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Elucidating how adaptive and maladaptive changes to the structural connectivity of brain networks influences neural synchrony, and how this structure-function coupling impacts cognition is an important question in human neuroscience. This study assesses these links in the default mode and executive control networks during resting state, a visual-motor task, and through computational modeling in the developing brain and in acquired brain injuries. Pediatric brain tumor survivors were used as an injury model as they are known to exhibit cognitive deficits, structural connectivity compromise, and perturbations in neural communication. Focusing on information processing speed to assess cognitive performance, we demonstrate that during the presence and absence of specific task demands, structural connectivity of these critical brain networks directly influences neural communication and information processing speed, and white matter compromise has an indirect adverse impact on reaction time via perturbed neural synchrony. Further, when our experimentally acquired structural connectomes simulated neural activity, the resulting functional simulations aligned with our empirical results and accurately predicted cognitive group differences. Overall, our synergistic findings further our understanding of the neural underpinnings of cognition and when it is perturbed. Further establishing alterations in structural-functional coupling as biomarkers of cognitive impairments could facilitate early intervention and monitoring of these deficits., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the efficacy of aerobic exercise training to improve controlled attention, information processing speed and neural communication during increasing task load and rest in pediatric brain tumor survivors (PBTS) treated with cranial radiation., Methods: Participants completed visual-motor Go and Go/No-Go tasks during magnetoencephalography recording prior to and following the completion of 12-weeks of exercise training. Exercise-related changes in response accuracy and visual-motor latency were evaluated with Linear Mixed models. The Phase Lag Index (PLI) was used to estimate functional connectivity during task performance and rest. Changes in PLI values after exercise training were assessed using Partial Least Squares analysis., Results: Exercise training predicted sustained (12-weeks) improvement in response accuracy (p<0.05) during No-Go trials. Altered functional connectivity was detected in theta (4-7Hz) alpha (8-12Hz) and high gamma (60-100Hz) frequency bands (p<0.001) during Go and Go/No-Go trials. Significant changes in response latency and resting state connectivity were not detected., Conclusion: These findings support the efficacy of aerobic exercise to improve controlled attention and enhance functional mechanisms under increasing task load in participants., Significance: It may be possible to harness the beneficial effects of exercise as therapy to promote cognitive recovery and enhance brain function in PBTS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Facial emotion recognition (FER) deficits are evident and pervasive across neurodevelopmental, psychiatric, and acquired brain disorders in children, including children treated for brain tumours. Such deficits are thought to perpetuate challenges with social relationships and decrease quality of life. The present study combined eye-tracking, neuroimaging and cognitive assessments to evaluate if visual attention, brain structure, and general cognitive function contribute to FER in children treated for posterior fossa (PF) tumours (patients: n = 36) and typically developing children (controls: n = 18). To assess FER, all participants completed the Diagnostic Analysis of Nonverbal Accuracy (DANVA2), a computerized task that measures FER using photographs, while their eye-movements were recorded. Patients made more FER errors than controls (p < .01). Although we detected subtle deficits in visual attention and general cognitive function in patients, we found no associations with FER. Compared to controls, patients had evidence of white matter (WM) damage, (i.e., lower fractional anisotropy [FA] and higher radial diffusivity [RD]), in multiple regions throughout the brain (all p < .05), but not in specific WM tracts associated with FER. Despite the distributed WM differences between groups, WM predicted FER in controls only. In patients, factors associated with their disease and treatment predicted FER. Our study provides insight into predictors of FER that may be unique to children treated for PF tumours, and highlights a divergence in associations between brain structure and behavioural outcomes in clinical and typically developing populations; a concept that may be broadly applicable to other neurodevelopmental and clinical populations that experience FER deficits., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

There is growing evidence that exercise induced experience dependent plasticity may foster structural and functional recovery following brain injury. We examined the efficacy of exercise training for neural and cognitive recovery in long-term pediatric brain tumor survivors treated with radiation. We conducted a controlled clinical trial with crossover of exercise training (vs. no training) in a volunteer sample of 28 children treated with cranial radiation for brain tumors (mean age = 11.5 yrs.; mean time since diagnosis = 5.7 yrs). The endpoints were anatomical T1 MRI data and multiple behavioral outcomes presenting a broader analysis of structural MRI data across the entire brain. This included an analysis of changes in cortical thickness and brain volume using automated, user unbiased approaches. A series of general linear mixed effects models evaluating the effects of exercise training on cortical thickness were performed in a voxel and vertex-wise manner, as well as for specific regions of interest. In exploratory analyses, we evaluated the relationship between changes in cortical thickness after exercise with multiple behavioral outcomes, as well as the relation of these measures at baseline. Exercise was associated with increases in cortical thickness within the right pre and postcentral gyri. Other notable areas of increased thickness related to training were present in the left pre and postcentral gyri, left temporal pole, left superior temporal gyrus, and left parahippocampal gyrus. Further, we observed that compared to a separate cohort of healthy children, participants displayed multiple areas with a significantly thinner cortex prior to training and fewer differences following training, indicating amelioration of anatomical deficits. Partial least squares analysis (PLS) revealed specific patterns of relations between cortical thickness and various behavioral outcomes both after training and at baseline. Overall, our results indicate that exercise training in pediatric brain tumor patients treated with radiation has a beneficial impact on brain structure. We argue that exercise training should be incorporated into the development of neuro-rehabilitative treatments for long-term pediatric brain tumor survivors and other populations with acquired brain injury. (ClinicalTrials.gov, NCT01944761).

