Abstract Background Re-irradiation (re-RT) has gained popularity in the treatment of recurrent or progressive glioblastoma (rGBM) after first-line treatment. However, uncertainties regarding optimal treatment dose, fraction size and target volume definition remain. In this multicenter analysis of the Western German Cancer Center (WTZ), we analyze prognostic factors for patients treated with re-RT for rGBM with different fraction regimens. Methods We analyzed patients with rGBM (CNS-WHO °4, IDH-wildtype) who received re-RT after standard first-line treatment (±salvage resection/chemotherapy) between 01/2010 and 12/2021. Clinical, histopathological, and radiological data were evaluated to identify prognostic factors influencing event-free and overall survival, as well as treatment tolerability. Results We identified 118 patients of whom 87 received normofractionated (1.8-2 Gy/fx) re-RT with a mean dose of 40.8 Gy using a mean GTV-PTV margin of 8.8 mm. 31 patients were treated with moderate hypofractionation (2.4-3.5 Gy/fx) up to a mean dose of 36 Gy with a mean GTV-PTV margin of 4.1 mm. Propensity score weighting was used to compensate prognostic factors between these two cohorts. Re-resection classification (no, STR, GTR, p < 0.0001), age at diagnosis (p = 0.0082), unifocal vs. multifocal progression (p = 0.021) and time between first and second RT (p = 0.0109) were identified as significant prognostic factors using stepwise parameter selection. The propensity score weighted survival was 8.8 months for normofractionation and 9.9 months for hypofractionation (p = 0.63). Conclusion Age at initial diagnosis, progression pattern and time between first and second RT are prognostic for patients undergoing re-irradiation. No significant survival difference between normofractionated and hypofractionated approaches was detected, which should be further investigated.
Background:The global burden of central nervous system (CNS) cancers is rising unevenly. Existing studies lack a framework linking macro trends to underlying drivers across scales. Methods:We constructed a "macro-meso-micro" framework, integrating Global Burden of Disease 2021 data (macro perspective) and US SEER registry data (meso perspective). Global/regional/national incidence and mortality trends (1990-2021) were analyzed using descriptive statistics and Bayesian models, alongside subtype-specific clinical patterns. Results:The global age-standardized incidence rate (ASIR) increased from 3.82 to 4.28 per 100,000 population (1990-2021), while the age-standardized mortality rate (ASMR) declined slowly (3.08-3.06), revealing a core "incidence-mortality decoupling." Incidence correlated positively with the socio-demographic index (SDI), but some high-SDI regions achieved superior mortality control, indicating healthcare disparities. SEER data clarified that this plateau was driven by the dismal survival of aggressive subtypes like glioblastoma (GBM), contrasting sharply with the rising detection of benign/low-grade tumors (eg, meningioma). For GBM, standard care has reached a low therapeutic ceiling, with most patients relapsing into a treatment void. Conclusions:CNS cancer burden evolution resulted from multi-scale diagnostic, therapeutic, and biological interactions. Our framework connected macro trends, meso subtype heterogeneity, and micro resistance mechanisms, pinpointing the conquest of therapy-resistant, high-grade tumors (especially GBM) as the central challenge. A translational pathway of "macro surveillance for target identification-clinical problem definition-mechanistic research for breakthrough" was proposed to guide future intervention.
