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.

Impact of the COVID-19 pandemic on paediatric renal tumour presentation and management, a SIOP renal tumour study group study.

BACKGROUND: The COVID-19 pandemic had global catastrophic effects on the management of non-communicable diseases including paediatric cancers. Restrictions during the start of 2020 complicated timely referrals of patients to specialized centres. We aimed to evaluate the pandemic's impact on the number of new diagnoses, disease characteristics and management delay for paediatric renal tumour patients included in the SIOP-RTSG-UMBRELLA study, as compared with data from a historical SIOP-RTSG trial (2005-2009). METHODS: The number of intensive care admissions, population mobility rates and national lockdown periods/restrictions were used as proxies of the pandemic's severity and impact on societies. Clinical and tumour data were extracted from the SIOP-RTSG-UMBRELLA study and from historical SIOP-RTSG trials. RESULTS: During the first lockdown in Europe, the number of newly diagnosed patients decreased following restrictions and population immobilisation. Additionally, there was a higher proportion of advanced disease (37% vs. 17% before and after COVID-9, p < 0.001) and larger median tumour volume (559 cm3 vs. 328 and 434 cm3 before and after, p < 0.0001). Also in Brazil, the proportion of advanced disease was higher during the national decrease in mobilisation and start of restrictions (50% and 24% vs. 11% and 18% before and after, p < 0.01). Tumour volume in Brazil was also higher during the first months of COVID-19 (599 cm3 vs. 459 and 514 cm3 ), although not significant (p = 0.17). We did not observe any delays in referral time nor in time to start treatment, even though COVID-19 restrictions may have caused children to reach care later. CONCLUSION: The COVID-19 pandemic briefly changed the tumour characteristics of children presenting with renal tumours. The longer-term impact on clinical outcomes will be kept under review.

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.

International Comparisons of Clinical Demographics and Outcomes in the International Society of Pediatric Oncology Wilms Tumor 2001 Trial and Study.

PURPOSE: International comparisons of patient demographics, tumor characteristics, and survival can shed light on areas for health care system improvement. The International Society of Pediatric Oncology Wilms Tumor 2001 trial/study registered patients through national clinical study groups in Western Europe and Brazil. This retrospective post hoc analysis of the International Society of Pediatric Oncology Wilms Tumor 2001 database aims to make visible and suggest reasons for any variations in outcomes. METHODS: All patients with unilateral Wilms tumor (WT), age > 6 months, treated with preoperative chemotherapy as per protocol, and registered between 2001 and 2011 were eligible. Countries were grouped to give comparable case numbers and geographical representation. Cox univariable and multivariable (MVA) statistics were applied, with the German collaborative group (Gesellschaft für Pädiatrische Onkologie und Hämatologie-Austria, Germany, and Switzerland) as reference for hazard ratios for event-free survival (EFS) and overall survival (OS). RESULTS: A total of 3,176 eligible patients were registered from 24 countries assigned into six groups. Age and histologic risk group distribution were similar across all groupings. The distribution of WT stage varied by country grouping, with 14.9% (range, 11.1%-18.2%) metastatic at diagnosis. Median follow-up was 78.9 months. For localized WT, 5-year EFS varied from 80% (Brazilian group) to 91% (French group; P < .0001), retaining significance only for Brazil in MVA (P = .001). Five-year OS varied from 89% (Brazilian group) to 98% (French group; P < .0001). In MVA, only superior OS in France was significant (P = .001). Five-year EFS/OS for stage IV did not vary significantly. High-risk histology and tumor volume at surgery were significantly associated with increased risk of death in MVA for metastatic disease. CONCLUSION: International benchmarking of survival rates from WT within a large trial/study database has demonstrated statistically significant differences. Clinical interpretation should take account of variation in tumor stage but also treatment factors.

A Metabonomic View on Wilms Tumor by High-Resolution Magic-Angle Spinning Nuclear Magnetic Resonance Spectroscopy.

