Development and validation of thromboembolism diagnostic algorithms in children with cancer from real-world data.

OBJECTIVE: To evaluate the accuracy of diagnostic algorithms developed using the International Classification of Diseases (ICD-9-CM and ICD-10-CA) diagnostic codes and physician billing codes for thromboembolism (TE) from health administrative data compared to chart review diagnoses of TE in children with cancer. METHODS: Using data linkage between the Pediatric Oncology Group of Ontario Network Information System (Ontario pediatric cancer registry) and various administrative data housed at ICES, eight algorithms were developed including a single reference to one of the billing codes, multiple references with varying time intervals, and combinations of various billing codes during primary cancer therapy for the whole cohort and, for early (<04/2002) and later (≥04/2002, solely ICD-10 codes) periods. Reference standard was chart review data from prior studies (from 1990 to 2016) among children (≤19 years) with cancer and radiologically confirmed TE. RESULTS: Records of 2056 patients diagnosed with cancer at two participating sites during study period were reviewed; 112 had radiologically confirmed TE. The algorithm with addition of anticoagulation utilization codes was the best performing algorithm (sensitivity = 0.76;specificity = 0.85). With use of ICD-10 only codes, sensitivity of the same algorithm improved to 0.84 with specificity of 0.80. CONCLUSION: This study provides a valid approach for ascertaining pediatric TE using real-world data. IMPACT: Research in pediatric thrombosis, especially cancer-related thrombosis, is limited mainly due to small-sized studies. Real-world data provide ready access to large and diverse populations. However, there are no validated algorithms for identifying thrombosis in real-world data for children. An algorithm based on combination of thrombosis and anticoagulation utilization codes had 76% sensitivity and 85% specificity to identify diagnosis of thrombosis in children in administrative data. This study provides a valid approach for ascertaining pediatric thrombosis using real-world data and offers a good avenue to advance pediatric thrombosis research.

Psychiatric disorders in childhood cancer survivors: A retrospective matched cohort study of inpatient hospitalisations and community-based mental health services utilisation in Western Australia.

OBJECTIVE: We examined the impact of long-term mental health outcomes on healthcare services utilisation among childhood cancer survivors in Western Australia using linked hospitalisations and community-based mental healthcare records from 1987 to 2019. METHOD: The study cohort included 2977 childhood cancer survivors diagnosed with cancer at age < 18 years in Western Australia from 1982 to 2014 and a matched non-cancer control group of 24,994 individuals. Adjusted hazard ratios of recurrent events were estimated using the Andersen-Gill model. The cumulative burden of events over time was assessed using the method of mean cumulative count. The annual percentage change in events was estimated using the negative binomial regression model. RESULTS: The results showed higher community-based service contacts (rate/100 person-years: 30.2, 95% confidence interval = [29.7-30.7] vs 22.8, 95% confidence interval = [22.6-22.9]) and hospitalisations (rate/1000 person-years: 14.8, 95% confidence interval = [13.6-16.0] vs 12.7, 95% confidence interval = [12.3-13.1]) in childhood cancer survivors compared to the control group. Childhood cancer survivors had a significantly higher risk of any event (adjusted hazard ratio = 1.5, 95% confidence interval = [1.1-2.0]). The cumulative burden of events increased with time since diagnosis and across age groups. The annual percentage change for hospitalisations and service contacts significantly increased over time (p < 0.05). Substance abuse was the leading cause of hospitalisations, while mood/affective and anxiety disorders were common causes of service contacts. Risk factors associated with increased service events included cancer diagnosis at age < 5 years, leukaemia diagnosis, high socioeconomic deprivation, and an attained age of < 18 years. CONCLUSIONS: The elevated utilisation of healthcare services observed among childhood cancer survivors emphasises the need for periodic assessment of psychiatric disorders, particularly in high-risk survivors, to facilitate early management and optimise healthcare resources.

Treatment patterns and outcomes in adolescents and young adults with nodular lymphocyte-predominant Hodgkin lymphoma: an IMPACT cohort study.

