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Asparaginase (ASNase) is an effective treatment of pediatric acute lymphoblastic leukemia (ALL). Changes in ASNase activity may lead to suboptimal treatment and poorer outcomes. The gut microbiome produces metabolites that could impact ASNase therapy, however, remains uninvestigated. We examined gut-microbial community and microbial-ASNase and asparagine synthetase (ASNS) genes using 16SrRNA and metagenomic sequence data from stool samples of pediatric ALL patients. Comparing ASNase activity between consecutive ASNase-doses, we found microbial communities differed between decreased- and increased-activity samples. Escherichia predominated in the decreased-activity community while Bacteroides and Streptococcus predominated in the increased-activity community. In addition microbial ASNS was significantly (p=.004) negatively correlated with change in serum ASNase activity. These preliminary findings suggest microbial communities prior to treatment could affect serum ASNase levels, although the mechanism is unknown. Replication in an independent cohort is needed, and future research on manipulation of these communities and genes could prove useful in optimizing ASNase therapy.

The present population-based study evaluates the management and complications of peripherally inserted central catheters (PICC) in all pediatric oncology patients diagnosed in Maritimes, Canada from 2000 to 2014. A total of 107 PICCs were placed in 87 (10.1%) pediatric oncology patients. A high percentage (33% and 44%, respectively) of the first and second PICC lines was associated with complications. Thrombosis, occlusion, and infection were the most frequent complications. Age above 10 years and left body side of insertion were significantly associated with PICC complications. Given the frequent use of PICCs and the high incidence (>33%) of complications, there is a need to mitigate PICC line complications.

Background: L-asparaginase (ASNase) converts Asn to Asp and at sustained high levels depletes circulating Asn, leading to leukemic cell death. This dependency has led to the use of ASNase (in a peglyated form, PEGASNase) as an important therapy in the treatment of acute lymphoblastic leukemia (ALL) and has improved survival in patients with ALL. ASNase treatment efficacy relies on significant depletion of circulating Asn for sustained periods of time. Therapeutic monitoring is therefore critical to ensure sufficient levels of ASNase activity to maintain Asn depletion. Serum ASNase activity is monitored as a proxy for Asn levels, having an inverse relationship to Asn. The predictors of serum levels of ASNase activity are not clear however with variation in levels within the same patient between doses. The gut microbiome plays a role in human health and disease, producing metabolites that could impact ASNase therapy. To date, the role of the gut microbiome community in impacting serum ASNase activity levels has not been investigated. Methods: We investigated 12 paediatric ALL patients for which serum ASNase levels were measured (7 days post treatment) for two consecutive doses of PEGASNase and a stool sample was collected between these two doses (17 samples). Change in serum ASNase activity was determined by examining the difference in consecutive serum ASNase levels. Activity was considered to have decreased when change was negative (serum ASNase levels declined from previous measurement). Gut microbial community composition of the stool samples was determined from a portion of the 16S rRNA gene. In addition whole shotgun metagenome sequencing was used to investigate the relationship between microbial ASNase and ASNS genes and changes in serum ASNase levels during treatment. We utilized a Bayesian model to examine the microbial community structure in serum ASNase decreasing (SD) vs increasing (SI) samples. We used Mann-Whitney U test to examine differences in counts of bacterial ASNase and ASNS genes in SD and SI groups. Finally we investigated counts of bacterial ASNase and ASNS genes along with age, gender, disease risk, dose number, serum ASNase level at previous dose and time between stool sample and dose at predicting change in serum ASNase activity levels using regression models after applying lasso reduction. Results: Patients in this study were 50% male and had an average age of 5 years ranging from 1 month to 14.6 years. Among samples examined 35% had decreased serum activity compared to measurements from the previous dose. We identified differing assemblages of microbial taxa prior to PEGASNase treatment. The SD community was predominated by Escherichia prior to treatment while Bacteroides and Streptococcus predominated in the SI community (Fig 1). We found that counts of microbial ASNS were significantly (p=0.003) negatively correlated with change in serum ASNase activity levels (Fig 2), however neither bacterial ASNase gene (ansA or ansB) was significant. Including covariates and applying model reduction we find that ASNS (p=0.0005), dose number (p= 0.001), age at diagnosis (p= 0.001), serum ASNase levels at previous dose (p= 0.008), and counts of ansA (p=0.04) predict change in serum ASNase levels (adjusted R2=0.826, p= 0.0002). Only dose-number was positively correlated with change in serum ASNase level. Conclusions: We found differences in the microbial community prior to PEGASNase treatment possibly suggesting that modifying the microbiome (decreasing contribution of Escherichia) prior to treatment could result in increased serum ASNase activity. This data also suggests that increased amounts of bacterial ASNS genes present may be associated with a decrease in serum ASNase activity. Future work should focus on a larger and more diverse set of samples in order to further investigate SD and SI community-level properties and the role of covariates (e.g., age and dose number), and further exam the interplay between serum ASNase activity, and bacterial ASNS. Disclosures No relevant conflicts of interest to declare.

