Selumetinib in adults with NF1 and inoperable plexiform neurofibroma: a phase 2 trial.

The MEK inhibitor selumetinib induces objective responses and provides clinical benefit in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). To evaluate whether similar outcomes were possible in adult patients, in whom PN growth is generally slower than in pediatric patients, we conducted an open-label phase 2 study of selumetinib in adults with NF1 PNs. The study was designed to evaluate objective response rate (primary objective), tumor volumetric responses, patient-reported outcomes and pharmacodynamic effects in PN biopsies.

Consensus recommendations for an integrated diagnostic approach to peripheral nerve sheath tumors arising in the setting of Neurofibromatosis type 1 (NF1).

Consensus recommendation published in 2017 histologically defining atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) and malignant peripheral nerve sheath tumor (MPNST) were codified in the 2021 WHO Classification of Tumors of the Central Nervous System and the 2022 WHO Classification of Tumors of Soft Tissue and Bone. However, given the shift in diagnostic pathology toward the use of integrated histopathologic and genomic approaches, the incorporation of additional molecular strata in the classification of Neurofibromatosis Type 1 (NF1)-associated peripheral nerve sheath tumors should be formalized to aid in accurate diagnosis and early identification of malignant transformation to enable appropriate intervention for affected patients. To this end, we assembled a multi-institutional expert pathology working group as part of a "Symposium on Atypical Neurofibroma: State of the Science".

Anthropometric measurements of children with neurofibromatosis type I: impact of plexiform neurofibroma volume and treatment.

Background: In children and adolescents/young adults (CAYA) with neurofibromatosis type I (NF1), associations between anthropometric measurements, plexiform neurofibroma (pNF) tumor volume (TV), and treatment history are unknown.

Methods: We retrospectively investigated anthropometrics in CAYA on the National Cancer Institute (NCI) NF1 Natural History Study who had pNF TV assessed by imaging (n = 106). We determined CDC height/weight percentiles and estimated Preece-Baines (PB) height growth curve parameters.

Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis: A potential model for rare diseases.

Background: Neurofibromatosis type 1, -related schwannomatosis and non--related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments.

Methods: Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF.

snRNA-seq of human cutaneous neurofibromas before and after selumetinib treatment implicates role of altered Schwann cell states, inter-cellular signaling, and extracellular matrix in treatment response.

Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor.

Selumetinib for children with neurofibromatosis type 1 and plexiform neurofibromas: A plain language summary of SPRINT.

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.

Contemporary Approach to Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors.

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.

The Landscape of US and Global Rare Tumor Research Programs: A Systematic Review.

Rare cancers and other rare nonmalignant tumors comprise 25% of all cancer diagnoses and account for 25% of all cancer deaths. They are difficult to study due to many factors, including infrequent occurrence, lack of a universal infrastructure for data and/or tissue collection, and a paucity of disease models to test potential treatments. For each individual rare cancer, the limited number of diagnosed cases makes it difficult to recruit sufficient patients for clinical studies, and rare cancer research studies are often siloed.

Estimated Prevalence, Tumor Spectrum, and Neurofibromatosis Type 1-Like Phenotype of CDKN2A-Related Melanoma-Astrocytoma Syndrome.

Importance: Knowledge about the prevalence and tumor types of CDKN2A-related melanoma-astrocytoma syndrome (MAS) is limited and could improve disease recognition.

Objective: To estimate the prevalence and describe the tumor types of MAS.

Design, Setting, And Participants: This retrospective cohort study analyzed all available MAS cases from medical centers in the US (2 sites) and Europe (2 sites) and from biomedical population genomic databases (UK Biobank [United Kingdom], Geisinger MyCode [US]) between January 1, 1976, and December 31, 2020.

Clinical and molecular features of NDM-producing Acinetobacter baumannii in a multicenter study in Israel.

Background: NDM-producing Acinetobacter baumannii (NDMAb) were reported sporadically worldwide but little is known about the transmission, epidemiology and clinical features of NDMAb-infected patients. The goals of this study were to characterize (1) the epidemiology and clinical features of NDMAb-infected patients; (2) the microbiological and molecular features of NDMAb isolates and (3) the transmission networks of NDMAb within healthcare facilities.

Methods: The study was conducted at the Tel-Aviv Sourasky, Rambam and Sha'are-Zedek Medical centers (TASMC, RMC and SZMC, respectively) in Israel.

Consensus-Based Best Practice Guidelines for the Management of Spinal Deformity and Associated Tumors in Pediatric Neurofibromatosis Type 1: Screening and Surveillance, Surgical Intervention, and Medical Therapy.

Background: Spinal conditions, such as scoliosis and spinal tumors, are prevalent in neurofibromatosis type 1 (NF1). Despite the recognized importance of their early detection and treatment, there remain knowledge gaps in how to approach these manifestations. The purpose of this study was to utilize the experience of a multidisciplinary committee of experts to establish consensus-based best practice guidelines (BPGs) for spinal screening and surveillance, surgical intervention, and medical therapy in pediatric patients with NF1.

Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas.

Background: Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies.

Molecular features and transmission of NDM-producing Enterobacterales in Israeli hospitals.

Objectives: NDM-producing Enterobacterales (NDME) account for 34.9% of new carbapenemase-producing Enterobacterales cases in Israeli hospitals. The goals of this study were to characterize the genomic composition of NDME isolates and mobile genetic elements (MGEs) and to identify NDME transmission events (TEs).

Audiometric and Otologic Findings in Children and Young Adults with Neurofibromatosis Type 1 and Plexiform Neurofibromas.

Objectives: To characterize otologic and audiologic manifestations in our NF1 cohort and explore the relationship between otologic and audiologic findings in a subset of patients with ear-related plexiform neurofibromas (PNs).

Methods: Audiologic and otologic clinical evaluations were conducted on 102 patients with NF1 in a natural history study (5-45 years; M = 14.4 years; Mdn = 14).

Cancer incidence and surveillance strategies in individuals with RASopathies.

RASopathies are a set of clinical syndromes that have molecular and clinical overlap. Genetically, these syndromes are defined by germline pathogenic variants in RAS/MAPK pathway genes resulting in activation of this pathway. Clinically, their common molecular signature leads to comparable phenotypes, including cardiac anomalies, neurologic disorders and notably, elevated cancer risk.

The surgical management of highly unstable fragility fractures of the sacrum with spinopelvic dissociation: A case series and proposal of a surgical treatment algorithm.

Introduction: U- and H-shaped fragility fractures of the sacrum (FFP IVb) are unstable fractures. Non-operative treatment may be associated with impaired walking abilities, chronic pain and the potential loss of independency. However, different treatment options are still controversially debated.

MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus.

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 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere.

Management of neurofibromatosis type 1-associated plexiform neurofibromas.

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.