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  • 1
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    Expansion of Human Mesenchymal Stromal/Stem Cells Using Standardized Xeno-Free, Serum-Free Culture Condition
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3253-3253
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3253-3253
    Abstract: Aims: mesenchymal stromal/stem cells (MSCs) is one of the most promising cell therapies to treat immune related diseases such as GvHD, Crohn's disease, osteoarthritis as well as to support function of heart, liver, and central nervous system. Many advanced clinical trials has been taking place to investigate the safety and efficacy of MSC therapy, however, it remains challenging to compare the results of these trials due to variations in culture conditions and tissue origins. These variations pose the urgent need of a standardized large-scale production and quality control of these cells become more urgent, as the use of MSCs are spreading around the globe and disease backgrounds. Numerous culture protocols for MSCs are available using FBS-containing, human platelet lysate/plasma supplementing, or serum-free xeno-free condition, either commercial or self-prepared media. In this study, we have established a standardized expansion protocol that can be used for MSCs derived from bone marrow (BM), adipose tissue (AD), and umbilical cord (UC). Methods: we tested commercial xeno-free, serum-free media (MesenCult™-ACF Plus Medium/Stem Cell Technologies, MSC NutriStem® XF Medium/BI, Stempro® MSC SFM Medium/ThermoFisher, PowerStem MSC1 Medium/PAN, and StemMACS™ MSC Expansion Media/Miltenyi) in order to identify a common culture condition for all of these MSC sources. The cells were analysed for their population doubling time from P2 to P6, expression of surface markers including the positive markers CD73, CD90, and CD105, and the negative markers CD34, CD45, CD11b, CD19, and HLA-DR. Karyotype was conducted at early and later passage (P3 and P6, respectively). MSCs were tested for their differentiation capacity into osteoblast/osteocyte, adipocyte, and chondrocyte lineages. Bacterial and fungal sterility and mycoplasma test were performed and endotoxin concentration was determined before the cells were transfused into patients. Results: using UC for the primary screening, we identified two medium candidates that supported the isolation and culture of UC-MSCs. MSCs derived from BM and AD are capable of expansion in these media as well. However, one candidate induced an increased HLA-DR expression so that it failed to fulfill the minimal criteria of MSCs (Dominici et al., 2006). The last one showed the best results for MSCs from all tested tissues. Under our established protocol, MSCs grew exponentially until P6, which was the highest analyzed passage. The cells expressed CD73, CD90, CD105 in more than 95% cells and showed less than 2% of negative markers (CD34, CD45, CD11b, CD19, and HLA-DR). Karyotype analysis confirmed no chromosomal aberrations of the cultured cells. The cells were able to differentiate into osteoblast/osteocyte, adipocyte, and chondrocyte lineages. We are now conducting phase 1 clinical trial to address the safety and feasibility of UC-MSCs in the treatment of bronchopulmonary dysplasia and chronic obstructive pulmonary disease. Conclusion: we have established a standardized protocol for the xeno-free, serum-free culture of MSCs from different sources. BM-, AD-, and UC-derived MSCs expand in large-scale and maintain their cellular characteristics, karyotype integrity, and can be applied for cell therapy. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-132140
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 2
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    Impact of Outpatient Administration of Cytarabine Consolidation Chemotherapy on Hospital Length of Stay in Adults with Acute Myeloid Leukemia
    American Society of Hematology ; 2023
    In:  Blood Vol. 142, No. Supplement 1 ( 2023-11-02), p. 3723-3723
    Details
    In: Blood, American Society of Hematology, Vol. 142, No. Supplement 1 ( 2023-11-02), p. 3723-3723
    Abstract: Background: Administration of 3-4 cycles of high/intermediate dose cytarabine (H/IDAC) reduces relapse of acute myeloid leukemia (AML) and bridges patients (pts) to allograft. There is no accepted standard model of safely delivering H/IDAC in these pts. To reduce reliance on inpatient (inpt) chemotherapy administration and safely avoid or forestall hospitalization during cycles, we developed an outpatient (outpt) protocol to deliver H/IDAC. Pts were assigned outpt or inpt treatment at their hematologist's discretion. We aimed to evaluate the benefits and safety of our model in this retrospective observational study. Methods: Pts diagnosed with AML and treated with intensive induction chemotherapy between 2015 and 2020 were identified; included