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Le diagnostic de rhabdomyosarcome alvéolaire (aRMS) est classiquement histologique et immunohistochimique. Ce sous-type tumoral présente des transcrits de fusion spécifiques appelés PAX3-FOXO1 et PAX7-FOXO1. La détection, par RT-PCR, d’un de ces transcrits, au niveau médullaire ou sanguin, permet de diagnostiquer des métastases infra-cytologiques. L’objectif de ce travail est de déterminer la fréquence de la détection de la maladie minime médullaire (MMM) et sanguine (MMS) au diagnostic et d’évaluer sa valeur pronostique.

Malignant pheochromocytomas are rare in childhood and the prognosis of children with this tumor is not well known. We present 2 pediatric observations of malignant pelvic pheochromocytoma. Symptoms in both cases were headache and hypertension. The tumor invaded the sacral bone. Angiogram helped to localize the tumor and metastases, and allowed preoperative embolization of the tumor in 1 case. The first child underwent incomplete surgical resection, 131I-MIBG therapy and radiotherapy, and is still alive 2 years after diagnosis. The second child died from metastatic invasion a few weeks after discovery of the tumor. We reviewed previous reports of children with malignant pheochromocytomas (30 cases). Primary tumor was extraadrenal in 50% of cases. The 3-year survival rate was 73 ± 9% (mean ± SD). Apart from surgical resection, no particular treatment appeared to be more effective than others in reducing mortality.

A retrospective multifactorial analysis on 261 previously untreated patients with Ewing's sarcoma (Es) of bone has been carried out in order to ascertain the prognostic value of several histological variables on survival. Among those cases accepted as Es, 208 (80% of the patients) were considered to be “typical Es”, while 40 (15%) displayed a large cell predominance, being subclassified as “atypical large cell Es”. Furthermore, 13 patients (5%) possessed tumours of endothelial-like appearance. Eleven cases which displayed a mixed histological configuration were finally included within one of the three previous groups according to their predominant histological pattern.

Recently, Ewing's tumours have been shown to carry specific hybrid transcripts resulting from the fusion of the EWS gene with FLI-1 or ERG genes. Based on the sensitivity and specificity of the detection of these alterations by the reverse transcriptase-polymerase chain reaction technique, we have developed an assay to search for small numbers of Ewing cells in various sites from patients with Ewing's tumour. This method enables the detection of fewer than one tumour cell per million blood mononuclear cells. A total of 28 primary sites and 51 peripheral samples from 36 patients were investigated. Tumour cells could be detected in 4/18 blood samples, 4/15 bone marrow aspirates and 2/18 peripheral stem cell harvests. EWS/FLI-1 and EWS/ERG transcripts being observed in eight and two cases respectively. The type of fusion transcript detected in peripheral site(s) was identical to that observed in the primary site. At diagnosis 5/16 patients (31%) demonstrated either circulating tumour cells or/and occult bone marrow metastasis. After induction therapy, tumour cells were detected in 3/21 patients. This highly sensitive method should be a relevant tool to allow a more accurate clinical assessment of the dissemination of Ewing's tumours.

Because genetic predisposition probably plays an important role in the aetiology of most of childhood cancers, studies of second primaries occurring after these cancers may be particularly informative about possible common genetic mechanisms in both of these cancers. We have studied the incidence of thyroid tumours occurring after cancer in childhood in a cohort of 592 children treated before 1970. Among these children, six later developed a thyroid carcinoma, and 18 developed a thyroid adenoma. Radiation doses received to the thyroid by each of the irradiated children have been estimated using individual radiotherapeutic technical records. Thyroid carcinomas and thyroid adenomas were five times more frequent after irradiation for neuroblastoma than after irradiation for any other first cancer. This ratio did not depend on sex, nor on time elapsed since irradiation, nor on dose of radiation received for the thyroid gland. This result suggests that there is a common mechanism for the occurrence of neuroblastoma and of differentiated thyroid tumour.

During recent years the combination of surgery, radiotherapy, and multiple chemotherapy in the treatment of patients with cancer has resulted in increased survival periods and, in some cases, complete cures. In children, however, the subsequent development of other and apparently unrelated malignancies has been observed 20 times more commonly than in a control group. This paper reports the occurrence of chondrosarcoma of the femur in two children who had been treated successfully for malignant tumours of soft tissue. One of these tumours was a malignant fibrous histiocytoma in the muscles of the forearm; the other was a rhabdomyosarcoma of the cheek. The intervals between termination of treatment of these lesions and recognition of the chondrosarcoma were five years and 10 years, respectively. In addition to surgical and radiotherapeutic measures, both children had received high doses of chemotherapy.

