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.

Fucosylated haptoglobin is a novel predictive marker of hepatocellular carcinoma after hepatitis C virus elimination in patients with advanced liver fibrosis.

BACKGROUND: Patients with advanced fibrosis are at risk for developing hepatocellular carcinoma (HCC) even after hepatitis C virus (HCV) elimination. We previously reported that serum fucosylated haptoglobin (Fuc-Hp) levels increase as the disease progresses from chronic hepatitis to cirrhosis and then HCC. However, it remains unclear whether serum Fuc-Hp levels can stratify the risk of HCC occurrence after a sustained virological response (SVR) is achieved with direct-acting antivirals (DAAs) in patients with advanced liver fibrosis. METHODS: Among 3,550 patients with chronic hepatitis C treated with DAAs at Osaka University Hospital and related hospitals, the stored sera of 140 patients who were diagnosed with F3 or F4 by liver biopsy before DAA treatment, achieved SVR, and had no history of HCC were available at both baseline and the end of treatment (EOT). We measured the Fuc-Hp levels in these samples. RESULTS: The median serum levels of Fuc-Hp at EOT were significantly lower than those at baseline. During the 54.4-month follow-up period, 16 of 140 patients developed HCC. Multivariate Cox proportional hazards analysis revealed that high Fuc-Hp at EOT, high body mass index (BMI), and low albumin at EOT were independent risk factors for HCC occurrence. Patients with all three factors-high Fuc-Hp, high BMI, and low albumin-had a higher incidence of HCC than patients without these factors. CONCLUSIONS: High serum Fuc-Hp levels at EOT were an independent risk factor for HCC occurrence after SVR. Combined with BMI and albumin, Fuc-Hp can stratify the risk of HCC occurrence among those with advanced fibrosis.

Prognostic impact of worsening of esophageal varices after balloon-occluded retrograde transvenous obliteration.

BACKGROUND AND AIM: Balloon-occluded retrograde transvenous obliteration (BRTO) is widely performed for treating gastric varices (GVs). However, worsening of esophageal varices (EVs) can be observed after BRTO. This study aimed to investigate the impact of EV worsening on prognosis after BRTO. METHODS: Overall, 258 patients who underwent initial BRTO for GV treatment between January 2004 and May 2019 at 12 institutions were retrospectively registered. RESULTS: Technical success was achieved in 235 patients (91.1%). Based on the exclusion criteria, 37 patients were excluded, and 198 were evaluated. The cumulative worsening rates of EVs at 1, 2, and 3 years were 39.0%, 59.4%, and 68.4%, respectively. In the univariate Cox proportional hazards model, sex, EV size, history of EV treatment, left gastric vein dilatation, platelet count, aspartate transaminase (AST), alanine aminotransferase (ALT), total bilirubin, albumin, albumin-bilirubin score, prothrombin time-international normalized ratio, fibrosis-4 index, AST to platelet ratio index, and spleen width were significantly associated with worsening of EV after BRTO. Multivariate analysis showed that sex (adjusted hazard ratio [aHR] 1.72; 95% confidence interval [CI] 1.03-2.86; P = 0.04), left gastric vein dilatation (aHR 1.90; 95% CI 1.17-3.10; P = 0.01), ALT (aHR 1.01; 95% CI 1.00-1.03; P = 0.02), albumin (aHR 0.61; 95% CI 0.43-0.87; P < 0.01), and spleen width (aHR 1.02; 95% CI 1.01-1.03; P < 0.01) were independent risk factors for worsening of EV after BRTO. Patients with EV worsening within 1 year after BRTO had a significantly worse prognosis than the other patients (P = 0.007). CONCLUSIONS: Early worsening of EV after BRTO was associated with poor prognosis after BRTO.

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.

Prognostic Factors for Patients With a Large Number of Hepatocellular Carcinoma Nodules.

