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Purpose: Survivors of Wilms tumor (WT) are at risk for adverse health and social outcomes but risks beyond 30 years from diagnosis remain uncertain. We investigated the risks of adverse outcomes among 5-year survivors of WT, in particular, those between 30 and 50 years from diagnosis., Patients and Methods: The British Childhood Cancer Survivor Study includes 1,441 5-year survivors of WT. We investigated cause-specific mortality, risk of subsequent primary neoplasms (SPNs), and, for those who completed a questionnaire, the extent of smoking and drinking, educational achievement, health status, and health service use compared with the general population., Results: Cumulative risk of death from all causes, excluding recurrence, increased substantially from 5.4% to 22.7% at 30 years and 50 years, respectively, after WT diagnosis-75% of excess deaths beyond 30 years from diagnosis were attributable to SPNs (50%) and cardiac diseases (25%). Digestive cancer, most frequently bowel, accounted for 41% of excess cancers beyond 30 years., Conclusion: Between 30 and 50 years from diagnosis, survivors of WT are at a substantially increased risk of premature mortality, and 75% of excess deaths were accounted for by SPNs and cardiac diseases. Radiotherapy exposure was a risk factor for both outcomes. The proportion of patients with WT who are exposed to radiotherapy has reduced substantially in recent decades because of initiatives such as the SIOP WT 2001 clinical trial, which sought to reduce late effects; however, the majority of current survivors, who are at least 30 years from diagnosis, received radiotherapy. Surveillance of this group should focus on SPNs, in particular, bowel and breast cancers, and cardiac conditions., (© 2016 by American Society of Clinical Oncology.)

Wilms tumor is the most common childhood renal cancer. To identify mutations that predispose to Wilms tumor, we are conducting exome sequencing studies. Here we describe 11 different inactivating mutations in the REST gene (encoding RE1-silencing transcription factor) in four familial Wilms tumor pedigrees and nine non-familial cases. Notably, no similar mutations were identified in the ICR1000 control series (13/558 versus 0/993; P < 0.0001) or in the ExAC series (13/558 versus 0/61,312; P < 0.0001). We identified a second mutational event in two tumors, suggesting that REST may act as a tumor-suppressor gene in Wilms tumor pathogenesis. REST is a zinc-finger transcription factor that functions in cellular differentiation and embryonic development. Notably, ten of 11 mutations clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these mutations compromise REST transcriptional repression. These data establish REST as a Wilms tumor predisposition gene accounting for ∼2% of Wilms tumor.

Over the last few decades advances in the treatment of childhood and young adult cancer have greatly improved survival. As a result most children diagnosed with Wilms' tumor (the most common renal tumor in childhood) or other renal tumors become long-term survivors, living with surgically solitary kidneys. As physical activity is gaining credibility as a therapy enhancing well-being, encouraging cancer survivors do exercise during adolescence and adulthood is advisable. Discussing current evidence-based information would help to provide a framework for the harmonization of guidelines for sport participation of childhood and young adult renal tumor survivors.

Background: The randomised findings of the UKW3 trial were that preoperative chemotherapy was associated with a more advantageous stage distribution and reduction in therapy burden versus immediate nephrectomy without compromising outcome in localised Wilms' tumour (WT). We analysed outcome in all WT registered in UKW3., Patients and Methods: Seven hundred and eighteen WT cases (7% anaplastic) were registered in UKW3. We assigned a treatment stage and conducted survival analysis., Results: Five-year event-free survival (EFS) and overall survival (OS) were 77.2% [95% confidence interval (CI) 73.9-80.2] and 87.5% (95% CI 84.8-89.7) after median follow-up of 9.5 years and 10.0 years, respectively. Five-year OS in localised non-anaplastic cases was 92.9% (95% CI 90.2-94.9). Anaplasia was associated with adverse outcome compared with non-anaplastic cases: 5-year EFS of 42.0% (95% CI 28.3-55.1) versus 79.8% (95% CI 76.5-82.7) and 5-year OS of 60% (95% CI 45.1-72.0) versus 89.6% (95% CI 87.0-91.7), respectively. Outcomes were similar for non-anaplastic stage I or II but significantly poorer in stage III cases than stage I. Five-year OS after relapse was 54.1% (95% CI 44.5-62.8). Forty-seven percent of non-anaplastic WT received anthracycline; 27% were treated with radiotherapy first line., Conclusion: These outcomes provide a baseline for future comparisons of WT treatment approach, burden and patient outcome.

