Combined therapy in children and adolescents with classical Hodgkin's lymphoma: A report from the SFCE on MDH-03 national guidelines.

Hodgkin's lymphoma (HL) in children and adolescents is highly curable, but children are at risk of long-term toxicity. The MDH-03 guidelines were established in order to decrease the burden of treatment in good-responder patients, and this report should be considered a step toward further optimization of treatment within large collaborative trials. We report the therapy and long-term outcomes of 417 children and adolescents treated according to the national guidelines, which were applied between 2003 and 2007 in France. The patients were stratified into three groups according to disease extension. Chemotherapy consisted of four cycles of VBVP (vinblastine, bleomycin, VP16, prednisone) in localized stages (G1/95 pts/23%), four cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, adriamycin, bleomycin, vinblastine) cycles in intermediate stages (G2/184 pts/44%) and three cycles of OPPA (vincristine, procarbazine, prednisone, adriamycin) plus three cycles of COPP in advanced stages (G3/138 pts/33%). Radiation therapy of the involved field was given to 97% of the patients, with the dose limited to 20 Gy in good responders (88%). With a median follow-up of 6.6 years, the 5-year event-free survival (EFS) and overall survival (OS) were 86.7% (83.1-89.7%) and 97% (94.5-98.1%), respectively. EFS and OS for G1, G2, and G3 were 98% and 100%, 81% and 97%, and 87% and 95%, respectively. Low-risk patients treated without alkylating agents and anthracycline had excellent outcomes and a low expected incidence of late effects. Intensification with a third OPPA cycle in high-risk group patients, including stage IV patients, allowed for very good outcomes, without increased toxicity.

Surgical management of thymic epithelial tumors in children: lessons from the French Society of Pediatric Oncology and review of the literature.

PURPOSE: We report the results of a French multicenter retrospective study based on a period of more than 30 years and a review of the literature in order to more clearly define the surgical approach and specific pediatric risk factors. METHODS: Clinical data of children comprising all histologic subtypes of thymic epithelial tumors (TET) treated between 1979 and 2009 in French pediatric oncology centers were retrospectively analyzed and discussed in the light of a review of all pediatric cases reported in the literature. RESULTS: Nine cases were identified, corresponding to five females and four males with a median age of 13 years (range: 7.5-17). Histologic subtypes were type AB (n = 1), type B (n = 5) and type C (n = 3). Treatment consisted of tumor resection (4 R0, 4 R1, 1 R2) via right anterior thoracotomy, posterolateral thoracotomy, left thoracoscopy, sternotomy and cervicosternotomy, and/or chemotherapy, mainly cyclophosphamide-doxorubicin-cisplatin (CAP; n = 5), and/or radiotherapy (n = 4). Two patients with TET type C died. All other patients are alive with a median follow-up of 4 years (range: 1.5-20). Review of a total of 93 pediatric cases reported in the literature showed statistically significant associations between less favorable histologic subtypes and male gender (P = 0.012), advanced Masaoka stage (P < 0.001) and quality of resection (P < 0.001) respectively. CONCLUSIONS: A review of the literature and our series identified several risk factors to take into account in the therapeutically decision. Complete resection through a sternotomy is highly recommended.

Long-term morbidity and mortality in 2-year hepatoblastoma survivors treated with SIOPEL risk-adapted strategies.

