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Background Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) often progresses despite multiple therapies. Identifying clinical and molecular characteristics of progressive tumors may aid in prognostication and treatment. Methods We collected 72 unresectable, non-neurofibromatosis type 1-associated hypothalamic/optic pathway PA to identify clinical and biologic factors associated with tumor progression. Tumors that progressed after therapy, metastasized, or resulted in death were categorized into Cohort B; those that did not meet these criteria were categorized into Cohort A. DNA methylation and transcriptome analyses were performed on treatment-naïve tumors, and the findings were validated by immunohistochemistry (IHC). Results The median follow-up of the entire cohort was 12.3 years. Cohort B was associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs 6.7 years, P = .005), and high incidence of KIAA1549-BRAF fusion (81.5% vs 38.5%, P = .0032). Cohort B demonstrated decreased CpG methylation and increased RNA expression in mitochondrial genes and genes downstream of E2F and NKX2.3. Transcriptome analysis identified transcription factor TBX3 and protein kinase PIM1 as common downstream targets of E2F and NKX2.3. IHC confirmed increased expression of TBX3 and PIM1 in Cohort B tumors. Gene enrichment analysis identified enrichment of MYC targets and MAPK, PI3K/AKT/mTOR, and p53 pathways, as well as pathways related to mitochondrial function. Conclusions We identified risk factors associated with progressive PA. Our results support the model in which the p53-PIM1-MYC axis and TBX3 act alongside MAPK and PI3K/AKT/mTOR pathways to promote tumor progression, highlighting potential new targets for combination therapy and refining disease prognostication.

Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) can be challenging to manage due to repeated progressions despite multiple lines of therapy. To identify clinical and biologic factors associated with tumor progression, we retrospectively identified 72 unresectable non-NF1-associated hypothalamic/optic pathway PA. Tumors were classified as high-risk (50%) if they progressed after three or more lines of chemotherapy/targeted therapy, progressed after radiation, developed metastatic disease, or died of disease. DNA methylation profiling and transcriptome analysis (RNA sequencing) were performed on treatment-naïve tumors with available tissue (n=40), and the findings were validated by immunohistochemistry (IHC) on additional tumor tissue. The median follow-up of the entire cohort was 12.3 years. High-risk tumors were associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs. 6.7 years, P = 0.005), and high incidence of KIAA1549-BRAF fusion (81.5% vs. 38.5%, P = 0.0032). High-risk tumors demonstrated decreased CpG methylation and increased RNA expression in many mitochondrial genes and genes downstream of E2F and NKX2.3 transcription factors. Transcriptome analysis identified transcription factor TBX3 and proto-oncogene serine/threonine protein kinase PIM1 as common downstream targets of both E2F and NKX2.3 and potential drivers of tumor progression. IHC confirmed increased expression of TBX3 and PIM1 in high-risk tumors. PIM1 is known to increase the stability and transcriptional activity of MYC, and gene enrichment analysis identified enrichment of MYC targets. Signaling pathways known to be implicated in PA, such as MAPK and PI3K/AKT/mTOR, were also enriched, in addition to pathways related to mitochondrial biogenesis and oxidative phosphorylation. Our results support the model in which the p53-PIM1-MYC axis and TBX3 act alongside MAPK and PI3K/AKT/mTOR pathways to promote tumor progression, highlighting potential new targets for combination therapy and refining disease prognosis.

Background Management of unresectable pediatric low-grade glioma and glioneuronal tumor (LGG/LGGNT) is controversial. There are no validated prognostic features to guide use of radiation therapy (RT). Our study aimed to identify negative prognostic features in patients treated with RT using clinicopathologic and molecular data and validate these findings in an external dataset. Methods Children with non-metastatic, biopsy-proven unresectable LGG/LGGNT treated with RT at a single institution between 1997 and 2017 were identified. Recursive partitioning analysis (RPA) was used to stratify patients into low- and high-risk prognostic groups based on overall survival (OS). CNS9702 data were used for validation. Results One hundred and fifty patients met inclusion criteria. Median follow-up was 11.4 years. RPA yielded low- and high-risk groups with 10-year OS of 95.6% versus 76.4% (95% CI: 88.7%–98.4% vs 59.3%–87.1%, P = 0.003), respectively. These risk groups were validated using CNS9702 dataset (n = 48) (4-year OS: low-risk vs high-risk: 100% vs 64%, P < 0.001). High-risk tumors included diffuse astrocytoma or location within thalamus/midbrain. Low-risk tumors included pilocytic astrocytoma/ganglioglioma located outside of the thalamus/midbrain. In the subgroup with known BRAF status (n = 49), risk stratification remained prognostic independently of BRAF alteration (V600E or fusion). Within the high-risk group, delayed RT, defined as RT after at least one line of chemotherapy, was associated with a further decrement in overall survival (P = 0.021). Conclusion A high-risk subgroup of patients, defined by diffuse astrocytoma histology or midbrain/thalamus tumor location, have suboptimal long-term survival and might benefit from timely use of RT. These results require validation.

