BACKGROUND:Bone metastases occur in one third of patients with metastatic clear cell renal cell carcinoma (mccRCC) and are associated with poor prognosis. Optimal first-line treatment for this subgroup of patients remains undefined. METHODS:We conducted a multicenter retrospective study of patients with bone-metastatic (BM+) mccRCC treated with first-line immune checkpoint inhibitor (ICI)-based combinations between January 2015 and February 2024 across 8 French centers. The primary endpoint was time to next treatment (TTNT). Secondary endpoints included overall survival (OS), bone progression-free survival (bPFS), incidence of skeletal-related events (SREs) and changes in bone pain. RESULTS:A total of 124 patients were included; 55% received ICI-ICI and 45% an ICI plus a tyrosine kinase inhibitor (TKI). Median follow-up was 36.8 months. Median TTNT was 11.7 months (95% CI, 8.38-20.0), OS 28.8 months (95% CI, 23.7-40.2) and bPFS 11.7 months (95% CI, 7.69-21.7). Median TTNT was numerically longer with ICI-TKI compared to ICI-ICI (17.9 vs. 8.5 months; P = .40), with no significant difference in OS or bPFS between treatment groups. SREs occurred in 32% of patients. Bone progression was observed in 48%, with a concomitant SRE in 54% mostly involving preexisting lesions (78%). Bone pain improved in 45% of evaluable patients. No significant differences were observed between treatment groups for SRE incidence or bone pain improvement. Hypercalcemia was associated with shorter OS and bPFS, while bone-only disease correlated with improved OS. Use of bone-targeting agents (BTAs) was independently associated with longer bPFS. CONCLUSION:ICI-CI and ICI-TKI combinations showed comparable outcomes in BM+ mccRCC. Bone progression and SREs remained frequent and often involved preexisting bone lesions. These findings support early integration of local treatments as well as BTAs, which were independently associated with longer bPFS.
Background: Soft-tissue sarcomas (STSs) are rare and heterogeneous malignancies with generally poor and unpredictable prognosis. Tertiary lymphoid structures (TLSs) have been identified as favorable prognostic indicators in several cancer types, yet their role in STS remains poorly defined. This study investigates the prognostic relevance of TLS presence, maturity, location and density in resected STSs. Methods: We retrospectively analyzed 219 cases of primary STS surgically resected at the Bergonié Institute (France) between 1990 and 2020. TLSs were assessed for presence, spatial distribution, semi-quantitative density and degree of maturity using CD20 and CD23 immunohistochemistry, categorizing tumors as fully mature TLS-positive (fmTLS+) or -negative (fmTLS-). RNA sequencing was performed on 126 formalin-fixed paraffin-embedded samples to characterize immune microenvironment profiles. Survival outcomes-including overall survival (OS), time to locoregional progression (TTLRP), and time to distant progression (TTDP)-were analyzed using Kaplan-Meier estimates and Cox proportional hazards models. Results: The presence of fmTLS was significantly associated with improved 5-year OS (p = 0.012) and cause-specific survival (p = 0.006). Unexpectedly, fmTLS+ tumors showed a higher rate of local recurrence (22.9% vs. 8.1%, p = 0.002). On multivariate analysis, high-density fmTLS+ tumors conferred a 2.68-fold increased risk of locoregional progression (95% CI: 1.28-5.59, p = 0.009). Transcriptomic profiling confirmed a significant correlation between fmTLS+ status and a high-immune phenotype (Φ = 0.30, p < 0.001). Conclusions: STSs with fmTLS are associated with improved OS but increased risk of local recurrence. These findings support fmTLS as a dual prognostic biomarker and highlight the need for tailored surveillance and adjuvant strategies in fmTLS+ patients.
To meet the clinical need for small-diameter vascular grafts, we propose a new generation of Tissue-Engineered Vascular Grafts (TEVGs) based on the textile assembly of the Cell-Assembled extracellular Matrix (CAM): a non-cross-linked, entirely biological, and human biomaterial produced by cells in culture. Previously, we demonstrated the feasibility of producing woven CAM tubes with mechanical properties suitable for use as vascular grafts. In this study, we demonstrate, for the first time, the long-term use of these woven TEVGs in vivo. Miniaturized human TEVGs were produced, thanks to the versatility of the weaving process, and successfully implanted in the abdominal aorta of immunosuppressed rats. After one year, ultrasound images revealed flow through the TEVGs (overall patency: 86%). A neo-media was observed on the luminal surface as early as 1 month and was composed of differentiated muscular cells and elastin, covered by a monolayer of confluent and aligned endothelial cells. The immune response to TEVGs, mainly driven by M2-type macrophages, was mild and decreased over time. Unexpectedly, CAM calcification was observed in areas of high biomaterial compaction, a phenomenon never observed in previous in vivo CAM studies. This work showed that CAM-based textiles persist for at least one year in a vascular graft position. In conclusion, the woven assembly of the CAM produced a highly promising vascular graft, given its excellent in vivo stability and integration.