Purpose: Prospective and longitudinal neuroimaging studies of posterior fossa tumors are scarce. Here we evaluate the early changes in white matter and intellectual outcome up to 3 years after diagnosis., Patients and Methods: Twenty-two children with posterior fossa tumors and 24 similarly-aged healthy children participated. Patients included: (a) 12 individuals who received surgery, cranial-spinal radiation (CSR), and focal radiation to the tumor bed (CSR group) and (b) 10 individuals who received local therapy, either surgery only or surgery and focal radiation to the tumor bed (Local group). Diffusion tensor imaging (DTI) and intelligence measures were obtained an average of 3 months after diagnosis and then at 12, 24, and 36 months later. DTI tractography and voxel-wise approaches were employed. The Neurological Predictor Scale was used to summarize the type and amount of treatment for PF tumor patients. Linear mixed modelling was used to evaluate group differences at baseline and changes over time in DTI metrics for both the specific white matter tracts and voxel-wise, as well as for intelligence measures., Results: Based on tractography, patients treated with CSR had significantly higher Axial and Mean diffusivity in the cortical-spinal tracts (CST) 3 month after diagnosis - particularly on the right side, p < .003, compared to healthy children. Mean diffusivity in right CST decreased over time in this group of patients, p = .001. No differences compared to controls were evident in specific tracts for the Local group, p > .10. Voxel-wise analyses revealed multiple areas of white matter compromise in both patients groups. Notably, both patient groups had lower scores on intelligence measures compared to the Control group: The CSR group displayed lower performance 3 months following diagnosis, ps < 0.001, and their performance remained stable over time ps > 0.10, whereas the Local group displayed no differences at 3 months, ps> 0.10, but their performance declined over time, ps < 0.01. At baseline, higher MD in right CST predicted lower Perceptual Reasoning scores across all participants, p = .001. Furthermore, lower FA in left IFOF at baseline predicted decline in Processing Speed over time, p = .001. In patients, more aggressive treatment protocols and presence of mutism were related to lower performance on intelligence measures at baseline, ps < 0.04., Conclusions: Children treated with CSR displayed diffuse white matter compromise and poor intellectual outcome shortly after radiation treatment. There was evidence of subsequent growth of white matter structure, but stable intellectual insult. Conversely, in children treated with either surgery only or surgery and focal radiation to the tumor bed we observed less compromise of white matter early following treatment and no intellectual insult compared to healthy children. However, declines in intellectual function were evident for these children, though their performance remained within the average normative range. Overall, results suggest that early intervention is necessary to circumvent these deficits., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We describe parental attitudes toward the return of targeted and incidental genomic research results in the setting of high-risk pediatric cancer and inherited childhood diseases., Methods: A validated 36-item questionnaire was mailed to participants in three large-scale genome research consortia examining attitudes toward receipt of genomic research results and the influence of certainty, severity, and onset of the condition, in addition to responsibilities to extended family and provision of results even after death of the proband., Results: Of the 563 participants who were sent questionnaires, 362 (64%) responded. Most of them stated a positive right to receive results related to the target condition (97%) or to incidental findings (86%); no difference was found in results between participants with cancer and those with orphan diseases. Furthermore, 92% indicated that genomic research for childhood-onset conditions should occur. The majority wanted incidental results predicting susceptibility even to untreatable fatal conditions (83%), to multiple conditions (87%), or to those with uncertain impact (70%). Most felt sibling genomic results showing serious conditions, whether treatable (93%) or not (88%), and/or results discovered after death of the proband should be shared with family (74%)., Conclusion: Many parents of children in pediatric genomic research indicated a strong desire to receive a broader range of results than is described in consensus recommendations. Clear delineation of what will be offered should be established at the time of consent.

Purpose: The purpose of this study was to explore the attitudes of genomics researchers in a pediatric setting in the context of regulatory guidance recommending the disclosure of clinically significant research findings., Methods: A validated 32-item questionnaire was sent to 107 researchers with two large-scale projects (the Canadian Pediatric Cancer Genome Consortium and the Finding of Rare Genes Canada Consortium). We examined researchers' attitudes toward obligations to offer genomic research results (including if the participant was deceased, a relative, or a child), influence of the certainty/severity of the condition on this obligation, and personal experiences., Results: Of the 107 researchers, 74 (69%) responded. Researchers did not feel a strong responsibility to look for meaningful incidental results in the research genomic data set (n = 27, 37%). However, once identified, they felt participants had a strong right to receive them, irrespective of being incidental (n = 50, 68%) or primary targets (n = 64, 87%). There was a high degree of support for informing siblings of genomic results (n = 46, 62%), especially for treatable conditions (n = 56, 76%). Less than half of the participants indicated that their research ethics board required an offer of results (n = 34, 46%) or provided a detailed process (n = 16, 22%)., Conclusion: Researchers strongly support the offer of targeted and incidental genomic research results to participants. Greater regulatory guidance is needed for a consistent approach.