Background Hippocampal avoidance has been suggested as a strategy to reduce short-term memory decline in adults receiving whole-brain radiation therapy (RT). The purpose of this study was to determine whether the hippocampal dose in children and adolescents undergoing RT for low-grade glioma was associated with memory, as measured by verbal recall. Methods Eighty patients aged at least 6 years but less than 21 years with low-grade glioma were treated with RT to 54 Gy on a phase II protocol. Patients underwent age-appropriate cognitive testing at baseline, 6 months posttreatment, yearly through 5 years posttreatment, year 7 or 8, and year 10 posttreatment. Random coefficient models were used to estimate the longitudinal trends in cognitive assessment scores. Results Median neurocognitive follow-up was 9.8 years. There was a significant decline in short-delay recall (slope = −0.01 standard deviation [SD]/year, P < 0.001), total recall (slope = −0.09 SD/y, P = 0.005), and long-delay recall (slope = −0.01 SD/y, P = 0.002). On multivariate regression, after accounting for hydrocephalus, decline in short-delay recall was associated with the volume of right (slope = −0.001 SD/y, P = 0.019) or left hippocampus (slope = −0.001 SD/y, P = 0.025) receiving 40 Gy (V40 Gy). On univariate regression, decline in total recall was only associated with right hippocampal dosimetry (V40 Gy slope = −0.002, P = 0.025). In children Conclusion In this 10-year longitudinal study, greater hippocampal dose was associated with a greater decline in delayed recall. Such findings might be informative for radiation therapy planning, warranting prospective evaluation.

BACKGROUND: The objective of this study was to evaluate the contribution of radiation dose to different intracranial structures on changes in intellectual function for children with brain tumors. METHODS: We evaluated children with brain tumors treated in 2005–2017 who had longitudinal neuropsychological assessments and available photon dosimetric data (if radiation therapy [RT] given). Full Scale Intelligence Quotient (FSIQ) and index scores were evaluated (perceptual reasoning index [PRI], processing speed index [PSI], verbal comprehension index [VCI], and working memory index [WMI]). Multivariable linear mixed effects models were used to model endpoints, with age at RT and dose to different brain regions as fixed effects and patient-specific random intercepts. P-values (P*) were adjusted for multiple comparisons. RESULTS: Sixty-nine patients were included, 56 of whom received RT. Median neuropsychological follow-up was 3.2 years. Right temporal lobe mean dose was strongly associated with decline in FSIQ (P* = 0.005); with each gray increase in mean dose, there was a decrease of 0.052 FSIQ points per year. Dose to 50% (D50) of the supratentorial brain was associated with decline in PSI (P* = 0.006) and WMI (P* = 0.001). Right and left hippocampus D50 were individually strongly associated with declines in VCI (P* = 0.009 for each). Presence of a ventriculoperitoneal shunt decreased FSIQ by 10 points. CONCLUSIONS: We reported associations between dosimetry to specific brain regions and intellectual outcomes, with suggested avoidance structures during RT planning. These models can help clinicians anticipate changes in neurocognition post-RT and guide selection of an optimal RT plan.

