Faculty Bibliography

BACKGROUND:Neurofibromatosis 1 (NF1) is a rare, neurogenetic disorder predisposing individuals to multiple tumors and other issues requiring expert care and regular health monitoring. We sought to assess U.S. patients' access to specialized NF1 clinics and receipt of evidence-informed health surveillance. METHODS:An online survey was distributed to NF Registry participants in May 2021. Rate of NF1 clinic attendance and self-reported receipt of health surveillance amongst NF Registry participants was estimated using inverse propensity scores. Differences in these outcomes based on participant demographics were assessed using weighted logistic regression and robust linear regression, respectively. RESULTS:322 individuals responded (160 adults, 162 parents; 4.7% overall response rate). We estimate that 51.7% of children and 35.6% of adults attend NF1 clinics. Younger children were more likely to attend an NF1 clinic, as were adults living in urban areas, with a college degree or higher, or with a household income ≥ $130,000 (all ps < 0.05). Completion rates for each individual health surveillance evaluation ranged from 41 to 79% for children and 33-61% for adults. Higher rates of recommended evaluations were reported by both adults and children who attend a specialized NF1 clinic, non-Hispanic White adults, and adults with commercial or Medicare insurance (all ps < 0.05). CONCLUSIONS:Adults with NF1 experience significant sociodemographic disparities in care, and patients of all ages attending NF1 specialty clinics receive more recommended health surveillance. Given the limited access to specialty NF clinics, quality improvement efforts are needed to increase access for underserved adults and improve provision of recommended health surveillance outside specialty clinics.

Individuals with neurofibromatosis type 1 (NF1) are prone to the evolution of neurodevelopmental symptomatology including motor delays, learning disabilities, autism, and attention deficits. Caused by heterozygous germline mutations in the NF1 gene, this monogenic condition offers unique opportunities to study the genetic etiologies for neurodevelopmental disorders and the mechanisms that underlie their formation. Although numerous small animal models have been generated to elucidate the causes of these alterations, there is little consensus on how to align preclinical observations with clinical outcomes, harmonize findings across species, and consolidate these insights to chart a cohesive path forward. Capitalizing on expertise from clinicians; human, animal, and cellular model research scientists; and bioinformatics researchers, the first Cognition and Behavior in NF1 (CABIN) meeting was convened at the Banbury Center of Cold Spring Harbor Laboratory in October 2024. This Perspective summarizes the state of our understanding and a proposed plan for future investigation and exploration to improve the quality of life of those with NF1.

BACKGROUND:Binimetinib and selumetinib are two mitogen-activated protein kinase kinase (MEK) inhibitors used to treat low-grade gliomas and plexiform neurofibromas. Cutaneous toxicities are commonly associated with MEK inhibitors; however, limited studies have examined cutaneous effects in a pediatric population or whether toxicities vary between MEK inhibitors. METHODS:We conducted an IRB-approved, single-center, retrospective review of pediatric neuro-oncology patients on binimetinib or selumetinib who presented to NYU from April 2016 through July 2022. RESULTS:Forty-six children met inclusion criteria (23 females, 23 males) with a mean age of 11.7 years. Thirty-three were treated with binimetinib and 13 with selumetinib. Dermatologic adverse events were encountered in 97.8% of the cohort, and the most common were acneiform eruption (63.0%), paronychia (58.7%), and xerosis (54.3%). Children 12 years and older were more likely to have acneiform eruption (p < 0.001) and seborrheic dermatitis (p < 0.001), while children under 12 were more likely to have xerosis (p = 0.037). The incidence of cutaneous adverse events was significantly different between MEK inhibitors for folliculitis and hair pigment dilution (39.4% binimetinib, 0% selumetinib, p = 0.009). Significantly, more patients required MEK inhibitor dose reduction/hold on binimetinib (87.9%) than selumetinib (46.2%) (p = 0.006). Severity of cutaneous disease was not associated with tumor response. CONCLUSIONS:Our study confirms dermatologic adverse events are common in children on MEK inhibitors. Age appears to be associated with increased likelihood of certain cutaneous reactions. Overall, the selumetinib patients in our cohort presented with less severe adverse events and decreased risk of MEK inhibitor dose reduction/hold. Our results will aid clinicians in providing appropriate counseling, treatments, and improved preventive care.

