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1.  Multidisciplinary clinical management of paroxysmal nocturnal hemoglobinuria 
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease caused by clonal expansion of one or more hematopoietic stem cell (HSC) lines due to a somatic mutation of the phosphatidylinositol glycan anchor (PIG-A) gene located on Xp22.1. PNH incidence is 1.5-2 cases per million of the population per year. PNH can affect multiple systems in the body and requires multidisciplinary clinical management. Patients can manifest with severe pancytopenia, life-threatening thrombosis affecting the hepatic, abdominal, cerebral, and subdermal veins, and high requirements for blood transfusion due to haemolytic anemia. PNH can also be associated with bone marrow failure. Advances in diagnostic techniques and a targeted therapeutic approach for PNH have emerged in the last two decades. Eculizumab, a promising humanized monoclonal antibody against C5, is the first approved therapy for PNH.
PMCID: PMC4497492  PMID: 26171279
Paroxysmal nocturnal hemoglobinuria; diagnosis; treatment; eculizumab
2.  AF4 and AF4N protein complexes: recruitment of P-TEFb kinase, their interactome and potential functions 
AF4/AFF1 and AF5/AFF4 are the molecular backbone to assemble “super-elongation complexes” (SECs) that have two main functions: (1) control of transcriptional elongation by recruiting the positive transcription elongation factor b (P-TEFb = CyclinT1/CDK9) that is usually stored in inhibitory 7SK RNPs; (2) binding of different histone methyltransferases, like DOT1L, NSD1 and CARM1. This way, transcribed genes obtain specific histone signatures (e.g. H3K79me2/3, H3K36me2) to generate a transcriptional memory system. Here we addressed several questions: how is P-TEFb recruited into SEC, how is the AF4 interactome composed, and what is the function of the naturally occuring AF4N protein variant which exhibits only the first 360 amino acids of the AF4 full-length protein. Noteworthy, shorter protein variants are a specific feature of all AFF protein family members. Here, we demonstrate that full-length AF4 and AF4N are both catalyzing the transition of P-TEFb from 7SK RNP to their N-terminal domain. We have also mapped the protein-protein interaction network within both complexes. In addition, we have first evidence that the AF4N protein also recruits TFIIH and the tumor suppressor MEN1. This indicate that AF4N may have additional functions in transcriptional initiation and in MEN1-dependend transcriptional processes.
PMCID: PMC4497493  PMID: 26171280
AF4/AF4N; P-TEFb; elongation control; RNA polymerase II; 7SK RNP
3.  Type B lactic acidosis: a rare but life threatening hematologic emergency. A case illustration and brief review 
Major strides have been made in improving the treatment of medical emergencies associated with malignancies. Nonetheless, metabolic emergencies in cancer patients can often times be life-threatening. Type B lactic acidosis is a rare but potentially fatal paraneoplastic phenomenon that has been described in association with hematologic and solid malignancies and portends a poor prognosis if not rapidly recognized and treated. It is believed that this occurs as a result of cancer cells switching their glucose metabolism from an oxidative oxygen- dependent pathway towards a glycolytic phenotype, also known as the “Warburg effect”. Though rare, it is important to consider this entity in the differential diagnosis of type B lactic acidosis since prompt identification and treatment may help improve outcomes in this otherwise fatal process. We present a case of type B lactic acidosis in a patient with chronic lymphocytic leukemia along with a brief review of the literature.
PMCID: PMC4497494  PMID: 26171281
Lactic acidosis; malignancy; hematologic emergency
4.  PNH is a debilitating, fatal but treatable disease: same disease, different clinical presentations 
Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by chronic persistent hemolysis, multi-organ damage and eventually multiple organ failure. PNH develops as a result of increased sensitivity to complement due to an acquired deficiency of certain glycosylphosphatidylinositol (GPI)-linked proteins. The clinical presentation of PNH varies greatly from one patient to another. We present three cases of PNH with different clinical presentations to illustrate the debilitating nature of the disease, possible fatal outcomes, and the need to timely diagnosis and targeted therapy. These cases also underline the need for increased awareness of PNH among relevant healthcare specialties. PNH should be considered as a differential diagnosis in patients with unexplained abdominal pain, dyspnea, renal failure, thrombosis and non-immune hemolytic anemia.
