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Cancers May 2023Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that increases one's risk for both benign and malignant tumors. NF1 affects every... (Review)
Review
Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that increases one's risk for both benign and malignant tumors. NF1 affects every organ in the body, but the most distinctive symptoms that are often the most bothersome to patients are the cutaneous manifestations, which can be unsightly, cause pain or pruritus, and have limited therapeutic options. In an effort to increase awareness of lesser-known dermatologic associations and to promote multidisciplinary care, we conducted a narrative review to shed light on dermatologic associations of NF1 as well as emerging treatment options. Topics covered include cutaneous neurofibromas, plexiform neurofibromas, diffuse neurofibromas, distinct nodular lesions, malignant peripheral nerve sheath tumors, glomus tumors, juvenile xanthogranulomas, skin cancer, and cutaneous T-cell lymphoma.
PubMed: 37345107
DOI: 10.3390/cancers15102770 -
Clinical Pharmacokinetics Mar 2021Selumetinib, a highly specific mitogen-activated protein kinase 1/2 inhibitor, is approved for children older than 2 years of age with neurofibromatosis 1 who have... (Review)
Review
Selumetinib, a highly specific mitogen-activated protein kinase 1/2 inhibitor, is approved for children older than 2 years of age with neurofibromatosis 1 who have inoperable plexiform neurofibromas. By selectively binding to mitogen-activated protein kinase 1/2 proteins, selumetinib can arrest the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway that regulates critical cellular responses. Selumetinib has shown promising results as a single agent or in combination with conventional chemotherapy and other targeted therapies both preclinically and clinically, in multiple cancers including pediatric low-grade glioma, non-small cell lung cancer, and melanoma, among others. The pharmacokinetic profiles of selumetinib and its active metabolite N-desmethyl selumetinib have been well characterized in both adults and children. Both compounds exhibited rapid absorption and mean terminal elimination half-lives of about 7.5 h, with minimal accumulation at steady state. Three population pharmacokinetic models have been developed in adults and children, characterizing large inter- and intra-patient variabilities, and identifying significant covariates including food intake on selumetinib absorption, weight metrics, age, co-administration of cytochrome modulators, and Asian ethnicity on selumetinib apparent oral clearance. The most common side effects associated with selumetinib are dermatologic, gastrointestinal toxicities, and fatigue. Most toxicities are mild or moderate, generally tolerated and manageable. Cardiovascular and ocular toxicities remain less frequent but can be potentially more severe and require close monitoring. Overall, selumetinib exhibits a favorable safety profile and pharmacokinetic properties, with promising activity in multiple solid tumors, supporting current and further evaluation in combination with conventional chemotherapy and other targeted agents.
Topics: Adult; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Child; Child, Preschool; Humans; Lung Neoplasms; Neurofibroma, Plexiform; Protein Kinase Inhibitors
PubMed: 33354735
DOI: 10.1007/s40262-020-00967-y -
Child's Nervous System : ChNS :... Oct 2020Neurofibromatosis type 1 (NF1) patients may present a wide spectrum of spinal pathologies. Osseous changes may lead to severe deformities with significant implications... (Review)
Review
BACKGROUND
Neurofibromatosis type 1 (NF1) patients may present a wide spectrum of spinal pathologies. Osseous changes may lead to severe deformities with significant implications on growth and quality of life. Neurogenic tumors and soft tissue abnormalities may cause neuropathic pain and dysfunction ranging from minor paresthesias to profound motor and sensory deficits. Advanced imaging such as whole-body MRI, and volumetric tumor burden assessment have an evolving role in the evaluation and follow-up of patients with high spinal tumor load. Novel biological agents that target the hyperactivated ras pathway are currently under investigation and are reshaping current and future treatment paradigms. Surgical interventions for benign and malignant tumors, as well as deformity correction remain pivotal in treatment frameworks and require careful assessment by a dedicated multidisciplinary team.
PURPOSE
In this manuscript we review the various spinal manifestations of NF1 patients, indication for surgical intervention and oncological treatments.
