bluuebunny/crossref_metadata_2025_split huggingface dataset:
Central Nervous System Involvement in Mantle Cell Lymphoma: Clinical Features, Prognostic Factors and Outcomes from Multi-Centers in China
Authors: Yang Ping , Li Chunyuan , Yang Yuan , Liu Shuozi , Zhang Weilong , Wang Jing , Chen Yingtong , Hao Xiaoyu , Jing Hongmei 
Published: December 2024

Background: Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon, with the incidence of 3 to 5%. The median survival time was 3 to 6 months. Meanwhile, it is lower in Asia and previously mainly reported by case.
Patients and methods: We present the data on 16 patients with MCL who developed CNS involvement, from a database of 861 consecutively treated patients at 19 institutions.
Results: The crude incidence of CNS involvement in our cohort was 1.9%. In terms of clinical features, 25.0% patients were blastiod MCL, and 50% were high-risk group by MIPI score.46.7% were complex karyotypes. Eleven patients underwent second-generation sequencing, and the results showed the presence of high-risk gene mutations such as TP53 (3/11) NOTCH1 (3/11), ATM (3/11), KMT2D (2/11), CCND1 (2/11). One patient also had CDKN2A deletion and C-myc amplification. 43.8% of patients received high-dose cytarabine treatment, 50.0% received BTKi treatment, and 43.8% received BTKi+BCL-2i. The median treatment lines were 3 (1-6) lines. 75.0% of patients were early disease progression (POD24). The median time from diagnosis to central involvement is 22.0 (4-144) months. Six patients were treated with R-High-dose MTX , six cases were treated with R-BTKi ± other targeted drugs and three patients were treated with R-BTKi -high-dose MTX regimen, and one patient received local radiotherapy. CR and ORR were 12.5% and 31.3%, the median progression free survival after CNS involvement(PFS2) was 2.0 months and the median survival (OS2) was 7.0 months. Elevated levels of β 2-microglobulin, previous used BTKi, and SD/PD were poor prognostic factors for PFS2. In addition to the above factors, ECOG score ≥ 2 were inferior prognostic factors for OS2.
Conclusions: CNS involvement ,especially for patients who involved after BTKi treatment, the prognosis was extremely poor and there was a lack of effective treatment options.
Trends in the Renal Manifestations of Sickle Cell Disease over the Last 10 Years: A Nationwide Analysis
Authors: Solipuram Divya , Iqbal Rabia , Solipuram Swathi , Kumarasinghe Chathula , Kumar Suneet , Podrumar Alida I. 
Published: December 2024

Background:
The rising number of adults with sickle cell disease (SCD) has underscored a notable increase in end-organ dysfunction like sickle cell hepatopathy, nephropathy and cardiomyopathy. No report to date has examined the trends in the renal manifestations of SCD
Aim:
To determine the morbidity and mortality associated with renal dysfunction in patients with and without SCD across a decade using national database
Methods:
We included all admissions with renal conditions to acute care hospitals across the United States from 2012 to 2021. Confounders were accounted for using multivariable regression analyses
Results:
Inpatient hospitalizations due to renal issues steadily increased from 1543031 to 2313787 from 2012 to 2021, among them 4070 had SCD in 2012 while 8529 had SCD in 2021. Incidence of renal issues in SCD reduced from 5217 per 100,000 to 4802 per 100,000 during this period. In-hospital mortality rates from renal issues increased from 3.6% to 4.9%[adjusted odds ratio- 1.06; CI 1.0-1.13; trend p 0.04] in those patients with SCD while it increased from 4.4% to 6.2%[adjusted odds ratio-1.05; CI 1.05-1.06; trend p 0.000] in those without SCD from 2012 to 2021. Renal transplantation rate was 1.47% and 1.09% for patients with and without SCD in 2012, that increased to 1.64% for patients with SCD while it decreased to 1.06% for patients without SCD in 2021. ESRD and dialysis rates reduced significantly from 56% to 39% in patients without SCD while in patients with SCD a higher rate of ESRD and dialysis with only a minor reduction in rates from 68% to 64% was noted from 2012 to 2021. Mean length of hospitalization was higher and showed an increasing trend from 2012 to 2021 for patients with [7.1 to 7.5d]and without SCD[6.4 to 7d] with a trend p value of 0.000. A similar increase in hospitalization charges from $75219 to $98152 in SCD vs $71369 to $96534 in those without SCD[trend p 0.000] was noted during the same period.
Conclusion:
Though there is slight reduction in incidence of renal issues in SCD over the last decade, in-hospital mortality significantly increased. SCD patients with renal issues had higher rates of ESRD, dialysis and transplantation compared to non-SCD patients with renal issues. A higher morbidity rates in terms of hospitalization charges and duration was also noted
Treatment Outcomes of BTK Inhibitors and Venetoclax with/without Anti-CD20 Monoclonal Antibody in Patients with Relapsed or Refractory Mantle Cell Lymphoma: A Real-World Experience
Authors: Yang Ping , Li Chunyuan , Liu Shuozi , Wang Jing , Chen Yingtong , Zhang Weilong , Jing Hongmei 
Published: December 2024