Intravenous (IV) administration of pegaspargase in children with acute lymphoblastic leukemia (ALL) may be associated with an increased risk of allergic reactions, and thus the need for more costly intramuscular (IM) erwinia asparaginase. In 128 patients allergic reactions were documented in 3% and 14% of those who received IM and IV pegaspargase, respectively (P=0.029). These reactions were primarily contributed to by high risk (HR)-ALL patients (P

Asparaginase is integral in the treatment of pediatric leukemia/lymphoma. Since its introduction into protocols in the 1960s, survival rates have increased to 90%. Asparaginase levels can be measur...

Venous thrombotic events (VTE) are a well-recognized complication in pediatric cancer patients. Population-based data on the incidence and characteristics of VTE in all pediatric cancer patients are limited. This information is crucial to identify patients at high risk and design targeted interventions accordingly. The present study was designed to determine the incidence and characteristics of VTE in the pediatric oncology population.We conducted a retrospective, population-based, cohort study of patients treated in the Maritimes, Canada between 1995 and 2015.There were 1210 pediatric hematology/oncology patients from the Maritimes, Canada, treated at the IWK Health Centre between 1995 and 2015. Fifty-eight (4.8%) experienced at least 1 VTE and the majority of patients experienced it within 6 months of cancer diagnosis. The median age of patients who experienced VTE was 10.7 years (SD = 6.0). The most common presenting symptom of thrombosis was central venous line dysfunction, and the most common location for thrombosis was within the upper venous system. We observed that 65.6% of the patients with VTE required1 central venous catheters (CVC). The presence of a VTE increased the odds of requiring1 CVC to 3.6 (95% confidence interval: 1.76-7.3).Thus, in this large, population-based study, we present the incidence and characteristics of VTE in the pediatric oncology population and demonstrate the clinical impact of VTE in terms of loss of CVC. Larger, prospective studies are required to confirm these findings and to develop a risk model for managing and preventing VTE in this patient population.

Objectives: To explore the health literacy of children diagnosed with Acute Lymphoblastic Leukemia (ALL) through their knowledge of their medications.Methods: Within the Basic Interpretive approach to qualitative research, semi-structured interviews were conducted with children from ages 6 to18 years (n=16) between May and September 2009 to determine their knowledge of medication properties, medication habits and medication teaching. REB approval was obtained.Results: The younger children (mean age 7.5 years) correctly answered, on average, 51% of the questions on colour, 26% of the questions on name, 25% of the questions on frequency, and 8% of the questions on the purposes of their medications. The older children (mean age 16 years) scored at least 35% higher for each characteristic. All of the younger children reported that physicians consistently directed medication education to parents only, and that the younger children were rarely present during these sessions. 13 of the 16 children stated that they want to learn more about and be more involved in education sessions addressing their medications.Conclusion: Children with ALL at the IWK Health Centre do not have a good knowledge of their medications, however most children expressed that they want to know more about their medications. Keywords: Health Literacy. Health Knowledge, Attitudes, Practice. Neoplasms. Child. Adolescent. Canada.

Objectives To describe the safety and efficacy of nabilone given to pediatric patients to prevent acute chemotherapy-induced nausea and vomiting (CINV). Methods A multicenter, retrospective review of pediatric patients who received nabilone for acute CINV prophylaxis between December 1, 2010 and August 1, 2015 was undertaken. One course of nabilone was evaluated per patient. Adverse effects associated with nabilone use were noted. The proportion of patients who experienced complete acute chemotherapy-induced vomiting (CIV) control during the acute phase was determined. The acute phase was defined as starting with the first chemotherapy dose and continuing until 24 h after administration of the last chemotherapy dose of the chemotherapy block. Results One hundred ten eligible patients (median age: 14.0 years, range: 1.1-18.0 years; 65 male) were identified. Most (109/110) received nabilone plus a 5-HT3 antagonist for CINV prophylaxis. Adverse effects associated with nabilone were experienced by 34% (37/110) of children. All were of CTCAE Version 4.03 Grade 2 or less. Sedation (20.0%), dizziness (10.0%), and euphoria (3.6%) were the most commonly reported adverse events. Nabilone was discontinued in 10 patients due to an adverse event. The proportions of patients receiving highly or moderately emetogenic chemotherapy who experienced complete acute CIV control were 50.6% (42/83) and 53.8% (14/26), respectively. Conclusion Adverse events associated with nabilone were common but of minor clinical significance. Acute CIV control in children receiving nabilone as a part of their antiemetic regimen was poor. Future work should focus on implementation of guideline-consistent CINV prophylaxis and treatment.

