bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibiting Free Fatty Acid Transport to Improve CAR-T Cell Therapy of Relapsed B-Cell Acute Lymphoblastic Leukemia
Authors: Garcia Clarissa , Lyons Kaylyn , Liu Tian , Iacobucci Ilaria , Novak Amanda , Argabright Amy , Donnelly Alexis , Grandvallet Contreras Julian , Geng Huimin , Smith Sabrina , Zhou Xin , Müschen Markus , Dick John Edgar , Haines Julie R , D'Alessandro Angelo , Mullighan Charles G. , Phang Tzu , Kohler M. Eric , Witkowski Matthew 
Published: December 2024

Introduction: B-cell acute lymphoblastic leukemia (B-ALL) resistant to conventional chemotherapy is a leading cause of cancer-related mortality in children and young adults. Although CD19-directed Chimeric Antigen Receptor T-cell (CAR-T) therapy shows promise for relapsed/refractory B-ALL, its effectiveness is often compromised by leukemia-intrinsic resistance mechanisms that remain unclear. Recent evidence suggests that TP53 mutations negatively affect the long-term efficacy of CD19 CAR-T therapy in B-ALL, despite initial trials not identifying high-risk genetic features impacting early clinical responses. TP53 loss-of-function mutations, although rare at diagnosis, are enriched in relapsed B-ALL and associated with chemotherapy resistance and poor survival.
Methods and Results: To dissect the B-ALL-intrinsic role of p53 during CAR-T therapy, we found that TP53 loss-of-function mutations in a subset of human B-ALL cell lines conferred resistance to CAR-T cell killing in vitro and in vivo. To elucidate the pathways driving CAR-T resistance in TP53-mutated (mut) B-ALL cells, we performed genome-wide CRISPR/Cas9 screening on isogenic TP53-wildtype (wt) and TP53-mut CD19+ B-ALL cell lines treated with CD19-CAR-T cells ex vivo. This screening approach identified the free fatty acid transporter FATP2 (encoded by SLC27A2) as a critical factor; as its genetic ablation enhanced CAR-T efficacy against TP53-mut B-ALL lines. Analysis of RNA-seq data from 1104 pediatric B-ALL patients revealed that high SLC27A2 mRNA expression at B-ALL diagnosis correlated with poor overall survival and increased free fatty acid metabolism. To understand the mechanism of FATP2 activity in B-ALL survival, we found FATP2-expressing B-ALL lines internalize long-chain free fatty acids more efficiently than non-FATP2-expressing human B-ALL cell lines. Additionally, FATP2-mediated CAR-T resistance in TP53-mut B-ALL cells was reversible by depleting exogenous fatty acids. Stable isotope free fatty acid uptake tracing revealed a role for FATP2 in promoting succinate accumulation in TP53-mutated B-ALL cells, thus significantly altering cellular metabolism that may have contributed to CAR-T resistance. Ongoing experiments aim to identify the precise mechanisms contributing to leukemia-intrinsic, FATP2-dependent CAR-T resistance.
Conclusions: Our studies suggest that FATP2 expression drives TP53-mutant B-ALL CAR-T resistance by facilitating the uptake of exogenous free fatty acids. Collectively, we propose targeting free fatty acid transport as a specific metabolic vulnerability in B-ALL that might improve CAR-T therapy outcomes.
Evaluating the Effectiveness and Security of Antifungal Prophylaxis in Acute Lymphoblastic Leukemia Induction Chemotherapy
Authors: Zhou Yang , Zhou Hongsheng , Liu Qifa 
Published: December 2024

Background and objectives: Patients suffering from hematologic malignancies face a high risk of developing invasive fungal disease (IFD). Primary antifungal prophylaxis (PAP) is a key strategy to reduce the incidence of IFD in patients with acute myeloid leukemia (AML), those receiving hematopoietic stem cell transplantation (HSCT), and those with myelodysplastic syndrome (MDS). Nonetheless, clinical data regarding PAP in ALL patients is scarce, owing to major drug interactions. This paper aims to evaluate the efficacy and safety of PAP in ALL patients through real-world research.
Methods: A retrospective cohort study was carried out at a single center, focusing on ALL patients aged over 14 who received their first induction chemotherapy at our hospital from January 2011 to January 2021. Our study excluded individuals with a background of IFD, those who declined treatment and were released from the hospital, and those whose cases were inaccessible. The identification of IFD adhered to the guidelines set by the European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG).
