Citations

Lay Summary Glioblastoma is an aggressive brain cancer, and it can be difficult to tell whether changes seen on scans after radiation treatment represent tumor growth or treatment-related effects. The authors of this study wanted to evaluate whether a specialized imaging test called PSMA PET could help define tumor boundaries for radiation planning and distinguish tumor progression from treatment-related changes. To do this, they performed PSMA PET scans in 27 patients with high-grade gliomas, including patients undergoing radiation planning and patients being evaluated for possible tumor recurrence. They found that tumors showed higher PSMA PET signal than surrounding tissue, that PSMA PET sometimes identified tumor beyond what was visible on standard MRI, and that it correctly distinguished tumor progression from treatment-related changes in most patients.

Background Glioblastoma (GBM) remains the most aggressive primary adult brain cancer attributed to its immunosuppressive nature. Radiation therapy (RT) and concurrent temozolomide chemotherapy are the standard treatments for GBM. Emerging evidence indicates that metformin has potential as an anti-tumor agent that can reshape the immune landscape across various malignancies. We thus postulate that metformin may enhance the anti-tumor effect of RT by modulating the immunosuppressive milieu in GBM. Methods We first explore multiple in vitro conditions, with or without pre-induction, and mimicked a tumor microenvironment to demonstrate a highly context-dependent effect of metformin on the polarization of bone marrow-derived macrophages (BMDMs). We then investigated the antitumor activity and immune-modulatory effects of metformin in combination with RT in GBM-bearing mice. Results The in vitro experiment showed that metformin inhibited the immunosuppressive effects of IL-4/IL-13 but also the immunostimulatory effects of Lipopolysaccharide (LPS) on BMDMs, demonstrating bidirectional immunomodulatory properties that depend on the baseline inflammatory stimulus. In tumor cell co-culture environment, metformin exhibited context-dependent immunoregulatory effects, predominantly promoting M1-associated activation. Notably, concurrent metformin treatment counteracted M2 polarization typically induced by the tumor microenvironment. In a high m-MCSF inducted M2-dominated condition, metformin preferentially shifted the highly polarized M2 phenotype toward an M1-like state in a time and dose-dependent manner but with limited promotion of M1 subtype maturation. RNAseq results on BMDM treated with metformin showed increased homeostasis. Metformin showed dose-dependent immunomodulatory effects when combined with RT in vitro . In syngeneic GBM mouse models, concurrent metformin + RT significantly prolonged survival and reduced tumor burden by reprogramming tumor-associated macrophages (TAMs), elevating intratumoral CD8+ T-cell infiltration and the CD8+/Treg ratio, increasing circulating CD8+ T cells, reversing RT-induced expansion of monocytic myeloid-derived suppressor cells (mMDSCs), and expanding CD4+ and CD8+ effector memory populations in peripheral blood. Conclusion Metformin demonstrates inhibitory effects on M2 phenotype of macrophages. However, it is not a simple M2 inhibitor; instead, it functions primarily as a neutralizer of highly polarized macrophage states by promoting transcriptomic homeostasis. This context-dependent activity enables metformin to relieve the profoundly immunosuppressive TME of GBM to potentiate the anti-tumor effects of RT and by enhancing systemic immune memory.

Abstract INTRODUCTION Centiloid (CL) scaling standardizes amyloid positron emission tomography (PET) quantification across tracers and platforms; however, variability across software implementations may affect diagnostic classification. This study evaluated inter‐software variability and diagnostic performance across five platforms using identical 1 8 F‐florbetapir datasets. METHODS Retrospectively, 192 patients undergoing 1 8 F‐florbetapir PET/computed tomography (CT) and magnetic resonance imaging (MRI) were analyzed. CL values were generated using four US Food and Drug Administration (FDA) ‐cleared platforms and an in‐house Centiloid standard pipeline. Agreement was assessed using intraclass correlation coefficient, with bias and limits of agreement evaluated by linear modeling and Bland–Altman analysis. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis and classification against visual interpretation. RESULTS Agreement was excellent (intraclass correlation coefficient [ICC] 0.969; 95%CI 0.961–0.975). Some platforms produced systematically higher CL values versus others slightly lower. LoA reached ± 30 CL. Diagnostic accuracy was high (area under the curve [AUC]: 0.949–0.975), with sensitivity 0.923–0.968 and specificity 0.667–0.806. DISCUSSION Despite excellent agreement, systematic differences persist and may affect classification near thresholds, supporting consistent use of a single processing pipeline.