Background:The study was conducted to determine the level of ornithine decarboxylase (ODC) activity in several types of peripheral nerve sheath tumors to assess ODC as a potential target for alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC. Methods:A formalin-fixed paraffin-embedded peripheral nerve sheath tumor tissue microarray was developed in the Department of Anatomic Pathology, MD Anderson Cancer Center. ODC levels were measured using immunofluorescence with a polyclonal antibody to ODC and Alexa-Fluor 647 goat anti-rabbit IgG using previously validated and established methodology. Results:Nuclear and cytoplasmic ODC levels were assessed to determine surrogate ODC activity based on immunofluorescence from 11 patients with a spectrum of nerve sheath tumors, including malignant peripheral nerve sheath tumors (MPNSTs), plexiform neurofibroma, WHO Grade 1 (NF), atypical neurofibroma neoplasm of uncertain biologic potential (ANNUBP), and schwannoma. ODC activity was less than 5 nmol/30 min/min/ug ODC protein in many MPNST, NF, and schwannomas, but higher than 10 nmol/min/ug protein in ANNUBP tumors and one NF tumor. Conclusion:Nuclear ODC activity varied across peripheral nerve sheath tumors, with relatively low to moderate levels observed in MPNSTs and higher levels in ANNUBP tumors within the small cohort studied. Since DFMO, an irreversible ODC inhibitor, is more effective in slow-growing grade 2 and 3 gliomas with low ODC levels than in higher malignancy grade 4 glioma with high ODC activity, it is reasonable to assume that MPNSTs and neurofibromas, WHO grade, with relatively low to moderate levels of ODC activity may be suitable candidates for DFMO therapy. However, larger studies are needed to validate ODC activity as a predictive biomarker and to determine the therapeutic efficacy of DFMO in peripheral nerve sheath tumors.
Abstract Background Neurofibromatosis type 1 (NF1)–associated malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with poor outcomes and limited therapeutic options. Although mitogen-activated protein kinase kinase (MEK) inhibitors are active in benign plexiform neurofibromas, their efficacy in MPNST treatment is modest. Enhancer of zeste homolog 2 (EZH2) inhibitors are preclinically efficacious in MPNST treatment, but their mechanisms of action remain unclear. We evaluated the therapeutic potential and molecular mechanism of combined EZH2 and MEK inhibitors in NF1-associated MPNST. Methods Five human NF1-associated MPNST cell lines were exposed to EZH2 and/or MEK inhibitors. Cell growth and apoptosis were quantified over time. Therapeutic efficacy was tested in a subcutaneous xenograft model. Proliferation and apoptosis in tumors were assessed using standard histologic markers, and intracellular localization of phosphorylated extracellular signal-regulated kinase (pERK) was examined using fluorescent immunohistochemistry. Results Monotherapy with EZH2 or MEK inhibitors reduced proliferation and increased apoptosis across all MPNST lines. Combination therapy produced greater tumor cell growth suppression and marked increases in apoptosis. In vivo, the combination significantly delayed tumor progression compared with monotherapy, with concomitant reductions in proliferative indices and increases in apoptotic indices. EZH2 inhibitor limited nuclear pERK entry. Conclusions Dual EZH2 and MEK inhibitors yields additive antitumor activity in NF1-associated MPNST. Although the molecular mechanism could not be elucidated, our findings suggest that EZH2 inhibitors exhibited a polycomb repressive complex 2-independent, noncanonical mechanism characterized by pERK nuclear translocation restriction, providing a strong rationale for clinical evaluation of this combination in NF1-associated MPNST.
Background:We conducted a multicenter study to investigate the utility of postoperative antiseizure medication (ASM) in the occurrence of late seizure in glioblastoma. In addition, we analyzed whether postoperative ASM affects survival. Methods:1132 consecutive patients with newly diagnosed glioblastoma at 39 centers were enrolled. In patients treated with postoperative ASM (levetiracetam [LEV], lacosamide [LCM], or perampanel [PER]), as well as in those who received no medication, the cumulative incidence of late seizure, adverse events, and survival outcomes were analyzed. Results:In total, 1099 patients (female: 482, male: 617, mean age: 67.2 years) were included, among whom, 287 developed postoperative late seizure. The mean onset time of late seizure was 193.6 days after surgery. Postoperative ASMs were administered in 628 cases, LEV in 344, LCM in 124, and PER in 160. The cumulative incidence of late seizure at 12 months was as follows: no medication in 30.9%, LEV in 17.8%, LCM in 28.8%, and PER in 16.2%. Multivariable analysis disclosed that LEV and PER displayed significantly lower cumulative incidences of postoperative late seizure compared with no medication and LCM. By contrast, median progression-free survival/overall survival did not significantly differ among ASMs. However, during the 12-24 month interval, the PER group demonstrated a more favorable prognosis than the other groups. Conclusions:LEV and PER after glioblastoma surgery were associated with a reduced risk of late seizure compared with LCM or no medication. LEV or PER may be considered as postoperative ASMs to optimize seizure control and potentially help preserve patients' QOL.
