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Child's Nervous System : ChNS :... Jun 2024The extent of resection of pediatric low-grade glioma mostly improves progression-free survival. In chiasmatic hypothalamic glioma (CHG), complete resections are limited...
OBJECTIVE
The extent of resection of pediatric low-grade glioma mostly improves progression-free survival. In chiasmatic hypothalamic glioma (CHG), complete resections are limited due to the relevantly high risk of associated neurological and endocrinological deficits. Still, surgery might have its role in the framework of a multidisciplinary team (MDT) approach. We report our retrospective experience from two centers on surgical options and their impact on long-term outcomes.
METHODS
Medical records of surgically treated pediatric CHG patients between 2004 and 2022 were analyzed. Patient characteristics, surgical interventions, histology, and non-surgical therapy were retrieved together with outcome measures such as visual acuity, endocrine function, and survival.
RESULTS
A total of 63 patients (33 female, NF-1, n = 8) were included. Age at first diagnosis was 4.6 years (range 0.2-16.9) and cohort follow-up was 108 ± 72 months. Twenty patients were surgically treated with a biopsy and 43 patients with debulking at a median age of 6.5 years (range 0.16-16.9). Patients received a median of 2 tumor surgeries (range 1-5). Cyst drainage was accomplished in 15 patients, and 27 patients had ventriculoperitoneal shunt implantation. Non-surgical therapy was given in 69.8%. At the end of follow-up, 74.6% of patients had stable disease. The cohort had a median Karnofsky score of 90 (range 0-100). Four patients died. Hormone substitution was necessary in 30.2%, and visual acuity was impaired in 66% of patients.
CONCLUSION
Pediatric CHG is a chronic disease due to overall high survival with multiple progressions. Surgical therapy remains a key treatment option offering biopsy, limited tumor-debulking, cyst fenestration, and hydrocephalus management in the framework of MDT decision-making. Team experience contributes to reducing possible deficits in this challenging cohort.
PubMed: 38918262
DOI: 10.1007/s00381-024-06498-2 -
Child's Nervous System : ChNS :... Jun 2024Pediatric low-grade gliomas (pLGGs) are the most common brain tumor types affecting children. Although gross-total resection remains the treatment of choice, many tumors...
Pediatric low-grade gliomas (pLGGs) are the most common brain tumor types affecting children. Although gross-total resection remains the treatment of choice, many tumors are not amenable to complete removal, because they either involve midline structures, such as the optic chiasm or hypothalamus, and are not conducive to aggressive resection, or have diffuse biological features and blend with the surrounding brain. Historically, radiation therapy was used as the second-line option for disease control, but with the recognition that this often led to adverse long-term sequelae, particularly in young children, conventional chemotherapy assumed a greater role in initial therapy for unresectable tumors. A variety of agents demonstrated activity, but long-term disease control was suboptimal, with more than 50% of tumors exhibiting disease progression within 5 years. More recently, it has been recognized that a high percentage of these tumors in children exhibit constitutive activation of the mitogen-activated protein kinase (MAPK) pathway because of BRAF translocations or mutations, NFI mutations, or a host of other anomalies that converged on MAPK. This led to phase 1, 2, and 3 trials that explored the activity of blocking this signaling pathway, and the efficacy of this approach compared to conventional chemotherapy. Despite initial promise of these strategies, not all children tolerate this therapy, and many tumors resume growth once MAPK inhibition is stopped, raising concern that long-term and potentially life-long treatment will be required to maintain tumor control, even among responders. This observation has led to interest in other treatments, such as immunotherapy, that may delay or avoid the need for additional treatments. This chapter will summarize the place of immunotherapy in the current armamentarium for these tumors and discuss prior results and future options to improve disease control, with a focus on our prior efforts and experience in this field.
PubMed: 38884777
DOI: 10.1007/s00381-024-06491-9 -
Clinical Oncology (Royal College of... May 2024This study aimed to demonstrate the feasibility and evaluate the dosimetric effect and clinical impact of dose-painting proton radiotherapy (PRT) guided by functional...
AIMS
This study aimed to demonstrate the feasibility and evaluate the dosimetric effect and clinical impact of dose-painting proton radiotherapy (PRT) guided by functional MRI in non-enhancing high-grade gliomas (NE-HGGs).
