Citations

Odontogenic myxoma (OM) is an uncommon, locally aggressive odontogenic neoplasm with characteristic histologic and clinico-radiographic features but with potential for histologic overlap with other odontogenic and non-odontogenic entities and a non-specific immunoprofile. Widespread loss of heterozygosity (LOH) has been recently described in rare cases of OM. The aim of this study was to determine whether widespread LOH represents a recurrent molecular signature that can be leveraged for clinical decision-making. Allele-specific copy number variation data from chromosomal microarray were generated from 7 OM, comprising a combined prospective and retrospective cohort. Four tumors arose in the mandible and 3 in the maxilla in patients ranging in age from 18 to 94 years (median: 44), with tumor size ranging from 2.2 to 13.0 cm. Variable amounts of fibrous stroma (odontogenic “fibromyxoma”) were present in 4/7 OM, and hypercellularity not typically appreciated in conventional OM was present in 3/7 cases. All OM (7/7) demonstrated widespread LOH, with 5 cases showing a near-haploid/low hypodiploid genomes (multiple monosomies) and 2 cases showing evidence of pseudo-hyperdiploidy due to probable endoreduplication. Both pseudo-hyperdiploid cases were ≥10 cm in size; 1 represented local recurrence. Chromosomes 1 to 3, 6, 9, 11, 13, 15, and 22 demonstrated LOH in ≥75% of cases (chromosomes 1 to 3, 6, and 9 in 100% of cases), while chromosomes 5, 12, 19, and 20 universally retained heterozygosity. Altogether, widespread LOH is a recurrent event in OM and a novel finding in odontogenic pathology, and allele-specific copy number variation analysis can serve as a diagnostic adjunct in challenging cases.

The NCCN Guidelines for Survivorship offer guidance for health care providers who care for survivors of adult-onset cancer. These guidelines include screening, evaluation, and treatment recommendations for common physical and psychosocial problems resulting from cancer and its treatment and provide a framework for care coordination. They also present guidance for helping cancer survivors to enhance their wellness and maintain a healthy lifestyle. This article summarizes the panel’s current recommendations and recent updates regarding anxiety, depression, distress, and trauma in cancer survivors.

The effect of induced hypertension (iHTN) on functional outcomes in noncardioembolic acute ischemic stroke (AIS) with early neurological deterioration remains unclear. We performed a systematic review and meta-analysis evaluating the safety and efficacy of iHTN vs medical management. A literature search of PubMed/MEDLINE, Web of Science, Ovid Embase, and Scopus from inception through November 6th, 2025. The protocol was registered in PROSPERO (CRD420261282211). Studies evaluating iHTN within 72 h of AIS onset and reporting 90-day functional independence (modified Rankin Scale [mRS] 0-2) were included. Safety outcome was hemorrhagic transformation. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were estimated using random-effects model based on Restricted Maximum-Likelihood (REML) methods. Three studies were included, comprising 366 patients (iHTN, n = 180; control, n = 186). Mean age was 65.8 ± 11.8 years, 60.9% were men, and the mean initial NIHSS was 5.4 ± 3.5. Target systolic blood pressure (SBP) was a 15-25% increase from baseline SBP using phenylephrine. Functional independence at 90-days occurred more often in the iHTN group than in controls (68.8% vs 50.5%; RR = 1.37; 95% CI, 1.09-1.73; P = 0.007). Hemorrhagic transformation was uncommon and did not differ significantly between groups (3.3% vs 0.5%; RR = 2.08; 95% CI, 0.05-88.07; P = 0.70). In our study, phenylephrine-induced hypertension was associated with greater 90-day functional independence in selected AIS subtypes,without a significant increase in hemorrhagic transformation. However, the limited studies, predominance of retrospective designs, exclusively Asian cohorts, and heterogeneity in treatment protocols and populations warrant cautious interpretation and underscore the need for larger multicenter RCTs.