Background:Radiation-induced brain injury (RBI) is a serious sequela in long-term survivals of patients with brain tumors or nasopharyngeal carcinoma after receiving radiotherapy. The role of multiple glial cell types in driving major RBI pathologies remains largely unclear. Methods:The late-phase radiation response in mouse brain was profiled and analyzed using bulk tissue RNA-sequencing and single-nucleus mRNA sequencing (snRNA-seq). Glia crosstalk was investigated by using primary culture and co-culture. Results:We found substantial loss of mature oligodendrocytes and microglia-derived neuroinflammation as 2 major features in late phase of RBI. Loss of oligodendrocytes coincides with the emergence of a radiation-induced reactive microglial subpopulation (RRM_1) characterized by enhanced phagocytosis activity, specialized for myelin debris clearance. Myelin debris phagocytosis induces a M2-to-M1 phenotypic transition in irradiated microglia. Astrocyte-microglia lactate shuttle (AMLS), mediated by monocarboxylate transporters (MCT4/MCT1), suppresses M1-like polarization of microglia. M2-like phenotype could be enhanced by secreted secreted phosphoprotein 1 (SPP1) via boosting AMLS. Conclusions:Taken together, we found demyelination and neuroinflammation are two intimately related features in irradiated brain. Microglia and astrocyte collectively contribute to tissue homeostasis by stably scavenging myelin/cellular debris. Our data reveal a correlative glial metabolic cascade (oligodendrocytes, microglia, and astrocytes) linked to chronic neuroinflammation. These findings provide new insights into therapeutic strategies for RBI.
Abstract Background Bevacizumab combination therapy has shown response in approximately 25% of recurrent Glioblastoma (GBM) patients. This study aimed to investigate the value of O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography ([18F]FET PET) imaging and the relevance of the PET-based response assessment criteria for diffuse gliomas (PET RANO) criteria in assessing response to bevacizumab combination therapy in recurrent GBM. Material and methods All recurrent GBM IDH-wildtype patients treated with bevacizumab plus irinotecan at Rigshospitalet (year 2018-2022) and evaluated with consecutive [18F]FET PET imaging at baseline and after 2 cycles of treatment were included. Metabolic tumour volumes (MTV), maximum tumour-to-background ratios (TBRmax), mean tumour-to-background ratios (TBRmean) and associated changes were determined. Cox regression and receiver operating characteristic analyses were used to identify predictors of survival beyond the median overall survival (OS). Results 82 patients (median OS 9.3 months, 95% Confidence interval: 8.3–10.4) were included. Tumours were smaller and less metabolically active at follow-up. PET RANO showed a 68% response rate and was independently associated with a longer OS (p < 0.001). Analysis of individual PET parameters identified three thresholds that independently predicted longer OS with response rates of 35–40%: i) more than 76% reduction in MTV, ii) more than 21% reduction in TBRmax iii) follow-up MTV under 3.5 cm3. Conclusion On using [18F]FET PET for response assessment during bevacizumab treatment, the proposed response criteria improved identification of responders when compared with the PET RANO criteria. Nevertheless, further refinement and validation is needed to enhance PET-based response assessment.
