bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between Provoked and Unprovoked Venous Thromboembolism and Malignancy: A Cross-Sectional Retrospective Cohort Study
Authors: Naqvi Syeda Hira , Cheekati Mahija , Saad Firas , Caulfield Joseph , Farber Charles M. , Pillai Anjana 
Published: December 2024

Introduction:
A strong association exists between incidences of deep venous thrombosis (DVT), pulmonary embolism (PE), or venous thromboembolism (VTE) in cancer patients. Evidence for subsequent incidence of new malignancy in patients with VTE is poor and controversial. There is even less evidence to demonstrate an association between malignancy and provoked and unprovoked VTE. Despite this, extensive invasive and non-invasive diagnostic investigations are often performed during hospitalizations for VTE to rule out malignancy in patients. Through our study, we sought to further investigate the association of incidences of malignancy between provoked and unprovoked VTE patients.
Methods:
A retrospective search was first conducted to identify adult hospitalizations for VTE at a single tertiary care center for 2019. Through manual chart review for inciting risk factors, these patients were categorized as provoked and unprovoked. The two cohorts were longitudinally followed over a subsequent 5-year period (2020-2024). for the incidence of new malignancies. Patients with known malignancy and those who were lost to follow-up over the 5 years were excluded from the final analysis pool. Final data was analyzed using StataBE18 software to perform the Chi-squared test and Risk Ratio.
Results:
We identified 221 VTE hospitalizations in the year 2019, of which 155 were categorized as provoked and 66 as unprovoked. After excluding patients lost to follow-up and patients with active malignancy (75 provoked and 12 unprovoked), the final analysis included 80 provoked and 54 unprovoked VTE cases. Of the 54 unprovoked VTE patients, 5 (9.26%) were diagnosed with new malignancy during the follow-up period. Of the 80 provoked patients, 7 (8.75%) patients were diagnosed with new malignancy. We performed a Pearson's Chi-squared test to evaluate statistically significant differences in incidences of new cancer between each of the cohorts and found that the incidences were similar (chi2=0.0103; p-value 0.919) with a risk ratio of 1.03 and a 95% Confidence Interval between 0.51-2.10.
Conclusions:
Our analysis indicates that there is no statistically significant relationship between unprovoked or provoked VTE and the diagnosis of new malignancy. The incidence rates were almost similar in both cohorts. Therefore, patients with either provoked or unprovoked VTE should not require additional aggressive testing for malignancy. They should be expected to undergo age-appropriate screening as otherwise indicated. Excessive testing can lead to anxiety, prolonged hospitalization, misallocation of resources, and increased healthcare spending. Our study limitations include a small sample size and single-center analysis. Future larger studies comparing outcomes at different centers can provide further clarity to streamline our findings, given historically conflicting reports.
Evaluation of the Individual Components of the International Metabolic Prognostic Index (IMPI) in the Context of CAR T-Cell Treatment of Lymphoma
Authors: Winkelmann Michael , Rejeski Kai , Blumenberg Viktoria , Sheikh Gabriel , Buecklein Veit L. , Brendel Matthias , Von Bergwelt Michael , Subklewe Marion , Kunz Wolfgang G 
Published: December 2024

CD19 specific chimeric antigen receptor (CAR) T-cell therapy with patient-derived T cells has emerged as novel and effective treatment for relapsed or refractory (r/r) lymphoma. Imaging biomarkers are becoming increasingly important in risk assessment. Recently, the International Prognostic Metabolic Index (IMPI) consisting of metabolic tumor volume (MTV), patient age and Ann Arbor stage was introduced for prognostic assessment in NHL. Since higher patient age is a favorable prognostic factor and a high MTV is a negative prognostic factor in the context of CART, we compared the predictive value of the individual components of the IMPI for progression-free survival (PFS) and overall survival (OS).
Consecutive r/r NHL patients treated with CD19 CAR T-cell therapy and 18F FDG-PET/CT imaging at baseline less than 2 weeks before lymphodepletion and infusion of CAR T cells were included. Patient age was calculated at the time of lymphodepletion. Ann Arbor stages were determined at the baseline PET/CT. MTV was also quantified on the same PET/CT scan before CART and quantified with LIFEx software using semi-automated segmentation with an absolute SUV cutoff of 4 defining metabolic active lymphoma. Survival analysis of PFS and OS was analyzed and plotted with Kaplan-Meier curves.
Out of all examined patients 43 patients were included (37% female, 63% male) with a median age of 66 years and a median baseline MTV of 276 mL. The Ann Arbor stage was I in 4 patients, II in 11 patients, III in 8 patients and IV in 4 patients. The distribution of patients in to two different groups by median IMPI showed minor, non-significant differences in median PFS (97 vs 364 days; p=0.198) and OS (657 days vs not reached; p=0.718). Dichotomization by median MTV alone showed a larger, statistically significant difference (p=0.037) in median PFS (87 vs 659 days) and a larger, non-significant difference in OS (p=0.300). Patients with older age had slightly longer PFS (153 vs 97 days) and a comparable OS (686 vs 657 days), but these findings were not statistically significant (both p&gt;0.05). In addition, there were no relevant differences when the patients were divided into subgroups according to their Ann Arbor stages.
For r/r NHL patients on CART, the IMPI is a promising tool. However, in our study, the MTV alone was superior in estimating prognosis. Future studies with a larger cohort should investigate the best combination of the individual components. The integration of multiple diagnostic modalities as in IMPI offers a promising method to clinically assess patient risk in CART treated lymphoma patients and should be further investigated.
The Procoagulant Effect of Plasma-Derived Preparations of Apo H (b2-glycoprotein I) on Thrombin Generation Is Mediated By FXIa Contaminant
Authors: Liang Yideng , Tarandovskiy Ivan , Yang Hailing , Wang Yonggang , Eller Nancy , Surov Stepan , Parunov Leonid , Scott Dorothy E , Sauna Zuben E. , Ovanesov Mikhail 
Published: December 2024

