Protocol to evaluate the efficacy and safety of tolvaptan in patients with refractory ascites after liver resection: an open-label, single-arm phase I/II study.

Background: In patients with chronic liver diseases such as cirrhosis, massive ascites after hepatic resection is the cause of prolonged hospitalization and worsening prognosis. Recently, the efficacy of tolvaptan in refractory ascites has been reported; however, there are no reports on the efficacy or safety of tolvaptan for refractory ascites after hepatic resection. This study aims to evaluate the efficacy of early administration of tolvaptan in patients with refractory ascites after hepatic resection. Materials and methods: This is an open-label, single-arm phase I/II study. This study subject will comprise patients scheduled for hepatic resection of a liver tumor. Patients with refractory ascites after hepatic resection (drainage volume on postoperative day 1 ≥5 ml/body weight 1 kg/day) will be treated with tolvaptan. The primary endpoint will include the maximum change in body weight after hepatic resection relative to the preoperative baseline. The secondary endpoints will include drainage volume, abdominal circumference, urine output, postoperative complication rate (heart failure and respiratory failure), number of days required for postoperative weight gain because of ascites to decrease to preoperative weight, change in improvement of postoperative pleural effusion, total amount of albumin or fresh frozen plasma transfusion, type and amount of diuretics used, and postoperative hospitalization days. Conclusion: This trial will evaluate the efficacy and safety of tolvaptan prophylaxis for refractory ascites after hepatic resection. As there are no reports demonstrating the efficacy of tolvaptan prophylaxis for refractory ascites after hepatic resection, the authors expect that these findings will lead to future phase III trials and provide valuable indications for the selection of treatments for refractory postoperative ascites.

Immunotherapy Using Activated Natural Killer Cells Improves Postoperative Neutrophil-to-Lymphocyte Ratio and Long-Term Prognosis of Living Donor Liver Transplant Recipients With Hepatocellular Carcinoma.

OBJECTIVE: Preoperative neutrophil-to-lymphocyte ratio (NLR) is a well-known prognostic indicator in various malignancies; however, the impact of postoperative NLR on living donor liver transplant (LDLT) recipients is unknown. Immunotherapy with donor liver-derived activated natural killer (NK) cells may improve postoperative NLR by coactivating immune cells or suppressing activated neutrophils. This study aims to clarify the clinical significance of postoperative NLR in recipients after LDLT with HCC and assess whether immunotherapy improves postoperative NLR. METHODS: We conducted a retrospective study of LDLT recipients between 2001 and 2022 to evaluate the clinical significance of postoperative NLR. Furthermore, the correlation between postoperative NLR and the activation marker of infused NK cells was also evaluated. The postoperative NLR was examined 4 weeks after LDLT. RESULTS: The postoperative high NLR group (N = 78) had preoperative lower NLR and higher model for end-stage liver disease and a higher rate of postoperative infection within 30 days after LDLT than the postoperative low NLR group (N = 41). Postoperative high NLR (hazard ratio [HR], 2.62; 95% confidence interval [CI], 1.01-6.79; P = .047) and nontreatment of immunotherapy (HR, 3.10; 95% CI, 1.33-7.22; P < .01) were independent risk factors for poor overall survival in multivariate analysis. Furthermore, the activation marker of infused NK cells is inversely correlated with decreased postoperative NLR. CONCLUSIONS: The higher level of postoperative NLR was independently associated with poor prognosis in patients after LDLT with HCC. Immunotherapy using activated NK cells may improve postoperative NLR and long-term prognosis.

Effect of Abdominal Aortic Calcification on Recurrence Following Initial Hepatectomy for Colorectal Liver Metastases.

