Cognitive Dysfunction in Non-CNS Metastatic Cancer: Comparing Brain Metastasis, Non-CNS Metastasis, and Healthy Controls.

Limited research has compared cognition of people with non-central nervous system metastatic cancer (NCM) vs. metastatic brain cancer (BM). This prospective cross-sectional study was comprised 37 healthy controls (HC), 40 NCM, and 61 BM completing 10 neuropsychological tests. The NCM performed below HCs on processing speed and executive functioning tasks, while the BM group demonstrated lower performance across tests. Tasks of processing speed, verbal fluency, and verbal memory differentiated the clinical groups (BM < NCM). Nearly 20% of the NCM group was impaired on at least three neuropsychological tests whereas approximately 40% of the BM group demonstrated the same level of impairment.

Longitudinal brain volumetrics in glioma survivors.

OBJECTIVE: Radiation therapy (RT) is used selectively for patients with low-grade glioma (LGG) given the concerns for potential cognitive effects in survivors, but prior cognitive outcome studies among LGG survivors have had inconsistent findings. Translational studies that characterize changes in brain anatomy and physiology after treatment of LGG may help to both contextualize cognitive findings and improve the overall understanding of radiation effects in normal brain tissue. This study aimed to investigate the hypothesis that patients with LGG who are treated with RT will experience greater brain volume loss than those who do not receive RT. METHODS: This retrospective longitudinal study included all patients with WHO grade 2 glioma who received posttreatment surveillance MRI at the University of Alabama at Birmingham. Volumetric analysis of contralateral cortical white matter (WM), cortical gray matter (GM), and hippocampus was performed on all posttreatment T1-weighted MRI sequences using the SynthSeg script. The effect of clinical and treatment variables on brain volumes was assessed using two-level hierarchical linear models. RESULTS: The final study cohort consisted of 105 patients with 1974 time points analyzed. The median length of imaging follow-up was 4.6 years (range 0.36-18.9 years), and the median number of time points analyzed per patient was 12 (range 2-40). Resection was performed in 79 (75.2%) patients, RT was administered to 61 (58.1%) patients, and chemotherapy was administered to 66 (62.9%) patients. Age at diagnosis (ß = -0.06, p < 0.001) and use of RT (ß = -1.12, p = 0.002) were associated with the slope of the contralateral cortical GM volume model (i.e., change in GM over time). Age at diagnosis (ß = -0.08, p < 0.001), midline involvement (ß = 1.31, p = 0.006), and use of RT (ß = -1.45, p = 0.001) were associated with slope of the contralateral cortical WM volume model. Age (ß = -0.0027, p = 0.001), tumor resection (ß = -0.069, p < 0.001), use of chemotherapy (ß = -0.0597, p = 0.003), and use of RT (ß = -0.0589, p < 0.001) were associated with the slope of the contralateral hippocampus volume model. CONCLUSIONS: This study demonstrated volume loss in contralateral brain structures among LGG survivors, and patients who received RT experienced greater volume loss than those who did not. The results of this study may help to provide context for cognitive outcome research in LGG survivors and inform the design of future strategies to preserve cognition.

Adoptive cell therapy for high grade gliomas using simultaneous temozolomide and intracranial mgmt-modified γδ t cells following standard post-resection chemotherapy and radiotherapy: current strategy and future directions.

Cellular therapies, including chimeric antigen receptor T cell therapies (CAR-T), while generally successful in hematologic malignancies, face substantial challenges against solid tumors such as glioblastoma (GBM) due to rapid growth, antigen heterogeneity, and inadequate depth of response to cytoreductive and immune therapies, We have previously shown that GBM constitutively express stress associated NKG2D ligands (NKG2DL) recognized by gamma delta (γδ) T cells, a minor lymphocyte subset that innately recognize target molecules via the γδ T cell receptor (TCR), NKG2D, and multiple other mechanisms. Given that NKG2DL expression is often insufficient on GBM cells to elicit a meaningful response to γδ T cell immunotherapy, we then demonstrated that NKG2DL expression can be transiently upregulated by activation of the DNA damage response (DDR) pathway using alkylating agents such as Temozolomide (TMZ). TMZ, however, is also toxic to γδ T cells. Using a p140K/MGMT lentivector, which confers resistance to TMZ by expression of O(6)-methylguanine-DNA-methyltransferase (MGMT), we genetically engineered γδ T cells that maintain full effector function in the presence of therapeutic doses of TMZ. We then validated a therapeutic system that we termed Drug Resistance Immunotherapy (DRI) that combines a standard regimen of TMZ concomitantly with simultaneous intracranial infusion of TMZ-resistant γδ T cells in a first-in-human Phase I clinical trial (NCT04165941). This manuscript will discuss DRI as a rational therapeutic approach to newly diagnosed GBM and the importance of repeated administration of DRI in combination with the standard-of-care Stupp regimen in patients with stable minimal residual disease.

Activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrence of glioblastoma.

INTRODUCTION: Hypoxia inducible factor 2-alpha (HIF2α) mediates cellular responses to hypoxia and is over-expressed in glioblastoma (GBM). PT2385 is an oral HIF2α inhibitor with in vivo activity against GBM. METHODS: A two-stage single-arm open-label phase II study of adults with GBM at first recurrence following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (ORR = complete response + partial response, CR + PR); secondary outcomes were safety, overall survival (OS), and progression free survival (PFS). Exploratory objectives included pharmacokinetics (day 15 Cmin), pharmacodynamics (erythropoietin, vascular endothelial growth factor), and pH-weighted amine- chemical exchange saturation transfer (CEST) MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤ 1 ORR. RESULTS: Of the 24 enrolled patients, median age was 62.1 (38.7-76.7) years, median KPS 80, MGMT promoter was methylated in 46% of tumors. PT2385 was well tolerated. Grade ≥ 3 drug-related adverse events were hypoxia (n = 2), hyponatremia (2), lymphopenia (1), anemia (1), and hyperglycemia (1). No objective radiographic responses were observed; median PFS was 1.8 months (95% CI 1.6-2.5) and OS was 7.7 months (95% CI 4.9-12.6). Drug exposure varied widely and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, p = 0.009). Baseline acidity by pH-weighted CEST MRI correlated significantly with treatment duration (R2 = 0.49, p = 0.017). Non-enhancing infiltrative disease with high acidity gave rise to recurrence. CONCLUSIONS: PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied.

Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization.

PURPOSE: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS: Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780). RESULTS: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05). CONCLUSION: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

Clinical and descriptive characteristics associated with high-grade meningioma in a large clinical series.

PURPOSE: We studied 571 patients with intracranial meningioma for clinical characteristics and tumor location associated with high grade meningioma (WHO II/III). MATERIALS AND METHODS: Patients were participants in a multicentre epidemiologic study of risk factors for primary brain tumors including meningioma recruited from September 2005 to November 2019. We included patients 18 or older with a recent diagnosis of a primary intracranial meningioma of any subtype (ICD9/10: 9530-0, 9531-0, 9532-0, 9537-0, 9533-0, 9534-0, 9530-0, 9538-1, 9538-3) who were enrolled at neuro-oncology and neuro-surgery clinics in the southeastern U.S. RESULTS: The median patient age was 58 years (IQR: 48-68) and the majority of patients were female (n = 415; 72.7%) and Caucasian (n = 516; 90.4%). Most patients were symptomatic (n = 460; 80.6%) and their tumours more commonly occurred in a non-skull base location (n = 298; 52.2%). A total of 86 patients (15.0%) had a WHO grade II/III meningioma. Compared to patients with WHO grade I tumours, patients with WHO II/III meningiomas were over 3-times more likely to be male (odds ratio (OR): 3.25; 95% confidence interval (CI): 1.98, 5.35) adjusting for age, race, symptomatic presentation, and skull-based location. Moreover, a WHO grade II/III meningioma was substantially less likely to be observed in asymptomatic patients (OR: 0.15, 95% CI: 0.04, 0.42), and in patients with a skull-based tumour (OR: 0.40, 95% CI: 0.24, 0.66), adjusting for other factors. Male gender, symptomatic tumour, and a non-skull base location were independently associated with WHO grade II/III meningioma. CONCLUSION: These findings may shed additional light on the underlying pathogenesis of meningioma.

