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This study examined a woman's clearly articulated sexual boundary and its effect on college students' discrimination of when a woman wants her date to stop making sexual advances. Male and female participants listened to an audio recording of a date rape vignette and signaled when the man should stop making sexual advances. Relative to participants in the no-boundary condition, participants who heard a discussion including a sexual boundary before intimate physical contact occurred displayed significantly shorter latencies to identify the inappropriateness of the man's behavior. No significant difference was observed between male and female participants. [ABSTRACT FROM AUTHOR]

This study examined the pharmacological and psychological effects of alcohol on women's recognition of and response to dating sexual aggression. Female participants completed measures of prior sexual victimization experiences, sex related alcohol expectancies, general alcohol expectancies, and drinking habits. Using a 2 (alcohol) x 2 (expectancy) balanced placebo research design, women were exposed to an audiotape date rape vignette and asked to press a button when the man's sexual advances had gone to far. Upon pressing the button, the tape was stopped and participants were instructed to imagine themselves in the same situation and generate a response describing what they would say and/or do at that point. Results indicated that although alcohol and expectancy were not related to risk perception, individuals who consumed alcohol displayed significantly less resistant role play refusals. A significant interaction between expectancy set and pre-existing sex-related alcohol expectancies was observed indicating participants believing alcohol affects sexual behavior generated less resistant refusal responses when they expected to receive alcohol. Moreover, for those who expected to receive alcohol, stronger pre-existing sex-related alcohol expectancies predicted less resistant refusal responses over above the effects of blood alcohol level and general alcohol expectancies. The implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

Obtaining consistent and accurate rates of women's sexual assault experiences and men's history of sexual aggression has proved difficult and rates vary tremendously throughout the literature [Koss, M.P. (1993a). Detecting the scope of rape: A review of prevalence research methods. Journal of Interpersonal Violence, 8 (2), 198-222].It has been suggested that methodological factors influence the detection of women's sexual assault experiences and contribute to the rate disparities [Fisher, B. S., Cullen, F. T. & Turner, M. G. (2000). The sexual victimization of college women (NCJ 182369). Washington, DC: Bureau of Justice Statistics,National Institute of Justice.; Hamby, S. L. & Koss, M. (2003). Shades of gray: A quantitative study of terms used in the measurement of sexual victimization. Psychology of Women Quarterly, 27, 243-255.; Koss, M.P. (1993a). Detecting the scope of rape: A review of prevalence research methods. Journal of Interpersonal Violence, 8 (2), 198-222].Survey methods are commonly used in the assessment of women's experience with sexual assault victimization. Men's history of sexually aggressive behaviors is typically examined using parallel versions of the survey instruments used with women.While much is known about variables affecting the reliability, validity, and utility of these assessment methods when applied to women, less is known about the influence of these factors in the assessment of men's self-reported aggression. This paper discusses current sexual victimization and perpetration incidence and prevalence rates.An overview of the major sources of these data, as well as a review of the methodological factors known to influence levels of rape detection in women is presented. An examination of how these issues may be relevant in the measurement of male sexual aggression is discussed with suggestions for future research. [ABSTRACT FROM AUTHOR]

This study investigated the prevalence and nature of bullying and victimization utilizing a cross-sectional design, targeting children in grades 5, 6, and 10. Multiple measures of aggression and bullying/victimization were completed by children, parents, and teachers. Analyses revealed rates of bullying consistent with those observed in the literature. Consistent with expectations, males were rated overall as engaging in more fighting and overt aggression than females. However, contrary to expectations, no support was found for the notion that bullying behavior would decrease with age. Examination of gender differences suggested that in grade 6, boys demonstrated higher levels of overt bullying behavior, and in grade 10 girls exhibited higher levels of relational bullying behavior. Implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

