Stratification of ßSß+ Compound Heterozygotes Based on L-Glutamine Administration and RDW: Focusing on Disease Severity.

Sickle cell disease (SCD) is heterogeneous in terms of manifestation severity, even more so when in compound heterozygosity with beta-thalassemia. The aim of the present study was to stratify ßSß+ patient blood samples in a severity-dependent manner. Blood from thirty-two patients with HbS/ß-thalassemia compound heterozygosity was examined for several parameters (e.g., hemostasis, inflammation, redox equilibrium) against healthy controls. Additionally, SCD patients were a posteriori (a) categorized based on the L-glutamine dose and (b) clustered into high-/low-RDW subgroups. The patient cohort was characterized by anemia, inflammation, and elevated coagulation. Higher-dose administration of L-glutamine was associated with decreased markers of inflammation and oxidation (e.g., intracellular reactive oxygen species) and an altered coagulation profile. The higher-RDW group was characterized by increased hemolysis, elevated markers of inflammation and stress erythropoiesis, and oxidative phenomena (e.g., membrane-bound hemoglobin). Moreover, the levels of hemostasis parameters (e.g., D-Dimers) were greater compared to the lower-RDW subgroup. The administration of higher doses of L-glutamine along with hydroxyurea seems to attenuate several features in SCD patients, probably by enhancing antioxidant power. Moreover, anisocytosis may alter erythrocytes' coagulation processes and hemolytic propensity. This results in the disruption of the redox and pro-/anti-inflammatory equilibria, creating a positive feedback loop by inducing stress erythropoiesis and, thus, the occurrence of a mixed erythrocyte population.

Clinical significance of mutational variants in beta and alpha genes in patients with hemoglobinopathies from two large Greek centers: a complex interplay between genotype and phenotype.

Hemoglobinopathies affect patients in the wider Mediterranean area consisting of 4 distinct subgroups: beta thalassemia major (TM), beta thalassemia intermedia (TI), sickle cell disease (SCD) and hemoglobin H disease (alpha thalassemia). The clinical spectrum varies from mild to severe. Complex interactions between genes and environmental factors form the clinical manifestations. There is an unmet need to clarify these multifactorial mechanisms. This is the first Greek study describing mutational alleles (HBB and HBA1/HBA2 gene variants) in 217 patients with hemoglobinopathies of two large centers in Greece (Larissa and Athens) and associating particular genotypes or gene variants with clinical manifestations (transfusion frequency, complications). Thus, the complex interplay between corresponding genotypes and phenotypes was investigated. Our results are in accordance with previous national studies with limited variations, due to regional prevalence of specific gene variants, as expected. It is also a description of the prevalence of hemoglobinopathies in the Greek population. The type and prevalence of beta and alpha globin gene variants differ significantly among countries. We also confirm the well-known observation of many studies that in our beta thalassemic or SCD patients, co-inheritance of variants in the alpha globin genes, leading to absence or reduction of alpha globin synthesis were associated with milder clinical course, whereas the inheritance of additional alpha genes (triplication) led to a more severe clinical phenotype. In cases in whom the genotype and phenotype did not correlate, factors like the function or modification of possible regulatory genes or additional nutritional-environmental effects should be investigated. KEY MESSAGES: • This is the first Greek study, fully molecularly defining the beta and alpha mutational alleles in 217 patients with hemoglobinopathies of two large centers in Greece and correlating particular genotypes or gene variants with clinical manifestations (transfusion frequency, complications). • In the beta thalassemic or SCD patients of our cohort, co-inheritance of variants in the alpha globin genes, leading to absence or reduction of alpha globin synthesis were associated with milder clinical course (confirmation of a well-known previous observation). • The inheritance of additional alpha genes (triplication) led to a more severe clinical phenotype (confirmation of a well known previous observation). • The function or modification of possible regulatory genes should be investigated in cases in whom the genotype and phenotype did not correlate.

Progress toward Better Treatment of Therapy-Related AML.

Therapy-related acute myeloid leukemia (t-AML) comprises 10-20% of all newly diagnosed cases of AML and is related to previous use of chemotherapy or ionizing radiotherapy for an unrelated malignant non-myeloid disorder or autoimmune disease. Classic examples include alkylating agents and topoisomerase II inhibitors, whereas newer targeted therapies such as poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors have emerged as causative agents. Typically, t-AML is characterized by adverse karyotypic abnormalities and molecular lesions that confer a poor prognosis. Nevertheless, there are also cases of t-AML without poor-risk features. The management of these patients remains controversial. We describe the causes and pathophysiology of t-AML, putting emphasis on its mutational heterogeneity, and present recent advances in its treatment including CPX-351, hypomethylating agent plus venetoclax combination, and novel, molecularly targeted agents that promise to improve the cure rates. Evidence supporting personalized medicine for patients with t-AML is presented, as well as the authors' clinical recommendations.

Large irritation fibroma of hard palate: a case report of a rare clinical entity.

Fibromas are benign tumors of connective tissue common in the oral cavity but rare on hard palate. This paper reports on an asymptomatic, slowly growing mass on the hard palate of a 90-year-old lady, with a reported use of denture for two decades. The patient presented with a 2.2cm, smooth-surfaced, well-circumscribed nodule attached with a stalk to the palatal mucosa. After excision, the histopathological examination revealed a mass of fibrous connective tissue, covered by stratified squamous epithelium with focal low-medium grade hyperplasia and hyperkeratosis. These findings were consistent with irritation fibroma of hard palate, a rare entity, which should be considered as a possible diagnosis for tumors of the area by every physician.