Diffuse Leptomeningeal Glioneuronal Tumour: Molecular Diagnosis, Evolution and Treatment

Diffuse Leptomeningeal Glioneuronal Tumour: Molecular Diagnosis, Evolution and Treatment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Diffuse Leptomeningeal Glioneuronal Tumour: Molecular Diagnosis, Evolution and Treatment Anastasia Campanelli, Alice Métais, Yassine Bouchoucha, Kevin Beccaria, and 20 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6597257/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Oct, 2025 Read the published version in Acta Neuropathologica Communications → Version 1 posted 9 You are reading this latest preprint version Abstract Diffuse leptomeningeal glioneuronal tumour (DLGNT) is rare a glioneuronal neoplasm of the central nervous system, which occurs mainly in children and adolescents characterized by the presence of MAPK pathway alteration and 1p deletion. Clinical, radiological and molecular data from 20 patients diagnosed with DLGNT from May 2001 to May 2023 were collected. Clinical presentation was polymorphous, with intracranial hypertension and back pain as most common symptoms. Patients underwent multiple lines of treatment (median of 4, range 1-8) in addition to surgery with a median follow up of 94 months (range 7–241). Radiotherapy and carboplatin-based chemotherapy were the 2 treatments with the higher number of partial response (PR) and stable disease (SD) of 7/10 and 2/10 for radiotherapy and 7/12 and 5/12 for carboplatin-based chemotherapy. All patients treated with trametinib progressed before 2 years, while 2-years PFS was of 52% (95% CI 20-77%), for carboplatin-based chemotherapy, 40% (95% CI 10-70%) for radiotherapy, 29% (95% CI 9-53%) for Temozolomide and 13% (95% CI 1-42%) for Vinblastine/Vinorelbine. Neurological sequelae concerned 70% of patients with at least on neurological impairment at last follow-up. In total, 7 patients died including 5 from disease progression. The 5-years and 10-years OS were of 88% (95% CI 59-97%) and 78% (95% CI 45-93%) respectively. Our work reports the outcome and treatment response of a retrospective cohort of DLGNT. Close monitoring appears to be the key to early treatment initiation and limiting patient disability. Further prospective studies in multi-institutional cohorts are needed to better define a standardized treatment approach. Low grade glioma MAP kinase targeted therapy chemotherapy central nervous system tumor molecular diagnosis Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Diffuse leptomeningeal glioneuronal tumour (DLGNT) is a rare tumour entity that was first introduced in the WHO Classification of Tumours of the Central Nervous System in 2016 [ 1 ]. This low-grade tumour occurs mainly in children and adolescents, but several cases were also diagnosed in young adults. This disease affects preferentially males with a sex ratio of 1.6 [ 2 , 3 ]. Clinical presentations are highly variable [ 4 ]. Patients may present with a range of symptoms, including increased intracranial pressure, meningeal syndrome, cranial nerve dysfunction, ataxia, seizures or progressive neurological deficits [ 5 , 6 ]. Radiological presentation are multiple and leptomeningeal enhancement is not always present at diagnosis [ 7 ]. Histopathological analysis reveals the presence of lesions with low to moderate cellularity, composed of relatively monomorphic oligodendrocyte-like cells [ 8 ]. Neuronal markers, such as synaptophysin, are often accompanied by glial markers, including glial fibrillary acidic protein, oligodendrocyte transcription factor 2, and S-100 protein [ 9 ]. Given the wide range of clinical, radiological, and histopathological features, molecular biology plays a pivotal role for diagnosis. The 2021 WHO Classification of Tumours of the Central Nervous System requires two molecular characteristics: (1) alteration of the Mitogen-Activated Protein Kinase (MAPK) pathway, most frequently BRAF rearrangements/duplications, and (2) deletion of chromosome 1p [ 10 , 11 ]. Metais et al. confirmed the specificity of the 1p deletion for DLGNTs that allows to exclude the diagnosis of pilocytic astrocytomas (PA) [ 12 , 13 ]. Recently, 1q gain was described as an adverse prognostic factor [ 14 ]. Clinical evolution of DLGNT is very diverse. While the majority of patients experience a relatively slow tumour evolution, some patients display rapid progression which can ultimately result in fatal outcomes [ 5 ]. Regarding the therapeutic approach, DLGNTs are usually not amenable to complete resection due to the extent of the disease. There is little data in the literature on DLGNT treatment. Response rate to either chemotherapy, radiotherapy or targeted therapy is still not well defined. To date, there is no evidence-based therapeutic recommendations, underscoring an urgent need for further research to inform the development of novel therapeutic strategies. In this study, we conducted a comprehensive analysis of the biology and the medical history of a cohort of patients with DLGNT diagnosed after 2000, evaluating their clinical presentation, the treatments they received, and their outcome. MATERIAL AND METHODS Patients Patients treated in Gustave Roussy (Villejuif, France), Institut Curie (Paris, France) and Toulouse Oncopole (Toulouse, France) were identified in the hospitals database. Parents or guardians gave consent for a retrospective analysis according to the institutional review board of Gustave Roussy (IRB: N° 2024 − 446). The inclusion criteria were the diagnosis of DLGNT on histopathology, by expert neuropathologists from GHU Paris Psychiatry and Neurosciences, with both alteration in the MAPK pathway (including BRAF alterations, NTRK rearrangement or FGFR alterations) and a deletion of chromosome 1p. Patients who did not have these molecular characteristics or who had other molecular alterations such as H3K28 or loss of trimethylation were not included ( Supplementary Fig. 1 ). Clinical and radiological data at the time of diagnosis were retrospectively collected, including sex, age, clinical symptoms, in particular information on neurological impairment, endocrinological deficiencies, vision status, tumour location and the presence of leptomeningeal contrast enhancement. Radiological evaluation Brain and spinal MRI was used to assess radiological response to treatment using the Radiological Assessment in Pediatric Neuro-Oncology (RApNO) criteria by a neuro-oncologist and a neuroradiologist [ 15 ]. All diseases progression were discussed in neuro-oncology tumour board. No central review was performed. Responses were assessed based on pre-treatment baseline MRIs. The response criteria were defined as follows: - Complete response (CR): No evidence of residual or recurrent tumour or dissemination; - Partial response (PR): Tumour volume reduction of at least 50% without the presence of new lesions; - Stable disease (SD): Tumour volume changes between + 25% and − 25% without the appearance of new lesions; - Progressive disease (PD): ≥ 25% increase in tumour size or presence of new lesions. Molecular biology BRAF or NTRK rearrangements were identified by fluorescence in situ hybridization (FISH) or RNA sequencing. Deletion of chromosome 1p and gain of chromosome 1q were analysed with either FISH or found in the copy number variation (CNV) profile obtained from DNA methylation profiling using the Illumina Infinium Methylation assay as previously described, using DNA methylation-based classification of CNS tumours from Deutsches Krebsforschungszentrum—German Cancer Research Center [ 12 ]. Neuropathological examination was performed at GHU Paris Sainte Anne for 13 patients who were also included in the 2022 study by Metais A et al. [ 12 ]. Treatment Patients in our cohort received several lines of treatment including surgery (partial resection or gross total resection), radiotherapy, chemotherapy and targeted therapy. Chemotherapy plans comprised carboplatin and vincristine according to the SIOP LGG 2004 protocol or other therapeutic regimens, temozolomide, vinblastine and vinorelbine[ 16 – 20 ]. In some cases with life threatening symptoms or acute risk of neurological worsening including vision impairment, bevacizumab was added to the SIOP LGG chemotherapy after decision in tumor board by the treating center as it showed activity in low grade gliomas [ 21 ]. Fourteen patients were treated with the MEK inhibitor trametinib and NTRK inhibitors such as selitrectinib, larotrectinib, repotrectinib and entrectinib[ 22 – 25 ]. Focal and craniospinal irradiation was performed using either photon (n = 9) or proton (n = 1). We describe for each patient the various lines of treatment, considering surgery (partial resection or gross total resection), radiotherapy, chemotherapy and targeted therapy. Each line of treatment was assessed for its duration, the best radiological response (reviewed in a neuro-oncology tumour board), the clinical response (defined as improvement, stability or worsening of the symptoms presented at the time of the start of treatment) and the time from discontinuation to new disease progression. Statistics Survival analysis was conducted according to Kaplan-Meier methods using Graphpad software (GraphPad Prism version 10.2.1 for Windows, GraphPad Software, Boston, Massachusetts USA) in order to analyse overall survival (OS) in our cohort and progression free survival (PFS) for each line of treatment performed by at least two patients. The Cox proportional hazard models for multivariable analysis were adjusted for age, gender and 1q gain status. Interaction tests were calculated. R packages survminer (0.5.0) and survival (3.8-3) were used. RESULTS Clinical presentation and molecular diagnosis. Thirty-one patients were initially identified with a presumptive diagnosis of DLGNT over a 22 years period from May 2001 to May 2023. Of these, 11 were excluded from the study due to a central revision of the diagnosis ( Supplementary Fig. 1) . All the patients had a MAPK alteration and a 1p loss. The median age at diagnosis was 6 years and 2 months, with a range of 19 months to 17 years and 9 months. The sex ratio was 7:13 (females:males). The median follow-up was 94.3 months (range 7–241). With regard to molecular biology analysis, the 1q gain was observed in half of the patient. DNA methylation profiling was performed for 7 patients (6 methylation class 1 and 1 methylation class 2) and they all fell into the DLGNT methylation class with a score above 0.9. The clinical presentation of the disease is highly heterogeneous, with intracranial hypertension and back pain being the most common symptoms, occurring in 8 and 6 patients, respectively. Leptomeningeal contrast enhancement was identified in 12 patients (60%). Of these, 10 patients had multiple localisations and 2 patients had a localised intraparenchymal tumour. Among the 8 patients without leptomeningeal involvement, 6 patients had localised disease and 2 had multiple localisations. Altogether, 12 patients had evidence of metastatic disease that affected both spinal and intracranial compartment. In 15 patients with a molecularly proven diagnosis of DLGNT, the initial histological assessment pointed towards differential diagnoses: pilocytic astrocytoma, oligodendroglioma and diffuse leptomeningeal gliomatosis. In 13 cases, definitive diagnosis of DLGNT required a new biopsy and molecular biology analysis (Table 1, Supplementary Table 1 ). The five patients who were diagnosed with DLGNT as their initial diagnosis were identified after 2018. Interestingly, we describe for the first time a patient with proven DLGNT harbouring a FGFR1 duplication found on bulk RNA sequencing as a MAP kinase pathway alteration ( Supplementary Figure 2 ). Table 1 Median age at diagnosis 6 y 2 m (19 m – 17 y 9 m) Sex ratio (females/males) 7/13 Localization Spinal only 7 (35%) Intracranial only 1 (5%) Both 12 (60%) Leptomeningeal contrast enhancement 12 (60%) Clinical symptoms Hydrocephalus 8 (40%) Back pain 6 (30%) Seizures 2 (10%) Diplopia/decreased visual acuity 2 (10%) Neck pain 2 (10%) Balance disorder / ataxia 2 (10%) Headache (not related to IH) 1 (5%) Nystagmus 1 (5%) Spastic paraplegia 1 (5%) Weight loss 1 (5%) MAPK pathway alteration BRAF rearrangement (1) 15 (75%) NTRK fusion 3 (15%) RAF1::QKI fusion 1 (5%) Duplication FGFR1 1 (5%) Gain 1q Present 10 (50%) Absent 9 (45%) Unknown 1 (5%) Table 1. Patients’ characteristics Characteristics of patients at diagnosis. Regarding molecular biology, chromosome 1p deletion is mandatory for the diagnosis of DLGNT as well as MAPK pathway alteration; among the BRAF rearrangements identified, KIAA1549::BRAF fusion was detected in 12 patients while 3 patients had only BRAF rearrangement detected by FISH (1) Response to treatment Patients received from 1 to 8 lines of treatment with a median of 4, considering chemotherapy, targeted therapy and radiotherapy. We analysed the radiological and clinical response to each treatment received by two or more patients, assessed after the treatment itself ( Figure 1 ). All treatments are represented in figure 2 and listed in supplementary table 1 . Half of the patients received radiation therapy. Of these 10 patients, 2 received focal irradiation. One patient received spinal irradiation, and the other 7 patients received craniospinal irradiation. We observed a partial response (PR) in 7/10 patients (70%) ( Figure 1A ). All patients who received radiotherapy were symptomatic. Six of the 7 patients who had a PR to radiotherapy also experienced a clinical improvement, while the latter had a clinical stability ( Figure 1B ). Chemotherapy was the most common treatment, with all but one patient receiving at least one line of chemotherapy, ranging from 1 to 6 lines of chemotherapy with a median of 2 lines. Twelve patients received carboplatin-based chemotherapy at some point during their treatment. PR was observed in 7/12 (58%) patients ( Figure 1A ). Three of the 11 patients who received SIOP LGG also received bevacizumab and all of them experienced a PR. Carboplatin-based chemotherapy was the first line of treatment in 9 patients; in this subgroup, 4 patients had PR and 5 patients had SD. Twelve patients had symptoms prior to carboplatin-based chemotherapy, 6 experienced an improvement and 4 were stabilized. Two patients who received bevacizumab in combination with SIOP-LGG showed clinical improvement and the remaining had his symptoms stabilized. None of the patients treated with carboplatin-based chemotherapy experienced PD during treatment, but two had worsening of neurologic condition secondary to treatment related toxicity ( Figure 2 ). Temozolomide was the most widely used treatment with 17 patients receiving it. The best radiological response was PR in 2 patients (12%). Both cases were associated with clinical improvement, in terms of balance disorder with neck pain for patient #11 and paraplegia for patient #15. SD was observed in 8 (47%) patients, while 7 (41%) had PD. Eight patients received vinblastine or vinorelbine at some point during their treatment. PR was observed in 2 patients, SD and PD in 4 and 2 patients, respectively. Considering all chemotherapies together, we observed that 11/37 (30%) experienced a PR and 17/37 (46%) experienced a SD as the best radiological response. Therefore, the radiological disease control rate defined by PR+SD was 28/37 (76%), which is close to the clinical control rate defined by improvement+stability of 29/37 (78%). A total of 13 patients received targeted therapy and 4 patients received more than one line of targeted therapy. Of the 10 patients who received trametinib, 2 patients had a PR, 4 had a SD and 4 had a PD as their best radiological response. Only one patient, patient #10, experienced improvement of paraplegia associated with SD, which may also be related to intensive rehabilitation and physiotherapy. NTRK inhibitors were administered to the 3 patients in whom a NTRK rearrangement was identified. One patient received larotrectinib with radiological and clinical stabilization. The other two patients received more than one type of NTRK inhibitor: Patient #5 received larotrectinib, selitrectinib and entrectinib with disease progression and clinical worsening with all three drugs. Patient #7 had a partial response to larotrectinib within LOXO-TRK-15003 study [22]. After a PD at only one site, she was switched to repotrectinib. Interestingly, while her symptoms stabilized on larotrectinib, she showed clinical improvement on reprotrectinib. She was bridged to radiotherapy and presented with a new PD 4 months after completion of radiotherapy. ( Figure 1A and 2, supplementary table 1 ). Patients’ outcome Despite the diversity of the population, we conducted an analysis of patients' progression-free survival (PFS) for each treatment ( Figure 3 ). The two-year PFS rate for radiotherapy was 40% (95% CI 10-70%). With regard to chemotherapy, the two-year PFS rates for carboplatin-based chemotherapy, temozolomide and vinblastine/vinorelbine were 52% (95% CI 20-77%), 29% (95% CI 9-53%) and 13% (95% CI 1-42%), respectively. Ultimately, all the 11 patients who received trametinib experienced disease progression within two years, 9 of them while on treatment. No statistical differences were found between the treatments (log-rank test). Prolonged control of over a year was observed with radiotherapy (3/10), carboplatin-based chemotherapy (1/12), temozolomide (1/17) after discontinuing treatment and with TRK inhibitors (1/7) with ongoing treatment. The individual data evolution are presented in Figure 2 . In contrast, all patients treated with trametinib or vinblastine/vinorelbine experienced a PD within 1 and 20 months and within 3 and 37 months respectively. To evaluate whether the number of treatment lines impacts the outcome, we evaluated the PFS for first line treatment, all treatment combined. Two-year PFS was 45% (CI 95% 22-66%). When comparing the PFS of the first line treatment with the PFS of the second and third lines, no statistically significant difference was found (log-rank test), although a slight downward trend in PFS was identified for the second and third lines of treatment which is respectively 26% (CI 95% 7-50%) and 24% (CI 95% 5-52%) ( Figure 4A ). Only three patients received a single line of treatment. Patient #3 had a response to radiotherapy, with a disease control over ten years. Patient #12 achieved clinical and radiological stabilisation following the SIOP LGG protocol, with a follow-up period of 6.5 years. The third patient (#17) received SIOP LGG with Bevacizumab and is also controlled with a follow-up period of seven months. A total of seven patients died during follow-up, with five deaths attributed to disease progression, one to pulmonary infection in a situation of neurological deterioration and one to suicide. Two of the deaths occurred within the first five years of diagnosis (one due to disease progression and the other due to pulmonary infection), while four occurred between nine and 11 years after diagnosis, and one occurred 20 years after diagnosis. The five-year and ten-year overall survival rates were 88% (95% CI 59-97%) and 78% (95% CI 45-93%), respectively. ( Figure 4B ). Finally, there was no difference in outcome between patients with and without 1q gain regarding PFS and OS in univariable or multivariable analysis ( Supplementary Figure 3 ). Neurological impairment In patients with LGG, neurological disorders represent a significant cause of disability, constituting a primary rationale for initiating treatment. Our observations revealed that 14 out of 20 patients (70%) exhibited neurological impairment at the last follow-up. Among the 13 patients who developed new symptoms during their treatment and surveillance, 10 appeared while on treatment and 3 during surveillance. The full spectrum of neurological disorders at the last follow-up is documented in Table 2 . ABSENT 6/20 PRESENT Motor disorders 14/20 12/14 (86%) Sphincter function disorders 3/14 (21%) Facial paralysis 2/14 (14%) Sensitive disorders (hypoesthesia) 2/14 (14%) Balance disorders 1/14 (7%) Visual impairment 1/14 (7%) Table 2. Table 2. Neurological impairment at last follow-up Neurological impairment was evaluated considering the symptoms at last follow up. DISCUSSION In this study, we analysed a series of DLGNT, an entity that is often misdiagnosed and treated