We leveraged population-based clinical and healthcare data to identify treatment patterns and long-term outcomes among adolescents and young adults (AYA) with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). All Ontario, Canada, AYA aged 15-21 years at diagnosis with NLPHL between 1992 and 2012 were identified, and their detailed clinical data were collected. Linkage to healthcare databases identified additional events (subsequent malignant neoplasms [SMN], relapses and deaths). Event-free survival (EFS) and overall survival (OS) were compared by locus of care (adult vs. paediatric) and predictors of outcomes determined. Of 1014 AYA with Hodgkin lymphoma, 54 (5.3%) had NLPHL; 15 (27.8%) were treated at a paediatric centre. No paediatric centre patient received radiation only versus 16 (41.0%) of adult centre patients. Excision only was more common in paediatric centres (p < 0.001). The 20-year EFS and OS rates were 82.9% ± 5.2% and 100% respectively. Advanced stage (hazard ratio: 4.9, 95% CI: 1.3-18.4; p = 0.02) was associated with inferior EFS. Although the 25-year cumulative incidence of SMN was 19.3% ± 9.6% for the entire cohort, there were no SMN among the patients treated with excision only. AYA with NLPHL have outstanding long-term survival. Resection alone was rare outside of paediatric institutions but associated with excellent outcomes. Given substantial SMN risks, chemotherapy-sparing and radiation-sparing strategies for appropriate subsets of patients are warranted.

Immediate and Ongoing Impact of COVID-19 on Chlamydia Treatment in Australia.

BACKGROUND: The COVID-19 pandemic has impacted the sexual health and well-being of individuals, directly through risk of contracting COVID-19, and indirectly through government lockdowns. Government restrictions were especially strict and long-lasting in Australia, they also varied by state, offering an interesting opportunity to study the impacts of varying restrictions. This study compares the impact of the COVID-19 pandemic and resulting restrictions on chlamydia treatment prescriptions during 2020, through to July 2021 between different states and demographic groups in Australia. METHODS: The rate of prescriptions per 100,000 population filled each month from January 2017 to July 2021 from Australia's Pharmaceutical Benefits Scheme for Azithromycin with a restricted indication to treat Chlamydia trachomatis was used to measure chlamydia treatment. The impact of COVID-19 lockdowns was modeled using an interrupted time-series Poisson regression model. RESULTS: The data included 520,025 prescriptions to treat chlamydia, averaging 37.5 prescriptions per month per 100,000 population. Prescriptions declined 26% in April to May 2020 when initial COVID-19 lockdowns began in Australia; prescriptions increased in the following months but remained on average 21% below prepandemic (2017-2019) levels through to July 2021. Prescriptions declined the most in 1 Australian state, Victoria, both in the initial lockdown and the following period; generally, states with more COVID-19 cases saw bigger reductions in prescriptions. CONCLUSIONS: This is the first study to examine how treatment for chlamydia in Australia was impacted by the COVID-19 pandemic and restrictions not only in the immediate-term, but also ongoing up to July 2021, providing important information for planning for sexual health services in future pandemics.

Childhood cancer survival and avoided deaths in Australia, 1983-2016.

BACKGROUND: Large improvements in childhood cancer survival have been reported over recent decades. Data from cancer registries have the advantage of providing a 'whole of population' approach to gauge the success of cancer control efforts. OBJECTIVES: The aim of this study was to investigate recent survival estimates for children diagnosed with cancer Australia and to examine the extent of changes in survival over the last 35 years. For the first time, we also estimated the number of deaths among Australian children that were potentially avoided due to improvements in survival. METHODS: A retrospective, population-based cohort study design was used. Case information was extracted from the Australian Childhood Cancer Registry for 1983-2016, with follow-up to 31 December 2017. Eligible children were aged 0-14 with a basis of diagnosis other than autopsy or death certificate only. Five-year relative survival was calculated using the semi-complete cohort method for three diagnosis periods (1983-1994, 1995-2006 and 2007-2016), and changes in survival over time were assessed via flexible parametric models. Avoided deaths within 5 years for those diagnosed between 1995 and 2016 were estimated under the assumption that survival rates remained the same as for 1983-1994. RESULTS: Overall 5-year survival within the study cohort (n = 20,871) increased from 72.8% between 1983 and1994 to 86.1% between 2007 and 2016, equating to an adjusted excess mortality hazard ratio of 1.82 (95% confidence interval 1.67, 1.97). Most cancers showed improvements in survival; other gliomas, hepatoblastoma and osteosarcoma were exceptions. Among children diagnosed between 1995 and 2016, 38.7% of expected deaths within 5 years of diagnosis (n = 1537 of 3970) were avoided due to temporal improvements in survival. CONCLUSIONS: Survival for childhood cancer has continued to improve over recent years, thanks mainly to ongoing progress in treatment development combined with improved supportive care. Providing innovative measures of survival, such as avoided deaths, may assist with understanding outcome data produced by cancer registries.

Rates and predictors of visits to primary care physicians during and after treatment of childhood acute lymphoblastic leukemia: A population-based cohort study.

