bluuebunny/crossref_metadata_2025 huggingface dataset:
Innovative Treatment for Post-COVID Syndrome: A Clinical Breakthrough
Authors: Chen Ying Chieh , Rosenthal Joseph , Su Gili , Lau Ernest , Chen Chinhhsin , Martinez Aristides Canalejo , Wang Jonas , Lee Tong Young
Published: December 2024

As of July 2024, over 775 million people worldwide have confirmed cases of COVID-19, according to the World Health Organization. While the majority recover fully, studies reveal that 10 to 20% of these individuals experience persistent symptoms, known as post-COVID syndrome (long COVID). This condition affects multiple organ systems, with fatigue being the most frequently reported and burdensome symptom by 87% of patients. Post-COVID syndrome significantly impairs daily functioning and quality of life, highlighting the urgent need for effective treatments.

RegeneCyte® (HPC, cord blood, hUCB), developed by StemCyte Inc., is a pioneering regenerative medicine therapy (RMT). It is rich in monocytes, lymphocytes, stem cells (CD34+ cells), and progenitor cells. The safe and effective use of hUCB transplantation in treating various conditions, from hematological malignancies to neurological disorders, positions it as a promising candidate for addressing post-COVID syndrome, particularly in alleviating fatigue.

Our phase IIa clinical trial (NCT#05682560) investigates the safety, tolerability, and efficacy of RegeneCyte® for post-COVID syndrome. The randomized, single-blind, placebo-controlled study involves 30 subjects aged 18 to 65 years, with persistent post-COVID symptoms for over 6 months but not exceeding 18 months. Subjects are randomized in a 2:1 ratio between the treatment and placebo arms. Fatigue severity is assessed using the Chalder Fatigue Scale (CFQ-11) as the effectiveness endpoint. Twenty subjects in the treatment arm receive three intravenous doses of RegeneCyte® every three weeks, with follow-up over 20 weeks. Each dose contains at least 1 × 10^7 total nucleated cells (TNC)/kg, with a cumulative dose of at least 3 × 10^7 TNC/kg per subject. This is the first clinical trial which use three units of HPC in one subject in the past decades.

Preliminary data from the first 15 subjects show no trends in the changes of clinical safety laboratory parameters between the RegeneCyte® and placebo groups. Efficacy results at week 12 reveal that 90% of RegeneCyte®-treated subjects are classified as “non-fatigue” cases, compared to 100% in the placebo group remaining “fatigue” cases. Furthermore, 80% of RegeneCyte®-treated subjects show improvement to a “normal” level of physical fatigue, whereas all placebo recipients remain at the “fatigue” level. These findings demonstrate that RegeneCyte® is safe, well-tolerated, and significantly improves fatigue symptoms in post-COVID syndrome patients.

In conclusion, RegeneCyte®, a first-in-class regenerative medicine therapy, shows significant potential in treating post-COVID syndrome. The clinical evidence of profound fatigue reduction and a high safety profile underscores its therapeutic promise. RegeneCyte® infusion presents a viable treatment option for post-COVID syndrome, addressing unmet medical needs and expanding the scope of RegeneCyte® applications.
Allogeneic Hematopoietic Progenitor Cell from Peripheral Whole Blood in Acute Myeloid Leukemia
Authors: Amaru Ricardo , Mamani Reyna , Velarde Jeaneth , Carrasco Mireya , Quispe Soto Edgar Teddy , Mancilla Silvia , Valencia Juan Carlos , Paton Daniela , Amaru Ariel
Published: December 2024

Acute Myeloid Leukemia (AML) standard treatment involves initial induction therapy administrating two cycles of the 3+7 protocol (3 days anthracycline + 7 days cytarabine), and post-remission therapy of 3 cycles of high-dose cytarabine. The 5-year overall survival is 20 % (PMID: 33734442). During prolonged aplasia, infections and hemorrhages can cause treatment failure and death (PMID: 32236160). That is why transfusions of allogeneic hematopoietic progenitor cells (Allo-HPC) from whole peripheral blood to reduce the time of aplasia and complications were of interest.

We studied 6 patients (3 males, 3 females) with AML (M1, M2), average age 35 years (18-60 years), who received Allo-HPC from whole peripheral blood during aplasia after each 3+7 regimen. The transfusion was performed at day 14 (day 12-16) post-regimen, when patients had neutrophils <100/ul (0-100/ul). Regarding donors, one corresponded to HLA identical sibling, and 5 to haploidentical (2 fathers, 2 mothers and 1 brother), they received G-CSF 300 μg subcutaneously every 12 hours over 3 days, then 450 ml phlebotomy was performed. Phlebotomy displayed median WBC 27,310/ul, neutrophils 21,830/ul, CD34+ cells 9/ul, hemoglobin 14.8 g/dl, and platelets 218,000/ul. Thus, whole peripheral blood obtained was transfused through patients' CVC after premedication with dexamethasone 8 mg and metamizole 1 g. FISH (Y chromosome, Vysis CEP-Y DYZ1) and RT-PCR (HUMARA gene) studies were performed for chimerism analysis.

Recovery of neutrophils >500/ul was observed at day 9 and platelets >20,000/ul at day 6. One case of cutaneous rush was observed as an adverse event. MRD after each cycle reflected 0.01% average. Three patients remain alive with follow-up of 4 years, 5 years and 1 year respectively. Two patients relapsed and died during 1year follow-up. One patient developed optic neuritis and did not receive high-dose cytarabine therapy, relapsed and died after 6 months. None of the patients presented acute or chronic GVHD. Regarding the results of chimerism, one male patient (1year follow-up) showed mixed chimera by FISH (Y=95%) and by RT-PCR (HUMARA gene), such studies were still in progress in the other two women patients.

