bluuebunny/crossref_metadata_2025 huggingface dataset:
Influenza Training of Granulopoiesis Promotes Long-Term Anti-Leukemia Activity
Authors: Liu Yi , Chen Nianci , Zhou Yile , Zhu Li , Lv Zuopo , Li Chenying , Huang Jiansong , Tong Yanhong , Meng Haitao , Jin Jie , You Liangshun
Published: December 2023

Abstract

Influenza viral infections have the ability to reprogram the immune system of the host and alter its functions to fight infections. However, the exact mechanisms and functions of virus-induced innate immunity in the context of leukemia are not yet fully understood. Our previous research has shown that a patient with refractory acute myeloid leukemia (AML) achieved complete remission (CR) after being infected with the Influenza A virus (IAV, H1N1 subtype), and this was functionally validated in two different animal disease relevant models. Our recent study demonstrates that mice pre-trained with the IAV promotes a long-term anti-leukemia effect. The anti-leukemia activity of IAV-induced trained immunity is due to the transcriptomic rewiring of hematopoietic stem and progenitor cells (HSPCs), resulting in a sustained enhancement of myeloid cells reprogramming toward an antitumor phenotype. This mechanism involves the upregulation of type I interferons (IFNs) and subsequent downregulation of inflammatory proteins. Our findings shed light on the dynamic changes in innate immune cells following viral infections and indicate a novel anti-leukemia facet of appropriate rewiring of granulopoiesis via upregulation of type I IFNs.

Statement of significance

The study profiles the dynamic changes in immune cells during exposure to the Influenza virus and sheds light on the role of Influenza trained innate immunity in anti-leukemia effect. The study also explores a novel anti-leukemia facet of appropriate rewiring of granulopoiesis via upregulation of the type I IFN pathway. These findings suggest that innate immune training could be a promising adjuvant therapy for cancer and warrant further investigation.

Legend for Figure 5 . H1N1 reprogrammed granulopoiesis via up-regulation of type I interferon pathway.

(A-C) FCM analyses and absolute counts of BM progenitor cells on day 7 after training with H1N1 or PBS. FCM, flow cytometry; BM, bone marrow; LK, Lin-c-kit+Sac1-; LSK, Lin-c-kit+Sac1+; GMP, granulocyte-monocyte progenitors (Lin-c-kit+Sac1-CD16/32 hiCD34+); CMP, common myeloid progenitors (Lin-c-kit+Sac1-CD16/32 intCD34+); MEP, megakaryocyte-erythroid progenitor cell (Lin-c-kit+Sac1-CD16/32-CD34-).

(D) T-SNE plot of top 7 progenitor cells population changes. t-SNE, t-distributed stochastic neighbor embedding.

(E) Heatmap visualization of the expression of different genes in HSPCs. The upregulated genes related to the type I IFNs pathway are listed on the right. HSPCs and hematopoietic stem/progenitor cells.

(F) The top enriched GO terms of biological processes for upregulated genes in H1N1 trained group. GO, gene ontology.

(G-H) Heatmap and t-SNE plot of type I IFN-associated upregulation genes in progenitor cells of HSPCs, GMP, CMP, and MEP. t-SNE, t-distributed stochastic neighbor embedding.
Inaccuracy of Initial Clinical Mobility Assessment in Venous Thromboembolism Risk Stratification
Authors: Hoyer Erik , Brotman Daniel J. , Streiff Michael
Published: December 2023

Background: The risk of Venous Thromboembolism (VTE) often escalates in hospital settings in part due to reduced patient mobility. However, mobility assessment for VTE risk determination is often clouded by lack of clear definitions and standards. This vagueness can result in erroneous evaluations, especially near the time of admission, particularly since a patient's mobility is not static but fluctuates throughout the hospital stay.

Methods: We conducted a retrospective cohort analysis of patients who were discharged from medicine services in a large academic hospital. For each of these patients, daily nurse-collected Johns Hopkins-Highest Level of Mobility (JH-HLM) scores were used to calculate an objective measure of mobility. Reduced mobility was defined as an JH-HLM score of ≤3 on three consecutive days during hospitalization. We compared this definition of reduced mobility with clinician reported immobility as reflected by Padua scores entered on admission as part of mandatory VTE risk stratification. We also assessed the association between immobility and VTE using an adjusted odds ratio controlling for other VTE risk factors.

Results: Out of 1715 included patients, clinicians identified only 111 (6.5%) as having reduced mobility compared with 328 patients (19.1%) using the JH-HLM calculated approach. If the JH-HLM calculated measure of reduced mobility had been utilized, it would have led to the reclassification of 37 patients from a low-risk category to a high-risk category for VTE. In the cohort, 33 of 1715 (1.9%) patients developed VTE. Among these patients, JH-HLM calculated reduced mobility was identified in 12/33 (36%) of patients, whereas clinicians identified reduced mobility in 3/33 (9%) of patients. Presence of JH-HLM calculated reduced mobility was significantly associated with VTE events (aOR: 2.53, 95% CI: 1.23 - 5.22, P = 0.012). Clinician assessed reduced mobility at the time of admission was not associated with VTE events.

