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Pupose: Medulloblastoma is the most common primary malignant central nervous system tumor in childhood, accounting for 16-25% of cases (1). New treatment approaches have led to improved survival rates; however toxicities are still a major concern., Patients and Methods: Participants were selected from the records of patients who were treated with craniospinal irradiation for medulloblastoma. Between January 2008 and December 2012, 62 patients were diagnosed with medulloblastoma at the national institute of oncology Rabat, 27 patients were still alive at the time of the study, of which n=16 patients were included in the study. The mean age of patients at the time of the study was 9.6 years. All children were treated with radiation therapy and chemotherapy, according to standard protocols. Median follow-up between treatment and evaluation was 4 years. All the children were assessed with the Wechsler Intelligence Scale for Children - fourth Edition (WISC-IV) three to five years after completion of radiotherapy. The test was administered by two well-trained psychologists in a distraction-free environment. The scoring was then reviewed by a psychologist from Brooklyn College., Results: The mean standard score Full-Scale Intelligence Quotient (FSIQ) (M=63, SD=12.6) was found to be in the extremely low range and in the 1st percentile rank (PR), compared to the general population. All the measured primary index scales were below typical performance: verbal comprehension (M=67.7, SD=13.1), perceptual reasoning (M=63.5, SD=13.8) and processing speed (M=62.7, SD=15.5) were all found to be in the extremely low range, while xorking memory (M=75.5, SD=10.8) was found to be in the borderline range compared to the general population. To identify factors influencing the results, we performed both univariate and multivariate analyses. Age at the time of radiotherapy, initial clinical stage, total cranial radiotherapy dose, socioeconomic status, and the time of evaluation were identified as significantly impacting cognitive scores in the univariate analysis. In the multivariate analysis, only age at the time of radiotherapy and initial clinical stage remained factors significantly impacting cognitive outcomes with P=0.001 and P<0.001 respectively., Conclusion: Our study is evidence that tremendous efforts are still to be made in low-income countries to correctly measure neurocognitive dysfunction in medulloblastoma survivors and to prepare those patients to a typical life after the completion of treatment., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST)., Methods: We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts., Results: Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others., Conclusion: Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: To report the results of the first European prospective nonrandomized trial dedicated to pediatric synovial sarcoma., Patients and Methods: From August 2005 to August 2012, 138 patients <21 years old with nonmetastatic synovial sarcoma were registered in 9 different countries (and 60 centers). Patients were treated with a multimodal therapy including ifosfamide-doxorubicin chemotherapy and radiotherapy, according to a risk stratification based on surgical stage, tumor size and site, and nodal involvement., Results: With a median follow-up of 52.1 months (range 13.8-104.4 months), event-free survival (EFS) was 81.9% and 80.7%, and overall survival (OS) was 97.2% and 90.7%, at 3 and 5 years, respectively. The only significant prognostic variable at univariate analysis was the risk group: 3-year EFS was 91.7% for low-risk, 91.2% for intermediate-risk, and 74.4% for high-risk cases. In 24 low-risk patients (completely resected tumor ≤5 cm in size) treated with surgery alone, there were two local relapses and no metastatic recurrences. Among 67 high-risk patients (unresected, or axial tumor or nodal involvement), 66 underwent surgery after neoadjuvant chemotherapy. Response to chemotherapy was 55.2%, including 22.4% cases with complete or major partial remissions, and 32.8% with minor partial remissions., Conclusion: This study demonstrates that collaborative prospective studies on rare pediatric sarcomas are feasible even on a European scale, with excellent treatment compliance. The overall results of treatment were satisfactory, with higher survival rates than those previously published by pediatric groups. Nonetheless, larger, international projects are needed, based on a cooperative effort of pediatric and adult oncologists., Clinical Trials Number: European Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Parameningeal (PM) site is a well-known adverse prognostic factor in children with localized rhabdomyosarcoma (RMS). To identify risk factors associated with outcome at this site, we pooled data from 1105 patients treated in 10 studies conducted by European and North American cooperative groups between 1984 and 2004., Patients and Methods: Clinical factors including age, histology, size, invasiveness, nodal involvement, Intergroup Rhabdomyosarcoma Study (IRS) clinical group, site, risk factors for meningeal involvement (MI), study group, and application of radiotherapy (RT) were studied for their impact on event-free and overall survival (EFS and OS)., Results: Ten-year EFS and OS were 62.6 and 66.1% for the whole group. Patients without initial RT showed worse survival (10-year OS 40.8% versus 68.5% for RT treated patients). Multivariate analysis focusing on 862 patients who received RT as part of their initial treatment revealed four unfavorable prognostic factors: age <3 or >10 years, signs of MI, unfavorable site, and tumor size. Utilizing these prognostic factors, patients could be classified into different risk groups with 10-year OS ranging between 51.1 and 80.9%., Conclusions: While, in general, PM localization is regarded as an adverse prognostic factor, the current analysis differentiates those with good prognosis (36% patients with 0-1 risk factor: 10-year OS 80.9%) from high-risk PM patients (28% with 3-4 factors: 10-year OS 51.1%). Furthermore, this analysis reinforces the necessity for RT in PM RMS.

