bluuebunny/crossref_metadata_2025_split huggingface dataset:
From Harmless to Harmful: Meta-Analysis and Systematic Review of Adverse Clinical Outcomes in Sickle Cell Trait
Authors: Pokima Ngowari , El-gharib Khalil , Khamis Zaid , Marseille Melissa , Keesari Praneeth Reddy , Owolabi Mary , Wang Kai , Odaimi Marcel 
Published: December 2024

Background: Sickle cell trait (SCT) has traditionally been considered a benign condition; however, emerging evidence suggests it may have serious clinical consequences. This systematic review and meta-analysis aim to synthesize current research on the adverse clinical outcomes associated with SCT.
Methods: A systematic review search was conducted on PubMed, Embase, and Central Cochrane Registry to identify studies reporting on the clinical outcomes of SCT. Studies were included if they evaluated conditions such as diabetes, end-stage renal disease (ESRD), pulmonary embolism (PE), deep vein thrombosis (DVT), and chronic kidney disease (CKD)(EGFR &lt;60) in individuals with SCT against a matched sample of controls without a history of SCT (matched on age, race, sex). Cross-sectional studies were included. Data extraction and quality assessment were performed independently by two reviewers. From 88 records initially identified from bibliographic databases, 12 studies were eligible and therefore included the meta-analysis. For measuring association between SCT and DVT, PE, CKD, ESRD and diabetes a meta-analysis using the random-effects method was performed to pool weighted odds ratios (OR) of risk estimates, and heterogeneity was assessed using the I² statistic. For effect sizes, a confidence interval of 95% was used, and a p-value of less than 0.05 was used for statistical significance
Results: The meta-analysis included 12 studies, including a total of 1128624 individuals with either SCT or no SCT/SCD. The pooled analysis revealed significant associations between SCT and CKD, ESRD, DVT and PE. Individuals with SCT had an increased risk of ESRD (pooled OR = 2.21, 95% CI: 1.87-2.85, p&lt;0.01), PE (pooled OR = 1.75, 95% CI: 1.53-2.01, p&lt;0.01), DVT (pooled OR = 1.54, 95% CI: 0.99-2.30, p=0.05), and CKD (pooled OR = 1.79, 95% CI: 1.54-2.08). There was no significant association seen with SCT and diabetes. Low heterogeneity was observed in the outcomes of ESRD and CKD (I² = 0% and 43%, respectively), warranting further investigation into underlying factors.
Conclusions: This systematic review and meta-analysis demonstrate that SCT is associated with an increased risk of several serious clinical conditions, challenging the traditional view of SCT as a benign trait. These results may have important public policy implications for risk stratification and genetic counseling of SCT carriers as well as the need for heightened clinical awareness and monitoring of individuals with SCT to prevent and manage potential complications
Keywords: Sickle Cell Trait, Diabetes, End-Stage Renal Disease, Pulmonary Embolism, Deep Vein Thrombosis, Chronic Kidney Disease, Meta-Analysis, Systematic Review
Phosphorylation-Dependent ANXA2 Relocation on the Membrane and TLR4 Engagement: A Novel Signaling Axis Promoted By PIM1 Mutation in Diffuse Large B Cell Lymphoma
Authors: Lu Yaxiao , Zhang Ning , Zhang Yidan , Xu Xiyue , Wang Xianhuo , Zhang Huilai 
Published: December 2024

Background：Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and has an overall cure rate of approximately 60%. Previously, we observed high PIM1 mutation rates in DLBCL patients with poor outcome. However, the mechanism whether they lead to enhanced PIM1 kinase activity and contribute to lymphomagenesis is currently unknown.
Methods：In this study, a multifaceted approach was employed to elucidate the functional consequences of PIM1 gene mutations and their implications in DLBCL. Recurrent PIM1 gene mutations that exhibited high frequencies across various hematological cancer cohorts were screened from public databases and patient outcomes were stratified by PIM1 mutation status. Liquid chromatography-mass spectrometry (LC-MS) proteomics and bioinformatic tools were utilized to identify proteins involved in critical cellular pathways relevant to PIM1 mutation. A high-throughput drug screening platform was leveraged to find potential therapeutic vulnerabilities unique to PIM1 mutant cells. The antiproliferative effects of PIM1 and PI3K inhibitor were evaluated in DLBCL cell lines and further validated in NSG mouse xenograft models.
