Multimodality detection of tumour rupture in children with Wilms tumour.

BACKGROUND AND AIMS: Tumour rupture (TR) signifies stage III disease and requires treatment intensification, which includes radiotherapy. We studied the associations between radiological, surgical and pathology TR in children with Wilms tumour (WT) in a United Kingdom multicentre clinical study. PATIENTS AND METHODS: The IMPORT (Improving Population Outcomes for Renal Tumours of Childhood) study registered 712 patients between 2012 and 2021. Children with TR on central radiology review (CRR) at diagnosis and/or indication of preoperative TR on surgical forms were included. Correlation between radiology/surgery/pathology findings was made. RESULTS: Total 141 patients had TR identified (69 on CRR, 43 on surgical form and 29 on both), and 124/141 had images available for CRR, and 98/124 had features suggestive of TR on diagnostic CRR (63 magnetic resonance imaging/35 computed tomography). TR was limited to the renal fossa in 47/98 (48%) and intraperitoneal in 51/98 (52%). Three of 98(3%) had upfront surgery, and 87/95 (92%) had TR confirmed on post-chemotherapy preoperative scans. Among 80/98 (82%) cases with TR on CRR and available surgical forms, TR was not confirmed on surgery or pathology in 38/80, giving a false-positive rate of 48%. Preoperative TR was indicated on 72 surgical forms, with images available for CRR in 55. Twenty-six of 55 (47%) were false-negative for TR on CRR and of those 10/26 (38%) had TR confirmed on pathology. CONCLUSIONS: Radiology alone should not be used to define TR, as it does not accurately correlate with surgical or pathology findings, and therefore cannot be relied upon for definitive staging and treatment. A multidisciplinary team should take the decision regarding the final abdominal stage and treatment using a multimodality approach considering clinical, radiological, surgical and pathological findings.

Targeted therapies in children with renal cell carcinoma (RCC): An International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG)-related retrospective descriptive study.

INTRODUCTION: Introduction: Renal cell carcinoma (RCC) is a very rare pediatric renal tumor. Robust evidence to guide treatment is lacking and knowledge on targeted therapies and immunotherapy is mainly based on adult studies. Currently, the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG) 2016 UMBRELLA protocol recommends sunitinib for metastatic or unresectable RCC. METHODS: This retrospective study describes the effects of tyrosine kinase inhibitors (TKI), anti-programmed cell death 1 (PD-(L)1) monoclonal antibodies, and immunotherapeutic regimens in advanced-stage and relapsed pediatric RCC. RESULTS: Of the 31 identified patients (0-18 years) with histologically proven RCC, 3/31 presented with TNM stage I/II, 8/31 with TNM stage III, and 20/31 with TNM stage IV at diagnosis. The majority were diagnosed with translocation type RCC (MiT-RCC) (21/31) and the remaining patients mainly presented with papillary or clear-cell RCC. Treatment in a neoadjuvant or adjuvant setting, or upon relapse or progression, included mono- or combination therapy with a large variety of drugs, illustrating center specific choices in most patients. Sunitinib was often administered as first choice and predominantly resulted in stable disease (53%). Other frequently used drugs included axitinib, cabozantinib, sorafenib, and nivolumab; however, no treatment seemed more promising than sunitinib. Overall, 15/31 patients died of disease, 12/31 are alive with active disease, and only four patients had a complete response. The sample size and heterogeneity of this cohort only allowed descriptive statistical analysis. CONCLUSION: This study provides an overview of a unique series of clinical and treatment characteristics of pediatric patients with RCC treated with targeted therapies.

Performing [18F]MFBG Long-Axial-Field-of-View PET/CT Without Sedation or General Anesthesia for Imaging of Children with Neuroblastoma.

