E-ISSN: 1308-5263
Turk J Hematol: 17 (4)
Volume: 17  Issue: 4 - 2000
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1.Chemotherapy resistance in Acute Leukemia
Thomas R. Chauncey
Pages 155 - 162
Drug resistance markers are often predictive of treatment response and outcome in patients with acute myeloid leukemia. The immunologic detection of drug efflux pumps such as P-glycoprotein (Pgp) and multidrug resistance associated protein 1 (MRP1) rrelate with functional assays of drug resistance and these drug accumulation defects also appear operable in ALL. Other markers such as LRP, bcl- 2, and BRCP, have been described in patients with AML although their pathophysiology and clinical relevance is less clear and methodology for their quantification not well standardized. Preclinical tudies have shown that small molecules capable of reversing efflux can restore drug sensitivity in resistant tumor models. While initial clinical studies were limited by both potency and specificity of the reverser, later studies with more effective reversers have in many instances been limited by pharmacokinetic interactions exacerbating the clinical toxicities of chemotherapy. Nonetheless, one large randomized study using cyclosporine has demonstrated a proven survival advantage without increased toxicity, although the inconsistent results with other modulators raises doubt as to the utility and overall strategy of using drug efflux blockers in patients with established Pgp overexpression. Most of these patients have additional mechanisms of resistance and achieving meaningful clinical responses will likely require more complex clinical strategies. Preventing or delaying development of drug resistance in chemosensitive patientsrepresents another therapeutic strategy to be tested.

2.The Differential Diagnosis of Lymphocyte-rich Classical Hodgkin’s Lymphoma and Lymphocyte Predominant Hodgkin’s Lymphoma Using the R.E.A.L. Criteria. An Immunohistochemical Study on 45 Cases
Mine Hekimgil, Saliha Soydan, Başak Doğanavşargil Yakut, Yeşim Ertan
Pages 163 - 170
In the present study, the two types, lymphocyte-rich classical HL (LRCHL) and nodular lymphocytepredominant type (NLPHL), which were grouped together before the R.E.A.L. classification, were questioned on the basis of differential criteria and 45 cases were retrieved from last ten years’ archival material. On histopathological examination, nodular pattern, the cytological features and intensity of Reed- Sternberg (RS) cells, the pattern and intensity of histiocytes, the presence of germinal centers with progressive transformation were analysed. An immunohistochemical study was performed using antibodies against CD20, CD45RO, CD3, CD30, CD15 antigens and streptavidin-biotin procedure. The cases were classified into three groups according to the histologic pattern and immunophenotypical features ofthe RS cells: I) diffuse, LRCHL (CD20-, CD30+/-, CD15+/-): n= 28; II) NLPHL (CD20+, CD30-, CD15-): n= 11; III) cases which could not be evaluated in former groups: n= 6. Four cases in the latter group showed a nodular pattern with RS cells negative for all markers, except for one case, which expressed both CD20 and CD15. The remaining two cases exhibited a diffuse pattern and the RS cells were CD20+, coexpressing CD30 in one. These findings suggest that, differential diagnosis according to the R.E.A.L. criteria is not distinctive between the two categories of HL in about 13% of cases, and further criteria need to be established to define the grey zone between the two entities which might lead to further therapeutic trials.