Purpose:To characterize the radiological response to procarbazine and CCNU (chloroethyl-cyclohexyl-nitrosourea) (PC) polychemotherapy in patients with oligodendroglioma. Methods:In this retrospective single-center cohort study, patients with Central Nervous System World Health Organization (CNS WHO) grade 2 or 3 oligodendroglioma treated with PC between 2003 and 2019 were included. Tumor characteristics were assessed on magnetic resonance imaging (MRI) and [18F]Fluoroethyltyrosine positron emission tomography ([18F]FET PET) before and after completion of PC. The T1/T2 ratio was assessed to characterize diffuse versus sharply delineated MRI phenotype. Progression-free survival (PFS) and overall survival (OS) were analyzed. Results:Forty-six patients with a median follow-up of 118 months were identified. Median absolute T2 tumor volume was 52 cm³ (range 10-285) prior to PC and 29 cm³ (range 3-286) after. Median tumor volume decrease was -30% (range -96% to +113%). In treatment-naïve patients, median tumor volume decrease was -41% (range -92% to +14%) versus -7% (range -96% to +113%) in pretreated patients (P < .01). Stratification according to CNS WHO grade (P = .89) or contrast enhancement (P = .07) did not yield significant differences. The T1/T2 ratio was lower after PC (0.69 vs 0.50, P = .04), and higher T1/T2 ratios were associated with shorter PFS (P = .04) in multivariate analysis. On [18F]FET PET, there was a trend towards lower maximum tumor-to-brain ratios (TBRmax) after PC (P = .07). Conclusion:PC polychemotherapy induces substantial tumor volume reductions in subsets of patients with oligodendroglioma, particularly in treatment-naïve patients. The observations that circumscript oligodendrogliomas may be associated with earlier progression and that PC treatment may induce a shift toward a more diffuse phenotype require prospective validation.
Background:To evaluate whether blood-brain barrier (BBB) mapping via arterial spin-labeling (ASL)-derived exchange time (T ex) can differentiate high-grade gliomas from brain metastases and to compare regional BBB alterations with dynamic susceptibility contrast (DSC)-derived leakage parameters (K2). Methods:A total of 18 patients with therapy-naive cerebral masses (11 gliomas, 7 metastases) underwent multi-echo-ASL and DSC perfusion MRI. T ex maps were obtained using a validated extended two-compartment model. K2 maps were derived from single-echo DSC. T ex and absolute K2 (|K2|) were quantified in contrast-enhancing tumor (CET), peritumoral T2/FLAIR hyperintense region (PTR), gray matter (GM), and white matter (WM). Regional differences were assessed using Wilcoxon signed-rank and Mann-Whitney U tests. Receiver operating characteristic (ROC) analyses evaluated discrimination between gliomas and metastases. Results:T ex was significantly lower in PTR of gliomas versus metastases (P = 0.046). In receiver operating characteristic analysis, T ex slightly outperformed |K2| alone (area under the curve [AUC] = 0.792, 95% confidence interval [CI] [0.535, 0.986] vs. AUC = 0.760, 95% CI [0.508, 0.959]), with further improvement upon combination (AUC = 0.833, 95% CI [0.577, 1.000]). In gliomas, T ex was significantly lower in CET than in GM and WM (both P < 0.01) and PTR showed significantly lower T ex than WM (p < .01). |K2| was significantly higher in CET than all other regions (all p < .01) but did not differ between PTR and GM/WM. Conclusion:In this exploratory study, ASL-derived T ex suggests stronger BBB alterations in peritumoral tissue of high-grade gliomas compared with brain metastases. Adding |K2| further improved discrimination. This supports ASL-based BBB mapping as a complement to DSC leakage imaging. Validation in larger multicenter cohorts is warranted.
Background:We sought to develop a deep learning (DL) model to enable fully automated 3D segmentation and volumetric assessment of meningioma burden with a specific emphasis on generalizing to high-grade and posttreatment meningiomas to improve interobserver variability and decrease reader time investment in tumor response assessment. Methods:In total, 450 postcontrast T1-weighted brain MRIs from 104 patients with meningiomas were obtained from Massachusetts General Hospital and Dana-Farber Cancer Institute. The cohort was unique among prior DL segmentation models in that it encompassed meningiomas of all grades, postoperative, and postradiated meningiomas. Preprocessed MRIs and manually generated tumor segmentations were used to train a U-Net with a joint Dice-cross entropy loss function. Results:When tested on internal data, our model achieved a median Dice of 0.741 and a median 95th percentile Hausdorff Distance (HD95) of 26 mm on a high-grade test set and a median Dice of 0.848 and median HD95 of 1.41 mm on a test set with low-grade tumors. Lesion-wise metrics were equivalent to global metrics for low-grade tumors, which contained only single lesions, but were substantially lower for high-grade tumors, with a median lesion-wise Dice of 0.45 and median lesion-wise HD95 of 130 mm, reflecting greater difficulty delineating individual high-grade lesions. Our model also generalized well to 1000 studies from 944 patients selected from the public BraTS dataset, achieving a median Dice of 0.923 and median HD95 of 2.24 mm. Conclusions:The study produced a model that addresses an unmet need for automated volumetric measurements of meningiomas and created a reliable metric for quantifying meningioma burden. In comparison to prior DL approaches, our model achieved competitive performance on external data and improved Dice scores on high-grade and posttreatment meningiomas. The trained model, volumetric evaluation code, and accompanying documentation are available online at https://github.com/mccle/tumor_segmentation.
