-
American Journal of Translational... 2022Neurofibromatosis type 1 (NF1) predisposes to the development of dermal and plexiform neurofibromas and serum of NF1 patients stimulates neurofibroma proliferation in...
Neurofibromatosis type 1 (NF1) predisposes to the development of dermal and plexiform neurofibromas and serum of NF1 patients stimulates neurofibroma proliferation in vitro. This study aimed to determine whether, in NF1 patients, serum levels of midkine (MK) and fibroblast growth factor 2 (FGF2) were associated with the number and/or type of neurofibromas. In addition, their concentrations were correlated with serum levels of dehydroepiandrosterone sulfate (DHEAS), a neurosteroid secreted by the peripheral nervous system. We performed a case control-study and measured, by ELISA assay, serum concentrations of MK, FGF2, and DHEAS in 20 NF1 patients and 30 controls. We found increased serum levels of MK and FGF2 in NF1 patients between 30 and 50 years old. Their concentrations were significantly higher in NF1 patients with plexiform neurofibromas than in controls (P=0.003 for MK and P=0.008 for FGF2). As an underlying hormonal regulation was suspected, DHEAS serum levels were measured but no difference was observed between patients and controls. We also observed a strong association between MK and FGF2 levels (P=0.0001) in NF1 patients and controls. In conclusion, we point out MK and FGF2 as biomarkers for plexiform neurofibroma in NF1 patients. As both growth factors are estrogen-responsive genes and neurofibromin is a co-repressor of estrogen receptor alpha activity, we suggest that the increased serum levels of MK and FGF2 observed in NF1 patients might be due to estradiol hypersensitivity.
PubMed: 35702135
DOI: No ID Found -
ANZ Journal of Surgery Apr 2022
Topics: Abdominal Pain; Humans; Mesentery; Neurofibroma, Plexiform; Neurofibromatosis 1
PubMed: 34473877
DOI: 10.1111/ans.17186 -
European Journal of Medical Genetics May 2023Surgery is a treatment option for neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN), but complete resection is often not feasible. Real-world studies...
Surgery is a treatment option for neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN), but complete resection is often not feasible. Real-world studies are warranted to understand disease burden, progression, and need for medical treatment in patients with inoperable PN. CASSIOPEA was a retrospective study of French pediatric patients (aged ≥3 to <18 years) presenting at a national multidisciplinary team (MDT) review with NF1 and ≥1 symptomatic, inoperable PN. Medical records were reviewed from the time of MDT review and over a follow-up period of up to 2 years. Primary objectives were to describe patient characteristics and target PN-associated therapy patterns. A secondary objective was evolution of target PN-related morbidities. Patients with prior, ongoing, or MDT recommendation of mitogen-activated protein kinase kinase (MEK) inhibitor treatment were excluded. Overall, 78 target PN were identified in 76 patients. At MDT review, median age was 8.4 years, with approximately 30% of patients aged 3-6 years. Target PN were primarily internal (77.3%), and 43.2% were progressive. Target PN location was evenly distributed. 34 target PN had documented MDT recommendations; of these, a majority (76.5%) were for non-medication management, including surveillance. At least one follow-up visit was recorded for 74 target PN. Despite initially being considered inoperable, 12.3% of patients underwent surgery for target PN. At MDT review, most (98.7%) target PN were associated with ≥1 morbidity, primarily pain (61.5%) and deformity (24.4%); severe morbidities were identified in 10.3%. Of 74 target PN with follow-up data, 89.2% were associated with ≥1 morbidity, primarily pain (60.8%) and deformity (25.7%). Of 45 target PN associated with pain, pain improved in 26.7%, was stable in 44.4%, and deteriorated in 28.9%. Deformity improved in 15.8% and remained stable in 84.2% of 19 target PN associated with deformity. None deteriorated. In this real-world study in France, NF1-PN disease burden was considerable, and a considerable proportion of patients were very young. Most patients received only supportive care without medication for target PN management. Target PN-related morbidities were frequent, heterogeneous, and generally did not improve during follow-up. These data highlight the importance of effective treatments that target PN progression and improve disease burden.
Topics: Child; Humans; Adolescent; Neurofibromatosis 1; Neurofibroma, Plexiform; Retrospective Studies; Treatment Outcome; Mitogen-Activated Protein Kinase Kinases; Pain
PubMed: 36868501
DOI: 10.1016/j.ejmg.2023.104734 -
Cancers May 2023Limited therapies exist for neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN). For this reason, the activity of vinblastine (VBL) and methotrexate...