Embryonal brain tumors, which include medulloblastoma and the more aggressive supratentorial primitive neuroectodermal tumor (sPNET), comprise one of the largest group of malignant pediatric brain tumors. We observed in high resolution array comparative genomic hybridization and polymerase chain reaction analyses that several different components of the CDK/CYCLIND/pRB regulatory complex, including the CDK4/6 and CCND1/2 loci, are targets of gene amplification in medulloblastoma and sPNET. CDK6 and CCND1 gene amplification were respectively most common and robust, and overall CDK/CYCLIND gene amplification was more commonly observed in sPNET (25%) than medulloblastoma (1-5%). CDK6 overexpression enhanced in vitro and in vivo oncogenicity and endogenous CDK6 or CCND1 knockdown decreased pRB phosphorylation and impaired cell cycle progression in both medulloblastoma and sPNET cell lines. Although animal models implicate the pRB tumor suppressor pathway in medulloblastoma and sPNET, mutations of RB1 or the related INK4 tumor suppressor loci are rare in primary human tumors. Our data suggest that CDK/CYCLIND gene amplification may represent important mechanisms for functional inactivation of pRB in medulloblastoma and sPNET., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Advances in the management of pediatric brain tumors have been less successful than in other areas of pediatric oncology. This gap in outcome is essentially related to specific aspects of these tumors in this age group such as the fact that the surrounding brain is still developing, vital structures limit aggressive attempts at removing infiltrating lesions, drug penetration into the central nervous system is often poor and short and long term toxicities of some treatments to the surrounding brain are significant. This review describes new therapeutic strategies and their impact in the pediatric neuro-oncology practice. Although the number of new active antineoplastic agents has been limited during the last decade, significant improvements in the chemotherapeutic management of pediatric brain tumors have been observed. These relate to the optimization of chemotherapy protocols, the development of new schedules of administration such as metronomic schedules, sequential high dose chemotherapy, concomitant administration of chemotherapy and radiation, or the introduction of intrathecal or intraventricular chemotherapy in specific protocols. Technological advances in radiotherapy allow delivering optimal doses to the target volume while decreasing the volume of normal surrounding tissue receiving radiation. As a consequence, conformal radiation therapy currently plays a major role in the management of several pediatric brain tumors, including in infants where radiation has been traditionally avoided. The role of molecularly targeted agents is still unclear and a number of phase I and II trials are ongoing to better define the future of these new therapies in pediatric brain tumors., (2010 Elsevier Ltd. All rights reserved.)

Spontaneous tumor regression of pediatric low-grade gliomas (PLGG). We speculated that lack of telomere maintenance is responsible for this behavior. We first looked for evidence of telomerase activity and alternative lengthening of telomeres (ALT) in 56 PLGG. Telomerase activity was observed in 0 of 11 PLGG, in contrast to 10 of 13 high-grade pediatric brain tumors. There was no ALT in 45 of 45 samples. We then applied Q-FISH to eight patients whose indolent PLGG underwent two metachronous biopsies over a lag of several years. Telomere shortening was observed in the second biopsy in all tumors, but not in normal brain control (P < .0001), indicating that lack of telomere maintenance is associated with continuous telomere erosion. Based on these observations, we found that younger PLGG patients, who exhibit more aggressive and frequently recurrent tumors, had significantly longer telomeres than older ones (P = .00014). Tumors with a terminal restriction fragment length <7.5 did not recur, whereas the presence of longer telomeres (>8.0) conferred a high likelihood of late recurrences in PLGG. Our findings provide a plausible biologic mechanism to explain the tendency of PLGG to exhibit growth arrest and spontaneous regression. Telomere maintenance may therefore represent the first known biologic prognostic marker in PLGG.

Unlabelled: Complete staging (extensive marrow investigation and meta-iodo benzylguanine (MIBG) scan) is considered as mandatory both at diagnosis and after chemotherapy for assessment of metastases in neuroblastomas. However the correlation between bone marrow invasion and uptake of MIBG at metastatic sites remains unclear. This study investigates whether MIBG alone is sufficiently sensitive to make these procedures redundant., Patients and Methods: 20 children over one year of age, with histologically proven metastatic neuroblastoma were studied. Extensive bone marrow assessment and MIBG bone scan performed both at diagnosis and after completion of induction chemotherapy were reviewed., Results: At diagnosis metastases were detected by marrow investigation alone in 2, MIBG alone in 2 and both procedures in 16. After induction chemotherapy metastases were detected by only marrow investigation in 2, by only MIBG in 3, by both procedures in 6 patients, and by none in 9., Conclusions: Whether marrow investigations and MIBG scan explore the same phenomenon remains unclear. However it appears that marrow disease that is histologically detectable may remain MIBG negative both at diagnosis and after treatment. Both procedures are still justified at time of diagnosis and evaluation of response., (Copyright John Libbey Eurotext 2003.)

