Eltrombopag for the Treatment of Refractory Pure RBC Aplasia after Major ABO Incompatible Hematopoietic Stem Cell Transplantation

Pure RBC aplasia (PRCS) is a well-recognized complication after allogeneic hematopoietic stem cell transplantation (HSCT). Many therapeutic options are available to treat this condition, including erythropoietin, rituximab, bortezomib, plasma exchange, immunoadsorption, donor lymphocyte infusion, mesenchymal stem cells, antithymocyte globulin, and high-dose steroids; however, treatment outcomes are often variable and can sometimes lead to disappointing results. In this brief article we report our experience with 2 patients with PRCA after major ABO-incompatible HSCT who were resistant to multiple therapeutic interventions and who eventually benefited from treatment with eltrombopag, a thrombopoietin mimetic approved by the US Food and Drug Administration for the treatment of patients with immune thrombocytopenic purpura or severe aplastic anemia refractory to immunosuppressive agents or not eligible for HSCT. Data from these 2 patients show that eltrombopag was effective in treating erythroid aplasia and transfusion dependence after HSCT in patients who did not benefit from multiple previous treatments. Moreover, eltrombopag was well tolerated, with only a transient thrombocytosis requiring dose adjustment and no evidence of clonal evolution. Based on the positive results obtained in these 2 patients, we suggest that eltrombopag may have a favorable effect on unilineage cytopenias such as PRCA. Further studies in a large proportion of patients are mandatory to confirm these preliminary results.     

The impact of detoxifying and repair gene polymorphisms on oxidative stress in ischemic stroke

Stroke is a multifactorial disease caused by the combination of certain risk factors and genetic factors. There are possible risk factors having important role in the pathogenesis of stroke. The most important environmental factors are cigarette smoking and oxidative stress which have different sources. GST (M1, T1, P1) have major roles in detoxification of the products of oxidative stress and they are polymorphic. DNA damages can also be repaired by repair enzymes such as OGG1 and XRCC1 which are highly polymorphic and have pivotal roles in repair systems. In the present study, we investigated that polymorphisms in genes involved in detoxification and DNA-repair pathways might modify the individual’s risk for ischemic stroke. Furthermore, the products of oxidative stress and antioxidant capacity were measured and the impact of gene polymorphism on them was evaluated. Our data showed that OGG1 Ser326Cys and XRCC1 Arg399Gln gene polymorphisms had impacts on the development of stroke.     

PRAME mRNA levels in cases with acute leukemia: clinical importance and future prospects

The PRAME (preferentially expressed antigen of melanoma) gene has been shown to be expressed in high levels in some solid tumors and hemopoietic neoplasias but not or only weakly expressed in normal tissues. It encodes an antigen recognized by autologous cytolytic T lymphocytes. PRAME is a good candidate for tumor immunotherapy and is a useful marker gene for detection of minimal residual disease (MRD). In this study, PRAME mRNA using real-time RT-PCR was studied in 74 adult cases with acute leukemia-68 had de-novo acute leukemia, 3 had chronic myeloid leukemia-blastic crisis (CML-BC), and 3 had myelodysplastic/myeloproliferative syndrome-blastic transformation (MDS/MPD-BT)-and the results were compared with 30 age-matched healthy volunteers. Nineteen of 74 cases with leukemia expressed PRAME, while only 2 controls showed weak expression. The prevalence of PRAME expression in AML and ALL cases was 30% and 17%, respectively. We did not find any important correlation between PRAME expression and clinical characteristics, such as age, sex, organomegaly/lymphadenopathy, Hb, WBC count, platelet count, LDH level, alkaline phosphatase, albumin, cell-surface antigens, response to therapy, or progression-free and overall survival. PRAME was monitored in 15 cases during remission and/or relapse. There was a good correlation between PRAME mRNA and hematological remission and/or relapse. Interestingly, PRAME was very high in one case with AML but was not found 3 months after allogeneic transplantation. PRAME mRNA is observed in about one-third of AML cases; it may be a useful marker to detect MRD, and it may also be a good predictor for the timing of donor lymphocyte infusions (DLI) in the post-transplant period in cases of molecular relapse.     

The combination of ınterleukin-10 -1082 and tumor necrosis factor α -308 or ınterleukin-6 -174 genes polymorphisms suggests an association with susceptibility to Hashimoto's thyroiditis

BackgroundThe etiopathogenesis of Hashimoto's thyroiditis (HT) has not been clearly elucidated although the role of chronical inflammation and endothelial dysfunction has been established. The imbalance between pro- and anti-inflammatory cytokines may play a role in the etiology. The aim of the present study was to investigate whether cytokine gene polymorphisms are associated with HT, and to evaluate the relationship between genotypes and clinical/laboratory manifestation of HT.MethodsTumor necrosis factor α (TNFα) G-308A (rs 1800629), interleukin-6 (IL-6) G-174C (rs 1800795) and IL-10 G-1082A (rs 1800896) single nucleotide polymorphisms (SNPs) in DNA from peripheral blood leukocytes of 190 patients with HT and 231 healthy controls were investigated by real-time PCR combined with melting curve analysis using fluorescence-labeled hybridization probes.ResultsThere was no notable risk for HT afflicted by TNFα ? 308, IL-6 ? 174 and IL-10 ? 1082 polymorphisms alone. However, carriers of variant alleles of both IL-10 ? 1082 and TNFα ? 308 polymorphisms had four-fold times higher risk for HT in comparison with non-carriers. Additionally, concomitant presence of both mutant IL-10 ? 1082 A and IL-6 ? 174 C alleles raised three-fold the HT risk.ConclusionOur results suggest that the combined effects of TNFα ? 308, IL-6 ? 174 and IL-10 ? 1082 variant alleles may be more decisive to induce functional differences and modify the risk for HT.     

