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. 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).

Development and pilot validation of a novel disfigurement severity scale for plexiform neurofibromas in children with neurofibromatosis type 1.

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.

Recommendations for assessing appearance concerns related to plexiform and cutaneous neurofibromas in neurofibromatosis 1 clinical trials.

BACKGROUND/AIMS: Individuals with neurofibromatosis 1 may experience changes in their appearance due to physical manifestations of the disorders and/or treatment sequelae. Appearance concerns related to these physical changes can lead to psychological distress and poorer quality of life. While many neurofibromatosis 1 clinical trials focus on assessing changes in tumor volume, evaluating patients' perspectives on corresponding changes in symptoms such as physical appearance can be key secondary outcomes. We aimed to determine whether any existing patient-reported outcome measures are appropriate for evaluating changes in appearance concerns within neurofibromatosis 1 clinical trials. METHODS: After updating our previously published systematic review process, we used it to identify and rate existing patient-reported outcome measures related to disfigurement and appearance. Using a systematic literature search and initial triage process, we focused on identifying patient-reported outcome measures that could be used to evaluate changes in appearance concerns in plexiform or cutaneous neurofibroma clinical trials in neurofibromatosis 1. Our revised Patient-Reported Outcome Rating and Acceptance Tool for Endpoints then was used to evaluate each published patient-reported outcome measures in five domains, including (1) respondent characteristics, (2) content validity, (3) scoring format and interpretability, (4) psychometric data, and (5) feasibility. The highest-rated patient-reported outcome measures were then re-reviewed in a side-by-side comparison to generate a final consensus recommendation. RESULTS: Eleven measures assessing appearance concerns were reviewed and rated; no measures were explicitly designed to assess appearance concerns related to neurofibromatosis 1. The FACE-Q Craniofacial Module-Appearance Distress scale was the top-rated measure for potential use in neurofibromatosis 1 clinical trials. Strengths of the measure included that it was rigorously developed, included individuals with neurofibromatosis 1 in the validation sample, was applicable to children and adults, covered item topics deemed important by neurofibromatosis 1 patient representatives, exhibited good psychometric properties, and was feasible for use in neurofibromatosis 1 trials. Limitations included a lack of validation in older adults, no published information regarding sensitivity to change in clinical trials, and limited availability in languages other than English. CONCLUSION: The Response Evaluation in Neurofibromatosis and Schwannomatosis patient-reported outcome working group currently recommends the FACE-Q Craniofacial Module Appearance Distress scale to evaluate patient-reported changes in appearance concerns in clinical trials for neurofibromatosis 1-related plexiform or cutaneous neurofibromas. Additional research is needed to validate this measure in people with neurofibromatosis 1, including older adults and those with tumors in various body locations, and explore the effects of nontumor manifestations on appearance concerns in people with neurofibromatosis 1 and schwannomatosis.

Selumetinib in Children with Inoperable Plexiform Neurofibromas.

BACKGROUND: No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS: We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS: A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia. CONCLUSIONS: In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).

Adolescents and young adults with neurofibromatosis type 1: A descriptive study of adaptive functioning.

Neurofibromatosis type 1 (NF1) is a genetic syndrome affecting about 1 in 3500 individuals; many of those affected have plexiform neurofibroma (pNF) tumors and associated symptoms and complications. Furthermore, learning and attention problems, as well as deficits in adaptive functioning, are common, often beginning in early childhood. This study aimed to describe adaptive functioning and to examine relationships between adaptive functioning and cognitive and academic variables and level of independence among adolescents and young adults (AYA) with NF1 and pNF tumors. Fifty-five AYA aged 16-31 years participated in a series of neuropsychological evaluations while parents completed the Vineland Adaptive Behavior Scales (VABS-II) as part of a larger natural history study. Over one-third (35%) of AYA were neither in school nor employed. Mean VABS-II daily living and socialization scores were low average while mean Verbal and Performance IQ scores were average. VABS-II scores were positively correlated with processing speed, executive functioning, and working memory scores. Verbal IQ was the only significant predictor of work/school status. Identification of the correlates and predictors of adaptive functioning and life achievement can help guide healthcare providers with the early identification of risk factors and possible areas for intervention.

