bluuebunny/crossref_metadata_2025_split huggingface dataset:
Desiccation Stress Triggers and Exacerbates Experimental Ocular Graft-Versus-Host-Disease
Authors: Steven Philipp , Gehlsen Uta , Maass Martina , Pasparakis Manolis , de Paiva Cintia S. , Holtick Udo , Scheid Christof , Stern Michael E. 
Published: December 2024

Introduction:
Ocular Graft-versus-Host Disease (oGVHD) is a rapidly progressing, sight-threatening condition of the eye following allogeneic hematopoetic stem cell transplantation (aSCT). Previously we reported in two retrospective studies, adverse environmental stress (AES) such as high air flow and low humidity during the stay on the transplant unit may be a risk factor for chronic oGVHD. To investigate which pathophysiological processes may be triggered by AES in the early phase after transplantation, we performed experiments using a mouse model of oGVHD under different environmental conditions.
Methods:
A minor mismatch-mouse model (129S2-&gt;C57BL/6) was used where mice either remained in standard housing (&gt;50% humidity, no air flow) or were subjected to AES (&lt;30% humidity, constant air flow) for 18 days after bone marrow transplantation (BMT). Systemic and ocular GVHD were monitored for up to 28 days and histological, immunohistochemical and flow-cytometric analyses of ocular tissue, tear film, lacrimal gland, ocular draining-lymph nodes and spleen were performed.
Results:
AES led to a significantly higher systemic and oGVHD score than in animals without AES at days 7 and days 14 after BMT. Corneal staining and blepharitis remained significantly elevated after discontinuation of AES until day 28. Tear film analysis demonstrated early elevation of Tumor Necrosis Factor (TNF), whereas increase of CD8+ T-cells, higher activation of dendritic cells and early loss of Treg activity was detected in cervical lymph nodes together with an early corneal lymphangiogenesis in desiccated animals, but not in animals kept under normal housing conditions.
Conclusions:
These data confirm the hypothesis that AES is an independent risk factor for oGvHD. Low humidity conditions after aSCT in the mouse model worsen the severity of systemic GVHD in the mouse model, implicating that AES has not only a local effect.
Therefor avoiding AES and targeting early activation of ocular surface immune mechanisms could help to reduce both oGVHD and systemic GvHD in patients undergoing aSCT.
Post-Transplant Bendamustine Extends Survival and Reduces GvHD in a Xenogeneic NSG Transplant Model Compared to Post-Transplant Cyclophosphamide
Authors: Cracchiolo Megan , Davini Dan , Simpson Richard , Katsanis Emmanuel 
Published: December 2024

Acute graft-versus-host disease (GvHD) is a significant complication following allogeneic hematopoietic stem cell transplantation. This process begins with the activation of donor T-cells that recognize host tissue antigens as foreign, resulting in an immune attack primarily targeting the skin, gastrointestinal tract and liver. Post-transplant cyclophosphamide (PT-CY) has significantly reduced GvHD in haploidentical and other allogeneic transplant settings, although relapse, viral reactivations, hemorrhagic cystitis and cardiotoxicity remain common. Our laboratory has investigated the use of bendamustine, another nitrogen mustard agent, as a post-transplant GvHD prophylaxis. The goal is to reduce GvHD while preserving graft-versus-leukemia (GvL) effects and avoiding the significant side effects associated with PT-CY.
Using a xenogeneic GvHD (xGvHD) model of irradiated NSG mice infused with human peripheral blood mononuclear cells (PBMCs), we found that a day +3 dose of 30 mg/kg of post-transplant bendamustine (PT-BEN) confers better survival and reduces xGvHD more effectively than PT-CY (50 mg/kg). These results were also maintained in a xGvHD model of NSG mice receiving PT-CY (25 mg/kg) on days +3 and +4 as compared to PT-BEN (15 mg/kg). Engraftment of human lymphocytes on days +7, +14, +21, +28, +42, and +70 was tracked using flow cytometric analysis of peripheral blood samples. Interestingly, we observed higher rates of human engraftment in PT-CY treated mice which was associated with a more pronounced reduction in murine CD45+ cells in the peripheral blood. Our findings indicate that a dose of 25 mg/kg PT-CY on days +3 and +4, previously reported to be optimal in mice, or a single PT-CY dose of 50 mg/kg on day +3 does not significantly extend survival in our xGvHD model. Additionally, PT-BEN can significantly prolong survival and reduce acute GvHD, although this may be partially attributed to a reduced circulating number of engrafted human lymphocytes. Ongoing experiments include investigation into the early deleterious effects of PT-CY on murine CD45+ populations and use of xenogeneic GvL models to examine whether the engrafted cells maintain a GvL effect in the presence of reduced GvHD. Additionally, single cell RNA-sequencing on engrafted hCD45+ cells will be performed to assess changes in gene expression across T-cell populations in xGvHD mice treated with either PT-CY or PT-BEN.
Enhancing Compliance to a Bloodless Management Protocol for Severe Anemia through Avomd Technology Integration
Authors: Imhoff Santiago , Bag Angila , Pope Danielle , Kaufman Margit , Gandhi Nisha 
Published: December 2024

