The “Rare” or “Non-LCH” Histiocytic Disorders in Childhood: A Brief Overview 2 2 Diseases of the monocyte, macrophage and dendritic cell system are referred to as histiocytoses. Based on improved understanding of their pathobiology and molecular background histiocytoses have been recently re-classified into five groups. Nevertheless, for practical reasons the histiocytoses are grouped into: Langerhans cell histiocytosis (the most common entity), hemophagocytic lymphohistiocytosis (encompassing primary and secondary hyperinflammatory syndromes), non-Langerhans cell histiocytoses (encompassing entities and syndromes not belonging to one of the first two categories), and true histiocytic malignancies. Proliferation of bone marrow-derived mature histiocytes with CD68+/CD163+/CD1a-/CD207- phenotype is the common denominator of the non-Langerhans cell histiocytoses (non-LCH). The clinical manifestations are extremely heterogeneous, though partially overlapping. There are some distinct disease forms (particularly those belonging to the juvenile xanthogranuloma family) confined to the skin. Some other entities may present as systemic diseases requiring differential diagnosis with hematopoietic malignancies and solid tumors. This paper provides a brief overview on key clinical features, diagnostic criteria, and management of the most common systemic non-LCH entities: Juvenile Xanthogranuloma (JXG), Rosai-Dorfman disease (RDD), and Erdheim-Chester disease (ECD). The non-LCH histiocytoses with systemic manifestation are uncommon diseases in the pediatric hematology/oncology praxis. Due to their broad spectrum of manifestations, keeping in mind their key features and an adequate index of suspicion are important for timely and correct diagnosis. Non-LCH histiocytoses have to be considered in the differential diagnosis of papulonodular cutaneous lesions with xanthomatous appearance, osteolytic and osteosclerotic lesions with benign morphology and histiocytic infiltration, orbital lesions with proptosis, suprasellar masses presenting with central diabetes insipidus, as well as leptomeningeal mass lesions. 101 107 2018/12/31 1397/10/10 2018/12/31 1397/10/10 Milen Minkov Milen Minkov Head, International LCH Study Reference Center, CCRI, St. Anna Kinderkrebsforschung, Vienna, Austria LCH histiocytoses Non LCH-histiocytoses Juvenile xanthogranuloma Rosai-Dorfman disease Erdheim-Chester disease ## ##

Biology and Treatment of Hemophagocytic Lymphohistiocytosis 2 2 Hemophagocytic lymphohistocytosis (HLH) is a hyperinflammatory syndrome that occurs at all ages and is characterized by high levels of cytokines, secreted by activated T-lymphocytes and macrophages. All symptoms and laboratory changes can be explained by organ infiltration by these cells and hypercytokinemia. HLH occurs as an inherited form (genetic, primary HLH) with mutations primarily in the cytotoxic vesicle pathway, and an acquired form that, in children, is triggered mostly by infections, but also by autoinflammatory/autoimmune diseases, malignancies and metabolic diseases. The pathogenesis of genetic forms of HLH can be explained by the inability of cytotoxic cells to induce apoptosis in (infected) target cells and to terminate the immune response for which perforin is essential. The pathogenesis of acquired forms is multifactorial, and several factors may have to be present for the development of HLH: e.g. acquired immune defects; stimulation of the innate immune system via toll-like receptors or danger signals; interference of viruses and tumor cells with cytotoxicity and apoptosis; secretion of cytokines by tumor cells; mutations or single nucleotide polymorphisms in genes important for the immune response; heterozygous mutations in HLH-genes; environmental factors. Treatment of HLH is a balancing act between too little and too much therapy; cytokines have to be downregulated without destroying all immune defenses. Once HLH is controlled, therapy can be ended in acquired cases, whereas genetic cases need hematopoietic stem cell transplantation for cure. Therapy with corticosteroids and etoposide, as in the international HLH studies, is still the standard of care. New promising drugs are available; clinical trials have to confirm their efficacy. 108 113 2018/12/312018/12/31 1397/10/10 2018/12/312018/12/31 1397/10/10 Gritta Janka Gritta Janka University Medical Center, Department of Pediatric Hematology and Oncology, Hamburg, Germany Hemophagocytic lymphohistocytosis Pathophysiology Biology ## ##

