bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Better Efficacy of an Escalating Strategy over Thrombopoietin Receptor Agonist-Based Second-Line Therapy in Children Severe Persistent/Chronic Thrombocytopenia: A Multicenter Prospective Study from China
Authors: Wu Runhui , Fu Lingling , Lin Xi 
Published: December 2024

Background: The first international recommendations for second-line therapy in children with severe persistent/chronic thrombocytopenia (SP/CITP) are thrombopoietin receptor agonists (TRAs) or TRAs-based strategies, however, only 30% of them could achieve sustain response off treatment (SRoT), leading to a heavy medical burden, especially for the SP/CITP children in developing countries. The result of our previous escalating treatment pilot study showed the possibility to solve this problem.
Objective: Comparing the efficacy of the escalating treatment to TRAs-based second-line treatment, to provide a better treatment option for children SP/CITP.
Methods: A prospective, multicenter clinical cohort study enrolled SP/CITP children, with one-year follow-up, we compared the escalating group to the group using TRAs-based second-line treatment directly, for the treatment outcomes (response/remission of platelet count, bleeding control, side effects related to treatment) and costs outcomes (escalation status, SRoT and treatment costs).
Results: A total of 143 analyzable cases were enrolled (72 males, 71 females), with 110 cases in the escalating group (EG) and 33 patients in the TRAs-based second-line treatment group (TG) (12 cases using TRAs monotherapy and 21cases using TRAs-based combination therapies). There were without differences in baseline characteristics (Ps&gt;0.05).
Comparison between EG and TG showed that without differences in duration response(DR), remission(R) rates and also the grades of bleeding at 6 and 12 months (Ps&gt;0.05), but with fewer side effects related to treatment (9.0% in EG and 39.4% in TG, P＜0.001).
In EG, with 57% responding to HDD and 26% to RTX, only 16% of them needed to escalate to add TRAs, leading to 74.5% achieving SRoT within 150（75-180）treatment days whereas 0% in TG. The cost of treatment was significantly lower in EG ($68.26/kg/year) than either the monotherapy group ($395.11/kg/year) or the combination therapies group ($373.85/kg/year) from TG during 12 months of follow-up period (P&lt;0.001).
Conclusion: The escalating strategy achieved comparable clinical efficacy with fewer treatment-related side effects to TRA-based second-line treatment. By utilizing individualized and stratified treatment, the escalating strategy could shorten the treatment duration, attain treatment discontinuation, and save treatment costs significantly. It is a better option second-line treatment strategy for children SP/CITP.
Clinical Implications of Residual Immunophenotypically Normal Plasma Cells within Bone Marrow at Various Disease Stages in Multiple Myeloma
Authors: Yan Wenqiang , Shi Lihui , Xu Jingyu , Li Lingna , Cui Jian , DU Chenxing , Yu Tengteng , Zhang Shuaishuai , Lv Rui , Sui Weiwei , Deng Shuhui , Xu Yan , Zou Dehui , Qiu Lu-Gui , Hao Mu , An Gang 
Published: December 2024

Introduction
Residual normal plasma cells (NPCs) within bone marrow (BM) act as competitors of abnormal plasma cells, playing an important clinical role during the malignant transformation and disease aggressiveness in plasma cell disorders. Previous studies have described the relationship between the persistence of NPCs and survival outcomes at several timepoints, but its clinical significance remain to be fully elucidated across various disease courses. Following the clearance of tumor plasma cells post-treatment, the numerical or proportional alterations in NPCs during the minimal residual disease (MRD) phase could also indicate the evolution of response depth and changes in the immune microenvironment. To date, however, there has been a scarce of research specifically addressing residual NPCs at the MRD stage.
Methods
In light of this, we conducted a comprehensive retrospective study utilizing a substantial flow cytometry dataset comprising 1363 MM patients and nearly 5000 MRD samples across all disease courses from the National Longitudinal Cohort of Hematological Diseases in China (NICHE, NCT04645199).
