bluuebunny/crossref_metadata_2025_split huggingface dataset:
Young and Distinct: Clinical Characteristics and Outcomes of Patients 50 or Younger with Multiple Myeloma
Authors: Tufano-Sugarman Andrea , Islam Shahidul , Davies Faith E. , Morgan Gareth J. , Kaminetzky David , Braunstein Marc 
Published: December 2023

Introduction: Multiple Myeloma (MM) presents at a median age of 69. Patients age 50 or younger represent only 10% of diagnoses and are less well-characterized. Some studies have suggested that younger MM patients are more likely to present with lytic lesions, be IgD subtype, have high-risk cytogenetics, and have relatively improved survival. We aimed to characterize this understudied population in the modern era.
Methods: We conducted a retrospective chart review of patients age &lt;50 meeting IMWG criteria for symptomatic MM treated across our institution's cancer center network between 2010 and 2023. Overall survival was defined as time in months from diagnosis to last follow-up or death. Time to relapse after transplant was captured.
Results: We identified 97 younger MM patients, with a median age of 44 (range 26-50). Males and females represented 50.5% and 49.5% of cases respectively. Complete demographics are listed in the table. The most common MM subtype was IgG Kappa (40%), and 23% had light chain-only disease. Incidentally found cases, defined as abnormalities on imaging or labs ordered for another reason, represented 11% of cases. 61% of patients presented with a skeletal issue such as bone pain and/or pathologic fracture. Presenting features are described in the table. At time of diagnosis, 77% of patients were found to have lytic lesions. Few patients had previously identified MGUS (3%) or smoldering MM (5%). Regarding cytogenetics, 18% had one or more high-risk features. The most common frontline treatment was VRD. As shown in the table, 66% and 29% received 3 and 4 drug induction regimens respectively. Of note, 91% were referred for autologous stem cell transplant (ASCT), and 72% proceeded. 4 patients were deceased at the time of analysis. Survival for the entire population was 95.9% at a median follow up time of 65.5 months. In the patients who underwent ASCT, 41.2% relapsed with median progression-free survival of 57 (44-71) months.
Conclusions: MM patients age &lt;50 were found to be distinct from the known characteristics of the general population in several notable ways. There was equipoise among demographic features, with a nearly equivalent prevalence in males and females, and similar median ages across racial groups. We found a greater enrichment of light chain disease than expected, but less renal dysfunction at presentation. IgD subtype does not appear increased in this population. Younger patients do not appear more likely to have high risk cytogenetics. Lastly, survival for younger patients was higher compared to the reported 5-year survival of MM, which may be explained by the finding that these patients were treated primarily with triplet or quadruplet anti-myeloma regimens and often proceeded to ASCT.
Repressing HIF-1α-Induced HDAC9 Contributes to the Synergistic Effect of Venetoclax and Menin Inhibitor in KMT2Ar AML
Authors: Ling Qing 
Published: December 2023

Background: MLL-rearranged acute myeloid leukemia (MLLr-AML) is one aggressive subtype of AML, and is conferred one extremely poor prognosis under the current therapeutic strategy. Up to now, it still lacked one effective treatment to maintain the long-term survival for patients with MLLr-AML, while the developments of targeted therapy brought hopes. At present, the star drug BCL-2 inhibitor Venetoclax combined with Azacitidine (AZA) or low-dose Cytarabine (LDAC) has become the first-line scheme for elderly AML, which is not beneficial for MLLr-AML patients. So we are committed to finding a more suitable partner for VEN because MLLr-AML is very sensitive to VEN in vitro studies. The MLL-menin complex is crucial for maintaining MLLr-AML, and the research and application of MLL-menin inhibitors (MEN1i) is currently one of the hotspots in the AML field. Therefore in this study, we aimed to uncover the synergistic effect and mechanism of MEN1i combined with Venetoclax in treating MLLr-AML.
Methods: Cell culture and transfection, Cell proliferation, apoptosis and Cell cycle assay, Quantitative RT-PCR, and Western blotting analysis were used to explore biological phenotypes. RNA-seq profiling was performed for DMSO, VEN, MEN1i, and combination of VEN and MEN1i groups in three MLLr-AML cell lines MV4-11, MOLM13, THP-1. Bioinformatic tools were used for differential analysis.
Results: MLLr-AML cells were sensitive to VEN or MEN1i monotherapy, and the combination of two drugs had a strong synergistic effect in vitro and in vivo. Furthermore, we found that combination of VEN and MEN1i significantly enhanced apoptotic induction to influence the MLLr-AML survival. To uncover the synergetic mechanism of VEN and MEN1i, we displayed RNA-Sequencing for DMSO, VEN, MEN1i, and combination of VEN and MEN1i groups in three MLLr-AML cell lines MV4-11, MOLM13, THP-1. Finally we found that repressing HIF-1α-induced HDAC9 contributes to the synergistic effect of Venetoclax and MEN1i in MLLr-AML.
Conclusion: VEN combined with MEN1i had a strong synergistic effect in the treatment of MLLr-AML. Repressing HIF-1α-induced HDAC9 contributes to the synergistic effect of Venetoclax and MEN1i in MLLr-AML.
Efficacy and Safety of Low-Dose Venetoclax Combined with Voriconazole Inpatients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy
Authors: Meng Danchen , Ruan Min , Liu Xinyao , Wu Wei , Zhuang Junling , Ge Jian , Huang Zhenqi , Long Zhangbiao 
Published: December 2023