Given the excellent survival rate of children and teenagers treated for cancer, careful should be given in order to minimize long-term late effects of treatments and to improve quality of life. In this regard, fertility preservation is particularly important. Age, sex and concomitant therapies have an impact on the level of risk of hypofertility, with a stronger risk for chemotherapeutic regimens including alkylating agents, and gonads or hypothalamo-pituitary axis radiotherapy. Assessment of gonadotoxic impact of treatment strategy and fertility preservation techniques are crucial for limiting late effects. The objective of this literature review is to develop guidance for pediatric oncologists and hematologists relative to fertility preservation methods, in children and teenagers receiving gonadotoxic treatment. Specific follow-up after treatment is also proposed.

Brachytherapy in paediatric malignancies is rarely used, limited to expert institutions. The most frequent tumour sites treated with brachytherapy are gynaecological rhabdomyosarcomas, and prostate/bladder rhabdomyosarcomas. Ballistic advantages make brachytherapy technique the treatment of choice, with a high and selective protection of organs at risk. Techniques, brachytherapy modalities (low dose-rate, high dose-rate, pulsed dose-rate), doses and indications vary according to centres. Brachytherapy advantages are in relation with ballistic properties, allowing a very high dose to the target with normal tissue sparing. This review analyzes brachytherapy techniques, indications and results according to the two most frequent tumour sites: gynaecological and bladder/prostate tumours. This technique requires a muldisciplinary approach., (Copyright © 2013. Published by Elsevier SAS.)

Background: Right hepatectomy (RH) is the most common type of major hepatectomy and can be achieved without portal triad clamping (PTC) in non-cirrhotic liver. The present study reviews our standardized policy of performing RH without systematic PTC., Methods: One hundred and eighty-one consecutive RH were performed in non-cirrhotic patients, with division of the right afferent and efferent blood vessels prior to transection, without systematically using PTC. Prospectively collected data were analysed, focusing on the following endpoints: need for salvage PTC, ischaemic time, blood loss and post-operative outcome., Results: Extra-hepatic division of the right hepatic vessels was feasible in all patients, but was ineffective in 48 patients (26.5%) who required salvage PTC during transection. In those patients, the median ischaemic time was 20 min. The median blood loss was 500 ml (50-3000). Six patients (3.3%) experienced post-operative liver failure. Overall morbidity, severe morbidity and mortality were 42%, 12.1% and 1.6%, respectively, with peri-operative transfusion rate (16.6%) being the only factor associated with morbidity., Discussion: By performing RH with extra-hepatic vascular division prior to transection, PTC can be safely avoided in the majority of patients., (© 2012 International Hepato-Pancreato-Biliary Association.)

Publications on brachytherapy in paediatric malignancies are scarce, limited to expert institutions. Techniques, brachytherapy modalities (low dose-rate, high dose-rate, pulsed dose-rate), doses and indications vary according to centres. The most frequent tumor sites treated with brachytherapy are gynaecological rhabdomyosarcomas, prostate/bladder rhabdomyosarcomas and soft-tissue sarcomas. Brachytherapy advantages are in relation with ballistic properties, allowing a very high dose to the target with normal tissue sparing. This review analyzes brachytherapy techniques and indications according to tumor sites, brachytherapy results and perspectives. This technique requires a muldisciplinary approach.

