bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Completely Oral Regimen Including Oral Etoposide As Cytoreductive Chemotherapy Combined with All Trans Retinoic Acid and Oral Arsenic for Induction Therapy in Patients with High-Risk APL：Comparable to Intravenous Cytoreductive Therapy
Authors: Tang Feifei , Duan Wen-Bing , Liu Xiao-Hong , Lu Sheng-Ye , Zhao Xiao-Su , Qin Ya-Zhen , Jia Jin-Song , Wang Jing , Gong Li-Zhong , Jiang Qian , Ting Zhao , Shi Hong-Xia , Chang Ying-Jun , Huang Xiao-Jun , Jiang Hao 
Published: December 2023

Background ：Under the pandemic of coronavirus disease 2019 (COVID-19), in addition to all trans retinoic acid (ATRA) and oral arsenic(RIF), high-risk acute promyelocytic leukemia (APL) patients might lack of the necessity of intravenous cytotoxic chemotherapy infusions timely. Therefore, there is an urgent need for an oral, efficient and safe regimen for high-risk APL.
Methods ：We retrospectively analyzed 66 high-risk APL patients from January 2017 to to July 2022, of which 6 (9.1%, 6/66) patients died in the emergency room without treatment within 24 hours of arriving at our hospital (cerebral hemorrhage in 4 cases and multiple organ failure in 2 cases) and were excluded from the final analysis. A total of 60 patients received anti-leukemia treatment: 22 inpatients receiving oral etoposide (VP16) as cytoreductive chemotherapy from February 2020 to July 2022, and 38 inpatients receiving intravenous cytoreductive chemotherapy as historical control group from January 2017 to December 2019.
Results ：The median age of oral VP16 group and the control group were 35 years (21-65) and 34.5 years (16-62) (P=0.75). The median dose of oral VP16 was 1000mg (range, 400 to 1550). Differentiation syndrome occurred in 4 patients (18.2%) without severe forms in oral VP16 group and 7 patients (18.4%) in intravenous cytoreductive group(P=0.98). Except for one patient died of early death during induction therapy in the control group, all 59 evaluable patients (100%) achieved complete hematological remission(CHR) after induction therapy and complete molecular remission (CMR) after consolidation therapy. The median time to CHR and CMR was 36 days (range, 28-55) vs. 35 days (range, 28-52) (P=0.75) and 3 months (range, 1.1-5.5) vs. 3.3 months (range, 0.9-5.8) (P=0.58) in oral VP16 group and the control group, respectively. The median follow-up time was 56.6 months (range,10.3-76.4). Two (9.1%) patients in oral VP16 group and 3 (7.9%) patients in the control group experienced molecular relapse. The 2-year estimated OS and EFS was 100% vs. 94.7%(P=0.37) and 90.9% vs. 89.5%(P=0.88), respectively.
Conclusions ：A completely oral, efficient and safe induction regimen including oral VP16 as cytoreductive chemotherapy combined with ATRA and RIF is more convenient to administer for patients with high-risk APL.
A Model of Cumulative Risk of Disease Progression Among Patients with Indolent Systemic Mastocytosis
Authors: Mukherjee Sudipto , Cattie Douglas J , Shaheen Daniel , Green Teresa , Powell Dakota 
Published: December 2023

