bluuebunny/crossref_metadata_2025 huggingface dataset:
Chromosome Abnormality Spectra and Clinical Impact in 1,787 Cases of Acute Leukemia in Koreans
Authors: Son Dong Geun , Jang Ho Cheol , Lee Young Eun , Choi Yong Jun , Park Joo Heon , Baek Hee Jo , Kook Hoon , Kim Mihee , Song Ga-Young , Ahn Seo-Yeon , Jung Sung-Hoon , Yang Deok-Hwan , Lee Je-Jung , Kim Hyeoung-Joon , Ahn Jae-Sook , Shin Myung Geun
Published: December 2024

In acute leukemia, chromosomal alterations serve as diagnostic and prognostic markers, detectable via various techniques. Our institution previously studied chromosomal abnormalities over two periods of time, noting any differences. This study investigated the frequency of these abnormalities and clinical trends in acute leukemia in Korea across three time periods.

We reviewed data from 1,787 acute leukemia patients (319 children, 1,468 adults) diagnosed between 2006 and 2020. Conventional cytogenetics, fluorescence in situ hybridization (FISH), and multiplex RT-PCR were used for analysis. Patients were grouped into three periods: 2006-2009 (I), 2010-2015 (II), and 2016-2020 (III).

Chromosomal aberrations were identified in 92% of patients using conventional cytogenetics, with PML::RARA being the most frequent. Age-specific patterns showed significant differences in fusion genes between children and adults, with some abnormalities detectable only using specific methods. In adult patients, a significant increase in the median age receiving intensive chemotherapy was observed (median years: 48 vs. 53 vs. 60 in periods I, II, and III, respectively, P <0.001). An improvement in overall survival during period III was particularly evident in patients over 50 years old (P=0.003).

Over the 15-year period, chromosomal aberrations showed minimal changes, with consistent common fusion transcripts. In children, acute lymphoblastic leukemia (ALL) is more prevalent, with significant ETV6::RUNX1 and RUNX1::RUNX1T1 aberrations. In adults, the incidence has increased, with PML::RARA remaining common. Clinically, advances in transplantation and supportive care have allowed for increased intensive chemotherapy administration to older patients, improving survival rates.
Investigating the Impact of an Efficacy-Based Nursing Program Integrated with Nutritional Intervention Strategies on the Outcomes of Multiple Myeloma Patients Experiencing Renal Failure
Authors: Liu Tingting , Jiang Cuiting , Xu Luxiang , Liu Yao
Published: December 2024

Objective: Assessing the Effectiveness of a Nutritional Intervention Combined with an Efficacy-Grounded Nursing Plan for Patients with Multiple Myeloma (MM) and Renal Failure.

Methods: A prospective selection was conducted on 92 patients with MM complicated with renal failure admitted to our hospital from April 2022 to April 2024. They were randomly divided into a control group (46 cases, receiving routine nursing care) and an observation group (46 cases, receiving a nursing plan based on efficacy theory combined with nutritional intervention). Compare the changes in self-efficacy CDSES score, psychological resilience CD-RISC score, cancer-related fatigue CFS score, and quality of life FLIC score between two groups.

Results: Following the intervention, there was a notable elevation in CDSES and CD-RISC scores for both groups, with the combined observation group exhibiting higher scores than the control group. Additionally, CFS scores reduced in both groups at 1 week, 1 month, and 3 months post-intervention compared to T0, with the combined regimen patients displaying apparently lower scores than the control group (P<0.05). Marked improvements were observed in domains of physical and psychological well-being, cancer-related hardship, and social well-being for both groups, with the combined observation group achieving higher scores than the control. Nausea scores decreased clearly in both groups post-intervention, though the control group experienced a more pronounced decline compared to the combined care patients (P<0.05).

Conclusions: The integration of an efficacy theory-grounded nursing plan with nutritional intervention exhibits beneficial effects on MM patients with renal failure, enhancing their self-efficacy, bolstering psychological resilience, mitigating cancer-related fatigue, and optimizing nutritional status and overall quality of life.
Prophylaxis with Thiotepa and High-Dose Methotrexate Showed Low CNS Relapse Rate in Diffuse Large B-Cell Lymphoma with High Risk of CNS Relapse
Authors: Zeng Ruolan , Ouyang Zhou , Li Yajun , He Yizi , Wang Caiqin , Xia Chen , Wang Zhongtai , Li Yixue , Liu Yinhua , Tang Weiqiang , Ouyang Qianying , Liang Liang , Su Chang , Lu Guige , Zhu Xueting , Hu Qianyu , Xiao Ling , Zhou Hui
Published: December 2024

Background: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) results in dismal prognosis. There is controversy over the treatment method and efficacy of CNS prophylaxis in high risk DLBCL. Although methotrexate (MTX) is the most widely used therapy for CNS prophylaxis, results from previous studies investigating the optimal regimen for CNS prophylaxis remains unclear. Therefore, additional strategies for preventing CNS relapse in DLBCL patients are required. We evaluated the efficacy and safety of different prophylactic regimens (thiotepa plus high-dose methotrexate, high-dose methotrexate alone or intrathecal methotrexate and cytarabine) in newly diagnosed DLBCL patients with high-risk for CNS relapse.

Methods: We retrospectively analyzed records of all newly diagnosed DLBCL patients at high risk for CNS relapse treated at Hunan Cancer Hospital between November 2009 and January 2024. Patients received either thiotepa plus high-dose methotrexate (thiotepa 40mg/ m2, methotrexate 3.5g/m2, T-HD-MTX), high-dose methotrexate alone (methotrexate 3.5g/m2, HD-MTX), or intrathecal methotrexate and cytarabine (IT). The primary endpoint was the rate of CNS relapse, and the secondary endpoints included progression-free survival (PFS) and adverse events (AEs).

