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The prevalence of PE and mortality due to PE is high in cancer patients. Risk stratification for venous thromboembolism (VTE) should be done in all cancer patients and thromboprophylaxis should be optimally used.

An increase in the incidence of deep vein thrombosis (DVT) has been reported in pediatric patients over the past decade. The presence of central venous line (CVL) is a major contributing risk factor with conflicting data on the relative risk of DVT with various types of central lines. We aimed to assess the incidence of and identify potential risk factors for DVT overall and with different types of CVL individually. A retrospective chart review of pediatric patients with a CVL placed at Cleveland Clinic Children’s from 2011 to 2016 was conducted. Data collected included demographics, potential risk factors, CVL characteristics and related thrombotic events. The study cohort consisted of 376 CVLs in 325 patients between 0 and 26 years of age. There were 1.6 thrombi per 10,000 line-days (95% confidence interval: 1.0, 2.5), and the overall incidence of DVT was 5.1%. The incidence of DVT was highest with tunneled catheters (5/16=31%) versus with peripherally inserted central catheters (4/111=3.6%) or with ports (10/249=4%, P<0.001), and whereas there were overarching significant risk factors for CVL-associated thrombi, these risk factors differed in significance when analyzed by the CVL type. The study supports the need for continued improvement in pediatric hospital practices for early identification of patients at a higher thrombosis risk.

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FLT3-ITD mutations are seen in 20-30% of adult and 15% of pediatric acute myeloid leukemia (AML) patients and are associated with poor prognosis with higher rates of relapse and therapy resistance. FLT3 tyrosine kinase inhibitors (TKIs) have shown some success in treatment of FLT3-ITD AML, but responses are often not complete or sustained. Multiple potential mechanisms of drug resistance could be active in patients with FLT3-ITD AML including mutations in the FLT3 kinase, exogenous signaling from the bone marrow microenvironment, and altered epigenetic regulation. Mutations involving epigenetic modifiers such as DNMT3A, IDH1/2, TET2, ASXL1 and MLL1 are often co-expressed with the FLT3-ITD mutation. In addition, over-expression of EZH2, DOT1L and protein arginine methyl-transferase (PRMT) have also been reported. However, the role of different epigenetic mechanisms in regulating growth of FLT3-ITD AML cells and to modulate ability of TKIs to target FLT3-ITD AML cells has not been systematically studied. The objective of our study was to identify epigenetic targets in FLT3-ITD AML by screening a panel of epigenetic modifiers for their ability to inhibit growth of FLT3-ITD AML cells, and to enhance growth inhibition in combination with a FLT3 TKI. We used a carefully curated and well validated collection of epigenetic inhibitors (Structural Genomics consortium, Epigenetics Probes Collection, SGC Toronto; www.thesgc.org) that included 38 probes that target a spectrum of proteins involved in epigenetic regulation. We exposed MOLM-13 and MV4-11 human FLT3-ITD positive AML cells to each inhibitor by itself and in combination with the TKI Quizartinib/AC220 (500pM, IC20). Cell growth was measured using the CellTiter-Glo® Luminescent Cell Viability Assay. The FLT3-ITD negative AML cell line OCI-AML3 (FLT3-WT) was studied as a control. The combined results of three experiments carried out using triplicate wells in each experiment were analyzed. Apoptosis was measured by flow cytometry using Annexin-V/FITC labeling and data analyzed by FlowJo V10. Statistical analysis was performed using GraphPad Prism 8.1.1 software. Of a total of 38 epigenetic inhibitors, less than a third resulted in reduction in cell proliferation after 72 hours of treatment (greater than 10% decrease, 13 for MOLM13, 9 for MV4-11 cell line). When used in combination with TKI (AC220), several epigenetic inhibitors resulted in significantly increased inhibition of proliferation of FLT3-ITD positive AML cells compared to either agent alone (21 for MOLM13, 10 for MV4-11 cell line) (p<0.05). These included several Bromodomain inhibitors (L-moses, SGC-CBP30, OF1), EZH2/H1 inhibitors (GSK343, UNC1999) and PRMT1 and PRMT5 inhibitors (MSO23, GSK591, LLY283). The combinatorial effect was not seen in the control FLT3-WT OCI-AML3 cells. Given the selective effect of the combination of PRMT5 and TKI on FLT3-ITD positive AML cells in our screen, and reports of over-expression of PRMT5 in hematologic malignancies and its described direct influence on FLT3 gene transcription, we further studied the effect of PRMT5 inhibitors in combination with TKI on FLT3-ITD positive AML cells. The effectiveness of the combination of PRMT5 inhibitor and TKI in MOLM13 and MV4-11 cells but not OCI-AML3 cells was confirmed by fixed-ratio dose-response analysis. We further show that the combination of PRMT5 inhibitors (GSK591, LLY283 5μM) with AC220 (500pM) resulted in increased inhibition of cell proliferation and increased induction of apoptosis compared to TKI alone, p<0.05 (Figure 1a-c). In conclusion, our studies using an unbiased approach have identified PRMT5 inhibition as a novel and selective approach to enhance targeting of FLT3-ITD AML cells in combination with FLT3 TKI. These results support our ongoing studies to evaluate the cellular and molecular mechanisms underlying these combinatorial effects, and to determine the translational therapeutic potential of this combination using primary patient samples and mouse models. Disclosures No relevant conflicts of interest to declare.

