A Multi-Center Study on the Efficacy of Eltrombopag in Management of Refractory Chronic Immune Thrombocytopenia: A Real-Life Experience

Objective: The aim of the present study was to evaluate the efficacy and safety of eltrombopag, an oral thrombopoietin receptor agonist, in patients with chronic immune thrombocytopenia (ITP). Materials and Methods: A total of 285 chronic ITP patients (187 women, 65.6%; 98 men, 34.4%) followed in 55 centers were enrolled in this retrospective cohort. Response to treatment was assessed according to platelet count (/mm3) and defined as complete (platelet count of >100,000/mm3), partial (30,000-100,000/mm3 or doubling of platelet count after treatment), or unresponsive (<30,000/mm3). Clinical findings, descriptive features, response to treatment, and side effects were recorded. Correlations between descriptive, clinical, and hematological parameters were analyzed. Results: The median age at diagnosis was 43.9±20.6 (range: 3-95) years and the duration of follow-up was 18.0±6.4 (range: 6-28.2) months. Overall response rate was 86.7% (n=247). Complete and partial responses were observed in 182 (63.8%) and 65 (22.8%) patients, respectively. Thirty-eight patients (13.4%) did not respond to eltrombopag treatment. For patients above 60 years old (n=68), overall response rate was 89.7% (n=61), and for those above 80 years old (n=12), overall response rate was 83% (n=10). Considering thrombocyte count before treatment, eltrombopag significantly increased platelet count at the 1st, 2nd, 3rd, 4th, and 8th weeks of treatment. As the time required for partial or complete response increased, response to treatment was significantly reduced. The time to reach the maximum platelet levels after treatment was quite variable (1-202 weeks). Notably, the higher the maximum platelet count after eltrombopag treatment, the more likely that side effects would occur. The most common side effects were headache (21.6%), weakness (13.7%), hepatotoxicity (11.8%), and thrombosis (5.9%). Conclusion: Results of the current study imply that eltrombopag is an effective therapeutic option even in elderly patients with chronic ITP. However, patients must be closely monitored for response and side effects during treatment. Since both response and side effects may be variable throughout the follow-up period, patients should be evaluated dynamically, especially in terms of thrombotic risk factors.

Central nervous system involvement of T-cell prolymphocytic leukemia diagnosed with stereotactic brain biopsy: case report.

Prolymphocytic leukemia (PLL) is a generalized malignancy of the lymphoid tissue characterized by the accumulation of monoclonal lymphocytes, usually of B cell type. Involvement of the central nervous system (CNS) is an extremely rare complication of T-cell prolymphocytic leukemia (T-PLL). We describe a case of T-PLL presenting with symptomatic infiltration of the brain that was histopathologically proven by stereotactic brain biopsy. We emphasize the importance of rapid diagnosis and immediate treatment for patients presenting with CNS involvement and a history of leukemia or lymphoma.

Frequency of inherited variants in the MEFV gene in myelodysplastic syndrome and acute myeloid leukemia.

We investigated the frequency of inherited variants in the MEFV gene, which is mutated in familial Mediterranean fever (FMF), in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Eight MEFV gene variants (M694I, M694V, M680I (G/C-A), V726A, R761H, E148Q and P369S) were analyzed in 33 MDS patients, 47 AML patients and 65 healthy controls; none had a history or family history compatible with FMF. We identified two homozygous (E148Q/E148Q), one compound heterozygous (M694V/E148Q) and five heterozygous inherited variants in the MEFV gene in AML patients. We also identified nine heterozygous variants in MDS patients, while we found 11 heterozygous variants in controls. The mean overall frequency of inherited variants in the MEFV gene rate was higher in MDS (χ² = 4.241; P = 0.039) and AML (χ² = 3.870; P = 0.043) patients than in healthy controls. In conclusion, this study reports high frequency of inherited variants in the MEFV gene in patients with MDS and AML. However, the hypothesis that MEFV is a cancer susceptibility gene at this point remains speculative. Additional evidence from future studies is needed to allow a more thorough evaluation of this hypothesis.

Therapeutical potential of autologous peripheral blood mononuclear cell transplantation in patients with type 2 diabetic critical limb ischemia.

