bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Comprehensive Stratification Integrated the Clinical, Pathological, and Molecular Biological Features to Distinguish High-Risk Mantle Cell Lymphoma
Authors: Yang Ping , Li Chunyuan , Liu Shuozi , Yang Yuan , Zhang Weilong , Wang Jing , Chen Yingtong , Jing Hongmei 
Published: December 2024

Background The heterogeneity of the clinical course, biology and genomics manifestations has observed in MCL patient. The unified consensus information on high-risk MCL definition is sparse and unclear. A more refined risk stratification are imperative needed for MCL patients. In our study, we aimed to define the generalized high-risk group who had more than one factors including MIPI, aggressive pathological features, TP53 alterations and complex karyotypes.
Methods This retrospective study analyzed data for adult patients diagnosed with MCL from January 2000 to October 2022 at 19 comprehensive hospitals in China with the total of 1017 patients. 861 patients with complete medical records and follow-up data were included in the analysis. Among of them,150 patients belonged to the narrow definition of high-risk group by MIPI score, 284 patients were the generalized high-risk group by comprehensive factors(Figure 1).
Result According to the narrow definition of high-risk stratification, the median PFS was 46.0 and 21.0 months, and the 5-year PFS was 39.3% and 15.6% in low-risk group(n=659) and high-risk group(n=150), respectively. The median OS was 106 and 47.0 months, the 5-year OS was 72.3% and 46.1%((all p&lt;0.05). According to generalized high-risk stratification, the median PFS was 51.0 and 23.0 months in the low-risk group (n=562) and high-risk group(n=283), and the 5-year PFS was 42.8% and 17.9%, respectively. The median OS was 118.0 and 57.0 months, with the 5-year OS of 78.3 % and 49.2%, respectively (all p&lt;0.05, Figure 2). Furtherly, prognostic analysis in the generalized high-risk grouprevealed that high-risk group according to MIPI score and patients with TP53 alterations were independent prognostic factors for PFS.TP53 alterations combined with other high-risk genes, elevated β-2 microglobulin levels, and the presence of B symptoms were independent prognostic factors for OS in this study.
Conclusions Our study indicated that the generalized high-risk group that integrated the clinical, pathological, and molecular biological features had a good predictive value in the prognosis of MCL. It is a simple and feasible method to distinguish high-risk mantle cell lymphoma and provide better treatment decisions for clinical practice.
Gut Microbial Metabolite Butyrate Alleviates the Susceptibility to Septic DIC By Suppressing Caspase-11/ Gsdmd-Dependent Macrophage Pyroptosis
Authors: Li Yingying , Wu Zhong , Jiang Huiwen , Chen Zhaozhao , Xu Min , Shu Jinhui , Wang Jingming , Xie Qinying , Deng Jun , Hu Yu , Luo Lili , Mei Heng 
Published: December 2024

Introduction: Disseminated intravascular coagulation (DIC), a prevalent complication of sepsis, is a significant contributor to multiple organ dysfunction syndrome (MODS) and mortality in septic patients. The intestine has been considered as the motor of MODS in sepsis. We identified a disparate predisposition to DIC in septic mice, which we categorized into two groups-DIC-resistant (Res) and DIC-sensitive (Sen) mice. However, the mechanism behind this phenomenon remains unclear.
Methods: Cecal ligation and puncture (CLP) was used to induce septic DIC. Feces were collected before CLP to detect intestinal flora composition by 16S rRNA and short-chain fatty acids by targeted metabolome. Fecal microbiota transplantation was performed to study the role of gut microbiota and its metabolites in susceptibility to septic DIC.Macrophage pyroptosis were comprehensively assessed by morphology, levels of IL-1β and lactate dehydrogenase (LDH) in plasma and supernatants. The Western blotting was used to confirmed pyroptosis at the molecular level.
Results: The Sen mice were more likely to develop DIC and multiple organ failure than Res mice. The relative abundance of butyric-producing bacteria, Firmicutes and the concentration of butyrate in Res mice were significantly higher compared to the Sen mice. Intriguingly, the susceptibility to septic DIC could be transmitted via the intestinal microbiota. Meanwhile, butyrate can effectively reduce the mortality of DIC, concurrently alleviating coagulopathy and mitigating MODS. Mechanistically, the proportion of peritoneal macrophage pyroptosis, plasma levels of IL-1β and LDH in Sen mice were statistically higher than that in Res mice, and butyrate could reduce these indicators and downregulate the expression of histone deacetylase 3 (HDAC3). For LPS-transfected bone marrow derived macrophages (BMDMs), sodium butyrate (NaB), HDAC3 inhibitor, caspase-11 inhibitor, and GSDMD inhibitor could improve the changes of morphology, which was manifested by diminished cellular antennae, augmented swelling, and the presence of distinct pyroptosis vesicles. In addition, the release of IL-1β was significantly reduced by NaB and inhibitors above, compared to LPS-transfected BMDMs. Under LPS-transfected condition, NaB could impeded HDAC3 expression compared to the control and HDAC3 inhibitor groups. Moreover, NaB and HDAC3 inhibitor effectively inhibited the cleavage of caspase-11 and GSDMD.
