Uncovering the molecular landscape of meningiomas and the impact of perioperative steroids on patient survival.

BACKGROUND: The current literature on meningioma reveals a gap in knowledge regarding the impact of genetic factors on patient survival. Furthermore, there is a lack of data on the relationship between the perioperative use of corticosteroids and patient survival in meningioma patients. Our study aims to overcome these gaps by investigating the correlation between genetic factors and overall survival and the effect of postoperative corticosteroids and other clinical characteristics on patient outcomes in meningioma patients. METHODS: A retrospective analysis of the medical records of 85 newly diagnosed meningioma patients treated from 2016 to 2017 with follow-up until December 2022 was performed. RESULTS: NF2 mutations occurred in 60% of tumors, AKT1 mutations in 8.2%, and TRAF7 mutations in 3.6%. Most tumors in the parasagittal region had the NF2 mutation. On the other hand, almost all tumors in the sphenoid ridge area did not have the NF2 mutation. AKT-1-mutated meningiomas had more frequent peritumoral edema. Patients who received steroids perioperatively had worse overall survival (OS) than those without steroids (p = 0.034). Moreover, preoperative peri-meningioma edema also was associated with worse OS (p < 0.003). Contrarily, NF2 mutations did not influence survival. CONCLUSIONS: The combination of clinical, pathomorphological, and genetic data allows us to characterize the tumor better and assess its prognosis. Corticosteroids perioperatively and peri-meningioma edema were associated with shorter OS, according to our study. Glucocorticoids should be used judiciously for the shortest time required to achieve symptomatic relief.

Killer-cell immunoglobulin-like receptor genotype and haplotype combinations in children treated for acute lymphoblastic leukemia.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children. The factors predisposing to ALL remain mostly unknown. Natural killer (NK) cells are a component of innate immunity. Their role is to eliminate cells that were infected with viruses or underwent a neoplastic transformation. The activity of NK cells is regulated by their activating and inhibitory receptors, inter alia killer-cell immunoglobulin-like receptors (KIRs). The available data about a link between the incidence of ALL and KIR genotype are highly inconclusive, and further research is needed to explain whether such a relationship truly exists. The aim of this study was to analyze KIR genotype and haplotype combinations in children treated for ALL. MATERIAL AND METHODS: The study included 49 children diagnosed with ALL at 1.2-19.8 years of age. The control group was composed of 43 healthy subjects aged between 1.2 and 21.9 years. DNA was isolated using QIAamp DNA Mini kits. KIR genotypes were identified by a polymerase chain reaction (PCR) with sequence-specific primers (SSPs). The analysis also included KIR haplotype combinations: AA, AB and BB. RESULTS: Patients with ALL and controls did not differ significantly in the frequencies of individual KIR genes and haplotypes. However, the overall frequency of all 6 activating KIR genes in patients with ALL was significantly higher than in the controls (24.5% vs. 4.7%, p = 0.019). CONCLUSIONS: The findings presented here imply that individual KIR genes do not play a significant role in the pathogenesis of ALL. Nevertheless, a higher number of activating KIR genes may constitute a risk factor for this malignancy.

The impact of adjuvant radiotherapy on molecular prognostic markers in gliomas.

PURPOSE: Changes in MGMT promoter methylation, IDH1 and IDH2 mutation, and 1p/19q co-deletion status in gliomas between first and subsequent resections and their associated clinical factors are poorly described. In this study, we assayed these biomarkers in the clinical setting. PATIENTS AND METHODS: We used multiplex ligation-dependent probe amplification to measure MGMT promoter methylation, IDH mutation status, and 1p/19q co-deletion in 45 paired tumor samples from patients undergoing resection and subsequent re-resections for gliomas. RESULTS: Molecular changes were present in 20 patients (44%). At least one molecular characteristic changed over time in 89% of patients with primary grade III tumors. Gliomas with IDH wild-type and/or non-co-deleted were stable, but IDH1/2 mutation and/or co-deletion were sometimes lost at the time of recurrence. In a multivariate analysis, adjuvant radiotherapy alone was independently associated (P=0.02) with changes in molecular profile. CONCLUSION: Molecular biomarkers change in gliomas during the course of the disease, most often MGMT methylation status. These changes in genetic profiles are related to adjuvant treatment with radiotherapy alone, which might be important for individualized treatment planning over the disease course.

