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Localized Pelvic Neuroblastoma: Excellent Survival and Low Morbidity With Tailored Therapy—The 10-Year Experience of the French Society of Pediatric Oncology

From the Service de Chirurgie Infantile and Service d'Oncologie Pédiatrique, Hôpital Mère-Enfant, CHU de Nantes, Nantes; Département de Pédiatrie, Institut Gustave Roussy, Villejuif; Service de Chirurgie Pédiatrique, CHRU Dupuytren, Limoges; Département de Radiothérapie, Institut Gustave Regaud; and Unité d'Hémato-oncologie, Hôpital des enfants, Toulouse, France

Address reprint requests to Marc-David Leclair, MD, Service de Chirurgie Infantile, Hôpital Mère-Enfant, CHU de Nantes, 44093 Nantes Cedex 01, France; e-mail: marcdavid.leclair{at}chu-nantes.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Authors' Disclosures of... REFERENCES

 
PURPOSE: To assess the results and morbidity of treatment of children with localized pelvic neuroblastoma (NB).

PATIENTS AND METHODS: All consecutive cases of localized pelvic NB registered in the French multicenter prospective studies NBL90 and NBL94 between 1990 and 1999 were reviewed. Resectability was decided on the basis of clinical and radiologic evaluation. In unresectable tumors, primary chemotherapy (combinations of carboplatin-etoposide and vincristine-cyclophosphamide-doxorubicine) was administered before surgery.

RESULTS: Forty-seven children (with 26 resectable tumors and 21 unresectable) were included in this study. At the end of treatment, 31 children were in complete remission (66%). Long-term neurologic sequelae were observed in seven patients (15%), directly attributable to surgery in three cases. After a median follow-up of 48 months (range, 13 to 129 months), 44 patients are alive. Six children experienced local relapse; four of these children achieved subsequent remission. The projected overall survival and event-free survival (EFS) rates at 5 years are, respectively, 93% ± 4% and 84% ± 5%. Survival of children treated with preoperative chemotherapy are similar to those treated by primary surgery (80% and 88% respectively). The extent of surgical resection seemed to have no influence on the outcome (EFS rates 76% and 89% in case of gross residue and complete resection or microscopic residue, respectively).

CONCLUSION: Our data confirm the excellent survival of localized pelvic NBs. Considering the efficacy of preoperative chemotherapy, patients with pelvic NB should be carefully screened for primary surgery. The risk of neurologic impairment during radical excision should be balanced with the good survival of children with minimal residual disease.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Authors' Disclosures of... REFERENCES

 
Neuroblastoma (NB) is the most common extracerebral solid tumor in childhood.¹ Because this embryonal malignancy arises in cells derived from the neural crest, the primary tumor can develop anywhere from the neck to the pelvis where sympathetic tissue is present. The pelvic NB is a rare location (5% of all NBs) and is usually known to carry a good prognosis,² although it is unclear whether extra-abdominal location influences the outcome.^3,4 However, surgery of pelvic NB is a technical challenge, whereas completeness of resection is believed to play a major prognostic role in the treatment of localized NB.^5–7 Furthermore, surgical resection of a pelvic tumor can lead to major organ dysfunction, affecting survivors' subsequent quality of life.² The aim of this study was to assess the morbidity and the outcome after treatment of pelvic localized NB in the experience of the French Society of Pediatric Oncology (SFOP) over 10 years.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Authors' Disclosures of... REFERENCES

 
Patients
We reviewed the records of children consecutively treated for a localized pelvic NB in the SFOP NBL90 and NBL94 prospective studies between 1990 and 1999. All untreated cases of histologically proven NB in children were eligible and accrued onto those studies after informed parental consent was obtained. All children with pelvic primary tumor were included in the present study, except those presenting with pelvic extension of an abdominal NB.

