bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prophylaxis and Treatment of Bleeding or Thrombosis with Fibrinogen Concentrate (Fibryga) in Patients with Congenital Hypofibrinogenemia or Dysfibrinogenemia
Authors: Tarantino Michael D. , Ansteatt Kristin , Mistretta Jessica 
Published: December 2023

Congenital fibrinogen disorders (CFDs) are rare and make up approximately 0.6% of all inherited bleeding disorders. Two subtypes include a quantitative deficiency of fibrinogen, congenital afibrinogenemia (CA), congenital hypofibrinogenemia (CH), and qualitative defect of the fibrinogen molecule, congenital dysfibrinogenemia (CD). Patients with CD may have a thrombotic as well as a hemorrhagic disease phenotype. In the past, fresh frozen plasma or cryoprecipitate were the only options available for treatment and prevention of bleeding in patients with CFD. Today in the US, human plasma-derived concentrates (FIBRYGA, Octapharma, Lachlen, Switzerland, and RiaSTAP, CSL, Melbourne, Australia) are available and considered safe and effective treatment options for CD and CH. Guidelines for the treatment and prevention of bleeding is not established for CFDs, and especially for CD.
We present eight clinical cases of patients with hypo- or dysfibrinogenemia that were effectively treated with a pooled, plasma-derived fibrinogen concentrate (FIBRYGA) either prophylactically for elective or urgent surgery, or post-traumatic injury. The mean age of patients treated was 34 years (min-max 8-70 years). Three patients were male and five, female. Four patients had CH and four, CD. FIBRYGA was used to prophylactically treat a total of ten surgical procedures and two post-traumatic events in these patients. Dosing of FIBRYGA was based on the goal peak plasma fibrinogen concentration and the manufacturer's prescribing information, but modified to align with local laboratory reference ranges for the functional fibrinogen test. No acute or delayed infusion reactions (nausea, fever, rigors, headache) and no hypersensitivity reactions were noted. One patient developed two adverse events, one thrombotic and one hemorrhagic. This patient underwent left, above the knee amputation (AKA) and had a complicated postoperative period due to her multiple comorbidities including type 2 diabetes, hypertension, and long standing, poorly-controlled, severe peripheral arterial disease. She presented nineteen days after receiving FIBRGYA with a PE and multiple DVTs. Fifty-nine days later she presented with wound dehiscence and underwent an extensive excisional debridement with postoperative bleeding deemed to be secondary to her strap sliding during surgery and acting as a tourniquet for venous blood flow.
For the majority (86%) of our patients described here with CH and CD, FIBRYGA was well tolerated and effective in preventing post procedural or post traumatic bleeding complications. The post procedural bleeding noted in one patient may have been due to inadequate fibrinogen concentration or other comorbid conditions. Further clinical studies are needed to determine the role of FIBRGYA and other HFC in the treatment of patients with CFD, especially those with CD.
Cost-Effectiveness of Emicizumab Vs Efanesoctocog Alfa, Standard Half Life (SHL) and Other Extended Half Life (EHL) FVIII Products for Prophylaxis in People with Severe Hemophilia a without Inhibitors
Authors: Curtis Randall , Decker-Palmer Marquita , Wilson Michele R , McDade Cheryl L , Lin Chia-Wei , Wallick Chris , Ko Richard H 
Published: December 2023

Background: Hemophilia A is a bleeding disorder characterized by a deficiency in factor VIII (FVIII). Routine prophylaxis with FVIII products or emicizumab is the recommended approach to management for people with hemophilia A (PwHA). The burden of lifelong prophylaxis treatments to prevent bleeding events for PwHA is substantial, impacting both the patients and the healthcare system. The objective of this study is to estimate the relative cost-effectiveness of these prophylactic therapies for PwHA, including the newly approved efanesoctocog alfa.
Methods: A Markov model was developed with four FVIII-based health states (normal clotting function, mild hemophilia, moderate hemophilia, severe hemophilia) and death to compare emicizumab, efanesoctocog alfa, standard half-life (SHL) and other extended half-life (EHL) FVIII products as prophylaxis for PwHA in the United States (US). Advate and Eloctate data were used to represent SHL and EHL, respectively. The model considered a cohort of 38 years old hemophilia A patients with average weight of 94.4 kg treated with prophylaxis. Probability of experiencing each health state was based on each product's pharmacokinetic data, where FVIII activity levels were used to determine disease severity. Other clinical inputs, including annualized bleed rates and adverse event risks, were estimated from clinical trial data. Wholesale acquisition cost (WAC) of drugs and healthcare costs of bleed management and adverse events were included and were estimated from published literature. Utilities by disease severity were derived from published real-world health-related quality of life studies for hemophilia patients. Disutility of infusion was obtained from the published literature. Costs (in 2023 US dollars), quality-adjusted life-year (QALY), and total bleeds were estimated over a lifetime horizon. Cost-effectiveness was estimated as incremental cost per QALY gained. One-way and probabilistic sensitivity analyses were conducted.
