Pilomyxoid Astrocytoma Research Articles

EPID-20. PRIMARY INTRAMEDULLARY PILOMYXOID ASTROCYTOMA OF SPINAL CORD (PIPASC): A SYSTEMATIC REVIEW OF CASE REPORTS AND CASE SERIES OF TWO DECADES

Abstract BACKGROUND Pilomyxoid Astrocytoma (PMA), new variant of pilocytic astrocytoma, is more aggressive and relatively rare, mostly seen in children and commonly found in brain. Primary intramedullary pilomyxoid astrocytoma of spinal cord (PIPASC) is extremely rare. The distinct aggressive and pathological behavior, poor prognosis and the diversity in response to various treatment modalities makes the PIPASC an oncologic enigma. We aim to evaluate the clinical manifestations, histopathologic spectrum and onco-surgical management of this neoplasm. MATERIALS AND METHODS After an extensive literature search using PubMed Central and Google Scholar, eight case reports and one case series of patients with spinal PA were retrieved and included using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines without applying any filter of time, study type or place. Case presentations of 12 patients were analyzed in this review. RESULTS Pediatric preponderance of the neoplasm (75%) with the mean age of 7.90 ± 4.51 years was noted. Sensory deficits and scoliotic deformity were the most common presenting symptom and sign in 83.33% and 33.33% of patients, respectively. Thoracic spine (50%) was most commonly affected region. MRI showed the most consistent findings of cord compression in 100% cases and the lesion appeared hypointense on T1- weighted images (T1WI) and hyperintense on T2-weighted images (33.33%). The average post treatment survival duration was found to be more than 2 years. CONCLUSIONS Occurrence of PIPASC among pediatric population is rare. They have possibility of extraneural metastasis, can differentiate into more malignant glioma and get recurrent due to which they require a long-term follow-up of the patients. Further studies are required to investigate the utility of chemotherapy and radiotherapy in its management.

La sindrome diencefalica: magro, lungo e sorridente

The Authors describe the case of a 10-month-old boy with growth arrest and nystagmus related to a pilomyxoid astrocytoma in a paramedian suprasellar location.

LGG-11. UNDERSTANDING THE TRANSCRIPTIONAL HETEROGENEITY OF PEDIATRIC LOW-GRADE GLIOMAS AND ITS IMPLICATION FOR TUMOR PATHOPHYSIOLOGY

Abstract BACKGROUND Pediatric low-grade gliomas (pLGGs) are the most frequent brain tumors in children and comprise a heterogeneous group of tumors with different locations, histologic subtypes, ages at presentation, and clinical behavior. Tumors frequently respond to treatment with chemotherapy or radiation therapy, but they can regrow after a period of quiescence, requiring further therapy. Thus, a deeper understanding of the molecular processes involved in these tumors is required to develop therapeutic strategies that are effective against their disease mechanisms. METHODS To better understand the cellular behaviors of this heterogenous group of tumors, we have employed single-cell and single-nuclei RNA sequencing technologies to analyze a large-scale dataset (>250,000 cells) of 55 pLGGs across many histological subtypes (pilocytic astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, DNET, ganglioglioma, RGNT, diffuse astrocytoma, SEGA, glioneuronal, oligodendroglioma). RESULTS Analysis of this data identified a heterogenous population of cell types and cell states, detecting mature and progenitor-like astrocytes and oligodendrocytes, as well as cells exhibiting senescence or cycling programs. Moreover, we identify a significant immune infiltrate, comprised primarily of microglia. In addition to heterogeneity within pLGG tumors, heterogeneity between LGG subtypes represents another layer that stratifies pLGG biology. We performed a compositional analysis of the cell types present in these tumors and compared transcription signatures and gene expression programs across shared cellular populations of histologically and genetically distinct pLGGs. Finally, we used spatial transcriptomic data to investigate and annotate the cellular architecture of multiple pLGGs with BRAF mutations and draw comparisons to findings from our single-cell and single-nuclei transcriptomic analysis. CONCLUSIONS Our analysis of human pLGGs at the single-cell and single-nuclei resolution provides critical insight into the heterogenous biological activities that constitute these tumors.