BACKGROUND:Neurofibromatosis type 1 (NF1) is a multisystemic autosomal dominant disorder that includes intracranial lesions such as unidentified bright objects (UBOs)-areas of increased T2 signal on magnetic resonance imaging (MRI)-and tumors known as gliomas. The presence of these lesions in the corpus callosum (CC) has not been previously studied in a large cohort. METHODS:We reviewed medical records of 681 patients (aged three months to 86 years) followed at our institution from 2000 to 2023 with NF1 and one or more brain MRI. Patients with lesions in the CC were identified, and RAPNO/RANO criteria were used to determine changes in size over time, where a change of 25% in the product of perpendicular measurements indicates growth or shrinkage. RESULTS:Forty-seven patients had CC UBOs, most of which were in the splenium (66.0%). Seventeen patients had CC gliomas (10% of those with any glioma), two of whom had two gliomas. Seventeen of 19 gliomas were in the splenium. Over follow-up, eight of 19 remained stable, three shrunk, and eight grew. The mean percentage change in the product of the dimensions was 311.5% (ranging from -46.7% to 2566.6%). Of the eight lesions that grew, one required treatment. CONCLUSIONS:There is a 6.9% and 2.5% prevalence of CC UBOs and gliomas, respectively, in our cohort of patients with NF1. Most lesions are present in the splenium, and although some gliomas demonstrate significant growth, they rarely require treatment. This work is the largest series of CC lesions in NF1 and adds to the growing data to inform appropriate follow-up.

BACKGROUND: METHODS:-SWN and progressive tumors were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumor and up to five nontarget tumors in each patient. The primary outcome was radiographic response in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response, and patient-reported outcomes. RESULTS:A total of 40 patients (median age, 26 years) with progressive target tumors (10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas, and 2 ependymomas) received treatment with brigatinib. After a median follow-up of 10.4 months, the percentage of tumors with a radiographic response was 10% (95% confidence interval [CI], 3 to 24) for target tumors and 23% (95% CI, 16 to 30) for all tumors; meningiomas and nonvestibular schwannomas had the greatest benefit. Annualized growth rates decreased for all tumor types during treatment. Hearing improvement occurred in 35% (95% CI, 20 to 53) of eligible ears. Exploratory analyses suggested a decrease in self-reported pain severity during treatment (-0.013 units per month; 95% CI, -0.002 to -0.029) on a scale from 0 (no pain) to 3 (severe pain). No grade 4 or 5 treatment-related adverse events were reported. CONCLUSIONS:-SWN. (Funded by the Children's Tumor Foundation and others; INTUITT-NF2 ClinicalTrials.gov number, NCT04374305.).

PURPOSE/OBJECTIVE:Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGF-β coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. EXPERIMENTAL DESIGN/METHODS:ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathway activation and in vivo MPNST growth and metastasis were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. RESULTS:ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Moreover, combination of anti-ENG therapy with MEK inhibition effectively reduced tumor cell growth and angiogenesis. CONCLUSIONS:Our data unveil a tumor-promoting function of ENG in MPNSTs and support the use of this protein as a novel biomarker and a promising therapeutic target for this disease.

PURPOSE/OBJECTIVE:People with pre-existing conditions may be more susceptible to severe COVID-19 when infected by SARS-CoV-2. The relative risk and severity of SARS-CoV-2 infection in people with rare diseases such as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), or schwannomatosis (SWN) is unknown. METHODS:We investigated the proportions of people with NF1, NF2, or SWN in the National COVID Cohort Collaborative (N3C) electronic health record data set who had a positive test result for SARS-CoV-2 or COVID-19. RESULTS:The cohort sizes in N3C were 2501 (NF1), 665 (NF2), and 762 (SWN). We compared these with N3C cohorts of patients with other rare diseases (98-9844 individuals) and the general non-NF population of 5.6 million. The site- and age-adjusted proportion of people with NF1, NF2, or SWN who had a positive test result for SARS-CoV-2 or COVID-19 (collectively termed positive cases) was not significantly higher than in individuals without NF or other selected rare diseases. There were no severe outcomes reported in the NF2 or SWN cohorts. The proportion of patients experiencing severe outcomes was no greater for people with NF1 than in cohorts with other rare diseases or the general population. CONCLUSION/CONCLUSIONS:Having NF1, NF2, or SWN does not appear to increase the risk of being SARS-CoV-2 positive or of being a patient with COVID-19 or of developing severe complications from SARS-CoV-2.

The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 has made it the first medical therapy approved for this indication in the United States, the European Union and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefit for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.

Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multi-disciplinary NF1 experts.

PURPOSE/OBJECTIVE:Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging. METHODS:We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups. RESULTS:We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1. CONCLUSION/CONCLUSIONS:The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity.