Optic Pathway Gliomas Research Articles

NCOG-05. HEALTH-RELATED QUALITY OF LIFE (HRQOL) IN THE PHASE 2 FIREFLY-1 (PNOC026) TRIAL OF THE TYPE II RAF INHIBITOR TOVORAFENIB IN RELAPSED/REFRACTORY (R/R) PEDIATRIC LOW-GRADE GLIOMA (PLGG)

Abstract BACKGROUND Despite favorable long-term survival, ongoing disease and treatment-related morbidity substantially impact the HRQOL of patients with pLGG. Tovorafenib is a selective, CNS-penetrant, type II RAF inhibitor. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) showed clinically meaningful responses and a manageable safety profile in pLGG. Vision remained stable or improved in 89% of evaluable patients with optic pathway gliomas (Nysom K, et al. Neuro-Oncol. 2023). METHODS FIREFLY-1 arm 1 patients 6 months–25 years of age with RAF-altered r/r pLGG received tovorafenib 420 mg/m2 weekly (600 mg max) in 28-day cycles. Exploratory measures included longitudinal assessment of PedsQL in patients ≥2 years of age. PedsQL 3.0 Cancer Module child self-reports Total Score and 8 subscales were used to assess HRQOL from 0 (worst)–100 (fewer problems/symptoms) (as of December 22, 2022) baseline (BL) to cycle 13 (C13) in patients ≥5 years of age. RESULTS For the PedsQL 3.0 Cancer Module, 51 completed self-reports at BL, and 32 at C13 due to continued attrition over time. Median Total Score was 81.5 (range: 46.3-100) at BL and 85.2 (range: 50-100) at C13. At C4, 16% worsened (decrease >10 points) and 11% improved (increase >10 points); by C13, 11% worsened and 33% improved. For Cognitive Problems, patients scored a median of 75 (range: 5-100) at BL and 85 (range: 20-100) at C13, with 11% and 26% improved at C4 and C13, respectively. A similar trend was seen with Nausea. Pain and Hurt remained even throughout (median: 87.5). Treatment Anxiety was not a major concern (median: 100, C1-C13); Procedural Anxiety improved over time (median: 58.3 BL; 79.2 at C13). CONCLUSIONS HRQOL generally remained stable, or improved, in the majority of patients with r/r pLGG during the first year of treatment with tovorafenib.

CNSC-07. OLIGODENDROGLIAL IMPAIRMENT IN WHITE MATTER TRACTS FOLLOWING NEUROFIBROMATOSIS TYPE 1 (NF1) GERMLINE MUTATION OR CARBOPLATIN TREATMENT

Abstract Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome due to mutations in the NF1 gene. The disease affects 1 in 2500-3000 people worldwide and patients are predisposed to neoplasms such as optic pathway glioma, plexiform neurofibroma. In addition, NF1 patients often experience neurological issues such as learning difficulties. Unfortunately, there is no cure for NF1 yet. Chemotherapy (e.g., carboplatin) remains the first-line treatment for NF1-associated low-grade glioma; while effective in reducing tumor burden, it does not reliably restore neuronal function. In this study, we sought to determine how chemotherapy and Nf1 germline mutations influence neurological function, using genetically engineered mice of NF1. Nf1-heterozygous mice received carboplatin (60 mg/kg/day) or vehicle every other day for one week. Their optic nerves were collected and processed for immunofluorescence and transmission electron microscopy (EM). We found that carboplatin treatment reduces the density of oligodendrocytes in Nf1-heterozygous mice and impairs myelination. Moreover, a similar effect of carboplatin was observed in wild-type mice, suggesting that carboplatin impairs oligodendroglia independent of the NF1 status and the effect of carboplatin should also be evaluated in the non-NF1 context. In another set of experiments, we sought to understand how germline Nf1 mutations influences oligodendroglia. Whereas we did not observe a difference in optic nerve oligodendrocyte density in mice with an engineered mutation targeting the GTPase-activating protein-related domain (GRD) domain of the Nf1 gene, a reduction of oligodendrocyte density was observed in mice harboring a patient-derived mutation (R1809C), which localizes outside of the GRD. A similar effect was observed in the corpus callosum of Nf1+/R1809C mice together with myelin impairment, suggesting a RAS-independent mechanism of Nf1 regulation of oligodendrocytes. Together, these findings indicate that both Nf1 germline mutations and chemotherapy could contribute to oligodendrocyte and myelin deficits in white matter tracts.

