Accurate childhood cancer survival estimates are crucial for policy makers and clinicians for priority-setting and planning decisions. However, observed survival estimates are lacking for many ...countries, and when available, wide variation in outcomes is reported. Understanding the barriers to optimising survival can help improve childhood cancer outcomes. We aimed to provide estimates of global childhood cancer survival, accounting for the impact of multiple factors that affect cancer outcomes in children.
We developed a microsimulation model to simulate childhood cancer survival for 200 countries and territories worldwide, accounting for clinical and epidemiologic factors, including country-specific treatment variables, such as availability of chemotherapy, radiation, and surgery. To ensure model results were consistent with reported survival data, we calibrated the model to estimates from the CONCORD-2 and CONCORD-3 studies using an Approximate Bayesian Computation approach. We estimated 5-year net survival for diagnosed cases of childhood cancer in each country and territory and estimated potential survival gains of seven policy interventions focused on improving treatment availability and delivery (ie, increasing the availability of chemotherapy, radiation, general surgery, neurosurgery, or ophthalmic surgery, reducing treatment abandonment, and improving the quality of care to the mean of high-income countries) implemented in isolation or as packages.
Our model estimated that, for diagnosed cases, global 5-year net childhood cancer survival is currently 37·4% (95% uncertainty interval 34·7–39·8), with large variation by region, ranging from 8·1% (4·4–13·7) in eastern Africa to 83·0% (81·6–84·4) in North America. Among the seven policy interventions modelled, each individually provided small gains, increasing global 5-year net survival to between 38·4% (35·8–40·9) and 44·6% (41·7–47·4). 5-year net survival increased more substantially when policy interventions were bundled into packages that improved service delivery (5-year net survival 50·2% 47·3–53·0) or that expanded treatment access (54·1% 50·1–58·5). A comprehensive systems approach consisting of all policy interventions yielded superadditive gains with a global 5-year net survival of 53·6% (51·5–55·6) at 50% scale-up and 80·8% (79·5–82·1) at full implementation.
Childhood cancer survival varies widely by region, with especially poor survival in Africa. Although expanding access to treatment (chemotherapy, radiation, and surgery) and addressing financial toxicity are essential, investments that improve the quality of care, at both the health-system and facility level, are needed to improve childhood cancer outcomes globally.
Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard TH Chan School of Public Health, Harvard Medical School, National Cancer Institute, SickKids, St Jude Children's Research Hospital, Union for International Cancer Control, Children with Cancer UK Davidson and O'Gorman Fellowship.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Accurate estimates of childhood cancer incidence are important for policy makers to inform priority setting and planning decisions. However, many countries do not have cancer registries that quantify ...the incidence of childhood cancer. Moreover, even when registries do exist, they might substantially underestimate the true incidence, since children with cancer might not be diagnosed. We therefore aimed to provide estimates of total childhood cancer incidence accounting for underdiagnosis.
We developed a microsimulation model to simulate childhood cancer incidence for 200 countries and territories worldwide, taking into account trends in population growth and urbanicity, geographical variation in cancer incidence, and health system barriers to access and referral that contribute to underdiagnosis. To ensure model results were consistent with epidemiological data, we calibrated the model to publicly available cancer registry data using a Bayesian approach in which the observed data are fixed and the model parameters (cancer incidence and probabilities of health system access and referral) are random variables. We estimated the total incidence of childhood cancer (diagnosed and undiagnosed) in each country in 2015 and projected the number of cases from 2015 to 2030.
Our model estimated that there were 397 000 (95% uncertainty interval UI 377 000–426 000) incident cases of childhood cancer worldwide in 2015, of which only 224 000 (95% UI 216 000–237 000) were diagnosed. This finding suggests that 43% (172 000 of 397 000) of childhood cancer cases were undiagnosed globally, with substantial variation by region, ranging from 3% in western Europe (120 of 4300) and North America (300 of 10 900) to 57% (43 000 of 76 000) in western Africa. In south Asia (including southeastern Asia and south-central Asia), the overall proportion of undiagnosed cases was estimated to be 49% (67 000 of 137 000). Taking into account population projections, we estimated that there will be 6·7 million (95% UI 6·3–7·2) cases of childhood cancer worldwide from 2015 to 2030. At current levels of health system performance, we estimated that 2·9 million (95% UI 2·7–3·3) cases of childhood cancer will be missed between 2015 and 2030.