Meta-[123I]iodobenzylguanidine ([123I]MIBG) scintigraphy with SPECT/CT is the standard of care for diagnosing and monitoring neuroblastoma. Replacing [123I]MIBG with the new PET tracer meta-[18F]fluorobenzylguanidine ([18F]MFBG) and further improving sensitivity and reducing noise in a new long-axial-field-of-view (LAFOV) PET/CT scanner enable increased image quality and a faster acquisition time, allowing examinations to be performed without sedation or general anesthesia (GA). Focusing on feasibility, we present our first experience with [18F]MFBG LAFOV PET/CT and compare it with [123I]MIBG scintigraphy plus SPECT/CT for imaging in neuroblastoma in children. Methods: A pilot of our prospective, single-center study recruited children with neuroblastoma who were referred for [123I]MIBG scintigraphy with SPECT/CT. Within 1 wk of [123I]MIBG scintigraphy and SPECT/low-dose CT, [18F]MFBG LAFOV PET/ultra-low-dose CT was performed 1 h after injection (1.5-3 MBq/kg) without sedation or GA, in contrast to the 24-h postinjection interval needed for scanning with [123I]MIBG, the 2- to 2.5-h acquisition time, and the GA often needed in children less than 6 y old. Based on the spirocyclic iodonium-ylide precursor, [18F]MFBG was produced in a fully automated good manufacturing practice-compliant procedure. We present the feasibility of the study. Results: In the first paired scans of the first 10 children included (5 at diagnosis, 2 during treatment, 2 during surveillance, and 1 at relapse), [18F]MFBG PET/CT scan showed a higher number of radiotracer-avid lesions in 80% of the cases and an equal number of lesions in 20% of the cases. The SIOPEN score was higher in 50% of the cases, and the Curie score was higher in 70% of the cases. In particular, intraspinal, retroperitoneal lymph node, and bone marrow involvement was diagnosed with much higher precision. None of the children (median age, 1.6 y; range, 0.1-7.9 y) had sedation or GA during the PET procedure, whereas 80% had GA during [123I]MIBG scintigraphy with SPECT/CT. A PET acquisition time of only 2 min without motion artifacts was the data requirement of the 10-min acquisition time for reconstruction to provide a clinically useful image. Conclusion: This pilot study demonstrates the feasibility of performing [18F]MFBG LAFOV PET/CT for imaging of neuroblastoma. Further, an increased number of radiotracer-avid lesions, an increased SIOPEN score, and an increased Curie score were seen on [18F]MFBG LAFOV PET/CT compared with [123I]MIBG scintigraphy with SPECT/CT, and GA and sedation was avoided in all patients. Thus, with a 1-d protocol, a significantly shorter scan time, a higher sensitivity, and the avoidance of GA and sedation, [18F]MFBG LAFOV PET/CT shows promise for future staging and response assessment and may also have a clinical impact on therapeutic decision-making for children with neuroblastoma.

Bevacizumab-containing treatment for relapsed or refractory Wilms tumor.

INTRODUCTION: Angiogenesis is critical for tumor growth and metastasis. Bevacizumab is an antiangiogenic drug used to treat various adult and childhood solid tumors. Its potential efficacy in Wilms tumor (WT) with poor prognosis is not established. AREAS COVERED: The response to bevacizumab-containing regimens in relapsed or refractory WT was reviewed in available literature. Searches were conducted using PubMed, Scopus, and ClinicalTrials.gov databases. Eight papers were identified, published between 2007 and 2020, including six treatment regimens, predominantly vincristine, irinotecan, and bevacizumab (VIB) ± temozolomide (VITB). Among 16 evaluable patients, there were two complete responses, seven partial responses, five patients achieved stable disease (SD), and two patients had progressive disease. Objective responses (OR) were observed in 56% of all cases. OR or SD was observed in 89% (8/9) patients who received VIB/VITB. Bevacizumab was generally well tolerated. Related toxicities included hypertension, proteinuria, and delayed wound healing. EXPERT OPINION: This review suggests potential effectiveness and good tolerability of bevacizumab in the setting of relapsed/refractory WT when used in combination with other drugs. Such combination therapies may serve as a bridging treatment option to other interventions and more personalized treatment options in the future; however, focused trials are needed to obtain additional evidence.

Epidemiological Study of Malignant Paediatric Liver Tumours in Denmark 1985-2020.

BACKGROUND: Malignant liver tumours in children are rare and national outcomes for this tumour entity are rarely published. This study mapped paediatric liver tumours in Denmark over 35 years and reported on the incidence, outcomes and long-term adverse events. METHODS: We identified all liver tumours from the Danish Childhood Cancer Registry and reviewed the case records for patient and tumour characteristics, treatment and clinical outcome. RESULTS: We included 79 patients in the analyses. Overall crude incidence was ~2.29 per 1 million children (<15 yr) per year, with 61 hepatoblastomas (HB), 9 hepatocellular carcinomas and 9 other hepatic tumours. Overall 5-year survival was 84%, 78% and 44%, respectively. Nine patients had underlying liver disease or predisposition syndrome. Seventeen children underwent liver transplantation, with two late complications, biliary stenosis and liver fibrosis. For HB, age ≥ 8 years and diagnosis prior to 2000 were significant predictors of a poorer outcome. Adverse events included reduced renal function in 10%, reduced cardiac function in 6% and impaired hearing function in 60% (19% needed hearing aids). Behavioural conditions requiring additional support in school were registered in 10 children. CONCLUSIONS: In Denmark, incidences of malignant liver tumours during the last four decades have been increasing, as reported in the literature. HB survival has improved since the year 2000 and is comparable with international results. Reduced hearing is the major treatment-related side effect and affects approximately 60% of patients.

Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort.

BACKGROUND: Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse. METHODS: We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes. RESULTS: Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1 and REST). Only one patient had a family history of WT (3 cases), segregating with the REST variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1, FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01). CONCLUSION: We find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.

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

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

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

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

Home-Based Specialized Pediatric Palliative Care: A Systematic Review and Meta-Analysis.

CONTEXT: Although specialized pediatric palliative care (SPPC) teams increasingly provide home-based care, the evidence of its impact has not yet been systematically evaluated. OBJECTIVES: To examine the impact of home-based SPPC in children and adolescents with life-limiting conditions, regarding place of death, quality of life and symptom burden. METHODS: We searched Medline, EMBASE, CINAHL, PsycINFO, the Cochrane Central Register of Controlled Trials, Web of Science and Scopus for studies comparing children and adolescents with life-limiting conditions receiving home-based SPPC with children and adolescents not receiving home-based SPPC, or studies reporting before-and-after measurements. We included studies that reported on place of death, quality of life and/or symptoms. Two authors independently screened the articles, extracted data, and assessed quality. Results were synthesized as a systematic narrative synthesis and meta-analysis, using a random-effects model. RESULTS: We included five studies, which reported on 392 children and adolescents. Meta-analysis showed that receiving home-based SPPC was associated with a more than fourfold increased likelihood of home death (risk ratio 4.64, 95% confidence interval 3.06-7.04; 3 studies; n=296). Most studies reported improved quality of life and reduced symptom burden. The included studies were of low to moderate quality with a high risk of bias. CONCLUSION: This systematic review suggests that home-based SPPC is associated with increased likelihood of home death, and might be associated with improved quality of life and reduced symptom burden. The small number of studies and an overall high risk of bias, however, makes the overall strength of evidence low.

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study.

Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for ∼80% of genetic driver alterations in neoplastic LCH cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)-risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of single-system (SS)-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival in the overall cohort, neither BRAF nor MAP2K1 mutations associated with event-free survival when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH but also question the independent prognostic value of lesional BRAFV600E status.

Risk factors for neonatal sepsis in Sub-Saharan Africa: a systematic review with meta-analysis.

OBJECTIVES: To identify the risk factors for neonatal sepsis in Sub-Saharan Africa. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, Web of Science, African Index Medicus and ClinicalTrials.gov were searched for observational studies from January 2010 to August 2020. SETTING: Sub-Saharan Africa, at all levels of healthcare facilities. PARTICIPANTS: 'Neonates' (<28 days of age) at risk of developing either clinical and/or laboratory-dependent diagnosis of sepsis. OUTCOME MEASURES: Identification of any risk factors for neonatal sepsis. RESULTS: A total of 36 studies with 23 605 patients from secondary or tertiary level of care facilities in 10 countries were included. Six studies were rated as good quality, 8 as fair and 22 as poor. Four studies were omitted in the meta-analysis due to insufficient data. The significant risk factors were resuscitation (OR 2.70, 95% CI 1.36 to 5.35), low birth weight <1.5 kg (OR 3.37, 95% CI 1.59 to 7.13) and 1.5-2.5 kg (OR 1.36, 95% CI 1.01 to 1.83), low Apgar score at the first minute (OR 3.69, 95% CI 2.34 to 5.81) and fifth minute (OR 2.55, 95% CI 1.46 to 4.45), prematurity <37 weeks (OR 1.91, 95% CI 1.27 to 2.86), no crying at birth (OR 3.49, 95% CI 1.42 to 8.55), male sex (OR 1.30, 95% CI 1.01 to 1.67), prolonged labour (OR 1.57, 95% CI 1.08 to 2.27), premature rupture of membranes (OR 2.15, 95% CI 1.34 to 3.47), multiple digital vaginal examinations (OR 2.22, 95% CI 1.27 to 3.89), meconium-stained amniotic fluid (OR 2.72, 95% CI 1.58 to 4.69), intrapartum maternal fever (OR 2.28, 95% CI 1.18 to 4.39), foul-smelling vaginal discharge (OR 3.31, 95% CI 2.16 to 5.09) and low socioeconomic status (OR 1.93, 95% CI 1.11 to 3.35). We found considerable heterogeneity in the meta-analysis of 11 out of 15 identified risk factors. CONCLUSION: Multiple risk factors for neonatal sepsis in Sub-Saharan Africa were identified. We revealed risk factors not listed by the WHO guidelines. The included studies overall had high risk of bias and high heterogeneity and thus, additional research of high quality is needed. PROSPERO REGISTRATION NUMBER: CRD42020191067.

