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INTRODUCTION: Introduction: Renal cell carcinoma (RCC) is a very rare pediatric renal tumor. Robust evidence to guide treatment is lacking and knowledge on targeted therapies and immunotherapy is mainly based on adult studies. Currently, the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG) 2016 UMBRELLA protocol recommends sunitinib for metastatic or unresectable RCC. METHODS: This retrospective study describes the effects of tyrosine kinase inhibitors (TKI), anti-programmed cell death 1 (PD-(L)1) monoclonal antibodies, and immunotherapeutic regimens in advanced-stage and relapsed pediatric RCC. RESULTS: Of the 31 identified patients (0-18 years) with histologically proven RCC, 3/31 presented with TNM stage I/II, 8/31 with TNM stage III, and 20/31 with TNM stage IV at diagnosis. The majority were diagnosed with translocation type RCC (MiT-RCC) (21/31) and the remaining patients mainly presented with papillary or clear-cell RCC. Treatment in a neoadjuvant or adjuvant setting, or upon relapse or progression, included mono- or combination therapy with a large variety of drugs, illustrating center specific choices in most patients. Sunitinib was often administered as first choice and predominantly resulted in stable disease (53%). Other frequently used drugs included axitinib, cabozantinib, sorafenib, and nivolumab; however, no treatment seemed more promising than sunitinib. Overall, 15/31 patients died of disease, 12/31 are alive with active disease, and only four patients had a complete response. The sample size and heterogeneity of this cohort only allowed descriptive statistical analysis. CONCLUSION: This study provides an overview of a unique series of clinical and treatment characteristics of pediatric patients with RCC treated with targeted therapies.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Niño , Estudios Retrospectivos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/mortalidad , Masculino , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Femenino , Adolescente , Preescolar , Lactante , Terapia Molecular Dirigida , Sunitinib/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Recién Nacido , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estadificación de NeoplasiasRESUMEN
PURPOSE: This phase Ib study defined the safety, MTD, and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were evaluation of antitumor activity and pharmacokinetics (PK) of regorafenib and irinotecan. PATIENTS AND METHODS: Patients aged 6 months to <18 years with relapsed/refractory solid malignancies [≥50% with rhabdomyosarcoma (RMS)] received regorafenib (starting dose 72 mg/m2/day) concomitantly or sequentially with vincristine 1.5 mg/m2 on days 1 and 8, and irinotecan 50 mg/m2 on days 1-5 (21-day cycle). Adverse events (AE) and tumor response were assessed. PK (regorafenib and irinotecan) were evaluated using a population PK model. RESULTS: We enrolled 21 patients [median age, 10 years; 12, RMS; 5, Ewing sarcoma (EWS)]. The MTD/RP2D of regorafenib in the sequential schedule was 82 mg/m2. The concomitant dosing schedule was discontinued because of dose-limiting toxicities in 2 of 2 patients treated. Most common grade 3/4 (>30% of patients) AEs were neutropenia, anemia, thrombocytopenia, and leukopenia. The overall response rate was 48% and disease control rate [complete response (CR)/partial response/stable disease/non-CR/non-progressive disease] was 86%. Median progression-free survival was 7.0 months [95% confidence interval (CI), 2.9-14.8] and median overall survival was 8.7 months (95% CI, 5.5-16.3). When combined with VI, regorafenib PK was similar to single-agent PK in children and adults (treated with regorafenib 160 mg/day). CONCLUSIONS: Regorafenib can be combined sequentially with standard dose VI in pediatric patients with relapsed/refractory solid tumors with appropriate dose modifications. Clinical activity was observed in patients with RMS and EWS (ClinicalTrials.gov NCT02085148).
