Assessing survival in non-small cell lung cancer brain metastases after stereotactic radiosurgery: before and after the start of the targetable mutation era.

PURPOSE: Targeted treatment options for non-small cell lung cancer (NSCLC) brain metastases (BMs) may be combined with stereotactic radiosurgery (SRS) to optimize survival. We assessed patient outcomes after SRS for NSCLC BMs, identifying survival trajectories associated with targetable mutations. METHODS: In this retrospective time-dependent analysis, we analyzed median overall survival of patients who received ≥ 1 SRS courses for BM from NSCLC from 2001 to 2021. We compared survival of patients with and without targetable mutations based on clinical variables and treatment. RESULTS: Among the 213 patients included, 87 (40.8%) had targetable mutations-primarily EGFR (22.5%)-and 126 (59.2%) did not. Patients with targetable mutations were more often female (63.2%, p <.001) and nonsmokers (58.6%, p <.001); had higher initial lung-molGPA (2.0 vs. 1.5, p <.001) and lower cumulative tumor volume (3.7 vs. 10.6 cm3, p <.001); and received more concurrent (55.2% vs. 36.5%, p =.007) and total (median 3 vs. 2, p <.001) systemic therapies. These patients had lower mortality rates (74.7% vs. 91.3%, p <.001) and risk (HR 0.298 [95%CI 0.190-0.469], p <.001) and longer median overall survival (20.2 vs. 7.4 months, p <.001), including survival ≥ 3 years (p =.001). Survival was best predicted by SRS with tumor resection in patients with non-targetable mutations (HR 0.491 [95%CI 0.318-757], p =.001) and by systemic therapy with SRS for those with targetable mutations (HR 0.124 [95%CI 0.013-1.153], p =.067). CONCLUSION: The presence of targetable mutations enhances survival in patients receiving SRS for NSCLC BM, particularly when used with systemic therapies. Survival for patients without targetable mutations was longest with SRS and surgical resection. These results inform best practices for managing patients with NSCLC BM based on driver mutation status.

High-grade glioma imaging volumes and survival: a single-institution analysis of 101 patients after resection using intraoperative MRI.

PURPOSE: Intraoperative magnetic resonance imaging (iMRI) has been efficacious in maximizing resection of high-grade gliomas (HGGs). In this single-institution study of patients with HGGs who underwent resection using iMRI, the authors present a volumetric-based survival analysis to evaluate progression-free survival (PFS) and overall survival (OS), as well as the impact of additional resection on survival. METHODS: This retrospective analysis included patients with HGGs who underwent resection using iMRI from 2011 to 2021. Volumetric analyses of T1-weighted contrast-enhancing (T1W-CE), T2-weighted (T2W), and T2W fluid-attenuated inversion recovery (FLAIR) MRI sequences were assessed at preoperative, intraoperative, immediate postoperative, and three-month postoperative timepoints. Statistical analyses were carried out using log-rank and multivariable Cox proportional hazard regression analyses. RESULTS: A total of 101 patients (median age 57.0 years) were treated. In keeping with prior studies, statistically significant associations between greater EOR and longer PFS and OS were seen (p = 0.012 and p = 0.006, respectively). The results demonstrated significant associations of lower preoperative T2W, 3-month postoperative T2W, and 3-month postoperative FLAIR volumes with longer PFS and OS (p = 0.045 and p = 0.026, p = 0.031 and p = 0.006, p = 0.018 and p = 0.004, respectively), as well as associations between lower immediate postoperative T2W and immediate postoperative FLAIR volumes with longer OS (p = 0.002 and p = 0.02). There was no observed association in either PFS or OS for patients undergoing additional resection after initial iMRI scan (p = 0.387 and p = 0.592). CONCLUSION: This study of 101 patients with new or recurrent HGGs shows three-month postoperative T2W and FLAIR imaging volumes were significant prognosticators with respect to PFS and OS.

Work relative value units and perioperative outcomes in patients undergoing brain tumor surgery.

