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Summary 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, Societe Francaise des Cancers de l'Enfant and Association Leon Berard Enfant Cancereux and Enfant et Sante, Gesellschaft fur Padiatrische Onkologie und Hamatologie and Deutsche Krebshilfe, Grupo Cooperativo Brasileiro para o Tratamento do Tumor de Wilms and Sociedade Brasileira de Oncologia Pediatrica, the Spanish Society of Pediatric Haematology and Oncology and the Spanish Association Against Cancer, and SIOP–Netherlands.

The International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP-RTSG) has developed a new protocol for the diagnosis, treatment, and follow-up monitoring of childhood renal tumours - the UMBRELLA SIOP-RTSG 2016 protocol (the UMBRELLA protocol). This protocol has been designed to continue international collaboration in the treatment of childhood renal tumours and will be implemented in over 50 different countries. Clear cell sarcoma of the kidney, which is a rare paediatric renal tumour that most commonly occurs in children between 2 and 4 years of age, is specifically addressed in the UMBRELLA protocol.

The present study aimed to compare cancer incidence and trends in survival for children diagnosed in Japan and England, using population-based cancer registry data. The analysis was based on 5192 children with cancer (age 0-14 years) from 6 prefectural cancer registries in Japan and 21 295 children diagnosed in England during 1993-2010. Differences in incidence rates between the 2 countries were measured with Poisson regression models. Overall survival was estimated using the Kaplan-Meier method. Incidence rates for Hodgkin lymphoma, renal tumors and Ewing sarcomas in England were more than twice as high as those in Japan. Incidence of germ cell tumors, hepatic tumors, neuroblastoma and acute myeloid leukemia (AML) was higher in Japan than in England. Incidence of all cancers combined decreased in Japan throughout the period 1993 to 2010, which was mainly explained by a decrease in registration of neuroblastoma in infants. For many cancers, 5-year survival improved in both countries. The improvement in survival in chronic myeloid leukemia (CML) was particularly dramatic in both countries. However, 5-year survival remained less than 80% in 2005-2008 in both countries for AML, brain tumors, soft tissue sarcomas, malignant bone tumors and neuroblastoma (age 1-14 years). There were significant differences in incidence of several cancers between countries, suggesting variation in genetic susceptibility and possibly environmental factors. The decrease in incidence for all cancers combined in Japan was related to the cessation of the national screening program for neuroblastoma. The large improvement in survival in CML coincided with the introduction of effective therapy (imatinib).

Survival rates for patients with Wilms' tumour (WT) approximate 90% with refined use of currently available interventions. However, a subgroup of patients, with initial high-risk histopathology or relapsing disease, have a poor prognosis, and it is a challenge to identify and prioritise the development of new innovative approaches for these subgroups. We conducted a systematic literature search for published phase I and II clinical trials that registered patients with WTs and characterised the early phase trial activity, quantified response rates and highlighted avenues for further development. We identified 63 trials (48 phase I, three phase I/II, and 12 phase II trials) enrolling 214 patients with WTs, alongside other malignancies. The number of annually recruited WTs did not change significantly and was less than 20% of the potential candidates. The vast majority of the trials were conducted in North America, and 56 different interventions were investigated, including conventional chemotherapy and biologically targeted therapies. Overall, 33 WTs revealed some degree of tumour control. Of these, five patients demonstrated complete remission (2%), 15 patients partial response (7%) and 13 patients stable disease (6%). None of the included novel biologically targeted therapies emerged as promising interventions, and only conventional chemotherapy was able to induce a complete and partial response. We conclude that early phase trial recruitment of WTs is below expected levels, and the clinical outcome of the included patients is dismal. Improvement of the availability and recruitment to early phase trials for WTs, especially in Europe, is needed.

The cell-surface glycoprotein CD56 has three major isoforms that play important roles in cell adhesion and signaling, which may promote cell proliferation, differentiation, survival, or migration. It is an important molecule in normal kidney development and acts as a key marker in Wilms tumor stem and progenitor cells. Here, we review the structural and genetic features of the CD56 glycoprotein, and summarize its roles in the normal versus diseased metanephric blastema. We discuss areas of CD56-related research that may complement or improve existing Wilms tumor treatment strategies, including the antibody-drug conjugate lorvotuzumab mertansine that binds to CD56.

Wilms’ tumour 1 (WT1) is a transcription factor and a tumour suppressor, essential for the development and homeostasis of multiple tissues derived from the intermediate and lateral plate mesoderm. Germline WT1 mutations result in the eponymous paediatric kidney cancer, genitourinary anomalies and in some cases congenital diaphragmatic hernia One common feature in Wilms’ Tumours (WT), is upregulation of IGF2 through genetic and/or epigenetic mechanisms. Recent studies have identified both somatic and germline mutations in microRNA processing genes (MIRPG) in WT. Whether these different epigenetic and genetic causes converge on common targets and the mechanisms by which they act are still unclear. WT1 is involved in RNA binding and regulates the RNA stability of important developmental genes. We now show that WT1 interacts with let-7 family of microRNAs, and the absence of WT1 results in reduced levels of mature microRNA in cell lines and kidney mesenchyme. As a consequence, let-7 targets, including Igf1 receptor (Igf1r), are upregulated in the absence of Wt1, thus confirming the presence of a WT1-let7-Igf1r axis. These findings suggest a possible mechanism by which WT1 mutations lead to WT, and reinforce the idea that the perturbation of the microRNA and IGF signalling pathways are important contributing factors in the aetiology of WT.

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.

The 13th African continental meeting of the international society of paediatric oncology, held on 6-9 March 2019 in Cairo, was organised in collaboration with the Children Cancer Hospital (57357) in Egypt and the global parents' organisation (Childhood Cancer International) and supported by a large international faculty. With 629 delegates from 37 countries (24 African), this was the largest forum of healthcare professionals focused on children and young people with cancer in Africa to showcase advances and discuss further improvements. Three targeted workshops, on nursing care, pharmacy and nutrition, attracted large numbers and catalysed new collaborative initiatives in supportive care studies, extended roles for pharmacists in quality control and care delivery and addressed malnutrition concurrently with cancer treatment. The Collaborative Wilms Tumour Africa Project, open in seven sub-Saharan countries, and the trials in Burkitt's lymphoma reported encouraging outcomes with further initiatives in supportive care (the supportive care for children with cancer in Africa project). While acknowledging deficits in radiotherapy provision, available in only 23 of 52 African countries, centres with facilities reported their technical advances that benefit patients. Of great importance for children with brain tumours, who are underdiagnosed in Africa, was the first announcement of African paediatric neuro-oncology society, whose 63 current members aim to tackle the shortage of neurosurgeons through training fellowships, workshops and a dedicated conference. The congress provided the opportunity to discuss how African countries will work with the WHO global initiative aiming to improve childhood cancer survival to 60% in all countries by 2030. This conference report is dedicated to the three Kenyan delegates who died tragically on the Ethiopian Airlines flight ET302 on their way home, full of new ideas and pride in what they had achieved so far. All those who heard their presentations are determined to continue their excellent work to improve cancer care for children in Africa.