Association of pre-radiotherapy tumour burden and overall survival in newly diagnosed glioblastoma adjusted for MGMT promoter methylation status.

PURPOSE: We retrospectively evaluated the association between postoperative pre-radiotherapy tumour burden and overall survival (OS) adjusted for the prognostic value of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in patients with newly diagnosed glioblastoma treated with radio-/chemotherapy with temozolomide. MATERIALS AND METHODS: Patients were included from the CENTRIC (EORTC 26071-22072) and CORE trials if postoperative magnetic resonance imaging scans were available within a timeframe of up to 4weeks before radiotherapy, including both pre- and post-contrast T1w images and at least one T2w sequence (T2w or T2w-FLAIR). Postoperative (residual) pre-radiotherapy contrast-enhanced tumour (CET) volumes and non-enhanced T2w abnormalities (NT2A) tissue volumes were obtained by three-dimensional segmentation. Cox proportional hazard models and Kaplan Meier estimates were used to assess the association of pre-radiotherapy CET/NT2A volume with OS adjusted for known prognostic factors (age, performance status, MGMT status). RESULTS: 408 tumour (of which 270 MGMT methylated) segmentations were included. Median OS in patients with MGMT methylated tumours was 117 weeks versus 61weeks in MGMT unmethylated tumours (p < 0.001). When stratified for MGMT methylation status, higher CET volume (HR 1.020; 95% confidence interval CI [1.013-1.027]; p < 0.001) and older age (HR 1.664; 95% CI [1.214-2.281]; p = 0.002) were significantly associated with shorter OS while NT2A volume and performance status were not. CONCLUSION: Pre-radiotherapy CET volume was strongly associated with OS in patients receiving radio-/chemotherapy for newly diagnosed glioblastoma stratified by MGMT promoter methylation status.

"It's Not Just the Seizures": Brain Tumor Caregivers' Experiences and Educational Needs in Out-of-Hospital Seizure Management.

Objective: Family caregivers (FCGs) of persons with primary brain tumors (PBTs) report high levels of distress related to concerns about out-of-hospital seizures. This study aims to explore their experiences and needs with seizure management. Methods: Semi-structured interviews were held with 15 FCGs of persons with PBTs, both those who have and those who have not experienced a seizure, to elicit their concerns about out-of-hospital seizure management and related information needs. A qualitative descriptive study using thematic analysis was conducted based on interview data. Results: Three primary themes were identified relative to FCG experiences and needs related to care of PBTs patients, especially seizure management: (1) FCGs' experiences with caring for persons with PBTs; (2) FCGs' educational needs for seizure preparation and resources; and (3) FCGs' desired type of educational resources and information about seizures. Often FCGs were reported being fearful of seizures and nearly all expressed difficulty knowing when to call emergency services. FCGs equally desired written and online resources, and most preferred graphics or videos detailing seizures. Most FCGs thought that seizure-related training should come after rather than at the time of PBTs diagnosis. FCGs of patients who have not experienced seizures were significantly less prepared to manage seizures than those with a prior seizure. Conclusions: Recognizing and managing out-of-hospital seizures can be a difficult and distressing task for FCGs of patients with PBTs and seizure-related resources are needed. Our results suggest that FCGs of care recipients with PBTs need early supportive interventions to provide self-care strategies and problem-solving skills to manage their roles as caregivers. Interventions should include educational components to assist them in understanding the best mechanisms to maintain a safe environment for their care recipients, and those that deepen knowledge about when to contact EMS.

RNA regulation of inflammatory responses in glia and its potential as a therapeutic target in central nervous system disorders.

A major hallmark of neuroinflammation is the activation of microglia and astrocytes with the induction of inflammatory mediators such as IL-1ß, TNF-α, iNOS, and IL-6. Neuroinflammation contributes to disease progression in a plethora of neurological disorders ranging from acute CNS trauma to chronic neurodegenerative disease. Posttranscriptional pathways of mRNA stability and translational efficiency are major drivers for the expression of these inflammatory mediators. A common element in this level of regulation centers around the adenine- and uridine-rich element (ARE) which is present in the 3' untranslated region (UTR) of the mRNAs encoding these inflammatory mediators. (ARE)-binding proteins (AUBPs) such as Human antigen R (HuR), Tristetraprolin (TTP) and KH- type splicing regulatory protein (KSRP) are key nodes for directing these posttranscriptional pathways and either promote (HuR) or suppress (TTP and KSRP) glial production of inflammatory mediators. This review will discuss basic concepts of ARE-mediated RNA regulation and its impact on glial-driven neuroinflammatory diseases. We will discuss strategies to target this novel level of gene regulation for therapeutic effect and review exciting preliminary studies that underscore its potential for treating neurological disorders.