Background: Venetoclax combined with hypomethylating agents is the standard regime for elderly patients with acute myeloid leukemia unfit for intensive induction therapy. Nevertheless, many patients struggle with finances and forgo treatments due to the high costs of venetoclax. Concurrent application of venetoclax and CYP3A4 inhibitors such as voriconazole in low-income patients maybe is a feasible strategy to reduce the dose of ventoclax.
Methods: We conducted a single-institutional, non-randomized, open-label, prospective study. Between June 2020 and March 2023, 57 elderly or unfit patients with newly diagnosed acute myeloid leukemia at the first affiliated hospital of Anhui medical university were enrolled. Twenty-three patients received low-dose venetoclax plus voriconazole plus azacitidine (cohort 1), whereas another 34 patients received standard dose venetoclax plus azacitidine (cohort 2). The efficacy of the two regimes between cohorts was analyzed and compared, the peak venetoclax concentration (C max) and side effects of the patients were also detected.
Results: Totally, there were 35 males and 22 females, with a median age of 67 (range 46-91) years old. 86% (49/57) of patients were adverse/intermediate risk in the whole cohort. The baseline characteristics were all balanced differently between the two cohorts. The venetoclax Cmax in cohort 1 was 1930±225ng/mL, whereas the venetoclax Cmax in cohort 2 was 2371±274ng/mL, there was no significant difference between the two cohorts ( P＝0.3138). The overall response rates were 91% (21/23) and 85% (29/34) in cohort 1 and cohort 2, respectively ( P＝0.0834). At a median of 16 months of follow-up, the median progression-free survivals were 16 and 12 months in two cohorts, respectively ( P＝0.2651) with a hazard ratio of 0.6507. The median overall survivals were not reached and 14 months in the two cohorts, respectively ( P＝0.4636) with a hazard ratio of 0.7466. The most common hematological adverse events were neutropenia, thrombocytopenia, and anemia, whereas the most frequent non-hematological adverse events include infections, vomiting, diarrhea, and hypokalemia.
Conclusions: The combination of low-dose venetoclax and voriconazole is well tolerated and effective in unfit AML patients. Concurrent application of venetoclax provided a feasible and sustainable strategy for low-income patients.
Keywords: Venetoclax, low-dose, voriconazole, Unfit, Acute myeloid leukemia
Super-Enhancer-Driven IGF2BP2 and IGF2BP3 Promote DDX21 Expression in Acute Myeloid Leukemia
Authors: Zhao Yanchun , Jin Jie 
Published: December 2023

