34 results on '"Doz, F."'
Search Results
2. Assessment of Puberty and Hypothalamic-Pituitary-Gonadal Axis Function After Childhood Brain Tumor Treatment.
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Rosimont M, Kariyawasam D, Samara-Boustani D, Giani E, Beltrand J, Bolle S, Fresneau B, Puget S, Sainte-Rose C, Alapetite C, Pinto G, Touraine P, Piketty ML, Brabant S, Abbou S, Aerts I, Beccaria K, Bourgeois M, Roujeau T, Blauwblomme T, Rocco FD, Thalassinos C, Rigaud C, James S, Busiah K, Simon A, Bourdeaut F, Lemelle L, Guerrini-Rousseau L, Orbach D, Doz F, Dufour C, Grill J, Polak M, and Briceño LG
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- Child, Humans, Hypothalamic-Pituitary-Gonadal Axis, Retrospective Studies, Puberty, Brain Neoplasms epidemiology, Brain Neoplasms therapy, Glioma
- Abstract
Context: Endocrine complications are common in pediatric brain tumor patients., Objective: To describe hypothalamic-pituitary-gonadal axis (HPGA) function in patients treated in childhood for a primary brain tumor more than 5 years earlier, in order to identify risk factors for HPGA impairment., Methods: We retrospectively included 204 patients diagnosed with a primary brain tumor before 18 years of age and monitored at the pediatric endocrinology unit of the Necker Enfants-Malades University Hospital (Paris, France) between January 2010 and December 2015. Patients with pituitary adenoma or untreated glioma were excluded., Results: Among patients with suprasellar glioma not treated by radiotherapy, the prevalence of advanced puberty was 65% overall and 70% when the diagnosis occurred before 5 years of age. Medulloblastoma chemotherapy caused gonadal toxicity in 70% of all patients and in 87.5% of those younger than 5 years at diagnosis. In the group with craniopharyngioma, 70% of patients had hypogonadotropic hypogonadism, which was consistently accompanied by growth hormone deficiency., Conclusion: Tumor type, location, and treatment were the risk main factors for HPGA impairment. Awareness that onset can be delayed is essential to guide information of parents and patients, patient monitoring, and timely hormone replacement therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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3. How can we differentiate supratentorial tumor recurrence from postradiation imaging changes in children treated for primary malignant brain tumors?
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Zittoun J, Dangouloff-Ros V, Cardoen L, Rutten C, Bolle S, Alapetite C, Levy R, Grévent D, Grill J, Brisse HJ, Doz F, Blauwblomme T, Beccaria K, Charpy S, Roux CJ, Varlet P, Dufour C, Puget S, and Boddaert N
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- Humans, Child, Neoplasm Recurrence, Local diagnostic imaging, Retrospective Studies, Magnetic Resonance Imaging methods, Diffusion Magnetic Resonance Imaging methods, Brain Neoplasms diagnostic imaging, Brain Neoplasms radiotherapy, Brain Neoplasms surgery, Supratentorial Neoplasms diagnostic imaging, Supratentorial Neoplasms radiotherapy, Supratentorial Neoplasms surgery
- Abstract
Objective: Distinguishing tumor recurrence from therapy-induced imaging changes (TIIC) on brain MRI in children treated for primary malignant brain tumors may be challenging. The authors aimed to assess the diagnostic ability of multimodal MRI in differentiating TIIC from tumor recurrence., Methods: The authors retrospectively included children with abnormal supratentorial brain MRI findings after treatment for primary malignant brain tumors (regardless of their localization) with complete resection and radiotherapy. A total of 18 patients with TIIC and 25 patients with tumor recurrence were compared, according to structural, apparent diffusion coefficient (ADC), and arterial spin labeling (ASL) imaging data accrued over time. TIIC were defined by a new MRI scan that was stable for at least 1 year or had regressed, or by histopathology findings in specimens obtained when the anomaly was surgically treated., Results: The time interval between completion of radiotherapy and the appearance of abnormal brain MRI findings was significantly shorter in the TIIC group compared with the tumor recurrence group (median 6 vs 35 months; p < 0.001). TIIC appeared as foci of increased T2-weighted signal intensity, without nodule, associated with variable contrast enhancement. Tumor recurrence appeared as a well-defined nodule with intermediate signal intensity on T2-weighted images with nodular contrast enhancement. Relative ADC values were significantly higher in the TIIC group (median 1.43 vs 0.88; p < 0.001). Relative ASL-cerebral blood flow (CBF) values were significantly lower in the TIIC group (median 0.27 vs 0.43; p = 0.04). On follow-up MRI, TIIC could progress, regress, or remain stable. In most instances (72%), they decreased in size or remained stable at 4 years of follow-up., Conclusions: MRI features of TIIC include foci of increased signal intensity without a demonstrable nodule on T2-weighted images, high ADC values, and lower ASL-CBF values, whereas tumor recurrence appears as a well-defined nodule with low ADC values and higher ASL-CBF values.
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- 2023
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4. Pediatric spinal pilocytic astrocytomas form a distinct epigenetic subclass from pilocytic astrocytomas of other locations and diffuse leptomeningeal glioneuronal tumours.
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Métais A, Bouchoucha Y, Kergrohen T, Dangouloff-Ros V, Maynadier X, Ajlil Y, Carton M, Yacoub W, Saffroy R, Figarella-Branger D, Uro-Coste E, Sevely A, Larrieu-Ciron D, Faisant M, Machet MC, Wahler E, Roux A, Benichi S, Beccaria K, Blauwblomme T, Boddaert N, Chrétien F, Doz F, Dufour C, Grill J, Debily MA, Varlet P, and Tauziède-Espariat A
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- Humans, Child, Child, Preschool, Retrospective Studies, Epigenesis, Genetic, Astrocytoma pathology, Central Nervous System Neoplasms genetics, Glioma genetics, Brain Neoplasms genetics
- Abstract
Pediatric spinal low-grade glioma (LGG) and glioneuronal tumours are rare, accounting for less 2.8-5.2% of pediatric LGG. New tumour types frequently found in spinal location such as diffuse leptomeningeal glioneuronal tumours (DLGNT) have been added to the World Health Organization (WHO) classification of tumours of the central nervous system since 2016, but their distinction from others gliomas and particularly from pilocytic astrocytoma (PA) are poorly defined. Most large studies on this subject were published before the era of the molecular diagnosis and did not address the differential diagnosis between PAs and DLGNTs in this peculiar location. Our study retrospectively examined a cohort of 28 children with LGGs and glioneuronal intramedullary tumours using detailed radiological, clinico-pathological and molecular analysis. 25% of spinal PAs were reclassified as DLGNTs. PA and DLGNT are nearly indistinguishable in histopathology or neuroradiology. 83% of spinal DLGNTs presented first without leptomeningeal contrast enhancement. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that spinal PAs formed a unique methylation cluster distinct from reference midline and posterior fossa PAs, whereas spinal DLGNTs clustered with reference DLGNT cohort. FGFR1 alterations were found in 36% of spinal tumours and were restricted to PAs. Spinal PAs affected significantly younger patients (median age 2 years old) than DLGNTs (median age 8.2 years old). Progression-free survival was similar among the two groups. In this location, histopathology and radiology are of limited interest, but molecular data (methyloma, 1p and FGFR1 status) represent important tools differentiating these two mitogen-activated protein kinase (MAPK) altered tumour types, PA and DLGNT. Thus, these molecular alterations should systematically be explored in this type of tumour in a spinal location., (© 2022. The Author(s).)
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- 2023
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5. High Prevalence of Early Endocrine Disorders After Childhood Brain Tumors in a Large Cohort.