Isocitrate dehydrogenase (IDH) mutant gliomas: A Society for Neuro-Oncology (SNO) consensus review on diagnosis, management, and future directions.

Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed.

Targeting the TREM1-positive myeloid microenvironment in glioblastoma.

Background: Tumor cellular and molecular heterogeneity is a hallmark of glioblastoma and underlies treatment resistance and recurrence. This manuscript investigated the myeloid-derived microenvironment as a driver of glioblastoma heterogeneity and provided a pharmacological pathway for its suppression. Methods: Transcriptomic signatures of glioblastoma infiltrated myeloid-derived cells were assessed using R2: genomic platform, Ivy Glioblastoma Spatial Atlas, and single-cell RNA-seq data of primary and recurrent glioblastomas. Myeloid-derived cell prints were evaluated in five PDX cell lines using RNA-seq data. Two immunocompetent mouse glioblastoma models were utilized to isolate and characterize tumor-infiltrated myeloid-derived cells and glioblastoma/host cell hybrids. The ability of an inhibitor of HuR dimerization SRI42127 to suppress TREM1+-microenvironment and glioblastoma/myeloid-derived cell interaction was assessed in vivo and in vitro. Results: TREM1+-microenvironment is enriched in glioblastoma peri-necrotic zones. TREM1 appearance is enhanced with tumor grade and associated with poor patient outcomes. We confirmed an expression of a variety of myeloid-derived cell markers, including TREM1, in PDX cell lines. In mouse glioblastoma models, we demonstrated a reduction in the TREM1+-microenvironment and glioblastoma/host cell fusion after treatment with SRI42127. In vitro assays confirmed inhibition of cell fusion events and reduction of myeloid-derived cell migration towards glioblastoma cells by SRI42127 and TREM1 decoy peptide (LP17) versus control treatments. Conclusions: TREM1+-myeloid-derived microenvironment promulgates glioblastoma heterogeneity and is a therapeutic target. Pharmacological inhibition of HuR dimerization leads to suppression of the TREM1+-myeloid-derived microenvironment and the neoplastic/non-neoplastic fusogenic cell network.

Generation of chromosome 1p/19q co-deletion by CRISPR/Cas9-guided genomic editing.

Background: Chromosomal translocation has been detected in many human cancers including gliomas and is considered a driving force in tumorigenesis. Co-deletion of chromosome arms 1p and 19q is a hallmark for oligodendrogliomas. On the molecular level, 1p/19q co-deletion results from t(1;19)(q10;p10), which leads to the concomitant formation of a hybrid chromosome containing the 1q and 19p arms. A method to generate 1p/19q co-deletion is lacking, which hinders the investigation of how 1p/19q co-deletion contributes to gliomagenesis. Methods: We hypothesized that chromosomal translocation, such as t(1;19)(q10;p10) resulting in the 1p/19q co-deletion, may be induced by simultaneously introducing DNA double-strand breaks (DSBs) into chromosomes 1p and 19q using CRISPR/Cas9. We developed a CRISPR/Cas9-based strategy to induce t(1;19)(q10;p10) and droplet digital PCR (ddPCR) assays to detect the hybrid 1q/19p and 1p/19q chromosomes. Results: After translocation induction, we detected both 1p/19q and 1q/19p hybrid chromosomes by PCR amplification of the junction regions in HEK 293T, and U-251 and LN-229 glioblastoma cells. Sequencing analyses of the PCR products confirmed DNA sequences matching both chromosomes 1 and 19. Furthermore, the 1p/19q hybrid chromosome was rapidly lost in all tested cell lines. The 1q/19p hybrid chromosome also become undetectable over time likely due to cell survival disadvantage. Conclusion: We demonstrated that t(1;19)(q10;p10) may be induced by CRISPR/Cas9-mediated genomic editing. This method represents an important step toward engineering the 1p/19q co-deletion to model oligodendrogliomas. This method may also be generalizable to engineering other cancer-relevant translocations, which may facilitate the understanding of translocation roles in cancer progression.

