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ABSTRACT: In cases of neuroblastoma, recurring genetic alterations-losses of the 1p, 3p, 4p, and 11q and/or gains of 1q, 2p, and 17q chromosome arms-are currently used to define the therapeutic strategy in therapeutic protocols for low- and intermediate-risk patients. Different genome-wide analysis techniques, such as array comparative genomic hybridization (aCGH) or multiplex ligation-dependent probe amplification (MLPA), have been suggested for detecting chromosome segmental abnormalities. In this study, we compared the results of the two technologies in the analyses of the DNA of tumor samples from 91 neuroblastoma patients. Similar results were obtained with the two techniques for 75 samples (82%). In five cases (5.5%), the MLPA results were not interpretable. Discrepancies between the aCGH and MLPA results were observed in 11 cases (12%). Among the discrepancies, a 18q21.2-qter gain and 16p11.2 and 11q14.1-q14.3 losses were detected only by aCGH. The MLPA results showed that the 7p, 7q, and 14q chromosome arms were affected in six cases, while in two cases, 2p and 17q gains were observed; these results were confirmed by neither aCGH nor fluorescence in situ hybridization (FISH) analysis. Because of the higher sensitivity and specificity of genome-wide information, reasonable cost, and shorter time of aCGH analysis, we recommend the aCGH procedure for the analysis of genomic alterations in neuroblastoma.
Cancer Genetics 12/2012;
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ABSTRACT: PURPOSE The purpose of this study was to determine the outcome of children with nephroblastoma and pulmonary metastases (PM) treated according to International Society of Pediatric Oncology (SIOP) 93-01 recommendations using pulmonary radiotherapy (RT) in selected patients. PATIENTS AND METHODS Patients (6 months to 18 years) were treated with preoperative chemotherapy consisting of 6 weeks of vincristine, dactinomycin, and epirubicin or doxorubicin. If pulmonary complete remission (CR) was not obtained, metastasectomy was considered. Patients in CR received three-drug postoperative chemotherapy, whereas patients not in CR were switched to a high-risk (HR) regimen with an assessment at week 11. If CR was not obtained, pulmonary RT was mandatory. Results Two hundred thirty-four of 1,770 patients had PM. Patients with PM were older (P < .001) and had larger tumor volumes compared with nonmetastatic patients (P < .001). Eighty-four percent of patients were in CR postoperatively, with 17% requiring metastasectomy. Thirty-five patients (16%) had multiple inoperable PM and required the HR protocol. Only 14% of patients received pulmonary RT during first-line treatment. For patients with PM, 5-year event-free survival rate was 73% (95% CI, 68% to 79%), and 5-year overall survival (OS) rate was 82% (95% CI, 77% to 88%). Five-year OS was similar for patients with local stage I and II disease (92% and 90%, respectively) but lower for patients with local stage III disease (68%; P < .001). Patients in CR after chemotherapy only and patients in CR after chemotherapy and metastasectomy had a better outcome than patients with multiple unresectable PM (5-year OS, 88%, 92%, and 48%, respectively; P < .001). CONCLUSION Following the SIOP protocol, pulmonary RT can be omitted for a majority of patients with PM and results in a relatively good outcome.
Journal of Clinical Oncology 08/2012; 30(28):3533-9. · 18.37 Impact Factor
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Norbert Graf,
Harm van Tinteren, Christophe Bergeron,
François Pein,
Marry M van den Heuvel-Eibrink,
Bengt Sandstedt,
Jens-Peter Schenk,
Jan Godzinski,
Foppe Oldenburger,
Rhoikos Furtwängler,
Jan de Kraker
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ABSTRACT: PURPOSE: To determine the prognosis of children with stage II and III of low or intermediate risk histology (SIOP classification) in unilateral localised Wilms tumour (WT) after neoadjuvant chemotherapy according to the trial and study of the International Society of Paediatric Oncology, SIOP 93-01. PATIENTS AND METHODS: Patients with unilateral localised WT and stage II or III with low (LR) or intermediate risk (IR) histology between 6months and 18years of age, were selected from the total sample of patients registered in the SIOP 93-01 study between June 1993 and December 2001. All patients received 4weeks of actinomycin-D/vincristine before surgery. Postoperative chemotherapy consisted of actinomycin-D, vincristine and epirubicin/doxorubicin for 27weeks. Flank or whole abdomen irradiation was given for stage III. Event-free survival (EFS) and overall survival (OS) were analysed for various subgroups. RESULTS: Of 1476 registered patients 594 (40%) met the inclusion criteria for this analysis. Four hundred and two (67%) had stage II disease and 563 (95%) had intermediate risk histology. Median tumour volume was 439ml at diagnosis and 163ml after preoperative chemotherapy. With a median follow-up of 8years, 5-year EFS was 90% (95% confidence interval [95% CI]: 87-92%) and OS 95% (95% CI: 93-97%). Patients with stage III, blastemal type histology and a large volume at surgery had a worse outcome. CONCLUSION: Treatment for stage II and III LR or IR WT is successful in a neoadjuvant setting as advised by the SIOP. Stage, tumour volume and blastemal type histology are the most important prognostic factors.
