Birsen Ülkü

T-cell-rich B-cell lymphoma: a clinicopathologic study of 21 cases and comparison with 43 cases of diffuse large B-cell lymphoma

Clinicopathologic features of 21 patients with T-cell-rich B-cell lymphoma (TCRBCL) were reviewed and compared to 43 patients with diffuse large B-cell lymphoma (DLBCL) to determine if there were distinguishing clinical characteristics and differences in response or survival to CHOP therapy. For the diagnosis of TCRBCL, the current WHO criteria was used. In all of our cases, the majority of cells are non-neoplastic T cells and <10% large neoplastic B cells are present. The initial pathologic diagnosis was nodular lymphocyte predominant Hodgkins lymphoma (NLPHL) in two cases. Patients with TCRBCL were significantly younger (median: 46 years) and had a significantly higher incidence of B symptoms (62%), hepatomegaly (33%) and marrow infiltration (33%) at presentation when compared to DLBCL (P<0.03). The CR rate after treatment was 48% for TCRBCL patients versus 79% for the DLBCL (P<0.003). Although the CR rates in between the two groups are significant, the difference in 3 years survival rates in each CR groups was insignificant (80% versus 77%). The overall survival time in the two groups was 17 months. Event-free survival time in TCRBCL was 12 months, compared with 17 months in the DLBCL (P>0.05). The frequency of patients with TCRBCL achieving CR was 52.6% whereas that of patients with DLBCL was 79% (P<0.003). The TCRBCL 3 years event-free survival 48% and overall survival 64% were 63 and 72% for DLBCL, respectively.

A mutation in a functional Sp1 binding site of the telomerase RNA gene (hTERC) promoter in a patient with Paroxysmal Nocturnal Haemoglobinuria.

BackgroundMutations in the gene coding for the RNA component of telomerase, hTERC, have been found in autosomal dominant dyskeratosis congenita (DC) and aplastic anemia. Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal blood disorder associated with aplastic anemia and characterized by the presence of one or more clones of blood cells lacking glycosylphosphatidylinositol (GPI) anchored proteins due to a somatic mutation in the PIGA gene.MethodsWe searched for mutations in DNA extracted from PNH patients by amplification of the hTERC gene and denaturing high performance liquid chromatography (dHPLC). After a mutation was found in a potential transcription factor binding site in one patient electrophoretic mobility shift assays were used to detect binding of transcription factors to that site. The effect of the mutation on the function of the promoter was tested by transient transfection constructs in which the promoter is used to drive a reporter gene.ResultsHere we report the finding of a novel promoter mutation (-99C->G) in the hTERC gene in a patient with PNH. The mutation disrupts an Sp1 binding site and destroys its ability to bind Sp1. Transient transfection assays show that mutations in this hTERC site including C-99G cause either up- or down-regulation of promoter activity and suggest that the site regulates core promoter activity in a context dependent manner in cancer cells.ConclusionsThese data are the first report of an hTERC promoter mutation from a patient sample which can modulate core promoter activity in vitro, raising the possibility that the mutation may affect the transcription of the gene in hematopoietic stem cells in vivo, and that dysregulation of telomerase may play a role in the development of bone marrow failure and the evolution of PNH clones.

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.

Chronic lymphocytic leukemia in Turkey: Experience of a single center in Istanbul

Background In this study, the clinical characteristics, survival, and prognostic factors of 200 patients diagnosed as having chronic lymphocytic leukemia (CLL) were analyzed. Methods The medical charts of 200 CLL patients registered to our center between 1984 and 2000 were retrospectively evaluated. Results Of all patients, 129 were men and 71 were women (male/female ratio, 1.82). The median age at the time of initial diagnosis was 63 years (range, 38–90 years). Sixty patients were classified as Binet’s Stage A, 49 as Stage B, and 91 as Stage C. Sixty-two cases were diagnosed during routine laboratory examinations when they were asymptomatic. Forty-three patients were lost to follow-up, and 157 patients have been followed regularly until the end of the study period. Hemolytic anemia developed in nine (5.7%) patients, second primary cancer in six (3.8%), and Richter’s syndrome in two (1.2%). Forty-eight percent of CLL patients were treated immediately after initial diagnosis. The overall response (complete or partial) to first-line and second-line therapies was 61.6% and 54.4%, respectively. The median time of follow-up for patients followed up regularly was 47 months (range, 1–195 months). Sixty-three patients died during the follow-up: the deaths of 39 (62%) of these were attributable to CLL-related causes. The median survival time was 48 months. The 5-year survival rate was 36.5% and the 10-year survival rate was 8%. Stage according to Rai’s classification, lymphocyte count, and age showed a significant prognostic effect on survival by univariate analysis. On multivariate analysis, advanced age and lymphocyte count were independent prognostic parameters. Conclusion In our study, more asymptomatic CLL patients have been diagnosed in recent years. The survival, especially of our early-stage patients, was shorter than that in other CLL series of Western origin. Rai’s staging system was seen to determine prognosis better than Binet’s staging system.