BACKGROUND AND AIMS: Prognosis of hepatoblastoma patients has increased with cisplatin-based chemotherapy and high-quality resection including liver transplant. Consequently current risk-adapted therapeutic strategy aims to reduce long-term side effects in patients with standard risk disease. METHODS: We report long-term mortality and morbidity data concerning 151 2-year hepatoblastoma survivors treated with SIOPEL risk-adapted strategies (sex-ratio M/F = 1.6, median age at diagnosis = 2.6 years [range 0-17.7], median year at diagnosis = 2008 [1994-2017]). Fifty-three patients had loco-regional risk factors VPEFR, 12 were PRETEXT-IV and 30 were metastatic. All received cisplatin and 84 anthracyclines. Twelve had liver transplant. To assess hearing, renal and cardiac functions, audiograms were performed in 116/151 patients (76.8%), glomerular filtration rate in 113/151 (74.8%) and cardiac ultrasound in 65/84 (77.4%) anthracycline-exposed patients. RESULTS: With a median follow-up of 9.4 years (range 2.1-25.8), four late relapses, one second malignancy (Acute Myeloid Leukemia AML-M5) and two deaths (one from hepatoblastoma, one from AML) occurred. The 10-years event free survival and overall survival probabilities were 95.5% (95% CI 91.9-99.1) and 98.7% (95% CI 96.8-100), respectively. Sixty-eight non-oncologic health-events included 57 cases of hearing loss (including 25 Brock 3-4), three liver cirrhosis, three pre-operative portal cavernoma, two focal nodular hyperplasia, two grade-1 chronic kidney diseases and one asymptomatic cardiac dysfunction were reported. Ototoxicity was significantly associated with cisplatin cumulative dose (OR = 2.07, 95% CI 1.32-3.24, p = 0.001) and carboplatin exposure (OR = 3.14, 95% CI 1.30-7.58, p = 0.01) in multivariable analysis adjusted for sex and age at diagnosis. CONCLUSIONS: With current risk-adapted strategies, hepatoblastoma is a highly curable disease, with very rare relapses, and few late effects except hearing loss which remains a serious condition in these very young patients.

Analysis of diagnosis announcements in Abidjan pediatric oncology unit 2 years after introduction of the African Pediatric Cancer Announcement Guideline.

INTRODUCTION: Announcing the diagnosis allows the therapeutic alliance between physicians and patients to be sealed and it prevents abandonment of treatment. To compensate for the deficit in information received by the families, the Franco-African Group of Pediatric Oncology (FAGPO) has published an "African Pediatric Cancer Announcement Guide" for the group's pediatric oncology units. OBJECTIVE: To analyze the announcements made to parents and children 2 years after the provision of this guide. METHODS: Cross-sectional survey conducted from March to July 2016. In total, 69 parents of children followed up in the pediatric oncology unit of Abidjan were interviewed regarding the characteristics of the announcement that was made to them and the information given to the sick child. RESULTS: Of all the accompanying individuals, 91% reported having benefited from the announcement made with empathy, mainly by a physician. In approximately one quarter of the cases the information had been given to a third party. The main barriers to information were: the negative experiences of parents, the medical terminology, and communication problems. The sick child was rarely informed. DISCUSSION: The information given was in accordance, in content and form, with the data from Western and African literature. The lack of information given to the child has a dual explanation: the primacy of the community over the individual advocated by African culture and the non-integration of the rights of children in the current code of ethics. CONCLUSION: The information provided could be improved by practical training of physicians in the technique of breaking bad news to patients and their families and the use of a code of ethics in accordance with the principle of autonomy.

[Evaluation of a screening strategy after occurrence of two simultaneous contaminating tuberculosis cases in a pediatric oncology department]. / Stratégie de prise en charge de contages tuberculeux dans un service d'oncologie-pédiatrique.

BACKGROUND: A medical staff and an administrative staff of our paediatric oncology department have contracted a pulmonary tuberculosis. This is a rare situation and the management of this infection threat in a paediatric oncology department is not clearly defined. Recommendations tell we must treat all patients. Nevertheless, antituberculosis agent expose to increased toxic effects and immunocompromised patients have an increased risk of experiencing progression of latent mycobacterium tuberculosis infection to active tuberculosis disease. OBJECTIVE: This study aims at the evaluation of a screening and a treatment strategy adapted for a paediatric oncology department. METHOD: From April 2004 to April 2005, 80 children with a solid tumour were screened for tuberculosis according to a screening and treatment protocol established by a multidisciplinary committee. Two risk groups were defined according to age and immunodepression status. The "high risk" group is composed of less than 2 years old children and children who underwent an haematological peripheral stem cell transplantation. All other children were included in the "low risk" group. The screening was based on clinical, biological and radiological data performed three times spaced out by 2 or 3 months. At the end of each part of screening, the multidisciplinary committee analyzed the results and discussed the utility of an antituberculosis treatment. RESULTS: 80 children (31 boys and 49 girl) with a median age of 7,3 years (0,3-24) participated to the screening. Sixty children were still undergoing anticancer treatments. Twenty belonged to the high risk group. The complete screening was performed in 32% of the patients. Three antituberculosis' treatment were initiated: 2 for prophylaxis purpose and 1 for a tuberculosis prime-infection. A child had an additional check-up because of an abnormal chest X-ray. Our management strategy allowed us to treat significantly less patients when compared to national guidelines (3 vs 80 test Chi-2 p<0.001). No side effects of antituberculosis agents were noted. No tuberculosis has been observed in our population 28 months after the completion of the treatment. CONCLUSION: The proposed screening allowed us to treat a minimum of children and thus, to reduce the potential toxicity induced by antituberculosis' treatments.