Results：We have identified PIM1 mutations, specifically P81S, E135K, L184F, and S97N, as frequently occurring variants, with the former three significantly associated with poor outcome. Our cohort data revealed a trend towards elevated PIM1 protein expression following PIM1 mutations. PIM1-mutated DLBCL tumors exhibited accelerated proliferation and reduced apoptosis, while in vivo animal models demonstrated faster tumor growth. Mechanistically, PIM1 mutations were found to interact with ANXA2, activating it through phosphorylation of serine 26 on the ANXA2 gene. Activated ANXA2 then translocated from the cytoplasm to the cell membrane, binding with TLR4 and further activating the PI3K/AKT/mTOR signaling pathway. Additionally, high-throughput drug screening highlighted the sensitivity of PIM1-mutated cells to multiple PI3K inhibitors. Notably, the PIM1 inhibitor SMI-4a demonstrated synergistic antitumor effects with the PI3K inhibitor Linperlisib in vitro and in vivo, offering a potentially more effective therapeutic strategy for patients harboring PIM1 mutations.
Conclusions: Taken together, we identify recurrent somatic PIM1 L184F mutations that may contribute to the pathogenesis of DLBCL and establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in PIM1-mutated DLBCL.
Keywords: PIM1, Mutation, ANXA2, Diffuse large B-cell lymphoma, Targeted therapy
HPK1 Inhibition and Venetoclax Combination Suppressed AML By Enhancing Cytotoxic T-Cell Response to Leukaemia
Authors: Zeng Xiaoyuan , Tong Kwui-Wa , Chan Koon Chuen , Zheng Li-Chuan , Lam Stephen , Bray Mark Robert , Mak Tak-Wah , Man Cheuk-Him , Leung Anskar Y. H. 
Published: December 2024

Background: Immune escape is one of the major causes of treatment failure in cancer therapy and modulation of immune cell function has become an emerging therapeutic strategy. Haematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T cell signaling and its inhibition promotes T cell function. Venetoclax, a BCL2 inhibitor, has become a standard of care for unfit or elderly patients with acute myeloid leukaemia (AML) and may enhance anti-leukaemic effector T-cell function. We hypothesize that HPK1 inhibitor (HPK1i) may synergize with venetoclax and improve treatment outcome in AML by co-activating cell-death pathway and T cell immunity.
Methods: Human T cells were activated by anti-CD3/CD28 antibodies in vitro. Proliferation, cytokine production, T-cell subsets and exhaustion were examined by flow cytometry after 3-day treatment of HPK1i. Recipient mice engrafting with MLL-AF9 AML were treated with HPK1i singly or in combination with venetoclax. Leukaemic burden, apoptosis and T cell functions and exhaustion were examined.
Results: In vitro, HPK1i treatment of activated human T-cells induced cellular proliferation and expression of TNF-α and INF-γ. It increased effector memory T-cell (CD62L-CD45RA-) and decreased naïve T-cell population (CD62L+CD45RA+). Furthermore, it reduced exhaustion markers including PD-1 and TIM3. In vivo, HPK1i and venetoclax combination significantly decreased the burden and induced apoptosis of leukaemic cells on 18th DPT (days post transplantation), and prolonged survival of non-irradiated mice that were transplanted with donor mouse MLL-AF9 AML cells. Cytotoxic T-cells were activated, associated with increase in TNF-α and INF-γ expression and increase in the effector memory T cell subset. There was a decrease in naïve T cell population and T cell exhaustion marker PD-1. Single cell transcriptomes of serial bone marrow samples from mice treated with the combination were being analyzed and will be presented in the meeting.
Conclusion: HPK1i and venetoclax reduced the leukaemic burden and enhanced the anti-leukemic ability of T cells in MLL-AF9 AML mouse model.