Primary heart tumors are uncommon in children. The majority of them are benign, with only 10% malignant. Among malignant cardiac tumors, sarcoma (rhabdomyosarcoma, angiosarcoma, synovial sarcoma) and lymphoma (Burkitt's lymphoma, large B-cell lymphoma, lymphoblastic lymphoma) predominate. There are few published pediatric series on malignant primary cardiac tumors. We report here 3 observations of primary malignant cardiac tumors, 2 cases of sarcoma (angiosarcoma and synovial sarcoma) and 1 case of Burkitt's lymphoma. A precise pathological diagnosis is necessary for the proper management of these patients. For sarcoma, treatment associates surgery and chemotherapy. Surgery should be as complete as possible because of the lack of chemotherapy sensitivity of some sarcomas, mainly angiosarcoma and synovial sarcoma. Therefore, the prognosis of cardiac sarcoma remains poor. For primary cardiac lymphoma, management should not be different from lymphoma in other locations. Chemotherapy is the main treatment, and surgery has to be used only when complications occur. Prognosis depends on histology and not lymphoma location, and so is better than the prognosis for sarcoma., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Soft tissue tumors account for approximately 25% of neonatal tumors and are most often benign (more than 2/3 of cases). Vascular tumors are the most frequent benign tumors and infantile hemangioma accounts for 32% of these tumors, affecting 1 out of 200 children at birth. Kaposiform hemangioendothelioma (KH) is a rare vascular tumor with locally aggressive behavior. More than 50% of KH are associated with the Kasabach-Merritt phenomenon, a condition characterized by thrombocytopenia and consumptive coagulopathy. Malignant soft tissue tumors are, after neuroblastoma, the second cause of cancer in neonates. Infantile fibrosarcoma (IF) is a rare tumor that most often affects the extremities of children aged 4 years or younger. A recurrent t(12;15) (p13;q25) rearrangement fusing the ETV6 gene with the NTRK3 neurotrophin-3 receptor gene has been identified in IF. Complete conservative surgical resection is usually curative. Chemotherapy is indicated when initial surgical removal cannot be accomplished without unacceptable morbidity. Prognosis of IF is excellent, with reported overall survival rates ranging from 80 to 100%. Neonatal rhabdomyosarcoma (RMS) is a rare tumor (0.5-1% of RMS). The primary tumor predominantly involves the limbs and the genitourinary tract. Treatment is based on age-adapted chemotherapy and surgery. Prognosis of RMS in children less than 1 year old appears to be comparable with that of older children.

Patients and Methods: Forty-six patients with localised RMS of the limbs entered the MMT 89 and 95 study in France. We studied potential risk factors that were predictive of relapse and survival to propose a therapeutic approach of surgery and radiotherapy appropriate to the risk of relapse., Results: Median age at diagnosis was 6.5 years [9 months to 15.5 years]. At time of diagnosis, 43% had marginal surgery and only 13% radical intervention. Primary re-excision was performed in 12% of the patients. All patients received chemotherapy, 43% had second look surgery and 37% received radiotherapy. Fifty-four percent of all tumors relapsed: local relapse 36%, nodes l8%, metastatic 40%, local and metastatic 16%. Estimated overall 5-year event-free survival (EFS) and overall survival (OS) were 40 and 57%, respectively., Conclusions: Prognosis of RMS of the limbs is bad but only 37% of the patients had radiotherapy. We could define patients with very high risk among those with limbs RMS as nodal involvement (5 years overall survival OS 22%), alveolar histology (OS 38%) and site of hand and foot (4 survivors out of 10 patients). In further studies, these patients should be treated even more aggressive with early surgery followed by re-excision if necessary, chemotherapy including alkylating agents and systematic radiotherapy.