Results: 232 newly diagnosed DLBCL patients (128 males; median age 59 years, range, 19-76) with high-risk for CNS relapse was included in this study, of whom 170 patients were Ⅲ-Ⅳ stage, 136 patients were non-GCB and 46 patients were CD5 positive. Prophylactic regimens were as follows: IT MTX in 84 patients (36.2%), HD-MTX in 105 patients (45.3%), and T-HD-MTX in 43 patients (18.5%). With a median follow-up of 43 months, CNS relapse rate was 22.6% (19/84) in IT group, 8.6% (9/105) in HD-MTX group, 2.3% (1/43) in T-HD-MTX group (P＜0.001). The most common AEs were leukopenia (56.5%), thrombocytopenia (32.8%), and anemia (37.5%). Grade 3-4 AEs included leukopenia (10.8%), thrombocytopenia (2.2%), and pneumonia (3.4%), and no severe AEs reported.

Conclusion: Thiotepa plus high-dose methotrexate is an effective and well-tolerated CNS prophylactic regimen for high-risk newly diagnosed DLBCL patients.
Intensified Conditioning Containing Decitabine Versus Standard Myeloablative Conditioning for Adult Patients with KMT2A-Rearranged Leukemia: A Multicenter Retrospective Study
Authors: Hu Zhongli , He Hai , Liu Shiqi , Dong Ying , Fan Zhiping , Li Yiqing , Huang Fen , Xu Na , Liu Can , Zeng Yunxin , Zhu Ping , Lin Ren , Jin Hua , Zhang Xiong , Sun Ruijuan , Liu Qifa , Xuan Li
Published: December 2024

Background: KMT2A-rearranged (KMT2A-r) leukemia has a poor prognosis. Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is recommended for patients with this disease, but relapse remains high. In addition to disease-associated factors, intensities of conditioning are an essential factor affecting relapse post-transplantation. We aimed to determine whether intensified conditioning containing decitabine (Dec) could reduce relapse compared with standard myeloablative conditioning in adult patients with KMT2A-r leukemia.

Methods: We performed a multicenter retrospective study at six institutions in China. Eligible patients were aged 14 years or older at transplantation, had a diagnosis of KMT2A-r leukemia, and underwent first allo-HSCT. Standard myeloablative conditioning regimens (standard group) included BuCy (busulfan 3.2 mg/kg/day on days -7 to -4; cyclophosphamide 60 mg/kg/day on days -3 to -2) and TBI-Cy (total body irradiation 4.5 Gy/day on days -5 to -4; cyclophosphamide 60 mg/kg/day on days -3 to -2). Intensified conditioning regimens containing Dec (intensified group) consisted of Dec-BuCy (Dec 20 mg/m2/day on days -14 to -10; the same dose of BuCy) and Dec-TBI-Cy (Dec 20 mg/m2/day on days -10 to -6; the same dose of TBI-Cy).

Results: Between April 2009 and December 2019, 218 patients were enrolled including 105 in the intensified group and 113 in the standard group. The 3-year cumulative incidence of relapse was 19.4% and 37.0%, overall survival was 71.3% and 61.0%, disease-free survival was 70.1% and 56.0%, and non-relapse mortality was 13.0% and 11.1% in the intensified and standard groups, respectively (P = 0.001; P = 0.034; P = 0.005; P = 0.850). Subgroup analysis showed the relapse rate of intensified conditioning was lower than that of standard conditioning in multiple subgroups, including different leukemia types and disease status at transplantation, high-risk cytogenetics and busulfan-based regimens. Grade 3 or worse RRT occurred in 11 (10.5%) and 10 (8.8%) patients in the intensified and standard groups, respectively. One (1.0%) patient in the intensified group died of heart toxicity, and one (0.9%) in the standard group died of kidney toxicity. There was no difference in engraftment or graft-versus-host disease between the intensified and standard groups.

Conclusions: These results suggest that intensified conditioning containing Dec might be a better strategy than standard myeloablative conditioning for adult patients with KMT2A-r leukemia undergoing allo-HSCT, which requires further confirmation in prospective, randomized controlled studies.
White Blood Cell Count, Neutrophil to Lymphocyte Ratio and Serum Lactate Dehydrogenase Level Associated with Thrombosis Risk Prediction in Essential Thrombocytosis
Authors: Oh Yu Been , Lee Young Eun , Lim Ha Jin , Kwon Yong Jun , Choi Yong Jun , Park Joo Heon , Choi Hyun-Jung , Choi Hyun-Woo , Kee Seung-Jung , Kim Soo Hyun , Shin Jong Hee , Shin Myung Geun
Published: December 2024

Risk assessment systems, including International Prognosis Score of thrombosis in Essential Thrombocythemia (IPSET-t), have been developed to predict the risk of thrombosis in essential thrombocythemia (ET) patients. However, these systems have not been extensively validated. This study aims to assess the clinical utility of conventional risk stratification, IPSET-t, and a revised IPSET-t system in Korean ET patients. Additionally, this study identified markers that could predict thrombosis in ET using routine laboratory test results.

A total of 359 ET patients were diagnosed through blood tests, bone marrow tests, genetic tests, and chromosome tests. Markers that predict thrombosis were identified using blood tests and clinical chemistry test results performed at the time of diagnosis. The patients were classified using conventional risk stratification, IPSET-t, and revised IPSET-t systems.

The average age of ET patients was 61.8 years with 52.9% of female patients. Chromosomal abnormalities were observed in 5.1% of patients. Thrombosis-free survival (TFS) analysis revealed statistically significant differences in survival between the low and high-risk groups without showing statistical significance. No differences in progression-free survival (PFS) were observed between groups for the IPSET-t and revised IPSET-t risk prediction systems. White blood cell (WBC) count, neutrophil to lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) levels were significantly associated with risk stratification, with higher values observed in higher-risk categories.

