Characteristics and outcome of synchronous bilateral Wilms tumour in the SIOP WT 2001 Study: Report from the SIOP Renal Tumour Study Group (SIOP-RTSG).

BACKGROUND: Among patients with nephroblastoma, those with bilateral disease are a unique population where maximising tumour control must be balanced with preserving renal parenchyma. METHODS: The SIOP 2001 protocol recommended surgery after neoadjuvant cycle(s) of Dactinomycin and Vincristine (AV) with response-adapted intensification, if needed. Adjuvant treatment was given based on the lesion with the worst histology. RESULTS: Three hundred and twenty seven patients with stage V disease were evaluable: 174 had bilateral Wilms tumour (BWT), 101 unilateral WT and contralateral nephroblastomatosis (NB) and 52 bilateral nephroblastomatosis. In these three groups, the estimated 5y-EFS was 76.1%, 84.6%, and 74.9%, respectively. AV chemotherapy alone was the successful chemotherapy for 58.7% of all the patients and 65.6% of the non-metastatic patients. Among the 174 patients with BWT, 149 (88.2%) had at least one nephron-sparing surgery. Twenty of 61 bilateral stage I patients were treated with four-week AV postoperatively achieving 94.4% 5y-EFS. At last follow-up, 87% of patients had normal renal function. CONCLUSIONS: This study demonstrates that AV without anthracyclines is sufficient to achieve NSS and good survival in the majority of patients. For patients with bilateral stage I WT and intermediate risk histology, only four weeks adjuvant AV seems to be sufficient. CLINICAL TRIAL REGISTRATION: NCT00047138.

Advances in the clinical management of high-risk Wilms tumors.

Outcomes are excellent for the majority of patients with Wilms tumors (WT). However, there remain WT subgroups for which the survival rate is approximately 50% or lower. Acknowledging that the composition of this high-risk group has changed over time reflecting improvements in therapy, we introduce the authors' view of the historical and current approach to the classification and treatment of high-risk WT. For this review, we consider high-risk WT to include patients with newly diagnosed metastatic blastemal-type or diffuse anaplastic histology, those who relapse after having been initially treated with three or more different chemotherapeutics, or those who relapse more than once. In certain low- or low middle-income settings, socio-economic factors expand the definition of what constitutes a high-risk WT. As conventional therapies are inadequate to cure the majority of high-risk WT patients, advancement of laboratory and early-phase clinical investigations to identify active agents is urgently needed.

Advances in the clinical management of high-risk Wilms tumors.

Outcomes are excellent for the majority of patients with Wilms tumors (WT). However, there remain WT subgroups for which the survival rate is approximately 50% or lower. Acknowledging that the composition of this high-risk group has changed over time reflecting improvements in therapy, we introduce the authors' view of the historical and current approach to the classification and treatment of high-risk WT. For this review, we consider high-risk WT to include patients with newly diagnosed metastatic blastemal-type or diffuse anaplastic histology, those who relapse after having been initially treated with three or more different chemotherapeutics, or those who relapse more than once. In certain low- or low middle-income settings, socio-economic factors expand the definition of what constitutes a high-risk WT. As conventional therapies are inadequate to cure the majority of high-risk WT patients, advancement of laboratory and early-phase clinical investigations to identify active agents is urgently needed.

The do-not-resuscitate-like (DNRL) order, a medical directive for limiting life-sustaining treatment in the end-of-life care of children with cancer: experience of major cancer center in Brazil.

PURPOSE: In the last few decades, interest in palliative care and advance care planning has grown in Brazil and worldwide. Empirical studies are needed to reduce therapeutic obstinacy and medical futility in the end-of-life care of children with incurable cancer. The aim of this study was to investigate the effects of do-not-resuscitate-like (DNRL) orders on the quality of end-of-life care of children with incurable solid tumors at a cancer center in Brazil. METHODS: A retrospective observational cohort study of 181 pediatric patients with solid tumors followed at the Pediatric Oncology Department of the Brazilian National Cancer Institute, Rio de Janeiro, Brazil, who died due to disease progression from 2009 to 2013. Medical records were reviewed for indicators of quality of end-of-life care, including overtreatment, care planning, and care at death, in addition to documentation of the diagnosis of life-limiting illness and the presence of a DNRL order. Data were summarized using descriptive statistics. Univariate and multivariate logistic regression analyses were used to examine associations between demographics, disease, treatment, and indicators of end-of-life care with a DNRL order. RESULTS: A documented DNRL order was associated with lower odds of dying in the intensive care unit or emergency room (80%), dying within 30 days of endotracheal tube placement (80%), or cardiopulmonary resuscitation (CPR) administration at the time of death (96%). CONCLUSION: Placement of DNRL orders early in the disease process is critical in reducing futile treatment in pediatric patients with incurable cancer.