Introduction
Indolent systemic mastocytosis (ISM), a clonal mast cell disease driven by the KIT D816V mutation in ~95% of cases, can cause lifelong debilitating cutaneous, gastrointestinal, and neurocognitive symptoms with some cases progressing to advanced systemic mastocytosis (AdvSM). While several studies have quantified variable rates of disease progression from ISM to AdvSM based on the absolute frequency of these events, these studies were limited by short median follow-up time considering the long clinical course of this condition sometimes in decades, thereby leading to underestimation of the cumulate rates of progression from ISM to AdvSM. We conducted a Markov analysis using population level data in the US to estimate the lifetime risk of progression for ISM patients.
Methods
We modeled the total course of SM as a discrete-time Markov chain, enabling us to estimate cumulative rates of disease progression based on fixed-interval empirical observations from the literature and, where there is no literature available, expert opinion. The Markov model assumes that patients enter the model as at-risk ISM, not-at-risk ISM, or de novo AdvSM, based on the assumed relative incidence of each subtype. Not-at-risk patients will then move to death after a period of time, with an annualized risk of death from disease. At-risk patients with ISM will remain in that state, progress to AdvSM (which may be tyrosine kinase inhibitor treated or not) or die. Finally, those who progress to AdvSM will either remain in their state or die. See Figure 1 for details, where each model parameter is reflected as a line between states and modeled based on an annualized rate of state transition. See Figure 2 for a full list of model parameters. Two hundred trials were performed, in which the model parameters were statistically sampled from a range of likely values, based on a triangular distribution between minimum, mode, and maximum. For each trial, the disease course for 5000 patients with SM was then simulated from initial SM diagnosis until death.
Results
Based on the rates of disease incidence, progression, treatment, and survival documented within various studies, we estimate the cumulative risk (± standard deviation) of disease progression from ISM to AdvSM to be 18.0% ± 3.1%, based on a probabilistic sampling of the underlying assumptions.
Conclusions
This study suggests that the cumulative rate of disease progression among patients with ISM may be higher than previously recognized. In our earlier work, we showed a higher rate of disease progression in ISM patients with high symptom burden (Mukherjee S, et al. ASH 2022). These data highlight the importance of close monitoring for signs of progression and warrant further research to identify subsets of ISM patients who may have a higher underlying risk of progression.
Ceftazidime-Avibactam in the Treatment of Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacteria in Hematological Patients: Experience in a Single Center
Authors: Zhen Sisi , Lin Qingsong , Zhai Weihua , Jiang Erlie , Feng Sizhou 
Published: December 2023

Background: Experience with ceftazidime-avibactam (CAZ-AVI) for bacteremia caused by carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) in hematological patients is limited.
Methods: We performed a single-center, retrospective, observational study including patients receiving CAZ-AVI for bacteremia due to CRE or CRPA between 2018 and 2022. The primary outcome was 30-day survival. To identify predictors of survival, multivariable analysis was performed.
Results: 56 patients were included and 57 (41 CRE and 16 CRPA) strains were isolated. 35 strains produced carbapenemase (25 MBL, 10 serine-beta-lactamase). 48 (85.7%) patients received combination therapy. All patients with MBL-CRE bacteremia (n=24) received combination therapy with aztreonam. The susceptibility rates to CAZ-AVI were only 25.0% (10/40) in CRE and 80.0% (8/10) in CRPA. The 30-day survival rates were 85.0% (34/40) and 81.3% (13/16) in CRE and CRPA group, respectively. In patients with MBL-CRE bacteremia, 30-day survival was high to 91.7% (22/24) due to combination with aztreonam. Ceftazidime did not influence the activity of aztreonam-avibactam against MBL-CRE in-vitro. Multivariable cox analysis revealed neutropenia &gt; 14 days (P=0.002, HR: 0.029, 95%CI: 0.003~0.260) and higher Pitt bacteremia score (P=0.005, HR: 0.482, 95%CI: 0.291~0.798) were risk factors of 30-day survival.
Conclusions: CAZ-AVI is highly effective for bacteremia due to CRPA and serine-beta-lactamase CRE. Avibactam in combination with aztreonam is highly active for bacteremia due to aztreonam-resistant MBL producers.
Development of an Evidence-Based Clinical Tool for Childhood Cancer Survivorship Care in Tanzania
Authors: Spiegl Rosie , Ajuaye Gaudence , Noyd David , Chapman Hutton , Kashaigili Heronima J , Schroeder Kristin 
Published: December 2023

CONCLUSIONS
Three in every four childhood cancer survivors experience late effects from treatment. As childhood cancer outcomes improve globally, it is important for providers to screen for these potential late effects to reduce morbidity. The present study aims to increase survivorship care capacity in low-resource settings by developing a digital clinical tool that integrates patient diagnosis and treatment exposure with evidenced-based surveillance recommendations to provide comprehensive childhood cancer follow-up guidelines.
Surveys with key stakeholders at each of the four childhood cancer treatment centers in Tanzania were completed to determine the current capacity to provide off-therapy surveillance. This informed the selection of late-effect screening tests by the International Late Effects of Childhood Cancer Guideline Harmonization Group's 2023 guidelines that were both evidenced-based and feasible in our setting. Qualtrics software was utilized to create a provider-facing digital survey to enter patient diagnosis, treatment exposures, and cumulative dosing.
The clinical tool was successfully created and implemented in our setting. In addition to entering patient demographic data, the survey burden for providers is anywhere from 5 to 11 questions in length. Using entered treatment exposures, the clinical tool uses a programmed algorithm to determine the late effect risk category, cardiovascular risk score, and personalized screening recommendations. Recommendations include both screening tests and frequency, to improve provider compliance with current best practice guidelines.
This tool can be adapted for other settings based on current capacity and provides personalized surveillance recommendations. This can help standardize treatment guidelines by increasing provider capacity and knowledge, with the potential to improve adherence to follow-up guidelines among childhood cancer survivors in LMICs, like Tanzania.
Rps19 and Rpl5 Play Distinct Roles in hematopoietic Stem Cell maintenance and Erythroid Differentiation
Authors: Tang Yuefeng , Ling Te , Khan Mushran , Rao Riaz , Schulz Vincent P , Papoin Julien , Narla Anupama , Lipton Jeffrey Michael , Palis James , Steiner Laurie A. , Gallagher Patrick G , Narla Mohandas , Crispino John D. , Blanc Lionel 
Published: December 2023

