Search Results (318)

Ultrasonography can assist in the preoperative evaluation and postoperative surveillance of superficial soft tissue tumors of the hand. We present an ultrasound-based identification of a neurofibroma in a patient with neurofibromatosis type 1 (NF1). A 45-year-old male presented with a slowly enlarging subcutaneous mass over the dorsal aspect of the hand associated with localized paresthesia. Physical examination revealed characteristic NF1 stigmata, including café-au-lait macules, axillary freckling, and craniofacial asymmetry suggestive of sphenoid wing dysplasia. High-resolution ultrasonography demonstrated a well-defined hypoechoic fusiform lesion along the course of a digital nerve, suggestive of a peripheral nerve sheath tumor. Magnetic resonance imaging showed a T2-hyperintense lesion compatible with a nerve sheath tumor. Surgical excision was subsequently performed, and histopathological examination confirmed a localized neurofibroma with incorporation of native nerve fascicles within a myxoid spindle cell matrix. Serial postoperative ultrasonography at 3 and 12 months demonstrated no evidence of local recurrence. This case highlights ultrasonography as a practical, radiation-free, and cost-effective modality for both preoperative assessment and longitudinal follow-up of superficial NF1-associated neurofibromas. Full article

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative neoplasm of early childhood characterized by constitutive activation of the RAS-MAPK signaling pathway. RASopathies are a heterogeneous group of complex genetic disorders arising from germline mutations that dysregulate RAS-MAPK signaling. Noonan syndrome, CBL syndrome, and neurofibromatosis type 1 (NF1) are the three major RASopathies predisposing to JMML. More than 90% of JMML cases harbor germline or somatic mutations in one of five canonical driver genes—PTPN11, NRAS, KRAS, NF1, or CBL—establishing JMML as the prototypical malignant manifestation of RASopathy biology. The fifth edition of the World Health Organization Classification of Tumours reclassified JMML as a myeloproliferative neoplasm while the International Consensus Classification adopted JMML under pediatric and/or germline mutation-associated disorders, introducing a JMML-like category for cases lacking five canonical mutations but harboring emerging drivers such as SH2B3::LNK alterations and ALK::ROS1 fusions. The distinction between germline and somatic mutations profoundly influences prognosis: e.g., germline PTPN11-associated myeloproliferations and many germline CBL cases undergo spontaneous resolution, whereas somatic PTPN11- and NF1-mutated JMML is more aggressive and requires prompt allogeneic hematopoietic stem cell transplantation. DNA methylation profiling has emerged as the most robust prognostic framework, with consensus defining high-, intermediate-, and low-methylation subgroups that independently predict outcome. Both genotype and DNA methylation subclassification have been integrated into clinical decision-making, incorporating pretransplant azacitidine, watch-and-wait approaches for favorable-risk patients, and emerging targeted therapies including MEK inhibitors. This review synthesizes recent advances in understanding JMML as a bona fide RASopathy; provides a diagnostic algorithm, molecular landscapes, and prognostic models; and highlights opportunities for molecularly targeted therapeutic intervention. Full article

Moyamoya angiopathy (MMA) is a rare, chronic progressive cerebrovascular condition characterized by bilateral stenosis or occlusion of the terminal internal carotid arteries and their major branches. This progressive occlusion triggers the development of telangiectatic and fragile vessels at the base of the brain, creating the characteristic angiographic appearance of a “puff of smoke.” Depending on the etiology, MMA is classified as Moyamoya Disease (MMD) when idiopathic and primary or Moyamoya Syndrome (MMS) when associated with underlying systemic conditions. While the RNF213 gene, particularly the p.R4810K variant, is recognized as the major susceptibility locus for MMD in East Asian populations, it does not fully account for the global genetic landscape or the phenotypic diversity of the disease. This review provides a comprehensive overview of the genetic architecture of the entire MMA spectrum, exploring loci beyond RNF213. We analyze the role of genes involved in vascular smooth muscle cell contractility (ACTA2, MYH11), TGF-β signaling, and DNA repair mechanisms that drive MMS, alongside the genetic basis of syndromic forms associated with neurofibromatosis type 1, trisomy 21, and RASopathies. Understanding these diverse genetic drivers is crucial for early diagnosis, risk stratification, and the development of targeted molecular therapies. Full article