European journal of cancer (Oxford, England: 1990) 07/2012; · 4.12 Impact Factor
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Odile Oberlin,
Annie Rey,
José Sanchez de Toledo,
Hélène Martelli,
Meriel E M Jenney,
Marcelo Scopinaro, Christophe Bergeron,
Johannes H M Merks,
Nathalie Bouvet,
Caroline Ellershaw,
Anna Kelsey,
David Spooner,
Michael C G Stevens
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ABSTRACT: MMT95 was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial.
From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m(2) (both arms), epirubicin 450 mg/m(2), etoposide 1,350 mg/m(2) (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other arm. Delivery of radiotherapy was determined according to site and/or response to chemotherapy with or without surgery.
Overall survival (OS) for all patients was 81% (95% CI, 77% to 84%) at 3 years. No significant difference in outcome in either OS or event-free survival was noted between the two arms (3-year OS: 82% [95% CI, 76% to 86%] for IVA and 80% [95% CI, 74% to 85%] for the six-drug arm). Toxicity was significantly greater (infection, myelosuppression, and mucositis) in the six-drug arm. Overall burden of local therapy was consistent with data from previous SIOP studies and showed no difference between the two chemotherapy regimens.
Intensification of chemotherapy for nonmetastatic RMS and other chemotherapy-sensitive STS provides no survival advantage or reduction in the intensity of local therapy and adds toxicity.
Journal of Clinical Oncology 06/2012; 30(20):2457-65. · 18.37 Impact Factor
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Véronique Minard-Colin,
Jean-Laurent Ichante,
Laurent Nguyen,
Angelo Paci,
Daniel Orbach, Christophe Bergeron,
Anne-Sophie Defachelles,
Nicolas André,
Nadège Corradini,
Claudine Schmitt,
Marie-Dominique Tabone,
Pascale Blouin,
Nicolas Sirvent,
Gisele Goma,
Birgit Geoerger,
Odile Oberlin
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ABSTRACT: This phase II study evaluated efficacy, safety and pharmacokinetics (PK) profile of combination intravenous vinorelbine (VNL) and continuous low doses oral cyclophosphamide (CPM) combination in children and young adults with a recurrent or refractory solid tumour.
A total of 117 patients (median age, 12years) within six disease strata received intravenous VNL 25mg/m(2) on days 1, 8 and 15 of each 28-day cycle combined with continuous daily oral CPM 25mg/m(2). Tumour response was assessed every two cycles according to WHO (World Health Organisation) criteria. PK of VNL was investigated in a subset of 18 patients aged 4-15years.
In rhabdomyosarcoma (RMS) (n=50), the best overall response rate (ORR) was 36% with four complete (8%) and 14 partial responses (28%). The best ORR was 13% in Ewing's sarcoma (n=15), 6% in non-RMS soft tissue sarcoma (n=16) and 6% in neuroblastoma (n=16). No response was observed in osteosarcoma (n=10) and medulloblastoma (n=7). The main grade 3/4 toxicity was neutropenia (38%). Other severe toxicities were limited with 3% of peripheral neuropathy and no haemorrhagic cystitis. The PK analysis revealed equivalent blood exposure to VNL between children >4years and adult series when the VNL dose was based on the body surface area-based dosing. CONCLUDING STATEMENT: In heavily pre-treated children, VNL combined with CPM showed an interesting response rate in RMS and an acceptable toxicity profile supporting further evaluation of these agents in phase III trials.