with very different strategies in the absence of specific recommendations. We report the clinical and radiological presentation of this disease in a retrospective cohort of 20 patients and describe the different treatment strategies with their respective responses. Among these, carboplatin-based chemotherapy and radiotherapy seem interesting, although this needs to be carefully understood given the small number of patients. As mentioned, patients received multiple lines of different treatment approaches. Our results suggest that a carboplatin-based chemotherapy and radiotherapy exhibited the most favourable outcome. Bevacizumab, which is often used in combination with chemotherapy in low grade gliomas, was added in too few patients to draw any conclusions. However, it is interesting to note, however, that all types of chemotherapy were shown to have some efficacy in treating patients, even after multiple lines of treatment. It is important to emphasise that protocols based on carboplatin and vinca alkaloids are recognised for their lack of long-term toxicity and should therefore remain a preferred therapeutic option when feasible. Several small series report stable disease and rare partial responses to chemotherapy, including carboplatine based, TMZ and VBL [ 11 , 26 , 27 ] However, the numbers are still very small and there is little clinical data available on treatment response. Radiotherapy is an effective treatment for paediatric low-grade glioma with good control in the majority of patients in our cohort. Responses have also been reported in case reports, but it remains a second choice treatment in young patients due to its neurocognitive toxicity [ 26 , 28 – 34 ] . Targeted therapies were used in cases where a known targetable alteration was identified. Although clinical and radiological responses were observed, these were not sustained over time. Trametinib, a MEK inhibitor, was given in the context of a BRAF rearrangement, given that MEK inhibitors have been shown to be effective in the treatment of pilocytic astrocytoma with the same BRAF rearrangement and different NTRK inhibitors (repotrectinib, entrectinib, larotrectinib, selitrectinib) were used in patients with NTRK mutation [ 15 , 35 , 36 ]. Clinical presentation of DLGNT is highly variable. In our cohort, we observed a considerable degree of clinical heterogeneity with no specific presentation. Furthermore, although the terms “diffuse” and “leptomeningeal” being inherent in the disease's name, we confirmed that DLGNT can be localised and without leptomeningeal involvement. Therefore, molecular biology plays a key role in the diagnosis of DLGNT as defined in the latest WHO classification [ 10 ]. This study exclusively encompasses patients exhibiting a MAPK pathway alteration associated with chromosomal deletion, as previously described [ 8 , 12 ]. Molecular alterations in the MAP kinase pathway have been identified both at the receptor level (e.g. FGFR) and downstream of the signalling pathway, with the common and well-known BRAF alterations. Indeed, to our knowledge, we describe for the first time a DLGNT with an FGFR1 duplication. Histology and molecular pathology results should always be considered in the diagnosis of low-grade glioma, even in the face of a localised spinal or intracranial lesion in the absence of leptomeningeal involvement [ 3 , 12 , 37 ]. The presence of the molecular criteria is essential for the differential diagnosis of DLGNT from other tumour entities, such as pilocytic astrocytoma or other low-grade tumours. Thus, the absence of the classic KIAA1549::BRAF translocation or the BRAF V600E mutation should prompt a search for other alterations. This is a crucial aspect not only in terms of diagnosis, but also for the selection of appropriate therapeutic options. As we previously stated, some patients from this cohort were heavily treated with many different lines. While low-grade glioma is generally acknowledged to be less aggressive in older patients, this does not appear to be the case with DLGNT. Our observations show that, in some cases, multiple lines of treatment are required after a period of relatively stable disease, as illustrated in Fig. 2 . This raises the question of whether, for some patients, the disease may evolve to a more aggressive form. In light of this, a new biopsy to characterize this potential different entity could be proposed for future patients. Although chromosome 1q gain has been shown in other studies to be a negative prognostic factor that may adversely affect progression-free survival, it did not show a significant impact on outcome in our cohort [ 14 ]. While the number of patients analysed may partially explain this difference, with 32 patients in the study by Chiang et al. versus 20 in our cohort, the type of treatment received is a major potential source of bias that must be considered. In previous publications, treatments are not extensively detailed, making it impossible to compare cohorts. It would be useful to expand these analyses including data on molecular abnormalities and treatment modalities. We also observed a high incidence of neurological impairment in our cohort. The type of neurological disorders and their degree of severity are variable but can have an important impact on the quality of life of patients, requiring further treatments and comprehensive care. Since the long-term sequelae of the pathology are added to the sequelae of the treatments received, patients with DLGNT need a long-term oncological, hormonal and neurological follow up [ 38 – 40 ]. DLGNT is a rare disease entity that it is important to diagnose correctly using molecular biology to differentiate it from other low-grade CNS tumours from which it would be difficult to distinguish based solely on clinical, radiological and pathological presentation. Our work provides new insights into the potential responses to different lines of treatment, particularly radiotherapy and chemotherapy using the vincristine-carboplatin combination. Further studies on larger samples would be needed to better define optimal treatment approaches. Considering the high incidence of neurological impairment and its impact on patients' quality of life, close monitoring and initiation of treatment in case of clinical and radiological progression seems important in order to limit the patient's disability and improve their quality of life. Abbreviations DLGNT Diffuse leptomeningeal glioneuronal tumour MAPK Mitogen-activated protein kinase PR Partial response SD Stable disease PD Progressive disease PFS Progression free survival OS Overall survival PA Pilocytic Astrocytoma NTRK Neurotrophic tyrosine receptor kinase FGFR Fibroblast growth factor receptor LGG Low-grade glioma TMZ Temozolomide VBL Vinblastine Declarations AUTHOR CONTRIBUTIONS SA and AC conceived and designed the project, analysed the data, prepared figures and wrote the manuscript. JG and CD collaborated in the design of the project and were major contributors in writing the manuscript. AM, ATE and PV contributed to the recruitment of patients, anatomopathological and molecular analysis and revised the paper. FD, YB, FB, LGR and MS substantively revised the paper and contributed to the recruitment of patients. CK contributed to the creation of the swimmer plot. AL contributed to the recruitment of patients. KB, TB, LG and SB evaluated surgical management. NB and VDR supervised the interpretation of the imaging. AM and RA have contributed to the realisation of the “Supplementary figure 2”. SB, VM and NS evaluated the radiotherapy treatment and revised the paper. All authors read and approved the final manuscript. Ethics approval and consent to participate Parents or guardians gave consent for a retrospective analysis according to the institutional review board of Gustave Roussy (IRB: N° 2024-446). Consent for publication Not applicable Competing interests SA: FORE pharmaceutical, Lilly and Ipsen: research funding support as a consultant. 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Contemporary outcomes of diffuse leptomeningeal glioneuronal tumor in pediatric patients: A case series and literature review. Clin Neurol Neurosurg. 2022;218:107265. Ajithkumar T, Taylor R, Kortmann RD. Radiotherapy in the Management of Paediatric Low-Grade Gliomas. Clin Oncol (R Coll Radiol). 2019;31:151–61. Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol. 2004;5:399–408. Weusthof K, Lüttich P, Regnery S, König L, Bernhardt D, Witt O, et al. Neurocognitive Outcomes in Pediatric Patients Following Brain Irradiation. Cancers (Basel). 2021;13:3538. Satragno C, Kieffer V, Dufour C, Martin V, Sellami N, Lanfranchi F, et al. QOL-29. COGNITIVE DEVELOPMENT WITHIN TWO YEARS AFTER CRANIOSPINAL IRRADIATION IN CHILDREN TREATED FOR MEDULLOBLASTOMA: A COMPREHENSIVE ASSESSMENT USING AGE-APPROPRIATE SCALES. Neuro Oncol. 2024;26:0. Doger de Speville E, Robert C, Perez-Guevara M, Grigis A, Bolle S, Pinaud C, et al. Relationships between Regional Radiation Doses and Cognitive Decline in Children Treated with Cranio-Spinal Irradiation for Posterior Fossa Tumors. Front Oncol. 2017;7:166. Geenen MM, Cardous-Ubbink MC, Kremer LCM, van den Bos C, van der Pal HJH, Heinen RC, et al. Medical Assessment of Adverse Health Outcomes in Long-term Survivors of Childhood Cancer. JAMA. 2007;297:2705–15. Mulder RL, Kremer LCM, Santen HM van, Ket JL, Trotsenburg ASP van, Koning CCE, et al. Prevalence and risk factors of radiation-induced growth hormone deficiency in childhood cancer survivors: A systematic review. Cancer Treatment Reviews. 2009;35:616–32. Fangusaro J, Onar-Thomas A, Young Poussaint T, Wu S, Ligon AH, Lindeman N, et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019;20:1011–22. Lamoureux A-A, Fisher MJ, Lemelle L, Pfaff E, Amir-Yazdani P, Kramm C, et al. Clinical Characteristics and Outcomes of Central Nervous System Tumors Harboring NTRK Gene Fusions. Clin Cancer Res. 2025;31:561–72. Appay R, Pages M, Colin C, Jones DTW, Varlet P, Figarella-Branger D. Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases. Acta Neuropathol Commun. 