OPTIC PATHWAY GLIOMAS AFTER TRANSITIONING INTO ADULTHOOD – AN INSTITUTIONAL EXPERIENCE

Abstract AIMS Optic pathway gliomas (OPG) are rare tumors affecting the optic nerve and the chiasm that occur predominantly during childhood and are generally managed by pediatric neurosurgeons/ pediatric oncologists. Prognosis is quite good for these benign tumors, and many patients survive into adulthood. While clinical care for these patients in childhood is well-standardized, the clinical course of patients with OPG after transitioning into adulthood is not well studied.We herein aimed to characterize patients with OPG diagnosed in childhood after transitioning into adult neurosurgical care in order in order to ellucidate the clinical course of OPG in adulthood and to identify potential problems with clinical care of these special patients in adult neurosurgery or neuro-oncology services. METHOD Clinical and radiographical data from adult patients (> 16 years of age) with OPG diagnosed in childhood and treated in our institution were collected from patient charts. Descriptive statistics and outcome analysis were performed using commercial statistical software. RESULTS Of 124 patients with OPG diagnosed in childhood, 35 patients transitioned into adulthood. The population included equal distribution of male (18, 51.4%) vs female (17, 48.6%) patients. Median age at diagnosis was 8.0 years (range 0.5 – 15.0) and median age at last follow up was 20.8 years (range 17.1 – 38.6). 12 patients were positive for NF (34.3%). 9 patients had undergone surgery for the OPG (25.7%), 11 had chemotherapy (31.4%) and 15 (42.8%) had received radiotherapy. 8 patients showed an endocrine deficiency (22.9%), 4 hypothalamic dysfunction (11.4%) and 8 cognitive/behavioral difficulties (22.9%). Visual acuity impairment was detected in 12 patients (34.3%). 9 patients experienced recurrence (25.7%). CONCLUSION Patients with OPG transition into adulthood frequently and experience a wide range of clinical problems. Close neurosurgical/neuro-oncology specialist follow-up is recommendable.

LGGL-03 TREATMENT OUTCOMES ON OPTIC GLIOMA: A CASE STUDY

Abstract 11 year old male presented in December 2021 with complaints of headache and visual impairment. On examination [he had] multiple freckles in the right axilla and cafe au lait lesions all over his body with largest being 3cm in the inguinal region. Pretreatment MRI showed minimally enhancing mass seen in the optic chiasm extending anteriorly into the distal optic nerves bilaterally and the optic tract posteriorly with extensive vasogenic edema along the optic pathway into the lateral thalamus and extending into the bilateral lentiform nuclei. H-MR spectroscopy of the mass demonstrated a choline peak. Findings in keeping with optic pathway glioma. The baseline fundoscopy showed a normal anterior segment, slightly pale disc on the posterior segment. The patient was commenced on weekly Vinblastine via chemo port. At 24 weeks of treatment patient was assessed MRI and fundoscopy. MRI showed a mild interval decrease in size of lobulated mass lesion involving the optic chiasma, bilateral optic nerves up to intraorbital segments and optic tracts. The lesion also involves the infundibular stalk and tuber cinereum. No interval change in hyperintense T2/FLAIR signal with no enhancement seen at the lateral geniculate bodies, hippocampi, bilateral lentiform nuclei and lateral thalami. He completed 72 weeks of Vinblastine with good clinical Response. NF 1 can cause tumors to form and optic nerve gliomas that may occur in about 15 percent of children with this disease in about 2/3 of the time the tumors stop growing and disappears however there are some tumors that may require treatment.

Clinical and MRI findings in patients with pediatric optic pathway glioma presenting with initial leptomeningeal dissemination

AIMAlthough leptomeningeal dissemination (LMD) is a hallmark of malignant brain tumors, optic pathway glioma (OPG) of various grades can initially present with LMD, which is thenceforth interpreted as an aggressive tumor. In this study, we aimed to evaluate the clinical and imaging findings of pediatric OPG (POPG) patients who presented with initial LMD to ensure a prompt diagnosis and better outcomes. MATERIALS AND METHODSBetween 2000 and 2022, 35 pediatric patients with pathologically proven OPG who presented with and without LMD at our institute were retrospectively reviewed. We compared the demographic and histopathology characteristics, MRI features, and clinical outcomes of the initial LMD group and the non-LMD group. RESULTSCompared with those in the non-LMD group (n=27), POPGs in the LMD group (n=8) were more symmetrically midline-positioned (75% versus 22.2%, p=0.006) and had more ill-defined tumor borders (25% versus 0%, p=0.007), and patients were more likely to develop hydrocephalus (100% versus 63%, p=0.042). There was no significant difference regarding the histopathology (p=0.686) and outcome of tumor recurrence/progression (p=0.341). However, the mortality rate was higher in the LMD group than in the non-LMD group (62.5% versus 18.5%, p=0.016). CONCLUSIONSFeatures of a more symmetrical midline-positioned POPG with indistinct tumor borders and hydrocephalus are risk factors for initial LMD regardless of histopathology. Compared with those without initial LMD, patients with POPG with initial LMD had poorer outcomes, which may suggest the need for a more aggressive treatment protocol.

