Impact of CALR and JAK2V617F Mutations on Clinical Course and Disease Outcomes in Essential Thrombocythemia: A Multicenter Retrospective Study in Turkish Patients.

Objective: In this study, we investigated the effects of calreticulin (CALR) and JAK2V617F mutational status on clinical course and disease outcomes in Turkish patients with essential thrombocythemia (ET). Materials and Methods: Seventeen centers from Türkiye participated in the study and CALR- and JAK2V617F-mutated ET patients were evaluated retrospectively. Results: A total of 302 patients were included, of whom 203 (67.2%) and 99 (32.8%) were JAK2V617F- and CALR-positive, respectively. CALR-mutated patients were significantly younger (51 years vs. 57.5 years, p=0.03), with higher median platelet counts (987x109/L vs. 709x109/L, p<0.001) and lower median hemoglobin levels (13.1 g/dL vs. 14.1 g/dL, p<0.001) compared to JAK2V617F-mutated patients. Thromboembolic events (TEEs) occurred in 54 patients (17.9%), 77.8% of which were arterial. Compared to CALR mutation, JAK2V617F was associated with a higher risk of thrombosis (8.1% vs. 22.7%, p=0.002). Rates of transformation to myelofibrosis (MF) and leukemia were 4% and 0.7%, respectively, and these rates were comparable between JAK2V617F- and CALR-mutated cases. The estimated overall survival (OS) and MF-free survival of the entire cohort were 265.1 months and 235.7 months, respectively. OS and MF-free survival durations were similar between JAK2V617F- and CALR-mutated patients. Thrombosis-free survival (TFS) was superior in CALR-mutated patients compared to JAK2V617F-positive patients (5-year TFS: 90% vs. 71%, respectively; p=0.001). Age at diagnosis was an independent factor affecting the incidence of TEEs. Conclusion: In our ET cohort, CALR mutations resulted in higher platelet counts and lower hemoglobin levels than JAK2V617F and were associated with younger age at diagnosis. JAK2V617F was strongly associated with thrombosis and worse TFS. Hydroxyurea was the most preferred cytoreductive agent for patients with high thrombosis risk.

Effect of Clinical, Endoscopic, Radiological Findings, and Complications on Survival in Patients with Primary Gastrointestinal Lymphoma.

BACKGROUND: The purpose of this study was to evaluate the clinical, endoscopic, and radiological characteristics, complications, survival outcomes, and prognostic factors of patients with primary gastrointestinal lymphoma. METHODS: This study retrospectively analyzed the demographic, laboratory, endoscopic, and radiological characteristics and treatment outcomes of 43 patients with newly diagnosed primary gastrointestinal lymphoma. RESULTS: The median age was 62 years (range: 26-83). The primary lesion location was the gastric in 33 (77%) patients and the intestinal in 10 (23%) patients. The most common lesions were the corpus (33%) and corpus+antrum (24%) in primary gastric lymphoma and the ileum (60%) in primary intestinal lymphoma. The most common endoscopic findings were diffuse infiltrative lesion (23%) and massforming (33%), while the most common computed tomography finding was wall thickening (53%). Wall thickening and mass-forming at computed tomography were greater in primary intestinal lymphoma than in primary gastric lymphoma (P = .034). Complications were observed in 9 (21%) patients and 13 (31%) patients who underwent surgery. Complication and surgery rates were higher in primary intestinal lymphoma than in primary gastric lymphoma (P = .003 and P = .014, respectively). Five-year overall survival and 5-year eventfree survival rates were 75% and 72%, respectively. Univariate analysis showed that intestinal involvement, advanced clinical stage, a high International Prognostic Index score, mass-forming and wall thickening at computed tomography, extranodal involvement, and complication were found to adversely affect survival. Multivariate analysis revealed that intestinal involvement and a high International Prognostic Index score were independent prognostic factors for overall survival and event-free survival. CONCLUSION: Patients with primary gastrointestinal lymphoma with intestinal involvement and high International Prognostic Index score should be followed closely.

Turkey real-life data: demographic features, treatment results and effects of comorbidities in chronic myeloid leukemia.