Background : Acute myeloid leukemia (AML) is a hematological malignancy with a median overall survival (OS) of 8.5 months and a 5-year OS rate of 24.0%. Considering that relapse and drug resistance are major obstacles affecting the survival of AML patients, it is urgent to investigate the deeper pathogenesis of AML. Epigenetic modifications are extensively involved in the leukemogenesis of AML, especially N6-methyladenosine (m 6A) RNA methylation and super-enhancers (SEs). However, the relationship between m 6A and SEs in AML has not been elucidated.
Methods : Chromatin immunoprecipitation (ChIP) sequencing data from Gene Expression Omnibus (GEO) cohort were analyzed to search SE-related genes. The mechanisms of m 6A-binding proteins IGF2BP2 and IGF2BP3 on DDX21 were explored via methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP) and luciferase reporter assays. The potential roles of DDX21 in AML were verified through functional assays in vitro and in vivo.
Results: Two SE-associated genes, IGF2BP2 and IGF2BP3, were identified in AML. There were high enrichment of H3K27ac, H3K4me1 and BRD4 in IGF2BP2 and IGF2BP3. BRD4 inhibitor JQ1 or BRD4 knockdown could lead to the suppression of IGF2BP2/3 expression, indicating the activation by SE machinery on the transcription of IGF2BP2/3. As m 6A-binding proteins, IGF2BP2 and IGF2BP3 enhanced the stability of DDX21 mRNA in an m 6A-dependent manner. DDX21 was highly expressed in AML patients, and elevated DDX21 expression suggested a poor survival. Functionally, DDX21 deficiency inhibited proliferation, facilitated apoptosis and arrested cell cycle of AML cells in vitro . I n vivo, knockdown of DDX21 substantially reduced tumor load and prolonged survival of recipient mice.
Conclusions: Dysregulation of SE-IGF2BP2/IGF2BP3-DDX21 axis promotes the progression of AML, which paves the way to develop more effective therapeutic strategies.
Clime: CLL Immune Micro-Environment and Risk of Infections Pre- and Post-Diagnosis: A Population-Based Study
Authors: Banerji Versha , Dawe David E , Xue Lin , Bucher Oliver , Yang Lin , Johnston James B. , Gibson Spencer Bruce , Decker Kathleen 
Published: December 2023

Background: Immune dysfunction precedes a diagnosis of chronic lymphocytic leukemia (CLL) in some patients. More information is needed about which patients experience immune dysfunction and how it impacts disease progression, as well as the development of post-diagnosis infections and second malignancies. The objectives of this study were to 1) examine the rate of pre-diagnosis infection for individuals diagnosed with CLL compared to population controls, 2) evaluate the impact of pre-diagnosis infection on time to first treatment, 3) compare the rate of immune dysfunction before the start of treatment by stage, and 4) compare the rate of immune dysfunction before the start of treatment for each year post-treatment.
Methods: We used a retrospective matched cohort study design that included all individuals in Manitoba diagnosed with CLL from 2006 to 2019. Individuals were identified from the Manitoba CLL database and the Manitoba Cancer Registry (MCR). Individuals with CLL were matched by age, sex, and area of residence (urban versus rural) to population controls identified from the Manitoba Health Population Registry. Provincial pharmacy, hospital admissions, medical claims, and MCR data were used to determine infection, second malignancies, and IgR therapy. Immune dysfunction was defined as two or more infections, a diagnosis with a secondary malignancy, or receipt of IgR therapy. The pre-diagnosis time period was defined as three to 15 months prior to diagnosis. The pre-treatment time period was defined as 12 months prior to treatment. The following analyses were used: conditional logistic regression for objective 1, competing risk for objective 2, logistic regression for objective 3, and logistic GEE models for objective 4.
Results: A total of 1,776 CLL patients were matched to 17,760 non-CLL controls. Sixty-two percent were male, the mean age at diagnosis was 71 years, and 62% lived in an urban area. Fifty-one percent of CLL patients had a pre-diagnosis infection compared to 46% of controls. Compared to individuals with no prior infection, those who had a prior infection were more likely to be diagnosed with CLL (Odds Ratio (OR) 1.17, 95% confidence Interval (CI) 1.03, 1.33 for one infection, OR 1.29, 95% CI 1.15, 1.45 for two or more infections). After adjusting for the number of outpatient visits and comorbidity, individuals with two or more infections were 14% more likely to be diagnosed with CLL (OR 1.14, 95% CI 1.00-1.30).
Conclusions: We found that infections that occurred in the three to 15 months before diagnosis increased the odds of being diagnosed with CLL. Work is ongoing examining time to treatment, immune dysfunction by stage, as well comparing immune dysfunction before and after treatment.
CAR-T Cells for Systemic Lupus Erythematosus
Authors: Doglio Matteo , Ugolini Alessia , Bercher Clara , Toma Cristiano , Bonini Chiara , Ciceri Fabio , Camisa Barbara , Norata Rossana , Del Rosso Stefania , Sanvito Francesca , Casucci Monica , Manfredi Angelo 
Published: December 2023