BACKGROUND/AIM: The aim of the study was to analyze the association between abdominal aortic calcification (AAC) and patient prognosis following resection of colorectal liver metastases (CRLM). AAC potentially reflects intrahepatic immunity and is involved in tumor development and progression. However, the clinical effects of AAC on colorectal cancer (CRC) prognosis after curative-intent liver resection for CRLM remain unclear. PATIENTS AND METHODS: We evaluated the effect of AAC on the clinical prognosis and metastatic patterns in 99 patients who underwent hepatectomy for CRLM between 2010 and 2019. RESULTS: The high-AAC group had significantly worse overall survival (OS) and remnant liver recurrence rate (RR) after propensity score matching to adjust for differences in baseline characteristics of patients and tumors. In multivariate Cox regression analyses, high AAC volume was an independent risk factor for poor OS and liver RR, but not poor lung RR. The expression of tumor necrosis factor-related apoptosis-inducing ligand, known as an anti-tumor marker, in liver natural killer (NK) cells was lower in the high-AAC group than in the low-AAC group. CONCLUSION: High AAC volume showed a strong relationship with remnant liver RR after curative resection of CRLM. High AAC volume may be responsible for the suppression of anti-tumor activity of liver NK cells, which results in an increased risk of liver recurrence and poor prognosis.

Association of Abdominal Aortic Calcification With the Postoperative Metabolic Syndrome Components After Liver Transplantation.

BACKGROUND: This study aimed to assess the risk factors for components of metabolic syndrome, such as diabetes mellitus, hypertension, and dyslipidemia, more than a year after liver transplantation. METHODS: This study included 164 patients with liver failure secondary to acute and chronic liver disease or hepatocellular carcinoma who underwent liver transplantation between 2000 and 2019. Univariate and multivariate analyses were performed to identify the risk factors associated with metabolic syndrome components after liver transplantation. RESULTS: The median follow-up period was 10.5 years. Of the 164 patients who underwent liver transplantation, 144 (87.8%) developed components of metabolic syndrome after liver transplantation. The most common cause of liver failure was hepatitis C virus infection (34.1%). The incidence of hepatocellular carcinoma was 36.0%. In univariate analysis, preoperative diabetes mellitus was a significantly more common component of metabolic syndrome than the others. In multivariate analysis, preoperative abdominal aortic calcification was a risk factor for the new onset of all components of metabolic syndrome after liver transplantation, despite the varying degree of calcification at risk of development (odds ratio for diabetes mellitus = 3.487, P = .0069; odds ratio for hypertension = 2.914, P = .0471; odds ratio for dyslipidemia = 3.553, P = .0030). CONCLUSIONS: Preoperative abdominal aortic calcification was significantly associated with the development of each metabolic syndrome component after liver transplantation.

Impact of KIR-HLA Genotype on Natural-Killer-Cell-Based Immunotherapy for Preventing Hepatocellular Carcinoma after Living-Donor Liver Transplantation.

Natural killer (NK) cells have immunosurveillance potential in hepatocellular carcinoma (HCC). We performed adaptive immunotherapy using donor-liver-derived natural killer (NK) cells after living-donor liver transplantation (LDLT) to prevent HCC recurrence. Dominant inhibitory signals tightly regulate NK cell activity via human leukocyte antigen (HLA)-specific inhibitory receptors, such as killer immunoglobulin-like receptors (KIRs). The functional recognition of HLA through KIR raises the NK cell capacity, which is a process termed "licensing." Here, we investigated the effect of polymorphic KIR-HLA genotypes on the efficacy of NK-cell-based immunotherapy after LDLT. Seventy-seven Japanese recipients with HCC who underwent LDLT and their corresponding donors between 1996 and 2016 were enrolled in this study. The median follow-up period was 8.3 years. The HCC recurrence risk was stratified using radiological and pathological assessments according to the Milan criteria. Of the 77 recipients, 38 received immunotherapy. Immunotherapy improves early post-transplantation survival and lowers the recurrence rate in the intermediate-risk recipients. We analyzed the genotypes of five inhibitory KIRs and HLA using sequence-specific polymorphism-based typing. The polymorphic KIR-HLA genotype revealed that genetically vulnerable liver transplant recipients with a poorly licensed NK genotype have an improved prognosis by immunotherapy with donor-liver-derived NK cells. Thus, the combination of recipient and donor KIR-HLA genotypes is worthy of attention for further investigation, especially considering the clinical application of NK-cell-based immunotherapy.

