bluuebunny/crossref_metadata_2025_split huggingface dataset:
MPO and Trh within Leukemia Stem Cells Increased Chemosensitivity in Acute Myeloid Leukemia: A Single-Cell RNA Sequencing Approach
Authors: Teng Chieh-Lin Jerry , Chen Chung-Hsing , Hsiao Tzu-Hung , Wu Ting-Shuan , Liao Yu-Min 
Published: December 2023

Introduction
The “7+3” regimen is widely recognized as the established standard induction therapy for newly diagnosed acute myeloid leukemia (AML), exhibiting a complete remission (CR) rate of 70%. However, the prognosis for patients who do not achieve CR following induction remains discouraging. Leukemia stem cells (LSCs) are recognized as major contributors to chemoresistance in AML. Hence, it is crucial to identify potential targets within LSCs that can overcome chemoresistance.
Patients and methods
This prospective study involved 20 consecutive de novo AML patients who underwent “7+3” induction therapy. These patients were divided into CR (n=15) and non-CR (n=5) groups. By employing single-cell RNA sequencing (scRNA-seq), we meticulously examined the cellular states of bone marrow mononuclear cells from AML patients at the time of diagnosis and identified LSCs among these cells. The genetic profiles of the LSCs were subsequently compared between the CR and non-CR groups and further validated using independent cohorts.
Results
The non-CR AML patients exhibited a significant increase in the proportion of immature cells during hematopoiesis within the AML cell populations. Moreover, we found that expressions of MPO and TRH within LSCs were significantly higher in the CR than non-CR groups, which were further validated by independent cohorts. Furthermore, patients with higher expression of TRH and MPO demonstrated substantially improved relapse-free survival (p = 0.009 for TRH; p = 0.002 for MPO) and overall survival (p &lt; 0.001 for TRH; p = 0.002 for MPO). The dysregulation of the OXPHOS pathway, along with altered interferon alpha and gamma responses, disrupted cholesterol homeostasis, and aberrant MYC activity, may contribute as underlying mechanisms for the observed association between MPO or TRH and chemotherapy response.
Conclusions
MPO and TRH in LSCs may increase chemosensitivity in AML and serve as chemoresponse biomarkers, offering potential benefits in guiding induction strategies for newly diagnosed AML patients
Blastic Plasmacytoid Dendritic Cell Neoplasm Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database
Authors: Haddad Philip A , Gaddam Shiva Jashwanth 
Published: December 2023

Background:
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with a propensity for cutaneous involvement. This disorder has gone through many reiterations over the years, being classified initially as a blastic NK-cell lymphoma, then a subset of AML, and finally recognized as a unique myeloid neoplasm. However, due to the poor understanding and the rarity of the disease, varied treatment approaches have historically been implemented, and no optimal data or guidelines for managing BPDCN are available. Therefore, we conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies that influence survival in this disease.
Methods:
To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 273 cases that fit the diagnostic criteria for BPDCN. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS).
Results:
A total of 273 patients with confirmed BPDCN were identified. The median age was 61.5. There was a male preponderance with M:F of 2.4. The median duration of symptoms before diagnosis was 5 months. Eighty-one percent of patients presented with skin lesions, 65% of which were disseminated. Involvement of Lymph nodes (LN), bone marrow (BM), spleen, peripheral blood, and CNS occurred in 62%, 73%, 55%, 71%, and 57%. Constitutional symptoms were reported in 13%. The median OS and DFS of the whole group were 16 and 13 months, respectively. Patients younger than 60 had better median OS (30 vs. 10 months, p &lt; 0.0001). The involvement of LN (p = 0.03), BM (p = 0.007), spleen (p = 0.02), and peripheral blood (p = 0.01) was associated with worse OS. Furthermore, disseminated skin involvement had worse OS than focal (p = 0.001). Though CNS involvement, presence of constitutional symptoms, elevated LDH, and TdT negative status had numerically worse OS, it did not reach statistical significance. Sex did not impact OS. Compared to no treatment, non-dose-intense chemotherapy, dose-intense chemotherapy, and stem cell transplant had incrementally superior OS (3 vs. 10 vs. 22 vs. 66 months, p &lt; 0.0001). Patients who attained CR as their best response also had a superior median OS (26 vs. 5 months, p &lt; 0.0001).