Conclusion: The initial clinician's assessment of mobility during VTE risk assessment did not accurately capture the extent of reduced mobility during the patient's hospitalization. These findings highlight the importance of employing objective measures of patient mobility for assessing and reassessing VTE risk throughout the hospital stay. Healthcare organizations should consider implementing objective measures of mobility like the JH-HLM to improve VTE risk assessment and potentially reduce the occurrence of VTE.
Extravascular Factor IX Pool Fed By Prophylaxis Is a True Hemostatic Barrier Against Bleeding
Authors: Leuci Alexandre , Enjolras Nathalie , Marano Muriel , Daniel Melanie , Brevet Marie , Connes Philippe , Dargaud Yesim G.
Published: December 2023

Factor IX (FIX) can bind to type-IV collagen in the endothelial basement membrane and diffuse into extravascular spaces. Previous studies in rodents have reported a large biodistribution of FIX. However, the potential hemostatic activity of extravascular FIX and its role in protecting against joint bleeds have not been demonstrated. The capacity of 4 different FIX molecules (plasma derived [pd] and recombinants) to bind type I and type IV collagen was studied here. FIX molecules were also administered intravenously at doses of 50 to 3000 IU/kg in FIX knock-out (KO) mice. A specific FIX signal was detected in immunohistochemistry in the liver as well as in muscles and knee joints with recombinant FIX molecules injected at 1000 and 3000 IU/kg but not at the usual clinical doses of 50-100 IU/kg, while pdFIX generated a FIX signal at all doses including 50 IU/kg. After five 100 IU/kg daily infusions of rFIX, a clear accumulation of FIX was seen in the liver and joints of animals having received 5-day daily FIX infusions with all FIX molecules, with a higher FIX labelling intensity compared to that observed after a single infusion of FIX 100 IU/kg or a single infusion of FIX 500 IU/kg.

The extravascular procoagulant activity of FIX was assessed in saphenous vein bleeding assays performed 7 days after a single infusion of FIX 100 IU/kg. An additional group of FIX KO mice received intravenously for 5 days a single daily dose of 100 IU/Kg of one the four types of FIX concentrate in order to mimic prophylaxis. The number of clots formed in 15 minutes was significantly greater in mice having received prophylaxis during 5 days with 100 IU/kg FIX compared to untreated FIX KO mice (p=0.009) and to mice having received a single infusion of FIX 100 IU/kg (p<0.0001) (Figure 1).

Taken together, these results show that in individuals with severe hemophilia B receiving regular prophylaxis with FIX, extravascular accumulation of FIX over time may have a significant impact on the coagulation capacity and protection towards bleeding.
CUX1 Levels Control Hematopoietic Stem Cell Fate and Plasticity
Authors: Martinez Tanner C. , Jotte Matthew R. M. , McNerney Megan E.
Published: December 2023

Hematopoietic stem cells (HSCs) sustain lifelong, multipotent output, however, the molecular mechanisms governing HSC homeostasis remain unclear. Elucidating this process is key to understanding the imbalanced differentiation and self-renewal evident in myeloid malignancies. CUX1 is a transcription factor that is monoallelically mutated or deleted in high-risk myeloid malignancies. We previously reported that CUX1 has critical, dose-dependent roles in hematopoiesis and myeloid neoplasia. The haploinsufficient nature of CUX1 in myeloid neoplasia and the broad dose-dependent requirement of CUX1 in hematopoiesis led us investigate the role of CUX1 in earliest stages of hematopoiesis. We generated a CUX1 reporter mouse in which mCherry is fused in-frame with the C-terminus of CUX1 to study how the level of CUX1 in HSCs affects their behavior. Overall, we find that CUX1 protein levels within the HSC compartment delineates stem cell activity. Stringently defined immunophenotypic HSCs with low CUX1 levels (CUX1 Dim) are phenotypically dormant, as assessed by transcriptional profiling and proliferation assays, as opposed to CUX1 Bright HSCs which have greater cell cycle participation. In transplantation assays, CUX1 Dim HSCs are initially platelet-biased but give rise to long-term, multilineage reconstitution. CUX1 Bright HSCs are initially erythroid-biased but lack long-term HSC activity and the capacity for self-renewal. In other words, despite immunophenotypic HSC markers, CUX1 Bright HSCs are not, by definition, HSCs. By most metrics, CUX1 Intermediate HSCs exhibit a distinct, albeit intermediate, phenotype. Therefore, along a continuous gradient of CUX1 expression, HSCs gradually lose the ability to self-renew as CUX1 expression increases. Remarkably, knockdown of CUX1 in CUX1 Bright HSCs re-endows these cells with the capacity for long-term multilineage chimerism, suggesting low levels of CUX1 are required for stem cell activity in HSCs. Inversely, overexpression of CUX1 in HSCs promotes their expansion and ultimate exhaustion, further demonstrating that the level of CUX1 controls HSC fate. Altogether, we report that low CUX1 levels are required for HSC self-renewal and implicate CUX1 as a molecular rheostat for HSC behaviors such as cell division and differentiation. Further, we describe an unprecedented capacity for cells without demonstrated HSC activity to acquire HSC capacity and a novel role for CUX1 in preventing this plasticity.
New Aplastic Anemia Preconditioned with Fludarabine, Thiotepa, Cyclophosphamide, and Anti-Thymocyte Globulin
Authors: Liu Wenbin , Tan Zhengwei , Zhao Yuechao , Hu Huijin , Wu Dijiong , Ye Baodong
Published: December 2023

