Hakan Ozdogu

Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group.

The combination of melphalan–prednisone–thalidomide (MPT) has been investigated in several clinical studies that differed significantly with regard to patient characteristics and treatment schedules. This prospective trial differs from previous melphalan–prednisone (MP) vs. MPT trials by treatment dosing, duration, routine anticoagulation, and permission for a crossover. Newly diagnosed patients with multiple myeloma (MM) (n = 122) aged greater than 55 yr, not eligible for transplantation were randomized to receive 8 cycles of M (9 mg/m2/d) and P (60 mg/m2/d) for 4 d every 6 wk (n = 62) or MP and thalidomide (100 mg/d) continuously (n = 60). Primary endpoint was treatment response and toxicities following 4 and 8 cycles of therapy. Secondary endpoints were disease‐free (DFS) and overall survival (OS). Overall, MPT‐treated patients were younger (median 69 yr vs. 72 yr; P = 0.016) and had a higher incidence of renal impairment (RI, 19% vs. 7%, respectively; P = 0.057). After 4 cycles of treatment (n = 115), there were more partial responses or better in the MPT arm than in the MP arm (57.9% vs. 37.5%; P = 0.030). However, DFS and OS were not significantly different between the arms after a median of 23 months follow‐up (median OS 26.0 vs. 28.0 months, P = 0.655; DFS 21.0 vs. 14.0 months, P = 0.342, respectively). Crossover to MPT was required in 11 patients, 57% of whom responded to treatment. A higher rate of grade 3–4 infections was observed in the MPT arm compared with the MP arm (22.4% vs. 7.0%; P = 0.033). However, none of these infections were associated with febrile neutropenia. Death within the first 3 months was observed more frequently in the MP arm (n = 8, 14.0%) than in the MPT arm (n = 2, 3.4%; P = 0.053). Long‐term discontinuation and dose reduction rates were also analyzed (MPT: 15.5% vs. MP: 5.3%; P = 0.072). Although patients treated with MPT were relatively younger and had more frequent RI, better responses and less early mortality were observed in all age groups despite more frequent discontinuation. This study is registered at http://www.clinicaltrials.gov as #NCT00934154.

Human bone marrow mesenchymal cells express NG2: possible increase in discriminative ability of flow cytometry during mesenchymal stromal cell identification

BACKGROUND AIMS Mesenchymal stromal cells (MSC) exhibit non-specific hematopoietic cell and/or stromal cell markers (e.g. CD73, CD105 and CD166) that have been used to identify MSC by flow cytometry. Because a neural glial antigen, NG2 (a progenitor cell marker in the central nervous system), is expressed by several tissue cells originating in the mesenchyme but not hematopoietic cells, it might be useful for isolating and identifying MSC. We investigated NG2 expression on culture-expanded MSC by flow cytometry. METHODS Human bone marrow (BM) samples taken from 12 donors were cultured for MSC to be used in up to nine serial passages. Using flow cytometry, the neural glial antigen NG2 and commonly used MSC markers CD73, CD105 and CD166, were analyzed on the surface of culture-expanded MSC. The multipotential differentiation of the MSC was examined by adipogenic and osteogenic induction. RESULTS The percentage of cells positive for NG2 was similar to the percentages of cells positive for CD73, CD105 and CD166 in all passages of BM samples. The mean fluorescent intensities of NG2 did not change with culture passage. The MSC was successfully differentiated into adipogenic and osteogenic lines. The cells showed no karyotypic abnormalities. CONCLUSIONS NG2 seems to be a promising marker for investigating the biology of MSC.

Conventional and molecular cytogenetic findings of myelodysplastic syndrome patients.

AbstractMyelodysplastic syndrome (MDS) involves myeloid cells of the bone marrow, which is important in progressive bone marrow insufficiency. Of all MDS patients, 40%–50% have at least one chromosomal rearrangement. Loss of specific chromosomal regions like 5q– and 7q– are usually the secondary cytogenetic abnormalities associated with MDS. In order to detect chromosome abnormalities associated with MDS, bone marrow samples from 26 patients diagnosed as MDS were obtained prior to chemotherapy. Both conventional cytogenetic analyses and fluorescence in situ hybridisation (FISH) methods were performed and locus–specific probes for 5q and 7q were used. Results obtained were compared. Twenty–one patients had normal karyotypes and four patients had abnormal karyotypes, while in one patient we could not obtain metaphases from cultures. Three patients with normal karyotypes revealed del (5q), two patients had del (7q) and one patient had monosomy (7). A total of 10 of 26 patients had chromosome changes visualised by either conventional or molecular cytogenetics (~38.5%). Our results show that both methods are important in diagnosis and follow up of MDS patients. When used together, conventional cytogenetics and FISH detect clinically significant chromosome abnormalities in MDS patients.

Prophylactic red blood cell exchange may be beneficial in the management of sickle cell disease in pregnancy

Sickle cell disease (SCD) is associated with chronic hemolysis and painful episodes. Pregnancy accelerates sickle cell complications, including prepartum and postpartum vasoocclusive crisis, pulmonary complications, and preeclampsia or eclampsia. Fetal complications include preterm birth and its associated risks, intrauterine growth restriction, and a high rate of perinatal mortality. The purpose of this study was to evaluate pregnancy outcomes in patients with SCD who underwent planned preventive red blood cell exchange (RBCX).