Conclusion: Butyrate, a metabolite of enteric Firmicutes, exerts a suppressive influence on the activation of the caspase-11/GSDMD pathway in macrophages by modulating the activity of HDAC3, subsequently impeding the onset and progression of DIC in sepsis, providing a novel theoretical basis for targeted intervention in sepsis and DIC.
Association between Venetoclax Plasma Concentrations and Treatment Response of Acute Myeloid Leukemia
Authors: Yang Yufei , Zhao Lei , Yang Jinjun , Li Xuefeng , Wu Yu 
Published: December 2024

Background:
Venetoclax (VEN) as a BCL-2 inhibitor, has shown promising results in treating adult acute myeloid leukemia (AML). However, studies on the relationship between VEN plasma concentrations and clinical efficacy and prognosis are still insufficient. According to the importance of plasma concentrations in clinical treatment, this study aims to analyze the impact of VEN plasma concentrations on the efficacy and prognosis of AML treatment.
Method:
This retrospective study included AML patients treated with VEN who were assessed for efficacy and at least one measurement of VEN plasma concentrations at West China Hospital from November 2021 to June 2024.
Results:
A total of 92 AML patients treated with VEN were included, encompassing both newly diagnosed and relapsed/refractory patients. In these patients, overall response rates (ORR), including CR, CRh, CRi, and PR, were 52.2%. Patients with response had higher VEN plasma concentrations compared with those no response (Wilcoxon, 2387.0 ng/ml vs. 1733.5 ng/ml, P=0.043) and had a significantly better overall survival (691d vs. 257d, P=0.014). There was a certain correlation between VEN plasma concentrations and efficacy (P=0.043). The optimal cut-off for VEN plasma concentrations was 2250 ng/ml and patients with higher VEN plasma concentrations (N=38) showed better response than lower concentrations (N=54) (chi-square, 65.8% vs. 42.6%, P=0.047). But there was no significant difference in survival on either side of 2250 ng/ml (358d vs. 268d, P=0.725).
Conclusion:
VEN plasma concentrations were associated with clinical response, suggesting that VEN plasma concentrations above 2250 ng/ml might achieve beneficial clinical outcomes. However, higher concentrations do not mean longer survival, which may be related to adverse reactions caused by high concentrations.
Comparing Estimated Glomerular Filtration (eGFR) Equations in Patients with Transfusion-Dependent Thalassemia
Authors: Ogunsanya Olubunmi , Kirpalani Amrit , Zavitz Jennifer , Geerlinks Ashley , Tole Soumitra 
Published: December 2024

Renal dysfunction is a well-described complication in children with transfusion-dependent thalassemia (TDT), and is linked to chronic anemia, hypoxia, hemolysis as well as nephrotoxicity from free iron and chelating agents. Nuclear medicine-based (DTPA) measurement of glomerular filtration rate (nmGFR) remains the gold standard test of renal function but is expensive, invasive and unsuitable for routine screening. Creatinine is the most used biomarker for renal function but is less accurate in children and those with low muscle mass. Cystatin C has been widely adopted as a more accurate marker but can be affected by iron chelation therapy. While early detection of renal dysfunction is important to guide management, there remain limited data on the most reliable method to estimate eGFR in children with TDT.
We designed a single-center retrospective cohort study to explore the correlation between nmGFR and eGFR equations based on creatinine, cystatin C, or both. Patients with TDT aged 0-17 years who had a nmDTPA study and serum cystatin C between 2013-2023 were included. Cystatin C measurements taken on the same day or up to 7 days from their DTPA scan were used. Eight eGFR calculations were performed (Schwartz, Schwartz-Lyon, Cr CKID U25, Filler, CysC Zapatelli, CysC CKID U25, Cr-CysC Zapatelli, Cr-CysC CKID U25). The Pearson correlation (rho) was used to measure the correlation of each eGFR equation versus the nmGFR. Mean bias (95% confidence intervals, CI) was calculated using the Bland-Altman method assuming constant variance.