Overt-relational and reactive-proactive subtypes of aggression have demonstrated a reliable network of relationships with social-adjustment variables and these variables have been shown to be effective predictors of future behavior problems and social maladjustment. In this study, the two measures representing these classification systems were examined and compared in terms of the internal structure of behavioral items used to reflect dimensions of aggressive behavior and their pattern of social-adjustment correlates. Results for the relational-overt measure (Children's Social Behavioral Scale) demonstrate findings consistent with previous research and provide additional construct validity for these subtypes. Within the present sample, the reactive-proactive measure failed to replicate the indicated two factors and examination of the social-adjustment relationships for proactive aggression produces unanticipated results. The implications of the findings are discussed. [ABSTRACT FROM AUTHOR]

Examined response decision processes of rejected-reactive aggressive, rejected-nonaggressive and average children in terms of the presence or absence of behavioral response alternatives. This study is an extension of the Dodge and Coie (1987) work. In the present study, 116 thirdand fourth-grade children were identified as rejected-reactive aggressive, rejected-nonaggressive, or average status on the basis of peer sociometric nominations and the Teacher Checklist of Social Behavior (Dodge & Coie, 1987). Of this sample, 75 children participated in a hypothetical situation task to assess assignment of intent and response decision processes. Congruent with previous research, rejected-reactive aggressive children made significantly more hostile attributions and generated a higher number of aggressive responses than nonaggressive peers. When presented with response alternatives, rejected-reactive aggressive children's selection of aggressive responses for hypothetical behavioral enactment declined significantly and they did not differ significantly from nonaggressive peers in their response decisions. Results are discussed in terms of developing potentially successful components for intervention programs with rejected-aggressive and rejected-nonaggressive youth. [ABSTRACT FROM AUTHOR]

Differences in the rate and quality of parent-child communication in parents of socially anxious and normal children 9-12-years-old were examined. Socially anxious and control children were videotapcd with their parents completing a puzzle task under three conditions, mother with child, father with child, and mother and father with child. Videotapes were coded for six types of verbalizations. Group differences were found in parents for frequency of total verhalizations, as well as frequency of types of verbalizations, with parents of anxious children using fewer total verbalizations, less positive feedback, and more negative feedback than control group parents. No difference was observed in the three observation conditions. Like their parents, socially anxious children engaged in fewer total verbalizations, and used more negative feedback and less positive feedback than control group children. Sequential analyses revealed that parents and children in the control group displayed similar patterns of communication in that they showed a strong tendency to mirror the quality of the other's verbalizations. Socially anxious children, like the control group children, tended to mirror the verbalizations of their parents. In contrast, parents of socially anxious children did not show the same similarities in responsiveness. Implications of the findings are discussed. [ABSTRACT FROM AUTHOR]

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. The objective response rate was 63.6% (21/33 participants). Median maximal PN volume decrease was 23.6% (range: -48.1% to 5.5%). No disease progression relative to baseline PN volumes occurred before data cutoff, with a median of 28 cycles completed (range: 1-78, 28 d per cycle). Participants experienced decreased tumor pain intensity and pain interference. Adverse events (AEs) were similar to those of the pediatric trial; acneiform rash was the most prevalent AE. Phosphorylation ratios of ERK1/2 decreased significantly (ERK1 median change: -64.6% (range: -99.5% to 90.7%), ERK2 median change: -57.3% (range: -99.9% to 84.4%)) in paired PN biopsies (P ≤ 0.001 for both isoforms) without compensatory phosphorylation of AKT1/2/3. The sustained PN volume decreases, associated improvement in pain and manageable AE profile indicate that selumetinib provides benefit to adults with NF1 and inoperable PNs. ClinicalTrials.gov identifier: NCT02407405 ., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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". Herein, we provide a suggested framework for adequate interventional radiology and surgical sampling, and recommend molecular profiling for clinically or radiologically worrisome non-cutaneous lesions in patients with NF1 to identify diagnostically-relevant molecular features, including CDKN2A/B inactivation for ANNUBP, as well as SUZ12, EED, or TP53 inactivating mutations, or significant aneuploidy for MPNST. We also propose renaming "low-grade MPNST" to "ANNUBP with increased proliferation" to avoid the use of the "malignant" term in this group of tumors with persistent unknown biologic potential. This refined integrated diagnostic approach for NF1-associated peripheral nerve sheath tumors should continue to evolve in concert with our understanding of these neoplasms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Neurofibromatosis type 1 (NF1), Noonan syndrome, and related syndromes, grouped as RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together, RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared with the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the past decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multidisciplinary care needed for such individuals, specifically those with NF1. This perspective, which originated from the 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop, serves to update pediatric oncologists, neurologists, geneticists, counselors, and other health care professionals on revised diagnostic criteria, review previously published surveillance guidelines, and harmonize updated surveillance recommendations for patients with NF1 or RASopathies., (©2024 American Association for Cancer Research.)