Methylation Status of SMG1 Gene Promoter in Multiple Myeloma 2 2 Background: Epigenetic modifications, such as methylation can occur in multiple myeloma. SMG1is an important gene involved in cell growth which defect in methylation of its promoter leads to reduction of cell apoptosis and uncontrolled proliferation. In this study, we identified the methylation status of the SMG1 gene promoter in patients with multiple myeloma. Methods: Methylation status of SMG1 promoter in 9 patients with multiple myeloma and 4 healthy subjects as control was determined by Methylation-specific PCR (MSP) method. Results: SMG1 promoter in all myeloma patients was hemi-methylated. Meanwhile, in healthy subjects, two cases were hemi-methylated and the other two were normal. Conclusion: The results of this study indicated that the prevalence of SMG1 promoter methylation in patients with multiple myeloma was higher than general population which could be important in understanding the pathogenesis of the disease. 114 116 2018/12/312018/12/312018/09/7 1397/6/16 2018/12/312018/12/312018/11/10 1397/8/19 Hamid Gholipour Hamid Gholipour Hematology Department, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran Saeid Abroun Saeid Abroun Hematology Department, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran Mehrdad Noruzinia Mehrdad Noruzinia Hematology Department, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran Sasan Ghaffari Sasan Ghaffari Hematology Department, School of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran. Amirhosein Maali Amirhosein Maali Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran Mehdi Azad Mehdi Azad Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran Multiple Myeloma DNA methylation SMG1 gene ## ##

Risk Factors of Deep Vein Thrombosis in Cancer Patients 2 2 Background: Venous thromboembolism (VTE) is a significant complication in cancer patients which was found in 4-20% of the patients. This study was aimed to evaluate risk factors of deep vein thrombosis (DVT) in cancer patients in an oncology center in Indonesia. Methods: This was a retrospective cohort study. Data were obtained from medical records of adult cancer patients with DVT referring to Dharmais National Cancer Center in Indonesia since 2013-2016. Control group were adult cancer patients without DVT. Association of risk factors (sex, age, presence of metastasis, Khorana score, complete blood count and D-dimer level) with DVT were compared and analyzed between DVT patients and control group. Results: A total of 129 cancer patients with DVT at Dharmais Cancer Hospital during year 2013-2016 met the inclusion criteria. Median age of the patients was 56 years old. Multivariate logistic regression analysis was performed to investigate the effect of sex, age, hypertension, diabetes, chemotherapeutic agents, hemoglobin level, leukocyte counts and D-dimer level to the occurrence of DVT in cancer patients. Hypertension (OR 16.7, P<0.001), chemotherapy (OR 5.0, P=0.012), D-dimer level (OR 1.00, P=0.030) and leukocyte counts (OR 1.00, P=0.017) were significant risk factors to have contribution to the occurrence of DVT in cancer patients. Conclusion: Hypertension, history of chemotherapy, leukocytosis, and D-dimer level were significant risk factors for DVT in cancer patients. 117 123 2018/12/312018/12/312018/09/72018/09/22 1397/6/31 2018/12/312018/12/312018/11/102018/12/16 1397/9/25 Noorwati Sutandyo Noorwati Sutandyo Division of Hematology and Medical Oncology, Department of Internal Medicine, Dharmais National Cancer Centre Hospital – Jakarta noorwatisoetandyo@gmail.com Demak Tobing Demak Tobing Department of Clinical Pathology, Dharmais National Cancer Centre Hospital – Jakarta demakltobing@gmail.com Kardinah Kardinah Kardinah Kardinah Department of Radiology, Dharmais National Centre Hospital – Jakarta kardinahradiologi@gmail.com Deep vein thrombosis Cancer Risk factors D-dimer Hypertension Leuokocytosis ## ##

Cytotoxicity of Metoprolol on Leukemic Cells in Vitro 2 2 Background: β-Blockers have shown considerable cytotoxic, anti-tumor and anti-angiogenic effects. Metoprolol, a β-Blocker with anti-inflammation, anti-tumor and anti-angiogenic properties has been widely used for treatment of some cardiovascular diseases such as angina, hypertension, heart failure and myocardial infraction. Limited data exist about the cytotoxic effects of metoprolol on human cancer cells. The aim of this study was to investigate the cytotoxic effect of metoprolol on U937 and MOLT-4 cells in vitro. Methods: Human leukemic T cell (MOLT-4) and monocyte (U937) were cultured in Roswell Park Memorial Institute (RPMI) 1640 complete medium. Then, the cultured U937 and MOLT-4 cells were treated with different concentration of metoprolol (1, 10, 50, 100, 500 and 1000 μg/ml) for 24, 48 and 72 hours. The cytotoxicity of metoprolol was determined by using MTT (3-[4, 5 dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide) assay. Results: Metoprolol significantly decreased the viability of U937 and MOLT-4 cells at 1000μg/ml (3740.14µM) concentration after 48 hours incubation time (P<0.01). In addition, metoprolol significantly reduced the viability of U937 cells at ≥500 μg/ml (≥1870.07µM) concentrations after 72 hours incubation time (P<0.001). Moreover, metoprolol significantly decreased the viability of MOLT-4 cells at ≥100 μg/ml (≥374.01µM) concentrations after 72 hours incubation (P<0.001). Conclusion: According to the results of this study, metoprolol showed cytotoxic effect on U937 and MOLT-4 cells dose and time dependently. Therefore, metoprolol might have potential implication in therapy of leukemia as well as other malignancies. 124 129 2018/12/312018/12/312018/09/72018/09/222018/10/10 1397/7/18 2018/12/312018/12/312018/11/102018/12/162018/12/25 1397/10/4 Baran Hajatbeigi Baran Hajatbeigi Department of Immunology, Faculty of Medicine, Shahed University, Tehran, Iran baran.hajatbeigi@shahed.ac.ir Fatemeh Hajighasemi Fatemeh Hajighasemi Department of Immunology, Faculty of Medicine, Shahed University, Tehran, Iran fatimahajighasemi@gmail.com Metoprolol U937 MOLT-4 Cytotoxic ## ##