2020;8:95. Rosimont M, Kariyawasam D, Samara-Boustani D, Giani E, Beltrand J, Bolle S, et al. Assessment of Puberty and Hypothalamic-Pituitary-Gonadal Axis Function After Childhood Brain Tumor Treatment. J Clin Endocrinol Metab. 2023;108:e823–31. González Briceño LG, Kariyawasam D, Samara-Boustani D, Giani E, Beltrand J, Bolle S, et al. High Prevalence of Early Endocrine Disorders After Childhood Brain Tumors in a Large Cohort. J Clin Endocrinol Metab. 2022;107:e2156–66. Morin A, Allodji R, Kariyawasam D, Touraine P, Puget S, Beccaria K, et al. Very long-term outcomes of pediatric patients treated for optic pathway gliomas: A longitudinal cohort study. Neuro Oncol. 2024;noae045. Additional Declarations Competing interest reported. S.A.: FORE pharmaceutical, Lilly and Ipsen: research funding support as a consultant. Patent for oral suspension of temozolomide. Y.B.: Institut Servier Other authors declare no competing interests. Supplementary Files SupplementaryFiguresandTables.docx Cite Share Download PDF Status: Published Journal Publication published 01 Oct, 2025 Read the published version in Acta Neuropathologica Communications → Version 1 posted Editorial decision: Revision requested 11 Jun, 2025 Reviews received at journal 04 Jun, 2025 Reviews received at journal 02 Jun, 2025 Reviewers agreed at journal 16 May, 2025 Reviewers agreed at journal 15 May, 2025 Reviewers invited by journal 15 May, 2025 Editor assigned by journal 07 May, 2025 Submission checks completed at journal 07 May, 2025 First submitted to journal 05 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6597257","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":457434217,"identity":"96554055-8542-4395-a936-f2978742af13","order_by":0,"name":"Anastasia Campanelli","email":"","orcid":"","institution":"Gustave Roussy Cancer Campus","correspondingAuthor":false,"prefix":"","firstName":"Anastasia","middleName":"","lastName":"Campanelli","suffix":""},{"id":457434218,"identity":"d8cb34f4-4c88-4747-bad0-2522343ceed7","order_by":1,"name":"Alice Métais","email":"","orcid":"","institution":"Sainte-Anne 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20:38:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6597257/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6597257/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40478-025-02100-1","type":"published","date":"2025-10-01T15:56:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83148951,"identity":"0ab55405-bb44-435f-b153-bc1bf8babdc3","added_by":"auto","created_at":"2025-05-20 13:29:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":910622,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003eRadiological (A) and clinical (B) response\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eBubble charts showing radiological (\u003cstrong\u003eA\u003c/strong\u003e) and clinical (\u003cstrong\u003eB\u003c/strong\u003e) response to treatment. The size of each circle is proportional to the percentage of patient for each treatment/column independently with the absolute number of patients within the circle. Each individual treatment line is considered therefore patients may be represented in multiple columns. In 4 cases a patient received the same type of treatment more than once: patient #2 received vinblastine and vinorelbine, patient #5 and #7 received different NTRK inhibitors and patient #11 received temozolomide twice (\u003cem\u003eSupplementary Table 1\u003c/em\u003e)\u003cem\u003e. \u003c/em\u003eBest radiological response was defined as PR, SD, and PD. Clinical response was defined as improvement, stability or worsening of the symptoms. PR: Partial response, SD: stable disease, PD: progressive disease.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6597257/v1/5adbd31b64311409947be651.png"},{"id":83148953,"identity":"da3ea3ee-ca86-4a66-8d9b-44c0d42d2821","added_by":"auto","created_at":"2025-05-20 13:29:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1656228,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003eSwimmer plot\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis figure depicts patients’ evolution throughout time in years, considering the different treatments received and the radiological evolution. The dashed line represents the patient's follow-up time. Black arrows indicate that the current treatment is ongoing. The crossed black square indicates the death of the patient. The empty rectangles represent the treatments received and their length reflects the treatment time; blue rectangles represent chemotherapy and purple rectangles represent targeted therapy. Radiation therapy is represented by lightning bolts. The best radiological response to treatment and other significant radiological assessments are represented with a green square for PR, a yellow circle for SD, and a red triangle for PD. Notably, patient #3 showed a significant clinical and radiological response with resolution of neuropathic pain that had been present prior to irradiation and allowed discontinuation of gabapentin. Similarly, patient #8 experienced a significant improvement in balance disorders secondary to craniospinal radiotherapy, which allowed resolution of a major walking disorder. Patient #14 demonstrated a remarkable clinical and radiological response to treatment with SIOP-LGG protocol. Prior to treatment, the patient had symptoms of neuropathic pain and an inability to walk without assistance. After treatment, she reported a reduction in pain and recovery of motor and sensory function, including the ability to walk again. \u0026nbsp;Patient #1 experienced a severe clinical deterioration due to a PRESS syndrome. Patient #6, who initially presented with upper limb motor deficit, developed a severe polyneuropathy with flaccid tetraparesis and cranial nerves involvement. Vincristine was discontinued, resulting in partial recovery. PR: Partial response, SD: stable disease, PD: progressive disease.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6597257/v1/54f989282ebd0ffc4f3f9108.png"},{"id":83148972,"identity":"f6c364cb-7415-4960-8ddc-493883f7c2dd","added_by":"auto","created_at":"2025-05-20 13:29:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":228044,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003eProgression Free Survival.\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eKaplan-Meier method was used to evaluate the progression free survival for each treatment received by 2 or more patients. Dashes in the curves represent patients who did not experience progression. No Kaplan-Meier analysis was done for NTRK inhibitors because of the small number of patients, as only 3 patients received this treatment with a total of 7 courses. PFS: Progression free survival.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6597257/v1/fe64f37c3ffda1afca7c3fba.png"},{"id":83149388,"identity":"2f541a6f-7213-4477-a888-668ce9af5398","added_by":"auto","created_at":"2025-05-20 13:37:55","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":186791,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003eProgression Free Survival and Overall Survival\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eFigure 4A. PFS 1\u003csup\u003est, \u003c/sup\u003e2\u003csup\u003end\u003c/sup\u003e and 3\u003csup\u003erd\u003c/sup\u003e line of treatment. Kaplan-Meier method was used to evaluate the progression free survival for the first (black), second (red) and third (blue) line of treatment, all treatments combined. Dashes in the curves represent patients who did not experience progression.\u003c/p\u003e\n\u003cp\u003eFigure 4B. Overall Survival. Kaplan-Meier analysis was performed to evaluate the overall survival at 15 years. Dashes in the curve represent patients who are alive at last follow up. The coloured area around the curve represents the confidence interval. PFS: Progression free survival. OS: Overall survival.\u0026nbsp;\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6597257/v1/8d105595f90ad4ad0589fd58.png"},{"id":92883949,"identity":"f4f74e79-b788-476d-b110-84eaf2b5a961","added_by":"auto","created_at":"2025-10-06 16:11:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4016399,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6597257/v1/bbf67369-b2d5-40db-b3f8-7a810446f4d3.pdf"},{"id":83148949,"identity":"7fe3edd0-8898-4d1d-83ac-b221c2d0c30e","added_by":"auto","created_at":"2025-05-20 13:29:55","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":522951,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFiguresandTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6597257/v1/06306db3862add32837151f8.docx"}],"financialInterests":"Competing interest reported. S.A.: FORE pharmaceutical, Lilly and Ipsen: research funding support as a consultant. Patent for oral suspension of temozolomide. \nY.B.: Institut Servier\nOther authors declare no competing interests.","formattedTitle":"\u003cp\u003eDiffuse Leptomeningeal Glioneuronal Tumour: Molecular Diagnosis, Evolution and Treatment\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eDiffuse leptomeningeal glioneuronal tumour (DLGNT) is a rare tumour entity that was first introduced in the WHO Classification of Tumours of the Central Nervous System in 2016 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This low-grade tumour occurs mainly in children and adolescents, but several cases were also diagnosed in young adults. This disease affects preferentially males with a sex ratio of 1.6 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Clinical presentations are highly variable [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Patients may present with a range of symptoms, including increased intracranial pressure, meningeal syndrome, cranial nerve dysfunction, ataxia, seizures or progressive neurological deficits [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Radiological presentation are multiple and leptomeningeal enhancement is not always present at diagnosis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHistopathological analysis reveals the presence of lesions with low to moderate cellularity, composed of relatively monomorphic oligodendrocyte-like cells [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Neuronal markers, such as synaptophysin, are often accompanied by glial markers, including glial fibrillary acidic protein, oligodendrocyte transcription factor 2, and S-100 protein [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the wide range of clinical, radiological, and histopathological features, molecular biology plays a pivotal role for diagnosis. The 2021 WHO Classification of Tumours of the Central Nervous System requires two molecular characteristics: (1) alteration of the Mitogen-Activated Protein Kinase (MAPK) pathway, most frequently \u003cem\u003eBRAF\u003c/em\u003e rearrangements/duplications, and (2) deletion of chromosome 1p [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Metais et al. confirmed the specificity of the 1p deletion for DLGNTs that allows to exclude the diagnosis of pilocytic astrocytomas (PA) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Recently, 1q gain was described as an adverse prognostic factor [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinical evolution of DLGNT is very diverse. While the majority of patients experience a relatively slow tumour evolution, some patients display rapid progression which can ultimately result in fatal outcomes [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Regarding the therapeutic approach, DLGNTs are usually not amenable to complete resection due to the extent of the disease. There is little data in the literature on DLGNT treatment. Response rate to either chemotherapy, radiotherapy or targeted therapy is still not well defined.