BACKGROUND: The prognostic factors and treatment strategies for hepatocellular carcinoma (HCC) patients with a large number of tumor nodules have not been fully elucidated. Clinical factors influencing prognosis were investigated in HCC patients with 30 or more tumor nodules. METHODS: Forty-six HCC patients with 30 or more tumor nodules participated in this study. None of them had vascular invasion and extrahepatic metastasis. Kaplan-Meier curve and Cox proportional hazard model were used for analysis. RESULTS: The median survival time of our patients was no more than 15 months, suggesting that patients with 30 or more tumor nodules may be regarded as a progressive subgroup showing poorer prognosis. In multivariate analysis, presence of between 30 and 59 tumor nodules (P = 0.002), male gender (P = 0.002), lower total bilirubin (total bilirubin < 1.0 mg/dL) (P = 0.011), transarterial chemoembolization (TACE) as an initial therapy (P = 0.027) and higher prothrombin time (P = 0.049) were significant independent factors for better overall survival. Among 39 patients who underwent TACE as an initial therapy, patients who received sorafenib therapy during follow-up showed better overall survival than those who did not (P = 0.026). Efficacy of sorafenib appeared to be more evident in patients who needed repeated transarterial treatment. CONCLUSIONS: In HCC patients with 30 or more tumor nodules, TACE as an initial therapy may be correlated with better prognosis. Sorafenib administration after the prior transarterial treatment may improve antitumor efficacy.

Development of a thrombus in the superior mesenteric artery associated with sequential therapy with tyrosine kinase inhibitors for hepatocellular carcinoma.

Tyrosine kinase inhibitors (TKIs) are widely used for systemic chemotherapy of hepatocellular carcinoma (HCC). Arterial thromboembolism (ATE) has been reported to be an adverse event associated with TKI therapy, but its incidence is rare. Here, we report a case of an HCC patient who developed a thrombus in the superior mesenteric artery (SMA) while on TKI therapy. The patient was a 78-year-old Japanese man with hepatitis C virus-associated HCC with multiple nodules. Several sessions of transarterial chemoembolization therapy caused him to become refractory to the treatment. Sorafenib and regorafenib therapy had also been previously performed, but his disease continued to progress gradually. Therefore, we started lenvatinib therapy. When a contrast-enhanced computed tomography (CT) examination was performed 2 months later, we found a thrombus in the SMA. Retrospective analysis of the CT images revealed that the thrombus formed during the sorafenib-regorafenib sequential therapy and it developed rapidly, especially during the lenvatinib therapy. An HCC patient developed a thrombus in the SMA during TKI therapy. The incidence of ATE is rare in TKI treatment; however, long-term or sequential TKI therapy may increase the frequency of ATE. Further study is needed.

Chemotherapy-Induced Sclerosing Cholangitis Caused by Systemic Chemotherapy.

A 61-year-old woman diagnosed with cervical cancer received systemic chemotherapy using paclitaxel and bevacizumab. Marked elevation of liver enzyme levels was observed. Ultrasonography and computed tomography showed wall thickening of the extrahepatic and intrahepatic bile ducts accompanied by stricture and dilatation. According to these, she was diagnosed as chemotherapy-induced sclerosing cholangitis (CISC), a form of secondary sclerosing cholangitis. Although CISC triggered by systemic chemotherapy is rare, CISC should be considered as a clinically important adverse event of chemotherapy because it causes rapid deterioration of liver function and necessitates interruption of chemotherapy.

Two-step progression of varenicline-induced autoimmune hepatitis.

We describe a rare case of drug-induced hepatitis due to the smoking cessation agent varenicline in a 46-year-old Asian woman. The liver injury progressed in two steps. First, the liver injury started in the absence of viral/autoimmune responses, and withdrawal of varenicline lowered the increase in the levels of liver enzymes immediately. Such findings suggested varenicline-induced liver injury. Second, hepatitis recurred in association with conversion of antinuclear antibody from negative to positive about 8 weeks after the initial episode. Histology upon recurrence of liver injury revealed interface hepatitis with lymphocytic and lymphoplasmacytic portal inflammatory infiltrates extending into lobules. Such findings suggested autoimmune hepatitis. Corticosteroid treatment was effective for recurrent hepatitis. The clinical course suggests that varenicline caused drug-induced liver injury and subsequent autoimmune hepatitis. Some autoimmune changes were probably involved in the mechanism of varenicline-induced liver injury.

Prospective Comparison of Gd-EOB-DTPA-Enhanced MRI with Dynamic CT for Detecting Recurrence of HCC after Radiofrequency Ablation.

