Significance of changes in tumor markers in patients treated with durvalumab plus tremelimumab combination therapy as a surrogate marker for tumor response to unresectable hepatocellular carcinoma.

AIM: When evaluating response to immune checkpoint inhibitor therapy, the tumor sometimes initially swells before shrinking and ultimately responding, also called pseudo-progression. In this study, we analyzed whether tumor markers were useful for reflecting the treatment response. METHODS: Thirty-three patients who were treated with durvalumab plus tremelimumab combination therapy (Dur + Tre) were enrolled. Their functional reserve was Child-Pugh grade A. Their tumor markers α-fetoprotein (AFP), des-γ-carboxy prothrombin (DCP), or AFP-Lectin 3 fraction (AFP-L3) were positive. Tumor markers were evaluated before treatment and at 1, 4, and 8 weeks after the start of treatment. The first radiological evaluation was carried out at 4 weeks and the second evaluation at 8-12 weeks. The responders included those with complete response and partial response and the nonresponders included those with stable disease (SD) and progression disease at best response evaluated by Response Evaluation Criteria in Solid Tumors. RESULTS: In the responder group, the change ratio of AFP, DCP, and AFP-L3 specifically decreased at 8 weeks. In the nonresponder group, the change ratio of DCP specifically increased at 4 weeks. The optimal cut-off value to divide responders and nonresponders at 4 weeks was approximately -40%. The ratio of responders was 72.7% in the patients whose AFP or DCP decreased over 40% at 4 weeks. CONCLUSIONS: The change in tumor markers is a more useful predicter of tumor response to Dur + Tre than imaging evaluation alone.

Impact and usefulness of the transition to the new MAFLD classification for non-B, non-C HCC: a retrospective cohort study.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a new classification system for fatty liver disease. In this study, we investigated the clinical characteristics of patients with MAFLD-hepatocellular carcinoma (HCC) in comparison with those with nonalcoholic fatty liver disease (NAFLD) and considered the validity and challenges of the new criteria. METHODS: This study included 237 untreated non-B, non-C HCC patients with hepatic steatosis. We examined the profile and laboratory findings of patients with MAFLD-HCC and NAFLD-HCC. We also classified MAFLD-HCC patients according to the factors on which the diagnosis was based and compared their clinical characteristics. RESULTS: A total of 222 (94%) and 101 (43%) patients were diagnosed with MAFLD and NAFLD, respectively. MAFLD-HCC patients were more likely to be male than NAFLD-HCC, but there were no significant differences in metabolic indices, noninvasive liver fibrosis score or HCC status. In a study of MAFLD-HCC patients by diagnostic factor, those with overweight only were younger and had advanced liver fibrosis histologically, and when limited to patients younger than 70 years, the majority were overweight. Redefinition of overweight as BMI ≥ 25 reduced the number of MAFLD-HCC patients by only 5, from 222 to 217. CONCLUSIONS: MAFLD accounted for the majority of non-B, non-C HCC cases with hepatic steatosis. Examination of additional cases and revision of the detailed criteria is needed so that it can be used to efficiently select patients with fatty liver who are at high risk of developing HCC.

Correlation between serum pro-inflammatory cytokine levels and the prognosis of the patients with acute liver failure.

BACKGROUND AND AIM: The prognosis of acute liver failure (ALF) remains poor, and liver transplantation is an alternative treatment option. Assessing the prognosis of ALF is important in determining treatment strategies. Here, we investigated clinical factors including serum pro-inflammatory cytokine levels that are associated with the prognosis of ALF. METHODS: Sixty-six patients who developed ALF were enrolled in this study. Serum concentrations of 12 pro-inflammatory cytokines were measured on admission. The prognosis and factors associated with survival and development of hepatic coma were analyzed. RESULTS: Of 66 patients, 4 patients underwent liver transplantation, and 49 patients were rescued without liver transplantation, while the remaining 13 patients died. Serum concentrations of interleukin (IL)-1ß, IL-4, IL-6, IL-8, IL-13, TNF, IFN -γ, IP-10, and G-CSF were significantly elevated in ALF patients. IL-4 and IL-8 levels were higher in patients who underwent liver transplantation or died than in rescued patients. Multivariable analysis identified age ≥ 55 years and IL-4 ≥ 1.2 pg/mL on admission as independent factors for mortality. Serum IL-8 levels were higher in patients with hepatic coma, and prothrombin-international normalized ratio ≥ 3.5 and IL-8 ≥ 77.2 pg/mL on admission were associated with development of hepatic coma after admission. CONCLUSION: Serum levels of several pro-inflammatory cytokines were elevated in ALF patients. IL-4 and IL-8 were correlated with survival and development of hepatic coma after admission, respectively. Measurement of serum pro-inflammatory cytokines seems to be useful for the management of ALF.