AIM: The aim was to evaluate the therapeutic effectiveness of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood mononuclear cells (PBMNCs) in critical limb ischemia (CLI) of type 2 diabetic patients. METHOD: Forty diabetic patients with CLI were enrolled and randomized to treatment and control groups. In the treatment group, the patients received subcutaneous injections of recombinant human G-CSF (30 MU/day) for 5 days to mobilize stem cells. PBMNCs were collected and transplanted by multiple intramuscular injections of 1 ml in 1-1.5-cm depth into ischemic limbs. RESULTS: At the end of 12 weeks of follow-up, the baseline and end point results in transplant group were as follows: Fontaine score improved from 3.8±03 to 3±0.5 (P=.0001), ankle brachial pressure index increased from 0.68±0.24 to 0.87±024 (P=.001), transcutaneous oxygen increased from 33±14 mmHg to 44±10 mmHg (P=.0001), and 6-min walking distance improved from 280±82 m to 338±98 m (P=.0001). Pain score decreased from 8.2±1.3 to 5.63±1.6 (P=.001), and the number of patients with limb ulcers was reduced from 9/20 (45%) to 3/20 (15%) (P=.031). In the control group, Fontaine score, 6-min walking distance, and pain score were improved; ankle brachial pressure index and transcutaneous oxygen pressure were not improved. The number of patients with limb ulcers did not change in the control group. There are improvement in amputation rates, collateral vessel development, and number of limb ulcers healed. CONCLUSIONS: These results indicate that the autologous transplantation of G-CSF that mobilized PBMNCs in CLI diabetic patients is safe and effective in patient compliant reduction and improved perfusion.

Increased iron and oxidative stress are separately related to cognitive decline in elderly.

AIM: The aim of this study is to examine the relation between body iron, oxidative stress and cognitive function in elderly. METHODS: Eighty-seven elderly residents from nursing homes were the subjects of our study. Cognitive status was screened by the Mini-Mental State Examination (MMSE). Of the 87 eligible subjects, 46 patients who obtained 24 or fewer points on the MMSE scale were considered as subjects with cognitive dysfunction. The control group consisted of 41 subjects who obtained more than 24 points on the MMSE. Routine biochemical analyses, parameters of iron metabolism, malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) were determined in all subjects. RESULTS: There were statistically significant increases in serum iron, transferrin saturation, ferritin and MDA levels; whereas there was a statistically significant decrease in serum GSH-Px enzyme activity and serum sodium levels in subjects with cognitive dysfunction. A significant negative correlation was found between serum iron, transferrin saturation, ferritin and MMSE score. There was a negative correlation between MMSE score and serum MDA; however, a positive significant correlation was found between MMSE score and both GSH-Px enzyme activity and serum sodium. CONCLUSION: Our study provides evidence of increased markers of iron deposition and oxidative stress in patients with cognitive dysfunction. It seems likely that these markers negatively affect the MMSE score. Interestingly, we did not find any correlation between the markers of iron deposition and oxidative stress. Future studies will be required to demonstrate whether diminishing iron and oxidative stress will enhance MMSE score and thereby ameliorate cognitive impairment.

High Frequency of Inherited Variants in the MEFV Gene in Acute Lymphocytic Leukemia.

In the present study, we aimed to determine the frequency of inherited variants in the MEFV (Mediterranean FeVer), the gene responsible for familial Mediterranean fever (FMF), gene in patients with acute lymphocytic leukemia (ALL). The eight MEFV gene variants (M694I, M694V, M680I (G/C-A), V726A, R761H, E148Q and P369S) were detected in 36 patients with ALL and 65 healthy controls; none had own and/or family history compatible with FMF. We identified 11 heterozygous inherited variants in the MEFV gene in both ALL patients and controls. The mean overall frequency of inherited variants in the MEFV gene rate was higher in ALL patients than healthy controls (P = 0.040). It is interesting to note that M680I/0 is predominant variant in patients with ALL. In addition, E148Q variant frequency was also significantly higher in the patient group than the controls (P = 0.012). In conclusion, overall frequency of inherited variants in the MEFV gene was found to be higher in patients with ALL. Based on the present data, it is difficult to reach a definitive conclusion regarding the possibility that inherited variants in the MEFV gene could represent a causative role in ALL. However, the data of our study may provide some new insights in understanding of individual genetic differences in susceptibility to these neoplasms. Further investigations are needed to determine the actual role of inherited variants in the MEFV gene in pathogenesis of ALL.

High frequency of MEFV gene mutations in patients with myeloid neoplasm.

