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  • 1
    In: The Lancet Oncology, Elsevier BV, Vol. 21, No. 5 ( 2020-05), p. 699-709
    Type of Medium: Online Resource
    ISSN: 1470-2045
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2049730-1
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. TPS10072-TPS10072
    Abstract: TPS10072 Background: Risk of relapse for children with high-risk solid tumors (ST) remains unacceptably high despite aggressive multimodal therapy. Maintenance therapy is an emerging option to improve outcomes. Sirolimus, an inhibitor of mammalian target of rapamycin, is a potent immunosuppressant with antiproliferative and antiangiogenic effects. Low-dose metronomic chemotherapy along with the cyclooxygenase-2 inhibitor celecoxib also decreases neovascularization in in vitro and in vivo systems. The maximum tolerated dose (MTD) of sirolimus in combination with celecoxib and etoposide alternating with cyclophosphamide was determined in a phase I study in pediatric patients with relapsed/refractory ST. The regimen was well-tolerated and showed best response of stable disease in 8/18 subjects and partial response in 1/18. The efficacy of this regimen in relapsed/refractory ST is being tested in a Phase II study (NCT02574728). We hypothesize that patients with high-risk ST administered a 12-month course of this maintenance regimen will have improved 2-year progression-free survival (PFS) when compared to matched historical patients who were observed following completion of upfront therapy. Methods: This is a phase II study of sirolimus in combination with celecoxib and alternating low-dose etoposide and cyclophosphamide delivered as maintenance therapy. Sirolimus will be given at the MTD of 2mg/m 2 /day with celecoxib 100mg twice daily and oral etoposide 50mg/m2/day (max 100mg) alternating every 21 days with oral cyclophosphamide 2.5mg/kg/day (max 100mg). This study includes: 1) a prospective cohort of patients with high-risk ST in first complete remission (CR), 2) a prospective cohort of patients with recurrent ST in second CR, and 3) a historical cohort matched 2:1 with cohort 1 on diagnosis, age, metastatic sites, and date of diagnosis treated with observation following upfront therapy. The study will enroll up to 38 patients in cohort 1. Eligible subjects are children (1-30 years) with a diagnosis of high-risk extracranial ST (metastatic sarcoma, desmoplastic small round cell tumor, malignant rhabdoid tumor) in first CR or any ST in second CR. Patients enrolled in upfront clinical trials are excluded. Primary endpoint is 2-year PFS of cohort 1 compared to the historical cohort. Secondary endpoints are median PFS of cohort 1, 2-year PFS and overall survival of cohorts 1 and 2, incidence of severe toxicities, and feasibility of completing the 12-month course following standard upfront therapy. Exploratory objectives include evaluation of circulating tumor DNA (ctDNA) in this population of patients in CR or with minimal disease burden and correlation of clinically obtained tumor molecular profiling with outcomes. As of January 2023, 12 subjects are enrolled, 9 in cohort 1 and 3 in cohort 2. Clinical trial information: NCT04469530 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 3
    Online Resource
    Online Resource
    American Academy of Pediatrics (AAP) ; 2020
    In:  Pediatrics Vol. 145, No. 5 ( 2020-05-01)
    In: Pediatrics, American Academy of Pediatrics (AAP), Vol. 145, No. 5 ( 2020-05-01)
    Abstract: We describe an atypical pediatric case of immunoglobulin A vasculitis (IgAV), also referred to as Henoch-Schönlein purpura, in which formation of spontaneous hematoma of the paraspinal muscles developed. Spontaneous or unprovoked hematomas rarely occur in IgAV. These manifestations have not been described specifically in the pediatric literature as coinciding with IgAV. These findings are alarming for nonaccidental trauma, particularly in a patient without underlying blood dyscrasia. Our objective for this report is to highlight the possible association of muscular hematoma formation with IgAV and to help providers consider this association when trauma and hemophilia has been ruled out.
