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Background/aim: MHC-class I-related chain A (MICA) functions as a ligand for natural killer group D, an activating receptor on natural killer (NK) cells, and its expression correlates with the carcinogenesis and progression of hepatocellular carcinoma (HCC). Although membranous MICA (mMICA) activates NK cells, soluble forms of MICA (sMICA), shed by cleaving enzymes, such as A disintegrin and metalloprotease (ADAM) 9, suppress NK cells. Therefore, the prevention of MICA shedding through the inhibition of ADAM9 has the potential to activate cancer immunity. Although we have discovered several ADAM inhibitors, many did not sufficiently activate NK cells without being cytotoxic, and, thus, new ADAM9 inhibitor candidates are needed., Materials and Methods: To identify possible compounds for drug development, chemical library screening (a total of 741 compounds) was conducted using a fluorescence assay. Compounds with reduced fluorescence intensity were used as hit compounds in a subsequent analysis. Their impact on sMICA and mMICA in HCC cell lines was assessed using ELISA and flow cytometry, respectively. The cytotoxicity of NK cells was also evaluated by co-culturing NK cells with HCC cells., Results: CCL347, a symmetrical compound with five benzene rings, was identified as a hit compound. CCL347 significantly reduced sMICA levels in the culture medium supernatant with negligible cytotoxicity. Although mMICA was also reduced, CCL347 successfully enhanced NK cell cytotoxicity in co-cultures of NK cells and HCC cells., Conclusion: CCL347 has potential as a novel therapeutic drug for HCC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Previous RNA immunoprecipitation followed by proteomic approaches successfully demonstrated that Embryonic Lethal, Abnormal Vision, Drosophila-Like 1 (ELAVL1) interacts with hepatitis B virus (HBV)-derived RNAs. Although ELAVL family proteins stabilize AU-rich element (ARE)-containing mRNAs, their role in HBV transcription remains unclear. This study conducted loss-of-function assays of ELAVL1 for inducible HBV-replicating HepAD38 cells and HBx -overexpressed HepG2 cells. In addition, clinicopathological analyses in primary hepatocellular carcinoma (HCC) surgical samples were also conducted. Lentivirus-mediated short hairpin RNA knockdown of ELAVL1 resulted in a decrease in both viral RNA transcription and production of viral proteins, including HBs and HBx, probably due to RNA stabilization by ELAVL1. Cell growth of HepAD38 cells was more significantly impaired in ELAVL1 -knockdown than those in the control group, with or without HBV replication, indicating that ELAVL1 is involved in proliferation by factors other than HBV-derived RNAs. Immunohistochemical analyses of 77 paired HCC surgical specimens demonstrated that diffuse ELAVL1 expression was detected more frequently in HCC tissues (61.0%) than in non-tumor tissues (27.3%). In addition, the abundant expression of ELAVL1 tended to affect postoperative recurrence in HBV-related HCC patients. In conclusion, ELAVL1 contributes not only to HBV replication but also to HCC cell growth. It may be a potent therapeutic target for HBV-related HCC treatment.

The Japanese gastric cancer clinical practice guideline recommends FOLFOX as one of the first-line chemotherapy for advanced gastric cancer. Since FOLFOX is administered intravenously, it is helpful for patients who have difficulty in oral intake. Herein, we report a patient in which FOLFOX was significantly effective after failure to treatment with S-1 plus CDDP. A 75-year-old gastric cancer patient with paraaortic lymph node metastasis and multiple liver metastases(Stage ⅣB)was treated. Severe stomatitis and impaired consciousness due to dehydration appeared after administration of S-1 plus CDDP. After his general condition recovered, we changed his regimen to FOLFOX. No serious adverse events were observed, and partial response was achieved after 4 courses of treatment. Partial response was maintained until the onset of oxaliplatin drug allergy in the 10th course. FOLFOX is a promising option for patients with difficulties in oral intake.

Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2 low H3K27me3 high cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC., (© 2021. The Author(s).)

Purpose: Portal vein thrombosis (PVT) following hepatectomy is potentially life-threatening. We aimed to evaluate the incidence of PVT after hepatectomy for hepatocellular carcinoma and identify coagulation and fibrinolytic factors that could predict early-stage postoperative PVT., Methods: A retrospective analysis was conducted on 65 hepatocellular carcinoma patients who underwent radical hepatectomy. The risk factors for postoperative PVT were identified based on univariate and multivariate analyses, and the levels of coagulation and fibrinolytic factors were measured during the perioperative period., Results: The incidence of PVT after hepatectomy was 20.0%. The patients were divided into two groups: those with PVT (n=13; PVT group) and those without PVT (n=52; no-PVT group). The frequency of the use of the Pringle maneuver during surgery was higher in the PVT group than in the no-PVT group, and the postoperative/preoperative ratios of thrombin-antithrombin III complex (TAT) and of D-dimer were significantly higher in the PVT group., Conclusion: A high incidence of PVT was found in hepatocellular carcinoma patients after hepatectomy. The frequency of the Pringle maneuver is a potential risk factor for postoperative PVT, and the postoperative/preoperative TAT and D-dimer ratios may be used as early predictors of PVT after hepatectomy for hepatocellular carcinoma.

Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Lenvatinib-resistant HCC cell lines were established by exposure to serially escalated doses of lenvatinib over 2 months. The biological characteristics of these cells were examined by in vitro assays. To investigate the cytokine profile of lenvatinib-resistant HCC cells, the supernatant derived from lenvatinib-resistant Huh7 cells was subjected to nitrocellulose membrane-based sandwich immunoassay. Both activation of the MAPK/MEK/ERK signaling pathway and upregulation of epithelial mesenchymal transition markers were observed in lenvatinib-resistant cells. Concordant with these findings, proliferation and invasion abilities were enhanced in these cells compared with control cells. Screening of a cytokine array spotted with 105 different antibodies to human cytokines enabled us to identify 16 upregulated cytokines in lenvatinib-resistant cells. Among them, 3 angiogenic cytokines: vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and angiogenin, were increased significantly. Conditioned medium from lenvatinib-resistant cells accelerated tube formation of human umbilical vein cells. In conclusion, lenvatinib-resistant HCC cells were characterized by enhanced proliferation and invasion abilities. These findings might contribute to the establishment of new combination therapies with lenvatinib., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19 high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19 low (n = 105) patients, there were no significant differences between FGF19 high (n = 21) and FGF19 low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.

Background: COVID-19 has been giving the devastating impact on the current medical care system. There are quite many guidelines on COVID-19, but only a few on the management of hepatocellular carcinoma (HCC) during COVID-19 pandemic., Aims: We develop these recommendations to preserve adequate clinical practice for the management of HCC., Methods: Experts of HCC in the Asia-Pacific region exchanged opinions via webinar, and these recommendations were formed., Results: Close contact should be minimized to reduce possible exposure of both medical staff and patients to the novel coronavirus. To prevent transmission of the virus, meticulous hygiene measures are important. With the decrease in regular medical service, the medical staff may be mobilized to provide COVID-19-related patient care. However, diagnosis and treatment of HCC should not be delayed because of COVID-19 pandemic. The management of HCC should be the same as in non-pandemic circumstances. HCC is highly malignant, thus it is recommended not to delay curative treatment such as surgery and ablation. However, a kind of triage is necessary even among patients with HCC when resources are insufficient for all to be treated. Curative treatments should be periodized and cytoreductive or non-curative treatment such as vascular interventions and systemic therapy may be postponed until it can be performed safely with sufficient resources. For patients with confirmed or suspected to be infected with the novel coronavirus, diagnosis and treatment should be postponed until the virus is eliminated or they are confirmed as not being infected with it., Conclusions: These are collection of measures implemented by front-line medical professionals. We would evolve these recommendations over time as more real-world data becomes available.