Conclusions:
This study presents updated clinicopathologic data from a large, pooled cohort of patients with BPDCN. It identifies age, organ involvement, type of therapy, and quality of response to treatment as critical determinants of OS.
Establishing an AML Ex Vivo Platform to Generate Physiologically Relevant Models
Authors: Tavana Omid , Willis Brandon , Liu Siyu , Christie Amanda , Andersen Courtney L , Roderick-Richardson Justine , Robichaud Amanda , Prickett Laura , Reimer Corinne , Drew Lisa 
Published: December 2023

Acute myelogenous leukemia (AML) comprises a highly polyclonal and heterogeneous disease containing leukemic stem cells, progenitors, and differentiated blasts. Despite advances in treatment, the long-term relapse-free survival for AML remains poor. Due to complex mutational profiles and highly divergent subtypes in AML, the use of physiologically relevant, patient-derived models is needed. Traditional cell line models of AML almost exclusively represent differentiated blasts, are homogenous in clonality, and often do not encompass major genetic subtypes. To address these gaps, we have established a culture system that supports the growth of higher-order AML samples ex vivo.
By optimizing culture conditions, we successfully cultivated 70% (10/14) of AML disseminated PDX models ex vivo and demonstrated they continue to proliferate after long term cultures. We established a 16-color flow panel to characterize their cell maturity state and show they maintain cell surface heterogeneity. Importantly, these models have not ‘drifted’ transcriptomically after multiple passages. Our platform includes 2 NPM1c mutant and 3 IDH1/2 mutant ex vivo lines, in addition to other subtypes underrepresented in traditional culture methods.
Furthermore, we treated AML PDXs in vivo with a clinically-relevant dose of venetoclax + azacytidine (Ven/AZA) for 2 cycles (14 days) and then evaluated post-VEN/AZA cells in our ex vivo assay. Growing these models ex vivo, we show using our flow panel that Ven/AZA treatment shifts the differentiation status from a stem-like state to a more mature-like cell state which is consistent with literature evidence of treatment resistance. Additionally, a second PDX model treated with three cycles of Ven/AZA in vivo and harvested in ex vivo culture conditions maintained both Ven and AZA resistance. Interestingly, compared with the vehicle treatment, Ven/AZA treatment caused resistance to other cell death agents including selective MCL1 and dual Bcl2/xL inhibitors. Lastly, we performed a 7-day cell compound panel screen using common standard of care agents for the treatment of AML. Many of the targeted agent activity correlated with expected genetic subtypes, such as FLT3 inhibitors in FLT3-ITD mutants and venetoclax in WT TP53 models. This established ex vivo platform provides physiologically relevant models to explore novel target biology, better understand compound mechanism of action (MoA), and generate drug resistant models through in vivo driven clinically relevant dose scheduling using standard of care agents.
A Phase 1b Double-Blind, Placebo-Controlled Study of DISC-0974, an Anti-Hemojuvelin Antibody, in Patients with Non-Dialysis Dependent Chronic Kidney Disease and Anemia
Authors: Arora Samir , Monroy Jorge , Pergola Pablo , Silva Arnold , Buch Akshay , Novikov Natasha , Pelletier Olivia , Savage William 
Published: December 2023

Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) and anemia. Elevations in hepcidin contribute to the onset, maintenance, and severity of anemia. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin (HJV), a co-receptor in the bone morphogenetic protein-signaling pathway regulating hepcidin expression.
In a healthy volunteer study, DISC-0974 demonstrated dose-dependent reductions in serum hepcidin, increases in serum iron with doses up to 56 mg administered subcutaneously (SC), and increasing trends in reticulocyte count, reticulocyte hemoglobin, mean corpuscular hemoglobin, total hemoglobin (Hgb), and red blood cell count. In a rat model of anemia in CKD, DISC-0974 decreased hepcidin, increased serum iron, and normalized hemoglobin (Wu et al., ASH 2022).
