RECAM-J 2023-Validation and development of the Japanese version of RECAM for the diagnosis of drug-induced liver injury.

AIM: The diagnosis of drug-induced liver injury (DILI) is challenging. We modified the revised electronic version of the Roussel Uclaf Causality Assessment Method (RUCAM) for the diagnosis of DILI (RECAM), the scoring system developed in US and Spanish cohorts in 2022, and developed RECAM-J 2023 to align with the clinical practice in Japan. In the current study, we introduce RECAM-J 2023 and verify its performance in the context of Japanese patients with DILI. METHODS: After translation of RECAM into Japanese, modifications were made to develop RECAM-J 2023 without any alteration to the scores. To examine the validity and performance of RECAM-J 2023, clinical information on DILI and non-DILI cases in Japan were retrospectively collected. The diagnosis of DILI was made by expert's decision. Then we scored each case using RECAM-J 2023, and calculated area under curve (AUC) values for identification for DILI. RESULTS: We collected data from 538 DILI and 128 non-DILI cases. The sum of highly probable (HP) and probable (PR) cases categorized by RECAM-J 2023 were only 206 (38%) in DILI cases. As the primary cause of low scores was the deduction with missing hepatitis virus markers, which is unlikely to be an issue in prospective applications, we rescored without these deductions. At this time, the sum of HP and PR was raised to 421 (78%). The AUCs of RECAM-J 2023 without deductions were 0.70 and 0.88 for identifying at least HP, and at least PR, respectively. CONCLUSION: RECAM-J 2023, when prospectively used without any missing hepatitis virus markers, provides acceptable performance for identifying at least PR DILI cases in Japanese daily clinical practice.

Progression pattern and post-progression survival following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.

BACKGROUND: Although the combination of atezolizumab and bevacizumab (ATZ + BEV) is a standard treatment for advanced hepatocellular carcinoma (HCC), strategies for addressing treatment failure and prognostic factors of post-progression survival (PPS) remain unestablished. METHODS: We conducted a multicentre retrospective study to evaluate PPS following ATZ + BEV treatment in patients with advanced HCC. We classified the patients into three groups: BCLC stage B and BCLC stage C without or with new extrahepatic lesions (BCLCp-C1 and BCLCp-C2, respectively) at the time of progression. RESULTS: Of the 204 patients who started ATZ + BEV treatment between October 2020 and September 2022, 110 showed disease progression, with 33, 55 and 22 showing the BCLCp-B, BCLCp-C1 and BCLCp-C2 stages of the disease, respectively. Specifically, patients with the BCLCp-B stage of the disease showed better overall survival than those with the BCLCp-C1 and BCLCp-C2 stages (hazard ratios: 1.93 [95% confidence interval, CI, 1.06-3.51] and 2.64 [95% CI, 1.32-5.30] for HCC stages BCLCp-C1 and BCLCp-C2, respectively). Via multivariable analysis, we identified the BCLCp-C1 and BCLCp-C2 stages, as well as performance status, Child-Pugh class and alpha-fetoprotein as poor prognostic factors for PPS. CONCLUSIONS: BCLCp-B1 stage was identified as a better prognostic factor for PPS following ATZ + BEV treatment compared with BCLCp-C1 and BCLCp-C2 stages. This may help in making decisions regarding subsequent treatment after ATZ + BEV.

Low-grade Appendiceal Mucinous Neoplasm with Appendiceal Reduction and Re-expansion Over a Two-year Period: A Case Report.

A 71-year-old woman was found to have submucosal tumor-like lesion on colonoscopy (CS) before gastric surgery, and computed tomography (CT) showed a 12-mm structure at the base of the appendix. The lesion could not be clearly detected on CT nine months later, but it had enlarged again on CT one year later; therefore, CS and endoscopic ultrasound (EUS) were performed. The lesion was determined to be cystic with viscous contents, and laparoscopic appendicectomy was performed. This is the first report of low-grade appendiceal mucinous neoplasm (LAMN) diagnosed by a histopathologic examination of a resected specimen showing shrinkage and re-expansion of the appendix.

Impact of body composition for patients with hepatocellular carcinoma who received atezolizumab plus bevacizumab therapy.