Mutations in ribosomal proteins (RPs) lead to ribosomopathies. Mechanistic basis underlying the failure of erythropoiesis due to mutations in various RPs is yet to be fully defined. Lack of relevant murine models of ribosomapathies has hindered significant progress. To fill this gap, we generated Rps19 and Rpl5 floxed mice using CRISPR/Cas9 technologies and characterized their hematologic phenotype following crossing them to a Vav-iCremice. Vav-iCre;Rps19 fl/+mice are born at expected Mendelian rates with severe macrocytic anemia and reticulocytopenia. These mice die by post-natal day 10 (P10), due to bone marrow failure and absence of splenic stress erythropoiesis. Analysis of fetal erythropoiesis revealed a 40% reduction in the total number of erythroid cells in Vav-iCre;Rps19 fl/+, however erythroblasts at all stages of terminal erythroid differentiation were found. Intriguingly, studies of hematopoietic stem and progenitor cell s demonstrated a progressive exhaustion of the stem cell compartment.
scRNAseq studies of Vav-iCre;Rps19 fl/+ fetal livers demonstrated increased expression of RUNX1, a transcription factor implicated in the regulation of ribosome biogenesis. Accordingly, we observed that hematopoietic progenitors of Vav-iCre,Rps19 fl/+had enhanced global protein synthesis along with increased RUNX1 protein, despite ribosomal protein haploinsufficiency demonstrated by polysome profiling.
In marked contrast, Vav-iCre;Rpl5 fl/+ mice presented with a more severe phenotype and died perinatally from anemia. Further analysis revealed a failure of erythropoiesis at erythroid progenitor stages in Vav-iCre;Rpl5 fl/+. In striking contrast with the Rps19 model, Vav-iCre;Rpl5 fl/+ mice had an expansion of the hematopoietic stem and progenitor cell compartment that also had an increased protein translation rate . This increased translation occurred in the context of normal expression levels of RUNX1. Interestingly Vav-iCre;Rpl5 fl/+ micehad reduced mTORC1 activity and a dramatic reduction in the expression of other ribosomal proteins. Consistent with previous studies about the pivotal role of mTORC1 in erythropoiesis Vav-iCre,Raptor fl/fl(mTORC1 conditional knockout) had reduced expressions of RPs in fetal liver.
In summary, we report different requirements for Rps19 and Rpl5 during fetal hematopoiesis in regulating erythroid progenitor biology. While Rps19 plays an essential role at the HSC level to maintain the generation of erythroid progenitors, Rpl5 is critical once progenitors are committed towards an erythroid fate. Along with the findings that translation is increased in RP haploinsufficient models, our study unravels potential compensatory mechanisms during fetal hematopoiesis.
Hospital Associated Disability Among Older Adults with Plasma Cell Disorders Receiving Autologous Stem Cell Transplant
Authors: Kidwell Kyle , Zhu Rui , Bal Susan , Godby Kelly , Ravi Gayathri , Costa Luciano , Shrestha Sadeep , Williams Grant , Bhatia Smita , Giri Smith 
Published: December 2023