We read with interest the article by de la Monneraye et al on the experience of the Institut Curie of renal tumor biopsy in children treated according to SIOP protocols over a 22‐year period. By presenting the relative proportion of children with non‐Wilms tumors who had clinical, radiological, and biochemical features that are considered “atypical” of Wilms tumors (WT), they support a change to an evidence‐based approach to biopsy in the SIOP community. However, some of their recommendations are not adequately supported by a single institutional series, and we would like to add some reflections from our work based on the national‐ and population‐level data.

Background It is generally agreed to centralise treatment of childhood cancers (CCs). We analysed (1) the degree of centralisation of CCs in European countries and 2) the relations between centralisation and survival. Patients and methods The analysis comprised 4415 CCs, diagnosed between 2000 and 2007 and followed up to the end of 2013, from Belgium, Bulgaria, Finland, Ireland, the Netherlands and Slovenia. All these countries had national population-based cancer registries and were able to provide information on diagnosis, treatment, treatment hospitals, and survival. Each case was then classified according to whether the patient was treated in a high- or a low-volume hospital among those providing CC treatment. A Cox proportional hazard model was used to calculate the relation between volume category and five-year survival, adjusting by age, sex and diagnostic group. Results The number of hospitals providing treatment for CCs ranged from six (Slovenia) to slightly more than 40 (the Netherlands and Belgium). We identified a single higher volume hospital in Ireland and in Slovenia, treating 80% and 97% of cases, respectively, and three to five major hospitals in the other countries, treating between 65% and 93% of cases. Outcome was significantly better when primary treatment was given in high-volume hospitals compared to low-volume hospitals for central nervous system tumours (relative risk [RR] = 0.71), haematologic tumours (RR = 0.74) and for all CC combined (RR = 0.83). Conclusion Treatment centralisation is associated with survival benefits and should be further strengthened in these countries. New plans for centralisation should include ongoing evaluation.

INTRODUCTION: The International Society of Paediatric Oncology (SIOP) protocols recommend pre-operative chemotherapy appropriate for Wilms tumours (WT) in children with renal tumours aged ≥6 months, reserving biopsy for ‘atypical’ cases. The Children’s Cancer and Leukaemia Group (CCLG) joined the SIOP-WT-2001 study but continued the national practice of biopsy at presentation. METHOD: Retrospective study of concordance between locally reported renal tumour biopsies and central pathology review nephrectomy diagnoses of children enrolled by CCLG centres in SIOP-WT-2001 Study. RESULTS: Biopsy reports were available for 552/787 children with unilateral tumours. 36/552 (6.5%) were non–diagnostic: 2 normal tissue, 12 necrotic, 9 insufficient sample and 13 indeterminate results (disproportionately non-WTs). The sensitivity and specificity of biopsy to identify tumours that did not require SIOP empirical pre-operative chemotherapy were 86.0% and 99.6%, respectively. 13/548 (2.4%) biopsy results were discordant with nephrectomy; non-WTs other than renal cell carcinoma and clear cell sarcoma (CCSK) were poorly recognised. In children aged 6-119 months, 480/518 (91.6%) had WT or nephroblastomatosis. 5/518 (1%) had benign tumours, only one diagnosed on biopsy. Biopsy results correctly changed clinical management in 25/518 (4.8%), including identifying 19/20 CCSKs, but would have led to overtreatment in 5/518 (1%) or undertreatment in 4/518 (0.8%). In children aged ≥10 years, biopsy correctly changed management in 5/19 (26%) cases with no discordance. CONCLUSION: Biopsy is less effective at identifying non-WTs than WTs and rarely changes management in younger children. Biopsy should be reserved in SIOP protocols for children ≥10 years and in younger children with clinical or radiological features inconsistent with WT.

Background: To enhance risk stratification for Wilms' tumour (WT) in a pre-operative chemotherapy setting, we explored the prognostic significance and optimal age cutoffs in patients treated according to International Society of Paediatric Oncology Renal Tumour Study Group (SIOP-RTSG) protocols. Methods: Patients (6 months-18 years) with unilateral WT, treated with pre-operative chemotherapy, were selected from prospective SIOP 93-01 and 2001 studies (1993-2016). Martingale residual analysis was used to explore optimal age cutoffs. Outcome according to age was analyzed by uni- and multivariable analysis, adjusted for sex, biopsy (yes/no), stage, histological classification and tumour volume at surgery. Findings: 5631 SIOP-registered WT patients were included with a median age of 3·4 years (interquartile range, IQR: 2-5·1). Median follow-up was 6·3 years (IQR: 3·0-8·7). Estimated 5-year event-free survival (EFS) and overall survival (OS) were 85% (95%CI 83·5-85·5) and 93% (95%CI 92·0- 93·4), respectively. Martingale residual plots detected no optimal age cutoffs. Multivariable analysis showed lower EFS with increasing age (linear trend p

Rare cancers are not so rare, their incidence is increasing and, as a group, they have worse survival than the common cancers. These factors emphasise the societal need to ensure sufficient focus on research into their biological basis, aetiological factors, new more effective therapies and organisation of healthcare to improve access to best practice and innovation. Accuracy of diagnosis is one of the first hurdles to be overcome, with around one third of tumours being reclassified - by type or risk group - when subject to a centralised pathology review process. Timely access to appropriate expert knowledge is a second challenge for patients - in Europe this is being addressed by the establishment of European Reference Networks (ERNs) as part of the EU cross border healthcare initiative. There are ERNs for adult solid and haematological cancers and childhood cancers, all of which are individually rare. These ERNs will facilitate creation of large databases of rare tumours that will incorporate knowledge of their molecular features and build an evidence base for the effectiveness of innovative, biology-directed therapies. With an increasing focus on 'real world' outcome data, research methodologies are evolving, to include randomised registry trials and data linkage approaches that exploit the ever-richer information held on patients in routine health care data. The inclusion of genomic analysis into cancer diagnosis, treatment and risk prediction raises many issues for the conduct of clinical research and cohort studies and personal data sharing. Sophisticated means of pseudonymisation, together with full involvement of affected and 'at risk' patients, are supporting novel research designs and access to data that will continue to build the evidence base to improve outcomes for patients with rare cancers.

