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Sixty children treated for solid tumors with high-dose chemotherapy followed by bone marrow transplantation were randomly assigned to one of two antibiotic protocols. Group A received prophylaxis consisting of ceftazidime plus teicoplanin beginning before the onset of aplasia and fever; group B received exactly the same antibiotic regimen but beginning at the onset of fever. The two groups were compared in terms of the rate of septicemia, fever of unknown origin, the time-lapse before the appearance of septicemia, the sensitivity of the causative organisms to the antibiotics, the effect of the latter on the intestinal flora, and the rate of fungal infections. The incidence of septicemia was significantly lower in group A (6.6%) than in group B (24.0%), mainly due to the prevention of episodes of early onset. Similarly, the appearance of the first episode of fever was delayed in group A, and the overall duration was reduced. Amphotericin B was prescribed empirically with the same rule in both groups, but three children in group A did not require amphotericin B. The effect on the intestinal flora was similar in the two groups; it must, however, be closely monitored so that the presence of potential pathogens can be dealt with appropriately.

Neuroblastic tumours may occur in a predisposition context. Two main genes are involved: PHOX2B, observed in familial cases and frequently associated with other neurocristopathies (Ondine's and Hirschsprung's disease); and ALK, mostly in familial tumours. We have assessed the frequency of mutations of these two genes in patients with a presumable higher risk of predisposition. We sequenced both genes in 26 perinatal cases (prebirth and 1 month) cases, 3 pairs of affected relatives and 8 patients with multiple malignancies. The whole coding sequences of the two genes were analysed in tumour and/or constitutional DNAs. We found three ALK germline mutations, all in a context of multifocal tumours. Two mutations (T1151R and R1192P) were inherited and shared by several unaffected patients, thus illustrating an incomplete penetrance. Younger age at tumour onset did not seem to offer a relevant selection criterion for ALK analyses. Conversely, multifocal tumours might be the most to benefit from the genetic screening. Finally, no PHOX2B germline mutation was found in this series. In conclusion, ALK deleterious mutations are rare events in patients with a high probability of predisposition. Other predisposing genes remain to be discovered.

Purpose: To identify factors relevant to long-term outcome in newly diagnosed hepatoblastoma, and define subgroups for clinical research on tailoring treatment to the individual patient. Patients and methods: Between 1995 and 2006 the SIOPEL group conducted two clinical trials which established risk-adapted therapy for hepatoblastoma patients. Patients were stratified into high-risk (AFP 1,200,000 ng/mL, patient age, platelet count and histology were further explored. The outcome measure was event-free survival (EFS). Results: In 541 patients, reduced EFS correlated significantly with AFP = 1.2 x 10(6) ng/mL (2.48, 1.47-4.17), metastatic disease (3.02, 2.05-4.44), PRETEXT IV (2.15, 1.19-3.87), multifocality (1.59, 1.01-2.50), age>5 years (2.76, 1.68-4.53); borderline with small cell undifferentiated (SCU) histology (2.29, 95% confidence interval 0.91-5.77); but not with PRETEXT III, age 30-60 months, platelet count or V+/P+/E+. By using the significant factors and SCU to stratify the population, we have identified three distinct prognostic groups: PRETEXT I/II/III, and no other factors, have 3 year EFS of 90%, PRETEXT IV and/or multifocal tumour and/or age > 5 years and/or AFP > 1.2 x 10(6) have 3 year EFS of 71% and SCU and/or AFP

The purpose of the current study was to describe pure and mixed fibrolamellar hepatocellular carcinoma (FL-HCC).Consecutive patients with pure and mixed FL-HCC were identified from a central pathological review using Edmondson's criteria. Clinical, pathological, and epigenetic characteristics of patients who underwent curative surgery were evaluated. Overall and disease-free survival as well as patterns of disease recurrence were examined. Methylation levels of L1 retrotransposon (LINE-1) repetitive elements and Ras association domain family 1A gene (RASSF1) promoter were also assessed using pyrosequencing.Forty of 53 patients with a median age of 22 years (range, 9 years-;65 years) met the criteria for analysis. Central pathological review found that 30 patients (75%) had pure and 10 patients (25%) had mixed FL-HCC. Pure FL-HCC typically occurred in patients aged30 years. These patients often presented with lymph node metastasis at the time of diagnosis and frequently experienced extrahepatic recurrences (n = 16). Conversely, mixed FL-HCC appeared to resemble to classic HCC, occurring in patients aged40 years and frequently involving the liver as the primary site of disease recurrence. With a median follow-up of 7.8 years, the median overall survival from the time of diagnosis in all patients was 6.4 years (range, 3.2 years-12 years). Multivariate analysis found that the risk of death was increased in patients with higher American Joint Committee on Cancer disease stages (P = .003) and those with mixed FL-HCC (P = .03). Methylation analysis of LINE-1 repetitive elements and RASSF1 promoter revealed different methylation levels between pure and mixed FL-HCC, suggesting a different epigenetic background.Pure and mixed FL-HCC display distinct clinical presentations and epigenetic backgrounds leading to different prognoses and as such may be regarded as separate clinical entities.

Tumors and pseudotumors of the liver account for less than 2% of all childhood tumors and vary considerably in incidence throughout the pediatric age range, with hepatoblastoma, rhabdoid tumor of the liver, hemangioendothelioma, biliary tract rhabdomyosarcoma, and mesenchymal hamartoma in the first 2 years of life and hepatocellular carcinoma, focal nodular hyperplasia, and undifferentiated sarcoma in older children and adolescents. The main elements for the diagnosis are age at presentation, the clinical symptoms, the association with an underlying disease, the alphafetoprotein (AFP) level, and the radiological characteristics. In most cases, a biopsy is mandatory to confirm the diagnosis.

