Spectral CT-Based Iodized Oil Quantification to Predict Tumor Response Following Chemoembolization of Hepatocellular Carcinoma.

PURPOSE: To quantify iodized oil retention in tumors after transarterial chemoembolization using spectral computed tomography (CT) imaging in patients with hepatocellular carcinoma (HCC) and evaluate its performance in predicting 12-month tumor responses. MATERIALS AND METHODS: From September 2017 to December 2018, 111 patients with HCC underwent initial conventional transarterial chemoembolization. Immediately after the procedure, unenhanced CT was performed using a spectral CT scanner, and the iodized oil densities in index tumors were measured. In tumor-level analyses, a threshold level of iodized oil density in the tumors was calculated using clustered receiver operating characteristic curve analyses to predict the 12-month tumor responses. In patient-level analyses, significant factors associated with a 12-month complete response, including the presence of tumors below the threshold value (ie, suspected residual tumors), were evaluated by logistic regression. RESULTS: Forty-eight HCCs in 39 patients were included in the analyses. The lower 10th percentile of the iodine density was identified as the threshold for determining the 12-month nonviable responses. The area under the curve of the iodine density measurements in predicting the 12-month nonviable responses was 0.893 (95% confidence interval, 0.797-0.989). The threshold value of the iodine density of 10.68 mg/mL yielded a sensitivity of 82.76% and specificity of 94.74% (P < .001). In the patient-level analysis, the 12-month complete response was significantly associated with the presence of a suspected residual tumor, with an odds ratio of 72.0 (95% confidence interval, 7.273-712.770). CONCLUSIONS: Spectral CT imaging using quantitative analysis of the iodized oil retention in target HCCs can predict tumor responses after a conventional transarterial chemoembolization procedure.

Glue Embolization of Lymphopseudoaneurysm for Chylous Ascites after Retroperitoneal Surgery.

OBJECTIVE: To assess the safety and efficacy of lymphopseudoaneurysm (LPA) glue (n-butyl cyanoacrylate [NBCA]) embolization in the management of chylous ascites after retroperitoneal surgery. MATERIALS AND METHODS: A retrospective analysis from January 2014 to October 2018 was performed in six patients (4 females and 2 males; mean age, 45.3 ± 14.2 years; range, 26-61 years) who underwent LPA embolization for chylous ascites developing after retroperitoneal surgery involving the perirenal space (four donor nephrectomies, one partial nephrectomy, and one retroperitoneal lymphadenectomy). After placing a percutaneous drainage catheter into the LPA or adjacent lymphocele, embolization was performed by filling the LPA itself with a mixture of glue and Lipiodol (Guerbet). RESULTS: Daily drainage from percutaneously placed drains exceeded 300 mL/day despite medical and surgical treatment (volume: mean, 1173 ± 1098 mL; range, 305-2800 mL). Intranodal lymphangiography was performed in four of the six patients and revealed leakage in 2 patients. Percutaneous embolization of the LPA was successful in all patients using an NBCA and Lipiodol mixture in a ratio of 1:1-1:2 (volume: mean, 4.3 ± 1.1 mL; range, 3-6 mL). Chylous ascites was resolved and the drainage catheter was removed in all patients within 4 days after the procedure (mean, 2.0 ± 1.8 days; range, 0-4 days). No procedure-related complications or recurrence of chylous ascites occurred during a mean follow-up period of 37.3 months (range, 21.1-48.4 months). CONCLUSION: Glue embolization of LPA has the potential to be a feasible and effective treatment method for the management of chylous ascites after retroperitoneal surgery.

Early Experience in the Management of Postoperative Lymphatic Leakage Using Lipiodol Lymphangiography and Adjunctive Glue Embolization.