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.

Background: Abnormal autocrine fibroblast growth factor 19 (FGF19) production has been observed in several types of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the potential of serum FGF19 as a novel tumor marker of HCC based on a sandwich enzyme-linked immunosorbent assay (ELISA)., Methods: The serum FGF19 levels of 304 patients with HCC was measured by ELISA. The serum levels of existing markers, including alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) were determined by chemiluminescence enzyme immunoassay. Both diagnostic value of FGF19 and its changes after curative ablation therapy was further examined., Results: The median FGF19 levels in controls, chronic liver disease patients, and primary HCC patients, were 78.8 pg/mL, 100.1 pg/mL, and 214.5 pg/mL, respectively. The subsequent receiver operating characteristic curves (ROC) successfully determined an optimal cut-off value of 200.0 pg/mL. The area under the ROC curve (AUC) of FGF19 for HCC detection was comparable to those of AFP and DCP. Of importance, FGF19 showed higher sensitivity for the detection of small HCC (solitary cancer with diameter < 20 mm) than those of existing markers. In addition, 43 out of 79 cases (54.4%) with normal AFP and DCP (so-called "double negative HCC") exhibited serum FGF19 level ≥ 200 pg/mL. In 45 HCC patients treated with curative ablation therapy, serum FGF19 levels changed from 257.4 pg/mL to 112.0 pg/mL after the treatment., Conclusion: Our findings reveal that FGF19 can be a potential novel biomarker for HCC. Although FGF19 is not necessarily a substitute for existing markers, it may help improve the prognosis in HCC patients owing to its resourceful use in various aspects of HCC management and treatment.

A 59-year-old woman who complained of melena and lightheadedness visited the outpatient clinic at our hospital.According to her blood test result, she had anemia, and her tumor marker levels were high.Enhanced computed tomography(CT) findings showed small intestinal cancer with multiple liver metastases.Partial resection of the small bowel for the small intestinal cancer was performed.Following the administration of fourth-line outpatient chemotherapy containing S-1 plus irinotecan( IRIS)and IRIS plus bevacizumab(IRIS plus Bev), S-1 plus oxaliplatin plus Bev(SOX plus Bev), and weekly paclitaxel (wPAC), she survived with good condition for 19 months after the surgery.

Background: Although direct-acting antiviral (DAA) developments make most of hepatitis C virus (HCV) infection curable, some HCV patients develop hepatocellular carcinoma (HCC) after curative treatment of HCV. There is much dispute whether the rapid clearance of the virus enhances the HCC development. In advance of the dispute, we should make clear the characteristics of the patients with very early occurrence and recurrence of HCC after DAA therapy because it was still unclear., Methods: We prospectively followed consecutive patients with HCV who had received sofosbuvir (SOF)-based treatment at two hospitals. The baseline characteristics, laboratory data, and liver imaging findings were acquired. We evaluated the rate of HCC occurrence and recurrence within 1-year after DAA therapy and analyzed the associated factors of very early HCC occurrence and recurrence right after SOF therapy., Results: Between July 2013 and October 2016, we studied two cohorts with HCV infection that received SOF therapy. 402 and 462 patients in Yamanashi Central Hospital and Chiba University Hospital were included in this analysis, respectively. The SVR12 rates of genotypes 1 and 2 were 98.9% (561/567) and 96.0% (285/297), respectively. 41 patients developed HCC within 1 year after SOF therapy. The cumulative HCC occurrence and recurrence rate after SOF therapy was 5.0%. The common associated factor of 1-year HCC occurrence and recurrence in all cohorts was the existence of imaging "dysplastic nodule"., Conclusions: SOF regimens for HCV also have very high rates of SVR 12 in the post-market distribution. The appearance of imaging "dysplastic nodule" was an associated factor of 1-year HCC occurrence and recurrence. To investigate existence of "dysplastic nodule" by imaging surveillance before DAA treatment is useful to detect high-risk patients of very early HCC occurrence and recurrence and it should be performed.

Background Regorafenib has been investigated for its efficacy and safety as a second-line treatment in patients with advanced hepatocellular carcinoma (HCC). We assessed the characteristics of patients with HCC treated with sorafenib who might be eligible for second-line treatment in general and regorafenib in particular. Methods Patients with HCC treated with sorafenib were retrospectively analyzed. We defined second-line candidate patients as maintaining Child-Pugh A and ECOG-PS ≤1 at the time of sorafenib failure. We also defined regorafenib candidate patients as follows: 1) continuing sorafenib at the time of radiological progression, 2) maintaining Child-Pugh A and ECOG-PS ≤ 1 at the time of sorafenib failure, and 3) continuing sorafenib 400 mg or more without intolerable adverse events at least 20 days of the last 28 days of treatment. Results Of 185 patients, 130 (70%) and 69 (37%) were candidates for second-line treatment and regorafenib. Child-Pugh score 6 and ECOG-PS 1 at the time of starting sorafenib were significantly lower in both second-line treatment and regorafenib candidate patients. Moreover, hand-foot skin reaction and liver failure during sorafenib treatment were associated with significantly low and high probabilities, respectively, of both Child-Pugh score > 6 and ECOG-PS > 1 at the time of sorafenib failure. Conclusion Regorafenib candidate patients after sorafenib failure are limited, and generally fewer than those who are candidates for second-line treatment. A lower Child-Pugh score and a better ECOG-PS were predictors of eligibility for second-line therapy and regorafenib treatment in sorafenib-treated patients with advanced HCC patients.

This retrospective study aimed to assess the diagnostic performance of contrast-enhanced ultrasound with Sonazoid (S-CEUS) for liver metastasis. We enrolled in this study 98 patients with 148 histologically proven liver lesions, with 121 metastases and 27 non-metastases. The S-CEUS technique showed sensitivity in 95.0% (115 of 121), specificity in 44.4% (12 of 27) and accuracy in 85.8% (127 of 148) for the diagnosis of metastasis. Higher body mass index had a negative influence on the positive predictive value and accuracy, and a greater depth of the lesion had a negative influence on the accuracy. The management was changed in 8 patients (8.2%) because of S-CEUS findings. In conclusion, the addition of S-CEUS may offer a great benefit by improvement of the quality of diagnosis and management for patients with cancer who have a tentative diagnosis of liver metastasis by contrast-enhanced computed tomography., (Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) represents primary liver cancer. Because the development of HCC limits the prognosis as well as the quality of life of the patients, its management should be properly conducted based on an accurate diagnosis. The liver is the major target organ of ultrasound (US), which is the simple, non-invasive, and real-time imaging method available worldwide. Microbubble-based contrast agents are safe and reliable and have become popular, which has resulted in the improvement of diagnostic performances of US due to the increased detectability of the peripheral blood flow. Sonazoid (GE Healthcare, Waukesha, WI, USA), a second-generation contrast agent, shows the unique property of accumulation in the liver and spleen. Contrast-enhanced US with Sonazoid is now one of the most frequently used modalities in the practical management of liver tumors, including the detection and characterization of the nodule, evaluation of the effects of non-surgical treatment, intraoperative support, and post-treatment surveillance. This article reviews the 10-year evidence for contrast-enhanced US with Sonazoid in the practical management of HCC.

