Search Results (37)

Objective: Optic pathway glioma (OPG) diagnosed in adults represents a rare and understudied tumor subtype. While pediatric OPGs are typically benign and associated with NF1 and RAS/MAPK pathway dysregulation, less is known about the clinical characteristics and prognostic drivers of OPGs in adults. Methods: A systematic review was conducted in accordance with PRISMA guidelines across multiple databases. Studies reporting patient-level data and follow-up for patients diagnosed with optic pathway glioma at age ≥ 18 years were included. Results: Ninety-six studies comprising 149 adult patients were analyzed. Median patient age was 47 years (range: 18–90), and 51.0% of tumors were high-grade (WHO grade 3–4). Increasing age at diagnosis was significantly correlated with higher WHO grade (ρ = 0.600, p < 0.001), and optic tract involvement was associated with high-grade disease (χ² = 8.08, p = 0.004; ϕ = 0.26). Median follow-up was 12 months, with 74 patients alive and 75 deceased at last follow-up. WHO grade was strongly associated with overall survival (log-rank p < 0.0001), with 24-month survival ranging from 96.9% for grade 1 tumors to 11.3% for grade 4 tumors. Compared with observation or steroid-only management, both surgical and non-surgical oncologic treatments were associated with longer observed survival, although no significant difference was observed between active treatment modalities. Conclusions: Optic pathway gliomas in adults exhibit a multimodal biologic distribution, encompassing both indolent low-grade tumors and aggressive high-grade malignancies. Survival outcomes appear to be primarily driven by tumor biology, with age and anatomic involvement correlating with tumor grade. Prospective, multicenter studies with comprehensive molecular profiling are needed to refine prognostic stratification and guide evidence-based management of this rare disease. Full article

Background/Objectives: Diencephalic syndrome (DS) is an uncommon pediatric disorder presenting with severe failure to thrive despite adequate caloric intake and preserved linear growth. First characterized by Russell, this condition predominantly affects infants under 12 months and remains diagnostically challenging. Methods: We performed a comprehensive literature review examining clinical presentation, underlying pathophysiology, associated pathology, diagnostic approaches, and long-term outcomes of DS. Results: DS typically manifests in the first year of life with profound cachexia, normal or increased appetite, preserved height velocity, and characteristic features including hyperactivity, euphorism, and visual pathway involvement. Low-grade gliomas of the hypothalamic–chiasmatic region, particularly pilocytic astrocytomas, represent the predominant underlying pathology. The pathophysiological mechanisms remain incompletely understood but likely involve complex dysregulation of hypothalamic energy homeostasis. While overall survival exceeds 90% at five years, most patients experience significant long-term morbidity including visual impairment, multiple endocrine deficiencies, and hypothalamic obesity. Diagnostic delays averaging 11 months contribute to irreversible complications. Conclusions: Early recognition of DS is essential to prevent permanent visual loss and optimize outcomes. Multidisciplinary management incorporating chemotherapy as first-line treatment for underlying gliomas has improved survival while reducing radiation-associated toxicities. However, survivors face substantial lifelong sequelae requiring comprehensive monitoring and intervention. Future research should focus on elucidating precise pathophysiological mechanisms, developing targeted molecular therapies, and improving management of hypothalamic obesity and other late effects. Full article

Neurofibromatosis type 1 (NF1) is an inherited, autosomal dominant syndrome that affects about 1 in every 3000 people worldwide. Early tumor detection is crucial for surveillance and intervention, especially given the potential for serious complications, including visual impairment, skeletal deformities, and malignancy. Therefore, it is essential for pediatricians and other healthcare professionals who provide care to these patients to be aware of all signs, treatments, and management strategies to deliver the best possible care. This study aims to develop a consensus for the diagnosis, treatment, and management of benign and malignant tumors associated with pediatric patients with NF1. Delphi methodology was used to achieve consensus among experts on the diagnostic accuracy, therapeutic efficacy, safety, and surveillance of pediatric patients with NF1. The consensus made 24 recommendations: gliomas in the optic pathway—6 statements, non-optical gliomas—2 statements, plexiform neurofibromas—5 statements, malignant peripheral nerve sheath tumors (MPNST)—6 statements, melanoma—1 statement, juvenile myelomonocytic leukemia (JMML)—1 statement, pheochromocytoma and paraganglioma—2 statements, and gastrointestinal stromal tumors (GIST)—1 statement. This consensus represents the first Brazilian recommendations on malignant and benign tumors in pediatric patients with NF1, providing a framework to standardize and optimize the clinical application for this disease. Full article

