E-ISSN: 1308-5263
Turkish Journal of Hematology - Turk J Hematol: 35 (4)
Volume: 35  Issue: 4 - 2018
FULL TEXT
1. Turkish Journal of Hematology (Volume: 35 Issue: 4, 2018)

Pages 216 - 314
Abstract |Full Text PDF

REVIEW
2. CAR-T Cell Therapy: A Door Is Open to Find Innumerable Possibilities of Treatments for Cancer Patients
Lorena Perez - Amill, Berta Marzal, Alvaro Urbano - Ispizua, Manel Juan, Beatriz Martín - Antonio
doi: 10.4274/tjh.2018.0196  Pages 217 - 228
Seven years ago a chronic lymphocytic leukemia patient was for the first time successfully treated with chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) to target CD19 overexpression in tumor cells. This was the beginning of the development of a new type of immunotherapy treatment in cancer patients. Since then, identification of novel antigens expressed in tumor cells and optimization of both CAR constructs and protocols of administration have opened up new avenues for the successful treatment of other hematological malignancies. However, research still continues to avoid some problems such as toxicities associated with the treatment and to find strategies to avoid tumor cell immune evasion mechanisms. On the other hand, for solid tumors, CAR-T therapy results are still in an early phase. In contrast to hematological malignancies, the complex tumor heterogeneity of solid tumors has led to the research of novel and challenging strategies to improve CAR-T cell activity. Here, we will review the main clinical results obtained with CAR-T cells in hematological malignancies, specifically focusing on CAR-T-19 and CAR-T against B-cell maturation antigen (CAR-T-BCMA). Moreover, we will mention the main problems that decrease CAR-T cell activity in solid tumors and the strategies to overcome them. Finally, we will present some of the first clinical results obtained for solid tumors.

RESEARCH ARTICLE
3. Both Granulocytic and Non-Granulocytic Blood Cells Are Affected in Patients with Severe Congenital Neutropenia and Their Non- Neutropenic Family Members: An Evaluation of Morphology, Function, and Cell Death
Lale Olcay, Şule Ünal, Hüseyin Onay, Esra Erdemli, Ayşenur Öztürk, Deniz Billur, Ayşe Metin, Hamza Okur, Yıldız Yıldırmak, Yahya Büyükaşık, Aydan İkincioğulları, Mesude Yılmaz Falay, Gülsüm Özet, Sevgi Yetgin
doi: 10.4274/tjh.2017.0160  Pages 229 - 259
Objective: To examine granulocytic and non-granulocytic cells in children with severe congenital neutropenia (SCN) and their nonneutropenic parents.
Materials and Methods: Fifteen patients with SCN and 21 nonneutropenic parents were evaluated for a) CD95, CD95 ligand, annexin V, propidium iodide, cell cycle, and lymphocyte subsets by flow cytometry; b) rapid cell senescence (of leukocytes) by senescenceassociated β-galactosidase stain; c) aggregation tests by aggregometer; d) in vitro bleeding time by PFA-100 instrument; e) mepacrine-labeled dense granule number of thrombocytes by fluorescence microscope; and f) hematomorphology by light and electron microscope. HAX1, ELANE, G6PC3, CSF3R, and JAGN1 mutations associated with SCN were studied in patients and several parents.
Results: Significant increase in apoptosis and secondary necrosis in monocytes, lymphocytes, and granulocytes of the patients and parents was detected, irrespective of the mutation type. CD95 and CD95 ligand results implied that apoptosis was non-CD95- mediated. Leukocytes of 25%, 12.5%, and 0% of patients, parents, and controls showed rapid cell senescence. The cell cycle analysis testable in four cases showed G1 arrest and apoptosis in lymphocytes of three. The patients had HAX1 (n=6), ELANE (n=2), G6PC3 (n=2), and unidentified (n=5) mutations. The CD3, CD4, and NK lymphocytes were below normal levels in 16.6%, 8.3%, and 36.4% of the patients and in 0%, 0%, and 15.4% of the parents (controls: 0%, 0%, 5.6%). The thrombocytes aggregated at low rates, dense granule number/ thrombocyte ratio was low, and in vitro bleeding time was prolonged in 37.5%-66.6% of patients and 33.3%-63.2% of parents (vs. 0% in controls). Under electron and/or light microscope, the neutrophils, monocytes, lymphocytes, and thrombocytes in the peripheral blood of both patients and parents were dysplastic and the bone marrow of patients revealed increased phagocytic activity, dysmegakaryopoiesis, and necrotic and apoptotic cells. Ultrastructurally, thrombocyte adhesion, aggregation, and release were inadequate.
Conclusion: In cases of SCN, patients’ pluripotent hematopoietic stem cells and their non-neutropenic parents are both affected irrespective of the genetic defect.

