bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maintenance Therapy with Chidamide Decreases the Relapse in Fusion Gene-Positive AML Patients with MRD-Positive or ELN-High Risk
Authors: Yu Guopan , Yin Zhao , Huang Jixian , He Huiqing , Jiang Xuejie , Zhou Hongsheng , Huang Pengcheng , Zhang Yu 
Published: December 2023

Purpose: Acute myeloid leukemia (AML) patients with fusion gene-positive including core binding factor (CBF), mixed-lineage leukemia (MLL) gene rearrangement have a high incidence of relapse if they are continious measurable residual disease (MRD)-positive or in ELN-high risk and could not be bridged to allogenetic heamatopoitic stem cell transplantation (allo-HSCT). As known histone deacetylase (HDAC) is abnormally recruited in these fusion gene-positive AML, also RUNX1 mutated AML, and could be a therapy target. Aim of this study is to assess the effect and safety of HDAC inhibitor chidamide as maintemance therapy in these AML patients.
Methods: A multi-center retrospective study was performed. Patients with MRD-positive CBF-AML, MLL rearrangement or RUNX1 mutation AML, without being bridged to allo-HSCT were included. Maintemance with chidamide was started one to three months after consolidation for at least six months, at a dose of 10mg/day or 30mg twice a week.
Results: Twelve patients were enrolled, included 8 with AML1-ETO-positive, 3 with RUNX1 mutation, 1 with MLL rearrangement. The median age was 33(16-62) years old. The ratio of male to female was 6 to 5. They previously experienced median 6(4-8) cycles of chemotherapy, included one with allo-HSCT, one with autologous-HSCT. They were all maintemanced with chidamide, except one with chidamide plus sorafenib. Eleven patients were available for outcome assessment. With a median follow-up of 14(2-67) months, among the 9 patients with MRD-positive, 6(66.7%) achieved MRD-negative, 1 stable disease, 2 relapsed and died. The median time to achieved MRD-negative was 2.5(1-12) months. The other 2 patients was contenious MRD-negative. The cumulative incidence of relapse was 2/11(18.2%). The rate of MRD-nagetive was 8/11(72.7%). The mortality rate was 2/11(18.2%). During the maintemance, 4 patients underwent bone marrow suppression, including 2 with grade 3, 2 with grade 1/2. One patients had an anorexia of grade 2.
Conclusion: Maintenance therapy with chidamide might decrease the relapse in fusion gene-positive AML patients with MRD-positive or ELN-high risk, who could not take allo-HSCT, and prolong their survival, with a well toleration.
Key words: chidamide, maintenance, fusion gene, acute myeloid leukemia
Prospective Cohort Study on Paediatric and Adult Haemophilia a Patients Correlating Emicizumab Levels with Clinical Experience
Authors: P'ng Stephanie , Carter Tina , Kaminskis Lisa , Modica Natasha , Michalopoulos Nick , Goruppi Marina , Pepperell Dominic 
Published: December 2023

Aim:
The efficacy of Emicizumab in preventing bleeds in patients with Haemophilia A has been demonstrated in the HAVEN studies. Emicizumab is not universally available at the recommended dosages and there is a push towards reducing frequency and dose to increase availability. This study aims to provide data on Emicizumab levels and corresponding clinical response in the real world.
Method:
Moderate-severe Haemophilia A patients who transitioned to Emicizumab were identified from 2 Centres in Western Australia between November,2017 to December,2022. Bleeds requiring factor replacement were recorded 12 months prior to transition and 12 months following. These were obtained from the Australian Bleeding Disorders Registry and patient hospital notes. Available steady state Emicizumab levels were also recorded.
Results:
31/32 paediatric patients had the same or improved bleeding rates since transition to Emicizumab. No patient had a spontaneous bleed since transition. One patient continued to have high bleeding rates due to adherence issues, with an Emicizumab level of 10µg/ml. Of the 16/32 patients had Emicizumab levels measured with a mean 55.54µg/ml (range 38.8 - 81).