LGG-27. LOWER GRADE GLIOMA (LGG) IN INFANTS. ANALYSIS OF 25 NON-NF1 PATIENTS

Abstract INTRODUCTION Infants constitute approximately 5% of all pediatric LGG. This group is identified as having aggressive course and worse prognosis as compared to older children. No specific therapeutic guidelines are yet available for this specific age group. AIM: Retrospective analysis of infants diagnosed and treated for LGG. METHODOLOGY: 25 patients treated between 2001-2023 were analyzed for: sex, age, tumor location, pathology, treatment and outcome. NF1 patients were excluded. RESULTS There were 13 boys and 12 girls, aged 3 months-11 months, median 6 months. 12 had optic chiasm tumors, 6 of visual pathway, 3 had tumors of posterior fossa, 2 of pineal region and 1 spinal tumor. Pathology was available for 16 children revealing Pilocytic astrocytoma in 9, Pilomyxoid astrocytoma in 6, ganglioglioma in 1. Resection as first line treatment was performed in posterior fossa and spinal locations, in 4 cases of visual tracts tumors. All patients were treated with chemotherapy with a maximum of 6 subsequent episodes in a patient with visual pathway tumor. MEK inhibitors were given to 3 pts (in 2 discontinued due to cardiotoxicity). Radiotherapy was applied in 5 (older than 4 years). Twenty two patients are alive, from 4 months to 22 years 4 months (median 8 years 11 months) from diagnosis. Three patients died (midline tumors) 2 from electrolyte disorders and 1 from radiation related cerebral bleeding with observation time of 3, 10, 9 years. Among children with visual tract tumors 5 are blind, 3 have impaired vision. Five patients with very good response to first line treatment have excellent quality of life. Ten patients are disabled, requiring help in everyday life. CONCLUSIONS The risk of disability or death is highest in infants of all LGG patients, those who respond the first line treatment have very good quality of life.

LGG-48. CLINICAL CHARACTERIZATION OF FGFR-ALTERED, PEDIATRIC LOW-GRADE GLIOMAS

Abstract BACKGROUND Pediatric low-grade glioma (pLGG) is the most common central nervous system tumor of childhood. Most pLGGs are driven by BRAF alterations, but a subset harbor activating mutations or fusions of FGFR1/2/3. Significantly less is known about the biologic activity, clinical course, and response to targeted inhibition of these FGFR-altered gliomas (FGFR pLGG). We sought to define the epidemiologic characteristics, molecular signature, prognostic markers, and clinical course of patients with FGFR pLGG. METHODS We performed a multi-institution, retrospective chart review of pediatric neuro-oncology patients treated at two large, academic cancer centers from 2012 – 2023 with tumor molecular profiling demonstrating any FGFR alteration. RESULTS Sixteen eligible patients were identified; 9 (56%) were female and median age was 12 years of age (range 6 - 18 years). Reported histologies included pilocytic astrocytoma (4), rosette-forming glioneuronal tumor (3), low grade glial/glioneuronal tumor (3), low grade glioma NOS (2), intermediate grade astrocytoma (1), dysembryoblastic neuroepithelial tumor (2), and pilomyxoid astrocytoma (1). FGFR point mutations were seen in 10/16 (62.5%) patients followed by FGFR-TACC1 fusions in 4/16 (25%) patients and two patients with FGFR1 tandem duplication. Metastatic disease was noted at diagnosis in two patients and upfront gross total resection was achieved in four patients. The most common systemic therapy for the remaining patients was Vincristine and/or Carboplatin. All sixteen patients are alive at median follow up of 52 months (range 6 - 198 months). CONCLUSIONS FGFR pLGG represent a distinct subset of tumors with unique biologic properties and clinical activity. Additional studies are needed to investigate this unique patient population to appropriately adapt our therapeutic approach and improve patient outcomes.

Glioma of the anterior visual pathway in children. Part II. Current treatment trends

The literature review presents modern treatment aspects for anterior optic pathway gliomas (OPGs), which are low-grade brain tumors accounting for 20%–30% of childhood gliomas, can occur anywhere along the visual pathways and in the development of the surrounding structure, and are predominantly benign. The predominant histological type of tumor in this localization is piloid astrocytoma (PA), less commonly pilomyxoid astrocytoma (PMA). However, the course of anterior OPGs is unpredictable and varies from spontaneous regression to progression with severe visual, neurological, and endocrine disorders, affecting treatment and disease prognosis. Although there have been advances in clinical studies based on histological and molecular genetic analyses, no fundamental changes in survival rates and recurrence-free periods and improvements in functional outcomes have been achieved. Furthermore, no studies have comprehensively analyzed the functional results depending on the management tactics of pediatric patients with anterior visual pathway gliomas. Anterior optic pathway glioma treatment is challenging and complex problem, which depends on the patient’s age, clinical picture, localization, surgical resectability, and histological and molecular genetic study results. It includes surgical treatment, chemotherapy, radiation therapy, the use of targeted therapy drugs, and additional advanced techniques that are still under development and research. Optimal treatment of anterior optic pathway gliomas in children remains a topic of discussion in the current literature.

