RESUMEN
PURPOSE: Wilms tumor (WT), or nephroblastoma, is an embryonic tumor that constitutes the most common renal tumor in children. Little is known about the etiology of WT. The aim of this study was to investigate whether maternal or perinatal characteristics were associated with the risk of WT. METHODS: The ESTELLE study is a national-based case-control study that included 117 cases of WT and 1,100 controls younger than 11 years old. The cases were children diagnosed in France in 2010-2011 and the controls were frequency matched with cases by age and gender. The mothers of case and control children responded to a telephone questionnaire addressing sociodemographic and perinatal characteristics, childhood environment, and lifestyle. Unconditional logistic regression models adjusted on potential cofounders were used to estimate the odds ratios (OR) and their confidence intervals (95% CI). RESULTS: High birth weight and the presence of congenital malformation were associated with WT (OR 1.9 [95% CI 1.0-3.7] and OR 2.5 [95% CI 1.1-5.8], respectively). No association with breastfeeding or folic acid supplementation was observed. CONCLUSIONS: Although potential recall bias cannot be excluded, our findings reinforce the hypothesis that high birth weight and the presence of congenital malformation may be associated with an increased risk of WT. Further investigations are needed to further elucidate the possible role of maternal characteristics in the etiology of WT.
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Neoplasias Renales/patología , Tumor de Wilms/patología , Adulto , Peso al Nacer , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Francia , Humanos , Lactante , Recién Nacido , Masculino , Madres , Embarazo , Factores de Riesgo , Encuestas y Cuestionarios , Adulto JovenRESUMEN
The Ethics committee of Gustave Roussy cancer center is devoted to both reflection and action. The group has 40 members, professionals, patients and outside experts. These meet in plenary meetings or in specific working sessions and intervene at the request of any professional faced with ethical questions in the care. This Ethics Committee has voluntarily a double vocation: on one hand, a reflective group on major issues of ethics in health and its involvement in hospital life; on the other hand, a working group embedded in the daily lives of the care. The themes addressed at the meetings (plenary sessions, annual meetings) include shared-decision making, advance directives, refusal of care, religious aspects, or biomedical research Daily activity centered on the care revolves around several times a week meetings, in various services, "Supportive Collegial Meetings" such as proposed in the 3rd French Cancer Plan; these include nursing staff members, oncologists, intensive and palliative care specialists, psychologist, around difficult medical and/or ethical situations. In case of situation requiring an urgent discussion, a referral to the Ethics Committee brings together within 24hours four to five members of the Committee and the care team. Moreover, the Ethics Committee helped develop Aid to Decision making Form upon care gradation for hospitalized cancer patients. Through these interventions on a daily basis, assistance of professionals, reflexive vocation or even delivery of training, the Ethics Committee contributes to an acculturation around anticipation and collegiality in the care. Its double polarity aims to reconcile "philosophical time' for the ethics process, and the connection with the routine issues raised by patients, their families and caregivers.
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Instituciones Oncológicas/ética , Comités de Ética , Discusiones Bioéticas , Instituciones Oncológicas/organización & administración , Toma de Decisiones Clínicas/ética , Congresos como Asunto/organización & administración , Sistemas de Apoyo a Decisiones Clínicas , Francia , HumanosRESUMEN
BACKGROUND: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma. METHODS: We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m2 per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6â×â106 IU/m2 per day on days 1-5 and days 8-12 of each cycle) with the minimisation method to balance randomisation for national groups and type of high-dose therapy. All participants received oral isotretinoin (160 mg/m2 per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17, and recruitment to this randomisation is closed. FINDINGS: Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4·7 years (IQR 3·9-5·3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p<0·0001). 