Tanzina Chowdhury

Introduction: Nephrogenic rests (NRs) and nephroblastomatosis (NBM) are precursor lesions for development of Wilms tumor (WT). Their association with the risk of relapse has not been properly assessed, partly due to misunderstanding of their diagnostic criteria and terminology. Patients and Methods: Retrospective data analysis of patients with WT with and without associated NRs/NBM diagnosed and treated according to the International Society of Paediatric Oncology‐WT‐2001 protocol in the United Kingdom (UK) Children's Cancer and Leukaemia Group (UK‐CCLG) and Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) groups' participation in the WT trials and studies (2001–2022). Results: There were 1465 (59.5%) patients with no NRs (Group A), and 996 (40.7%) with NRs (Group B); the latter included 678 (68.1%) patients with perilobar NRs (PLNRs) (Group C), 250 (25.1%) with intralobar NRs (ILNRs) (Group D), and 68 (6.8%) with combined PL/ILNRs (Group E). There was no significant difference in relapse‐free survival (RFS) and overall survival (OS) between Groups A–D. Univariate Cox regression analyses showed no significant prognostic impact on RFS or OS of age at diagnosis (only RFS), local stage, metastatic disease, and histology and no impact on NRs. Multivariate Cox regression analysis, including age, sex, histology, local stage, metastatic disease, and NRs, showed no significant effect on either RFS or OS for Group A versus B, Group A versus C, or Group A versus D. Conclusions: The study showed that the presence of NRs/NBM in unilateral WT is of no significance for RFS and OS, and therefore, these patients should not be treated or followed up differently from patients with WT without NRs/NBM.

Contains Supplementary Figures 1-9. Supplementary Figure 1 shows age of diagnosis of children and indel burden and rearrangement burden for tumours from predisposed children versus those with sporadic disease. Supplementary Figure 2 shows genomic evidence for novel predispositions. Supplementary Figure 3 shows global methylation patterns. Supplementary Figure 4 shows differential gene expression. Supplementary Figure 5 shows mutational signatures. Supplementary Figure 6 shows histological subtypes across predispositions and across somatic drivers. Supplementary Figure 7 shows polyclonal versus clonal enrichment of 11p LOH in normal kidneys. Supplementary Figure 8 shows phylogenies in children with multiple neoplasms and either WT1 or TRIM28 predispositions. Supplementary Figure 9 shows phylogenies in children with non WT1/ non TRIM28 predispositions or sporadic disease.

Contains Supplementary Tables 1-8. Supplementary Table 1 shows characteristics of discovery cohort. Supplementary Table 2 shows genes included in predisposition analysis. Supplementary Table 3 shows evidence underlying novel predispositions. Supplementary Table 4 shows variants that would be detectable by current clinical assays. Supplementary Table 5 shows substitutions and indels. Supplementary Table 6 shows rearrangements. Supplementary Table 7 shows 10,000 most variable probes. Supplementary Table 8 shows differentially expressed genes.

BACKGROUND AND SCOPE: Historical data sources for rare cancers are valuable for data-driven research. The International Society of Pediatric Oncology Renal Tumors Study Group (SIOP-RTSG) has been conducting clinical research on pediatric renal tumors for more than 50 years. Since 1993, data have been collected across multiple countries, using standardized paper-based case report forms that were digitally transcribed into electronic databases. Until 2019, prospectively collected data are present in nine different electronic sources from three consecutive clinical studies. More than 10,000 patient cases of kidney cancer in children are registered in totality. However, the necessary merging of numerous sources to answer a research question is repetitive, time consuming, and unsustainable in the long term. SOLUTION: By mapping and formatting the structure of these nine databases, a single database was created that was similar in design to the prospective study database. This allows the data from the past and current studies to be accessed and queried efficiently with standardized syntax and reports. EVALUATION: We validated this new database by reviewing whether uploads were complete and successful, mapped items were coded correctly, or discrepancy appeared in the export. Comparisons with retrospective reports were made to ensure the datasets were reproducible. RELEVANCE: Researchers have access to a large number of patients through this validated aggregated database. Data maintenance and extraction is efficient, and it offers the possibility to complete missing data directly into the central database. This ultimately ensures long-term availability in a secure, flexible, and responsible manner, in accordance with FAIR principles. HOW TO ACCESS/USE: Researchers can send questions to SIOP-RTSG and, if necessary, gain access to the database after short training. Access granted would depend on user's role.

