The detrimental effect of biopsy preceding resection in surgically accessible glioblastoma: results from the national cancer database.

PURPOSE: Aggressive resection in surgically-accessible glioblastoma (GBM) correlates with improved survival over less extensive resections. However, the clinical impact of performing a biopsy before definitive resection have not been previously evaluated. METHODS: We analyzed 17,334 GBM patients from the NCDB from 2010-2014. We categorized them into: "upfront resection" and "biopsy followed by resection". The outcomes of interes included OS, 30-day readmission/mortality, 90-day mortality, and length of hospital stay (LOS). The Kaplan-Meier methods and accelerated failure time (AFT) models were applied for survival analysis. Multivariable binary logistic regression were performed to compare differences among groups. Multiple imputation and propensity score matching (PSM) were conducted for validation. RESULTS: "Upfront resection" had superior OS over "biopsy followed by resection" (median OS:12.4 versus 11.1 months, log-rank p = 0.001). Similarly, multivariable AFT models favored "upfront resection" (time ratio[TR]:0.83, 95%CI: 0.75-0.93, p = 0.001). Patients undergoing "upfront gross-total resection (GTR)" had higher OS over "upfront subtotal resection (STR)", "GTR following STR", and "GTR or STR following initial biopsy" (14.4 vs. 10.3, 13.5, 13.3, and 9.1 months;TR: 1.00 [Ref.], 0.75, 0.82, 0.88, and 0.67). Recent years of diagnosis, higher income, facilities located in Southern regions, and treatment at academic facilities were significantly associated with the higher likelihood of undergoing upfront resection. Multivariable regression showed a decreased 30 and 90-day mortality for patients undergoing "upfront resection", 73% and 44%, respectively (p < 0.001). CONCLUSIONS: Pre-operative biopsies for surgically accessible GBM are associated with worse survival despite subsequent resection compared to patients undergoing upfront resection.

Imaging predictors of 4q12 amplified and RB1 mutated glioblastoma IDH-wildtype.

INTRODUCTION: Recent studies have identified that glioblastoma IDH-wildtype consists of different molecular subgroups with distinct prognoses. In order to accurately describe and classify gliomas, the Visually AcceSAble Rembrandt Images (VASARI) system was developed. The goal of this study was to evaluate the VASARI characteristics in molecular subgroups of IDH-wildtype glioblastoma. METHODS: A retrospective analysis of glioblastoma IDH- wildtype with comprehensive next-generation sequencing and pre-operative and post-operative MRI was performed. VASARI characteristics and 205 genes were evaluated. Multiple comparison adjustment by the Bejamin-Hochberg false discovery rate (BH-FDR) was performed. A 1:3 propensity score match (PSM) with a Caliper of 0.2 was done. RESULTS: 178 patients with GBM IDH-WT met the inclusion criteria. 4q12 amplified patients (n = 20) were associated with cyst presence (30% vs. 12%, p = 0.042), decreased hemorrhage (35% vs. 62%, p = 0.028), and non-restricting/mixed (35%/60%) rather than restricting diffusion pattern (5%), meanwhile, 4q12 non-amplified patients had mostly restricting (47.4%) rather than a non-restricting/mixed diffusion pattern (28.4%/23.4%). This remained statistically significant after BH-FDR adjustment (p = 0.002). PSM by 4q12 amplification showed that diffusion characteristics continued to be significantly different. Among RB1-mutant patients, 96% had well-defined enhancing margins vs. 70.6% of RB1-WT (p = 0.018), however, this was not significant after BH-FDR or PSM. CONCLUSIONS: Patients with glioblastoma IDH-wildtype harboring 4q12 amplification rarely have restricting DWI patterns compared to their wildtype counterparts, in which this DWI pattern is present in ~ 50% of patients. This suggests that some phenotypic imaging characteristics can be identified among molecular subtypes of IDH-wildtype glioblastoma.

Prognostic value of surgical resection over biopsy in elderly patients with glioblastoma: a meta-analysis.

