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Background To compare the efficacy and safety between conventional transarterial chemoembolization (cTACE) and drug-eluting beads TACE (DEB-TACE) in patients with infiltrative hepatocellular carcinoma (iHCC). Methods A total of 89 iHCC patients who were treated with either cTACE ( n  = 33) or DEB-TACE ( n  = 56) between April 2013 and September 2017 were included in this retrospective study. Patients with the situations that might have a poor outcome were defined as advanced disease including Child-Pugh class B, bilobar lesions, tumor size greater than 10 cm, ECOG 1–2, tumor burden of 50–70%, and the presence of ascites, arterioportal shunt (APS), and portal venous tumor thrombus (PVTT). The tumor response was measured 1-month and 3-month after the procedure. Progression-free survival (PFS) was calculated. Toxicity was graded by Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0). The differences in tumor response, PFS, and toxicity were compared between the DEB-TACE group and cTACE group. Results At 1-month and 3-month after the procedure, the objective response rate (ORR) in the overall study population was similar in DEB-TACE group and cTACE group. The disease control rate (DCR), at 1-month after the procedure, was significantly higher in the patients treated with DEB-TACE relative to those treated with cTACE ( P  = 0.034), while after 3 months, the difference did not differ between two groups. DEB-TACE showed a higher DCR than cTACE in patients with tumor size greater than 10 cm ( P  = 0.036) or associated with APS ( P  = 0.030) at 1-month after the procedure, while after 3 months, the difference was only noted in patients with APS (P = 0.036). The median PFS in DEB-TACE group was 96 days, while in cTACE group was 94 days, and there was no difference in PFS between two groups ( P  = 0.831). In the side effect analysis, abdominal pain ( P  = 0.034) and fever ( P  = 0.009) were more frequently present in the cTACE group than DEB-TACE group, but there was no difference in high grade liver toxicity between the two groups. Conclusions Compared to cTACE, DEB-TACE offers slightly better DCR and tolerability for iHCC patients, particularly in patients associated with APS and large tumor size. However, DEB-TACE does not provide higher PFS than cTACE.

Objectives To compare transarterial chemoembolization (TACE)-related hepatic toxicities of conventional TACE (cTACE) and drug-eluting beads TACE (DEB-TACE) in patients with intermediate-stage hepatocellular carcinoma. Methods In this retrospective study, 151 consecutive patients undergoing cTACE or DEB-TACE and MRI 3-6 weeks before and after therapy were included. Toxicity was assessed on imaging (global hepatic damages (GHD), overall biliary injuries, biliary cast, bile duct dilatation, intrahepatic biloma, portal thrombosis), and clinico-biological follow-ups. Tumour response, time to progression (TTP), and overall survival were assessed. Factors influencing complication rate were identified by generalized equation logistic regression model. Results Biliary injuries and intrahepatic biloma incidence were significantly higher following DEB-TACE ( p  < 0.001). DEB-TACE showed a significant increased risk of GHD (OR: 3.13 [1.74-5.63], p  < 0.001) and biliary injuries (OR: 4.53 [2.37-8.67], p  < 0.001). A significant relationship was found between baseline prothrombin value and GHD, biliary injuries and intrahepatic biloma (all p  < 0.01), and between the dose of chemotherapy and intrahepatic biloma ( p  = 0.001). Only TTP was significantly shorter following DEB-TACE compared to cTACE ( p  = 0.025). Conclusions DEB-TACE was associated with increased hepatic toxicities compared to cTACE. GHD, biliary injuries, and intrahepatic biloma were more frequently observed with high baseline prothrombin value, suggesting that cTACE might be more appropriate than DEB-TACE in patients with less advanced cirrhosis. Key points • DEB-TACE demonstrated more therapy-related hepatic locoregional complications compared to cTACE . • TACE-related hepatic locoregional toxicities occurred more frequently with high baseline PT value . • cTACE may be more appropriate in patients with high baseline PT value .