3-year event-free survival was 56% (95% CI 49-63) with dinutuximab beta (83 patients had an event) and 60% (53-66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0·76). Four patients died of toxicity (n=2 in each group); one patient in each group while receiving immunotherapy (n=1 congestive heart failure and pulmonary hypertension due to capillary leak syndrome; n=1 infection-related acute respiratory distress syndrome), and one patient in each group after five cycles of immunotherapy (n=1 fungal infection and multi-organ failure; n=1 pulmonary fibrosis). The most common grade 3-4 adverse events were hypersensitivity reactions (19 [10%] of 185 patients in the dinutuximab beta group vs 39 [20%] of 191 patients in the dinutuximab plus subcutaneous IL-2 group), capillary leak (five [4%] of 119 vs 19 [15%] of 125), fever (25 [14%] of 185 vs 76 [40%] of 190), infection (47 [25%] of 185 vs 64 [33%] of 191), immunotherapy-related pain (19 [16%] of 122 vs 32 [26%] of 124), and impaired general condition (30 [16%] of 185 vs 78 [41%] of 192). INTERPRETATION: There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available. FUNDING: European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Interleucina-2/administración & dosificación , Neuroblastoma/tratamiento farmacológico , Adolescente , Factores de Edad , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Interleucina-2/efectos adversos , Isotretinoína/administración & dosificación , Masculino , Neuroblastoma/inmunología , Neuroblastoma/mortalidad , Neuroblastoma/patología , Supervivencia sin Progresión , Factores de Riesgo , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: Metastatic response to induction therapy for high-risk neuroblastoma is a prognostic factor. In the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol, only patients with metastatic complete response (CR) or partial response (PR) with ≤ three abnormal skeletal areas on iodine 123-metaiodobenzylguanidine ([123I]mIBG) scintigraphy and no bone marrow disease proceed to high dose therapy (HDT). In this study, topotecan-vincristine-doxorubicin (TVD) was evaluated in patients failing to achieve these criteria, with the aim of improving the metastatic response rate. MATERIALS AND METHODS: Patients with metastatic high-risk neuroblastoma who had not achieved the SIOPEN criteria for HDT after induction received two courses of topotecan 1.5 mg/m2/day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m2, and doxorubicin, 45 mg/m2. RESULTS: Sixty-three patients were eligible and evaluable. Following two courses of TVD, four (6.4%) patients had an overall CR, while 28 (44.4%) had a PR with a combined response rate of 50.8% (95% confidence interval [CI], 37.9 to 63.6). Of these, 23 patients achieved a metastatic CR or a PR with ≤ 3 mIBG skeletal areas and no bone marrow disease (36.5%; 95% CI, 24.7 to 49.6) and were eligible to receive HDT. Toxicity was mostly haematological, affecting 106 of the 126 courses (84.1%; 95% CI, 76.5 to 90.0), and dose reduction was necessary in six patients. Stomatitis was the second most common nonhematological toxicity, occurring in 20 patients (31.7%). CONCLUSION: TVD was effective in improving the response rate of high-risk neuroblastoma patients after induction with COJEC enabling them to proceed to HDT. However, the long-term benefits of TVD needs to be determined in randomized clinical trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neuroblastoma/tratamiento farmacológico , Adulto , Anciano , Doxorrubicina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neuroblastoma/patología , Factores de Riesgo , Inhibidores de Topoisomerasa I/administración & dosificación , Topotecan/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
INTRODUCTION: Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.
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Antineoplásicos/farmacología , Diseño de Fármacos , Neuroblastoma/tratamiento farmacológico , Adolescente , Antineoplásicos/efectos adversos , Niño , Evaluación Preclínica de Medicamentos/métodos , Humanos , Terapia Molecular Dirigida , Neuroblastoma/patología , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de TiempoRESUMEN
Neuroblastoma (NB), an embryonic tumour arising from neural crest cells, is the most common malignancy among infants. The aetiology of NB is largely unknown. We conducted a pooled analysis to explore whether there is an association between NB and preconception and perinatal factors using data from two French national population-based case-control studies. The mothers of 357 NB cases and 1783 controls younger than 6 years, frequency-matched by age and gender, responded to a telephone interview that focused on demographic, socioeconomic and perinatal characteristics, childhood environment, life-style and maternal reproductive history. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. After controlling for matching variables, study of origin and potential confounders, being born either small (OR 1.4 95% CI 1.0-2.0) or large (OR 1.5 95% CI 1.1-2.2) for gestational age and, among children younger than 18 months, having congenital malformations (OR 3.6 95% CI 1.3-8.9), were significantly associated with NB. Inverse associations were observed with breastfeeding (OR 0.7 95% CI 0.5-1.0) and maternal use of any supplements containing folic acid, vitamins or minerals (OR 0.5 95% CI 0.3-0.9) during the preconception period. Our findings reinforce the hypothesis that fetal growth anomalies and congenital malformations may be associated with an increased risk of NB. Further investigations are needed in order to clarify the role of folic acid supplementation and breastfeeding, given their potential importance in NB prevention.