PURPOSE: Maximal-safe resection has been shown to improve overall survival in elderly patients with glioblastoma in observational studies, however, the only clinical trial comparing resection versus biopsy in elderly patients with surgically-accessible glioblastoma showed no improvements in overall survival. A meta-analysis is needed to assess whether surgical resection of glioblastoma in older patients improves surgical outcomes when compared to biopsy alone. METHODS: A search was conducted until October 9th, 2023, to identify published studies reporting the clinical outcomes of glioblastoma patients > 65 years undergoing resection or biopsy (PubMed, MEDLINE, EMBASE, and COCHRANE). Primary outcomes were overall survival (OS), progression-free survival (PFS), and complications. We analyzed mean difference (MD) and hazard ratio (HR) for survival outcomes. Postoperative complications were analyzed as a dichotomic categorical variable with risk ratio (RR). RESULTS: From 784 articles, 20 cohort studies and 1 randomized controlled trial met our inclusion criteria, considering 20,523 patients for analysis. Patients undergoing surgical resection had an overall survival MD of 6.13 months (CI 95%=2.43-9.82, p = < 0.001) with a HR of 0.43 (95% CI = 0.35-0.52, p = < 0.00001). The progression-free survival MD was 2.34 months (95%CI = 0.79-3.89, p = 0.003) with a 0.50 h favoring resection (95%CI = 0.37-0.68, p = < 0.00001). The complication RR was higher in the resection group favoring biopsy (1.49, 95%CI = 1.06-2.10). CONCLUSIONS: Our meta-analysis suggests that upfront resection is associated with improved overall survival and progression-free survival in elderly patients with newly diagnosed glioblastoma over biopsy. However, postoperative complications are more common with resection. Future clinical trials are essential to provide more robust evaluation in this challenging patient population.

Rapid detection of mutations in CSF-cfTNA with the Genexus Integrated Sequencer.

PURPOSE: Genomic alterations are fundamental for molecular-guided therapy in patients with breast and lung cancer. However, the turn-around time of standard next-generation sequencing assays is a limiting factor in the timely delivery of genomic information for clinical decision-making. METHODS: In this study, we evaluated genomic alterations in 54 cerebrospinal fluid samples from 33 patients with metastatic lung cancer and metastatic breast cancer to the brain using the Oncomine Precision Assay on the Genexus sequencer. There were nine patients with samples collected at multiple time points. RESULTS: Cell-free total nucleic acids (cfTNA) were extracted from CSF (0.1-11.2 ng/µl). Median base coverage was 31,963× with cfDNA input ranging from 2 to 20 ng. Mutations were detected in 30/54 CSF samples. Nineteen (19/24) samples with no mutations detected had suboptimal DNA input (< 20 ng). The EGFR exon-19 deletion and PIK3CA mutations were detected in two patients with increasing mutant allele fraction over time, highlighting the potential of CSF-cfTNA analysis for monitoring patients. Moreover, the EGFR T790M mutation was detected in one patient with prior EGFR inhibitor treatment. Additionally, ESR1 D538G and ESR1::CCDC170 alterations, associated with endocrine therapy resistance, were detected in 2 mBC patients. The average TAT from cfTNA-to-results was < 24 h. CONCLUSION: In summary, our results indicate that CSF-cfTNA analysis with the Genexus-OPA can provide clinically relevant information in patients with brain metastases with short TAT.

BRAF/MEK Dual Inhibitors Therapy in Progressive and Anaplastic Pleomorphic Xanthoastrocytoma: Case Series and Literature Review.

Recurrent and anaplastic pleomorphic xanthoastrocytoma (r&aPXA) is a rare primary brain tumor that is challenging to treat. Two-thirds of PXA tumors harbor a BRAF gene mutation. BRAF inhibitors have been shown to improve tumor control. However, resistance to BRAF inhibition develops in most cases. Concurrent therapy with MEK inhibitors may improve tumor control and patient survival. In this study, we identified 5 patients diagnosed with BRAF-mutated PXA who received BRAF and MEK inhibitors over a 10-year interval at our institution. Patient records were evaluated, including treatments, adverse effects (AEs), outcomes, pathology, next-generation sequencing, and MRI. The median age was 22 years (range, 14-66 years), 60% male, and 60% anaplastic PXA. Median overall survival was 72 months (range, 19-112 months); 1 patient died of tumor-related hemorrhage while off therapy, and the other 4 experienced long-term disease control (21, 72, 98, and 112 months, respectively). Dual BRAF/MEK inhibitors were well tolerated, with only grade 1-2 AEs, including rash, neutropenia, fatigue, abdominal discomfort, and diarrhea. No grade 3-5 AEs were detected. A literature review was also performed of patients diagnosed with BRAF-mutated PXA and treated with BRAF and/or MEK inhibitors through August 2021, with a total of 32 cases identified. The median age was 29 years (range, 8-57 years) and the median PFS and OS were 8.5 months (range, 2-35 months) and 35 months (range, 10-80 months), respectively. The most common AEs were grade 1-2 fatigue and skin rash. Results of this case series and literature review indicate that dual-drug therapy with BRAF and MEK inhibitors for r&aPXA with BRAF V600E mutation may delay tumor progression without unexpected AEs.