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Rabdomiosarcoma , Sarcoma de Ewing , Adulto , Niño , Humanos , Irinotecán , Vincristina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Rabdomiosarcoma/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológico , Terapias en InvestigaciónRESUMEN
PURPOSE: Society of International Pediatric Oncology - Renal Tumor Study Group (SIOP-RTSG) treatment recommendations for relapsed Wilms tumour (WT) are stratified by the intensity of first-line treatment. To explore the evidence for the treatment of patients relapsing after vincristine and actinomycin-D (VA) treatment for primary WT, we retrospectively evaluated rescue treatment and survival of this patient group. PATIENTS AND METHODS: We included 109 patients with relapse after VA therapy (no radiotherapy) for stage I-II primary low- or intermediate-risk WT from the SIOP 93-01 and SIOP 2001 studies. Univariate Cox regression analysis was performed to study the effect of relapse treatment intensity on event-free survival (EFS) and overall survival (OS). Relapse treatment intensity was classified into vincristine, actinomycin-D, and either doxorubicin or epirubicin (VAD), and more intensive therapies (ifosfamide/carboplatin/etoposide [ICE]/≥ 4 drugs/high-dose chemotherapy with haematopoietic stem cell transplantation [HD HSCT]). RESULTS: Relapse treatment regimens included either VAD, or cyclophosphamide/carboplatin/etoposide/doxorubicin (CyCED), or ICE backbones. Radiotherapy was administered in 62 patients and HD HSCT in 15 patients. Overall, 5-year EFS and OS after relapse were 72.3% (95% confidence interval [CI]: 64.0-81.6%) and 79.3% (95% CI: 71.5-88.0%), respectively. Patients treated with VAD did not fare worse when compared with patients treated with more intensive therapies (hazard ratio EFS: 0.611 [95% CI: 0.228-1.638] [p-value = 0.327] and hazard ratio OS: 0.438 [95% CI: 0.126-1.700] [p-value = 0.193]). CONCLUSION: Patients with relapsed WT after initial VA-only treatment showed no inferior EFS and OS when treated with VAD regimens compared with more intensive rescue regimens. A subset of patients relapsing after VA may benefit from less intensive rescue treatment than ICE/CyCED-based regimens and deserve to be pinpointed by identifying additional (molecular) prognostic factors in future studies.
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Neoplasias Renales , Tumor de Wilms , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino , Niño , Dactinomicina , Supervivencia sin Enfermedad , Doxorrubicina , Etopósido , Femenino , Humanos , Ifosfamida/uso terapéutico , Neoplasias Renales/patología , Masculino , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Estudios Retrospectivos , Vincristina , Tumor de Wilms/terapiaRESUMEN
BACKGROUND AND OBJECTIVE: Population pharmacokinetic analysis explored the pharmacokinetics of sunitinib and its primary active metabolite, SU012662, in children and evaluated the sunitinib dose(s) that produce comparable plasma exposures to adults receiving the approved daily dose. METHODS: Data were from 65 children with gastrointestinal stromal tumors (GIST) or solid tumors. Pharmacokinetic models of sunitinib and SU012662 were developed using a systematic multi-step approach employing nonlinear mixed-effects modeling. The effect of predefined covariates on pharmacokinetic parameters was assessed. Final models were validated using visual predictive check and statistical techniques. RESULTS: The final dataset comprised 439 sunitinib and 417 SU012662 post-baseline plasma observations. Base models were characterized by two-compartment models with first-order absorption and lag time. Body surface area (BSA) was the only covariate that affected (P < 0.001) pharmacokinetic parameters for sunitinib and SU012662 and was incorporated into the final models. Bootstrap results indicated that the final models represented the final dataset adequately. Based on the final models, a sunitinib dose of ~ 20mg/m2/day in children with GIST aged 6-17 years would be expected to lead to similar total plasma exposures of sunitinib and SU012661 as a dose of 50 mg/day in an adult with GIST on schedule 4/2. CONCLUSIONS: In children with GIST or solid tumors receiving sunitinib, population pharmacokinetic analysis identified BSA as the only covariate that affected pharmacokinetic parameters and predicted a dose of ~ 20 mg/m2/day as achieving equivalent exposure to 50 mg/day in adults with GIST on schedule 4/2. TRIAL REGISTRATION: ClinicalTrials.gov identifiers (date registered): NCT01396148 (July 2011); NCT01462695 (October 2011); NCT00387920 (October 2006).