Results: The study included 482 patients, 316 of whom undergoing PAP treatment. Of the 482 patients, 13 developed proven or probable IFD (2.7%), and 60 developed possible IFD. There was a notably reduced occurrence of IFD in the prevention group compared to the non-prevention group (36/316, 11.4% vs. 37/166, 22.3%, P = 0.002). The multifactorial Cox regression analysis revealed a notable decrease in IFD occurrences due to PAP (HR = 0.306, P &lt; 0.001). The primary medications administered in PAP included caspofungin (n = 113), voriconazole (n = 99), and micafungin (n = 53). The caspofungin group exhibited no adverse drug reactions. Patients experiencing neutropenia for more than 10 days and those on corticosteroids for 7 days or more showed a reduced mortality risk in the PAP group compared to the nonprophylactic group (HR = 0.615, P = 0.021).
Conclusions: The practical research we conducted revealed that PAP independently safeguards against IFD in ALL patients undergoing induction therapy. Furthermore, caspofungin's safety record for treating PAP in ALL patients is positive.
Treatment of First Relapse of Multiple Myeloma in Australia and New Zealand (ANZ): Treatment Patterns and Outcomes: An ANZ Myeloma and Related Diseases Registry (ANZ MRDR) Analysis
Authors: Gration Betty , Wellard Cameron , Moore Elizabeth , Tan Marianne , Murphy Matthew , Lim Kenneth J C , Rowland James , Hamad Nada , Rajagopal Rajeev , Mollee Peter , Spencer Andrew , Quach Hang , McCaughan Georgia 
Published: December 2024

Aim:
There remains lack of consensus regarding whether relapsed multiple myeloma should be treated at clinical progression (CP) or biochemical progression (BP), and the ensuing clinical outcome. We described practices in Australia and New Zealand (ANZ) and the outcomes in these cohorts.
Method:
We conducted a retrospective review of ANZ Myeloma and Related Diseases Registry (ANZ MRDR) patients across 5 sites, that had progressed following first line therapy. Additional information was sought regarding timing of treatment at myeloma relapse (BP or CP) and presence of end organ damage (EOD) at 3-6 months. We determined progression free survival (PFS) and overall survival (OS) in these cohorts using Kaplan Meier methods.
Results:
Among 258 patients, 52% were treated at BP and 48% at CP. There was no significant difference in age, gender, ECOG, stage (ISS-3) or high-risk cytogenetics at diagnosis between groups. There was no significant difference in time to first progression (CP=20.6 months vs BP=21.7 months) or time between progression and initiation of therapy (CP=1.7 vs. BP=2.1 months). Patients treated at CP had a higher rate of persistent opioid requirement at 6 months (CP=32% vs BP=13.9%, p=0.001) and need for a mobility aid at 6 months (CP=12.7% vs. BP=3.5%, p=0.012), but there was no difference in fracture rates between the groups at 6 months (CP=10.6% vs. BP=10.5%, p=0.99). 68% of patients with renal EOD had no renal response as per IMWG at 3 months. There was a trend toward longer PFS and improved OS from initiation of second line therapy for those treated at BP versus those treated at CP however no statistical significance recognised at this study power (PFS: CP=8.5 months vs. BP=11.2 months, p=0.203, OS: CP=23.5 months vs. BP=33.7 months, p=0.06).
Conclusion:
Initial disease characteristics, time to first progression and time from progression to initiation of second line therapy did not differ between patients treated at BP versus those treated at CP. Treatment at CP was associated with more persistent EOD measured by requirement for opioids and mobility aids and the majority of those with renal EOD failed to have a renal response. Those treated at BP showed a trend towards improved PFS and OS compared to treatment at CP. This trend may be related to persistent EOD or more aggressive disease biology. The lack of statistical significance likely reflects poor power and warrants further investigation.
Analysis of Arterial Occlusive Events (AOE) in CML Patients Using Real-World Data : A Large Cohort
Authors: Takaku Tomoiku , Kojima Yoshitsugu , Yanai Yoshiaki 
Published: December 2024

Background
While the prognosis of chronic myeloid leukemia (CML) has been significantly improved by the development of tyrosine kinase inhibitors (TKIs), the importance of managing various adverse events associated with long-term TKI treatment is increasing. In particular, arterial occlusive events (AOEs) can be fatal and potentially cause irreversible sequelae in patients, requiring the choice of TKIs according to individual patient risk and proactive therapeutic interventions for prevention. In this study, we conducted an analysis using data from the DPC database, MDV (Medical Data Vision Co., Ltd., and examined AOE in the real-world setting of a large cohort.