Incidence of aplastic anemia in Turkey: A hospital-based prospective multicentre study

The incidence of aplastic anemia among hospitalized adult patients was prospectively determined in this first study in Turkey. New cases of aplastic anemia among patients 14 years and older who were admitted to the study centers were included in a 3 year survey. Seventy-three patients fulfilled the diagnostic criteria, yielding a mean annual incidence rate of 1.14 cases in 10(3) admissions. The male-to-female ratio of the cases (1.6:1) differed from the almost equal ratio of the larger population of Turkey. The median age was 30 years and females were younger at diagnosis. The age distribution of the cases was different from that of the population; showing two incidence peaks in both sexes. The majority of the patients (89%) had severe disease.

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.

Variant Philadelphia translocations with different breakpoints in six chronic myeloid leukemia patients.

OBJECTIVE The Philadelphia (Ph) chromosome, consisting of the t(9;22)(q34;q11) translocation, is observed in ~90% of patients with chronic myeloid leukemia (CML). Variant Ph translocations are observed in 5%-10% of CML patients. In variant translocations 3 and possibly more chromosomes are involved. Herein we report 6 CML patients with variant Ph translocations. METHODS Bone marrow samples were examined using conventional cytogenetic meth ods. Fluorescence in situ hybridization (FISH) with whole-chromosome paints and BCR-ABL 1D probes were used to confirm and/or complement the findings, and identify rearrangements beyond the resolution of conventional cytogenetic methods. RESULTS Variant Ph translocations in the 6 patients were as follows: t(7;22)(p22;q11), t(9;22;15)(q34;q11;q22), t(15;22)(p11;q11), t(1;9;22;3)(q24;q34;q11;q21), t(12;22)(p13;q11), and t(4;8;9;22)(q11;q13;q34;q11). CONCLUSION Among the patients, 3 had simple and 3 had complex variant Ph translocations. Two of the presented cases had variant Ph chromosomes not previously described, 1 of which had a new complex Ph translocation involving chromosomes 1, 3, 9, 22, and t(1;9;22;3)(q24;q34;q11;q21) apart from a clone with a classical Ph, and the other case had variant Ph translocation with chromosomes 4, 8, 9, and 22, and t(4;8;9;22)(q11;q13;q34;q11) full complex translocation. Number of studies reported that some patients with variant Ph translocation were poor responders to imatinib. All of our patients with variant Ph translocations had suboptimal responses to imatinib, denoting a poor prognosis also. Variant Ph translocations may be important as they are associated with prognosis and therapy for CML patients.

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.

Mitoxantrone and cytosine arabinoside as first-line induction therapy in newly diagnosed acute nonlymphocytic leukemia

Thirty-three patients (22 men and 11 women; median age, 44 years) with newly diagnosed acute nonlymphocytic leukemia (ANLL) were treated with a combination of mitoxantrone, an anthracenedione derivative, 10 mg/m2/d for 3 days, plus cytosine arabinoside (ara-c), 100 mg/m2/d for 7 days. Patients not responding after two courses of therapy were considered treatment failures. Responding patients received two consolidation courses. Complete remission was achieved in 24 patients (73%), half of whom responded after a single course of therapy. Two patients were refractory and 7 died due to bone marrow depression. The median disease-free survival was 390 days, and the median overall survival was 450 days; 2 patients were still alive after 979 and 1166 days, respectively. Apart from hematologic findings, the most commonly observed toxicities were nausea/vomiting, alopecia, and infection. Mitoxantrone combined with ara-c is an effective and safe combination in the treatment of newly diagnosed ANLL.