The long-term impact of cerebellar tumor resection on executive functioning, anxiety, and fear of pain: A mixed methodology pilot study.

This pilot study investigated the long-term impact of a surgery-only treatment (no exposure to other treatments, such as chemotherapy and radiation) for pediatric cerebellar low-grade gliomas on executive function, anxiety, and fear of pain (FOP) beliefs. Twelve patients who underwent surgical glioma resection during childhood (surgery age was 4-16 years, study visit age was 10-28 years), and 12 pain-free controls matched for age, sex, race, and handedness were tested. The spatial extent of resection was precisely mapped using magnetic resonance imaging (MRI). Executive function, anxiety, and FOP were assessed using validated self-report age-appropriate questionnaires for children and adults. Structured clinical interviews at a post-surgery follow-up visit were completed (average: 89 months, range: 20-99). No significant differences in FOP (FOPQ-C t[14 = 1.81, p = 0.09; FOPQ-III t[4] = 0.29, p = 0.79), executive function scores (BRIEF t[20] = 0.30, p = 0.28), or anxiety scores (MASC t[16] = 0.19, p = 0.85; MAQ t[4] = 1.80, p = 0.15) were found in pediatric or adult patients compared to pain-free controls. Clinical interviews mainly categorized pediatric patients as not anxious. One participant reported mild/subclinical anxiety, and one had moderate clinical anxiety. Neither psychologists nor patients endorsed impairments to executive functioning, anxiety, or FOP. Our pilot results suggest that pediatric cerebellar tumor survivors treated with surgery-only have favorable long-term functioning related to these themes. While these results are promising, they will need to be replicated in a larger patient sample.

The Relationship Between Choroidal Abnormalities and Visual Outcomes in Pediatric Patients With NF1-Associated Optic Pathway Gliomas.

BACKGROUND: Choroidal abnormalities (CAs) visualized on near-infrared reflectance (NIR) imaging are a new diagnostic criterion for neurofibromatosis type 1 (NF1), but the association between the presence of CAs and visual function remains unknown. This study evaluated the relationship between visual acuity (VA) with the presence, number, or total area of CAs visualized by NIR in children with NF1-associated optic pathway gliomas (NF1-OPGs). METHODS: Patients (<18 years) enrolled in a prospective longitudinal study of children with NF1-associated OPGs from 3 institutions were eligible if they had optical coherence tomography (OCT) of the macula (Heidelberg Spectralis) with ≥1 year of follow-up. The central 30° NIR images were reviewed by 2 neuro-ophthalmologists who manually calculated the number and total area of CAs. VA (logMAR) was measured using a standardized protocol. Cross-sectional associations of presence, number, and total area of CAs with VA, retinal nerve fiber layer thickness (RNFL), and ganglion cell-inner plexiform layer thickness were evaluated at the first and most recent visits using regression models. Intereye correlation was accounted for using generalized estimating equations. RESULTS: Eighty-two eyes of 41 children (56% female) were included. The mean ± SD age at the first OCT was 10.1 ± 3.3 years, with a mean follow-up of 20.4 ± 7.2 months. At study entry, CAs were present in 46% of eyes with a mean number of 2.1 ± 1.7 and a mean total area of 2.0 ± 1.7 mm 2 per eye. At the most recent follow-up, CAs were present in 48% of eyes with a mean number of 2.2 ± 1.8 lesions and a mean total area of 2.3 ± 2.1 mm 2 per eye. Neither VA nor OCT parameters at first and follow-up visits were associated with the presence, number, or total area of CAs (all P > 0.05). CONCLUSIONS: CAs are prevalent but not ubiquitous, in children with NF1-OPGs. Although CAs are a diagnostic criterion for NF1, their presence and size do not appear to be associated with visual function.

Discontinuation of Antiseizure Medications in Patients With Brain Tumors.

Patients with brain tumors will experience seizures during their disease course. While providers can use antiseizure medications to control these events, patients with brain tumors can experience side effects, ranging from mild to severe, from these medications. Providers in subspecialties such as neurology, neuro-oncology, neurosurgery, radiation oncology, and medical oncology often work with patients with brain tumor to balance seizure control and the adverse toxicity of antiseizure medications. In this study, we sought to explore the problem of brain tumor-related seizures/epilepsy in the context of how and when to consider antiseizure medication discontinuation. Moreover, we thoroughly evaluate the literature on antiseizure medication discontinuation for adult and pediatric patients and highlight recommendations relevant to patients with both brain tumors and seizures.

Potential endpoints for assessment of bone health in persons with neurofibromatosis type 1.

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.