21/24 adult patients experienced the same or improved bleeding rates post transition. 7 patients did not have completed bleed data. 3 patients had worse bleeding rates since transition with 1 bleed each. Their Emicizumab levels ranged 58.54-79.15µg/ml. Emicizumab levels were recorded in 16, with a mean of 53.08µg/ml (range 18.47 - 85.22).
6 adult patients had surgical procedures with 2 bleeds; 1 bleed occurred 10 days after colonoscopy with emicizumab level 18.47ug/mL and 2nd bleed occurred 1 day after pharyngeal level 42.42ug/mL.
Conclusion:
In both paediatric and adult patients, Emicizumab was an effective treatment in preventing bleeds. The mean and range of Emicizumab levels in both groups who had an effective response were similar. The wide range of therapeutic levels may be of important for dosing changes, particularly with the paediatric cohort
Histiocytic Necrotizing Lymphadenitis with Hemophagocytic Lymphohistiocytosis: A Single-Center Analysis of Five Cases
Authors: Miao Yi , Chen Qingqing , Shi Wenyu , Zhang Jing , Li Jianyong 
Published: December 2023

Introduction: Histiocytic necrotizing lymphadenitis (HNL) is a benign, self-limiting disease that presents with few nonspecific symptoms such as fever and swollen lymph nodes in the neck. Histiocytic necrotizing lymphadenitis with hemophagocytic lymphohistiocytosis (HNL-HLH) is rare and case series have been reported in children. HNL-HLH in adults has not been systematically analyzed.
Methods: We aimed at exploring the clinical, laboratory, and radiological features and outcomes of adult patients with HNL-HLH. We collected the clinical data of patients with HNL-HLH admitted to the First Affiliated Hospital of Nanjing Medical University from October 2010 to June 2015. All the patients underwent lymph node biopsy and have a pathological diagnosis of HNL. The age, gender, clinical presentation, lymph node signs, laboratory findings and imaging data, and pathological findings of the patients were collected.
Results: In this study, we reported five adult patients with HNL-HLH, including 3 females and 2 males. The median age was 37 years (range: 20-57). All five patients showed enlarged lymph nodes and prolonged fever. Laboratory findings were consistent with the diagnosis of HLH. All five patients had hyperferritinemia and the levels of ferritin were all higher than 1000 ug/L. Serum lactate dehydrogenase (LDH) and aminotransferase were significantly elevated in all five patients. 18F-FDG PET/CT showed enlarged lymph nodes with increased FDG uptake and splenic hypermetabolism could be present. Pathological findings were consistent with HNL (Fig A) and hemophagocytosis in the lymph node was present in two cases (Fig B). All the patients responded well to corticosteroids and had a good prognosis. Two of the five patients were diagnosed with systemic lupus erythematosus (SLE) during the follow-up.
Conclusion: Our study demonstrated that adult patients with HNL-HLH showed distinct clinical, laboratory, and radiological features. And the prognosis is good and patients could be managed with steroids and supportive care.
Zanubrutinib Combined Regimen As Bridging Treatment on Promising Clinical Outcome of CD19 Chimeric Antigen Receptor T-Cell Therapies in Relapsed or Refractory Large B-Cell Lymphoma
Authors: Lu Yan , Ye Shiguang , Zhou Lili , Li Ping , Li Shaoguang , Liang Aibin 
Published: December 2023

Background
Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) shows poor clinical outcomes. Anti-CD19 chimeric antigen receptor-T cells (CAR-T) therapy is emerging as the second-line therapy of choice, but in real-world studies its efficacy and long term follow is not promising. Effective bridging therapy can reduce tumor burden and improve CAR-T efficacy. Zanubrutinib, a selective Bruton tyrosine kinase (BTK) inhibitors, combined regimens have established therapeutic activity by targeting B-cell receptor signaling and have individually shown efficacy in patients with R/R DLBCL. Thus, the present study evaluated the efficacy and safety of zanubrutinib-combined regimen as bridging treatment in CD19 CAR-T therapy.
