bluuebunny/crossref_metadata_2025_split huggingface dataset:
Management and Evolution after VTE Recurrence and/or Bleeding in Cancer Patients Receiving Anticoagulant Therapy for VTE: A Nationwide Cohort Study in France
Authors: Mahe Isabelle , Gusto Gaelle , Quignot Nadia , Khachatryan Artak , Chaves José , Moniot Audrey , André Lucas , Van Roy Sylvain , Mokgokong Ruth , Bertoletti Laurent 
Published: December 2023

CONCLUSION
Until recently, the standard of care for treatment of venous thromboembolism ( VTE) in cancer patients was low molecular weight heparins (LMWH). Despite anticoagulation therapy (AC), patients remain at high risk of treatment failure (VTE recurrence and/or bleeding).
To determine the characteristics, management and the course of treatment after experiencing a recurrent VTE and/or bleeding event in VTE cancer patients receiving LMWH.
A nationwide retrospective cohort study of all adult patients (identified via the French national health data system: SNDS) with VTE and active cancer prescribed LMWH from 2013 to 2018.
Of 31,771 patients administered LMWH, 1,256 patients (mean age 64.1 years) experienced a recurrent VTE (median time to the first recurrent VTE event: 1.2 months) and 1,129 patients (mean age 67.5 years) experienced a bleeding event leading to hospitalization (median time to the first bleeding event: 1.5 months) during the first six months, and among them 46.7% and 40.9% patients experienced the event within the first month.
The proportion of patients with recurrent VTE and bleeding varied according to cancer sites (7.3%, 6.5% and 5.1% for recurrent VTE and 5.0%, 6.1% and 4.1% for bleeding, respectively in lung, colorectal and breast cancer) (Figure 1).
The management of patients with recurrent VTE consisted of a switch to another AC treatment in 370 patients, in whom 262 switched to an oral AC (179 to a DOAC and 83 to a VKA), the remaining continuing LMWH.
The management of patients with bleeding consisted of a switch to another AC treatment in 159 patients. Among the 159 switched patients, 94 switched to an oral AC (73 to a DOAC and 21 to a VKA), &lt;10 stopped AC (Figure 2).
Our results indicate that recurrent VTE and bleeding events lead to a heterogenous switch of AC therapy. Further research is needed to optimize secondary AC management in VTE cancer patients.
This study was sponsored by Pfizer and Bristol Myers Squibb
Keywords : venous thromboembolism; cancer; anticoagulants; bleeding; low molecular weight heparin; treatment pattern
Primary Effusion Lymphoma (PEL) and Primary Effusion-like Lymphoma (PEL-LL): A Comparative Study of Clinicopathologic Features and Outcomes
Authors: Gupta Supriya , Graham Christopher , Haddad Philip A 
Published: December 2023

Background:
While PEL is a well-established distinct WHO entity, PEL-LL is poorly defined and has been characterized differently by different researchers. Over the years, it encompassed PEL that expressed mature B-cell markers, extra-cavitary solid PEL, and recently the HHV8-unrelated PEL-like lymphomas. For this study, we defined PEL-LL as PEL-like lymphomas expressing mature B-cell phenotype. We conducted this study to compare the clinicopathological characteristics of PEL and PEL-LL and their impact on clinical outcomes.
Methods:
To study the clinicopathologic characteristics, therapeutic interventions, overall survival (OS), disease-free survival (DFS), and prognostic factors, we compiled a pooled database of 381 cases of PEL and PEL-LL. Chi-square and t-test were used to test the statistical significance of differences in parameters. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of clinicopathologic factors on OS and DFS.