Background
Englewood Hospital (EH) has over 25 years of experience in patient blood management (PBM) for patients who decline blood transfusions due to religious or personal reasons. The Bloodless Medicine and Surgery Institute has developed a comprehensive protocol for managing severe anemia in bloodless patients, aiming to optimize patient hematopoietic capacity. [1] This approach has been shown to reduce costs, transfusion reactions, and hospital stays. [2] However, the progressive nature of bloodless medicine has presented challenges in physician compliance with hospital guidelines and policies, leading to frequent referrals to the specialized PBM department for guidance. Tools like AvoMD, a clinical decision support (CDS) platform, have helped reduce referrals by providing structured guidance on evidence-based algorithms.
Methods
EH collaborated with AvoMD to integrate our customized PBM protocol into an interactive interface. This platform enables physicians to select among various clinical conditions, such as patients who are actively bleeding, critically ill or those undergoing a surgical intervention. Management recommendations are then provided based on hemoglobin values according to established protocols. In this study, we closely monitored the number of referrals to the PBM department over a 12-month period after implementation of our PBM protocol via AvoMD.
Results
The implementation of the AvoMD platform led to a 73% decrease in referrals to the PBM department.
Conclusion
Managing severe anemia when transfusion is not an option can be challenging. CDS systems integrate patient information with a digital knowledge base to enhance clinical decision-making processes and can be particularly helpful in unique scenarios such as severe anemia in bloodless patients. These systems have shown to decrease misdiagnosis rates and improve patient safety. [4] AvoMD is designed to streamline clinical decision-making by simplifying evidence-based guidelines and algorithms. The implementation of AvoMD decreased the number of PMB referrals in our hospital by empowering physicians with point-of-care recommendations. This CDS integration has proven to reduce the need for specialist consultations and improve guideline adherence in other institutions. [3, 5]
Integrating EH PBM protocols into the clinical workflow through the AvoMD platform represents a significant advancement in patient care quality. This project highlights the potential of technology to deliver comprehensive care, enhance patient safety and improve clinical outcomes. The field of CDS is evolving rapidly, and the advent of artificial intelligence (AI) is set to accelerate this transformation. Numerous studies are exploring how AI can improve decision-making processes, increase accuracy, and ultimately lead to better clinical outcomes. [6,7]
Cytoreductive Paradigms for Hyperleukocytosis in Acute Leukemia (AL) Using Venetoclax based Regimen. Single Center Experience from United Arab Emirates
Authors: Alam Arif , Alam Nida , Al Qawasmeh Khaled , McCarthy Philip L. 
Published: December 2024

