REVIEW | |
1. | Recommendations for Risk Categorization and Prophylaxis of Invasive Fungal Diseases in Hematological Malignancies: A Critical Review of Evidence and Expert Opinion (TEO-4) Can Boğa, Zahit Bolaman, Seçkin Çağırgan, İhsan Karadoğan, Mehmet Ali Özcan, Fahir Özkalemkaş, Rabin Saba, Mehmet Sönmez, Esin Şenol, Hamdi Akan, Murat Akova doi: 10.4274/tjh.2014.0277 Pages 100 - 117 This is the last of a series of articles on invasive fungal infections prepared by opinion leaders in Turkey. The aim of these articles is to guide clinicians in managing invasive fungal diseases in hematological malignancies and stem cell transplantation based on the available best evidence in this field. The previous articles summarized the diagnosis and treatment of invasive fungal disease and this article aims to explain the risk categorization and guide the antifungal prophylaxis in invasive fungal disease. |
RESEARCH ARTICLE | |
2. | A Novel Natural Product, KL-21, Inhibits Proliferation and Induces Apoptosis in Chronic Lymphocytic Leukemia Cells Aysun Adan Gökbulut, Mustafa Yaşar, Yusuf Baran doi: 10.4274/Tjh.2013.0381 Pages 118 - 126 INTRODUCTION: The aims of this study were to examine the cytotoxic and apoptotic effects of KL-21, a novel plant product (produced by Naturin Natural Products, İzmir, Turkey), on 232B4 chronic lymphocytic leukemia (CLL) cells and to determine the cytotoxic effects on healthy BEAS-2B human bronchial epithelial cells. METHODS: The cytotoxic effect of KL-21 was determined by MTT cell proliferation assay. Changes in caspase-3 enzyme activity were measured using the caspase-3 colorimetric assay. Changes in mitochondrial membrane potential were determined using the JC-1 dye-based method. Annexin V-FITC/PI double staining was performed to measure the apoptotic cell population. Effects of KL-21 on cell cycle profiles of CLL cells were investigated by flow cytometry. RESULTS: We detected time- and concentration-dependent increases in the cytotoxic effect of KL-21 on 232B4 CLL cells. However, we also showed that, especially at higher concentrations, KL-21 was less cytotoxic towards BEAS-2B healthy cells than towards CLL cells. Annexin-V/PI double staining results showed that the apoptotic cell population increased in 232B4 cells. Increasing concentrations of KL-21 increased caspase-3 enzyme activity and induced loss of mitochondrial membrane potential. KL-21 administration resulted in small increases in the percentage of the cells in the G0/G1 phase while it decreased the S phase cell population up to 1 mg/mL. At the highest concentration, most of the cells accumulated in the G0/G1 phase. DISCUSSION AND CONCLUSION: KL-21 has a growth-inhibitory effect on 232B4 CLL cells. KL-21 causes apoptosis and cell cycle arrest at G0/G1. |
3. | A possible role for WNT5A hypermethylation in Pediatric Acute Lymphoblastic Leukemia Özden Hatırnaz Ng, Sinem Fırtına, İsmail Can, Zeynep Karakaş, Leyla Ağaoğlu, Ömer Doğru, Tiraje Celkan, Arzu Akçay, Yıldız Yıldırmak, Çetin Timur, Uğur Özbek, Müge Sayitoğlu doi: 10.4274/Tjh.2013.0296 Pages 127 - 135 INTRODUCTION: WNT5A is one of the most studied noncanonical WNT ligands and is shown to be deregulated in different tumor types. Our aim was to clarify whether hypermethylation might be the cause of low WNT5A mRNA levels and whether we could restore this downregulation by reversing the event. METHODS: The expression of WNT5A mRNA was studied in a large acute lymphoblastic leukemia (ALL) patient group (n=86) by quantitative real-time PCR. The methylation status was detected by methylation-specific PCR (MSPCR) and bisulphate sequencing. In order to determine whether methylation has a direct effect on WNT5A expression, disease-representative cell lines were treated by 5’-aza-20-deoxycytidine. RESULTS: Here we designed a validation experiment of the WNT5A gene, which was previously examined and found to be differentially expressed by microarray study in 31 T-cell ALL patients. The expression levels were confirmed by quantitative real-time PCR and the expression levels were significantly lower in T-cell ALL patients than in control thymic subsets (p=0.007). MSPCR revealed that 86% of the patients were hypermethylated in the WNT5A promoter region. Jurkat and RPMI cell lines were treated with 5’-aza-20-deoxycytidine and WNT5A mRNA expression was restored after treatment. DISCUSSION AND CONCLUSION: According to our results, WNT5A hypermethylation does occur in ALL patients and it has a direct effect on mRNA expression. Our findings show that epigenetic changes of WNT signaling can play a role in ALL pathogenesis and reversing methylation might be useful as a possible treatment of leukemia. |