Methods
We extracted data from MDV for 2,113 patients aged 18-100 (average age 61.3; 1,326 men and 787 women) who were diagnosed with CML and received TKI treatment from Jan 2017 to Dec 2020. We used logistic regression analysis to analyze the frequency and timing of AOE, and individual AOE risk factors such as gender, age, and history of cardiovascular event, hypertension, diabetes, and dyslipidemia, by various TKI treatment lines.
Results
Of the 2,113 MDV registrants, 1,381 were 1st-line TKI treatment patients, 550 were 2nd-line, 150 were 3rd-line, and 32 were 4th-line or later. The incidence of AOE by treatment line was increasing with the later treatment lines (8.5% for 1st-line, 12.5% for 2nd, and 14.7% for 3rd: p=0.0079 (1st vs 2nd), p=0.0164 (1st vs 3rd)). The person-year method (/1000 person-years) was 37.7 for 1st-line, 95.1 for 2nd-line, and 143.9 for 3rd-line. The median time to AOE onset was 27.0 days for 1st-line, 25.0 days for 2nd-line, and 25.5 days for 3rd-line. Furthermore, analyzed by type of AOEs, we found that the median time of stroke and peripheral arterial occlusive disease were similar regardless of the treatment line. However, incident rate of myocardial infarction was increased at later line (26.0 days for 1st-line, 29.0 days for 2nd-line, and 45.0 days for 3rd-line).
In the analysis of AOE risk factors, all factors showed significant differences in the comparison between 1st-line and 2nd-line in univariate analysis, but in multivariate analysis, age, gender, dyslipidemia, and hypertension were significant risk factors in 1st-line, while age and hypertension were significant in 2nd-line. On the other hand, hypertension, diabetes, and dyslipidemia were significant in univariate analysis, and diabetes was significant in multivariate analysis in 3rd-line group.
【Conclusion】The results of the real-world data analysis of a large cohort using the DPC database showed that the incidence of AOE increased with the estimation of treatment lines, and significant risk factors varied in each treatment line. In particular, hypertension and diabetes were significant risk factors for AOE in all treatment lines in both univariate and multivariate analyses, suggesting that the proactive therapeutic interventions are strongly recommended for these risk factors.
SLC25A1 Reprograms Mitochondrial and Fatty Acid Metabolism to Promote the Progression of Acute Myeloid Leukemia
Authors: Yan Xiaojing , Chen Miao , Tao Yuan , Kang Sijing , Yue Pengjie , Ge Rui 
Published: December 2024

Metabolic reprogramming is a hallmark of tumors, contributing to tumor initiation, progression and drug resistance. In acute myeloid leukemia, cells usually depend on both enhanced glycolysis and oxidative phosphorylation for their energy needs. The persistence of therapy resistance in some AML patients underscores the urgency of identifying novel metabolic targets. Here, we revealed the vital role of citrate transporter SLC25A1 in maintaining AML cell survival and regulating its drug sensitivity, establishing it as a promising metabolic target for AML therapy.
We first showed that the SLC25A1 expressions were elevated in AML patients both on mRNA and protein level, which were associated with poorer outcomes. Genetic and pharmacological inhibition of SLC25A1 significantly suppressed the proliferation and clonogenicity, promoted apoptosis of leukemic cell lines, as well as the primary AML cells from patients. The specific inhibitor of SLC25A1 had no effect on the proliferation of mononuclear cells (MNCs) from healthy bone marrow at the same concentrations. Our data indicated that SLC25A1 was a potential target for AML therapy, which was further confirmed in AML mice carrying with AE9a or MLL-AF9.
Functionally, inhibition of SLC25A1 revealed the mitochondrial damage and ROS increasing in AML cells by transmission electron microscopy (TEM), mitochondrial membrane potential and extracellular flux analysis, as well as flow cytometry and fluorescence microscopy. The restoration of cell viability by ROS scavenger N-acetyl-L-cysteine (NAC) in the context of SLC25A1 inhibition suggested that SLC25A1 deficiency inhibited cell survival through the upregulation of ROS. Given this, we found that targeting SLC25A1 could enhance the sensitivities of AML cells to two clinically available anti-leukemic drugs, BCL-2 inhibitor venetoclax and chemotherapy drug daunorubicin (DNR).
