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Acta Medica Portuguesa Dec 2023
Topics: Humans; Neurofibroma, Plexiform; Neurofibromatosis 1
PubMed: 37205744
DOI: 10.20344/amp.19477 -
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 -
Archives of Gynecology and Obstetrics Feb 2022
Topics: Female; Humans; Neurofibroma, Plexiform; Pelvis; Uterus
PubMed: 34839387
DOI: 10.1007/s00404-021-06341-y -
BMC Cancer Dec 2019Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the...
BACKGROUND
Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study.
METHODS
The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment.
DISCUSSION
Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.
Topics: Adolescent; Child; Child, Preschool; Humans; Infant; Young Adult; Antineoplastic Agents; Canada; Glioma; MAP Kinase Signaling System; Neurofibroma, Plexiform; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Treatment Outcome; Clinical Trials, Phase II as Topic; Multicenter Studies as Topic
PubMed: 31881853
DOI: 10.1186/s12885-019-6442-2 -
Cleveland Clinic Journal of Medicine Nov 2016
Topics: Adult; Aftercare; Female; Head and Neck Neoplasms; Humans; Neurofibroma, Plexiform; Tumor Burden; Watchful Waiting
PubMed: 27824540
DOI: 10.3949/ccjm.83a.16002 -
The Journal of Craniofacial Surgery May 2022Plexiform variants of neurofibromas and schwannomas are rare and typically arise in superficial soft tissues in the head and neck region. The treatment of these tumors...
Plexiform variants of neurofibromas and schwannomas are rare and typically arise in superficial soft tissues in the head and neck region. The treatment of these tumors is challenging and no generally accepted guidelines exist for their optimal management. The purpose of this study was to review the management and longterm prognosis of head and neck plexiform neurofibromas and schwannomas at 2 tertiary care academic hospitals in Finland over a 31-year period. The pathology files were searched for plexiform neurofibromas and schwannomas between the years 1990 and 2020. The case notes were reviewed for full management details. Two plexiform schwannomas and 6 plexiform neurofibromas were identified. Five of the 6 plexiform neurofibromas were managed operatively. All patients with a surgically managed plexiform neurofibroma underwent multiple operations. Sclerotherapy abolished 1 patient's cutaneous plexiform neurofibromas. The management of plexiform neurofibromas and plexiform schwannomas remains challenging. Sclerotherapy may offer a promising management option for cutaneous plexiform neurofibromas.
Topics: Head and Neck Neoplasms; Humans; Neurilemmoma; Neurofibroma, Plexiform; Prognosis
PubMed: 34855632
DOI: 10.1097/SCS.0000000000008381 -
Current Opinion in Hematology Jul 2010Tumorigenic cells can co-opt normal functions of nonmalignant hematopoietic cells, promoting tumor progression. Recent mouse and human studies indicate that mast cells... (Review)
Review
PURPOSE OF REVIEW
Tumorigenic cells can co-opt normal functions of nonmalignant hematopoietic cells, promoting tumor progression. Recent mouse and human studies indicate that mast cells underpin inflammation in the plexiform neurofibroma microenvironment of neurofibromatosis type 1. In this model, Nf1 homozygous-deficient Schwann cells recruit hyperactive mast cells, promoting tumorigenesis. Here, we discuss the importance of Nf1 gene dosage, delineate hematopoietic contributions to the plexiform neurofibroma microenvironment, and highlight applications to human treatment.
RECENT FINDINGS
Previous studies found that plexiform neurofibroma formation in a mouse model requires biallelic loss of Nf1 in Schwann cells and an Nf1 heterozygous cellular background. Now, transplantation and pharmacological experiments have indicated that tumor formation specifically requires Nf1 heterozygosity of c-kit-dependent bone marrow.
SUMMARY
Neurofibromatosis type 1 results from autosomal dominant mutations of the NF1 tumor suppressor gene. Although unpredictable second-hit mutations in the remaining NF1 allele precede local manifestations such as tumor formation, human and mouse data indicate that NF1/Nf1 gene haploinsufficiency modulates cellular physiology and disease pathogeneses. In particular, Nf1 haplo insufficient mast cells demonstrate multiple gain-in-functions, and mast cells permeate neurofibroma tissue. Transplantation experiments have shown that these aberrant mast cells critically underpin the tumor microenvironment. Using these findings, clinicians have medically treated a patient with a debilitating plexiform neurofibroma.
