bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence, Epidemiology, Mortality and Morbidity of Thrombotic Events in SLE: A Nationwide Study in the United States
Authors: Singhal Sachi , Jotwani Pooja , Desai Devashish , Styler Michael
Published: December 2023

CONCLUSION

Thrombotic events (TE) are a major cause of morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE). Data is scant, however, on the prevalence, epidemiological characteristics, in hospital morbidity and mortality of TEs in this population.

To perform a comprehensive epidemiological study on patients with SLE and DVT, PE or atypical thrombosis and their variation by gender, geographic region and hospital status. We also aimed to explore the associated morbidity and mortality for each TE and potential associations with other risk factors such as obesity and smoking.

We conducted a retrospective cohort study, using the 2003-2018 Nationwide Inpatient Sample (NIS) database. All adult patients with a diagnosis of SLE using ICD-9 and 10 codes were included. The ICD 9 and 10 codes were also used to find other TE variables including DVT, PE, Cerebral venous sinus thrombosis (CVST), Splanchnic thrombosis (ST)and Arterial thrombosis (AT).

Of the 513,904 SLE patients included, PE, DVT, ST, CVST and AT were identified in 1.38%, 3.07%, 1.34%, 0.04% and 0.35% patients respectively. Each TE (except CVST) had a statistically significant increase in length of hospital stay, cost of hospitalization and all-cause in-hospital mortality. Higher prevalence of PE, DVT, ST and AT were reported in males with SLE, and higher prevalence of obesity was seen in SLE patients with TEs, except AT, which interestingly was associated with a lower prevalence of obesity. Despite comprising only one third of the cohort, African Americans (AAs) faced the highest burden of PEs and DVTs. No significant differences were seen between geographic regions.

This study is limited by administrative claims data, lack of antiphospholipid antibody status, and only includes inpatient encounters. Additionally, this is an observational retrospective study, and the assessment is limited to association of these thrombotic events in the SLE population.

Arterial, venous and atypical thrombosis exert significant morbidity and mortality in patients with SLE. Racial and gender variations exist in each category of thrombosis, and identifying these differences is crucial while taking management decisions for patients with SLE. Particular attention should be directed to AAs with SLE, who appear to be particularly vulnerable.
Arginine Therapy Supplements Improves the LDH Level in Sickle Cell Patients in Steady States: Preliminary Results from Kinshasa, the Democratic Republic of Congo
Authors: Ngonde Mambakasa Ange Christian
Published: December 2023

Aim: SCD is a congenital hemolytic anemia of autosomal recessive inheritance. The disease has the characteristics of a chronic inflammatory disease. Due to chronic sickling process by intracellular polymerization of red blood cell and precipitation of mutated sickle hemoglobin. It was recently well-established that arginase released from lysed RBCs consumes the eNOS substrate arginine, with a depletion of plasma arginine, the essential substrate for NO production by NO synthase, leading to acute and chronic complications. L-arginine was shown to significantly increase NO levels and decrease oxidative stress and lipid peroxidation, in recent studies. Despite high incidence of the disease in sub-Saharan Africa, there is still very little information on the benefits of arginine dietary supplement, in sickle cell patients.

Methods: We carried out a retrospective study to assess the benefit of arginine supplement on the level of LDH. The study group consisted of 31 patients who received 500 mg of Arginine per day for SCDs from 1 to 14 years old and 1000 mg per day from 15 years old. Three follow-up periods were defined: (i) before starting treatment with hydroxyurea (HU); (ii) a period of taking HU, greater than 3 months; (iii) a period of taking HU+ arginine supplement, greater than 3 months.

Results: The median age of this group was 12 years (range; 2 years-43 years). During the three periods of the study, the LDH value was above the norms, respectively 649,7 ± 364,2 U/L in period 1, 661,6 ± 367 U/L in period 2, and 529,9± 346,3 U/L in period 3. By comparing the different periods of the study, There is a significant increase (p=0.4589; Kruskal Wallis test) in the mean LDH value in the period 2 compared to the period 1. There is a significant decrease in the mean LDH value in period 3 compared to period 1, and period 2 ( p= 0,4589, Kruskal Wallis test).

Conclusion: This study found that the sickle cell patients who received arginine supplements with HU decreased significantly the level of LDH. However, the present study had some limitations. These include its hospital-based retrospective design limiting the potential to make conclusions. On the other hand, further investigations including a large sample in a prospective study with a control group and other biological parameters data will be interesting in our midst.
Comparison of Two Therapeutic Approaches (Pediatric vs. Adult) for Treating Acute Lymphoblastic Leukemia. Experience of Two Centers in Mexico City
Authors: Ramos Peñafiel Christian Omar , Gallardo-Rodríguez Adán Germán , Pérez Sámano Daniela , Martinez Moreno Emmanuel , Cabrera García Álvaro , Balderas Delgado Carolina , Castellanos Sinco Humberto Baldemar , Martínez Murillo Carlos
Published: December 2023

