Masashi Hirooka

Liver Fibrosis in Patients with Chronic Hepatitis C: Noninvasive Diagnosis by Means of Real-time Tissue Elastography—Establishment of the Method for Measurement

PURPOSE To prospectively measure liver stiffness with real-time tissue elastography in patients with chronic hepatitis C and to compare the results with those of clinical assessment of fibrosis by using histologic stage as the reference standard. MATERIALS AND METHODS All subjects gave informed consent, and the study was approved by the institutional ethics committee. Seventy hospitalized patients (46 men, 24 women; mean age, 65.5 years ± 11.7 [standard deviation]; age range, 33-87 years) with chronic hepatitis C underwent real-time elastography between January 2009 and September 2009. Elastography was performed at four liver locations by two independent observers. The elastic ratio (ratio of the value in the intrahepatic venous small vessels divided by the value in the hepatic parenchyma) was calculated and was compared with histologic fibrosis stage at liver biopsy. The elastic ratio and clinical fibrosis markers were assessed by using receiver operating characteristic (ROC) analysis. The differences between body site and observers were assessed with κ statistics and intraclass correlation coefficients (ICCs). RESULTS Real-time tissue elastography cutoff values were 2.73 for F of 2 or greater, 3.25 for F of 3 or greater, and 3.93 for F of 4. No site differences were observed (κ = 0.835, ICC = 0.966), and the elastic ratio measurement was correlated between the two examiners (r(2) = 0.869, P < .0001). The areas under the ROC curves for elastic ratio, hyaluronic acid, type IV collagen, aspartate aminotransferase-to-platelet ratio index, FibroIndex, Forns score, and Hepascore were 0.95, 0.32, 0.73, 0.76, 0.76, 0.87, and 0.70, respectively; the elastic ratio performed better than the serum fibrosis markers and other scores. CONCLUSION Real-time tissue elastography is not invasive and could be used to evaluate liver fibrosis in patients with chronic hepatitis C. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100319/-/DC1.

FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma

The response rate to sorafenib in hepatocellular carcinoma (HCC) is relatively low (0.7%‐3%), however, rapid and drastic tumor regression is occasionally observed. The molecular backgrounds and clinico‐pathological features of these responders remain largely unclear. We analyzed the clinical and molecular backgrounds of 13 responders to sorafenib with significant tumor shrinkage in a retrospective study. A comparative genomic hybridization analysis using one frozen HCC sample from a responder demonstrated that the 11q13 region, a rare amplicon in HCC including the loci for FGF3 and FGF4, was highly amplified. A real‐time polymerase chain reaction–based copy number assay revealed that FGF3/FGF4 amplification was observed in three of the 10 HCC samples from responders in which DNA was evaluable, whereas amplification was not observed in 38 patients with stable or progressive disease (P = 0.006). Fluorescence in situ hybridization analysis confirmed FGF3 amplification. In addition, the clinico‐pathological features showed that multiple lung metastases (5/13, P = 0.006) and a poorly differentiated histological type (5/13, P = 0.13) were frequently observed in responders. A growth inhibitory assay showed that only one FGF3/FGF4‐amplified and three FGFR2‐amplified cancer cell lines exhibited hypersensitivity to sorafenib in vitro. Finally, an in vivo study revealed that treatment with a low dose of sorafenib was partially effective for stably and exogenously expressed FGF4 tumors, while being less effective in tumors expressing EGFP or FGF3. Conclusion: FGF3/FGF4 amplification was observed in around 2% of HCCs. Although the sample size was relatively small, FGF3/FGF4 amplification, a poorly differentiated histological type, and multiple lung metastases were frequently observed in responders to sorafenib. Our findings may provide a novel insight into the molecular background of HCC and sorafenib responders, warranting further prospective biomarker studies. (HEPATOLOGY 2013)

Percutaneous ultrasound-guided radiofrequency ablation of hepatocellular carcinoma with artificially induced pleural effusion and ascites.