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González Briceño LG, Kariyawasam D, Samara-Boustani D, Giani E, Beltrand J, Bolle S, Fresneau B, Puget S, Sainte-Rose C, Alapetite C, Pinto G, Piketty ML, Brabant S, Abbou S, Aerts I, Beccaria K, Bourgeois M, Roujeau T, Blauwblomme T, Di Rocco F, Thalassinos C, Pauwels C, Rigaud C, James S, Busiah K, Simon A, Bourdeaut F, Lemelle L, Guerrini-Rousseau L, Orbach D, Touraine P, Doz F, Dufour C, Grill J, and Polak M
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- Adult, Child, Female, Humans, Male, Prevalence, Retrospective Studies, Brain Neoplasms epidemiology, Brain Neoplasms radiotherapy, Cerebellar Neoplasms complications, Cerebellar Neoplasms radiotherapy, Endocrine System Diseases diagnosis, Endocrine System Diseases epidemiology, Endocrine System Diseases etiology, Pituitary Neoplasms complications, Pituitary Neoplasms epidemiology
- Abstract
Context: Endocrine complications are common in pediatric brain tumor patients., Objective: We aimed to describe the endocrine follow-up of patients with primary brain tumors., Methods: This is a noninterventional observational study based on data collection from medical records of 221 patients followed at a Pediatric Endocrinology Department., Results: Median age at diagnosis was 6.7 years (range, 0-15.9), median follow-up 6.7 years (0.3-26.6), 48.9% female. Main tumor types were medulloblastoma (37.6%), craniopharyngioma (29.0%), and glioma (20.4%). By anatomic location, 48% were suprasellar (SS) and 52% non-suprasellar (NSS). Growth hormone deficiency (GHD) prevalence was similar in both groups (SS: 83.0%, NSS: 76.5%; P = 0.338), appearing at median 1.8 years (-0.8 to 12.4) after diagnosis; postradiotherapy GHD appeared median 1.6 years after radiotherapy (0.2-10.7). Hypothyroidism was more prevalent in SS (76.4%), than NSS (33.9%) (P < 0.001), as well as ACTH deficiency (SS: 69.8%, NSS: 6.1%; P < 0.001). Early puberty was similar in SS (16%) and NSS (12.2%). Hypogonadotropic hypogonadism was predominant in SS (63.1%) vs NSS (1.3%), P < 0.001, and postchemotherapy gonadal toxicity in NSS (29.6%) vs SS (2.8%), P < 0.001. Adult height was lower for NSS compared to target height (-1.0 SD, P < 0.0001) and to SS patients (P < 0.0001). Thyroid nodules were found in 13/45 patients (28.8%), including 4 cancers (4.8-11.5 years after radiotherapy). Last follow-up visit BMI was higher in both groups (P = 0.0001), and obesity incidence was higher for SS (46.2%) than NSS (17.4%)., Conclusion: We found a high incidence of early-onset endocrine disorders. An endocrine consultation and nutritional evaluation should be mandatory for all patients with a brain tumor, especially when the tumor is suprasellar or after hypothalamus/pituitary irradiation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
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6. Imaging Features with Histopathologic Correlation of CNS High-Grade Neuroepithelial Tumors with a BCOR Internal Tandem Duplication.
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Cardoen L, Tauziède-Espariat A, Dangouloff-Ros V, Moalla S, Nicolas N, Roux CJ, Bouchoucha Y, Bourdeaut F, Beccaria K, Bolle S, Pierron G, Dufour C, Doz F, Boddaert N, and Brisse HJ
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- Child, Child, Preschool, Humans, Magnetic Resonance Imaging, Proto-Oncogene Proteins genetics, Repressor Proteins genetics, Retrospective Studies, Brain Neoplasms diagnostic imaging, Brain Neoplasms genetics, Brain Neoplasms pathology, Neoplasms, Neuroepithelial diagnostic imaging, Neoplasms, Neuroepithelial genetics, Neoplasms, Neuroepithelial pathology
- Abstract
Background and Purpose: A new brain tumor entity occurring in early childhood characterized by a somatic BCL6 corepressor gene internal tandem duplication was recently described. The aim of this study was to describe the radiologic pattern of these tumors and correlate this pattern with histopathologic findings., Materials and Methods: This retrospective, noninterventional study included 10 children diagnosed with a CNS tumor, either by ribonucleic acid-sequencing analysis or deoxyribonucleic acid methylation analysis. Clinical, radiologic, and histopathologic data were collected. A neuropathologist reviewed 9 tumor samples. Preoperative images were analyzed in consensus by 7 pediatric radiologists., Results: All tumors were relatively large (range, 4.7-9.2 cm) intra-axial peripheral masses with well-defined borders and no peritumoral edema. All tumors showed mild and heterogeneous enhancement and marked restriction on DWI of the solid portions. Perfusion imaging showed a relatively lower CBF in the tumor than in the adjacent normal parenchyma. Nine of 10 tumors showed areas of necrosis, with the presence of hemorrhage in 8/10 and calcifications in 4/7. Large intratumoral macroscopic veins were observed in 9/10 patients. No intracranial or spinal leptomeningeal dissemination was noted at diagnosis., Conclusions: CNS tumors with a BCL6 corepressor gene internal tandem duplication present as large intra-axial peripheral masses with well-defined borders, no edema, restricted diffusion, weak contrast enhancement, frequent central necrosis, hemorrhage and calcifications, intratumoral veins, and no leptomeningeal dissemination at the time of diagnosis. Knowledge of these imaging characteristics may aid in histologic, genomic, and molecular profiling of brain tumors in young children., (© 2022 by American Journal of Neuroradiology.)
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- 2022
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7. CAR-T cells for pediatric brain tumors: Present and future.
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Leruste A, Beccaria K, and Doz F
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- Antigens, Neoplasm immunology, Blood-Brain Barrier, Brain Neoplasms genetics, Brain Neoplasms immunology, Child, Clinical Trials as Topic, Humans, Immunologic Memory, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive trends, T-Lymphocytes immunology, Tumor Microenvironment immunology, Brain Neoplasms therapy, Immunotherapy, Adoptive methods, Receptors, Chimeric Antigen immunology, T-Lymphocytes transplantation
- Abstract
Chimeric Antigen Receptor T (CAR-T) cells are currently approved for B cell malignancies only, in children and adults. Despite a lack of robust evidence to approve such cellular immunotherapy for pediatric solid tumors, there is a growing interest for this approach in the treatment of pediatric brain tumors. Following the identification of tumor antigens as targets, the first clinical trials demonstrated some degree of clinical and biological responses to CAR-T cells for such tumor types. Additionaly, several preclinical studies have recently identified new attractive targets and antigen combination strategies, along with a superior tumor trafficking following locoregional administration. We review here the preclinical and clinical knowledge at the basis of the current clinical development of CAR-T cells for pediatric brain tumors., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
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8. High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts.
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Roux A, Pallud J, Saffroy R, Edjlali-Goujon M, Debily MA, Boddaert N, Sanson M, Puget S, Knafo S, Adam C, Faillot T, Cazals-Hatem D, Mandonnet E, Polivka M, Dorfmüller G, Dauta A, Desplanques M, Gareton A, Pages M, Tauziede-Espariat A, Grill J, Bourdeaut F, Doz F, Dhermain F, Mokhtari K, Chretien F, Figarella-Branger D, and Varlet P
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- Adolescent, Adult, Age Factors, Female, Humans, Isocitrate Dehydrogenase genetics, Male, Mutation, Neoplasm Grading, Oligodendroglioma enzymology, Oligodendroglioma genetics, Oligodendroglioma pathology, Retrospective Studies, Young Adult, Brain Neoplasms genetics, Brain Neoplasms pathology, Glioma enzymology, Glioma genetics, Glioma pathology
- Abstract
Background: Considering that pediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs)., Methods: We performed a multicentric retrospective study of 112 AYAs from adult and pediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyze their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25 years, histopathological HGG diagnosis, available clinical data, and preoperative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next-generation sequencing, whole exome sequencing, and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 World Health Organization (WHO) classification., Results: Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of pediatric subtypes (histone H3-mutants, 40%) but also adult subtypes (isocitrate dehydrogenase [IDH] mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH mutants, and 1p/19q codeletion and the relative high frequency of "rare adult IDH mutations" (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to what is observed in children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance., Conclusions: HGGs in AYAs could benefit from a specific classification, driven by molecular subtyping rather than age group. Collaborative efforts are needed from pediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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9. The histomolecular criteria established for adult anaplastic pilocytic astrocytoma are not applicable to the pediatric population.