3.Donor Leukocyte Infusions for the Treatment of Leukemia Relapse After Allogeneic Hematopoietic Cell Transplantation with Myeloablative Conditioning
Günhan Gürman
Pages 171 - 181
Leukemic relapse after allogeneic transplantation is a difficult problem. Conventional treatment modalities or second transplants have not provided the sustained complete remissions on the whole. Reinfusion and activation of cytotoxic T lymphocytes of the donor seem to be effective and it has been understood that the success of the transplantation depends mainly on graft versus leukemia effect. Thirteen patients with leukemia (8 CML, 5 AML) who had relapsed after allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning, have received donor leukocyte infusions (DLI). The median time between transplantation and relapse was 18 months (4-57 months). For CML patients who had cytogenetic or hematologic relapse, IFN alpha 2b was started at a dose of 5 million units/m2/d for every consecutive days. Starting from the fifth week of this treatment, unprimed donor peripheral blood mononuclear cells were infused to the patients once a week for four weeks. IFN treatment was not cessated during these infusions, and was given for 12 weeks totally. For relapsed acute leukemia patients, standart chemotherapy regimens as for AML were used. After the treatment, donor lymphocytes which were obtained from the original HCT donor who was primed with G-CSF were given. After recovery, IFN alfa2b was started 5 million U/m2/d each consecutive day until the GVHD findings were observed. GVHD prophylaxis was not made after DLIs. Acute GVHD was seen in 11 of 13 patients. Four patients developed chronicGVHD. Among 13 patients, four patients are alive and they have been in complete remission for 23 to 76 months. The other patients were not alive due to mostly disease progression. Two patients died because of advanced GVHD. In our practice, the patients with progressive disease were not the well responded ones. These observations suggest that there is a limit for the immune effect regarding the number of the tumor cells and their proliferative capacity. Chemotherapy, which does not suppress immunity, may give time and chance to allogeneic lymphocytes to affect.

4.Prognostic significance of wilms tumor 1 gene in childhood acute Lymphoblastic Leukemia
Ünsal Özgen, Sema Anak, Uğur Özbek, Nazan Sarper, Ertuğrul Eryılmaz, Leyla Ağaoğlu, Ömer Devecioğlu, Nevin Yalman, Gündüz Gedikoğlu
Pages 183 - 188
Wilms tumor 1 (WT1) gene is a tumor supressor gene, expressed in malignant and normal hematopoietic progenitor cells. Prognostic significance of this gene in childhood acute lymphoid leukemia (ALL) is not clear. We evaluated the presence of WT1 expression in bone marrow samples of 28 children with de novo ALL at diagnosis by two step RT-PCR. Expression of WT1 gene was detected in 78.5% of patients. There was no correlation between WT1 gene expression and age, sex, FAB type, leukocyte count, and presence of t(4;11) and t(9;22). All patients were treated with modified BFM 86 protocol. There was no difference in the complete remission (CR) rate between WT1 positive and negative patients. Event free survival (EFS) and overall survival (OS) of WT1 positive and negative patients were also not significant. We conclude that expression of WT1 gene is not associated with specific characteristics of ALL blast cells and is not a prognostic factor for CR, remission duration and overall survival.

5.Biological Dosimetry of Co-60 Gamma Irradiation
Aslı Top, Münevver Coşkun, Tuncay Orta
Pages 189 - 196
Development of radiation technology has resulted in increasing numbers of people working with it. Therefore it has increasingly been important to monitor the radiation in order to ensure public safety. Physical dosimetry plays an important role in monitoring. But a need arise for biological dosimetry where physical dosimetry is absent or its presence is insufficient. In this study Co-60 gamma radiation dose-response curves for chromosome aberrations were determined for use as controls in biological dosimetry. Peripheral blood that were taken from healthy individuals not working with radiation were irradiated at different radiation doses. The relationship between unstable chromosome aberrations in metaphaseblocked cells and radiation dose were drawn by using the linear-quadratic (LQ) formula. The absorbed radiation doses of the test group consisting of five people that had been working with Co-60 teletherapy machines were estimated using the LQ parameters of control dose-response curves in the Qdr method. Estimated radiation doses were below the permissible radiation dose-limits for four workers, but one worker's estimated dose was higher than these limits.

