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Journal of Neurology May 2024The approval of selumetinib in patients with neurofibromatosis type 1(NF1) and inoperable plexiform neurofibromas (PN) has reshaped the landscape of clinical management... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The approval of selumetinib in patients with neurofibromatosis type 1(NF1) and inoperable plexiform neurofibromas (PN) has reshaped the landscape of clinical management of the disease, and further comprehensive evaluation of the drug's efficacy and safety is needed.
METHODS
Original articles reporting on the efficacy and safety of elumetinib in patients with NF1 were comprehensively searched in the Pubmed database, Embase database, Cochrane Library, and Web of Science database and screened for inclusion of studies that met the criteria. We pooled the objective response rate (ORR), disease control rate (DCR), disease progression rate (DPR), and the rate of improvement in PN-related complications using meta-analysis. The incidence of drug-related adverse events was also statistically analyzed.
RESULTS
This study included 10 clinical trials involving 268 patients. The pooled ORR was 68.0% (95% CI 58.0-77.3%), the DCR was 96.8% (95% CI 90.8-99.7%) and the DPR was only 1.4% (95% CI 0-4.3%). The pooled improvement rate was 75.3% (95% CI 56.2-90.9%) for pain and 77.8% (95% CI 63.1-92.5%) for motor disorders. Most adverse events were mild, with the most common being gastrointestinal reactions (diarrhea: 62.5%; vomiting: 54.5%).
CONCLUSION
Our study demonstrates that selumetinib is effective in patients with NF1 and PN, significantly improving the serious complications associated with PN as well as having tolerable toxicities. Our findings help to increase clinicians' confidence in applying selumetinib and promote the clinical adoption and benefit of the new drug.
Topics: Humans; Neurofibroma, Plexiform; Neurofibromatosis 1; Benzimidazoles; Protein Kinase Inhibitors
PubMed: 38502338
DOI: 10.1007/s00415-024-12301-8 -
The American Journal of Dermatopathology Dec 2022Plexiform neurofibromas are benign neural tumors observed in association with neurofibromatosis. Isolated lesions exist. We conducted a systematic review of the...
Plexiform neurofibromas are benign neural tumors observed in association with neurofibromatosis. Isolated lesions exist. We conducted a systematic review of the published literature indexed in the PubMed/Medline database using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Thirty-five studies describing isolated plexiform neurofibromas were included detailing 41 tumors. Isolated lesions occur in all age groups, in both sexes and in all races. Cutaneous and mucosal lesions were reported. Asymptomatic, slowly enlarging masses were the most common clinical presentation, but lesions could be painful. Trauma-associated lesions were uncommon, but reported. Histopathologic features were similar to syndromic counterparts, but well-circumscribed/encapsulated lesions, rare association with diffuse neurofibroma, lack of reported malignant degeneration, and rare named-nerve origin were observed. Excision was curative in many cases, but recurrence could occur. Plexiform neurofibromas occur without neurofibromatosis in a subset of patients with isolated tumors.
Topics: Male; Female; Humans; Neurofibroma, Plexiform; Neurofibroma; Neurofibromatosis 1; Skin
PubMed: 36395447
DOI: 10.1097/DAD.0000000000002322 -
Pharmaceuticals (Basel, Switzerland) Jul 2022Trametinib has been used in neurofibromatosis type 1 (NF1) patients, especially those with unresectable nerve tumors, but no systematic review based on the latest... (Review)
Review
Trametinib has been used in neurofibromatosis type 1 (NF1) patients, especially those with unresectable nerve tumors, but no systematic review based on the latest studies has been published. We conducted this meta-analysis to evaluate the effectiveness and safety of trametinib in treating NF1-related nerve tumors. Original articles reporting the efficacy and safety of trametinib in NF1 patents were identified in PubMed, EMBASE, and Web of Science up to 1 June 2022. Using R software and the 'meta' package, the objective response rates (ORRs) and disease control rates (DCRs) were calculated to evaluate the efficacy, and the pooled proportion of adverse events (AEs) was calculated. The Grading of Recommendations, Assessment, Development and Evaluation system was used to assess the quality of evidence. Eight studies involving 92 patients were included, which had a very low to moderate quality of evidence. The pooled ORR was 45.3% (95% CI: 28.9-62.1%, I = 0%), and the DCR was 99.8% (95% CI: 95.5-100%, I = 0%). The most common AEs was paronychia, with a pooled rate of 60.7% (95% CI: 48.8-72.7%, I = 0%). Our results indicate the satisfactory ability to stabilize tumor progression but a more limited ability to shrink tumors of trametinib in NF1-related nerve tumors. The safety profile of trametinib is satisfactory.