Results
Our results revealed that 47 (4.5%) newly diagnosed myeloma patients with high NPC ratio (≥5%) within bone marrow (BM) exhibited distinct indolent features, characterized by lower tumor burden, reduced frequencies of cytopenia, immunoparesis, and high-risk cytogenetics. Importantly, high residual NPC ratio at diagnosis or relapse was independently associated with favorable survival outcomes. Furthermore, high absolute level of NPCs at undetectable MRD timepoint was also related with superior clinical benefit and immune reconstitution. Among MRD-positive patients, NPCs ratio within BMPCs was significantly negatively correlated with residual tumor cell levels post-treatment. In addition to MRD status, grouping based on NPC ratio (&lt; 50%, 50-90%, ≥90%) at MRD phase demonstrated better risk stratification for detectable MRD patients compared to residual tumor log levels. The dynamic NPC ratio time-dependent model could classify patients into three groups with diverse longitudinal change trends, which lead to distinct survival outcomes.
Conclusions
Collectively, the persistence of residual NPCS serves not only as a valuable complementary biomarker for risk stratification but also provides valuable insights on reclassifications and kinetics of MRD.
Effect of Sarcopenia and Nutritional Risk Factors in Patients with Multiple Myeloma
Authors: Shen Xuxing , Yu Jiapei , Cheng Xin , Yao Ye , Jin Yuan , Shi Qinglin , Li Jianyong , Chen Lijuan 
Published: December 2024

Background:
Multiple myeloma (MM) is a hematological malignancy with poor prognosis. Fitness-based prognosis predict may help facilitate therapeutic strategies. This study was objective to explore the prognostic significance of sarcopenia, prognostic nutritional index (PNI), and controlling nutritional status (CONUT) in patients with MM.
Methods:
We conducted a retrospective analysis of the data derived from 214 patients with newly diagnosed multiple myeloma (NDMM) at Jiangsu Province Hospital from January, 2016 to December, 2022. Skeletal muscle mass was measured by whole-body low-dose CT/PETCT images at diagnosis and further normalized for stature to calculate the skeletal muscle index (SMI). Patients with a low SMI were defined as sarcopenic. Prognostic nutritional index (PNI) was calculated by the following equation: PNI=serum albumin (g/L)+5×peripheral blood lymphocyte count(×109/L). Elements including serum albumin, total cholesterol, and peripheral blood lymphocyte count were collected for estimating the Controlling Nutritional Status (CONUT) score. The thresholds of sarcopenia, PNI, and CONUT were determined by ROC curve analysis, and participants were divided into three groups according to these three metrics. The Kaplan-Meier survival analysis was utilized to investigate the relationship between these indicators as well as collectively prognosis. Independent prognostic predictors of overall survival (OS) were identified using the Cox regression model.
Results:
A total of 72(33.6%) patients were confirmed as sarcopenic, with a higher prevalence in female(P＜0.001), over 65 years of age (P=0.022), and those with a BMI below 24 kg/m2(P＜0.001). Survival curves showed that sarcopenia, low PNI, and high CONUT were all correlated with adverse survival outcomes. The combined model was apparently associated with PFS (P=0.0284) and OS (P=0.0004), and patients with concurrent sarcopenia, low PNI, and high CONUT had the worst survival rates. Multivariate analysis indicated that sarcopenia emerged as a significant and independent predictor of inferior OS (HR=1.820, P=0.048) in NDMM patients.
Conclusion:
In conclusion, sarcopenia served as an autonomous prognostic indicator OS in individuals with NDMM. The integration of PNI and CONUT with sarcopenia was effective in predicting prognosis in MM patients.
Clinicopathological Features of Kikuchi-Fujimoto Disease: Retrospective Observational Study
Authors: Nishimura Yoshito , Nishimura Midori Filiz , Sakao Chikako , Nishikori Asami , Habermann Thomas M. , Dispenzieri Angela , Sato Yasuharu 
Published: December 2024

Introduction:
Kikuchi-Fujimoto disease (KFD), is a rare inflammatory disease of unknown etiology, typically presenting with transient fever and cervical lymphadenopathy. It is recently classified as a tumor-like lesion in the World Health Organization Classification 5th Edition. There are few large-scale studies on patient demographics and clinical course. This study aims to report detailed clinicopathological features of KFD.
