Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival

Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival

Fasting Intervention for Children With Unilateral Renal Tumors to Reduce Toxicity

Childhood renal tumors account for around 6% of all childhood cancers and 90% of these cases are Wilms tumor. In Europe, the SIOP-RTSG approach is considered standard of care and has resulted in five-year survival rates of over 90%. Efforts to decrease toxicity are now being pursued. Short-term fasting (STF), a short but strong reduction in calorie-intake, is associated with improved fitness, enhanced coping with acute physical stress and a lower risk of age-associated diseases. STF temporarily reduces growth to boost resilience, maintenance, and defense-mechanisms, by which toxic side-effects of (oxidative) damage and inflammation are largely prevented. Renal surgery for Wilms tumor carries a risk of acute kidney injury (AKI) and pediatric patients that had an episode of AKI are at increased risk for developing chronic renal disease. STF could mitigate surgery-induced stress and could further improve outcomes. We aim to investigate the effect of STF on renal function recovery after renal tumor surgery by conducting a single-center, prospective, randomized, non-blinded, intervention study. Children diagnosed with a unilateral renal tumor and opting for curative treatment are eligible for inclusion. The main study objective is to investigate the potential decrease in occurrence of AKI due to STF. Secondary objectives include renal function recovery, child's wellbeing, physical functioning, and feasibility of and adherence to STF in children with cancer

Malignant extracranial germ cell tumors in the Netherlands between 1990 and 2018: Stable incidence and improved survival

Background: Population-based studies assessing long-term patterns of incidence and disease characteristics of germ cell tumors (GCTs) in children are scarce. We investigated incidence and survival trends of malignant extracranial GCTs in children using population-based nationwide data from the Netherlands. Methods: All malignant extracranial GCTs diagnosed in patients aged 0–18 years between 1990 and 2018 were selected from the Netherlands Cancer Registry. Incidence rates were calculated as the average annual number of cases per 1 million person-years. Five-year overall survival (OS) was calculated. Results: A total of 815 cases were identified. Gonadal GCTs (n=665, testis n=485, ovarian n=180) were more common than extragonadal GCTs (n=149). Stage distribution for testicular and extragonadal GCTs shifted between 1990 and 2004 and 2005–2018 towards more localized disease. The overall incidence remained stable over time, but a significant increase was noted for extragonadal GCTs in the 0–9 years age group. Survival of extragonadal GCTs (5-year OS 84.1%, 95% CI 77.1–89.1), in particular mediastinal GCTs (5-year OS 66.7%, 95% CI 45.7–81.1), was lower than that of gonadal GCTs (5-year OS testis 95.0%, 95% CI 92.7–96.7;ovary 97.8%, 95% CI 94.2–99.2). The 5-year OS of our entire cohort was 93.6% (95% CI 91.7–95.1). Five-year OS significantly increased from 89.5% (95% CI 86.1–92.2) in 1990–2004–97.4% (95% CI 95.3–98.5) in 2005–2018. Conclusions: Although the incidence of all malignant pediatric extracranial GCTs remained stable during 1990–2018, an increase was observed for extragonadal GCTs in younger children (0–9 years). There was a shift towards more localized disease for testicular and extragonadal GCTs. Five-year OS increased over time exceeding 90% (91.4%, 95% CI 82.7–95.8) in the most recent diagnostic period. Mediastinal GCTs had the lowest OS, supporting the need for future research

Research perspectives in the etiology of congenital anorectal malformations using data of the International Consortium on Anorectal Malformations: Evidence for risk factors across different populations

Purpose: The recently established International Consortium on Anorectal Malformations aims to identify genetic and environmental risk factors in the etiology of syndromic and nonsyndromic anorectal malformations (ARM) by promoting collaboration through data sharing and combined research activities. Methods: The consortium attempts to recruit at least 1,000 ARM cases. DNA samples are collected from case-parent triads to identify genetic factors involved in ARM. Several genetic techniques will be applied, including SNP arrays, gene and whole exome sequencing, and a genome-wide association study. Questionnaires inquiring about circumstances before and during pregnancy will be used to obtain environmental risk factor data. Results: Currently, 701 ARM cases have been recruited throughout Europe. Clinical data are available from all cases, and DNA samples and questionnaire data mainly from the Dutch and German cases. Preliminary analyses on environmental risk factors in the Dutch and German cohort found associations between ARM and family history of ARM, fever during first trimester of pregnancy and maternal job exposure to cleaning agents and solvents. Conclusion: First results show that both genetic and environmental factors may contribute to the multifactorial etiology of ARM. The International Consortium on Anorectal Malformations will provide possibilities to study and detect important genes and environmental risk factors for ARM, ultimately resulting in better genetic counseling, improved therapies, and primary prevention. © 2010 The Author(s)