Objective. —Neurofibromatosis 1 and neurofibromatosis 2 are autosomal dominant genetic disorders in which affected individuals develop both benign and malignant tumors at an increased frequency. Since the original National Institutes of Health Consensus Development Conference in 1987, there has been significant progress toward a more complete understanding of the molecular bases for neurofibromatosis 1 and neurofibromatosis 2. Our objective was to determine the diagnostic criteria for neurofibromatosis 1 and neurofibromatosis 2, recommendations for the care of patients and their families at diagnosis and during routine follow-up, and the role of DNA diagnostic testing in the evaluation of these disorders. Data Sources. —Published reports from 1966 through 1996 obtained by MEDLINE search and studies presented at national and international meetings. Study Selection. —All studies were reviewed and analyzed by consensus from multiple authors. Data Extraction. —Peer-reviewed published data were critically evaluated by independent extraction by multiple authors. Data Synthesis. —The main results of the review were qualitative and were reviewed by neurofibromatosis clinical directors worldwide through an Internet Web site. Conclusions. —On the basis of the information presented in this review, we propose a comprehensive approach to the diagnosis and treatment of individuals with neurofibromatosis 1 and neurofibromatosis 2.

https://jamanetwork.com/journals/jama/articlepdf/417288/jama_278_1_042.pdf

The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2.

Scope of the report This report is concerned with the evaluation of measures broadly designed to measure quality of life (QoL) in children and adolescents, either by self-report or proxy raters. Four research questions were identified: (1) To what extent are adult measures used in the evaluation of healthcare interventions in children? (2) How appropriate are adult measures for use with children? (3) To what extent do child self-reports correspond with assessments made by parents and carers? (4) How feasible and reliable are proxy measures of QoL in different disease contexts? Objectives (1) To review the state of the art with regard to measurement of QoL for children. (2) To make recommendations regarding the value of currently available measures for different purposes. (3) To identify further research needs. Method Electronic databases were searched for the period 1980-July 1999 for articles relating to measures of QoL, health status or well-being in children (under 18 years) with chronic disease. Handsearching of relevant journals and cross-referencing with reference lists in identified articles was also carried out. Key workers in the field were contacted for additional information, and the Internet was searched for relevant websites. Results Forty-three measures were identified (19 generic and 24 disease-specific). Sixteen measures allowed for completion by children and parent/caregiver; seven only allowed for completion by a proxy, and the remainder (n = 17) allowed only for child completion. The measures were described as QoL (n = 30), health status, (n = 2), perception of illness (n = 1), life satisfaction (n = 1) and quality of well-being (n = 1). RESULTS - TO WHAT EXTENT ARE ADULT MEASURES USED IN THE EVALUATION OF HEALTHCARE INTERVENTIONS IN CHILDREN?: Three studies were identified where adult measures were used with very few changes made for children. In 11 studies involving nine separate measures of QoL, adult measures were used as a model for work with children. RESULTS - HOW APPROPRIATE ARE ADULT MEASURES FOR USE WITH CHILDREN?: Adult measures may fail to tap the specific aspects of QoL that are important to the child. Measures based on adult work impose considerable response burden for children, in terms of length, reading skills and response scale. Wording and format of adult measures may need to be modified to account for children's cognitive and language skills. More basic research is needed to determine the level of response burden that children of different ages can manage. Assessments of difficulty (e.g. reading age) need to be routinely included with information about new measures. RESULTS - TO WHAT EXTENT DO CHILD SELF-REPORTS CORRESPOND WITH ASSESSMENTS MADE BY PARENTS AND CARERS?: Fourteen studies were identified in which concor-dance between child and parent was investigated, often as part of the development of a new measure. There was some evidence for greater concordance between child and parent for physical functioning compared with social and emotional domains, but greater heterogeneity in the latter measures may contribute to inconsistent results. There was no simple relationship between concordance and moderating variables such as age, gender and illness, but this conclusion was addressed only very rarely. RESULTS - HOW FEASIBLE AND RELIABLE ARE PROXY MEASURES OF QOL IN DIFFERENT DISEASE CONTEXTS?: Only five papers fulfilled the review criteria. Evaluation is difficult because authors fail to justify their choice of measures, and do not report critical information such as completion rates or missing data. Use of existing measures can potentially eliminate the time and expense required to develop a comprehensive measure of QoL, but a full battery of standardised tests may be expensive in terms of time for administration and scoring. In addition, battery measures tend to be lengthy and therefore demanding for sick patients. They are not recommended for work with children. RECOMMENDATIONS FOR RESEARCH - MINIMUM CRITERIA FOR NEW MEASURES: A set of procedures needs to be established for the development of new measures. These need to draw on the experience gained in development of child and adult measures to date. Basic research to enhance understanding of how children interpret questions in QoL measures is recommended. We need to understand the differences in meaning of items between children and adults, and between children of different ages. Some attempt to develop measures for children of 6 years or more have been reported, and these should be further developed. (ABSTRACT TRUNCATED)

Quality-of-life measures in chronic diseases of childhood

Neurofibromatosis 1 (NF1) is a common neurocutaneous condition with an autosomal dominant pattern of inheritance. The complications are diverse and disease expression varies, even within families. Progress in molecular biology and neuroimaging and the development of mouse models have helped to elucidate the aetiology of NF1 and its clinical manifestations. Furthermore, these advances have raised the prospect of therapeutic intervention for this complex and distressing disease. Members of the United Kingdom Neurofibromatosis Association Clinical Advisory Board collaborated to produce a consensus statement on the current guidelines for diagnosis and management of NF1. The proposals are based on published clinical studies and on the pooled knowledge of experts in neurofibromatosis with experience of providing multidisciplinary clinical and molecular services for NF1 patients. The consensus statement discusses the diagnostic criteria, major differential diagnoses, clinical manifestations and the present strategies for monitoring and management of NF1 complications.