pts received ≥1 consolidation cycle of 1-3g/m² cytarabine over 3 hours BID, dose adjusted for age and renal function, on days 1, 3 & 5 of a planned 28-day cycle. Outpts received H/IDAC via computerized ambulatory delivery device (CADD) pump and central venous access device (CVAD), attended days 1-6, then 3 times a week for blood product support until count recovery; elective readmission was not mandated. Pts were educated to present to hospital if unwell. Inpts were admitted for H/IDAC but could be discharged prior to count recovery. Antimicrobial prophylaxis consisted of antifungal agents and valaciclovir. The primary endpoint was mean duration of hospital admission (LOS) per consolidation cycle. As pts may have been treated on an inpt and/or outpt basis, generalized estimating equations were used to compare LOS clustered by pt. Secondary outcomes included death during H/IDAC; intensive care unit (ICU) admission; time to admission; blood product use; cycle length; bacteremia; time to count recovery; relapse free survival (RFS) and overall survival (OS). Results: Of 109 pts identified, 62 pts were included and 47 pts excluded (not AML=3; induction death=7; refractory leukemia=14; alternative=13; no consolidation=10). Median age was 55.2 years (range 18.2-70.3); 31 (50%) males; ELN 2010 fav=23 (37.1%), Int-2/3 = 30 (48.4%), Adv=8 (12.9%); denovo AML in 60 (96.7%); and therapy related in 2 (3.2%). FLT3-ITD, NPM1 and bi-allelic CEBPA mutations detected in 11 (17.7%), 27 (43.5%) and 2 (3.2%) pts, respectively. Fifty-nine pts (95.1%) received 7+3 idarubicin induction and 7 (11.3%) received midostaurin. A total of 131 cycles of H/IDAC were administered; 81 (61.8%) were commenced as outpt and 50 (38.2%) as inpt. Twenty-seven (43.6%) pts commenced all cycles as an outpt. Those commencing consolidation as an outpt spent, on average, 10.3 fewer days in hospital per cycle. The mean (SD) LOS for outpt and inpt was 11 (8.3) versus 21.3 (8) days (p & lt;0.001), respectively. For each consolidation cycle, outpts spent less time in hospital (mean, [SD]): cycle 1, 12.6 (10.3) vs 20.7 (8.0) days (RR 1.6, p=0.007); cycle 2, 11.6 (7.2) vs 21.4 (8.3) days (RR 1.8, p=0.001); cycle 3, 8.4 (5.8) vs 24.6 (7.4) days (RR 2.9, p & lt;0.001). There were no deaths among inpts and one death in outpts (septic shock). ICU admission occurred in 8/81 (9.9%) cycles in outpts vs 1/50 cycles (2%) in inpts (p=0.12). Mean ICU LOS for outpts vs inpts in cycle 1 was 17.6 days vs 1.6; cycle 2, 5.1 vs 0 days; and cycle 3, 4.2 vs 0 days. Bacteremia was detected in 41 cycles (31.3%), with 38 isolates (gram pos=17, gram neg=21) in 31 outpt cycles (38.2%) and 15 isolates (gram pos=6, gram neg=9) in 10 inpt cycles (20%). Median time to admission in outpts was 14 days (IQR, 3-21); 15 (18.5%) cycles did not result in pt admission. There were no differences in timing of admissions by cycle number nor time-point to prompt elective admission (Fig.1). There was no difference in packed cell or platelet transfusion requirement between inpts and outpts. Time to blood count recovery was similar. No improvement was seen in cycle length. The proportion undergoing allogeneic transplant in first remission was 37.1%, and at any time, 59.7%. Over a median follow up of 3.3 years, median RFS was 2 years and OS, not reached. Conclusion: In selected pts, outpt based AML H/IDAC consolidation therapy significantly reduced hospital length of stay compared with inpts. There was no impact on cycle length. Bacteremia and ICU admission rates were higher in outpts, and strategies such as remote monitoring or pre-emptive hospitalization could be considered. Our findings suggest outpt consolidation should be considered in a supported clinical setting.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2023-187963
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
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  • 3
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    Establishing Mental Wellness Screening As Standard of Care in Pediatric Sickle Cell Patients
    American Society of Hematology ; 2023
    In:  Blood Vol. 142, No. Supplement 1 ( 2023-11-02), p. 5057-5057
    Details
    In: Blood, American Society of Hematology, Vol. 142, No. Supplement 1 ( 2023-11-02), p. 5057-5057
