bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival and Causes of Death in Patients with Alpha and Beta-Thalassemia
Authors: Tantiworawit Adisak , Kamolsripat Thansita , Piriyakhuntorn Pokpong , Rattanathammethee Thanawat , Hantrakool Sasinee , Chaiadisaksopha Chatree , Ekarat Rattarittamrong Ekarat , Norasetthada Lalita , Fanhchaksai Kanda , Charoenkwan Pimlak 
Published: December 2023

Background: Thalassemia is the most common hereditary anemia worldwide. The prevalence is high in the malaria-endemic areas, including Southeast Asia, and Thailand. Severe thalassemia can result in shortened survival due to disease-related complications. In the last three decades, with regular red cell transfusions and iron chelators, the survivals of patients with thalassemia, especially for TDT, have significantly improved. The most distinctive change was the decrease in the iron-overloaded cardiomyopathy. Both alpha and beta-thalassemia are prevalent in Thailand. We aimed to study the survival, and the causes of death in the patients with thalassemia across the disease severity from NTDT to TDT, and to explore the factors influencing the survival.
Methods: A retrospective review of patients with thalassemia who were followed up at Chiang Mai University Hospital was conducted. The survival status was determined from medical records and the Thai National database (Official statistics registration systems). The survival and clinical factors associated with survival were analyzed.
Results: Our study cohort comprised 789 patients with thalassemia, who were registered in the Departments of Internal Medicine and Pediatrics. The median age (IQR) at the end of follow-up was 18∙8 (11∙7) years. There were 301 patients (38∙1%) with Hb H disease, 279 patients with Hb E/beta-thalassemia (35∙4%), and 209 patients (26∙5%) with beta-thalassemia major, respectively. Half of the patients (395, 50∙1%) had transfusion-dependent thalassemia (TDT). Sixty-five (8∙2%) patients had died. The mean age at death was 17∙0 ± 0∙9 years. Multivariable analysis showed that TDT (adjusted HR 3.68, 95%CI 1.39-9.72, p 0∙008) and mean serum ferritin level ≥3,000 ng/mL (adjusted HR 4∙18, 95%CI 2.20-7.92, p&lt;0∙001) were independently associated with poorer survival. The two major cause of death were infection-related causes (36∙9%), cardiac complications (27∙7%), thalassemia/anemia (13∙8%), trauma (6∙2%), and other causes (15∙4%).
Conclusions: TDT and mean serum ferritin level ≥3,000 ng/mL were the main factors associated with poorer survival in thalassemia patients. Infections and cardiac complications were the two major causes of death.
Score to Guide Donor Choice in Haploidentical Stem Cell Transplant Using Post-Transplant Cyclophosphamide for Patients with Acute Myeloid Leukemia: A Study from the Acute Leukemia Working Party of the EBMT
Authors: Sanz Jaime , Labopin Myriam , Blaise Didier , Raiola Anna Maria , Busca Alessandro , Vydra Jan , Tischer Johanna , Chevallier Patrice , Bramanti Stefania , Fanin Renato , Socié Gerard , Forcade Edouard , Kröger Nicolaus , Koc Yener , Itäla-remes Maija , Zecca Marco , Nagler Arnon , Brissot Eolia , Spyridonidis Alexandros , Bazarbachi Ali , Giebel Sebastian , Piemontese Simona , Mohty Mohamad , Ciceri Fabio 
Published: December 2023

Introduction: There is paucity of information to guide selection of the most appropriate stem cell donor for haploidentical (Haplo) hematopoietic stem cell transplant (HSCT).
Patients and Methods: We retrospectively analyzed the characteristics of haploidentical family donors that may affect transplant outcomes in patients with acute myeloid leukemia (AML) who received graft-versus-host disease (GVHD) prophylaxis with postransplant cyclophosphamide (PTCy) registered in the EBMT database. The primary endpoint was GVHD and relapse-free survival (GRFS).