Chylous pleural effusion: A rare presentation of Non-Hodgkin- Lymphoma 2 2 Chylous pleural effusion is characterized by milky-appearing fluid with elevated triglyceride content and presence of chylomicrons in the pleural space. Even though patients with lymphoma sometimes present with malignant pleural effusion, chylous effusion is rarely encountered as a presenting feature in such patients. We present a 47-year-old woman diagnosed as follicular lymphoma who presented with chylothorax. Complete response to combination chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone was achieved. The patient is asymptomatic, in remission at 18 months of follow up. 130 132 2018/12/312018/12/312018/09/72018/09/222018/10/102018/08/10 1397/5/19 2018/12/312018/12/312018/11/102018/12/162018/12/252018/11/13 1397/8/22 M T Sugeeth M T Sugeeth Regional Cancer Centre, Trivandrum 695011, India. sugeethmt@ymail.com Geetha Narayanan Geetha Narayanan Regional Cancer Centre, Trivandrum 695011, India geenarayanan@yahoo.com Lali V.Soman Lali V.Soman Regional Cancer Centre, Trivandrum 695011, India. Chylous pleural effusion Non Hodgkin lymphoma First presentation Flowcytometry ## ##

Can Macrothrombocytopenia Mislead the Treatment of Idiopathic Thrombocytopenia Purpura? 2 2 Idiopathic thrombocytopenia purpura (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia and mucocutaneous bleeding. The former has a primary role in the diagnosis and treatment of ITP. One of the leading causes of miscounted platelets in patients who suffer from ITP is giant platelets which may indicate factitiously a severe false thrombocytopenia. Here, a case of macrothrombocytopenia is presented in an ITP patient. Giant platelets of this patient not only resulted in miscounting platelets but also falsely increased reading of RBC counts. By counting platelets through peripheral blood smear and hemocytometer, the patient was saved from an unnecessary splenectomy. 133 135 2018/12/312018/12/312018/09/72018/09/222018/10/102018/08/102018/08/2 1397/5/11 2018/12/312018/12/312018/11/102018/12/162018/12/252018/11/132018/11/10 1397/8/19 Mohammad Ghorbani Mohammad Ghorbani MSc of Hematology and Blood Blanking, Faculty member of Gonabad University of medical sciences, Gonabad, Iran sbmu_mohamad@yahoo.com Hamid Reza Niazkar Hamid Reza Niazkar Medical Student, Student Research Committee, Gonabad University of Medical Sciences, Gonabad, Iran hrn185@hotmail.com Mohammad Mehdi Ejtehadi Mohammad Mehdi Ejtehadi Laboratory technical manager,Shahid Hasheminejad Hospital,Mashhad University of Medical Sciences,Mashhad,Irane jtehadilab@gmail.com Reza Mahmoudi Reza Mahmoudi Internist specialist,Department of Internal Medicine, Faculty of Medicine, Gonabad University of Medical Sciences mehrnaz.mehraban@yahoo.com Abbasali Abbasnezhad Abbasali Abbasnezhad Department of Physiology, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran abbasnezhad.abbasali@gmail.com Idiopathic thrombocytopenic purpura Giant platelet Macrothrombocytopenia Factitious thrombocytopenia ## ##

Mediterranean Stomatocytosis/macrothrombocytopenia in A 9-Year-Old Girl 2 136 137 2018/12/312018/12/312018/09/72018/09/222018/10/102018/08/102018/08/22018/10/7 1397/7/15 2018/12/312018/12/312018/11/102018/12/162018/12/252018/11/132018/11/102018/12/11 1397/9/20 Hossein Karami Hossein Karami Department Of Pediatrics Hematology & Oncology, Thalassemia Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences karami_oncologist@yahoo.com Mohammad Naderisorki Mohammad Naderisorki Department Of Pediatrics Hematology & Oncology, Thalassemia Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences dr.naderisorki@gmail.com Nayersadat Tahami Nayersadat Tahami Department of Pediatrics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran ## ##