PMCID: PMC4497495  PMID: 26171282
Paroxysmal nocturnal hemoglobinuria (PNH); thrombosis; abdominal pain; eculizumab
5.  Towards an off-the-shelf vaccine therapy targeting shared B-cell tumor idiotypes 
The ideal tumor antigen is one expressed selectively by the tumor, present in all cancer patients, essential for tumor survival and nonetheless able to induce both humoral and cellular immune response. The personalized idiotype (Id) of the surface immunoglobulin is a tumor specific antigen in that it is expressed on clonal B-cell tumors, mediates B-cell survival, and induces tumor specific immunity in both human and animal models. With the availability of monoclonal antibodies against B cells, such as rituximab, the cellular immune response mediated by specific T cells has gained more importance as a combination therapy for the complete elimination of residual tumor cells in lymphoma and myeloma.
PMCID: PMC4348793  PMID: 25755905
Myeloma; allogeneic T cells; immunotherapy
6.  The role of glucocorticoid receptor (GR) polymorphisms in human erythropoiesis 
Glucocorticoids are endogenous steroid hormones that regulate several biological functions including proliferation, differentiation and apoptosis in numerous cell types in response to stress. Synthetic glucocorticoids, such as dexamethasone (Dex) are used to treat a variety of diseases ranging from allergy to depression. Glucocorticoids exert their effects by passively entering into cells and binding to a specific Glucocorticoid Receptor (GR) present in the cytoplasm. Once activated by its ligand, GR may elicit cytoplasmic (mainly suppression of p53), and nuclear (regulation of transcription of GR responsive genes), responses. Human GR is highly polymorphic and may encode > 260 different isoforms. This polymorphism is emerging as the leading cause for the variability of phenotype and response to glucocorticoid therapy observed in human populations. Studies in mice and clinical observations indicate that GR controls also the response to erythroid stress. This knowledge has been exploited in-vivo by using synthetic GR agonists for treatment of the erythropoietin-refractory congenic Diamond Blackfan Anemia and in-vitro to develop culture conditions that may theoretically generate red cells in numbers sufficient for transfusion. However, the effect exerted by GR polymorphism on the variability of the phenotype of genetic and acquired erythroid disorders observed in the human population is still poorly appreciated. This review will summarize current knowledge on the biological activity of GR and of its polymorphism in non-hematopoietic diseases and discuss the implications of these observations for erythropoiesis.
PMCID: PMC4348794  PMID: 25755906
Dexamethasone (Dex); glucocorticoid receptor (GR); single nucleotide polymorphism (SNP); erythropoietin-resistant anemia; erythrocytosis
7.  Dkk-1 and IL-7 in plasma of patients with multiple myeloma prevent differentiation of mesenchymal stem cells into osteoblasts 
Bone disease is the leading cause of morbidity associated with multiple myeloma (MM). Lytic bone lesions have been detected in 90% of patients diagnosed with MM and present a great therapeutic challenge. After the removal of the tumor burden, the bone lesions persist and the bone remodeling homeostasis is not restored even in patients in clinical remission. To determine whether systemic factors generated by malignant MM cells can skew the osteoblast (OB) differentiation program of normal mesenchymal stem cells (MSCs), we generated an immortalized bone marrow MSC line (hTERT-MSC). The hTERT-MSCs were exposed to plasma from healthy donors and patients with MM. Cells grown in media supplemented with plasma from MM patients failed to differentiate into OBs, while the hTERT-MSCs grown in the presence of normal human plasma generated OB clusters that mineralized calcium, expressed Runx2, and were positive for alkaline phosphatase, fibronectin, collagen I, osteocalcin, and osteopontin. Blocking Dickkopf-1 (Dkk-1) and interleukin-7 (IL-7) in MM plasma restored proper OB differentiation of hTERT-MSCs. Finally, we show that hTERT-MSCs cultured in the presence of MM plasma adopt a cancer-associated stroma phenotype. Thus, we show, that systemic factors present in the plasma of patients with MM affect the behavior of non-malignant MSCs and contribute to the sustained bone disease reported in MM.