Purpose: Early detection of neurofibromatosis type 1 (NF1)-associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, enabling early definitive treatment and potentially averting deadly outcomes. In this study, we describe a cell-free DNA (cfDNA) fragmentomic approach that distinguishes nonmalignant, premalignant, and malignant forms of PNST in the cancer predisposition syndrome, NF1., Experimental Design: cfDNA was isolated from plasma samples of a novel cohort of 101 patients with NF1 and 21 healthy controls and underwent whole-genome sequencing. We investigated diagnosis-specific signatures of copy-number alterations with in silico size selection as well as fragment profiles. Fragmentomics were analyzed using complementary feature types: bin-wise fragment size ratios, end motifs, and fragment non-negative matrix factorization signatures., Results: The novel cohort of patients with NF1 validated that our previous cfDNA copy-number alteration-based approach identifies malignant PNST (MPNST) but cannot distinguish between benign and premalignant states. Fragmentomic methods were able to differentiate premalignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management., Conclusions: Novel cfDNA fragmentomic signatures distinguish AN from benign plexiform neurofibromas and MPNST, enabling more precise clinical diagnosis and management. This study pioneers the early detection of malignant and premalignant PNST in NF1 and provides a blueprint for decentralizing noninvasive cancer surveillance in hereditary cancer predisposition syndromes., (©2024 The Authors; Published by the American Association for Cancer Research.)

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. We evaluated variables that could impact height/weight including: (1) pNF volume, (2) pNF directed therapy, and (3) serum IGF-1., Results: 23% of males and 20% of females had height <5th percentile; 13% of males had weight <5th percentile. Estimated median final adult height for males was 171.6 cm (CDC 23rd percentile) and for females was 156.2 cm (CDC 14th percentile). Inverse associations between height and weight percentiles and pNF volume were observed (Spearman's r = -0.277, -0.216, respectively). Estimated median final height was not meaningfully affected by patients who received pNF-directed treatment with MEK inhibitor. 52% of low serum IGF-1 measurements were concurrent with a height percentile <5th., Conclusions: Greater than expected percentages of patients had height/weight <5th percentile, and median final adult heights were

Objective: This work sought to assess relationships between sexually aggressive behavior occurring through the use of technology and social media, perceived social norms of sexually aggressive behavior, and face-to-face sexual aggression and coercion. Participants: Participants were 663 undergraduate students (73.1% Female). Methods: Participants completed measures assessing perceived social norms of sexually aggressive strategies, personal sexual strategies used, alcohol use, cyberbullying, sexual victimization, personal wellbeing, and socially desirable responding. Results: Thirty percent of participants reported engaging in some form of sexually aggressive behavior offline; 15.6% endorsed engaging in sexual cyberbullying. However, 100% of participants endorsed the belief that their peers were engaging in some form of sexually aggressive behavior either online or offline. Conditional process modeling revealed a significant indirect effect of perceived social norms of sexually aggressive behavior on face-to-face sexual aggression via sexual cyberbullying ( b = .0015, p < .001, 95% CI [.0030, .0110]), indicating mediation. Conclusions: The present work highlights the importance of further research in the domain of sexual cyberbullying.