Contrasting patients who received Allo-HPC from the ones who do not, statistically differences were found in neutrophils recovery and hospital staying, the former displayed 9 + 3 days vs 14 + 4 days (p=0.008) and 19 +5 days vs 25 + 4 days (p=0.009) respectively, infections also decreased from 83% to 25%.

Transfusion of Allogeneic Hematopoietic Progenitor Cell from Peripheral whole blood reduces the duration of aplasia, infections, inpatient stays, and increases survival.
Incidence of Engraftment Syndrome with and without Budesonide Prophylaxis in Patient with Multiple Myeloma Undergoing Autologous Stem Cell Transplant
Authors: Daniels Stephanie , Gloe Lucy , Kota Vamsi K. , Rakestraw Alexandria , Clemmons Amber
Published: December 2024

Engraftment syndrome (ES), a rare post-transplant complication, has been defined differently across the existing literature. This study aims to determine if budesonide prophylaxis reduces the incidence of ES after autologous hematopoietic cell (auto-HCT) for patients with multiple myeloma (MM), as defined by three separate published criteria - Spitzer1, Maiolino2, and Dhakal3, respectively.

A single-center, IRB-approved, retrospective review was conducted on adult patients who received auto-HCT for the treatment of MM between January 2017-October 2023. Based on results of the Dhakal study reporting the benefit of budesonide to prevent ES, our local institution made a practice change in October 2021 to prescribe budesonide 3mg by mouth three times a day, beginning on day +5 until discharge, for ES prophylaxis in all patients with a diagnosis of MM undergoing auto-HCT. Patients were divided into those who did not receive budesonide prophylaxis (n=169) and those who did receive budesonide prophylaxis (n=144). Primary endpoint was incidence of ES by each criteria. Secondary endpoints included receipt of steroids to treat ES, time to engraftment, and 30- and 100-day mortality rates. Exploratory endpoints were new start antibiotics in the peri-engraftment period and number of doses of anti-diarrheal and anti-emetic agents.

Overall, most patients were Caucasian or African-American, male, and the median age was 66 years. No difference existed between groups for any demographic factor including dose of melphalan, receipt of plerixafor, or median number of CD34 cells infused (all p>0.05). No difference existed between the two groups with respect to the primary outcome of incidence of ES by Spitzer, Maiolino, or Dhakal criteria or by provider documented ES (all p>0.05). Further, no difference existed between the groups with respect to the secondary or exploratory outcomes (all p>0.05); however, those who received budesonide were less likely to receive new treatment with an antibiotics within 3 days before or 10 days after neutrophil engraftment (20.9% vs 47.5%, p<0.001).

Our findings show budesonide does not appear to reduce the incidence of ES when utilizing Spitzer or Mailoino criteria. The low overall rates of ES by Spitzer, Mailoloino, and provider documentation in this study suggest a preventative strategy may not be warranted. However, reduction in incidence of new onset febrile neutropenia in the peri-engraftment period warrants further study.
Efficacy and Safety Profile of Busulfan Plus Low Dose Melphalan (BUMEL) Versus High Dose Melphalan (HDMEL) As a Conditioning Regimen for Autologous Hematopoietic Stem Cells Transplantation (Auto-SCT) in Multiple Myeloma Patients: A Systematic Review and Meta-Analysis
Authors: Kakar Imran , Maqbool Shahzaib , Rehman Abdur , Faraz Fatima , Shahzad Moazzam
Published: December 2024

Introduction:

Multiple myeloma (MM) is a hematological malignancy characterized by the abnormal proliferation of monoclonal plasma cells in the bone marrow, leading to symptoms such as bone pain, hypercalcemia, and renal dysfunction. A significant advancement in the treatment of MM is autologous hematopoietic stem cell transplantation, which has been effectively utilized to improve patient outcomes. This meta-analysis aims to explore the comparative efficacy and safety profile of Busulfan plus low dose Melphalan (BUMEL) versus High dose Melphalan (HDMEL) as a conditioning regimen for Autologous Hematopoietic stem cells transplantation in patients of Multiple Myeloma.

Methods:

A comprehensive literature review including 13 final studies was conducted using PubMed, Cochrane, and Embase. We included randomized controlled trials focused on patients with multiple myeloma treated with Busulfan plus low-dose Melphalan and high-dose Melphalan. A hazard ratio (HR) corresponding to a 95% confidence Interval (CI) was adopted to assess OS and PFS. The DerSimonian and Laird random effects model was used to pool Hazard ratios (HR) and dichotomous outcomes were pooled using risk ratio while continuously using Mean difference. The random effects model was used using the inverse variance method. a p-value of <0.5 was considered statistically significant.

Results:

The BUMEL-based conditioning regimen was found to be more favorable regarding progression-free survival (PFS) compared to the HDMEL regimen (HR 0.89; 95% CI 0.77-0.97, P = 0.006). However, overall survival (OS) was comparable between the two therapeutic groups, with no statistically significant difference observed (HR 1.12; 95% CI 0.82-1.43, P = 0.76). Regarding the safety profile, gastrointestinal side effects were less common with the BUMEL regimen (OR 0.81; 95% CI 0.57-0.90, P < 0.004) compared to HDMEL. Conversely, other side effects such as mucositis, infections, and hepatic toxicity were more prevalent with BUMEL-based therapy.