Objective: Significance of portal hemodynamics for non-invasive marker of cirrhosis remains unclear. The aim was to determine the value of portal hemodynamics on Doppler ultrasound for predicting decompensation and prognosis in cirrhosis., Methods: This retrospective study comprised 236 cirrhotic patients (132 males, 104 females; age 63.7 ± 11.3 years; 110 compensated, 126 decompensated). Clinical data, including Doppler findings, were analyzed with respect to decompensation and prognosis. The median follow-up period was 33.2 months (0.1-95.4)., Results: Fifty-three patients developed clinical decompensation, 13 patients received liver transplantation, and 71 died. Higher model for end-stage liver disease score (p < 0.001) at baseline was the significant factor for the presence of decompensation. Higher alanine transaminase (p = 0.020), lower albumin (p = 0.002) and lower mean velocity in the portal trunk (p = 0.038) were significant factors for developing decompensation (best cut-off value: Alanine transaminase > 31 IU/L, albumin < 3.6 g/dL, and portal trunk < 12.8 cm/s). The cumulative incidence of decompensation was higher in patients with portal trunk < 12.8 cm/s (22.5% at 1 year, 71.2% at 5 years) than those without (6.9% at 1 year, 35.4% at 5 years; p < 0.001). The significant prognostic factors were hepatocellular carcinoma (p = 0.036) and lower albumin (p = 0.008) for compensated patients, and reversed portal flow (p = 0.028), overt ascites (p < 0.001), and higher bilirubin (p < 0.001) for decompensated patients., Conclusion: Portal hemodynamics offer a non-invasive marker for decompensation and prognosis of cirrhosis, suggesting a future direction for practical management.

This prospective study aimed to elucidate the effect of phase-related quantitative parameters of contrast-enhanced ultrasound (CEUS) with perflubutane microbubble agent to assess the cellular differentiation of hepatocellular carcinoma (HCC). Intensity was analyzed in 94 lesions (19.4 ± 4.9 mm, 86 patients), 47 well-differentiated HCCs (wHCCs) and 47 moderately-differentiated HCCs (mHCCs): I(e) (early phase) = I(te) (tumor) - I(le) (liver), I(p) (post-vascular phase) = I(tp) (tumor) - I(lp) (liver), I(ep) = I(e) - I(p). The area under the receiver operating characteristic curve with the best cutoff value (I(e), 13.2, I(p), -4.5, I(ep), 21.3) for discriminating between wHCC and mHCC was 0.6922 for Ie, 0.7680 for Ip and 0.7925 for Iep, which indicated a significantly greater ability to differentiate between wHCC and mHCC compared with visual/qualitative assessment (early phase, 0.6170, p = 0.04; post-vascular phase, 0.6702, p = 0.01; both phases, 0.7021, p = 0.04). In conclusion, I(ep) was found to have the highest diagnostic ability, suggesting it is a promising parameter for the cellular differentiation of HCCs with CEUS., (Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Aim: We aimed to retrospectively examine the tolerability and efficacy of transarterial chemoembolization (TACE) in patients with advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT)., Patients and Methods: Adverse events were assessed using the Common Terminology Criteria for Adverse Events, version 4.0. The efficacy of TACE in parenchymal tumors (parenchymal response) and PVTT (PVTT response) was separately evaluated by dynamic computed tomography 1 to 2 months after TACE according to the Response Evaluation Criteria in Cancer of the Liver (RECICL). Patients with complete remission plus partial response in parenchymal tumors and PVTT were assessed as parenchymal response-positive and PVTT response-positive, respectively., Results: A total of 33 HCC patients with PVTT were analyzed. Grade 3/4 toxicities included elevated aspartate aminotransferase levels (69.7%), elevated alanine aminotransferase levels (54.5%), hyponatremia (6.1%), thrombocytopenia (6.1%), hyperbilirubinemia (3.0%), leukopenia (3.0%) and anemia (3.0%). All these findings returned to the pre-treatment levels within 1 month after TACE. The number of parenchymal response-positive/negative and PVTT response-positive/negative patients was 20/13 and 13/20, respectively. Kaplan-Meier analyses revealed that the cumulative survival rate was significantly higher in parenchymal response-positive (p=0.04) and PVTT response-positive (p<0.01) patients than in their negative counterparts. PVTT response was a favorable prognostic factor for overall survival in multivariate analysis (p=0.03)., Conclusion: TACE was feasible in HCC patients with PVTT and could improve their survival by showing direct therapeutic effect against PVTT., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Objective: The purpose of this study is to examine whether pretreatment findings in hepatocellular carcinoma (HCC) using contrast-enhanced ultrasound can predict local or distant recurrence after radiofrequency ablation (RFA)., Subjects and Methods: Subjects of the prospective study were 54 patients with HCC lesions treated by RFA. Intensity differences between lesion and liver parenchyma at early arterial (4 seconds) and peak enhancement times and washout at late phase were provided on contrast-enhanced sonograms with perflubutane microbubble agent. The pretreatment findings were examined with respect to intrahepatic local and distant recurrence., Results: Univariate analysis showed that intensity differences at the early arterial time (hazard ratio [HR], 2.2; 95% CI, 1.0-4.6; p = 0.042) and lesion frequency (HR, 2.3; 95% CI, 1.0-5.0; p = 0.044) were risk factors for distant recurrence. Multivariate analysis showed that intensity differences at the early arterial time (HR, 2.7; 95% CI, 1.2-5.8; p = 0.014) and lesion frequency (HR, 2.9; 95% CI, 1.3-6.5; p = 0.015) were risk factors for distant recurrence. The cumulative distant recurrence rate for patients with intensity differences at the early arterial time was greater at less than 10 dB than at 10 dB or higher (33.3% and 91.3% vs 23.9% and 65.1% at 1 and 2 years, respectively; p = 0.035). The cumulative distant recurrence rate was 16.5% and 61.1% at 1 and 2 years, respectively, in patients with solitary lesions and 54.7% and 77.4% at 1 and 2 years, respectively, in patients with multiple lesions (p = 0.0296). No pretreatment findings were predictive for local recurrence., Conclusion: HCC lesions with gradual enhancement in the early arterial time displayed potential distant recurrence risk after RFA, requiring careful posttreatment surveillance.