BackgroundUltrasound-guided procedures are sometimes of limited use because the tumor is located under the diaphragm or near the surface of the liver. We investigated the safety and efficacy of radiofrequency ablation (RFA) with artificial pleural effusion and/or artificial ascites.MethodsBetween January 2002 and May 2006, 43 lesions in 36 patients with hepatocellular carcinoma (HCC) were treated by RFA with artificial pleural effusion and/or artificial ascites.ResultsArtificial pleural effusion allowed visualization of the whole tumor for 36 (83.7%) of the 43 lesions that were otherwise not detectable or poorly visible. Artificial ascites was also helpful in visualizing whole tumors that could not be visualized with only artificial pleural effusion. In all lesions, artificial pleural effusion and/or artificial ascites were helpful in performing percutaneous RFA. Artificial ascites was useful for creating a space between the livers surface and the skin or diaphragm to avoid burns. Adverse effects after the induction of artificial pleural effusion included pneumonia in one patient and temporary atelectasis in another patient. Severe side effects were not observed. Complete necrosis after RFA was obtained in 43 (100%) of the 43 lesions. During a mean follow-up period of 31.8 ± 5.8 months, local recurrence at the ablation site was found in none of the 43 lesions.ConclusionsPercutaneous RFA with artificial pleural effusion and/or artificial ascites was a safe and useful treatment that resulted in good local control of HCC.

Phase I/II study of immunotherapy using tumor antigen-pulsed dendritic cells in patients with hepatocellular carcinoma

Dendritic cells (DCs) are increasingly used as adjuvants for vaccination strategies; however, there has been very little development in DC vaccines for patients with hepatocellular carcinoma (HCC). In this study, we assessed the safety, feasibility and efficacy of a multiple tumor-associated antigen (TAA)-pulsed DC vaccine in 5 patients with advanced HCC. DCs were generated by culturing blood monocytes in the presence of granulocyte macrophage-colony stimulating factor and interleukin-4 for 5 days. The DC vaccine was prepared by pulsing DCs with cytoplasmic transduction peptide-attached α-fetoprotein, glypican-3 and MAGE-1 recombinant fusion proteins and cultivating them in the presence of maturation cocktail. DCs were injected subcutaneously near the inguinal lymph nodes, followed by topical application of toll-like receptor-7 agonist around the injection site. We showed that our DC vaccine was safe and well-tolerated over 6 vaccinations in 5 patients. All 5 patients showed T cell responses against TAAs. Clinical benefit was observed in one of the 5 patients. In conclusion, the feasibility, safety and immune activity of DCs pulsed with TAAs were confirmed in HCC patients. However, clinical response was detected only in one patient. Future trials may consider applying this therapy in a less advanced stage to obtain better clinical responses.

Real‐time tissue elastography for evaluation of hepatic fibrosis and portal hypertension in nonalcoholic fatty liver diseases

The aim of this study was to prospectively measure liver stiffness with real‐time tissue elastography in patients with nonalcoholic fatty liver diseases (NAFLD) and to compare the result with the clinical assessment of fibrosis using histological stage. One hundred and eighty‐one prospectively enrolled patients underwent real‐time tissue elastography, with the first 106 being analyzed as the training set and the remaining 75 being evaluated as the validation set. Hepatic and splenic elastic ratios were calculated and compared with stage of histological fibrosis. Portal hypertension (PH) was assessed. Real‐time tissue elastography cut‐off values by stage in the training set were 2.47 for F1, 2.67 for F2, 3.02 for F3, and 3.36 for F4. Using these cut‐off values, the diagnostic accuracy of hepatic fibrosis in the validation set was 82.6%‐96.0% in all stages. Only portal fibrosis correlated with the hepatic elastic ratio by multivariate analysis. The area under the receiver operating characteristic curve of elastic ratio better correlated than serum fibrosis markers in both early and advanced fibrosis stages. Patients with PH, defined by splenic elasticity, had early fibrosis. Patients with severe PH were found only in the group with cirrhosis. Conclusion: Real‐time tissue elastography is useful in evaluating hepatic fibrosis and PH in patients with NAFLD. (HEPATOLOGY 2012)

Virtual Sonographic Radiofrequency Ablation of Hepatocellular Carcinoma Visualized on CT but Not on Conventional Sonography

OBJECTIVE Some nodules cannot be visualized clearly on conventional sonography but can be visualized on CT. In the present study, we evaluated the usefulness of real-time percutaneous ablation therapy under virtual sonographic guidance for these nodules. SUBJECTS AND METHODS In vitro experiments were performed with gelatin gel to evaluate the accuracy of virtual sonography. We also studied 50 patients with 58 hepatocellular carcinoma nodules, of whom 18 patients (21 nodules) underwent radiofrequency ablation by virtual sonography. This was the initial treatment for seven of these patients and an additional treatment for 11 patients. Thirty-two patients (37 nodules) received radiofrequency ablation without virtual imaging. The patients receiving standard radiofrequency ablation were retrospectively selected as the historical control group under the same conditions as the study group. RESULTS The in vitro gelatin gel study revealed that all punctures had been performed accurately. In both the initial-treatment group and the additional-treatment group, the mean number of treatments with virtual sonography was significantly lower than that without virtual sonography (p = 0.003 for both groups). The rates of local recurrence and complications did not differ significantly between the two groups. CONCLUSION In the treatment of nodules not depicted on sonography, radiofrequency ablation assisted by virtual sonography is an efficacious alternative.