[Pediatric non-Hodgkin's lymphoma: primary surgical management of patients presenting with abdominal symptoms. Recommendations of the Lymphoma Committee of the French Society to Combat Pediatric Cancers (SFCE)]. / Lymphome non-Hodgkinien de l'enfant: prise en charge chirurgicale lors d'un tableau abdominal révélateur.

Over the past two decades, dramatic improvements in the treatment of children with Non-Hodgkin's Lymphoma have led to cure rates close to 90%, even in advanced-stage disease. The most frequent localization is abdominal, where Burkitt or Burkitt-like subtypes are predominant. Initial management often occurs in the setting of a urgent surgical intervention where multiple complications may gravely threaten prognosis within days or even hours. The SFCE Lymphoma Committee's guidelines for optimal management include: 1) The diagnosis of lymphoma should be systematically evoked whenever the clinical context is not consistent with idiopathic intussusception, particularly in children over the age of 3 or when clinical and/or ultrasound findings are not typical; 2) Limited bowel resection should be performed only if it allows complete tumor removal and is technically simple without extensive dissection or risk of major complications; 3) If surgical resection is likely to be difficult, risky, or incomplete, surgery should be limited to sampling of peritoneal fluid and tumor; 4) In all cases, adequate tissue should be obtained and sent to the pathology department in appropriate media Analysis of tumor material may require, in addition to histology and cytology, immunophenotyping, cytogenetics, and molecular biology studies in order to arrive at an accurate diagnosis and prognosis and to guide treatment choices.

[Not Available]. / Lymphome non-Hodgkinien de l'enfant : prise en charge chirurgicale lors d'un tableau abdominal révélateur: Recommandations du « Comité lymphome ¼ de la Société française de lutte contre les cancers de l'enfant et de l'adolescent (SFCE).

A. Delarue, C. Bergeron, F. Mechinaud-Lacroix, C. Coze, M. Raphael, C. Patte, pour le « Comité Lymphome ¼ de la SFCE Over the past two decades, dramatic improvements in the treatment of children with Non-Hodgkin's Lymphoma have led to cure rates close to 90%, even in advanced-stage disease. The most frequent localization is abdominal, where Burkitt or Burkitt-like subtypes are predominant. Initial management often occurs in the setting of a urgent surgical intervention where multiple complications may gravely threaten prognosis within days or even hours. The SFCE Lymphoma Committee's guidelines for optimal management include: 1) The diagnosis of lymphoma should be systematically evoked whenever the clinical context is not consistent with idiopathic intussusception, particularly in children over the age of 3 or when clinical and/or ultrasound findings are not typical; 2) Limited bowel resection should be performed only if it allows complete tumor removal and is technically simple without extensive dissection or risk of major complications; 3) If surgical resection is likely to be difficult, risky, or incomplete, surgery should be limited to sampling of peritoneal fluid and tumor; 4) In all cases, adequate tissue should be obtained and sent to the pathology department in appropriate media Analysis of tumor material may require, in addition to histology and cytology, immunophenotyping, cytogenetics, and molecular biology studies in order to arrive at an accurate diagnosis and prognosis and to guide treatment choices.

Vancomycin in Pediatric Patients with Solid or Hematological Malignant Disease: Predictive Performance of a Population Pharmacokinetic Model and New Optimized Dosing Regimens.