Phase IB study of tovorafenib for children with relapsed/recurrent low-grade gliomas and other MAPK pathway activated tumors.

10001 Background: LGGs present a therapeutic challenge often occurring in areas of brain and spine not amenable to resection and carrying high morbidity with currently available therapies. The majority harbor alterations in the MAPK pathway. Our study (NCT03429803) aimed to establish the recommended phase 2 dose (RP2D) and assess the safety, tolerability and preliminary efficacy of type II RAF-inhibitor tovorafenib in such tumors. Methods: Eligible patients were > 1 year and < 25 years old with radiographically recurrent/progressive MAPK pathway-altered tumors. We applied a novel 2S-Sub-TITE design to determine a RP2D with posterior probability of toxicity closest to the 20% target for patients with BSA ≤1.5 and > 1.5 m2 based on preliminary exposure-efficacy data. Toxicities were graded according to CTCAE version 5. Patients with complete response (CR), partial response (PR) or stable disease (SD) were designated responders. Results: We treated 35 eligible patients, including 20 KIAA1549:BRAF-, 9 BRAF V600E- and 1 FGFR1-altered tumors; 5 possessed novel RAF fusions. Histologically, there were 27 grade 1 gliomas, 3 anaplastic pleomorphic xanthoastrocytomas, 3 pilomyxoid astrocytomas, 1 high-grade glioma and 1 soft tissue sarcoma. There were 6 grade 3 DLTs (2 fatigue, 3 rash, 1 menorrhagia) in 30 evaluable patients: 3 in each BSA subgroup, all at 530 mg/m2/dose. Using AAP guidelines for minimum pubertal peak growth velocities (GV) in males (7 cm/year) and females (6 cm/year), decreased GV (median 0.09 cm/year; range 0.02-0.3) was an unexpected, related AE observed in all 13 of 13 pre-pubertal females < 14 or males < 16 years of age receiving >6 months of protocol 1B therapy. Three of 13 patients with decreased GV were treated at 420 mg/m2. Three of the remaining 10 patients with decreased GV originally treated at 530 mg/m2 were dose reduced for other toxicities and hence, 6 of 13 patients with decreased GV were treated at the RP2D. For patients with follow-up data available, GV appears to show recovery off drug. The 2S-Sub-TITE model recommended 530 mg/m2 for BSA ≤1.5m2 and 420 mg/m2 for BSA > 1.5m2. Dose modifications were required in 8/22 versus 1/13 patients treated at 530 and 420 mg/m2, respectively. Twenty-seven of 35 patients were evaluable for objective response performed by an independent single reader. Overall, 25 patients had SD, PR or CR with median duration of response of 11.3 months (range 0.03-35.4) at data cutoff. Conclusions: Oral weekly tovorafenib is well tolerated and shows preliminary efficacy. Decreased GV was observed in pre-pubertal patients on drug and warrants further investigation to understand the mechanism of action. Based on the number of dose modifications required for toxicity, the chosen RP2D for weekly oral dosing of tovorafenib was 420 mg/m2. Clinical trial information: NCT03429803 .

A preliminary enrichment analysis of tumor genes in patients suffering from rectal cancer with and without CNS metastasis.

e16381 Background: Colorectal cancers have been touted as the third most common cancer and the third leading cause of cancer death worldwide. Of these, rectal cancers often have a more favorable outcome, and are generally responsive to chemotherapy and radiation, due to metastasis limited to local tissues via lymphatics. However, in recent years, cases of rectal cancer with distant metastasis to the CNS have been noted at an urban community hospital serving a primarily Hispanic population in central New Jersey. Methods: We used genetic data from 51 patients at our local cancer center over 5 years to delineate risk factors associated with CNS metastasis. Of these patients, two had CNS metastasis with available tumor genetic information. We performed a gene enrichment analysis to determine phenotypic terms and molecular pathways associated with each gene set using Enrichr. Results: Of 51 patients, genetic data was available on 20, of which 18 had rectal cancer without CNS metastasis. Mutations involving 23 genes were found in this cohort, analysis of which found enrichment of the terms “Lynch Syndrome” and “Constitutional mismatch repair deficiency syndrome”, which are classically implicated in CRCs. In addition, enrichment of the terms “rectal cancer childhood”, “colorectal cancer childhood”, and “Familial colorectal cancer” were found. Of the two patients who had metastasis to the CNS, mutations involving 14 genes were found. Interestingly, both patients had mutations involving KRAS. Analysis of these genes found enrichment of the terms “pilomyxoid astrocytoma”, “giant cell glioblastoma” and “gliosarcoma”. Interestingly, common to both cohorts were the classic CRC-associated genes KRAS, APC and TP53, further solidifying their role in general CRCs. Conclusions: While this study is ongoing, preliminary data suggest that genetic analysis of tumors in patients with rectal cancer can determine whether a patient is susceptible to CNS metastasis. Given the heterogeneity of these cancers, further studies involving tumor and germ-line genetic analysis, which follow patients longitudinally may benefit in predicting which tumors are prone to CNS metastasis before they metastasize.