Sixty children with Hodgkin's disease were clinically staged and treated by MOPP primary chemotherapy followed by 40 Gy nodal radiation limited to involved fields. Overall 5-year survival is 93% while relapse-free survival is 86%. Four patients relapsed. These results confirm that laparotomy no longer has a place in routine staging when chemotherapy is given to all patients and that radiotherapy of localized disease (IA and IIA) can be limited to involved fields. On the basis of these results and data of other published series, the French Society of Clinical Oncology and Hopital Saint Louis initiated a new joint national study to minimize the late effects of combined modality therapy without jeopardizing the good survival. Outlines and preliminary results of this study are presented.

This report describes a case of rhabdomyosarcoma associated with a 2;13 translocation and multiple double minute chromosomes. The origin of the amplified DNA was identified using comparative genomic hybridization, which pinpointed a unique spot at 12q→13q14. Band 12q13 has been shown to contain several genes that are occasionally amplified in other sarcomas. Fluorescence in situ hybridization to tumor metaphases with probes specific for this region indicated that the double minutes contained the MDM2 gene but not the CDK4 gene. MDM2 amplification was further quantified by Southern hybridization, which showed a mean value of 25 copies per haploid genome. This is the first example of MDM2 amplification in a rhabdomyosarcoma.

Of a cohort of 634 children treated from 1942 to 1969 at the Gustave Roussy Institute for a first cancer and alive 5 years after treatment, 32 later developed second malignant neoplasms (SMN). A case-control study was performed to determine the relationship between the dose of radiotherapy received on a given anatomical site for the treatment of a first cancer, and the risk of SMN development at the same anatomical site. Another aim of the study was to analyse the effects of the association of radiotherapy with chemotherapy on the risk of SMN. The 32 cases of second malignant neoplasms were individually matched with one to nine patients of the cohort (a total of 162) who did not develop a SMN after a first cancer, matching on age, sex, type of first cancer and follow-up duration. The doses of radiotherapy delivered for the treatment of the first cancer were retrospectively estimated at the 26 anatomical sites of SMN. When the SMN was a leukaemia, the mean active bone-marrow dose was estimated as a weighted mean of the doses received by 20 bone sites. As compared to anatomical sites in children who had not received radiotherapy, the sites which had received 50 Gy or more had a relative risk of SMN of 5.8 (P less than 0.05). When taking into account the dose received at the site of the SMN, neither the number of fractions nor the type of radiations were related to the risk of SMN. Children who had received chemotherapy had a relative risk of SMN of 2.7 (95% CI: 1.2-6.4), adjusted for the dose of radiotherapy, as compared to those who had not. The relative risk of SMN did not vary with the dose nor the duration of the chemotherapy. Dactinomycin was found to increase the relative risk of second soft tissue and bone sarcomas. Cyclophosphamide was found to be less carcinogenic than the other alkylants. The relative risk of SMN was equal to 2.0 (n.s.) after radiotherapy of more than 25 Gy, to 4.4 (n.s.) after chemotherapy, and to 21.4 (P less than 0.01) after the combination of these two treatments modalities, as compared to patients treated by surgery alone. This study suggests that the oncogenic effect of radiations might be increased by chemotherapy, and that the combination of the two treatment modalities might be one of the major factors responsible for overall risk of SMN.

The risk of subsequent second malignant neoplasm was studied in a cohort of 634 patients, treated for a childhood cancer at the Gustave Roussy Institute between 1942 and 1969, and in complete remission five years after diagnosis. The most frequent types of first primary cancers (FPC) were Wilms' tumours (28% of the children), neuroblastomas (16%), lymphomas (12%) and soft tissue sarcomas (11%). Median follow-up duration after FPC was 19 years. Thirty-two patients (obs = 32) developed a total of 35 second cancers. Bone, thyroid, connective tissues and skin were the most frequent types of second cancer, with six patients for each type. The average annual incidence of second cancer was 0.36%. The average annual incidence for the periods 5-9, 10-14, 15-19, 20-24 and 25+ years after FPC was respectively 0.16%, 0.34%, 0.36%, 0.71% and 1.18%. The cumulative incidence of second cancer for the periods 5-20, 5-25 and 5-30 years after FPC was, respectively, 4.3% (95% CI: 2.8-6.6%), 7.8% (95% CI: 5.1-11.8%) and 13.0% (95% CI: 8.2-20.0%). The expected number of cancers in the cohort, computed from Danish cancer incidence data, was exp = 2.2. When compared to this expected number, the average annual excess incidence of second cancer, defined as obs-exp divided by the number of person years of observation, was 0.33%. This rose from 0.15% for the period 5-9 years after FPC to 1.09% for the period beginning 25 years after FPC. The standardised incidence ratio of second cancer (i.e. obs/exp) was 15 (95% CI: 10-21), and was fairly constant in the period extending from 15 to 20 years after FPC diagnosis. Obs/exp was equal to 25 for the patients who had had chemotherapy and equal to 9 for those who had not. Cyclophosphamide seemed less carcinogenic than the other alkylating agents. Obs/exp was similar for the patients who had received radiotherapy and for those who had not. The risk of cancer increased with age in the reference population and increased faster in the cohort, because the standardised incidence ratio is constant over a long period.