INTRODUCTION: Patient re-engagement with primary care physicians (PCPs) after cancer treatment is essential to facilitate survivorship care and to meet non-oncology primary care needs. We identified rates and predictors of PCP visits both during and after treatment among a population-based cohort of children with acute lymphoblastic leukemia (ALL). METHODS: Children of age less than 18 years at ALL diagnosis in Ontario between 2002 and 2012 were linked to administrative data and matched to controls without cancer. PCPs at diagnosis were identified and PCP visit rates during treatment compared between patients and controls. Post-treatment PCP visit rates were also calculated. Predictors included demographic-, disease-, and PCP-related variables. RESULTS: A total of 743/793 (94%) patients and 3112/3947 (79%) controls had a PCP at diagnosis. Almost half of patients (361/743, 45%) did not visit their PCP during treatment. Visit rate during treatment was 0.64 per person per year (PPPY) versus 1.4 PPPY among controls (adjusted rate ratio [aRR] 0.47, 95th confidence interval [95CI]: 0.40-0.54; p < .0001). No disease- or PCP-related factors were associated with visit rates. Total 711 patients completed frontline therapy; 287 (40.4%) did not have a PCP visit after treatment. Nonetheless, survivors overall visited PCPs post treatment more often than controls (aRR 1.4, 95CI: 1.2-1.6; p < .0001). Survivors who saw their PCP during treatment had post-treatment visit rates twice that of other survivors (aRR 2.0, 95CI: 1.6-2.5; p < .0001). CONCLUSIONS: Only a portion of children with ALL see their PCPs during treatment and return to PCP care following treatment completion. Post-treatment engagement with PCPs may be improved by PCP involvement during ALL treatment.

Machine learning clinical prediction models for acute kidney injury: the impact of baseline creatinine on prediction efficacy.

BACKGROUND: There are many Machine Learning (ML) models which predict acute kidney injury (AKI) for hospitalised patients. While a primary goal of these models is to support clinical decision-making, the adoption of inconsistent methods of estimating baseline serum creatinine (sCr) may result in a poor understanding of these models' effectiveness in clinical practice. Until now, the performance of such models with different baselines has not been compared on a single dataset. Additionally, AKI prediction models are known to have a high rate of false positive (FP) events regardless of baseline methods. This warrants further exploration of FP events to provide insight into potential underlying reasons. OBJECTIVE: The first aim of this study was to assess the variance in performance of ML models using three methods of baseline sCr on a retrospective dataset. The second aim was to conduct an error analysis to gain insight into the underlying factors contributing to FP events. MATERIALS AND METHODS: The Intensive Care Unit (ICU) patients of the Medical Information Mart for Intensive Care (MIMIC)-IV dataset was used with the KDIGO (Kidney Disease Improving Global Outcome) definition to identify AKI episodes. Three different methods of estimating baseline sCr were defined as (1) the minimum sCr, (2) the Modification of Diet in Renal Disease (MDRD) equation and the minimum sCr and (3) the MDRD equation and the mean of preadmission sCr. For the first aim of this study, a suite of ML models was developed for each baseline and the performance of the models was assessed. An analysis of variance was performed to assess the significant difference between eXtreme Gradient Boosting (XGB) models across all baselines. To address the second aim, Explainable AI (XAI) methods were used to analyse the XGB errors with Baseline 3. RESULTS: Regarding the first aim, we observed variances in discriminative metrics and calibration errors of ML models when different baseline methods were adopted. Using Baseline 1 resulted in a 14% reduction in the f1 score for both Baseline 2 and Baseline 3. There was no significant difference observed in the results between Baseline 2 and Baseline 3. For the second aim, the FP cohort was analysed using the XAI methods which led to relabelling data with the mean of sCr in 180 to 0 days pre-ICU as the preferred sCr baseline method. The XGB model using this relabelled data achieved an AUC of 0.85, recall of 0.63, precision of 0.54 and f1 score of 0.58. The cohort size was 31,586 admissions, of which 5,473 (17.32%) had AKI. CONCLUSION: In the absence of a widely accepted method of baseline sCr, AKI prediction studies need to consider the impact of different baseline methods on the effectiveness of ML models and their potential implications in real-world implementations. The utilisation of XAI methods can be effective in providing insight into the occurrence of prediction errors. This can potentially augment the success rate of ML implementation in routine care.

Locus-of-care disparities in end-of-life care intensity among adolescents and young adults with cancer: A population-based study using the IMPACT cohort.