The incidence rates of pediatric cancer, like adult cancer, are increasing, though to a lesser degree. Options for the treatment of childhood cancers are continually changing and improving and overall survival has increased dramatically over the last 60 years. This paper discusses the incidence and survival trends of childhood cancer. The biology and epidemiology of the most common cancers seen in children and the late effects of treatment for childhood cancer will also be discussed. A basic understanding of childhood cancer is important for both hospital and community pharmacists, since many young adults in North America are now survivors of childhood cancer and may experience long-term consequences of chemotherapy.

BACKGROUND Central venous catheter (CVC) dysfunction is a common complication among pediatric cancer patients. Tissue plasminogen activator (tPA) is administered to resolve CVC dysfunction. The present study was designed to determine risk factors associated with requirement of tPA for CVC dysfunction and to assess the clinical impact of CVC dysfunction in terms of CVC loss and venous thrombotic events (VTE). PROCEDURE Case records of all pediatric patients with cancer from the Maritimes, Canada were reviewed following ethics approval. Data regarding demographics, clinical diagnosis, CVC dysfunction, characteristics of CVCs, and VTE were pooled from multiple data sources. RESULTS Seven hundred and forty-one patients required ≥1 CVC. 26.3% of patients required tPA for ≥1 episodes of CVC dysfunction. Requirement of one or more doses of tPA for episodes of CVC dysfunction increased the odds of VTE by two times (95% confidence interval, 1.1-3.6). Patients that required ≥1 doses of tPA required significantly more CVCs (2.05 ± 1.29 per individual patient, 55% of the patients needed >1 CVCs) as compared to the remainder (1.52 ± 0.95 per individual patient, 32% needed >1 CVCs) (P = 0.0001). Multivariate analysis revealed age > 10 years, diagnosis of sarcoma, and tunneled line were independently associated with tPA requirement. CONCLUSION We determined independent risk factors associated with requirement of tPA for CVC dysfunction. Requirement of tPA for CVC dysfunction was associated with significantly increased risk of VTE and requirement of more CVCs. These observations can assist in identification of patients at increased risk of CVC dysfunction and inform approaches to reduce CVC loss and VTE.

This guideline provides clinicians with evidence-based recommendations on the use of antifungal prophylaxis in children with cancer and undergoing hematopoietic stem cell transplantation (HSCT). Recommendations are divided into: (1) allogeneic HSCT (2) autologous HSCT (3) acute myeloid leukemia or myelodysplastic syndrome and (4) patients with malignancy and neutropenia for7 days. A systematic review was conducted and evidence summaries compiled. The quality of evidence and strength of each recommendation was determined using GRADE. Implementation of these recommendations will require adaptation to local context. The contribution of this guideline in the prevention of invasive fungal infections requires prospective evaluation.

Background: Symptomatic venous thrombotic events (sVTE) are a well-recognized complication in pediatric cancer patients. Accurate data on true incidence of sVTE is limited due to large variability in design and methodology of previously published reports. As well, risk factors are unclear. Moreover, the limitations of several of the previously described risk factors for sVTE include (i) limited generalizability to all pediatric cancers, (ii) hemostatic protein lab values are altered by cancer itself, (iii) long turn-around times from laboratories and (iv) testing restricted to specialized labs. There is a need to identify risk factors for sVTE in pediatric cancer patients that are easily evaluated at the time of cancer diagnosis. Aims: Establish incidence of sVTE and identify risk factors associated with sVTE in pediatric cancer patients. Methods: All pediatric cancer patients in the 3 Maritime Provinces of Nova Scotia, New Brunswick and Prince Edward Island are treated at IWK Health Center (IWK) in a shared care model. This provides a population-based cohort of pediatric cancer patients from the Maritimes. After ethics approval, all pediatric cancer patients treated at the IWK from 1995 to 2014 with sVTE were identified through a conceptual framework as follows. Clinical (including sVTE) and laboratory data was extracted from the: (i) Pediatric oncology hospital database (ii) Provincial Cancer in Young People registry (iii) Electronic medical records (iv) Pharmacy database (v) IWK Central Venous Access Database and (vi) Hospital health records. After extraction, data from all sources was amalgamated and cross-verified. SPSS version 21 was used for statistical analysis. Central veins were defined as veins including and proximal to the axillary vein in the upper extremity and femoral vein in the lower extremity. sVTE was defined as radiologically documented VTE with at least one sign/symptom directly associated with VTE. Patients with VTE during relapsed disease and those with asymptomatic/incidentally diagnosed VTE were excluded from analysis. Results: Forty-seven (4.356±0.01%) of the 1079 patients had sVTE. The mean age at diagnosis for sVTE patients was 10.142 years. The mean age at diagnosis of the remaining patients (n=1032) was 7.451 years. The difference in the mean ages in the 2 categories was statistically significant (p=0.001). The gender ratio was M:F: 1.765:1 in patients with sVTE as compared to M:F: 1.123:1 in the remainder of the patients (p=0.336). Central veins were the most common location for sVTE (72.3%, n=34). Other less common locations included 1 each of sinovenous, mesenteric, cardiac, renal vein thrombosis and pulmonary embolism. On univariate analysis for risk factors, age > 10 years at diagnosis (P = 0.021), type of cancer (P = 0.028) and non-O blood group (P = 0.043) were associated with sVTE, while gender (p=0.336) and use of asparaginase (p=0.663) were not. On multivariate analysis, age > 10 years at diagnosis (odds ratio [OR]: 1.737 [1.066-2.831], p=0.027), and type of cancer (non-brain tumor; OR: 11.154 [1.527-81.451], P=0.017) were associated with sVTE. The association of non-O blood group with sVTE trended towards significance (OR: 1.886 [0.962-3.695], p=0.065) likely due to small numbers and difficulty identifying sVTE retrospectively. Conclusion: In a large population-based cohort of patients, we established incidence of sVTE in pediatric cancer patients. The study identified that sVTE occur in central veins in almost 3/4th of the patients. As well, we evaluated easily available and independent risk factors for sVTE in pediatric cancer patients. Further larger prospective and multicenter studies are needed to validate these observations and develop a risk prediction model for sVTE in pediatric cancer patients. Disclosures No relevant conflicts of interest to declare.