The work relative value unit (wRVU) is a commonly cited surrogate for surgical complexity; however, it is highly susceptible to subjective interpretation and external forces. Our objective was to evaluate whether wRVU is associated with perioperative outcomes, including complications, after brain tumor surgery. The 2006-2014 American College of Surgeons National Surgical Quality Improvement Program database was queried to identify patients ≥ 18 years who underwent brain tumor resection. Patients were categorized into approximate quintiles based on total wRVU. The relationship between wRVU and several perioperative outcomes was assessed with univariate and multivariate analyses. Subgroup analyses were performed using a Current Procedural Terminology code common to all wRVU groups. The 16,884 patients were categorized into wRVU ranges 0-30.83 (4664 patients), 30.84-34.58 (2548 patients), 34.59-38.04 (3147 patients), 38.05-45.38 (3173 patients), and ≥ 45.39 (3352 patients). In multivariate logistic regression analysis, increasing wRVU did not predict more 30-day postoperative complications, except respiratory complications and need for blood transfusion. Linear regression analysis showed that wRVU was poorly correlated with operative duration and length of stay. On multivariate analysis of the craniectomy subgroup, wRVU was not associated with overall or respiratory complications. The highest wRVU group was still associated with greater risk of requiring blood transfusion (OR 3.01, p < 0.001). Increasing wRVU generally did not correlate with 30 days postoperative complications in patients undergoing any surgery for brain tumor resection; however, the highest wRVU groups may be associated with greater risk of respiratory complications and need for transfusion. These finding suggests that wRVU may be a poor surrogate for case complexity.

Development of a residents-as-teachers curriculum for neurosurgical training programs.

Neurosurgery residents spend a significant amount of their time teaching patients, families, students, residents, and other health professionals. To help ensure competence in their residents' teaching abilities, many specialties have established formal residents-as-teachers (RAT) curricula; however, such formalized curricula are often lacking in neurosurgery programs. The authors' goal was to develop and implement a formal RAT curriculum, designed with neurosurgery residents' other responsibilities in mind, to improve residents' formal and informal teaching abilities. Here, the authors report on the design of a formalized teaching curriculum tailored for the needs of neurosurgical residents, with a focus on deliberate practice and minimal time needed for preparation. The curriculum, designed using Kern's 6 steps of curriculum design as a framework, comprises 5 lecture series spread over 3 years, repeated twice through a resident's training, with each lecture series outlined with its respective topics and objectives. Opportunities for observed teaching as well as informal and formal evaluation will be provided to residents. The program will be evaluated on a yearly basis using direct and anonymized resident feedback on the RAT curriculum. Measures of program success will also include pre- and postprogram medical student and peer evaluation of residents. These data will be used for continual improvement of the curriculum as it is implemented. Successes and shortcomings of this program will be disseminated by publication, presentations, and placement on the authors' department website and social media. This paper may serve as a foundation for other neurosurgical programs to develop RAT curricula for greater enhancement of resident teaching abilities.

Extracellular glutamate and IDH1R132H inhibitor promote glioma growth by boosting redox potential.

PURPOSE: Somatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, mostly substituting Arg132 with histidine, are associated with better patient survival, but glioma recurrence and progression are nearly inevitable, resulting in disproportionate morbidity and mortality. Our previous studies demonstrated that in contrast to hemizygous IDH1R132H (loss of wild-type allele), heterozygous IDH1R132H is intrinsically glioma suppressive but its suppression of three-dimensional (3D) growth is negated by extracellular glutamate and reducing equivalent. This study sought to understand the importance of 3D culture in IDH1R132H biology and the underlying mechanism of the glutamate effect. METHODS: RNA sequencing data of IDH1R132H-heterozygous and IDH1R132H-hemizygous glioma cells cultured under two-dimensional (2D) and 3D conditions were subjected to unsupervised hierarchal clustering and gene set enrichment analysis. IDH1R132H-heterozygous and IDH1R132H-hemizygous tumor growth were compared in subcutaneous and intracranial transplantations. Short-hairpin RNA against glutamate dehydrogenase 2 gene (GLUD2) expression was employed to determine the effects of glutamate and the mutant IDH1 inhibitor AGI-5198 on redox potential in IDH1R132H-heterozygous cells. RESULTS: In contrast to IDH1R132H-heterozygous cells, 3D-cultured but not 2D-cultured IDH1R132H-hemizygous cells were clustered with more malignant gliomas, possessed the glioblastoma mesenchymal signature, and exhibited aggressive tumor growth. Although both extracellular glutamate and AGI-5198 stimulated redox potential for 3D growth of IDH1R132H-heterozygous cells, GLUD2 expression was required for glutamate, but not AGI-5198, stimulation. CONCLUSION: 3D culture is more relevant to IDH1R132H glioma biology. The importance of redox homeostasis in IDH1R132H glioma suggests that metabolic pathway(s) can be explored for therapeutic targeting, whereas IDH1R132H inhibitors may have counterproductive consequences in patient treatment.