Conclusion:

In our meta-analysis, the BUMEL-based regimen demonstrated higher effectiveness in terms of progression-free survival (PFS), with this comparison being statistically significant. Although overall survival (OS) also favored the BUMEL-based therapy, there was no statistically significant difference between the two groups. The overall toxicity profile was higher in the BUMEL group, except gastrointestinal toxicity, which was less common, thus balancing the efficacy and safety profiles between the BUMEL and HDMEL regimens.

Keywords: Autologous Hematopoietic stem cell transplantation, BUMEL, HDMEL, Multiple Myeloma.
Mechanistic Investigation of Human DPP9 Deficiency
Authors: Xiao Tianli , Brewer James Richard , Zhou Liqun , Han Ailin , Takabe Yamato , Carlino Maximillian , Blackburn Holly Nicole , Flavell Richard
Published: December 2024

Inflammasomes serve as sensors of infection and cellular stress. Although studies of murine inflammasomes have shed key insights on their human counterpart, the regulation and components differ between mouse and human. For instance, the mouse genome contains homologs of human NLRP1 but not CARD8. However, studying human inflammasomes in vivo remains technically prohibitive. DPP9 is a negative regulator of human NLRP1 and CARD8, and patients with DPP9 deficiency exhibit pancytopenia and other immune-associated defects. However, Dpp9 deletion in conventional laboratory mouse strains do not recapitulate the loss of hematopoietic cells seen in patients, suggesting specie-specific functions. We study human DPP9 deficiency using a humanized mouse model called MISTRG6, which enables the development of human immune system after engraftment with primary human hematopoietic stem and progenitor cells (HSPCs). Using CRISPR editing approaches, we efficiently knock out DPP9 in human HSPCs and found that DPP9 deficiency led to pancytopenia due to the loss of human stem cells in vivo. We then sought to identify the inflammasome involved and found that CARD8 activation induced loss of human HSPCs, since simultaneous CARD8 and DPP9 deletion rescued pancytopenia and HSPC loss. In contrast, NLRP1 was dispensable for DPP9-induced pancytopenia. HSPCs undergo pyroptosis since concurrent caspase-1 deletion also rescues DPP9-/- HSPCs. Taken together, we identify a novel regulatory pathway of human hematopoiesis by a human-specific inflammasome, and find potential therapeutic targets for patients with DPP9 deficiency.
Lived Experiences and Coping Strategies of Adults with Sickle Cell Disease in Uganda: Implications for Improving Health and Well-Being
Authors: Ahebwe Shivan , Rujumba Joseph , Green Nancy S. S. , Idro Richard
Published: December 2024

Introduction: Sickle cell disease (SCD) is a significant contributor to childhood morbidity and mortality in Uganda and sub-Saharan Africa. However, with improvements in clinical care, many children have reached adulthood. However, there is a paucity of data on their experiences despite the importance of patient-reported perspectives to inform interventions for improving their quality of life. We explored the lived experiences and coping strategies of adults living with SCD in Kampala, Uganda.

Methods: We conducted a qualitative study at the oldest and largest sickle cell clinic in Uganda located at Mulago National Referral Hospital in Kampala between March and July 2022. Data were collected through in-depth interviews with 15 adults aged 25 to 40 years living with SCD attending the clinic, as well as five key informant interviews with healthcare workers at the sickle cell clinic, the Ministry of Health and a non-government organization providing support to people living with SCD. All interviews were audio recorded, transcribed verbatim and analyzed using a content thematic approach.

Results: The adults living with SCD described facing significant physical, social and emotional challenges such as stigma and discrimination at family, community and institutional levels in the context characterized by inadequate support. Furthermore, adults with SCD encountered difficulties in attaining education, securing employment and accessing health care services, each of which they perceive as having negatively affected their quality of life. The major coping strategies adopted were drawing on religious beliefs, striving to attain adherence to medical treatment and seeking support from their networks, especially their families.

Conclusions: The voices of adults living with SCD in this study depict the intersecting social, economic and psychological challenges and vulnerabilities that negatively affect the quality of life of affected adults. Stigma, challenges from health care, educational and vocational systems, as well as a general lack of formal support, dominate the everyday experiences of adults living with SCD in Uganda. Affected adults draw on religion, adherence to medical treatment and support, especially from their families, as major coping strategies. There is a need to strengthen support from health care, social, religious and vocational support for patients with SCD beyond childhood. Addressing this gap in support will require more investment from public and private sectors with local, national and global resources to optimize the health and well-being of young adults living with SCD.
Laboratory Reference Intervals Influence Referral Patterns for Hemoglobin Abnormalities in the Ontario Virtual Care System
Authors: Ahmad Maud , Hsia Cyrus , Chin-Yee Benjamin , Chin-Yee Ian , Hedley Benjamin
Published: December 2024

This retrospective cross-sectional study investigates the impact of laboratory-specific hemoglobin reference intervals on electronic consultation (eConsult) referral patterns for suspected anemia and elevated hemoglobin at a tertiary care center in London, Ontario that serves Southwestern Ontario.The study analyzed referrals through the Ontario Telemedicine Network's eConsult platform for hemoglobin abnormalities, excluding patients under 18 years old, between July 1, 2019, and June 30, 2023.The main outcome measures were influence of hemoglobin reference intervals on the referral patterns for suspected anemia and elevated hemoglobin, as well as the extent of pre-referral laboratory testing. Of the 619 eConsults reviewed, 251 referrals for suspected anemia and 93 for elevated hemoglobin were analyzed. Referral patterns showed significant variance in hemoglobin levels based on different laboratory thresholds. Referrals for suspected anemia in females from laboratories whose lower limit of normal was 120 g/L or greater had a hemoglobin concentration 7.5 g/L greater than referrals that used laboratories with a threshold lower than 120 g/L. The study also identified potential areas for improvement in pre-referral investigations; 44% of eConsults did not provide a ferritin level, 53% were missing a B12 level, and 81% were missing a reticulocyte count. In conclusion, laboratory reference intervals for hemoglobin significantly influence referral patterns for suspected hemoglobin abnormalities in Ontario's eConsult system. There is a need for standardized reference intervals and comprehensive pre-referral testing to avoid unnecessary medicalization and referrals. We propose an anemia management algorithm to guide primary care providers in the pre-referral investigation process.
Echinocandin-Resistant Candidemia, the Next Upcoming Threat in the Era of Echinocandin Prophylaxis Among Pediatric Hematological Malignancies in Limited Resources Countries
Authors: Madney Youssef , Khedr Reham , Hafiz Hanfy , Shalby Lobna , Gaber Mervat , ELsheshtawy Khaled , Adel Naglaa , Alhaddad Alaa
Published: December 2024