Results: Overall, 2200 patients were included with a median age of 56 years (range, 18-75); 1742 (79%) were in complete remission and 1246 (56.6) received reduced intensity conditioning. Regarding donors, the median age was 37 years (range, 8-71), 820 (37%) were females of which 458 (21%) were used for male recipients, 1252 (57%) had positive CMV serostatus, 1631 (74%) donated peripheral blood (PB) and 1638 (75%) had ≥ 4/8 HLA mismatch with the recipient. 100-day acute GVHD grade II-IV and III-IV and 2-year chronic and chronic extensive GVHD were 28% (95% CI 26-30), 11% (95% CI 10-12), 33% (95% CI 31-35) and 14% (95% CI 12-15), respectively. After median follow-up of 24 months, the cumulative incidence of relapse and non-relapse mortality (NRM) and the probability of leukemia-free survival (LFS), overall survival (OS) and GRFS were 26% (95% CI 24-28), 22% (95% CI 20-24), 52% (95% CI 50-55), 57% (95% CI 55-60) and 41% (95% CI 39-43), respectively. In multivariable analysis, donor-related risk factors with a negative impact on GRFS were older age (HR 1.1; 95% CI 1.04-1.15), use of PB (HR 1.19; 95% CI 1.04-1.37), and female donors to male recipients (HR 1.25; 95% CI 1.09-1.43). We further developed a score that distinguished 4 groups with 0 (241), 1 (913), 2 (863) or 3 (183) donor-related risk factors. GRFS was 57% (95% CI 50-63), 43% (95% CI 39-46), 37% (95% CI 33-40), and 30% (95% CI 23-38), respectively (P &lt; 0.001) (Figure 1). The score was also able to stratify risk groups for acute and chronic GVHD, NRM, LFS and OS.
Conclusion: Donor variables have an important impact on AML patient's outcome after Haplo-HSCT using PTCy. With three simple donor characteristics, age, gender and stem cell source, we were able to generate a score that may help to select the most appropriate donor in clinical practice.
Development of a Targeted NGS Panel for Hematologic Malignancies According to Who/ICC 2022 Guidelines
Authors: Lee Young Eun , Kim Hye Ran , Lim Ha Jin , Choi Yong Jun , Park Joo Heon , Choi Hyun-Woo , Choi Hyun-Jung , Kee Seung-Jung , Kim Soo Hyun , Shin Jong Hee , Park Chang Soo , Shin Myung Geun 
Published: December 2023

Introduction: Since 2020, we have successfully developed a targeted blood cancer NGS panel and have been using it efficiently in clinical settings. However, it needed to be upgraded due to recent new blood cancer diagnosis and classification guidelines by the World Health Organization and the International Collaboration for Cancer Classification (ICC) in 2022. Therefore, in this study, an updated targeted NGS panel that covers the updated guidelines was evaluated using clinical samples.
Methods: To adhere to the recent guidelines, the currently used targeted NGS panel (KBB DNA/RNAseq NGS Leukemia PHB; KBlueBio Inc., Hwasun, Korea) was reviewed. Its analytical performance was validated using standard NA12878 and clinical samples. The clinical samples consisted of 19 genomic DNA and 20 total RNA samples extracted from the bone marrow or peripheral blood of patients with hematologic malignancies, including acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome/myeloproliferative neoplasm, multiple myeloma, and lymphoma.
Results: The updated DNA panel comprises 125 genes including 6 new genes ( BCORL1, BLM, GNB1, PRPF8, SAMD9 and SAMD9L). The updated RNA panel has 116 genes including 31 new genes ( FLT3, CBFA2T3, RPN1, BCL11B, ZNF362, HLF, NUTM1, UBRF, CDX2, ZEB2, CDK6, ZMYM2, AFDN, ELL, NSD1, HOXA9, KDM5A, ZBTB16, GLIS2, PRDM16, NPM1, KAT6A, MNX1, TAF15, MLLT1, P2RY8, HNRNPUL1, ECM1, ENAM, JCHAIN (IGJ) and MDFIC). The accuracy, repeatability, reproducibility, sensitivity, and detection limit of the updated NGS panels were evaluated using standard materials, and the results met the predefined criteria. A comparison of the updated DNA panel with the old panel using 19 clinical samples revealed an overall concordance rate of 100% between the two panels for all mutations (95% confidence interval (CI): 99.72-100.00%). Similarly, the updated RNA panel also met the predefined criteria. The overall concordance rate between the updated RNA panel and the old panel was 99.72% in 20 clinical samples (95% CI: 99.00-99.72%).
Conclusions: The old targeted DNA/RNA NGS panel was successfully updated according to the 2022 WHO and ICC guidelines, and can be used to accurately and efficiently detect the genetic variants of blood cancers.
