Διαταραχές αιμόστασης σε μυελοϋπερπλαστικά νοσήματα

Aσθενείς με Φιλαδέλφεια χρωμόσωμα αρνητικά μυελοϋπερπλαστικά νεοπλάσματα (Ph- ΜΥΝ), όπως η αληθής πολυκυτταραιμία (ΑΠ), η ιδιοπαθής θρομβοκυττάρωση (ΙΘ) και η πρωτοπαθής μυελοΐνωση (ΠΜ), εμφανίζουν αυξημένο κίνδυνο εμφάνισης θρομβώσεων. Η θρομβοελαστομετρία σε σύγκριση με τις κλασικές δοκιμασίες πήξης φαίνεται να είναι περισσότερο επαρκής ως προς την εκτίμηση του θρομβωτικού κινδύνου του ασθενή. Στην μελέτη αυτή, βασισμένη σε δεδομένα από 114 ασθενείς με Ph- ΜΥΝ από ένα κέντρο στην Ελλάδα, η αιμοστατική εικόνα εκτιμήθηκε με κλασικές δοκιμασίες πήξης, σφαιρική θρομβοελαστομετρία (ROTEM) και αναλυτή λειτουργικότητας αιμοπεταλίων (PFA-100). Ακολούθησε συσχετισμός με κλινικά και εργαστηριακά χαρακτηριστικά, με την χορηγούμενη θεραπεία, με μεταλλάξεις των γονιδίων Janus kinase 2 (JAK2), καλρετικουλίνης (CALR), του υποδοχέα της θρομβοποιητίνης (MPL) και τον πολυμορφισμό rs1136410 της πολύ(ΑDP-ριβόζης) πολυμεράσης-1 (PARP-1). Με βάση τις παραμέτρους της ROTEM, οι ασθενείς με ΙΘ εμφάνισαν μεγαλύτερη υπερπηκτικότητα σε σύγκριση με τους ασθενείς με ΑΠ και ΠΜ (p ≤ 0,001). Σε όλους τους ασθενείς παρατηρήθηκε στατιστικά σημαντική θετική συσχέτιση μεταξύ της γωνίας άλφα και του αριθμού των αιμοπεταλίων (ΑΜΠ) και μεταξύ της μέγιστης σταθερότητας θρόμβου (MCF) και των ΑΜΠ (p < 0,001). Στους ασθενείς με ΑΠ που έφεραν την μετάλλαξη JAK2, η απουσία του πολυμορφισμού της PARP-1 συσχετίστηκε με την εμφάνιση θρομβώσεων μετά την διάγνωση του Ph- MYN (p= 0,019). Aπό τους 47 ασθενείς που λάμβαναν θεραπεία με ασπιρίνη και εμφάνιζαν πλήρη αναστολή της λειτουργικότητας των αιμοπεταλίων σύμφωνα με τον PFA-100, κανένας ασθενής δεν εκδήλωσε θρομβωτικό επεισόδιο κατά την διάρκεια παρακολούθησης της μελέτης (p= 0,006). Σύμφωνα με τα αποτελέσματα της μελέτης μας, παγκόσμιες αιμοστατικές δοκιμασίες όπως η ROTEM σε συνδυασμό με άλλες παραμέτρους θα μπορούσαν να βοηθήσουν στην ανίχνευση ασθενών με Ph- ΜΥΝ με υψηλό θρομβωτικό κίνδυνο και στην προσαρμογή του είδους και της δοσολογίας της θεραπείας.  Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (PN-MPN) such as polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), are at a higher risk for venous thrombosis. Thromboelastometry may prove more efficient than conventional hemostatic laboratory tests to evaluate the patient’s thrombotic risk. In this study, based on data from 114 patients with PN-MPN from a single center in Greece, hemostatic profile was assessed with routine coagulation tests, Rotational Tromboelastometry (ROTEM), and Platelet Function Analyzer (PFA-100) and correlated with clinical, laboratory, treatment characteristics, mutations of the Janus kinase 2 gene (JAK2), the calreticulin gene (CALR), the thrombopoietin gene (MPL) and the polymorphism rs1136410 of poly (ADP-ribose) polymerase-1 (PARP-1). According to ROTEM parameters, patients with ET had a more hypercoagulable status compared to patients with PV and MF (p ≤ 0.001). Ιn all patients there was a statistically positive correlation between alpha angle and platelet count and between maximum clot firmness (MCF) and platelet count (p < 0.001). In JAK2 positive patients with PV, the absence of the PARP-1 polymorphism was correlated with thrombosis after diagnosis of PN-MPN (p= 0.019). Among 47 patients under treatment with aspirin and complete platelet inhibition based on PFA-100, no patient had a thrombotic episode during follow-up period (p= 0.006). Based on our results, global hemostatic assays such as ROTEM in combination with other parameters could help identify patients with PN-MPN at higher thrombotic risk and adjust the type and dose of appropriate treatment