Methods:
We reviewed 112 cases of KFD diagnosed at Okayama University Department of Pathology and Oncology, Okayama, Japan between 2012 and 2022. Patients who were diagnosed with autoimmune diseases or bacterial/tuberculous lymphadenitis after the initial presentation as KFD were excluded.
Results:
The average age of the included cases was 29.4 years (range:6 to 77 years) with slight female predominance (n = 51/115, 44.3% for male; n = 61/115, 53.0% for female). For the included cases of 30 years or older, there were more females than males. The cervical lymph nodes were the most commonly affected sites (85%). For the 70 patients who had complete follow-up data available in the electric medical records, the recurrence rate was 23%, without a difference between males and females. Laboratory tests demonstrated significantly lower complement 4 (C4) levels (p = 0.038) and a higher rate of positive antinuclear antibodies (p = 0.007) in the relapsed cases than in the cases without documented recurrence. The mean number of days prior to confirm the diagnosis was 71.5 days. Among the representative lymph node histology classification, proliferative type was the most common (n = 75; 77%), followed by necrotizing (n = 22; 22%), and xanthomatous (n = 1; 1%). The patients with necrotizing type had significantly enlarged lymph nodes (p = 0.047) and longer duration of symptoms (p = 0.009) compared to the proliferating type.
Discussion:
The present study provides data from a large KFD cohort to provide comprehensive clinicopathological information to date. While KFD is known to predominantly affect female, there were considerably more males up to age 30 than females, Being young and adolescent male KFD patients was associated with atypical features. Future studies are warranted to confirm the findings noted in the results, to clarify clinicopathological differences in the male young adolescent KFD, and further characterize the classical female KFD cases, including histological features, treatment responses, and association with autoimmune or malignant hematology conditions.
Conclusion:
In this study, we analyzed a large number of KFD cases and clarified characteristics. The comprehensive clinicopathological features provided by the present results may be useful in elucidating the pathogenesis and predicting the clinical course of such clinically challenging cases, including association with autoimmune diseases and its long-term outcomes.
Estimated Prevalence of β-Thalassemia in the United States in 2023
Authors: Fu Kasey , Lawson-Michod Katherine , Goodman Michael , Lally Cathy , Ojodu Jelili 
Published: December 2024

Introduction: The number of β-thalassemia (BT) prevalent cases in the US was previously estimated at 2,600 and state-specific prevalence data are limited. Here, we use newborn screening data to estimate the current number of BT and transfusion dependent β-thalassemia (TDT) cases in the US.
Methodology: We requested results for newborn screening data for BT from 26 state public health programs. The goal was to estimate the total number of clinically significant BT cases that included BT subgroups: β-thalassemia major (BTM), β-thalassemia intermedia (BTI), and hemoglobin E β-thalassemia (HbEBT). As BT primarily affects individuals of Mediterranean and Southeast Asian ancestry, and very few cases are expected to occur in smaller states with relatively homogeneous US-born populations, we included states with at least 500,000 foreign-born residents, or states with a population of at least 5 million. Due to how the states' data collection and reporting varied, cases were standardized into BTM, BTI, and HbEBT consistent with reporting in the literature. The total prevalence of BT in the US in 2023 was estimated using a modified life table model based on the median US birth incidence for all BT groups and survival probabilities. State-specific BT birth incidence and the median for the census region were used in a sensitivity analysis. Additional sensitivity analyses using varying definitions of TDT were conducted.
Results: Based on 17 states reporting data sufficient for analysis, the national median BT birth incidence was 1.46 cases per 100,000 live births. When applying the US median birth incidence to all states in the life table model, the total number of BT cases in the US in 2023 was 3,665, equivalent to 1.07 per 100,000 persons. However, based on sensitivity analyses the estimated prevalence was as high as 4,214 cases (1.23 per 100,000). The number of prevalent TDT cases was 2,611 and as high as 3,036 in sensitivity analyses.