PURPOSE: To evaluate the safety and efficacy of Lipiodol lymphangiography and 3 adjunctive N-butyl cyanoacrylate (NBCA) glue embolization techniques for the management of postoperative lymphatic leakage. MATERIALS AND METHODS: This retrospective study included 27 patients with postoperative lymphatic leakage (17 with ascites, 3 with chylothorax, 6 with lymphoceles, and 1 with a skin fistula) who underwent Lipiodol lymphangiography for diagnostic and therapeutic purposes in 3 tertiary referral centers between August 2010 and January 2016. Adjunctive glue embolization was performed as needed by using 3 different techniques: "lymphopseudoaneurysm" embolization, closest upstream lymph node embolization, or direct upstream lymphatic vessel embolization. RESULTS: Sixteen patients were observed to determine the therapeutic effect of lymphangiography, and 8 patients (50%) recovered without further embolization. In 16 patients, including 11 who underwent immediate embolization after lymphangiography and 5 who underwent delayed embolization, a total of 28 embolizations (12 lymphopseudoaneurysms, 14 lymph nodes, and 2 lymphatic vessels) were performed. The technical and clinical success rates of the adjunctive embolizations were 89% (25 of 28) and 94% (15 of 16), respectively. The overall clinical success rate was 85% (23 of 27). The median time from initial lymphangiography to recovery was 5 days. No procedure-related major complications were reported. CONCLUSIONS: Lipiodol lymphangiography and adjunctive glue embolization techniques appear safe and provide promising efficacy for the management of postoperative lymphatic leakage.

Does Establishing a Safety Margin Reduce Local Recurrence in Subsegmental Transarterial Chemoembolization for Small Nodular Hepatocellular Carcinomas?

OBJECTIVE: To test the hypothesis that a safety margin may affect local tumor recurrence (LTR) in subsegmental chemoembolization. MATERIALS AND METHODS: In 101 patients with 128 hepatocellular carcinoma (HCC) nodules (1-3 cm in size and ≤ 3 in number), cone-beam CT-assisted subsegmental lipiodol chemoembolization was performed. Immediately thereafter, a non-contrast thin-section CT image was obtained to evaluate the presence or absence of intra-tumoral lipiodol uptake defect and safety margin. The effect of lipiodol uptake defect and safety margin on LTR was evaluated. Univariate and multivariate analyses were performed to indentify determinant factors of LTR. RESULTS: Of the 128 HCC nodules in 101 patients, 49 (38.3%) nodules in 40 patients showed LTR during follow-up period (median, 34.1 months). Cumulative 1- and 2-year LTR rates of nodules with lipiodol uptake defect (n = 27) and those without defect (n = 101) were 58.1% vs. 10.1% and 72.1% vs. 19.5%, respectively (p < 0.001). Among the 101 nodules without a defect, the 1- and 2-year cumulative LTR rates for nodules with complete safety margin (n = 52) and those with incomplete safety margin (n = 49) were 9.8% vs. 12.8% and 18.9% vs. 19.0% (p = 0.912). In multivariate analyses, ascites (p = 0.035), indistinct tumor margin on cone-beam CT (p = 0.039), heterogeneous lipiodol uptake (p = 0.023), and intra-tumoral lipiodol uptake defect (p < 0.001) were determinant factors of higher LTR. CONCLUSION: In lipiodol chemoembolization, the safety margin in completely lipiodolized nodule without defect will not affect LTR in small nodular HCCs.

Repeated intra-arterial therapy via the cystic artery for hepatocellular carcinoma.

PURPOSE: To evaluate the postprocedural imaging findings and safety of repeated intra-arterial therapy via the cystic artery in patients with hepatocellular carcinoma (HCC). METHODS: This retrospective study was approved by our institutional review board. From February 2002 to January 2012, we performed repeated (two or more) chemotherapeutic infusion or chemoembolization via the cystic artery using iodized oil in 132 patients with HCCs. Computed tomographic (CT) scans, digital subtraction angiograms, and medical records were retrospectively reviewed by consensus. RESULTS: A total of 340 sessions of intra-arterial therapy (160 sessions of chemotherapeutic infusion and 180 sessions of chemoembolization) via the cystic artery were undertaken in 132 patients. Fifty-five of 132 patients received both chemotherapeutic infusion and chemoembolization. The incidence of gallbladder wall thickening on follow-up contrast-enhanced CT was significantly higher in chemoembolization (48 of 180, 26.7 %) than in chemotherapeutic infusion (27 of 160, 16.9 %) (P = 0.035). Persistent gallbladder wall thickening was more frequently observed in chemoembolization (48 of 107, 44.9 %) than in chemotherapeutic infusion (27 of 90, 30 %) (P = 0.039). The major complication rate was 15 of 340 sessions (4.4 %) with 11 of 132 patients (8.3 %). Acute cholecystitis, which was related to intra-arterial therapy via the cystic artery, developed in two patients and was managed by conservative treatment. CONCLUSION: HCC supplied by the cystic artery can be safely treated by repeated intra-arterial chemotherapeutic infusion or chemoembolization using iodized oil through the cystic artery.