Introduction:
Hyperleukocytosis is traditionally defined as White Blood Count (WBC) greater than 100000/microliter. It is seen in Acute Leukemia (AL) and Chronic Leukemia (CL). However, the complications of leukocytosis with leukostasis, Diffuse Intravascular Coagulation (DIC) and tumor lysis (TLS) are usually hallmarks of AL particularly Acute Myeloid Leukemia (AML). There is no standard for management and controversy exists regarding the use of leukapheresis (Stahl M et al Leukaemia 2020) versus initiation of chemotherapy (Zhao J et al. Leuk Lymphoma 2021). Venetoclax is a bcl2 inhibitor that is being used in the management of AL. Here we report our experience using novel combination targeted therapy with Venetoclax for cytoreduction.
Methods:
This is a retrospective analysis of AL patients seen in a public tertiary care hospital in the emirates of Abu Dhabi in United Arab Emirates. The study period is between January 2023 to June 2024. Data was abstracted from the electronic medical records including patient demographics, diagnosis, laboratory values and treatment.
Results:
During the study period sixty-five patients presented with clinical features suggestive of AL. Fourteen (21 %) patients had hyperleukocytosis. The median age of the patients was 30 years (range 19 to 60 years). The median WBC was 134000/microliter (range 104-432,000/microliter).
Diagnostic work up included bone marrow biopsy with flow cytometry, karyotype analysis, Fluorescence in situ hybridization (FISH) and molecular studies (30 gene panel and FLT3 PCR).
The median period of reporting of the bone marrow result was 3 days (range 0-7 days).
Cytoreductive therapy was given with Dexamethasone 20 -40 mg intravenously daily with Hydroxyurea 2000 mg orally daily and Venetoclax orally (escalating from 100 mg day 1, 200 mg day 2 and 400 mg day 3 and onwards) while awaiting diagnosis.
There was a 50 % reduction of WBC by day 3 in most patients (64%). A WBC of less than 50000/microliter was achieved by day 4 in 57% of the cohort.
There was biochemical evidence of tumor lysis. This was managed medically by hydration, prevention of hyperuricemia and correction of electrolytes. Dialysis and critical care were not required.
Six patients refused further therapy and were lost to follow-up. Three patients died during induction period. Two patients went for allogeneic hematopoietic stem cell transplant, two patients had relapsed and refractory disease while one patient is in sustained remission post consolidation chemotherapy.
Conclusion:
The current experience using dexamethasone, Hydroxyurea and Venetoclax gives an alternate (leukapheresis and Cyclophosphamide/Cytarabine) and safe option for cytoreduction prior to exact diagnosis and initiation of therapy.
Efficacy of Axatilimab in the Management of Chronic Graft-Versus-Host Disease
Authors: Shahzad Moazzam , Javed Muhammad Jawad , Irfan Sohaib , Khan Muhammad Atif , Amin Muhammad Kashif , Vyas Abhinav , Chaudhary Sibgha Gull , Anwar Iqra , Nelson Maggie , Abhyankar Sunil , McGuirk Joseph P. , Mushtaq Muhammad Umair 
Published: December 2024

BACKGROUND
Chronic graft versus host disease (cGVHD) is a major cause of late non-relapse morbidity and subsequent mortality in patients with allogeneic hematopoietic stem cell transplant (HSCT). Despite various treatment options, therapy failure is common which highlights the necessity for exploration of newer therapies. This systematic review aims to evaluate the efficacy of axatilimab, a monoclonal antibody that inhibits Colony-stimulating factor 1 receptor (CSF-1R), in managing refractory cGVHD.

METHODS
We conducted a systematic review per PRISMA Statement 2020 guidelines and included 3 studies after searching 5 major databases, PubMed, Cochrane, Medline, Embase, and Clinicaltrials.gov. Inter-study variance was calculated, and a pooled analysis was performed using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2).

RESULTS
A total of 292 patients from three studies were included in this systematic review and meta-analysis. The included studies were phase I 1(33.33%), phase I/II 1(33.33%) and phase II 1(33.33%). The median age of the patients was 58 years (range: 16-73) and 63% were male (184/292). The median time from cGVHD to the first dose of axatilimab was 3.57 years. The median time to response was 6 weeks (range: 4.5-12). The pooled overall response was 64% (95% CI 0.58-0.69, I²=0%, p=0.86) and the mortality rate was 6% (95% CI 0.04-0.10, I²=0%, p=0.72). One study reported that greater than 50 % of patients maintained a response for greater than 12 months. The gastrointestinal tract exhibited the most favorable response to treatment, whereas the eyes and skin showed modest improvement. The response rate in Esophagus was 74% (95%CI: 0.50-0.89, I²=74%, p=0.02), musculoskeletal was 67% (95% CI: 0.53-0.79, I²=51%, p=0.13) and skin was 26% (95% CI: 0.15-0.40, I²=50%, p=0.14). The pooled incidence of 7-point improvement in LEE score was 49% (95% CI 0.42-0.56, I²=0%, p=0.47) and the incidence of grade 3 or above treatment-related adverse effects was 28% (95% CI 0.17-0.42, I²=61%, p=0.11). AST elevation was the most common adverse effect with a pooled incidence of 35% (95% CI 0.30-0.41, I²=0%, p=0.42) followed by CPK elevation 34% (95% CI 0.29-0.40, I²=0%, p=0.45) and amylase elevation 20% (95% CI, 0.16-0.26, I²=14%, p=0.31). The pooled incidence of drug discontinuation due to treatment-related adverse events was 16% (95% CI: 0.12-0.20, I²=0%, p=0.94).