Optic pathway gliomas in children: Clinical characteristics, treatment, and outcome of 95 patients in a single center over a 31-year period. Can we avoid radiotherapy?

Optic pathway gliomas (OPG) are rare tumors in children. Lesion extent, visual functions, neurofibromatosis 1 (NF1), and age are factors that guide treatment. This study evaluates the clinical characteristics, treatment, and outcome of children and adolescents with OPG treated over a 31-year period in a single center. Ninety-five patients with OPG diagnosed between January 1990 and December 2021 were retrospectively evaluated. First-line chemotherapy regimen consisted of vincristine and carboplatinum for 1year. Radiotherapy was not used as first-line treatment and tried to be avoided in the ones who progressed after first-line treatment. Ninety-five children (44 male, 51 female) with a median age of 52 (1-216) months were evaluated. Sixty-three (66.3%) had NF1 and 10 (10,5%) diencephalic syndrome. The most common presenting symptoms were visual abnormalities and/or proptosis, nistagmus, and behavioral changes. Twenty-one (22.1%) patients with NF1 had stable disease throughout the follow-up period and received no treatment. Sixty-three of 74 patients received treatment at diagnosis and 11 due to progression during follow-up. Only one adolescent received radiotherapy at progression. Patients who progressed, received further line systemic treatment (vinblastine; bevacizumab; vincristine-cisplatinum-etoposide). Ten-year overall survival in all patients, in patients with NF1, and without NF1 were 97.2%, 98%, and 95.8% (p>.05), respectively; 10-year progression-free survival (PFS) in all patients, in patients with NF1, and without NF1 were 71.6%, 85.7%, and 54.2% (p=.001), respectively. In children with symptomatic/progressive OPG, chemotherapy consisting of vincristine-carboplatinum (VC) is effective. Radiotherapy may be avoided, especially in patients with NF1.

Neurofibromatosis type 1: short review and clinical case

Neurofibromatosis type 1 (NF1) is acommon (1/3000) autosomal dominant disorder associated with amutation in the NF1 gene, located on the long arm of chromosome 17 (17q11.2). NF1 is diagnosed using well-known clinical criteria: café au lait spots, axillary and inguinal freckles, cutaneous and subcutaneous neurofibromas, optic pathway gliomas, and specific bone abnormalities. The pathognomonic feature of the disease is plexiform neurofibroma (PN), which is abenign peripheral nerve sheath tumor that occurs in 30-50% of patients with NF1. In addition to awide range of clinical manifestations, such as pain, motor, respiratory disorders, neurological deficits, cosmetic defects, etc., there is about a15% risk for the development of malignant peripheral nerve sheath tumors (MPNST). And it should be noted that the treatment of PN is acomplex task that does not have one standard solution. Thus, surgical treatment, which was the “gold standard” and remains one of the main methods of therapy, carries significant risks, such as postoperative neurological deficit, ahigh risk of intraoperative bleeding and is accompanied by ahigh percentage of relapses. Therefore, the emergence of targeted therapy and its use in the Russian Federation since 2021 has made asignificant contribution to the treatment of symptomatic inoperable plexiform neurofibromas.

Visual deterioration outcomes following optic pathway glioma treatment: a 12-year single institution retrospective study.

The surgical treatment of optic pathway gliomas (OPG) remains controversial, with visual outcomes often unpredictable. The present study explored surgical and clinical factors influencing visual acuity (VA) after OPG treatment and developed anatomical subtypes correlated with clinical symptoms. Children with OPG who underwent initial partial tumor resection at Beijing Tiantan Hospital from January 2011 to December 2022 were retrospectively analyzed. Multivariate logistic regression and random forest analyses were performed to identify risk factors for post-treatment VA deterioration and a decision tree model was created based on significant factors. A total of 140 patients were enrolled. Multivariate logistic regression analysis identified surgical approach and initial VA as independent predictors of post-treatment VA deterioration (P < 0.05). Surgical approach, initial VA, and extent of tumor resection were the most significant factors for risk assessment and were included in the decision tree model, with surgical approach as the most important "root" node. The model demonstrated good predictive performance, with area under the curve values of 0.75 and 0.66 for the training and test datasets, respectively. A simple anatomical classification was developed, which revealed clinical characteristic differences among OPG types. Meanwhile, a correlation analysis of post-treatment visual deterioration was performed for each of the three anatomical types. This study offers a predictive model for visual outcomes following initial tumor-reduction surgery in OPG patients, which may help in visual outcomes risk stratification. Additionally, the anatomical classification effectively indicates OPG growth direction, offering potential insights into clinical symptoms.

