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Endocrine-related Cancer Oct 2023This article is a summary of the plenary lecture presented by Jared Rosenblum that was awarded the Manger Prize at the Sixth International Symposium on... (Review)
Review
This article is a summary of the plenary lecture presented by Jared Rosenblum that was awarded the Manger Prize at the Sixth International Symposium on Pheochromocytoma/Paraganglioma held on 19-22 October 2022 in Prague, Czech Republic. Herein, we review our initial identification of a new syndrome of multiple paragangliomas, somatostatinomas, and polycythemia caused by early postzygotic mosaic mutations in EPAS1, encoding hypoxia-inducible factor 2 alpha (HIF-2α), and our continued exploration of new disease phenotypes in this syndrome, including vascular malformations and neural tube defects. Continued recruitment and close monitoring of patients with this syndrome as well as the generation and study of a corresponding disease mouse model as afforded by the pheochromocytoma/paraganglioma translational program at the National Institutes of Health has provided new insights into the natural history of these developmental anomalies and the pathophysiologic role of HIF-2α. Further, these studies have highlighted the importance of the timing of genetic defects in the development of related disease phenotypes. The recent discovery and continued study of this syndrome has not only rapidly evolved our understanding of pheochromocytoma and paraganglioma but also deepened our understanding of other developmental tumor syndromes, heritable syndromes, and sporadic diseases.
Topics: Animals; Mice; Pheochromocytoma; Syndrome; Paraganglioma; Basic Helix-Loop-Helix Transcription Factors; Adrenal Gland Neoplasms
PubMed: 37450881
DOI: 10.1530/ERC-23-0050 -
Therapeutic Advances in Hematology 2024Interferons are cytokines with immunomodulatory properties and disease-modifying effects that have been used to treat myeloproliferative neoplasms (MPNs) for more than... (Review)
Review
Interferons are cytokines with immunomodulatory properties and disease-modifying effects that have been used to treat myeloproliferative neoplasms (MPNs) for more than 35 years. The initial use of interferons was limited due to difficulties with administration and a significant toxicity profile. Many of these shortcomings were addressed by covalently binding polyethylene glycol to the interferon structure, which increases the stability, prolongs activity, and reduces immunogenicity of the molecule. In the current therapeutic landscape, pegylated interferons are recommended for use in the treatment of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We review recent efficacy, molecular response, and safety data for the two available pegylated interferons, peginterferon alfa-2a (Pegasys) and ropeginterferon alfa-2b-njft (BESREMi). The practical management of interferon-based therapies is discussed, along with our opinions on whether to and how to switch from hydroxyurea to one of these therapies. Key topics and questions related to use of interferons, such as their safety and tolerability, the significance of variant allele frequency, advantages of early treatment, and what the future of interferon therapy may look like, will be examined. Pegylated interferons represent an important therapeutic option for patients with MPNs; however, more research is still required to further refine interferon therapy.
PubMed: 38380373
DOI: 10.1177/20406207241229588 -
Current Hematologic Malignancy Reports Oct 2023Chronic myeloproliferative neoplasms (MPN) represent a group of diseases characterised by constitutive activation of the JAK/STAT pathway in a clonal myeloid precursor.... (Review)
Review
PURPOSE OF REVIEW
Chronic myeloproliferative neoplasms (MPN) represent a group of diseases characterised by constitutive activation of the JAK/STAT pathway in a clonal myeloid precursor. The therapeutic approach aims to treat the symptom burden (headache, itching, debilitation), splenomegaly, slow down the fibrotic proliferation in the bone marrow and reduce the risk of thrombosis/bleeding whilst avoiding leukaemic transformation.
RECENT FINDINGS
In recent years, the advent of JAK inhibitors (JAKi) has significantly broadened treatment options for these patients. In myelofibrosis, symptom control and splenomegaly reduction can improve quality of life with improved overall survival, not impacting progression into acute leukaemia. Several JAKi are available and used worldwide, and combination approaches are now being explored. In this chapter, we review the approved JAKi, highlighting its strengths, exploring potential guidelines in choosing which one to use and reasoning towards future perspectives, where the combinations of therapies seem to promise the best results.
Topics: Humans; Janus Kinase Inhibitors; Polycythemia Vera; Janus Kinases; Splenomegaly; Quality of Life; Thrombocythemia, Essential; Signal Transduction; STAT Transcription Factors; Myeloproliferative Disorders
PubMed: 37395943
DOI: 10.1007/s11899-023-00702-x -
Revue Medicale de Liege Feb 2024Polycythemia is suspected when hemoglobin and/or hematocrit levels exceed established norms based on gender and age. This biological anomaly can arise from a...
Polycythemia is suspected when hemoglobin and/or hematocrit levels exceed established norms based on gender and age. This biological anomaly can arise from a myeloproliferative neoplasm known as polycythemia vera, or be secondary to excess erythropoietin (EPO) or decreased in plasma volume. Faced with polycythemia, the search for JAK2 mutations and measurement of serum EPO levels can guide toward the etiology. In polycythemia vera, thromboembolic events are the most lethal complications and unfortunately often the initial manifestation of the disease. The condition can also progress to myelofibrosis or acute leukemia. Management aims at reducing the hematocrit below 45 %, in order to limit, but not completely prevent, thrombo-embolic complications. This article elaborates on the clinical considerations around this biological anomaly, relevant complementary examinations, and briefly the therapeutic management.