Acknowledgements
This research is supported by the Centre for Oncology and Immunology under the Health@InnoHK Initiative funded by the Innovation and Technology Commission, Theme-based Research Scheme (T12-702/20-N), Hong Kong Jockey Club Charities Trust, Li Shu Fan Medical Foundation, Croucher Foundation, S.K.Yee Medical Foundation (260940161, 260940149, 260940187), Tang King Yin Research Fund, Mr. Ying Wan Leung Research Fund, Madam Madeline Tong Lai-Sheung Cancer Research Fund (A.Y.H.L), The Government of Hong Kong SAR, China.
Combination of Olverembatinib and VP Regimen for Newly Diagnosed Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Authors: Tan Xu , Chen Guo , Ma Yingying , Wang Maihong , Wen Qin , Liu Hong , Zhang Xi , Zhang Cheng 
Published: December 2024

Background Philadelphia Chromosome -positive acute lymphoblastic leukemia (PH+ALL) is a common type of adult ALL, and TKI combined with chemotherapy is the main treatment option; early achievement of molecular remission has been found to be an important factor affecting long-term survival. The combination of third-generation TKI Ponatinib can achieve a higher percentage of early molecular remission and significantly improve the prognosis, but the safety is unsatisfactory; Olverembatinib is a novel third-generation TKI, which has demonstrated better efficacy and safety in patients with CML; This study is intended to explore the efficacy and safety of Olverembatinib in combination with VP regimen in the treatment of newly diagnosed adult PH+ALL.
Methods This is a single-arm, prospective trial that enrolled adult patients with newly diagnosed Ph+ ALL. Patients were treated with a combination of Olverembatinib (40mg QOD d1-28), Vindesine 4mg d1,8,15, Prednisone1mg/Kg/d d1-14, and then gradually tapered off for 28d in induction therapy, Post-induction treatment to be decided by each centre.
Results From February 2022 to December 2023, a total of 26 pts were enrolled and all pts completed induction therapy. Among all , Male 12 and Female 14, the median Age was 52(18-70) years old. Sixteen pts (61.5%) expressed the p190 transcript and ten pts (38.4%) expressed the p210 transcript. IKZF1 mutation detected in 5 patients by second-generation sequencing. All patients achieved CR at the end of induction therapy, and no tumor lysis syndrome or treatment-related deaths occurred. No patients had adverse reactions leading to dose reduction or discontinuation, and no treatment-related non-hematological adverse reactions were observed. Molecular response at the end of induction therapy was MMR in 16 patients (53.8%), CMR in 10 (30.8%). The demand for blood transfusion and the incidence of infections were significantly lower compared with our historical data treating with 2nd generation TKI plus chemotherapy treating with low-intensive chemotherapy plus TKIs. During a median follow-up of 354 days, one patient died of transplant complications, while all the remaining survived without relapse.
Conclusion The combination of Olverembatinib and reduced-intensity chemotherapy (VP) is a safe and effective regimen in patients with newly diagnosed Ph+ ALL. The regimen results in high rates of CMR in the absence of intensive chemotherapy, and promises to improve long-term survival in patients with PH+ALL.
Anti-CD38 Monoclonal Antibody Is a Salvage Regimen in Relapsed/Refractory Aplastic Anemia
Authors: Li Weiwang , Zhang Lele , Pan Hong , Gao Zhen , Li Jianping , Nie Neng , Zhao Xin , Huang Jinbo , Zhao Jingyu , Yu Xiao , Kuang Zhexiang , Fang Liwei , Ge Meili , Yuan Weiping , Shi Jun 
Published: December 2024

Background: About half of patients with aplastic anemia (AA) are in a refractory or relapsed state after first-line immunosuppressive therapy (IST). The persistent pancytopenia in relapsed/refractory AA (r/r AA) patients affects their quality of life and even is life-threatening. Hematopoietic stem cell transplantation, second course of IST and TPO receptor agonist ameliorate the disease in more than half of these people. But patients not eligible for these treatments are still lack of proper choice.
Methods: We conducted a retrospective study to evaluate the efficacy and safety of daratumumab, a monoclonal CD38 antibody, in treating r/r AA. Daratumumab was given 8mg/kg weekly for 4 weeks to 10 r/r AA patients. Ciclosporin or danazol was given as concurrent treatment to 5 patients who had already received the drug for at least 6 months. Patients achieved response during 12 weeks would receive the second cycle treatment.
