bluuebunny/crossref_metadata_2025_split huggingface dataset:
Racial Differences in the Association of Glucagon-like Peptide 1 Agonist Use and the Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma in US Veterans with Diabetes Mellitus
Authors: Grandhi Nikhil , Liu Lawrence , Wang Mei , Thomas Theodore , Kumar Akhil , Gao Feng , Sanfilippo Kristen M. , Colditz Graham , Chang Su-Hsin 
Published: December 2023

Background: Glucagon-like peptide 1 (GLP-1) agonists are antidiabetic medications that exert cardiac and renal benefits in addition to their well-established antihyperglycemic effects. A prior analysis has shown that GLP-1 agonist use is associated with a 65% reduction in the risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) in US Veterans with diabetes mellitus (DM). However, it is unknown whether there are racial differences to this effect of GLP-1 agonists. We aimed to assess the racial differences in the association between GLP-1 agonist use and the progression risk in diabetic patients with MGUS.
Methods: Patients diagnosed with MGUS in the Veterans Health Administration (VHA) database from 10/1/99-12/31/21 were identified using ICD codes. A natural language processing algorithm was used to confirm MGUS diagnosis and progression to smoldering MM or MM. Patients diagnosed with MGUS before DM and those who experienced progression within 1 year of MGUS diagnosis or within 2 years of DM diagnosis were excluded. For each race, we performed 1:2 matching for patients with and without GLP-1 agonist use based on follow-up time. The outcome was progression to smoldering MM or MM. Cumulative incidence functions stratified by GLP-1 agonist use (ever vs. never use) were plotted and a Gray's test was performed to detect the difference between the functions. The association between time-varying GLP-1 agonist use and MGUS progression was estimated using a multivariable Fine-Gray subdistribution hazard model with death as a competing event.
Results: Our NLP algorithm confirmed 20,832 patients with DM and MGUS. After applying our inclusion and exclusion criteria, we had 9,294 white patients and 4,981 black patients, of which 909 and 403, respectively, were GLP-1 agonist users. After matching, our analytic cohort included 2,718 white patients (33.3% with GLP-1 agonist use) and 1,191 black patients (33.3% with GLP-1 agonist use). GLP-1 agonist use was associated with a dramatically significant reduction in progression rate in white patients (aHR 0.25; 95% CI 0.09-0.68), while the association was not shown in black patients (aHR 1.01; 95% CI 0.36-2.90).
Conclusion: For patients with MGUS and DM, GLP-1 agonist use is associated with a 75% reduction in progression risk in white patients and no significant reduction in black patients. This highlights a racial disparity in the potential role of GLP-1 agonist for chemoprevention in the management of MGUS.
A Cytochrome c Variant Enhances Megakaryocytic Maturation
Authors: Shafaei Pishabad Zahra , Wan Yuen On Anna , Ledgerwood Elizabeth 
Published: December 2023

Mutations in genes which play a role in the processes of megakaryopoiesis and platelet production cause thrombocytopenia. Five pathogenic variants in the gene encoding cytochrome c ( CYCS) associated with mild autosomal dominant thrombocytopenia have been reported. The role of cytochrome c in megakaryopoiesis and platelet formation is unknown, and it is unclear how mutations in cytochrome c cause thrombocytopenia. The goal of this project is to understand how CYCS mutations cause thrombocytopenia.
We are using the human leukemic K562 cell line as a model system to study the impact of CYCS mutations on megakaryocyte differentiation and mitochondrial function. One of the CYCS pathogenic variants (c.145T&gt;C; p.Tyr49His) was introduced into K562 cells using the CRISPR-Cas9 base-editing method. K562 cells have three copies of CYCS-containing chromosome 7 and we isolated CYCSWT/WT/WT, CYCSWT/WT/Y49H, CYCSWT/Y49H/Y49H, CYCSY49H/Y49H/Y49H clonal lines, confirmed by sequencing and mass spectrometry. K562 cells undergo megakaryocyte differentiation in response to PMA. We monitored the expression of megakaryocyte markers CD61 and CD41a by flow cytometry in response to PMA in all clonal lines. The K562- CYCSY49H/Y49H/Y49H line showed faster maturation compared to all other clonal lines and the parental K562 cells. We assessed mitochondrial function using the Seahorse XFe96 Analyzer. Our results show that the mutation does not impact mitochondrial respiratory function. Finally, we have introduced the Y49H mutation into WTC11 iPSCs. Investigations of the impact of the Y49H variant on apoptosis showed that there is no significant differences in apoptosis between WT and the clonal line carrying the Y49H variant. Our results suggest that the pathogenic c.145T&gt;C; p.Tyr49His CYCS variant enhances megakaryocyte maturation.
Comparison of the Efficacy between 81 Mg Bid of Aspirin and 162 Mg Od of Aspirin in Splenectomized Thalassemic Patients with Aspirin Resistance
Authors: Kaokunakorn Thanapon , Ruchutrakool Theera , Suwanawiboon Bundarika , Hantaweepant Chattree , Rungjirajittranon Tarinee , Nakkinkun Yupa , Binhama Tasneem , Chinthammitr Yingyong 
Published: December 2023

