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Journal of Neuro-oncology May 2024The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II...
PURPOSE
The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation.
METHODS
Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change.
RESULTS
Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes.
CONCLUSION
These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.
Topics: Humans; Pyridones; Pyrimidinones; Male; Female; Adolescent; Child; Neurofibromatosis 1; Young Adult; Child, Preschool; Neuropsychological Tests; Glioma; Brain Neoplasms; Adult; Protein Kinase Inhibitors; Antineoplastic Agents
PubMed: 38443693
DOI: 10.1007/s11060-024-04624-3 -
Orbit (Amsterdam, Netherlands) Oct 2023Neurofibromatosis type 1 (NF1) affects cell growth in neural tissues, resulting in neurofibromas of the internal organs, peripheral nerves and/or autonomic nerves. We... (Review)
Review
Neurofibromatosis type 1 (NF1) affects cell growth in neural tissues, resulting in neurofibromas of the internal organs, peripheral nerves and/or autonomic nerves. We describe a highly unusual case of plexiform neurofibroma presenting with lacrimal gland enlargement in an 18 year old male, which led to a diagnosis of NF1.
Topics: Male; Humans; Adolescent; Neurofibroma, Plexiform; Lacrimal Apparatus; Neurofibromatosis 1; Neurofibroma; Peripheral Nerves
PubMed: 35312416
DOI: 10.1080/01676830.2022.2052112 -
The Journal of Investigative Dermatology Jan 2024Neurofibromatosis 1 is a prevalent hereditary neurocutaneous disorder. Among the clinical phenotypes of neurofibromatosis 1, cutaneous neurofibroma (cNF) and plexiform...
Neurofibromatosis 1 is a prevalent hereditary neurocutaneous disorder. Among the clinical phenotypes of neurofibromatosis 1, cutaneous neurofibroma (cNF) and plexiform neurofibroma (pNF) have distinct clinical manifestations, and pNF should be closely monitored owing to its malignant potential. However, the detailed distinct features of neurofibromatosis 1 phenotypes remain unknown. To determine whether the transcriptional features and microenvironment of cNF and pNF differ, single-cell RNA sequencing was performed on isolated cNF and pNF cells from the same patient. Six cNF and five pNF specimens from different subjects were also immunohistochemically analyzed. Our findings revealed that cNF and pNF had distinct transcriptional profiles even within the same subject. pNF is enriched in Schwann cells with characteristics similar to those of their malignant counterpart, fibroblasts, with a cancer-associated fibroblast-like phenotype, angiogenic endothelial cells, and M2-like macrophages, whereas cNF is enriched in CD8 T cells with tissue residency markers. The results of immunohistochemical analyses performed on different subjects agreed with those of single-cell RNA sequencing. This study found that cNF and pNF, the different neurofibromatosis phenotypes in neurofibromatosis 1, from the same subject are transcriptionally distinct in terms of the cell types involved, including T cells.
Topics: Humans; Endothelial Cells; Neurofibroma; Neurofibroma, Plexiform; Neurofibromatosis 1; Skin Neoplasms; Tumor Microenvironment
PubMed: 37301319
DOI: 10.1016/j.jid.2023.03.1688 -
Ophthalmic Plastic and Reconstructive...A 27-year-old woman with well-documented neurofibromatosis 2 developed a soft, painless, nodular lesion on the skin surface of the left upper eyelid over 2 years....
A 27-year-old woman with well-documented neurofibromatosis 2 developed a soft, painless, nodular lesion on the skin surface of the left upper eyelid over 2 years. Following excision, histopathology revealed a plexiform neurofibroma with intradermal nodules comprised of benign round and spindle cells that reacted diffusely with immunohistochemical stains SOX-10 and S100. A subset showed focal reactivity for neurofilament and CD34. A perineurium surrounded each nodule with cells staining positively for markers EMA (epithelial membrane antigen) and GLUT1 (glucose transporter 1). Plexiform neurofibromas are rare tumors that occur in 5%-15% of patients with neurofibromatosis 1. Cutaneous abnormalities in neurofibromatosis 2 have not been widely studied although reports have described schwannomas, plexiform schwannomas, and occasional neurofibromas. Plexiform neurofibromas in neurofibromatosis 2 have rarely been illustrated and the current case represents a unique bona fide eyelid example to date.
