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  • American Society of Hematology  (4)
  • 2020-2024  (4)
  • Medicine  (4)
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  • American Society of Hematology  (4)
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  • 2020-2024  (4)
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  • Medicine  (4)
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  • 1
    Online Resource
    Online Resource
    Mobile-Health Tool to Improve Care of Patients with Hematological Malignancies
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 35-36
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 35-36
    Abstract: INTRODUCTION Adverse effects are common during treatment of hematological malignancies. Treatment toxicities can impact quality of life [1], impose financial hardship and cause cancer related distress[2] . Symptom monitoring using electronic technology can facilitate early detection of complications[3], reduce symptom burden[4] , cost of care[5] and improve survival[6] . Cancer treatment also increases risk of mortality from infections such as coronavirus disease 2019 (COVID-19) and routine screening has been recommended[7]. METHODS We developed an application that periodically delivers toxicity questionnaires to patients during treatment . Based on NCI- PRO-CTCAE™, the questions are delivered through SMS or e-mail. Patient responses crossing prespecified thresholds trigger automated alerts on a dashboard, resulting in additional interventions as needed. Nature and time to intervention is tracked. Patient experience is measured using a Likert-scale and free-text box. Centers for Disease Control recommended COVID-19 screening questions were incorporated. Finally, a distress thermometer for cancer distress screening has been recently added. The app was offered to patients with hematological cancers in a community-based cancer center. RESULTS Since introduction in April 2020, we have enrolled 37 patients. 9 patients had chronic lymphocytic leukemia, 6 diffuse large B cell, 5 mantle cell, 4 Hodgkin's and 3 follicular lymphoma. 2 each had chronic myelogenous, multiple myeloma and Richter's syndrome. 1 each had hairy cell leukemia, acute myelogenous leukemia and T Cell lymphoma. Median age was 64 years (range 24-85). Patient experience has been favorable. On a scale of 1-5, 85.5% rated the experience as 3 or higher. Median patient engagement, calculated by dividing the number of forms completions by number of days enrolled was 34.2% (0.9-66.2 %). Symptom tracker captured 536 responses. Fatigue (153), no symptoms (152), shortness of breath (57), nausea/vomiting, diarrhea (46) and numbness/tingling (28) were the most common response categories. Of 1107 completed check ins, 75 triggered flags. There were 2 hospitalizations for neutropenic fever with the remainder managed as outpatients. Average time between patient generated response and provider intervention was 90.9 minutes. 88% follow-ups were completed within 1 business day. COVID-19 screening module captured 1096 responses. 988 were no symptoms. All positive responses (44 diarrhea, 39 cough, 23 shortness of breath and 2 fever) were false positives. Distress thermometer implemented a week before data cut-off captured 2 responses, 1 in the physical and 1 in the psychological domain. CONCLUSION We demonstrate feasibility of electronic capture of treatment toxicities and offer proof of concept that a mobile app can be used for infection screening. Additionally, the quick response time by care team indicated a high adoption rate. REFERENCES Doorduijn J, B.I., Holt B, Steijaert M, Uyl-de Groot C, Sonneveld P., Self-reported quality of life in elderly patients with aggressive non-Hodgkin's lymphoma treated with CHOP chemotherapy. . European Journal of Hemtology 2005. 75(2): p. 116-123.Troy JD, L.S., Samsa GP, Feliciano J, Richhariya A, LeBlanc TW., Patient-reported distress in Hodgkin lymphoma across the survivorship continuum. Supportive Care Cancer, 2019. 27(7): p. 2453-2462.Stover A M, H.S., Deal A M, Stricker C T, Bennett A V, Carr P M, Jansen J, Kottschade L A, Dueck A C, Basch E M, Methods for alerting clinicians to concerning symptom questionnaire responses during cancer care: Approaches from two randomized trials (STAR, AFT-39 PRO-TECT). Journal of Clinical Oncology 2018. 36(30 supplement): p. 158.Mooney KH, B.S., Wong B, Whisenant M, Donaldson G, Automated home monitoring and management of patient-reported symptoms during chemotherapy: results of the symptom care at home RCT. Cancer Medicine, 2017. 6(3): p. 537-546.Barkley R, S.M.-J., Wang J, Blau S, Page RD, Reducing Cancer Costs Through Symptom Management and Triage Pathways. Journal of Oncology Practice, 2019. 15(2): p. e91-e97.Denis F, B.E., Septans AL, Urban T, Dueck AC, Letellier C., Two-Year Survival Comparing Web-Based Symptom Monitoring vs Routine Surveillance Following Treatment for Lung Cancer. JAMA, 2019. 321(3): p. 306-307.ASCO Special Report: A guide to cancer care delivery during COVID-19 pandemic. 2020, ASCO: Alexandria, VA. Disclosures Janssen: wellbe Inc.: Current Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-143405