Background. Apolipoprotein-H (APOH), also known as b2-Glycoprotein I (b2GPI), is a plasma protein that was found in immune globulin product lots associated with thrombotic complications. Previously, APOH demonstrated anticoagulant activity, on the contrary, Lackner et al reported that APOH has procoagulant function. In the present study, we show that plasma derived APOH (pdAPOH) can be contaminated with activated coagulation factor XI (FXIa).
Methods. In-house modified simultaneous thrombin and fibrin generation assay (TGA) along with FXIa activity chromogenic assay (FXIa:C) were used to detect FXIa function. In parallel, high-performance liquid chromatography (HPLC) was used to demonstrate presence of FXIa in the procoagulant APOH.
Results. Functional FXIa activity was detected in plasma derived APOH (pdAPOH-FIT). This activity was comparable to that measured in purified FXIa and procoagulant immune globulin product (IGIV) batches known to contain FXIa. Anti-FXIa antibody blocked procoagulant activity of pdAPOH-FIT in the TGA. An APOH sample from another source pdAPOH-2 and recombinant APOH did not show any activity in the TGA. Presence of FXIa in pdAPOH-FIT was confirmed using the chromogenic assay. Using HPLC, we show that peaks for pdAPOH-FIT and pdAPOH-2 differed. However, procoagulant pdAPOH-FIT demonstrated peaks similar to pdAPOH-2 when spiked with FXIa.
Conclusions. APOH does not demonstrate procoagulant activity in TG assay in plasma. plasma derived APOH products may contain procoagulant FXIa contaminant in the amounts sufficient to impact TG which may be misinterpreted as procoagulant activity of APOH.
BTK Inhibitors and Chidamide-Combined Therapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma with MYC+
Authors: Zhou Lili , Ye Shiguang , Li Ping , Li Bing , Lu Yan , Li Shaoguang , Liang Aibin 
Published: December 2024

Background:
Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) shows poor clinical outcomes, particularly in patients with MYC rearrangement or mutations. Monotherapy Bruton tyrosine kinase inhibitors (BTKi) have established modest antitumor effect in R/R DLBCL by targeting B-cell receptor signaling, with median progression-free survival (PFS) and overall survival (OS) of 1.64-2.8 months and 6.4-8.4 months, respectively. Chidamide is a selective oral histone deacetylase inhibitors (HDACi) that shows promising treatment for DLBCL and may overcome BTKi resistance. So, we evaluated the efficacy and safety of BTKis and chidamide-combined therapy in R/R DLBCL with MYC+ .
Methods:
This retrospective study consists of 12 R/R DLBCL who received combination therapy of chidamide and BTK inhibitors between January 2023 and July 2024. Chidamide was orally administered at a dose of 20 mg twice a week, while the BTK inhibitor was administered daily. Patient clinical characteristics were collected upon patient enrollment. Efficacy outcomes included overall response rate (ORR), PFS and OS, whereas safety outcomes included incidence of adverse events.
Results:
12 R/R DLBCL patients were enrolled. Median age was 63 years (range, 39-73), and 83.33% of the patients had non-germinal center B-cell-like (non-GCB) DLBCL, two had transformed DLBCL. The median number of previous treatment lines was 3 (range, 1-8). 10 patients (83.33%) received treatment with BTK inhibitors before. The best ORR was 66.67%, with 8 of 12 patients acquired objective disease remission after 1-2 cycles. Among them, 6 patients (50%) achieved complete response, and 2 patients (16.67%) achieved partial remission. With a median follow-up of 6.5 months, the median PFS and median OS was not yet reached. In terms of adverse events, the most common hematologic toxicities observed were neutropenia (50%, 6/12) and anemia (66.67%, 8/12). This study was registered as ChiCTR2300073233.
Conclusion:
This study revealed promising results. Chidamide combined with BTK inhibitors showed high efficacy and manageable tolerability in R/R DLBCL patients with MYC+. Although the majority of patients were treated with BTK inhibitors and experienced relapse and resistance, the addition of chidamide brought patients back into remission, suggesting that chidamide can enhance the efficacy of BTK inhibitors and overcome acquired resistance.
Keywords: BTK inhibitors, Chidamide, R/R DLBCL, MYC，efficacy and safety
Identification of Amino Acid Residues in Protein S LG Domains Responsible for Binding to and Inhibiting Factor IXa
Authors: Yasmin Rafika , Kumar Narender , Vandana  , Satish Vijaya Pilli , Majumder Rinku 
Published: December 2024

