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Haematologica Oct 2023Under normal conditions, iron metabolism is carefully regulated to sustain normal cellular functions and the production of hemoglobin in erythroid cells. Perturbation to... (Review)
Review
Under normal conditions, iron metabolism is carefully regulated to sustain normal cellular functions and the production of hemoglobin in erythroid cells. Perturbation to the erythropoiesis-iron metabolism axis can result in iron imbalances and cause anemia or organ toxicity. Various congenital and acquired diseases associated with abnormal red cell production are characterized by aberrant iron absorption. Several recent studies have shown that improvements in red blood cell production also ameliorate iron metabolism and vice versa. Many therapeutics are now under development with the potential to improve a variety of hematologic diseases, from β-thalassemia and iron-refractory iron deficiency anemia to anemia of inflammation and polycythemia vera. This review summarizes selected mechanisms related to red cell production and iron metabolism and describes potential therapeutics and their current uses. We also consider the potential application of the discussed therapeutics on various diseases, alone or in combination. The vast repertoire of drugs under development offers new opportunities to improve the clinical care of patients suffering from congenital or acquired red blood cell disorders with limited or no treatment options.
Topics: Humans; Erythropoiesis; Erythrocytes; Anemia, Iron-Deficiency; Iron; beta-Thalassemia; Hematologic Diseases
PubMed: 37345473
DOI: 10.3324/haematol.2023.283057 -
Clinical Cardiology Jan 2024Pulmonary arterial hypertension (PAH) is a widespread condition that affects around 1% of the global population, with a higher prevalence among older individuals. The... (Meta-Analysis)
Meta-Analysis Review
Pulmonary arterial hypertension (PAH) is a widespread condition that affects around 1% of the global population, with a higher prevalence among older individuals. The approach to managing PAH has undergone significant changes, requiring extensive treatment strategies. Sotatercept, an FDA-approved medication, has recently attracted attention for its potential role in PAH therapy. However, information on its safety and effectiveness is scarce. In this study, we performed a meta-analysis of existing randomized clinical trials to assess the impact of Sotatercept on PAH patients. Our findings revealed that those treated with Sotatercept showed greater improvement in pulmonary vascular resistance and World Health Organization functional class compared with placebo recipients. The occurrence of adverse events was similar between both groups. Importantly, the Sotatercept group displayed a considerably higher number of cases with an increase in hemoglobin levels. Considering that about 33% of PAH patients experience anemia and both anemia and polycythemia can adversely affect disease prognosis, additional research is necessary to establish the potential advantages and disadvantages of Sotatercept as a treatment choice, specifically regarding its erythropoietic properties.
Topics: Humans; Anemia; Prognosis; Pulmonary Arterial Hypertension; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins
PubMed: 37819149
DOI: 10.1002/clc.24173 -
Expert Opinion on Drug Safety Jan 2024Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm hallmarked by deregulated proliferation of hematopoietic stem cells leading to prevalent expansion of red... (Review)
Review
INTRODUCTION
Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm hallmarked by deregulated proliferation of hematopoietic stem cells leading to prevalent expansion of red cell mass, increased rate of vascular events, splenomegaly, disease-associated symptoms, and risk of evolution to secondary myelofibrosis and blast phase. PV is pathogenetically associated with autonomously persistent activation of JAK2, which causes overproduction of blood cells and an inflammatory condition responsible for the clinical manifestations of the disease. Extensively supported by preclinical studies, targeting JAK2-dependent signaling represents a rational therapeutic approach to PV, finally leading to the approval of ruxolitinib, a JAK1/2 inhibitor.
AREAS COVERED (LITERATURE RESEARCH)
We analyzed reports of phase 2 and phase 3 trials with ruxolitinib in PV and relevant literature dealing with efficacy and safety aspects, including most recent real-world reports.
EXPERT OPINION
Ruxolitinib is the only JAK2 inhibitor approved for the treatment of PV with well-known efficacy for splenomegaly, symptoms, and potentially reduction of vascular events. The treatment regimen is notably manageable and safe, with the most prevalent side effects primarily encompassing myelosuppression, hyperlipidemia, non-melanoma skin cancer and infections, mainly reactivation of Herpes Zoster. These effects necessitate ongoing surveillance and proactive preventive measures.