Background: Chemotherapy is the most frequently used strategy in treating adult acute lymphoblastic leukemia (ALL) in conjunction with monoclonal antibodies and tyrosine kinase inhibitors. One of the primary considerations is the type of treatment based on pediatric inspiration regimens (CALGB10403, BFM, St Jude XIII) or regimens for adult patients (HyperCVAD), with pediatric regimens being those that have improved the prognosis in the young adult population. Along with this scheme, strict monitoring through measurable residual disease (MRD) is the main dynamic prognostic factor since its positivity is associated with a greater risk of relapse. We aimed to compare the effect on the clinical prognosis of two treatment regimens based on a pediatric regimen versus an adult regimen in patients with ALL. Material and methods: A retrospective, observational, descriptive study of 5 years of follow-up was carried out in patients with ALL at the Hospital General de México and the Hospital Regional de Alta Especialidad de Ixtapaluca, classifying the treatment into two types of regimens (adult regimen vs. pediatric inspiration) evaluating the impact on survival as well as the association of different factors both to diagnosis and measurable residual disease (MRD). Results: A total of 450 patients were studied, 50.4% (n=227) were male, and 49.6% (n=223) were female. 21.1% (n=95) received a pediatric-inspired protocol (CALGB-10403), and 78.9% (n=355) received an adult protocol (Hyper-CVAD). 71.8% (n=323) were considered high risk, and 8.4% (n=38) were identified with Philadelphia positive ALL. 94.4% had a B-cell precursor phenotype ALL, and 8.7% had a nervous system infiltration at diagnosis. Overall, 60.4% integrated complete remission (n=272), with 31.3% (n=141) post-induction MRD negative. The percentage of negative MRD was higher in the pediatric protocol (38.5% vs 29.6%, p=0.000). Relapses occurred in 34% (n=153), and 21.3% (n=96) had a relapse to the central nervous system. Survival at 1000 days of follow-up was 32%, with significant differences in favor of the pediatric protocol (Log Rank 0.000) with 42% at 1000 days (Figure 1), the use of MRD as an impact tool with the prognosis (0.000) (Figure 2), the presence of a post-induction MRD+ (0.000) and high risk (Log-Rank 0.004) were the significant variables. Conclusions: The prognosis of a patient with ALL depends on the type of treatment. The prognosis is favorable when treated with a pediatric protocol. The detection of MRD by flow cytometry is the best follow-up tool, and its positivity decreases survival in adults with ALL.
Comparison of Time to Relapse between Low-Fixed Dose Versus Standard-Dose Rituximab in the Treatment of ITP, TTP, and AIHA
Authors: Powell Frankie , Hasan Yousef , Shi Runhua , Ramadas Poornima
Published: December 2023

Background:

The optimal Rituximab dosing regimen for the treatment of immune thrombocytopenia purpura (ITP), autoimmune hemolytic anemia (AIHA), or thrombotic thrombocytopenia purpura (TTP) has not been well established. To our knowledge, there has not been a randomized trial examining the time to relapse with the different Rituximab dosing regimens (low-fixed dose of 100 mg x 4 weekly doses versus standard dose of 375 mg/m2 x 4 weekly doses) in the treatment of ITP, TTP, and AIHA. Previous comparative studies have shown that the weekly low-fixed Rituximab dosing regimen has been shown to be just as effective in treating these diseases as demonstrated by similar response and duration of response. Therefore, we conducted a comparative analysis to evaluate the time to first recurrence after being treated with Rituximab.

Methods:

We collected clinical data from a single center of patients with diagnosis of ITP, TTP, or AIHA and were treated with 4 weekly low-fixed or standard dose Rituximab. Time to first recurrence was measured to compare if there was a significant difference between the two Rituximab dosing regimens. Kaplan-Meier time to recurrence estimates were used to generate time to recurrence curves.

Results:

Of the 30 patients analyzed, 10 patients were diagnosed with AIHA, 12 patients with ITP, and 8 with TTP. All patients had a complete response (CR) per the specific disease CR definition prior to first disease recurrence. 17 patients were treated with standard dose Rituximab and 13 patients were treated with low-fixed dose Rituximab. 17 patients did not have a recurrence in the selected time frame of the study. Recurrence was observed in 40% of the AIHA patients, 50% of the TTP patients, and 37.5% of TTP (P=0.8297). 47% females had a recurrence compared to 36% males (P=0.7084). Recurrence was observed in 61% patients who received the low-fixed dose Rituximab and 29% of patients who received the standard dose Rituximab (P=0.1376). The median time of recurrence was 16 and 27 months among patients who received low-fixed dose vs standard dose Rituximab, respectively (P=0.1914).

Conclusions:

The use of low-fixed dose Rituximab versus standard dose Rituximab for treatment of ITP, TTP, and AIHA appears to have a higher recurrence rate but did not meet statistical significance. The median time difference in recurrence was 9 months. This could potentially be significant in a larger study population. Further investigation through large, randomized controlled trials is needed to assess if there is a significant difference in recurrence rate and time to recurrence between the two Rituximab dosing regimens.
BRG1 Regulates Adult B-Cell Acute Lymphoblastic Leukemia Proliferation and Apoptosis By Interacting with c-MYC and Activating PI3K/AKT Pathway
Authors: Kang Qian , Zhao Peng , Ni Ming , Fang Qin , Wang Jishi
Published: December 2023

Background and objective：Adult B-cell acute lymphoblastic leukemia（B-ALL）has historically had a dismal prognosis, with limited treatment options and cure rates less than 40%. Only 25% of patients older than 50 years old were alive 5 years after diagnosis, highlighting the need for further improvements in treatment for older adult patients (≥40 years). Recently years, genome profiling revealed that cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype and proliferation. Brahma-related gene 1（BRG1）, a core catalytic ATPase subunits of the SWI/SNF chromatin remodelling complex, has been reported to support oncogenic transcriptional program and sustain leukaemogenic transformation in leukemia. However, the specific role and mechanisms of BRG1 in B-ALL development and progression remains largely unknown. Therefore, elucidating the underlying maintenance mechanisms is essential to develop novel effective treatment strategies.

