The prediction of early progressive disease in patients with hepatocellular carcinoma receiving atezolizumab plus bevacizumab.

BACKGROUND AND AIMS: The IMbrave 150 trial revealed the usefulness of atezolizumab plus bevacizumab therapy in patients with unresectable hepatocellular carcinoma (HCC), making it now considered the first-line systemic chemotherapy agent for HCC. The present study investigated factors associated with early tumor progression of atezolizumab plus bevacizumab in patients with advanced HCC in real-world clinical practice. METHODS: A total of 184 HCC patients who received atezolizumab plus bevacizumab therapy were studied. We investigated the frequency of early progressive disease (e-PD; PD within 9 weeks) and analyzed the risk factors for e-PD. RESULTS: There were 47 patients (25.5%) diagnosed as e-PD. Patients with e-PD had a worse performance status (PS) and albumin-bilirubin (ALBI) and Child-Pugh (C-P) scores and a significantly higher rate of a systemic therapy than those with non-e-PD. A multivariate analysis showed that PS ≥1 (odds ratio [OR] = 4.5, 95% confidence interval [CI] = 1.9-10, p < 0.001), ALBI score ≥-2.30 (OR = 2.1, 95% CI = 1.0-4.5, p = 0.044) and the history of a systemic therapy (OR = 3.0, 95% CI = 1.4-6.4, p = 0.0038) were significant and independent determinants of e-PD. When examining the liver function trends in e-PD patients, the ALBI scores at 3 and 6 weeks after starting therapy were significantly higher than before the treatment (p < 0.001). CONCLUSIONS: The liver function and systemic therapy are useful predictors of e-PD in HCC patients treated with atezolizumab plus bevacizumab in real-world clinical practice.

Monitoring serum proangiogenic cytokines from hepatocellular carcinoma patients treated with sorafenib.

BACKGROUND AND AIM: Several factors, including proangiogenic cytokines, have been reported as predictive markers for the treatment effect of sorafenib in patients with hepatocellular carcinoma (HCC); however, most of them were determined based on one-time measurements before treatment. METHODS: We consecutively recruited 80 advanced HCC patients who were treated with sorafenib prospectively. Serum levels of eight proangiogenic cytokines and the appearance of adverse events were monitored periodically, and their correlations with the prognoses of the patients were evaluated. RESULTS: Among six significant risk factors for overall survival in univariate analyses, high angiopoietin-2 (hazard ratio, 2.06), high hepatocyte growth factor (hazard ratio, 2.08), and poor performance status before the treatment (hazard ratio, 2.48) were determined as independent risk factors. In addition, high angiopoietin-2 at the time of progressive disease was a marker of short post-progression survival (hazard ratio, 4.27). However, there was no significant variable that predicted short progression-free survival except the presence of hepatitis B virus surface antigen. CONCLUSIONS: Predictions of overall survival and post-progression survival were possible by periodically measuring serum proangiogenic cytokines, especially angiopoietin-2, in patients with HCC treated with sorafenib.

Nomograms to Predict the Disease-free Survival and Overall Survival after Radiofrequency Ablation for Hepatocellular Carcinoma.

Objective The purpose of this study was to construct nomograms for the disease-free survival (DFS) and overall survival (OS) of post-radiofrequency ablation (RFA) patients with hepatocellular carcinoma (HCC). Furthermore, we compared the prognostic predictive ability of these nomograms for estimating per-patient outcomes with that of traditional staging systems. Methods We retrospectively enrolled 298 patients in the training set and 272 patients in the validation set who underwent RFA for HCC. The nomograms for the DFS and OS were constructed from the training set using the multivariate Cox proportional hazards model. The discriminatory accuracy of the models was compared with traditional staging systems by analyzing the Harrell's C-index. Results The DFS nomogram was developed based on the tumor size, tumor number, aspartate aminotransferase (AST), albumin, age, and α-fetoprotein. The OS nomogram was developed based on the tumor size, the model for end-stage liver disease, AST, and albumin. Our DFS and OS nomograms had good calibration and discriminatory abilities in the training set, with C-indexes of 0.640 and 0.692, respectively, that were greater than those of traditional staging systems. The C-indexes of our DFS and OS nomograms were also greater than those of traditional staging systems in the validation set, with C-indexes of 0.614 and 0.657, respectively. RFA patients were stratified into low- and high-risk groups based on the median nomogram scores. High-risk patients receiving surgical resection (SR) were associated with a better DFS and OS than those undergoing RFA. However, the DFS and OS were similar between the low-risk RFA and SR groups. Conclusion We constructed reliable and useful nomograms that accurately predict the DFS and OS after RFA for early-stage HCC patients. These graphical tools are easy to use and will assist physicians during the therapeutic decision-making process.