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Anomalías Congénitas/epidemiología , Suplementos Dietéticos/estadística & datos numéricos , Neuroblastoma/epidemiología , Complicaciones del Embarazo/epidemiología , Adolescente , Adulto , Peso al Nacer , Lactancia Materna , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Francia/epidemiología , Humanos , Lactante , Recién Nacido , Entrevistas como Asunto , Modelos Logísticos , Masculino , Embarazo , Complicaciones del Embarazo/etiología , Adulto JovenRESUMEN
PURPOSE: Busulfan-melphalan high-dose chemotherapy followed by autologous stem cell transplantation is an essential consolidation treatment of high-risk neuroblastoma in children. Main treatment limitation is hepatic veno-occlusive disease, the most severe and frequent extra-hematological toxicity. This life threatening toxicity has been related to a drug interaction between busulfan and melphalan which might be increased by prior disturbance of iron homeostasis, i.e. an increased plasma ferritin level. METHODS: We performed an experimental study of busulfan and melphalan pharmacodynamic and pharmacokinetics in iron overloaded mice. RESULTS: Iron excess dramatically increased the toxicity of melphalan or busulfan melphalan combination in mice but it did not modify the clearance of either busulfan or melphalan. We show that prior busulfan treatment impairs the clearance of melphalan. This clearance alteration was exacerbated in iron overloaded mice demonstrating a pharmacokinetic interaction. Additionally, iron overload increased melphalan toxicity without altering its pharmacokinetics, suggesting a pharmacodynamic interaction between iron and melphalan. Based on iron homeostasis disturbance, we postulated that prior induction of ferritin, through Nrf2 activation after oxidative stress, may be associated with the alteration of melphalan metabolism. CONCLUSION: Iron overload increases melphalan and busulfan-melphalan toxicity through a pharmacodynamic interaction and reveals a pharmacokinetic drug interaction between busulfan and melphalan.
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Busulfano/metabolismo , Busulfano/toxicidad , Sobrecarga de Hierro/metabolismo , Melfalán/metabolismo , Melfalán/toxicidad , Animales , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/toxicidad , Interacciones Farmacológicas/fisiología , Sobrecarga de Hierro/patología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Peritoneal carcinomatosis from abdominal tumors is an uncommon condition in children usually associated with dismal prognosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) following complete macroscopic surgery has been demonstrated to be safe and of benefit in selected cases. Experience in pediatrics is scarce. METHODS: We retrospectively reviewed the medical files of patients under the age of 18years with an abdominal malignancy and peritoneal carcinomatosis who had been treated with HIPEC in our institution between March 2001 and April 2012. HIPEC had been administered using the open technique with oxaliplatin (300mg/m(2)) and irinotecan (200mg/m(2)) or oxaliplatin alone (460mg/m(2)) in the peritoneal cavity for 30minutes at 43°C and an intravenous perfusion of leucovorin (20mg/m(2)) and 5-fluorouracil (400mg/m(2)). RESULTS: Nine patients had undergone HIPEC. Grade 3-4 complications had occurred in seven patients and were intraabdominal (n=3) or extraabdominal (n=8). No procedure-related deaths had occurred. Four patients are alive and in complete remission after a median follow-up of 4.9years (1.7-9.6). However one relapsed after HIPEC and required additional salvage therapy. CONCLUSIONS: HIPEC could be considered in patients with peritoneal carcinomatosis from primary abdominal tumors. Its complications are manageable by an experienced multidisciplinary team. There are four long-term survivors, one after a relapse.
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Antineoplásicos/administración & dosificación , Quimioterapia del Cáncer por Perfusión Regional/métodos , Procedimientos Quirúrgicos de Citorreducción/métodos , Hipertermia Inducida/métodos , Neoplasias Peritoneales/terapia , Adolescente , Antineoplásicos/uso terapéutico , Niño , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Intraperitoneales , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
We present three pediatric patients with BRAFV600E mutant high-grade gliomas treated by vemurafenib on a nominative authorization level at our institution. One patient with anaplastic ganglioglioma experienced confirmed partial tumor response and significant clinical improvement and she is alive 20 months after start of treatment. A second patient with ganglioglioma responded transiently to re-introduction of vemurafenib after immunotherapy. Pharmacokinetic studies suggest that maximum concentration and exposure of vemurafenib at steady-state is dose-dependent and similar in children to that reported in adults. These cases suggest that BRAFV600 is an oncogenic driver in pediatric gliomas. Further exploration in clinical studies is ongoing.