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Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Sunitinib/farmacocinética , Adolescente , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/patología , Humanos , Indoles/farmacocinética , Lactante , Masculino , Pirroles/farmacocinética , Sunitinib/administración & dosificación , Adulto JovenRESUMEN
OBJECTIVE: Wilms tumour (WT) patients with a localised completely necrotic nephroblastoma after preoperative chemotherapy are a favourable outcome group. Since the introduction of the SIOP 2001 protocol, the SIOP- Renal Tumour Study Group (SIOP-RTSG) has omitted radiotherapy for such patients with low-risk, local stage III in an attempt to reduce treatment burden. However, for metastatic patients with local stage III, completely necrotic WT, the recommendations led to ambiguous use. The purpose of this descriptive study is to demonstrate the outcomes of patients with metastatic, completely necrotic and local stage III WT in relation to the application of radiotherapy or not. METHODS AND MATERIALS: all metastatic patients with local stage III, completely necrotic WT after 6 weeks of preoperative chemotherapy who were registered in the SIOP 2001 study were included in this analysis. The pattern of recurrence according to the usage of radiation treatment and 5 year event-free survival (EFS) and overall survival (OS) was analysed. RESULTS: seven hundred and three metastatic WT patients were registered in the SIOP 2001 database. Of them, 47 patients had a completely necrotic, local stage III WT: 45 lung metastases (11 combined localisations), 1 liver/peritoneal, and 1 tumour thrombus in the renal vein and the inferior vena cava with bilateral pulmonary arterial embolism. Abdominal radiotherapy was administered in 29 patients (62%; 29 flank/abdominal irradiation and 9 combined with lung irradiation). Eighteen patients did not receive radiotherapy. Median follow-up was 6.6 years (range 1-151 months). Two of the 47 patients (4%) developed disease recurrence in the lung (one combined with abdominal relapse) and eventually died of the disease. Both patients had received abdominal radiotherapy, one of them combined with lung irradiation. Five-year EFS and OS were 95% and 95%, respectively. CONCLUSIONS: the outcome of patients with stage IV, local stage III, completely necrotic Wilms tumours is excellent. Our results suggest that abdominal irradiation in this patient category may not be of added value in first-line treatment, consistent with the current recommendation in the SIOP-RTSG 2016 UMBRELLA protocol.
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BACKGROUND: Wilms tumour (WT) has various subtypes that are correlated with prognosis and require distinct therapy. Stromal predominant (SpWT) and epithelial WT (EpWT) have previously been associated with a good outcome. The current analysis describes the outcome and (tumour) characteristics of all patients with SpWT, EpWT, including highly differentiated epithelial type (HDET), treated according to the International Society of Pediatric Oncology (SIOP) 93-01 study. PROCEDURE: All children older than 6 months and below 18 years of age with localized or metastatic WT and intermediate risk (IR) histology or HDET treated with pre-operative chemotherapy were included in the present analysis. RESULTS: A total of 1,389 eligible patients had IR or HDET histology: 1% HDET, 4% EpWT, 10% SpWT, and 85% other IR. For EpWT/HDET, 93% had stage I/IIN-, 5-year EFS was 90.2% and overall survival of (OS) 98.4%, as compared to 84.0% and 92.5% in other IR histology (NS). Stage I EpWT/HDET had a significant better outcome than stage I of other IR. In SpWT 82% of cases had stage I/IIN-; 5-year EFS was 94.3% and OS 99.2%, significantly better compared to other IR histology. All patients with stage I are alive (2/149 relapses); 3/52 stage IIN-, 2/21 stage IIN+/III, and 6/12 stage IV patients relapsed (1 deceased per stage group). CONCLUSIONS: The good outcome for EpWT and SpWT generally is very good which may be related to low age and low stage in most cases. A reduction of treatment intensity and/or duration may be justified especially for low stage SpWT that has an EFS close to 100%.
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Células Epiteliales/patología , Células del Estroma/patología , Tumor de Wilms/patología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Niño , Preescolar , Femenino , Humanos , Lactante , Neoplasias Renales , Masculino , Estadificación de Neoplasias , Nefrectomía , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento , Tumor de Wilms/mortalidad , Tumor de Wilms/terapiaRESUMEN
Pediatric renal cell carcinoma (RCC) is a rare type of kidney cancer, most commonly occurring in teenagers and young adolescents. Few relatively large series of pediatric RCC have been reported. Knowledge of clinical characteristics, outcome and treatment strategies are often based on the more frequently occurring adult types of RCC. However, published pediatric data suggest that clinical, molecular and histological characteristics of pediatric RCC differ from adult RCC. This paper summarizes reported series consisting of ≥10 RCC pediatric patients in order to create an up-to-date overview of the clinical and histopathological characteristics, treatment and outcome of pediatric RCC patients.