OBJECTIVE: To investigate the association between body composition and prognosis in patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab. METHODS: This cohort study analysed 119 patients who received atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. We investigated the association between body composition and progression-free survival and overall survival. Body composition was quantified by the visceral fat index, subcutaneous fat index, and skeletal muscle index. A high or low index score was defined as that above or below the median of these indices. RESULTS: Poor prognosis was observed in the low visceral fat index and low subcutaneous fat index groups. The mean progression-free survival in the low visceral fat index and low subcutaneous fat index groups vs. the other groups were 194 and 270 days, respectively [95% confidence interval (CI), 153-236 and 230-311 days, respectively; P = 0.015], while the mean overall survival was 349 vs. 422 days, respectively (95% CI, 302-396 and 387-458 days, respectively; P = 0.027). In the multivariate analysis, both a low subcutaneous fat index and low visceral fat index were statistically associated with lower progression-free and overall survival rates [hazard ratio (HR) 1.721; 95% CI, 1.101-2.688; P = 0.017; and HR 2.214; 95% CI, 1.207-4.184; P = 0.011, respectively]. CONCLUSION: Low visceral fat index and subcutaneous fat index scores were independent predictors of poor prognosis in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

Association Between Immune-Related Adverse Events and Survival in Patients with Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective for advanced hepatocellular carcinoma (HCC). However, there are few reports on the correlation between the clinical efficacy of ICIs and the development of immune-related adverse events (irAEs) in patients with HCC. The aim of this study was to investigate the association between irAE development and survival in patients with HCC treated with atezolizumab plus bevacizumab. PATIENTS AND METHODS: We enrolled 150 patients with advanced HCC treated with atezolizumab plus bevacizumab between October 2020 and October 2021 at 5 territorial institutions. We compared the efficacy of atezolizumab plus bevacizumab between patients who experienced irAEs (irAE group) and those who did not (non-irAE group). RESULTS: Thirty-two patients (21.3%) developed irAEs of any grade. Grade 3/4 irAEs were observed in 9 patients (6.0%). The median progression-free survivals (PFS) in the irAE and non-irAE groups were 273 and 189 days, respectively (P = .055). The median overall survivals (OS) in the irAE and non-irAE groups were not reached and 458 days, respectively (P = .036). Grade 1/2 irAEs significantly prolonged PFS (P = .014) and OS (P = .003). Grade 1/2 irAEs were significantly associated with PFS (hazard ratio [HR], 0.339; 95% confidence interval [CI], 0.166-0.691; P = .003) and OS (HR, 0.086; 95% CI, 0.012-0.641; P = .017) on multivariate analysis. CONCLUSION: The development of irAEs was associated with increased survival in a real-world population of patients with advanced HCC treated with atezolizumab plus bevacizumab. Grade 1/2 irAEs were strongly correlated with PFS and OS.

First reports of clinical effects of transjugular intrahepatic portosystemic shunt in four patients with cirrhotic ascites refractory to tolvaptan.

OBJECTIVE: Ascites in patients with decompensated cirrhosis can lead to abdominal distention and decrease quality of life. Tolvaptan, a vasopressin V2 receptor antagonist, is an effective agent in the treatment of ascites, whereas some patients are refractory to tolvaptan. The efficacy of transjugular intrahepatic portosystemic shunt (TIPS) for these patients is not known. In this study, we performed TIPS for tolvaptan-refractory cirrhotic patients and analysed its efficacy and safety in these patients. DESIGN: This retrospective analysis included patients with liver cirrhosis who received TIPS for ascites or hydrothorax refractory to tolvaptan therapy along with conventional diuretics between January 2015 and May 2018 at Tokai University Hospital. We evaluated the efficacy and safety of TIPS. RESULTS: This study included four patients. All patients presented with Child-Pugh class B liver cirrhosis and model for end-stage liver disease-sodium scores were 10/12/14/16. TIPS was generated successfully without any major complications in all patients. The body weight decreased by a mean of 4.7 (SD=1.0) kg and estimated glomerular filtration rate improved from a mean of 38.2 (SD=10.3) to 59.5 (SD=25.0) mL/min/1.73 m2 in a month after TIPS procedure. CONCLUSION: TIPS is an effective potential treatment for ascites in patients with tolvaptan refractory condition. In appropriate patients who can tolerate TIPS, the treatment may lead towards renal function improvement.

Adherent-invasive E. coli - induced specific IgA limits pathobiont localization to the epithelial niche in the gut.