Staging
The primary tumor measurements were obtained from ultrasound examination and computed tomography scan or magnetic resonance imaging. Imaging analysis focused on the morphologic features of the tumor, such as tumor arising or crossing the presacral midline, involvement of pelvic organs or major iliac vessels, or presence of intraspinal extension. The clinical workup to rule out metastatic spread included skeletal study by iodine¹²³ metaiodobenzylguanidine (MIBG) scintigraphy,⁸ Tc⁹⁹ scan in the absence of MIBG primary tumor uptake, complete skeletal x-ray examination in infants, and extensive bone-marrow staging (four bone marrow aspirates and two trephine biopsies). Diagnostic workup also included measurements of urinary excretion of vanillylmandelic acids and homovanillic acids, dopamine levels,⁹ serum lactate dehydrogenase¹⁰ and ferritin levels.¹¹ The diagnosis of NB was confirmed histologically either after primary excision or fine-needle biopsy in case of unresectable tumor, according to the International Neuroblastoma Pathology Committee (INPC) classification.¹² The primary tumor was staged according to tumor-node-metastasis system¹³ (Table 1) and International Neuroblastoma Staging System (INSS) criteria.¹⁴ The volume of the tumor was approximated by calculating the product of length x width x thickness x 0.523. Analysis of MYCN genomic content by Southern blot analysis¹⁵ using second-exon probes was recommended for all children and was mandatory in some cases (infants in NBL90 and all children in NBL94). MYCN amplification was defined as the presence of more than 10 copies per haploid genome.

Chemotherapy
Two combinations of chemotherapy were given in the NBL90 study, as previously detailed.^3,16 Briefly, all children with unresectable tumor received two courses of carboplatin and etoposide (CE) followed by two courses of vincristine, cyclophosphamide and doxorubicin (CAdO). Postoperative chemotherapy was indicated in children older than 1 year in case of residual disease (even microscopic) or lymph node involvement. These patients were given four courses (two of CE plus two of CAdO) in the case of primary surgery, or two alternating courses in the case of preoperative chemotherapy. As a whole, children received a maximum of three courses of each combination. In case of persistent macroscopic residue after chemotherapy, a second-look surgical procedure was recommended. In infants, no postoperative treatment was indicated whatever the extent of the surgical resection.

The NBL94 study evaluated the efficacy of a less intensive adjuvant therapy in children without MYCN amplification. Infants with unresectable NB were to receive low-dose chemotherapy combining two to four courses of cyclophosphamide (5 mg/kg/d days 1 to 5) and vincristine (0.05 mg/kg day 1) in four cycles (CV). Children with resectable tumor received no further treatment after surgical resection whatever the age and the extent of resection. Children with unresectable NBs were treated as in NBL90 study.

After 1997, children with MYCN amplification received intensive chemotherapy (combination of high-dose busulfan and melphalan) followed by stem-cell rescue and locoregional irradiation.

Radiotherapy
In the NBL90 study, a locoregional irradiation was indicated in case of persisting macroscopic residue at the end of treatment, in children older than 1 year. In the NBL94 study, these indications of radiotherapy were restricted to children with nonevaluable or amplified MYCN, whatever the age at diagnosis and postoperative status. In both studies, the target field encompassed the extent of the tumor before surgery. The total radiation dose was the same in both studies, either 24 or 34 Gy for children younger and older than 2 years, respectively.

Evaluation of Response to Therapy
Response to therapy was assessed according to the International Neuroblastoma Response Criteria¹⁴ during induction therapy, before and 1 month after surgery, at the end of treatment, and every 3 months during follow-up.

Statistical Analysis
To avoid bias and facilitate comparison with other series, all consecutive patients with newly diagnosed localized pelvic NB were included in this study. Comparison between proportions were performed with the ² test corrected for heterogeneity, or Fisher's exact two-tailed test¹⁷ when appropriate. Probabilities of overall survival (OS) and event-free survival (EFS) were calculated from the time of diagnosis to relapse, death, or last follow-up evaluation according to the Kaplan-Meier product-limit method,¹⁸ and given at 5 years. In the EFS analysis, disease progression, relapse and death for any reason were considered events. Differences between survival curves were tested for statistical significance in univariate analysis by the log-rank test.¹⁹

	RESULTS

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Patient Characteristics
Between 1990 and 1999, 623 consecutive children with localized NB were registered in the NBL90 and NBL94 studies, of whom 47 (7.5%) had a pelvic primary tumor. Patient characteristics are detailed in Table 2. The median age at the time of diagnosis was 15 months (range, 0 to 178 months). Fourteen children (30%) presented with neurologic motor or sensory dysfunction, or sphincteric difficulties; the most common symptoms (11 cases) were urinary retention, constipation, or urinary incontinence. Two children presented with opsomyoclonus syndrome, and one presented with severe watery diarrhea due to vasoactive intestinal peptide secretion.