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Gareton A, Tauziède-Espariat A, Dangouloff-Ros V, Roux A, Saffroy R, Castel D, Kergrohen T, Fina F, Figarella-Branger D, Pagès M, Bourdeaut F, Doz F, Puget S, Dufour C, Lechapt E, Chrétien F, Grill J, and Varlet P
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- Adolescent, Age Factors, Astrocytoma mortality, Brain Neoplasms mortality, Child, Child, Preschool, DNA Methylation, Female, Humans, Infant, Infant, Newborn, Male, Progression-Free Survival, Retrospective Studies, Survival Rate, Astrocytoma genetics, Astrocytoma pathology, Brain Neoplasms genetics, Brain Neoplasms pathology
- Abstract
Pilocytic astrocytoma (PA) is the most common pediatric glioma, arising from a single driver MAPK pathway alteration. Classified as a grade I tumor according to the 2016 WHO classification, prognosis is excellent with a 10-year survival rate > 95% after surgery. However, rare cases present with anaplastic features, including an unexpected high mitotic/proliferative index, thus posing a diagnostic and therapeutic challenge. Based on small histomolecular series and case reports, such tumors arising at the time of diagnosis or recurrence have been designated by many names including pilocytic astrocytoma with anaplastic features (PAAF). Recent DNA methylation-profiling studies performed mainly on adult cases have revealed that PAAF exhibit a specific methylation signature, thus constituting a distinct methylation class from typical PA [methylation class anaplastic astrocytoma with piloid features-(MC-AAP)]. However, the diagnostic and prognostic significance of MC-AAP remains to be determined in children. We performed an integrative work on the largest pediatric cohort of PAAF, defined according to strict criteria: morphology compatible with the diagnosis of PA, with or without necrosis, ≥ 4 mitoses for 2.3 mm
2 , and MAPK pathway alteration. We subjected 31 tumors to clinical, imaging, morphological and molecular analyses, including DNA methylation profiling. We identified only one tumor belonging to the MC-AAP (3%), the others exhibiting a methylation profile typical for PA (77%), IDH-wild-type glioblastoma (7%), and diffuse leptomeningeal glioneuronal tumor (3%), while three cases (10%) did not match to a known DNA methylation class. No significant outcome differences were observed between PAAF with necrosis versus no necrosis (p = 0.07), or with 4-6 mitoses versus 7 or more mitoses (p = 0.857). Our findings argue that the diagnostic histomolecular criteria established for anaplasia in adult PA are not of diagnostic or prognostic value in a pediatric setting. Further extensive and comprehensive integrative studies are necessary to accurately define this exceptional entity in children.- Published
- 2020
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10. Hippocampal Sparing During Craniospinal Irradiation: What Did We Learn About the Incidence of Perihippocampus Metastases?
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Padovani L, Chapon F, André N, Boucekine M, Geoffray A, Bourdeau F, Masliah-Planchon J, Claude L, Huchet A, Laprie A, Supiot S, Coche-Dequéant B, Kerr C, Alapetite C, Leseur J, Nguyen T, Chapet S, Bernier V, Bondiau PY, Noel G, Habrand JL, Bolle S, Doz F, Dufour C, Muracciole X, and Carrie C
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- Adolescent, Brain Neoplasms diagnostic imaging, Cerebellar Neoplasms diagnostic imaging, Child, Child, Preschool, Female, Hippocampus diagnostic imaging, Humans, Magnetic Resonance Imaging, Male, Medulloblastoma diagnostic imaging, Neurocognitive Disorders etiology, Progression-Free Survival, Retrospective Studies, Survival Rate trends, Brain Neoplasms secondary, Cerebellar Neoplasms radiotherapy, Craniospinal Irradiation methods, Hippocampus radiation effects, Medulloblastoma radiotherapy, Medulloblastoma secondary, Neurocognitive Disorders prevention & control, Organ Sparing Treatments methods
- Abstract
Purpose: To identify the incidence of patients with perihippocampal metastases to assess the risk of brain relapse when sparing the hippocampal area. Medulloblastoma (MB) represents 20% of pediatric brain tumors. For high-risk MB patients, the 3- to 5-year event-free survival rate has recently improved from 50% to >76%. Many survivors, however, experience neurocognitive side effects. Several retrospective studies of patients receiving whole brain irradiation (WBI) have suggested a relationship between the radiation dose to the hippocampus and neurocognitive decline. The hippocampal avoidance-WBI (HA-WBI) approach could partially reduce neurocognitive impairment in children treated for high-risk MB., Methods and Materials: From 2008 to 2011, 51 patients with high-risk MB were treated according to the French trial primitive neuroectodermal tumor HR+5. Hippocampal contouring was manually generated on 3-dimensional magnetic resonance images according to the Radiation Therapy Oncology Group 0933 atlas. The distribution of metastases was assessed relative to the hippocampus: 0 to 5 mm for the first perihippocampal area and 5 to 15 mm for the rest of the perihippocampal area., Results: The median patient age was 8.79 years (33% female). After a follow-up of 2.4 years, 43 patients were alive; 28 had had brain metastasis at diagnosis and 2 at relapse, with 16% in the first perihippocampal area and 43% in the rest of the perihippocampal area. Of the 18 patients without brain metastases at diagnosis, including M1 patients, none developed secondary lesions within the first or the rest of the perihippocampal area, after receiving 36 Gy. No clinical or biological factor was significantly associated with the development of perihippocampal metastases., Conclusions: Our results suggest the HA-WBI strategy should be evaluated for the subgroup of high-risk MB patients without metastatic disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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11. Childhood brain tumours, early infections and immune stimulation: A pooled analysis of the ESCALE and ESTELLE case-control studies (SFCE, France).
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Lupatsch JE, Bailey HD, Lacour B, Dufour C, Bertozzi AI, Leblond P, Faure-Conter C, Pellier I, Freycon C, Doz F, Puget S, Ducassou S, Orsi L, and Clavel J
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- Adolescent, Animals, Brain Neoplasms epidemiology, Case-Control Studies, Child, Child, Preschool, Female, France epidemiology, Humans, Hypersensitivity physiopathology, Infant, Infections physiopathology, Male, Prevalence, Risk Factors, Brain Neoplasms etiology, Hypersensitivity complications, Infections complications, Registries statistics & numerical data
- Abstract
Background: Few studies have investigated whether early infections and factors potentially related to early immune stimulation might be involved in the aetiology of childhood brain tumours (CBT). In this study, we investigated the associations between CBT with early day-care attendance, history of early common infections, atopic conditions (asthma/wheezing, eczema, allergic rhinitis), early farm residence/visits and contact with animals., Methods: We pooled data from two nationwide French case-control studies, the ESCALE and ESTELLE studies. Children with a CBT diagnosed between 1 and 14 years of age were identified directly from the French National Registry of Childhood Cancers, while population controls were recruited from telephone subscribers. Odds-ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression adjusted for potential confounders., Results: The analyses included 469 cases and 2719 controls. We found no association between attending a day-care centre (OR: 0.9, 95%CI: 0.7-1.2) or having had repeated common infections (OR: 0.9, 95%CI: 0.7-1.2) in the first year of life and the risk of CBT. There was also no association with a history of asthma/wheezing (OR: 0.8, 95%CI: 0.56-1.1). Farm visits (OR: 0.6, 95%CI: 0.5-0.8) as well as contact with pets (OR: 0.8, 95%CI: 0.6-1.0) in the first year of life were inversely associated with CBT., Conclusions: Our findings suggest a protective effect of early farm visits and contact with pets, but not with other markers of early immune stimulation. This might be related to immune stimulation but needs further investigation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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12. Maternal residential pesticide use during pregnancy and risk of malignant childhood brain tumors: A pooled analysis of the ESCALE and ESTELLE studies (SFCE).
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Vidart d'Egurbide Bagazgoïtia N, Bailey HD, Orsi L, Lacour B, Guerrini-Rousseau L, Bertozzi AI, Leblond P, Faure-Conter C, Pellier I, Freycon C, Doz F, Puget S, Ducassou S, and Clavel J
- Subjects
- Adolescent, Adult, Case-Control Studies, Child, Child, Preschool, Environmental Exposure, Female, France epidemiology, Humans, Male, Pregnancy, Risk, Young Adult, Brain Neoplasms epidemiology, Maternal Exposure statistics & numerical data, Pesticides poisoning, Prenatal Exposure Delayed Effects epidemiology
- Abstract
Some previous epidemiological studies have suggested that pesticide exposure during pregnancy may have a possible role in the development of childhood brain tumors (CBT). We pooled data from two French national population-based, case-control studies to investigate the association between maternal residential use of pesticides during pregnancy and the risk of CBT. The mothers of 437 CBT cases and 3,102 controls aged under 15 years who resided in France at diagnosis/interview, frequency-matched by age and gender, answered a structured telephone interview conducted by trained interviewers. Unconditional logistic regression was used to estimate pooled odds ratio (OR) and 95% confidence intervals (95% CI). CBT was significantly associated with the maternal home use of pesticides during pregnancy (OR 1.4, 95% CI 1.2-1.8) and, more specifically, with insecticide (OR 1.4, 1.2-1.8). We could not draw any conclusions about herbicides and/or fungicides because few women used them during pregnancy and most of these mothers also used insecticides. Although potential recall bias cannot be excluded, our findings of this pooled analysis support the hypothesis that residential maternal use of pesticides during pregnancy and particularly insecticides may increase the risk of CBT. Future investigations to verify these findings and to explore for CBT subtypes and dose-response are necessary to have a better understanding of the possible role of pesticides in etiology of CBT., (© 2017 UICC.)