Safety of chemotherapeutic infusion or chemoembolization for hepatocellular carcinoma supplied exclusively by the cystic artery.

PURPOSE: This study was designed to evaluate the safety of chemotherapeutic infusion or chemoembolization by way of the cystic artery in patients with hepatocellular carcinoma (HCC) supplied exclusively by the cystic artery. METHODS: Between Jan 2002 and Dec 2011, we performed chemotherapeutic infusion or chemoembolization using iodized oil for the treatment of 27 patients with HCC supplied exclusively by the cystic artery. Computed tomography (CT) scans, digital subtraction angiograms, and medical records were retrospectively reviewed by consensus. RESULTS: The cystic artery originated from the main right hepatic artery in 24 (89 %) patients, from the right anterior hepatic artery in 2 (7 %) patients, and from the left hepatic artery in 1 (4 %) patient. Selective catheterization of the cystic artery was achieved in all patients. Superselection of tumor-feeding vessels from the cystic artery was achieved in 7 patients (26 %). Chemotherapeutic infusion was performed in 18 patients (67 %), and chemoembolization was performed in 9 patients (33 %). There were no major complications and only 2 minor complications, including vasovagal syncope and nausea with vomiting. Individual tumor response supplied exclusively by the cystic artery at the follow-up enhanced CT scan were complete response (n = 16), partial response (n = 3), and stable disease (n = 8). CONCLUSION: HCC supplied exclusively by the cystic artery can be safely treated without severe complications by chemotherapeutic infusion or chemoembolization using iodized oil through the cystic artery.

Chemoembolization via branches from the splenic artery in patients with hepatocellular carcinoma.

PURPOSE: This study was designed to evaluate the radiologic findings and imaging response of chemoembolization via branches of the splenic artery in patients with hepatocellular carcinoma (HCC). METHODS: From January 2001 to July 2010, we observed tumor staining supplied by branches of the splenic artery in 34 (0.6%) of 5,413 patients with HCC. Computed tomography (CT) scans and digital subtraction angiograms of these patients were retrospectively reviewed in consensus by two investigators. RESULTS: A total of 39 tumor feeding-vessels in 34 patients were identified: omental branches from the left gastroepiploic artery (n = 5), branches from the short gastric artery (n = 9), and omental branches directly from the splenic artery (n = 25). Branches of the splenic artery that supplied tumors were revealed on the celiac angiogram in 29 (85%) of 34 patients and were detected on pre-procedure CT images in 27 (79%) of 34 patients. Selective chemoembolization was achieved in 38 of 39 tumor-feeding vessels. Complete or partial response of the tumor fed by branches of the splenic artery, as depicted on follow-up CT scans, was achieved in 21 (62%) patients. No patient developed severe complications directly related to chemoembolization via branches of the splenic artery. CONCLUSIONS: Omental branches directly from the splenic artery are common tumor-feeding vessels of the splenic artery in cases of advanced HCC with multiple previous chemoembolizations. Tumor-feeding vessels of the splenic artery are usually visualized on the celiac angiogram or CT scan, and chemoembolization through them can be safely performed in most patients.

Augmentation of chemotherapeutic infusion effect by TSU-68, an oral targeted antiangiogenic agent, in a rabbit VX2 liver tumor model.

PURPOSE: This study was designed to investigate the in vivo effects of combination therapy with TSU-68 and chemotherapeutic infusion in a rabbit VX2 liver tumor model. METHODS: This study was approved by the animal care committee at our institute. Three weeks before chemotherapeutic infusion, VX2 carcinoma was implanted into the livers of 32 rabbits. One week after chemotherapeutic infusion, vehicle was administered orally for 3 weeks in the control group (n = 16), and TSU-68 was administered orally at a daily dose of 200 mg/kg for 3 weeks in the treated group (n = 16). Computed tomography (CT) was performed before and 1, 2, 3, and 4 weeks after chemotherapeutic infusion. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) on CT scan. The maximum thickness of viable tumor was measured on microscopic sections. RESULTS: According to the RECIST, stable disease was observed in 9 (56%) rabbits and progressive disease in 7 (44%) in the control group, whereas partial response was observed in 1 (6%) rabbit and stable disease in 15 (94%) in the treated group. On pathologic examination, a viable lesion was present in 12 (75%) rabbits in the control group and in 6 (38%) rabbits in the treated group (P = 0.073). The mean maximum thickness of viable tumor in the treated group was significantly smaller than that in the control group (0.74 mm vs. 3.39 mm; P = 0.02). CONCLUSIONS: Oral administration of TSU-68 augmented the effect of chemotherapeutic infusion in a rabbit VX2 liver tumor model.

