bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a Personalized Near-Peer Mentoring Programme for Final-Year Medical Students with Residents as Mentors
Authors: Yap Angela Frances, Hui Wen , Ruan Xucong , Fong Warren Weng Seng
Published: November 2021

Background

Near-peer mentoring is a process where a mentor is close to the social, professional, or age level of the mentee. Near-peer mentors are better able to interact with and understand the struggles of students.

Objective

The aim of the programme was to increase confidence of students in the final year examination.

Methods

Following a needs analysis of final-year medical students, a near-peer mentoring programme was designed using peer-assisted learning framework. In the programme conducted between November 2019 and March 2020, trained Internal Medicine junior residents were assigned to students grouped according to the examination domains they most needed improvement in. Pre- and post-intervention data on students’ confidence in each of the examination domains using a 5-point Likert scale (1: Not confident at all and 5: Very confident), mock examination scores and feedback on the programme were collected.

Results

Fifty-one students were enrolled. Thirty-one students completed the post-programme survey, of which 71.0% felt more confident in the final year examination. Of the twenty-eight students who completed both the pre- and post-programme survey, 78.6%, 78.6% and 60.7% of them showed an increase in confidence in the communications, physical examination and history component of the examination, respectively. There was no association found between confidence level and examination performance.

Conclusion

A personalized near-peer mentoring programme is effective in increasing confidence of students in examinations and serves as a platform for residents to hone their skills as mentors. Its role as part of the medical school curriculum is worth exploring.
Psychometry: Cutting-Off Points and Standardization of the Jefferson Empathy Scale Adapted for Students of Kinesiology
Authors: Reyes-Reyes Alejandro , Calzadilla-Núñez Aracelis , Torres-Martínez Pilar , Díaz-Calzadilla Patricia , Pastén-Hidalgo Wilson , Bracho-Milic Fanny , Díaz-Narváez Víctor
Published: November 2021

Currently, the most common measurement of empathy is obtained using scales that offer a continuum between a minimum and a maximum value. The objectives of this study were to establish a norm and estimate cut-off points that would make it possible to assess the Jefferson Scale of Empathy (JSE) version for Health Professions students (HPS-version), and to determine its psychometric properties in Chilean physical therapy students. A secondary analysis was done on a data set from three schools of physical therapy ([ n = 850], 412 women [48.5%], and 438 men [51.5%]), applying confirmatory factor analysis (CFA) and hierarchical cluster analysis. A CFA replicated the original three-factor model of empathy with sufficiently fit the data. A hierarchical cluster analysis yielded four categories for the level of empathy: high, medium-high, medium-low, and low. Multi-group analyses supported the assumption of a gender-invariant factor structure. Results confirmed the reliability of the global scale (α = .835), and the Perspective Taking (α = .732), Compassionate Care (α = .842), and Walking in Patient’s Shoes (α = .686) dimensions. The instrument made it possible to establish four ordinal categories in the level of students’ empathy. We conclude that the HPS-version of the JSE has adequate psychometric properties; namely validity, reliability, and cut-off points that justify administering it to Chilean physical therapy students.
A Magic “Bullet”: Exploring Sport Fan Usage of On-Screen, Ephemeral Posts During Live Stream Sessions
Authors: Li Bo , Naraine Michael L. , Zhao Liang , Li Chenyang
Published: November 2021

The bullet-screen function is an augmented comment feature that has been adopted by the majority of Over-the-Top (OTT) services to foster users’ interaction and watching experience. This feature empowers sports customers to post and view numerous, short, and fast-moving comments that overlap over the screen while watching live stream sports events in real time. This research aims to investigate how sports fans embrace the bullet-screen feature while watching live stream sports. Through a combination of thematic analyzing bullet-screen comments from a National Basketball Association Finals game, and semi-structured interviews among bullet-screen users ( N = 15), the results indicate that sport fans’ bullet-screen messages could be classified into five categories: critical commentary, socialization, supportive interactions, random messages, and trash talk. Four motives for sports fans to engage with bullet-screen posting were identified: entertainment, gathering information, interaction, and finding belonging. The study also showed that the inappropriateness of comments and too much overlay on the screen could prevent sports fans from utilizing the service. Theoretical and practical implications have also been discussed.
A Content Analysis of Emergency Department Discharge Instructions for Acute Pediatric Febrile Illnesses: The Current State and Opportunities for Improvement
Authors: Overmann Kevin M. , Vukovic Adam A. , Britto Maria T.
Published: November 2021

Quality emergency department (ED) discharge communication is critical to understanding of disease progression, home management, and return instructions. Addressing social aspects of disease burden are important to improving satisfaction and healthcare utilization. The objective of this study was to understand the extent to which written ED discharge instructions address multifaceted aspects of disease to meet the comprehensive needs of families with common childhood illnesses. We analyzed a national sample of 28 written discharge instructions from pediatric EDs using thematic and inductive content analysis. Seven themes were identified. Nearly all discharge instructions devoted a majority of content to themes related to disease physiology. Other themes common to instructions were related to parental instructions for caring for the child and when to return for further care. Content on caregiver reassurance, returning to daily activities, improving well-being, and promoting community health were not a focus of discharge instructions. Inclusion of multifaceted discharge materials which address both medical and social aspects of disease may help improve family-centered emergency care and the quality of care transitions for common childhood illnesses.
Use of Receptor Occupancy Assays on Cells from Peripheral Blood As a Model to Determine Therapeutic Efficacy
Authors: Jones Nicholas , Davis Floyd , Fancke Benjamin , Ngo Brian , Limson Jessica
Published: November 2021