Histologic subtype of the tumor was neuroblastoma in 32 cases and ganglioneuroblastoma in 15 cases. Histopathologic data according to International Neuroblastoma Pathology Classification were available for resectable tumors only, because diagnosis was obtained by fine-needle biopsy in unresectable cases. In the 13 resectable tumors evaluable (NBL94), two of 13 had unfavorable histology.

Of the 37 children evaluated for MYCN genomic content, MYCN amplification was found in only one child (2.7%).

Morphologic features of the tumors are detailed in Table 2. In nine children (19%), there was a dumbbell NB with intraspinal extension. Of great importance in such a young population was the size of the primary, in that 38 children (81%) had a tumor diameter larger than 5 cm.

Twenty-one tumors (45%) were considered unresectable on the basis of clinical and imaging data. Distribution of the T stage in the resectable tumors group was not significantly different from unresectable group, indicating that tumor size was not the only criterion to determine resectability. There was no difference in resectability rate between the two successive studies (12 of 22 tumors in NBL90, v 14 of 25 tumors in NBL94; P = .99).

Treatment
Primary chemotherapy. Twenty-one children (45%) had a tumor considered unresectable and were given primary chemotherapy: 19 received two courses of CE two courses of CAdO (including one infant after no response with two courses of CV), and two infants received four courses of CV. Of the 20 children assessable of the 21 total, the overall response rate to preoperative chemotherapy was 70%, with very good partial response in five children, partial response (PR) in nine, and no response in six. Following this treatment, surgical resection was attempted in all children.

Surgery. Among the 21 children with unresectable NB, preoperative treatment allowed grossly complete resection in 11 cases (52%), including microscopic residue in seven. Twenty-six children (55%) underwent primary surgery for a tumor considered resectable: complete gross removal of the tumor was achieved in 17 patients (65%), of whom 10 had a microscopic residual disease. It should be noted that in the group of children with "resectable" tumors, surgical resection was grossly incomplete, with measurable residue in nine cases (35%).

Of the 47 children, the result of the surgical procedure was complete resection in 11 (23%), grossly complete resection with microscopic residue in 17 (36%), and gross residual disease in 19 (41%). There was no significant difference in the extent of surgical resection when comparing the resectable tumors group to the unresectable tumors group (P = 0.64).

Adjuvant therapy. Among the 36 patients with either microscopic or gross residual disease, 19 (53%) received postoperative treatment. Chemotherapy was administered in nine of 17 children with microscopic residue and ten of 19 with gross residual disease. The remaining nine children with gross residue had no indication to receive adjuvant therapy according to protocol guidelines, due to their age or protocol of treatment. There were no detectable long-term sequelae related to chemotherapy. Radiation therapy was given in five children in addition to postoperative chemotherapy, for persistent gross residue. The median dose delivered was 36 Gy (range, 25 to 45 Gy). No immediate toxicity was reported. On long-term evaluation (median, 55 months), four of them were alive without evidence of affected pelvic growth at a median age of 187 months (range, 75 to 212 months). Two girls presented neuropathic bladder (attributed to surgery (n = 1), or present at diagnosis (n = 1), of whom one also had radiation-induced ovarian insufficiency.