Eleven children (55% female) with TDT (73% β0/β0 or β0/β+, 9% E0/β0, 18% non-deletional alpha thalassemia) with median age of 13 years were included. Nine (82%) children were receiving deferasirox for iron chelation, one (9%) was receiving deferoxamine and one (9%) was being phlebotomized having undergone a hematopoietic stem cell transplant. Two (18%) children were concurrently receiving hydroxyurea.
The mean nmGFR was 94.1+/-20.9 mL/min/1.73 m2, 72.3% had a normal nmGFR &gt; 90 mL/min/1.73 m2. The Cr-CysC CKID U25 equation showed the strongest correlation to nmGFR (rho=0.84, p=0.002) with the lowest risk of bias (-3.01, 95% CI -28.5-25.1). The Cr CKID U25 and CysC CKID U25 equations showed moderate correlations [(rho=0.61, p=0.045) and (rho=0.64, p=0.047)] but showed significant bias [(-21.8, 95% CI -58.1-14.6) and (19.2, 95% CI -10.3 - 48.7)]. The Schwartz, Schwartz-Lyon, Filler, CysC Zapatelli, Cr-CysC Zapatelli equations did not correlate well with the nmGFR.
Most commonly used eGFR calculations poorly estimate renal function in children with transfusion-dependent thalassemia. The Cr-CysC CKID U25 equation showed strong correlation with the nmGFR and may represent a better biomarker for renal dysfunction in this population. A large prospective cohort study is needed to confirm and validate these findings.
Real-World Experience of Blinatumomab for 8 Years Regarding Predictive Factors Including Lymphocyte Kinetics for Response and Survival Outcome in Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia
Authors: Lee Seonghan , Yoon Jae-Ho , Kwag Daehun , Min Gi-June , Park Sung-Soo , Park Silvia , Lee Sung-Eun , Cho Byung-Sik , Eom Ki-Seong , Kim Yoo-Jin , Kim Hee-Je , Min Chang-Ki , Cho Seok-Goo , Lee Seok 
Published: December 2024

Background: Blinatumomab became available in Korea since 2016 and has proved its efficiency for remission and safe bridging role to allo-HCT in patients with R/R BCP-ALL. This T-cell engager system has changed the paradigm of ALL treatment in terms of safe chemotherapy-free approach and need for understanding T-cell immunology.
Aim: Here, we report our long-term experience of blinatumomab regarding well-known traditional factors and lymphocyte kinetics during blinatumomab treatment.
Methods: We analyzed 152 adult patients (median age 59.5 years, range 18-79) with R/R BCP-ALL treated with blinatumomab between 2016 and 2023 (110 Ph-negative, 42 Ph-positive). Ph-negative BCP-ALL could be treated with blinatumomab from first line salvage while Ph-positive BCP-ALL after Dasatinib failure, thus at least from second line salvage. The standard protocol consisted of pre-phase dexamethasone, first cycle blinatumomab 28 days (9mcg during initial 7 days followed by 28mcg for 21 days) was followed by 2-week resting period and second or more cycle of 28mcg blinatumomab for 28 days. For post-remission therapy, allo-HCT was conducted as early as possible.
Results: After first cycle, CR was achieved in 98 (64.5%) and best response was in 104 (68.4%) patients after median 2 cycles, and 74 responders (48.7%) subsequently proceeded to allo-HCT. After median follow-up of 45.2 months, 4-year OS and CIR was 25.7% and 61.0% in entire cohort, and 37.0% and 47.9% after allo-HCT. We observed higher relapse rate with short CR duration, PB blast prior to blinatumomab, and later-line salvage were related with poor response to blinatumomab and old age and early relapse for poor OS even after allo-HCT. Regarding absolute lymphocyte count (ALC), ALC at first day of blinatumomab was not significantly associated with CR rate (OR=1.00, P=0.0523), OS (ALC≥500: 21.8% vs. ALC&lt;500 36.6; P=0.160), as well as CIR (ALC≥500: 50.2% vs. ALC&lt;500 55.7; P=0.819). However, we observed ALC decrement&gt;2000/mcL at 2-weeks after blinatumomab was predictive for poor response (OR 2.88, P=0.011), and that ALC&lt;250/mcL and decrement&gt;2000/mcL at 2-weeks after blinatumomab was associated with poor survival (Figure).
Conclusions: Our data shows that blinatumomab can be effective even in patients with low ALC at first day of blinatumomab, and that lesser decrease in ALC predicts higher CR in adult patients with R/R ALL.
