Welcome to SIOP 2022 Interactive Programme
The Congress will officially run on CET time zone (Central European Time, Barcelona)
- Catherine G. Lam (United States of America)
- Austin Brown (United States of America)
NOVEL AND REPLICATED GENETIC PREDICTORS FOR NEPHROTOXICITY AND DELAYED METHOTREXATE CLEARANCE: NATIVE AMERICAN ANCESTRY AND THE GENES SLCO1B1, SLC19A1, ABCC4
- Mark Zobeck (United States of America)
Abstract
Background and Aims
High-dose methotrexate (HD MTX) is a key component of treatment for high-risk pediatric acute lymphoblastic leukemia (ALL) but may cause acute kidney injury and prolonged hospitalization due to delayed clearance in some patients. We conducted a retrospective cohort study to identify genetic factors that may predict which children are at risk for creatinine increase and prolonged MTX clearance.
Methods
We identified ALL patients who received HD MTX doses between 4,000-5,000mg/m2 at Texas Children’s Cancer Center from September 2010 to December 2017. We performed germline genotyping to determine genetic ancestry and allele status for 49 single nucleotide polymorphisms (SNPs) identified from the literature as related to MTX disposition. Two Bayesian hierarchical ordinal regression models for creatinine increase and for prolonged MTX clearance were developed to estimate the odds ratios (OR) and 95% compatibility intervals (95%CI) for the genetic risk factors and outcomes. Each SNP model adjusted for the effects of genetic ancestry, dose reduction, and use of an intensive MTX level monitoring protocol that previously was demonstrated to lower toxicity.
Results
Native American ancestry, which correlated with self-reported Hispanic ethnicity (Pearson correlation 0.84), was associated with increased risk for creatinine increase (OR 2.07[95%CI 1.18-3.69]). Each additional A allele of rs2838958 in SLC19A1 demonstrated an OR of 1.73(1.24-2.38) for prolonged MTX clearance and 1.35(0.99-1.81) for increased creatinine. The G allele of rs7317112 in ABCC4 was associated with prolonged MTX clearance (OR 1.70[1.18-2.43]). The G allele of rs2306283 in SLCO1B1 demonstrated a decreased risk for prolonged clearance (0.72[0.53-0.97]). Leave-one-out cross validation demonstrated that combined models with genetic and clinical predictors improved predictions for prolonged MTX clearance compared to clinical or genetic predictors alone.
Conclusions
We identified genetic predictors of MTX toxicities that may allow more precise individualized toxicity risk prediction. More work is needed to refine, calibrate, and validate the prediction models.
GERMLINE CANCER PREDISPOSITION VARIANTS ARE ASSOCIATED WITH SURVIVAL IN CHILDREN WITH RHABDOMYOSARCOMA
- Philip Lupo (United States of America)
Abstract
Background and Aims
Rhabdomyosarcoma is the most common childhood soft-tissue sarcoma. Although germline cancer predisposition variants (CPVs) contribute to approximately 7% of rhabdomyosarcoma cases, there are limited data regarding whether CPVs influence outcome in these patients. We present an analysis of the association of CPVs and survival in children with rhabdomyosarcoma.
Methods
We analyzed existing germline exome and survival data on 580 individuals with newly diagnosed rhabdomyosarcoma who were consented to Children’s Oncology Group protocols. To evaluate the impact of CPVs in 63 cancer predisposition genes on overall survival (OS) and event-free survival (EFS), we used the Kaplan-Meier estimator and Cox proportional hazards regression adjusted for clinical covariates. Lastly, we stratified these analyses by tumor histology and PAX3/7-FOXO1 fusion status, known prognostic factors.
Results
In multivariable models, presence of a CPV was significantly associated with worse OS (adjusted hazard ratio [aHR]=1.79, P=0.04). Effects were stronger among those with embryonal histology who harbored a CPV in a subset of 24 rhabdomyosarcoma-associated predisposition genes (OS: aHR=3.00, P=9.27x10-4; EFS: aHR=2.33, P=4.86x10-3). Specifically, we observed significant effects of CPVs in TP53 and HRAS on OS and EFS. Lastly, in children with fusion-negative rhabdomyosarcoma, survival was significantly worse for individuals with CPVs compared to those without CPVs in a rhabdomyosarcoma-associated predisposition gene (OS: aHR=2.85, P=1.12x10-3; EFS: aHR=2.30, P=4.43x10-3). Survival for children with fusion-negative rhabdomyosarcoma with a CPV compared to children with fusion-positive rhabdomyosarcoma was not significantly different (OS: P=0.14; EFS: P=0.37).