PMCID: PMC4348795  PMID: 25755907
Multiple myeloma; lytic bone lesions; osteoblast differentiation; Dkk-1; IL-7
8.  Comparative of three methods (ELIZA, MAIPA and flow cytometry) to determine anti-platelet antibody in children with ITP 
Immune (idiopathic) thrombocytopenic purpurea (ITP) is an autoimmune disease characterized by the increased anti-platelet antibodies in the patient’s sera and decreased platelets in the blood circulation. This study has determined and characterized the antiplatelet glycoproteins in children with ITP. Thirty eight children, who were hospitalized with clinical signs of ITP in Mofid Children Hospital (Tehran, Iran) during 18 months, went under our clinical studies in a research project. ELISA, Flow cytometry and MAIPA (Monoclonal Antibody Immobilization of Platelet Antigens) methods were employed to determine serum anti-platelet antibodies level. The anti-platelet antibodies level above mean + 3SD of control group was assumed as positive. The platelet counts ranged between 2 × 109/L and 100 × 109/L. Among the patients 63.5% of them were anti-platelet antibodies positive with ELISA method. Results of platelet lysate method showed that 51.7% of patients had antibodies against platelet antigens. Antibody against platelet GPIIb/IIIa, GPIb/IX and GPIa/IIa using MAIPA method were 48%, 54% and 25% respectively. In flow cytometry 62% of patients showed anti-platelet antibodies. The comparison of three methods shows that since MAIPA is the specific method for the detection of very small amount of antibody against glycoprotein antigens, it has the advantage of differentiating between immune and non-immune thrombocytopenia.
PMCID: PMC4348796  PMID: 25755908
Anti-platelet antibody; ELIZA; MAIPA; flow cytometry
9.  Imported visceral leishmaniasis – unexpected bone marrow diagnosis in a patient with fever, pancytopenia, and splenomegaly 
Leishmaniasis is spreading from mediterranean countries to the north of Europe. The Alps are not an endemic region and there are only few reports of sporadic cases. We report the case of a 72 year old male who presented after a syncope with fever, cough and a sacral skin rash. Clinical examination revealed splenomegaly, elevated liver enzymes and pancytopenia; differential diagnosis included myeloproliferative or lymphoproliferative disorders, infections and auto-immune conditions that cause enlargement of the spleen and liver diseases, however, all tests were negative. In 18FDG PET computerized tomography, pathological and diffuse uptake in the spleen was seen, with mild and homogeneous FDG uptake in the bone marrow and normal tracer uptake elsewhere in the body. Bone marrow aspiration revealed the presence of numerous intra- and extracellular Leishmania amastigotes. Travel history indicated that he had been in Sardinia for a 7-day vacation several months ago. The patient promptly responded to treatment with liposomal amphotericin B. Imported visceral leishmaniasis is likely to be seen more frequently in non-endemic regions and fever, pancytopenia and splenomegaly are diagnostic clues, whereas diagnostic confirmation may be done by detection of Leishmania spp. amastigotes in the bone marrow.
PMCID: PMC4348797  PMID: 25755910
Immunocompetent; imported; visceral leishmaniasis; imaging; hypersplenism
10.  Long-lasting complete response to imatinib in a patient with systemic mastocytosis exhibiting wild type KIT  
Systemic mastocytosis (SM) is a hematopoietic disorder characterized by abnormal expansion of mast cells (MCs) in visceral organs. The skin is involved in most cases. In adult patients the transforming KIT mutation D816V is usually present and confers resistance against imatinib. Therefore, imatinib is not recommended for patients with KIT D816V+ SM. Nonetheless, imatinib may work in patients with SM lacking KIT D816V. However, little is known about long-term efficacy and safety of this drug in SM. We report on a 62-year-old female patient with indolent SM (ISM) who suffered from severe debilitating skin involvement despite therapy with anti-mediator-type drugs, psoralen and ultraviolet-A-radiation. Although multifocal MC infiltrates were detected in the bone marrow by immunohistochemistry, no KIT mutation was found by sequencing analysis. In 2003, treatment with imatinib (induction, 400 mg/day; maintenance, 200 mg/day) was initiated. During therapy, skin lesions and tryptase levels decreased. Treatment was well tolerated without any side effects. After 10 years, skin lesions have disappeared and the tryptase level is within normal range. This case-study confirms the long-term efficacy and safety of imatinib in patients with SM lacking activating KIT mutations. Imatinib should be considered in select cases of SM in whom MCs exhibit wild-type KIT.