Background: An increasing number of older adults with Plasma Cell Disorders (PCDs) are receiving autologous stem cell transplant (ASCT) in the US. Hospital associated disability (HAD) is a loss in independence in one or more activities of daily living associated with acute care hospitalization and is a common complication among older adults. The prevalence and prognostic significance of HAD among older adults with PCDs undergoing ASCT is unknown.
Methods: This retrospective cohort study used consecutive adults receiving ASCT at a large U.S. comprehensive medical center between 1/2013 and 5/2023. Trained nursing staff assessed Katz Activities of Daily Living (ADL) at admission and every 3 days thereafter under our Virtual Acute Care for Elders program. The primary outcome was development of HAD defined as ≥1 point decline on the Katz ADL scale from hospital admission to discharge. We also examined the association between development of HAD and various predictors including age, Karnofsky Performance Status (KPS), and Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) using modified Poisson regression models with robust variance estimators. Using similar models, we studied the impact of HAD on unplanned 30-day readmission rates.
Results: Of 870 patients undergoing ASCT during the study period, 778 had at least two Katz ADL assessments and were included. The study population was comprised of 56% Caucasian/white ethnicity and 56% male with a median age of 62y (IQR 55-68y). In the overall population, 112 (14.4%) developed HAD. The incidence of HAD was much higher among adults ≥65y compared to their younger counterparts (22% vs. 9%; p=&lt;0.01). In multivariate analysis, age ≥65y (RR 2.22; 95% CI 1.56-3.15; p=&lt;0.001) and baseline KPS &lt;=70 (RR 1.83; 95% CI 1.15-2.92; p=0.011) was associated with increased risk of developing HAD; HCT-CI scores did not have a significant association with HAD. Those with HAD had a two-fold higher risk of 30-day readmission as compared to those without HAD (RR 2.18; 95% CI 1.20-3.66; p=0.003).
Conclusions: Nearly 1 in 4 adults ≥65y developed HAD while undergoing ASCT, which was associated with a two-fold increased risk of 30-day readmission. Interventions to prevent HAD and its downstream consequences are critically needed.
MAIT Cell Proliferation Is a Potential Early Diagnosis Marker for Blood Stream Infection in AML Patients
Authors: Feng Sizhou , Fan Yuping , Zhang Sudong , Feng Xiaomeng , Xu Yuanfu , Jiang Erlie 
Published: December 2023

Objectives
To explore the role and dynamics of MAIT (Mucosal-associated invariant T) cells in blood stream infection of AML (Acute myeloid leukemia) patients.
Methods
Healthy adults and hospitalized adult AML patients that with blood stream infection, non-infection, or in completely remission (CR) were prospectively enrolled. Characteristics of MAIT cells in peripheral blood of enrolled subjects were analyzed by flow cytometry.
Results
Both gram negative and gram positive bacteria could induce sepsis in AML patients. MAIT cells significantly increased in AML patients with blood stream infection comparing with non-infected AML patients, healthy subjects and AML patients in completely remission. Increased MAIT cells were mainly consists of CD8+ T cells and were activated. There is no significant difference in the recruitment and death of MAIT cells, while their proliferation is significantly increased. The proliferation of MAIT cells occurs before traditional infection indicators such as CRP, PCT, endotoxin in plasma and fever. MAIT cells in neutropenic blood stream infected mice were increased as we observed in AML patients.
Conclusions
MAIT cells increased without bacterial specificity, and were activated and proliferated in AML patients with blood stream infection that caused by various bacteria. They may enhance host defense and play a vital role in fighting against pathogenic microbial infections. Proliferation of MAIT cells can be applied as a monitoring indicator for blood stream infection in AML patients, which helps to reduce the mortality rate of them.
The Optimal Busulfan Dose of Conditioning Regimens for Allogeneic Hematopoietic Cell Transplantation in Younger Patients with Acute Myeloid Leukemia
Authors: Choi Yunsuk , Choi Eun-Ji , Park Han-Seung , Lee Jung-Hee , Lee Kyoo-Hyung , Lee Young-Shin , Kang Young-A , Jeon Mijin , Woo Ji Min , Kang Hyeran , Lee Je-Hwan 
Published: December 2023