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INTRODUCTION: High-risk (HR) metastatic (stage IV) Wilms tumours (WTs) have a particular poor outcome. METHODS: Here, we report the results of HR (diffuse anaplastic [DA] or blastemal type [BT]) stage IV WT treated patients according to the HR arm in the SIOP2001 prospective study. RESULTS: From January 2002 to August 2014, 3559 patients with WT were included in the SIOP2001 trial. Among the 525 patients (15%) with metastatic WT, 74 (14%) had stage IV HR-WT. The median age at diagnosis was 5.5 years (range: 1.4-18.3). Thirty-four patients (47%) had BT-WT and 40 (53%) had DA-WT. Five-year event-free survival rates were 44 ± 17% and 28 ± 15% for BT-WT and DA-WT, respectively (p = 0.09). Five-year overall survival rates were 53 ± 17% and 29 ± 16% for BT-WT and DA-WT, respectively (p = 0.03). Metastatic complete response after preoperative treatment was significantly associated with outcome in univariate and multivariate analyses (hazards ratio = 0.3; p = 0.01). Postoperative radiotherapy of metastatic sites might also be beneficial. Forty-three of 74 patients experienced a relapse or progression predominantly in the lungs (80%). The median time to relapse/progression after diagnosis was 7.3 months (range: 1.6-33.3) and 4.9 months (range: 0.7-28.4) for BT-WT and DA-WT, respectively (p = 0.67). This is the first prospective evidence of inferior survival of stage IV BT-WT as compared with historical intermediate-risk WT. Survival of patients with stage IV DA-WT has not improved compared to the previous SIOP93-01 study. CONCLUSION: These results call for new treatment approaches for patients with HR stage IV WT.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Recurrencia Local de Neoplasia/epidemiología , Tumor de Wilms/tratamiento farmacológico , Adolescente , Niño , Preescolar , Dactinomicina/uso terapéutico , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Estudios Prospectivos , Tasa de Supervivencia , Factores de Tiempo , Vincristina/uso terapéutico , Tumor de Wilms/mortalidad , Tumor de Wilms/patologíaRESUMEN
BACKGROUND: Vincristine (VCR) and actinomycin D (ACD) form the backbone of chemotherapeutic regimens of Wilms tumor treatment. Veno-occlusive disease (VOD) is a potentially life-threatening complication of ACD. OBJECTIVES: To investigate the incidence of VOD after preoperative chemotherapy and assess the effect of dose and frequency of administrating ACD on the occurrence of VOD. METHODS: A single-center retrospective study of patients where liver biopsies were performed after 4 or 8 weeks of preoperative chemotherapy. Patients had localized or metastatic Wilms tumor and were treated according to SIOP 9, 93-1, or 2001 protocol. A correlation was analyzed between histologically confirmed VOD, laboratory parameters, and mode and frequency of ACD administration. Long-term hepatic toxicity was assessed 5 years after the end of therapy. RESULTS: Ninety-one patients were included in this analysis. Forty-one patients (45.1%) had histological evidence of VOD. The incidence of histologically proven VOD was significantly correlated with single administration of 45 microg/kg ACD (SIOP 2001 protocol) as compared to repeated dosing of l5 microg/kg (P = 0.003). Fifty-two percent of all patients had mild-to-severe abnormal liver enzymes 5 years after accomplishing therapy. CONCLUSION: Despite short-course preoperative chemotherapy regimen, patients are at risk of developing histological VOD. This risk is higher when ACD is administered in a 1-day 45 microg/kg regimen as compared to 3 days l5 microg/kg.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Neoplasias Renales/tratamiento farmacológico , Terapia Neoadyuvante/efectos adversos , Tumor de Wilms/tratamiento farmacológico , Alanina Transaminasa/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aspartato Aminotransferasas/sangre , Quimioterapia Adyuvante/efectos adversos , Niño , Preescolar , Dactinomicina/administración & dosificación , Dactinomicina/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Femenino , Enfermedad Veno-Oclusiva Hepática/epidemiología , Enfermedad Veno-Oclusiva Hepática/patología , Humanos , Incidencia , Lactante , Neoplasias Renales/cirugía , Hígado/diagnóstico por imagen , Hígado/enzimología , Hígado/patología , Masculino , Nefrectomía , Complicaciones Posoperatorias/inducido químicamente , Estudios Retrospectivos , Ultrasonografía , Tumor de Wilms/cirugíaRESUMEN