Three risk assessment systems were confirmed to be useful in predicting TFS but showed limitations in predicting PFS. Meanwhile, the WBC count, NLR and LDH levels were useful as blood test markers for predicting the prognosis.
Efficacy and Safety of Rituximab Biosimilar (DRL_RI) Versus Mabthera in Low Tumor Burden Follicular Lymphoma: The Flinter Study
Authors: Maharaj Narendra , Uppada Dharma Rao , Eswaraiah Anand , Kakkattu Ranjith , Reddy Pramod , Kalenik Volha A , Belada David , Oliveira Ana C , Kim Jin Seok , Baranau Yauheni V
Published: December 2024

Objective: This randomized, double-blind, phase 3 study evaluated the efficacy, safety, and immunogenicity of biosimilar rituximab (DRL_RI) versus rituximab (MabThera®) in patients with low-tumor-burden follicular lymphoma (LTB-FL).

Methods: Previously untreated, stage II-IV, CD20-positive LTB-FL patients (N=317) were randomized (1:1) to receive DRL_RI (n=162) or MabThera® (n=155) as intravenous infusions of 375 mg/m² weekly for 4 weeks (induction period), and thereafter 8 weekly from Week 12 to Week 36 (maintenance treatment) and followed up till Week 52. The primary endpoint was best overall response rate (BORR) up to Week 28 based on blinded independent central review. Efficacy equivalence was demonstrated if the two-sided 90% CI for BORR difference was within the prespecified equivalence margin (±17%). Secondary endpoints included objective and complete responses, duration of response, progression-free survival, overall survival, safety, immunogenicity and exploratory endpoints included mean serum drug concentrations, and pharmacodynamics (PD).

Results: The BORR up to Week 28 was 80.2% vs. 79.4% for DRL_RI vs. MabThera® group; with a difference of 0.89% [90% CI: -6.67-8.48; 95% CI: -8.05-9.93 within the prespecified margin]. Both treatment groups were comparable for all secondary efficacy endpoints. Treatment-emergent adverse events were reported in 68.6% of patients; safety, immunogenicity, and mean serum drug concentrations were similar between groups. Peripheral B-cell counts declined below quantifiable limits in most patients, with a median time to B-cell depletion of 6.9 days vs. 7.0 days for DRL_RI vs. MabThera®.

Conclusion: The study demonstrated efficacy equivalence of DRL_RI to MabThera®; with comparable safety, immunogenicity, serum drug concentrations, and PD between groups.

Clinical Trial Registry Information: This trial was registered at ClinicalTrials.gov identifier: NCT03976102 and EudraCT (2018-004223-36).
Association of Dietary Profiles and Nutritional Status Among Patients with Hematologic Diseases: A Prospective Cohort Study
Authors: Yu Xiao , Zhao Jingyu , Xu Jing , Li Liyun , Dong Jin , Yuan Weiping , Shi Jun , Kuang Zhexiang
Published: December 2024

Objectives Hematologic patients need to maintain a reasonable diet during treatment to enhance their nutritional status, as it is crucial in supporting their overall health and facilitating recovery. This study aims to explore the latent profiles of dietary intake among patients with hematologic diseases and identify the association of dietary profiles with nutrition status.

Methods A prospective cohort study involving 159 hematologic patients would receive the immunosuppressive therapy or chemotherapy was conducted. Nutritional risk screening (NRS-2002) and Malnutrition Universal Screening Tool (MUST) were used for nutritional screening at admission and post-treatment. The dietary intake was consistently recorded by clinical research nurses in real-time daily throughout treatment. Latent profile analysis was performed to identify mutually exclusive profiles based on the daily intake of six food categories, including cereals and tubers, vegetables, fruits, dairy products, poultry and meat, and eggs. Multinomial logistic regression was employed to measure the association of dietary profiles and nutritional status by adjusting sociodemographic and treatment-related variables.

Results A statistically significant difference was observed in the risk changes of nutritional status as screened by both NRS-2002 and MUST between individuals before and after treatment (P were all <0.001). Three dietary profiles were identified with varying consumption of different types of foods, characterized by low, moderate, and high intake of most foods. Assessed by MUST, patients in the low intake group had a higher risk of malnutrition post-treatment than those in the moderate intake group (OR=3.14, 95%CI: 1.11-8.90). However, there was no difference in malnutrition risk changes across treatment between moderate intake and high intake groups (OR=1.57, 95%CI: 0.66-3.74). The results of multinomial logistic regression showed no significant difference in risk changes across treatments as assessed by NRS-2002 among the three dietary profiles.

Conclusions Hematologic patients with lower food intake in both quantity and variety during treatment may have an increased risk of malnutrition. Improving dietary practices for hematologic patients is essential to achieve better health outcomes.
Safety and Feasibility of a 41BB Co-Stimulated CD19 CAR-NK Cell Therapy in Refractory/Relapsed Large B-Cell Lymphoma
Authors: Qian Wenbin , Lei Wen , Liu Hui , Chen Wei , Liang Yun , Sun Yi Eve , Tong Xiangmin , Liang Aibin
Published: December 2024