4. | The Hematological and Molecular Spectrum of α-Thalassemias in Turkey: The Hacettepe Experience Şule Ünal, Fatma Gümrük doi: 10.4274/tjh.2014.0200 Pages 136 - 143 INTRODUCTION: The spectrum of α-thalassemias correlates well with the number of affected α-globin genes. Additionally, combinations of the several non-deletional types of mutations with a large trans deletion comprising the 2 α-globin genes have an impact on the clinical severity. The objective of this study was to analyze the hematological and molecular data of 35 patients with Hb H disease from a single center in order to identify the genotypes of Hb H disease and genotype-phenotype correlations. METHODS: Herein, we report the hematological and mutational spectrum of patients with Hb H disease (n=35). Additionally, genotypes of α-gene mutations of 78 individuals, who were referred to our institution for α-gene screening, were analyzed. RESULTS: Supporting the previous data from Turkey, -α3.7 was the most common mutation among patients with Hb H disease (62.8%) and in the other 78 subjects (39.7%). Of the patients with Hb H disease, the most common genotypes were -α3.7/--20.5, -α3.7/--26.5, and -α3.7/--17.5 in 10 (28.6%), 6 (17.1%), and 6 (17.1%) patients, respectively. Another small deletion, -4.2 alpha, and several non-deletional types of α-gene mutations, namely α (-5nt): IVS-I donor site (GAG.GTG.AGG->GAG.G-----); α (PA-2): AATAAA>AATGGA, and α (cd59): GGC->GAC, were found to be associated with Hb H disease when present at trans loci of one of the large deletions given above. The combinations consisting of 1 non-deletional and 1 of the large deletional types of mutations (αTα/--) at trans loci were found to result in a more severe phenotype compared to the genotypes composed of 1 small trans deletion of a large deletion (-α/--). The combination of α (Cd59) and -- in trans was associated with severe phenotype and the disease was associated with an increase in Hb Bart’s level with null Hb H. In spite of the presence of 2 intact α-globin genes, homozygosity for PA-2 mutation resulted in severe Hb H disease. DISCUSSION AND CONCLUSION: This study indicated that Hb H disease is not rare in Turkey and its genotype is quite heterogeneous. |
5. | Cohort Study: Central Venous Catheter-Related Complications in Children with Hematologic Diseases at a Single Center Ayhan Pektaş, Ateş Kara, Aytemiz Gürgey doi: 10.4274/Tjh.2013.0403 Pages 144 - 151 INTRODUCTION: This study aims to document and analyze the central venous catheter (CVC)-related complications in children with hematological diseases who were treated within a single institution. METHODS: A retrospective investigation was conducted in 106 pediatric patients in whom 203 CVCs were inserted. A total of 175 catheter-related complications occurred in 5 years. RESULTS: The rates of clinical catheter infections, local catheter infections, venous thromboembolism, bleeding, and mechanical complications were 2.6, 1.1, 0.2, 0.2, and 0.2 per 1000 catheter days. Methicillin-resistant Staphylococcus epidermidis was the predominant infectious organism in blood and catheter cultures. The children with leukemia had a significantly higher frequency of clinical catheter infections (p=0.046). The children who underwent bone marrow transplantation had a significantly lower frequency of clinical catheter infections (p=0.043) and higher frequency of local catheter infections (p=0.003). The children with implanted catheters had a significantly lower frequency of clinical catheter infections (p=0.048). The children with thrombocytopenia had significantly fewer local catheter infections and significantly more clinical catheter infections and catheter-related bleeding (respectively p=0.001, p=0.042, and p=0.024). DISCUSSION AND CONCLUSION: Leukemia, bone marrow transplantation, and thrombocytopenia are risk factors for CVC-associated complications. The relatively higher number of interventions performed via permanent catheters may be responsible for the significantly increased incidence of systemic infections and mechanical injury. |
