Undifferentiated pleomorphic sarcoma (UPS) is a rare and aggressive soft tissue tumor of unknown histogenesis. UPS most often arises in the extremities or trunk, where wide surgical excision is feasible. Rarely, UPS involves the intracranial space, where critical structures may inhibit complete resection. Given its rarity and historical misclassification as malignant fibrous histiocytoma (MFH), knowledge of intracranial UPS is limited, and there are no clear treatment guidelines. We systematically reviewed all available cases of intracranial UPS to consolidate existing literature and assess prognosis and management considerations. A systematic review was conducted according to PRISMA guidelines. PubMed and Embase were searched for reports of intracranial UPS or storiform-pleomorphic MFH. Eligible studies included at least one histologically confirmed case treated with surgery, chemotherapy, or radiotherapy and reported outcomes. Data on demographics, tumor location, treatment, follow-up, and survival were extracted. Event-free survival (EFS) and overall survival (OS) were analyzed by treatment modality, age, sex, and tumor location using Kaplan-Meier and log-rank tests. From 801 records, 40 studies with 48 patients were included. The median age was 45 years, and 50% were female. 15% had prior radiotherapy. Most tumors were extra-axial (45%) and nearly all patients underwent surgery, with 82.1% achieving gross total resection. Median EFS and OS were 18 and 24 months, respectively. No survival differences were seen by treatment modality, age, or sex. Overall survival was longer for extra-axial tumors compared to intra-axial or skull base tumors ( p = 0.016). Intracranial UPS is a rare and aggressive tumor, with worse prognosis compared to those that are extracranial. Among factors that we evaluated, extra-axial location was the strongest positive prognostic factor. Surgical resection with adjuvant chemoradiation showed the longest median survival. Ongoing case reports are required to refine management guidelines and improve patient outcomes.

Background/Objectives: Sphenoid wing meningiomas are skull base meningiomas whose resection is often complicated by involvement of the optic canal, cavernous sinus, orbit, and internal carotid artery. However, prior studies use heterogeneous classification systems that may conflate tumor site of origin with patterns of extension, making comparisons by location difficult. We evaluated sphenoid wing meningiomas using an origin-based classification to assess differences in extent of resection according to tumor origin and cavernous sinus invasion. Methods: We retrospectively reviewed 39 patients who underwent resection of histopathologically confirmed sphenoid wing meningiomas at a single center between 2010 and 2024. Tumors were classified as medial or lateral according to their dominant dural attachment on MRI. An exploratory stratified analysis compared GTR rates between medial and lateral tumors according to cavernous sinus invasion status. Results: GTR was achieved in 4 of 15 medial tumors (26.7%) and 18 of 24 lateral tumors (75.0%; p = 0.007). Cavernous sinus invasion occurred in 9 of 15 medial and 2 of 24 lateral tumors. Among tumors without cavernous sinus invasion, GTR was achieved in 4 of 6 medial and 18 of 22 lateral tumors (66.7% vs. 81.8%; p = 0.58). All six events were progression after STR, with no recurrence after GTR. The 1-year recurrence-free survival after GTR and progression-free survival after less-than-GTR were 100% and 73.9%, respectively (p = 0.005). Conclusions: Medial sphenoid wing meningiomas more often involve critical skull base structures and are less likely to undergo GTR. The smaller observed difference among non-invaded tumors is hypothesis-generating because this subgroup only comprised six medial tumors.

Glioblastoma (GBM), the most common and aggressive primary malignant brain tumor in adults, has a median survival of 14.6 months. To identify drivers of GBM pathogenesis, we conducted a CRISPR-knockout screen, which revealed THO Complex 1 (THOC1) as a key driver. Knocking down THOC1 significantly reduced GBM cell viability across patient-derived xenograft (PDX) lines, enhancing survival (p<0.01) in primary PDX models. Conversely, overexpressing THOC1 in non-cancerous neural stem cells bolstered transformation capacity, decreasing survival and causing tumor engraftment in vivo (p<0.01). Further investigation revealed THOC1's interaction with SIN3A, a histone deacetylase complex. Histone deacetylation has been previously shown to prevent the buildup of R-loops, structures that form normally during transcription but can be lethal in excess. We found that THOC1-knockdown leads to elevated R-loop levels and reduced histone deacetylation levels. RNA-sequencing analysis revealed that THOC1's role in R-loop prevention primarily affects telomeres, critical regions for cell replication. We further show that THOC1-knockdown results in significantly increased telomeric R-loop levels and shortened telomeres. Ultimately, this study suggests that targeting THOC1 is a promising therapeutic strategy to disrupt the delicate R-loop landscape and undermine GBM's replicative potential. STATEMENT OF SIGNIFICANCE: Glioblastoma, the most aggressive malignant brain tumor in adults, relies on a delicate R-loop landscape to promote cell replication while avoiding DNA damage. Targeting THOC1 represents a promising therapeutic strategy to disrupt the delicate R-loop landscape and undermine GBM's replicative potential.

