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Cureus May 2024Plexiform neurofibroma is a rare variant of neurofibromatosis type 1. Diagnosis is challenging due to the highly variable clinical presentation. Early diagnosis is...
Plexiform neurofibroma is a rare variant of neurofibromatosis type 1. Diagnosis is challenging due to the highly variable clinical presentation. Early diagnosis is essential for appropriate treatment and prevention of complications. This report describes a sporadic solitary plexiform neurofibroma in the temporal region of a seven-year-old girl. The growth of the mass began at birth and grew steadily over five years. Subsequently, the mass began to expand rapidly. The patient underwent complete surgical resection under general anesthesia. Histopathological examination revealed a plexiform neurofibroma. In conclusion, surgical excision is the gold standard for cases with symptomatic, visible, large superficial lesions.
PubMed: 38903359
DOI: 10.7759/cureus.60798 -
PloS One 2024Neurofibromatosis Type I (NF1) is a rare genetic disorder. NF1 patients frequently develop a benign tumor in peripheral nerve plexuses called plexiform neurofibroma. In...
Neurofibromatosis Type I (NF1) is a rare genetic disorder. NF1 patients frequently develop a benign tumor in peripheral nerve plexuses called plexiform neurofibroma. In the past two decades, tissue-specific Nf1 knockout mouse models were developed using commercially available tissue-specific Cre recombinase and the Nf1 flox mice to mimic neurofibroma development. However, these models develop para-spinal neurofibroma, recapitulating a rare type of neurofibroma found in NF1 patients. The NPcis mouse model developed a malignant version of neurofibroma called malignant peripheral nerve sheath tumor (MPNST) within 3 to 6 months but intriguingly without apparent benign precursor lesion. Here, we revisited the NPcis model and discovered that about 20% display clinical signs similar to Nf1 tissue-specific knockout mice models. However, a systematic histological analysis could not explain the clinical signs we observed although we noticed lesions reminiscent of a neurofibroma in a peripheral nerve, a cutaneous neurofibroma, and para-spinal neurofibroma on rare occasions in NPcis mice. We also observed that 10% of the mice developed a malignant peripheral nerve sheath tumor (MPNST) spontaneously, coinciding with their earring tag identification. Strikingly, half of the sciatic nerves from NPcis mice developed plexiform neurofibroma within 1-6 months when intentionally injured. Thus, we provided a procedure to turn the widely used NPcis sarcoma model into a model recapitulating plexiform neurofibroma.
Topics: Animals; Neurofibroma, Plexiform; Disease Models, Animal; Mice; Sciatic Nerve; Mice, Knockout; Neurofibromatosis 1; Neurofibromin 1
PubMed: 38900740
DOI: 10.1371/journal.pone.0301040 -
Future Oncology (London, England) May 2024This summary describes a publication about a study called SPRINT. The SPRINT study included 50 children with neurofibromatosis type 1 (NF1) and plexiform neurofibroma... (Clinical Trial)
Clinical Trial
WHAT IS THIS SUMMARY ABOUT?
This summary describes a publication about a study called SPRINT. The SPRINT study included 50 children with neurofibromatosis type 1 (NF1) and plexiform neurofibroma (PN) that could not be removed with surgery. PNs are tumors that grow along nerves and can cause various problems for children, such as pain, changes to appearance, and muscle weakness. In SPRINT, the study team wanted to learn whether a medication called selumetinib was able to shrink the PN caused by NF1 (also known as NF1-related PN), and if shrinking PNs helped relieve children of the problems caused by it. To assess how selumetinib might help, children had scans to measure the size of their PN, completed questionnaires, and had a variety of other tests done by their doctor. Their caregivers also completed questionnaires about their child. The children took selumetinib capsules twice a day on an empty stomach.
WHAT WERE THE RESULTS?
The results showed that selumetinib was able to shrink the PN for most children (68%). The results also showed that the problems caused by the children's PNs mostly improved while on selumetinib treatment. SPRINT also showed that the side effects of selumetinib were mainly mild and could be managed by doctors.
WHAT DO THE RESULTS MEAN?
Before SPRINT, there were not many treatment options for children with NF1 and PN as there were no medications that had been shown to shrink PN, and surgery was not always possible. SPRINT showed that this medication shrinks most PNs and could help children with NF1 and PN. In April 2020, selumetinib was approved by the US Food and Drug Administration (FDA) because of the results of SPRINT. Selumetinib was the first and, as of February 2024, is the only medicine that can be prescribed by doctors to help children with NF1-related PN. : NCT01362803 (SPRINT) (ClinicalTrials.gov).