Purpose: Imaging-based differentiation of hepatic lesions (≤ 30 mm) between well-differentiated hepatocellular carcinomas (w-HCC) and regenerative nodules (RN) presents difficulties. The aim was to compare the diagnostic abilities to differentiate w-HCC from RN using contrast-enhanced ultrasound and magnetic resonance imaging (MRI) both with liver-specific contrast agents., Materials and Methods: This prospective study included 67 pathologically proven hepatic lesions (17.5 ± 5.4mm, 54 w-HCCs, 13 RNs) in 56 patients with chronic hepatitis/cirrhosis (male 40, female 16; 29-79y). Hepatic-arterial/liver-specific phase enhancements were assessed quantitatively by ultrasound with perflubutane microbubble agent and MRI with gadolinium-ethoxybenzyl-diethylenetriamine with respect to the histological findings., Results: Sensitivity, specificity and accuracy of hepatic-arterial phase hyper-enhancement for w-HCC were 59.3%, 100% and 67.2% by ultrasound and 46.3%, 100% and 56.7% by MRI without significant difference. Meanwhile, those of liver-specific-phase hypo-enhancement for w-HCC were 44.4%, 100% and 55.2% by ultrasound and 87.0% (p<0.0001), 46.2% (p=0.0052) and 79.1% (p=0.0032) by MRI. Diagnostic accuracies for w-HCC by area under the receiver operating characteristic curves were higher in the hepatic-arterial phase in ultrasound (0.8316) than MRI (0.6659, p=0.0101) and similar in the liver-specific phase in ultrasound (0.7225) and MRI (0.7347, p=0.8814)., Conclusions: Hypervascularity is a significant feature which distinguishes w-HCC from RN, and ultrasound exerts a beneficial impact better than MRI for such characterization. However, both imaging have comparable abilities in the characterization of non-hypervascular lesions, compensating mutually for the poor sensitivity of ultrasound and the poor specificity of MRI in the liver-specific phase., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

This prospective study was performed in 179 hepatocellular carcinoma (HCC) lesions treated by radio-frequency ablation (RFA) to explore the clinical outcome of "linear enhancement" on contrast-enhanced sonogram. Thirty-three lesions (18.4%) showed linear enhancement, a linear-shaped positive enhancement in the RFA-treated area. Seventeen of them were followed up with no treatment (remaining 16; dropout in eight, additional RFA in six and ineffective treatment in two) and three lesions (3/17, 17.6%) showed local tumor progression corresponding to linear enhancement at 7, 14, 19 months after RFA. Although there was no significant difference in local recurrence rate between the lesions with (3/17) and without linear enhancement (10/35), local tumor progression inside the ablation zone occurred only in the lesions with linear enhancement. In conclusion, linear enhancement inside the RFA-treated area should be followed up within 7 months because it has a risk of local tumor progression. Histology of linear enhancement and its influence on distant recurrence remain to be solved., (Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this prospective study was to elucidate the efficacy of using contrast-enhanced ultrasound to characterise focal hepatic lesions appearing non-hypervascular on contrast-enhanced CT in chronic liver diseases., Methods: The study population included 22 patients with cirrhosis or chronic hepatitis, who between them had 27 focal hepatic lesions smaller than 20 mm (mean 13.9 ± 3.4) that appeared non-hypervascular on contrast-enhanced CT. Contrast-enhanced ultrasound with perflubutane microbubble agent (Sonazoid, 0.0075 ml kg(-1)) was performed prior to ultrasound-guided needle biopsy, and intensity analysis was done for hepatic lesions in the early phase (-60 s) and late phase (600 s post injection)., Results: All seven early-phase hyperenhanced lesions were hepatocellular carcinoma (HCC). 20 lesions iso- or hypoenhanced during the early phase consisted of 11 regenerative nodules (RNs) and 9 HCCs. HCC was more frequent in early-phase hyperenhanced lesions than in iso- or hypoenhanced lesions (p=0.0108). Both late-phase hypoenhanced lesions were HCCs, whereas 25 late-phase isoenhanced lesions consisted of 11 RNs and 14 HCCs. The enhancement patterns of the 11 RNs included isoenhanced appearance in both the early and late phases in 8 lesions, and early-phase hypoenhancement combined with late-phase isoenhancement in the remaining 3. Both of these enhancement patterns (i.e. either iso-iso or hypo-iso) were found in 9 malignant lesions, 9 (75%) of the 12 well-differentiated HCCs., Conclusion: Hypervascularity on contrast-enhanced ultrasound with Sonazoid strongly suggested HCC regardless of non-hypervascularity on CT, and late-phase hypoenhancement was another possible finding of HCC. However, characterisation of hepatic lesions with other enhancement patterns was difficult using our technique.

This prospective study aimed to elucidate the possibility of differentiating well-differentiated hepatocellular carcinoma (wHCC) from regenerative nodule (RN) on the basis of the heterogeneity of microbubble accumulation. Intensity analysis was conducted on early-phase and late-phase (60 s and 900 s post-injection; perflubutane microbubble) harmonic sonograms in 33 focal hepatic lesions (≤ 15 mm; 30 patients with chronic liver disease) that were histologically proven as wHCC or RN. Heterogeneity of enhancement, an average of standard deviation of late-phase enhancement in three different sections in the lesions with late-phase iso-enhancement, was examined with respect to the histologic findings. Heterogeneity of enhancement was higher in wHCC (28.7 ± 3.8) than RN (19.8 ± 2.1, p = 0.0213) in the 29 late-phase iso-enhancement lesions. The best cut-off value of the heterogeneity for the diagnosis of wHCC was 25.58, and the sensitivity and specificity were 77.8% and 100%, respectively. A novel parameter, heterogeneity of microbubble accumulation, facilitates differentiation between wHCC and RN showing a late-phase, iso-enhancement appearance., (Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

We present a rare case of hepatocellular carcinoma (HCC) in which spontaneous complete necrosis was confirmed with surgical resection. An 80-year-old man with HCC was referred to Nippon Medical School Tama Nagayama Hospital. The medical history included hypertension, managed with medication, and partial lobectomy of the lung owing to a lung schwannoma. A previously untreated abdominal aortic aneurysm, 51 mm in maximum diameter, was detected. The serum concentration of proteins induced by vitamin k antagonism or absence (PIVKA-2) was 14,300 mAU/mL, and that of alpha-fetoprotein was 184.2 ng/mL. Antibodies against hepatitis B surface antigens and hepatitis C virus were not detected in the serum. Computed tomography (CT) demonstrated a hypervascular tumor, 68 mm in diameter, in the left paramedian sector of the liver with washout of contrast medium in the delayed phase. An HCC in the left paramedian sector was diagnosed. Laparotomy was performed 40 days after CT scanning. Intraoperative ultrasonography showed that the HCC had shrunk to 30 mm in diameter. A left paramedian sectionectomy was performed. On macroscopic examination the surgical specimen was a firm mass, 30 mm in diameter, with a fibrous capsule. Histologic examination showed that the tumor in the cirrhotic liver had been completely replaced by central coagulative necrosis, circumferential fibrosis, and dense infiltrates of inflammatory cells. No viable HCC cells were observed in the coagulative necrosis. Organized thrombi in the hepatic artery were detected in the tumor. The tumor also contained multiple foci of old hemorrhage, ductular proliferation, and granulation tissue. The patient was discharged 10 days after the operation. After 1 month, the serum concentrations of PIVKA-2 (25 mAU/mL) and alpha-fetoprotein (5.9 ng/mL) had decreased to within their normal ranges.

