Search Results (53)

Plexiform neurofibromas (hereafter called pNF1) are often diagnosed in early childhood and occur in about 30% of neurofibromatosis type 1 (NF1) patients. pNF1 exhibits aggressive growth along a nerve in the body and has substantial potential for progression to malignant peripheral nerve sheath tumors that are rarely curable. There are two recently FDA-approved drugs, selumetinib and mirdametinib, for pNF1 patients who have symptomatic and inoperable plexiform neurofibromas; however, these treatments achieve only approximately 30% tumor shrinkage. Fibroblasts, the most abundant cell types within the pNF1 tumor microenvironment, are implicated in pNF1 growth and invasion; however, how fibroblasts affect a drug response of pNF1 remains poorly understood. In the present study, we focused on contributions of fibroblasts to the drug resistance in pNF1 via their secretome. We employed our established three-dimensional (3D) culture system incorporating human pNF1 tumor cells (Nf1^−/−) and primary fibroblasts (Nf1^+/−) grown in our patented microfluidic culture chips for monocultures and parallel cocultures in which 3D pNF1 structures and fibroblasts share their secretome without direct cell-to-cell contact. Three-dimensional pNF1 structures in 3D parallel cocultures with fibroblasts exhibited greater drug resistance than ones in monocultures. We found that pNF1 tumor cells showed increased P-glycoprotein expression when incubated with fibroblast-derived conditioned media or parallel cocultured with fibroblasts, compared to control conditions. Pharmacological inhibition of P-glycoprotein partially restored drug sensitivity. Additionally, fibroblasts showed higher resistance to selumetinib and mirdametinib than pNF1 tumor structures, likely due to elevated P-glycoprotein levels. This study is the first to define precise roles of fibroblasts in pNF1 drug resistance, emphasizing the potential of fibroblast-targeted therapies as a promising approach to improve pNF1 treatment outcomes. Full article

Neurocutaneous syndromes, known as phakomatoses, encompass a diverse group of congenital conditions affecting the nervous system and skin, with neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) among the most clinically significant. Both disorders are inherited in an autosomal dominant manner. NF1 presents with café-au-lait macules; cutaneous, subcutaneous, and plexiform neurofibromas; skeletal abnormalities; learning disabilities; and optic pathway gliomas, while NF2 is characterised by bilateral vestibular schwannomas, multiple meningiomas, ependymomas, and peripheral nerve schwannomas. Although germline mutations in the NF1 and NF2 tumour suppressor genes are well established, they do not fully explain the broad clinical variability observed, even among individuals carrying identical mutations. As increasingly recognised in other genetic diseases, epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodelling, and non-coding RNA (ncRNA) regulation, play a critical role in modulating gene expression and influencing disease severity. Despite important findings, the research remains fragmented, and a unified model is lacking. This review organises the current knowledge, emphasising how epigenetic alterations impact disease behaviour and outlining their potential as prognostic biomarkers and therapeutic targets. A deeper understanding of these mechanisms could lead to improved personalised management and the development of targeted epigenetic therapies for individuals with NF1 and NF2. Full article

Background/Objectives: Plexiform neurofibromas (pNFs) are one of the cardinal presentations of NF1 patients, often arising during early childhood. Since selumetinib was approved by the FDA in 2020, the long-term side effects and various responses of mitogen-activated protein kinase inhibitors (MEKi) in pediatric patients necessitate a new strategy. We propose that combining selumetinib with heat shock protein 90 inhibitors (HSP90i) can enhance the inhibitory effects as well as reduce the dosage of selumetinib in combination. We validated the synergistic effects and the significantly improved treatment effects of the combination of selumetinib and HSP90i in pNFs. Methods: We used drug screen data mining to predict the combination of selumetinib and HSP90i. Using cell lines and in vivo mouse models for pNFs, we tested a series of combinations with different concentrations. We validated the in vivo inhibitory effects using the transplanted tumors from DhhCreNf1^f/f mouse models. Results: We demonstrated that combining selumetinib and SNX-2112 or retaspimycin can achieve better tumor inhibition with synergistic effects. The combination significantly delays the progression of mouse pNFs. Conclusions: The combination of selumetinib and HSP90i has significant synergistic effects, provides therapeutic inhibitor effects, and reduces the selumetinib dosage in combination. Full article