European journal of cancer (Oxford, England: 1990) 05/2012; 48(15):2409-16. · 4.12 Impact Factor
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Lionel Perrier,
Alessandra Buja,
Giuseppe Mastrangelo,
Antonella Vecchiato,
Paolo Sandonà,
Françoise Ducimetière,
Jean-Yves Blay,
François Noël Gilly,
Carole Siani,
Pierre Biron,
Dominique Ranchère-Vince,
Anne-Valérie Decouvelaere,
Philippe Thiesse, Christophe Bergeron,
Angelo Paolo Dei Tos,
Jean-Michel Coindre,
Carlo Riccardo Rossi,
Isabelle Ray-Coquard
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ABSTRACT: Although the management of sarcoma is improving, non adherence to clinical practice guidelines (CPGs) remains high, mainly because of the low incidence of the disease and the variety of histological subtypes. Since little is known about the health economics of sarcoma, we undertook a cost-effectiveness analysis (within the CONnective TIssue CAncer NETwork, CONTICANET) comparing costs and outcomes when clinicians adhered to CPGs and when they did not.
Patients studied had a histological diagnosis of sarcoma, were older than 15 years, and had been treated in the Rhône-Alpes region of France (in 2005/2006) or in the Veneto region of Italy (in 2007). Data collected retrospectively for the three years after diagnosis were used to determine relapse free survival and health costs (adopting the hospital's perspective and a microcosting approach). All costs were expressed in euros (€) at their 2009 value. A 4% annual discount rate was applied to both costs and effects. The incremental cost-effectiveness ratio (ICER) was expressed as cost per relapse-free year gained when management was compliant with CPGs compared with when it was not. To capture uncertainty surrounding ICER, a probabilistic sensitivity analysis was performed based on a non-parametric bootstrap method.
A total of 219 patients were included in the study. Compliance with CPGs was observed for 118 patients (54%). Average total costs reached 23,571 euros when treatment was in accordance with CPGs and 27,313 euros when it was not. In relation to relapse-free survival, compliance with CPGs strictly dominates non compliance, i.e. it is both less costly and more effective. Taking uncertainty into account, the probability that compliance with CPGs still strictly dominates was 75%.
Our findings should encourage physicians to increase their compliance with CPGs and healthcare administrators to invest in the implementation of CPGs in the management of sarcoma.
BMC Health Services Research 03/2012; 12:82. · 1.66 Impact Factor
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ABSTRACT: The treatment of bilateral Wilms tumors (WT) requires multimodality therapy with individualized decision to ensure cure while preserving as much renal parenchyma as possible.
We analyzed the clinical records of 49 children with bilateral WT treated in France between 1993 and 2001, according to the SIOP-93 guidelines (individual treatment program: Treatment was continued as long as there was imaging evidence of tumor regression). Pathology reports, duration of preoperative chemotherapy and surgical records were also reviewed. Overall Survival (OS) and Event-Free Survival (EFS) rates were studied and relationships between possible prognostic factors and survival were assessed.
Imaging studies revealed bilateral involvement in 98% of the cases. Whatever the response to preoperative chemotherapy, the mean duration of neoadjuvant chemotherapy was 80 days (Q1-Q3: 47-89 days). Forty-eight children underwent nephron sparing surgery (NSS) at least for one kidney and 19 for both. Five-year EFS and OS rates were, respectively, 83.4 and 89.5%. Only the most advanced stages were shown to affect OS (P = 0.03). At study endpoint, end-stage renal disease (ESRD) was reported in seven children, associated with a predisposing phenotype in three.
Results of this study demonstrate a favorable outcome of patients with bilateral WT receiving an individual treatment program. With a tailored approach to treatment according to the tumor response, 77% of our patients were operated before the third month of preoperative chemotherapy. In spite of good survival, 14% of our patients have ESRD.