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- 2018
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13. Minimal methylation classifier (MIMIC): A novel method for derivation and rapid diagnostic detection of disease-associated DNA methylation signatures.
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Schwalbe EC, Hicks D, Rafiee G, Bashton M, Gohlke H, Enshaei A, Potluri S, Matthiesen J, Mather M, Taleongpong P, Chaston R, Silmon A, Curtis A, Lindsey JC, Crosier S, Smith AJ, Goschzik T, Doz F, Rutkowski S, Lannering B, Pietsch T, Bailey S, Williamson D, and Clifford SC
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- Brain Neoplasms diagnosis, Child, CpG Islands, Genetic Predisposition to Disease, Humans, Medulloblastoma diagnosis, Software, Brain Neoplasms genetics, DNA Methylation, Genetic Testing methods, Medulloblastoma genetics, Sequence Analysis, DNA methods
- Abstract
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.
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- 2017
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14. Parental smoking, maternal alcohol, coffee and tea consumption and the risk of childhood brain tumours: the ESTELLE and ESCALE studies (SFCE, France).
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Bailey HD, Lacour B, Guerrini-Rousseau L, Bertozzi AI, Leblond P, Faure-Conter C, Pellier I, Freycon C, Doz F, Puget S, Ducassou S, Orsi L, and Clavel J
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- Adolescent, Adult, Alcohol Drinking, Case-Control Studies, Child, Child, Preschool, Coffee, Female, France epidemiology, Humans, Infant, Infant, Newborn, Logistic Models, Male, Mothers, Odds Ratio, Pregnancy, Risk Factors, Smoking, Tea, Astrocytoma epidemiology, Brain Neoplasms epidemiology, Fathers
- Abstract
Purpose: To investigate whether parental smoking around the time of pregnancy or maternal consumption of beverages (alcohol, coffee, or tea) during pregnancy were associated with the risk of CBT., Methods: We pooled data from two French national population-based case-control studies with similar designs conducted in 2003-2004 and 2010-2011. The mothers of 510 CBT cases (directly recruited from the national childhood cancer register) and 3,102 controls aged under 15 years, frequency matched by age and gender, were interviewed through telephone, which included questions about prenatal parental smoking and maternal consumption of alcohol, coffee and tea. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusted for age, sex and study of origin., Results: No association was seen between CBT and the mother smoking or drinking alcohol, coffee, or tea during the index pregnancy. The OR between CBT and paternal smoking in the year before birth (as reported by the mother) was 1.25 (95% CI 1.03, 1.52) with an OR of 1.09 (0.99, 1.19) for every 10 cigarettes per day (CPD) smoked. The association between paternal smoking and CBT appeared to be stronger in children diagnosed before the age of five years (OR 1.52, 95% CI 1.14, 2.02) and for astrocytoma (OR 1.86, 95% CI 1.26, 2.74)., Conclusion: We found some evidence of a weak association between paternal smoking in the year before the child's birth and CBT, especially astrocytomas. These findings need to be replicated in other samples, using similar classifications of tumour subtypes.
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- 2017
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15. Bromodomain and extraterminal protein inhibitors in pediatrics: A review of the literature.
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Jiménez I, Baruchel A, Doz F, and Schulte J
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- Antineoplastic Agents therapeutic use, Cell Cycle Proteins, Child, Child, Preschool, Humans, Transcriptional Activation drug effects, Brain Neoplasms drug therapy, Hematologic Neoplasms drug therapy, Neuroblastoma drug therapy, Nuclear Proteins antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors, RNA-Binding Proteins antagonists & inhibitors, Transcription Factors antagonists & inhibitors
- Abstract
The last few years have seen the identification of pharmacologic approaches to target bromodomain and extraterminal (BET) proteins for cancer treatment. These proteins have an essential role in gene transcription regulation by binding acetylated lysine residues on histone tails, activating gene transcription. BET inhibitors have been tested in preclinical models including pediatric malignancies and several adult clinical trials are ongoing. Since the development of new drugs in pediatric cancer has long lagged behind programs for adults, the aim of this review is to show the importance of these therapies in pediatric malignancies to support their development in pediatric oncology/hematology., (© 2016 Wiley Periodicals, Inc.)
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- 2017
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16. Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study.
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Sabel M, Fleischhack G, Tippelt S, Gustafsson G, Doz F, Kortmann R, Massimino M, Navajas A, von Hoff K, Rutkowski S, Warmuth-Metz M, Clifford SC, Pietsch T, Pizer B, and Lannering B
- Subjects
- Adolescent, Antineoplastic Agents therapeutic use, Brain Neoplasms diagnostic imaging, Brain Neoplasms genetics, Brain Neoplasms mortality, Child, Child, Preschool, Disease-Free Survival, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Medulloblastoma diagnostic imaging, Medulloblastoma genetics, Medulloblastoma mortality, Mutation genetics, N-Myc Proto-Oncogene Protein genetics, Neoplasm Recurrence, Local, Radiotherapy Dosage, Recurrence, Regression Analysis, Secondary Prevention, Young Adult, beta Catenin genetics, Brain Neoplasms radiotherapy, Combined Modality Therapy methods, Medulloblastoma radiotherapy, Treatment Outcome
- Abstract
The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001-2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 ± 2 % and 78 ± 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. >5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 ± 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour., Competing Interests: The authors declare that they have no conflict of interest.
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- 2016
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17. Water and electrolyte disorders at long-term post-treatment follow-up in paediatric patients with suprasellar tumours include unexpected persistent cerebral salt-wasting syndrome.
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González Briceño L, Grill J, Bourdeaut F, Doz F, Beltrand J, Benabbad I, Brugières L, Dufour C, Valteau-Couanet D, Guerrini-Rousseau L, Aerts I, Orbach D, Alapetite C, Samara-Boustani D, Pinto G, Simon A, Touraine P, Sainte-Rose C, Zerah M, Puget S, Elie C, and Polak M
- Subjects
- Adolescent, Brain Neoplasms complications, Brain Neoplasms therapy, Child, Child, Preschool, Craniopharyngioma complications, Craniopharyngioma therapy, Female, Follow-Up Studies, Glioma complications, Glioma therapy, Humans, Inappropriate ADH Syndrome etiology, Incidence, Infant, Male, Pituitary Neoplasms complications, Postoperative Complications epidemiology, Retrospective Studies, Wasting Syndrome etiology, Water-Electrolyte Imbalance etiology, Brain Neoplasms epidemiology, Craniopharyngioma epidemiology, Glioma epidemiology, Inappropriate ADH Syndrome epidemiology, Pituitary Neoplasms epidemiology, Wasting Syndrome epidemiology, Water-Electrolyte Imbalance epidemiology
- Abstract
Background: Patients with brain tumours have a high risk of water and electrolyte disorders (WED). Postsurgery diabetes insipidus (DI) may be transient or permanent, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt-wasting syndrome (CSWS) are usually transient., Methods: Retrospective study, including patients with suprasellar tumours, treated at Hôpital Necker, Institut Gustave-Roussy or Institut Curie, in Île-de-France, between 2007 and 2011. WED were noted if they persisted >1 month after surgery., Results: 159 patients were included, 54.1% girls, 43.9% boys. Tumour types were: glioma (43.4%), craniopharyngioma (43.4%), germinoma (11.3%), others (1.9%). Age at diagnosis was 7.1 ± 4.6 years. The median time from end of treatment was 1.9 (0-7.8) years. DI was the most frequent disorder after tumour treatment (50.3%) and was significantly associated with surgery (p < 0.001). Persistent CSWS was present in 3.6%, persistent SIADH in 1.3%. Two cases of hypernatraemia were due to adipsia. Thyrotropin deficiency after treatment was noted in 68.9% of patients tested, adrenocorticotropin deficiency in 66.2%., Conclusions: Patients with suprasellar tumours have a high incidence of long-term WED, mainly DI. Assessment of thyrotroph and corticotroph function, and thirst sensation, is necessary to diagnose and manage these disorders correctly. CSWS may be persistent in few patients and requires special attention to prescribe the appropriate care., (© 2014 S. Karger AG, Basel.)