Neurologic morbidity and functional independence in adult survivors of childhood cancer.

OBJECTIVE: To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)-directed therapies. METHODS: A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS-treated]; median age [range] = 25.5 years [18-48]; time since diagnosis = 17.7 years [6.8-30.2]) and 8039 without CNS-directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal care needs, ability to work/attend school, attainment of driver's license, marital/partner status). Multivariable regression models, adjusted for age, sex, race/ethnicity, and chronic health conditions, estimated odds ratios (OR) or relative risks (RR) for associations between neurologic morbidity, functional independence, and emotional distress. RESULTS: Among CNS-treated survivors, three classes of independence were identified: (1) moderately independent, never married, and non-independent living (78.7%); (2) moderately independent, unable to drive (15.6%); and (3) non-independent (5.7%). In contrast to 50% of non-CNS-treated survivors and 60% of siblings, a fourth fully independent class of CNS-treated survivors was not identified. History of stroke (OR = 2.50, 95% CI: 1.70-3.68), seizure (OR = 9.70, 95% CI: 7.37-12.8), neurosensory deficits (OR = 2.67, 95% CI: 2.16-3.31), and focal neurologic dysfunction (OR = 3.05, 95% CI: 2.40-3.88) were associated with non-independence among CNS-treated survivors. Non-independence was associated with emotional distress symptoms. INTERPRETATION: CNS-treated survivors do not attain full independence comparable to non-CNS-treated survivors or siblings. Interventions to promote independence may be beneficial for survivors with treatment-related neurological sequalae.

Cerebral Vasculopathy in Children with Neurofibromatosis Type 1.

Cerebrovascular abnormalities are a severe and often underrecognized complication of childhood neurofibromatosis type 1 (NF1). There are no prospective studies of cerebral vasculopathy in NF1; thus, the estimated frequency of vasculopathy varies between studies. The data is difficult to interpret due to the retrospective data collection and variability in whether imaging is done based on screening/surveillance or due to acute neurologic symptoms. The prevalent NF1-associated cerebral vasculopathy is moyamoya syndrome (MMS). Vascular changes can present without symptoms or with acute TIA or stroke-like symptoms or a range of progressive neurologic deficits. Advanced imaging may enhance sensitivity of neuroimaging in children. Medical and/or surgical interventions may prevent short- and long-term complications. Challenges for establishment of a screening protocol for cerebral vasculopathy in children with NF1 include the relatively large number of patients with NF1, the potential need for sedation to achieve quality imaging and the broad age range at time of detection for cerebral vascular changes. The goal of this review is to present the epidemiology, clinical presentation, imaging features and medical/surgical management of cerebral arteriopathies in children with NF1.

Children's Oncology Group's 2023 blueprint for research: Cancer control and supportive care.

The objective of the Cancer Control and Supportive Care (CCL) Committee in the Children's Oncology Group (COG) is to reduce the overall morbidity and mortality of therapy-related toxicities in children, adolescents, and young adults with cancer. We have targeted five major domains that cause clinically important toxicity: (i) infections and inflammation; (ii) malnutrition and metabolic dysfunction; (iii) chemotherapy-induced nausea and vomiting; (iv) neuro- and oto-toxicty; and (v) patient-reported outcomes and health-related quality of life. Subcommittees for each domain prioritize randomized controlled trials and biology aims to determine which strategies best mitigate the toxicities. The findings of these trials are impactful, informing clinical practice guidelines (CPGs) and directly leading to changes in the standard of care for oncology practice. With the development of new therapies, there will be new toxicities, and the COG CCL Committee is dedicated to developing interventions to minimize acute and delayed toxicities, lessen morbidity and mortality, and improve quality of life in pediatric and young adult patients with cancer.

A single-institution pediatric and young adult interventional oncology collaborative: Novel therapeutic options for relapsed/refractory solid tumors.

BACKGROUND: Pediatric interventional oncology (PIO) is a growing field intended to provide additional or alternative treatment options for pediatric patients with benign or malignant tumors. Large series of patients treated uniformly and subjected to rigorous endpoints for efficacy are not available. METHODS: We designed a collaborative initiative to capture data from pediatric patients with benign and malignant tumors who underwent a therapeutic interventional radiology procedure. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was utilized as a measure of radiologic response and data were collected regarding improvement in pain and functional endpoints. Cumulative incidence of progressive disease was calculated using both the treated site and the patient as the analytic unit. FINDINGS: Forty patients, 16 with malignant tumors and 24 with benign tumors, underwent a total of 88 procedures. Cryo- and radiofrequency ablation were the most frequently utilized techniques for both cohorts of patients. A complete or partial response, or prolonged disease stability, were achieved in approximately 40% of patients with malignant tumors and 60% of patients with benign tumors. No patients had progressive disease as their best response. Resolution of pain and improved mobility with return-to-baseline activity were demonstrated across patients from both cohorts. Only minor complications were experienced. INTERPRETATION: Interventional radiology-guided interventions can serve as an alternative or complementary approach to the treatment of benign and malignant tumors in pediatric patients. Prospective, multi-institutional trials are required to adequately study utility, treatment endpoints, and durability of response.