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BACKGROUND:The survival of patients with acute promyelocytic leukemia (APL) has dramatically improved with the use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, because of the complexity of the initial management, early mortality (EM) remains a major contributor to treatment failure. It is less known whether advances in treatment, urgent access to specialized care, and broad availability of ATRA/ATO have reduced EM in the last 2 decades. Furthermore, the influence of sociodemographic factors on the risk of EM also remains unclear. METHODS: This study used the Surveillance, Epidemiology, and End Results program to characterize the impact of sociodemographic factors on the rates of EM and overall survival (OS) in patients with APL diagnosed between 1992 and 2015. RESULTS: In all, 2224 cases were identified (895 who were younger than 40 years and 1329 who were 40 years old or older); 47.9% had a county-level median household income of $59,630 or higher, 49.0% belonged to counties where more than 31% of adults held at least a bachelor's degree, and 86.0% resided in urban areas. The rate of EM declined from 31.5% in 1992-1995 to 15.9% in 2012-2015 for all patients. It improved for patients younger than 40 years (27.4% in 1992-1995 vs 5.4% in 2012-2015; P < .001) and for patients 40 years old or older but not to the same extent (35.2% in 1992-1995 vs 22.2% in 2012-2015; P = .02). Importantly, improvements in EM were not seen among patients residing in rural areas, with the rate remaining higher than 20% in 2012-2015. The 3-year OS rate was 49.2% for patients with APL diagnosed in 1992-1995 and 76.4% for patients diagnosed in 2012-2015. CONCLUSIONS: These findings confirm consistent improvements in EM and OS for patients with APL and point to the challenge of further extending these improvements in EM rates to older patients and to those living in rural areas.

Objectives:The prevalence of obesity is rapidly increasing among Indian children, who, in general, are more prone to develop metabolic complications at an early age. Valproate and phenytoin are commonly used antiepileptic drugs in children. This study aimed to assess the parameters of the metabolic syndrome in Indian children with epilepsy on valproate or phenytoin monotherapy.Methods:This cross-sectional study recruited children from the Pediatric Epilepsy Clinic, Department of Pediatrics, Kalawati Saran Children Hospital, New Delhi from March 2012 to September 2012. All consecutive children diagnosed with epilepsy as per International League Against Epilepsy definition aged 3–18 years on valproate or phenytoin monotherapy for at least 6 months were enrolled at a tertiary care children's hospital in Northern India. After clinical and anthropometric evaluation (including body mass index [BMI] and waist circumference), the blood samples were analyzed for fasting serum glucose, total cholesterol, high-density lipoprotein-cholesterol, and serum triglyceride.Results:Children with BMI >95th centile and waist circumference >90th centile were not significantly different among children on valproate and phenytoin monotherapy. Children on valproate had significantly higher mean serum triglyceride (96.9 mg/dL vs. 77.6 mg/dL; P < 0.001) and total cholesterol (148.3 mg/dL vs. 132.8 mg/dL; P = 0.002) levels as compared to children on phenytoin monotherapy.Conclusions:The lipid abnormalities may be observed in children on valproate or phenytoin therapy and may warrant periodic screening.