Protein S (PS) is a key negative regulator of blood coagulation. Protein S deficiency and dysfunction cause life-threatening thrombotic conditions such as neonatal purpura fulminans, deep vein thrombosis, arterial thrombosis, and pulmonary embolism. Protein S has long been described as a cofactor for both Activated Protein C and Tissue Factor Pathway Inhibitor. However, we discovered that PS has an important regulatory function in the coagulation cascade, namely, direct inhibition of activated Factor IX (FIXa). This function is performed by binding between the laminin G (LG) domains of PS and the heparin-binding exosite of FIXa.
Our goal in this study was to identify the amino acid residues of PS involved in binding FIXa. In silico interaction studies predicted candidate FIXa interaction sites within PS LG domains. These sites were mutated to obtain single amino acid substitutions D345A, T372A, S394A, E435A, and E437A and a double mutant E453A/E437A, all successfully expressed in E.coli. The purity of these proteins was confirmed by SDS-PAGE followed by silver staining and immunoblotting. Using fluorescence-based interaction methods, we identified the amino acid residues that are vital for PS-FIXa interaction. The double mutant E453A/E437A had the lowest binding affinity of the mutants. The mutants were further analyzed by in vitro biochemical assays to measure their ability to inhibit FIXa's activity of converting FX to activated FXa. Interestingly, both the E453A/E437A double mutant and the single mutants E453A and E437A showed minimal inhibition of FIXa. These data suggested that the glutamic acid (E) residues at positions 453 and 437 of PS are important both for binding FIXa and for inhibiting FIXa activity.
In summary, we identified two amino acid residues in the PS LG domain required for binding FIXa and inhibition of FIXa enzymatic activity. Our results explain the structure-function relation between PS and FIXa in hemostasis. Further measurement of effects these mutants in vivo will provide a comprehensive understanding of the PS function in the coagulation pathway and potentially identify targets for therapeutic interventions to manage coagulation disorders.
Clinical and Molecular Differences in Diffuse Large B-Cell Lymphoma with and without Testicular Involvement: A Cbioportal Analysis
Authors: Bahar Furkan , Khaddour Karam 
Published: December 2024

Background: Diffuse Large B-Cell Lymphoma (DLBCL) exhibits diverse clinical behaviors. Testicular DLBCL can have distinct clinical presentation and genetic landscape compared to non-testicular DLBCL. This study aims to characterize these differences to improve diagnostic precision and therapeutic strategies.
Methods: By using cBioPortal (1), we detected 1,658 DLBCL cases from six studies that were previously published, focusing on 722 cases with recorded testicular involvement status. We compared demographic data, survival, tumor mutational burden (TMB), and gene alteration profiles between groups with and without testicular involvement in DLBCL.
Results: Among the 722 cases, 80 (11.1%) had testicular tumor infiltration. Patients with testicular DLBCL presented at a significantly younger age (mean is 60.82 years, 95% CI: 59.49-61.87) compared to those without testicular involvement (mean is 67.56 years, 95% CI: 65.05-70.07). Moreover, testicular involvement was associated with a higher incidence of pleural and intraabdominal lesions (p=2.11E-3 and p=1.53E-4, respectively). Both groups had statistically similar overall survival. Consistent with previous small cohort studies, mutational analysis revealed that, MYD88 gene, a critical mediator in the NF-kB signaling pathway which influences B-cell survival and proliferation, showed significant mutation enrichment in the testicular group (45.88% vs. 15.8% in the non-testicular group, p=1.42E-9). Other mutations such as PIM1(p=2.694E-4), CDKN2A(p=1.844E-3), and ARID1A(p=6.845E-3) were also significantly higher in the testicular group despite similar TMB in both groups, suggesting a distinct pathogenic mechanism in these lymphomas.
Conclusions: Patients with testicular DLBCL present at a younger age compared to the patients with non-testicular DLBCL. The high prevalence of MYD88 mutations in the testicular subgroup suggests potential therapeutic targets and warrants further investigation into tailored treatment protocols for this population. In addition, non-testicular DLBCL patients with MYD88 mutations might benefit from regular testicular examination with ultrasound for early detection.
Impact of Daratumumab in Transplant Eligible/Ineligible Patients with Newly Diagnosed Multiple Myeloma: An Updated Meta-Analysis of Phase-III Trials
Authors: Fernandes Bolivia Crocete Aloysia , Shah Vedant , Ali Muhammad Ashar , Shah Abhi , Madine Makarand , Gottumukkala Mounika , Pandeti Sucharitha , Syed Safa , Nookala Vinod 
Published: December 2024