Background: High-risk MCL patients with disease refractory/relapsed (R/R) lack effective treatment options and exhibit poor outcomes, posing challenges in management. The combination of BTK inhibitors (BTKi) and venetoclax obtained high complete remission (CR) and overall response rate (ORR) in clinical trials. The combination data for R/R MCL patients in the real-word is fewer. The aim of the study is to descibe the clinical characteristics and prognosis of BTKi combined venetoclax with or without anti-CD20 antibody in the R/R MCL patients of China.
Methods: A total of 49 patients treated with BTKi and venetoclax 200mg daily (Dual combination, n=17) or in combination with anti-CD20 monoclonal antibody (Triple combination, n=32) between June 2018 and February 2022 at our department were included in this retrospective analysis. All analyses were conducted using statistical language R (version 4.1.2). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.
Results: The median age was 62.0 years and the male-to-female ratio was 3.08:1.Patients had high-risk features including ki67≥30% (89.8%), blastoid/pleomorphic histology (36.7%), high-risk group of MCL International Prognostic Index (MIPI) (42.9%) complex karyotype (27.7%), TP53 mutations (71.4%), TP53 mutations combined with other high-risk gene mutations (57.1%) and 65.3% of progression of disease within 24 months (POD24). The basic clinical characteristics and cytogenetic features in the dual and triple combination were similar. The best ORR and CR were 67.4% and 53.1% in this study, and the 3-year PFS and OS were 37.5% and 50.8%, respectively. Except of TP53 mutations combined with other high-risk genes associating with worse OS, other high-risk factors including high-risk MIPI score, B/PMCL, Ki-67≥50%, POD24, and complex karyotype had the similar efficacy and prognosis to the low-risk. In the MA analysis, SD/PD after combination therapy was independent predictors for PFS and ECOG≥2, TP53 mutations with other high-risk genes mutation and SD/PD after combination treatment were the independent factors for poor OS. The most common adverse reactions were hematological toxicity and pulmonary infection. Finally, the most common death cause was disease progression (19/22) and 7 of them had secondary central nervous system involvement.
Conclusions: The combination of BTKi and venetoclax 200mg daily with or without CD20 antibody had a good efficacy for R/R MCL patients especially in early lines in our study.
Efficacy and Safety of CAR-T Therapy Targeting CLL1 in Patients with Extramedullary Diseases of Acute Myeloid Leukemia
Authors: Zhao Yifan , Bai Xue , Guo Shujing , Zhang Xiaomei , Zhao Mingfeng 
Published: December 2024

O bjective
Approximately 10-20% of patients diagnosed with acute myeloid leukemia (AML) present with extramedullary diseases (EMDs), which exhibit a significantly distinct etiology, therapeutic response, and prognosis compared to AML patients without EMDs. The proportion of patients with EMDs further increases in those with refractory and relapsed AML. The objective of this study is to evaluate potential disparities in the efficacy and adverse effects of Chimeric Antigen Receptor T-cell therapy (CAR-T) therapy targeting CLL1 between patients with and without EMDs.
Methods
A total of 47 patients, including 20 patients with EMDs, were prospectively enrolled in this prospective study, which has obtained approval from the institutional review board of Tianjin First Center Hospital and has been duly registered with the China Clinical Trial Registration Center (Clinical Trial Number: ChiCTR2000041054). All patients underwent lymphodepletion chemotherapy with a 3-day regimen of fludarabine (25 mg/m2) and cyclophosphamide (300 mg/m2) prior to the infusion of CAR-T cells. Afterwards, we thoroughly evaluated the effectiveness and occurrence of side effects during the treatment process, while also comparing the differences in laboratory indicators between patients with and without EMDs.
Results
Among the 20 patients with EMDs and the 27 individuals without EMDs, complete remission was achieved by 65.00% and 81.48% of patients, respectively, resulting in long-term survival through subsequent hematopoietic stem cell transplantation. Although the overall survival, progression-free survival, and duration of remission period appeared to be shorter for patients with EMDs compared to those without EMDs, this difference did not reach statistical significance. The incidence rates of complications, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematological toxicities, were similar in both groups. Meanwhile, there were no significant differences observed in the levels of CAR-T cell proliferation and accompanying cytokines release between patients with and without EMDs.
Conclusion
The results of our study have demonstrated the efficacy of CLL1 CAR-T therapy in the treatment of AML patients with EMDs. Despite a high incidence of CRS, ICANS, and hematological side effects, most patients were effectively managed through systemic treatment and subsequent bridged HSCT. Therefore, we recommend CLL1 CAR-T therapy as an efficient and safe therapeutic option for AML patients, irrespective of the presence of EMDs.
Long-Term Efficacy and Safety of CD19-Specific CAR-T Cells Armed with IL-7 and CCL19 in Patients with Relapsed or Refractory Large B-Cell Lymphoma: A Multi-Center Prospective Study
Authors: Qian Wenbin , Liu Hui , Lei Wen , Wang Linqin , Chen Panpan 
Published: December 2024