Wilms tumor is the most common renal malignancy of childhood. To identify common variants that confer susceptibility to Wilms tumor, we conducted a genome-wide association study in 757 individuals with Wilms tumor (cases) and 1,879 controls. We evaluated ten SNPs in regions significantly associated at P < 5 × 10(-5) in two independent replication series from the UK (769 cases and 2,814 controls) and the United States (719 cases and 1,037 controls). We identified clear significant associations at 2p24 (rs3755132, P = 1.03 × 10(-14); rs807624, P = 1.32 × 10(-14)) and 11q14 (rs790356, P = 4.25 × 10(-15)). Both regions contain genes that are plausibly related to Wilms tumorigenesis. We also identified candidate association signals at 5q14, 22q12 and Xp22.

Wilms' tumour is the second most common paediatric solid tumour. Prognosis is good although higher stage disease carries significant mortality and treatment related morbidity. In the UK, risk stratification is based on histological response to pre-operative chemotherapy. F(18)-Fluorodeoxyglucose Positron Emission Tomography (F(18)FDG-PET) is an emerging functional imaging technique in paediatric oncology. Little is known about the relationship between F(18)FDG-PET images and the disease process of Wilms' tumour. We performed F(18)FDG-PET/CT scans in seven children with Wilms' tumour after induction chemotherapy, immediately before surgery. The standard uptake values (SUV) of F(18)FDG-PET/CT images were related to conventional imaging and histopathological findings. In total seven children were studied. F(18)FDG-PET/CT was consistently safely performed. All tumours showed F(18)FDG activity. Four tumours had activity with SUV/bw max >5 g/ml. Histological examination of these active areas revealed viable anaplastic Wilms' tumour. Furthermore, in these four tumours GLUT-1 and Ki67 immunostaining was strongly positive. Three further tumours demonstrated lower uptake (SUV/bw max <5 g/ml), which represented areas of microscopic foci of residual viable tumour mixed with post chemotherapy change. Metastatic disease was F(18)FDG avid in two of four children with stage four diseases. In conclusion, following chemotherapy, active Wilms' tumour is F(18)FDG avid and higher SUV was seen in histologically high risk disease., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Most Wilms tumours occur in otherwise healthy children, but a small proportion occur in children with genetic syndromes associated with increased risks of Wilms tumour. Surveillance for Wilms tumour has become widespread, despite a lack of clarity about which children are at increased risk of these tumours and limited evidence of the efficacy of screening or guidance as to how screening should be implemented., Methods: The available literature was reviewed., Results: The potential risks and benefits of Wilms tumour surveillance are finely balanced and there is no clear evidence that screening reduces mortality or morbidity. Prospective evidence-based data on the efficacy of Wilms tumour screening would be difficult and costly to generate and are unlikely to become available in the foreseeable future., Conclusions: The following pragmatic recommendations have been formulated for Wilms tumour surveillance in children at risk, based on our review: (1) Surveillance should be offered to children at >5% risk of Wilms tumour. (2) Surveillance should only be offered after review by a clinical geneticist. (3) Surveillance should be carried out by renal ultrasonography every 3-4 months. (4) Surveillance should continue until 5 years of age in all conditions except Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome and some familial Wilms tumour pedigrees where it should continue until 7 years. (5) Surveillance can be undertaken at a local centre, but should be carried out by someone with experience in paediatric ultrasonography. (6) Screen-detected lesions should be managed at a specialist centre.

