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Sample records for hematologic malignancies final

  1. Improved radioimmunotherapy of hematologic malignancies. [Final report

    SciTech Connect

    Press, O.W.

    1992-03-24

    This research project proposes to develop novel new approaches of improving the radioimmunodetection and radioimmunotherapy of malignancies by augmenting retention of radioimmunoconjugates by tumor cells. The approaches shown to be effective in these laboratory experiments will subsequently be incorporated into out ongoing clinical trials in patients. Specific project objectives include: to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells; To examine the effects of lysosomotropic amines (e.g. chloroquine, amantadine), carboxylic ionophores (monensin, nigericin), and thioamides (propylthiouracil), on the retention of radiolabeled MoAbs by tumor cells; to examine the impact of newer radioiodination techniques (tyramine cellobiose, paraiodobenzoyl) on the metabolic degradation of radioiodinated antibodies; to compare the endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with different radionuclides ({sup 131}Iodine, {sup 111}Indium, {sup 90}Yttrium, {sup 99m}Technetium, {sup 186}Rhenium); and to examine the utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer.

  2. Hematologic malignancies

    SciTech Connect

    Hoogstraten, B.

    1986-01-01

    The principle aim of this book is to give practical guidelines to the modern treatment of the six important hematologic malignancies. Topics considered include the treatment of the chronic leukemias; acute leukemia in adults; the myeloproliferative disorders: polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis/agnogenic myeloid metaplasia; Hodgkin's Disease; non-Hodgkin's lymphoma; and Multiple Myeloma.

  3. Telomerase Activation in Hematological Malignancies.

    PubMed

    Ropio, Joana; Merlio, Jean-Philippe; Soares, Paula; Chevret, Edith

    2016-01-01

    Telomerase expression and telomere maintenance are critical for cell proliferation and survival, and they play important roles in development and cancer, including hematological malignancies. Transcriptional regulation of the rate-limiting subunit of human telomerase reverse transcriptase gen (hTERT) is a complex process, and unveiling the mechanisms behind its reactivation is an important step for the development of diagnostic and therapeutic applications. Here, we review the main mechanisms of telomerase activation and the associated hematologic malignancies. PMID:27618103

  4. Epigenetics in the hematologic malignancies

    PubMed Central

    Fong, Chun Yew; Morison, Jessica; Dawson, Mark A.

    2014-01-01

    A wealth of genomic and epigenomic data has identified abnormal regulation of epigenetic processes as a prominent theme in hematologic malignancies. Recurrent somatic alterations in myeloid malignancies of key proteins involved in DNA methylation, post-translational histone modification and chromatin remodeling have highlighted the importance of epigenetic regulation of gene expression in the initiation and maintenance of various malignancies. The rational use of targeted epigenetic therapies requires a thorough understanding of the underlying mechanisms of malignant transformation driven by aberrant epigenetic regulators. In this review we provide an overview of the major protagonists in epigenetic regulation, their aberrant role in myeloid malignancies, prognostic significance and potential for therapeutic targeting. PMID:25472952

  5. B-Cell Hematologic Malignancy Vaccination Registry

    ClinicalTrials.gov

    2015-09-15

    Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Waldenstrom Macroglobulinemia; Lymphocytosis; Lymphoma, Non-Hodgkin; B-Cell Chronic Lymphocytic Leukemia; Hematological Malignancies

  6. Novel immunotherapies for hematological malignancies

    PubMed Central

    Nelson, Michelle H.; Paulos, Chrystal M.

    2014-01-01

    Summary The immune system is designed to discriminate between self and tumor tissue. Through genetic recombination, there is fundamentally no limit to the number of tumor antigens that immune cells can recognize. Yet, tumors use a variety of immunosuppressive mechanisms to evade immunity. Insight into how the immune system interacts with tumors is expanding rapidly and has accelerated the translation of immunotherapies into medical breakthroughs. Herein, we appraise the state of the art in immunotherapy with a focus on strategies that exploit the patient’s immune system to kill cancer. We review various forms of immune-based therapies, which have shown significant promise in patients with hematological malignancies, including (i) conventional monoclonal therapies like rituximab, (ii) engineered monoclonal antibodies called bispecific T cell engagers (BiTEs), (iii) monoclonal antibodies and pharmaceutical drugs that block inhibitory T-cell pathways (i.e. PD-1, CTLA-4 and IDO), and (iv) adoptive cell transfer (ACT) therapy with T cells engineered to express chimeric antigen receptors (CARs) or T-cell receptors (TCRs). We also assess the idea of using these therapies in combination and conclude by suggesting multi-prong approaches to improve treatment outcomes and curative responses in patients. PMID:25510273

  7. Novel immunotherapies for hematologic malignancies.

    PubMed

    Nelson, Michelle H; Paulos, Chrystal M

    2015-01-01

    The immune system is designed to discriminate between self and tumor tissue. Through genetic recombination, there is fundamentally no limit to the number of tumor antigens that immune cells can recognize. Yet, tumors use a variety of immunosuppressive mechanisms to evade immunity. Insight into how the immune system interacts with tumors is expanding rapidly and has accelerated the translation of immunotherapies into medical breakthroughs. Herein, we appraise novel strategies that exploit the patient's immune system to kill cancer. We review various forms of immune-based therapies, which have shown significant promise in patients with hematologic malignancies, including (i) conventional monoclonal therapies like rituximab; (ii) engineered monoclonal antibodies called bispecific T-cell engagers; (iii) monoclonal antibodies and pharmaceutical drugs that block inhibitory T-cell pathways (i.e. PD-1, CTLA-4, and IDO); and (iv) adoptive cell transfer therapy with T cells engineered to express chimeric antigen receptors or T-cell receptors. We also assess the idea of using these therapies in combination and conclude by suggesting multi-prong approaches to improve treatment outcomes and curative responses in patients. PMID:25510273

  8. Cancer associated fibroblasts in hematological malignancies

    PubMed Central

    Raffaghello, Lizzia; Vacca, Angelo; Pistoia, Vito; Ribatti, Domenico

    2015-01-01

    Tumor microenvironment plays an important role in cancer initiation and progression. In hematological malignancies, the bone marrow represents the paradigmatic anatomical site in which tumor microenvironment expresses its morphofunctional features. Among the cells participating in the composition of this microenvironment, cancer associated fibrobasts (CAFs) have received less attention in hematopoietic tumors compared to solid cancers. In this review article, we discuss the involvement of CAFs in progression of hematological malignancies and the potential targeting of CAFs in a therapeutic perspective. PMID:25474039

  9. Current Role of Genetics in Hematologic Malignancies.

    PubMed

    Prakash, Gaurav; Kaur, Anupriya; Malhotra, Pankaj; Khadwal, Alka; Sharma, Prashant; Suri, Vikas; Varma, Neelam; Varma, Subhash

    2016-03-01

    Rapidly changing field of genetic technology and its application in the management of hematological malignancies has brought significant improvement in treatment and outcome of these disorders. Today, genetics plays pivotal role in diagnosis and prognostication of most hematologic neoplasms. The utilization of genetic tests in deciding specific treatment of various hematologic malignancies as well as for evaluation of depth of treatment response is rapidly advancing. Therefore, it is imperative for practitioners working in the field of hemato-oncology to have sufficient understanding of the basic concepts of genetics in order to comprehend upcoming molecular research in this area and to translate the same for patient care. PMID:26855503

  10. MicroRNAs in Myeloid Hematological Malignancies

    PubMed Central

    Ciccone, Maria; Calin, George Adrian

    2015-01-01

    MicroRNAs are 19-24 nucleotides noncoding RNAs which silence modulate the expression of target genes by binding to the messenger RNAs. Myeloid malignancies include a broad spectrum of acute and chronic disorders originating from from the clonal transformation of a hematopoietic stem cell. Specific genetic abnormalities may define myeloid malignancies, such as translocation t(9;22) that represent the hallmark of chronic myeloid leukemia. Although next-generation sequencing pro-vided new insights in the genetic characterization and pathogenesis of myeloid neoplasms, the molecular mechanisms underlying myeloid neoplasms are lacking in most cases. Recently, several studies have demonstrated that the expression levels of specific miRNAs may vary among patients with myeloid malignancies compared with healthy individuals and partially unveiled how miRNAs participate in the leukemic transformation process. Finally, in vitro experiments and pre-clinical model provided preliminary data of the safety and efficacy of miRNA inhibitory molecules, opening new avenue in the treatment of myeloid hematological malignancies. PMID:27047254

  11. Hematologic malignancies during pregnancy: A review.

    PubMed

    Mahmoud, Hossam K; Samra, Mohamed A; Fathy, Gamal M

    2016-07-01

    Malignancy is the second most common cause of mortality in the reproductive period and it complicates up to one out of every 1000 pregnancies. When cancer is diagnosed during pregnancy, the management approach must take into consideration both the mother and her fetus. Hematologic cancers diagnosed in pregnancy are not common, resulting in paucity of randomized controlled trials. Diagnosis of such malignancies may be missed or delayed, as their symptoms are similar to those encountered during normal pregnancy. Also, many imaging studies may be hazardous during pregnancy. Management of these malignancies during pregnancy induces many treatment-related risks for mother and baby and should consider patient's preferences for pregnancy continuation. In this article, hematologic malignancies diagnosed in pregnant patients including acute leukemias, chronic myeloid leukemia, lymphomas, multiple myeloma and myeloproliferative neoplasms, will be reviewed, including diagnostic and management strategies and their impact on the pregnant patient and the developing fetus. PMID:27408762

  12. New sources of drugs for hematologic malignancies

    PubMed Central

    Sukhai, Mahadeo A.; Spagnuolo, Paul A.; Weir, Scott; Kasper, James; Patton, Lavonne

    2011-01-01

    Advancing novel therapeutic agents for the treatment of malignancy into the marketplace is an increasingly costly and lengthy process. As such, new strategies for drug discovery are needed. Drug repurposing represents an opportunity to rapidly advance new therapeutic strategies into clinical trials at a relatively low cost. Known on-patent or off-patent drugs with unrecognized anticancer activity can be rapidly advanced into clinical testing for this new indication by leveraging their known pharmacology, pharmacokinetics, and toxicology. Using this approach, academic groups can participate in the drug discovery field and smaller biotechnology companies can “de-risk” early-stage drug discovery projects. Here, several scientific approaches used to identify drug repurposing opportunities are highlighted, with a focus on hematologic malignancies. In addition, a discussion of the regulatory issues that are unique to drug repurposing and how they impact developing old drugs for new indications is included. Finally, the mechanisms to enhance drug repurposing through increased collaborations between academia, industry, and nonprofit charitable organizations are discussed. PMID:21511957

  13. Pretargeted Radioimmunotherapy for Hematologic and Other Malignancies

    PubMed Central

    Press, Oliver W.; Pagel, John M.

    2010-01-01

    Summation Radioimmunotherapy (RIT) has emerged as one of the most promising treatment options, particularly for hematologic malignancies. However, this approach has generally been limited by a suboptimal therapeutic index (target-to-nontarget ratio) and an inability to deliver sufficient radiation doses to tumors selectively. Pretargeted RIT (PRIT) circumvents these limitations by separating the targeting vehicle from the subsequently administered therapeutic radioisotope, which binds to the tumor-localized antibody or is quickly excreted if unbound. A growing number of preclinical proof-of-principle studies demonstrate that PRIT is feasible and safe and provides improved directed radionuclide delivery to malignant cells compared with conventional RIT while sparing normal cells from nonspecific radiotoxicity. Early phase clinical studies corroborate these preclinical findings and suggest better efficacy and lesser toxicities in patients with hematologic and other malignancies. With continued research, PRIT-based treatment strategies promise to become cornerstones to improved outcomes for cancer patients despite their complexities. PMID:20423225

  14. Gene and virotherapy for hematological malignancies.

    PubMed

    Domingo-Musibay, Evidio; Yamamoto, Masato

    2016-07-01

    Recent years have seen a transformation in the treatment of hematological malignancies. Advances in gene therapy and molecular techniques and significant gains in computational abilities have supported the rapid development of safer and better tolerated therapies for many patients with hematologic cancers. In this review, we discuss novel applications of gene therapy, including immunomodulation and gene silencing, and report on the rise of oncolytic viruses for use in the treatment of malignancies arising in cells of the blood, lymph, and marrow. We discuss the relationship of the tropism of wildtype viruses and their oncolytic behavior as well as the tumoricidal and immunostimulatory properties of a number of attenuated and recombinant viruses currently in clinical development in countries around the world. While we have focused on promising virotherapy applications for future development, we also present a historical perspective and identify areas of potential clinical and regulatory practice change. We outline several of the virus systems being developed for applications in hematology, and summarize efficacy data in the context of ongoing or future human clinical testing. We also present the advantages and limitations of gene and virus therapy, including challenges and opportunities for improved treatment tolerability and outcomes for patients with hematologic malignancies. PMID:27289361

  15. Vaccinations in patients with hematological malignancies.

    PubMed

    Tsigrelis, C; Ljungman, P

    2016-03-01

    Patients with hematological malignancies are at risk for a number of infections that are potentially preventable by vaccinations such as pneumococcal infections and influenza. Treatment, especially with anti-B-cell antibodies and hematopoietic stem cell transplantation (HSCT), negatively impacts the response to vaccination for several months. It is therefore recommended that patients be vaccinated before initiating immunosuppressive therapy if possible. The risk of side-effects with inactivated vaccines is low, but care has to be taken with live vaccines, such as varicella-zoster virus vaccine, since severe and fatal complications have been reported. HSCT patients require repeated doses of most vaccines to achieve long-lasting immune responses. New therapeutic options for patients with hematological malignancies that are rapidly being introduced into clinical practice will require additional research regarding the efficacy of vaccinations. New vaccines are also in development that will require well-designed studies to ascertain efficacy and safety. PMID:26602587

  16. Fertility issues in patients with hematologic malignancies.

    PubMed

    Loren, Alison W

    2015-01-01

    An essential component of a cancer patient's comprehensive care is addressing potential threats to his or her reproductive health. Providers should discuss the risk of infertility with newly diagnosed patients and offer the chance to consult with a reproductive specialist as early as possible. Standard fertility preservation options include embryo or oocyte cryopreservation for women and sperm banking for men; all options for pre-pubertal children are experimental. Patients with hematologic malignancies are a distinct population in whom standard options may present special challenges, and alternative management strategies are being explored. Unique approaches in hematologic malignancy patients include experimental techniques, such as hormonal therapy, referrals to reproductive specialists after cancer treatment, or discontinuation of tyrosine kinase inhibitor therapy in appropriate chronic myelogenous leukemia patients. Importantly, expedited communication between hematologists and reproductive specialists may greatly enhance the quality of care for these patients. Facilitation of referrals will both improve the quality-of-life and expand the prospect of parenthood in survivors. There are ample opportunities to advance the field of oncofertility through additional research, especially in hematologic malignancy patients. PMID:26637713

  17. Improved radioimmunotherapy of hematologic malignancies

    SciTech Connect

    Press, O.W.

    1992-03-24

    This research project proposes to develop novel new approaches of improving the radioimmunodetection and radioimmunotherapy of malignancies by augmenting retention of radioimmunoconjugates by tumor cells. The approaches shown to be effective in these laboratory experiments will subsequently be incorporated into out ongoing clinical trials in patients. Specific project objectives include: to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells; To examine the effects of lysosomotropic amines (e.g. chloroquine, amantadine), carboxylic ionophores (monensin, nigericin), and thioamides (propylthiouracil), on the retention of radiolabeled MoAbs by tumor cells; to examine the impact of newer radioiodination techniques (tyramine cellobiose, paraiodobenzoyl) on the metabolic degradation of radioiodinated antibodies; to compare the endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with different radionuclides ({sup 131}Iodine, {sup 111}Indium, {sup 90}Yttrium, {sup 99m}Technetium, {sup 186}Rhenium); and to examine the utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer.

  18. Pulmonary disease in patients with hematologic malignancies.

    PubMed

    Poletti, Venerino; Trisolini, Rocco; Tura, Sante

    2002-03-01

    Patients with hematologic neoplasms frequently experience pulmonary disease. The possibility of a malignant involvement of the lung parenchyma is a well recognized and not unusual event, secondary spread due to lymphoproliferative disorders being the most common situation. Furthermore, the development and the advances in treatment options such as hematopoietic stem cell transplantation, radiation therapy and/or combined drug regimen use have significantly widened the spectrum of non-neoplastic pulmonary complications that can crop up in these patients. Infections, drug/radiation-induced toxicity, and graft-versus-host disease (GVHD)-related complications account by now for most pulmonary problems in hematologic patients and represent a difficult challenge both in diagnostic and in therapeutic terms for the clinician. The aim of this review is to highlight the clinicopathologic spectrum of lung diseases which can occur in the setting of hematologic malignancies. A particular emphasis is devoted to the diagnostic approach, high-resolution computed tomography (HRCT) assuming a key role since different patterns of CT abnormalities are associated with a different yield of the available diagnostic tools and may help in narrowing the differential diagnosis. PMID:12002382

  19. Role of Extracellular Vesicles in Hematological Malignancies

    PubMed Central

    Raimondo, Stefania; Corrado, Chiara; Raimondi, Lavinia; De Leo, Giacomo; Alessandro, Riccardo

    2015-01-01

    In recent years the role of tumor microenvironment in the progression of hematological malignancies has been widely recognized. Recent studies have focused on how cancer cells communicate within the microenvironment. Among several factors (cytokines, growth factors, and ECM molecules), a key role has been attributed to extracellular vesicles (EV), released from different cell types. EV (microvesicles and exosomes) may affect stroma remodeling, host cell functions, and tumor angiogenesis by inducing gene expression modulation in target cells, thus promoting cancer progression and metastasis. Microvesicles and exosomes can be recovered from the blood and other body fluids of cancer patients and contain and deliver genetic and proteomic contents that reflect the cell of origin, thus constituting a source of new predictive biomarkers involved in cancer development and serving as possible targets for therapies. Moreover, due to their specific cell-tropism and bioavailability, EV can be considered natural vehicles suitable for drug delivery. Here we will discuss the recent advances in the field of EV as actors in hematological cancer progression, pointing out the role of these vesicles in the tumor-host interplay and in their use as biomarkers for hematological malignancies. PMID:26583135

  20. Targeting oncogenic Ras signaling in hematologic malignancies

    PubMed Central

    Ward, Ashley F.; Braun, Benjamin S.

    2012-01-01

    Ras proteins are critical nodes in cellular signaling that integrate inputs from activated cell surface receptors and other stimuli to modulate cell fate through a complex network of effector pathways. Oncogenic RAS mutations are found in ∼ 25% of human cancers and are highly prevalent in hematopoietic malignancies. Because of their structural and biochemical properties, oncogenic Ras proteins are exceedingly difficult targets for rational drug discovery, and no mechanism-based therapies exist for cancers with RAS mutations. This article reviews the properties of normal and oncogenic Ras proteins, the prevalence and likely pathogenic role of NRAS, KRAS, and NF1 mutations in hematopoietic malignancies, relevant animal models of these cancers, and implications for drug discovery. Because hematologic malignancies are experimentally tractable, they are especially valuable platforms for addressing the fundamental question of how to reverse the adverse biochemical output of oncogenic Ras in cancer. PMID:22898602

  1. Classification of hematologic malignancies using texton signatures.

    PubMed

    Tuzel, Oncel; Yang, Lin; Meer, Peter; Foran, David J

    2007-10-01

    We describe a decision support system to distinguish among hematology cases directly from microscopic specimens. The system uses an image database containing digitized specimens from normal and four different hematologic malignancies. Initially, the nuclei and cytoplasmic components of the specimens are segmented using a robust color gradient vector flow active contour model. Using a few cell images from each class, the basic texture elements (textons) for the nuclei and cytoplasm are learned, and the cells are represented through texton histograms. We propose to use support vector machines on the texton histogram based cell representation and achieve major improvement over the commonly used classification methods in texture research. Experiments with 3,691 cell images from 105 patients which originated from four different hospitals indicate more than 84% classification performance for individual cells and 89% for case based classification for the five class problem. PMID:19890460

  2. Targeting the Apoptosis Pathway in Hematologic Malignancies

    PubMed Central

    Zaman, Shadia; Wang, Rui; Gandhi, Varsha

    2014-01-01

    Apoptosis is a cell death program that is well-orchestrated for normal tissue homeostasis and for removal of damaged, old, or infected cells. It is regulated by intrinsic and extrinsic pathways. The intrinsic pathway responds to signals such as ultraviolet radiation or DNA damage and activates “executioner” caspases through a mitochondria-dependent pathway. The extrinsic pathway is activated by death signals induced, for example, by an infection that activates the immune system or receptor-mediated pathways. The extrinsic pathway signals also cascade down to executioner caspases that cleave target proteins and lead to cell death. Strict control of cellular apoptosis is important for the hematopoietic system as it has a high turnover rate. However, the apoptosis program is often deregulated in hematologic malignancies leading to the accumulation of malignant cells. Therefore, apoptosis pathways have been identified for development of anticancer therapeutics. We review here the proteins that have been targeted for anticancer drug development in hematologic malignancies. These include BCL-2 family proteins, death ligands and receptors, inhibitor of apoptosis family proteins, and caspases. Except for caspase activators, drugs that target each of these classes of proteins have advanced into clinical trials. PMID:24295132

  3. Leptin and its receptor in hematologic malignancies

    PubMed Central

    Han, Tian-Jie; Wang, Xin

    2015-01-01

    Leptin is an adipocyte-derived cytokine coded by the obese gene, not only regulates metabolism, but also participates in hematopoiesis. Aberrant leptin levels in patients with hematologic malignancies were observed and associates with clinical characters, such as body mass index (BMI), gender, blast cell percentage. Leptin concentrations alter while diseases progress or remission. Leptin receptor is expressed in hematopoietic CD34+ stem cells, erythrocytes, lymphocytes, blast cells and samples in leukemia and lymphoma patients. The adipokine stimulates cell proliferation, cytokine secretion and protects malignant cells from apoptosis through Janus kinase-signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase and extracellular signal activated kinase 1/2 (MAPK/ERK1/2), or 3 kinase (PI3K) signaling pathways. These findings indicate leptin signaling possibility take part in occurrence, progression and prognosis of hematologic malignancies. This article reviews leptin/leptin receptor expression and the correlations with clinical characters, treatment and prognosis in myeloid and lymphoid neoplasms. PMID:26884894

  4. Secondary pulmonary alveolar proteinosis in hematologic malignancies.

    PubMed

    Chaulagain, Chakra P; Pilichowska, Monika; Brinckerhoff, Laurence; Tabba, Maher; Erban, John K

    2014-12-01

    Pulmonary alveolar proteinosis (PAP), characterized by deposition of intra-alveolar PAS positive protein and lipid rich material, is a rare cause of progressive respiratory failure first described by Rosen et al. in 1958. The intra-alveolar lipoproteinaceous material was subsequently proven to have been derived from pulmonary surfactant in 1980 by Singh et al. Levinson et al. also reported in 1958 the case of 19-year-old female with panmyelosis afflicted with a diffuse pulmonary disease characterized by filling of the alveoli with amorphous material described as "intra-alveolar coagulum". This is probably the first reported case of PAP in relation to hematologic malignancy. Much progress has been made on PAP first described by Rosen which is currently classified as idiopathic or primary or autoimmune PAP. Idiopathic PAP occurs as a result of auto-antibodies directed against granulocyte-macrophage colony stimulating factor (GM-CSF) impeding the surfactant clearing function of alveolar macrophages leading to progressive respiratory failure. Whole lung lavage and GM-CSF therapy has improved outcomes in patients with idiopathic PAP. Despite major advancement in the management of hematologic malignancy and its complications, little is known about the type of PAP first described by Levinson and now known as secondary PAP; a term also used when PAP occurs due to other causes such as occupational dusts. In this article we review and analyze the limited literature available in secondary PAP due to hematologic malignancies and present a case of PAP associated with chronic lymphocytic leukemia successfully treated with bendamustine and rituximab. PMID:25300566

  5. BMI1: A Biomarker of Hematologic Malignancies

    PubMed Central

    Sahasrabuddhe, Anagh A.

    2016-01-01

    BMI1 oncogene is a catalytic member of epigenetic repressor polycomb group proteins. It plays a critical role in the regulation of gene expression pattern and consequently several cellular processes during development, including cell cycle progression, senescence, aging, apoptosis, angiogenesis, and importantly self-renewal of adult stem cells of several lineages. Preponderance of evidences indicates that deregulated expression of PcG protein BMI1 is associated with several human malignancies, cancer stem cell maintenance, and propagation. Importantly, overexpression of BMI1 correlates with therapy failure in cancer patients and tumor relapse. This review discusses the diverse mode of BMI1 regulation at transcriptional, posttranscriptional, and posttranslational levels as well as at various critical signaling pathways regulated by BMI1 activity. Furthermore, this review highlights the role of BMI1 as a biomarker and therapeutic target for several subtypes of hematologic malignancies and the importance to target this biomarker for therapeutic applications. PMID:27168727

  6. Targeting cell cycle regulators in hematologic malignancies

    PubMed Central

    Aleem, Eiman; Arceci, Robert J.

    2015-01-01

    Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC) that maintains its ability of self-renewal. Cyclin-dependent kinases (CDKs) not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair. Chromosomal translocations, amplification, overexpression and altered CDK activities have been described in different types of human cancer, which have made them attractive targets for pharmacological inhibition. Mouse models deficient for one or more CDKs have significantly contributed to our current understanding of the physiological functions of CDKs, as well as their roles in human cancer. The present review focuses on selected cell cycle kinases with recent emerging key functions in hematopoiesis and in hematopoietic malignancies, such as CDK6 and its role in MLL-rearranged leukemia and acute lymphocytic leukemia, CDK1 and its regulator WEE-1 in acute myeloid leukemia (AML), and cyclin C/CDK8/CDK19 complexes in T-cell acute lymphocytic leukemia. The knowledge gained from gene knockout experiments in mice of these kinases is also summarized. An overview of compounds targeting these kinases, which are currently in clinical development in various solid tumors and hematopoietic malignances, is presented. These include the CDK4/CDK6 inhibitors (palbociclib, LEE011, LY2835219), pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol, AT7519, TG02, P276-00, terampeprocol and RGB 286638) as well as the WEE-1 kinase inhibitor, MK-1775. The advantage of combination therapy of cell cycle inhibitors with conventional chemotherapeutic agents used in the treatment of AML, such as cytarabine, is discussed. PMID:25914884

  7. Vorinostat in solid and hematologic malignancies

    PubMed Central

    Siegel, David; Hussein, Mohamad; Belani, Chandra; Robert, Francisco; Galanis, Evanthia; Richon, Victoria M; Garcia-Vargas, José; Sanz-Rodriguez, Cesar; Rizvi, Syed

    2009-01-01

    Vorinostat (Zolinza®), a histone deacetylase inhibitor, was approved by the US Food and Drug Administration in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. This review summarizes evidence on the use of vorinostat in solid and hematologic malignancies and collated tolerability data from the vorinostat clinical trial program. Pooled vorinostat clinical trial data from 498 patients with solid or hematologic malignancies show that vorinostat was well tolerated as monotherapy or combination therapy. The most commonly reported drug-related adverse events (AEs) associated with monotherapy (n = 341) were fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%), and Grade 3/4 drug-related AEs included fatigue (12.0%), thrombocytopenia (10.6%), dehydration (7.3%), and decreased platelet count (5.3%). The most common drug-related AEs observed with vorinostat in combination therapy (n = 157, most of whom received vorinostat 400 mg qd for 14 days) were nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), vomiting (31.2%), and anorexia (20.4%), with the majority of AEs being Grade 2 or less. In Phase I trials, combinations with vorinostat were generally well tolerated and preliminary evidence of anticancer activity as monotherapy or in combination with other systemic therapies has been observed across a range of malignancies. Ongoing and planned studies will further evaluate the potential of vorinostat in combination therapy, including combinations with radiation, in patients with diverse malignancy types, including non-small-cell lung cancer, glioblastoma multiforme, multiple myeloma, and myelodysplastic syndrome. PMID:19635146

  8. Nucleoporins and nucleocytoplasmic transport in hematologic malignancies.

    PubMed

    Takeda, Akiko; Yaseen, Nabeel R

    2014-08-01

    Hematologic malignancies are often associated with chromosomal rearrangements that lead to the expression of chimeric fusion proteins. Rearrangements of the genes encoding two nucleoporins, NUP98 and NUP214, have been implicated in the pathogenesis of several types of hematologic malignancies, particularly acute myeloid leukemia. NUP98 rearrangements result in fusion of an N-terminal portion of NUP98 to one of numerous proteins. These rearrangements often follow treatment with topoisomerase II inhibitors and tend to occur in younger patients. They have been shown to induce leukemia in mice and to enhance proliferation and disrupt differentiation in primary human hematopoietic precursors. NUP214 has only a few fusion partners. DEK-NUP214 is the most common NUP214 fusion in AML; it tends to occur in younger patients and is usually associated with FLT3 internal tandem duplications. The leukemogenic activity of NUP214 fusions is less well characterized. Normal nucleoporins, including NUP98 and NUP214, have important functions in nucleocytoplasmic transport, transcription, and mitosis. These functions and their disruptions by oncogenic nucleoporin fusions are discussed. PMID:24657637

  9. Monoclonal antibodies targeting CD38 in hematological malignancies and beyond.

    PubMed

    van de Donk, Niels W C J; Janmaat, Maarten L; Mutis, Tuna; Lammerts van Bueren, Jeroen J; Ahmadi, Tahamtan; Sasser, A Kate; Lokhorst, Henk M; Parren, Paul W H I

    2016-03-01

    CD38 is a multifunctional cell surface protein that has receptor as well as enzyme functions. The protein is generally expressed at low levels on various hematological and solid tissues, while plasma cells express particularly high levels of CD38. The protein is also expressed in a subset of hematological tumors, and shows especially broad and high expression levels in plasma cell tumors such as multiple myeloma (MM). Together, this triggered the development of various therapeutic CD38 antibodies, including daratumumab, isatuximab, and MOR202. Daratumumab binds a unique CD38 epitope and showed strong anti-tumor activity in preclinical models. The antibody engages diverse mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, programmed cell death, modulation of enzymatic activity, and immunomodulatory activity. CD38-targeting antibodies have a favorable toxicity profile in patients, and early clinical data show a marked activity in MM, while studies in other hematological malignancies are ongoing. Daratumumab has single agent activity and a limited toxicity profile, allowing favorable combination therapies with existing as well as emerging therapies, which are currently evaluated in the clinic. Finally, CD38 antibodies may have a role in the treatment of diseases beyond hematological malignancies, including solid tumors and antibody-mediated autoimmune diseases. PMID:26864107

  10. Endothelial progenitor cells in hematologic malignancies

    PubMed Central

    Saulle, Ernestina; Castelli, Germana; Pelosi, Elvira

    2016-01-01

    Studies carried out in the last years have improved the understanding of the cellular and molecular mechanisms controlling angiogenesis during adult life in normal and pathological conditions. Some of these studies have led to the identification of some progenitor cells that sustain angiogenesis through indirect, paracrine mechanisms (hematopoietic angiogenic cells) and through direct mechanisms, i.e., through their capacity to generate a progeny of phenotypically and functionally competent endothelial cells [endothelial colony forming cells (ECFCs)]. The contribution of these progenitors to angiogenetic processes under physiological and pathological conditions is intensively investigated. Angiogenetic mechanisms are stimulated in various hematological malignancies, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndromes and multiple myeloma, resulting in an increased angiogenesis that contributes to disease progression. In some of these conditions there is preliminary evidence that some endothelial cells could derive from the malignant clone, thus leading to the speculation that the leukemic cell derives from the malignant transformation of a hemangioblastic progenitor, i.e., of a cell capable of differentiation to the hematopoietic and to the endothelial cell lineages. Our understanding of the mechanisms underlying increased angiogenesis in these malignancies not only contributed to a better knowledge of the mechanisms responsible for tumor progression, but also offered the way for the discovery of new therapeutic targets. PMID:27583252

  11. Endothelial progenitor cells in hematologic malignancies.

    PubMed

    Testa, Ugo; Saulle, Ernestina; Castelli, Germana; Pelosi, Elvira

    2016-01-01

    Studies carried out in the last years have improved the understanding of the cellular and molecular mechanisms controlling angiogenesis during adult life in normal and pathological conditions. Some of these studies have led to the identification of some progenitor cells that sustain angiogenesis through indirect, paracrine mechanisms (hematopoietic angiogenic cells) and through direct mechanisms, i.e., through their capacity to generate a progeny of phenotypically and functionally competent endothelial cells [endothelial colony forming cells (ECFCs)]. The contribution of these progenitors to angiogenetic processes under physiological and pathological conditions is intensively investigated. Angiogenetic mechanisms are stimulated in various hematological malignancies, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndromes and multiple myeloma, resulting in an increased angiogenesis that contributes to disease progression. In some of these conditions there is preliminary evidence that some endothelial cells could derive from the malignant clone, thus leading to the speculation that the leukemic cell derives from the malignant transformation of a hemangioblastic progenitor, i.e., of a cell capable of differentiation to the hematopoietic and to the endothelial cell lineages. Our understanding of the mechanisms underlying increased angiogenesis in these malignancies not only contributed to a better knowledge of the mechanisms responsible for tumor progression, but also offered the way for the discovery of new therapeutic targets. PMID:27583252

  12. Cap-Independent Translation in Hematological Malignancies

    PubMed Central

    Horvilleur, Emilie; Wilson, Lindsay A.; Bastide, Amandine; Piñeiro, David; Pöyry, Tuija A. A.; Willis, Anne E.