Longitudinal changes in retinal ganglion cell function in optic pathway glioma evaluated by photopic negative response

Photopic negative response (PhNR), an index of retinal ganglion cell (RGC) function, is impaired in patients with optic pathway gliomas (OPGs). The aim of this longitudinal study was to evaluate whether PhNR deteriorates over time in OPG patients. Fourteen pediatric patients affected by OPG (4 males and 10 females, mean age 12.4 ± 5.7 years, 8 with neurofibromatosis type 1 [NF1]) with ≥12 months of follow-up and ≥2 evaluations, were included in this retrospective study. All patients had received chemotherapy, with or without OPG surgical resection, at least 5 years prior to the study. At baseline, all patients underwent a complete ophthalmological examination. Follow-up included clinical examination and PhNR measurement as well as brain MRI (according to pediatric oncologist indications) every 6 or 12 months. Mean follow-up duration was 16.7 ± 7.5 months (range 12–36 months). Photopic electroretinograms were elicited by 2.0 cd-s/m2 Ganzfeld white flashes presented on a steady 20 cd/m2 white background. The PhNR amplitude was measured as the difference between baseline and the maximal negative amplitude (minimum) of the negative wave, following the photopic b-wave. Compared to baseline, mean PhNR amplitude was significantly decreased at the end of follow-up (p = 0.008). NF1-related OPGs exhibited a decline in PhNR amplitude (p = 0.005) and an increase in PhNR peak-time during the follow-up (p = 0.013), whereas sporadic OPGs showed no significant changes. Tumor size remained stable in all patients on MRI. PhNR amplitude decreased over the observation period, suggesting progressive RGC dysfunction in NF1-related pediatric OPGs, despite stable size on MRI imaging. PhNR could serve as a non-invasive objective tool for assessing longitudinal changes in RGC function in the clinical management of childhood OPG.

Analysis of visual evoked potentials in patients with neurofibromatosis type 1: new concepts.

Neurofibromatosis type 1 (NF type 1) is an autosomal dominant disease with typical clinical manifestations, such as skin lesions, Lisch nodules, optic pathway gliomas, and neurofibromas, caused by the mutation of the NF1 gene. Visual evoked potentials (VEP) present a measure of the electrophysiological response of visual cortex to a visual stimulus. The role of VEP in the pathophysiology of NF type 1 is very complex and requires additional research. We examined the differences between NF type 1 patients with normal and altered VEP and analyzed the correlation between the prolongation of P100 latency and disease severity. Two groups were formed: a control group and a study group with NF type 1 patients. Based on the control group analysis, a threshold value for a normal VEP finding of 116 ms was obtained, and it was used to divide the study group into subgroups with normal and altered VEP. We proceeded with examining the differences in clinical manifestations of the disease between the subgroups, after which we checked if there is a correlation between the prolongation of the P100 latency and the severity of the clinical picture according to the Riccardi scale. Statistical analysis was performed using the Pearson chi-square test and the Spearman correlation test in the program SPSS 28.0, with levels of statistical significance p = 0.05 and p = 0.001. In the group with the abnormal VEP we found a statistically significant more frequent occurrence of optic tract glioma (p = 0.008), tumors (p = 0.032), epilepsy (p = 0.043), and cognitive disorders (p = 0.028), while the other clinical signs had an equal prevalence in both groups. A moderately strong correlation (r s = 0.665) was observed between the prolongation of P100 latency and the severity of the clinical picture. Our results showed the important role of VEP in the description of clinical phenotypes of NF type 1. The authors of the study propose VEP to be included in the diagnostic algorithms designed for patients with NF type 1.

Maternal obesogenic diet operates at the tumor cell of origin to increase incidence and decrease latency of Neurofibromatosis Type 1 optic pathway glioma.

Pediatric low-grade glioma incidence has been rising in the U.S., mirroring the rising rates of pediatric and maternal obesity. Recently, children of obese mothers were demonstrated to develop brain tumors at higher rates. Importantly, obesity in the U.S. is largely driven by diet, given the prevalence of high fat and high sugar (HFHS) food choices. Since high-fat diet exposure can increase embryonic neuroglial progenitor cell (NPC) proliferation, the potential cells of origin for low-grade glioma, we hypothesized that in utero exposure to an obesogenic diet would modify pediatric brain penetrance and latency by affecting the tumor cell of origin. We employed several murine models of the Neurofibromatosis type 1 (NF1) pediatric brain tumor predisposition syndrome, in which optic pathway gliomas (Nf1-OPGs) arise from NPCs in the embryonic third ventricular zone (TVZ). We exposed dams and offspring to an obesogenic HFHS diet or control chow and analysed fetal neurodevelopment at E19.5 and tumor formation at 6w-3mo. Progeny from HFHS diet-exposed dams demonstrated increased TVZ NPC proliferation and glial differentiation. Dietary switch cohorts confirmed that these effects were dependent upon maternal diet, rather than maternal weight. Obesogenic diet (Ob) similarly accelerated glioma formation in a high-penetrance Nf1-OPG strain and increased glioma penetrance in two low-penetrance Nf1-OPG strains. In contrast, Ob exposure in the postnatal period alone did not recapitulate these effects. These findings establish maternal obesogenic diet as a risk factor for murine Nf1-OPG formation, acting in part through in utero effects on the tumor cell of origin.