Background: Hematological cancer patients are at risk for developing candidemia, and echinocandins are commonly employed for prophylaxis in those patients. The rising resistance of Candida spp. to echinocandins poses an emerging threat. Our study aims to identify echinocandin-resistant Candida patterns and their impact on clinical outcomes among pediatric hematological malignancies in limited-resource countries.

Patients and Methods:From 2014 to 2020, Echinocandins were the primary antifungal prophylaxis for children with acute and relapsing leukemias. We conducted a retrospective analysis of patients with candidemia at the Children's Cancer Hospital Egypt (CCHE). The analysis included patterns of resistant Candida species and their outcomes. Breakthrough candidemia was defined as candidemia occurring during antifungal agent administration. Identification of Candida spp. was performed using the Vitek and Vitek2 systems.

Results: Three hundred fifty (350) pediatric cancer patients with candidemia were included in the study, with a median age of 4 years (range: 4 months to 18 years). The main underlying diseases were hematological malignancies (70%) with acute lymphoblastic leukemia being the most prevalent, followed by acute myeloid leukemia. Non-Albicans candida species constituted the majority (73%) of isolates compared to Candida Albicans (27%). The most frequently isolated species included: C. Albicans (27%), C.Tropicalis(29%), C.parapsilosis (21%), C. krusei (7%), C.glabrata(3%), C. famata (2%) and C. guilliermondii (1.5%). Resistant candida was reported among 74 (21%) patients. Echinocandin-resistant candida strains reported in 17(5%) patients: C. parasitosis (7), C. albicans (4), C. tropicalis (2), C. krusei (3) and C. lipolytica (1). Breakthrough candidemia occurred in 62 (17%) patients receiving echinocandin prophylaxis, with C. parapsilosis being the most common isolated pathogen (31 cases, 50%). Unfortunately, ten patients (16%) with breakthrough candidemia died secondary to candida sepsis syndrome. The overall 30 -day mortality rate was 24% (85/350 patients). Patients with Echinocandin-resistant candida were associated with high-risk mortality (20%).

Conclusion: Echinocandin-resistant Candida is a major threat in high-risk hematological pediatric cancer patients with a high mortality rate. Therefore, clinicians should pay attention to resistance and Breakthrough Candida even in patients under echinocandin prophylaxis. Antifungal stewardship may be helpful.
Relative Efficacy of Systemic Treatments for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: A Network Meta-Analysis According to 17p Deletion/TP53 Mutations
Authors: Kim Jinchul , Cho Jinhyun , Lim Joo Han , Lee Moon Hee , Lee Myung-Won
Published: December 2024

Introduction: The treatment landscape forrelapsed/refractory chronic lymphocytic leukemia (R/R CLL) has significantly advanced with the introduction of novel targeted therapies. Although these treatments have shown improved outcomes for R/R CLL patients, no single standard of care has been established. This network meta-analysis aims to evaluate the relative efficacy of systemic treatments for R/R CLL, focusing on key genetic mutations, specifically 17p deletion and TP53 mutations.

Methods: We conducted a systematic literature review to identify all publicly available randomized controlled trials (RCTs) using PubMed, EMBASE, the Cochrane database, and several meeting abstracts through February 2024. A Bayesian network meta-analysis with fixed-effects models was employed to estimate hazard ratios (HRs) for progression-free survival (PFS) with 95% credible intervals (CIs) across all treatment options and to determine the ranking of the included regimens. Ibrutinib was used as reference treatment.

Results: Twelve trials involving 4,437 patients and 13 treatment options were included in the meta-analysis: three Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, and zanubrutinib), two BTK inhibitors combined with other treatments (ibrutinib plus rituximab plus bendamustine [RB] and ibrutinib plus rituximab), two phosphoinositide 3-kinase (PI3K) inhibitors (idelalisib and duvelisib), three PI3K inhibitors combined with other treatments (idelalisib plus ofatumumab, idelalisib plus RB, idelalisib plus rituximab), three anti-CD20-based treatment (RB, ofatumumab, and rituximab), and one BCL-2 inhibitor (venetoclax plus rituximab). Venetoclax plus rituximab and zanubrutinib emerged as the most effective treatments for the overall R/R CLL population, showing the lowest hazard ratios (HR 0.62, 95% CI 0.32-1.20 and HR 0.65, 95% CI 0.49-0.86, respectively) versus ibrutinib, and were ranked as the best agents (surface under the cumulative ranking curve [SUCRA] value of 90% for both) among the included drugs. In the 17p deletion/TP53 mutation subgroup, zanubrutinib demonstrated the most favorable efficacy (HR 0.52, 95% CI 0.31-0.88 versus ibrutinib) with the highest SUCRA value (97%). For patients without these mutations, venetoclax plus rituximab was the most effective (HR 0.49, 95% CI 0.26-0.94 versus ibrutinib) with a SUCRA value of 94%.