Pediatric Blood & Cancer 01/2012; 59(1):57-61. · 1.89 Impact Factor
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Heidi Segers,
Marry M van den Heuvel-Eibrink,
Kathy Pritchard-Jones,
Max J Coppes,
Michael Aitchison, Christophe Bergeron,
Beatriz de Camargo,
Jeffrey S Dome,
Paul Grundy,
Gemma Gatta,
Norbert Graf,
John A Kalapurakal,
Jan de Kraker,
Elizabeth J Perlman,
Harald Reinhard,
Filippo Spreafico,
Gordan Vujanic,
Anne B Warwick
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ABSTRACT: Since Wilms' tumor occurs rarely in adults, there are no standard treatments available. Most adult patients will be diagnosed unexpectedly following nephrectomy for presumed renal cell carcinoma. Outcome for adults is inferior compared with children, although better results are reported when treated within pediatric trials. Multiple factors, including the unfamiliarity of adult oncologists and pathologists with Wilms' tumors, lack of standardized treatment and consequent delays in initiating the appropriate risk-adapted therapy, may contribute to the poor outcome. A standardized approach for the management of adult Wilms' tumors is proposed with the aim to limit treatment delay after surgery and encourage a uniform approach for this rare disease and thereby improve survival. These recommendations are based on discussions held with representatives of the renal tumor committees of the Society of Paediatric Oncology and Children's Oncology Group, and have been updated with a review of more recently published institutional and trial experience of adults treated on pediatric protocols. They provide a critical evaluation of the current evidence for the management of adult Wilms' tumors and propose details of how current pediatric therapeutic guidelines could be adapted for use in adults.
Expert Review of Anti-infective Therapy 07/2011; 11(7):1105-13. · 2.65 Impact Factor
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ABSTRACT: The SIOP 2001 nephroblastoma study hypothesised that patients with 'CT-only' pulmonary nodules would have the same outcome as patients with localised disease of same stage and histology.
Unilateral Wilms' tumour (WT) patients, who had chest CT scans at diagnosis showing any sized pulmonary nodules undetected on chest X-ray, between November 2001 and November 2009, were selected from the SIOP 2001 database.
Among 2532 WT patients, 103 unilateral nephroblastoma patients with CT-only lung lesions were found. Thirty-seven patients received preoperative treatment according to the localised-disease protocol, and 66 according to the metastatic-disease protocol. The 3-year event-free survival (EFS) was 70% (95% CI: 55-89%) and 77% (95% CI: 66-89%), respectively. Corresponding 3-year overall survival (OS) was 89% (95% CI: 77-100%) and 85% (95% CI: 75-96%), respectively (p-value not significant). EFS and OS of all 2071 patients with true localised disease were 87% (95% CI: 86-89%) and 96% (95% CI: 94-97%), respectively. Patients with metastatic disease (n = 358) had 3-year EFS and OS estimates of 68% (95% CI: 63-74%) and 77% (95% CI: 72-82%), respectively.
EFS and OS of patients with CT-only lung lesions were inferior to that of true localised-disease patients and superior to that of patients with metastatic disease. However, no significant difference was found in EFS and OS between CT-only patients treated for localised or metastatic disease. The clinician's preference to treat patients with CT-only pulmonary nodules as metastatic disease is not evidence-based. Chest CT at diagnosis does not improve outcome but presents paediatric oncologists with a difficult dilemma.
European journal of cancer (Oxford, England: 1990) 06/2011; 48(7):1060-5. · 4.12 Impact Factor
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ABSTRACT: Retrospective studies have demonstrated the prognostic impact of genomic profiles in neuroblastoma (NB). Segmental chromosome alterations have been found useful for identifying tumors with a high risk of relapse. As the gain of chromosome arm 17q is the most frequent chromosome alteration reported in NB primary tumors, we evaluated the presence of this 17q gain in the peripheral blood of patients with NB.
Using duplex quantitative real-time PCR, we quantified simultaneously MPO (17q.23.1) and a reference gene, p53, and Survivin (17q25) and p53. MPO and Survivin copy numbers were evaluated as MPO/p53 and Survivin/p53 ratios in 142 serum or plasma samples in which 17q status had been determined by array-based comparative genomic hybridization (aCGH) or multiplex ligation-dependent probe amplification (MLPA).
In patients <18 months of age, serum-based determination of 17q gain in DNA sequences had good specificity (94.4%) and 58.8% sensitivity (P < 0.001). In contrast, for patients over 18 months of age, the approach exhibited moderate specificity (71.4%) and 51.2% sensitivity (P = ns). Similar results were observed in patients with tumors without MYCN amplification.
Our results show that 17q gain determination in circulating DNA is possible and suggest that this non-invasive test could be useful for very young children when no reliable information on genomic alterations is obtained by aCGH or MPLA analysis of tumor samples This test is complementary to previously developed techniques for detecting circulating MYCN DNA sequences.