4. Tendency of K562 Chronic Myeloid Leukemia Cells Towards Cell Reprogramming
Açelya Yılmazer Aktuna
doi: 10.4274/tjh.2018.0106  Pages 260 - 264
Objective: Cancer cell reprogramming is a potential tool to study cancer progression, disease pathology, and drug sensitivity. Prior to performing cancer reprogramming studies, it is important to evaluate the stemness predisposition of cells that will be reprogrammed. We performed a proof-of-concept study with chronic myeloid leukemia K562 cells in order to evaluate their tendency for cancer cell reprogramming.
Materials and Methods: Expression of reprogramming factors, pluripotency markers, and tumor-suppressor genes was analyzed at gene and protein levels via real-time reverse transcription-polymerase chain reaction and flow cytometry. Human peripheral blood mononuclear cells (PBMCs) were used as a positive control.
Results: K562 cells were shown to express higher levels of most of the reprogramming factors and pluripotency markers. Expression of p53, which is one of the main regulators during the generation of induced pluripotent stem cells, was found to be lower in K562 cells compared to PBMCs, whereas the other tumor-suppressor genes showed higher expression levels.
Conclusion: This study suggested that, similar to healthy human PBMCs, K526 cells could be used in cancer cell reprogramming studies. Generating induced pluripotent stem cells from leukemia cells could help scientists to establish chronic myeloid leukemia models in vitro for a better understanding of therapy resistance and development of novel therapeutic targets.

5. Plasma Ischemia-Modified Albumin Levels and Dynamic Thiol/ Disulfide Balance in Sickle Cell Disease: A Case-Control Study
Oğuzhan Özcan, Hüseyin Erdal, Gül İlhan, Damla Demir, Ahmet Burak Gürpınar, Salim Neşelioğlu, Özcan Erel
doi: 10.4274/tjh.2018.0119  Pages 265 - 270
Objective: Sickle cell disease (SCD), described as a group of inherited blood disorders, affects millions of people throughout the world and is particularly common in the southern part of Turkey. We aimed to determine the relationship between ischemia-modified albumin (IMA) and the dynamic thiol/disulfide balance in SCD.
Materials and Methods: Fifty-four adult SCD patients and 30 healthy controls were included in the study. The 54 adult patients included 30 (56%) males and 24 (44%) females with a mean age of 28.3±8.4 years (minimum-maximum: 18-46 years). Of the 54 patients, 46 had homozygous sickle cell anemia (HbSS) and 8 had sickle/β-thalassemia (HbS/β+-thalassemia). Fasting blood samples were collected. After centrifugation at 1500×g for 10 min, plasma samples were portioned and stored at -80 °C. IMA levels were determined by albumin cobalt binding test, a colorimetric method. Total and native thiols and disulfide were analyzed with a novel spectrophotometric method.
Results: We found significantly lower levels of native thiol (-SH) (284.0±86.3 μmol/L), disulfide levels (14.6±7 μmol/L), and total thiols (-SH + -S-S-) (313.0±89.3 μmol/L) in SCD patients compared to healthy controls (respectively 417.0±54.2, 22.7±11.3, and 462.0±58.7 μmol/L). Plasma albumin levels (34.9±7.9 g/L) were lower and IMA levels (13.6±3.1 g/L) were higher in SCD patients compared to controls (respectively 43.5±3.1 and 8.4±1.6 g/L). Plasma albumin levels were strongly correlated with both plasma native (r=0.853; p=0.0001) and total thiols (r=0.866; p=0.0001).
Conclusion: Decreased plasma native and total thiol levels and increased IMA levels are related to increased oxidative stress and provide an indirect and quick reflection of the oxidative damage in SCD patients.