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by an abnormal inflammatory response against nuclear antigens with consequent tissue damage. Autoreactive B cells and auto-antibodies have a fundamental role in SLE pathogenesis. Lupus nephritis (LN) has a great impact on patients' survival and quality of life and still represents and unmet clinical need due to the lack of specific treatments and to the poor response to conventional immunosuppression. Regulatory T cells (Tregs) physiologically maintain the immune tolerance and are impaired in SLE. Polyclonal Treg transfer obtained unsatisfactory results due to the low number of disease-relevant antigen-specific cells. Chimeric Antigen Receptors (CARs) are molecules capable of redirecting T cell specificity. CAR-Tregs proved effective in pre-clinical mouse models of autoimmunity.
We aimed at developing a CAR-Treg based product to be employed in SLE in particular in LN.
We isolated Tregs from Healthy Donors Peripheral Blood Mononuclear Cells (PBMCs) and expanded them with IL-2 and rapamycin. We transduced Tregs with a Lentiviral Vector encoding for a second-generation anti-CD19 CAR, considering the relevant role of autoreactive B cells and autoantibodies in SLE. Engineered cells retained their immune suppressive capabilities upon polyclonal stimulation. Noticeably, they acquired new antigen-specific suppressive capacities, being able to block autologous B cell proliferation. We set up a humanized mouse model of SLE. In vivo, CAR-Tregs delayed the occurrence of B cell lymphopenia, producing immunomodulatory cytokines and without showing toxicity or reprogramming towards Th17 pro-inflammatory cells. In inflamed organs, CAR-Tregs restored the normal composition of the immune system.
In conclusion, we efficiently generated anti-CD19 CAR-Tregs and proved their efficacy both in vitro and in an in vivo humanized mouse model of lupus.
A Pilot Study to Determine the Safety and Efficacy of Repeated Hyperbaric Oxygen Therapy in Multiple Myeloma Patients Undergoing High-Dose Therapy and Autologous Stem/Progenitor Cell Transplantation
Authors: Huselton Eric J , Langstein Howard , Liesveld Jane L. , Aljitawi Omar 
Published: December 2023

Background
Serum erythropoietin (EPO) negatively impacts hematopoietic stem cell homing and engraftment. Hyperbaric oxygen (HBO) therapy can reduce serum EPO in healthy volunteers and when given prior to stem cell infusion may improve engraftment after hematopoietic stem cell transplant (HSCT).
We previously performed a phase II trial randomizing patients with multiple myeloma undergoing high dose melphalan and autologous HSCT 1:1 between a single HBO treatment and no HBO. HBO was given as 100% oxygen, 2.5 ATA for a total of 90 min, in a single treatment on Day 0 prior to the transplant. A total of 99 patients were enrolled with 52 randomized to HBO. HBO significantly reduced EPO levels for the first 24 hours after auto transplant, but EPO levels quickly rebounded by 48 hours after transplant.
We hypothesized multiple HBO treatments will keep EPO levels low during the duration of stem cell homing (i.e: the first 72 hours after HSCT) and may improve neutrophil and NK cell recovery.
Methods
We performed a pilot study to evaluate the safety and tolerability of multiple HBO treatments during autologous HSCT. Patients with multiple myeloma undergoing autologous HSCT were eligible. Patients received HBO therapy, consisting of hyperbaric oxygen at 2.5 ATA for a total of 90 minutes breathing 100% oxygen on days 0 (prior to HSCT), 1, and 2 of transplant. The primary objective of this pilot study was to determine the safety of repeated HBO therapy in the setting, as defined by treatment limiting toxicity (TLT) including occurrence of seizure disorder, pneumothorax, death, or any irreversible grade Ill or any grade IV toxicity within 24 hours of HBO therapy. Secondary objectives were to determine the effects of multiple HBO therapy on neutrophil count recovery and the effect of multiple HBO on serum EPO.
Results
10 patients have been enrolled that are evaluable for the primary objective. All patients had multiple myeloma and 4 were female. 9/10 patients successfully completed all 3 HBO treatments and 1/10 completed HBO on days 1 and 2 only because of ear pain on day 0. No patients experienced treatment limiting toxicity. The median times to neutrophil and platelet engraftment was 12 days (range 11-14) and 16 days (range 14-28), respectively. The median length of hospitalization was 13 days (range 12-16). Febrile neutropenia occurred in 3/10 patients with just one incidence of documented infection. This was significantly less than the rate of febrile neutropenia in patients receiving a single treatment of HBO or no HBO (81% and 47%, respectively, p&lt;0.05). 3 patients required red blood cell transfusion and 5 platelet transfusion.
Conclusions
Multiple HBO treatment were well tolerated without treatment limiting toxicity during autologous HSCT for multiple myeloma.
Predictors of unsustained measurable residual disease negativity in transplant-eligible patients with multiple myeloma
Authors: Guerrero Camila , Puig Noemi , Cedena María-Teresa , Calasanz María-José , Gutierrez Norma C. , Fernandez Manuela , Oriol Albert , Ríos-Tamayo Rafael , Hernandez Miguel-Teodoro , Martínez-Martínez Rafael , Bargay Joan , de Arriba Felipe , Palomera Luis , Gonzalez-Rodriguez Ana Pilar , Gonzalez Perez Marta-Sonia , Orfao Alberto , Mateos María-Victoria , Martinez-Lopez Joaquin , Rosiñol Laura , Bladé Joan , Lahuerta Juan-Jose , San-Miguel Jesus F. , Paiva Bruno 
Published: December 2023