Pediatric Blood & Cancer 05/2011; 56(5):757-61. · 1.89 Impact Factor
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Jan Godzinski,
Harm van Tinteren,
Jan de Kraker,
Norbert Graf, Christophe Bergeron,
Hugo Heij,
Dietrich von Schweinitz,
Joerg Fuchs,
Giovanni Cecchetto,
George Audry,
Frederic Gauthier,
Bengt Sandstedt
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ABSTRACT: Partial nephrectomy (NSS) for unilateral nephroblastoma may be beneficial, although in case of regional lymph node (LN) involvement, radiotherapy counteracts the functional benefit of NSS. The aim is to verify whether decrease of tumor volume under preoperative chemotherapy implies clearance of regional LN.
SIOP 9301 (1993-2001) collected 1,450 localized nephroblastoma patients of whom 1,360 (93%) had sufficiently available data and were retrospectively reviewed.
Histologic subtypes were classically distributed. Patients were divided in those with tumor positive LN (76, 5.5%) and those with tumor negative LN (1,284, 94.5%) at surgery. In the LN(+) group, the tumor volume changed from a median of 554 (318-772) to 192 (63-458) ml = 67% (27-88%) during preoperative ChT. In the LN(-) group-377 (200-612) to 130 (44-294) ml = 62% (28-83%) (NS). Increase of tumor volume was observed in 16% of patients with LN(+), and 11% of those with LN(-) (NS); ranges are interquartile. Initial tumor volume was significantly larger in the LN(+) patients (P = 0.00091) but not different (NS) at surgery; patients with initial tumor volume under 318 ml had the regional LN involved significantly less frequently (P = 0.00751).
Change in tumor volume under preoperative chemotherapy is not a predictor for LN status at surgery, although larger initial volume is associated with a higher risk of LN invasion. The decrease of tumor volume is not a good criterion for the safety of NSS. The low rate of LN(+) (5.5%) indicates that this risk is low.
Pediatric Blood & Cancer 04/2011; 57(7):1266-9. · 1.89 Impact Factor
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Jérémie Rudant,
Laurent Orsi,
Alain Monnereau,
Catherine Patte,
Hélène Pacquement,
Judith Landman-Parker, Christophe Bergeron,
Alain Robert,
Gérard Michel,
Anne Lambilliotte,
Nathalie Aladjidi,
Virginie Gandemer,
Patrick Lutz,
Geneviève Margueritte,
Dominique Plantaz,
Françoise Méchinaud,
Denis Hémon,
Jacqueline Clavel
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ABSTRACT: The study investigated the role of factors considered related to the early stimulation of the immune system in the aetiology of childhood lymphoma. The national registry-based case–control study, Escale, was carried out in France over the period 2003–2004. Population controls were frequency matched with the cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. Odds ratios (ORs) were estimated using unconditional regression models adjusted for potential confounders. Data from 128 cases of Hodgkin's lymphoma (HL) aged 5–14 years, 164 cases of non-Hodgkin's lymphoma (NHL) aged 2–14 years and 1,312 controls were analyzed. Negative associations were observed between HL and day care attendance [OR = 0.5 (0.2–1.2)] and between HL and repeated early common infections among non-breastfed children [OR = 0.3 (.2–0.7), p = 0.003] [OR for breastfed children: 1.0 (.5–2.1)], but not for the other factors investigated. Negative associations were observed between NHL and birth order 3 or more [OR = 0.7 (0.4–1.1)], prolonged breastfeeding [OR = 0.5 (0.3–1.0)], regular contact with farm animals [OR = 0.5 (0.3–1.0)], frequent farm visits in early life [OR = 0.6 (0.4–1.1)] and history of asthma [OR = 0.6 (0.3–1.1)]. In conclusion, the results partly support the hypothesis that an abnormal maturation of the immune system may play a role in childhood HL or NHL, and call for further investigations.
International Journal of Cancer 03/2011; 129(9):2236 - 2247. · 5.44 Impact Factor
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Ruth Ladenstein,
Ulrike Pötschger,
Dimitris Siabalis,
Alberto Garaventa, Christophe Bergeron,
Ian J Lewis,
Jerry Stein,
Janice Kohler,
Peter J Shaw,
Wolfgang Holter,
Vito Pistoia,
Jean Michon
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ABSTRACT: To establish a safe dose of subcutaneous (SC) recombinant interleukin 2 (rIL-2) in an outpatient setting for children with stage 4 neuroblastoma after megatherapy (MGT) and autologous stem-cell reinfusion (ASCR) that is able to sustain an increase of natural-killer cells (NKCs) above the level previously reported for immunomodulatory potency.
