M. Cem Ar

Successful management of cryoglobulinemia-induced leukocytoclastic vasculitis with thalidomide in a patient with multiple myeloma

Leukocytoclastic vasculitis (LV) is a systemic inflammatory disorder involving mostly the small vessels. It is characterised by segmental angiocentric neutrophilic inflammation, endothelial cell damage and fibrinoid necrosis. LV is related to a variety of clinical disorders including cryoglobulinemia and, very rarely, multiple myeloma (MM), among many others. The development of LV in patients with MM has been linked to cryoglobulinemia, infections, drugs and paraneoplasia. It has been speculated that myeloma patients with a poorer prognosis and progressive disease are more prone to develop LV. Thalidomide is a rediscovered old drug with anti-angiogenic, immunomodulatory and anti-inflammatory properties. It is highly effective in the treatment of MM and other clinical disorders such as leprosy, various cancers, graft-versus-host disease and autoimmune diseases. We report here a female patient with Durie–Salmon stage IIA MM who initially presented with cryoglobulinemia and LV. LV in this patient was primarily considered to be the result of progressive cryoglobulinemia, which was closely associated with MM. She was successfully managed with thalidomide and dexamethasone.

The Impact of Prothrombotic Mutations on Factor Consumption in Adult Patients with Severe Hemophilia

About 10% of patients with severe hemophilia exhibit a milder clinical phenotype with less frequent bleeds. Among many other factors, coinheritance of prothrombotic mutations have been proposed to act as modulators of clinical severity in severe hemophilia. We conducted a study to evaluate the impact of 3 prothrombotic mutations (factor V Leiden, factor II, and methylenetetrahydrofolate reductase mutations) on clinical phenotype of patients with severe hemophilia in our institution. For this purpose we compared the average annual factor concentrate consumption between carriers and noncarriers of prothrombotic mutations. A total of 38 hemophilia A and B patients with factor levels less than 1 were recruited between October 2006 and October 2007. Prothrombotic mutations were detected in venous blood using polymerase chain reaction amplification technique. Eighteen patients (47%) carried no prothrombotic mutations. The remaining 20 patients (53%) were found to be carriers of either 1 or 2 mutations. Median age in both carrier and the non-carrier groups was 27 years. None of the patients in either group gave a history of thromboembolic event. Median annual factor concentrate consumptions in carriers and noncarriers were 610 ± 530 units/kg and 770 ± 670 units/kg, respectively (P = .203). Our results demonstrated no significant difference in annual factor concentrate consumption between carriers and noncarriers of prothrombotic mutations. Considering that average annual factor consumption is a surrogate indicator of clinical phenotype, we concluded that coinheritance of prothrombotic mutations was not associated with occurrence of different clinical phenotypes in severe hemophilia.

The Changing Epidemiology of Bloodstream Infections and Resistance in Hematopoietic Stem Cell Transplantation Recipients

Objective: Patients receiving hematopoietic stem cell transplantation (HSCT) are exposed to highly immunosuppressive conditions and bloodstream infections (BSIs) are one of the most common major complications within this period. Our aim, in this study, was to evaluate the epidemiology of BSIs in these patients retrospectively. Materials and Methods: The epidemiological properties of 312 patients with HSCT were retrospectively evaluated. Results: A total of 312 patients, followed between 2000 and 2011, who underwent autologous (62%) and allogeneic (38%) HSCT were included in the study. The most common underlying malignancies were multiple myeloma (28%) and Hodgkin lymphoma (21.5%). A total of 142 (45%) patients developed at least 1 episode of BSI and 193 separate pathogens were isolated from the blood cultures. There was a trend of increase in the numbers of BSIs in 2005-2008 and a relative increase in the proportion of gram-positive infections in recent years (2009-2011), and central venous catheter-related BSI was found to be most common source. Coagulase-negative staphylococci (49.2%) and Acinetobacter baumannii (8.8%) were the most common pathogens. Extended-spectrum beta-lactamase-producing strains were 23% and 22% among Escherichia coli and Klebsiella spp. isolates, respectively. Quinolone resistance was detected in 10% of Enterobacteriaceae. Resistance to carbapenems was not detected in Enterobacteriaceae, while it was seen at 11.1% and 23.5% in Pseudomonas and Acinetobacter strains, respectively. Conclusion: A shift was detected from gram-negative bacteria to gram-positive in the etiology over the years and central lines were the most common sources of BSIs.

Sarcoidosis mimicking lymphoma on positron emission tomography-computed tomography in two patients treated for lymphoma: two case reports.