Predictors of cognitive development in children with neurofibromatosis type 1 and plexiform neurofibromas.

AIM: To describe the cognitive development of children with neurofibromatosis type 1 (NF1) and plexiform neurofibromas, and identify predictors of cognitive development. METHOD: Participants included 88 children with NF1 and plexiform neurofibromas (50 males, 38 females, aged 6-18y, mean=12y, SD=3y 7mo) on a natural history study at the National Cancer Institute. Neuropsychological assessments (e.g. IQ, academic achievement, attention, and executive functioning) were administered three times over 6 years. RESULTS: Relative to normative peers, the total sample of children with NF1 and plexiform neurofibromas demonstrated significantly lower scores in most cognitive domains and decreasing z-scores over time in math, writing, inhibitory control, and working memory. Children who had parents with (vs without) NF1 were more likely to experience decreased z-scores in performance IQ, reading, writing, attention, and working memory. Higher (vs lower) parental education was related to higher levels of IQ, math, reading, and cognitive flexibility and a slower decrease in math z-scores. Children's sex and the number of NF1 disease-related complications were not related to most cognitive outcomes. INTERPRETATION: Children with NF1 and plexiform neurofibromas are at high risk for cognitive difficulties and declining z-scores in various domains of cognitive functioning over time. The findings highlight the need for a better understanding of the within-group differences in these children and their need for individualized educational plans. WHAT THIS PAPER ADDS: Math, writing, inhibitory control, and working memory scores decreased over time. The proportion of children with clinically significant cognitive deficits increased over time. Parental neurofibromatosis type 1 and low education were related to greater cognitive difficulties in children.

Supporting partners of mothers with severe mental illness through text - a feasibility study.

OBJECTIVE: During the perinatal period, partners of mothers with severe mental illness (SMI) play an important role in managing the new baby and supporting the mothers' wellbeing. Providing information via mobile phone on infant care, partner support and self-care may assist partners in their support role. METHOD: Partners (n = 23) of mothers with SMI were enrolled in a partner-focused SMS service sending brief texts 14 times per month for a maximum of 10 months. Partners (n = 16) were interviewed on exit and their responses analysed for acceptability and perceived usefulness of the texts. RESULTS: Partners remained with the programme and expressed high acceptability of the texts. Participants identified effects such as increased knowledge of and interaction with their baby; effective support for their partner; and reassurance that 'things were normal'. Few partners sought support for their own mental health. CONCLUSIONS: Texts supplied to mobile phones of partners of new mothers with SMI may increase partners' support. The texts in this study were acceptable to partners and were reported to enhance a partner's focus on the mother's needs, raise the partner's awareness of the infant's needs, and support the partner's confidence and competence in infant care.

Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas.

BACKGROUND: Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling. METHODS: We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. RESULTS: A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. CONCLUSIONS: Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).

Identifying Symptoms of Distress in Youth Living with Neurofibromatosis Type 1 (NF1).

Children and adolescents with Neurofibromatosis type 1 (NF1) are at increased risk for wide-ranging behavioral, developmental, and cognitive impairments and decreased quality of life. To date, no psychosocial screening tool has been developed to quickly assess the symptoms that 1) can be addressed during routine medical appointments in children with NF1, 2) can produce interpretable and actionable results, 3) can be integrated into medical care, and 4) can quickly identify patients at risk in order to better address that the provision of appropriate care are available. This study was conducted to test the overall usability of the Distress Thermometer (DT) and symptom checklist and concordance of DT ratings between pediatric patients, their caregivers and medical providers. Eighty youth (ages 7-21) living with NF1 completed the DT and an accompanying checklist. The findings of this study suggest the DT and symptom checklist was acceptable and feasible to complete in a clinic setting. A small subset reported high distress that required further assessment and intervention. Significant discordance between distress ratings of caregivers and children and healthcare providers was also found. Overall, the DT and accompanying symptom checklist provide important information to identify the presence of distress and contextualize the child's distress but is limited by not assessing whether these symptoms interfere with the child's daily life.

The Relationship Between Heart Rate Variability, Psychological Flexibility, and Pain in Neurofibromatosis Type 1.