MATERIALS AND METHODS
The 3D-ASL and T2 FLAIR MR images of ten patients with NE-HGGs before radiotherapy were studied retrospectively. The hyperintensity on T2 FLAIR was used to generate the planning target volume (PTV), and the high-perfusion volume on 3D-ASL (PTV-ASL) was used to generate the simultaneous integrated boost (SIB) volume. Each patient received pencil beam scanning PRT and photon intensity-modulated radiotherapy (IMRT). There were five plans in each modality: (1) Uniform plans (IMRT60 vs. PRT60): 60Gy in 30 fractions to the PTV. (2)-(5) SIB plans (IMRT72, 84, 96, 108 vs. PRT72, 84, 96, 108): Uniform plan plus additional dose boost to PTV-ASL in 30 fractions to 72, 84, 96, 108 Gy. The dosimetric differences between various plans were compared. The clinical effects of target volume and organs at risk (OARs) were assessed using biological models for both tumor control probability (TCP) and normal tissue complication probability (NTCP).
RESULTS
Compared with the IMRT plan, the D2 and D50 of the PRT plans with the same prescription dose increased by 1.27-4.12% and 0.64-2.01%, respectively; the R30 decreased by > 32%; the dose of brainstem and chiasma decreased by > 27% and >32%; and the dose of normal brain tissue (Br-PTV), optic nerves, eyeballs, lens, cochlea, spinal cord, and hippocampus decreased by > 50% (P < 0.05). The maximum necessary dose was 96GyE to achieve >98% TCP for PRT, and it was 84Gy to achieve >91% TCP for IMRT. The average NTCP of Br-PTV was 1.30% and 1.90% for PRT and IMRT at the maximum dose escalation, respectively. The NTCP values of the remaining OARs approached zero in all PRT plans.
CONCLUSION
The functional MRI-guided dose escalation using PRT is feasible while sparing the OARs constraints and demonstrates a potential clinical benefit by improving TCP with no or minimal increase in NCTP for tissues outside the PTV. This retrospective study suggested that the use of PRT-based SIB guided by functional MRI may represent a strategy to provide benefits for patients with NE-HGGs.
PubMed: 38876805
DOI: 10.1016/j.clon.2024.05.011 -
PNAS Nexus Jun 2024Molecular genetics is highly related with prognosis of high-grade glioma. Accordingly, the latest WHO guideline recommends that molecular subgroups of the genes,...
Molecular genetics is highly related with prognosis of high-grade glioma. Accordingly, the latest WHO guideline recommends that molecular subgroups of the genes, including IDH, 1p/19q, MGMT, TERT, EGFR, Chromosome 7/10, CDKN2A/B, need to be detected to better classify glioma and guide surgery and treatment. Unfortunately, there is no preoperative or intraoperative technology available for accurate and comprehensive molecular subgrouping of glioma. Here, we develop a deep learning-assisted fiber-optic Raman diagnostic platform for accurate and rapid molecular subgrouping of high-grade glioma. Specifically, a total of 2,354 fingerprint Raman spectra was obtained from 743 tissue sites (astrocytoma: 151; oligodendroglioma: 150; glioblastoma (GBM): 442) of 44 high-grade glioma patients. The convolutional neural networks (ResNet) model was then established and optimized for molecular subgrouping. The mean area under receiver operating characteristic curves (AUC) for identifying the molecular subgroups of high-grade glioma reached 0.904, with mean sensitivity of 83.3%, mean specificity of 85.0%, mean accuracy of 83.3%, and mean time expense of 10.6 s. The diagnosis performance using ResNet model was shown to be superior to PCA-SVM and UMAP models, suggesting that high dimensional information from Raman spectra would be helpful. In addition, for the molecular subgroups of GBM, the mean AUC reached 0.932, with mean sensitivity of 87.8%, mean specificity of 83.6%, and mean accuracy of 84.1%. Furthermore, according to saliency maps, the specific Raman features corresponding to tumor-associated biomolecules (e.g. nucleic acid, tyrosine, tryptophan, cholesteryl ester, fatty acid, and collagen) were found to contribute to the accurate molecular subgrouping. Collectively, this study opens up new opportunities for accurate and rapid molecular subgrouping of high-grade glioma, which would assist optimal surgical resection and instant post-operative decision-making.