Plexiform neurofibromas (pNF1s) are benign peripheral nerve sheath tumors caused by NF1 loss, leading to dysregulated RAS/mitogen-activated protein kinase (MAPK) signaling. While the mitogen-activated protein kinase kinase (MEK) inhibitors, selumetinib and mirdametinib, can reduce tumor volume, surgical resection remains the primary treatment for immediate debulking and symptom relief. Complete removal is often limited by tumor infiltration along nerve plexuses, and residual tumors may undergo postsurgical tissue remodeling, producing localized regions of stiffened extracellular matrix (ECM). The impact of ECM stiffness on pNF1 growth and drug responses remains unclear. Using immortalized patient-derived pNF1 tumor cell lines cultured in 3D hydrogels with defined stiffness (1.5 kPa, soft; 7 kPa, stiff), we found that stiff ECM promoted spread morphology, increased growth, and progressive intracellular softening. Stiff ECM also reduced lysyl oxidase (LOX) expression, suggesting mechanoadaptive ECM remodeling, and increased P-glycoprotein expression. Under the same conditions, stiff ECM was associated with reduced sensitivity to selumetinib. These results provide the first evidence that ECM stiffening, including that plausibly associated with postsurgical remodeling, may contribute to pNF1 growth and reduced sensitivity to selumetinib in this 3D pNF1 culture model. Our findings highlight mechanobiology as a key regulator of tumor behavior and support further investigation of ECM-targeted strategies to improve outcomes in neurofibromatosis type 1 (NF1). Full article

Background: To investigate the risk factors for and prognostic implications of massive blood loss during posterior spinal instrumentation and fusion (PSIF) in pediatric patients with scoliosis. Methods: We retrospectively analyzed the electronic medical records of 460 children who underwent scheduled PSIF under general anesthesia between June 2021 and January 2024. Patients were grouped based on intraoperative blood loss: massive (estimated blood loss [EBL]/estimated blood volume [EBV] ≥ 30%) and nonmassive (EBL/EBV < 30%). Perioperative parameters were compared. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for massive intraoperative blood loss. Results: Among the 460 patients with scoliosis who underwent PSIF, 188 were male and 272 were female (mean age 9.4 ± 4.1 years). Massive intraoperative blood loss occurred in 126 (27%) patients. Factors associated with massive blood loss included age, preoperative Cobb angle, history of heart disease or neurofibromatosis, number of previous scoliosis surgeries, operative time, number of fused levels, number of pedicle screws inserted, and whether osteotomy was performed. Multivariate analysis identified younger age (odds ratios [OR] = 0.829, 95% confidence interval [CI], 0.751–0.914, p < 0.001), history of heart disease (OR = 4.338, 95% CI: 1.637–11.498, p = 0.003), greater number of fused levels (OR = 1.118, 95% CI: 1.014–1.233, p = 0.025), and longer operative time (OR = 1.008, 95% CI: 1.005–1.012, p < 0.001) as independent risk factors. Additionally, the massive blood loss group had a longer postoperative hospital stay (p = 0.008) and a higher rate of postoperative allogeneic blood transfusion (7.1% vs. 1.2%, p = 0.002) than the nonmassive blood loss group. Conclusions: Younger age, preexisting heart disease, a greater number of fused levels, and longer operation duration are independent risk factors for massive intraoperative blood loss in children undergoing PSIF for scoliosis. Full article

Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). By cross-comparison of RNA sequencing and RUNX1-CHIP sequencing data on mouse PNFs, we found that transcripts encoding the NF1-interacting p97/valosin-containing protein (VCP) gene are overexpressed in PNFs. Co-immunoprecipitation confirmed that VCP bounded to neurofibromin. Western blot and immunostaining confirmed VCP overexpression in both mouse and human PNFs. Treatment of primary mouse PNF Schwann cells with CB-5083, a p97/VCP inhibitor, led to accumulation of poly-ubiquitinated proteins and generation of irresolvable proteotoxic stress. Pharmacological or genetic inhibition of VCP reduced mouse PNF cell-derived sphere number, and genetic inhibition of Vcp in Schwann cell precursors decreased tumor-like lesion numbers in a cell transplantation model. In vivo treatment with CB-5083 in Nf1^fl/fl;DhhCre PNF mice significantly inhibited cell proliferation, increased cell apoptosis and reduced PNF volume. The combination with a MEK inhibitor did not increase efficacy compared to the single agent, supporting the hypothesis that VCP functions in parallel to, and may be modulated by, RAS–MAPK signaling under stress or oncogenic conditions. The significant effects of VCP inhibition in this pre-clinical study suggest a potential novel therapy for patients with PNFs. Full article