PMCID: PMC4351647  PMID: 25755909
Mastocytosis; tryptase; KIT D816V; imatinib; long-term efficacy; drug safety
11.  Concomitant use of radiotherapy and two topoisomerase inhibitors to treat adult T-cell leukemia with a radiotherapy-resistant bulky disease: a case series 
Concomitant chemoradiotherapy is established as the standard treatment to improve the prognosis of several types of solid tumor, but has not been the general practice for hematological malignancies. Here, I report two cases of adult T-cell leukemia (ATL) with a radiotherapy-resistant bulky disease treated with concomitant radiotherapy and two topoisomerase inhibitors: etoposide (VP-16) and irinotecan (CPT-11). Patient 1 was a 78-year-old man with chemotherapy-resistant inguinal bulky mass. Radiotherapy (total 40 Gy) for this inguinal lesion was started; however, the bulky disease was found to be resistant to radiotherapy and progressed. VP-16 and CPT-11 were administered in addition to radiotherapy (after a total of 20 Gy of radiotherapy). Patient 2 was a 71-year-old man with a solitary bulky mass in left cervical lesion. Various previous chemotherapy and radiotherapy approaches had not been able to control the disease. Six months after first radiotherapy, the bulky disease rapidly progressed with the occurrence of pain. Second radiotherapy (30 Gy) was started with simultaneous administration of CPT-11 and VP-16. In both cases, the bulky disease gradually regressed and completely disappeared by the end of radiotherapy. Thus, flexible adaptation of concomitant chemoradiotherapy including two topoisomerase inhibitors may offer a potential therapeutic option for radiotherapy-resistant bulky diseases, even in hematological malignancies.
PMCID: PMC4351648  PMID: 25755911
Adult T-cell leukemia; topoisomerase; radiotherapy
12.  STAT5 N-domain deleted isoforms are naturally occurring hypomorphs partially rescued in hematopoiesis by transgenic Bcl-2 expression 
Signal transducer and activator of transcription 5 (STAT5) is a critical regulator of normal and leukemic lympho-myeloid development through activation downstream of early-acting cytokines, their receptors, and JAKs. Truncation of STAT5 can be mediated through alternative translation initiation from an internal start codon giving rise to N-terminally deleted isoforms. To determine whether these isoforms could be detected naturally in normal murine tissues, Western blot analyses were performed on heart, lung, brain, spleen, liver, and kidney. Relative expression of full-length to truncated STAT5 was variable among tissues. Since we have previously demonstrated that STAT5abΔN lacks the ability to effectively upregulate pro-survival signals and bcl-2 expression, we used a transgenic mouse approach to next determine whether constitutive expression of human Bcl-2 in STAT5abΔN/ΔN mouse hematopoietic cells could restore normal hematopoiesis. Transgenic H2K-Bcl-2 expression in hypomorphic STAT5abΔN/ΔN mice largely rescued peripheral B and T lymphocyte numbers whereas multilineage donor contribution was only rescued to levels about 10% of normal. At the hematopoietic stem cell level, direct competitive repopulation with H2K-Bcl-2/STAT5abΔN/ΔN against STAT5abΔN/ΔN competitor showed a corrective effect of Bcl-2 expression whether the STAT5abΔN/ΔN genotype was competed as the donor or as the host versus H2K-Bcl-2/STAT5abΔN/ΔN genotype bone marrow cells. Therefore, STAT5abΔN isoforms are heterogeneously expressed and lack key functional activities that can be partially rescued by adding back Bcl-2.
