Clinical factors associated with the therapeutic efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma: A multicenter prospective observational study.

The treatment efficiency and predictors of atezolizumab plus bevacizumab therapy for unresectable hepatocellular carcinoma in real-world practice have not been established. This study aimed to assess the efficacy and safety of atezolizumab plus bevacizumab and to investigate predictors of progression-free survival and overall survival. Patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab therapy in 19 hospitals were enrolled before treatment and observed prospectively. The outcomes of 222 patients in this cohort were analyzed. The objective response rate and disease control rate were 22.0% and 70.6%, respectively, whereas the median progression-free survival was 5.7 months. Independent risk factors for shortened progression-free survival were younger age (<75 years; 3.9 months vs. 8.6 months), higher number of intrahepatic tumors (≥5; 4.0 months vs. 7.9 months), macrovascular invasion (2.3 months vs. 6.7 months), and higher neutrophil-to-lymphocyte ratio (≥3.03; 3.0 months vs. 7.8 months). The median overall survival was not reached; however, independent risk factors for shortened overall survival were absence of hyperlipidemia, higher number of intrahepatic tumors (≥5), macrovascular invasion, higher α-fetoprotein level (≥400 ng/mL), worse Child-Pugh score (≥6), and higher neutrophil-to-lymphocyte ratio (≥3.03). Severe adverse events (grade ≥3) were observed in 96 patients (36.0%), with proteinuria being the most frequent. In conclusion, patients with older age, lower number of intrahepatic tumors, absent macrovascular invasion, and lower neutrophil-to-lymphocyte ratio are expected to have better progression-free survival with atezolizumab plus bevacizumab therapy for unresectable hepatocellular carcinoma.

Pretreatment with antibiotics is associated with reduced therapeutic response to atezolizumab plus bevacizumab in patients with hepatocellular carcinoma.

AIM: Alterations in microbial composition of gut microbiota due to antibiotics (ATB) may lead to resistance to immune checkpoint inhibitors (ICIs). This study aimed to assess the impact of ATB use on therapeutic response in patients with hepatocellular carcinoma (HCC) receiving atezolizumab plus bevacizumab. METHODS: This study retrospectively analyzed 105 patients with HCC treated with atezolizumab plus bevacizumab as a primary systemic therapy from prospectively-registered, multicenter, cohorts. Nineteen patients who received prior ATB were included in the ATB (+) group; 86 patients who did not receive prior ATB were included in the ATB (-) group. The therapeutic outcomes were compared between the two groups. RESULTS: Most of the patients' baseline characteristics were not significantly different between the two groups. The objective response rates according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (30.1% vs. 11.1%; p = 0.143) and modified RECIST (mRECIST) (44.6% vs. 27.8%; p = 0.190) were not significantly different between the ATB (-) and ATB (+) groups. The disease control rates were higher in the ATB (-) group than in the ATB (+) group according to RECIST v1.1 (74.7% vs. 44.4%; p = 0.012) and mRECIST (78.3% vs. 50.0%; p = 0.020). Prior ATB use was found to be independently associated with radiological progressive disease of the first therapeutic assessment. The median progression-free survival according to RECIST v1.1 (9.1 months vs. 3.0 months; p = 0.049) and mRECIST (9.1 months vs. 3.0 months; p = 0.036), and overall survival (not reached vs. 11.4 months; p = 0.015) were longer in the ATB (-) group than in the ATB (+) group. CONCLUSIONS: Prior ATB use was associated with reduced therapeutic responses in patients with HCC receiving atezolizumab plus bevacizumab.

Thrombospondin-2 as a Predictive Biomarker for Hepatocellular Carcinoma after Hepatitis C Virus Elimination by Direct-Acting Antiviral.