    Type of Medium: Online Resource
    ISSN: 0031-4005 , 1098-4275
    Language: English
    Publisher: American Academy of Pediatrics (AAP)
    Publication Date: 2020
    detail.hit.zdb_id: 1477004-0
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  • 4
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2072-2072
    Abstract: A subset of patients with chronic bleeding remain undiagnosed even after extensive diagnostic evaluation are labeled as "bleeding of unknown cause" (BUC). The key barrier to treating these patients is that they have a clinical bleeding tendency in the presence of normal diagnostic tests, and optimal methods for monitoring and treating patients with BUC remain unknown. While patients with BUC have symptoms of a primary hemostatic disorder, there is no diagnostic test or biomarker that can accurately identify which patients are at risk for bleeding such as those with mild Von Willebrand Disease (VWD) which comprise a broad spectrum of patients with varying degrees of bleeding. In order to fill this diagnostic gap in disorders of primary hemostasis, there is a clinical need for more assays of platelet function. To that end, we have engineered multiple new biophysical assays to assess disorders of primary hemostasis and apply this panel of platelet function testing to potentially define new bleeding disorders, characterize platelet phenotypes in patients with BUC, and refine the definition of mild VWD. Our panel of platelet function tests (Fig 1) collectively enables us to simultaneously assess different facets of primary hemostasis from the microscopic level of single-platelet physiology to hemostatic plug formation, thereby capturing various aspects of platelet function with a single blood sample. Our platelet function panel ranges from platelet adhesion and bulk clot contraction assays to spatially-regulated platelet granule secretion assay, single-platelet contraction cytometry, microfluidics, and a microengineered vascularized bleeding model. As such, we are leveraging these biophysical assays to correlate platelet function with bleeding phenotype severity and establish the dynamic range of this diagnostic panel. We have now established that our assays can be utilized to study blood samples from patients with disorders including hemophilia A, Hermansky-Pudlak Syndrome, FLI-1 mutation, and sickle cell disease among others (Fig 2), demonstrating the clinical utility of our platelet function panel. Our panel can also be used to assess the effects of novel therapeutics on different aspects of platelet function simultaneously. To investigate how crizanlizumab (p-selectin inhibitor) affects hemostatic plug formation, healthy human blood was treated with crizanlizumab. Platelet α-granule secretion enables exposure of P-selectin, and with crizanlizumab we observed restricted platelet filopodial extension and diminished α-granule exocytosis, and an overall decrease in adhered platelets to the fibrinogen micropattern (Fig 3A). The adhesion assay demonstrated a decrease in spreading and adhesion of platelets to collagen and fibrinogen with treatment (Fig 3B). Using the bleeding model, hemostasis was achieved within the normal established range and platelets contracted normally. This suggests that p-selectin has a limited role in the setting of minor injury. Utilizing the bulk contraction assay, we exhibited increased contraction early in clot formation, however over time the treated platelets contracted similarly to the control (Fig 3C). Interestingly, the effect of crizanlizumab-induced restriction of filopodial extension did not correlate with impaired bulk clot contraction or time to form hemostatic plug. Our work suggests crizanlizumab affects platelet spreading at the single-cell level but does not impair platelet function in achieving primary hemostasis at the whole blood level. Here we demonstrate the translational utility of our platelet function panel in providing a deeper understanding of platelet biophysics as it relates to hematologic conditions, with implications for investigation to include pharmaceutical applications. The versatility of this novel panel in capturing platelet function from single-platelet contraction to providing in vitro models with the bleeding device provides multiple dimensions to platelet investigation for primary hemostatic disorders and BUC that have not yet been elucidated. Ongoing research is being conducted using our comprehensive platelet function panel to investigate platelet properties in BUC and mild VWD and correlate these biophysics with bleeding phenotypes. Using this approach we aim to provide novel diagnostic testing with clinical relevance for disorders that have been incompletely characterized until now. Figure 1 Figure 1. Disclosures Meeks: National Institutes of Health: Research Funding; Hemophilia of Georgia: Research Funding; National Hemophilia Foundation: Research Funding; Spark Therapeutics: Consultancy; Sangamo Therapeutics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Takeda: Consultancy. Lam: Sanguina, Inc.: Current holder of individual stocks in a privately-held company.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 5
    Online Resource
    Online Resource
    Elsevier BV ; 2023
    In:  Journal of Thrombosis and Haemostasis Vol. 21, No. 9 ( 2023-09), p. 2339-2353
    In: Journal of Thrombosis and Haemostasis, Elsevier BV, Vol. 21, No. 9 ( 2023-09), p. 2339-2353
    Type of Medium: Online Resource
    ISSN: 1538-7836
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2099291-9
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  • 6
    In: Research and Practice in Thrombosis and Haemostasis, Elsevier BV, Vol. 7 ( 2023-08), p. 100202-
    Type of Medium: Online Resource
    ISSN: 2475-0379
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2901840-7
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  • 7
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2023-08-18)
    Abstract: While microscopy-based cellular assays, including microfluidics, have significantly advanced over the last several decades, there has not been concurrent development of widely-accessible techniques to analyze time-dependent microscopy data incorporating phenomena such as fluid flow and dynamic cell adhesion. As such, experimentalists typically rely on error-prone and time-consuming manual analysis, resulting in lost resolution and missed opportunities for innovative metrics. We present a user-adaptable toolkit packaged into the open-source, standalone Interactive Cellular assay Labeled Observation and Tracking Software (iCLOTS). We benchmark cell adhesion, single-cell tracking, velocity profile, and multiscale microfluidic-centric applications with blood samples, the prototypical biofluid specimen. Moreover, machine learning algorithms characterize previously imperceptible data groupings from numerical outputs. Free to download/use, iCLOTS addresses a need for a field stymied by a lack of analytical tools for innovative, physiologically-relevant assays of any design, democratizing use of well-validated algorithms for all end-user biomedical researchers who would benefit from advanced computational methods.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2553671-0
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  • 8
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 5538-5539
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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