Conclusion: Our results suggest that the previously reported number of 2,600 individuals receiving care for thalassemia in the US is likely an underestimate. Variations observed in the reported BT birth incidence by state could be due to true population differences as well as variation in newborn screening reporting. More research is needed to understand the epidemiological trends of BT in the US as the implications of undercounting BT cases are significant when considering healthcare resource planning.
Effective Treatment of Refractory Aplastic Anemia with Romiplostim after Failure of Multiple Thrombopoietin Receptor Agonists: A Single-Center Retrospective Study
Authors: Lin Xijuan , Yang Chen , Liu Ziwei , Zhuang Junling , Chen Miao , Han Bing 
Published: December 2024

Background: Romiplostim (ROMI), a second-generation thrombopoietin receptor agonist (TPO-RA), has shown promising results in patients with refractory aplastic anemia (AA); however, its optimal dosage, efficacy, and safety in patients with refractory AA who experienced treatment failure with immunosuppressive therapy (IST) and other types of TPO-RAs remain unclear. In the present study, we aimed to retrospectively assess the efficacy and safety of high-dose ROMI (with an initial dosage of 20 μg/kg per week) in these patients.
Patients and m ethods: Patients who received ROMI consecutively for at least 3 months between April 8, 2023 and October 23, 2023, and were followed up for at least 6 months after therapy were analyzed. All enrolled patients had failed to respond and stopped the previous treatments for at least 3 months before receiving ROMI.
Results: Eleven patients were followed up for at least 6 months; all experienced treatment failure with IST and at least two types of other TPO-RAs. They had a median age of 54 years (range: 27-77 years), and eight (72.7%) were women. The patients' initial and maximal ROMI dose was 20 μg/kg per week. At a median follow-up of 8 months (range, 6-8 months), 72.7% (8/11) of the patients reached the response criteria at a median of 1 month (range: 1-3 months). Of these patients, 54.5% (6/11) met the criteria for a complete response at a median of 2.5 months (range: 1-3 months), and 27.3% (3/11) achieved a trilineage response. No severe ROMI-related adverse events that led to treatment discontinuation or dosage reduction were observed. Notably, 12.5% (1/8) of the responders relapsed at 5 months after stopping ROMI for 2 months.
Conclusion: High-dose ROMI with an initial dosage of 20 μg/kg per week is effective and safe for patients with refractory AA who experienced treatment failure with IST and multiple oral TPO-RAs, exerting a rapid response.
Elevated Dosing of Recombinant Human Thrombopoietin Accelerates Platelet Engraftment in Allogeneic Hematopoietic Stem Cell Transplantation: A Prospective, Dosage-Optimization, Controlled Clinical Study
Authors: Feng Dan , Liu Qingzhen , MA Qiaoling , Jiang Erlie 
Published: December 2024

Objective: The optimal dosage of recombinant human thrombopoietin (rhTPO) for enhancing platelet engraftment following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains undefined. We have crafted a prospective, dose-exploration, controlled clinical study to evaluate the effectiveness and safety of escalating doses rhTPO in facilitating platelet engraftment post-transplantation.
Methods: The study encompassed 57 individuals undergoing allo-HSCT. Commencing day +1 post-transplantation, patients were administered rhTPO therapy. The experimental group, comprising 27 patients, received a continous daily dosage of 22500 U of rhTPO until platelet engraftment was achieved. While the control group, consisting of 30 participants, was given a continuous daily dosage of 15000 U of rhTPO，also until platelet engraftment occurred.