BACKGROUND: Adolescents and young adults (AYAs) with cancer may experience elevated rates of high-intensity end-of-life (HI-EOL) care. Locus-of-care (LOC) disparities (pediatric vs adult) in AYA end-of-life (EOL) care are unstudied. METHODS: A decedent population-based cohort of Ontario AYAs diagnosed between 1992 and 2012 at the ages of 15 to 21 years was linked to administrative data. The authors determined the prevalence and associations of a composite outcome of HI-EOL care that included any of the following: intravenous chemotherapy within 14 days of death, more than 1 emergency department visit, more than 1 hospitalization, or an intensive care unit (ICU) admission within 30 days of death. Secondary outcomes included measures of the most invasive EOL care (ventilation within 14 days of death and ICU death) and in-hospital death. RESULTS: There were 483 decedents: 60.5% experienced HI-EOL care, 20.3% were ventilated, and 22.8% died in the ICU. Compared with patients with solid tumors, patients with hematological malignancies had the greatest odds of HI-EOL care (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.5-3.4), ventilation (OR, 4.7; 95% CI, 2.7-8.3), and ICU death (OR, 4.4; 95% CI, 2.6-4.4). Subjects treated in pediatric centers versus adult centers near death (OR, 2.4; 95% CI, 1.2-4.8) and those living in rural areas (OR, 2.1; 95% CI, 1.1-3.9) were more likely to experience ICU death. CONCLUSIONS: AYAs with cancer experience high rates of HI-EOL care, with patients in pediatric centers and those living in rural areas having the highest odds of ICU death. This study is the first to identify LOC-based disparities in EOL care for AYAs, and it highlights the need to explore the mechanisms underlying these disparities.

Superior outcomes with paediatric protocols in adolescents and young adults with aggressive B-cell non-Hodgkin lymphoma.

Survival disparities by locus of care (LOC; paediatric versus adult) among adolescents and young adults (AYA) with acute lymphoblastic leukaemia (ALL) are well documented. Whether similar disparities exist among AYA with aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) is unknown. We identified all Ontario, Canada AYA aged 15-21 years at diagnosis of B-NHL between 1992 and 2012. Demographic, disease, treatment and outcome data were chart abstracted. The impact of LOC on event-free (EFS) and overall survival (OS) were determined, adjusted for patient and disease covariates. Among 176 AYA with B-NHL, 62 (35·2%) received therapy at paediatric centres. The 5-year EFS and OS [± standard error (SE)] for the overall cohort were 72·2 [3·4]% and 76·1 [3·2]% respectively. Both EFS and OS were superior among paediatric centre AYA [EFS (± SE) 82·2 (4·9)% vs. 66·7 (4·4)%, P = 0·02; OS 85·5 (4·5)% vs. 71·1 (4·3)%, P = 0·03]. Adjusted for histology, stage and time period, adult centre AYA had inferior EFS [hazard ratio (HR) 2·4, 95% confidence interval (CI) 1·1-4·9, P = 0·02] and OS (HR 2·5, 95% CI 1·1-5·7, P = 0·03). Sensitivity analyses restricted to the latest time period, when most adult centre AYA received rituximab, demonstrated similar disparities. Similar to AYA with ALL, AYA with B-NHL may benefit from being treated with paediatric protocols. Studies prospectively validating these results are warranted.

Quantifying cancer risk from exposures to medical imaging in the Risk of Pediatric and Adolescent Cancer Associated with Medical Imaging (RIC) Study: research methods and cohort profile.

PURPOSE: The Risk of Pediatric and Adolescent Cancer Associated with Medical Imaging (RIC) Study is quantifying the association between cumulative radiation exposure from fetal and/or childhood medical imaging and subsequent cancer risk. This manuscript describes the study cohorts and research methods. METHODS: The RIC Study is a longitudinal study of children in two retrospective cohorts from 6 U.S. healthcare systems and from Ontario, Canada over the period 1995-2017. The fetal-exposure cohort includes children whose mothers were enrolled in the healthcare system during their entire pregnancy and followed to age 20. The childhood-exposure cohort includes children born into the system and followed while continuously enrolled. Imaging utilization was determined using administrative data. Computed tomography (CT) parameters were collected to estimate individualized patient organ dosimetry. Organ dose libraries for average exposures were constructed for radiography, fluoroscopy, and angiography, while diagnostic radiopharmaceutical biokinetic models were applied to estimate organ doses received in nuclear medicine procedures. Cancers were ascertained from local and state/provincial cancer registry linkages. RESULTS: The fetal-exposure cohort includes 3,474,000 children among whom 6,606 cancers (2394 leukemias) were diagnosed over 37,659,582 person-years; 0.5% had in utero exposure to CT, 4.0% radiography, 0.5% fluoroscopy, 0.04% angiography, 0.2% nuclear medicine. The childhood-exposure cohort includes 3,724,632 children in whom 6,358 cancers (2,372 leukemias) were diagnosed over 36,190,027 person-years; 5.9% were exposed to CT, 61.1% radiography, 6.0% fluoroscopy, 0.4% angiography, 1.5% nuclear medicine. CONCLUSION: The RIC Study is poised to be the largest study addressing risk of childhood and adolescent cancer associated with ionizing radiation from medical imaging, estimated with individualized patient organ dosimetry.

