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Cancers Feb 2023Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma with limited therapeutic options and a poor prognosis. Although neurofibromatosis... (Review)
Review
Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma with limited therapeutic options and a poor prognosis. Although neurofibromatosis type 1 (NF1) and radiation exposure have been identified as risk factors for MPNST, the genetic and molecular mechanisms underlying MPNST pathogenesis have only lately been roughly elucidated. Plexiform neurofibroma (PN) and atypical neurofibromatous neoplasm of unknown biological potential (ANNUBP) are novel concepts of MPNST precancerous lesions, which revealed sequential mutations in MPNST development. This review summarized the current understanding of MPNST and the latest consensus from its diagnosis to treatment, with highlights on molecular biomarkers and targeted therapies. Additionally, we discussed the current challenges and prospects for MPNST management.
PubMed: 36831419
DOI: 10.3390/cancers15041077 -
BMC Cancer Jun 2023Neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome, occurs when NF1 gene variants result in loss of neurofibromin, a negative regulator of RAS... (Review)
Review
Neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome, occurs when NF1 gene variants result in loss of neurofibromin, a negative regulator of RAS activity. Plexiform neurofibromas (PN) are peripheral nerve sheath tumors that develop in patients with NF1 and are associated with substantial morbidity and for which, until recently, the only treatment was surgical resection. However, surgery carries several risks and a proportion of PN are considered inoperable. Understanding the genetic underpinnings of PN led to the investigation of targeted therapies as medical treatment options, and the MEK1/2 inhibitor selumetinib has shown promising efficacy in pediatric patients with NF1 and symptomatic, inoperable PN. In a phase I/II trial, most children (approximately 70%) achieved reduction in tumor volume accompanied by improvements in patient-reported outcomes (decreased tumor-related pain and improvements in quality of life, strength, and range of motion). Selumetinib is currently the only licensed medical therapy indicated for use in pediatric patients with symptomatic, inoperable NF1-PN, with approval based on the results of this pivotal clinical study. Several other MEK inhibitors (binimetinib, mirdametinib, trametinib) and the tyrosine kinase inhibitor cabozantinib are also being investigated as medical therapies for NF1-PN. Careful consideration of multiple aspects of both disease and treatments is vital to reduce morbidity and improve outcomes in patients with this complex and heterogeneous disease, and clinicians should be fully aware of the risks and benefits of available treatments. There is no single treatment pathway for patients with NF1-PN; surgery, watchful waiting, and/or medical treatment are options. Treatment should be individualized based on recommendations from a multidisciplinary team, considering the size and location of PN, effects on adjacent tissues, and patient and family preferences. This review outlines the treatment strategies currently available for patients with NF1-PN and the evidence supporting the use of MEK inhibitors, and discusses key considerations in clinical decision-making.
Topics: Child; Humans; Neurofibromatosis 1; Neurofibroma, Plexiform; Quality of Life; Protein Kinase Inhibitors; Mitogen-Activated Protein Kinase Kinases
PubMed: 37328781
DOI: 10.1186/s12885-023-10996-y -
JCI Insight Sep 2022To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome. Affected individuals develop...
To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome. Affected individuals develop neurofibromas, benign tumors driven by NF1 loss in Schwann cells (SCs). By comparing normal nerve cells to plexiform neurofibroma (PN) cells using single-cell and bulk RNA sequencing, we identified changes in 5 SC populations, including a de novo SC progenitor-like (SCP-like) population. Long after Nf1 loss, SC populations developed PN-specific expression of Dcn, Postn, and Cd74, with sustained expression of the injury response gene Postn and showed dramatic expansion of immune and stromal cell populations; in corresponding human PNs, the immune and stromal cells comprised 90% of cells. Comparisons between injury-related and tumor monocytes/macrophages support early monocyte recruitment and aberrant macrophage differentiation. Cross-species analysis verified each SC population and unique conserved patterns of predicted cell-cell communication in each SC population. This analysis identified PROS1-AXL, FGF-FGFR, and MIF-CD74 and its effector pathway NF-κB as deregulated in NF1 SC populations, including SCP-like cells predicted to influence other types of SCs, stromal cells, and/or immune cells in mouse and human. These findings highlight remarkable changes in multiple types of SCs and identify therapeutic targets for PN.