Aplastic anemia (AA) is one of life-threatening hematological disorder that can be cured by hematopoietic stem cell transplantation. When the absence of a matched sibling donor, haploidentical stem cell transplantation (haplo-HSCT) becomes an alternative choice for AA patients. We used a prospective study aimed to confirm the feasibility of Thiotepa-based modified post-transplantation cyclophosphamide (PTCY) strategy in haplo-HSCT for AA patients. We analyzed the outcomes of 15 patients who had undergone haplo-HSCT between October 2021-May 2023 in our clinical center. The modified condition regimen consisted of anti-thymoglobulin/antilymphocyte globulin, fludarabine, thiotepa, busulfan and modified low and high-dose cyclophosphamide, mycophenolate mofetil (MMF) and tacrolimus (FK-506)/cyclosporin (CsA) were administered as graft versus host disease (GVHD) prophylaxis after transplantation. The median follow-up time was 267 (range 97-532) days. All 15 patients were successfully implanted (100%), the median times for neutrophil and platelet engraftment were 14 (range 12-19) days and 12 (range 8-25) days, respectively. But one patient developed secondary graft failure because of infected with COVID-19、cytomegalovirus and H1N1. Fortunately, she subsequently underwent a successful secondary haplo-HSCT. The most common regimen-related toxicity was canker sore, hemorrhagic cystitis occurred in 3 patients during transplantation. The cumulative incidence of grade Ⅰ-Ⅱ aGVHD and cGVHD were 13.3% and 6.7% respectively, whereas the incidence of grade Ⅲ-Ⅳ aGVHD was not found so far. All 15 patients are alive, with a failure-free survival rate of 100% and GVHD relapse-free survival rate of 100%. The efficacy evaluation of haplo-HSCT, 14 patients achieved CR and 1 patient achieved PR. Because of 7 patients received the prevention strategy of Letermovir since August 2022, the reactivation rate of cytomegalovirus (CMV) was only 20% and 60% of Epstein-Barr virus (EBV) reactivation, but the CMV diseases and post-transplantation lymphoproliferative disorder (PTLD) were rare. Our study using Thiotepa-based modified haplo-HSCT demonstrated an encouraging result with prolonged survival and reduced complications for aplastic anemia patients.
Establishment of a Dynamic Ctdna Monitoring System to Predict the Prognosis of CAR-T Cell Therapy in R/R B-NHL Patients
Authors: Zhou Linghui , Cheng Tao , HU Yongxian , Huang He
Published: December 2023

Introduction: The objective of this study is to establish a prediction system using circulating tumor DNA (ctDNA) to determine the effectiveness of CAR-T cell therapy in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). Furthermore, the study aims to compare the mutation characteristics between different therapeutic groups to provide guidance for the prevention and follow-up treatment of patients who fail CAR-T cell therapy.

Methods: In this part of the study, a total of 79 (192 serum samples) R/R B-NHL patients with CAR-T cell therapy were collected for ctDNA detection (187 lymphoma-related gene panel), including 62 samples before treatment (T0), 69 samples at 1 week (T1) and 62 samples at 4 weeks (T2) after reinfusion. Differences of categorical variables were tested using the chi-square test or Fisher's exact test, and differences in survival events between different groups were compared using Kaplan-Meier analysis and log-rank test.