    2015-01-01

    Hematological malignancies are a heterogeneous group of diseases deriving from blood cells progenitors. Although many genes involved in blood cancers contain internal ribosome entry sites (IRESes), there has been only few studies focusing on the role of cap-independent translation in leukemia and lymphomas. Expression of IRES trans-acting factors can also be altered, and interestingly, BCL-ABL1 fusion protein expressed from “Philadelphia” chromosome, found in some types of leukemia, regulates several of them. A mechanism involving c-Myc IRES and cap-independent translation and leading to resistance to chemotherapy in multiple myeloma emphasize the contribution of cap-independent translation in blood cancers and the need for more work to be done to clarify the roles of known IRESes in pathology and response to chemotherapeutics. PMID:26734574

  13. [Angiogenesis in patients with hematologic malignancies].

    PubMed

    Mesters, R M; Padró, T; Steins, M; Bieker, R; Retzlaff, S; Kessler, T; Kienast, J; Berdel, W E

    2001-09-01

    Angiogenesis in Patients with Hematologic Malignancies The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. Emerging data suggest an involvement of angiogenesis in the pathophysiology of hematologic malignancies as well. Recently, we and others have reported increased angiogenesis in the bone marrow of patients with acute myeloid leukemia (AML) and normalization of bone marrow microvessel density when patients achieved a complete remission (CR) after induction chemotherapy. Tumor angiogenesis depends on the expression of specific mediators that initiate a cascade of events leading to the formation of new microvessels. Among these, VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor) and angiopoietins play a pivotal role in the induction of neovascularization in solid tumors. These cytokines stimulate migration and proliferation of endothelial cells and induce angiogenesis in vivo. Recent data suggest an important role for these mediators in hematologic malignancies as well. Isolated AML blasts overexpress VEGF and VEGF receptor 2. Thus, the VEGF/VEGFR-2 pathway can promote the growth of leukemic blasts in an autocrine and paracrine manner. Therefore, neovascularization and angiogenic mediators/receptors may be promising targets for anti-angiogenic and anti-leukemic treatment strategies. The immunomodulatory drug thalidomide inhibits angiogenesis in animal models. Moreover, it has significant activity in refractory multiple myeloma. In a current phase II study for patients with primary refractory or relapsed multiple myeloma using a combination of thalidomide with hyperfractionated cyclophosphamide and dexamethasone (Hyper-CDT), we observed a partial remission in 12 of 14 evaluable patients (86%). Thus, this combination seems to be very potent. Furthermore, we evaluated the safety and efficacy of thalidomide in patients with AML not qualifying for intensive cytotoxic chemotherapy. 20

  14. Expanding role of lenalidomide in hematologic malignancies

    PubMed Central

    Ghosh, Nilanjan; Grunwald, Michael R; Fasan, Omotayo; Bhutani, Manisha

    2015-01-01

    Lenalidomide is an immunomodulatory agent that has been approved by the US Food and Drug Administration for treatment of multiple myeloma, deletion 5q myelodysplastic syndrome, and mantle cell lymphoma. In addition, it has clinical activity in lymphoproliferative disorders and acute myeloid leukemia. The mode of action includes immunomodulatory, anti-inflammatory, antiangiogenic, and antiproliferative mechanisms. The antitumor effect is a result of direct interference of key pathways in tumor cells and indirect modulation of the tumor microenvironment. There has been no recent collective review on lenalidomide in multiple myeloma, myelodysplastic syndrome/acute myeloid leukemia, and lymphoma. This review summarizes the results of current clinical studies of lenalidomide, alone and in combination with other agents, as a therapeutic option for various hematologic malignancies. PMID:25999761

  15. Cytogenetic effect of 5-azacytidine in patients with hematological malignancies

    PubMed Central

    Tsuda, Jessica Romy; Segato, Rosimeire; Barbosa, Waldênia; Smith, Marília de Arruda Cardoso; Payão, Spencer Luiz Marques

    2011-01-01

    Background Recently, the importance of cytogenetics has grown in the diagnosis, prognosis and treatment of leukemias and myelodysplastic syndromes. 5-azacytidine is a drug that has well-known cytogenetical effects and is approved in the treatment of myelodysplastic syndromes. To date, no studies have been performed to evaluate the impact of 5-azacytidine on the chromosomes of patients with hematological neoplasias. This study aimed to investigate the effects of 5-azacytidine on chromosomes of patients with different hematological malignancies using G-band analyses to identify possible cytogenetical alterations. Methods The peripheral blood of 18 patients with hematological malignancies and 18 controls was collected in heparinized tubes. 5-azacytidine was added, at a final concentration of 10-5M, to cultures 7 hours prior to harvest. Results Uncoiled centromeric/pericentromeric heterochromatin of chromosomes-1, 9 and 16 occurred more frequently in the patients than in controls. This higher frequency of uncoiled heterochromatin was statistically significant (p-value = 0.004) for chromosome-9. Conversely, we observed that the fragile site at 19q13 was more frequent in controls (p-value = 0.0468). Conclusions The results of this study suggest that satellite sequences, located in the heterochromatin of chromosome-9, are hypomethylated in hematological malignancies. This hypomethylation may contribute to the disease, activating transposable elements and/or promoting genomic instability, enabling the loss of heterozygosity of important tumor suppressor genes. An investigation of the 19q13 region may help to understand whether or not the predominant occurrence of the fragile site at 19q13 in controls is due to hypermethylation of this region. PMID:23049342

  16. Risk of hematological malignancies among Chernobyl liquidators

    PubMed Central

    Kesminiene, Ausrele; Evrard, Anne-Sophie; Ivanov, Viktor K.; Malakhova, Irina V.; Kurtinaitis, Juozas; Stengrevics, Aivars; Tekkel, Mare; Anspaugh, Lynn R.; Bouville, André; Chekin, Sergei; Chumak, Vadim V.; Drozdovitch, Vladimir; Gapanovich, Vladimir; Golovanov, Ivan; Hubert, Phillip; Illichev, Sergei V.; Khait, Svetlana E.; Krjuchkov, Viktor P.; Maceika, Evaldas; Maksyoutov, Marat; Mirkhaidarov, Anatoly K.; Polyakov, Semion; Shchukina, Natalia; Tenet, Vanessa; Tserakhovich, Tatyana I.; Tsykalo, Aleksandr; Tukov, Aleksandr R.; Cardis, Elisabeth

    2010-01-01

    A case-control study of hematological malignancies was conducted among Chernobyl liquidators (accident recovery workers) from Belarus, Russia and Baltic countries in order to assess the effect of low-to-medium dose protracted radiation exposures on the relative risk of these diseases. The study was nested within cohorts of liquidators who had worked in 1986–87 around the Chernobyl plant. 117 cases (69 leukemia, 34 non-Hodgkin Lymphoma (NHL) and 14 other malignancies of lymphoid and hematopoietic tissue) and 481 matched controls were included in the study. Individual dose to the bone marrow and uncertainties were estimated for each subject. The main analyses were restricted to 70 cases (40 leukemia, 20 NHL and 10 other) and their 287 matched controls with reliable information on work in the Chernobyl area. Most subjects received very low doses (median 13 mGy). For all diagnoses combined, a significantly elevated OR was seen at doses of 200 mGy and above. The Excess Relative Risk (ERR) per 100 mGy was 0.60 (90% confidence interval (CI): −0.02, 2.35). The corresponding estimate for leukemia excluding chronic lymphoid leukemia (CLL) was 0.50 (90%CI −0.38, 5.7). It is slightly higher than, but statistically compatible with, those estimated from a-bomb survivors and recent low dose-rate studies. Although sensitivity analyses showed generally similar results, we cannot rule out the possibility that biases and uncertainties could have led to over or underestimation of the risk in this study. PMID:19138033

  17. Risk of hematological malignancies among Chernobyl liquidators.

    PubMed

    Kesminiene, Ausrele; Evrard, Anne-Sophie; Ivanov, Viktor K; Malakhova, Irina V; Kurtinaitis, Juozas; Stengrevics, Aivars; Tekkel, Mare; Anspaugh, Lynn R; Bouville, André; Chekin, Sergei; Chumak, Vadim V; Drozdovitch, Vladimir; Gapanovich, Vladimir; Golovanov, Ivan; Hubert, Phillipe; Illichev, Sergei V; Khait, Svetlana E; Kryuchkov, Viktor P; Maceika, Evaldas; Maksyoutov, Marat; Mirkhaidarov, Anatoly K; Polyakov, Semion; Shchukina, Natalia; Tenet, Vanessa; Tserakhovich, Tatyana I; Tsykalo, Aleksandr; Tukov, Aleksandr R; Cardis, Elisabeth

    2008-12-01

    A case-control study of hematological malignancies was conducted among Chernobyl liquidators (accident recovery workers) from Belarus, Russia and Baltic countries to assess the effect of low- to medium-dose protracted radiation exposures on the relative risk of these diseases. The study was nested within cohorts of liquidators who had worked around the Chernobyl plant in 1986-1987. A total of 117 cases [69 leukemia, 34 non-Hodgkin lymphoma (NHL) and 14 other malignancies of lymphoid and hematopoietic tissue] and 481 matched controls were included in the study. Individual dose to the bone marrow and uncertainties were estimated for each subject. The main analyses were restricted to 70 cases (40 leukemia, 20 NHL and 10 other) and their 287 matched controls with reliable information on work in the Chernobyl area. Most subjects received very low doses (median 13 mGy). For all diagnoses combined, a significantly elevated OR was seen at doses of 200 mGy and above. The excess relative risk (ERR) per 100 mGy was 0.60 [90% confidence interval (CI) -0.02, 2.35]. The corresponding estimate for leukemia excluding chronic lymphoid leukemia (CLL) was 0.50 (90% CI -0.38, 5.7). It is slightly higher than but statistically compatible with those estimated from A-bomb survivors and recent low-dose-rate studies. Although sensitivity analyses showed generally similar results, we cannot rule out the possibility that biases and uncertainties could have led to over- or underestimation of the risk in this study. PMID:19138033

  18. Natural Killer Cells Modulation in Hematological Malignancies

    PubMed Central

    Baier, Céline; Fino, Aurore; Sanchez, Carole; Farnault, Laure; Rihet, Pascal; Kahn-Perlès, Brigitte; Costello, Régis T.

    2013-01-01

    Hematological malignancies (HM) treatment improved over the last years resulting in increased achievement of complete or partial remission, but unfortunately high relapse rates are still observed, due to remaining minimal residual disease. Therefore, sustainment of long-term remission is crucial, using either drug maintenance treatment or by boosting or prolonging an immune response. Immune system has a key role in tumor surveillance. Nonetheless, tumor-cells evade the specific T-lymphocyte mediated immune surveillance using many mechanisms but especially by the down-regulation of the expression of HLA class I antigens. In theory, these tumor-cells lacking normal expression of HLA class I molecules should be destroyed by natural killer (NK) cells, according to the missing-self hypothesis. NK cells, at the frontier of innate and adaptive immune system, have a central role in tumor-cells surveillance as demonstrated in the setting of allogenic stem cell transplantation. Nevertheless, tumors develop various mechanisms to escape from NK innate immune pressure. Abnormal NK cytolytic functions have been described in many HM. We present here various mechanisms involved in the escape of HM from NK-cell surveillance, i.e., NK-cells quantitative and qualitative abnormalities. PMID:24391641

  19. Ribavirin for Chronic Hepatitis Prevention among Patients with Hematologic Malignancies

    PubMed Central

    Tavitian, Suzanne; Peron, Jean-Marie; Huguet, Françoise; Kamar, Nassim; Abravanel, Florence; Beyne-Rauzy, Odile; Oberic, Lucie; Faguer, Stanislas; Alric, Laurent; Roussel, Murielle; Gaudin, Clément; Ysebaert, Loïc; Huynh, Anne

    2015-01-01

    Findings among a cohort of 26 patients who had hematologic malignancies and hepatitis E virus (HEV) infection support that HEV can induce chronic hepatitis. However, a 3-month course of ribavirin can induce a rapid viral clearance, reducing the risk for chronic hepatitis and enabling continuation of cytotoxic treatments for underlying malignancies. PMID:26197210

  20. Exploring Big Data in Hematological Malignancies: Challenges and Opportunities.

    PubMed

    Westin, Gustavo F; Dias, Ajoy L; Go, Ronald S

    2016-08-01

    Secondary analysis of large datasets has become a useful alternative to address research questions outside the reach of clinical trials. It is increasingly utilized in hematology and oncology. In this review, we provided an overview of some examples of commonly used large datasets in the USA and described common research themes that can be pursued using such a methodology. We selected a sample of 14 articles on adult hematologic malignancies published in 2015 and highlighted their contributions as well as limitations. PMID:27177742

  1. Liminal reproductive experiences after therapies for hematological malignancy.

    PubMed

    Halliday, Lesley E; Boughton, Maureen A; Kerridge, Ian

    2015-03-01

    In this article, we discuss the psychosocial health of young women related to fertility, pregnancy, and motherhood after therapies for hematological malignancies. We utilized a hermeneutical phenomenological approach to conduct in-depth interviews with 12 women who had previously received treatment for a hematological malignancy and had experienced uncertainty surrounding their ability to start or extend their biological family. Our presented findings are interpretations of the women's own words as they articulated how they inhabited a liminal space. We concluded that although fertility and motherhood possibly might not be immediate concerns when they received a diagnosis of hematological malignancy, young women could subsequently experience ongoing issues and concerns related to reproductive uncertainty and motherhood capabilities, which have the potential to affect emotionally and psychosocially on their lives. These issues might possibly require longer-term support, counseling, and informational resources. We also discuss the strengths, limitations, and implications of the study. PMID:25216861

  2. Hematologic malignancies: at the forefront of immunotherapeutic innovation

    PubMed Central

    Bachireddy, Pavan; Burkhardt, Ute E.; Rajasagi, Mohini; Wu, Catherine J.

    2015-01-01

    The recent successes of cancer immunotherapy have stimulated interest for the potential widespread application of these approaches; hematologic malignancies have provided both initial proofs-of-concept and an informative testing ground for a variety of immune-based therapeutics. The immune-cell origin of many of the blood malignancies provides a unique opportunity to both understand the mechanisms of human immune-responsiveness and immune-evasion as well as to exploit the unique therapeutic opportunities they provide. PMID:25786696

  3. EZH2 in normal hematopoiesis and hematological malignancies.

    PubMed

    Herviou, Laurie; Cavalli, Giacomo; Cartron, Guillaume; Klein, Bernard; Moreaux, Jérôme

    2016-01-19

    Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, inhibits gene expression through methylation on lysine 27 of histone H3. EZH2 regulates normal hematopoietic stem cell self-renewal and differentiation. EZH2 also controls normal B cell differentiation. EZH2 deregulation has been described in many cancer types including hematological malignancies. Specific small molecules have been recently developed to exploit the oncogenic addiction of tumor cells to EZH2. Their therapeutic potential is currently under evaluation. This review summarizes the roles of EZH2 in normal and pathologic hematological processes and recent advances in the development of EZH2 inhibitors for the personalized treatment of patients with hematological malignancies. PMID:26497210

  4. Bacterial Infections Following Splenectomy for Malignant and Nonmalignant Hematologic Diseases

    PubMed Central

    Leone, Giuseppe; Pizzigallo, Eligio

    2015-01-01

    Splenectomy, while often necessary in otherwise healthy patients after major trauma, finds its primary indication for patients with underlying malignant or nonmalignant hematologic diseases. Indications of splenectomy for hematologic diseases have been reducing in the last few years, due to improved diagnostic and therapeutic tools. In high-income countries, there is a clear decrease over calendar time in the incidence of all indication splenectomy except nonmalignant hematologic diseases. However, splenectomy, even if with different modalities including laparoscopic splenectomy and partial splenectomy, continue to be a current surgical practice both in nonmalignant hematologic diseases, such as Immune Thrombocytopenic Purpura (ITP), Autoimmune Hemolytic Anemia (AIHA), Congenital Hemolytic Anemia such as Spherocytosis, Sickle Cell Anemia and Thalassemia and Malignant Hematological Disease, such as lymphoma. Today millions of people in the world are splenectomized. Splenectomy, independently of its cause, induces an early and late increase in the incidence of venous thromboembolism and infections. Infections remain the most dangerous complication of splenectomy. After splenectomy, the levels of antibody are preserved but there is a loss of memory B cells against pneumococcus and tetanus, and the loss of marginal zone monocytes deputed to immunological defense from capsulated bacteria. Commonly, the infections strictly correlated to the absence of the spleen or a decreased or absent splenic function are due to encapsulated bacteria that are the most virulent pathogens in this set of patients. Vaccination with polysaccharide and conjugate vaccines again Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis should be performed before the splenectomy. This practice reduces but does not eliminate the occurrence of overwhelming infections due to capsulated bacteria. At present, most of infections found in splenectomized patients are due to Gram

  5. Chemotherapy-induced peripheral neuropathies in hematological malignancies.

    PubMed

    Jongen, Joost Louis Marie; Broijl, Annemiek; Sonneveld, Pieter

    2015-01-01

    Recent developments in the treatment of hematological malignancies, especially with the advent of proteasome inhibitors and immunomodulatory drugs in plasma cell dyscrasias, call for an increased collaboration between hematologists and neurologists. This collaboration involves differentiating chemotherapy-induced peripheral neuropathies (CiPN) from disease-related neurologic complications, early recognition of CiPN and treatment of neuropathic pain. Multiple myeloma, Waldenstrom's macroglobulinemia and light-chain amyloidosis frequently present with peripheral neuropathy. In addition, multiple myeloma, non-Hodgkin lymphomas and leukemia's may mimic peripheral neuropathy by compression or invasion of the extra/intradural space. Platinum compounds, vinca alkaloids, proteasome inhibitors and immunomodulatory drugs may all cause CiPN, each with different and often specific clinical characteristics. Early recognition, by identifying the distinct clinical phenotype of CiPN, is of crucial importance to prevent irreversible neurological damage. No recommendations can be given on the use of neuroprotective strategies because of a lack of convincing clinical evidence. Finally, CiPN caused by vinca-alkaloids, proteasome inhibitors and immunomodulatory drugs is often painful and neurologists are best equipped to treat this kind of painful neuropathy. PMID:25326770

  6. Nonengraftment Haploidentical Cellular Therapy for Hematologic Malignancies

    PubMed Central

    Reagan, John L.; Fast, Loren D.; Winer, Eric S.; Safran, Howard; Butera, James N.; Quesenberry, Peter J.

    2012-01-01

    Much of the therapeutic benefit of allogeneic transplant is by a graft versus tumor effect. Further data shows that transplant engraftment is not dependant on myeloablation, instead relying on quantitative competition between donor and host cells. In the clinical setting, engraftment by competition alone is not feasible due to the need for large numbers of infused cells. Instead, low-level host irradiation has proven to be an effective engraftment strategy that is stem cell toxic but not myeloablative. The above observations served as the foundation for clinical trials utilizing allogeneic matched and haploidentical peripheral blood stem cell infusions with minimal conditioning in patients with refractory malignancies. Although engraftment was transient or not apparent, there were compelling responses in a heavily pretreated patient population that appear to result from the breaking of tumor immune tolerance by the host through the actions of IFNγ, invariant NK T cells, CD8 T cells, NK cells, or antigen presenting cells. PMID:22312367

  7. Target Therapy in Hematological Malignances: New Monoclonal Antibodies

    PubMed Central

    Szymczyk, Agnieszka; Pawlowski, Johannes

    2014-01-01

    Apart from radio- and chemotherapy, monoclonal antibodies (MoAbs) represent a new, more selective tool in the treatment of hematological malignancies. MoAbs bind with the specific antigens of the tumors. This interaction is a basis for targeted therapies which exhibit few side effects and significant antitumor activity. This review provides an overview of the functional characteristics of MoAbs, with some examples of their clinical application. The promising results in the treatment of hematological malignancies have led to the more frequent usage of MoAbs in the therapy. Development of MoAbs is a subject of extensive research. They are a promising method of cancer treatment in the future.

  8. Polo-like kinase inhibitors in hematologic malignancies.

    PubMed

    Talati, Chetasi; Griffiths, Elizabeth A; Wetzler, Meir; Wang, Eunice S

    2016-02-01

    Polo-like kinases (Plk) are key regulators of the cell cycle and multiple aspects of mitosis. Two agents that inhibit the Plk signaling pathway have shown promising activity in patients with hematologic malignancies and are currently in phase III trials. Volasertib is a Plk inhibitor under evaluation combined with low-dose cytarabine in older patients with acute myeloid leukemia (AML) ineligible for intensive induction therapy. Rigosertib, a dual inhibitor of the Plk and phosphatidylinositol 3-kinase pathways, is under investigation in patients with myelodysplastic syndrome (MDS) who have failed azacitidine or decitabine treatment. The prognosis for patients with AML, who are ineligible for intensive induction therapy, and for those with MDS refractory/relapsed after a hypomethylating agent, remains poor. Novel approaches, such as Plk inhibitors, are urgently needed for these patients. Here, we provide a comprehensive overview of the current state of development of Plk inhibitors for the treatment of hematologic malignancies. PMID:26597019

  9. The TET2 interactors and their links to hematological malignancies

    PubMed Central

    Pan, Feng; Weeks, Ophelia; Yang, Feng-Chun; Xu, Mingjiang

    2016-01-01

    Ten-eleven translocation family proteins are dioxygenases that oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine in DNA, early steps of active DNA demethylation. TET2, the second member of TET protein family, is frequently mutated in patients with hematological malignancies, leading to aberrant DNA methylation profiling and decreased 5hmC levels. Located in the nucleus and acting as a DNA-modifying enzyme, TET2 is thought to exert its function via TET2-containing protein complexes. Identifying the interactome network of TET2 likely holds the key to uncover the mechanisms by which TET2 exerts its function in cells. Here, we review recent literature on TET2 interactors and discuss their possible roles in TET2 loss-mediated dysregulation of hematopoiesis and pathogenesis of hematological malignancies. PMID:26099018

  10. [Extracellular vesicles and their role in hematological malignancies].

    PubMed

    Rzepiel, Andrea; Kutszegi, Nóra; Cs Sági, Judit; Kelemen, Andrea; Pálóczi, Krisztina; F Semsei, Ágnes; Buzás, Edit; Erdélyi, Dániel János

    2016-08-01

    Extracellular vesicles are produced in all organisms. The most intensively investigated categories of extracellular vesicles include apoptotic bodies, microvesicles and exosomes. Among a very wide range of areas, their role has been confirmed in intercellular communication, immune response and angiogenesis (in both physiological and pathological conditions). Their alterations suggest the potential use of them as biomarkers. In this paper the authors give an insight into the research of extracellular vesicles in general, and then focus on published findings in hematological malignancies. Quantitative and qualitative changes of microvesicles and exosomes may have value in diagnostics, prognostics and minimal residual disease monitoring of hematological malignancies. The function of extracellular vesicles in downregulation of natural killer cells' activity has been demonstrated in acute myeloid leukemia. In chronic lymphocytic leukemia, microvesicles seem to play a role in drug resistance. Orv. Hetil., 2016, 157(35), 1379-1384. PMID:27569460

  11. Galectins as therapeutic targets for hematological malignancies: a hopeful sweetness.

    PubMed

    Pena, Camilo; Mirandola, Leonardo; Figueroa, Jose A; Hosiriluck, Nattamol; Suvorava, Natallia; Trotter, Kayley; Reidy, Adair; Rakhshanda, Rahman; Payne, Drew; Jenkins, Marjorie; Grizzi, Fabio; Littlefield, Lauren; Chiriva-Internati, Maurizio; Cobos, Everardo

    2014-09-01

    Galectins are family of galactose-binding proteins known to play critical roles in inflammation and neoplastic progression. Galectins facilitate the growth and survival of neoplastic cells by regulating their cross-talk with the extracellular microenvironment and hampering anti-neoplastic immunity. Here, we review the role of galectins in the biology of hematological malignancies and their promise as potential therapeutic agents in these diseases. PMID:25405162

  12. Galectins as therapeutic targets for hematological malignancies: a hopeful sweetness

    PubMed Central

    Pena, Camilo; Mirandola, Leonardo; Figueroa, Jose A.; Hosiriluck, Nattamol; Suvorava, Natallia; Trotter, Kayley; Reidy, Adair; Rakhshanda, Rahman; Payne, Drew; Jenkins, Marjorie; Grizzi, Fabio; Littlefield, Lauren; Cobos, Everardo

    2014-01-01

    Galectins are family of galactose-binding proteins known to play critical roles in inflammation and neoplastic progression. Galectins facilitate the growth and survival of neoplastic cells by regulating their cross-talk with the extracellular microenvironment and hampering anti-neoplastic immunity. Here, we review the role of galectins in the biology of hematological malignancies and their promise as potential therapeutic agents in these diseases. PMID:25405162

  13. FDG-PET imaging in hematological malignancies.

    PubMed

    Valls, L; Badve, C; Avril, S; Herrmann, K; Faulhaber, P; O'Donnell, J; Avril, N

    2016-07-01

    The majority of aggressive lymphomas is characterized by an up regulated glycolytic activity, which enables the visualization by F-18 FDG-PET/CT. One-stop hybrid FDG-PET/CT combines the functional and morphologic information, outperforming both, CT and FDG-PET as separate imaging modalities. This has resulted in several recommendations using FDG-PET/CT for staging, restaging, monitoring during therapy, and assessment of treatment response as well as identification of malignant transformation. FDG-PET/CT may obviate the need for a bone marrow biopsy in patients with Hodgkin's lymphoma and diffuse large B cell lymphoma. FDG-PET/CT response assessment is recommended for FDG-avid lymphomas, whereas CT-based response evaluation remains important in lymphomas with low or variable FDG avidity. The treatment induced change in metabolic activity allows for assessment of response after completion of therapy as well as prediction of outcome early during therapy. The five-point scale Deauville Criteria allows the assessment of treatment response based on visual FDG-PET analysis. Although the use of FDG-PET/CT for prediction of therapeutic response is promising it should only be conducted in the context of clinical trials. Surveillance FDG-PET/CT after complete remission is discouraged due to the relative high number of false-positive findings, which in turn may result in further unnecessary investigations. Future directions include the use of new PET tracers such as F-18 fluorothymidine (FLT), a surrogate biomarker of cellular proliferation and Ga-68 CXCR4, a chemokine receptor imaging biomarker as well as innovative digital PET/CT and PET/MRI techniques. PMID:27090170