Repeat radiation with bevacizumab and minocycline in bevacizumab-refractory high grade gliomas: a prospective phase 1 trial.

INTRODUCTION: There are no effective treatments for gliomas after progression on radiation, temozolomide, and bevacizumab. Microglia activation may be involved in radiation resistance and can be inhibited by the brain penetrating antibiotic minocycline. In this phase 1 trial, we examined the safety and effect on survival, symptom burden, and neurocognitive function of reirradiation, minocycline, and bevacizumab. METHODS: The trial used a 3 + 3 design for dose escalation followed by a ten person dose expansion. Patients received reirradiation with dosing based on radiation oncologist judgment, bevacizumab 10 mg/kg IV every two weeks, and oral minocycline twice a day. Symptom burden was measured using MDASI-BT. Neurocognitive function was measured using the COGSTATE battery. RESULTS: The maximum tolerated dose of minocycline was 400 mg twice a day with no unexpected toxicities. The PFS3 was 64.6%, and median overall survival was 6.4 months. Symptom burden and neurocognitive function did not decline in the interval between treatment completion and tumor progression. CONCLUSIONS: Minocycline 400 mg orally twice a day with bevacizumab and reirradiation is well tolerated by physician and patient reported outcomes in people with gliomas that progress on bevacizumab.

Liquid biopsies for the diagnosis and surveillance of primary pediatric central nervous system tumors: a review for practicing neurosurgeons.

OBJECTIVE: Primary brain tumors are the most common cause of cancer-related deaths in children and pose difficult questions for the treating physician regarding issues such as the risk/benefit of performing a biopsy, the accuracy of monitoring methods, and the availability of prognostic indicators. It has been recently shown that tumor-specific DNA and proteins can be successfully isolated in liquid biopsies, and it may be possible to exploit this potential as a particularly useful tool for the clinician in addressing these issues. METHODS: A review of the current literature was conducted by searching PubMed and Scopus. MeSH terms for the search included "liquid biopsy," "brain," "tumor," and "pediatrics" in all fields. Articles were reviewed to identify the type of brain tumor involved, the method of tumor DNA/protein analysis, and the potential clinical utility. All articles involving primary studies of pediatric brain tumors were included, but reviews were excluded. RESULTS: The successful isolation of circulating tumor DNA (ctDNA), extracellular vesicles, and tumor-specific proteins from liquid biopsies has been consistently demonstrated. This most commonly occurs through CSF analysis, but it has also been successfully demonstrated using plasma and urine samples. Tumor-related gene mutations and alterations in protein expression are identifiable and, in some cases, have been correlated to specific neoplasms. The quantity of ctDNA isolated also appears to have a direct relationship with tumor progression and response to treatment. CONCLUSIONS: The use of liquid biopsies for the diagnosis and monitoring of primary pediatric brain tumors is a foreseeable possibility, as the requisite developmental steps have largely been demonstrated. Increasingly advanced molecular methods are being developed to improve the identification of tumor subtypes and tumor grades, and they may offer a method for monitoring treatment response. These minimally invasive markers will likely be used in the clinical treatment of pediatric brain tumors in the future.

Effect of patient age on glioblastoma perioperative treatment costs: a value driven outcome database analysis.

