Search

In this study, we elucidated for the first time the role of anti-cancer drugs in transarterial chemoembolization (TACE) via direct visualization of the spatial distribution of drugs with respect to blood vessels in intact transparent hepatocellular carcinoma (HCC) tissues. To date, precise estimation of drug penetration into tumors using thin 3D tissue sections has been challenging. This study utilized the tissue optical clearing technique to resolve the lack of tissue clarity, thereby enabling deep tissue imaging for the quantitative assessment of drug delivery following TACE. We compared the drug delivery effect, time-dependent embolic effect, and immunogenic response following conventional TACE (cTACE), drug-eluting embolic TACE (DEE-TACE), and transarterial embolization (TAE) in a rat model of HCC. After each treatment, three-dimensional drug delivery was quantitatively evaluated via the transparent liver tumor imaging, and time-dependent tumor necrosis was analyzed by serial tumor harvesting and histological staining. The results showed that chemotherapeutic agents travel only short distances after cTACE (∼80µm) and DEE-TACE (∼110µm), whereas necrosis occurs extensively within 24 h of treatment (85.3-97.2% of tumor cells). In addition, the percentages of CD4 and IL-17+ CD4 T cells increased significantly following treatment; however, drug-loading did not appear to affect the immune response following TACE. In conclusion, transarterially delivered chemotherapeutic agents appeared to exert a limited role, owing to the rapid and overwhelming effect of embolization. STATEMENT OF SIGNIFICANCE: TACE has been widely used for the treatment of HCC, especially for unresectable intermediate and advanced HCCs. Drug use in TACE is expected to provide patients with synergistic therapeutic benefits with the effect of embolic agents; however, the role of chemotherapeutic agents in TACE remains controversial. This study quantitatively verified that chemotherapeutic agents travel only short distances after TACE, while necrosis occurs extensively within 24h, and drug loading does not significantly affect immune responses following TACE. Three-dimensional imaging of intact transparent HCC can contribute to a better understanding of drug delivery mechanisms associated with TACE and also reveal that drug use in TACE may need to be reconsidered and limited to situations when embolization is expected to be insufficient.

To establish a rabbit osteoarthritis model for genicular artery embolization (GAE) experiments and to investigate the cellular mechanism of action of this novel procedure for interventional radiologists.Rabbit knee osteoarthritis was surgically modeled by anterior cruciate ligament transection and medial partial meniscectomy of the bilateral hindlimbs followed by 10 weeks of incubation. Rabbits exhibiting synovitis on magnetic resonance imaging were randomly divided into two groups: the bilateral GAE group and the control (sham procedure) group. Four weeks later, the rabbits' mobility (moving time, sec/10 min) and the histopathological features of each knee were assessed, and inter-group differences were evaluated using Student's t-test and ordinal/linear logistic models with generalized estimating equations.Osteoarthritis modeling and endovascular procedures were successful in 15 of 20 rabbits (8 and 7 in the GAE and control groups, respectively). There was no significant difference in moving times between the two groups (p = .958). The degree of structural cartilage damage was similar in both groups (p = .780). However, the synovial proliferation (p = .016), synovial hypertrophy (p.001), and villous hyperplasia of the synovial stroma (p = .002) scores were significantly lower in the GAE group than in the control group. The CD3+ cell density (p = .018) and CD3 + cell-infiltrated area (p = .019) were also significantly lower in the GAE group than in the control group.GAE can limit inflammatory processes in the synovium of osteoarthritis-affected knees.Surgical transection of the anterior cruciate ligament and medial partial meniscectomy of rabbit knees provides a useful animal model for research of genicular artery embolization. Osteoarthritic knees treated by genicular artery embolization showed milder synovial proliferation (p = .016), synovial hypertrophy (p.001), and villous hyperplasia of the synovial stroma (p = .002) than the untreated knees. Osteoarthritic knees treated by genicular artery embolization presented lower CD3+ cell density (p = .018) and CD3+ cell-infiltrated area (p = .019) in the synovium than the untreated knees.

PDF file - 121K, Correlation between the NMR spectral markers and the thickness of the LC infiltration in the 7 day-LC animals

PDF file - 130K, Representative HR-MAS spectra of CSF with full scale lactate peak

PDF file - 164K

PDF file - 66K, The absolute concentration of the marker metabolites at each experimental time points

PDF file - 360K, Isolation of glioma cells expressing GFP

PDF file - 133K, The OPLS-DA method

PDF file - 173K, Marker metabolites for the LC group established using breast cancer cells

The surgical treatment for large hepatocellular carcinoma (HCC) remains controversial because of a high risk of recurrence after resection. This study aimed to compare long-term outcomes of transarterial radioembolization (TARE) with resection for patients with large HCC.