  14. Targeting p53 by small molecules in hematological malignancies.

    PubMed

    Saha, Manujendra N; Qiu, Lugui; Chang, Hong

    2013-01-01

    p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target. A breakthrough in cancer research came from the discovery of the drugs which are capable of reactivating p53 function. Most anti-cancer agents, from traditional chemo- and radiation therapies to more recently developed non-peptide small molecules exert their effects by enhancing the anti-proliferative activities of p53. Small molecules such as nutlin, RITA, and PRIMA-1 that can activate p53 have shown their anti-tumor effects in different types of hematological malignancies. Importantly, nutlin and PRIMA-1 have successfully reached the stage of phase I/II clinical trials in at least one type of hematological cancer. Thus, the pharmacological activation of p53 by these small molecules has a major clinical impact on prognostic use and targeted drug design. In the current review, we present the recent achievements in p53 research using small molecules in hematological malignancies. Anticancer activity of different classes of compounds targeting the p53 signaling pathway and their mechanism of action are discussed. In addition, we discuss how p53 tumor suppressor protein holds promise as a drug target for recent and future novel therapies in these diseases. PMID:23531342

  15. Approaches to Managing Safety With Lenalidomide in Hematologic Malignancies

    PubMed Central

    Blumel, Susan; Broadway-Duren, Jackie

    2014-01-01

    Lenalidomide is an oral immunomodulatory agent approved in relapsed multiple myeloma with dexamethasone, for transfusion-dependent anemia in myelodysplastic syndrome associated with deletion 5q, and in relapsed/progressive mantle cell lymphoma following bortezomib. In recent clinical trials, lenalidomide has shown promising activity in hematologic malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Starting doses and dosing schedules vary by malignancy, with lenalidomide started at a lower dose for CLL than for NHL or multiple myeloma. Certain adverse events (AEs) are common across tumor types (e.g., neutropenia, thrombocytopenia, fatigue), whereas others are more often associated with CLL patients (e.g., tumor lysis syndrome and tumor flare reaction). Effective management requires awareness of these differences as well as appropriate prophylaxis, monitoring, and treatment of AEs. This article reviews the efficacy and safety of lenalidomide in CLL and NHL, focusing on approaches for the advanced practitioner to improve patient quality of life through optimal management of side effects. With these steps, lenalidomide can be administered safely, at the best starting doses and with minimal dose interruptions or reductions across hematologic malignancies. PMID:26110071

  16. How I treat influenza in patients with hematologic malignancies

    PubMed Central

    Casper, Corey; Englund, Janet

    2010-01-01

    The 2009 H1N1 influenza pandemic has heightened the interest of clinicians for options in the prevention and management of influenza virus infection in immunocompromised patients. Even before the emergence of the novel 2009 H1N1 strain, influenza disease was a serious complication in patients with hematologic malignancies receiving chemotherapy or undergoing hematopoietic cell transplantation. Here we review the clinical manifestations of seasonal and 2009 H1N1 influenza and discuss current diagnosis, antiviral treatment, and prophylaxis options. We also summarize infection control and vaccination strategies for patients, family members, and caregivers. PMID:20009037

  17. Tetraspanins: Spanning from solid tumors to hematologic malignancies.

    PubMed

    Yang, Ying-Gui; Sari, Ita Novita; Zia, Mohammad Farid; Lee, Sung Ryul; Song, Su Jung; Kwon, Hyog Young

    2016-05-01

    Tetraspanins (tetraspans or TM4SF) are a family of integral membrane proteins with four transmembrane helices, a small extracellular loop, and a large extracellular loop. Although tetraspanins are expressed in many types of cells, including immune cells, their biological roles are not fully defined. Nonetheless, recent studies have revealed the important roles of tetraspanins in solid tumors and hematologic malignancies, and expression of tetraspanins is associated with the malignancy of human tumors. Furthermore, genetic mouse models of tetraspanins highlight their contribution to tumorigenesis. In this review, we summarize the implication of tetraspanins in cancer with a special focus on tetraspanin 3 in myeloid leukemia. Our increasing knowledge of tetraspanins and the pathologies that alter their function will undoubtedly inform the rational design of novel cancer therapies. PMID:26930362

  18. The immunoproteasome as a target in hematologic malignancies.

    PubMed

    Kuhn, Deborah J; Orlowski, Robert Z

    2012-07-01

    Suppression of proteasome function with the first-in-class small molecule inhibitor bortezomib is a rational therapeutic strategy against several hematologic malignancies, including multiple myeloma and mantle cell lymphoma. Second-generation inhibitors such as carfilzomib, ixazomib, and marizomib that, like bortezomib, target both the constitutive proteasome and the immunoproteasome, are also in clinical trials and showing encouraging activity. While the efficacy of these agents is well documented, toxicities associated with their use, such as peripheral neuropathy and gastrointestinal effects, can necessitate dose reductions or even discontinuations, possibly hampering their anti-neoplastic effects. These findings suggested that it could be possible to improve the therapeutic index of this class of drugs by specifically targeting only the immunoproteasome. Since the immunoproteasome is a unique target found in lymphoid-derived cells, immunoproteasome-specific inhibitors (IPSIs) could preserve efficacy while reducing treatment-emergent toxicities since they would spare other tissues with little to no immunoproteasome expression. This review discusses the current state of development of IPSIs, and the potential of using such agents for the treatment of hematologic malignancies. PMID:22726549

  19. Mucorales-Specific T Cells in Patients with Hematologic Malignancies

    PubMed Central

    Forghieri, Fabio; Candoni, Anna; Cesaro, Simone; Quadrelli, Chiara; Maertens, Johan; Rossi, Giulio; Morselli, Monica; Codeluppi, Mauro; Mussini, Cristina; Colaci, Elisabetta; Messerotti, Andrea; Paolini, Ambra; Maccaferri, Monica; Fantuzzi, Valeria; Del Giovane, Cinzia; Stefani, Alessandro; Morandi, Uliano; Maffei, Rossana; Marasca, Roberto; Narni, Franco; Fanin, Renato; Comoli, Patrizia; Romani, Luigina; Beauvais, Anne; Viale, Pier Luigi; Latgè, Jean Paul; Luppi, Mario

    2016-01-01

    Background Invasive mucormycosis (IM) is an emerging life-threatening fungal infection. It is difficult to obtain a definite diagnosis and to initiate timely intervention. Mucorales-specific T cells occur during the course of IM and are involved in the clearance of the infection. We have evaluated the feasibility of detecting Mucorales-specific T cells in hematological patients at risk for IM, and have correlated the detection of such cells with the clinical conditions of the patients. Methods and Findings By using an enzyme linked immunospot assay, the presence of Mucorales-specific T cells in peripheral blood (PB) samples has been investigated at three time points during high-dose chemotherapy for hematologic malignancies. Mucorales-specific T cells producing interferon-γ, interleukin-10 and interleukin-4 were analysed in order to detect a correlation between the immune response and the clinical picture. Twenty-one (10.3%) of 204 patients, accounting for 32 (5.3%) of 598 PB samples, tested positive for Mucorales-specific T cells. Two groups could be identified. Group 1, including 15 patients without signs or symptoms of invasive fungal diseases (IFD), showed a predominance of Mucorales-specific T cells producing interferon-gamma. Group 2 included 6 patients with a clinical picture consistent with invasive fungal disease (IFD): 2 cases of proven IM and 4 cases of possible IFD. The proven patients had significantly higher number of Mucorales-specific T cells producing interleukin-10 and interleukin-4 and higher rates of positive samples by using derived diagnostic cut-offs when compared with the 15 patients without IFD. Conclusions Mucorales-specific T cells can be detected and monitored in patients with hematologic malignancies at risk for IM. Mucorales-specific T cells polarized to the production of T helper type 2 cytokines are associated with proven IM and may be evaluated as a surrogate diagnostic marker for IM. PMID:26871570

  20. Extracorporeal Life Support in Patients with Hematologic Malignancies: A Single Center Experience

    PubMed Central

    Choi, Kuk Bin; Kim, Hwan Wook; Jo, Keon Hyon; Kim, Do Yeon; Choi, Hang Jun; Hong, Seok Beom

    2016-01-01

    Background Extracorporeal life support (ECLS) in patients with hematologic malignancies is considered to have a poor prognosis. However, to date, there is only one case series reported in the literature. In this study, we compared the in-hospital survival of ECLS in patients with and without hematologic malignancies. Methods We reviewed a total of 66 patients who underwent ECLS for treatment of acute respiratory failure from January 2012 to December 2014. Of these patients, 22 (32%) were diagnosed with hematologic malignancies, and 13 (59%) underwent stem cell transplantation before ECLS. Results The in-hospital survival rate of patients with hematologic malignancies was 5% (1/22), while that of patients without malignancies was 26% (12/46). The number of platelet transfusions was significantly higher in patients with hematologic malignancies (9.69±7.55 vs. 3.12±3.42 units/day). Multivariate analysis showed that the presence of hematologic malignancies was a significant negative predictor of survival to discharge (odds ratio, 0.07; 95% confidence interval, 0.01–0.79); p=0.031). Conclusion ECLS in patients with hematologic malignancies had a lower in-hospital survival rate, compared to patients without hematologic malignancies. PMID:27525237

  1. Natural products against hematological malignancies and identification of their targets.

    PubMed

    Xu, Ying; Liu, JinBao; Wu, YingLi; Guo, QingLong; Sun, HanDong; Chen, GuoQiang

    2015-12-01

    Naturally occurring molecules derived from higher plants, animals, microorganisms and minerals play an important role in the discovery and development of novel therapeutic agents. The identification of molecular targets is of interest to elucidate the mode of action of these compounds, and it may be employed to set up target-based assays and allow structure-activity relationship studies to guide medicinal chemistry efforts toward lead optimization. In recent years, plant-derived natural compounds possessing potential anti-tumor activities have been garnering much interest and efforts are underway to identify their molecular targets. Here, we attempt to summarize the discoveries of several natural compounds with activities against hematological malignancies, such as adenanthin, oridonin, gambogic acid and wogonoside, the identification of their targets, and their modes of actions. PMID:26566803

  2. Tetraspanins as therapeutic targets in hematological malignancy: a concise review

    PubMed Central

    Beckwith, Kyle A.; Byrd, John C.; Muthusamy, Natarajan

    2015-01-01

    Tetraspanins belong to a family of transmembrane proteins which play a major role in the organization of the plasma membrane. While all immune cells express tetraspanins, most of these are present in a variety of other cell types. There are a select few, such as CD37 and CD53, which are restricted to hematopoietic lineages. Tetraspanins associate with numerous partners involved in a diverse set of biological processes, including cell activation, survival, proliferation, adhesion, and migration. The historical view has assigned them a scaffolding role, but recent discoveries suggest some tetraspanins can directly participate in signaling through interactions with cytoplasmic proteins. Given their potential roles in supporting tumor survival and immune evasion, an improved understanding of tetraspanin activity could prove clinically valuable. This review will focus on emerging data in the study of tetraspanins, advances in the clinical development of anti-CD37 therapeutics, and the future prospects of targeting tetraspanins in hematological malignancy. PMID:25852576

  3. Role of Sphingolipids and Metabolizing Enzymes in Hematological Malignancies.

    PubMed

    Kitatani, Kazuyuki; Taniguchi, Makoto; Okazaki, Toshiro

    2015-06-01

    Sphingolipids such as ceramide, sphingosine-1-phosphate and sphingomyelin have been emerging as bioactive lipids since ceramide was reported to play a role in human leukemia HL-60 cell differentiation and death. Recently, it is well-known that ceramide acts as an inducer of cell death, that sphingomyelin works as a regulator for microdomain function of the cell membrane, and that sphingosine-1-phosphate plays a role in cell survival/proliferation. The lipids are metabolized by the specific enzymes, and each metabolite could be again returned to the original form by the reverse action of the different enzyme or after a long journey of many metabolizing/synthesizing pathways. In addition, the metabolites may serve as reciprocal bio-modulators like the rheostat between ceramide and sphingosine-1-phosphate. Therefore, the change of lipid amount in the cells, the subcellular localization and the downstream signal in a specific subcellular organelle should be clarified to understand the pathobiological significance of sphingolipids when extracellular stimulation induces a diverse of cell functions such as cell death, proliferation and migration. In this review, we focus on how sphingolipids and their metabolizing enzymes cooperatively exert their function in proliferation, migration, autophagy and death of hematopoetic cells, and discuss the way developing a novel therapeutic device through the regulation of sphingolipids for effectively inhibiting cell proliferation and inducing cell death in hematological malignancies such as leukemia, malignant lymphoma and multiple myeloma. PMID:25997737

  4. Role of Sphingolipids and Metabolizing Enzymes in Hematological Malignancies

    PubMed Central

    Kitatani, Kazuyuki; Taniguchi, Makoto; Okazaki, Toshiro

    2015-01-01

    Sphingolipids such as ceramide, sphingosine-1-phosphate and sphingomyelin have been emerging as bioactive lipids since ceramide was reported to play a role in human leukemia HL-60 cell differentiation and death. Recently, it is well-known that ceramide acts as an inducer of cell death, that sphingomyelin works as a regulator for microdomain function of the cell membrane, and that sphingosine-1-phosphate plays a role in cell survival/proliferation. The lipids are metabolized by the specific enzymes, and each metabolite could be again returned to the original form by the reverse action of the different enzyme or after a long journey of many metabolizing/synthesizing pathways. In addition, the metabolites may serve as reciprocal bio-modulators like the rheostat between ceramide and sphingosine-1-phosphate. Therefore, the change of lipid amount in the cells, the subcellular localization and the downstream signal in a specific subcellular organelle should be clarified to understand the pathobiological significance of sphingolipids when extracellular stimulation induces a diverse of cell functions such as cell death, proliferation and migration. In this review, we focus on how sphingolipids and their metabolizing enzymes cooperatively exert their function in proliferation, migration, autophagy and death of hematopoetic cells, and discuss the way developing a novel therapeutic device through the regulation of sphingolipids for effectively inhibiting cell proliferation and inducing cell death in hematological malignancies such as leukemia, malignant lymphoma and multiple myeloma. PMID:25997737

  5. The growing threat of multidrug-resistant Gram-negative infections in patients with hematologic malignancies.

    PubMed

    Baker, Thomas M; Satlin, Michael J

    2016-10-01

    Prolonged neutropenia and chemotherapy-induced mucositis render patients with hematologic malignancies highly vulnerable to Gram-negative bacteremia. Unfortunately, multidrug-resistant (MDR) Gram-negative bacteria are increasingly encountered globally, and current guidelines for empirical antibiotic coverage in these patients may not adequately treat these bacteria. This expansion of resistance, coupled with traditional culturing techniques requiring 2-4 days for bacterial identification and antimicrobial susceptibility results, have grave implications for these immunocompromised hosts. This review characterizes the epidemiology, risk factors, resistance mechanisms, recommended treatments, and outcomes of the MDR Gram-negative bacteria that commonly cause infections in patients with hematologic malignancies. We also examine the infection prevention strategies in hematology patients, such as infection control practices, antimicrobial stewardship, and targeted decolonization. Finally, we assess the strategies to improve outcomes of the infected patients, including gastrointestinal screening to guide empirical antibiotic therapy, new rapid diagnostic tools for expeditious identification of MDR pathogens, and use of two new antimicrobial agents, ceftolozane/tazobactam and ceftazidime/avibactam. PMID:27339405

  6. Ewing's Sarcoma as a Second Malignancy in Long-Term Survivors of Childhood Hematologic Malignancies

    PubMed Central

    Grotzer, Michael A.; Niggli, Felix; Zimmermann, Dieter; Rushing, Elisabeth

    2016-01-01

    Modern multimodal treatment has significantly increased survival for patients affected by hematologic malignancies, especially in childhood. Following remission, however, the risk of developing a further malignancy is an important issue. The long-term estimated risk of developing a sarcoma as a secondary malignancy is increased severalfold in comparison to the general population. Ewing's sarcoma family encompasses a group of highly aggressive, undifferentiated, intra- and extraosseous, mesenchymal tumors, caused by several types of translocations usually involving the EWSR1 gene. Translocation associated sarcomas, such as Ewing sarcoma, are only rarely encountered as therapy associated secondary tumors. We describe the clinical course and management of three patients from a single institution with Ewing's sarcoma that followed successfully treated lymphoblastic T-cell leukemia or non-Hodgkin lymphoma. The literature on secondary Ewing's sarcoma is summarized and possible pathogenic mechanisms are critically discussed. PMID:27524931

  7. Clonal Non-Malignant Hematological Disorders: Unraveling Molecular Pathogenic Mechanisms to Develop Novel Targeted Therapeutics

    PubMed Central

    Risitano, Antonio M.; Selleri, Carmine

    2014-01-01

    Clonal non-malignant hematological disorders are a heterogeneous group of diseases that are particularly challenging for hematologists. Indeed, most obvious and frequent hematological diseases include a broad spectrum of malignancies, such as leukemias, lymphomas, myeloma, and other myeloproliferative or lymphoproliferative disorders. In recent years, all these diseases have been categorized by the WHO according to a novel classification of myeloid and lymphoid malignancies, which takes in account the outstanding progress in our understanding of molecular defects underlying hematological malignancies. Regardless of a number of novel technologies, hematologists continue to deal daily with conditions where a clear diagnosis of a malignancy is missing: this is the case of several clonal hematological disorders, which are considered bona fide non-malignant. Some myelodysplastic syndromes, chronic T and NK disorders of granular lymphocytes, myelofibrosis, monoclonal gammopathies, monoclonal B-cel lymphocytosis, mastocytosis and paroxysmal nocturnal hemoglobinuria are paradigmatic examples of how clonal disorders are clearly different from cancers, even if they may share with hematological malignancies similar molecular, genetic, epigenetic and immunological processes. Indeed, it is not entirely clear whether in individual conditions such pathogenic mechanisms may represent initial step(s) of malignant transformation, making a bridge between these clonal non-malignant disorders and typical hematological cancers. Some of these non-malignant disorders imply specific pathogenic mechanisms and/or clinical course, and so they have been definitely established with their own biological and clinical identity. However, the obvious question whether some of these clonal non-malignant hematological diseases form some a kind of disease-continuum with their corresponding malignant counterpart is still to be answered. PMID:24778992

  8. Acquired uniparental disomy of chromosome 9p in hematologic malignancies.

    PubMed

    Wang, Linghua; Wheeler, David A; Prchal, Josef T

    2016-08-01

    Acquired uniparental disomy (aUPD) is a common and recurrent molecular event in human cancers that leads to homozygosity for tumor suppressor genes as well as oncogenes, while retaining the diploid chromosomal complement. Because of the lack of copy number change, aUPD is undetectable by comparative genome hybridization, so the magnitude of this genetic change was underappreciated in the past. 9p aUPD was first described in 2002 in patients with polycythemia vera (PV). Since then, systematic application of genomewide single-nucleotide polymorphism arrays has indicated that 9p aUPD is the most common chromosomal aberration in myeloproliferative neoplasms (MPNs), contributing to discovery of the PV-defining mutation JAK2V617F21. It was also found in other myeloid and lymphoid malignancies, though at a relatively lower frequency. By leading to JAK2V617F 23 homozygosity, 9p aUPD plays a causal role in the development of PV and is also associated with less favorable clinical outcomes. It is also possible that new targets other than JAK2V617F 25 are present within 9p aUPD that may contribute to diversity of PV outcome and phenotype. This review summarizes recent discoveries on 9p aUPD in hematologic malignancies and discusses possible underlying mechanisms and potential roles of 9p aUPD in the pathogenesis of PV, the relationship between 9p aUPD and JAK2V617F29, and possible new cancer-related targets within the 9p aUPD region. PMID:26646991

  9. MLL-SEPTIN gene fusions in hematological malignancies.

    PubMed

    Cerveira, Nuno; Bizarro, Susana; Teixeira, Manuel R

    2011-08-01

    The mixed lineage leukemia (MLL) locus is involved in more than 60 different rearrangements with a remarkably diverse group of fusion partners in approximately 10% of human leukemias. MLL rearrangements include chromosomal translocations, gene internal duplications, chromosome 11q deletions or inversions and MLL gene insertions into other chromosomes, or vice versa. MLL fusion partners can be classified into four distinct categories: nuclear proteins, cytoplasmatic proteins, histone acetyltransferases and septins. Five different septin genes (SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11) have been identified as MLL fusion partners, giving rise to chimeric fusion proteins in which the N terminus of MLL is fused, in frame, to almost the entire open reading frame of the septin partner gene. The rearranged alleles result from heterogeneous breaks in distinct introns of both MLL and its septin fusion partner, originating distinct gene fusion variants. MLL-SEPTIN rearrangements have been repeatedly identified in de novo and therapy related myeloid neoplasia in both children and adults, and some clinicopathogenetic associations are being uncovered. The fundamental roles of septins in cytokinesis, membrane remodeling and compartmentalization can provide some clues on how abnormalities in the septin cytoskeleton and MLL deregulation could be involved in the pathogenesis of hematological malignancies. PMID:21714766

  10. Clinical management of HIV-associated hematologic malignancies.

    PubMed

    Wang, Chia-Ching J; Kaplan, Lawrence D

    2016-01-01

    HIV is associated with an excess risk for lymphoid malignancies. Although the risk of lymphoma has decreased in HIV-infected individuals in the era of effective combination antiretroviral therapy, it remains high. Treatment outcomes have improved due to improvements in HIV and cancer therapeutics for the common HIV-associated lymphomas. R-CHOP/R-EPOCH are the standard of care for HIV-associated diffuse large B-cell lymphoma. HIV-infected patients with Burkitt lymphoma and good performance status should receive dose-intensive regimens. HIV-infected patients with primary central nervous system lymphoma can respond favorably to high-dose methotrexate-based therapy. In many cases, treatment and expected outcomes for HIV-infected patients with either Hodgkin or non-Hodgkin's lymphomas are very similar to HIV-negative patients. There is currently no standard treatment for HIV-associated multicentric Castleman disease or primary effusion lymphoma. For those hematologic cancers in which transplantation is part of standard care, this modality should be considered an option in those with well-controlled HIV infection. PMID:26652941

  11. Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

    PubMed Central

    Barrett, David; Brown, Valerie I.; Grupp, Stephan A.; Teachey, David T.

    2014-01-01

    TORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers. PMID:22845486

  12. The role of protein kinase C-alpha in hematologic malignancies.

    PubMed

    Lahn, Michael; Sundell, Karen; Köhler, Gabriele

    2006-01-01

    In recent years advances in histopathological and molecular understanding of hematologic malignancies have led to the development of drugs which selectively target proteins associated with hematologic tumorigenesis. One such targeted agent is the antisense oligonucleotide aprinocarsen, which specifically inhibits the signaling protein, protein kinase C-alpha (PKC-alpha). Although PKC-alpha has been associated with tumorigenesis, its role and expression levels in patients with hematologic malignancies are not well understood. We here review studies investigating the expression and role of PKC-alpha in hematologic malignancies. Such a review may offer new insights on how to develop strategies in identifying patients that might best benefit from PKC-alpha inhibition. PMID:16424642

  13. Perceptions of palliative care among hematologic malignancy specialists: a mixed-methods study

    PubMed Central

    LeBlanc, Thomas W.; O'Donnell, Jonathan D.; Crowley-Matoka, Megan; Rabow, Michael W.; Smith, Cardinale B.; White, Douglas B.; Tiver, Greer A.; Arnold, Robert M.; Schenker, Yael

    2016-01-01

    Background Patients with hematologic malignancies are less likely to receive specialist palliative care services than patients with solid tumors. Reasons for this difference are poorly understood. Methods This was a multisite, mixed-methods study to understand and contrast perceptions of palliative care among hematologic and solid tumor oncologists, using surveys assessing referral practices, and in-depth semi-structured interviews exploring views of palliative care. We compared referral patterns using standard statistical methods. We analyzed qualitative interview data using constant comparative methods, to explore reasons for observed differences. Results Among 66 interviewees, 23 oncologists cared exclusively for patients with hematologic malignancies; 43 treated only patients with solid tumors. Seven of 23 hematologic oncologists (30%) reported never referring to palliative care; all solid tumor oncologists had previously referred. In qualitative analyses, most hematologic oncologists viewed palliative care as end-of-life care, while most solid tumor oncologists viewed palliative care as a subspecialty that could assist with complex cases. Solid tumor oncologists emphasized practical barriers to palliative care referral, such as appointment availability and reimbursement issues. Hematologic oncologists emphasized philosophical concerns about palliative care referrals, including different treatment goals, responsiveness to chemotherapy, and a preference to control even palliative aspects of patient care. Conclusions Most hematologic oncologists view palliative care as end-of-life care, while solid tumor oncologists more often view palliative care as a subspecialty for co-managing complex patients. Efforts to integrate palliative care into hematologic malignancy practices will require solutions that address unique barriers to palliative care referral experienced by hematologic malignancy specialists. PMID:25784580

  14. Targeted Marrow Irradiation, Fludarabine Phosphate, and Busulfan Before Donor Progenitor Cell Transplant in Treating Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2016-06-03

    Acute Myeloid Leukemia; Hematologic Malignancies; Acute Lymphocytic Leukemia; Non Hodgkin Lymphoma; Hodgkin Lymphoma,; Multiple Myeloma; Myelodysplastic Syndrome; Chronic Lymphocytic Leukemia; Chronic Myeloid Leukemia; Myelofibrosis; Myeloproliferative Syndrome

  15. Antibody-modified T cells: CARs take the front seat for hematologic malignancies

    PubMed Central

    Maus, Marcela V.; Grupp, Stephan A.; Porter, David L.

    2014-01-01

    T cells redirected to specific antigen targets with engineered chimeric antigen receptors (CARs) are emerging as powerful therapies in hematologic malignancies. Various CAR designs, manufacturing processes, and study populations, among other variables, have been tested and reported in over 10 clinical trials. Here, we review and compare the results of the reported clinical trials and discuss the progress and key emerging factors that may play a role in effecting tumor responses. We also discuss the outlook for CAR T-cell therapies, including managing toxicities and expanding the availability of personalized cell therapy as a promising approach to all hematologic malignancies. Many questions remain in the field of CAR T cells directed to hematologic malignancies, but the encouraging response rates pave a wide road for future investigation. PMID:24578504

  16. Allopurinol hypersensitivity syndrome in patients with hematological malignancies: characteristics and clinical outcomes

    PubMed Central

    Min, Hong Ki; Lee, Boin; Kwok, Seung-Ki; Ju, Ji Hyeon; Kim, Wan-Uk; Park, Young Min

    2015-01-01

    Background/Aims Allopurinol is a urate-lowering agent that is commonly used to prevent chemotherapy-related hyperuricemia. Allopurinol hypersensitivity syndrome (AHS) is a disorder involving multiple organs, which may be accompanied by cutaneous adverse reactions. We identified the characteristics and clinical outcomes of chemotherapy-associated AHS in patients with hematological malignancies. Methods This retrospective single-center study included 26 AHS patients (11 with and 15 without hematological malignancies) admitted to Seoul St. Mary's Hospital. AHS was defined using the criteria of Singer and Wallace. Comparisons were made using the Mann-Whitney U test and Fisher exact test as appropriate. Results In patients with a hematological malignancy and AHS, statistically significant differences were observed in terms of younger age at onset; shorter duration of exposure; higher starting and maintenance doses of allopurinol; lower incidence of eosinophilia, leukocytosis, and underlying renal insufficiency; and more frequent occurrence of fever compared to AHS patients without a hematological malignancy. Two AHS patients with a hematological malignancy were examined for human leukocyte antigen (HLA)-B typing, but neither patient harbored the HLA-B*5801 allele. All of the patients ceased allopurinol treatment, with most patients making a full recovery. Two patients in the study died; however, these deaths were unrelated to AHS. One patient developed serious sequelae of AHS that required hemodialysis. Conclusions Physicians who prescribe allopurinol for the prevention of chemotherapy-related hyperuricemia should be aware of the unique risk of AHS, even in patients with hematological malignancies who do not have known risk factors for AHS. Novel urate-lowering agents should be considered alternative treatments. PMID:26161019

  17. Fludarabine Based Conditioning for Allogeneic Transplantation for Advanced Hematologic Malignancies

    ClinicalTrials.gov

    2014-03-27

    Acute Myeloid Leukemia; Acute Leukemia; Chronic Myelogenous Leukemia; Malignant Lymphoma; Hodgkin's Disease; Multiple Myeloma; Lymphocytic Leukemia; Myeloproliferative Disorder; Polycythemia Vera; Myelofibrosis; Aplastic Anemia

  18. Nanomedicine strategies for hematological malignancies: what is next?

    PubMed

    Visani, Giuseppe; Loscocco, Federica; Isidori, Alessandro

    2014-10-01

    The major obstacle in treating cancer depends on the low therapeutic index of most anticancer drugs. The lack of specificity, coupled with the large volumes of distribution, translates into a nonpreferential distribution of anticancer drugs to the tumor. Accordingly, the dose of the anticancer drug that is achievable within tumor is limited, resulting in suboptimal treatment and unwanted toxicity. Nanoparticles applied as drug-delivery systems are submicron-sized (3-200 nm) particles, that can enhance the selectivity of the active drug to cancer cells through a change of its pharmacokinetic profile, while avoiding toxicity in normal cells. This review will discuss the current uses of nanodrugs in hematology, with a focus on the most promising nanoparticles in development for the treatment of hematologic tumors. PMID:25413858

  19. Phosphatase of regenerating liver in hematopoietic stem cells and hematological malignancies

    PubMed Central

    Kobayashi, Michihiro; Chen, Sisi; Gao, Rui; Bai, Yunpeng; Zhang, Zhong-Yin; Liu, Yan

    2014-01-01

    The phosphatases of regenerating liver (PRLs), consisting PRL1, PRL2 and PRL3, are dual-specificity protein phosphatases that have been implicated as biomarkers and therapeutic targets in several solid tumors. However, their roles in hematological malignancies are largely unknown. Recent findings demonstrate that PRL2 is important for hematopoietic stem cell self-renewal and proliferation. In addition, both PRL2 and PRL3 are highly expressed in some hematological malignancies, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Moreover, PRL deficiency impairs the proliferation and survival of leukemia cells through regulating oncogenic signaling pathways. While PRLs are potential novel therapeutic targets in hematological malignancies, their exact biological function and cellular substrates remain unclear. This review will discuss how PRLs regulate hematopoietic stem cell behavior, what signaling pathways are regulated by PRLs, and how to target PRLs in hematological malignancies. An improved understanding of how PRLs function and how they are regulated may facilitate the development of PRL inhibitors that are effective in cancer treatment. PMID:25486470

  20. Exploring Therapeutic Potentials of Baicalin and Its Aglycone Baicalein for Hematological Malignancies

    PubMed Central

    Chen, Haijun; Gao, Yu; Wu, Jianlei; Chen, Yingyu; Chen, Buyuan; Hu, Jianda; Zhou, Jia

    2014-01-01

    Despite tremendous advances in the targeted therapy for various types of hematological malignancies with successful improvements in the survival rates, emerging resistance issues are startlingly high and novel therapeutic strategies are urgently needed. In addition, chemoprevention is currently becoming an elusive goal. Plant-derived natural products have garnered considerable attention in recent years due to the potential dual functions as chemotherapeutics and dietary chemoprevention. One of the particularly ubiquitous families is the polyphenolic flavonoids. Among them, baicalin and its aglycone baicalein have been widely investigated in hematological malignancies because both of them exhibit remarkable pharmacological properties. This review focuses on the recent achievements in drug discovery research associated with baicalin and baicalein for hematological malignancy therapies. The promising anticancer activities of these two flavonoids targeting diverse signaling pathways and their potential biological mechanisms in different types of hematological malignancies, as well as the combination strategy with baicalin or baicalein as chemotherapeutic adjuvants for recent therapies in these intractable diseases are discussed. Meanwhile, the biotransformation of baicalin and baicalein and the relevant approaches to improve their bioavailability are also summarized. PMID:25128647

  1. Invasive infection due to Saprochaete capitata in a young patient with hematological malignancies.

    PubMed

    Parahym, Ana Maria Rabelo de Carvalho; Rolim Neto, Pedro José; da Silva, Carolina Maria; Domingos, Igor de Farias; Gonçalves, Sarah Santos; Leite, Edinalva Pereira; de Morais, Vera Lúcia Lins; Macêdo, Danielle Patrícia Cerqueira; de Lima Neto, Reginaldo Gonçalves; Neves, Rejane Pereira

    2015-06-01

    We report a case of invasive infection due to Saprochaete capitata in a patient with hematological malignancies after chemotherapy treatment and empiric antifungal therapy with caspofungin. Although severely immunocompromised the patient survived been treated with amphotericin B lipid complex associated with voriconazole. PMID:26273269

  2. Course and outcome of Early Lyme borreliosis in patients with hematological malignancies.

    PubMed

    Maraspin, Vera; Ružić-Sabljić, Eva; Lusa, Lara; Strle, Franc

    2015-08-01

    Patients with erythema migrans and underlying hematological malignancy more often had signs of disseminated Lyme borreliosis and more frequently needed antibiotic retreatment than sex-, age-, and antibiotic treatment-matched immunocompetent persons with erythema migrans. However, the outcome was excellent in both groups. PMID:25956890

  3. The safety profile of vorinostat (suberoylanilide hydroxamic acid) in hematologic malignancies: A review of clinical studies.