Topics: Humans; Polycythemia Vera; Splenomegaly; Nitriles; Pyrimidines; Janus Kinase Inhibitors; Pyrazoles
PubMed: 38156903
DOI: 10.1080/14740338.2023.2299391 -
International Journal of Molecular... Aug 2023The Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis... (Review)
Review
The Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are enduring and well-known conditions. These disorders are characterized by the abnormal growth of one or more hematopoietic cell lineages in the body's stem cells, leading to the enlargement of organs and the manifestation of constitutional symptoms. Numerous studies have provided evidence indicating that the pathogenesis of these diseases involves the dysregulation of the immune system and the presence of chronic inflammation, both of which are significant factors. Lately, the treatment of cancer including hematological malignancy has progressed on the agents aiming for the immune system, cytokine environment, immunotherapy agents, and targeted immune therapy. Immune checkpoints are the molecules that regulate T cell function in the tumor microenvironment (TME). The first line of primary immune checkpoints are programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Immune checkpoint inhibitor therapy (ICIT) exerts its anti-tumor actions by blocking the inhibitory pathways in T cells and has reformed cancer treatment. Despite the impressive clinical success of ICIT, tumor internal resistance poses a challenge for oncologists leading to a low response rate in solid tumors and hematological malignancies. A Phase II trial on nivolumab for patients with post-essential thrombocythemia myelofibrosis, primary myelofibrosis, or post-polycythemia myelofibrosis was performed (Identifier: NCT02421354). This trial tested the efficacy of a PD-1 blockade agent, namely nivolumab, but was terminated prematurely due to adverse events and lack of efficacy. A multicenter, Phase II, single-arm open-label study was conducted including pembrolizumab in patients with primary thrombocythemia, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. This study showed that pembrolizumab treatment did not have many adverse events, but there were no pertinent clinical responses hence it was terminated after the first stage was completed. To avail the benefits from immunotherapy, the paradigm has shifted to new immune checkpoints in the TME such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain immunoglobulin-containing suppressor of T cell activation (VISTA), and human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) forming the basis of next-generation ICIT. The primary aim of this article is to underscore and elucidate the significance of next-generation ICIT in the context of MPN. Specifically, we aim to explore the potential of monoclonal antibodies as targeted immunotherapy and the development of vaccines targeting specific MPN epitopes, with the intent of augmenting tumor-related immune responses. It is anticipated that these therapeutic modalities rooted in immunotherapy will not only expand but also enhance the existing treatment regimens for patients afflicted with MPN. Preliminary studies from our laboratory showed over-expressed MDSC and over-expressed VISTA in MDSC, and in progenitor and immune cells directing the need for more clinical trials using next-generation ICI in the treatment of MPN.
PubMed: 37569880
DOI: 10.3390/ijms241512502 -
Data in Brief Oct 2023Tumorous cancer has been a widely known and well-studied medical phenomenon; however, rare diseases like Myeloproliferative Neoplasm (MPN) have received less attention,...
Tumorous cancer has been a widely known and well-studied medical phenomenon; however, rare diseases like Myeloproliferative Neoplasm (MPN) have received less attention, leading to delayed diagnosis. Despite the availability of advanced technology in diagnostic tools that can boost the procedure, the morphological assessment of bone marrow trephine (BMT) images remains critical to confirm and differentiate MPN subtypes. This paper reports a histopathological imagery dataset that was created to focus on the most common MPN from the Philadelphia Chromosome (Ph)-negative type, namely Essential Thrombocythemia (ET), Polycythemia Vera (PV), and Primary Myelofibrosis (MF). The dataset consisted of 300 BMT images that can be used to enable computer vision applications, such as image segmentation, disease classification, and object recognition, in assisting the classification of the MPN disease. Ethical approval was obtained from the Ministry of Health, Malaysia and the bone marrow trephine images were captured using a digital microscope from the Olympus model (BX41 Dual head microscope) with x10, x20, and x40 lens types. The development of comprehensive tools deployed from this dataset can assist medical practitioners in diagnosing diseases, thus overcoming the current challenges.