Abstract Background Upstream regulators of the homologous recombination (HR) repair pathway are promising targets for overcoming temozolomide (TMZ) resistance. We investigated whether pharmacologic inhibition of Retinoblastoma Binding Protein 4 (RBBP4)/p300-mediated HR activity by CCS1477 or NEO2734 sensitizes glioblastoma (GBM) to TMZ. Methods Lentiviral-mediated shRNA was used to silence RBBP4 and EP300 (p300). A fluorescence-based multiplex flow-cytometric host cell reactivation assay was used to measure DNA repair activity, while TMZ-induced double-strand breaks (DSBs) were assessed using a comet assay and γ-H2AX foci formation. Cytotoxicity was monitored using an Incucyte device, and survival analysis was performed to evaluate efficacy in orthotopic tumor models. Drug distribution was assessed using liquid chromatography-mass spectrometry (LC-MS/MS) and acetylation of lysine 27 of histone H3 (H3K27Ac) immunofluorescence for target inhibition. Promoter occupancy was determined using chromatin immunoprecipitation. Results GBM patient-derived xenograft tumors with high RBBP4 expression showed elevated levels of 6 HR genes (RAD51, RAD50, BRCA1, BARD1, BRIP1, and FIGNL1), with RAD51 and BRIP1 correlating strongly with RBBP4 and p300. Silencing RBBP4 or p300 decreased HR and microhomologous-mediated end joining (MMEJ) activity and delayed repair of TMZ-induced DSBs. CCS1477 and NEO2734 suppressed RAD51 and MYC in a concentration-dependent manner, prolonged γ-H2AX foci, and enhanced TMZ sensitivity. Both compounds inhibited H3K27Ac and were detectable in orthotopic tumors by LC-MS/MS and significantly extended survival alone and in combination with TMZ. Conclusion These findings suggest that the RBBP4/p300-axis is a key regulator of HR-mediated repair of TMZ-induced DSBs, and inhibition by either CCS1477 or NEO2734 may be beneficial as monotherapy, but further studies are needed to determine the benefit of combining these agents with TMZ.

Abstract Neuromodulatory subcortical systems (NSSs) are uniquely susceptible to dementia‐related pathology, leading to frequent molecular and behavioral impairments associated with altered function of these nuclei. Some of these systems display clear sex‐specific cytoarchitecture and signaling leading to distinct physiology and behavioral outputs in males and females, while other regions display nominal sex differences. However, the relevance of sex differences in modulating dysfunction of NSSs in Alzheimer's disease (AD) and related dementias is not well understood. This review is a joint effort by the Neuromodulatory Subcortical Systems and Sex and Gender Differences in Alzheimer's Disease Professional Interest Areas of the Alzheimer's Association. We review sex differences in NSSs, both in non‐disease states and in AD models and patients. We highlight the possible role of NSSs in driving sex‐specific AD susceptibility and potential footholds for sex‐based interventions targeting these systems. We conclude by outlining immediate and long‐term actions to address the intersection of NSSs, sex, and AD.

Cancer stem cells (CSCs) are increasingly recognized as central drivers of tumorigenesis, therapeutic resistance, and recurrence across diverse malignancies. This review synthesizes our current understanding of CSC biology across CNS tumors, with a focus on glioblastoma, where stem-like cells are sustained by specialized and overlapping tumor microenvironmental niches. Perivascular, hypoxic, invasive, immunosuppressive, and extracellular matrix-associated niches cooperatively enforce stemness, metabolic adaptability, immune evasion, and phenotypic plasticity, enabling CSC persistence despite maximal surgical resection and standard-of-care therapy. Notably, CSCs extend beyond radiographically defined tumor margins and populate peritumoral regions, providing a biological basis for near-universal recurrence. Advances in multiparametric imaging, stem cell-based ex vivo and in vivo models, and single-cell and spatial profiling have refined insight into CSC heterogeneity, niche dependence, and treatment resistance. Together, these findings reframe therapeutic strategies, highlighting the need for function-preserving maximal resection and multimodal therapies that target both CSC-intrinsic pathways and their supportive microenvironments.