6. | The Effect of FcγRIIIA Gene Polymorphism on the Treatment of Diffuse Large B-cell Non-Hodgkin Lymphoma: A Multicenter Prospective Observational Study Nurhilal Büyükkurt, Mehmet Ali Özcan, Ülkü Ergene, Bahriye Payzın, Sunay Tunalı, Fatih Demirkan, Hayri Özsan, Özden Pişkin, Bülent Ündar doi: 10.4274/Tjh.2013.0367 Pages 152 - 157 INTRODUCTION: The curative treatment approach for diffuse large B-cell lymphoma (DLBCL) is controversial even in the rituximab (R) era. The aim of this study was to examine the FcγRIIIA gene polymorphism distribution of DLBCL patients who had been treated with R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Furthermore, we investigated the impact of FcγRIIIA gene polymorphism on the overall response rate (ORR) and overall survival (OS). METHODS: Patients from 3 centers in the Aegean region of Turkey who had newly diagnosed CD20-positive DLBCL were enrolled in the study. The single nucleotide polymorphisms of the FcγRIIIA gene were analyzed by real time-PCR. The response to treatment was determined in the middle and at the end of the protocol. During 2 years of follow-up, the patients were clinically and radiologically evaluated for disease status every 3 months. RESULTS: Thirty-six patients were included in the study and the distributions of F/F, V/F, and V/V types of alleles of FcγRIIIA were 25%, 50%, and 25%, respectively. Twenty-seven patients were considered as evaluable according to ORR and OS. The patients’ ORR was 87.5%, 100%, and 50% in the F/F, V/F, and V/V allele groups, respectively. We did not establish any statistically significant differences among the 3 alleles groups in respect to ORR (p=0.93). The OS within 2 years in the F/F, V/F, and V/V allele groups was 62.5%, 100%, and 100%, respectively. The OS in the F/F allele group was found to be lower than in the other 2 allele groups (p=0.01). DISCUSSION AND CONCLUSION: The distribution of gene polymorphisms in our study group was similar to those of previous studies. While ORR was similar between the groups, our results highlight a lower OS in F/F patients ompared to other allele groups of FcγRIIIA. |
7. | Presence of Essential Hypertension or Diabetes Mellitus Is a Predictor of Intracranial Bleeding in Elderly Patients: A Study of 108 Patients with Isolated Thrombocytopenia from a Single Reference Center Rajan Kapoor, Hara Prasad Pati, Manoranjan Mahapatra, Anuradha Monga doi: 10.4274/Tjh.2013.0161 Pages 158 - 162 INTRODUCTION: Thrombocytopenia poses a significant problem in the elderly. Not only are there varied causes, but it is also associated with significant morbidity and mortality. We carried out a study to learn the causes of isolated thrombocytopenia in elderly patients and to correlate the severity of thrombocytopenia and bleeding manifestations with various etiologic factors and comorbidities. METHODS: A total of 108 patients above 50 years of age presenting with isolated thrombocytopenia (platelet counts of <100x109/L with normal hemoglobin and total leukocyte counts) were enrolled in the study. Detailed history and clinical examinations were carried out for each patient. Complete blood counts were analyzed by automated cell counter. Peripheral smears were examined in all cases. HbsAg, anti-HCV, and anti-HIV testing by enzyme-linked immunosorbent assay was done in all patients. Wherever clinically indicated, bone marrow aspiration biopsy and cytogenetic studies were done. RESULTS: Out of 108 patients, 102 (94.4%) presented with bleeding tendencies. Twenty-nine (26.8%) presented