Aim: This study aimed to identify patient characteristics, treatment patterns and outcomes and to evaluate the effects of presence of comorbidities at diagnosis in chronic phase (CP)-chronic myeloid leukemia (CML) patients in Turkey. Materials & methods: Hospital records between 2005 and 2018 were retrospectively reviewed. Results: Of 861 CP-CML patients included, 31% had at least one comorbidity at diagnosis. Sex, cardiovascular disease status at diagnosis and molecular (at least major) and cytogenetic (partial and complete) responses were the independent predictors of survival. Conclusion: The response rates of CP-CML patients to the tyrosine kinase inhibitors were satisfactory. In addition to tolerability and side effect profiles of drugs, comorbidity status of patients should also be considered in treatment choice in CML patients.

This study aimed to identify patient characteristics, treatment patterns and outcomes and to evaluate the effects of presence of comorbidities at diagnosis in chronic phase (CP)-chronic myeloid leukemia (CML) patients in Turkey. Hospital records of patients between 2005 and 2018 were retrospectively reviewed. Of the included 861 CP-CML patients, 31% had at least one comorbidity at diagnosis. The survival of the patients was affected by sex, cardiovascular disease status at diagnosis, and molecular (at least major) and cytogenetic (partial and complete) responses. The response rates of CP-CML patients to the tyrosine kinase inhibitors were satisfactory. In addition to tolerability and side effect profiles of drugs, comorbidity status of patients should also be considered in treatment choice in CML patients.

Assessment of Long-Term Hematologic Effects in Differentiated Thyroid Cancer Patients Treated with Radioactive Iodine

Objective: Radioactive iodine (RAI) therapy may cause hematologic abnormalities. The aim of this study is to evaluate long-term hematologic effects in differentiated thyroid cancer (DTC) patients after RAI therapy. Materials and Methods: A total of 1389 patients with DTC who were treated with RAI were retrospectively evaluated. Complete blood cell counts before RAI therapy and at last follow-up and hematologic malignancy development were obtained from the electronic records. Results: In the long-term analysis, thrombocytopenia and lymphopenia were observed significantly in patients over 60 years of age. Thrombocytopenia was observed more frequently in men. Leukopenia, thrombocytopenia, and lymphopenia were observed significantly with doses of >175 mCi. Thrombocytopenia and lymphopenia were observed significantly with multiple dose administration. Higher frequencies of anemia, thrombocytopenia, leukopenia, neutropenia, and lymphopenia were found in patients with advanced-stage disease. However, patients with advanced-stage disease had higher doses and more multiple doses than patients with early-stage disease. The rate of hematologic malignancy was found to be higher than in the general population. Conclusion: We suggest that cytopenia be surveyed more carefully in patients older than 60 years of age. The most important risk factor for lower platelets after RAI therapy is male gender. Clinically, the most important predictor for cytopenia is advanced disease stage, which is related to the combined effects of applied high dose activity, multiple dose applications, and high tumor burden.

Serum carbonic anhydrase I and II autoantibodies in patients with chronic lymphocytic leukaemia.

Cancer is the second most important cause of mortality, and millions of people either have or have had the disease. Leukaemia is one of the most common forms of cancer. Autoantibodies that have developed against the organism's self-antigens are detected in the sera of subjects with cancer. In recent years carbonic anhydrase (CA) autoantibodies have been determined in some autoimmune diseases and carcinomas, but the mechanisms underlying this immune response have not yet been fully explained. The purpose of this study was to determine CA I and II autoantibodies in subjects with chronic lymphocytic leukaemia (CLL) and to provide a novel perspective regarding the autoimmune basis of the disease. Autoantibody levels were investigated using enzyme-linked immunosorbent assay (ELISA) in serum samples from 37 patients with CLL and 37 healthy peers. Anti-CA I titres in the CLL group were significantly higher compared with the control group (p = 0.0001). However, there was no significant difference between CLL and control groups in terms of anti-CA II titres (p = 0.278). The prevalences of CA I and II autoantibodies in patients with CLL in this study were 27% and 24.3%, respectively. Our results suggest that these autoantibodies may be involved in the pathogenesis of CLL. More extensive studies are now needed to reveal the entire mechanism.

Comparison between Hyper-CVAD and PETHEMA ALL-93 in Adult Acute Lymphoblastic Leukemia: A Single-Center Study.

