C-Arm Computed Tomographic Image Fusion for Repetitive Transarterial Chemoembolization of Hepatocellular Carcinoma.

OBJECTIVE: The aim of this study was to evaluate the potential implications of fusion imaging with C-arm computed tomography (CACT) scans for repetitive conventional transarterial chemoembolization (cTACE) for hepatocellular carcinoma. MATERIALS AND METHODS: Fifty-six cTACE sessions were performed using fusion CACT images from September 2020 to June 2021 in a tertiary referral center, and the data were retrospectively analyzed. Fusion of unenhanced and enhanced CACT images was considered when previously accumulated iodized oil hampered the identification of local tumor progression or intrahepatic distant metastasis (indication A), when a tumor was supplied by multiple arteries with different origins from the aorta and missing tumor enhancement was suspected (indication B), or when iodized oil distribution on immediate post-cTACE CACT images needed to be precisely compared with the pre-cTACE images (indication C). Fusion image quality, initial tumor response, time to local progression (TTLP) of index tumors, and time to progression (TTP) were evaluated. RESULTS: The fusion quality was satisfactory with a mean misregistration distance of 1.4 mm. For the 40 patients with indication A, the initial tumor responses at 3 months were nonviable, equivocal, and viable in 27 (67.5%), 4 (10.0%), and 9 (22.5%) index tumors, respectively. The median TTLP and TTP were 14.8 months and 4.5 months, respectively. For 10 patients with indication B, the median TTLP and TTP were 8.3 months and 2.6 months, respectively. Among the 6 patients with indication C, 2 patients were additionally treated at the same cTACE session after confirming incomplete iodized oil uptake on fusion imaging. CONCLUSIONS: Fusion CACT images are useful in patients with hepatocellular carcinoma undergoing repetitive cTACE.

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.

Spectral CT Imaging-Based Quantification of Iodized Oil Retention following Chemoembolization: Phantom and Animal Studies.

PURPOSE: To evaluate accuracy of iodine quantification using spectral CT and the potential of quantitative iodized oil analysis as an imaging biomarker of chemoembolization. MATERIALS AND METHODS: A phantom of an artificial liver with 6 artificial tumors containing different amounts of iodized oil (0-8 vol%) was scanned by spectral CT, and iodized oil density (mg/mL) and Hounsfield unit (HU) values were measured. In addition, VX2 hepatoma was induced in 23 rabbits. After chemoembolization using iodized oil chemoemulsion, the rabbits were scanned by spectral CT. The accumulation of iodized oil in the tumor was quantified in terms of iodized oil density and HUs, and the performances in predicting a pathologic complete response (CR) were evaluated by receiver operating characteristic curve analyses. RESULTS: The mean difference between true iodine densities and spectral image-based measurements was 0.5 mg/mL. Mean HU values were highly correlated with mean iodine density (r2 = 1.000, P < .001). In the animal study, a pathologic CR was observed in 17 of 23 rabbits (73.9%). The range of area under the curve values of iodine and HU measurements was 0.863-0.882. A tumoral iodine density of 3.57 mg/mL, which corresponds to 0.7 vol% iodized oil in the tumor, predicted a pathologic CR with a sensitivity of 70.6% and a specificity of 100.0%. CONCLUSIONS: Spectral CT imaging has a potential to predict tumor responses after chemoembolization by quantitatively assessing iodized oil in targets.

Synergistic Oxygen Generation and Reactive Oxygen Species Scavenging by Manganese Ferrite/Ceria Co-decorated Nanoparticles for Rheumatoid Arthritis Treatment.

Poor O2 supply to the infiltrated immune cells in the joint synovium of rheumatoid arthritis (RA) up-regulates hypoxia-inducible factor (HIF-1α) expression and induces reactive oxygen species (ROS) generation, both of which exacerbate synovial inflammation. Synovial inflammation in RA can be resolved by eliminating pro-inflammatory M1 macrophages and inducing anti-inflammatory M2 macrophages. Because hypoxia and ROS in the RA synovium play a crucial role in the induction of M1 macrophages and reduction of M2 macrophages, herein, we develop manganese ferrite and ceria nanoparticle-anchored mesoporous silica nanoparticles (MFC-MSNs) that can synergistically scavenge ROS and produce O2 for reducing M1 macrophage levels and inducing M2 macrophages for RA treatment. MFC-MSNs exhibit a synergistic effect on O2 generation and ROS scavenging that is attributed to the complementary reaction of ceria nanoparticles (NPs) that can scavenge intermediate hydroxyl radicals generated by manganese ferrite NPs in the process of O2 generation during the Fenton reaction, leading to the efficient polarization of M1 to M2 macrophages both in vitro and in vivo. Intra-articular administration of MFC-MSNs to rat RA models alleviated hypoxia, inflammation, and pathological features in the joint. Furthermore, MSNs were used as a drug-delivery vehicle, releasing the anti-rheumatic drug methotrexate in a sustained manner to augment the therapeutic effect of MFC-MSNs. This study highlights the therapeutic potential of MFC-MSNs that simultaneously generate O2 and scavenge ROS, subsequently driving inflammatory macrophages to the anti-inflammatory subtype for RA treatment.