To evaluate the roles of hypothalamic-pituitary and spinal irradiations and chemotherapy in gonadal deficiency after treatment for medulloblastoma or posterior fossa ependymoma by measuring levels of plasma inhibin B and antimüllerian hormone (AMH).A total of 34 boys and 22 girls were classified as having normal levels of plasma follicle-stimulating hormone (FSH;9 IU/L), or abnormal levels of FSH (9 IU/L) and luteinizing hormone (LH;5 or5 IUL).Two boys had partial gonadotropin deficiency, combined with testicular deficiency in one boy. Six boys had increased levels of FSH, indicating tubular deficiency, combined with Leydig cell deficiency in 5 boys. The 7 boys with inhibin B levels100 ng/mL included the one with combined deficiencies and the 6 with testicular deficiency. Puberty did not progress in 7 girls; 3 had gonadotropin deficiency, combined with ovarian deficiency in one, and 4 had increased FSH levels, indicating ovarian deficiency. Inhibin B and AMH levels were low in the girl with combined deficiencies, in the 4 girls with ovarian deficiency, and in 4 girls with normal clinical-biological ovarian function, including 2 who underwent ovarian transposition before irradiation.The plasma concentrations of inhibin B and AMH are useful means of detecting primary gonad deficiency in patients with no increase in their plasma gonadotropin levels because of radiation-induced gonadotropin deficiency.

ALCL99 protocol including six courses of chemotherapy derived from the NHL-BFM protocol is widely used for the treatment of paediatric anaplastic large-cell lymphoma. In the ALCL99 trial, patients were randomised to receive MTX 1 g/m² in 24 hr with intrathecal injection (MTX1) versus MTX 3 g/m² in 3 hr without intrathecal (MTX3); then to receive or not vinblastine (high-risk patients). The present study provides information about the acute adverse reactions (ARs) during the six courses of the ALCL99 treatment, assesses risk factors for ARs and evaluates the risk of overweight related to treatment.Data concerning ARs were assessed using CTCv2 and analysed overall and according to the type of course.Between 1999 and 2005, 352 patients were recruited. Toxicity assessed after 2050 courses included grade 4 neutropaenia (70% of courses), grade 3-4 stomatitis (13%), grade 3-4 transaminase elevation (10%) and grade 3-4 infection (5%). Four patients (1%) died of toxicity. The toxicity profile differed between courses-A (significantly more haematological toxicity) and courses-B (significantly more stomatitis). The percentage of ARs was higher after the first course than after subsequent courses. Severe toxicity was more frequent after MTX1 than after MTX3 courses but did not differ between courses with or without vinblastine. Overall 20% of patients had a weight gain exceeding 20%.The high rate of acute toxicity should be considered when using the ALCL99 protocol. Chemotherapy including MTX 3 g/m² in 3 hr was less toxic than the same regimen with MTX 1 g/m² in 24 hr. Adding vinblastine did not increase the risk of toxicity.

Purpose The primary objective was to determine the efficacy of a newly designed preoperative chemotherapy regimen in an attempt to improve the cure rate of children with high-risk hepatoblastoma. Patients and Methods High risk was defined as follows: tumor in all liver sections (ie, Pretreatment Extension IV [PRETEXT-IV]), or vascular invasion (portal vein [P+], three hepatic veins [V+]), or intra-abdominal extrahepatic extension (E+), or metastatic disease, or α-fetoprotein less than 100 ng/mL at diagnosis. Patients were treated with alternating cycles of cisplatin and carboplatin plus doxorubicin (preoperatively, n = 7; postoperatively, n = 3) and delayed tumor resection. Results Of the 151 patients (150 evaluable for response) 118 (78.7%) achieved a partial response to chemotherapy. Complete resection of the liver tumor could be achieved in 115 patients (76.2%) either by partial hepatectomy (55.6%) or by liver transplantation (20.6%). In 106 children (70.2%), complete resection of all tumor lesions (including metastases) was achieved. Among the patients with initial lung metastases, 52.2% achieved complete remission of the lung lesions with chemotherapy alone. In half of the patients with initial PRETEXT-IV tumor as the only high-risk feature, the tumor could be completely resected with partial hepatectomy. Event-free (EFS) and overall survival (OS) estimates at 3 years were 65% (95% CI, 57% to 73%) and 69% (95% CI, 62% to 77%) for the whole group. EFS and OS for all patients with PRETEXT-IV tumor were 68% and 69%, respectively, and they were 56% and 62%, respectively, for patients with metastasis. Conclusion The applied treatment rendered a great proportion of tumors resectable, and, in comparison with previously published results, led to an improved survival in patients with high-risk hepatoblastoma.

Purpose The impact of adding vinblastine to a 4-month chemotherapy regimen, based on the Non-Hodgkin's Lymphoma Berlin-Frankfurt-Münster 90 protocol, in childhood high-risk anaplastic large-cell lymphoma (ALCL) was assessed. Patients and Methods Children and adolescents with high-risk ALCL, defined by mediastinal, lung, liver, spleen, or skin involvement, were eligible for the trial. After a prephase and one chemotherapy course, patients were randomly assigned to receive either five further chemotherapy courses without vinblastine or the same regimen with one vinblastine injection (6 mg/m2) during each course followed by weekly vinblastine to complete a total of 1 year of treatment. The primary end point was event-free survival (EFS), analyzed on the intent-to-treat population. Results Between November 1999 and June 2006, 110 patients were randomly assigned to receive vinblastine, and 107 were randomly assigned not to receive vinblastine. Median follow-up was 4.8 years. Patients in the vinblastine arm had a significantly reduced risk of events during the first year (hazard ratio [HR] = 0.31; 95% CI, 0.15 to 0.67; P = .002) followed by an increased risk thereafter (HR = 4.98; 95% CI, 1.65 to 15.0; P = .003). Consequently, EFS at 1 year differed significantly (91% in the vinblastine group v 74% in the no-vinblastine group), with no difference at 2 years (73% and 70%, respectively). Overall EFS curves did not differ significantly (HR = 0.91; 95% CI, 0.55 to 1.5; P = .71). Thirty-one percent of weekly doses of vinblastine were reduced as a result of hematologic toxicity, although vinblastine was discontinued for toxicity in only three patients. Conclusion Adding vinblastine during induction and as maintenance for a total treatment duration of 1 year significantly delayed the occurrence of relapses but did not reduce the risk of failure.