Intra-arterial treatment has been identified as one of the mainstays in the management of unresectable hepatocellular carcinoma. A thorough knowledge of tumor arterial supply enables selective therapy, which improves both safety and efficacy. The inferior phrenic artery (IPA) is the most common extrahepatic collateral artery that feeds hepatocellular carcinoma. The bilateral IPAs are known to have a specific vascular anatomy. A systemic-to-pulmonary shunt and a gastric branch from the IPAs may be present and should not be confused with tumor blush. The supraceliac aorta and celiac trunk are the common origin sites of the IPAs, and their orifice may be compressed by the diaphragm. Various techniques and catheters are used for catheterization of the IPAs, depending on their origin sites. Because the IPA is normally connected with the intercostal, internal mammary, retroperitoneal, and hepatic arteries, its hemodynamics may be altered when its orifice is occluded. In general, superselective chemoembolization via the target branch of the IPA is safe and effective. When a systemic-to-pulmonary shunt from the IPA is adequately embolized with coils or particles, radioembolization through the IPA can be performed safely in most cases. The cystic artery branches into deep and superficial cystic arteries; deep cystic arteries often supply tumors near the gallbladder. Chemoembolization through the cystic artery is relatively safe, with transient embolic materials. Radioembolization through the cystic artery has been recently tried, with acceptable efficacy and toxicity results, but it requires further investigation.

Magnetic resonance angiography (MRA) is an important imaging technique that can be used to identify and characterize various types of vascular diseases. However, currently used molecular contrast agents are unsuitable for MRA due to the short intravascular retention time, the whole-body distribution, and the relatively low contrast effect. In this study, we developed a vascular analysis contrast agent (i.e., VasCA) for MRA, which is a simple and biocompatible 1:1 host-guest assembly of PEGylated β-cyclodextrin and gadolinium chelate with renal clearable size and high relaxivity (r1 = 9.27 mM-1 s-1). Its biocompatibility was confirmed by in vivo animal studies as well as in vitro 3D cell culture. In a tumor-bearing rat model, VasCA circulated in the blood vessels much longer (4.3-fold increase) than gadoterate meglumine (Dotarem) and was mainly excreted by the renal system after intravenous injection. This feature of VasCA allows characterization of tumor microvasculature (e.g., feeding and draining vessels) as well as visualization of small vessels in the brain and body organs. Furthermore, after treatment with an angiogenesis inhibitor (i.e., sorafenib), VasCA revealed the vessel normalization process and allowed the assessment of viable and necrotic tumor regions. Our study provides a useful tool for diverse MRA applications, including tumor characterization, early-stage evaluation of drug efficacy, and treatment planning, as well as diagnosis of cardiovascular diseases.

OBJECTIVE: To assess the two-year treatment outcomes of chemoembolization with drug-eluting embolics (DEE) for nodular hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This study was a prospective, multicenter, registry-based, single-arm trial conducted at five university hospitals in Korea. Patients were recruited between May 2011 and April 2013, with a target population of 200. A DC Bead loaded with doxorubicin was used as the DEE agent. Patients were followed up for two years. Per-patient and per-lesion tumor response analysis, per-patient overall survival (OS) and progression-free survival (PFS) analysis, and per-lesion tumor control analysis were performed. RESULTS: The final study population included 152 patients, with 207 target lesions for the per-lesion analysis. At one-month, six-month, one-year, and two-year per-patient assessments, complete response (CR) rates were 40.1%, 43.0%, 33.3%, and 19.6%, respectively. The objective response (OR) rates were 91.4%, 55.4%, 35.1%, and 19.6%, respectively. The cumulative two-year OS rate was 79.7%. The cumulative two-year PFS rate was 22.4% and the median survival was 9.3 months. In multivariable analysis, the Child-Pugh score (p = 0.019) was an independent predictor of OS, and tumor multiplicity (p < 0.001), tumor size (p = 0.020), and Child-Pugh score (p = 0.006) were independent predictors of PFS. In per-lesion analysis, one-month, six-month, one-year and two-year CR rates were 57.5%, 58.5%, 45.2%, and 33.3%, respectively, and the OR rates were 84.1%, 65.2%, 46.6%, and 33.3%, respectively. The cumulative two-year per-lesion tumor control rate was 36.2%, and the median time was 14.1 months. The Child-Pugh score (p < 0.001) was the only independent predictor of tumor control. Serious adverse events were reported in 11 patients (7.2%). CONCLUSION: DEE chemoembolization for nodular HCCs in the Korean population showed acceptable survival, tumor response, and safety profiles after a two-year follow-up. Good liver function (Child-Pugh score A5) was a key predictor of per-patient OS, PFS, and per-lesion tumor control.