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. 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.

Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma.

BACKGROUND: Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). METHODS: Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. RESULTS: Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. CONCLUSIONS: Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.

Pediatric central nervous system tumor survivor and caregiver experiences with multidisciplinary telehealth.

PURPOSE: Telehealth use to facilitate cancer survivorship care is accelerating; however, patient satisfaction and barriers to facilitation have not been studied amongst pediatric central nervous system (CNS) tumor survivors. We assessed the telehealth experiences of survivors and caregivers in the Pediatric Neuro-Oncology Outcomes Clinic at Dana-Farber/ Boston Children's Hospital. METHODS: Cross-sectional study of completed surveys among patients and caregivers with ≥ 1 telehealth multidisciplinary survivorship appointment from January 2021 through March 2022. RESULTS: Thirty-three adult survivors and 41 caregivers participated. The majority agreed or strongly agreed that telehealth visits started on time [65/67 (97%)], scheduling was convenient [59/61 (97%)], clinician's explanations were easy-to-understand [59/61 (97%)], listened carefully/addressed concerns [56/60 (93%)], and spent enough time with them [56/59 (95%)]. However, only 58% (n = 35/60) of respondents agreed or strongly agreed they would like to continue with telehealth and 48% (n = 32/67) agreed telehealth was as effective as in person office visits. Adult survivors were more likely than caregivers to prefer office visits for personal connection [23/32 (72%) vs. 18/39 (46%), p = 0.027]. CONCLUSION: Offering telehealth multi-disciplinary services may provide more efficient and accessible care for a subset of pediatric CNS tumor survivors. Despite some advantages, patients and caregivers were divided on whether they would like to continue with telehealth and whether telehealth was as effective as office visits. To improve survivor and caregiver satisfaction, initiatives to refine patient selection as well as enhance personal communication through telehealth systems should be undertaken.

Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA.

Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis. SIGNIFICANCE: MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517.

Consensus Recommendations for Managing Childhood Cancer Survivors at Risk for Stroke After Cranial Irradiation: A Delphi Study.

BACKGROUND AND OBJECTIVES: There is insufficient evidence to support stroke prevention guidelines for childhood cancer survivors (CCS) treated with cranial irradiation for CNS tumors or other childhood cancers involving the CNS. We used a systematic consensus-building methodology to develop expert recommendations and define areas of controversy in managing asymptomatic CCS at risk for stroke. METHODS: A Delphi process was used to query a multispecialty panel of 45 physicians from the United States/Canada, with expertise in CCS, about their stroke screening and management practices (imaging, referrals, laboratory testing, and medications). Three iterative rounds of anonymous, scenario-based questionnaires, building on panelists' aggregate responses, were used to reach consensus (≥90% agreement), agreement (89%-70% agree), or to understand the rationale for disagreement (<70% agree). RESULTS: All 45 physicians participated in the first 2 rounds and 44 in the third. Panelists reached consensus on indications for referral to neurology and laboratory screening for modifiable cerebral vascular disease (CVD) risk factors in most scenarios. Panelists agreed that aspirin therapy is not recommended in the scenario of normal neuroimaging (86% agreed). Decisions about aspirin therapy in scenarios with abnormal neuroimaging were deferred to specialists; almost all agreed with not using aspirin for cavernomas with no evidence for previous hemorrhage (93%) and using aspirin for both large vessel CVD (93%) and small vessel CVD with evidence of previous stroke (86%). Clinical decisions that remain controversial (less than 70% agreement) include neuroimaging to screen asymptomatic CCS for CVD, referral to neurology for cavernomas, aspirin use in the setting of cavernomas with previous hemorrhage, or with evidence for small vessel CVD and no previous stroke, and indications for statins. Overall, pediatric neurologists/neuro-oncologists and radiation oncologists were more likely to advocate for screening and interventions. DISCUSSION: Despite lack of evidence to guide the management of CCS at risk for stroke, expert recommendations and rationale developed by consensus methodology are helpful to support clinical decision-making.

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. 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.

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. 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.

Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation.

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

Practical guidance for telemedicine use in neuro-oncology.

