Epidemiology of clinically unsuspected venous thromboembolism in children with cancer: A population-based study from Maritimes, Canada.

Inconsistencies in the definition of clinically unsuspected venous thromboembolism (VTE) in pediatric patients recently led to the recommendation of standardizing this terminology. Clinically unsuspected VTE (cuVTE) is defined as the presence of VTE on diagnostic imaging performed for indications unrelated to VTE in a patient without symptoms or clinical history of VTE. The prevalence of cuVTE in pediatric cancer patients is unclear. Therefore, the main objective of our study was to determine the prevalence of cuVTE in pediatric cancer patients. All patients 0-18 years old, treated at the IWK in Halifax, Nova Scotia, from August 2005 through December 2019 with a known cancer diagnosis and at least one imaging study were eligible (n = 743). All radiology reports available for these patients were reviewed (n = 18,120). The VTE event was labeled a priori as cuVTE event for radiology reports that included descriptive texts indicating a diagnosis of thrombosis including thrombus, central venous catheter-related, thrombosed aneurysm, tumor thrombosis, non-occlusive thrombus, intraluminal filling defect, or small fragment clot for patients without documentation of clinical history and or signs of VTE. A total of 18,120 radiology reports were included in the review. The prevalence of cuVTE was 5.5% (41/743). Echocardiography and computed tomography had the highest rate of cuVTE detection, and the most common terminologies used to diagnose cuVTE were thrombus and non-occlusive thrombus. The diagnosis of cuVTE was not associated with age, sex, and type of cancer. Future efforts should focus on streamlining radiology reports to characterize thrombi. The clinical significance of these cuVTE findings and their application to management, post-thrombotic syndrome, and survival compared to cases with symptomatic VTE and patients without VTE should be further studied.

Antibiotic and antifungal use in pediatric leukemia and lymphoma patients are associated with increasing opportunistic pathogens and decreasing bacteria responsible for activities that enhance colonic defense.

Due to decreased immunity, both antibiotics and antifungals are regularly used in pediatric hematologic-cancer patients as a means to prevent severe infections and febrile neutropenia. The general effect of antibiotics on the human gut microbiome is profound, yielding decreased diversity and changes in community structure. However, the specific effect on pediatric oncology patients is not well-studied. The effect of antifungal use is even less understood, having been studied only in mouse models. Because the composition of the gut microbiome is associated with regulation of hematopoiesis, immune function and gastrointestinal integrity, changes within the patient gut can have implications for the clinical management of hematologic malignancies. The pediatric population is particularly challenging because the composition of the microbiome is age dependent, with some of the most pronounced changes occurring in the first three years of life. We investigated how antibiotic and antifungal use shapes the taxonomic composition of the stool microbiome in pediatric patients with leukemia and lymphoma, as inferred from both 16S rRNA and metagenome data. Associations with age, antibiotic use and antifungal use were investigated using multiple analysis methods. In addition, multivariable differential abundance was used to identify and assess specific taxa that were associated with multiple variables. Both antibiotics and antifungals were linked to a general decline in diversity in stool samples, which included a decrease in relative abundance in butyrate producers that play a critical role in host gut physiology (e.g., Faecalibacterium, Anaerostipes, Dorea, Blautia),. Furthermore, antifungal use was associated with a significant increase in relative abundance of opportunistic pathogens. Collectively, these findings have important implications for the treatment of leukemia and lymphoma patients. Butyrate is important for gastrointestinal integrity; it inhibits inflammation, reinforces colonic defense, mucosal immunity. and decreases oxidative stress. The routine use of broad-spectrum anti-infectives in pediatric oncology patients could simultaneously contribute to a decline in gastrointestinal integrity and colonic defense while promoting increases in opportunistic pathogens within the patient gut. Because the gut microbiome has been linked to both short-term clinical outcomes, and longer-lasting health effects, systematic characterization of the gut microbiome in pediatric patients during, and beyond, treatment is warranted.