BACKGROUND: The application of population pharmacokinetic models and Bayesian methods offers the potential to develop individualized therapeutic approaches. OBJECTIVES: The current study presents an external evaluation of a vancomycin pharmacokinetic model in a pediatric cancer population and proposes an easy-to-use chart for clinicians for a priori vancomycin schedule adaptation to achieve target concentration. METHODS: External evaluation of a population pharmacokinetic model of vancomycin administered via continuous infusion was realized in a new retrospective dataset of pediatric patients with cancer. The published population pharmacokinetic model was implemented in NONMEM 7.3 with the structural and variance parameter values set equal to estimates previously reported. Predictive performance was assessed by quantifying bias and accuracy of model prediction. Normalized prediction distribution errors were also evaluated. Dosage simulations were performed according to the target concentration. RESULTS: A total of 77 patients were included in this study, representing 146 vancomycin courses and 289 concentrations. The model adequately predicted vancomycin concentrations (median prediction error % of - 9.4%, median |PE|% of 24.1%). Based on simulation results, vancomycin dosage (mg/kg) should be adapted for each child on the basis of body weight and cyclosporine coadministration. CONCLUSION: The model previously proposed by Guilhaumou et al. in pediatric patients with solid or hematological malignant disease was externally validated. Simulations have enabled the description of new dosage schedules and creation of a chart to help clinicians adapt vancomycin dosage.

[Understanding nephroblastoma. Information dedicated to parents and relatives]. / Comprendre le néphroblastome. Information à l'usage des parents et des proches d'un enfant malade.

In response to the evolution of the information-seeking behaviour of patients and concerns from health professionals regarding cancer patient information, the French National Federation of Comprehensive Cancer Centres (FNCLCC) introduced, in 1998, an information and education program dedicated to patients and relatives, the SOR SAVOIR PATIENT program. The methodology of this program adheres to established quality criteria regarding the elaboration of patient information. Cancer patient information developed in this program is based on clinical practice guidelines produced by the FNCLCC and the twenty French regional cancer centres,the National League against Cancer, The National Cancer Institute, the French Hospital Federation, the National Oncology Federation of Regional and University Hospitals, the French Oncology Federation of General Hospitals, many learned societies, as well as an active participation of patients, former patients and caregivers. The handbook SOR SAVOIR PATIENT Understanding nephroblastoma is an adapted version of various scientific publications and international clinical practice guidelines, validated by oncology experts and by the Nephroblastoma Committee of the French Society against Cancers and Leukaemias in children and adolescents (SFCE). It was elaborated with the active participation of parents and other family members. It is meant to provide a basis for the explanation of the disease, to help parents asking questions, and to facilitate discussions with the healthcare team. It is available from the FNCLCC (101, rue de Tolbiac, 75013 PARIS, Tel. (0033)1 76 64 78 00, www.fnclcc.fr). This document was validated at the end of 2005 and published in May 2006. SOR SAVOIR PATIENT guides are systematically updated when new research becomes available. Information leaflets, extracted from the handbook SOR SAVOIR PATIENT Understanding nephroblastoma and published in this edition of the Cancer et Radiothérapie, describe the physiopathology of nephroblastoma, as well as treatments and follow-up. The guide allows parents and relatives to better understand the disease and the treatments proposed. It also offers health professionals a synthetic evidence-based patient information source which facilitates discussions with the patient.

A lack of neuroblastoma in Down syndrome: a study from 11 European countries.

An epidemiological investigation in 11 European countries comprising a total childhood population of 54.1 million children and using 8 separate data sources was conducted to evaluate the occurrence of neuroblastoma in Down syndrome (DS). No cases of DS were detected among 6724 infants and children with neuroblastoma, although more than five were expected. This highly significant result (P = 0.0045 according to the Poisson test) is consistent with data in the literature, which contains only two poorly detailed cases in epidemiological studies and one ganglioneuroma in a DS mosaic patient. Like other tumors, such as leukemias, testicular germ cell tumors and lymphomas are in excess in DS patients; the lack of neuroblastomas does not reflect a general decreased incidence of cancer but rather a specific underrepresentation of this precise tumor. S-100 b protein, the gene for which maps to the long arm of chromosome 21, (a) is overproduced in DS patients, (b) produces growth inhibition and differentiation of neural cells in vitro, (c) is abundant in good-prognosis neuroblastomas, and (d) has been shown to induce growth inhibition and differentiation and cell death in several human and murine neuroblastoma cell lines and could be responsible for this variation. Additional epidemiological and experimental studies are warranted to confirm our interpretation of these data.