Results:
A total of 381 (268 PEL, 113 PEL-LL) patients were identified. PEL and PEL-LL median ages were 51 and 74 (p &lt; 0.0001), respectively. There was a male preponderance with M:F of 7 with PEL versus 2 with PEL-LL (p &lt; 0.0001). The median OS was 6 months for PEL and 16 months for PEL-LL (p = 0.006). Compared to the thoracic cavity, involvement of the peritoneal cavity was associated with worse OS in both PEL and PEL-LL. Still, PEL-LL maintained better outcomes for each risk group (24 and 7 vs. 11 and 4 months, p &lt; 0.0001). In the absence of HIV infection, PEL-LL has a superior OS to PEL (19 vs. 6 months, p = 0.002). However, HIV infection erases this survival advantage (6 vs. 6.5 months). In both entities, active treatment was associated with better OS (19 vs. 10 and 9 vs. 2 months, p &lt; 0.0001). However, the untreated PEL-LL arm did as well as the treated PEL arm. Achieving CR as the best response to therapy in both PEL-LL and PEL was associated with superior OS (108 vs. 7 and 70 vs. 2 months, p &lt; 0.0001). While dose-intense chemotherapy regimens did not impact OS in PEL-LL, they were associated with better OS in PEL (22 vs. 18 and 15 vs. 8 months, p = 0.03).
Conclusions:
This is the first study to compare PEL and PEL-LL expressing mature B-cell phenotype. It identifies key factors that impact OS that vary between the two entities. It also supports that PEL and PEL-LL represent two different disease entities regardless of their similar presentation.
Incidence and Predictive Factors of Heparin-Induced Thrombocytopenia: A Comprehensive Analysis Using National Inpatient Data
Authors: Al-Alwan Ahmad , Awidi Muhammad , Vyas Charmee , Singh Vinit , Khalid Farhan , Du Doantrang , Eltoukhy Hussam 
Published: December 2023

Introduction:
Heparin-induced thrombocytopenia (HIT) is a serious complication associated with heparin therapy, characterized by an immune reaction involving antibodies against heparin-platelet factor 4 (PF4). This immune complex formation triggers platelet activation, blood clotting, and reduced platelet counts. Several factors, including previous heparin exposure, duration of exposure, and certain comorbidities, have been examined as potential risk factors for HIT development. In this study, our objective was to determine the incidence of HIT and identify predictive factors associated with its occurrence.
Methods:
We conducted an analysis using the National Inpatient Sample (NIS) data from 2020 to investigate the incidence of HIT during that year and its correlation with specific comorbidities. Patient identification was based on the International Classification of Diseases (ICD-10) code D75.82. The incidence and associated comorbidities were evaluated using multivariate logistic analysis with Stata 17.
Results:
Among the 32,355,827 adult patients admitted throughout the United States in 2020, a total of 11,380 cases of HIT were identified. The incidence of HIT was significantly higher in male patients, obese individuals, those with acute kidney injury (AKI), chronic kidney disease (CKD), type II diabetes mellitus (DMII), heart failure (HF), primary hypercoagulable states, and autoimmune diseases such as systemic lupus erythematosus (SLE). The highest risk of developing HIT was observed in patients with thrombophilia (OR 4.17, 95% CI 3.66-4.75, P = .000), AKI (OR 3.53, 95% CI 3.19-3.91, P = .000), and HF (OR 2.10, 95% CI 1.90-2.33, P = .000). Among autoimmune diseases studied, only SLE was associated with an increased odds ratio for developing HIT (OR 1.60, 95% CI 1.06-2.41, P = .026).
Conclusion:
The incidence of HIT varies and is influenced by the presence of specific comorbidities. Further studies are recommended to investigate additional factors that may increase the likelihood of HIT development. This information could aid in validating and implementing standard precautionary measures in patients at higher risk of developing HIT.
Zanubrutinib, Lenalidomide Combined with R-CHOP As the Frontline Treatment for Mantle Cell Lymphoma
Authors: Zeng Zhiyong , Yang Apeng 
Published: December 2023

Objectives
Mantle cell lymphoma (MCL) has poor prognosis with existing available therapies. Zanubrutinib, a novel BTK inhibitor, has shown promising outcomes in relapsed/refractory MCL. The aim of this retrospective study was to evaluate the efficacy and safety of zanubrutinib combined with R2-CHOP (lenalidomide, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in newly diagnosed MCL.