BackgroundA diverse clinical course after the spontaneous rupture of hepatocellular carcinoma (HCC) renders nonstandardized treatment protocols.PurposeTo evaluate clinical course and role of transcatheter arterial embolization (TAE) in patients with rupture of HCC.Materials and methodsThis retrospective study included 127 patients who were treated for ruptured HCC at single institution between 2005 and 2014. After multidisciplinary discussion, patients underwent medical management, TAE, emergency surgery or staged surgery. Patients were retrospectively divided into two groups based on the intent of treatment: curative and palliative. The rebleeding rate and 1-month and overall survival (OS) were compared between two groups. The incidence and survival of patients with intraperitoneal drop metastasis (IPDM) were also analyzed.ResultsThe overall rebleeding rate in patients who underwent TAE was 3.1% (3/96). One-month mortality rate was 6.3% (8/127). The rebleeding and 1-month mortality rates were not significantly different between two groups. OS was significantly higher in the curative treatment group (median: 12.0 vs 2.2 months,ppConclusionTAE provided effective immediate hemostasis with a low rebleeding rate and may serve as a bridge to elective surgery. IPDM frequently occurred within 1 year and manifested poor survival; thus, close surveillance should be considered for patients with spontaneous rupture of HCC.

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancer-related deaths worldwide. Transarterial chemoembolization (TACE) is the current standard of care for patients with intermediate-stage HCC. While TACE has been widely used for the treatment of HCC, there are unsolved questions on the use of chemotherapeutics agents in TACE. TACE has been thought to induce necrosis in HCC due to the complex effects of embolism and intra-arterial delivery of anticancer drugs; however, it is unclear how far a drug is delivered from the arteries before the tumor undergoes necrosis induced by embolization-induced ischemia.Methods: In this study, the drug delivery effect, time-dependent embolic effect, and immunogenic response were compared following conventional TACE (cTACE), drug-eluting embolic TACE (DEE-TACE), and transarterial embolization (TAE) in a rat model of HCC. Following each treatment, three-dimensional drug delivery was evaluated via the transparent liver tumor imaging. Time-dependent tumor necrosis was analyzed by serial tumor harvesting and histological staining. Early (24-h) and residual (7-day) immune responses were evaluated by flow cytometric analyses and immunohistochemistry. Results: The intratumoral blood vessel structure became damaged after treatment due to embolization-induced ischemia. The more severe the vascular damage caused over time or by treatment type, the greater the distance traveled by drugs. In the first 24-h, most chemotherapeutic agents were located within 80 and 110 µm of the nearest vessels after cTACE and DEE-TACE, respectively, while 85.3–97.2% of tumor cells underwent necrosis. The percentages of CD4 and IL-17+ CD4 T cells were significantly increased following treatment, but drug loading did not affect the early and residual immune responses. Conclusion: Transarterially delivered chemotherapeutic agents appeared to exert a limited role, owing to the rapid and overwhelming effect of embolization.

To evaluate the impact of virtual tumor absorbed dose (vTAD) on tumor response in patients with hepatocellular carcinoma (HCC) treated with yttrium-90 radioembolization.The institutional review board approved this retrospective single center study, which comprised 100 patients with nodular HCC who underwent yttrium-90 radioembolization between November 2015 and December 2019. The vTAD was calculated assuming that all infused microspheres were distributed only in the tumor. The ability of mean absorbed dose (mAD) and vTAD in predicting complete response were evaluated by receiver operating characteristic (ROC) curve analyses.The mAD was 263.9 Gy ± 125.8, and the mean vTAD was 2005.8 Gy ± 2348.9. In terms of tumor response, 63 patients had complete response, 25 partial response, and 12 stable disease. For predicting complete response, ROC curve analyses revealed that the area under the curve (AUC) value of the vTAD was significantly higher (p0.001) than that of the mAD. Multivariate analysis revealed that Child-Pugh class A5, unilobar disease, and vTAD (952 Gy) were significant factors in predicting complete response.High vTAD (952 Gy) plays a significant role in complete response in patients with nodular HCC.

Pancreatic neuroendocrine tumors (PNETs) are rare, but the frequency of detection is constantly increasing due to recent advances in diagnostic technology. Since liver metastasis (LM) of PNETs is highly correlated with long-term survival, active treatment is important. Liver-directed treatment is recommended for patients with unresectable LM from PNET if symptomatic or progressing despite medical management. Liverdirected intervention treatment, including locally ablative techniques and hepatic arterial embolotherapy has a vital role in controlling symptoms and improving overall survival rates. The purpose of this article is to address the recent advances in liverdirected intervention treatments for the treatment of LM of PNETs.