BACKGROUND: Although cure rates in pediatric acute lymphoblastic leukemia (ALL) are quite high with combined chemotherapy regimens, complete response (CR) and long-term survival rates in adults are 80-90 and 30-40%, respectively. Currently, combined chemotherapy regimens, such as Hyper-CVAD and PETHEMA, are used in patients with adult ALL. However, there has been no study comparing the results of Hyper-CVAD and PETHEMA ALL-93. METHODS: In this retrospective single-center study, we evaluated the results of Hyper-CVAD and PETHEMA ALL-93 in 51 ALL patients treated between September 2008 and March 2017 at the Department of Hematology, Faculty of Medicine, Karadeniz Technical University. RESULTS: Thirty-eight patients were treated with Hyper-CVAD and 13 with PETHEMA ALL-93. CR was obtained in 90 and 100% of patients, respectively. Survival estimates were comparable between Hyper-CVAD and PE-THEMA ALL-93, with a median overall survival (OS) and a median disease-free survival (DFS) of 17.5 and 12.1 months, respectively, for Hyper-CVAD and of 18.6 and 12.9 months, respectively, for PETHEMA ALL-93. The 2-year OS rates for Hyper-CVAD and PETHEMA ALL-93 were 30 and 40%, respectively, and the 2-year DFS rates were 28 and 44%, respectively. PETHEMA ALL-93 resulted in more hepatotoxicity, hypofibrinogenemia, aspergillus infection, and skin rash than Hyper-CVAD. CONCLUSIONS: Although Hyper-CVAD and PE-THEMA ALL-93 showed similar effects, Hyper-CVAD was tolerated better. Age and comorbidities should be taken into account before a chemotherapy regimen is determined for patients with ALL.

Autoantibodies Against Carbonic Anhydrase I and II in Patients with Acute Myeloid Leukemia.

OBJECTIVE: Cancer, one of the principal causes of death, is a global social health problem. Autoantibodies developed against the organism's self-antigens are detected in the sera of subjects with cancer. In recent years carbonic anhydrase (CA) I and II autoantibodies have been shown in some autoimmune diseases and carcinomas, but the mechanisms underlying this immune response have not yet been explained. The aim of this study was to evaluate CA I and II autoantibodies in patients with acute myeloid leukemia (AML) and to provide a novel perspective regarding the autoimmune basis of the disease. MATERIALS AND METHODS: Anti-CA I and II antibody levels were investigated using ELISA in serum samples from 30 patients with AML and 30 healthy peers. RESULTS: Anti-CA I and II antibody titers in the AML group were significantly higher compared with the control group (p=0.0001 and 0.018, respectively). A strong positive correlation was also determined between titers of anti-CA I and II antibodies (r=0.613, p=0.0001). CONCLUSION: Our results suggest that these autoantibodies may be involved in the pathogenesis of AML. More extensive studies are now needed to reveal the entire mechanism.

The Prognostic Significance of Soluble Urokinase Plasminogen Activator Receptor in Acute Myeloid Leukemia.

OBJECTIVE: The soluble urokinase plasminogen activator receptor (suPAR) is a soluble form of the urokinase plasminogen activator receptor expressed in various immune and cancer cells. The levels of suPAR have been demonstrated to correlate with prognosis in various cancers. This study was intended to investigate serum suPAR levels and their effect on prognosis in patients with acute myeloid leukemia (AML). MATERIALS AND METHODS: Thirty newly diagnosed patients with AML and 29 healthy individuals were enrolled. Serum suPAR levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: Serum suPAR levels were significantly higher in patients with AML than in healthy individuals (9±5.9 ng/mL and 2.4±1.4 ng/mL, respectively; p<0.001). Positive correlation was determined between suPAR levels and white blood cell counts (p<0.01). Serum suPAR levels were lower in patients who achieved complete response than in patients not achieving complete response (5.5±2.2 ng/mL and 12±6.6 ng/mL, respectively; p<0.001). The median overall survival was longer in patients with serum suPAR levels below 6.71 ng/mL than in those with serum suPAR levels above 6.71 ng/mL (12.6±13.2 months and 1.71±0.6 months, respectively; p=0.02). Multivariate Cox regression analysis showed that suPAR had independent prognostic value (95% confidence interval: 1.029-6.259; p<0.05) in AML. CONCLUSION: Serum suPAR levels can be used as a prognostic marker in AML.

The indicator of hypoxia in acute leukemia: Ischemia-modified albumin.

