Manabu Takamura

Gd-EOB-DTPA-enhanced magnetic resonance images of hepatocellular carcinoma: correlation with histological grading and portal blood flow

Objective:To retrospectively investigate enhancement patterns of hepatocellular carcinoma (HCC) and dysplastic nodule (DN) in the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced MRI in relation to histological grading and portal blood flow.Methods:Sixty-nine consecutive patients with 83 histologically proven HCCs and DNs were studied. To assess Gd-EOB-DTPA uptake, we calculated the EOB enhancement ratio, which is the ratio of the relative intensity of tumorous lesion to surrounding nontumorous area on hepatobiliary phase images (post-contrast EOB ratio) to that on unenhanced images (pre-contrast EOB ratio). Portal blood flow was evaluated by CT during arterial portography.Results:Post-contrast EOB ratios significantly decreased as the degree of differentiation declined in DNs (1.00 ± 0.14) and well, moderately and poorly differentiated HCCs (0.79 ± 0.19, 0.60 ± 0.27, 0.49 ± 0.10 respectively). Gd-EOB-DTPA uptake, assessed by EOB enhancement ratios, deceased slightly in DNs and still more in HCCs, while there was no statistical difference in the decrease between different histological grades of HCC. Reductions in portal blood flow were observed less frequently than decreases in Gd-EOB-DTPA uptake in DNs and well-differentiated HCCs.Conclusions:Reduced Gd-EOB-DTPA uptake might be an early event of hepatocarcinogenesis, preceding portal blood flow reduction. The hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI may help estimate histological grading, although difficulties exist in differentiating HCCs from DNs.

Hypervascular hepatocellular carcinomas: detection with gadoxetate disodium-enhanced MR imaging and multiphasic multidetector CT

ObjectivesTo retrospectively compare the accuracy of detection of hypervascular hepatocellular carcinoma (HCC) by multiphasic multidetector CT and by gadoxetate disodium-enhanced MR imaging.MethodsAfter ethical approval, we analysed a total of 73 hypervascular HCC lesions from 31 patients suspected of having HCC, who underwent both gadoxetate disodium-enhanced MR imaging and multiphasic multidetector CT. Five blinded observers independently reviewed CT images, as well as dynamic MR images alone and combined with hepatobiliary phase MR images. Diagnostic accuracy (Az values), sensitivities and positive predictive values were compared by using the Scheffe post hoc test.ResultsThe mean Az value for dynamic and hepatobiliary phase MR combined (0.81) or dynamic MR images alone (0.78) was significantly higher than that for CT images (0.67, P < 0.001, 0.005, respectively). The mean sensitivity of the combined MR images (0.67) was significantly higher than that of dynamic MR alone (0.52, P < 0.05) or CT images (0.44, P < 0.05). The mean positive predictive values were 0.96, 0.95 and 0.94, for CT, dynamic MR alone and combined MR images, respectively.ConclusionsCompared with multiphasic multidetector CT, gadoxetate disodium-enhanced MR imaging combining dynamic and hepatobiliary phase images results in significantly improved sensitivity and diagnostic accuracy for detection of hypervascular HCC.Key Points• Gadoxetate disodium is a new liver-specific MR imaging contrast agent. Gadoxetate disodium-enhanced MRI helps the assessment of patients with liver disease.• It showed high diagnostic accuracy for the detection of hepatocellular carcinoma.

Percutaneous Microwave Tumor Coagulation for Hepatocellular Carcinomas with Interruption of Segmental Hepatic Blood Flow