Individuals with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) can experience chronic pain. Previous research has examined the relationship between heart rate variability (HRV) and persistent pain. HRV is an index of autonomic nervous system functioning, and reflects the variability in time elapsed between heartbeats. Patients with chronic pain tend to exhibit lower HRV, which has been associated with poor adaptability, or psychological flexibility, to stress. The aim of the current study was to examine relationships between HRV, psychological flexibility, and pain in a sample of adolescents and young adults (AYAs) with NF1 and PNs. AYA participants (n = 40) 16 to 34 years of age with NF1 completed baseline measures of pain and psychological functioning, and underwent a 5-minute electrocardiogram (ECG). A subset of 20 participants completed follow-up questionnaires and a second ECG 8 weeks later. Spectral analyses of ECGs yielded a measure of high-frequency heart rate variability (HF-HRV). Baseline correlations revealed that lower HF-HRV is related to greater inflexibility and more pain interference, but not pain intensity. Moreover, psychological inflexibility significantly mediated the relationship between HF-HRV and pain interference. Finally, regression models indicated that baseline psychological inflexibility is a significant predictor of HF-HRV at follow-up and, separately, that baseline HF-HRV significantly predicted pain intensity at follow-up. These findings suggest complex mind-body processes in the experience of pain in NF1, which have not been studied previously. Implications for pain-related interventions and future research are discussed.

Genetic modifiers of neurofibromatosis type 1-associated café-au-lait macule count identified using multi-platform analysis.

Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM) count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161) between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B) were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6) was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count.

Acceptance and commitment therapy in youth with neurofibromatosis type 1 (NF1) and chronic pain and their parents: A pilot study of feasibility and preliminary efficacy.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder affecting about 1 in 3,500 individuals. Chronic pain is commonly reported among individuals with NF1 and plexiform neurofibroma tumors (PNs). Acceptance and Commitment Therapy (ACT), an empirically supported method for addressing chronic pain, helps individuals re-focus on valued relationships and activities. This pilot study investigated the feasibility and preliminary efficacy of a brief ACT workshop in the NF1 population. Eligible participants included adolescents and young adults (AYA; 12-21 years) with NF1 and chronic pain that interfered with daily functioning and their parents. Patients and parents completed baseline measures of pain interference, pain intensity, functional disability, pain acceptance, depression, and anxiety. Then, AYA and parents participated separately in a 2-day small-group ACT workshop. A telephone booster session occurred 1 month post-intervention. Three-month post-treatment measures were completed by mail. Ten adolescents (4 males; M age = 16.9 years) and seven parents provided baseline and 3-month data. Mean satisfaction with the study was moderate to high (3.9 for patients and 4.6 for parents on a 1-5 scales). Patients and parents reported significant declines in patients' pain interference at 3 months post-treatment. Patient-reported pain intensity significantly declined from baseline to 3 months. Parents reported marginally greater acceptance of their child's pain. No changes emerged in functional ability or mood. Preliminary findings suggest that a brief ACT group intervention is feasible and may help AYA with NF1 and PNs cope with their chronic pain, although larger randomized studies are needed to confirm treatment efficacy. © 2016 Wiley Periodicals, Inc.

Pain interference in youth with neurofibromatosis type 1 and plexiform neurofibromas and relation to disease severity, social-emotional functioning, and quality of life.

The physical manifestations of neurofibromatosis type 1 (NF1) can cause chronic pain. This study investigated the impact of pain in youth with NF1 and plexiform neurofibromas (PNs) and its relationship to disease factors, social-emotional functioning, and quality of life (QOL) within a biopsychosocial framework. Caregivers of 59 children and adolescents with NF1 and PNs (6-18 years), and 41 of these youth (10-18 years), completed questionnaires assessing social-emotional functioning and QOL, including an item on pain interference. Measures of disease severity included total PN volume by percent body weight and number of disease complications. Both caregiver (73%) and self-report (59%) ratings indicated that pain interferes with the child's daily functioning despite 33% taking pain medication. Based on caregivers' behavior ratings, more symptoms of anxiety and larger tumor volumes predicted greater pain interference, while greater pain interference, worse depressive symptoms, and more disease complications predicted poorer QOL. As rated by adolescents, more symptoms of anxiety predicted greater pain interference, while greater pain interference and social stress predicted poorer QOL. Further, social-emotional problems mediate the relationship between pain interference and QOL. Thus, pain interferes with daily functioning in the majority of youth with NF1 and PNs even when using pain medication. The impact of pain interference, disease severity, and particularly social-emotional problems on QOL highlights the interaction between physical and psychological states in NF1. Future research and treatment of pain in this population should utilize a biopsychosocial approach and involve multidisciplinary therapies including psychological interventions that target social-emotional functioning.