with serious (World Health Organization grade 3/4) bleedings. Major findings were immune thrombocytopenic purpura in 79 (73.1%), myelodysplastic syndrome in 7 (6.5%), drug-induced thrombocytopenia in 7 (6.5%), and connective tissue disorder in 4 (3.7%) cases. Ten patients presented with intracranial bleedings. Upon logistic regression analysis, comorbidities in the form of essential hypertension and diabetes mellitus were significantly associated with occurrence of intracranial bleeding. There was no correlation of serious bleedings with platelet counts. DISCUSSION AND CONCLUSION: Isolated thrombocytopenia in the elderly is associated with significant morbidity. Diligent clinical and laboratory evaluation is required to elucidate the cause of thrombocytopenia in the elderly. Comorbidities in this population are associated with serious bleedings and not low platelet counts as is commonly thought. |
BRIEF REPORT | |
8. | Pharmacobiological Approach for the Clinical Development of Ruxolitinib in Myeloproliferative Neoplasms Eylem Eliaçık, Ayşe Işık, Salih Aksu, Ayşegül Üner, Yahya Büyükaşık, Nilgün Sayınalp, Hakan Göker, Osman İ. Özcebe, İbrahim C. Haznedaroğlu doi: 10.4274/Tjh.2013.0265 Pages 163 - 167 Ruxolitinib, JAK1 ve JAK2 inhibitörü olarak işlev gören bir ilaçtır. Semptomatik splenomegalisi olan orta- veya yüksek-risk myelofibrozis hastalarında kullanımı uluslararası onam almıştır. Bu bağlamda ruxolitinib, Philadelphia kromozomu negatif myeloproliferatif neoplaziler (MPN) için klinik yararı gösterilen ilk hedefe yönelik ajan konumundadır. Bu yazının amacı, ruxolitinibin MPN’nin klinik tablolarındaki potansiyel kullanım alanları konusunda farmakobiyolojik yönleri tartışmaktır. Ruxolitinib onamları başlıca hastalık risk faktörleri üzerinden yapılmaktadır. Ancak klinik kullanımda hastalığın ve ilacın farmakobiyolojik yönlerini de dikkate alma gerekliliği vardır. Bu hipotezimizi tartışırken splenektomize bir MPN hastamızda, hiperproliferatif bir kemik iliği ve orta derecede fibrozis mevcutken uyguladığımız ruxolitinib tedavisinden elde ettiğimiz deneyimlere dayandık. İlacın gelecekte klinik geliştirilmesi gerçekleştirilirken MPN risk profili yanı sıra farmakobiyolojik değerlendirmelerin de yapılması gerektiği düşüncesindeyiz. |
CASE REPORT | |
9. | Possible Role of Interleukin-31/33 Axis in Imatinib Mesylate-Associated Skin Toxicity Caterina Musolino, Alessandro Allegra, Carmen Mannucci, Sabina Russo, Andrea Alonci, Valerio Maisano, Gioacchino Calapai, Sebastiano Gangemi doi: 10.4274/Tjh.2014.0021 Pages 168 - 171 Imatinib mesylate is a small-molecule tyrosine kinase inhibitor (TKi) designed to target c-ABL and BCR-ABL, approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Adverse cutaneous reactions induced by imatinib are frequent, generally moderate, and dose-dependent. The aim of this work was to investigate the possible contribution of interleukin (IL)-33 and IL-31, cytokines involved in disorders associated with itching, in the pathogenesis of pruritus in a patient undergoing imatinib mesylate treatment. His IL-31 and IL-33 serum levels were significantly higher than in the control group (respectively 96.6 pg/mL vs. 7.623±7.681 pg/mL and 27.566 pg/mL vs. 6.170±7.060 pg/mL). In light of these findings, imatinib mesylate-related symptoms of dermatologic toxicities might be related to the release of IL-31 and IL-33. In particular, it is supposable that TKi usage could cause keratinocyte injury, the release of IL-33, and the consequent interaction with its receptor on mast cells that induces the secretion of several factors capable of causing skin manifestations, including IL-31, a known pruritus-inducing cytokine. This report, to the best of our knowledge, is the first work describing the possible involvement of the IL-31/IL-33 axis in the pathogenesis of skin side effects related to imatinib mesylate treatment. |