Changes in cancer incidence and survival among Aboriginal and Torres Strait Islander children in Australia, 1997-2016.

BACKGROUND: This study reports cancer incidence and survival among Aboriginal and Torres Strait Islander children and other Australian children, and assesses changes over time. PROCEDURE: Data were from the population-based Australian Childhood Cancer Registry. The study comprised children aged under 15 diagnosed between 1997 and 2016 and with mortality follow-up until 31 December 2017. Incidence trends were analysed using JoinPoint regression. Five-year cancer-specific survival was calculated using the semi-complete approach with survival comparisons made using multivariable flexible parametric models. RESULTS: Aboriginal and Torres Strait Islander children accounted for 506 of 13,299 eligible cases (3.8%). Incidence rates for Aboriginal and Torres Strait Islander children across the study period increased by 2.3% annually (95% confidence interval [CI]: +0.6% to +4.0%) and for other Australian children increased by 0.6% annually (95% CI: +0.3% to +0.9%; p = .05). Nonetheless, cancer incidence was consistently lower for Aboriginal and Torres Strait Islander children, with an incidence rate ratio of 0.73 (95% CI: 0.62-0.85; p < .01) between 2012 and 2016. Survival for Aboriginal and Torres Strait Islander children with solid tumours was 70.6% (95% CI: 62.5%-77.3%) and for other Australian children was 83.5% (95% CI: 82.3%-84.7%; p < .01), with indications of this difference diminishing in recent years. CONCLUSIONS: Improvements in identification, particularly in urban areas, most likely accounts for the greater increase in cancer incidence rates among Aboriginal and Torres Strait Islander children. Examination of data on stage at diagnosis and treatment may provide important insights into survival for children with solid tumours.

Healthcare utilization and costs associated with acute lymphoblastic leukemia in children with and without Down syndrome.

BACKGROUND: Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are at increased risk of treatment-related morbidity and mortality compared to non-DS-ALL, requiring increased supportive care. We examined the healthcare utilization and costs in DS-ALL patients to inform future evaluations of novel therapies. METHODS: A provincial registry identified all children (1-17 years) diagnosed with B-lineage ALL in Ontario, Canada between 2002 and 2012. Detailed demographic, disease, treatment, and outcome data were abstracted. Linkage to population-based health services databases identified all outpatient and emergency department (ED) visits, hospitalizations, and physician billings. Healthcare utilization costs were available for patients diagnosed during 2006-2012 using validated algorithms (2018 Canadian dollars). Healthcare utilization rates and costs were compared between DS and non-DS patients using regression models, adjusting for all covariates. RESULTS: Of 711 patients, 28 (3.9%) had DS. Adjusting for all covariates, children with DS-ALL experienced substantially higher rates of ED visits (rate ratio [RR] 1.5, 95% confidence interval [95% CI]: 1.2-2.0; p = .001) and inpatient days (RR 2.5, 95% CI: 1.4-4.5; p = .002) compared to non-DS children. Outpatient visit rates were similar (RR 1.1, 95% CI: 0.9-1.3; p = .41). Among patients with available cost data (N = 533, DS = 19), median 5-year healthcare utilization cost was $247,700 among DS patients (interquartile range [IQR]: 200,900-354,500) and $196,200 among non-DS patients (IQR: 148,900-280,300; p = .02). In adjusted analyses, DS-associated costs were 50% higher (RR 1.5, 95% CI: 1.2-1.9; p < .002). CONCLUSIONS: Healthcare utilization and treatment costs of DS-ALL patients are substantially higher than those of non-DS-ALL. Our data provide a baseline for future DS-specific cost-effectiveness studies.

Positive predictive value and sensitivity of ICD-9-CM codes for identifying pediatric leukemia.