BACKGROUND: Sunitinib is approved for treatment of adults with imatinib-resistant gastrointestinal stromal tumor (GIST) or imatinib intolerance. METHODS: This single-arm, multicenter, multinational phase I/II clinical trial (NCT01396148) enrolled eligible patients aged 6 to < 18 years with advanced, unresectable GIST with non-mutant KIT, or who demonstrated disease progression or intolerance to imatinib. Patients received sunitinib 15 mg/m2 per day, 4-weeks-on/2-weeks-off (schedule 4/2), for ≤ 18 cycles over 24 months. Intra-patient dose escalation to 22.5 and subsequently 30 mg/m2 were permitted based on individual patient tolerability and supported by real-time pharmacokinetics (PK). Primary objective was PK characterization. Secondary objectives included safety, antitumor activity and PK/pharmacodynamic relationships. RESULTS: Six patients were enrolled with median (range) age of 14 (13-16) years. All six patients completed at least three treatment cycles, with one completing all 18 cycles. Five patients had a dose increase to 22.5 mg/m2; two of them had a further dose increase to 30 mg/m2. The average daily dose at cycle 3 was 21.1 mg/m2 (n = 6). Steady-state plasma concentrations were reached by day 15, cycle 1. No tumor responses were observed, but three patients had stabilization of the disease (50%). Median progression-free survival was 5.8 months (95% CI 2.3-not reached). There were no serious adverse events. CONCLUSIONS: The tolerable dose of sunitinib in chemotherapy-naïve pediatric patients is at least 20 mg/m2 on schedule 4/2. The safety profile and PK of sunitinib in pediatric patients with GIST are comparable to those in adults.
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Antineoplásicos/administración & dosificación , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Sunitinib/administración & dosificación , Adolescente , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Femenino , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/patología , Humanos , Mesilato de Imatinib/administración & dosificación , Masculino , Supervivencia sin Progresión , Sunitinib/efectos adversos , Sunitinib/farmacocinética , Resultado del TratamientoRESUMEN
PURPOSE: To determine the response to radionuclide targeted therapy with I-131-metaiodobenzylguanidine ((131)I-MIBG) as induction therapy in high-risk neuroblastoma patients. PATIENTS AND METHODS: The protocol dictated at least two cycles of (131)I-MIBG with a fixed dose of 7.4 and 3.7 GBq, respectively, followed by surgery, if feasible, or followed by neoadjuvant chemotherapy and surgery. This was followed by consolidation with four courses of chemotherapy myeloablative chemotherapy and autologous stem-cell transplantation (ASCT). Consolidation therapy with 13-cis-retinoic acid was given for 6 months. RESULTS: Of 44 consecutive patients, 41 were evaluable after two courses of (131)I-MIBG. The objective response rate at this point was 66%. In 24 patients, (131)I-MIBG was continued as pre-operative induction treatment. Seventeen patients required additional chemotherapy before surgery. After pre-operative therapy and surgery, the overall response rate was 73%. CONCLUSION: First line (131)I-MIBG-targeted therapy is a valuable tool in the treatment of MIBG-positive high-risk neuroblastoma patients.
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3-Yodobencilguanidina/uso terapéutico , Antineoplásicos/uso terapéutico , Neuroblastoma/radioterapia , Radiofármacos/uso terapéutico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea/métodos , Niño , Preescolar , Terapia Combinada , Evaluación de Medicamentos , Estudios de Factibilidad , Femenino , Humanos , Lactante , Isotretinoína/uso terapéutico , Masculino , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/cirugía , Trasplante de Células Madre de Sangre Periférica/métodos , Trasplante Autólogo , Resultado del TratamientoRESUMEN
The Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP-RTSG) has developed a new protocol for the diagnosis and treatment of childhood renal tumours, the UMBRELLA SIOP-RTSG 2016 (the UMBRELLA protocol), to continue international collaboration in the treatment of childhood renal tumours. This protocol will support integrated biomarker and imaging research, focussing on assessing the independent prognostic value of genomic changes within the tumour and the volume of the blastemal component that survives preoperative chemotherapy. Treatment guidelines for Wilms tumours in the UMBRELLA protocol include recommendations for localized, metastatic, and bilateral disease, for all age groups, and for relapsed disease. These recommendations have been established by a multidisciplinary panel of leading experts on renal tumours within the SIOP-RTSG. The UMBRELLA protocol should promote international collaboration and research and serve as the SIOP-RTSG best available treatment standard.
