Amélia Pereira

A possible role for oxidation stress in lymphoid leukaemias and therapeutic failure

The aim of this study was to evaluate the role of oxidative stress in the pathobiology of lymphoid leukaemias and its involvement in leukaemic relapse. For this purpose the generation of peroxides by mononuclear cells, the erythrocyte activity of superoxide-dismutase (SOD) and glutathione peroxidase (GL-PX), and the plasma levels of reduced glutathione (GSH) and vitamin E (VIT E) were determined in 52 patients with two different types of lymphoid leukaemias, chronic lymphocytic leukaemia (CLL) and acute lymphoblastic leukaemia (ALL), 36 prior to chemotherapy and 16 treated patients. A decrease in SOD and GL-PX activities was observed in ALL patients prior to therapy, while a decrease in GSH and VIT E plasma levels was observed in untreated CLL, as compared to age-matched controls. An increase in peroxides formation occurred in both types of leukaemia, as compared to age-matched controls. There are significant differences for GSH, VIT E and peroxides generation between the different types of leukaemias. In relapsed ALL patients a decrease in peroxides generation was observed which may be due to the increase of the non-enzymatic defences GSH and VIT E. These data suggest the involvement of oxidative stress in acute and chronic lymphoid leukaemias and leukaemic relapse.

Oxidative stress levels are correlated with P15 and P16 gene promoter methylation in myelodysplastic syndrome patients

Oxidative stress and abnormal DNA methylation have been implicated in some types of cancer, namely in myelodysplastic syndromes (MDS). Since both mechanisms are observed in MDS patients, we analyzed the correlation of intracellular levels of peroxides, superoxide anion, and glutathione (GSH), as well as ratios of peroxides/GSH and superoxide/GSH, with the methylation status of P15 and P16 gene promoters in bone marrow leukocytes from MDS patients. Compared to controls, these patients had lower GSH content, higher peroxide levels, peroxides/GSH and superoxide/GSH ratios, as well as higher methylation frequency of P15 and P16 gene promoters. Moreover, patients with methylated P15 gene had higher oxidative stress levels than patients without methylation (peroxides: 460xa0±xa042 MIF vs 229xa0±xa025 MIF, pxa0=xa00.001; superoxide: 383xa0±xa048 MIF vs 243xa0±xa017 MIF, pxa0=xa00.022; peroxides/GSH: 2.50xa0±xa00.08 vs 1.04xa0±xa00.34, pxa0<xa00.001; superoxide/GSH: 1.76xa0±xa00.21 vs 1.31xa0±xa00.10, pxa0=xa00.007). Patients with methylated P16 and at least one methylated gene had higher peroxide levels as well as peroxides/GSH ratio than patients without methylation. Interestingly, oxidative stress levels allow the discrimination of patients without methylation from ones with methylated P15, methylated P16, or at least one methylated (P15 or P16) promoter. Taken together, these findings support the hypothesis that oxidative stress is correlated with P15 and P16 hypermethylation.

Health-related quality of life and utilities in gastric premalignant conditions and malignant lesions: a multicentre study in a high prevalence country

BACKGROUND AND AIMSnA recent review of economic studies relating to gastric cancer revealed that authors use different tests to estimate utilities in patients with and without gastric cancer. Our aim was to determine the utilities of gastric premalignant conditions and adenocarcinoma with a single standardized health measure instrument.nnnMETHODSnCross-sectional nationwide study of patients undergoing upper endoscopy (n=1,434) using the EQ-5D-5L quality of life (QoL) questionnaire.nnnRESULTSnAccording to EQ-5D-5L, utilities in individuals without gastric lesions were 0.78 (95% confidence interval: 0.76-0.80), with gastric premalignant conditions 0.79 (0.77-0.81), previously treated for gastric cancer 0.77 (0.73-0.81) and with present cancer 0.68 (0.55-0.81). Self-reported QoL according to the visual analogue scale (VAS) for the same groups were 0.67 (0.66-0.69), 0.67 (0.66-0.69), 0.62 (0.59-0.65) and 0.62 (0.54-0.70) respectively. Utilities were consistently lower in women versus men (no lesions 0.71 vs. 0.78; premalignant conditions 0.70 vs. 0.82; treated for cancer 0.72 vs. 0.78 and present cancer 0.66 vs. 0.70).nnnCONCLUSIONnThe health-related QoL utilities of patients with premalignant conditions are similar to those without gastric diseases whereas patients with present cancer show decreased utilities. Moreover, women had consistently lower utilities than men. These results confirm that the use of a single standardized instrument such as the EQ-5D-5L for all stages of the gastric carcinogenesis cascade is feasible and that it captures differences between conditions and gender dissimilarities, being relevant information for authors pretending to conduct further cost-utility analysis.