P.073 Spontaneous fluctuation of contrast enhancement in adult pilocytic astrocytoma and other low-grade brain tumors

Background: Pilocytic astrocytoma and other circumscribed low-grade brain tumors can exhibit spontaneous enhancement changes despite stable size and clinical status. We aimed to describe this phenomenon in adults. Methods: We performed a retrospective review of our MRI database (2011-2021) to identify cases with enhancement changes in otherwise stable tumors. We searched for reports containing: “pilocytic”, “pilomyxoid”, “RGNT”, “rosette”, “glioneuronal”, “DNET”, and “dysembryoplastic”. Exclusion criteria included WHO grade 3/4 tumors, patients <19 years, equivocal diagnostic findings, and no serial MRIs. We reviewed 238 patients. Results: We identified 12 adult patients with the desired phenomenon: 6 pilocytic astrocytoma, 1 pilomyxoid astrocytoma, 2 rosette-forming glioneuronal tumor, 1 unverified low-grade glioma, and 2 cases without biopsy. Seven were untreated, while five were residual or recurrent tumors. Six showed a pattern of new/increasing and subsequent decreasing/disappearing enhancement over 1-4 years. One exhibited spontaneous regression of enhancement over 1 year. Five showed repeating cycles of increasing and decreasing enhancement over longer monitoring periods of 7-15 years, with mean duration of increasing enhancement prior to decline of 21.4 months (SD 5.9). Conclusions: Spontaneous contrast enhancement fluctuation in adult pilocytic astrocytoma and other circumscribed low-grade brain tumors can occur, and on its own should not be misconstrued as evidence of tumor progression/regression.

PAEDIATRIC-12 MANAGEMENT OF PAEDIATRIC LOW-GRADE GLIOMA IN CAPE TOWN, SOUTH AFRICA

Abstract OBJECTIVE To assess the management of paediatric low-grade gliomas by the combined neuro-oncology services of the University of Cape Town. METHODS A retrospective analysis was performed on the folders of patients diagnosed at the Red Cross War Memorial Children’s Hospital (RCWMCH) and Groote Schuur Hospital (GSH) between 2000 and 2022. The data includes 2 patient cohorts, the first cohort being patient data collected from 2000-2016 and the second from 2017-2022. RESULTS A total of 127 patients, aged 0.38-13.76 years (mean 5.71) were treated at RCWMCH and GSH. Predisposition syndromes observed included Neurofibromatosis 1 11, Tuberous sclerosis 6, and Trisomy 21 1. The most common sites were the cerebellum 27%, hypothalamus 17%, cerebrum 12%, and optic pathway 13%. Metastatic disease was noted in 12 patients (9%). Gross total resection (or debulking) was performed in 67 (53%) of patients, 40 had biopsy only, and 20 had no surgery (mostly OPGs). Histology was predominantly Juvenile Pilocytic Astrocytoma 70%, Diffuse Astrocytoma 9%, Low-Grade Glioma Nos 8%,5% Subependymal Giant cell Astrocytoma, and 5% Pilomyxoid Astrocytoma. BRAF v600E mutation was tested in 17 patients: all were negative. Forty-four (35%) received chemotherapy and 36 (82%) as first-line therapy with vincristine and carboplatin as the most used agents. Newer therapies Bevacizumab/irinotecan and Trametinib were recently used in 10 patients as third or fourth-line regimens. There was an increase in chemotherapy usage for patients with irresectable tumours between the 2 cohorts, from 27% in the first cohort to 49% in the second. Thirty (23.6%) patients received radiotherapy and of those 8 were in an upfront setting. There was no difference in the 5-year OS between the 2 cohorts, 84% in the first and 85.7% in the second. CONCLUSION Multi-disciplinary treatment of paediatric LGG in LMIC is essential. Patterns of management have changed without affecting outcomes.