Topics: Humans; Magnetic Resonance Imaging; Neurofibromatosis 1; Quality of Life; Spine; Tumor Burden
PubMed: 32564155
DOI: 10.1007/s00381-020-04754-9 -
Neuro-oncology Advances Jul 2020Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome, with a wide clinicopathologic spectrum. It is defined by characteristic central... (Review)
Review
Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome, with a wide clinicopathologic spectrum. It is defined by characteristic central nervous system, cutaneous and osseous manifestations, and by mutations in the NF1 gene, which is involved in proliferation via p21, RAS, and MAP kinase pathways. Up to 25% of NF1 patients develop intra-abdominal neoplastic manifestations including neurogenic (commonly plexiform neurofibromas and malignant peripheral nerve sheath tumors), interstitial cells of Cajal (hyperplasia, gastrointestinal stromal tumors), neuroendocrine, and embryonal tumors (rhabdomyosarcoma). Nonspecific symptoms, multifocal disease, or coexistence of 2 or more tumor types make patients challenging to diagnose and manage. Screening for intra-abdominal tumors in NF1 patients remains controversial, and currently no guidelines are established. Management decisions are complex and often informed by single-center experiences or case studies in the literature, though the field is rapidly evolving. Thus, NF1 patients should be followed in specialist centers familiar with their wide spectrum of pathology and with multidisciplinary care including specialized pathology and radiology. This review will (1) provide a contemporaneous synthesis of the literature and our multi-institutional clinical experiences with intra-abdominal neoplasms in NF1 patients, (2) present a classification framework for this heterogeneous group of disorders, and (3) outline approaches to screening, surveillance, diagnosis, and management.
PubMed: 32642738
DOI: 10.1093/noajnl/vdaa032 -
Journal of Clinical Pathology Apr 2020The () gene was first discovered to be amplified in glioblastoma multiforme. It encodes for a zinc-finger transcription factor in the Kruppel family of proteins and is...
The () gene was first discovered to be amplified in glioblastoma multiforme. It encodes for a zinc-finger transcription factor in the Kruppel family of proteins and is important in the sonic hedgehog signalling pathway. also plays a role in several other pathways and is important for proliferation, migration, invasion, growth and angioinvasion, and cancer stem cell self-renewal in a variety of malignancies. GLI-1 is amplified in several malignancies, including an epithelioid, pericytomatous soft tissue neoplasm that can exhibit malignant behaviour. More recently, fusions with other partner genes have been found in three rare tumours: a pericytomatous tumour with a t(7;12) translocation, where it partners with , and gastroblastoma and plexiform fibromyxoma, where the partner gene is , respectively.
Topics: Gene Amplification; Gene Fusion; Hemangiopericytoma; Humans; Neurofibroma, Plexiform; Stomach Neoplasms; Zinc Finger Protein GLI1
PubMed: 31980562
DOI: 10.1136/jclinpath-2020-206431 -
The Journal of Pharmacology and... May 2023Individuals with neurofibromatosis type 1 develop rat sarcoma virus (RAS)-mitogen-activated protein kinase-mitogen-activated and extracellular signal-regulated kinase...
Individuals with neurofibromatosis type 1 develop rat sarcoma virus (RAS)-mitogen-activated protein kinase-mitogen-activated and extracellular signal-regulated kinase (RAS-MAPK-MEK)-driven nerve tumors called neurofibromas. Although MEK inhibitors transiently reduce volumes of most plexiform neurofibromas in mouse models and in neurofibromatosis type 1 (NF1) patients, therapies that increase the efficacy of MEK inhibitors are needed. BI-3406 is a small molecule that prevents Son of Sevenless (SOS)1 interaction with Kirsten rat sarcoma viral oncoprotein (KRAS)-GDP, interfering with the RAS-MAPK cascade upstream of MEK. Single agent SOS1 inhibition had no significant effect in the DhhCre;Nf1 mouse model of plexiform neurofibroma, but pharmacokinetics (PK)-driven combination of selumetinib with BI-3406 significantly improved tumor parameters. Tumor volumes and neurofibroma cell proliferation, reduced by MEK inhibition, were further reduced by the combination. Neurofibromas are rich in ionized calcium binding adaptor molecule 1 (Iba1)+ macrophages; combination treatment resulted in small and round macrophages, with altered cytokine expression indicative of altered activation. The significant effects of MEK inhibitor plus SOS1 inhibition in this preclinical study suggest potential clinical benefit of dual targeting of the RAS-MAPK pathway in neurofibromas. SIGNIFICANCE STATEMENT: Interfering with the RAS-mitogen-activated protein kinase (RAS-MAPK) cascade upstream of mitogen activated protein kinase kinase (MEK), together with MEK inhibition, augment effects of MEK inhibition on neurofibroma volume and tumor macrophages in a preclinical model system. This study emphasizes the critical role of the RAS-MAPK pathway in controlling tumor cell proliferation and the tumor microenvironment in benign neurofibromas.