Methods
We retrospectively analyzed newly diagnosed MCL between September 2020, to March 2023 in a single-center in China. All patients received zanubrutinib 160 mg twice daily, lenalidomide 25 mg daily (days 1 to day 14), rituximab 375 mg/m 2, cyclophosphamide 750 mg/m 2 (day 1), doxorubicin 50 mg/m 2 or liposome doxorubicin 40 mg (day 1), vincristine 1.4 mg/m 2 (day 1), and prednisone 100 mg (day 1 to day 5) every 3 weeks. After 4 cycles, autologous hematopoietic stem cell transplantation (ASCT) was performed according to the patient's condition. After 6 cycles of induction or ASCT, patients with an objective response (complete or partial response) continued to receive zanubrutinib twice daily plus rituximab maintenance therapy, administered every 12 weeks for up to 8 additional doses. All patients underwent CT or PET-CT scans to evaluate mid-term efficacy. After 6 cycles, PET-CT scans were evaluated for patients whose mid-term efficacy did not achieve complete metabolic response (CMR).
Results
All of 5 patients treated with ZR2-CHOP were enrolled. The median age was 50 years (range: 44-66 years), 3 patients were females, 2 patients were males. 3 patients were classical MCL, 1 patient was pleomorphic MCL, and 1 patient was blastoid-variant MCL. The overall response rate was 100% (5 of 5), and all of them achieved CMR (Figure 1). Three patients achieved CMR after 4 cycles received ASCT, two received 6 cycles. At the mid-term evaluation after 4 cycles, 4 patients achieved CMR, 1 patient achieved PR but achieved CMR after 6 cycles. At data cutoff (22 March 2023), the median follow-up time was 26.1 (range, 12.5-32.4) months. The median PFS and OS rates were not reached. The 2-year PFS rate and the 2-year OS rates were both 100% (Figure 2). The most common grade 3/4 adverse events were neutropenia (60%) and thrombocytopenia (40%), all of which were controllable and resolved. The results of WES analysis showed that the most common gene mutations were KMT2D (frequency, 60%) and DDR2 (frequency, 40%). ctDNA was dynamically detected in four patients. Matched analysis of WES and ctDNA showed that gene mutations detected by these two methods were highly consistent, with 3 out of 4 patients being consistent. Among them, one showed negative ctDNA before and after treatment, while the other three patients indicated a decreasing trend in ctDNA mutation rate after 4 or 6 cycles, including a 50% decline or a change from baseline to negative.
Conclusions:
ZR2-CHOP showed promising preliminary efficacy and acceptable safety in previously untreated patients with MCL.
Burden of Chemotherapy-Related Myelodysplastic Syndrome/Acute Myeloid Leukemia in the Chemotherapeutic Armamentarium
Authors: Gaddam Shiva Jashwanth , Grewal Udhayvir , Thevuthasan Sindhu , Ramadas Poornima 
Published: December 2023

Introduction:
Therapy related Myelodysplastic Syndrome and Acute Myeloid Leukemia (t-MDS/AML) is a well-established adverse event (AE) associated with conventional chemotherapy drugs and has historically carried a poorer prognosis when compared to de novo disease. Newer chemo medicines like PARP inhibitors have also been implicated in developing this complication. However, comprehensive real-world data is lacking pertaining to the AE burden relative to individual drug classes.
Methods:
We used the FDA Adverse Events Report System (FAERS) public dashboard to obtain the data. Data was available for the years 1970 - 2023. We retrieved the number of events that were reported as “Myelodysplastic Syndrome” or “Acute Myeloid Leukemia” for individual chemotherapy classes that have historically been known to cause t-MDS/AML. Disproportionality analysis was performed by calculating the reporting odds ratio (ROR) with its 95% confidence interval (CI).
Results:
The drug class with the highest ROR of MDS/AML was the topoisomerase inhibitors - ROR 2.38 (95% CI 2.27-2.49). Intercalating agents like anthracyclines and mitoxantrone had the next highest ROR of 2.12 (95% CI 2.04 - 2.21). The novel drug class PARP inhibitors had the third most burden of t-MDS/AML with an ROR of 1.57 (95% CI 1.46 - 1.69). Table 1. depicts the individual drug classes and their ROR for associated MDS/AML. Table 1 depicts the individual drug classes and their ROR for associated MDS/AML.
Conclusions:
From this retrospective analysis, we identified that among all the chemotherapy drug classes, the topoisomerase II inhibitors were associated with the highest burden of t-MDS/AML, followed by intercalating agents and PARP inhibitors. Further data is essential to identify the patient characteristics associated with higher risk of developing this dreaded complication. This could improve patient-counseling prior to treatment initiation, assist with alternate drug choices when applicable, and perhaps also aid in developing strategies for closer monitoring in high-risk patients.