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.

Objective Oesophageal cancer patients have complex care needs. Cancer clinical nurse specialists play a key role in coordinating their care but often have heavy workloads. Digital health interventions can improve patient care but there are few examples for oesophageal cancer. This paper aims to describe the multidisciplinary co-design process of a digital health intervention to improve the experience of care and reduce unmet needs among patients with oesophageal cancer. Methods A theory-based, multi-disciplinary, co-design approach was used to inform the developmental process of the digital health intervention. Key user needs were elicited using mixed methodology from systematic reviews, focus groups and interviews and holistic need assessments. Overarching decisions were discussed among a core team of patients, carers, health care professionals including oncologists and cancer clinical nurse specialists, researchers and digital health providers. A series of workshops incorporating a summary of findings of key user needs resulted in the development of a minimum viable product. This was further refined after a pilot study based on feedback from end users. Results The final digital health intervention consists of a mobile app feature for patients and carers connected to a dashboard with supporting additional features for clinical nurse specialist. It contains a one-way messaging function for clinical nurse specialists to communicate with patients, functions for patients to record weight and holistic need assessment results which could be viewed by their clinical nurse specialists as well as a library of informative articles. Conclusions The multidisciplinary co-design of a digital health intervention providing support for oesophageal cancer patients and health care professionals has been described. Future studies to establish its impact on patient outcomes are planned.

Many patients with cancer are diagnosed through an emergency presentation, which is associated with inferior clinical and patient-reported outcomes compared with those of patients who are diagnosed electively or through screening. Reducing the proportion of patients with cancer who are diagnosed as emergencies is, therefore, desirable; however, the optimal means of achieving this aim are uncertain owing to the involvement of different tumour, patient and health-care factors, often in combination. Most relevant evidence relates to patients with colorectal or lung cancer in a few economically developed countries, and defines emergency presentations contextually (that is, whether patients presented to emergency health-care services and/or received emergency treatment shortly before their diagnosis) as opposed to clinically (whether patients presented with life-threatening manifestations of their cancer). Consistent inequalities in the risk of emergency presentations by patient characteristics and cancer type have been described, but limited evidence is available on whether, and how, such presentations can be prevented. Evidence on patients' symptoms and health-care use before presentation as an emergency is sparse. In this Review, we describe the extent, causes and implications of a diagnosis of cancer following an emergency presentation, and provide recommendations for public health and health-care interventions, and research efforts aimed at addressing this under-researched aspect of cancer diagnosis.

Despite an impressive increase in survival rate over the past decades, there is still a need to improve the survival of specific subgroups of Wilms tumor (anaplastic, metastatic, and bilateral) and to decrease the late effects of treatment in terms of renal function and heart toxicity. We aim to explore new areas of improvement, from diagnosis to treatment: in the field of radiology the increased use of MRI and exploration of its diffusion-weighted imaging capabilities to predict WT histology at diagnosis and for preoperative assessment; in biology the emergence of new biomarkers that could be integrated into the decision-making process; and surgical techniques with more accurate indication of nephron-sparing surgery that is no longer reserved for bilateral WT and the minimally invasive approach. The long-term outcome of patients with WT should thus be a strong indicator of the improvement in adapting and personalizing the treatment to each individual.

Summary Each year, approximately 1/10,000 children worldwide will be diagnosed with a renal tumour, with almost four-fold variation by ethnicity and geography. Wilms’ tumour (WT) or nephroblastoma is by far the most common subgroup, accounting for nearly 90% of renal tumours and 6% of all childhood cancers. In Europe, most cases are managed with neoadjuvant chemotherapy prior to surgery, whereas in North America, children usually undergo immediate surgery. Both groups use stage of disease and histology to risk stratify and dictate postoperative treatment. Irrespective of protocol, almost 90% of WT patients survive. For the non-WT, prognosis is more variable and treatment is usually more intensive. Improvements in risk stratification and relapse monitoring are needed, as approximately half of the 15% of children who relapse do not survive. Several molecular biomarkers with prognostic significance have been identified but most await validation prior to clinical use. As many patients experience severe acute or long-term treatment-related toxicity, a further priority is to identify children for whom a reduction in treatment would not compromise survival. Increased understanding of WT biology, and the advent of cell and animal models for drug testing, has guided development of targeted therapies. Translating these preclinical results into a clinical difference for high-risk patients is challenging, due to the small numbers of children suitable for early phase trials, the genetic heterogeneity of WT and the low prevalence of known somatic mutations. A remaining challenge is the geographical variation in survival seen both within Europe and more dramatically across other continents, such as Africa. To improve these inequalities, the current priority is to standardise diagnostics, monitoring and treatment through international collaboration in well-designed prospective clinical observational studies and trials.

Population-based cancer registries generate estimates of incidence and survival that are essential for cancer surveillance, research, and control strategies. Although data on cancer stage allow meaningful assessments of changes in cancer incidence and outcomes, stage is not recorded by most population-based cancer registries. The main method of staging adult cancers is the TNM classification. The criteria for staging paediatric cancers, however, vary by diagnosis, have evolved over time, and sometimes vary by cooperative trial group. Consistency in the collection of staging data has therefore been challenging for population-based cancer registries. We assembled key experts and stakeholders (oncologists, cancer registrars, epidemiologists) and used a modified Delphi approach to establish principles for paediatric cancer stage collection. In this Review, we make recommendations on which staging systems should be adopted by population-based cancer registries for the major childhood cancers, including adaptations for low-income countries. Wide adoption of these guidelines in registries will ease international comparative incidence and outcome studies.

