bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time to Lymphoma Treatment within 24 Months in Watchful Waiting Follicular Lymphoma Defines Patients at High Risk for Progression: A Multicenter Analysis
Authors: Gao Fenghua , Liu Jing , Wang Jiesong , Liu Lihong , Li Zhiming , Song Yuqin , Zhang Xudong , Zhou Hui , Sun Xiuhua , Zhang Wei , Xu Bing , Su Liping , Shujuan Wen , Tao Rong , Bai Ou , Zhang Qingyuan , Zou Liqun , Wang Xianhuo , Zhang Huilai 
Published: December 2023

Purpose Follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease, watch and wait (W&W) remains a management therapeutic option in patients with advanced-stage, low-tumor-burden and asymptomatic FL in the rituximab era. We continue to use Groupe d'Etudes des Lymphomes Folliculaires criteria for active disease to initiate therapy. We sought to understand whether time to lymphoma treatment (TLT) after diagnosis in patients who managed by W&W was a factor affecting survival outcomes in FL.
Patients and Methods Between 2008 and 2022, 411 FL patients from 16 institutions in China were managed by W&W strategy, and their TLT was retrospectively evaluated. Patients were further divided into training and validation Cohorts. Logistic regression was used to identify and incorporate independent predictors of early TLT into a model with variable scoring. Model performance was evaluated through the area under the receiver operating characteristic curve (AUC) and goodness-of-fit statistics.
Results After a median follow-up of 46 months, 35 percent of W&W patients experience TLT within 24 months (TLT24) after diagnosis, and the 5-year progression free survival (PFS) rate was significantly lower than that of patients who were treatment-free at 24 months (62.3% vs. 89.5%). In multivariable analysis, five clinical factors were identified as independent predictors of TLT24: stage III-IV, β 2 microglobulin ≥ 3mg/L, lymphocyte-to-monocyte ratio＜3.8, bone marrow involved and spleen enlargement. We calculated risk scores (TLT24PI) for each patient and defined three risk groups: low (0-1 points), intermediate (2 points), or high (3-5 points). Its AUC for TLT24 was 0.761 (95% CI, 0.698 - 0.823) in the development cohort and 0.761 (95% CI, 0.698 - 0.823) in the validation cohort. Risk groups were also associated with PFS ( P&lt;0.001).
Conclusion In patients with FL who initially managed by W&W, TLT within 24 months after diagnosis was associated with poor outcomes. We developed a multivariable model that incorporates clinical and laboratory factors to identify patients at high risk for TLT24, which may be useful to identify candidates for early interventional treatment.
Real-World Study of Adherence to Anticoagulant Treatment Guidelines in Patients with Cancer-Associated Thrombosis (CAT)
Authors: Jain Rahul , Yi Alexander , Li Ang , Vigna Chelsea , Khder Yasser , Bebi Ted , Galaznik Aaron , Rusli Emelly , Bloomfield Daniel 
Published: December 2023

Background and Objectives:
Clinical guidelines recommend using anticoagulant therapy for 3-6 months to treat cancer-associated thrombosis (CAT). Limited data are available on real-world compliance with these guidelines in the US. This analysis aimed to describe treatment patterns for CAT in the US.
Methods:
A retrospective cohort study on adult patients with active cancer who developed CAT between January 2018 to December 2019 was conducted using integrated closed medical and pharmacy claims data from HelthVerity PS 20 database. Patients were categorized as treated cohort if they initiated anticoagulant or inferior vena cava filter within 15 days prior or 45 days after the first CAT event. Patients were required to have a continuous enrollment of ≥ 12 months prior and ≥45 days after the first CAT date. Clinical characteristics during the baseline period and treatment patterns during the follow-up period were described.
Results:
A total of 2,119 patients met the inclusion and exclusion criteria, with 1,536 (72.5%) patients assigned to the treated cohort (Quan-Charlson comorbidity index [QCI] 2.11±2.0; HAS-BLED score 1.91±1.1 and VTE-BLEED risk score 3.65±1.3). Among the treated cohort, 43.9% initiated treatment with a DOAC; the median treatment duration was 164 days. Of the treated patients, 33.8% had &lt;91 days of treatment duration. Relative to patients with ≥91 days of treatment, patients with &lt;91 days of treatment had a higher comorbidity burden [QCI 2.43±2.2 vs. 1.88±1.9; p-value &lt;0.001], a higher HAS-BLED score [2.07±1.1 vs. 1.8±1.0; p-value &lt;0.001], and higher average VTE-BLEED risk score [3.82±1.3 vs. 3.54±1.2; p-value &lt;0.001].
Conclusion:
Compliance with clinical guidelines on the use of anticoagulation in CAT is suboptimal. Patients who receive &lt;91 days of treatment are more likely to have higher risk features than those who receive ≥91 days of treatment.
The Potential Utility of Cerebral Fluid sLR11 and sIL-2R As a Marker for CNS Involvement of Malignant Lymphoma
Authors: Shimizu Naomi , Nakao Sanshiro , Nakaseko Chiaki , Shimizu Tomo , Ebinuma Hiroyuki , Bujo Hideaki 
Published: December 2023