CONCLUSION
In this systematic review, axatilimab exhibited promising therapeutic outcomes for refractory cGVHD based on the findings from Phase I and II clinical trials, with an acceptable safety profile. However, prospective clinical trials with randomization are needed to consolidate these findings.
Anticoagulation for Patients with Essential Thrombocythemia or Polycythemia Vera-Associated Venous Thromboembolism
Authors: Tamdin Tenzin , Chang Yu-Cheng , Chiang Cho-Han , Song Junmin , Chi Kuan-Yu , Chang Yu , Peng Chun-Yu , Gao Wenli 
Published: December 2024

Introduction: Essential thrombocytopenia (ET) and polycythemia vera (PV) are characterized by a high risk of thrombosis. Current guideline recommended low-dose aspirin for primary thromboprophylaxis in patients with ET or PV, but there is limited data describing the optimal anticoagulation strategies for managing venous thrombosis in these patients. We aimed to compare the effects of direct oral anticoagulant (DOAC) monotherapy versus DOAC-aspirin combined therapy on outcomes of patients with ET or PV-associated venous thrombosis.
Methods: We performed a retrospective, propensity score-matched cohort study by utilizing the TriNetX Analytics Network database. The TriNetX database is a collaborative research platform with de-identified electronic health records from more than 120 healthcare organizations. We included patients with a diagnosis of ET or PV who developed deep vein thrombosis (DVT) or pulmonary embolism (PE). Patients on a DOAC monotherapy were compared to those on a DOAC-aspirin combined therapy. The index date was defined as the start date of DOAC monotherapy or DOAC-aspirin combined therapy. Patients with atrial fibrillation before index date were excluded. The efficacy outcomes were recurrent venous thrombosis, which included PE and DVT, and arterial thrombosis comprising of ischemic stroke and acute myocardial infarction. The safety outcomes were gastrointestinal bleeding, intracranial bleeding, and hematuria.
Results: We identified 2839 patients eligible for inclusion. We matched 445 patients on a DOAC monotherapy to those on a DOAC-aspirin combined therapy. In Cox proportional hazards analyses, patients on a DOAC monotherapy had a similar efficacy in the prevention of recurrent venous thromboembolism (Hazard ratio (HR), 1.02 [95% CI: 0.67-1.54]), recurrent PE (HR, 1.13 [95% CI: 0.64-1.99]) and recurrent DVT (HR, 0.87 [95% CI: 0.49-1.56]) as well as ischemic stroke (HR, 0.68 [95% CI: 0.36-1.29]) and myocardial infarction (HR, 0.87 [95% CI: 0.42-1.80]) compared to patients on a DOAC-aspirin combined therapy. DOAC monotherapy was associated with lower risk of gastrointestinal bleeding (HR, 0.52 [95% CI: 0.28-0.97]) compare to DOAC-Aspirin combined therapy. There is no significant difference in the risk of intracranial bleed (HR, 0.95 [95% CI: 0.19-4.71]) and hematuria (HR, 1.02 [95% CI: 0.54-1.95]) between DOAC-aspirin combined therapy and DOAC monotherapy cohort.
Conclusion: DOAC monotherapy had a lower risk of gastrointestinal bleed but similar efficacy in the prevention of recurrent venous than DOAC-aspirin combined therapy among patients with ET or PV-associated venous thrombosis.
Dexamethasone and Daratumumab Impair T-Cell Mediated Killing in Multiple Myeloma: Implications for Sequential Therapies
Authors: Dulcamare Ilaria , Marino Sara , Parrinello Nunziatina Laura , Scandura Grazia , La Spina Enrico , Cambria Daniela , Scuderi Grazia , Giallongo Cesarina , Tibullo Daniele , Romano Alessandra , Di Raimondo Francesco 
Published: December 2024