BACKGROUND: To facilitate community-based epidemiologic studies of pediatric leukemia, we validated use of ICD-9-CM diagnosis codes to identify pediatric leukemia cases in electronic medical records of six U.S. integrated health plans from 1996-2015 and evaluated the additional contributions of procedure codes for diagnosis/treatment. PROCEDURES: Subjects (N = 408) were children and adolescents born in the health systems and enrolled for at least 120 days after the date of the first leukemia ICD-9-CM code or tumor registry diagnosis. The gold standard was the health system tumor registry and/or medical record review. We calculated positive predictive value (PPV) and sensitivity by number of ICD-9-CM codes received in the 120-day period following and including the first code. We evaluated whether adding chemotherapy and/or bone marrow biopsy/aspiration procedure codes improved PPV and/or sensitivity. RESULTS: Requiring receipt of one or more codes resulted in 99% sensitivity (95% confidence interval [CI]: 98-100%) but poor PPV (70%; 95% CI: 66-75%). Receipt of two or more codes improved PPV to 90% (95% CI: 86-93%) with 96% sensitivity (95% CI: 93-98%). Requiring at least four codes maximized PPV (95%; 95% CI: 92-98%) without sacrificing sensitivity (93%; 95% CI: 89-95%). Across health plans, PPV for four codes ranged from 84-100% and sensitivity ranged from 83-95%. Including at least one code for a bone marrow procedure or chemotherapy treatment had minimal impact on PPV or sensitivity. CONCLUSIONS: The use of diagnosis codes from the electronic health record has high PPV and sensitivity for identifying leukemia in children and adolescents if more than one code is required.

Temporal clustering of neuroblastic tumours in children and young adults from Ontario, Canada.

BACKGROUND: The aetiology of neuroblastic tumours is likely to involve both genetic and environmental factors. A number of possible environmental risk factors have been suggested, including infection. If an irregular temporal pattern in incidence is found, this might suggest that a transient agent, such as an infection, is implicated. Previous work has found evidence for temporal clustering in children and young adults living in northern England. METHODS: We examined data from a second population-based registry from Ontario, Canada to determine whether there was evidence of temporal clustering of neuroblastic tumours. Cases diagnosed in children and young adults aged 0-19 years between 1985 and 2016 were extracted from the population-based Pediatric Oncology Group of Ontario Networked Information System (POGONIS). A modified version of the Potthoff-Whittinghill method was used to test for temporal clustering. Estimates of extra-Poisson variation (EPV) and standard errors (SE) were obtained. RESULTS: Eight hundred seventy-six cases of neuroblastic tumours were diagnosed during the study period. Overall, no evidence of temporal clustering was found between fortnights, between months or between quarters within years. However, significant EPV was found between years within the full study period (EPV = 1.05, SE = 0.25; P = 0.005). CONCLUSIONS: The findings are consistent with the possibility that a transient agent, such as an infection that is characterised by 'peaks and troughs' in its occurrence, might be implicated in the aetiology of neuroblastic tumours. However, this pattern may also reflect a long-term increase in the numbers of cases, rather than peaks and troughs.

The Impact of Hospital Surgical Volume on Healthcare Utilization Outcomes After Pediatric Thyroidectomy.

BACKGROUND: A positive relationship between an individual surgeon's operative volume and clinical outcomes after pediatric and adult thyroidectomy is well-established. The impact of a hospital's pediatric operative volume on surgical outcomes and healthcare utilization, however, are infrequently reported. We investigated associations between hospital volume and healthcare utilization outcomes following pediatric thyroidectomy in Canada's largest province, Ontario. METHODS: Retrospective analysis of administrative and health-related population-level data from 1993 to 2017. A cohort of 1908 pediatric (<18 years) index thyroidectomies was established. Hospital volume was defined per-case as thyroidectomies performed in the preceding year. Healthcare utilization outcomes: length of stay (LOS), same day surgery (SDS), readmission, and emergency department (ED) visits were measured. Multivariate analysis adjusted for patient-level, disease and hospital-level co-variates. RESULTS: Hospitals with the lowest volume of pediatric thyroidectomies, accounted for 30% of thyroidectomies province-wide and performed 0-1 thyroidectomies/year. The highest-volume hospitals performed 19-60 cases/year. LOS was 0.64 days longer in the highest, versus the lowest quartile. SDS was 83% less likely at the highest, versus the lowest quartile. Hospital volume was not associated with rate of readmission or ED visits. Increased ED visits were, however, associated with male sex, increased material deprivation, and rurality. CONCLUSIONS: Increased hospital pediatric surgical volume was associated with increased LOS and lower likelihood of SDS. This may reflect patient complexity at such centers. In this cohort, low-volume hospitals were not associated with poorer healthcare utilization outcomes. Further study of groups disproportionately accessing the ED post-operatively may help direct resources to these populations.