Between August 1997 and November 2000, 33 patients with stage 4 neuroblastoma entered the study from six countries after receiving MGT/ASCR according to national protocols. Dose levels of 3, 6, and 9 × 10(6) U rIL-2/m(2) were given SC in six 5-day cycles every 2 weeks.
Median age at registration was 4.1 years (range, 1.8 to 7.4). Median observation time was 5 years (range, 4 to 9.8). Increase of NKCs was achieved in 89% of courses, with more than 100% increase over baseline and/or more than 1,000 NKCs/μL in 58%. On the basis of outpatient dose-limiting toxicity at dose level 3, dose level 2 was chosen for the confirmation stage. At dose level 2, the median increase in absolute NKCs was 1,180 cells/μL for all 83 cycles, corresponding to a median relative NKC increase over baseline of 711%. Fever was frequent but controllable with adequate supportive care; 6.5% of patients were hospitalized. Localized pain was moderate and acceptable. Event-free and overall survival rates at 5 years were 45% (± 9 standard deviation [SD]) and 48% (± 9 SD), respectively.
The low toxicity profile and ability to sustain an increase in NKCs of IL-2 at 6 × 10(6) U/m(2) SC allows its integration in an outpatient setting.
Journal of Clinical Oncology 02/2011; 29(4):441-8. · 18.37 Impact Factor
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Stéphane Ducassou,
Céline Ferlay, Christophe Bergeron,
Sandrine Girard,
Geneviève Laureys,
Hélène Pacquement,
Dominique Plantaz,
Patrick Lutz,
Jean-Pierre Vannier,
Anna Uyttebroeck,
Yves Bertrand
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ABSTRACT: In children, lymphoblastic lymphomas represent 30% of Non-Hodgkin lymphomas (NHL), and approximately 15% are precursor B-cell lymphomas (PBLL). Our study evaluated their main clinical characteristics, evolution, and prognosis in three trials. From 1989 to 2008, 53 children with PBLL (median age 7·75 years) were included in three protocols: Malignant Lymphoma Therapy (LMT) 96, European Organization for Research and Treatment of Cancer (EORTC) 58881, and EORTC 58951 using Berlin-Frankfürt-Münster-derived acute lymphoblastic leukaemia (ALL) therapy. There were 10 stage I disease, 9 stage II, 9 stage III and 25 stage IV. Clinical presentation was heterogeneous with a majority of bone lesions and cutaneous or subcutaneous manifestations. At diagnosis 23 patients had bone marrow involvement, and only three had central nervous system involvement. The median follow-up was 74 months. At last follow-up, 45 patients were in continuous complete remission, whereas eight had progressed or had relapsed (7 Stages IV and 1 Stage III) and died. Two patients had a secondary neoplasia, and are still alive. Disease stage was a major prognostic factor, with better overall survival (OS) and event-free survival (EFS) (P < 0·05) rates observed in patients with Stage I to III as compared to those with Stage IV. Treatment with protocols derived from ALL therapy are efficient with an 82% EFS and an 85% OS at 5 years.
British Journal of Haematology 02/2011; 152(4):441-51. · 4.94 Impact Factor
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Françoise Ducimetière,
Antoine Lurkin,
Dominique Ranchère-Vince,
Anne-Valérie Decouvelaere,
Michel Péoc'h,
Luc Istier,
Philippe Chalabreysse,
Christine Muller,
Laurent Alberti,
Pierre-Paul Bringuier,
Jean-Yves Scoazec,
Anne-Marie Schott, Christophe Bergeron,
Dominic Cellier,
Jean-Yves Blay,
Isabelle Ray-Coquard
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ABSTRACT: The exact overall incidence of sarcoma and sarcoma subtypes is not known. The objective of the present population-based study was to determine this incidence in a European region (Rhone-Alpes) of six million inhabitants, based on a central pathological review of the cases.
