François Doz

Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas

Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (nxa0=xa0402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future.

Proceedings of the consensus meetings from the International Retinoblastoma Staging Working Group on the pathology guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma.

Retinoblastoma is the most common intraocular malignant childhood tumor in need of prospective clinical trials to address important unanswered questions about biology, treatment, and prognostic factors. Currently, there is controversy about the definitions for choroidal invasion and an inconsistency in the handling of eyes with retinoblastoma. The International Retinoblastoma Staging Working Group (IRSWG) composed of 58 participants from 24 countries on 4 continents had a series of Internet meetings to discuss the staging and tissue handling guidelines to reach consensus for adequate processing, establishing definitions of histopathologic risk factors, and reporting of enucleated eyes with retinoblastoma to serve as the basis for clinical trials and studies to validate the proposed criteria. The meetings were facilitated by the International Outreach Program of the St. Jude Childrens Research Hospital through Cure4Kids. The retinoblastoma guidelines from the Childrens Oncology Group, the French Society for Pediatric Cancers, the Association of Directors of Anatomic and Surgical Pathology, and some published data were the basis for this consensus document. Discussions of the feasibility, practicality, and efficacy of the guidelines and criteria resulted in this report. The consensus definitions reached included definition of massive choroidal invasion stated as a maximum diameter of invasive tumor focus of 3 mm or more that may reach the scleral tissue. Focal choroidal invasion is defined as a tumor focus of less than 3 mm and not reaching the sclera. Optic nerve invasion is classified as prelaminar, laminar, retrolaminar, or tumor at surgical margin, and the measurement of the depth of invasion should also be recorded. These guidelines also address handling of the enucleated eye with retinoblastoma in an efficient, practical, and feasible manner for a meaningful diagnosis. The consensus criteria reached by the IRSWG should be validated through prospective clinical trials and studies.

Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma

Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10−20; odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10−17; OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10−9; OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.

Quality-of-life, mood and executive functioning after childhood craniopharyngioma treated with surgery and proton beam therapy.

Primary objective: Childhood craniopharyngioma, a benign tumour with a good survival rate, is associated with important neurocognitive and psychological morbidity, reducing quality‐of‐life (QoL). Method: This retrospective study analysed QoL, mood disorders, everyday executive functioning and diseases impact on family life in 29 patients (mean age at diagnosis 7 years 10 months (SDu2009=u20094.1); mean follow‐up period 6 years 2 months (SDu2009=u20094.5)) treated for childhood craniopharyngioma by surgery combined with radiotherapy using proton beam. Assessment included a semi‐structured interview and standardized scales evaluating self‐report of QoL (Kidscreen 52) and depression (MDI‐C) and proxy‐reports of QoL (Kidscreen 52), executive functioning (BRIEF) and diseases impact (Hoare and Russel Questionnaire). Results: Twenty‐three families answered the questionnaires completely. Overall QoL self‐report was within the normal range. QoL proxy‐report was lower than self‐report. Eleven patients reported depression; 24–38% had dysexecutive symptoms. A majority of families felt ‘very concerned’ by the disease. Depression and low parental educational level were associated with lower QoL and higher levels of executive dysfunction. Conclusion: Given the high morbidity of childhood craniopharyngioma, screening for psychosocial outcome, cognitive functioning, including executive functions, mood and QoL should be systematic and specific interventions should be developed and implemented.

Hypothalamic-Pituitary Lesions in Pediatric Patients: Endocrine Symptoms Often Precede Neuro-Ophthalmic Presenting Symptoms

OBJECTIVEnTo evaluate whether analyses of clinical and endocrine presenting symptoms could help to shorten the time to diagnosis of hypothalamic-pituitary lesions in children.nnnSTUDY DESIGNnA retrospective, single-center, cohort study of 176 patients (93 boys), aged 6 years (range, 0.2-18 years), with hypothalamic-pituitary lesions was performed.nnnRESULTSnThe lesions were craniopharyngioma (n = 56), optic pathway glioma (n = 54), suprasellar arachnoid cyst (n = 25), hamartoma (n = 22), germ cell tumor (n = 12), and hypothalamic-pituitary astrocytoma (n = 7). The most common presenting symptoms were neurologic (50%) and/or visual complaints (38%), followed by solitary endocrine symptoms (28%). Precocious puberty led to diagnosis in 19% of prepubertal patients (n = 131), occurring earlier in patients with hamartoma than in patients with optic-pathway glioma (P < .02). Isolated diabetes insipidus led to diagnosis for all germ-cell tumors. For 122 patients with neuro-ophthalmic presenting symptoms, the mean symptom interval was 0.5 year (95% CI, 0.4-0.6 year), although 66% of patients had abnormal body mass index or growth velocity, which preceded the presenting symptom interval onset by 1.9 years (95% CI, 1.5-2.4 years) (P < .0001) and 1.4 years (95% CI, 1-1.8 years) (P < .0001), respectively. Among them, 41 patients were obese before diagnosis (median 2.2 years [IQR, 1-3 years] prior to diagnosis) and 35 of them had normal growth velocity at the onset of obesity. The sensitivity of current guidelines for management of childhood obesity failed to identify 61%-85% of obese children with an underlying hypothalamic-pituitary lesion in our series.nnnCONCLUSIONSnEndocrine disorders occurred in two-thirds of patients prior to the onset of the neuro-ophthalmic presenting symptom but were missed. Identifying them may help to diagnose hypothalamic-pituitary lesions earlier.