Le cancer est une pathologie rare chez l’adolescent et l’adulte jeune puisque les cancers diagnostiques entre 15 et 24 ans ne representent que 0,6 % de l’ensemble des cancers. Il constitue neanmoins la troisieme cause de deces dans cette tranche d’âge apres les accidents et les suicides. L’attention de la communaute medicale et scientifi que a ete attiree depuis plusieurs annees sur cette pathologie, en raison d’une part des besoins specifi ques des patients de cette tranche d’âge en matiere de support psycho-social, et d’autre part de la grande diversite de prise en charge de ces patients en fonction de leur lieu de traitement (oncologie adulte et pediatrique) (1).

Les tumeurs des glandes endocrines de l’enfant sont des maladies rares qui necessitent une collaboration multidisciplinaire (chirurgiens, endocrinologues, oncologues, medecins nucleaires, geneticiens). Leur prise en charge ne differe pas de celles des adultes atteints de ces memes maladies.

From May 1981 to June 1989, 84 children with non-B-cell lymphoma (82 lymphoblastic, 1 T-cell immunoblastic, 1 unclassified diffuse lymphoma) were treated in the pediatric department of the Institut Gustave Roussy according to a protocol called LMT81, which was derived from the LSA2L2 protocol of Wollner and modified by the adjunction of 10 courses of high dose methotrexate to improve the CNS prophylaxis. No planned irradiation was performed except in cases of initial tests (2 patients) or CNS (5 patients) involvement and residual mass (2 patients). Sixty patients had mediastinal involvement; for the others, primaries were in the head and neck (7), nodes (2), (sub)cutaneous (4), bone (7), and elsewhere (2). According to Murphy's staging system, there were 2 stage I, 6 stage II, 33 stage III, and 43 stage IV. Among the stage IV patients, 41 had bone marrow involvement, 24 of them with more than 25% blast cells in bone marrow and 19 with blast cells in blood; 7 had CNS involvement. Three patients did not achieve complete remission, 4 died in remission (two measles, one post-transfusion AIDS, one unexplained definitive aplasia) and 13 relapsed at 2 to 29 months (median-13 months). Among the 77 patients without initial CNS involvement, there was only one isolated CNS relapse. With a median follow-up of 57 months (10-106 months), the event-free survival is 75% (SE 2.5) for the 84 patients with a plateau at 29 months, 73% (SE 8) for stage I and II patients, 79% (SE 4) for stage III, and 72% (SE 4) for stage IV patients. Survival was similar in each stage group. Reasons for failure of treatment, however, were different, being toxic deaths in stage II; initial therapy resistance, early relapses, and toxic deaths in stage III; and tumor failures in stage IV. In conclusion, this protocol is efficacious on T and non-T, non-B childhood lymphoma with a low incidence of CNS relapse. A future study will seek to diminish toxicity and long-term sequellae while at least maintaining the same cure rate of patients.

Purpose To evaluate the efficacy of vinblastine for relapsed/refractory anaplastic large-cell lymphoma (ALCL). Patients and Methods Data were reviewed on all 36 patients included prospectively in the French database for pediatric ALCL who were treated with vinblastine (6 mg/m2/wk) for resistant primary disease (one), a first relapse (15), or subsequent relapses (20). Fifteen patients had undergone hematopoietic stem-cell transplantation (HSCT) for a previous relapse. Results Six patients were not evaluable for response, 25 (83%) of 30 evaluable patients achieved a complete remission (CR), and five experienced progressive disease. Among the 31 patients who achieved a CR with vinblastine or before its initiation, six patients were treated with HSCT and 25 with vinblastine alone (median duration, 14 months). Overall, nine of 25 patients treated with vinblastine alone have remained in CR (median, 7 years since the end of treatment), and 16 patients have relapsed. Vinblastine was still efficient for subsequent relapses. With a median follow-up of 9.2 years, 12 patients have died (four as a result of toxicity after HSCT and eight as a result of disease), and 24 patients are alive (15 following treatment with single-agent vinblastine for the last event). Five-year overall survival is 65% (95% CI, 48% to 79%), and 5-year event-free survival is 30% (95% CI, 17% to 47%). Conclusion Vinblastine is highly efficient in relapsed ALCL and may produce durable remissions. The optimal treatment duration still has to be assessed. These results should be borne in mind when designing future phase II studies with the targeted therapies directed against anaplastic lymphoma kinase.