Inhibition of the RNA Regulator HuR by SRI-42127 Attenuates Neuropathic Pain After Nerve Injury Through Suppression of Neuroinflammatory Responses.

Microglial activation with the production of pro-inflammatory mediators such as IL-6, TNF-α, and IL-1ß, is a major driver of neuropathic pain (NP) following peripheral nerve injury. We have previously shown that the RNA binding protein, HuR, is a positive node of regulation for many of these inflammatory mediators in glia and that its chemical inhibition or genetic deletion attenuates their production. In this report, we show that systemic administration of SRI-42127, a novel small molecule HuR inhibitor, attenuates mechanical allodynia, a hallmark of NP, in the early and chronic phases after spared nerve injury in male and female mice. Flow cytometry of lumbar spinal cords in SRI-42127-treated mice shows a reduction in infiltrating macrophages and a concomitant decrease in microglial populations expressing IL-6, TNF-α, IL-1ß, and CCL2. Immunohistochemistry, ELISA, and qPCR of lumbar spinal cord tissue indicate suppression of these cytokines and other inflammatory mediators. ELISA of plasma samples in the acute phase also shows attenuation of inflammatory responses. In summary, inhibition of HuR by SRI-42127 leads to the suppression of neuroinflammatory responses and allodynia after nerve injury and represents a promising new direction in the treatment of NP.

College students' attitudes about ways family, friends, significant others and media affect their eating and exercise behaviors and weight perceptions.

Objective: This study examined college students' perceptions of how parents, family, friends, significant others, and the media influenced eating and exercise behaviors and weight perceptions. Participants: Forty-one college students, mostly female, participated in interviews. Methods: A Grounded Theory approach, using open coding and memoing, was used to uncover key themes. Results: Healthy cooking and exercise role models at home were viewed as positive, encouraging healthy eating and exercise. Criticism was perceived as negative for healthy habits and weight perceptions. Friends and significant others who practiced positive health habits and were body accepting were uplifting. Cultural transmission of the thin ideal could occur through the media. Some noted that media messages were becoming more positive. Conclusions: Using peers, especially friends, as collaborators in interventions, and discussing parental influences on eating, exercise, and weight perceptions may positively impact obesity prevention programs and interventions for college students.

High-dose methotrexate and rituximab induction regimen in immunocompetent patients with primary CNS lymphoma: a retrospective single-center study of survival predictors.

PURPOSE: Primary Central Nervous System Lymphoma (PCNSL) is an aggressive tumor that is confined to the CNS. Although the provision of high-dose methotrexate (HD-MTX) has remarkably improved outcomes in PCNSL patients, the optimal treatment regimens and standard MTX dose for induction therapy have been largely controversial. Herein, we sought to explore the impact of adjuvant rituximab and different dosages of induction HD-MTX on survival outcomes of immunocompetent patients with PCNSL. METHODS: In this study, we examined patients with PCNSL treated at a single NCI-designated comprehensive cancer center to evaluate their survival outcomes. We conducted a retrospective analysis of 51 immunocompetent patients with PCNSL who received their induction chemotherapy at the University of Alabama at Birmingham (UAB) between 2001 and 2019. Only adult patients with a confirmed diagnosis of PCNSL who had either HD-MTX alone or in combination with rituximab were included. Patients' demographics, clinical characteristics, and survival data were collected and analyzed. RESULTS: There is no significant difference in survival among patients who received MTX alone versus MTX plus rituximab (HR = 0.996 (95% CI: 0.398-2.493), p = 0.994). Lower doses of MTX were associated with worse survival outcomes (HR = 0.680 (95% CI: 0.530-0.872), p = 0.002); however, this difference in survival was not significant when adjusted to age (HR = 0.797 (95% CI: 0.584-1.088), p = 0.153). CONCLUSION: Our experience challenges the role of rituximab in PCNSL during induction therapy. Our study also highlights the shorter survival in elderly patients with PCNSL which can be related, to some extent, to the relatively lower doses of HD-MTX. There is an unmet need to establish a consensus on the most effective upfront regimen in PCNSL through prospective studies.