Prechiasmatic Transection of the Unilateral Dodge Class Ⅰ Optic Pathway Glioma without Neurofibromatosis Type 1: Technical Description and Clinical Prognosis

For unilateral Dodge Class Ⅰ optic pathway glioma (OPG-uDCⅠ) without neurofibromatosis type 1, unilateral isolated optic nerve gliomas before the optic chiasm have been confirmed to possibly cause visual deterioration and poor prognosis. For this type of highly selective localized tumor, we explored surgery as the only treatment method. This article retrospectively analyzed and summarized the clinical data of this case series, with the aim of exploring the main technical details and clinical prognosis. Included were patients with OPG-uDCⅠ without neurofibromatosis type 1 and experiencing vision loss on the affected side. The fronto-orbital approach was used, which was mainly divided into 3 parts: intraorbital, optic canal, and intracranial. All patients underwent prechiasmatic resection without any adjuvant treatments. The follow-up period was 3months after surgery, and magnetic resonance imaging and contralateral visual acuity were reviewed annually after surgery. All OPG-uDCⅠ cases were completely removed without any adjuvant treatments, and there was no recurrence during the follow-up period. Pathological results showed that, except for 1 adult patient with pilomyxoid astrocytoma (World Health Organization grade Ⅱ), the others all had pilocytic astrocytoma (World Health Organization grade Ⅰ). Five patients experienced transient ptosis, and all recovered 3months after surgery. For OPG-uDCⅠ without neurofibromatosis type 1, radical prechiasmatic resection of the tumor is possible, without the need for postoperative radiotherapy and chemotherapy.

LGG-10. TREATMENT-RELATED MYELODYSPLASTIC SYNDROME FOLLOWING CHEMOTHERAPY FOR PEDIATRIC LOW-GRADE GLIOMA

Abstract Treatment-related myeloid neoplasms are rare though well-defined secondary malignancies associated with prior cytotoxic treatment, (particularly alkylating agents and topoisomerase inhibitors). They are rarely associated with primary central nervous system tumours and have historically carried a very poor prognosis. Pediatric low-grade gliomas (pLGG) are the most common CNS tumours of childhood, and up to 50% of patients will require adjuvant therapy. This has traditionally consisted of low-dose metronomic chemotherapy, although the advent of genomic profiling and identification of molecular drivers of pLGG means novel targeted therapies are changing this paradigm. There has only been a single reported case of treatment-related myeloid leukaemia secondary to pLGG treatment. We present a novel case of a 17-year-old girl with treatment-related myelodysplastic syndrome following chemotherapeutic treatment for pLGG. The patient was initially diagnosed at age 4 with a metastatic pilomyxoid astrocytoma (primary suprasellar lesion with spinal metastases) and received first-line treatment with a vincristine and carboplatin regimen. She had disease progression at age 7 and received second-line treatment with thioguanine, procarbazine, lomustine and vincristine. Following further progression at age 16, a biopsy of the suprasellar mass showed a pilocytic astrocytoma with a KIAA1549-BRAF fusion. Prior to commencing a targeted treatment as third-line therapy, she was noted to have a macrocytic anaemia, which subsequently evolved to a bicytopenia. Bone marrow analysis showed a hypocellular marrow with an abnormal myeloid clone with a chromosomal 1q gain, consistent with a diagnosis of treatment-related myelodysplastic syndrome. Germline analysis was negative for bone marrow failure predisposition gene abnormalities. She is currently undergoing workup for bone marrow transplant. Given the poor prognosis of treatment-related myeloid neoplasms, this case represents an important note of caution when choosing appropriate therapy for pLGG, especially given the evolving role for targeted treatments in this disease with otherwise very favourable long-term survival.

Successful Treatment of Pure Aqueductal Pilomyxoid Astrocytoma and Arrested Hydrocephalus With Endoscopic Tumor Resection Followed by Chemotherapy: A Case Report and Technical Considerations

BACKGROUND AND IMPORTANCE Pure aqueductal tumors are extremely rare and may lead to death, regardless of histopathology. We report the first case of pure aqueductal pilomyxoid astrocytoma in an adult woman with arrested hydrocephalus. Endoscopic tumor resection for securing aqueductal patency followed by chemotherapy allowed control of both the tumor and the hydrocephalus. CLINICAL PRESENTATION: A 20-year-old woman presented with mild cognitive dysfunction and marked ventricular dilatation. She had no preoperative symptoms of intracranial hypertension, and her head circumference was more than 2 SDs above the 98th percentile. The aqueduct of Sylvius was entirely occupied by a neoplastic lesion with 2 periventricular nodules at the wall of the third ventricle and anterior horn of the right lateral ventricle. She was treated successfully with endoscopic tumor resection followed by chemotherapy, and the patency of the aqueduct of Sylvius was secured throughout the duration of treatment. CONCLUSION: Pure aqueductal tumors may be an appropriate indication for endoscopic tumor resection to secure the aqueductal patency of cerebrospinal fluid. This case demonstrates the surgical technique of a combined rigid-flexible endoscopic transforaminal approach, which was a useful surgical intervention for the management of this patient.