PubMed: 36015104
DOI: 10.3390/ph15080956 -
Pediatric Neurology Sep 2022The neurofibromatoses comprise three different genetic conditions causing considerable morbidity and mortality: neurofibromatosis type 1 (NF1), neurofibromatosis type 2... (Review)
Review
INTRODUCTION
The neurofibromatoses comprise three different genetic conditions causing considerable morbidity and mortality: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). This review summarizes recent and ongoing clinical trials involving patients with neurofibromatoses to better understand the current state of clinical trial research centered around these conditions and inform areas of need.
METHODS
A search was conducted using the Cochrane Central Register of Controlled Trials and clinicaltrials.gov databases. Inclusion and exclusion criteria were designed to identify clinical trials focused on patients with NF1, NF2, or SWN completed in or after 2010 and in process as of December 31, 2021. Information was collected using standardized guidelines.
RESULTS
A total of 134 clinical trials were included, with 75 (56%) completed and 59 (44%) in process. For completed trials, 74% (n = 56) involved patients with NF1, and of those based on specific tumors (n = 26, 46%), the majority focused on plexiform neurofibromas (PNs) (n = 12, 46%). For ongoing trials, 79% (n = 47) involve patients with NF1, and of those based on specific tumors (n = 29, 61%), the majority are focused on PNs (n = 13, 45%).
CONCLUSION
Both recent and ongoing clinical trials have primarily focused on patients with NF1 and the treatment of PNs. This research has led to the first FDA-approved drug for NF1-PN and has changed management of these tumors, allowing for systemic therapy rather than reliance on only a surgical modality. Trials evaluating comorbid psychiatric conditions and quality of life among patients with any of the neurofibromatoses appear less common. These areas may warrant focus in future studies to improve clinical management.
Topics: Humans; Neurilemmoma; Neurofibroma, Plexiform; Neurofibromatoses; Neurofibromatosis 1; Neurofibromatosis 2; Quality of Life; Skin Neoplasms
PubMed: 35759947
DOI: 10.1016/j.pediatrneurol.2022.06.003 -
Neurology Mar 2022Although the recent approval of selumetinib is expected to transform the management of children with neurofibromatosis type 1 (NF1), particularly those with symptomatic... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
Although the recent approval of selumetinib is expected to transform the management of children with neurofibromatosis type 1 (NF1), particularly those with symptomatic and inoperable plexiform neurofibromas, no systematic review has summarized its efficacy and safety based on the latest studies. This study was conducted to systematically evaluate the efficacy and safety of selumetinib in children with NF1.
METHODS
Original articles reporting the efficacy and safety of selumetinib in patients with NF1 were identified in PubMed and EMBASE up to January 28, 2021. The pooled objective response rates (ORRs) and disease control rates (DCRs) were calculated using the DerSimonian-Laird method based on random-effects modeling. The pooled proportion of adverse events (AEs) was also calculated. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation system.
RESULTS
Five studies involving 126 patients were included in our analysis. The studies had a very low to moderate quality of the evidence. The pooled ORR was 73.8% (95% CI 57.3%-85.5%) and the DCR was 92.5% (95% CI 66.5%-98.7%). The 2 most common AEs were diarrhea, which had a pooled rate of 63.8% (95% CI 52.9%-73.4%), and an increase in creatine kinase levels, which had a pooled rate of 63.3% (95% CI 35.6%-84.3%).