Results: The results of Kaplan-Meier analysis showed that patients with ctDNA mutation genes >10 before CAR-T cell therapy had poorer OS (1-year OS rate: 0% vs 74.9%, 2-year OS rate: 0% vs 68%, P<0.001) and PFS (1-year PFS rate: 0% vs 52.5%, 2-year PFS rate: 0% vs 36.6%, P=0.0056). Patients with MYD88, FAT1 and BTG2 mutation before CAR-T cell therapy had poorer OS, while patients with MUC16 mutation had better OS. The CR rate in patients with TP53 mutation before CAR-T cell treatment was significantly lower than that of patients without TP53 mutation (33.3% vs 68.1%, P=0.02). However, the TP53 mutation status before treatment did not have an impact on the long-term survival of patients. All patients with TP53 mutations at 4 weeks after CAR-T cell therapy failed to achieve CR, and OS was poorer (1-year OS rate: 37.5% vs 66.4%; 2-year OS rate: 12.5% vs 56.3%, P=0.0023). For CR patients, patients with BCR mutation at 4 weeks after treatment had poorer OS (2-year OS rate: 40.9% vs 76.1%, P=0.035). At one week after CAR-T cell therapy(Figure 1), patients without mutations of CDKN2A, CBLB, APC, SPEN, KMT2D, CARD11, FOXO1 and PDGFRB, were more likely to achieve CR (76.6% vs 28.6%, P<0.001), and had better OS (1-year OS rate: 81.5% vs 38.9%, 2-year OS rate: 62.2% vs 5%, P<0.001) and PFS (1-year PFS rate: 67.2% vs 0%, P<0.001).

Conclusions: In this study, we evaluated the characteristics of gene mutation between different therapeutic groups, and a gene set was screened to predict the efficacy of CAR-T cell therapy in R/R B-NHL patients, helping clinicians accurately evaluate the efficacy and assisting in decision-making of treatment options.
Efficacy of Hetrombopag in Treatment of Cancer Therapy-Induced Thrombocytopenia in Lymphoma and Multiple Myeloma Patients
Authors: Huang Wen-Rong , Chen Junli
Published: December 2023

Background: Chemotherapy and its combination are the mainstay of lymphoma and multiple myeloma (MM) treatment, with high-intensity regimens frequently causing cancer therapy-induced thrombocytopenia（CTIT）, which results in dose reductions and treatment delays. Hetrombopag, a novel oral non-peptide thrombopoietin receptor agonist, is approved in China for immune thrombocytopenic purpura and severe aplastic anemia. This study retrospectively evaluated the efficacy of hetrombopag in treating CTIT among lymphoma and MM patients.

Methods: In this retrospective study, lymphoma and MM patients experiencing≥grade 2 thrombocytopenia (PLT<75×10 9/L) after anti-tumor treatment at the Fifth Medical Center of PLA General Hospital from July 2021 to May 2022 who received hetrombopag were included. All patients were treated with 5 mg hetrombopag once daily until PLT≥100×10 9/L or treatment discontinuation as directed by physicians.

Results: A total of 60 patients (4 Hodgkin's lymphoma, 40 non-Hodgkin's lymphoma, and 16 MM) were analyzed. Their baseline characteristics are presented in Table 1. The median age was 58.0 years (range 14, 86), with 51 (85%) stage Ⅲ/Ⅳdiseases. Most patients received chemotherapy alone (40.0%, 24/60) or combined with targeted therapy (48.3%, 29/60). Notably, 90% patients received a combination of ≥3 chemotherapy drugs. The mean PLT before hetrombopag treatment was (38.8±15.6) ×10 9/L, with 81.7% (49/60) of grade 3/4 thrombocytopenia (PLT＜50×10 9/L). The median treatment duration with hetrombopag was 8 days (range 2, 28). The median time for PLT recovery to 75×10 9/L, and 100×10 9/L from hetrombopag initiation was 7 days (range 3, 14), and 9 days (range 3, 13), respectively. The mean PLT counts on days 3, 5, and 10 of hetrombopag treatment showed notable increases to (40.9±30.9) ×10 9/L, (54.9±37.8) ×10 9/L, and (94.4±70.5) ×10 9/L, respectively. Only 3 patients (5%) developed bleeding events, and 50% of patients avoided platelet transfusion. No hetrombopag-related adverse events were observed.

Conclusion: With the limit of a retrospective evaluation, we observed that hetrombopag might increase PLT, shorten the duration of thrombocytopenia, with no significant toxicity, for lymphoma and MM patients who developed CTIT of ≥grade 2 in this study.
Genetic Study of Patients with Severe Dense Granule Deficiency: Unraveling the Underlying Genetic Complexity of Hermansky-Pudlak Syndrome
Authors: Pruthi Rajiv K. , Majerus Julie , Chen Dong
Published: December 2023