PURPOSE To assess the effect of hepatic artery occlusion with or without hepatic venous outflow interruption on coagulation diameter during percutaneous microwave coagulation therapy (PMCT) for hepatocellular carcinoma (HCC) by a prospective and randomized trial. MATERIALS AND METHODS Thirty-one patients with 36 HCCs (10-38 mm in diameter) were randomly separated into two treatment groups as follows: group 1 (14 tumors in 14 patients) was treated with PMCT in conjunction with both segmental hepatic artery embolization with gelatin sponge particles and temporary interruption of hepatic venous flow by means of a 6-F balloon catheter to reduce the portal venous flow; group 2 (22 tumors in 17 patients) was treated with PMCT with segmental hepatic artery embolization only. PMCT under ultrasound (US) guidance was performed with 2,450 MHz of microwave frequency at 40-60 W and a needle applicator 1.6 mm in diameter. The coagulated area was measured at the maximum diameter perpendicular to the needle tract on enhanced computed tomography (CT) performed immediately after PMCT. The local effect of the treatment was evaluated by follow-up enhanced CT (6-33 mo). RESULTS Patients in group 1 had a significantly larger coagulation area (mean +/-SD = 42.9 mm +/- 8.3), with coagulation times of 5.3 min +/- 1.4, than patients in group 2 (32.6 mm +/- 8.0), with coagulation times of 4.2 min +/- 1.3 (P <.05). Follow-up enhanced CT showed no local enhancement of the tumor, indicating complete necrosis and no local recurrence, except for four tumors. There were no major complications after PMCT except liver abscess that developed after PMCT in one patient with pneumobilia. CONCLUSIONS PMCT with combined hepatic arterial embolization and temporary hepatic venous flow interruption can coagulate significantly larger volumes of tumor than PMCT with only hepatic arterial embolization.

Microwave Coagulation Therapy with Interruption of Hepatic Blood Inor Outflow: An Experimental Study

PURPOSE To determine how interruption of hepatic blood in- or outflow affects the coagulation diameter of microwave coagulation therapy (MCT) in the liver. MATERIALS AND METHODS Laparotomic MCT at 60 W for 1 minute was performed in 11 Landrace pigs. MCT was performed under six different conditions: without occlusion (Group N; in seven lobes of seven pigs); with occlusion of the hepatic artery (Group A; in five lobes of five pigs); with occlusion of the portal vein (Group P; in five lobes of five pigs); with occlusion of the hepatic artery and portal vein (Group AP; in six lobes of six pigs); with occlusion of the hepatic vein (Group V; in five lobes of four pigs); and with occlusion of the hepatic artery and vein (Group AV; in seven lobes of seven pigs). The maximum diameters for each group were compared. RESULTS The coagulation diameters (mean +/- SD) were 8.5 mm +/- 2.0, 10.0 mm +/- 1.6, 14.3 mm +/- 2.5, 14.4 mm +/- 2.4, 13.0 mm +/- 0.8, and 14.4 mm +/- 1.5 for Groups N, A, P, AP, V, and AV, respectively. The coagulation diameters for groups P, AP, V, and AV were statistically larger than those for groups N and A (P < .05). There was no significant difference between the coagulation diameters of Groups P, AP, V, and AV. CONCLUSION The coagulation diameter depends mainly on the portal venous flow. In addition of direct interruption of the portal vein, interruption of the hepatic vein can also result in a substantial increase in the coagulation diameter.

Comparison of enhancement patterns of histologically confirmed hepatocellular carcinoma between gadoxetate- and ferucarbotran-enhanced magnetic resonance imaging

To compare enhancenent patterns of hepatocellular carcinoma (HCC) and dysplastic nodule (DN) between gadoxetate‐ and ferucarbotran‐enhanced MRI.

Detection of hypervascular hepatocellular carcinoma: comparison of SPIO-enhanced MRI with dynamic helical CT.

Purpose The purpose of this study was to compare the diagnostic performance of superparamagnetic iron oxide (SPIO)-enhanced MRI for the detection of hypervascular hepatocellular carcinoma (HCC) with dynamic helical CT. Methods SPIO-enhanced MR and dynamic helical CT images obtained from 41 patients with 52 hypervascular HCCs (5–130 mm; mean, 27 mm) were retrospectively analyzed. MRI were obtained with 1.5 T scanners using T2-weighted and proton density-weighted spin-echo (or fast spin-echo) sequences for all cases and a T2*-weighted gradient echo sequence for 36 cases. Four blinded observers reviewed images independently. Diagnostic accuracy was evaluated using alternative-free response receiver operating characteristic (AFROC) method. Sensitivities and positive predictive values (PPV) were also evaluated. Results The areas under the AFROC curves for each observer were greater for MR than for CT (means, 0.81 and 0.76; p < 0.05). The mean sensitivities for MR and CT were 0.75 and 0.71, respectively (p = 0.13). The mean PPVs were 0.83 and 0.79 (p = 0.21). Conclusion SPIO-enhanced MRI showed slightly better diagnostic performance than dynamic helical CT for the detection of hypervascular HCCs.