Pediatric hepatic cancer incidence and survival: 30-year trends in Ontario, Canada; the United States; and Australia.

BACKGROUND: Pediatric hepatic cancer is a rare malignancy, comprising only approximately 2% of all cancers diagnosed in children aged <15 years. The authors sought to describe trends in pediatric hepatic cancer incidence and survival in Ontario, Canada; the United States; and Australia. METHODS: Children aged <15 years who were diagnosed with hepatic cancer from 1985 through 2013 were ascertained through population-based registries and followed from the time of diagnosis until December 31, 2015. Age-standardized incidence and 5-year relative survival were calculated for each jurisdiction. Multivariable flexible parametric survival models were used to explore predictors of hepatic cancer mortality. RESULTS: A total of 794 children were identified in Ontario (148 children), the United States (400 children), and Australia (246 children). The average annual incidence increased by 2.2% (95% CI, 0.5%-4.0%) in Australia, 2.1% (95% CI, 0.9%-3.3%) in the United States, and 1.3% (95% CI, -0.4% to 3.0%) in Ontario. The 5-year relative survival rate improved from 60% to 82% (P = .08) in Ontario and 62% to 78% (P = .02) in the United States between the diagnostic periods 1985 through 1994 and 2005 through 2013, whereas in Australia the rate remained constant (between 74% and 77%) during the study period. On multivariable analysis, there was no significant difference noted with regard to the hazard of death between jurisdictions (P = .06). Older age, the presence of metastatic disease, and being diagnosed with hepatocellular carcinoma were found to be associated with mortality. CONCLUSIONS: The incidence of hepatic cancer in children appears to have increased over the last 30 years in Australia and North America. Survival differences between Australia; Ontario, Canada; and the United States observed in the 1980s and 1990s were no longer apparent and only marginal geographical differences in the hazard of mortality were observed.

Leukemia Risk in a Cohort of 3.9 Million Children with and without Down Syndrome.

OBJECTIVE: To assess leukemia risks among children with Down syndrome in a large, contemporary cohort. STUDY DESIGN: Retrospective cohort study including 3 905 399 children born 1996-2016 in 7 US healthcare systems or Ontario, Canada, and followed from birth to cancer diagnosis, death, age 15 years, disenrollment, or December 30, 2016. Down syndrome was identified using International Classification of Diseases, Ninth and Tenth Revisions, diagnosis codes. Cancer diagnoses were identified through linkages to tumor registries. Incidence and hazard ratios (HRs) of leukemia were estimated for children with Down syndrome and other children adjusting for health system, child's age at diagnosis, birth year, and sex. RESULTS: Leukemia was diagnosed in 124 of 4401 children with Down syndrome and 1941 of 3 900 998 other children. In children with Down syndrome, the cumulative incidence of acute myeloid leukemia (AML) was 1405/100 000 (95% CI 1076-1806) at age 4 years and unchanged at age 14 years. The cumulative incidence of acute lymphoid leukemia in children with Down syndrome was 1059/100 000 (95% CI 755-1451) at age 4 and 1714/100 000 (95% CI 1264-2276) at age 14 years. Children with Down syndrome had a greater risk of AML before age 5 years than other children (HR 399, 95% CI 281-566). Largest HRs were for megakaryoblastic leukemia before age 5 years (HR 1500, 95% CI 555-4070). Children with Down syndrome had a greater risk of acute lymphoid leukemia than other children regardless of age (<5 years: HR 28, 95% CI 20-40, ≥5 years HR 21, 95% CI 12-38). CONCLUSIONS: Down syndrome remains a strong risk factor for childhood leukemia, and associations with AML are stronger than previously reported.

Thrombosis is associated with worse survival in children with acute lymphoblastic leukemia: A report from CYP-C.