Background Neuroendocrine tumors (NETs) are the second most common gastrointestinal malignancy after colon cancer. Up to 90% of patients with NETs develop liver metastases, which are a major determinant of symptoms and survival. Current guidelines recommend embolotherapy for progressive or symptomatic NET liver metastases, but the optimal technique among bland embolization, lipiodol chemoembolization, and drug-eluting bead chemoembolization remains unknown and controversial. Methods/design A prospective, open-label, multicenter randomized controlled trial will be conducted in patients with progressive or symptomatic unresectable NET liver metastases. Patients will be randomized to treatment with bland embolization, lipiodol chemoembolization, or drug-eluting microsphere chemoembolization, with 60 enrollees per arm. The primary endpoint will be hepatic progression-free survival (HPFS) following initial embolotherapy by RECIST criteria. The sample size is powered to detect an HR of 1.78 for HPFS following chemoembolization compared with bland embolization, which was estimated on the basis of existing retrospective studies. Secondary endpoints include overall progression-free survival, duration of symptom control, quality of life, rate of adverse events, and interval between embolotherapy cycles. Interim safety analyses will be performed at 10 and 30 patients per arm. Discussion The RETNET trial is a prospective, multicenter randomized controlled trial designed to determine the optimal embolotherapy technique for NET liver metastases. Trial registration ClinicalTrials.gov, NCT02724540 . Registered on March 31, 2016.

Pregnancy outcomes in women with recurrent implantation failure (RIF) undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI): does treatment with lipiodol flush matter? In this propensity score–matched study, we recruited 966 RIF patients who underwent IVF/ICSI from two tertiary hospitals. These patients were divided into groups based on whether they received lipiodol flush or not. Further stratification was applied to investigate the effect of lipiodol flush on pregnancy outcomes in RIF patients with different cycle type of embryo transferred. Then, patients subjected to lipiodol flush were categorized into three groups based on the duration of the interval: short interval (≤ 3 months), moderate interval (3–6 months), and long interval (≥ 6 months). The groups were well-matched at baseline. The lipiodol flush group exhibited a significantly lower incidence of biochemical pregnancy (46.27% vs. 56.22%, p = 0.046) and live birth (25.87% vs. 37.31%, p = 0.014). Subgroup analysis for fresh embryo transfer cycles revealed no significant differences in pregnancy outcomes. Among RIF patients underwent frozen-thawed embryo transfer cycle, a statistically significant difference in the live birth rate was observed in the lipiodol flush group when compared to the control group (26.40% vs. 37.21%, p = 0.030). Analysis of different lipiodol flush intervals demonstrated a significantly lower live birth rate in the lipiodol flush group. Our results challenge the value of lipiodol use in clinical practice for the treatment of RIF. Trial registration: Chinese Clinical Trial Registry, ChiCTR1900024273. Registered 4 July 2019.

Because diagnostic tools for discriminating between hepatocellular carcinoma (HCC) and advanced cirrhosis are poor, HCC is often detected in a stage where transarterial chemoembolization (TACE) is the best treatment option, even though it provides a poor survival gain. Despite having been used worldwide for several decades, TACE still has many limitations. First, there is a vast heterogeneity in the cellular composition and metabolism of HCCs as well as in the patient population, which renders it difficult to identify patients who would benefit from TACE. Often the delivered drug does not penetrate sufficiently selectively and deeply into the tumour and the drug delivery system is not releasing the drug at an optimal clinical rate. In addition, therapeutic effectiveness is limited by the crosstalk between the tumour cells and components of the cirrhotic tumour microenvironment. To improve this widely used treatment of one of our most common and deadly cancers, we need to better understand the complex interactions between drug delivery, local pharmacology, tumour targeting mechanisms, liver pathophysiology, patient and tumour heterogeneity, and resistance mechanisms. This review provides a novel and important overview of clinical data and discusses the role of the tumour microenvironment and lymphatic system in the cirrhotic liver, its potential response to TACE, and current and possible novel DDSs for locoregional treatment.