IDH1 p.R132H ctDNA and D-2-hydroxyglutarate as CSF biomarkers in patients with IDH-mutant gliomas.

INTRODUCTION: We aimed to evaluate IDH1 p.R132H mutation and 2-hydroxyglutarate (2HG) in cerebrospinal fluid (CSF) as biomarkers for patients with IDH-mutant gliomas. METHODS: CSF was collected from patients with infiltrating glioma, and 2HG levels were measured by liquid chromatography-mass spectrometry. IDH1 p.R132H mutant allele frequency (MAF) in CSF-ctDNA was measured by digital droplet PCR (ddPCR). Tumor volume was measured from standard-of-care magnetic resonance images. RESULTS: The study included 48 patients, 6 with IDH-mutant and 42 with IDH-wildtype gliomas, and 57 samples, 9 from the patients with IDH-mutant and 48 from the patients with IDH-wildtype gliomas. ctDNA was detected in 7 of the 9 samples from patients with IDH-mutant glioma, and IDH1 p.R132H mutation was detected in 5 of the 7 samples. The MAF ranged from 0.3 to 39.95%. Total 2HG level, D-2HG level, and D/L-2HG ratio in CSF were significantly higher in patients with IDH-mutant gliomas than in patients with IDH-wildtype gliomas. D-2HG level and D/L-2HG ratio correlated with total tumor volume in patients with IDH-mutant gliomas but not in patients with IDH-wildtype gliomas. CONCLUSION: Our results suggest that detection of IDH1 p.R132H mutation by ddPCR and increased D-2HG level in CSF may help identify IDH-mutant gliomas. Our results also suggest that D-2HG level and D/L-2HG ratio correlate with tumor volume in patients with IDH-mutant gliomas. Further prospective studies with larger cohorts are needed to validate these findings.

Impacts of genotypic variants on survival following reoperation for recurrent glioblastoma.

INTRODUCTION: Recurrent glioblastoma (rGBM) prognosis is dismal. In the absence of effective adjuvant treatments for rGBM, re-resections remain prominent in our arsenal. This study evaluates the impact of reoperation on post-progression survival (PPS) considering rGBM genetic makeup. METHODS: To assess the genetic heterogeneity and treatment-related changes (TRC) roles in re-operated or medically managed rGBMs, we compiled demographic, clinical, histopathological, and next-generation genetic sequencing (NGS) characteristics of these tumors from 01/2005 to 10/2019. Survival data and reoperation were analyzed using conventional and random survival forest analysis (RSF). RESULTS: Patients harboring CDKN2A/B loss (p = 0.017) and KDR mutations (p = 0.031) had notably shorter survival. Reoperation or bevacizumab were associated with longer PPS (11.2 vs. 7.4-months, p = 0.006; 13.1 vs 6.2, p < 0.001). Reoperated patients were younger, had better performance status and greater initial resection. In 136/273 (49%) rGBMs undergoing re-operation, CDKN2A/B loss (p = 0.03) and KDR mutations (p = 0.02) were associated with shorter survival. In IDH-WT rGBMs with NGS data (n = 166), reoperation resulted in 7.0-month longer survival (p = 0.004) than those managed medically. This reoperation benefit was independently identified by RSF analysis. Stratification analysis revealed that EGFR-mutant, CDKN2A/B-mutant, NF1-WT, and TP53-WT rGBM IDH-WT subgroups benefit most from reoperation (p = 0.03). Lastly, whether or not TRC was prominent at re-operation does not have any significant impact on PPS (10.5 vs. 11.5-months, p = 0.77). CONCLUSIONS: Maximal safe re-resection significantly lengthens PPS regardless of genetic makeup, but reoperations are especially beneficial for IDH-WT rGBMs with EGFR and CDKN2A/B mutations with TP53-WT, and NF1-WT. Histopathology at recurrence may be an imperfect gauge of disease severity at progression and the imaging progression may be more reflective of the prognosis.

Tumor recurrence or treatment-related changes following chemoradiation in patients with glioblastoma: does pathology predict outcomes?