In the development of monoclonal antibodies for the treatment of liquid or solid tumors, monitoring receptor occupancy (RO) on peripheral blood lymphocytes can help illustrate potential therapeutic activity occurring systemically, or in the tumor environment. There is increased interest in using these assessments on cells from the periphery to assess the efficacy of investigational therapies. In this area of therapeutic development, much focus has been placed on checkpoint inhibition proteins/receptors such as PD-1, PD-L1, TIM3, CTLA-4, TIGIT, and multiple others. These immune checkpoint inhibitors are suitable targets since they can be highly modulated on exhausted T cells in cancer patients. In the case of solid tumors, assessing the expression of these markers in the tumor itself via biopsy would be an invasive process that could not be performed sequentially and, therefore, would provide little information to correlate with pharmacokinetic results throughout the course of a clinical trial to determine timing and optimal dose selection. However, assessment of the receptor expression and occupancy in combination with pharmacokinetics can lead to a better understanding of drug levels required to achieve optimal therapeutic performance. Monitoring the expression and binding of these molecules by a drug can determine specific treatment based on the ability of the patient's own immune system to act, while providing information to identify therapeutic responses against cancer. This poster will present an example of receptor occupancy (RO) assessment in its development and implementation.

Disclosures

No relevant conflicts of interest to declare.
Diagnosis and Management of Diffuse Large B Cell Lymphoma in Resource Constraint Settings: Society of Medical Oncology Pakistan, Pakistan Society of Haematology and Pakistan Society of Clinical Oncology Joint Clinical Practice Guideline
Authors: Iftikhar Raheel , Ayaz Mir Muhammad , Moosajee Munira , Rasheed Kamran , Imam Bukhari Syed Waqas , Nadeem Abbasi Ahmed , Shamsi Tahir Sultan , Khan Maryam , Ahmed Parvez , ud Din Hafeez , Chaudhry Qamar un Nisa , Ahmad Imran N , Ali Natasha , Umair Muhammad , Bangash Mussavir , Ahmad Usman , Sattar Wasim , Zargham Anum , Shafi Azhar , Shamshad Ghassan U. , Rizvi Qurratulain , Usman Shaikh Mohammad , Muhammad Irfan Syed , Zaidi Uzma , Naqi Naeem , Mahmood Humera , Hussain Asghar , Ijaz Masood Ahmed , Siddiqui Neelam , Masood Misbah , Faheem Mohammad , Adil Salman Naseem , Aziz Zeba
Published: November 2021

Purpose: To provide evidence-based recommendations for health care professionals on diagnosis and management of diffuse large B cell lymphoma (DLBCL) in resource constraint settings with variable and often limited access to standard of care and advanced diagnostic and therapeutic facilities.

Methods: Modified Delphi methodology[1] was used to generate consensus by experts of three major cancer societies of Pakistan; namely Society of Medical Oncology Pakistan (SMOP), Pakistan Society of Hematology (PSH) and Pakistan Society of Clinical Oncology (PSCO). Guidelines questions were drafted and meetings were convened by steering committee to develop initial recommendations based on local challenges and review of the literature. Consensus panel reviewed the initial draft recommendations and rated the guidelines on five-point Likert scale; recommendations achieving more than 75% consensus were accepted. Resource grouping initially suggested by Breast Health Global Initiative[2] was applied for resource stratification into basic, core and enhanced resource settings.

Results: The expert panel advised use of limited immunohistochemistry (IHC) including CD20, CD3 and Ki67% for initial diagnosis in core (limited) resource settings and extended panel in enhanced resources. Cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) with or without rituximab (as per resource setting) remains the standard first line treatment while second line treatment should be offered based on resource availability and patient related factors. Both intra thecal and high dose methotrexate can be used for CNS prophylaxis. Recommendations by guideline committee are listed in Table 1.

Conclusion: Diagnosis and treatment recommendations in resource constraint settings should be developed based on available diagnostic, therapeutic resources and management expertise.

References: Niederberger, M. and J.J.F.i.p.h. Spranger, Delphi Technique in Health Sciences: A Map. 2020. 8: p. 457.Eniu, A., et al., Guideline implementation for breast healthcare in low-and middle-Income countries: Treatment resource allocation. 2008. 113(S8): p. 2269-2281.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Lenalidomide, Rituximab and Methotrexate（R2-MTX）in Newly Diagnosed Primary Central Nervous System Lymphoma
Authors: Yuan Xianggui , Liang Yun , Liu Hui , Xu Yang , Zhao Aiqi , Xu Xiaohua , Qian Wenbin
Published: November 2021

Background

Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal non-Hodgkin's lymphoma with poor prognosis. High-dose methotrexate (HD-MTX) is the cornerstone for treatment. However, there is no consensus on the best combination chemotherapy regimen. This study aimed to explore the efficacy and safety study of R2-MTX (Lenalidomide, Rituximab and Methotrexate) as a first-line induction regimen in the treatment of newly diagnosed PCNSLs.

Methods

This is a single-arm, prospective phase II study. Immunocompetent patients (18 to 75 years of age) with newly diagnosed PCNSLs were treated with 6 cycles of R2-MTX induction chemotherapy. Lenalidomide was dosed at 25mg daily (day 1-10); rituximab was dosed at 375mg/m2 (d0), MTX was dosed at 3.5g/m2 (d1). Every 21 days were as a course of treatment. Patients who did not reach CR after 6 courses of treatment were given salvage whole-brain radiotherapy (WBRT) to 30-36 Gy followed by a limited field to gross disease to 45 Gy. Then the patients received R2 maintenance (Rituximab 375mg/m 2 d1, lenalidomide 25mg d1-14, 29-42, 56 days per cycle) for 4 cycles. The primary endpoint is the objective response rate.