- Published
- 2014
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18. Neuropathological and neuroradiological spectrum of pediatric malignant gliomas: correlation with outcome.
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Puget S, Boddaert N, Veillard AS, Garnett M, Miquel C, Andreiuolo F, Sainte-Rose C, Roujeau T, DiRocco F, Bourgeois M, Zerah M, Doz F, Grill J, and Varlet P
- Subjects
- Adolescent, Brain metabolism, Brain Neoplasms mortality, Brain Neoplasms surgery, Child, Child, Preschool, Chromosomal Proteins, Non-Histone metabolism, DNA-Binding Proteins metabolism, Female, Glioma mortality, Glioma surgery, Humans, Infant, Infant, Newborn, Ki-67 Antigen metabolism, Longitudinal Studies, Magnetic Resonance Imaging methods, Male, Nerve Tissue Proteins metabolism, Radiography, Regression Analysis, Reproducibility of Results, Retrospective Studies, SMARCB1 Protein, Survival Analysis, Transcription Factors metabolism, Brain diagnostic imaging, Brain pathology, Brain Neoplasms diagnosis, Glioma diagnosis
- Abstract
Background: The diagnostic accuracy and reproducibility for glioma histological diagnosis are suboptimal., Objective: To characterize radiological and histological features in pediatric malignant gliomas and to determine whether they had an impact on survival., Methods: We retrospectively reviewed a series of 96 pediatric malignant gliomas. All histological samples were blindly and independently reviewed and classified according to World Health Organization 2007 and Sainte-Anne classifications. Radiological features were reviewed independently. Statistical analyses were performed to investigate the relationship between clinical, radiological, and histological features and survival., Results: Cohort median age was 7.8 years; median follow-up was 4.8 years. Tumors involved cerebral hemispheres or basal ganglia in 82% of cases and brainstem in the remaining 18%. After histopathological review, low-grade gliomas and nonglial tumors were excluded (n = 27). The World Health Organization classification was not able to demonstrate differences between groups and patients survival. The Sainte-Anne classification identified a 3-year survival rate difference between the histological subgroups (oligodendroglioma A, oligodendroglioma B, malignant glioneuronal tumors, and glioblastomas; P = .02). The malignant glioneuronal tumor was the only glioma subtype with specific radiological features. Tumor location was significantly associated with 3-year survival rate (P = .005). Meningeal attachment was the only radiological criteria associated with longer survival (P = .02)., Conclusion: The Sainte-Anne classification was better able to distinguish pediatric malignant gliomas in terms of survival compared with the World Health Organization classification. In this series, neither of these 2 histological classifications provided a prognostic stratification of the patients.
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- 2011
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19. [Proton beam therapy in pediatric radiotherapy].
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Habrand JL, Bolle S, Datchary J, Alapetite C, Petras S, Helfre S, Feuvret L, Calugaru V, De Marzi L, Bouyon-Monteau A, Dendale R, Kalifa C, Grill J, and Doz F
- Subjects
- Bone Neoplasms mortality, Bone Neoplasms radiotherapy, Brain Neoplasms mortality, Child, Ependymoma mortality, Ependymoma radiotherapy, Glioma mortality, Humans, Neoplasms mortality, Photons therapeutic use, Proton Therapy, Radiotherapy adverse effects, Radiotherapy instrumentation, Radiotherapy Dosage, Sarcoma mortality, Sarcoma radiotherapy, Survival Rate, Brain Neoplasms radiotherapy, Glioma radiotherapy, Neoplasms radiotherapy, Radiotherapy methods
- Abstract
Pediatric tumors still represent a formidable challenge despite the considerable therapeutical advances that have been reported for the past 30 years. This is largely related with the untowards side-effects of local therapy that are still acknowledged as the "price for cure". In this setting, Proton therapy a sophisticated radiotherapeutical modality seems to represent a real breakthrough due to its unique ability to spare close and distant normal organs compared with modern photons techniques. We summarize in this paper current clinical and dosimetrical evidences including an update of the Orsay series on 108 children.
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- 2009
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20. Brainstem gliomas in children and adults.
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Laigle-Donadey F, Doz F, and Delattre JY
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- Adult, Angiogenesis Inhibitors therapeutic use, Antineoplastic Agents therapeutic use, Biopsy, Brain Neoplasms pathology, Child, Drug Delivery Systems, Glioma pathology, Humans, Magnetic Resonance Imaging methods, Medical Oncology methods, Neoplasm Metastasis, Neurofibromatosis 1 drug therapy, Neurofibromatosis 1 pathology, Signal Transduction, Brain Neoplasms drug therapy, Brain Stem pathology, Glioma drug therapy
- Abstract
Purpose of Review: The purpose of this review is to determine if recent advances in diagnostic and treatment modalities result in improvement in the pattern of care of brainstem gliomas., Recent Findings: New MRI techniques may contribute to differential diagnosis and aid neurosurgeons in removing resectable brainstem tumors. A better radiological analysis of these heterogeneous tumors improves their classification and helps to better distinguish prognosis subgroups. However, biopsy remains indicated in many contrast enhancing brainstem masses in adults because of the great variety of differential diagnosis., Summary: Diffuse brainstem glioma is the most common subtype of brainstem tumor and remains a devastating malignancy in children. Conventional radiotherapy is the standard of care and chemotherapy has been disappointing to date. Given the lack of efficacy of conventional drugs, a better understanding of the biology of this tumor is the key to more targeted therapy.
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- 2008
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21. [A multidisciplinary consultation for children with brain tumors].
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Kieffer V, Oppenheim D, Laroussinie F, Gadalou G, Coutinho V, Ribaille C, Raquin MA, Doz F, Hartmann O, Kalifa C, Laurent-Vannier A, and Grill J
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- Adolescent, Child, Child, Preschool, Developmental Disabilities diagnosis, Developmental Disabilities epidemiology, Female, France epidemiology, Humans, Infant, Male, Neuropsychological Tests, Brain Neoplasms epidemiology, Patient Care Team, Referral and Consultation
- Abstract
Unlabelled: School achievement of children with brain tumors is hampered by progressive neurologic and cognitive sequelae. To help the children and their family, we have created in 1997 a multidisciplinary consultation together with Necker's hospital., Material and Methods: The study describes the organization of the consultation and analyses the files of 69 children seen between September 2001 and June 2002., Results and Conclusion: The authors conclude that this consultation is an irreplaceable mean to coordinate the complex rehabilitation process of a child treated for a brain tumor.
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- 2007
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22. High-grade glioma in children under 5 years of age: a chemotherapy only approach with the BBSFOP protocol.
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Dufour C, Grill J, Lellouch-Tubiana A, Puget S, Chastagner P, Frappaz D, Doz F, Pichon F, Plantaz D, Gentet JC, Raquin MA, and Kalifa C
- Subjects
- Antineoplastic Combined Chemotherapy Protocols administration & dosage, Carboplatin administration & dosage, Child, Preschool, Cisplatin administration & dosage, Cyclophosphamide administration & dosage, Disease-Free Survival, Etoposide administration & dosage, Female, Humans, Infant, Male, Neoplasm, Residual, Procarbazine administration & dosage, Risk Factors, Survival Analysis, Treatment Outcome, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms drug therapy, Glioma drug therapy
- Abstract
The aim of this study was to evaluate a chemotherapy strategy that avoids radiotherapy in first-line treatment of young children with high-grade glioma. A total of 21 children under 5 years of age received the BBSFOP protocol, comprising seven cycles of three drug pairs (carboplatin/procarbazine, cisplatin/etoposide and vincristine/cyclophosphamide) administered over a 16 month period. Radiotherapy was performed in case of recurrence/progression. Median age at diagnosis was 23 months. Histology was classified as World Health Organisation (WHO) grade III in 13 and grade IV in 8. Of the 13 children with a residual tumour, chemotherapy induced 2 partial responses (PR), 1 minor response (MR) and 1 stable disease (SD) with no recurrent disease. Five-year progression-free survival was 35% and 5-year overall survival was 59%, with a median follow-up of 5.2 years. At the last update, 12 children were alive (10 without radiotherapy). In conclusion, this study shows that an adjuvant chemotherapy first approach is safe and allows radiotherapy to be avoided in selected children.