\u003c/p\u003e \u003cp\u003eTo date, there is no evidence-based therapeutic recommendations, underscoring an urgent need for further research to inform the development of novel therapeutic strategies.\u003c/p\u003e \u003cp\u003eIn this study, we conducted a comprehensive analysis of the biology and the medical history of a cohort of patients with DLGNT diagnosed after 2000, evaluating their clinical presentation, the treatments they received, and their outcome.\u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003ePatients\u003c/h2\u003e\n \u003cp\u003ePatients treated in Gustave Roussy (Villejuif, France), Institut Curie (Paris, France) and Toulouse Oncopole (Toulouse, France) were identified in the hospitals database. Parents or guardians gave consent for a retrospective analysis according to the institutional review board of Gustave Roussy (IRB: N\u0026deg; 2024\u0026thinsp;\u0026minus;\u0026thinsp;446).\u003c/p\u003e\n \u003cp\u003eThe inclusion criteria were the diagnosis of DLGNT on histopathology, by expert neuropathologists from GHU Paris Psychiatry and Neurosciences, with both alteration in the MAPK pathway (including \u003cem\u003eBRAF\u003c/em\u003e alterations, \u003cem\u003eNTRK\u003c/em\u003e rearrangement or \u003cem\u003eFGFR\u003c/em\u003e alterations) and a deletion of chromosome 1p. Patients who did not have these molecular characteristics or who had other molecular alterations such as H3K28 or loss of trimethylation were not included (\u003cstrong\u003eSupplementary Fig.\u0026nbsp;1\u003c/strong\u003e). Clinical and radiological data at the time of diagnosis were retrospectively collected, including sex, age, clinical symptoms, in particular information on neurological impairment, endocrinological deficiencies, vision status, tumour location and the presence of leptomeningeal contrast enhancement.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eRadiological evaluation\u003c/h3\u003e\n\u003cp\u003eBrain and spinal MRI was used to assess radiological response to treatment using the Radiological Assessment in Pediatric Neuro-Oncology (RApNO) criteria by a neuro-oncologist and a neuroradiologist [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]. All diseases progression were discussed in neuro-oncology tumour board. No central review was performed. Responses were assessed based on pre-treatment baseline MRIs. The response criteria were defined as follows:\u003c/p\u003e\n\u003cp\u003e- Complete response (CR): No evidence of residual or recurrent tumour or dissemination;\u003c/p\u003e\n\u003cp\u003e- Partial response (PR): Tumour volume reduction of at least 50% without the presence of new lesions;\u003c/p\u003e\n\u003cp\u003e- Stable disease (SD): Tumour volume changes between +\u0026thinsp;25% and \u0026minus;\u0026thinsp;25% without the appearance of new lesions;\u003c/p\u003e\n\u003cp\u003e- Progressive disease (PD): \u0026ge; 25% increase in tumour size or presence of new lesions.\u003c/p\u003e\n\u003cp\u003eMolecular biology\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBRAF\u003c/em\u003e or \u003cem\u003eNTRK\u003c/em\u003e rearrangements were identified by fluorescence in situ hybridization (FISH) or RNA sequencing. Deletion of chromosome 1p and gain of chromosome 1q were analysed with either FISH or found in the copy number variation (CNV) profile obtained from DNA methylation profiling using the Illumina Infinium Methylation assay as previously described, using DNA methylation-based classification of CNS tumours from Deutsches Krebsforschungszentrum\u0026mdash;German Cancer Research Center [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. Neuropathological examination was performed at GHU Paris Sainte Anne for 13 patients who were also included in the 2022 study by Metais A et al. [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003ePatients in our cohort received several lines of treatment including surgery (partial resection or gross total resection), radiotherapy, chemotherapy and targeted therapy. Chemotherapy plans comprised carboplatin and vincristine according to the SIOP LGG 2004 protocol or other therapeutic regimens, temozolomide, vinblastine and vinorelbine[\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]. In some cases with life threatening symptoms or acute risk of neurological worsening including vision impairment, bevacizumab was added to the SIOP LGG chemotherapy after decision in tumor board by the treating center as it showed activity in low grade gliomas [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. Fourteen patients were treated with the MEK inhibitor trametinib and NTRK inhibitors such as selitrectinib, larotrectinib, repotrectinib and entrectinib[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eFocal and craniospinal irradiation was performed using either photon (n\u0026thinsp;=\u0026thinsp;9) or proton (n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e\n\u003cp\u003eWe describe for each patient the various lines of treatment, considering surgery (partial resection or gross total resection), radiotherapy, chemotherapy and targeted therapy. Each line of treatment was assessed for its duration, the best radiological response (reviewed in a neuro-oncology tumour board), the clinical response (defined as improvement, stability or worsening of the symptoms presented at the time of the start of treatment) and the time from discontinuation to new disease progression.\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistics\u003c/h2\u003e\n \u003cp\u003eSurvival analysis was conducted according to Kaplan-Meier methods using Graphpad software (GraphPad Prism version 10.2.1 for Windows, GraphPad Software, Boston, Massachusetts USA) in order to analyse overall survival (OS) in our cohort and progression free survival (PFS) for each line of treatment performed by at least two patients. The Cox proportional hazard models for multivariable analysis were adjusted for age, gender and 1q gain status. Interaction tests were calculated. R packages survminer (0.5.0) and survival (3.8-3) were used.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cem\u003eClinical presentation and molecular diagnosis.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThirty-one patients were initially identified with a presumptive diagnosis of DLGNT over a 22 years period from May 2001 to May 2023. Of these, 11 were excluded from the study due to a central revision of the diagnosis (\u003cstrong\u003eSupplementary Fig.\u0026nbsp;1)\u003c/strong\u003e. All the patients had a MAPK alteration and a 1p loss. The median age at diagnosis was 6 years and 2 months, with a range of 19 months to 17 years and 9 months. The sex ratio was 7:13 (females:males). The median follow-up was 94.3 months (range 7–241). With regard to molecular biology analysis, the 1q gain was observed in half of the patient. DNA methylation profiling was performed for 7 patients (6 methylation class 1 and 1 methylation class 2) and they all fell into the DLGNT methylation class with a score above 0.9. The clinical presentation of the disease is highly heterogeneous, with intracranial hypertension and back pain being the most common symptoms, occurring in 8 and 6 patients, respectively.\u003c/p\u003e\n\u003cp\u003eLeptomeningeal contrast enhancement was identified in 12 patients (60%). Of these, 10 patients had multiple localisations and 2 patients had a localised intraparenchymal tumour. Among the 8 patients without leptomeningeal involvement, 6 patients had localised disease and 2 had multiple localisations. Altogether, 12 patients had evidence of metastatic disease that affected both spinal and intracranial compartment.\u003c/p\u003e\n\u003cp\u003eIn 15 patients with a molecularly proven diagnosis of DLGNT, the initial histological assessment pointed towards differential diagnoses: pilocytic astrocytoma, oligodendroglioma and diffuse leptomeningeal gliomatosis. In 13 cases, definitive diagnosis of DLGNT required a new biopsy and molecular biology analysis (Table 1, \u003cstrong\u003eSupplementary Table\u0026nbsp;1\u003c/strong\u003e). The five patients who were diagnosed with DLGNT as their initial diagnosis were identified after 2018.