Background:Dexamethasone (DEXA) is the routine therapy for tumor- or treatment-associated edema management in glioblastoma, whereas bevacizumab (BEV) is increasingly used as a steroid-sparing alternative. Although both reduce edema, their broader immunometabolic effects remain ill-defined. Here, we examine how DEXA and BEV differentially affect tumor metabolism and microenvironment in patient samples and experimental models. Methods:We integrated 1H-NMR-based metabolomics of human glioblastoma specimens with mechanistic in vitro studies to compare DEXA and BEV. Microenvironmental modulation by DEXA vs BEV was further investigated in vivo in a syngeneic, immunocompetent orthotopic glioma mouse model by flow cytometry and immunohistochemistry, followed by ex vivo co-culture models. Results:Tumors from DEXA-treated patients (n = 12) vs steroid-naive controls (n = 18) showed nine significantly altered metabolites, including increased lactate, cystathionine, and 2-hydroxybutyrate, indicating a metabolically accelerated, proliferation-associated state. In an immunocompetent orthotopic glioma model, DEXA reduced intratumoral T cell infiltration and induced cytokine conditions favoring regulatory T cells (Tregs) and myeloid recruitment. In contrast, BEV elicited a coordinated immunostimulatory phenotype: it increased chemotactic cytokines in vitro (eg CCL5), decreased intratumoral Tregs (CD4+FOXP3+), enhanced activated, Granzyme B (GzmB) expressing effector T cells (CD4+GzmB+) in vivo, and improved spleenocyte-mediated tumor cell killing ex vivo. Conclusions:Together, DEXA promotes an immunosuppressive, metabolically active tumor microenvironment, whereas BEV supports immune infiltration and activation. These data, combining tissue-derived metabolomics with functional and mechanistic studies in vitro, ex vivo, and in vivo, reveal fundamentally divergent immunometabolic effects of anti-edematous therapies with direct implications in clinical practice, particularly alongside immunotherapy in glioblastoma.
Background:Amino acid PET with 18F-fluoroethyltyrosine (18F-FET) complements MRI to improve specificity of tumor detection. We evaluated whether threshold-based volumetric metrics (TBRthres) provide complementary diagnostic and prognostic information to single-voxel tumor-to-brain ratio maximum (TBRmax). Methods:This retrospective single-institution study included 100 previously treated glioma patients (WHO Grade 2-4) who underwent 18F-FET PET/MRI (N = 96) or PET/CT (N = 4) following equivocal findings of tumor progression versus treatment-related changes. Patients received 693.8 ± 79.6 MBq of 18F-FET, with PET analysis based on the 20-40 minute averaged static sequence acquired post-injection. Diagnostic performance, reproducibility, and survival associations were assessed using ROC analysis, intraclass correlation coefficients (ICC), and Cox proportional hazards models. Results:TBRthres map generation was highly reproducible (ICC > 0.86) and significantly associated with overall survival in univariate analyses (HR range: 3.07-4.45). Volumetric metrics demonstrated diagnostic performance comparable to TBRmax (AUC up to 0.91). TBRmax showed moderate correlation with tumor volume (R 2 ≈ 0.35-0.40), indicating partially overlapping but non-redundant information. In multivariate models adjusting for clinical covariates, neither volumetric metrics nor TBRmax remained statistically significant. However, in models adjusting for TBRmax, volumetric TBRthres metrics remained significantly associated with survival. Combined models improved predictive performance at selected thresholds, particularly TBRthres ≥ 1.6 (AUC 0.62 to 0.70, P = .009) and TBRthres ≥2.0 (AUC 0.62 to 0.72, P = .019), with smaller improvement at TBRthres ≥ 2.5. Conclusion:Volumetric 18F-FET PET metrics provide reproducible measures of tumor burden with diagnostic and prognostic performance comparable to TBRmax. They offer complementary information and, at selected thresholds, modest incremental predictive value beyond TBRmax.