https://jmg.bmj.com/content/jmedgenet/early/2006/11/14/jmg.2006.045906.full.pdf

Guidelines for the diagnosis and management of individuals with neurofibromatosis 1

We examined 18 atypical teratoid and rhabdoid tumors of the brain and 7 renal and 4 extrarenal rhabdoid tumors for mutations in the candidate rhabdoid tumor suppressor gene, INI1. Fifteen tumors had homozygous deletions of one or more exons of the INI1 gene, and the other 14 tumors demonstrated mutations. Germ-line mutations of INI1 were identified in four children, one with an atypical teratoid tumor of the brain and three with renal rhabdoid tumors. These studies suggest that INI1 is a tumor suppressor gene involved in rhabdoid tumors of the brain, kidney, and other extrarenal sites.

https://cancerres.aacrjournals.org/content/canres/59/1/74.full.pdf

Germ-Line and Acquired Mutations of INI1 in Atypical Teratoid and Rhabdoid Tumors

Summary Background Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. Methods After resection, patients were classified as having average-risk medulloblastoma (≤1·5 cm 2 residual tumour and no metastatic disease) or high-risk medulloblastoma (>1·5 cm 2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23·4 Gy for average-risk disease and 36·0–39·6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. Findings Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75–94) in patients in the average-risk group and 70% (54–84) in those in the high-risk group (p=0·04); 5-year event-free survival was 83% (73–93) and 70% (55–85), respectively (p=0·046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0·04): 84% (74–95) for classic histology, 77% (49–100) for desmoplastic tumours, and 57% (33–80) for large-cell anaplastic tumours. Interpretation Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(06)70867-1.pdf

Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial

✓ It has previously been reported in a single-institution trial that progression-free survival of children with medulloblastoma treated with radiotherapy and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), cisplatin, and vincristine chemotherapy during and after radiotherapy was better than the outcome in children treated with radiotherapy alone. To better characterize long-term outcome and duration of disease control, this treatment approach was used for 10 years and expanded to three institutions. Sixty-three children with posterior fossa medulloblastomas were treated with craniospinal local-boost radiotherapy and adjuvant chemotherapy with vincristine weekly during radiotherapy followed by eight 6-week cycles of cisplatin, CCNU, and vincristine. To be eligible for study entry, patients had to be older than 18 months of age at diagnosis and have a subtotal resection, evidence of metastatic disease, and/or brainstem involvement. Patients younger than 5 years of age and without these poor risk factor...

Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy

PURPOSEThis study investigates the response rate to and toxicity of carboplatin and vincristine in children with recurrent low-grade gliomas (LGGs) or patients younger than 60 months with newly diagnosed LGGs.PATIENTS AND METHODSTwenty-three children with recurrent and 37 children with newly diagnosed LGGs were treated with a 10-week induction cycle of carboplatin and vincristine, followed by maintenance treatment with the same drugs. Patients were evaluated for response to treatment and toxicity.RESULTSTwelve of 23 (52% +/- 10%; 95% confidence interval [CI], 0.32 to 0.72) assessable children with recurrent disease had an objective response to treatment, which included a greater than 50% reduction in tumor size in seven of 23 (30% +/- 10%; 95% CI, 0.10 to 0.50). Twenty-three of 37 (62% +/- .08; 95% CI, 0.46 to 0.78) of newly diagnosed patients had an objective response, 16 of 37 (43% +/- 0.08%; 95% CI, 0.27 to 0.59) with greater than 50% reduction in tumor size. The majority of those with an objective res...

Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood

Carboplatin and Vincristine Chemotherapy for Children with Newly Diagnosed Progressive Low-Grade Gliomas

The reported success of treatment for children with medulloblastoma must be balanced against the effect that treatment has on the quality of life of long-term survivors. The outcome of long-term survivors reported in previous studies has been conflicting. The authors evaluate the mental and behavioral skills of a group of medulloblastoma survivors from their institution, all of whom had survived for more than 5 years postdiagnosis. A review of the institutional records yielded 32 patients. Twenty-three families were interviewed by telephone and, of these, 13 subjects came to the hospital for detailed neuropsychological and neurological evaluations. Intelligence quotient (IQ) was less than 90 for all participants tested, and patients diagnosed before the age of 3 years had lower IQ scores on average than those diagnosed later. Mean IQ and achievement test scores in reading, spelling, and mathematics were all higher in survivors who had undergone shunting. Achievement test results were often not in accord with intellectual potential, and individual intellectual skills varied widely. Perceptual-motor task performance was below average in more than 50% of the participants, but motor dexterity was more severely affected than perception. Problems in learning and a delay in both physical growth and development were seen in a majority of participants. This study directs attention to the serious difficulties faced by long-term survivors of medulloblastoma and their families, and underscores the importance of routine neuropsychological testing. Moreover, the study provides further impetus to seek alternatives to irradiation in the treatment of malignant brain tumors.

Quality of long-term survival in young children with medulloblastoma

PurposeLittle is known of the outcome of long-term survivors of childhood medulloblastoma, one of the most common pediatric malignancies. To determine the potential for secondary malignancies, a retrospective outcome evaluation in 88 consecutive cases of childhood medulloblastoma was performed.Patie

H S Nicholson

Papers

Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy

Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood

Carboplatin and Vincristine Chemotherapy for Children with Newly Diagnosed Progressive Low-Grade Gliomas

Quality of long-term survival in young children with medulloblastoma

Prognostic factors and secondary malignancies in childhood medulloblastoma.