A Cross-Sectional, Multicentric, Disease-Specific, Health-Related Quality of Life Study in Greek Transfusion Dependent Thalassemia Patients.

The assessment of health-related quality of life (HRQoL) in thalassemia offers a holistic approach to the disease and facilitates better communication between physicians and patients. This study aimed to evaluate the HRQoL of transfusion-dependent thalassemia (TDT) patients in Greece. This was a multicentric, cross-sectional study conducted in 2017 involving 283 adult TDT patients. All participants completed a set of two QoL questionnaires, the generic SF-36v2 and the disease-specific TranQol. Demographic and clinical characteristics were used to predefine patient subgroups. Significant factors identified in the univariate analysis were entered into a multivariate analysis to assess their effect on HRQoL. The SF-36 scores of TDT patients were consistently lower compared to the general population in Greece. The mean summary score of TranQol was relatively high (71 ± 14%), exceeding levels observed in national surveys in other countries. Employment emerged as the most significant independent factor associated with better HRQoL, whereas age had the most significant negative effect. This study represents the first comprehensive QoL assessment of a representative sample of the TDT population in Greece. The implementation of TranQol allowed for the quantification of HRQoL in Greece, establishing a baseline for future follow-up, and identifying more vulnerable patient subgroups.

Genome-wide analysis toward the epigenetic aetiology of myelodysplastic syndrome disease progression and pharmacoepigenomic basis of hypomethylating agents drug treatment response.

Myelodysplastic syndromes (MDS) consist of a group of hematological malignancies characterized by ineffective hematopoiesis, cytogenetic abnormalities, and often a high risk of transformation to acute myeloid leukemia (AML). So far, there have been only a very limited number of studies assessing the epigenetics component contributing to the pathophysiology of these disorders, but not a single study assessing this at a genome-wide level. Here, we implemented a generic high throughput epigenomics approach, using methylated DNA sequencing (MeD-seq) of LpnPI digested fragments to identify potential epigenomic targets associated with MDS subtypes. Our results highlighted that PCDHG and ZNF gene families harbor potential epigenomic targets, which have been shown to be differentially methylated in a variety of comparisons between different MDS subtypes. Specifically, CpG islands, transcription start sites and post-transcriptional start sites within ZNF124, ZNF497 and PCDHG family are differentially methylated with fold change above 3,5. Overall, these findings highlight important aspects of the epigenomic component of MDS syndromes pathogenesis and the pharmacoepigenomic basis to the hypomethylating agents drug treatment response, while this generic high throughput whole epigenome sequencing approach could be readily implemented to other genetic diseases with a strong epigenetic component.

Allogeneic Hematopoietic Stem Cell Transplantation for Mixed or Overlap Myelodysplastic/Myeloproliferative Disorders.

Chronic myelomonocytic leukemia (CMML) and the remaining, less frequent hybrid, mixed, or overlap myelodysplastic syndromes/myeloproliferative neoplasms (MDSs/MPNs) are difficult to treat neoplastic hematological disorders, exhibiting substantial clinical and prognostic heterogeneity, for which clear therapeutic guidelines or effective treatment options are still missing. CMML has an overall survival ranging from a few months to several years. Although patients with proliferative or dysplastic features may benefit from hydroxyurea and hypomethylating agent treatment, respectively, none of these treatments can establish long-term remission and prevent the inevitable transformation to acute leukemia. Novel targeted treatment approaches are emerging but are still under investigation. Therefore, currently, allogeneic stem cell transplantation (allo-SCT) remains the only treatment modality with a curative potential, but its widespread application is limited, due to significant morbidity and mortality associated with the procedure, especially in the elderly and in patients with comorbidities. Recognition of patient eligibility for allo-SCT is crucial, and the procedure should be addressed to patients with a good performance status without severe comorbidities and mainly to those in intermediate- to high-risk category, with a suitable stem cell donor available. The issues of best timing for performing transplantation, patient and donor eligibility, the type of conditioning regimen, and the outcomes after various allo-SCT procedures are the topics of this review.

High Frequency of Post-Transfusion Microchimerism Among Multi-Transfused Beta-Thalassemic Patients.

BACKGROUND: Transfusion-associated microchimerism implies the presence of allogeneic hematopoietic cells in an individual, following the transfusion of a blood product. It is a transfusion-related adverse effect/long-term consequence, which has not been well-investigated among regularly transfused patients with thalassemia. PATIENTS AND METHODS: We investigated 64 regularly transfused, homozygous ß-thalassemic patients and 21 never-transfused healthy volunteer blood donors (controls) for the presence of microchimerism in their sera, using real-time PCR targeting circulating allogeneic, both, Human Leukocyte Antigen-DR isotype (HLA-DR) and non-HLA alleles. The investigation was longitudinally repeated in patient subsets for more than 2 years. Results were correlated with clinical and laboratory parameters, peripheral blood lymphocyte immunophenotype, blood storage time, and donor's gender to identify potential contributing factors for microchimerism generation. RESULTS: Overall, microchimerism was detected in 52 of the 64 patients (81.2%) and in 6 of the 21 controls (28.5%, p = 0.0001). Forty-four patients (68.7%) exhibited long-term microchimerism (persisted for more than 6 months), confirmed at all time-points investigated. Microchimerism was more frequent among elderly, women, splenectomized and more heavily transfused patients, and among those who exhibit higher serum ferritin levels. In these patients, a distinct descending pattern of CD16dim+CD56dim+ natural killer (NK)-cells (p < 0.001) and an ascending pattern of CD4+CD25brightCD127- regulatory T-cells (p = 0.022) for increasing allelic burden were noticed, suggesting the establishment of recipient immune tolerance against the donor-derived chimeric alleles. Both splenectomized and non-splenectomized thalassemic patients exhibited the same trend. The storage time of transfused blood products and donor/gender mismatch had no impact on the development of microchimerism. DISCUSSION-CONCLUSIVE REMARKS: Transfusion-associated microchimerism appears to be a very common complication among multi-transfused thalassemic patients. The potential clinical consequences of this phenomenon remain as yet unclear. Immune tolerance attributed to disease itself and to repeated transfusions might at least in part explain its appearance.