Characteristics and outcome of pediatric renal cell carcinoma patients registered in the International Society of Pediatric Oncology (SIOP) 93-01, 2001 and UK-IMPORT database: A report of the SIOP-Renal Tumor Study Group.

In children, renal cell carcinoma (RCC) is rare. This study is the first report of pediatric patients with RCC registered by the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG). Pediatric patients with histologically confirmed RCC, registered in SIOP 93-01, 2001 and UK-IMPORT databases, were included. Event-free survival (EFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Between 1993 and 2019, 122 pediatric patients with RCC were registered. Available detailed data (n = 111) revealed 56 localized, 30 regionally advanced, 25 metastatic and no bilateral cases. Histological classification according to World Health Organization 2004, including immunohistochemical and molecular testing for transcription factor E3 (TFE3) and/or EB (TFEB) translocation, was available for 65/122 patients. In this group, the most common histological subtypes were translocation type RCC (MiT-RCC) (36/64, 56.3%), papillary type (19/64, 29.7%) and clear cell type (4/64, 6.3%). One histological subtype was not reported. In the remaining 57 patients, translocation testing could not be performed, or TFE-cytogenetics and/or immunohistochemistry results were missing. In this group, the most common RCC histological subtypes were papillary type (21/47, 44.7%) and clear cell type (11/47, 23.4%). Ten histological subtypes were not reported. Estimated 5-year (5y) EFS and 5y OS of the total group was 70.5% (95% CI = 61.7%-80.6%) and 84.5% (95% CI = 77.5%-92.2%), respectively. Estimated 5y OS for localized, regionally advanced, and metastatic disease was 96.8%, 92.3%, and 45.6%, respectively. In conclusion, the registered pediatric patients with RCC showed a reasonable outcome. Survival was substantially lower for patients with metastatic disease. This descriptive study stresses the importance of full, prospective registration including TFE-testing.

Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: The 30-year SIOP-RTSG experience.

BACKGROUND: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence. METHODS: Clinical characteristics, treatments, and outcomes were analyzed for patients with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) registries and the SIOP-RTSG network (1989-2019). Events were defined as relapse, metachronous tumors, or death. RESULTS: Forty-three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6-44 months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease. Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12 mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients with WT, the 5-year event-free survival rate was 84.3% (95% confidence interval, 72.4%-98.1%), and the overall survival rate was 91.2% (95% confidence interval, 82.1%-100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1). CONCLUSIONS: Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised. LAY SUMMARY: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with an increased risk of developing Wilms tumor. In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) and the SIOP-RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur. Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols. However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised.

Development of paediatric non-stage prognosticator guidelines for population-based cancer registries and updates to the 2014 Toronto Paediatric Cancer Stage Guidelines.

Population-based cancer registries (PBCRs) generate measures of cancer incidence and survival that are essential for cancer surveillance, research, and cancer control strategies. In 2014, the Toronto Paediatric Cancer Stage Guidelines were developed to standardise how PBCRs collect data on the stage at diagnosis for childhood cancer cases. These guidelines have been implemented in multiple jurisdictions worldwide to facilitate international comparative studies of incidence and outcome. Robust stratification by risk also requires data on key non-stage prognosticators (NSPs). Key experts and stakeholders used a modified Delphi approach to establish principles guiding paediatric cancer NSP data collection. With the use of these principles, recommendations were made on which NSPs should be collected for the major malignancies in children. The 2014 Toronto Stage Guidelines were also reviewed and updated where necessary. Wide adoption of the resultant Paediatric NSP Guidelines and updated Toronto Stage Guidelines will enhance the harmonisation and use of childhood cancer data provided by PBCRs.

Is radiotherapy required in first-line treatment of stage I diffuse anaplastic Wilms tumor? A report of SIOP-RTSG, AIEOP, JWiTS, and UKCCSG.