Methods
This retrospective study includes all patients participant in the clinical trail (NCT 02537977) between January 2020 and December 2022. All 21 heavily treated patients with r/r DLBCL who received zanubrutinib-combined regimens as bridging therapy are included. Patient clinical characteristics were collected upon patient enrollment. Efficacy outcomes included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), whereas safety outcomes included incidence of adverse events. The zanubrutinib combined regimens are zanubrutinib with IMIDs, chemotherapy and/or rituximab.
Results: Of the 21 evaluable patients, median age of patients is 57 year old and median treatment line is 3. 19 patients (90%) are non-GCB subtype and 18 patients(86%) are IPI score &gt;3. 14 patients(67%) are double expression and 7 patients (33%) have TP53 mutation. Objective response rate(ORR) is 81%; of whom, 10 patients(48%) got complete remission(CR) and 7 patients(33%) got partial remission(PR). With a median follow-up of 25 months, the median PFS was 12.8 months and median OS was not yet reached. 8 CR patients and 3 PR patients maintain long-term remission and are still under followup. 18 patients (86%) has grade 1-2 cytokines release syndrome(CRS) and 3 patients(14%) has grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS). No severe CRS and &gt;1 grade ICANS were observed. The most common hematologic toxicities included grade ≥3 neutropenia (90%) and grade 3/4 thrombocytopenia (71%). No patients had grade ≥3 non hematologic toxicities.
Conclusion:
Zanubrutinib-combined regimens are effective and safe as bridging therapy in CD19 CAR-T therapy. More prospective studies are further command.
A Real-World Efficacy of Letermovir Primary Prophylaxis for Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation in China: A Single-Center Retrospective Analysis
Authors: Zhang Xiaoyu , Yang Donglin , Pang Aiming , He Yi , Wei Jialin , Zhang Rongli , Zhai Weihua , MA Qiaoling , Chen Xin , Han Mingzhe , Feng Sizhou , Jiang Erlie 
Published: December 2023

Introduction: Cytomegalovirus (CMV) infection is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with increased mortality. Letermovir (LET) is a novel antiviral drug used to prevent CMV infection.
Methods: We retrospectively analyzed 167 consecutive patients who underwent allo-HSCT between August 2022 and May 2023, who received LET 240 mg/day, to evaluate the efficacy and safety of LET in primary prophylaxis for clinically significant CMV infection (csCMVi), defined as CMV disease or CMV viremia reactivation, in real-world situations in China.
Results: Among the enrolled 167 patients, 95.21% (159/167) of patients underwent a haploidentical donor (HID) transplant and 4.79% (8/167) a matched unrelated donor (MUD) transplant. 96.41% of the recipients were CMV seropositive, and only 6 recipients were CMV seronegative but donor seropositive. The median interval from allo-HSCT to the administration of LET was 7 (2-55) days. A total of 121 patients received LET within 14 days after HSCT. With the median follow-up 162(74-397) days post-HSCT, the incidence of CMV viremia was 11.98% (20/167). 3 patients developed CMV viremia after discontinuation of LET medication. Among the 20 patients with CMV viremia, the median duration of preemptive therapy was 9 (3-28) days, and the peak level of CMV-DNA was 1867 (1228-22383) copies/ml. Only 1 patient developed refractory CMV viremia with prolonged preemptive anti-CMV treatment. No patients were diagnosed with clinically significant CMV disease. Patients who developed CMV viremia or not were similar with respect to the CMV IgG status of the recipient at HSCT, donor CMV IgG, and GVHD incidence. Notably, the CMV viremia incidences of patients who received LET within 14 days and after 14 days post-HSCT were 7.44% and 23.91%, respectively (p=0.005). The incidence of EBV viremia was 17.16% (29/169), and 9 developed PTLD. The six-month overall survival was 93.4±2.1% in all patients who received LET prophylaxis. Meanwhile, LET prophylaxis was well tolerated. No drug-related death or permanent discontinuation was reported due to toxicity.