While the COVID-19 pandemic has catalyzed the expansion of telemedicine into nearly every specialty of medicine, few articles have summarized current practices and recommendations for integrating virtual care in the practice of neuro-oncology. This article identifies current telemedicine practice, provides practical guidance for conducting telemedicine visits, and generates recommendations for integrating virtual care into neuro-oncology practice. Practical aspects of telemedicine are summarized including when to use and not use telemedicine, how to conduct a virtual visit, who to include in the virtual encounter, unique aspects of telehealth in neuro-oncology, and emerging innovations.

Awareness and agreement with neurofibromatosis care guidelines among U.S. neurofibromatosis specialists.

INTRODUCTION: The neurofibromatoses (NF) are a group of rare, genetic diseases sharing a predisposition to develop multiple benign nervous system tumors. Given the wide range of NF symptoms and medical specialties involved in NF care, we sought to evaluate the level of awareness of, and agreement with, published NF clinical guidelines among NF specialists in the United States. METHODS: An anonymous, cross-sectional, online survey was distributed to U.S.-based NF clinicians. Respondents self-reported demographics, practice characteristics, awareness of seven NF guideline publications, and level of agreement with up to 40 individual recommendations using a 5-point Likert scale. We calculated the proportion of recommendations that each clinician rated "strongly agree", and assessed for differences in guideline awareness and agreement by respondent characteristics. RESULTS: Sixty-three clinicians (49% female; 80% academic practice) across > 8 medical specialties completed the survey. Awareness of each guideline publication ranged from 53%-79% of respondents; specialists had higher awareness of publications endorsed by their medical professional organization (p < 0.05). The proportion of respondents who "strongly agree" with individual recommendations ranged from 17%-83%; for 16 guidelines, less than 50% of respondents "strongly agree". There were no significant differences in overall agreement with recommendations based on clinicians' gender, race, specialty, years in practice, practice type (academic/private practice/other), practice location (urban/suburban/rural), or involvement in NF research (p > 0.05 for all). CONCLUSIONS: We identified wide variability in both awareness of, and agreement with, published NF care guidelines among NF experts. Future quality improvement efforts should focus on evidence-based, consensus-driven methods to update and disseminate guidelines across this multi-specialty group of providers. Patients and caregivers should also be consulted to proactively anticipate barriers to accessing and implementing guideline-driven care. These recommendations for improving guideline knowledge and adoption may also be useful for other rare diseases requiring multi-specialty care coordination.

Long-term neurocognitive and quality of life outcomes in survivors of pediatric hematopoietic cell transplant.

PURPOSE: Pediatric patients who undergo hematopoietic cell transplant (HCT) are at risk for neurocognitive impairments, which can impact quality of life. Given limited long-term studies, we aimed to characterize the late neurocognitive outcomes in a cohort of pediatric HCT survivors. METHODS: Eligible survivors (HCT at age < 21 year and ≥ 1 year post-HCT) completed a 60-question survey of neurocognitive function and quality of life, which included the Childhood Cancer Survivor Study Neurocognitive Questionnaire (CCSS-NCQ) and the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL). Analyses of risk factors included univariate comparisons and multivariable logistic regression. RESULTS: Participants (n = 199, 50.3% female, 53.3% acute leukemia, 87.9% allogeneic transplants) were surveyed at median age of 37.8 years (interquartile range [IQR] 28.5-48.8) at survey and median 27.6 years (IQR 17.0-34.0) from transplant. On the CCSS-NCQ, 18.9-32.5% of survivors reported impairments (Z score > 1.28) in task efficiency, memory, emotional regulation, or organization, compared with expected 10% in the general population (all p < 0.01). In contrast, survivors reported average Neuro-QoL (T score 49.6±0.7) compared with population normative value of 50 (p = 0.52). In multivariable regression, impaired Neuro-QoL (T score < 40) was independently associated with hearing issues (OR 4.97, 95% CI 1.96-12.6), history of stroke or seizure (OR 4.46, 95% CI 1.44-13.8), and sleep disturbances (OR 6.95, 95% CI 2.53-19.1). CONCLUSIONS: Although long-term survivors of pediatric HCT reported higher rates of impairment in specific neurocognitive domains, cognitive quality of life was perceived as similar to the general population. Subsets of survivors with certain co-morbidities had substantially worse neurocognitive outcomes. IMPLICATIONS FOR CANCER SURVIVORS: While the long-term impact of pediatric HCT can include neurocognitive deficits, survivors report average cognitive quality of life.

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation.

PURPOSE: By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). METHODS: We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. CONCLUSION: The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.