bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Change of Complement Deposition after Complement Inhibitor Treatment in Paroxysmal Nocturnal Hemoglobinuria Patients
Authors: Zhang Menglu , Wang Xuan , Yang Chen , Chen Miao , Zhuang Junling , Han Bing 
Published: December 2023

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disease in which abnormal complement activation results in hemolysis and thromboembolic events (TEE). Complement inhibitors (CI) have been proved to be able to suppress intravascular hemolysis (IVH) and reduce the risk of TEE. Few studies were available on the changes of complement deposition after CI and their relationship with efficacy.
Methods: PNH patients treated with full dose eculizumab, crovalimab or iptacopan at Peking Union Medical Colleague Hospital from Oct 2021 to Jul 2023 were enrolled.Patients' clinical information and blood samples were collected after 0, 1, 3, 6, 9 and 12 months of treatment. The deposition of C5b-9, C3, C4b and factor B (FB) on peripheral red blood cells (RBC), white blood cells (WBC) and platelets (PLT) was detected by double-color staining flow cytometric assay. The efficacy of each CI was correlated with complement deposition levels on three blood lineages.
Results: 23 PNH patients were enrolled. Among them, 13 patients were treated with C5 inhibitors (4 with eculizumab and 9 with crovalimab), 10 were treated with iptacopan (FB inhibitor). For patients treated with eculizumab, C5b-9+/RBC and C5b-9+/WBC significantly decreased after 3, 6 and 12 months of treatment(P&lt;0.05); however, C3+/WBC and C3+/PLT significantly increased after 12 months (P&lt;0.05). For covalimab-treated patients, C5b-9+/RBC significantly decreased after 6 and 12 months (P&lt;0.05), while C3+/RBC, C3+/WBC, C4b+/RBC and C4b+/WBC increased (P&lt;0.05) after 6 months. For those treated with iptacopan, after 1, 3, 6, 9 and 12 months, the deposition of C5b-9 on all three blood lineages significantly decreased (P&lt;0.05), meanwhile, C3 and FB on all three lineages decreased (P&lt;0.05); moreover, C4b+/WBC and C4b+/PLT decreased after 3, 6, 9 and 12 months (P&lt;0.05). C5b-9+/RBC and C5b-9+/WBC were significantly associated with hemoglobin improvement after eculizumab treatment (P=0.004 and 0.018, respectively). C5b-9+/RBC was positively correlated with bilirubin (P=0.023) and C3+/RBC was positively correlated with absolute reticulocyte counts (Ret, P=0.001) after crovalimab treatment. After iptacopan treatment, C3+/RBC was positively correlated with Ret (P=0.010), C4b+/RBC was positively correlated with Ret (P=0.032) and lactose dehydrogenase (LDH, P=0.003), and FB+/RBC was positively correlated with LDH.
Conclusion: Complement inhibitors could effectively reduce C5b-9 deposition. Unlike C5 inhibitors, iptacopan also reduced the deposition of C3, C4b, and FB. C5b-9+/RBC may be correlated with the efficacy of inhibiting intravascular hemolysis. Upstream complement deposition is probably associated with breakthrough hemolysis or extravascular hemolysis.
【Key words】Paroxysmal nocturnal hemoglobinuria, complement inhibitor, complement deposition, flow cytometric assay, hemolysis
Role of Pegylated Liposomal Doxorubicin in Heavily Pretreated Relapsed Refractory Hodgkin Lymphoma Eligible for Autologous or Allogeneic Transplantation
Authors: Casadei Beatrice , Pellegrini Cinzia , Sutto Emanuele , Cantelli Martina , Argnani Lisa , Zoli Sabrina , Coppola Paolo Elia , Gentilini Marianna , Morigi Alice , Carella Matteo , Gugliotta Gabriele , Bagnato Gianmarco , Nanni Laura , Broccoli Alessandro , Stefoni Vittorio , Zinzani Pier Luigi 
Published: December 2023

In the context of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), various conventional single agents and salvage chemotherapy regimens have been explored, including bendamustine, brentuximab vedotin, nivolumab, and pembrolizumab. However, there is another drug, pegylated liposomal doxorubicin (PLD), which has shown interesting results but is comparatively less recognized and mostly used in combination.
