Incomplete radiofrequency ablation (IRFA) triggers mild protective autophagy in residual tumor cells and results in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and causes resistance to anti-PD-1/PDL1 therapy, which bringing a great clinical challenge in residual tumors immunotherapy. Mild autophagy activation can promote cancer cell survival while further amplification of autophagy contributes to immunogenic cell death (ICD). To this regard, we constructed active targeting zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) loaded with STF62247 or both STF62247 and BMS202, namely STF62247@ZIF-8/PEG-FA (SZP) or STF62247-BMS202@ZIF-8/PEG-FA (SBZP) NPs. We found that SZP NPs inhibited proliferation and stimulated apoptosis of residual tumor cells exposed to sublethal heat stress in an autophagy-dependent manner. Further results discovered that SZP NPs could amplify autophagy in residual tumor cells and evoke their ICD, which dramatically boosted the maturation of dendritic cells (DCs). Through vaccination experiments, we found for the first time that vaccination with heat + SZP treatment could efficiently suppress the growth of new tumors and establish long-term immunological memory. Furthermore, SBZP NPs could remarkably promote the ICD of residual tumor cells, obviously activate the anti-tumor immune microenvironment, and significantly inhibit the growth of residual tumors. Thus, amplified autophagy coupled with anti-PD-1/PDL1 therapy is potentially a novel strategy for treating residual tumors after IRFA. Graphical Abstract

Background: Insufficient radiofrequency ablation (IRFA) can promote the local recurrence and distal metastasis of residual hepatocellular carcinoma (HCC), which makes clinical treatment extremely challenging. In this study, the malignant transition of residual tumors after IRFA was explored. Then, arsenic-loaded zeolitic imidazolate framework-8 nanoparticles (As@ZIF-8 NPs) were constructed, and their therapeutic effect on residual tumors was studied. Results: Our data showed that IRFA can dramatically promote the proliferation, induce the metastasis, activate the epithelial–mesenchymal transition (EMT) and accelerate the angiogenesis of residual tumors. Interestingly, we found, for the first time, that extensive angiogenesis after IRFA can augment the enhanced permeability and retention (EPR) effect and enhance the enrichment of ZIF-8 nanocarriers in residual tumors. Encouraged by this unique finding, we successfully prepared As@ZIF-8 NPs with good biocompatibility and confirmed that they were more effective than free arsenic trioxide (ATO) in sublethal heat-induced cell proliferation suppression, apoptosis induction, cell migration and invasion inhibition, and EMT reversal in vitro. Furthermore, compared with free ATO, As@ZIF-8 NPs exhibited remarkably increased therapeutic effects by repressing residual tumor growth and metastasis in vivo. Conclusions: This work provides a new paradigm for the treatment of residual HCC after IRFA. Graphical

Background Liver Imaging Reporting and Data System (LI-RADS) was designed for contrast-enhanced US (CEUS) with pure blood pool agents to diagnose hepatocellularfcarcinoma (HCC), such as sulfur hexafluoride (SHF), but Kupffer-cell agents, such as perfluorobutane (PFB), allow additional lesion characterization in the Kupffer phase yet remain unaddressed. Purpose To compare the diagnostic performance of three algorithms for HCC diagnosis: two algorithms based on CEUS LI-RADS version 2017 for both SHF and PFB and a modified algorithm incorporating Kupffer-phase findings for PFB. Materials and Methods This multicenter prospective study enrolled high-risk patients for HCC from June 2021 to December 2021. Each participant underwent same-day SHF-enhanced US followed by PFB-enhanced US. Each liver observation was assigned three LI-RADS categories according to each algorithm: LI-RADS SHF, LI-RADS PFB, and modified PFB. For modified PFB, observations at least 10 mm with nonrim arterial phase hyperenhancement were upgraded LR-4 to LR-5 if there was no washout with a Kupffer defect and were reassigned LR-M to LR-5 if there was early washout with mild Kupffer defect. The reference standard was pathologic confirmation or composite (typical CT or MRI features, or 1-year size stability and/or reduction). Diagnostic metrics of LR-5 for HCC using the three algorithms were calculated and compared using the McNemar test. Results Overall, 375 patients (mean age, 56 years ± 11 [SD]; 318 male patients, 57 female patients) with 424 observations (345 HCCs, 40 non-HCC malignancies, 39 benign lesions) were enrolled. PFB and SHF both using LI-RADS showed no significant difference in sensitivity (60% vs 58%; P = .41) and specificity (96% vs 95%; P > .99). The modified algorithm with PFB had increased sensitivity (80% vs 58%; P < .001) and a nonsignificant decrease in specificity (92% vs 95%; P = .73) compared with LI-RADS SHF. Conclusion Based on CEUS LI-RADS version 2017, both SHF and PFB achieved high specificity and relatively low sensitivity for HCC diagnosis. When incorporating Kupffer-phase findings, PFB had higher sensitivity without loss of specificity. Chinese Clinical Trial Registry no. ChiCTR2100047035 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kim in this issue.