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Male; Benzimidazoles; Neurofibroma, Plexiform; Neurofibromatosis 1; Protein Kinase Inhibitors; Treatment Outcome
PubMed: 38869947
DOI: 10.2217/fon-2023-0565 -
The American Journal of Dermatopathology Jun 2024Close relationship between melanocytes and neural cells is accepted to reflect their common derivation from the neural crest and tumors combining both elements. We...
Close relationship between melanocytes and neural cells is accepted to reflect their common derivation from the neural crest and tumors combining both elements. We present a series of 10 patients with giant congenital melanocytic nevi (CMN) in which a secondary proliferation (11 lesions) with schwannian and/or perineuriomatous differentiation developed in the course of the disease. The age of the patients (4 male and 6 female) at the time of surgery and histological assessment varied from 3 months to 57 years. Histopathologically, the following subgroups were delineated: (1) nodular/tumoriform "neurotization" in CMN, (2) diffuse neurofibroma-like proliferation within CMN, (3) plexiform neurofibroma-like proliferation within CMN, and (4) diffuse perineuriomatous (hybrid schwannomatous-perineuriomatous) differentiation in CMN. We review the pertinent literature, including the role of recently identified Schwann cell precursors which are believed to represent the nerve-associated state of neural crest-like cells that persists into later developmental stages.
PubMed: 38842402
DOI: 10.1097/DAD.0000000000002754 -
Clinical Neuropathology May 2024Expression patterns of key proteins involved in RAS signaling and connected pathways were determined and correlated to possibly provide information for therapeutic...
AIMS
Expression patterns of key proteins involved in RAS signaling and connected pathways were determined and correlated to possibly provide information for therapeutic application of RAS inhibitors in neurofibromatosis type 1 (NF1)-associated peripheral nerve sheath tumors (PNST).
MATERIALS AND METHODS
Clinical variables (age, sex), histological parameters (cell density, mitoses), and expression of immunohistochemically evaluated ligand and receptor proteins (neuregulin 1 (NRG1), ErbB2, ErbB3), RAS pathway proteins (mTor, Rho, phosphorylated MEK), transcription factors (Pax7, Sox9), and proliferation marker Ki-67, were correlated in cutaneous (CNF, n = 136), diffuse (DNF, n = 123)/diffuse plexiform (DPNF, n = 113), and plexiform neurofibroma (PNF, n = 126), and in malignant PNST (MPNST, n = 22).
RESULTS
In CNF, NRG1 correlated with Ki-67 and Pax7. Further, mTOR correlated with ErbB3, Sox9, Pax7, and Ki-67. In DNF/DPNF, expression of NRG1 correlated with pMEK and Pax7. mTOR correlated with pMEK, Sox9, and Pax7. Noteworthy, pMEK was weakly expressed in some DNF but not in DPNF. ErbB3 correlated with mTor and Ki-67. Furthermore, Rho correlated with Pax7 and Ki-67. In PNF, ErbB3 expression was associated with Sox9, mTOR, pMEK, and Pax7 as well as mTOR with Sox9 and Pax7, Rho with pMEK and Pax7, and pMEK with Pax7 and Sox9. In MPNST, only few correlations were observed, ErbB2 correlated with Ki-67, and Rho with pMEK.
CONCLUSION
Signaling networks of the RAS pathway could be retraced by correlation analysis of protein expression in subgroups of NF1 associated benign PNST. In regard to treatment of PNST, MEK inhibitors, which are presently evaluated for PNF, may possibly also be effective to some extent in DNF.
PubMed: 38818730
DOI: 10.5414/NP301624 -
Journal of Neuro-oncology May 2024Selumetinib is an FDA-approved targeted therapy for plexiform neurofibromas in neurofibromatosis type 1(NF1) with durable response rates seen in most, but not all...
PURPOSE
Selumetinib is an FDA-approved targeted therapy for plexiform neurofibromas in neurofibromatosis type 1(NF1) with durable response rates seen in most, but not all patients. In this proof-of-concept study, we demonstrate single-cell RNA sequencing(scRNAseq) as a technique for quantifying drug response to selumetinib at the single cell level.
METHODS
scRNAseq data from neurofibroma biopsies was obtained from a public genomics repository. Schwann cell populations were identified through standard clustering techniques and single-cell selumetinib sensitivity was quantified on a scale of 0(resistant) to 1(sensitive) based on the expression pattern of a 500 gene selumetinib sensitivity signature from the BeyondCell sensitivity library.
RESULTS
A total of seven plexiform neurofibromas were included in our final analysis. The median absolute number of Schwann cells across samples was 658 cells (IQR: 1,029 cells, Q1-Q3: 135 cells to 1,163 cells). There was a statistically significant difference in selumetinib sensitivity profiles across samples (p < 0.001). The tumor with the highest median selumetinib sensitivity score had a median selumetinib sensitivity score of 0.64(IQR: 0.14, Q1-Q3: 0.59-0.70, n = 112 cells) and the tumor with the lowest median selumetinib sensitivity score had a median score of 0.37 (IQR: 0.21, Q1-Q3: 0.27-0.48, n = 1,034 cells).