Topics: Female; Humans; Adult; Neurofibroma, Plexiform; Neurofibromatosis 2; Neurofibromatosis 1; Neurilemmoma; Eyelids; Neurofibroma
PubMed: 37338324
DOI: 10.1097/IOP.0000000000002432 -
American Society of Clinical Oncology... Jun 2024Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a... (Review)
Review
Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a significantly elevated estimated lifetime frequency of 8%-13%. In the setting of NF1, MPNSTs arise from malignant transformation of benign plexiform neurofibroma and borderline atypical neurofibromas. Composed of neoplastic cells from the Schwannian lineage, these cancers recur in approximately 50% of individuals, and most patients die within five years of diagnosis, despite surgical resection, radiation, and chemotherapy. Treatment for metastatic disease is limited to cytotoxic chemotherapy and investigational clinical trials. In this article, we review the pathophysiology of this aggressive cancer and current approaches to surveillance and treatment.
Topics: Humans; Neurofibromatosis 1; Nerve Sheath Neoplasms
PubMed: 38710002
DOI: 10.1200/EDBK_432242 -
Child Neuropsychology : a Journal on... Feb 2024Neurofibromatosis type 1 (NF1) is associated with below average writing achievement. However, little is known about specific aspects of written language impacted by NF1,...
Neurofibromatosis type 1 (NF1) is associated with below average writing achievement. However, little is known about specific aspects of written language impacted by NF1, changes in writing over time, and associations between cognitive aspects of the NF1 phenotype and writing. At three timepoints over six years, children with NF1 and plexiform neurofibromas (PNs) completed Woodcock-Johnson tests of writing mechanics (Spelling, Punctuation & Capitalization, handwriting), written expression of ideas (Writing Samples), writing speed (Writing Fluency), and tests of general cognitive ability, executive function, memory, and attention. Children ( = 76, mean age = 12.8 ± 3.4 years) completed at least one baseline writing subtest. Overall writing scores were in the Average range ( = 93.4, = 17.4), but lower than population norms ( = 0.002). Scores were highest on Writing Samples ( = 95.2, = 17.3), and lowest for Punctuation & Capitalization ( = 87.9, = 18.8, = 0.034). Writing scores were mostly stable over time. Nonverbal reasoning was related to some tests of writing mechanics and written expression of ideas. Short-term memory and inattention explained additional variance in Writing Samples and Spelling. Poor handwriting was associated with writing content beyond the impact of cognitive factors. Children with NF1 and PNs may benefit from early screening and writing support. Interventions should address the contribution of both cognitive and handwriting difficulties in written language.
PubMed: 38318699
DOI: 10.1080/09297049.2024.2307663 -
Cancers Feb 2024Neurofibromatosis type 1 (NF1) is a common genetic disorder resulting in the development of both benign and malignant tumors of the peripheral nervous system. NF1 is... (Review)
Review
Neurofibromatosis type 1 (NF1) is a common genetic disorder resulting in the development of both benign and malignant tumors of the peripheral nervous system. NF1 is caused by germline pathogenic variants or deletions of the tumor suppressor gene, which encodes the protein neurofibromin that functions as negative regulator of p21 RAS. Loss of heterozygosity in Schwann cells (SCs), the cells of origin for these nerve sheath-derived tumors, leads to the formation of plexiform neurofibromas (PNF)-benign yet complex neoplasms involving multiple nerve fascicles and comprised of a myriad of infiltrating stromal and immune cells. PNF development and progression are shaped by dynamic interactions between SCs and immune cells, including mast cells, macrophages, and T cells. In this review, we explore the current state of the field and critical knowledge gaps regarding the role of haploinsufficiency on immune cell function, as well as the putative impact of Schwann cell lineage states on immune cell recruitment and function within the tumor field. Furthermore, we review emerging evidence suggesting a dueling role of immune cells along the neurofibroma to MPNST continuum, on one hand propitiating PNF initiation, while on the other, potentially impeding the malignant transformation of plexiform and atypical neurofibroma precursor lesions. Finally, we underscore the potential implications of these discoveries and advocate for further research directed at illuminating the contributions of various immune cells subsets in discrete stages of tumor initiation, progression, and malignant transformation to facilitate the discovery and translation of innovative diagnostic and therapeutic approaches to transform risk-adapted care.