Backgroud: Currently, aspirin is widely used in splenectomized thalassemic patients. Despite taking 81 mg of aspirin daily, some patients develop venous thromboembolic complications, and these patients are referred to as “aspirin-resistance”. Then, increasing dose of aspirin to 162 mg/day is one of treatment options. It is not known if which regimen of aspirin at dose of 162 mg/day (1 tab po bid VS 2 tabs po once daily) is more effective in these patients.
Methods: This is a prospective randomized cross-over study in splenectomized thalassemic patients between 2022 and 2023 at Siriraj Hospital. All splenectomized thalassemic patients aged from 18 to 60 years who have been taking aspirin of 81 mg/day were enrolled and evaluated for aspirin resistance (ASA-resist) by platelet aggregation test using arachidonic acid as agonist (PAT-AA). Patients with 81-mg aspirin resistance were randomly assigned to the following 7-day regimens in a crossover design: aspirin 81 mg twice daily (ASA1x2) or aspirin 162 mg once daily (ASA2x1), and their PAT-AA was assessed after each regimen.
Results: A total of 64 patients (41 women) with a median age of 32.5 years were mostly Hb E/beta-thalassemia (86%) whereas 53% were transfusion-dependent thalassemia (TDT). ASA-resist was found in 24 patients (37.5%). The 'ASA1x2' showed a higher prevalence of ASA-resist than 'ASA2x1' but no statistical significance (52.4% vs.35%; OR 2.0; 95%CI, 0.58-7.17; p=0.265). For 'ASA1x2' regimen, serum ferritin level of ≥1200 ng/mL was significantly associated with ASA-resist (OR 10.7; 95%CI, 1.4-82.0; p=0.030). For 'ASA2x1' regimen, ASA-resist was significantly associated with TDT (p=0.015) and serum ferritin level of ≥1200 ng/mL (OR 20.0; 95%CI, 1.7-238.6; p=0.017).
Conclusions: The “aspirin 81 mg twice daily” regimen showed a higher prevalence of aspirin resistance than “aspirin 162 mg once daily” regimen in splenectomized thalassemic patients with aspirin resistance, and an elevated serum ferritin level was significantly associated with aspirin resistance in both regimens.
Targeting B-Cell Malignancies with Anti-ROR1 CAR T-Cell Therapy
Authors: Weng Jinsheng , Le Cao Cuong , Pan Yong , Perutelli Francesca , Cheng Xiaoyun , Cao Jingjing , Agbedia Owhofasa , Kuang Shao-Qing , Liu Jingwei , Chu Fuliang , Patchva Sridevi , Saini Neeraj Y. , Neelapu Sattva S. 
Published: December 2023

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has been shown to induce high
complete response rates in the majority of B-cell lymphoma patients. However, over 50% of
patients relapse within one year. A major cause of failure appears to be due to loss of CD19
expression on the tumor cell surface. This indicates that novel therapeutic strategies are still
needed in clinic. Receptor tyrosine kinase like orphan receptor 1(ROR1) is an oncofetal receptor
for Wnt5α that is expressed in multiple embryotic tissues but absent in virtually all adult tissues.
However, ROR1 is expressed at high levels in chronic lymphocytic leukemia (CLL), mantle cell
lymphoma (MCL), diffuse Large B-Cell Lymphoma (DLBCL), and several solid tumors. The high
expression level of ROR1 in tumor cells is associated with adverse clinical prognosis. In
addition, a small percentage of cancer cells with characteristics of undifferentiated leukemia
cells or cancer stem cells were found to overexpress ROR1. Using hybridoma technology, we
generated an anti-ROR1 monoclonal antibody that specifically recognized ROR1 protein. The
antibody bound to ROR1-expressing MCL cell lines but not to normal donor T cells, B cells, or
monocytes, indicating the specificity of the antibody. Lentiviral transduction of a CAR molecule
derived from the anti-ROR1 antibody into primary human T cells redirected their specificity
against B-cell lymphoma cell lines. We found the anti-ROR1 CAR T cells specifically lysed B-
cell lymphoma tumor cells at high efficiency but not normal B cells. At an effector: target ratio of
1:1, the anti-ROR1 CAR T cells lysed over 95% of B-cell lymphoma tumor cells during 3-days of
coculture. To determine the optimal CAR construct, we evaluated various hinge
transmembrane, and costimulatory domains in the CAR molecule. We found that incorporation
of the CD28 hinge and transmembrane domain in the CAR construct dramatically enhanced the
in vitro lysis efficiency of anti-ROR1 CAR-T cells. In conclusion, we developed a novel and
potent anti-ROR1 CAR T-cell therapy product that may be used for treatment of various B-cell
malignancies and ROR1-expressing solid tumors.
Treatment with GT1708F, an Oral Smoothened Inhibitor, in Patients with Myeloid Malignancies: A Phase I Study
Authors: Jin Jie , Qi Junyuan , Zhao Weihua , Wang Huafeng , Song Lin , Lin Yu , Tong Youzhi , Ni Xiang , Dong Min , He Xiaohan 
Published: December 2023