Presentation and evolution of organic central precocious puberty according to the type of CNS lesion

Objectiveu2002 To evaluate the influence of the type and treatment of CNS lesion causing central precocious puberty (CPP) on the presentation, hypothalamic‐pituitary function and final height.

Minimal methylation classifier (MIMIC): A novel method for derivation and rapid diagnostic detection of disease-associated DNA methylation signatures

Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of minimal methylation classifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality samples remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis. Using this approach, we identify critical DNA methylation patterns from previously inaccessible cohorts, and reveal novel survival differences between the medulloblastoma disease subgroups with significant potential for clinical exploitation.

Quality of survival and growth in children and young adults in the PNET4 European controlled trial of hyperfractionated versus conventional radiation therapy for standard-risk medulloblastoma.

PURPOSEnTo compare quality of survival in standard-risk medulloblastoma after hyperfractionated radiation therapy of the central nervous system with that after standard radiation therapy, combined with a chemotherapy regimen common to both treatment arms, in the PNET4 randomised controlled trial.nnnMETHODS AND MATERIALSnParticipants in the PNET4 trial and their parents/caregivers in 7 participating anonymized countries completed standardized questionnaires in their own language on executive function, health status, behavior, health-related quality of life, and medical, educational, employment, and social information. Pre- and postoperative neurologic status and serial heights and weights were also recorded.nnnRESULTSnData were provided by 151 of 244 eligible survivors (62%) at a median age at assessment of 15.2 years and median interval from diagnosis of 5.8 years. Compared with standard radiation therapy, hyperfractionated radiation therapy was associated with lower (ie, better) z-scores for executive function in all participants (mean intergroup difference 0.48 SDs, 95% confidence interval 0.16-0.81, P=.004), but health status, behavioral difficulties, and health-related quality of life z-scores were similar in the 2 treatment arms. Data on hearing impairment were equivocal. Hyperfractionated radiation therapy was also associated with greater decrement in height z-scores (mean intergroup difference 0.43 SDs, 95% confidence interval 0.10-0.76, P=.011).nnnCONCLUSIONSnHyperfractionated radiation therapy was associated with better executive function and worse growth but without accompanying change in health status, behavior, or quality of life.

Inhibin B and Antimüllerian Hormone as Markers of Gonadal Function after Treatment for Medulloblastoma or Posterior Fossa Ependymoma during Childhood

OBJECTIVEnTo evaluate the roles of hypothalamic-pituitary and spinal irradiations and chemotherapy in gonadal deficiency after treatment for medulloblastoma or posterior fossa ependymoma by measuring levels of plasma inhibin B and antimüllerian hormone (AMH).nnnSTUDY DESIGNnA total of 34 boys and 22 girls were classified as having normal levels of plasma follicle-stimulating hormone (FSH; <9 IU/L), or abnormal levels of FSH (>9 IU/L) and luteinizing hormone (LH; <5 or >5 IUL).nnnRESULTSnTwo boys had partial gonadotropin deficiency, combined with testicular deficiency in one boy. Six boys had increased levels of FSH, indicating tubular deficiency, combined with Leydig cell deficiency in 5 boys. The 7 boys with inhibin B levels <100 ng/mL included the one with combined deficiencies and the 6 with testicular deficiency. Puberty did not progress in 7 girls; 3 had gonadotropin deficiency, combined with ovarian deficiency in one, and 4 had increased FSH levels, indicating ovarian deficiency. Inhibin B and AMH levels were low in the girl with combined deficiencies, in the 4 girls with ovarian deficiency, and in 4 girls with normal clinical-biological ovarian function, including 2 who underwent ovarian transposition before irradiation.nnnCONCLUSIONnThe plasma concentrations of inhibin B and AMH are useful means of detecting primary gonad deficiency in patients with no increase in their plasma gonadotropin levels because of radiation-induced gonadotropin deficiency.

Readability of the Written Study Information in Pediatric Research in France

Background The aim was to evaluate the readability of research information leaflets (RIL) for minors asked to participate in biomedical research studies and to assess the factors influencing this readability. Methods and Findings All the pediatric protocols from three French pediatric clinical research units were included (Nu200a=u200a104). Three criteria were used to evaluate readability: length of the text, Fleschs readability score and presence of illustrations. We compared the readability of RIL to texts specifically written for children (school textbooks, school exams or extracts from literary works). We assessed the effect of protocol characteristics on readability. The RIL had a median length of 608 words [350 words, 25th percentile; 1005 words, 75th percentile], corresponding to two pages. The readability of the RIL, with a median Flesch score of 40 [30; 47], was much poorer than that of pediatric reference texts, with a Flesch score of 67 [60; 73]. A small proportion of RIL (13/91; 14%) were illustrated. The RIL were longer (p<0.001), more readable (p<0.001) and more likely to be illustrated (p<0.009) for industrial than for institutional sponsors. Conclusion Researchers should routinely compute the reading ease of study information sheets and make greater efforts to improve the readability of written documents for potential participants.