Results: Patients in the experimental group, who received 22,500 U/day rhTPO, achieved a significantly earlier median time to platelet engraftment compared to the control group (12 vs. 13 days, P=0.042, z=4.142) and reached platelet counts of ≥30×109/L more rapidly (13 vs. 16 days, z=3.936, P=0.047). There was a noticeable trend in the experimental group towards earlier attainment of higher platelet thresholds of 50×109/L, 75×109/L, and 100×109/L (15 vs. 20 days, 18 vs. 22 days, 22.5 vs. 28 days). No instances of delayed platelet engraftment were noted in either group. By day 21, the cumulative platelet engraftment rate stood at 96.3% for the experimental group and 83.3% for the control group. By day 60, both groups had achieved a full 100% engraftment rate. Additionally, the experimental group experienced an earlier median time to neutrophil engraftment (11 vs. 12.5 days, z=4.534, P=0.033). During the follow-up period, both groups showed a 100% one-year overall survival rate. The one-year relapse-free survival rates were 96.3% for the experimental group and 93.3% for the control group, indicating no significant disparity. Notably, the cumulative incidence of moderate to severe acute graft-versus-host disease (aGVHD) was significantly lower in the experimental group (14.8% vs. 40.0%, P=0.043). Safety assessments, encompassing evaluations of adverse events such as thrombosis and bleeding, confirmed that the higher dosage of rhTPO was both safe and reliable.
Conclusion: Escalating the dosage of rhTPO injections demonstrates a safe and efficacious approach to enhancing platelet engraftment in patients following allo-HSCT. This strategy not only accelerates the recovery of platelet levels but also contributes to the overall therapeutic regimen without compromising patient safety.
Metabolic Rewiring of AML-Experienced Hematopoietic Stem and Progenitor Cells
Authors: Chen Ding-Wen , Wafula Eric K. , Schrey Julie M. , Fan Jian-Meng , Adams Sarah , Jung Seul K , Taylor Deanne M , Kurre Peter 
Published: December 2024

Relapse is the leading cause of mortality in acute myeloid leukemia (AML). Inflammation is linked to disease prognosis in AML, but its role in remission and relapse are not well understood. Inflammation is also a known regulator of hematopoietic stem and progenitor cells (HSPCs), and recent studies identified an unexpected role in their long term innate immune reprogramming.
We recently reported in a murine model of AML that residual healthy HSPCs contribute to the inflammatory bone marrow (BM) microenvironment. In additional interim pilot studies, we adoptively transferred “AML-experienced” HSPCs (HSPCAML) to naïve recipients, followed 16 weeks later by a lipopolysaccharide (LPS) challenge. Bulk RNA-Seq from these HSPCAML revealed significant transcriptional changes compared to a control cohort. To further test whether HSPCAML develop a long-term innate immune memory of sterile inflammation in the AML BM niche, we turned to a clinically relevant inducible model of KMT2A AML (MLL-AF9). We generated chimera by co-transplanting BM from inducible (i)MLL-AF9 transgenic mice (CD45.1; rtTA+/+ hMLL-AF9-IRES-NGFR+/+) and WT mice (CD45.1/2) into WT recipients (CD45.2). This provides a dynamic fully tractable model where leukemia exposure of healthy HSPC and remission can be dynamically controlled in vivo via doxycycline (DOX).
Recent studies in experimental infection have defined altered immunometabolism as a key component of inflammatory HSPC immune reprogramming. We induced AML for 5 weeks (on DOX), followed by 4 weeks off DOX, and harvested FACS-purified HSPCAML (CD45.1/2+ NGFR- Lin- cKit+ Sca1+) to perform a real-time metabolic function assay (Seahorse). Results showed elevated basal extracellular acidification rate (ECAR) indicative of heightened basal glycolysis in HSPCAML. Consistent with this observation, RNA-Seq analysis of HSPCAML from identically prepared cohorts revealed 3974 differentially expressed genes (DEGs), with gene set enrichment for glycolysis pathways. Models of trained immunity (TI) indicate that memory generation is epigenetically imprinted, and ATAC-Seq analysis of HSPCAML revealed a significant increase in differentially accessible regions in HSPCAML. Through GSEA analysis of differentially accessible promoters and enhancer regions, we observed enrichment for inflammation and metabolic related pathways in HSPCAML. Lastly, by subjecting chimeric animals off DOX to LPS challenge, we found enrichment of tumor necrosis factor (TNF) associated gene sets in HSPCAML via RNA Seq analysis, demonstrating a heighten inflammatory response consistent with trained cells.
Altogether, our data suggest that sterile inflammation in the AML BM niche trains healthy HSPC through a process of immune reprogramming, consistent with a model whereby leukemia may durably alter hematopoietic function.