Hepatic venous pressure gradient after balloon-occluded retrograde transvenous obliteration and liver stiffness measurement predict the prognosis of patients with gastric varices.

BACKGROUND: Balloon-occluded retrograde transvenous obliteration (BRTO) is a treatment option for patients with gastric varices (GVs). This study aimed to clarify the clinical significance of portal hypertension estimated by the hepatic venous pressure gradient (HVPG), subsequent exacerbation of esophageal varices (EVs), and prognosis of patients who underwent BRTO for GVs. METHODS: Thirty-six patients with GVs treated with BRTO were enrolled in this study, and their HVPG was measured before (pre-HVPG) and on the day after BRTO (post-HVPG). After BRTO, patients were followed-up for a median interval of 24.5 (3-140) months. Clinical factors related to EVs exacerbation and prognosis after BRTO were retrospectively analyzed. RESULTS: Post-HVPG increased compared to pre-HVPG in 21 out of 36 patients (58%), and post-HVPG was overall significantly higher compared to pre-HVPG (P = 0.009). During the observation period, 19 patients (53%) developed EVs exacerbation, and the cumulative EVs exacerbation rates at 1, 3 and 5 years after BRTO were 27%, 67%, and 73%, respectively. Pre-HVPG was not related to EVs exacerbation, although elevation of post-HVPG to ≥ 13 mmHg (P < 0.01) and high level of serum aspartate aminotransferase (P < 0.05) were significant independent risk factors for EVs exacerbation after BRTO. Fourteen patients (38.9%) died during the observation period. An elevated value of liver stiffness measurement (LSM) of ≥ 21 kPa was a significant independent risk factor for poor prognosis after BRTO (P < 0.05). CONCLUSIONS: HVPG increases after BRTO. HVPG after BRTO has greater predictive ability for subsequent EVs exacerbation than HVPG before BRTO. LSM is a potential prognostic parameter in patients who undergo BRTO.

Peripheral T Cell Subpopulations as a Potential Surrogate Biomarker during Atezolizumab plus Bevacizumab Treatment for Hepatocellular Carcinoma.

The therapeutic benefits of the immunotherapeutic combination of atezolizumab and bevacizumab (Atez/Bev) in hepatocellular carcinoma (HCC) vary. Therapeutic biomarkers might help improve outcomes for HCC patients receiving Atez/Bev therapy. The role of systemic immune profiles in HCC progression also remains unclear. This study aimed to evaluate the status and dynamics of peripheral T cell subpopulations in HCC patients receiving Atez/Bev treatment and to explore biomarkers predictive of a therapeutic response. We enrolled 83 unresectable advanced HCC patients who commenced Atez/Bev treatment at our hospital between October 2020 and June 2022. Peripheral T cell subpopulations in peripheral blood mononuclear cells at baseline and 3 weeks post-treatment were investigated using flow cytometry and compared with those in control samples from 18 healthy individuals. We retrospectively analyzed the association between peripheral T cell subpopulation profiles and clinical outcomes. Baseline peripheral T cell subpopulations could be profiled in 70 patients with sufficient cell counts, among whom 3-week subpopulations could be evaluated in 51 patients. Multivariate analysis showed that a high baseline proportion of CD8+ central memory T (TCM) cells was independently associated with longer progression-free survival (PFS). Further, overall survival (OS) was significantly prolonged in patients with increased CD8+ effector memory T (TEM) cell proportions. In conclusion, TCM proportion at baseline might be a good indicator of the efficacy of Atez/Bev therapy. Furthermore, observation of increasing TEM proportions might be an early predictor of the potential clinical benefits of treatment.

Risk Factors for Early Onset of Proteinuria in Patients Receiving Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma.

Introduction: Proteinuria is one of the adverse events of atezolizumab plus bevacizumab combination therapy (Atezo + Bev) and can cause interruption in the use of Bev. However, the risk factors for proteinuria in patients with hepatocellular carcinoma (HCC) who are receiving Atezo + Bev have not yet been investigated. The aim of this study was to identify the risk factors for early onset of proteinuria in Atezo + Bev for patients with unresectable HCC. Methods: Sixty-four patients with Child-Pugh scores of 5-7, an Eastern Cooperative Oncology Group performance status of 0 or 1, and low level of proteinuria (1+ or less on a dipstick test and urine protein-to-creatinine ratio (UPCR) less than 2.0 g/g Cr) at the initiation of therapy were analyzed. The level of proteinuria was evaluated based on the Common Terminology Criteria for Adverse Events version 5.0. We adopted the UPCR for the quantitative test instead of a 24-h urine collection. The incidence of proteinuria and changes in liver function were retrospectively investigated. Results: The cumulative incidence of proteinuria over a 24-week period was 34.4%. Multivariate analysis showed that a low estimated glomerular filtration rate (hazard ratio [HR], 3.807; 95% confidence interval [CI], 1.579-9.180; p = 0.003), treatment for hypertension (HR, 6.224; 95% CI, 1.614-24.010; p = 0.008), and high systolic blood pressure (SBP) (HR, 2.649; 95% CI, 1.133-6.194; p = 0.025) were risk factors for proteinuria. Serum albumin levels and albumin-bilirubin scores in patients with proteinuria worsened. In addition, a mean SBP ≥135 mm Hg during treatment was the only risk factor for the development of severe proteinuria (UPCR >2 g/g Cr). Conclusion: Our study found that controlling blood pressure is extremely important for the management of proteinuria in patients with HCC who are receiving Atezo + Bev.