Abstract
The role of measurable residual disease (MRD) negativity as a biomarker to stop treatment is being investigated in transplant-eligible patients with multiple myeloma (MM). Thus, it is important to identify risk factors of MRD resurgence and/or progressive disease (PD) among patients achieving undetectable MRD to avoid undertreating them. Here, we studied 267 newly diagnosed transplant-eligible patients with MM enrolled in the GEM2012MENOS65 and GEM2014MAIN clinical trials who achieved MRD negativity by next-generation flow cytometry. After a median follow-up of 73 months since the first MRD negative assessment, 111 of the 267 (42%) patients showed MRD resurgence and/or PD. The only prognostic factors at diagnosis that predicted MRD resurgence and/or PD were an International Staging System (ISS) 3 and the presence of ≥0.01% circulating tumor cells (CTCs). Failure to achieve MRD negativity after induction also predicted higher risk of MRD resurgence and/or PD. Patients having 0 vs 1 vs ≥2 risk factors (ISS 3, ≥0.01% CTCs, and late MRD negativity) showed 5-year rates of MRD resurgence and/or PD of 16%, 33%, and 57%, respectively (P &lt; .001). Thus, these easily measurable risk factors could help refine the selection of patients for whom treatment cessation after MRD negativity is being investigated in clinical trials. This trial was registered at www.clinicaltrials.gov as NCT01916252 and NCT02406144.
Impaired O2 unloading from stored blood results in diffusion-limited O2 release at tissues: evidence from human kidneys
Authors: Dumbill Richard , Rabcuka Julija , Fallon John , Knight Simon , Hunter James , Voyce Daniel , Barrett Jacob , Ellen Matt , Weissenbacher Annemarie , Kurniawan Tetuko , Blonski Slawomir , Korczyk Piotr Michal , Ploeg Rutger , Coussios Constantin , Friend Peter , Swietach Pawel 
Published: December 2023

Abstract
The volume of oxygen drawn from systemic capillaries down a partial pressure gradient is determined by the oxygen content of red blood cells (RBCs) and their oxygen-unloading kinetics, although the latter is assumed to be rapid and, therefore, not a meaningful factor. Under this paradigm, oxygen transfer to tissues is perfusion-limited. Consequently, clinical treatments to optimize oxygen delivery aim at improving blood flow and arterial oxygen content, rather than RBC oxygen handling. Although the oxygen-carrying capacity of blood is increased with transfusion, studies have shown that stored blood undergoes kinetic attrition of oxygen release, which may compromise overall oxygen delivery to tissues by causing transport to become diffusion-limited. We sought evidence for diffusion-limited oxygen release in viable human kidneys, normothermically perfused with stored blood. In a cohort of kidneys that went on to be transplanted, renal respiration correlated inversely with the time-constant of oxygen unloading from RBCs used for perfusion. Furthermore, the renal respiratory rate did not correlate with arterial O2 delivery unless this factored the rate of oxygen-release from RBCs, as expected from diffusion-limited transport. To test for a rescue effect, perfusion of kidneys deemed unsuitable for transplantation was alternated between stored and rejuvenated RBCs of the same donation. This experiment controlled oxygen-unloading, without intervening ischemia, holding all non-RBC parameters constant. Rejuvenated oxygen-unloading kinetics improved the kidney’s oxygen diffusion capacity and increased cortical oxygen partial pressure by 60%. Thus, oxygen delivery to tissues can become diffusion-limited during perfusion with stored blood, which has implications in scenarios, such as ex vivo organ perfusion, major hemorrhage, and pediatric transfusion. This trial was registered at www.clinicaltrials.gov as #ISRCTN13292277.