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- 2006
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23. Presentation and evolution of organic central precocious puberty according to the type of CNS lesion.
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Trivin C, Couto-Silva AC, Sainte-Rose C, Chemaitilly W, Kalifa C, Doz F, Zerah M, and Brauner R
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- Adolescent, Adult, Arachnoid Cysts blood, Arachnoid Cysts complications, Astrocytoma blood, Astrocytoma complications, Body Height, Brain Neoplasms blood, Child, Child, Preschool, Female, Follicle Stimulating Hormone blood, Gonadal Steroid Hormones blood, Growth Hormone blood, Growth Hormone-Releasing Hormone, Hamartoma blood, Hamartoma complications, Humans, Hydrocephalus blood, Hydrocephalus complications, Hydrocortisone blood, Hypothalamic Neoplasms blood, Hypothalamic Neoplasms complications, Luteinizing Hormone blood, Male, Meningomyelocele blood, Meningomyelocele complications, Optic Nerve Glioma blood, Optic Nerve Glioma complications, Pituitary Diseases blood, Puberty, Precocious blood, Statistics, Nonparametric, Brain Neoplasms complications, Hypothalamic Diseases etiology, Pituitary Diseases etiology, Puberty, Precocious etiology
- Abstract
Objective: 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., Patients: One hundred patients with CPP caused by central nervous system (CNS) lesion., Results: The CPP was the presenting symptom of the lesion in 25 (10 boys) and occurred in 75 patients (23 boys) previously treated for lesions. These were optic glioma or astrocytoma (n = 45), hydrocephalus (n = 22), hypothalamic hamartoma (n = 15), suprasellar arachnoid cyst (n = 10) and others (n = 8). The percentages of patients with increased height, bone age advance, testicular volume, LH/FSH peaks ratio after gonadotrophin-releasing hormone (GnRH) test and plasma testosterone concentration in boys and oestradiol in girls varied from one aetiology to another. The boys with hamartoma were significantly taller and had greater bone age advance, LH peak and testosterone than boys with optic glioma. The girls with hamartoma and suprasellar arachnoid cyst were significantly younger and had greater LH peak than girls in the other groups. All patients treated for optic glioma had hypothalamic-pituitary deficiencies, including GH (100%), thyrotrophin (71.4%), corticotrophin (12.5%) and pubertal (34.3%) deficiencies. Sixty percent of those with suprasellar cysts lacked GH. Final height was below -2 SD in 15/59 (25%) patients, including 5/11 not treated with GnRH analogue, 3/5 not treated with GH despite GH deficiency, and 2 with hydrocephalus as a result of meningomyelocele., Conclusions: The type of CNS lesion influences the presentation of CPP. This is probably caused by differences in the mechanisms inducing puberty and to the hypothalamic-pituitary deficiencies associated with the CPP as a result of a lesion and/or its treatment.
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- 2006
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24. Temozolomide in malignant gliomas of childhood: a United Kingdom Children's Cancer Study Group and French Society for Pediatric Oncology Intergroup Study.
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Lashford LS, Thiesse P, Jouvet A, Jaspan T, Couanet D, Griffiths PD, Doz F, Ironside J, Robson K, Hobson R, Dugan M, Pearson AD, Vassal G, and Frappaz D
- Subjects
- Adolescent, Antineoplastic Agents, Alkylating administration & dosage, Antineoplastic Agents, Alkylating adverse effects, Bone Marrow drug effects, Child, Child, Preschool, Dacarbazine administration & dosage, Dacarbazine adverse effects, Female, Humans, Male, Temozolomide, Thrombocytopenia chemically induced, Antineoplastic Agents, Alkylating therapeutic use, Brain Neoplasms drug therapy, Dacarbazine analogs & derivatives, Dacarbazine therapeutic use, Glioma drug therapy
- Abstract
Purpose: To determine the response rate of the malignant gliomas of childhood to an oral, daily schedule of temozolomide., Patients and Methods: A multicenter, phase II evaluation of an oral, daily schedule of temozolomide (200 mg/m(2) on 5 consecutive days) was undertaken in children with relapsed or progressive, biopsy-proven, high-grade glioma (arm A) and progressive, diffuse, intrinsic brainstem glioma (arm B). Evidence of activity was defined by radiologic evidence of a sustained reduction in tumor size on serial magnetic resonance imaging scans., Results: Fifty-five patients were recruited (34 to arm A and 21 to arm B) and received 215 cycles of chemotherapy. Grade 3/4 thrombocytopenia was the most frequent toxic event (7% of cycles). Prolonged myelosuppression resulted in significant treatment delays and dose reductions (17% and 22% of cycles, respectively). Two toxic deaths were documented and were related to myelosuppression and sepsis in one patient and pneumonia in a second. The overall (best) response rate was 12% for arm A (95% confidence interval [CI], 3 to 28 in the study cohort, and 2 to 31 for eligible patients) and 5% and 6%, respectively, for arm B (95% CI, 0 to 26 in the study cohort, and 0 to 27 for eligible patients). Stabilization of disease was also documented and was most noteworthy for brainstem gliomas, where two patients achieved both radiologic static disease and discontinued steroid medication., Conclusion: Despite moderate toxicity, objective response rates to temozolomide have been low, indicating that temozolomide has minimal activity in the high-grade gliomas of childhood.
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- 2002
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25. Comparative genomic hybridization detects specific cytogenetic abnormalities in pediatric ependymomas and choroid plexus papillomas.
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Grill J, Avet-Loiseau H, Lellouch-Tubiana A, Sévenet N, Terrier-Lacombe MJ, Vénuat AM, Doz F, Sainte-Rose C, Kalifa C, and Vassal G
- Subjects
- Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 22, Humans, Infant, Male, Brain Neoplasms genetics, Choroid Plexus Neoplasms genetics, Chromosome Aberrations, Ependymoma genetics, Nucleic Acid Hybridization, Papilloma genetics
- Abstract
Pathogenesis and genetic abnormalities of ependymomas are not well known and differential diagnosis with choroid plexus tumors may be difficult when these tumors are located in the ventricles. We analyzed 16 samples of primary pediatric ependymomas and seven choroid plexus tumors for significant gains or losses of genomic DNA, using comparative genomic hybridization (CGH). Four ependymoma samples were obtained after surgery for relapse, including one patient whose tumor was analyzed at diagnosis and at first and second relapses. Three out of 16 ependymomas and none of the choroid plexus tumors appeared normal by CGH. In the remaining ependymomas, the number of regions with genomic imbalance was limited. The most frequent copy number abnormality in ependymomas was 22q loss. In one patient from whom multiple samples could be analyzed during tumor progression, no abnormality was present at diagnosis; gain of chromosome 9 and loss of 6q were observed at first relapse and, at second relapse, additional genomic imbalances were loss of 3p, 10q, and chromosome 15. In choroid plexus tumors, recurrent abnormalities were gains of chromosome 7 and region 12q. The recurrent chromosomal abnormalities were clearly different between ependymomas and choroid plexus papillomas (CPP). Recurrent loss of 22q suggests that this region harbors tumor suppressor genes important in the pathogenesis of ependymomas; however, other pathogenic pathways may exist involving 6q and chromosome 10 losses or gain of 1q and chromosome 9. CPP can be distinguished from ependymoma on the basis of CGH abnormalities.
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- 2002
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26. Supratentorial embryonal tumors in children under 5 years of age: an SFOP study of treatment with postoperative chemotherapy alone.