Establishment of a cell culture platform for human liver organoids and its application for lipid metabolism research.

Human liver organoids (HLOs) are reliable tools to represent physiological human liver biology. However, their use is limited especially in basic sciences. One of the reasons for this would be the insufficient systematic methodology to handle HLOs, including culture system, functional assessment, and gene transduction. Here, we generated and characterized mouse L cells stably and simultaneously overexpressing R-spondin1, hepatocyte growth factor, fibroblast growth factor (FGF) 7, and FGF10 via lentiviral transduction. The conditioned medium of the cells contributed to HLO growth as a replacement of commercially available recombinant proteins, which leads to a significant reduction of their culture cost. Proliferative and maturation phases of the cells were controlled by switching the medium to facilitate the evaluation of hepatocyte function, including insulin responsiveness and intracellular lipid accumulation. Gene expression analysis revealed that HLOs highly expressed genes involved in lipid metabolism. Importantly, HLOs secreted physiologically matured very low-density lipoprotein, which is rarely observed in mice and in established cell lines. Efficient gene transduction into HLOs was achieved via a transient 2-dimensional culture during viral infection. This study provides an invaluable platform for utilizing HLOs in various research fields, such as molecular biology, pharmacology, toxicology, and regenerative medicine.

Prognostic impact of pre- and postoperative tumor markers in patients with intrahepatic cholangiocarcinoma.

PURPOSE: The present study assessed the impact of pre- and postoperative tumor markers on the survival of patients with intrahepatic cholangiocarcinoma. METHODS: Medical records of 73 patients with intrahepatic cholangiocarcinoma were reviewed retrospectively. The pre- and postoperative carcinoembryonic antigen and carbohydrate antigen 19-9 levels were assessed. Patient characteristics, clinicopathological factors, and prognostic factors were analyzed. RESULTS: The median recurrence-free survival and overall survival were 30.0 and 90.9 months, respectively. A multivariate survival analysis revealed that elevated postoperative carbohydrate antigen 19-9 (p = 0.023) was the only independent poor prognostic factor. The median overall survival of patients with normal and elevated postoperative carbohydrate antigen 19-9 levels was 101.4 and 15.7 months (p < 0.001), respectively. Multivariate logistic regression identified elevated preoperative carbohydrate antigen 19-9 as an independent preoperative risk factor for elevated postoperative carbohydrate antigen 19-9. The optimal cutoff value of preoperative carbohydrate antigen 19-9 for predicting elevated postoperative carbohydrate antigen 19-9 was 40 U/mL, with a sensitivity and specificity of 92% and 87%, respectively (area under curve = 0.915). CONCLUSIONS: Elevated postoperative carbohydrate antigen 19-9 was an independent poor prognostic factor. Preoperative predictors, such as elevated preoperative carbohydrate antigen 19-9, may indicate the need for neoadjuvant therapies to improve the survival.

Impact of atherothrombotic risk stratification in patients with heavily calcified lesions following rotational atherectomy.

BACKGROUND: Patients who undergo percutaneous coronary intervention (PCI) with rotational atherectomy (RA) are at high risk of adverse clinical outcomes, and there are few clinical risk stratification tools for these patients. METHODS: We conducted a study with 196 patients who underwent PCI with RA out of 7391 patients who underwent PCI using a multicenter, prospective cohort registry. Patients were divided into three groups according to the tertiles of the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS 2°P): 65 patients in the T1 group (TRS 2°P < 3), 66 patients in the T2 group (TRS 2°P = 3), and 65 patients in the T3 group (TRS 2°P > 3). The primary endpoint was the cumulative 2-year incidence of major adverse cardiovascular and cerebrovascular events (MACCE), defined as a composite of cardiac death, acute coronary syndrome, and ischemic stroke. RESULTS: Cumulative 2-year MACCE occurred in 41 patients (24 %) during the follow-up period. The cumulative incidence of MACCE was significantly higher in the T3 group than in the T1 group (log-rank test, p = 0.02). Multivariate Cox analyses revealed that the T3 group was associated with an increased risk of MACCE compared to that of the T1 group (adjusted hazard ratio, 2.66; 95 % confidence interval, 1.04-6.77; p = 0.04). The addition of TRS 2°P to conventional risk factors, including male sex, number of diseased vessels, and low-density lipoprotein cholesterol levels, improved the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.39, p = 0.027; IDI 0.072, p < 0.001). CONCLUSIONS: Atherothrombotic risk stratification using TRS 2°P was useful in identifying high-risk patients with heavily calcified lesions following RA.

Predictive Value of CHADS2, CHA2DS2-VASc and R2-CHADS2 Scores for Short- and Long-Term Major Adverse Cardiac Events in Non-ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Non-ST-elevation myocardial infarction (NSTEMI) carries a poor prognosis, and accurately prognostication has significant clinical importance. In this study, we analyzed the predictive value of the CHADS2, CHA2DS2-VASc, and R2-CHADS2scores for major adverse cardiac events (MACE) following percutaneous coronary intervention (PCI) in patients with NSTEMI using data from a prospective multicenter registry.Methods and Results: The registry included 440 consecutive patients with NSTEMI and coronary artery disease who underwent successful PCI. Patients were clinically followed for up to 3 years or until the occurrence of MACE. MACE was defined as a composite of all-cause death and nonfatal MI. During the follow-up period, 55 patients (12.5%) experienced MACE. Risk analysis of MACE occurrence, adjusted for the multivariable model, demonstrated a significant increase in risk with higher CHADS2, CHA2DS2-VASc, and R2-CHADS2scores. Kaplan-Meier analysis showed a higher incidence of MACE in patients with higher CHADS2, CHA2DS2-VASc, and R2-CHADS2scores, both in the short- and long-term periods. CONCLUSIONS: Patients with NSTEMI and higher CHADS2, CHA2DS2-VASc, and R2-CHADS2scores displayed a greater incidence of MACE.

Comparison of postoperative outcomes in cases achieving sustained virological response with direct-acting antiviral and interferon therapy.

BACKGROUND/PURPOSE: The effect of direct-acting antiviral agents (DAAs) on hepatocellular carcinoma (HCC) recurrence after curative hepatectomy remains uncertain. This retrospective study aimed to evaluate the effect of sustained virological response (SVR) with DAAs or interferon (IFN) therapy on recurrence and overall survival (OS) after hepatectomy. METHODS: We enrolled 593 patients who underwent curative resections between January 2010 and December 2017. Among them, 186 achieved SVR before hepatectomy: a total of 51 (27.4%) in the DAA-SVR group and 132 (72.6%) in the IFN-based SVR group. RESULTS: SVR before hepatectomy was an independent predictor of OS, and the 5-year OS rate was significantly higher in the SVR group than that in the non-SVR group (82.2% vs. 63.9%). There were no significant differences in the recurrence rates or OS between DAA and IFN treatments in achieving SVR before hepatectomy, regardless of poor hepatic function in the DAA therapy group. CONCLUSIONS: There was no significant difference in OS and recurrence-free survival (RFS) between the preoperative SVR achieved with DAA and IFN groups in this study, although liver function was significantly worse at the time of surgery in the DAA group compared to the IFN group.

A Multicenter, Open-Label, Single-Arm Phase I Trial of Dual-Wield Parenchymal Transection: A New Technique of Liver Resection Using the Cavitron Ultrasonic Surgical Aspirator and Water-Jet Scalpel Simultaneously (HiSCO-14 Trial).

