Lukas, Rimas V.

Brain tumor-related epilepsy (BTRE) is a common and debilitating symptom of central nervous system (CNS) tumors. The epileptogenic zone, defined as cortex responsible for seizure generation, is located at the peritumoral region for most tumors, and lower-grade intrinsic brain tumors have the highest seizure incidence. Surgery is often the most effective treatment for the reduction in seizures in BTRE. However, surgical decisions have historically often been made exclusively for oncologic reasons, with less emphasis on seizure control. Surgical approaches for all tumor types are reviewed, highlighting relevant risk factors. Adjunctive tools during surgery, such as intraoperative electrocorticography (ECoG), may help identify and remove surrounding brain areas which are epileptogenic. Minimally invasive surgery is also gaining traction, given its utility in treating seizures deep-seated tumors. This review explores epileptogenic brain tumors, surgery for BTRE, and emerging strategies to better achieve seizure control.

Importance Molecular techniques, including next-generation sequencing, genomic copy number profiling, fusion transcript detection, and genomic DNA methylation arrays, are now indispensable tools for the workup of central nervous system (CNS) tumors. Yet there remains a great deal of heterogeneity in using such biomarker testing across institutions and hospital systems. This is in large part because there is a persistent reluctance among third-party payers to cover molecular testing. The objective of this Review is to describe why comprehensive molecular biomarker testing is now required for the accurate diagnosis and grading and prognostication of CNS tumors and, in so doing, to justify more widespread use by clinicians and coverage by third-party payers. Observations The 5th edition of the World Health Organization (WHO) classification system for CNS tumors incorporates specific molecular signatures into the essential diagnostic criteria for most tumor entities. Many CNS tumor types cannot be reliably diagnosed according to current WHO guidelines without molecular testing. The National Comprehensive Cancer Network also incorporates molecular testing into their guidelines for CNS tumors. Both sets of guidelines are maximally effective if they are implemented routinely for all patients with CNS tumors. Moreover, the cost of these tests is less than 5% of the overall average cost of caring for patients with CNS tumors and consistently improves management. This includes more accurate diagnosis and prognostication, clinical trial eligibility, and prediction of response to specific treatments. Each major group of CNS tumors in the WHO classification is evaluated and how molecular diagnostics enhances patient care is described. Conclusions and Relevance Routine advanced multidimensional molecular profiling is now required to provide optimal standard of care for patients with CNS tumors.

Abstract BACKGROUND Glioblastoma (GBM) is an aggressive central nervous system (CNS) malignancy with poor prognosis. TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability. TTFields therapy is approved for recurrent and newly diagnosed GBM, and pleural mesothelioma. We report long-term safety data from pediatric, adult and elderly patients with CNS malignancies receiving TTFields, from a global post-marketing surveillance (PMS) dataset. METHODS Unsolicited PMS data were collected from patients receiving TTFields (October 2011–October 2022). AEs were categorized using MedDRA version 25.1, and data stratified by age group (< 18, 18–65, and > 65 years). RESULTS Overall, 25,898 patients from the US, Europe, Israel, and Japan were included. Of these, 93 (0.4%) were < 18 years (pediatric), 17,817 (69%) were 18–65 years (adult), and 7,808 (30%) were > 65 years (elderly). Two-thirds (66%) of all patients were male. Demographic characteristics were therefore consistent with a typical GBM population. Of pediatric patients, 62% experienced ≥ 1 AE, with 53% related to TTFields. This was comparable in adults (72% and 56%, respectively), and elderly patients (75% and 57%, respectively). The most common TTFields-related AEs were skin reaction (pediatric: 39%; adult: 42%; elderly: 45%), heat (warmth) sensation (pediatric: 14%; adult: 12%; elderly: 12%), and electric (tingling) sensation (pediatric: 10%; adult: 15%; elderly: 10%). All-cause serious AEs occurred in 14%, 21% and 25% of pediatric, adult and elderly patients, respectively. No systemic toxicities were reported, regardless of age. CONCLUSIONS These long-term, real-world PMS data demonstrate that TTFields has a tolerable safety profile in pediatric, adult and elderly patients with CNS malignancies, with no new safety signals in any age group. Most AEs were localized skin reactions which are manageable. These data provide supportive evidence of the safety and broad applicability of TTFields, regardless of patient age.

Abstract Purpose: Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan. Experimental Design: Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy. Results: Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice. Conclusions: This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.

AbstractNeuro-oncology encompasses a broad field focusing on an array of neoplasms, many of which can mimic several diseases. Neurologists will often be involved in the initial diagnostic evaluation and management of these patients. Their insight is central to optimizing the diagnostic yield and providing high-level clinical care. Several neuro-oncologic cases are reviewed with a goal of increasing the understanding of these diseases in a clinically relevant manner and providing updates on the contemporary thinking in the subspecialty.

Abstract Tumor Treating Fields therapy (TTFields; 200 kHz) is a noninvasive, locoregional, antimitotic treatment approved for newly diagnosed glioblastoma (ndGBM), recurrent (r) GBM, malignant pleural mesothelioma, and is being investigated in additional solid tumors. Approval in GBM was based on results of the phase 3 EF-11 (TTFields monotherapy; rGBM) and EF-14 (TTFields therapy/maintenance temozolomide; ndGBM), which showed clinical benefit without an increase in adverse events (AEs). Here we review post-marketing surveillance (PMS) data from patients with brain tumors who received TTFields therapy over an 11-year period. Unsolicited PMS data from patients with brain tumors who received TTFields therapy between October 2011 and March 2022, were included. Overall 23,822 patients were included in this analysis. Most patients (72%) were from North America; 24% from Europe, Middle East and Africa, and 4% from Japan. Birth year was available for 23,784 patients; of these, the average age at treatment start was 57 years (range: 3–103). Diagnoses were ndGBM (67%), rGBM (27%), astrocytoma (WHO grade 3; 4%) and other (2%). Overall, 71% of patients reported ≥ 1 AE, with the most common being skin reaction (42%), electric (tingling) sensation (14%), heat (warmth) sensation (12%), and seizure (11%). Furthermore, 56% of patients reported AEs possibly related to TTFields therapy, with the most frequently reported being skin reaction (42%), electric sensation (14%) and heat sensation (12%), occurring underneath the arrays. Numbers and types of AEs were comparable between age and diagnosis groups. PMS data from > 23,000 patients with brain tumors show that TTFields therapy (200 kHz) is well-tolerated, consistent with the known safety profile; no new safety signals were identified. TTFields therapy is not associated with systemic toxicity; most common possibly-related AEs are localized dermatologic events that can be managed with appropriate prophylaxis and treatment strategies.

Abstract In the following brief report, we highlight the advances in the neuro-oncology space from the ASCO 2022 Annual Meeting. We put into context the phase 2 and 3 trials and how these may alter the standard of care going forward. In addition, we highlight some other earlier work that will lead to future and potentially practice-changing trials.

Abstract 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.