For heavily pretreated R/R cHL patients this drug, presenting a reduced cardiac toxicity compared to non-liposomal doxorubicin, may be considered as bridging therapy (BT) to transplantation (both autologous [ASCT] and allogeneic [alloSCT]).
The present retrospective study aims to determine the role of PLD monotherapy in terms of safety and effectiveness in heavily pretreated R/R cHL patients as BT to ASCT or alloSCT.
Our case series comprises 22 R/R cHL patients who were potentially eligible for transplantation and underwent PLD treatment successfully. These patients had a median of five previous treatments (range, 3-9), including ASCT in 50% of the cases and radiotherapy in 7 out of 22 cases. Of the total, 77% were primary refractory, and 63.6% remained refractory to the last previous therapy before PLD. Additionally, eight patients had advanced stage disease at the time of PLD treatment.
PLD was administered at a fixed dose of 60 mg every 21 days with a median of 4 cycles (range, 1-8). No dose reduction was needed. Few toxicities occurred. In detail, four hematological adverse events (AE) were reported in 3 patients (all grade ≥3, drug related but rapidly resolved without sequalae). Only one grade 3 extra-hematological occurred (deep vein thrombosis). Final overall response rate (ORR) was 31.8%, with 4 complete and 3 partial responses (CR, PR). Best ORR of 54.5% was reached at the third cycle (5 CR and 7 PR). Five patients subsequently proceeded to ASCT and 2 to alloSCT with 5 final CR (two patients converted from a PR and 1 from a stable disease). At a median follow-up of 6 years, median overall survival was reached at 4 years.
The findings from this retrospective analysis suggest that PLD monotherapy may be effective in treating a subset of patients with multi-relapsed or refractory cHL. PLD could be considered as a strategic and relatively low-toxicity bridging therapy option for patients undergoing transplantation.
Low Disease Relapse and High Survival in Non-Myeloablative Two-Step Haploidentical Transplant, Results of a Prospective Trial
Authors: Bi Xia , Grosso Dolores A. , Wagner John L. , Filicko-O'Hara Joanne , O'Hara William , Flomenberg Neal , Gergis Usama 
Published: December 2023

Introduction
We previously developed a two-step approach that separates the lymphoid and myeloid portions of the graft, allowing a consistent T cell dosing and sparing the stem cells from the effect of cyclophosphamide. The two-step approach demonstrated safety and efficacy in patients treated with a myeloablative conditioning protocol. Here, we extended our 2-step platform to older and less fit patients and explored the effects of using a high dose of T cells on disease relapse and transplant outcomes.
Methods
Patients received fludarabine 30mg/m 2 IV daily for 3 days, from day -10 to day -8. Two hundred cGy total body irradiation (TBI) was given on day -7. This was increased to 400 cGy TBI in 2 doses after 13 patients had been treated. A fixed dose of 2 x 10 8/kg CD3+ T cells was given on day -6, followed 2 days later by cyclophosphamide 60mg/kg IV daily on day -3 and day -2. Tacrolimus and mycophenolic acid were started on day -1, followed by infusion of CD34-selected stem cells on day 0.
Results
Thirty-three patients with hematologic malignancies were treated (Table 1). Majority were haploidentical transplants (91%), and the rest were matched related donors. Median age was 68 (range, 33-76) years, with 64% patients &gt;65 years old. Median follow-up was 31 months (range, 0-76 months). Median HCT-comorbidity score was 4 (range, 0-9). Forty-seven percent had high or very high-risk disease risk index. Twenty-seven percent had prior autologous transplant.
Overall survival was 75% at 1 year and 50% at 3 years. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were 22% and 31% at 3 years. However, the CI of relapse was much lower for patients treated with 400 cGy TBI versus those treated with 200 cGy TBI (6% vs 54%, p = 0.017) (Figure 1), while NRM was similar (25% vs 15%, p = 0.348). This contributed to a very high survival of 69% in patients who received the higher dose of TBI at 3 years, with median OS not reached.
The median time to neutrophil and platelet recovery was 11 and 17 days, respectively. The median donor CD3+ T cell chimerism at day +28 was 100% (range, 71% to 100%). The CI of grade II acute graft-versus-host-disease (GVHD) was 23% and 27% at 100 days and 6 months, respectively. The CI of chronic GVHD was 8% at 3 years. There were no grade III or IV acute GVHD, no severe chronic GVHD and no deaths attributable to acute or chronic GVHD. There were 13 deaths in the study, of which 7 died from disease relapse, 3 died from toxicity related to treatment regimen, and 2 died from infection.