PMCID: PMC4165113  PMID: 25232501
Cytokine signaling; JAK/STAT; hematopoiesis; apoptosis; Bcl-2
13.  The transcription factor Miz-1 is required for embryonic and stress-induced erythropoiesis but dispensable for adult erythropoiesis 
Myc-interacting zinc finger protein 1 (Miz-1) is a BTB/POZ domain transcription factor that regulates complex processes such as proliferation and apoptosis. Constitutively Miz-1-deficient animals arrest embryonic development at E14.5 due to severe anemia and fetal liver cells lacking Miz-1 show a high cell death rate and a significant reduction of mature Ter119+ckit- or Ter119+CD71-/low cells. Consistently, the numbers of BFU-Es and CFU-Es were severely reduced in colony forming assays. Mice with conditional Miz-1 alleles deleted around E14.5 were born at expected ratios, but had reduced numbers of erythrocytes, and showed an increase in reticulocytes and Macro-RBCs in the peripheral blood. When challenged with the hemolytic agent phenylhydrazine (PHZ), Miz-1 deficient mice responded with a severe anemia after 4 days of treatment, but showed a delay in the recovery from this anemia with regard to RBC counts, hematocrit and hemoglobin levels compared to controls. In addition, an accumulation of immature CD71+Ter119+ cells occurred in the bone marrow and spleen of mice lacking a functional Miz-1. We conclude from our studies that Miz-1 is important for erythroid differentiation and development. Moreover, Miz-1 is necessary to maintain a peripheral red blood cell homeostasis in particular in response to hemolysis after oxidative stress.
PMCID: PMC4165114  PMID: 25232500
BTB/POZ domain; transcription factor; Miz-1; erythropoiesis; Epo; STAT5
14.  Multiplex amplification refractory mutation system (MARMS) for the detection of β-globin gene mutations among the transfusion-dependent β-thalassemia Malay patients in Kelantan, Northeast of Peninsular Malaysia 
The aim of this study was to adapt MARMS with some modifications to detect beta mutation in our cohort of thalassemia patients. We focused only on transfusion-dependent thalassemia Malay patients, the predominant ethnic group (95%) in the Kelantanese population. Eight mutations were identified in 46 out of 48 (95.83%) beta thalassemia alleles. Most of the patients (54.2%) were compound heterozygous with co-inheritance Cd 26 (G>A). The frequencies of spectrum beta chain mutation among these patients are presented in Table 2. Among the transfusion dependent beta thalassemia Malay patients studied, 26 patients were found to be compound heterozygous and the main alleles were Cd 26 (G>A). Compound heterozygous mutation of Cd 26 (G>A) and IVS 1-5 (G>C) were 12 (46.2%), Cd 26 (G>A) and Cd 41/42 (TTCT) were 9 (34.6%), Cd 26 (G>A) and IVS 1-1 (G>C) were 2 (7.7%) respectively. Meanwhile the minority were made of a single compound heterozygous of Cd 26 (G>A) and Cd 71/72, Cd 26 (>A) and Cd 17 (A>T), Cd 26 (G>A) and -28 (G>A) respectively. Twenty out of forty six patients were shown to have homozygous of IVS 1-5 (G>C) were 2 (10.0%), Cd 26 (G>A) were 15 (75.0%), Cd 19 (A>G) were 1 (5.0%), and IVS 1-1 (G>T) were 2 (10.0%). The beta chain mutations among the Kelantanese Malays followed closely the distribution of beta chain mutations among the Thais and the Malays of the Southern Thailand. The G-C transition at position 5 of the IVS 1-5 mutation was predominant among the Malay patients. In conclusion, this method has successfully identified the mutation spectrum in our cohort of transfusion-dependent beta thalassemia patients, and this method is equally effective in screening for mutation among thalassemia patients.
PMCID: PMC4165115  PMID: 25232503
MARMS-PCR; β-globin gene; thalassemia; Malay; mutation
15.  Concomitant a novel ALAS2 mutation and GATA1 mutation in a newborn: a case report and review of the literature 
GATA-1, an X-linked gene, encodes a transcription factor that plays a role in erythropoiesis and megakaryopoiesis. GATA-1 mutations have been associated with various diseases, such as X-linked thrombocytopenia. ALAS2 is an X-linked erythroid-specific isoenzyme expressed during erythropoiesis. Mutations of ALAS2 were associated with X-linked sideroblastic anemia. We report a case of newborn twin boy with anemia and thrombocytopenia at birth. A bone marrow biopsy at 4 months of age showed marked dyserythropoiesis, dysmegakaryopoiesis, and rare ringed sideroblasts. Gene sequencing study showed a previously reported mutation in GATA-1 at c.622G>A location (G208R) and a novel ALAS2 mutation at c.1436G>A location (R479Q).