From 1975 to 1997, thirty seven newly diagnosed children aged 2 mos. to 14.3 years with diffuse medulla oblongata or pontine tumours were referred to the Centre Léon Bérard. Surgical biopsies were performed in 9 patients. All but one received radiation therapy. The mean dose of radiation was 53 Gy. Thirty two received chemotherapy. All patients died, one from related toxicity, and the rest from progressive disease. Relapses always occurred in the radiotherapy field. Medulla oblongata and pontine tumours would appear to have the worst outcome of all brain stem gliomas and should be separately analysed.

The continuing growth of the Internet has transformed the access to medical information. However, there are still little data on the quality of e-Health information available. This study examined the content and readability of paediatric neuro-oncology information on the Internet in the French language. The first 30 uniform/universal resource locators (URLs) from each of six search engines using the search terms "medulloblastoma", "ependymoma", "craniopharyngioma", "brainstem glioma" and "low grade glioma" were retrieved for accuracy and evaluation when appropriate. Eligible web sites were rated using the Discern instrument and a 13-items checklist. Readability was assessed using Flesch Reading Ease score. Out of 815 sites visited, only 22 fulfilled the evaluation criteria. Most sites rated either fair (25%), poor (59%) or very poor (13%). The mean readability score was 19.8 (6-32), indicative of poor accessibility by readability and complex vocabulary content. The poor quality of e-Health information is not specific of Web sites in French. The role of cooperative groups and the Health Care System in providing and disseminating clear and compelling medical information is essential., (Copyright John Libbey Eurotext 2003.)

School integration of children with brain tumor is part of the quality of their life. It may also become a nightmare both for the child and for the teacher when no recommendation has been addressed to the latter. In France, official recommendations allow the meeting and information exchanges in the school between teachers and all the people who take care medically of the child. We report our experience in Centre Léon-Bérard of Lyon, concerning 38 children with brain tumors (102 meetings). Though difficult to assess scientifically, the benefit from these meetings is obvious. For the teachers: the knowledge and understanding of the physiopathology of brain tumors and secondary sequellae facilitates teaching. For the child: the disappearance of surrounding fears and fantasms make life easier. This experience is so rich that it should be extended to other pathologies.

Unlabelled: Brain tumours constitute the most common type of solid malignancy in childhood. Despite intensive efforts developed since the mid-1970s in paediatric neuro-oncology, survivors still have a wide range of sequelae leading to frequent failure in academic achievements. Very few studies have detailed the educational outcome of these children., Patients and Methods: The study was based on a questionnaire sent to the parents of children diagnosed with a brain tumour and treated at the Centre Léon-Bérard between 1987 and 1993. Children had to be under 12 years old at the time of diagnosis and with at least three years of follow-up since diagnosis. Questions focused on the child's education before diagnosis, his progress during and after treatment, the measures taken when the child experienced learning difficulties and their consequences on the child's socioprofessional integration., Results: Twenty-seven responses were obtained out of 34 questionnaires. Twenty-six children were reported to experience learning difficulties. Only four children had a normal education. The main problems are associated with slowness, memory and comprehension difficulties. The main disciplines affected are mathematics, reading and spelling. Fifteen children did benefit from extra support, with large interindividual variations in the amount and the quality of this support. Half of the parents play an active role in their child's extra support., Conclusions: This study provides additional information to previous reports on progressive I.Q. decline following the treatment of a brain tumour in childhood. Learning difficulties are nearly constant and adversely influence the child's curriculum. They also affect the parents who experience questions about the future of their ideal child. The severity and complexity of these learning difficulties urge for an early multidisciplinary educational and psychological management. The main characteristics of these remedial efforts should be assessed in prospective studies.

Effective chemotherapy using PCV (procarbazine, lomustine and vincristine) has been documented in anaplastic oligodendrogliomas and oligoastrocytomas. A pilot study using PCV was conducted for relapsing patients with anaplastic oligodendrogliomas and oligoastrocytomas. Preliminary results are reported. Fourteen patients were enrolled. All received at least two courses of PCV and were evaluable for response. Eleven patients (78%) responded to chemotherapy with complete responses in 2 patients. Response was more obvious regarding contrast enhanced areas than volumes changes (11 responses versus 7). A story of seizure was the main clinical prognostic factor for response. All toxicities were manageable and no treatment related death occurred. Chemotherapy is an effective treatment in aggressive oligodendrogliomas. Further studies must assess the role of chemotherapy in the multidisciplinary management of oligodendroglioma.