Purpose Selection of the most appropriate chemotherapy dosing regimens for neonates treated within the first weeks of life represents a significant clinical dilemma. Due to a lack of information relating to the clinical pharmacology of anticancer drugs in these challenging patients, current dosing guidelines are based on limited scientific rationale. In the current study, we investigate the utilisation of therapeutic drug monitoring approaches in neonates with localised hepatoblastoma, Wilms’ tumour and stage 4S neuroblastoma, being treated with widely used anticancer drugs. Methods Plasma concentrations of cisplatin, vincristine, etoposide and carboplatin were quantified in two neonates being treated within the first 3 weeks of life and in a 32-week preterm infant treated at a gestational age of 40 weeks. Therapeutic drug monitoring was carried out where appropriate, based on the pharmacokinetic data obtained in conjunction with clinical response and toxicity. Results Treatment of a child aged 2 weeks with a recommended cisplatin dose reduction for weight to 1.8 mg/kg resulted in achievement of unbound cisplatin plasma concentrations of 0.01–0.08 µg/mL, markedly lower than exposures previously reported in infants and older children. A dose increase to 2.7 mg/kg was implemented, leading to the achievement of levels more in-line with those previously reported. This increased dose level was well tolerated over six courses of treatment, resulting in a good response to cisplatin monotherapy and the patient remains in remission at 3.5 years. In contrast, a 50 % vincristine dose reduction for weight in a 3-week-old neonate resulted in plasma concentrations comparable to levels observed in older children, leading to successful treatment and continued remission at 2 years. In a third patient, etoposide and carboplatin clearance values normalised to body weight were comparable to those reported in older children, resulting in comparatively lower exposures following reduced dosing. Conclusions The current report provides unique data on the pharmacokinetics of several widely used anticancer drugs in neonates treated within the first few weeks of life. The provision of these data acts as a useful reference point to support future dosing decisions to be made by clinicians in the treatment of these challenging patients.

Recent advances in in vitro culture technologies, such as adult stem cell-derived organoids, have opened up new avenues for the development of novel, more physiologic human cancer models. Such preclinical models are essential for efficient translation of basic cancer research into novel treatment regimens. We succeeded in growing organoids from a range of pediatric solid tumors, including Wilms’ tumors, renal cell carcinomas, and different types of rhabdoid tumors (i.e., AT/RT, MRT). Tumor organoids retain many characteristics of parental tumor tissue. For instance, Wilms’ tumor organoids retain the cellular heterogeneity of tumors, as they are composed of an intricate network of different cell types. Moreover, we demonstrate that tumor organoids are amenable to gene editing and high-throughput drug screens. In conclusion, our pediatric cancer organoids capture disease and tissue heterogeneity and provide a platform for basic cancer research, drug screening, and personalized medicine. Citation Format: Camilla Calandrini, Frans Schutgens, Rurika Oka, Thanasis Margaritis, Tito Candelli, Luka Mathijsen, Carola Ammerlaan, Ravian van Ineveld, Sepideh Derakhshan, Lars Custers, Philip Lijnzaad, Harry Begthel, Hinri Kerstens, Maarten Rookmaker, Marianne Verhaar, Patrick Kemmeren, Ronald de Krijger, Kathy Pritchard-Jones, Anne Rios, Marry van den Heuvel-Eibrink, Frank Holstege, Ruben van Boxtel, Hans Clevers, Jarno Drost. Patient-derived organoids in pediatric cancer research [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA27.

The impact of biopsying Wilms tumour (WT) at diagnosis on assigning the tumour stage and recommended treatment remains controversial. To address this important question, we analysed the potential association of all types of biopsy with local recurrence in patients treated in the SIOP WT 2001 trial, where needle biopsy was permitted without 'upstaging' the tumour to stage III. Only open biopsy required treatment as stage III.Among 2971 patients with unilateral WT (stages I-IV), 420 relapsed (139 local). Risk factors for recurrence were analysed by Cox proportional hazard methods.Biopsy was performed in 969 of 2971 (33%) patients (64% cutting needle, 30% fine needle aspiration [FNA] and 6% open biopsy). Biopsied patients were older, with larger tumours and a greater proportion with high-risk histology. In multivariate analysis that included all factors associated with local recurrence in univariate analysis, only high-risk histology (hazard ratio [HR] = 2.32; 95% confidence interval [CI]: 1.58-3.42, p=0.0001), age≥2 years (HR = 2.24; 95% CI: 1.22-4.09, p = 0.01) and preoperative tumour volume (HR = 1.07 per 100 ml; 95% CI: 1.02-1.12, p = 0.01) were significant. The HR for the association of local recurrence and event-free and overall survival with biopsy was not significant (HR = 1.4; 95% CI: 0.9-2.17, p = 0.13; HR = 1.1; 95% CI: 0.85-1.42, p = 0.46 and HR = 1.13; 95% CI: 0.79-1.62, p = 0.51, respectively). These results were not materially different whether FNA or open biopsy were included in the biopsy group or not.This post hoc analysis provides some reassurance that needle biopsy is not an independent adverse factor for either local recurrence or survival after adjustment for all relevant risk factors. Needle biopsy should not be an automatic criterion to 'upstage' WT.

Background: Stage of cancer at diagnosis is one of the strongest predictors of survival and is essential for population cancer surveillance, comparison of cancer outcomes and to guide national cancer control strategies. Our aim was to describe, for the first time, the distribution of cases by stage at diagnosis and differences in stage-specific survival on a population basis for a range of childhood solid cancers in Australia. Methods: The study cohort was drawn from the population-based Australian Childhood Cancer Registry and comprised children (

Objective: To evaluate the value of radiotherapy boost omission in patients with intermediate‐risk, stage III Wilms tumours (WT) with positive lymph nodes (LN). Methods and materials: All patients with intermediate‐risk, stage III (LN positive) WT consecutively registered in the SIOP‐WT‐2001 study were included in this analysis. Endpoints were 5‐year event‐free survival (EFS), loco‐regional control (LRC) and overall survival (OS). Results: Between June 2001 and May 2015, 2,569 patients with stage I to III WT after preoperative chemotherapy were registered in the SIOP‐WT‐2001 study. Five hundred and twenty‐three (20%) had stage III disease, of which 113 patients had stage III due to positive LN only. Of those, 101 (89%) received radiotherapy, 36 of which (36%) received, apart from flank irradiation, a boost dose to the LN positive area. Four patients (4%) did not receive any adjuvant radiotherapy. In eight patients information on radiotherapy was not available. With a median follow‐up of 71 months, no difference in 5‐year EFS (84% vs. 83%, P = 0.77) and LRC (96% vs. 97%, P = 0.91) was observed between patients receiving a radiotherapy boost and those without boost, respectively. Five‐year OS, including salvage therapy, was excellent (boost vs. no boost: 97% vs. 95%, P = 0.58). Conclusions: Outcome data demonstrate that omission of the radiotherapy boost to the loco‐regional positive lymph nodes in patients with intermediate‐risk, stage III WT who receive preoperative chemotherapy and postoperative flank irradiation (14.4 Gy) can be considered a safe approach for future SIOP protocols.