The clinical impact of observer variability in lung nodule classification in children with Wilms tumour.

OBJECTIVES: To investigate the extent to which observer variability of computed tomography (CT) lung nodule assessment may affect clinical treatment stratification in Wilms tumour (WT) patients, according to the recent Société Internationale d'Oncologie Pédiatrique Renal Tumour Study Group (SIOP-RTSG) UMBRELLA protocol. METHODS: I: CT thoraces of children with WT submitted for central review were used to estimate size distribution of lung metastases. II: Scans were selected for blinded review by five radiologists to determine intra- and inter-observer variability. They assessed identical scans on two occasions 6 months apart. III: Monte Carlo simulation (MCMC) was used to predict the clinical impact of observer variation when applying the UMBRELLA protocol size criteria. RESULTS: Lung nodules were found in 84 out of 360 (23%) children with WT. For 21 identified lung nodules, inter-observer limits of agreement (LOA) for the five readers were ±2.4 and ±1.4 mm (AP diameter), ±1.9 and ±1.8 mm (TS diameter) and ±2.0 and ±2.4 mm (LS diameter) at assessments 1 and 2. Intra-observer LOA across the three dimensions were ±1.5, ±2.2, ±3.5, ±3.1 and ±2.6 mm (readers 1-5). MCMC demonstrated that 17% of the patients with a 'true' nodule size of ≥3 mm will be scored as <3 mm, and 21% of the patients with a 'true' nodule size of <3 mm will be scored as being ≥3 mm. CONCLUSION: A significant intra-inter observer variation was found when measuring lung nodules on CT for patients with WT. This may have significant implications on treatment stratification, and thereby outcome, when applying a threshold of ≥3 mm for a lung nodule to dictate metastatic status.

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

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

A Phase II Trial of a Personalized, Dose-Intense Administration Schedule of 177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-Risk Neuroblastoma-LuDO-N.

Background: Half the children with high-risk neuroblastoma die with widespread metastases. Molecular radiotherapy is an attractive systemic treatment for this relatively radiosensitive tumor. 131I-mIBG is the most widely used form in current use, but is not universally effective. Clinical trials of 177Lutetium DOTATATE have so far had disappointing results, possibly because the administered activity was too low, and the courses were spread over too long a period of time, for a rapidly proliferating tumor. We have devised an alternative administration schedule to overcome these limitations. This involves two high-activity administrations of single agent 177Lu-DOTATATE given 2 weeks apart, prescribed as a personalized whole body radiation absorbed dose, rather than a fixed administered activity. "A phase II trial of 177Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma - LuDO-N" (EudraCT No: 2020-004445-36, ClinicalTrials.gov Identifier: NCT04903899) evaluates this new dosing schedule. Methods: The LuDO-N trial is a phase II, open label, multi-center, single arm, two stage design clinical trial. Children aged 18 months to 18 years are eligible. The trial is conducted by the Nordic Society for Pediatric Hematology and Oncology (NOPHO) and it has been endorsed by SIOPEN (https://www.siopen.net). The Karolinska University Hospital, is the sponsor of the LuDO-N trial, which is conducted in collaboration with Advanced Accelerator Applications, a Novartis company. All Scandinavian countries, Lithuania and the Netherlands participate in the trial and the UK has voiced an interest in joining in 2022. Results: The pediatric use of the Investigational Medicinal Product (IMP) 177Lu-DOTATATE, as well as non-IMPs SomaKit TOC® (68Ga-DOTATOC) and LysaKare® amino acid solution for renal protection, have been approved for pediatric use, within the LuDO-N Trial by the European Medicines Agency (EMA). The trial is currently recruiting. Recruitment is estimated to be finalized within 3-5 years. Discussion: In this paper we present the protocol of the LuDO-N Trial. The rationale and design of the trial are discussed in relation to other ongoing, or planned trials with similar objectives. Further, we discuss the rapid development of targeted radiopharmaceutical therapy and the future perspectives for developing novel therapies for high-risk neuroblastoma and other pediatric solid tumors.

