OBJECTIVE:Radiation necrosis (RN) is a well-recognized late complication most commonly occurring within 2 years of stereotactic radiosurgery (SRS); however, late RN (LRN), RN occurring or recurring > 5 years after SRS, has been poorly described. This study analyzes the incidence of and risk factors for LRN occurring > 5 years after SRS. METHODS:This retrospective analysis included patients treated with linear accelerator-based SRS for tumors or arteriovenous malformations with > 5 years of clinical and serial MRI follow-up. LRN was defined as new neurological symptoms with neuroanatomically correlated imaging findings without disease recurrence. Univariate and multivariate analyses for LRN were performed using the Cox proportional hazards model. RESULTS:The authors identified a cumulative 297 lesions in 219 patients treated to a median dose of 17 Gy with a median follow-up of 7.4 years. In total, 290 (97.6%) lesions were treated in a single fraction, and 64 (21.5%) were treated after resection. The LRN occurred in 19 (8.7%) patients and in 23 (7.7%) lesions at a median of 6.1 years (range 5.1-13.9 years) after SRS. Fifteen of the 23 (65.2%) lesions were managed with steroids, bevacizumab, and/or antiepileptic drugs. The remaining 8 (34.8%) were resected; histopathology confirmed necrosis without disease recurrence in each. On multivariate analysis, only > 5-cm3 volume of the brain receiving 12 Gy (brain V12Gy) (HR 6.01, 95% CI 1.77-20.48; p = 0.004) and a history of early, previously resolved RN (HR 9.53, 95% CI 2.00-45.61; p = 0.005) remained significantly associated with LRN. CONCLUSIONS:RN risk persists well beyond 5 years after SRS, and recognizing LRN as an entity has important implications in managing these patients. LRN risk was highest in those with a brain V12Gy > 5 cm3 and a history of early RN after SRS, warranting close follow-up in perpetuity for select patients.

Introduction: Treatment for primary central nervous system lymphoma (PCNSL) includes high-dose methotrexate (HD-MTX)-based systemic therapy. Multiple regimens exist with no clear standard of care. We evaluated the impact of different therapies on PCNSL outcomes at a single institution. Materials and Methods: A total of 95 consecutive patients with PCNSL from 2002 to 2021 were retrospectively reviewed. The overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method. The log-rank test and univariate and multivariable Cox regression analysis were used to evaluate the relationship between clinicopathologic and treatment variables with outcomes. Results: Among the 62 patients treated with definitive systemic therapy, the median age was 58; 71% had a Karnofsky performance status > 70, 49% had a single lesion, 31% received HD-MTX alone, and 61% had HD-MTX + rituximab. The two-year OS and PFS were 64% (95% CI: 49.8–75.0%) and 49% (95% CI: 35.0–60.9%), respectively. On multivariable analysis, the completion of > six cycles of HD-MTX (HR 0.40; 95% CI: 0.21–0.76; p = 0.01) was associated with superior OS, while the use of rituximab was associated with inferior OS (HR 2.82; 95% CI: 1.37–5.83; p = 0.01). There were no significant associations between the OS and PFS with temozolomide, the extent of surgical resection, radiation, or the size or number of initial lesions (all p > 0.05). Discussion: Innovation is needed to improve the outcomes for patients with PCNSL.