BACKGROUND: Diffuse anaplastic Wilms tumor (DAWT) is a rare, high-risk subtype that is often missed on diagnostic needle biopsy. Somatic mutations in TP53 are associated with the development of anaplasia and with poorer survival, particularly in advanced-stage disease. Early identification of DAWT harboring TP53 abnormalities could improve risk stratification of initial therapy and monitoring for recurrence. METHODS: Droplet digital polymerase chain reaction (ddPCR) was used to evaluate 21 samples from 4 patients with DAWT. For each patient, we assessed TP53 status in frozen tumor, matched germline DNA, and circulating tumor DNA (ctDNA) from plasma, serum, and urine collected throughout treatment. RESULTS: Mutant TP53 was detectable in ctDNA from plasma and serum in all patients. We did not detect variant TP53 in the same volume (200 μl) of urine. One patient displayed heterogeneity of TP53 in the tumor despite both histological sections displaying anaplasia. Concentration of ctDNA from plasma/serum taken prenephrectomy varied significantly between patients, ranging from 0.44 (0.05-0.90) to 125.25 (109.75-140.25) copies/μl. We observed variation in ctDNA throughout treatment, and in all but one patient, ctDNA levels fell significantly following nephrectomy. CONCLUSION: We demonstrate for the first time that ddPCR is an effective method for detection of mutant TP53 in ctDNA from children with DAWT even when there is intratumoral somatic heterogeneity. This should be further explored in a larger cohort of patients, as early detection of circulating variant TP53 may have significant clinical impact on future risk stratification and surveillance.

Background Centralizing specialist cancer surgery services aims to reduce variations in quality of care and improve patient outcomes, but increases travel demands on patients and families. This study aimed to evaluate preferences of patients, health professionals and members of the public for the characteristics associated with centralization. Methods A discrete‐choice experiment was conducted, using paper and electronic surveys. Participants comprised: former and current patients (at any stage of treatment) with prostate, bladder, kidney or oesophagogastric cancer who previously participated in the National Cancer Patient Experience Survey; health professionals with experience of cancer care (11 types including surgeons, nurses and oncologists); and members of the public. Choice scenarios were based on the following attributes: travel time to hospital, risk of serious complications, risk of death, annual number of operations at the centre, access to a specialist multidisciplinary team (MDT) and specialist surgeon cover after surgery. Results Responses were obtained from 444 individuals (206 patients, 111 health professionals and 127 members of the public). The response rate was 52·8 per cent for the patient sample; it was unknown for the other groups as the survey was distributed via multiple overlapping methods. Preferences were particularly influenced by risk of complications, risk of death and access to a specialist MDT. Participants were willing to travel, on average, 75 min longer in order to reduce their risk of complications by 1 per cent, and over 5 h longer to reduce risk of death by 1 per cent. Findings were similar across groups. Conclusion Respondents' preferences in this selected sample were consistent with centralization., Most favour it

The International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP-RTSG) has developed a new protocol for the diagnosis, treatment, and follow-up monitoring of childhood renal tumours - the UMBRELLA SIOP-RTSG 2016 protocol (the UMBRELLA protocol). This protocol has been designed to continue international collaboration in the treatment of childhood renal tumours and will be implemented in over 50 different countries. Clear cell sarcoma of the kidney, which is a rare paediatric renal tumour that most commonly occurs in children between 2 and 4 years of age, is specifically addressed in the UMBRELLA protocol.

Background The centralisation of specialist cancer surgical services across London Cancer and Greater Manchester Cancer, England, may significantly change how patients experience care. These centres are changing specialist surgical pathways for several cancers including prostate, bladder, kidney, and oesophago-gastric cancers, increasing the specialisation of centres and providing surgery in fewer hospitals. While there are potential benefits related to centralising services, changes of this kind are often controversial. The aim of this study was to identify factors related to the centralisation of specialist surgical services that are important to patients, carers and health care professionals. Methods This was a questionnaire-based study involving a convenience sample of patient and public involvement (PPI) and cancer health care professional (HCP) sub-groups in London and Greater Manchester (n = 186). Participants were asked to identify which of a list of factors potentially influenced by the centralisation of specialist cancer surgery were important to them and to rank these in order of importance. We ranked and shortlisted the most important factors. Results We obtained 52 responses (28% response rate). The factors across both groups rated most important were: highly trained staff; likelihood and severity of complications; waiting time for cancer surgery; and access to staff members from various disciplines with specialised skills in cancer. These factors were also ranked as being important separately by the PPI and HCP sub-groups. There was considerable heterogeneity in the relative ordering of factors within sub-groups and overall. Conclusions This study examines and ranks factors important to patients and carers, and health care professionals in order to inform the implementation of centralisation of specialist cancer surgical services. The most important factors were similar in the two stakeholder sub-groups. Planners should consider the impact of reorganising services on these factors, and disseminate this information to patients, the public and health care professionals when deciding whether or not and how to centralise specialist cancer surgical services. Electronic supplementary material The online version of this article (10.1186/s12885-018-4137-8) contains supplementary material, which is available to authorized users.