Topics: Humans; Polycythemia; Polycythemia Vera; Janus Kinase 2; Thromboembolism
PubMed: 38356428
DOI: No ID Found -
Cancers Apr 2024Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal... (Review)
Review
Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of the molecular pathogenesis of these diseases, with the discovery of key mutations in the , , and genes being pivotal. This review provides a comprehensive update on the molecular landscape of PV, ET, and PMF, highlighting the diagnostic, prognostic, and therapeutic implications of these genetic findings. We delve into the challenges of diagnosing and treating patients with prognostic mutations, clonal evolution, and the impact of emerging technologies like next-generation sequencing and single-cell genomics on the field. The future of MPN management lies in leveraging these molecular insights to develop personalized treatment strategies, aiming for precision medicine that optimizes outcomes for patients. This article synthesizes current knowledge on molecular diagnostics in MPNs, underscoring the critical role of genetic profiling in enhancing patient care and pointing towards future research directions that promise to further refine our approach to these complex disorders.
PubMed: 38730632
DOI: 10.3390/cancers16091679 -
Expert Opinion on Pharmacotherapy 2023Polycythemia vera (PV) is driven by mutations in JAK2 kinase and subsequent JAK/STAT activation, presentation can range from an asymptomatic state to micro or... (Review)
Review
INTRODUCTION
Polycythemia vera (PV) is driven by mutations in JAK2 kinase and subsequent JAK/STAT activation, presentation can range from an asymptomatic state to micro or macrovascular events. Characteristic aquagenic pruritus and fatigue can have a substantial impact on quality of life. Over time, a minority will transform into more aggressive conditions such as post-PV myelofibrosis or acute myeloid leukemia. The JAK1 and 2 inhibitor Ruxolitinib has been approved for the treatment of PV after the failure of first-line therapies. Other JAK inhibitors have not been extensively tested in PV.
AREAS COVERED
In this article, we describe how PV is diagnosed and conventional treatments before moving to cover the status of JAK inhibitors as a therapeutic option for this disease and other novel therapies following a literature review.
EXPERT OPINION
Ruxolitinib when used for PV delivers control of blood counts and reduces disease-related symptoms. Recent data have also suggested that treatment with Ruxolitinib can improve event-free survival and may be associated with disease modification. Adverse effects of Ruxolitinib such as the increased risk of infection and squamous cell skin cancers, most likely to be linked to immunosuppression and prior lines of therapies, require careful consideration.
Topics: Humans; Polycythemia Vera; Janus Kinase Inhibitors; Quality of Life; Pyrazoles; Nitriles; Janus Kinase 2
PubMed: 37343285
DOI: 10.1080/14656566.2023.2228688 -
Clinical and Experimental Medicine Jan 2024Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no...
Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no other causes identified. This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, < 10%) in only 14 (25%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.
Topics: Humans; Polycythemia; Polycythemia Vera; Mutation; Iron; Germ Cells
PubMed: 38244120
DOI: 10.1007/s10238-023-01283-y -
Immunological Medicine Sep 2023JAK inhibitors are important therapeutic options for hematological disorders, especially myeloproliferative neoplasms. Ruxolitinib, the first JAK inhibitor approved for... (Review)
Review
JAK inhibitors are important therapeutic options for hematological disorders, especially myeloproliferative neoplasms. Ruxolitinib, the first JAK inhibitor approved for clinical use, improves splenomegaly and ameliorates constitutional symptoms in both myelofibrosis and polycythemia vera patients. Ruxolitinib is also useful for controlling hematocrit levels in polycythemia vera patients who were inadequately controlled by conventional therapies. Furthermore, pretransplantation use of ruxolitinib may improve the outcome of allo-hematopoietic stem cell transplantation in myelofibrosis. In contrast to these clinical merits, evidence of the disease-modifying action of ruxolitinib, i.e., reduction of malignant clones or improvement of bone marrow pathological findings, is limited, and many myelofibrosis patients discontinued ruxolitinib due to adverse events or disease progression. To overcome these limitations of ruxolitinib, several new types of JAK inhibitors have been developed. Among them, fedratinib was proven to provide clinical merits even in patients who were resistant or intolerant to ruxolitinib. Pacritinib and momelotinib have shown merits for myelofibrosis patients with thrombocytopenia or anemia, respectively. In addition to treatment for myeloproliferative neoplasms, recent studies have demonstrated that JAK inhibitors are novel and attractive therapeutic options for corticosteroid-refractory acute as well as chronic graft versus host disease.
Topics: Humans; Polycythemia Vera; Janus Kinase Inhibitors; Primary Myelofibrosis; Janus Kinase 2; Protein Kinase Inhibitors; Myeloproliferative Disorders
PubMed: 36305377
DOI: 10.1080/25785826.2022.2139317