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In this study, we investigated the impact of simple measurement of psoas muscle index (PMI) on the tolerability of sorafenib treatment of switch from sorafenib to regorafenib.This retrospective study enrolled 109 patients with Child-Pugh A hepatocellular carcinoma (HCC) treated with sorafenib. Pretreatment PMI was calculated by measuring and multiplying the greatest anterior/posterior and transverse diameters of the psoas muscles on axial computed tomography images at the L3 vertebral level, and normalizing the sum of bilateral psoas muscle areas by the square of the height in meters. We, then, statistically analyzed the association between PMI and adverse events (AEs) to treatment, tolerability of sorafenib, time to treatment failure (TTF), and prognosis in patients stratified according to PMI.Patients were divided into high PMI (n = 41) and low PMI (n = 68) groups based on the cutoff PMI values (men: 7.04 cm2/m2; women: 4.40 cm2/m2) determined by receiver operating characteristic curve analysis to determine sorafenib tolerability. Frequencies of all types of severe AEs were higher in the low PMI group (50.0%) than in the high PMI group (29.3%; P = 0.045). The high PMI group (51.2%) had greater tolerance to sorafenib than the low PMI group (25.0%; P = 0.007). Moreover, in multivariable analysis, PMI was associated with sorafenib tolerability (odds ratio 0.26; P = 0.008) and was a prognostic factor affecting TTF (hazard ratio 1.77; P = 0.021).PMI might be a predictive marker of tolerance to treatment and TTF in HCC patients receiving sorafenib treatment.

Background In clinical practice, many hepatocellular carcinoma (HCC) patients in Barcelona Clinical Liver Cancer (BCLC) stage A4–B1 cannot receive the curative treatments of liver transplantation, resection, and radiofrequency ablation (RFA), which are the recommended options according to liver cancer guidelines. Our aim is to study the feasibility of RFA and stereotactic body radiotherapy (SBRT) as a curative treatment for different multifocal HCCs in BCLC stage A4–B1 patients. Methods From September 2014 to August 2019, 39 multifocal HCC lesions (median diameter: 16.6 mm) from 15 patients (median age: 73 years) were retrospectively selected. Among them, 23 were treated by RFA and the other 16 by SBRT because of predictable insufficiency and/or risk related to RFA performance. The indicators for evaluating this novel therapy were the tumor response, prognosis (recurrence and survival), and adverse effects (deterioration of laboratory test values and severe complications). Results The median follow-up duration was 31.3 months (range: 15.1–71.9 months). The total patients with a one-year complete response, stable disease, or disease progression were 11, 1, and 3, respectively. In total, 8 and 2 patients had confronted intrahepatic or local recurrence, respectively. The one-year progression-free survival rate and local control rate were 80% (12/15 patients) and 97.4% (38/39 lesions), respectively. The median time to progression was 20.1 (2.8–45.1) months. The one- and two-year survival rates were 100 and 88.9%, respectively. In up to five months’ observation, no patient showed severe complications. Seven, four, and two patients had slight changes in their white blood cells, platelet count, or albumin–bilirubin grade, respectively. Conclusions For patients with BCLC stage A4–B1, RFA and SBRT treatment for different multifocal HCCs may be a potential option because of the favorable prognosis and safety. However, before its application in clinical practice, prospective, controlled, large-scale studies are needed to further confirm our conclusions.

Background & Aims Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3–5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. Methods This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7–B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Results Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5–25%) with 6 patients responding; disease control rate was 55% (95% CI 40–69%). Median time to response was 2.7 months (interquartile range, 1.4–4.2), and median duration of response was 9.9 months (95% CI 9.7–9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. Conclusions Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. Lay summary In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. Clinical trial number NCT01658878 .

We evaluated the efficacy of fusion imaging combining contrast-enhanced ultrasonography (CEUS) images and arterial phase contrast-enhanced CT (CECT) or hepatobiliary phase magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (EOB-MRI) images for the early evaluation of the effectiveness of radiofrequency ablation (RFA) for small hypervascular hepatocellular carcinoma (HCC) with iso-echoic or unclear margins on conventional US. Forty HCCs (22 iso-echoic and 18 unclear margin lesions) with mean diameters of 13.7 mm were treated using RFA under the guidance of fusion imaging with CEUS. The adequacy of RFA was evaluated using fusion imaging with CEUS 1 day after RFA. CECT or EOB-MRI was performed 1 month after RFA. We reviewed the images obtained using both modalities. When the 1-month CECT or EOB-MRI scans were used as the reference standard, the sensitivity, specificity, and accuracy of the 1-day fusion imaging for the diagnosis of the adequate ablation of these HCCs were 97, 100, and 98%, respectively; the kappa value for the agreement between the findings using the two modalities was 0.655. Fusion imaging with CEUS appears to be a useful method for the early evaluation of the efficacy of RFA for the treatment of HCCs with iso-echoic or unclear margins on conventional US.

Purpose This study evaluated the usefulness of intraprocedural contrast-enhanced ultrasound (CEUS)/ultrasound (US) fusion imaging using a perflubutane-based contrast agent combined with preprocedural auto sweep three-dimensional US to obtain volume data for guidance and evaluation of the therapeutic efficacy of radiofrequency ablation (RFA). Methods This uncontrolled clinical trial included 50 hepatocellular carcinomas (HCCs) with a mean diameter of 15.3 mm that had been treated by RFA. The efficacy of RFA was evaluated by CEUS/US fusion imaging during the procedure. If the ablation was deemed to be inadequate, further ablation was performed until adequate ablation was achieved. Contrast-enhanced computed tomography (CECT) or contrast-enhanced magnetic resonance imaging (CEMRI) was performed a month after RFA, and the images obtained using each modality were reviewed to evaluate the efficacy of RFA. Results Thirty-three of the 50 lesions were evaluated by CEUS/US fusion imaging as having been adequately ablated after the first RFA procedure. The ablation was evaluated as inadequate in the remaining 17 lesions, for which additional ablation was performed. Ninety-eight (49/50) of all HCCs were evaluated as having been eventually adequately ablated on intraprocedural CEUS/US fusion imaging. The concordance rate for evaluations between intraprocedural CEUS/US fusion imaging and CECT/CEMRI performed 1 month after RFA was 88% (44/50). The kappa value for agreement between the two methods of evaluation was 0.792. Conclusion Intraprocedural fusion imaging combining CEUS and auto sweep three-dimensional US appears to be a useful modality for RFA guidance and evaluation of therapeutic efficacy of RFA in patients with HCC.

Background A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79–1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported. Methods The intent-to-treat population enrolled in Japan was analyzed. Results Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62–1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm. Conclusions The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC. Trial registration ID ClinicalTrials.gov. No. NCT01761266.

Background & Aims Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040. Methods CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018. Results There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations. Conclusion Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients. Lay summary The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878.

Potentially curative treatments for early-stage hepatocellular carcinoma (HCC) have drawbacks and contraindications. Recently, radiotherapy has achieved good outcomes. We compared the outcomes of radiotherapy and radiofrequency ablation (RFA) for early-stage HCC. Consecutive patients with ≤3 early-stage HCC lesions and tumor diameters ≤3 cm treated with RFA or radiotherapy were reviewed. RFA was the first choice for HCC unsuitable for surgery. Otherwise, stereotactic body radiotherapy in five fractions was mainly performed. For HCC adjacent to the gastrointestinal tract, radiotherapy with mild hypofractionation was performed. Propensity score matching was performed to reduce the selection bias between the RFA and radiotherapy groups. Between 2012 and 2016, a total of 231 patients with 474 tumors and 143 patients with 221 tumors were eligible and were treated with RFA and radiotherapy, respectively. In an unmatched comparison, the 3-year local recurrence rate was significantly lower for radiotherapy than for RFA (5.3%; 95% confidence interval [CI], 2.7-9.2; versus 12.9%, 95% CI, 9.9-16.2) (P < 0.01). A propensity score matching analysis of 106 patients in each group successfully matched the two treatment groups with regard to Barcelona Clinic Liver Cancer staging, T stage, and tumor size but not the adjacency of the tumor to risk organs or first or salvage treatment. The 3-year overall survival rates for RFA and radiotherapy patients were comparable (69.1%; 95% CI, 58.2-77.7; and 70.4%; 95% CI, 58.5-79.4, respectively; P = 0.86). Conclusion: Radiotherapy has excellent local control and comparable overall survival in patients with well-compensated liver function, exhibiting advantageous characteristics and compensating for the deficiencies of other treatment modalities; radiotherapy appears to be an acceptable alternative treatment option for patients who are not candidates for RFA.