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

PURPOSE: Society of International Pediatric Oncology - Renal Tumor Study Group (SIOP-RTSG) treatment recommendations for relapsed Wilms tumour (WT) are stratified by the intensity of first-line treatment. To explore the evidence for the treatment of patients relapsing after vincristine and actinomycin-D (VA) treatment for primary WT, we retrospectively evaluated rescue treatment and survival of this patient group. PATIENTS AND METHODS: We included 109 patients with relapse after VA therapy (no radiotherapy) for stage I-II primary low- or intermediate-risk WT from the SIOP 93-01 and SIOP 2001 studies. Univariate Cox regression analysis was performed to study the effect of relapse treatment intensity on event-free survival (EFS) and overall survival (OS). Relapse treatment intensity was classified into vincristine, actinomycin-D, and either doxorubicin or epirubicin (VAD), and more intensive therapies (ifosfamide/carboplatin/etoposide [ICE]/≥ 4 drugs/high-dose chemotherapy with haematopoietic stem cell transplantation [HD HSCT]). RESULTS: Relapse treatment regimens included either VAD, or cyclophosphamide/carboplatin/etoposide/doxorubicin (CyCED), or ICE backbones. Radiotherapy was administered in 62 patients and HD HSCT in 15 patients. Overall, 5-year EFS and OS after relapse were 72.3% (95% confidence interval [CI]: 64.0-81.6%) and 79.3% (95% CI: 71.5-88.0%), respectively. Patients treated with VAD did not fare worse when compared with patients treated with more intensive therapies (hazard ratio EFS: 0.611 [95% CI: 0.228-1.638] [p-value = 0.327] and hazard ratio OS: 0.438 [95% CI: 0.126-1.700] [p-value = 0.193]). CONCLUSION: Patients with relapsed WT after initial VA-only treatment showed no inferior EFS and OS when treated with VAD regimens compared with more intensive rescue regimens. A subset of patients relapsing after VA may benefit from less intensive rescue treatment than ICE/CyCED-based regimens and deserve to be pinpointed by identifying additional (molecular) prognostic factors in future studies.

Background sensitivity to chemotherapy-induced nausea and vomiting and response to antiemetics in paediatric patients: a genetic association study.

Chemotherapy-induced nausea and vomiting (CINV) remains a common adverse effect for children with cancer. In children, chemotherapy emetogenicity and patient factors such as susceptibility to motion sickness and age group determine a patient's risk of CINV. Besides known risk factors, genetic factors may play a role in interindividual variation in the occurrence of CINV. We investigated the influence of candidate gene polymorphisms on the efficacy of antiemetics and on the background sensitivity to CINV in children. This prospective study included 100 children with cancer (median age 6.4 years, range 0.8-17.9) who received moderately to highly emetogenic chemotherapy. Participants registered nausea and vomiting episodes in a mobile app. Genotypes were determined by whole-genome sequencing (n = 79) or Sanger sequencing (n = 21) for 71 genetic polymorphisms involved in motion sickness and antiemetic pathways. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate associations between acute CINV and genotypes adjusting for susceptibility to motion sickness and age group. Rs3782025 in the 5-hydroxytryptamine type 3 (5-HT3) receptor gene (HTR3B) [minor allele frequency (MAF): 0.48] affected response to 5-HT3 receptor antagonists; acute CINV occurred in 76% of patients with GA/AA genotypes and in 41% of patients with GG genotype (OR 5.59; 95% CI 1.74-17.9, dominant genetic model). Rs2975226 in the dopamine transporter gene (SLC6A3) (MAF: 0.54) was associated with acute CINV (OR 5.79; 95% CI 1.09-30.67, recessive genetic model). Polymorphisms in HTR3B and SLC6A3 may contribute to the variability in response to antiemetic prophylaxis for CINV in children.

Long-term kidney function in children with Wilms tumour and constitutional WT1 pathogenic variant.