BACKGROUND: As a significant proportion of relapses occurred in the tumor bed or abdomen on patients with the fifth National Wilms Tumor Study stage I anaplastic Wilms tumor (WT), flank radiotherapy was added for stage I anaplastic WT in the subsequent study of the Children's Oncology Group (AREN0321). Preliminary results revealed reduction of relapse rate and improved survival. In cases treated with preoperative chemotherapy, such as in International Society of Pediatric Oncology (SIOP), the value of radiotherapy has never been studied. The aim of this observational study is to describe the pattern of recurrence and survival of patients with stage I diffuse anaplastic WT (DAWT) after induction chemotherapy. METHODS: Retrospective data analysis of the pattern of relapse and survival of all patients with stage I DAWT were included in recent SIOP, L'Associazone Italiana Ematologica Oncologia Pediatrica (AIEOP), Japan Wilms Tumor Study Group (JWiTS), United Kingdom Children's Cancer Study Group (UKCCSG) renal tumor registries. Postoperative treatment consisted of actinomycin D, vincristine, and doxorubicin for 28 weeks without local irradiation. RESULTS: One hundred nine cases with stage I DAWT were identified, of which 95 cases received preoperative chemotherapy. Of these, seven patients underwent preoperative true-cut biopsy. Sixteen of the 95 patients relapsed (17%), six locally, four at distant site, and six combined, and all treated according to SIOP 2001 relapse protocol, which resulted in a 5-year overall survival of 93%. CONCLUSION: Despite 13% locoregional relapse rate, an excellent rescue rate was achieved after salvage treatment, in patients with stage I DAWT whose first-line treatment comprised three-drug chemotherapy (including doxorubicin), without flank irradiation. Therefore, we continue not to advocate the use of radiotherapy in first-line treatment after preoperative chemotherapy in stage I DAWT in the next SIOP protocol.

Rare cancers in childhood and adolescence in Brazil: First report of data from 19 population-based cancer registries.

BACKGROUND: Rare childhood cancer is challenging to define. The Italian Pediatric Rare Tumor (TREP) Study considers rare tumors to include solid malignancies characterized by an annual incidence rate of <2 cases per 1 million and not enrolled in clinical trials. The objective of the current study was to analyze the population incidence rate of rare tumors among children and adolescents (those aged birth-19 years) in Brazil. METHODS: Incidence data were obtained from 19 population-based cancer registries covering the 5 geographic regions in Brazil. Newly diagnosed cases were selected according to the TREP definition, using the International Classification of Diseases for Oncology. To calculate the crude incidence rate, the numbers of incident children and adolescents with a specific rare cancer were divided by the corresponding person-years lived for the population aged <20 years during the same period. RESULTS: Two tumors had an incidence rate that was >2 cases per 1 million (thyroid and skin cancers) in adolescents only. Several tumors demonstrated variations in incidence across the Brazilian regions. Adrenocortical carcinoma had a high incidence rate (4 cases per 1 million) in the south region among children aged <10 years. Thyroid and skin carcinoma had higher incidence rates in the midwest, southeast, and south regions. CONCLUSIONS: Due to the extraordinary rarity of these events, networking is important for improving basic research, clinical studies, and trials. Centralization of diagnosis is the only way to improve the diagnosis and treatment of children affected by these rare diseases. The registration and surveillance of rare pediatric cancers are crucial from a public health point of view, and therefore the quality of registration has to be improved.

Survival and risk factors for mortality in pediatric patients with acute myeloid leukemia in a single reference center in low-middle-income country.

Despite advances in therapy and care for children with acute myeloid leukemia (AML), survival rates for children in low- and middle-income countries (LMICs) remain poor. We studied risk factors for mortality and survival in children with AML in a LMIC to develop strategies to improve survival for AML children in these countries. This retrospective cohort (2000-2014) analyzed newly diagnosed AML patients (age < 19 years) at a reference center in Brazil. Demographic and clinical variables were reviewed by AML subtype: acute promyelocytic leukemia (APL), AML with Down syndrome (AML-DS), and other AML subtypes. Cumulative hazard risk for early death (ED) until 6 weeks of treatment and risk factors for mortality were determined by the multivariate Cox hazard models. Survival was assessed for each AML subtypes. A total of 220 patients were diagnosed: APL 50 (22.7%), AML-DS 16 (7.3%), and other AML subtypes 154 (70.0%). The cumulative hazard function values for ED for all patients with AML were 12.5% (95% CI 8.5-18.4%); for each AML patients subtypes: APL, 21.7% (95% CI 11.7-40.5%); AML-DS, 6.2% (95% CI 0.9-44.4%); and other AML subtypes, 10.2% (95% CI 6.2-17.0%). White blood cell count (cutoff 10 × 109/L for APL and 100 × 109/L for other AML subtypes) and Afro-descendance were significant risk factors for mortality in APL and other AML subtypes, respectively. Overall survival for patients with APL, AML-DS, and other AML subtypes was 66.8%, 62.5%, and 38.0%, respectively. APL patients had the highest incidence of ED and those with other subtypes had increased relapse risk. We also observed high rates of death in complete remission mainly due to infection. Better risk classification and identification of risk factors for infection may improve the survival of these patients.