BACKGROUND: Hypoxia plays an important role in the development and progression of hematologic malignancies. OBJECTIVE: This study was intended to investigate the effectiveness of ischemia-modified albumin (IMA) for demonstrating hypoxia in patients with acute leukemia. METHODS: Blood specimens were collected from 132 subjects (44 acute leukemia patients, 40 iron deficiency anemia (IDA) patients and 48 healthy controls). Serum levels of IMA and malondialdehyde (MDA) were analyzed using conventional methods. RESULTS: Serum levels of IMA were higher in patients with acute leukemia than in those with IDA and healthy controls (acute leukemia patients; 0.69 ± 0.14 ABSUs, IDA patients; 0.61 ± 0.09 ABSUs, controls; 0.50 ± 0.09 ABSUs, respectively). There was a negative correlation between serum IMA levels and hemoglobin (Hb) values (r = - 0.312) and between serum IMA levels and hematocrit (Hct) values, (r = - 0.305) in patients with acute leukemia. Serum levels of MDA were higher in patients with acute leukemia than in those with IDA. But there was no difference in patients with acute leukemia and IDA compared to healthy controls (acute leukemia patients; 2.23 ± 1.82 nmol/mL, IDA patients; 1.36 ± 0.94 nmol/mL, healthy controls; 1.79 ± 0.78 nmol/mL, respectively). CONCLUSIONS: IMA can be effective for demonstrating hypoxia in patients with acute leukemia.

Anti-carbonic anhydrase antibodies in iron deficiency anemia.

OBJECTIVES: Studies on experimental animals have shown that elevated oxidative stress in erythrocytes leads to the formation of autoantibodies against carbonic anhydrase (CA) and anemia. This study investigated the presence of CA I and II autoantibodies in patients with iron deficiency anemia (IDA). METHODS: Forty patients with IDA and 40 healthy controls were included in the study. Serum CA I and II autoantibody levels were analyzed using enzyme-linked immunosorbent assay. Serum malondialdehyde (MDA) levels were also measured in order to evaluate oxidative stress. RESULTS: CA I and II antibody titers in patients with IDA were higher than those in the controls (P = 0.005 and 0.010, respectively). A weak negative correlation was determined between anti-CA I antibody titers and ferritin, iron and mean cell volume (MCV) levels (P = 0.013, 0.042, and 0.021, respectively). Serum MDA levels were also significantly higher in the IDA group (P < 0.001). At an anti-CA I cut-off point of 0.155 absorbance unit (ABSU), sensitivity was 70% and specificity 65%. At an anti-CA II cut-off point of 0.088 ABSU, sensitivity was 60% and specificity 75%. DISCUSSION AND CONCLUSION: In conclusion, an immune response against CA I and II develops in IDA. CA I autoantibodies are correlated with hematological parameters used in the diagnosis of IDA and have the potential to be used in treatment.

Relation of HLA-A, -B, -DRB1 alleles and haplotypes in patients with acute leukemia: a case control study.

BACKGROUND AND AIMS: A relationship between acute leukemia and HLA alleles has been demonstrated in several studies. However, the frequencies of HLA class I (A, B) and class II (DRB1) alleles and haplotypes has not already been determined in Turkish patients with acute leukemia. METHODS: We investigated the relation of the HLA alleles and haplotypes in 237 adult acute leukemia patients [103 acute lymphoblastic leukemia (ALL), 134 acute myeloid leukemia, (AML)] and 360 unrelated normal subjects by PCR-SSOP method using Luminex technology. RESULTS: Allele frequencies of HLA-A*03, and B*51 were higher in patients with AML compared with the controls (p = 0.019, and p = 0.001; respectively). Furthermore, HLA-A*11 and DRB1*01 allele frequencies were determined to be higher in patients with ALL (p = 0.01, p = 0.001; respectively), whereas DRB1*13 allele frequencies lower than controls (p = 0.003). The most observed haplotypes A*03 B*51 DRB1*11 (3.73 vs. 0%) in patients with AML; A*02 B*35 DRB1*01 (2.91 vs. 0%) and A*02 B*51 DRB1*11 (2.91 vs. 1.96%) in patients with ALL were determined. On the contrary, the most observed haplotype was A*02 B*35 DRB1*13 (2.19%) in the controls. We found A*02 B*39 DRB1*16 haplotype negatively associated with AML, whereas A*02 B*35 DRB1*13 was in ALL (p = 0.015, and p = 0.017; respectively). CONCLUSIONS: These results suggest that HLA-A*03 and B*51 alleles may play a presumptive predisposing factor in AML. In addition, HLA-A*11 and DRB*01 alleles have been found to be associated with ALL, whereas DRB1*13 allele was determined to be negatively associated.