Craniospinal irradiation is the gold standard treatment used in non metastatic medulloblastoma as prophylaxis against central nervous system (CNS) metastases. However, given the severe late effects caused by this procedure in children under 3 years of age, most pediatric oncologists are currently treating these patients with conventional chemotherapy in order to postpone or even avoid irradiation. In the French Society of Pediatric Oncology (SFOP) this attitude has been adopted since 1990. Among the patients treated without radiotherapy, 20 relapsed while on conventional chemotherapy and were entered in a study of high-dose chemotherapy (HDC) followed by autologous bone marrow transplantation (ABMT). Their median age at diagnosis was 23 months (range: 5-71 months) and the relapse occurred at a median time of 6.3 months after the initiation of chemotherapy. Complete surgical removal of the local relapse was the first treatment in 4/20 patients who were not evaluable for response. Sixteen of the 20 patients had measurable disease at the primary site (9 patients), or at metastatic sites (3 patients) or both (4 patients). The conditioning regimen consisted of combination busulfan 600 mg/m2 over 4 days and thiotepa 900 mg/m2 over 3 days. After recovery from aplasia, patients with a local relapse received local radiotherapy limited to posterior fossa. Among the 16 patients with measurable disease, 6 complete responses, 6 partial responses, 3 non response, were observed following HDC (response rate 75%). One patient was not evaluable. For the 20 patients, the event free survival (EFS) is 50%. Among the surviving patients, the median follow-up is 39.5 months post BMT (range: 21-92 months). Ten patients who developed a local relapse or local progression are alive with non evidence of disease (NED) without craniospinal irradiation. Among the 7 patients who developed a metastases or progression of metastases, only 1 is alive. Toxicity was high but manageable. One complication-related death occurred 1 month post BMT. With a 75% response rate, this HDC proved to be very efficient in relapsed medulloblastoma. A longer follow-up is necessary to demonstrate whether, after a local relapse, HDC could replace craniospinal irradiation as prophylaxis against CNS metastases.

Background: Outcome of patients with retinoblastoma is strongly related to the extent of the disease at diagnosis. Thus, prognosis of extra-ocular retinoblastoma is poor and metastases to central nervous system are usually fatal., Case Report: An 8-year-old child presented with a late recurrence of bilateral retinoblastoma. Initial treatment had associated enuclation of the left eye and radiation therapy on the right. At time of tumour recurrence, clinical examination showed cervical lymph nodes. There was a large frontal metastasis on the CT scan and bone marrow examination showed a minimal involvement by malignant cells. The patient achieved complete remission with high dose etoposide and carboplatin; he subsequently underwent massive chemotherapy followed by bone marrow rescue, and received additional radiation therapy on the frontal and cervical areas. He is well, five years after relapse., Conclusions: This case highlights efficacy of chemotherapy in advanced retinoblastomas. Intensive chemotherapy is a promising and potentially curative approach in the management of advanced or metastatic retinoblastomas.

Unlabelled: Bloom syndrome is characterized by growth failure, skin anomalies with sun sensitivity, minor anatomic defects, excessive chromosomic fragility and usually severe immune deficiency. The chromosome fragility predisposes these children to the development of hematologic malignancies and solid tumors., Case Report: Morgan, a 4-year-old boy with Bloom syndrome, developed a Wilms tumor. Chemotherapy was poorly tolerated. Two years later, the child died from an uncontrolled progressive disease., Conclusion: This is the fourth reported case of Wilms tumor occurring in a child with Bloom syndrome. This possibility requires repeated abdominal ultrasonography in such patients.

Background: School intervention programs for children and adolescents with cancer have been developed in France during the last years. Their primary objective is to improve the pschychosocial adaptation of these children to normal life through school integration. These programs are however inadequate for these children who will ultimately die from their disease and may require a specific school intervention., Material and Methods: School data from 30 children requiring palliative care were prospectively collected. School interest, its evolution and specific adaptations according to the child's status were analysed., Results: Sixty per cent of the children showed a continuous desire for school education throughout their life's end. Reading, mathematics and computer work were the most favorite topics. Physical disability and fatigue may change their request during the evolution of the disease. School refusal occurred in 40% of the children and is mainly due to other extra-academic topics, or related to uncontrolled pain., Conclusion: Objectives of life's end school are different from educational programs proposed for children with cancer. They must be part of palliative care and have to be defined as a specific entity.

The usual sites of initial metastatic deposits in neuroblastoma are osteo-medullary. With modern therapies including megatherapy and hematopoietic rescue, prolonged survival is obtained. However, unusual metastatic sites are more and more often described during the prolonged evolution of these patients such as brain metastases. A case of isolated intracerebral metastatic relapse is reported here in a patient who had received 4 months before a megatherapy in first complete remission. Pathogeny and therapeutical implications are discussed.