[Predictive value of apolipoproteine E genotypes].

Apolipoprotein E is a transport protein, which by binding to lipids forms a lipoprotein particle. It is responsible for transport and redistribution of lipids between cells and tissues. Apolipoprotein E circulates in blood mainly as a component of VLDL (very low density lipoproteins) HDL (high density lipoproteins) chylomicrons and chylomicron remnants. It assists in the flow of cholesterol from peripheral cells to extracellular space. Apolipoprotein E is one of the most studied apolipoproteins. There are three isoforms of this protein: E2, E3 and E4. Six polymorphic variants are defined by of the ApoE gene. Isoforms vary in their ability to bind to receptors for ApoE and LDL (low density lipoproteins) and affinity to lipoproteins. This is why we observe different metabolic responses in patients with various isoforms. The ApoE4 variant correlates with higher level of cholesterol in blood and thus with increased risk of atherosclerosis progression. Apolipoprotein E plays a key role in a wide range of actions. It is associated with lipids metabolism dysfunction which leads to cardiovascular diseases and also with neurodegenerative diseases of the central nervous system. In addition to classical methods of cardiac prevention, genetic tests should be performed more commonly. This could be useful in better evaluation of predisposition to pathological processes.

[Predictive value of apolipoproteine E genotypes].

Apolipoprotein E is a transport protein, which by binding to lipids forms a lipoprotein particle. It is responsible for transport and redistribution of lipids between cells and tissues. Apolipoprotein E circulates in blood mainly as a component of VLDL (very low density lipoproteins) HDL (high density lipoproteins) chylomicrons and chylomicron remnants. It assists in the flow of cholesterol from peripheral cells to extracellular space. Apolipoprotein E is one of the most studied apolipoproteins. There are three isoforms of this protein: E2, E3 and E4. Six polymorphic variants are defined by of the ApoE gene. Isoforms vary in their ability to bind to receptors for ApoE and LDL (low density lipoproteins) and affinity to lipoproteins. This is why we observe different metabolic responses in patients with various isoforms. The ApoE4 variant correlates with higher level of cholesterol in blood and thus with increased risk of atherosclerosis progression. Apolipoprotein E plays a key role in a wide range of actions. It is associated with lipids metabolism dysfunction which leads to cardiovascular diseases and also with neurodegenerative diseases of the central nervous system. In addition to classical methods of cardiac prevention, genetic tests should be performed more commonly. This could be useful in better evaluation of predisposition to pathological processes.

CEBPA copy number variations in normal karyotype acute myeloid leukemia: Possible role of breakpoint-associated microhomology and chromatin status in CEBPA mutagenesis.

Copy number variations (CNV) in CEBPA locus represent heterogeneous group of mutations accompanying acute myeloid leukemia (AML). The aim of this study was to characterize different CEBPA mutation categories in regard to biological data like age, cytology, CD7, and molecular markers, and identify possible factors affecting their etiology. We report here the incidence of 12.6% of CEBPA mutants in the population of 262 normal karyotype AML (NK-AML) patients. We confirmed that double mutant AMLs presented uniform biological features when compared to single CEBPA mutations and accompanied mostly younger patients. We hypothesized that pathogenesis of distinct CEBPA mutation categories might be influenced by different factors. The detailed sequence analysis revealed frequent breakpoint-associated microhomologies of 2 to 12bp. The analysis of distribution of microhomology motifs along CEBPA gene showed that longer stretches of microhomology at the mutational junctions were relatively rare by chance which suggests their functional role in the CEBPA mutagenesis. Additionally, accurate quantification of CEBPA transcript levels showed that double CEBPA mutations correlated with high-level CEBPA expression, whereas single N-terminal CEBPA mutations were associated with low-level CEBPA expression. This might suggest that high-level CEBPA expression and/or accessibility of CEBPA locus contribute to B-ZIP in-frame duplications.

[Molecular diagnostic tests for thrombophilia in patients referred to genetic counseling clinic because due to recurrent pregnancy failure. One center's experience]. / Badania molekularne w kierunku trombofilii u pacjentek skierowanych do poradni genetycznej z powodu niepowodzen ciazowych. Doswiadczena jednego osrodka.