To further improve expansion, infiltration, persistence, and especially outcome, adjusting the Chimeric antigen receptor (CAR) structure to enhance antitumor efficiency is an important strategy. In this pattern, fourth-generation CAR-T, also named “armored CAR-T” or T cells redirected for universal cytokine killing (TRUCK), with the ability of expressing cytokines or chemokines, has been thoroughly evaluated in preclinical studies and clinical trials across various malignancies.
In our previous study, we developed a CD19-specific fourth-generation CAR-T expressing interleukin (IL)-7 and chemokine (C-C motif) ligand 19 (CCL19), named 7×19 CAR-T. In this long-term follow-up study of up to 5 years (NCT04833504), the 39 patients in the interim report were followed up for extended time.
Among these patients enrolled, the median age was 55 years (range, 29-73). Most of the patients (66.7%) had stage III or IV disease, 41% had an ECOG performance status score of 2 or 3, 64.1% had extranodal organ involvement, 51.3% had received at least three lines of previous therapies, 46.2% had received more than 10 times of prior treatment regimen, 51.3% had refractory disease, 7.7% experienced autologous stem cell transplantation (ASCT) and 46.2% had bulky disease defined as the presence of any mass with a single diameter over 7cm.
During a median follow-up of 63 months by reverse Kaplan-Meier method, 15 patients (38.5%) continued to survive at data cutoff. The median OS was 31 months, with an estimated 5-year OS of 43.6% (95% CI: 27.9 to 58.3%) among all patients and 64.6% among those achieving a CR. After excluding deaths unrelated to disease progression, the estimated disease-specific survival at 5 years reach 48.7% (95% CI: 32.4% to 63.2%). The median PFS was 13 months, with an estimated 5-year PFS of 30.8% (95% CI: 17.3% to 45.4%).
there was no significant difference between patients with or without bulky disease considering OS or PFS, which indicates that this armored CAR-T can to some extent overcome the adverse effect of bulky disease.
In summary, this updated 5-year analysis demonstrated the continued benefit of 7×19 CAR-T for in patients with Rel/Ref LBCL with satisfactory safety signals. The development of this study has laid a solid foundation for future frontline use or combined clinical research.
Cyclophosphamide Combined with Standard Immunosuppressive Therapy Improves Early Response Outcomes in Severe Aplastic Anemia
Authors: Pan Hong , Zhang Lele , Gao Zhen , Li Weiwang , Li Jianping , Nie Neng , Xiong Youzhen , Zhao Xin , Huang Jinbo , Zhao Jingyu , Yu Xiao , Kuang Zhexiang , Fang Liwei , Ge Meili , Yuan Weiping , Shi Jun 
Published: December 2024