Background: Lumbar puncture is a common procedure in pediatric onco-hematology. Repeated invasive painful procedures may contribute to increase distress displayed during medical treatment, and cause regression, depression and other psychological disorders., Material and Methods: A two-year workshop of the Société française d'oncologie pédiatrique was reviewed through a questionnaire assessing changes in technical management of lumbar puncture, local anesthesia, sedation and cognitive-behavioral interventions., Results: Significant changes were found for pain assessment, local anesthesia procedures, and nitrous oxide administration. The extensive use of the Emla cream largely contributed to reduce pain. Anxiety however remained an unsolved problem, particularly among young children., Conclusion: Pain in pediatrics remains a major challenge. This workshop is a model of reflexion to achieve a better management of pain during invasive medical procedures.

In most reported series, less than 20% of patients with primary cerebral non-Hodgkin's lymphoma (PCL) and no known cause of immunodepression are alive and disease-free 5 years after the initial diagnosis. Whether chemotherapy improves the outcome of these patients remains unclear. We report a pilot study of a protocol (C5R) with 5 courses of chemotherapy followed by cranial radiotherapy in 25 adult patients with PCL and no known cause of immunodepression. The median age was 51 years (range, 16 to 70 years) and the median performance status was 2 (range, 1 to 4) in this series. Fourteen patients (56%) achieved a complete response and 4 (16%) achieved a partial response 1 month after the completion of the treatment. Four patients died in the first month of treatment because of progression (n = 1) or toxicity (n = 3). In 3 patients, the treatment could not be performed because of patient refusal (n = 1) or severe infections (n = 2). Myelosuppression was the most frequent side effect; febrile neutropenia occurred in 96%, 89%, 69%, and 74% of the patients after the second, third, fourth, and fifth courses of chemotherapy, respectively. Grade 4 thrombocytopenia occurred in 20% of the patients. With a median follow-up of 24 months, the projected survival of the group at 2 and 5 years is 70% and 56%, respectively. The 4 early deaths occurred in the subgroup of 6 patients greater than 60 years of age with an international prognostic index (IPI) greater than 3. In the 19 remaining patients (76% of this series) less than 61 years of age or with an IPI less than 4, the projected overall survival at 2 and 5 years is 88% and 70%, respectively. The C5R protocol is a highly efficient regimen in nonimmunosuppressed patients with PCL less than 61 years of age or with an IPI less than 4.

Despite high local control rate in Ewing's sarcoma the exact indication of radiation therapy is still controversial as well as the choice of the target volume and the optimal dose of radiation. The importance of the quality of radiotherapy has been stressed in recently published data and has shown a significant impact on long term local control with adequate radiation therapy. The dramatic improvement of precision allowed by the conformal therapy and three dimensional dosimetry allow to expect a decrease of late effects expected for second malignancies. However, late sequellae and radio-induced osteosarcoma still remain the major side effects after radiotherapy. The authors discuss the results of the main trials on Ewing's sarcoma on the choice of dose and target volume. Surgery is still the preferred choice for small tumors if the foreseen outcome is identical.

Background: The relationship between constitutional chromosome aberrations and a predisposition to malignancy has already been established., Case Report: A 4 year-old boy was admitted suffering from abdominal mass. Biopsies of the tumor and bone marrow showed a stage IV Burkitt's lymphoma. Karyotype showed a constitutional t(1;6)(p36;q22) in initial bone marrow samples and peripheral lymphocytes. No classic Burkitt's type translocation was demonstrated in the malignant bone marrow cells., Conclusion: Our case is similar to four other reported cases. The break-points 1p36 and 6q22 seem to be involved in several malignant tumors, especially lymphomas.

In order to perform melphalan dosage adjustment, the linearity of melphalan kinetics was studied, in the case of previous carboplatin administration. Eleven patients with various solid tumors entered the present study. Carboplatin was administered during 5 days over 1-hour infusions; the day after, the melphalan test-dose was administered and followed 24 hours after by the complement dose. Melphalan kinetics were determined from only three plasma samples by using bayesian estimation. The present study showed that previous carboplatin administrations induced wide variations of melphalan pharmacokinetic parameters between the two administrations. As part of this protocol, the order of drug administration should be taken into account, in order to perform melphalan dosage adjustment.

Retinoblastoma (RB) is the most frequent ocular tumor in childhood. Due to recent advances in molecular biology, RB has become a study model for cancer suppressor genes, and antenatal diagnosis has now become feasible. The goals of therapy include an improved survival rate, decrease in iatrogenic sequelae (especially enucleation), and avoidance of radio-induced neoplasias. This review examines recent data from the literature.