Objective: To evaluate the impact of surgery as first-line treatment on event-free survival (EFS) of primary aggressive fibromatosis., Patients and Methods: Treatments were categorized into: surgery with or without radiotherapy and nonsurgical strategies with systemic treatment alone or wait and see policy. Eighty-nine patients had initial resection of their primary tumour followed by postoperative radiotherapy in 13 cases. Twenty-three did not undergo surgery but received systemic treatment or watch and wait policy., Results: Median follow-up was 76 months. Overall 3 years EFS was 49%. In the univariate analysis, patients with microscopically complete surgery had a similar outcome to patients in the no-surgery group (3 years EFS of 65% and 68%, respectively). Gender, age, tumour size, treatment period and strategy (surgery versus no-surgery) were not statistically significant. Quality of resection according to margins and the tumour site were the only prognostic factors. There was a significant correlation between tumour site and quality of surgery (p=0.0002)., Conclusions: A subset of patients with extra-abdominal fibromatosis could be managed with a nonaggressive policy, as growth arrest concerned 2/3 of nonoperated patients. When surgery is finally necessary, it should be performed with the aim of achieving negative margins.

Introduction: Ifosfamide is an alkylating agent used in the treatment of germ-cell tumors, sarcomas and lymphomas. One of its main side effects is the encephalopathy of which the incidence may reach 30% in the literature, in adults and children just as well., Objectives: Based on both our experience and a review of the literature, we propose some recommendations for the management of this complication., Patients and Methods: We report 15 encephalopathy cases in non-brain tumor patients, which occurred between January 1987 and March 2002 in children from 2 to 17 years old, treated for solid tumors at the Institut Gustave Roussy. Ifosfamide was administered at a posology between 5.4 and 15 g/m(2)/course, associated with other antimitotics such as actinomycin D, etoposide or vincristine., Results: Six patients experienced a grade III neurological toxicity according to the NCI classification, which developed as excess drowsiness lasting up to 36 hours. Six other patients developed grade IV neurotoxicity, including two comas resolving within 4 days and four short generalized convulsions. Three other children experienced grade II drowsiness. Brain MRIs were normal and EEG showed an aspecific encephalopathy tracing. This early central neurotoxicity appeared right from the first administration, and occurred immediately after the first injection or during the second or third day of treatment. It was most often reversible, usually 3 to 5 days after the last ifosfamide administration. Five patients were administered a treatment with Methylene Blue with a demonstrable efficacy in only one case. No death or neurological sequelae have been noted. Ifosfamide has been renewed after the neurological accident in 7 of those patients. Only 1 of those 7 patients developed grade IV neurotoxicity during the next course of treatment. In 2 of those 7 children, Methylene Blue was used in a prophylactic way. No neurological disorders have been noted during the next courses of treatment., Discussion: In the literature, the following are described as risk factors for ifosfamide encephalopathy: advanced pelvic disease, previous cisplatyl treatment and renal failure. We have not found any of these predisposing factors in our series, but three of the fifteen patients had severe neurotoxicity associated with Vincristin during previous treatments., Conclusion: Facing a clinical diagnosis of ifosfamide encephalopathy, it is recommended to discontinue administration of ifosfamide and inject by intravenous route 50 mg Methylene Blue every 4 hours until the symptomatology recedes. The re-challenge of Ifosfamide is not contra-indicated and should be performed under prophylactic treatment with Methylene Blue by intravenous route at the dose of 50 mg every 6 hours.