DISC-0974-103 is a Phase 1b, double-blind, placebo-controlled, single-ascending dose study (NCT05745883) to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DISC-0974 in patients with NDD-CKD and anemia. Eligible participants include patients over 18 years of age with NDD-CKD, stages 2-5, hemoglobin (Hgb) &lt;10.5 g/dL in women and &lt;11.0 g/dL in men, serum ferritin ≥100 μg/L, and transferrin saturation (TSAT) ≤30%. Major exclusionary criteria include: concomitant treatment with therapeutic oral iron, intravenous iron, erythropoietin-stimulating agents, or blood transfusions; splenectomy; and nutritional, genetic, infectious, or autoimmune causes of anemia. Approximately 32 participants will be enrolled.
On Day 1, participants will receive a single dose of DISC-0974 SC with evaluations for safety, PK, and PD through 57 days of follow-up. Dose escalation is planned across 4 cohorts consisting of 8 participants each, randomized 3:1 active treatment to placebo, treated at single doses of 28, 40, 60, and 90 mg SC DISC-0974. Safety Review Committee assessments are planned to gate escalation decisions.
Primary endpoints include adverse events (AEs), clinical laboratory assessments, vital signs, physical examinations, and electrocardiograms. Secondary endpoints include changes in serum hepcidin-25, iron, TSAT, ferritin, Hgb, and other hematology biomarkers.
Enrollment is currently ongoing, and available study results will be presented at the meeting.
Racial Disparities in the Outcome of Tumor Lysis Sydrome (TLS) - a Five Year Population Based Analysis
Authors: Kamal Syeda Ashna Fatima , Prakash Vivek , Maiocco Giuseppe , Hussain Mohammad Junaid , Shah Ejaz , Agarwal Ishan , Goel Ruchika 
Published: December 2023

DISCUSSION
Tumor lysis syndrome (TLS) is a potentially life-threatening complication that occurs in the setting of rapid tumor cell destruction. While several studies have explored the risk factors and management strategies for TLS [1], the impact of racial disparities on the incidence, severity, and outcomes of this syndrome remains understudied. We aim to investigate the impact of race on the outcomes of TLS.
Using weighted data from the Nationwide Inpatient Sample (NIS) database from 2016 to 2020, we assessed the outcomes (mortality, hospital utilization, total healthcare charges, complications) of individuals admitted with a primary diagnosis of TLS among races (non-Hispanic Whites, non-Hispanic Blacks, Hispanics, and Others including Native Americans, Asians, and other races/ethnicities). Baseline characteristics (table 1) were analyzed using T-test and Chi-Square, and a multivariate regression analysis was used to estimate outcomes between races, adjusted for patient and hospital confounders. Data analysis was performed using STATA® Version 17.0/SE Software, with statistical significance set at p &lt; 0.05.
A total of 4340 were admitted with a primary diagnosis of TLS from 2016 to 2020. Among these, Blacks were the most prevalent (46%), followed by others (34%), Hispanics and whites (33% each). There was no significant difference in comorbid conditions between races. Moreover, no significant differences in the total healthcare expenditures or length of hospital stays were found among races. Pertaining to TLS outcomes, When compared to Whites, Blacks had a statistically significant increase in mortality (OR 2.35, 95%CI: 1.14-4.87). Considering manifestations of TLS, Others (Native Americans, Asians, and other races/ethnicities) had an increased likelihood of cardiac arrest (OR 9.14, 95%CI: 1.11-75.6). No statistically significant difference between races was found for gastrointestinal (GI) bleeding, acute kidney injury (AKI) or sepsis.
Our study highlights racial disparities in the outcomes of individuals hospitalized with TLS, including increased mortality in Blacks, and cardiac arrests in Others (Native Americans, Asians, and other races/ethnicities). Interestingly, there were no statistically significant differences in GI bleeding, or sepsis, which are commonly associated with increased mortality in TLS. Further investigations are warranted, particularly through prospective or retrospective studies, to elucidate the underlying factors contributing to these disparities.