DISCUSSION
Our results indicate that selumetinib is an effective and safe treatment for pediatric patients with symptomatic, inoperable plexiform neurofibromas. Further larger-scale randomized controlled studies are needed to confirm the long-term outcome of patients treated with this drug.
Topics: Benzimidazoles; Child; Diarrhea; Humans; Neurofibroma, Plexiform; Neurofibromatosis 1
PubMed: 35017312
DOI: 10.1212/WNL.0000000000013296 -
Neurological Sciences : Official... Feb 2022Patients with neurofibromatosis type-1 (NF-1) and associated plexiform neurofibromas (PNs) often have a high burden of illness owing to debilitating symptoms of these...
PURPOSE
Patients with neurofibromatosis type-1 (NF-1) and associated plexiform neurofibromas (PNs) often have a high burden of illness owing to debilitating symptoms of these tumors and limited management options. To investigate this complex disease, a systematic literature review (SLR) was conducted on the epidemiology of pediatric NF-1 and associated PNs, the burden of illness, and outcomes of surgical resection of these tumors.
METHODS
Searches of MEDLINE and Embase (from database inception to October 2019) and conference proceedings (2017-2019) were performed to identify relevant studies. The review methodology was informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
RESULTS
Twenty studies were identified. Evidence confirmed NF-1 is rare but that occurrence may differ geographically. Only limited data on the birth incidence of NF-1 were identified. Prevalence estimates for pediatric NF-1 varied from one per 960 individuals (aged 17 years) to one per 5681 children (aged < 16 years) across five large registry/surveillance studies (each involving > 19,000 individuals). The prevalence of associated PNs was 0-29.6%. PNs carried increased mortality risk in pediatric NF-1 in both studies that explored this potential association. Patients with PNs reported high use of analgesics. The complication rate post-surgery for PNs was around 17-19%. The recurrence rate (18-68%) was dependent on the extent of excision achieved during surgery.
CONCLUSIONS
Data suggest NF-1 is a rare disease with increased morbidity and mortality in children with associated PNs. Surgical outcomes for PNs are often poor. These findings suggest significant unmet needs in patients with NF-1-associated PNs.
Topics: Child; Humans; Neurofibroma, Plexiform; Neurofibromatosis 1
PubMed: 34143343
DOI: 10.1007/s10072-021-05361-5 -
Ophthalmic Plastic and Reconstructive... 2018To summarize the clinical, radiographic, and intraoperative characteristics of isolated neurofibromas of the orbit (INFO) in the literature and report a case of INFO. (Review)
Review
PURPOSE
To summarize the clinical, radiographic, and intraoperative characteristics of isolated neurofibromas of the orbit (INFO) in the literature and report a case of INFO.
METHODS
Case report and a systematic review of the literature.
RESULTS
A total of 45 patients were identified from 18 previous studies. There was no sex predilection and mean ages were between 32.3 and 40.0 years with a standard deviation of 9.8 to 19.5 years, median age was 32 to 38 years with a range of 1.5 to 82 years. On CT imaging, INFO reveals homogeneous precontrast radiodensity similar to that of extraocular muscles. On MR imaging, INFO appears hypointense to orbital fat and isointense to brain on precontrast T1-weighted images. On T2-weighted images, they have been described as being predominantly hyperintense with possible hypointense intralesional islands. To the best of our knowledge, our case identifies the youngest patient with the myxoid histologic variant of INFO.
CONCLUSIONS
Patients with orbital neurofibromas should be evaluated for the presence of systemic neurofibromatosis, and the plexiform variant is a commonly associated subtype. The myxoid variant can be part of a lesser known condition called NAME syndrome (nevi, atrial myxoma, myxoid neurofibroma, and ephelides) which may warrant echocardiography in patients to evaluate for associated cardiac tumors.
