Papers by Eleftheria Hatzimichael
HemaSphere
Background: Background: ITP incidence is known to increase in adults aged >60 years and even more... more Background: Background: ITP incidence is known to increase in adults aged >60 years and even more in men aged >75 years (Moulis G et al., Blood 2014; 124(22):3308). As population aging and life-expectancy continues to increase worldwide, ITP in the elderly is a growing concern in everyday clinical practice. There are only a few studies regarding the features of ITP in patients (pts) aged >60-65 years and data are even scarcer in pts aged ≥75 years Aims: Aims: To describe real world characteristics at diagnosis and evaluate disease outcome in a group of pts aged 60-74 years (Group-1) as compared to very old pts (≥75 years; Group-2) with primary ITP, using data from the national database (ITP registry) operated under the auspices of the Hellenic Society of Hematology Methods: Methods: The Greek ITP registry recruits pts (n=1560, to date) nationally through a network of 25 sites. In the present study we retrospectively analyzed data from pts with primary ITP aged ≥60 years, who were diagnosed from 1979 to 2021. Results: Results: The total number of evaluable pts was 298. Group-1 consisted of 180 and Group-2 of 118 pts. The mean age at diagnosis was 68 years (60.1-74.9) in Group-1 and 81 years (75.2-97.1) in Group-2. The female to male ratio did not
Pathology - Research and Practice
In Vivo
Background/Aim: Primary mediastinal large Bcell lymphoma (PMLBCL) is an aggressive B-cell non-Hod... more Background/Aim: Primary mediastinal large Bcell lymphoma (PMLBCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL), whose prognosis has greatly improved since the incorporation of the anti-CD20 monoclonal antibody rituximab into current therapeutic regimens. Evidence, however, on the optimal time interval between consecutive chemoimmunotherapy (CIT) cycles is still scarce. This study aimed to evaluate the efficacy outcomes of the more commonly administered 3-weekly regimens to the biweekly ones in a PMLBCL patients' population, who were mostly treated with rituximab,
The Oncologist, 2021
Background R-CHOP can cure approximately 75% of patients with primary mediastinal large B-cell ly... more Background R-CHOP can cure approximately 75% of patients with primary mediastinal large B-cell lymphoma (PMLBCL), but prognostic factors have not been sufficiently evaluated yet. R-da- EPOCH is potentially more effective but also more toxic than R-CHOP. Reliable prognostic classification is needed to guide treatment decisions. Materials and Methods We analyzed the impact of clinical prognostic factors on the outcome of 332 PMLBCL patients ≤65 years treated with R-CHOP ± radiotherapy in a multicenter setting in Greece and Cyprus. Results With a median follow-up of 69 months, 5-year freedom from progression (FFP) was 78% and 5-year lymphoma specific survival (LSS) was 89%. On multivariate analysis, extranodal involvement (E/IV) and lactate dehydrogenase (LDH) ≥2 times upper limit of normal (model A) were significantly associated with FFP; E/IV and bulky disease (model B) were associated with LSS. Both models performed better than the International Prognostic Index (IPI) and the age-ad...
Therapeutic Advances in Hematology, 2020
Background:5-azacytidine (5-AZA) improves survival of patients with higher-risk myelodysplastic s... more Background:5-azacytidine (5-AZA) improves survival of patients with higher-risk myelodysplastic syndromes (MDSs) and oligoblastic acute myeloid leukemia (AML); however, predictive factors for response and outcome have not been consistently studied.Methods:This study of the Hellenic MDS Study Group included 687 consecutive patients with higher-risk MDS and oligoblastic AML treated with 5-AZA.Results:The International Prognostic Scoring System (IPSS) revised version (IPSS-R), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 or 1 versus ⩾2) and baseline serum ferritin (SF) levels > 520 ng/ml were shown to independently predict response to 5-AZA. In the survival analysis, the IPSS and IPSS-R risk classification systems along with the ECOG PS and SF levels > 520 ng/ml proved to be independent prognosticators for overall survival (OS), as well as for leukemia-free survival (LFS). Next, we built new multivariate models for OS and LFS, incorporating only ECOG PS and ...