Measuring Thrombin Generation in Platelet Rich Plasma with the ST Genesia
Authors: Ninivaggi Marisa , De Laat-Kremers Romy , De Laat Bas 
Published: December 2023

Background: Thrombin generation (TG) is nowadays used more and more for diagnosing and monitoring of patients. The ST Genesia is a fully automated device for measuring TG in platelet poor plasma (PPP). As the samples are not being inverted prior to the measurement once loaded in the device, it was not known whether it was possible to measure TG in platelet rich plasma (PRP). Platelets can sediment in time possibly affecting TG results. The goal of this study was to evaluate the use of the ST Genesia for measuring TG in PRP in time and to investigate whether the assay is sensitive to platelet antagonists.
Methods: Blood was taken from 6 healthy donors and PRP was immediately prepared by centrifuging the blood once for 15 minutes at 220g. The PRP was divided into 14 tubes: 11 tubes for measuring TG in time; i.e. after 0, 15, 30, 45, 60, 75, 90, 105, 120, 180, 240 minutes after the samples were loaded on board; 1 tube for platelet count measurement, 1 tube for TG with the Calibrated Automated Thrombogram (CAT) assay and 1 tube for freezing the PRP. The PRP reagent of the CAT assay was used for triggering TG that contains a low tissue factor concentration. Tukey's multiple comparisons test was used for statistical analysis.
Results: The platelet count remained stable in time even without inverting the vial prior to the measurement up to 3 hours. After 4 hours, platelet count was significantly lower (p&lt;0.01). TG in PRP remained stable in time up to 3 hours, after that lagtime and time-to-peak were extended by an average of 48% and 16%, respectively (p-values &lt;0.0001 and 0.0121, respectively), while ETP and peak height remained stable (with low CV's of &lt;6.0% and &lt;7.3%, respectively). The ST Genesia proved to be sensitive to platelet antagonists aspirin (100µM) and Cangrelor (500nM) as peak height decreased with 22% and 24%, respectively. TG measured with the CAT and the ST Genesia was comparable. Measuring TG in PRP after being frozen at -80°C resulted TG kinetics similar to TG in PPP, with a shorter lagtime (-67%) and time-to-peak (-64%), with an increased peak height (+82%), and velocity index (+383%), and an unaffected ETP.
Conclusion: The ST Genesia can be used for the reproducible measurement of TG in PRP up to two hours after loading the samples in the device.
Venetoclax Combined with Daunorubicin and Cytarabine (2 + 6) in Acute Myeloid Leukemia: Updated Results of a Phase II Trial
Authors: Suo Xiaohui , Wang Dongmei , Zheng Fang , Zhang Suping , Zhang Congcong , Li Yinling , Shi Rui , Wu Yan , Yang Sisi , Zhao Liyun , Jiao Zongjiu , Liu Jie , Zhang Ling , Li Ling , Zhang Zhihua , Lu Xinxiao , Yuan Linyu , Gao Sifeng , Zhang Jilei , Zhao Xingli , Bai Guanchen , Mi Yingchang , Liu Kaiqi 
Published: December 2023

INTRODUCTION
Venetoclax (Ven) combined with intensive chemotherapy had been proven effectively in the management of newly diagnosed acute myeloid leukemia (AML). Our previous study showed that Ven combined with DA (2 + 6) is a highly effective and safe induction therapy for adults with newly diagnosed AML. To further validate the efficacy and safety of this induction regimen, the study continued to enroll young patients with newly diagnosed AML. Now, we have updated the results of this phase 2, multicenter, single-arm trial.
METHODS
Details of the Study design, participants, inclusion and exclusion criteria, procedures, efficacy and safety evaluation were provided in our previous article “Venetoclax combined with daunorubicin and cytarabine (2 + 6) as induction treatment in adults with newly diagnosed acute myeloid leukemia: a phase 2, multicenter, single-arm trial” which published in the Journal of “Experimental Hematology & Oncology”.