Childhood cancer is substantially underdiagnosed, especially in south Asia and sub-Saharan Africa (including western, eastern, and southern Africa). In addition to improving treatment for childhood cancer, health systems must be strengthened to accurately diagnose and effectively care for all children with cancer. As countries expand universal health coverage, these estimates of total incidence will hopefully help guide efforts to appropriately increase health system capacity to ensure access to effective childhood cancer care.
Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard T H Chan School of Public Health, Harvard Medical School, National Cancer Institute, SickKids, St Jude Children's Research Hospital, and Union for International Cancer Control.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUND
Males with Klinefelter syndrome (KS) (47,XXY) may be more likely to develop germ cell tumors (GCTs), particularly mediastinal GCTs. To date, there are no reports characterizing the ...prevalence of KS among male GCT cases.
METHODS
The authors used array genotyping data from a Children’s Oncology Group epidemiology study to estimate the prevalence of KS in males with GCTs (433 males aged birth‐19 years). Using Fisher’s exact tests, the authors examined differences in age at diagnosis, race/ethnicity, tumor location and histology, and several birth characteristics between cases of KS‐GCT and GCT cases without chromosomal abnormalities. Using publicly available data, the authors estimated the 1‐year risk, risk ratio, and corresponding 95% confidence interval of GCTs among KS cases.
RESULTS
Based on analysis of array genotyping data, 3% of male GCT cases (13 cases) had KS. The additional X chromosome was of maternal origin in 7 of the 13 cases. Of these 13 KS cases, 5 of 9 KS‐GCT cases with parental questionnaire data (56%) reported a diagnosis of KS. No significant differences were observed with regard to patient or birth characteristics between KS‐GCT and non–KS‐GCT cases. KS‐GCT cases were significantly more likely to be diagnosed with mediastinal tumors than non–KS‐GCT cases (P<.01). The authors estimated the risk of developing a GCT among males with KS to be 0.00025, or 1 per 4000 males (risk ratio, 18.8; 95% confidence interval, 11.7‐30.0).
CONCLUSIONS
Compared with males without chromosomal abnormalities, males with KS are more likely to be diagnosed with a mediastinal GCT. The presence of KS should be considered in males with a diagnosis of mediastinal GCT. In the current study, the authors report that approximately one‐third of males with mediastinal germ cell tumors have Klinefelter syndrome, and therefore screening of these individuals for the syndrome may be warranted. Males with Klinefelter syndrome are 19 times as likely as males without Klinefelter syndrome to develop germ cell tumors.
The authors observed 1/3 of males with mediastinal germ cell tumors had Klinefelter syndrome; therefore, screening of these cases for Klinefelter syndrome may be warranted. Klinefelter syndrome males are 19 times as likely as non‐Klinefelter males to develop germ cell tumors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Survival differences by racial and ethnic group have been reported in children and adolescents with germ cell tumors (GCTs), but whether these differences depend on stage of disease is unclear. Using ...the SEER 18 registries (2000–2015), we examined GCT survival differences by race/ethnicity (non‐Hispanic white NHW, Black, Asian/Pacific Islander API, Hispanic) separately for males and females aged 0–19 years at diagnosis. We used Kaplan–Meier survival curves (Log‐Rank p values) to characterize survival differences. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between race/ethnicity and death. Using an inverse odds weighting mediation analysis, we estimated the association between race/ethnicity and death treating stage of disease as the mediator. There were no significant racial/ethnic survival differences among females. Male survival differed by race/ethnicity (p < 0.0001) with NHW males having the best survival. Compared to NHW, API and Hispanic males had significantly higher risks of death (API HR: 2.18; 95% CI: 1.32–3.56; Hispanic HR: 1.98; 95% CI: 1.42–2.78) (model adjusted for age and year at diagnosis, tumor histology and location, stage). This association was mediated by stage of disease only among Hispanic males with gonadal tumors (indirect HR: 1.18; 95% CI: 1.03–1.35). The increased risk of death after a testicular GCT diagnosis observed among Hispanic males was mediated by stage of disease. For API males and Hispanic males with extragonadal tumors, other unidentified factors including differences in exposures, tumor biology or treatment received may impact the observed racial/ethnic survival disparities.
What's new?