CONCLUSIONS
scRNAseq of plexiform neurofibroma biopsies reveals differential susceptibilities to selumetinib on a single cell level. These findings may explain the partial responses seen in clinical trials of selumetinib for NF1 and demonstrate the value of collecting scRNAseq data for future NF1 trials.
PubMed: 38739187
DOI: 10.1007/s11060-024-04711-5 -
Neuro-oncology Advances 2024Selumetinib is approved for the treatment of pediatric patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) in...
BACKGROUND
Selumetinib is approved for the treatment of pediatric patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) in multiple countries, including the USA (≥ 2 years). Until recently, individuals had to take selumetinib twice daily (BID) in a fasted state. This study evaluated the effect of a low-fat meal on selumetinib PK parameters and gastrointestinal (GI) tolerability in adolescent participants with NF1-PN.
METHODS
Eligible participants aged ≥ 12 to < 18 years took 25 mg/m selumetinib BID with a low-fat meal (T1) for 28 days, followed by a 7-day washout, and then administration in a fasted state (T2) for another 28 days. Primary objectives were to evaluate the effect of a low-fat meal on AUC and GI tolerability after multiple selumetinib doses in T1 versus T2. Key secondary objectives were additional PK parameters and adverse events (AEs).
RESULTS
At primary data cut-off, all 24 participants completed T1, and 23 participants completed T2. There were no significant differences in AUC between T1 and T2. In T1 and T2, 29.2% and 33.3% participants, respectively, reported ≥ 1 GI AE. No GI AEs Grade ≥ 3, or serious AEs, or GI AEs resulting in treatment interruptions, discontinuation, or dose reductions were reported in T1 and T2.
CONCLUSIONS
Dosing selumetinib with a low-fat meal had no clinically relevant impact on selumetinib AUC nor GI tolerability in adolescents with NF1-PN.
TRIAL REGISTRATION CLINICALTRIALSGOV ID
NCT05101148.
PubMed: 38721358
DOI: 10.1093/noajnl/vdae036 -
JMA Journal Apr 2024Even though an MEK inhibitor has been recently launched, neurofibroma still negatively affects the well-being of patients with neurofibromatosis type 1 (NF1). The...
INTRODUCTION
Even though an MEK inhibitor has been recently launched, neurofibroma still negatively affects the well-being of patients with neurofibromatosis type 1 (NF1). The coronavirus disease 2019 (COVID-19) pandemic resulted in restricted access to medical care. The present study was conducted to investigate the real-world settings of patients with NF1 who underwent surgery with or without restricted medical access during the COVID-19 pandemic.
METHODS
Based on data obtained from medical records, the present study examined 123 and 260 patients who underwent surgery for neurofibromas with and without restricted medical access, respectively.
RESULTS
The mean numbers of surgeries performed during the periods with and without restricted medical access were 5.8 and 9.8 per month, respectively, and there were 1.18- and 1.46-fold more female patients than male patients for each group, respectively. Regardless of whether medical access was restricted, the majority of patients who underwent surgery were middle-aged females with multiple or severe neurofibromas and mild extracutaneous symptoms. Tumor burden was the most common reason for surgery. However, cutaneous neurofibromas were more likely to be treated than plexiform neurofibromas under restricted medical access.
CONCLUSIONS
Patients with NF1, particularly middle-aged females with severe cutaneous manifestations and mild extracutaneous manifestations, still underwent surgery for neurofibromas regardless of whether medical access was restricted.
PubMed: 38721077
DOI: 10.31662/jmaj.2023-0161 -
American Society of Clinical Oncology... Jun 2024Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a... (Review)
Review
Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a significantly elevated estimated lifetime frequency of 8%-13%. In the setting of NF1, MPNSTs arise from malignant transformation of benign plexiform neurofibroma and borderline atypical neurofibromas. Composed of neoplastic cells from the Schwannian lineage, these cancers recur in approximately 50% of individuals, and most patients die within five years of diagnosis, despite surgical resection, radiation, and chemotherapy. Treatment for metastatic disease is limited to cytotoxic chemotherapy and investigational clinical trials. In this article, we review the pathophysiology of this aggressive cancer and current approaches to surveillance and treatment.
Topics: Humans; Neurofibromatosis 1; Nerve Sheath Neoplasms
PubMed: 38710002
DOI: 10.1200/EDBK_432242 -
Clinical Cancer Research : An Official... May 2024
PubMed: 38690594
DOI: 10.1158/1078-0432.CCR-24-0635