A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFORINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.

Aim To evaluate the safety and efficacy of the administration of radiofrequency ablation (RFA) and stereotactic body radiotherapy (SBRT) in the short term to the same patients in Barcelona Clinical Liver Cancer (BCLC) stages 0–B1. Methods From April 2014 to June 2019, we retrospectively reviewed BCLC stage 0–B1 patients with fresh hepatocellular carcinoma (HCC) lesions that were repeatedly treated by RFA (control group, n = 72), and by RFA and subsequent SBRT (case group, n = 26). Propensity score matching (PSM) was performed to reduce the selection bias between two groups. Recurrence, survival, Child–Pugh scores and short-term side effects (fever, bleeding, skin change, abdominal pain and fatigue) were recorded and analyzed. Results After PSM, 21 patients remained in each group. Seventeen and 20 patients in the case and control groups experienced recurrence. For these patients, the median times to progression and follow-up were 10.7 and 35.8 months, respectively. After PSM, the 1-year progression-free survival rate in case and control groups were 66.7% and 52.4%, respectively (P = 0.313). The inter-group overall survival (OS) was comparable (3 and 5-year OS rates in case groups were 87.3% and 74.8%, while rates in control groups were 73.7% and 46.3%, respectively; P = 0.090). The short-term side effects were mild, and the incidence showed no inter-group difference. The 1-year rates of the Child–Pugh score deterioration of ≥2 in case and control groups were 23.8% and 33.3% (P > 0.05), respectively. Conclusion The short-term administration of RFA and SBRT to the same BCLC stage 0–B1 patients may be feasible and effective because of their good prognosis and safety.

By analyzing possible factors contributing to imaging misevaluation of arterial phase (AP) vascularity, we aimed to provide a more proper way to detect AP hypervascularity of hepatocellular carcinomas (HCCs) using the noninvasive imaging modalities magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS).We retrospectively recruited 164 pathologically confirmed HCC lesions from 128 patients. Using CEUS with Sonazoid (SCEUS) and gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid MRI (EOB-MRI), AP vascularity of the lesions was evaluated and inconsistencies in interpretation were examined. Indicators of margin, echogenicity, and halo and mosaic signs of lesions on grayscale US; depth of lesions on SCEUS; and tumoral homogeneity, signal contrast ratio of lesions to the surrounding area on precontrast and AP images on EOB-MRI, and histological grade were investigated.When precontrast images were used to adjust the AP enhancement ratio, the proportion of inconsistent interpretations of AP vascularity declined from 26.2% (43/164; 29 non-hypervascularity instances using EOB-MRI and 14 using SCEUS) to 16.5% (27/164; 7 using EOB-MRI and 20 using SCEUS). Greater lesion depth (P = 0.017), ill-defined tumoral margin (P = 0.028), absence of halo sign (P = 0.034), and histologically early HCC (P = 0.007) on SCEUS, and small size (P = 0.012) and heterogeneity (P = 0.013) of lesions and slight enhancement (low AP enhancement ratio) (P = 0.018 and 0.009 before and after adjustment) on EOB-MRI, may relate to undetectable hypervascularity.SCEUS and EOB-MRI may show discrepancies in evaluating AP vascularity in the case of deep, ill-defined, heterogeneous, slightly enhanced lesions, and histologically early HCCs. We recommend adjusting AP with precontrast images in EOB-MRI, and combining both modalities to detect hypervascularity.

We investigated whether or not nitric oxide synthase 3 (NOS3) rs2070744 genotypes can affect the response for lenvatinib treatment in patients with hepatocellular carcinoma (HCC). We evaluated the relation of the NOS3 rs2070744 genotypes to the tumor response, progression-free survival (PFS), and overall survival (OS) as the response for lenvatinib. We also examined the association between fibroblast growth factor receptor (FGFR) gene polymorphisms, a potential feature of lenvatinib, and the response. There were no significant differences between the studies for either PFS or OS, even though patients with the TT genotype had a longer mean PFS (hazard ratio [HR] 0.60; p = 0.069) and mean OS (HR 0.46; p = 0.075) than those with the TC/CC genotypes. However, patients with a single-nucleotide polymorphism (SNP) combination pattern of the NOS3 rs2070744 TC/CC and FGFR4 rs351855 CT/TT genotypes had a significantly shorter mean PFS (HR 2.56; p = 0.006) and mean OS (HR 3.36; p = 0.013) than those with the other genotypes. The NOS3 rs2070744 genotypes did not influence the clinical response. However, the SNP combination pattern of the NOS3 rs2070744 and FGFR4 rs351855 genotypes may be helpful as treatment effect predictors and prognostic factors for HCC patients treated with lenvatinib.

Background To evaluate the efficacy and safety of cabozantinib in Japanese patients with advanced hepatocellular carcinoma (HCC) who had progressed following one or two lines of systemic therapy including sorafenib. An exploratory evaluation in sorafenib-naïve patients was performed. Methods In this open-label, single-arm, phase 2 trial, patients received oral cabozantinib 60 mg once daily. The primary endpoint was progression-free survival (PFS) rate at Week 24. Secondary endpoints included PFS, overall survival (OS), objective response rate (ORR, best response of complete/partial response), disease control rate (DCR, objective response or stable disease) and safety. Results Thirty-four patients received cabozantinib across 17 centers (prior sorafenib cohort, n = 20; sorafenib-naïve cohort, n = 14). PFS rate at 24 weeks was 59.8% [90% confidence interval (CI) 36.1–77.2%] in the prior sorafenib cohort, 16.7% (90% CI 4.0–36.8%) in the sorafenib-naïve cohort and 40.1% (90% CI 24.8–55.0%) overall. Median PFS was 7.4 months for the prior sorafenib cohort, 3.6 months for the sorafenib-naïve cohort, and 5.6 months overall. OS rate at 6 months was 100.0%, 78.6% and 91.1%, respectively; DCR was 85.0%, 64.3% and 76.5%, respectively. The ORR was 0.0% for both cohorts. All patients required dose modifications due to adverse events, the most common of these were palmar–plantar erythrodysesthesia syndrome and diarrhea. Three patients (8.8%) discontinued due to adverse events other than disease progression. Conclusions Cabozantinib 60 mg/day has a favorable benefit/risk profile for Japanese patients with advanced HCC who have previously received one or two lines of systemic anticancer therapy including sorafenib. (Clinical trial registration: NCT03586973)

Ultrasound (US) is a cost-effective and noninvasive procedure without radiation exposure, with real-time evaluation and high spatial resolution. Although it is useful for the detection of gallbladder (GB) polyps, including gallbladder cancer, adenoma, and benign polyps, conventional US is insufficient for differential diagnosis because it is not capable of evaluating hemodynamic information, unlike computed tomography or magnetic resonance imaging. With recent technological advances in US equipment and contrast agents, Doppler imaging and contrast-enhanced ultrasonography (CEUS) are being used to characterize GB polyps, and several reports on evaluation of the vascularity of GB polyp have been published. In this review, we aimed to report the latest developments in the hemodynamic diagnosis of GB polyps based on previous reports, with an emphasis on CEUS, and to evaluate the efficacy for differential diagnosis. The information in this article is expected to enable early diagnosis and prompt surgical treatment for gallbladder cancer.

Summary Background Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding Merck & Co, Inc.