Results: Over a lifetime, emicizumab was estimated to be less costly (total cost at $17.0 million for emicizumab vs $24.0 million, $19.3 million, and $18.2 million for efanesoctocog alfa, SHL, and EHL) and more effective (18.61 vs 18.58, 16.91, and 17.33 QALY) compared with efanesoctocog alfa, SHL, and EHL FVIII, respectively. Although efanesoctocog led to fewer bleeds (26.58 vs 59.91 bleeds over a lifetime), PwHA on emicizumab were expected to incur fewer bleeds (59.91 vs 198.45, and 108.58 bleeds) compared with EHL and SHL. Results were robust to one-way and probabilistic sensitivity analyses.
Conclusions: Findings in this cost-effectiveness analysis suggest that emicizumab is less costly and more effective (i.e., dominant) over a lifetime compared with available FVIII prophylaxis in pediatrics and adult PwHA in the US.
Insights on Sickle Cell Disease Therapies in Sierra Leone
Authors: Willard Rachele E. , Buscetta Ashley , Ramirez Hasmin C. , Jaja Cheedy , Bonham Vence L. 
Published: December 2023

Introduction: Ongoing sickle cell disease (SCD) gene therapy clinical trials in the United States and other high resource countries have shown promising results, and several therapies are under U.S. Food and Drug Administration review in 2023. Despite these advances, the current evidence-based practices are not accessible to much of the world's sickle cell population. As treatment advances are made for SCD, the integration of these therapies in sub-Saharan African countries-which have the highest prevalence of SCD-requires a global partnership. Sierra Leone ranks 9 th in burden in sub-Saharan Africa with annual SCD births between 4000-5000. Efforts are underway in Sierra Leone to improve awareness and healthcare infrastructure for the SCD population; however, the country still lacks a national screening program for diagnosis and faces challenges in providing comprehensive care across the lifespan. This study examines adult SCD patients' knowledge of current evidence-based care and novel gene therapies in Sierra Leone.
Methods: In 2021-2022, a cohort (n=123) of adults living with SCD in Sierra Leone were surveyed as part of the INSIGHTS Study (NCT02156102). A mixed-methods recruitment strategy was used, including via public service announcements hosted on local radio stations, information disseminated via a WhatsApp group, and snowball sampling. Recruitment was conducted in two settings, one urban (Freetown) and one rural (Kono). Participants completed this cross-sectional study from September 2021-February 2022. Questions were asked regarding participants' perspectives and knowledge of hydroxyurea, the current standard of care treatment for SCD, and novel experimental gene therapy.
Results: The mean age of respondents was 23.6 years (range 18-63). The majority of respondents were female (65.6%), educated at or above the senior secondary school level (78.7%), and students (70.3%). Respondents predominantly had the HbSS genotype (89.4%). Most study participants lacked awareness of hydroxyurea and gene therapy (93.5% had never heard of hydroxyurea; 95.1% had never taken hydroxyurea; 94.8% had never heard of gene therapy for SCD treatment) (Table 1). Despite this gap in knowledge, the majority (95.0%) agreed that genetic research is a necessary way to learn about treatments for SCD (Table 1).
Discussion: Our results highlight disparities in current standard of care treatment and knowledge in a country with a high prevalence of SCD. While our cohort indicated a favorable attitude toward SCD research and a willingness to participate, these results highlight a significant barrier for successful implementation of current treatment and the adoption of curative genetic therapies in limited resource settings like Sierra Leone. Given the significant lack of knowledge around hydroxyurea, it is important that public health initiatives and research should be directed toward both established standard of care and creating awareness of experimental therapies.