Mechanically, we found that SLC25A1 was closely correlated with ROS metabolic process, extrinsic apoptotic signaling pathway and oxidative phosphorylation, as well as nicotinate metabolism and fatty acid metabolism, analyzed by gene expression data and metabolic data. We next verified that a series of key enzymes involved in fatty acid metabolism were down-regulated following SLC25A1 KD, accompanied by metabolites in fatty acid synthesized pathway. We also revealed that a self-protection mechanism after stress by up-regulating phosphoglycerides (PGs) and triglycerides (TAGs) in SLC25A1 KD cells, and the effect could be reversed by inhibiting DGAT1, a key enzyme catalyzing the conversion of fatty acids to TAGs.
In conclusion, targeting mitochondrial metabolism and fatty acid metabolism using the SLC25A1 inhibitor might be a potential novel strategy for enhancing AML therapy and overcoming drug resistance.
Implementation of a Mass Spectroscopic Method (Mass-Fix) to Replace Traditional Electrophoresis Methods for Patients with Monoclonal Gammopathies
Authors: Murray David , Kohlhagen Mindy , Coker Jon , Willrich Maria Alice V. , Dasari Surendra , Dispenzieri Angela 
Published: December 2024

Background
The detection, isotyping and quantitation of over-expressed immunoglobulin(s) (Igs) (M-protein) is key for diagnosing and monitoring patients with monoclonal gammopathies. Traditionally, our lab has used a combination of agarose gel protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) for these purposes. In 2018, a mass spectrometric method (Mass-Fix) was implemented to replace IFE for M-protein isotyping. This work documents the validation of a quantitative version (Q-Mass-Fix) to replace both SPEP and IFE.
Methods
24,645 samples submitted for M-protein testing between 7/2018 and 9/2023 with quantitative IgG, IgA and IgM measurements, Mass-Fix analysis and SPEP results were utilized for this study. A separate cohort of 100,000 M-protein negative samples were utilized to mathematically model the spectral shapes IgG, IgA and IgM polyclonal background. To detect M-proteins, software was developed that fits the polyclonal Ig portion of the spectra and M-proteins are detected as peaks above the polyclonal background. M-proteins isotypes are determined by matching similar peaks in spectra in 5 sperate immuno enrichments (IgG, IgA, IgM, kappa and lambda). M-protein quantitation was obtained by multiplying total M-protein isotype quantity by the fraction area of the M-protein in the spectra. M-protein dilutional studies were used to examine the linearity and level of detection of Q-Mass-Fix.
Results
SPEP and Q-Mass-Fix M-protein quantitation had the best agreement between the range of 10 to 40 g/L. Below 10 g/L, Q-Mass Fix had on average, lower M-protein values. Above 40 g/dL, Q-Mass-Fix values were on average, higher than SPEP. The automated isotyping assignment was 98.8 percent consistent with the isotype assigned by visual inspection. Dilutional studies revealed that Q-Mass-Fix quantitation was linear over a range of 70 to 0.04 g/L (slope 1.0, r2 0.99) with an analytical limit of quantitation of 0.1 g/L and a limit of detection of 0.04 g/L.
Conclusion
Q-Mass-Fix represents a significant improvement in comparison to our current SPEP method. Q-Mass-Fix is more capable of removing the interference of polyclonal Igs below 10 g/L and is not subjective to the dye saturation effect at high M-protein levels. The increased analytical measuring range and improved limit of detection of detection could be beneficial in tracking patient's response. Q-Mass Fix is more automated than SPEP and the workflow in our laboratory.
Clinician's Knowledge and Awareness of Patient-Reported Outcomes in Immune Thrombocytopenia: Results of a National Survey (ITP NET, GIMEMA Working Group Anemia and Thrombocytopenia)
Authors: Oliva Esther Natalie , Efficace Fabio , Valvano Maria Rosa , Arcuri Paola , Battistini Roberta , Buzzatti Elisa , Clissa Cristina , Danesin Cristina , Salemme Alessia , Sparano Francesco , Chiurazzi Federico 
Published: December 2024

Background: Patient-reported outcomes (PROs) are gaining attention in hematological diseases. Nonetheless, clinicians' knowledge of PROs is not widespread. Immune thrombocytopenia (ITP) is an autoimmune hematological disease in which fatigue significantly impacts patients' quality of life (QoL).This national Italian study focused on assessing the knowledge of PROs among hematologists experienced in ITP within the ITP NET network.