Characterization of spinal findings in children and adults with neurofibromatosis type 1 enrolled in a natural history study using magnetic resonance imaging.

To characterize spinal abnormalities in patients with neurofibromatosis type 1 (NF1) using magnetic resonance imaging (MRI). NF1 patients with at least one spine MRI were selected from participants prospectively enrolled in the National Cancer Institute NF1 Natural History Study. Data were analyzed retrospectively. Ninety-seven patients (38 females, median age 14.2 years, standard deviation [SD] 7.6) had baseline imaging of the spine, and 26 patients (27 %) had one follow-up spine MRI (follow up time 2.5 years, SD 1.1, range 0.7-4.7). Seventy-eight patients (80 %) had spinal neurofibromas, with rising frequency from 70 % in patients younger than 10 years to 80 % in patients aged 10-18 years to 89 % in individuals older than 18 years of age. At baseline, 33/97 patients (34 %) had MRI changes consistent with spinal cord compression that was most prevalent at the cervical (43 %) and lumbar spine region (40 %). Seven of nine patients with progression of their spinal neurofibromas developed cord compression. Paraspinal plexiform neurofibromas (PNs) were present in 77/97 patients (79 %), of which 68 patients (88 %) had concomitant spinal neurofibromas. Spinal curvature abnormality was present in 50/97 patients (51 %, 20 females, median age 14.6 years, SD 7.6). Patients with paraspinal PNs had six-fold higher odds of developing spinal curvature abnormalities compared to patients without PN (OR = 5.9, 95 % CI 1.81 to 19.44, p = 0.0033). A total of 58/97 patients (60 %, median age 16.1 years, SD 7.8, range 4.8-48.2 years) presented with neurologic abnormalities that progressed in 12/26 patients (46 %). Substantial spinal neurofibroma and paraspinal PN burden was observed in our study population, which represents a selective group of patients with specifically more severe tumor involvement than the general NF1 population. Occurrence and progression of spinal neurofibromas on repeat evaluations highlight the need for longitudinal clinical monitoring in patients with known spinal disease.

Development and validation of the English Pain Interference Index and Pain Interference Index-Parent report.

OBJECTIVE: Measurement of pain interference in children is challenged by a lack of validated measures with a parent proxy report. This study investigated the psychometric properties of the Pain Interference Index (PII), a six-item questionnaire originally developed in Swedish, in chronically ill youth. METHODS: We adapted the PII for English-speaking participants and created a parallel parent proxy measure. Respondents indicate how much pain has interfered with the child's life in the past 2 weeks (0-6 scale); higher scores indicate more pain interference. Eligible participants included individuals 6-25 years with neurofibromatosis type 1 (NF1) and cancer. Internal consistency was assessed; validity was examined by correlating PII scores with existing measures of pain interference (Modified Brief Pain Inventory [MBPI]) and pain intensity (visual analogue scale [VAS]), and with measures of disease severity. RESULTS: Among 60 participants (mean age 14.7 years, range 6-24) and their parents, PII internal consistency was 0.84 and 0.96, respectively. PII scores correlated with MBPI (r = 0.81, P < 0.0001) and VAS (r = 0.55, P < 0.0001) scores and differentiated between patients with mild vs moderate/severe NF1 disease severity (P < 0.05). The PII-Parent was significantly correlated with the mothers' and fathers' VAS rating of the child's pain intensity (Ps < 0.01). CONCLUSIONS: Internal consistency of the English PII is high; validity is supported by the PII's correlations with other measures of pain interference and pain intensity, and with disease severity in patients with NF1. Preliminary data indicate that the English PII is a reliable, valid, feasible pain interference measure for youth with NF1 and cancer.

Puberty and plexiform neurofibroma tumor growth in patients with neurofibromatosis type I.