Gut bacterial gene changes following pegaspargase treatment in pediatric patients with acute lymphoblastic leukemia.

Treatment of pediatric acute lymphoblastic leukemia (ALL) with pegaspargase exploits ALL cells dependency on asparagine. Pegaspargase depletes asparagine, consequentially affecting aspartate, glutamine and glutamate. The gut as a confounding source of these amino acids (AAs) and the role of gut microbiome metabolism of AAs has not been examined. We examined asparagine, aspartate, glutamine and glutamate in stool samples from patients over pegaspargase treatment. Microbial gene-products, which interact with these AAs were identified. Stool asparagine declined significantly, and 31 microbial genes changed over treatment. Changes were complex, and included genes involved in AA metabolism, nutrient sensing, and pathways increased in cancers. While we identified changes in a gene (iaaA) with limited asparaginase activity, it lacked significance after correction leaving open other mechanisms for asparagine decline, possibly including loss from gut to blood. Understanding pathways that change AA availability, including by microbes in the gut, could be useful in optimizing pegaspargase therapy.

Use of Tissue Plasminogen Activator as a Surrogate Measure for Central Venous Catheter Dysfunction and Survival Outcome in Children with Cancer: A Population-Based Retrospective Cohort Study.

Central venous catheter (CVC) dysfunction is often associated with thrombosis, which in turn has been linked with poorer survival outcomes in cancer patients. Our objective was to examine the association of tissue plasminogen activator (tPA) administration as a surrogate measure of CVC dysfunction with survival in pediatric cancer patients. The present study uses data from a population-based retrospective cohort of pediatric oncology patients from the Canadian Maritime provinces treated between 2000 and 2017 at the IWK Health Centre, Halifax, NS. Demographics, diagnosis, date of death or date of last visit, and tPA use for CVC dysfunction were obtained from clinical databases and the provincial Cancer in Young People in Canada registry. The association between tPA administration and survival was examined using a Cox regression model adjusted for sex, age at diagnosis, cancer type, thrombosis, CVC duration, diagnosis era, and treatment modalities. Out of 821 patients, 206 received one or more doses of tPA during upfront therapy. The death rate was 21% and 15% respectively in patients who did and did not receive tPA. In the adjusted regression model, after receiving one or more doses of tPA, children had significantly poorer survival as compared to those that did not receive tPA (HR: 1.496, 95% CI: 1.019, 2.197). CVC dysfunction may be associated with a poorer prognosis in pediatric cancer patients. Future studies should corroborate these findings in other populations, examine the influence of other potential confounders, and determine the role of CVC dysfunction in prognostic models of cancer survival.

Correction to: The association of venous thromboembolism with survival in pediatric cancer patients: a population-based cohort study.

The Figure 1 used in the originally published version of this article was incorrect.

The association of venous thromboembolism with survival in pediatric cancer patients: a population-based cohort study.

Venous thromboembolism (VTE) is a well-recognized complication in pediatric oncology patients. Studies in adult oncology patients have suggested a potential negative association between VTE and survival, but this association has not been examined in pediatric patients yet. The aim of this study was to assess the association of VTE with survival in pediatric oncology patients. Data from all pediatric oncology patients treated at the two tertiary care centers in Atlantic Canada were pooled to create a population-based cohort. The association between VTE and survival was analyzed using a Cox proportional hazards model stratified by diagnosis group (leukemia, lymphoma, and other; sarcoma) and adjusted for age at diagnosis and sex. Out of 939 patients included in this study, 73 had a VTE (8%) and 131 (14%) patients died during the study period. Children in the leukemia/lymphoma/other group with a VTE had significantly poorer survival relative to children in the same group who did not have a VTE. Although children with sarcoma and VTE had poorer survival compared to children with sarcoma with no VTE, this association was not statistically significant. In this population-based study, we found a negative association between VTE and survival in pediatric oncology patients. If future studies confirm this association, this finding may have prognostic implications and potentially offer new avenues for the management of pediatric patients with cancer.