Background and purpose To describe the outcome of patients with stage III Wilms tumours (WT) treated in the UKW3 trial. Material and methods Patients with a pathologically confirmed stage III non-anaplastic WT at nephrectomy (Group A) or with an ‘inoperable’ tumour at diagnosis managed by biopsy and pre-operative chemotherapy (Actinomycin D-Vincristine-Doxorubicin) but stage I or II at subsequent nephrectomy (Group B) were included. Results The 4-year overall (OS)/event free survival (EFS) for Group A (n = 117) patients was 90%(95%CI:83–94)/81%(CI:73–87) and for Group B (n = 32) 94%(CI:77–98)/88%(CI:70–95). The 4-year OS/EFS of patients with pathological stage III WT according to whether they received flank/abdominal radiotherapy (95 patients) or not (37 patients, 22 from UKW3 pooled with 17 patients from UKW2) were 91%(CI:83–95)/82%(CI:73–89), and 84%(CI:67–92)/78%(CI:61–89), respectively. The 4-year OS/EFS for patients having one reason to be stage III versus two or three was 92%(CI:84–96)/83%(CI:73–90) and 85%(CI:70–93)/78%(CI:61–88), respectively. Conclusion Our findings question the inclusion of biopsy or pre-operative chemotherapy as sole criterion for assigning a tumour stage III. Selected patients with pathological stage III WT can survive without radiotherapy. Whilst cautious interpretation is needed due to the post hoc nature of these analyses, further biological studies may better characterise those who could benefit from reduced therapy.

Background: Currently, there are between 300,000 and 500,000 childhood cancer survivors (CCSs) in Europe. A significant proportion is at high risk, and at least 60% of them develop adverse health-related outcomes that can appear several years after treatment completion. Many survivors are unaware of their personal risk, and there seems to be a general lack of information among healthcare providers about pathophysiology and natural history of treatment-related complications. This can generate incorrect or delayed diagnosis and treatments. Method: The Survivorship Passport (SurPass) consists of electronic documents, which summarise the clinical history of the childhood or adolescent cancer survivor. It was developed by paediatric oncologists of the PanCare and SIOPE networks and IT experts of Cineca, together with parents, patients, and survivors’ organisations within the European Union–funded European Network for Cancer research in Children and Adolescents. It consists of a template of a web-based, simply written document, translatable in all European languages, to be given to each CCS. The SurPass provides a summary of each survivor's clinical history, with detailed information about the original cancer and of treatments received, together with personalised follow-up and screening recommendations based on guidelines published by the International Guidelines Harmonization Group and PanCareSurFup. Results: The SurPass data schema contains a maximum of 168 variables and uses internationally approved nomenclature, except for radiotherapy fields, where a new classification was defined by radiotherapy experts. The survivor-specific screening recommendations are mainly based on treatment received and are automatically suggested, thanks to built-in algorithms. These may be adapted and further individualised by the treating physician in case of special disease and survivor circumstances. The SurPass was tested at the Istituto Giannina Gaslini, Italy, and received positive feedback. It is now being integrated at the institutional, regional and national level. Conclusions: The SurPass is potentially an essential tool for improved and more harmonised follow-up of CCS. It also has the potential to be a useful tool for empowering CCSs to be responsible for their own well-being and preventing adverse events whenever possible. With sufficient commitment on the European level, this solution should increase the capacity to respond more effectively to the needs of European CCS.

Introduction Although prior research has demonstrated lower lung cancer survival in England than in the United States, more detailed comparisons are needed. We conducted a population-based analysis to compare diagnostic, treatment, and survival patterns. Methods Data from cancer registries and administrative databases were linked for older patients with a diagnosis of NSCLC in England and the United States (2008–2012). We compared patient and clinical characteristics, as well as the distribution of age-standardized receipt of treatment by stage. We compared relative survival overall by stage and treatment. Finally, we assessed the degree to which stage distribution and stage-specific survival contributed to survival differences. Results Among patients age 66 years or older with a diagnosis of NSCLC in England (n = 86,978) and the United States (n = 84,415), the rate of pathological confirmation was 63% in England compared with 85% in the United States (a 22.2% difference [99% confidence interval: 22.8%–21.7%]). The rate of receipt of active treatment was lower in England than in the United States (46% versus 60%, for a difference of 14.0% [99% confidence interval: 13.3%–14.7%]). In England, we identified 98 excess deaths per 1000 patients with pathologically confirmed NSCLC; these additional deaths could be partially mitigated by adjusting stage at diagnosis (reduction to 54 excess deaths) or stage-specific survival (reduction to 36 excess deaths). Conclusions Compared with patients with NSCLC in the United States, patients with NSCLC in England are less likely to present with early-stage disease and receive treatment and are more likely to die. Future work should explore whether the intensity of resources directed to diagnostic and therapeutic activity may help mitigate disparities in outcomes.

Background and Purpose: Wilms tumor (WT) is the commonest pediatric renal malignancy. A significant minority of cases have mutations in known genes or recurrent copy number aberrations, but few of these have prognostic value. We have previously observed MYCN copy number gain in WT, an aberration associated with poor outcome in several other childhood cancers. We therefore set out to assess the prognostic significance of MYCN gain in a large WT series, and to explore other mechanisms by which the function of this gene may be dysregulated. Methods: MYCN copy number was measured in 293 tumours by Multiplex ligation-dependent probe amplification. Whole exome sequencing (Agilent SureSelect V4+UTR/Illumina HiSeq) was carried out on 51 WT tumour/germline pairs. Sanger sequencing was used to confirm variants of interest and to assess an independent panel of 168 WTs. 65 WTs were profiled on Affymetrix SNP arrays (250K Nsp or SNP 6.0), Illumina HumanMethylation450 arrays, and Illumina HumanHT-12 expression arrays, and additional selected tumors on Illumina HumanCytoSNP-12 arrays. Results: MYCN gain is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. A somatic p.P44L (c.131C>t) mutation was detected in 3/45 exomes that gave informative data at this position, and in 5/168 additional tumors screened for this variant, an overall frequency of 3.8%. MYCN overexpression in high risk tumors was associated with hypomethylation at specific loci. We observed parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumors of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolved over time. In a second bilateral case, we detected MYCN gain as a germline aberration. Conclusions: MYCN gain is associated with poor outcome and anaplastic histology in WT. MYCN also appears to be disrupted by other mechanisms in WT, including DNA hypomethylation and a recurrent potential gain of function mutation, P44L. The discovery of a germline aberration suggests that MYCN dysregulation may contribute to tumor predisposition. Citation Format: Richard D. Williams, Tasnim Chagtai, Marisa Alcaide-German, John Apps, Jenny Wegert, Sergey Popov, Gordan Vujanic, Harm van Tinteren, Marry M. van den Heuvel-Eibrink, Marcel Kool, David Gisselsson, Norbert Graf, Manfred Gessler, Kathy Pritchard-Jones. Multiple mechanisms of MYCN dysregulation in Wilms tumor. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-59.