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. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies., (© 2024. The Author(s).)

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. Treatment for metastatic disease is limited to cytotoxic chemotherapy and investigational clinical trials. In this article, we review the pathophysiology of this aggressive cancer and current approaches to surveillance and treatment.

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. In SPRINT, the study team wanted to learn whether a medication called selumetinib was able to shrink the PN caused by NF1 (also known as NF1-related PN), and if shrinking PNs helped relieve children of the problems caused by it. To assess how selumetinib might help, children had scans to measure the size of their PN, completed questionnaires, and had a variety of other tests done by their doctor. Their caregivers also completed questionnaires about their child. The children took selumetinib capsules twice a day on an empty stomach., What Were the Results?: The results showed that selumetinib was able to shrink the PN for most children (68%). The results also showed that the problems caused by the children's PNs mostly improved while on selumetinib treatment. SPRINT also showed that the side effects of selumetinib were mainly mild and could be managed by doctors., What Do the Results Mean?: Before SPRINT, there were not many treatment options for children with NF1 and PN as there were no medications that had been shown to shrink PN, and surgery was not always possible. SPRINT showed that this medication shrinks most PNs and could help children with NF1 and PN. In April 2020, selumetinib was approved by the US Food and Drug Administration (FDA) because of the results of SPRINT. Selumetinib was the first and, as of February 2024, is the only medicine that can be prescribed by doctors to help children with NF1-related PN. Clinical Trial Registration : NCT01362803 (SPRINT) (ClinicalTrials.gov).

Background/aims: We developed an observer disfigurement severity scale for neurofibroma-related plexiform neurofibromas to assess change in plexiform neurofibroma-related disfigurement and evaluated its feasibility, reliability, and validity., Methods: Twenty-eight raters, divided into four cohorts based on neurofibromatosis type 1 familiarity and clinical experience, were shown photographs of children in a clinical trial (NCT01362803) at baseline and 1 year on selumetinib treatment for plexiform neurofibromas ( n  = 20) and of untreated participants with plexiform neurofibromas ( n  = 4). Raters, blinded to treatment and timepoint, completed the 0-10 disfigurement severity score for plexiform neurofibroma on each image (0 = not at all disfigured, 10 = very disfigured). Raters evaluated the ease of completing the scale, and a subset repeated the procedure to assess intra-rater reliability., Results: Mean baseline disfigurement severity score for plexiform neurofibroma ratings were similar for the selumetinib group (6.23) and controls (6.38). Mean paired differences between pre- and on-treatment ratings was -1.01 (less disfigurement) in the selumetinib group and 0.09 in the control ( p  = 0.005). For the disfigurement severity score for plexiform neurofibroma ratings, there was moderate-to-substantial agreement within rater cohorts (weighted kappa range = 0.46-0.66) and agreement between scores of the same raters at repeat sessions ( p  > 0.05). In the selumetinib group, change in disfigurement severity score for plexiform neurofibroma ratings was moderately correlated with change in plexiform neurofibroma volume with treatment ( r  = 0.60)., Conclusion: This study demonstrates that our observer-rated disfigurement severity score for plexiform neurofibroma was feasible, reliable, and documented improvement in disfigurement in participants with plexiform neurofibroma shrinkage. Prospective studies in larger samples are needed to validate this scale further., Competing Interests: Declaration of conflicting interestsDr B.C.W. and Dr A.M.G. have unpaid advisory roles for AstraZeneca and SpringWorks. Dr M.J.F. has paid advisory roles for AstraZeneca and SpringWorks and research support from AstraZeneca, Array BioPharma, and Exelixis for plexiform neurofibroma clinical trials. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Dr M. B. has a paid advisory role on the external advisory board for the Koselugo Registry through Alexion.

Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 101 NF1 patients and 21 healthy controls, we validated that our previous cfDNA copy number alteration (CNA)-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. We therefore investigated the ability of fragment-based cfDNA features to differentiate NF1-associated tumors including binned genome-wide fragment length ratios, end motif analysis, and non-negative matrix factorization deconvolution of fragment lengths. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Overall, this study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 patients using plasma cfDNA fragmentomics. In addition to screening applications, this novel approach distinguishes atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management., Competing Interests: Disclosures: R.T.S., J.J.S., A.A.C., A.C.H., A.P, and J.F.S. have patent filings related to cancer biomarkers. A.A.C has served as a consultant/advisor to Roche, Tempus, Geneoscopy, NuProbe, Daiichi Sankyo, AstraZeneca, Fenix Group International and Guidepoint. A.A.C. has received honoraria from Agilent, Roche, and Dava Oncology. A.A.C. has stock options in Geneoscopy, research support from Roche, Illumina and Tempus, and ownership interests in Droplet Biosciences and LiquidCell Dx. A.C.H. has served on advisory boards for AstraZeneca/Alexion and Springworks Therapeutics. A.E.A. has served as a consultant for Springworks Therapeutics and has served on advisory boards for Alexion. C.A.P. has served as a consultant for Day One Biopharmaceuticals, and has research support from Kura Oncology and Novartis Institute for Biomedical Research, and has patent filings related to cancer biomarkers and treatment. No potential conflicts of interest were disclosed by the other authors.

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. As a result, progress has been slow for many of these cancers. While rare cancer research efforts have increased over time, the breadth of the research landscape is not known. A recent literature search revealed a sharp increase in rare tumor, and rare cancer publications began in the early 2000s. To identify rare cancer research efforts being conducted in the US and globally, we conducted an online search of rare tumor/rare cancer research programs and identified 76 programs. To gain a deeper understanding of these programs, we composed and conducted a survey to ask programs for details about their research efforts. Of the 42 programs contacted to complete the survey, 23 programs responded. Survey results show most programs are collecting clinical data, molecular data, and biospecimens, and many are conducting molecular analyses. This landscape analysis demonstrates that multiple rare cancer research efforts are ongoing, and the rare cancer community may benefit from collaboration among stakeholders to accelerate research and improve patient outcomes., (Published by Oxford University Press 2023.)

Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Neurofibromatosis type 1 is a genetic syndrome characterized by a wide variety of tumor and non-tumor manifestations. Bone-related issues, such as scoliosis, tibial dysplasia, and low bone mineral density, are a significant source of morbidity for this population with limited treatment options. Some of the challenges to developing such treatments include the lack of consensus regarding the optimal methods to assess bone health in neurofibromatosis type 1 and limited data regarding the natural history of these manifestations. In this review, the Functional Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration: (1) presents the available techniques for measuring overall bone health and metabolism in persons with neurofibromatosis type 1, (2) reviews data for use of each of these measures in the neurofibromatosis type 1 population, and (3) describes the strengths and limitations for each method as they might be used in clinical trials targeting neurofibromatosis type 1 bone manifestations. The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration supports the development of a prospective, longitudinal natural history study focusing on the bone-related manifestations and relevant biomarkers of neurofibromatosis type 1. In addition, we suggest that the neurofibromatosis type 1 research community consider adding the less burdensome measurements of bone health as exploratory endpoints in ongoing or planned clinical trials for other neurofibromatosis type 1 manifestations to expand knowledge in the field., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AMG and LJK have served as unpaid advisors for AstraZeneca/Alexion; AMG has been an unpaid advisor for SpringWorks Therapeutics. DAS has been a paid consultant for Alexion. HS is CEO of Infixion Bioscience, Inc., a pharmaceutical R&D company targeting NF1.

