Nelma Clementino

The levels of IL-17A and of the cytokines involved in Th17 cell commitment are increased in patients with chronic immune thrombocytopenia

Th17 cells have been associated with immune-mediated diseases in humans but it has still not been determined whether they play a role in immune thrombocytopenia. We evaluated representative cytokines of the Th17, Th1, Th2 and Treg cell commitment in the serum of patients with chronic immune thrombocytopenia, as well as the cell source of IL-17A. Higher levels of IL-17A and Th17-related cytokines, and an increased percentage of IL-17A producing CD4+ and neutrophils were observed in patients. The levels of cytokines involved in Th1 cell commitment IFN-γ, IL-2, IL12-p70 and the percentages of Th1 cells were also increased, but IL-4 was not detected. Although the concentrations of IL-10 were higher, the levels of TGF-β were similar in both groups. In conclusion, our results point to a putative role for Th-17 cells/IL-17A cytokine in the pathogenesis of chronic immune thrombocytopenia.

An evaluation of the cardiotoxicity of imatinib mesylate

We studied 103 consecutive patients with chronic myeloid leukaemia on treatment with imatinib (IM) and 57 patients with chronic myeloproliferative disorders not treated with IM in order to evaluate its cardiotoxicity. There was no statistical difference regarding cardiac symptoms and signs, BNP levels and echocardiographic measurements for IM and control groups, except for peripheral oedema, more frequent in the IM group. Four patients in the IM group presented a BNP level >100pg/ml, one of them with depressed LVEF. IM was not related to systematic deterioration of cardiac function, but there is still a possibility of isolated cases of cardiotoxicity.

Imatinib treatment duration is related to decreased estimated glomerular filtration rate in chronic myeloid leukemia patients

BACKGROUND We analyzed the incidence of acute kidney injury and chronic renal failure in chronic myeloid leukemia (CML) patients using imatinib and investigated whether there is a relation between duration of imatinib therapy and decrease in estimated glomerular filtration rate (GFR). PATIENTS AND METHODS One hundred five CML patients on imatinib therapy were enrolled. Creatinine, urea, uric acid, and potassium measurements from imatinib treatment onset until the end of follow-up (median 4.5 years) were included in the analysis. GFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS During follow-up, 7% of patients developed acute kidney injury; creatinine levels returned to baseline in only one of them. According to the regression equation, the mean baseline value of the estimated GFR was 88.9 ml/min/1.73 m(2). Estimated GFR decreased significantly with imatinib treatment duration; the mean decrease per year was 2.77 ml/min/1.73 m(2) (P < 0.001); 12% of patients developed chronic renal failure. Age, hypertension, and a history of chronic renal failure or interferon usage were not significantly related to the mean decrease in the estimated GFR over time. CONCLUSION The introduction of imatinib therapy in nonclinical trial CML patients is associated with potentially irreversible acute renal injury, and the long-term treatment may cause a clinically relevant decrease in the estimated GFR.

Long-term effect of Helicobacter pylori eradication on plasma homocysteine in elderly patients with cobalamin deficiency

Background:Helicobacter pylori gastritis may lead to impairment of the production of pepsinogen and acid, which are essential to cobalamin absorption. In turn, cobalamin deficiency leads to hyperhomocysteinaemia, a risk factor for cardio and cerebrovascular diseases. Aim: To evaluate the effect of H pylori eradication on plasma homocysteine levels in elderly patients. Patients: Sixty-two H pylori-positive elderly patients with cobalamin deficiency were prospectively studied. Methods: Homocysteine and cobalamin concentrations were determined before, 6 and 12 months after H pylori eradication. Results: Corpus atrophy was observed in a few patients; otherwise, in most of them, the degree of corpus gastritis was moderate to severe. The initial homocysteine mean (SD) levels decreased from 41.0 (27.1) to 21.6 (10.1) μmol/l at the 6 month follow-up (p<0.001) and to 13.1 (3.8) μmol/l 12 months after H pylori eradication (p<0.001). Conversely, initial cobalamin mean levels increased from 145.5 (48.7) pmol/l to 209.8 (87.1) pmol/l and to 271.2 (140.8) pmol/l, 6 and 12 months after treatment, respectively (p<0.001 for both). Although the erythrocyte mean corpuscular volume was within reference intervals, it decreased significantly 6 (p = 0.002) and 12 (p<0.001) months after treatment. Conclusions: The results of the current study demonstrated that the eradication of H pylori in elderly patients with cobalamin deficiency is followed by increasing of cobalamin and decreasing of homocysteine blood levels.