We evaluated the value of secreted glycoprotein thrombospondin-2 (TSP-2) to predict hepatocellular carcinoma (HCC) occurrence in chronic hepatitis C (CHC) patients after Hepatitis C virus (HCV) elimination by direct-acting antiviral agents (DAAs). A total of 786 CHC patients without an HCC history who achieved a sustained virological response (SVR) with DAAs were randomly assigned 2:1, with 524 patients as the derivation cohort and 262 patients as the validation cohort. Serum TSP-2 levels at the end of treatment were measured by enzyme-linked immunosorbent assay (ELISA). In the derivation cohort, the cumulative HCC rate was significantly higher in the high TSP-2 group than in the low TSP-2 group. Multivariate Cox proportional hazards analysis revealed that TSP-2, α-fetoprotein (AFP), and the fibrosis-4 (FIB-4) index were independent HCC risk factors. The area under the receiver operating characteristic curve (AUROC) of the score calculated from these three factors (AFT score) for predicting HCC was 0.83, which was significantly higher than that of each factor alone (TSP-2: 0.70, AFP: 0.72, FIB-4: 0.69). The AFT score was used to stratify patients according to the risk of HCC occurrence in the validation cohort. Lastly, in patients with a FIB-4 index < 3.25, the serum TSP-2 levels could be used to identify those patients with a high risk of HCC occurrence. Serum TSP-2 levels are a predictive biomarker of HCC occurrence in CHC patients after HCV elimination by DAA treatment. The AFT score using TSP-2, AFP, and the FIB-4 index may identify those who require HCC surveillance.

Effect of sofosbuvir and velpatasvir therapy on clinical outcome in hepatitis C virus patients with decompensated cirrhosis.

AIM: To determine the impact of direct-acting antiviral therapy on the long-term prognosis of decompensated cirrhotic patients. METHODS: A total of 37 patients with hepatitis C virus-induced decompensated cirrhosis treated with sofosbuvir and velpatasvir (SOF/VEL group) were prospectively enrolled. For historical control, 65 hepatitis C virus-positive decompensated cirrhotic patients who did not receive direct-acting antiviral therapy were included (control group). The incidence rates of hepatocellular carcinoma (HCC), decompensated events with hospitalization, and overall survival were compared between both groups. RESULTS: A total of 41 patients experienced decompensated events during 15.0 months in the control group, and six patients during 21.6 months in the SOF/VEL group. The cumulative incidence rates of decompensated events after 2 years were significantly higher in the control group (53.1%) than in the SOF/VEL group (14.5%; p < 0.001). A total of 27 patients died within 22.0 months in the control group, and three patients died within 25.6 months in the SOF/VEL group. The overall survival rates after 2 years were significantly lower in the control group (67.6%) than in the SOF/VEL group (91.3%; p = 0.010). A total of 13 patients in the control group developed HCC during 15.8 months, and 10 patients during 17.3 months in the SOF/VEL group. The HCC incidence rates after 2 years were 20.3% and 29.6% in the control and SOF/VEL groups, respectively, with no significant difference (p = 0.327). CONCLUSIONS: SOF/VEL therapy may suppress the development of decompensated events and improve the prognosis in decompensated cirrhotic patients; however, the incidence of HCC remains prevalent in these patients irrespective of SOF/VEL therapy.

Improved Liver Function After Sustained Virologic Response Enhanced Prognosis in Hepatitis C with Compensated Advanced Liver Fibrosis.