Conclusion: Letermovir was effective and safty as primary prophylaxis of csCMVi, particularly initiating early post-HSCT.
Homoharringtonine Overcomes the Negative Impact of Genetic Patterns on Venetoclax Plus Azacitidine Regimen in Relapsed/Refractory Acute Myeloid Leukemia: A Multi-Center, Cohort Study
Authors: Yu Guopan , Zhang Yu , Jin Hua , Yin Zhao , Weng Guangyang , Yu Sijian , Xu Na , Du Xin , Lin Dongjun , Xiao Jie , Sun Zhiqiang , Zhang Hongyu , Liang Xinquan , Guo Ziwen , Zhao Weihua , Dai Min , Jiang Xuejie , Xuan Li , Shi Pengcheng 
Published: December 2023

Objective: Whether other agents added to venetoclax (VEN) plus hypomethylating agents (HMA) regimen could overcome the negative impact of genetic patterns on response in patients with relapsed/refractory acute myeloid leukemia (RR-AML) remains unclear. Aim of this study was to evaluate whether homoharringtonine (HHT) added to VEN plus azacitidine (AZA) regimen could improve the response and overcome the negative impact of genetic patterns in patients with RR-AML .
Methods: A multi-center, cohort study of the response and the genetic patterns of response of VEN plus AZA and HHT (VAH) versus VEN plus AZA (VA) regimens as salvage treatment in the patients with RR-AML was performed. Patients were enrolled from four studies from October 2018 to December 2022 at nine medical centers in china.
Results: A total of 321 patients were analyzed, including 150 females and 171 males, with a median age at 46 (IQR, 35-61) years. There were 172 patients in the VAH and 149 in the VA group. VAH significantly improved CRc rate (66.3% vs. 44.3%, P&lt;0.001) and prolonged OS (median OS, not reach vs. 14.3 months, P=0.004), to compared with VA. Multivariate analysis showed that VAH was the independently protective factor for CRc and survival. In addition, VAH significantly overcame the negative impact of FLT3-ITD/TKD, N/KRAS, TET2, DNMT3A mutations, and t(8;21)/AML1-ETO, as well as non-adverse ELN risk, also apparently in adverse ELN risk or complex karyotype, on the response of VA regimen.
Conclusion: The impact of genetic patterns on the response presented diversely in different VEN-based regimens. HHT added to VA regimen might improve the response and overcome the negative impact of part genetic patterns in RR-AML.
Key words: homoharringtonine, venetoclax, relapsed/refractory, acute myeloid leukemia, genetic pattern
Targeting RBM39-MEK5 Axis Synergizes with Bortezomib to Inhibit Multiple Myeloma Malignancy
Authors: Liu Jia , Zhang Zilu , Xu Wenbin , Jia Ming-Yuan , Wu Chengyu , Hua Yan 
Published: December 2023

Multiple myeloma (MM) is a type of haematological malignancy characterised by the accumulation and expansion of malignant plasma cells in the bone marrow (BM). Despite recent advances in chemotherapy, MM remains an incurable disease for most patients and therefore requires novel therapies. Abnormal alternative splicing is a hallmark of cancer and is associated with poor survival and an ultra-high-risk population in MM (Bauer et. al. Haematologica 2021). Targeting splicing is a promising therapeutic strategy in MM. Our previous study showed that RBM39 is highly expressed in primary MM cells and cell lines and correlates with poor overall survival (Tong et. al. Haematologica 2020). To investigate the underlying role of RBM39 in MM, we knocked down RBM39 in MM cell lines. We found that knockdown of RBM39 inhibited MM cell proliferation, induced apoptosis and cell cycle arrest at the G2/M phase, and inhibited subcutaneous tumour growth. Indisulam has been reported to induce RBM39 degradation via the proteasomal pathway by acting as a molecular glue to link RBM39 to the E3 ubiquitin ligase DCAF15 (Han et. al. Science 2017). In our study, Indisulam treatment in MM cells was shown to degrade RBM39 via DCAF15. Indisulam could induce apoptosis and G2/M phase arrest in MM cell lines and inhibite tumour growth in vivo. It also significantly decreased MM cell viability in a co-culture system with MM BM-derived mesenchymal stromal cells. Indisulam was also able to inhibit primary CD138+ cells isolated from newly diagnosed MM patients.