Limited therapies exist for neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN). For this reason, the activity of vinblastine (VBL) and methotrexate (MTX) was evaluated in children and young adults with NF1 and PN. Patients ≤ 25 years of age with progressive and/or inoperable NF1-PN received VBL 6 mg/m and MTX 30 mg/m weekly for 26 weeks, followed by every 2 weeks for 26 weeks. Objective response rate was the primary endpoint. Of 25 participants enrolled, 23 were evaluable. The median age of participants was 6.6 years (range 0.3-20.7). The most frequent toxicities were neutropenia and elevation of transaminases. On two-dimensional (2D) imaging, 20 participants (87%) had stable tumor, with a median time to progression of 41.5 months (95% confidence interval 16.9, 64.9). Two of eight participants (25%) with airway involvement demonstrated functional improvements including decreased positive pressure requirements and apnea-hypopnea index. A post hoc three-dimensional (3D) analysis of PN volumes was completed on 15 participants with amenable imaging; 7 participants (46%) had progressive disease on or by the end of therapy. VBL/MTX was well-tolerated but did not result in objective volumetric response. Furthermore, 3D volumetric analysis highlighted the lack of sensitivity of 2D imaging for PN response evaluation.
PubMed: 37174087
DOI: 10.3390/cancers15092621 -
Current Treatment Options in Oncology Aug 2020Though the majority of nervous system tumors are sporadic, several clinically relevant genetic syndromes are associated with a predisposition to tumors of the central... (Review)
Review
Though the majority of nervous system tumors are sporadic, several clinically relevant genetic syndromes are associated with a predisposition to tumors of the central and peripheral nervous system including neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis (SWN). These represent prototypical tumor suppressor syndromes where loss of a tumor suppressor gene-protein impairs the cell's ability to regulate cell proliferation. While clinical manifestations vary widely for each of these syndromes, tumors arising in the peripheral nerve sheath are a unifying feature. Clinical clues should prompt the clinician to recognize the underlying genetic syndrome and screen for associated tumors including, among others, plexiform neurofibromas and gliomas in NF1 and vestibular schwannomas, meningiomas, and spinal ependymomas in NF2. Improvements in mechanistic understanding of how the genetic mutations that underlie these syndromes contribute to tumor formation have led to new advances in targeted therapies. MEK inhibitors have shown promise for treating progressive plexiform neurofibromas in NF1. Bevacizumab has been shown to improve hearing and treat vestibular schwannomas in NF2. This article reviews the currently available data on management of tumors associated with these three syndromes.
Topics: Animals; Antineoplastic Agents, Immunological; Bevacizumab; Humans; Nervous System Neoplasms; Neurilemmoma; Neurofibromatoses; Prognosis; Skin Neoplasms
PubMed: 32767156
DOI: 10.1007/s11864-020-00779-z -
Neuro-oncology Advances Jul 2020Plexiform neurofibromas (PNF) are peripheral nerve tumors caused by bi-allelic loss of in the Schwann cell (SC) lineage. PNF are common in individuals with... (Review)
Review
Plexiform neurofibromas (PNF) are peripheral nerve tumors caused by bi-allelic loss of in the Schwann cell (SC) lineage. PNF are common in individuals with Neurofibromatosis type I (NF1) and can cause significant patient morbidity, spurring research into potential therapies. Immune cells are rare in peripheral nerve, whereas in PNF 30% of the cells are monocytes/macrophages. Mast cells, T cells, and dendritic cells (DCs) are also present. mutant neurofibroma SCs with elevated Ras-GTP signaling resemble injury-induced repair SCs, in producing growth factors and cytokines not normally present in SCs. This provides a cytokine-rich environment facilitating PNF immune cell recruitment and fibrosis. We propose a model based on genetic and pharmacologic evidence in which, after loss of in the SC lineage, a lag occurs. Then, mast cells and macrophages are recruited to nerve. Later, T cell/DC recruitment through CXCL10/CXCR3 drives neurofibroma initiation and sustains PNF macrophages and tumor growth. Stat3 signaling is an additional critical mediator of neurofibroma initiation, cytokine production, and PNF growth. At each stage of PNF development therapeutic benefit should be achievable through pharmacologic modulation of leukocyte recruitment and function.
PubMed: 32642730
DOI: 10.1093/noajnl/vdz045 -
Frontiers in Oncology 2021The neurofibromatosis syndromes, including NF1, NF2, and schwannomatosis, are tumor suppressor syndromes characterized by multiple nervous system tumors, particularly... (Review)
Review
The neurofibromatosis syndromes, including NF1, NF2, and schwannomatosis, are tumor suppressor syndromes characterized by multiple nervous system tumors, particularly Schwann cell neoplasms. NF-related tumors are mainly treated by surgery, and some of them have been treated by but are refractory to conventional chemotherapy. Recent advances in molecular genetics and genomics alongside the development of multiple animal models have provided a better understanding of NF tumor biology and facilitated target identification and therapeutic evaluation. Many targeted therapies have been evaluated in preclinical models and patients with limited success. One major advance is the FDA approval of the MEK inhibitor selumetinib for the treatment of NF1-associated plexiform neurofibroma. Due to their anti-neoplastic, antioxidant, and anti-inflammatory properties, selected natural compounds could be useful as a primary therapy or as an adjuvant therapy prior to or following surgery and/or radiation for patients with tumor predisposition syndromes, as patients often take them as dietary supplements and for health enhancement purposes. Here we review the natural compounds that have been evaluated in NF models. Some have demonstrated potent anti-tumor effects and may become viable treatments in the future.