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., Methods: This manuscript includes data from the phase 1 and phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety and efficacy data through February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) ≥20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (pain interference index)., Results: For the 74 children (median age 10.3 years; range 3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment., Conclusions: With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2023.)

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. Patients with MAS with CDKN2A germline pathogenic variants and 1 or more neural tumors were included. Data were analyzed from June 1, 2022, to January 31, 2023., Main Outcomes and Measures: Disease prevalence and tumor frequency., Results: Prevalence of MAS ranged from 1 in 170 503 (n = 1 case; 95% CI, 1:30 098-1:965 887) in Geisinger MyCode (n = 170 503; mean [SD] age, 58.9 [19.1] years; 60.6% women; 96.2% White) to 1 in 39 149 (n = 12 cases; 95% CI, 1:22 396-1:68 434) in UK Biobank (n = 469 789; mean [SD] age, 70.0 [8.0] years; 54.2% women; 94.8% White). Among UK Biobank patients with MAS (n = 12) identified using an unbiased genomic ascertainment approach, brain neoplasms (4 of 12, 33%; 1 glioblastoma, 1 gliosarcoma, 1 astrocytoma, 1 unspecified type) and schwannomas (3 of 12, 25%) were the most common malignant and benign neural tumors, while cutaneous melanoma (2 of 12, 17%) and head and neck squamous cell carcinoma (2 of 12, 17%) were the most common nonneural malignant neoplasms. In a separate case series of 14 patients with MAS from the US and Europe, brain neoplasms (4 of 14, 29%; 2 glioblastomas, 2 unspecified type) and malignant peripheral nerve sheath tumor (2 of 14, 14%) were the most common neural cancers, while cutaneous melanoma (4 of 14, 29%) and sarcomas (2 of 14, 14%; 1 liposarcoma, 1 unspecified type) were the most common nonneural cancers. Cutaneous neurofibromas (7 of 14, 50%) and schwannomas (2 of 14, 14%) were also common. In 1 US family, a father and son with MAS had clinical diagnoses of neurofibromatosis type 1 (NF1). Genetic testing of the son detected a pathogenic CDKN2A splicing variant (c.151-1G>C) and was negative for NF1 genetic alterations. In UK Biobank, 2 in 150 (1.3%) individuals with clinical NF1 diagnoses had likely pathogenic variants in CDKN2A, including 1 individual with no detected variants in the NF1 gene., Conclusions and Relevance: This cohort study estimates the prevalence and describes the tumors of MAS. Additional studies are needed in genetically diverse populations to further define population prevalence and disease phenotypes.

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). Testing included pure tone and speech audiometry, middle ear function, neurodiagnostic auditory brainstem response (ABR), auditory processing, and MRIs of the head and neck region. Patients referred to this study had an overall higher incidence and burden of PNs than the overall NF1 population., Results: The majority of subjects in this cohort had normal hearing sensitivity (81%) and normal middle ear function (78%). Nineteen participants had hearing loss that ranged in degree from mild to profound, with the majority in the mild range. Hearing loss was twice as likely to be conductive than sensorineural. In patients with ear-related PNs (n = 12), hearing loss was predominantly conductive (60%). Seventy-five percent of ears with PNs had atypical tympanometric tracings that could not be characterized by the classic categories. In all 20 patients with a PN in the temporal bone, the ear canal was affected, and the PNs often extended to the surrounding soft tissue regions., Conclusions: People with NF1-related PNs in the temporal bone and adjacent skull base should have audiometric and otologic monitoring. Addressing hearing concerns should be part of routine clinical evaluations in patients with NF1. Magnetic resonance imaging (MRI) should be performed in patients with NF1 who have hearing loss., Level of Evidence: 3 Laryngoscope, 133:2770-2778, 2023., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA.)

Purpose: Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701)., Patients and Methods: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT)., Results: Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response., Conclusions: The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months., (©2023 American Association for Cancer Research.)