PURPOSE: This study evaluated the safety and feasibility of a technique of liver resection named dual-wield parenchymal transection technique (DWT), using cavitron ultrasonic surgical aspirator (CUSA) and water-jet scalpel simultaneously. METHODS: This multicenter, prospective, open-label, and single-arm phase I trial included patients aged 20 years or older with hepatic tumors indicated for surgical resection and scheduled for open radical resection. This study was conducted at two institutions affiliated with the Hiroshima Surgical Study Group of Clinical Oncology (HiSCO). The primary endpoint was the proportion of massive intraoperative blood loss (≥ 1000 mL). The secondary endpoints were the amount of blood loss, operative time, parenchymal transection speed, postoperative complications, and mortality. The safety endpoints were device failure and adverse events associated with devices. RESULTS: From June 2022 to May 2023, 20 patients were enrolled; one was excluded and 19 were included in the full analysis set (FAS). In the FAS, segmentectomy was performed in nine cases, sectionectomy in four cases, and hemihepatectomy in six cases. Radical resection was achieved in all patients. Intraoperative blood loss greater than 1000 mL was observed in five patients (26.3%). The median amount of blood loss was 545 mL (range, 180-4413), and blood transfusions were performed on two patients (10.5%). The median operative time was 346 minutes (range, 238-543) and the median parenchymal transection speed was 1.2 cm2/minute (range, 0.5-5.1). Postoperative complications of Clavien-Dindo classification ≥ Grade 3 occurred in four patients (21.1%). No mortalities occurred in this study. In the safety analysis, there were no device failures or adverse events associated with devices. CONCLUSIONS: This study demonstrated the safety and feasibility of DWT for liver resection. The efficacy of the DWT will be evaluated in future clinical trials.

Impact of a new liver immune status index among patients with hepatocellular carcinoma after initial hepatectomy.

Aim: The anti-tumor effects of natural killer (NK) cells vary among individuals. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expressed on liver NK cells is a marker of anti-tumor cytotoxicity against hepatocellular carcinoma (HCC) in immune cell therapy. This study aimed to develop a liver immune status index (LISI) that predicts low TRAIL expression and validates its ability to predict recurrence after initial hepatectomy for primary HCC. Methods: A functional analysis of liver NK cells co-cultured with interleukin-2 for 3 days was performed of 40 liver transplant donors. The LISI, which predicted low TRAIL expression (25% quartile: <33%) in liver NK cells, was calculated using multiple logistic regression analysis. Next, 586 initial hepatectomy cases were analyzed based on the LISI. Results: Our model was based on the Fibrosis-4 index+0.1 (odds ratio [OR], 1.33), body mass index (OR, 0.61), and albumin levels+0.1 (OR, 0.54). The area under the receiver operating characteristic curve (AUC) of the LISI for low TRAIL expression was 0.89. Stratification of the recurrence rates (RR) revealed that LISI was an independent predictive factor of RR (moderate risk: hazard ratio, 1.44; high risk: hazard ratio, 3.02). The AUC was similar for the LISI, albumin-indocyanine green evaluation grade, albumin-bilirubin score, and geriatric nutritional risk index for predicting RR. Among the vascular invasion cases, the LISI was more useful than the other indexes. Conclusion: Our model facilitates the prediction of RR in high-risk patients by providing LISI to predict the anti-tumor effects of NK cells.

Outcomes and Prognostic Analysis of Surgical Resection for Oligometastasis from Hepatocellular Carcinoma.