Successful Lenvatinib Re-challenge following Atezolizumab Plus Bevacizumab Combination Therapy Failure for Unresectable Hepatocellular Carcinoma.

To our knowledge, there have been no reports of first-line lenvatinib (LEN) and LEN re-challenge following atezolizumab/bevacizumab (Atezo-Bev) failure in the same patient. We herein report a patient with advanced hepatocellular carcinoma who failed either 1st line LEN and 2nd line Atezo-Bev, and successfully achieved complete response to LEN rechallenge with sequencial transcatheter arterial chemoembolization (TACE). This patient had a poor response to TACE before immunotherapy and introduction of molecular-targeted drugs but showed a good response to selective TACE after LEN rechallenge. Our findings suggest the need to reconsider the use of molecular-targeted drugs and TACE with advances in immunotherapy.

Serum interleukin-6 level predicts the prognosis for patients with alcohol-related acute-on-chronic liver failure.

AIM: Heavy alcohol consumption is the most common etiology of acute-on-chronic liver failure (ACLF) in Japan. In some patients, ACLF is associated with a fatal outcome in less than 6 months. We evaluated the prognosis of patients with alcohol-related ACLF in our cohort and explored the prognostic factors. METHODS: Forty-six patients with alcoholic liver cirrhosis who fulfilled the Japanese diagnostic criteria for ACLF, including those classified as extended and/or probable, were enrolled in this study. Serum concentrations of inflammatory cytokines (interleukin [IL]-1ß, IL-6, IL-8, IL-10, IL-12p70 and TNFα) were measured. We assessed prognosis and identified factors associated with survival. RESULTS: During the median 33-day observation period, 19 patients died, and 3 patients underwent living donor liver transplantation. Cumulative survival rates of patients treated without liver transplantation were 69, 48, 41, and 36% at 1, 3, 6, and 12 months, respectively. Eighteen of the 19 deceased patients died within 6 months after ACLF diagnosis. Serum concentrations of inflammatory cytokines were significantly elevated, and patients who underwent liver transplantation or who died within 6 months after admission had significantly higher serum IL-6 levels than the survival group. Multivariate analysis identified IL-6 > 23.3 pg/mL at admission and model for end-stage liver disease (MELD) score ≥ 25 on day 4 of admission as significant independent factors for mortality within 6 months. CONCLUSION: Serum IL-6 level and Day-4 MELD were prognostic factors for alcohol-related ACLF. Early liver transplantation is a potential treatment option for patients whose prognosis is expected to be poor.

Benign Recurrent Intrahepatic Cholestasis Type 1 with Novel Nonsense Mutations in the ATP8B1 Gene.

Benign recurrent intrahepatic cholestasis (BRIC) is a group of genetically heterogeneous autosomal recessive liver disorders characterized by recurrent episodes of jaundice and pruritus. BRIC is divided into two groups, BRIC type 1 (BRIC1) and BRIC type 2 (BRIC2), caused by mutations in the ATP8B1 and ABCB11 genes. We show that novel nonsense mutations in ATP8B1 (c.2989G>A, c.1547T>A) are the cause of BRIC1. A 16-year-old girl presented with severe jaundice. Acute and chronic liver diseases with infectious (hepatitis virus), metabolic, and autoimmune etiologies were excluded. Imaging revealed normal intra- and extra-hepatic bile ducts. Liver biopsy revealed severe intrahepatic bile stasis with bile plugs. She had similar symptoms at the age of 0 years. The BRIC criteria were satisfied, and ATP8B1 and ABCB11 gene analyses performed. Surprisingly, novel nonsense variants of the ATP8B1 gene (c.2989G>A and c.1547T>A) in heterozygosis were found, which were identified in each of her parents. Therefore, the compound heterozygote was thought to cause BRIC1 in these patients. Genetic mutations that differ from those already known may help diagnose patients with BRIC.

Calcium channel blockers improve the prognosis of patients with intrahepatic cholangiocarcinoma after resection.