Surgical Procedures and Morbidity
Surgical resection was conducted via a laparotomy in most cases, except in three children in whom the procedure was performed via sacroperineal approach and one child by a combined abdominal and perineal approach. None of the nine children with a dumbbell tumor needed laminotomy for emergency decompression at diagnosis or during clinical course. In four of them, intraspinal component of the tumor was later removed via a neurosurgical approach, after laparotomy. Concerning surgical complications and morbidity, two children presented serious bleeding during excision, and nephrectomy was performed in three cases, in violation of protocol recommendations. There were long-term persisting neurologic sequelae in seven patients (15%) including complete or partial cauda-equina syndrome (n = 3), neuropathic bladder (n = 2), radicular or truncal nerve palsy (n = 2), and leg weakness (n = 2). In three cases, these complications clearly occurred postoperatively in children without any neurologic symptom at diagnosis. The remaining four children already had neurologic dysfunction at diagnosis, but no evidence of worsening after surgery. Conversely, it should be noted that among the 14 patients with neurologic symptoms at the diagnosis, 10 (71%) recovered and had no neurologic deficiency at the end of treatment. There was no significant difference in incidence of surgical complications according to resectability: neurologic complications, bleeding, or nephrectomy occurred in four of the 26 children with resectable tumors, compared with four of 21 children treated by preoperative chemotherapy (P = .99).

Outcome
At the end of treatment, disease status was CR in 31 children (66%), very good partial response in 12 children (26%), PR in three children, (6%) and no response in one child. As of July 2002, the median follow-up was 48 months (range, 13 to 129 months). A local relapse occurred in six patients, at a median time of 15.5 months (range, 5 to 49 months) after diagnosis. The primary tumor was staged INSS 2B (n = 1) or INSS 3 (n = 5) at diagnosis and was incompletely resected in four of six patients. Four of these six patients had received postoperative treatment, including radiotherapy in two. Four of them are still alive 44 months (27 to 51) after their relapse treatment. Three children died 27, 30, and 32 months after diagnosis; one death was accidental, and two were disease-related. The 5-year projected overall survival and EFS of the entire population of localized pelvic neuroblastoma are, respectively, 93% ± 4% and 84% ± 5% (Fig 1).

View larger version (12K): [in this window] [in a new window]   Fig 1. 5-year projected overall survival (OS) and event-free survival (EFS) rates: OS, 93% ± 4%; EFS, 84% ± 5%.

View larger version (10K): [in this window] [in a new window]   Fig 2. Event-free survival rate according to tumor size (tumor-node-metastasis stage). T1 + T2 (diameter < 10 cm [n = 38]): 92% ± 5%; T3 (diameter > 10 cm [n = 9]): 53% ± 17%; P = .01.

View larger version (12K): [in this window] [in a new window]   Fig 3. Event-free survival rate according to extent of resection. Complete resection or microscopic residual disease (n = 28): 89% ± 6%; gross residue (n = 19): 76% ± 11%; P = .27.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Authors' Disclosures of... REFERENCES

 
This study confirms the excellent survival of children with localized pelvic neuroblastoma but highlights the difficulties of surgical treatment and the risk of functional sequelae.

The pelvis is a rare location for NB, and the incidence in these two consecutive studies (7.5%) is similar to that in previous reports.^2,20 This location has particular clinical features, with high incidence (20% to 35%) of neurologic symptoms at diagnosis and significant proportion of dumbbell tumors (20% in our experience).^2,20 Conversely, in the present study, the other main characteristics of patients, such as age, sex ratio, and MIBG uptake or biologic parameters, were comparable with those of other localized NBs.^3,4,21