Topics: Animals; Humans; Mice; NF-kappa B; Neurofibroma, Plexiform; Neurofibromatosis 1; Schwann Cells; Tumor Microenvironment
PubMed: 36134665
DOI: 10.1172/jci.insight.154513 -
The Annals of Pharmacotherapy Jun 2022To evaluate the safety and efficacy of selumetinib, a novel MEK inhibitor, for the treatment of plexiform neurofibromas (PN) in patients with neurofibromatosis type 1... (Review)
Review
OBJECTIVE
To evaluate the safety and efficacy of selumetinib, a novel MEK inhibitor, for the treatment of plexiform neurofibromas (PN) in patients with neurofibromatosis type 1 (NF1).
DATA SOURCES
An English-based literature search of PubMed, EMBASE, and ClinicalTrials.gov was conducted using the terms AND from inception to August 1, 2021.
STUDY SELECTION AND DATA EXTRACTION
Relevant prescribing information, abstracts, and articles identified through the search were considered for inclusion in this review.
DATA SYNTHESIS
The open-label, multicenter, single-arm, phase II SPRINT trial demonstrated clinically significant improvements in PN-related complications. Of 50 symptomatic patients, 68% experienced a partial response, with a median change in tumor volume of -27.9% from baseline. Estimated progression-free survival at 3 years was 84%. Additionally, clinically meaningful improvements were seen on patient- and parent-reported assessments evaluating pain, range of motion, disfigurement, and quality of life. Overall, the adverse effect profile for selumetinib appears mild and manageable.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
Selumetinib is the first FDA-approved treatment for inoperable PN in patients with NF1, demonstrating that MEK inhibition is a promising therapeutic strategy. Studies are ongoing to assess the effect of selumetinib on other NF1-associated tumor types and to determine the optimal dosing schedule and treatment duration. Cost and treatment burden must be considered when selecting selumetinib therapy.
CONCLUSION
Selumetinib exhibits impressive antitumor activity and sustained clinical benefit in patients lacking other viable treatment options. Further studies are warranted to determine the optimal age of initiation, treatment duration, and overall cost-effectiveness of selumetinib.
Topics: Benzimidazoles; Humans; Mitogen-Activated Protein Kinase Kinases; Multicenter Studies as Topic; Neurofibroma, Plexiform; Neurofibromatosis 1; Quality of Life
PubMed: 34541874
DOI: 10.1177/10600280211046298 -
Neuro-oncology Nov 2022Selumetinib was recently approved for the treatment of inoperable symptomatic plexiform neurofibromas (PNs) in children with neurofibromatosis type 1 (NF1). This...
BACKGROUND
Selumetinib was recently approved for the treatment of inoperable symptomatic plexiform neurofibromas (PNs) in children with neurofibromatosis type 1 (NF1). This parallel phase II study determined the response rate to selumetinib in children with NF1 PN without clinically significant morbidity.
METHODS
Children with NF1 and inoperable PNs, which were not yet causing clinically significant morbidity but had the potential to cause symptoms, received selumetinib at 25 mg/m2 orally twice daily (1 cycle = 28 days). Volumetric magnetic resonance imaging analysis and outcome assessments, including patient-reported (PRO), observer-reported, and functional outcome measures were performed every 4 cycles for 2 years, with changes assessed over time. A confirmed partial response (cPR) was defined as PN volume decrease of ≥20% on at least 2 consecutive scans ≥3 months apart.
RESULTS
72% of subjects experienced a cPR on selumetinib. Participants received selumetinib for a median of 41 cycles (min 2, max 67) at data cutoff. Approximately half of the children rated having some target tumor pain at baseline, which significantly decreased by pre-cycle 13. Most objectively measured baseline functions, including visual, motor, bowel/bladder, or airway function were within normal limits and did not clinically or statistically worsen during treatment.
CONCLUSIONS
Selumetinib resulted in PN shrinkage in most subjects with NF1 PN without clinically significant morbidity. No new PN-related symptoms developed while on selumetinib, and PRO measures indicated declines in tumor-related pain intensity. This supports that selumetinib treatment may prevent the development of PN-related morbidities, though future prospective studies are needed to confirm these results.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov NCT01362803.
Topics: Child; Humans; Neurofibroma, Plexiform; Neurofibromatosis 1; Benzimidazoles; Morbidity; Pain
PubMed: 35467749
DOI: 10.1093/neuonc/noac109 -
Neuro-oncology Oct 2023Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our...
BACKGROUND
Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies.
METHODS
This manuscript includes data from the phase 1 and phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety and efficacy data through February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) ≥20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (pain interference index).
RESULTS
For the 74 children (median age 10.3 years; range 3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment.
CONCLUSIONS
With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues.
Topics: Child; Humans; Neurofibromatosis 1; Neurofibroma, Plexiform; Benzimidazoles; Pain
PubMed: 37115514
DOI: 10.1093/neuonc/noad086 -
The Journal of Craniofacial Surgery Sep 2020The postauricular region (PR) is an anatomic area that has been neglected until now, due to the fact that the significant cosmetic changes and features of this region...