IntroductionSarcoidosis is a granulomatous disease that mostly involves the lungs. Its association with malignancies has been well documented. Several mechanisms have been proposed that may underlie this concurrence including triggering tumour antigens and defective cellular immunity.Case presentationsWe briefly review the literature on malignancy associated sarcoidosis and report two female lymphoma patients of 49 and 56 years of age who, during their course of disease, developed sarcoidosis that was misinterpreted as a lymphoma relapse on positron emission tomography-computed tomography.ConclusionWe hypothesise that T cell dysfunction and exposure to tumour associated antigens might be the underlying mechanisms of development of sarcoidosis in patients with lymphoma. Positron emission tomography-positive lesions do not always indicate malignancy and therefore a tissue biopsy is always mandatory to confirm the diagnosis.

The Impact of Obesity and Insulin Resistance on Iron and Red Blood Cell Parameters: A Single Center, Cross-Sectional Study

Objective: Obesity and iron deficiency (ID) are the 2 most common nutritional disorders worldwide causing significant public health implications. Obesity is characterized by the presence of low-grade inflammation, which may lead to a number of diseases including insulin resistance (IR) and type 2 diabetes. Increased levels of acute-phase proteins such as C-reactive protein (CRP) have been reported in obesity-related inflammation. The aim of this study was to investigate the impact of obesity/IR on iron and red blood cell related parameters. Materials and Methods: A total of 206 patients and 45 control subjects of normal weight were included in this cross-sectional study. Venous blood samples were taken from each patient to measure hemoglobin (Hb), serum iron (Fe), iron-binding capacity (IBC), ferritin, CRP, fasting blood glucose, and fasting insulin. Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated for each patient. IR was determined using the HOMA-IR formula. Results: Subjects were divided into 3 groups according to BMI. There were 152 severely obese (BMI: 42.6±10.1), 54 mildly obese (BMI: 32.4±2.1), and 45 normal-weight (BMI: 24.3±1.3) patients. Hb levels in severely obese patients and normal controls were 12.8±1.3 g/dL and 13.6±1.8 g/dL, respectively. We found decreasing Fe levels with increasing weight (14.9±6.9 µmol/L, 13.6±6.3 µmol/L, and 10.9±4.6 µmol/L for normal controls and mildly and severely obese patients, respectively). Hb levels were slightly lower in patients with higher HOMA-IR values (13.1±1.5 g/dL vs. 13.2±1.2 g/dL; p=0.36). Serum iron levels were significantly higher in the group with low HOMA-IR values (13.6±5.9 µmol/L vs. 11.6±4.9 µmol/L; p=0.008). IBC was found to be similar in both groups (60.2±11.4 µmol/L vs. 61.9±10.7 µmol/L; p=0.23). Ferritin was slightly higher in patients with higher HOMA-IR values (156.1±209.5 pmol/L vs. 145.3±131.5 pmol/L; p=0.62). Conclusion: Elevated BMI and IR are associated with lower Fe and hemoglobin levels. These findings may be explained by the chronic inflammation of obesity and may contribute to obesity-related co-morbidities. People with IR may present with ID without anemia.

Detailed Analysis of Diffuse Large B Cell Lymphoma Patients: A Single-Center, Retrospective Study

The aim of this single-center, retrospective study was to investigate the impact of rituximab, reconsider the validity of International Prognostic Index (IPI), and evaluate the prognostic role of the cell of origin (CoO) in a relatively young cohort. Three hundred twelve diffuse large B cell lymphoma patients (median age: 52) were included. Rituximab significantly improved the 3- and 5-year progression free survival (PFS) (70% versus 65% and 41% versus 36%, resp.; P < 0.001) but led only to a slight, insignificant increase in 3- and 5-year overall survival (OS) (71% versus 77.3% and %67 versus 74.5%, resp.; P = 0.264). In the young, low risk patient subgroup (aaIPI = 0&1; n = 129), rituximab improved 3- and 5-year PFS and OS rates (P < 0.001 and P = 0.048, resp.). The efficacy of rituximab in young high risk patients was comparable to the literature. CoO data were available in 190 patients. The OS at 3 years was 79% for GC and 64% for non-GC subgroups (P = 0.014). To the best of our knowledge, this is the first study which investigated the impact of R-CHOP in the context of CoO and IPI in a relatively young cohort. CoO was not an independent risk factor for prognosis in the multivariate analysis although patients with GC showed a significant survival advantage in the univariate analysis. CoO was also found to be a significant determinant of response in refractory/relapsed patients. Our results confirm the efficacy of rituximab in low and high risk, young patients outside of a randomized clinical trial setting.