We describe the surgical treatment of a patient with diaphragmatic invasion by a ruptured hepatocellular carcinoma (HCC) associated with biliary and portal venous tumor thrombi. A 67-year-old man was admitted because of jaundice (total serum bilirubin, 6.6 mg/dL). The serum concentration of alpha-fetoprotein was 236.1 ng/mL. The anti-hepatitis C virus antibodies were present in the serum. Computed tomography showed a large hypervascular mass in the right subphrenic region, surrounded by local effusion. Endoscopic retrograde cholangiography revealed dilatation of the left intrahepatic bile duct caused by biliary tumor thrombi extending from the right hepatic duct to the common bile duct. Endoscopic nasobiliary drainage was performed, and the total serum bilirubin level returned to the normal range. Angiography revealed a hypervascular tumor without extravasation of contrast medium in the right lobe and obstruction of the right anterior branch of the portal vein. Right hepatectomy was attempted 15 days after drainage. Severe invasion of the diaphragm by the ruptured HCC was detected. Bleeding of the ruptured HCC stopped spontaneously. Partial resection of the diaphragm was performed, followed by primary suture, without an artificial patch. Tumor thrombectomy was performed from the common bile duct. Macroscopic examination revealed that the ruptured HCC had invaded the diaphragm. Biliary and portal venous tumor thrombi were present. Histopathological examination showed a moderately differentiated HCC with biliary and portal venous tumor thrombi. The postoperative course was uneventful. The patient was discharged on postoperative day 14. Five months after the operation, local and intrahepatic recurrences of HCC were detected. Six months after operation, the patient died of liver failure. In conclusion, the outcome of a patient with diaphragmatic invasion by a ruptured HCC with biliary tumor thrombi was poor, even after curative hepatic resection.

Objective: The aim of this study was to evaluate the effectiveness of contrast-enhanced ultrasound with a perflubutane microbubble agent in the assessment of cellular differentiation of hepatocellular carcinoma (HCC)., Subjects and Methods: Continuous harmonic imaging with a low mechanical index (0.21-0.30) was performed 1, 5, and 10 minutes after i.v. contrast injection (0.0075 mL/kg). Tumor enhancement was evaluated by both subjective reading and objective intensity analysis based on the signal distribution in the nontumor parenchyma. Tumor vascularity was assessed with CT during hepatic arteriography., Results: Sixty-four patients with 77 histologically proved HCCs (mean greatest dimension, 19.1 ± 5.3 mm)--six poorly differentiated HCCs, 45 moderately differentiated HCCs, and 26 well-differentiated HCCs--were enrolled in this prospective study. Among 64 hyperenhancing lesions on peak enhancement sonograms, four poorly differentiated HCCs and eight moderately differentiated HCCs exhibited washout within 1 minute. In addition to these 12 lesions, 36 lesions exhibited washout 5 minutes after injection, resulting in a total of 48 washout lesions. Fifty-four lesions exhibited washout 10 minutes after contrast injection (six poorly differentiated, 38 moderately differentiated, and 10 well-differentiated HCCs). Washout was more frequent in poorly than in moderately differentiated HCC (p = 0.0117) and well-differentiated HCC (p = 0.0003) in the 1-minute phase and was more frequent in moderately differentiated than in well-differentiated HCC in the 5-minute (p = 0.0026) and 10-minute (p = 0.0117) phases. Thirteen lesions were isoenhancing or hypoenhancing on peak enhancement sonograms (three moderately differentiated and 10 well-differentiated HCCs). Contrast-enhanced ultrasound and CT during hepatic arteriography did not differ significantly with respect to rate of detection of hyperenhancing lesions., Conclusion: The findings at contrast-enhanced ultrasound with the perflubutane microbubble agent may be predictive of cellular differentiation of HCC without needle biopsy.

We describe a patient with symptomatic giant hepatic hemangioma treated with hepatectomy. A 53-year-old woman presented with upper abdominal distension and appetite loss. The medical history included multiple hepatic hemangiomas that had been detected 2 years earlier but were left untreated. Initial laboratory tests revealed pancytopenia and mild coagulopathy. Computed tomography and magnetic resonance imaging demonstrated a giant hemangioma, 27 cm in diameter, in the enlarged right lobe of the liver. The inferior vena cava was compressed by tumor without thrombus in the infrahepatic vena cava. The portal venous phase of supramesenteric arteriography revealed compression of the portal vein. There were several hemangiomas in the left lobe. Gastric outlet obstruction due to giant hepatic hemangioma in the right lobe was diagnosed. Laparotomy was performed, and a markedly enlarged liver was detected. Right hepatectomy was performed with an anterior approach. The liver-hanging maneuver could not be performed because of tumor compression of the inferior vena cava. Right hepatectomy was performed with intermittent clamping (Pringle maneuver). Hepatic hemangiomas of the left lobe were not resected because the remnant liver would be reduced. The weight of the resected specimen was 2,100 g. Pathologic examination of the surgical specimen confirmed the presence of benign hepatic hemangiomas. The postoperative course was uneventful, and the patient's appetite improved. The patient was discharged 8 days after the operation. Abdominal distension decreased and laboratory data improved after the operation. Computed tomography revealed hypertrophy of the left lobe of the liver after the operation.

Purpose: To elucidate the changes in tumor vascularity and microbubble accumulation on contrast-enhanced sonograms, in relation to the dedifferentiation of hepatocellular carcinoma (HCC)., Materials and Methods: This prospective study enrolled 10 patients with histologically proven HCC (14.4-39.0mm, 26.1+/-7.4) showing nodule-in-nodule appearance upon contrast-enhanced computed tomography. Contrast-enhanced ultrasound was performed by harmonic imaging under a low mechanical index (0.22-0.25) during the vascular phase (agent injection to 1 min) and late phase (15 min) following the injection of Sonazoid (0.0075 ml/kg). Contrast enhancement in the inner and outer nodules was assessed in comparison with that in adjacent liver parenchyma as hyper-, iso-, or hypo-enhanced., Results: Vascular-phase enhancement of all 10 inner nodules was hyper-enhanced, and that of outer nodules was hyper-enhanced in 3, iso-enhanced in 2, and hypo-enhanced in 5. Late-phase enhancement of inner nodules was hypo-enhanced in 8 and iso-enhanced in 2. Furthermore, late-phase enhancement of outer nodules was iso-enhanced in the 7 lesions that showed iso- or hypo-enhancement in the vascular phase, and hypo-enhanced in the 3 with hyper-enhancement in the vascular phase. Late-phase hypo-enhancement was significantly more frequent in the nodules showing early-phase hyper-enhancement (11/13) than in the nodules showing early-phase iso- or hypo-enhancement (0/7) in both the inner and outer nodules., Conclusion: Dedifferentiation of HCC may be accompanied by changes in tumor vascularity prior to a reduction in microbubble accumulation. Observation of the vascular phase may be more useful than late-phase imaging for the early recognition of HCC dedifferentiation when using contrast-enhanced ultrasound with Sonazoid., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Background/aims: The aim was to examine the efficacy of contrast-enhanced ultrasound (US) with Sonazoid to demonstrate ultrasonically unrecognizable hypervascular hepatocellular carcinoma (HCC) and apply percutaneous US-guided treatments., Methods: The subjects of this prospective study were 44 cirrhotic patients with 55 hypervascular lesions (12.7+/-4.5 mm) found by contrast-enhanced computed tomography but unrecognized by non-contrast US. Contrast-enhanced US was performed to demonstrate these hepatic lesions after an intravenous injection of Sonazoid (0.0075 ml/kg). The sonograms in both the early phase (for 1 min after injection) and the late phase (5-10 min after) were taken in the harmonic imaging mode under a low mechanical index (0.24-0.3)., Results: Fifty-three lesions were demonstrated by contrast-enhanced US, 52 with positive enhancement in the early phase and 44 with negative enhancement in the late phase. Percutaneous US-guided treatments were successfully performed for 42 lesions (ethanol injection in 20 and radiofrequency ablation in 22) in 32 patients with reference to contrast-enhanced US findings. Six patients were treated by transarterial chemoembolization alone because they had more than three lesions in the liver. In the remaining seven lesions in six patients, six were diagnosed as non-HCC lesions: five with vascular abnormalities such as arterioportal or arteriovenous communication and the other one with benign lesion in alcoholic liver disease. These six lesions and one HCC lesion with severe liver damage were followed up without any treatment., Conclusions: As the detectability of ultrasonically unrecognizable hypervascular HCC improved by contrast-enhanced US with Sonazoid, a wider application of percutaneous US-guided treatments may be possible.