We aimed to investigate the rate of MEFV, the gene mutated in familial Mediterranean fever, mutations in patients with myeloid neoplasm and to determine if known mutations of MEFV cause a tendency for myeloid neoplasms. The frequency of the five most common MEFV gene mutations (M694V, M680I, V726A, E148Q and M694I) was determined in 26 patients with myeloid neoplasm. We identified 1 homozygous (E148Q/E148Q), 1 compound heterozygous (M694V/E148Q) and 5 heterozygous MEFV gene mutations; none had their own and/or family history compatible with familial Mediterranean fever. The mean overall mutation rate was 0.269. We found a high frequency of carriers in patients with myelodysplastic syndrome (66.6%), polycythemia vera (33.3%) and acute myeloid leukemia (28.6%). However, there was no MEFV gene mutation in patients with chronic myeloid leukemia. In conclusion, this study reports for the first time a possibly high prevalence of MEFV gene mutations in patients with myeloid neoplasm, especially myelodysplastic syndrome, polycythemia vera and acute myeloid leukemia. Our findings could open new perspectives for MEFV gene mutations in myeloid neoplasms and its association with tumor promotion. Further research is needed to determine the actual role of MEFV gene mutations in these malignancies.

Relationship between anaemia and cognitive functions in elderly people.

BACKGROUND: The primary goal of the present study was to investigate the effects of anaemia on the cognitive functions and daily living activities in elderly people. METHODS: This sectional study was performed using 180 elderly people. Face-to-face interviews and questionnaires were conducted to evaluate daily activities. To evaluate cognitive functions we used the Folstein's Mini-Mental State Examination (MMSE). RESULTS: The mean age of the anaemic group and the nonanaemic group were 76.0+/-11.7 and 72.5+/-15.2 years, respectively. The average haemoglobin level among the anaemic population was 10.4 g/dL compared with 13.6 g/dL among the nonanaemic population; a statistically significant difference. There was more impairment in functional status (Katz ADL) (6.8+/-4.3 vs 9.3+/-3.7) and cognition (MMSE) (17.9+/-6.4 vs 21.7+/-6.7) in anaemic than nonanaemic groups, respectively. Albumin and body mass index were lower and the percentage of two or more comorbidities was higher in anaemic group compared to the nonanaemic group, which was a statistically significant variation. The anaemic group was more dependent in terms of bathing, dressing, toileting and transferring. CONCLUSION: In the elderly anaemic group, the dependency for daily activities that require physical effort was higher compared to the nonanaemic group. The MMSE score in the elderly anaemic group was lower than subjects who had normal haemoglobin levels. We conclude that anaemia may impair cognitive functions and some daily living activities in the elderly.

Albumin, hemoglobin, body mass index, cognitive and functional performance in elderly persons living in nursing homes.

The aim of this study is to produce the relation between cognitive and functional performance and some biochemical parameters in elderly population. So, we searched for the correlation between the activities of daily living (ADL), mini-mental state examination (MMSE) and body weight, age, hemoglobin, albumin, serum sodium level of 180 elderly people in five nursing homes. Face-to-face interviews and questionnaires were applied to evaluate ADL. To evaluate the cognitive function we used the MMSE. The average age of 180 people contacted was 71.5+/-5.1 (+/-S.D.), ranging 65-91 years; 112 of them were women (62.2%), 68 were men (37.8%). Of these elderly people, 25% had no medically diagnosed illnesses, whereas 17 of them (9.4%) were bedridden. There was a positive correlation between ADL and hemoglobin, albumin, body weight, cognitive function parameters and a negative one with age and serum sodium. There was a positive correlation between cognitive functions and hemoglobin, body weight, ADL and a negative one with serum sodium. Hemoglobin concentrations indicating anemia were observed in 30% of subjects, 3.9% of them had hyponatremia and 26.7% displayed a hypernatremia. There was a positive correlation between cognitive and physical function scores and hemoglobin, albumin levels in elderly patients. These results suggest that restoration of hemoglobin and albumin levels could improve cognitive and physical functional status in the elderly population.

Mean platelet volume increase after tamoxifen, but not after anastrazole in adjuvant therapy of breast cancer.