BACKGROUND: Despite surgical resection and chemoradiation, all patients with GBM invariably recur. Radiological imaging is limited in differentiating tumor recurrence (TR) from treatment-related changes (TRC); therefore, re-resection is often needed. Few studies have assessed the relationship between re-resection histopathology and overall survival (OS). We performed a large retrospective study to analyze the clinical significance of histopathology following re-resection and its influence on genomic sequencing results. METHODS: Clinical, radiographic, and histological information was compiled from 675 patients with GBM (2005-2017). 137-patients met the inclusion criteria. IDH1 p.R132H immunohistochemistry was performed in all patients. Next-generation sequencing interrogating 205 tumor-related genes was performed in 68-patients. Molecular alterations from initial and subsequent resections were compared in a subset of cases. RESULTS: There were no differences in OS (17.3-months TRC vs. 21-months TR, p = 0.881) and survival from progression (9.0 vs. 11.7-months, p = 0.778) between patients with TR and TRC on re-resection. TR patients were more likely to receive salvage radiotherapy (26% vs. 0%) and tumor-treating fields (25% vs. 5%,) after the 2nd surgery than the TRC group (p = < 0.045). There was no correlation between mutations and TRC. IDH status was not predictive of TRC. Fifteen-patients had sequencing results from multiple surgeries without evident differences in genomic alterations. CONCLUSIONS: Histopathologic findings following chemoradiation do not correlate with clinical outcomes. Such findings should be considered during patient management and clinical trial enrollment. Standardization of tissue sampling and interpretation following reoperation is urgently needed. Future work is required to understand the relationship between the mutation profile following TRC and outcomes.

PTEN mutations predict benefit from tumor treating fields (TTFields) therapy in patients with recurrent glioblastoma.

INTRODUCTION: Optimal treatment for recurrent glioblastoma isocitrate dehydrogenase 1 and 2 wild-type (rGBM IDH-WT) is not standardized, resulting in multiple therapeutic approaches. A phase III clinical trial showed that tumor treating fields (TTFields) monotherapy provided comparable survival benefits to physician's chemotherapy choice in rGBM. However, patients did not equally benefit from TTFields, highlighting the importance of identifying predictive biomarkers of TTFields efficacy. METHODS: A retrospective review of an institutional database with 530 patients with infiltrating gliomas was performed. Patients with IDH-WT rGBM receiving TTFields at first recurrence were included. Tumors were evaluated by next-generation sequencing for mutations in 205 cancer-related genes. Post-progression survival (PPS) was examined using the log-rank test and multivariate Cox-regression analysis. RESULTS: 149 rGBM patients were identified of which 29 (19%) were treated with TTFields. No significant difference in median PPS was observed between rGBM patients who received versus did not receive TTFields (13.9 versus 10.9 months, p = 0.068). However, within the TTFields-treated group (n = 29), PPS was improved in PTEN-mutant (n = 14) versus PTEN-WT (n = 15) rGBM, (22.2 versus 11.6 months, p = 0.017). Within the PTEN-mutant group (n = 70, 47%), patients treated with TTFields (n = 14) had longer median PPS (22.2 versus 9.3 months, p = 0.005). No PPS benefit was observed in PTEN-WT patients receiving TTFields (n = 79, 53%). CONCLUSIONS: TTFields therapy conferred a significant PPS benefit in PTEN-mutant rGBM. Understanding the molecular mechanisms underpinning the differences in response to TTFields therapy could help elucidate the mechanism of action of TTFields and identify the rGBM patients most likely to benefit from this therapeutic option.

Genomic alterations predictive of response to radiosurgery in recurrent IDH-WT glioblastoma.

INTRODUCTION: Despite aggressive treatment, glioblastoma invariably recurs. The optimal treatment for recurrent glioblastoma (rGBM) is not well defined. Stereotactic radiosurgery (SRS) for rGBM has demonstrated favorable outcomes for selected patients; however, its efficacy in molecular GBM subtypes is unknown. We sought to identify genetic alterations that predict response/outcomes from SRS in rGBM-IDH-wild-type (IDH-WT). METHODS: rGBM-IDH-WT patients undergoing SRS at first recurrence and tested by next-generation sequencing (NGS) were reviewed (2009-2018). Demographic, clinical, and molecular characteristics were evaluated. NGS interrogating 205-genes was performed. Primary outcome was survival from GK-SRS assessed by Kaplan-Meier method and multivariable Cox proportional-hazards. RESULTS: Sixty-three lesions (43-patients) were treated at 1st recurrence. Median age was 61-years. All patients were treated with resection and chemoradiotherapy. Median time from diagnosis to 1st recurrence was 8.7-months. Median cumulative volume was 2.895 cm3 and SRS median marginal dose was 18 Gy (median isodose-54%). Bevacizumab was administered in 81.4% patients. PFS from SRS was 12.9-months. Survival from SRS was 18.2-months. PTEN-mutant patients had a longer PFS (p = 0.049) and survival from SRS (p = 0.013) in multivariable analysis. Although no statistically significant PTEN-mutants patients had higher frequency of radiation necrosis (21.4% vs. 3.4%) and lower in-field recurrence (28.6% vs. 37.9%) compared to PTEN-WT patients. CONCLUSIONS: SRS is a safe and effective treatment option for selected rGBM-IDH-WT patients following first recurrence. rGBM-IDH-WT harboring PTEN-mutation have improved survival with salvage SRS compared to PTEN-WT patients. PTEN may be used as a molecular biomarker to identify a subset of rGBM patients who may benefit the most from SRS.