Background/Objectives: Neurofibromatosis Type 1 (NF1) plexiform neurofibroma (PN) can cause morbidity, including disfigurement that can negatively impact social functioning. Historically, the mainstay treatment is surgical resection. However, complete resection is often prohibitive due to multiple nerve involvement. Moreover, post-operative recurrence is common. MEK inhibitors, including selumetinib and mirdametinib, have recently changed the treatment paradigm for these tumors. In 2020, selumetinib was FDA-approved for pediatric NF1 patients with inoperable symptomatic PNs, but selumetinib remains under investigation for their adult counterparts. In 2025, mirdametinib was FDA-approved for use in adults with symptomatic incompletely resectable NF1 PNs. Lower partial response rates have been reported with mirdametinib compared to selumetinib, but direct comparative analyses have not been conducted to establish the superiority of one agent over the other. Results: We present a case of a 38-year-old male with a right facial PN successfully treated with selumetinib, resulting in a 16.77% tumor volumetric reduction over 7 months. Selumetinib was well tolerated in our patient, with an asymptomatic Grade 3 CPK elevation that subsequently improved with a dose reduction. Conclusion: Our case adds to the growing body of evidence suggesting that selumetinib is effective and well tolerated in adult patients with NF1-associated PNs. Full article

Background/Objectives: Neurofibromatosis type 1 (NF1) is a prevalent inherited disorder, with approximately 50% of affected individuals developing plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). While selumetinib is FDA-approved for PNFs, its efficacy in MPNSTs is limited and associated with dose-limiting toxicities. NF1 deficiency drives tumorigenesis and alters immune dynamics via RAS hyperactivation. Given the substantial macrophage infiltration in NF1 lesions and its association with disease progression, we hypothesized that targeting tumor-promoting immune cells with the retinoid X receptor (RXR) agonist MSU-42011 could be an alternative therapeutic strategy, as it has shown promise in KRAS-driven cancers by decreasing pERK levels and reducing tumor-promoting immune cells. Methods: We examined the effects of MSU-42011 and selumetinib, alone and in combination, on NF1-deficient cells and in a syngeneic MPNST model. Results: In vivo, the combination of MSU-42011 and selumetinib significantly reduced tumor growth, pERK levels, and tumor-promoting macrophages and increased activated CD8⁺ T cells in syngeneic MPNST models. In NF1-deficient cells, MSU-42011 or selumetinib reduced pERK levels, with combination treatment achieving greater reductions. Conditioned media (CM) from NF1-deficient cells increased the protein and mRNA levels of several cytokines and chemokines in human THP1 cells and bone marrow-derived macrophages (BMDMs). MSU-42011 and selumetinib, alone or in combination, partially reversed this induction. Conclusions: These findings suggest RXR agonists may have therapeutic potential against NF1, and their combination with MEK inhibitors could represent a promising strategy for NF1-associated tumors. Further studies are needed to validate these results and assess their translational relevance. Full article

Background: Selumetinib, an MEK inhibitor, was approved by the U.S. Food and Drug Administration in April 2020 and became reimbursable in Italy in January 2020, for treating patients aged ≥3 years with neurofibromatosis type 1 (NF1) complicated by symptomatic, inoperable plexiform neurofibromas (PNs). Selumetinib has been shown to effectively reduce the volume of target PNs and alleviate neuropathic pain even in long-term-treated patients. We report the impact of Selumetinib on pain in three NF1 cases with inoperable symptomatic plexiform neurofibromas. Case Series: Three patients with NF1 (aged 13–27 years) presented with symptomatic, inoperable plexiform neurofibromas (PNs) associated with severe neuropathic pain. Following selumetinib administration, a marked reduction in or disappearance of neuropathic pain was observed within a few weeks, allowing the complete discontinuation of pain therapy. Interestingly, pain recurred whenever selumetinib was temporarily suspended, requiring patients to resume analgesic therapy. Conclusions: Selumetinib treatment has been shown to effectively reduce neuropathic pain in patients with NF1. These findings represent a significant advancement in managing pain related to PNs and support its potential application in treating other forms of neuropathic pain. Full article