There are conflicting data about whether the development of cancer-associated thrombo-embolism (TE) negatively impacts survival in children. The objective was to determine whether TE during treatment was associated with overall survival (OS) and event-free survival (EFS) in children with acute lymphoblastic leukemia (ALL). We performed a population-based retrospective cohort study using the Cancer in Young People-Canada registry. Children <15 years of age were diagnosed with de novo ALL (2000-2016). The primary exposure variable was radiologically-confirmed thrombo-embolism requiring medical intervention. Multivariable Cox regression models were used to determine the impact of thrombo-embolism on survival, where TE was time-dependent. We included 2006 children (median age: 4 years, 88.5% precursor B-cell ALL). Thrombo-embolism occurred in 113 patients (5.6%), at a median time of 107 days (interquartile range: 35-184 days) after ALL diagnosis. Among standard/low-risk patients, 41/1165 (3.5%) developed TE while among high/very high-risk patients, 72/841 (8.6%) developed TE. Patients with TE had a significantly worse OS (adjusted HR [aHR] of death: 2.61, 95% CI: 1.62-4.22, p < 0.001) and EFS (aHR of an event [death, relapse, second malignancy]: 2.03, 95% CI: 1.35-3.05, p = 0.001), compared with patients without TE. No statistically significant difference was seen in standard/low risk ALL for OS and EFS, but TE was associated with a significantly lower OS and EFS in children with high/very high-risk ALL (aHR of death: 2.90, 95% CI: 1.79-4.72, p < 0.001; aHR of an event: 2.02, 95% CI: 1.30-3.12, p = 0.002). Thus, TE led to a statistically significant reduction in OS and EFS in children with high risk/very high-risk leukemia.

Late mortality from other diseases following childhood cancer in Australia and the impact of intensity of treatment.

BACKGROUND: People who receive treatment for cancer during childhood often experience subsequent complications of therapy, known as late effects, which can lead to an increased risk of death. PROCEDURE: Using deidentified population-based data from the Australian Childhood Cancer Registry for children aged 0-14 diagnosed with cancer during the period 1983-2011 and who survived for a minimum of 5 years, we examined disease-related deaths (other than cancer recurrence or second primary cancers) that occurred up to 31 December 2016. Risk of death relative to the general population was approximated using standardised mortality ratios (SMRs). Treatment received was stratified according to the intensity of treatment rating, version 3 (ITR-3). RESULTS: During the study period, 82 noncancer disease-related deaths were recorded among 13 432 childhood cancer survivors, four times higher than expected (SMR = 4.43, 95% CI = 3.57-5.50). A clear link to treatment intensity was observed, with the relative risk of noncancer disease-related mortality being twice as high for children who underwent 'most intensive' treatment (SMR = 5.94, 95% CI = 3.69-9.55) compared to the 'least intensive' treatment group (SMR = 2.98, 95% CI = 1.42-6.24; Ptrend  = .01). Thirty-year cumulative mortality from noncancer disease-related deaths was estimated at 1.4% (95% CI = 1.1-1.9) after adjusting for competing causes of death such as cancer, accidents, or injuries. CONCLUSIONS: Although childhood cancer survivors are at increased relative risk of death from noncancer diseases, particularly those who undergo more intensive treatment, the cumulative mortality within 30 years of diagnosis remains small. Knowledge of late effects can guide surveillance of survivors and treatment modification, without wanting to compromise the high rates of survival.

Adolescents and young adult acute myeloid leukemia outcomes at pediatric versus adult centers: A population-based study.

BACKGROUND: Adolescents and young adult (AYA) acute myeloid leukemia (AML) outcomes remain poor. The impact of locus of care (LOC; adult vs pediatric) in this population is unknown. PROCEDURE: The IMPACT cohort comprises detailed data for all Ontario, Canada, AYA aged 15-21 years diagnosed with AML between 1992 and 2012, linked to population-based health administrative data. We determined the impact of LOC on event-free survival (EFS) and overall survival (OS), treatment-related mortality (TRM), and relapse/progression. RESULTS: Among 140 AYA, 51 (36.4%) received therapy at pediatric centers. The five-year EFS and OS for the whole cohort were 35.0% ± 4.0% and 53.6% ± 4.2%. Cumulative doses of anthracycline were higher among pediatric center AYA [median 355 mg/m2 , interquartile range (IQR) 135-492 vs 202 mg/m2 , IQR 140-364; P = 0.003]. In multivariable analyses, LOC was not predictive of either EFS [adult vs pediatric center hazard ratio (HR) 1.3, 95% confidence interval (CI) 0.8-2.2, P = 0.27] or OS (HR 1.0, CI 0.6-1.6, P = 0.97). However, patterns of treatment failure varied; higher two-year incidence of TRM in pediatric centers (23.5% ± 6.0% vs.10.1% ± 3.2%; P = 0.046) was balanced by lower five-year incidence of relapse/progression (33.3% ± 6.7% vs 56.2% ± 5.3%; P = 0.002). CONCLUSIONS: AYA AML survival outcomes did not vary between pediatric and adult settings. Causes of treatment failure were different, with higher intensity pediatric protocols associated with higher TRM but lower relapse/progression. Careful risk stratification and enhanced supportive care may be of substantial benefit to AYA with AML by allocating maximal treatment intensity to patients who most benefit while minimizing the risk of TRM.