Purpose: Stereotactic radiosurgery (SRS) is the standard of care for brain metastases, providing effective local tumor control while avoiding the neurocognitive effects of whole-brain radiation therapy. However, large brain metastases have been excluded from the randomized studies of single-fraction SRS, and there are limited data regarding neurocognitive outcomes with multifraction radiosurgery approaches for large intact or resected brain metastases. Methods and Materials: We performed a prospective phase 1 dose-escalation study of multifraction SRS for intact or resected brain metastases 3 to 6 cm in diameter from 2012 to 2021. Patients longitudinally completed the Hopkins Verbal Learning Test (HVLT), Mini-Mental State Examination, Functional Assessment of Cancer Therapy—Brain, and Medical Outcomes Cognitive Scale. Reliable Change Index is used to assess HVLT change from baseline to 4 months. Significance is defined as greater than 1 SD change. Analysis of variance comparisons were performed for clinicodemographic characteristics associated with neurocognitive outcomes or quality-of-life metrics. Results: Of the 24 patients treated in the trial, 15 completed both baseline and 4-month neurocognitive assessments. For the 15 patients with neurocognitive assessments, median age was 57 years (range, 37-74 years), median baseline Karnofsky Performance Status was 80 (range, 70-90), and median volume of radiation target was 15.9 cm3 (range, 7.7-57.2 cm3). At 4 months, 20% of patients had a significant decline in HVLT Total Recall scores, 33% had no significant change, and 47% had significant improvement. Mean neurocognitive function and quality-of-life scores were either stable or improved over time up to the last evaluation at 25 months. There were no clinical or treatment characteristics significantly associated with changes in neurocognitive function or quality-of-life scores. Conclusions: Of the evaluable patients with large brain metastases treated with dose-escalated, multifraction SRS, the majority of patients demonstrated stable or improved neurocognitive function and quality of life in follow-up.

Background: Pediatric high-grade glioma (pHGG) is a highly aggressive cancer with unique biology distinct from adult high-grade glioma, limiting the effectiveness of standard treatment protocols derived from adult research. Objective: The purpose of this report is to present preliminary results from an ongoing pilot study integrating spectroscopic magnetic resonance imaging (sMRI) to guide proton beam therapy and longitudinal imaging analysis in pediatric patients with high-grade glioma (pHGG). Methods: Thirteen pediatric patients under 21 years old with supratentorial WHO grade III-IV glioma underwent baseline and serial whole-brain spectroscopic MRI alongside standard structural MRIs. Radiation targets were defined using T1-weighted contrast enhanced, T2-FLAIR, and Cho/NAA ≥ 2X maps. Longitudinal analyses included voxel-level metabolic change maps and spatial overlap metrics comparing pre-proton therapy and post-. Results: Six patients had sufficient longitudinal data; five received sMRI-guided PBT. Significant positive correlation (R2 = 0.89, p < 0.0001) was observed between T2-FLAIR and Cho/NAA ≥ 2X volumes. Voxel-level difference maps of Cho/NAA and Choline revealed dynamic metabolic changes across follow-up scans. Analyzing Cho/NAA and Cho changes over time allowed differentiation between true progression and pseudoprogression, which conventional MRI alone struggles to achieve. Conclusions: Longitudinal sMRI enhanced metabolic tracking in pHGG, detects early tumor changes, and refines RT targeting beyond structural imaging. This first in-kind study highlights the potential of sMRI biomarkers in tracking treatment effects and emphasizes the complementary roles of metabolic and radiographic metrics in evaluating therapy response in pHGG.

BACKGROUND:Rhabdomyosarcoma (RMS) is a rare malignancy of undifferentiated skeletal muscle tissue and is the most common pediatric soft tissue sarcoma. Adolescent and young adult (AYA) patients (15-21 years of age) experience poorer outcomes compared with younger patients, primarily due to unfavorable histological subtypes, primary location, and tumor size. Tumors that arise from the skull base called parameningeal RMS have a poor prognosis due to anatomical complexity and the risk of leptomeningeal metastasis. OBSERVATIONS:The authors present the case of an 18-year-old female patient with a 4-month history of multiple progressive cranial neuropathies. MRI demonstrated a large left-sided mass centered at the foramen ovale with significant intracranial and infratemporal extension. Following near-total resection, pathology revealed embryonal RMS with anaplastic features. She subsequently began six cycles of high-dose vincristine, actinomycin, and cyclophosphamide therapy and proton radiation therapy. Two weeks after completing radiation therapy, follow-up imaging revealed a recurrence with leptomeningeal metastasis. Despite treatment with vincristine, irinotecan, and temozolomide chemotherapy, and craniospinal irradiation, the patient died of disease 5 months after spinal metastasis diagnosis. LESSONS:Genomic profiling might be considered for early integration as a standard practice in this population in cases of such aggressive and rare malignancies. https://thejns.org/doi/10.3171/CASE24755.