PURPOSE: The International Society of Paediatric Oncology–Renal Tumour Study Group (SIOP-RTSG) classifies blastemal-type Wilms tumor (WT) after preoperative chemotherapy as high-risk (HRWT). It remains unresolved whether residual absolute volume of blastema (AVB) functions as an independent prognostic factor across WT subtypes. MATERIALS AND METHODS: AVB was calculated from preoperative tumor volume, necrosis percentage, and viable blastema using prospectively collected data from 3,459 patients with unilateral WT treated in the SIOP WT 2001 study between 2001 and 2018. Martingale residual plots defined AVB thresholds discriminating survival in localized HRWT, intermediate-/low-risk WT (IRWT/LRWT), and metastatic WT (stage IV). Complete AVB data were available for 1,802 patients (51.2%); 298 (16.5%) had stage IV disease. Of 1,504 patients with localized WT, 265 (17.6%) had HRWT, 1,203 (79.9%) had IRWT, and 36 (2.4%) had LRWT. RESULTS: Multivariable Cox regression adjusted for age, sex, and local stage confirmed significantly worse survival for patients exceeding these AVB thresholds: (1) IRWT (≥20 mL): Hazard ratio for event-free survival (EFS) 2.93 (95% CI, 2.08 to 4.12) and overall survival (OS) 2.76 (95% CI, 1.32 to 5.77); (2) HRWT (≥100 mL): EFS 2.89 (95% CI, 1.59 to 5.26) and OS 3.25 (95% CI, 1.45 to 7.27); and (3) stage IV (≥10 mL): EFS 5.78 (95% CI, 3.65 to 9.17) and OS 4.59 (95% CI, 2.57 to 8.17). Patients above these thresholds had significantly lower 2-year EFS ( P < .0001). In stage II to III IRWT patients with AVB ≥20 mL, those treated with doxorubicin had superior EFS versus those without (87.6%, 95% CI, 81.5 to 94.1 v 69.2%, 95% CI, 59.8 to 80.1; P = .0064). CONCLUSION: AVB after preoperative chemotherapy is a strong, independent predictor of both EFS and OS in WT across risk groups. An AVB of ≥20 mL identifies a clinically relevant subset of patients with IRWT who may benefit from intensified therapy with doxorubicin. These findings support the use of AVB as a stratification criterion in future SIOP-RTSG protocols.

Background: The Improving Population Outcomes for Renal Tumours of childhood (IMPORT) is a prospective clinical observational study capturing detailed demographic and outcome data on children and young people diagnosed with renal tumours in the United Kingdom and the Republic of Ireland. Methods: Data were extracted from the IMPORT database for all newly diagnosed cases of Wilms tumour (WT) registered between November 2012 and December 2022. Kaplan–Meier survival was estimated at one, three and five years. For children aged 0–14 years with unilateral WT, Cox proportional hazards models were used to examine patient/tumour characteristics in relation to the excess hazard of death. Results: Among 620 patients, 570 had unilateral and 50 (8%) bilateral disease; 582 (94%) patients received pre‐operative chemotherapy and 38 (6%) immediate surgery. Median age was 41 months (IQR: 41–65). Median tumour volume at diagnosis was 595 cm ³ (IQR: 348–914) and 228 cm ³ (IQR: 83–535) after pre‐operative chemotherapy, with 123/443 (28%) ≥500 cm ³ . Of 570 patients with unilateral WT, 419 (73.5%) had localised and 151 (26.5%) metastatic disease. Five‐year survival was highest for children aged 0–4 years (94.8%). Five‐year survival by Toronto stage (assessed at nephrectomy) was 97.0% (stage I/yI), 93.8% (stage II/yII), 85.2% (stage III/yIII) and 88.9% (stage IV), and by histology 74.6% (high risk), 95.2% (intermediate risk) and 100% (low risk). In univariate analysis, histological risk group, age (</≥ 4 years), stage and tumour volume ≥500 cm ³ after pre‐operative chemotherapy were significantly associated with excess risk of death. In multivariate modelling, only high‐risk histology (HR 10.8, 95% CI: 4.0–29.1) retained significance. Conclusions: Five‐year survival for children with WT in the United Kingdom and Ireland is generally above 90%, with high‐risk histology as the most important adverse prognostic factor. However, median tumour volume at diagnosis and after pre‐operative chemotherapy remains large.