Over the past 15 years, significant progress has been made in the understanding of the molecular mechanism involved in malignant transformation of lymphocytes as well as in the management and treatment of non-Hodgkin's lymphoma (NHL) in childhood. Cyto-histological classifications and immunophenotyping of different types of NHL have contributed to the characterisation of three major subtypes of NHL in children i.e. Burkitt's lymphoma (BL), lymphoblastic lymphoma (LL) and large cell lymphoma (LCL). Precise staging of the disease at diagnosis is necessary before the onset of the treatment and should be performed as quickly as possible. Presence of bone marrow and central nervous system (CNS) involvement are major prognosis criteria. In most cases, surgery has no therapeutic role and is required only for diagnostic procedures. Similarly, several studies have demonstrated that irradiation of various sites including the CNS does not improve survival. Thus, NHL patients are usually treated with chemotherapy alone. BL and LL have distinct clinical presentations and require completely different chemotherapy protocols. After comparable induction phases with intensive chemotherapy regimens, the former is usually treated with a short consolidation phase while the latter receives a long lasting consolidation consisting of intermittent chemotherapy for at least one year. The prognosis of stage I-II, and III-IV bone marrow negative NHL of children is excellent with respectively 95% and 75% long term survival. However, patients with concomittent CNS and bone marrow involvement in both histological subtypes have a considerably worse prognosis with only 30% long term survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Medulloblastoma is a frequent brain tumor in childhood. Recent advances in histogenesis, management of early and late side-effects, and prognosis are discussed in this review.

Despite great histological polymorphism, clinical features of supratentorial brain tumors are mainly limited to neurological deficit, and focal epilepsy and/or symptoms secondary to raised intracranial pressure. The treatment relies on surgery and radiotherapy; chemotherapy has not yet demonstrated its efficacy. Failures are explained by the limitation of neurosurgery, and by the toxicity of the radiotherapy that precludes the use of high dosages. Some good vital results are hampered by neuropsychic sequellae.

With the use of modern radiological imaging (US, CT-scan, MRI), the most important informations to recognize a tumor remain the morphological features (localization, size, extension, number of lesions...). The precision of these informations is constantly improved (use of contrast medium, various slices angulations...) and in this field, MRI is the most precise examination. Moreover, these less aggressive investigations allow a repeated and more efficient therapeutic follow-up. In contrast with initial expectations, these radiological investigations do not always allow a formal histological characterization of the different tumor types of the central nervous system, even if some intratumoral components are recognized (fat, calcifications, liquids...).

Treatment modalities of childhood brain tumors are associated with adverse neuropsychologic sequelae that may be manifested years after therapy. Based on recent published studies, the authors review the etiological factors, the symptoms and the evolutive features of these disorders and their management.

We studied 10 massive - 70 degrees C frozen dried allografts (7 terminal intermediate) in children between the ages of 9 and 16 with malignant tumors (8 primary osteogenic sarcomas and 2 Ewing sarcomas). A good response to chemotherapy was observed. The average follow-up is 2 years (7-36 months). Results showed 4 mechanical complications (2 plate failures, 2 graft fractures) and no deaths. The surgical procedure and postoperative management are discussed and compared to prosthetic reconstruction.

Forty-seven patients with renal carcinoma were included in first line or rescue protocols of immunotherapy including IL2 alone or in association with LAK cells, INF alpha or TNF. The toxicity was mild and the mortality was 2% (1 patient). The response rate was 26%. Nineteen children with neuroblastoma received IL2 either alone or in combination with LAK cells. The morbidity and mortality were higher in patients with end stage disease who had previously received high dose and prolonged chemotherapy. In contrast, the toxicity was mild and transient in patients treated in the months following autologous bone marrow transplantation. The only complete response observed was in 1 child treated with IL2, 4 months after high dose chemotherapy and ABMT. Immunological analysis showed that the immunomodulatory effect of IL2 is very different depending on whether IL2 is used alone or in combination with other cytokines; moreover, the biological effect of IL2 is dependent on the immunological status of the patients prior to IL2 therapy.

Intensive chemotherapy and high dose chemotherapy with bone marrow transplantation are 2 complementary therapeutic procedures for non Hodgkin's lymphomas. In children, indications for BMT in NHL are limited to patients who fail to achieve complete remission and for patients in sensitive relapse. In adults, the role of BMT is also recognized for patients who fail to achieve remission with initial therapy. The advantage of either conventional regimens or massive therapy with BMT for patients with poor prognostic criteria is still under evaluation (LNH 87 protocol). The PARMA protocol tests, in a multicenter randomized study, the value of BMT for patients in sensitive relapse. Results of BMT for patients with refractory NHL and resistant relapse, remain poor. The role of BMT in low grade lymphomas is debatable. The trials for evaluation of massive chemotherapy and BMT in NHL will contribute to defining the potential role of this therapy in France: a potential 1,000 cases per year may be treated by this method.