Topics: Animals; Genetic Predisposition to Disease; Humans; Mast Cells; Mice; Models, Genetic; Neurofibroma, Plexiform; Neurofibromin 1; Schwann Cells
PubMed: 20571392
DOI: 10.1097/MOH.0b013e328339511b -
Neurology India 2018
Topics: Adolescent; Female; Humans; Mesentery; Neurofibroma, Plexiform; Peritoneal Neoplasms; Tomography, X-Ray Computed
PubMed: 30233045
DOI: 10.4103/0028-3886.241333 -
Hand Surgery & Rehabilitation Dec 2023Plexiform neurofibroma is a benign peripheral nerve-sheath tumor, rarely involving major nerves of the extremities. In the literature, there are no clear treatment...
Plexiform neurofibroma is a benign peripheral nerve-sheath tumor, rarely involving major nerves of the extremities. In the literature, there are no clear treatment strategies for plexiform neurofibroma of major peripheral nerves. Our experience encountered two patients with plexiform neurofibroma of the median nerve, presenting with a palmar mass and symptoms of carpal tunnel compression. Preoperatively, plexiform neurofibroma was diagnosed on MRI and clinical examination. Both patients also experienced significant neurological deterioration, with finger numbness and increased nerve/tumor size. Potential malignant transformation was also considered. For these reasons, resection of the involved area of the nerve and repair were indicated. In both patients, intraoperative pathological diagnosis was plexiform neurofibroma. The 45-year-old male patient refused further surgery after carpal tunnel release, which was performed under axillary block. One year postoperatively, nerve compression symptoms decreased moderately. In the other patient, a 7-year-old boy, a significantly enlarged area of the median nerve was resected, and neurorrhaphy was performed. One year postoperatively, median nerve motor-sensory functions recovered completely. Four years postoperatively, no enlargement of the residual tumor was observed.
Topics: Male; Humans; Middle Aged; Child; Neurofibroma, Plexiform; Median Nerve; Hamartoma; Carpal Tunnel Syndrome; Peripheral Nervous System Neoplasms; Upper Extremity
PubMed: 37714515
DOI: 10.1016/j.hansur.2023.08.007 -
The Journal of Clinical Investigation Jul 2018Neurofibromatosis type 1 associates with multiple neoplasms, and the Schwann cell tumor neurofibroma is the most prevalent. A hallmark feature of neurofibroma is mast...
Neurofibromatosis type 1 associates with multiple neoplasms, and the Schwann cell tumor neurofibroma is the most prevalent. A hallmark feature of neurofibroma is mast cell infiltration, which is recruited by chemoattractant stem cell factor (SCF) and has been suggested to sustain neurofibroma tumorigenesis. In the present study, we use new, genetically engineered Scf mice to decipher the contributions of tumor-derived SCF and mast cells to neurofibroma development. We demonstrate that mast cell infiltration is dependent on SCF from tumor Schwann cells. However, removal of mast cells by depleting the main SCF source only slightly affects neurofibroma progression. Other inflammation signatures show that all neurofibromas are associated with high levels of macrophages regardless of Scf status. These findings suggest an active inflammation in neurofibromas and partly explain why mast cell removal alone is not sufficient to relieve tumor burden in this experimental neurofibroma model. Furthermore, we show that plexiform neurofibromas are highly associated with injury-prone spinal nerves that are close to flexible vertebras. In summary, our study details the role of inflammation in neurofibromagenesis. Our data indicate that prevention of inflammation and possibly also nerve injury at the observed tumor locations are therapeutic approaches for neurofibroma prophylaxis and that such treatment should be explored.
Topics: Animals; Carcinogenesis; Disease Progression; Female; Genes, Neurofibromatosis 1; Humans; Inflammation; Male; Mast Cells; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Neurofibroma, Plexiform; Neurofibromatosis 1; Schwann Cells; Stem Cell Factor; Tumor Microenvironment
PubMed: 29596064
DOI: 10.1172/JCI99424