Conclusions
We have demonstrated that germline CPVs are associated with poorer outcomes among children with rhabdomyosarcoma. Notably, children with PAX3/7-FOXO1 fusion-negative rhabdomyosarcoma with germline CPVs had outcomes similar to children with fusion-positive rhabdomyosarcoma. Our findings highlight germline CPV status in guiding risk stratification, surveillance, and cascade testing.
SURVIVAL FROM CHILDHOOD LEUKAEMIA: TEMPORAL PATTERNS IN EASTERN AND WESTERN GERMANY SINCE GERMAN REUNIFICATION
- Maike Wellbrock (Germany)
Abstract
Background and Aims
The reunification of Germany offers a unique opportunity to evaluate survival trends in childhood leukaemia in two merging countries whose initial social conditions, welfare and healthcare systems were remarkably different. We sought to evaluate temporal patterns and differences of survival in children with leukaemia in Eastern and Western Germany.
Methods
We conducted a register-based survival study assessing five-year overall survival from childhood leukaemia. The study population comprised all children with a first primary lymphoblastic (LL) or acute myeloid leukaemia (AML) diagnosed at ages 0-14 years between 1991 and 2015 in Germany. Cox proportional hazard models estimating hazard ratios (HR) with 95% confidence intervals (CI) and Kaplan-Meier curves were used to compare five-year overall survival from LL and AML between children residing in Eastern and Western Germany. We also performed trend analyses to assess temporal changes in the comparison of survival estimates over time.
Results
Overall five-year survival from both LL and AML improved over time in both parts of Germany. HRs of the survival comparison between Eastern and Western Germany for LL decreased by diagnostic period (from HR 1.28, 95% CI 0.98, 1.66, for 1991-1995 to HR 0.59, 95% CI 0.34, 1.05, for 2011-2015; p for trend = 0.002), indicating initially lower survival probabilities in Eastern Germany improving to somewhat superior survival probabilities compared to Western Germany since around 2006. This trend was most pronounced in children aged 5-14 years at diagnosis. Survival estimates for AML in Western Germany still slightly exceed those in Eastern Germany, whereas the gap has narrowed in recent years.
Conclusions
Children diagnosed with LL at ages 5-14 years in particular may have benefited from the improvements in socioeconomic conditions and healthcare in Eastern Germany. Further research including social conditions on an individual level is warranted to address the mechanisms underlying the observed survival inequalities.
SURVIVAL OUTCOMES FOR ADOLESCENT AND YOUNG ADULT CANCER IN LOW-AND MIDDLE-INCOME COUNTRIES: A SYSTEMATIC REVIEW
- Krista Ariello (Canada)
Abstract
Background and Aims
Adolescent and young adult (AYA) patients with cancer are recognized as a vulnerable subpopulation in high-income countries (HICs). Though survival gaps between HIC and low- and middle-income country (LMIC) children with cancer are well described, LMIC AYAs have been neglected. We thus conducted a systematic review to describe cancer outcomes among LMIC AYA.
Methods
We captured English-language studies published from 2010 onwards reporting LMIC AYA cancer survival outcomes. LMICs were defined according to World Bank 2019 classifications, while AYAs were defined as diagnosed between 15-39 years of age. Cohorts were considered as AYA if >75% of patients were AYA, the mean/median age and SD were between 15-39 years, or the range was within 5 years of the AYA range (i.e. 10-54 years). Cohort characteristics, including country, cancer type, and cancer outcomes were abstracted.
Results
Of 6,207 studies identified by the search strategy, 658 underwent full-text review; 60 met inclusion criteria. No low-income countries were represented. 44 (73.3%) studies were conducted in upper-middle-income countries (UMIC), though these represented only 12 of 55 countries currently classified as UMICs. The most common cancers studied were acute lymphoblastic leukemia (ALL)(n=13 studies), breast cancer (n=5), and osteosarcoma (n=3). 5-year overall survival was highly variable, ranging from 39%-63% for ALL, 60%-85% for breast cancer and 47%-83% for osteosarcoma.
Conclusions
Though three billion AYA reside in LMICs, their cancer outcomes are neglected in current literature. Existing data indicate variable survival, ranging from comparable to HIC outcomes to substantially inferior. These studies however represent only a limited number of LMICs and are biased towards UMICs. Systematic efforts to describe and improve LMIC AYA cancer outcomes are required.