AIM: To investigate differences of platelet indices in breast cancer patients after tamoxifen (tmx) and anastrazole adjuvant treatment. METHODS: In this retrospective study, 46 postmenopausal women (20 with tmx and 26 with anastrazole) with breast cancer who received adjuvant hormone therapy were enrolled. The biochemical and complete blood count (CBC) parameters were documented before hormone treatment start and after 1 year. RESULTS: The lymphocyte count was higher after tmx use, but not anastrazole. Total white blood cells were increased both after 1-year tmx and anastrazole using. Mean platelet volume (MPV) increased after tmx use (8.2 +/- 0.94-8.97 +/- 0.97; P: 0.041), while it was not different after anastrazole use (7.96 +/- 1.08-7.89 +/- 0.99; P: 0.585). Other platelet parameters did not alter with tmx or anastrazole treatment. CONCLUSION: We found increased MPV after tmx treatment, but did not after anastrazole treatment. The advanced studies which explore biological significance of high MPV in breast cancer patients used endocrine therapy, should be established.

CD8+CD28- cells and CD4+CD25+ regulatory T cells in the peripheral blood of advanced stage lung cancer patients.

AIM: To evaluate the CD8+CD28- and CD4+CD25+ regulatory T (Treg) cells in addition to other some lymphocyte subgroups in peripheral blood of advanced stage lung cancer patients. METHODS: The study group (n = 28) comprised chemotherapy and radiotherapy naïve patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The control group (n = 22) consisted of age- and sex-matched healthy volunteers. Flow cytometry was used to count T cells, natural killer (NK) cells and CD4+CD25 Treg cells, and for CD8+ T cell subgroup analysis. Flow cytometry was performed and annexin V binding was used for apoptotic cell evaluation. RESULTS: In patient group, the percentage of CD8+CD28- cells among lymphocytes was elevated, and there was also an increase in the CD28-/CD28+ cell ratio among CD8 lymphocyte population. The distribution of CD8 cells was different in lung cancer patients when compared with the control group. The absolute count of CD4+CD25(bright) cells and the percentages of these cells among total lymphocytes were higher in the patient group. The Annexin V(+) cell percentages among CD8+CD28- and CD8+CD28+ lymphocytes were higher in the patient group than in the control group. No differences were found between the NSCLC and SCLC patients with respect to the hematological parameters and the distribution of lymphocyte subgroups. In NSCLC patients, the percentage of CD8+CD28- cells among the lymphocyte population was higher in patients with stage IV than those with stage III. CONCLUSION: These findings may reflect the possibility of tumor-induced immunosuppression and they should be complemented with further studies.

Acute myeloid leukemia complicating multiple myeloma: a case successfully treated with etoposide, thioguanine, and cytarabine.

BACKGROUND: The association of acute leukemia and multiple myeloma (MM) has been usually described not only as a complication of chemotherapy but also in the absence of chemotherapy or together at the time of diagnosis. Such leukemias are typically acute myeloid leukemia (AML). The myelomonocytic subtype is particularly found. CASE REPORT: We report a case of a 68-year-old female who developed AML 2 years after the diagnosis of light chain (kappa) myeloma. She had been treated with oral melphalan and prednisone for MM. The patient was treated with an anthracycline-lacking therapy consisting of etoposide 120 mg/m2, thioguanine 100 mg/m2 orally twice daily on 1-5 days, and cytarabine 40 mg/m2 subcutaneously on day 1 (ETC) because of poor cardiac performance. CONCLUSION: Following ETC therapy our particular patient has been in complete hematologic remission for 29 months. This therapy might be a safe alternative in secondary leukemia especially for elderly patients.

Increased asymmetric dimethylarginine levels in young men with familial Mediterranean fever (FMF): is it early evidence of interaction between inflammation and endothelial dysfunction in FMF?

OBJECTIVE: Unlike in many other chronic inflammatory rheumatic diseases, studies investigating endothelial dysfunction and atherosclerosis in familial Mediterranean fever (FMF) are limited, and the results are controversial. Asymmetric dimethylarginine (ADMA) is considered an indicator for endothelial dysfunction and a sensitive marker for cardiovascular risk. There have been no reports on serum ADMA levels in patients with FMF. METHODS: We aimed (1) to determine serum ADMA concentrations in 38 young male patients with FMF and 23 age- and body mass index-matched healthy volunteers; (2) to evaluate its correlations with MEFV mutations, C-reactive protein (CRP) levels, and lipid profile; and (3) to compare effects of colchicine on circulating ADMA concentrations. RESULTS: In patients with FMF, ADMA and CRP levels were higher than in healthy controls. The mean levels of ADMA and CRP were higher during acute attacks than in attack-free periods. Patients taking colchicine had lower serum ADMA levels than non-colchicine users. There was a positive strong correlation between ADMA and CRP in patients with FMF. Stepwise linear regression analysis in patients with FMF revealed that age and CRP levels were independently associated with serum ADMA levels. CONCLUSION: Our data imply that higher serum ADMA levels in FMF may indicate inflammation-related "endothelial dysfunction." It seems likely that regular use of colchicine is effective in preventing the development of and reversing not only amyloidosis but also endothelial dysfunction in patients with FMF.