Results

14 patients were enrolled from Feb 2020 to June 2021. Six (42.9%) patients were male and the median age was 59 (range 44-73). Ten (83.3%) patients were mediate or high-risk group (2-5 points) according to IELSG score. The last follow-up was July 15th 2021. Twelve patients were evaluable for response (one patient withdrew the consent; another patient was found with chronic lymphocytic leukemia). The overall response rate (ORR) was 91.7% (11/12). Nine patients achieved complete remission, and two patients achieved partial remission at the last follow-up. The median follow-up time was 11.3 (1.3-16.9) months. Only one patient did not respond and died for disease progression (Figure 1). The most common grade ≥3 adverse events (AEs) included elevated alanine transaminase (ALT) (16.7%), neutropenia (16.7%), thrombocytopenia (8.3%), infection (8.3%), and acute kidney injury (8.3%) (One patient with MTX overdose suffered from all these ≥3AEs). The most common grade 1-2 AEs were neutropenia (66.7%), anemia (58.3%), thrombocytopenia (16.7%) elevated ALT (41.7%).

Conclusion

R2-MTX regimen is an effective and well-tolerated combination treatment for newly diagnosed PCNSLs. More clinical data will be updated.

Keyword(s): Primary Central Nervous System Lymphoma, Lymphoma therapy, Methotrexate, Rituximab, Methotrexate, Lenalidomide

Trial registration: ClinicalTrials.gov NCT04934579.

Conflict of Interest: The authors declare that they have no conflict of interest.

Figure 1 Swimmer plots of all PCNSL patients evaluable for response.

Each bar represents one patient; the length of the bars shows the time between the initiation of treatment and the last follow-up.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Thrombocytopenia Caused By Compound Heterozygous Missense Mutations C.3946G>a in Vwf Gene and C.1825C>T in MYO5A Gene?
Authors: Zhou Rong-Fu , Gao Wenjin , Xu Yueyi
Published: November 2021

Objective: One patient with thrombocytopenia from childhood was examined to identify the cause of thrombocytopenia.

Methods: The previous medical history of the patient was comprehensively reviewed, with blood routine examination , reticular platelet count, autoantibodies, hepatitis virus full set, thyroid function, plasma coagulation factor VIII activity, vWF activity and antigen testing, and NGS with peripheral blood to detect thrombosis and hemostatic related genes.

Results: The female patient, 43 years old, was presented with thrombocytopenia for more than 40 years. She had no history of fever or bleeding with no significant menstrual volume increasing. His father had similar thrombocytopenia but died four years ago. On third June,2021, she had no skin bruises or enlarged spleen. Blood routine test showed wbc 7.4x10 9/l, HB 112g/l, Plt 47x10 9/l and reticular platelet count 1.85%. Hepatitis B surface antibody was 147.08mIU/ml. FVIII:C was 62.0% with vWF:A 17.4% and vWF:Ag 61.9%. NGS results suggested that there was a heterozygous c.3946G> A missense mutations in Exon28 of vWF gene (chr12:6128638) , resulting in p.Val1316Met. The variation is rare in the East Asian population and is shown in the human disease database to cause type 2B vWD, which causes increased platelet clearance due to variation in vWF molecule-platelet binding regions, clinically manifested as mild to moderate platelet reduction. there was also a heterozygous c.1825C>T missense mutation in Exon15 of MYO5A gene (chr15:52676447) , resulting in p.Arg609Cys. There are adverse effects on the structure / function of the MYH12 protein encoded by the MYO5A gene. The MYH12 protein is involved in cell metabolism and cytoskeletal activity, and this protein deficiency might also cause thrombocytopenia, which is clearly warranted to further investigation.

Conclusions：compound heterozygous missense mutations c.3946G>A in vWF gene and c.1825C>T in MYO5A gene might caused thrombocytopenia in the patient.

Disclosures

No relevant conflicts of interest to declare.
USB1 Is a miRNA Deadenylase That Regulates Hematopoietic Development
Authors: Jeong Ho-Chang , Shukla Siddharth , Parker Roy , Batista Luis
Published: November 2021

Poikiloderma with neutropenia (PN)is an autosomal-recessive bone marrow failure (BMF) syndrome in which patients harbor homozygous or compound heterozygous mutations in the human gene C16orf57, which encodes the evolutionarily conserved RNA 3' to 5' exonuclease U6 biogenesis 1 (USB1). USB1 is required for the proper maturation of U6 and U6atac snRNAs, core components of the spliceosome, and consequently, splicing defects have been observed in yeast and zebrafish models with USB1 deficiency. However, lymphoblastoid cells from PN patients do not exhibit reduced U6 snRNA levels and have normal pre-mRNA splicing, establishing PN as a singular BMF syndrome, where the underlying genetic cause has been identified but the molecular mechanisms leading to tissue failure remain obscure.

To investigate the role of USB1 in a physiological context, we utilized CRISPR/Cas9 to create human embryonic stem cells (hESCs) containing a frequently occurring c.531_del_A loss-of-function mutation in the USB1 gene (USB1_c.531_del_A hESCs). USB1_c.531_del_A hESCs have normal karyotype, normal growth rate, and retain pluripotency, indicating that clinically-relevant mutations in USB1 are not deleterious in undifferentiated hESCs. To elucidate the role of USB1 during hematopoiesis, we performed serum-free hematopoietic differentiations to derive hematopoietic progenitor cells from WT and USB1_c.531_del_A hESCs. The formation of definitive hematopoietic progenitors (CD45+) was decreased in USB1 mutant cells compared to WT cells, and definitive colony potential analysis showed compromised colony formation in USB1 mutants. These observations indicate that loss-of-function mutations in USB1 negatively influence hematopoiesis. Additionally, as PN is associated with severe non-cyclic neutropenia, we analyzed the potential of neutrophil formation in WT and USB1 mutant cells. USB1 mutants have reduced formation of CD15+/CD66b+ lineages, indicating abnormal neutrophil development. Conditional expression of WT USB1 in USB1_c.531_del_A mutant cells rescued these phenotypes, leading to normal hematopoietic development.