Background and Aim: Although hypervascular appearance is characteristic in hepatocellular carcinoma (HCC), hepatic nodules without hypervascular appearance are sometimes found in patients with chronic liver disease (CLD). The aim of the present study was to clarify the efficacy of contrast-enhanced ultrasound (CEUS) with Levovist to characterize small, non-hypervascular hepatic nodules on contrast-enhanced computed tomography (CECT) in patients with CLD., Methods: The subject was 41 hepatic nodules (<30 mm, 18.5 +/- 5.6 mm) which showed non-hypervascular appearance on CECT in 35 patients with CLD; their histological results were 31 HCC (15 well, 14 moderate, and two poor) and 10 regenerative nodules (RN). CEUS with Levovist was performed under intermittent scanning (1-s interval) using APLIO at the early phase and the liver-specific phase, and the contrast enhancement of the nodule was assessed in comparison to that of the surrounding liver parenchyma. The contrast-enhanced findings with the time-intensity analysis were compared with the histological results., Results: Twelve nodules with weak enhancement in the liver-specific phase were HCC, regardless of their early-phase appearances. The other 29 nodules with equivalent or weak enhancement in the early phase and equivalent enhancement in the liver-specific phase were 19 HCC and 10 RN. Among them, the maximum-intensity ratio of tumor to non-tumor in the early phase was significantly higher in HCC than in RN (P < 0.01, n = 16), and the receiver-operating characteristic analysis showed a sensitivity of 1.0 and a specificity of 0.83 for their characterization., Conclusion: CEUS with Levovist may be an alternative to biopsy to characterize small, non-hypervascular hepatic nodules on CECT in patients with CLD.

Backgrounds/aims: To elucidate the diagnostic confidence of contrast-enhanced ultrasound (CEUS) with Levovist for hepatic hemangioma., Methodology: The subjects were 34 patients with 38 hemangiomas and 12 patients with 15 hypervascular hepatocellular carcinomas. The early-phase (15-60 second) and liver-specific phase (after 5 min) were observed by the first injection. The 2nd injection was done for solo-phase method to observe liver-specific phase images without taking early-phase sonograms. The 3rd injection was done for changing posture method to observe liver-specific sonograms under left lateral ducubitus position., Results: In the early-phase of hemangioma, nodular enhancement (NE) was found transiently in 13 lesions (34%) and continuously in 25 lesions (66%), while hepatocellular carcinoma (HCC, n = 15) did not show this pattern. Intratumoral arterioportal shunt was closely related to the short duration of NE. Two enhancement patterns were observed in the liver-specific phase of hemangioma, diffuse in 12 lesions (31%) and partial in 26 lesions (69%), which were dependent on the early-phase enhancement. Liver-specific findings were also affected by taking early-phase sonograms or changing the posture of the patient. This method provided sensitivity of 79% and specificity of 100% for the diagnosis of hemangioma., Conclusions: CEUS with Levovist may be promising method for the diagnosis of hepatic hemangioma.

A 75-year-old man with advanced gastric cancer underwent distal gastrectomy with lymph node dissection(D1)and Roux-en Y reconstruction. Pathological staging was Stage IV (T3N3P1CY1M1), and curability was Cur C. He started adjuvant chemotherapy with oral administration of S-1(100 mg/body weight), but experienced grade 3 anorexia for one month. Abdominal computed tomography(CT)2 months postoperatively showed multiple liver metastases and ascites. We then conducted tailored S-1/CPT-11 as second-line chemotherapy(S-1 80 mg/body weight on days 1-5 and 8-12, CPT-11 60 mg/body weight on days 1 and 8). After 5 courses of this therapy, CT showed that the liver metastases and ascites had disappeared, leading to a complete response(CR). The only adverse event was general grade 1 fatigue. He continues to undergo oral administration of S-1(80 mg/body weight)as maintenance therapy, and maintained CR for 12 months since undergoing chemotherapy. Adverse events in tailored S-1/CPT-11 combination therapy are mild and tolerable, making this regimen a potential therapeutic strategy for patients with advanced or recurrent gastric cancer.

A 39-year-old male underwent distal gastrectomy for a high grade gastrointestinal stromal tumor (GIST). Computed tomography (CT) and magnetic resonance imaging (MRI) 107 mo after the operation, revealed a cystic mass (14 cm in diameter) and a solid mass (9 cm in diameter) in the right and left lobes of the liver, respectively. A biopsy specimen of the solid mass showed a liver metastasis of GIST. The patient received imatinib mesylate (IM) treatment, 400 mg/day orally. Following the IM treatment for a period of 35 mo, the patient underwent partial hepatectomy (S4 + S5). The effect of IM on the metastatic lesions was interpreted as pathologic complete response (CR). Pathologically verified cases showing therapeutic efficacy of IM have been rarely reported.

Hepatocellular carcinoma (HCC) has a decisive influence on the prognosis of cirrhotic patients. Although alpha-fetoprotein (AFP) is a known and specific tumor maker for HCC, it is not suitable for the screening and surveillance of HCC because of its poor predictive value and low sensitivity. The use of imaging modalities is essential for the screening, diagnosis and treatment of HCC. Ultrasound (US) plays a major role among them, because it provides real-time and non-invasive observation by a simple and easy technique. In addition, US-guided needle puncture methods are frequently required for the diagnosis and/or treatment process of HCC. The development of digital technology has led to the detection of blood flow by color Doppler US, and the sensitivity for detecting tumor vascularity has shown remarkable improvement with the introduction of microbubble contrast agents. Moreover, near real-time 3-dimensional US images are now available. As for the treatment of HCC, high intensity focused ultrasound (HIFU) was developed as a novel technology that provides transcutaneous ablation effect without needle puncture. These advancements in the US field have led to rapid progress in HCC management, and continuing advances are expected. This article reviews the current application of US for HCC in clinical practice.