Background: Severe platelet (plt) dense granule (DG) deficiency is a hallmark of Hermansky-Pudlak syndrome (HPS), a rare, heterogeneous group of genetic disorders characterized by oculocutaneous albinism, bleeding diathesis, and lysosomal storage defects. A subset of HPS patients (pt) who has HPS1, HPS2, and HPS4 may also experience pulmonary fibrosis, granulomatous colitis, and/or immunodeficiency (syndromic HPS). Platelet transmission electron microscopy (PTEM) has been considered a valuable tool to screen such patients, and molecular testing aids in confirming te diagnosis, subclassifying the HPS and providing information on prognosis in pt. To elucidate the effectiveness of PTEM and next-generation sequencing (NGS) to identify and subclassify HPS pt, we conducted a comprehensive study on a cohort of pt with severe plt DG deficiency. Methods: After IRB approval, consecutive samples submitted to our reference laboratory for PTEM testing were analyzed. Whole mount (WM) PTEM tests were performed on all pt. Targeted NGS of the ISTH tier 1 genes (including 11 HPS-related genes) was performed on a cohort of patients who had < 0.3 mean DG/plt (200 plt counted) by PTEM. Data collected included demographics, PTEM findings, and genetic variants classified based on the 2015 ACMG criteria. Results: A total of 38 pt met our study criteria, the median age at PTEM testing was 39 years (range, 5 months to 76 years), and 22 (58%) were female. Ethnic backgrounds included Caucasian, Albanian, Puerto Rican, and other (unavailable). The mean DG/plt was 0 (0-0.2). A variant in an HPS-related gene was found in 26/38 patients (68%). The spectrum of variants in HPS-related genes is shown in Table 1, encompassing single-nucleotide substitutions, insertions, deletions, and frameshift mutations involving HPS1, HPS3, HPS5, HPS6, and HPS7 ( DTNBP1) genes. In addition to the previously reported pathogenic variants, several novel/previously unreported variants were discovered (Table 1). Interestingly, some patients presented with multiple variants, suggesting potential compound heterozygosity. No variants were found for the remaining 12 patients (32%). Conclusion: Our NGS-based genetic study of 38 patients with severe DG deficiency provides valuable insights into the complexity of this rare disorder. The high yield of finding variants in HPS-related genes verified that WM-PTEM is a useful screening tool for identifying HPS patients. The identification of known variants in HPS-associated genes confirms the importance of genetic testing not only in the diagnosis of HPS but also provides information on prognosis in syndromic HPS. Pathogenicity of novel variants remains to be elucidated. Moreover, the observed 32% of patients who had negative NGS results suggest the existence of as yet undiscovered genetic mechanisms for the severe platelet DG deficiency.
Trends in Diffuse Large B-Cell Lymphoma Mortality in the United States: A Comprehensive Review from 2000 to 2020
Authors: Al Armashi Abdul Rahman , Al Zubaidi Anas , Mahmood Omar , Thierheimer Marisa , Alkrekshi Akram , Abdulhaq Haifaa
Published: December 2023

Introduction:

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of Non-Hodgkin Lymphoma (NHL), accounting for approximately 30% of all cases. While NHL mortality rates have shown a downward trend over the last two decades, comprehensive investigations into DLBCL mortality trends and disparities across racial, ethnic, gender, and geographical categories in the United States are notably scarce.

Methods:

Utilizing the Centers for Disease Control and Prevention's (CDC) WONDER database we identified all patients who died from NHL and DLBCL from 2000 to 2020. Age-adjusted mortality rates per 100,000 persons (AAMR) were calculated and standardized to the 2000 US census data. The National Cancer Institute (NCI) Joinpoint Regression Program was used to analyze these data to calculate annual percent changes (APCs) and average annual percent changes (AAPCs). Statistically significant changes were confirmed when the confidence interval for the APC or AAPC did not encompass zero. Additionally, subgroup analyses were conducted based on race, ethnicity, gender, and geographic location.

Results:

The study identified 434,419 NHL and 46,252 DLBCL deaths. NHL mortality showed a statistically significant average annual decrease of 2.5% (95% CI: -2.7 to -2.4). DLBCL mortality trends varied, initially decreasing from 2000 to 2008, then notably increasing from 2008 to 2011, and subsequently rising moderately from 2011 to 2020. This pattern culminated in a statistically significant overall average annual increase of 3.5% (95% CI: 0.4 to 6.7) in DLBCL mortality. Subgroup analyses revealed that males, Blacks, and Asians or Pacific Islanders experienced the most marked upward trends in DLBCL mortality. Both metropolitan and non-metropolitan areas reported an increase in DLBCL mortality, with metropolitan areas showing a more pronounced rise.

Conclusion:

Representing the most comprehensive analysis of DLBCL mortality trends to date, our study revealed intriguing disparities among the subgroups we investigated, along with an upward trend in mortality rates that departs from previously reported data. The divergence could be attributed, in part, to the expansive population coverage of the database we utilized and the use of death certificates, which may present discrepant results from other cancer registries. These findings underscore the necessity for ongoing research, guiding the development of targeted intervention strategies for DLBCL and informing efforts to bridge the identified disparities.
A Novel Nomogram Predicting Rituximab-Associated Interstitial Pneumonia in Patients with Diffuse Large B-Cell Lymphoma: A Retrospective Analysis of Single-Center
Authors: Guo Jia , Wang Chengji , Liang Yuanzheng , Wang Liang
Published: December 2023

Background: The incidence rate of rituximab-induced interstitial lung disease (RILD) was reported to be 3.7%-16.7%. The onset of RILD was insidious, and the clinical symptoms were atypical. The course of the RILD progressed rapidly without timely treatment. However, there were no models reported to predict the risk of RILD. Herein, we investigated the incidence of RILD in consecutive patients with diffuse large B-cell lymphoma (DLBCL) and its correlation with clinicopathological features, and a novel nomogram was constructed to successfully predict the risk of RILD.