Interestingly, USB1 mutants showed no reduction in the overall levels of U6 and U6atac snRNAs, similar to what was observed in patient cells. To identify other possible targets of USB1, we sequenced the transcriptome and miRome of WT and USB1 mutant cells in different stages of hematopoietic development. Through these analyses, we demonstrate that hematopoietic failure in USB1 mutants is caused by dysregulated miRNA levels during blood development, due to a failure to remove destabilizing 3' end oligo(A) tails added by PAPD5/7. Moreover, we demonstrate that modulation of oligoadenylation through genetic or chemical inhibition of PAPD5/7 rescues the defective hematopoiesis observed in USB1 mutants.

This work indicates USB1 acts as a miRNA deadenylase and suggests PAPD5/7 inhibition as a potential therapy for PN.

Disclosures

Parker: Faze Therapeutics: Other: Co-founder.
The Ability of CBFβ-SMMHC to Increase RUNX1 Binding Affinity to Target DNA Correlates with Its Leukemogenic Potential
Authors: Zhen Tao , Dou Tongyi , Chen Yun , Yang Wei , Jiang Jiansen , Liu Paul P.
Published: November 2021

Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. We recently showed that RUNX1 is indispensable for Cbfb-MYH11-induced leukemogenesis in a mouse model. We found that RUNX1 interacted with CBFβ-SMMHC, the fusion protein encoded by CBFB-MYH11, to directly regulate critical genes for leukemogenesis (Zhen et al., Blood, 2020). However, our current understanding of the interaction between CBFβ-SMMHC and RUNX1 does not provide adequate explanation on how the RUNX1-CBFβ-SMMHC complex forms and how the complex interacts with DNA for leukemogenesis as CBFβ-SMMHC without the RUNX1 high-affinity-binding-domain (CBFβ-SMMHC-ΔHABD) is also able to induce leukemia while CBFβ-SMMHC with mutations in the C-terminal multimerization domain (CBFβ-SMMHC-mDE) is not able to induce leukemia in mice.

To address this question, we used RHD domain of RUNX1, CBFβ, CBFβ-SMMHC, CBFβ-SMMHC-ΔHABD and CBFβ-SMMHC-mDE proteins, which were purified from E. coli overexpressing these proteins, to explore how the HABD and DE domains affect the interactions between CBFβ-SMMHC, RHD and RUNX1-target DNA Bio-Layer Interferometry (BLI) and negative staining. As expected, deletion of the HABD domain significantly reduced CBFβ-SMMHC's binding affinity to RHD by BLI assay. Interestingly, differences in binding affinity between RHD and different versions of CBFβ-SMMHC did not correlate with their leukemogenic capability. On the other hand, the binding affinity between RHD and its target oligo was more significantly enhanced by CBFβ-SMMHC and CBFβ-SMMHC-ΔHABD that can induce leukemia than CBFβ-SMMHC-DE, which cannot. We also found that both CBFβ-SMMHC and CBFβ-SMMHC-ΔHABD, but not CBFβ-SMMHC-mDE, could form a filament structure by negative staining, suggesting the filament formation ability is important for leukemogenesis by CBFβ-SMMHC. In addition, RHD reduces filament formation by CBFβ-SMMHC, which was overcome when target oligo was added. In contrast, RHD could not inhibit filament formation by CBFβ-SMMHC-ΔHABD, suggesting that HABD interaction is required for RHD to disrupt filament formation by CBFβ-SMMHC.

Overall, we found that leukemogenic capability of CBFβ-SMMHC correlates with its ability to enhance binding between RHD and its target DNA and to form multimerized filaments. The results also suggest that HABD and DE domains of CBFβ-SMMHC are required for the formation of the RUNX1-CBFβ-SMMHC complex with higher binding affinity to target DNA.

Disclosures

No relevant conflicts of interest to declare.
CD30 Promotes Proliferation Via ERK 1/2 and p38 MAPK Signal Pathways in ABC-Diffuse Large B Cell Lymphoma
Authors: Huang Weimin , Wei Xiaolei , Wei Yongqiang , Feng Ru
Published: November 2021

Background

CD30 was expressed in about 40% diffuse large B cell lymphoma (DLBCL), epically in activated B cell subtype DLBCL(ABC-DLBCL) and implied superior outcome. however, the underlying mechanisms remains unclear.

Methods

Three ABC-DLBCL cell lines (SuDHL2, TMD8, HBL1) were used for construction of stably CD30 expression cell lines. The proliferation of these cell lines was measured by MTT assay. Cell cycles were detected by Flow Cytometry after staining with PI. Expression of CyclinD1, p27, CDK2, ERK, phosphorylation-ERK, p38, phosphorylation p38 was detected by Western Blot. Nude mice were used in vivo study.

Results

With CD30 overexpression, the proliferation and division of SuDHL2, TMD8 and HBL1 cell lines were promoted. CyclilnD1, CDK2 were upregulated and p27 was downregulated after of CD30 overexpression. Furthermore, CD30 was knock down by treated CD30 shRNA in CD30 overexpression cell lines. CD30 KD could reverse the the proliferation induced by CD30 expression. CD30 overexpression increased the phosphorylation of ERK and p38 in ABC-DLBCL cells. In vivo study, CD30 overexpression was correlated with cell proliferation and division.

Conclusion

Taken together, our date showed CD30 promotes proliferation and division by activating ERK 1/2 and p38 MAPK signal pathways, and targeting CD30 may be a novel therapeutic approach for improving the effectiveness of chemotherapy in ABC-DLBCLs.