RHINO-ORBITAL-CEREBRAL MUCORMYCOSIS WITH DIFFERENT CEREBRAL INVOLVEMENTS: INFARCT, HEMORRHAGE, AND OPHTHALMOPLEGIA

Rhino-orbital-cerebral mucormycosis is a rare but often fatal opportunistic necrotizing infection of the sinuses, orbit, and brain caused by saprophytic fungi. It usually develops in patients with diabetes or immune system deficiency. In this study, imaging features in 3 patients with rhino-orbital-cerebral mucormycosis who presented with various symptoms and different cerebral involvements are discussed. Headache, blurred vision, fever, painful ophthalmoplegia, and cranial nerve involvement were among the clinical findings. Computed tomography and magnetic resonance imaging are the best imaging methods for assessing the extent of this disease. Relatively typical but nonspecific characteristics are bone destruction, vascular invasion, and central hypointensity in the paranasal sinuses or an intracranial mass that is revealed by T2-weighted magnetic resonance imaging. Imaging findings include cavernous sinus involvement, cerebral infarct, and intracerebral hemorrhage. Because of the invasive and fulminant nature of rhino-orbital-cerebral mucormycosis, successful treatment seems to be based on early diagnosis and on the management of underlying immunologic problems.

Detecting methylation patterns of p16, MGMT, DAPK and E-cadherin genes in multiple myeloma patients.

Multiple myeloma (MM) is a B‐cell neoplasia characterized by the clonal proliferation of plasma cells. Besides known genetic abnormalities, epigenetic changes are also known to effect MM pathogenesis. DNA methylation is an epigenetic mechanism that silences genes by adding methyl groups to cytosine‐guanine dinucleotides at the promoter regions. In this study, the methylation status of four genes; p16, O6‐methyl guanine DNA methyl transferase (MGMT), death‐associated protein kinase (DAPK) and E‐cadherin (ECAD); at the time of diagnosis was investigated using methylation‐specific polymerase chain reaction (MS‐PCR). In the 20 cases studied; methylation of the promoter regions of p16, MGMT, DAPK and ECAD genes was detected in 10%, 40%, 10% and 45% of the cases, respectively. In 65% (13/20) of cases, at least one of the genes studied had promoter methylation; while 35% of cases (7/20) had methylated promoters of more than one gene. There was a significant correlation between promoter hypermethylation of MGMT and the presence of extramedullary involvement; but for the other genes no correlation was found regarding disease properties like age, disease stage, clinical course and the presence of lytic bone lesions. Determining the methylation profiles of genes in MM, could lead to a new understanding of the disease pathogenesis and guide the assessment of treatment options.

Fluorescent in situ hybridization studies in multiple myeloma.

Abstract Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) results of bone marrow samples of 36 multiple myeloma (MM) patients at the time of diagnosis have been evaluated. Three probes for chromosome 13q (RB1, D13S319, D13S25), one for 14q32 (IgH) and one for 17p13 (p53) have been used for hybridization with fixed cells. Twenty patients (55·5%) had normal karyotypes, whereas eight (22·2%) had numerical or structural chromosomal abnormalities. We did not find metaphases for chromosome analysis in eight (22·2%) patients. Fluorescence in situ hybridization analyses revealed at least one or more abnormal results in 25 (69·5%) cases, whereas 11(30·5%) cases had no abnormal findings. 14q32 rearrangement was the most common finding in FISH analyses and has been detected in 21 cases (58·3%). 13q deletion and 17p deletion have been detected in 11 (30·5%) and 5 (13·9%) cases, respectively. Fluorescence in situ hybridization studies including 14q32 and 17p13 chromosome regions may yield quite significant results during clinical follow-up of MM.

Pregnancy and sickle cell disease: A review of the current literature.

Sickle cell disease (SCD) is the most common hereditary disease worldwide, presenting with anemia and intermittent severe pain. Pregnancy in a patient with SCD is associated with high levels of maternal and fetal morbidity and mortality; the maternal and fetal death rates during pregnancy can attain 11.4% and 20%, respectively. Patient care has improved over time. However, certain management issues remain unresolved; these include the optimum policy in terms of prophylactic blood transfusion, and the use of antiplatelet drugs. Such issues are attributable to the heterogeneous nature of clinical SCD features, and the limitations of uncontrolled and prospective trials. In this review, we seek to facilitate a better understanding of relevant issues via creation of a comparative data profile extracted from current studies. This report may also encourage the drafting of standard operating procedure for management of pregnancy in SCD patients.

Long-term colchicine therapy in a patient with Behçet's disease and acute promyelocytic leukemia

Behçet’s disease causes a continuous T-lymphocytic mediated inflammatory reaction in the small arterioles, which results in gradual destruction of any human organ or system. The benefit of treatment with colchicine in patients with Behçet’s disease has been reported in literature. Acute leukemia has seldom been associated with Behçet’s disease, although acute promyelocytic leukemia is a particular subtype of leukemia that is often characterized by special cytogenetic abnormalities. We report a male patient with acute promyelocytic leukemia and Behçet’s disease who had received long-term treatment with colchicine. To our knowledge, this is the first report of the concomitant occurrence of acute promyelocytic leukemia and Behçet’s disease, which suggests that long-term colchicine therapy has a role in the pathogenesis of acute promyelocytic leukemia. The patient described has been treated with retinoic acid and idarubicin (the ATRA-IDA protocol). At the time of this writing, his disease is in clinical remission.

Beta-thalassemia intermedia associated with moyamoya syndrome.

Moyamoya syndrome (MMS) is a progressive disorder. We report a 19-year-old boy with beta-thalassemia who presented with a left hemiparesis. Brain MRI showed old middle cerebral artery and left frontal subcortical white matter infarcts. Brain magnetic resonance angiography and digital subtraction angiography revealed occlusion of the bilateral internal carotid arteries with a rich network of basal collateral vessels. To our knowledge this is the third report of beta-thalassemia intermedia and MMS, and the first report of a patient in Turkey. It emphasizes the potential for cerebral infarct due to anemia, protein S and thrombocytosis.