Regorafenib as Second-Line Systemic Therapy May Change the Treatment Strategy and Management Paradigm for Hepatocellular Carcinoma

At the European Society of Medical Oncology World Congress of Gastrointestinal Cancer held in Barcelona, Spain, on 30th June 2016, positive outcomes were reported by the Study of Regorafenib after Sorafenib in Patients with Hepatocellular Carcinoma (RESORCE) trial, which investigated the efficacy of regorafenib as second-line therapy after sorafenib failure [1]. In this clinical trial, the group who received regorafenib achieved a survival benefit of approximately 2.8 months compared to the placebo group. Overall survival (OS) was 10.6 months in the regorafenib arm compared with 7.8 months in the placebo arm, with a hazard ratio (HR) of 0.62 (95% confidence interval [CI]: 0.50–0.78; p<0.001). These are groundbreaking results. The positive outcome achieved by this second-line systemic therapy is a major development, especially after the numerous reports of failures in clinical studies of first-and second-line systemic therapeutic agents (table ​(table1).1). Regorafenib therapy is expected to significantly prolong life expectancy by approximately 2.8 months in patients with hepatocellular carcinoma (HCC) who develop progressive disease (PD) during sorafenib therapy. This development will certainly lead to drastic changes in the treatment strategy and management paradigm for HCC. Table 1 Phase III Clinical Trials of Japanese Participation for HCC Design of the RESORCE Trial The RESORCE trial enrolled 573 patients with advanced HCC corresponding to Barcelona Clinic Liver Cancer (BCLC) stage B or C who were unresponsive to sorafenib. The patients were divided into placebo and regorafenib arms at a 1:2 ratio for the daily administration of placebo and oral regorafenib (160 mg), respectively, for three weeks on and one week off (four weeks/cycle) (fig. ​(fig.1).1). Geographic region, performance status on the Eastern Cooperative Oncology Group scale, α-fetoprotein level (≥400 or <400 ng/mL), macrovascular invasion, and extrahepatic disease were used as allocation factors. This study excluded patients who were intolerant of sorafenib and who discontinued the treatment because of side effects. It enrolled only those patients who discontinued sorafenib because of evidence of PD on imaging studies. In addition, patients were included only if they had received ≥400 mg sorafenib for at least 20 of 28 days immediately prior to radiologically detected PD. In other words, this trial was designed (1) to ensure regorafenib tolerance among patients, and to reduce the occurrence of the drug-specific skin symptoms because the compound is structurally similar to sorafenib [2,3] (fig. ​(fig.2)2) and (2) to reduce the effect of post-trial treatment on OS in both the placebo and treatment arms by using a homogeneous group of patients who developed PD due to sorafenib failure. Fig. 1 Design of the RESORCE Trial. ECOG PS=Eastern Cooperative Oncology Group Performance Status; RECIST=Response Evaluation Criteria in Solid Tumors. Fig. 2 Chemical structure of Regorafenib is very similar to that of Sorafenib. In general, post-progression survival (PPS) is defined as the time interval between the diagnosis of PD after primary treatment and the patients death, and OS is the sum of PPS and progression-free survival (PFS). Therefore, even significant differences in PFS can be canceled out because PPS is prolonged. Indeed, OS showed a stronger correlation with PPS than with PFS in a clinical trial of sorafenib [4]. Because HCC responds extremely well to locoregional therapy, it is often used as post-trial treatment even in cases in which locoregional therapy is no longer applicable and molecular targeted agents are subsequently administered in accordance with the protocol, provided that the patients general condition is stable. This rarely happens with other types of cancer and is therefore essentially unique to HCC, owing to the availability of powerful locoregional therapies such as intra-arterial infusion chemotherapy [5, 6, 7], transcatheter arterial chemoembolization (TACE) [8, 9], and radiofrequency ablation [10, 11, 12]. These post-trial treatments are capable of canceling out any difference in the primary endpoint OS by prolonging PPS [13]. Indeed, previous clinical trials of second-line agents other than regorafenib have always included patients intolerant to sorafenib, which may have increased the influence of post-trial treatment and thus contributed to their negative outcomes. Patients unresponsive to sorafenib are those who develop PD during sorafenib therapy and are likely to have relatively poor hepatic function and overall general condition. By contrast, patients intolerant to sorafenib are those who discontinue the treatment because of side effects; these patients are in relatively stable conditions because of negligible amounts of internalized sorafenib, and a lack of HCC progression. Because of their clinical stability, patients intolerant to sorafenib are inevitably treated by locoregional therapy or various other post-trial treatments, including the re-administration of sorafenib, regardless of whether they received an actual second-line agent or placebo during the trial. With this in mind, clinical trials of second-line agents should enroll only patients who are unresponsive to sorafenib [14]. The RESORCE trial was the first clinical study to reflect this point in the trial design (fig. ​(fig.1).1). The benefit of excluding patients intolerant to sorafenib was demonstrated in the subanalysis of a previous phase II study of axitinib, which generated an excellent HR and a significant study outcome [15, 16]. The second noteworthy point in the design of the RESORCE trial is that the allocation factors of macrovascular invasion and extrahepatic disease were treated as independent stratification factors. In general, the designs of previous clinical trials of molecular targeted agents involved allocation factors specifying “vascular invasion and/or extrahepatic spread” or “neither.” However, because vascular invasion is an extremely poor prognostic factor for HCC, assigning vascular invasion to the same category as extrahepatic spread may have influenced the outcome of these clinical trials. For example, when the treatment group contains more patients with vascular invasion but the placebo group includes more patients with extrahepatic spread, such sampling bias will put the treatment group at a significant disadvantage. In fact, such allocation imbalance apparently contributed to a negative outcome in a clinical trial of brivanib as second-line therapy [17] (table ​(table22). Table 2 Imbalance between Brivanib and Placebo Arm in BRISK-PS Trial The design of the RESORCE trial is excellent because it reflects what was learned from the negative outcomes of past trials and the reasons for those outcomes.