Blood Cancer Journal, 2021
Blood, 2015
Introduction: We evaluated the expression of a panel of apoptosis-associated microRNAs (miRNAs) i... more Introduction: We evaluated the expression of a panel of apoptosis-associated microRNAs (miRNAs) in leukemic blasts isolated from AML patients and investigated their predicted targets. Patients and Methods: We used bone marrow or peripheral blood that were donated by nine AML patients (5 male, 4 female) at diagnosis. Mononuclear cells were isolated by Ficoll-Histopaque (Sigma Aldrich) density gradient centrifugation and were cryopreserved in liquid nitrogen at the Cancer Biobank Center of the University of Ioannina. MicroBeads technology (Miltenyl Biotec) was used for magnetic cell sorting of CD34+ cells of patients' samples, while mononuclear blood cells from healthy individuals were used as controls. Small RNA (< 200 b) was isolated using the NucleoSpin® miRNA kit (Macherey Nagel). Simultaneous quantification of 84 apoptosis- associated miRNAs was performed by using the miScript miRNA PCR Array Human Apoptosis (MIHS-114ZF, Qiagen) in a LightCycler® 480 instrument (Roche AG, ...
Clinical Cancer Drugs, 2018
Background: Acute promyelocytic leukemia (APL) is characterized by chromosomal translocations, wh... more Background: Acute promyelocytic leukemia (APL) is characterized by chromosomal translocations, which generate fusion oncogenic proteins. In 95% of cases, in frame fusion of the RARα gene to the PML gene, gives rise to the PML-RARα chimeric gene in patients with t(15;17)q22;q21. In addition, in 99% of cases, APL cells also express the germ cell-specific Cyclin A1 protein, which has been shown to contribute to APL-like disease in mouse models. Re-localization and degradation of PML-RARα with pharmacologic levels of all-trans retinoic acid (ATRA) may cause serious side effects such as the development of myelodysplastic syndrome, cutaneous T-cell lymphoma and skin cancers. Here, we exploit the expression of cyclin A1 and of the fusion protein and show that combined, sub-pharmacologic doses of ATRA and cyclin-dependent kinase inhibitors are more efficacious than either agent alone at inducing etc at inducing APL cell differentiation. Methods: Cultured NB4 APL cells were used to compare the degree of differentiation by ATRA and olomoucine or roscovitine, two cyclin-dependent kinase inhibitors alone or in combination. Differentiation was monitored with the NBT reaction, quantitation of proliferation and monitoring the levels of CDK4, PML-RARα and C/EBP proteins using immunoblots. Results: ATRA or roscovitine alone are effective at inducing inhibition of proliferation and differentiation at pharmacologic levels whereas olomoucine alone is not. In contrast, the combined use of sub-pharmacologic doses of ATRA with either olomoucine or roscovitine is more effective at inhibiting APL cell proliferation than ATRA, olomoucine or roscovitine alone with implications for the treatment of APL. Conclusion: We demonstrate that in NB4 cells, the combination of ATRA/ olomoucine or ATRA/roscovitine leads to more potent differentiation accompanied by a reduction in CDK4 protein levels, decreased degradation of the fusion protein and up-regulation of the transcription factor C/EBPε.
American journal of hematology, Jan 16, 2018
In this study, we investigated the incidence and prognostic impact of monosomal karyotype (MK) in... more In this study, we investigated the incidence and prognostic impact of monosomal karyotype (MK) in 405 higher-risk Myelodysplastic Syndromes (MDS) patients treated with 5-AZA. The MK was present in 66 out of 405 (16.3%) patients, most of whom had complex karyotype (CK). MK was strongly associated with CK and the cytogenetic risk defined according to IPSS-R, as well as with high-risk disease, according to IPSS (P = .029), IPSS-R (P < .001), and WPSS (P < .001) classification systems. The overall response rate (ORR) was not different between MK+ and MK- patients (46.6% vs. 46.2%). At 28 months median follow-up, the median duration of response was 11 months in the entire cohort, 9.5 months in MK+ patients and 11 months in MK-patients (P = .024). The estimated median time to transformation to acute myeloid leukemia for MK+ patients was 17 months vs. 23 months for MK- patients (P = .025). The estimated median OS for MK+ patients was 12 months vs. 18 months for MK- patients (P < ....