Introduction: LR11 is a type I membrane protein that releases serum-soluble LR11 (sLR11) by proteolytic shedding. In the past, we reported that patients with acute leukemia and malignant lymphoma showed significantly increased serum sLR11 levels compared to those in normal controls. The diagnosis of central nervous system involvement of malignant lymphoma (CNS ML) is often difficult to diagnose by cytology. This study analyzed the potential utility of cerebral fluids (CFs) sLR11 and sIL-2R as diagnostic markers for CNS ML.
Materials and Methods: We enrolled patients suspected of CNS ML and administrated intrathecal anticancer drugs from 2017 to 2023. We analyzed CFs levels of sLR11 and sIL-2R, and cytological malignant grades. Then, we analyzed the relationship between changes in these CFs markers and clinical outcomes.
Results: We studied 26 patients (16 men and 10 women; mean age: 72 years old). The 20 patients were diagnosed as CNS ML in clinical conditions, and the other 6 patients were treated with prevention because of ML of the testis and adrenal glands. The sLR11 of CFs levels significantly and positively correlated with the sIL-2R of CFs levels (r = 0.6618, p = 0.0002) (Figure 1A). As shown in Figure 1B, in CNS invasion groups, only four patients showed class V in the cytology of CFs, the other patients showed negative results. There were no relations between the number of cell numbers and sLR11 and sIL-2R of CFs. As shown in Figure 2, the levels of sLR11 of CFs in diagnosis tended to be higher (p = 0.1831) in the CNS invasion group (36.5±30.0 ng/ml) than in the no-invasive group (23.9±5.8 ng/ml). The levels of sIL-2R of CFs in diagnosis were significantly higher (p = 0.0035) in the CNS invasion group (986.0±1274.3 U/ml) than in the no-invasive group (74.2±78.2 U/ml). The LR11 and sIL-2R of CFs post-treatment were lower in the remission group (n=9; 13.46±6.37 ng/ml, &lt;50.0 U/ml) than non-remission group (n=5; 22.40±14.32 ng/ml, 78.4±41.1 U/ml), p = 0.2861, 0.0629 respectively.
Conclusions: Patients diagnosed with CNS ML showed high levels of sLR11 and sIL-2R of CFs. These two may be good markers for evaluating diagnosis and treatment effects. Further examination of a large number of cases is required to elucidate these mechanisms.
Pathophysiology and Treatment Opportunities of CX3CL1 in Liver Acute Gvhd
Authors: Xu Ziwei , Zhao Xiaoyan , Li Ziying , Hu Yu , Wang Huafang 
Published: December 2023

Acute graft-versus-host disease (aGVHD) is one of the most familiar and severe complications of hematopoietic stem cell transplantation (HSCT). Liver aGVHD, which has limited response to treatment and high mortality, is a critical concern among clinicians in the field. Chemokine (C-X3-C motif) ligand 1 (CX3CL1), also called fractalkine, as a chemokine and adhesion molecule, plays an important role in the pathogenesis of rheumatoid arthritis, primary biliary cirrhosis, and multiple sclerosis. Whether CX3CL1 is involved in liver aGVHD has not been investigated. We collected peripheral blood samples from 10 patients with liver aGVHD during the onset phase and 15 patients without aGVHD after HSCT. The results of the enzyme-linked immunosorbent assay (ELISA) indicated a significant increase in serum CX3CL1 levels among patients with liver aGVHD. Similarly, we observed elevated levels of CX3CL1 in the serum of a mouse model with aGVHD, and found a positive correlation between elevated bilirubin levels and higher serum CX3CL1 levels. The expression of CX3CL1 was markedly elevated in the liver of aGVHD mice by real-time quantitative polymerase chain reaction (RT-qPCR), western blotting (WB). The results of immunohistochemistry showed that the expression of CX3CL1 in the bile duct epitheliums of aGVHD mice was significantly increased compared with those of control mice, but not in hepatocytes. To further analyze CX3CL1 expression, we isolated hepatocytes and bile duct epitheliums from mice and measured the levels using RT-qPCR and WB. Similar to the results of immunohistochemistry, the expression level of CX3CL1 in bile duct epitheliums from aGVHD mice was increased significantly, while the expression level in hepatocytes was unchanged. The prominent bile duct damage observed in liver aGVHD may be attributed to the high CX3CL1 expression in bile duct epitheliums instead of hepatocytes. Anti-CX3CL1 monoclonal antibody (mAb) significantly improved the clinical symptoms and survival rates of liver aGVHD mice, and the liver enzymes and bilirubin levels were decreased remarkably after treatment. Additionally, HE staining showed that the application of anti-CX3CL1 mAb obviously reduced the infiltration of inflammatory cells in bile duct epithelium of liver aGVHD mice. In conclusion, these results provide evidence for the close relationship between CX3CL1 and the pathogenesis of liver aGVHD, suggesting anti-CX3CL1 mAb as a promising strategy for the management of liver aGVHD.
Keywords: Hematopoietic stem cell transplantation, Liver aGVHD, CX3CL1, Bile duct
Emicizumab Versus Immunosuppression for Acquired Hemophilia Α (AHA)
Authors: Hart Christina , Klamroth Robert , Sachs Ulrich J. , Greil Richard , Knoebl Paul N. , Oldenburg Johannes , Miesbach Wolfgang , Pfrepper Christian , Trautmann-Grill Karolin , Pekrul Isabell , Holstein Katharina , Eichler Hermann , Weigt Carmen , Schipp Dorothea , Werwitzke Sonja , Tiede Andreas 
Published: December 2023