Aim: To evaluate the efficacy of contrast-enhanced ultrasound for the localization of ultrasonically invisible hypervascular lesions in the liver to facilitate percutaneous ultrasound-guided treatment., Materials and Methods: Forty patients with 47 ultrasonically invisible hypervascular lesions (5-20mm) diagnosed on contrast-enhanced computed tomography were enrolled in the retrospective study. Contrast-enhanced ultrasound (CEUS) with Levovist was performed to localize the lesions both in the early phase and liver-specific phase. Diagnosis of was confirmed by percutaneous needle biopsy where feasible, and on the basis of on treatment outcomes or changes in computed tomography findings in those not amenable to biopsy., Results: Thirty-two lesions were diagnosed as hepatocellular carcinoma (HCC). Contrast-enhanced ultrasound localized hepatocellular carcinoma in 24/32 (75%) lesions, the mean diameter (15.1+/-4.9mm), as measured using computed tomography, being significantly larger than that of the remaining eight lesions (10.5+/-2.1mm). Ultrasound-guided treatment was performed in 19 of the 24 lesions, and transarterial chemoembolization (TACE) was applied for the other five lesions because of difficult percutaneous access. Five of the eight non-visualised lesions were treated by transarterial chemoembolization, and the other three by surgical resection. The beneficial effect of CEUS was significantly greater when the reason for poor initial visualisation was the coarse liver architecture (17/17) than when it was due to adverse location (seven of 15, p<0.005). Fifteen of the CT-detected hypervascular lesions were considered to represent false positives for HCC, based on their behaviour during follow-up., Conclusion: Contrast-enhanced ultrasound with Levovist facilitates the application of percutaneous ultrasound-guided treatment by improving localization of ultrasonically invisible hypervascular hepatocellular carcinomas in the liver.

The patient was a 66-year-old male who had descending colon cancer with multiple liver metastases and paraaortic lymph node metastases. He underwent a left colectomy with lymph node dissection, but the operation resulted in curability C. The serum CEA level before the operation was 205.5 ng/ml. After 2 courses of 5-FU/LV as first-line chemotherapy, this treatment could not be continued due to grade 3 anorexia. As second-line chemotherapy, the patient was treated with daily oral administration of TS-1 (100 mg/day) for 3 weeks. Due to grade 3 anorexia, this treatment could not be continued. Tailored TS-1/CPT-11 (TS-1 80 mg/day from day 1 to day 21, CPT-11 65 mg/m(2) day 1, 15) combination therapy was then chosen as third-line chemotherapy. After 6 courses of combination therapy, the tumor marker (CEA) was decreased and para-aortic lymph nodes could not be detected by computed tomography (CT). Only grade 1 fatigue was noted as an adverse reaction to the treatment. The patient's good QOL was achieved during follow-up over 24 months with the cancer controlled. This case suggests that patients with non-curative resected colon cancer could benefit from TS-1/CPT-11 combination therapy as a second-line or third-line treatment.

Ultrasound (US) has the advantages of real-time observation, simple technique, and a noninvasive procedure compared to other imaging modalities. The recent development of digital technologies has enabled the observation of sonograms with improved signal-to-noise ratio, penetration, and spatial and contrast resolutions. Furthermore, microbubble contrast agents have increased the diagnostic ability of US examination, and the use of three-dimensional sonograms is now not unusual. These advances have furthered the usefulness of US for liver tumors in clinical practice. This article reviews the recent applications of US in the diagnosis and treatment of hepatocellular carcinoma.

Objective: This study was conducted to determine whether contrast-enhanced 3-dimensional (3D) fusion ultrasonography with combined use of the plane shift and opacity control modes can serve as a useful tool for identifying the vascular characteristics of hepatic tumors in 3D perspective., Methods: Contrast-enhanced 3D fusion ultrasonography was performed in 31 patients with hepatic tumors after the intravenous injection of contrast media. The shapes, courses, and distributions of tumor vessels, displayed in 3D perspective, were examined to identify the characteristic vascular flow patterns of various tumors. Images before and after contrast media administration were compared for evaluation of the effectiveness of contrast enhancement with regard to tumor diameter for various types of tumors. The images were interpreted in a blinded manner by 3 physicians specializing in abdominal ultrasonography, and vascular flow patterns were determined on the basis of consensus., Results: The characteristic vascular flow patterns observed in hepatocellular carcinomas are reticular flow within the tumor and flow showing a ringlike distribution surrounding the tumor. Metastatic tumors show a vascular flow pattern running between adjacent tumor nodules, and hemangiomas show localized nodular flow at the tumor margins. Contrast enhancement was found to be useful for showing the vascular flow patterns in small hepatocellular carcinomas and hemangiomas., Conclusions: Contrast-enhanced 3D fusion ultrasonography makes it possible to display images combining the plane shift and opacity control modes to show tumor vessels, including minute vascular flow within hepatic tumors, in 3D perspective and to identify tumor-specific vascular flow patterns.

We have treated a case of hepatic metastasis of gastric cancer that has responded well to TS-1. The patient was a 68-year-old male, who underwent distal gastrectomy for gastric cancer. After surgery 5'-deoxy-5-fluorouridine (5'-DFUR) 800 mg/day was administered orally for two months. Grade 4 diarrhea appeared, so administration of 5'-DFUR was discontinued. Afterward the patient was followed with no chemotherapy. Liver metastasis (S6, 3 cm in diameter) was found at twelve months after surgery. 5'-DFUR (800 mg/day) was administered orally everyday. Grade 3 diarrhea appeared and metastasis showed NC after four weeks. 5'-DFUR administration was discontinued. Seventeen days later TS-1 (80 mg/day) was administered orally everyday for 2 weeks, followed by 1 week rest, as one course. Two courses of TS-1 administration resulted in a marked reduction of the liver metastasis, for a PR (75% reduction). After 3 courses, the liver metastasis showed CR. The patient is alive without recurrence after 12 courses. This TS-1 administration regimen was effective and tolerable for a patient with liver metastasis from gastric cancer.

Background: Features of enhanced color flow images in small hepatocellular carcinoma (HCC) are not fully elucidated. The purpose of this study was to clarify the characteristic vascular images in small HCC observed by enhanced color Doppler., Methods: Enhanced color Doppler using the contrast agent Levovist was performed on 13 patients with HCC smaller than 30 mm. Enhanced color flow appearance was compared with angiographic findings. Time-intensity changes after injection of the contrast agent were analyzed in HCC nodules., Results: Significant improvement in the detection of color flow signals was obtained in small HCC using Levovist, from 33% in precontrast to 92% in postcontrast (p < 0.005). Three patterns of enhanced color flow images, which were related to the angiographic findings, were observed. The time-intensity curve was classified into two types by "time to peak" and "time on plateau" and was associated with the patterns of enhanced images., Conclusion: Enhanced color flow imaging promises to be a useful method for evaluating tumor vascularity noninvasively and to contribute to the elucidation of the hemodynamics in small HCC.

We experienced a case of multiple liver metastasis from postoperative gastric cancer who showed long-term survival with hepatic arterial infusion chemotherapy (HAI) of MMC and pirarubicin. A catheter was inserted into the hepatic artery, and 4 mg of MMC and 20 mg of pirarubicin were administered through an implantable port catheter every two to four weeks. The total dose of MMC and pirarubicin by the time of this report was 164 mg and 820 mg, respectively. The follow-up CT scan 2 months after the beginning of HAI showed a decrement of the liver tumors. The decrease rate at 12 and 17 months was 50% and 70%, respectively, which was diagnosed as partial response (PR). The therapeutic effect at 49 months is still PR without any sign of tumor enlargement of extra hepatic lesion.