Lipid Nanoparticle Library Towards Development of Next Generation Genomic Medicines
Authors: Jain Nikita , Nazaripour Sedigheh , Chen Zhengyu , Abraham Suraj , Yee Leanna , Sadat Sams , Mehar Namala Gayatri , Son Helena “” , Chemmannur Sijo , Tickner Kobe , Anantha Malathi , Sharma Ruchi , Abbina Sri , Thambatti Seetalakshmi , Mayya Vinay , Soon Emily , Paquette Jay , Thomas Anitha , Nguyen Viet 
Published: December 2023

Ionizable amino lipids are a major constituent of the lipid nanoparticles for delivering nucleic acid therapeutics (e.g., DLin-MC3-DMA in ONPATTRO®, ALC-0315 in Comirnaty®, SM-102 in Spikevax®). Scarcity of lipids that are suitable for cell therapy, vaccination, and gene therapies continue to be a problem in advancing many potential diagnostic/therapeutic/vaccine candidates to the clinic.
Herein, we describe the development of novel ionizable lipids to be used as functional excipients for designing vehicles for nucleic acid therapeutics/vaccines in vivo or ex vivo use in cell therapy applications. We first studied the transfection efficiency (TE) of LNP-based mRNA formulations of these ionizable lipid candidates in primary human T cells and established a workflow for engineering of primary immune T cells. We then adapted this workflow towards bioengineering of CAR constructs to T cells towards non-viral CAR T therapy. Lipids were also tested in rodents for vaccine applications using self-amplifying RNA (saRNA) encoding various antigens. We have then evaluated various ionizable lipid candidates and their biodistribution along with the mRNA/DNA translation exploration using various LNP compositions. Further, using ionizable lipids from the library, we have shown gene editing of various targets in rodents.
We believe that these studies will pave the path to the advancement in nucleic acid based therapeutics and vaccines, or cell & gene therapy agents for early diagnosis and detection of cancer, and for targeted genomic medicines towards cancer treatment and diagnosis.
The Impact of Immune Function on Hematopoietic Reconstitution and Infection in Patients with Lymphoma after Autologous Hematopoietic Stem Cell Transplantation
Authors: Hu Renzhi , Liu Jun , Liang Xiping , Zhang Wenjun , Zhou Yixing , Li Qiying , Liu Yao 
Published: December 2023

Objective
To investigate the impact of immune function on hematopoietic reconstitution and infection in lymphoma patients after autologous hematopoietic stem cell transplantation (auto-HSCT).
Methods:
A total of 20 patients with lymphoma who underwent auto-HSCT in Chongqing University Cancer Hospital from January 2021 to December 2021 were retrospectively analyzed. According to whether the number of CD4+T cells was greater than or equal to 200 cells /ul, the patients were divided into normal immune function group and immunocompromised group. The hematopoietic reconstitution of the two groups was observed, including the time of neutrophil engraftment and platelet engraftment, as well as the occurrence of infection, including the pathogen could not be identified in some patients with neutropenia, it was necessary to judge according to physical examination, laboratory and imaging examination or empirical antimicrobial treatment was effective.
Results
1. Immunocompetent and immunocompromised patients included 10 patients, respectively. The durations of neutrophil engraftment were 9.5 (7-12) days and 12 (8-15) days (P = 0.007), and the durations of grade 3 neutropenia were 1.5 (0-4) days and 3 (1-7) days (P = 0.030), respectively. The duration of grade 4 neutropenia was 9 (5-16) days and 11 (6-20) days, respectively (P = 0.010). There was no significant difference in platelet engraftment time and incidence of grade IV anemia between the two groups (P &gt;0.05). 2. The incidence of febrile neutropenia in immunocompetent group and immunocompromised group was 60% and 80%, respectively, and the median duration of febrile neutropenia was 3.5 (1-10) days and 5 (1-20) days, respectively (P = 0.005). 3. The incidence of infection in immunocompetent group and immunocompromised group was 20% and 30%, and the incidence of bloodstream infection was 20% and 30%. 4. The length of hospital stay in immunocompetent group and immunocompromised group was 31.5 (23-43) days and 37 (25-75) days, respectively (P&lt;0.001).
Conclusion
The immune function of lymphoma patients before transplantation has a certain impact on hematopoietic reconstitution and infection. Normal immune function is superior to immunocompromised in terms of neutrophil engraftment, shortening the duration of febrile neutropenia, and the incidence of infection after transplantation.