Introduction: AHA is a serious autoimmune bleeding disorder caused by neutralizing antibodies against coagulation factor VIII (FVIII). Standard of care involves immunosuppressive therapy (IST) to suppress formation of anti-FVIII autoantibodies. Recently, prophylaxis with emicizumab (EMI) has been used instead of IST to manage patients with AHA.
Aim: This analysis aimed to compare outcomes of treatment with EMI or IST in patients with AHA. It was prospectively planned as an exploratory analysis of the GTH-AHA-EMI trial (NCT04188639, registered at www.clinicaltrials.gov).
Methods: Individual patient data were retrieved from the GTH-AHA-EMI (n=47, treatment with EMI) and the GTH-AH 01/2010 (n=101, treatment with IST). Propensity score (PS) matching was used accounting for covariates that were previously established to influence bleeding risk and overall survival. Standardized mean differences were used to compare baseline characteristics before and after matching.
Results: Baseline characteristics of the study populations were very similar and further improved by PS matching. IST treated patients had a high risk of bleeding in the first 3 weeks (0.25 to 0.30 clinically relevant new bleeds [CRNB] per patient-week), whereas EMI treated patients were largely protected from bleeding throughout the entire observation period (&lt;0.1 CRNB per patient-week). For the first 12 weeks of observation, the negative-binomial model-based mean bleeding rate of EMI treated patients was 68% lower as compared to IST treated patients (incident rate ratio 0.325, 95% confidence interval [CI] 0.182-0.581, p&lt;0.001). During the first 12 weeks, infections occurred with similar frequency but were less often fatal (IST: 36 events in 29 patients [29% of patients], 11 fatal events; EMI: 11 events in 10 patients [21%], no fatal events). Thromboembolic events were less frequent with EMI (1 event (2%], no fatal event) as compared with IST (7 events in 7 patients [7%], 4 fatal events). Overall survival after 24 weeks was 91% and 76% (hazard ratio 0.44, 95% CI 0.24-0.81, p=0.008, figure).
Conclusions: This PS-matched individual patient data analysis showed better bleed protection and improved survival in patients treated with EMI as compared to patients treated with IST. These observations suggest a change of clinical practice. Patients with newly diagnosed AHA should be offered prophylaxis with EMI to reduce the risk bleeding, and provided sufficient time to allow for clinical stabilization and improvement of their general health status before IST is considered.
Preclinical Studies Support the Clinical Development of LP-284 in Relapsed and Refractory B-Cell Lymphomas
Authors: Zhou Jianli , Sturtevant Drew , Kulkarni Aditya , Bhatia Kishor , Ewesuedo Reginald 
Published: December 2023