Melanoma Management, 2014
British Journal of Cancer, 2012
BACKGROUND: Prolyl hydroxylation is a post-translational modification that affects the structure,... more BACKGROUND: Prolyl hydroxylation is a post-translational modification that affects the structure, stability and function of proteins including collagen by catalysing hydroxylation of proline to hydroxyproline through action of collagen prolyl hydroxylases3 (C-P3H) and 4 (C-P4H). Three C-P3Hs (nomenclature was amended according to approval by the HGNC symbols and names at http:// www.genenames.org/ and Entrez database at http://www.ncbi.nlm.nih.gov/gene) leucineproline-enriched proteoglycan (leprecan) 1 (Lepre1), leprecan-like 1 (Leprel1), leprecan-like 2 (Leprel2) and two paralogs Cartilage-Related Protein (CRTAP) and leprecan-like 4 (Leprel4) are found in humans. The C-P4Hs are tetrameric proteins comprising a variable a subunit, encoded by the P4HA1, P4HA2 and P4HA3 genes and a constant b subunit encoded by P4HB. METHODS: We used RT-PCR, qPCR, pyrosequencing, methylation-specific PCR, western blotting and immunohistochemistry to investigate expression and regulation of the C-P3H and C-P4H genes in B lymphomas and normal bone marrow. RESULTS: C-P3H and C-P4H are downregulated in lymphoma. Down-regulation is associated with methylation in the CpG islands and is detected in almost all common types of B-cell lymphoma, but the CpG islands are unmethylated or methylated at lower levels in DNA isolated from normal bone marrow and lymphoblastoid cell lines. Methylation of multiple C-P3H and C-P4H genes is present in some lymphomas, particularly Burkitt's lymphoma. CONCLUSIONS: Methylation of C-P3H and C-P4H is common in B lymphomas and may have utility in differentiating disease subtypes.
Molecules, 2011
We are currently witnessing a decline in the development of efficient new anticancer drugs, despi... more We are currently witnessing a decline in the development of efficient new anticancer drugs, despite the salient efforts made on all fronts of cancer drug discovery. This trend presumably relates to the substantial heterogeneity and the inherent biological complexity of cancer, which hinder drug development success. Protein-protein interactions (PPIs) are key players in numerous cellular processes and aberrant interruption of this complex network provides a basis for various disease states, including cancer. Thus, it is now believed that cancer drug discovery, in addition to the design of single-targeted bioactive compounds, should also incorporate diversity-oriented synthesis (DOS) and other combinatorial strategies in order to exploit the ability of multi-functional scaffolds to modulate multiple protein-protein interactions (biological hubs). Throughout the review, we highlight the chemistry driven approaches to access diversity space for the discovery of small molecules that disrupt oncogenic PPIs, namely the p53-Mdm2, Bcl-2/Bcl-xL-BH3, Myc-Max, and p53-Mdmx/Mdm2 interactions.
Leukemia, 2014
Suppression of uninvolved immunoglobulins is common in multiple myeloma (MM) but the prognostic s... more Suppression of uninvolved immunoglobulins is common in multiple myeloma (MM) but the prognostic significance of this phenomenon has not been assessed. We evaluated the prognostic significance of the preservation of uninvolved immunoglobulins in 1755 consecutive, unselected, patients with newly diagnosed, symptomatic MM with pre-therapy immunoglobulin levels measured by nephelometry. Suppression of at least one uninvolved immunoglobulin was observed in 87% of patients and was more common in patients with immunoglobulin A myeloma, those aged over 65 years, in patients with advanced-International Staging System (ISS) stage, extensive-bone marrow infiltration, anemia, low platelet counts, high levels of serum M-monoclonal protein or renal dysfunction. Patients with preserved immunoglobulins had a better survival than patients with suppressed immunoglobulins (median survival 55 vs 41.5 months, Po0.001). In multivariate analysis, preservation of uninvolved immunoglobulins was independently associated with better survival (hazard ratio: 0.781, 95% confidence interval: 0.618-0.987, P ¼ 0.039); irrespective of the treatment. In a subset of 500 patients, which were strictly followed for disease progression, preservation of uninvolved immunoglobulins was associated with a significantly longer progression-free survival (60 vs 25 months, Po0.001), independently of other common prognostic factors. In conclusion, preservation of uninvolved immunoglobulins in newly diagnosed patients with symptomatic MM was independently associated with long term disease control and improved survival.