Abstract Background Brain metastases (BM) are a devastating complication of metastatic breast cancer (MBC), with limited data comparing isolated BM versus BM with concurrent extracranial metastases (ECM) across molecular subtypes. We investigated survival outcomes and treatment patterns of isolated versus non-isolated BM in de novo stage IV breast cancer by molecular subtype. Methods Using SEER 17 (2010–2022), we identified de novo MBC patients with known BM status classified by subtype (HR+/HER2−, HR+/HER2+, HR−/HER2+, TNBC) and metastatic pattern: isolated BM (no concurrent bone, liver, or lung metastases) versus BM with ECM. Kaplan-Meier and log-rank tests compared overall survival (OS). Chi-square tests assessed treatment differences. Results Among 36,853 de novo MBC patients, 2,703 (7.3%) had BM at diagnosis; 2,358 had known subtypes. Of these, 417 (17.7%) had isolated BM and 1,941 (82.3%) had BM with ECM. The isolated BM cohort was enriched for TNBC (30.9% vs. 19.8%, p < 0.001) with higher surgical rates (25.4% vs. 9.5%, p < 0.001). Overall, isolated BM patients had superior OS (mOS 13 vs. 11 months, p = 0.0005). The survival benefit was subtype-dependent. HR−/HER2+ patients showed the most striking differential: mOS 29 vs 11 months, 2-year OS 57.4% vs. 28.9% (p = 0.0002). TNBC patients with isolated BM also benefited (mOS 8 vs. 6 months, p = 0.0009), while no difference was seen in HR+/HER2− disease (p = 0.10). Among isolated BM patients, surgery (mOS 23 vs. 10 months, p = 0.0001), radiation (mOS 17 vs. 6 months, p < 0.0001), and chemotherapy (mOS 22 vs 4 months, p < 0.0001) each improved survival. Increasing extracranial burden showed stepwise decrement: 0 sites (13 months), 1 (14), 2 (11), 3 (7 months). Conclusions Isolated BM in de novo MBC represent a distinct entity with subtype-specific prognostic implications. HR−/HER2+ patients with isolated BM demonstrate a nearly 3-fold survival advantage over those with concurrent ECM, supporting subtype-stratified treatment and aggressive multimodal intervention.
Background:Hippocampal avoidance whole brain radiotherapy (HA-WBRT) with memantine is standard of care for patients with extensive brain metastases requiring radiation. However, other brain structures have critical memory and cognition roles, including the corpus callosum, fornix, amygdala, hypothalamus, and pituitary. A subset of patients enrolled on a Phase 2 Randomized Controlled Trial received an advanced "memory-avoidance" WBRT (MA-WBRT) approach that spared these substructures in addition to the hippocampus. Methods:Patients with >15 brain metastases were enrolled in the ATHENA Trial and received MA-WBRT. All patients received 30 Gy in 10 fractions of MA-WBRT and were prescribed memantine. Cognition was measured by Hopkins Verbal Learning Test-Revised, Controlled Oral Word Association Test, and Trail Making Test A/B, with cognitive decline defined as decline on at least one assessment using the reliable change index. Results:Between August 2022 and May 2024, 29 patients were prescribed MA-WBRT. Decline in neurocognitive function at 3 and 6 months for patients receiving MA-WBRT was 17.2% and 48.3%, respectively. There was only 1 failure in a memory avoidance substructure (occurring in the right fornix 10 months after enrollment), and this was associated with concurrent distant intracranial failure outside the memory avoidance zone. Conclusions:The cognitive decline rates of 17.2% and 48.3% at 3 and 6 months for patients receiving MA-WBRT compare favorably to the 3- and 6-month cognitive decline rates of 50% and 60% seen on NRG CC001. A direct comparison of MA-WBRT plus memantine vs. HA-WBRT plus memantine is forthcoming in a randomized phase 2 trial (NCT07248228).