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
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  • 2
    Online Resource
    Online Resource
    Recurrent Germline Variant in the Cohesin Complex Gene RAD21 Predisposes Children to Lymphoblastic Leukemia and Lymphoma
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3358-3358
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3358-3358
    Abstract: Introduction: Cohesin complex genes are commonly mutated in cancer particularly in myeloid malignancies. Yet patients with germline mutations in cohesin genes, leading to cohesinopathies like Cornelia-de-Lange syndrome (CdLS) are generally not known to be tumor-prone. The complex plays a major role in chromosome alignment and segregation (Uhlmann, Nature Reviews Molecular Cell Biology, 2016), homologous recombination-driven DNA repair (Ström et al., Molecular Cell, 2004) and regulation of gene expression (Busslinger et al., Nature, 2017). To deepen the understanding of cohesin variants in cancer predisposition, we performed TRIO Sequencing in two independent pediatric cancer cohorts. Thereby, we identified a novel recurrent heterozygous germline variant in the cohesin gene RAD21 not described in CdLS patients , located in the binding domain of the cofactors WAPL and PDS5B . Methods: Whole exome sequencing (WES) in a TRIO (child-parent datasets) setting was carried out in two independent, unselected cancer cohorts (TRIO-D, n=158 (Wagener et al., European Journal of Human Genetics, 2021) and TRIO-DD, n=60). To investigate the oncogenic potential of the novel RAD21 variant molecular and functional assessment was performed focusing on potential implications on the complex. Results: The newly identified RAD21 variant at amino acid position 298 resulting in a Proline to Serine (p.P298S) and a Proline to Alanine exchange, respectively, (p.P298A) is only rarely mutated in the general population (gnomAD database n=118,479; RAD21 p.P298S MAF & lt;10 -6 and RAD21 p.P298A MAF & lt;10 -5). While both patients did not show any signs of CdLS, they both have a remarkable family history of cancer. Patient 1 (13y) was diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) whose father had died from breast cancer (41y), while patient 2 (2y) presented with precursor B-cell lymphoblastic lymphoma (pB-LBL) whose uncle had died from pediatric cancer of unknown subtype (8y). To assess the influence of RAD21 p.P298S/A on the binding capacity of the complex, RAD21 variants and the wildtype (WT) were cloned and transfected into HEK293T cells, respectively. Immunoprecipitation analysis of RAD21 with the cofactors WAPL and PDS5B showed no differential binding between the WT and the variants, suggesting that RAD21 p.P298S/A does not impact the formation of the complex. Nevertheless, on a transcriptional level 83 genes were significantly differentially expressed in RAD21 p.P298S and p.P298A compared to the wildtype (fc & gt;1.5, adj. p-value & lt;0.05) with enrichment of genes in p53 signaling pathways. We further observed an increased number of γH2AX and 53BP1 co-localized foci compared to the WT (p≤0.01; Student's t-test). In line, following ionizing radiation, primary patients' samples showed increased cell cycle arrest at G2/M cell-cycle stage compared to a healthy control (p.P298S: p=0.0049 [6Gy]; p=0.0026 [10Gy] ; p.P298A: p=0.0054 [6Gy]; p=0.0006 [10Gy] ; Student's t-test). For cross-validation of the germline variant RAD21 p.P298S/A and its potential role in pediatric lymphoblastic malignancies, we analysed a third cohort of 150 children with relapsed ALL (IntReALL) for RAD21 p.P298S/A. We again identified RAD21 p.P298A in a boy (12y) with B-cell precursor acute lymphoblastic leukemia. To compare our data to a non-pediatric cancer setting, a cohort of 2300 young adults ( & lt;51 years) with cancer was mined (MASTER program). Here, one patient carrying RAD21 p.P298A with a solid tumor was identified. Therefore, amongst all cohorts, RAD21 p.P298S/A was found to be enriched in pediatric vs. adult cancers (3/479 vs. 1/2299; Fisher's exact test; p=0.018). Conclusion: Taken together, we present for the first time the potential role of RAD21 germline variants in pediatric lymphoblastic malignancies. This may shed new light on the many roles of the cohesin complex and its implication outside the typical syndromal presentation. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-150284
