Phototheranostic nanoparticles with aggregation-induced emission as a four-modal imaging platform for image-guided photothermal therapy and ferroptosis of tumor cells.

Due to the aggregation-caused quenching (ACQ) and weak photo-penetrating ability, the application of phototheranostic agents in drug delivery field is greatly limited. Ferroptosis, a newly discovered cell death mode, has not been extensively studied in the field of phototherapy up to now. Here, a new near-infrared II (NIR-II) molecule with aggregation-induced emission (AIE) property (named TSST) co-assembled with DHA-PEG and ferrocene as nanoparticles (DFT-NP), which was rationally designed and synthesized. The DFT-NP exhibited enhanced NIR-II fluorescence, photothermal, photoacoustic, magnetic resonance imaging, AIE and ferroptosis capacities. The NIR-II fluorescence intensity of obtained nanoparticles was improved, owing to the strong interaction between DHA and TSST, which limited the intramolecular rotation restriction and non-radiative attenuation of TSST to discourage energy dissipation in aggregation state. Inspiringly, the generated photothermal effect by DFT-NP can promote the Fenton reaction of ferrocene and H2O2, resulting in dissolution of the nanoparticles and cancer cells expedited ferroptosis via accumulation lipid free radicals of DHA. The released TSST enhanced the photothermal and photoacoustic imaging effects through removing the DHA restriction to restore the non-radiative attenuation. This work is the first example of nanoparticles that integrates four-mode imaging, photothermal and ferroptosis-induced therapy functions, which offers great advantages for potential clinical applications.

Microvascular Invasion as a Predictor of Response to Treatment with Sorafenib and Transarterial Chemoembolization for Recurrent Intermediate-Stage Hepatocellular Carcinoma.

Background The evidence of combining sorafenib with transarterial chemoembolization (TACE) for intermediate-stage recurrent hepatocellular carcinoma (HCC) is limited. Patient responses to this treatment varied because of the heterogeneous nature of intermediate-stage recurrent HCC, making it important to identify patients who are most likely to benefit from this combination therapy. Purpose To compare sorafenib administered in combination with TACE versus TACE alone in the treatment of recurrent intermediate-stage HCC after initial hepatectomy and to determine the relationship of microvascular invasion (MVI) to survival. Materials and Methods In this retrospective multicenter study, 3652 consecutive patients were found to have intrahepatic recurrences after initial hepatectomy of primary HCC from January 2010 to December 2016. Of these, 260 patients with intermediate-stage recurrent HCC underwent combination treatment with sorafenib and TACE or TACE alone. Overall survival (OS) and progression-free survival (PFS) were compared between these two treatments according to MVI status by using log-rank tests. Results A total of 128 patients were administered combination therapy (mean age, 55 years ± 7.6 [standard deviation]; 107 men) and 132 patients were administered TACE alone (mean age, 56 years ± 8.3; 110 men). The 5-year OS and PFS were higher in the combination group than in the TACE group (OS: 38.9% vs 20.5%, respectively, P = .01; PFS, 37.5% vs 18.7%, respectively, P = .003). For patients with MVI-positive lesions, the median OS and PFS after combination treatment (n = 55) were longer than those after TACE alone (n = 72; OS: 17.2 months vs 12.1 months, respectively, P = .02; PFS: 17.0 months vs 11.0 months, respectively, P = .02). Multivariable analysis showed that tumor number, MVI status, and treatment allocation were significant predictors of OS and PFS, whereas tumor size was a prognostic factor for PFS. Conclusion Patients with recurrent intermediate-stage hepatocellular carcinoma and lesions positive for microvascular invasion (MVI) had longer survival times by using a combined treatment of sorafenib with transarterial chemoembolization (TACE) compared with TACE alone; patients with MVI-negative lesions did not show survival benefit from combined therapy. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Malloy in this issue.

Sorafenib versus Transarterial chemoembolization for advanced-stage hepatocellular carcinoma: a cost-effectiveness analysis.