Background Systemic corticosteroids (SCS) remain the cornerstone of eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES) therapy but are associated with substantial toxicity. Mepolizumab, an anti-interleukin-5 biologic, has demonstrated steroid-sparing effects in addition to EGPA and HES disease control, yet evidence of reductions in SCS-related complications is limited. Methods This retrospective cohort study used US claims data from the Komodo Research Database to quantify SCS-related complications, healthcare resource utilization, and costs in patients with EGPA or HES treated with mepolizumab vs. chronic SCS. Patients were stratified as mepolizumab (300 mg) or chronic SCS users (≥6 months continuous SCS use with >7.5 mg/day for EGPA and >10 mg/day for HES) based on treatment received during a 6-month landmark period post-index (first claim of mepolizumab or SCS). An inverse probability of treatment weighting approach was applied to the cohorts to minimize confounding. Outcomes were assessed up to 12 months post-landmark. Results 578 patients with EGPA (305 mepolizumab users vs. 273 chronic SCS users) and 272 patients with HES (161 vs. 111) were included. In patients with EGPA, rates of any SCS-related complications were 39% lower with mepolizumab compared with chronic SCS (rate ratio [95% confidence interval]: 0.61 [0.49, 0.76], p < 0.001). Mepolizumab users had 57% lower rate of all-cause hospitalizations (0.43 [0.27, 0.69], p < 0.001), and lower outpatient and emergency department (ED) visits vs. chronic SCS. Patients with HES had significantly lower rates of any SCS-related complications with mepolizumab vs. chronic SCS (0.59 [0.42, 0.82], p = 0.002). Mepolizumab users had 66% lower rates of all-cause hospitalizations (0.34 [0.17, 0.65], p = 0.001), and lower outpatient visits relative to chronic SCS users. In EGPA and HES SCS-complication-related hospitalizations and ED visits were lower with mepolizumab compared with chronic SCS. SCS-complication-related medical costs per patient per year were $16,194 ( p = 0.008) and $3,976 ( p = 0.676) lower, in the mepolizumab vs. chronic SCS cohort of patients with EGPA and HES, respectively. Conclusion This first of its kind study suggests that real-world mepolizumab use is associated with reduced SCS-related complications in EGPA and HES, reinforcing its clinical and economic steroid-sparing benefits in reducing healthcare burden among EGPA and HES populations.

Aneuploidy is a hallmark of cancer often associated with inferior prognosis. Copy number gains of chromosome 8 (chr8) are recurrent in multiple cancers, including breast, prostate, colorectal cancers, and sarcomas such as malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are aggressive, hard-to-treat sarcomas frequently linked to the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. To investigate the role of chr8 gain in MPNST pathogenesis, we performed a CRISPR knockout screen and identified 58 essential genes on chr8, including PTK2, which encodes focal adhesion kinase (FAK). We evaluated FAK as a therapeutic target and tested small-molecule FAK inhibitors (FAKi) alone or combined with RAF/MEK inhibitors (RAF/MEKi), a class of agents relevant to NF1-deficient tumors with ERK pathway hyperactivation. Both pharmacological and genetic inhibition of FAK reduced MPNST cell proliferation in vitro and tumor growth in vivo. Combined FAKi and RAF/MEKi treatment further suppressed phosphorylation of FAK, STAT3, and AKT while increasing cleaved caspase-3 and PARP-1, indicating enhanced apoptosis. In MPNST patient-derived xenograft (PDX) models, combination therapy significantly reduced tumor growth, showing superior efficacy, particularly in chr8 gain MPNST-PDX. These results support FAK/RAF/MEK co-targeting as a promising therapeutic strategy for chr8 gain MPNST and related tumors.

Abstract Background Meningiomas lack effective therapies for recurrent or aggressive disease. NF2 inactivation, commonly in meningioma, may sensitize tumors to FAK inhibition and interact with MAPK signaling. This study investigated the therapeutic activity of defactinib (FAK inhibitor) and avutometinib (RAF/MEK inhibitor) alone and in combination in preclinical meningioma models. Methods MAPK-altered meningioma cell lines, IOMM-Lee (NF2 wild-type, BRAF p.V600E) and CH157-MN (NF2 mutant, NRAS p.Q61K), BenMen-1 (NF2 mutant, MAPK wild-type), and three patient-derived NF2 mutant cell lines were cultured in matrigel and treated with defactinib and avutometinib in 3D cell viability assays. In vivo, flank and intracranial xenograft models of IOMM-Lee and CH157-MN were treated with VS-4718 (FAK inhibitor, superior pharmokinetics in mice), avutometinib, or combination. Tumor growth, survival, and pharmacokinetic/pharmacodynamic properties were assessed. Results In vitro, combination therapy showed synergistic or additive effects in CH157-MN and IOMM-Lee cells, respectively. Defactinib alone demonstrated activity in NF2-mutant patient-derived and BenMen-1 cells, while avutometinib did not. In vivo, avutometinib monotherapy suppressed tumor growth and extended survival in both flank and intracranial xenograft models, with evidence of favorable pharmacokinetic properties and target pathway inhibition in intracranial tumors. Combination therapy provided enhanced and sustained control of flank CH157-MN meningioma compared to avutometinib alone but did not significantly improve survival over avutometinib alone in intracranial models. Conclusions Avutometinib demonstrated robust anti-tumor effects in flank and intracranial models of MAPK-altered meningioma. Combination benefits were context dependent. Defactinib activity in NF2-mutant patient-derived cells without targetable MAPK-kinase alterations highlights the importance of genomic biomarkers to guide personalized strategies.

Abstract The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches (GeoMx, Visium, CosMx) with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages. We observed a loss of canonical zone signatures in aged mouse livers characterized by “expansion” of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A “no-zone” hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation. Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.