Background and aim: Adherent-invasive E. coli (AIEC) has been identified as a pathobiont associated with Crohn's disease (CD), that prefers to grow in inflammatory conditions. Although the colonization by AIEC is implicated in the progression of the disease and exacerbates inflammation in murine colitis models, the recognition and response of host immunity to AIEC remains elusive. Methods: Antibiotic treated female C57BL/6 mice were inoculated by commensal E. coli and LF82 AIEC strains. Luminal-IgA fractions were prepared from feces and their binding to AIEC and other strains was assessed to confirm specificity. IgA binding to isogenic mutant strains was performed to identify the functional molecules that are recognized by AIEC specific IgA. The effect of IgA on epithelial invasion of LF82 strain was confirmed using in vitro invasion assay and in vivo colonization of the colonic epithelium. Results: Persistent colonization by AIEC LF82 induced secretion of luminal IgA, while commensal E. coli strain did not. Induced anti-LF82 IgA showed specific binding to other AIEC strains but not to the commensal, non-AIEC E. coli strains. Induced IgA showed decreased binding to LF82 strains with mutated adhesin and outer membrane proteins which are involved in AIEC - epithelial cell interaction. Consistently, LF82-specific IgA limited the adhesion and invasion of LF82 in cultured epithelial cells, which seems to be required for the elimination in the colonic epithelium in mice. Conclusion: These results demonstrate that host immunity selectively recognizes pathobiont E. coli, such as AIEC, and develop specific IgA. The induced IgA specific to pathobiont E. coli, in turn, contributes to preventing the pathobionts from accessing the epithelium.

Clinical outcomes of antithrombin III-based therapy for patients with portal vein thrombosis: A retrospective, multicenter study.

AIM: The association between thrombolytic therapy and the outcome in patients with portal vein thrombosis (PVT) remains controversial. This study aimed to evaluate the outcome in patients with PVT who received antithrombin III-based therapy. METHODS: This study was a retrospective, multicenter study to investigate the liver-related events and the survival rates in 240 patients with PVT who received the therapy. RESULTS: The patients comprised 151 men and 89 women, with a median age of 69 years. The rate of favorable response, defined as maximum area of PVT changed to ≤75%, was 67.5% (162/240). The cumulative rates of liver-related events at 1, 2, and 3 years were 38.2%, 53.9%, and 68.5%, respectively. The multivariate analysis showed that viable hepatocellular carcinoma, absence of maintenance therapy, non-responder, and PVT progression were significantly associated with liver-related events. The PVT progression was observed in 23.3% (56/240). The multivariate analysis identified older age, absence of maintenance therapy, and non-responder as independent factors associated with PVT progression. The multivariate analysis revealed that younger age, no hepatocellular carcinoma, presence of maintenance therapy, and lower Model for End-stage Liver Disease-Sodium score significantly contributed to 3-year survival. Of the 240 patients, 13 (8.9%) prematurely discontinued treatment due to any adverse events. CONCLUSIONS: This study suggests that maintenance therapy, favorable response, and absence of PVT progression may suppress or control liver-related events in antithrombin III-based therapy for patients with PVT. Specifically, maintenance therapy could suppress not only liver-related events, but also PVT progression and improve the prognosis.

Significant association between HLA-B*35:01 and onset of drug-induced liver injury caused by Kampo medicines in Japanese patients.

AIM: Drug-induced liver injury (DILI) is a severe and life-threatening immune-mediated adverse effect, occurring rarely among treated patients. We examined genomic biomarkers in the Japanese population that predict the onset of DILI after using a certain class of drugs, such as Kampo products (Japanese traditional medicines). METHODS: A total of 287 patients diagnosed as DILI by hepatology specialists were recruited after written informed consent was obtained. A genome-wide association analysis and human leukocyte antigen (HLA) typing in four digits were performed. RESULTS: We found a significant association (p = 9.41 × 10-10 ) of rs146644517 (G > A) with Kampo product-related DILI. As this polymorphism is located in the HLA region, we evaluated the association of HLA types and found that 12 (63.2%) of 19 Kampo-DILI patients contained HLA-B*35:01, whereas only 15.2% were positive for this HLA among healthy volunteers. The odds ratio was 9.56 (95% confidence interval 3.75-24.46; p = 2.98 × 10-6 , corrected p = 4.17 × 10-5 ), and it increased to 13.55 compared with the DILI patients not exposed to Kampo products. The individual crude drug components in the Kampo products, including Scutellaria root (ougon in Japanese), rhubarb (daiou), Gardenia fruit (sanshishi), and Glycyrrhiza (kanzou), were significantly associated with HLA-B*35:01. CONCLUSIONS: HLA-B*35:01 is a genetic risk factor and a potential predictive biomarker for Kampo-induced DILI in the Japanese population.