Topics: Animals; Mice; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Mitogen-Activated Protein Kinase Kinases; Neurofibroma; Neurofibroma, Plexiform; Neurofibromatosis 1; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Tumor Microenvironment; SOS1 Protein
PubMed: 36849412
DOI: 10.1124/jpet.122.001431 -
Cancer Control : Journal of the Moffitt... 2023Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main...
INTRODUCTION
Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main treatment option in these patients, but it is burdened with a low efficacy rate and a high incidence of side effects as well as recurrence. In recent years, MEK inhibitors (MEKi) such as selumetinib and trametinib have shown great promise.
METHODS
We retrospectively describe a single center cohort of NF1 patients affected by PN1 and treated with MEKi since 2019 to 2021. Patients recruited in the study were affected by PN that were not eligible to complete surgical excision, symptomatic or with major cosmetic deformation or functional neurological deficits.
RESULTS
Most patients experienced improvement in clinical symptoms and quality of life, with reduction or stabilization of lesions. However, no complete response was achieved. The most common adverse effects involved the skin, affecting every patient. Importantly, no life-threatening adverse effects occurred.
CONCLUSIONS
In our experience, MEKi treatment has been shown to be both safe and effective in improving symptomatology and quality of life.
Topics: Humans; Neurofibroma, Plexiform; Retrospective Studies; Quality of Life; Neurofibromatosis 1; Protein Kinase Inhibitors; Mitogen-Activated Protein Kinase Kinases
PubMed: 36598023
DOI: 10.1177/10732748221144930 -
Clinical Cancer Research : An Official... Aug 2021On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1...
On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma-related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51-79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit-risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable.
Topics: Adolescent; Benzimidazoles; Child; Child, Preschool; Drug Approval; Female; Humans; Male; Neurofibroma, Plexiform; United States
PubMed: 33712511
DOI: 10.1158/1078-0432.CCR-20-5032 -
Journal of Oral and Maxillofacial... 2021Plexiform neurofibroma (PNF) is a rare form of neurofibromatosis type 1 which is rarely seen isolated. This generally spreads along the peripheral nerve and may affect...
Plexiform neurofibroma (PNF) is a rare form of neurofibromatosis type 1 which is rarely seen isolated. This generally spreads along the peripheral nerve and may affect some nervous rami. This is a poorly circumscribed and locally invasive tumor. About 21% of patients with NF-I are affected with PNFs. The nevus of Ota also called oculodermal melanocytosis is a macular discoloration of the face. It is most commonly found in the Japanese and very rare in the Indian subcontinent. It is unilateral oculodermal melanosis along the first two branches of the trigeminal nerve. We hereby present a very rare case of occurrence of isolated PNF (not associated with neurofibromatosis type 1) along with nevus of ota of the left side of the face in a 28-year-old female with thorough radiographic work up.
PubMed: 34703146
DOI: 10.4103/0973-029X.325263 -
The Journal of Hand Surgery... Oct 2023Plexiform schwannoma is an uncommon benign tumour that grows in a plexiform pattern. We report a 47-year-old man with a mass on the palmar aspect of the...
Plexiform schwannoma is an uncommon benign tumour that grows in a plexiform pattern. We report a 47-year-old man with a mass on the palmar aspect of the metacarpophalangeal joint of the right index finger that had been growing gradually for more than 10 years. The mass was palpated from the distal carpal tunnel to the ulnar aspect of the proximal interphalangeal joint of the index finger, with tingling and numbness sensation. The tumour was a multinodular tumour involving the first common palmar digital nerve to the ulnar proper palmar digital nerve. It was resected and reconstructed with a sural nerve graft. Plexiform schwannoma is rare in the digital nerve, with only six cases reported. Generally, classic schwannomas can be enucleated without causing neurologic deficits; however, plexiform schwannoma may require nerve resection. There have been reports of recurrence of plexiform schwannoma; definitive resection and long-term follow-up are necessary. Level V (Therapeutic).
Topics: Male; Humans; Middle Aged; Neurilemmoma; Paresthesia; Fingers; Neurosurgical Procedures; Wrist
PubMed: 37881820
DOI: 10.1142/S2424835523720190