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Marec-Berard P, Jouvet A, Thiesse P, Kalifa C, Doz F, and Frappaz D
- Subjects
- Brain Neoplasms mortality, Brain Neoplasms pathology, Brain Neoplasms surgery, Child, Preschool, Combined Modality Therapy, Disease-Free Survival, Female, France epidemiology, Humans, Infant, Infant, Newborn, Life Tables, Male, Neuroectodermal Tumors, Primitive mortality, Neuroectodermal Tumors, Primitive pathology, Neuroectodermal Tumors, Primitive surgery, Prognosis, Retrospective Studies, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms drug therapy, Neuroectodermal Tumors, Primitive drug therapy
- Abstract
Background: To determine the effectiveness of multiagent chemotherapy as sole post-operative treatment of supratentorial central nervous system (CNS) embryonal tumors in young children., Procedure: The data of 25 children under 5 years of age diagnosed with supratentorial embryonal tumors (17 primitive neuroectodermal tumors, four pinealoblastomas, and four medulloepitheliomas) treated exclusively by postoperative chemotherapy (CT) between 1990 and 1997 were reviewed., Results: Fifteen tumors were hemispheric and 10 were deeply seated. Four children presented with disseminated leptomeningeal disease. Total resection was performed in nine patients, subtotal in 9, partial in 3, and a diagnostic biopsy only in 2. Two children did not undergo surgery. Twenty-four children relapsed with a median time of 5.5 months. The median overall survival was 12 months, and the 2-, and 5- year survivals were 30 and 14%, respectively. The 2- year disease-free survival was 4%. There was a significantly worse prognosis in patients undergoing incomplete resection and in the group with deeply situated tumors. Four relapses were treated by second surgery followed by high-dose chemotherapy and radiotherapy. Two of them remain in CR2, and all these children are free of late sequelae., Conclusions: CT alone failed to maintain disease-free survival in most of the children, although, disease progression was delayed to some extent. Children under 5 years with supratentorial embryonal tumors should undergo total surgical resection if possible., (Copyright 2002 Wiley-Liss, Inc.)
- Published
- 2002
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27. Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: a multicenter trial of the French Society of Pediatric Oncology.
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Grill J, Le Deley MC, Gambarelli D, Raquin MA, Couanet D, Pierre-Kahn A, Habrand JL, Doz F, Frappaz D, Gentet JC, Edan C, Chastagner P, and Kalifa C
- Subjects
- Brain Neoplasms surgery, Carboplatin administration & dosage, Chemotherapy, Adjuvant, Child, Preschool, Cisplatin administration & dosage, Cyclophosphamide administration & dosage, Disease-Free Survival, Ependymoma surgery, Etoposide administration & dosage, Female, Humans, Infant, Male, Neoplasm Recurrence, Local, Procarbazine administration & dosage, Prognosis, Treatment Outcome, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms drug therapy, Ependymoma drug therapy
- Abstract
Purpose: To evaluate a strategy that avoids radiotherapy in first-line treatment in children under 5 years of age with brain or posterior fossa ependymoma, by exclusively administering 16 months of adjuvant multiagent chemotherapy after surgery., Patients and Methods: Between June 1990 and October 1998, 73 children with ependymoma (82% with high-grade tumors) were enrolled onto this multicenter trial. Children received adjuvant conventional chemotherapy after surgery consisting of seven cycles of three courses alternating two drugs at each course (procarbazine and carboplatin, etoposide and cisplatin, vincristine and cyclophosphamide) over a year and a half. Systematic irradiation was not envisaged at the end of chemotherapy. In the event of relapse or progression, salvage treatment consisted of a second surgical procedure followed by local irradiation with or without second-line chemotherapy., Results: Conventional chemotherapy was well tolerated and could be administered in outpatient clinics. No radiologically documented response to chemotherapy more than 50% was observed. With a median follow-up of 4.7 years (range, 5 months to 8 years), the 4-year progression-free survival rate in this series was 22% (95% confidence interval [CI], 13% to 43%) and the overall survival rate was 59% (95% CI, 47% to 71%). Overall, 40% (95% CI, 29% to 51%) of the patients were alive having never received radiotherapy 2 years after the initiation of chemotherapy and 23% (95% CI, 14% to 35%) were still alive at 4 years without recourse to this modality. In the multivariate analysis, the two factors associated with a favorable outcome were a supratentorial tumor location (P =.0004) and complete surgery (P =.0009). Overall survival at 4 years was 74% (95% CI, 59% to 86%) for the patients in whom resection was radiologically complete and 35% (95% CI, 18% to 56%) for the patients with incomplete resection., Conclusion: A significant proportion of children with ependymoma can avoid radiotherapy with prolonged adjuvant chemotherapy. Deferring irradiation at the time of relapse did not compromise overall survival of the entire patient population.
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- 2001
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28. A high-dose busulfan-thiotepa combination followed by autologous bone marrow transplantation in childhood recurrent ependymoma. A phase-II study.
- Author
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Grill J, Kalifa C, Doz F, Schoepfer C, Sainte-Rose C, Couanet D, Terrier-Lacombe MJ, Valteau-Couanet D, and Hartmann O
- Subjects
- Adolescent, Antineoplastic Combined Chemotherapy Protocols adverse effects, Brain Neoplasms radiotherapy, Brain Neoplasms surgery, Busulfan administration & dosage, Chemotherapy, Adjuvant, Child, Child, Preschool, Combined Modality Therapy, Cranial Irradiation, Dose-Response Relationship, Drug, Ependymoma radiotherapy, Ependymoma surgery, Female, Follow-Up Studies, Humans, Infant, Male, Neoplasm Recurrence, Local radiotherapy, Neoplasm Recurrence, Local surgery, Radiotherapy, Adjuvant, Reoperation, Thiotepa administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation, Brain Neoplasms drug therapy, Ependymoma drug therapy, Neoplasm Recurrence, Local drug therapy
- Abstract
Sixteen children with refractory or relapsed ependymoma were entered in a phase-II study of high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT). The conditioning regimen consisted of busulfan 150 mg/m2/day for 4 days and thiotepa 300 mg/m2/day for the 3 following days. All patients had previously been treated by surgery and conventional chemotherapy. Eight of them had also received irradiation at doses ranging from 45 to 55 Gy at the tumor site. At the time of transplantation, 9 patients were in first relapse, 5 in second relapse and 2 in third relapse or more; all had measurable disease; 15 patients were evaluable for response. No radiologic response > 50% was observed. Stable disease and progressive disease were documented in 10 and 5 cases, respectively. The duration of response to this treatment, which lasted for a median time of 7 months (range: 5-8 months), was only evaluable in 5 patients who did not receive further treatment after ABMT. To date, there are 3 disease-free survivors at 15, 25 and 27 months all of whom were treated with second complete surgical resection and local radiotherapy (55 Gy). Toxicity was severe, mainly digestive and cutaneous, and 1 toxicity-related death occurred. Unlike medulloblastomas, ependymomas do not appear to be sensitive to this combination therapy. New therapeutic approaches are warranted.
- Published
- 1996
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29. A phase II study of intravenous carboplatin for the treatment of recurrent gliomas.
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Warnick RE, Prados MD, Mack EE, Chandler KL, Doz F, Rabbitt JE, and Malec MK
- Subjects
- Adult, Aged, Carboplatin administration & dosage, Carboplatin adverse effects, Disease Progression, Female, Humans, Infusions, Intravenous, Magnetic Resonance Imaging, Male, Middle Aged, Neoplasm Recurrence, Local, Tomography, X-Ray Computed, Brain Neoplasms drug therapy, Carboplatin therapeutic use, Glioma drug therapy
- Abstract
Thirty-two patients with recurrent glioma who had previously received radiation therapy and chemotherapy with nitrosoureas were treated with intravenous carboplatin every 3 weeks, starting at a dose of 350 mg/m2, with a dose escalation of 25 mg/m2 every 6 weeks until a level 4 hematologic toxicity was reached. Of the 28 patients who could be evaluated for a response, 50% demonstrated a response or had stabilization of their disease after two infusions of carboplatin. Their median time to tumor progression and median duration of survival were 19 weeks and 38 weeks. Thrombocytopenia was the major toxicity and was severe in one-third of the patients. No neurologic or renal toxicities were noted. Carboplatin has demonstrated activity against recurrent gliomas in patients who have already had extensive chemotherapy. Increasing the dose of carboplatin may improve the rate of response and the duration of progression-free survival in patients with recurrent glioma.
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- 1994
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30. Effect of pharmacologic doses of zinc on the therapeutic index of brain tumor chemotherapy with carmustine.