Background: Early adjustment of treatment may benefit the patient. In order to guide treatment adjustment, use of early response (ER) or early complete response (ECR), judged after the few initial cycles of chemotherapy, is common in pediatric and also adult Hodgkin's and non-Hodgkin's studies. Paradoxically, almost no data support this strategy., Patients and Methods: The influence of ECR on outcome was evaluated in three series of advanced Hodgkin's disease (HD), leading to a series of questions., Results: The 1982 EORTC study assessed prospectively the time frame needed to reach an apparent complete response (CR) through repeated tumor measurements. In patients assessed at mid-treatment before the fifth cycle, both 15 year freedom from progression (FFP) and overall survival (OS) were superior in ECR patients compared with other patients continued on the same treatment (61% versus 37%; P < 0.001). A series of questions arise from these observations. Question 1: is the shortening of treatment detrimental? In a randomized Swedish trial, in one arm treatment was shortened in patients evaluated from the fifth cycle as ECR as compared with the standard eight cycles arm, 10 year cause-specific-survival (CSS) was 53 versus 69% [not significant (ns)]; 10 year OS 49% versus 58% (ns). Conversely, in the EORTC 20884 study, ECR patients given only six cycles did as well as patients entering CR later and, for this reason, given eight cycles (identical 6 year event-free survival 75%). Question 2: is early treatment adaptation in patients who failed to reach ER beneficial? In the French MDH 90 trial, 15% of children failed to reach ECR after four cycles; in these children only, anthracyclines plus alkylating agents were given and the dose of radiotherapy increased, improving the results observed in the previous trial. In the EORTC 20884 study, patients who failed to reach an ECR were switched earlier to involved field RT: their results matched those of ECR patients, at the difference of the previous trial. Question 3: is ER a predicting factor that can be used with any type of treatment? Probably not, based on the German Hodgkin's Lymphoma Study Group trial HD 9: ECR is highly dependent on specific interval from treatment start and on treatment intensity., Discussion: More general questions stem from these results. Question 4: is the definition of ER secured? With conventional imaging, the different methods for response assessment at end treatment also lead to different response rates; the assessment in the middle of treatment itself and the use of newer imaging techniques may further increase the variation. Indeed, question 5 is: is ER a concept based on any biology? Correlation to markers, 99mTc uptake, PET and hematological tolerance might help to pinpoint how and why ER represents a surrogate for final outcome., Conclusion: ER is a surrogate for final outcome, reflecting both tumor burden and activity. This predictability may, and possibly should, impact on treatment.

Ewing sarcoma is an uncommon malignancy that has been frequently managed differently in childhood and adults. This is a review of the international experience that conducted to a common European study called Euro Ewing. This study was launched in 1999.

Brachytherapy has been widely used at the Institut Gustave-Roussy since 1972 in pediatric oncology. In genitourinary rhabdomyosarcoma, because of its ballistic and physical characteristics, it represents the optimal treatment whenever irradiation is required and brachytherapy feasible. Between 1976 and 1998, 23 children with bladder or prostate rhabdomyosarcoma were treated with a protocol including brachytherapy, with five of them treated with a salvage brachytherapy. All but one brachytherapy was performed during the surgery. Among the 18 brachytherapies performed as a first-line treatment, eight presented a tumoral evolution: five presented a local evolution, one a local and nodal evolution and two a nodal evolution. Brachytherapy allowed a conservative treatment among ten out of 11 children alive with no evidence of disease. Among the five patients with salvage brachytherapy, two presented a second recurrence. Sequelae were minimal, consisting of one grade I rectitis and one asymptomatic vesical and ureteral reflux. These results are consistent with the published data using more radical treatment. Brachytherapy can represent an alternative to radical surgery, when indications are clearly defined in bladder or prostate rhabdomyosarcoma. This type of treatment can be performed only integrated with other treatments, more particularly with surgery. This approach requires a close cooperation between the different specialists: pediatricians, surgeons and brachytherapists.

The significant progress made in pediatric oncology during recent years has been due to a major breakthrough in the field of molecular biology and the introduction of new therapeutic strategies that take into account both the quality and the duration of life. Molecular biology has already been instrumental in more fully categorizing the 'small round-cell tumor' group, and in reclassifying the 'Ewing family' tumors. It also provides a valuable tool for the prognostic evaluation of neuroblastomas through the analysis of the N-myc oncogene. In addition, it has permitted the identification of the Li-Fraumeni syndrome of predisposition to cancer in the child, thereby raising the problematical ethical issue of communicating relevant information to subjects at risk. Two examples illustrate innovative strategic concepts: 1) Burkitt's lymphoma, or an example of the successful de-intensification of treatment; and 2) brain tumors in young children, regarding which the desire to improve the quality of life has led to innovative attempts to replace radiotherapy by chemotherapy. Considerable progress has been made in the field of neuropsychology, thereby permitting an improved assessment of disorders and a better management of rehabilitation programs. New anti-cancer agents and also chemo- and radiotherapy that spare healthy tissue are also being developed. Gene therapy and molecular biology will play a major role in future therapeutic strategies; and are now at the preclinical trial stage. This significant overall progress leads to a reconsideration of the organizational approach toward treatment of the pediatric patient population suffering from cancer, and a critical assessment of disease management, which should take into account not only the technical aspects of the disease but also familial and social considerations.