OBJECTIVE: Pediatric oncology patients may require a peripherally inserted central catheter (PICC) for their therapy. Data from adult oncology studies indicate a high risk of complications associated with PICC lines. However, little data exists on the management experience of PICCs in pediatric oncology population. The aim of the present study was to document and analyze the management experience and complications with use of PICC lines in pediatric cancer patients at our center. METHODS: All pediatric cancer patients in the three Maritime Provinces of Nova Scotia, New Brunswick and Prince Edward Island are managed at the IWK health center in Halifax, Nova Scotia in a shared care model with regional hospitals. After ethics approval, all pediatric cancer patients managed at the IWK health center from January 1st 2000 through Dec 31st 2014 who received a PICC line were identified for inclusion in the study. The following databases were used to integrate data on the study patients: (i) pediatric oncology hospital database, (ii) Provincial Cancer in Young People database, (iii) Electronic medical records, (iv) Pharmacy database (v) IWK central line database and (v) Hospital Health records. Patients who received PICC line for an indication not related to their oncologic diagnosis or management were excluded from analysis. SPSS version 22 was used for statistical analysis. RESULTS: A total of 125 PICCs were placed in 102 (11.8%) of the 864 oncology patients. Of these 86 patients received 103 PICCs for oncology related indications. Fifteen (17%) patients required >1 PICC line. For the study cohort, gender ratio was 1:1. The median age at cancer diagnosis was 9.8 years (range: 0-19.3 years). Among the 86 patients who received PICC line, 37% had leukemia, 19% had lymphoma, 13% had brain tumor, 4% had sarcoma, and 28% had other diagnoses. For the first PICC, catheter duration ranged from 0 to 175 days (median 18 days) for a total of 2370 catheter days. The site of insertion was through the antecubital (16%), basilic (31%), brachial (2%), cephalic (41%), jugular (8%), saphenous (2%) veins, and was unknown in 2 patients. In 44% of patients the insertion was through the right side, 56% the left side and was unknown in 2 patients. The indication of the first PICC line included: (i) administration of chemotherapy or bone marrow transplant: 34 (39.5%), (ii) failure of a previous central venous catheter: 15 (17.4%) and (iii) supportive care such as antibiotics, parenteral nutrition or intravenous access: 37 (43.0%). The reasons for removal were as follows: (i) Complications: 24 (28.2%), (ii) elective removal: 55 (64.7%) and (iii) other reasons: 6 (7.1%). Among the 55 PICCs removed electively, 12 (14.0%) were removed at the completion of cancer treatment, 23 (26.7%) at the completion of supportive care, and 20 (23.3%) were replaced with another type of central venous catheter. Among the 24 PICCs removed due to complications, 6 were removed due to infection, 15 due to mechanical complications and 3 due to thrombosis. CONCLUSION: We found that PICC lines are frequently used in pediatric cancer patients for a variety of indications. Seventeen percent of the patients needed >1 PICC line. Further, close to 1/3rd of the patients experienced a complication related to their PICC line. Our experience highlights the need to conduct further studies addressing (i) indications of PICC line insertion in pediatric oncology (ii) determination of causes of PICC line related complications to help guide PICC line indications. Identifying patients at high risk of PICC line related complications will aid judicious choice of PICC line in pediatric cancer patients. Disclosures No relevant conflicts of interest to declare.