Purpose To compare the efficacy and safety of two methotrexate doses and administration schedules in children with anaplastic large-cell lymphoma (ALCL). Patients and Methods This randomized trial for children with ALCL was based on the Non-Hodgkin's Lymphoma–Berlin-Frankfurt-Muenster 90 (NHL-BFM90) study protocol and compared six courses of methotrexate 1 g/m2 over 24 hours and an intrathecal injection (IT) followed by folinic acid rescue at 42 hours (MTX1 arm) with six courses of methotrexate 3 g/m2 over 3 hours followed by folinic acid rescue at 24 hours without IT (MTX3 arm). This trial involved most European pediatric/lymphoma study groups and a Japanese group. Results Overall, 352 patients (96% ALK positive) were recruited between 1999 and 2005; 175 were randomly assigned to the MTX1 arm, and 177 were assigned to the MTX3 arm. Ninety-two percent of patients received protocol treatment. Median follow-up time is 3.7 years. Event-free survival (EFS) curves were superimposed with 2-year EFS rates (73.6% and 74.5% in the MTX1 and MTX3 arms, respectively; hazard ratio = 0.98; 91.76% CI, 0.69 to 1.38). Two-year overall survival rates were 90.1% and 94.9% in MTX1 and MTX3, respectively. Only two CNS relapses occurred (both in the MTX1 arm). Toxicity was assessed after 2,050 courses and included grade 4 hematologic toxicity after 79% and 64% of MTX1 and MTX3 courses, respectively (P < .0001); infection after 50% and 32% of courses, respectively (P < .0001); and grade 3 to 4 stomatitis after 21% and 6% of courses, respectively (P < .0001). Conclusion The results of the NHL-BFM90 study were reproduced in this large international trial. The methotrexate schedule of the NHL-BFM90 protocol including IT therapy can be safely replaced by a less toxic schedule of methotrexate 3 g/m2 in a 3-hour infusion without IT therapy.

From 1974 to 1987, 450 children with non-Hodgkins' lymphoma (NHL) were seen at the Institut Gustave Roussy (IGR); 14 children had malignant lymphoma of bone (MLB). Eleven of the 14 were newly diagnosed, whereas three presented in relapse. Nine patients presented with multifocal bone involvement. The median age of these eight girls and six boys was 9.5 years (range 1.25–15 years). Bone pain was present in all patients as the initial symptom. Evaluation included physical examination, routine serum chemistries, complete blood count, chest roentgenography, skeletal survey, radionuclide bone scan, lumbar puncture, bone marrow aspiration, and intravenous pyelography, and/or abdominal ultrasonography. Hypercalcemia was found in six patients. Biopsy was performed in 12 patients, revealing high-grade lymphoblastic lymphomas in all. In two patients diagnosis was made on cytological examination of bone marrow aspirate. Immunophenotyping in four cases, demonstrated non-B, non-T cell origin in three and pre-B cell origin in one. Three patients were treated prior to 1982 with Cyclophosphamide/Oncovin/Prednisone/ADriamycin (COPAD) and seven patients, seen after 1982, were treated with a modified LSA2L2 protocol (LMT). None of the previously untreated patients received radiotherapy. All patients treated with CO-PAD have died, whereas four out of seven treated with LMT are alive with a median follow up of 51 months (range 36–82 months). One child treated on a pilot study died. One of the three children seen at relapse is disease-free with a follow-up of 98 months after high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT). Five out of six patients presenting with hypercalcemia have died. Results with LMT are encouraging and together with published results suggest that sufficiently intensive chemotherapy can result in complete remission and cure in MLB. Radiotherapy does not seem to be necessary, avoiding possible serious long-term effects. Hypercalcemia is a bad prognostic feature.

From 1982 to 1987, 40 children with non-metastatic thoracic neuroblastoma were treated with the same therapeutic regimen. According to TNM staging, there were 11 CS I, 19 CS II, and 10 CS III. All patients underwent surgery; 30 had primary surgical excision; in 10 whose tumors were deemed unresectable, surgery was delayed until after a trial of chemotherapy. Operation was completed by several courses of chemotherapy in case of microscopic residual disease or regional lymph node involvement; radiotherapy was delivered in case of gross residual disease. Using this therapeutic approach, EFS is 92% with a median follow-up of 40 months. Severe complications were rare and sequellae appear to be related to the disease, i.e., neurologic consequences of cord compression.

Between January 1982 and December 1987, of 283 children with neuroblastoma treated in the Pediatric Department of Institut Gustave Roussy, 34 were stage IV-S. Two groups were distinguished according to the initial clinical presentation: 16/34 patients had life-threatening symptoms and needed immediate treatment, and 18/34 had no life-threatening symptoms. Hepatic irradiation was used in 12/16 patients of the first group with respiratory distress. Chemotherapy was used in three patients. Of these 16 patients, three patients died of progressive disease (one patient died of a reason not related to the tumor). Twelve are alive in first complete remission and one in second complete remission. Of the 18, patients of the second group, eight had spontaneous complete remission, and one of them relapsed thereafter and died despite treatment. Ten patients needed treatment, radiotherapy, and/or chemotherapy depending on the site of disease progression. Two of them died of the disease. The overall disease-free survival for these 34 patients is 75% at 90 months postdiagnosis. Using this therapeutic strategy, it was possible to avoid any treatment of metastases in 25% of the patients.

Background Rhabdoid tumours (RTs) are aggressive malignancies of childhood, mainly occurring in the kidney and brain. We describe a national multi-centre retrospective analysis of extra-renal non-cranial RTs (ERRTs). Procedure Diagnosis relied on central histological review and/or on hSNF5/INI1 defect, evidenced by immunohistochemistry or molecular screening. Clinical data were obtained from physicians. Results Twenty six patients fulfilled the inclusion criteria. Median age at diagnosis was 28 months [0–366], including late childhood and young adults cases. Surgery, either initial or secondary, was complete in three. All but three patients received chemotherapy, with variable regimens. Additional radiotherapy was used in six patients. Median time to recurrence or progression was 5 months [0–44], and one patient remained free of disease at 7 years. Conclusions ERRTs share the same chemosensitivity, early recurrence, and poor prognosis as renal and cerebral RTs. No chemotherapy regimen demonstrates a superior response. Pediatr Blood Cancer 2008;51:363–368. © 2008 Wiley-Liss, Inc.