PubMed: 37636134
DOI: 10.1016/j.dib.2023.109484 -
Cancers Aug 2023Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10-30 years... (Review)
Review
Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10-30 years from the earliest cancer stages (essential thrombocythemia, polycythemia vera) towards the advanced myelofibrosis stage with bone marrow failure. The mutation is the most prevalent driver mutation. Chronic inflammation is considered to be a major pathogenetic player, both as a trigger of MPN development and as a driver of disease progression. Chronic inflammation in MPNs is characterized by persistent connective tissue remodeling, which leads to organ dysfunction and ultimately, organ failure, due to excessive accumulation of extracellular matrix (ECM). Considering that MPNs are acquired clonal stem cell diseases developing in an inflammatory microenvironment in which the hematopoietic cell populations are progressively replaced by stromal proliferation-"a wound that never heals"-we herein aim to provide a comprehensive review of previous promising research in the field of circulating ECM fragments in the diagnosis, treatment and monitoring of MPNs. We address the rationales and highlight new perspectives for the use of circulating ECM protein fragments as biologically plausible, noninvasive disease markers in the management of MPNs.
PubMed: 37686599
DOI: 10.3390/cancers15174323 -
American Journal of Respiratory and... Sep 2023Precapillary pulmonary hypertension (PH) is a rare and largely unrecognized complication of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV),...
Precapillary pulmonary hypertension (PH) is a rare and largely unrecognized complication of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). To describe characteristics and outcomes of MPN-associated PH. We report clinical, functional, and hemodynamic characteristics, classification, and outcomes of patients with PV, ET, or primary MF in the French PH registry. Ninety patients with MPN (42 PV, 35 ET, 13 primary MF) presented with precapillary PH with severe hemodynamic impairment, with a median mean pulmonary arterial pressure and pulmonary vascular resistance of 42 mm Hg and 6.7 Wood units, respectively, and impaired clinical conditions, with 71% in New York Heart Association functional classes III/IV and having a median 6-minute-walk distance of 310 m. Half of the patients were diagnosed with chronic thromboembolic PH (CTEPH); the other half were considered to have group 5 PH. MF was preferentially associated with group 5 PH, whereas PV and ET were generally related to CTEPH. Proximal lesions were diagnosed in half of the patients with CTEPH. Thromboendarterectomy was performed in 18 selected patients with high risk of complications (5 early deaths). Overall survival at 1, 3, and 5 years was 67%, 50%, and 34% in group 5 PH and 81%, 66%, and 42% in CTEPH, respectively. PH is a life-threatening condition potentially occurring in MPN. There are multiple mechanisms, with equal diagnoses of CTEPH and group 5 PH. Physicians should be aware that PH strongly affects the burden of patients with MPN, especially in group 5 PH, with unknown pathophysiological mechanisms.
Topics: Humans; Hypertension, Pulmonary; Myeloproliferative Disorders; Polycythemia Vera; Thrombocythemia, Essential; Registries
PubMed: 37311222
DOI: 10.1164/rccm.202210-1941OC -
Transgender Health Dec 2023We assessed the efficacy and short-term adverse effects of testosterone pellet use in transgender men to broaden therapeutic options.
PURPOSE
We assessed the efficacy and short-term adverse effects of testosterone pellet use in transgender men to broaden therapeutic options.
METHODS
We conducted a retrospective study of 30 transgender men who started testosterone pellets between 2018 and 2020.
RESULTS
Testosterone pellets were started at dosages 675-825 mg per cycle and dose was adjusted according to testosterone levels obtained 1 to 6 months post-testosterone pellet insertion. Pharmacokinetics of testosterone pellet in transgender men was similar to those in cisgender men. Total testosterone levels reached a peak in 1 month and remained in the therapeutic range for ∼4 months in the range of 300-800 ng/dL. After switching over to testosterone pellets, 100% of patients continued to achieve amenorrhea and deepening of their voice. Most of the patients noticed increased hair growth in androgen-dependent regions (96.3%) and improved libido (70%). Adverse events were notable for a rate of polycythemia that was unexpectedly high at 46.67%. Pellet extrusion was found in 13.33% of patients. There was a low rate of pellet site hematoma (6.67%) and cellulitis (3.33%). No thromboembolic or cardiovascular events occurred in any of the patients.
