Faculty Bibliography

BACKGROUND:Small tectal gliomas (TGs) may be unrecognized at initial diagnosis of noncommunicating hydrocephalus, with the etiology typically attributed to idiopathic congenital aqueductal stenosis (CAS). There are 2 published cases of TGs found on follow-up imaging after treatment with endoscopic third ventriculostomy (ETV). The authors investigated for this phenomenon in a large cohort of patients with TG or CAS treated with ETV or CSF shunting. OBSERVATIONS/METHODS:The authors reviewed records at their institution from 1999 to 2024, identifying 10 patients initially diagnosed with presumed idiopathic CAS and later found to have underlying TG. Of these, 7 were younger than 1 year of age at hydrocephalus presentation. The median time from CAS to glioma diagnosis was 13 months. Reasons for repeat imaging that identified glioma included postoperative surveillance and recurrent hydrocephalus. Five (50%) lesions grew over follow-up, and 2 required chemotherapy. LESSONS/CONCLUSIONS:The authors describe the eventual emergence of TG as a probable cause of hydrocephalus in a cohort of patients initially diagnosed with CAS. As most of these cases were identified incidentally on interval imaging to evaluate adequate function of CSF diversion procedures, follow-up imaging to evaluate for tectal expansion should be considered in children, particularly infants, with a new diagnosis of idiopathic CAS. https://thejns.org/doi/10.3171/CASE24695.

PURPOSE/OBJECTIVE:Bevacizumab treatment is associated with imaging and hearing responses in progressive vestibular schwannoma (VS) caused by NF2-related schwannomatosis (NF2-SWN). However, its effect on co-existing intracranial non-vestibular schwannomas (NVS) and meningiomas is unclear. METHODS:We retrospectively analyzed tumor volumes of non-target intracranial NVS and meningiomas in patients with NF2-SWN and progressive VS who were prospectively treated with bevacizumab for two years on the Neurofibromatosis Clinical Trials Consortium (NFCTC) trial NF104 (NCT01767792). Radiographic response (RR) or progression (PD) were defined as ≥ 20% decrease or ≥ 20% increase in tumor volume compared to baseline, respectively. All other responses were defined as stable disease. RESULTS:A total of 40 meningiomas in eight patients and 12 NVS in six patients were evaluated across 22 enrolled trial participants. On best response analysis, RR occurred in 13% (5/40) of meningiomas and in 42% (5/12) of NVS. On a per-patient basis, RR for meningioma occurred in 38% (3/8) of patients and for NVS in 67% (4/6) of patients. RR in two NVS were durable throughout the study period. During two years of treatment, PD occurred in 55% (22/40) of meningiomas and in 8% (1/12) of NVS. Median time to tumor progression was 15 months for meningiomas and was not reached for NVS. CONCLUSIONS:We observed greater activity of bevacizumab against intracranial NVS compared to meningioma, evidenced by more favorable RR rates, durability of response, and rates of PD. Potential biological differences between meningiomas and schwannomas that underlie this differential response to bevacizumab warrant further investigation.

BACKGROUND:This study evaluated the safety and pharmacokinetics (PK) of oral ONC201 administered twice-weekly on consecutive days (D1D2) in pediatric patients with newly diagnosed DIPG and/or recurrent/refractory H3 K27M glioma. METHODS:This phase 1 dose-escalation and expansion study included pediatric patients with H3 K27M-mutant glioma and/or DIPG following ≥1 line of therapy (NCT03416530). ONC201 was administered D1D2 at three dose levels (DLs; -1, 1, and 2). Actual administered dose within DLs was dependent on weight. Safety was assessed in all DLs; PK analysis was conducted in DL2. Patients receiving once-weekly ONC201 (D1) served as a PK comparator.1. RESULTS:Twelve patients received D1D2 ONC201 (DL-1, n=3; DL1, n=3; DL2, n=6); no dose-limiting toxicities or grade ≥3 treatment-related adverse events occurred. PK analyses at DL2 (D1-250mg, n=3; D1-625mg, n=3; D1D2-250mg, n=2; D1D2-625mg, n=2) demonstrated variability in Cmax, AUC0-24, and AUC0-48, with comparable exposures across weight groups. No accumulation occurred with D1D2 dosing; the majority of ONC201 cleared before administration of the second dose. Cmax was variable between groups but did not appear to increase with D1D2 dosing. AUC0-48 was greater with D1D2 than once-weekly. CONCLUSIONS:ONC201 given D1D2 was well-tolerated at all DLs and associated with greater AUC0-48.

BACKGROUND/UNASSIGNED:Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). METHODS/UNASSIGNED:A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers. RESULTS/UNASSIGNED:A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. CONCLUSIONS/UNASSIGNED:GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy.

UNLABELLED:DNA methylation is an essential molecular assay for central nervous system (CNS) tumor diagnostics. While some fusions define specific brain tumors, others occur across many different diagnoses. We performed a retrospective analysis of 219 primary CNS tumors with whole genome DNA methylation and RNA next-generation sequencing. DNA methylation profiling results were compared with RNAseq detected gene fusions. We detected 105 rare fusions involving 31 driver genes, including 23 fusions previously not implicated in brain tumors. In addition, we identified 6 multi-fusion tumors. Rare fusions and multi-fusion events can impact the diagnostic accuracy of DNA methylation by decreasing confidence in the result, such as BRAF, RAF, or FGFR1 fusions, or result in a complete mismatch, such as NTRK, EWSR1, FGFR, and ALK fusions. IMPLICATIONS/UNASSIGNED:DNA methylation signatures need to be interpreted in the context of pathology and discordant results warrant testing for novel and rare gene fusions.

BACKGROUND:Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). METHODS:Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. RESULTS:Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. CONCLUSIONS:Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.

BACKGROUND/UNASSIGNED:Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. METHODS/UNASSIGNED:We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. RESULTS/UNASSIGNED:Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. CONCLUSIONS/UNASSIGNED:DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64 years (range 1-82) and the overall median survival was 397 days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (p = 0.366) or radiation (p = 0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.

The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have simultaneously developed with success treatment strategies with specific attention paid to long-term sequelae. Neurological sequelae may be reduced by establishing a diagnosis with an endoscopic biopsy and/or cerebrospinal fluid (CSF) and/or serum analysis, deferring the need to perform a radical surgery. Depending on markers and/or histological characteristics, patients are treated as either germinoma or non-germinomatous germ cell tumors (NGGCT). Metastatic disease is defined by a positive CSF cytology and/or distant drops in craniospinal MRI. The combination of surgery and/or chemotherapy and radiation therapy is tailored according to grouping and staging. With more than 90% 5-year event-free survival (EFS), localized germinomas can be managed without aggressive surgery, and benefit from chemotherapy followed by whole ventricular irradiation with local boost. Bifocal germinomas are treated as non-metastatic entities. Metastatic germinomas may be cured with craniospinal irradiation. With a 5-year EFS over 70%, NGGCT benefit from chemotherapy followed by delayed surgery in case of residual disease, and some form of radiotherapy. Future strategies will aim at decreasing long-term side effects while preserving high cure rates.