Relapse of Wilms' tumour and detection methods: a retrospective analysis of the 2001 Renal Tumour Study Group-International Society of Paediatric Oncology Wilms' tumour protocol database.

BACKGROUND: Wilms' tumour is the most common renal cancer in childhood and about 15% of patients will relapse. There is scarce evidence about optimal surveillance schedules and methods for detection of tumour relapse after therapy. METHODS: The Renal Tumour Study Group-International Society of Paediatric Oncology (RTSG-SIOP) Wilms' tumour 2001 trial and study is an international, multicentre, prospective registration, biological study with an embedded randomised clinical trial for children with renal tumours aged between 6 months and 18 years. The study covers 243 different centres in 27 countries grouped into five consortia. The current protocol of SIOP surveillance for Wilms' tumour recommends that abdominal ultrasound and chest x-ray should be done every 3 months for the first 2 years after treatment and be repeated every 4-6 months in the third and fourth year and annually in the fifth year. In this retrospective cohort study of the protocol database, we analysed data from participating institutions on timing, anatomical site, and mode of detection of all first relapses of Wilms' tumour. The primary outcomes were how relapse of Wilms' tumour was detected (ie, at or between scheduled surveillance and with or without clinical symptoms, scan modality, and physical examination) and to estimate the number of scans needed to capture one subclinical relapse. The RTSG-SIOP study is registered with Eudra-CT, number 2007-004591-39. FINDINGS: Between June 26, 2001, and May 8, 2015, of 4271 eligible patients in the 2001 RTSG-SIOP Wilms' tumour database, 538 (13%) relapsed. Median follow-up from surgery was 62 months (IQR 32-93). The method used to detect relapse was registered for 410 (76%) of 538 relapses. Planned surveillance imaging captured 289 (70%) of these 410 relapses. The primary imaging modality used to detect relapse was reported for 251 patients, among which relapse was identified by abdominal ultrasound (80 [32%] patients), chest x-ray (78 [31%]), CT scan of the chest (64 [25%]) or abdomen (20 [8%]), and abdominal MRI (nine [4%]). 279 (68%) of 410 relapses were not detectable by physical examination and 261 (64%) patients did not have clinical symptoms at relapse. The estimated number of scans needed to detect one subclinical relapse during the first 2 years after nephrectomy was 112 (95% CI 106-119) and, for 2-5 years after nephrectomy, 500 (416-588). INTERPRETATION: Planned surveillance imaging captured more than two-thirds of predominantly asymptomatic relapses of Wilms' tumours, with most detected by abdominal ultrasound, chest x-ray, or chest CT scan. Beyond 2 years post-nephrectomy, a substantial number of surveillance scans are needed to capture one relapse, which places a burden on families and health-care systems. FUNDING: Great Ormond Street Hospital Children's Charity, the European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment, The Danish Childhood Cancer Foundation, Cancer Research UK, the UK National Cancer Research Network and Children's Cancer and Leukaemia Group, Société Française des Cancers de l'Enfant and Association Leon Berard Enfant Cancéreux and Enfant et Santé, Gesellschaft für Pädiatrische Onkologie und Hämatologie and Deutsche Krebshilfe, Grupo Cooperativo Brasileiro para o Tratamento do Tumor de Wilms and Sociedade Brasileira de Oncologia Pediátrica, the Spanish Society of Pediatric Haematology and Oncology and the Spanish Association Against Cancer, and SIOP-Netherlands.

Incidence and survival of childhood leukemia in Recife, Brazil: A population-based analysis.