The high chemosensitivity of pediatric tumors along with their natural propensity for an early distant dissemination have stimulated the interest for chemo-radiation combinations in children since the mid 50s. Following the early experiments in nephroblastomas on the interaction of Actinomycin-D and radiotherapy, multiple national and international studies have been conducted since the mid 70s with considerable success: nowadays most pediatric tumors enjoy a long term survival in excess of 70%. Like their adult counterparts, these associations aim to induce an early control of the primary tumor and distant spreading (spatial cooperation) but also, more specifically in children, to limit the toxicity on normal tissues when treatment intensity can be further reduced. The association of an initial chemotherapy followed by local radiation at a dose and in a volume adapted to the response to chemotherapy along with associated prognostic factors has become widely tested in national and international studies conducted in Hodgkin's disease, Ewing's sarcoma, medulloblastomas, and brain tumors in the very young. Conversely, concomitant associations have remained limited to high-risk subgroups (parameningeal rhabdomyosarcomas for example) due to their potential hazards.

Background: Radiotherapy and chemotherapy are associated with an increased risk of second malignant neoplasm (SMN). An association between SMN and familial aggregation has also been shown. The aim of this study was to investigate the role of familial factors in the risk of SMN and their potential interaction with the effect of treatment., Methods: We devised a case-control study of 25 children with SMN (cases) and 96 children with no SMN after a cancer treatment (controls), taken from a cohort of 649 children treated at our institution between 1953 and 1985. A complete family history was obtained for patients and controls and a familial index defined to evaluate the degree of familial aggregation. The radiation dose given at 151 sites in the body was estimated for each radiotherapy course for each child., Findings: Among family members of the 25 SMN cases, there were ten with early-onset (< or = 45 years) cancer, compared with eight among relatives of the 96 controls. Compared with patients who had no family history of early-onset cancer, those with one or more affected family members had an odds ratio for SMN of 4.7 (95% CI 1.3-17.1; p = 0.02). Adjustment for local radiation dose and exclusion of patients known to be predisposed to SMN (carriers of p53 mutation and those with Recklinghausen's disease) did not affect this risk substantially., Interpretation: Both genetic factors and exposure to ionising radiation have independent effects on the risk of SMN. Follow-up of children treated for cancer should be especially vigilant when there is a family history of early-onset cancer.

Although most pediatric tumors can be cured with lower doses of radiation than their adult counterparts, long-term radiation-induced complications and sequelae remain a major concern both in terms of frequency and intensity. Most of them have been extensively documented in the pre-chemotherapeutic era like those affecting bone, cartilage and soft tissue growth or CNS and endocrine glands. More recently the emphasis has been put on the apparent increasing incidence of reported second malignancies. This could have been favored by the chemo-radiation combinations used in most children but also has been made possible mainly by the extensive follow-up of the increasing cohort of cured children.

Malignant tumors of soft tissue constitute a very heterogeneous group of tumors which is composed of more than 50 different entities derived from either the mesenchyme or the neuroectoderm. Diagnostic problems can be linked to the difficulty to firmly establish the diagnosis of malignancy and to the precise determination of the type of sarcoma. The prognostic is largely dependent on local and distant extension of the cancer. The study of the genotype of tumor cells has enabled the detection and characterization of genetic alterations. These alterations, frequently chromosome translocations, are specific markers for subgroups of tumors and can thus be of clinical relevance. These markers can be detected by cytogenetic, in situ hybridization or molecular biology techniques. The specificity of these alterations for tumor cells and the possibility to detect them with the highly sensitive polymerase chain reaction (PCR) technique have enabled development of tests aimed at the detection of tumor cells within potential metastatic sites.