INTRODUCTION: Identification of groups of patients or interventions with higher associated treatment costs may be beneficial in efforts to decrease the overall financial burden of glioblastoma (GBM) treatment. The authors' objective was to evaluate perioperative surgical treatment cost differences between elderly and nonelderly patients with GBM using the Value Driven Outcome (VDO) database. METHODS: The authors obtained data from a retrospective cohort of GBM patients treated surgically (resection or biopsy) at their institution from August 2011 to February 2018. Data were compiled using medical records and the VDO database. RESULTS: A total of 181 patients with GBM were included. Patients were grouped into age < 70 years at time of surgery (nonelderly; n = 121) and ≥ 70 years (elderly; n = 60). Costs were approximately 38% higher in the elderly group on average (each patient was mean 0.68% of total cohort cost vs. 0.49%, p = 0.044). Higher age significantly, but weakly, correlated with higher treatment cost on linear regression analysis (p = 0.007; R2 = 0.04). Length of stay was significantly associated with increased cost on linear regression (p < 0.001, R2 = 0.84) and was significantly longer in the elderly group (8.7 ± 11.3 vs. 5.2 ± 4.3 days, p = 0.025). The cost breakdown by facility, pharmacy, supply/implants, imaging, and laboratory costs was not significantly different between age groups. Elderly patients with any postoperative complication had 2.1 times greater total costs than those without complication (p = 0.094), 2.9 times greater total costs than nonelderly patients with complication (p = 0.013), and 2.3 times greater total costs than nonelderly patients without complication (p = 0.022). CONCLUSIONS: GBM surgical treatment costs are higher in older patients, particularly those who experience postoperative complications.

Evaluation of pediatric glioma outcomes using intraoperative MRI: a multicenter cohort study.

BACKGROUND: The use of intraoperative MRI (iMRI) during treatment of gliomas may increase extent of resection (EOR), decrease need for early reoperation, and increase progression-free and overall survival, but has not been fully validated, particularly in the pediatric population. OBJECTIVE: To assess the accuracy of iMRI to identify residual tumor in pediatric patients with glioma and determine the effect of iMRI on decisions for resection, complication rates, and other outcomes. METHODS: We retrospectively analyzed a multicenter database of pediatric patients (age ≤ 18 years) who underwent resection of pathologically confirmed gliomas. RESULTS: We identified 314 patients (mean age 9.7 ± 4.6 years) with mean follow-up of 48.3 ± 33.6 months (range 0.03-182.07 months) who underwent surgery with iMRI. There were 201 (64.0%) WHO grade I tumors, 57 (18.2%) grade II, 24 (7.6%) grade III, 9 (2.9%) grade IV, and 23 (7.3%) not classified. Among 280 patients who underwent resection using iMRI, 131 (46.8%) had some residual tumor and underwent additional resection after the first iMRI. Of the 33 tissue specimens sent for pathological analysis after iMRI, 29 (87.9%) showed positive tumor pathology. Gross total resection was identified in 156 patients (55.7%), but this was limited by 69 (24.6%) patients with unknown EOR. CONCLUSIONS: Analysis of the largest multicenter database of pediatric gliomas resected using iMRI demonstrated additional tumor resection in a substantial portion of cases. However, determining the impact of iMRI on EOR and outcomes remains challenging because iMRI use varies among providers nationally. Continued refinement of iMRI techniques for use in pediatric patients with glioma may improve outcomes.

Surgical treatment of glioblastoma in the elderly: the impact of complications.

The diagnosis of glioblastoma (GBM) often carries a dismal prognosis, with a median survival of 14.6 months. A particular challenge is the diagnosis of GBM in the elderly population (age > 75 years), who have significant comorbidities, present with worse functional status, and are at higher risk with surgical treatments. We sought to evaluate the impact of current GBM treatment, specifically in the elderly population. The authors undertook a retrospective review of all patients aged 75 or older who underwent treatment for GBM from 1997 to 2016. Patient outcomes were evaluated with regards to demographics, surgical variables, postoperative treatment, and complications. A total of 82 patients (mean age 80.5 ± 3.8 years) were seen. Most patients presented with confusion (57.3%) and associated comorbidities, and prior anticoagulation use was common in this age group. Extent of resection (EOR) included no surgery (9.8%), biopsy (22.0%), subtotal resection (40.2%), and gross-total resection (23.2%). Postoperative adjuvant therapy included temozolomide (36.1%), radiation (52.5%), and bevacizumab (11.9%). A mean overall survival of 6.3 ± 1.2 months was observed. There were 34 complications in 23 patients. Improved survival was seen with increased EOR only for patients without postoperative complications. A multivariate Cox proportional hazards model showed that complications (HR = 5.43, 95% CI 1.73, 17.04, p = 0.004) predicted poor outcome. Long-term survivors (> 12 months survival) and short-term survivors had similar median preoperative Karnofsky Performance Scale (KPS) score (80 vs. 80, p = 0.43), but long-term survivors had unchanged postoperative KPS (80 vs. 60, p = 0.02) and no complications (0/9 vs. 23/72, p = 0.04). The benefit of glioblastoma treatment in our series was limited by the postoperative complications and KPS. Presence of a complication served as an independent risk factor for worsened overall survival in this age group. It is likely that decreased patient function limits postoperative adjuvant therapy and predisposes to higher morbidity especially in this age group.