Methods: The clinicopathological data of 110 consecutive patients with DLBCL who were treated in the Department of Hematology of Beijing Tongren Hospital from January 2020 to December 2022 were retrospectively collected, and all patients received first-line treatment regimens containing rituximab. The occurrence of interstitial pneumonia was assessed by chest CT or interim PET-CT. Efficacy was assessed according to Lugano criteria, and chi-square test was used to assess the difference in RILD in different characteristic groups.

Results: The complete remission rate of 110 patients with DLBCL after treatment was 84.2%. Twenty-one patients (19.1%) developed RILD during treatment, and the median time of occurrence was the 4th cycle（range: 2~8). The median duration of treatment for RILD was 10 days (range: 5~60). Except for 5 patients with no obvious symptoms, all 16 patients received glucocorticoid-containing regimens, and all patients improved after treatment. The incidence of RILD was significantly higher in patients who received liposomal doxorubicin-containing regimens than those treated with adriamycin regimens (29.7% versus 13.7%, P=0.043). Smoking ( P=0.298) and advanced age ( P=0.156) were associated with a high incidence of RILD. Then we developed a RILD risk prediction model according to the risk factors, and the patients were divided into high-risk and low-risk groups, and the incidence of RILD was significantly different between the two groups ( P=0.027). Finally, a novel nomogram related to the occurrence of RILD in DLBCL patients was developed to scientifically and accurately predict the incidence of RILD.

Conclusion: Patients with DLBCL should be alert to the occurrence of RILD after chemotherapy with rituximab-containing regimen, especially in smoking and elderly patients, and the prevention and monitoring of RILD should be strengthened after the application of liposomal doxorubicin.
Lack of Standardized Coding Limits Accuracy of Electronic Clinical Quality Measure for Pulmonary Embolism Diagnosis
Authors: Baumann Kreuziger Lisa , Keenan Megan , Dykhoff Hayley , Hall Marie , Campbell Kyle , Cahill Emily , Hanson Ryan , McEvoy Dustin , He Wei , Dutta Sayon , Rosovsky Rachel P. , Houghton Damon E.
Published: December 2023

Introduction: ASH Guidelines for diagnosis of pulmonary embolism (PE) start with risk assessment using a pretest probability tool (PTP) followed by D-dimer testing or CT pulmonary angiography (CTPA) depending on risk. We aimed to develop an electronic clinical quality measure (eCQM) to encourage broader use of a validated PTP scoring tool in emergency departments (EDs). The Centers for Medicare & Medicaid Services require reporting of eCQMs which consist of value sets or lists of standardized codes linked to patient data within the electronic health record. We sought to identify a standardized way to identify CTPA and abnormal D-dimer tests using administrative codes (i.e. CPT, LOINC, SNOMEDCT codes) across three institutions.

Methods: Value sets identifying CTPA and D-dimers were reviewed from existing eCQMs. Three institutions representing 38 EDs from across the country submitted data from all ED encounters between September 12, 2022 and January 11, 2023. Imaging types were reviewed from each of the CPT codes and LOINC (Logical Observation Identifiers Names and Codes). We determined the number of ED encounters, pre-test probability tool use, and diagnosis of PE using different codes. We calculated sensitivity, specificity, positive and negative predictive value (PPV and NPV, respectively).

Results: Over the 4-month study period, 270,214 encounters were identified across 38 EDs. Each institution identified CTPA with site-specific codes (Table 1). The Full CTPA Value Set identified 55% more encounters than the site-specific codes (Full set 15,054/9679 site-specific codes). LOINC code 88322-3 was only used at one site. CPT code 71275 had the best sensitivity and specificity, but still had false positives (PPV 82%) (Table 2).

D-dimer values were identified as LOINC code 48065-7 and 91556-1 at Site 1 and 48067-3 at Site 2. SNOMEDCT codes were not used at any site despite being the way other eCQMs identify elevated D-dimer results. Different D-dimer tests with different normal ranges were used at each site. All sites did not have an electronically extractable positive indicator for D-dimer.