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Roosen N, Doz F, Yeomans KL, Dougherty DV, and Rosenblum ML
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- Animals, Bone Marrow drug effects, Bone Marrow metabolism, Carmustine toxicity, Cell Division drug effects, Dose-Response Relationship, Drug, Drug Interactions, Granulocyte Colony-Stimulating Factor, Humans, Injections, Intraperitoneal, Mice, Mice, Inbred BALB C, Mice, Nude, Premedication, Rats, Tumor Cells, Cultured, Zinc administration & dosage, Zinc toxicity, Brain Neoplasms drug therapy, Carmustine therapeutic use, Glioma drug therapy, Zinc therapeutic use
- Abstract
To evaluate the potential differential effect of pretreatment with pharmacologic doses of the trace element zinc on the chemosensitivity of glioma cells and bone marrow cells for carmustine (BCNU), we performed in vitro and in vivo studies of zinc toxicity as well as of the combined treatment with zinc and the anticancer drug. We studied the in vitro effects on established human and rat glioma cell lines using a microcolorimetric growth assay and on murine bone marrow using a clonogenic assay for committed progenitor cells of the granulocyte-monocyte lineage. Zinc exposures of up to 100 microM for 120 h did not influence the growth of six of seven human glioma cell lines. Only U87MG demonstrated statistically significant toxicity during high zinc exposure (100 microM over 120 h). Dose-response growth curves generated for BCNU did not show protection against the anticancer agents by a 48-h pretreatment with different zinc concentrations. The clonogenic capacity of bone marrow cells was slightly reduced by in vitro culture for 24 and 48 h. Although this effect appeared to be more prominent in the presence of zinc supplementation, overall a statistically significant inhibition was seen only after exposure to a concentration of 100 microM zinc over 48 h. As compared with chemotherapy alone, in vitro pretreatment with 50 microM zinc over 48 h followed by chemotherapy resulted in an increased number of colony-forming unit-granulocyte monocyte (CFU-GM): CFU-GM increased by a factor of 2 for BCNU (60 microM x 2 h). This statistically significant in vitro chemoprotection would translate into a dose-protection factor of 1.5, i.e., for the same level of myelosuppression, zinc pretreatment would allow administration of a 50% increased dose of BCNU. The in vivo studies were performed in an s.c. xenograft model of the human glioma cell line U87MG in athymic mice. The maximal tolerable pretreatment with zinc was determined to be a 10-day course of daily i.p. injections of 10 mg/kg ZnCl2. The subsequent i.p. administration of the dose lethal to 10% of the mice (LD10) and of a 1.5 x LD10 dose of BCNU resulted in less bone marrow toxicity in pretreated animals than in non-zinc-pretreated mice as determined in a CFU-GM assay. Glioma colony-forming efficiency (CFE) assays, on the other hand, did not show any zinc-related difference in the BCNU sensitivity of U87MG.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1994
- Full Text
- View/download PDF
31. [Malignant cerebral tumors in children].
- Author
-
Doz F
- Subjects
- Brain Neoplasms pathology, Child, Ependymoma therapy, Glioma pathology, Humans, Brain Neoplasms therapy, Cerebellar Neoplasms therapy, Glioma therapy, Medulloblastoma therapy
- Abstract
Malignant brain tumours (mainly medulloblastoma, glioma, and ependymoma) are the first cause of solid tumours in children, and a major cause of mortality from cancer in paediatrics. The most frequent circumstance of discovery is intracranial hypertension. Early and atypical signs should give the alarm and call for emergency neuroradiological explorations. Major therapeutic advances have been made in the last ten years in the fields of neurosurgery, radiotherapy and chemotherapy of brain tumours in children. Multidisciplinary care is now indispensable usually as part of multicentre cooperative clinical trials. Therapeutic approaches are guided by a concern not only for effectiveness, but also for low toxicity, in order to reduce the long-term sequelae often caused by irradiation of the developing central nervous system.
- Published
- 1993
32. Metallothionein and anticancer agents: the role of metallothionein in cancer chemotherapy.
- Author
-
Doz F, Roosen N, and Rosenblum ML
- Subjects
- Alkylating Agents pharmacology, Animals, Cell Division drug effects, Drug Resistance, Humans, Platinum Compounds pharmacology, Antineoplastic Agents pharmacology, Brain Neoplasms drug therapy, Metallothionein physiology
- Abstract
Metallothioneins (MTs) are intracellular proteins containing the highest amount of thiol groups within the cytoplasm. These thiol groups are able to bind several cytotoxic agents, such as platinum compounds and alkylating agents. Increased levels of MT are one mechanism of resistance to these anticancer drugs, as intracytoplasmic binding of MT prevents the active molecules from reaching their target, the intranuclear DNA of tumor cells. MT synthesis can easily be induced by physiologic heavy metals such as zinc and copper. Pharmacological modulation of MT levels has been used to increase the MT pool in normal tissues and decrease their susceptibility to the toxicity of anticancer drugs. In the case of tumors arising in the brain, where the inducibility of MT synthesis is low, this approach would allow protection of normal tissues without decreasing the antitumor activity of the cytotoxic agents. The interaction of MT with cytotoxic agents is not limited to covalent binding. A correlation between MT synthesis and amplification of oncogenes such as ras has been reported. Furthermore, the cytotoxic drugs are bound by MT after competition with zinc and copper; these metals are cofactors of numerous metalloenzymes, some of which are involved in the metabolism of nucleic acids. Competitive displacement of these metals might modify nucleic acid metabolism and influence cellular proliferation. On the other hand, increased MT levels could provide a zinc cofactor reserve that increases the cell's reparative potential when faced by DNA damage by cytotoxic agents.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1993
- Full Text
- View/download PDF
33. Experimental basis for increasing the therapeutic index of cis-diamminedicarboxylatocyclobutaneplatinum(II) in brain tumor therapy by a high-zinc diet.
- Author
-
Doz F, Berens ME, Deschepper CF, Dougherty DV, Bigornia V, Barker M, and Rosenblum ML
- Subjects
- Animals, Blotting, Northern, Brain drug effects, Brain metabolism, Brain Neoplasms blood, Carboplatin adverse effects, Carboplatin pharmacology, Diet, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells metabolism, Kidney drug effects, Kidney metabolism, Metallothionein genetics, Mice, RNA, Messenger analysis, Rats, Tumor Stem Cell Assay, Zinc pharmacology, Brain Neoplasms drug therapy, Carboplatin administration & dosage, Metallothionein biosynthesis, Zinc administration & dosage
- Abstract
Metallothionein (MT), a ubiquitous intracellular protein, confers resistance to the toxic effects of platinum compounds. Since a high-zinc diet has been shown to induce MT synthesis in extracerebral tissues but not in brain, we investigated whether it could provide an experimental basis for decreasing the hematotoxicity of carboplatin without impairing its activity against brain tumors. After 2 weeks on either a high-zinc diet or a control diet (zinc content, 180 vs 10 ppm), mice and rats received various doses of carboplatin or Hanks' balanced salt solution by i.p. injection. The hematotoxicity of carboplatin was evaluated with an assay of colony-forming units of granulocytes and mononuclear cells in mice. The high-zinc diet enabled a 50% increase in the carboplatin dose without increasing hematotoxicity. The antitumor activity was evaluated with an assay of the colony-forming efficiency of gliosarcoma cells from 9L brain tumors in rats. The high-zinc diet did not alter the efficacy of carboplatin against this brain tumor. Northern blot analysis confirmed that the high-zinc diet induced MT mRNA in the kidney but not in the brain of mice and rats; it also showed MT mRNA induction in bone marrow cells of mice but not in rat 9L brain tumors. These results suggest that increasing the dietary intake of zinc might increase the therapeutic index of carboplatin in the treatment of brain tumors.
- Published
- 1992
- Full Text
- View/download PDF
34. Experimental basis for increasing the therapeutic index of carboplatin in brain tumor therapy by pretreatment with WR compounds.
- Author
-
Doz F, Berens ME, Spencer DR, Dougherty DV, and Rosenblum ML
- Subjects
- Bone Marrow drug effects, Bone Marrow Cells, Carboplatin toxicity, Cell Line, Cells, Cultured drug effects, Colony-Forming Units Assay, Drug Interactions, Drug Screening Assays, Antitumor, Glioma drug therapy, Humans, Tumor Cells, Cultured drug effects, Brain Neoplasms drug therapy, Carboplatin therapeutic use, Mercaptoethylamines therapeutic use
- Abstract
We tested an experimental strategy to decrease the dose-limiting hematotoxicity of carboplatin without compromising its activity against brain tumors. The effect of pretreatment with WR-1065, a chemomodifier that penetrates brain poorly, on carboplatin's cytotoxicity was evaluated in human hematopoietic granulocyte-monocyte progenitor cells and in three human glioblastoma cell lines. WR-1065 reduced bone marrow toxicity without decreasing carboplatin's activity against glioblastoma cells. These results suggest that the therapeutic index of carboplatin might be increased in the treatment of malignant brain tumors.
- Published
- 1991
- Full Text
- View/download PDF
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