PURPOSE To determine the value of preprocedural MR imaging in genicular artery embolization (GAE) for patients with osteoarthritic knee pain. MATERIALS AND METHODS This single-center study retrospectively analyzed 28 knees in 18 patients who underwent GAE for intractable knee pain < 1 month after MR imaging. The pain experienced in each knee was evaluated on a 100-mm visual analog scale (VAS) at baseline and 1- and 3-month after GAE. "GAE responders" were defined as knees that exhibited greater than 30% reduction of VAS pain scores from baseline at both follow-up visits. Musculoskeletal radiologists evaluated MR images of the affected knee compartment regarding cartilage defects, osteophytes, subchondral cysts, bone marrow lesions (BMLs), meniscal injury, and joint effusion. The performances of Kellgren-Lawrence (KL) grading and MR findings in predicting GAE responders was estimated based on receiver operating characteristic curves. RESULTS The mean VAS pain score was 84.3 mm. BML (area under the curve [AUC], 0.860; P < .001), meniscal injury (AUC, 0.811; P = .003), and KL grading (AUC, 0.898; P < .001) were significantly associated with GAE outcome. To predict GAE responders, KL grade ≤ 2 yielded a sensitivity of 87.5% and a specificity of 60.9%, BML grade ≤ 1 yielded a sensitivity of 75.0% and a specificity of 69.6%, and meniscal injury grade ≤ 2 yielded a sensitivity of 83.3% and a specificity of 72.7%. CONCLUSIONS Large BMLs and severe meniscal injuries on MR imaging, as well as high KL grades, indicated poor responses to GAE.

To optimize future translational research, this study aimed to determine the ideal range of sizes for embolic agents in interventional oncology experiments utilizing rat models of hepatocellular carcinoma.Fifty-five male Sprague-Dawley rats were divided into two groups to evaluate the distribution of microparticles and tumor response rates. After implanting hepatoma cells into rodent liver, fluorescent microparticles of diverse size ranges were administered via the hepatic artery. In the first group, the distribution of microparticles was evaluated in hepatoma-free rats, and tumor necrosis rates following administration of a pre-determined aliquot of microparticles (0.4 mL) were measured in tumor-bearing rats. Thereafter, the three microparticle sizes associated with the best tumor response rates were chosen for analysis of tumor necrosis rates following hepatic artery embolization until angiographic stasis is achieved in the second group.The tendency for microparticles to distribute in non-target organs increased as microparticle size decreased below 15 μm. Tumor necrosis rates tended to be higher in rats treated with 15-19 μm microparticles than in those treated with 19-24 μm or 25-35 μm microparticles. The in-group deviation of tumor necrosis rates was highest for microparticle sizes of 19-24 μm and 25-35 μm, which implies the proximal embolization of the hepatic artery for larger microparticle sizes. However, there was no statistical significance among the three groups (p = .095).15-19 μm embolic agents are ideal for delivering the maximum embolic effect in the transarterial treatments of rat HCC models.

Backgrounds/aims To evaluate our initial experience of bridging role of trans-arterial radio-embolization (TARE) before major hepatectomy for hepatocellular carcinoma (HCC) in risky patients with small expected remnant liver volume (ERLV). Methods We reviewed the data of patients with HCC who underwent major hepatectomy after TARE during the period between March and December 2017. Patients included had uni-lobar large HCC (＞5 cm) requiring major hepatectomy with small ERLV. Results Five patients were included in our study. All patients were Child Pugh class A. A single session of TARE was applied in all patients. None developed any adverse events related to irradiation. The mean tumor size at baseline was 8.4 cm and 6.1 cm after TARE (p=0.077). The mean % of tumor shrinkage was 24.5%. ERLV improved from 354.6 ml at baseline to 500.8 ml after TARE (p=0.012). ERLV percentage improved from 27.2% at baseline to 38.1% after TARE (p=0.004). The mean % of ERLV was 39.5%. The mean interval time between TARE and resection was 99.6 days. Four patients (80%) underwent right hemi-hepatectomy and one patient (20%) underwent extended right hemi-hepatectomy. The mean operation time was 151 minutes, and mean blood loss was 56 ml. The mean hospital stay was 13.8 days, and one patient (20%) developed postoperative morbidity. After a mean follow-up of 15 months, all patients were alive with no recurrence. Conclusions Yttrium-90 TARE can play a bridging role before major hepatectomy for borderline resectable HCC in risky patients with small ERLV.