Pediatric cancer NMR-metabonomics might be a powerful tool to discover modified biochemical pathways in tumor development, improve cancer diagnosis, and, consequently, treatment. Wilms tumor (WT) is the most common kidney tumor in young children whose genetic and epigenetic abnormalities lead to cell metabolism alterations, but, so far, investigation of metabolic pathways in WT is scarce. We aimed to explore the high-resolution magic-angle spinning nuclear magnetic resonance (HR-MAS NMR) metabonomics of WT and normal kidney (NK) samples. For this study, 14 WT and 7 NK tissue samples were obtained from the same patients and analyzed. One-dimensional and two-dimensional HR-MAS NMR spectra were processed, and the one-dimensional NMR data were analyzed using chemometrics. Chemometrics enabled us to elucidate the most significant differences between the tumor and normal tissues and to discover intrinsic metabolite alterations in WT. The metabolic differences in WT tissues were revealed by a validated PLS-DA applied on HR-MAS T2-edited 1H-NMR and were assigned to 16 metabolites, such as lipids, glucose, and branched-chain amino acids (BCAAs), among others. The WT compared to NK samples showed 13 metabolites with increased concentrations and 3 metabolites with decreased concentrations. The relative BCAA concentrations were decreased in the WT while lipids, lactate, and glutamine/glutamate showed increased levels. Sixteen tissue metabolites distinguish the analyzed WT samples and point to altered glycolysis, glutaminolysis, TCA cycle, and lipid and BCAA metabolism in WT. Significant variation in the concentrations of metabolites, such as glutamine/glutamate, lipids, lactate, and BCAAs, was observed in WT and opened up a perspective for their further study and clinical validation.

Outcome of SIOP patients with low- or intermediate-risk Wilms tumour relapsing after initial vincristine and actinomycin-D therapy only - the SIOP 93-01 and 2001 protocols.

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.

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.

Non-coding RNAs in Wilms' tumor: biological function, mechanism, and clinical implications.

Non-coding RNAs are involved with maintenance and regulation of physiological mechanisms and are involved in pathological processes, such as cancer. Among the small ncRNAs, miRNAs are the most explored in tumorigenesis, metastasis development, and resistance to chemotherapy. These small molecules of ~ 22 nucleotides are modulated during early renal development, involved in the regulation of gene expression and Wilms' tumor progression. Wilms' tumors are embryonic tumors with few mutations and complex epigenetic dysregulation. In recent years, the small ncRNAs have been explored as potentially related both in physiological development and in the tumorigenesis of several types of cancer. Besides, genes regulated by miRNAs are related to biological pathways as PI3K, Wnt, TGF-ß, and Hippo signaling pathways, among others, which may be involved with the underlying mechanisms of resistance to chemotherapy, and in this way, it has emerged as potential targets for cancer therapies, including for Wilms' tumors.

Outcome of Stage IV Completely Necrotic Wilms Tumour and Local Stage III Treated According to the SIOP 2001 Protocol.

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.

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.

Challenges on participation in a cooperative group of childhood renal tumors in Brasil.

OBJECTIVE: Children with renal tumors included in clinical trials have significantly better outcomes. In Brasil, the enrollment of patients in clinical trials remains challenging. Here we aimed to describe participation accrual in the Brazilian Wilms Tumor Study Group (BWTSG) and to identify barriers to trial registration of children with renal tumors. METHODS: We determined the numbers of renal tumor diagnoses in 105 hospital-based cancer registries from 2001-2009. We then compared these totals with the numbers of renal tumor cases registered in the BWTSG from the same hospitals during the same time period. We also invited members of the Brazilian Pediatric Oncology Society to complete a 5-point Likert-type scale questionnaire regarding their opinions of the importance of participation in cooperative group trials. RESULTS: The accrual rate of patient participation per hospital varied from 25% to 76%, and was highest in the South region. The accrual rate of hospital participation also varied according to the region (20-31%) and was highest in the Southeast region. For the questionnaire regarding the importance of participation in cooperative groups, the responses showed an agreement of >75% on 10 of the 13 statements. CONCLUSION: Our results demonstrated low accrual of participation in a cooperative group trial in Brasil. We identified variations in registration rates according to geographic region and hospital, which may help targeted efforts to increase registration rates. The survey responses demonstrated that colleagues understand the importance of trial participation.

Thyroid carcinoma in children, adolescents, and young adults in Brazil: A report from 11 population-based cancer registries.

BACKGROUND: The increasing incidence of thyroid cancer has been described worldwide. Overdiagnosis, improved imaging, and increased environmental risk factors have contributed to the rising incidence. The objective of this study was to analyze the population incidence rate and trends during the period of 2000-2013 in children, adolescents and young adults (AYAs) in Brazil. METHODS: Data were extracted from 11 population-based cancer registries (PBCRs) encompassing the five geographic regions of Brazil. Incidence rates per million in children (0-14) and AYAs (15-39) according to world population were analyzed according to sex, age, and type of carcinoma. Incidence trends were evaluated using joinpoint regression. RESULTS: During 2000 to 2013, we identified 11,081 children and AYAs (0-39 years) with thyroid carcinoma in 11 PBCRs, with an age-adjusted incidence rate (AAIR) of 42 cases per million. Females had a higher AAIR of 66 cases per million versus 14 cases per million in males. Age-specific incidence rate (ASR) increased with age. Geographic variation was also observed; the Midwest and Southeast regions had the highest ASR in all age groups. The lowest ASR in all age groups was seen in the North region. Papillary subtype was the most common. Overall, the incidence rates in children and AYAs significantly increased from 0.2 in 2000 to 2.8 in 2013 and from 47.1 to 115.3, respectively, with an annual average percent change of 18.8 [8.1; 30.6] for children and 7.9 [CI 5.6; 10.3] for AYAs. CONCLUSIONS: Rates of thyroid cancer, particularly the papillary subtype, are steadily increasing in children and AYAs, especially among females. There are variations among geographic areas. This increased incidence is unlikely to be explained by screening, as children less than 14 years of age do not typically undergo medical surveillance. Environmental risk factors must be investigated.