Novel intraarterial therapy for liver cancer using ethylbromopyruvate dissolved in an iodized oil.

RATIONALE AND OBJECTIVES: In spite of various therapies developed, hepatocellular carcinoma still shows poor prognosis. In this study, we introduced ethylbromopyruvate (EBrP), a hydrophobic derivative of 3-bromopyruvate, as an agent for intraarterial therapy of hepatocellular carcinoma. MATERIALS AND METHODS: In in vitro study, we evaluated whether EBrP induced apoptotic cell death in Huh-BAT cells. Chemical degradation products of EBrP were identified by performing proton nuclear magnetic resonance spectroscopy and thin layer chromatography. VX2 carcinoma was implanted and grown in the liver of 25 rabbits for in vivo study. By transfemoral intraarterial approach, 0.4 mL of 10 mM and 40 mM EBrP dissolved in an iodized oil (Lipiodol) was infused into the proper hepatic artery in 8 and 10 rabbits, respectively. In the remaining seven rabbits, 0.4 mL of Lipiodol alone was intraarterially injected as a control. One week later, tumor necrosis rate was calculated with histopathologic examination and hepatotoxicity was evaluated with biochemical analysis. RESULTS: EBrP induced apoptosis in human HCC cells via mitochondrial apoptotic signaling cascades. EBrP dissociated into 3-bromopyruvate and ethanol in the aqueous environment. In VX2 liver tumor models, the group of intraarterial delivery of 40 mM EBrP/Lipiodol solution showed higher tumor necrosis rates (96.1% ± 3.8) than the other groups (38.9% ± 15.9 of a control, 90.5% ± 2.9 in 10 mM) (P < .05). There was transient elevation of AST and ALT enzyme levels without any mortality. CONCLUSIONS: Intraarterial infusion of EBrP/Lipiodol solution is a feasible intraarterial therapy for liver tumors with potent antitumor effects and transient hepatotoxicity.

Caudate lobe hepatocellular carcinoma treated with selective chemoembolization.

PURPOSE: To analyze the clinical outcomes of chemoembolization for solitary caudate lobe hepatocellular carcinoma (HCC) found at initial presentation. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board; the requirement for informed patient consent was waived. From July 1998 to June 2009, 40 patients (28 men, 12 women; mean age, 57 years) found to have a single HCC lesion in the caudate lobe at initial presentation were treated with chemoembolization and evaluated for overall survival and progression-free survival. Multivariate analyses for potential clinical and radiologic factors were performed by using the Cox proportional hazard model. RESULTS: Selective chemoembolization via the caudate artery was achieved in 34 (85%) patients. Overall survival rates at 1, 2, 3, 4, and 5 years were 92%, 79%, 65%, 56%, and 56%, respectively. Selective chemoembolization of the caudate artery was a critically important factor in longer overall survival (hazard ratio, 0.091; 95% confidence interval [CI]: 0.021, 0.389; P < .001), and portal vein tumor thrombosis (hazard ratio, 31.25; 95% CI: 4.88, 200.1; P < .001) and multiple tumor-feeding vessels (hazard ratio, 6.87; 95% CI: 1.47, 32.1; P = .014) were significant factors in shorter overall survival. Selective chemoembolization of the caudate artery was also a significant factor in longer progression-free survival (hazard ratio, 0.278; 95% CI: 0.10, 0.76; P = .013). CONCLUSION: Selective chemoembolization via the caudate artery is possible in most patients with caudate lobe HCC and a critical factor in longer overall survival and longer progression-free survival.

The antitumor effect and hepatotoxicity of a hexokinase II inhibitor 3-bromopyruvate: in vivo investigation of intraarterial administration in a rabbit VX2 hepatoma model.

