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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 -
Epilepsy Research May 2024Studies have shown an increased risk of epilepsy in patients with neurofibromatosis type 1 (NF1). However, most reports focus on the pediatric population. In this study,...
PURPOSE
Studies have shown an increased risk of epilepsy in patients with neurofibromatosis type 1 (NF1). However, most reports focus on the pediatric population. In this study, we describe the trajectory of patients with NF1 and epilepsy beyond childhood.
METHODS
Patients with NF1 ≥18 years-old consecutively seen at a multidisciplinary neurofibromatosis clinic during a four-year period were prospectively enrolled and offered routine EEG, MRI, and genetic testing. The lifelong and point prevalence of epilepsy in patients with NF1 were calculated. Demographic, genetic, radiological, and clinical features found to be statistically associated with having received a diagnosis of epilepsy were incorporated into a logistic regression model.
RESULTS
Among 113 patients with NF1 included in this study (median age at study inclusion: 33 years), the lifelong prevalence of epilepsy was 11% (CI=6-18%) and point prevalence 7% (CI= 3-13%). Most patients (73%) were diagnosed with epilepsy before the age of 18 and achieved seizure-freedom by adulthood. At study inclusion, three-quarters of patients with a diagnosis of epilepsy had been seizure-free for more than one year and a third had resolved epilepsy. A routine EEG with epileptiform discharges had a sensitivity of 25% (CI=3-65) and specificity of 99% (CI=93-100) for identifying adult patients with NF1 and unresolved epilepsy. A history of epilepsy was associated with having a low-grade glioma (OR: 38.2; CI=2.2-674.7; p<0.01), learning disability (OR: 5.7; CI=1.0-31.5; p<0.05), and no plexiform neurofibroma (OR: 0.05; CI=0.0-0.8; p=0.04). No single mutation type was associated with the development of epilepsy.
CONCLUSIONS
In patients with NF1, although resolution of epilepsy over time was observed in many cases, the prevalence of epilepsy was higher among adults with NF1 than that reported in the general population. Epileptogenesis in NF1 likely requires the combination of multiple genetic and environmental factors and suggests involvement of a network that spreads beyond the borders of a well-defined parenchymal lesion.
Topics: Humans; Neurofibromatosis 1; Epilepsy; Male; Female; Adult; Prevalence; Young Adult; Electroencephalography; Phenotype; Middle Aged; Genotype; Adolescent; Magnetic Resonance Imaging; Prospective Studies
PubMed: 38471245
DOI: 10.1016/j.eplepsyres.2024.107336 -
Life Science Alliance May 2024Plexiform neurofibromas (PNFs) are nerve tumors caused by loss of and dysregulation of RAS-MAPK signaling in Schwann cells. Most PNFs shrink in response to MEK...
Plexiform neurofibromas (PNFs) are nerve tumors caused by loss of and dysregulation of RAS-MAPK signaling in Schwann cells. Most PNFs shrink in response to MEK inhibition, but targets with increased and durable effects are needed. We identified the anaphylatoxin C5a as increased in PNFs and expressed largely by PNF m acrophages. We defined pharmacokinetic and immunomodulatory properties of a C5aR1/2 antagonist and tested if peptide antagonists augment the effects of MEK inhibition. MEK inhibition recruited C5AR1 to the macrophage surface; short-term inhibition of C5aR elevated macrophage apoptosis and Schwann cell death, without affecting MEK-induced tumor shrinkage. PNF macrophages lacking C5aR1 increased the engulfment of dying Schwann cells, allowing their visualization. Halting combination therapy resulted in altered T-cell distribution, elevated Iba1+ and CD169+ immunoreactivity, and profoundly altered cytokine expression, but not sustained trumor shrinkage. Thus, C5aRA inhibition independently induces macrophage cell death and causes sustained and durable effects on the PNF microenvironment.
Topics: Humans; Cytophagocytosis; Macrophages; Mitogen-Activated Protein Kinase Kinases; Neurofibroma, Plexiform; Signal Transduction; Tumor Microenvironment
PubMed: 38458648
DOI: 10.26508/lsa.202302229 -
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 -
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 -
Journal of Neuro-oncology May 2024Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein...
PURPOSE
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. However, cutaneous adverse events (CAEs) are common and may hinder patients' abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1.
METHODS
We reviewed institutional medical records of patients under 30 years with a diagnosis of "NF1," "NF2," or "other neurofibromatoses" on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response.
RESULTS
Our cohort consisted of 40 patients with NF1 (median age, 14 years). Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi. There was no significant association between CAE presence and tumor response (p = 0.39).
CONCLUSIONS
Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.
Topics: Humans; Neurofibromatosis 1; Female; Male; Adolescent; Child; Young Adult; Adult; Protein Kinase Inhibitors; Retrospective Studies; Child, Preschool; Neurofibroma, Plexiform; Follow-Up Studies; Drug Eruptions; Prognosis
PubMed: 38443692
DOI: 10.1007/s11060-024-04617-2 -
International Journal of Surgery Case... Mar 2024Neurofibromatosis type 1 is a benign peripheral nerve tumor, often manifests as plexiform neurofibroma that may cause severe dysfunction, pain, and disfigurement....
Case report: Remarkable efficacy of negative-pressure wound therapy in giant lower extremity elephantiasis neuromatosa for vascularization, skin grafting, and fluid control.