Purpose: To determine if patients receiving preoperative chemotherapy with vincristine and actinomycin D for non-metastatic Wilms' tumour have a more advantageous stage distribution and so need less treatment compared to patients who have immediate nephrectomy, without adversely affecting outcome., Methods: Between 1991 and 2001, a total of 205 patients with newly diagnosed non-metastatic renal tumours, of which 186 had Wilms' histologies, were randomly assigned either to immediate surgery or to 6 weeks preoperative chemotherapy and then delayed surgery. Both groups of children received postoperative chemotherapy according to tumour stage and histology determined at the time of nephrectomy., Results: There was a significant improvement in the stage distribution for patients with Wilms' histologies receiving delayed surgery compared to those having immediate nephrectomy (stage I: 65.2% versus 54.3%; stage II: 23.9% versus 14.9%; stage III: 9.8% versus 29.8%, chi2 test for trend=7.02, p=0.008). This improvement resulted in 20% fewer children receiving radiotherapy or doxorubicin yet event-free and overall survivals at 5 years of 79.6% and 89.0%, respectively, were similar in the two groups., Conclusion: Six weeks of preoperative chemotherapy with vincristine and actinomycin D results in a significant shift towards a more advantageous stage distribution and hence reduction in therapy, while maintaining excellent event free and overall survival in children with non-metastatic Wilms' tumour. Around 20% of survivors were therefore spared the late-effects of doxorubicin or radiotherapy. Our results suggest that all children with non-metastatic Wilms' tumour should receive chemotherapy prior to tumour resection.

Purpose: This study sought to determine whether the identification of minimal pulmonary metastatic disease by chest computed tomography (CT) performed at diagnosis in patients with Wilms' tumor and normal chest x-rays (CXR) could predict a subgroup of children at increased risk of pulmonary relapse., Patients and Methods: A retrospective analysis was carried out of the records of 449 children entered onto the United Kingdom Childrens' Cancer Study Group Second Wilms' Tumor Study between July 1986 and September 1991. The imaging protocol did not stipulate chest CT at diagnosis, but 141 children who had normal frontal and lateral CXRs and a chest CT scan performed at diagnosis were eligible for analysis. After surgery, children with stage I Wilms' tumor received single-agent chemotherapy (vincristine), whereas children with stages II, III, and bilateral Wilms' tumor received combination chemotherapy. Most children with stage III tumors were also treated with abdominal radiotherapy (20 Gy)., Results: In 31 patients (22%), pulmonary nodules were visible on chest CT; eight experienced relapse, four (15%) in the lungs. When only stage I patients were analyzed, there was a significant difference between the pulmonary relapse rate of 43% (three of seven) in the CT-positive group and 10% (five of 48) in the CT-negative group (P =.02). Four of eight patients with stage I disease with pulmonary relapse died., Conclusion: CT seemed to identify a subgroup of stage I patients who were at increased risk of pulmonary relapse. These children had received only single-agent chemotherapy. A prospective randomized trial is needed to clarify whether these children would benefit from combination chemotherapy.

Background: Current treatment of stage III favorable histology (FH) Wilms tumor is surgery, radiotherapy to residual disease, and "triple" chemotherapy (vincristine, dactinomycin, and doxorubicin) for 12 months. This study tests the hypothesis that some stage III patients, especially very young children with minimal residual abdominal disease, might be successfully treated without radiotherapy, thereby avoiding the adverse late effects associated with radiotherapy., Procedure: From 1984, radiotherapy was omitted from the treatment of 8 carefully selected children who were younger than 3 years of age at diagnosis with stage III Wilms tumor by virtue of microscopic residual disease after surgery and whose lymph nodes were not involved by tumors. They were followed with bimonthly abdominal ultrasound examinations to assess local control., Results: Follow-up is now from 2 to 12 years (median 6 years) and 7 of the 8 children are alive and well with no abdominal recurrence. One child relapsed in the lungs and despite further treatment died of progressive disease. The disease-free survival (DFS) and overall survival (OS) are therefore both 87.5%., Conclusions: The DFS and OS in this admittedly small sample are consistent with the survival rates for stage III FH Wilms tumor in the first United Kingdom Children's Cancer Study Group (UKCCSG), North American (NWTS), and European (SIOP) Wilms Tumor studies, Larger numbers of patients are needed to determine whether or not this treatment approach is generally applicable, but we conclude that some children in this stage III "substage" may be treated successfully without radiotherapy.