Mitochondrial DNA sequence variation and risk of glioma.

BACKGROUND: Malignant gliomas are the most common primary adult brain tumors, with a poor prognosis and ill-defined etiology. Mitochondrial DNA (mtDNA) sequence variation has been linked with certain cancers; however, research on glioma is lacking. METHODS: We examined the association of common (minor allele frequency ≥ 5%) germline mtDNA variants and haplogroups with glioma risk in 1,566 glioma cases and 1,017 controls from a US case-control study, and 425 glioma cases and 1,534 matched controls from the UK Biobank cohort (UKB). DNA samples were genotyped using the UK Biobank array that included a set of common and rare mtDNA variants. Risk associations were examined separately for glioblastoma (GBM) and lower grade tumors (non-GBM). RESULTS: In the US study, haplogroup W was inversely associated with glioma when compared with haplogroup H (OR = 0.43, 95%CI: 0.23-0.79); this association was not demonstrated in the UKB (OR = 1.07, 95%CI: 0.47-2.43). In the UKB, the variant m.3010G > A was significantly associated with GBM (OR = 1.32; 95%CI: 1.01-1.73; p = 0.04), but not non-GBM (1.23; 95%CI: 0.78-1.95; p = 0.38); no similar association was observed in the US study. In the US study, the variant m.14798 T > C, was significantly associated with non-GBM (OR = 0.72; 95%CI: 0.53-0.99), but not GBM (OR = 0.86; 95%CI: 0.66-1.11), whereas in the UKB, a positive association was observed between this variant and GBM (OR = 1.46; 95%CI: 1.06-2.02) but not non-GBM (OR = 0.92; 95%CI: 0.52-1.63). None of these associations were significant after adjustment for multiple testing. CONCLUSION: The association of inherited mtDNA variation, including rare and singleton variants, with glioma risk merits further study.

Mitochondrial DNA sequence variation and risk of meningioma.

BACKGROUND: Risk factors for meningioma include female gender, African American race, high body mass index (BMI), and exposure to ionizing radiation. Although genome-wide association studies (GWAS) have identified two nuclear genome risk loci for meningioma (rs12770228 and rs2686876), the relation between mitochondrial DNA (mtDNA) sequence variants and meningioma is unknown. METHODS: We examined the association of 42 common germline mtDNA variants (minor allele frequency ≥ 5%), haplogroups, and genes with meningioma in 1080 controls and 478 meningioma cases from a case-control study conducted at medical centers in the southeastern United States. Associations were examined separately for meningioma overall and by WHO grade (n = 409 grade I and n = 69 grade II/III). RESULTS: Overall, meningioma was significantly associated with being female (OR 2.85; 95% CI 2.21-3.69), self-reported African American race (OR 2.38, 95% CI 1.41-3.99), and being overweight (OR 1.48; 95% CI 1.11-1.97) or obese (OR 1.70; 95% CI 1.25-2.31). The variant m.16362T > C (rs62581341) in the mitochondrial control region was positively associated with grade II/III meningiomas (OR 2.33; 95% CI 1.14-4.77), but not grade I tumors (OR 0.99; 95% CI 0.64-1.53). Haplogroup L, a marker for African ancestry, was associated with meningioma overall (OR 2.92; 95% CI 1.01-8.44). However, after stratifying by self-reported race, this association was only apparent among the few self-reported Caucasians with this haplogroup (OR 6.35; 95% CI 1.56-25.9). No other mtDNA variant, haplogroup, or gene was associated with meningioma. CONCLUSION: Common mtDNA variants and major mtDNA haplogroups do not appear to have associations with the odds of developing meningioma.

A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas.