Bevacizumab is often used off-label in pediatric neuro-oncology, and evidence for indications of bevacizumab use in pediatric neuro-oncology is often fragmented. Therefore, this review aims to provide an organized summary of efficacy across different types of tumors, highlight outcomes, and link findings to the underlying biology. Gaps in the literature were also identified to guide future research. We narratively synthesized various pediatric studies, and the following tumor categories were identified for discussion: low-grade glioma, high-grade glioma, diffuse intrinsic pontine glioma, schwannoma, medulloblastoma, radiation necrosis, and cerebral edema. Key outcomes considered included overall survival, event-free survival, progression-free survival, vision and/or hearing improvements, steroid use, quality of life, and toxicity. The greatest benefits were observed in cases such as recurrent medulloblastoma in combination with temozolomide and irinotecan, optic pathway glioma visual function, and diminished steroid use in radiation necrosis. Results were poorer in cases of newly diagnosed high-grade gliomas and diffuse intrinsic pontine gliomas. The medication was overall well tolerated, with adverse events like hypertension, proteinuria, and epistaxis often being manageable with surveillance. In consideration of the results, bevacizumab should be considered based on the tumor profile, and its outcome measured along functional endpoints, besides radiological evolution. Continued investigations into outcome measures, as well as combination with targeted treatments and optimizing therapy, will contribute to improving outcomes in this vulnerable population. Full article

Optic pathway glioma (OPG) is a rare pediatric low-grade glioma, frequently associated with neurofibromatosis type 1 (NF–1), that presents unique therapeutic challenges due to its anatomical location and its potential to impair vision, endocrine function, and developmental trajectories. Current clinical management prioritizes a multidisciplinary, patient-specific approach aimed at tumor control while preserving long-term quality of life. Strategies vary based on clinical presentation, ranging from observation in asymptomatic cases to chemotherapy for progressive or symptomatic tumors. Surgical and radiation options are limited due to potential risks and complications. In recent years, advances in molecular characterization have guided the development of targeted therapies, particularly MEK inhibitors, which demonstrate encouraging efficacy and reduced toxicity profiles. In parallel, investigational therapies including immunotherapy and precision medicine-based approaches are under clinical evaluation. This review provides a synthesis of current standard practices, emerging targeted treatments, and ongoing clinical trials, drawing on relevant literature and expert consensus to inform clinicians and families about available therapeutic options. Literature discussed in this review was identified through a non-systematic search of published articles, clinical trial registries, and authoritative guidelines, with selection based on relevance, clinical significance, and contribution to understanding current and emerging management strategies for OPG. Full article

Neurocutaneous syndromes, known as phakomatoses, encompass a diverse group of congenital conditions affecting the nervous system and skin, with neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) among the most clinically significant. Both disorders are inherited in an autosomal dominant manner. NF1 presents with café-au-lait macules; cutaneous, subcutaneous, and plexiform neurofibromas; skeletal abnormalities; learning disabilities; and optic pathway gliomas, while NF2 is characterised by bilateral vestibular schwannomas, multiple meningiomas, ependymomas, and peripheral nerve schwannomas. Although germline mutations in the NF1 and NF2 tumour suppressor genes are well established, they do not fully explain the broad clinical variability observed, even among individuals carrying identical mutations. As increasingly recognised in other genetic diseases, epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodelling, and non-coding RNA (ncRNA) regulation, play a critical role in modulating gene expression and influencing disease severity. Despite important findings, the research remains fragmented, and a unified model is lacking. This review organises the current knowledge, emphasising how epigenetic alterations impact disease behaviour and outlining their potential as prognostic biomarkers and therapeutic targets. A deeper understanding of these mechanisms could lead to improved personalised management and the development of targeted epigenetic therapies for individuals with NF1 and NF2. Full article