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    PGE2 Dependent Inhibition of Macrophage Pyroptosis By MSCs Contributes to Alleviating aGVHD
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 15-15
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 15-15
    Abstract: Introduction Mesenchymal stem cells (MSCs) are being recognized as one of the treatment options for acute graft versus host disease (aGVHD), but their therapeutic mechanisms have not been fully elucidated. Pyroptosis, a novel form of inflammation related programmed cell death, often occurs in myeloid cells. Many studies have found that macrophage pyroptosis plays an important role in multiple inflammatory and autoimmune diseases (Journal of Autoimmunity, 2018). As an immune disease with involvement of various inflammatory factors, aGVHD exhibits macrophage dysfunction according to our previous study (Sci China Life Sci, 2020). However, whether macrophages undergo pyroptosis and their role in aGVHD remain unknown. MSCs have been reported to inhibit pyroptosis, and some cytokines that suppress pyroptosis can also be secreted by MSCs (Nature Immunology, 2016). Whether inhibition of macrophage pyroptosis represents a therapeutic mechanism for MSCs to alleviate aGVHD needs further exploration. Methods Twenty patients with aGVHD and 20 patients without aGVHD after hematopoietic stem cell transplantation were enrolled in our study. Macrophages were derived from CD14+ monocytes of patients and the THP-1 cell line. CD4+ T cells were isolated from peripheral blood mononuclear cells (PBMCs) of healthy volunteers. MSCs were obtained from fresh umbilical cord of healthy puerpera. Morphological analysis of macrophages was performed by scanning electron microscopy. Expression of GSDMD and NLRP3 inflammasome associated components was assessed by real-time transcription-polymerase chain reaction (RT-PCR), western blot and immunofluorescent staining. The subgroup of CD4+T cells was analyzed by flow cytometry. RT-PCR, ELISA and RNA interference were used to evaluate relevant immunomodulatory factors which were involved in the inhibitory effect of MSCs on macrophage pyroptosis. Additionally, an aGVHD mouse model was established to observe the therapeutic effect and mechanism of MSCs on macrophage pyroptosis. Results Scanning electron microscopy images showed the formation of membrane pores in macrophages of aGVHD patients. Meanwhile, expression of the pyroptosis executioner GSDMD, NLRP3 inflammasome associated components, IL-1β, IL-18, and LDH release were elevated in macrophages from aGVHD patients, indicating that macrophages in aGVHD underwent NLRP3 inflammasome activation and pyroptosis. Furthermore, NLRP3 inhibition reduced macrophages pyroptosis, suggesting that macrophages pyroptosis in aGVHD are mediated by NLRP3 inflammasome activation. Since CD4+T cells play a critical role in the pathogenesis of aGVHD, we investigated the effect of macrophage pyroptosis on CD4+T cells. In vitro, macrophage pyroptosis increased the proportion of CD69+, Th1 and Th17 cells among CD4+T cells, which was partially reversed by blocking IL-1β/IL-1R and IL-18/IL-18R signaling. We also observed that the proportion of macrophage pyroptosis was more increased in patients with III-IV aGVHD than in those with I-II aGVHD. In addition, administration of a pyroptosis inhibitor into aGVHD model mice greatly attenuated clinical and histopathological scores. Taken together, these results indicate that macrophage pyroptosis might be involved the development of aGVHD. Expression of GSDMD, NLRP3 inflammasome associated components, IL-1β, IL-18, and LDH release in aGVHD macrophages were reduced when cells were cocultured with MSCs, indicating that MSCs inhibit aGVHD macrophage pyroptosis by suppressing NLRP3 inflammasome activation. Furthermore, secretion of prostaglandin E2 (PGE2) was increased in MSCs cocultured with aGVHD macrophages, blocking which by small interfering RNA (siRNA) or inhibition of PGE2 induced CAMP-PKA signaling with antagonists both largely abrogated MSC effects. Consistently, the effect of MSCs on macrophage pyroptosis and the NLRP3 inflammasome in vivo was also dampened after transfection with prostaglandin E synthase (PTGES) siRNA, and the therapeutic effect in the aGVHD mouse model was impaired. Conclusions Our results demonstrate that macrophage pyroptosis plays a crucial role in the pathogenesis of aGVHD by promoting activation and differentiation of CD4+ T cells. MSCs suppress macrophage pyroptosis in aGVHD via PGE2/cAMP/PKA signaling, which might represent a therapeutic mechanism of MSCs for aGVHD. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-138388