Introduction: With the recent advancement in multiple myeloma, Daratumumab a monoclonal antibody against CD38 has been shown promising results especially in those with who were refractory to other treatments. In this meta-analysis, we aimed to analyze the efficacy of daratumumab in newly diagnosed patients with multiple myeloma who were or were not eligible for transplant therapy.
Methods: A thorough search was conducted in PubMed, Cochrane, and Clinicaltrials.gov using the MeSH terms “daratumumab” or “Darzalex” and “multiple myeloma” covering the period from 2000 to 2024. Studies that compared daratumumab combined with other therapies versus combination therapy alone were included. The Mantel-Haenzel formula was employed to calculate the pooled risk ratio (RR), and the Generic Inverse Variance method was used to determine the pooled hazard ratio for disease progression, using RevMan version 5.4 with a 95% confidence interval (CI). A P value of less than 0.05 was deemed significant.
Results: A total of 6 phase-III RCTs 3664 patients were analyzed. The use of daratumumab was associated with 39% fewer events of progression of disease or deaths in TE group (RR= 0.61; 95% CI= 0.39 to 0.93; p=0.02) and 29% lower in TIE group (RR= 0.71; 95% CI= 0.53 to 0.94; p=0.02). The hazard ratio for progression or death with daratumumab group versus control in both transplant eligible (TE) (HR= 0.44; 95% CI= 0.35 to 0.57; p&lt;0.00001) or transplant ineligible (TIE) (HR= 0.47; 95% CI= 0.38 to 0.59; p&lt;0.00001) group was significantly lower. Daratumumab significantly increased overall response rate (ORR) (RR= 1.20; 95% CI= 1.11 to 1.30 ; p&lt;0.00001) and complete response (CR) (RR= 1.34; 95% CI= 1.02 to 1.76; p=0.04) in the TIE group only. Interestingly, the rate of minimal residual disease (MRD)-negative was increased only in the TIE group (RR= 4.09; 95% CI= 2.81 to 5.94; p&lt;0.00001) with the use of daratumumab compared to the TE group.
Conclusion: Use of daratumumab showed benefits in both TE and TIE patients with newly diagnosed multiple myeloma (NDMM). It significantly reduced the risk for disease progression or deaths and improved clinical outcomes in terms of ORR and CR. The most notable improvements were observed in the TIE-NDMM group, suggesting an effective treatment option in these patient groups.
Allogeneic Haematopoietic Stem Cell Transplantation Is Safe and Effective for Myeloid Neoplasms with Germline DDX41 Mutation
Authors: Nelles Ricky , Butler Jason , Curley Cameron , Henden Andrea S , Hunt Stewart , Morton James , Subramoniapillai Elango , Stewart Caroline , Tey Siok-Keen , Kennedy Glen A , Scott Ashleigh P 
Published: December 2024