Results: The overall response rate was 5 of 10 patients (50%) with multilineage responses in 4 of them. The median response time was 6 weeks (range, 5-10 weeks). Patients sustained response with a median 5.5 months duration time (range, 2-13.5 months), including 2 responders still during follow-up. Infection and infusion-related reaction are the most common adverse events with an 80% and 70% incidence respectively, including 1 patient with grade 3/4 infection. Incidence of hematologic adverse events was 50% and 80% of them were grade 3/4, and the median time of recovering to grade 1/2 was 3 days (range, 1-15 days).
Conclusion: Anti-CD38 monoclonal antibody may be a promising option for r/r AA patients with an appreciable efficacy, rapid response, and accepted adverse events.
Efficacy and Safety of a New Regime Containing PD1 Antibody and Pegaspargase for Advanced-Stage or Relapsed/Refractory Natural Killer/T Cell Lymphoma
Authors: Chen Jie , Zhao Linjun , Wu Chongyang , Yu Haifeng , Li Zhenling , Liu Lihong , Gao Da , Sun Ying , Wei Xiaolei , Wu Yuanbin , Wang Yue , Song Yuqin , Zhu Jun , Liu Weiping 
Published: December 2024

Background: Patients with advanced-stage or relapsed/refractory (r/r) natural killer/T cell lymphoma (NKTCL) had a poor prognosis. The anti-programmed death 1 (PD-1) antibody has demonstrated satisfactory efficacy and good tolerance for r/r NKTCL. In this report, we present the efficacy and safety analysis of a new regimen containing dexamethasone, azacytidine, pegaspargase, and tislelizumab (named as DAPT) for advanced-stage or r/r NKTCL in a prospective multicenter phase II study.
Methods: Patients with advanced-stage or r/r NKTCL, aged over 18 years, were eligible for participation. The DAPT regimen chemotherapy was administered as the protocol treatment, which included dexamethasone 10 mg on days 1-3, azacytidine 100 mg on days 1-5, pegaspargase 3,750 IU on day 1, and tislelizumab 200 mg on day 6. Cycles were repeated every 21 days. The primary endpoint was the overall response rate (ORR) .
Results: A total of 39 eligible patients were enrolled. The median age of 52 years (range, 32 to 72 years) and with a male-to-female ratio of 2.42:1. Twenty-four (61.5%) patients had newly diagnosed disease with stage IV, while 15 (38.5%) had r/r disease. Among 31 patients with available response, the ORR and complete remission (CR) rates were 77.4% and 33.3% for the entire cohort, 84.2% and 63.6% for newly diagnosed stage IV disease, and 31.6% and 27.3% for r/r disease, respectively. Ten patients underwent autologous hematopoietic stem cell transplantation (ASCT). The median progression-free survival (PFS) was 7.3 months in patients who completed 6 cycles of DAPT therapy. Moreover, the median PFS were 14.0,3.6 and 2.6 months in patients who achieved CR, PR and non-response, respectively. The median PFS was longer in those who achieved ASCT than those who did not experience transplantation (11.5 vs. 2.6 months). The most common treatment-related adverse events were was neutropenia (63.4%), followed by elevated alanine aminotransferase (43.9%), decreased fibrinogen (39.0%) and hypofibrinogenemia (39.0%). The incidence of ≥3 treatment-related adverse events was 26.8%, which included neutropenia (n=8), immune-related rash (n=2), and drug-induced liver injury (n=1) .No treatment-related deaths were observed.
Conclusion: The DAPT regimen chemotherapy is an effective and tolerable treatment for advanced-stage or r/r NKTCL.
Keywords: Lymphoma; Extranodal NK-T-Cell; Immunotherapy; Therapeutics; Prognosis
Brentuximab Vedotin (BV) and Nivolumab (nivo) for Untreated Patients with Hodgkin Lymphoma (HL): Long-Term Results
Authors: Cheson Bruce D. , Bartlett Nancy L. , LaPlant Betsy R. , Lee Hun Ju , Advani Ranjana H. , Christian Beth , Diefenbach Catherine S. , Feldman Tatyana , Ansell Stephen M. 