BACKGROUND: We prospectively compared the efficacy of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) with that of dynamic multidetector computed tomography (MDCT) for detection of recurrent hypervascular hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). METHODS: Institutional review board approval and written informed consent were obtained for this multicenter study. Ninety-seven HCC patients treated with curative RFA underwent both Gd-EOB-DTPA-enhanced MRI and dynamic MDCT every 3-4 months. HCC diagnosis was made based on the typical enhancement pattern of HCC on MRI and/or CT by on-site consensus reading. Two blinded observers independently assessed image datasets to compare diagnostic accuracy, sensitivity, specificity, and the areas under the receiver operating characteristic curve (AUROC). RESULTS: Recurrence was observed in 48 of 97 patients. Among these, 22 were diagnosed by both Gd-EOB-DTPA-enhanced MRI and MDCT; the remainder were diagnosed by only one of these 2 modalities. Recurrence was diagnosed in more patients by Gd-EOB-DTPA-enhanced MRI than by MDCT (44 vs. 26 patients, p < 0.001). Patient-based analysis revealed that the accuracy, sensitivity, and AUROC of Gd-EOB-DTPA-enhanced MRI were significantly higher than those of MDCT for both observers (p < 0.005). The AUROC of Gd-EOB-DTPA- enhanced MRI and MDCT was 0.95 and 0.76 for observer 1 and 0.90 and 0.74 for observer 2, respectively. The κ values for MRI and MDCT were 0.83 and 0.70, respectively. CONCLUSIONS: Compared with dynamic MDCT, Gd-EOB-DTPA-enhanced MRI had higher diagnostic accuracy and sensitivity for detection of recurrent hypervascular HCC and may be a better tool for following patients after RFA.

The Effectiveness of a Liver Disease Education Class for Providing Information to Patients and Their Families.

BACKGROUND: We have been conducting liver disease education classes regularly in our hospital for the purpose of providing health information to patients and their families. METHODS: In order to evaluate the effectiveness of these classes, we conducted a questionnaire survey of patients and family members who attended the classes held three times in 2012. The cumulative total number of participants was 80 (49 patients, 26 family members, and five others). The classes focused on the following areas: 1) prevention of hepatic cancer; 2) treatment of hepatic cancer; 3) iron restriction diet for hepatitis C patients; and 4) importance of branched-chain amino acid preparations. Self-evaluation of knowledge in these areas was based on a four-point scale. RESULTS: A comparison of knowledge levels between the patients and their family members revealed no statistically significant differences. Therefore, subsequent analyses were performed by combining the patients and their families into one group. The knowledge level of the participants increased with the number of class attendances; that is, the more often they attended, the more they accumulated knowledge (Kruskal-Wallis test: P < 0.0001; P = 0.0368; P = 0.0021; and P < 0.0001). In addition, the results of the questionnaire administered immediately before and after the education class showed significant improvement in the knowledge level for each area. CONCLUSION: The results of this study indicate the liver disease education class to be effective for improving the knowledge of patients and their families. The importance of repeated information provision was also demonstrated.

Subclassification of patients with intermediate-stage (Barcelona Clinic Liver Cancer stage-B) hepatocellular carcinoma using the up-to-seven criteria and serum tumor markers.

BACKGROUND: Intermediate-stage [Barcelona Clinic Liver Cancer stage-B (BCLC-B)] hepatocellular carcinoma (HCC) comprises of a heterogeneous population of patients with a wide range of tumor burdens. We therefore formulated a subclassification of BCLC-B HCC using the up-to-seven criteria and tumor markers according to the results of a retrospective analysis of these patients. METHODS: This study included 125 patients newly diagnosed with BCLC-B HCC who underwent transarterial chemoembolization. Among them, 39 and 86 were within or beyond the up-to-seven criteria, respectively. Multivariate Cox proportional hazards analysis was performed to investigate factors that contributed to better prognosis associated with the criteria. RESULTS: Cumulative overall survival (OS) and disease-free survival rates were significantly higher for patients within the up-to-seven criteria compared with those beyond (p = 0.034 and p = 0.001, respectively). Multivariate analysis revealed that low concentrations of des-γ-carboxy prothrombin (DCP) (<150 mAU/ml) and α-fetoprotein (AFP) (<100 ng/ml) were independent contributors to better OS of patients within or beyond the up-to-seven criteria, respectively. Accordingly, the patients were classified as follows: group A (patients within the up-to-seven criteria with DCP <150 mAU/ml), group C (patients beyond the up-to-seven criteria with AFP ≥100 ng/ml), and group B (other patients). OS differed significantly among groups (p < 0.001), and the median survival times of group A, B, and C were 4.2, 2.7, and 1.5 years, respectively. CONCLUSION: The subclassification system incorporating the up-to-seven criteria combined with DCP and AFP levels may serve as better predictors of prognosis that may guide efforts to improve treatment strategies.

Quick and stable parallel puncture of hepatic tumors using a double-barreled needle direction system for ultrasound-guided bipolar radiofrequency ablation.