Summary Background Unresectable advanced hepatocellular carcinoma is a heterogeneous disease, for which sorafenib is the first targeted agent approved for first-line therapy, and treatment options for patients with sorafenib-refractory advanced hepatocellular carcinoma are limited. We assessed the efficacy and safety of S-1, a chemotherapeutic agent based on fluorouracil, in patients with sorafenib-refractory advanced hepatocellular carcinoma. Methods We did a randomised, double-blind, placebo-controlled, phase 3 study done at 57 sites in Japan. Patients with advanced hepatocellular carcinoma who were ineligible for surgical or local-regional therapy and judged refractory to sorafenib (ie, had progressed on sorafenib or had discontinued sorafenib because of adverse events) were randomly assigned (2:1) to receive oral S-1 (weight-banded 80 mg/m 2 [80–120 mg per day]), or placebo, twice per day for 28 days consecutively, followed by a minimum 14 day drug-free period. This cycle was repeated until disease progression or the patient became intolerant to the study treatment. Patients were stratified by site and presence or absence of extrahepatic metastasis or vascular invasion. The primary endpoint was overall survival, assessed in the full analysis set (ie, all patients who were treated with study drug except any individuals who were found not to have hepatocellular carcinoma or who were found to have active double cancer). Patients, medical staff, investigators, and the sponsor were masked to treatment assignment. Blinding was maintained even after study treatment concluded. This study is registered with JapicCTI, number JapicCTI-090920, and has been completed. Findings Between Oct 26, 2009, and Aug 22, 2012, we screened 399 patients. 65 patients were excluded due to not meeting criteria (n=61), declining to participate (n=3), or other reasons (n=1). 334 patients were randomly assigned to receive either S-1 (n=223) or placebo (n=111). One patient in the S-1 group did not receive treatment, and was thus excluded from analyses. At data cutoff, median follow-up was 32·4 months (IQR 24·0–34·7) in the S-1 group and 32·9 months (23·7–39·5) in the placebo group. Median overall survival was 11·1 months (95% CI 9·7–13·1) in the S-1 group and 11·2 months (9·2–12·8) in the placebo group (hazard ratio 0·86, 95% CI 0·67–1·10; p=0·220). The most frequently reported adverse events were skin hyperpigmentation (123 [55%] of 222 patients in the S-1 group vs nine [8%] of 111 patients in the placebo group), decreased appetite (104 [47%] vs 21 [19%]), fatigue (102 [46%] vs 20 [18%]), diarrhoea (77 [35%] vs 14 [13%]), and increased blood bilirubin (77 [35%] vs 14 [13%]). Serious adverse events were reported in 90 (41%) of 222 patients in the S-1 group and 24 (22%) of 111 patients in the placebo group. Five treatment-related deaths were reported in the S-1 group. Interpretation S-1 did not prolong overall survival in patients with sorafenib-refractory advanced hepatocellular carcinoma. Further research is needed to identify subgroups of patients who might benefit from S-1. Funding Taiho Pharmaceuticals.

The purpose of this study was to evaluate whether the hypervascularity of hepatocellular carcinomas (HCCs) on contrast-enhanced ultrasonography (CEUS) prior to radiofrequency ablation (RFA) is a significant risk factor for local recurrence after RFA.Institutional review board approval and informed consent were obtained. Overall, 208 patients (mean age, 71.7 years; range, 50-87 years; 137 men, 71 women) with 282 HCCs treated with RFA were analyzed retrospectively. The mean maximum tumor diameter was 15.7mm. We compared the abilities of CEUS and contrast-enhanced computed tomography (CECT) to detect hypervascularity in HCCs. We then classified the HCCs into two groups according to the arterial-phase CEUS findings: a "hypervascular group" with whole or partial hypervascular areas within the lesions compared with the surrounding liver parenchyma, and a "non-hypervascular group" with isovascular or hypovascular areas within the lesions. We assessed the cumulative rate of local recurrence after RFA, and we also evaluated the risk factors for local recurrence using a univariate analysis.The detection rate for hypervascular HCCs was significantly higher using CEUS (78%, 221/282) than that using CECT (66%, 186/282) (P0.001). Using the CEUS findings, the cumulative rate of local recurrence was significantly higher in the hypervascular group (41.2%, 56/221) than in the non-hypervascular group (18.4%, 6/61) (P=0.007). A univariate analysis revealed that hypervascularity on CEUS was an independent risk factor for local recurrence (P=0.010).Hypervascularity in HCCs as observed using CEUS is a significant risk factor for local recurrence after RFA.

The purpose of the study is to evaluate the utility of contrast-enhanced ultrasound (CEUS) for the differential diagnosis of gallbladder polypoid lesions (GPLs). Thirty-six patients with GPLs (17 with gallbladder cancer, 19 with benign polyps) who underwent CEUS were enrolled in the study. The mean age of patients was 65.7 ± 12.6 years. Perflubutane-based contrast agent and high-mechanical index mode, which can eliminate the background B-mode and provide precise visualization of tumor vessels, were used for CEUS, and two blinded readers evaluated the images, retrospectively. Patient age and size of malignant GPLs (72.4 ± 9.4 years and 23.4 ± 7.5 mm) were significantly greater than those for benign lesions (59.6 ± 12.3 years and 12.4 ± 2.9 mm) (P

Oral direct-acting antiviral (DAA) treatment leads to >95% sustained virological response (SVR) and could be clinically useful in regression of liver fibrosis in chronic hepatitis C virus (HCV) infection. We evaluated if ledipasvir/sofosbuvir or sofosbuvir + ribavirin is associated with regression of fibrosis in HCV patients who achieved SVR.In this prospective cohort study performed at 3 sites in Japan, patients with genotype 1 and genotype 2 were given standard treatment of ledipasvir 90 mg/sofosbuvir 400 mg and sofosbuvir 400 mg + 200-1000 mg/day ribavirin, respectively, for 12 weeks. Liver fibrosis was assessed using Mac-2-binding protein glycosylation isomer (M2BPGi) and other fibrosis markers (platelet count, Fib-4 index, liver stiffness measurement [LSM]) in patients who achieved SVR.A total of 98.1% of (n = 101/103) patients in genotype 1 cohort and 100% (n = 16/16) in the genotype 2 cohort achieved SVR12. Based on per-protocol analysis, M2BPGi levels showed a significant decrease (-2.2 cut-off index [COI], P

Using the low mechanical index (MI) contrast mode and the high MI contrast mode of contrast-enhanced ultrasonography, we evaluated which method is more sensitive for detecting Sonazoid microbubbles in the liver of normal subjects. Thirteen normal subjects received an intravenous bolus injection of 0.2 mL of Sonazoid. We defined the intensity difference as the intensity post-injection minus the intensity pre-injection. We evaluated the intensity difference at the portal vein using both the low MI (0.21–0.23) and the high MI (0.7–1.2) at 1 min, at every 10 min between 10 to 60 min, and at every 30 min between 60 to 300 min post-injection. The intensity difference at the liver parenchyma was also evaluated at eight points (1, 10, 30, 60, 120, 180, 240, and 300 min) using the low MI and at three points (1, 10, and 300 min) using the high MI. The intensity differences at the portal vein measured using high MI were significantly higher than those measured using the low MI at each point between 1 and 240 min (P

The therapeutic effect of regorafenib was previously demonstrated in patients with advanced hepatocellular carcinoma (HCC) and Child–Pugh classification A (CP-A) whose disease progressed during sorafenib treatment in a phase III trial. However, treatment options are limited for patients with advanced HCC other than CP-A. In this study, we aimed to evaluate the therapeutic effect of regorafenib on advanced HCC patients including those with Child–Pugh classification B (CP-B). We retrospectively analyzed the medical records of 21 patients with advanced HCC who were treated with regorafenib after sorafenib monotherapy at our hospital from July 2017 to April 2018 and were followed up until September 2019. Patients were classified according to liver function and adverse events experienced during sorafenib treatment and were started on regorafenib with a pre-defined reduced starting dose along with a dose reduction and schedule change based on the judgement of the attending physician. At regorafenib initiation, 13 and 8 patients were classified as CP-A and CP-B, respectively. In all patients with CP-B, the starting dose of regorafenib was reduced, and the pre-defined starting-dose sets were applied to 17 (81%) patients. The median duration of regorafenib treatment in patients with CP-A and CP-B were 4.1 months and 2.0 months, respectively, with no significant difference. The median overall survival from regorafenib initiation (OS-r) and sorafenib initiation (OS-s) was 13.2 months and 30.9 months, respectively. In subgroup analysis, OS-r was 16.3 months in patients with CP-A and 10.1 months with CP-B with no significant difference (P = .44), whereas OS-r was 16.3 months in patients with modified albumin-bilirubin Grade 1/2a and 13.2 months in patients with Grade 2b, with no significant difference. There was no clear difference in the incidence rate of ≥grade 3 adverse events between CP-A and CP-B. OS-r and OS-s were significantly correlated. Even patients with impaired liver function achieved the desired therapeutic effects by safely reducing the starting dose of regorafenib according to both impaired liver function and adverse events during pretreatment. Regorafenib may be considered to be an effective treatment after sorafenib monotherapy in patients with impaired liver function.

