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Clinical Medicine Insights. Case Reports 2023Neurofibromatoses are a rare group of autosomal dominant tumor suppressor phacomatoses syndromes. Neurofibromatosis type 1 (NF1 or Von Recklinghausen's disease) is the...
BACKGROUND
Neurofibromatoses are a rare group of autosomal dominant tumor suppressor phacomatoses syndromes. Neurofibromatosis type 1 (NF1 or Von Recklinghausen's disease) is the most commonly found type of neurofibromatosis, and constitutes the most commonly found autosomal dominant disease of the nervous system.
CASE PRESENTATION
We report a case of a 14-year-old boy who reported a 3-year-history of a slowly enlarging right lateral cervical mass. He has a medical history of a progressive limping gait disorder with scoliotic attitude. MRI identified a dumb-bell shaped intradural right cervical process through right paravertebral gutter on C2 to C4, a second intradural dorsal mass with the same characteristics through left paravertebral gutter on D4 and D5 and a large tissue-like mass infiltrating the lumbosacral subcutaneous soft tissues. A Surgical excision of the cervical and lumbar masses was performed with a good outcome after surgical excision.
CONCLUSIONS
This case illustrates the need for a collaboration of both neurological and head and neck surgeons in terms of managing difficulties related to a cervical neurofibroma. Benign plexiform neurofibromas are rapidly growing tumors, particularly in children and adolescents, which makes all the importance of early detection and appropriate treatment. Repeated interventions are usually needed in order to adapt and stabilize the tumors extension.
PubMed: 37009325
DOI: 10.1177/11795476231164380 -
In Vivo (Athens, Greece) 2023Neurofibromas (NF) are the most common benign nerve sheath tumors in the tongue, gingiva, major salivary glands, and jaw bones. Nowadays, tissue engineering is a...
BACKGROUND/AIM
Neurofibromas (NF) are the most common benign nerve sheath tumors in the tongue, gingiva, major salivary glands, and jaw bones. Nowadays, tissue engineering is a revolutionary technique for reconstructing tissues. To explore the feasibility of using stem cells derived from NF teeth to treat orofacial bone defects, the differences in cell biological properties between an NF teeth group and Normal teeth group.
PATIENTS AND METHODS
The intra-dental pulp tissues from each tooth were extracted. The cell survival rates, morphology, proliferation rates, cell activity, and differentiation abilities were contrastively analyzed between the NF teeth group and Normal teeth group.
RESULTS
Between the two groups, there were no differences in the primary generation (P0) cells (p>0.05), the cell yield, and the time required for the cells to grow out of the pulp tissue and attach to the culture plate. Furthermore, no differences were found at the first generation (passage) between the two groups in colony formation rate and cell survival rate. The proliferation capacity, cell growth curve, and surface marker expression of dental pulp cells was not altered in the third generation (p>0.05).
CONCLUSION
Dental pulp stem cells from NF teeth were successfully obtained and were not different from normal dental pulp stem cells. Although, clinical research using tissue-engineered bone to repair bone defects is still in its infancy, it will eventually enter the clinic and become a routine means of bone defect reconstruction treatment as related disciplines and technologies develop.
Topics: Humans; Neurofibromatosis 1; Dental Pulp; Tissue Engineering; Bone and Bones; Gingiva
PubMed: 36881087
DOI: 10.21873/invivo.13113 -
European Journal of Medical Genetics May 2023Surgery is a treatment option for neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN), but complete resection is often not feasible. Real-world studies...