PMCID: PMC4165116  PMID: 25232504
GATA1 mutation; ALAS2 mutation; macrothrombocytopenia; dysmegakaryopoiesis; dyserythropoiesis; ringed sideroblasts
16.  Renal complications of beta-thalassemia major in children 
The success that has been made in the care of patients with thalassemia has led to the emergence of unrecognized complications including several renal abnormalities. Chronic anemia and iron overload as well as the use of iron chelator are believed to lie behind these abnormalities. Many investigators document the presence of tubular dysfunction and abnormalities in glomerular filtration rate in these patients. In this review we will discuss the updates in the diagnosis, pathogenesis and prevention of renal complications of thalassemia.
PMCID: PMC4165117  PMID: 25232499
Children; thalassemia; renal complications
17.  Transfusion-independent β0-thalassemia after bone marrow transplantation failure: proposed involvement of high parental HbF and an epigenetic mechanism 
Currently, bone marrow transplantation is the only curative treatment for β-thalassemia and sickle cell disease. In rare cases, sustained and full fetal hemoglobin production was observed in patients after failure of bone marrow transplantation. This rendered the patients transfusion-free, despite genetic disease and transplant rejection. The mechanisms underlying this phenomenon remain unexplored. We have studied a trio (father-mother-child) in which the affected child became transfusion-independent after rejection of an allogeneic bone marrow graft. Remarkably, we found that his non-thalassemic mother also expressed unusually high levels of γ-globin. High HbF in one of the parents may therefore be of prognostic value in these rare cases. Genotyping of the HBB locus and the HbF quantitative trait loci HBS1L-MYB, KLF1 and BCL11A, and protein expression analysis of KLF1 and BCL11A, failed to explain the increased HbF levels, indicating that an as yet unidentified HbF modifier locus may be involved. We hypothesize that epigenetic events brought about by the transplantation procedure allow therapeutic levels of HbF expression in the child. Potential implications of our observations for reactivation of γ-globin expression and interpretation of the French globin gene therapy case are discussed.
PMCID: PMC4165118  PMID: 25232502
β-thalassemia; bone marrow transplantation; HbF; transfusion-independence; epigenetics; MYB; KLF1; BCL11A; HBB
18.  N-cadherin impedes proliferation of the multiple myeloma cancer stem cells 
Multiple myeloma (MM) is an incurable malignancy of the plasma cells localized to the bone marrow. A rare population of MM cancer stem cells (MM-CSCs) has been shown to be responsible for maintaining the pull of residual disease and to contribute to myeloma relapse. The stem cells are found in a bone marrow niche in contact with the stromal cells that are responsible for maintaining the proliferative quiescence of the MM-CSC and regulate its self-renewal and differentiation decisions. Here we show that both MM and bone marrow stromal cells express N-cadherin, a cell-cell adhesion molecule shown to maintain a pool of leukemic stem cells. Inhibition of N-cadherin using a neutralizing antibody led to an increase in the MM cell proliferation. A decrease in MM cell adhesion to the bone marrow stroma was observed in the first 24 hours of co-culture followed by a 2.3-30-fold expansion of the adherent cells. Moreover, inhibition of N-cadherin led to a 4.8-9.6-fold expansion of the MM-CSC population. Surprisingly, addition of the N-cadherin antagonist peptide resulted in massive death of the non-adherent MM cells, while the viability of the adherent cells and MM-CSCs remained unaffected. Interestingly, the proliferative effects of N-cadherin inhibition were not mediated by the nuclear translocation of β-catenin. Taken together, our findings demonstrate the crucial role of N-cadherin in regulating MM cell proliferation and viability and open an interesting avenue of investigation to understand how structural modifications of N-cadherin can affect MM cell behavior. Our findings suggest that targeting N-cadherin may be a useful therapeutic strategy to treat MM in conjunction with an agent that has anti-MM-CSC activity.
PMCID: PMC3875273  PMID: 24396705
Multiple myeloma; cancer stem cells; N-cadherin
19.  Chronic myelogenous leukemia after postoperative adjuvant S-1 therapy for rectal cancer: a case report 
We report a case in which chronic myelogenous leukemia (CML) developed after postoperative adjuvant S-1 therapy for rectal cancer. A 56-year-old man was diagnosed with rectal adenocarcinoma, which was treated with abdominoperineal resection followed by a year of adjuvant S-1 therapy. At 39 postoperative months, he was diagnosed with CML. Although it remains unclear that CML that develops after treatment involving cytotoxic agents is treatment-related, clinicians should be aware of the possibility of CML developing after S-1 therapy.