IDH-Mutant Low-grade Glioma: Advances in Molecular Diagnosis, Management, and Future Directions.

PURPOSE OF REVIEW: IDH-mutant low-grade gliomas (LGG) have emerged as a distinct clinical and molecular entity with unique treatment considerations. Here, we review updates in IDH-mutant LGG diagnosis and classification, imaging biomarkers, therapies, and neurocognitive and patient-reported outcomes. RECENT FINDINGS: CDKN2A/B homozygous deletion in IDH-mutant astrocytoma is associated with shorter survival, similar to WHO grade 4. The T2-FLAIR mismatch, a highly specific but insensitive sign, is diagnostic of IDH-mutant astrocytoma. Maximal safe resection is currently indicated in all LGG cases. Radiotherapy with subsequent PCV (procarbazine, lomustine, vincristine) provides longer overall survival compared to radiotherapy alone. Temozolomide in place of PCV is reasonable, but high-level evidence is still lacking. LGG adjuvant treatment has important quality of life and neurocognitive side effects that should be considered. Although incurable, IDH-mutant LGG have a favorable survival compared to IDH-WT glioma. Recent advances in molecular-based classification, imaging, and targeted therapies will hopefully improve survival and quality of life.

Variable expression of CXCR4 in molecular subtypes of infiltrating gliomas.

AIM: Glioblastomas (GBMs) and diffuse intrinsic pontine gliomas (DIPGs) are infiltrating gliomas with poor prognosis. CXCR4 has been linked to glioma cell invasion, survival, proliferation, and angiogenesis. This study aimed to evaluate the expression of CXCR4 in molecular subtypes of adult and pediatric infiltrating gliomas. MATERIALS AND METHODS: We evaluated the expression of CXCR4 in 21 DIPGs and 44 adult infiltrating gliomas (25 GBM, 8 astrocytomas, and 11 oligodendrogliomas) by immunohistochemistry. Mutations in 315 cancer genes and rearrangements in 28 genes were evaluated by next-generation sequencing. RESULTS: CXCR4 was expressed in -DIPGs and adult infiltrating gliomas in tumor cells (28.6% and 5.6%, respectively) and endothelial cells (14.3% and 19.4%?, respectively). In adult gliomas, there was a correlation between CXCR4 expression and mutations in EGFR, PIK3CA, TERT promoter, and CDKN2A/B loss. In contrast, CXCR4 expression was not detected in IDH1/IDH2 mutant gliomas. These associations were confirmed using The Cancer Genome Atlas (TCGA) database. CONCLUSION: CXCR4 is expressed in a subset of DIPGs and GBMs, but it is not expressed in astrocytomas or oligodendrogliomas. CXCR4 expression is variable and it is influenced by tumor genomic alterations. It is important to consider CXCR4 expression in clinical trials that evaluate the efficacy of CXCR4 inhibitors in the treatment of gliomas.

Molecular characteristics and clinical features of multifocal glioblastoma.

INTRODUCTION: Glioblastomas (GBMs) usually occur as a solitary lesion; however, about 0.5-35% present with multiple lesions (M-GBM). The genetic landscape of GBMs have been thoroughly investigated; nevertheless, differences between M-GBM and single-foci GBM (S-GBM) remains unclear. The present study aimed to determine differences in clinical and molecular characteristics between M-GBM and S-GBM. METHODS: A retrospective review of multifocal/multicentric infiltrative gliomas (M-IG) from our institutional database was performed. Demographics, clinical, radiological, and genetic features were obtained and compared between M-GBM IDH-wild type (IDH-WT) vs 193 S-GBM IDH-WT. Mutations were examined by a targeted next-generation sequencing assay interrogating 315 genes. RESULTS: 33M-IG were identified from which 94% were diagnosed as M-GBM IDH-WT, the remaining 6% were diagnosed as astrocytomas IDH-mutant. M-GBM and S-GBM comparison revealed that EGFR alterations were more frequent in M-GBM (65% vs 42% p = 0.019). Furthermore, concomitant EGFR/PTEN alterations were more common in M-GBM vs. S-GBM (36% vs 19%) as well as compared to TCGA (21%). No statistically significant differences in overall survival were observed between M-GBM and S-GBM; however, within the M-GBM cohort, patients harboring KDR alterations had a worse survival (KDR-altered 6.7 vs KDR-WT 16.6 months, p = 0.038). CONCLUSIONS: The results of the present study demonstrate that M-GBM genetically resembles S-GBM, however, M-GBM harbor higher frequency of EGFR alterations and co-occurrence of EGFR/PTEN alterations, which may account for their highly malignant and invasive phenotype. Further study of genetic alterations including differences between multifocal and multicentric GBMs are warranted, which may identify potential targets for this aggressive tumor.