Survival differences by racial and ethnic group have been reported in children and adolescents with germ cell tumors (GCTs), but whether these differences depend on stage of disease is unclear. Using data from 3,300 children and adolescents diagnosed with a GCT, here the authors observed significant racial/ethnic differences in survival among males but not females, with Hispanic and Asian/Pacific Islander males having worse survival than whites. This association was not mediated by stage of disease, except for gonadal tumors in Hispanic males. For Asian/Pacific Islander and Hispanic males with extragonadal tumors, other unidentified factors may be driving the observed disparity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
5-year net survival of children and adolescents diagnosed with cancer is approximately 80% in many high-income countries. This estimate is encouraging as it shows the substantial progress that has ...been made in the diagnosis and treatment of childhood cancer. Unfortunately, scarce data are available for low-income and middle-income countries (LMICs), where nearly 90% of children with cancer reside, suggesting that global survival estimates are substantially worse in these regions. As LMICs are undergoing a rapid epidemiological transition, with a shifting burden from infectious diseases to non-communicable diseases, cancer care for all ages has become a global focus. To improve outcomes for children and adolescents diagnosed with cancer worldwide, an accurate appraisal of the global burden of childhood cancer is a necessary first step. In this Review, we analyse four studies of the global cancer burden that included data for children and adolescents. Each study used various overlapping and non-overlapping statistical approaches and outcome metrics. Moreover, to provide guidance on improving future estimates of the childhood global cancer burden, we propose several recommendations to strengthen data collection and standardise analyses. Ultimately, these data could help stakeholders to develop plans for national and institutional cancer programmes, with the overall aim of helping to reduce the global burden of cancer in children and adolescents.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective To investigate trends in incidence of differentiated thyroid carcinomas among children and adolescents and young adults. Study design In this ecological time-trends study, we selected cases ...of differentiated thyroid carcinomas (1984-2010) in patients <30 years from Surveillance, Epidemiology, and End Results 9 cancer registries by using International Classification of Diseases for Oncology , 3rd edition , codes for papillary and follicular cancers. Patients with multiple other primary diseases before differentiated thyroid carcinomas were excluded. SEER*Stat software, version 8.0.4 (National Cancer Institute, Bethesda, Maryland) was used to calculate age-standardized rates (estimated per 1 000 000/persons) and annual percentage changes (APCs) were calculated by the Joinpoint model (Joinpoint software, version 4.0.4; National Cancer Institute). Results Rates ranged from 2.77 (1990) to 9.63 (2009) and from 18.35 (1987) to 50.99 (2009), for male and female subjects, respectively. A significant increasing trend in incidence was observed for both male (APC 3.44; 95% CI 2.60-4.28) and female (APC 3.81; 95% CI 3.38-4.24) patients. When a stratified analysis on the basis of tumor size was performed, significant increasing trends were noted for the following categories: <0.5 cm (females: APC 5.09, 95% CI 3.54-6.65), 0.5-0.9 cm (females: APC 8.45, 95% CI 7.09-9.82), 1.0-1.9 cm (males: APC 5.09, 95% CI 3.20-7.01; females: APC 3.42, 95% CI 2.78-4.07), and ≥2 cm (males: APC 2.62, 95% CI 1.64-3.60; females: APC 2.96, 95% CI 2.34-3.59). Conclusions Incidence rates for differentiated thyroid carcinomas are increasing among children and adolescents and young adults in the US. The increasing trends for larger tumors rules out diagnostic scrutiny as the only explanation for the observed results. Environmental, dietary, and genetic influences should be investigated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Background
Although adolescent and young adult (AYA) cancers represent a unique spectrum of malignancies, epidemiological studies of cancer incidence often group AYAs together with younger ...or older populations, obscuring patterns specific to this population.
Methods
We examined AYA cancer incidence trends in 41 countries over a 15-year period using the CI5plus database. Truncated age-standardized incidence rates were calculated and the annual percentage change was assessed, with statistical significance corresponding to a 95% confidence interval that does not include zero.
Results
From 1998 to 2012, the 41 included countries contributed a total of 1 846 588 cancer cases and 3.1 billion person-years among AYAs. Although statistically significant increases in the overall cancer burden were observed in 23 countries, the magnitude varied considerably, with the greatest increase in incidence observed in South Korea (annual percentage change2002–2012 = 8.5%, 95% confidence interval = 7.6% to 9.4%) due to thyroid cancer. Notable trends included sharp increases in the incidence of obesity-related malignancies among AYAs; indeed, statistically significant increases were observed among AYAs for 10 of 11 and 9 of 11 obesity-related cancer sites in the US and UK, respectively, with at least five obesity-related cancers statistically significantly increasing in Canada, Japan, South Korea, Australia, and the Netherlands. Other striking trends were noted for thyroid and testicular cancer, with statistically significantly increasing rates observed in 33 and 22 countries, respectively, whereas statistically significant declines in incidence were observed for smoking-related cancers, cervical cancer, and Kaposi sarcoma in many countries.