Clinical potential of meningioma genomic insights: a practical review for neurosurgeons.

Meningiomas are among the most common intracranial pathological conditions, accounting for 36% of intracranial lesions treated by neurosurgeons. Although the majority of these lesions are benign, the classical categorization of tumors by histological type or World Health Organization (WHO) grade has not fully captured the potential for meningioma progression and recurrence. Many targeted treatments have failed to generate a long-lasting effect on these tumors. Recently, several seminal studies evaluating the genomics of intracranial meningiomas have rapidly changed the understanding of the disease. The importance of NF2 (neurofibromin 2), TRAF7 (tumor necrosis factor [TNF] receptor-associated factor 7), KLF4 (Kruppel-like factor 4), AKT1, SMO (smoothened), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), and POLR2 (RNA polymerase II subunit A) demonstrates that there are at least 6 distinct mutational classes of meningiomas. In addition, 6 methylation classes of meningioma have been appreciated, enabling improved prediction of prognosis compared with traditional WHO grades. Genomic studies have shed light on the nature of recurrent meningioma, distinct intracranial locations and mutational patterns, and a potential embryonic cancer stem cell-like origin. However, despite these exciting findings, the clinical relevance of these findings remains elusive. The authors review the key findings from recent genomic studies in meningiomas, specifically focusing on how these findings relate to clinical insights for the practicing neurosurgeon.

New Molecular Considerations for Glioma: IDH, ATRX, BRAF, TERT, H3 K27M.

PURPOSE OF REVIEW: This review will discuss the role of several key players in glioma classification and biology, namely isocitrate dehydrogenase 1 and 2 (IDH1/2), alpha thalassemia/mental retardation syndrome X-linked (ATRX), B-Raf (BRAF), telomerase reverse transcriptase (TERT), and H3K27M. RECENT FINDINGS: IDH1/2 mutation delineates oligoden-droglioma, astrocytoma, and secondary glioblastoma (GBM) from primary GBM and lower-grade gliomas with biology similar to GBM. Additional mutations including TERT, 1p/19q, and ATRX further guide glioma classification and diagnosis, as well as pointing directions toward individualized treatments for these distinct molecular subtypes. ATRX and TERT mutations suggest the importance of telomere maintenance in gliomagenesis. BRAF alterations are key in certain low-grade gliomas and pediatric gliomas but rarely in high-grade gliomas in adults. Histone mutations (e.g., H3K27M) and their effect on chromatin modulation are novel mechanisms of cancer generation and uniquely seen in midline gliomas in children and young adults. Over the past decade, a remarkable accumulation of knowledge from the genomic study of gliomas has led to reclassification of tumors, new understanding of oncogenic mechanisms, and novel treatment strategies.

OKN-007 decreases tumor necrosis and tumor cell proliferation and increases apoptosis in a preclinical F98 rat glioma model.

BACKGROUND: Glioblastoma is a malignant World Health Organization (WHO) grade IV glioma with a poor prognosis in humans. New therapeutics are desperately required. The nitrone OKN-007 (2,4-disulfophenyl-PBN) has demonstrated effective anti-glioma properties in several rodent models and is currently being used as a clinical investigational drug for recurrent gliomas. We assessed the regional effects of OKN-007 in the tumor necrotic core and non-necrotic tumor parenchyma. METHODS: An F98 rat glioma model was evaluated using proton magnetic resonance spectroscopy ((1) H-MRS), diffusion-weighted imaging (DWI), morphological T2-weighted imaging (T2W) at 7 Tesla (30 cm-bore MRI), as well as immunohistochemistry and microarray assessments, at maximum tumor volumes (15-23 days following cell implantation in untreated (UT) tumors, and 18-35 days in OKN-007-treated tumors). RESULTS: (1) H-MRS data indicates that Lip0.9/Cho, Lip0.9/Cr, Lip1.3/Cho, and Lip1.3/Cr ratios are significantly decreased (all P < 0.05) in the OKN-007-treated group compared with UT F98 gliomas. The Cho/Cr ratio is also significantly decreased in the OKN-007-treated group compared with UT gliomas. In addition, the OKN-007-treated group demonstrates significantly lower ADC values in the necrotic tumor core and the nonnecrotic tumor parenchyma (both P < 0.05) compared with the UT group. There was also an increase in apoptosis following OKN-007 treatment (P < 0.01) compared with UT. CONCLUSION: OKN-007 reduces both necrosis and tumor cell proliferation, as well as seems to mediate multiple effects in different tumor regions (tumor necrotic core and nonnecrotic tumor parenchyma) in F98 gliomas, indicating the efficacy of OKN-007 as an anti-cancer agent and its potential clinical use.