PMCID: PMC3875274  PMID: 24396706
Chronic myelogenous leukemia; rectal cancer; fluoropyrimidine; S-1
20.  Granulocytic sarcoma: a systematic review 
Granulocytic sarcoma also called myeloid sarcoma is an extramedullary tumor of immature granulocytic cells. It is a rare entity, and mostly accompanied by acute myeloid leukemia. It is observed during the course of myeloproliferative disorders especially in chronic myeloid leukemia and myelodysplastic syndromes. In some rare circumstances, it is detected before clinical signs of leukemia or other diseases. When the bone marrow biopsy reveals no other hematologic malignancies, the granulocytic sarcoma is described as nonleukemic, primary or isolated. It is observed at any part of the body but the most common locations are soft tissues, bone, peritoneum and lymph nodes. Presenting signs or symptoms are mainly due to mass effect of the tumor and dysfunction of the organ, or the tissue that is affected. The diagnosis is performed by biopsy of the tumor. The tumor consists of immature granulocytic cells, which could be documented by H&E, immunohistochemistry, and flow cytometric methods. Fluorescence in-situ hybridization and molecular analysis are also performed. The optimal time and type of treatment is not clear. Surgery could be an option especially for tumors, which cause organ dysfunction and/or obstruction. Systemic treatment should be considered in all patients because without systemic treatment, relapses and progression to acute myeloid leukemia is the ultimate fate of the disease in many cases. Cytarabine-containing remission-induction chemotherapies have been the most applied therapeutic strategies, but it is not clear whether the consolidation therapies are required or not, and what kind of regimens are appropriate. The role of hematopoietic stem cell transplantation (HSC) as a consolidation regimen is not clear, but, after the relapse of the disease with or without bone marrow involvement, HSC transplantation should be considered in suitable patients after the reinduction performed by AML chemotherapies. There is only limited data about the role of radiotherapy in these patients. It could be used in patients with relapsed disease, organ dysfunction which should be quickly relieved and inadequate response to chemotherapy. The effect of radiotherapy on overall survival is not known. New prospective studies and clinical trials are needed to generate guidelines for the treatment of primary granulocytic sarcomas.
PMCID: PMC3875275  PMID: 24396704
Granulocytic sarcoma; treatment; chemotherapy; leukemia
21.  The Epstein-Barr virus microRNA BART11-5p targets the early B-cell transcription factor EBF1 
Epstein-Barr virus (EBV) is a ubiquitous B-cell trophic herpesvirus associated with a variety of histologically diverse B-cell lymphomas, each associated with specific viral-latency gene expression programs. Initial infection drives resting B-cells to differentiate via an atypical germinal centre reaction into memory B-cells, where the virus resides in a latent state. The mechanisms that underpin this process have yet to be fully elucidated. EBV expresses more than 40 microRNAs (miRNAs). The alternatively spliced BamHI A rightward transcripts (BARTs) are the template for two large miRNA clusters (BARTs A and B), that comprise the majority of all known EBV-miRNAs. Although BART-miRNAs are abundantly expressed in all latency programs, few BART-miRNA targets have been identified and their function is poorly understood. The early B-cell factor 1 (EBF1) was identified using bioinformaticss analysis as a novel target of EBV-miRNA BART11-5p, encoded by BART cluster B. EBF1 is an important B-cell transcription factor that regulates many B-cell specific genes including Pax5, BCR and CD40 and is critical for germinal centre formation. Using luciferase reporter assays and a series of BART-constructs, we confirmed silencing via the EBF1 3’ untranslated region (UTR) and identified the target site as 2137-2159 bp after the stop codon. Results were confirmed following transfection of a BART11-5p mimic, which was able to silence via the predicted target site. Our findings highlight a potential role of BART-miRNAs in the regulation of B-cell differentiation.