Hemostasis disorders in myeloproliferative diseases

Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (PN-MPN) such as polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), are at a higher risk for venous thrombosis. Thromboelastometry may prove more efficient than conventional hemostatic laboratory tests to evaluate the patient’s thrombotic risk.In this study, based on data from 114 patients with PN-MPN from a single center in Greece, hemostatic profile was assessed with routine coagulation tests, Rotational Tromboelastometry (ROTEM), and Platelet Function Analyzer (PFA-100) and correlated with clinical, laboratory, treatment characteristics, mutations of the Janus kinase 2 gene (JAK2), the calreticulin gene (CALR), the thrombopoietin gene (MPL) and the polymorphism rs1136410 of poly (ADP-ribose) polymerase-1 (PARP-1).According to ROTEM parameters, patients with ET had a more hypercoagulable status compared to patients with PV and MF (p ≤ 0.001). Ιn all patients there was a statistically positive correlation between alpha angle and platelet count and between maximum clot firmness (MCF) and platelet count (p < 0.001). In JAK2 positive patients with PV, the absence of the PARP-1 polymorphism was correlated with thrombosis after diagnosis of PN-MPN (p= 0.019). Among 47 patients under treatment with aspirin and complete platelet inhibition based on PFA-100, no patient had a thrombotic episode during follow-up period (p= 0.006).Based on our results, global hemostatic assays such as ROTEM in combination with other parameters could help identify patients with PN-MPN at higher thrombotic risk and adjust the type and dose of appropriate treatment.Aσθενείς με Φιλαδέλφεια χρωμόσωμα αρνητικά μυελοϋπερπλαστικά νεοπλάσματα (Ph- ΜΥΝ), όπως η αληθής πολυκυτταραιμία (ΑΠ), η ιδιοπαθής θρομβοκυττάρωση (ΙΘ) και η πρωτοπαθής μυελοΐνωση (ΠΜ), εμφανίζουν αυξημένο κίνδυνο εμφάνισης θρομβώσεων. Η θρομβοελαστομετρία σε σύγκριση με τις κλασικές δοκιμασίες πήξης φαίνεται να είναι περισσότερο επαρκής ως προς την εκτίμηση του θρομβωτικού κινδύνου του ασθενή.Στην μελέτη αυτή, βασισμένη σε δεδομένα από 114 ασθενείς με Ph- ΜΥΝ από ένα κέντρο στην Ελλάδα, η αιμοστατική εικόνα εκτιμήθηκε με κλασικές δοκιμασίες πήξης, σφαιρική θρομβοελαστομετρία (ROTEM) και αναλυτή λειτουργικότητας αιμοπεταλίων (PFA-100). Ακολούθησε συσχετισμός με κλινικά και εργαστηριακά χαρακτηριστικά, με την χορηγούμενη θεραπεία, με μεταλλάξεις των γονιδίων Janus kinase 2 (JAK2), καλρετικουλίνης (CALR), του υποδοχέα της θρομβοποιητίνης (MPL) και τον πολυμορφισμό rs1136410 της πολύ(ΑDP-ριβόζης) πολυμεράσης-1 (PARP-1). Με βάση τις παραμέτρους της ROTEM, οι ασθενείς με ΙΘ εμφάνισαν μεγαλύτερη υπερπηκτικότητα σε σύγκριση με τους ασθενείς με ΑΠ και ΠΜ (p ≤ 0,001). Σε όλους τους ασθενείς παρατηρήθηκε στατιστικά σημαντική θετική συσχέτιση μεταξύ της γωνίας άλφα και του αριθμού των αιμοπεταλίων (ΑΜΠ) και μεταξύ της μέγιστης σταθερότητας θρόμβου (MCF) και των ΑΜΠ (p < 0,001). Στους ασθενείς με ΑΠ που έφεραν την μετάλλαξη JAK2, η απουσία του πολυμορφισμού της PARP-1 συσχετίστηκε με την εμφάνιση θρομβώσεων μετά την διάγνωση του Ph- MYN (p= 0,019). Aπό τους 47 ασθενείς που λάμβαναν θεραπεία με ασπιρίνη και εμφάνιζαν πλήρη αναστολή της λειτουργικότητας των αιμοπεταλίων σύμφωνα με τον PFA-100, κανένας ασθενής δεν εκδήλωσε θρομβωτικό επεισόδιο κατά την διάρκεια παρακολούθησης της μελέτης (p= 0,006).Σύμφωνα με τα αποτελέσματα της μελέτης μας, παγκόσμιες αιμοστατικές δοκιμασίες όπως η ROTEM σε συνδυασμό με άλλες παραμέτρους θα μπορούσαν να βοηθήσουν στην ανίχνευση ασθενών με Ph- ΜΥΝ με υψηλό θρομβωτικό κίνδυνο και στην προσαρμογή του είδους και της δοσολογίας της θεραπείας