Published: December 2024

Background: Whereas major improvements have been made in the treatment of advanced HL outcomes of patients &gt; 60 yrs are generally suboptimal compared with younger patients, and generally with more toxicity. To address this issue we conducted the first phase II study of BV-nivo in older pts with HL (ACCRU RU0515051, NCT02758717), with initial results reported at a median of 20.2 mo of follow-up. (Cheson et al, Lancet Haem, 11:e808, 2020). Herein we present the 5-year follow-up for this study.
Methods: Eligible pts were either &gt;60 yrs or considered unsuitable for standard chemotherapy because of cardiac, pulmonary or renal dysfunction. Pts received BV at 1∙8 mg/kg (dose cap at 180 mg) and nivo at 3 mg/kg both intravenously every 21 days for 8 cycles.The primary endpoint was overall response rate (ORR).
Results: Follow-up data were available for 39 of the original 46 pts. At a median follow-up of 58.5 months (0.45-65.4 mo), the median duration of response was 17.2 mo (11.6-45.2). 58.7% of the patients had progressed with the median progression-free survival of 18.3 mo (12.8-46.3 mo); thus 41.3% had still not experienced a progression event. Median overall survival was not yet reached with 84.8% of patients still alive.
Conclusions: BV-nivo is an effective regimen for patients &gt;60 yr, curing approximately 40% of pts. For those not cured by initial therapy, outcome with subsequent treatment is excellent, suggesting check point inhibitor sensitization, or other factors. Optimization of dose and schedule, and incorporation of other novel agents will result in a successful chemo-free approach for older patients with HL, especially those unable to receive an anthracycline.
“I Really Wish We Had a Talk on Advocacy That Wasn't Boring”: Toward a Health Advocacy Curriculum That Meets the Needs of Canadian Hematology Residents
Authors: Chaudhary Mitali , Trinkaus Martina , Tseng Eric , Schneider Francine , Scott Michael Douglas 
Published: December 2024

Background: There is an ongoing need to incorporate health advocacy training into postgraduate medical education. In Canadian hematology training, there are no existing dedicated health advocacy curricula. As a first step toward the development of such curricula, we sought to determine what the health advocate role entails for hematologists, identify necessary health advocacy competencies in hematology, and understand how these competencies could be learned in hematology residency training.
Methods: Semi-structured interviews were conducted with practicing hematologists in Ontario, Canada to elicit key health advocacy competencies for hematologists and learn how these are acquired. Participants were selected using a purposeful, maximal variation sampling strategy. Interviews were recorded in their entirety and transcribed by hand. Data were deidentified after collection and a computer software (NVivo) was used to create codes through an iterative approach. The codes were analyzed using the thematic analysis technique outline by Braun and Clarke (Braun & Clarke, 2006). A deductive approach was employed, incorporating the CanMEDs framework and previously described conceptual frameworks pertaining to health advocacy.
Results: 8 hematologists (5 academic-based, 3 community-based; 4 malignant hematologists and 4 non-malignant hematologists) were included. Hematologists engage in advocacy activities at the clinical, paraclinical, and supraclinical levels and conduct advocacy work most commonly through a directed agency strategy. Drug access was the most prominent advocacy challenge encountered by hematologists. Health disparities that were identified included the rural/remote divide and socioeconomic status. Health advocacy competencies employed by hematologists closely resembled those used by other physicians, with some difference on emphasis. Skills that hematologists found were important to advocacy training were leveraging interprofessional connections, using research as advocacy, and acquiring health systems knowledge. Early exposure to advocacy in training, effective mentorship, and learning from practical examples and experience were viewed as the most effective ways to learn health advocacy skills.
Conclusion: This study identified the breadth of advocacy activities conducted by hematologists and identified numerous competencies that are important to being an effective health advocate. Health advocacy education in hematology training programs should start early, be practical and engaging, be integrated longitudinally into existing teaching and learning activities, and harness the power of mentorship relationships. This work is the first step in addressing the informational gap required to design a novel health advocacy curriculum for hematology residents.