We describe a case of a 3-year-old girl with neurofibromatosis type 1 presenting with arterial hypertension, in whom multimodal vascular imaging identified significant right renal artery stenosis. The patient was successfully treated with percutaneous transluminal renal angioplasty; however, post-procedural Doppler ultrasound revealed a transient vascular fistula. Changes in renal arterial inflow during the procedure may have temporarily altered pressure gradients, facilitating the opening of communication involving pre-existing compensatory collateral vessels. This case illustrates the diagnostic value of multimodal vascular imaging in pediatric hypertension and highlights a rare, self-limiting post-interventional vascular phenomenon. Full article

Neurofibromatosis type 1 (NF1) and NF2-related schwannomatosis (NF2-SWN) are major genetic tumor predisposition syndromes characterized by progressive, often debilitating neoplasms of the peripheral and central nervous systems. Over the past five years, substantial advances in molecular genetics, signaling biology, and targeted therapeutic development have reshaped diagnostic and management paradigms for both disorders. This Perspective synthesizes recent developments, including gene-based reclassification, emergence of MEK inhibitor therapy in NF1, renewed evaluation of bevacizumab and kinase-pathway inhibitor brigatinib, the discovery of a novel TβR1-RKIP pathogenic axis, and a brain-penetrant HDAC inhibitor in NF2-SWN. These insights highlight a shift toward precision-medicine strategies and mechanistically driven therapies poised to redefine future clinical care. Full article

Background: Difficult benign intracranial tumors (including meningiomas, schwannomas, neurofibromatosis-related tumors, and pituitary neuroendocrine tumors) have substantial morbidity in patients. Due to their limited treatment options, there is a need for individualized treatment beyond histological and surgical approaches. Objective: To summarize how novel treatment innovations have been implemented for these tumors, meningiomas and schwannomas are prioritized, followed by NF-associated neoplasms, and then pituitary neuroendocrine tumors in comparison to low-grade gliomas. Methods: We summarize the current knowledge relating to targeted therapies for gliomas, meningiomas, schwannomas, neurofibromatosis (NF) tumors, and pituitary neuroendocrine tumors to investigate an individual’s treatment options for difficult benign brain tumors. This review synthesizes evidence on tumor genomics and molecular markers, supported by methylation-based classification, immunohistochemistry, and functional assays, emphasizing current clinical applications. Evidence Synthesis: The recent data show that DNA methylation-based models can predict post-surgical outcomes and radiotherapy responses, enabling risk stratification and radiotherapy benefit prediction. Early signals support target-directed treatment, including cMET blockade that radiosensitizes NF2 schwannoma models, brigatinib-associated tumor shrinkage in NF2-deficient models, and PitNET organoid data. Conclusions: We support clinical decision-making that utilizes molecular profiling with functional testing to guide targeted treatment. We also identify evidence gaps such as biomarker-defined prospective trials that are needed for broader clinical implementation. Full article

There is no approved drug therapy for schwannomas associated with NF2-related schwannomatosis (NF2-SWN). Neither life-saving surgical resection or radiation are curative and can compound the debilitating neurological effects of the schwannomas. We previously identified fimepinostat, a dual histone deacetylase (HDAC)/phosphoinositide-3 kinase (PI3K) inhibitor, as a promising drug candidate with pro-apoptotic effects on NF2-related schwannomas. This preclinical study used the pharmaceutical formulation of fimepinostat to confirm its efficacy in schwannomas and identify pro-apoptotic signaling pathways. Fimepinostat was tested in human schwannoma model cells, patient-derived primary vestibular and non-vestibular schwannoma cells, and in a sciatic nerve allograft model. The signaling pathways leading to caspase-3-dependent apoptosis were elucidated using immune assays, flow cytometry, imaging, proteome, and acetylome analysis. Acute exposure to fimepinostat led to p21-dependent cell cycle inhibition, upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL R2), and downregulation of tumor necrosis factor receptor 1 (TNFR1), Yes-associated protein (YAP), and inhibitors of apoptosis. Moreover, fimepinostat downregulated cytokine and chemokine secretion increased by merlin loss in schwannoma cells. Fimepinostat is a promising new drug intervention for NF2-SWN patients with the potential to promote tumor regression. Full article