PubMed: 38860145
DOI: 10.1093/pnasnexus/pgae208 -
Neuro-oncology Advances 2024Brain tumors are the leading cause of cancer-related death in children, where low-grade gliomas (LGGs) predominate. One common hereditary cause for LGGs involves... (Review)
Review
Leveraging murine models of the neurofibromatosis type 1 cancer predisposition syndrome to elucidate the cellular circuits that drive pediatric low-grade glioma formation and progression.
Brain tumors are the leading cause of cancer-related death in children, where low-grade gliomas (LGGs) predominate. One common hereditary cause for LGGs involves neurofibromatosis-1 (NF1) gene mutation, as seen in individuals with the NF1 cancer predisposition syndrome. As such, children with NF1 are at increased risk of developing LGGs of the optic pathway, brainstem, cerebellum, and midline brain structures. Using genetically engineered mouse models, studies have revealed both cell-intrinsic (MEK signaling) and stromal dependencies that underlie their formation and growth. Importantly, these dependencies represent vulnerabilities against which targeted agents can be used for preclinical investigation prior to clinical translation.
PubMed: 38855054
DOI: 10.1093/noajnl/vdae054 -
Frontiers in Oncology 2024We report a case of slipped capital femoral epiphysis (SCFE), an on target skeletal toxicity of a pan-FGFR TKI inhibitor, erdafitinib. A 13-year-old boy was diagnosed to...
We report a case of slipped capital femoral epiphysis (SCFE), an on target skeletal toxicity of a pan-FGFR TKI inhibitor, erdafitinib. A 13-year-old boy was diagnosed to have an optic pathway/hypothalamic glioma with signs of increased intracranial pressure and obstructive hydrocephalus requiring placement of ventriculo-peritoneal (VP) shunt. Sequencing of the tumor showed FGFR1-tyrosine kinase domain internal tandem duplication (FGFR1-KD-ITD). He developed hypothalamic obesity with rapid weight gain and BMI >30. At 12 weeks of treatment with erdafitinib, he developed persistent knee pain. X-ray of the right hip showed SCFE. Erdafitinib was discontinued, and he underwent surgical pinning of the right hip. MRI at discontinuation of erdafitinib showed a 30% decrease in the size of the tumor, which has remained stable at 6 months follow-up. Our experience and literature review suggest that pediatric patients who are treated with pan-FGFR TKIs should be regularly monitored for skeletal side effects.
PubMed: 38854731
DOI: 10.3389/fonc.2024.1399356 -
Investigative Ophthalmology & Visual... Jun 2024Optic pathway gliomas (OPGs) are most predominant pilocytic astrocytomas, which are typically diagnosed within the first decade of life. The majority of affected... (Review)
Review
Optic pathway gliomas (OPGs) are most predominant pilocytic astrocytomas, which are typically diagnosed within the first decade of life. The majority of affected children with OPGs also present with neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome. OPGs in individuals with NF1 primarily affect the optic pathway and lead to visual disturbance. However, it is challenging to assess risk in asymptomatic patients without valid biomarkers. On the other hand, for symptomatic patients, there is still no effective treatment to prevent or recover vision loss. Therefore, this review summarizes current knowledge regarding the pathogenesis of NF1-associated OPGs (NF1-OPGs) from preclinical studies to seek potential prognostic markers and therapeutic targets. First, the loss of the NF1 gene activates 3 distinct Ras effector pathways, including the PI3K/AKT/mTOR pathway, the MEK/ERK pathway, and the cAMP pathway, which mediate glioma tumorigenesis. Meanwhile, non-neoplastic cells from the tumor microenvironment (microglia, T cells, neurons, etc.) also contribute to gliomagenesis via various soluble factors. Subsequently, we investigated potential genetic risk factors, molecularly targeted therapies, and neuroprotective strategies for tumor prevention and vision recovery. Last, potential directions and promising preclinical models of NF1-OPGs are presented for further research. On the whole, NF1-OPGs develop as a result of the interaction between glioma cells and the tumor microenvironment. Developing effective treatments require a better understanding of tumor molecular characteristics, as well as multistage interventions targeting both neoplastic cells and non-neoplastic cells.