Objectives: Progression of PCNSL remains a challenge with salvage therapies, including the risk of substantial morbidity and mortality. We report patterns of first tumor progression to inform opportunities for improvement. Methods: This is an institutional retrospective review from 2002 to 2021 of 95 consecutive patients with pathologically confirmed PCNSL, of whom 29 experienced progressive disease. Kaplan-Meier method, log-rank test, and Cox proportional hazard models are used to characterize associations of patient, tumor, and treatment variables with LC, PFS, and patterns of first failure. Results: Most patients were below 65 years old (62%) with KPS >70 (64%) and negative CSF cytology (70%). In 70 patients with MRIs, the median tumor volume was 12.6 mL (range: 0.5 to 67.8 mL). After a median follow-up of 11 months, 1-year PFS was 48% and 1-year LC was 80%. Of the 29 patients with progression, 24% were distant only, 17% were distant and local, and 59% were local only. On MVA, LC was associated with age (HR: 1.08/y, P=0.02), KPS (HR: 0.10, P=0.02), completion of >6 cycles of HD-MTX (HR: 0.10, P<0.01), and use of intrathecal chemotherapy (HR: 0.03, P<0.01). On UVA, local only first failure trended to be increased with >14 mL tumors (OR: 5.06, P=0.08) with 1-year LC 83% (<14 mL) versus 64% (>14mL). There were no significant associations with LC and WBRT (P=0.37), Rituximab (P=0.12), or attempted gross total resection (P=0.72). Conclusions: Our findings reaffirm the importance of systemic and intrathecal therapies for local control in PCNSL. However, bulky tumors trend to fail locally, warranting further investigation about the role of local therapies or systemic therapy intensification.

We report a case of a 10-year-old male with a right frontal diffuse pediatric-type high-grade glioma (HGG), H3-wild-type (WT), and IDH-WT, diagnosed at the age of 9 years, who underwent gross total resection, 60 Gy focal proton radiation in 30 fractions to the resection cavity with concurrent temozolomide followed by maintenance chemotherapy with temozolomide and lomustine. One month after completion of maintenance chemotherapy, he developed subcutaneous swelling in the right temporal region and was treated with antibiotics for presumed lymphadenitis.Two months later, he developed a recurrent painless right parietal soft tissue mass that failed to respond to antibiotic therapy.This prompted evaluation by MRI which revealed new enhancing masses in the cerebellum and extracranial soft tissue mass in the right temporal region. He underwent gross total resection of both masses. Pathologic analysis confirmed both masses as recurrent HGG. Molecular markers, however, differed between the 2 sites of recurrence. He proceeded to complete hypofractionated proton therapy at sites of recurrence.Three months later, he was found to have tumor dissemination into the spine and brain for which he received proton therapy to the whole spine and brain. Due to the presence of CDK4 amplification at diagnosis and both sites of tumor recurrence, he then received palliative treatment with the CDK4/6 inhibitor, abemaciclib, for the final 5 months of his life. Since extracranial HGG is a rare presentation, with few cases reported in the pediatric population, we report this case and review previously published literature.