Genetic variants involved in oxidative stress, base excision repair, DNA methylation, and folate metabolism pathways influence myeloid neoplasias susceptibility and prognosis.

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) share common features: elevated oxidative stress, DNA repair deficiency, and aberrant DNA methylation. We performed a hospital‐based case‐control study to evaluate the association in variants of genes involved in oxidative stress, folate metabolism, DNA repair, and DNA methylation with susceptibility and prognosis of these malignancies. To that end, 16 SNPs (one per gene: CAT, CYBA, DNMT1, DNMT3A, DNMT3B, GPX1, KEAP1, MPO, MTRR, NEIL1, NFE2F2, OGG1, SLC19A1, SOD1, SOD2, and XRCC1) were genotyped in 191 patients (101 MDS and 90 AML) and 261 controls. We also measured oxidative stress (reactive oxygen species/total antioxidant status ratio), DNA damage (8‐hydroxy‐2′‐deoxyguanosine), and DNA methylation (5‐methylcytosine) in 50 subjects (40 MDS and 10 controls). Results showed that five genes (GPX1, NEIL1, NFE2L2, OGG1, and SOD2) were associated with MDS, two (DNMT3B and SLC19A1) with AML, and two (CYBA and DNMT1) with both diseases. We observed a correlation of CYBA TT, GPX1 TT, and SOD2 CC genotypes with increased oxidative stress levels, as well as NEIL1 TT and OGG1 GG genotypes with higher DNA damage. The 5‐methylcytosine levels were negatively associated with DNMT1 CC, DNMT3A CC, and MTRR AA genotypes, and positively with DNMT3B CC genotype. Furthermore, DNMT3A, MTRR, NEIL1, and OGG1 variants modulated AML transformation in MDS patients. Additionally, DNMT3A, OGG1, GPX1, and KEAP1 variants influenced survival of MDS and AML patients. Altogether, data suggest that genetic variability influence predisposition and prognosis of MDS and AML patients, as well AML transformation rate in MDS patients.

Spontaneous pneumomediastinum: case report

OBJECTIVEnThe description of this case is due to the rarity of this clinical entity and its semiotic diversity, which implies a high level of suspicion for a correct diagnosis.nnnMETHODSnDescription of a clinical case, based on the data referred to in the clinical process.nnnRESULTSnThe case describes a young male patient, attended to at the emergency room due to right chest pain, which further investigation revealed to be consistent with spontaneous pneumomediastinum. He underwent medical treatment, with favorable outcome.nnnCONCLUSIONnThe clinical course is usually benign, self-limited, involves only conservative treatment, and use of drugs is recommended only in symptomatic patients.

Pneumomediastino espontâneo: relato de um caso

OBJECTIVE: The description of this case is due to the rarity of this clinical entity and its semiotic diversity, which implies a high level of suspicion for a correct diagnosis. METHODS: Description of a clinical case, based on the data referred to in the clinical process. RESULTS: The case describes a young male patient, attended to at the emergency room due to right chest pain, which further investigation revealed to be consistent with spontaneous pneumomediastinum. He underwent medical treatment, with favorable outcome. CONCLUSION: The clinical course is usually benign, self-limited, involves only conservative treatment, and use of drugs is recommended only in symptomatic patients.

Concomitant chronic myeloid leukemia and monoclonal B cell lymphocytosis – a very rare condition

Chronic lymphocytic leukemia (CLL) is the commonest leukemia in adults. It is defined, according to the latest guidelines, as >5 × 103/ L circulating B lymphocytes (BL) expressing a typical cell surface marker signature (CD5+, CD10−, CD19+ and CD20dim, surface immonuglobulindim, CD23+, CD43+/− and cyclin D1−).1 If lymph node enlargement and/or hepatosplenomegaly is present in a patient with <5 × 103/ L monoclonal circulating BL, the diagnosis of small lymphocytic lymphoma (SLL) is reached and treatment may be required.2 The identification of CLL-like cells in healthy people due to increasingly more sensitive immunophenotyping methods led to the definition in the 2008 World Health Organization (WHO) classification of lymphoid neoplasms of monoclonal B cell lymphocytosis (MBL) as up to 5 × 103/ L monoclonal BL in peripheral blood (PB), phenotypically similar to CLL cells, but without cytopenias or palpable lymphadenopathies. MBL is subdivided into two subgroups, “lowcount” MBL (<0.5 × 103/ L), with a residual chance to boost into CLL/SLL and “high-count” MBL, which share phenotypic and molecular/genetic features with Rai staging system 0 CLL and