Purpose: To study late cardiac function in a single diagnostic group (children with Wilms' tumor) with good long-term survival; to compare patients treated with anthracyclines (doxorubicin) with patients treated without anthracyclines and with a normal child/adolescent group; and to examine the risk factors involved in late cardiac dysfunction., Patients and Methods: Echocardiographic studies were performed on 97 Wilms' tumor patients treated with anthracyclines (mean cumulative dose, 303 mg/m2) with a mean follow-up time of 7.1 years, on 39 Wilms' tumor patients treated without anthracyclines with a mean follow-up time of 8.9 years, and on 50 normal subjects. Left ventricular (LV) dimensions, end systolic wall stress (a measure of afterload), and load-dependent and -independent measures of contractility were compared between groups. Potential risk factors, including age at diagnosis, follow-up duration, sex, pubertal status, cardiac irradiation, dose-intensity, and cumulative dose of anthracyclines, were studied by multivariate analysis., Results: Twenty-five percent of the anthracycline-treated group showed cardiac abnormalities. All but one of these patients had increased LV afterload. Risk factors for increased afterload were anthracycline cumulative dose (P < .05) and anthracycline dose-intensity (P < .02). Wilms' tumor patients treated without anthracyclines had thickened LV walls compared with normal subjects (P < .05)., Conclusion: Total dose and dose-intensity of anthracycline were risk factors for increased LV afterload in long-term Wilms' tumor survivors treated on standard protocols. The increase in afterload accounted for reduced LV shortening, whereas contractility was rarely abnormal. The new finding that Wilms' tumor survivors who do not receive anthracyclines have mild LV hypertrophy may provide some protection against anthracycline-induced cardiotoxic effects.

Purpose: Despite a high cure rate of approximately 85% in Wilms' tumor by multimodality therapy, to date only four drugs are known to be active against such tumors. There is a clear need for new active drugs., Patients and Methods: Thirty-one patients with relapsed or refractory Wilms' tumor from three British and 14 French centers were treated with intravenous (IV) etoposide 200 mg/m2 daily for 5 days. Original stage was I (n = 3), II (n = 7), III (n = 9), IV (n = 10), and V (n = 2). Prior chemotherapy, administered initially or at relapse, included vincristine and dactinomycin in all cases, doxorubicin or epirubicin in 30, and ifosfamide in 20. Sites of relapse or resistant disease were lung in 13, abdomen or pelvis in six, liver in one, and multiple in 11. When entered onto the study, 12 patients were in first relapse, 10 in second relapse, and four in third or more relapse. Five had never obtained a complete remission. All but two (progressing) patients received two courses of etoposide, the second course being administered at day 21., Results: A complete response (CR) was documented in two patients, partial response (PR) in 11, stable disease in 10, and progressive disease (PD) in eight. The duration of response could not be evaluated, because all responding patients were subsequently treated with multimodality therapy. The major toxicities observed were neutropenia and thrombocytopenia, but most patients had been heavily pretreated. No toxic death clearly associated with etoposide was noted., Conclusion: It is concluded that etoposide in this schedule is an active agent in Wilms' tumor and should be considered for inclusion in regimens for high-risk patients, such as those with metastatic disease at diagnosis and those who relapse after multiagent chemotherapy.

Now that most patients with Wilms' tumour are cured, it is practicable to study the long-term morbidity of their treatment and use this information to reduce treatment sequelae in the future. In this study we evaluate the size and function of the remaining kidney in 53 survivors of Wilms' tumour with a mean off treatment follow-up of 13 years. There was evidence of renal dysfunction in 17 (32%), including ten (19%) with a low GFR (< 80 ml/min/1.73 m2SA), six (11%) with hypertension and five (9%) with increased urinary albumin excretion. Measurements of renal size showed 'good' renal compensatory hypertrophy in only 55% of patients. 'Good' refers to renal size of more than 2 s.d. above the mean renal length for children with two kidneys. There were no correlations between GFR, renal size, blood pressure, microalbuminuria or type of treatment. However, children less than 24 months at diagnosis and children receiving chemotherapy with radiation doses to remaining kidney of more than 1200 cGy had a worse renal prognosis. Patients whose Wilms' tumour is diagnosed in infancy should have careful long-term follow-up of renal function and size. Older patients may safely be followed up less often, unless their remaining kidney was received > 1200 cGy.