    PubMed

    Duvic, Madeleine; Dimopoulos, Meletios

    2016-02-01

    Histone acetyltransferases and histone deacetylases (HDACs) are multifunctional enzymes that posttranslationally modify both histone and nonhistone acetylation sites, affecting a broad range of cellular processes (e.g., cell cycle, apoptosis, and protein folding) often dysregulated in cancer. HDAC inhibitors are small molecules that directly interact with HDAC catalytic sites preventing the removal of acetyl groups, thereby counteracting the effects of HDACs. Since the first HDAC inhibitor, valproic acid, was investigated as a potential antitumor agent, there have been a number of other HDAC inhibitors developed to improve efficacy and safety. Despite significant progress in the management of patients with hematologic malignancies, overall survival is still poor. The discovery that HDACs may play a role in hematologic malignancies and preclinical studies showing promising activity with HDAC inhibitors in various tumor types, led to clinical evaluation of HDAC inhibitors as potential treatment options for patients with advanced hematologic malignancies. The Food and Drug Administration has approved two HDAC inhibitors, vorinostat (2006) and romidepsin (2009), for the treatment of cutaneous T-cell lymphoma. This review highlights the safety of HDAC inhibitors currently approved or being investigated for the treatment of hematologic malignancies, with a specific focus on the safety experience with vorinostat in cutaneous T-cell lymphoma. PMID:26827693

  4. Hematological Malignancies Escape from NK Cell Innate Immune Surveillance: Mechanisms and Therapeutic Implications

    PubMed Central

    Farnault, Laure; Sanchez, Carole; Baier, Céline; Le Treut, Thérèse; Costello, Régis T.

    2012-01-01

    Hematological malignancies treatment improved over the last years resulting in increased achievement of complete or partial remission, but unfortunately high relapse rates are still observed. Therefore, sustainment of long-term remission is crucial. Immune system has a key role in tumor surveillance. Natural killer (NK) cells, at the frontier of innate and adaptive immune system, have a central role in tumor cells surveillance as demonstrated in the setting of allogenic stem cell transplantation. Nevertheless, tumor cells develop various mechanisms to escape from NK cells innate immune pressure. Abnormal NK cytolytic functions have been described in nearly all hematological malignancies. We present here various mechanisms involved in the escape of hematological malignancies from NK cells surveillance: NK cells quantitative deficiency and NK cell qualitative deficiency by increased inhibition signaling or decreased activating stimuli. A challenge of immunotherapy is to restore an efficient antitumor response. A combination of classical therapy plus immune modulation strategies will soon become a standard of care for hematological malignancies. PMID:22899948

  5. Invasive infection due to Saprochaete capitata in a young patient with hematological malignancies

    PubMed Central

    Parahym, Ana Maria Rabelo de Carvalho; Rolim, Pedro José; da Silva, Carolina Maria; Domingos, Igor de Farias; Gonçalves, Sarah Santos; Leite, Edinalva Pereira; de Morais, Vera Lúcia Lins; Macêdo, Danielle Patrícia Cerqueira; de Lima, Reginaldo Gonçalves; Neves, Rejane Pereira

    2015-01-01

    We report a case of invasive infection due to Saprochaete capitata in a patient with hematological malignancies after chemotherapy treatment and empiric antifungal therapy with caspofungin. Although severely immunocompromised the patient survived been treated with amphotericin B lipid complex associated with voriconazole. PMID:26273269

  6. T-Regulatory Cell and CD3 Depleted Double Umbilical Cord Blood Transplantation in Hematologic Malignancies

    ClinicalTrials.gov

    2014-03-04

    Hematologic Malignancy; Acute Myeloid Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia in Blast Crisis; Anemia, Refractory, With Excess of Blasts; Chronic Myeloproliferative Disease; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Marginal Zone B-cell Lymphoma; Follicular Lymphoma; Lymphoplasmacytic Lymphoma; Mantle-Cell Lymphoma; Prolymphocytic Lymphoma; Large Cell Non-Hodgkin's Lymphoma; Lymphoblastic Lymphoma; Burkitt's Lymphoma; High Grade Non-Hodgkin's Lymphoma

  7. The role of telomeres and telomerase in hematologic malignancies and hematopoietic stem cell transplantation

    PubMed Central

    2014-01-01

    Telomeres are specific nucleoprotein structures at the ends of eukaryotic chromosomes. Telomeres and telomere-associated proteins maintain genome stability by protecting the ends of chromosomes from fusion and degradation. In normal somatic cells, the length of the telomeres gradually becomes shortened with cell division. In tumor cells, the shortening of telomeres length is accelerated under the increased proliferation pressure. However, it will be maintained at an extremely short length as the result of activation of telomerase. Significantly shortened telomeres, activation of telomerase, and altered expression of telomere-associated proteins are common features of various hematologic malignancies and are related with progression or chemotherapy resistance in these diseases. In patients who have received hematopoietic stem cell transplantation (HSCT), the telomere length and the telomerase activity of the engrafted donor cells have a significant influence on HSCT outcomes. Transplantation-related factors should be taken into consideration because of their impacts on telomere homeostasis. As activation of telomerase is widespread in tumor cells, it has been employed as a target point in the treatment of neoplastic hematologic disorders. In this review, the characteristics and roles of telomeres and telomerase both in hematologic malignancies and in HSCT will be summarized. The current status of telomerase-targeted therapies utilized in the treatment of hematologic malignancies will also be reviewed. PMID:25139287

  8. The role of telomeres and telomerase in hematologic malignancies and hematopoietic stem cell transplantation.

    PubMed

    Wang, Limengmeng; Xiao, Haowen; Zhang, Xing; Wang, Chong; Huang, He

    2014-01-01

    Telomeres are specific nucleoprotein structures at the ends of eukaryotic chromosomes. Telomeres and telomere-associated proteins maintain genome stability by protecting the ends of chromosomes from fusion and degradation. In normal somatic cells, the length of the telomeres gradually becomes shortened with cell division. In tumor cells, the shortening of telomeres length is accelerated under the increased proliferation pressure. However, it will be maintained at an extremely short length as the result of activation of telomerase. Significantly shortened telomeres, activation of telomerase, and altered expression of telomere-associated proteins are common features of various hematologic malignancies and are related with progression or chemotherapy resistance in these diseases. In patients who have received hematopoietic stem cell transplantation (HSCT), the telomere length and the telomerase activity of the engrafted donor cells have a significant influence on HSCT outcomes. Transplantation-related factors should be taken into consideration because of their impacts on telomere homeostasis. As activation of telomerase is widespread in tumor cells, it has been employed as a target point in the treatment of neoplastic hematologic disorders. In this review, the characteristics and roles of telomeres and telomerase both in hematologic malignancies and in HSCT will be summarized. The current status of telomerase-targeted therapies utilized in the treatment of hematologic malignancies will also be reviewed. PMID:25139287

  9. Meeting the challenge of hematologic malignancies in sub-Saharan Africa

    PubMed Central

    Wood, William A.; Lee, Stephanie J.; Shea, Thomas C.; Naresh, Kikkeri N.; Kazembe, Peter N.; Casper, Corey; Hesseling, Peter B.; Mitsuyasu, Ronald T.

    2012-01-01

    Cancer is a leading cause of death and disability in sub-Saharan Africa and will eclipse infectious diseases within the next several decades if current trends continue. Hematologic malignancies, including non-Hodgkin lymphoma, leukemia, Hodgkin lymphoma, and multiple myeloma, account for nearly 10% of the overall cancer burden in the region, and the incidence of non-Hodgkin lymphoma and Hodgkin lymphoma is rapidly increasing as a result of HIV. Despite an increasing burden, mechanisms for diagnosing, treating, and palliating malignant hematologic disorders are inadequate. In this review, we describe the scope of the problem, including the impact of endemic infections, such as HIV, Epstein-Barr virus, malaria, and Kaposi sarcoma–associated herpesvirus. We additionally describe current limitations in hematopathology, chemotherapy, radiotherapy, hematopoietic stem cell transplantation, and supportive care and palliation. We review contemporary treatment and outcomes of hematologic malignancies in the region and outline a clinical service and research agenda, which builds on recent global health successes combating HIV and other infectious diseases. Achieving similar progress against hematologic cancers in sub-Saharan Africa will require the sustained collaboration and advocacy of the entire global cancer community. PMID:22461494

  10. Unmet Needs for Psychosocial Care in Hematologic Malignancies and Hematopoietic Cell Transplant.

    PubMed

    Barata, Anna; Wood, William A; Choi, Sung Won; Jim, Heather S L

    2016-08-01

    Individuals diagnosed with hematologic malignancies experience significant unmet psychological, physical, informational, financial, and spiritual needs. The goal of the current review is to summarize and highlight recent research focused on these issues in the diagnosis and treatment periods and beyond. The review also describes the needs of adolescent and young adult (AYA) and pediatric patients. While a large body of research has reported on unmet needs among adult hematologic cancer patients, there is far less data regarding the challenges confronted by AYA and pediatric populations. Available data suggests that among all age groups, hematopoietic cell transplantation (HCT) is a risk factor for greater unmet needs. Recommendations for screening and evidence-based interventions to prevent or ameliorate unmet needs are provided. Future research is needed to develop additional evidence-based psychosocial interventions with a focus on hematologic cancer. PMID:27113094

  11. Myeloid-Derived Suppressor Cells as Therapeutic Target in Hematological Malignancies

    PubMed Central

    De Veirman, Kim; Van Valckenborgh, Els; Lahmar, Qods; Geeraerts, Xenia; De Bruyne, Elke; Menu, Eline; Van Riet, Ivan; Vanderkerken, Karin; Van Ginderachter, Jo A.

    2014-01-01

    Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that accumulate during pathological conditions such as cancer and are associated with a poor clinical outcome. MDSC expansion hampers the host anti-tumor immune response by inhibition of T cell proliferation, cytokine secretion, and recruitment of regulatory T cells. In addition, MDSC exert non-immunological functions including the promotion of angiogenesis, tumor invasion, and metastasis. Recent years, MDSC are considered as a potential target in solid tumors and hematological malignancies to enhance the effects of currently used immune modulating agents. This review focuses on the characteristics, distribution, functions, cell–cell interactions, and targeting of MDSC in hematological malignancies including multiple myeloma, lymphoma, and leukemia. PMID:25538893

  12. Comparison of survival of adolescents and young adults with hematologic malignancies in Osaka, Japan.

    PubMed

    Nakata-Yamada, Kayo; Inoue, Masami; Ioka, Akiko; Ito, Yuri; Tabuchi, Takahiro; Miyashiro, Isao; Masaie, Hiroaki; Ishikawa, Jun; Hino, Masayuki; Tsukuma, Hideaki

    2016-06-01

    The survival gap between adolescents and young adults (AYAs) with hematological malignancies persists in many countries. To determine to what extent it does in Japan, we investigated survival and treatment regimens in 211 Japanese AYAs (15-29 years) in the Osaka Cancer Registry diagnosed during 2001-2005 with hematological malignancies, and compared adolescents (15-19 years) with young adults (20-29 years). AYAs with acute lymphoblastic leukemia (ALL) had a poor 5-year survival (44%), particularly young adults (29% vs. 64% in adolescents, p = 0.01). Additional investigation for patients with ALL revealed that only 19% of young adults were treated with pediatric treatment regimens compared with 45% of adolescents (p = 0.05). Our data indicate that we need to focus on young adults with ALL and to consider establishing appropriate cancer care system and guidelines for them in Japan. PMID:26695739

  13. The Global Challenge of Carbapenem-Resistant Enterobacteriaceae in Transplant Recipients and Patients With Hematologic Malignancies

    PubMed Central

    Satlin, Michael J.; Jenkins, Stephen G.; Walsh, Thomas J.

    2014-01-01

    Carbapenem-resistant Enterobacteriaceae (CRE) are emerging global pathogens. The spread of CRE to transplant recipients and patients with hematologic malignancies has ominous implications. These patients rely on timely, active antibacterial therapy to combat gram-negative infections; however, recommended empirical regimens are not active against CRE. Approximately 3%–10% of solid organ transplant (SOT) recipients in CRE-endemic areas develop CRE infection, and the infection site correlates with the transplanted organ. Mortality rates associated with CRE infections approach 40% in SOT recipients and 65% in patients with hematologic malignancies. Given that the current antimicrobial armamentarium to combat CRE is extremely limited, a multifaceted approach that includes antimicrobial stewardship and active surveillance is needed to prevent CRE infections in immunocompromised hosts. Improving outcomes of established infections will require the use of risk factor–based prediction tools and molecular assays to more rapidly administer CRE-active therapy and the development of new antimicrobial agents with activity against CRE. PMID:24463280

  14. Clinical trials of dendritic cell-based cancer vaccines in hematologic malignancies

    PubMed Central

    Pyzer, Athalia R; Avigan, David E; Rosenblatt, Jacalyn

    2015-01-01

    The potential for the immune system to target hematological malignancies is demonstrated in the allogeneic transplant setting, where durable responses can be achieved. However, allogeneic transplantation is associated with significant morbidity and mortality related to graft versus host disease. Cancer immunotherapy has the capacity to direct a specific cytotoxic immune response against cancer cells, particularly residual cancer cells, in order to reduce the likelihood of disease relapse in a more targeted and tolerated manner. Ex vivo dendritic cells can be primed in various ways to present tumor associated antigen to the immune system, in the context of co-stimulatory molecules, eliciting a tumor specific cytotoxic response in patients. Several approaches to prime dendritic cells and overcome the immunosuppressive microenvironment have been evaluated in pre-clinical and early clinical trials with promising results. In this review, we summarize the clinical data evaluating dendritic cell based vaccines for the treatment of hematological malignancies. PMID:25625926

  15. Exaggerated NT-proBNP production in patients with hematologic malignancies: a case series.

    PubMed

    Andreu, Aileen; Guglin, Maya

    2012-01-01

    ©2011 Wiley Periodicals Inc. Extremely elevated serum brain natriuretic peptide (BNP) in cancer patients is a poorly understood phenomenon. The authors report three cases of patients with hematologic malignancies and serial N-terminal pro-BNP (NT-proBNP) measurements with values in the range of tens to hundred thousands pg/mL. Through matching NT-proBNP results with clinical, laboratory, echocardiographic and radiologic data, the authors found that these patients demonstrated exaggerated responses to fluid overload. Patients with hematologic malignancies may have higher than expected values of NT-proBNP in response to hypervolemic states. The authors hypothesize that this may be related to possible infiltration of the myocardium by substances produced in the setting of these diseases or due to proteins interfering with the assay.Congest Heart Fail. PMID:23167814

  16. Recent advances in the development of Aurora kinases inhibitors in hematological malignancies

    PubMed Central

    Choudary, Iqra; Barr, Paul M.; Friedberg, Jonathan

    2015-01-01

    Over the last two decades, since the discovery of Drosophila mutants in 1995, much effort has been made to understand Aurora kinase biology. Three mammalian subtypes have been identified thus far which include the Aurora A, B and C kinases. These regulatory proteins specifically work at the cytoskeleton and chromosomal structures between the kinetochores and have vital functions in the early phases of the mitotic cell cycle. Today, there are multiple phase I and phase II clinical trials as well as numerous preclinical studies taking place looking at Aurora kinase inhibitors in both hematologic and solid malignancies. This review focuses on the preclinical and clinical development of Aurora kinase inhibitors in hematological malignancy and discusses their therapeutic potential. PMID:26622997

  17. Laparoscopic Splenectomy in the Management of Benign and Malignant Hematologic Diseases

    PubMed Central

    Boru, Cristian Eugeniu; Fantini, Aldo; Raparelli, Luigi; Greco, Francesco; Rizzello, Mario; Pecchia, Alessandro; Fabiano, Paolo; Basso, Nicola

    2006-01-01

    Objectives: The use of laparoscopy to treat malignant hematological diseases is not completely accepted. Our aim was to analyze operative and postoperative results of laparoscopic splenectomy performed for benign versus malignant hematological disorders. Methods: Between 1994 and 2003, 76 consecutive patients underwent laparoscopic splenectomy. The first 38 cases were performed by using an anterior approach, whereas in the remaining 38 cases a semilateral position was used. Results: Baseline characteristics showed that patients with malignant diseases were significantly older (56.9 vs 32.6 years, P<0.001). Seventy-two (94.7%) procedures were completed laparoscopically. Conversion was required in 4 cases (5.2%). Mean operative time was 138.5 minutes for benign and 151.0 minutes for malignant diseases, (P>0.05, ns). The hand-assisted technique was used in 3 patients with massive splenomegaly. Pathologic features showed that spleen volume was higher in patients with malignant diseases (mean interpole diameter 18.1 cm vs 13.7 cm, P<0.001). Massive splenomegaly (interpole diameter over 20 cm, weight over 1000 g) was present in 13 patients (17.1%); 9 had malignant diseases. Overall perioperative mortality was 1.3% and major postoperative complications occurred in 6 patients (7.8%). Postoperative splenoportal partial thrombosis was identified in 9.7% of patients. Conclusions: Laparoscopic splenectomy is a well-accepted, less-invasive procedure for hematological disorders. Neoplastic diseases or splenomegaly, or both, do not seem to limit the indications for a minimally invasive approach after the learning curve. PMID:16882420

  18. Combination epigenetic and immunotherapy overcomes resistance to monoclonal antibodies in hematologic malignancies: A new therapeutic approach.

    PubMed

    Epner, Elliot M; Saroya, Bikramajit Singh; Hasanali, Zainul S; Loughran, Thomas P

    2016-03-01

    We recently reported that addition of epigenetic agents could overcome resistance of leukemic cells to monoclonal antibody-mediated anti-tumor effects in T-cell prolymphocytic leukemia. We also reported that epigenetic agents could induce expression of the CD30 gene, thus providing a therapeutic target for the antibody drug conjugate brentuximab vedotin. Here we discuss these findings and their generality to treatment of other hematologic and solid malignancies. PMID:26802532

  19. Obinutuzumab in hematologic malignancies: lessons learned to date.

    PubMed

    Illidge, Tim; Klein, Christian; Sehn, Laurie H; Davies, Andrew; Salles, Gilles; Cartron, Guillaume

    2015-11-01

    The routine use of anti-CD20 monoclonal antibodies (mAbs) has improved patient outcomes in CD20-positive non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite the clinical success achieved with rituximab, relapses are still common with further improvements in anti-CD20 mAb efficacy required. Many novel anti-CD20 antibodies are in development, but obinutuzumab is currently the only type II glycoengineered anti-CD20 mAb in clinical testing. Obinutuzumab has increased antibody-dependent cell-mediated cytotoxicity, reduced complement-dependent cytotoxicity and enhanced direct non-apoptotic cell death. In preclinical models, obinutuzumab induced superior tumor remission compared with rituximab at the equivalent dose levels, and was active in rituximab-refractory tumors. Obinutuzumab exhibits encouraging efficacy as monotherapy in NHL, and combined with chemotherapy in relapsed/refractory NHL and treatment-naïve symptomatic CLL. In a recent randomized, phase III trial in patients with untreated comorbid CLL, overall response rate was significantly greater (78% vs. 65%, P<0.0001) and median progression-free survival was significantly prolonged (26.7 vs. 15.2months, P<0.0001) for obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil. Obinutuzumab is a type II anti-CD20 antibody that utilizes distinct mechanisms of action relative to type I antibodies like rituximab and has led to significant clinical improvement over rituximab in a phase III trial in CLL. Further trials are ongoing to determine whether such improvements in outcome will be seen in CD20-positive B-cell malignancies. PMID:26190254

  20. Optimizing T-cell receptor gene therapy for hematologic malignancies.

    PubMed

    Morris, Emma C; Stauss, Hans J

    2016-06-30

    Recent advances in genetic engineering have enabled the delivery of clinical trials using patient T cells redirected to recognize tumor-associated antigens. The most dramatic results have been seen with T cells engineered to express a chimeric antigen receptor (CAR) specific for CD19, a differentiation antigen expressed in B cells and B lineage malignancies. We propose that antigen expression in nonmalignant cells may contribute to the efficacy of T-cell therapy by maintaining effector function and promoting memory. Although CAR recognition is limited to cell surface structures, T-cell receptors (TCRs) can recognize intracellular proteins. This not only expands the range of tumor-associated self-antigens that are amenable for T-cell therapy, but also allows TCR targeting of the cancer mutagenome. We will highlight biological bottlenecks that potentially limit mutation-specific T-cell therapy and may require high-avidity TCRs that are capable of activating effector function when the concentrations of mutant peptides are low. Unexpectedly, modified TCRs with artificially high affinities function poorly in response to low concentration of cognate peptide but pose an increased safety risk as they may respond optimally to cross-reactive peptides. Recent gene-editing tools, such as transcription activator-like effector nucleases and clustered regularly interspaced short palindromic repeats, provide a platform to delete endogenous TCR and HLA genes, which removes alloreactivity and decreases immunogenicity of third-party T cells. This represents an important step toward generic off-the-shelf T-cell products that may be used in the future for the treatment of large numbers of patients. PMID:27207802

  1. Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy

    PubMed Central

    Wang, Ying-Hua; Kalaitzidis, Demetrios; Ramachandran, Janani; Sykes, David B.; Raje, Noopur; Scadden, David T.

    2016-01-01

    Regulation of STAT3 activation is critical for normal and malignant hematopoietic cell proliferation. Here, we have reported that the endogenous transmembrane protein upstream-of-mTORC2 (UT2) negatively regulates activation of STAT3. Specifically, we determined that UT2 interacts directly with GP130 and inhibits phosphorylation of STAT3 on tyrosine 705 (STAT3Y705). This reduces cytokine signaling including IL6 that is implicated in multiple myeloma and other hematopoietic malignancies. Modulation of UT2 resulted in inverse effects on animal survival in myeloma models. Samples from multiple myeloma patients also revealed a decreased copy number of UT2 and decreased expression of UT2 in genomic and transcriptomic analyses, respectively. Together, these studies identify a transmembrane protein that functions to negatively regulate cytokine signaling through GP130 and pSTAT3Y705 and is molecularly and mechanistically distinct from the suppressors of cytokine signaling (SOCS) family of genes. Moreover, this work provides evidence that perturbations of this activation-dampening molecule participate in hematologic malignancies and may serve as a key determinant of multiple myeloma pathophysiology. UT2 is a negative regulator shared across STAT3 and mTORC2 signaling cascades, functioning as a tumor suppressor in hematologic malignancies driven by those pathways. PMID:26927669

  2. Advances in haploidentical stem cell transplantation for hematologic malignancies.

    PubMed

    Montoro, Juan; Sanz, Jaime; Sanz, Guillermo F; Sanz, Miguel A

    2016-08-01

    One of the most important advances in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the use of alternative donors and cell sources, such as haploidentical transplants (haplo-HSCT) from family donors. Several approaches have been developed to overcome the challenging bidirectional alloreactivity. We discuss these approaches, including ex vivo T-cell-depleted grafts with megadose of CD34(+) cells, not requiring immunosuppression after allogeneic transplantation for graft-versus-host disease (GVHD) prophylaxis, and other strategies using unmanipulated T-cell-replete grafts with intensive immunosuppression or post-transplantation cyclophosphamide to minimize the GVHD. We also address the role of other strategies developed in the context of the haplo-HSCT platforms, such as ex vivo selective depletion of alloreactive donor T-cell subpopulations, infusion of antigen-specific T-cells against several pathogens, and infusion of regulatory T-cells, among other experimental approaches. Finally, some considerations about the selection of the most suitable donor, when more than one family member is available, are also addressed. PMID:27424663

  3. Genetic modification of human T lymphocytes for the treatment of hematologic malignancies

    PubMed Central

    Hoyos, Valentina; Savoldo, Barbara; Dotti, Gianpietro

    2012-01-01

    Modern chemotherapy regimens and supportive care have produced remarkable improvements in the overall survival of patients with hematologic malignancies. However, the development of targeted small molecules, monoclonal antibodies, and biological therapies that demonstrate greater efficacy and lower toxicity remains highly desirable in hematology, and oncology in general. In the context of biological therapies, T-lymphocyte based treatments have enormous potential. Donor lymphocyte infusion in patients relapsed after allogeneic hematopoietic stem cell transplant pioneered the concept that T lymphocytes can effectively control tumor growth, and this was then followed by the development of cell culture strategies to generate T lymphocytes with selective activity against tumor cells. Over the past decade, it has become clear that the adoptive transfer of ex vivo expanded antigen-specific cytotoxic T lymphocytes promotes sustained antitumor effects in patients with virus-associated lymphomas, such as Epstein-Barr virus related post-transplant lymphomas and Hodgkin's lymphomas. Because of this compelling clinical evidence and the concomitant development of methodologies for robust gene transfer to human T lymphocytes, the field has rapidly evolved, offering new opportunities to extend T-cell based therapies. This review summarizes the most recent biological and clinical developments using genetically manipulated T cells for the treatment of hematologic malignancies. PMID:22929977

  4. Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy

    PubMed Central

    Al-Shammari, Ahmed Majeed; Rameez, Huda; Al-Taee, Maha F

    2016-01-01

    Hematological malignancies are important diseases that need more powerful therapeutics. Even with current targeting therapies, such as rituximab and other chemotherapeutic agents, there is a need to develop new treatment strategies. Combination therapy seems the best option to target the tumor cells by different mechanisms. Virotherapy is a very promising treatment modality, as it is selective, safe, and causes cancer destruction. The Iraqi strain of Newcastle disease virus (NDV) has proved to be effective both in vitro and in vivo. In the current work, we tested its ability on anti-hematological tumors and enhanced current treatments with combination therapy, and studied this combination using Chou–Talalay analysis. p53 concentration was measured to evaluate the mechanism of this proposed synergism. The results showed that NDV was synergistic with doxorubicin in low doses on plasmacytoma cells, with no involvement of p53 pathways, but involved p53 when the combination was used on non-Hodgkin lymphoma cells. NDV in combination with rituximab showed enhanced cytotoxicity that was p53-independent. In conclusion, this work proposes a novel combination modality for treatment of some hematological malignancies. PMID:27579294

  5. Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy.