Surgical resection of the primary is considered a major step for cure but represents a particularly challenging issue in the pelvic site^2,20,22–23 because of the funnel-shaped configuration of the pelvis and characteristics of the tumors. In the present series, more than 80% of tumors had a diameter larger than 50 mm and were in close contact or even encasing major pelvic vessels. Because neuroblastoma arises in paraspinal ganglia from sympathetic nerves, the pelvic location develops from the organ of Zuckerkandle, near the midline, in contact with major sacral nerve trunks. For these reasons, deep surgical access to the tumor, and especially to its lower pole, is technically challenging and may be a source bladder damage or rectal innervation. In these cases, excision may be facilitated by a sacroperineal approach or combined abdominal and perineal routes, used in three cases and one case in this study, respectively. In these indications, the use of the posterior sagittal sacroperineal approach described by A. Peña²⁴ for anorectal malformation repair is of great interest, allowing safe dissection, under direct vision, of the tumor adherent to the lower sacrum.²³ We report less than 60% complete resection, which is consistent with findings of previously published series of pelvic NB.^2,20 This rate seems significantly lower than the 74% complete resection of the 316 children included in the NBL90 study.³ In the early nineties, definition of unresectability was the result of a subjective evaluation, influenced by the imaging techniques accuracy and the surgical team expertise.⁴ Thus, assessing the tumor's resectability is a crucial point, given that an inappropriate decision to undertake surgical resection can lead to incomplete excision and/or sacral nerve injury. In our study, almost one third of the children who underwent primary surgical resection had a postoperative detectable gross residue, suggesting that the decision to consider these tumors resectable was not appropriate. In children with unresectable NBs, efficacy and safety of CE and CAdO combination has previously been reported,²⁵ with a long-term survivor rate as high as 90%.¹⁶ In our study, primary chemotherapy allowed in half of the cases subsequent complete surgical removal of primary unresectable tumors, resulting in an EFS comparable with that of resectable NBs. Considering the efficacy of preoperative chemotherapy, we believe that when primary resection is attempted but finally appears too risky, a simple biopsy should be performed before starting primary chemotherapy.

It has been shown that most patients with localized low-stage NBs could be cured with surgery alone and that extent of surgical resection did not influence the outcome.^26,27 In children with advanced nonmetastatic disease, usually INSS 3 or Evans' stage III unresectable NBs, the benefit of large excision attempts is more debatable, considering stage III tumors may have a different biologic behavior.²⁶ Haase et al suggested that complete surgical resection improved the outcome in all groups of stage III patients and concluded that aggressive attempts at complete resection could be beneficial.^5,28 In the present study, although most of the patients were INSS 3, the extent of surgical resection seemed to have no significant influence on the outcome. Patients with residual disease had similar outcome than patients with complete resection, and children with PR at the end of treatment had the same survival rate than patients who achieved CR. However, one must notice that some patients with residual disease received more intensive adjuvant therapy.

In the present series, more than 70% of the tumors were classified INSS 3, with a remarkable EFS of 81%. For anatomic reasons, pelvic primary tumors always arise near the midline, which could contribute to explain the high rate of INSS stage III patients. Some of these "bilateral" tumors would have been classified as lower stage primary if they had arisen in other site than pelvis, explaining the good outcome of this subset of patients.

Previous studies have shown the adverse prognostic role of abdominal location.⁴ Conversely, pelvic NB is known to be a favorable location, possibly due to a different biologic behavior and a lower incidence of advanced stages. The incidence of pelvic site was 7.5% in this cohort of localized NBs, significantly higher than the mere 2% in a Children's Cancer Study Group large series of stage IV NBs²⁹ and 1.6% in the SFOP experience.³⁰ In a large European survey,³¹ the overall incidence of pelvic primary tumor was 3% (43 of 1,277 tumors), with a 7.2% incidence in nonmetastatic stages, as compared with 1.4% in stage IV. Furthermore, MYCN amplification occurred in only one of 37 patients in the pelvic primary site, compared with 10% incidence in contemporary SFOP series of localized NB.³ With the present follow-up, the 93% overall survival of these children with localized pelvic NB is remarkable, although only two thirds of them achieved CR.

Pelvic surgery is likely to produce postoperative functional troubles, due to urinary or anorectal sphincter damage and sacral nerve root injury. Previously published series of pelvic NBs^2,20,22 reported sequelae rates from 11% to 57%, consistent with our findings. We found 15% permanent neurologic complications, including fecal and/or urinary incontinence in five children, although it is unclear in some cases whether it was persistence of neurologic impairment due to the primary tumor at diagnosis or onset of postsurgical neurologic complications. This rate may be underestimated, considering that nine children (19%) were less than 3 years old and not toilet-trained at the end of follow-up.