Keeping up with the Cartashians - Classical Hematology Drug Approvals over Past 5 Years
Authors: Shah Surbhi , Padrnos Leslie , Pruthi Rajiv K. , Go Ronald S. 
Published: December 2023

Classical hematological disorders encompass a broad array of congenital and acquired blood conditions, ranging from thrombotic and hemorrhagic disorders, hemoglobinopathies such as sickle cell disease/thalassemia, abnormalities in blood counts, disorders of iron metabolism, obstetric hematologic conditions, and rare genetic hematologic diseases. The past decade has seen a revolution in research and therapeutic development for these disorders. It has led to FDA approval of novel therapies such as gene therapies for hemophilia and hemoglobinopathies, targeted therapies for coagulation and complement disorders, factor VIII mimetics, new immunotherapeutic targets for cytopenia and genomic-directed diagnosis and therapy for a wide range of blood disorders.
Between January 2018 and July 2023, 34 new drugs have been approved for different classical hematological disorders, and several more have received approval for new or expanded indications. This is changing how we treat patients with classical hematological conditions. Most classical hematological disorders have an impact on patients' quality of life as well as life span, and for decades, many of these disorders were managed with limited therapy options with variable efficacy.
Rare hemolytic disorders such as cold agglutinin disease, paroxysmal nocturnal hemoglobinuria, thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome, sickle cell disease, thalassemia, porphyria all have expanded options. Newer agents for the management of anemia, thrombocytopenia and leukopenia in different clinical settings are available. Lastly, management of hemophilia is being revolutionized by extended half-life products, non-factor options and gene therapy. Hemophilia care has always been deemed to be costly, but gene therapy is getting additional attention due to the high price tag.
We have compiled the list of all new drugs that got FDA approval for classical hematological disorders over past 5 years and plan to present this in the form of an infographic providing details on the drug along with its indication, trial leading to approval and cost implications of each therapy. Our intention is to summarize the drug development for classical hematology and highlight “not so benign” nature of these disorders and related therapy particularly in terms of financial toxicity for the patients.
Lung Megakaryocytes Arise from a Flt3 - Cell Lineage and Contribute to Recovery of Platelet Counts in Thrombocytopenic States
Authors: Livada Alison C. , McGrath Kathleen E. , Blick-Nitko Sara , Li Chen , Kingsley Paul D. , Vit Leah A. , Ture Sara , Koniski Anne , Palis James , Morrell Craig 
Published: December 2023

Platelet-producing megakaryocytes (Mks) are present in the lung, and we have described an immune modulatory phenotype of lung Mks. It is assumed that the extravascular lung Mks are ‘seeded’ from the bone marrow (BM). To investigate lung Mk origin and how origin may impact function, we used complementary models to lineage trace lung Mks and their platelets.
FlkSwitch mTmG mice label all progeny from Flt3 + progenitors with GFP while all other cells are labeled with Tomato. We leveraged the FlkSwitch mouse model to compare BM and lung Mk origins. In 18 week old mice, the vast majority of BM and spleen Mks were GFP +, while lung Mks were largely Tomato + (Figure 1A). These data implied that in the adult mouse lung Mks arise from a Flt3 - pathway that is distinct from BM megakaryopoiesis in homeostatic conditions.
We next used a lineage tracing model (MDS1-Cre-ERT2 Tomato) where tamoxifen (TAM) administration induces a Tomato reporter in hematopoietic stem cell (HSC)-derived cells. Mice were dosed with TAM at 18 weeks and sacrificed at 32 weeks. Lung and BM Mks were largely Tomato + (~75%) and matched Tomato levels of BM Lineage - Sca1 + c-Kit + (LSK). Next, we dosed mice with TAM at 8 weeks, sacrificed the mice at 14 weeks and found similarly high levels of Tomato in BM LSK, BM Mk, and lung Mk. In MDS1-Cre-ERT2 Tomato mice, both BM and lung Mks were Tomato +/HSC-dependent, suggesting that lung Mks arise from HSCs in adult mice.