AIM: In bipolar radiofrequency ablation (RFA) therapy, insertion of multiple needles at appropriate points on a target is difficult. The aim of our study was to evaluate a simplified method for multi-electrode insertion using a newly developed double-barreled needle guidance system for percutaneous RFA of hepatic tumors. METHODS: RFA using two bipolar electrodes was performed in 15 consecutive patients (nine men, six women; mean age, 72.0 ± 8.2 years) with a solitary small (≤3 cm) hepatic tumor. The first five nodules were treated using the conventional puncture method with the standard attachment, then 10 nodules were ablated using the parallel puncture method with the double-barreled attachment. The times required for double-needle placement and the shapes of the ablated areas were compared between the two puncture methods. RESULTS: The parallel puncture method required a shorter time for double-needle placement than the conventional method (12 s [range, 8-24] vs 96 s [range, 50-240]; P = 0.0003), and allowed continuous observation of the tip of all needles and the size of the ablated area as it increased until completion of the ablation. The method also provided a stable ellipsoidal ablated area. The median height, width and thickness were 30 mm (range, 22-34), 30 mm (range, 21-33) and 20 mm (range, 7-25), respectively, using 20-mm electrodes, and 34 mm (range, 32-41), 36 mm (range, 35-38) and 24 mm (range, 23-24), respectively, using 30-mm electrodes. CONCLUSION: The parallel puncture method may be a feasible procedure for multi-needle RFA therapy.

Factors related to shift from hepatic borderline lesion to overt HCC diagnosed by CT.

BACKGROUND/AIMS: Factors contributing to the shift from the hepatic borderline lesion to overt hepatocellular carcinoma (HCC) were investigated. METHODOLOGY: Ninety-five borderline nodules from 69 patients were followed-up for 6-55 (median 24) months. The borderline lesion was diagnosed when the CT image demonstrated low density in the portal phase and lacked enhancement in the arterial phase. RESULTS: The shift to overt HCC was seen in 32 nodules from 27 patients. Using multivariate analysis, only size was a significant factor contributing to the shift to overt HCC (p = 0.009). The cumulative incidence of the shift to overt HCC was higher in nodules of ≥13 mm in size than in those of < 13 mm (p = 0.034). Among nodules of ≥13 mm, nodules showing iso density in the arterial phase and low density in the portal phase had a higher cumulative incidence of the shift to overt HCC than those showing low density in the arterial and portal phases on CT (p=0.007). CONCLUSIONS: In hepatic borderline nodules diagnosed by CT, greater size, and iso density in the arterial phase and low density in the portal phase may be risk factors associated with the shift to overt HCC.

Three-dimensional registration of images obtained before and after radiofrequency ablation of hepatocellular carcinoma to assess treatment adequacy.

OBJECTIVE: The aim of our study was to evaluate the value of 3D registration images reconstructed by fusion of pre- and posttreatment CT or MRI for the assessment of ablative margins after percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: From January 2007 to May 2011, we performed RFA in 84 patients to treat 139 HCC nodules, the margins of which had been assessed by comparing pre- and postablation images side by side. The same nodules were retrospectively assessed again with 3D registration images after classification into four margin grades. We analyzed the cumulative local recurrence rate for each grade and reviewed the origin of recurrence. RESULTS: Three-dimensional registration images predicted local recurrences more accurately than did the conventional side-by-side method (area under the curve, 0.678 and 0.536, respectively; p = 0.0144). The cumulative rates of local recurrence were significantly different among the margin grades assessed with 3D registration images (p = 0.0088). Three-dimensional registration images detected that the major origins of recurrence (n = 22) were residuals (n = 13) and sites of no margin (n = 6), especially proximate to blood vessels more than 3 mm in diameter. CONCLUSION: Three-dimensional registration of pre- and postablation CT or MRI more accurately assesses the ablative margin than the conventional method. It can predict a proclivity for local recurrence after RFA according to margin grade. It also indicated that residuals and sites of no margin proximate to blood vessels that are more than 3 mm in diameter are high-risk locations for local recurrence after ablation.

Computed tomography during hepatic arteriography pattern may predict hepatocellular carcinoma recurrence following transarterial chemoembolization.

