Polymersome-stabilized doxorubicin-lipiodol emulsions for high-efficacy chemoembolization therapy.

Transarterial chemoembolization (TACE) with free doxorubicin-lipiodol emulsions (free DOX/L) is a favored clinical treatment for advanced hepatocellular carcinoma (HCC) patients ineligible for radical therapies; however, its inferior colloidal stability not only greatly reduces its tumor retention but also hastens drug release into blood circulation, leading to suboptimal clinical outcomes. Here, we find that disulfide-crosslinked polymersomes carrying doxorubicin (Ps-DOX) form super-stable and homogenous water-in-oil microemulsions with lipiodol (Ps-DOX/L). Ps-DOX/L microemulsions had tunable sizes ranging from 14 to 44 µm depending on the amount of Ps-DOX, were stable over 2 months storage as well as centrifugation, and exhibited nearly zero-order DOX release within 15 days. Of note, Ps-DOX induced 2.3-13.4 fold better inhibitory activity in all tested rat, murine and human liver tumor cells than free DOX likely due to its efficient redox-triggered intracellular drug release. Interestingly, transarterial administration of Ps-DOX/L microemulsions in orthotopic rat N1S1 syngeneic HCC model showed minimal systemic DOX exposure, high and long hepatic DOX retention, complete tumor elimination, effective inhibition of angiogenesis, and depleted adverse effects, significantly outperforming clinically used free DOX/L emulsions. This smart polymersome stabilization of doxorubicin-lipiodol microemulsions provides a novel TACE strategy for advanced tumors.

Prognosis Nomogram for Hepatocellular Carcinoma Patients with Portal Vein Invasion Undergoing Transarterial Chemoembolization Plus Sorafenib Treatment: A Retrospective Multicentre Study.

OBJECTIVES: To explore the outcomes of combined transarterial chemoembolization (TACE) with sorafenib in hepatocellular carcinoma (HCC) patients with portal vein tumour thrombus (PVTT) and to establish a prognostic prediction nomogram to differentiate target patients and stratify risk. MATERIALS AND METHODS: This multicentre, retrospective study consisted of 185 consecutive treatment-naïve patients with HCC and PVTT treated with TACE plus sorafenib from three institutions between January 1st, 2012 and December 31st, 2017. The primary outcome measurement of the study was overall survival (OS). The type of PVTT was classified by the Liver Cancer Study Group of Japan. The prognostic nomogram was established based on the predictors and was performed with interval validation. RESULTS: The median OS of the Vp1-3 and Vp4 groups was 12.4 months (11.7-18.9) and 8.5 months (7.6-11.2) (P = 0.00098), respectively, and there was a significant difference in the median OS between the Vp1-2 and Vp3 subgroups (16.4 months (12.2-27.9) vs. 10.9 months (8.4-18.1), P = 0.041). The multivariate Cox regression analysis suggested that tumour size, albumin-bilirubin grade, and PVTT type were independent prognostic factors. The C-index value of the nomogram based on these predictors in the entire cohort was 0.731 (0.628-0.833). CONCLUSIONS: After the combined therapy of TACE and sorafenib, advanced HCC patients with segmental or subsegmental PVTT showed better survival than those with main PVTT. The nomogram can be applied to identify advanced HCC patients with PVTT who may benefit most from the combination treatment and be helpful for making decision in clinical practice.

Imaging Changes and Clinical Complications After Drug-Eluting Bead Versus Conventional Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma: Multicenter Study.