Topics: Child, Preschool; Diagnosis, Differential; Female; Humans; Magnetic Resonance Imaging; Neurofibroma; Orbit; Orbital Neoplasms; Tomography, X-Ray Computed
PubMed: 28582370
DOI: 10.1097/IOP.0000000000000930 -
International Journal of Surgical... 2016. Malignant peripheral nerve sheath tumours (MPNSTs) are difficult to diagnose and treat and contribute to significant morbidity and mortality for patients with... (Review)
Review
. Malignant peripheral nerve sheath tumours (MPNSTs) are difficult to diagnose and treat and contribute to significant morbidity and mortality for patients with Neurofibromatosis-1 (NF-1). FDG-PET/CT is being increasingly used as an imaging modality to discriminate between benign and malignant plexiform neurofibromas. . To assess the value of FDG-PET/CT in differentiating between benign and malignant peripheral nerve lesions for patients with Neurofibromatosis-1. . A systematic review of the literature was performed prior to application of stringent selection criteria. Ultimately 13 articles with 796 tumours were deemed eligible for inclusion into the review. . There was a significant difference between mean SUV of benign and malignant lesions (1.93 versus 7.48, resp.). Sensitivity ranged from 89 to 100% and specificity from 72 to 94%. ROC analysis was performed to maximise sensitivity and specificity of SUV cut-off; however no clear value was identified (range 3.1-6.1). Significant overlap was found between the SUV of benign and malignant lesions making differentiation of lesions difficult. Many of the studies suffered from having a small cohort and from not providing histological data on all lesions which underwent FDG-PET/CT. . This systematic review is able to demonstrate that FDG-PET/CT is a useful noninvasive test for discriminating between benign and malignant lesions but has limitations and requires further prospective trials.
Topics: Cell Transformation, Neoplastic; Diagnosis, Differential; Fluorodeoxyglucose F18; Humans; Neurofibroma, Plexiform; Neurofibromatosis 1; Positron Emission Tomography Computed Tomography; ROC Curve; Radiopharmaceuticals; Sensitivity and Specificity; Tomography, X-Ray Computed
PubMed: 28058117
DOI: 10.1155/2016/6162182 -
Pediatric Neurology Jul 2016The first sign of neurofibromatosis type 1 (NF1) in a child is often the presence of multiple café-au-lait macules. Although previous studies reported that almost... (Review)
Review
BACKGROUND
The first sign of neurofibromatosis type 1 (NF1) in a child is often the presence of multiple café-au-lait macules. Although previous studies reported that almost individuals with multiple café-au-lait macules will eventually develop NF1 based on clinical criteria, recent studies and clinical observations suggest that a significant percentage of them do not have NF1.
METHODS
We conducted the first systematic review of the literature on the prevalence of definitive NF1 among patients referred for isolated café-au-lait macules, searching more precisely for the proportion of those patients who do not have NF1. Because we now know that the presence of café-au-lait macules and freckling might not distinguish between NF1 and other conditions such as Legius syndrome, definitive NF1 was defined as the presence of café-au-lait macules with or without freckling plus one of the following: Lisch nodules, neurofibroma, plexiform neurofibroma, bone dysplasia, optic pathway glioma, or familial history of NF1.
RESULTS
Six articles reported sufficient data to meet our inclusion criteria. Grouping all studies together, we found that 19.5% to 57.1% of all patients with isolated café-au-lait macules did not have a diagnosis of NF1 after follow-up or genetic testing.
CONCLUSION
A significant portion of the patients presenting with isolated café-au-lait macules at initial consultation might not have NF1. Genetic testing could help guide the follow-up of those patients, but further evidence is required to make recommendations.
Topics: Cafe-au-Lait Spots; Humans; Neurofibromatosis 1
PubMed: 27212418
DOI: 10.1016/j.pediatrneurol.2016.03.003