The ASC4OPT non-comparative phase 3b study (NCT04948333) evaluates asciminib once daily (QD) or twice daily (BID) in chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 tyrosine kinase inhibitors (TKIs). This study enrolled 169 patients not in major molecular response (MMR), with unsatisfactory response (intolerant, warning or failure) as defined by European LeukemiaNet (ELN) 2020 criteria. Patients intolerant to their most recent TKI and in MMR at baseline (n = 30) were also enrolled. The primary endpoint was the MMR rate at Week 48 for patients not in MMR at baseline. Results showed an overall MMR rate of 39.4% at Week 48 (40 mg BID, 43.4%; 80 mg QD, 35.4%) and 43.6% at Week 96 (40 mg BID, 45.8%; 80 mg QD, 41.5%) in patients not in MMR at baseline. Among 40 patients who had their asciminib dose escalated to 200 mg QD, 17.5% were in MMR at Week 96. Most patients in MMR at baseline remained in MMR at 48 and 96 weeks (93.3% and 86.7%, respectively). Safety for both dosing regimens was consistent with that of previous studies. Findings support asciminib as a potential standard of care for patients with CML-CP who have not responded optimally to prior TKI therapy.
Background:Whether adjuvant chemotherapy (AC) improves overall survival (OS) after complete resection in localized soft tissue sarcoma (STS) remains unproven and optional in guidelines. We measured OS in patients with operated non-metastatic STS treated with or without AC in the nationwide exhaustive NETSARC+ registry. Methods:The DEEPSARC project linked the NETSARC+ registry and the French nationwide health data system (SNDS) into a retrospective cohort. Adults with non-metastatic, undergoing primary surgical resection between 2012 and 2017 were included, excluding those with incomplete linkage data or prior neoadjuvant chemotherapy. We analysed the entire series of 8331 patients with successful linkage and a complete-case subset of 4296 patients. Survival with or without AC were compared using crude and multivariate Cox proportional hazards regression models, including adjustment for confounders and inverse probability of treatment weighting (IPTW). Sensitivity analyses and subgroups analysis in high-risk patients were performed. Findings:In the complete-case series, the commonest histotypes were liposarcoma (30%), undifferentiated pleomorphic sarcoma (23%) and leiomyosarcoma (17%). Overall, 389 (9.1%) patients received AC and, compared with those not receiving AC, had fewer comorbidities and presented more high-risk tumour features. With 5.8 years median follow-up, 5-yr OS was 61% (95%CI: 60-63) in the entire series, and 64% (95%CI: 63-66) in the complete-case analysis. 5-yr OS was inferior in patients receiving AC, both in the entire series (50% [47%-54%] vs. 63% [61%-64%]) and in the complete-case analysis (53% [48-59%] vs. 65% [64-67%]). After adjustment (HR = 1.46 [1.12-1.93]) or IPTW (HR = 1.56 [1.17-2.08]), AC remained associated with inferior OS. Findings were consistent across sensitivity and subgroup analyses. Interpretation:In this real-world nationwide study, AC was not associated with superior OS, but rather with an inferior OS in patients operated of a localized STS and did not compensate for the adverse prognostic profile of treated patients. Future research should therefore focus on identifying predictive biomarkers in order to better identify patients who are likely to derive real benefit from systemic treatment. Funding:This work was supported by the Health Data Hub; the Institut National Du Cancer and the French Ministry of Health (Direction Générale de l'Offre de Soins, DGOS) for the NETSARC, RRePS and RESOS networks; the INTERSARC+ program; the Agence Nationale de la Recherche; the LYriCAN+ program; the Ligue Nationale contre le Cancer; the Ligue contre le Cancer (Comité de l'Ain); the Fondation ARC; and the European Reference Network for Rare Adult Solid Cancers.