Genotype-Phenotype Correlation in Neurofibromatosis Type 1: Evidence for a Mild Phenotype Associated with Splicing Variants Leading to In-Frame Skipping of NF1 Exon 24 [19a

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by loss-of-function variants in the NF1 gene. As of 20 November 2023, over 5000 distinct pathogenic or likely pathogenic variants have been reported in public databases. However, only a few NF1 genotype-phenotype correlations have been established so far. In this study, we present findings on 40 individuals with NF1, comprising 26 unrelated probands and 14 affected relatives, who carry one of nine NF1 heterozygous pathogenic splicing variants, all of which result in the in-frame skipping of exon 24 [19a] (NM_000267.3:r.3114_3197del, p.Asn1039_Arg1066del). These variants include c.3114-2A>G, c.3114-1G>A, c.3196A>G, c.3197G>A, c.3197G>T, c.3197+1G>A, c.3197+1G>T, c.3197+2T>C, and c.3197+3A>T. Among individuals with these variants, none exhibit externally visible plexiform neurofibromas, histopathologically confirmed cutaneous or subcutaneous neurofibromas, symptomatic spinal neurofibromas, or symptomatic optic pathway gliomas. The most prevalent, and sometimes sole, clinical feature observed in this cohort is multiple café-au-lait macules, with or without skinfold freckles: 85% and 60.5% of the individuals display six or more café-au-lait macules and freckles, respectively. In comparison to established NF1 genotype-phenotype correlations, these patients demonstrate highly similar clinical presentations to those associated with the NF1 pathogenic variant c.2970_2972del (p.Met992del), known for resulting in the mildest clinical features. Despite the generally mild phenotype, cognitive impairment, developmental delay, and/or learning difficulties are still observed in 33.3% of these patients, suggesting that learning challenges remain a prominent aspect of the phenotypic presentation in these individuals and necessitate specialized care. This newly established genotype-phenotype correlation will assist clinicians in improving the management of patients harboring NF1 exon 24 [19a] skipping variants and provide a new therapeutic target for NF1 treatment.

NFS-17. CORRELATIONS BETWEEN OPTICAL COHERENCE TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING IN NEUROFIBROMATOSIS TYPE 1 – RELATED OPTIC PATHWAY GLIOMAS

Abstract BACKGROUND Optic pathway glioma (OPG) is a prevalent tumor affecting children with Neurofibromatosis type 1 (NF1), representing a diagnostic hallmark. OPGs, typically WHO grade 1 pilocytic astrocytomas, are characterized by an indolent course. Diagnosis and surveillance traditionally rely on Magnetic Resonance Imaging (MRI). Routine NF1 pediatric surveillance includes annual eye examinations, encompassing visual acuity (VA) and Optical Coherence Tomography (OCT), with MRI reserved for ophthalmological abnormalities. However, the precise correlation between altered OCT findings and OPG presence or size remains unclear, while the role of MRI in screening is contentious due to cost and anesthesia requirements. METHODS In this retrospective study, we sought to establish correlations between OCT changes and MRI-observed tumor volume in NF1-diagnosed children at a tertiary center. Clinical and ophthalmological data, including VA, fundoscopy, and OCT, were collected. Tumor volumes were assessed using the software Sophia DDMTM for Radiomics in two consecutive MRI scans in a randomly selected cohort of 50 untreated patients. RESULTS Among 409 NF1 patients, 132 (31%) were diagnosed with OPG (48% females = 64), revealing a significant association with plexiform neurofibroma (pNF) (p=0.03), thus indicating an elevated risk of concurrent tumor development. In the subcohort of patients in whom volumetric analysis was performed, the mean age at OPG diagnosis was 5.56 ± 3.59 years. While tumor volume on MRI correlated with VA (p=0.0007), OCT values did not: larger OPGs did not consistently result in thinner retinal nerve fiber layers, suggesting independence between OCT alterations and OPG size. CONCLUSIONS The observed lack of correlation among VA, retinal thickness (OCT), and tumor volume (MRI) underscores the importance of MRI as the gold standard for diagnosis. The strong association between pNFs and OPGs suggests considering whole-body MRI when an OPG is detected, facilitating comprehensive evaluation in NF1 patients.