A molecular study of pediatric pilomyxoid and pilocytic astrocytomas: Genome-wide copy number screening, retrospective analysis of clinicopathological features and long-term clinical outcome.

Pilocytic Astrocytoma (PA) is the most common pediatric brain tumors. PAs are slow-growing tumors with high survival rates. However, a distinct subgroup of tumors defined as pilomyxoid astrocytoma (PMA) presents unique histological characteristics and have more aggressive clinical course. The studies on genetics of PMA are scarce. In this study, we report one of the largest cohort of pediatric patients with pilomyxoid (PMA) and pilocytic astrocytomas (PA) in Saudi population providing a comprehensive clinical picture, retrospective analysis with long-term follow-up, genome-wide copy number changes, and clinical outcome of these pediatric tumors. We examined and compared genome-wide copy number aberrations (CNAs) and the clinical outcome of the patients with PA and PMA. The median progression free survival for the whole cohort was 156 months and it was 111 months for the PMA, however, not statistically significantly different between the groups (log-rank test, P = 0.726). We have identified 41 CNAs (34 gains and 7 losses) in all tested patients. Our study yielded the previously reported KIAA1549-BRAF Fusion gene in over 88% of the tested patients (89% and 80% in PMA and PA, respectively). Besides the fusion gene, twelve patients had additional genomic CNAs. Furthermore, pathway and gene network analyses of genes in the fusion region revealed alterations in retinoic acid mediated apoptosis and MAPK signaling pathways and key hub genes that may potentially be involved in tumor growth and progression, including BRAF, LUC7L2, MKRN1, RICTOR, TP53, HIPK2, HNF4A, POU5F, and SOX4. Our study is the first report of a large cohort of patients with PMA and PA in the Saudi population that provides detailed clinical features, genomic copy number changes, and outcome of these pediatric tumors and may help better diagnosis and characterization of PMA.

Long-term follow-up of surgical intervention pattern in pediatric low-grade gliomas: report from the German SIOP-LGG 2004 cohort.

Neurosurgical treatment is an integral part of the treatment algorithms for pediatric low-grade glioma (LGG), yet patterns of surgical procedures are rarely challenged. The objective of this study was to evaluate surgical treatment patterns in pediatric LGG. The German Societé Internationale d'Oncologie Pédiatrique (SIOP)-LGG 2004 cohort was analyzed to identify relevant patient and tumor characteristics associated with time to death, next surgery, number of resections, and radiological outcome. A total of 1271 patients underwent 1713 neurosurgical interventions (1 intervention in 947, 2 in 230, 3 in 70, and 4-6 in 24). The median age of the study population was 8.57 years at first surgery, and 46.1% were female. Neurofibromatosis type 1 (NF1) was found in 4.4%, and 5.4% had tumor dissemination. Three hundred fifty-four patients (27.9%) had chemotherapy and/or radiotherapy. The cumulative incidence of second surgery at 10 years was 26%, and was higher for infants, those with spinal and supratentorial midline (SML) tumors, and those with pilomyxoid astrocytomas. The hazard ratio for subsequent surgery was higher given dissemination and noncomplete initial resection, and lower for caudal brainstem and SML tumors. Among 1225 patients with fully documented surgical records and radiological outcome, 613 reached complete remission during the observation period, and 50 patients died. Patients with pilocytic astrocytoma had higher chances for a final complete remission, whereas patients with initial partial or subtotal tumor resection, dissemination, NF1, or primary tumor sites in the spinal cord and SML had lower chances. Neurosurgery is a key element of pediatric LGG treatment. In almost 50% of the patients, however, at least some tumor burden will remain during long-term follow-up. This study found that most of these patients reached a stable disease status without further surgeries. Multidisciplinary team decisions must balance the goal of complete resection, risk factors, repeated surgeries, and possible treatment alternatives in a wide range of heterogeneous entities. Procedural details and neurological outcome should be recorded to better assess their impact on long-term outcome.

Spectrum of qualitative and quantitative imaging of pilomyxoid, intermediate pilomyxoid and pilocytic astrocytomas in relation to their genetic alterations.