From March 2005 to February 2007, pathology reports and tumor blocks were prospectively collected from the 158 pathologists of the Rhone-Alpes region. All diagnosed or suspected cases of sarcoma were collected, reviewed centrally, examined for molecular alterations and classified according to the 2002 World Health Organization classification. Of the 1287 patients screened during the study period, 748 met the criteria for inclusion in the study. The overall crude and world age-standardized incidence rates were respectively 6.2 and 4.8 per 100,000/year. Incidence rates for soft tissue, visceral and bone sarcomas were respectively 3.6, 2.0 and 0.6 per 100,000. The most frequent histological subtypes were gastrointestinal stromal tumor (18%; 1.1/100,000), unclassified sarcoma (16%; 1/100,000), liposarcoma (15%; 0.9/100,000) and leiomyosarcoma (11%; 0.7/100,000).
The observed incidence of sarcomas was higher than expected. This study is the first detailed investigation of the crude incidence of histological and molecular subtypes of sarcomas.
PLoS ONE 01/2011; 6(8):e20294. · 4.09 Impact Factor
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Franck Bourdeaut,
Delphine Lequin,
Laurence Brugières,
Stéphanie Reynaud,
Christelle Dufour,
François Doz,
Nicolas André,
Jean-Louis Stephan,
Yves Pérel,
Odile Oberlin, [......],
Georges Audry,
Stéphanie Puget,
D Gareth Evans,
Joan Carles Ferreres Pinas,
Valeria Capra,
Véronique Mosseri,
Isabelle Coupier,
Marion Gauthier-Villars,
Gaëlle Pierron,
Olivier Delattre
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ABSTRACT: Germline hSNF5/INI1 mutations are responsible for hereditary cases of rhabdoid tumors (RT) that constitute the rhabdoid predisposition syndrome (RPS). Our study provides the first precise overview of the prevalence of RPS within a large cohort of RT.
hSNF5/INI1 coding exons were investigated by sequencing and by multiplex ligation-dependent probe amplification.
Seventy-four constitutional DNAs from 115 apparently sporadic RT were analyzed from 1999 to 2009. Germline mutations were found in 26 patients (35%). Data from 9 individuals from 5 RPS families (siblings) were also studied. The median age at diagnosis was much lower (6 months) in patients with germline mutation (P < 0.01) than in patients without (18 months). Nevertheless, 7 of 35 patients with germline mutation (20%) developed the disease after 2 years of age. The mutation could be detected in only 1 parent whereas germline blood DNA was wild type in the 20 other parent pairs, therefore indicating the very high proportion of germ-cell mosaicism or of de novo mutations in RPS. The former hypothesis could be clearly documented in 1 case in which prenatal diagnosis was positive in a new pregnancy. Finally, the 2 years' overall survival was 7% in mutated and 29% in wild-type patients, mainly due to the worse outcome of RT in younger patients.
Our results show a high proportion of germline mutations in patients with RT that can be found at any age and up to 60% in the youngest patients. Genetic counseling is recommended given the low but actual risk of familial recurrence.
Clinical Cancer Research 01/2011; 17(1):31-8. · 7.74 Impact Factor
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The Journal of pediatrics 09/2010; 157(3):511. · 4.02 Impact Factor
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Gudrun Schleiermacher,
Isabelle Janoueix-Lerosey,
Agnès Ribeiro,
Jerzy Klijanienko,
Jérôme Couturier,
Gaëlle Pierron,
Véronique Mosseri,
Alexander Valent,
Nathalie Auger,
Dominique Plantaz,
Hervé Rubie,
Dominique Valteau-Couanet,
Franck Bourdeaut,
Valérie Combaret, Christophe Bergeron,
Jean Michon,
Olivier Delattre
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ABSTRACT: Neuroblastoma is characterized by two distinct types of genetic profiles, consisting of either numerical or segmental chromosome alterations. The latter are associated with a higher risk of relapse, even when occurring together with numerical alterations. We explored the role of segmental alterations in tumor progression and the possibility of evolution from indolent to aggressive genomic types.
Array-based comparative genomic hybridization data of 394 neuroblastoma samples were analyzed and linked to clinical data.
Integration of ploidy and genomic data indicated that pseudotriploid tumors with mixed numerical and segmental profiles may be derived from pseudotriploid tumors with numerical alterations only. This was confirmed by the analysis of paired samples, at diagnosis and at relapse, as in tumors with a purely numerical profile at diagnosis additional segmental alterations at relapse were frequently observed. New segmental alterations at relapse were also seen in patients with segmental alterations at diagnosis. This was not linked to secondary effects of cytotoxic treatments since it occurred even in patients treated with surgery alone. A higher number of chromosome breakpoints were correlated with advanced age at diagnosis, advanced stage of disease, with a higher risk of relapse, and a poorer outcome.