Topics: Humans; Neurofibromatosis 1; Optic Nerve Glioma; Risk Factors; Animals; Neurofibromin 1; Optic Nerve Neoplasms
PubMed: 38837168
DOI: 10.1167/iovs.65.6.8 -
Vision (Basel, Switzerland) May 2024Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder primarily affecting children and adolescents characterized by multisystemic clinical... (Review)
Review
Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder primarily affecting children and adolescents characterized by multisystemic clinical manifestations. Mutations in neurofibromin, the protein encoded by the tumor suppressor gene, result in dysregulation of the RAS/MAPK pathway leading to uncontrolled cell growth and migration. Neurofibromin is highly expressed in several cell lineages including melanocytes, glial cells, neurons, and Schwann cells. Individuals with NF1 possess a genetic predisposition to central nervous system neoplasms, particularly gliomas affecting the visual pathway, known as optic pathway gliomas (OPGs). While OPGs are typically asymptomatic and benign, they can induce visual impairment in some patients. This review provides insight into the spectrum and visual outcomes of NF1, current diagnostic techniques and therapeutic interventions, and explores the influence of NF1-OPGS on visual abnormalities. We focus on recent advancements in preclinical animal models to elucidate the underlying mechanisms of NF1 pathology and therapies targeting NF1-OPGs. Overall, our review highlights the involvement of retinal ganglion cell dysfunction and degeneration in NF1 disease, and the need for further research to transform scientific laboratory discoveries to improved patient outcomes.
PubMed: 38804352
DOI: 10.3390/vision8020031 -
Current Oncology (Toronto, Ont.) May 2024MEK inhibitors (MEKi) represent innovative and promising treatments for managing manifestations of neurofibromatosis type 1 (NF1). To mitigate potential ophthalmic side...
MEK inhibitors (MEKi) represent innovative and promising treatments for managing manifestations of neurofibromatosis type 1 (NF1). To mitigate potential ophthalmic side effects, such as MEKi-associated retinopathy (MEKAR), patients undergoing MEKi therapy routinely receive ophthalmology evaluations. Our study aims to assess the necessity of this regular screening within a predominantly pediatric NF1 population by examining the occurrence of ocular adverse events (OAE). A retrospective study evaluated 45 NF1 patients receiving MEKi. Inclusion criteria included baseline and follow-up examinations following the initiation of MEKi therapy. At each assessment, a comprehensive eye evaluation was performed, comprising a dilated fundus examination, ocular coherence tomography of the macula and nerve fiber layer, and Humphrey visual field testing. Twenty-six patients, with an average age of 13 years (range 2-23 years) and an average follow-up duration of 413 days were included in the analysis. Three different MEKi were used: selumetinib (77%), trametinib (23%), and mirdametinib (4%). None of the patients experienced retinopathy at any point during the study. Some patients had pre-existing optic neuropathies (27%), but no instances of nerve changes occurred after commencing MEKi therapy. Four patients (15%) exhibited symptoms of dry eye, all of which were effectively managed with topical lubrication.
Topics: Humans; Neurofibromatosis 1; Child; Female; Male; Adolescent; Protein Kinase Inhibitors; Child, Preschool; Young Adult; Retrospective Studies; Incidence; Eye Diseases; Adult; Benzimidazoles; Pyridones; Pyrimidinones
PubMed: 38785480
DOI: 10.3390/curroncol31050199 -
Child's Nervous System : ChNS :... May 2024Optic pathway gliomas (OPGs) represent a unique subset of brain tumours that primarily affect the paediatric population. Traditionally, these tumours are managed...
Optic pathway gliomas (OPGs) represent a unique subset of brain tumours that primarily affect the paediatric population. Traditionally, these tumours are managed conservatively due to their location to and association with vital structures. This article explores the evolving role of surgery in the management of OPGs, particularly in the context of advancements in precision medicine. The advent of targeted therapy, especially for tumours with specific genetic alterations, such as BRAF V600E mutations, has revolutionized the treatment landscape, offering new avenues for patient-specific therapy. However, surgery still plays a crucial role, especially for debulking in cases of hydrocephalus or when standard therapies are ineffective. Advances in surgical techniques, including neuronavigation, endoscopic approaches, and intraoperative neurophysiological monitoring, have enhanced the safety and efficacy of operative interventions. Despite these developments, the complexity of OPGs necessitates a multidisciplinary approach, focusing on long-term outcomes and quality of life. Future research is needed to further elucidate the role of surgery in an era increasingly dominated by molecular genetics and targeted therapies.
PubMed: 38743267
DOI: 10.1007/s00381-024-06450-4