Surgery is a treatment option for neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN), but complete resection is often not feasible. Real-world studies are warranted to understand disease burden, progression, and need for medical treatment in patients with inoperable PN. CASSIOPEA was a retrospective study of French pediatric patients (aged ≥3 to <18 years) presenting at a national multidisciplinary team (MDT) review with NF1 and ≥1 symptomatic, inoperable PN. Medical records were reviewed from the time of MDT review and over a follow-up period of up to 2 years. Primary objectives were to describe patient characteristics and target PN-associated therapy patterns. A secondary objective was evolution of target PN-related morbidities. Patients with prior, ongoing, or MDT recommendation of mitogen-activated protein kinase kinase (MEK) inhibitor treatment were excluded. Overall, 78 target PN were identified in 76 patients. At MDT review, median age was 8.4 years, with approximately 30% of patients aged 3-6 years. Target PN were primarily internal (77.3%), and 43.2% were progressive. Target PN location was evenly distributed. 34 target PN had documented MDT recommendations; of these, a majority (76.5%) were for non-medication management, including surveillance. At least one follow-up visit was recorded for 74 target PN. Despite initially being considered inoperable, 12.3% of patients underwent surgery for target PN. At MDT review, most (98.7%) target PN were associated with ≥1 morbidity, primarily pain (61.5%) and deformity (24.4%); severe morbidities were identified in 10.3%. Of 74 target PN with follow-up data, 89.2% were associated with ≥1 morbidity, primarily pain (60.8%) and deformity (25.7%). Of 45 target PN associated with pain, pain improved in 26.7%, was stable in 44.4%, and deteriorated in 28.9%. Deformity improved in 15.8% and remained stable in 84.2% of 19 target PN associated with deformity. None deteriorated. In this real-world study in France, NF1-PN disease burden was considerable, and a considerable proportion of patients were very young. Most patients received only supportive care without medication for target PN management. Target PN-related morbidities were frequent, heterogeneous, and generally did not improve during follow-up. These data highlight the importance of effective treatments that target PN progression and improve disease burden.
Topics: Child; Humans; Adolescent; Neurofibromatosis 1; Neurofibroma, Plexiform; Retrospective Studies; Treatment Outcome; Mitogen-Activated Protein Kinase Kinases; Pain
PubMed: 36868501
DOI: 10.1016/j.ejmg.2023.104734 -
Neuro-oncology Sep 2023Plexiform neurofibromas can transform into atypical neurofibromas (ANF) and then further progress to aggressive malignant peripheral nerve sheath tumors (MPNST). ANF...
BACKGROUND
Plexiform neurofibromas can transform into atypical neurofibromas (ANF) and then further progress to aggressive malignant peripheral nerve sheath tumors (MPNST). ANF have been described to harbor distinct histological features and frequent loss of CDKN2A/B. However, histological evaluation may be rater-dependent, and detailed knowledge about the molecular mechanisms of malignant transformation is scarce. In general, malignant transformation can be accompanied by significant epigenetic changes, and global DNA methylation profiling is able to differentiate relevant tumor subgroups. Therefore, epigenetic profiling might provide a valuable tool to distinguish and characterize ANF with differing extent of histopathological atypia from neurofibromas and MPNST.
METHODS
We investigated 40 tumors histologically diagnosed as ANF and compared their global methylation profile to other peripheral nerve sheath tumors.
RESULTS
Unsupervised class discovery and t-SNE analysis indicated that 36/40 ANF cluster with benign peripheral nerve sheath tumors with clear separation from MPNST. 21 ANF formed a molecularly distinct cluster in proximity to schwannomas. Tumors in this cluster had a frequent heterozygous or homozygous loss of CDKN2A/B and significantly more lymphocyte infiltration than MPNST, schwannomas, and NF. Few ANF clustered closely with neurofibromas, schwannomas, or MPNST, raising the question, whether diagnosis based on histological features alone might pose a risk to both over- and underestimate the aggressiveness of these lesions.
CONCLUSIONS
Our data suggest that ANF with varying histological morphology show distinct epigenetic similarities and cluster in proximity to benign peripheral nerve sheath tumor entities. Future investigations should pay special respect to correlating this methylation pattern to clinical outcomes.
Topics: Humans; Neurofibromatosis 1; Neurofibrosarcoma; Neurofibroma; Nerve Sheath Neoplasms; Neurofibromatoses; Neurilemmoma; Epigenesis, Genetic
PubMed: 36866403
DOI: 10.1093/neuonc/noad053 -
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 -
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 -
Internal Medicine (Tokyo, Japan) Oct 2023Plexiform neurofibromas (PNs) occur in approximately 50% of patients with neurofibromatosis type 1 (NF1). PNs are rare in the abdominal cavity and especially rare in...
Plexiform neurofibromas (PNs) occur in approximately 50% of patients with neurofibromatosis type 1 (NF1). PNs are rare in the abdominal cavity and especially rare in hepatobiliary lesions. A 31-year-old man with NF1 had a tumor extending along the celiac artery, superior mesenteric artery, and intrahepatic portal vein. We diagnosed him with diffuse PN based on liver tumor biopsy findings and the tumor form. Because the tumor had invaded along the intrahepatic portal vein, surgical resection was deemed difficult, and the patient was followed up with imaging studies. The patient remained asymptomatic without tumor growth.
