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.

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.

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.

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.

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.

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.

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.

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.

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.

Prognostic Factors for Wilms Tumor Recurrence: A Review of the Literature.

In high-income countries, the overall survival of children with Wilms tumors (WT) is ~90%. However, overall, 15% of patients experience tumor recurrence. The adverse prognostic factors currently used for risk stratification (advanced stage, high risk histology, and combined loss of heterozygosity at 1p and 16q in chemotherapy-naïve WTs) are present in only one third of these cases, and the significance of these factors is prone to change with advancing knowledge and improved treatment regimens. Therefore, we present a comprehensive, updated overview of the published prognostic variables for WT recurrence, ranging from patient-, tumor- and treatment-related characteristics to geographic and socioeconomic factors. Improved first-line treatment regimens based on clinicopathological characteristics and advancing knowledge on copy number variations unveil the importance of further investigating the significance of biological markers for WT recurrence in international collaborations.

Unmet needs for relapsed or refractory Wilms tumour: Mapping the molecular features, exploring organoids and designing early phase trials - A collaborative SIOP-RTSG, COG and ITCC session at the first SIOPE meeting.

Wilms tumour (WT) accounts for about 6% of all childhood cancers and overall survival of WT is about 90% in international protocols. However, for WT subgroups with much poorer prognoses, i.e. typically high-risk (unfavorable) histology and/or relapse, there is an unmet need to better understand the biology of WT and to translate biological findings into clinics through early phase clinical trials that evaluate innovative therapies. The main challenges are the small numbers of children suitable for early phase trials, the genetic heterogeneity of WT and the low number of somatic mutations that are currently considered 'druggable'. Accordingly, a joint meeting between clinical and biology experts from the international cooperative groups of the Renal Tumour Study Group of the International Society of Paediatric Oncology, the Renal Tumour Committee of the Children's Oncology Group and the European Innovative Therapies for Children with Cancer consortium and parents representatives was organised during the first SIOPE meeting in Prague, 2019. We reviewed WT molecular features, ongoing/planned early phase trials and explored available knowledge on organoid technology. The key messages were: (1) relapsed WT should undergo whenever possible thorough molecular characterization and be enrolled in protocols or trials with systematic data collecting and reporting; (2) WT displays few known 'actionable' targets and currently no novel agent has appeared promising; (3) we need to improve the enrolment rate of WT candidates in early phase trials especially for the relatively small subgroup of relapses with an adverse prognostic signature; (4) despite some agnostic early phase trials existing, development of WT-focused trials are warranted; (5) growing organoids with parallel testing of drug panels seems feasible and may direct individual treatment and encourage clinical researchers to incorporate the most promising agents into early phase trials.

[Magnesium sulphate treatment decreases the risk of cerebral palsy after preterm birth].

Children born preterm have an increased risk of severe morbidity, e.g. cerebral palsy (CP), compared to children born at term. CP cannot be treated, which is why a prophylactic approach is essential, as argued in this review. Six randomised controlled trials (RCTs) have provided data on MgSO4 treatment as CP neuroprotection in preterm birth, including a new RCT from Denmark. Recently, an updated meta-analysis with trial sequential analysis detected a significant neuroprotective effect of MgSO4 treatment in preterm birth. There is now sufficient evidence, that MgSO4 treatment should be used as neuroprotection in preterm birth.

Smartphone App to Self-Monitor Nausea During Pediatric Chemotherapy Treatment: User-Centered Design Process.

BACKGROUND: Nausea and vomiting are common and distressing side effects for children receiving chemotherapy. Limited evidence is available to guide antiemetic recommendations; therefore, prospective and reliable evaluation of antiemetic efficacy is needed. Smartphone apps can be used to effortlessly and precisely collect patient-reported outcomes in real time. OBJECTIVE: Our objective was to develop a smartphone app to monitor nausea and vomiting episodes in pediatric cancer patients aged 0 to 18 years and to test its usability and adherence to its use. METHODS: We used a user-centered design process and the evolutionary prototype model to develop and evaluate the app. Multidisciplinary group discussions and several rounds of patient feedback and modification were conducted. We translated the validated Pediatric Nausea Assessment Tool to assess nausea severity in children aged 4 to 18 years. The child's own term for nausea was interactively incorporated in the nausea severity question, with response options expressed as 4 illustrative faces. Parent-reported outcomes were used for children aged 0 to 3 years. Reminders were sent using push notifications in order to ensure high response rates. Children aged 0 to 18 years who were undergoing chemotherapy were recruited from the Department of Pediatric Oncology at Copenhagen University Hospital Rigshospitalet to evaluate the app. RESULTS: The app's most important function was to record nausea severity in children. After assistance from a researcher, children aged 4 to 18 years were able to report their symptoms in the app, and parents were able to report symptoms for their children aged 0 to 3 years. Children (n=20, aged 2.0-17.5 years) and their parents evaluated the app prospectively during a collective total of 60 chemotherapy cycles. They expressed that the app was user-friendly, intuitive, and that the time spent on data entry was fair. The response rates were on average 92%, 93%, and 80% for the day before, the first day of, and the next 3 days after chemotherapy, respectively. Researchers and clinicians were able to obtain an overview of the patient's chemotherapy dates and responses through a secure and encrypted web-based administrative portal. Data could be downloaded for further analysis. CONCLUSIONS: The user-friendly app could be used to facilitate future pediatric antiemetic trials and to refine antiemetic treatment during chemotherapy.