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.
Background:Isocitrate dehydrogenase (IDH)-mutant gliomas are infiltrative brain tumors with heterogeneous clinical courses. Predicting individual responses to chemotherapy and long-term outcomes remains challenging. We aimed to characterize distinct patterns of tumor evolution during first-line chemotherapy using longitudinal tumor volume dynamics and clinical outcomes. Methods:We retrospectively included 195 patients treated at a single institution and analyzed 1956 MRI examinations obtained during chemotherapy. Tumor volume and mean tumor diameter (MTD) were quantified on T2/FLAIR-weighted images using an automated nnU-Net-based segmentation algorithm. Tumor evolution was analyzed using latent class joint models integrating longitudinal tumor measurements and time-to-event outcomes. Results:Modeling based on MTD trajectories and overall survival (OS) identified 3 distinct response classes. The non-response class (13.8%) was characterized by early tumor growth from treatment initiation and poor outcomes (median progression-free survival [PFS]: 8.1 months; median time to anaplastic transformation [TAT]: 19.9 months; median OS: 41.1 months). The durable response class (57.4%) showed stable or slightly decreasing MTD trajectories and favorable outcomes (median PFS: 73.2 months; median TAT: 93.2 months; median OS: 169.3 months). Conversely, the transient response class (28.7%) exhibited an initial decrease in tumor size followed by rapid regrowth within 2 years (median PFS: 31.4 months; median TAT: 27.9 months; median OS: 54.2 months). Conclusions:Longitudinal modeling of MTD trajectories together with OS identified clinically meaningful chemotherapy response patterns in IDH-mutant gliomas, strongly associated with progression and malignant transformation. While most patients exhibited durable responses, others showed unfavorable trajectories, highlighting the need for early biomarkers to tailor treatment strategies.
Abstract Background High-grade gliomas are the most prevalent type of malignant brain tumor in adults and the second leading cause of cancer-related death. This study assesses epidemiology, pattern of care, and treatment outcome of high-grade glioma in Ethiopia. Methods A Prospective cohort study. Data collected were analyzed using SPSS. Frequency distribution was used to describe the characteristics of the study participants. Chi-squared tests and survival analysis were used to assess the treatment outcomes. Variables with P < .05 were considered as significant. Results There was a total of 40 patients. The median age at diagnosis was 47 years. Headache was the commonest presenting symptom (97.5%), followed by seizure (52.5%) and weakness (50%). The pre-operative tumor volume ranged between 3.9 and 168 cm3, with a mean volume of 80.38 cm3. A total of 22 patients had ≥97% extent of resection. About 17.5% of the patients died post-treatment. The mean survival time was 20.77 months (95% CI: 18.46-23.09 months). There was significant association with higher Karnofsky performance status (KPS) scale (≥70), pre-operative GCS, and post-operative adjuvant therapy with survival outcome (χ2 = 10.19 P = .006, χ2 = 12.9 P = .005, χ2 = 6.716 P = .035), respectively. Conclusion In our study, the mean survival time was 20.77 months. Higher KPS, pre-operative Glasgow Coma Scale (GCS) of 15, and patients receiving post-op adjuvant therapy had a significant favorable association with survival in our study.