The Impacts of Genetic Polymorphisms on the Von Willebrand Factor Level in Type 1 Von Willebrand Disease
Authors: Chen Yeu-Chin , Chang Chia-Yau , Cheng Shin-Nan , Lai Shiue-Wei , Hu Shu-Hsia 
Published: December 2023

Background: von Willebrand disease (VWD) is the most common inherited bleeding disease, which results from deficiency or defect of von Willebrand factor (VWF). In type 1 VWD, there are only 53-81% patient whose mutations of VWF gene can be identified. Some studies reported that variants outside the VWF gene may also contribute to the VWF level. There are 7 genetic variants of single nucleotide polymorphism ( SNP ) reported to be associated with the variation of VWF levels, including CLEC4M, STXBP5, SCARA5, ABO, VWF, STAB2 and UFM1. The aims of this study were to explore the frequency of SNPs of the 7 genes among type 1 VWD patients and the effects of the 7 genetic variants on the VWF levels in type 1 VWD patients.
Patients and methods: There were 62 patients ( the ratio of M/F: 1 ) with type 1 VWD enrolled in this study, including 35 (56.5%) patients with found mutations of VWF gene. Each patient's bleeding symptoms were assessed by the MCMDM-1 VWD bleeding score. The results of VWF levels: VWF:Ag and VWF activity ( VWF:ACL or VWF:RCo ) and FVIII: C at the VWD diagnosis were retrospectively collected, as shown in Table 1. Each enrolled patient's genomic DNA was extracted and the SNPs of the 7 gene were targeted by PCR amplification followed by direct sequencing.
Results: There was high correlations between VWF:Ag and VWF activity ( r = 0.73, p &lt; 0.0001 ) and between VWF:Ag and FVIII:C ( r = 0.60, p &lt; 0.0001 ), respectively. The patients without variant ( A/A) of UFM1 has significantly lower median VWF:Ag of 33% than 44.7% of patients with heterozygous variant ( A/C ) type ( p = 0.033 ). Patients without variant (A/A ) of STXBP gene had both significantly lower median value of VWF:Ag ( 31.9% vs 46.1%, p = 0.017 ) and VWF activity (26.55% vs 30.4%, p = 0.0467 ) than those patients with heterozygous variant ( A/G ). Four alleles substitution of SNP of UFM1( C&gt;A ) and STXBP genes ( G&gt;A ) variant has remarkably lowest median VWF antigen level of 27.4%, which was significantly lower than 43.05% of the three alleles substitution ( p = 0.0014 ) and the 48.6% of the two alleles substitution ( p = 0.0279 ), as shown in Figure 1.
Conclusions: Our study demonstrates that both C to A variant of UFM1 gene and G to A variant of STXBP5 gene were associated with lower VWF: Ag level than those without variant, respectively. The combination of four allelic variant of UFM1 and STXBP5 genes had the most reducing effect on VWF: Ag level.
Increased Circulating 2-Methylbutyrate Following Fecal Microbiota Transplantation in Patients with Refractory-Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation
Authors: Du Jing , Huang Fen , Yang Kaibo , Xu Na , Fan Zhiping , Xuan Li , Liu Qifa 
Published: December 2023

Introduction
Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment for patients with hematological malignancies. Steroid-refractory chronic GVHD (SR-cGVHD) remains the major cause of non-relapse mortality and life-threatening disease late after allo-HCT. Several groups reported that perturbation in the gut microbiome and impaired production of microbial metabolites such as short chain fatty acids (SFCAs) have involved in cGVHD pathogenesis and severity. Currently, there is no acceptable consensus and no standard second-line treatments for patients with SR-cGVHD. Our pilot study (NCT04622475) using fecal microbiota transplantation (FMT) from healthy donor to treat patients with SR-cGVHD provide a new insight into therapeutic strategies for SR-cGVHD. To investigated whether FMT improves the SR-cGVHD clinical outcome through SCFAs, the measurement of SCFAs concentration was performed in the plasma from SR-cGVHD patients after FMT. Here we report the preliminary results of this study.
Method
12 patients aged 16-60 years with SR-cGVHD after allo-HCT were enrolled. A total of 31 FMTs were performed via colonoscopy in 12 patients with SR-cGvHD over three consecutive months. FMT courses were repeated from the same donor. To characterize the impact of the FMT on the gut microbiota, stool samples and plasma from recipients were collected the day before FMT treatment and 4 weeks after each FMT treatment then carried out 16s rRNA sequencing and LC-MS. Complete response was defined as the complete resolution of GVHD manifestations in all organs. Partial response was defined as a decrease at least one stage in severity of GVHD or able to taper steroid dose. No response was defined as unable to taper steroid dose or need to increase or add immunosuppressor for controlling GVHD progression.