Pilomyxoid astrocytomas (PMA) are pediatric brain tumors predominantly located in the suprasellar region, third ventricle and posterior fossa, which are considered to be more clinically aggressive than pilocytic astrocytomas (PA). Another entity, intermediate pilomyxoid tumors (IPT), exists within the spectrum of pilocytic/pilomyxoid astrocytomas. The 2021 WHO CNS classification refrained from assigning grade 1 or 2 status to PMA, thereby reflecting the need to further elucidate their clinical and imaging characteristics. We included a total of 15 patients with PMA, IPT and suprasellar PA. We retrospectively evaluated immunohistochemistry, imaging findings and diffusion characteristics within these tumors as well as whole exome sequencing for three of the cases. 87% of the tumors were supratentorial with 11 cases suprasellar in location, 1 case located in the frontal white matter and 1 in the hippocampus. 6 cases demonstrated intraventricular extension. ADC values were higher in PMA and IPT than PA. 3 cases demonstrated KIAA1549-BRAF-fusion, 2 had BRAF[Formula: see text]-mutation and 6 were BRAF-wildtype. All cases had recurrence/progression on follow-up. PMA and IPT do not demonstrate aggressive imaging characteristics in respect to their diffusion imaging with ADC values being higher than PA. Lack of BRAF-alteration in PMA corresponded to atypical location of tumors with atypical driver mutations and mechanisms.

Rethinking the Management of Optic Pathway Gliomas: A Single Center Experience.

BackgroundOptic pathway gliomas (OPGs) are rare neoplasms in children with an unpredictable clinical course. Approximately 15% of OPGs occur in patients affected by neurofibromatosis type 1 (NF1): the clinical course of these cases is more indolently than sporadic ones, and NF1 patients less frequently require treatment including surgery. Instead, over 90% of sporadic OPGs require one or more therapeutic approaches. The management of OPG is controversial. They are also characterized by a high risk of morbidity including hypothalamic damage, endocrine deficits, visual deficit and/or neurological impairment.Materials and MethodsIn this paper, we evaluated visual and endocrinological outcomes of a population of OPG followed at our center from 2013 to 2021, with a particular emphasis on the role of surgery.ResultsTwenty-six patients were included in this study (mean age of 40.7 months). Tumor location on imaging was described by the Dodge classification. Five cases had NF 1. Thirteen cases received biopsy and 13 were partially resected. Histopathology revealed 19 cases of pilocytic astrocytomas, 2 pilomyxoid astrocytoma and 5 ganglioglioma. All the patients required a post-surgical adjuvant treatment according to current indications for low-grade gliomas. Molecular studies (BRAF status and mTOR/pmTOR pathway) have been performed in 24/26 patients, following for the use of target therapy in 11 of these patients. In our study we found that patients underwent biopsy have a better visual and endocrinological outcomes rather than patients with a tumor debulking. The five-year overall survival rate is 98% with a mean follow-up of 60 months.ConclusionsMany children with OPGs survive with a residual tumor. They suffer from chronic diseases such as endocrine dysfunction, visual disturbance, motor deficits and poor quality of life. All patients need comprehensive diagnostic work-up including neuroimaging, clinical evaluations and neuropathology approach; at the same time, they need therapeutic decisions and concepts for the choice of timing and type of neurosurgical intervention, chemotherapy and target therapy as well as surveillance and rehabilitation to maximize survival and overall functional outcomes. Our study showed that minimal invasive surgery with the purpose of molecular characterization of the tumor is desirable to reduce morbidity correlate to surgery.