In conclusion, our data show the excellent survival of children treated for a nonmetastatic pelvic NB and underline the risk of long-term sequelae after surgery. The efficacy of preoperative chemotherapy strategy suggests that patients should be screened carefully for resectability before attempting primary surgical resection, because of the risk of neurologic impairment. Considering the very good outcome of children with minimal residual disease, leaving a minimal residue seems acceptable when major neurologic sacrifice is necessary to achieve complete removal after primary chemotherapy. However, the goal of surgery in localized pelvic NB should remain complete resection of the primary tumor.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Authors' Disclosures of... REFERENCES

 
The following French institutions (with main investigators) participated in the NBL90 and NBL94 studies: Service Hématologie Infantile, CHRU Nord, Amiens (Dr B. Pautard); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier, Angers (X. Rialland, I. Pellier); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier St. Jacques, Besançon (E. Plouvier); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier Pellegrin, Bordeaux (Y. Pérel); Unité d'Hémato-Oncologie Pédiatrique, Centre hospitalier, Brest (P. Lemoine); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier, Caen (P. Boutard); Unité d'Hémato-Oncologie Pédiatrique, Hôtel Dieu (F. Demeocq), Clermont-Ferrand; Département de Pédiatrie (J. Michon, J.M. Zucker, F. Doz) and Laboratoire de Génétique des tumeurs (O. Delattre, J. Couturier), Institut Curie, Paris; Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier, Dijon (G. Couillault); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier, Grenoble (D. Plantaz); Unité d'Oncologie Pédiatrique, Centre Oscar Lambret, Lille (M.C. Baranzelli); Unité d'Hématologie Pédiatrique, Centre Hospitalier Huriez, Lille (A. Lambilliotte, F. Mazingue, A.S. Defachelles); Service de Néonatologie, Hôpital St-Antoine, Lille (F. Dusol); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier Dupuytren, Limoges (L. de Lumley); Département de Pédiatrie, Centre Léon Bérard, Lyon (C. Bergeron, D. Frappaz, T. Philip, C. Carrié, V. Combaret); Unité d'Oncologie Pédiatrique, Hôpital la Timone, Marseille (J.L. Bernard, C. Coze, J.C. Gentet); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier Villeneuve, Montpellier (G. Marguerite, F. Bernard); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier de Nancy-Brabois, Vandoeuvre (P. Chastagner, C. Schmitt, D. Sommelet); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier, Nantes (F. Méchinaud, C. Thomas); Unité d'Hémato-Oncologie Pédiatrique, Hôpital Lenval, Nice (A. Deville, C. Soler); Centre Antoine Lacassagne, Nice (A. Thyss); Service de Pédiatrie, Hôpital de l'Archet, Nice (N. Sirvent); Service de Pédiatrie, Hôpital de Cimiez, Nice (F. Montpoux); Unité d'Hémato-Oncologie Pédiatrique, Hôpital Trousseau, Paris (G. Leverger, J. Landman-Parker); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier La Miletrie, Poitiers (F. Millot); Unité d'Hémato-Oncologie Pédiatrique, Hôpital Américain, Reims (C. Béhar, M. Munzer); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier Sud, Rennes (E. Legall, V. Gandemer); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier Charles Nicolle, Rouen (P. Tron, J.P. Vannier); Unité d'Hémato-Oncologie Pédiatrique, Centre Hospitalier Nord, Saint-Etienne (J.L. Stephan); Unité d'Hémato-Oncologie Pédiatrique, Institut de Puériculture, Hôpital Civil, Strasbourg (A. Babin-Boilletot, P. Lutz); Unité d'Hémato-Oncologie Pédiatrique, Hôpital des Enfants, Toulouse (A. Robert, H. Rubie, A.I. Bertozzi, C. Baunin, J. Guitard); Unité d'Oncologie Pédiatrique, Hôpital Clocheville, Tours (O. Lejars, J.L. Lamagnère); Département de Pédiatrie (O. Hartmann, JK Lemerle, F. Pein, D. Valteau-Couanet, C. Kalifa, O. Oberlin, L. Brugières) and Laboratoire de Biologie Moléculaire (J. Bénard), Institut Gustave Roussy, Villejuif.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by the Association for Cancer Research and the Clinical Research Program of the French Ministry of Health (grant No. [3]95-06-N).

Presented in part at the 13th Annual Meeting of the European Society for Pediatric Urology, April 2002, Budapest, Hungary.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted April 8, 2003; accepted February 23, 2004.

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