Result
The circulating SCFAs levels of SR-cGVHD patients associated to FMT outcome (Figure A). After FMT, the concentrations of butyric acid, isovaleric acid, valeric acid, 4-Methylvaleric acid and hexanoic acid had a higher trend in the plasma of responders, but not in the non-responders (Figure B). Notably, 2-Methylbutyrate markedly increased in the plasma of responders after FMT, when compared to non-responder after FMT(Figure C).
Conclusion
The present study indicates that FMT improved SR-cGVHD patients by increasing the circulating SCFAs, particularly 2-Methylbutyrate levels. 2-Methylbutyrate might play a role in FMT therapy for SR-cGVHD.
Disclosures
No relevant conflicts of interest to declare.
A 5-Stage System for ASCT Multiple Myeloma
Authors: Guo Wancheng , Mery David E. , Siegel Eric , Sun Fumou , Cheng Yan , Wanchai Visanu , Ashby Cody , Bailey Clyde , Alapat Daisy V. , Peng Hongling , Al Hadidi Samer , Thanendrarajan Sharmilan , Schinke Carolina , Zangari Maurizio , van Rhee Frits , Tricot Guido , Shaughnessy, Jr John D , Zhan Fenghuang 
Published: December 2023

652. Multiple Myeloma: Clinical and Epidemiological
INTRODUCTION:
In the last three decades, significant advancements in multiple myeloma (MM) treatment, including immunomodulators, targeted therapies, chemotherapy combinations, autologous stem cell transplantation (ASCT), and CAR-T therapy, have emerged. ASCT offers hope for MM patients by using high-dose chemotherapy with stem cell support. However, it carries risks of severe toxicity. Despite evaluating factors like age, performance status, and co-morbidities for ASCT eligibility, outcomes for MM patients still vary greatly. Various models, such as the ISS-series systems, have been developed to assess risk factors for progression-free and overall survival We conducted a study on 5,259 ASCT patients since 1989, identifying 7 easy variables (ISS stage, diagnosis-transplant interval, ferritin, transferrin, LDH, age, and gender) and creating a 5-stage system. This system helps evaluate the risk of MM patients before ASCT.
METHODS:
In this retrospective study, data from 5,259 MM patients receiving ASCT (1989-2022) were collected (median follow-up: 57 months). We assessed 30 clinical variables pre-ASCT. Multiple imputation was used to deal with the missing values. Patients were split into a 70% training set and a 30% validation set. Univariate/multivariate Cox regression analysis identified 7 clinical and demographic signatures. Signatures were scored based on hazard ratios normalized to ISS III vs. ISS I&II. K-adaptive partitioning generated a 5-stage system, ATM5S, evenly distributed and validated in the training set. Harrel's c-index was used to compare ATM5S with the current myeloma systems.
RESULTS:
3683 patients (70%) in the test cohort had a median age of 59.6, median PFS 38.8 month and median OS 56.1 month. IgG was the most common isotype (55%). Univariate Cox analysis showed that 27 variables were significant predictors for both PFS and OS. Multivariate Cox analysis showed that time from diagnosis to transplant, ferritin, transferrin, LDH, ISS stage, lymphocytes, platelets, calcium, gender and age were independent prognostic factors for both OS and PFS. We selected the most easy, understandable and well-distributed (with high-risk group&gt;20%) 7 variables: ISS, time from diagnosis to transplant, ferritin, transferrin, LDH, age and gender and developed a score system, which resulted into a 5-stage system (ATM5S) by k-adaptive partitioning. This staging system also demonstrated a significant discriminatory effect in the validation set (30%, 1576 patients).
CONCLUSIONS:
The Arkansas Transplant-Myeloma 5-Stage System (ATM5S) showed a promising performance in both training and validation cohorts.