    PubMed

    Al-Shammari, Ahmed Majeed; Rameez, Huda; Al-Taee, Maha F

    2016-01-01

    Hematological malignancies are important diseases that need more powerful therapeutics. Even with current targeting therapies, such as rituximab and other chemotherapeutic agents, there is a need to develop new treatment strategies. Combination therapy seems the best option to target the tumor cells by different mechanisms. Virotherapy is a very promising treatment modality, as it is selective, safe, and causes cancer destruction. The Iraqi strain of Newcastle disease virus (NDV) has proved to be effective both in vitro and in vivo. In the current work, we tested its ability on anti-hematological tumors and enhanced current treatments with combination therapy, and studied this combination using Chou-Talalay analysis. p53 concentration was measured to evaluate the mechanism of this proposed synergism. The results showed that NDV was synergistic with doxorubicin in low doses on plasmacytoma cells, with no involvement of p53 pathways, but involved p53 when the combination was used on non-Hodgkin lymphoma cells. NDV in combination with rituximab showed enhanced cytotoxicity that was p53-independent. In conclusion, this work proposes a novel combination modality for treatment of some hematological malignancies. PMID:27579294

  6. Detection and Identification of Hematologic Malignancies and Solid Tumors by an Electrochemical Technique

    PubMed Central

    Zhang, Bowen; Zhang, Xiaoping; Wang, Xuemei; Cheng, Jian; Chen, Baoan

    2016-01-01

    Purpose Develop and evaluate an electrochemical method to identify healthy individuals, malignant hematopathic patients and solid tumor patients by detecting the leukocytes in whole-blood. Methods A total of 114 individual blood samples obtained from our affiliated hospital in China (June 2015- August 2015) were divided into three groups: healthy individuals (n = 35), hematologic malignancies (n = 41) and solid tumors (n = 38). An electrochemical workstation system was used to measure differential pulse voltammetry due to the different electrochemical behaviors of leukocytes in blood samples. Then, one-way analysis of variance (ANOVA) was applied to analyze the scanning curves and to compare the peak potential and peak current. Results The scanning curve demonstrated the specific electrochemical behaviors of the blank potassium ferricyanide solution and that mixed with blood samples in different groups. Significant differences in mean peak potentials of mixture and shifts (ΔEp (mV)) were observed of the three groups (P< = 0.001). 106.00±9.00 and 3.14±7.48 for Group healthy individuals, 120.90±11.18 and 18.10±8.81 for Group hematologic malignancies, 136.84±11.53 and 32.89±10.50 for Group solid tumors, respectively. In contrast, there were no significant differences in the peak currents and shifts. Conclusions The newly developed method to apply the electrochemical workstation system to identify hematologic malignancies and solid tumors with good sensitivity and specificity might be effective, suggesting a potential utility in clinical application. PMID:27115355

  7. Targeting the mitochondrial apoptotic pathway: a preferred approach in hematologic malignancies?

    PubMed Central

    Brinkmann, K; Kashkar, H

    2014-01-01

    Acquired resistance toward apoptosis represents one of the hallmarks of human cancer and a major cause of the inefficacy of most anticancer treatment regimens. Based on its ability to inhibit apoptosis, the B-cell lymphoma/leukemia 2 (Bcl-2) protein family has garnered the most attention as a promising therapeutic target in cancer. Accordingly, efforts have lately been focused on the development of drugs targeting Bcl-2 proteins with considerable therapeutic success, particularly in hematologic malignancies. Here, we review the previous studies and highlight the pivotal role of the Bcl-2 protein family in the homeostasis of hematologic tissue compartment. This knowledge provides more insight into why some cancers are more sensitive to Bcl-2 targeting than others and will foster the clinical evaluation of Bcl-2-targeting strategies in cancer by avoiding severe on-target side effects in the development of healthy tissues. PMID:24603326

  8. PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

    PubMed Central

    Brault, Laurent; Gasser, Christelle; Bracher, Franz; Huber, Kilian; Knapp, Stefan; Schwaller, Jürg

    2010-01-01

    The identification as cooperating targets of Proviral Integrations of Moloney virus in murine lymphomas suggested early on that PIM serine/threonine kinases play an important role in cancer biology. Whereas elevated levels of PIM1 and PIM2 were mostly found in hematologic malignancies and prostate cancer, increased PIM3 expression was observed in different solid tumors. PIM kinases are constitutively active and their activity supports in vitro and in vivo tumor cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators. PIM1 but not PIM2 seems also to mediate homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that PIM kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets. Determination of the protein structure facilitated identification of an increasing number of potent small molecule PIM kinase inhibitors with in vitro and in vivo anticancer activity. Ongoing efforts aim to identify isoform-specific PIM inhibitors that would not only help to dissect the kinase function but hopefully also provide targeted therapeutics. Here, we summarize the current knowledge about the role of PIM serine/threonine kinases for the pathogenesis and therapy of hematologic malignancies and solid cancers, and we highlight structural principles and recent progress on small molecule PIM kinase inhibitors that are on their way into first clinical trials. PMID:20145274

  9. Bloodstream infections in patients with hematological malignancies: which is more fatal – cancer or resistant pathogens?

    PubMed Central

    Gedik, Habip; Şimşek, Funda; Kantürk, Arzu; Yildirmak, Taner; Arica, Deniz; Aydin, Demet; Demirel, Naciye; Yokuş, Osman

    2014-01-01

    Background The primary objective of this study was to report the incidence of bloodstream infections (BSIs) and clinically or microbiologically proven bacterial or fungal BSIs during neutropenic episodes in patients with hematological malignancies. Methods In this retrospective observational study, all patients in the hematology department older than 14 years who developed febrile neutropenia during chemotherapy for hematological cancers were evaluated. Patients were included if they had experienced at least one neutropenic episode between November 2010 and November 2012 due to chemotherapy in the hematology ward. Results During 282 febrile episodes in 126 patients, 66 (23%) episodes of bacteremia and 24 (8%) episodes of fungemia were recorded in 48 (38%) and 18 (14%) patients, respectively. Gram-negative bacteria caused 74% (n=49) of all bacteremic episodes. Carbapenem-resistant Gram-negative bacteria (n=6) caused 12% and 9% of Gram-negative bacteremia episodes and all bacteremia episodes, respectively. Carbapenem-resistant Gram-negative bacteria included Acinetobacter baumannii (n=4), Pseudomonas aeruginosa (n=1), and Serratia marcescens (n=1). Culture-proven invasive fungal infection occurred in 24 episodes in 18 cases during the study period, with 15 episodes in ten cases occurring in the first study year and nine episodes in eight cases in the second study year. In 13 of 18 cases (72%) with bloodstream yeast infections, previous azole exposure was recorded. Candida parapsilosis, C. glabrata, and C. albicans isolates were resistant to voriconazole and fluconazole. Conclusion BSIs that occur during febrile neutropenic episodes in hematology patients due to Gram-negative bacteria should be treated initially with non-carbapenem-based antipseudomonal therapy taking into consideration antimicrobial stewardship. Non-azole antifungal drugs, including caspofungin and liposomal amphotericin B, should be preferred as empirical antifungal therapy in the events of possible

  10. Hematological Toxicity After Robotic Stereotactic Body Radiosurgery for Treatment of Metastatic Gynecologic Malignancies

    SciTech Connect

    Kunos, Charles A.; Debernardo, Robert; Radivoyevitch, Tomas; Fabien, Jeffrey; Dobbins, Donald C.; Zhang Yuxia; Brindle, James

    2012-09-01

    Purpose: To evaluate hematological toxicity after robotic stereotactic body radiosurgery (SBRT) for treatment of women with metastatic abdominopelvic gynecologic malignancies. Methods and Materials: A total of 61 women with stage IV gynecologic malignancies treated with abdominopelvic SBRT were analyzed after ablative radiation (2400 cGy/3 divided consecutive daily doses) delivered by a robotic-armed Cyberknife SBRT system. Abdominopelvic bone marrow was identified using computed tomography-guided contouring. Fatigue and hematologic toxicities were graded by retrospective assignment of common toxicity criteria for adverse events (version 4.0). Bone marrow volume receiving 1000 cGy (V10) was tested for association with post-therapy (median 32 days [25%-75% quartile, 28-45 days]) white- or red-cell counts, hemoglobin levels, and platelet counts as marrow toxicity surrogates. Results: In all, 61 women undergoing abdominopelvic SBRT had a median bone marrow V10 of 2% (25%-75% quartile: 0%-8%). Fifty-seven (93%) of 61 women had received at least 1 pre-SBRT marrow-taxing chemotherapy regimen for metastatic disease. Bone marrow V10 did not associate with hematological adverse events. In all, 15 grade 2 (25%) and 2 grade 3 (3%) fatigue symptoms were self-reported among the 61 women within the first 10 days post-therapy, with fatigue resolved spontaneously in all 17 women by 30 days post-therapy. Neutropenia was not observed. Three (5%) women had a grade 1 drop in hemoglobin level to <10.0 g/dL. Single grade 1, 2, and 3 thrombocytopenias were documented in 3 women. Conclusions: Abdominopelvic SBRT provided ablative radiation dose to cancer targets without increased bone marrow toxicity. Abdominopelvic SBRT for metastatic gynecologic malignancies warrants further study.

  11. Prediction of Clinical Deterioration in Hospitalized Adult Patients with Hematologic Malignancies Using a Neural Network Model

    PubMed Central

    Hu, Scott B.; Wong, Deborah J. L.; Correa, Aditi; Li, Ning; Deng, Jane C.

    2016-01-01

    Introduction Clinical deterioration (ICU transfer and cardiac arrest) occurs during approximately 5–10% of hospital admissions. Existing prediction models have a high false positive rate, leading to multiple false alarms and alarm fatigue. We used routine vital signs and laboratory values obtained from the electronic medical record (EMR) along with a machine learning algorithm called a neural network to develop a prediction model that would increase the predictive accuracy and decrease false alarm rates. Design Retrospective cohort study. Setting The hematologic malignancy unit in an academic medical center in the United States. Patient Population Adult patients admitted to the hematologic malignancy unit from 2009 to 2010. Intervention None. Measurements and Main Results Vital signs and laboratory values were obtained from the electronic medical record system and then used as predictors (features). A neural network was used to build a model to predict clinical deterioration events (ICU transfer and cardiac arrest). The performance of the neural network model was compared to the VitalPac Early Warning Score (ViEWS). Five hundred sixty five consecutive total admissions were available with 43 admissions resulting in clinical deterioration. Using simulation, the neural network outperformed the ViEWS model with a positive predictive value of 82% compared to 24%, respectively. Conclusion We developed and tested a neural network-based prediction model for clinical deterioration in patients hospitalized in the hematologic malignancy unit. Our neural network model outperformed an existing model, substantially increasing the positive predictive value, allowing the clinician to be confident in the alarm raised. This system can be readily implemented in a real-time fashion in existing EMR systems. PMID:27532679

  12. Fertility-Preserving Treatment Options in Patients with Malignant Hematological Diseases

    PubMed Central

    Küçük, Mert; Bolaman, Ali Zahit; Yavaşoğlu, İrfan; Kadıköylü, Gürhan

    2012-01-01

    The number of patients of reproductive age diagnosed with various malignant hematological diseases increases every year. These patients undergo chemotherapy, radiotherapy, and various other treatments that may have gonadotoxic effects. The life expectancy of these patients is increasing rapidly due to the variety of treatment options. As such, an increasing number of patients—as well as their parents and spouses—express their concerns about the patient’s fertility post treatment. In the present review it was aimed to provide an overview of current fertility-preserving treatment options and the future of fertility preservation. PMID:24744663

  13. Diagnostic methods for invasive fungal diseases in patients with hematologic malignancies

    PubMed Central

    Riwes, Mary Mansour; Wingard, John R

    2013-01-01

    Invasive fungal disease is associated with increased morbidity and mortality in hematologic malignancy patients and hematopoietic stem cell transplant recipients. Timely recognition and treatment of invasive fungal diseases in these patients are essential and decrease mortality. However, conventional definitive diagnostic methods are difficult and time consuming. While conventional microbiological and histopathological methods are still needed for a definitive diagnosis of invasive fungal disease, new noninvasive diagnostic methods including serologic and molecular biomarkers are now available. These new diagnostic methods facilitate an early diagnosis of invasive fungal disease and allow for utilization of a pre-emptive treatment approach, which may ultimately lead to improved treatment outcomes and reduced toxicity. PMID:23216596

  14. Emerging therapeutic paradigms to target the dysregulated JAK/STAT pathways in hematological malignancies

    PubMed Central

    Mughal, Tariq I.; Girnius, Saulius; Rosen, Steven T.; Kumar, Shaji; Wiestner, Adrian; Abdel-Wahab, Omar; Kiladjian, Jean-Jacques; Wilson, Wyndham H.; Van Etten, Richard A.

    2014-01-01

    Over the past decade, there has been increasing biochemical evidence that the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is aberrantly activated in malignant cells from patients with a wide spectrum of cancers of the blood and immune systems. The emerging availability of small molecule inhibitors of JAK kinases and other signaling molecules in the JAK-STAT pathway has allowed preclinical studies validating an important role of this pathway in the pathogenesis of many hematologic malignancies, and provided motivation for new strategies for treatment of these diseases. Here, a roundtable panel of experts reviews the current preclinical and clinical landscape of the JAK-STAT pathway in acute lymphoid and myeloid leukemias, lymphomas and myeloma, and chronic myeloid neoplasms. PMID:24206094

  15. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date.

    PubMed

    Park, Jae H; Geyer, Mark B; Brentjens, Renier J

    2016-06-30

    Adoptive transfer of T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 has produced impressive results in treating patients with B-cell malignancies. Although these CAR-modified T cells target the same antigen, the designs of CARs vary as well as several key aspects of the clinical trials in which these CARs have been studied. It is unclear whether these differences have any impact on clinical outcome and treatment-related toxicities. Herein, we review clinical results reflecting the investigational use of CD19-targeted CAR T-cell therapeutics in patients with B-cell hematologic malignancies, in light of differences in CAR design and production, and outline the limitations inherent in comparing outcomes between studies. PMID:27207800

  16. Limited miR-17-92 overexpression drives hematologic malignancies.

    PubMed

    Danielson, Laura S; Reavie, Linsey; Coussens, Marc; Davalos, Veronica; Castillo-Martin, Mireia; Guijarro, Maria V; Coffre, Maryaline; Cordon-Cardo, Carlos; Aifantis, Iannis; Ibrahim, Sherif; Liu, Cynthia; Koralov, Sergei B; Hernando, Eva

    2015-03-01

    The overexpression of microRNA cluster miR-17-92 has been implicated in development of solid tumors and hematological malignancies. The role of miR-17-92 in lymphomagenesis has been extensively investigated; however, because of the developmental defects caused by miR-17-92 dysregulation, its ability to drive tumorigenesis has remained undetermined until recently. Here we demonstrate that overexpression of miR-17-92 in a limited number of hematopoietic cells is sufficient to cause B cell malignancies. In sum, our study provides a novel and physiologically relevant model that exposes the potent ability of miR-17-92 to act as a driver of tumorigenesis. PMID:25597017

  17. [Research Progress on Co-stimulating Molecule B7-H3 in Hematological Malignancies].

    PubMed

    Zhang, Wei; Wang, Jing; Ke, Xiao-Yan

    2015-12-01

    Costimulatory molecule B7-H3 is a new member of the B7 immunoregulatory family identified in 2001. Although B7-H3 mRNA is widely detected in a variety of lymphoid and nonlymphoid organs, but the B7-H3 protein is distributed limitedly, generally absent or low expressed in normal tissues. The triggering receptor expressed on myeloid cell (TREM)-like transcript 2 (TLT-2) is a possible receptor for B7-H3, but it is not confirmed. B7-H3 has an important immunologic function having costimulatory or coinhibitory immunoregulatory effects in adaptive immune responses, but its exact mechanism remains contentious. The recent studies reported that aberrant overexpression of B7-H3 was found in a wide range of solid cancer tissues and cells, and associated with more advanced disease and poor prognosis, and directly performed nonimmunological functions in oncogenesis. However, more and more studies demonstrate that B7-H3 also plays an important role in progression of hematologic malignancies. The overexpression of B7-H3 is significantly associated with the malignant degree, relapse, progression and prognosis in haematological malignancies. Thus, B7-H3 represents a novel diagnostic marker and potential therapeutic target for cancers. The immunotherapy targeting to B7-H3 become one of the hotspots of recent researches, and some monoclonal antibodies have already entered into clinical trials. This review summarizes the available data on the relationship between B7-H3 and hematologic malignancies, and further focusing on B7-H3 as a potential therapeutic target in these tumors. PMID:26708906

  18. Mold colonization of fiberglass insulation of the air distribution system: effects on patients with hematological malignancies.

    PubMed

    Takuma, Takahiro; Okada, Kaoru; Yamagata, Akihiro; Shimono, Nobuyuki; Niki, Yoshihito

    2011-02-01

    We investigated mold colonization of air handling units (AHUs) of heating, ventilating, and air conditioning (HVAC) systems and its effects, including invasive pulmonary mycoses and febrile neutropenia, in patients with hematological malignancies. Sample collection with transparent adhesive tape and culture swabs revealed that AHUs were heavily colonized with molds, including thermotolerant, variously distributed Penicillium spp. Cases of nosocomial invasive pulmonary mycosis were not clustered in specific patient rooms but did occur frequently when the HVAC systems were not in use, prior to intervention (i.e., sealing and disuse of AHUs in private room), and during construction of a new hospital building. Multivariate logistic regression analysis of initial episodes of febrile neutropenia showed that the rate of febrile neutropenia was significantly associated with the duration of neutropenia (odds ratio [OR]: 1.16; 95% confidence interval [CI]: 1.07-1.27) and with sex (OR: 0.469; CI: 0.239-0.902). An evaluation of private rooms showed that female patients also had a lower rate of fever after intervention (OR: 0.0016; 95% CI: 0.000-0.209). The reduced rate of febrile neutropenia after intervention suggests that mold colonization of AHUs had adverse effects on patients with hematological malignancies. PMID:20807030

  19. Abdominal ultrasound findings mimicking hematological malignancies in a study of 218 Gaucher patients.

    PubMed

    Neudorfer, O; Hadas-Halpern, I; Elstein, D; Abrahamov, A; Zimran, A

    1997-05-01

    Gaucher disease, the most prevalent sphingolipidosis, generally presents with splenomegaly, anemia, and thrombocytopenia. Hence, hematologists are often the specialists involved in diagnosis and management of these patients. We present ultrasonographic characteristics in a cohort of 218 consecutive Gaucher patients evaluated in our clinic during the past 5 years. Our data emphasize the high prevalence of lesions mimicking hematological malignancies in Gaucher disease. One fifth of 184 non-splenectomized patients had intra-splenic lesions, 6% of all patients had similar lesions in the liver, and 32% of 34 splenectomized patients (but none of the other patients) had marked retroperitoneal or peri-portal lymphadenopathy. The presence of splenic lesions correlated with age and splenic size, but not with extent of bone involvement or genotype. Interestingly, they were not affected by reduction in splenomegaly following enzyme replacement therapy. The importance of these findings is to include Gaucher disease in the differential diagnosis of splenic or hepatic lesions, especially in Ashkenazi Jews. Conversely, they are relevant for follow-up of all Gaucher patients, including asymptomatic individuals, because of the reported increased incidence of hematological malignancies in Gaucher disease. PMID:9136914

  20. When and why should patients with hematologic malignancies see a palliative care specialist?

    PubMed

    LeBlanc, Thomas W; El-Jawahri, Areej

    2015-01-01

    Palliative care is a multidisciplinary approach to symptom management, psychosocial support, and assistance in treatment decision-making for patients with serious illness and their families. It emphasizes well-being at any point along the disease trajectory, regardless of prognosis. The term "palliative care" is often incorrectly used as a synonym for end-of-life care, or "hospice care". However, palliative care does not require a terminal diagnosis or proximity to death, a misconception that we will address in this article. Multiple randomized clinical trials demonstrate the many benefits of early integration of palliative care for patients with cancer, including reductions in symptom burden, improvements in quality-of-life, mood, and overall survival, as well as improved caregiver outcomes. Thus, early concurrent palliative care integrated with cancer-directed care has emerged as a standard-of-care practice for patients with cancer. However, patients with hematologic malignancies rarely utilize palliative care services, despite their many unmet palliative care needs, and are much less likely to use palliative care compared to patients with solid tumors. In this article, we will define "palliative care" and address some common misconceptions regarding its role as part of high-quality care for patients with cancer. We will then review the evidence supporting the integration of palliative care into comprehensive cancer care, discuss perceived barriers to palliative care in hematologic malignancies, and suggest opportunities and triggers for earlier and more frequent palliative care referral in this population. PMID:26637760

  1. Effector Functions of Natural Killer Cell Subsets in the Control of Hematological Malignancies

    PubMed Central

    Gismondi, Angela; Stabile, Helena; Nisti, Paolo; Santoni, Angela

    2015-01-01

    Treatment of hematological malignant disorders has been improved over the last years, but high relapse rate mainly attributable to the presence of minimal residual disease still persists. Therefore, it is of great interest to explore novel therapeutic strategies to obtain long-term remission. Immune effector cells, and especially natural killer (NK) cells, play a crucial role in the control of hematological malignancies. In this regard, the efficiency of allogeneic stem cell transplantation clearly depends on the immune-mediated graft versus leukemia effect without the risk of inducing graft versus host disease. Alloreactive donor NK cells generated following hematopoietic stem cell transplantation ameliorate the outcome of leukemia patients; in addition, in vivo transfer of in vitro expanded NK cells represents a crucial tool for leukemia treatment. To improve NK cell effector functions against resistant leukemia cells, novel immunotherapeutic strategies are oriented to the identification, isolation, expansion, and administration of particular NK cell subsets endowed with multifunctional anti-tumor potential and tropism toward tumor sites. Moreover, the relationship between the emergence and persistence of distinct NK cell subsets during post-graft reconstitution and the maintenance of a remission state is still rather unclear. PMID:26594216

  2. Recombinant Immunotoxins Containing Truncated Bacterial Toxins for the Treatment of Hematologic Malignancies

    PubMed Central

    Kreitman, Robert J.

    2009-01-01

    Immunotoxins are molecules that contain a protein toxin and a ligand that is either an antibody or a growth factor. The ligand binds to a target cell antigen, and the target cell internalizes the immunotoxin, allowing the toxin to migrate to the cytoplasm where it can kill the cell. In the case of recombinant immunotoxins, the ligand and toxin are encoded in DNA that is then expressed in bacteria, and the purified immunotoxin contains the ligand and toxin fused together. Among the most active recombinant immunotoxins clinically tested are those that are targeted to hematologic malignancies. One agent, containing human interleukin-2 and truncated diphtheria toxin (denileukin diftitox), has been approved for use in cutaneous T-cell lymphoma, and has shown activity in other hematologic malignancies, including leukemias and lymphomas. Diphtheria toxin has also been targeted by other ligands, including granulocyte-macrophage colony-stimulating factor and interleukin-3, to target myelogenous leukemia cells. Single-chain antibodies containing variable heavy and light antibody domains have been fused to truncated Pseudomonas exotoxin to target lymphomas and lymphocytic leukemias. Recombinant immunotoxins anti-Tac(Fv)-PE38 (LMB-2), targeting CD25, and RFB4(dsFv)-PE38 (BL22, CAT-3888), targeting CD22, have each been tested in patients. Major responses have been observed after failure of standard chemotherapy. The most successful application of recombinant immunotoxins today is in hairy cell leukemia, where BL22 has induced complete remissions in most patients who were previously treated with optimal chemotherapy. PMID:19344187

  3. Chimeric T-cell receptors: new challenges for targeted immunotherapy in hematologic malignancies.

    PubMed

    Biagi, Ettore; Marin, Virna; Giordano Attianese, Greta Maria Paola; Dander, Erica; D'Amico, Giovanna; Biondi, Andrea

    2007-03-01

    Chimeric T-cell receptors (ChTCR), are a fascinating technological step in the field of immunotherapy for orienting the activity of immune cells towards specific molecular targets expressed on the cell surface of various tumors, including hematologic malignancies. The main characteristics of ChTCR are their ability to redirect T-cell specificity and their killing/effector activity toward a selected target in a non MHC-restricted manner, exploiting the antigen binding properties of monoclonal antibodies. ChTCR are, in fact, artificial T-cell receptors constituted by an antigen-recognizing antibody molecule linked to a T-cell triggering domain. Various hematologic malignancies represent optimal targets for the exploitation of ChTCR, because of the bright expression of specific antigens on the surface of tumor cells. Thus, CD19 and CD20 have been targeted for B-cell lymphoid tumors (acute lymphoblastic leukemia-ALL, lymphomas and chronic lymphocytic leukemia-CLL), CD33 for myeloid leukemia, and CD30 for lymphomas. Even though technical and safety progresses are still needed to improve the profile of gene transfer and protein expression of ChTCR, phase 1 trials will be carried out in the near future to demonstrate the feasibility of their clinical translation and, it is be hoped, give preliminary indications about their anti-tumor efficacy. PMID:17339188

  4. Evaluation of the risk factors for febrile neutropenia associated with hematological malignancy.

    PubMed

    Nakagawa, Yasunori; Suzuki, Kenshi; Masaoka, Toru

    2009-06-01

    Febrile neutropenia (FN) can frequently become a very serious problem. In 2002, Klastersky and colleagues established the Multinational Association for Supportive Care in Cancer (MASCC) score, which consisted of risk factors for conditions that included solid tumors. However, hematopoietic tumors, in comparison to solid tumors, are plagued by such problems as the quantity and quality of abnormalities associated with leukocytes and neutrophils and the requirement for higher dosages of both radio- and chemotherapy. FN is a complication associated with hematological malignancies that can lead to a fatal outcome, but it is avoidable if the appropriate preventive treatment is performed at an early stage. The subjects of the present study consisted of 354 patients with hematopoietic malignancies who were treated at the Japanese Red Cross Medical Center Hospital, Tokyo, between August 2000 and September 2004. They were retrospectively evaluated for the risk factors of FN by applying Wilcoxon's rank sum test. A scoring index was defined and the patients were classified into high- and low-risk groups before evaluation. The following nine risk factors, which may significantly influence the relationship between the time required for defervescence and the duration of neutropenia - age; hematological diseases; the leukocyte count during the febrile period; the reduction in leukocyte count per day before the onset of FN; the prophylactic administration of antimycotic agents; sterilization of the intestinal tract; and urine albumin content, creatine level, and C-reactive protein (CRP) level - were expressed in points and their sum was termed risk points. The range of risk points was classified as 0-3 and 4-9. The time required for defervescence was 5.1 days when the risk points were in the range of 0-3 and 8.1 days when the points were in the range of 4-9. These figures were distributed normally and there was a significant difference between the two groups (P = 0.0016). FN

  5. Liquid biopsies for liquid tumors: emerging potential of circulating free nucleic acid evaluation for the management of hematologic malignancies

    PubMed Central

    Hocking, Jay; Mithraprabhu, Sridurga; Kalff, Anna; Spencer, Andrew

    2016-01-01

    Circulating free nucleic acids; cell free DNA and circulating micro-RNA, are found in the plasma of patients with hematologic and solid malignancies at levels higher than that of healthy individuals. In patients with hematologic malignancy cell free DNA reflects the underlying tumor mutational profile, whilst micro-RNAs reflect genetic interference mechanisms within a tumor and potentially the surrounding microenvironment and immune effector cells. These circulating nucleic acids offer a potentially simple, non-invasive, repeatable analysis that can aid in diagnosis, prognosis and therapeutic decisions in cancer treatment. PMID:27458529

  6. A retrospective examination of mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study

    PubMed Central

    BLACKBURN, NICHOLAS B.; CHARLESWORTH, JAC C.; MARTHICK, JAMES R.; TEGG, ELIZABETH M.; MARSDEN, KATHERINE A.; SRIKANTH, VELANDAI; BLANGERO, JOHN; LOWENTHAL, RAY M.; FOOTE, SIMON J.; DICKINSON, JOANNE L.

    2015-01-01

    Telomere length has a biological link to cancer, with excessive telomere shortening leading to genetic instability and resultant malignant transformation. Telomere length is heritable and genetic variants determining telomere length have been identified. Telomere biology has been implicated in the development of hematological malignancies (HMs), therefore, closer examination of telomere length in HMs may provide further insight into genetic etiology of disease development and support for telomere length as a prognostic factor in HMs. We retrospectively examined mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study using a quantitative PCR method on genomic DNA from peripheral blood samples. Fifty-five familial HM cases, 191 unaffected relatives of familial HM cases and 75 non-familial HM cases were compared with 758 population controls. Variance components modeling was employed to identify factors influencing variation in telomere length. Overall, HM cases had shorter mean relative telomere length (P=2.9×10−6) and this was observed across both familial and non-familial HM cases (P=2.2×10−4 and 2.2×10−5, respectively) as well as additional subgroupings of HM cases according to broad subtypes. Mean relative telomere length was also significantly heritable (62.6%; P=4.7×10−5) in the HM families in the present study. We present new evidence of significantly shorter mean relative telomere length in both familial and non-familial HM cases from the same population adding further support to the potential use of telomere length as a prognostic factor in HMs. Whether telomere shortening is the cause of or the result of HMs is yet to be determined, but as telomere length was found to be highly heritable in our HM families this suggests that genetics driving the variation in telomere length is related to HM disease risk. PMID:25351806

  7. Diagnosed hematological malignancies in Bangladesh - a retrospective analysis of over 5000 cases from 10 specialized hospitals

    PubMed Central

    2014-01-01

    Background The global burden from cancer is rising, especially as low-income countries like Bangladesh observe rapid aging. So far, there are no comprehensive descriptions reporting diagnosed cancer group that include hematological malignancies in Bangladesh. Methods This was a multi-center hospital-based retrospective descriptive study of over 5000 confirmed hematological cancer cases in between January 2008 to December 2012. Morphological typing was carried out using the “French American British” classification system. Results A total of 5013 patients aged between 2 to 90 years had been diagnosed with malignant hematological disorders. A 69.2% were males (n = 3468) and 30.8% females (n = 1545), with a male to female ratio of 2.2:1. The overall median age at diagnosis was 42 years. Acute myeloid leukemia was most frequent (28.3%) with a median age of 35 years, followed by chronic myeloid leukemia with 18.2% (median age 40 years), non-Hodgkin lymphoma (16.9%; median age 48 years), acute lymphoblastic leukemia (14.1%; median age 27 years), multiple myeloma (10.5%; median age 55 years), myelodysplastic syndromes (4.5%; median age 57 years) and Hodgkin’s lymphoma (3.9%; median age 36 years). The least common was chronic lymphocytic leukemia (3.7%; median age 60 years). Below the age of 20 years, acute lymphoblastic leukemia was predominant (37.3%), followed by acute myeloid leukemia (34%). Chronic lymphocytic leukemia and multiple myeloma had mostly occurred among older patients, aged 50-over. Conclusions For the first time, our study presents the pattern and distribution of diagnosed hematological cancers in Bangladesh. It shows differences in population distributions as compared to other settings with possibly a lower presence of non-Hodgkin lymphoma. There might be under-reporting of affected women. Further studies are necessary on the epidemiology, genetics and potential environmental risk factors within this rapidly aging country. PMID

  8. Challenges in the Role of Gammaglobulin Replacement Therapy and Vaccination Strategies for Hematological Malignancy

    PubMed Central

    Sánchez-Ramón, Silvia; Dhalla, Fatima; Chapel, Helen

    2016-01-01

    Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are prone to present with antibody production deficits associated with recurrent or severe bacterial infections that might benefit from human immunoglobulin (Ig) (IVIg/SCIg) replacement therapy. However, the original IVIg trial data were done before modern therapies were available, and the current indications do not take into account the shift in the immune situation of current treatment combinations and changes in the spectrum of infections. Besides, patients affected by other B cell malignancies present with similar immunodeficiency and manifestations while they are not covered by the current IVIg indications. A potential beneficial strategy could be to vaccinate patients at monoclonal B lymphocytosis and monoclonal gammopathy of undetermined significance stages (for CLL and MM, respectively) or at B-cell malignancy diagnosis, when better antibody responses are attained. We have to re-emphasize the need for assessing and monitoring specific antibody responses; these are warranted to select adequately those patients for whom early intervention with prophylactic anti-infective therapy and/or IVIg is preferred. This review provides an overview of the current scenario, with a focus on prevention of infection in patients with hematological malignancies and the role of Ig replacement therapy. PMID:27597852

  9. Challenges in the Role of Gammaglobulin Replacement Therapy and Vaccination Strategies for Hematological Malignancy.

    PubMed

    Sánchez-Ramón, Silvia; Dhalla, Fatima; Chapel, Helen

    2016-01-01

    Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are prone to present with antibody production deficits associated with recurrent or severe bacterial infections that might benefit from human immunoglobulin (Ig) (IVIg/SCIg) replacement therapy. However, the original IVIg trial data were done before modern therapies were available, and the current indications do not take into account the shift in the immune situation of current treatment combinations and changes in the spectrum of infections. Besides, patients affected by other B cell malignancies present with similar immunodeficiency and manifestations while they are not covered by the current IVIg indications. A potential beneficial strategy could be to vaccinate patients at monoclonal B lymphocytosis and monoclonal gammopathy of undetermined significance stages (for CLL and MM, respectively) or at B-cell malignancy diagnosis, when better antibody responses are attained. We have to re-emphasize the need for assessing and monitoring specific antibody responses; these are warranted to select adequately those patients for whom early intervention with prophylactic anti-infective therapy and/or IVIg is preferred. This review provides an overview of the current scenario, with a focus on prevention of infection in patients with hematological malignancies and the role of Ig replacement therapy. PMID:27597852

  10. Targeting protein-protein interactions in hematologic malignancies: still a challenge or a great opportunity for future therapies?