Abstract Background Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor mostly affecting young children. Improved and less toxic therapies for children with ATRT are imperative due to the toxicities associated with current treatments. Furthermore, existing therapies do not address the underlying genetic drivers of ATRT. In this study, we sought to determine whether exportin-1 (XPO1) is a genetic dependency and therapeutic target in ATRT. Methods We utilized an integrative approach harnessing patient-derived ATRT cell lines, functional genomics, pharmacologic assays, transcriptomics, and in vivo intracranial xenograft models to systematically test the hypothesis that XPO1 is a novel dependency in ATRT. Results Analysis of RNA-sequencing datasets revealed high XPO1 expression in ATRT cells compared to other pediatric brain tumor cell lines. Both CRISPR/Cas9 genetic knockdown and pharmacologic inhibition of XPO1 using six selective inhibitors of nuclear export (SINEs) in patient-derived ATRT cells led to significant reduction in cell viability and proliferation. Furthermore, we observed increased apoptosis, G0 phase cell cycle arrest, and upregulation of TP53 signaling pathways in cells treated with the SINE selinexor. Consistently, our transcriptomic data revealed the upregulation of apoptosis and TP53 signaling pathways and concomitant depletion of cell cycle gene sets. In vivo, selinexor in combination with radiation and cyclophosphamide led to significant reduction in tumor volume and increased animal survival in intracranial ATRT xenograft models. Conclusions Our data reveal XPO1 as a novel genetic dependency and potent therapeutic target in ATRT.
Background:Pediatric central nervous system (CNS) tumors are the leading cause of cancer-related death among children and adolescents globally. Despite the complex and multidisciplinary care needed, there is limited evidence on standardized quality indicators (QIs) for pediatric neuro-oncology (PNO). Methods:A modified Delphi process was conducted to develop consensus-based QIs for PNO. Candidate indicators were identified through a systematic review of published literature. After expert screening, indicators were evaluated by a multidisciplinary panel through 2 rounds of Delphi surveys. Consensus was defined as ≥75% agreement. A subsequent consensus meeting and tiering process were conducted to categorize the selected indicators. Results:The systematic review identified 35 studies containing 124 relevant indicators; these were subsequently refined to 63 candidate indicators for evaluation in 2 Delphi surveys. Thirty-two experts from 5 specialties and 15 countries participated in the consensus process. A consensus was established that included that indicators would have the following 3 characteristics: reflect the continuum of PNO care, be continuous variables, and be feasible to measure across diverse resource settings. Through 2 rounds of Delphi surveys, a total of 48 indicators met the consensus threshold. Indicators were subsequently consolidated to 31, following discussion and merging of overlapping items. Final indicators were categorized into 2 sets: 19 core indicators and 12 extended indicators. Conclusions:By providing a framework for evaluating quality across the continuum of PNO care, these indicators can aid benchmarking and guide quality improvement interventions. Prospective validation and assessment of their impact on patient outcomes are still needed.
Background:A significant proportion of meningiomas are resistant to current treatments. Somatostatin receptor 2 (SSTR2) is highly and consistently expressed in most meningiomas, providing a promising target for localized chimeric antigen receptor (CAR)-T cell therapy. Short-lived small-molecule CAR adapters can potentially prevent CAR-T cell exhaustion in solid tumors by alternating between active and resting states. Methods:We developed the CAR adapter peptide Octofluo, which combines fluorescein-5-isothiocyanate (FITC) with a high-avidity SSTR2 antagonist. After determining its biodistribution, killing efficiency of CAR-T cells plus Octofluo against human meningioma was evaluated in vitro and ex vivo. Therapeutic capacity was assessed in vivo against xenograft and syngeneic genetically engineered mouse meningioma models. Results:We herein demonstrate rapid tissue diffusion and transient tumor persistence for only a few hours after intravenous administration of Octofluo, making a suitable switch for on-demand CAR-T cell activation. Nanomolar concentrations of Octofluo effectively directed FITC-specific CAR-T cells against SSTR2-expressing meningioma cells. Combined intratumoral CAR-T cell delivery and intravenous octofluo infusion at periodic intervals showed limited efficacy in an immunocompromised xenograft model but cured most mice with an intact immune system harboring highly aggressive, genetically induced higher grade meningiomas. Cures were accompanied by CAR-T cell expansion and an endogenous T cell response, suggesting a role for the host immune system in tumor elimination. Ex vivo lysis of patient-derived meningioma cells was observed. Conclusions:The combination of systemic octofluo administration and locally applied CAR-T cells is a promising strategy for future clinical development for patients with refractory meningiomas.