AIM: This study aimed to determine the role of morphological patterns seen on imaging in predicting hepatocellular carcinoma recurrence following transarterial chemoembolization therapy. METHODS: Forty-seven patients from a single center who underwent transarterial chemoembolization to treat unresectable hepatocellular carcinomas between January 2011 and June 2012 were included in this study. We investigated whether the two pretreatment findings on computed tomography during hepatic arteriography (pattern 1, the single nodule pattern; pattern 2, at least one nodule showing the contiguous multinodular pattern) and other factors (age, sex, etiology, serum total bilirubin, serum albumin, prothrombin time, platelet count, serum level of protein induced by vitamin K absence/antagonist-II, serum α-fetoprotein, number of previous treatments for hepatocellular carcinoma, tumor number and maximum tumor size, presence of hypovascular lesions) could predict post-treatment recurrence. RESULTS: In a univariate analysis using Cox's proportional hazards model, serum total bilirubin, the serum level of protein induced by vitamin K absence/antagonist-II (≤100 vs ≥101 mAU/mL), tumor morphology (pattern 1 vs 2) and tumor number (≤3 vs ≥4) showed statistical significance (≤0.05). In a multivariate analysis of these factors, morphology and tumor number showed significance. According to Kaplan-Meier estimation, the cumulative disease-free survival rates were significantly lower in patients with four or more lesions than in those with three or less lesions and in patients showing pattern 2 than in those showing pattern 1. CONCLUSION: Patients with pattern 2 hepatocellular carcinoma and/or four or more lesions may have a relatively high recurrence rate after transarterial chemoembolization.

Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection.

BACKGROUND: Altered functions of dendritic cells (DCs) and/or increases of regulatory T cells (Tregs) are involved in the pathogenesis of chronic hepatitis C virus (HCV) infection. A tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO), is reported to be an inducer of immune tolerance. Our aim was to clarify whether or not IDO is activated in chronic hepatitis C patients and its role in immune responses. METHODS: This study enrolled 176 patients with chronic HCV infection and 37 healthy volunteers. Serum kynurenine concentration was evaluated by high-performance liquid chromatography, and its correlation with clinical parameters was examined. Monocyte-derived DCs were prepared from the subjects and subsequently stimulated with a combination of lipopolysaccharide and interferon-gamma to induce functional IDO (defined as IDO-DCs). The phenotypes, kynurenine or cytokine production, and T-cell responses with IDO-DCs were compared between the patients and healthy volunteers. RESULTS: The serum kynurenine level in the patients was significantly higher than that in the healthy volunteers, and the level of serum kynurenine was positively correlated with the histological activity or fibrosis score. IDO activity in IDO-DCs from the patients was significantly higher than that in IDO-DCs from the volunteers. Furthermore, IDO-DCs from the patients induced more Tregs in vitro compared with those from the volunteers, and the frequency of induced Tregs by IDO-DCs was decreased with an IDO-specific inhibitor. CONCLUSIONS: Systemic IDO activity is enhanced in chronic hepatitis C patients in correlation with the degree of liver inflammation and fibrosis. In response to inflammatory stimuli, DCs from the patients tend to induce Tregs, with some of this action being dependent on IDO.

TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis.

UNLABELLED: Angiogenesis is a critical step in the development and progression of hepatocellular carcinoma (HCC). Myeloid lineage cells, such as macrophages and monocytes, have been reported to regulate angiogenesis in mouse tumor models. TIE2, a receptor of angiopoietins, conveys pro-angiogenic signals and identifies a monocyte/macrophage subset with pro-angiogenic activity. Here, we analyzed the occurrence and kinetics of TIE2-expressing monocytes/macrophages (TEMs) in HCC patients. This study enrolled 168 HCV-infected patients including 89 with HCC. We examined the frequency of TEMs, as defined as CD14+CD16+TIE2+ cells, in the peripheral blood and liver. The localization of TEMs in the liver was determined by immunofluorescence staining. Micro-vessel density in the liver was measured by counting CD34+ vascular structures. We found that the frequency of circulating TEMs was significantly higher in HCC than non-HCC patients, while being higher in the liver than in the blood. In patients who underwent local radio-ablation or resection of HCC, the frequency of TEMs dynamically changed in the blood in parallel with HCC recurrence. Most TEMs were identified in the perivascular areas of tumor tissue. A significant positive correlation was observed between micro-vessel density in HCC and frequency of TEMs in the blood or tumors, suggesting that TEMs are involved in HCC angiogenesis. Receiver operating characteristic analyses revealed the superiority of TEM frequency to AFP, PIVKA-II and ANG-2 serum levels as diagnostic marker for HCC. CONCLUSION: TEMs increase in patients with HCC and their frequency changes with the therapeutic response or recurrence. We thus suggest that TEM frequency can be used as a diagnostic marker for HCC, potentially reflecting angiogenesis in the liver.