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Antineoplásicos/uso terapéutico , Astrocitoma/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Ganglioglioma/tratamiento farmacológico , Indoles/uso terapéutico , Mutación Missense , Proteínas de Neoplasias/antagonistas & inhibidores , Mutación Puntual , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/enzimología , Bevacizumab , Neoplasias Encefálicas/enzimología , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Vacunas contra el Cáncer/uso terapéutico , Niño , Terapia Combinada , Irradiación Craneana , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Evaluación de Medicamentos , Resultado Fatal , Ganglioglioma/enzimología , Ganglioglioma/radioterapia , Ganglioglioma/cirugía , Humanos , Inmunoterapia , Indoles/efectos adversos , Indoles/farmacocinética , Lactante , Irinotecán , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiología , Polietilenglicoles/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/fisiología , Terapia Recuperativa , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Temozolomida , Tálamo , Resultado del Tratamiento , VemurafenibRESUMEN
OBJECTIVE: To evaluate whether analyses of clinical and endocrine presenting symptoms could help to shorten the time to diagnosis of hypothalamic-pituitary lesions in children. STUDY DESIGN: A retrospective, single-center, cohort study of 176 patients (93 boys), aged 6 years (range, 0.2-18 years), with hypothalamic-pituitary lesions was performed. RESULTS: The lesions were craniopharyngioma (n = 56), optic pathway glioma (n = 54), suprasellar arachnoid cyst (n = 25), hamartoma (n = 22), germ cell tumor (n = 12), and hypothalamic-pituitary astrocytoma (n = 7). The most common presenting symptoms were neurologic (50%) and/or visual complaints (38%), followed by solitary endocrine symptoms (28%). Precocious puberty led to diagnosis in 19% of prepubertal patients (n = 131), occurring earlier in patients with hamartoma than in patients with optic-pathway glioma (P < .02). Isolated diabetes insipidus led to diagnosis for all germ-cell tumors. For 122 patients with neuro-ophthalmic presenting symptoms, the mean symptom interval was 0.5 year (95% CI, 0.4-0.6 year), although 66% of patients had abnormal body mass index or growth velocity, which preceded the presenting symptom interval onset by 1.9 years (95% CI, 1.5-2.4 years) (P < .0001) and 1.4 years (95% CI, 1-1.8 years) (P < .0001), respectively. Among them, 41 patients were obese before diagnosis (median 2.2 years [IQR, 1-3 years] prior to diagnosis) and 35 of them had normal growth velocity at the onset of obesity. The sensitivity of current guidelines for management of childhood obesity failed to identify 61%-85% of obese children with an underlying hypothalamic-pituitary lesion in our series. CONCLUSIONS: Endocrine disorders occurred in two-thirds of patients prior to the onset of the neuro-ophthalmic presenting symptom but were missed. Identifying them may help to diagnose hypothalamic-pituitary lesions earlier.
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Enfermedades del Sistema Endocrino/diagnóstico , Sistema Hipotálamo-Hipofisario/fisiología , Adolescente , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/diagnóstico , Niño , Preescolar , Estudios de Cohortes , Enfermedades del Sistema Endocrino/complicaciones , Femenino , Glioma/complicaciones , Glioma/diagnóstico , Humanos , Neoplasias Hipotalámicas/complicaciones , Neoplasias Hipotalámicas/diagnóstico , Hipotálamo/patología , Lactante , Recién Nacido , Masculino , Pediatría/métodos , Hipófisis/patología , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/diagnóstico , Estudios Retrospectivos , Factores de Tiempo , Trastornos de la Visión/complicaciones , Trastornos de la Visión/diagnósticoRESUMEN
OBJECTIVE: To evaluate bone mineral density (BMD), fractures, and vitamin D deficiency in pediatric patients in complete remission of solid tumor; and to identify risk factors for these three abnormalities. STUDY DESIGN: Data were collected prospectively after completion of cancer treatment. Hormonal and vitamin D deficiencies were treated. The patients were evaluated again 1 year later. PATIENTS: 52 consecutive patients, 30 boys and 22 girls. Among them, 21 completed the second evaluation. MEASUREMENTS: A clinical examination, nutritional assessment, and laboratory workup were performed. BMD was measured by absorptiometry. RESULTS: Calcium intake was inadequate in 75% of patients and vitamin D reserves were low in 61.5%. BMD was low at the spine in 32.7%, and at the femur in 24% of patients. Spinal and femoral BMD Z-scores correlated significantly with each other. Femoral BMD Z-score showed significant positive correlations with changes in body mass index, urinary calcium/creatinine ratio, and time since treatment completion, and a significant negative correlation with treatment duration. Fractures were noted in 10 patients but were not correlated with BMD. In the 21 re-evaluated patients, no significant improvements were found in calcium intake, vitamin D status, or BMD Z-score. CONCLUSIONS: Survivors of childhood solid cancer have high rates of insufficient calcium intake, vitamin D deficiency, low bone mass and fractures.