RESULTS
Until June 30, 2023, seventy patients were enrolled and treated with Ven combined with DA (2 + 6) as induction therapy. The median age was 44 (range, 16-60) years, and 37 (52.9%) patients were male. According to the European Leukemia Network prognostic group (2022), 32 (45.7%), 9 (12.9%), and 29 (41.4%) patients were considered to belong to the favorable, intermediate, and adverse groups, respectively.
The ORR after one cycle of induction was 92.9% (65/70)with a composite complete response rate (CR + CRi) of 90.0% (CR 61/70, CRi 2/70). Moreover, 89.5% (51/57) of the patients reached CR with undetectable MRD. Grade 3 or worse adverse effects included neutropenia (100%), thrombocytopenia (100%), febrile neutropenia, and one mortality. The median neutrophil and platelet recovery times were 13 (5-36) and 13 (8-48) days, respectively. (Table 1)
Until Jan 30, 2023, with with a median follow-up of 9 (1-18) months, 6 patients proceed Allo-HSCT, the estimated 12-month OS, EFS, and DFS rates were 84.9%、81.0%、81.6%, respectively. (Figure 1)
Conclusion: Ven with DA (2 + 6) is a highly effective and safe induction therapy for adults with newly diagnosed AML.
Keywords Venetoclax, DA(2+6), induction treatment, acute myeloid leukemia
Infection Outcomes and Hypogammaglobulinemia in Patients with Chronic Lymphocytic Leukemia Treated with Immunoglobulin Replacement Therapy
Authors: Soumerai Jacob , Gift Thais , Yousif Zaid , Desai Raj , Huynh Lynn , Belsky Gregory , Duh Mei Sheng , Sanchirico Marie 
Published: December 2023

CONCLUSIONS
Hypogammaglobulinemia (HGG), a secondary immunodeficiency (SID), can manifest in patients with chronic lymphocytic leukemia (CLL) due to the disease and its treatments. Up to half of all deaths from CLL are attributed to infection; however, use of immunoglobulin replacement therapy (IgRT) for the prevention of infections in selected patients varies. We aimed to assess real-world IgRT utilization and infection outcomes in patients with CLL.
A retrospective, longitudinal study evaluating real-world IgRT use in adult patients with CLL diagnosed after 2010, with ≥ 3 visits/year and ≥ 12 months of clinical data, was conducted. De-identified clinical data came from the Massachusetts General Brigham Research Patient Data Registry. Immunoglobulin G (IgG) testing, infection outcomes, and antimicrobial use were compared before versus after IgRT initiation. Generalized estimating equation logistic regression models calculated odds ratios (ORs), 95% CIs, and P-values.
Of 3960 patients with CLL assessed, 2652 (67.0%) patients had IgG testing (29.0% tested at CLL diagnosis); 917 (34.6%) had HGG (IgG level &lt; 500mg/dL). Median (interquartile range [IQR]) age was 68.0 (60.0, 76.0) years, 61.2% were men, 67.8% were treatment-naïve, and median (IQR) follow-up duration was 4.8 (2.4, 7.4) years. Among recipients of IgRT (n = 259), 56.8% received ≥ 2 administrations and the median (IQR) number of IgRT administrations was 2.0 (1.0, 4.0). Median (IQR) time from CLL diagnosis to IgRT initiation was 38.0 (11.4, 64.7) months. Significantly fewer patients had HGG 3 months after IgRT versus 3 months before (33.8% vs 72.8%; P &lt; 0.0001). Significantly lower odds of infections and antimicrobial use were observed after IgRT initiation in 3- and 6-month time periods for: all infections, sinopulmonary and skin or soft tissue infections, infections requiring antimicrobials, all severe infections, severe sinopulmonary and skin or soft tissue infections, and severe infections requiring antimicrobials ( Table).
In this real-world study of patients with CLL, IgRT was associated with significant reductions in HGG, infection rates, and infections requiring antimicrobials. Guidelines are needed to optimize IgG testing, IgRT initiation, and SID management for patients with CLL.