LMIC-07. OUTCOMES OF NEUROFIBROMATOSIS TYPE 1-ASSOCIATED OPTIC PATHWAY GLIOMAS AT A SINGLE TERTIARY PEDIATRIC ONCOLOGY CENTER IN EGYPT: BORG EL ARAB UNIVERSITY HOSPITAL (BAUH) EXPERIENCE

Abstract BACKGROUND Neurofibromatosis type 1 (NF-1) is a multisystem disease inherited in an autosomal dominant fashion. About 15% of the pediatric cases have associated brain tumors, among which the optic pathway gliomas (OPG) remain the most common. Due to their location, OPG can cause visual impairment, and endocrinal dysfunction, hence requiring therapeutic interventions, more commonly in sporadic non-NF-1 cases. METHODS NF-1 children with associated OPG followed at a single tertiary pediatric oncology center since its establishment from 2018 to 2023 were retrospectively evaluated. RESULTS Forty patients were identified either as firstly diagnosed NF-1 cases in our center or referred to us for follow up. Twenty-three of them who had associated OPG (mean age at diagnosis 83.7 months) were included in our study. The commonest clinical presentation was the bilateral initial visual affection occurring in 13 patients. Six had hormonal imbalance and four presented with seizures. Biopsy was taken only in 30%, with histopathology being mainly pilocytic astrocytoma. In terms of treatment, 10 cases received only one line of chemotherapy, six patients were kept on follow up, and the rest received more than one line of therapy. Overall survival (OS) was 100% throughout the study period, and progression-free survival was 64.1% at 1.5 years, and 46.8% at 5 years. Visual assessment at the end of treatment was stable in 71%, better in 22%, and worse in 7% of cases. Same pattern was observed in MRI assessment post therapy showing 57% stable disease, 39% regression, and 4% progression. CONCLUSIONS Survival of children with OPG is different in every center of the world as decisions regarding their management being challenging. Therefore, NF-1 multidisciplinary clinics are important to be established, with a high emphasis on early detection and referral of patients, standardization of symptoms grading and indications to start treatment.

GCT-02. OPTIC PATHWAY PRIMARY GERMINOMA: DON´T MISS THE DIAGNOSIS

Abstract BACKGROUND Germ Cell tumors usually arise in the midline of brain; location in optic pathway (OP) is extremely rare. This case illustrates an OP primary Germinoma. METHODS A 9 years old female debuted with diminished visual acuity, it was diagnosed and treated as optic neuritis without improvement, a MRI evidenced a gadolinium enhancement with a very subtle thickening on the optic chiasm, along 3 non conclusive vascular like images in the left Virchow space. A differential diagnosis between endophytic Optic pathway glioma and germ cell tumor was made. RESULTS Assessment of AFP and Sub HCG in both blood and CFS was negative, endocrine evaluation confirmed Diabetes insipidus. A stereotaxic biopsy was performed and Pathology confirmed a Pure Germinoma. Non metastatic disease was confirmed as negative Spine MRI and acellular CFS. As a relevant familiar History the father had testicular Germinoma in his teenage. She was treated with 9 weeks of Carboplatin/V16 and radiotherapy as follows: whole ventricular 24 Gy and primary site 16.5 Gy for a total dose of 40.05 Gy. She is free of tumor at 3 follow up years with improvement in visual acuity and arginine vasopressin dependence. CONCLUSIONS This case illustrates a germ cell tumor primary arising in the optic pathway and aware us to consider it as a differential diagnosis with non-exophytic optic pathway Glioma being the biopsy mandatory to establish the correct diagnosis

LMIC-20. REAL-WORLD EXPERIENCE IN DEALING WITH CHILDREN WITH SUSPECTED CENTRAL NERVOUS SYSTEM (CNS) TUMORS AT THE CHILDREN’S HOSPITAL LAHORE (UCHS), PAKISTAN

Abstract BACKGROUND CNS tumors are the leading cause of cancer-related deaths in children in HICs, but data from LMICs are scarce. The objectives of this study were to document the trajectory of children with CNS tumors at a tertiary-care hospital in Pakistan. METHODS This prospective, analytic, cohort study recorded all new cases of suspected CNS tumors (birth to 16 years) presented from 2023/01/01 to 2023/12/31 at UCHS, Lahore. RESULTS A total of 145 cases were included. Median age at presentation was 7.0 years (1.5 months–15 years); male-to-female ratio was 1.4:1. Median time to presentation was 2 months (0.1 – 96 months); delay of &amp;gt;6 months was observed in 30.5% cases due to delayed presentation to medical facility (74%) and healthcare delay (26%). Headaches and vomiting (56%), focal neurological deficit (23%), and seizures (15%) were the most common presenting complaints. Consanguinity (46%), and family history of cancers (19%) were frequent; café au lait macules were observed in 9.7%. 50% tumors were infratentorial, 46% supratentorial and 4% spinal. Tumor excision was done in 45%, VP-shunts in 42%, and upfront chemotherapy in 2%. Only 60% had a final diagnosis. Tissue diagnosis in 39% cases showed Medulloblastoma (18 patients, 32%), Pilocytic Astrocytoma (27%), and High-grade glioma (16%) as the commonest diagnoses, while 21% had a radiological diagnosis based on CT/MRI features: DIPG/DMG (12%), Craniopharyngioma (7.6%), and Optic Pathway Glioma (1.4%). Of 18 medulloblastoma patients, only 7 received postoperative radiotherapy. Seventy (48%) patients expired (including 38 before surgery), 27% are on follow-up and 25% are LAMA/LTFU/defaulted treatment. One-year survival was 36% with median survival of 4 months (0.07-96 months). CONCLUSION Less than half of the patients with CNS tumors undergo active treatment, a large proportion leave treatment/follow-up and have poor overall survival. Considerable cases with cancer predisposition syndromes were suspected.