Purpose/Objective(s) To evaluate patterns of care and clinical outcomes among Wilms tumor patients treated with proton beam radiation therapy (PBT). Materials/Methods Eligible patients were children <22 years old with Wilms tumor treated with proton therapy and enrolled on the Pediatric Proton/Photon Consortium registry. Patient demographic, disease, treatment, and outcome data were prospective collected and are reported in descriptive statistics. Results Eighteen patients received proton therapy from September 2012- February 2024 at 11 institutions. Median age at diagnosis was 4.3 years (range 1.2 – 17.3). Patients were most commonly White (n = 12), Non-Hispanic or Latino (N = 11), Male (n = 10), with favorable histology (n = 15) and Stage III (n = 7) or Stage IV (n = 8) disease at diagnosis. Eight patients (44%) were treated for relapsed disease. Patients were treated to the abdomen (n = 12, median dose 19.5 GyRBE (range 10.5-36), thorax (n = 8, median dose 15.8 Gy(RBE) (range = 12-39.6), or other metastases (n = 1, 25.2 GyRBE). Pencil beam scanning was most commonly used (n = 16). Three patients received combination photon-proton radiation, and two required a proton replan during treatment due to moving an extremity position (n = 1) or change in bowel gas pattern (n = 1). All patients completed the full prescribed dose with no recorded delays or breaks in treatment. Median follow-up of 3.1 years (range = 0.3-8.7 years). Among 12 patients with complete follow-up data, 2/6 patients treated for relapse and 1/6 patients treated at initial diagnosis experienced a distant progression at a median time of 21 months (range 4-38 months) from proton therapy. Al last follow-up 11 (83%) patients are alive with no evidence of disease, 1 patient has stable disease, and 1 patient has died of disease. Conclusion his multi-institutional study is the first to report clinical outcomes for pediatric Wilms tumor patients treated with proton therapy. Results demonstrate that proton therapy is feasible and well tolerated for Wilms Tumor abdominal and thoracic targets. Clinical outcomes are as expected for this heterogenous and high-risk population.

Abstract BACKGROUND Brain tumors are the leading cause of pediatric cancer-related death. METHODS We report interim outcome data from an ongoing multi-site phase 2 study (NCT04049669) of indoximod-based chemo-immunotherapy for patients 3-21 years of age with either recurrent brain cancer (ependymoma, medulloblastoma, high-grade glioma) or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Treatment is oral IDO pathway-inhibitor indoximod (38.4 mg/kg/day, divided BID) plus temozolomide (200 mg/m2/day for 5 days) in 28-day cycles. Patients who may benefit from additional irradiation receive indoximod during the radiation regimen and are analyzed separately. RESULTS Planned accrual is 140; 80 patients have been treated to date. Estimated median follow-up time was 23.5 months (range 0.2 - 42.7 months), and indoximod-based therapy has been well tolerated. Estimated median overall survival (OS) was 23.8 months for recurrent ependymoma (n=31); 11.5 months for recurrent medulloblastoma (n=22); 5.7 months for recurrent HGG (n=18, includes diffuse midline glioma except primary DIPG); and 15.0 months for newly diagnosed DIPG (n=9). Single-cell TCR and RNA sequencing of serially collected blood samples was used to identify expanded CD8+ T cell clones with late-effector phenotypes, and their emergence was associated with significantly improved survival. In patients treated with immunotherapy, radiographic measurement of objective response is challenging, owing to the high incidence of mixed responses and pseudoprogression events. In our recently published phase 1 trial of indoximod (NCT02502708, Neuro-Oncology 26:348-361, 2024) we showed that 41% of relapsed patients had MRI evidence of objective response in at least one tumor using RAPNO criteria, and that these “responder” patients had 3-fold better median OS (25.2 months, p=0.007) than non-responders (7.3 months). To date, the phase 2 data is similar. CONCLUSIONS The GCC1949 phase 2 study is replicating the published phase 1 results, and we will present updated results from the first 80 patients in the GCC1949 trial.