BACKGROUND AND AIM: Liver function can be improved in patients with chronic hepatitis C virus (HCV) infection who achieved sustained virologic response (SVR) with direct-acting antiviral (DAA) treatment. However, to our knowledge, the impact of liver function improvement after SVR on prognosis has not been investigated. METHODS: A total of 716 patients with chronic HCV infection and compensated advanced liver fibrosis who began receiving DAA treatment between September 2014 and August 2018 in 25 Japanese hospitals and achieved SVR were enrolled. RESULTS: The median age was 73 years, and 336 (47%) and 380 (53%) patients had albumin-bilirubin (ALBI) grade 1 and grade 2, respectively. Improvement to ALBI grade 1 at 1 year after the end of treatment (EOT) was observed in 76% of the patients with baseline ALBI grade 2. Among 380 patients with baseline ALBI grade 2, alanine aminotransferase (ALT) levels ≥ 40 U/L (p < 0.001) and modified ALBI (mALBI) grade 2a (p < 0.001) were significantly associated with improvement to ALBI grade 1 at 1 year after EOT in multivariate analysis. During the median observation period of 51.8 months, 4 and 10 patients with baseline ALBI grade 1 and 2, respectively, died. In patients with baseline ALBI grade 2, only the absence of improvement to ALBI grade 1 at 1 year after EOT was significantly associated with all-cause mortality in univariate analysis. CONCLUSIONS: Baseline ALT levels and mALBI grade were significantly associated with improvement in liver function after SVR. Patients whose liver function improved after SVR could have better prognosis.

The Ventricular Hypokinesis at the Apical Pacing Site due to the Early Shortening and Rebound Stretch in a Case with Fontan Procedure.

The left ventricular (LV) apex is recommended as the first choice for positioning the epicardial pacing. We encountered a patient with congenital heart disease (CHD) showing hypokinesis of the LV apical pacing site after implantation of a pacemaker with epicardial leads. This phenomenon was revealed by the early shortening and systolic rebound stretch of the same lesion on two-dimensional speckle tracking echocardiography, which developed in the intraventricular dyssynchrony between the LV apex and base. Cardiac resynchronization therapy provided an excellent result around the hypokinetic lesion. It is wise to arrange detailed evaluations in each patient with complicated CHD, aiming at a successful treatment to enable ventricular synchronicity.

Incidence and risk factors of hepatocellular carcinoma in patients with hepatitis C who achieved a sustained virological response through direct-acting antiviral agents among the working population in Japan.

Background and Aim: The development of hepatocarcinogenesis after a sustained virological response (SVR) remains an important issue affecting the balance between treatment and occupational life of workers with chronic hepatitis C virus (HCV) infection in Japan. Here, we aimed to evaluate the hepatocellular carcinoma (HCC) reducing effect and risk factors for developing HCC after SVR in patients treated with direct-acting antiviral agents (DAAs) among the working population. Methods: We studied 2579 working patients with chronic HCV infection who achieved SVR after antiviral treatment. We compared the difference in the cumulative incidence of post-SVR HCC between the interferon (IFN)-based n = 1615 and DAA (n = 964) groups. The risk factors for post-SVR HCC development were determined in the DAA group. Results: After propensity score matching (n = 644 in each group), the HCC development rates were not significantly different between the groups (P = 0.186). Multivariate Cox regression and the cutoff values determined by the receiver operating characteristic curve analyses revealed that age ≥61 years, diabetes, lower serum albumin levels <4.0 g/dL at 24 weeks after the end of treatment (EOT), and higher serum α-fetoprotein levels ≥4.1 ng/mL at 24 weeks after the EOT were associated with the development of HCC. Conclusion: The HCC suppressing effect after SVR through DAA treatment is equivalent to that of IFN treatment in patients in the working population. Intensive follow-up is required after SVR with DAA treatment in Japanese workers with these risk factors to ensure the promotion of health and employment support.

Risk of hepatocellular carcinoma after sustained virologic response in hepatitis C virus patients without advanced liver fibrosis.