KSHV/HHV-8 Associated Multicentric Castleman Disease in 80 HIV Negative Patients
Authors: Stemmler Romain , Malphettes Marion , Galicier Lionel , Gerard Laurence , Meignin Veronique , Boutboul David , Oksenhendler Eric 
Published: December 2023

Introduction : KSHV/HHV-8 associated multicentric Castleman disease (HHV-8 MCD) is a rare lymphoproliferative disorder associating lymphadenopathy, splenomegaly, fever and inflammatory symptoms with high serum CRP, hypergammaglobulinemia and high plasma HHV-8 DNA viral load. HHV-8 MCD mainly affects HIV infected patients but can also be observed in HIV negative patients born in countries with high HHV-8 prevalence or in men who have sex with men. In a large cohort of HIV negative patients, we sought to describe patient and disease characteristics and to compare them with those observed in a large cohort of HIV-infected patients with HHV8 MCD.
Methods : We analysed a cohort of 80 HIV negative patients with HHV8+ MCD and compared them to 228 HIV-infected patients with HHV8+ MCD. These patients have been prospectively enrolled in the national registry for Castleman disease held by the Reference Center for Castleman Disease in Paris, over a 30-year period.
Results : Most of these patients (67,5 %) originated from Sub saharan or Northern Africa. The baseline characteristics were similar in HIV- and HIV+ patients although HIV negative patients were older at MCD diagnosis (median, 67 vs 43 years) with 20% of the patients above 75 years, and the male predominance was slightly lower in the HIV negative population (74% vs 82%). They also presented less frequently with previous Kaposi sarcoma lesions (34% vs 52%). Biological markers including cytopenia, serum CRP and gamma globulins levels as well as blood HHV8 DNA viral load were very similar in both groups, although MCD attacks in HIV negative patients were rather less agressive than in HIV-infected patients. Of notice, the median CD4 + T cell count was normal in the HIV negative group (600 x10 6/L)
The incidence of lymphoma during follow-up remains high but very similar in both groups : 3,12 /100 pt.y. in HIV negative patients and 3,10 /100 pt.y. in HIV-infected patients
The median overall survival (OS) was 8,8 years (95%CI, 5,5-15) in HIV- patients and 20,6 years (95%CI, 6,3-24,1) in HIV-infected patients (p=0.19). Although the follow-up was shorter in HIV negative patients (24 vs 56 months), the 5-year probability of survival (79,2%; 95%CI 61,7-89,4) was very similar to that observed in HIV-infected patients (81,2% ; CI95% 74,6-86,2). Death was related to HHV8 complications or treatment in 6 /15 (40%) HIV negative patients and in 31 /57 (54%) HIV-infected patients. The slightly higher proportion of deaths not related to HHV8 in the HIV negative population might be explained by the older age of these patients.
Conclusions : Using a large cohort of HIV negative patients, we could show that HHV8 MCD in this population is very similar to that observed in HIV-infected patients. Despite the fact that these patients were older at diagnosis, the overall survival was similar to that observed in HIV-infected patients, at least at 5-year from diagnosis.
Comparison of Two Venetoclax-Based Regimens As Salvage Therapies Bridged to Allogeneic Hematopoietic Cell Transplantation in Patients with Relapsed/Refractory Acute Myeloid Leukemia
Authors: Ye Yiling , Chen Yanqiu , Yu Guopan , Weng Guangyang , Liu Qifa , Jin Hua 
Published: December 2023

Introduction ：
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for relapsed or refractory acute myeloid leukemia (R/R-AML) patients. However, it is not clear about appropriate salvage therapy bridged to allo-HSCT for R/R-AML patients. In this study, we compared the outcomes of R/R-AML patients treated with venetoclax plus hypomethylating agents (VEN-HMA) regimen or venetoclax plus azacitidine and homoharringtonine (VAH) regimen as salvage therapies bridged to allo-HSCT.
Methods ：
A total of 105 R/R-AML patients treated with VEN-HMA regimen or VAH regimen bridged to allo-HSCT between September 2018 and February 2023 were enrolled. The outcomes including survival, relapse and NRM after allo-HSCT were analyzed in two groups.