A case of breast cancer with extensive colon metastasis.

Breast cancer is one of the most common malignancies in women worldwide. Although most breast cancers are curable, in cases of metastasis, many are often found in the lungs, bones, liver, and central nervous system; however, metastasis to the gastrointestinal tract is rare. Invasive lobular carcinoma, which represents only 5%-10% of breast cancers, has a higher risk of metastasis to the gastrointestinal tract than invasive ductal carcinoma. Here, we report a rare case of gastrointestinal metastasis of invasive lobular carcinoma that spread extensively to the colonic mucosa. Given the improved survival rates of breast cancer patients with current treatments, many rarer metastatic diseases, including gastrointestinal metastases, are likely to be increased in the future.

Cell-free and concentrated ascites reinfusion therapy versus large-volume paracentesis for the treatment of cirrhotic patients with refractory ascites: A multicenter prospective observational study.

AIM: Cell-free and concentrated ascites reinfusion therapy (CART) and large-volume paracentesis (LVP) with albumin infusion are useful for managing refractory ascites (RA). However, it remains unclear which therapy is more effective in patients with cirrhosis with RA. METHODS: From June 2018 to March 2022, 25 patients with RA treated with CART or LVP with albumin infusion were enrolled in this multicenter prospective observational study to investigate the number of abdominal paracenteses, albumin preparations used, and drainage volume during an 8-week observation period. RESULTS: Among all patients at entry (median age, 63 years; 52% men; 60% Child-Pugh B and 40% Child-Pugh C), 92% were treated with furosemide (median, 20 mg/day), 92% with spironolactone (25 mg/day), and all with tolvaptan (7.5 mg/day). Patients with RA had a poor health-related quality of life (HRQOL) and prominent ascites-related symptoms. Four of the 20 eligible patients were treated with CART, 11 with LVP with albumin infusion, and five with their combination. The median number of paracenteses, total drainage volume, and albumin infusions were 1.5, 7.4 L, and 0, respectively, in the CART group; 5.0, 22.0 L, and 5.0, respectively, in the LVP group; and 5.0, 30.0 L, and 5.0, respectively in their combination group. The treatment effects did not differ significantly among the three groups regarding weight loss, liver function, renal function, electrolytes, and HRQOL. However, patients treated with CART had fewer paracenteses and albumin infusions than those treated with LVP. CONCLUSIONS: CART and LVP have comparable therapeutic efficacy for RA in patients with cirrhosis.

Efficacy and Safety of Endoscopic Removal for Asymptomatic Common Bile Duct Stones in Comparison with Symptomatic Stones.

OBJECTIVE: Endoscopic removal is recommended for common bile duct stones (CBDs). However, in patients with asymptomatic CBDs, follow-up without treatment may be recommended because of the increased complication risks associated with asymptomatic CBDs removal. The objective of our study was to investigate the efficacy and safety of CBDs removal in asymptomatic patients. METHODS: Consecutive patients with naive papilla who underwent endoscopic retrograde cholangiopancreatography (ERCP) for the treatment of CBDs from April 2016 to August 2020 were retrospectively analyzed. We compared the efficacy and safety of CBDs removal in asymptomatic and symptomatic patients. RESULTS: We enrolled 300 patients, 53 asymptomatic and 247 symptomatic patients. Endoscopic CBDs removal was successful in all patients, except one symptomatic patient. However, the complete stone removal rate in a single session was significantly higher in the asymptomatic group than that in the symptomatic group. ERCP-related complications did not differ between the asymptomatic and symptomatic patients. The incidence of post-ERCP pancreatitis was similar and liver cirrhosis was the only significant risk factor for pancreatitis. CONCLUSION: Complication risks associated with endoscopic CBDs removal was not significantly different between asymptomatic and symptomatic patients. Liver cirrhosis was a significant risk factor of ERCP-related pancreatitis.