Background: Glioblastoma (GBM) adapts to therapy through coordinated malignant-cell and microenvironmental responses, but the mechanisms linking treatment-associated inflammation to tumor-cell phenotypic plasticity remain poorly defined. Here, we investigated whether preoperative temozolomide exposure is associated with inflammatory-repair remodeling and a ROCK-linked therapeutic vulnerability in recurrent GBM using a window-of-opportunity clinical trial cohort. Methods: We integrated patient-resolved single-cell transcriptomics, spatial RNA profiling and multiplex protein imaging with experimental perturbations and orthotopic glioblastoma models. In the presurgical window-of-opportunity subgroup of NCT05236036 , four patients with recurrent glioblastoma received additional preoperative temozolomide (TMZ; 150 mg/m2/day for 5 days) before resection and were compared with three recurrent comparators who did not receive additional preoperative TMZ. Results: Across seven tumors, malignant-cell inflammatory activity covaried with integrin-binding and wound-healing programs (median partial ρ = 0.45 and 0.42, respectively). Tumors exposed to preoperative TMZ showed enrichment of inflammatory, chemokine, adhesion and wound-healing programs (GSEA q < 0.05), with the direction of enrichment preserved in all leave-one-patient-out analyses. In two tumors exposed to preoperative TMZ, CXCL12 localized to vascular territories, whereas chemokine and wound-repair programs increased near injury-reference regions. Across seven specimens analyzed by multiplex protein imaging, MYL9 abundance correlated with local CXCL12 (ρ = 0.61), phosphorylated MYPT1 (ρ = 0.48) and nuclear phosphorylated STAT3 (ρ = 0.45), with positive associations in every specimen. Experimentally, TMZ increased CXCL8 and reactive-state markers and enhanced subsequent scratch closure, while CXCL8 and CXCL12 increased MLC2 phosphorylation. Fasudil attenuated TNF-NF-κB, inflammatory-response and IFN-γ-response programs in TMZ-treated cells and reduced scratch closure and p-MLC2 in complementary assays. Across three orthotopic models, fasudil plus TMZ prolonged survival versus TMZ alone (model-stratified HR, 0.21; 95% CI, 0.07-0.61; P = 0.001). Conclusions: These findings link treatment-associated inflammatory-repair programs with cytoskeletal remodeling and support further translational evaluation of fasudil plus TMZ in glioblastoma.

Background/Objectives: Preoperative antithrombotic therapy is common among patients undergoing subdural hematoma (SDH) evacuation. However, the association with postoperative outcomes remains uncertain. We evaluated this potential association using a multicenter electronic health record cohort and a single-center cohort. Methods: We performed a retrospective cohort study using TriNetX, a multicenter electronic health record (EHR) database, and a single-center cohort. TriNetX was used to identify adults undergoing evacuation of nontraumatic subdural hematoma between 2005 and 2025. The exposed cohort was defined as documented oral anticoagulant or antiplatelet exposure within 7 days before surgery, after which patients were propensity-score matched 1:1. The single-center cohort included surgically treated subdural hematoma patients with clinical, radiographic, laboratory, and operative data. Postoperative outcomes included 30-day mortality, short-term thrombotic complications, and 90-day repeat subdural hematoma surgery. Results: In TriNetX, 15,651 eligible patients were identified. Matched cohorts included 1455 exposed and 1455 unexposed patients. Preoperative antithrombotic exposure was associated with higher 90-day repeat surgery (9.7% vs. 6.5%; hazard ratio [HR] 1.52; p = 0.001), whereas 30-day mortality and 14-day thrombotic complications did not differ significantly. The single-center cohort included 164 surgically treated patients, including 103 exposed and 61 unexposed patients. The reoperation association was not reproduced. However, exposed patients had higher unadjusted 30-day and overall mortality that attenuated after multivariable Cox adjustment. Conclusions: Preoperative antithrombotic exposure was associated with repeat surgery in the TriNetX cohort but not in the single-center cohort. Together, these findings suggest that antithrombotic exposure may identify a medically complex surgical SDH population requiring individualized postoperative surveillance.