    Abstract: Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized with multi-organ involvement and frequent pain crises. Somatic complaints can give rise to neuropsychiatric disorders, among which anxiety and depression are the most common. Although mental health plays an important role in health outcomes, there is not a standardized approach to screen sickle cell patients for depression at most sickle cell centers across the country and at Texas Children's Hospital (TCH). The long-term goal of this project is to screen sickle cell patients over the age of 12 for depression across TCH hospitals: TCH-West Campus (TCH-WC), TCH-Woodlands (TCH-WL) and TCH-Medical Center (TCH-MC). Over the past two years, we successfully implemented depression screening at TCH-WC as standard of care through a series of PDSA cycles. The focus of this quality improvement project is to implement depression screening at TCH-WL. At TCH-WC, all sickle cell patients aged 12 years of greater are screened for depression using the Patient Health Questionnaire-9 modified for Adolescents (PHQ-A) . From October 2022 to July 2023, 71% of the patients that qualified for screening identified low risk, 16% identified mild risk and 12% identified moderate to severe risk of depression. Eleven percent endorsed suicidality. Psychology/Social Work (SW) saw 77.4% of patients with moderate to severe depression and 100% who screened positive for suicidality on the same day as screening. Now that our depression screening protocol is standard of care at TCH-WC, we extended this screening to TCH-WL in February 2023. Our goal is to increase the annual depression screening rate from 0 to 50% in English/Spanish speaking patients aged 12 years and older with sickle cell disease who present for follow-up care to the TCH-WL. During our first PDSA cycle at TCH-WL, one hematologist administered the PHQ-A to sickle cell patients & gt; 12 years. No intervention was needed if patient scored 0-6 on the PHQ-A. Psychological resources were provided via handout if patient scored 7-9. SW referral was placed and patient was preferably seen same day if patient scored & gt; 10 on the PHQ-A. If unable to be seen same day, SW followed-up via phone call. If patient screened positive for suicidality, an urgent SW referral was made and patient was seen in clinic the same day. Three sickle cell patients & gt;12 years presented for follow up with the assigned provider. Two-thirds (67%) of patients were given the PHQ-A; half (50%) screened positive. During the second PDSA cycle at TCH-WL, all patients with SCD over the age of 12 who presented to TCH-WL Hematology Clinic were screened. The patients were given the PHQ-A by the Medical Assistant/nurse prior to the start of the appointment and then they followed the outlined and detailed algorithm listed above based on score.Forty-five patients were eligible for screening. Forty-two percent (19/45) were given the PHQ-A; 73% endorsed mild risk of depression; 26% endorsed moderate to severe risk; 22% endorsed suicidal ideation. 80% of patients with moderate to severe risk received same day SW assessment; 100% of patients with suicidal ideation received same day SW assessment. Over the course of our project, we have been able to maintain our goals at TCH-WC and came close to achieving our goal of screening 50% of eligible patients for depression at TCH-WL. We are working with staff and providers at TCH-WL to determine barriers and optimize clinic flow in order to achieve & gt;50% screening. In the future, we plan to expand our project to our largest sickle cell clinic, TCH-Medical Center, and for depression screening to become standard of care for all sickle cell patients at Texas Children's Hospital.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2023-187377
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
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  • 4
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    Social and Demographic Factors Contributing to COVID-19 Vaccine Hesitancy in Patients with Hematologic Malignancies
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 841-841
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 841-841
    Abstract: Background Vaccine hesitancy, defined as the delay in acceptance or refusal of safe vaccines, remains a challenge in the general population. Given that patients with hematologic malignancies frequently encounter healthcare professionals and are at high risk of severe COVID-19 infection, their attitudes towards vaccines may differ from other patient groups. We therefore performed a survey-based study to investigate vaccine hesitancy within an ethnically diverse group of patients diagnosed with hematologic malignancies. Methods We administered a 122-item questionnaire from December 2020 to January 2021 (prior to commercial availability of the COVID-19 vaccines) to 60 patients with hematologic malignancies. Questions were separated into the following categories: demographic and socioeconomic data; personal impact of COVID-19 infection; COVID-19 pandemic experience; COVID-19 infection perceptions; COVID-19 vaccine perceptions; and baseline COVID-19 vaccine knowledge. Results The majority of patients were Black (n=33, 55%) or Hispanic (n=11, 18.3%) and were undergoing active treatment (n=43, 71.7%) or had received prior hematopoietic stem cell transplantation (n=9, 15%). Eight (13.3%) patients had prior COVID-19 infection. Sixteen (26.7%) patients reported infection in an immediate family member while 15 (25%) reported infection in a friend. 