Autologous chimeric antigen receptor (CAR) T-cells have greatly changed the therapeutic landscape for the treatment of hematological malignancies. Nevertheless, the use of allogeneic CAR natural killer (NK) cells offers several advantages over CAR-T cells, including the potential as an off-the-shelf product with broad clinical applications, reduced cost, lower risks of graft-versus-host disease (GvHD) and less toxicity, especially with respect to cytokine-release syndrome (CRS) and neurotoxicity. A limited number of clinical studies have demonstrated the safety and efficacy of CAR-NK therapy. However, it remains unclear, to date, whether CAR-NK cells can induce sustained, durable remissions. Here, we generated anti-CD19 CAR-modified NK cells (CD19-BBz CAR-NK) by transduction of cord blood-derived NK cells and demonstrated their anti-lymphoma activity in a preclinical study. Additionally, we performed a phase 1 dose trial involving repetitive administration of CD19-BBz CAR-NK cells in patients with relapsed or refractory (R/R) large B-cell lymphoma (NCT05472558). Importantly, none of the 9 treated patients experienced CRS, neurotoxicity, or GvHD. The overall response rate at day 30 was 66.7% (6 of 9), with 5 patients (55.6%) achieving complete response. At a median follow-up time of 12 months from the time of CAR-NK infusion, the median progression-free survival was 9 months and estimated the overall survival rate was 58.33% at the end of the study. Single-cell RNA sequencing (scRNA-seq) of CAR-NK products revealed molecular features of CAR-NK cells associated with therapeutic efficacy. Moreover, scRNA-seq of patients' peripheral blood mono-nuclear cells (PBMC) post-treatment demonstrated efficacy-related immune cell interaction networks. In conclusion, CD19-BBz CAR-NK cells were feasible and safe, capable of inducing durable remission in R/R large B-cell lymphoma patients.
Identifying the Key Genes of Epstein Barr Virus Regulated Tumour Immune Microenvironment of Diffuse Large B Cell Lymphoma
Authors: Luo Qingqing , Yu Li , Luo Yi
Published: December 2024

Objective: Epstein Barr virus (EBV) plays a crucial role in the pathogenesis of diffuse large B cell lymphoma (DLBCL) by infecting normal cells and influencing the composition of the tumor immue microenvironment (TIME). However, a systematic bioinformatics analysis of key genes regulating immune infiltration in EBV+ DLBCL is currently lacking.

Methods: We utilized the GEO database to identify differential genes (DEGs) and analyze immune infiltration profiles in EBV+ DLBCL (N=23) and EBV- DLBCL (N=28). Weighted gene co-expression analysis (WGCNA) was employed to identify gene modules associated with EBV-induced immune infiltration. Immune-related genes were sourced from the ImmPort database. Immune-related hub genes in EBV+ DLBCL were identified through an integrated analysis of DEGs, WGCNA, ImmPort data, and protein-protein interaction (PPI) networks. Additionally, single-cell RNA sequencing (scRNA-seq) was performed on tumor tissue from one EBV+ DLBCL case to validate hub gene expression in immune cells.

Results: We identified 1215 genes with differential expression between EBV+ and EBV- DLBCL, and enrichment analysis showed that DEGs were mainly enriched in immune-related pathways. EBV+ DLBCL exhibited distinct profiles of tumor-infiltrating immune cells compared to EBV- DLBCL, with more plasma cells, CD8+ T cells, T cell CD4 memory-activated, NK cell-activated, monocytes, macrophage M1, dendritic cell-activated, thymocyte-activated, oocytes, neutrophils and less B-cell naive, T-cell CD4 naive, T-cell CD4 memory resting, T-cell follicular helper, T-cell regulatory, macrophage M0, and dendritic cell resting. Ultimately, we identified three immune-related hub genes-CD28, IL18, and CD247-that were down-regulated and correlated with poor prognosis in EBV+ DLBCL. scRNA-seq confirmed that these hub genes were predominantly expressed in T cell, NK cell and monocytes clusters.

Conclusions: EBV infection significantly alters the TIME of DLBCL, potentially through the down-regulation of CD28, IL18, and CD247, which may contribute to the observed poor prognosis in EBV+ DLBCL patients. These identified hub genes provide new insights into potential prognostic markers and therapeutic targets for EBV+ DLBCL.
Nationwide Analysis on Incidences and Treatment Outcomes of T-Cell Subtype Lymphomas Based on Health Insurance Review & Assessment Service
Authors: Lee Jungmin , Jang Youngeun , Lee Yunji , Cho Hee Jeong , Moon Joon Ho , Do Young Rok , Sohn Sang Kyun , Baek Dong Won
Published: December 2024

Background

The incidence of T-cell lymphomas varies by region worldwide, with a higher occurrence in Far East Asian countries compared to Western countries. There is a lack of recent statistical data on the incidence and clinical outcomes of T-cell lymphomas. The current standard treatment is an anthracycline-containing chemotherapy, but the treatment outcomes indicate that further improvement is needed. Therefore, upfront stem cell transplantation (SCT) is performed for patients who are suitable candidates. The aim of this study is to analyze the incidence and clinical outcomes of T-cell lymphomas in Korea.

Methods

Using data from the Health Insurance Review and Assessment Service of South Korea, we retrospectively analyzed newly diagnosed T-cell lymphomas patients from January 2005 to December 2021. We studied 12,616 patients, 43 patients were excluded from the study due to data error.