BACKGROUND/AIM: This study aimed to evaluate the outcomes of patients who underwent resection for oligometastasis from hepatocellular carcinoma (HCC) and identify the prognostic factors associated with poor survival. PATIENTS AND METHODS: Patients who underwent resection for oligometastasis from HCC between January 2000 and April 2021 were retrospectively investigated. Oligometastasis was defined as 1-5 single organ metastases that were detected preoperatively in this study. Clinical characteristics and treatment outcomes were analyzed, and independent risk factors for poor prognosis were identified using cox proportional hazards model. RESULTS: A total of 33 patients were included in this study. Eleven oligometastases were located in the intraabdominal lymph node, 8 in the adrenal gland, 5 in the lung, 4 in the peritoneum, 3 in the pleura, and 1 each in the supraclavicular lymph node and abdominal wall. No re-operation or operative death occurred in this study. The median OS was 44.6 months (range=5.1-150.6 months), and the median survival after primary HCC diagnosis was 116.5 months (range=7.1-253.6 months). The median cumulative incidence of recurrent HCC was 7.2 months (range=0.3-94.7 months). The multivariate analysis showed that an alpha-fetoprotein level ≥20 ng/ml and multiple primary HCC tumors were independent poor prognostic factors. CONCLUSION: Clinical characteristics and treatment outcomes of patients who underwent resection for oligometastasis from HCC were demonstrated. A high alpha-fetoprotein level and multiple primary HCC tumors were independent poor prognostic factors. Surgical resection can be one of the treatment options for oligometastasis from HCC.

The efficacy and safety of pure laparoscopic liver resection for hepatocellular carcinoma in super-elderly patients over 80 years: A multicenter propensity analysis.

BACKGROUND: Very few reports have evaluated the safety of laparoscopic liver resection in super-elderly patients. We assessed the short-term outcomes of laparoscopic liver resection in patients with hepatocellular carcinoma aged ≥80 years, using propensity score matching. METHODS: We retrospectively analyzed the data of 287 patients (aged ≥80 years) who underwent liver resection for hepatocellular carcinoma at eight hospitals belonging to Hiroshima Surgical study group of Clinical Oncology, between January 2012 and December 2021. The perioperative outcomes were compared between laparoscopic and open liver resection, using propensity score matching. RESULTS: Of the 287 patients, 83 and 204 were included in the laparoscopic and open liver resection groups, respectively. Propensity score matching was performed, and 52 patients were included in each group. The operation (p = .68) and pringle maneuver (p = .11) time were not different between the groups. There were no significant differences in the incidences of bile leakage or organ failure. The laparoscopic liver resection group had significantly less intraoperative bleeding and a lower incidence of cardiopulmonary complications (both p < .01). CONCLUSIONS: Laparoscopic liver resection can be safely performed in elderly patients aged ≥80 years.

Preoperative percutaneous or transvascular marking for curative resection of small liver tumours with potential for missing during hepatectomy: a study protocol for an open-label, single-arm phase II study.

INTRODUCTION: Small liver tumours are difficult to identify during hepatectomy, which prevents curative tumour excision. Preoperative marking is a standard practice for small, deep-seated tumours in other solid organs; however, its effectiveness for liver tumours has not been validated. The objective of this study is to evaluate the effectiveness of preoperative markings for curative resection of small liver tumours. METHODS AND ANALYSIS: This is an open-label, single-arm, single-centre, phase II study. Patients with liver tumours of ≤15 mm requiring hepatectomy will be enrolled and will undergo preoperative marking by placing a microcoil near the tumour using either the percutaneous or transvascular approach. The tumours, including the indwelling markers, will be excised. The primary endpoint will be the successful resection rate of liver tumours, defined as achieving a surgical margin of ≥5 mm and ≤15 mm. Secondary endpoints will include the results of preoperative marking and hepatectomy. ETHICS AND DISSEMINATION: Ethical approval for this trial was obtained from the Ethical Committee for Clinical Research of Hiroshima University, Japan. The results will be published at an academic conference or by submitting a paper to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCTs062220088.

[Measurement of Average Glandular Dose Using Multiparameter X-ray Measuring Instrument].

The average glandular dose (AGD) is very important in the quality control of mammography. The AGD calculation requires measurements of half-value layer (HVL) and entrance surface air karma (ESAK). The HVL is measured by the Al-attenuation method using a non-energy-dependent ionization dosimeter. As the Al-attenuation method performs measurements using a succession of added filters, it requires lots of X-ray exposure and measurement time. In recent years, measuring instruments that can measure tube voltage, irradiation time, exposure dose, HVL, and other factors, at the same time, using one shot of X-rays have been developed. In this study, measurement of the AGD using multiparameter X-ray measuring instrument about rhodium (Rh) and tungsten (W) anode X-ray tubes. A comparative study was performed using standard ionization dosimeters. The error in measurements was as follows: HVL 5.8%, ESAK 3.3%, and AGD 2.9%. The AGD measurement using a multiparameter X-ray measuring instrument is simple and can significantly reduce the measurement time while maintaining accuracy.