Methods: From April 4 to 20, 2023, 63 hematologists from 49 Italian centers were contacted to complete a 63-item online survey covering physician's knowledge of QoL issues and the impact of QoL on physician behaviour, decision making and patient care.
Results: Thirty-nine hematologists (72% from Northern Italy), 72% female, with a mean age of 44 (SD 11), completed the survey. Median years of practice were 15 (IQR 9-24), and median years of experience treating ITP were 6 (IQR 4-16). In the previous 12 months, each respondent saw a median of 50 (IQR 20-150) ITP patients with a median of 40 (IQR 20-77) patients undergoing treatment. Knowledge of PROs was unspecific in 36% and absent in 10%. Thirty-one percent had experience only in research, 8% used PROs in clinical practice, and 15% had knowledge without use. Discrepancies included subsequent 51% reporting frequency of PRO use in research (28% once, 23% several times) and 56% reporting general use of QoL studies in their practice. Clinicians with &gt;17 years of medical practice had more knowledge of PRO studies than those with ≤17 years of practice (72% vs. 38%, respectively; p=0.033), as those with &gt;4 years ITP experience (64% vs. 27%, p=0.037). Physicians with larger ITP practices had more PRO experience in clinical trials (p=0.0345) and more recognition of the value of PROs in severely ill patients (100% vs. 73%, p=0.027), If QoL results were easier to understand, 93% of physicians working in northern Italy would be more likely to use them, versus 64% of physicians working in southern Italy (p=0.042).
Conclusions: There is a general lack of knowledge and use of PROs among hematologists, highlighting the need for further education and awareness. More experienced hematologists and those with larger ITP practices have better knowledge and use of PROs, suggesting that experience plays a crucial role in understanding and implementing PROs. The study serves as a foundation for future initiatives aimed at improving awareness and implementation of PROs, ultimately striving for more comprehensive and patient-focused care in ITP.
Development and Validation of a Machine Learning-Based Early Warning System for Predicting Venous Thromboembolism Risk in Hospitalized Lymphoma Patients Undergoing Chemotherapy: A Multicentre, Retrospective Cohort Study
Authors: Jiang Tingting , Yang Zailin , Tang Xinyi , Zhang Yakun , Chen Shuang , Peng Yu , Zhang Xiaomei , Jun Li , Guo Bingling , Li Jieping , Liu Tingting , Lei Haike , Hu Zuhai , Fang Na , Wei Xia , Liu Xuefen , Chen Yong , Liu Yao 
Published: December 2024

Background: Hospitalized lymphoma patients undergoing chemotherapy face a heightened risk of Venous thromboembolism (VTE) due to prolonged treatment and extended bed rest. However, predicting VTE risk early in these patients is challenging. The objective of this study was to develop a machine learning-based early warning system for VTE tailored to this patient group.
Methods: Data were collected from 1,141 patients at four academic medical centers from January 2019 to February 2024. Twelve variables were included and six machine learning algorithms were utilized to develop a VTE early warning system. Models were evaluated based on accuracy, precision, sensitivity, specificity, and area under the curve (AUC). Subsequently, the variables importance of each model was analyzed and comprehensively evaluated by permutation importance analysis. Finally, we visualized the VTE early warning system (VTE-EWS) using a nomogram and compared its performance to the classic Khorana Score (KS) system.
Results: Among the 1141 patients, 799 from Chongqing University Cancer Hospital were evaluated as a training set, while 342 from other three academic hospitals were the external validation set. In the external validation set, all six models demonstrated strong predictive performance, with accuracy ranging from 0.71 to 0.87, AUC from 0.78 to 0.84, sensitivity from 0.62 to 0.73, and specificity from 0.73 to 0.90. Subsequently, we identified the six most important variables-white blood cell (WBC), D-dimer, central venous catheter (CVC), age, chemotherapy cycles, and Eastern Cooperative Oncology Group performance status (ECOG score)-to be included in the nomogram for scoring and visually predicting the risk of VTE. Finally, compared to the KS, VTE-EWS identified more patients at VTE high risk (24/37) and demonstrated a higher probability of clinical benefit within a range of 1% to 78%.
Conclusions: We developed a visual and online VTE-EWS based on machine learning algorithms. Based on simple indicators, VTE-EWS can accurately identify, visually predict, and interpret the risk of VTE in hospitalized lymphoma patients undergoing chemotherapy.