Results

A total of 12,573 patients were registered between January 2005 and December 2021. The disease incidence was higher among Koreans in age groups 60-69 (n = 2598, 20.7%) (Figure 1A). Male had a higher incidence (n = 7615, 61%) than female (n = 4958, 39%). Peripheral T-Cell Lymphoma-not otherwise specified (PTCL-NOS) was the most common subtype (n = 3200, 25.5%), followed by Extranodal natural killer (NK)/T- cell lymphoma, nasal type (n = 1671, 13.3%), other mature T/NK-cell lymphoma (n = 1659, 13.2%), mycosis fungoides (n = 1644, 13.1%), angioimmunoblastic T-cell lymphoma (AITL, n = 1483, 11.8%), ALK-positive anaplastic large cell lymphoma (ALCL, n = 396, 3.1%), and ALK-negative ALCL (n = 328, 2.6%) (Figure 1B). CHOP (n = 2859, 56.4%) and CHOEP (n = 577, 11.4%) were used as first-line regimens in PTCL, ALCL and AITL. NK/T cell lymphoma was treated as a first-line therapy with cisplatin plus concurrent radiotherapy (n=389, 7.7%), VIPD(n= 145, 2.8%), VIDL(n= 5, 0.1%) and SMILE (n= 635, 12.5%). Stem cell transplantation was given as a part of front-line therapy (n = 890, 17.5%). Autologous SCT was given to 149 patients (2.9%) and allogeneic SCT was 741 patients (14.6%). The 5-year overall survival (OS) of T-cell lymphomas were 57.8% in patients who received SCT and 42.1% in patients who did not receive SCT (Figure2A). The 5-year OS of PTCL-NOS were 54.2% in patients who received SCT and 30.7% in patients who did not receive SCT. (Figure 2C). Upfront use of combined treatment with chemotherapy and SCT showed better OS than chemotherapy alone in T-cell lymphomas. Patients who received allogeneic SCT had a more favorable progression-free survival.

Conclusions

The incidence was highest in the age group 60-69 years. PTCL-NOS was the most common subtype of T cell lymphomas. Upfront SCT was significantly related to survival benefit.
Identification of Factor V Leiden Genotypes in Normal Pools
Authors: Reddy Bharath V , Barra RamReddy , Vaidyula Vamsikrishna R , Vaidyula Vijender R R
Published: December 2024

Protein C serves as a natural anticoagulant, becoming active when thrombin binds to thrombomodulin on endothelial cell surfaces. Activated Protein C (APC) normally breaks down factor Va and factor VIIIa, inhibiting them reduce thrombin production and thus regulating anticoagulant activity. Conversely, poor APC cleavage can lead to decreased anticoagulant activity and increased blood coagulation, resulting in a hypercoagulable state known as “Resistance to APC (Rosen, SB, 1997 and Dahlback, B, 1999). APC resistance is a major risk factor for venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). Additionally, APC resistance can be inherited genetically( De Stefano, V and Leaone, G, 1995) or acquired through factors like oral contraceptives (OC) or hormonal therapy (HT) (Nicolaes,GA, 2003). One common cause of APC resistance is the Factor V Leiden (FVL) mutation, where Arg is replaced by Gly at position 506 (Factor V: Q506). The FVL mutation is inherited in an autosomal dominant manner. In this study, citrated plasma samples of 120 healthy individuals (median age: 42; age range: 24-62; number of female participants: 40 and male participants 80) were collected and tested for Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), and Fibrinogen levels to assess blood clotting ability to prepare laboratory normal pool plasma. For all participants, PT (10.2-13.4 s), APTT (26-36 s), and Fibrinogen (2.5-4.4 g/L) were within normal ranges, indicating no abnormalities. However, medical chart review revealed that one participant (patient X) had a family history of DVT, OC/HT use, and the second participant (patient Y) had a history of DVT. Since PT and APTT clot times were normal, subset of 22 normal samples, including subject X and Y citrated plasma samples were further evaluated for coagulation clotting factors factor V and VIII levels and APTT-based APC Resistance test (APC-RV) for Factor V Leiden, Subjects X and Y coagulation clotting factors FVC levels were 78%, 96% & FVIIIC 95% & 112%, respectively and found to be in normal range of 50-150%.The subject X; patient Y; and 20 patients with no history of VTE, OC, or HT. APC ratios of 1.82 and 1.90 were obtained for subject X and Y, respectively, and these ratios fell within the laboratory-established FVL Heterozygous cutoff ratio of >1.4 to <=2.20. On the other hand, APC ratios of >=2.25 to <=4.2 were obtained for the no-history patients, indicating a FVL genotype. The two heterozygous phenotype patients, patients X and Y, were recommended for genetic testing to confirm the presence of the FVL mutation and removed from Normal Plasma Pool. In conclusion, this study demonstrates that it is important to evaluate personal and family medical history, to prepare a laboratory normal pool which is key factor to interpret clotting time values and if necessary, perform specialty screening tests.
Indolent Lymphoma: Well Tolerated, Fixed Duration Treatment Involving Bendamustine, Rituximab and Acalabrutinib for Front-Line Waldenström's Macroglobulinaemia That Induce Deep Clinical Responses
Authors: Suleman Adam , Roos Kim , Mangoff Kathryn , Jiang Yidi , Klein Gail , McClure Rebecca , Forward Nicholas Allen , Shafey Mona , Nikonova Anna , Sebag Michael , MacDonald David , Villa Diego , Sandhu Irwindeep , Aljama Mohammed , Larouche Jean-Francois , Simmons Heidi , Gallucci Monica , Tomlinson George A. , Berinstein Neil
Published: December 2024

Background: Waldenström's macroglobulinaemia (WM) is an uncommon lymphoproliferative disorder. An optimal first-line therapy for WM has not been defined. We postulated that combining bendamustine and rituximab (BR) with the second generation covalent BTK inhibitor Acalabrutinib would result in deeper responses as measured by complete response (CR) and very good partial response (VGPR) rates, and provide a longer duration of response.

Objectives: The primary objective of this trial is to document the CR and VGPR rates.

Methods: The BRAWM clinical trial (NCT04624906) combines BR with acalabrutinib in a one-year, fixed duration treatment course of six 28-day cycles BR and 365 days of concurrent acalabrutinib. This ongoing trial is taking place at 9 clinical sites across Canada. The Intent to Treat (ITT) population includes all participants who have started treatment and were evaluable for safety. Participants who reached cycle 7 were evaluable for response. The sample size was calculated to be able to detect a CR + VGPR rate whose lower level of confidence is greater that the historically defined CR + VGPR rates of 23%. Clinical responses were defined using 6th IWWM. Minimal residual disease (MRD) negativity, assessed with clonoSEQ assay, was a secondary endpoint.