Methods：For clinical sample, we analyzed the mRNA expression level of BRG1 in newly diagnosed B-ALL patients(n=576) and healthy donors(n=74) in the GSE13159 subset from GEO database. Then, quantitative reverse transcription-PCR (RT-PCR) and Western blot were used to detect the expression of BRG1 in 38 newly diagnosed B-ALL patients and 25 healthy donors in our department. For further exploring the effects of BRG1 on B-ALL , lentiviral transfection were used to knock down BRG1 in SUP-B15 and Nalm-6 cells and overexpress BRG1 in RS4:11 cell, and CCK-8, Edu, clone formation assay, cell cycle, apoptosis, IF, RT-PCR and Western Blot were used to detect the effects. In addition, TMT proteomics was used to analyze the differential proteins between sh-ctrl and sh-BRG1 of Nalm-6 cell. Western Bolt was used to detect the changes of key proteins in related pathways.

Results: Our investigation of SMARCA4 revealed that BRG1 is over-expressed in the 576 newly diagnosed B-ALL patients from GSE13159 dataset, as well as in 38 of our department. Downregulated BRG1 inhibited growth and increased the apoptosis of ALL, while ectopic expression of BRG1 showed the opposite effects. Mechanistically, TMT proteomics analysis and vitro experiments further revealed that BRG1 exerted these functions through its interaction with c-MYC and regulated the expression of CDK4/6, BCL-2 and BCL-xl.

Conclusion: Our study demonstrates that BRG1 upregulation is closely associated with proliferation and anti-apoptosis in adult B-ALL.
SLC16A7 Facilitates aGVHD through Regulating Calcium Influx and Lipid Metabolism of CD4 + T Cells
Authors: Cheng Qiao , Lai Xiaoxuan , Ding Zhengwen , Xu Yang , Wu Depei
Published: December 2023

T cell metabolic disorders in patients with acute graft-versus-host disease (aGVHD) have been studied, but the underlying mechanisms remain poorly understood. Solute carrier (SLC) transporters play a crucial role in cell metabolism, but their involvement in T cell-mediated aGVHD has not been investigated. In this study, we observed that SLC16A7 levels were down-regulated in CD4 + T cells of both aGVHD mice and patients, which in turn increased calcium (Ca 2+) influx in activated CD4 + T cells and promoted the differentiation of Th1 and Th17 cells, leading to the exacerbated aGVHD cascade. Moreover, deficiency of SLC16A7 promoted calcium overload in activated CD4 + T cells through regulating SERCA3 proteins and altered characteristics of lipid metabolism, decreasing levels of oleic acid, thereby aggravating aGVHD. Interestingly, supplementation of oleic acid rescued the survival of aGVHD mice. This study characterized a previously unknown role of SLC16A7 in T cell-mediated aGVHD and provided a promising therapeutic strategy to target T cell metabolism for the alleviation of aGVHD.
IDH1/2-Mutated B-ALL Presents As Burkitt's Leukemia/Lymphoma-like ALL
Authors: Qian Yu , Jin Jie
Published: December 2023

Background: Burkitt leukemia/lymphoma (BL) is a highly aggressive hematological malignancy, which is characterized by the FAB L3 morphology of monotonous medium-sized cells containing abundant basophilic cytoplasm and lipid vacuoles, with mature B cell immunophenotype. Interestingly, some B-cell acute lymphoblastic leukemia (B-ALL) could resemble BL in morphology, but with immature B-cell immunophenotype. In this study, we aimed to explore the molecular and clinical characteristics of these “BL-like B-ALL” patients.

Methods: We analyzed the molecular and clinical characteristics of B-ALL patients in the First Affiliated Hospital of Zhejiang University. RNA-seq analysis of BL-like B-ALL was performed to study the mechanisms of L3 morphology.

Results: We analyzed the population of patients with B-ALL of FAB L3 morphology, among 68 patients, 17 cases with IDH1 mutation and 1 case with IDH2 mutation. In subgroups of 260 B-ALL patients, OS and EFS were significant shorter in BL-like patients compared with others (median 567 days vs not reached, median 238 days vs 566 days; p=0.0024, 0.0122, respectively). Gene set enrichment analysis (GSEA) analysis of RNA-seq with 27 cases of BL-like B-ALL patients revealed significant enrichment in fatty acid metabolism pathway, compared with 203 B-ALL patients in TARGET database. Therefore, we measured levels of serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) in 251 B-ALL patients at diagnosis, among which TG and TC levels of 62 BL-like B-ALL patients were significant higher (p=0.0006, p=0.0040), while LDL-C and HDL-C levels showed no significant differences between two groups. Furthermore, we tracked a IDH1-mutated BL-like patient and found that IDH1 mutation and L3 morphology were not detected in remission, but both reappeared with disease relapse. Meanwhile, IDH1/2-mutated B-ALL patients in our center had significant shorter EFS compared with other B-ALL patients (p=0.0087).

Conclusion: IDH1/2-mutated B-ALL presents as Burkitt's leukemia/lymphoma-like ALL. BL-like ALL patients have higher levels of lipid metabolism with worse prognosis.
Pre-treatment 18f-FDG PET/CT for Assessing and Predicting Bone Marrow Involvement in Patients with Newly Diagnosed Peripheral T-Cell Lymphoma
Authors: Chen Jing , Cai Zhen , Zhao Yi
Published: December 2023

Objective: To explore the value of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in assessing and predicting bone marrow involvement (BMI) in patients with newly diagnosed peripheral T-cell lymphoma (PTCL) prior to treatment.