Efficacy and safety of lenvatinib-transcatheter arterial chemoembolisation sequential therapy followed by surgical resection for intermediate-stage hepatocellular carcinoma beyond Up-to-7 criteria: a study protocol for a multicentre, single-arm, prospective study.

INTRODUCTION: The feasibility and efficacy of surgical resection following systemic therapy for intermediate-stage hepatocellular carcinoma (HCC) beyond the Up-to-7 criteria is unclear. The combination of lenvatinib (LEN) and transcatheter arterial chemoembolisation (TACE), termed LEN-TACE sequential therapy, has shown a high response rate and survival benefit in patients with intermediate-stage HCC. This trial aims to evaluate the efficacy and safety of LEN-TACE sequential therapy and the feasibility of surgical resection for intermediate-stage HCC beyond the Up-to-7 criteria. METHODS AND ANALYSIS: This is a multicentre, single-arm, prospective clinical trial. Thirty patients with intermediate-stage HCC beyond the Up-to-7 criteria will be enrolled. Patients eligible for this study will undergo LEN-TACE sequential therapy in which LEN is administered for 4 weeks, followed by TACE, and then further LEN for another 4 weeks. Patients will be assessed for efficacy of LEN-TACE sequential therapy and resectability, and surgical resection will be performed if the HCC is considered radically resectable. The primary outcome of this study is the resection rate after LEN-TACE sequential therapy. The secondary outcomes are the objective response rate of LEN-TACE sequential therapy, safety, curative resection rate, overall survival and recurrence-free survival. ETHICS AND DISSEMINATION: This trial was approved by the Institutional Review Board of Hiroshima University, Japan (approval no. CRB210003), and has been registered with the Japan Registry of Clinical Trials (jRCTs061220007). The results of this study will be submitted for publication in a peer-reviewed journal and shared with the scientific community at international conferences. TRIAL REGISTRATION NUMBER: jRCTs061220007 (https://jrct.niph.go.jp/latest-detail/jRCTs061220007).

Association of Hepatobiliary Phase of Gadoxetic-Acid-Enhanced MRI Imaging with Immune Microenvironment and Response to Atezolizumab Plus Bevacizumab Treatment.

It has been reported that high intensity in the hepatobiliary (HB) phase of Gd-EOB-DTPA-enhanced MRI (EOB-MRI) is associated with an immune-cold microenvironment in HCC. The aim of this study is to reveal whether non-high-intensity HCCs are homogeneous with respect to the immune microenvironment and to investigate the predictive ability of EOB-MRI for the response to atezolizumab + bevacizumab therapy (Atezo/Bev). The association between differences in stepwise signal intensity of HB phase and molecular subtypes and somatic mutations associated with the immune microenvironment was investigated in 65 HCC patients (cohort 1). The association between EOB-MRI and the therapeutic effect of Atezo/Bev was evaluated in the Atezo/Bev cohort (60 patients in cohort 2). The proportion of HCCs having CTNNB1 mutations and classified as Chiang CTNNB1 and Hoshida S3 was high in the high-intensity HB-phase group. Infiltration of tumor-associated macrophages (TAM) and regulatory T-lymphocytes (Treg) was characteristic of the high-intensity and low-intensity groups, respectively. Although EOB-MRI could not predict the response to Atezo/Bev treatment, our results demonstrate that EOB-MRI could serve as a surrogate marker predicting the immune microenvironment. This suggests that Atezo/Bev treatment can be selected regardless of signal intensity in the EOB-MRI HB phase.