Conclusions
Our results highlight the future health-care needs related to treatment as well as the urgency for public health initiatives that can mitigate the increasing burden of cancer in AYAs.
We estimate that there will be 13·7 million new cases of childhood cancer globally between 2020 and 2050. At current levels of health system performance (including access and referral), 6·1 million ...(44·9%) of these children will be undiagnosed. Between 2020 and 2050, 11·1 million children will die from cancer if no additional investments are made to improve access to health-care services or childhood cancer treatment. Of this total, 9·3 million children (84·1%) will be in low-income and lower-middle-income countries. This burden could be vastly reduced with new funding to scale up cost-effective interventions. Simultaneous comprehensive scale-up of interventions could avert 6·2 million deaths in children with cancer in this period, more than half (56·1%) of the total number of deaths otherwise projected. Taking excess mortality risk into consideration, this reduction in the number of deaths is projected to produce a gain of 318 million life-years. In addition, the global lifetime productivity gains of US$2580 billion in 2020–50 would be four times greater than the cumulative treatment costs of $594 billion, producing a net benefit of $1986 billion on the global investment: a net return of $3 for every $1 invested. In sum, the burden of childhood cancer, which has been grossly underestimated in the past, can be effectively diminished to realise massive health and economic benefits and to avert millions of needless deaths.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abnormal DNA methylation may be important in germ cell tumour (GCT) aetiology, as germ cells undergo complete epigenetic reprogramming during development. GCTs show differences in global and promoter ...methylation patterns by histologic subtype. We conducted an epigenome-wide study to identify methylation differences by GCT histology.
Using the Illumina HumanMethylation450K array we measured methylation in 154 paediatric GCTs (21 germinomas/seminomas/dysgerminoma, 70 yolk sac tumours YST, 9 teratomas, and 54 mixed histology tumours). We identified differentially methylated regions (DMRs) between GCT histologies by comparing methylation beta values.
We identified 8,481 DMRs (FWER < 0.05). Unsupervised hierarchical clustering of individual probes within DMRs resulted in four high level clusters closely corresponding to tumour histology. Clusters corresponding to age, location, sex and FFPE status were not observed within these DMRs. Germinomas displayed lower levels of methylation across the DMRs relative to the other histologic subtypes. Pathway analysis on the top 10% of genes with differential methylation in germinomas/seminomas/dysgerminoma compared to YST suggested angiogenesis and immune cell-related pathways displayed decreased methylation in germinomas/seminomas/dysgerminoma relative to YST.
Paediatric GCT histologies have differential methylation patterns. The genes that are differentially methylated may provide insights into GCT aetiology including the timing of GCT initiation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To study associations of maternal gestational weight gain with offspring weight status in adolescence.
We surveyed 11,994 adolescents aged 9-14 years enrolled in the Growing Up Today Study cohort and ...their mothers, members of the Nurses' Health Study II. We used multivariable linear and logistic regression to study associations of gestational weight gain with offspring adiposity.
Mean (standard deviation) gestational weight gain was 31.5 (11.2) pounds, and offspring body mass index (BMI) z score (BMI standardized for age and sex) was 0.15 (1.0) units; 6.5% of adolescents were obese (BMI 95th percentile or higher) (BMI is calculated as weight kg/height (m)2). Gestational gain was linearly associated with adolescent adiposity: compared with 20-24 pounds, gain less than 10 pounds was associated with child BMI z score 0.25 units lower (95% confidence interval CI -0.47 to -0.04), and gain 45 pounds or more with BMI z score 0.18 units higher (95% CI 0.11-0.25). Compared with women with adequate gain according to 1990 Institute of Medicine guidelines, women with excessive gain had children with higher BMI z scores (0.14 units, 95% CI 0.09-0.18) and risk of obesity (odds ratio 1.42, 95% CI 1.19-1.70). The predicted prevalence of term low birth weight declined modestly across the range of gain (2% for gain less than 10 pounds, 1% for gain 45 pounds or more), whereas term high birth weight increased dramatically with higher gain (10% for gain less than 10 pounds, 35% for gain of 45 pounds or more).
Gestational weight gain is directly associated with BMI and risk of obesity in adolescence. Revised gestational weight-gain guidelines should account for influences on child weight.
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