BACKGROUND: Intrahepatic cholangiocarcinoma is the second most common primary cancer of the liver. It is highly malignant and its prognosis is very poor. Although there have been various reports on the effects of calcium channel blockers on cancer, the effects of calcium channel blockers on intrahepatic cholangiocarcinoma have not been reported so far. METHODS: Seventy-nine patients diagnosed with intrahepatic cholangiocarcinoma by hepatectomy between January 2002 and May 2019 were retrospectively evaluated. We compared prognosis and time to recurrence between patients treated with calcium channel blockers (CCBs) (n = 29) and those not treated with CCBs (n = 50). Propensity score matching reduced confounding biases and yielded 25 matched patient pairs. Survival between groups was compared using Kaplan-Meier analyses, logrank tests, and Cox proportional hazard regression models. RESULTS: Overall survival and recurrence-free survival of the CCBs group were significantly longer than those of the non-CCBs group OS in the original cohort and matched cohort (98 months vs 45 months, p = 0.010; 96 months vs 22 months, p = 0.020, respectively). Multivariate analyses showed that CCBs treatment was independently associated with overall survival (HR, 0.37; 95% CI 0.16-0.85; p = 0.019) and recurrence-free survival (HR, 0.39; 95% CI 0.17-0.90; p = 0.020) in the original cohort and matched cohort, respectively. CONCLUSION: CCBs treatment might improve prognosis of patients with intrahepatic cholangiocarcinoma.

The importance of body composition assessment for patients with advanced hepatocellular carcinoma by bioelectrical impedance analysis in lenvatinib treatment.

BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Body composition assessment by BIA before and after lenvatinib treatment is useful in predicting prognosis in lenvatinib-treated patients with HCC.

Analysis of Survival and Response to Lenvatinib in Unresectable Hepatocellular Carcinoma.

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

Advanced hepatocellular carcinoma with response to lenvatinib after atezolizumab plus bevacizumab.

RATIONALE: Various treatments are available for treating hepatocellular carcinoma (HCC). The immune checkpoint inhibitor combination of atezolizumab plus bevacizumab was recently approved for the treatment of unresectable HCC, but there are few reports on the failure of the combination treatment. Here, we present a case of unresectable HCC with adrenal metastasis that was eventually operated on after lenvatinib (LEN) treatment that followed failed treatment with atezolizumab plus bevacizumab. PATIENT CONCERNS: A 68-year-old man was diagnosed with non-alcoholic steatohepatitis-based HCC with adrenal metastasis. DIAGNOSIS: Cirrhosis was classified as Child-Pugh score of 5. HCC was diagnosed as Barcelona Clinic Liver Cancer stage C. INTERVENTIONS: We initiated treatment with atezolizumab plus bevacizumab. Liver dysfunction appeared 2 days after the first administration but was improved by intravenous rehydration and did not appear after the second course. The HCC shrank, but the adrenal metastasis grew bigger after the fourth course, so we changed the therapy to LEN. After HCC and adrenal metastasis were necrotic by LEN, conversion surgery was performed. OUTCOMES: After successful conversion therapy, the general condition of the patient was good, and has been carefully followed for 4 months to date without any evidence of further recurrences. LESSONS: This case showed that even if atezolizumab plus bevacizumab is not effective, multidisciplinary treatment such as LEN and conversion surgery is possible. Given the efficacy of LEN after atezolizumab plus bevacizumab, it is important to consider that there is a possibility of cure even when first-line treatment is not effective for a patient with unresectable HCC.

Early Tumor Response and Safety of Atezolizumab Plus Bevacizumab for Patients with Unresectable Hepatocellular Carcinoma in Real-World Practice.

The aim of this study was to investigate the early tumor response and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma in real-world practice. Forty patients with Child-Pugh class A liver function and eastern cooperative oncology group performance status 0 or 1 were enrolled. The objective response rate (ORR) at six weeks after the start of treatment, changes in α-fetoprotein (AFP) and des-γ-carboxyprothrombin, incidence of adverse events (AEs), and changes in albumin-bilirubin (ALBI) score and serum ammonia level, were evaluated. Among 40 patients, 24 had histories of prior molecular targeted agents (MTAs). The ORR was 22.5% based on mRECIST. Multivariate analysis showed that an AFP ratio <1.0 at three weeks (odds ratio 39.2, 95% confidence interval CI 2.37-649.0, p = 0.0103) was the only significant factor for predicting early response. There was no significant difference in the frequency of AEs between patients receiving first-line treatments and others. Fatigue, proteinuria, and ascites were more frequent in patients who experienced prior treatment. No decrease in ALBI score or increase in serum ammonia level was observed. Our study demonstrated that AFP may be useful in assessing early response and that this treatment is safe, including in patients with prior MTA treatments.