Surgical Resection for Hepatocellular Carcinoma with Cardiac Cirrhosis after the Fontan Procedure.

A 29-year-old woman who underwent the Fontan procedure at 10 years of age had an incidental finding of liver masses on abdominal ultrasonography. Subsequent gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid magnetic resonance imaging showed a 15 mm hypervascular mass with washout in the hepatobiliary phase in liver segment 4 (S4), and an 18 mm hypervascular mass without washout in the hepatobiliary phase in liver segment 2 (S2). The S2 liver mass was pathologically diagnosed to be a regenerative nodule by an ultrasound-guided needle biopsy, and the S4 liver mass was pathologically diagnosed as a poorly differentiated hepatocellular carcinoma after partial hepatectomy.

Application of radiofrequency ablation for the treatment of metastatic liver cancers.

BACKGROUND/AIMS: The aim of this study is to elucidate the effectiveness of radiofrequency ablation (RFA) for the treatment of metastatic liver cancers. METHODOLOGY: From 74 patients with metastatic liver cancers treated by RFA, 40 patients including 23 colon cancer who had received curative resection of the primary tumor were analyzed. RESULTS: Recurrence of the tumor was observed in 29 (72.5%) patients. The most prevalent site of recurrence was the liver in both colon cancer (10/15, 66.7%) and non-colon cancer patients (12/14, 85.7%). Among the recurrence in the liver, the rate of intrahepatic distant recurrence (recurrence outside of the RFA-treated segment) was high in both colon cancer (55.6%) and non-colon cancer patients (69.0%). Local recurrence (recurrence at the RFA-treated segment) rate was low (32.6% and 32.9%, respectively) and none of single tumor less than 2 cm in diameter showed local recurrence. The intrahepatic recurrence was single in 67.6% of the patients and 59.1% of the patients were re-treated by RFA. CONCLUSIONS: RFA is a less-invasive method for the treatment of metastatic liver tumors and can be performed repetitively. Although the rate of intra-hepatic distant recurrence and extra-hepatic recurrence was high, good local control can be achieved by RFA.

A case of hepatocellular carcinoma with skin injury of the upper abdominal wall after transcatheter arterial chemoembolization: a case report.

INTRODUCTION: Transcatheter arterial chemoembolization has been widely used to treat advanced hepatocellular carcinoma that cannot be treated by local ablation therapies or surgical resection. The effectiveness of transcatheter arterial chemoembolization in prolonging survival has been well established, and approximately one third of newly discovered hepatocellular carcinoma patients were repeatedly treated by transcatheter arterial chemoembolization in Japan. Various kinds of complications have been reported, and many of which are general complications such as hepatic coma, jaundice, fever-up, ascites, and bile duct injury. The hepatic falciform artery is found frequently during postmortem anatomic dissection and the incidence of hepatic falciform artery is reported to be over 60%. Hepatic falciform artery is known to be the responsible artery for supraumbilical skin rash development after arterial chemo infusion therapy; however, skin complications after transcatheter arterial chemoembolization are rare. CASE PRESENTATION: A 70-year-old female with chronic hepatitis C infection was diagnosed as having hepatocellular carcinoma (S4, 20 mm in diameter). Transcatheter arterial chemoembolization was performed via the left hepatic artery, which was a feeding artery of the hepatocellular carcinoma. Two days after that, supraumbilical skin rash with local tenderness and redness appeared. Retrospective analysis revealed that occlusion of the hepatic falciform artery branching from the left hepatic artery with micromaterials caused the skin lesion. CONCLUSION: We should keep in mind that anticancer drugs or embolic materials can flow into the HFA and may cause abdominal wall injury after transcatheter arterial chemoembolization.

[Case of pseudoaneurysm ruptured into gallbladder and successfully treated with arterial embolization].

A 79-year-old man was admitted with hematemesis. Emergency upper gastrointestinal tract endoscopy revealed bleeding from the papilla of Vater. Computed tomography showed cholecystitis with a gallstone and a hematoma in the gallbladder. Angiography demonstrated a pseudoaneurysm of the anterior branch of the right hepatic artery. Emergency selective transcatheter arterial embolization (TAE) was performed, with intravascular microcoils, and complete occlusion of the pseudoaneurysm was achieved. This case shows embolization is effective in the treatment of pseudoaneurysm rupturing in the gallbladder.

Cost-effectiveness of the surveillance program of hepatocellular carcinoma depends on the medical circumstances.