Mutational analysis of screening biopsy samples from participants with adequate sample for assessment (n=56), showed 50 with MYD88 L265P mutation, 16 with a CXCR4 mutation of which 8 were S338fs, and 1 with a TP53 l195T mutation. Preliminary minimal residual disease (MRD) analysis of peripheral blood (PB) and bone marrow (BM), using next generation sequencing with a sensitivity of 10-6, shows that most evaluable participants (those with MRD samples at two or more time-points) have become MRD negative in PB, with increasing rates of BM MRD negativity over time. From baseline screening levels, there was a median log reduction in the PB of 4.42 (IQR 1.32) by cycle 7, 4.11 (IQR 1.25) by cycle 12, and 4.06 (IQR 0.81) by month 18. Uni- and multi-variate analyses of clinical variables that may be associated with clinical and MRD outcomes are underway.

Conclusions: Bendamustine, rituximab and acalabrutinib front-line therapy for WM is safe and well tolerated in a relatively elderly population with a toxicity profile consistent with the utilized drugs and not greater than that seen with BR and Placebo in the randomized ECHO trial in untreated Mantle Cell Lymphoma. Initial clinical results show that this treatment is associated with a very high proportion of CR + VGPRs as well as MRD negativity.
PU.1 Promotes Monocyte Development in Part By Transcriptionally Activating c-Fos, Egr-1 and Egr-2
Authors: Bashir Hafiza Sidra , G C Binod , Dong Fan
Published: December 2024

PU.1 is an Ets family transcription factor with multiple roles in hematopoiesis. In addition to its critical involvement in regulating the function of hematopoietic stem cells, PU.1 has been shown to regulate myeloid and lymphoid development in a graded manner with high levels of PU.1 favoring monocyte development and low expression levels inducing B cell fate. The molecular mechanism by which PU.1 promotes monocyte development remains incompletely understood. We show here that in murine myeloid 32D and PUER cells, and lineage negative (Lin-) bone marrow (BM) cells expressing PUER protein in which PU.1 was fused to the estrogen receptor ligand binding domains, treatment with 4-hydroxytamoxifen (4-HT), which activated PU.1, augmented the expression of c-Fos, Egr-1 and Egr-2. In contrast, PU.1 knockdown using shRNAs reduced c-Fos, Egr-1 and Egr-2 expression. c-Fos, Egr-1 and Egr-2 are the immediate early response genes of the Erk1/2 pathway and have been shown to promote monocyte development. A PU.1 mutant defective in c-Jun interaction failed to augment c-Fos, Egr-1 and Egr-2 expression, indicating that PU.1-mediated upregulation of c-Fos, Egr-1 and Egr-2 was dependent on its interaction with c-Jun. Using ChIP and luciferase reporter assays, we further demonstrate that PU.1 transcriptionally activated c-Fos, Egr-1 and Egr-2 through directly binding to their promoters. Activation of PU.1 with 4-HT in 32D, PUER and Lin- BM cells induced monocyte development. Notably, shRNA-mediated knockdown of c-Fos or Egr-1 resulted in a shift in the development from monocytes to neutrophils in response to PU.1 activation. Knockdown of c-Fos and Egr-1 also affected the expression of other myeloid-specific transcription factors, including C/EBPα and Gfi1. PU.1-induced upregulation of c-Fos, Egr-1 and Egr-2 in PUER cells was abolished upon inhibition of Erk1/2 signaling with the Mek1/2 inhibitors U0126 or PD032901. Interestingly, treatment of PUER cells with either Mek1/2 inhibitor redirected PUER cells to develop along the neutrophil lineage at the expense of monocyte fate in response to PU.1 activation. Together, these results reveal an important mechanism by which PU.1 promotes monocyte development, i.e., through transcriptional activation of c-Fos, Egr-1, and Egr-2.
Machine Learning Analysis Was Conducted to Construct a Novel Model for Modulating the Clinical Manifestations and Predicting the Response to Glucocorticoids in Immune Thrombocytopenia
Authors: Zhang Jing , Chen Jia , Yang Renchi , Zhang Lei
Published: December 2024

Abstract:

Aim: In this study, a novel prediction model was established using Recursive Feature Elimination (RFE) to predict the clinical manifestations of Immune Thrombocytopenia (ITP) and the response to glucocorticoids.

Methods: This study consisted of two parts: the establishment and validation of the prediction model. A total of 1019 ITP patients were included, and general information such as age, gender, medical history, and laboratory test results were recorded. RFE, SVM, and Logistic regression models were compared by ROC analysis, and the raw data were preprocessed for feature extraction. The RFE was then used to construct the prediction model, and patients were classified into high-risk group (n=464) and low-risk group (n=555) based on their risk levels. The model performance was evaluated using cross-validation, and the results were subsequently predicted.

Results: The results of this study showed that the RFE prediction model established had good predictive efficacy for the clinical manifestations of ITP patients. A total of 39 variables were extracted, and univariate analysis revealed that age, B lymphocyte surface antigen (CD19B), mean corpuscular volume (MCV), and hemoglobin (Hb) were the main influencing variables (P<0.05). After comparing the models, the ROC of RFE was 0.902 (0.884-0.920), SVM was 0.511 (0.501-0.522), and Logistic regression was 0.680 (0.646-0.715). Since RFE had the highest ROC, it was selected as the prediction model for this study. In the training cohort, the RFE model had a specificity of 0.789 and a sensitivity of 0.858. The threshold for high and low-risk classification was set at 0.33. In the prediction of clinical and laboratory differences, the threshold of the RFE model cutoff value was 16.5, with a specificity of 0.43 and a sensitivity of 0.70. In the validation cohort, the RFE model had a ROC of 0.962, which was higher than the other two models.