Impact of megatherapy on survival after relapse from stage 4 neuroblastoma in patients over 1 year of age at diagnosis: a report from the European Group for Bone Marrow Transplantation.

PURPOSE: Relapse from stage 4 neuroblastoma usually carries a poor prognosis. A retrospective study using the European Bone Marrow Transplant (EBMT) Solid Tumor Registry was undertaken to define the role of megatherapy (MGT) in relapsed patients. PATIENTS AND METHODS: After relapse, 33 boys and 15 girls with previous stage 4 neuroblastoma received intensification by MGT followed by either autologous (n = 42) or allogeneic (n = 6) bone marrow rescue in 11 European institutions. The median age at diagnosis was 47 months (range, 14 to 134) and the median interval from diagnosis to relapse was 16 months (range, 4 to 94). Thirty patients had received only conventional-dose primary treatments (group A), whereas 18 patients had previously received intensification with MGT (group B). The median follow-up time of the total group is 95 months (range, 25 to 185). RESULTS: The actuarial overall survival rate at 2 years after MGT for relapse is 27% for group A and 0% for group B (P = .02). Three adverse, independent prognostic factors were confirmed by multivariate analysis using the Cox proportional hazards regression model: an interval of less than 12 months between diagnosis and relapse (P < .0001), nonresponding or untreated relapse (P = .0002), and previous MGT during primary treatments (P = .055). None of the other variables analyzed, such as sex, age, bone or bone marrow involvement at diagnosis or at relapse, and type of MGT at relapse, influenced outcome in this patient cohort. CONCLUSION: Responding patients who relapse more than 12 months from diagnosis who had not received previous MGT appear to benefit from consolidation MGT. Relapse patients who do not fulfill these criteria gain no advantage from this cost-intensive procedure and should be treated differently.

LMCE3 treatment strategy: results in 99 consecutively diagnosed stage 4 neuroblastomas in children older than 1 year at diagnosis.

PURPOSE: To tailor postinduction therapy for stage 4 neuroblastoma in children who are older than 1 year at diagnosis according to status after induction. PATIENTS AND METHODS: From March 1987 to December 1992, 99 patients who were consecutively admitted were included in the Lyon-Marseille-Curie East of France (LMCE)3 strategy. After induction with the French Society of Pediatric Oncology NB87 regimen and surgery, patients who were in complete remission immediately proceeded to consolidation therapy with vincristine, melphalan, and fractionated total-body irradiation (VMT). All other patients underwent a postinduction strategy before VMT, either an additional megatherapy regimen or further chemotherapy with etoposide/carboplatin. RESULTS: The progression-free survival (PFS) is 29% at 7 years from diagnosis, which compares favorably with that of a similar cohort of 72 patients previously reported by our group (LMCE1; PFS of 20% at 5 years and 8% at 14 years, P =.004). In the multivariate analysis, only age younger than 3 years at diagnosis (P =.0085) and achievement of complete or very good partial remission after NB87 and surgery (P =.00024) remained significant. The PFS of the 87 patients who were included in the postinduction strategy was significantly better than that of the comparable 62 patients on the LMCE1 study (32% v 11% at 7 years; P =.005). CONCLUSION: The progressive improvements in the LMCE results over the last 10 years suggest that improvements in supportive care measures and increases in each component of this strategy (induction, postinduction, consolidation) may all contribute to increased survival rates.

Localized childhood Hodgkin's disease: response-adapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low-dose radiation therapy-results of the French Society of Pediatric Oncology Study MDH90.