Background: Thrombopoietin receptor agonists combined with ALG/ATG and cyclosporine are the standard immunosuppressive therapy for severe aplastic anemia (SAA). However, early response rates remain suboptimal. Cyclophosphamide has shown efficacy in relapsed/ refractory AA. Therefore, we designed a clinical trial to evaluate cyclophosphamide combined with the standard immunosuppressive therapy as a first-line treatment for SAA and very severe aplastic anemia (VSAA) to improve early response rates.
Methods: This study was a single-arm, prospective, phase II clinical trial using a Simon two-stage design. The primary endpoint was the overall response rate (ORR) at 3 months. Newly diagnosed SAA/VSAA patients received a combination treatment as follows: porcine ALG at 25 mg/kg/day from days 1 to 5, cyclosporine at 3-5 mg/kg/day continuously, herombopag at 15 mg/day starting from day 1 and continued for 6 months, cyclophosphamide at 20 mg/kg/day on days 29-30 and days 43-44.
Results: Among the 36 patients evaluable for the primary endpoint, the 3-month ORR was 66.7% (24/36), with a complete response (CR) rate of 8.3% (3/36) and a superior remission rate of 22.2% (8/36). 28 patients were evaluable for the 6-month efficacy, the ORR at 6 months was 75% (21/28), with a CR rate of 28.6% (8/28) and a superior remission rate of 64.3% (18/28). The most common adverse events after cyclophosphamide were grade 1-2 gastrointestinal reactions (100%) and grade 3-4 neutropenia (66.7%), with a median duration of 6 days (range: 4-33 days). The infection rate within 3 months was 58.3% (21/36). The mortality rate within 3 months was 0%.
Conclusion: Cyclophosphamide in combination with standard immunosuppressive therapy as first-line treatment shows good safety and efficacy, with two-thirds of patients achieving a response and becoming transfusion-independent within 3 months.
Preclinical Efficacy of Decoy-Resistant IL-18 in Hematological Malignancies
Authors: Lindquist Jeffrey N , Qin Kai , Liu Jeffrey M , Ring Aaron M , Uppal Hirdesh 
Published: December 2024

Interleukin-18 (IL18) is a proinflammatory cytokine that modulates both innate and adaptive immune responses. Historically, wild-type recombinant IL-18 has shown limited anti-tumor efficacy in preclinical models and clinical trials, likely due to upregulation of IL-18 binding protein (IL-18BP), a negative regulator of IL-18 signaling. Accordingly, Decoy-Resistant IL-18 (DR-18), an engineered IL-18 cytokine capable of interacting with the IL-18 receptor but resistant to IL-18BP inhibition, has demonstrated enhanced therapeutic potential in mouse solid tumor models, both as a single agent and in combination with anti-PD-1 [Zhou T, et al. Nature. 2020;583(7817):609-614.], and in leukemia following allogeneic bone marrow transplantation (alloBMT) [Minnie SA et al. Sci Immunol. 2022;7(76):eabo3420]. Here we evaluated murine DR-18 in a diverse set of mouse hematological tumor models, including in combination with conventional chemotoxic and immunotherapeutic agents. mDR-18's effect on survival was assessed and the immune cells required for mDR-18 activity were identified by depletion studies.
Results: Treatment with mDR-18 elicited strong efficacy as a single agent and showed combination activity across diverse syngeneic mouse models of hematological tumors. mDR-18 demonstrated robust single agent activity in tumor growth inhibition for subcutaneously implanted A20 B-cell lymphoma (95%), C1498 Acute myeloid leukemia (85%), and MPC-11 Plasma cell myeloma (50%). Combination treatment of mDR-18 with Aza+Vento chemotherapy increased treatment efficacy in C1498 (95%). mDR18 also showed increased survival as a single agent that was enhanced in combination with Aza+Vento. To ascertain the immune cells required for this activity of mDR-18, animals with C1498 tumors were treated with mDR-18 while depleting either CD4+, CD8+, NK1.1+, or both CD4+ & CD8+ cells from the mice. The activity of mDR-18 was abrogated in CD8+ and CD4+/CD8+ cell depleted animals. Examining the role of mDR-18 in combination with Blinatumomab, a CD3-CD19 bi-specific T-Cell engager, demonstrated greater tumor growth inhibition and a more durable response than monotherapy with either agent.
Conclusion: These studies extend the efficacy of DR-18 therapy in hematologic malignancies and demonstrate the potential benefit of combining DR-18 with additional agents beyond anti-PD-1, including chemotherapy and T cell engagers. These findings strengthen the rationale for expanding the use of the Phase I human DR-18 cytokine (ST-067, NCT04787042 & NCT06492707) in combination therapies for patients with hematological tumors.
YM155 Exerts Anti-Myeloma Effects Via Myc/BBC3 Signaling Pathway in Vitro
Authors: Jin Xianghong , Zhang Fujing , He Huiwen , Li Ziping , Zhuang Junling 
Published: December 2024