Background: The combination of oral pentoxifylline (Ptx) and vitamin E (VitE) has been used to treat radiation-induced fibrosis and soft tissue injury. Here, we review outcomes and perform a radiomic analysis of treatment effects in patients prescribed Ptx + VitE at our institution for the treatment of radiation necrosis (RN). Methods: A total of 48 patients treated with stereotactic radiosurgery (SRS) had evidence of RN and had MRI before and after starting Ptx + VitE. The radiation oncologist’s impression of the imaging in the electronic medical record was used to score response to treatment. Support Vector Machine (SVM) was used to train a model of radiomics features derived from radiation necrosis on pre- and 1st post-treatment T1 post-contrast MRIs that can classify the ultimate response to treatment with Ptx + VitE. Results: A total of 43.8% of patients showed evidence of improvement, 18.8% showed no change, and 25% showed worsening RN upon imaging after starting Ptx + VitE. The median time-to-response assessment was 3.17 months. Nine patients progressed significantly and required Bevacizumab, hyperbaric oxygen therapy, or surgery. Patients who had multiple lesions treated with SRS were less likely to show improvement (p = 0.037). A total of 34 patients were also prescribed dexamethasone, either before (7), with (16), or after starting (11) treatment. The use of dexamethasone was not associated with an improved response to Ptx + VitE (p = 0.471). Three patients stopped treatment due to side effects. Finally, we were able to develop a machine learning (SVM) model of radiomic features derived from pre- and 1st post-treatment MRIs that was able to predict the ultimate treatment response to Ptx + VitE with receiver operating characteristic (ROC) area under curve (AUC) of 0.69. Conclusions: Ptx + VitE appears safe for the treatment of RN, but randomized data are needed to assess efficacy and validate radiomic models, which may assist with prognostication.

Purpose/Objective(s) There are few patient reported outcomes (PROs) data following brain reRT. We hypothesized that the short-term toxicity profile of proton-based brain reRT is modest. Materials/Methods We examined patients with prior brain-directed RT who received overlapping brain reRT with pencil beam proton therapy and completed pretreatment and 3-month post-radiation (postRT) PROs as part of a prospective outcomes registry which included PROMIS Fatigue (PF, a 4-point change is the median estimate of a clinically meaningful difference) and Cognitive (PC) instruments and the MD Anderson Symptom Inventory for Brain Tumors (MDASI-BT). Changes in PRO scores over time were analyzed with a Wilcoxon signed rank test for paired data and Mann-Whitney U test to assess correlations with clinical variables. Results 26 patients were evaluable with a median age of 54 years (20-75). The most common indications for reRT were progressive or recurrent meningioma (n = 10) or glioma (n = 7). None received craniospinal re-RT; 7 received concurrent systemic therapy. The prior overlapping RT was fractionated in 19 and SRS in 9, with 4 having multiple prior courses. For reRT, 19 received conventional fractionation (range = 45 – 60 Gy), 6 moderate hypofractionation (range = 35 – 50 Gy), and 1 proton-based SBRT (30 Gy, 5 fxs). The median nominal cumulative dose was 102 Gy. The median interval from prior RT was 40 months (9-240). There was no statistically significant difference between baseline and 3-month postRT scores for the PF, PC, or mean MDASI-BT Symptom or Interference scores. 11 patients had a 4-point worsening in PF scores at 3 months post-RT: 7 newly entering the moderate severity range and none newly entering severe. For PC, no patient newly reported moderate or worse cognitive impairment at 3 months postRT. Comparing the (baseline, 3-month postRT) median MDASI-BT scores, there was a statistically significant higher (worse) median score for drowsiness (3, 4.5), dry mouth (0, 2), difficulty understanding (1, 2) and appearance (0, 0.5) though the median scores remained low, below a moderate level of severity on the 0-10 MDASI-BT scale. At baseline and 3 months postRT, those with an ECOG performance status (PS) of 1+ (n = 13) reported a statistically significant worse PF and MDASI-BT Interference scores compared to those with a baseline ECOG PS = 0 (n = 12). At 3 months postRT, the four patients requiring steroids reported statistically worse MDASI-BT Interference scores, particularly in relationships and enjoyment of life. Conclusion CNS-directed proton reRT was associated with modest changes in patient reported outcomes with ∼27% reporting a new moderate level of fatigue at 3 months postRT. Those with a worse baseline ECOG PS and those requiring steroids reported a greater detriment on quality of life. These data are helpful in counseling on short term side effects and shared decision making when considering CNS proton reRT.