20 of these cases were moderate in severity requiring healthcare interaction, and 17 of these cases were reported to result in severe infection (n=7, 9.6%) or death (n=10, 13.7%). Only 16 (29.6%) patients perceived themselves to be at high or very high risk of COVID-19 infection. The COVID-19 pandemic was reported to moderately or severely affect employment/income in 10 (22.8%) patients and led to worse mental health in 10 (22.3%) patients. However, the majority of patients reported no negative impact on their cancer treatment (n=37, 88.1%) or prognosis (n=45, 93.8%). Of the 60 patients, 22 (40.7%) reported that if a COVID-19 vaccine was made publicly available in the next 30 days, they would not vaccinate themselves, either due to safety concerns (n=4, 20%) or indifference (n=6, 30%). Despite this, 43 (78.2%) patients stated that vaccination was an important tool in ending the pandemic. More patients agreed to accept the vaccine if it was made available in 6 months from the time of survey (n=40, 76.9%). Only 32 (59.3%) patients were extremely or very likely to accept a yearly vaccine. In terms of perception on cancer outcomes, 31 (62%) patients were uncertain if the vaccine would interact negatively with their current chemotherapy treatment, while 27 (52.9%) believed the vaccine would make their cancer worse. The biggest fear patients had about COVID-19 vaccines were side effects or death (n=15, 38.5%) and complications to cancer/cancer therapy (n=5, 12.8%). Only 6 (15.4%) patients stated they had no fears related to COVID-19 vaccination. In fact, only 21 (39.6%) patients agreed or strongly agreed that the side effects of most vaccines outweigh the benefits. In a modified (age- and sex-adjusted) Poisson regression model (Table 1) that included baseline demographics and answers to select survey questions, older age was associated with a stronger likelihood of vaccine acceptance (RR 1.73, 95% CI 1.11-2.71; p=0.016), while female gender was associated with less likelihood to accept the vaccine (RR 0.58, 95% CI 0.37-0.90; p=0.016). Patients reported as "other" race (e.g., Asian) were more inclined to accept the vaccine (RR. 2.21, 95% CI 1.16-4.20; p=0.016) compared to White patients. Finally, when compared to patients who receive information primarily from medical professionals, those patients who received their information from social media or friends were far less likely to accept the vaccine (RR 0.02, 95% CI 0.01-0.04; p & lt;0.001). Conclusion This is the first study to report that although patients with hematologic malignancies experienced significant medical and social burdens from the COVID-19 pandemic and have frequent interaction with healthcare professionals, a high rate of COVID-19 vaccine hesitancy still exists. We provide in depth information on the potential reasons for vaccine refusal in a diverse patient population and highlight potential areas for improvement in patient education. In particular, we show that vaccine disinformation received from friends and social media is a significant reason for vaccine refusal. Figure 1 Figure 1. Disclosures Calip: Pfizer: Research Funding; Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Rondelli: Vertex: Membership on an entity's Board of Directors or advisory committees. Patel: Celgene: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-154339
    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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  • 5
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    Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. 15 ( 2021-10-14), p. 1331-1344
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. 15 ( 2021-10-14), p. 1331-1344
    Abstract: The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here, we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA and DNA interactions with the broadly expressed Runt-related transcription factor 1 (RUNX1), we identified the long noncoding RNA (lncRNA) originating from the upstream regulatory element of PU.1 (LOUP). This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia (AML), wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein, RUNX1-ETO, limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell-type–specific RNAs and transcription factors, as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2020007920
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
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  • 6
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    The Quest for Improving Sickle Cell Care: Creating High-Level Quality Improvement Goals with a Care Process Team
    American Society of Hematology ; 2023
    In:  Blood Vol. 142, No. Supplement 1 ( 2023-11-02), p. 3682-3682
    Details
    In: Blood, American Society of Hematology, Vol. 142, No. Supplement 1 ( 2023-11-02), p. 3682-3682