Conclusion: Due to persistent false positives using CPT Code 71275 for identification of CTPA, using this code would lead to inclusion of patients for whom PTP was not required or recommended. Additionally, coding for an abnormal D-dimer test result are not standardized across institutions. Therefore, administrative codes cannot be used to develop eCQMs whose aim is to evaluate whether CTPA is ordered appropriately based on the PTP risk level and laboratory testing.
Spatiotemporal Impact of Sars-Cov-2 Infection on the Transcriptome of Bone Marrow Megakaryocytes
Authors: Allaeys Isabelle , Leclercq Mickael , Tilburg Julia , Stone Andrew , Fleury Maude , Lacasse Emile , Machlus Kellie , Droit Arnaud , Flamand Louis , Boilard Eric
Published: December 2023

Megakaryocytes, integral to platelet production, predominantly reside in the bone marrow, undergoing regulated fragmentation within sinusoid vessels to release platelets into the bloodstream. Inflammatory states and infections have been shown to influence megakaryocyte transcription, potentially affecting platelet functionality. Notably, COVID-19 has been associated with altered platelet transcriptome. In this study, we hypothesized that SARS-CoV-2 infection could impact the transcriptome of bone marrow megakaryocytes, particularly those in direct proximity to the blood. Utilizing spatial transcriptomic analysis and machine learning techniques, we observed that the transcriptome of healthy mouse bone marrow megakaryocytes exhibited minimal alteration based on proximity to sinusoid vessels. Similar findings were observed during peak SARS-CoV-2 viremia, when the disease primarily affected the lungs. Conversely, a significant divergence in the transcriptome of megakaryocytes was observed during systemic inflammation, even when SARS-CoV-2 was no longer detectable in the lungs or bone marrow. Under these conditions, the transcriptional landscape was enriched in genes associated with structural and translational activities, platelet degranulation, netosis, and auto-immunity. Of the approximately ~19,000 genes identified in megakaryocytes during systemic inflammation, machine learning pinpointed 30 genes significantly altered in cells closely adjacent to sinusoid vessels, with gene ontology attributing these changes primarily to protein deSUMOylation. Intriguingly, the type-I interferon signature and calprotectin (S100A8/A9) were not induced under any condition. Inflammatory cytokines were elevated in the blood of COVID-19 mice, but not in bone marrow plasma, suggesting a preferential impact of inflammation on this specific subset of cells. Collectively, our data indicate that distinct subpopulations of bone marrow megakaryocytes may emerge based on spatial localization and the stage of COVID-19 pathogenesis.
A Preliminary Report of Clinical Study on Immunosuppressive Therapy Combined with Avatrombopag As the First-Line Treatment for Severe Aplastic Anaemia in Elderly Patients
Authors: Ye Lei , Zhao Xin , Jing Liping , Peng Guangxin , Zhang Fengkui , Zhang Li
Published: December 2023

Objective The objective is to evaluate the early hematologic response (HR) rate and safety of immunosuppressive therapy (IST) combined with avatrombopag as the first-line treatment for severe/very sever aplastic anaemia(V/SAA) in elderly patients. Methods Prospective，multi-center, single-arm, clinical research. IST treatment regimen: pig anti-human lymphocyte globulin (ALG-p, Wuhan Institute of Biological Products Co., Ltd. China) 20 mg/kg/d for five days and cyclosporin A (CsA) 3 mg/kg/d with adjusted concentration of 150-250 ng/mL, and oral avatrombopag 40 mg/d from the first day of IST initiation up to six months. The patients' treatment responses were evaluated and the major adverse events were collected. Results Ten patients have been enrolled in the study at our centre from June 2022 to October 2022.Among 10 patients, six had SAA and four had VSAA; male: female = 1:1, median age of 68 (60-82) years, and median time from diagnosis to treatment of 44 (20-480) days. The patients' treatment responses were evaluated after initiation of IST, at 3 months: 7 HR [1 complete response (CR), 3 good partial response (GPR), 3 partial response (PR), and 3 no response (NR)]; and at 6 months: 8 HR (1 CR, 5 GPR, 2 PR) and 2 deaths due to infection. The median time of red-cell transfusion independence was 60 (3-168) days in HR patients and that of platelets was 60 (16-153) days. No relapse and clonal evolution occurred within six months. Major adverse events within three months were infection in five cases, electrolyte disturbance in five cases, and cardiac insufficiency in three cases. Liver function abnormalities occurred in two cases, both of which showed elevated alanine aminotransferase up to 174 μ/L and 208.7 μ/L on day 8 and 20 of IST treatment, respectively. Two of the five infected patients had sepsis caused by Enterobacter cloacae. Except for infection, the remaining adverse events were of grade I-II. All the adverse events were effectively controlled. Table 1 summarises the characteristics and clinical status of patients before and after the treatment.

Conclusion This preliminary study of IST combined with avatrombopag for the treatment of elderly patients with V/SAA showed the potential of the combination to improve haematologic response rate and quality in elderly patients with AA, and it is well tolerated as well.