Multiple sclerosis patients—benefit-risk preferences: Serious adverse event risks versus treatment efficacy

Abstract Objective:   The aim of this study is to estimate the willingness of multiple sclerosis (MS) patients to accept life-threatening adverse event risks in exchange for improvements in their MS related health outcomes. Methods:   MS patients completed a survey questionnaire that included a series of choice-format conjoint tradeoff tasks. Patients chose hypothetical treatments from pairs of treatment alternatives with varying levels of clinical efficacy and associated risks. Results:   Among the 651 patients who completed the survey, delay in years to disability progression was the most important factor in treatment preferences. In return for decreases in relapse rates from 4 to 1 and increases in delay in progression from 3 to 5 years, patients were willing to accept a 0.38% annual risk of death or disability from PML, a 0.39% annual risk of death from liver failure or a 0.48% annual risk of death from leukemia. Conclusions:   Medical interventions carry risks of adverse outcomes that must be evaluated against their clinical benefits. Most MS patients indicated they are willing to accept risks in exchange for clinical efficacy. Patient preferences for potential benefits and risks can assist in decision-making.     

The effect of risedronate treatment on serum cytokines in postmenopausal osteoporosis: a 6-month randomized and controlled study

There is much evidence suggesting that the decline in ovarian function after menopause is associated with spontaneous increases in proinflammatory cytokines. Treatment with risedronate is accompanied by significant changes in bone turnover and bone mineral density. The objective of this study was to determine the effects of risedronate treatment on the level of serum cytokines including receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin among postmenopausal women with osteoporosis. The study group consisted of 61 postmenopausal women with osteoporosis. Patients were randomly divided in two groups: In group 1 (n = 41) postmenopausal women received oral risedronate (35 mg/week), calcium (1,000 mg/day), and vitamin D (400 IU/day) for 12 months. In group 2 (control group; n = 20) patients received only oral calcium (1,000 mg/day) and vitamin D (400 IU/day). Bone mineral density (BMD) of lumbar spine (L1–L4) and proximal femur were determined using dual X-ray absorptiometry at baseline and after one year. Venous blood samples were obtained for determination of serum cytokines including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), RANKL, osteoprotegerin, and markers of bone formation and resorption. Levels of serum cytokines were measured before therapy and after three and 6 months. Markers of bone metabolism were studied before therapy and after 6 months. In group 1 (risedronate plus calcium/vitamin D-treated patients), serum levels of RANKL and IL-1β significantly decreased and the level of osteoprotegerin significantly increased after three and 6 months, but no significant difference was found in TNF-α level. In group 2, however, the level of serum cytokines did not change after three and 6 months. In cases of bone turnover, both markers of bone resorption and formation significantly decreased after 6 months in group 1. In conclusion risedronate could improve osteoporosis by increasing osteoprotegerin and reducing RANKL and IL-1β.     

Prevalence of pleural effusions post orthotopic heart transplantation

BACKGROUND AND OBJECTIVE: The prevalence and natural history of pleural effusions occurring after orthotopic heart transplantations (OHT) are essentially unknown. The objective of this study was to determine the prevalence, laterality, size and prognosis of pleural effusions occurring after OHT. METHODS: Eighty-three patients who underwent OHT between August 1997 and January 2003 were screened retrospectively. CXR and chest CT scans of all patients were reviewed. Chart review was performed for patients with large effusions (occupying 25% or more of a hemithorax) with specific attention to thoracentesis results. RESULTS: Seventy-two patients were included in the study. Sixty-one (85%) developed an effusion at some time during the first 365 postoperative days. The majority of post-OHT effusions were bilateral and small, occupying less than 25% of the hemithorax. Pleural effusions occupying 25% or more of a hemithorax occurred in 17% (12/72) of the patients within 12 months of OHT. Overall, the majority of effusions resolved within the first year after transplantation. CONCLUSIONS: The prevalence of pleural effusions within 12 months following OHT is high (85%). Most effusions are small, bilateral and resolve within 1 year.     

Predictors and clinical significance of angiographically detected distal embolization after primary percutaneous coronary interventions

OBJECTIVES: The aim of this study was to investigate clinical, angiographic and procedural predictors of distal embolization (DE) on angiography after primary percutaneous coronary intervention (PCI). The impact of DE on outcome in the first 30 days was also assessed. METHODS: Between January 2004 and April 2006, primary PCI was performed in 212 consecutive patients with acute myocardial infarction (AMI) of < or = 12-h duration. RESULTS: Distal embolization was present in 27 patients (12.7%) and more often observed in female sex (27.5 vs. 10.4%, P=0.01), in patients with right coronary artery involvement (52 vs. 28%, P=0.02), prerevascularization thrombolysis in myocardial infarction flow < or = 1 (89 vs. 69%, P=0.03), in the presence of high thrombus burden (92.6 vs. 39.5%, P=0.0009), and a long target lesion in the infarct-related artery (>14.5 mm, 74 vs. 29%, P<0.0001). By multiple stepwise logistic regression analysis, only the presence of high thrombus burden before the PCI procedure [odds ratio (OR)=5.2, 95% confidence interval (CI)=1.09-24.97, P=0.03)] and target lesion length (>14.5 mm, OR=3.9, 95% CI=1.45-10.60, P=0.007) were found independent predictors of DE. Patients with DE had an increased risk of target vessel revascularization (26 vs. 5%, P=0.001) and short-term mortality (29.6 vs. 7.5%, P=0.002) when compared with patients without angiographic signs of embolization. CONCLUSIONS: In patients who undergo primary PCI, high thrombus burden on angiography before PCI and/or a long target lesion in the infarct-related artery increase the risk of DE and subsequent short-term mortality.