10. | Severe Clinical Course in a Patient with Congenital Amegakaryocytic Thrombocytopenia Due to a Missense Mutation of the c-MPL Gene İkbal Ok Bozkaya, Neşe Yaralı, Pamir Işık, Rukiye Ünsal Saç, Betül Tavil, Bahattin Tunç doi: 10.4274/Tjh.2013.0191 Pages 172 - 174 Congenital amegakaryocytic thrombocytopenia (CAMT) generally begins at birth with severe thrombocytopenia and progresses to pancytopenia. It is caused by mutations in the thrombopoietin receptor gene, the myeloproliferative leukemia virus oncogene (c-MPL). The association between CAMT and c-MPL mutation type has been reported in the literature. Patients with CAMT have been categorized according to their clinical symptoms caused by different mutations. Missense mutations of c-MPL have been classified as type II and these patients have delayed onset of bone marrow failure compared to type I patients. Here we present a girl with severe clinical course of CAMT II having a missense mutation in exon 4 of the c-MPL gene who was admitted to our hospital with intracranial hemorrhage during the newborn period. |
11. | Management of Two Juvenile Myelomonocytic Leukemia Patients According to Clinical and Genetic Features Özlem Tüfekçi, Hale Ören, Fatma Demir Yenigürbüz, Salih Gözmen, Tuba Hilkay Karapınar, Gülersu İrken doi: 10.4274/tjh.2014.0034 Pages 175 - 179 Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder of childhood. Major progress has been achieved in diagnosis and the understanding of the pathogenesis of JMML by identifying the genetic pathologies that occur in patients. Mutations of RAS, NF1, PTPN11, and CBL are found in approximately 80% of JMML patients. Distinct clinical features have been reported to be associated with specific gene mutations. The advent of genomic studies and recent identification of novel genetic mutations in JMML are important not only in diagnosis but also in the management and prognosis of the disease. Herein, we present 2 patients with JMML harboring different mutations, NRAS and c-CBL, respectively, with distinct clinical features and different therapeutic approaches. |
12. | Ruxolitinib Treatment in a Patient with Primary Myelofibrosis Resistant to Conventional Therapies and Splenectomy: A Case Report Meltem Aylı, Muhit Özcan, Güldane Cengiz Seval doi: 10.4274/tjh.2013.0338 Pages 180 - 183 A 67-year-old male patient who was diagnosed with primary myelofibrosis 4 years ago did not respond to conventional therapies. The splenomegaly progressively increased, which caused spleen infarctions and led to the decision to perform a splenectomy procedure. After splenectomy, the patient started treatment with ruxolitinib. In the first month of ruxolitinib treatment, the patient became transfusion-free and all constitutional symptoms disappeared. However, in the sixth month of ruxolitinib treatment, the disease transformed to acute myeloblastic leukemia, and the patient died 1 month later. This is the first case report that shows the effects of ruxolitinib in a splenectomized patient. |
LETTER TO EDITOR | |
13. | Thiopurine S-Methyltransferase and Methylenetetrahydrofolate Reductase Polymorphisms in Leukemia Serhan Küpeli doi: 10.4274/tjh.2015.0001 Pages 184 - 185 Abstract | |
14. | Platelet Levels of High- and Mega-Dose Methylprednisolone Treatment in Acute Immune Thrombocytopenia Ali Ayçiçek doi: 10.4274/tjh.2014.0436 Pages 186 - 187 Abstract | |
15. | Gaucher Disease and Gaucher Cells Sevgi Gözdaşoğlu doi: 10.4274/tjh.2015.0043 Pages 187 - 188 Abstract | |
16. | Terbinafine and Neutropenia İrfan Yavasoğlu doi: 10.4274/tjh.2014.0486 Page 189 Abstract | |
17. | Multiple Myeloma and Alkaline Phosphatase İrfan Yavaşoğlu, Gürhan Kadıköylü, Zahit Bolaman doi: 10.4274/tjh.2014.0495 Pages 189 - 190 Abstract | |
IMAGES IN HEMATOLOGY | |
18. | Disseminated Histoplasmosis in an Immunocompetent Host Presenting as Pancytopenia with Bilateral Adrenal Masses Smeeta Gajendra, Bhawna Jha, Tushar Sahni, Shalini Goel, Vimarsh Raina, Ritesh Sachdev doi: 10.4274/Tjh.2014.0084 Pages 191 - 192 Abstract | |
19. | Promyelocytic Blastic Crisis in Chronic Myeloid Leukemia During Imatinib Treatment Federico Angriman, Maria Nelly Gutierrez Acevedo, Maria Sol Rossi, Alberto Daniel Gimenez Conca, Victoria Otero, Jorge Alberto Arbelbide, Hernán Michelángelo doi: 10.4274/tjh.2014.0211 Pages 193 - 194 Abstract | |