CONCLUSION
This study reveals that testosterone pellets are a reasonable alternative to other testosterone modalities in transgender men but would use caution in patients with a history of polycythemia or higher risk for thromboembolic events.
PubMed: 38130978
DOI: 10.1089/trgh.2021.0205 -
Hematology (Amsterdam, Netherlands) Dec 2023This Japanese cross-sectional survey evaluated the symptoms, daily living activities, and treatment needs of patients with polycythemia vera (PV), as perceived by...
OBJECTIVES
This Japanese cross-sectional survey evaluated the symptoms, daily living activities, and treatment needs of patients with polycythemia vera (PV), as perceived by patients themselves and their physicians.
METHODS
The study was conducted at 112 centers (March to July 2022) and included PV patients aged ≥20 years ( = 265) and their attending physicians ( = 151). The patient and physician questionnaires included 34 and 29 questions, respectively, to assess daily living, PV symptoms, treatment goals, and physician-patient communication.
RESULTS
Concerning daily living (primary endpoint), work (13.2%), leisure activities (11.3%), and family life (9.6%) were most affected by PV symptoms. Patients aged <60 years more frequently reported an impact on daily living than patients aged ≥60 years. Some patients (30%) reported anxiety about their future condition. The most common symptoms were pruritus (13.6%) and fatigue (10.9%). Pruritus was ranked as the first treatment need for patients, while physicians ranked it fourth. Concerning treatment goals, physicians prioritized thrombosis/vascular event prevention, while patients prioritized delaying PV progression. Physicians were less satisfied with physician-patient communication than patients.
CONCLUSIONS
Patients' daily living was largely affected by PV symptoms. There are differences in physician and patient perceptions of symptoms, daily living, and treatment needs in Japan.
TRIAL REGISTRATION
UMIN Japan identifier: UMIN000047047.
Topics: Humans; Cross-Sectional Studies; Japan; Polycythemia Vera; Physicians; Pruritus
PubMed: 37431845
DOI: 10.1080/16078454.2023.2227817 -
Frontiers in Oncology 2023Abnormal hematocrit values, including anemia and polycythemia, are common in patients undergoing craniotomy, but the extent to which preoperative anemia or polycythemia...
BACKGROUND
Abnormal hematocrit values, including anemia and polycythemia, are common in patients undergoing craniotomy, but the extent to which preoperative anemia or polycythemia independently increases the risk of mortality is unclear. This retrospective cohort study aimed to examine the association between preoperative anemia and polycythemia and postoperative mortality in patients who underwent craniotomy for brain tumor resection.
METHODS
We retrospectively analyzed data from 12,170 patients diagnosed with a brain tumor who underwent cranial surgery at West China Hospital between January 2011 and March 2021. The preoperative hematocrit value was defined as the last hematocrit value within 7 days before the operation, and patients were grouped according to the severity of their anemia or polycythemia. We assessed the primary outcome of 30-day postoperative mortality using logistic regression analysis adjusted for potential confounding factors.
RESULTS
Multivariable logistic regression analysis reported that the 30-day mortality risk was raised with increasing severity of both anemia and polycythemia. Odds ratios for mild, moderate, and severe anemia were 1.12 (95% CI: 0.79-1.60), 1.66 (95% CI: 1.06-2.58), and 2.24 (95% CI: 0.99-5.06), respectively. Odds ratios for mild, moderate, and severe polycythemia were 1.40 (95% CI: 0.95-2.07), 2.81 (95% CI: 1.32-5.99), and 14.32 (95% CI: 3.84-53.44), respectively.
CONCLUSIONS
This study demonstrated that moderate to severe anemia and polycythemia are independently associated with increased postoperative mortality in patients undergoing craniotomy for brain tumor resection. These findings underscore the importance of identifying and managing abnormal hematocrit values before craniotomy surgery.
PubMed: 37916178
DOI: 10.3389/fonc.2023.1246220