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Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is expressed in > 90% of all adult-resected glioblastoma (GBM) and potently suppresses the anti-GBM immune response. IDO expression is increased by GBM-infiltrating T cells and therefore represents a key mechanism of resistance to immune-based therapies, since targeted approaches that aim to enhance T-cell infiltration into GBM will in turn result in a compensatory increase of IDO expression and suppression of the anti-GBM immune response. Importantly, the high intratumoral IDO expression is associated with a significant decrease of GBM patient survival and increased immunosuppressive regulatory T cells (CD4+ CD25+ FoxP3+). Since IDO is canonically characterized as a rate-limiting enzyme that metabolizes the essential amino acid, tryptophan (Trp), into kynurenine (Kyn), the depletion of Trp and/or accumulation of Kyn has been the presumed mechanism of how IDO suppresses the anti-GBM immune response. However, our work has challenged this hypothesis, and here we provide a comprehensive update of IDO effects in adults with GBM.

INTRODUCTION We previously determined that advanced age plays a negative role in the survival outcome of human recurrent glioblastoma (GBM) patients treated with immune checkpoint blockade. Here we investigate the immunologic “signature” of younger patients who are < 65 years of age and older adult GBM patients who are ≥ 65 years of age that undergo simultaneous treatment with standard radiation, nivolumab (anti-PD-1 mAb), and BMS-986205 (a potent IDO enzyme inhibitor) and are newly diagnosed with O6-methylguanine-DNA methyl-transferase (MGMT) unmethylated GBM. Our objective was to identify age-dependent immunologic changes before and after treatment with immunotherapy. METHODS Patients ≥ 18 years old with newly diagnosed MGMT unmethylated GBM, KPS ≥ 70, and minimal steroid use were eligible for enrollment in this phase 1 trial. PBMCs and serum were drawn at baseline and routine post-treatment time points followed by mass spec analysis of kynurenine (Kyn) and tryptophan (Trp) metabolites, RNAseq, and 18-color flow cytometric analysis. RESULTS 8 younger adults with a median age of 50 years old and 4 older adults with a median age of 68.5 years old were studied. The median overall survival of younger and older adults was 368 and 108.5 days, respectively (p=0.032, HR 4.8 for age). BMS-986205 treatment decreased the Kyn/Trp ratio of all patients irrespective of age. RNAseq analysis found significant age-related changes using Gene Ontology pathway analysis of T cell related immunity, lymphocyte activation, and NK cell mediated immunity. Flow cytometric analysis is ongoing. CONCLUSIONS Similar to what was reported in older adult mice treated with simultaneous RT, anti-PD-1 mAb, and IDO enzyme inhibitor, advanced age negatively affected the survival in older adult human GBM patients treated with an analogous clinical approach. Future determination of whether the age-related biomarker profile can be used diagnostically and therapeutically is now under investigation.

Glioblastoma is the most common primary malignant brain tumor in adults. Age is a prognostic factor for grade IV glioma (GIV) survival, where older adults 65 and older, tend to have quicker mortality compared to adults 18-64. This may be due to intrinsic aspects of the aged host, including age-dependent changes to the brain and immune systems. We studied pharmacologic management of GIV patients treated with medications affecting the brain, immune, and other systems for associations with age and survival. Electronic records for 1,208 GIV patients were collected at a single institution from 1/1/2000 to 9/8/2021 and used to construct a multivariable time-dependent cox model that examined intra-cohort hazards associated with 14 different categories of outpatient medications. Date of diagnosis was identified as the start-time and subject death was used to define the event-time. Patients who were alive or lost to follow-up were censored to last recorded date. Survival time was calculated as the difference between diagnosis date and event time or censorship. For positive control, we confirmed that younger and older patients experienced an improved hazard with temozolomide. Strikingly, younger, but not older patients, experienced increased hazard with a steroid prescription (1.46 [1.12,1.90], **). In contrast, older, but not younger patients experienced improvements in hazard with prescription of neurological medications including benzodiazepines (0.47 [0.27, 0.80] **) and anti-convulsants (0.28 [0.08, 0.90] *), in addition to heart failure treatments including angiotensin II inhibitors (0.48 [0.27, 0.85] *) and diuretics (0.30 [0.15, 0.87] *). Patients prescribed antidepressants didn’t show improved hazard across younger and older GIV patients, which consistent with our previously published work. These data indicate novel associative benefits due to prescription of select pharmacologic agents that vary with patient age. This work may be used to better understand therapeutic approaches that selectively benefit younger vs. older adults with GIV.