Fifteen patients with primary Ewing's sarcoma of the ribs were entered into the same protocol: thirteen of them had localized disease while two had metastatic disease. The protocol consisted of (1) initial chemotherapy according to size of tumor: patients with a small tumor were given rwo courses of VAC (vincristine, actinomycine D. cyclophosphamide); patients with a large tumor, pleuraj effusion or metastatic disease were given alternating courses of VAC and VAd (vincristine. adriamycine) until maximum regression of the tumor: (2) local radiotherapy: (3) maintenance chemotherapy with VAC/VAd: (4) complete surgical excision at diagnosis in 4 patients, after primary chemotherapy in 6 patients, after chemotherapy and radiotherapy in 2 patients. Six of the 9 evaluable patients had tumor regression higher than 50% after primary chemotherapy. Fourteen patients achieved complete remission. Six patients with localized disease remained disease-free for a median duration of 50 months. These 6 patients were treated by chemotherapy, complete surgical excision and radiotherapy. The results suggest that aggressive treatment with chemotherapy and surgery improve disease-free survival in patients with Ewing's sarcoma of the ribs. Chemotherapy, Ewing's Sarcoma, Rib, Surgery

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.

Malignant fibrohistiocytoma (MFH) is one of the most frequent malignant tumours of soft tissues [6]. Its classification as a bone tumour, however, is relatively recent [1]. In addition to primary MFH in bone, the entity has been observed to occur as a secondary phenomenon, some cases having complicated pre-existing infarcts of bone [4]. This paper reports three cases of MFH of bone developing as a consequence of previous radiation therapy.

Summary Phase II studies using ifosfamide both alone and combined with vindesine and cisplatin have shown the effectiveness of this drug in patients with Ewing's sarcoma (ES) who had relapsed during VAC (vincristine, actinomycin, cyclosphosphamide)/VAd (vincristine, Adriamycin) therapy. In November 1984, these results led the SFOP to adopt a protocol consisting of (1) initial chemotherapy with three cycles of IVA ifosfamide, 3 g/m2 on days 1 and 2; actinomycin D, 750 µg/m2 on days 1–3; vincristine, 1.5 mg/m2 on day 1 alternating every 3 weeks with IVAd (vincristine on day 22; ifosfamide on days 21–23; Adriamycin, 60 mg/m2 on day 22); (2) radical surgery if possible; (3) local radiotherapy (RT); and (4) maintenance chemotherapy with alternating IVA and VAd (vincristine, Adriamycin) for up to 9 months. In May 1987, 87 patients with previously untreated ES entered the study; 61 had localized ES. To date, 54 patients with localized disease and 22 with metastatic disease have finished initial chemotherapy; 40 patients with localized disease have been evaluated. In all, 28 patients (70%) were in complete remission (17 patients) or had a tumor regression of >50% (11 patients) and were considered to be good responders; 12 patients were considered to be poor responders. After local radiotherapy in all but 7 patients and surgical resection in 29, 52 of 54 were considered to be in clinical remission. A total of 13 patients with metastatic disease were good responders at the completion of the initial chemotherapy. These results confirm the efficacy of primary chemotherapy using ifosfamide for the treatment of ES.

Une santé dégradée pendant l’enfance ou l’adolescence, parce qu’elle peut avoir un impact sur la réussite scolaire ou les stratégies éducatives, peut réduire les chances de mobilité sociale et peut, par conséquent, contribuer à la formation des inégalités sociales de santé. Cependant, les études tendent à confondre les pathologies, rendant difficile l’exploration des mécanismes à l’œuvre. Nous proposons d’étudier ici le cas des cancers de l’enfant et de l’adolescent au travers d’une recherche à méthodes mixtes.