To explore the mechanistic role of RBM39 in promoting MM malignancy, we performed RNA immunoprecipitation (RIP)-Seq and RNA sequencing in RBM39 knockdown MM cells to investigate the alternative splicing targets of RBM39. KEGG pathway analysis of differentially expressed and alternatively spliced genes revealed the enrichment of the MAPK pathway. We then identified MEK5, a non-redundant member of the MAPK family, as a potential target of RBM39, which is highly expressed in MM. Full-length MEK5 contributes to increased proliferation and survival of MM cells. We further demonstrated that MEK5 is bound and alternatively spliced by RBM39 and that splicing of full-length MEK5 is dependent on RBM39. Given the importance of the RBM39-MEK5 axis in MM, we also found that inhibition of RBM39 with Indisulam or MEK5 with the inhibitor BIX02189 increased the cytotoxicity of bortezomib in vivo and in vitro.
In conclusion, we have demonstrated that the RBM39-MEK5 axis, in which RBM39 maintains splicing of full-length MEK5, is essential for MM cell survival and proliferation. Mechanistically, shRNA-mediated knockdown or Indisulam-mediated degradation of RBM39 caused extensive altered splicing, including mis-splicing of MEK5. Targeting RBM39 or MEK5 could not only inhibit MM malignancy, but also enhance the cytotoxicity of bortezomib for MM.
Selinexor in Combination with Salvage Regimen for Refractory Peripheral T-Cell Lymphoma (PTCL) Patients
Authors: Wang Li , CAI Mingci , Huang Yaohui , Xu Pengpeng , Chen Shu , Zhao Weili 
Published: December 2023

Background
Peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS) are a diverse and aggressive type of non-Hodgkin lymphomas with a poor prognosis when treated with conventional chemotherapy. The standard CHOP chemotherapy regimen typically yields an overall response rate (ORR) of 60-80%, a complete response (CR) rate of 30-40%, and long-term survival, measured by 5-yr OS，in the range of 20-30% in non-ALCL (anaplastic large cell lymphoma) subtypes. Azacitidine plus CHOP has achievied a 75% CR in newly diagnosed PTCL, but patients with DNMT3A mutation showed adverse progression-free survival (PFS), indicating that genetic mutations may influence resistance to chemotherapy. Selinexor has shown promising results in refractory lymphoma patients by inhibiting oncogenes, therefore, the efficacy of selinexor combined salvage regimen in refractory PTCL remains great interest.
Method
Refractory PTCL patients were enrolled to be treated with selinexor plus GDP/ICE/Gemox since December 2021 at our center. Selinexor was administered orally (40 mg day 1, 8, 15) plus GDP (gemcitabine 1g/m2*d1, cisplatin 25mg/m2 d1-d3, dexamethasone 40mg d1-d4), ICE (ifosfamide 1.5g/m2*3d, carboplatin (AUC 5) and etoposide 100mg/m2*3d), Gemox (gemcitabine 1g/m2*d1, oxaliplatin 100mg/m2*d1) every 3 weeks as per physician's choice. Objective response rate (ORR) was evaluated every 3 cycles based on Lugano 2014 criteria and Adverse events (AE) were rated according to the NCI CTCAE 5.0.