Key words: CD30, ERK 1/2, p38 MAPK, ABC- diffuse large B cell lymphoma

Disclosures

No relevant conflicts of interest to declare.
Recombinant Human Thrombopoietin Accelerates the Recovery of Platelet in Patients with Lower-Risk Myelodysplastic Syndrome: A Prospective Cohort Study
Authors: Yang Yuan , Wang Zhao , Han Bing
Published: November 2021

Aim: The effect of recombinant human thrombopoietin (rhTPO) is largely unknown in lower-risk myelodysplastic syndrome (LR-MDS). This study aimed at investigating the safety and efficacy of rhTPO in patients with LR-MDS.

Methods: This was a prospective study. Patients newly diagnosed as LR-MDS patients from 2018 to 2020 were enrolled and randomized into two groups. They were either treated with rhTPO+ stanozolol 2mgtid (rhTPO group) or stanozolol 2mgtid alone (non-rhTPO). rhTPO was given at 15000U qd for 7days/months for at least three months. Patients stopped rhTPO if platelet count was higher than50×10 9/L, or had no effects after 3-month treatment. The overall response (OR), complete response (CR), platelet response, side effects, clone evolution and clinical outcome were evaluated.

Result: 35 patients were enrolled, the median age (range) was 55 (41-91) years and 17 patients were males, 18 patients were females. 20 (57.1%) patients were enrolled in rhTPO group and 15 (42.9%) patients in non-rhTPO group. The demographic and baseline characteristic were balanced between the two groups. The platelet response was higher at 1 month and 2 months, as compared with that in non-rhTPO group (40% vs 0%, p = 0.006; 55.0% vs 0%, p = 0.001, respectively). Meanwhile, rhTPO group had a shorter time to achieve platelet transfusion free compared with non-rhTPO group (2 (1-6) months vs 4.5 (2-12) months, p=0.034). No significant difference in overall response, complete response, or hematologic response at 1/2/3/6/12months between the two groups. One patient in rhTPO group evolved into higher risk MDS, one patient died of intracranial hemorrhage. No significant difference in disease progression, infection, gastrointestinal disorders or drug-related liver/renal injuries were found between the two groups (p>0.05).

Conclusion: Adding short-term rhTPO can accelerate the early platelet response and decrease platelet transfusion with no obvious side effects.

Disclosures

No relevant conflicts of interest to declare.
Pomalidomide Promotes the Maturation of Healthy Donors and Multiple Myeloma Patients Derived-Dendritic Cells
Authors: Wang Xi , Che Feifei , Cao Wanjun , Ye Zichen , Zheng Hong , Huang Xiaobing , Xiao Rong , Wang Wen , Ye Xuemei , He Lin , Dai Jingying
Published: November 2021

Abstract: Objective To investigate the effect of pomalidomide on the maturation of monocyte derived dendritic cells (moDCs) from healthy donors (HDs) and multiple myeloma (MM) patients. Method Peripheral blood mononuclear cells (PBMCs) were isolated from the peripheral blood of HDs and MM patients. The generation of moDCs from monocytes in PBMCs was conducted by the incubation of 7 days in a medium consisting of RPMI 1640 medium, 5% human serum, 800U/mL GM-CSF, 500U/mL IL-4, 100U/mL penicillin and 0.1mg/mL streptomycin. During this period, the incubation system was administrated with pomalidomide at 10 µM or 1×PBS as the control group. On the 8 th day, cells were harvested, and the immunophenotyping of cells were analyzed by the flow cytometry. The CD80+CD86+ cell population in total cells is gated as DCs in the FACS analyzing system. Then, the median fluorescence intensity (MFI) of surface markers CD40 and HLA-DR as well as the proportion of CD40+ DCs and HLA-DR+ DCs in total DCs were analyzed respectively. In addition, supernatant from the incubation system with or without pomalidomide administration was collected and detected for the concentration of cytokines IL-12, TNF-α and MIP-1α. Results The proportion of CD80+CD86+ cells in total cells was higher in HD group (n=15) than in MM patient group (n=11), but there was no statistically significant difference (93.49%±6.43% vs 77.04%±27.17%, P=0.094). When analyzing all the HD-derived moDCs (n=15), pomalidomide significantly enhanced the MFI of CD40 (P=0.003) and HLA-DR (P=0.040) on moDCs when compared with the control group. Meanwhile, the proportion of CD40+ DCs (P=0.008) and HLA-DR+ DCs (P=0.032) in total DCs was significantly higher in pomalidomide group than in control group. When analyzing all MM patients-derived moDCs (n=11), pomalidomide significantly enhanced the MFI of CD40 (P=0.047) and HLA-DR (P=0.006) on moDCs when compared with the control group. Meanwhile, the proportion of HLA-DR+ DCs in total DCs was significantly higher in pomalidomide group than in the control group (P=0.000). Moreover, pomalidomide treated HD-derived moDCs (n=8) produced 192% IL-12 (P=0.020), 110% TNF-α (P=0.006) and 112% MIP-1α (P=0.055) of untreated moDCs. However, when analyzing MM patients-derived moDCs (n=10), the expression of IL-12 (P=0.458), TNF-α (P=0.377) and MIP-1α (P=0.248) from moDCs showed no significant difference between pomalidomide group and the control group. Conclusions Pomalidomide at 10 µM can promote the maturation of both HD-derived moDCs and MM patients-derived moDCs. Pomalidomide shows potential to be a DC adjuvant for DC-based therapeutic strategies, such as DC vaccine and DC cell-therapy in MM.