We evaluated the detection rates for perfusion defects in hypervascular hepatocellular carcinomas comparing the low mechanical index (MI) and high MI contrast modes during the post-vascular phase (PVP) of contrast-enhanced ultrasonography.Seventy-eight patients with 84 hypervascular hepatocellular carcinomas (mean diameter, 23.4 ± 11.2 mm) were selected for this retrospective study. All the patients underwent whole-liver scanning using conventional ultrasonography before injection of a perflubutane-based contrast agent (Sonazoid), and all the detected nodules were classified as either hypoechoic or hyperechoic nodules. Next, hypoechoic and hyperechoic nodules were evaluated using contrast-enhanced ultrasonography, and the presence of a perfusion defect was assessed for each nodule using both the low MI (0.2-0.3) and the high MI (0.7-1.2) contrast modes during the PVP (10 minutes after injection). The data were analyzed using the McNemar test.Forty-four nodules were classified as hypoechoic nodules, and the remaining 40 nodules were classified as hyperechoic nodules using conventional ultrasonography. The detection rate for perfusion defects determined using the high MI contrast mode was higher than that determined using the low MI contrast mode in hyperechoic nodules during the PVP (low MI, 58% [23 of 40]; high MI, 90% [36 of 40]; P .0001). However, no significant difference was observed between the low MI and the high MI contrast modes in hypoechoic nodules (low MI, 80% [35 of 44]; high MI, 89% [39 of 44]; P = .125).Compared with the low MI contrast mode, the high MI contrast mode was more sensitive for detecting perfusion defects in hypervascular hepatocellular carcinomas in patients with hyperechoic nodules during the PVP.

It remains unknown whether Kupffer-phase images in Sonazoid-enhanced ultrasonography (US) can be used to predict hypervascularization of borderline lesions. Therefore, we aimed to clarify whether Kupffer-phase images in Sonazoid-enhanced ultrasonography can predict subsequent hypervascularization in hypovascular borderline lesions detected on hepatobiliary-phase gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging.From January 2008 to March 2012, 616 low-intensity hypovascular nodules were detected in hepatobiliary-phase images of Gd-EOB-DTPA-enhanced MRI at nine institutions. Among these, 167 nodules, which were confirmed as hypovascular by Gd-EOB-DTPA-enhanced MRI and Sonazoid-enhanced US, were evaluated in this study. Potential hypervascularization factors were selected based on their clinical significance and the results of previous reports. The Kaplan-Meier model and log-rank test were used for univariate analysis and the Cox regression model was used for multivariate analysis.The cumulative incidence of hypervascularization of borderline lesions was 18, 37, and 43 % at 1, 2, and 3 years, respectively. Univariate analyses showed that tumor size (p = 0.0012) and hypoperfusion on Kupffer-phase images in Sonazoid-enhanced US (p = 0.004) were associated with hypervascularization of the tumor. Multivariate analysis showed that tumor size [HR: 1.086, 95 % confidence interval = 1.027-1.148, p = 0.004] and hypo perfusion on Kupffer-phase images [HR: 3.684, 95 % confidence interval = 1.798-7.546, p = 0.0004] were significantly different.Kupffer-phase images in Sonazoid-enhanced US and tumor diameter can predict hypervascularization of hypointense borderline lesions detected on hepatobiliary-phase Gd-EOB-DTPA-enhanced MRI.

We evaluated the use of tumor vessel patterns observed during arterial-phase contrast-enhanced ultrasonography (US) to differentiate regenerative nodules (RN) from early hepatocellular carcinoma (HCC) or high-grade dysplastic nodules (HGDN) in patients with chronic liver disease. Pathologically confirmed lesions (83 early HCC, 6 HGDN, and 13 RN with mean maximal diameters of 15.4, 15.3, and 16.2 mm, respectively) were enrolled in this retrospective study. We performed contrast-enhanced US using a perflubutane-based contrast agent. We then classified the tumor vessels observed during the arterial phase of contrast-enhanced US into two patterns: peripheral vessels (centripetal pattern) and central vessels (centrifugal pattern). Eighty-one (97.6%) of the 83 early HCC exhibited various enhancement patterns (hypovascular, 44.6%; isovascular, 25.3%; and hypervascular, 27.7%) and a peripheral vessel pattern, while the remaining 2 lesions (2.4%) exhibited hypovascular enhancement and a central vessel pattern. All 6 HGDN lesions were hypovascular with a peripheral vessel pattern. Twelve (92.3%) of the 13 RN were hypovascular with a central vessel pattern, and the remaining one (7.7%) was hypervascular with a central vessel pattern. When lesions exhibiting a central vessel pattern during arterial-phase contrast-enhanced US were diagnosed as RN, the sensitivity, specificity, and accuracy of these diagnoses were 100%, 97.8%, and 98.0%, respectively. The tumor vessel patterns observed during arterial-phase contrast-enhanced US may be useful for differentiating RN from early HCC or HGDN in patients with chronic liver disease.

Reducing blood flow in the liver during radiofrequency ablation causes enlargement of the ablation area. In this animal study, we evaluated the extended effects of radiofrequency ablation combined with transarterial embolization using various embolic agents. We treated 38 radiofrequency ablation lesions after embolization in 13 pigs using the following embolic agents: gelatin sponge (Group A); iodized oil followed by gelatin sponge (Group B); 700–900 µm calibrated microspheres (Group C); and 100–300 µm calibrated microspheres (Group D). Lesion size and pathological evaluations of these ablation lesions were compared with those receiving radiofrequency ablation alone (control). Both the long- and short-axis diameters of the ablation lesions for Groups A, B, C, and D were significantly longer than those of controls (long axis/short axis for Groups A, B, C, D, and controls were 27.2/23.2, 30.2/26.0, 28.2/22.2, 32.0/24.4, and 23.2 mm/18.5 mm, respectively) (P

Objective The aim of this prospective study was to evaluate the efficacy of transarterial chemoembolization using miriplatin, a platinum-based anticancer drug, as a retreatment regimen for hepatocellular carcinoma (HCC) unresponsive to chemoembolization using epirubicin. Methods Between April 2013 and December 2014, we enrolled 57 consecutive chamoembolization-naive patients with unresectable HCC, and performed chemoembolization with epirubicin. Treatment effect, necrotizing rate of the target nodules, was evaluated at 1-3 months after treatment using contrast-enhanced CT or MRI. We subsequently included retreatment chemoembolization with miriplatin for patients whose treatment effect was

To investigate optimal flip angle (FA) of three-dimensional fat-suppressed T1-weighted image on Gd-EOB-DTPA-enhanced MRI. Forty-five patients with 35 hepatocellular carcinomas (HCCs) and 16 liver metastases (METs) were investigated. Signal-to-noise ratio (SNR), tumor-to-liver contrast (TLC) of HCC and MET, visual image quality (IQ) and lesion conspicuity (LeCo) were evaluated at hepatobiliary phase with different FAs (FA15°–30°–45°–60° in 13 patients, FA5°–10°–15°–20°–25° in 32 patients). TLC gradually showed better in range from FA15° to FA60° and FA5° to FA25°, but SNRs gradually decreased. SNR and TLC-MET at FA15° were significantly better than those at FA45° and FA60°. SNR at FA10° was significantly higher than at FA5°, FA20°, and FA25°. TLC-HCC and TLC-MET at FA5° were inferior to other FAs. IQs and LeCos at FA15° and FA30° were superior to those at FA45° and FA60°. IQs at FA5° and FA25° were significantly lower than those at FA10°–20°, although LeCos for HCC and MET at FA25° were superior to those at FA5°–20°. FA ranging from 10° to 20° is suitable for hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI, to image HCC and MET.

Objective We evaluated the contrast-enhanced ultrasonography (US) imaging features of early hepatocellular carcinomas (HCCs) and compared these findings with those obtained using contrast-enhanced computed tomography (CT). Subjects and methods Forty-three patients with 52 early HCCs with a mean maximal diameter of 15.6 mm were enrolled in this retrospective study. After confirming the location of the target lesion using fusion imaging combining conventional US and hepatobiliary phase of contrast-enhanced magnetic resonance (MR) imaging with gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid, we evaluated findings of contrast-enhanced US using a perflubutane-based contrast agent. The contrast-enhanced US detection rates for hyper-vascularity in early HCCs were compared with those obtained for contrast-enhanced CT. Results Transient hypo-vascularity subsequent to iso-vascularity during arterial phase and iso-vascularity during portal and post-vascular phases were the predominant contrast-enhanced US findings seen for 25 (48.1%) of the 52 early HCCs. Nine (17.3%) showed iso-vascularity during all three phases, while 1 (1.9%) showed hypo-vascularity during all three phases. The remaining 17 (32.7%) showed partial or whole hyper-vascularity during arterial phase, iso-vascularity during portal phase, and iso- or hypo-vascularity during post-vascular phase. The detection rate for the hyper-vascularity of early HCCs using contrast-enhanced US (32.7%, 17/52) was significantly higher than that obtained using contrast-enhanced CT (21.2%, 11/52) ( P Conclusion Hypo-vascularity, iso-vascularity, and hyper-vascularity were observed during the arterial phase of contrast-enhanced US in 50.0%, 17.3%, and 32.7% of the early HCCs, respectively. Contrast-enhanced US was more sensitive than contrast-enhanced CT for the detection of hyper-vascularity in early HCCs. Of note, early HCCs might not exhibit the early arterial enhancement that is generally considered to be a typical finding for HCCs.