PURPOSE: The French Society of Pediatric Oncology MDH82 study demonstrated the effectiveness of 20 Gy irradiation of involved fields after doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or mechlorethamine, vincristine, procarbazine, and prednisone/ABVD chemotherapy in children with localized Hodgkin's disease (HD). The response to primary chemotherapy was the only predictor of survival. To reduce long-term treatment complications without compromising efficacy, the MDH90 study was based on a new chemotherapy regimen devoid of both alkylating agents and anthracycline, followed by 20 Gy of radiotherapy (RT) for good responders. PATIENTS AND METHODS: From January 1990 to July 1996, 202 children were enrolled from 30 institutions. Good responders to four cycles of vinblastine, bleomycin, etoposide (VP16), and prednisone (VBVP) were given 20 Gy of RT and no further therapy. Poor responders were given vincristine, procarbazine, prednisone, and doxorubicin. After a second evaluation, good responders were given 20 Gy of RT, and poor responders were given 40 Gy of RT. RESULTS: One hundred seventy-one patients (85%) were good responders to VBVP, 27 (15%) were poor responders, and four did not respond. With a median follow-up of 74 months (range, 25 to 117 months), the 5-year overall survival rate (mean +/- SD) is 97.5% +/- 2.1%, and the event-free survival rate (mean +/- SD) is 91.1% +/- 1.8%. Significant predictors of worse event-free survival in multivariate analysis were hemoglobin < 10.5 g/L, "b" biologic class, and nodular sclerosis. CONCLUSION: These results suggest that most children with clinical stage I and II HD can be treated with chemotherapy devoid of alkylating agents and anthracycline, followed by low-dose RT.

Multivariate analysis of risk factors in stage 4 neuroblastoma patients over the age of one year treated with megatherapy and stem-cell transplantation: a report from the European Bone Marrow Transplantation Solid Tumor Registry.

PURPOSE: The European Bone Marrow Transplantation (EBMT) Solid Tumor Registry (STR) contains detailed information on children with advanced neuroblastoma who, after standard-dose induction chemotherapy and surgery, received myeloablative megatherapy (MGT) followed by stem-cell transplantation (SCT). This data base was analyzed to identify factors that predict event-free survival (EFS). PATIENTS AND METHODS: Eligibility criteria were stage IV neuroblastoma, age over 1 year at diagnosis, and no relapse before MGT/SCT. Between February 1978 and July 1992, 549 patients were registered by 36 European transplant centers. The median age at diagnosis was 36 months (range, 13 to 216 months) and the male-female ratio was 1:45. Before MGT, 157 patients were in complete remission (CR), 156 in very good partial remission (VGPR), and 208 in partial remission (PR), whereas 24 had had only a minor response (MR). One hundred ten of 546 patients had undergone two successive MGT procedures. The median observation time was 60 months (range, 12 to 187 months). RESULTS: Actuarial EFS is 26% at 5 years. Multivariate analysis by the Cox proportional hazards regression model included 529 patients with complete data sets. After adjustment for treatment duration before MGT and double MGT procedures, two adverse, independent risk factors that influenced EFS were identified: (1) persisting skeletal lesions before MGT as defined by technetium (99TC) scans and/or meta-iodobenzylguanidine (mIBG) scans (P = .004) and (2) persisting bone marrow involvement before MGT (P = .03). CONCLUSION: After induction treatment, persisting skeletal disease as defined above and persisting bone marrow involvement may be predictive of a particularly poor outcome. Physicians may consider this an additional important tool to decide the patient's management.

NB87 induction protocol for stage 4 neuroblastoma in children over 1 year of age: a report from the French Society of Pediatric Oncology.

PURPOSE: NB87 was designed to test the efficacy of a short, non cross-resistant, induction protocol for unselected patients over 1 year of age with stage 4 neuroblastoma. A secondary objective was to compare in a randomized study the toxicity of two modalities of cisplatin administration. PATIENTS AND METHODS: A total of 183 patients received two cycles of alternating sequences: cyclophosphamide 300 mg/m2/d on days 1 to 5, vincristine 1.5 mg/m2/d on days 1 and 5, and doxorubicin 60 mg/m2/d on day 5 (CADO); and cisplatin 40 mg/m2/d and etoposide 100 mg/m2/d on days 1 to 5 (CVP), followed by surgery of the primary tumor (126 patients). Ninety-one were randomized to receive cisplatin either as bolus (BO; n = 48) or continuous infusion (CI; n = 43). International Neuroblastoma Staging System (INSS) and Response Criteria (INRC) were used with emphasis on skeletal evaluation by meta-iodobenzylguanidine (MIBG). RESULTS: Hematotoxicity was predominant, with a higher incidence of neutropenia (P = .01) for CADO and of thrombocytopenia for CVP (P < .001). Severe infections, as well as nonhematologic toxicities, occurred more often after the first sequence. Gastrointestinal complications were predominant during both courses of CVP. The toxic death rate, including surgery, was 3%. Complete remissions (CRs) were less frequent on MIBG (45%) compared with marrow (66%) or other metastases (61%). Combining all metastatic sites resulted in a 39% CR rate. After surgery, the final CR rate was 42%. Nephrotoxicity was minimal in both arms (92% normal clearance for CI v 82% for BO). Hearing loss greater than 40 dB at 6,000 to 8,000 Hz was reported equally in both arms (n = 6 for CI v n = 5 for BO). CONCLUSION: Intensified chemotherapy using CADO/CVP increases CR rates despite a shorter induction duration. However, the rate of MIBG normalization remains unsatisfactory and could be raised through the dose-intensive use of agents such as cyclophosphamide.

