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.
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.
Radiologic-pathologic correlation is essential for diagnostic accuracy, particularly when dealing with primary bone tumors. This investigation explores the unique radiographic and pathologic features of NFATC2- rearranged bone sarcomas. Inclusion criteria focused on primary bone sarcomas with NFATC2 fusions while excluding soft tissue sarcomas, benign bone cysts, and vascular neoplasms with similar fusions. Our cohort comprised 16 patients (12 males, 4 females) with a mean age of 45.6 years (range: 15 to 77 y). Tumors were located in the femur (n=9), tibia (n=3), humerus (n=2), ulna (n=1), and radius (n=1). Symptoms generally followed a long latency period and several were incidentally discovered for other reasons, with a mean tumor size of 9.7 cm (range: 3.0 to 19.7 cm). Histologic examination revealed typical features of NFATC2 -rearranged sarcomas, including uniform epithelioid, round, or spindle cells growing in cords, chains, clusters, and sheets suspended in a richly vascularized fibromyxoid to variably sclerotic stroma. Mitotic activity varied dramatically between and within tumors (from <5 to >50 per 10 HPF). By immunohistochemistry, positive stains included CD99 (12/14), NKX2.2 (7/7), AGGRECAN (3/3), SMA (6/7), CAM5.2 (3/4), SATB2 (8/9), and ERG (5/8) with more limited expression of CK AE1/AE3 (3/12) and NKX3.1 (2/8). All had an NFATC2 gene fusion, with 9 harboring FUS and 7 EWSR1 as 5' partners. Additional genetic analysis beyond the targeted fusion panel (n=7) demonstrated that all cases harbored a range of secondary genomic alterations in addition to the driver NFATC2 fusion. On radiography and CT imaging, all showed lucent lesions with peripheral sclerosis and narrow transition zones. Expansile cortical remodeling (n=8; 50%) varied from minimal to extensive. Despite generally indolent-appearing radiographic features, 87.5% (14/16) demonstrated soft tissue extension, ranging from focal to extensive. Internal septations were present in 62.5% (10/16). MRI, performed on 15 tumors, revealed hypointensity on T1-weighted images and heterogeneously hyperintense on fluid-sensitive sequences. After contrast administration, avid enhancement was seen in all tumors with perilesional edema and enhancement in 26.7% (4/15). In summary, the imaging of NFATC2 -rearranged bone sarcomas differs significantly from Ewing sarcoma, suggesting a tumor of longer duration characterized by a lytic nature, areas of peripheral sclerosis, expansile cortical remodeling, and frequent extraosseous extension. However, these features may not correlate with prognosis. This study represents the first systematic radiologic evaluation of NFATC2 -rearranged bone sarcomas, highlighting distinctive characteristics that may aid pathologists in their initial diagnostic assessments.
Purpose: Undifferentiated pleomorphic sarcoma (UPS) is an aggressive subtype of soft tissue sarcoma with poor outcomes, particularly in metastatic cases. The mechanisms driving metastasis in UPS remain poorly understood, limiting therapeutic advances.Experimental Design: A multi-omics approach was used to analyze paired primary and metastatic UPS tumor samples. Spatial transcriptomics, bulk RNA sequencing, and deconvolution analyses were performed to identify molecular pathways and immune microenvironment alterations associated with metastasis. Functional assays using CRISPR-Cas9 knockout (KO) UPS cell lines, alongside in vivo models, were used for functional validation experiments.Results: Transcriptomic analyses on 13 patients with UPS revealed significant upregulation of hypoxia, epithelial-mesenchymal transition, and immune-suppressive pathways in metastatic UPS. ADORA2B was identified as a key driver of these processes, with elevated expression correlating with poor disease-free survival in patients with UPS. Functional studies confirmed that ADORA2B promotes proliferation, migration, invasion, and matrix remodeling via metalloprotease regulation. In vivo, ADORA2B KO reduced primary tumor growth and metastatic dissemination in UPS models.Conclusions: This study identifies ADORA2B as a critical regulator of metastatic progression in UPS, implicating it as a promising therapeutic target. Ongoing clinical trials targeting adenosine pathways further support the translational potential of ADORA2B inhibition to disrupt metastasis and improve outcomes for patients with UPS.