Introduction: Activation of the Hedgehog signaling pathway has been correlated with the development and disease progression of myeloid leukemia. This Phase I clinical trial aimed to evaluate the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety and tolerability of GT1708F in patients with myeloid malignancies.
Methods: This Phase I study enrolled patients with myeloid malignancies who were refractory, resistant or intolerant to previous treatments at three centers in China. Eligible patients were enrolled at each dose cohort to evaluate DLTs during the first continuous 28-day dosing period. The dose levels were determined employing the escalation with overdose control (EWOC) method, guided by an adaptive Bayesian logical analysis model (ABLRM). The decision to escalate the dosage to the subsequent cohort was informed by the recommendations of the safety monitoring committee after each round. Pharmacokinetic blood samples were collected in the first cycle of the treatment.
Results: As of May 25, 2023, 18 patients have been enrolled in 7 dose cohorts: 15 with acute myeloid leukemia (AML) and 3 with myelodysplastic syndromes (MDS). Patients received GT1708F once daily orally at 20 mg QD (n=1), 40 mg QD (n=1), 80 mg QD (n=4), 120 mg QD (n=3), 180 mg QD (n=3), 240 mg QD (n=3), 320 mg QD (n=3). No DLT was reported across these dose cohorts and the MTD was not reached. 17(93.3%) patients experienced at least one treatment-emergent adverse event (TEAE). 13 (72.2%) patients experienced at least one treatment related AE (TRAE). 11(61%) patients experienced at least one TEAE of Grade 3 or higher in severity, 4 (22.2%) of whom had TRAE(s) including lung infection, anemia, pharyngitis, and creatine kinase increased. Eight patients experienced 13 serious adverse events (SAE), two of which were assessed by the investigator as possibly related to GT1708F, both being lung infections. 15 patients completed at least one efficacy evaluation. No patient achieved complete or partial remission while 5 AML patients achieved stable disease with one patient lasting for 6 cycles and 2 patients lasting for 3 cycles. GT1708F is rapidly absorbed in the body with a peak time of 0.5-1hr after a single oral dose. As the dose increased from 20mg QD to 320 QD, the maximum concentration of the drug in the body increased linearly, showing quasi-linear pharmacokinetic characteristics.
Conclusions: Our study indicated good safety and tolerability of GT1708F in patients with myeloid malignancies. In addition, a potential efficacy signal of GT1708F for these patients was observed, providing a rationale for further exploration in combination with other therapeutic modalities.
Establishing Standard of Care in Predicting Serious Complications for Patients Planned to Undergo Allogenic Hematopeotic Stem Cell Transplantation
Authors: Reschke Madlen , Gross Jonathan P. , Hegner Janina , Seiler Jonas , Sürücü Gülüstan , Penack Olaf , Weschke Daniel , Higgins David , Oevermann Lena 
Published: December 2023