Conclusion: In this study, we successfully constructed a new model using machine learning techniques that can analyze and predict the clinical manifestations of patients with immune thrombocytopenia (ITP), as well as predict their response to glucocorticoid treatment. This model holds promise in providing more accurate treatment recommendations to clinical physicians and aiding in the development of individualized treatment strategies, thereby improving the treatment outcomes and quality of life for ITP patients. Further research can be conducted to expand the sample size and integrate other clinical data to further optimize and validate the performance of this model.

Keywords: Machine learning; Predictive model; Immune thrombocytopenia; Clinical manifestations; Glucocorticoids therapy
Novel Cell Lines Identify Cell-Intrinsic and Targetable Features of Angioimmunoblastic T-Cell Lymphoma
Authors: Mottram Alexis , Ramseier Michelle , Tseng Yuen-Yi (Moony) , Louissaint Abner , Ng Samuel
Published: December 2024

Outcomes for patients with Nodal T-follicular helper lymphoma, angioimmunoblastic subtype (AITL) are poor compared to most B-cell Non-Hodgkin Lymphoma in part due to a dearth of pre-clinical models to guide development of novel therapeutic approaches. We have developed two unprecedented AITL cell lines through culture of cells from patient-derived xenograft models. Mutational profiling reveals that each cell line carries independent TET2 deleterious frameshift and stop-gain nonsense mutations, and neither produces detectable levels of Tet2 protein. We identified the characteristic AITL mutation RHOA G17V in one line but not the other, and this result combined with the TET2 loss-of-function mutations is consistent with the two most common genotypes identified in clinical AITL samples. RNA-seq analysis of AITL cell lines demonstrates enrichment in gene signatures driven by MYC, E2F, and enhanced metabolic demands, consistent with a malignant phenotype and shared with other T-cell Lymphoma (TCL) cell lines. Gene sets specifically enriched in AITL cell lines include inflammatory gene signatures as a defining feature, and assessment of media from cultured cells indicate that they secrete an abundance of cytokines that suggests primary malignant cells drive the inflammatory environment observed in clinical AITL samples. Using single-cell RNA-seq (scRNA-seq), we identified gene signatures enriched in individual primary malignant AITL cells compared to follicular-helper T cells (Tfh), which are the non-malignant counterpart of AITL. These signatures were also highly enriched in AITL cell lines compared to Tfh, validating both gene signatures from the scRNA-seq analysis and the AITL cell lines as consistent with a malignant AITL cell phenotype. We further confirmed enrichment of primary cell-intrinsic malignant gene expression in the AITL cell lines using a gene signature generated from an independent scRNA-seq analysis of AITL clinical samples. Finally, we performed functional studies that identify potentially translatable and targetable genetic vulnerabilities. Taken together this indicates that these novel AITL cell lines maintain genetic and transcriptomic fidelity to primary malignant AITL cells and that these models can be used to identify novel targeted therapeutic strategies for clinical studies of AITL.
Health Care Utilization for Patients with Triple Class Exposed Relapsed and Refractory Multiple Myeloma: Experience from a Canadian Center
Authors: Jimenez-Zepeda Victor H. , Cheung Winson Y. , Mathew Stephen Mariet , Chan Henry
Published: December 2024

Background: Multiple Myeloma (MM) is a plasma cell disorder characterized by the presence of remissions and relapses. The purpose of this project was to explore Canadian-specific real-world treatment patterns, and healthcare resource utilization (HCRU) in triple class exposed (TCE) relapsed/refractory MM (RRMM) patients in Canada. Methods: This is a retrospective observational cohort study using multiple administrative databases in Alberta, Canada. Outcomes were captured for TCE patients receiving a subsequent line of therapy (LOT) and included: treatment regimen details, time to next treatment (TTNT), overall survival (OS), and health care utilization. Results: Briefly, 567 TCE RRMM were identified. A median of 50 unique healthcare encounters were observed. In addition, 30.2% of readmissions were seen at 30 days from the start of next therapy in patients with TCE RRMM. On average at the patient level, there were 2 emergency department visits, 2 inpatient admissions, 51 total clinical visits and 5 infusion appointments. Overall, the average days spent on lab tests was 27 and the median duration of each inpatient admission was approximately 6-7 days. Median overall survival from initiating next line of therapy in TCE RRMM was 18.7 months (16-24.3 months). Conclusions: The present data provides further insights about healthcare resource utilization for patients with TCE RRMM in Alberta, Canada and may inform healthcare system planning as novel therapies continue to be developed for this patient population.
The Effect of Bariatric Surgery on Rivaroxaban Plasma Concentration; Long-Term Follow-up Study
Authors: Alqahtani Saeed , Al Gahtani Farjah Hassan
Published: December 2024

Background: The thromboembolic events are considered a potentially serious complication in the bariatric surgery patients. Rivaroxaban has been investigated in bariatric surgery patients in few studies. More evidence on whether the postsurgical anatomical and the physiological changes effect rivaroxaban pharmacokinetics need to be identified. Objective: The aim of this study is to investigate the pharmacokinetics parameters of rivaroxaban in obese patients undergoing bariatric surgery. Methods: The study includes 20 obese patients who were admitted for bariatric surgery and intended to receive prophylaxis doses of Rivaroxaban. High-performance liquid chromatography (HPLC) was used to determine pre and postoperative rivaroxaban plasma concentration. This study assessed the participants' efficacy and safety of rivaroxaban by following up these outcomes 6 and 9 months after the surgery. Results: Twenty patients were included in the study of which 40% are male. The average age was 33.9 ± 10 years and the mean body weight was 117.6 ± 21.2 kg. The average maximum concentrations (Cmax) were 0.31 ± 0.1 μg/ml, 0.23 ± 0.12 μg/ml, and 0.28 ± 0.1 in pre- and post-surgery and 7 days after bariatric surgery, respectively. There was no statistical significance between the measured levels of rivaroxaban. No significant bleeding events,or other side effects which others ???associated with rivaroxaban medication were reported during the trial period. In addition, no DVT or PE events were reported over 6,9 months Conclusions: Rivaroxaban shows promise as a potential medication for VTE prophylaxis after bariatric surgery. However, more research is needed to determine its optimal dosage and long-term safety profile in this patient population. Keywords: anticoagulants; bariatric surgery; rivaroxaban; thromboprophylaxis.
Stabilization of HIF-1α By the Prolyl Hydroxylase Inhibitor Roxadustat Reduces Gastrointestinal Graft-Versus-Host Disease
Authors: Raguraman Vasantharaja , Mohiyuddin Shanid , Benge Catherine , Banker Linnea , Plank Tyler , Hammer Richard D , Palaniyandi Senthilnathan , Hildebrandt Gerhard C
Published: December 2024