Glioblastomas are the most common primary malignant brain tumor in adults. Subject age is a strong prognostic factor for survival. We performed a co-morbidity analysis of younger vs. older (greater than 65 years) adults with grade IV gliomas (GIV) to understand inherent differences that vary with subject age. Electronic health records for 1,208 GIV patients were collected at a single center between 1/1/2000 and 9/8/2021 and used to construct a multivariable time-dependent cox model that examined intra-cohort hazards associated with 33 measures of co-morbidity and tumor related symptoms. The date of GIV diagnosis was identified as the start time, and subject death was used to define event time. Patients that were alive or lost to follow-up were censored at the last recorded date. Survival time was calculated as the difference between diagnosis date and event time or censorship. GIV was stratified by IDH and MGMT promoter methylation status when available. Younger patients experienced a greater hazard with: limitations to movement (1.88 [1.46, 2.43] ****), gait (1.72 [1.17, 2.52] **), weakness (1.96 [1.26, 3.06] **), seizures (1.28 [1.04, 1.58] *), epilepsy (1.47 [1.09, 1.99] *), and anxiety disorders (2.37 [1.44, 3.92], **). Older GIV patients experienced an increased hazard with: confusion and altered mental status (4.3 [2.08, 8.89], ****). Both age groups experienced increases with eye/visual systems and plegia. These data indicate novel comorbid enrichments varying by subject age that, from a mechanistic perspective, may be used to better understand why older adults with GIV survive significantly less than younger counterparts.

OBJECTIVE Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) may be used to treat degenerative spinal pathologies while reducing risks associated with open procedures. As an increasing number of lumbar fusions are performed in the aging United States population, MIS-TLIF has been widely adopted into clinical practice in recent years. However, its complication rate and functional outcomes in elderly patients remain poorly characterized. The objective of this study was to assess complication rates and functional outcomes in elderly patients (≥ 65 years old) undergoing MIS-TLIF. METHODS The PubMed, Embase, and Scopus databases were searched for relevant records in accordance with the PRISMA guidelines. Inclusion criteria were peer-reviewed original research; English language; full text available; use of MIS-TLIF; and an elderly cohort of at least 5 patients. Risk of bias was assessed using the ROBINS-I (Risk of Bias in Nonrandomized Studies—of Interventions) tool. Pooled complication rates were calculated for elderly patients, with subgroup analyses performed for single versus multiple-level fusions. Complication rates in elderly compared to nonelderly patients were also assessed. Postoperative changes in patient-reported outcomes, including Oswestry Disability Index (ODI) and visual analog scale (VAS) back pain (BP) and leg pain (LP) scores, were calculated. RESULTS Twelve studies were included in the final analysis. Compared to nonelderly patients, MIS-TLIF in elderly patients resulted in significantly higher rates of major (OR 2.15, 95% CI 1.07–4.34) and minor (OR 2.20, 95% CI 1.22–3.95) complications. The pooled major complication rate in elderly patients was 0.05 (95% CI 0.03–0.08) and the pooled minor complication rate was 0.20 (95% CI 0.13–0.30). Single-level MIS-TLIF had lower major and minor complication rates than multilevel MIS-TLIF, although not reaching significance. At a minimum follow-up of 6 months, the postoperative change in ODI (−30.70, 95% CI −41.84 to −19.55), VAS-BP (−3.87, 95% CI −4.97 to −2.77), and VAS-LP (−5.11, 95% CI −6.69 to −3.53) in elderly patients all exceeded the respective minimum clinically important difference. The pooled rate of fusion was 0.86 (95% CI 0.80–0.90). CONCLUSIONS MIS-TLIF in elderly patients results in a high rate of fusion and significant improvement of patient-reported outcomes, but has significantly higher complication rates than in nonelderly patients. Limitations of this study include heterogeneity in the definition of elderly and limited reporting of risk factors among included studies. Further study of the impact of complications and the factors predisposing elderly patients to poor outcomes is needed.

Background Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDHwt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDHwt GBM have a median age of diagnosis at 68–70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM. Methods The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship. Results Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve. Conclusions Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDHwt GBM patient outcomes.