Ultrasonography fusion imaging system increases the chance of radiofrequency ablation for hepatocellular carcinoma with poor conspicuity on conventional ultrasonography.

Objectives: To investigate the usefulness of the ultrasonography (US) fusion imaging system for radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). Methods: Since the US fusion imaging system became available in 2010, we have conducted RFA with this system in all cases. The characteristics of 75 patients with 120 HCCs and 89 patients with 123 HCCs who underwent RFA before the introduction of this system (period A) and after it (period B), respectively, were retrospectively compared. Results: Significant difference in the characteristics of the patients and HCCs between the two periods was found only in the proportion of HCCs with poor conspicuity on grayscale US treated with RFA (1.7%, 2/120 for period A vs. 15.4%, 19/123 for period B, p < 0.01). Among the 19 HCCs with poor conspicuity on grayscale US for period B, 5 and 9 HCCs were identified on grayscale US and contrast-enhanced US, respectively, by the use of the US fusion imaging system, whereas the 5 remaining undetectable HCCs were treated by using the system in conjunction with reference images displayed side-by-side with grayscale US. Conclusion: Since the introduction of the US fusion imaging system, it has become possible to perform RFA for HCCs with poor conspicuity on grayscale US.

Utility of computed tomography fusion imaging for the evaluation of the ablative margin of radiofrequency ablation for hepatocellular carcinoma and the correlation to local tumor progression

To demonstrate the usefulness of the computed tomography (CT) fusion imaging for the evaluation of treatment effect of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC).

Sonazoid-enhanced ultrasonography for the diagnosis of an intrapancreatic accessory spleen: A case report

We report a case of an intrapancreatic accessory spleen in 59‐year‐old man, in which contrast‐enhanced sonography (US) using Sonazoid, a second‐generation contrast agent, was useful for the diagnosis. Sonazoid‐enhanced US could prove both hypervascularity and the existence of reticuloendothelial cell systems in the mass, which is the key to the diagnosis of an accessory spleen. Sonazoid‐enhanced US might become a standard imaging technique for the diagnosis of an accessory spleen.