The fundamental purposes underlying formal health care transition from the pediatric to adult setting for young adult survivors of childhood cancer are to facilitate the continuous, medically and developmentally appropriate implementation of risk-based guidelines for the monitoring and management of late effects of childhood cancer and its treatment; and to support the normal maturational processes involved with growing from childhood to adulthood. To achieve these, this article identifies specific goals and action items in the following key areas: Models of Transitional Care, Survivor/Family Education, Post-Transitional Care Outcomes, Education of Health Care Professionals, and Health Care Policy and Advocacy.

SummaryHepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/β-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. β-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy.

We report a clinical trial with carboplatin (CBDCA) in 15 children with malignant solid tumors recurrent after or resistant to conventional treatment. Based on previous phase I clinical trials, these children were given a dose of CBDCA 560 mg/m2 by intravenous infusion every 4 weeks. The study includes a pharmacokinetic analysis of CBDCA in three patients. This clinical trial shows the feasibility of this CBDCA schedule, even after high cumulative doses of previous chemotherapy. As expected the main toxicity was hematologic but the risk of renal and ototoxicity is not excluded and these functions have still to be monitored when this relatively high dose of CBDCA chemotherapy is used.

To investigate the characteristics of patients with hepatoblastoma and low serum alpha-fetoprotein (AFP) at diagnosis. Inclusion of all 21 patients accrued onto SIOPEL trials, whose serum AFP was

Purpose Previous therapy, genetic susceptibility, and the type of first malignant neoplasm (FMN) are known to be associated with the risk of second malignant neoplasm (SMN) among patients treated for a childhood cancer. The aim of this study was to investigate the independent role of the FMN in the onset of any SMN. Patients and Methods A case-control study nested in a European cohort of 4,581 patients treated for a solid cancer during childhood was conducted. One hundred forty-six patients with an SMN and 417 controls were matched for sex, age at FMN, chemotherapy, radiotherapy, the local radiation dose received at the site of SMN for patient cases and at the same site for the matched controls, and follow-up. Results A significantly increased risk of developing any SMN was observed after Hodgkin's lymphoma, retinoblastoma, malignant bone tumor, soft tissue sarcoma (STS), and germ cell tumor as FMN, after adjustment for chemotherapy and family cancer syndrome. No significant risk of developing a carcinoma was observed among patients who had developed Hodgkin's lymphoma as FMN. A significantly increased risk of developing a sarcoma was observed among patients who had developed a retinoblastoma (adjusted odds ratio [ORa] = 7.5; 95% CI, 1.2 to 46), a malignant bone tumor (ORa = 13.3; 95% CI, 1.5 to 117), an STS (ORa = 4.8; 95% CI, 1.3 to 18), or a carcinoma (ORa = 9.4; 95% CI, 1.1 to 82) as FMN. Conclusion Survivors of Hodgkin's lymphoma, retinoblastoma, malignant bone tumor, STS, and germ cell tumor should receive close surveillance because they are at increased risk of developing any SMN.

In France, adolescents (15-20 years) with non Hodgkin's lymphoma (NHL) are referred either to paediatric or to adult onco-haematological departments. According to data obtained from regional tumour registries (covering about 10% of France), their 5 year survival rate was 59% whereas it was 87% for children (or =14 years) treated for NHL during a similar period of time. We reviewed the management of NHL either by the paediatricians or the onco-hematologists for adults. The categories of NHL that are reviewed and whose clinical and biological characteristics are presented are: Burkitt, lymphoblastic and large cell, either B or anaplastic. This review shows that, in most series, outcome was better in children than in adults. This raises the reasons of this difference: is it due to the different therapeutic approaches, to different tolerance of chemotherapy, to different biology within the same histological type ? Further studies specific to the adolescents are needed to better know the biology of their lymphoma and to determine the best therapeutic approach.

International audience; We report an adolescent cancer pathway from referral, through diagnosis and treatment, to follow-up in France. All cases of cancer among 15-19 years, diagnosed from 1988 to 1997, recorded by nine French population-based cancer registries (10% of French population) were included. The management of adolescent cancer by paediatricians was rare. An adolescents' pathway through cancer care can be summarized as first visit to general practitioner, referral to adult oncologist for haematological malignancy and medical or surgical specialists for solid tumours, treatment in adult unit, and follow-up by adult oncologist, adult medical or surgical specialist, or general practitioner. Only 9% of the 15-19 years are entered into a clinical trial (respectively 6% and 3% into adult and paediatric clinical trial). The inclusion rate changes according to the diagnosis, higher for acute lymphoblastic leukaemia (39%), non-Hodgkin's lymphomas (NHL) (27%), and acute non-lymphoblastic leukaemia (20%). Only 4% of adolescent cancers were managed on shared adult/paediatric departments, especially for soft-tissue sarcomas (14.9%), malignant bone tumours (13.4), central nervous system tumours (6.2%), and NHL (4.4%). Whatever the reasons for lack of participation in clinical trials, an ideal model requiring communication and cooperation between all adult and paediatric specialists involved in adolescent cancer treatment should reduce the large gap in access to cooperative groups.