Background: There is no reliable way to predict the individual risk of suffering from relevant complications during the course of Hematopoetic Stem Cell Transplantation (HSCT), because the huge amount of multidimensional parameters influencing clinical outcome is impossible for a human to compute accurately.
Reliable prediction of complications: supports patients and physicians to make informed decisions, simplifies choosing best matched HSCT donors to avoid complications and enables superior, individualized planning of conditioning and prophylaxis. Up to now prediction is not based on evidence but rather experience, which differs amongst physicians.
MatchGraft.AI is an artificial intelligence based machine learning tool that predicts the individual risk of acute Graft versus Host Disease, recurrence of basic disease and overall risk of death, using only pre transplant data (Table 1). The model was trained and tested on retrospective data of an international, multicenter cohort.
Aim: Explore standard of care of choosing an HSCT donor and compare choice with real world data and MatchGraft.AI.
Method: We developed an electronic questionnaire with 200 short patient histories including all parameters Matchgraft.AI is using. Pediatric and adult, benign and malignant cases with different donor types (matched unrelated, matched sibling, haploidentical family donor) are represented. This real world data is derived from a retrospective cohort of pediatric and adult patients of Charité Universitätsmedizin. 50 international experts in HSCT will: 1. choose a donor 2. predict individual risk of acute Graft versus Host Disease, risk of relapse and overall death for 50 individual patients.
Cases are randomly allotted according to the physician's specialty (adult/pediatric treater, both). Questionnaires are anonymized. Answers are not traceable to the expert. Personal results compared with real world outcome and MatchGraft.AI can be provided to participants, if they wish.
Results: We compare sensitivity and specificity of MatchGraft.AI to the standard of care, which is expert opinion and real world outcome.
We examine: 1. whether the choosing of a donor is dependent on the individual physician or consistent throughout different HSCT experts. 2. how precise HSCT experts can predict the occurrence of severe complications for patients planned to undergo HSCT. 3. how well MatchGraft.AI can predict the occurrence of severe complications for patients planned to undergo HSCT in comparison.
Conclusion: This study will provide important data about the standard of care in HSCT donor choosing and for the planned prospective study evaluating MatchGraft.AI.
A Phase II Study of the Efficacy and Safety of the Srmt (Sintilimab, Rituximab, Methotrexate, and Temozolomide) Regimen in Newly Diagnosed Primary Central Nervous System Lymphoma
Authors: Zeng Zhiyong , Yang Apeng , Lin Yuanxiang , Chen Junmin 
Published: December 2023

BACKGROUND
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive subtype of lymphoma with poor prognosis. One potential therapeutic approach could involve targeting the programmed death-1 (PD-1) immune checkpoint pathway, as these tumors often express PD-L1. However, the efficacy of this strategy using sintilimab in combination with immunochemotherapy as frontline therapy for patients with newly diagnosed PCNSL remains uncertain.
METHODS
In this phase II trial with a safety run-in, we enrolled treatment-naive PCNSL patients between the ages of 18 and 70, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. All patients were given sintilimab combined with rituximab, high-dose methotrexate and temozolomide (SRMT) regimen (six cycles every 21 days): sintilimab (200 mg, i.v., Day-0), rituximab (375 mg/m 2, i.v., Day-0), methotrexate (3.0 g/m 2, i.v., Day-1 or 1.0 g/m 2 for patients aged ≥65 years, and temozolamide (150 mg/m 2/d, p.o., Days 1-5). The primary outcome was overall response rate (ORR), with secondary outcomes including duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and potential biomarkers.
RESULTS
Between 3 April 2020 and 23 August 2022, a total of 28 patients were enrolled. No dose-limiting toxicities were observed during the safety run-in period. Among 27 evaluable patients, the primary outcome was met with an impressive ORR of 96.3% (95% CI: 81-99.9%). In detail, 25 patients (92.6%) achieved a complete response and one (3.7%) exhibited a partial response. As of 7 April 2023, the median follow-up was 20.8 months. The Medians for DOR, PFS, and OS were not reached. Remarkably, 2-year PFS and 2-year OS were 65.4% (48.1-88.8%) and 88.5% (74.1-100%), respectively. The most common grade 3-4 treatment-related toxicities were increased levels of alanine aminotransferase (18.5%) and aspartate aminotransferase (14.8%). Additionally, the receiver operating characteristic analysis revealed that the baseline IL10/IL6 ratio in cerebrospinal fluid exhibited promising performance in predicting PFS, achieving an area under curve of 0.91 at 2 years.
CONCLUSIONS
The SRMT regimen as frontline treatment for PCNSL is highly efficacious and well tolerated. (Chinese Clinical Trial Registry number: ChiCTR1900027433).
Genetic Variations in Multiple Myeloma with Extramedullary Disease
Authors: Kim Dajung , Jeong Seri , Song Kevin , Jo Jae-Cheol , Lee JiHyun , Jeong Jee-Yeong , Lee Ho Sup 
Published: December 2023