Conclusions
The NMA two-step approach allo-SCT showed a low disease relapse rate and high survival in patients treated with 400 cGy TBI, despite a generally older and more medically compromised patient population.
Neutrophil-Lymphocyte Ratio and Platelet-Lymphocyte Ratio for an Early Detection of Venous Thromboembolism in COVID-19 Patients
Authors: Gharib Hussein Khalil , Szpunar Susanna , Bhargava Ashsih , Kafri Zyad 
Published: December 2023

Background: Venous Thromboembolism (VTE) is an umbrella term that includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). COVID-19 infection has emerged as a risk factor for VTE; however, traditional methods of testing (D-dimer and Well's score) have been less than optimal. The neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte Ratio (PLR) have a role in diagnosing DVT in non-COVID19 patients. These two inexpensive values are readily available from the complete blood count (CBC).
Objective: To determine the association of NLR and PLR on admission and imaging day with the incidence of VTE in COVID-19 patients.
Methods: This was a historical cohort study of all patients admitted with COVID-19 from 2020-2021, who underwent duplex ultrasound (US) and/or computed tomography angiography (CTA) of the chest, and serial complete blood counts (CBC) with differential measurements during hospitalization. Patients who had risk factors for VTE (active malignancy, history of thrombophilia disorders and any anticoagulation therapy) were excluded. The NLR and PLR were calculated on admission and upon imaging for eligible patients. Data were analyzed using Student's t-test, analysis of variance, the x2 test and logistic regression.
Results: We included 234 patients, 51.3% (120/234) female, 57.3% Black (134/234) with mean age 59.2 ± 15.9 years. The mean NLR on admission for all admitted patients was higher in the VTE group vs non-VTE group, 11.24 ±11.33 vs 7.66 ±5.16 respectively, (p=0.002). The mean NLR on admission for non-ICU patients was higher in the VTE group vs non-VTE group, 9.06 ± 5.72 vs 7.04 ± 4.53 respectively, (p=0.02). For ICU patients, the mean NLR on admission was higher in the VTE group vs non-VTE group, 14.49 ±16.01 vs 8.6±4.53 respectively, (p=0.02).. There was no association between PLR on admission, NLR and PLR on imaging and incidence of VTE. After controlling for sex, every unit increase in NLR at admission increased the risk of VTE by 6.8% (OR=1.068, p=0.005).
Conclusion: NLR on admission may be a useful, readily available and inexpensive method of screening for VTE in patients with COVID-19 infection.
Phenotype Molding of Monocytes in the Multiple Myeloma Microenvironment
Authors: Cui Jian , Wang Jingwei , Qiu Lugui , An Gang 
Published: December 2023

Human monocytes are mononuclear phagocytes that comprise a major population of innate immune cells. Various monocyte-derived cells, including osteoclasts, dendritic cells, and macrophages, have been implicated in immunosuppression within the multiple myeloma (MM) tumor microenvironment (TME). Despite recent developments in understanding the link between monocyte-derived cells and immunosuppression in myeloma, there are still critical knowledge gaps in the association between monocytes themselves and immunosuppression within the context of MM. Specifically, the functional and developmental alterations of monocytes in the MM TME have not been explored based on the single-cell studies.
In the present study, we generated a comprehensive single-cell map of peripheral blood (PB) and bone marrow (BM) monocytes from both healthy donors (HDs) and MM patients. Specifically, Heparin-anticoagulated PB samples or BM aspirates were collected from seven newly diagnosed MM (NDMM) patients and healthy donors (HDs). Paired BM aspirates were obtained from 10 MM patients at the time of diagnosis and after induction therapy.
Differential expression analysis showed that type I interferon (IFN) response was upregulated in MM monocytes. And BM monocytes derived from MM patients exhibited impaired T cell attraction abilities and demonstrated an elevated capacity for suppressing T cell function. Moreover, immune checkpoint molecules, including CD274 (encoding PD-L1) and PDCD1LG2 (encoding PD-L2), were significantly upregulated in MM monocytes. Additionally, a positive correlation was observed between type I IFN response and T cell suppression capacity of MM monocytes. Trajectory analyses revealed an IFN-focused disruption of developmental pathways of both BM and PB monocytes in MM. Lastly, we included 10 MM patients at the time of diagnosis and after induction therapy to monitor transcriptional changes over time. Our results revealed that anti-tumor therapy successfully mitigated the excessive type-I interferon response of BM monocytes in MM.