Abstract Background Intracranial mesenchymal tumors, FET::CREB fusion-positive (ICMT), show fusions involving FET RNA-binding protein family genes (EWSR1 or FUS) and CREB family of transcription factors (ATF1, CREB1, or CREM). The methylation signature(s), gene expression characteristics, and clinical behavior of this important tumor type require further characterization. Methods We study the methylation profiles of 81 ICMT cases (61 newly profiled cases and 20 cases from publicly available sources). Clinicopathologic and genomic data were recorded for each case when available. Results ICMT showed a relatively distinct methylation signature compared to related tumors. Among the 65 cases where fusion types were documented, the identified fusions included EWSR1::ATF1 (25 cases), EWSR1::CREB1 (12 cases), EWSR1::CREM (21 cases), FUS::CREM (3 cases), and SMARCA2::CREM (4 cases). We confirmed the prior description of 2 distinct subgroups of ICMT (subclasses A and B). The majority of the cases belonged to subclass A (n = 69; 85%), which showed a higher median age compared to subclass B patients (26 years vs. 15 years). Subclass B cases (n = 12; 15%) showed shorter progression-free survival (P < 0.01). Gene expression analysis of ICMT showed key overexpressed markers in ICMT, with significant CREM overexpression regardless of fusion type, when compared to either meningioma alone or a larger group of CNS tumors. Conclusions This work provides further characterization of ICMT as an important CNS mesenchymal neoplasm that is prone to tumor recurrence, showing 2 prognostically relevant methylation subclasses and warranting diagnostic distinction from other epigenetically and histologically related tumors. ICMTs show substantial overexpression of the CREM gene, independent of fusion type.

292 Background: Fibroblast activation protein (FAP) has high expression in cancer associated fibroblasts (CAFs) in the tumor microenvironment of many solid tumor malignancies. [ 18 F]FAPI-74 is a fluorine-18 labeled FAP-targeting PET imaging tracer with promising characteristics for detection of malignant disease in a variety of cancers. In this multicenter prospective Phase 2 trial, we hypothesized that [ 18 F]FAPI-74 PET would have a high positive predictive value (PPV) for detecting FAP-expressing tumor tissue in a variety of gastrointestinal (GI) malignancies. Methods: This Phase 2 multicenter trial was conducted in the United States at MGH, MSKCC, BAMF, Northwell, UCLA and Mayo (NCT05641896). Eligible GI cancers in the study included hepatocellular carcinoma, cholangiocarcinoma, gastric, esophageal, pancreatic, and colorectal cancer. Each subject underwent one [ 18 F]FAPI-74 PET scan, and a tissue sample was obtained by biopsy and/or surgical resection. The imaging reads were performed centrally by experienced PET readers. The primary objective was to evaluate the PPV of [ 18 F]FAPI-74 PET in detecting FAP-expressing cells from patient collected tissues using centrally evaluated immunohistochemistry (IHC) with positivity defined by the sponsor as an H score higher than 50. The secondary objective was to evaluate the safety profile of [ 18 F]FAPI-74 and its PPV in detecting the presence of GI malignancies using histopathology as the standard of truth. Results: The trial was activated in May 2023, with the last patient imaged in Jan 2025. Of 103 subjects with GI malignancies, the primary site was gastroesophageal in 46 (45%), pancreatic in 22 (21%), colorectal in 17 (17%), hepatobiliary in 10 (10%) and of other GI origin in 8 (8%) cancers. 60 participants were male and 43 female. In total, 60 patients had viable and representative tissue data for efficacy analysis of primary and secondary endpoints. No serious adverse events were reported because of the investigational product. The PPV of [ 18 F]FAPI-74 PET to detect FAP-expressing cells using IHC was 100% (52/52). The sensitivity and specificity for the detection of FAP were 90% (52/58) and 100% (2/2) respectively. The PPVs of [ 18 F]FAPI-74 PET to detect cancer using histopathology as truth standard was 94% (49/52). The sensitivity for the detection of disease was 91% (49/54). Conclusions: The Phase 2 study in GI cancers demonstrates that [ 18 F]FAPI-74 PET detects FAP expression and presence of disease in cancers of the GI tract. PPV of 100% for primary objective and 94% for secondary objective were determined. These results support initiation of a Phase 3 study of [ 18 F]FAPI-74 PET in patients with GI cancers. In addition, [ 18 F]FAPI-74 PET’s reliability in visualizing FAP expression cells in the tumor microenvironment supports a further role in selection of patients for FAP-directed therapies. Clinical trial information: NCT05641896 .