Homozygous or compound heterozygous, that is, biallelic, germ-line mutations in one of the four mismatch repair (MMR) genes cause a rare condition that has only recently been recognised as a distinct childhood cancer susceptibility syndrome. As such there is still a lack of awareness of the condition among paediatric oncologists. Timely recognition of the condition that results in an extraordinarily high cancer risk also has far-reaching consequences for other family members. It is therefore important that the medical and scientific community reaches agreement on a standard name for this condition, because the use of different names could potentially create confusion. It is for this reason that we …

The dismal prognosis of osteosarcoma of the limbs treated by amputation alone can be improved dramatically by including chemotherapy in an interdisciplinary regimen. Neoadjuvant chemotherapy is commonly used in order to eradicate the micrometastases and to prepare for limb-salvage surgery. To-days conservative surgery is possible in the majority of patients, including young children, and relapse-free survival attains 50-80%. High-dose methotrexate, doxorubicine, cis-platin and ifosfamide are considered the most active drugs against osteosarcoma. However, the best combination of drugs remains controversial with pending questions regarding the number of drugs to give for the preoperative phase of treatment and the value of salvage chemotherapy in poor histological responders. Furthermore long term toxicity of the drugs need to be better assessed. In order to answer these questions, treatment should be administered within the scope of prospective multi-centre trials.

With the use of microarray gene-expression profiling, we analyzed a homogeneous series of 32 patients with systemic anaplastic large-cell lymphoma (ALCL) and 5 ALCL cell lines. Unsupervised analysis classified ALCL in 2 clusters, corresponding essentially to morphologic subgroups (ie, common type vs small cell and “mixed” variants) and clinical variables. Patients with a morphologic variant of ALCL had advanced-stage disease. This group included a significant number of patients who experienced early relapse. Supervised analysis showed that ALK+ALCL and ALK− ALCL have different gene-expression profiles, further confirming that they are different entities. Among the most significantly differentially expressed genes between ALK+ and ALK− samples, we found BCL6, PTPN12, CEBPB, and SERPINA1 genes to be overexpressed in ALK+ ALCL. This result was confirmed at the protein level for BCL-6, C/EBPβ and serpinA1 through tissue microarrays. The molecular signature of ALK− ALCL included overexpression of CCR7, CNTFR, IL22, and IL21 genes but did not provide any obvious clues to the molecular mechanism underlying this tumor subtype. Once confirmed on a larger number of patients, the results of the present study could be used for clinical and therapeutic management of patients at the time of diagnosis.

Background Loss of fertility is one of the long-term adverse effects of high-dose chemotherapy or total body irradiation for cancer, even in children. Ovarian tissue cryopreservation (OTC) may make it possible for survivors of childhood cancer to have children. We evaluated the feasibility of this technique for prepubertal girls. Methods Between September 2000 and February 2005, 49 prepubertal girls were referred to the Reproductive Biology Unit for OTC before sterilizing treatment. Results One ovary each was collected from 47 patients, by laparoscopy in 24 patients and laporotomy in the others. In 16 cases, the ovary was harvested during laparotomy to resect a residual abdominal tumor. No complications occurred after operations. Ovarian tissue was frozen by a slow-cooling protocol, using DMSO and sucrose as cryoprotectants. An mean of 17.6 ± 6.5 ovarian tissue fragments was cryopreserved per patient. Follicle concentration was evaluated histologically for 46 patients and a strong correlation was found between age and follicular density. None of the cases had visible ovarian tumor components. Ovarian cryopreservation was not carried out for two patients. Conclusion The cryopreservation of ovarian tissue could be systematically offered even to prepubertal girls at risk of sterility due to gonadotoxic treatment. Pediatr Blood Cancer 2007;49:74–78. © 2006 Wiley-Liss, Inc.

International audience; Cancer is the third most significant cause of mortality in French adolescents. The aim of this study was to investigate survival of adolescents with cancer. Overall (OS), disease-specific (DSS) and event-free survival (EFS) were used for the outcome analysis of adolescents (15-19 years) with cancer, recorded by nine French population-based registries during the 1988-1997 period. Five-year OS, DSS and EFS were, respectively, 74.0% (70.7-77.4), 74.5% (71.2-77.9), and 69.0% (65.4-72.5). Five-year DSS was 94% for carcinomas, 89% for germ-cell tumours, 85% for lymphomas, 67% for soft-tissue sarcomas, 64% for CNS tumours, 55% for malignant bone tumours, and 41% for leukaemia. Compared with paediatric series, poor results in acute lymphoblastic leukaemia, malignant bone tumours, and soft-tissue sarcomas have to be highlighted, and deserve further studies concerning the type of regimens used for these patients. Multidisciplinary management of adolescent cancer in paediatric, adult, or specialized units will improve cure rates and treatment outcomes for these patients.

Anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) are recognized as biologically distinct entities. However, occasionally, these two entities may share some morphologic features responsible for diagnostic difficulties. In the last 10 years, we have collected 380 cases of ALK-positive ALCL of which 10 cases were originally diagnosed as nodular sclerosis classic HL (NSHL) on conventional histopathological examination. After immunostaining, these cases proved to be ALK-positive ALCL mimicking HL (so-called Hodgkin-like ALCL). These cases account for 2.6% of our cases of ALK-positive ALCL (10 of 380 cases). Median age was 11 years (3-92 years) with a female predominance (male/female ratio, 3:7). Characteristically, these lesions showed thick nodular fibrosing bands highly suggestive of NSHL. Neoplastic cells were scarce in 6 cases, whereas in the 4 remaining cases, sheets of tumor cells were also present. A perivascular and a sinusoidal growth pattern was observed in various degrees in all cases. Few binucleated Reed-Sternberg-like cells were present in every case in a background of small lymphocytes. Inflammatory cells (ie, granulocytes, eosinophils, and histiocytes) were rare. Neoplastic cells were positive for CD30 (10 of 10 cases), ALK protein (10 of 10 cases), epithelial membrane antigen (EMA) (9 of 9 cases), CD43 (6 of 9 cases), and perforin (8 of 8 cases), but negative for CD15 (10 of 10 cases), CD20 (10 of 10 cases), Pax5/BSAP (6 of 6 cases), and EBV (8 of 8 cases). In addition, in 7 cases, neoplastic cells were of T-phenotype, whereas the 3 remaining cases were considered to be of null/undetermined phenotype. Although rare, Hodgkin-like ALCL may mimic NSHL, and it is advisable to include EMA in the first line panel and to ask for ALK staining in EMA-positive, CD15-negative lesions with morphologic features suggestive of NSHL.