BACKGROUND. Drug-eluting bead transarterial chemoembolization (DEB-TACE) has emerged as an alternative to conventional TACE (cTACE) for treatment of hepatocellular carcinoma (HCC), although selection between the approaches remains controversial. OBJECTIVE. The purpose of this study was to compare DEB-TACE and cTACE in the treatment of patients with unresectable HCC in terms of hepatobiliary changes on imaging and clinical complications. METHODS. This retrospective study included 1002 patients (871 men, 131 women; mean age, 59 ± 12 years) from three centers who had previously untreated unresectable HCC and underwent DEB-TACE with epirubicin (780 procedures in 394 patients) or cTACE with ethiodized oil mixed with doxorubicin and oxaliplatin (1187 procedures in 608 patients) between May 2016 and November 2018. Among these patients 83.4% had hepatitis B-related liver disease, 57.6% had Barcelona Clinic Liver Cancer (BCLC) stage A or B HCC, and 42.4% had three or more nodules. Mean tumor size was 6.3 ± 4.2 cm. Hepatobiliary changes and tumor response were evaluated with CT or MRI 1 month after TACE. Clinical records were reviewed for adverse events. RESULTS. Bile duct dilatation (p < .001) and portal vein narrowing (p = .006) on imaging and liver failure (p = .03) and grade 3 abdominal pain (p < .001) in clinical follow-up occurred at higher frequency in the DEB-TACE group (15.5%, 4.6%, 2.3%, and 6.1%) than in the cTACE (7.4%, 1.6%, 0.7%, and 2.1%) group. Higher frequency of bile duct dilation in patients who underwent DEB-TACE was observed in subgroup analyses that included patients with BCLC stage A or B HCC (p = .001), with cirrhosis (p < .001), without cirrhosis (p = .04), and without main portal vein tumor thrombus (p = .002). Total bilirubin level 1 month after treatment was 1.5 ± 2.4 mg/dL (95% CI, 1.2-1.8 mg/dL) for DEB-TACE versus 1.3 ± 2.0 mg/dL (95% CI, 1.1-1.5 mg/dL) for cTACE (p = .02). The cTACE and DEB-TACE groups did not differ in other manifestations of postembolization syndrome or systemic toxicity (p > .05). Local tumor disease control rates did not differ between the cTACE and DEB-TACE groups (1 month, 96.7% vs 98.5%, p = .06; 3 months, 81.8% vs 82.4%, p = .87), but overall DCR was significantly higher in the cTACE than in the DEB-TACE group (1 month, 87.5% vs 80.0%, p = .001; 3 months, 78.5% vs 72.1%, p = .02). CONCLUSION. Compared with cTACE, DEB-TACE was associated with greater frequency of hepatobiliary injury and severe abdominal pain. CLINICAL IMPACT. Greater caution and closer follow-up are warranted for patients who undergo DEB-TACE for unresectable HCC than for those who undergo cTACE.

Occurrence of Vascular Lake Phenomenon Before Embolization for the Prediction of Lipiodol Uptake for Intermediate-Stage Hepatocellular Carcinoma Patients that Underwent cTACE.

PURPOSE: To compare Lipiodol uptake and tumor response in intermediate-stage hepatocellular carcinoma (HCC) with and without pre-embolization vascular lake phenomenon (VLP) and to identify the incidence and predictive factors of this phenomenon, in patients treated by conventional transarterial chemoembolization (cTACE). MATERIALS AND METHODS: This retrospective study included 151 consecutive patients with intermediate HCC totaling 232 nodules, who underwent cTACE from June 2015 to October 2018. Patients were divided into two groups according to the presence of VLP before embolization. Initial Lipiodol uptake was assessed using post-cTACE computed tomography (CT) within 1-1.5 months after cTACE. Enhanced CT or magnetic resonance imaging was performed at 6 months after the procedure to assess local recurrence and distant metastasis. RESULTS: The VLP was demonstrated in 21.85% (33/151) patients and 16.81% (39/232) nodules on the super-selective angiography. On nodule-based analysis, significantly better Lipiodol uptake (p < 0.001) and higher ORR (60.61% vs. 26.49%, p < 0.001) and DCR (87.88% vs. 51.66%, p < 0.001) were observed in the VLP group compared to the non-VLP group. The multivariate logistic regression analysis showed that the presence of VLP (OR 6.431, 95% CI 2.495-16.579) might be a predictive factor for better Lipiodol uptake. Univariate and multivariate logistic regression analysis showed that poor differentiation of tumor (OR 6.397, 95% CI 2.804-19.635) remained predictive for the VLP. CONCLUSION: The incidence of VLP before embolization is 21.19%. The presence of VLP is well correlated with tumor Lipiodol uptake after cTACE and may be a new predictive factor for evaluation of cTACE efficacy and prognosis of intermediate HCC.