Results
10 patients were treated with selinexor plus salvage regimen in this study and received more than two cycles of the treatment, making them eligible for response evaluation in this poster. The median age of the 10 patients was 65 years (range from 42 to 79), 8 (80%) were male, 9 (90%) had disease stage III-IV at screening, and 60% of all patients had an IPI intermediate to high risk. All of the patients were refractory to the last line of treatment. Among 10 patients, 2 were angioimmunoblastic T-cell lymphoma (AITL), 3 with PTCL-NOS, 3 with ALK-ALCL, 2 with monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). As shown in Figure 1, 3 patients had TP53 alterations, 2 patients with DNMT3A mutation. Patients received a median of three cycles (range, 2-6) of selinexor 40mg once a week combined with salvage regimen（4 patients received Selinexor-GDP, 3 with selinexor-ICE, 3 with selinexor-Gemox）.
The best overall and complete response rates were 70% and 50%, respectively. In terms of MEITL refractory to conventional CHOP treatment, 1 achieved PR but progressed and died after stop treatment for three months due to Covid19 and 1 in CR with selinexor maintenance.
Conclusions
There are limited options for the treatment of refractory PTCL. We identified a dosing schedule of selinexor (40mg qw) with GDP/ICE/Gemox that is efficiency inrefractory PTCL and is worthy of further study on its mechanism of action.
Preliminary Study on the Role of Kynurenic Acid in Inhibiting the Physiological Changes of Astrocyte Induced By HIV-1 Envelope Protein gp120
Authors: Chen Xiaoliang , Tang Yi , Wang Zixuan , Long Min , Cao Hong 
Published: December 2023

Background
Since the introduction of combined antiretroviral therapy, acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) has transformed from an incurable fatal disease to a chronic treatable disease. HIV-associated neurocognitive disorder (HAND) is a common long-term complication of AIDS. Astrocytes are believed to play an essential role in the development of HAND. Therefore this study aims to find out how astrocytes change and how to resist this change in the process of hand.
Methods
Cortical astrocytes were dissected from Sprague-Dawley (SD) neonatal rats (1-3 days) with the aseptic operation and digested with 0.25% trypsin 37℃ for 20 min. The cell suspension was dispersed through the cell strainer and seeded into the poly-D-lysine coated T-75 flasks supplemented with 10% FBS and 1% penicillin/streptomycin. After ten days of incubation, the cells were purified in a shaking incubator (250 r/min) at 37℃ for 24 h, and astrocytes were cultured at desired densities in 6-well plates. The cells were identified as &gt;98% pure astrocytes by Cy3-conjugated GFAP immunostaining. Cultured astrocytes were treated with 150 pM HIV-1 gp120 CM for 12 h before applying 5 or 25 μM kynurenic acid(KYNA) for 12 h. Afterward, western blotting technology was used to detect the expression levels of different proteins in each group, and Fuji Image J software was used to analyze the bands.
Results
Compared with the control group, the expression levels of AKT, PI3K and P62 proteins in astrocyte of mice added with gp120 were significantly reduced, which were 38%, 41% and 40%, respectively, while KYNA alone had no significant change; Compared with the addition of gp120 group, the trend of decreased AKT (P&lt;0.05) and PI3K protein expression was inhibited when both gp120 and KYNA were added, with an increase of 43% and 52%, respectively. We observed that the expression level of p-AKT had a similar trend but the expression level of p-PI3K had an opposite trend. This suggests that the effect of gp120 on the PI3K/AKT pathway may have begun with an upregulation of PI3K activation levels.
Conclusion
HIV-1 gp120 can cause changes in the physiological status of astrocytes, and KYNA can counteract this change, which indicates that KYNA may have a potential therapeutic effect on HAND. ( Acknowledgements:National Natural Science Foundation of China, No. 82172259 to H.C.; Undergraduate Training Program for Innovation and Entrepreneurship of SMU, China, No. 202212121247; Corresponding author: Hong Cao, gzhcao@smu.edu.cn )
Keywords：HIV-1 gp120, Kynurenic acid, Astrocyte, AKT, PI3K disorder