Methods: This retrospective study included 201 eligible patients of PTCL who received bone marrow biopsy (BMB) and PET/CT between January 2017 and December 2022. Extra subgroup analysis was designed considering the variation of avidity of FDG in different distinct entities. The status of bone marrow (BM) by PET was assessed using a visual examination and a quantitative index (the highest SUV of BM divided by the mean SUV of the liver [M/L]). Prognostic value of BM findings was also evaluated regarding progression free survival (PFS) and overall survival (OS).

Results: The sensitivity and specificity of PET/CT for patients with confirmed PTCL by BMB were 43.2% and 90.2%, respectively. As for subgroup analysis, the kappa value reflecting the agreement between BMB and visual analysis in angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALCL) as well as nodal T-follicular helper (TFH) cell lymphoma (PTCL-TFH) was 0.315, 0.307, 0.426 and 0.581, respectively. (Give the number of cases in each lymphoma group) PET score was an independent factor for PFS (P =0.011) but not for OS (P =0.840). In addition, 25 patients with stage I to II disease had no evidence of BMI by either PET/CT or BMB. Image-guided biopsy was also recommended when PET/CT showed a focal FDG uptake outside the iliac crest. Quantitative analysis revealed the differences in the two-level of M/L; however, they were not statistically significant for both PFS and OS (P =0.246 and P =0.227).

Conclusion: PET/CT has a complementary role in assessing BMI and prognosis in PTCL patients.
Long COVID-19 Infections and Organizing Pneumonia in a Series of Patients with Indolent Lymphoma Treated with Rituximab
Authors: Savage David , Xavier Marin , Mason James , Chang Jacqueline , Escobar Steven
Published: December 2023

Background: Patients with hematologic malignancies have an increased risk of complications and mortality from COVID-19 (SARS-CoV-2). These patients are often more susceptible to protracted COVID-19 infections (e.g., long COVID-19). In addition, patients treated with the CD20-targeted immunotherapy rituximab in B-cell lymphomas are at greater risk for a protracted clinical course with COVID-19, including care in the ICU for respiratory failure. Hypogammaglobulinemia is an independent predictor of increased risk for long-COVID19. Immune depletion both leads to a persistent detection of SARS-CoV-2 and an inability to mount a sustained immune response. Other authors have reported on the appearance of a delayed organizing pneumonia (OP) after acute COVID-19 infection, but these patients were not immunocompromised by rituximab. In this case series, we report on three patients with indolent lymphoma who had the delayed presentation of long COVID-19 after an acute infection. All three were previously treated with rituximab, and each case was notable for prolonged OP that was refractory to steroid therapy.

Methods: Summative data for the three patient cases was aggregated from the medical record including available physician notes, diagnostic body imaging, and laboratory data.

Results: In total, we found three cases of long COVID-19 in patients with indolent lymphoma from our institution (Table 1). Patient 1 received just two doses of rituximab, Patient 2 received three doses of rituximab, and Patient 3 was treated with rituximab intermittently for nearly three years. All three patients experienced their first COVID-19 infections in August 2022 and had low IgG. This was followed by complications including acute hypoxemic respiratory failure, pulmonary embolism, and organizing pneumonia in these patients two to three months thereafter. These patients continue to have ongoing chronic hypoxemic respiratory failure requiring immune suppression and continuous oxygen support.

Conclusions: Immune depletion with rituximab in patients with indolent lymphomas can put them at significant risk of long COVID-19, OP, and chronic hypoxemic respiratory failure after contracting SARS-Cov-2. Such patients may benefit from prolonged immune suppression, but the exact duration remains unclear. The mechanism of long COVID-19 and refractory OP is unclear and complex. Possible mechanisms may include inadequate clearance of virus or a dysfunctional immune response.

Table 1: Lymphoma patients who received rituximab and then developed long COVID-19
CD56briCD27+CD11b+/- NK Cells Mediated Remission of Agvhd Via Immunoregulation
Authors: Ni Ming , Zhao Peng , Kang Qian , Pan Chengyun , Hu Xiuying , Hu Tianzhen , Fang Qin , Wang Jishi
Published: December 2023

Background: In our previous study, CD56briCD27+CD11b+/- NK cells show the potential of the remission of aGvHD, while the mechanism behind it is still unknown. Thus, in the present study, samples from patient after allo-HSCT within 100 days has been investigated deeply.

Method: 90 samples of patients after allo-HSCT were collected in the affiliated hospital of Guizhou medical university. Immunomonitoring with respect to the phenotype and function of CD56briCD27+CD11b+/- NK cells was performed on rested peripheral blood mononuclear cells (PBMCs) using multiparametric flow cytometry. Furthermore, CD56briCD27+CD11b+/- NK cells have been co-cultured with T cells and ELISPot as well as CFSE staining has been performed to determine the affect of NK cells on T cells. Sorted CD56briCD27+CD11b+/- NK cells have been analyzed by bulk RNA sequencing to elucidate the profile of gene expression. On the other hand, CD56briCD27+CD11b+/- NK cells have been administrated into xgeneic mice agvhd model to observe whether CD56briCD27+CD11b+/- NK cells influence on the onset of aGvHD.

