Assessment of Macrovascular Invasion in Advanced Hepatocellular Carcinoma: Clinical Implications and Treatment Outcomes with Systemic Therapy

Introduction: Macrovascular invasion (MVI) is a strong prognostic factor for advanced hepatocellular carcinoma (HCC). The current criteria for radiological assessment are unclear in evaluating the impact of MVI on systemic therapy. In this study, we standardized the assessment of MVI and validated its clinical relevance. Methods: Clinical data were collected from patients with advanced HCC and MVI who received first-line systemic therapy at four medical centers in Japan. First, we used macrovascular invasion progression disease (MVI-PD) to track MVI progression, and Response Evaluation Criteria in Solid Tumours version 1.1 progression disease (RECIST v1.1-PD) to evaluate tumor enlargement other than MVI and the appearance of new lesions. Next, we assessed the prognostic value of MVI-PD and RECIST v1.1-PD. Results: Of the 207 advanced HCC patients with MVI, 189 received appropriate imaging evaluation. 40 (21.2%) patients had MVI-PD and RECIST v1.1-PD, 51 (27.0%) had prior MVI-PD, and 61 (32.3%) had prior RECIST v1.1-PD. In a landmark analysis, the prognosis of 163 patients who survived more than three months was analyzed based on the assessment of imaging response during the first three months. The median overall survival (OS) was 5.4 months in those who had MVI-PD and RECIST v1.1-PD, 7.4 months in those who had RECIST v1.1-PD only, 7.2 months in those who had MVI-PD only, and 19.7 months in patients who had neither (p<0.001). The correlation coefficients between progression-free survival and OS in patients with appropriate imaging assessments were similar for MVI-PD (0.515) and RECIST v1.1-PD (0.498). Conclusion: Our findings demonstrate the link between MVI progression and poor OS in systemic therapy for advanced HCC, emphasizing the importance of an accurate method for assessing MVI progression

Fatal Diaphragmatic Hernia following Radiofrequency Ablation for Hepatocellular Carcinoma: A Case Report and Literature Review

An 81-year-old man was admitted to our hospital because of right quadrant abdominal pain. On admission, his liver function was Child-Pugh grade C (10 points). Computed tomography (CT) revealed a diaphragmatic herniation of bowel loops into the right thoracic cavity, accompanied by pleural effusion. Although diaphragmatic hernia was successfully repaired by emergency surgery, he died of liver failure 23 days after the surgery. A retrospective reading of CT images revealed the presence of diaphragmatic injury after radiofrequency ablation (RFA) which had been conducted 33 months before the development of diaphragmatic hernia. Of importance, the lesion of the diaphragmatic injury was located on the estimated needle track of RFA for hepatocellular carcinomas in segment 5 and segment 5/8, but not adjacent to their ablation areas. Subsequently, diaphragmatic perforation had been observed 24 months before admission. This suggests that diaphragmatic hernia caused by RFA is not necessarily due to thermal damage of ablation and is possibly life-threatening, at least in some patients with an impaired liver function

Successful Interventional Treatment for Arterioportal Fistula Caused by Radiofrequency Ablation for Hepatocellular Carcinoma

Radiofrequency ablation (RFA) is commonly used as a treatment for small hepatocellular carcinoma (HCC). Although several complications such as intraperitoneal bleeding are often observed after RFA, hepatic arterioportal fistula (APF) is a less frequently occurring complication. In this study, we describe two cases of APF caused by RFA, which was successfully occluded by an interventional approach. Case 1 involved a 68-year-old man with solitary HCC in segment VIII of the liver. Both contrast-enhanced computed tomography and color Doppler sonography indicated an APF between the anterosuperior branch of the right hepatic artery (A8) and the portal branch (P8). Concordant with these findings, digital subtraction angiography (DSA) revealed an APF in segment VIII of the liver. Subsequently, the APF was successfully occluded by transarterial embolization (TAE) using gelatin sponge particles. Case 2 involved a 67-year-old man with solitary HCC in segment VII of the liver. Although he developed obstructive jaundice because of hemobilia after RFA, it was improved by endoscopic nasobiliary drainage and the systemic administration of antibiotics. In addition, color Doppler sonography revealed a disturbed flow of the right branch of the portal vein. Similar to case 1, DSA showed an APF between A8 and P8. The APF was successfully embolized by TAE using microcoils. In conclusion, it appears that the formation of APF should be checked after RFA. It is preferable to treat RFA-induced APF promptly by an interventional approach to avoid secondary complications such as portal hypertension and liver dysfunction