Primary meningeal melanomatosis is an extremely rare tumor with very few documented responses to treatment. A 3-year-old male with a complex past medical history, including prematurity and shunted hydrocephalus, was diagnosed with primary meningeal melanomatosis with peritoneal implants. Molecular testing revealed an NRAS Q61R mutation. The patient received proton craniospinal radiation followed by immunotherapy with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) IV every 3 weeks and, upon progression, he was switched to a higher dose of nivolumab (3 mg/kg IV every 2 weeks) and binimetinib (24 mg/m2/dose, twice a day). The patient had significant improvement of CNS disease with radiation therapy and initial immunotherapy but progression of extracranial metastatic peritoneal and abdominal disease. Radiation was not administered to the whole abdomen. After two cycles of nivolumab and treatment with the MEK inhibitor binimetinib, he had radiographic and clinical improvement in abdominal metastasis and ascitis. He ultimately died from RSV infection, Klebsiella sepsis, and subdural hemorrhage without evidence of tumor progression. This is the first report of a child with primary meningeal melanomatosis with extracranial metastatic disease with response to a combination of radiation, immunotherapy and MEK inhibitor therapy.

Purpose:To review our initial experience with proton-based SBRT to evaluate the planning outcomes and initial patient tolerance of treatment. Patients and methods:From Sep. 2019 to Dec. 2020, 52 patients were treated with proton SBRT to 62 lesions. Fractionation varied by indication and site with a median of 5 fractions and median fractional dose of 8 Gy. Planning outcomes, including plan heterogeneity, conformity, and PTV volume receiving 100% of the prescription dose (PTV V100%) were evaluated. Acute toxicities were prospectively recorded, and patient reported outcomes were assessed prior to and at completion of treatment using the MD Anderson Symptom Inventory (MDASI) and EQ-5D5L visual analogue score (VAS). Results:All treated patients completed their course of proton-based SBRT. The mean conformity index was 1.05 (range 0.51-1.48). R50% values were comparable to ideal photon parameters. PTV V100% was 89.9% on average (40.44% - 99.76%). 5 patients (10%) required plan modification due to setup or tumor changes. No patients developed a new grade 3 or greater toxicity during treatment. Comparing pretreatment to end of treatment timepoints, there was a significant improvement in the mean VAS (65 to 75, p = 0.014), with no significant change in the mean MDASI symptom (1.7, 1.8; p = 0.79) or interference (2.3, 2.4; p = 0.452) scores. Conclusion:Proton-based SBRT can achieve dosimetric goals required by major clinical photon trials. It was well-tolerated with no decrement in patient reported outcomes and a mean 10-point improvement in VAS at the conclusion of SBRT. Further follow-up is necessary for tumor control and late effects analysis.