\u0026nbsp;Interestingly, we describe for the first time a patient with proven DLGNT harbouring a FGFR1 duplication found on bulk RNA sequencing as a MAP kinase pathway alteration (\u003cstrong\u003eSupplementary Figure 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eTable 1\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Taba\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eMedian age at diagnosis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e6 y 2 m (19 m – 17 y 9 m)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex ratio (females/males)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7/13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocalization\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpinal only\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntracranial only\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBoth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeptomeningeal contrast enhancement\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"10\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical symptoms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydrocephalus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBack pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSeizures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiplopia/decreased visual acuity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeck pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBalance disorder / ataxia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHeadache (not related to IH)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNystagmus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpastic paraplegia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeight loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eMAPK pathway alteration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBRAF rearrangement\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNTRK fusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRAF1::QKI fusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDuplication FGFR1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eGain 1q\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cu\u003eTable 1. Patients’ characteristics\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eCharacteristics of patients at diagnosis. Regarding molecular biology, chromosome 1p deletion is mandatory for the diagnosis of DLGNT as well as MAPK pathway alteration; among the BRAF rearrangements identified, KIAA1549::BRAF fusion was detected in 12 patients while 3 patients had only BRAF rearrangement detected by FISH\u003csup\u003e(1)\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003cp\u003e\u003cem\u003eResponse to treatment\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003ePatients received from 1 to 8 lines of treatment with a median of 4, considering chemotherapy, targeted therapy and radiotherapy.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eWe analysed the radiological and clinical response to each treatment received by two or more patients, assessed after the treatment itself (\u003cstrong\u003eFigure 1\u003c/strong\u003e). All treatments are represented in \u003cstrong\u003efigure 2\u0026nbsp;\u003c/strong\u003eand listed in\u003cstrong\u003e\u0026nbsp;supplementary table 1\u003c/strong\u003e.\u003c/p\u003e\n \u003cp\u003eHalf of the patients received radiation therapy. Of these 10 patients, 2 received focal irradiation. One patient received spinal irradiation, and the other 7 patients received craniospinal irradiation. We observed a partial response (PR) in 7/10 patients (70%) (\u003cstrong\u003eFigure 1A\u003c/strong\u003e). All patients who received radiotherapy were symptomatic. Six of the 7 patients who had a PR to radiotherapy also experienced a clinical improvement, while the latter had a clinical stability (\u003cstrong\u003eFigure 1B\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eChemotherapy was the most common treatment, with all but one patient receiving at least one line of chemotherapy, ranging from 1 to 6 lines of chemotherapy with a median of 2 lines. Twelve patients received carboplatin-based chemotherapy at some point during their treatment. PR was observed in 7/12 (58%) patients (\u003cstrong\u003eFigure 1A\u003c/strong\u003e). Three of the 11 patients who received SIOP LGG also received bevacizumab and all of them experienced a PR. Carboplatin-based chemotherapy was the first line of treatment in 9 patients; in this subgroup, 4 patients had PR and 5 patients had SD. Twelve patients had symptoms prior to carboplatin-based chemotherapy, 6 experienced an improvement and 4 were stabilized. Two patients who received bevacizumab in combination with SIOP-LGG showed clinical improvement and the remaining had his symptoms stabilized. None of the patients treated with carboplatin-based chemotherapy experienced PD during treatment, but two had worsening of neurologic condition secondary to treatment related toxicity (\u003cstrong\u003eFigure 2\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eTemozolomide was the most widely used treatment with 17 patients receiving it. The best radiological response was PR in 2 patients (12%). Both cases were associated with clinical improvement, in terms of balance disorder with neck pain for patient #11 and paraplegia for patient #15. SD was observed in 8 (47%) patients, while 7 (41%) had PD.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eEight patients received vinblastine or vinorelbine at some point during their treatment. PR was observed in 2 patients, SD and PD in 4 and 2 patients, respectively.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eConsidering all chemotherapies together, we observed that 11/37 (30%) experienced a PR and 17/37 (46%) experienced a SD as the best radiological response. Therefore, the radiological disease control rate defined by PR+SD was 28/37 (76%), which is close to the clinical control rate defined by improvement+stability of 29/37 (78%).\u003c/p\u003e\n \u003cp\u003eA total of 13 patients received targeted therapy and 4 patients received more than one line of targeted therapy. Of the 10 patients who received trametinib, 2 patients had a PR, 4 had a SD and 4 had a PD as their best radiological response. Only one patient, patient #10, experienced improvement of paraplegia associated with SD, which may also be related to intensive rehabilitation and physiotherapy.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNTRK inhibitors were administered to the 3 patients in whom a \u003cem\u003eNTRK\u003c/em\u003e rearrangement was identified. One patient received larotrectinib with radiological and clinical stabilization. The other two patients received more than one type of NTRK inhibitor: Patient #5 received larotrectinib, selitrectinib and entrectinib with disease progression and clinical worsening with all three drugs. Patient #7 had a partial response to larotrectinib within LOXO-TRK-15003 study [22]. After a PD at only one site, she was switched to repotrectinib. Interestingly, while her symptoms stabilized on larotrectinib, she showed clinical improvement on reprotrectinib. She was bridged to radiotherapy and presented with a new PD 4 months after completion of radiotherapy. (\u003cstrong\u003eFigure 1A and 2, supplementary table 1\u003c/strong\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ePatients’ outcome\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eDespite the diversity of the population, we conducted an analysis of patients' progression-free survival (PFS) for each treatment (\u003cstrong\u003eFigure 3\u003c/strong\u003e). The two-year PFS rate for radiotherapy was 40% (95% CI 10-70%). With regard to chemotherapy, the two-year PFS rates for carboplatin-based chemotherapy, temozolomide and vinblastine/vinorelbine were 52% (95% CI 20-77%), 29% (95% CI 9-53%) and 13% (95% CI 1-42%), respectively. Ultimately, all the 11 patients who received trametinib experienced disease progression within two years, 9 of them while on treatment. No statistical differences were found between the treatments (log-rank test).\u003c/p\u003e\n \u003cp\u003eProlonged control of over a year was observed with radiotherapy (3/10), carboplatin-based chemotherapy (1/12), temozolomide (1/17) after discontinuing treatment and with TRK inhibitors (1/7) with ongoing treatment. The individual data evolution are presented in \u003cstrong\u003eFigure 2\u003c/strong\u003e. In contrast, all patients treated with trametinib or vinblastine/vinorelbine experienced a PD within 1 and 20 months and within 3 and 37 months respectively.\u003c/p\u003e\n \u003cp\u003eTo evaluate whether the number of treatment lines impacts the outcome, we evaluated the PFS for first line treatment, all treatment combined. Two-year PFS was 45% (CI 95% 22-66%). When comparing the PFS of the first line treatment with the PFS of the second and third lines, no statistically significant difference was found (log-rank test), although a slight downward trend in PFS was identified for the second and third lines of treatment which is respectively 26% (CI 95% 7-50%) and 24% (CI 95% 5-52%) (\u003cstrong\u003eFigure 4A\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eOnly three patients received a single line of treatment. Patient #3 had a response to radiotherapy, with a disease control over ten years. Patient #12 achieved clinical and radiological stabilisation following the SIOP LGG protocol, with a follow-up period of 6.5 years. The third patient (#17) received SIOP LGG with Bevacizumab and is also controlled with a follow-up period of seven months.\u003c/p\u003e\n \u003cp\u003eA total of seven patients died during follow-up, with five deaths attributed to disease progression, one to pulmonary infection in a situation of neurological deterioration and one to suicide. Two of the deaths occurred within the first five years of diagnosis (one due to disease progression and the other due to pulmonary infection), while four occurred between nine and 11 years after diagnosis, and one occurred 20 years after diagnosis. The five-year and ten-year overall survival rates were 88% (95% CI 59-97%) and 78% (95% CI 45-93%), respectively. (\u003cstrong\u003eFigure 4B\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFinally, there was no difference in outcome between patients with and without 1q gain regarding PFS and OS in univariable or multivariable analysis (\u003cstrong\u003eSupplementary Figure 3\u003c/strong\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eNeurological impairment\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eIn patients with LGG, neurological disorders represent a significant cause of disability, constituting a primary rationale for initiating treatment. Our observations revealed that 14 out of 20 patients (70%) exhibited neurological impairment at the last follow-up. Among the 13 patients who developed new symptoms during their treatment and surveillance, 10 appeared while on treatment and 3 during surveillance. The full spectrum of neurological disorders at the last follow-up is documented in \u003cstrong\u003eTable 2\u003c/strong\u003e.