Key words: Pomalidomide; Monocyte derived Dendritic Cells; Multiple Myeloma; DC Adjuvant

Disclosures

No relevant conflicts of interest to declare.
Comparable Outcomes Among Adult Patients Allotransplanted for Myelodysplastic Syndrome Using Haploidentical, Matched Unrelated or Matched Sibling Donors: A Single-Center Study
Authors: Garnier Alice , Jullien Maxime , Guillaume Thierry , Peterlin Pierre , Le Bourgeois Amandine , Mahé Béatrice , Dubruille Viviane , Blin Nicolas , Touzeau Cyrille , Gastinne Thomas , Lok Anne , Tessoulin Benoit , Vantyghem Sophie , Bene Marie C , Moreau Philippe , Le Gouill Steven , Chevallier Patrice
Published: November 2021

Introduction: Allogeneic stem cell transplantation (allo-SCT) remains the only curative option for patients with myelodysplastic syndrome (MDS). If recent data have shown encouraging results with haploidentical (haplo) donors in this context, no comparison with allo-SCT using other source of graft (matched sibling [MSD] or unrelated [MUD] donors) has been reported so far.

Methods: We retrospectively considered 102 consecutive adults transplanted for MDS between March 2010 and August 2020 in our Department, comparing outcomes between those receiving a graft from a MSD, a MUD or a haplo-donor.

Results : Thirty-three, 48 and 21 patients respectively received a graft from a MSD, MUD or haplo donor. Peripheral blood stem cells (PBSC) were the source of graft for all patients. The median age of the whole cohort was 63 years old (range: 20-74) and the median follow-up was 23 months (range: 0-125). The three groups shared similar characteristics (gender, type of MDS, disease status, disease risk index, CMV status, ABO compatibility, peripheral blood stem cells graft count, conditioning regimen) except median recipient age which was younger in matched patients ( 61 vs 65 MUD vs 65 Haplo, p=0,04) and median donor age which was older in matched transplant ( 61 vs 34 MUD vs 42 Haplo, p< 0,001) (Table 1). With a median follow-up of 46,4 months, the 4-year OS (Figure 1) was comparable between the three groups (haplo: 60.1 % ± 11,0 % , MSD: 59,0 % ±9,4 % and MUD: 61.2 % ± 7,2 %, p = 0.88) as well as the 4-year DFS (Figure 2) (55.9 % ± 11,1 % vs 51,2 % ±9,2 % vs 59.6 % ± 7,2 %, p = 0.78) and the cumulative incidence (CI) of NRM (34.6 % ±12,4 % , 15,4% ± 6,4% and 23.8 % ± 6,4 %, p = 0.21). Also, the 4-year CI of acute grade 3-4 GVHD (14,3% vs 15,2% vs 20,8%, p=0.79) and of moderate/severe chronic GVHD (14,3% vs 24.2% vs 27,1%, p=0.56) were not significantly different. The 4-year GRFS seemed better with haplo (Figure 3) but this was not statistically significant (56,1 % ± 11,0% vs 28,1% ±9,2 % vs 32,8 % ± 7,4%,p=0 .41).

Conclusions: These data suggest that haplo-identical donors represent a valid alternative in MDS patients lacking a MSD or a MUD for allo-SCT.

Figure 1 Figure 1.

Disclosures

Moreau: Oncopeptides: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria.
The Non-Erythropoietic EPO Analogue (Cibinetide) Preserves Bone Mass in Mice
Authors: Awida Zamzam , Bachar Almog , Saed Hussam , Gorodov Anton , Ben-Califa Nathalie , Ibrahim Maria , Kolomansky Albert , Iden Jennifer Ana , Graniewitz Visacovsky Liad , Liron Tamar , Hiram-Bab Sahar , Brines Michael , Gabet Yankel , Neumann Drorit
Published: November 2021

Background and aims: Erythropoietin (EPO) is a pleiotropic cytokine, which besides its classical role in driving erythropoiesis, displays tissue protective and immunomodulatory activities. EPO also induces bone loss. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. Cibinetide (CIB), a non-erythropoietic analogue of EPO, specifically binds to the heteromeric receptor and confers tissue protection. Our published findings that EPO stimulates osteoclast precursors and entrains a decrease in bone density, raise questions regarding the underlying molecular mechanisms. Here, we evaluated the role of the heteromeric complex in bone metabolism using CIB alone and in combination with EPO in vivo and in vitro.

Results: CIB injections to 12-week-old female mice (120 µg/kg thrice weekly for 4 weeks) resulted in a significant increase in tissue mineral density in cortical bone by 5.8% (1416.4±39.27 vs 1338.74±16.56 mgHA/cm 3) and in trabecular bone by 5.2% (1056.52±30.94 vs 1004.13±16.91 mg HA/cm 3) (n=10 in each group, p< 0.05 versus saline-injected controls), as measured by microCT (Figure 1A).

To evaluate the capacity of CIB to attenuate EPO mediated bone loss, we administered CIB (300 µg/kg) for 5 consecutive days, to 13-week-old female mice that also received 2 injections of 120U EPO on days 1 and 4. Flow cytometry analysis revealed a 1.8-fold reduction in the number of osteoclast progenitors, defined as Lin -CD11b −CD115 +Ly6C hi, in the EPO + CIB injected mice, compared to the mice injected with EPO alone (n=7 in each group, p< 0.05). Hemoglobin levels and TER119 + bone marrow (BM) erythroid progenitors were similar in both groups.

In vitro, EPO administration to BM-derived macrophages (BMDM) enhanced osteoclastogenesis, whereas CIB had an opposite, dose-dependent effect. Combining CIB with EPO inhibited osteoclastogenesis in BMDM, suggesting that CIB overrides the pro-osteoclastogenic effect of EPO (Figure 1B).

Conclusions: Our findings highlight the increasing complexity of EPOR signaling in bone and pave the way for clinical translation through potential combination therapy of EPO and CIB in anemic and in cancer patients. Adjunctive administration of CIB may prevent or attenuate bone loss while preserving the erythropoietic actions of EPO.