Conclusions: Our findings highlight the superior efficacy of venetoclax plus rituximab and zanubrutinib for treating R/R CLL and confirm that the role of each regimen may vary depending on clinically significant mutations.
A Phase II Investigator-Initiated Trial of Epcoritamab with Gemcitabine, Dexamethasone, and Cisplatin (GDP) Salvage Chemotherapy in Relapsed Refractory Large B-Cell Lymphoma
Authors: Modi Dipenkumar , Kim Seongho , Domagalski Mary , Mittal Varun
Published: December 2024

Background and Significance: Approximately 30% of patients with large B cell lymphoma (LBCL) relapse after receiving rituximab-containing chemoimmunotherapy. Patients with rapidly progressing and symptomatic disease often require effective bridging therapy while awaiting CAR T-cell therapy. In addition, a salvage chemotherapy, which offers high response rates, is warranted to improve long-term outcomes. Epcoritamab is a CD3xCD20 bispecific antibody approved for relapsed refractory (RR) DLBCL after ≥2 prior lines of therapy. We hypothesized that the combination of epcoritamab, and gemcitabine, dexamethasone, and cisplatin (GDP) salvage chemotherapy could be effective for RR LBCL patients eligible for CAR T-cell therapy or stem cell transplant.

Study Design and Methods: This is a phase II investigator-initiated multicenter trial evaluating safety and efficacy of epcoritamab with GDP salvage chemotherapy in RR LBCL. Key eligibility criteria will include patients ≥18 years of age with CD20 positive RR LBCL with an eligible subtype, ³1 prior line of therapy, and eligible for CAR T-cell therapy or stem cell transplant (SCT), ECOG PS 0-2, and FDG avid and measurable disease by PET. All patients will receive 3 cycles of epcoritamab and GDP in the outpatient setting. No hospitalization for CRS monitoring is mandated. Epcoritamab will be administered subcutaneously during cycle 1 as weekly step-up doses (0.16/0.8/48 mg) and then weekly from cycle 2 day 1(cycle 2-3). GDP consists of gemcitabine 1000 mg/m2 IV on days 1 and 8, cisplatin 75 mg/m2 IV on day 1, and dexamethasone 40 mg orally days 1 through 4. Patients can proceed to CAR T-cell therapy or SCT upon completion of cycle 3 per investigator discretion. Patients who do not undergo CAR T-cell therapy or SCT may remain in the study and receive epcoritamab monotherapy for 6 cycles (cycle 4 through cycle 9, each cycle= 28 days), or until unacceptable toxicity, or disease progression per the Lugano Criteria.

The primary end point is complete remission (CR) rate per the Lugano criteria. Secondary end points include overall response rate, duration of response, progression-free survival, overall survival, safety and tolerability of epcoritamab and GDP, and feasibility of peripheral blood T-lymphocytes collection or stem cell mobilization. The sample size is justified using Simon's two-stage minimax design for the alternative CR rate of 65% against the null CR rate of 40%. In the first stage, 14 patients will be accrued. If there are 5 or less CR in these patients, the study will be stopped. Otherwise, 18 additional patients will be accrued for a total of 32. This design will yield a 1-sided type I error rate of 2.5% and power of 80% when the true CR rate is 65%. The study is currently enrolling. The clinicalTrials.gov ID is NCT05852717.
Exploring the Interplay between Anxiety, Depression, and Quality of Life Following Pulmonary Embolism
Authors: Rajasekar Bhairavi , Hurley Karen , Cameron Scott J , Tefera Leben
Published: December 2024

Background

Pulmonary embolism (PE) is the third leading cause of cardiovascular death. It has been shown to be accompanied by significant decreases in quality of life. The prevalence and longitudinal trends of anxiety, depression, and quality of life in PE patients remains largely understudied.

Methods

We conducted a prospective observational study examining 192 PE patients attending a dedicated Pulmonary Embolism Response Team (PERT) Clinic. Participants completed standardized assessments using the Pulmonary Embolism Quality of Life (PEmb-QoL) Questionnaire, Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire (PHQ-9) following their PE diagnosis and ensuing treatment.

Results

Our findings revealed noteworthy gender disparities in the psychological impact of PE on survivors. Of the 192 participants, 51% were women and 49% were men. Among women, 42% reported anxiety and 44% reported depression. Through all dimensions evaluated by the PEmb-QoL, women reported a lower quality of life post-PE. Patients with higher levels of anxiety and depression experienced worse quality of life. Younger patients reported worse quality of life in the categories of increased frequency of complaints and emotional complaints. They additionally expressed greater feelings of worry in ceasing anticoagulant medications in comparison to older counterparts.

Conclusion

This study represents one of the largest dedicated prospective studies to date to examine the psychological impact of PE on patients' psyche and quality of life, highlighting the significant psychological toll of PE on patients' recovery. We noted women experienced higher rates of anxiety and depression and lower overall quality of life scores when compared to men. Furthermore, regardless of gender, we observed a decrease in quality of life with the prevalence of anxiety and depression. The results indicated that age influenced a patient's tendency to report worse quality of life. These findings underscore the importance of psychosocial support strategies in addressing the emotional needs of patients in the aftermath of a PE diagnosis.