Next, we used CFSE dye given oropharyngeal (OP) to label only lung cells. We detected CFSE + lung Mks for up to 120 days post administration without any CFSE + Mks in BM or spleen. These data suggested there is a long-lived Mk population in the lung. Taken together, these complementary models imply that lung Mks arise from a Flt3 - lineage that is HSC-dependent, which yields Mks that can live in the lung for extended periods of time.
The CFSE OP method labeled only lung cells, which enabled us to track lung Mk-derived platelets. We found that about 10% of the steady-state circulating platelet pool is lung derived. In a model of thrombocytopenia using diphtheria toxin mediated platelet depletion in PF4-Cre-iDTR mice, we observed a doubling of CFSE + lung-derived circulating platelets (about 20%). We also used Plasmodium yoelli murine malaria as a model of infection associated with more chronic thrombocytopenia. Using CFSE OP labeling of lung Mk-derived platelets, we saw a marked increase in CFSE + lung-derived platelets early post- P. Yoelli infection (Figure 1B).
Our studies suggest that lung Mks arise from a Flt3 - HSC-dependent pathway and contribute relatively more platelets during acute and chronic thrombocytopenia. Ongoing work aims to describe the role of lung megakaryopoiesis via a Flt3 - HSC-dependent pathway in early development and in models of thrombocytopenia.
Influence of Human and Viral IL-6 on KSHV Infection in Human Tonsil Lymphocytes
Authors: Zakir Wajd , Osborn Jessica , Totonchy Jennifer 
Published: December 2023

Background: Infection of B cells by lymphotropic gamma-herpesvirus Kaposi sarcoma-associated herpesvirus (KSHV) causes Multicentric Castleman Disease, Primary Effusion Lymphoma, and the newly-identified inflammatory syndrome designated KICS.1 Despite proven connections to lymphoproliferative disorders, little is known about how KSHV invades the human immune system or the early events governing infection in B lymphocytes. IL-6 signaling plays a critical role in KSHV-mediated disease, where elevated hIL-6 levels are positively associated with KSHV viral load and disease progression.2 This dynamic is even more complex due to the co-existence of human IL-6 (hIL6) and KSHV-encoded viral IL-6 (vIL6) in these diseases. Although the impact of IL-6 signaling is well-established in the context of KSHV disease, its role in the early stages of infection in B cells remains undefined.
Hypothesis: We hypothesize that hIL6 and vIL6 play critical roles in the early stages of KSHV infection in B cells and the establishment of KSHV-infected plasma cells.
Method: In this study, we use ex vivo infection of tonsil lymphocytes with recombinant KSHV as a model to investigate early infection events. Our main objective is to utilize multiple approaches, including molecular knockout of vIL6 from the KSHV genome, knockout of human IL6 through CRISPR-Cas9 gene editing as well as recombinant proteins and neutralizing antibodies to manipulate signaling from hIL6 and vIL6. We will examine how these manipulations affect the viability, differentiation, and proliferation of tonsil lymphocyte cultures as well as the magnitude and distribution of KSHV infection via flow cytometry analysis.
Results: In our investigations, successful knockdown of hIL-6 in non-B cells resulted in reduced B cell viability, with IL6 knockdown correlating with decreased B cell survival in the cultures as well as decreased KSHV infection, particularly in plasma cells. Neutralization of hIL6 reduced proliferation in B cell cultures and this effect was more profound when hIL6 was neutralized in the context of infection with the vIL6 mutant virus. Moreover, hIL-6 neutralization had little effect on total infection in the context of WT KSHV, but vIL6 mutant virus had a reduced ability to establish infection when hIL6 was neutralized. We will also present results showing the effects of vIL6 and hIL6 on B cell differentiation in response to KSHV infection. Overall, our findings suggest that hIL6 and vIL6 have complementary but separable roles in the early stages of KSHV infection in B cells.
References:
1. Thakker S, Verma SC. Co-infections and Pathogenesis of KSHV-Associated Malignancies. Front Microbiol. 2016;7. Accessed July 20, 2023. https://www.frontiersin.org/articles/10.3389/fmicb.2016.00151
2. N, Totonchy J. Cytokine-Targeted Therapeutics for KSHV-Associated Disease. Viruses. 2020;12(10):1097. doi:10.3390/v12101097