This study was supported by a grant from the Dotan Hemato-oncology Fund, the Cancer Biology Research Center, Tel Aviv University to DN and YG.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Vaccine-Induced Thrombotic Thrombocytopenia: Novelty Testing in the Diagnostic Work-up?
Authors: Cacciola Rossella Rosari , Vecchio Veronica , Gentilini Cacciola Elio , Cacciola Emma
Published: November 2021

COVID-19 vaccination campagnies with several vaccines types are currently undeway. Recently, the ASTRA ZENECA vaccine has raised public alarm with concerns regarding the development of thrombotic events known as vaccine-induced thrombotic thrombocytopenia (VITT). Early and limited studies have implicated an antibody-mediated platelet activation as the mechanism of the clotting events. Aim of this study was to investigate the platelet and coagulation activation using specialized tests. In this study we enrolled 60 patients (40 men, 20 women; mean age 55±10 years) without cardiovascular risk factors or a history of thrombosis who reported having poplitea deep vein thrombosis (35/60) and pulmonary embolism (25/60) revealed with lower-limb ultrasonography and computed tomography (CT) angiography, respectively, 7 days after vaccination with ASTRA ZENECA. All patients were evaluated for initial testing such as platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib) and D-dimer (DD). Platelets were measured by automated analyzer, PT and APTT by coagulometric test, Fib using Clauss method, and DD using ELISA. Complete blood hemostasis was studied by platelet function assay (PFA-100) on Collagen/ADP (CT-ADP) and Collagen/Epinephrine (CT-EPI) cartridges and Thromboelastometry method on Clotting Time (CT), Clotting Formation Time (CFT), Maximum Clot Firmness (MCF), and clot lysis at 30 minutes (LY-30). All patients had thrombocytopenia (60±5x109/L), longer PT (28±10 s) and PTT (50±10 s), lower Fib (80±20 mg/dl), higher DD ((550±100 mg/l). All patients had shorter C/ADP and C/EPI (C/ADP, n.v. 68-121 s (42±10 s) and C/EPI n.v. 84-160 s (38±5 s) and shorter CT (CT, unit: s. n.v. 100-240 s) (INTEM 30±20 s, EXTEM 18±10 s), shorter CFT (CFT, unit: s, n.v. 30-160 s (INTEM 11±10 s, EXTEM 19±10 s), longer MCF (MCF, unit: mm, n.v. 50-72 mm (INTEM 128±10 mm, EXTEM 110±10 mm), and lower LY-30 (LY-30, %: v.n. 15% (INTEM 0.8%, EXTEM 0.7%). These interesting findings may be the novelty in the diagnostic work-up of the VITT. If these tests may aid in the diagnosis of VITT deserve to be confirmed and need reproducing in other studies.

Disclosures

No relevant conflicts of interest to declare.
Efficacy and Safety of Apixaban for Primary Prevention of Thromboembolism in Cancer Patients with a Newly Inserted Central Venous Catheter: A Post-Hoc Analysis of the Avert Trial
Authors: Brandt Willem , Brown Cameron , Zahrai Amin , Mallick Ranjeeta , Wells Philip S. , Carrier Marc
Published: November 2021

Background

Venous thromboembolism (VTE) is a common complication in ambulatory patients with cancer initiating systemic chemotherapy. Central venous catheters (CVCs) used for chemotherapy administration are associated with a heightened risk of VTE in this patient population. Primary thromboprophylaxis using a direct oral anticoagulant decreases the risk of VTE without significantly increasing the risk of major bleeding complications in ambulatory cancer patients at intermediate-to-high risk of VTE with a Khorana risk score of ≥ 2. We sought to determine the efficacy and safety of apixaban in intermediate-to-high risk patients with cancer and a CVC.

Methods

This post-hoc analysis was done using the AVERT trial data, which was a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban for primary thromboprophylaxis in intermediate-to-high risk patients with cancer initiating chemotherapy. The primary efficacy outcome was major VTE within 180 days of randomization and the primary safety outcome was major bleeding. The hazard ratios (HRs) for the primary efficacy and safety outcomes in patients with and without CVC were calculated using a Cox regression model controlling for age, gender, and study center.

Results

A total of 217 patients were included in the subgroup analyses with 126 and 91 patients receiving apixaban or placebo, respectively. The baseline characteristics are depicted in Table 1. Major VTE occurred in 6 (4.8%) patients in the apixaban group and 17 (18.7%) patients in the placebo group (HR 0.26; 95% CI, 0.14-0.47; p<0.0001). Major bleeding occurred in 2 (1.6%) patients in the apixaban group and 2 (2.2%) patients in the placebo group (HR 0.69; 95% CI, 0.20-2.35; p=0.556).

Conclusions

Primary thromboprophylaxis with apixaban in patients with cancer and a CVC seems to reduce the risk of VTE without increasing the risk of major bleeding. Future studies are needed to confirm these findings.

Figure 1 Figure 1.

Disclosures

Wells: BMS/Pfizer: Research Funding; Bayer: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Servier: Honoraria. Carrier: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aspen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; Servier: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Transcriptomic Profiling of Circulating Extrafollicular Helper T-like Cells in Patients with Active Chronic Graft-Versus-Host Disease Reveals Distinct Apoptosis Resistance
Authors: Liu Jiapei , Yang Kaibo , Jin Hua , Liu Qifa
Published: November 2021