Background and Purpose: Treatment of Wilms tumor (WT) patients under International Society of Paediatric Oncology (SIOP) protocols is currently stratified by staging and histopathology at nephrectomy after neoadjuvant chemotherapy. However, most relapses occur in cases without specific histopathological risk factors, and there is a clinical need for better prognostic biomarkers. Combined loss of heterozygosity (LOH) of 1p and 16q has recently been introduced in the US as an adverse prognostic indicator, while previous work in our and other laboratories suggests that 1q gain may have a similar association with poor outcome. To examine the clinical significance of 1q gain and assess its potential as a WT biomarker, we developed a simple, effective assay that measures its genomic copy number together with that of several other loci of interest, and applied it to a large tumor series. Methods: 686 frozen tumor samples from the SIOP WT 2001 trial (from a total of 7 countries) were assayed using a rapid multiplex ligation-dependent probe amplification (MLPA) assay that was developed and optimized in association with MRC-Holland b.v. to assess the copy number status of 1p, 1q, 16q, WT1, WTX, TP53, MYCN and FBXW7. Analyses were conducted in 3 laboratories, with exchange of a blinded quality assurance sample set. Results: 1q gain was present in 28% (190/686) of the cases. The 5- year Event Free Survival (EFS) rate was 72.6% (95% Confidence Interval (CI), 66.3%-85%) for those with 1q gain and 86.4% (95% CI, 83.4%-89.6%) for those who lacked 1q gain (p= Conclusion: Gain of 1q is a potential adverse biomarker for WT. Its association with high risk histological features after pre-operative chemotherapy and independent impact on survival require assessment in a larger number of patients before consideration for clinical use. Citation Format: Tasnim Chagtai, Christina Zill, Linda Dainese, Jenny Wegert, Mariana Maschietto, Gordan Vujanic, Neil Sebire, Ivo Leuschner, Peter Ambros, Maureen O'Sullivan, Christophe Bergeron, David Gisselsson, Marcel Kool, Marry van den Heuvel-Eibrink, Norbert Graf, Harm van Tinteren, Aurore Coulomb, Manfred Gessler, Richard Williams, Kathy Pritchard-Jones. Prognostic significance of copy number aberrations in Wilms tumor. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-67.

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.

Clinical trials in Wilms tumor (WT) have resulted in overall survival rates of greater than 90%. This achievement is especially remarkable because improvements in disease-specific survival have occurred concurrently with a reduction of therapy for large patient subgroups. However, the outcomes for certain patient subgroups, including those with unfavorable histologic and molecular features, bilateral disease, and recurrent disease, remain well below the benchmark survival rate of 90%. Therapy for WT has been advanced in part by an increasingly complex risk-stratification system based on patient age; tumor stage, histology, and volume; response to chemotherapy; and loss of heterozygosity at chromosomes 1p and 16q. A consequence of this system has been the apportionment of patients into such small subgroups that only collaboration between large international WT study groups will support clinical trials that are sufficiently powered to answer challenging questions that move the field forward. This article gives an overview of the Children's Oncology Group and International Society of Pediatric Oncology approaches to WT and focuses on four subgroups (stage IV, initially inoperable, bilateral, and relapsed WT) for which international collaboration is pressing. In addition, biologic insights resulting from collaborative laboratory research are discussed. A coordinated expansion of international collaboration in both clinical trials and laboratory science will provide real opportunity to improve the treatment and outcomes for children with renal tumors on a global level.

Wilms' tumours (WTs) are large heterogeneous tumours, which typically consist of a mixture of histological cell types, together with regions of chemotherapy-induced regressive change and necrosis. The predominant cell type in a WT is assessed histologically following nephrectomy, and used to assess the tumour subtype and potential risk. The purpose of this study was to develop a mathematical model to identify subregions within WTs with distinct cellular environments in vivo, determined using apparent diffusion coefficient (ADC) values from diffusion-weighted imaging (DWI). We recorded the WT subtype from the histopathology of 32 tumours resected in patients who received DWI prior to surgery after pre-operative chemotherapy had been administered. In 23 of these tumours, DWI data were also available prior to chemotherapy. Histograms of ADC values were analysed using a multi-Gaussian model fitting procedure, which identified 'subpopulations' with distinct cellular environments within the tumour volume. The mean and lower quartile ADC values of the predominant viable tissue subpopulation (ADC1MEAN , ADC1LQ ), together with the same parameters from the entire tumour volume (ADC0MEAN , ADC0LQ ), were tested as predictors of WT subtype. ADC1LQ from the multi-Gaussian model was the most effective parameter for the stratification of WT subtype, with significantly lower values observed in high-risk blastemal-type WTs compared with intermediate-risk stromal, regressive and mixed-type WTs (p

Wilms’ tumor, or nephroblastoma, is the most common pediatric renal cancer. The tumors morphologically resemble embryonic kidneys with a disrupted architecture and are associated with undifferentiated metanephric precursors. Here, we discuss genetic and epigenetic findings in Wilms’ tumor in the context of renal development. Many of the genes implicated in Wilms’ tumorigenesis are involved in the control of nephron progenitors or the microRNA (miRNA) processing pathway. Whereas the first group of genes has been extensively studied in normal development, the second finding suggests important roles for miRNAs in general—and specific miRNAs in particular—in normal kidney development that still await further analysis. The recent identification of Wilms’ tumor cancer stem cells could provide a framework to integrate these pathways and translate them into new or improved therapeutic interventions.

SummaryBlastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find therapeutic leads for this subgroup, we analyzed 58 blastemal type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large replication cohort. Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (18.2% of blastemal cases); mutations in DICER1 and DIS3L2; and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations strongly altered miRNA expression patterns in tumors, which was functionally validated in cell lines expressing mutant DROSHA.