MTHFR C677T polymorphism and its relationship to myocardial infarction in the Eastern Black Sea region of Turkey.

BACKGROUND AND AIMS: An association of homozygous MTHFR 677T genotypes with elevated plasma homocysteine level has been documented, but results are still controversial. We aimed to investigate prevalence of the C677T polymorphism in patients with acute myocardial infarction (MI) in the Eastern Black Sea region of Turkey. METHODS: We studied genomic DNA of 231 unrelated patients (aged 59 ± 13 years; 175 male, 56 female) with first anterior acute MI and 242 healthy controls (aged 54 ± 19 years; 182 male, 60 female) using real-time polymerase chain reaction kits for the MTHFR C677T mutation. RESULTS: Prevalence of MTHFR C677T mutant genotype was 49.1% (CT: 45.8%, TT: 3.3%) in controls and 48.45% (CT: 38.5%, TT: 9.95%) in patients with acute MI. The TT mutation was more frequent in patients with acute MI than in controls (9.95 vs. 3.3%) (OR; 3.23, 95% CI; [1.34-8.05], p = 0.003). CONCLUSIONS: The MTHFR gene homozygote TT mutation is a risk factor for patients with MI in the eastern Black Sea Turkish Population.

Treatment related changes in antifibrinolytic activity in patients with polycythemia vera.

Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by predominantly excessive erythrocyte production. During the course of the disease, bleeding or thrombosis may be observed. In PV patients, the influence of antifibrinolytic activities on development of thrombohemorrhagic complications remains to be elucidated. In the present study, alterations in antifibrinolytic activity of PV patients and the effects of treatments on these alterations were investigated. Newly diagnosed and therapy-naive 22 PV patients were included. Thrombomodulin (TM), plasmin-alpha 2-antiplasmin complex (PAP), plasminogen activator inhibitor-1 (PAI-1) and thrombin activable fibrinolysis inhibitor antigen (TAFIa) levels were measured in all individuals and after phlebotomy and 5-hydroxyurea (5-HU) therapy in PV patients. TM, PAP, PAI-1 and TAFIa values of the patient group were higher than those of the controls. After phlebotomy, no changes were detected in TM, PAI-1 and TAFIa values, but PAP values decreased. On the contrary, 5-HU treatment resulted in a marked decrease in TM, PAI-1, PAP and TAFIa levels. These findings suggested that the changes in antifibrinolytic activity and endothelial dysfunction might be contributed to formation of intravascular thrombosis in PV patients, even though not clinically overt. 5-HU in addition to phlebotomy affects antifibrinolytic activity and may have an influence on diminishing predisposition of thrombosis.

Can ischemia-modified albumin be a valuable indicator of tissue ischemia in polycythemia vera?

The red cell expansion in polycythemia vera (PV) causes hyperviscosity affecting blood flow, which plays a major role in the pathogenesis of both microcirculatory disturbances and ultimately thromboses. Ischemia-modified albumin (IMA) is produced during an ischemic states and is present in blood in early and easily detectable levels. This study investigated whether IMA is a useful adjunct in the determination of ischemia in patients with PV, prior to them exhibiting clinical evidence of thrombotic complications. Blood IMA levels were determined in 20 PV patients and in 20 healthy individuals using a method described by Bar-Or. Mean IMA levels in the PV group were significantly higher than those of the control group (P<0.05). At the optimum cutoff point (0.193 absorbance units), the sensitivity and specificity of IMA were 80 and 100% to ischemia, respectively. In conclusion, IMA may be a valuable biochemical marker in predicting tissue ischemia in PV before the signs of vascular disturbances occur.

Familial Hodgkin's lymphoma from the perspective of HLA.

Although the incidence of Hodgkin lymphoma (HL)--a lymphoid tissue malignity--increases in the presence of several viruses, particularly EBV, as well as with autoimmune diseases and following transplantation, although to date, the exact etiopathogenesis is not known. The higher frequency of HL among family members suggests involvement of genetic factors in its etiology. Studies aiming to elucidate the etiopathogenesis of patients with familial HL (FHL) have reported that human leukocyte antigen (HLA) haplotypes might be involved. In this case presentation, the associations between HLs diagnosed in a father of consanguineous marriage and his two children and HLAs in other family members were investigated and the findings are discussed in view of the published literature; no direct association was found between HLA alleles and the development of the disease in the present case with familial HL.