Result: (1) Our result shows a positive correlation between CD56briCD27+CD11b+/- NK cells and Th22, Tfh as well as Th1 like Tfh cells. Interestingly, a dramatic higher expression of homing marker CD62L has been observed on CD56briCD27+CD11b+/- NK cells. Thus we hypothesis that the CD56briCD27+CD11b+/- NK cells may migrate into the lymphoid tissues and regulate the differentiation of naïve T cells. (2) On the other hand, an elevated percentage of NKG2D has been found on CD56briCD27+CD11b+/- NK cells in patients with aGvHD. Meanwhile a high expression of Fas and exhaustion markers have been observed on CD4+ and CD8+ T cells. These results suggest that T cells may be eliminated by CD56briCD27+CD11b+/- NK cells. (3) Both the cytokine secretion and proliferation of T cells has been inhibited by CD56briCD27+CD11b+/- NK cells. (4) CD56briCD27+CD11b+/- NK cells could delay the onset of aGvHD in mice model.

Conclusion: According to these findings, the CD56briCD27+CD11b+/- NK cells may result in the remission of aGvHD via immunoregulation by regulation of T cells.
Cellular Components in Whole Blood Contribute to the Development of Thromboembolic Events in Patients with Pancreatic Cancer
Authors: Willems Ruth A.L. , Roest Mark , de Vos-Geelen Judith , de Laat Bas , Ten Cate Hugo
Published: December 2023

Introduction

Thromboembolic disease is a major complication in patients with pancreatic ductal adenocarcinoma (PDAC), causing morbidity and mortality. One in five patients with newly diagnosed PDAC develops a venous thromboembolism (VTE), which is associated with a decreased overall survival time . Patients with PDAC often have altered blood cell counts, which are further affected by systemic therapy. The high thromboembolic risk in patients with PDAC may be caused by pro-coagulant effects of pancreatic cancer on blood cells. Currently, there are no risk assessment tools or biomarkers available that can identify PDAC patients at highest risk of VTE.

Aims To investigate the impact of PDAC on blood cell dependent coagulation, to characterize the high thrombosis risk in PDAC patients. To predict thromboembolic events in patients with PDAC using blood cell dependent assays, performed in whole blood.

Methods

Patients with locally advanced or metastatic PDAC (n=18) were included in a prospective, observational, case-control study (TROCOPAC study). At inclusion, before the initiation of chemotherapy, blood was collected to study whole blood (WB) coagulation profiles. Thrombin generation (TG) was measured in WB and platelet poor plasma (PPP) of 18 patients with PDAC and 18 healthy individuals matched for age and sex. The capacity of platelets to release granules was measured in a time-dependent manner upon stimulation with a PAR1 receptor agonist in WB. Patients were followed for 6 months upon inclusion. The primary endpoint was the onset of thromboembolic events, both VTE and arterial thromboembolism (ATE).

Results

Patients with PDAC have an increased endogenous thrombin potential (ETP) in whole blood. This difference was not observed in PPP, indicating a procoagulant effect caused by blood cells. Furthermore, patients with PDAC have a prolonged lag time in whole blood, while the lag time in PPP was not different between patients and controls. Platelet and white blood cell counts (WBC) significantly correlated with the WB ETP and peak in patients with PDAC, which was not observed in healthy controls. Of the 18 PDAC patients, 4 developed a VTE (22%) and 1 an ATE (6%). A shorter lag time of WB-TG and an increased maximum capacity of platelets to release granules, at study inclusion, were associated with incident thromboembolic events.

Conclusions

Patients with PDAC have an imbalanced WB-TG profile. The lag time in WB-TG and the granule release capacity of platelets predict an increased incidence of thromboembolic events. Red blood cell and white blood cell abnormalities in PDAC are associated with this disturbance in thrombin generation. Platelets and white blood cells hence appear to be a driving force in the development of thrombosis in patients with PDAC. As such, measuring hemostasis in whole blood would improve the thrombosis risk estimation in PDAC patients.
Comparative Analysis of Patient Characteristics, BTK Treatment, and Treatment Outcomes in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Cross-National Study between the United States and China
Authors: Liu Yin , Chen Yanfei , Xiao Yue , Huang Ruijian , Jiang Feng , Zhou Jifang
Published: December 2023

Background: Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment landscape for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Real-world data can provide insights into factors influencing BTK inhibitor initiation and switching, enabling a comprehensive understanding of treatment patterns. This study aimed to evaluate these factors in CLL/SLL patients in the United States and Tianjin, China, and compare overall survival outcomes among patients using different BTK inhibitor types.

Methods: We conducted a comparative analysis utilizing real-world data from two sources: the Flatiron Database in the US and Tianjin Regional Healthcare Data in China. Data from both databases were analyzed to identify factors associated with BTK inhibitor initiation and switching in CLL/SLL patients. Additionally, overall survival outcomes were assessed among patients using various types of BTK inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib.

Results: Our analysis revealed key differences in patient characteristics. Median age of US BTK users was 66 years (IQR: 58-73) vs. 61 years (IQR: 59-69) in China. Notably, the US exhibited higher rates of hypertension (40.3% vs. 9.6%), diabetes (12.4% vs, 9.1%) and infections (22.1% vs. 8.1%). BTK treatment utilization differed between the US and China: Ibrutinib 82.3% vs. 81.6%; Zanubrutinib 0.2% vs. 17.2%; and Acalabrutinib 17.5% vs. 0%.