Challenges on participation in a cooperative group of childhood renal tumors in Brasil

SUMMARY OBJECTIVE Children with renal tumors included in clinical trials have significantly better outcomes. In Brasil, the enrollment of patients in clinical trials remains challenging. Here we aimed to describe participation accrual in the Brazilian Wilms Tumor Study Group (BWTSG) and to identify barriers to trial registration of children with renal tumors. METHODS We determined the numbers of renal tumor diagnoses in 105 hospital-based cancer registries from 2001-2009. We then compared these totals with the numbers of renal tumor cases registered in the BWTSG from the same hospitals during the same time period. We also invited members of the Brazilian Pediatric Oncology Society to complete a 5-point Likert-type scale questionnaire regarding their opinions of the importance of participation in cooperative group trials. RESULTS The accrual rate of patient participation per hospital varied from 25% to 76%, and was highest in the South region. The accrual rate of hospital participation also varied according to the region (20-31%) and was highest in the Southeast region. For the questionnaire regarding the importance of participation in cooperative groups, the responses showed an agreement of >75% on 10 of the 13 statements. CONCLUSION Our results demonstrated low accrual of participation in a cooperative group trial in Brasil. We identified variations in registration rates according to geographic region and hospital, which may help targeted efforts to increase registration rates. The survey responses demonstrated that colleagues understand the importance of trial participation.

RESUMO OBJETIVO Crianças com tumores renais incluídas em ensaios clínicos apresentam melhora significativa na sobrevida. No entanto, o envolvimento desses pacientes em ensaios clínicos continua sendo um desafio no Brasil. Nosso objetivo neste estudo é descrever a taxa de aderência e adesão no Grupo Cooperativo Brasileiro para tratamento de Tumor de Wilms (GCBTTW) e identificar barreiras na participação ao protocolo. MÉTODOS Identificamos o número de casos de tumores renais diagnosticados em 105 registros hospitalares de câncer no período de 2001 a 2009. O número total desses casos foi então comparado ao número de casos de tumores renais registrados no GCBTTW provenientes das mesmas unidades hospitalares e durante o mesmo período. Os membros da Sociedade Brasileira de Oncologia Pediátrica foram convidados para completar um questionário com escala do tipo likert com o objetivo de conhecer suas opiniões sobre a importância e as dificuldades na participação em ensaios clínicos de grupos cooperativos. RESULTADOS A aderência de pacientes por hospital variou de 25% a 76% e foi maior na região Sul. A adesão da participação do hospital também variou de acordo com a região (20-31%) e foi maior na região Sudeste. Com relação ao questionário referente à importância da participação em grupos cooperativos, as respostas mostraram concordância de mais de 75% em 10 das 13 afirmações. CONCLUSÃO Nossos resultados demonstraram uma baixa participação em grupos cooperativos no Brasil. Houve variações nas taxas de adesão e aderência de acordo com a região geográfica e unidade hospitalar, o que pode auxiliar em futuros esforços para a melhora dessas taxas. As respostas ao questionário demonstraram que os profissionais entendem a importância da participação em grupos cooperativos.

Outcome of patients with stage IV high-risk Wilms tumour treated according to the SIOP2001 protocol: A report of the SIOP Renal Tumour Study Group.

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.

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.

Intra-tumor genetic heterogeneity in Wilms tumor samples

SUMMARY Childhood renal tumors account for ~7% of all childhood cancers, and most cases are embryonic Wilms' tumors (WT). Children with WT are usually treated by either COG or SIOP. The later treats the children using preoperative chemotherapy, but both have around 90% of overall survival in five years. WT is a genetically heterogeneous group with a low prevalence of known somatic alterations. Only around 30% of the cases present mutation in known genes, and there is a relatively high degree of intra-tumor genetic heterogeneity (ITGH). Besides potentially having an impact on the clinical outcome of patients, ITGH may interfere with the search for molecular markers that are prospectively being tested by COG and SIOP. In this review, we present the proposal of the current UMBRELLA SIOP Study 2017/Brazilian Renal Tumor Group that requires the multi-sampling collection of each tumor to better evaluate possible molecular markers, as well as to understand WT biology