N-Myc gene amplification is a major prognostic factor in localized neuroblastoma: results of the French NBL 90 study. Neuroblastoma Study Group of the Société Francaise d'Oncologie Pédiatrique.

PURPOSE: To assess the relevance of N-Myc gene amplification (NMA) as a prognostic factor in localized neuroblastoma (NB) and to evaluate whether less intensive adjuvant treatment is advisable in infants without NMA. PATIENTS AND METHODS: Assessment of NBs included clinical and imaging data to allow tumor-node-metastasis (TNM) staging, biologic determinations (N-Myc gene analysis), and standard histology and work-up to eliminate metastatic spread (metaiodobenzylguanidine [MIBG] scintigraphy and extensive bone marrow staging). Resectability was defined according to imaging findings. Chemotherapy was indicated in children older than 1 year at diagnosis who had postoperative residual disease or lymph node (LN) involvement, in infants with NMA, or as primary treatment in children with an unresectable NB, including dumbbell tumors. Radiotherapy was recommended in children older than 1 who presented with persistent gross residual disease at the end of therapy. RESULTS: Between 1990 and 1994, 316 consecutive children who presented with a localized NB were registered in the NBL 90 study. The median age was 12 months, and 42 patients had dumbbell tumors (13%). NMA was found in 22 of 225 assessable children (10%) and correlated with adverse prognostic indicators such as age older than 1 year, an abdominal primary tumor, a large tumor (T3), and unresectability. Among 186 children who had primary excision, five died of surgery-related complications. Primary chemotherapy was given to 130 patients, which allowed removal of the tumor in all but four. The 5-year overall survival (OS) and event-free survival (EFS) rates were, respectively, 91% and 84% with a median follow-up time of 36 months. The outcome of infants and older children was similar (P = .2). EFS of patients with resectable tumors was slightly better than with unresectable primary tumors (EFS, 89% v 78%; P = .02). In dumbbell NBs, neurologic recovery was achieved in 74% of cases that presented with symptoms, and initial laminectomy was avoided in 75% of children. In a univariate analysis, large tumors, high neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) levels, positive LNs, macroscopic residue, and NMA adversely influenced outcome. In the multivariate analysis, NMA was the most powerful unfavorable predictive indicator: OS and EFS rates for these children were 36% and 32%, compared with 98% and 90% in nonamplified tumors (P < .001). CONCLUSION: Our data confirm the overall good prognosis of localized NBs, even when unresectable. NMA is the most relevant adverse prognostic factor in localized NBs, and more intensive treatment should be investigated in these patients. Prospective studies of other biologic factors are warranted to tailor therapy more accurately. The EFS of children who underwent primary surgery was excellent, and further justifies elimination of adjuvant treatment provided they have no NMA. Despite the elimination of postoperative therapy, infants with non-NMA tumors have an excellent outcome, which suggests that initial chemotherapy can be further reduced in case of unresectable NBs.

[Infectious complications postengrafment in the first year after autologous stem cell transplantation in children]. / Autogreffes de cellules souches hématopoïétiques en oncologie pédiatrique; étude des complications infectieuses survenant au cours de la première année après sortie d'aplasie.