AIM: Hepatocellular carcinoma (HCC) after sustained virologic response (SVR) has been observed even in hepatitis C virus (HCV) patients without advanced liver fibrosis. Identifying predictors for HCC incidence in patients without advanced liver fibrosis will enable efficient post-SVR HCC surveillance. This study aimed to develop a scoring system to predict the incidence of HCC after SVR in HCV patients without advanced liver fibrosis. METHODS: A total of 1682 HCV patients without advanced liver fibrosis (defined as Fibrosis-4 index <3.25) with no history of HCC who initiated direct-acting antiviral treatment between September 2014 and October 2020 at 26 institutions, and achieved SVR24, were included. We divided 1682 patients into training (1122) and validation (560) cohorts. RESULTS: In the multivariate analysis, baseline age ≥ 65 years (p = 0.030), alanine aminotransferase (ALT) levels at SVR24 ≥ 30 U/l (p = 0.001), and α-fetoprotein (AFP) levels at SVR24 ≥ 5.0 ng/ml (p = 0.001) were independent predictors for HCC incidence in the training cohort. We developed a scoring system to predict HCC incidence after SVR24 using these three factors (1 point was added for each factor). The cumulative HCC incidence rates at 5 years were 7.1% in patients who scored 2 or 3, and no patients developed HCC in those who scored 0 in the validation cohort. CONCLUSIONS: Our scoring system using the three factors of baseline age, ALT levels at SVR, and AFP levels at SVR is useful for post-SVR HCC surveillance of patients without advanced liver fibrosis.

[A case of eosinophilic gastroenteritis caused after the use of Seprafilm®].

Eosinophilic gastroenteritis is a fairly uncommon condition. It has been suggested that allergic reactions may have played a role in the development of this illness. The case of a 66-year-old woman who had a total hysterectomy due to a right ovarian tumor is described here. At this operation, a sodium hyaluronate carboxymethylcellulose bioresorbable membrane (Seprafilm®) was used. She was admitted to our hospital 47 days after the operation with abdominal pain. Laboratory data indicated elevated WBC (29450/µl) and eosinophilia (69.2%), and CT scan showed thickening of intestinal wall and ascites around there. Ascites cytology showed a significant increase of eosinophils (94.0%). She began taking oral steroids after being diagnosed with eosinophilic gastroenteritis, and her symptoms improved quickly. Despite the fact that Seprafilm® was thought to be a reliable and safe tool, it was suggested that a foreign body reaction to Seprafilm® could lead to eosinophilic gastroenteritis.

Prediction Model for Intrahepatic Distant Recurrence After Radiofrequency Ablation for Primary Hepatocellular Carcinoma 2 cm or Smaller.

BACKGROUND: Intrahepatic hepatocellular carcinoma (HCC) has a high recurrence rate after radiofrequency ablation (RFA). However, to date, no standalone predictive factors for intrahepatic distant recurrence after curative ablation have been reported. AIMS: The aim of this study was to investigate predictive factors for intrahepatic distant recurrence after curative treatment with RFA for HCCs. METHODS: This multicenter study consisted of 17 institutions that registered 821 patients. The risk factors for intrahepatic distant recurrence after complete ablation by RFA for primary HCC ≤ 2 cm in diameter were identified in a retrospectively collected training set (n = 636) and then validated in a prospectively collected validation set (n = 185). RESULTS: The cumulative intrahepatic distant and local recurrence rates (i.e., entire recurrence rate) in the training set were 23.6% and 53.7% at 1 and 3 years, respectively. The cumulative intrahepatic distant recurrence rates in the training set were 17.0% and 43.8% at 1 and 3 years, respectively. Multivariate analysis of the training set showed that tumor number and serum levels of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) were independent risk factors for both entire recurrence and intrahepatic distant recurrence. Intrahepatic distant recurrence risk in both the training and validation cohorts was stratified using a scoring system with three factors: tumor number (single or multiple), AFP (< 10 ng/ml or ≥ 10 ng/ml), and DCP (< 50 mAU/ml or ≥ 50 mAU/ml). CONCLUSION: The scoring system composed of tumor number, AFP, and DCP is useful for classifying the risk of intrahepatic distant recurrence after curative ablation for HCC.

Significance of in vitro photodynamic cytodiagnosis with 5-aminolevulinic acid in biliary brush cytology for malignant biliary stricture.