De novo acute myeloid leukemia in adults younger than 60 years of age: socioeconomic aspects and treatment results in a Brazilian university center.

We retrospectively studied the outcomes of adults with de novo acute myeloid leukemia treated in a reference center in Brazil and analyzed the association with the human development index (HDI) of the United Nations used as a socioeconomic factor. Among 123 patients, 46 (37%) died during induction, 65 (53%) reached complete remission and 45 (37%) received high-dose cytarabine (Hidac) consolidation. The 5-year overall survival and leukemia-free survival (LFS) were 17 and 26%, respectively, for all patients and 36 and 30%, respectively, for those receiving Hidac. In multivariate analysis, an HDI <0.660 was associated with a lower probability to receive Hidac (P = 0.001), a trend for higher mortality in remission induction (P = 0.062) and a decreased LFS (P < 0.0001). However, it was not associated with outcomes for patients receiving Hidac. In conclusion, survival for patients who received Hidac consolidation is satisfactory; however, socioeconomic factors may have selected patients to receive intensive Hidac consolidation.

research paper: IL1RN VNTR and IL2−330 polymorphic genes are independently associated with chronic immune thrombocytopenia

Chronic Immune Thrombocytopenia (cITP) is an acquired immune‐mediated disease associated with a T‐helper cell type 1 (Th1) immune polarization, whose genetic risk factors, however, are largely unknown. We investigated polymorphisms in promoter regions of genes that code molecules involved in proinflammatory immune response [IL1B−31T/C, IL1RN variable number tandem repeats (VNTR), IL2−330T/G, and TNF−307G/A] as well as in genes that code Toll like receptors (TLR) (TLR2 Arg753Gln, TLR4 Asp299Gly and TLR5 Arg392stop) in 122 patients with cITP and 541 blood donors. The frequencies of the IL1RN polymorphic allele 2 (P = 0·001) and of the IL2−330 polymorphic allele G (P = 0·004) were significantly higher in cITP patients than in blood donors. In logistic analysis adjusting for age and gender, the polymorphisms remained independently associated with cITP. Enhanced serum concentrations of interleukin (IL)‐1α and IL‐1β were observed in cITP (P < 10−3) and blood donor (P = 0·04) carriers of the IL1RN*2. Also, the serum levels of IL‐2 and γ‐interferon (IFN‐γ) were increased in cITP patients (P < 10−3 and P = 0·04 respectively) and blood donors (P < 10−3 and P = 0·03 respectively) harbouring the IL2−330G allele. Here we demonstrated that IL2−330G and IL1RN*2 are independently associated with cITP and are functional in vivo, which strongly suggests that they contribute to the pathogenesis of cITP.

IL1RN VNTR and IL2 )330 polymorphic genes are independently associated with chronic immune thrombocytopenia

Chronic Immune Thrombocytopenia (cITP) is an acquired immune‐mediated disease associated with a T‐helper cell type 1 (Th1) immune polarization, whose genetic risk factors, however, are largely unknown. We investigated polymorphisms in promoter regions of genes that code molecules involved in proinflammatory immune response [IL1B−31T/C, IL1RN variable number tandem repeats (VNTR), IL2−330T/G, and TNF−307G/A] as well as in genes that code Toll like receptors (TLR) (TLR2 Arg753Gln, TLR4 Asp299Gly and TLR5 Arg392stop) in 122 patients with cITP and 541 blood donors. The frequencies of the IL1RN polymorphic allele 2 (P = 0·001) and of the IL2−330 polymorphic allele G (P = 0·004) were significantly higher in cITP patients than in blood donors. In logistic analysis adjusting for age and gender, the polymorphisms remained independently associated with cITP. Enhanced serum concentrations of interleukin (IL)‐1α and IL‐1β were observed in cITP (P < 10−3) and blood donor (P = 0·04) carriers of the IL1RN*2. Also, the serum levels of IL‐2 and γ‐interferon (IFN‐γ) were increased in cITP patients (P < 10−3 and P = 0·04 respectively) and blood donors (P < 10−3 and P = 0·03 respectively) harbouring the IL2−330G allele. Here we demonstrated that IL2−330G and IL1RN*2 are independently associated with cITP and are functional in vivo, which strongly suggests that they contribute to the pathogenesis of cITP.