NFS-23. ASSOCIATION OF LOCALIZED MAGNETIC RESONANCE IMAGING FEATURES IN ANTERIOR VISUAL PATHWAY WITH VISUAL ACUITY LOSS AMONG CHILDREN WITH NF1-OPG

Abstract BACKGROUND Half of children with optic pathway gliomas associated with neurofibromatosis type 1 (NF1-OPG) are at risk for vision acuity (VA) loss. NF1-OPGs manifest along the anterior visual pathway (AVP), where the overall shape and volume from MRI have been recently associated with VA loss. To investigate the added value of localized features within the optic nerves (ONs) and chiasm, we propose an automatic deep-learning framework for VA loss prediction from volumetric and radiomic analysis of ONs, chiasm, and AVP. METHODS We collected MRIs of 60 children with NF1-OPG from Children’s National Hospital (CNH, GE platform) and 75 from Children’s Hospital of Philadelphia (CHOP, Siemens platform). MRI sequences included T1-, T2-weighted and T2-FLAIR. Experts annotated the AVP to establish ground truth. Neuro-ophthalmic evaluation identified VA loss (LogMAR &amp;gt;= 0.2) in 52/135 children. Automatic AVP segmentation was performed using the Swin transformer network. ONs and chiasm were split through template-based registration. Brain volume, tumor location, child age, and 1,172 radiomic features were used to predict VA loss using support vector machines. Sequential feature selection associated with risk VA loss was done using sensitivity and univariate statistical tests (ANOVA). We compared predictions based on new ON and chiasm analysis with results based on AVP alone. RESULTS Balanced accuracy, sensitivity, specificity, and AUROC of VA loss prediction were 0.865, 0.882, 0.857, 0.899, respectively. Significant risk factors were maximal image intensity and gray level run length entropy in T2-FLAIR for ONs, and image intensity range in T2-FLAIR for chiasm. AUROC based on analysis of AVP alone dropped to 0.728 (p-value=0.028). CONCLUSIONS Deep learning-based analysis indicates an association of new localized MRI features in ONs and chiasm with VA loss, which show enhanced capability in predicting VA loss. This automated framework has the potential to accelerate and guide the treatment decisions for children with NF1-OPGs.

LGG-49. EVALUATING THE EFFECTS OF MIRDAMETINIB IN NF1-MUTANT LOW-GRADE GLIOMAS USING BOTH CULTURED CELLS AND A NOVEL ZEBRAFISH XENOGRAFT MODEL

Abstract BACKGROUND Pediatric low-grade gliomas (LGGs) with NF1 mutations represent a significant portion of childhood brain tumors. NF1 mutations lead to the dysregulation of the MAPK kinase and mTOR pathways, contributing to tumor growth. However, obtaining cell lines and xenograft animal models for NF1-mutated LGGs remains challenging due to their slow growth and less aggressive nature. Methods and RESULTS We examined the therapeutic efficacy of a novel MEK inhibitor mirdametinib in targeting the MAPK pathway within JHH-NF1-PA1 cells, a cell line derived from a low-grade optic pathway glioma originating from a patient with type 1 neurofibromatosis. Mirdametinib decreased p-ERK protein expression levels on western blot within four hours. We confirmed that mirdametinib significantly suppressed tumor cell proliferation by approximately 60% (BrdU staining (P&amp;lt;0.05), CellTiter Blue assay). β-galactosidase staining revealed approximately a 50% induction of cellular senescence in JHH-NF1-PA1 cells following mirdametinib treatment (P&amp;lt;0.05). We confirmed our findings using murine Nf1-null low grade glioma cell lines 1861 and 1491. To establish an in vivo model for drug testing, we utilized zebrafish due to their transparency, rapid reproduction, and short development time. Injecting RFP-labeled JHH-NF1-PA1 cells into the zebrafish at the 1000-cell stage, we monitored tumor growth using TECAN fluorescence detection from the third to eighth days post-injection. The fluorescence signals obtained from TECAN were validated by fluorescence microscopy. Western blot analysis confirmed a decrease in p-ERK levels within the zebrafish following mirdametinib treatment. We are evaluating the effect of mirdametinib on NF1 low grade glioma cell survival, migration and senescence in the zebrafish brain. CONCLUSION Our findings show that mirdametinib inhibits cell proliferation and induces senescence in NF1-mutated LGGs. Moreover, our zebrafish model provides a valuable tool for evaluating the efficacy of MEK inhibitors in vivo, particularly in cases where traditional xenograft models are difficult to establish.