We document that MM monocytes exhibited an augmented type-I IFN response compared to monocytes from HDs, while their overall heterogeneity remained unchanged. Furthermore, we extended the knowledge on immunosuppression of the MM TME that the excessive type-I IFN response in MM had a significant impact on the differentiation of both BM and PB monocytes, leading to T-cell immunosuppression, specifically in BM monocytes. In the cohort that we longitudinally followed, we observed a decrease in the type-I IFN response across nearly all monocyte subsets in MM BM monocytes after induction therapy, accompanied by a reduction in the expression of the T-cell suppression gene set. In sum, our findings indicates that monocytes in the BM promotes the immunosuppression of the MM TME and represents potential therapeutic targets for modulating the MM TME.
The Glass Wall: Gendered Authorship Disparities in in CD 19 and BCMA CAR-T Clinical Trials for Lymphoma and Myeloma
Authors: Khaliq Aroog , Wesson William , Logan Emerson , Tabak Carine , Rashid Aliya , Mansour Razan , Mushtaq Muhammad Umair , McGuirk Joseph P , Hashmi Hamza , Hamadani Mehdi , Abdallah Al-Ola , Ahmed Nausheen 
Published: December 2023

Introduction: Existing literature suggests that women are significantly underrepresented in the field of hematology-oncology. Data from 2021 suggests that women make up 35.6% of hematologists, and thus the disparity continues in clinical trial research authorship. Minorities including women receive fewer awards, deliver fewer board review lectures, and hold fewer professorships, and leadership positions in clinical departments and professional organizations. To further investigate this issue, we conducted a study to assess the gender gap in authorship across 13 pivotal clinical trials that led to the approval of CD19 and BCMA Chimeric antigen receptor T cell (CAR-T) therapies.
Methods: We included the 13 pivotal trials that led to the approval of CART for Acute Lymphoblastic leukemia (ALL), lymphoma and myeloma , published between 2017-2022. These included the trials: ELIANA, ZUMA-1, JULIET, ZUMA-2, KarMMa, TRANSCEND, ZUMA-5, CARTITUDE-1, ZUMA-7, ZUMA-3, TRANSFORM, PILOT, and ELARA.
We examined the overall number of female authors, the number of lead female authors as defined as first, second, or last author, and the ratio of all authors to female authors. 367 total authors were included in the analysis, with several authors being included more than once for their work on separate studies.
Results: Table 1 summarizes the results. Of the 367 authors assessed, 109 were female, correlating to 28.9% female authorship. The only study with female authorship &gt;50% was ELIANA, a 2017 pediatric study, while all others had &gt;50% male authorship. 7 (54%) of the 13 studies had females as lead authors; of note, 6 out of 7 of these studies were published after 2021.
Conclusion: Gender inequities in research authorship are pervasive in many areas of medicine, including the field of immune effector cell therapy. Publications in the field broadly are overwhelmingly male dominated, possibly reflective of lower female representation in transplant and cellular therapy. Despite this, we observed improved gender equality in authorship in more recent publications since 2021, and in certain research areas such as pediatric hematology-oncology. Recognizing these seemingly invisible barriers is the first step in bringing gender equity to the field of hematopoietic stem cell transplant and cellular therapy, with gender serving as one of many domains in which underrepresented groups' ability to scale the glass wall must be supported.
Table 1.
Efficacy and Safety Analysis of Carfilzomib-Containing Regimen in the Treatment of Multiple Myeloma：a Multicenter Real-World Study
Authors: Liu Na , WANG Luqun , Liu Rentong , Zhong Yuping , Feng Xianqi , Sun Zhongliang , Li Jie , Meng Fanjun , MA Junjie , Yuan Changyong , Li Hao , Wang Ling , Xu Zhilong , Yu Jie , Zhang Hao , Chunyan Chen 
Published: December 2023

Purpose
To investigate the efficacy and safety of carfilzomib-containing regimens in the treatment of multiple myeloma（MM） in different lines of treatment.