OBJECTIVE: To assess the relationship between pubertal progression and change in plexiform neurofibroma (PN) burden over time in pediatric and young adult patients with neurofibromatosis type 1 and PNs. STUDY DESIGN: Analyses accounted for sex, age, race, and chemotherapy. Forty-one patients with neurofibromatosis type 1 (15 female and 26 male patients) were studied at the National Institutes of Health. Tanner stage, testosterone, progesterone, estradiol, insulin-like growth factor -1, luteinizing hormone, and follicle-stimulating hormone were assessed. Tumor volume was measured using magnetic resonance imaging and lesion detection software developed locally. Patients were divided into 2 groups based on whether they were actively progressing through puberty (n = 16) or were peripubertal (n = 25) and were followed for an average of 20 months. Tumor growth rates in the puberty and peripubertal group were analyzed for a subset of patients. RESULTS: There was no statistically significant difference in tumor burden change over time (cm(2)/kg per month) between the pubertal and peripubertal groups (-0.16 ± 0.34 vs 0.03 ± 1.8, P = .31) and in the PN growth rates before and during puberty (P = .90). Change in tumor volume/patient weight/time did not correlate with testosterone change/time in males or estradiol change/time in females. CONCLUSION: These findings support that hormonal changes of puberty do not accelerate PN growth. Additional long-term follow-up of patients is necessary to further characterize the interaction between puberty and tumor growth.

Attitudes about internet support groups among adolescents and young adults with neurofibromatosis type 1 and their parents.

Youth with neurofibromatosis type 1 (NF1) have multiple, complex symptoms associated with physical, social-emotional, and cognitive difficulties. In addition, caring for a child with NF1 can be extremely challenging for parents. Since research with other chronic illness populations suggests that social support, including internet support groups (ISGs), can be beneficial, this survey study aimed to determine the attitudes and preferences of adolescents and young adults with NF1 and parents of a child with NF1 regarding ISGs. Thirty patients and 30 caregivers completed a 24-item survey about ISGs. Many patients and parents are not aware of any ISGs for NF1, but are interested in using one in the future for a variety of reasons, including to get answers to their questions about NF1, to find out about research studies, and to discuss problems and concerns about NF1. Specific concerns of interest include physical, social-emotional, and cognitive aspects of NF1. ISGs have potential as a social support intervention within the NF1 community. ISGs for the NF1 population should include patients with NF1 (or parents of children with NF1) as well as a health professional, and both chat rooms and discussion boards likely would be well-received.

18-fluorodeoxyglucose-positron emission tomography (FDG-PET) evaluation of nodular lesions in patients with Neurofibromatosis type 1 and plexiform neurofibromas (PN) or malignant peripheral nerve sheath tumors (MPNST).

BACKGROUND: Individuals with Neurofibromatosis type 1 (NF1) are at risk for developing malignant peripheral nerve sheath tumors (MPNST), which frequently arise in preexisting plexiform neurofibromas (PN). Magnetic resonance imaging (MRI) with volumetric analysis and 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) were utilized to monitor symptomatic nodular lesions. PROCEDURE: Patients with NF1 and PN on a NCI natural history trial were monitored for total body tumor volume (TTV) using volumetric MRI. FDG-PET was performed in individuals with a nodular well-demarcated lesion ≥3 cm if they were growing, painful, or there was a prior history of MPNST (target lesions). Asymptomatic nodular lesions were evaluated as non-target lesions. RESULTS: Fifteen patients (8m, 7f) median age of 18.3 years (range, 10-45 years) had a single target and non-target (n = 46) nodular lesions identified on MRI. Target lesions arose within (n = 8) or outside (n = 3) a PN, and all but 1 had increased FDG uptake. FDG uptake was increased in non-target lesions but to a lesser degree. FDG uptake in the surrounding PN was low, similar to background activity. Pathologic evaluation performed in 11 patients demonstrated neurofibroma (n = 6), atypical neurofibroma (n = 2) and malignancy (n = 3). CONCLUSIONS: Nodular target lesions identified on MRI in individuals with NF1 and PN demonstrate increased FDG uptake similar to MPNST, but may be benign on biopsy. Nodular target lesions may be at greater risk for malignant transformation, but their biologic and clinical behavior has not been well studied. Careful longitudinal evaluation will be required to better understand the malignant potential of these lesions.

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). 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.

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. 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.