Acute Liver Failure Occurring during the First Trimester of Pregnancy Successfully Treated with Living Donor Liver Transplantation

Acute liver failure (ALF) during pregnancy remains difficult to treat, and despite advances in treatment, liver transplantation must be selected as treatment option in certain cases. We report a 30-year-old woman with ALF of unknown etiology, occurring during the first trimester of pregnancy. Her condition was complicated by consciousness disturbance and coagulopathy due to ALF, but she was successfully treated with living donor liver transplantation 7 days after dilatation and curettage. At 9-month followup, she was in good medical condition. Liver transplantation has been reported as one of the treatment options for ALF during pregnancy with the prognosis varying depending on the trimester, from living donor or deceased donor liver transplantation. Of importance is that clinicians always think of emergent liver transplantation as a therapeutic option in ALF even in the first trimester of pregnancy

Phase Ib trial of durvalumab plus tremelimumab in combination with particle radiotherapy in advanced hepatocellular carcinoma patients with macrovascular invasion: DEPARTURE trial

Background: Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all HCC cases, due to its uniqueness of disease condition. Development of revolutionary therapeutic approaches to improve prognosis in these patients is an essential medical issue. A phase I/II trial demonstrated that treatment with durvalumab, an anti-programmed death-ligand 1 antibody, alone or in combination with tremelimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody, exhibited potential efficacy in patients with advanced HCC. Conversely, particle radiotherapy, including carbon-ion radiotherapy, has been shown to achieve unique dose distribution by delivering high-dose radiation to the target tumor while reducing the radiation dose to normal tissues due to its physical characteristics. Studies demonstrated that particle radiotherapy could achieve good local control in patients with HCC, including those with MVI. Additionally, particle radiotherapy as well as photon irradiation not only mediate localized tumor killing but also modify the tumor microenvironment, thereby potentiating the efficacy of immune checkpoint inhibitors. The DEPARTURE trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle radiotherapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI.Methods: This is a phase Ib, multi-center, open-label, single-arm, investigator-initiated clinical trial to assess the safety of durvalumab monotherapy in combination with particle radiotherapy (Cohort A) and that of durvalumab plus tremelimumab in combination with particle radiotherapy (Cohort B) in advanced HCC patients with MVI who are ineligible for standard systemic therapy and Child–Pugh A liver disease. Cohort A will receive 1500 mg durvalumab every four weeks in principle. Cohort B will receive 1500 mg durvalumab every four weeks in principle and 300 mg tremelimumab only on day 1 of the first cycle. Carbon-ion radiotherapy will be administered after day 8 of the first cycle, following the first dose of either durvalumab or durvalumab plus tremelimumab on day 1. Dose prescription and fractionations are 60 Gy (RBE) in four fractions/1 week. Intrahepatic nodule with MVI is the target lesion for carbon-ion radiotherapy. Primary study endpoints are rates of all and severe adverse events including DLTs. Secondary endpoints include rates of overall survival, 6-month survival, objective response, and 6-month progression-free survival as well as time to progression

Potential of circulating receptor-interacting protein kinase 3 levels as a marker of acute liver injury

Abstract The pathogenesis of acute liver failure (ALF) involves cell death. Necroptosis is a newly suggested programmed cell death, and receptor-interacting protein kinase 3 (RIPK3) has been reported as a marker for necroptosis. However, there are few reports on necroptosis in ALF. Therefore, we evaluated the role of cell death markers such as cytokeratin (CK) 18, cleaved CK (cCK) 18, and RIPK3 in ALF, as well as cytokines and hepatocyte growth factor (HGF). Seventy-one hospitalized patients with acute liver injury (38 nonsevere hepatitis [non-SH]/22 severe hepatitis [SH]/11 ALF) were studied. No significant difference was found for cytokines, but a substantial increase in HGF levels was found following the severity of hepatitis. The non-SH group had lower levels of CK18 and cCK18 than the SH/ALF group. RIPK3 was significantly lower in the non-SH/SH group than in the ALF group. HGF, RIPK3, and albumin levels were found to be important predictive variables. The present study suggests that cCK18, CK18, and RIPK3 are associated with the severity of hepatitis. RIPK3 and other markers related cell death may be useful for understanding the pathogenesis of ALF and as a prognostic marker of acute liver injury