BACKGROUND AND AIM: The clinical features of hepatocellular carcinoma (HCC) and the medical environment are diverse in different geographic areas. The aim of this study is to evaluate the cost-effectiveness of the surveillance of HCC in different medical circumstances. METHODS: The Markov model focused on variables that differ from country to country and may change in the future, especially in regards to the proportion of small HCC detected incidentally. The target population was 45-year-old patients with Child-Pugh class A cirrhosis, and the intervention was surveillance with ultrasonography every 6 months. RESULTS: The additional cost of the surveillance was $US15 100, the gain in quality-adjusted life years (QALYs) was 0.50 years, and the incremental cost-effectiveness ratio (ICER) was $US29 900/QALY in a base-case analysis (annual incidence of HCC = 4%). If 40% of small HCC were detected incidentally without surveillance, the gain in QALY decreased to 0.15 and the ICER increased to $US47 900/QALY. The increase in the annual incidence of HCC to 8% resulted in the increase of QALYs to 0.81, and the decrease of the ICER to $US25 400/QALY. The adoption of liver transplantation increased the gain in QALYs and the ICER to 0.84 and $US59 900/QALY, respectively. CONCLUSIONS: The gain in QALYs and the ICER due to the surveillance of HCC varies between different patient subgroups and it critically depends on the rate of small HCC detected incidentally without surveillance, as well as the annual incidence of HCC and the adoption of liver transplantation.

Prediction of the ablated area by the spread of microbubbles during radiofrequency ablation of hepatocellular carcinoma.

BACKGROUND/AIM: Radiofrequency ablation (RFA) is effective for the treatment of hepatocellular carcinoma (HCC). To prevent the ablation of adjacent organs and vessels, the spread of microbubbles generated by heating during RFA was observed by ultrasonography (US) and used to predict the ablated area; however, several reports documented that discrepancies existed between the spread of microbubbles and the ablated area. PATIENTS AND METHODS: The spread of microbubbles during RFA was observed by US in 24 patients with HCC and the areas were compared with the defect of enhancement in contrast enhanced (CE)-US, using Levovist in the same plane. RESULTS: During the ablation, the posterior margin was obscure but the border could be visualized 5 min after the ablation. The size of the area of hyperechogenicity 5 min after ablation and that of the defect observed by CE-US was found to correlate (r(2)=0.91, P<0.0001). The shape of the hyperechogenicity corresponded well to the defect area, even in cases showing irregular spread of the microbubbles. CONCLUSION: The observation of microbubbles during RFA can predict the ablated area and might be useful to prevent the unfavorable ablation of adjacent organs and vessels.

Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinoma.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) in humans is characterized by hypervascularity. In the present study, the expressions of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) and endostatin were analyzed in patients with chronic liver disease to clarify the effect of these major angiogenic factors. METHODS: Serum concentrations of VEGF, FGF-2 and endostatin in 24 patients with HCC, 16 patients with liver cirrhosis (LC) and 13 healthy volunteers were measured by enzyme-linked immunosorbent assay. The expression of VEGF in 21 surgically resected HCC samples was analyzed by immunohistochemistry, and that of VEGF isoforms in 15 HCC samples was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Serum VEGF, FGF-2 and endostatin concentrations were significantly elevated in patients with HCC compared with healthy volunteers; but there was no significant difference between patients with HCC and those with non-HCC liver disease. Immunohistochemical analysis showed that VEGF protein was strongly expressed in both well-differentiated HCC cells and non-cancerous hepatocytes, whereas in moderately and poorly differentiated HCC the expression was stronger in the endothelial cells (EC) lining intratumor vessels than in the cancer cells. On RT-PCR for VEGF isoforms it was found that VEGF-121, VEGF-165 and VEGF-189 were expressed in all but one of the HCC samples and in all corresponding non-HCC samples. CONCLUSIONS: The results suggest that VEGF, FGF-2, and endostatin concentrations are elevated prior to the emergence of HCC and that the distribution of VEGF changes dynamically during the development of HCC.

Regression of hepatocellular carcinoma during vitamin K administration.

An 85-year-old man with HCV infection and diabetes mellitus was diagnosed as having hepatocellular carcinoma (HCC, 13 cm in diameter) based on high serum alpha-fetoprotein (AFP), AFP-L3, and des-gamma-carboxy prothrombin levels as well as typical enhancement pattern on contrast-enhanced CT. The patient did not receive any interventional treatments because of advanced age and the advanced stage of HCC. He chose to take vitamin K, which was reported to suppress the growth of HCC in vitro. Three months after starting vitamin K, all three tumor markers were normalized and HCC was markedly regressed, showing no enhancement in the early arterial phase on CT. Here we present the report describing the regression of HCC during the administration of vitamin K.