Results ：
Forty-four patients were treated with VEN-HMA regimen, and 61 with VAH regimen. Seventy-four patients had primary refractory AML and 31 relapsed AML, including 19 relapsed after chemotherapy and 12 relapsed after allo-HSCT. Thirty-one (70.5%) patients achieved composite complete remission (CRc) in VEN-HMA group including 20 (45.5%) with minimal residual disease (MRD) negative, as well as 52 (85.2%) with CRc including 40 (65.6%) with MRD negative in VAH group (P=0.09). Twenty-five (56.8%) patients were stratified with adverse risk in VEN-HMA group and 45 (73.8%) in VAH group according to the 2022 European Leukemia Net (ELN) classification (P=0.07). The 2-year overall survival (OS) and event-free survival (EFS) in VAH group were higher (78.4% vs 58.7%, P=0.03; 68.3% vs 38.7%, P=0.003), as well as 2-year cumulative incidence of relapse (CIR) was lower than VEN-HMA group (23.2% vs 42.4%, P=0.04). Among patients with CRc, the 2-year OS, EFS and CIR was 67.5%, 48.9% and 37.0% in VEN-HMA group, as well as 82.5%, 72.5% and 23.6% in VAH group (P=0.15, 0.05 and 0.24). Among patients with MRD negative, the 2-year OS, EFS and CIR was 75.5%, 55.5% and 31.6% in VEN-HMA group, as well as 90.8%, 80.0% and 17.5% in VAH group (P=0.15, 0.10 and 0.28). Among patients with adverse risk, the 2-year OS and EFS in VAH group were higher (79.3% vs 47.7%, P=0.01; 70.9% vs 24.1%, P=0.0002), as well as 2-year CIR was lower than VEN-HMA group (17.4% vs 45.8%, P=0.01). Non-relapse mortality (NRM) was similar between VEN-HMA group and VAH group (18.9% vs 8.5%, P=0.12).
Conclusion ：
VAH regimen is an effective salvage therapy bridged to allo-HSCT for R/R-AML patients compared with VEN-HMA regimen.
Keywords ：
Venetoclax, Azacitidine, Homoharringtonine, Relapsed/Refractory AML, Allogeneic Hematopoietic Cell Transplantation.
Three-Day Decitabine Combined with Venetoclax in Patients with Newly Diagnosed or Relapsed/Refractory AML
Authors: Suo Xiaohui , Bai Guanchen , Zhao Xingli , Zhang Congcong , Li Yinling , Gao Sifeng , Zhang Jilei , Lu Xinxiao , Yuan Linyu , Mi Yingchang , Liu Kaiqi 
Published: December 2023

INTRODUCTION
Venetolax (VEN) combined with azacytidine (AZA), decitabine (DEC), and low-dose cytarabine has been the first-line therapy for newly diagnosed (ND) AML patients who are elderly or unfit for intensive chemotherapy. Previous reports shown that ten-day DEC with VEN (DEC 10-VEN) was an effective therapy for newly diagnosed elderly patients. Though higher remission rate in ND AML compared five-day DEC with VEN, DEC 10-VEN induced prolonged myelosuppression. Therefore, optimizing the combination of DEC with VEN is still being explored.
In this study, we retrospectively collected and analyzed the clinical data of three-day DEC combined with VEN (DEC 3-VEN) ( Tianjin-Handan regimen) in twelve patients with ND or relapsed/refractory (R/R) AML who were elder or ineligible for intensive chemotherapy to evaluate the efficacy and safety of the regimen.
METHODS
Retrospectively collected and analyzed the clinical data of twelve ND or R/R AML patients treated with three-day DEC combined with VEN as induction therapy between July 2022 and June 2023 at 4 hospitals in china.
The induction regimen consisted of oral Ven (100mg Day 1; 200mg Day 2; 400mg Day 3-9 or 3-14), intravenous DEC (20mg/m²/q8h, days 4-6), sorafenib were administered (600mg days 8-14) in relapsed/refractory patients with FLT3/ITD. The primary objective was composite complete response rate (CR + CRi) and the secondary objectives was safety.
RESULTS
Until June 2023, twelve patients with de novo or relapsed/refractory AML were treated with three-day DEC combined with VEN as induction therapy. The median age of the twelve patinets was 67 years (range, 32-76), with 58.3% (7/12) male. Seven (58.3%) patients were ND AML, and five patients (41.7%) were R/R AML. The clinical data and treatment information of the patients are shown in table 1.
The composite complete response rate (CR + CRi) after one cycle of induction was 100% (CR 10/12, CRi 2/12). For patients who achieved CR or CRi, MRD negative rate was 77.8% (7/9) by flow cytometry. None of patients died during the induction therapy.The median time to recovery of the absolute white blood count (WBC) to ≥1.0 × 10 9/L and the platelet count to ≥20 × 10 9/L after induction was 13 (range: 7-25) and 15 days (range: 0-27), respectively.
CONCLUSION:
DEC 3-VEN is a highly effective and safe induction therapy for ND and R/R AML patients who are elderly or unfit for intensive chemotherapy. Further study with more patients will be updated.
【Keywords】Venetoclax; decitabine; AML; induction treatment.