    PubMed Central

    Cierpicki, Tomasz; Grembecka, Jolanta

    2015-01-01

    Summary Over the past several years, there has been an increasing research effort focused on inhibition of protein-protein interactions (PPIs) to develop novel therapeutic approaches for cancer, including hematologic malignancies. These efforts have led to development of small molecule inhibitors of PPIs, some of which already advanced to the stage of clinical trials while others are at different stages of pre-clinical optimization, emphasizing PPIs as an emerging and attractive class of drug targets. Here, we review several examples of recently developed inhibitors of protein-protein interactions highly relevant to hematologic cancers. We address the existing skepticism about feasibility of targeting PPIs and emphasize potential therapeutic benefit from blocking PPIs in hematologic malignancies. We then use these examples to discuss the approaches for successful identification of PPI inhibitors and provide analysis of the protein-protein interfaces, with the goal to address ‘druggability’ of new PPIs relevant to hematology. We discuss lessons learned to improve the success of targeting new protein-protein interactions and evaluate prospects and limits of the research in this field. We conclude that not all PPIs are equally tractable for blocking by small molecules, and detailed analysis of PPI interfaces is critical for selection of those with the highest chance of success. Together, our analysis uncovers patterns that should help to advance drug discovery in hematologic malignancies by successful targeting of new protein-protein interactions. PMID:25510283

  11. Cytochrome P450 2J2 Is Highly Expressed in Hematologic Malignant Diseases and Promotes Tumor Cell GrowthS⃞

    PubMed Central

    Chen, Chen; Wei, Xin; Rao, Xiaoquan; Wu, Jun; Yang, Shenglan; Chen, Fuqiong; Ma, Ding; Zhou, Jianfeng; Dackor, Ryan T.; Zeldin, Darryl C.

    2011-01-01

    Cytochrome P450 2J2 (CYP2J2) epoxygenase converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs) that exert multiple biological effects in the cardiovascular system and in various human solid cancers. However, it is unknown whether this enzyme is expressed or plays any role in malignant hematological diseases. In this study, we found strong and highly selective CYP2J2 expression in five human-derived malignant hematological cell lines and in leukemia cells from peripheral blood and bone marrow in 36 of 42 patients (86%) with malignant hematologic diseases. Furthermore, increased levels of EETs were detected in urine and blood samples from these patients. Addition of exogenous EET or CYP2J2 overexpression in cultured human-derived malignant hematologic cell lines markedly accelerated proliferation and attenuated apoptosis. Addition of the selective CYP2J2 inhibitor compound 26 (C26; 1-[4-(vinyl) phenyl]-4-[4-(diphenyl-hydroxymethyl)-piperidinyl]-butanone hydrochloride) inhibited cell proliferation and increased apoptosis, an effect that was significantly reversed by EET. CYP2J2 overexpression and exogenous EET activated AMP-activated protein kinase, c-Jun NH2-terminal kinase, and phosphatidylinositol 3-kinase/Akt signaling pathways, and increased epidermal growth factor receptor phosphorylation levels. CYP2J2 overexpression also enhanced malignant xenograft growth, which was efficiently inhibited by oral administration of C26 in Tie2-CYP2J2 transgenic mice and in severe combined immunodeficiency (SCID) xenograft mice. Together, these results suggest that CYP2J2 plays a key role in the pathogenesis of human hematologic malignant diseases. Selective inhibition of CYP2J2 may be a promising therapeutic strategy for these conditions. PMID:21030485

  12. A novel antibody–drug conjugate targeting SAIL for the treatment of hematologic malignancies

    PubMed Central

    Kim, S Y; Theunissen, J-W; Balibalos, J; Liao-Chan, S; Babcock, M C; Wong, T; Cairns, B; Gonzalez, D; van der Horst, E H; Perez, M; Levashova, Z; Chinn, L; D‘Alessio, J A; Flory, M; Bermudez, A; Jackson, D Y; Ha, E; Monteon, J; Bruhns, M F; Chen, G; Migone, T-S

    2015-01-01

    Although several new therapeutic approaches have improved outcomes in the treatment of hematologic malignancies, unmet need persists in acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin's lymphoma. Here we describe the proteomic identification of a novel cancer target, SAIL (Surface Antigen In Leukemia), whose expression is observed in AML, MM, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). While SAIL is widely expressed in CLL, AML, MM, DLBCL and FL patient samples, expression in cancer cell lines is mostly limited to cells of AML origin. We evaluated the antitumor activity of anti-SAIL monoclonal antibodies, 7-1C and 67-7A, conjugated to monomethyl auristatin F. Following internalization, anti-SAIL antibody–drug conjugates (ADCs) exhibited subnanomolar IC50 values against AML cell lines in vitro. In pharmacology studies employing AML cell line xenografts, anti-SAIL ADCs resulted in significant tumor growth inhibition. The restricted expression profile of this target in normal tissues, the high prevalence in different types of hematologic cancers and the observed preclinical activity support the clinical development of SAIL-targeted ADCs. PMID:26024286

  13. New strategies of DLI in the management of relapse of hematological malignancies after allogeneic hematopoietic SCT.

    PubMed

    Chang, X; Zang, X; Xia, C-Q

    2016-03-01

    DLI is an effective strategy for patients with recurrent hematological malignancies after allogeneic hematopoietic SCT (allo-HSCT). DLI has been widely applied to boost the graft vs tumor (GVT) or GVL effects. However, given the potentially severe complications associated with conventional DLI and transient GVL effect, new strategies for DLI are emerging. In this review, we have discussed the recent important studies on DLI as a prophylactic or therapeutic modality for relapsed hematological disorders after allo-HSCT. The strategies to separate GVL from GVHD have also been discussed. Leukemia-targeting therapy and lymphodepletion combined with DLI, and prophylactic DLI after allo-HSCT are often employed for patients with high risk of relapse, which has been reviewed as well. In addition, we have also discussed the issues on DLI to be further addressed, such as the doses, timing and frequency of DLI in different clinical settings, leukemic antigen-specific DLI as well as how to augment GVL effect while attenuating GVHD. PMID:26595077

  14. Emerging therapies targeting tumor vasculature in multiple myeloma and other hematologic and solid malignancies.

    PubMed

    Podar, K; Anderson, K C

    2011-11-01

    Research on the formation of new blood vessels (angiogenesis) in general and vascular endothelial growth factor (VEGF) in particular is a major focus in biomedicine and has led to the clinical approval of the monoclonal anti- VEGF antibody bevazicumab; and the second-generation multitargeted receptor kinase inhibitors (RTKIs) sorafenib, sunitinib, and pazopanib. Although these agents show significant preclinical and clinical anti-cancer activity, they prolong overall survival of cancer patients for only months, followed by a restoration of tumor growth and progression. Therefore, there is a clear need to increase our understanding of tumor angiogenesis and the development of resistance. In this review we discuss up-to-date knowledge on mechanisms of tumor angiogenesis, and summarize preclinical and clinical data on existing and potential future anti-angiogenic agents and treatment strategies for Multiple Myeloma (MM) and other hematologic and solid malignancies. PMID:21933109

  15. Coping Styles, Health Status and Advance Care Planning in Patients with Hematologic Malignancies

    PubMed Central

    Loberiza, Fausto R; Swore-Flecther, Barbara A.; Block, Susan D.; Back, Anthony L.; Goldman, Roberta E.; Tulsky, James A.; Lee, Stephanie J.

    2014-01-01

    This study evaluated if measures of psychological well-being, including coping style are associated with advance care planning (ACP). Data were from the HEMA-COMM study, a prospective observational study of physician-patient communication in patients with hematologic malignancies. ACP was defined as having a living will, having a health care proxy, discussing life support with family or friends, and discussing life support with a doctor or nurse. 293 patients participated: only 45 (15%) had all the elements of ACP, 215 (73%) had at least 1 element of ACP, while 33 (11%) did not engage in ACP. In multivariate analysis, specific coping styles but not other measures of psychosocial well being were associated with having written ACP. Verbal ACP was associated with patient-reported health and physician estimate of life expectancy. Our study suggests that tailoring ACP discussions to a patient’s coping style may increase engagement in ACP. PMID:21851220

  16. Discovery of selective phosphatidylinositol 3-kinase inhibitors to treat hematological malignancies.

    PubMed

    Zhu, Jingyu; Hou, Tingjun; Mao, Xinliang

    2015-08-01

    The phosphatidylinositol 3-kinase (PI3K) signaling pathway is associated with chemoresistance and poor prognosis of many cancers, including hematological malignancies (HM), such as leukemia, lymphomas, and multiple myeloma (MM). Targeting PI3K is emerging as a promising strategy in the treatment of these blood cancers. Recent approval of idelalisib, a specific inhibitor of PI3Kδ, for the treatment of several types of HM, is likely to attract more interest in search for novel PI3K inhibitors. Here, we discuss classic and cutting-edge techniques and strategies to identify PI3K inhibitors for the treatment of HM. Each technique has its own strengths and limitations, and their combined application will accelerate the drug discovery process with fewer associated costs. PMID:25857437

  17. Advances in haplo-identical stem cell transplantation in adults with high-risk hematological malignancies

    PubMed Central

    Ricci, Michael J; Medin, Jeffrey A; Foley, Ronan S

    2014-01-01

    Allogeneic bone marrow transplant is a life-saving procedure for adults and children that have high-risk or relapsed hematological malignancies. Incremental advances in the procedure, as well as expanded sources of donor hematopoietic cell grafts have significantly improved overall rates of success. Yet, the outcomes for patients for whom suitable donors cannot be found remain a significant limitation. These patients may benefit from a hematopoietic cell transplant wherein a relative donor is fully haplotype mismatched. Previously this procedure was limited by graft rejection, lethal graft-versus-host disease, and increased treatment-related toxicity. Recent approaches in haplo-identical transplantation have demonstrated significantly improved outcomes. Based on years of incremental pre-clinical research into this unique form of bone marrow transplant, a range of approaches have now been studied in patients in relatively large phase II trials that will be summarized in this review. PMID:25258660

  18. Advances in haplo-identical stem cell transplantation in adults with high-risk hematological malignancies.

    PubMed

    Ricci, Michael J; Medin, Jeffrey A; Foley, Ronan S

    2014-09-26

    Allogeneic bone marrow transplant is a life-saving procedure for adults and children that have high-risk or relapsed hematological malignancies. Incremental advances in the procedure, as well as expanded sources of donor hematopoietic cell grafts have significantly improved overall rates of success. Yet, the outcomes for patients for whom suitable donors cannot be found remain a significant limitation. These patients may benefit from a hematopoietic cell transplant wherein a relative donor is fully haplotype mismatched. Previously this procedure was limited by graft rejection, lethal graft-versus-host disease, and increased treatment-related toxicity. Recent approaches in haplo-identical transplantation have demonstrated significantly improved outcomes. Based on years of incremental pre-clinical research into this unique form of bone marrow transplant, a range of approaches have now been studied in patients in relatively large phase II trials that will be summarized in this review. PMID:25258660

  19. Oral Chemotherapy in Patients with Hematological Malignancies-Care Process, Pharmacoeconomic and Policy Implications.

    PubMed

    Betcher, Jeffrey; Dow, Elizabeth; Khera, Nandita

    2016-08-01

    Patients with hematologic malignancies are increasing being prescribed oral anticancer medications (OAMs) and/or biologics. These newer targeted OAMs are associated with a host of practical and pharmacoeconomic implications for patients and healthcare providers. Issues such as safety, procurement challenges, and the need for proactive involvement of all stakeholders to optimize adherence for successful use of these agents are increasingly being recognized. The current reactive model is negatively impacting the patient experience through delays in care, financial toxicity, and decreased safety. It also impacts the healthcare providers in the form of lost revenue and staff burnout due to labor-intensive procurement and patient financial assistance burdens. In this review, we describe some of the issues identified and discuss potential strategies to improve patient access, minimize healthcare burden, and review current policy initiatives and patient advocacy efforts to reduce financial toxicity. PMID:27086140

  20. Mortality in Hematologic Malignancy and Hematopoietic Stem Cell Transplant Patients with Mucormycosis, 2001 to 2009▿

    PubMed Central

    Hammond, Sarah P.; Baden, Lindsey R.; Marty, Francisco M.

    2011-01-01

    Mortality due to mucormycosis is high. We assessed clinical characteristics and mortality among stem cell transplant and hematologic malignancy patients diagnosed with mucormycosis from 2001 to 2009. Thirty patients were diagnosed with probable or proven mucormycosis during the study. Twenty-six were diagnosed premortem, and most were treated with liposomal amphotericin B single-agent antifungal therapy initially. While the initial antifungal and surgical treatment approach remained stable throughout the study period, 6-week mortality significantly declined over time (67% in 2001 to 2003 versus 45% in 2004 to 2006 versus 20% in 2007 to 2009 [P = 0.04]), as did 12-week mortality (78% in 2001 to 2003 versus 55% in 2004 to 2006 versus 20% in 2007 to 2009 [P = 0.01]). PMID:21876046

  1. Pulmonary complications in survivors of childhood hematological malignancies: single-center experience.

    PubMed

    Tantawy, Azza Abdel Gawad; Elbarbary, Nancy; Ahmed, Asmaa; Mohamed, Nancy Abdraoaf; Ezz-Elarab, Sahar

    2011-08-01

    Children treated for cancer face the risk of complications later in life, including pulmonary dysfunction. The objective of this study was to evaluate frequency and severity of pulmonary complications in survivors of childhood leukemia and lymphoma treated with chemotherapy alone or combined with radiotherapy. Seventy cancer survivors of hematological malignancies were evaluated for pulmonary complications through history taking, chest examination, high-resolution computed tomography (HRCT) chest, and pulmonary function testing (PFTs). Although most survivors were not clinically compromised, the spectrum of impaired PFTs included obstructive pattern (14.3%), restrictive pattern (5.7%), and mixed pattern (20%). Significant pulmonary dysfunction was seen in children older than 10 years of age (P = .003), and in patients treated with combined chemotherapy and radiotherapy (72.7%) compared with those treated with chemotherapy alone (25%) (P = .001). Cumulative dose of bleomycin was significantly associated with abnormal PFTs (P = .04). Multivariate analysis revealed methotrexate therapy as significant predictor of abnormal PFTs (P = .002). Male patients who received combined therapy showed higher frequency of restrictive, obstructive lung disease, abnormal respiratory reactance, and peripheral airway disease (P = .007, P = .04, P = .002, P = .003, P = .05, respectively). Those with abnormal CT findings (n = 14) had lower forced vital capacity (FVC%), forced expiratory volume in 1 second (FEV(1)%), and peak expiratory flow (PEF%) when compared to cases with normal CT (P = .001, P < 0.001, P = .001, respectively). Subclinical pulmonary function abnormalities are found in survivors of childhood hematological malignancies previously treated and off therapy. Pulmonary dysfunction is more evident with combined chemotherapy and radiotherapy, bleomycin, and methotrexate are the most incriminated chemotherapeutic agents, and males are at higher risk than females; therefore a

  2. Residential radon exposure and risk of incident hematologic malignancies in the Cancer Prevention Study-II Nutrition Cohort.

    PubMed

    Teras, Lauren R; Diver, W Ryan; Turner, Michelle C; Krewski, Daniel; Sahar, Liora; Ward, Elizabeth; Gapstur, Susan M

    2016-07-01

    Dosimetric models show that radon, an established cause of lung cancer, delivers a non-negligible dose of alpha radiation to the bone marrow, as well as to lymphocytes in the tracheobronchial epithelium, and therefore could be related to risk of hematologic cancers. Studies of radon and hematologic cancer risk, however, have produced inconsistent results. To date there is no published prospective, population-based study of residential radon exposure and hematologic malignancy incidence. We used data from the American Cancer Society Cancer Prevention Study-II Nutrition Cohort established in 1992, to examine the association between county-level residential radon exposure and risk of hematologic cancer. The analytic cohort included 140,652 participants (66,572 men, 74,080 women) among which 3019 incident hematologic cancer cases (1711 men, 1308 women) were identified during 19 years of follow-up. Cox proportional hazard regression was used to calculate multivariable-adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for radon exposure and hematologic cancer risk. Women living in counties with the highest mean radon concentrations (>148Bq/m(3)) had a statistically significant higher risk of hematologic cancer compared to those living in counties with the lowest (<74Bq/m(3)) radon levels (HR=1.63, 95% CI:1.23-2.18), and there was evidence of a dose-response relationship (HRcontinuous=1.38, 95% CI:1.15-1.65 per 100Bq/m(3); p-trend=0.001). There was no association between county-level radon and hematologic cancer risk among men. The findings of this large, prospective study suggest residential radon may be a risk factor for lymphoid malignancies among women. Further study is needed to confirm these findings. PMID:27015563

  3. Stem cell transplant as an immunomodulatory tool for children with hematologic malignancies.

    PubMed

    LaBelle, James L; Cunningham, John M

    2013-01-01

    Allogeneic stem cell transplantation (alloHSCT) is the most common and effective form of immunotherapy used for treatment of pediatric leukemias. A combination of graft manipulation, donor selection, fine-tuning of conditioning regimens, and use of lower and novel forms of immunosuppression following transplant has maximized the tolerability of alloHSCT in children. This outcome has facilitated new advances in disease-specific transplant regimens that seek to amplify the antitumor effects of the allograft, while reducing transplant-related mortality. However, disease relapse remains the preeminent challenge to the success of transplantation as a modality for successful treatment of high-risk disease. Separating graft versus host disease (GVHD) from graft versus leukemia (GVL) remains the most significant obstacle to enhancing disease-free survival. However, with increased clarity and discrimination in the effector mechanisms responsible for GVHD and/or GVL in patients of all ages, a new wave of clinical trials has become feasible that harnesses GVL effects to treat patients with high-risk myeloid and lymphoid malignancies. Exciting progress is being made in the use of alloHSCT with donor lymphocyte infusions (DLIs) in almost all forms of pediatric hematologic malignancies. This advance sets the stage for the use of HSCT and/or DLI in conjunction with novel disease-specific post-transplant therapies using small molecule therapeutics, tumor vaccines, and novel antibody therapies. PMID:23714543

  4. [Phase II study of recombinant leukocyte A interferon (Ro 22-8181) in hematological malignancies].

    PubMed

    1985-04-01

    A Phase II study of recombinant leukocyte A interferon (rIFN-alpha A, Ro 22-8181) was performed in 121 patients with hematological malignancies at 33 institutions from July, 1982 to May, 1984. Patients received Ro 22-8181 by intramuscular injection daily for more than 4 weeks. Daily doses were escalated from 3 X 10(6) to 6X, 9X, 18X, 36X and 50X 10(6) units every 3-7 days. Among 70 evaluable cases, complete or partial responses were observed in 15 patients (21.4%). One complete and 10 partial responses (22.4%) were noted in 49 cases of multiple myeloma, 2 partial remissions (18.2%) in 11 cases of malignant lymphoma and 2 partial remissions (25.0%) in 8 cases of leukemia. Side effects included fever (57.0%), anorexia (34.2%), nausea-vomiting (22.8%), malaise (19.0%), leukopenia (44.3%), thrombocytopenia (45.6%) and increase of GOT or GPT (26.6% or 22.8%). They were all not serious and disappeared quickly after the discontinuation of Ro 22-8181. PMID:3885864

  5. Improved radioimmunotherapy of hematologic malignancies. Final technical report

    SciTech Connect

    Press, O.W.

    1996-08-15

    Experiments were performed to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells. An attempt was made to examine in vivo the effects of lysosomotropic amines and thioamides on the retention of radiolabeled monoclonal antibodies by tumor cells. Experiments also examined the impact of newer radioiodination techniques on the metabolic degradation of radioiodinated antibodies, and on the radioimmunoscintigraphy and radioimmunotherapy of neoplasms. The endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with I-131, In-111, and Y-90 were compared. The utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer was investigated.

  6. A randomized controlled study evaluating the efficacy of aprepitant for highly/moderately emetogenic chemotherapies in hematological malignancies.

    PubMed

    Nasu, R; Nannya, Y; Kurokawa, M

    2015-04-01

    Chemotherapy-induced nausea and vomiting (CINV) is a serious complication of treatments of hematological malignancies. Although aprepitant, an NK1 receptor antagonist, has been shown to control CINV in highly emetogenic therapies for solid tumors, the antiemetic effect of this agent in hematological chemotherapies is not well established. In this randomized controlled trial, we examined the additional effect of aprepitant in combination with conventional 5HT3 blocker-based prophylaxis for CINV in highly or moderately emetic chemotherapies for hematological malignancies (n = 41). The complete response rate, defined as no emetic episodes and no salvage treatments, was significantly higher in the aprepitant arm than the control arm (82 versus 47 %, p = 0.026), with no increase in severe adverse effects. However, the difference of nausea, measured with visual analog scale, and of oral intake impairment was moderate, which suggests insufficiency of blocking NK receptor for these events. Furthermore, sub-group analysis revealed that merit of aprepitant addition depends on treatment regimens. Our results indicate the overall advantage of applying aprepitant in the control of CINV in hematological malignancies and the need for further refinement of anti-CINV strategies, including stratification according to regimen. PMID:25644148

  7. Mutational analysis of JAK2, CBL, RUNX1, and NPM1 genes in familial aggregation of hematological malignancies.

    PubMed

    Hamadou, Walid S; Bourdon, Violaine; Gaildrat, Pascaline; Besbes, Sawsen; Fabre, Aurélie; Youssef, Yosra B; Regaieg, Haifa; Laatiri, Mohamed A; Eisinger, François; Mari, Véronique; Gesta, Paul; Dreyfus, Hélène; Bonadona, Valérie; Dugast, Catherine; Zattara, Hélène; Faivre, Laurence; Jemni, Saloua Yacoub; Noguchi, Testsuro; Khélif, Abderrahim; Sobol, Hagay; Soua, Zohra

    2016-06-01

    Familial aggregation of hematological malignancies has been reported highlighting inherited genetic predisposition. In this study, we targeted four candidate genes: JAK2 and RUNX1 genes assuring a prominent function in hematological process and CBL and NPM1 as proto-oncogenes. Their disruption was described in several sporadic hematological malignancies. The aim of this study is to determine whether JAK2, CBL, RUNX1, and NPM1 germline genes mutations are involved in familial hematological malignancies. Using direct sequencing, we analyzed JAK2 (exons 12 and 14); CBL (exons 7, 8 and 9); NPM1 (exon 12) and the entire RUNX1 in 88 independent families belonging to Tunisian and French populations. Twenty-one sporadic acute leukemias were included in this study. We reported a heterozygous intronic c.1641 + 6 T > C JAK2 variant (rs182123615) found in two independent familial cases diagnosed with gastric lymphoma and Hodgkin lymphoma. The in silico analysis suggested a potential impact on splicing, but the functional splicing minigene reporter assay on rs182123615 variant showed no aberrant transcripts. In one sporadic acute myeloblastic leukemia, we reported an insertion 846 in. TGTT in exon 12 of NPM1 gene that may impact the normal reading frame. The rs182123615 JAK2 variant was described in several contexts including myeloproliferative neoplasms and congenital erythrocytosis and was supposed to be pathogenic. Through this current study, we established the assessment of pathogenicity of rs182123615 and we classified it rather as rare polymorphism. PMID:27106701

  8. Alternative donor transplants for patients with advanced hematologic malignancies, conditioned with thiotepa, cyclophosphamide and antithymocyte globulin.

    PubMed

    Lamparelli, T; van Lint, M T; Gualandi, F; Raiola, A M; Barbanti, M; Sacchi, N; Ficai, G; Ghinatti, C; Bregante, S; Berisso, G; Dominietto, A; Di Grazia, C; Bruno, B; Sessarego, M; Casarino, L; Verdiani, S; Bacigalupo, A

    2000-12-01

    Preparative regimens without total body irradiation (TBI) have been reported for alternative donor hemopoietic stem cell transplants (HSCT). Between 7 September 1994 and 7 June 1999 48 patients with advanced hematologic malignancies were conditioned with thiotepa (THIO) 15 mg/kg, cyclophosphamide (CY) 150 mg/kg and antithymocyte globulin (ATG). Donors were HLA mismatched family members (1-2 antigens) (FAM) (n = 24, median age 31 years) or HLA matched unrelated donors (UD) (n = 24, median age 34 years). GVHD prophylaxis was cyclosporine and methotrexate. Stem cell source was peripheral blood (n = 8) or bone marrow (n = 40). Hematologic recovery was seen in 42/46 (91%) evaluable patients and complete chimerism in 31/37 patients (85%). Acute GVHD grades III-IV were seen in 10/46 patients surviving 10 days (21%) and extensive chronic GVHD in 2/36 patients surviving 100 days (5%). Twenty-six patients died (54%), eight of recurrent disease (17%) and 18 of transplant-related complications (37%): main causes of TRM were GVHD (15%), infections (15%) and graft failure (4%). Twenty-two patients (46%) survive with a median follow-up of 877 days (287-1840). The actuarial 3-year survival is 49% for FAM and 42% for UD transplants. Results obtained with this regimen in unrelated grafts for advanced CML (n = 15) were not significantly different when compared to 21 concurrent UD grafts for advanced CML prepared with CY-TBI. In conclusion, the combination of THIO-CY-ATG allows engraftment of alternative donor hemopoietic stem cells. Results are similar when using unrelated matched donors or partially mismatched family donors, and not significantly different when compared to patients conditioned with CY-TBI. PMID:11223970

  9. Detection of acquired hemoglobinopathy in children with hematological malignancies at disease onset: results form a national referral centre.

    PubMed

    Maritsi, Despoina N; Kosmidis, Helen V; Douna, Varvara; Traeger-Synodinos, Joanne; Tsolia, Maria N; Kossiva, Lydia

    2013-11-01

    Abnormal hemoglobin synthesis is usually inherited but may also arise as a secondary manifestation of a hematological neoplasia. The objective of this study is to identify the presence of acquired hemoglobinopathy in children diagnosed with hematological malignancies and compare these against healthy controls. Prospective matched case-control study held from 2010 to 2012. For each patient with hematological malignancy two healthy controls matched on gender, age and race were recruited. Patients with other co-morbidities were excluded. All samples underwent supravital staining and high-performance liquid chromatography (HPLC) electrophoresis. Following identification of abnormal results, molecular genetic testing for all α- and β-thalassemia mutations prevalent in the Greek population was performed. Other causes of anemia were ruled out based on specific testing. A total of 44 (32 males) patients with a mean age of 7.1 years were enrolled in the study. Hematological disorders included acute lymphocytic leukemia (24), acute myeloid leukemia (8), non-Hodgkin lymphoma (8), Hodgkin disease (3), and Langerhans cell histiocytosis (1). Following exclusion of congenital hemoglobinopathies, atypical HPLC electrophoretic findings persisted in 18.1 % of the patient group, compared to 0 % in the control group (p < 0.001). The patient group showed marked microcytic anemia (p < 0.01) and detection of small inclusions (p = 0.034) on supravital staining. Comparison of the HPLC findings between the groups demonstrated significantly lower percentages of HbA (p = 0.02), normal HbA2 and higher percentage of fast moving Hb bands (p = 0.04) in the patient group. Interestingly, the majority of these patients belonged to the high-risk group. Acquired hemoglobinopathy is recognized in adult patients. This is a novel study describing evidence of abnormal erythropoiesis in children with hematological malignancies and in particular those classified as high-risk cancer patients according to

  10. RARalpha is a regulatory factor for Am-80-induced cell growth inhibition of hematologic malignant cells.

    PubMed

    Jimi, Shiro; Mashima, Kota; Matsumoto, Taichi; Hara, Shuji; Suzumiya, Junji; Tamura, Kazuo

    2007-08-01

    Retinoids are used for treatment of acute promyelocytic leukemia (APL). Am-80, Tamibarotene, binds to retinoic acid receptor alpha (RARalpha) more specifically than all-trans retinoic acid. We studied the tumor cell suppressive effects of Am-80, with respect to cytotoxicity and growth inhibition using eight myeloid and lymphoid malignant cells in culture (HL-60, HL-60R, K-562, Kasumi-1, MEG01, Raji, U266B1, and U937). The effects of Am-80 were examined during 9 days of incubation with 10(-7)-10(-5) M of Am-80 in culture medium, which was changed every 3 days. HL-60 were the only cells sensitive to Am-80-induced cytotoxicity; the latter reached more than 95% after 9 days of incubation, and death was primarily through apoptosis. The total mass of RARalpha in HL-60 was significantly greater (p<0.006) than in ATRA-resistant HL-60 (HL-60R) as well as all of other cells tested. However, in all cells excluding HL-60, Am-80 induced time- and dose-dependent cell growth inhibition without noticeable cytotoxicity. TGF-beta2 was released into the media containing cells incubated with Am-80 for 3 days. A dose-dependent increment of phosphorylation of Smad-2 was also detected. The relative amount of secreted TGF-beta2 correlated with the growth inhibition rates in all cells tested excluding HL-60, and with the total mass of RARalpha in the cells (p=0.0137). Our results indicate that Am-80-induced cell-type non-specific growth inhibition is mediated by TGF-beta2, where the total mass of RARalpha could be an important regulatory factor in hematologic malignant cells. PMID:17611697

  11. Echocardiographic evaluation of the early cardiotoxic effect of hematopoietic stem cell transplantation in patients with hematologic malignancies.