Seventy-two patients with a localized osteosarcoma were treated between September 1979 and December 1987 by neoadjuvant chemotherapy, local surgery and post-operative chemotherapy. Chemotherapy regimens varied throughout the years but always comprised high dose methotrexate with leucovorin rescue and adriamycin pre-operatively for children under the age of 15, and ifosfamid and cis platinum in adults. Post-operative chemotherapy for bad responders (greater than 10% of residual malignant cells), was at first an association of adriamycin and cis platinum, and later of holoxan and cis platinum. Surgery changed from amputation to local conservative surgery (graft or prosthesis) which is now the most frequent surgery--61% of the patients are alive and disease-free at 5 years. Good responders to pre-operative chemotherapy have a much better prognosis (81% at 5 years) than bad responders (45%). There is no significant difference according to age or pre-operative chemotherapy regimen.

The most frequent solid tumors in the pediatric age group are central nervous system tumors. Despite dramatic improvements in neurosurgery, radiotherapy and chemotherapy, the overall prognosis remains poor, and is often associated with late deleterious effects, including neuropsychologic disorders, endocrine deficiencies and physical abnormalities. In part I, we describe the common presenting symptoms and signs in children with brain tumors. We expose the significant advances in histology, immunohistochemistry, cytogenetic, radiology and therapeutic approaches during the past ten years.

Nine children with poor prognosis neuroblastoma have been treated by continuous infusion of IL-2 and autologous LAK cells, as described previously by West et al. in adult patients. Six patients were in relapse after high-dose chemotherapy and autologous BMT and three presented with primary refractory disease after conventional therapy. Although patients were very young (median age 6 years; average weight 17 kg), infusion of IL-2, cytapheresis and reinjection of LAK cells appeared feasible with the usual and transient complications observed with IL-2. Haematological toxicity, although reversible, was more important than usually described and due to the presence of bone-marrow metastases in 8 of the 9 patients. Life-threatening toxicity was observed in only one of the admission centres and was probably due to the rapid reinjection of a very large number of activated cells. Two patients presenting with very active disease after high-dose chemotherapy and autologous or allogeneic BMT received IL-2 alone, at 120 days and at 90 days after the graft. The reactivation of grade-II GVHD was the major complication in the patient treated after an allograft, whereas no BMT-related toxicity was observed in the patient treated after the autologous BMT. Immunological modifications induced by IL-2 were very different between these patients. As expected, a preferential outgrowth of NK cells with both NK and LAK activity was observed in the patient treated just after the autograft. In contrast, in the patient treated after an allograft and in the 9 patients in relapse, T lymphocytes remained the major mononuclear cell population with a very large excess of CD8+ T cells. All patients progressed after the first induction cycle with the exception of the only patient treated after autologous BMT who reached a very good partial remission with disappearance of the local tumor and bone metastases. Although very preliminary, these data clearly show that the efficacy of IL-2 largely depends on the patient's immunological status with the optimal effect being observed when IL-2 is given in the first few months following an autograft.

In part I of this article, we reviewed the general aspects of childhood brain tumors. In part II, we present the most common neoplasms and their treatment. The quality of the surgical resection appears to be of first importance in the prognosis. Progress in radiotherapy and chemotherapy have contributed to the improvement of long-term results. However, they are responsible of late deleterious effects. Further progress in therapy must be assessed with in view a critical evaluation of the quality of life.

Anthracyclines induced cardiotoxicity in children remains a major problem. Classical data are found: cumulative dose, way of injection, anterior cardiopathy, cardiac area irradiation, interaction with other cytotoxic drugs ad age. 2 kinds of disorders are recorded: 1) Acute rhythmic dysfunctions, early and often transitory; 2) congestive heart failure often not reversible and depending on total dose. Prognostic is still poor and intricate with prognostic of the tumor. Over all incidence is 2.7%. Very young children seem to be more sensitive. Continuous infusion is less toxic than IV bolus. Studies with new anthracyclines are yet uncommon but seems to be comparative with adult literature. Monitoring is identical to adults. EKG is of minor interest. Endomyocardial biopsies have been reported. There is no prognostic value of ultrasound tomogram, but exercise echocardiography can be performed. Nuclide fraction ejection is more reliable.

Eleven autologous bone marrow transplantations (ABMT) were performed in 10 patients with T lymphoblastic lymphoma. All patients were grafted because of a very bad prognosis: 2 cases of progressive disease (1 primary failure, 1 resistant relapse): 0/2 alive, 2 late complete remissions: 1/2 alive, 7 sensitive relapses (2/7 alive). Finally, 3 out of 10 patients are survived. This salvage therapy for a failure of a front line strategy with 78% disease-free survival without ABMT seems of interest. ABMT is still indicated as salvage therapy for 20% of these patients.

The authors report a case of massive haemoperitoneum in a 2-year-old child after percutaneous liver biopsy for hepatoblastoma. Bleeding was successfully prevented by emergency embolization. Major complications after percutaneous biopsy and interest of embolization are discussed.

Renal and pancreatic calcifications were observed in an infant who had been surgically treated for Cushing's syndrome associated with an adrenal adenoma. On examination of the relation between this secondary complication and Cushing's syndrome, was carried out and the possible role of the post-operative substitutive treatment is discussed. Close echographic surveillance is advocated in these cases.