A higher proportion of US BTK users were exposed to immunochemotherapy (50.8% vs. 19.1%). Overall survival rates at 1-year and 3-years from 1 st BTK were comparable (US 95.2% vs. China 96.4%; US 90.2% vs. China 92.3%); and from 2 nd BTK (US 98.6% vs. China 100%, US 96.4% vs. China 100%).

Conclusion: This study contributes to a comprehensive understanding of real-world BTK inhibitor initiation and switching in CLL/SLL patients from the United States and Tianjin, China. Additionally, the 1-year and 3-year OS rates from both 1st and 2nd BTK treatments were generally favorable in both regions, suggesting the effectiveness of BTK therapies in B-cell malignancies. These findings have implications for treatment decision-making and optimizing patient care in CLL/SLL.
IGF2BP1 Promotes Multiple Myeloma with Chromosome 1q Gain Via Increasing CDC5L Expression in an m6A-Dependent Manner
Authors: Xu Jiadai , Liu Peng
Published: December 2023

Background: Multiple myeloma (MM) patients with chromosome 1q gain (1q+) are clinically and biologically heterogeneous. The underlying molecular mechanisms are still under investigation, while identification of targets for effective therapy of this subgroup of MM patients is urgently needed. We aimed to investigate the clinical significance and the regulatory mechanisms of insulin-like growth factor 2 messenger RNA (mRNA) binding proteins 1 (IGF2BP1), a N6-methyladenosine (m6A) reader, in MM patients with 1q+.

Methods: Comprehensive in silico analyses of existed public datasets (MMRF CoMMpass study) and in-house generated high-throughput sequencing datasets (RNA-sequencing, methylated RNA immunoprecipitation sequencing, and crosslinking immunoprecipitation sequencing), along with routine molecular and cellular in vitro assays, as well as in vivo animal model studies, were conducted.

Results: IGF2BP1 displays a high expression level in MM patients with 1q+ and its high expression predicts poor prognosis in these patients. IGF2BP1 overexpression promoted cell proliferation and G1-to-S phase transition of the cell cycle in H929 cells. Combinatory analyses of MeRIP-seq, RNA-seq, CLIP-seq and patients' survival data identified CDC5L as a target of IGF2BP1, which can bind the m6A sites of CDC5L mRNA to upregulate its protein abundance. Higher CDC5L expression also predicted worse prognosis of MM patients with 1q+. Moreover, both knockdown and mutation of CDC5L attenuated the pro-proliferative effect of IGF2BP1. Furthermore, IGF2BP1 inhibitor BTYNB effectively inhibited CDC5L expression in MM cells with 1q+, and suppressed the proliferation of these cells in vitro and in vivo.

Conclusions: IGF2BP1 acts as a post-transcriptional enhancer of CDC5L in an m6A manner to promote the proliferation of MM cells with 1q+. Our work identified a novel IGF2BP1-CDC5L axis and provided new insight in developing targeted therapeutics for MM patients with 1q+.
Nynrin Preserves Hematopoietic Stem Cell Function Via the Ppif-Mediated Mitochondrial Permeability Transition
Authors: Zhou Chengfang , Kuang Mei , Wang Jianming , Luo Yu , Hou Yu
Published: December 2023

Mitochondria have recently been identified as a critical regulator for homeostasis of hematopoietic stem cells (HSCs). However, the mechanism underlying HSC regulation remains poorly clarified. Here, we identify transcription factor Nynrin as a novel regulator of HSC maintenance through modulation of mitochondrial function. We demonstrate that Nynrin knockout leads to significantly decreased long-term HSC frequency, markedly reduced HSC dormancy and self-renewal capacity in steady-state and stress hematopoiesis. Nynrin-deficient HSCs are more compromised in tolerance of irradiation- and 5-fluorouracil-induced stresses and exhibit typical phenotypes of necrosis. Mechanistically, Nynrin deletion induces transactivation of Ppif, its product cyclophilin D is one of the prominent members of mitochondrial permeability transition (mPT). Overexpression of Ppif exhausts long-term HSC, impairs genotoxic hematopoietic recovery, and enhances mPT, resulting in mitochondrial swelling and reactive oxygen species production. Suppression of Ppif essentially rescues the phenotypic and functional defects in Nynrin-deleted HSCs. Collectively, our data, for the first time, characterize Nynrin as a critical regulator of HSC function acting through the Ppif/ mPT mitochondria axis and highlight the importance of Nynrin in HSC maintenance. These observations provide new insights into the mechanisms for controlling HSC fate.
Deciphering the Epigenetic Landscape in Histiocytic Neoplasms
Authors: Salmon-Divon Mali , Meyuchas Refael , Benhamida Jamal , Shpilberg Ofer , Mazor Roei D. , Yabe Mariko , Petrova-drus Kseniya , Abdel-Wahab Omar , Diamond Eli L. , Hershkovitz-Rokah Oshrat
Published: December 2023

Background: Histiocytic neoplasms are driven by mutations activating the MAPK/ERK pathway; however, their epigenetic landscape remains poorly understood. MicroRNAs (miRNAs) are epigenetic regulators implicated in cancer development. Moreover, DNA methylation of miRNAs affects hematological malignancies development. Our previous study identified a unique miRNA expression signature in Erdheim-Chester Disease (ECD) patients. To further understand the biological mechanisms of ECD, we investigated the involvement of miRNAs, genes, and their methylation status in ECD, Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD).

Methods: Methylation profiles of 14 LCH, 6 ECD, and 10 RDD patients were determined from histyocitic infiltrated tissues (Illumina EPIC-methylation array). These were compared to controls, suture granulomas (n=4), localized inflammatory reactions characterized by non-neoplastic histiocytic infiltrates. miRNAome data was identified by NanoString analysis and qRT-PCR.