AIM To evaluate whether pathologically early hepatocellular carcinoma (HCC) exhibited local tumor progression after radiofrequency ablation (RFA) less often than typical HCC. METHODS Fifty pathologically early HCCs [tumor diameter (mm): mean, 15.8; range, 10-23; follow-up days after RFA: median, 1213; range, 216-2137] and 187 typical HCCs [tumor diameter (mm): mean, 15.6; range, 6-30; follow-up days after RFA: median, 1116; range, 190-2328] were enrolled in this retrospective study. The presence of stromal invasion (namely, tumor cell invasion into the intratumoral portal tracts) was considered to be the most important pathologic finding for the diagnosis of early HCCs. Typical HCC was defined as the presence of a hyper-vascular lesion accompanied by delayed washout using contrast-enhanced computed tomography or contrast-enhanced magnetic resonance imaging. Follow-up examinations were performed at 3-mo intervals to monitor for signs of local tumor progression. The local tumor progression rates of pathologically early HCCs and typical HCCs were then determined using the Kaplan-Meier method. RESULTS During the follow-up period for the 50 pathologically early HCCs, 49 (98%) of the nodules did not exhibit local tumor progression. However, 1 nodule (2%) was associated with a local tumor progression found 636 d after RFA. For the 187 typical HCCs, 46 (24.6%) of the nodules exhibited local recurrence after RFA. The follow-up period until the local tumor progression of typical HCC was a median of 605 d, ranging from 181 to 1741 d. Among the cases with typical HCCs, local tumor progression had occurred in 7.0% (7/187), 16.0% (30/187), 21.9% (41/187) and 24.6% (46/187) of the cases at 1, 2, 3 and 4 years, respectively. Pathologically early HCC was statistically associated with a lower rate of local tumor progression, compared with typical HCC, when evaluated using a log-rank test (P = 0.002). CONCLUSION The rate of local tumor progression for pathologically early HCCs after RFA was significantly lower than that for typical HCCs.

Background Recent reports have addressed the utility of plastic stent (PS) placement inside bile ducts for treating biliary obstructions. Here, we evaluated the utility and safety of PS placement inside bile ducts for treating unresectable malignant hilar biliary obstruction. Methods We conducted a retrospective study of 27 patients with unresectable malignant hilar biliary obstruction who underwent intraductal modified PS placement. We modified the PS, by cutting off the distal end to facilitate insertion through the papilla of Vater, and attached a nylon thread to the distal end for removal. We evaluated complications, the time to recurrent biliary obstruction (TRBO), and removability. Results Bilateral stenting was performed in nine of the 27 patients. Mild acute pancreatitis occurred in one patient (4%). Recurrent biliary obstruction (RBO) occurred in 16 patients (59%), with a median TRBO of 190 days (95% confidence interval: 174–205 days). Reintervention was necessary in 13 of the 16 patients (81%) with RBO, and we were able to remove the initial stents in all the patients who required reintervention. Conclusions A relatively long stent patency period (>6 months) and removability make placement of a modified PS inside bile ducts a viable treatment for unresectable malignant hilar biliary obstruction.

Objective We evaluated the efficacy of contrast-enhanced ultrasonography (US), compared with contrast-enhanced computed tomography (CT), for early assessments after transarterial chemoembolization (TACE) for the treatment of hypervascular hepatocellular carcinoma (HCC) lesions. Subjects and methods Thirty-two patients with 59 HCC lesions who were scheduled to receive TACE were enrolled in this prospective study. TACE was performed by injecting a mixture of iodized oil and miriplatin hydrate, followed by a gelatin sponge. Digital subtraction angiography (DSA) and/or contrast-enhanced CT were performed 2–6 months after TACE and were used as the reference standard for residual HCC; the detection rates for residual viable HCC using contrast-enhanced US with a perflubutane-based contrast agent and a high mechanical index (MI) mode performed one day after TACE were also compared with those obtained using contrast-enhanced CT performed one month after TACE. The comparisons were made using the McNemar test. Results Forty-seven (79.7%) of the 59 HCC lesions were diagnosed as having residual viability based on DSA and contrast-enhanced CT findings obtained 2–6 months after TACE. Eight (17.0%) of the 47 HCC lesions that were diagnosed as having residual viability using one-day contrast-enhanced US were not detected using one-month contrast-enhanced CT because of artifacts produced by the high attenuation of the iodized oil. The detection rate for residual HCC lesions using one-day contrast-enhanced US (95.7%, 45/47) was significantly higher than that using one-month contrast-enhanced CT (78.7%, 37/47) ( P Conclusion Contrast-enhanced US performed one day after TACE is more sensitive than contrast-enhanced CT performed one month after TACE for detecting residual viable HCC.

Objective This study evaluated the safety and efficacy of using radiofrequency ablation combined with transarterial chemoembolization to treat hepatocellular carcinoma in a subcapsular location, given the increased risk of complications when using radiofrequency ablation alone. Materials and methods From January 2000 to December 2011, 1213 patients with unresectable hepatocellular carcinoma (up to three nodules) were screened. Of these, 132 patients with 132 subcapsular nodules (mean size, 3.0 cm; range, 1.2–5.0 cm) were enrolled in the study. After transarterial chemoembolization, percutaneous radiofrequency ablation was performed under ultrasound or C-arm cone-beam computed tomography guidance, on the same day or within 3 days. Local recurrence and survival curves were obtained using the Kaplan–Meier method. Results Technical success of treatment was achieved in 130 patients (98.5%). Major complications, including pleural effusion, secondary peritonitis, and liver abscess, occurred in 3 patients (2.3%); the incidence of complications was associated with the number of needle insertions (1–2 vs. 3–4, P = 0.039, Fisher's exact test). No patients developed permanent sequelae, tumor seeding, or tumor bleeding. The 3-year local recurrence rate was 9.7%. Local recurrence was associated with the pretreatment serum des-gamma-carboxy prothrombin level (≤200 mAU/mL vs. >200 mAU/mL, P = 0.019, log-rank test). The 3-, 5-, and 7-year overall survival rates in treatment-naive cases ( n = 82) were 79.3%, 60.6%, and 50.9%, respectively. Conclusion Combination therapy using radiofrequency ablation and transarterial chemoembolization was a safe and useful therapeutic option for patients with subcapsular hepatocellular carcinoma.

We investigated the characteristic findings of regenerative nodules (RNs) for differentiating early hepatocellular carcinoma (HCC) from high-grade dysplastic nodules (HGDNs) using magnetic resonance imaging (MRI) with gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA; EOB-MRI) and contrast-enhanced ultrasonography (CEUS) in patients with chronic liver disease. Pathologically confirmed lesions (100 early HCCs, 7 HGDNs, and 20 RNs with a maximum diameter of more than 1 cm and mean maximal diameters of 15.5, 15.1, and 14.8 mm, respectively) were enrolled in this retrospective study. The signal intensities of these lesions during the hepatobiliary phase of EOB-MRI were investigated, and findings characteristic of RNs using this modality were also evaluated using CEUS. Ninety-eight of the 100 early HCCs that were hypo-intense (n = 95), iso-intense (n = 2), or hyper-intense (n = 1) and the seven HGDNs that were hypo-intense (n = 6) or hyper-intense (n = 1) during the hepatobiliary phase of EOB-MRI exhibited centripetal vessels during the arterial dominant phase of CEUS, although one early HCC that was hypo-intense exhibited both centrifugal and centripetal vessels. Eighteen of the 20 RNs and one early HCC that were hyper-intense with a small central hypo-intensity and the remaining two RNs that were hyper-intense on EOB-MRI exhibited centrifugal vessels during the arterial dominant phase of CEUS. The small central hypo-intense area corresponded to central vascular structures in the lesion, such as the hepatic artery and portal vein running from the center to the periphery, when viewed using CEUS. Central vascular structures may be a characteristic finding of RNs when observed during the hepatobiliary phase of EOB-MRI and the arterial dominant phase of CEUS.