NFS-19. ATYPICAL PRESENTATION OF GLIOMAS IN ADOLESCENTS WITH NEUROFIBROMATOSIS TYPE 1 (NF1): A CASE SERIES

Abstract BACKGROUND Patients with NF1 are at risk for developing gliomas, usually low-grade in childhood but may be high-grade in adults. In children, the most common sites of disease are the optic pathway and brainstem; tumors in these regions often arise in young children and display histological features characteristic of pilocytic astrocytoma (PA) when biopsied. Typical MRI findings include T2 hyperintense, T1 hypointense lesions with minimal contrast enhancement and no diffusion restriction. Due to the well-established pattern of low-grade tumor formation in children with NF1, as well as the surgically challenging areas in which these tumors develop, low-grade glioma (LGG) therapy is often initiated without histologic confirmation of the diagnosis in classic cases. In cases with atypical disease location, older age at presentation or imaging appearance, a biopsy may be considered to exclude higher-grade lesions. METHODS Retrospective chart review, case series RESULTS Four adolescent patients with NF1 presented with atypical suspected gliomas. All four patients underwent surgical biopsy/resection. Case 1 was a left temporal lesion in the previous radiation field for optic pathway glioma; biopsy confirmed LGG with MAP2K1 mutation and increased focal proliferation index (28%), but methylation did not match with any established classification. The patient progressed through multiple rounds of therapy and succumbed to her tumor. Case 2 was a left occipital lesion; biopsy confirmed PA with CDKN2A deletion. The tumor displayed rapid regrowth, but subsequently stabilized. Case 3 was a right frontal lesion; confirmed PA. The tumor demonstrated some regrowth but then stabilized. Case 4 was a basal ganglia lesion; confirmed PA. The patient has demonstrated stable MRI findings and has not required further intervention. CONCLUSIONS Biopsy yielded helpful prognostic information (additional mutations, proliferation rate) in half of these atypical cases. Biopsy should be carefully considered for NF1 patients with atypical presentation or a history of radiation.

IMG-29. IMPLICATIONS OF IMAGE HARMONIZATION FOR BRAIN TUMOR CLINICAL TRIALS

Abstract BACKGROUND Clinical trials for rare pediatric conditions like optic pathway gliomas associated with NF1 (NF1-OPGs) require numerous sites that utilize different MRI scanners and protocols. These MRIs must be harmonized for reliable comparison using machine learning tools. We propose a deep-learning based MRI harmonization that enables reproducible data analysis across multiple sites and MRI platforms. METHODS One-hundred eighty clinical T1-weighted-MRIs of pediatric NF1-OPG subjects were acquired from three sites [Children’s National Hospital (site A, N=60), Children’s Hospital Colorado (site B, N=60), and Children’s Hospital of Philadelphia (site C, N=60)] using different MR scanners (GE, Phillips, and Siemens, respectively). MRIs from A and B were used to train a branched neural network and C were used for testing. Using unsupervised learning, the neural network identified differences in imaging protocols and harmonized data to a chosen protocol, e.g., that of site A, while preserving the patient anatomy. The harmonization was evaluated using Wasserstein distance (nWD), which measured similarity between two gray scale appearances of MRI intensity histograms. Anatomy preservation metric (AP) measured relative volume changes in gray matter (GM) segmented using Freesurfer, before and after harmonization. For both metrics, 100% means the best possible harmonization was achieved. RESULTS Before harmonization, nWD between grayscale appearance of MRIs from sites A and B was 27.3±3.1%. After harmonization, the similarity became 94.2±2.0% with a GM volume error of 3.11±0.56ml which corresponded to AP of 93.1±4.7%. For the test data, nWD similarity post harmonization improved from 38.2±3.9% to 93.4±2.2% with GM volume error of 4.12±0.47ml which corresponded to AP of 90.3±3.5%. CONCLUSIONS Our approach enables MRI harmonization while preserving anatomy for precise analysis using machine learning tools. It scales to new sites to support multisite clinical trials that utilize imaging outcomes for brain tumors and other rare diseases.