A practical review of prognostic correlations of molecular biomarkers in glioblastoma.

Despite extensive efforts in research and therapeutics, achieving longer survival for patients with glioblastoma (GBM) remains a formidable challenge. Furthermore, because of rapid advances in the scientific understanding of GBM, communication with patients regarding the explanations and implications of genetic and molecular markers can be difficult. Understanding the important biomarkers that play a role in GBM pathogenesis may also help clinicians in educating patients about prognosis, potential clinical trials, and monitoring response to treatments. This article aims to provide an up-to-date review that can be discussed with patients regarding common molecular markers, namely O-6-methylguanine-DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 and 2 (IDH1/2), p53, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and 1p/19q. The importance of the distinction between a prognostic and a predictive biomarker as well as clinical trials regarding these markers and their relevance to clinical practice are discussed.

Molecular features assisting in diagnosis, surgery, and treatment decision making in low-grade gliomas.

The preferred management of suspected low-grade gliomas (LGGs) has been disputed, and the implications of molecular changes for medical and surgical management of LGGs are important to consider. Current strategies that make use of molecular markers and imaging techniques and therapeutic considerations offer additional options for management of LGGs. Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes suggest a role for this abnormal metabolic pathway in the pathogenesis and progression of these primary brain tumors. Use of magnetic resonance spectroscopy can provide preoperative detection of IDH-mutated gliomas and affect surgical planning. In addition, IDH1 and IDH2 mutation status may have an effect on surgical resectability of gliomas. The IDH-mutated tumors exhibit better prognosis throughout every grade of glioma, and mutation may be an early genetic event, preceding lineage-specific secondary and tertiary alterations that transform LGGs into secondary glioblastomas. The O6-methylguanine-DNAmethyltransferase (MGMT) promoter methylation and 1p19q codeletion status can predict sensitivity to chemotherapy and radiation in low- and intermediate-grade gliomas. Thus, these recent advances, which have led to a better understanding of how molecular, genetic, and epigenetic alterations influence the pathogenicity of the different histological grades of gliomas, can lead to better prognostication and may lead to specific targeted surgical interventions and medical therapies.

Hypoxia-inducible factor-1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor­1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1­ regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1­mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

D-TERMINED, a phase 1 trial in newly diagnosed high-grade glioma with temozolomide, radiation, and minocycline followed by adjuvant minocycline/temozolomide.

Background: Standard treatment for newly diagnosed high-grade gliomas remains suboptimal. Preclinical data indicate that mesenchymal transition and radiation resistance in glioblastoma are driven by NF-κB and microglia activation, which can be inhibited by minocycline. We assessed the safety and efficacy of minocycline combined with standard radiation and temozolomide in newly diagnosed high-grade gliomas. Methods: Adults with newly diagnosed high-grade glioma were eligible. Minocycline was given with concurrent and adjuvant temozolomide. Minocycline doses were escalated using a 3 + 3 design and expanded to identify the maximum tolerated dose (MTD) and adverse event profile. Individual progression-free survival (PFS) was compared to predicted PFS based on RTOG RPA class using a binomial test. The relationships between mesenchymal and microglial biomarkers were analyzed with immunohistochemistry. Results: The MTD of minocycline was 150 mg twice per day (N = 20); 1 patient (5%) experienced CTCAE grade 3 + nausea and dizziness, and 2 patients (10%) demonstrated thrombocytopenia requiring temozolomide interruptions. Twelve patients exceeded their predicted PFS (60%), which did not meet the predefined efficacy endpoint of 70%. Symptoms increased during post-radiation treatment but remained mild. No significant correlation was seen between biomarkers and PFS. Expression levels of P-p65, a marker of NF-κB activation, were correlated with the microglia marker IBA-1. Conclusions: Minocycline at 150 mg twice per day is well tolerated with standard chemoradiation in patients with newly diagnosed high-grade gliomas. PFS was not significantly increased with the addition of minocycline when compared to historical controls. NF-κB activation correlates with microglia levels in high-grade glioma.