BACKGROUND: Studies on the infectious complications postengrafment in pediatric stem cell transplantation patients are rare. The aim of this study was to assess the incidence, types, outcome and factors affecting late infections. PATIENTS AND METHODS: A single-institution retrospective analysis was done of infections recorded in the first year following engrafment in children who underwent autologous stem cell transplantation for solid tumors from January 1991 to December 2000. A systematic antimicrobial chemoprophylaxis of TMP/SMX was administered. Patients who were at high risk for varicella-zona virus infection received prophylactic acyclovir. RESULTS: Eighty-four assessable patients were enrolled. Fifty-four patients (64%) underwent autologous peripheral blood stem cell transplantation and 30 patients (36%) underwent bone marrow transplantation. Forty-nine episodes of infections were documented in 39 patients (46%) of whom 27 patients (32%) developed infections after the first 100 days post transplantation. Bacterial septicemia occurred in nine patients of whom four patients had a catheter-related septicemia. Twelve patients (14%) developed localized herpes zoster infection. Local fungal infection occurred in five patients. Infection-related death occurred in one patient with non-documented pneumonitis. Univariable analysis showed a correlation between the CD34(+) cell dose <7.5 10(6)/kg and the development of infections (P =0.04). Patients who did not go into remission after transplantation where at high risk for septicemia (P =0.007). Multivariate analysis showed that a history of varicella or pretransplant varicella-zona positivity was the only significant factor for development zoster infection (P =0.01). CONCLUSION: Our study shows that infections in the first year postengrafment following autologous stem cell transplantation for solid tumors have a good prognosis and that the use of TMP/SMX should be the single systematic antimicrobial prophylaxis. The CD34(+) cell dose seems to play a role in preventing late infections.

[Multidisciplinarity, education, and training in pediatric oncology-hematology]. / Multidisciplinarité et formation des spécialistes à l'oncologie et à l'hématologie maligne pédiatrique.

INTRODUCTION: According to the European Society of Pediatric Oncology (SIOPE) standard of care guidelines, high-quality care of children and adolescents with cancer needs to be delivered by well-trained multidisciplinary teams in specialist centers working with designated shared-care local centers in a so-called hub-and-spoke model. The Diplôme Inter-Universitaire d'Oncologie Pédiatrique (DIUOP) is the only European training program in pediatric oncology in French for all physicians involved in care of patients with pediatric malignancies. In agreement with the SIOPE syllabus, the DIUOP is composed of training courses (120h), on-site practical training in a specialist center, and a research project to be defended before an examining board. METHOD: All graduates received a questionnaire to describe their current professional position. A comprehensive PubMed analysis retrieved all papers published form DIUOP research projects. RESULTS: From 2000 to 2011, 290 physicians were trained: 242 pediatricians, 21 surgeons, and 19 radiation therapists. Eight had another specialty including imaging, hematology, and pathology. Ninety-two were initially trained outside of France: 50% in Europe (mainly in Italy, Belgium, and Switzerland), 42% in Africa and the Middle East, and 8% in South America. Of the 266 graduates, 74% answered the questionnaire, and 90% of them take care of children and adolescents with cancer. Sixty-nine articles, i.e., one out of four research projects, were published in 34 journals with a median impact factor of 3.5 (0-22.6), 85% in English. CONCLUSION: DIUOP is the only French-speaking European education program providing a high-quality, professionalizing, and comprehensive multidisciplinary training program for French and international specialists taking care of children and adolescents with cancer.

A phase-II study of adoptive immunotherapy with continuous infusion of interleukin-2 in children with advanced neuroblastoma. A report on 11 cases.

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

Immunomodulatory effects of human neuroblastoma cells transduced with a retroviral vector encoding interleukin-2.

We have investigated whether retroviral mediated transfer of the IL-2 gene renders human neuroblastoma cells immunogenic, justifying their use in a clinical tumor immunization study. Fourteen neuroblastoma cell lines were established from patients with disseminated neuroblastoma and transduced with the vector G1Ncvl2, which contains the neomycin phosphotransferase gene and the cDNA of the human interleukin-2 gene. Clones secreting > 150 pg/10(6) cells/24 h of IL-2 were selected for further study. Secretion of IL-2 was maintained for at least 3 weeks in nonselective media, implying that production of the cytokine would continue under in vivo conditions. Co-culture of IL-2 transduced cell lines with patient lymphocytes induced potent cytotoxic activity against both transduced and parental neuroblastoma cell lines. This activity was HLA unrestricted, and predominantly mediated by CD16+ or CD56+ and CD8- lymphocytes. These data form the preclinical justification for our current immunization protocol for patients with relapsed or resistant neuroblastoma.