Pediatric gliomas encompass the most common brain tumor in children and are subdivided into pediatric low-grade gliomas (pLGGs) and pediatric high-grade gliomas (pHGGs). The era of molecular diagnosis has shifted the treatment paradigms and management of these patients. RAS/MAPK pathway alterations serve as the driver in the majority of pLGGs, a subset of pHGG and NF1-related plexiform neurofibromas (PNs). The role of small molecule inhibitors in the treatment of these tumors has evolved in the past decade, facilitated through multiple clinical trials and moving into earlier stages of treatment. Although these developments hold promise, questions remain regarding targeted therapy, the long-term toxicities, the duration of treatment and the potential effects on the natural history of the tumor behavior. Full article

Background: Neurofibromatosis type 1 (NF1) is a rare multisystem disorder characterized by variable expressivity and increased tumor risk. Café-au-lait macules (CALMs) are a hallmark of the disease, often representing one of the earliest clinical manifestations and allowing a clinical NF1 diagnosis if six or more are present. In this study, we aimed to investigate the prognostic value of CALMs at birth in NF1 patients. Methods: We conducted a retrospective study in patients aged ≥ 4 years presenting with CALMs at our Institution between 2020 and 2021, with a minimum follow-up of four years. We retrospectively collected data on CALMs at birth and other clinical manifestations associated with NF1. Results: Among 208 patients evaluated, including 147 with a confirmed diagnosis of NF1, 110 did not show CALMs at birth, and 98 had at least one. The absence of CALMs at birth did not correlate with a lower likelihood of NF1. In contrast, the CALM number at birth directly correlated with the likelihood of NF1, up to 95% in patients with ≥5 macules. Additionally, a higher number of CALMs correlated with a greater prevalence of plexiform neurofibromas (p < 0.001). Conclusions: Our findings suggest that a higher number of CALMs may indicate a more severe form of NF1, with an increased risk of plexiform neurofibromas. These results emphasize the importance of a comprehensive evaluation of patients with CALMs, especially in case of multiple lesions, aiming at implementing early NF1 diagnosis, follow-up strategies, and overall patient management. Full article

Plexiform neurofibroma (PNF) is an immune cell-rich peripheral nerve sheath tumor that develops primarily in individuals with Neurofibromatosis Type 1 (NF1). Granulocyte-macrophage colony stimulating factor receptor-β (GM-CSFR-β^c) is a shared component of receptors for the cytokines GM-CSF, IL-3, and IL-5, ligands with immunomodulatory and tumor promoting roles. In the present study, we use genetically engineered mouse model of neurofibroma. We identified the expression of GM-CSFR-β^c and GM-CSFR-α on PNF cells and on macrophages and dendritic cells in the PNF, using the Nf1^f/f; DhhCre mouse model of neurofibroma formation. Genetic deletion of GM-CSFR-β^c in this model reduced the number of PNFs, which was associated with decreased numbers of tumor-associated Iba1+ macrophages and CD11c+ dendritic cells (DC), while loss of GM-CSFR-α had no effect. Deletion of GM-CSFR-α or GM-CSFR-β^c did not improve mouse survival or the structure of Remak bundles in peripheral nerves. Proteome analysis of tumor lysates showed altered levels of numerous cytokines after receptor loss, suggesting that the compensatory effects of other cyto/chemokines maintain a proinflammatory environment promoting neurofibroma. Thus, GM-CSFR-β^c signaling contributes modestly to neurofibroma formation, apparently independently of its ligand GM-CSF. Full article