RESUMO Os tumores renais pediátricos correspondem a aproximadamente 7% de todos os tumores infantis, sendo o mais frequente o tumor de Wilms (TW). Crianças com TW são geralmente tratadas seguindo dois distintos protocolos terapêuticos (COG ou SIOP), sendo que no último, os pacientes recebem tratamento quimioterápico pré-operatório. Ambos apresentam sobrevida global em cinco anos em torno de 90%. TW é geneticamente heterogêneo, apresentando baixa prevalência de alterações somáticas conhecidas, com cerca de 30% dos casos apresentando mutações em genes conhecidos e um alto grau de heterogeneidade genética intratumoral (HGIT). Além de potencialmente ter um impacto sobre o desfecho clínico dos pacientes, a HGIT pode interferir na busca de marcadores moleculares que estão sendo testados prospectivamente pelos grupos COG e Siop. Nesta revisão, apresentamos a proposta do atual estudo Umbrella Siop 2017/Grupo de Tumores Renais Brasileiros (GTRB), que orienta a coleta de três diferentes regiões do tumor para melhor avaliar possíveis marcadores moleculares, bem como para compreender a biologia do TW.

Delays in the health care system for children, adolescents, and young adults with bone tumors in Brazil / Atrasos no sistema de saúde para crianças, adolescentes e adultos jovens com tumores ósseos no Brasil

ABSTRACT Objective: To identify delays in the health care system experienced by children and adolescents and young adults (AYA; aged 0-29 years) with osteosarcoma and Ewing sarcoma using information from the Brazilian hospital-based cancer registries. Methods: Patient data were extracted from 161 Brazilian hospital-based cancer registries between 2007 and 2011. Hospital, diagnosis, and treatment delays were analyzed in patients without a previous histopathological diagnosis. Referral, hospital, and health care delays were calculated for patients with a previous histopathological diagnosis. The time interval was measured in days. Results: There was no difference between genders in overall delays. All delays increased at older ages. Patients without a previous histopathological diagnosis had the longest hospital delay when compared to patients with a previous histopathological diagnosis before first contact with the cancer center. Patients with Ewing sarcoma had longer referral and health care delays than those with osteosarcoma who had a previous histopathological diagnosis before first contact with the cancer center. The North and Northeast regions had the longest diagnosis delay, while the Northeast and Southeast regions had the longest treatment delay. Conclusion: Health care delay among patients with a previous diagnosis was longer, and was probably associated with the time taken for to referral to cancer centers. Patients without a previous histopathological diagnosis had longer hospital delays, which could be associated with possible difficulties regarding demand and high-cost procedures. Despite limitations, this study helps provide initial knowledge about the healthcare pathway delays for patients with bone cancer inside several Brazilian hospitals.

RESUMO Objetivo: Identificar atrasos no sistema de saúde em crianças e adolescentes e adultos jovens (AAJ; até 29 anos) com osteossarcoma e sarcoma de Ewing com informações dos registros de câncer de base hospitalar do Brasil. Métodos: Os dados dos pacientes foram extraídos de 161 registros de câncer de base hospitalar brasileiros entre 2007 e 2011. Os atrasos no hospital, no diagnóstico e no tratamento foram analisados em pacientes sem um diagnóstico histopatológico anterior. Os atrasos no encaminhamento, no hospital e no sistema de saúde foram calculados para pacientes com diagnóstico histopatológico anterior. O intervalo de tempo foi medido em dias. Resultados: Não houve diferença entre os sexos nos atrasos em geral. Todos os atrasos aumentaram na faixa etária mais velha. Os pacientes sem um diagnóstico histopatológico anterior apresentaram o atraso hospitalar mais longo em comparação com os pacientes com diagnóstico histopatológico anterior antes do primeiro contato com o centro de câncer. Os pacientes com sarcoma de Ewing apresentaram atrasos no encaminhamento e no sistema de saúde mais longos do que os com osteossarcoma, que apresentaram diagnóstico histopatológico anterior antes do primeiro contato com o centro oncológico. As regiões Norte e Nordeste apresentaram o atraso mais longo no diagnóstico, ao passo que as regiões Nordeste e Sul apresentaram o atraso mais longo no tratamento. Conclusão: O atraso no sistema de saúde entre os pacientes com diagnóstico anterior foi maior e provavelmente associado ao tempo de encaminhamento para os centros oncológicos. Os pacientes sem um diagnóstico histopatológico anterior apresentaram atrasos mais longos no hospital, o que pode ser associado a possíveis dificuldades com relação à demanda e aos procedimentos de alto custo. Apesar das limitações, nosso estudo ajuda a fornecer um conhecimento inicial sobre os atrasos no sistema de saúde para tratamento de pacientes com câncer em vários hospitais brasileiros.