PubMed: 38473354
DOI: 10.3390/cancers16050994 -
Clinical and Translational Medicine Mar 2024
Safety, pharmacokinetics and efficacy of selumetinib in Chinese adult and paediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas: The primary analysis of a phase 1 open-label study.
Topics: Adult; Humans; Child; Neurofibroma, Plexiform; Neurofibromatosis 1; Benzimidazoles; China
PubMed: 38456222
DOI: 10.1002/ctm2.1589 -
Child's Nervous System : ChNS :... Nov 2023Plexiform neurofibromas are the hallmark of neurofibromatosis type 1 (NF1) and significantly contribute to the overall burden of disease. While surgical excision has...
Plexiform neurofibromas are the hallmark of neurofibromatosis type 1 (NF1) and significantly contribute to the overall burden of disease. While surgical excision has long been the only available therapy, the MEK inhibitor (MEKi) selumetinib has been approved as a non-surgical treatment option for these tumors in 2020 (USA) and 2021 (Europe), respectively. However, selumetinib will result in tumor shrinkage only after several months of therapy and might not prevent malignant transformation of a plexiform neurofibroma that occurs with a frequency of 10-15%. Here, we demonstrate that surgical excision might be the therapy of choice in some plexiform neurofibromas despite the availability of MEKi therapy.
Topics: Humans; Neurofibroma, Plexiform; Neurofibroma; Neurofibromatosis 1; Europe
PubMed: 37344677
DOI: 10.1007/s00381-023-06029-5 -
Skeletal Radiology Apr 2024The aim of this study is to evaluate neurofibromatosis type 1 (NF1) patients with whole-body MRI (WBMRI) to investigate the frequency of plexiform neurofibromas (pNFs),...
OBJECTIVE
The aim of this study is to evaluate neurofibromatosis type 1 (NF1) patients with whole-body MRI (WBMRI) to investigate the frequency of plexiform neurofibromas (pNFs), diffuse neurofibromas (dNFs), and malignant peripheral nerve sheath tumors (MPNSTs).
MATERIALS AND METHODS
In this retrospective cross-sectional study, between the years 2015 and 2023, 83 consecutive patients with known NF1 underwent a total of 110 WBMRI screenings for MPNST using a standardized institutional protocol. The lesions are categorized as discrete lesions, pNFs, dNFs, and MPNSTs. Histopathology served as the reference standard for all MPNSTs.
RESULTS
Among the 83 patients analyzed, 53 (64%) were women and 30 were men (36%) of ages 36.94±14.43 years (range, 15-66 years). Of the 83 patients, 33 have a positive family history of NF1 and positive genetic studies. Seven of 83 (8%) have only dNF, 20/83 (24%) have pNF, 28/83 (34%) have both dNF and pNF, and 28/83 (34%) have neither. Of the 83 patients, eight (9.6%) were diagnosed with nine total MPNSTs. Age range for patients with MPNSTs at time of diagnosis was 22-51, with an average age of 33.4 years. Only one MPNST (11%) developed from underlying pNF 4 years after WBMRI along the right bronchial tree. Three of eight (37.5%) patients with MPNST died within 5 years of pathologic diagnosis.
CONCLUSION
This study suggests the absence of a predisposition for development of MPNST from pNFs and dNFs in the setting of NF1. As such, these lesions may not need special surveillance compared to discrete peripheral nerve sheath tumors.
Topics: Male; Humans; Female; Adult; Neurofibrosarcoma; Cross-Sectional Studies; Retrospective Studies; Neurofibroma; Neurofibromatosis 1; Neurofibroma, Plexiform; Nerve Sheath Neoplasms; Magnetic Resonance Imaging
PubMed: 37903998
DOI: 10.1007/s00256-023-04497-z