Background
Extramedullary disease (EM) is aggressive form of MM in which clonal plasma cells exist outside the BM. EM may be found in up to 30% of MM patients and is associated with an adverse prognosis. However, the genetic pathogenesis of EM have not yet been precisely elucidated.
Patients and Methods
From 2005 to 2020, among patients diagnosed with MM with EM (EMM) confirmed by image study, a total of 12 patients for whom tumor tissue or BM specimens could be obtained were enrolled. Both bone-related EM (EM-B) and soft-tissue-related EM (EM-S) were defined as EM.
We performed whole-exome sequencing (WES) and NanoString nCounter assay to investigate the genetic alterations in EMM patients. A total of 9 formalin-fixed paraffin-embeded (FFPE) tumor tissues and 6 BM specimen from 12 EMM patients were sequenced. Paired BM and FFPE were available for analysis in 3 patients. To clarify the genetic difference between MM and EMM, 8 BM samples of 5 MM patients were analyzed as controls. In addition, 4 buccal swabs from one EMM patient were sequenced for germline control.
Results
The median age was 57 years (range 50-65). Two patients had EM-S involving meninges and Lt. psoas muscle showed adverse prognosis compared to patients with EM-B, with survivals of 1 month and 11 months after diagnosis of EM. One of them had a gain (1q21) chromosomal aberration classified as high risk cytogenetics.
WES was performed on 12 EMM cases (BM=6, FFPE=8). In WES, MAP2K3, AHNAK2, CDC27, MUC4, and NBPF1 were the five genes with the most variation in both BM and FFPE (Fig. 1). In particular, CDC27 gene was altered only in FFPE (6 out of 8 samples).
We performed RNA analysis by NanoString in 9 EMM patients (BM=6, FFPE=6) and 5 MM patients. Compared with MM, ARG1, IRF4, and CEP55 were up-regulated and CDKN1C, IL15, and CD3E were down-regulated in the BM of EMM. Comparison of BM specimens from MM and plasmacytoma from EMM showed IRF4 up-regulation in EMM. In plasmacytoma, chemokine and chemokine receptor related genes such as CXCL8, S100A9, S100A8, CCR4, CXCR2, and CXCR4 were down-regulated. Up-regulation of IRF4 was also observed in EMM when comparing normal buccal swab and EMM specimens.
Conclusions
In our study, significant genetic alterations have been identified. Especially, in WES analysis, CDC27 was mutated only in FFPE of EMM patients, and in Nanostring analysis, IRF4 was up-regulated all EMM samples. Further studies are needed to confirm the genetic alterations in more EMM patients.
Real-World Treatment Patterns and Outcomes Among Patients with Primary Hemophagocytic Lymphohistiocytosis with and without Infection at Diagnosis and Treated with Emapalumab: The Real-HLH Study
Authors: Allen Carl E , Chandrakasan Shanmuganathan , Jordan Michael B. , Leiding Jennifer W , Oladapo Abiola , Pednekar Priti , Walkovich Kelly , Yee John 
Published: December 2023

Background: Primary hemophagocytic lymphohistiocytosis (pHLH), a rare, life-threatening, hyperinflammatory syndrome, characteristically shows overproduction of interferon gamma (IFNγ). Since FDA approval of emapalumab for refractory, recurrent, or progressive pHLH or intolerance with conventional therapy, there are limited real-world data on its use. The REAL-HLH study assessed real-world treatment patterns and outcomes among patients treated with emapalumab. Emapalumab treatment patterns and outcomes in the real world among patients with pHLH with or without infection at HLH diagnosis are presented.
Methods: Data were extracted via a retrospective medical chart review of patients with pHLH treated with ≥1 dose of emapalumab between Nov. 20, 2018, and Oct. 31, 2021, across 33 US hospitals from time of emapalumab initiation to end of data availability, death, or study end (Dec. 31, 2021). Data are presented as summary statistics and comparisons using χ 2 tests.
Results: Forty-six of 105 enrolled patients met the pHLH classification criteria; 25/46 (54.3%) had infection at diagnosis with viral infections being most common (18/25; 72.0%). Baseline characteristics are provided in Table 1. The median (range) times from HLH diagnosis to emapalumab initiation and treatment duration with emapalumab for the 2 groups are provided in Table 2. Median (range) starting, maximum single, and cumulative administered dose of emapalumab for the 2 groups are provided in Table 2. Overall survival rates from emapalumab initiation for patients with (18/25; 72.0%) and without infection (16/21;76.2%) were comparable; p=0.747. A greater proportion of eligible patients without infection (15/19; 78.9%) received hematopoietic stem cell transplantation (HSCT) compared with those with infection (16/23; 69.6%), but the difference was not statistically significant (p=0.491).
Conclusion: This is the first study to report real-world treatment patterns with emapalumab across a diverse patient population with pHLH with or without infection at diagnosis. Over 54% of the patients with pHLH presented with infection at diagnosis. The infection status at diagnosis did not affect the overall survival rate and the proportion of patients proceeding to HSCT after emapalumab treatment.