Background: In allogeneic hematopoietic cell transplantation (HCT) for younger patients with acute myeloid leukemia (AML), myeloablative conditioning (MAC) regimens have been considered as standard conditioning. MAC can reduce the risk of relapse, but increase non-relapse mortality, including organ toxicity and severe graft versus host disease. Therefore, the optimal busulfan dose in conditioning regimens has not been established in younger patients with AML. Thus, we aimed to investigate post-HCT outcomes according to the busulfan dose of conditioning regimens in younger patients with AML.
Methods: We retrospectively analyzed long-term outcomes according to the busulfan dose (2 days vs. 3 days vs. 4 days) in 686 adult patients (age &lt;55 years) with AML who had undergone HCT between 2000 and 2020 at the Asan Medical Center, Seoul, Korea. The clinical data was collected from the Asan Medical Center HCT registry. Patients with AML who had undergone a second or third HCT were excluded from this study.
Results: The median age was 41 (range 15-54). The 5-year overall survival (OS) and event-free survival (EFS) rate was 52.2% and 46.4%, respectively. The 3 days of busulfan (Bu3) (n=88) showed significantly higher OS than 4 days of busulfan (Bu4) (n=229) and 2 days of busulfan (Bu2) (n=369) (2-year OS; 76.1% vs. 65.1% and 56.3%, respectively; P&lt;0.001). The EFS rate of Bu3 and Bu4 was significantly higher than that of Bu2 (2-year EFS; 60.2% and 59.8% vs. 46.9%, respectively; P&lt;0.001). Among the three groups, there was no significant difference in GRFS (P=0.952). The cumulative incidence of relapse was significantly lower in Bu4 (26.2% at 2 years) than in Bu2 (40.4%) and Bu3 (36.4%) (P&lt;0.001). However, the NRM was significantly higher in Bu4 (13.9% at 2 years) and Bu2 (12.7%) than in Bu3 (3.4%) (P=0.005). In HCT at complete remission (CR) status, Bu3 showed significantly better OS than Bu4 and Bu2 (P=0.039), whereas there was no significant difference in EFS according to the busulfan dose (P=0.121). In patients with refractory disease, however, the higher dose of busulfan (Bu3 or Bu4) did not show survival advantages in terms of OS (P=0.153) and EFS (P=0.829) over Bu2. Regarding donor types, Bu3 showed significantly better OS than Bu2 in HCT from matched sibling donors (MSD) (P=0.030) and haploidentical family donors (HFD) (P&lt;0.001). However, in HCT from unrelated donors (URD), the Bu2 group showed the best GRFS, and OS in Bu2 or Bu3 was significantly longer than in Bu4 (P=0.028).
Conclusion: For younger patients with AML, Bu3 would be the optimal conditioning intensity in HCT from MSD or HFD at CR status. In URD, Bu2 or Bu3 would be appropriate. In refractory disease, increasing busulfan dose intensity could not improve post-HCT outcomes.
Genetic Variants Associated with High Plasma Levels of Factor VIII and Von Willebrand Factor in a Family with Thrombotic Episodes
Authors: Spena Silvia , Cairo Andrea , Gianniello Francesca , Pappalardo Emanuela , Mortarino Mimosa , Garagiola Isabella , Martinelli Ida , Peyvandi Flora 
Published: December 2023

Background: High levels of factor VIII (FVIII) and von Willebrand factor (vWF) have been indicated as independent risk factors for venous thromboembolism. However, the genetic factors responsible for their increase remain still poorly known. In a woman referred to our Thrombosis unit following a venous thrombotic event, very high levels of FVIII and vWF were found at the acute episode and in subsequent measurements. High levels of FVIII and vWF were also detected in other family members, suggesting a possible genetic cause (Figure 1).
Aim: To identify variants/genes associated with high levels of FVIII and vWF.
Methods: In a large Italian family with high levels of FVIII/vWF and thrombotic episodes, whole-exome sequencing was performed in 12 family members (SureSelect-Agilent). Data were analyzed according to the guidelines of the Broad Institute (https://software.broadinstitute.org/gatk/best-practices/). Variants were annotated (Annovar) and filtered (KGGseq) according to an autosomal dominant inheritance model of high levels of FVIII or vWF. RNA levels were evaluated in PBMCs by qPCR (Thermo Fisher).
Results: 20 variants, spread over a 8300-Kb region on chromosome 5, were identified in 12 genes, including the low frequency rs13158382 located upstream of the MIR143/145 genes. Since variants in the promoter of MIR143/145 have been reported to affect their expression and reduced levels of miR-145 have been associated with high vWF, the potential correlation between rs13158382 and vWF levels was evaluated. Lower levels of both miRNAs and higher level of vWF mRNA were measured in family members carrying the variant (n=3) compared to family members without the variant (n=3). Analysis of genetic and expression data from of a larger cohort of individuals from the 1000 Genomes and GEUVADIS project confirmed a statistically significant reduction (p=0.023) of miR-143 in heterozygous subjects (n=35) compared to homozygous wild-type individuals (n=386). Since low levels of pri-miRNA-143/145 were measured in heterozygous family members and structural changes of pre-miR-143 with rs13158382 was predicted by miRVaS tool, the reduction of mature miRNAs might result from a lowered synthesis of pri-miRNAs and/or from an aberrant processing of pre-miRNA.
Conclusion: This family-based study revealed a new genetic variant potentially involved in vWF increase by reducing the expression of miR-143/145.