Learning Objective

Disparities in anxiety and depression prevalence following PE diagnosis and treatment exist. This study highlights the importance of implementing tailored psychosocial support strategies to address the unique emotional needs of PE patients, particularly among women and younger patients.
Fast pH-Driven Solubilization Method of Realgar (As4S4) to Reduce the Toxicity of Arsenic [As(III)] for Therapeutic Use Against Acute Promyelocytic Leukemia and HIV
Authors: Lucic Bojana , Franciscato Douglas Santana , Curcio Marli , Nogueira Helton Pereira , Gallucci Lara , Junior Alceu Totti Silveira , Ismail Asma , Robinson Millie , Dallinger Teresa , Toledo Maytê , Dias Jessica , Tarek Mohammad , Dias Danilo , Sobhie Diaz Ricardo , ElHefnawi Mahmoud , Forcato Mattia , Monteiro Hugo , Lusic Marina , Shutaj Iart Luca , Savarino Andrea
Published: December 2024

Background: Acute promyelocytic leukemia (APL) accounts for 5-15% of acute myeloid leukemia cases. It is characterized by the (15;17) chromosomal translocation, producing the pathogenic retinoic acid receptor (RAR) alpha/promyelocytic leukemia (PML) fusion protein. Recently, remission of APL has been achieved using the first chemotherapy-independent oral drug regimen in anticancer therapy, consisting of all-trans retinoic acid (targeting RARalpha) and the arsenic sulfide realgar (targeting PML). However, clinical adoption of realgar and the characterization of its active breakdown products have been hampered by its poor solubility.Methods: Here, we describe a scalable pH/temperature-based process that partially mimics gut transition, achieving fast and reproducible solubilization of realgar. Five different spectroscopic and spectrometric techniques were employed to characterize solubilized realgar.Results: In solubilized realgar, we identified novel arsenic-derivative therapeutic candidates. Furthermore, we found that these solubilized compounds target PML, displaying wider in vitro therapeutic indices and lower off-target effects than arsenic trioxide, the current APL standard of care. Moreover, in line with evidence of an interplay between PML and HIV persistence, solubilized realgar can disrupt HIV latency, the main barrier to an HIV/AIDS cure, in CD4 T cells of people living with HIV.Conclusion: These findings may open avenues for streamlining realgar solubilization and designing less toxic, orally administrable arsenic-based therapies.
Targeting CDK16 Abrogates Growth-Factor Mediated TKI Resistance in AML
Authors: Kesarwani Meenu , Kincaid Zachary , Azhar Mohammad , Azam Mohammad
Published: December 2024

Introduction. Mutations in the Fms-like tyrosine kinase 3 (FLT3) gene are among the most common genetic lesions in AML, associated with poor prognosis and high relapse rates. Targeted TKI therapies against FLT3 have shown promise, yet clinical resistance remains a significant challenge. Using phospho and chemiproteomic analyses of FLT3ITD expressing cells revealed CDK16 drive treatment resistance to chemotherapy during growth factor signaling. Targeting CDK16 in combination with FLT3 tyrosine kinase inhibitor (TKI) or BCL2 inhibitor show synergistic response and significantly prolonged the survival of mice harboring AML.

Result. Using mouse cell lines expressing FLT3ITD treated with gilteritinib with and without growth factors (growth factor signaling confers resistance to TKI) were subjected to whole genome phosphoproteome and total proteome analyses. This analysis revealed significant changes in abundance and phosphorylation of CDK and MAPK family members in resistant cells. Notably, we noted persistent upregulation of CDK2, CDK 12, CDK13 and CDK20 in TKI resistant cells. Using CRISPR-CAS9 mediated knock-out of these target genes revealed that deletion of CDK12, CDK13 and CDK16 confers strong sensitivity to TKI treatment. Our findings demonstrate that CDK16 inhibition significantly reduces cell viability, induces apoptosis, and impairs clonogenic potential in FLT3-mutated AML cells. Mechanistically, CDK16 inhibition disrupts key signaling pathways that stabilizes P53, highlighting its potential to overcome resistance to FLT3-targeted therapies. Moreover, in vivo studies using xenograft models of FLT3-mutated AML revealed that CDK16 inhibition markedly suppresses tumor growth and enhances overall survival. These results suggest that CDK16 inhibitors could serve as a novel therapeutic strategy for FLT3-mutated AML, either as monotherapy or in combination with existing FLT3 inhibitors.

Conclusions. Our research underscores the therapeutic potential of CDK16 inhibition in FLT3-mutated AML, providing a compelling rationale for the clinical evaluation of CDK16 inhibitors in this challenging subset of AML patients. Further studies are warranted to explore the full therapeutic implications and to optimize combination strategies for improved patient outcomes.
Impact of Age on Autologous Stem Cell Transplantation Outcomes for AL Amyloidosis
Authors: Sami Sophiya S , Bashir Qaiser , Saini Neeraj Y. , Aljawai Yosra M. , Hosing Chitra , Popat Uday , Becnel Melody R. , Kaufman Gregory P. , Thomas Sheeba K. , Weber Donna M. , Orlowski Robert Z. , Champlin Richard E. , Shpall Elizabeth J. , Qazilbash Muzaffar H. , Srour Samer A.
Published: December 2024

Introduction:

Consolidation with high-dose chemotherapy and autologous stem cell transplantation (ASCT) for patients with light chain amyloidosis (AL) is associated with deeper responses and improved outcomes. Several factors are known to be associated with worse outcomes. Older patients with AL frequently present with more advanced disease and have generally inferior outcomes compared to younger patients. In this study, we aimed to explore the impact of age on survival outcomes for AL patients who underwent ASCT at our institution.

Methods:

All consecutive patients with AL who underwent their first ASCT between 09/2005 and 11/2021, using a single agent melphalan conditioning regimen, were included. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included non-relapse mortality (NRM).