\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"630\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eABSENT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e6/20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePRESENT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMotor disorders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e14/20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e12/14 (86%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSphincter function disorders\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e3/14 (21%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFacial paralysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2/14 (14%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSensitive disorders (hypoesthesia)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2/14 (14%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBalance disorders\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1/14 (7%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVisual impairment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1/14 (7%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cu\u003eTable 2.\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u003cu\u003eTable 2. Neurological impairment at last follow-up\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003eNeurological impairment was evaluated considering the symptoms at last follow up.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, we analysed a series of DLGNT, an entity that is often misdiagnosed and treated with very different strategies in the absence of specific recommendations. We report the clinical and radiological presentation of this disease in a retrospective cohort of 20 patients and describe the different treatment strategies with their respective responses. Among these, carboplatin-based chemotherapy and radiotherapy seem interesting, although this needs to be carefully understood given the small number of patients.\u003c/p\u003e \u003cp\u003eAs mentioned, patients received multiple lines of different treatment approaches. Our results suggest that a carboplatin-based chemotherapy and radiotherapy exhibited the most favourable outcome. Bevacizumab, which is often used in combination with chemotherapy in low grade gliomas, was added in too few patients to draw any conclusions. However, it is interesting to note, however, that all types of chemotherapy were shown to have some efficacy in treating patients, even after multiple lines of treatment. It is important to emphasise that protocols based on carboplatin and vinca alkaloids are recognised for their lack of long-term toxicity and should therefore remain a preferred therapeutic option when feasible. Several small series report stable disease and rare partial responses to chemotherapy, including carboplatine based, TMZ and VBL [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] However, the numbers are still very small and there is little clinical data available on treatment response.\u003c/p\u003e \u003cp\u003eRadiotherapy is an effective treatment for paediatric low-grade glioma with good control in the majority of patients in our cohort. Responses have also been reported in case reports, but it remains a second choice treatment in young patients due to its neurocognitive toxicity [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29 CR30 CR31 CR32 CR33\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] .\u003c/p\u003e \u003cp\u003eTargeted therapies were used in cases where a known targetable alteration was identified. Although clinical and radiological responses were observed, these were not sustained over time. Trametinib, a MEK inhibitor, was given in the context of a \u003cem\u003eBRAF\u003c/em\u003e rearrangement, given that MEK inhibitors have been shown to be effective in the treatment of pilocytic astrocytoma with the same \u003cem\u003eBRAF\u003c/em\u003e rearrangement and different NTRK inhibitors (repotrectinib, entrectinib, larotrectinib, selitrectinib) were used in patients with NTRK mutation [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinical presentation of DLGNT is highly variable. In our cohort, we observed a considerable degree of clinical heterogeneity with no specific presentation. Furthermore, although the terms \u0026ldquo;diffuse\u0026rdquo; and \u0026ldquo;leptomeningeal\u0026rdquo; being inherent in the disease's name, we confirmed that DLGNT can be localised and without leptomeningeal involvement. Therefore, molecular biology plays a key role in the diagnosis of DLGNT as defined in the latest WHO classification [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This study exclusively encompasses patients exhibiting a MAPK pathway alteration associated with chromosomal deletion, as previously described [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Molecular alterations in the MAP kinase pathway have been identified both at the receptor level (e.g. FGFR) and downstream of the signalling pathway, with the common and well-known \u003cem\u003eBRAF\u003c/em\u003e alterations. Indeed, to our knowledge, we describe for the first time a DLGNT with an FGFR1 duplication. Histology and molecular pathology results should always be considered in the diagnosis of low-grade glioma, even in the face of a localised spinal or intracranial lesion in the absence of leptomeningeal involvement [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The presence of the molecular criteria is essential for the differential diagnosis of DLGNT from other tumour entities, such as pilocytic astrocytoma or other low-grade tumours. Thus, the absence of the classic \u003cem\u003eKIAA1549::BRAF\u003c/em\u003e translocation or the \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003eV600E\u003c/sup\u003e mutation should prompt a search for other alterations. This is a crucial aspect not only in terms of diagnosis, but also for the selection of appropriate therapeutic options.\u003c/p\u003e \u003cp\u003eAs we previously stated, some patients from this cohort were heavily treated with many different lines. While low-grade glioma is generally acknowledged to be less aggressive in older patients, this does not appear to be the case with DLGNT. Our observations show that, in some cases, multiple lines of treatment are required after a period of relatively stable disease, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. This raises the question of whether, for some patients, the disease may evolve to a more aggressive form. In light of this, a new biopsy to characterize this potential different entity could be proposed for future patients. Although chromosome 1q gain has been shown in other studies to be a negative prognostic factor that may adversely affect progression-free survival, it did not show a significant impact on outcome in our cohort [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. While the number of patients analysed may partially explain this difference, with 32 patients in the study by Chiang et al. versus 20 in our cohort, the type of treatment received is a major potential source of bias that must be considered. In previous publications, treatments are not extensively detailed, making it impossible to compare cohorts. It would be useful to expand these analyses including data on molecular abnormalities and treatment modalities.\u003c/p\u003e \u003cp\u003eWe also observed a high incidence of neurological impairment in our cohort. The type of neurological disorders and their degree of severity are variable but can have an important impact on the quality of life of patients, requiring further treatments and comprehensive care. Since the long-term sequelae of the pathology are added to the sequelae of the treatments received, patients with DLGNT need a long-term oncological, hormonal and neurological follow up [\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDLGNT is a rare disease entity that it is important to diagnose correctly using molecular biology to differentiate it from other low-grade CNS tumours from which it would be difficult to distinguish based solely on clinical, radiological and pathological presentation. Our work provides new insights into the potential responses to different lines of treatment, particularly radiotherapy and chemotherapy using the vincristine-carboplatin combination. Further studies on larger samples would be needed to better define optimal treatment approaches. Considering the high incidence of neurological impairment and its impact on patients' quality of life, close monitoring and initiation of treatment in case of clinical and radiological progression seems important in order to limit the patient's disability and improve their quality of life.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eDLGNT Diffuse leptomeningeal glioneuronal tumour\u003c/p\u003e\n\u003cp\u003eMAPK Mitogen-activated protein kinase\u003c/p\u003e\n\u003cp\u003ePR Partial response\u003c/p\u003e\n\u003cp\u003eSD Stable disease\u003c/p\u003e\n\u003cp\u003ePD Progressive disease\u003c/p\u003e\n\u003cp\u003ePFS Progression free survival\u003c/p\u003e\n\u003cp\u003eOS Overall survival\u003c/p\u003e\n\u003cp\u003ePA Pilocytic Astrocytoma\u003c/p\u003e\n\u003cp\u003eNTRK Neurotrophic tyrosine receptor kinase\u003c/p\u003e\n\u003cp\u003eFGFR Fibroblast growth factor receptor\u003c/p\u003e\n\u003cp\u003eLGG Low-grade glioma\u003c/p\u003e\n\u003cp\u003eTMZ Temozolomide\u003c/p\u003e\n\u003cp\u003eVBL Vinblastine\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSA and AC conceived and designed the project, analysed the data, prepared figures and wrote the manuscript. JG and CD collaborated in the design of the project and were major contributors in writing the manuscript. AM, ATE and PV contributed to the recruitment of patients, anatomopathological and molecular analysis and revised the paper. FD, YB, FB, LGR and MS substantively revised the paper and contributed to the recruitment of patients. CK contributed to the creation of the swimmer plot. AL contributed to the recruitment of patients. KB, TB, LG and SB evaluated surgical management. NB and VDR supervised the interpretation of the imaging. AM and RA have contributed to the realisation of the \u0026ldquo;Supplementary figure 2\u0026rdquo;. SB, VM and NS evaluated the radiotherapy treatment and revised the paper. All authors read and approved the final\u0026nbsp;manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParents or guardians gave consent for a retrospective analysis according to the institutional review board of Gustave Roussy (IRB: N\u0026deg;\u0026nbsp;2024-446).