OBJECTIVE: The purpose of this study was to compare the antitumor effect and hepatotoxicity of an intraarterial delivery of low-dose and high-dose 3-bromopyruvate (3-BrPA) and those of a conventional Lipiodol-doxorubicin emulsion in a rabbit VX2 hepatoma model. MATERIALS AND METHODS: This experiment was approved by the animal care committee at our institution. VX2 carcinoma was implanted in the livers of 36 rabbits. Transcatheter intraarterial administration was performed using low dose 3-BrPA (25 mL in a 1 mM concentration, n = 10), high dose 3-BrPA (25 mL in a 5 mM concentration, n = 10) and Lipiodol-doxorubicin emulsion (1.6 mg doxorubicin/ 0.4 mL Lipiodol, n = 10), and six rabbits were treated with normal saline alone as a control group. One week later, the proportion of tumor necrosis was calculated based on histopathologic examination. The hepatotoxicity was evaluated by biochemical analysis. The differences between these groups were statistically assessed with using Mann-Whitney U tests and Kruskal-Wallis tests. RESULTS: The tumor necrosis rate was significantly higher in the high dose group (93% +/- 7.6 [mean +/- SD]) than that in the control group (48% +/- 21.7) (p = 0.0002), but the tumor necrosis rate was not significantly higher in the low dose group (62% +/- 20.0) (p = 0.2780). However, the tumor necrosis rate of the high dose group was significantly lower than that of the Lipiodol-doxorubicin treatment group (99% +/- 2.7) (p = 0.0015). The hepatotoxicity observed in the 3-BrPA groups was comparable to that of the Lipiodol-doxorubicin group. CONCLUSION: Even though intraarterial delivery of 3-BrPA shows a dose-related antitumor effect, single session treatment seems to have limited efficacy when compared with the conventional method.

A new and simple practical plane dividing hepatic segment 2 and 3 of the liver: evaluation of its validity.

OBJECTIVE: The conventional method of dividing hepatic segment 2 (S2) and 3 (S3) is subjective and CT interpretation is unclear. The purpose of our study was to test the validity of our hypothesis that the actual plane dividing S2 and S3 is a vertical plane of equal distance from the S2 and S3 portal veins in clinical situations. MATERIALS AND METHODS: We prospectively performed thin-section iodized-oil CT immediately after segmental chemoembolization of S2 or S3 in 27 consecutive patients and measured the angle of intersegmental plane on sagittal multiplanar reformation (MPR) images to verify its vertical nature. Our hypothetical plane dividing S2 and S3 is vertical and equidistant from the S2 and S3 portal veins (vertical method). To clinically validate this, we retrospectively collected 102 patients with small solitary hepatocellular carcinomas (HCC) on S2 or S3 the segmental location of which was confirmed angiographically. Two reviewers predicted the segmental location of each tumor at CT using the vertical method independently in blind trials. The agreement between CT interpretation and angiographic results was analyzed with Kappa values. We also compared the vertical method with the horizontal one. RESULTS: In MPR images, the average angle of the intersegmental plane was slanted 15 degrees anteriorly from the vertical plane. In predicting the segmental location of small HCC with the vertical method, the Kappa value between CT interpretation and angiographic result was 0.838 for reviewer 1 and 0.756 for reviewer 2. Inter-observer agreement was 0.918. The vertical method was superior to the horizontal method for localization of HCC in the left lobe (p < 0.0001 for reviewers 1 and 2). CONCLUSION: The proposed vertical plane equidistant from S2 and S3 portal vein is simple to use and useful for dividing S2 and S3 of the liver.

Hepatocellular carcinoma: transcatheter arterial chemoembolization of the gonadal artery.

Over the past 9 years, the authors have identified gonadal arteries supplying hepatocellular carcinoma in seven of 4,438 patients (0.16%) whom they attempted to treat by transcatheter arterial chemoembolization. All seven patients had tumors in the Couinaud segment 6 (S6) of the liver (mean size, 6.8 cm). The gonadal arteries in all seven patients showed anatomic variations, including a high origin (n = 3) and a common trunk with the adrenal artery (n = 4). The gonadal artery with anatomic variation may supply hepatocellular carcinomas located in liver S6.