Modified Rat Hepatocellular Carcinoma Models Overexpressing Vascular Endothelial Growth Factor.

PURPOSE: To compare tumor vascularity in 4 types of rat hepatocellular carcinoma (HCC) models: N1S1, vascular endothelial growth factor (VEGF)-transfected N1S1 (VEGF-N1S1), McA-RH7777, and VEGF-transfected McA-RH7777 (VEGF-McA-RH777) tumors. MATERIALS AND METHODS: The N1S1 and McA-RH7777 cell lines were transfected with expression vectors containing cDNA for rat VEGF. Eighty-eight male Sprague-Dawley rats (weight range, 400-450 g) were randomly divided into 4 groups (ie, 22 rats per model), and 4 types of tumor models were created by using the N1S1, VEGF-N1S1, McA-RH7777, and VEGF-McA-RH777 cell lines. Tumor vascularity was evaluated by perfusion computed tomography (CT), enzyme-linked immunosorbent assay of VEGF, CD34 staining, angiography, and Lipiodol transarterial embolization. Intergroup discrepancies were evaluated by Kruskal-Wallis test. RESULTS: Arterial perfusion (P < .001), portal perfusion (P = .015), total perfusion (P < .001), tumor VEGF level (P = .002), and microvessel density (MVD; P = .007) were significantly different among groups. VEGF-McA-RH7777 tumors showed the greatest arterial perfusion (46.7 mL/min/100 mL ± 15.5), total perfusion (60.7 mL/min/100 mL ± 21.8), tumor VEGF level (3,376.7 pg/mL ± 145.8), and MVD (34.5‰ ± 7.5). Whereas most tumors in the N1S1, VEGF-N1S1, and McA-RH7777 groups showed hypovascular staining on angiography and minimal Lipiodol uptake after embolization, 5 of 6 VEGF-McA-RH7777 tumors (83.3%) presented hypervascular tumor staining and moderate to compact Lipiodol uptake. CONCLUSIONS: McA-RH7777 tumors were more hypervascular than N1S1 tumors, and tumor vascularity was enhanced further by VEGF transfection. Therefore, the VEGF-McA-RH7777 tumor is recommended to mimic hypervascular human HCC in rats.

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.

Radioembolization Is a Safe and Effective Treatment for Hepatocellular Carcinoma with Portal Vein Thrombosis: A Propensity Score Analysis.

BACKGROUND/AIMS: Limited treatment options are available for patients with hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT). Transarterial radioembolization using Yttrium-90 microspheres is a new treatment modality for HCC with PVT. For this analysis, we compared responses to treatment with radioembolization and with sorafenib. METHODS: We evaluated 32 patients who were part of a multicenter retrospective cohort. All patients had PVT without extrahepatic metastasis and were treated with radioembolization in one of six tertiary referral hospitals in Korea. We retrospectively enrolled another 31 consecutive PVT patients without extrahepatic metastasis from a single center who received sorafenib treatment to serve as the control group. We used inverse probability weighting (IPW) using propensity scores to adjust for the between-group differences in baseline characteristics. RESULTS: At 3 months, the response rate and disease control rate were 32.1% (9/32) and 57.1% (16/32), respectively, in the radioembolization group and 3.2% (1/31) and 41.9% (13/31) in the sorafenib group. Median overall survival (OS) and time to progression (TTP) were not significantly different between the radioembolization group and the sorafenib group (13.8 months and 10.0 months, P = 0.22; and 6.0 months and 6.0 months, P = 0.08; respectively). No differences in OS (P = 0.97) or TTP (P = 0.34) were observed after IPW was applied to balance the population characteristics. The sorafenib group showed significantly more grade 3/4 adverse effects than the radioembolization group (P < 0.01). CONCLUSION: HCC patients with PVT who underwent radioembolization achieved comparable survival to patients who received sorafenib, even after application of IPW. The radioembolization group also experienced fewer severe adverse effects. Radioembolization can be considered a new treatment option for patients with HCC with PVT.

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.

Chemoembolization for hepatocellular carcinoma supplied by a lumbar artery.