6. Does Reinfusion of Stem Cell Products on Multiple Days Affect Engraftment?
Şerife Solmaz Medeni, Doğus Türkyılmaz, Celal Acar, Ömür Gökmen Sevindik, Faize Yüksel, Özden Pişkin, Mehmet Ali Özcan, Fatih Demirkan, Bülent Ündar, İnci Alacacıoğlu, Güner Hayri Özsan
doi: 10.4274/tjh.2018.0071  Pages 271 - 276
Objective: High-doses of melphalan treatment with autologous stem cell transplantation in multiple myeloma (MM) remains a major treatment modality in suitable patients. A minimal dose of 2x106/kg CD34+ cells is preferred to achieve engraftment. Some patients need multiple leukapheresis procedures to achieve the necessary number of CD34+ cells, but this can cause a high volume of stem cell product that cannot be given in a single day. Whether or not the number of infusion days affects engraftment has not been studied before. We aimed to evaluate the impact of reinfusion of stem cells on multiple days on engraftment results.
Materials and Methods: Demographic features, CD34+ cell doses, neutrophil and platelet engraftment days, hospitalization days, and number of infusion days of 149 autologous transplantations of 143 MM patients were evaluated retrospectively.
Results: The data of 143 MM patients who were transplanted were analyzed retrospectively. Median age was 55±8.5 (range: 26-70) years with a male/female ratio of 91/58. Hospitalization days for all patients were 24±6 (range: 14-50) days. Mean CD34+ cell number was (7.5±5.3) x106/kg (range: 1.5-31x106/kg). CD34+ cells were reinfused in 1 day in 80.5% (n=120) of the patients, 2 days in 18.2% of the patients (n=27), and 3 days in 1.3% of the patients (n=2). For 29 patients, reinfusion was applied in more than 1 day because of the high volume of stem cell product. We did not see any dimethyl sulfoxide toxicity, cardiac arrhythmia, or volume overload complications. Hypertensive attacks during infusion were easily controlled by furosemide treatment. In the group with multiple infusions, the infused CD34+ cell numbers had a mean of (4.8±2.8)x106/kg, and in the single infusion group the mean was (8.1±5.5)x106/kg. There were no statistical differences between the two groups regarding platelet and neutrophil engraftment days (p=0.850, r=0.820 and p=0.500, r=0.440). There was no statistical difference between the two groups for hospitalization days (p=0.060, r=0.050).
Conclusion: In cases with a high volume of stem cell product to acquire adequate stem cells, reinfusion can be safely applied across multiple days without any delay in engraftment.