Effect of corticosteroids on hemostasis and pulmonary arterial pressure during chronic obstructive pulmonary disease exacerbation.

BACKGROUND: Hemodynamic and hemostatic abnormalities are reportedly frequent in chronic obstructive pulmonary disease (COPD). OBJECTIVES: We investigated the changes in systolic pulmonary artery pressure (PAPs) and hemostatic status and the effects of systemic steroid treatment (SST) during COPD exacerbation. METHODS: Consecutive 26 male and 4 female patients as well as 10 controls were enrolled. The nonsteroid treatment (NST) group received standard treatment without steroids, and the other group received additional SST. Initial values of blood gases, spirometry and PAPs, P-selectin, D-dimer and fibrinogen levels, activities of thrombocyte aggregation, antithrombin III (AT III), protein C (PC), protein S, activated PC resistance (APCR), prothrombin time and partial thromboplastin time were obtained and compared with values at day 10. RESULTS: Improvement in spirometry and blood gases was more prominent with SST. At presentation, patients had higher PAPs, P-selectin, D-dimer and fibrinogen but lower AT III levels than controls. PAPs and fibrinogen levels significantly decreased in the SST group while P-selectin levels further increased in the NST group. The D-dimer level significantly decreased in both groups. Means of AT III, PC and protein S increased in the SST and decreased in the NST group, but only the decrease in PC in the NST group was meaningful. Compared with the controls, AT III levels in the NST group and activated PC resistance in the SST group were significantly decreased. Thrombocyte aggregation tests suggested an incline after 10 days in both groups. CONCLUSIONS: We suggest that in patients with COPD exacerbation, addition of systemic corticosteroids to treatment results in better outcome in normalization of PAPs, hemostasis, pulmonary functions and blood gases.

Recombinant activated factor VII for severe uterine bleeding after chemotherapy in a woman with acute myeloid leukemia.

Acute hemorrhage is sometimes a serious complication that may arise in patients with acute leukemia as a result of therapy-induced myelosuppression. In most cases, transfusion of platelets and red blood cells are used to manage this clinical entity. These therapeutic interventions are not always successful and a more direct approach to activating the coagulation system can be more effective and, in some instances, life saving. Recombinant activated factor VII (rFVIIa), which is used for management of hemophiliac patients with inhibitors, is a major alternative in such situations. Here we describe the use of rFVIIa in a 41-year-old patient with ongoing vaginal bleeding with acute myeloid leukemia. Our experience indicates that rFVIIa may be an effective salvage treatment in bleeding conditions related to leukemia.

Results of treatment of acute myeloid leukemia and myelodysplastic syndrome with etoposide, thioguanine, cytarabine (ETC) in elderly patients.

Treatment in elderly patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains controversial, and results have been poor with most regimens. In order to study the efficacy of a new regimen in the treatment of these diseases in elderly patients assessed as not tolerating full-scale anthracycline-containing intensive chemotherapy, 14 patients over 60 years were enrolled in our study. The median age was 69 years, range 60-85 years. Eight patients had MDS (one transformed to AML) and six had AML. Anthracycline-lacking therapy (ETC) consisted of etoposide 120 mg/m² and thioguanine 100 mg/m² p.o. twice daily on days 1-5 and cytarabine (araC) 40 mg/m² s.c. on day 1. The preliminary results were as follows: 7 of the 14 patients (50%) achieved complete remission. The median survival was 10 months. Days spent at hospital were 28. Neutropenia was observed for 11 days and thrombocytopenia for 15 days. No severe infection was detected. Early death was observed in 2 (14%) of the patients. In conclusion, this novel treatment with a complete response of 50% appears to be a simple, safe, cost-effective form of therapy for elderly patients.