Splenic Elasticity Measured with Real-time Tissue Elastography Is a Marker of Portal Hypertension

PURPOSE To prospectively correlate spleen elasticity and degree of portal hypertension estimated with the hepatic venous pressure gradient (HVPG) and to evaluate splenic elasticity as a predictor of gastroesophageal varices. MATERIALS AND METHODS The institutional review board approved this study, and patients provided written informed consent. In a pilot study of 60 patients with chronic liver damage, the authors measured liver and spleen elasticity with real-time tissue elastography (RTE), obtained serum markers related to fibrosis, examined hepatic and splenic blood flow with duplex Doppler ultrasonography, estimated HVPG, and performed upper gastrointestinal endoscopy. Then, with use of thresholds determined in the pilot study, the authors conducted a validation trial with another 210 patients, performing all studies except the measurement of HPVG. The relationship between HVPG and the other parameters was analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in the diagnosis of gastroesophageal varices were calculated by using cutoff values obtained from receiver operating characteristic curves. RESULTS Among the parameters associated with HVPG, correlation was closest with splenic elasticity (R = 0.854, P < .0001). When 8.24 was selected as the cutoff of splenic elasticity for predicting HVPG of more than 10 mm Hg, the accuracy of diagnosing gastroesophageal varix was 90% (sensitivity, 96%; specificity, 85%; PPV, 83%; NPV, 97%). The results of the validation trial showed that the 8.24 cutoff for splenic elasticity was associated with a diagnostic accuracy of 94.8% (sensitivity, 98%; specificity, 93.8%; PPV, 82.1%; NPV, 99.4%) for gastroesophageal varices. CONCLUSION Splenic elasticity determined with RTE is the most closely associated parameter for evaluating HVPG and is useful as a clinical marker of portal hypertension and a predictive marker of gastroesophageal varices.

JSUM ultrasound elastography practice guidelines: liver

In diffuse liver disease, it is extremely important to make an accurate diagnosis of liver fibrosis prior to determining indications for therapy or predicting treatment outcome and malignant potential. Although liver biopsy has long been the gold standard in the diagnosis of liver fibrosis, it is still an invasive method. In addition, the sampling error is an intrinsic problem of liver biopsy. Non-invasive serological methods for the diagnosis of liver fibrosis can be affected by factors unrelated to the liver. Recently, after the introduction of FibroScan, it became possible to measure liver fibrosis directly and non-invasively by elastography, which has attracted attention as a non-invasive imaging diagnostic tool for liver fibrosis. In addition, real-time tissue elastography is currently being used to conduct clinical trials at many institutions. Moreover, virtual touch quantification enables the observation of liver stiffness at any location by simply observing B-mode images. Furthermore, the recently developed ShearWave elastography visualizes liver stiffness on a color map. Elastography is thought to be useful for all types of diffuse liver diseases. Because of its association with portal hypertension and liver carcinogenesis, elastography is expected to function as a novel prognostic tool for liver disease. Although various elastographic devices have been developed by multiple companies, each device has its own measurement principle, method, and outcome, creating confusion in clinical settings. Therefore, it is extremely important to understand the characteristics of each device in advance. The objective of this guideline, which describes the characteristics of each device based on the latest knowledge, is for all users to be able to make the correct diagnosis of hepatic fibrosis by ultrasound elastography.

Diabetes pattern on the 75 g oral glucose tolerance test is a risk factor for hepatocellular carcinoma in patients with hepatitis C virus.

Background: Patients with hepatitis C virus (HCV) frequently show glucose intolerance. Diabetes mellitus (DM) has been proposed to be a risk factor for hepatocellular carcinoma (HCC).

Radiofrequency ablation therapy for hepatocellular carcinoma in elderly patients

Background and Aim:  With the aging of society, the number of elderly patients with hepatocellular carcinoma (HCC) has been increasing in Japan. The Government of Japan defines elderly as being over 65 and has divided the elderly into two stages: the first elderly stage (< 75 years old) and the second elderly stage (≥ 75). We investigated the efficacy and safety of radiofrequency ablation therapy (RFA) in patients in the second elderly stage in comparison with other HCC patients, retrospectively.