Excretion of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) in the bile may be related to liver function, because of elimination from the liver after preferential uptake by hepatocytes. The purpose of this study was to investigate the relation between liver and biliary enhancement in patients with or without liver dysfunction, and to compare the tumor-to-liver contrast in these patients.Forty patients [group 1: normal liver and Child-Pugh class A in 20 patients, group 2: Child-Pugh class B in 18 patients and Child-Pugh C in 2] were evaluated. All patients underwent MR imaging of the liver using a 1.5-Tesla system. T1-weighted 3D images were obtained at 5, 10, 15 and 20 minutes after Gd-EOB-DTPA injection. The relation between group 3 (total bilirubin1.8 mg/dL) and group 4 (total bilirubin ≥1.8 mg/dL) was investigated at 20 minutes. Liver and biliary signals were measured, and compared between groups 1 and 2 or groups 3 and 4. Tumor-to-liver ratio was also evaluated between groups 1 and 2. Scheffe's post-hoc test after two-way repeated-measures ANOVA and Pearson's correlation test were used for statistical analysis.Liver enhancement showed significant difference at all time points between groups 1 and 2. Biliary enhancement did not show a significant difference between groups 1 and 2 at 5 minutes, but did at 10, 15 and 20 minutes. At 20 minutes, significant differences between groups 3 and 4 were seen for liver and biliary enhancement. At all time points, liver enhancement correlated with biliary enhancement in both groups. At 5 minutes and 20 minutes, statistical differences between groups 1 and 2 were seen for tumor-to-liver ratio.The degree of biliary enhancement has a close correlation to that of liver enhancement. It is especially important that insufficient liver enhancement causes lower tumor-to-liver contrast in the hepatobiliary phase of Gd-EOB-DTPA.

Purpose We evaluated the efficacy of high-intensity focused ultrasound (HIFU) ablation for hepatocellular carcinoma (HCC), and a long-term study by follow-up multidetector-row computed tomography (CT) was conducted to evaluate the changes occurring in the treatment area following the HIFU ablation. Materials and methods HIFU ablation was carried out in 14 patients with small HCCs (≤3 lesions, ≤3 cm in diameter). The HIFU system (Chongqing Haifu Tech) was used under ultrasound guidance. The evaluations were performed by follow-up CT at 1 week, 1, 3, 6 and 12 months after the HIFU ablation. Results HIFU ablation was carried out successfully in 11 of the 14 patients. At 1 week after the HIFU, a peripheral rim enhancement was found in all cases (100%). This finding was persistent in 6 of the 11 cases (54.5%) at 1 month, and in 1 of the 11 (9%) cases at 3 months after HIFU ablation. In all cases, the rim enhancement disappeared by 6 or 12 months after the HIFU ablation. At the 12 months follow-up, a decrease in the diameter of the ablated lesions was found. The enhancement around the treated area was found to be persistent at the 12 months follow-up in the one case of recurrence of the treated site in which the safety margin was not sufficiently wide. During the follow-up period, there were 2 cases with residual of HCC tumors. We performed radiofrequency ablation (RFA) for these residual tumors after the HIFU ablation. Conclusion To ascertain the cause of the peripheral enhancement on follow-up CT images after the HIFU ablation, in particular, to determine whether it might be caused by residual tumor or recurrence at the treated site, careful follow-up is important, especially in cases where the safety margin of the ablated area was not sufficiently wide.

Background Endoscopic submucosal dissection (ESD) was introduced worldwide as a new treatment option for early gastric cancer, but curability prediction has not been evaluated on an individual basis. Objective To analyze factors contributing to the curability of early gastric cancer after ESD and to construct a risk assessment chart for the probability of curability. Design Single-institution retrospective review. Setting University hospital. Patients From June 2000 to April 2010, we treated 961 early gastric cancers in 784 patients (mean age 70.2 years). Intervention ESD procedures were performed using typical sequences. Main Outcome Measurements Risk factors related to resectability (en bloc or piecemeal resection) and curability (curative or noncurative resection) after ESD were analyzed using logistic regression analysis. Using this model, we constructed a risk assessment chart to predict the probability of noncurability from patient characteristics. Results The en bloc and curative resection rates were 98.9% and 88.1%, respectively, after ESD. Significant contributors to noncurative ESD were large lesions, upper location, and ulcer findings. Predicted noncurability probabilities were displayed in 4 colors for each risk level (light blue, blue, yellow, and red) by combining tumor size, tumor location, and ulcer findings. Probability of noncurability was highest (≥40%) in ulcerative large tumors (>30 mm in diameter) in the upper location (red) and lowest in nonulcerative small tumors (≤20 mm in diameter) in the lower location (light blue). Limitations Retrospective design and single-site data collection. Conclusions This risk assessment chart shows individuals their pretreatment curability assessment with successful ESD and may be an educational tool for trainees or a decision-making tool.

Purpose To assess the extended effects of transcatheter arterial embolization with iodized oil and gelatin sponge on liver histopathologic changes in radiofrequency (RF)–ablated zones and the surrounding liver parenchyma in a pig model. Materials and Methods Eighteen consecutive pigs subjected to 36 RF applications performed immediately after segmental embolization with iodized oil and gelatin sponge to the left lobe of the liver (embolization/RF ablation) were euthanized immediately after the procedure or 1 or 4 weeks later. The right lobes were used as controls for RF applications without embolization. The ablated zones and the surrounding liver parenchyma were measured and examined histopathologically. Results The average maximum ablated zone was significantly larger in the embolization/RF ablation specimens than in the RF ablation–alone specimens at all three follow-up time points. Ten of the 12 specimens obtained immediately after embolization/RF ablation showed wide hemorrhagic areas spreading to the periphery of the liver and microscopically showed marked intralobular congestion with sinusoidal dilation. This hemorrhagic change had disappeared in all the specimens obtained 1 week after embolization/RF ablation, but 10 of the 12 specimens showed wedge-shaped areas of segmental degenerative parenchyma beginning at the ablated zone and extending to the periphery of the liver; these were microscopically revealed to be areas of coagulative necrosis, indicating hepatic infarction. The sizes of these necrotic zones had decreased at 4 weeks after embolization/RF ablation. Conclusions RF ablation performed immediately after embolization in normal pig liver induced large ablated zones accompanied by wedge-shaped areas of segmental infarction.

Background HCV is the main causative agent of chronic liver disease, which could progress to liver cirrhosis and hepatocellular carcinoma. By using a recently developed genome-length HCV RNA replication reporter assay system, we found that hydroxyurea (HU), an inhibitor of DNA synthesis, inhibited HCV RNA replication. Methods To test the hypothesis that HU suppresses HCV replication in humans, we conducted a Phase I trial involving Japanese patients with chronic hepatitis C (CHC) and investigated the safety and effectiveness of a 4-week course of oral HU. Results A total of nine patients were treated with an HU dose level of 500 mg three times daily. Dose-limiting toxicity was not observed at this dose level. Of the nine patients, eight exhibited a moderate decrease in serum HCV RNA levels during the trial. A decrease in HCV RNA levels to nadir levels was achieved for the eight patients (median -0.27 log10 IU/ml [range -0.08– -0.44]) at various times during the 4 weeks after therapy initiation. Conclusions The results of this Phase I trial suggest that HU has potential as an anti-HCV agent that could be effective for the treatment of CHC patients.