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSA: FORE pharmaceutical, Lilly and Ipsen: research funding support as a consultant. Patent for oral suspension of temozolomide.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eYB: Institut Servier\u003c/p\u003e\n\u003cp\u003eOther authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eF\u003c/strong\u003e\u003cstrong\u003eunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLouis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131:803\u0026ndash;20. \u003c/li\u003e\n\u003cli\u003eCho HJ, Myung JK, Kim H, Park C-K, Kim S-K, Chung CK, et al. Primary diffuse leptomeningeal glioneuronal tumors. 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Neuro Oncol. 2022;24:1776\u0026ndash;89. \u003c/li\u003e\n\u003cli\u003eHanzlik E, Archambault B, El-Dairi M, Schroeder K, Patel MP, Lipp ES, et al. Use of Trametinib in Children and Young Adults With Progressive Low-grade Glioma and Glioneuronal Tumors. J Pediatr Hematol Oncol. 2023;45:e464\u0026ndash;70. \u003c/li\u003e\n\u003cli\u003eAguilera D, Castellino RC, Janss A, Schniederjan M, McNall R, MacDonald T, et al. Clinical responses of patients with diffuse leptomeningeal glioneuronal tumors to chemotherapy. Childs Nerv Syst. 2018;34:329\u0026ndash;34. \u003c/li\u003e\n\u003cli\u003eLu VM, Di L, Gernsback J, Eichberg DG, Luther EM, Shah AH, et al. Contemporary outcomes of diffuse leptomeningeal glioneuronal tumor in pediatric patients: A case series and literature review. Clin Neurol Neurosurg. 2022;218:107265. \u003c/li\u003e\n\u003cli\u003eAjithkumar T, Taylor R, Kortmann RD. Radiotherapy in the Management of Paediatric Low-Grade Gliomas. Clin Oncol (R Coll Radiol). 2019;31:151\u0026ndash;61. \u003c/li\u003e\n\u003cli\u003eMulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol. 2004;5:399\u0026ndash;408. \u003c/li\u003e\n\u003cli\u003eWeusthof K, L\u0026uuml;ttich P, Regnery S, K\u0026ouml;nig L, Bernhardt D, Witt O, et al. Neurocognitive Outcomes in Pediatric Patients Following Brain Irradiation. Cancers (Basel). 2021;13:3538. \u003c/li\u003e\n\u003cli\u003eSatragno C, Kieffer V, Dufour C, Martin V, Sellami N, Lanfranchi F, et al. QOL-29. COGNITIVE DEVELOPMENT WITHIN TWO YEARS AFTER CRANIOSPINAL IRRADIATION IN CHILDREN TREATED FOR MEDULLOBLASTOMA: A COMPREHENSIVE ASSESSMENT USING AGE-APPROPRIATE SCALES. Neuro Oncol. 2024;26:0. \u003c/li\u003e\n\u003cli\u003eDoger de Speville E, Robert C, Perez-Guevara M, Grigis A, Bolle S, Pinaud C, et al. Relationships between Regional Radiation Doses and Cognitive Decline in Children Treated with Cranio-Spinal Irradiation for Posterior Fossa Tumors. Front Oncol. 2017;7:166. \u003c/li\u003e\n\u003cli\u003eGeenen MM, Cardous-Ubbink MC, Kremer LCM, van den Bos C, van der Pal HJH, Heinen RC, et al. Medical Assessment of Adverse Health Outcomes in Long-term Survivors of Childhood Cancer. JAMA. 2007;297:2705\u0026ndash;15. \u003c/li\u003e\n\u003cli\u003eMulder RL, Kremer LCM, Santen HM van, Ket JL, Trotsenburg ASP van, Koning CCE, et al. Prevalence and risk factors of radiation-induced growth hormone deficiency in childhood cancer survivors: A systematic review. Cancer Treatment Reviews. 2009;35:616\u0026ndash;32. \u003c/li\u003e\n\u003cli\u003eFangusaro J, Onar-Thomas A, Young Poussaint T, Wu S, Ligon AH, Lindeman N, et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019;20:1011\u0026ndash;22. \u003c/li\u003e\n\u003cli\u003eLamoureux A-A, Fisher MJ, Lemelle L, Pfaff E, Amir-Yazdani P, Kramm C, et al. Clinical Characteristics and Outcomes of Central Nervous System Tumors Harboring NTRK Gene Fusions. Clin Cancer Res. 2025;31:561\u0026ndash;72. \u003c/li\u003e\n\u003cli\u003eAppay R, Pages M, Colin C, Jones DTW, Varlet P, Figarella-Branger D. Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases. Acta Neuropathol Commun. 2020;8:95. \u003c/li\u003e\n\u003cli\u003eRosimont M, Kariyawasam D, Samara-Boustani D, Giani E, Beltrand J, Bolle S, et al. Assessment of Puberty and Hypothalamic-Pituitary-Gonadal Axis Function After Childhood Brain Tumor Treatment. J Clin Endocrinol Metab. 2023;108:e823\u0026ndash;31. \u003c/li\u003e\n\u003cli\u003eGonz\u0026aacute;lez Brice\u0026ntilde;o LG, Kariyawasam D, Samara-Boustani D, Giani E, Beltrand J, Bolle S, et al. High Prevalence of Early Endocrine Disorders After Childhood Brain Tumors in a Large Cohort. J Clin Endocrinol Metab. 2022;107:e2156\u0026ndash;66. \u003c/li\u003e\n\u003cli\u003eMorin A, Allodji R, Kariyawasam D, Touraine P, Puget S, Beccaria K, et al. Very long-term outcomes of pediatric patients treated for optic pathway gliomas: A longitudinal cohort study. Neuro Oncol. 2024;noae045. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"acta-neuropathologica-communications","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anec","sideBox":"Learn more about [Acta Neuropathologica Communications](https://actaneurocomms.biomedcentral.com/)","snPcode":"40478","submissionUrl":"https://submission.springernature.com/new-submission/40478/3","title":"Acta Neuropathologica Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Low grade glioma, MAP kinase, targeted therapy, chemotherapy, central nervous system tumor, molecular diagnosis","lastPublishedDoi":"10.21203/rs.3.rs-6597257/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6597257/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDiffuse leptomeningeal glioneuronal tumour (DLGNT) is rare a glioneuronal neoplasm of the central nervous system, which occurs mainly in children and adolescents characterized by the presence of MAPK pathway alteration and 1p deletion.\u003c/p\u003e\n\u003cp\u003eClinical, radiological and molecular data from 20 patients diagnosed with DLGNT from May 2001 to May 2023 were collected.\u003c/p\u003e\n\u003cp\u003eClinical presentation was polymorphous, with intracranial hypertension and back pain as most common symptoms. Patients underwent multiple lines of treatment (median of 4, range 1-8) in addition to surgery with a median follow up of 94 months (range 7–241). Radiotherapy and carboplatin-based chemotherapy were the 2 treatments with the higher number of partial response (PR) and stable disease (SD) of 7/10 and 2/10 for radiotherapy and 7/12 and 5/12 for carboplatin-based chemotherapy. All patients treated with trametinib progressed before 2 years, while 2-years PFS was of 52% (95% CI 20-77%), for carboplatin-based chemotherapy, 40% (95% CI 10-70%) for radiotherapy, 29% (95% CI 9-53%) for Temozolomide and 13% (95% CI 1-42%) for Vinblastine/Vinorelbine. Neurological sequelae concerned 70% of patients with at least on neurological impairment at last follow-up. In total, 7 patients died including 5 from disease progression. The 5-years and 10-years OS were of 88% (95% CI 59-97%) and 78% (95% CI 45-93%) respectively. Our work reports the outcome and treatment response of a retrospective cohort of DLGNT. Close monitoring appears to be the key to early treatment initiation and limiting patient disability. Further prospective studies in multi-institutional cohorts are needed to better define a standardized treatment approach.\u003c/p\u003e","manuscriptTitle":"Diffuse Leptomeningeal Glioneuronal Tumour: Molecular Diagnosis, Evolution and Treatment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-20 13:29:50","doi":"10.21203/rs.3.rs-6597257/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-11T14:34:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-04T06:57:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-02T21:33:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"62667416541352984881001229202784599370","date":"2025-05-16T06:33:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"141225839151067435255490385349172866742","date":"2025-05-16T03:50:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-15T23:04:02+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-07T08:54:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-07T08:47:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Acta Neuropathologica Communications","date":"2025-05-05T20:31:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"acta-neuropathologica-communications","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anec","sideBox":"Learn more about [Acta Neuropathologica Communications](https://actaneurocomms.biomedcentral.com/)","snPcode":"40478","submissionUrl":"https://submission.springernature.com/new-submission/40478/3","title":"Acta Neuropathologica Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f54d2568-bc72-4f5e-9e80-4da019442df3","owner":[],"postedDate":"May 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-06T16:05:35+00:00","versionOfRecord":{"articleIdentity":"rs-6597257","link":"https://doi.org/10.1186/s40478-025-02100-1","journal":{"identity":"acta-neuropathologica-communications","isVorOnly":false,"title":"Acta Neuropathologica Communications"},"publishedOn":"2025-10-01 15:56:58","publishedOnDateReadable":"October 1st, 2025"},"versionCreatedAt":"2025-05-20 13:29:50","video":"","vorDoi":"10.1186/s40478-025-02100-1","vorDoiUrl":"https://doi.org/10.1186/s40478-025-02100-1","workflowStages":[]},"version":"v1","identity":"rs-6597257","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6597257","identity":"rs-6597257","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}