Chemotherapeutic drugs such as the alkylating agent Temozolomide (TMZ), in addition to reducing tumor mass, can also sensitize tumors to immune recognition by transient upregulation of multiple stress induced NKG2D ligands (NKG2DL). However, the potential for an effective response by innate lymphocyte effectors such as NK and γδ T cells that recognize NKG2DL is limited by the drug's concomitant lymphodepleting effects. We have previously shown that modification of γδ T cells with a methylguanine DNA methyltransferase (MGMT) transgene confers TMZ resistance via production of O6-alkylguanine DNA alkyltransferase (AGT) thereby enabling γδ T cell function in therapeutic concentrations of TMZ. In this study, we tested this strategy which we have termed Drug Resistant Immunotherapy (DRI) to examine whether combination therapy of TMZ and MGMT-modified γδ T cells could improve survival outcomes in four human/mouse xenograft models of primary and refractory GBM. Our results confirm that DRI leverages the innate response of γδ T cells to chemotherapy-induced stress associated antigen expression and achieves synergies that are significantly greater than either individual approach.

Data Matching to Support Analysis of Cancer Epidemiology Among Veterans Compared With Non-Veteran Populations-An Exemplar in Brain Tumors.

PURPOSE: State and national cancer registries do not systematically include Veteran data, which hinders analysis of the diagnosis patterns, treatment trajectories, and clinical outcomes of Veterans compared with non-Veteran populations. This study used data matching approaches to compare cases included in the Oncology Domain of the Veterans Affairs (VA) Corporate Data Warehouse and the Ohio Cancer Incidence Surveillance System, using brain tumors as an exemplar. METHODS: We used direct data matching, on the basis of protected health information (PHI) common to both databases, to compare primary brain tumors from Veterans and non-Veterans diagnosed from 2000 to 2016. Working with this matched data set, we used six data elements that did not contain PHI, to assess the feasibility of using deterministic data matching to compare Veterans and non-Veterans. RESULTS: Between 2000 and 2016, 223 Veterans from Ohio had a primary brain tumor; of those, 55 (25%) were not included in Ohio Cancer Incidence Surveillance System. Direct data matching showed that Veterans experienced a greater proportion of glioblastomas (41%) compared with non-Veterans (21%). Sex did not account for this difference. Deterministic data matching within the matched data set found that 75% (126 of 168) of Veterans had exact matches for at least five of six non-PHI variables common to both databases. CONCLUSION: This study indicated that direct and deterministic data matching approaches to compare brain tumors in Veterans and in non-Veterans is feasible. This approach has the potential to promote comparisons of the distribution of tumors, the impact of chemical and environmental exposures, treatment trajectories, and clinical outcomes among Veteran and non-Veteran populations with brain tumors as well as other cancers and rare diseases.

Human gut microbial communities dictate efficacy of anti-PD-1 therapy in a humanized microbiome mouse model of glioma.

BACKGROUND: Although immunotherapy works well in glioblastoma (GBM) preclinical mouse models, the therapy has not demonstrated efficacy in humans. To address this anomaly, we developed a novel humanized microbiome (HuM) model to study the response to immunotherapy in a preclinical mouse model of GBM. METHODS: We used 5 healthy human donors for fecal transplantation of gnotobiotic mice. After the transplanted microbiomes stabilized, the mice were bred to generate 5 independent humanized mouse lines (HuM1-HuM5). RESULTS: Analysis of shotgun metagenomic sequencing data from fecal samples revealed a unique microbiome with significant differences in diversity and microbial composition among HuM1-HuM5 lines. All HuM mouse lines were susceptible to GBM transplantation, and exhibited similar median survival ranging from 19 to 26 days. Interestingly, we found that HuM lines responded differently to the immune checkpoint inhibitor anti-PD-1. Specifically, we demonstrate that HuM1, HuM4, and HuM5 mice are nonresponders to anti-PD-1, while HuM2 and HuM3 mice are responsive to anti-PD-1 and displayed significantly increased survival compared to isotype controls. Bray-Curtis cluster analysis of the 5 HuM gut microbial communities revealed that responders HuM2 and HuM3 were closely related, and detailed taxonomic comparison analysis revealed that Bacteroides cellulosilyticus was commonly found in HuM2 and HuM3 with high abundances. CONCLUSIONS: The results of our study establish the utility of humanized microbiome mice as avatars to delineate features of the host interaction with gut microbial communities needed for effective immunotherapy against GBM.