Objective: We retrospectively evaluated the antitumor effect, survival and toxicities of hepatic arterial infusion therapy using a fine powder formulation of cisplatin (cisplatin powder) in hepatocellular carcinoma patients with portal vein tumor thrombosis. Methods: Twenty-four patients classified as Child‐Pugh class A or B underwent a single session of hepatic arterial infusion therapy using cisplatin powder. The treatment was repeated every 4‐6 weeks in patients with no evidence of tumor progression or unacceptable toxicity. The treatment response was evaluated using contrast-enhanced computed tomography performed 1 month after each treatment. The survival rate was evaluated using the Kaplan‐Meier method, and predictors of a better outcome were identified using univariate analysis. Results: The mean follow-up period was 11.2 months (range, 1.3‐44.2 months). A total of 57 sessions of intra-arterial infusion (1‐6 sessions per patient; mean, 2.4 sessions) with cisplatin powder were performed. A complete response and a partial response were obtained in one and four patients, respectively (objective response rate ¼ 20.8%). The median survival time for all the patients was 7.0 months; the median survival times for the 5 responders and 19 non-responders were 37.3 and 5.6 months, respectively. The 1- and 2-year survival rates were 38% and 16%, respectively. Significant prognostic factors related to survival were the therapeutic effect, patient age and serum alanine aminotransferase level. Severe adverse reactions resulting in treatment discontinuation were not observed, and all the toxicities were successfully managed using conservative treatment. Conclusions: Hepatic arterial infusion therapy with a fine powder formulation of cisplatin was safe, well-tolerated and might help to prolong the life span of advanced hepatocellular carcinoma patients with portal vein tumor thrombosis.

BACKGROUND: To improve the efficacy of radiofrequency ablation (RFA) for the treatment of intermediate-sized hepatocellular carcinomas (HCCs), the authors compared RFA combined with transcatheter arterial chemoembolization (TACE) to RFA alone. METHODS: The authors randomly assigned 37 patients with solitary HCCs (diameter, 3.1-5.0 cm in the greatest dimension) to 2 groups: the TACE-RFA group, in which the patients received TACE followed by RFA on the same day, and the RFA group, in which the patients received only RFA. RESULTS: Technical success was achieved after 1.4 ± 0.5 RFA sessions in the RFA group and after 1.1 ± 0.2 RFA sessions in the TACE-RFA group (P < .01). The mean diameters of the longer and shorter axes of the RFA-induced ablated areas were 50 ± 8.0 mm and 41 ± 7.1 mm, respectively, in the RFA group and 58 ± 13.2 mm and 50 ± 11.3 mm, respectively, in the TACE-RFA group; the mean diameters of the shorter axes were significantly different (P = .012). The rates of local tumor progression at the end of the third year in the RFA and TACE-RFA groups were 39% and 6%, respectively (P = .012). The 3-year survival rates of the patients in the RFA and TACE-RFA groups were 80% and 93%, respectively (P = .369). CONCLUSIONS: In patients with intermediate-sized HCCs, RFA combined with TACE is more effective than RFA alone for extending the ablated area in fewer treatment sessions and for decreasing the local tumor progression rate. Cancer 2010. © 2010 American Cancer Society.

Objective We investigated contrast-enhanced three-dimensional ultrasonography (CE 3D US) with contrast agent Sonazoid for evaluating the effect of percutaneous radiofrequency (RF) ablation of hepatocellular carcinomas (HCCs). Methods 63 HCCs were treated by US-guided percutaneous RF ablation. CE 3D US after bolus injection of 0.2 mL of Sonazoid was performed 5–7 days before and 1 day after RF ablation. CE 3D computed tomography (CT) was performed 5–7 days before and 1 month after the ablation, and during the follow-up period. Multiplanar images in three orthogonal planes and US/CT angiograms were reconstructed on both modalities. Two blinded observers reviewed the images on both modalities to evaluate the ablation effects. Results After RF ablation, the evaluation on CE 3D US and that on CE 3D CT achieved concordance in 61 lesions. Among them, 59 lesions were detected with the absence of tumor vessels and tumor enhancement and evaluated as adequate ablation, and the remaining two lesions were detected with residual tumors. The kappa value for agreement between the findings on the two modalities was 0.65. When 1-month CE 3D CT scans were used as reference standard, the sensitivity, specificity, and accuracy of 1-day CE 3D US for detecting adequate ablation were 97%, 100%, and 97%, respectively. Conclusion By demonstrating the ablated areas and residual tumors in three dimensions, CE 3D US with Sonazoid was shown to be useful for evaluating the effect of RF ablation of HCCs, and there was good concordance with the results obtained by CE 3D CT.

Objective: The aims of this study were to identify prognostic factors in patients who received a non-surgical second treatment for the development of recurrent hepatocellular carcinoma (HCC) after an initial percutaneous ablation therapy. Methods: We retrospectively studied 147 patients with HCC who had received an initially successful percutaneous ablation therapy. The patients were followed up using computed tomography and/or ultrasound every 3 months and a second treatment was performed for subsequent recurrent tumours. Results: The 3- and 5-year survival rates of the 147 patients were 90 and 65% respectively. During a mean follow-up period of 33 months, local or distant tumour recurrences developed in 77 of the 147 patients, and the 3- and 5-year survival rates after a second treatment in these 77 patients were 73 and 44% respectively. Forty-six of the 77 patients with up to three recurrent tumours received percutaneous ablation therapy for the second treatment, and the remaining 31 patients with more than three (multiple) recurrent tumours received transcatheter arterial chemoembolization for their second treatment. A multivariate analysis revealed the serum α-fetoprotein level at the time of the appearance of the recurrent HCC (

Objectives. We evaluated the usefulness of contrast-enhanced harmonic gray scale ultrasonographic findings for differential diagnosis of gallbladder diseases. Methods. We evaluated contrast-enhanced harmonic gray scale ultrasonographic images from 33 patients with 35 polypoid gallbladder disease lesions larger than 10 mm in diameter, consisting of 12 biliary sludge lesions, 8 cholesterol polyps, 1 inflammatory polyp, 2 adenomas, and 12 carcinomas. After a galactose-palmitic acid contrast agent was injected, lesions were scanned by contrast-enhanced harmonic gray scale ultrasonography in 2 phases: early vascular and late vascular. Results. None of the biliary sludge lesions (n = 12) showed either tumor vessels or tumor enhancement. Lesions showing tumor vessels and tumor enhancement on contrast-enhanced harmonic gray scale ultrasonography were diagnosed as cholesterol polyp, inflammatory polyp, adenoma, or carcinoma. Three (38%) of the 8 cholesterol polyps showed dottedtype tumor vessels. Branched-type tumor vessels were observed in 5 (62%) of the 8 cholesterol polyps, the 1 (100%) inflammatory polyp, both (100%) adenomas, and 3 (25%) of the 12 carcinomas. Tortuous-type tumor vessels were observed in 9 (75%) of the 12 carcinomas. Lesions with tumor enhancement and tortuous-type tumor vessels on contrast-enhanced harmonic gray scale ultrasonography were diagnosed as carcinomas, and the sensitivity, specificity, and accuracy of this diagnosis with the current modality were 75% (9/12), 100% (23/23), and 91% (32/35), respectively. Conclusions. Evaluation of tumor vessels on contrast-enhanced harmonic gray scale ultrasonography may be a useful modality for differentiating gallbladder carcinoma from other polypoid gallbladder disease lesions.

Background Modified response evaluation criteria in solid tumors (mRECIST) and RECIST are used to assess the effect of treatment with targeted agents for hepatocellular carcinoma (HCC). The aim of this study was to determine which set of criteria is superior in patients with advanced HCC treated with sorafenib. Methods A multicenter retrospective study to assess the tumor response and patient prognosis of 191 patients with HCC who had been treated with sorafenib from May 2009 through December 2011. We analyzed tumor responses as shown by contrast-enhanced computed tomography scan images according to RECIST 1.1 and mRECIST and compared the findings. Results The median duration of follow-up was 9.7 months and median overall survival was 10.8 months. Twenty-five patients (13.1 %) were assessed as responders by mRECIST and 15 (7.8 %) by RECIST 1.1. There was a significant difference in overall survival (OS) between responders and non-responders according to mRECIST (P = 0.0117), but no significant difference in OS between responders and non-responders according to RECIST 1.1 (P = 0.0722). Sixteen patients (8.4 %) had no measurable enhanced target lesions that could be assessed as required by mRECIST; however, these patients could be assessed by RECIST 1.1. According to RECIST 1.1, eight of them had stable disease (SD) and eight had progressive disease (PD). There was a significant difference in OS between these SD and PD patients (P = 0.0312). Conclusions Patients treated with sorafenib for HCC should be evaluated by mRECIST; RECIST 1.1 is preferable only for assessment of patients with lesions that are non-measurable according to mRESIST.