The prevalence and natural history of hepatic cysts examined by ultrasound: a health checkup population retrospective cohort study.

The prevalence of hepatic cysts in the general population and their natural history are largely unknown. This study aimed to assess the prevalence and natural history of hepatic cysts by investigating health checkup participants. Ultrasonographic data of health checkup participants (n = 38,842) were retrospectively evaluated to calculate its prevalence. In addition, we assessed the changes in the size and characteristics of hepatic cysts over 10 years (n = 7709). We found the prevalence of hepatic cysts was 21.9%. Older age, female sex, and presence of kidney cysts or pancreatic cysts were associated with the occurrence of hepatic cysts. Younger age, female sex, and the existence of multiple hepatic cysts were associated with cyst enlargement. Among 126 individuals who had hepatic cysts with a diameter of 30 mm or larger at the first visit, two (1.6%) required treatment. Remain 124 cases showed four patterns: 44 cases with enlargement, 47 stable, 11 regression after enlargement, and 22 regression. Hyperechoic fluid inside the cysts was observed in 54.5% (18 of 33), which was significantly higher than 6.6% (6 of 91) of the non-regression (OR = 17.0). The appearance of intracystic hyperechoic fluid by ultrasound may predict subsequent regression of the hepatic cyst.

Frequency of null genotypes of glutathione S-transferase M1 and T1 in Japanese patients with drug-induced liver injury.

AIM: Previous reports suggest that the null genotype (*0/*0) of glutathione S-transferase (GST) M1 and/or GSTT1 could be risk factors for drug-induced liver injury (DILI). However, multi-institutional pharmacogenetic research with various suspected drugs has rarely been performed in Japan. Therefore, the aim of this study was to investigate the role of GSTM1 and GSTT1 null genotype in the occurrence of DILI in Japanese patients. METHODS: Blood samples of 270 DILI patients from 23 hospitals throughout Japan collected between 2010 and 2018 were subjected to genotyping of null genotypes of GSTM1 and GSTT1 using the SmartAmp-2 method. We also collected information on DILI types, time to onset of DILI, pharmacological classification of suspected drugs and Digestive Disease Week-Japan score, as well as genotypes of GSTM1 and GSTT1 in each patient with DILI. RESULTS: The distribution of a combination of null genotypes of GSTM1 and GSTT1 in Japanese patients with DILI was significantly different from that reported in the general Japanese population. Notably, the incidence of the GSTM1 null genotype in patients with DILI was significantly higher than that of the control population. A significant relationship between the frequency of GSTM1 and GSTT1 null genotypes and pharmacological classification of suspected drugs, clinical laboratory data for liver function, time to onset of DILI, and Digestive Disease Week-Japan scores was not observed. CONCLUSIONS: The GSTM1 null genotype was associated with an increased incidence of DILI in Japanese patients.

Analysis of Comorbidity for Patients with Pancreatic Cysts in Medical Checkup Screening.

OBJECTIVES: We investigated whether there is a difference in the frequency of comorbidity between patients with pancreatic cysts and those without pancreatic cysts by abdominal ultrasonography in patients undergoing medical checkup screening. METHODS: The subjects were 6,627 patients who underwent abdominal ultrasonography at Tokai University Hachioji Hospital's Health Screening Center between April 2019 and March 2020. RESULTS: Of the total 6,627 patients, 158 (2.4%) were pointed out to have pancreatic cysts. Multivariate analysis revealed that the related factors were female sex, age 60 years or older, diabetes, lung cancer, and uterine/ovarian cancer. CONCLUSION: Unlike pancreatic cancer, pancreatic cysts are more common in women. In addition, it is known that pancreatic cysts have a high complication rate of cancers of other organs; lung cancer and uterine/ovarian cancer were identified as high-risk factors in this study.

Antiviral Therapy for Patients Chronically Infected with Hepatis C Virus at Tokai University Hospital.