Background: Vestibular schwannomas (VSs) are benign tumors that can cause significant morbidity, particularly in neurofibromatosis 2 (NF2) patients, in whom conventional treatments have important limitations. Merlin is a tumor suppressor protein encoded by the Neurofibromin 2 (NF2) gene, and the loss of its function leads to the activation of multiple signaling pathways, providing a rationale for targeted pharmacological therapies. Agents such as bevacizumab and other receptor tyrosine kinase inhibitors (TKIs) have shown variable efficacy but remain limited by toxicity and inconsistent responses. This review aims to evaluate the efficacy and safety of targeted therapies for VSs. Methods: This study was conducted according to PRISMA 2020 guidelines, using a PICO-based search of PubMed, EMBASE, and Scopus to identify studies on pharmacological therapies for VSs published between 2000 and 2025. Eligible human studies included clinical trials and observational studies reporting efficacy, safety, neuroimaging and audiological outcomes. Results: In total, 23 studies were analyzed, predominantly involving NF2-associated VSs. Treatment with bevacizumab was the most frequently investigated medical therapy and yielded the most consistent tumor control along with occasional hearing improvement, albeit with frequent but mostly manageable adverse events. Other targeted agents, including everolimus and TKIs, demonstrated limited or variable efficacy with acceptable toxicity profiles. Conclusions: VSs, particularly in NF2 patients, can cause significant morbidity and are often poorly managed by surgery or radiotherapy. Consequently, targeted medical therapies, especially anti-angiogenic agents, have emerged as valuable alternatives. Bevacizumab shows the most consistent benefits in tumor control, hearing stabilization, and quality of life, despite heterogeneous responses and notable toxicity. Evidence suggests that treatment discontinuation may lead to rapid tumor rebound, highlighting the need for long-term or maintenance strategies and careful monitoring. Future studies are needed to evaluate medical therapy integration with conventional treatments. Full article

Plexiform neurofibromas associated with neurofibromatosis type I (pNF1s) are benign tumors caused by the complete loss of function of the NF1 gene, which encodes a negative regulator of the RAS/mitogen-activated protein kinase (MAPK) pathway. pNF1s carry a significant risk of progression to malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive and largely incurable. FDA-approved mitogen-activated protein kinase kinase (MEK) inhibitors, selumetinib and mirdametinib, have shown ~30% tumor shrinkage in 70% and 42% pNF1 patients, respectively. However, not all pNF1s respond to MEK inhibition, and treatment is often associated with adverse effects such as dermatologic and gastrointestinal toxicities, underscoring the need for improved therapeutic strategies with minimal side effects. Here, we demonstrate that prolonged MEK inhibition increases proteolytic activity in 3D pNF1 tumor structures, consistent with enhanced extracellular matrix degradation. Prolonged treatment with four mechanistically and chemically distinct MEK inhibitors consistently reduced ERK phosphorylation, a downstream effector of the RAS/MAPK pathway, yet induced adaptive phosphorylation of MEK and AKT in pNF1 tumor cells. Phosphorylation of MEK is required for its catalytic activation and subsequent phosphorylation of ERK. Increased MEK phosphorylation in the presence of MEK inhibitors reflects upstream pathway reactivation but does not lead to ERK phosphorylation and activation because of the presence of the inhibitor. This response was also observed in MPNST cell lines treated with MEK inhibitors. These findings suggest that adaptive activation of upstream and parallel survival pathways may counteract the intended effects of MEK inhibition and support the rationale for combination strategies to improve therapeutic outcomes in NF1-associated tumors. Full article