Efficacy and Safty of Stem Cell Mobilization with Etoposide +Cytarabine Plus G-CSF in Patients with Lymphoma at High-Risk of Mobilizing Failure
Authors: Zhu Zhijuan , Li Xiaofan , Li Nainong 
Published: December 2023

Objective：Sufficient peripheral blood stem cell (PBSC) mobilization is important for performing successful autologous stem cell transplantation (ASCT) in patients with lymphoma. However, the optimal mobilization strategy remains a matter of debate in lymphoma.The aim of the study was to explore efficacy and safety of PBSC mobilization using etoposide combined with Cytarabine (EA) plus G-CSF in patients with lymphoma at high-risk of mobilizing failure.
Methods：This retrospective study explored efficacy and safety of PBSC mobilization using EA (etoposide 50~100 mg/m2 , qd d1~3; AraC 0.5 g/m2 , q12h d1~3) plus G-CSF (5 µg/kg/day, from d5 until the day of apheresis) in 81 patients with lymphoma at high-risk of mobilizing failure. As previously reported, patients were defined at high-risk of mobilizing failure if (i) previous collection attempts failed (no special instructions); (ii) previous extensive radiotherapy or a complete course of treatment had affected stem cell activity; or (iii) any of these conditions: advanced disease (2 lines of chemotherapy), refractory disease, extensive bone marrow involvement or cellularity &lt;30% at the time of mobilization or age 65 years.
Results：The mean total and first apheresis trial CD34+ cells collection was 20.37(range 1.08~138.96) and 18.56(range 0.1~138.96)×10^6 CD34+ cells/kg, respectively. Overall, 79(97.5%) patents harvested adequate mobilization (≥2×10^6 CD34+ cells/kg), while 65(80.2%) patients achieved optimal mobilization(≥5×10^6 CD34+ cells/kg). A single apheresis was sufficient to reached the target yield of adequate apheresis in 67(82.7%) patients on median 15th day (range 11~19). We observed acceptable hematological toxicity and exposure of antibiotic usage in 57 patients with a median of 4 days. No severe infections or mobilization-related mortality were observed.
Conclusion：Our resluts suggest that EA plus G-CSF is an effective and safe PBSC mobilization strategy for patients with lymphoma, including those predicted as poor mobilizers. The outcome should be evaluated in a randomized study.
The Potent and Selective Antitumor Activity of CO-1 and Fully Humanized CO-1bi in Treatment of B Cell Non-Hodgkin's Lymphoma
Authors: Matar Sittana , Skah Seham , E Diomande Liza , Kiil Blomhoff Heidi , Hestdal Kjetil , D Pettersen Rolf , Richartz Nina 
Published: December 2023

Recent advancements have identified CD47 blockade as a promising approach for the treatment of B cell Non-Hodgkin's Lymphoma (B-NHL). CD47 blockade inhibits the CD47-SIRPα axis, which inhibits a “don't eat me” signal that facilitates the phagocytosis of tumor cells by macrophages [1,2]. While the effect of anti-CD47 monoclonal antibodies (mAbs) as monotherapy has been limited in B-NHL, combining CD47 mAbs with conventional treatment such as rituximab has demonstrated more encouraging outcomes. This combinatory approach may be attributed to the need for additional cytotoxic mechanisms to achieve clinically meaningful responses with CD47-mediated therapy in B-NHL [3]. Additionally, CD47 blockage has raised concerns about off-target effects and red blood cell depletion [4].
To address these challenges and improve treatment possibilities we developed a fully humanized CO-1bi based on the chimeric CO-1. The bifunctional CO-1 is an agonistic IgG4 anti-CD47 mAb designed to induce direct and rapid programmed cancer cell death (PCCD) and stimulate phagocytosis through blockage of CD47-SIRPα binding. CO-1bi is a humanized bivalent scFv-Fc fusion of CO-1 with superior safety (no red blood cell hemagglutination) while maintaining the functionality of CO-1. In this study, we evaluated the antitumor activity of CO-1 and CO-1bi on different B-NHL cell lines in vitro as well as in xenografts of B-NHL established in NOD- scid IL2Rγ null (NSG) mice. Both constructs demonstrated potent and fast cell death induction in lymphoma cell lines while sparing normal B cells. The robust antitumor activity demonstrated by CO-1 and CO-1bi as single agents in xenograft models of Burkitt's lymphoma underscores the significance of their additional agonistic PCCD capabilities compared to other anti-CD47 agents.
The emergence of CO-1bi offers a unique strategy with dual functionality for the treatment of B-NHL and other malignancies without red blood cell depletion characterized by current anti-CD47 mAb in clinical trials. This innovative approach provides an improved and promising avenue for cancer treatment.