PubMed: 34604034
DOI: 10.3389/fonc.2021.698192 -
Journal of Neurosurgical Sciences Dec 2022Selumetinib is a MEK inhibitor, which is effective with an acceptable safety profile in reducing the volume of symptomatic inoperable plexiform neurofibromas in some...
INTRODUCTION
Selumetinib is a MEK inhibitor, which is effective with an acceptable safety profile in reducing the volume of symptomatic inoperable plexiform neurofibromas in some clinical trials and also has been recently approved by FDA for use in children aged 2 years or older. However, no systematic review has yet been performed to provide a collective estimate of the results of all these trials.
EVIDENCE ACQUISITION
Articles describing the use of selumetinib in patients with neurofibromatosis type-1 (NF1) with inoperable plexiform neurofibromas were searched from different electronic databases. The objectives were to provide a pooled estimate of efficacy evaluated by direct measurement and also by various functional measures, as well as the proportion of patients with adverse events. For determining pooled estimates, we included only studies with a minimum sample size of 15 with a prospective study design.
EVIDENCE SYNTHESIS
A total of eight articles with 137 patients were found and 134 patients in six uncontrolled trials were included in the quantitative review. Out of these 26 were adults (69% male; 33.2±18.4 years, range 18-60 years) and 108 were in the pediatric age group (74% boys, 10.9±2.3 years, range-2-18 years,). Total 77.86% (95% CI: 55.91-99.81%) patients had a partial response, 71.24% (95% CI: 53.62-89.93%) had a confirmed partial response, and 56.25% (95% CI: 37.53-72.49%) had a durable partial response. The average time to initial response was 7.3±2.9 cycles (range, 4 to 20), and the median time to best response was 15.4±5.8 cycles (range, 4 to 36). The average change in neurofibroma volume at best response was -28.15% (95% CI: -17.95%, -38.34%, range, -55.1% to 2.2%). Progression-free survival was observed in 93.12% of patients at the time of data cut-off. Overall, 73.26% (95% CI: 54.07%, 92.45%) patients had improvement in at least one of the functional or patient-reported outcome assessments. The most common adverse effects were grade 1 and 2 gastrointestinal symptoms (65%), an asymptomatic increase in the creatine phosphokinase level (31%), paronychia (6%), and acneiform rash (17%). A total of 17% patients required dose reduction due to these toxic effects and 10.5% (95% CI: 4.0%, 17.0%) of patients discontinued due to toxic effects.
CONCLUSIONS
Selumetinib can produce sustained shrinkage in the majority of patients with NF1 and symptomatic plexiform neurofibroma to provide clinically meaningful benefit in functional ability, with more robust evidence in children. The acceptable safety profile and absence of cumulative toxic effects permit long-term treatment with selumetinib.
Topics: Adult; Humans; Male; Child; Female; Neurofibroma, Plexiform; Prospective Studies; Benzimidazoles; Neurofibromatosis 1
PubMed: 35301838
DOI: 10.23736/S0390-5616.21.05528-4 -
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 -
Expert Opinion on Investigational Drugs Jan 2022Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic condition, which predisposes individuals to the development of plexiform neurofibromas (PN), benign nerve...
INTRODUCTION
Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic condition, which predisposes individuals to the development of plexiform neurofibromas (PN), benign nerve sheath tumors seen in 30-50% of patients with NF1. These tumors may cause significant pain and disfigurement or may compromise organ function. Given the morbidity associated with these tumors, therapeutic options for patients with NF1-related PN are necessary.
AREAS COVERED
We searched the www.clinicaltrials.gov database for 'plexiform neurofibroma.' This article summarizes completed and ongoing trials involving systemic therapies for PN.
EXPERT OPINION
Surgery is the mainstay treatment; however, complete resection is not possible in many cases. Numerous systemic therapies have been evaluated in patients with NF1, with MEK inhibitors (MEKi) showing the greatest efficacy for volumetric reduction and improvement in functional and patient-reported outcomes. The MEKi selumetinib is now FDA approved for the treatment of inoperable, symptomatic PN in pediatric NF1 patients. Questions remain regarding the use of this drug class in terms of when to initiate therapy, overall duration, reduced dosing schedules, and side effect management. Future studies are needed to fully understand the clinical application of MEKi and to evaluate other potential therapies through appropriate trial designs for this potentially devastating, manifestation in NF1.
Topics: Child; Humans; Neurofibroma, Plexiform; Neurofibromatosis 1; Pain; Protein Kinase Inhibitors
PubMed: 34932916
DOI: 10.1080/13543784.2022.2022120