Tectal glioma (TG) is an uncommon pediatric low-grade tumor with limited data on long-term outcome. A retrospective review of TG diagnosed in patients ≤ 21 years at our center between 1986 and 2013 identified 19 patients (males=13; median age at diagnosis=10 years [yrs]; range, 0.01-19.99). All patients were diagnosed based on MRI. Initial CSF diversion was necessary in 16 patients (ventriculoperitoneal [VP] shunt= 10; endoscopic third ventriculostomy=6). Ommaya reservoir was inserted in 5 patients. VP shunt revisions (1-12 times) were required in 7 patients; while 2 patients had subdural hematoma due to over-shunting. Biopsy or resection was performed in 7 patients (upfront=5, at progression=2), with histology showing pilocytic astrocytoma (n=6) or low-grade glioma, NOS (n=1). Duplication of chromosome 7q34, marker of KIAA1549-BRAF fusion, was detected in 2 of 4 patients tested. Adjuvant therapy was delivered in 8 patients mostly upon progression, and included focal radiation (n=4), systemic therapy (n=3), or a combination (n=1). The median duration of follow-up was 9.57 yrs (range, 3.64-16.98): 7 experienced progression at median of 0.68 yrs (range, 0.28-8.98), including 2 with metastases. One patient each died due to suicide, obstructive hydrocephalus, and suspected shunt malfunction. Respective 5- and 10yr overall-survival were 92.9 ± 6.9% and 85.1 ± 9.7%. Long-term morbidities included persistent headache (n=8) and visual symptoms (n=7). Significant impairments were seen on measures of intelligence (n=2/9; 22%), working memory (n=2/7; 29%), and processing speed (n=6/6; 100%). Long-term survival of children with TG is satisfactory. Regular follow-up is recommended due to risks of shunt failure, progression, and long-term morbidities.

PURPOSE: Pediatric low-grade glioma (PLGG) represents a heterogeneous group of tumors. The purpose of this study was to identify clinical prognostic factors for overall-survival (OS) in PLGG treated with radiation therapy (RT). METHODS: Between 1986 and 2017, 174 patients with non-metastatic, biopsy-proven PLGG were consecutively treated with RT at a single institution. OS was estimated using Kaplan-Meier methods. Prognostic factors were identified using Cox proportional hazards. Recursive partitioning analysis (RPA) was used to stratify patients into high and low-risk prognostic groups. RESULTS: Median follow-up was 11.3 years. Median age was 8.3 years. Common subtypes included: pilocytic astrocytoma (67%), astrocytoma not otherwise specified (12%), and diffuse astrocytoma (DA) (10%). Most were located in the optic pathway/hypothalamus (37%) or thalamus/midbrain (24%). Median tumor dimension was 2.8 cm. On multivariate analysis, tumor size (cm) (Hazard ratio [HR]: 1.81, 95% CI: 1.38-2.37, p4.6 cm or thalamic/midbrain or DA) with 10-year OS of 97% vs. 78% (95% CI: 91%-99% vs. 64%-86%, p

Low-grade glioma (LGG) diagnosed during infancy is associated with unique clinical profile and challenges in management. Morbidities in long-term survivors are not well described. We retrospectively reviewed patients with LGG diagnosed before 12 months of age managed at St. Jude Children’s Research Hospital from 1986-2013. Altogether, 51 patients were identified, 31 were males, 7 had neurofibromatosis. Primary tumor locations were hypothalamic/optic pathway (n=31), cerebral (n=6), brainstem (n=6), cerebellar (n=4), and spinal (n=4); 12 patients experienced metastasis. At diagnosis, 41 patients required active intervention: surgical resection (n=23; 5 with adjuvant chemotherapy), chemotherapy (n=16), radiation (n=1), or chemotherapy and radiation (n=1). Throughout the course of disease, 39/51 patients required chemotherapy (median number of regimens: 2; range, 1-13); 21 required radiation (focal=19; CSI=2); and 41 received tumor-directed surgeries (median number of operations: 2; range, 1-6). Twenty-nine patients had grade I tumors; 6 had grade II tumors, and 6 had tumors that could not be definitively graded. CSF diversion was performed in 31 patients. The mean duration of follow-up was 11.5y (range, 0.16-29.19y). Thirty-five patients experienced progression (median progressions: 2; range, 1-18), and 9 patients died (progression=3, malignant transformation=3, shunt infection=1, leukemia=1, unknown=1). The respective 5-year, 10-year, and 20-year overall-survival rates were 91.6 ± 4%, 86.4 ± 5.2%, and 71.9 ± 8.8%. Adverse health issues were documented in 49/51 patients; common morbidities included hearing impairment (n=15), visual impairment (n=31), neurocognitive deficit (n=31), hemiplegia/paraplegia (n=19), endocrinopathy (n=31), and cerebrovascular disease (n=15). LGG diagnosed during infancy was almost universally associated with long-term morbidities and survivors should be prioritized for multi-disciplinary surveillance.