PMCID: PMC3755520  PMID: 23997984
EBV; microRNA; BamHI A rightward transcripts; early B-cell transcription factor; B-cell
22.  Changes in molecular biology of chronic myeloid leukemia in tyrosine kinase inhibitor era 
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease characterized by a reciprocal translocation between long arms of chromosomes 9 and 22 t(9;22) that generates the BCR-ABL fusion gene. If left untreated, newly diagnosed chronic phase CML patients finally progress to accelerated and blastic phase. After the introduction of tyrosine kinase inhibitors (TKIs), treatment strategies of CML changed dramatically. However, the development of resistance to TKIs started to create problems over time. In this review, the current information about CML biology before and after imatinib mesylate treatment is summarized.
PMCID: PMC3755521  PMID: 23997982
Chronic myeloid leukemia; moleculer biology; imatinib mesylate
23.  Treatment of severe steroid resistant acute GVHD with mesenchymal stromal cells (MSC) 
Background: Several studies revealed that MSC from human bone marrow can downregulate graft-versus-host disease (GVHD) after allogeneic HSCT. Methods: Herein we present 50 patients with acute GVHD who got 74 (1-4) MSC infusions for 54 separate episodes of aGVHD. Results: aGVHD was defined as steroid resistant grade IV aGVHD in 42 cases. The major presentation was gastrointestinal GVHD; two (n=18) or more (n=21) systems were involved in the majority of cases. The 1st infusion with MSC was given on day +27 (range, 1 to 136); d+45 (range, +11 to +150) post diagnosis of aGVHD and HSCT, respectively. In 2/3 of the cases treatment was performed with frozen stocked MSCs; in 62 cases early passages (1-3) were used. The median number of infused cells was 1.14±0.47 million per kg in the first injection and up to 4.27 (1.70±1.10) millions in total. The two patients with aggressive liver GVHD received MSCs injections intra hepatic arteries without changes of blood flow or evidence cytolysis, but also without a visible effect. Disease free survival at 3.6 years was 56%. We observed better overall survival in patients with GVHD grade < 4, in responders to the 1st treatment with MSC, and in pediatric group. The multivariate analysis demonstrated independent influence on survival of initial response and younger age. There were no immediate or late toxicity or side effects. Conclusion: Injection of MSCs seems to be a promising and safe treatment of GVHD. The encouraging results obviously should be confirmed in a randomized prospective study.
PMCID: PMC3755522  PMID: 23997985
Mesenchymal stromal cells (MSC); mesenchymal stem cells; hematopoietic stem cell transplantation; graft versus host disease; steroid resistance
24.  Costs and quality of life in patients with myelodysplastic syndromes 
Myelodysplastic syndromes (MDS) encompass a range of myeloid neoplasms characterised by a defect in haematopoietic stem cell maturation, resulting in peripheral cytopenias. As a major consequence, most MDS patients become anaemic, so as to require red blood cell transfusions. To investigate the costs and the impact on quality of life (QOL) of MDS-separately in transfusion-independent (TI) and -dependent (TD) patients-a literature search was conducted. From Medline and Embase, 742 studies were identified, of which 17 were considered eligible. Total medical costs per patient/year range from $ 9,840 to $ 19,811 for the TI condition and from $ 29,608 to $ 51,066 in the TD condition, more than doubling when moving from the former condition to the latter. With regard to QOL, in the transition from TI to TD, QOL could be reduced by half depending on the studies. The TD condition negatively impacts on costs and the QOL of patients with MDS. Therapeutic strategies that reduce transfusion dependence may lead to broad benefits for patients and the community.
PMCID: PMC3755523  PMID: 23997987
Myelodysplastic syndromes; anemia; transfusion dependence; quality of life; medical costs
25.  Detection of immune suppressive neutrophils in peripheral blood samples of cancer patients 
Neutrophils provide first-line defense against infections and are potent effectors in innate and adaptive immunity. Recently neutrophils have been shown to play important roles in multiple antitumor reactions. A subset of mature neutrophils in human systemic inflammation has been identified as a unique circulating population of myeloid cells, which is capable of inhibiting T cell responses. These neutrophils show unique immunophenotype (CD11c bright/CD62L dim/CD11b bright/CD16 bright). This study reports detection of mature neutrophils with similar immunophenotype in the peripheral blood samples of cancer patients using flow cytometry analysis. This population of neutrophils is not detected in peripheral blood samples of normal controls. Thus this finding suggests the involvement of mature neutrophils in antitumor immunity.
PMCID: PMC3755524  PMID: 23997986
Neutrophils; immunosuppressive; cancer; CD62L

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