Results:

One-hundred-and-seventy-nine patients (109 males, 70 females) with a median age of 61 years (range, 27-77) were identified during the study period. Among these 102 (57%) were in the older age group (≥60 years) and 77 (43%) were in the younger age group (<60). Overall, there were no notable differences in baseline patient and disease characteristics between the two age groups, but a higher proportion of patients in the older group had an estimated glomerular filtration rate (eGFR) of <50 (31% vs. 19%, p=0.0765). With a median follow-up of 62 months (range 3.2-167.4), the 5-year PFS and OS for all study patients were 49% and 72%, respectively. The 5-year PFS for patients ≥60 was 44% compared to 55% for patients <60 (p=0.1022). The 5-year OS rate for patients ≥60 was 66% versus 80% for patients age <60 years (p=0.0081). The 1-year NRM was 11% for patients ≥60 compared to 2.6% for patients <60 (p=0.1246). Age and variables with p-value ≤0.15 in univariate analyses were included in multivariable analyses (MVA) for OS (HCT-Comorbidity Index, Beta-2 microglobulin, eGFR, Cardiac Involvement, Revised Mayo Staging). Age ≥60 (HR: 3.075; 95% CI: 1.374-6.884; p=0.0063) and Revised Mayo Stage III/IV (HR: 2.576, 95% CI: 1.145-5.796; p=0.0221) were significantly associated with inferior OS in MVA. In a subgroup analysis stratifying patients by their age and Revised Mayo Staging, patients age ≥60 with Mayo Stage III/IV had significantly inferior 5-year PFS/OS of 27%/37% vs 53%/77% vs. those in the same age group but with Mayo Stage I/II (p=0.02 for PFS; p=0.0012 for OS).

Conclusions:

For AL patients undergoing ASCT, our findings suggest that older patients with Mayo Stage I/II age have excellent long-term outcomes. Revised Mayo stage III/IV combined with age ≥60 years were predictive of poor outcomes, which warrants alternative treatment strategies for these patients.
Combined Coagulation Factor XI and Factor XII Deficiencies in an Asymptomatic Black Female
Authors: Rupani Karishma Vijay , Hawkins Katherine A. , Walsh Christopher
Published: December 2024

Background: While there are multiple studies describing combined coagulation factor deficiencies, their genetic defects and clinical significance remain largely unknown. We present the case of an asymptomatic Black female with deficiencies of both coagulation factor XI and factor XII. To our knowledge, the combination of coagulation factor XI and XII deficiencies has not previously been reported in a Black individual.

Case Report: In April 2024, a healthy 29 year old Black female from Honduras without personal or family history of bleeding or bruising, presented with a prolonged activated partial thromboplastin time (aPTT) that was incidentally found during a routine pre-operative evaluation for elective cosmetic surgery. Her prothrombin time (PT) was normal. Her aPTT was prolonged to 43.4 seconds (reference interval 25.4 - 34.9 seconds) and normalized with 1:1 mixing studies of patient and normal plasma. She was therefore evaluated for deficiencies in factors VIII, IX, and XI, as well as for the presence of a lupus anticoagulant. Her factor VIII and IX levels were normal. No lupus anticoagulant was detected. Her factor XI levels were decreased: 47% in April 2024, 56% in June 2024, and 58% in July 2024 (reference range 60 - 150%). Her factor XII levels were also decreased at 39% in April 2024 and borderline normal at 51% in July 2024 (reference range 50 - 150%). She has no past medical history and has never had excessive bleeding. She has been pregnant once and delivered a healthy baby via an uncomplicated spontaneous vaginal delivery at full term.

Conclusion: Although detection and identification of combinations of coagulation factor deficiencies is readily available, their underlying genetic defects and clinical significance requires ongoing investigation.
Outcomes and Associations in Hospitalized Patients with Concomitant Helicobacter Pylori Infection and Idiopathic Thrombocytopenic Purpura(ITP)
Authors: Olusoji Rahman , Abbey Enoch , Akpoigbe Kesiena , Genao Alvaro , Ahluwalia Meena
Published: December 2024

Background

Studies have shown that H. pylori infection could be associated with Idiopathic Thrombocytopenic (ITP) in some patients. Multiple studies have also reported improvement and resolution of ITP after H. pylori eradication therapy in these patients. This study explores adverse outcomes in hospitalized patients with ITP and H pylori infection, explicitly focusing on mortality rates and length of stay in affected patients.

Methods

This retrospective cohort study utilized the 2018 to 2020 National Inpatient Sample (NIS) database. The inclusion criteria included adults aged 18 and above diagnosed with idiopathic thrombocytopenic purpura during hospitalization, with or without H pylori infection. We defined ITP and H. pylori infection using ICD-10 codes. We analyzed the demographic data of these patients and their correlation with hospital outcomes, including length of stay, hospitalization costs, and mortality rates. Using univariate and multivariate logistics regression models, we measured mortality as the primary outcome.

Result

We identified 149,780 patients with ITP, among whom 350 (0.2%) had concomitant diagnosis of H. pylori infection. ITP patients were primarily female and white, with a mean age of 61. Patients with concomitant H. pylori infection had a significantly more extended stay of nine vs. seven days, p=0.02. Individuals with H. pylori infection exhibited lower odds of death on univariable and after multivariable regression. However, this fails to meet statistical significance [0.32, 95% CI (0.04-2.30)] and [0.30, 95% CI (0.04-2.16)], likely underpowered by the rarity of co-existing pathology.