Non-Driver Genomic Alterations and Venous Thromboembolism in Myeloproliferative Neoplasms
Authors: Ajufo Helen , Leader Avi , Derkach Andriy , Chrysafi Pavlina , Singh Rohan , Rampal Raajit , Mantha Simon , Zwicker Jeffrey I. 
Published: December 2024

Introduction: The most common cause of morbidity and mortality in the myeloproliferative neoplasms (MPNs) is thrombosis. Current risk scoring systems for essential thrombocythemia (ET) and polycythemia vera (PV) predict the risk of thrombosis. The influence of non-driver co-mutations such as those affecting epigenetic regulation in thrombosis is not established. This study seeks to further characterize the genomic landscape and genomic predictors of venous thromboembolism (VTE) in a comprehensive cohort of MPNs that may have implications for the use of cytoreductive therapy and antithrombotic therapy.
Methods: We assessed clinical and molecular risk factors of VTE in a cohort of patients from Memorial Sloan Kettering Cancer Center from 2017 to 2023 with annotated myeloid molecular data. VTE were identified through the use of the CEDARS+PINES natural language processing platform (Mantha et al, 2024) and instances were manually reviewed. Univariate and multivariate (stratified by MPN subtype) was conducted using cause specific Cox regression analysis to identify factors associated with VTE while adjusting for competing event of death. Cumulative incidences of thrombosis were estimated from date of genomic testing with death considered as a competing risk as well.
Results: The cohort included 656 patients with MPNs: 103 (16%) with essential thrombocythemia (ET), 117 (18%) with myelofibrosis (MF), 100 (15%) with polycythemia vera (PV), and 336 (51%) with an unclassified MPN. JAK2, CALR, and MPL mutations were present in 68%, 18% and 6% of patients, respectively. The most common non-driver somatic mutations identified were ASXL1 (14%), DNMT3A (11%), and TET2 (18%). The overall cumulative incidence of VTE at 3 years was 5.7% (95% confidence interval [CI] 3.7-8.4%). In a univariate analysis the factors associated with increased risk of VTE were older age (&gt;72 vs &lt;55 years; hazard ratio [HR] 6.12, 95% CI 1.38-27.13), MF (HR 3.84, 95% CI 1.02-14.37), prior history of VTE (HR 7.12, 95% CI 2.47-20.54), and presence of mutations in ASXL1 (HR 3.2, 95% CI 1.44-7.08), NRAS (HR 4.15, 95% CI 1.25-13.78), and TP53 (HR 5.43, 95% CI 1.27-23.22). In a multivariable model stratified by type of MPN, the HR for VTE associated with non-driver mutations was 5.39 for TP53 (p=0.029), 3.51 for NRAS (p=0.056), and 1.98 for ASXL1 (p=0.13). The risk was not further influenced by the presence of JAK2 mutations. Associations were similar when excluding patients with a history of VTE prior to genomic assessment.
Conclusions: Non-driver mutations appear to influence the risk of VTE in patients with MPN. Future studies are needed to evaluate how inclusion of non-driver mutations can improve the accuracy of thrombosis risk prediction models in MPNs and identification of patients most likely to benefit from antithrombotic prophylaxis.
Review of Rare Association between Chronic Lymphocytic Leukemia and Chromic Myeloid Leukemia
Authors: Abdalla Elmustafa , Fadul Abdalla , Osman Ahmed Elmudathir , Mohamed Gihan , Soliman Dina Sameh , Shawayli Hawra , Abuasab Tareq , Almahmood Motaz , Saied Amin , Mohamed Mohamed , Ahmed Shahd , Singh Kalpana , Mohamed Shehab 
Published: December 2024

Introduction:
Chronic lymphocytic leukemia (CLL) and chromic myeloid leukemia (CML) are the most found in elderly patients, with CLL being the most prevalent type of leukemia among older adults in Western nations. CML is the most common myeloproliferative neoplasm (MPNs). However, coexisting in a single patient is very rare and there are few documented cases of this in medical literature. Cases reported as sequential, where CML followed CLL diagnosis, vise versa or at the same time .
Methodology:
we preformed systematic literature review Our inclusion criteria included articles that presented cases of confirmed CLL associated with CML, whether diagnosed simultaneously or sequentially. Cases of CLL associated with Philadelphia negative MPNs were excluded from this review The search strategy used during our review with specified terms on both PubMed and Google Scholar.