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    Online Resource
    Pragmatic Evaluation of an Algorithm Using D-Dimer Adjusted to Clinical Probability in the Diagnosis of Pulmonary Embolism
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2128-2128
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2128-2128
    Abstract: BACKGROUND: Diagnosis of pulmonary embolism (PE) using clinical decision rules in combination with D-dimer (DD) values is a standard practice. The Wells score is the most commonly used rule, either in its original (3-category) or modified (2-category) versions, and in conjunction with a (DD) & lt;500 ng/mL allows to exclude a PE in approximately 30% of patients. The recent PEGeD study (Kearon et al. 2019) concluded that a PE can be safely excluded by using a DD threshold adjusted to the clinical pre-test probability (C-PTP). In that study PE was excluded in patients with low C-PTP and a DD & lt;1000 ng/mL or a moderate C-PTP and a DD & lt;500 ng/mL In the present study we aimed to evaluate the performance of the PEGeD algorithm in daily practice. METHODS: We conducted a retrospective cohort study involving all adult patients who presented at London Health Sciences Centre or St. Joseph's Health Care Emergency Departments in London, Ontario, Canada between November 1, 2018 and December 31, 2020 with signs or symptoms suggestive of a pulmonary embolism and for whom a DD was ordered electronically. They were excluded if they did not have complete follow-up information for at least 90 days from the initial visit, they were pregnant, they were on long term anticoagulation for other indications, or had chest imaging prior to DD order. Using the electronic hospital chart, we extracted demographics, imaging results, and the Wells score with all its individual components. In our center, information about the Wells score and its components is routinely and prospectively collected when ordering DD. Since the PEGeD algorithm is not routinely used in our hospital, data of the C-PTP was utilized to determine which DD cut-off should be applied to the patient. Decision to perform imaging studies was taken by the ED physician at the time of assessment. The outcome of interest was the proportion of a PE or DVT at 90 days after the visit to the ED in patients with a low or intermediate C-PTP and who did not receive an initial diagnosis of PE and 99% confidence intervals (CI) were estimated using the Wilson's score method. RESULTS: A total of 2769 patient charts were reviewed and 1070 were included (Table 1, Figure 1). Of the 1070 patients, 71 (7%) of patients had a pulmonary embolism on initial presentation to the emergency department. At 90 days of follow up none (99% CI 0, 0.84) of the 787 patients who had a low C-PTP or a moderate C-PTP score and a DD & lt;1000 ng/mL or & lt;500 ng/mL, respectively, were positive for a PE . This included 194 patients who had a low C-PTP and a DD level of 500-999 ng/mL and 26 patients who had an intermediate C-PTP and a DD level of & lt;500 ng/mL. Notably, 8 (1.02%, 99% CI 0.42-2.43) PEs would have been missed using the PEGeD protocol when using DD cut-off levels of & lt;1000 ng/mL in the low C-PTP group, or & lt;500 ng/mL in the intermediate C-PTP. CONCLUSIONS: In this cohort we found that if the PEGeD algorithm had been used, it would have resulted in a low risk of VTE during follow up in patients without an initial diagnosis of PE and who had either a low C-PTP and a DD & lt;1000 ng/mL or a moderate C-PTP and a DD & lt;500 ng/mL. We also found it would have been associated with 194 (48%) less diagnostic imaging studies in the low C-PTP range and 2 (6%) less studies in the intermediate C-PTP range. Despite this, 1% of patients with PE (99% upper confidence limit 2.43%) would have been missed. This study is limited by its retrospective nature with an inherent risk of misclassification. Further studies are needed before recommending the use of this algorithm in clinical practice. Work Cited Kearon, C., de Wit, K., Parpia, S., Schulman, S., Afilalo, M., Hirsch, A., Spencer, F. A., Sharma, S., D'Aragon, F., Deshaies, J.-F., Le Gal, G., Lazo-Langner, A., Wu, C., Rudd-Scott, L., Bates, S. M., & Julian, J. A. (2019). Diagnosis of Pulmonary Embolism with d -Dimer Adjusted to Clinical Probability. New England Journal of Medicine, 381(22), 2125-2134. https://doi.org/10.1056/NEJMoa1909159 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-151431
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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