Current Drug Safety, 2006
Cancer Research, 2011
Resistance to platinum- and taxane-based chemotherapy remains a major clinical impediment to effe... more Resistance to platinum- and taxane-based chemotherapy remains a major clinical impediment to effective management of epithelial ovarian cancer (EOC). To gain insights into resistance mechanisms, we compared gene and confirmed expression patterns of novel EOC cell lines selected for paclitaxel and carboplatin resistance. Here, we report that resistance can be conferred by downregulation of the Polo-like kinase Plk2. Mechanistic investigations revealed that downregulation occurred at the level of transcription via associated DNA methylation of the CpG island in the Plk2 gene promoter in cell lines, primary tumors, and patient sera. Inhibitory RNA (RNAi)-mediated knockdown and ectopic overexpression established a critical functional role for Plk2 in determining apoptotic sensitivity to paclitaxel and carboplatin. In drug-resistant human EOC cell lines, Plk2 promoter methylation varied with the degree of drug resistance and transcriptional silencing of the promoter. RNAi-dependent knock...
Cureus
Primary central nervous system (CNS) lymphoma or systemic non-Hodgkin lymphoma that infiltrates t... more Primary central nervous system (CNS) lymphoma or systemic non-Hodgkin lymphoma that infiltrates the CNS can cause central diabetes insipidus (CDI). Polyuria and polydipsia should raise the suspicion of CDI development in patients with lymphoma that infiltrates the CNS. CDI is effectively treated with desmopressin. However, careful monitoring of the patient's serum sodium, fluid intake, urine output, and weight is necessary because patients receiving desmopressin may develop hyponatremia, so they should be alert to recognize this side effect promptly. Moreover, CDI due to lymphoma can occasionally be reversible. Therefore, the dosage of desmopressin should be adapted during or after the treatment of lymphoma.
European Medical Journal
Thrombocytopenia may be associated with a variety of conditions and risks depending on its severi... more Thrombocytopenia may be associated with a variety of conditions and risks depending on its severity, ranging from mild epistaxis to life-threating bleeding. Many drugs or herbal remedies can cause thrombocytopenia by either inhibiting platelet production and/or enhancing their destruction from the peripheral blood mediated via an immunological mechanism implicating drug-dependent antibodies. The latter entity is called drug-induced immune thrombocytopenia: a life-threatening, under-recognised condition, which is often a diagnostic challenge. Rifampicin is a widely used, well-tolerated, and effective bactericidal drug. Adverse events, except for gastrointestinal effects, headache, skin rash, and pruritus, are uncommon. The authors herein report on a patient with isolated thrombocytopenia with a recent medical history of brucellosis on rifampicin and doxycycline. Thrombocytopenia was proved to be rifampicin-induced. Also presented is a short review of the literature on this rare subje...
Case Reports in Hematology, 2017
Background. Plasmablastic lymphoma (PBL) is a rare, aggressive B-cell lymphoma with poor prognosi... more Background. Plasmablastic lymphoma (PBL) is a rare, aggressive B-cell lymphoma with poor prognosis usually found in the oral cavity of HIV-positive patients. Chronic lymphocytic leukemia (CLL) is an indolent B-cell lymphoma with a variable clinical course. Transformation of CLL to PBL as Richter’s syndrome is rare while coexistence of CLL and PBL at diagnosis is even rarer.Case Report. We describe a case of a male immunocompetent patient with an ileum-cecum valve mass and a soft tissue mass at the left humerus with histologic evidence of PBL with coexistence of CLL in the bone marrow and peripheral blood. Amputation of the patient’s left arm was inevitable, and the patient was started on bortezomib and dexamethasone. However, prolonged hospitalization was complicated by aspiration pneumonia, and the patient passed away.Conclusions. No standard of care exists for patients with PBL, and prognosis remains dismal. Concomitant presentation of hematological malignancies becomes increasing...
Journal of Clinical Medicine, 2020
Hyponatremia is the most common electrolyte disorder in clinical practice and is associated with ... more Hyponatremia is the most common electrolyte disorder in clinical practice and is associated with increased morbidity and mortality. It is frequently encountered in hematologic patients with either benign or malignant diseases. Several underlying mechanisms, such as hypovolemia, infections, toxins, renal, endocrine, cardiac, and liver disorders, as well as the use of certain drugs appear to be involved in the development or the persistence of hyponatremia. This review describes the pathophysiology of hyponatremia and discusses thoroughly the contributing factors and mechanisms that may be encountered specifically in patients with hematologic disorders. The involvement of the syndrome of inappropriate antidiuretic hormone (SIADH) secretion and renal salt wasting syndrome (RSWS) in the development of hyponatremia in such patients, as well as their differential diagnosis and management, are also presented. Furthermore, the distinction between true hyponatremia and pseudohyponatremia is ...
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Papers by Eleftheria Hatzimichael