Several publications show that superselective conventional TransArterial ChemoEmbolization (cTACE), meaning cTACE performed selectively with a microcatheter positioned as close as possible to the tumor, improves outcomes, maximizing the anti-tumoral effect and minimizing the collateral damages of the surrounding liver parenchyma. Recent recommendations coming from the European Association for the Study of the Liver (EASL) and European Society of Medical Oncology (ESMO) highlighted that TACE must be used in Hepatocellular Carcinoma (HCC) “selectively targetable” and “accessible to supraselective catheterization.” The goal of the manuscript is to better define such population and to standardize superselective cTACE (ss-cTACE) technique. An expert panel with extensive clinical-procedural experience in TACE, have come together in a virtual meeting to generate recommendations and express their consensus. Experts recommend that anytime cTACE is proposed, it should be ss-cTACE, preferably with a 1.5–2.0 Fr microcatheter. Ideally, ss-cTACE should be proposed to patients with less than five lesions and a maximum number of two segments involved, with largest tumor smaller than 5 cm. Angio Cone-Beam Computed Tomography (CBCT) should be used to detect enhancing tumors, tumor feeders and guide tumor targeting. Whole tumor volume should be covered to obtain the best response. Adding peritumoral margins is encouraged but not mandatory. The treatment should involve a water-in-oil emulsion, whose quality is assessable with the “drop test.” Additional particulate embolization should be systematically performed, as per definition of cTACE procedure. Non-contrast CBCT or Multi-Detector Computed Tomography (MDCT) combined with angiography has been considered the gold standard for imaging during TACE, and should be used to assess tumor coverage during the procedure. Experts convene that superselectivity decreases incidence of adverse effects and improves tolerance. Experts recommend contrast-enhanced Computed Tomography (CT) as initial imaging on first follow-up after ss-cTACE, and Magnetic Resonance Imaging (MRI) if remaining tumor viability cannot be confidently assessed on CT. If no response is obtained after two ss-cTACE sessions within six months, patient must be considered unsuitable for TACE and proposed for alternative therapy. Patients are best served by multidisciplinary decision-making, and Interventional Radiologists should take an active role in patient selection, treatment allocation, and post-procedural care.

Conventional transarterial chemoembolization (cTACE) utilizing ethiodized oil as a chemotherapy carrier has become a standard treatment for intermediate-stage hepatocellular carcinoma (HCC) and has been adopted as a bridging and downstaging therapy for liver transplantation. Water-in-oil emulsion made up of ethiodized oil and chemotherapy solution is retained in tumor vasculature resulting in high tissue drug concentration and low systemic chemotherapy doses. The density and distribution pattern of ethiodized oil within the tumor on post-treatment imaging are predictive of the extent of tumor necrosis and duration of response to treatment. This review describes the multiple roles of ethiodized oil, particularly in its role as a biomarker of tumor response to cTACE. Clinical relevance With the increasing complexity of locoregional therapy options, including the use of combination therapies, treatment response assessment has become challenging; Ethiodized oil deposition patterns can serve as an imaging biomarker for the prediction of treatment response, and perhaps predict post-treatment prognosis. Key Points • Treatment response assessment after locoregional therapy to hepatocellular carcinoma is fraught with multiple challenges given the varied post-treatment imaging appearance. • Ethiodized oil is unique in that its’ radiopacity can serve as an imaging biomarker to help predict treatment response. • The pattern of deposition of ethiodozed oil has served as a mechanism to detect portions of tumor that are undertreated and can serve as an adjunct to enhancement in order to improve management in patients treated with intraarterial embolization with ethiodized oil.

PurposeTo evaluate a pumping emulsification device that can improve the physiochemical properties and stability of lipiodol emulsion for conventional transarterial chemoembolization.Materials and methodsA pumping emulsification device constructed of a glass membrane with a hydrophobic surface with pore size of 50 μm in diameter was placed between two syringe adaptors. Epirubicin solutions were mixed with lipiodol with pumping exchanges using the emulsification device or a three-way cock. The ratios of epirubicin solution to lipiodol were 1:2 or 1:1. A total of 120 emulsions were created.ResultsThe emulsification device showed significantly higher percentages of water-in-oil when compared with the three-way cock (97.9 % vs. 68.9 % in 1:2 ratio, and 82.1 % vs. 17.8 % in 1:1 ratio, p < .001). Droplet sizes in the emulsification device were more homogenous. Mean droplet sizes and viscosities in the emulsification device did not show any significant changes for 30 min after pumping, whereas in the three-way cock, the droplet sizes significantly enlarged and viscosities significantly decreased (p=.023 and p=.002).ConclusionThe emulsification device can form a high percentage of water-in-oil emulsion with stable droplets sizes and viscosities. This developed device is promising to increase therapeutic effects in conventional transarterial chemoembolization.Key points• We developed new device for transarterial chemoembolization for liver cancer.• The device can improve the physiochemical properties of lipiodol emulsion.• The device can increase the therapeutic effects in conventional transarterial chemoembolization.