Results: We identified significant alterations in 23,322 methylation sites (FDR<0.05, |Δß|≧20%) between controls and the histiocytosis group, indicating differential epigenetic regulation. ECD and LCH exhibited a shared methylation signature distinct from RDD. Pathway analyses revealed that the differentially methylated genes (DMGs) were involved in inflammatory response, RAS, TNF, and PI3K-mTOR signaling pathways, linked to histiocytic neoplasms. Specifically, we found DMG involvement in regulation and generation of non-coding RNAs. Notably, we observed significant downregulation of the let7-miRNA family, particularly let7b, in ECD and LCH patients. Subsequent analysis revealed hypermethylation of specific CpG islands in the let7b DNA sequence, potentially silencing let7b expression in these diseases. Given the let7-miRNA family's role in regulating the MAPK pathway, this suggests a novel mechanism in the pathogenesis of these neoplasms.

Conclusions: We provide valuable insights into differential methylation patterns in histiocytosis neoplasms, highlighting the involvement of epigenetic modifications in their development and progression. This enhances our understanding of histiocytosis development and may contribute to the identification of novel diagnostic and therapeutic approaches for these patients.
A Retrospective Comparison of Allogenic and Autologous Hematopoietic Stem Cell Transplantation in Patients with T-Cell Lymphoblastic Lymphoma
Authors: Zhu Ying , You Tao , Ai Sicheng , Jin Mao , Cong Mengya , Wu Depei , Huang Haiwen
Published: December 2023

Background: T-cell lymphoblastic lymphoma (T-LBL) is a rare type of non-Hodgkin's lymphoma accounting for 1%~2% of non-Hodgkin's lymphoma. T-cell lymphoblastic lymphoma is typically found in children and young adults, frequently affecting the mediastinum and bone marrow. It has a poor prognosis and develops quickly. It is anticipated that hematopoietic stem cell transplantation will significantly enhance the prognosis. We conducted a retrospective single center analysis aiming to compare the survival outcomes of autologous and allogeneic hematopoietic stem cell transplantation in patients with T-cell lymphoblastic lymphoma.

Methods: From our center's database, we track down 92 individuals who underwent T-LBL transplantation between August 2011 and June 2022, including 77 individuals who got allogeneic hematopoietic stem cell transplants and 15 patients who underwent autologous hematopoietic stem cell transplants.

Results：For the baseline characteristics of patients,there were significant differences in IPNHLSS staging, bone marrow involvement, IPI score and pre transplant status between Auto-HSCT group and Allo HSCT group.Group allo-HSCT had a higher proportion of bone marrow involvement (57.1% vs. 26.7%,p=0.031), a higher proportion of IPNHLSS staging as IV (57.1% vs. 26.7%,p=0.001) and a lower proportion of CR1 pre transplantations (51.9% vs. 86.7%,p=0.080).

Figure 1 had shown the survival between auto-HSCT group and allo-HSCT group.Among the 15 patients who received auto-HSCT, 2 patients received allogeneic transplantation after relapse, 1 patient died after 3.1 months of survival after secondary transplantation, and 1 patient still survived after secondary transplantation.The 3-year OS rate of auto-HSCT group was 87.7%, while the 3-year OS rate of allo-HSCT group was 65.0%（P=0.086).The 3-year PFS rate of auto-HSCT group was 74.0%, while the 3-year PFS rate of allo-HSCT patients was 73.3%（P=0.95). The 3-year NRM rate of auto-HSCT group was 0%, while the 3-year NRM rate of allo-HSCT group was 9.9%（P=0.127). The 3-year CIR rate of auto-HSCT group was 21.0%, while the 3-year NRM rate of allo-HSCT group was 25.3%（P=0.514).

Conclusion: Hematopoietic stem cell transplantation can significantly improve the prognosis of patients with T-cell lymphoblastic lymphoma. In our study, patients with T-cell lymphoblastic lymphomareceiving autologous hematopoietic stem cell transplantation and those receiving allogeneic hematopoietic stem cell transplantation have distinct baseline data, hence their survival rates also differ.
Effect of Demographic and Environmental Factors on Chronic Lymphocytic Leukemia(CLL) in the State of Colorado
Authors: Zou Yujia , Orfan Nicholas
Published: December 2023

Various publications have examined the relationship between environmental risk factors and the development of CLL. Factors such as household income, race, altitude and air pollution have been explored. Results have been inconclusive. In this study, we examine these four factors and their possible relationship to the prevalence of CLL.

We accessed the state of Colorado all payer claims database of about 3.6 million people with dates of service from Jan 2017 to June 2020. We calculated age and sex in CLL patients. We used propensity score matching based on age and sex to generate our comparator group on a 1:1 matching scheme. We accessed US EPA 2022 data to get air quality index (AQI) for all zip codes in Colorado and US census data for household income and racial distribution by zip code. We accessed US geological survey data to determine average elevation by zip code. We assess these four factors in relation to CLL and the comparator group.

We found 3622 cases of CLL in the total population. The average age of CLL patients was 69 and the sex distribution was 74% male. After propensity matching, we identified an equal number of non CLL patients as the comparator. In analyzing CLL patients versus the comparators, we found no relationship between average elevation, racial makeup, average household income, or air quality by zip code (P=NS).