Background Topotecan has been variably incorporated in the treatment of patients with relapsed Wilms tumour (WT) who failed initial treatment with three or more effective drugs. Our objective was to describe outcome and to retrospectively investigate the potential role of topotecan in relapsed WT patients. Methods Children who were treated with topotecan as part of their chemotherapeutic regimens for relapsed WT were identified and included in our retrospective study. Patient charts were reviewed for general patient characteristics, histology and stage at initial diagnosis, number and type of relapse, salvage treatment schedules, toxicity, response to treatment and outcome. Results From 2000 to 2012, 30 children (median age at relapse 5.5 years, range 1.6–14.5 years) were identified to have received topotecan as part of their salvage regimens (primary progressive disease n = 3, first, second and third relapse n = 13, 9 and 2 respectively, partial response n = 3). Topotecan was administered as a single agent (12 patients) or in combination with other drugs (18 patients). Sixteen patients had high-risk histology according to the SIOP classification, 15 died within 12 months because of progressive disease. Fourteen patients had SIOP intermediate-risk histology of which four patients displayed objective responses to topotecan. Overall, 6 out of 14 intermediate-risk patients survived (median follow up of 6 years), however, three of whom (stage V) had bilateral nephrectomy after topotecan treatment. Conclusions Topotecan does not seem to show effectiveness in the treatment of relapsed WT patients with initial high-risk histology. In patients with intermediate-risk histology, the role of topotecan might deserve further attention, to prove its efficacy.

While irinotecan has been studied in various pediatric solid tumors, its potential role in Wilms tumor (WT) is less clear. We evaluated response and outcome of irinotecan-containing regimens in relapsed WT and compared our results to the available literature. Among 14 evaluable patients, one complete response (CR) and two partial responses (PRs) were observed in patients with initial intermediate-risk (CR and PR) and blastemal-type histologies (PR). Two patients were alive at last follow-up showing no evidence of disease. Our results and the reviewed literature suggest some effectiveness of irinotecan in the setting of relapsed WT.

BACKGROUND: Nephrogenic rests (NRs) are abnormally persistent foci of embryonal cells, thought to be the precursor lesion of Wilms tumors (WTs). To date, their presence has not been systematically examined in WTs treated with preoperative chemotherapy. METHODS: A systematic analysis of the data on NRs in WTs treated with preoperative chemotherapy obtained from the UK cohort of the International Society of Pediatric Oncology (SIOP) WT 2001 Trial. The study was based on central pathology review of full sets of slides from pathological specimens, with a median of 28 slides reviewed per case. RESULTS: NRs were identified in 40% of unilateral WTs, including 25% perilobar nephrogenic rest (PLNR), 9% intralobar nephrogenic rest (ILNR), 5% both PLNR and ILNR, and 1% nephroblastomatosis, and in 93% of cases with bilateral lesions. ILNRs were associated with stromal histology and a younger age at diagnosis and found frequently in patients with congenital anomalies associated with WT1 mutation. PLNRs were found frequently in patients with overgrowth syndromes. CONCLUSIONS: The prevalence of NRs in WTs after preoperative chemotherapy observed in SIOP UK WT 2001 Trial is similar to the previously published data on NRs not treated with preoperative chemotherapy. Their epidemiology supports at least two pathways to Wilms tumorigenesis.

To evaluate whether progress continues in identifying more effective treatments for children and adolescents with cancer, the authors examined both overall and disease-specific childhood cancer mortality rates for the United States, focusing on data from 2000 to 2010.Age-adjusted US mortality trends from 1975 to 2010 were estimated using joinpoint regression analysis. Analyses of annual percentage change (APC) were performed on the same diagnostic groupings for the period restricted to 2000 through 2010 for groupings ages20 years,15 years, and 15 to 19 years.After a plateau in mortality rates during 1998 to 2002 (APC, 0.3%), the annual decline in childhood cancer mortality from 2002 to 2010 (APC, -2.4%) was similar to that observed from 1975 to 1998 (APC, -2.7%). Statistically significant declines in mortality rates from 2000 to 2010 were noted for acute lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, neuroblastoma, central nervous system cancers, and gonadal cancers. From 2000 to 2010, the rates of decline in mortality for the group ages 15 to 19 years generally were equal to or greater than the rates of decline for the group ages birth to 14 years. Improvements in treatment since 1975 resulted45,000 cancer deaths averted through 2010.Cancer mortality for both children and adolescents declined from 2000 to 2010, with significant declines observed for multiple cancer types. However, greater than 1900 cancer deaths still occur each year among children and adolescents in the United States, and many survivors experience long-term effects that limit their quality of life. Continued research directed toward identifying more effective treatments that produce fewer long-term sequelae is critical to address these remaining challenges.

Background: Clear cell sarcoma of the kidney (CCSK) is an uncommon paediatric renal tumour. Relapses occur in about 15% of the patients. Since detailed clinical information on relapsed CCSK is scarce, the current study aims to describe outcome of patients with relapsed CCSK treated according to recent European protocols. Patients and methods: We analysed prospectively collected data of all CCSK patients who developed a relapse after complete remission at the end of primary treatment, entered onto SIOP and AIEOP trials between 1992 and 2012. Results: Thirty-seven of 237 CCSK patients (16%) treated according to SIOP and AIEOP protocols developed a relapse. Median time from initial diagnosis to relapse was 17 months (range, 5.5 months - 6.6 years). Thirt-five out of thirty-seven relapses (95%) were metastatic; the most common sites of relapse were the brain (n=13), lungs (n=7) and bone (n=5). Relapse treatment consisted of chemotherapy (n=30), surgery (n=19) and/or radiotherapy (n=18), followed by high-dose chemotherapy and autologous bone marrow transplantation (ABMT) in 14 patients. Twenty-two out of thirty-seven patients (59%) achieved a second complete remission (CR); 15 of whom (68%) developed a second relapse. Five-year event-free survival (EFS) after relapse was 18% (95% CI: 4%–32%), and 5-year overall survival (OS) was 26% (95% CI: 10%–42%). Conclusions: In this largest series of relapsed CCSK patients ever described, overall outcome is poor. Most relapses are metastatic and brain relapses are more common than previously recognised. Intensive treatment aiming for local control, followed by high dose chemotherapy and ABMT, seems to be of benefit to enhance survival. Novel development of targeted therapy is urgently required.

The >90% rates of overall survival for children with Wilms tumour are remarkable and have been achieved at the same time as reducing treatment for most patients. However, beneath this headline figure, 20% of patients still relapse after first-line therapy and up to 25% of survivors report severe late effects. The aim of the SIOP-RTSG is to improve outcomes and to reduce acute and late treatment toxic effects in all children

In the version of this article initially published online it was not open access, this has now been corrected.