Purpose To reveal the mechanism of dense accumulation of lipiodol emulsion (LE) in hepatocellular carcinoma (HCC) during selective balloon-occluded transarterial chemoembolization (B-TACE). Methods Balloon-occluded arterial stump pressure (BOASP) at the embolization portion was measured during selective B-TACE for 43 nodules in 42 patients. Fluoroscopy and digital subtraction angiography were prospectively observed during selective B-TACE to note whether dense LE accumulation in HCC occurred. The LE concentration ratio of HCC to embolized liver parenchyma (LECHL ratio) was also calculated for each treatment on the basis of the computed tomographic scan obtained immediately after selective B-TACE. The relationships between degree of LE accumulation and the BOASP, as well as the LECHL ratio, were analyzed. Results Arterial flow beyond the catheter tip was maintained even after balloon inflation. In 39 of 43 treatments, LE inflow into the nontumorous liver parenchyma ceased immediately after LE droplets were filled in arteries of the nontumorous liver parenchyma while LE inflow into the HCC nodule continued (group 1). More dense LE accumulation in HCC nodule was obtained in these 39 treatments. In four treatments, LE inflow both into the nontumorous liver parenchyma and into the HCC nodule continued, and no dense LE accumulation in HCC nodule was observed (group 2). In these four treatments, thick anastomotic vessels with collateral artery were noted. The BOASP in group 1 was (mean ± SD) 33.8 ± 12.8 mmHg (range 13–64 mmHg) and that in group 2 was 92.3 ± 7.4 mmHg (range 83–100 mmHg). There was a statistically significant difference in BOASP between groups ( p  = 0.00004, Welch’s t test). The LECHL ratio in group 1 was 18.3 ± 13.9 (range 2.9–54.2) and that in group 2 was 2.6 ± 1.1 (range 1.7–4.2). There was a statistically significant difference in the LECHL ratio between the groups ( p  = 0.000034, Welch’s t test). Conclusion Selective B-TACE induced dense LE accumulation in HCC nodules in 39 (91 %) of 43 treatments in which BOASP was 64 mmHg or less.

Lutetium-177 ( Lu) is a promising radionuclide for targeted cancer therapy due to its favorable theranostic properties. Transarterial lipiodol embolization is widely used for hepatocellular carcinoma (HCC), but the potential of Lu emulsified into lipiodol ( Lu-lipiodol) remains underexplored. This study aimed to evaluate the partition coefficient, biodistribution, and antitumor efficacy of Lu-lipiodol in a preclinical xenograft model. After synthesizing Lu-oxine from Lu-chloride, the product was emulsified in lipiodol. Its radiochemical purity and partition coefficient were measured. F344 NJcl rnu/nu rats (n = 5) bearing bilateral thigh tumors (HC-4 cells) were randomized to receive Lu-lipiodol (2.8 MBq in 50 μL) or non-labeled lipiodol (50 μL) via surgical exposure and direct puncture of the right femoral artery. SPECT/CT images were acquired over 14 days, and biodistribution was confirmed by gamma counting at day 28. Tumor volumes and body weights were monitored to assess treatment response and toxicity. The Lu-lipiodol emulsion was obtained with a high radiochemical purity (> 99%). SPECT/CT showed high tumor accumulation (34.0% ± 4.4% immediately post-injection) that persisted up to day 28 (7.3% ± 1.2% of injected dose). Tumor growth was significantly suppressed with a treated-to-untreated volume ratio of 0.45 at day 14 (p = 0.017) and 0.59 at day 21 (p = 0.001). While off-target uptake was limited, moderate splenic accumulation (26.6% ± 17.5% ID) was noted. No marked body weight changes or gross organ abnormalities were observed. Lu-lipiodol for HCC therapy demonstrated effective tumor targeting and growth suppression of HCC in a preclinical xenograft model.