OBJECTIVE: Hepatitis C virus (HCV) was identified in 1989. In 2020, three decades after HCV identification, three researchers won the Nobel Prize in Physiology or Medicine for the discovery of this virus. In 1992, three years after the discovery, interferon (IFN) was launched as the first anti-HCV therapy in Japan; however, the efficacy of IFN therapy was far from acceptable due to severe adverse effects. The advent of IFN-free direct-acting antivirals (DAAs) in 2014 dramatically improved the outcomes of antiviral treatment without serious adverse effects. In this study, we aimed to summarize anti-HCV therapy at the Tokai University Hospital. METHODS: We identified patients who underwent anti-HCV therapy by searching medical records from January 1992 to December 2020, analyzed their background, and compared safety and efficacy among treatments. RESULTS: A total of 1777 treatments were given to 1299 patients. The sustained virologic response rate has dramatically increased over the past 30 years, with only 7% for IFN monotherapy and 95% or higher for recent IFN-free DAA therapies. CONCLUSIONS: We documented the results of anti-HCV therapy at the Tokai University Hospital. In the 30 years since the discovery of HCV, surprisingly successful progress has been accomplished in the anti-HCV treatment.

A prospective observational cohort study of lenvatinib as initial treatment in patients with BCLC-defined stage B hepatocellular carcinoma.

BACKGROUND: Transarterial chemoembolization (TACE) is the standard treatment for intermediate stage hepatocellular carcinoma (HCC) (Barcelona Clinic Liver Cancer [BCLC] B). However, it often leads to a poor prognosis and decreased hepatic function especially in patients with BCLC substage B2. Lenvatinib (LEN) was demonstrated to be efficacious in these patients in the REFLECT phase 3 trial. We therefore aimed to evaluate the efficacy and safety of LEN as a first-line treatment for the patients with HCC at BCLC substage B2. METHODS: This prospective observational study used LEN in TACE-naïve patients with HCC at BCLC substage B2 and preserved hepatic function. The primary endpoint was overall survival. A one-year survival rate threshold of 60% and an expected survival rate of 78%, based on previous reports of TACE, was assumed for setting the sample size. With a one-sided α-type error of 5% and 70% detection power, 25 patients were required over a 2-year enrollment period and 10-month follow-up period. RESULTS: Thirty-one patients were enrolled in this study from June 2018 to June 2020. The 1-year survival rate was 71.0% (90% confidence interval, 68.4-73.6%). Median overall and progression-free survival periods were 17.0 and 10.4 months, and the objective response rates according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 and modified RECIST criteria were 22.6% and 70.0%, respectively. Common adverse events (AEs) were fatigue (68%), hypertension (65%), anorexia (61%), palmar-plantar erythrodysesthesia (39%), and thrombocytopenia (32%) of any grade; aspartate aminotransferase increased (23%), alanine aminotransferase increased (16%), and grade ≥ 3 proteinuria (13%). Treatment interruption and dose reduction were required in 61% and 81% of patients, respectively. LEN was discontinued in 29 patients due to disease progression (n = 17), AEs (n = 9), conversion to curative treatments (n = 2), and sudden death (n = 1), whereas post-LEN treatments were administered in 18 patients, including systemic chemotherapy (n = 11), TACE (n = 6), transarterial infusion (n = 1) and clinical trial (n = 1). CONCLUSIONS: The results suggest that LEN provides treatment benefits as an initial therapeutic in patients with BCLC substage B2 HCC with a safety profile comparable to that previously reported.

Identification of CT Values That Could Be Predictive of Necrosis (N-CTav) in Hepatocellular Carcinoma after Lenvatinib Treatment.

Purpose: To assess the utility of measurement of the computed tomography (CT) attenuation value (CTav) in predicting tumor necrosis in hepatocellular carcinoma (HCC) patients who achieve a complete response (CR), defined using modified Response Evaluation Criteria in Solid Tumors (mRECIST), after lenvatinib treatment. Method: We compared CTav in arterial phase CT images with postoperative histopathology in four patients who underwent HCC resection after lenvatinib treatment, to determine CTav thresholds indicative of histological necrosis (N-CTav). Next, we confirmed the accuracy of the determined N-CTav in 15 cases with histopathologically proven necrosis in surgical specimens. Furthermore, the percentage of the tumor with N-CTav, i.e., the N-CTav occupancy rate, assessed using Image J software in 30 tumors in 12 patients with CR out of 571 HCC patients treated with lenvatinib, and its correlation with local recurrence following CR were examined. Results: Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off value of CTav of 30.2 HU, with 90.0% specificity and 65.0% sensitivity in discriminating between pathologically identified necrosis and degeneration, with a CTav of less than 30.2 HU indicating necrosis after lenvatinib treatment (N30-CTav). Furthermore, the optimal cut-off value of 30.6% for the N30-CTav occupancy rate by ROC analysis was a significant indicator of local recurrence following CR with 76.9% specificity and sensitivity (area under the ROC curve; 0.939), with the CR group with high N30-CTav occupancy (≥30.6%) after lenvatinib treatment showing significantly lower local recurrence (8.3% at 1 year) compared with the low (<30.6%) N30-CTav group (p < 0.001, 61.5% at 1 year). Conclusion: The cut-off value of 30.2 HU for CTav (N30-CTav) might be appropriate for identifying post-lenvatinib necrosis in HCC, and an N30-CTav occupancy rate of >30.6% might be a predictor of maintenance of CR. Use of these indicators have the potential to impact systemic chemotherapy for HCC.