The Lipoprotein Transport System in the Pathogenesis of Multiple Myeloma: Advances and Challenges.

Multiple myeloma (MM) is an incurable neoplastic hematologic disorder characterized by malignant plasma cells, mainly in the bone marrow. MM is associated with multiple factors, such as lipid metabolism, obesity, and age-associated disease development. Although, the precise pathogenetic mechanisms remain unknown, abnormal lipid and lipoprotein levels have been reported in patients with MM. Interestingly, patients with higher APOA1 levels, the major apolipoprotein of high density lipoprotein (HDL), have better overall survival. The limited existing studies regarding serum lipoproteins in MM are inconclusive, and often contradictory. Nevertheless, it appears that deregulation of the lipoprotein transport system may facilitate the development of the disease. Here, we provide a critical review of the literature on the role of lipids and lipoproteins in MM pathophysiology. We also propose novel mechanisms, linking the development and progression of MM to the metabolism of blood lipoproteins. We anticipate that proteomic and lipidomic analyses of serum lipoproteins along with analyses of their functionality may improve our understanding and shed light on novel mechanistic aspects of MM pathophysiology.

Choroidal Thickness Evaluation in a Transfusion-Dependent Beta-Thalassemia Greek Population.

PURPOSE: To evaluate choroidal thickness in a group of beta-thalassemia patients as assessed by enhanced depth imaging optical coherence tomography. PATIENTS AND METHODS: This single-center, observational study involved transfusion-dependent beta-thalassemia (TD-ß-thal) patients and healthy controls. One eye of each participant was included in the study. Submacular and peripapillary choroidal thickness, as well as central macular thickness and retinal nerve fiber layer thickness, were evaluated. RESULTS: Thirty-eight TD-ß-thal patients (mean age 42 ± 10.7 years) and 22 healthy controls (mean age 40.3 ± 10.2 years) were included in the study. Subfoveal choroidal thickness was 297.4 ± 74.5 µm in the patient group and 358.4 ± 71.4 µm in the control group (p=0.003). Overall, in the submacular area, the choroid was found to be significantly thinner in the beta-thalassemia population compared to controls in all evaluated points, except for the spot located 1500 µm nasally to the fovea (p=0.093). In the peripapillary area, choroidal thickness was also significantly lower in the thalassemic population compared to the controls (nasal p=0.033, temporal p=0.01, superior p=0.01), except for the inferior quadrant (p= 0.191). We did not observe statistically significant differences in the retinal nerve fiber layer thickness and the central macular thickness between the two groups (p=0.658 and p=0.276, respectively). No correlations with hemoglobin, serum ferritin or iron levels emerged. Patients with the intermediate subtype appeared to have significantly thinner choroids than the ones with thalassemia major. CONCLUSION: Our findings suggest that choroidal thickness in the submacular and peripapillary area is significantly reduced in thalassemic patients, compared to healthy individuals. Choroidal thinning in beta-thalassemia possibly reflects the effect of chronic anemia and underlying hemodynamic changes on choroidal tissue.

Occupational, dietary, and other risk factors for myelodysplastic syndromes in Western Greece.

PURPOSE: We have observed an increasing incidence of myelodysplastic syndromes (MDS) in the geographic area of Western Greece during the past two decades. The objective of this study was to investigate potential risk factors for the manifestation of MDS in this area of Greece. METHODS: A hospital-based case-control study was conducted in the public hospitals of the region. Participants were interviewed based on a questionnaire regarding demographics, occupational exposures, smoking, alcohol consumption, dietary, and domestic factors. RESULTS: A total of 228 individuals (126 cases, 102 controls) were recruited in this study. Univariate analysis showed that risk of MDS was associated with a family history of hematologic malignancy or solid tumor, exposure to pesticides, insecticides, herbicides, increased weekly intake of meat and eggs, and increased alcohol intake, whereas fruit intake had a protective effect. Analysis by pesticide ingredient showed a weak association of exposure to paraquat and glyphosate with the occurrence of MDS. Multivariate analysis showed that independent risk factors for the manifestation of MDS were family history of solid tumor (OR 2.47, 95% CI 1.32-4.65), meat intake for ≥5 days/week (OR 2.67, 95% CI 1.05-6.80) and exposure to pesticides (OR 3.25, 95% CI 1.73-6.11). CONCLUSIONS: Exposure to pesticides is a major risk factor of MDS in Western Greece. Family history of solid tumor and increased meat intake also appear to play a role in the pathogenesis of MDS. Public health authorities should implement policies to advise and protect farmers from the harmful effects of agrochemicals. Emphasis should also be given to health promotion advice including healthy eating.