In this large statewide population, there was no effect of race distribution, household income, elevation or air quality on the prevalence of CLL.
A Mouse Model of the PAR4 Sequence Variant P310L Shows Decreased Platelet Reactivity and Thrombosis
Authors: Knauss Elizabeth Ann , Han Xu , De La Fuente Maria Almudena , Li Wei , Luc Norman , McKenzie Steven Edward , Nieman Marvin T.
Published: December 2023

Protease activated receptors 1 and 4 (PAR1, PAR4) on platelets mediate thrombin signaling and are vital for thrombus development. Hypercoagulation and thrombin generation are major risk factors for thrombosis. Sustained thrombin signaling through PAR4 promotes platelet activation, phosphatidylserine exposure, and subsequent thrombin generation. A single-nucleotide polymorphism (SNP, rs2227376) leads to an amino acid change in extracellular loop 3 (ECL3) of PAR4, which decreases PAR4 activation (PAR4-P310L). This SNP is also associated with a significantly lower risk for venous thromboembolism (VTE) in a GWAS meta-analysis. We aim to determine the mechanism by which PAR4-P310L (rs2227376) impacts platelet function and reduces the risk of VTE using mice with a homologous mutation (PAR4-P322L). Ex vivo platelet function was determined using flow cytometry and aggregometry. Arterial and venous thrombosis was examined using the ferric-chloride induced carotid artery injury and inferior vena cava (IVC) stasis models, respectively. Platelets from heterozygous (PAR4-322P/L) and homozygous (PAR4-322L/L) mice had decreased thrombin-mediated aggregation and decreased PAR4 reactivity compared to wild types. These mice also had a prolonged time to occlusion in arterial thrombosis, with 55% of PAR4-322P/L mice unable to develop stable thrombi within 30 minutes. In venous thrombosis, wild-type mice developed clotted IVCs that averaged 31 mg after 48 hours, while global PAR4-knockout mice averaged 21 mg (p<0.01), PAR4-322P/L 23 mg (p<0.01), and PAR4-322L/L 28 mg. Since platelet procoagulant activity is known to drive venous thrombosis, we used lactadherin to show that PAR4-P322L platelets express less phosphatidylserine in response to thrombin (5 nM) and convulxin (1 nM). Platelet-rich plasma from PAR4-P322L mice also generated less thrombin compared to wild-types, and whole blood from mice lacking PAR4 showed delayed clot formation in rotational thromboelastometry. Altogether, this suggests a direct impact of PAR4 signaling on platelet-mediated thrombin generation. Our new mouse model shows that the polymorphism in ECL3, PAR4-322L, decreases platelet reactivity and thrombosis. We also show PAR4-322L leads to less procoagulant platelets and decreases the endogenous thrombin potential. This decreased ability to generate thrombin offers a mechanism for PAR4's role in VTE. Our findings highlight a key role of PAR4 signaling in platelet activation and procoagulant activity in thrombosis.
Deep Learning for Circulating Multiple Myeloma Cell (CMMC) Enumeration with the Cellsearch System
Authors: Biasiolli Luca , Campione Arianna , Ansaloni Pietro , Gentili Nicolò , Miserendino Ramona , Signorini Giulio , Medoro Gianni
Published: December 2023

Background

Circulating Multiple Myeloma Cell (CMMC) enumeration in blood samples with the CELLSEARCH® system is a minimally invasive assay used to quantify plasma cells in patients with Multiple Myeloma (MM) and in precursor stages MGUS and SMM 1 particularly during disease stages when a bone marrow aspirate is not desirable (Foulk et al. 2017). Currently, CMMC identification is performed by human reviewers through visual assessment, which is a time-consuming procedure that could be affected by subjective interpretations. Modern Deep Learning (DL) methods can provide a solution by automating the process of CMMC identification, thus eliminating subjectivity and producing faster and more reproducible results. The purpose of this study was to train and test an automated algorithm (for research use only) based on DL models for CMMC identification in CELLSEARCH® fluorescent images.

Methods

The DL algorithm was designed to analyze images using a segmentation and a classification network as presented in recent studies (Zeune et al. Nature MI 2020; Coumans et al. ACTC 2021). The DL classification model was trained on 5139 CMMC and 16235 non-CMMC images (training set) of fully anonymized blood samples from the CoMMpass study (NCT01454297 sponsored by the Multiple Myeloma Research Foundation) scanned by CELLTRACKS ANALYZER II® (CTAII). The test set was composed of 75 samples from the CoMMpass study with 1000 images per sample reviewed by an operator (with training and experience of reviewing CTAII images) and processed by the algorithm, for a total of 75000 images. The algorithm was compared with the human reviewer in terms of overall agreement and Cohen's Kappa of the image classification results and of correlation for the CMMC enumeration results per sample.

Results

In the test dataset, out of 75000 images in total the reviewer identified 32403 CMMCs and the algorithm 32842 CMMCs. The DL algorithm and the reviewer provided the same classification for 71711 images, thus showing very high agreement = 95.6% (Cohen's Kappa = 0.91). CMMC counts per sample and linear regression are shown in the figure: slope = 0.95 (95% CI = 0.02), intercept = 26.99 (95% CI = 11.56) and coefficient of determination R 2 = 0.99.

Conclusion

These preliminary results show the potential of applying automated algorithms to CMMC identification with the CELLSEARCH® system in order to remove human subjectivity from the review process, thus maximizing standardization among different research centers.

1) The CMMC assay is run in a CLIA/CAP certified laboratory in the US and is also New York State CLEP approved. In the EU, the CMMC assay is research use only (RUO).