With the dramatic improvement of therapeutic results in Hodgkin's disease patients, challenges still remain in identifying the minority of patients with a poor prognosis who need intensive therapy and in reducing the costs of therapy in the successful outcome of the disease in children as in adults. It has been progressively recognized that therapeutic problems of children are similar to those of adult patients. However, the late effects of staging splenectomy and of radiotherapy on growing patients are more severe in children and the most serious sequelae is that of developing a second malignancy in patients who will have a very long life span. Ways of decreasing the long-term effects of therapy have been different in adults and children. The wide use of efficient chemotherapy has allowed omission of staging laparotomy, and reduction of the fields and doses of radiation. Compared to treatment with chemotherapy alone, which requires high cumulative doses of drugs with a potential toxicity, combined modality therapy has emerged as the best treatment for children, with low-dose and limited-volume irradiation, short chemotherapy and without the administration of alkylating agents and anthracyclines in selected groups of patients.

The assessment of bone marrow involvement by tumor cells remains an essential problem at diagnosis in pediatric solid tumors. Besides the conventional cytological and histological methods, some modern cell density separation techniques have been described in order to improve the detection of minimal or scattered bone marrow involvement. Immunological or genetical (molecular biology) tools can be used for the recognition of separated cells. In terms of investigations, MRI and MIBG radionucleide scan, although giving no definite proof, have the ability to macroscopically study the scattering of bone marrow invasion in the particular case of neuroblastoma. In some pediatric tumors, especially neuroblastomas and non Hodgkin lymphomas, an extensive bone marrow investigation is mandatory at diagnosis. Such an investigation is only necessary in case of particular criteria at diagnosis of Hodgkin's disease, Ewing' sarcomas, rhabdomyosarcomas and retinoblastomas. All other pediatric solid tumors do not need to be investigated in terms of bone marrow involvement at diagnosis, with the exceptions of advanced disseminated disease or if an autologous bone marrow transplantation is planned.

Chemotherapy has considerably improved the prognosis of solid tumours in children, but may have very adverse effects, particularly on fertility. A study was conducted at the Gustave Roussy Institute to identify the toxic effect of chemotherapy on male fertility. At present, 205 patients, treated during childhood have entered the study. Basal FSH-LH have been assayed to assess possible germ cell damage although azoosperia can not be eliminated. Results were normal in 127 patients (62%) and increased basal FSH levels were found in 78 (38%). Endocrine function was not altered: all patients were either impubertal or intrapubertal at diagnosis and subsequently achieved normal puberty. Multivariate analysis revealed an obvious toxic effect of 2 alkylating drugs: cyclophosphamide and procarbazine. No toxic effect was observed for vincristine, dohorubicin or actinomycin D. Age and pubertal status at diagnosis were not correlated with toxic effects. At present, no conclusion for other drugs may be made but results high dose metotrexate are promising. For lomustine and cisplatin, less favourable, though nonsignificant, results have been obtained. Complete recovery is possible several years later.

Thirty-two children were treated for metastatic Ewing sarcoma by high-dose chemotherapy followed by autologous bone marrow transplantation. Fourteen patients entered phase II studies of high-dose alkylating agents. The response rate observed was 61%. High-dose chemotherapy was used as consolidation in complete remission of 18 patients. Disease free survival appears to be better than that observed under conventional altered chemotherapy. However, with only 4/18 long term survivors, these results remain unsatisfactory, taking into account the recent encouraging results of semi-continuous conventional chemotherapy.

The observed cure rates in childhood Hodgkin's disease (85 to 95%) and the knowledge of late complications of treatments, radiotherapy as well as chemotherapy, lead to studies aiming at decreasing the treatment burden without compromising these good results. An international workshop helped to make an update of the different presently used strategies. It appeared that the benefit and the risks of the staging laparotomy are still controversial, though most of the teams are now omitting this procedure. Different options have been selected in decreasing the treatments. If a few teams choose to treat by chemotherapy alone, the majority prefer to treat by combined modality therapy allowing to reduce at the same time the intensity of the radiation therapy (doses and fields) and of the chemotherapy (use of chemotherapy devoid of procarbazine and alkylating agents for the favorable cases). The presented french study shows the feasibility of such a strategy.