bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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&gt;a in Vwf Gene and C.1825C&gt;T in MYO5A Gene?
Authors: Zhou Rong-Fu , Gao Wenjin , Xu Yueyi 
Published: November 2021

Abstract
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&gt; 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&gt;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&gt;A in vWF gene and c.1825C&gt;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

Abstract
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

Abstract
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

Abstract
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

Abstract
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&gt;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
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.