PARP1 as a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

Poly(ADP-ribose) polymerase 1 (PARP1) is a key mediator of various forms of DNA damage repair and plays an important role in the progression of several cancer types. The enzyme is activated by binding to DNA single-strand and double-strand breaks. Its contribution to chromatin remodeling makes PARP1 crucial for gene expression regulation. Inhibition of its activity with small molecules leads to the synthetic lethal effect by impeding DNA repair in the treatment of cancer cells. At first, PARP1 inhibitors (PARPis) were developed to target breast cancer mutated cancer cells. Currently, PARPis are being studied to be used in a broader variety of patients either as single agents or in combination with chemotherapy, antiangiogenic agents, ionizing radiation, and immune checkpoint inhibitors. Ongoing clinical trials on olaparib, rucaparib, niraparib, veliparib, and the recent talazoparib show the advantage of these agents in overcoming PARPi resistance and underline their efficacy in targeted treatment of several hematologic malignancies. In this review, focusing on the crucial role of PARP1 in physiological and pathological effects in myelodysplastic syndrome and acute myeloid leukemia, we give an outline of the enzyme&apos;s mechanisms of action and its role in the pathophysiology and prognosis of myelodysplastic syndrome/acute myeloid leukemia and we analyze the available data on the use of PARPis, highlighting their promising advances in clinical application

The Role of Methylation in Chronic Lymphocytic Leukemia and Its Prognostic and Therapeutic Impacts in the Disease: A Systematic Review

Epigenetic regulation has been thoroughly investigated in recent years and has emerged as an important aspect of chronic lymphocytic leukemia (CLL) biology. Characteristic aberrant features such as methylation patterns and global DNA hypomethylation were the early findings of the research during the last decades. The investigation in this field led to the identification of a large number of genes where methylation features correlated with important clinical and laboratory parameters. Gene-specific analyses investigated methylation in the gene body enhancer regions as well as promoter regions. The findings included genes and proteins involved in key pathways that play central roles in the pathophysiology of the disease. Τhe application of these findings beyond the theoretical understanding can not only lead to the creation of prognostic and predictive models and scores but also to the design of novel therapeutic agents. The following is a review focusing on the present knowledge about single gene/gene promoter methylation or mRNA expression in CLL cases as well as records of older data that have been published in past papers