Comparative study between sorafenib and lenvatinib as the first-line therapy in the sequential treatment of unresectable hepatocellular carcinoma in a real-world setting.

AIMS: There is a paucity of comparative data on the use of sorafenib and lenvatinib for unresectable hepatocellular carcinoma. We assessed the real-world treatment outcomes between using sorafenib and lenvatinib for unresectable hepatocellular carcinoma in the multiple molecular-targeted therapy era. METHODS AND RESULTS: We enrolled 386 patients treated with sorafenib or lenvatinib as the first-line therapy for unresectable hepatocellular carcinoma at multiple centers. Propensity score matching was performed to adjust for differences in baseline and tumor characteristics between the two groups. Propensity score matching identified 110 patients in each treatment group. The median overall survival was similar between lenvatinib and sorafenib (14.8 and 13.0 months, respectively; P = 0.352). The median progression-free survival was longer with lenvatinib than with sorafenib (7.6 and 3.9 months, respectively; P < 0.001). The overall response rate (P < 0.001) and disease control rate (P = 0.015), as defined by the modified Response Evaluation Criteria in Solid Tumors, were significantly better with lenvatinib than with sorafenib. The median overall survival was longer in patients who received subsequent treatment than in those who did not in the sorafenib group (23.1 and 5.7 months, respectively; P < 0.001), whereas the median overall survival with or without subsequent treatment did not differ significantly in the lenvatinib group (17.8 and 14.7 months, respectively; P = 0.439). CONCLUSION: Overall survival with sorafenib and lenvatinib was not significantly different. However, patients who received subsequent treatments had longer overall survival than those who received only first-line treatment with sorafenib, whereas lenvatinib did not show this effect.

Safety and efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma in early clinical practice: A multicenter analysis.

PURPOSE: To assess the impact of clinical factors on the safety and efficacy of atezolizumab plus bevacizumab (ATZ + BV) treatment in patients with unresectable hepatocellular carcinoma (u-HCC). METHOD: Ninety-four u-HCC patients who were treated with ATZ + BV at multiple centers were enrolled. We defined Child-Pugh (CP)-A patients who received ATZ + BV treatment as a first line therapy as the 'meets the broad sense of the IMbrave150 criteria' group (B-IMbrave150-in, n = 46), and patients who received ATZ + BV treatment as a later line therapy or CP-B patients (regardless of whether ATZ + BV was a first line or later line therapy) as the B-IMbrave150-out group (n = 48). Patients were retrospectively analyzed for adverse events (AEs) and treatment outcomes according to their clinical characteristics, including neutrophil lymphocyte ratio (NLR) at baseline. RESULTS: The overall incidence of AEs was 87.2% (82/94 patients). The frequency of interruption of ATZ + BV treatment due to fatigue was higher in CP-B than CP-A patients (p = 0.030). Objective response (OR) rates of the B-IMbrave150-in group (28.3%, 39.1%) were significantly higher than those of the B-IMbrave150-out group (8.3%, 18.8%; p = 0.0157, 0.0401) using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST, respectively. In multivariate analysis, NLR (hazard ratio (HR), 4.591; p = 0.0160) and B-IMbrave150 criteria (HR, 4.108; p = 0.0261) were independent factors associated with the OR of ATZ + BV treatment using RECIST. CONCLUSION: In real-world practice, ATZ + BV treatment might offer significant benefits in patients who meet B-IMbrave150 criteria or have low NLR.