BACKGROUND: Leukemia is the most common pediatric cancer with incidence rates of around 48 per million for children under 15 years of age. The median age-adjusted incidence rate (AAIR) in children aged 0-14 years in Brazil is 53.3 per million. While overall survival rates for children with leukemia have improved significantly, data for incidence, trends, and relative survival among children and adolescents with leukemia in Recife, Brazil, remain incomplete, which hampers our analyses and provision of the best healthcare. The objective of this report is to provide that data. METHODS: Data from the Population-Based Cancer Registry of Recife were analyzed from 1998 to 2007. Our analyses included frequencies and AAIR, together with age-specific incidence rates for all leukemias, acute lymphoblastic leukemia, and acute myeloid leukemia. To evaluate incidence trends, joinpoint regression, including annual average percent change, were analyzed. Relative survival was calculated using the life-table method. RESULTS: One hundred seventy-five cases were identified, 51% in females. The review reduced the not otherwise specified (NOS) leukemia category by 50% and diagnosis by death certificate only from 5.7% to 1.1%. The AAIR for leukemia was 41.1 per million, with a peak among children aged 1-4 (78.3 per million). Incidence trends during the period were stable. The five-year relative survival rate was 69.8%. CONCLUSIONS: These data represent the incidence rate and survival of childhood leukemia in Recife, located in the northeast region of Brazil, using a high-quality database.

Birth weight and risk of childhood solid tumors in Brazil: a record linkage between population-based data sets.

OBJECTIVE: To analyze the relationship between the development of childhood solid tumors and 1) birth weight and 2) fetal growth, using two Brazilian population-based data sets. METHODS: A case-cohort study was performed using two population-based data sets, and linkage between the Live Birth Information System (Sistema de Informação sobre Nascidos Vivos, SINASC) and 14 population-based cancer registries (PBCRs) was established. Four controls per case were chosen randomly from the SINASC data set. Tumors were classified as central nervous system (CNS), non-CNS embryonal, and other tumors ("miscellaneous"). Adjustments were made for potential confounders (maternal age, mode of delivery, maternal education, birth order, gestational age, sex, and geographic region). Odds ratios (ORs) with 95% confidence intervals (CIs) were computed using unconditional logistic regression analysis. RESULTS: In a trend analysis, for every 500 g of additional birth weight, the crude OR was 1.12 (CI: 1.00-1.24) and the adjusted OR was 1.02 (CI: 0.90-1.16) for all tumors. For every 1 000 g of additional birth weight, the crude OR was 1.25 (CI: 1.00-1.55) and the adjusted OR was 1.04 (CI: 0.82-1.34) for all tumors. Among children diagnosed after reaching the age of 3 years, in the miscellaneous tumor category, the OR was significantly increased for every additional 500 g and 1 000 g of birth weight. CONCLUSIONS: The study data suggested that increased birth weight was associated with childhood solid tumor development, especially among children more than 3 years old with "miscellaneous" tumors.

The clinical phenotype of YWHAE-NUTM2B/E positive pediatric clear cell sarcoma of the kidney.

Clear cell sarcoma of the kidney (CCSK) although uncommon, is the second most frequent renal malignancy of childhood. Until now, the sole recurrent genetic aberration identified in CCSKs is t(10;17)(q22;p13), which gives rise to a fusion transcript of YWHAE and NUTM2B/E. So far, the clinical relevance of this fusion transcript is unknown. The aim of this descriptive study was to determine the clinical phenotype of t(10;17)(q22;p13) positive CCSKs. Snap-frozen tissues, formalin-fixed paraffin-embedded tissues or RNA previously extracted from CCSK samples throughout European, North-American and Japanese study groups were screened by RT-PCR for the YWHAE-NUTM2B/E transcript. Clinical characteristics, tumor characteristics, and outcome of patients with and without the fusion transcript were studied. The cohort comprised 51 previously published cases to which were added 139 internationally collected CCSK samples. RNA from 57 of these additionally collected cases was of sufficient quality to be successfully screened for the YWHAE-NUTM2B/E transcript. In total, seven of the 108 cases harbored the fusion transcript. Patients with tumors containing the fusion transcript were relatively young (median age 10 months), had associated low median tumor volumes and stage I disease was not observed in these patients. Two of seven patients relapsed and one of seven patients died of disease. Ranges of values were not overtly different between patients with and without the fusion transcript; however, the number of fusion transcript positive cases turned out to be too small to permit reliable statistical analysis. The current study did not identify an explicit clinical phenotype of CCSK cases harboring the YWHAE-NUTM2B/E fusion transcript.

Omission of doxorubicin from the treatment of stage II-III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. METHODS: For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 µg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants. FINDINGS: Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year event-free survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence. INTERPRETATION: Doxorubicin does not need to be included in treatment of stage II-III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification. FUNDING: See Acknowledgments for funders.

Cancer Incidence Among Adolescents and Young Adults (15 to 29 Years) in Brazil.