7. The Outcome of Antifungal Prophylaxis with Posaconazole in Patients with Acute Myeloid Leukemia: A Single-Center Study
Vildan Özkocaman, Fahir Özkalemkaş, Serdar Seyhan, Beyza Ener, Ahmet Ursavaş, Tuba Ersal, Esra Kazak, Ezgi Demirdöğen, Reşit Mıstık, Halis Akalın
doi: 10.4274/tjh.2017.0430  Pages 277 - 282
Objective: Invasive fungal infections (IFIs) are a significant cause of morbidity and mortality among neutropenic patients undergoing chemotherapy for acute myeloid leukemia (AML) and stem cell transplantation. The aim of this study was to evaluate the real-life impact of posaconazole prophylaxis.
Materials and Methods: Eighty-four adult patients were included with AML under remission induction chemotherapy and posaconazole prophylaxis. The 34 patients in the control group did not receive primary antifungal prophylaxis. The period between June 2006 and January 2009, when antifungal prophylaxis was not administered (control group), was retrospectively compared to the period between December 2010 and May 2012 when primary oral posaconazole prophylaxis was administered in similar conditions (posaconazole group) according to the use of antifungal agents for treatment, breakthrough infections, galactomannan performance, and the necessity for performing bronchoalveolar lavage (BAL) procedures.
Results: The two groups were compared according to the use of antifungal agents; progression to a different antifungal agent was found in 34/34 patients (100%) in the control group and in 9/84 patients (11%) in the posaconazole group (p<0.001). There were four breakthrough IFIs (4/84, 4.8%) in the posaconazole group and 34 IFIs in the control group (p<0.001). In addition, 15/34 patients (44%) in the control group required BAL compared to 11/84 patients (13%) in the posaconazole group (p<0.001). Posaconazole treatment was discontinued within 7-14 days in 7/84 patients (8.3%) due to poor oral compliance related to mucositis after chemotherapy.
Conclusion: Posaconazole appears to be effective and well-tolerated protection against IFIs for AML patients.

PERSPECTIVES IN HEMATOLOGY
8. Diagnostic Problems in Chronic Basophilic Leukemia
Cavit Çehreli
doi: 10.4274/tjh.2018.0129  Pages 283 - 289
Chronic basophilic leukemia (CBL) is an extremely rare type of leukemia. A literature review revealed six cases reported as primary CBL and five patients with secondary CBL. Patients with primary CBL may present with symptoms not related to leukemia. Dysplastic changes in peripheral blood and bone marrow were described and demonstrated in cases of primary and secondary CBL. The literature review also revealed that differential counts made by automated blood cell counters may not characterize cells as basophils in patients with primary and secondary CBL and may mislead physicians in making a differential diagnosis. For these reasons, laboratory studies for the diagnosis of CBL are required, including metachromatic staining by toluidine blue and antigen expressions by flow cytometric analysis, to detect the nature of the neoplastic cells as basophils for a reliable diagnosis of CBL. The literature review failed to reveal specific cytogenetic findings in patients with primary and secondary types of CBL.

BRIEF REPORT
9. Hematologic Adverse Effects of Prolonged Piperacillin- Tazobactam Use in Adults
Aysun Benli, Serap Şimşek Yavuz, Seniha Başaran, Atahan Çağatay, Halit Özsüt, Haluk Eraksoy
doi: 10.4274/tjh.2018.0127  Pages 290 - 295
Objective: We aimed to find the incidence and risk factors of hematologic adverse effects of piperacillin-tazobactam (TZP).
Materials and Methods: Adult patients who used TZP for more than 10 days were included in the study.
Results: The incidence of leukopenia, neutropenia, and eosinophilia in 110 TZP therapy episodes was found to be 16.3%, 10%, and 10%, respectively. Lower Charlson Comorbidity Index score, lower initial leukocyte count, combination of TZP with another antibiotic, and total duration of TZP therapy were found to be independent risk factors for leukopenia, while initial higher eosinophil count (IHEC) and usage of TZP for >20 days were independent risk factors for neutropenia and IHEC and total duration of TZP therapy were independent risk factors for eosinophilia.
Conclusion: Longer duration of therapy, combination with other antibiotics, younger age with fewer comorbidities, and IHEC could result in hematologic adverse effects in patients treated with TZP. Patients with IHEC may be more prone to allergic reactions, so immunological mechanisms may facilitate the development of hematological adverse effects of TZP.