Aim:
Germline DDX41 mutations define specific myeloid neoplasm subtypes including AML and MDS. Whilst DDX41-mutated patients often undergo allogeneic haematopoietic stem cell transplant (HSCT), recent retrospective analyses have reported higher severe acute and chronic graft vs host disease (GVHD)1 and inferior survival2 compared to non-DDX41 mutated patients. We aimed to review the outcomes of patients transplanted at our center for myeloid neoplasms with germline DDX41 (MN-DDX41).
Method:
We conducted a retrospective analysis of all patients treated at our institution for MN-DDX41 between January 2019 to January 2024. Data collected included disease characteristics, genomic data, treatment details, response outcomes and survival. The primary endpoint was overall survival (OS), with secondary endpoints including treatment-related mortality (TRM), relapse, and GVHD incidence.
Results:
22 patients with MN-DDX41 were identified (8 AML, 14 MDS). Median age at diagnosis was 64 (range 59-75 years), with 18 (87%) male. Donor source was matched sibling (1; 7%), matched unrelated (11; 79%) or mismatched unrelated (2; 14%); conditioning was reduced-intensity or non-myeloablative in 13 and 1 respectively; GVHD prophylaxis was CsA/MTX in 8 (57%) and PTCy/tacrolimus/MMF in 6 (43%). After median follow-up of 27 months (range 6-64mo), 17 (77%) are alive; 4 patients not receiving HSCT died from progressive/refractory disease, and 1 HSCT recipient died from infection soon after engraftment. For HSCT recipients, after median follow-up 18 months post-HSCT (range 1-45mo), 13 (93%) remain alive in remission. The cumulative incidences of acute (grade II-IV) and moderate-severe chronic GVHD are 35% and 50% respectively. OS following original diagnosis showed a non-significant trend for HSCT recipients vs non-recipients (2-yr OS 90% vs 65%; p=0.19).
Conclusion:
Despite adverse risk factors our early single-centre experience suggests that allogeneic HSCT is acceptably safe and efficacious for patients with MN-DDX41, and supports its use compared to non-HSCT alternatives. Confirmation in larger, multicentre studies with longer follow-up is warranted.
References: Saygin C, Roloff G, Hahn CN, Chhetri R, Gill S, Elmariah H, et al. Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies. Blood Adv. 2023 Feb 17;7(4):549-54. Baranwal A, Nanaa A, Viswanatha D, He R, Foran J, Badar T, et al. Outcomes of allogeneic transplant in patients with DDX41 mutated myelodysplastic syndrome and acute myeloid leukemia. Bone Marrow Transplant. 2022 Nov;57(11):1716-8.
Ixazomib, Pomalidomide and Dexamethasone (IxaPD) Pan-Oral Regimen in the Treatment of Refractory and Relapsed Multiple Myeloma
Authors: Chen Miao , Yu Hong , Liu Aijun , Wang Wei , Qin Xiaoqi , Li Ziping , Ma Yanping , Chen Wenming , Fu Rong , Zhuang Junling 
Published: December 2024

Aim To analyze the efficacy and safety of Ixazomib, pomalidomide and dexamethasone (IxaPD) regimen in patients with refractory and relapsed multiple myeloma（RRMM）.
Methods Clinical data of RRMM patients were prospectively collected from 5 centers in north China from Mar 2021 to Nov 2023 who were treated by IxaPD regimen for at least two courses. Overall response rate (ORR), time to next treatment (TTNT) and overall survival (OS) were analyzed as end points.
Results A total of 50 patients were enrolled, including 30 in multicenter real-world study and 20 in investigator initiated IxaPD trial (NCT04989140) who were naïve to ixazomib or pomalidomide with previous treatment of 1 to 3 lines. There were 28 males and 22 females with the median age 65.5 (range 41-82) years old. The median duration from diagnosis to enrollment was 30 months (range 1-170), including 26/50 (52.0%) patients were in first relapse. Twenty-three in 41 (56.1%) patients had high-risk cytogenetic abnormalities. Regarding previous history, 15.2% presented renal insufficiency, 4 cases (8.0%) had extramedullary diseases, and 7 case (14.0%) received autologous hematopoietic stem cell transplantation (ASCT). After median 8.5 courses (range 2-23) of IxaPD regimen, the ORR was 70.0%, with 54.0% VGPR or better. The median time to achieve the best response was 2 months (range 1-9). After a median follow-up of 18 months (range 3-47), 62.0% of patients progressed and the median TTNT was 9.5 months (range 2-31). The mortality rate was 24.0%, and the median OS was not reached. In the multivariate analysis, age, first relapse, R-ISS, high-risk cytogenetics abnormalities, and renal insufficiency and response to first-line induction therapy did not significantly affect TTNT. Neither did those factors also have significant impact on OS. Most of the adverse effects (AEs) were grade 1-2, mainly skin rash, peripheral neuropathy, constipation, diarrhea, edema, arthralgia, herpes zoster, and shortness of breath. There were only two grade 3 AEs, one for pulmonary infection and one for severe myelosuppression.
Conclusion The pan-oral IxaPD regimen showed anticipated effect and good tolerance for RRMM patients. More patients are being enrolled and update data will be reported.
【Key words】 Multiple myeloma; refractory and relapse; pan-oral regimen; ixazomib; pomalidomide