INTRODUCTION AND IMPORTANCE
Neurofibromatosis type 1 is a benign peripheral nerve tumor, often manifests as plexiform neurofibroma that may cause severe dysfunction, pain, and disfigurement. Bleeding has been reported as a complication of plexiform neurofibroma due to vascular fragility and vasculopathy that may develop into life-threatening bleeding especially after excision procedure. Consequently, post excision complications also include dehiscence and infection.
CASE PRESENTATION
We report a 23-year-old male with elephantiasis of the left lower extremity due to giant plexiform neurofibroma who underwent preoperative embolization followed by serial surgical mass reduction. There were postoperative complications consisting of hematoma, wound dehiscence, and infection.
CLINICAL DISCUSSION
Negative pressure wound therapy is often used to accelerate wound healing, including infected wounds. However, negative pressure wound therapy has been a debatable modality for wound care of neurofibroma due to reported risks of profuse bleeding during its use.
CONCLUSION
In this case, despite the size, negative-pressure wound therapy has shown good results for infected neurofibroma wounds and as an adjunct as wound dressing for defect closure of neurofibroma with split-thickness skin graft.
PubMed: 38428057
DOI: 10.1016/j.ijscr.2024.109428 -
Expert Review of Neurotherapeutics Apr 2024Neurofibromatosis type 1 (NF1) is a rare neurogenetic disorder characterized by multiple organ system involvement and a predisposition to benign and malignant tumor... (Review)
Review
INTRODUCTION
Neurofibromatosis type 1 (NF1) is a rare neurogenetic disorder characterized by multiple organ system involvement and a predisposition to benign and malignant tumor development. With revised NF1 clinical criteria and the availability of germline genetic testing, there is now an opportunity to render an early diagnosis, expedite medical surveillance, and initiate treatment in a prompt and targeted manner.
AREAS COVERED
The authors review the spectrum of medical problems associated with NF1, focusing specifically on children and young adults. The age-dependent appearance of NF1-associated features is highlighted, and the currently accepted medical treatments are discussed. Additionally, future directions for optimizing the care of this unique population of children are outlined.
EXPERT OPINION
The appearance of NF1-related medical problems is age dependent, requiring surveillance for those features most likely to occur at any given age during childhood. As such, we advocate a life stage-focused screening approach beginning in infancy and continuing through the transition to adult care. With early detection, it becomes possible to promptly institute therapies and reduce patient morbidity. Importantly, with continued advancement in our understanding of disease pathogenesis, future improvements in the care of children with NF1 might incorporate improved risk assessments and more personalized molecularly targeted treatments.
Topics: Child; Young Adult; Humans; Adolescent; Neurofibromatosis 1; Genetic Testing
PubMed: 38406862
DOI: 10.1080/14737175.2024.2324117 -
Journal of Indian Association of... 2024This case report describes a 4-year-old girl with an isolated neurofibroma in the sacrococcygeal region. Although initially resembling sacrococcygeal teratoma,...
This case report describes a 4-year-old girl with an isolated neurofibroma in the sacrococcygeal region. Although initially resembling sacrococcygeal teratoma, histopathology revealed a benign nerve sheath tumor. Wide local excision was performed, and the final diagnosis was plexiform neurofibroma. Diagnostic challenges in rare childhood tumors require stepwise evaluation and multidisciplinary team discussions.
PubMed: 38405243
DOI: 10.4103/jiaps.jiaps_136_23 -
Current Medical Research and Opinion Apr 2024The objectives of this study were to retrospectively investigate the patient characteristics, treatment patterns, healthcare resource utilization (HCRU), and healthcare...
Patient characteristics, treatment patterns, healthcare resource utilization, and costs among patients diagnosed with neurofibromatosis type 1 with and without plexiform neurofibromas in Japan.
OBJECTIVES
The objectives of this study were to retrospectively investigate the patient characteristics, treatment patterns, healthcare resource utilization (HCRU), and healthcare costs related to management of neurofibromatosis type 1 (NF1) in Japan.
METHODS
Cohorts of NF1 patients with or without plexiform neurofibromas (PN) were identified from the Medical Data Vision database in 2008-2019. Baseline characteristics, NF1 medications, HCRU, and associated costs were assessed using descriptive statistics. All-cause HCRU and costs following the first confirmed NF1 diagnosis date were analyzed per patient per year (PPPY) in Japanese Yen (JPY) and United States Dollar (USD).
RESULTS
A total of 4394 NF1 patients without PN and 370 NF1 patients with PN were identified. The mean age was 35.0 and 36.9 years, respectively. The proportion of patients with PN treated with medications was higher than that in patients without PN (except for antirheumatic/immunologic agents). Analgesics/non-steroidal anti-inflammatory drugs were the most frequently prescribed NF1 medications (44.3% and 56.0% in patients without and with PN, respectively), followed by inpatient prescriptions of opioids/opioid-like agents (17.8% and 27.6%, respectively). Inpatient admissions accounted for the highest costs in both cohorts with the average cost PPPY being JPY 2,133,277 (USD 19,861) for patients without PN and JPY 1,052,868 (USD 9802) for patients with PN.
CONCLUSIONS
NF1 is treated primarily with supportive care with analgesics/non-steroidal anti-inflammatory drugs being the most frequently prescribed NF1 medications in Japan. Findings underscored the unmet need and substantial economic burden among patients with NF1 and highlighted the need for new treatment options for patients with this disease.
Topics: Humans; Adult; Neurofibromatosis 1; Neurofibroma, Plexiform; Japan; Retrospective Studies; Health Care Costs; Analgesics; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 38404173
DOI: 10.1080/03007995.2024.2322698