Abstract BACKGROUND: Cyclin-dependent kinases 4 and 6 (CDK 4/6) control cell cycle progression through phosphorylation of Rb. Tumor tissue studies in diffuse intrinsic pontine glioma (DIPG) demonstrate frequent alterations in cell cycle regulatory proteins, including CDK 4/6, and infrequent deletions in Rb1. Preclinical DIPG studies have demonstrated prolonged survival when CDK 4/6 inhibition is added to radiation therapy (RT) compared to RT alone. Abemaciclib is a selective and potent, orally bioavailable small molecule CDK 4/6 inhibitor that crosses the blood brain barrier. We conducted a Phase 1 trial to determine the maximum tolerated dose (MTD) of abemaciclib administered concurrently with RT, and to describe the toxicity and pharmacokinetic (PK) profile, in patients with newly diagnosed DIPG. METHODS: Patients 2-25 years of age with newly diagnosed DIPG were eligible. A CDK 4/6 pathway alteration was not required, and patients with known RB1 mutations were excluded. Abemaciclib was administered orally twice daily on days 1-28 of a 28-day cycle. Four dose levels (DLs) were evaluated using a rolling-six design: 75 (DL0), 100 (DL1), 130 (DL2), and 170 (DL3) mg/m2/dose. Abemaciclib started concurrently with RT and was continued as maintenance after completion of RT until the patient experienced progression or unacceptable toxicity. The 6-week duration of RT (54 Gy in 30 fractions) constituted the dose-limiting toxicity (DLT) evaluation period. The PKs of abemaciclib were evaluated at serial timepoints. RESULTS: Median age of the 22 enrolled patients was 7.1 years (range: 2.6 - 20.1). Eleven (50%) patients were biopsied; 10 were histologically defined as H3K27M mutant diffuse midline glioma. In seventeen DLT-evaluable patients, there was 1 DLT during the DLT evaluation period, grade 3 nausea that occurred on DL3. There were 5 DLTs during maintenance: 3 episodes of prolonged grade 3 neutropenia (DL1=1 and DL2=2) and one episode of grade 4 neutropenia (DL0), and grade 3 weight loss (DL3). The predominant abemaciclib-related toxicities were low-grade and hematologic in nature, including leukopenia (80%), lymphopenia (70%), neutropenia (65%), diarrhea (60%), anemia (50%), and nausea (45%). PK analysis demonstrated that abemaciclib exposure increased with increasing dose. The apparent clearance (CL/F) increased with increasing weight/body surface area, and there was extensive variability in exposure across doses and weight ranges. Mean abemaciclib trough concentrations achieved the target associated with preclinical and clinical efficacy (200 ng/mL) at the 130 and 170 mg/m2 dose levels. The median progression-free survival for all patients was 7.5 months (range: 3.0-21.3) and median overall survival was 12.4 months (range: 2.6-29.0); 2 (10%) patients survived > 24 months. CONCLUSIONS: The MTD of abemaciclib administered concurrently with RT to pediatric patients with newly diagnosed DIPG was 170 mg/m2/dose administered orally twice daily on a 28-day cycle. Abemaciclib was well-tolerated with mainly low-grade hematologic toxicity and diarrhea. Citation Format: Thomas Cash, Dolly Aguilera, Zhulin He, Melissa Schink, Amanda Sykes, Celine Pitou, Erin Connelly, Bree Eaton, Natia Esiashvili, Ross Mangum, Margaret E. Macy, Robert C. Castellino, Jason Fangusaro, Tobey J. MacDonald, Cynthia Wetmore, Lindsey Hoffman. A phase 1 study of abemaciclib, a CDK 4/6 inhibitor, with radiation in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B065.

Background. Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy.Methods. We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing.Results. Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7-29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype.Conclusions. Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.

Purpose: We aimed to identify socioeconomic gaps in the administration of adjuvant radiotherapy for patients with atypical meningioma and secondarily to determine differences in survival between patients receiving radiation and those not receiving radiation at 12 and 60 months. Methods: The National Cancer Database was queried for patients receiving atypical meningioma surgery between 2004 and 2019. Statistical analyses were performed to assess the association between receipt of adjuvant radiation and social determinants. Secondarily, KM curves were used to compare overall patient survival between those that received radiation and those that did not. Results: Adjuvant radiation was less likely to be administered to patients over 65 (95% CI =0.53- 22 0.77) and more likely to be administered to males (95% CI =1.07-1.38). Compared to the Southern USA, patients were more likely to receive radiotherapy in the Northeastern (95% CI 24 =1.40–2.05), Midwestern (95% CI =1.06-1.54), and Western parts of the USA (95% 25 CI =1.31-2.00). Patients residing furthest from their facility were less likely to receive radiation (95% CI =0.65-0.98). Insured patients were more likely to receive radiation (p = 0.048) than uninsured patients. On multivariate analysis, no differences were found between racial groups regarding adjuvant radiation. For patients unstratified, radiation was shown to improve survival at 12 and 60 months. Conclusion: Disparities exist in the administration of adjuvant radiotherapy for atypical meningioma. Patients over 65, women, those residing in the southern USA, those living further from their facilities and uninsured patients are less likely to receive radiation than their counterparts.