UNLABELLED: The loss of three or more subsequent pregnancies before the end of the 22nd week is observed in 0.4-1% of women. Despite great advances in medicine, the causes of pregnancy failure (miscarriages, missed abortions and stillbirths), and the birth of a child or children with congenital abnormalities, are still not determined precisely THE AIM: The purpose of the research was to determine the association of polymorphisms and mutations of coagulation factors II and V genes, as well as methylenetethrahydrofolate reductase (MTHFR) gene polymorphism, with the course of pregnancy and the type of reproductive failure. METHODS: The research was performed in a group of 116 women referred to the Genetic Outpatient Clinic of the NCU SM in Bydgoszcz between 2009-2010 due to reproductive failures. The molecular tests for thrombophilia, i.e. mutation of the factor V Leiden, prothrombin gene mutation 20210G>A, and MTHFR polymorphism 677C>T were done in all patients. RESULTS: The Leiden mutation was found in 8 women (homozygotic in 2 of them) and prothrombin gene mutation in 3.85 women had the heterozygotic MTHFR polymorphism, while 24 the homozygotic one. Coexistence of the Leiden mutation and the MTHFR polymorphism was found in 3 patients with history of miscarriages. CONCLUSIONS: 1. The presence of the mutations that promote thrombophilia in the genes responsible for the foliate metabolism and for the plasma coagulation is often associated with pregnancy failures and may be their basic cause in some cases. 2. The percentage of women with pregnancy failures being heterozygotes (73.3%), homozygotes (20.7%) or both (94%) of the MTHFR gene 677C>T polymorphism is statistically significantly higher than the highest prevalence of these changes in the general population (55, 13%, and 68%, respectively). 3. The factor V gene Leiden mutation is associated mainly with recurrent spontaneous abortions. In the present study it was found only in the group of women with both early and late miscarriages.

The influence of lovastatin on thrombomodulin gene expression in vascular endothelial cells--in vitro study.

OBJECTIVE: Statins reduce lipids concentration in blood. The latest investigations show they also improved the function of vascular endothelial cells (ECs). Thrombomodulin (TM) is particularly important marker of ECs activity. We investigated the in vitro effect of lovastatin on the expression level of TM gene. METHODS AND RESULTS: ECs were incubated for 24 h in culture medium including lovastatin in 3 concentrations: 0.1, 1.0, 10.0 mol/l. The mRNA level of TM increased in correlation with rising concentrations of lovastatin to 600 % vs. control group. CONCLUSIONS: TM is essential antithrombotic factor in endothelial cells. Lovastatin significantly raises thrombomodulin gene expression. It is important characteristics of this medicine, which prevents cardiovascular events.

The application of conventional cytogenetics, FISH, and RT-PCR to detect genetic changes in 70 children with ALL.

We investigated bone marrow cells of 70 acute lymphoblastic leukemia children by conventional cytogenetics (CC), fluorescence in situ hybridization (FISH), and reverse transcription polymerase chain reaction (RT-PCR) methods. CC and RT-PCR for fusion genes BCR/ABL, MLL/AF4, E2A/PBX1, TEL/AML1 were performed at diagnosis in each patient. FISH was performed to verify the presence of fusion genes and MLL rearrangements and to estimate the percentage of abnormal cells. Karyotypes were obtained in 59 (84%) of 70 cases. Thirty-five (59%) of 59 cases revealed chromosome aberrations. Hyperdiploidy>50 chromosomes was present in nine cases, hyperdiploidy 47-50 chromosomes in six, pseudodiploidy in 15, and hypodiploidy in five. BCR/ABL was present in two cases, PBX1/E2A in two, and TEL/AML1 in 14. MLL/AF4 was not found, but the rearrangements of MLL gene were present in five children. The addition of RT-PCR and FISH to CC was of the utmost importance. One of two Ph translocations and one of two t(1;19) were first revealed by RT-PCR. Moreover, FISH showed the percentage of TEL/AML1(+) cells that turned to be an important prognostic factor. The outcome was the best for the children with hyperdiploidy>50 chromosomes without structural changes. It was also good for those with TEL/AML1 present in >or=80% of cells without chromosome aberrations. The presence of pseudodiploidy correlated with poor outcome. The outcome for patients with t(9;22)-BCR/ABL or 11q23-MLL rearrangement was the worst in study group. The presence of BCR/ABL caused eight times increase of risk of death; MLL rearrangements caused 12 times increase.