Genomic instability, a hallmark of many cancers, often results from corrupted DNA damage response/repair (DDR) pathways. Targeting DDR deficiencies in cancer therapy has been successful in solid tumors with dysfunctional homologous recombination repair (HR). However, while less recognized, lymphomas also carry DDR defects such as HR deficiency (HRD) and can account for approximately 18% of all lymphomas. LP-284 is a fully synthetic DNA-damaging agent that induces double-stranded DNA breaks and displays elevated potency in cancer cells with HRD or transcription-coupled nucleotide excision repair defects, including multiple advanced B-cell lymphomas. In preclinical pharmacology studies, the mantle cell lymphoma (MCL) xenograft tumor mouse model derived from JeKo-1, which has mutated TP53 and checkpoint kinase 2 (CHEK2), an HRD score of 46, and was refractory to ibrutinib and bortezomib, showed near complete response after LP-284 treatment. It is noteworthy that 40~50% of MCL patients may be HRD due to the presence of mutations in the ataxia-telangiectasia mutated (ATM) gene. HRD is also likely to be prevalent in high-grade lymphomas, as IGH/MYC translocation or BCL2 expression has been reported to be associated with HR inhibition. Studies of LP-284 in the MYC/BCL2 dual-translocated OCILY1 tumor xenograft model have shown a robust efficacy profile with an average of 99% tumor growth inhibition.
Key pharmacokinetic studies demonstrated that LP-284 is neither a substrate nor modulator of major CYP-450 enzymes, multi-drug resistance transporters, renal drug transporters, or hepatic drug transporters. Safety pharmacology studies indicated that LP-284 does not inhibit hERG potassium channel and has a low potential to affect cardiovascular functions. Toxicology repeat dose studies of LP-284 in Sprague Dawley rats and Beagle dogs, using intravenous infusion on Days 1, 8, and 15 in a 28-day cycle, were generally well tolerated with notable adverse effects in Beagle dogs consisting mainly of reversible hematologic toxicity and testicular toxicity. The highest non-severely toxic dose (HNSTD) in dogs was considered to be 0.4 mg/kg/dose. Overall, based on its impressive preclinical anti-tumor efficacy profile, low drug-drug interaction liability, and findings from toxicological studies, a Phase 1 study is currently planned with LP-284 to assess its safety, tolerability, pharmacokinetics, and clinical activity in patients with relapsed or refractory B-cell lymphoma. Clinical development will be informed by an emphasis on patient selection strategy based on DDR/HR biomarkers.
Interactive Case-Based Education on Pyruvate Kinase Deficiency Improves Hematologists' Competence in Implementing the Latest Diagnostic and Management Approaches
Authors: Rohani-Montez S Christy , Koekkoek Sanneke , Al-Samkari Hanny 
Published: December 2023

INTRODUCTION
The diagnosis of pyruvate kinase deficiency (PKD) is challenging, resulting in long diagnostic delays, sometimes into late adulthood. Management has previously only been supportive, but is evolving, therefore, physicians need to understand the latest evidence-based approaches. This study was conducted to determine whether online interactive case-based independent medical education could improve clinicians' competence in diagnosing and managing PKD according to the latest evidence.
METHODS
174 hematologists participated in a text, case-based activity, and completed pre- and post-questions (Al Samkari H. Investigating Anemia and the Possibility of Pyruvate Kinase Deficiency: What Is Your Next Step? www.medscape.org/viewarticle/989782) Educational effect was assessed using a 3-question repeated-pair design with pre-/post-assessment. A paired samples t-test was conducted for significance testing on overall average number of correct responses and for confidence rating, and a McNemar's test was conducted at the learning objective level (5% significance level, P &lt;.05). Cohen's d with correction for paired samples estimated the effect size of the education on number of correct responses. Data were collected from 3/21/2023-6/14/2023.
RESULTS
48 hematologists completed all pre- and post-assessment questions. Overall significant improvements were seen after participation: 56% average correct response rate at pre-assessment vs 81% at post-assessment; P&lt;.001, Cohen's d= 0.70. In addition, 65% of hematologists improved their competence, selecting correct responses in the post assessment after having selected incorrect responses in the pre-assessment. Significant improvements were achieved with regards to competence in diagnosing PKD and selecting an appropriate treatment approach (both P &lt;.01). After participating, 42% had measurable improved confidence (P&lt;.001) in their ability to implement new treatment approaches for patients with PKD.
CONCLUSIONS
This study demonstrates the success of online, interactive case-based education in improving clinicians' competence in diagnosing and managing PKD according to the latest evidence. Both improvement and reinforcement in the context of a linked learning assessment have been shown to positively correlate with increases in confidence as well as intention to make clinical practice changes (Lucero KS, Chen P. J Eur CME. 2020 Oct 12;9(1):1834759), suggesting that most clinicians who participated in this activity are likely to make improvements in their practice. This could lead to earlier appropriate treatment and improved overall outcomes for these patients.
Thrombocytopenia - Is It an Impactful Prognostic Indicator in Patients with Liver Cirrhosis?
Authors: Araji Ghada , Arafa Fatema , Mustafa Ahmad , Rajavel Anisha , Chehab Hamed , Niazi Muhammad , El-Sayegh Suzanne , Deeb Liliane 
Published: December 2023