    PubMed

    Poręba, Małgorzata; Gać, Paweł; Usnarska-Zubkiewicz, Lidia; Pilecki, Witold; Kuliczkowski, Kazimierz; Mazur, Grzegorz; Sobieszczańska, Małgorzata; Poręba, Rafał

    2016-09-01

    The purpose was to evaluate the early cardiotoxic effects of the treatment in the course of hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. The studies were conducted on 47 patients qualified for the HSCT. Echocardiography was carried out prior to the HSCT and after the HSCT. It was shown that higher age, administration of cyclophosphamide and higher glucose concentrations represented independent risk factors for the worsening of left ventricular diastolic function. Higher cumulative dose of anthracyclines in the previous cytostatic treatment, higher age and administration of cyclophosphamide represented independent risk factors for worsening of left ventricular systolic function. Peri-transplant therapy in the course of HSCT in patients with hematologic malignancies gives the negative effect on the diastolic and systolic left ventricular function, however, previous treatment is of importance, as higher cumulative dose of anthracyclines represents an independent risk factor for the worsening of left ventricular systolic function. PMID:26762118

  12. Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application.

    PubMed

    Furqan, Muhammad; Mukhi, Nikhil; Lee, Byung; Liu, Delong

    2013-01-01

    JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical role in transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune regulation, fertility, lactation, growth and embryogenesis. JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Negative regulators of JAK-STAT pathways include tyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of activated STATs (PIAS), suppressors of cytokine signaling (SOCS) proteins, and cytokine-inducible SH2-containing protein (CIS). Dysregulation of JAK-STAT pathway have been found to be key events in a variety of hematological malignancies. JAK inhibitors are among the first successful agents reaching clinical application. Ruxolitinib (Jakafi), a non-selective inhibitor of JAK1 & 2, has been approved by FDA for patients with intermediate to high risk primary or secondary myelofibrosis. This review will also summarize early data on selective JAK inhibitors, including SAR302503 (TG101348), lestaurtinib (CEP701), CYT387, SB1518 (pacritinib), LY2784544, XL019, BMS-911543, NS-018, and AZD1480. PMID:24252238

  13. Approaches to management of invasive fungal infections in patients with hematologic malignancies.

    PubMed

    Forrest, Graeme N; Walsh, Thomas J

    2004-10-01

    Invasive fungal infections have become increasingly common in patients with hematologic malignancies, especially in those at high risk with prolonged neutropenia and graft versus host disease after allogeneic stem cell transplantation, and are associated with significant morbidity, mortality, and cost. New diagnostic techniques and therapeutic agents have emerged recently to assist in the management of these infections. The galactomannan assay in association with routine clinical and radiologic screening may assist in the early diagnosis of invasive aspergillosis such that therapy may be initiated early. Also, several new antifungal agents have become available, allowing the practitioner more options in the prevention and treatment of fungal infections. New antifungal agents such as the lipid amphotericin B products, voriconazole, and the echinocandins appear to be safer to use than conventional amphotericin B. Voriconazole also has shown superiority to conventional amphotericin B in the treatment of invasive aspergillosis, and its well absorbed oral formulation makes it an excellent treatment to complete therapy as an outpatient. All these therapeutic options allow physicians to tailor antifungal therapy to the individual patient based on response and toxicity to prevent or treat invasive fungal infections. There are several new antifungal agents in development, and future studies will evaluate combination therapies to determine safety and efficacy. PMID:18628154

  14. Validation and Implementation of a Custom Next-Generation Sequencing Clinical Assay for Hematologic Malignancies.

    PubMed

    Kluk, Michael J; Lindsley, R Coleman; Aster, Jon C; Lindeman, Neal I; Szeto, David; Hall, Dimity; Kuo, Frank C

    2016-07-01

    Targeted next-generation sequencing panels to identify genetic alterations in cancers are increasingly becoming an integral part of clinical practice. We report here the design, validation, and implementation of a comprehensive 95-gene next-generation sequencing panel targeted for hematologic malignancies that we named rapid heme panel. Rapid heme panel is amplicon based and covers hotspot regions of oncogenes and most of the coding regions of tumor suppressor genes. It is composed of 1330 amplicons and covers 175 kb of genomic sequence in total. Rapid heme panel's average coverage is 1500× with <5% of the amplicons with <50× coverage, and it reproducibly detects single nucleotide variants and small insertions/deletions at allele frequencies of ≥5%. Comparison with a capture-based next-generation sequencing assay showed that there is >95% concordance among a wide array of variants across a range of allele frequencies. Read count analyses that used rapid heme panel showed high concordance with karyotypic results when tumor content was >30%. The average turnaround time was 7 days over a 6-month span with an average volume of ≥40 specimens per week and a low sample fail rate (<1%), demonstrating its suitability for clinical application. PMID:27339098

  15. Brca1 deficiency causes bone marrow failure and spontaneous hematologic malignancies in mice.

    PubMed

    Vasanthakumar, Aparna; Arnovitz, Stephen; Marquez, Rafael; Lepore, Janet; Rafidi, George; Asom, Anase; Weatherly, Madison; Davis, Elizabeth M; Neistadt, Barbara; Duszynski, Robert; Vardiman, James W; Le Beau, Michelle M; Godley, Lucy A; Churpek, Jane E

    2016-01-21

    BRCA1 is critical for maintenance of genomic stability and interacts directly with several proteins that regulate hematopoietic stem cell function and are part of the Fanconi anemia (FA) double-strand break DNA repair pathway. The effects of complete BRCA1 deficiency on bone marrow (BM) function are unknown. To test the hypothesis that Brca1 is essential in hematopoiesis, we developed a conditional mouse model with Mx1-Cre-mediated Brca1 deletion. Mice lacking Brca1 in the BM have baseline cytopenias and develop spontaneous bone marrow failure or diverse hematologic malignancies by 6 months of age. Brca1(-/-) BM cells have a reduced capacity to form hematopoietic colonies in vitro and to reconstitute hematopoiesis in irradiated recipients, consistent with a hematopoietic progenitor functional defect. Brca1(-/-) BM cells also show FA-like hypersensitivity to the DNA crosslinking agent mitomycin C, and karyotypes feature genomic instability. Taken together, our results show that loss of Brca1 in murine BM causes hematopoietic defects similar to those seen in people with FA, which provides strong evidence that Brca1 is critical for normal hematopoiesis and that Brca1 is a bona fide FA-like gene. PMID:26644450

  16. Primary Graft Failure after Myeloablative Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies

    PubMed Central

    Olsson, Richard F.; Logan, Brent R.; Chaudhury, Sonali; Zhu, Xiaochun; Akpek, Görgün; Bolwell, Brian J.; Bredeson, Christopher N.; Dvorak, Christopher C.; Gupta, Vikas; Ho, Vincent T.; Lazarus, Hillard M.; Marks, David I.; Ringdén, Olle T.H.; Pasquini, Marcelo C.; Schriber, Jeffrey R.; Cooke, Kenneth R.

    2015-01-01

    Clinical outcomes after primary graft failure (PGF) remain poor. Here we present a large retrospective analysis (n=23,272) which investigates means to prevent PGF and early detection of patients at high risk. In patients with hematologic malignancies, who underwent their first myeloablative allogeneic hematopoietic cell transplantation, PGF was reported in 1,278 (5.5%), and there was a marked difference in PGFs using peripheral blood stem cell compared to bone marrow grafts (2.5 vs. 7.3%; P<0.001). A 4-fold increase of PGF was observed in myeloproliferative disorders compared to acute leukemia (P<0.001). Other risk factors for PGF included recipient age below 30, HLA-mismatch, male recipients of female donor grafts, ABO-incompatibility, busulfan/cyclophosphamide conditioning, and cryopreservation. In bone marrow transplants, total nucleated cell doses ≤2.4 × 108/kg were associated with PGF (OR 1.39; P<0.001). The use of tacrolimus-based immunosuppression and granulocyte colony-stimulating factor were associated with decreased PGF risk. These data, allow clinicians to do more informed choices with respect to graft source, donor selection, conditioning and immunosuppressive regimens to reduce the risk of PGF. Moreover, a novel risk score determined on day 21 post-transplant may provide the rationale for an early request for additional hematopoietic stem cells. PMID:25772027

  17. Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting

    PubMed Central

    He, Jie; Abdel-Wahab, Omar; Nahas, Michelle K.; Wang, Kai; Rampal, Raajit K.; Intlekofer, Andrew M.; Patel, Jay; Krivstov, Andrei; Frampton, Garrett M.; Young, Lauren E.; Zhong, Shan; Bailey, Mark; White, Jared R.; Roels, Steven; Deffenbaugh, Jason; Fichtenholtz, Alex; Brennan, Timothy; Rosenzweig, Mark; Pelak, Kimberly; Knapp, Kristina M.; Brennan, Kristina W.; Donahue, Amy L.; Young, Geneva; Garcia, Lazaro; Beckstrom, Selmira T.; Zhao, Mandy; White, Emily; Banning, Vera; Buell, Jamie; Iwanik, Kiel; Ross, Jeffrey S.; Morosini, Deborah; Younes, Anas; Hanash, Alan M.; Paietta, Elisabeth; Roberts, Kathryn; Mullighan, Charles; Dogan, Ahmet; Armstrong, Scott A.; Mughal, Tariq; Vergilio, Jo-Anne; Labrecque, Elaine; Erlich, Rachel; Vietz, Christine; Yelensky, Roman; Stephens, Philip J.; Miller, Vincent A.; van den Brink, Marcel R. M.; Otto, Geoff A.; Lipson, Doron

    2016-01-01

    The spectrum of somatic alterations in hematologic malignancies includes substitutions, insertions/deletions (indels), copy number alterations (CNAs), and a wide range of gene fusions; no current clinically available single assay captures the different types of alterations. We developed a novel next-generation sequencing-based assay to identify all classes of genomic alterations using archived formalin-fixed paraffin-embedded blood and bone marrow samples with high accuracy in a clinically relevant time frame, which is performed in our Clinical Laboratory Improvement Amendments–certified College of American Pathologists–accredited laboratory. Targeted capture of DNA/RNA and next-generation sequencing reliably identifies substitutions, indels, CNAs, and gene fusions, with similar accuracy to lower-throughput assays that focus on specific genes and types of genomic alterations. Profiling of 3696 samples identified recurrent somatic alterations that impact diagnosis, prognosis, and therapy selection. This comprehensive genomic profiling approach has proved effective in detecting all types of genomic alterations, including fusion transcripts, which increases the ability to identify clinically relevant genomic alterations with therapeutic relevance. PMID:26966091

  18. Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting.

    PubMed

    He, Jie; Abdel-Wahab, Omar; Nahas, Michelle K; Wang, Kai; Rampal, Raajit K; Intlekofer, Andrew M; Patel, Jay; Krivstov, Andrei; Frampton, Garrett M; Young, Lauren E; Zhong, Shan; Bailey, Mark; White, Jared R; Roels, Steven; Deffenbaugh, Jason; Fichtenholtz, Alex; Brennan, Timothy; Rosenzweig, Mark; Pelak, Kimberly; Knapp, Kristina M; Brennan, Kristina W; Donahue, Amy L; Young, Geneva; Garcia, Lazaro; Beckstrom, Selmira T; Zhao, Mandy; White, Emily; Banning, Vera; Buell, Jamie; Iwanik, Kiel; Ross, Jeffrey S; Morosini, Deborah; Younes, Anas; Hanash, Alan M; Paietta, Elisabeth; Roberts, Kathryn; Mullighan, Charles; Dogan, Ahmet; Armstrong, Scott A; Mughal, Tariq; Vergilio, Jo-Anne; Labrecque, Elaine; Erlich, Rachel; Vietz, Christine; Yelensky, Roman; Stephens, Philip J; Miller, Vincent A; van den Brink, Marcel R M; Otto, Geoff A; Lipson, Doron; Levine, Ross L

    2016-06-16

    The spectrum of somatic alterations in hematologic malignancies includes substitutions, insertions/deletions (indels), copy number alterations (CNAs), and a wide range of gene fusions; no current clinically available single assay captures the different types of alterations. We developed a novel next-generation sequencing-based assay to identify all classes of genomic alterations using archived formalin-fixed paraffin-embedded blood and bone marrow samples with high accuracy in a clinically relevant time frame, which is performed in our Clinical Laboratory Improvement Amendments-certified College of American Pathologists-accredited laboratory. Targeted capture of DNA/RNA and next-generation sequencing reliably identifies substitutions, indels, CNAs, and gene fusions, with similar accuracy to lower-throughput assays that focus on specific genes and types of genomic alterations. Profiling of 3696 samples identified recurrent somatic alterations that impact diagnosis, prognosis, and therapy selection. This comprehensive genomic profiling approach has proved effective in detecting all types of genomic alterations, including fusion transcripts, which increases the ability to identify clinically relevant genomic alterations with therapeutic relevance. PMID:26966091

  19. Serum voriconazole level variability in patients with hematological malignancies receiving voriconazole therapy

    PubMed Central

    Saini, Lalit; Seki, Jack T; Kumar, Deepali; Atenafu, Eshetu G; Cole, David EC; Wong, Betty YL; Božović, Andrea; Brandwein, Joseph M

    2014-01-01

    INTRODUCTION: Voriconazole plasma concentrations have been correlated with oral dosing in healthy subjects, but have been poorly characterized in ill patients with hematological malignancies receiving intensive chemotherapy. METHODS: The relationship between orally administered voriconazole, plasma concentrations and liver toxicity was examined in a cohort of 69 primarily acute leukemia patients undergoing intensive chemotherapy. RESULTS: Oral administration of voriconazole was associated with significant interpatient variability, with voriconazole steady-state concentrations ranging from 0 μg/mL to 16.6 μg/mL. Approximately 20% of patients achieved steady-state concentrations <1 μg/mL. When adjusted for weight, patients receiving higher voriconazole doses tended toward higher plasma concentrations; however, there was no significant relationship between the plasma concentration and genotype, age, sex or use of concomitant proton pump inhibitors. Voriconazole concentrations were correlated with higher serum alkaline phosphatase levels at day 6 to 8, and with higher bilirubin and aspartate aminotransferase levels at day 14 to 16, but not with other liver enzyme levels. CONCLUSION: In ill patients with acute leukemia and related disorders undergoing treatment with oral voriconazole, there is a poor correlation between the voriconazole dose and plasma concentrations, and many patients achieve levels that are considered to be subtherapeutic. The findings support the routine use of therapeutic drug monitoring in these patients. PMID:25371690

  20. MicroRNA-regulated pathways in hematological malignancies: how to avoid cells playing out of tune.

    PubMed

    Fatica, Alessandro; Fazi, Francesco

    2013-01-01

    The coordinated expression and interplay among lineage specific transcription factors and microRNAs contribute to the regulation of gene expression and determination of cell specificity. In hematopoietic stem cells (HSCs), unique combinations of transcription factors largely control growth and maturation of different blood cell lineages through cooperative regulation of specific target genes. MicroRNAs provide an additional level of control beyond transcription factors. By acting as regulators of crucial lineage-specific genetic programs, microRNAs direct early multipotential progenitor cells to adopt a certain cell fate program. Thus, alteration of specific microRNA levels may affect proliferation, differentiation and genetic stability of HSCs, contributing to the onset of myeloproliferative disorders and leukemia. The major aim of this review is to highlight the critical role of microRNA-regulated pathways during the establishment and progression of hematological malignancies, with a particular attention to leukemia, lymphomas and myelodysplastic syndromes. This will give us the opportunity to discuss the potential use of microRNA-based therapeutic approaches in these diseases. MicroRNAs are indeed emerging as relevant tools to improve the efficacy of currently used therapeutic protocols. PMID:24145746

  1. Use of PIXE to measure serum copper, zinc, selenium, and bromine in patients with hematologic malignancies

    NASA Astrophysics Data System (ADS)

    Beguin, Y.; Bours, V.; Delbrouck, J.-M.; Robaye, G.; Roelandts, I.; Fillet, G.; Weber, G.

    1990-04-01

    The use of PIXE allowed for a simultaneous determination of serum copper (Cu), zinc (Zn), selenium (Se) and bromine (Br), in various groups of patients with hematologic malignancies. In 78 patients with acute nonlymphocytic leukemia, it was observed that (1) serum Se was significantly lower than in healthy controls and correlated inversely with the tumor burden; (2) serum bromine was normal at diagnosis but dropped dramatically after intensive chemotherapy, before recovering progressively over a period of months; and (3) pretreatment serum copper and zinc were significant prognostic factors of the chance to achieve a complete remission. In 50 patients with chronic lymphocytic leukemia, it was observed that (1) serum Cu and Cu/Zn ratio were useful indices of the disease activity, which were independent of a nonspecific acute phase reaction; and (2) Zn deficiency could contribute to immune dysfunction. In 119 patients with myeloproliferative disorders or myelodysplasic syndromes, serum Cu and Zn levels were mostly dependent on nonspecific factors, such as age and inflammation.

  2. T-Cell Receptor-Engineered Cells for the Treatment of Hematologic Malignancies.

    PubMed

    Hossain, Nasheed M; Chapuis, Aude G; Walter, Roland B

    2016-08-01

    Recent attention in adoptive immunotherapy for hematologic malignancies has focused on lymphocytes expressing chimeric antigen receptors. An alternative technique to redirect the immune system toward cancer cells involves the use of T-cells carrying an engineered tumor-recognizing T-cell receptor (TCR). This approach allows targeting of surface or intracellular/nuclear proteins as long as they are processed and presented on the cell surface by human leukocyte antigen molecules. Several trials in advanced solid tumors, particularly melanoma and synovial sarcoma, support the validity of this strategy, although tumor responses have often been short-lived. Emerging data from patients with multiple myeloma and myeloid neoplasms suggest that the benefit of TCR-modified cells may extend to blood cancers. Methodological refinements may be necessary to increase the in vivo persistence and functionality of these cells. Particularly with affinity-enhanced TCRs, however, more effective therapies may increase the potential for serious toxicity due to the unexpected on- or off-target reactivity. PMID:27095318

  3. Human metapneumovirus infections in hematopoietic cell transplant recipients and hematologic malignancy patients: A systematic review.

    PubMed

    Shah, Dimpy P; Shah, Pankil K; Azzi, Jacques M; El Chaer, Firas; Chemaly, Roy F

    2016-08-28

    Over the past decade, reported incidence of human metapneumovirus (hMPV) has increased owing to the use of molecular assays for diagnosis of respiratory viral infections in cancer patients. The seasonality of these infections, differences in sampling strategies across institutions, and small sample size of published studies make it difficult to appreciate the true incidence and impact of hMPV infections. In this systematic review, we summarized the published data on hMPV infections in hematopoietic cell transplant recipients and patients with hematologic malignancy, focusing on incidence, hMPV-associated lower respiratory tract infection (LRTI), mortality, prevention, and management with ribavirin and/or intravenous immunoglobulins. Although the incidence of hMPV infections and hMPV-associated LRTI in this patient population is similar to respiratory syncytial virus or parainfluenza virus and despite lack of directed antiviral therapy, the mortality rate remains low unless patients develop LRTI. In the absence of vaccine to prevent hMPV, infection control measures are recommended to reduce its burden in cancer patients. PMID:27260872

  4. Predictors of Poor Outcomes in Critically Ill Adults with Hematologic Malignancy

    PubMed Central

    Cornish, Marion; Butler, Michael B.; Green, Robert S.

    2016-01-01

    Background. Patients with hematologic malignancy (HM) often require intensive care unit (ICU) admission due to organ failure through disease progression or treatment-related complications. Objective. To determine mortality and prognostic variables in adult patients with HM who were admitted to ICU. Methods. Structured chart review of all adult patients (age ≥ 18 years) with HM admitted to ICU of a Canadian tertiary care hospital between 2004 and 2014. Outcome measures included mortality (ICU, 30-day, 60-day, and 12-month). Logistic regression was performed to determine predictors of mortality. Results. Overall, there were 206 cases of HM admitted to the ICU during the study (mean age: 51.3 ± 13.6 years; 60% male). Median stay was 3 days, with 14.1% requiring prolonged ICU admission. ICU mortality was 45.6% and increased to 59.2% at 30 days, 62.6% at 60 days, and 74.3% at 12 months. Predictors of increased ICU mortality included mechanical ventilation requirement and vasopressor therapy requirement, while admission to ICU postoperatively and having myeloma were associated with decreased mortality. Conclusions. Patients admitted to ICU with HM have high mortality (45.6%), which increased to 74.3% at 1 year. Analysis of multiple variables identified critical illness, postsurgical admission, and myeloma as predictors of patient outcomes. PMID:27445571

  5. Effect of body mass in children with hematologic malignancies undergoing allogeneic bone marrow transplantation

    PubMed Central

    Aplenc, Richard; Zhang, Mei-Jie; Sung, Lillian; Zhu, Xiaochun; Ho, Vincent T.; Cooke, Kenneth; Dvorak, Christopher; Hale, Gregory; Isola, Luis M.; Lazarus, Hillard M.; McCarthy, Philip L.; Olsson, Richard; Pulsipher, Michael; Bunin, Nancy

    2014-01-01

    The rising incidence of pediatric obesity may significantly affect bone marrow transplantation (BMT) outcomes. We analyzed outcomes in 3687 children worldwide who received cyclophosphamide-based BMT regimens for leukemias between 1990 and 2007. Recipients were classified according to age-adjusted body mass index (BMI) percentiles as underweight (UW), at risk of UW (RUW), normal, overweight (OW), or obese (OB). Median age and race were similar in all groups. Sixty-one percent of OB children were from the United States/Canada. Three-year relapse-free and overall survival ranged from 48% to 52% (P = .54) and 55% to 58% (P = .81) across BMI groups. Three-year leukemia relapses were 33%, 33%, 29%, 25%, and 21% in the UW, RUW, normal, OW, and OB groups, respectively (P < .001). Corresponding cumulative incidences for transplant-related mortality (TRM) were 18%, 19%, 21%, 22%, and 28% (P < .01). Multivariate analysis demonstrated a decreased risk of relapse compared with normal BMI (relative risk [RR] = 0.73; P < .01) and a trend toward higher TRM (RR = 1.28; P = .014). BMI in children is not significantly associated with different survival after BMT for hematologic malignancies. Obese children experience less relapse posttransplant compared with children with normal BMI; however, this benefit is offset by excess in TRM. PMID:24711663

  6. Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies.

    PubMed

    Petropoulos, D; Worth, L L; Mullen, C A; Madden, R; Mahajan, A; Choroszy, M; Ha, C S; Champlin, R C; Chan, K W

    2006-03-01

    We evaluated the efficacy and toxicity of adding 9 Gy of total body irradiation (TBI), in three single daily fractions of 3 Gy, to the reduced intensity regimen of fludarabine 30 mg/m2 i.v. x 4 days and melphalan 140 mg/m2 i.v. x 1 day in advanced pediatric hematologic malignancies. Twenty-two acute lymphoblastic leukemia (ALL), six acute myeloid leukemia (AML), and one non-Hodgkin lymphoma patients were transplanted. Of these, 13 were beyond second remission, and five had prior hematopoietic stem cell transplant (HSCT). Twenty-one donors were unrelated, of which 19 were from cord blood (CB) units. Three of the eight related donors were genotypically disparate. Oral mucositis and diarrhea were the most common toxicities. Twenty-seven patients achieved neutrophil engraftment (median 16 days), and 23 had platelet engraftment (median 42 days). One patient had primary graft failure. Seven patients died of non-relapse causes in the first 100 days. With a median follow-up of 52 months, seven of 22 ALL, five of six AML, and one of one lymphoma patients are alive and in remission. The regimen of TBI, fludarabine, and melphalan allows the engraftment of allogeneic hematopoietic stem cells (including mismatched CB). It was fairly well tolerated in pediatric patients, even for second transplants. Its efficacy requires further evaluation. PMID:16435013

  7. Potential Factors for Inadequate Voriconazole Plasma Concentrations in Intensive Care Unit Patients and Patients with Hematological Malignancies

    PubMed Central

    Duettmann, Wiebke; Raggam, Reinhard B.; Seeber, Katharina; Troppan, Katharina; Fruhwald, Sonja; Prueller, Florian; Wagner, Jasmin; Valentin, Thomas; Zollner-Schwetz, Ines; Wölfler, Albert

    2013-01-01

    Voriconazole plasma concentrations (VPCs) vary widely, and concentrations outside the therapeutic range are associated with either worse outcome in invasive aspergillosis (IA) or increased toxicity. The primary goal of this cohort study conducted in a real-life setting was to identify potential factors associated with inadequate VPCs in ICU patients and patients with hematological malignancies. Within a period of 12 months, trough VPCs were obtained and analyzed with high-performance liquid chromatography, and the adequate range was defined as 1.5 to 5.5 mg/liter. VPCs of <1.5 mg/liter were defined as low, whereas VPCs of >5.5 mg/liter were defined as potentially toxic. A total of 221 trough VPCs were obtained in 61 patients receiving voriconazole, and 124/221 VPCs (56%) were found to be low. Multivariate analysis revealed that low VPCs were significantly associated with clinical failure of voriconazole, prophylactic use, younger age, underlying hematological malignancy, concomitant proton pump inhibitor (PPI) (pantoprazole was used in 88% of the patients), and absence of side effects. Low VPCs remained an independent predictor of clinical failure of voriconazole. The defined adequate range was reached in 79/221 (36%) VPCs. In 18 samples (8%), potentially toxic levels were measured. Multivariate analysis revealed higher body mass index (BMI), absence of hematological malignancy, therapeutic application, and diarrhea as factors associated with potentially toxic VPCs. Neurotoxic adverse events occurred in six patients and were mostly associated with VPCs in the upper quartile of our defined adequate range. In conclusion, potential factors like younger age, prophylaxis, underlying hematological malignancy, BMI, and concomitant PPI should be considered within the algorithm of voriconazole treatment. PMID:23629724

  8. Hematologic malignancies in South Africa 2000-2006: analysis of data reported to the National Cancer Registry.

    PubMed

    Schonfeld, Sara J; Erdmann, Friederike; Wiggill, Tracey; Singh, Elvira; Kellett, Patricia; Babb, Chantal; Schüz, Joachim

    2016-04-01

    Little is known about the incidence patterns of hematologic malignancies in Sub-Saharan Africa, including South Africa. We estimated incidence rates of pathology-confirmed adult cases of leukemia, myeloma and related diseases (myeloma), Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL) reported to the National Cancer Registry of South Africa (NCR) between 2000 and2006, by age, gender, and population group (Black, White, Coloured, Asian/Indian). Gender-specific age-standardized rates were calculated overall and by population group and incidence rate ratios (IRRs) were estimated using Poisson regression models. Between 2000 and 2006, there were 14662 cases of leukemia, myeloma, HL, and NHL reported to the registry. Incidence rates of reported hematologic malignancies were generally 20-50% higher among males than females. Our analyses suggested marked differences in the rates of reported hematologic malignancies by population group which were most pronounced when comparing the White versus Black population groups (IRRs ranging from 1.6 for myeloma to 3.8 for HL for males and females combined). Challenges related to diagnosis and reporting of cancers may play a role in the patterns observed by population group while the set-up of the NCR (pathology-based) could lead to some degree of under-ascertainment in all groups. This is the first country-wide report of the incidence of hematologic malignancies in South Africa. Despite challenges, it is important to analyze and report available national cancer incidence data to raise awareness of the cancer burden and to characterize patterns by demographic characteristics so as ultimately to improve the provision of cancer-related health care. PMID:26773310

  9. Prevalence and Positive Correlates of Posttraumatic Stress Disorder Symptoms among Chinese Patients with Hematological Malignancies: A Cross-Sectional Study

    PubMed Central

    Liu, Li; Yang, Yi-Long; Wang, Zi-Yue; Wu, Hui; Wang, Yang; Wang, Lie

    2015-01-01

    Purpose Positive psychological constructs have been given increasing attention in research on the coping resources of cancer-related distresses. However, little research is available on posttraumatic stress disorder (PTSD) in patients with hematological malignancies. The purposes of this study were to assess the prevalence of PTSD symptoms and to explore the associations of perceived social support (PSS), hope, optimism and resilience with PTSD symptoms among Chinese patients with hematological malignancies. Methods A cross-sectional study was conducted during the period from July 2013 through April 2014. A total of 225 inpatients with hematological malignancies, which were eligible for the study, completed the Post-traumatic Stress Checklist-Civilian Version, Multidimensional Scale of Perceived Social Support, Adult Hope Scale, Life Orientation Scale-Revised, and Resilience Scale. Hierarchical regression analysis was performed to explore the correlates of PTSD symptoms. Results Overall, the prevalence of PTSD symptoms was 10.7%. Initially, PSS was negatively associated with PTSD symptoms (β = -0.248, P < 0.01). However, when positive psychological variables were added, optimism was negatively associated with PTSD symptoms (β = -0.452, P < 0.01), and gender had a significant effect on PTSD symptoms. Women were more vulnerable to these symptoms than men (β = 0.123, P < 0.05). When the analysis was performed separately by gender, only optimism showed a significantly negative association with PTSD symptoms in both men (β = -0.389, P < 0.01) and women (β = -0.493, P < 0.01). Conclusions Some patients with hematological malignancies suffer from PTSD symptoms. The positive effects of PSS and optimism on PTSD symptoms suggest that an integrated approach to psychosocial intervention from both external and internal perspectives could have practical significance. Gender difference should be considered in developing potential interventions in reducing cancer-related PTSD

  10. The MIF -173G/C gene polymorphism increase gastrointestinal cancer and hematological malignancy risk: evidence from a meta-analysis and FPRP test

    PubMed Central

    Tong, Xiang; Zheng, Bing; Tong, Qiaoyi; Liu, Sitong; Peng, Sifeng; Yang, Xin; Fan, Hong

    2015-01-01

    The macrophage migration inhibitory factor (MIF) -173G/C gene polymorphism has been implicated in the susceptibility to cancer, but the results are not conclusive. So the aim of study to investigate the association between MIF -173G/C gene polymorphism and cancer risk by a comprehensive meta-analysis. We searched the PubMed, Embase, Wanfang and China National Knowledge Internet (CNKI) databases, with the last updated search being performed on May 24, 2015. The odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the association. Statistical analysis was performed by STATA 11.0 software. Finally, 7,253 participants from 15 studies were included in the meta-analysis. The results of meta-analysis indicated the significant association between MIF -173G/C gene polymorphism and cancer susceptibility, especially in Asians (C vs. G, OR: 1.22, 95% CI=1.00-1.50). In addition, the significant relationship between MIF -173G/C gene polymorphism and gastrointestinal tumors (CC+CG vs. GG, OR: 1.25, 95% CI=1.05-1.50), hematological malignancy (CC+CG vs. GG, OR: 1.27, 95% CI=1.03-1.56), gynecolgical tumors (CC vs. CG+GG, OR: 1.51, 95% CI=1.04-2.19) risk was found. However, to avoid the “false positive report”, we investigated the significant associations observed in the present meta-analysis by the false positive report probabilities (FPRPs) test. Interestingly, the results of FPRP test indicated the MIF -173G/C gene polymorphism only associated with gastrointestinal cancer and hematological malignancy risk (FPRP=0.132, 0.067 respectively) at the level of a prior probability is 0.1. Therefore, the meta-analysis suggested MIF -173G/C gene polymorphism would be a risk factor for the gastrointestinal cancer and hematological malignancy. PMID:26629098

  11. Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy.