BACKGROUND: Sorafenib and transarterial chemoembolization (TACE) might both provide survival benefit for advanced hepatocellular carcinoma (HCC). Adopting either as a first-line therapy carries major cost and resource implications. We aimed to estimate the cost-effectiveness of sorafenib and TACE in advanced HCC. METHODS: A Markov model was constructed in a hypothetical cohort of patients aged 60 years with advanced HCC and Child-Pugh A/B cirrhosis over a 2-year time frame. Three strategies (full or dose-adjusted sorafenib and TACE) were compared in two cost settings: China and the USA. Transition probabilities, utility and costs were extracted from systematic review of 27 articles. Sensitivity analysis and Monte Carlo analysis were conducted. RESULTS: Full and dose-adjusted sorafenib respectively produced 0.435 and 0.482 quality-adjusted life years (QALYs) while TACE produced 0.375 QALYs. The incremental cost-effectiveness ratio (ICER) of full-dose sorafenib versus TACE was $101,028.83/QALY in China whereas full-dose sorafenib is a dominant strategy (ICER of -$1,014,507.20/ QALY) compared with TACE in the USA. Compared to full-dose sorafenib, dose-adjusted sorafenib was the dominant strategy with the negative ICERs in both China (-$132,238.94/QALY) and the USA (-$230,058.09/QALY). However, dose-adjusted sorafenib is not available currently, so full-dose sorafenib should be compared with TACE. As the acceptability curves shown, full-dose sorafenib was the optimal strategy at the accepted thresholds of WTP in these two countries. Specifically, full-dose sorafenib was the cost-effective treatment compared with TACE if a WTP was set above $21,670 in the USA, whereas in China, TACE could be more favorable than full-dose sorafenib if a WTP was set below $10,473. CONCLUSIONS: Dose-adjusted sorafenib may be cost-effective compared to full-dose sorafenib or TACE for advanced HCC patients. However, when confining the comparisons between full-dose sorafenib and TACE, full-dose sorafenib was cost-effective for these patients, under the accepted thresholds of WTP.

Advanced Recurrent Hepatocellular Carcinoma: Treatment with Sorafenib Alone or in Combination with Transarterial Chemoembolization and Radiofrequency Ablation.

Purpose To retrospectively investigate the safety and efficacy of sorafenib combined with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) (hereafter, TACE-RFA) in the treatment of recurrent hepatocellular carcinoma (rHCC) with portal vein tumor thrombosis, extrahepatic metastases (advanced hepatocellular carcinoma), or both after initial hepatectomy. Materials and Methods The study was centrally approved by the ethics committee of three tertiary medical centers in China. From January 2010 to January 2015, 207 consecutive patients with advanced rHCC after initial hepatectomy received sorafenib combined with TACE-RFA (combination group, n = 106) or sorafenib alone (sorafenib group, n = 101) at the three medical centers. Overall survival (OS) and time to progression (TTP) were compared between the two groups. Complications were assessed. Survival curves were constructed with the Kaplan-Meier method and were compared with the log-rank test. Results Baseline characteristics were balanced between the two groups. No treatment-related death occurred in either group. The toxicity profile in the combination group was similar to that in the sorafenib group. After treatment, median OS (14.0 vs 9.0 months, respectively; P < .001) and TTP (7.0 vs 4.0 months, respectively; P < .001) were significantly longer in the combination group than in the sorafenib group. Multivariate analysis showed that treatment allocation was a significant predictor of OS and TTP, while the number of intrahepatic tumors was another prognostic factor of OS. Conclusion Sorafenib combined with TACE-RFA was well tolerated and safe and was superior to sorafenib alone in improving survival outcomes in patients with advanced rHCC after initial hepatectomy. © RSNA, 2018 Online supplemental material is available for this article.

Hepatic resection versus transarterial lipiodol chemoembolization as the initial treatment for large, multiple, and resectable hepatocellular carcinomas: a prospective nonrandomized analysis.

PURPOSE: To compare the survival outcomes between hepatic resection and transarterial lipiodol chemoembolization (TACE) used as the initial treatment in patients with large (≥5 cm), multiple, and resectable hepatocellular carcinomas. MATERIALS AND METHODS: This study had local ethical committee approval; all patients gave written informed consent. Between January 2004 and December 2006, 168 consecutive patients were prospectively studied. As an initial treatment, 85 patients underwent hepatic resection and 83 underwent TACE. Of the 29 of 83 patients in whom there was a good response to TACE, 13 underwent subsequent hepatic resection. The remaining 16 patients, who refused hepatic resection, underwent TACE and local ablation. Repeated TACE was performed in patients with stable disease or progressive disease after initial TACE. The differences in survival between groups and subgroups were calculated with the Kaplan-Meier method. Univariate and multivariate analyses were performed to clarify the prognostic factors for survival. RESULTS: The 1-, 3-, and 5-year overall survival rates for the initial hepatic resection group and the initial TACE group were 70.6%, 35.3%, 23.9% and 67.2%, 26.0%, 18.9%, respectively (P = .26). Complication rates were significantly higher in the initial hepatic resection group than in the initial TACE group (P < .01). The 1-, 3-, and 5-year overall survival rates in patients who underwent initial TACE and subsequent hepatic resection were 92.3%, 67.3%, and 50.5%, respectively, which were significantly higher than rates in patients treated with initial hepatic resection (P = .04) but were not significantly higher than in patients who responded well to TACE but refused hepatic resection (P = .07). Tumor size was the independent risk factor for survival. CONCLUSION: TACE might be a better initial treatment in patients with large, multiple, and resectable hepatocellular carcinomas; hepatic resection should be recommended to patients who respond well to TACE.