Due to the complex anatomy of the pelvis, various tumors may arise in this region. Some of these tumors are well known and have distinctive features that allow them to be identified by magnetic resonance imaging (MRI). These include sacrococcygeal teratoma (SCT), the most prevalent congenital tumor in children, often diagnosed prenatally and most frequently occurring in this anatomical location, and ovarian teratoma, which in its mature form is the most common ovarian neoplasm in children and adolescents. Additionally, rhabdomyosarcoma (RMS), commonly found in the bladder in both genders and in the prostate in males, and Ewing sarcoma (ES), affecting the flat bones of the pelvis, are relatively common tumors. In this study, selected atypical pelvic tumors in children are presented. Most of them are tumors of the reproductive system, such as cervical cancer, small cell neuroendocrine carcinoma of the ovary, ES/primitive neuroectodermal tumor (PNET) of the ovary, diffuse large B-cell lymphoma (DLBCL) of the ovaries and ovarian Sertoli–Leydig cell tumor (SLCT) with RMS due to DICER1 syndrome. Additionally, tumors originating from the nervous system, including neuroblastoma (NBL) and plexiform neurofibroma (pNF), associated and not associated with neurofibromatosis type 1 (NF1), are discussed. Furthermore, Rosai–Dorfman disease involving the pelvic and inguinal lymph nodes is presented. By reviewing the literature and presenting our cases, we tried to find radiological features of individual tumors that would bring the radiologist closer to the correct diagnosis, ensuring the implementation of appropriate treatment. However, the MR images cannot be considered in isolation. Additional patient data, such as the clinical picture, comorbidities/syndromes, and laboratory test results, are necessary. Full article

Background: Oral therapeutic options for plexiform neurofibromas (PNs) in individuals with neurofibromatosis type 1 (NF1) are receiving attention in clinical research. The MEK inhibitor (MEKi) Selumetinib is FDA-approved in children ages 2+ years with inoperable PNs, and shows activity in adults. Prolonged therapy with selumetinib is necessary to maintain tumor reduction. Therefore, investigating long-term adherence is vital to understand patterns of adherence over time and its impact on clinical outcomes. Mixed methods research offers rich information about adherence that can inform future intervention trials, and can assist practitioners in addressing medication adherence concerns. Methods: This mixed-method pilot study is the first examination of the feasibility of a technology-based adherence assessment method, the medication events monitoring system (MEMS^TM), among individuals with NF1-PN. Adherence was monitored in a small sample of patients (N = 12; mean age = 34.36 years; 58% male) with NF1 and PN across eighteen 28-day treatment cycles. Qualitative data were obtained from individual interviews using inductive and deductive techniques for thematic analysis. Results: The predetermined criterion was met, suggesting that using MEMS^TM is feasible despite some challenges with the caps. Depression and overall stress were significantly related to reduced adherence, although these results should be considered hypothesis-generating. Barriers to medication adherence included forgetting and the timing of doses related to eating. Facilitators included consistency, reminders, and social support. Conclusions: This study highlights patient characteristics that may be related to increased risk for nonadherence, as well as challenges with electronic pill caps that should be considered in future clinical trials for NF1-related PN. Results can inform future adherence interventions for adults with NF1 and PNs. Future research with larger samples is needed to fully explore factors related to long-term medication adherence among individuals with NF1. Full article

Background: Neurofibromatosis type 1 (NF1) is a complex neurocutaneous disorder caused by pathogenic variants in the NF1 gene. Although genotype–phenotype correlation studies are increasing, robust clinically relevant correlations have remained limited. Methods: We conducted a retrospective analysis of data obtained from a cohort of 204 Hungarian individuals, with a mean age of 16 years (age range: 1–33 years). The data were collected over 15 years. Results: Among the cohort of 204 patients, 148 subjects fulfilled ≥2 criteria established by the National Health Institute. Genetic testing was performed in 70 patients, with an 82.8% detection rate, of which 13 patients were excluded. Among the remaining 45 pathogenic variants, 17 (37.7%) frameshift, 11 (24.4%) nonsense, 8 (17.8%) splice-site, 4 (8.9%) missense mutations, and 5 (11.11%) copy number variations (CNVs) were detected. Café-au-lait macules were present in all patients (100%). Intracranial malformations were the second most common feature (55.6%), followed by Lisch nodules (35.6%), neurofibromas (33.3%), and skeletal abnormalities (31.1%). Conclusions: In our cohort, patients with splice-site variants (8/45, 17.8%) demonstrated a notably more severe phenotype compared to findings reported in other studies, with a high prevalence of plexiform neurofibromas (37.5%), intracranial findings (62.5%), skeletal abnormalities (50%), Lisch nodules (50%), and even pseudarthrosis (25%). Correlating with the literature, missense variants represented a mild phenotype, while patients with microdeletion syndrome revealed a more severe phenotype. Full article