LGG-36. Analysis of BRAF-related mutations in pediatric low-grade glioma

BACKGROUND: Most pediatric low-grade gliomas (pLGGs) are driven by a single genetic event resulting in up-regulation of the RAS/MAPK pathway. BRAF-related mutations are the most freauent molecular alteration in the pathway. To explore BRAF-related mutations in pediatric low-grade glioma is helpful for clinical practice. METHODS: In this study, patients with low-grade glioma aged ≤18 years in Guangdong Sanjiu Brain Hospital were enrolled. All patients accepted the tests of BRAF-related mutations with tumor tissue by next-generation sequencing (NGS). Results: A total of 26 patients diagnosed low-grade glioma and underwent NGS detection were included in this study. The male to female ratio was 6:7, and the median age was 9.5 years. 8 patients had tumors located in the cerebral hemisphere, 6 in the third or fourth ventricle, 5 in the cerebellum, 4 in the optic pathway, and 3 in the brain stem. A total of 14 patients took BRAF-related mutations, such as BRAF-KIAA1549 fusion, BRAF p.V600E mutation and other fusion. BRAF-KIAA1549 fusion was detected in 7 patients with pilocytic astrocytoma or pilomyxoid astrocytoma. BRAF p.V600E mutation was detected in 6 patients, two of whom were pleomorphic xanthoastrocytoma. A rare genetic fusion, BCAS1-BRAF fusion, was detected in 1 patient who had brain stem ganglioglioma. Among the 26 patients, 2 patients without BRAF-related mutations had typical multiple cafe-au-lait macules and were diagnosed as NF1-pLGG. These patients were treated with surgery, radiation, chemotherapy and targeted therapy. Only 2 patients received targeted therapy by Trametinib, Vimofinib and Everolimus after progression of the tumor. However, due to the severity of the disease, they eventually died. CONCLUSIONS: More than half of pLGG patients have BRAF-related mutations, which have the opportunity for targeted therapy. However, the optimal timing of targeted therapy still needs further exploration.

LGG-42. Thromboembolic toxicity observed with concurrent trametinib and lenalidomide therapy

INTRODUCTION: Event-free survival of pediatric low-grade glioma (pLGG) is poor, and patients often require multiple treatment strategies. The hallmark of pLGGs are genetic aberrations of the mitogen-activated protein kinase pathway, which lead to constitutive pathway activation. MEK and RAF inhibitors target this pathway and are efficacious in early phase trials in recurrent pLGGs. However, not all patients respond to monotherapy, and many experience progression after completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. Lenalidomide is an immunomodulatory agent with an anti-tumor effect demonstrated in phase 1 trials in recurrent pediatric central nervous system (CNS) tumors. OBJECTIVE: To describe our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system (PNS) tumors. METHODS: Retrospective review of patients’ medical records. RESULTS: Four patients with locally recurrent primary CNS or PNS tumors, three with WHO grade II pilomyxoid astrocytomas and one with a plexiform neurofibroma, were treated with trametinib and lenalidomide concurrently. Two patients developed severe thromboembolic events. One patient was treated with combination therapy for seven months until trametinib and lenalidomide were held after urgent ventriculoperitoneal shunt revision. Shortly following shunt revision, he experienced near-complete vision loss. MRI of the brain demonstrated a left posterior watershed territory hypoxic-ischemic injury. In a second patient, after four months of combination therapy, surveillance echocardiogram showed an incidental finding of severe biventricular dysfunction with a left ventricular ejection fraction (LVEF) of 17.7% and two mural thrombi in the left ventricular apex. She started losartan and enoxaparin and discontinued trametinib and lenalidomide. Her LVEF normalized four months later, and the mural thrombi resolved. CONCLUSIONS: Given the severe thromboembolic events experienced by these patients treated with concomitant trametinib and lenalidomide, this combination requires further investigation, and we urge caution if used concurrently.

Optic Pathway-Hypothalamic Glioma Apoplexy: A Report of Two Cases and Systematic Review of the Literature.

BackgroundHemorrhage into optic pathway–hypothalamic glioma (OPHG) is rare. Variable clinical presentations and outcomes are associated with such pathology. We aim to present two infants presented with OPHG and a systematic review of the literature.MethodsWe describe two cases of infants presenting with sudden decreased vision, poor feeding, and irritability due to OPHG. Both patients underwent urgent craniotomy and subtotal resection followed by chemotherapy. We systematically reviewed the literature using PubMed, Google Scholar, and Embase. In addition, we included all English published reports for all ages discussing the optic pathway (optic nerve and optic chiasm) or hypothalamic glioma associated with hemorrhage from the year of the first reported case (1970) to January 2022.ResultsOf 17,949, 44 articles met the inclusion criteria of this review. A total of 56 cases were described with a mean of 21.35 years (0.5–70), with the male gender 52% and the female gender 45%. The hemorrhage location was sellar/suprasellar in 43% cases. Histopathology of included cases was pilocytic astrocytoma in 41%, followed by pilomyxoid astrocytoma in 16% cases. The outcome was unfavorable; 37.5% cases showed improvement, whereas 18% cases resulted in death.ConclusionApoplexy of the OPHG can be fatal and associated with poor outcomes. A systematic review of the literature has shown that younger age, pilocytic or pilomexyoid astrocytoma histopathology, and chiasmal/hypothalamic locations are associated with a higher risk of intertumoral hemorrhage and poor prognosis. Further genetic studies for OPHG may provide information for high-risk patients.