Background Childhood cancer survival has increased considerably during the last 3 decades. Until now, little has been known about the risk factors for death due to cardiovascular diseases in long-term survivors of a childhood cancer. Methods We investigated long-term mortality in a cohort of 4 122 5-year survivors (aged 0-15 years) of a childhood cancer treated between 1942 and 1986 in 8 centres in France and Great Britain as having a solid cancer and followed up over an average of 26 years. 98% of vital status were obtained from INSEE and 95% of causes of death from Cepi-Dc. Information about chemotherapy was collected, and the radiation dose received in all except for 159 of the 2 870 patients, who had received radiotherapy was estimated, The radiation dose received at 188 anatomical sites are estimated for each radiotherapy course of every child. The classification of causes of death was based on a comparison between the code topographic first cancer and the leading cause of death. The causes of death from heart disease the most common are: heart disease, heart failure and acute myocardial infarction Results A total of 603 patients died during the follow-up, i.e. 8.3-fold (95% CI 7.6-9.0) more than that expected in the general population. A total of 32 patients died of cardiovascular diseases, i.e. 4.8-fold (95% CI 3.3-6.7) more than expected, 21 of which were cardiac diseases, i.e. 6.0-fold (95% CI 3.8-9.0) more than expected. Patients who had received radiotherapy had a 5.4-fold (95% CI 1.6-33.0) higher risk of mortality due to cardiovascular disease than those who had not. Mortality due to cardiac disease was related to the administration of anthracyclines, alkylating agents and/or vinca alkaloids. Patients who had received between 5 to 14.9 Gy to the heart during radiotherapy had a 14.5-fold (95% CI 2-291) higher risk of mortality from cardiac diseases than patients who had not received radiotherapy. Patients who had received on average, more than 5 Gy to the brain were at a higher risk of developing vascular diseases (n=11). Conclusions Childhood cancer survivors are at a high long-term risk of mortality from cardiac diseases when treated with radiotherapy if the average radiation dose to the heart is higher than 5 Gy, or with anthracyclines, alkylating agents and/or vinca alkaloids. The cardiovascular diseases are the causes non-cancerous most frequent in the very long term after treatment for cancer of the child.

From July 1989 to December 1995, 16 children with metastatic Ewing's sarcoma or PNET were treated with high-dose chemotherapy (HDC) consisting of Busulfan (600mg/m2) and Melphalan (140 mg/m2) followed by autologous SCT. Eight/16 were metastatic at diagnosis: 6/8 were consolidated in first intention and 2 after treatment of a metastatic relapse, 8/16 were localized at diagnosis and received HDC as a consolidation after treatment of a metastatic relapse. Prior to HDC, conventional treatments consisted of chemotherapy for all the patients (pts), surgery of the primary tumor (12/16), surgery of the metastases (4/16), radiotherapy on the primary tumor (10/16). At the time of HDC, CR or GPR of the primary tumor was obtained in 13 and 3 pts, respectively. CR, GPR and PR of the metastases were observed in 10, 5 and 1 pt, respectively. Toxicity was severe but acceptable: 1 toxic death occurred (cerebral hemorrhage). The mean durations of neutropenia and thrombopenia were 10 days (d) (SD=5 d) and 39 d (SD=20 d), respectively. Overall survival at 5 years post SCT was 70% and DFS was 55%. All the 6 metastatic pts grafted in first intention are alive with NED with a median follow up (FU) of 21m (range 13–33m), the 2 metastatic pts grafted after a metastatic relapse died 12 and 22m post SCT. Among the pts with initially localized tumors, 5 are alive with NED with a median FU of 36m post SCT (range 15–59m), 1 is alive with disease, 1 is dead of PD and 1of toxic death. In conclusion, the HDC with Busulfan and Melphalan was toxic but feasible. Prognosis of these children with metastatic disease compares very favorably with historic controls.

205 patients treated by chemotherapy in the Institut Gustave-Roussy for childhood cancer between 1963 and 1990 have been assessed for fertility by serum basal FSH-LH level (200 pts), sperm count (22) and/or testicular biopsy (4) after the end of puberty and 1 to 21 years (m: 8 y) after the end of chemotherapy: They received various polychemotherapy including cyclophosphamide (129 pts), procarbazine (42 pts), CCNU (37 pts), D actinomycin (80 pts), doxorubicin (138 pts), methotrexate (69 pts), vincristine (182 pts). 127 pts (62%) had nOrnlal, and 78 abnormal results.A multivariate analysis showed that pubertus status of the children at time of the treatment had no influence, but that cyclophosphamide, procarbazine and CCNU were significantly associated to abnormal results. 32 pts treated only with D-actinomycin, vincristine + adriamycine had normal results.

From January 1988 to January 1992, 141 patients entered the EW88 protocol based on the chemotherapy (CT) used in St. Jude Hospital since 1978 (JCO7, 208–213, 1989). Among them, 44 were young adults (15 to 35 yrs, médian 20 yrs).Induction CT consisted in Cytoxan 150mg/m2p.o.×7 days followed by Adriamycin 35mg/m2IV on day 8 for 5 courses beginning days 1, 15, 29, 50 and 71. Surgery was recommended whenever possible. Radiation was based upon the quality of surgery and the histological response to CT. Maintenance CT was based on vincristine+actinomycin and cytoxan+adriamycin. Total duration of therapy was 10 months. In March 1995, médian follow-up of the cohort was 64 months (38–87m). Outcome was similar in adults and children.97 pts <15 yrs44 pts ≥15 yrsno. pts without initial control04no. pts with local relapse218no. pts with isolated métastases17125year DFS58% (±10)52% (±15)N.S.5 year Survival64% (±10)65% (±15)N.S.