Background: Microvascular invasion (MVI) is an independent risk factor for postoperative recurrence of hepatocellular carcinoma (HCC). To perform a meta-analysis to investigate the diagnostic performance of radiomics for the preoperative evaluation of MVI in HCC and the effect of potential factors.Materials and Methods: A systematic literature search was performed in PubMed, Embase, and the Cochrane Library for studies focusing on the preoperative evaluation of MVI in HCC with radiomics methods. Data extraction and quality assessment of the retrieved studies were performed. Statistical analysis included data pooling, heterogeneity testing and forest plot construction. Meta-regression and subgroup analyses were performed to reveal the effect of potential explanatory factors [design, combination of clinical factors, imaging modality, number of participants, and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) applicability risk] on the diagnostic performance.Results: Twenty-two studies with 4,129 patients focusing on radiomics for the preoperative prediction of MVI in HCC were included. The pooled sensitivity, specificity and area under the receiver operating characteristic curve (AUC) were 84% (95% CI: 81, 87), 83% (95% CI: 78, 87) and 0.90 (95% CI: 0.87, 0.92). Substantial heterogeneity was observed among the studies (I²=94%, 95% CI: 88, 99). Meta-regression showed that all investigative covariates contributed to the heterogeneity in the sensitivity analysis (P < 0.05). Combined clinical factors, MRI, CT and number of participants contributed to the heterogeneity in the specificity analysis (P < 0.05). Subgroup analysis showed that the pooled sensitivity, specificity and AUC estimates were similar among studies with CT or MRI.Conclusion: Radiomics is a promising noninvasive method that has high preoperative diagnostic performance for MVI status. Radiomics based on CT and MRI had a comparable predictive performance for MVI in HCC. Prospective, large-scale and multicenter studies with radiomics methods will improve the diagnostic power for MVI in the future.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=259363, identifier CRD42021259363.

Purpose: The objective of this study was to develop a multifunctional contrast agent for bioimaging and synergistic high-intensity focused ultrasound (HIFU) therapy to achieve theranostic. Materials and methods: A novel type of perfluorohexane-encapsulated fullerene (PFH-C₆₀) nanosphere was successfully developed via a vacuum ultrasonic emulsification and centrifugation method and subsequently used in ultrasound/computed tomography (CT) dual-modality and HIFU ablation of dissected bovine livers. In addition, transmission electron microscopic examination was employed to detect structural changes in the target tissue for HIFU ablation. Results: The use of composite nanospheres effectively enhanced ultrasound and CT imaging. Moreover, the HIFU ablation of dissected bovine livers was also significantly enhanced. Conclusion: Composite nanospheres demonstrate potential theranostic application as a multifunctional contrast agent for dual-modality biological imaging and highly efficient synergistic imaging-guided HIFU ablation.