Background/Aim: Among NF1-dependent tumors, the most common are optic pathway gliomas (OPGs). The objective of this study was the retrospective analysis of the course, indications for treatment, and effects of therapy for NF1-OPGs. Patients and Methods: We analyzed demographics, clinical and genetic data, imaging and ophthalmological parameters, their impact on therapeutic decisions, and the effectiveness of the therapy in 92 patients. Results: OPGs were unilateral in 55.4% of patients and bilateral in 44.6%. Post-contrast enhancement in MRI was observed in 67.4%. Oncological treatment was required in 16.3% of patients with median age 3.8 years. Factors significant in multivariate analysis contributing to the need of oncological treatment were: amblyopia and proptosis. Factors contributing to amblyopia were: strabismus, proptosis, co-occurrence of epilepsy, bilateral OPGs, and thickness of the optic nerve ≥ 8 mm. The first line of oncological treatment included vincristine + carboplatin or monotherapy with vinblastine. The use of subsequent lines of oncological treatment was necessary in 46.7% patients. Conclusions: The following conclusions, suggest modification of the approach in the management of patients with NF1-OPG, summarize the presented study: (1) perform the first MRI after the age of 1 year, (2) reduce the frequency of follow-up scans in the first year of observation in patients with isolated involvement of intraocular and/or intraorbital segments of the optic nerve, (3) refrain from administering contrast during control MRI examinations of the orbits after OPG diagnosis; (4) in patients with co-occurring psychomotor delay or treated with antiepileptic drugs, do not make decisions about oncological therapy when visual acuity deterioration is observed, without progression in optical coherence tomography (OCT), visual evoked potentials (VEP), and MRI. Full article

Background: The current standard therapy for pediatric optic pathway/hypothalamic glioma (OPHG) is systemic anticancer therapy (SAT) over surgery and radiotherapy. Nevertheless, recurrent radiological or clinical tumor progression after SAT forms a considerable challenge. Sporadic OPHGs are considered to have a higher tendency toward progression after first-line systemic anticancer therapy (SAT) compared to neurofibromatosis type-1-associated (NF1) OPHGs. Methods: The objective of this study was to conduct a national retrospective cohort analysis of children who received various treatments for a progressive OPHG, involving the hypothalamus and/or chiasm and/or optic radiations. The study aimed to examine the differences in clinical course and the range of treatment modalities applied to both sporadic and NF1-associated OPHGs between 1995 and 2020. Additionally, we sought to identify risk factors for 3- and 5-year progression following first- and second-order SAT. Results: In total, 136 children received treatment, of whom 49 of 136 (36.0%) had NF1. Within a median of 7.5 years (range: 0.1–23.8 years) of follow-up, sporadic OPHGs received more treatments compared to NF1-associated OPHGs (median of 2 (range: 1–8) vs. median of 1 (range: 1–7) (p < 0.01)). Nine children with sporadic OPHGs (6.6%) died. Of 112 children (82.4%) receiving SAT, 92% received combined first-line vincristine and carboplatin. These children had a 3- and 5-year progression-free survival of 61.8% (95% CI: 51.0–72.6%) and 48.4% (95% CI: 38.0–58.8%), respectively. Sporadic OPHGs had a higher rate of second progression (p < 0.01). Starting first-line vincristine and carboplatin at an age below one year was the only independent risk factor for progression. Conclusions: In this national historic cohort of pediatric OPHGs, four out of five children received SAT. Sporadic OPHGs received a higher number of various SATs compared to NF1-associated OPHGs, but the sporadic appearance of OPHGs was not an independent risk factor for progression after combined vincristine and carboplatin, as ‘age below one year at the start’ was the only factor. Full article

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

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 Nf1 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. Full article

In this paper, the authors present a clinical picture of the diagnosis and current treatment regimens of optic pathway glioma in the pediatric population, with an emphasis on the role of an ophthalmic diagnosis in the differentiation and monitoring of lesions. Glioma is the most common optic nerve tumor in children. Material: Articles in PubMed, Scholar and Website were reviewed, taking into account current standards of management related to sporadic or NF1-related optic glioma, epidemiology, location, course of the disease, clinical manifestations, histological types of the tumor, genetic predisposition, diagnostic ophthalmic tests currently applicable in therapeutic monitoring of the tumor, neurological diagnosis, therapeutic management and prognosis. The importance of current screening recommendations, in line with standards, was emphasized. Results: Glioma occurs in children most often in the first decade of life. Initially, they may be asymptomatic, and clinically ophthalmic changes are associated with the organ of vision or with systemic changes. Gliomas associated with the NF1 mutation have a better prognosis for sporadic gliomas. Diagnosis includes radiological imaging methods/MRI/ophthalmology/OCT and visual acuity log MAR assessment. The basis of treatment is clinical observation. In the case of disease progression, surgical treatment, chemotherapy and targeted therapy are used. Conclusion: Further research into novel techniques for detecting gliomas would allow for early monitoring of the disease. Full article