In our previous studies, we identiﬁed circulating extrafollicular helper T-like cells (CD44 hiCD62L loPSGL-1 loCD4 +, c-extrafollicular Th-like) in human peripheral blood. C-extrafollicular Th-like cells are associated with the development of cGVHD. However, the exact molecular mechanism of these cells in patient with active cGVHD is still unclear. We performed the whole transcriptome analysis of c-extrafollicular Th-like cells from patients with active cGVHD and without cGVHD to explore the molecular mechanism. We identified 4661 differentially expressed genes between two groups by RNA-sequencing. Upregulated expression of Ca2 + influx and protein kinase C signaling pathway induced genes that establish T cell receptor hyper-activation signature were observed in active cGVHD patients. Expression of several inflammation cytokines and receptors were also increased, including IL23, IL27, IL2RA, IL32, IL24 and IL7R. Furthermore, tumor necrosis factor receptor associated factor 1 (TRAF1) and Bcl-2 genes that linked to resist apoptosis were found upregulated. Consistently, we confirmed that the BCL-2 expression of c-extrafollicular helper Th-like cells was significant higher in active cGVHD patients than no cGVHD patients(P=0.02) by quantitative polymerase chain reaction (qPCR). Our study sheds new light on molecular mechanism of the c-extrafollicular Th-like in patient with active cGVHD. Targeting these signaling pathways might blunt the development of cGVHD.

Disclosures

No relevant conflicts of interest to declare.
Essential Roles of Transcription Factor MEF2D in the Maintenance of MLL-Rearranged Acute Myeloid Leukemia
Authors: Zhang Pengcheng , Zhao Lianzhong , Qiu Shaowei , Bhatia Ravi , Lu Rui
Published: November 2021

Acute myeloid leukemia (AML) is an aggressive disease with uncontrolled proliferation of myeloid progenitor cells and a failure of proper cell differentiation. Chromosomal translocations of the KMT2A (MLL) gene are found in about 10% AMLs affecting both children and adults. Patients harboring MLL rearrangement (MLL-r) have a high relapse rate and poor overall survival, emphasizing an unmet need to understand MLL-r AML pathogenesis and develop new therapeutic means. Through a comparative analysis of super-enhancers in AML cell lines and primary samples, we discovered that MLL-r leukemia cells preferentially gain super-enhancer signals at the MEF2D gene. MEF2D is aberrantly activated in MLL-r AML patient samples and predicts poor disease outcomes, implying a potential oncogenic role of MEF2D. Indeed, depletion of MEF2D inhibits human MLL-r leukemia growth and induces profound differentiation. Mechanistically, MEF2D directly represses CEBPE, a master regulator of myeloid differentiation. CEBPE depletion could rescue the growth defect and cell differentiation induced by MEF2D loss. We also demonstrated that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced anti-leukemia effects. Interestingly, MEF2C, a target of MLL fusion oncoproteins, is by far the most studied MEF2 family member with essential roles in MLL-r AML. Our genetic, biochemical, and integrative genomic data shows that MEF2D and MEF2C, both upregulated in MLL-r AML, interact with each other, colocalize genome-widely, and co-regulate target gene expression. We are currently investigating the molecular mechanisms underlying the interdependent function between MEF2 paralogs in MLL-r AML. Collectively, our findings suggest that MEF2D is a novel transcriptional dependency in MLL-r AML and uncover the MEF2-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block.

Disclosures

No relevant conflicts of interest to declare.
The Importance of Bone Marrow Lymphocyte Subtypes As Predicting Factors for Molecular Recurrence in Patients with Chronic Myeloid Leukemia after Discontinuation of Imatinib
Authors: Braga Arthur Gomes Oliveira , Pagnano Katia B , Campioni Marina Dal'Bó Pelegrini , Lopez Ana Beatriz P , Metze Konradin , Duarte Gislaine B O , Lorand-Metze Irene
Published: November 2021

Introduction: in recent years the feasibility of the discontinuation of tyrosine kinase treatment in chronic myeloid leukemia (CML) has been proven, and several clinical factors influencing the duration of treatment-free remission (TFR) after discontinuation have been studied.

Aim: we analyzed the influence of bone marrow (BM) lymphocyte subsets on the molecular recurrence after discontinuation of Imatinib (IM) in CML.

Methods: in a recent discontinuation study performed at our Institution (EDI-PIO trial) we assessed BM lymphocyte subsets before and after introduction of pioglitazone which was given 3 months before discontinuation of IM. Criterias for discontinuation were: patient in chronic phase at diagnosis, a minimum of 3 years on TKI and sustained molecular remission MR4.5 for at least 2 years. Lymphocyte populations studied: B, TCD8, TCD4, T CD4+CD8+ and T CD4- CD8- besides T naïve and memory, TCRαβ, TCRγδ, NK-t and NK cells. The influence of Sokal score at diagnosis, the duration of imatinib treatment together with the BM lymphoid subsets on the time of treatment-free remission (TFR) were examined by uni- and multivariate Cox regressions.

Results: we studied 30 out of 32 patients diagnosed between 1998 and 2013 that reached criteria for discontinuation that were included in EDI-PIO trial: 13 male and 17 female. Median age at diagnosis: 41 years (22-65). Median time of IM treatment: 116.3 months (38.2-209.3); 11 patients (36%) had a molecular recurrence in a median of 5,17 months (2.4-29.4). For patients remaining in TFR the median time of follow-up was 46 months (26.3-55.9). Median overall time of IM treatment (IM-Tr) was 65 months for patients recurring and 124 months for those remaining in TFR. In the univariate Cox regression a significant value was found for IM-Tr, higher percentages of T CD4+CD8+ and lower ones of TCRγδ lymphocytes at discontinuation. In the multivariate model only the T CD4+CD8+ remained.

Conclusion: discontinuation of IM is feasible in patients remaining in continuous MR4.5 for more than 2 years. A longer time of IM treatment and higher values of BM T CD4+CD8+ predict a lower risk of relapse.

Key words: chronic myeloid leukemia, imatinib, discontinuation, lymphocytes, pioglitazone

Disclosures

Pagnano: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pintpharma: Other: Lecture; EMS: Other: Lecture; Jansenn: Other: Lecture.