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Neoplasias Renales/terapia , Tumor de Wilms/terapia , Protocolos de Quimioterapia Combinada Antineoplásica , Niño , Preescolar , Dactinomicina , Humanos , Lactante , Neoplasias Renales/patología , Selección de Paciente , Guías de Práctica Clínica como Asunto , Vincristina , Tumor de Wilms/patologíaRESUMEN
Three patients with stage 4S neuroblastoma without MYC-N amplification who progressed to stage 4 with persistent liver involvement, were treated with iodine 131-meta-iodobenzylguanidine therapy, chemotherapy, and surgery. Successive histologic examination of the liver showed differentiation of the tumor in 2 patients and fibrosis in the third. One patient died of brain metastases at the age of 30 months. The other 2 patients are alive at 50 and 44 months. Diffuse liver involvement in patients with stage 4 progression of previous stage 4S without MYC-N amplification may differentiate after treatment. The aim of this report is to draw attention to major liver surgery that it may not be necessary in tumors without MYC-N amplification, despite the persistence of lesions in the liver.
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Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Neuroblastoma/secundario , Neuroblastoma/terapia , Progresión de la Enfermedad , Resultado Fatal , Femenino , Humanos , Lactante , Masculino , Estadificación de Neoplasias , Neuroblastoma/patologíaRESUMEN
Joubert syndrome is a rare disorder, characterized by hypoplasia, or aplasia of the cerebellar vermis, hypotonia, ataxia, and psychomotor retardation. The molecular basis underlying the disease is still unknown. There are various syndromes, which are associated with malignancies. Previously known associations between Joubert syndrome and tumors, are benign soft tissue tumors of the tongue and laryngeal lymphangioma. This report describes a 17-year-old boy known with Joubert syndrome, who was diagnosed with Burkitt lymphoma. The boy received chemotherapy, which successfully induced complete remission.
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Anomalías Múltiples , Linfoma de Burkitt , Ataxia Cerebelosa , Cerebelo/anomalías , Hipotonía Muscular , Trastornos Psicomotores , Adolescente , Humanos , Masculino , SíndromeRESUMEN
The cytotoxic effect of 1-beta-D-arabinofuranosyl cytosine (araC) depends on the intracellular phosphorylation into its active compound araCTP, on the degree of degradation of araCTP and on the incorporation of araCTP into DNA. Deoxycytidine triphosphate (dCTP) inhibits the phosphorylation of araC (by feedback inhibition of the enzyme deoxycytidine kinase) and the incorporation of araCTP into DNA (by competition for DNA polymerase). In a T-lymphoblastic cell line, we studied whether the cytotoxicity of araC (2 nM-50 microM) could be enhanced by decreasing the concentration of dCTP, using the nucleoside-analogue cyclopentenyl cytosine (CPEC), an inhibitor of the enzyme CTP synthetase. Preincubation of the cells with CPEC (100-1,600 nM) for 2 hr increased the concentrations of araCMP 1.6-9.5-fold, which was significant for each concentration of CPEC used. The concentration of araCDP remained low, whereas the concentration of araCTP changed depending on the concentration of araC used. With 2-15 microm of araC and a preincubation with 400 nM of CPEC, the araCTP concentration increased by 4-15% (not significant), and the total amount of araC nucleotides increased significantly by 21-45%. When using a concentration of araC of 2 nM after a preincubation with CPEC of 100 nM, the concentration of araCMP increased by 60% (p = 0.015), whereas that of araCTP decreased by 10% (p = 0.008). This was compensated by an increase of 41% (p = 0.005) of araCTP incorporation into DNA, which represented 43% of all araC metabolites. Moreover, by performing pulse/chase experiments with 400 nM of CPEC and 2 microM of araC, the retention of cytosolic araCTP and the incorporated amount of araCTP into DNA were increased by CPEC. The modulation by CPEC of araC metabolism was accompanied by a synergistic increase of araC-induced apoptosis and by an additive effect on the araC-induced growth inhibition.