BACKGROUND: Wilms tumour (WT) survivors, especially patients with associated syndromes or genitourinary anomalies due to constitutional WT1 pathogenic variant, have increased risk of kidney failure. We describe the long-term kidney function in children with WT and WT1 pathogenic variant to inform the surgical strategy and oncological management of such complex children. METHODS: Retrospective analysis of patients with WT and constitutional WT1 pathogenic variant treated at a single centre between 1993 and 2016, reviewing genotype, phenotype, tumour histology, laterality, treatment, patient survival, and kidney outcome. RESULTS: We identified 25 patients (60% male, median age at diagnosis 14 months, range 4-74 months) with WT1 deletion (4), missense (2), nonsense (8), frameshift (7), or splice site (4) pathogenic variant. Thirteen (52%) had bilateral disease, 3 (12%) had WT-aniridia, 1 had incomplete Denys-Drash syndrome, 11 (44%) had genitourinary malformation, and 10 (40%) had no phenotypic anomalies. Patient survival was 100% and 3 patients were in remission after relapse at median follow-up of 9 years. Seven patients (28%) commenced chronic dialysis of which 3 were after bilateral nephrectomies. The overall kidney survival for this cohort as mean time to start of dialysis was 13.38 years (95% CI: 10.3-16.4), where 7 patients experienced kidney failure at a median of 5.6 years. All of these 7 patients were subsequently transplanted. In addition, 2 patients have stage III and stage IV chronic kidney disease and 12 patients have albuminuria and/or treatment with ACE inhibitors. Four patients (3 frameshift; 1 WT1 deletion) had normal blood pressure and kidney function without proteinuria at follow-up from 1.5 to 12 years. CONCLUSIONS: Despite the known high risk of kidney disease in patients with WT and constitutional WT1 pathogenic variant, nearly two-thirds of patients had sustained native kidney function, suggesting that nephron-sparing surgery (NSS) should be attempted when possible without compromising oncological risk. Larger international studies are needed for accurate assessment of WT1genotype-kidney function phenotype correlation.

Surgical management, staging, and outcomes of Wilms tumours with intravascular extension: Results of the IMPORT study.

PURPOSE: To review surgical management, tumour stage and clinical outcomes in children with intravascular extension of Wilms tumour (WT) registered in a national clinical study (2012-19). METHODS: WTs with presence/suspicion of tumour thrombus in the renal vein (RV) or beyond on radiology, surgery or pathology case report forms were identified. Only cases where thrombus was confirmed by surgeon and/or reference pathologist were included. Surgical management, disease stage, overall (OS) and event free survival (EFS) were investigated. RESULTS: 69/583 (11.8%) patients met the inclusion criteria. Forty-six (67%) had abdominal stage III due to thrombus-related reasons: 11 had macroscopically incomplete resection, including 8 cases where cavotomy was not performed; 20 had piecemeal complete resection of thrombus; 15 had microscopically positive resection margins at the RV. 66% of tumour thrombi contained viable tumour. There were eight relapses and five deaths. EFS, but not OS, was significantly associated with completeness of surgical resection (P<0.05). OS and EFS were also significantly associated with histological risk group (P<0.05) but not with viability of tumour thrombus (P=0.19; P=0.59). CONCLUSIONS: WTs with intravascular extension have a high risk of local stage III due to thrombus-related reasons. Controlled complete removal of the thrombus should be the aim of surgery. LEVEL OF EVIDENCE: Level II.

Wilms tumour.

Wilms tumour (WT) is a childhood embryonal tumour that is paradigmatic of the intersection between disrupted organogenesis and tumorigenesis. Many WT genes play a critical (non-redundant) role in early nephrogenesis. Improving patient outcomes requires advances in understanding and targeting of the multiple genes and cellular control pathways now identified as active in WT development. Decades of clinical and basic research have helped to gradually optimize clinical care. Curative therapy is achievable in 90% of affected children, even those with disseminated disease, yet survival disparities within and between countries exist and deserve commitment to change. Updated epidemiological studies have also provided novel insights into global incidence variations. Introduction of biology-driven approaches to risk stratification and new drug development has been slower in WT than in other childhood tumours. Current prognostic classification for children with WT is grounded in clinical and pathological findings and in dedicated protocols on molecular alterations. Treatment includes conventional cytotoxic chemotherapy and surgery, and radiation therapy in some cases. Advanced imaging to capture tumour composition, optimizing irradiation techniques to reduce target volumes, and evaluation of newer surgical procedures are key areas for future research.