6.Detection of BCR/ABL transcripts by reverse transcriptase polimerase chain reaction in pediatric acute Lymphoblastic Leukemia: ıncidence and clinical eatures
Nazan Sarper, Uğur Özbek, Leyla Ağaoğlu, Ünsal Özgen, Ayten Kandilci, Sema Sırma, Sema Anak, Nevin Yalman, Ertuğrul Eryılmaz, Ömer Devecioğlu, Gündüz Gedikoğlu
Pages 197 - 206
BCR/ABL expression, which is the molecular equivalent of the Philadelphia chromosome, is an independent poor risk factor in acute lymphoblastic leukemia (ALL). We used a two-step (nested) reverse transcriptase polimerase chain reaction (RT-PCR) assay to examine BCR/ABL expression in the diagnostic bone marrow specimen of children with ALL, prospectively. Among 75 de novo ALL patients, 4 (%5.3) were found to be BCR/ABL- ositive, whereas 4 of 17 relapsed patients (23.5%) were positive. This preliminary study in Turkish children showed an incidence similar to reports from Europe and the U.S.A. More intensive chemotherapies and allogeneic bone marrow transplantations (BMT) uring the first remission were planned if a donor was available. Out of 8 BCR/ABL-positive patients, complete remission (CR) was achieved in 7 patients and partial remission (PR) was achieved in 1 patient. Three patients underwent allogeneic BMT during the first CR and 1 under went autologous BMT during the first PR. The Kaplan-Meier estimate of vent-free survival (EFS) of BCR/ABL negative de novo ALL patients was 78.36% at 3 years, whereas the EFS of positive patients was 31.25% at 26 ± 6.4 months. Molecular screening for the Philadelphia chromosome should become a part of the routine diagnostic panel in ALL patients in order to predict which patients have a poor prognosis and need tailored therapy.

7.Impact of Fluorescence in Situ Hybridization in the Detection of Cryptic Fusion Transcript PML/RARA and A Complex t(5;15;17) in a Case of Acute Promyelocytic Leukemia
Gönül Ogur, Turgay Fen, Gülsan Sucak, Pierre Heimann, Gaye Cankuş, Rauf Haznedar
Pages 207 - 212
Genetic aspects of a 28 year-old female patient with typical morphological and clinical features of acute promyelocytic leukemia is presented. Pml/rara fusion transcript and a complex translocation involving chromosomes 5, 15 and 17 were detected by fluorescence in situ hybridization (FISH) technique which was applied as in adjunct to conventional cytogenetics. The patient deceased soon in spite of the immediate ATRA and cytostatic therapy.

8.Paroxysmal Nocturnal Haemoglobinuria in the Differential Diagnosis of Unresponsive Iron Deficiency Anemia: A Case Report
İsmet Aydoğdu, İrfan Kuku, Alper Sevinç, Haluk Şavlı, Haluk Şavlı, N. Engin Aydın
Pages 213 - 215
A 16-year-old male patient who was on oral iron treatment for iron deficiency anemia for the last one year was seen at the Haematology clinic with complaints of weakness, pallor, and jaundice. A complete blood count revealed Hb of 4.2 mmol/L, Hct of 0.14, and MCV of 76 fl. A blood smear showed 50% neutrophils, 40% lymphocytes, and 10% monocytes with anisocytosis, poikilocytosis, polichromasia in erythrocytes and normoblasts. Reticulocyte count was under 1%. There was a slight erythroid hyperplasia in the bone marrow aspiration. Biochemical examinations showed total bilirubin of 3.9 mg/dL, indirect bilirubin of 3.4 mg/dL, and lactate dehydrogenase (LDH) of 6085 U/L (220-450). In re-evaluating the history of the patient, he was seen to be complaining of dark discoloration of morning urine. Perl’s reaction was found to be positive for hemosiderin in the urine sediment. Because Ham’s test was positive, the levels of CD55, 58, and 59 proteins on erythrocyte membranes were found to be lower. The patient was started 32 mg of methylprednisolone and his anaemia was improved by the 14th day of treatment. When evaluating iron deficiency anemia resistant to iron supplementation, PNH should be kept in mind.

9.Congenital Hypofibrinogenemia: A Newborn Infant with Cord Bleeding
Hacer Yapıcıoğlu, Nejat Narlı, Mehmet Satar, A. Bülent Antmen
Pages 217 - 219
The genetic disorders causing decreased fibrinogen synthesis may be caused by heterozygous (hypofibrinogenemia) or homozygous (afibrinogenemia) deficiency. The consequences of the disorders are gastrointestinal bleeding, cord bleeding, eccymoses, subcutaneous hematomas and hemarthroses especially due to traumatic delivery in the neonatal period. Laboratory evaluation of the patient with hypofibrinogenemia reveals prolongation of thrombin time, partial thromboplastin time, prothrombin time and decreased fibrinogen level. We report a 21 days old, congenital hypofibrinogenemia case with cord bleeding.


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