BACKGROUND: For the early diagnosis of malignant biliary stricture due to biliary-pancreatic carcinoma, conventional biliary brush cytology with endoscopic retrograde cholangiopancreatography (ERCP; the conventional method) is not sensitive enough. METHODS: Two hundred nine patients with biliary stricture who were admitted between September 2015 and June 2020 were enrolled in this study. Biliary brush cytology was performed on all patients. Samples were diagnosed independently by an expert pathologist and medical doctor with conventional cytology and photodynamic diagnosis (PDD) with 5-aminolevulinic acid. RESULTS: The definitive diagnoses were 49 benign and 160 malignant diseases. The conventional method had a sensitivity of 77.5% (124/160) and specificity of 100% (49/49). The PDD method had a sensitivity of 77.5% (124/160) and specificity of 67.3% (33/49). The conventional method identified 36 malignant diseases as false negatives, while the PDD method enabled successful diagnoses of malignant diseases in 19 of these 36 patients. When PDD was combined with the conventional method, the sensitivity significantly increased to 89.4% (143/160, P = 0.006), and for biliary tract diseases only, the sensitivity increased to 95.6% (88/92, P = 0.001). CONCLUSIONS: Malignant biliary stricture can be diagnosed effectively and safely with the in vitro PDD method. The sensitivity could be further increased by combining PDD with the conventional method.

Serum growth differentiation factor 15 predicts hepatocellular carcinoma occurrence after hepatitis C virus elimination.

BACKGROUND: After hepatitis C virus (HCV) elimination, patients should be followed up due to risk of hepatocellular carcinoma (HCC). Growth differentiation factor 15 (GDF15) is a cytokine induced by mitochondrial dysfunction or oxidative stress. Aim To evaluate the prognostic value of GDF15 for HCC occurrence after HCV elimination. METHODS: We measured GDF15 levels in stored serum from patients with chronic HCV infection without a history of HCC who had achieved sustained virological response with direct-acting antiviral agents (DAAs). The patients were randomly divided into derivation (n = 964) and validation (n = 642) cohorts. RESULTS: In the derivation cohort, serum GDF15 levels were higher in those with HCC occurrence after DAA treatment than in those without. Multivariate Cox proportional hazards analysis revealed baseline GDF15 (>1350 pg/mL, HR 2.54), AFP (>5 ng/mL, HR 2.00), and the FIB-4 index (>3.25, HR 2.69) to be independent risk factors for HCC. Scoring based on GDF15, AFP and the FIB-4 index stratified HCC occurrence risk. In the validation cohort, the cumulative HCC occurrence rate at 3 years was 0.64%, 3.27% and 15.3% in low-score (N = 171), medium-score (N = 300) and high-score (N = 166) groups, respectively. In the total cohort, scoring divided patients with a FIB-4 index ≤3.25, whose HCC occurrence rate was 2.0% at 3 years, into medium-score and low-score groups with HCC occurrence rates at 3 years of 3.76% and 0.24%, respectively. CONCLUSIONS: Serum GDF15 predicts de novo HCC occurrence. Scoring using GDF15, AFP, and the FIB-4 index can predict de novo HCC occurrence risk after HCV elimination.

Oral Zinc Supplementation Decreases the Risk of HCC Development in Patients With HCV Eradicated by DAA.

We have reported that the plasma zinc concentration gradually decreases with the progression of fibrosis and is related to hepatocellular carcinoma (HCC) development. The aim of this study was to examine the impact of the zinc concentration on HCC development (study 1) and the relationship between zinc intake and HCC development (study 2) in patients with hepatitis C virus (HCV) eradicated by direct-acting antivirals (DAAs). A total of 599 sustained virological response (SVR) patients treated with DAAs without a history of HCC were retrospectively analyzed in this study. Eighty patients received supplemental zinc (Zn treatment group), and 519 patients did not receive zinc (no Zn treatment group). In study 1, the cumulative incidence rate of HCC was compared between the Zn treatment group and the no Zn treatment group. In study 2, the risk factors for HCC development were examined in the no Zn treatment group. In study 1, in the Zn treatment group, HCC did not develop during follow-up, and the cumulative risk of HCC was significantly lower in the Zn treatment group than in the no Zn treatment group (P = 0.048). In study 2, the 1-year and 3-year cumulative incidence rates of HCC were 1.8% and 5.6%, respectively. The risk factors for HCC identified by multivariate analysis were male sex, cirrhosis, low platelet count before treatment, and low serum zinc concentration 12 weeks after the end of DAA therapy. Conclusion: The Zn concentration is related to HCC development in patients with HCV eradicated by DAA therapy. Oral zinc supplementation is recommended as a means of suppressing HCC development in patients who have achieved SVR.