CYTOGENETIC CLONAL EVOLUTION IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA

ABSTRACT Chronic myeloid leukaemia (CML) is a clonal haematological disease characterised by t(9;22)(q34;q11) which is called Philadelphia (Ph) chromosome. Highly improved haematological and cytogenetic results were obtained in chronic phase CML with the introduction of imatinib. Occurrence of additional cytogenetic abnormalities in Ph(+) cells is defined as clonal evolution (CE) and considered to be a preceding sign for acceleration. The most common additional chromosomal changes are +8, +Ph, i(17q), +19, -Y, +21, +17 and-7. The aims of this study were to delineate the occurrence pattern of cytogenetic clonal evolution in our cohort of CML patients and to investigate the impact on the course and prognosis of CML. Additional clonal chromosomal changes in Ph(+) cells were observed in 20 cases (19%). The abnormalities seen were monosomy 21 (%35), -17 (%30), -19 and +8 in (%25), -7, -8, -13, -15, -22, +Ph, and different marker chromosomes (%20), -Y, -12, -14, -16, -20 (%15), +Y, -10, -18 (%10), and -X, -3, -9, +20, der(7;17)(q10;q10), der3?, der12? (%5). The findings of-Y, -7, -8, +8, -14, -15, -17, -18, -21, +Ph, der(7;17)(q10;q10) and del(7)(q11) have been recorded in more than one samples in at least one case. The clinical data of the 20 cases with CE were compared to 7 cases with no or minor cytogenetic response without CE and no statistically significant differences found. Considering their high frequency and persistence in successive samples, we recommend to trace -21 and -17 with FISH in addition to classical cytogenetics in CML cases.

A Polymorphism in the IL-5 Gene is Associated with Inhibitor Development in Severe Hemophilia A Patients.

Objective: A severe complication in the replacement therapy of hemophilia A (HA) patients is the development of alloantibodies (inhibitors) against factor VIII, which neutralizes the substituted factor. The primary genetic risk factors influencing the development of inhibitors are F8 gene mutations. Interleukins and cytokines that are involved in the regulation of B-lymphocyte development are other possible targets as genetic risk factors. This study assesses the possible involvement of 9 selected single nucleotide gene polymorphisms (SNPs) with interleukins (IL-4, IL-5, and IL-10), transforming growth factor beta 1 (TGF-β1), and interferon gamma (IFN-γ) in inhibitor development in severely affected HA patients carrying a null mutation in the F8 gene. Materials and Methods: A total of 173 HA patients were screened for intron 22 inversion and null mutations (nonsense and deletions). Genotyping of a total of 9 SNPs in genes IL-4, IL-5, IL-10, TGF-β1, and IFN-γ in 103 patients and 100 healthy individuals was carried out. Results: An association analysis between 42 inhibitor (+) and 61 inhibitor (-) patients showed a significant association with the T allele of rs2069812 in the IL-5 gene promoter and patients with inhibitors (p=0.0251). The TT genotype was also significantly associated with this group with a p-value of 0.0082, odds ratio of about 7, and confidence interval of over 90%, suggesting that it is the recessive susceptibility allele and that the C allele is the dominant protective allele. Conclusion: The lack of other variants in the IL-5 gene of patients and controls suggests that rs2069812 may be a regulatory SNP and may have a role in B-lymphocyte development, constituting a genetic risk factor in antibody development.

Pulmonary radiological findings in patients with acute myeloid leukemia and their relationship to chemotherapy and prognosis: a single-center retrospective study.

Objective: Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Pulmonary are among the most common causes of mortality in AML. This single-center retrospective study aimed to evaluate the relationship between radiological findings of pulmonary at presentation and post chemotherapy on prognosis and clinical outcome in a group of AML patients. Material and Methods: The study included 278 AML patients. Clinical and radiological findings, laboratory findings, and microbiological culture results were evaluated. Pulmonary complications at presentation and post chemotherapy were compared. Results: Pulmonary complications were observed in 53 of the patients (19%). Mean age of the patients with and without pulmonary complications was 43.1 ± 15.2 years and 38.8 ± 16.3 years, respectively (P < 0.001). Pulmonary complications were not correlated with gender, AML subtype, or the serum lactate dehydrogenase (LDH) level. The most common cause of pulmonary complications was infection. Pulmonary complications were observed in 29% and 71% of the patients at presentation and post chemotherapy, respectively. Conclusion: Pulmonary complications were observed more frequently at presentation in neutropenic AML patients of advanced age. The mortality rate was higher among the AML patients that had pulmonary complications at presentation.

JAK2 V617F Mutation Is Not Associated with Thrombosis in Behcet Syndrome

The Janus kinase 2V617F (JAK2 V617F) mutation is an acquired genetic defect that is considered to enhance thrombosis in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Thrombosis is also a well-defined component of Behcet syndrome (BS). The aim of this study was to determine the frequency of JAK2 V617F mutation in BS-associated thrombosis. A total of 152 patients with BS (62 with thrombosis and 90 without thrombosis) were enrolled. An additional 186 patients with MPNs and 107 healthy blood donors were included to serve as diseased and healthy controls, respectively. None of the patients with BS and healthy controls carried the JAK2 V617F mutation, whereas 67% of patients with MPNs were positive for JAK2 V617F . The frequency of thrombosis in patients with MPNs was not statistically different between carriers and non-carriers of JAK2 V617F mutation. Our data suggest that JAK2 V617F is not directly related to thrombosis in MPNs and in other thrombotic entities, such as BS.