    Abstract: Background: A Care Process Team (CPT) is an interdisciplinary team focused on improvement effort across systems or a population cohort with high degree of variation in care, high volume, high cost, or institutional priority. The Texas Children's Hospital Quality & Safety Department has implemented CPTs for several disease populations including, asthma, diabetes, and pain management. In 2021, the sickle cell CPT (SCCPT) was launched in partnership with the Texas Children's Cancer and Hematology Center. An early step in developing a CPT is delineating goals via a balanced scorecard, a comprehensive framework that translates the team's strategic objectives into a coherent set of performance measures. After establishing priority quality metrics, the SCCPT sought to establish an operational structure and to define and implement specific quality improvement (QI) initiatives to improve outcomes. Methods: The SCCPT assembled a multi-disciplinary expert panel which included providers, nurses, division leadership, data architects, analysts, and quality specialists. After a systematic review of the literature identified metrics with best practice evidence, a modified-Delphi process was used to rank quality metrics according to standards set forth by the National Quality Forum. High-priority metrics were organized into a balanced scorecard. Goals were developed based on Institute of Healthcare QI methodology. A QlikView® dashboard was created to abstract patient data from the electronic medical record. Results: The expert panel met 7 times between January to October 2021. The systematic review found 26 quality measures for SCD and subsequently panel review expanded the list to 34 measures. Expert consensus was reached and 5 metrics were selected for the final SCCPT balanced scorecard. The SCCPT initiated routine meetings in January 2022. Three goals and SMART aims were prioritized from balanced scorecard metrics relating to stroke screenings, disease-modifying drug education and prescriptions, and assignment of a primary Hematology team. Baseline data revealed that 60% of eligible children with SCD had obtained a transcranial Doppler ultrasound within the last 15 months. Hydroxyurea was prescribed to 70% of patients with Hb SS or S/beta-0-thalassemia disease. Primary Hematologist and nurse coordinator teams were assigned to 50% and 23%, respectively. To design and implement QI projects, two teams were created: one focused on prevention-related metrics and the other on treatment-related metrics. Discussion: The successful launch of the SCCPT involved the convening a team of multi-disciplinary members, creation of a balanced scorecard, prioritizing goals, and analyzing baseline data to set SMART aims related to improving SCD care. Two operational teams were created and have proceeded to design and implement QI projects related to SMART aims.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2023-191064
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
    detail.hit.zdb_id: 1468538-3
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  • 7
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    Online Resource
    Tyrosine phosphorylation of DEP-1/CD148 as a mechanism controlling Src kinase activation, endothelial cell permeability, invasion, and capillary formation
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 13 ( 2012-09-27), p. 2745-2756
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 13 ( 2012-09-27), p. 2745-2756
    Abstract: DEP-1/CD148 is a receptor-like protein tyrosine phosphatase with antiproliferative and tumor-suppressive functions. Interestingly, it also positively regulates Src family kinases in hematopoietic and endothelial cells, where we showed it promotes VE-cadherin–associated Src activation and endothelial cell survival upon VEGF stimulation. However, the molecular mechanism involved and its biologic functions in endothelial cells remain ill-defined. We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1–catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin. Accordingly, RNA interference (RNAi)–mediated knockdown of DEP-1 or expression of DEP-1 Y1311F/Y1320F impairs Src-dependent biologic responses mediated by VEGF including permeability, invasion, and branching capillary formation. In addition, our work further reveals that above a threshold expression level, DEP-1 can also dephosphorylate Src Y418 and attenuate downstream signaling and biologic responses, consistent with the quiescent behavior of confluent endothelial cells that express the highest levels of endogenous DEP-1. Collectively, our findings identify the VEGF-dependent phosphorylation of DEP-1 as a novel mechanism controlling Src activation, and show this is essential for the proper regulation of permeability and the promotion of the angiogenic response.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2011-12-398040
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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