Malignant peripheral nerve sheath tumors (MPNSTs) are rare but aggressive malignancies with a low 5-year survival rate despite current treatments. MPNSTs frequently harbor mutations in key genes such as NF1, CDKN2A, TP53, and PRC2 components (EED or SUZ12) across different disease stages. With the rapid advancement of high-throughput sequencing technologies, the molecular characteristics driving MPNST development are becoming clearer. This review summarizes recent sequencing studies on peripheral nerve sheath tumors, including plexiform neurofibromas (PNs), atypical neurofibromatous neoplasm with uncertain biologic potential (ANNUBP), and MPNSTs, highlighting key mutation events in tumor progression from the perspectives of epigenetics, transcriptomics, genomics, proteomics, and metabolomics. We also discuss the therapeutic implications of these genomic findings, focusing on preclinical and clinical trials targeting these alterations. Finally, we conclude that overcoming tumor resistance through combined targeted therapies and personalized treatments based on the molecular characteristics of MPNSTs will be a key direction for future treatment strategies. Full article

Background: Plexiform neurofibromas (PNs) are histologically benign peripheral nerve sheath tumors associated with neurofibromatosis type 1 (NF1) and often lead to significant morbidity due to growth. Management includes watchful waiting, surgery for partial debulking, and, since recently, systemic treatment with MEK inhibitors. However, due to the scarcity of natural history studies, our understanding of the natural progression of PNs to guide clinicians in deciding in whom and when to intervene is scarce. This study aims to describe the characteristics of NF1 patients with PNs and compare those at high risk for PN progression or experiencing significant morbidity from PN (complex PN) with NF1 patients with PNs of lower complexity. Methods: In this retrospective cohort study using clinical data from hospital records of NF1 patients with PNs seen at the Sophia Children’s Hospital in the Netherlands between 2012 and 2023, we assessed determinants of clinical phenotypes and PN characteristics predictive of outcomes, including PN complexity and the timing of intervention for PN. We assessed the outcomes using logistic regression analysis and Cox regression. Results: Ninety patients with a median age at last evaluation of 15.7 years and a median follow-up duration of 9.8 years were included. Out of 90 individuals with a benign PN, 37 developed plexiform neurofibroma morbidity during follow-up. Older age was (corrected for pathogenic NF1 variant and PN location) significantly associated with plexiform neurofibroma morbidity. Cox regression revealed that craniofacial and trunk PNs were associated with a higher intervention hazard compared to limb PNs. Conclusion: Our pilot multivariate approach identified older age and the location of the PN to be mostly associated with a higher chance of plexiform neurofibroma morbidity and higher intervention hazard. This may contribute to decisions regarding in whom and when to initiate treatment in NF1 patients with PNs. Full article

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by the predisposition to develop tumors such as malignant peripheral nerve sheath tumors (MPNSTs) which represents the primary cause of death for NF1-affected patients. Regardless of the high incidence and mortality, the molecular mechanisms underneath MPNST growth and metastatic progression remain poorly understood. In this proof-of-concept study, we performed somatic whole-exome sequencing (WES) to profile the genomic alterations in four samples from a patient with NF1-associated MPNST, consisting of a benign plexiform neurofibroma, a primary MPNST, and metastases from lung and skin tissues. By comparing genomic patterns, we identified a high level of variability across samples with distinctive genetic changes which allow for the definition of profiles of the early phase with respect to the late metastatic stages. Pathogenic and likely pathogenic variants were abundant in the primary tumor, whereas the metastatic samples exhibited a high level of copy-number variations (CNVs), highlighting a possible genomic instability in the late phases. The most known MPNST-related genes, such as TP53 and SUZ12, were identified in CNVs observed within the primary tumor. Pathway analysis of altered early genes in MPNST pointed to a potential role in cell motility, division and metabolism. Moreover, we employed survival analysis with the TCGA sarcoma genomic dataset on 262 affected patients, in order to corroborate the predictive significance of the identified early and metastatic MPNST driver genes. Specifically, the expression changes related to the mutated genes, such as in RBMX, PNPLA6 and AGAP2, were associated with reduced patient survival, distinguishing them as potential prognostic biomarkers. This study underlines the relevance of integrating genomic results with clinical information for early diagnosis and prognostic understanding of tumor aggressiveness. Full article