Quantitative Measurement on Contrast-Enhanced CT Distinguishes Small Clear Cell Renal Cell Carcinoma From Benign Renal Tumors: A Multicenter Study.

RATIONALE AND OBJECTIVES: To evaluate the potential of quantitative measurements on contrast-enhanced CT (CECT) in differentiating small (≤4 cm) clear cell renal cell carcinoma (ccRCC) from benign renal tumors, including fat-poor angiomyolipoma (fpAML) and renal oncocytoma (RO). MATERIALS AND METHODS: 244 patients with pathologically confirmed ccRCC (n = 184) and benign renal tumors (fpAML, n = 50; RO, n = 10) were randomly assigned into training cohort (n = 193) and test cohort 1 (n = 51), while external test cohort 2 (n = 50) was from another hospital. Quantitative parameters were obtained from CECT (unenhanced phase, UP; corticomedullary phase, CMP; nephrographic phase, NP; excretory phase, EP) by measuring attenuation of renal mass and cortex and subsequently calculated. Univariable and multivariable logistic regression analyses were performed to evaluate the association between these parameters and ccRCC. Finally, the constructed models were compared with radiologists' diagnoses. RESULTS: In univariable analysis, UP-related parameters, particularly UPC-T (cortex minus tumor attenuation on UP), demonstrated AUC of 0.766 in training cohort, 0.901 in test cohort 1, 0.805 in test cohort 2. The heterogeneity-related parameter SD (standard deviation) showed AUC of 0.781, 0.834, and 0.875 respectively. In multivariable analysis, model 1 incorporating UPC-T, NPC-T (cortex minus tumor attenuation on NP), CMPT-UPT (tumor attenuation on CMP minus UP), and SD yielded AUC of 0.866, 0.923, and 0.949 respectively. When compared with radiologists, multivariate models demonstrated higher accuracy (0.800-0.860) and sensitivity (0.794-0.971) than radiologists' assessments (accuracy: 0.700-0.720, sensitivity: 0.588-0.706). CONCLUSION: Quantitative measurements on CECT, particularly UP- and heterogeneity-related parameters, have potential to discriminate ccRCC and benign renal tumors (fpAML, RO).

Nanoparticle-mediated blockade of CXCL12/CXCR4 signaling enhances glioblastoma immunotherapy: Monitoring early responses with MRI radiomics.

The limited therapeutic efficacy of checkpoint blockade immunotherapy against glioblastoma is closely related to the blood-brain barrier (BBB) and tumor immunosuppressive microenvironment, where the latter is driven primarily by tumor-associated myeloid cells (TAMCs). Targeting the C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling orchestrates the recruitment of TAMCs and has emerged as a promising approach for alleviating immunosuppression. Herein, we developed an iRGD ligand-modified polymeric nanoplatform for the co-delivery of CXCR4 antagonist AMD3100 and the small-molecule immune checkpoint inhibitor BMS-1. The iRGD peptide facilitated superior BBB crossing and tumor-targeting abilities both in vitro and in vivo. In mice bearing orthotopic GL261-Luc tumor, co-administration of AMD3100 and BMS-1 significantly inhibited tumor proliferation without adverse effects. A reprogramming of immunosuppression upon CXCL12/CXCR4 signaling blockade was observed, characterized by the reduction of TAMCs and regulatory T cells, and an increased proportion of CD8+T lymphocytes. The elevation of interferon-γ secreted from activated immune cells upregulated PD-L1 expression in tumor cells, highlighting the synergistic effect of BMS-1 in counteracting the PD-1/PD-L1 pathway. Finally, our research unveiled the ability of MRI radiomics to reveal early changes in the tumor immune microenvironment following immunotherapy, offering a powerful tool for monitoring treatment responses. STATEMENT OF SIGNIFICANCE: The insufficient BBB penetration and immunosuppressive tumor microenvironment greatly diminish the efficacy of immunotherapy for glioblastoma (GBM). In this study, we prepared iRGD-modified polymeric nanoparticles, loaded with a CXCR4 antagonist (AMD3100) and a small-molecule checkpoint inhibitor of PD-L1 (BMS-1) to overcome physical barriers and reprogram the immunosuppressive microenvironment in orthotopic GBM models. In this nanoplatform, AMD3100 converted the "cold" immune microenvironment into a "hot" one, while BMS-1 synergistically counteracted PD-L1 inhibition, enhancing GBM immunotherapy. Our findings underscore the potential of dual-blockade of CXCL12/CXCR4 and PD-1/PD-L1 pathways as a complementary approach to maximize therapeutic efficacy for GBM. Moreover, our study revealed that MRI radiomics provided a clinically translatable means to assess immunotherapeutic efficacy.

A manganese-phenolic network platform amplifying STING activation to potentiate MRI guided cancer chemo-/chemodynamic/immune therapy.

Low immune infiltration severely hinders the efficacy of cancer immunotherapy. Here, we developed a manganese-phenolic network platform (TMPD) to boost antitumor immunity via a stimulator of interferon gene (STING)-amplified activation cascade. TMPD is based on doxorubicin (DOX)-loaded PEG-PLGA nanoparticles and further coated with manganese (Mn2+)-tannic acid (TA) networks. Mechanistically, DOX-based chemotherapy and Mn2+-mediated chemodynamic therapy effectively promoted immunogenic cell death (ICD), characterized by abundant damage-associated molecular pattern (DAMP) exposure, which subsequently enhanced dendritic cells' (DCs) presentation of antigens. DOX-elicited DNA damage simultaneously caused cytoplasmic leakage of intracellular double-stranded DNA (dsDNA) as the STING signal initiator, while Mn2+ mediated significant upregulation in the expression of a STING pathway-related protein thereby amplifying the STING signal. Systemic intravenous administration of TMPD remarkably promoted DC maturation and CD8+ T cell infiltration, thus eliciting strong antitumor effects. Meanwhile, the released Mn2+ could serve as a contrast agent for tumor-specific T1-weighted magnetic resonance imaging (MRI). Moreover, TMPD combined with immune checkpoint blockade (ICB) immunotherapy significantly inhibited tumor growth and lung metastasis. Collectively, these findings indicate that TMPD has great potential in activating robust innate and adaptive immunity for MRI guided cancer chemo-/chemodynamic/immune therapy.