OBJECTIVE
The postauricular region (PR) is an anatomic area that has been neglected until now, due to the fact that the significant cosmetic changes and features of this region are often overlooked. There are limited and inconsistent data about postauricular masses in the literature and the definition of the PR and its borders remain unclear. The aim of the present study was to define the PR and evaluate benign and malignant masses that may arise in the PR.
METHODS
Fifty-two patients were enrolled in the study. The patients were evaluated retrospectively in terms of demographic data, including age, gender, operative method, lesion side and size, diagnostic tools, and histopathologic diagnosis of the masses.
RESULTS
The masses were categorized into 4 groups according to the etiology; neoplastic (n: 15, 28.8%), inflammatory (n: 13, 25%), congenital (n: 22, 42.3%) and traumatic (n: 2, 3.8%). Of the neoplastic masses, 6 (11.5%) were nonmelanoma skin cancer, comprising 4 (7.6%) basal cell carcinomas and 2 (3.8%) squamous cell carcinomas. A total of 9 (17.3%) neoplastic masses were benign, comprising 3 (5.7%) lipomas, 3 (5.7%) temporal bone osteomas, 2 (3.8%) nevi, and 1 (1.9%) plexiform neurofibroma. Of the 13 (25%) inflammatory masses, 12 (23%) were lymph nodes and 1 (1.9%) was pilonidal sinus. There were 22 (42.3%) congenital masses comprising 15 (28.8%) epidermal cysts, 4 (7.6%) dermoid cysts, and 3 (5.7%) hemangiomas. The 2 (3.8%) patients with traumatic lesion were both keloid patients.
CONCLUSION
The PR does not attract attention from the cosmetic point of view but many benign and malignant masses can be found in this region. Any masses detected in this area should be treated to prevent further growth.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Diagnosis, Differential; Ear, External; Epidermal Cyst; Female; Humans; Lymph Nodes; Male; Middle Aged; Neurofibroma, Plexiform; Retrospective Studies; Temporal Bone; Young Adult
PubMed: 32604279
DOI: 10.1097/SCS.0000000000006526 -
Nature Medicine Jan 2021Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of...
Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.
Topics: Adolescent; Adult; Anilides; Animals; Disease Models, Animal; Female; Genes, Neurofibromatosis 1; Humans; Male; Mice; Mice, Mutant Strains; Neurofibroma, Plexiform; Neurofibromatosis 1; Pain Measurement; Prospective Studies; Protein Kinase Inhibitors; Pyridines; Quality of Life; Receptor Protein-Tyrosine Kinases; Translational Research, Biomedical; Young Adult
PubMed: 33442015
DOI: 10.1038/s41591-020-01193-6 -
Acta Medica Portuguesa Dec 2023
Topics: Humans; Neurofibroma, Plexiform; Neurofibromatosis 1
PubMed: 37205744
DOI: 10.20344/amp.19477 -
ESMO Open Aug 2021Neurofibromatosis type 1 (NF1) is a genetic disorder that carries a higher risk of tumor development. Plexiform neurofibromas (PNs) are present in 50% of NF1 and cause... (Review)
Review
Neurofibromatosis type 1 (NF1) is a genetic disorder that carries a higher risk of tumor development. Plexiform neurofibromas (PNs) are present in 50% of NF1 and cause significant morbidity when surgery is not feasible. Systemic therapies had not succeeded to reduce PN tumor volume until 2016 when the first trial with an MAPK/extracellular-signal-regulated kinase (MEK) inhibitor was published. We performed a systematic research on novel targeted therapies for patients with NF1 and PNs in PubMed, EMBASE, and conference abstracts with the last update in February 2021. Since 2016, seven trials have reported positive results with MEK inhibitors and other molecular targeted therapies (cabozantinib). Selumetinib has shown an overall response rate of 68% in children with NF1 and symptomatic inoperable PNs, and was associated with pain improvement and a manageable adverse events profile. This led to Food and Drug Administration (FDA) approval of selumetinib in May 2020. Recently, cabozantinib and mirdametinib have also proven their efficacy in adult population. Other MEK inhibitors such as trametinib and binimetinib have also communicated promising preliminary results. Ongoing trials in different populations and with intermittent dosing strategies are underway.
Topics: Adult; Child; Humans; Molecular Targeted Therapy; Neurofibroma, Plexiform; Neurofibromatosis 1; Protein Kinase Inhibitors; Tumor Burden
PubMed: 34388689
DOI: 10.1016/j.esmoop.2021.100223