These data provide further evidence of the role of segmental alterations, suggesting that tumor progression is linked to the accumulation of segmental alterations in neuroblastoma. This possibility of genomic evolution should be taken into account in treatment strategies of low- and intermediate-risk neuroblastoma and should warrant biologic reinvestigation at the time of relapse.
Journal of Clinical Oncology 07/2010; 28(19):3122-30. · 18.37 Impact Factor
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Filippo Spreafico,
Kathy Pritchard Jones,
Marcio H Malogolowkin, Christophe Bergeron,
Juliet Hale,
Jan de Kraker,
Sandro Dallorso,
Thomás Acha,
Beatriz de Camargo,
Jeffrey S Dome,
Norbert Graf
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ABSTRACT: Treatment regimens for recurrent Wilms tumor (WT) are currently designed to include drugs that are not used during primary chemotherapy, using a risk-stratified approach. Therapy of recurrent disease depends on the nature of initial treatment, and of recognized prognostic indicators inherent in the primary tumor. Several highly effective chemotherapy regimens, including ifosfamide-carboplatin-etoposide, cyclophosphamide-etoposide and carboplatin-etoposide, are considered first treatment choice for recurrent disease. While intense-dose chemotherapy is uniformly accepted to treat high-risk recurrent WTs, the optimal therapy for standard-risk children has yet to be defined, owing to the small number of such patients and their relatively better prognosis compared with high-risk recurrences. Recurrent tumors among those defined as very-high risk are likely to develop chemoresistant disease, and novel therapeutic strategies will be necessary to cure these patients. Evidence on how to properly administer surgery and radiotherapy at relapse is more fragmentary. The authors have reviewed the available experiences concerning the treatment of recurrent WT, and have attempted to provide the most up-to-date recommendations regarding the optimal risk-based treatment for these patients.
Expert Review of Anti-infective Therapy 12/2009; 9(12):1807-15. · 2.65 Impact Factor
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Odile Oberlin,
Oumaya Fawaz,
Annie Rey,
Patrick Niaudet,
Vita Ridola,
Daniel Orbach, Christophe Bergeron,
Annie Sophie Defachelles,
Jean-Claude Gentet,
Claudine Schmitt,
Hervé Rubie,
Martine Munzer,
Dominique Plantaz,
Anne Deville,
Veronique Minard,
Nadège Corradini,
Guy Leverger,
Florent de Vathaire
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ABSTRACT: Ifosfamide is widely used in pediatric oncology but its nephrotoxicity may become a significant issue in survivors. This study is aimed at evaluating the incidence of late renal toxicity of ifosfamide and its risk factors.
Of the 183 patients prospectively investigated for renal function, 77 treated for rhabdomyosarcoma, 39 for other soft tissue sarcoma, 39 for Ewing's sarcoma, and 28 for osteosarcoma were investigated at least 5 years after treatment. No patients had received cisplatin and/or carboplatin. Glomerular and tubular functions were graded according to the Skinner system.
The median dose of ifosfamide was 54 g/m(2) (range, 18 to 117 g/m(2)). After a median follow-up of 10 years, 89.5% of patients had normal tubular function, and 78.5% had normal glomerular function rate (GFR). Serum bicarbonate and calcium were normal in all patients. Hypomagnesemia was observed in 1.2% and hypophosphatemia in 1%. The tubular threshold for phosphate was reduced in 24% of the patients (grade 1 in 15%, grade 2 in 8%, and grade 3 in 0.5%). Glycosuria was detected in 37% of the patients but was more than 0.5 g/24 hours in only 5%. Proteinuria was observed in 12%. Ifosfamide dose and interval from therapy to investigations were predictors of tubulopathy in univariate and multivariate analysis. In a multivariate analysis, an older age at diagnosis and the length of interval since treatment had independent impacts on the risk of abnormal GFR.
Renal toxicity is moderate with a moderate dose of ifosfamide. However, since it can be permanent and can get worse with time, repeated long-term evaluations are important, and this risk should be balanced against efficacy.
Journal of Clinical Oncology 10/2009; 27(32):5350-5. · 18.37 Impact Factor