PURPOSE: To describe the radiologic findings and imaging response of hepatocellular carcinoma (HCC) supplied by the lumbar artery. METHODS: Between April 2004 and December 2012, we encountered HCC supplied by a lumbar artery in 21 patients. Two investigators retrospectively reviewed clinical and radiological findings of HCC supplied by the lumbar artery using computed tomography (CT) scans and digital subtraction angiograms. RESULTS: Patients had received 1-27 sessions of previous chemoembolization procedures (mean 7.7 sessions, median 4 sessions). Mean tumor size was 5.3 cm. The locations of HCC supplied by lumbar artery were the bare area (n = 14, 67 %) and segment VI (n = 7, 33 %). Tumor-feeding arteries arose from the main lumbar artery (n = 7), proximal anterior division (n = 4), and distal anterior division (n = 14). In 20 patients, selective chemoembolization through the tumor-feeding arteries of the lumbar artery was achieved. In 1 patient, nonselective embolization at the main lumbar artery was performed. There was no complication such as skin necrosis or paralysis. On the first follow-up enhanced CT scan, target tumors fed by the lumbar artery showed complete response (n = 6), partial response (n = 4), stable disease (n = 3), and progressive disease (n = 8), but overall tumor response was partial response (n = 1) and progressive disease (n = 20). CONCLUSION: When HCC is located in the inferior tip or bare area of the liver, a lumbar artery may supply the tumor. Although selective chemoembolization via the tumor-feeding vessel of the lumbar artery can be achieved in most cases, overall tumor response is commonly unfavorable.

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.

Comparison of drug release and pharmacokinetics after transarterial chemoembolization using diverse lipiodol emulsions and drug-eluting beads.

In many studies for chemoembolization of hepatocellular carcinoma, the Lipiodol emulsion preparation protocols, especially the mixing steps, were unclear or even unrevealed at all. However, doxorubicin (DOX) release may depend on the composition and volume ratio (Lipiodol to DOX solution) of a Lipiodol emulsion. Therefore, we conducted a preclinical study to compare in-vitro drug release and in-vivo pharmacokinetics of DOX from diverse Lipiodol emulsions and drug-eluting beads (DEBs) and to compare the tumor response in a rabbit VX2 carcinoma model. DOX release profiles of four types of Lipiodol emulsions with different media (normal saline or Pamiray as an iodinated contrast medium), volume ratio (Lipiodol to DOX solution), and DEBs were investigated in-vitro. For the in-vivo study, 15 rabbits bearing VX2 carcinoma in the liver were treated with 4∶1 volume ratio Lipiodol emulsion (group A), 1∶1 volume ratio Lipiodol emulsion (group B), and DEBs (group C) chemoembolization. Blood and tissue sampling was conducted to evaluate DOX concentration in plasma and tissues, histological changes, and liver toxicity. The most stable emulsion was formed with Pamiray (including DOX) at a 4∶1 volume ratio. The AUC value of group A was significantly lower than that of group B (p = 0.003) but comparable to that of group C (p = 0.071). The Cmax value of group A was significantly different compared with those of group B (p = 0.004) and C (p = 0.015). The tissue drug concentration in group A was comparable to that in group C (p = 0.251). No viable tumor was detected in rabbits of group A and B. In group C, viable tumor less than 10% was seen in two of the five rabbits. There were no significant differences in liver enzyme levels after the procedure. In conclusion, DOX release and pharmacokinetics of presented emulsion systems depend substantially on their composition. Therefore, Lipiodol emulsion type should be considered when interpreting data and designing new studies dealing with chemoembolization.

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.

Sprague-Dawley rats bearing McA-RH7777 cells for study of hepatoma and transarterial chemoembolization.

AIM: To evaluate the feasibility of the McA-RH7777 tumor model in Sprague-Dawley (SD) rats, for study of hepatoma and transarterial chemoembolization. MATERIALS AND METHODS: McA-RH7777 rat hepatoma cells (1×10(7)) were inoculated into the left hepatic lobe of SD rats (n=38). Chemoembolization with left common carotid artery access was performed using an emulsion of iodized oil and doxorubicin, and polyvinyl alcohol particles. Tumor induction rate and response to chemoembolization were assessed by magnetic resonance imaging and histology. RESULTS: Tumor induction rate of McA-RH7777 in SD rat livers was 73.3% (11/15). Hematoxylin-and-eosin staining revealed hypercellular tumor with a trabecular pattern that mimics human hepatocellular carcinoma. Chemoembolization was successfully conducted in all rats. There was a significant difference in tumor growth rates between the chemoembolization-treated and control groups (p<0.0001). CONCLUSION: A rat tumor model of McA-RH7777 cells in SD rats is feasible and has the potential to be a good model for hepatoma and chemoembolization studies.

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.