International audience; Li-Fraumeni syndrome, resulting from p53 (TP53) germline mutations, represents one of the most devastating genetic predispositions to cancer. Recently, the MDM2 SNP309 (T-->G variation) was shown to be associated with accelerated tumour formation in p53 mutation carriers. The impact of the common p53 codon 72 polymorphism on cancer risk remains controversial. We therefore investigated the effect of these two polymorphisms in 61 French carriers of the p53 germline mutation. The mean age of tumour onset in MDMD2 SNP309 G allele carriers (19.6 years) was significantly different from that observed in patients homozygous for the T allele (29.9 years, p

Background Cervicothoracic neuroblastoma originates from the cervical sympathetic nerves and ganglia and thus presents a problem when dissecting the vascular and nervous elements of the subclavian region. The standard operation is based on thoracotomy or dual cervicotomy/thoracotomy, but these approaches do not provide optimal control of the subclavian vessels. We report our experience in children with cervicothoracic neuroblastoma by using a technique usually performed for apical lung cancer. Methods Four patients with localized cervicothoracic neuroblastoma with no N- myc amplification were resected after chemotherapy by this approach. The anatomic evaluation was performed preoperatively with angio–magnetic resonance imaging. This transmanubrial approach, performed through a manubrial L-shaped transection and first costal cartilage resection, affords excellent access to the subclavian region with safe control of the vessels and nerves and exposure of the first 4 thoracic intervertebral foramina. Results Removal of more than 90% of the tumor was possible in all cases. The postoperative course was uneventful in 3 cases, and the fourth patient with a left-sided tumor had a transient chylothorax. No recurrence occurred with a follow-up period of 8 to 32 months. Conclusions The transmanubrial approach is an osteomuscular-sparing technique that seems particularly suitable for the treatment of these tumors, which require a resection that is as complete as possible to avoid postoperative chemotherapy and tumor relapse.

The increasing complexity of present day medicine--with highly effective and yet risky treatments, individual and collective expectations, and evolving ideological and cultural landmarks--often gives rise to difficult ethical problems. Specific meetings are valuable for understanding such problems, acquiring the relevant skills and for gaining and transmitting experience on how to solve them. Parents and doctors may disagree about what is the best treatment. Such a difference of opinion is not rare but usually a solution can easily be found. This is not the case when the child is treated for a severe illness and when there is no clearly defined or satisfactory treatment for him\her. We present how a dramatic conflict arose between the parents and the doctors faced with such a case (mostly because the staff failed to understand early enough the psychological factors at the root of the father's demands), how clinical, institutional and ethical problems were analysed during a meeting, and how they were solved.

Introduction Advances in medical therapy have greatly improved the survival of children suffering from cancer. Although progress has been made in the eradication of malignant disease there is growing concern for the development of fungal infections in patients treated with chemotherapy. Materials and Methods We reviewed all episodes of pediatric candidemia that occurred between January 1988 and December 2000. We analyzed the general characteristics of this population, risk factors, microbiology features, treatment, complications, and outcome. Results Seventeen cases of candidemia were observed during the 12 years of the study at an estimated incidence of 0.4%. Neutropenia occurred at the onset of infection in 13/17 (76.5%) children. A central venous device was present in all cases. Seventy-seven percent of the infections were caused by Candida albicans and in 85% of patients, yeasts had colonized the gastrointestinal tract. In 9/17 patients visceral dissemination was documented. Overall, in 77% of the episodes the outcome was favorable. Conclusions Candidemia is a rare but severe complication in pediatric oncology. Even if the prognosis is better in children than in adults, Candida septicemia remains of great concern since a high percentage of these infections result in visceral dissemination and mortality is still elevated. © 2003 Wiley-Liss, Inc.

Genetic susceptibility to neuroblastoma (NB) is now highly probable and the likelihood that it may also confer a higher risk of other cancer types has been suggested. The aim of this study was to estimate the fraction of inherited cases and penetrance associated with a carrier status, and to investigate the hypothesis that susceptibility cancer genes might be non-specific.The family history of 426 children treated for NB at the Institut Gustave Roussy was obtained. The excess of relatives affected by NB or early-onset cancer (EOC) was sought using the standardized incidence ratio (SIR). The risk of NB among sibs was estimated taking into account the age of patients' sibs. Estimation of penetrance in hereditary cases and of the proportion of sporadic cases was obtained using segregation analysis of proband sibships.There was a positive family history of NB or ganglioneuroma in 5 of the 426 cases (1.2%). A highly significant excess of NB was found among relatives (SIR=11.4, 95% CI: 3.7-26.5). The excess of EOC (SIR=1.22, 95% CI=0.92-1.58) was non-significant, but it was of borderline significance among first-degree relatives (SIR=1.70, 95% CI=0.99-2.72). The risk of NB among sibs was estimated at 0.2% (95% CI=0.004-1.0%). Penetrance in hereditary cases was estimated at 11.4% and the proportion of inherited cases, 3.5%.The genetic factors heightening susceptibility to NB are most probably dominantly inherited with low penetrance and are involved in only a very small fraction of NB patients. The overall risk in sibs is very low and this should reassure parents with regard to their other children. We found some arguments for the existence of non-specific genetic susceptibility, which would slightly in crease the probability of developing any cancer.