Background: Our previous studies have demonstrated a strong link between Myc rearrangement (Myc-R) and poor prognosis in newly diagnosed multiple myeloma (NDMM). The survivin inhibitor YM155, a novel small molecule, is currently under clinical investigation for aggressive B-cell lymphomas with Myc translocation. However, its effects on myeloma cells remain unclear.
Objectives: This study aims to explore the anti-myeloma mechanisms of YM155 in vitro through cell-based experiments.
Methods: In vitro, six MM cell lines (AMO-1, MM.1S, RPMI-8226, NCI-H929, U266, and KMS-11) were treated with YM155 to determine the IC50 using the CCK8 assay. Cell apoptosis was assessed by flow cytometry. RNA sequencing was conducted on MM.1S and RPMI-8226 cells to identify relevant regulatory pathways. Protein-protein interaction and transcription factor target prediction analyses were performed to predict interactions between proteins and the binding sites of Myc and its target genes. The identified regulatory pathways were validated using qPCR and Western blot (WB).
Results: The IC50 of YM155 in various MM cell lines ranged from 2.5 to 15 nM, which was similar to that of bortezomib. YM155 demonstrated a time- and dose-dependent inhibition of cell viability and induced apoptosis, significantly downregulating Myc expression at mRNA and protein levels. The combination of YM155 and bortezomib showed superior cytotoxicity compared to either agent alone, suggesting a synergistic effect. RNA sequencing indicated that Myc expression was suppressed and P53 signaling pathway was activated after YM155 treatment. This was confirmed by RT-qPCR and WB, which showed activation of pro-apoptotic protein BBC3 and inhibition of anti-apoptotic protein BCL2. JASPAR bioinformatic analysis predicted that Myc might inhibit BBC3 expression by binding its promoter region, thereby activating P53 pathway. Additionally, the IC50 of YM155 in bortezomib-resistant cells was 10.56 nM, similar to that in naïve cells.
Conclusion: YM155 exhibits in vitro anti-myeloma activity in a dose- and time-dependent manner and has a synergistic anti-tumor effect with bortezomib, reversing resistance to some extent. YM155 exerts its anti-myeloma effects by inhibiting Myc and upregulating BBC3 expression, which activates the P53 pathway. This provides its potential role for the treatment of high-risk/relapsed refractory MM.
Keywords: Multiple myeloma, high-risk, YM155, Myc inhibitor, drug resistance
αIIbβ3-Dependent Platelet Procoagulant Activity Promotes Pulmonary Arterial Thrombosis Triggered By Blood-Borne Tissue Factor
Authors: Tashbook Sarah E. , Kaminski Tomasz W. , Sundd Prithu , Brzoska Tomasz 
Published: December 2024

Rationale. In situ pulmonary arterial thrombosis (PAT), in the absence of concomitant deep vein thrombosis, is a life-threatening complication linked to several settings, including chronic obstructive pulmonary disease, asthma, sickle cell disease, emergency and elective surgeries, and viral infections. The occurrence of thrombotic complications in these conditions is correlated with elevated concentrations and activity of blood-borne tissue factor (TF). While TF is a primary initiator of blood coagulation, activated platelets accelerate coagulation by externalizing anionic phospholipids, such as phosphatidylserine (PS), and providing a catalytic surface for the assembly of coagulation enzyme complexes. In vitro experiments demonstrate that anionic phospholipids regulate TF-initiated coagulation; however, there is a lack of in vivo data on whether or how platelets contribute to the blood-borne TF-dependent in situ PAT.
Methods. We employed state-of-the-art quantitative fluorescence intravital lung microscopy (qFILM) to investigate PAT development in C57BL/6 (WT) mice following intravascular (IV) TF administration. We examined the impact of coagulation inhibition with heparin, platelet αIIbβ3 inhibition using eptifibatide, and phosphatidylserine (PS) blocking with annexin A5 (ANX) on circulating TF-induced PAT in WT mice. Fluorochrome-conjugated anti-mouse CD49b antibody, anti-mouse fibrin antibody, and dextran were administered IV for in vivo staining and visualization of platelets, fibrin, and blood vessels, respectively. Additionally, a modified prothrombin time assay (mPTA) was used to investigate the effect of platelet procoagulant activity on mouse platelet-rich plasma (PRP) clotting.
Results. TF triggered dose-dependent PAT in mice in vivo, which involved the development of platelet-rich thrombi in the junctions of pulmonary arterioles and capillaries, resulting in transient ischemia in the arteriole and the downstream capillary tree. The PAT, triggered by IV TF, was entirely abrogated by IV administration of heparin, eptifibatide, and ANX. In addition, the mPTA study confirmed that modification of platelet procoagulant activity by αIIbβ3 inhibition significantly extended clotting times in WT mouse PRP samples.
Conclusions. Our findings strongly suggest that circulating TF may contribute to the development of in situ PAT. We demonstrate that TF's action is dependent on platelet αIIbβ3 signaling, which promotes platelet procoagulant activity, accelerates coagulation and leads to PAT. Both our models have potential applications in investigating the molecular determinants of PAT associated with various pulmonary disorders, and in evaluating the efficacy of new antithrombotic drugs.