Contains Supplementary Figures 1-9. Supplementary Figure 1 shows age of diagnosis of children and indel burden and rearrangement burden for tumours from predisposed children versus those with sporadic disease. Supplementary Figure 2 shows genomic evidence for novel predispositions. Supplementary Figure 3 shows global methylation patterns. Supplementary Figure 4 shows differential gene expression. Supplementary Figure 5 shows mutational signatures. Supplementary Figure 6 shows histological subtypes across predispositions and across somatic drivers. Supplementary Figure 7 shows polyclonal versus clonal enrichment of 11p LOH in normal kidneys. Supplementary Figure 8 shows phylogenies in children with multiple neoplasms and either WT1 or TRIM28 predispositions. Supplementary Figure 9 shows phylogenies in children with non WT1/ non TRIM28 predispositions or sporadic disease.

Contains Supplementary Tables 1-8. Supplementary Table 1 shows characteristics of discovery cohort. Supplementary Table 2 shows genes included in predisposition analysis. Supplementary Table 3 shows evidence underlying novel predispositions. Supplementary Table 4 shows variants that would be detectable by current clinical assays. Supplementary Table 5 shows substitutions and indels. Supplementary Table 6 shows rearrangements. Supplementary Table 7 shows 10,000 most variable probes. Supplementary Table 8 shows differentially expressed genes.

Approximately 10% of children with cancer harbor a mutation in a predisposition gene. In children with the kidney cancer Wilms tumor, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumorigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumor, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukemias), utilizing whole-genome sequencing, RNA sequencing, and genome-wide methylation, validating our findings in an independent cohort. Tumor development differed in children harboring a predisposition, depending on the variant gene and its developmental timing. Differences pervaded the repertoire of driver events, including high-risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Our findings indicate that predisposition may preordain Wilms tumorigenesis, suggesting a variant-specific approach to managing children merits consideration. Significance: Tumors that arise in children with a cancer predisposition may develop through the same mutational pathways as sporadic tumors. We examined this question in the childhood kidney cancer, Wilms tumor. We found that certain predispositions dictate the genetic development of tumors, with clinical implications for these children. See related commentary by Brzezinski and Malkin, p. 258

Intraoperative ultrasound is described widely in multiple pathological scenarios in adult practice and in image-guided interventions in children. We aim to describe the technique and range of potential uses of intraoperative ultrasound in paediatric urological surgery, from outlining the process of case selection, preparation, and logistics to demonstrating the ranging benefits of real-time, high spatial resolution ultrasound during resection. At our centre, we use intraoperative ultrasound to assist in a variety of operations. These include guiding excision margins in nephron-sparing surgery, assessing for vascular infiltration in renal tumours, and identifying salvageable testicular tissue in orchidectomy. By exhibiting these scenarios, we hope to display the unique value that intraoperative ultrasound can have to the paediatric surgeon and inspire additional uses further afield. Graphical Abstract