Gross Tumor and Intracranial Control Benefits with Fractionated Radiotherapy Compared with Stereotactic Radiosurgery for Patients with WHO Grade 2 Meningioma.

OBJECTIVE: Surgical resection is the mainstay of treatment for WHO grade 2 meningioma. Fractionated radiation therapy (RT) is frequently used after surgery, though many centers utilize stereotactic radiosurgery (SRS) for recurrence or progression. Herein, we report disease control outcomes from an institutional cohort with adjuvant fractionated RT versus salvage SRS. METHODS: We identified 32 patients from an institutional database with WHO grade 2 meningioma and residual/recurrent tumor treated with either SRS or fractionated RT. Patients were treated between 2007 and 2021 and had at least 1 year of follow-up. Kaplan-Meier estimators were used to determine gross tumor control (GTC) and intracranial control (IC). Univariate Cox proportional hazards models using biologically effective dose (BED) as a continuous parameter were used to assess for dose responses. RESULTS: With a median follow-up of 5.5 years, 13 patients (41%) received SRS to a recurrent or progressive nodule, 2 (6%) fractionated RT to a recurrent or progressive nodule, and 17 (53%) adjuvant fractionated RT following subtotal resection. Five-year GTC was higher with fractionated RT versus SRS (82% vs. 38%, P = 0.03). Five-year IC was also better with fractionated RT versus SRS (82% vs. 11%, P < 0.001). On univariate analysis, increasing BED10 was significantly associated with better GTC (P = 0.039); increasing BED3 was not (P = 0.82). CONCLUSIONS: In this patient cohort, GTC and IC were significantly higher in patients treated with adjuvant fractionated RT compared with salvage SRS. Increasing BED10 was associated with better GTC. Fractionated RT may provide a better therapeutic ratio than SRS for grade 2 meningiomas.

Subclonal Cancer Driver Mutations Are Prevalent in the Unresected Peritumoral Edema of Adult Diffuse Gliomas.

Adult diffuse gliomas commonly recur regardless of therapy. As recurrence typically arises from the peritumoral edema adjacent to the resected bulk tumor, the profiling of somatic mutations from infiltrative malignant cells within this critical, unresected region could provide important insights into residual disease. A key obstacle has been the inability to distinguish between next-generation sequencing (NGS) noise and the true but weak signal from tumor cells hidden among the noncancerous brain tissue of the peritumoral edema. Here, we developed and validated True2 sequencing to reduce NGS-associated errors to <1 false positive/100 kb panel positions while detecting 97.6% of somatic mutations with an allele frequency ≥0.1%. True2 was then used to study the tumor and peritumoral edema of 22 adult diffuse gliomas including glioblastoma, astrocytoma, oligodendroglioma, and NF1-related low-grade neuroglioma. The tumor and peritumoral edema displayed a similar mutation burden, indicating that surgery debulks these cancers physically but not molecularly. Moreover, variants in the peritumoral edema included unique cancer driver mutations absent in the bulk tumor. Finally, analysis of multiple samples from each patient revealed multiple subclones with unique mutations in the same gene in 17 of 22 patients, supporting the occurrence of convergent evolution in response to patient-specific selective pressures in the tumor microenvironment that may form the molecular foundation of recurrent disease. Collectively, True2 enables the detection of ultralow frequency mutations during molecular analyses of adult diffuse gliomas, which is necessary to understand cancer evolution, recurrence, and individual response to therapy. SIGNIFICANCE: True2 is a next-generation sequencing workflow that facilitates unbiased discovery of somatic mutations across the full range of variant allele frequencies, which could help identify residual disease vulnerabilities for targeted adjuvant therapies.