Additional genetic alterations in BRAF-mutant gliomas correlate with histologic diagnoses.

INTRODUCTION: Recently, the term "Diffuse glioma, BRAF V600E-mutant" has been recommended for IDH-wildtype gliomas with BRAF p.V600E mutation and without CDKN2A/B deletion. However, additional alterations in gliomas that coexist with BRAF-mutations are poorly defined. METHODS: We analyzed next-generation sequencing results in 315 cancer-associated genes for 372 gliomas from our institution (2010 to 2017). In addition, we reviewed IDH-WT gliomas with mutation and copy-number alterations available in cBioPortal, to further characterize BRAF-mutant gliomas. RESULTS: Seventeen (4.6%) showed BRAF mutations. Tumor types included 8 glioblastomas, 2 epithelioid glioblastomas (E-GBM), 2 pleomorphic xanthoastrocytomas (PXA), 1 anaplastic oligodendroglioma, 1 diffuse astrocytoma, and 3 pilocytic astrocytomas. Fifty-three percent (53%) of cases exhibited BRAF-alterations other than p.V600E. The majority of the tumors were localized in the temporal lobe (52.9%). In addition to BRAF mutations, glioblastomas showed concomitant mutations in TP53 (3/8), CDKN2A/B-loss (6/8), TERT-promoter (6/8), and/or PTEN (5/8). Both E-GBMs and PXAs showed CDKN2A/B-loss and BRAF p.V600E with absence of TERTp, TP53, and PTEN mutations. Similar findings were observed in BRAF-mutant infiltrating gliomas from cBioPortal. CONCLUSIONS: Knowledge of additional alterations that co-occur with BRAF-mutations in gliomas may improve diagnosis and help identify patients that could benefit from targeted therapies. Furthermore, we provide examples of two patients whose tumors responded to BRAF pathway inhibitors, arguing in favor of these therapies in patients with BRAF-mutant gliomas.

Extent of Resection Thresholds in Molecular Subgroups of Newly Diagnosed Isocitrate Dehydrogenase-Wildtype Glioblastoma.

BACKGROUND AND OBJECTIVES: Maximizing the extent of resection (EOR) improves outcomes in glioblastoma (GBM). However, previous GBM studies have not addressed the EOR impact in molecular subgroups beyond IDH1/IDH2 status. In the current article, we evaluate whether EOR confers a benefit in all GBM subtypes or only in particular molecular subgroups. METHODS: A retrospective cohort of newly diagnosed GBM isocitrate dehydrogenase (IDH)-wildtype undergoing resection were prospectively included in a database (n = 138). EOR and residual tumor volume (RTV) were quantified with semiautomated software. Formalin-fixed paraffin-embedded tumor tissues were analyzed by targeted next-generation sequencing. The association between recurrent genomic alterations and EOR/RTV was evaluated using a recursive partitioning analysis to identify thresholds of EOR or RTV that may predict survival. The Kaplan-Meier methods and multivariable Cox proportional hazards regression methods were applied for survival analysis. RESULTS: Patients with EOR ≥88% experienced 44% prolonged overall survival (OS) in multivariable analysis (hazard ratio: 0.56, P = .030). Patients with alterations in the TP53 pathway and EOR <89% showed reduced OS compared to TP53 pathway altered patients with EOR>89% (10.5 vs 18.8 months; HR: 2.78, P = .013); however, EOR/RTV was not associated with OS in patients without alterations in the TP53 pathway. Meanwhile, in all patients with EOR <88%, PTEN-altered had significantly worse OS than PTEN-wildtype (9.5 vs 15.4 months; HR: 4.53, P < .001). CONCLUSION: Our results suggest that a subset of molecularly defined GBM IDH-wildtype may benefit more from aggressive resections. Re-resections to optimize EOR might be beneficial in a subset of molecularly defined GBMs. Molecular alterations should be taken into consideration for surgical treatment decisions in GBM IDH-wildtype.

