and those with late diagnoses from 2010 to 2018. Results NBNC-HCC occurred in 514 patients (23.6%). The percentage of patients with HCC who had NBNC-HCC increased from 26.5% in 2009 to 46.3% in 2018. Patients with NBNC-HCC were older (median ages from 67 to 73 years). Type 2 diabetes mellitus (48.5–60.3%: P  = 0.008), hypertension (48.5–57.4%: P  = 0.047), and hyperlipidemia (39.2–53.8%: P  = 0.001) increased significantly in recent years. The median FIB-4 index decreased (4.37–3.61: P  = 0.026) and the median platelet count increased (15.1–17.9 × 10 4 /μL: P  = 0.013). Among the 514 patients with NBNC-HCC, 194 underwent hepatic resection for nonalcoholic steatohepatitis (NASH) (15%), alcoholic liver disease (ALD) (29%), and cryptogenic hepatitis (56%). Cirrhosis was detected in 72%, 39%, and 16% of patients with NASH, ALD, and cryptogenic hepatitis, respectively. The prevalence of cirrhosis in patients with NASH was significantly higher than the prevalence of cirrhosis in the other groups ( P  < 0.001). Overall, 70% of the non-malignant liver tissue of patients with NBNC-HCC was not involved with cirrhosis. On the other hand, the median FIB-4 index in patients with cryptogenic HCC was 2.56, which was a significantly lower value than those values in the other groups of patients. The FIB-4 index considered as one of useful screening of HCC. Conclusions The prevalence of NBNC-HCC has increased rapidly even in a regional university hospital. Metabolic syndrome may be an important risk factor for HCC. HCC was also found in patients with non-cirrhotic livers. The FIB-4 index may be a useful screening method for HCC in patients with NBNC.

The aim of this study was to investigate the relationship between body composition before lenvatinib treatment and prognosis in patients with hepatocellular carcinoma (HCC). We also assessed the relationship between the rate of change in body composition after lenvatinib treatment and prognosis. Eighty-one patients with advanced HCC who were treated with lenvatinib were enrolled. We assessed prognosis, various clinical data, body composition parameters obtained by bioelectrical impedance analysis (BIA), and handgrip strength. Multivariate analysis showed that an extracellular water to total body water ratio (ECW/TBW) ≤ 0.400 at treatment initiation was associated with longer overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS) (OS: hazard ratio [H0R], 4.72; 95% CI, 12.03-11.00; P < 0.001; PFS: HR, 2.66; 95% CI, 1.33-5.34; P = 0.0057; PPS: HR, 3.08; 95% CI, 1.32-7.18; P = 0.0093). Multivariate analysis also showed that the skeletal muscle mass index (SMI) of the arm at treatment initiation was associated with a longer PFS (HR, 2.12; 95% CI, 1.23-3.64; P = 0.0069). In the group with an ECW/TBW ≤ 0.400 before lenvatinib treatment, univariate analysis showed that the rate of change in only the arm SMI was associated with a longer OS and PFS. Body composition assessment by BIA before and after lenvatinib treatment is useful in predicting prognosis in lenvatinib-treated patients with HCC.

Ovarian yolk sac tumor (YST) is a highly aggressive malignancy arising in young women. Chemotherapy has dramatically improved the prognosis, and bleomycin, etoposide, and cisplatin (BEP) combination chemotherapy appears to be the most effective combination regimen. A 23-year-old woman was admitted to our hospital with worsening abdominal distention and a lower abdominal mass. She was diagnosed with a stage IIIc pure YST of the right ovary, and right salpingo-oophorectomy was performed; there were numerous disseminated peritoneal tumors within the abdominal cavity. A few days postoperatively, massive ascites developed, and right hydronephrosis occurred. Chemotherapy with BEP was started, and after 24 h of administration, oliguria and tumor lysis syndrome (TLS) developed. Continuous hemodiafiltration was started, and hemodialysis was initiated following full-dose standard cisplatin and etoposide on days 2–5 of the 1st cycle. After the electrolyte abnormalities and the elevation of creatinine became normal, the patient received an additional three cycles of BEP and achieved complete remission. However, she also suffered from severe non-hematological toxicities, including grade 3 left ventricular dysfunction and grade 4 pulmonary fibrosis. In the case of rapidly progressing and high-volume YST treated with BEP chemotherapy, special attention should be paid to bleomycin-induced pulmonary toxicity following TLS. Further study is required to optimize drug exposure to ensure efficacy and reduce the risk of side effects in this population.