method
The clinical data of 55 multiple myeloma patients who received carfilzomib treatment in 10 medical centers in Shandong from January 2022 to March 2023 were retrospectively analyzed , and grouped according to the number of MM treatment lines, they were divided into group A : newly diagnosed multiple myeloma ( NDMM ), group B : patients with first relapse, and group C : patients treated with carfilzomib in the third line or above. Del ( 17p ), t ( 4;14 ), t ( 14;16 ) were defined as high-risk cytogenetic abnormalities
result
All patients with multiple myeloma were treated with the combined regimen based on carfilzomib, including 24 patients in group A , 9 patients in group B , and 22 patients in group C. Among all patients, there were 27 cases ( 49.1% ) of high-risk cytogenetics, and 13 cases with ECOG score ≥ 3 points ( 23.6% ), 10 cases ( 18.2 ) had eGFR &lt;30 ml/min. The median follow-up time of patients in group A , group B and group C was 8 months, 9 months and 8 months. The overall response rate ( ORR ) was 91.7% , 88.9% and 77.3% for patients in Arms A , B and C who started carfilzomib, respectively . The ≥very good partial response ( VGPR ) rates were 75% and 66.7% for Arm A and B patients , respectively , while the ≥VGPR rate for Arm C patients was 41.0% . The negative rate of minimal residual disease ( MRD , sensitivity: 10 -6 ) in group A was 62.5% ( 15/24 ). Follow - up deadline is March 2023 On the 31st , the median progression-free survival ( PFS ) time and median overall survival ( OS ) time of patients in the three groups were not reached. After the application of carfilzomib, the incidence rate of grade 3-4 adverse events ( AE ) was 32.7% ( 18/55 ). The main hematological adverse reactions were anemia, thrombocytopenia, lymphopenia and neutropenia. Non-hematological adverse reactions were mainly infusion-related adverse reactions and infections.
in conclusion
Carfilzomib-based regimens in the treatment of multiple myeloma have good curative effect and safety, and the first-line and first-time relapse patients have better curative effect.
Selinexor Enhances Natural Killer Cell Function Against Multiple Myeloma Cells
Authors: Fisher Jack G , Doyle Amber DP , Graham Lara V , Forconi Francesco , Cragg Mark S , Walker Christopher J , Khakoo Salim I , Blunt Matthew D 
Published: December 2023

Introduction: Natural killer (NK) cells are innate immune effector cells which can mediate antibody dependent cellular cytotoxicity (ADCC) and lyse cancer cells. Harnessing NK cell function against multiple myeloma (MM) is of high interest and multiple strategies are currently under development.
Exportin-1 (XPO1) is a nuclear export protein which inhibits the function of tumour suppressor proteins and facilitates oncogene mRNA translation. Selinexor is a first-in-class XPO1 inhibitor approved for the treatment of relapsed or refractory MM that induces cancer cell apoptosis. In addition, selinexor has recently been shown to promote NK cell cytotoxicity against B cell lymphoma cells. This study aimed to determine whether selinexor augments NK cell activation against MM cells both alone, and in combination with the anti-CD38 antibody daratumumab.
Methods: A panel of MM cell lines (MM.1S, U266 and RPMI-8226) were incubated with clinically relevant concentrations of selinexor for 24 hours, then either assessed for expression of ligands for NK cell receptors (KIR, NKG2A, NKG2D and NKp46), or co-cultured with primary human NK cells ± daratumumab. Following co-culture, NK-mediated lysis of MM cells was assessed by propidium iodide staining and NK cell degranulation assessed by CD107a expression.
Results: Selinexor pre-treatment of MM cells significantly increased NK cell degranulation (p&lt;0.05) and enhanced NK specific lysis of MM targets (p&lt;0.05). Furthermore, selinexor pre-treatment significantly (p&lt;0.05) enhanced NK cell activation in combination with daratumumab compared to daratumumab alone. Importantly, selinexor did not alter surface expression of CD38 on MM cell lines. To investigate the mechanism behind this enhanced NK cell function, we assessed the effect of selinexor on the expression of NK cell ligands by MM cells. Selinexor increased the expression of ULBP1/2/5/6 (2-fold, p&lt;0.001) which bind to the NK cell activating receptor NKG2D. In addition, selinexor decreased MM cell expression of HLA-E (30% decrease, p&lt;0.05) which binds to the inhibitory NK receptor NKG2A.
Conclusions: These data suggest that selinexor may promote the efficacy of NK targeted therapeutics in multiple myeloma.