Early Sorafenib-related Biomarkers for Combination Treatment with Transarterial Chemoembolization and Sorafenib in Patients with Hepatocellular Carcinoma.

Purpose To identify early biomarkers for the prediction of the therapeutic response in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) and sorafenib (referred to as TACE plus sorafenib) and establish an effective prognostic nomogram. Materials and Methods The study was approved by the institutional ethics review boards at both participating centers. This retrospective study included all patients with HCC who underwent TACE plus sorafenib therapy between January 2010 and December 2013 at two institutions. On the basis of the overall survival (OS), early biomarkers were identified with univariate and multivariate analyses; then, a prognostic nomogram was established and internally validated by using the concordance c statistic. Results Ninety-seven patients (mean age, 55.0 years; range, 27-89 years) were included. Of these patients, 84 (86.6%) were men. The median OS was 25.7 months. After univariate and multivariate analyses, the onset of sorafenib-induced hypertension and/or dermatologic adverse events (AEs) (grade ≥2) within the first month of sorafenib initiation were demonstrated as independent predictors of OS. The median OS of patients with either of the two independent risk factors was 32.2 months, which was significantly longer than for those patients without (19.8 months; P = .005). Survival analyses showed that the earlier the AEs (sorafenib-related dermatologic AEs or hypertension) occurred, the better the outcome of the combination therapy. A prognostic nomogram was established and showed high accuracy of the nomogram with the c statistic of 0.73. Conclusion The early onset of hypertension and/or sorafenib-related dermatologic AEs are early biomarkers for the clinical prognosis of patients with HCC treated with TACE plus sorafenib. © RSNA, 2017.

Conventional stents versus stents loaded with (125)iodine seeds for the treatment of unresectable oesophageal cancer: a multicentre, randomised phase 3 trial.

BACKGROUND: The combination of stent insertion and single high-dose brachytherapy is a feasible and safe palliative treatment regimen in patients with unresectable oesophageal cancer. We aimed to further assess the efficacy of this treatment strategy compared to a conventional covered stent in patients with dysphagia caused by unresectable oesophageal cancer. METHODS: In this multicentre, single-blind, randomised, phase 3 trial, we enrolled patients with unresectable oesophageal cancer from 16 hospitals in China. We included adult patients (aged ≥ 20 years) with progressive dysphagia, unresectable tumours due to extensive lesions, metastases, or poor medical condition, and with clear consciousness, cooperation, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3. Eligible patients were randomly assigned (in 1:1 ratio, no stratification) to receive either a stent loaded with (125)iodine radioactive seeds (irradiation group) or a conventional oesophageal stent (control group). The primary endpoint was overall survival. Survival analyses were done in a modified intention-to-treat group. This study is registered with ClinicalTrials.gov, number NCT01054274. FINDINGS: Between Nov 1, 2009, and Oct 31, 2012, 160 patients were randomly assigned to receive treatment with either an irradiation stent (n=80) or a conventional stent (n=80). During a median follow-up of 138 days (IQR 72-207), 148 stents (73 in the irradiation group and 75 in the control group) were successfully placed into the diseased oesophagus in 148 participants. Median overall survival was 177 days (95% CI 153-201) in the irradiation group versus 147 days (124-170) in the control group (p=0.0046). Major complications and side-effects of the treatment were severe chest pain (17 [23%] of 73 patients in the irradiation group vs 15 [20%] of 75 patents in the control group), fistula formation (six [8%] vs five [7%]), aspiration pneumonia (11 [15%] vs 14 [19%]), haemorrhage (five [7%] vs five [7%]), and recurrent dysphagia (21 [28%] vs 20 [27%]). INTERPRETATION: In patients with unresectable oesophageal cancer, the insertion of an oesophageal stent loaded with (125)iodine seeds prolonged survival when compared with the insertion of a conventional covered self-expandable metallic stent.