IMPLEMENTING A PEDIATRIC HEMATOLOGY-ONCOLOGY CLINICAL DATA MONITORING AND EVALUATION PLATFORM IN SUB-SAHARAN AFRICA IMPROVED DATA ACCURACY, REPORTING TIMELINESS, AND ANALYTICAL UTILITY
- Mark Zobeck (United States of America)
Abstract
Background and Aims
Since 2016, Global Hematology-Oncology Pediatric Excellence (HOPE) has provided pediatric hematology-oncology care in Uganda, Malawi, and Botswana. Data collection for program monitoring and evaluation (M&E) is challenging due to manual data collection and inconsistent variable definitions. We conducted a project to improve the accuracy, timeliness, and utility of M&E data.
Methods
Global HOPE team members from Houston and Africa updated the M&E framework, standardized variable definitions, developed a REDCap™ database, strengthened quality control workflows, and automated reporting of key indicators. The new platform was implemented in April 2021. We compared baseline data from October 2020 to March 2021 to the period from July to December 2021. Accuracy was measured by types and number of data queries from quality control review. Timeliness was measured by the time to query closure. Utility was measured by the number and frequency of variables reported to Global HOPE stakeholders.
Results
There were 73%(intervention:114/baseline:427) fewer queries for new patients in the intervention period versus baseline, including 90% fewer missing data queries (29/325), 50% fewer classification errors (34/69), 48.5% fewer date logic errors (e.g., death before birth; 17/33), and 100% fewer date format errors (0/4). Duplicate ID errors increased by 36%(34/25). Query closure time was unmeasurable during the baseline period but estimated to be 60% at 60 days. Of the 754 eligible queries in the intervention period, 44% were closed within 30 days and 92% within 60 days. The baseline reporting dashboard included four variables from spreadsheet-based calculations updated every 3-6 months. The new M&E dashboard includes interactive, granular visualizations of 16 variables generated by R scripts which may be updated on-demand.
Conclusions
By improving the M&E framework, data collection, quality workflows, and technology use, we improved the accuracy, timeliness, and utility of the Global HOPE M&E data and created a platform for growth as a learning global health system.
PEDIATRIC RENAL TUMORS IN THE NETHERLANDS BETWEEN 1990 AND 2014: STABLE INCIDENCE AND SLIGHTLY IMPROVED SURVIVAL OF WILMS TUMORS
- Maya Schulpen (Netherlands)
Abstract
Background and Aims
This population-based study provides a comprehensive overview of trends in incidence and survival of children and adolescents diagnosed with renal malignancies in the Netherlands.
Methods
Data on all renal malignancies diagnosed in pediatric patients (0-18 years) between 1990-2014 were extracted from the Netherlands Cancer Registry [total N=648; Wilms tumor (WT) N=595; malignant rhabdoid tumor of the kidney (MRTK) N=10; clear cell sarcoma of the kidney (CCSK) N=22; renal cell carcinoma (RCC) N=21]. Five-year overall survival (OS) was estimated using the actuarial method. Time trends in incidence were assessed by calculating average annual percentage change (AAPC). A parametric survival model was created to compare the multivariable-adjusted risk of dying from WT between two diagnostic periods.
Results
The overall world standardized incidence rate (WSR) was 8 per million person-years and was constant over time (AAPC -0.8%, p=0.29). WSR were 7 per million for WT, 0.1 per million for MRTK, 0.3 per million for CCSK, and 0.2 per million for RCC. Patients with WT had a good prognosis; 5-year OS modestly increased from 88% in 1990-2001 to 91% in 2002-2014. Multivariable analysis showed that risk of dying from WT was not significantly decreased in the latest period (hazard ratio, 95% confidence interval: 0.7, 0.4-1.3) after adjustment for follow-up time, sex, age, and disease stage. Survival of WT decreased with increasing disease stage, ranging from 95-100% for stage I-II and about 80% for stage III-IV to 74% for bilateral disease. Five-year OS were 81% for RCC, 77% for CCSK, and 20% for MRTK.
Conclusions
Incidence of pediatric renal malignancies in the Netherlands has been stable since the 1990s. Five-year OS of WT modestly increased reaching 91% and was similar to findings for other developed countries. In contrast to the excellent outcome for most (non-)WT, long-term outcome of MRTK remained inferior.