Prediction model for hepatocellular carcinoma occurrence in patients with hepatitis C in the era of direct-acting anti-virals.

BACKGROUND: Several factors associated with hepatocellular carcinoma (HCC) occurrence after sustained virological response (SVR) in patients with hepatitis C have been reported. However, few validation studies have been performed in the era of direct-acting anti-virals (DAAs). AIMS: To develop a prediction model for HCC occurrence after DAA-mediated SVR and validate its usefulness. METHODS: We analysed 2209 patients with SVR and without a history of HCC who initiated DAA treatment at 24 Japanese hospitals. These patients were divided into a training set (1473 patients) and a validation set (736 patients). RESULTS: In the training set, multivariate Cox proportional hazards analysis showed that the baseline BMI (≥25.0 kg/m2 , P = 0.024), baseline fibrosis-4 (FIB-4) index (≥3.25, P = 0.001), albumin level at SVR (<4.0 g/dL, P = 0.010) and alpha-foetoprotein level at SVR (≥5.0 ng/mL, P = 0.006) were significantly associated with HCC occurrence. We constructed a prediction model for HCC occurrence with these four factors (2 points were added for the FIB-4 index, and 1 point was added for each of the other three factors). Receiver operating characteristics curve analysis identified a score of 2 as the optimal cut-off value for the prediction model (divided into 0-1 and 2-5). In the validation set, the sensitivity and negative predictive value for HCC occurrence were 87.5% and 99.7%, respectively, at 2 years and 71.4% and 98.0%, respectively, at 3 years. CONCLUSION: A prediction model combining these four factors contributes to an efficient surveillance strategy for HCC occurrence after DAA-mediated SVR.

Clinical course of hepatitis C virus-positive patients with decompensated liver cirrhosis in the era of direct-acting antiviral treatment.

AIM: The aim of the present study was to investigate the clinical course in hepatitis C virus (HCV)-positive patients with decompensated liver cirrhosis after direct-acting antivirals (DAAs) have been used for HCV infection. METHODS: This multicenter study prospectively analyzed a registered cohort composed of 73 HCV-positive patients with decompensated cirrhosis who attended our 11 institutions between January 2018 and July 2018. Prognoses, including changes in the liver reserve, hepatocellular carcinoma (HCC), decompensation events, and survival, were analyzed up to July 2020, as was the initiation of DAA treatment. RESULTS: Sixty-four (87.7%) and nine (12.3%) patients had Child-Pugh class (C-P) B and C at baseline, respectively. Within 2 years after enrollment, 17 patients (23.3%) received treatment with DAAs, and 31 patients (42.5%) developed uncontrolled HCC, switched to palliative care, or died. Patients who received DAA treatment were significantly younger and had significantly higher alanine aminotransferase levels and lower platelet counts than the patients who did not receive DAA treatment. The rates of overall survival, cumulative HCC occurrence, and cumulative hospitalization for any hepatic decompensation event at 2 years were 64.8%, 13.1%, and 65.6%, respectively. Overall survival was significantly shorter and the HCC occurrence and hospitalization rates were significantly higher in C-P C patients than in C-P B patients. CONCLUSIONS: Among HCV-positive patients with decompensated cirrhosis, approximately one-fourth received DAA treatment, but more than 40% of the patients lost the opportunity for treatment with DAAs.