Features of enhanced color flow images of small hepatocellular carcinoma (HCC) were studied to elucidate their usefulness in evaluating tumor hemodynamics. Enhanced color Doppler using the contrast agent "SH/TA508" was performed on 16 patients, 13 with HCC, 1 with regenerative nodule, and 2 with hemangiomas, in whom the size of the tumor were smaller than 30 mm. Enhanced color flow appearance was compared with angiographic findings. Significant improvement in the detection of color flow signals was obtained in small HCC using SH/TA508, from 33% in pre-contrast to 92% in post-contrast (p < 0.005). Three patterns of enhanced color flow images, which were related to the angiographic findings, were observed. Enhanced color flow imaging promises to be a useful method for evaluating tumor vascularity noninvasively, and to contribute to the elucidation of the hemodynamics in liver tumor.

Since 1988, 124 patients with hepatocellular carcinoma were treated in our departments. Among them, 31 cases treated by surgical resection and 30 cases administered a combination therapy (Lipiodol [Laboratoire Guerbet, Villepinte, France]-transcatheter arterial embolization [L-TAE] and lipiodol-percutaneous ethanol injection therapy [L-PEIT]) were analyzed retrospectively. The 1-, 3-, and 5-year survival rates were, respectively, 89.0%, 72.7%, and 63.6% for the surgical resection group and 93.3%, 72.8%, and 42.0% for the combination therapy group. The follow-up results at less than 4 years after the procedures revealed that the survival rate with the combination therapy was slightly better than that with the surgical treatment. However, in the subsequent 4 years, the survival rate of the combination therapy group decreased rapidly. The reasons for this deterioration were local recurrence and/or new primary lesions of hepatocellular carcinoma, mainly due to inappropriate ethanol injection. To achieve adequate and accurate injection of ethanol, a 10% volume of Lipiodol was mixed with the ethanol so that the location of the injected ethanol could be easily confirmed. The effectiveness of L-PEIT was thus confirmed by computed tomography, performed on the following day. Defective Lipiodol accumulation in the tumor and/ or neighboring tissues was able to be corrected by additional ethanol injections. With this L-PEIT technique, the tumor necrosis rate is now improving. Therefore, a better prognosis is expected.

Twelve patients with liver metastases of breast cancer were treated with hepatic arterial infusion chemotherapy using 20-30 mg/body of epi-adriamycin (epi-ADM) every 2 weeks and continuous infusion of 250 mg/body/day of 5-fluorouracil (5-FU). All patients were followed by systemic chemo-endocrine therapy with oral administration of 600-1,200 mg/day of me droxyprogesterone acetate (MPA) alone or with 600-800 mg/day of 5'-deoxy-5-flurouridine (5'-DFUR). The response rate was 41.7% (5/12 cases). Duration of response was 2-28 months (mean 10 months). At one year, the survival rate was 46.8% (Kaplan-Meier method). As for side effects, gastrointestinal disturbance, bone marrow depression and alopecia were mild. These results suggest that hepatic arterial infusion therapy in combination with MPA is safe and effective for controlling liver metastases of breast cancer.

Seventeen patients with liver metastases of breast cancer were treated with a combination of intra-arterial chemotherapy and endocrine therapy at our hospital from 1986 to 1994. Of 17 patients, 9 were treated with transarterial chemoembolization through hepatic artery using 40-50 mg/body of 4'epi-adriamycin (epi-ADM) and lipiodol, and the other 8 were treated with hepatic infusion chemotherapy using 20-30 mg/body of epi-ADM every 2 weeks. All patients were followed by endocrine therapy with oral administration of 800-1,200 mg/day of medroxyprogesterone acetate (MPA). The results were as follows: 1) The comparison of response rate between the two groups was not substantially changed (44.4% x 4/9 in TAE group and 50.0% x 4/8 in Reservoir group). 2) Duration of response was 4-45 months (mean 25 months) in TAE group and 3-15+ alpha months (mean 8.7 months) in Reservoir group. But in the latter group, 3 patients are now under treatment. 3) At one year, the survival rates were 44.4 percent in TAE group and 50.0 percent in Reservoir group. We conclude that combination of intra-arterial chemotherapy and endocrine therapy is a useful treatment modality for controlling liver metastases of breast cancer.

The subjects were 35 patients with unresectable hepatocellular carcinoma. The patients were divided into a transcatheter arterial embolization group (TAE group, 18 cases) and a combination therapy group receiving both TAE and percutaneous ethanol injection therapy (TAE+PEIT group, 17 cases). The 50% survival period was 21.1 months for the TAE group and 37.8 months for the TAE+PEIT group (P < 0.05). The longest survival period in the TAE group was 89 months. In the TAE+PEIT group, one patient has survived for 59 months. The actuarial 1-, 2-, and 3-year survival rates for the TAE group were 82%, 45%, and 22%, respectively. For the TAE+PEIT group the rates were 83%, 64%, and 64%, respectively. The TAE+PEIT group showed a significantly higher survival rate in the 895- to 1,074-day period as compared with the TAE group (P < 0.05). Overall, the survival rate tended to be higher in the TAE-PEIT group (P < 0.1). The therapeutic responses of tumors were measured by the maximal reduction rate within 6 months of TAE and PEIT. In the TAE group, a PR was seen in only four cases. In the TAE+PEIT group, CRs and PRs were achieved significantly more frequently than in the TAE group. When the patients were divided into a responder group (CR, PR, and MR) and a nonresponder group (NC and PD), survival was significantly longer in the responder group. The findings of the present study suggest that the combination therapy was useful for improving the survival of patients with unresectable hepatocellular carcinoma.

We studied and analysed the effects of combination therapy with TAE and PEIT for unresectable HCC. The subjects were 28 patients (21 males, 7 females) with 31 tumors treated in the Department of Surgery, Osaka Teishin Hospital. The patients were divided into four groups on the basis of the tumor size (< 3 cm, 3-5 cm, 5-8 cm, > 8 cm). The therapeutic effect on the tumors was evaluated on the basis of the maximum reduction rate within 3 months after TAE and PEIT. The response rates after treatment were 87.5%, 60.0%, 25.0% and 0% for < 3 cm, 3-5 cm, 5-8 cm, and > 8 cm tumor size, respectively. The 50% survival period was 50.9 months. The 1-, 2-, 3- and 5-year survival rates were 92%, 76%, 52% and 32%, respectively. In the cases of over 8 cm, this combination therapy had no effects on the survival period. The findings of the present study suggest that the combination therapy was useful for the unresectable HCC of under 5 cm in diameter.

The modifying effects of an immunosuppressive agent, 6-mercaptopurine (6-MP), on development of focal lesions in liver cirrhosis models induced by carbon tetrachloride (CCl4) or furfural were studied in male F344 rats. Feeding of 6-MP at 50 p.p.m. for 20 weeks to animals with pre-existing liver cirrhosis caused immunosuppression, and significantly enhanced the induction of gamma-glutamyltranspeptidase (GGT)-positive foci and nodules in the CCl4 but not furfural case. Glutathione S-transferase P (GST-P)-positive preneoplastic lesions were not affected. Moreover, phenobarbital (PB) also enhanced the induction of GGT-positive hepatocellular lesions only in the CCl4-induced liver cirrhosis model, no promotion influence being exerted after treatment with the non-carcinogenic furfural. This study, therefore, suggests that 6-MP can enhance the induction of one type of preneoplastic foci and nodules and that essential differences exist between focal lesions arising in cirrhotic livers caused by CCl4 as opposed to furfural.