Angiogenesis inhibition by the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) inhibitor sorafenib provides survival benefit in hepatocellular carcinoma (HCC); however, angiogenic escape from sorafenib may occur due to angiogenesis-associated fibroblast growth factor receptor (FGFR) pathway activation. In addition to VEGFR and PDGFR, dovitinib inhibits FGFR. Frontline oral dovitinib (500 mg/day, 5 days on, 2 days off; n = 82) versus sorafenib (400 mg twice daily; n = 83) was evaluated in an open-label, randomized phase 2 study of Asian-Pacific patients with advanced HCC. The primary and key secondary endpoints were overall survival (OS) and time to tumor progression (TTP) as determined by a local investigator, respectively. Patients included in the study were ineligible for surgical and/or locoregional therapies or had disease progression after receiving these therapies. The median OS (95% confidence interval [CI]) was 8.0 (6.6-9.1) months for dovitinib and 8.4 (5.4-11.3) months for sorafenib. The median TTP (95% CI) per investigator assessment was 4.1 (2.8-4.2) months and 4.1 (2.8-4.3) months for dovitinib and sorafenib, respectively. Common any-cause adverse events included diarrhea (62%), decreased appetite (43%), nausea (41%), vomiting (41%), fatigue (35%), rash (34%), and pyrexia (30%) for dovitinib and palmar-plantar erythrodysesthesia syndrome (66%) and decreased appetite (31%) for sorafenib. Subgroup analysis revealed a significantly higher median OS for patients in the dovitinib arm who had baseline plasma soluble VEGFR1 (sVEGFR1) and hepatocyte growth factor (HGF) below median levels versus at or above the median levels (median OS [95% CI]: sVEGFR1, 11.2 [9.0-13.8] and 5.7 [4.3-7.0] months, respectively [P = .0002]; HGF, 11.2 [8.9-13.8] and 5.9 [5.0-7.6] months, respectively [P = 0.0002]). Conclusion: Dovitinib was well tolerated, but activity was not greater than sorafenib as a frontline systemic therapy for HCC. Based on these data, no subsequent phase 3 study has been planned. (Hepatology 2016;64:774-784)

We aimed to evaluate the efficacy and tolerability of hepatic arterial infusion chemotherapy (HAIC) using cisplatin as an alternative to sorafenib for the treatment of hepatocellular carcinoma (HCC) patients who had not responded to transarterial chemoembolization (TACE).Medical records of 127 consecutive HCC patients without extrahepatic metastasis (cisplatin, n = 44; sorafenib, n = 83) who had not responded to prior TACE at four institutions were retrospectively reviewed. An inverse probability of treatment weighting using propensity scoring was used to adjust for the selection bias.Severe adverse events accounting for treatment discontinuation occurred in 2.3% of the patients in the cisplatin group and 32.5% of those in the sorafenib group. The median overall survival (OS) period was 11.2 months (95% CI 4.8-17.7) in the cisplatin group and 10.2 months (95% CI 8.8-11.5) in the sorafenib group, respectively. After an inverse probability of treatment weighting adjustment, the survival outcome of the HAIC treatment group was not inferior to that of the sorafenib treatment group (hazard ratio 0.758; 95% CI 0.471-1.219, P = 0.253).HAIC with cisplatin can be an alternative treatment for the selection of HCC patients who have not responded to prior TACE and cannot tolerate sorafenib.

We examined contrast-enhanced harmonic gray-scale sonographic findings of pancreatic carcinoma in relation to the pathological findings in resected specimens to evaluate correlations between observations made by this modality and the pathological findings.The pathological findings of surgical specimens obtained from 16 patients were examined in relation to the contrast-enhanced harmonic gray-scale sonography findings. Lesion vascularity was examined by contrast-enhanced harmonic gray-scale sonography from 20 to 50 s after the injection of Levovist (Schering, Berlin, Germany) (early phase), and lesion enhancement was also monitored at approximately 90 s after injection (delayed phase).Contrast-enhanced harmonic gray-scale sonography showed positive enhancement in 12 of the 16 lesions (peripheral tumor region alone, n = 9; entire tumor, n = 3), while the other 4 lesions showed no contrast enhancement in any region. Twelve enhanced regions (9 peripheral tumor region and 3 entire tumor regions) detected by contrast-enhanced harmonic gray-scale sonography showed: (1) mild fibrosis with inflammation, in 10 regions (83%); (2) the presence of both carcinoma cells and residual acinar cells in 8 (67%); and (3) presence of relatively large arteries in 2 (17%). In contrast, 13 non-enhanced regions (4 entire tumor regions and 9 central regions) showed: (1) severe fibrosis in 10 regions (77%); (2) necrosis in 7 (54%); and (3) mucin in 4 (31%).Contrast-enhanced harmonic gray-scale sonographic findings of pancreatic carcinoma are influenced by interstitial histological features associated with tumor growth.

To determine whether transcatheter arterial embolization (TAE) with iodized oil and gelatin sponge particles can be used to expand radiofrequency (RF)-induced coagulation necrosis, the morphology and histologic characteristics of ablation lesions were evaluated in the normal pig liver after three different TAE procedures.Ten consecutive animals with 33 ablation lesions produced with an RF ablation system were randomly assigned to one of three treatment groups and a control group: a group treated with TAE with iodized oil, a group treated with TAE with gelatin sponge, a group treated with TAE with iodized oil and gelatin sponge, and a control group in which TAE was not performed. After the completion of ablation, the lesions were excised for gross and histologic examination.The longest and shortest diameters of ablation lesions were greatest in the group treated with TAE with iodized oil and gelatin sponge, followed by the groups treated with TAE with gelatin sponge and TAE with iodized oil (P.05 vs controls, respectively). The hemorrhagic rim was also widest in the group treated with TAE with iodized oil and gelatin sponge (P.05 vs controls), and it spread toward the liver periphery like a segmental hemorrhagic area adjacent to the ablation lesion. Histochemical staining for lactate dehydrogenase, maleate dehydrogenase, and nicotinamide adenine dinucleotide diaphorase showed what appeared to be 100% cellular destruction in all the ablation lesions and their hemorrhagic rims.RF ablation combined with TAE with iodized oil and gelatin sponge induces the greatest area of coagulation necrosis accompanied by peripherally spreading segmental necrosis in normal pig liver tissue.

Objective To evaluate the usefulness of contrast-enhanced harmonic wideband gray scale sonographic images obtained after radio frequency-induced coagulation necrosis, we compared the morphologic and histopathologic characteristics of the ablated tumors with sonographic images of the tumors. Methods Forty-eight patients with 72 hepatocellular carcinomas with a maximal diameter of 3 cm or less were treated percutaneously using radio frequency ablation. Six treated tumors in 4 patients were resected 1 month after ablation; the remaining 66 treated tumors were evaluated by a biopsy procedure performed with an 18-gauge fine needle 1 month after ablation. The excised tumors and biopsy specimens were then examined by histopathologic methods, and the findings were compared with those obtained on contrast-enhanced harmonic wideband gray scale sonography. Hematoxylin-eosin-stained specimens were inconclusive as to whether cellular viability remained; therefore, cell viability was determined by a positive result after histochemical (lactate dehydrogenase and nicotinamide adenine dinucleotide phosphate-diaphorase) staining. Results Contrast-enhanced harmonic wideband gray scale sonography after radio frequency ablation showed residual tumor enhancement in 5 (6.9%) of the 72 tumors; the histopathologic results for these 5 tumors were also positive for tumor residue. The remaining 67 tumors (93.1%) did not show any residual tumor enhancement when examined by sonography; however, only 66 tumors did not reveal tumor residue when examined histopathologically. Contrast-enhanced harmonic wideband sonographic imaging provided results that were comparable with histopathologic findings, the criterion standard for diagnosis; the sensitivity and specificity of the sonographic images for the detection of residual tumor tissue in ablated tumors were 83.3% (5 of 6) and 100% (66 of 66), respectively. Conclusions Contrast-enhanced harmonic wideband gray scale sonography is a potentially useful technique for evaluating the therapeutic effects of radio frequency ablation on hepatocellular carcinoma.

Balloon-occluded retrograde transvenous obliteration of gastric varices by a microcatheter insertion method was performed in eight patients with large collateral veins or a large gastrorenal shunt. A 3-F microcatheter was selectively inserted into the gastric varices through a 6-F balloon catheter wedged in the left adrenal vein. Selective venography of the gastric varices and injection of the sclerosing agent, a mixture of 10% ethanolamine oleate and iopamidol, through the microcatheter system without occluding the collateral veins was accomplished in one treatment session in all patients. There have been no complications or recurrences of gastric varices in any of the patients during the follow-up period.