Survival outcomes and prognostic factors of infratentorial glioblastoma in the elderly.

INTRODUCTION: Infratentorial glioblastoma(itGBM) is a rare and rapidly progressive form of GBM with poor prognosis. However, no studies have adequately examined itGBM outcomes in elderly patients (>65 years). Here, we used a national database to fill this knowledge gap. METHODS: SEER 18 registries were utilized to identify adult itGBM patients diagnosed between 2000-2016. itGBM cases were further divided into cerebellar and brainstem GBM as cGBM and bGBM, respectively. Kaplan-Meier analysis and Cox hazards proportional regression models were performed to assess factors associated with overall survival (OS). RESULTS: Among 137 (33%) elderly patients from the study cohort (N = 420), median age was 74 years, 38% were female, and 85% were white. Median OS in elderly itGBM patients was shorter than younger adults (10 vs. 5-months, p < 0.001). Multivariate analysis by tumor location revealed that older age was associated with poor survival for cGBM, but not for bGBM. Gross-total resection (GTR) was associated with better outcomes for both cGBM and bGBM. Radiotherapy had survival benefits for cGBM; meanwhile, chemotherapy prolonged OS in bGBM. In the elderly, advanced age (80 + years) was associated with poor outcomes, while GTR, CT and RT were all associated with improved survival. CONCLUSIONS: In our study, while elderly patients had worse survival compared to younger adults for both cGBM and bGBM, GTR improved OS in elderly itGBM, with CT and RT exhibiting a location-dependent survival benefit. Thus, elderly itGBM patients should undergo a combination of maximal resection and adjuvant treatment guided by infratentorial tumor location for maximal survival benefit.

Validation and Comparison of Common Thoracolumbar Injury Classification Treatment Algorithms and a Novel Modification.

BACKGROUND AND OBJECTIVES: The most common thoracolumbar trauma classification systems are the Thoracolumbar Injury Classification and Severity Score (TLICS) and the Thoracolumbar AO Spine Injury Score (TL AOSIS). Predictive accuracy of treatment recommendations is a historical limitation. Our objective was to validate and compare TLICS, TL AOSIS, and a modified TLICS (mTLICS) that awards 2 points for the presence of fractured vertebral body height loss >50% and/or spinal canal stenosis >50% at the fracture site. METHODS: The medical records of adult patients with acute, traumatic thoracolumbar injuries at an urban, Level 1 trauma center were retrospectively reviewed. TLICS, mTLICS, and TL AOSIS scores were calculated for 476 patients using computed tomography, MRI, and the documented neurological examination. Treatment recommendations were compared with treatment received. Standard validity measures were calculated. RESULTS: Treatment recommendations matched actual treatments in 95.6% (455/476) of patients for mTLICS, 91.3% (435/476) for TLICS, and 92.6% (441/476) for TL AOSIS. The differences between the accuracy of mTLICS and TLICS (95.6% vs 91.3%, P < .001) and between mTLICS and TL AOSIS (95.6% vs 91.3%, P = .003) were significant. The sensitivity of mTLICS was higher than that of TLICS (96.3% vs 81.3%, P < .001), and the sensitivity of TL AOSIS was higher than that of TLICS (92.5% vs 81.3%, P < .001). The specificity of mTLICS was equal to that of TLICS (95.3%) and higher than that of TL AOSIS (95.3% vs 92.7%, P = .02). The modifier led to substantial outperformance of mTLICS over TLICS due to 38 patients (20 of whom received surgery) moving from a TLICS score of <4 to a mTLICS score equal to 4. CONCLUSION: All systems performed well. The mTLICS had improved sensitivity and accuracy compared with TLICS and higher accuracy and specificity than TL AOSIS. The sensitivity of TL AOSIS was higher than that of TLICS. Prospective, multi-institutional reliability and validity studies of this mTLICS are needed for adoption.

The genomic alterations in glioblastoma influence the levels of CSF metabolites.