In order to lower the long-term toxicity of chemotherapy for hepatoblastoma patients, a prospective study was designed based on pre-operative chemotherapy combining carboplatin and epirubicin (CE).Patients under 16 years of age with an epithelial hepatic tumor diagnosed by ultrasound or CT scan and a high serum alpha-foetoprotein (AFP) level were eligible. Patients were treated with a pre-operative chemotherapy regimen combining carboplatin 600 mg/m(2) and epirubicin 80 mg/m(2). Tumor resectability was assessed after four courses given at 3-week intervals. After surgery, patients were given two more courses of CE. Response was assessed based on a drop in serum AFP and tumor shrinkage.Between July 1988 and August 1995, 27 patients with a hepatoblastoma were included. The initial PRETEXT group according to the SIOPEL classification was: group 2 (5 pts), group 3 (15 pts), group 4 (5 pts), and 2 pts were not assessed. Six patients had lung metastases. Response was partial response (PR) in 20/27 (74%) patients, disease was stable in 3 and 4 had progressive disease (PD). A complete surgical resection was performed in 21 pts. Five-year overall and disease-free survival (DFS) were respectively 56% (95%CI: 37-72%) and 63% (95%CI: 44-78%). During the same time period, 7 pts with a hepatocellular carcinoma were treated according to this protocol. Only one achieved a PR. Toxicity was mostly hematologic withor =grade 3 leukopenia in 23% of the courses,or =grade 3 thrombocytopenia in 29% of the courses and anemia in 22%.The CE protocol is feasible and efficient in hepatoblastoma. However, only a randomized study will permit a valid comparison of the efficacy of cisplatin and carboplatin for the treatment of these patients.

✓ In patients with pineal tumors, clinical symptoms are due to direct compression of adjacent structures. The most common signs include increased intracranial pressure (80%) caused by obstruction of the sylvian aqueduct, and Parinaud syndrome (50%) caused by direct compression of the superior colliculi. Hearing loss is rare in patients with tumors in this location. The authors report on the case of a 12-year-old boy in whom a malignant pineal germ cell tumor was found together with the unusual occurrence of severe hearing loss due to direct bilateral compression of the inferior colliculi. This condition resolved completely after tumor regression.

Optic pathway tumors decrease adult height by central precocious puberty (PP) or hypothalamic-pituitary disorders, particularly growth hormone (GH) deficiency caused by the tumor, management of the tumor, or associated neurofibromatosis 1. The objective of this study was to evaluate the respective roles of these factors on disorders and adult height.Thirty-five patients with optic pathway tumors diagnosed at 6.4 +/- 0.6 years treated by cranial irradiation (30-56 Gy) reached adult height after treatment with GH alone (n = 16), gonadotropin hormone-releasing hormone analogue alone (n = 2), or both (n = 16).Central precocious puberty occurred before irradiation in four cases and after irradiation in 18. Eleven of the 17 patients with neurofibromatosis 1 had PP. Before irradiation, five of 21 patients lacked GH, zero of 21 lacked thyroid-stimulating hormone, and zero of 13 lacked adrenocorticotropin. After irradiation, 35 of 35 lacked GH, 28 of 35 lacked thyroid-stimulating hormone, and six of 35 lacked adrenocorticotropin; puberty was delayed in 15 patients. Adult height was -0.8 +/- 0.2 SD, below target height (0.2 +/- 0.2 SD, P.0001), similar in patients with and without PP, but lower in those with neurofibromatosis 1 (-1.4 +/- 0.4 SD) than in those without (-0.3 +/- 0.3 SD, P =.04).Optic pathway tumors cause PP, but cranial irradiation causes most of the other hypothalamic-pituitary disorders. Adult height of patients given GH or gonadotropin hormone-releasing hormone analogue seems to depend on neurofibromatosis 1.

Aim: Based on anti-tumour effect of zoledronate in vitro and in experimental models of rat osteosarcoma, we assessed whether zoledronate (Z) in combination with chemotherapy and surgery improved Event-Free Survival (EFS) in children and adult patients (pts) with osteosarcoma. Methods: Experimental treatment consisted of 10 Z-injections (4 pre and 6 postoperative), 4 mg/injection in adults, 0.05 mg/kg/injection in younger pts. Chemotherapy included methotrexate-etoposide-ifosfamide +/-adriamycine-cisplatin in children/adolescents, and doxorubicin-ifosfamide/doxorubicin-ifosfamide-cisplatinum in adults. Balanced randomisation between Z+arm and Z-arm was stratified by center, age, chemotherapy type and risk group (localised resectable disease versus unresectable primary and/or metastases). The study was planned as an open-label superiority trial, with 3 interim analyses (early stopping for efficacy or harm) disclosed to an independent safety monitoring board (DSMB). 470 pts (170 events) were required to achieve an 80%-power to detect a 13%-improvement of 3-year EFS (H1: 55% versus 68%, HR(event)=0.65) with zoledronate (2-sided alpha=0.05). Results: A second interim analysis was performed after 318 pts (82% with a localised and resectable tumour) have been recruited between April 2007 and February 2014: 158 Z- and 160 Z+. No significant increase in toxicity was found in Z+, except expected hypocalcemia grade 2-4 (p Conclusions: With current follow-up, the addition of zoledronate to chemotherapy did not reduce the risk of failure in osteosarcoma patients. Disclosure: All authors have declared no conflicts of interest.

4575 Background: To describe the specific features of malignant renal tumors occurring in young adults. Methods: Medical charts of all 15-35 yo pts diagnosed with a primary renal malignant tumor fr...