Conclusion

Our study shows that the mortality odds among individuals with idiopathic thrombocytopenic purpura were lower in patients with concurrent H. pylori infection than those without H pylori. Though limited by statistical power, it gives credence to previous studies showing that treating co-existing H pylori infections may permanently lead to platelet recovery and possible resolution of their ITP.
Agent Orange Exposure and Myelodysplastic Syndrome: A Single VA Medical Center Experience
Authors: Domb Chaim , O'Brien Timothy
Published: December 2024

Background:

Agent Orange (AO) exposure may be linked to the development of myeloid malignancies, including myelodysplastic syndrome (MDS). This is not yet definitive, though, and, unlike several other malignancies, MDS is not yet a service-connected diagnosis for AO exposed veterans. Although recent studies have not revealed AO associated specific mutations in MDS, clinical and pathological potential differences have not been well studied. In addition, determination of AO exposure is often not reported.

Methods:

All veterans diagnosed with MDS at the Cleveland VAMC from 2012-2023 were identified. Prior AO exposure was determined by Military Exposure tab in the EMR and confirmed with direct patient contact. Data collected included age and IPSS-R score at diagnosis; ring sideroblast percentage; mutations (on NGS); progression to AML and overall survival (OS).

Results:

129 veterans were identified, 48 of whom had AO exposure. The mean age was 70.7 years in the AO group and 73.3 in the non-AO group (p=0.098); average IPSS-R score was 3.14 in AO and 2.75 in non-AO group (p= 0.32). 8 (6%) of pts had high risk IPSS-R (4 in each group); 29 (22%) pts had intermed risk (13 AO and 10 non-AO exposed) and 92 pts (71%) were low risk (31 AO and 61 non-AO). In the AO group 4/48 (8.3%) progressed to AML vs 10/81 (12.3%) in the non-AO group; median OS was 39 months in AO vs 33 months in non-AO group (p=0.93). The most common mutations seen were TP53 (17%), SF3B1 (21%), SRSF2 (23%), DNMT (10%), ASXL1 (11%), and U2AF1 (11%), with no differences between the 2 groups. 50% of those in the AO group had 2 or more genetic mutations vs. 61% for the non-AO group. Average variant allele frequency (VAF) was 40.2% in the AO group vs. 44% in the non-AO group. 9/48 (19%) of pts in the AO group met criteria for MDS-RS vs 12/81 (15%) in the non-AO group (p= 0.74). The average ring sideroblasts seen was 6% for the AO group compared to 5.7% for the non-AO group, p = 0.89.

Conclusion:

This small retrospective study did not reveal statistically significant differences between AO vs non-AO exposed veterans with MDS, in terms of age at diagnosis, IPSS-R score, RS %, mutations (type, number or VAF load), progression to AML or OS. There were trends for AO exposed veterans presenting at a younger age and having a lower rate of progression to AML. Although we did not find any phenotypic or genotypic differences this was not a study of causality and does not exclude AO being associated with increased risk for MDS.
Hypoalbuminemia Increases Clot Fibrin Network Density and Reduces Fibrinolytic Susceptibility through a Paraoxonase 1 Dependent Mechanism
Authors: Waller Amanda , Wolfgang Katelyn , Stevenson Zachary , Kerlin Bryce
Published: December 2024

Introduction

Hypoalbuminemia is a predictor for thrombotic cardiovascular disease. Albumin is a negative acute phase reactant and may thus be a biomarker for thrombo-inflammation, but some data suggest a mechanistic role for albumin in fibrinolysis. The aim of this study was to investigate the mechanistic role of albumin in fibrinolysis. We hypothesized that albumin modifies clot structure and fibrinolytic susceptibility in two well-established rodent models of hypoalbuminemia and analbuminemia.

Methods

Blood or plasma from a hypoalbuminemic nephrotic syndrome rat model and an albumin knockout rat model were analyzed by thromboelastometry, clot lysis assays, fibrin clot turbidity, fibrin clot density, and plasma clot immunoblotting. Some studies were conducted without vs. with recombinant albumin repletion. We mined albumin and fibrin clot proteome datasets to identify proteins both carried by albumin and incorporated in clots, hypothesizing that albumin delivers proteins that alter fibrinolytic susceptibility to the forming clot.

Results

Albumin levels were proportional to fibrinolysis in a clot lysis assay in both nephrotic and albumin knockout rat plasma. Hypoalbuminemia accelerated fibrin clot formation in nephrotic rat plasma and fibrin clot network density was increased in hypoalbuminemic plasma clots from both nephrotic rats (p<0.01) and albumin knockout rats (p<0.001). Recombinant albumin repletion to healthy control concentrations corrected fibrin network density and fibrinolysis in both nephrotic rat and human plasma as well as in albumin knockout rat plasma (p<0.05). Paraoxonase 1 (PON1) enzyme was identified in both albumin and fibrin clot proteomes. Naringenin, a PON1-specific inhibitor decreased fibrin clot lysis in normal rat plasma in a dose-dependent manner (IC50= 1 uM; p<0.001), but did not alter clot lysis in albumin knockout plasma (p>0.9). Moreover, naringinen ameliorated the ability of recombinant albumin repletion to correct hypofibrinolysis (p<0.001 vs control).

Conclusions

Dense hypoalbuminemic clots demonstrated hypofibrinolysis, and albumin repletion corrected both clot density and hypofibrinolysis. PON1 inhibition decreased clot lysis in plasma with normal albumin levels and ameliorated the ability of albumin repletion to correct fibrinolysis in albumin knockout plasma. Collectively, these data suggest a mechanistic link between hypoalbuminemia and hypofibrinolysis and suggest that albumin indirectly regulates fibrinolysis via its effects on clot density, through a PON1 dependent mechanism.