Results
Twenty- six articles were found. All of them were cases reports. each case included one patient who had CML and CLL. Males were sightly predominant with 13/23(57%) compared to 10 females (3 cases they did not report) and mean age was 63.1. The mean of initial laboratory investigations at diagnosis showed HB 14.9 g/dl, WBC 52.6x10^3/uL, uL, Platelet 440x10^3/uL, . B symptoms were reported in 8 out 15 patients 57 %. The examination, a total of 13/21 (62%) found to have splenomegaly. CLL diagnosed first before CML in 13/26 (50%) of all cases and most common sequence. The second most common were concomitant presentation of CML and CLL presented at same time with 7 patients (27%). last group with 23 % those who had CML before CLL. The mean time difference between the two-diagnosis wither CLL first or CML around 44 months while the median was 48 (2 years). Cases of CLL First treated with wait and watch or chemotherapy 7/13 (54%) , chemotherapy protocols were FCR or Chlorambucil as most of reported cases before Bruton Tyrosine Kinase Inhibitors (BTK) era. The median exposure to chemotherapy was 36 months. Overall survival was 77 %, 6 patients died from different reasons including disease progression or febrile neutropenia and others.
Conclusion
CLL and CML associations is very rare only 26 cases reported in the literature till the moment. Both diseases can occur before each other or simultaneously.Since, majority of cases CLL diagnosed firstraising the possibility of therapy related mechanism secondary to chemotherapy previous exposure, specially most of them happened before BTKs . More studies and collaboration with large number is needed to study the mechanism and pathophysiology of this association. Currently there is no guidelines on how to treat patients with simultaneously CLL and CML .
Abbv-453: A Highly Potent and Selective Next Generation Small Molecule Inhibitor of BCL-2
Authors: Phillips Darren C , Robles-Cardona Luzivette , Alvey Cory , Ingram Justin , Lam Lloyd T , Yang Ziping , Riehm Jacob J , Chen Jun , Kurnick Matthew , Kovar Peter , Wang Jin , Doherty George , Bhat Vikram , Dai Yujia , Judd Andrew , Souers Andrew 
Published: December 2024

Evading apoptosis is a hallmark of cancer that is achieved by altering the dynamic binding interactions between pro-survival (BCL-2, BCL-XL, BCL-W, MCL-1, BFL-1) and pro-death (e.g., BAX, BAK, BAD, BIM, NOXA, PUMA) BCL-2 family members. BCL-2 itself plays a dominant role in survival of malignant hematologic cells; a dependency which has been exploited therapeutically as exemplified by the established clinical activity of BCL-2 inhibitors in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), multiple myeloma (MM), and acute myeloid leukemia (AML) (Fowler-Shorten et al., 2024).
ABBV-453, a next-generation BCL-2 inhibitor, was designed for enhanced molecular and biological properties to improve upon the patient experience relative to available therapies. Specifically, incorporation of macrocyclic elements into the hot-spot binding regions of BCL-2 afforded a constrained molecule with high potency, selectivity and durable in vivo activity at low doses. In vitro, ABBV-453 possesses sub-nM affinity for BCL-2 (KI = 0.228 nM) and high selectivity over family members BCL-XL and MCL-1. The high affinity and selectivity of ABBV-453 translates to potent cell killing activity human tumor cell lines dependent upon BCL-2, including the acute lymphocytic leukemia (ALL) cell line RS4;11 (EC50 = 4.7 nM in the presence of 10% human serum), and greatly decreased activity in human tumor cell lines dependent on BCL-XL (Molt-4 EC50 = 2.85 µM) and MCL-1 (H929 EC50 &gt;10 µM) for survival. Moreover, the cellular activity of ABBV-453 is on-target and mechanism-based as demonstrated by the disruption of BCL-2:BIM complexes and the rapid activation of the intrinsic apoptosis signaling pathway (as evidenced by caspase-3-7 activation and dissipation of the inner mitochondrial membrane potential) and the caspase dependent externalization of annexin-V at the plasma membrane of ABBV-453 treated tumor cells.
Activity of ABBV-453 monotherapy was compared to other clinically relevant BCL-2 inhibitors in an in vivo subcutaneous xenograft model of ALL. ABBV-453 demonstrated superior growth inhibition of the RS4;11 xenograft compared to both sonrotoclax or lisaftoclax at equivalent doses and schedule. ABBV-453 has the potential to be the best-in-class next-generation BCL-2 inhibitor and is actively being investigated in phase 1 clinical trials in relapsed or refractory (R/R) MM (ClinicalTrials.gov ID, NCT05308654) and R/R CLL/SLL (NCT06291220).