Topics: Male; Humans; Adult; Neurofibroma, Plexiform; Neurofibromatosis 1; Abdomen; Liver Neoplasms
PubMed: 36792186
DOI: 10.2169/internalmedicine.1372-22 -
Oncogene Mar 2023Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore...
Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers. We found that all three UPR pathways were activated in mouse and human PNFs, with protein kinase RNA [PKR]-like ER kinase (PERK) the most highly expressed. We tested if neurofibroma cells adapt to ER stress, leading to their growth. Pharmacological or genetic inhibition of PERK reduced mouse neurofibroma-sphere number, and genetic inhibition in PERK in Schwann cell precursors (SCPs) decreased tumor-like lesion numbers in a cell transplantation model. Further, in a PNF mouse model, deletion of PERK in Schwann cells (SCs) and SCPs reduced tumor size, number, and increased survival. Mechanistically, loss of Nf1 activated PERK-eIF2α-ATF4 signaling and increased ATF4 downstream target gene p21 translocation from nucleus to cytoplasm. This nucleus-cytoplasm translocation was mediated by exportin-1. Runx transcriptionally activated ribosome gene expression and increased protein synthesis to allow SCs to adapt to ER stress and tumor formation. We propose that targeting proteostasis might provide cytotoxic and/or potentially durable novel therapy for PNFs.
Topics: Animals; Humans; Mice; Core Binding Factor Alpha 2 Subunit; eIF-2 Kinase; Endoplasmic Reticulum Stress; Neurofibroma; Neurofibroma, Plexiform; Neurofibromatosis 1; Unfolded Protein Response
PubMed: 36759572
DOI: 10.1038/s41388-023-02620-x -
Journal of the International... Nov 2023To examine how executive functioning (EF) relates to academic achievement longitudinally in children with neurofibromatosis type 1 (NF1) and plexiform neurofibromas...
OBJECTIVE
To examine how executive functioning (EF) relates to academic achievement longitudinally in children with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) and whether age at baseline moderates this relationship.
METHOD
Participants included 88 children with NF1 and PNs (ages 6-18 years old, = 12.05, = 3.62, 50 males) enrolled in a natural history study. Neuropsychological assessments were administered three times over 6 years. EF (working memory, inhibitory control, cognitive flexibility, and attention) was assessed by performance-based (PB) and parent-reported (PR) measures. Multilevel growth modeling was used to examine how EF at baseline related to initial levels and changes in broad math, reading, and writing across time, controlling for demographic variables.
RESULTS
The relationship between EF and academic achievement varied across EF and academic domains. Cognitive flexibility (PB) uniquely explained more variances in initial math, reading, and writing scores; working memory (PB) uniquely explained more variances in initial levels of reading and writing. The associations between EF and academic achievement tended to remain consistent across age groups with one exception: Lower initial levels of inhibitory control (PR) were related to a greater decline in reading scores. This pattern was more evident among younger (versus older) children.
CONCLUSIONS
Findings emphasize the heterogeneous nature of academic development in NF1 and that EF skills could help explain the within-group variability in this population. Routine cognitive/academic monitoring via comprehensive assessments and early targeted treatments consisting of medication and/or systematic cognitive interventions are important to evaluate for improving academic performance in children with NF1 and PNs.
Topics: Male; Child; Humans; Adolescent; Executive Function; Neurofibromatosis 1; Academic Success; Neurofibroma, Plexiform; Longitudinal Studies; Reading
PubMed: 36750981
DOI: 10.1017/S1355617723000103 -
Cureus Dec 2022Neurofibroma (NF) is a tumour of peripheral nerves, which would be seldom seen in the limbs, particularly in children's limbs. Soft, skin-coloured papules or small...
Neurofibroma (NF) is a tumour of peripheral nerves, which would be seldom seen in the limbs, particularly in children's limbs. Soft, skin-coloured papules or small sub-mucosal nodules appear as these lesions. Neurofibroma is classified into three types: localized, diffuse, and plexiform. The vast majority of nerve injury is sporadic and localized, with an incredibly low risk of tumour formation. Neurofibromatosis can present as multiple skin lesions along with bone deformities in which a full investigation is critical where an undiscovered widespread illness may arise. This case study describes a neurofibroma on the common peroneal nerve of the left lower limb in a 6-year-old child who visited our hospital with chief complaints of pain and swelling around the left proximal leg.
PubMed: 36721607
DOI: 10.7759/cureus.33039