Cerebrospinal fluid (CSF) analysis is underutilized in patients with glioblastoma (GBM), partly due to a lack of studies demonstrating the clinical utility of CSF biomarkers. While some studies show the utility of CSF cell-free DNA analysis, studies analyzing CSF metabolites in patients with glioblastoma are limited. Diffuse gliomas have altered cellular metabolism. For example, mutations in isocitrate dehydrogenase enzymes (e.g., IDH1 and IDH2) are common in diffuse gliomas and lead to increased levels of D-2-hydroxyglutarate in CSF. However, there is a poor understanding of changes CSF metabolites in GBM patients. In this study, we performed targeted metabolomic analysis of CSF from n = 31 patients with GBM and n = 13 individuals with non-neoplastic conditions (controls), by mass spectrometry. Hierarchical clustering and sparse partial least square-discriminant analysis (sPLS-DA) revealed differences in CSF metabolites between GBM and control CSF, including metabolites associated with fatty acid oxidation and the gut microbiome (i.e., carnitine, 2-methylbutyrylcarnitine, shikimate, aminobutanal, uridine, N-acetylputrescine, and farnesyl diphosphate). In addition, we identified differences in CSF metabolites in GBM patients based on the presence/absence of TP53 or PTEN mutations, consistent with the idea that different mutations have different effects on tumor metabolism. In summary, our results increase the understanding of CSF metabolites in patients with diffuse gliomas and highlight several metabolites that could be informative biomarkers in patients with GBM.

Surgical management and outcome of newly diagnosed glioblastoma without contrast enhancement (low-grade appearance): a report of the RANO resect group.

BACKGROUND: Resection of the contrast-enhancing (CE) tumor represents the standard of care in newly diagnosed glioblastoma. However, some tumors ultimately diagnosed as glioblastoma lack contrast enhancement and have a 'low-grade appearance' on imaging (non-CE glioblastoma). We aimed to (a) volumetrically define the value of non-CE tumor resection in the absence of contrast enhancement, and to (b) delineate outcome differences between glioblastoma patients with and without contrast enhancement. METHODS: The RANO resect group retrospectively compiled a global, eight-center cohort of patients with newly diagnosed glioblastoma per WHO 2021 classification. The associations between postoperative tumor volumes and outcome were analyzed. Propensity score-matched analyses were constructed to compare glioblastomas with and without contrast enhancement. RESULTS: Among 1323 newly diagnosed IDH-wildtype glioblastomas, we identified 98 patients (7.4%) without contrast enhancement. In such patients, smaller postoperative tumor volumes were associated with more favorable outcome. There was an exponential increase in risk for death with larger residual non-CE tumor. Accordingly, extensive resection was associated with improved survival compared to lesion biopsy. These findings were retained on a multivariable analysis adjusting for demographic and clinical markers. Compared to CE glioblastoma, patients with non-CE glioblastoma had a more favorable clinical profile and superior outcome as confirmed in propensity score analyses by matching the patients with non-CE glioblastoma to patients with CE glioblastoma using a large set of clinical variables. CONCLUSIONS: The absence of contrast enhancement characterizes a less aggressive clinical phenotype of IDH-wildtype glioblastomas. Maximal resection of non-CE tumors has prognostic implications and translates into favorable outcome.

Pleomorphic Xanthoastrocytoma: Multi-Institutional Evaluation of Stereotactic Radiosurgery.

BACKGROUND AND OBJECTIVES: Pleomorphic xanthoastrocytoma (PXA) is a rare low-grade glial tumor primarily affecting young individuals. Surgery is the primary treatment option; however, managing residual/recurrent tumors remains uncertain. This international multi-institutional study retrospectively assessed the use of stereotactic radiosurgery (SRS) for PXA. METHODS: A total of 36 PXA patients (53 tumors) treated at 11 institutions between 1996 and 2023 were analyzed. Data included demographics, clinical variables, SRS parameters, tumor control, and clinical outcomes. Kaplan-Meier estimates summarized the local control (LC), progression-free survival, and overall survival (OS). Secondary end points addressed adverse radiation effects and the risk of malignant transformation. Cox regression analysis was used. RESULTS: A total of 38 tumors were grade 2, and 15 tumors were grade 3. Nine patients underwent initial gross total resection, and 10 received adjuvant therapy. The main reason for SRS was residual tumors (41.5%). The median follow-up was 34 months (range, 2-324 months). LC was achieved in 77.4% of tumors, with 6-month, 1-year, and 2-year LC estimates at 86.7%, 82.3%, and 77.8%, respectively. Younger age at SRS (hazard ratios [HR] 3.164), absence of peritumoral edema (HR 4.685), and higher marginal dose (HR 6.190) were significantly associated with better LC. OS estimates at 1, 2, and 5 years were 86%, 74%, and 49.3%, respectively, with a median OS of 44 months. Four patients died due to disease progression. Radiological adverse radiation effects included edema (n = 8) and hemorrhagic change (n = 1). One grade 3 PXA transformed into glioblastoma 13 months after SRS. CONCLUSION: SRS offers promising outcomes for PXA management, providing effective LC, reasonable progression-free survival, and minimal adverse events.