Background
For elderly patients the combination Daratumumab-lenalidomide-dexamethasone (D-Rd) is an emerging standard-of-care regimen, able to improve long-term outcomes in MM patients. Nevertheless, CD38 is ubiquitously expressed on both MM cells and immune cells, and the effect of daratumumab on MM microenvironment are still under investigation. Thus, we investigated the potential immunomodulatory effect of D-Rd on T-cells function in patients with newly diagnosed MM.
Material and methods
PB samples were collected from newly diagnosed MM patients receiving D-Rd (n=8) at baseline and after 2 months of therapy. PBMCs were obtained using Ficoll-Paque (GE Healthcare, Piscataway Township, NJ) and then used for in vitro experiments and flow cytometry analysis (T lymphocytes populations were identified as CD3+, CD4+/CD8+ cells). T-cells' activation was evaluated by flow cytometry (using a CD25, CD38, CD71, HLA-dr cocktail); mitochondrial mass was evaluated after cell staining with MitoTracker Green (Life Technologies); cell lysis was estimated by Annexin v FITC/7-ADD kit assay.
Results
Our data showed a redistribution of T cell subsets with decreased pool of terminal differentiated and highly differentiated end-stage CD8+ cells after 2 months of D-Rd (p&lt;0.05) (n=4), associated with a loss of mitochondrial mass (p&lt;0.0005) and an increase in percentage of dysfunctional mitochondria (p&lt;0.05) in T lymphocytes compared to baseline (n=8). Additionally, we observed that both CD4+ and CD8+ cells from MM patients who received D-Rd therapy lose their ability to activate when stimulated in vitro with phytohemagglutinin (n=8), while no differences in proliferation capacity were observed (n=4). Thus, to explore the impact of D-Rd therapy on T lymphocyte fitness, we treated T lymphocytes from healthy donors and newly diagnosed MM patients in vitro with single agent (daratumumab, lenalidomide, dexamethasone) and their combinations, evaluating mitochondrial functionality, activation capacity, and proliferation in vitro. Our results showed that T lymphocyte fitness was negatively affected only in conditions with dexamethasone (p&lt;0.0001). Furthermore, the tumor cell lysis capacity of T lymphocytes treated with dexamethasone, or its combinations, was significantly reduced. Finally, we observed that the negative effects on T lymphocyte functionality induced by dexamethasone were reversed by using a bispecific antibody, which enhanced tumor cell lysis capacity in vitro in T lymphocytes from healthy donor and newly diagnosed MM patients (p&lt;0.0001).
Conclusions
Taken together, our data suggest an impairment in T-cell function occurring upon up-front treatment that should be considered when new combinations and sequential treatments are designed.
Circulating Tumour DNA Measurements As an Early Prognostic Indicator for Newly Diagnosed Diffuse Large B-Cell Lymphoma Treated with Pola-R-CHP Regimen
Authors: Wen Xiaolian , Su Liping , Guan Tao , Liu Jie , Shen Xuliang 
Published: December 2024

Objective
The POLARIX trial showed that pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone) significantly improved 2-year event-free survival (EFS) and progression-free survival (PFS) compared with R-CHOP in DLBCL patients with intermediate- and high-risk. However, some patients still failed to achieve durable remission. Circulating tumour DNA (ctDNA) is a novel prognostic biomarker in diffuse large B-cell lymphoma, but its prognostic significance in DLBCL patients treated with pola-R-CHP has not been fully defined. This prospective multicentre study preliminarily evaluated the correlation between baseline ctDNA levels and early post-treatment ctDNA changes with efficacy in Chinese DLBCL patients receiving the pola-R-CHP regimen (ChiCTR2300077262).
Methods
Enrolled DLBCL patients were treated with the pola-R-CHP regimen. Patients' ctDNA samples were subjected to targeted next-generation sequencing (NGS) to analyse the mutational profiles of 168 gene panels. ctDNA testing was performed prior to treatment, on day 1 of cycle 2 (C2D1) and on day 1 of cycle 5 (C5D1), respectively, and imaging efficacy was assessed every 2 cycles.
Results
A total of 22 patients were enrolled between November 2023 and May 2024, of whom 21 (95.5%) had ctDNA mutations detected at baseline. The most frequently mutated genes were PIM1 (42%), TP53 (26%), TMSB4X (26%), BTG2 (26%) and TET2 (21%). Baseline ctDNA levels correlated with IPI but not with age, gender, lactate dehydrogenase(LDH), pathological subtype, stage, Bone marrow infiltration or not, and large masses. Patients in the IPI 4-5 group had significantly higher baseline ctDNA levels than those in the IPI 0-3 group (P = 0.0015). ctDNA was performed at C2D1 in 16 patients and all patients had a significantly lower ctDNA level, with the 8 patients with undetectable ctDNA in durable remission, while 1 of the 8 patients with detectable ctDNA had disease progression. In this case, the patient's ctDNA was found to be elevated from previous levels at C5D1, and was subsequently assessed as disease progression by imaging after 6 cycles, with the ctDNA elevation occurring earlier than the imaging assessment. With a median follow-up of 7.7 months (2.5-16.2), patients with ctDNA &gt;1000 hGE/ml had better PFS than patients with ctDNA ≤ 1000 hGE/ml, but no statistical significance was seen between the two groups (P=0.0612), possibly due to the small sample size and shorter follow-up.
Conclusions
Sustained remission status in DLBCL patients receiving pola-R-CHP may be associated with early clearance of ctDNA, and non-invasive ctDNA assessment may allow risk stratification and outcome prediction in this group of patients. We will subsequently continue to enroll more patients with extended follow-up to further clarify the long-term prognostic significance of ctDNA.