Background/Objectives: Neurofibromatosis Type 1 (NF1) is a genetic syndrome caused by pathogenic NF1 variants encoding neurofibromin, a Ras GTPase activating protein. Individuals with NF1 develop peripheral nerve sheath tumors called neurofibromas. Approximately 50% of NF1 patients develop plexiform neurofibromas (pNFs) which have up to 13% lifetime risk of transformation into malignant peripheral nerve sheath tumors (MPNSTs). Current therapeutic strategies emphasize surgical resection with wide margins, radiation, and traditional chemotherapy for unresectable MPNSTs. However, NF1 patients diagnosed with MPNSTs have 5-year survival rates as low as 16%. The two recently FDA-approved drugs for pNFs, the MEK inhibitors selumetinib and mirdametinib, are not used to prevent or treat MPNSTs. Methods: The MEK inhibitor trametinib and the dual HDAC/PI3K inhibitor fimepinostat were assessed for growth inhibitory effects in nine unique patient-derived MPNST cell lines, as both drugs have preclinical efficacy in other Schwann cell-derived tumors. Results: Trametinib, which is approved for malignant melanomas, promoted cell death in 7/9 MPNST cell lines with a geometric mean GI50 = 17 nM. When directly compared to selumetinib and mirdametinib in a subset of four MPNST cell lines, trametinib had the lowest mean GI50 (trametinib = 38 nM, mirdametinib = 1.6 µM, selumetinib = 4.9 µM). Trametinib was also superior to selumetinib and mirdametinib in blocking ERK1/2 phosphorylation for 24 h. Fimepinostat promoted cell death in all cell lines with a geometric mean GI50 = 17 pM. Conclusions: These studies demonstrate in vitro efficacy for two candidate MPNST therapeutics which could reduce tumor burden and metastasis in NF1 patients. Full article

Objective: The current study tested (1) how ADHD symptoms and internalizing or externalizing problems covaried across ages 3–18 in children with neurofibromatosis type 1 (NF1), and (2) whether demographic and NF1-specific factors moderated the associations. Method: We analyzed integrated cross-sectional data of 685 observations from 455 children and adolescents with NF1 (M_age = 9.79 years, SD = 3.88; 43% female) across six institutions in the United States and Australia. ADHD symptoms (inattention and hyperactivity/impulsivity) and internalizing/externalizing problems were assessed via parent-report measures. Time-varying effect modeling was employed to examine the age-specific associations between ADHD symptoms and internalizing/externalizing problems. Moderation analyses tested effects of sex, parental education, and NF1 inheritance mode (familial vs. sporadic). Results: Inattention and hyperactivity/impulsivity symptoms were associated with greater internalizing and externalizing problems across ages 3–17. Inattention links were similar across ages, while the hyperactivity/impulsivity-externalizing link was stronger in early childhood than during adolescence. NF1 inheritance mode significantly moderated the inattention-externalizing link, with stronger associations observed among children with familial NF1. Other moderators were nonsignificant. Conclusions: ADHD symptoms are robustly linked to internalizing and externalizing problems from childhood to middle adolescence in children with NF1, with familial NF1 emerging as a potentially elevated risk factor. Future longitudinal and experimental research is needed to inform integrated intervention approaches, especially for those with familial NF1. Full article

Background/Objectives: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by various clinical manifestations, including significant neurovascular complications. This review aims to synthesize current knowledge regarding intracranial stenoses and associated vascular abnormalities in patients with NF1, emphasizing the differences between pediatric and adult populations. Methods: A narrative review was conducted, analyzing the existing literature on the epidemiology, clinical manifestations, and management of neurovascular issues related to NF1. Data were collected from a range of studies, including retrospective analyses and case series, focusing on the incidence and outcomes of intracranial vascular abnormalities. Results: The study found that intracranial vasculopathy affects between 0.4% and 6.4% of NF1 patients, with children experiencing higher rates of stenotic lesions. However, vascular issues in adults are less understood, with 3.5% of adult patients presenting vascular abnormalities. The review highlights a significant underdiagnosis of these conditions due to the lack of routine use of magnetic resonance angiography (MRA) in standard evaluations. The management of NF1-related vascular conditions, particularly in adults, remains poorly defined, particularly regarding the efficacy of antithrombotic therapies. Conclusions: The management of neurovascular complications in NF1 requires urgent attention, with a need for standardized screening protocols and further research to elucidate the natural history and optimal treatment strategies for these patients. Enhanced diagnostic practices, including routine neuroimaging, are essential to improve outcomes and reduce the risk of significant vascular events. Full article