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., Methods: Using the results of a prior systematic review, 10 key questions that required further assessment were first identified. A committee of 20 experts across medical specialties was then chosen based on their clinical experience with spinal deformity and tumors in NF1. These were 9 orthopaedic surgeons, 4 neuro-oncologists/oncologists, 3 neurosurgeons, 2 neurologists, 1 pulmonologist, and 1 clinical geneticist. An initial online survey on current practices and opinions was conducted, followed by 2 additional surveys via a formal consensus-based modified Delphi method. The final survey involved voting on agreement or disagreement with 35 recommendations. Items reaching consensus (≥70% agreement or disagreement) were included in the final BPGs., Results: Consensus was reached for 30 total recommendations on the management of spinal deformity and tumors in NF1. These were 11 recommendations on screening and surveillance, 16 on surgical intervention, and 3 on medical therapy. Five recommendations did not achieve consensus and were excluded from the BPGs., Conclusion: We present a set of consensus-based BPGs comprised of 30 recommendations for spinal screening and surveillance, surgical intervention, and medical therapy in pediatric NF1., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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 multidisciplinary NF1 experts., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2022.)

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. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits 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., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2022.)

Background: Selumetinib was recently approved for the treatment of inoperable symptomatic plexiform neurofibromas (PNs) in children with neurofibromatosis type 1 (NF1). This parallel phase II study determined the response rate to selumetinib in children with NF1 PN without clinically significant morbidity., Methods: Children with NF1 and inoperable PNs, which were not yet causing clinically significant morbidity but had the potential to cause symptoms, received selumetinib at 25 mg/m2 orally twice daily (1 cycle = 28 days). Volumetric magnetic resonance imaging analysis and outcome assessments, including patient-reported (PRO), observer-reported, and functional outcome measures were performed every 4 cycles for 2 years, with changes assessed over time. A confirmed partial response (cPR) was defined as PN volume decrease of ≥20% on at least 2 consecutive scans ≥3 months apart., Results: 72% of subjects experienced a cPR on selumetinib. Participants received selumetinib for a median of 41 cycles (min 2, max 67) at data cutoff. Approximately half of the children rated having some target tumor pain at baseline, which significantly decreased by pre-cycle 13. Most objectively measured baseline functions, including visual, motor, bowel/bladder, or airway function were within normal limits and did not clinically or statistically worsen during treatment., Conclusions: Selumetinib resulted in PN shrinkage in most subjects with NF1 PN without clinically significant morbidity. No new PN-related symptoms developed while on selumetinib, and PRO measures indicated declines in tumor-related pain intensity. This supports that selumetinib treatment may prevent the development of PN-related morbidities, though future prospective studies are needed to confirm these results., Clinical Trial Registration: ClinicalTrials.gov NCT01362803., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2022.)