A Patient with Synchronous Gallbladder and Bone Plasmacytoma

Multiple myeloma (MM) is the most common primary bone-originating tumor, whereas extramedullary plasmacytoma (EMP) is a plasma cell tumor that arises outside the bone and is most commonly found in the head and neck area. Gastrointestinal and particularly gallbladder involvement is exceedingly rare, and symptoms, if any are present, are usually similar to those seen with cholelithiasis. Treatment options usually include surgical resection and/or chemotherapy. In this report, we present a rare case of a clinically unexpected plasmablastic extramedullary plasmacytoma that was found on abdominal ultrasound (US) and magnetic resonance imaging (MRI) in a 61-year-old asymptomatic patient and led him to undergo cholecystectomy. A fluorodeoxyglucose positron emission computed tomography (FDG PET-CT) that was performed due to the onset of left thigh pain also demonstrated concurrent bone plasmacytoma. The patient is currently receiving chemotherapy and is also being prepared for autologous stem cell transplantation. In this context, we further present the diagnostic, therapeutic and prognostic challenges of EMPs. Lastly, we point out the distinct features of the plasmablastic subtype and analyze its differences compared to other histologic subtypes in achieving a successful diagnosis and management

Progressive multifocal leukoencephalopathy in the context of newer therapies in hematology and review of new treatment strategies

Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal demyelinating disease of the central nervous system (CNS) caused by the reactivation of JC polyomavirus in the CNS. We present a case of a 54-year-old man with follicular lymphoma diagnosed with PML after being treated with anti-CD20 monoclonal antibody-based regimens for several years. Due to the lack of effective treatment choices for PML, the patient was treated with nivolumab, based on recent reports, but succumbed to his disease a few months after diagnosis. In this paper, we focus on reviewing the literature of PML cases correlated with newer agents used in hematology, possible factors affecting disease prognosis, as well as the available data on upcoming therapeutic options for patients with PML. Though newer promising treatments such as anti-PD1 monoclonal antibodies arise, a definitive treatment option is yet to be found. Vigilance, early detection, and prompt intervention play a crucial role in the prognosis of PML in patients with hematological malignancies

Isolated skeletal muscle recurrence of an originally nodal diffuse large B cell lymphoma A case report and review of the literature

Rationale: Diffuse large B cell lymphoma (DLBCL) is a malignancy of the B cells with extranodal primary involvement being estimated at 30% to 40% of cases. Primary skeletal muscle presentation of DLBCL is extremely rare, with an estimated incidence of about 0.5% of extranodal lymphomas, presenting mostly in the lower extremities. The possible mechanisms of muscle involvement of DLBCL include primary extranodal disease, extension from adjacent organs (such as lymph nodes) or disseminated disease. Patient concerns: We report a case of a 70-year-old woman with an advanced initially nodal DLBCL, treated with R-CHOP, that presented with an enlargement of her left thigh and restricted mobility 3 months after completion of chemotherapy. Imaging studies were performed, which showed possible infiltration of the muscles of the left thigh, without any nodal disease present. Diagnoses: Muscle biopsy documented the recurrence of the lymphoma at the left thigh. Interventions: The patient started second-line treatment with gemcitabine and vinorelbine. Outcomes: A partial response was achieved after the first cycle. Lessons: The remarkable element lies in the reappearance of the lymphoma at the left thigh muscles, with no radiographic or clinical evidence of involvement of lymph nodes, despite the extensive lymph node disease at initial presentation. The further management of such recurrences remains to be clarified, as the odd biological behavior of the malignant cells dictates a special handling of the disease

Bone marrow ribonucleotide reductase mRNA levels and methylation status as prognostic factors in patients with myelodysplastic syndrome treated with 5-Azacytidine

Ribonucleotide Reductase (RNR) is a two-subunit (RRM1, RRM2) enzyme, responsible for the conversion of ribonucleotides to deoxyribonucleotides required for DNA replication. To evaluate RNR as a biomarker of response to 5-azacytidine, we measured RNR mRNA levels by a quantitative real-time PCR in bone marrow samples of 98 patients with myelodysplastic syndrome (MDS) treated with 5-azacytidine with parallel quantification of the gene promoter&apos;s methylation. Patients with low RRM1 levels had a high RRM1 methylation status (p = 0.005) and a better response to treatment with 5-azacytidine (p = 0.019). A next-generation sequencing for genes of interest in MDS was also carried out in a subset of 61 samples. Splicing factor mutations were correlated with lower RRM1 mRNA levels (p = 0.044). Our results suggest that the expression of RNR is correlated with clinical outcomes, thus its expression could be used as a prognostic factor for response to 5-azacytidine and a possible therapeutic target in MDS