Background: Several prognostic scores have been developed to guide management strategies in cirrhotic patients. Child-Pugh and Model of End-stage Liver Disease (MELD) are the typical scores currently used to predict outcomes in cirrhosis, however both do not include platelet count. Although platelet count may provide clues regarding severity of the disease, there is scarcity of data supporting its utility as a prognostic factor in patients with cirrhosis. Hence our study aimed to investigate the association between thrombocytopenia and development of complications as well as mortality in cirrhotic patients.
Methods: TheNational Inpatient Sample (NIS) Database was used to sample individuals with liver cirrhosis between 2016 and 2018. Baseline demographics and comorbidities were collected using ICD-10-DM codes. Patients younger than 18, those with missing data, and with history of thromboembolism were excluded. Study patients were then stratified into those with and without thrombocytopenia. Greedy propensity matching using R was performed to match the two cohorts in 1:1 ratio on age, gender, race, use of anti-thrombotic agents, smoking, and nine other comorbidities including diabetes, dyslipidemia, hypertension, morbid obesity, chronic kidney disease, end stage renal disease, chronic heart failure, history of cancer, and history of transient ischemic attack or stroke. Multivariate logistic regression model was used to analyze outcomes. P-value of &lt;0.05 was considered statistically significant.
Results: Out of a total of 402,104 cirrhotic patients, 129,461 had thrombocytopenia. Thrombocytopenic patients were younger, male pre-dominant, and healthier with lower prevalence of all comorbidities and anti-thrombotic use. Thrombocytopenic patients had statistically significant higher mortality (6.4% vs 5.6%), venous thromboembolism (1.6% vs 1.5%), variceal bleeding (6.9% vs 4.3%), spontaneous bacterial peritonitis (3.9% vs 3%), portal hypertension (35.8% vs 23.9%), hepatorenal syndrome (5.5% vs 3.8%), hyponatremia (23.7% vs 19%), jaundice (0.6% vs 0.4%) and abnormal coagulation profile (2.2% vs 1.6%). Multivariate logistic regression model after matching showed similar outcomes with thrombocytopenic patients having higher mortality (OR: 1.13 [1.09 - 1.18];p&lt;0.001) and statistically significant higher rates of all other complications.
Conclusion: Thrombocytopenia was significantly associated with higher mortality and complications in liver cirrhosis. These findings highlight the importance of considering thrombocytopenia as a poor prognostic factor when evaluating patients with liver cirrhosis. Further randomized controlled trials are needed to corroborate these findings and explore the benefit of addition of platelet count to the current prognostic scores used in clinical practice to estimate outcomes in liver cirrhosis.
Metabolic Tumor Volume from Baseline PET/CT Improves Stratification in the High IPI Risk Patients with Diffuse Large B-Cell Lymphoma
Authors: Hanzhen Zhang , Wei Xiaolei , Zhou Wenlan , Xu Zihan , Chen Junjie , Wei Yongqiang , Wu Hubing , Feng Ru 
Published: December 2023

Background: In the rituximab era, the international prognostic index (IPI) risk stratification was not enough to predict outcome in patients with diffuse large B cell lymphoma (DLBCL). Previous studies showed the Metabolic tumor volume（MTV） from baseline [ 18F]FDG PET/CT could be used to predict outcome. In this study, we evaluated the prognostic value of IPI and MTV in DLBCL patients.
Patients and methods: A total of 262 de novo DLBCL patients who were treated with the R-like chemotherapy were retrospectively analyzed in this study. The IPI and MTV were compared to the Overall Survival (OS) and Progression Free Survival (PFS).
Results: The MTV is better than TLG and SUVmax for predicting disease progression. The cutoff value of MTV was 444 cm 3. Patients with high MTV showed inferior OS and PFS ( p &lt; 0.001, respectively). Although the IPI remains predictive it distinguishes only 2 risk groups, rather than the 4 groups originally described. Further analysis showed high MTV could identify a subgroup of patients with extremely inferior OS and PFS in high IPI risk patients ( p = 0.0089 and p= 0.024, respectively). Multivariate analysis revealed that high MTV is a significant poor prognostic factor for both OS (HR 3.168[1.81-5.56], p &lt;0.001) and PFS (HR 2.637 [1.51-3.71], p &lt;0.001).
Conclusions: Our study suggests that MTV from baseline PET/CT is an important prognostic factor in DLBCL patients, allowing the identification of an inferior outcome subgroup in high-risk patients, which may help to guide treatment in clinical trial.