Background/aim Tumoral calcification after chemotherapy or radiation therapy has been reported in various cancer patients, but not after radioembolization. The purpose of this study was to evaluate the prognostic value of radioembolization-induced tumor calcification of hepatocellular carcinoma (HCC) treated by radioembolization. Patients and methods This retrospective study comprised patients with single nodular HCC who underwent yttrium-90 radioembolization between November 2015 and April 2019. The presence of tumoral calcification was visually assessed on a follow-up computed tomography (CT) scan. Results Fifty-five patients (64.8±11.8 years, 43 men) were evaluated. Tumoral calcification was present in 21 (38.2%) of 55 patients in the one-month CT scan (calcification group). The complete response rate for the primary index tumor was 72.7% (40 of 55) in the total study population, and 100% (21 of 21) in the calcification group, respectively. The calcification group had a longer local progression-free survival rate than the non-calcification group (p=0.017). Conclusion Radioembolization-induced tumoral calcification is relatively common and can be used as an early surrogate marker of complete response.

This study was conducted in order to assess the performance of the Liver Imaging Reporting and Data System (LI-RADS) treatment response (TR) (LR-TR) categorization on gadoxetic acid-enhanced MRI (Gd-EOB-MRI) for detecting viable tumors in hepatocellular carcinoma (HCC) treated with locoregional treatment (LRT) and to investigate the added value of ancillary features (AFs) to conventional enhancement-based criteria.This retrospective study included 183 patients with Gd-EOB-MRI after LRT for HCC and appropriate reference standards for tumor viability (84 viable and 99 nonviable). Two independent radiologists assigned per-lesion mRECIST and TR categories (TR-nonviable, TR-equivocal, or TR-viable) according to the LR-TR algorithm and modified LR-TR algorithms including mLR-TR(TP) allowing transitional phase (TP) washout and mLR-TR(AF) allowing category adjustment by applying AFs. Diagnostic performances of imaging criteria were compared using the Cochran's Q test with post hoc analysis.For detecting viable tumors, LR-TR-viable resulted in sensitivities of 64.5%/39.3% and specificities of 98.0%/98.0% in reviewers 1/2. In comparison to LR-TR-viable, mRECIST-viable, mLR-TR(TP)-viable, and mLR-TR(AF)-viable showed significantly higher sensitivities (92.9%/94.0%, 77.4%/56.6%, and 86.9%/83.3% in reviewers 1/2) (ps 0.001). The specificity of mRECIST-viable (73.7%/62.6%) was significantly lower than that of LR-TR-viable (ps 0.001), while those of mLR-TR(TP)-viable and mLR-TR(AF)-viable were greater than 95% (98.0%/96.0% and 97.0%/96.0%), statistically equivalent to LR-TR-viable (ps 0.05). TR-equivocal was least assigned on mLR-TR(AF) (1.1%/7.7%) than LR-TR (15.8%/32.2%) or mLR-TR(TP) (6.6%/23.5%) in both reviewers.The LR-TR algorithm on Gd-EOB-MRI provides a specific diagnosis of viable tumor but with limited sensitivity. By applying AFs in the category adjustment, more sensitive and confident diagnosis can be achieved without significant loss of specificity.• The LI-RADS treatment response (LR-TR) algorithm on Gd-EOB-MRI provides a highly specific diagnosis of viable HCC but with limited sensitivity. • The inferior sensitivity of LR-TR-viable category to that of mRECIST can be improved by applying ancillary features in the category adjustment.

Background/aim The aim of this study was to address the feasibility of combination of 1st and 2nd week dosing of glass microspheres in the setting of selective radioembolization for large hepatocellular carcinoma (HCC). Patients and methods Yttrium-90 radioembolization was performed in 53 patients with single nodular hepatocellular carcinomas larger than 5 cm. A total of 32 patients underwent radioembolization with glass microspheres from a single calibration date (single-dosing group), and 21 patients were treated with a combination of 1st and 2nd week dosing of glass microspheres (combined-dosing group). In the combined-dosing group, the lobar hepatic arteries and subsidiary tumor-feeding arteries were commonly treated with 1st and 2nd week dosing of glass microspheres, respectively. Results The combined-dosing group tended to have a lower frequency of pain requiring analgesics without statistical significance (p=0.085). The objective response rate at 3 months in single-dosing group and combined-dosing group was 46.9% (15 out of 32) and 66.7% (14 out of 21), respectively. Conclusion The combined 1st and 2nd week dosing of glass microspheres demonstrated an acceptable toxicity and tumor response when both a lobar hepatic artery and a small tumor-feeding artery need to be treated in one session.