IMAGES IN HEMATOLOGY
10. Acanthocytosis and HyperCKemia
Uluç Yiş, Kerstin Becker, Şebnem Yılmaz Bengoa, Sebahattin Çırak
doi: 10.4274/Tjh.2017.0142  Pages 296 - 297
Abstract |Full Text PDF

11. Basophilic Stippling and Chronic Lead Poisoning
Yantian Zhao, Juan Lv
doi: 10.4274/tjh.2018.0195  Pages 298 - 299
Abstract |Full Text PDF

LETTER TO EDITOR
12. The Impact of Small Bowel Endoscopy in Patients with Hereditary Hemorrhagic Telangiectasia
Stefania Chetcuti Zammit, David S Sanders, Mark E Mcalindon, Reena Sidhu
doi: 10.4274/tjh.2018.0253  Pages 300 - 301
Abstract |Full Text PDF

13. Interleukin-2-330T/G and Interleukin-10-1082A/G Genetic Polymorphisms and B-Cell Non-Hodgkin Lymphoma
Beuy Joob, Viroj Wiwanitkit
doi: 10.4274/tjh.2018.0189  Pages 301 - 302
Abstract |Full Text PDF

14. On Being a “Physician Patient” with His Own Experimental Therapeutic Drug
Rafiye Çiftçiler, İbrahim C. Haznedaroğlu
doi: 10.4274/tjh.2018.0254  Pages 302 - 303
Abstract |Full Text PDF

15. Hematology Laboratory Survey
Rujittika Mungmunpuntipantip, Viroj Wiwanitkit
doi: 10.4274/tjh.2018.0273  Pages 303 - 304
Abstract |Full Text PDF

16. Successful Treatment of Recurrent Gastrointestinal Bleeding Due to Small Intestine Angiodysplasia and Multiple Myeloma with Thalidomide: Two Birds with One Stone
Ida Hude, Josip Batinic, Sandra Bašic Kinda, Drazen Pulanic
doi: 10.4274/tjh.2018.0074  Pages 305 - 306
Abstract |Full Text PDF

17. Treatment of Chronic Back and Chest Pain in a Patient with Sickle Cell Disease Using Spinal Cord Stimulation
Damla Yürük, İbrahim Aşık
doi: 10.4274/tjh.2017.0447  Pages 307 - 308
Abstract |Full Text PDF

18. Simultaneous Presence of Follicular Lymphoma, Diffuse Large B-cell Lymphoma, and Hodgkin-like Lymphoma
Alexandra Papoudou-bai, Leonidas Marinos, Konstantina Papathanasiou, Panagiotis Kanavaros, Eleni Kapsali
doi: 10.4274/tjh.2018.0183  Pages 308 - 309
Abstract |Full Text PDF

19. Skeletal Muscle Diffuse Large B-Cell Lymphoma in the Gluteal Region
Nereyda Gonzalez-benavides, Jesus Alberto Cardenas-de La Garza, Candelario Rodriguez-vivian, Jorge Ocampo-candiani, Oliverio Welsh
doi: 10.4274/tjh.2018.0186  Pages 310 - 311
Abstract |Full Text PDF

20. Early Direct Antiglobulin Test Negativity after Bendamustine and Rituximab Treatment in Chronic Lymphocytic Leukemia: Two Cases
Rafet Eren, Elif Suyanı
doi: 10.4274/tjh.2017.0464  Pages 312 - 313
Abstract |Full Text PDF

21. Demodicidosis Accompanying Acute Cutaneous Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation
Pelin Aytan, Mahmut Yeral, Çiğdem Gereklioğlu, Nazım Emrah Kocer, Nurhilal Buyukkurt, İlknur Kozanoğlu, Hakan Özdoğu, Can Boğa
doi: 10.4274/tjh.2018.0057  Pages 313 - 314
Abstract |Full Text PDF

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22. Advisory Board of This Issue

Page E1
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23. Author Index

Pages E2 - E4
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24. Subject Index

Pages E5 - E13
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