Mieloma múltiplo: características clínicas e laboratoriais ao diagnóstico e estudo prognóstico

Multiple myeloma (MM) is characterized by plasmocyte expansion in the bone marrow and the production of monoclonal immunoglobulin, causing bone destruction, renal failure, hematopoietic suppression and infections. Identification of clinical and laboratory factors in the diagnosis are important to predict survival. The Durie/Salmon staging system, used for the disease, is based on the correlation of clinical and laboratory parameters on tumoral mass. Studies of the combination of β2 microglobulin and albumin resulted in a simple staging system, known as the International Staging System (ISS), which is currently being used. The objectives of this work were to analyze clinical and laboratory characteristics in the diagnosis of MM patients and a study of survival. A non-competitive cohort study was performed of 101 MM patients attended in the Hematology Service/Hospital das Clinicas-UFMG who were diagnosed in the period of April 1994 to October 2006.A descriptive analysis of the characteristics at diagnosis and a study of survival were made. The descriptive analysis was achieved using the Kaplan-Meier technique and the Log-Rank test utilized for a comparison of survival curves. The Cox regression test was used for multivariate analysis. The average age of the patients was 63 years, 47.5% were men and 52.5% women, with 50.6% being white, 33.3% black and 16.1% mulattos. The most common clinical manifestations were: bone pain (83.2%) and weakness (70.3%). Radiographies of the skeleton showed alterations in 83.8% of the cases. In respect to the Durie/Salmon staging system, 63 (62.4%) patients were in stage III, 32 (31.7%) in stage II and 6 (5.9%) in stage I. Using the ISS classification, 22 (30.1%) patients were in stage III, 31 (42.5%) in stage II and 20 (27.4%) in stage I. Overall survival was 66.52 months with a follow-up of 20 months. In the univariate analysis, creatinine (p=0.006), hemoglobin (p=0.001), the Durie/Salmon staging system (p=0.009) and ISS (p=0.014) were significant. In the multivariate analysis only hemoglobin (p=0.012) was correlated to survival. Most of the patients presented in the advanced stage at diagnosis with repercussions on survival.

Cytokine profile of patients with chronic immune thrombocytopenia affects platelet count recovery after Helicobacter pylori eradication

Helicobacter pylori eradication induces platelet recovery in a subgroup of patients with chronic immune thrombocytopenia (cITP), but the mechanisms involved are still not understood. We aimed to evaluate the effect of H. pylori eradication on platelet response and to identify the associated serum cytokine profile in 95 patients with cITP. Serum cytokine concentrations were determined by enzyme‐linked immunosorbent assay prior to and 6 months after H. pylori eradication. Remission of cITP was observed in 17 (28·8%) of 59 patients in whom the bacterium was eradicated. Six months after treatment, a significant reduction in the concentrations of T‐helper (Th) 1 and Th17 cells and an increase in T regulatory (Treg) and Th2‐cell commitment cytokines were observed in patients who recovered, but not in those whose platelet count did not recover. Patients who had a platelet response to eradication of the bacteria had higher pre‐treatment serum levels of γ‐interferon (IFNG, IFN‐γ), transforming growth factor‐β (TGFB1, TGF‐β) and interleukin 17 (IL17A, IL‐17) than patients who did not respond, but only higher pre‐treatment TGFB1 levels was independently associated with platelet response. In conclusion, amelioration of cITP after eradication of H. pylori was linked to a more efficient suppression of Th1 and Th17 response and a more pronounced Treg cell response.

BCR-ABL Mutations in Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors and Impact on Survival

This is the largest Latin American study of BCR-ABL mutations in chronic myeloid leukemia (CML) patients, resistant to imatinib (IM). In 195/467 (41%) patients, mutations were detected. The most frequent mutation was T315I (n = 31, 16%). Progression-free (PFS) and overall survival (OS) at 5 years were lower in patients with BCR-ABL mutations (43% vs. 65%, p = 0.07 and 47% vs. 72%, p = 0.03, respectively) and in those with the T315I mutation (p = 0.003 and p = 0.03). OS and PFS were superior in subgroup who switched to second generation inhibitors (SGIs) after IM failure (OS: 50% vs. 39% p = 0.01; PFS: 48% vs. 30% p = 0.02). BCR-ABL mutations conferred a significant poor prognosis in CML patients.