Optic pathway glioma (OPG) is one of the causes of pediatric visual impairment. Unfortunately, there is as yet no cure for such a disease. Understanding the underlying mechanisms and the potential therapeutic strategies may help to delay the progression of OPG and rescue the visual morbidities. Here, we provide an overview of preclinical OPG studies and the regulatory pathways controlling OPG pathophysiology. We next discuss the role of microenvironmental cells (neurons, T cells, and tumor-associated microglia and macrophages) in OPG development. Last, we provide insight into potential therapeutic strategies for treating OPG and promoting axon regeneration. Full article

Optic pathway gliomas (OPGs) encompass two distinct categories: benign pediatric gliomas, which are characterized by favorable prognosis, and malignant adult gliomas, which are aggressive cancers associated with a poor outcome. Our review aims to explore the established standards of care for both types of tumors, highlight the emerging therapeutic strategies for OPG treatment, and propose potential alternative therapies that, while originally studied in a broader glioma context, may hold promise for OPGs pending further investigation. These potential therapies encompass immunotherapy approaches, molecular-targeted therapy, modulation of the tumor microenvironment, nanotechnologies, magnetic hyperthermia therapy, cyberKnife, cannabinoids, and the ketogenic diet. Restoring visual function is a significant challenge in cases where optic nerve damage has occurred due to the tumor or its therapeutic interventions. Numerous approaches, particularly those involving stem cells, are currently being investigated as potential facilitators of visual recovery in these patients. Full article

Neurofibromatosis type 1 (NF1) is a rare inherited neurocutaneous disorder with a major impact on the skin, nervous system and eyes. The ocular diagnostic hallmarks of this disease include iris Lisch nodules, ocular and eyelid neurofibromas, eyelid café-au-lait spots and optic pathway gliomas (OPGs). In the last years, new manifestations have been identified in the ocular district in NF1 including choroidal abnormalities (CAs), hyperpigmented spots (HSs) and retinal vascular abnormalities (RVAs). Recent advances in multi-modality imaging in ophthalmology have allowed for the improved characterization of these clinical signs. Accordingly, CAs, easily detectable as bright patchy nodules on near-infrared imaging, have recently been added to the revised diagnostic criteria for NF1 due to their high specificity and sensitivity. Furthermore, subclinical alterations of the visual pathways, regardless of the presence of OPGs, have been recently described in NF1, with a primary role of neurofibromin in the myelination process. In this paper, we reviewed the latest progress in the understanding of choroidal and retinal abnormalities in NF1 patients. The clinical significance of the recently revised diagnostic criteria for NF1 is discussed along with new updates in molecular diagnosis. New insights into NF1-related neuro-ophthalmic manifestations are also provided based on electrophysiological and optical coherence tomography (OCT) studies. Full article

Homologous recombination deficiency (HRD) is characterized by the inability of a cell to repair the double-stranded breaks using the homologous recombination repair (HRR) pathway. The deficiency of the HRR pathway results in defective DNA repair, leading to genomic instability and tumorigenesis. The presence of HRD has been found to make tumors sensitive to ICL-inducing platinum-based therapies and poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors (PARPi). However, there are no standardized methods to measure and report HRD phenotypes. Herein, we compare optical genome mapping (OGM), chromosomal microarray (CMA), and a 523-gene NGS panel for HRD score calculations. This retrospective study included the analysis of 196 samples, of which 10 were gliomas, 176 were hematological malignancy samples, and 10 were controls. The 10 gliomas were evaluated with both CMA and OGM, and 30 hematological malignancy samples were evaluated with both the NGS panel and OGM. To verify the scores in a larger cohort, 135 cases were evaluated with the NGS panel and 71 cases with OGM. The HRD scores were calculated using a combination of three HRD signatures that included loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transitions (LST). In the ten glioma cases analyzed with OGM and CMA using the same DNA (to remove any tumor percentage bias), the HRD scores (mean ± SEM) were 13.2 (±4.2) with OGM compared to 3.7 (±1.4) with CMA. In the 30 hematological malignancy cases analyzed with OGM and the 523-gene NGS panel, the HRD scores were 7.6 (±2.2) with OGM compared to 2.6 (±0.8) with the 523-gene NGS panel. OGM detected 70.8% and 66.8% of additional variants that are considered HRD signatures in gliomas and hematological malignancies, respectively. The higher sensitivity of OGM to capture HRD signature variants might enable a more accurate and precise correlation with response to PARPi and platinum-based drugs. This study reveals HRD signatures that are cryptic to current standard of care (SOC) methods used for assessing the HRD phenotype and presents OGM as an attractive alternative with higher resolution and sensitivity to accurately assess the HRD phenotype. Full article