Keywords: immunosuppressive therapy, severe aplastic anaemia, avatrombopag, elderly
Safety and Efficacy of Human Amniotic Epithelial Stem Cells Eye Dropin Ocular Chronic Graft-Versus-Host Disease
Authors: Cheng Xianjing , Huang Ruihao , Fan Wei , Zhao Yuancheng , Huang Shiqin , Yuan Rongdi , Wang Xiaoqi , Zhang Xi
Published: December 2023

Background

Approximately 50% of patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT) suffer from ocular chronic GVHD (ocGVHD), which causes severe dryness and visual impairment. However, current clinical treatments for ocGVHD, such as artificial tears, immunosuppression therapy, and punctual occlusion, typically offer only limited benefits. Amniotic membrane transplantation (AMT) can significantly alleviate ocular symptoms in patients with ocGVHD, but it is an invasive procedure that is not appropriate for all patients with ocGVHD. Therefore, we designed a clinical trial to demonstrate the safety and efficacy of eye drops containing human amniotic epithelial stem cells (hAESC) in ocGVHD.

M ethods

Register Number: ChiCTR2200057857. The enrolled eyes received 1*10 6 cells/mL of hAESC eye drops four times daily for one to three treatment cycles (A cycle was defined as two weeks of continuous administration and two weeks without hAESC eye drops). The primary outcome measure is safety following treatment with hAESC eye drops. In addition, other clinical indices, such as the ocular surface disease index (OSDI), NIH score(eye), Schirmer's test, corneal fluorescein staining (CFS) score, fluorescein tear breakup time (FTBUT), and in vivo confocal microscopy (IVCM) were essential parameters.

Results ：

19 of the 25 patients included in the study completed at least one round of treatment. The average length of follow-up was 9.4 months. There were no adverse events associated with hAESC. After one round of treatment(n=19), there was a significant decrease in OSDI score (P=0.0003) and eye NIH score (P0.0001), an increase in Schirmer basal secretion score (P=0.0237), and a significant improvement in CFS score (P0.0001), corneal subbasal nerve density(P=0.006), and corneal epithelial cell density(P=0.0349). It also produced statistically significant improvements in FTUBT after two rounds of treatment (n=14) (P= 0.024). After three rounds of treatment (n=11), we observed additional improvements in the OSDI (P=0.0001) and CFS (P0.001) scores.

Conclusion ：

The findings of this study indicated that hAESC eye drops are safe and effective at alleviating symptoms and signs in patients with ocGVHD, making them a promising therapeutic option for the treatment of ocGVHD.
Patient Characteristics and Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
Authors: Qazilbash Muzaffar H. , Khan Hina N. , Milton Denái R. , Pasvolsky Oren , Tanner Mark R. , Popat Uday R. , Kebriaei Partow , Hosing Chitra , Khouri Issa F. , Rezvani Katayoun , Nieto Yago , Oran Betul , Srour Samer A. , Saini Neeraj Y. , Olson Amanda L. , Ahmed Sairah , Alatrash Gheath , Rondon Gabriela , Konopleva Marina Y. , Champlin Richard E. , Shpall Elizabeth J. , Bashir Qaiser , Pemmaraju Naveen
Published: December 2023

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy arising from plasmacytoid dendritic cells. It commonly presents as skin lesions with or without bone marrow, lymph node, central nervous system (CNS), or systemic involvement. Limited retrospective data have shown durable remissions after allogeneic (allo) hematopoietic cell transplantation (HCT).

Methods: In this retrospective single-center analysis, we evaluated outcomes of 31 BPDCN patients treated with allo-HCT between September 2000 and June 2023 at our institution.

Results: Median age of our cohort was 52 years [range 16-76 y]. Patient characteristics are summarized in the attached Table. Only 6 patients (19%) had their disease confined to skin and 4 (13%) had CNS/CSF involvement at diagnosis. Four patients (13%) had prior hematologic malignancies (HM), and 9 patients (29%) had a cytogenetic abnormality at baseline. Thirteen (42%) patients, who were evaluated by a next-generation sequencing Leukemia Mutation Panel, had TET2 mutation. Median time from diagnosis to HCT was 6.2 (3.2-42.4) months. Eight (26%) patients received tagraxofusp, matched unrelated donor was the most common donor type (39%), and fludarabine + busulfan-based conditioning was used in 17 (55%) patients. Post-transplant cyclophosphamide (PTCy) was used for GVHD prophylaxis in 23 (74%) patients. Median follow up was 23.9 (0.9-119.9) months. One-hundred day and 1-year non-relapse mortality was 9.7% and 23.1%, respectively. Grade 2 acute GVHD was seen in 9 patients (29%), and no grade 3-4 GVHD has been seen so far. Limited or extensive chronic GVHD was seen in 6 (21%) of 28 evaluable patients. Only 6 of the 31 (19%) allo-HCT patients progressed after HCT. Two-year PFS and OS was 56% and 67%, respectively. Patients receiving allo-HCT in first remission had significantly better median PFS (not reached vs. 11.3 months; p=0.034) and OS (not reached vs. 12.6 months; p=0.045).

Conclusions: These results demonstrate the safety and efficacy of allo-HCT in BPDCN. Patients undergoing allo-HCT in first remission had significantly better outcomes. Prospective studies are needed to better define the role of allo-HCT in BPDCN.
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.