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for high-risk hematologic malignancies. The benefits of allo-HSCT are limited by the onset of graft-versus-host disease (GVHD) associated with morbidity and mortality. Acute GVHD (aGVHD) primarily affects epithelial cells of the gastrointestinal tract, skin, and liver by involving alloreactive T-cells and pro-inflammatory cytokines in the effector phase. The barrier-protective role of hypoxia-inducible factor (HIF) regulated by hydroxylase inhibitors was significantly implicated in hypoxic inflammatory diseases, including inflammatory bowel disease. In this study, roxadustat, a prolyl hydroxylase inhibitor was tested in the murine model of aGVHD which may have beneficial effects in decreasing hypoxia-mediated early gastrointestinal injury in aGVHD. Methods: Using a murine HSCT model, recipient BALB/c mice received a single dose of total body irradiation (750cGy), followed by intravenous infusion of 5 million bone marrow and 4 million splenocytes of either syngeneic (BALB/c) or allogeneic (C57BL/6) donors and were subsequently treated with roxadustat (25mg/kg body weight) or vehicle control once daily until day +7 and observed until day +42. Mice were monitored for clinical signs of GVHD, survival and analyzed on day +7 and day +42. Results: Roxadustat treatment significantly improves survival by day +42 (p = 0.01) with improved clinical GVHD symptoms from day 7 to 42 (day 7: p = 0.0009). Significantly reduced colon (p = 0.03) and small bowel pathology (p = 0.01) on day +7 in the Roxadustat was associated with significant reduction of serum inflammatory cytokines IFN- γ (p = 0.04) and TNF-α (p = 0.03). Roxadustat treatment with allogeneic recipients significantly decreased T-cell infiltration in the gut and prevented TNF-α induced intestinal epithelial cell apoptosis through repression of Fas-associated death domain protein (FADD), caspase 3, caspase 8 in an HIF-1α dependent manner. Moreover, roxadustat treatment significantly improved the integrity of tight junction proteins including ZO-1 and occludin in allogeneic recipients. Additionally, in vitro experiments demonstrated that roxadustat treatment suppressed TNF-α production by peritoneal macrophages and showed a significant reduction in antigen-presenting cells dependent T cell proliferation in mixed lymphocyte reaction. Conclusion: These results suggest that the administration of prolyl hydroxylase inhibitor roxadustat attenuates early gut injury and shows clinical benefit in a mouse model of allogeneic hematopoietic stem cell transplantation, which could represent an alternative preventive and possible treatment strategy for acute GVHD.
Thrombosis at High Altitude Is Not Associated with Increased Transferrin
Authors: Amaru Ricardo , Prchal Josef T. , Paton Daniela , Carrasco Mireya , Mancilla Emma , Gordeuk Victor R.
Published: December 2024

Bolivian Andean Aymara highlanders have been living at 4000 meters for 14,000 years, and have developed evolutionary genetic adaptations to hypoxia (PMID:28448578; PMID:29100088; PMID:36980912). These include EGLN1 encoding prolyl hydroxylase 2 (PHD2), a regulator of transferrin transcription. Transferrin increases in hypoxia and iron deficiency (PMID: 9242677); contrasting reports indicate that elevated transferrin associates with thrombosis in mice but decreased thrombosis in a congenital disorder of hypoxia-sensing (PMID: 36040436; PMID: 31310728; PMID: 8281634).

We analyzed clinical and laboratory data of Andean Aymara patients with High-Altitude Anemia (n=137, mean age 45 years, female gender 79%,) or High-Altitude Erythrocytosis (n=149, mean age 56 years, female gender 30%) with transferrin results in their medical records.

Iron deficiency was present in 57% of anemia and 23% of erythrocytosis patients. Mean (SD) transferrin concentration was 3.08 (1.25) g/L in anemia and 3.34 (0.84) g/L in erythrocytosis patients. Thrombosis history was present in 8% of anemia and 13% of erythrocytosis patients. In logistic regression analysis in High-Altitude Anemia patients with adjustment for age and gender, iron deficiency associated with increased thrombosis history (odds ratio [OR] 6.7, P=0.030) while higher serum transferrin associated with decreased thrombosis history (OR 0.4, P=0.013). In High-Altitude Erythrocytosis patients iron deficiency associated with increased thrombosis history (OR 5.0, P=0.005), but transferrin's association with thrombosis history was not statistically significant (OR 0.8, P=0.52). In anemia and erythrocytosis patients combined, iron deficiency associated with increased thrombosis history (OR 4.6, P=0.0006) while elevated transferrin associated with reduced thrombosis history (OR 0.62, P=0.038).

In individuals with extreme environmental hypoxia, we found no evidence that increasing transferrin is associated with increased thrombosis history, but rather observed a trend to decreased thrombosis history.