Purpose: Chemotherapy-induced nausea and vomiting (CINV) is a frequently seen burdensome adverse event of cancer therapy. The 5-HT3 receptor antagonist ondansetron has improved the rates of CINV but, unfortunately, up to 30% of patients do not obtain satisfactory control. This study examined whether genetic variations in a relevant drug-metabolizing enzyme (CYP2D6), transporter (ABCB1), or receptor (5-HT3) were associated with ondansetron failure., Methods: DNA was extracted from blood and used to genotype: ABCB1 (3435C > T (rs1045642) and G2677A/T (rs2032582)), 5-HT3RB (rs3758987 T > C and rs45460698 (delAAG/dupAAG)), and CYP2D6 variants. Ondansetron failure was determined by review of the medical records and by patient-reported outcomes (PROs)., Results: One hundred twenty-nine patients were approached; 103 consented. Participants were less than 1 to 33 years (mean 6.85). A total of 39.8% was female, 58.3% was White (22.3% Black, 19.4% other), and 24.3% was Hispanic. A majority had leukemia or lymphoma, and 41 (39.8%) met the definition of ondansetron failure. Of variants tested, rs45460698 independently showed a significant difference in risk of ondansetron failure between a mutant (any deletion) and normal allele (p = 0.0281, OR 2.67). Age and BMI were both predictive of ondansetron failure (age > 12 (OR 1.12, p = 0.0012) and higher BMI (OR 1.13, p = 0.0119)). In multivariate analysis, age > 12 was highly predictive of ondansetron failure (OR 7.108, p = 0.0008). rs45460698 was predictive when combined with an increased nausea phenotype variant of rs1045642 (OR 3.45, p = 0.0426)., Conclusion: Select phenotypes of 5-HT3RB and ABCB1, age, and potentially BMI can help predict increased risk for CINV in a diverse pediatric oncology population., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: As part of an evaluation of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration patient representative program, we surveyed REiNS members to (1) identify facilitators and barriers to involving patient representatives and (2) understand whether and how involving patient representatives affected recommendations for clinical trial outcomes., Methods: We administered an anonymous online survey to all REiNS members. Facilitators and barriers to patient representative involvement were solicited using a modified free listing technique; responses were inductively grouped into higher-order categories and ranked based on saliency score (Smith s ). Open-ended questions assessed patient representative expectations for engagement, perceived benefits/costs of patient engagement, and patient representative contributions; responses were analyzed using conventional content analysis., Results: A total of 63/172 (37%) members responded, including 18/30 (60%) patient representatives. Providing sufficient opportunities to meaningfully engage in research tasks and cultivating a respectful, inclusive atmosphere were key facilitators to patient representatives' satisfaction and ability to make an impact. Respondents perceived that patient representatives directly (through their input on research tasks) and indirectly (through effects on other stakeholders' knowledge and communication style) improved the organization's research, leading to selection of more meaningful, relevant, and feasible clinical trial outcome measures. Ongoing challenges to patient engagement include difficulty scheduling meetings and concerns about the level of scientific knowledge patient representatives needed to effectively engage., Conclusions: Involving patient representatives in REiNS improved perceived quality of neurofibromatosis clinical trial outcome measures. Negotiating sufficient opportunities to engage, fostering an inclusive atmosphere, and navigating time pressures are key to effective patient engagement., (© 2021 American Academy of Neurology.)

Objective: To determine a suitable outcome measure for assessing muscle strength in neurofibromatosis (NF) type 1 and NF2 clinical trials, we evaluated the intraobserver reliability of handheld dynamometry (HHD) and developed consensus recommendations for its use in NF clinical trials., Methods: Patients ≥5 years of age with weakness in at least 1 muscle group by manual muscle testing (MMT) were eligible. Maximal isometric muscle strength of a weak muscle group and the biceps of the dominant arm was measured by HHD. An average of 3 repetitions per session was used as an observation, and 3 sessions with rest period between each were performed on the same day by a single observer. Intrasession and intersession intraclass correlation coefficients (ICCs) and coefficients of variation (CVs) were calculated to assess reliability and measurement error., Results: Twenty patients with NF1 and 13 with NF2 were enrolled; median age was 12 years (interquartile range [IQR] 9-17 years) and 29 years (IQR 22-38 years), respectively. By MMT, weak muscle strength ranged from 2-/5 to 4+/5. Biceps strength was 5/5 in all patients. Intersession ICCs for the weak muscles were 0.98 and 0.99 in the NF1 and NF2 cohorts, respectively, and for biceps were 0.97 and 0.97, respectively. The median CVs for average session strength were 5.4% (IQR 2.6%-7.3%) and 2.9% (IQR 2.0%-6.2%) for weak muscles and biceps, respectively., Conclusion: HHD performed by a trained examiner with a well-defined protocol is a reliable technique to measure muscle strength in NF1 and NF2. Recommendations for strength testing in NF1 and NF2 trials are provided., (© 2021 American Academy of Neurology.)