The spectrum of cancers commonly found in adolescents and young adults (AYAs) differs from those in children and adults; therefore, the childhood classification is not appropriate for this population. Here we used a newly proposed classification system to reclassify cases of AYAs from Brazilian population-based cancer registries (PBCRs) in 5 geographic regions of Brazil. We aimed to describe the cancer incidence rates within this age group according to PBCR. Using the world population, incidence rates per million were analyzed in each diagnostic subgroup according to sex and age at diagnosis (15 to 19 y, 20 to 24 y, and 25 to 29 y). The median incidence rate was 232.31 per million for females and 218.07 per million for males. Incidence increased with age, with the highest rate observed for 25- to 29-year-olds in both sexes. Carcinomas, lymphomas, and skin tumors were most frequent among AYAs. High incidence rates of cervix-uterus carcinoma were observed in most PBCRs. AYAs present epidemiological characteristics that differ from those of children, reinforcing the need for a new classification. This study describes, for the first time, the cancer incidence rate in AYAs in Brazil, and we believe that our findings represent the Brazilian profile.

Early childhood leukemia incidence trends in Brazil.

Incidence rates of childhood leukemia vary between different regions of the world. The objective of this study was to test possible trends in incidence rate of early childhood leukemia (children <5 years old at the diagnosis) in Brazil. Data from 18 population-based cancer registries (PBCRs) were analyzed (period 1999-2010). The analysis consisted of frequencies, age-adjusted incidence rates, and joinpoint regression results, including annual average percent change (AAPC) in incidence rates and 95% confidence intervals (CIs). The median age-adjusted incidence rate (AAIR) of overall early childhood leukemia was 61 per million. The AAIR for acute lymphoid leukemia (ALL) was 44 per million and nonlymphoid acute leukemia (NLAL) was 14 per million. The median ALL/NLAL ratio was 3.0, suggesting higher incidence rate of NLAL in these settings. The joinpoint analysis demonstrated increased leukemia incidence rate in João Pessoa (AAPC = 20; 95% CI: 3.5, 39.4) and Salvador (AAPC = 8.68; 95% CI: 1.0, 16.9), respectively, whereas incidence rate in São Paulo PBCR decreased (AAPC = -4.02%; 95% CI: -6.1%, -1.9%). Correlation between ALL AAIR and selected variables of socioeconomic (SES) factors was not observed. Increased AAIR regionally overtime was observed. However, the interpretation for such phenomenon should be cautious because it might reflect the access to health care, diagnosis procedures, and improvement of PBCR´s quality. The observed trend supports the necessity of further ecological studies.

PON1 Q192R polymorphism (rs662) is associated with childhood embryonal tumors.

Genetic susceptibility and environment exposures are associated risk factors in carcinogenesis. Gene polymorphisms that decrease the activity of detoxifying carcinogen substances may modify the effect of exposures. We investigated whether the polymorphisms PON1 rs662 (Q192R), and PON1 rs854560 (L55M) would be associated with embryonal tumors in Brazilian children. Blood samples from 163 children with embryonal tumors and 342 as control group were genotyped by TaqMAN real-time PCR assays. Logistic regression was used to evaluate the association between the polymorphisms of cases and controls groups, adjusted by skin color and age strata. When all tumors were taken together, the presence of the PON1 rs662 (Q192R) variant genotype (RR) was associated with an increased risk of developing embryonal tumors (OR = 2.80, 95 % CI 1.12-7.02). The presence of at least one variant PON1 rs662 R allele increased the risk of developing Wilms´ Tumor although without statistical power. However, it was observed a significant association of PON1 rs662 (Q192R) variant genotype (RR) with retinoblastoma (OR = 4.08, 95 % CI 1.13-14.97), whereas the PON1 rs854560 (L55M) polymorphism was not associated with any tumor. These results indicate that PON1 polymorphisms may have an influence on the risk of developing embryonal tumors.

Large germline copy number variations as predisposing factor in childhood neoplasms.

AIMS: Constitutive genetic factors are believed to predispose to cancer in children. This study investigated the role of rare germline copy number variations (CNVs) in pediatric cancer predisposition. PATIENTS & METHODS: A total of 54 patients who developed cancer in infancy were screened by array-CGH for germline CNVs. RESULTS: In total, 12 rare CNVs were detected, including a Xq27.2 triplication, and two >1.8 Mb deletions: one of them at 13q31, containing only RNA genes, and another at 3q26.33-q27.1, in a patient with congenital malformations. Detected rare CNVs are significantly larger than those identified in controls, and encompass genes never implicated in cancer predisposition. CONCLUSION: Our results suggest that constitutive CNVs contribute to the etiology of pediatric neoplasms, revealing new candidate genes for tumorigenesis.