    PubMed

    Baldini, L; Guffanti, A; Cesana, B M; Colombi, M; Chiorboli, O; Damilano, I; Maiolo, A T

    1996-02-01

    The presenting clinico-hematologic features of 386 patients with nonmyelomatous monoclonal gammopathy (MG) were correlated with the frequency of malignant transformation to evaluate the most important variables conditioning its evolution into multiple myeloma (MM) or Waldenström macroglobulinemia (WM). Most of the patients (335) had monoclonal gammopathy of undetermined significance (MGUS: 39 IgA, 242 IgG, 54 IgM): the remaining 51 patients (12 IgA, 39 IgG) fulfilled all of the MGUS diagnostic criteria (according to Durie) except that bone marrow plasma cell (BMPC) content was 10% to 30%, and so they were defined as having monoclonal gammopathy of borderline significance (MGBS). There were no significant differences between the MGUS and MGBS groups in terms of age, sex, or median follow-up. After a median follow-up of 70 and 53 months, respectively, 23 of 335 MGUS and 19 of 51 MGBS patients had undergone a malignant evolution. Univariate analysis of the IgA and IgG patients showed that the cumulative probability of the disease evolving into MM correlated with diagnostic definition (MGBS v MGUS), BMPC content (> or = 10% v < 5% and < or = 5% v > 5%) and reduced serum polyclonal Ig. In the IgG cases, there was also a significant correlation with detectable Bence Jones proteinuria, serum monoclonal component (MC) levels and age at diagnosis (> 70 v < = or 55 years). In the IgG cases as a whole, the same variables remained in the Cox model where the BMPC percentage was considered after natural logarithmic transformation and the monoclonal component as g/dL value. The relative risks of developing MM are the following: 2.4 for each 1 g/dL increase of IgG, serum MC, 3.5 for detectable light chain proteinuria, 4.4 for the increase of 1 unit in log. BMPC percentage, 6.1 for age > 70, 3.6 and 13.1 for a reduction in one or two polyclonal Ig. In conclusion, our study allows the identification of a particular subset of MGUS patients (MC < = or 1.5 g/dL, BMPC < 5%, no

  12. Development of cyclin-dependent kinase modulators as novel therapeutic approaches for hematological malignancies.

    PubMed

    Senderowicz, A M

    2001-01-01

    infusional UCN-01 in combination with Ara-C or gemcitabine in patients with acute leukemia and CLL, respectively, have commenced. In conclusion, flavopiridol and UCN-01 are cdk modulators that reach biologically active concentrations effective in modulating CDK in vitro, and show encouraging results in early clinical trials in patients with refractory hematopoietic malignancies. Although important questions remain to be answered, these positive experiences will hopefully increase the therapeutic modalities in hematological malignancies. PMID:11243375

  13. (1, 3)-β-D-glucan assay for diagnosing invasive fungal infections in critically ill patients with hematological malignancies

    PubMed Central

    Azoulay, Elie; Guigue, Nicolas; Darmon, Michael; Mokart, Djamel; Lemiale, Virginie; Kouatchet, Achille; Mayaux, Julien; Vincent, François; Nyunga, Martine; Bruneel, Fabrice; Rabbat, Antoine; Bretagne, Stéphane; Lebert, Christine; Meert, Anne-Pascale; Benoit, Dominique; Pene, Frédéric

    2016-01-01

    Invasive fungal infections (IFIs) are life-threatening complications of hematological malignancies that must be diagnosed early to allow effective treatment. Few data are available on the performance of serum (1–3)-β-D-glucan (BG) assays for diagnosing IFI in patients with hematological malignancies admitted to the intensive care unit (ICU). In this study, 737 consecutive patients with hematological malignancies admitted to 17 ICUs routinely underwent a BG assay at ICU admission. IFIs were diagnosed using standard criteria applied by three independent specialists. Among the 737 patients, 439 (60%) required mechanical ventilation and 273 (37%) died before hospital discharge. Factors known to alter BG concentrations were identified in most patients. IFIs were documented in 78 (10.6%) patients (invasive pulmonary aspergillosis, n = 54; Pneumocystis jirovecii pneumonia, n = 13; candidemia, n = 13; and fusarium infections, n = 3). BG concentrations (pg/mL) were higher in patients with than without IFI (144 (77–510) vs. 50 (30–125), < 0.0001). With 80 pg/mL as the cutoff, sensitivity was 72%, specificity 65%, and area-under-the-curve 0.74 (0.68–0.79). Assuming a prevalence of 10%, the negative and positive predictive values were 94% and 21%. By multivariable analysis, factors independently associated with BG > 80 pg/mL were IFI, admission SOFA score, autologous bone-marrow or hematopoietic stem-cell transplantation, and microbiologically documented bacterial infection. In conclusion, in unselected critically ill hematology patients with factors known to affect serum BG, this biomarker showed only moderate diagnostic performance and rarely detected IFI. However, the negative predictive value was high. Studies are needed to assess whether a negative BG test indicates that antifungal de-escalation is safe. PMID:26910891

  14. Secondary Infections in Febrile Neutropenia in Hematological Malignancies: More Than Another Febrile Neutropenic Episode

    PubMed Central

    Demirel, Aslıhan; Tabak, Fehmi; Ar, M. Cem; Mete, Bilgül; Öngören, Şeniz; Yemişen, Mücahit; Özaras, Reşat; Eşkazan, Emre; Başlar, Zafer; Mert, Ali; Soysal, Teoman; Ferhanoğlu, Burhan; Aydın, Yıldız; Öztürk, Recep

    2015-01-01

    Objective: Febrile neutropenic episodes (FNEs) are among the major causes of mortality in patients with hematological malignancies. Secondary infections develop either during the empirical antibiotic therapy or 1 week after cessation of therapy for a FNE. The aim of this study was to investigate the risk factors associated with secondary infections in febrile neutropenic patients. Materials and Methods: We retrospectively analyzed 750 FNEs in 473 patients between January 2000 and December 2006. Results: Secondary infections were diagnosed in 152 (20%) of 750 FNEs. The median time to develop secondary infection was 10 days (range: 2-34 days). The duration of neutropenia over 10 days significantly increased the risk of secondary infections (p<0.001). The proportion of patients with microbiologically documented infections was found to be higher in primary infections (271/750, 36%) compared to secondary infections (43/152, 28%) (p=0.038). Age; sex; underlying disease; antibacterial, antifungal, or antiviral prophylaxis; blood transfusion or bone marrow transplantation; central venous catheter; and severity of neutropenia did not differ significantly between primary and secondary infections (p>0.05). While fever of unknown origin (p=0.005) and catheter-related bacteremia (p<0.001) were less frequently observed in secondary infections, the frequency of microbiologically (p=0.003) and clinically (p<0.001) documented infections, fungal pneumonias (p<0.001), infections related to gram-positive bacteria (p=0.04) and fungi (p<0.001), and 30-day mortality rate (p<0.001) were significantly higher in cases of secondary infections (p<0.001). Conclusion: Secondary infections should be regarded as life-threatening complications of febrile neutropenia. Secondary infections represent a more severe and mortal complication and cannot be regarded just as another FNE. PMID:25913035

  15. Robust Vaccine Responses in Adult and Pediatric Cord Blood Transplantation Recipients Treated for Hematologic Malignancies.

    PubMed

    Shah, Gunjan L; Shune, Leyla; Purtill, Duncan; Devlin, Sean; Lauer, Emily; Lubin, Marissa; Bhatt, Valkal; McElrath, Courtney; Kernan, Nancy A; Scaradavou, Andromachi; Giralt, Sergio; Perales, Miguel A; Ponce, Doris M; Young, James W; Shah, Monica; Papanicolaou, Genovefa; Barker, Juliet N

    2015-12-01

    Because cord blood (CB) lacks memory T and B cells and recent decreases in herd immunity to vaccine-preventable diseases in many developed countries have been documented, vaccine responses in CB transplantation (CBT) survivors are of great interest. We analyzed vaccine responses in double-unit CBT recipients transplanted for hematologic malignancies. In 103 vaccine-eligible patients, graft-versus-host disease (GVHD) most commonly precluded vaccination. Sixty-five patients (63%; engrafting units median HLA-allele match 5/8; range, 2 to 7/8) received protein conjugated vaccines, and 63 patients (median age, 34 years; range, .9 to 64) were evaluated for responses. Median vaccination time was 17 months (range, 7 to 45) post-CBT. GVHD (n = 42) and prior rituximab (n = 13) delayed vaccination. Responses to Prevnar 7 and/or 13 vaccines (serotypes 14, 19F, 23F) were seen in children and adults (60% versus 49%, P = .555). Responses to tetanus, diphtheria, pertussis, Haemophilus influenzae, and polio were observed in children (86% to 100%) and adults (53% to 89%) even if patients had prior GVHD or rituximab. CD4(+)CD45RA(+) and CD19(+) cell recovery significantly influenced tetanus and polio responses. In a smaller cohort responses were seen to measles (65%), mumps (50%), and rubella (100%) vaccines. No vaccine side effects were identified, and all vaccinated patients survived (median follow-up, 57 months). Although GVHD and rituximab can delay vaccination, CBT recipients (including adults and those with prior GVHD) have similar vaccine response rates to adult donor allograft recipients supporting vaccination in CBT recipients. PMID:26271191

  16. Revving up Natural Killer Cells and Cytokine-Induced Killer Cells Against Hematological Malignancies.

    PubMed

    Pittari, Gianfranco; Filippini, Perla; Gentilcore, Giusy; Grivel, Jean-Charles; Rutella, Sergio

    2015-01-01

    Natural killer (NK) cells belong to innate immunity and exhibit cytolytic activity against infectious pathogens and tumor cells. NK-cell function is finely tuned by receptors that transduce inhibitory or activating signals, such as killer immunoglobulin-like receptors, NK Group 2 member D (NKG2D), NKG2A/CD94, NKp46, and others, and recognize both foreign and self-antigens expressed by NK-susceptible targets. Recent insights into NK-cell developmental intermediates have translated into a more accurate definition of culture conditions for the in vitro generation and propagation of human NK cells. In this respect, interleukin (IL)-15 and IL-21 are instrumental in driving NK-cell differentiation and maturation, and hold great promise for the design of optimal NK-cell culture protocols. Cytokine-induced killer (CIK) cells possess phenotypic and functional hallmarks of both T cells and NK cells. Similar to T cells, they express CD3 and are expandable in culture, while not requiring functional priming for in vivo activity, like NK cells. CIK cells may offer some advantages over other cell therapy products, including ease of in vitro propagation and no need for exogenous administration of IL-2 for in vivo priming. NK cells and CIK cells can be expanded using a variety of clinical-grade approaches, before their infusion into patients with cancer. Herein, we discuss GMP-compliant strategies to isolate and expand human NK and CIK cells for immunotherapy purposes, focusing on clinical trials of adoptive transfer to patients with hematological malignancies. PMID:26029215

  17. Young patients with hematologic and lymphatic malignancies have an increased risk of hip and knee arthroplasty.

    PubMed

    Niinimäki, Tuukka T; Ohtonen, Pasi; Harila-Saari, Arja H; Niinimäki, Riitta A

    2016-05-01

    Background Skeletal complications such as osteonecrosis (ON) are potential adverse events in patients treated for cancer, especially in those treated for hematologic and lymphatic malignancies (HLMs). ON may damage the hip or knee joints and may lead to arthrosis requiring total joint arthroplasty (TJA). The aim of this study was to address the risk of TJA in patients with cancer, especially those treated for HLM, in a nationwide population-based setting. Material and methods All patients who had undergone TJA after cancer diagnosis between the years 2000 and 2012 were identified by linking the Arthroplasty Register and the Cancer Registry. Standardized incidence ratios (SIRs) of TJAs were calculated to assess whether patients with any cancer, but especially HLM, have increased risk for TJA when compared with the general population. Results In patients with HLM or other cancer, the overall SIRs were similar compared with the general population. However, in HLM patients under 50 years of age, the SIR was 7.6, and in patients under 35 years of age, it was 45.5. The corresponding SIRs in patients with other cancers were 3.6 and 6.6, respectively. The highest SIRs, including all age groups, were among patients with acute lymphoblastic leukemia (SIR = 4.5) and acute myeloid leukemia (SIR = 1.9). Discussion HLMs imply an increased risk for TJA compared with the general population. The risk is especially high in patients younger than 50 years, regardless of the type of HLM. Young patients with HLM, as well as their healthcare providers, should be aware of the highly increased risk of skeletal complications requiring TJA. PMID:26967713

  18. Adequacy of high-dose cefepime regimen in febrile neutropenic patients with hematological malignancies.

    PubMed

    Sime, Fekade Bruck; Roberts, Michael S; Tiong, Ing Soo; Gardner, Julia H; Lehman, Sheila; Peake, Sandra L; Hahn, Uwe; Warner, Morgyn S; Roberts, Jason A

    2015-09-01

    While guidelines recommend empirical cefepime therapy in febrile neutropenia, the mortality benefit of cefepime has been controversial. In light of this, recent reports on pharmacokinetic changes for several antibiotics in febrile neutropenia and the consequent suboptimal exposure call for a pharmacokinetic/pharmacodynamic evaluation of current dosing. This study aimed to assess pharmacokinetic/pharmacodynamic target attainment from a 2-g intravenous (i.v.) every 8 h (q8h) cefepime regimen in febrile neutropenic patients with hematological malignancies. Cefepime plasma concentrations were measured in the 3rd, 6th, and 9th dosing intervals at 60% of the interval and/or trough point. The selected pharmacokinetic/pharmacodynamic targets were the proportion of the dosing interval (60% and 100%) for which the free drug concentration remains above the MIC (fT>MIC). Target attainment was assessed in reference to the MIC of isolated organisms if available or empirical breakpoints if not. The percentage of fT>MIC was also estimated by log-linear regression analysis. All patients achieved >60% fT>MIC in the 3rd and 6th dosing intervals. A 100% fT>MIC was not attained in 6/12, 4/10, and 4/9 patients in the 3rd, 6th, and 9th dose intervals, respectively, or in 14/31 (45%) of the dosing intervals investigated. On the other hand, 29/31 (94%) of trough concentrations were at or above 4 mg/liter. In conclusion, for patients with normal renal function, a high-dose 2-g i.v. q8h cefepime regimen appears to provide appropriate exposure if the MIC of the organism is ≤4 mg/liter but may fail to cover less susceptible organisms. PMID:26124158

  19. Hematopoietic stem cell transplantation in children with hematological malignancies across HLA barriers--reasonable alternative?

    PubMed

    Sedlácek, P; Starý, J; Vodváková, S; Poloucková, A; Gasová, Z; Marinov, I; Formánková, R

    2001-01-01

    The aim of this study was to evaluate the efficiency and risks of T-cell depletion in prevention of graft versus host disease (GVHD) using HLA haploidentical family donors as an alternative source of hematopoietic stem cells (HSC) in children with hematological malignancies without suitable matched donor. Ten children, median age 12 years (range, 3-17), were transplanted from haploidentical family donors for acute lymphoblastic leukemia (n = 4), acute myelogenous leukemia (n=2), chronic myelogenous leukemia (n = 2), non-Hodgkin lymphoma (n = 1) and myelodysplastic syndrome (n = 1). Parents were donors for nine, sibling for one patient. T-cell depletion of HSC was performed using CellPro followed by antiCD2/CD3 depletion in 7, and CliniMacs magnetic sorting in 3 grafts. Primary engraftment was achieved in nine patients. Patient with graft failure was successfully re-grafted. Primary acute GVHD was diagnosed in one patient who got higher amount of T-cells in the graft. Secondary GVHD was induced by add-backs of lymphocytes in four patients. Three patients developed chronic GVHD. Four patients died due to transplant related mortality (40%), one from veno-occlusive disease, two due to CMV pneumonia and one of aspergillosis with extensive chronic GVHD. Four patients relapsed with leukemia within 35-98 days post transplant, three without previous signs of GVHD, and all died. Two patients are alive and well 26 and 42 months after transplant. Haploidentical family donors appear to be a reasonable alternative option for patients with urgent indications for allogeneic transplant and/or without a matched donor. PMID:11712683

  20. Adequacy of High-Dose Cefepime Regimen in Febrile Neutropenic Patients with Hematological Malignancies

    PubMed Central

    Roberts, Michael S.; Tiong, Ing Soo; Gardner, Julia H.; Lehman, Sheila; Peake, Sandra L.; Hahn, Uwe; Warner, Morgyn S.; Roberts, Jason A.

    2015-01-01

    While guidelines recommend empirical cefepime therapy in febrile neutropenia, the mortality benefit of cefepime has been controversial. In light of this, recent reports on pharmacokinetic changes for several antibiotics in febrile neutropenia and the consequent suboptimal exposure call for a pharmacokinetic/pharmacodynamic evaluation of current dosing. This study aimed to assess pharmacokinetic/pharmacodynamic target attainment from a 2-g intravenous (i.v.) every 8 h (q8h) cefepime regimen in febrile neutropenic patients with hematological malignancies. Cefepime plasma concentrations were measured in the 3rd, 6th, and 9th dosing intervals at 60% of the interval and/or trough point. The selected pharmacokinetic/pharmacodynamic targets were the proportion of the dosing interval (60% and 100%) for which the free drug concentration remains above the MIC (fT>MIC). Target attainment was assessed in reference to the MIC of isolated organisms if available or empirical breakpoints if not. The percentage of fT>MIC was also estimated by log-linear regression analysis. All patients achieved >60% fT>MIC in the 3rd and 6th dosing intervals. A 100% fT>MIC was not attained in 6/12, 4/10, and 4/9 patients in the 3rd, 6th, and 9th dose intervals, respectively, or in 14/31 (45%) of the dosing intervals investigated. On the other hand, 29/31 (94%) of trough concentrations were at or above 4 mg/liter. In conclusion, for patients with normal renal function, a high-dose 2-g i.v. q8h cefepime regimen appears to provide appropriate exposure if the MIC of the organism is ≤4 mg/liter but may fail to cover less susceptible organisms. PMID:26124158

  1. Revving up Natural Killer Cells and Cytokine-Induced Killer Cells Against Hematological Malignancies

    PubMed Central

    Pittari, Gianfranco; Filippini, Perla; Gentilcore, Giusy; Grivel, Jean-Charles; Rutella, Sergio

    2015-01-01

    Natural killer (NK) cells belong to innate immunity and exhibit cytolytic activity against infectious pathogens and tumor cells. NK-cell function is finely tuned by receptors that transduce inhibitory or activating signals, such as killer immunoglobulin-like receptors, NK Group 2 member D (NKG2D), NKG2A/CD94, NKp46, and others, and recognize both foreign and self-antigens expressed by NK-susceptible targets. Recent insights into NK-cell developmental intermediates have translated into a more accurate definition of culture conditions for the in vitro generation and propagation of human NK cells. In this respect, interleukin (IL)-15 and IL-21 are instrumental in driving NK-cell differentiation and maturation, and hold great promise for the design of optimal NK-cell culture protocols. Cytokine-induced killer (CIK) cells possess phenotypic and functional hallmarks of both T cells and NK cells. Similar to T cells, they express CD3 and are expandable in culture, while not requiring functional priming for in vivo activity, like NK cells. CIK cells may offer some advantages over other cell therapy products, including ease of in vitro propagation and no need for exogenous administration of IL-2 for in vivo priming. NK cells and CIK cells can be expanded using a variety of clinical-grade approaches, before their infusion into patients with cancer. Herein, we discuss GMP-compliant strategies to isolate and expand human NK and CIK cells for immunotherapy purposes, focusing on clinical trials of adoptive transfer to patients with hematological malignancies. PMID:26029215

  2. Flow cytometry of p53 protein expression in some hematological malignancies.

    PubMed

    Koníková, E; Kusenda, J; Babusíková, O

    1999-01-01

    p53 is a tumor suppressor gene encoding a nuclear phosphoprotein that plays an important role in the control of normal cell proliferation. We have tried to establish the value of the p53 protein expression in peripheral blood (PB) and/or bone marrow (BM) cells of patients with some hematological malignancies. A recently developed fixation/permeabilization method was modified for flow cytometric assessment of p53 protein expression using two anti-p53 monoclonal antibodies. p53 quantitation expressed as molecules of equivalent soluble fluorochrome per cell (MESF) providing valuable data contributing to a more precise definition of leukemic cells, was also applied. Our findings showed higher percentage of p53 expression in cells of AML patients at the time of diagnosis opposite to the controls. These data, in association with immunophenotype of cells, accompanied diagnosis of relapse or definition of remission after allogeneic BM transplantation. We observed also elevated levels of p53 protein at initial diagnosis of early B-ALL. According to our results quantitation of p53 protein allows better characterization of selected population of BM cells and should be used for the monitoring of blast persistence during and after therapy and might also be one of the methods to indicate early relapse. Percentage of p53 protein positivity varied in our group of B-CLL patients tested in connection with progression of disease. We documented also one case of Burkitt's lymphoma with high percentage of p53 positivity. Measurement of p53 protein expression by flow cytometry may be of clinical importance by indicating levels of positivity. Our results suggest, that p53 alteration is frequently involved at initial diagnosis of AML, in some T-cell disorders and on the contrary more frequently during early B-ALL relapse, in advanced stages of B-CLL and in Burkitt's lymphoma. p53 protein quantitation is of value to ascertain malignancy and provides additional parameter suitable for the

  3. JAK kinase targeting in hematologic malignancies: a sinuous pathway from identification of genetic alterations towards clinical indications

    PubMed Central

    Springuel, Lorraine; Renauld, Jean-Christophe; Knoops, Laurent

    2015-01-01

    Constitutive JAK-STAT pathway activation occurs in most myeloproliferative neoplasms as well as in a significant proportion of other hematologic malignancies, and is frequently a marker of poor prognosis. The underlying molecular alterations are heterogeneous as they include activating mutations in distinct components (cytokine receptor, JAK, STAT), overexpression (cytokine receptor, JAK) or rare JAK2 fusion proteins. In some cases, concomitant loss of negative regulators contributes to pathogenesis by further boosting the activation of the cascade. Exploiting the signaling bottleneck provided by the limited number of JAK kinases is an attractive therapeutic strategy for hematologic neoplasms driven by constitutive JAK-STAT pathway activation. However, given the conserved nature of the kinase domain among family members and the interrelated roles of JAK kinases in many physiological processes, including hematopoiesis and immunity, broad usage of JAK inhibitors in hematology is challenged by their narrow therapeutic window. Novel therapies are, therefore, needed. The development of more selective inhibitors is a questionable strategy as such inhibitors might abrogate the beneficial contribution of alleviating the cancer-related pro-inflammatory microenvironment and raise selective pressure to a threshold that allows the emergence of malignant subclones harboring drug-resistant mutations. In contrast, synergistic combinations of JAK inhibitors with drugs targeting cascades that work in concert with JAK-STAT pathway appear to be promising therapeutic alternatives to JAK inhibitors as monotherapies. PMID:26432382

  4. Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: a systematic review.

    PubMed

    Howard, Scott C; Trifilio, Steven; Gregory, Tara K; Baxter, Nadine; McBride, Ali

    2016-03-01

    Effective new treatments are now available for patients with hematologic malignancies. However, their propensity to cause tumor lysis syndrome (TLS) has not been systematically examined. A literature search identified published Phase I-III clinical trials of monoclonal antibodies (otlertuzumab, brentuximab, obinutuzumab, ibritumomab, ofatumumab); tyrosine kinase inhibitors (alvocidib [flavopiridol], dinaciclib, ibrutinib, nilotinib, dasatinib, idelalisib, venetoclax [ABT-199]); proteasome inhibitors (oprozomib, carfilzomib); chimeric antigen receptor (CAR) T cells; and the proapoptotic agent lenalidomide. Abstracts from major congresses were also reviewed. Idelalisib and ofatumumab had no reported TLS. TLS incidence was ≤5 % with brentuximab vedotin (for anaplastic large-cell lymphoma), carfilzomib and lenalidomide (for multiple myeloma), dasatinib (for acute lymphoblastic leukemia), and oprozomib (for various hematologic malignancies). TLS incidences were 8.3 and 8.9 % in two trials of venetoclax (for chronic lymphocytic leukemia [CLL]) and 10 % in trials of CAR T cells (for B-cell malignancies) and obinutuzumab (for non-Hodgkin lymphoma). TLS rates of 15 % with dinaciclib and 42 and 53 % with alvocidib (with sequential cytarabine and mitoxantrone) were seen in trials of acute leukemias. TLS mitigation was employed routinely in clinical trials of alvocidib and lenalidomide. However, TLS mitigation strategies were not mentioned or stated only in general terms for many studies of other agents. The risk of TLS persists in the current era of novel and targeted therapy for hematologic malignancies and was seen to some extent with most agents. Our findings underscore the importance of continued awareness, risk assessment, and prevention to reduce this serious potential complication of effective anticancer therapy. PMID:26758269

  5. Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy.

    PubMed

    Law, Man Fai; Ho, Rita; Cheung, Carmen K M; Tam, Lydia H P; Ma, Karen; So, Kent C Y; Ip, Bonaventure; So, Jacqueline; Lai, Jennifer; Ng, Joyce; Tam, Tommy H C

    2016-07-28

    Hepatitis due to hepatitis B virus (HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc). Patients found to be positive for HBsAg should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving high-risk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although

  6. Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy

    PubMed Central

    Law, Man Fai; Ho, Rita; Cheung, Carmen K M; Tam, Lydia H P; Ma, Karen; So, Kent C Y; Ip, Bonaventure; So, Jacqueline; Lai, Jennifer; Ng, Joyce; Tam, Tommy H C

    2016-01-01

    Hepatitis due to hepatitis B virus (HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc). Patients found to be positive for HBsAg should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving high-risk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although

  7. Microarray Gene Expression Analysis to Evaluate Cell Type Specific Expression of Targets Relevant for Immunotherapy of Hematological Malignancies

    PubMed Central

    Honders, M. W.; Kremer, A. N.; van Kooten, C.; Out, C.; Hiemstra, P. S.; de Boer, H. C.; Jager, M. J.; Schmelzer, E.; Vries, R. G.; Al Hinai, A. S.; Kroes, W. G.; Monajemi, R.; Goeman, J. J.; Böhringer, S.; Marijt, W. A. F.; Falkenburg, J. H. F.; Griffioen, M.

    2016-01-01

    Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate potential efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. We performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlations between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers. PMID:27171398

  8. Integration of microarray analysis into the clinical diagnosis of hematological malignancies: How much can we improve cytogenetic testing?

    PubMed Central

    Peterson, Jess F.; Aggarwal, Nidhi; Smith, Clayton A.; Gollin, Susanne M.; Surti, Urvashi; Rajkovic, Aleksandar; Swerdlow, Steven H.; Yatsenko, Svetlana A.

    2015-01-01

    Purpose To evaluate the clinical utility, diagnostic yield and rationale of integrating microarray analysis in the clinical diagnosis of hematological malignancies in comparison with classical chromosome karyotyping/fluorescence in situ hybridization (FISH). Methods G-banded chromosome analysis, FISH and microarray studies using customized CGH and CGH+SNP designs were performed on 27 samples from patients with hematological malignancies. A comprehensive comparison of the results obtained by three methods was conducted to evaluate benefits and limitations of these techniques for clinical diagnosis. Results Overall, 89.7% of chromosomal abnormalities identified by karyotyping/FISH studies were also detectable by microarray. Among 183 acquired copy number alterations (CNAs) identified by microarray, 94 were additional findings revealed in 14 cases (52%), and at least 30% of CNAs were in genomic regions of diagnostic/prognostic significance. Approximately 30% of novel alterations detected by microarray were >20 Mb in size. Balanced abnormalities were not detected by microarray; however, of the 19 apparently “balanced” rearrangements, 55% (6/11) of recurrent and 13% (1/8) of non-recurrent translocations had alterations at the breakpoints discovered by microarray. Conclusion Microarray technology enables accurate, cost-effective and time-efficient whole-genome analysis at a resolution significantly higher than that of conventional karyotyping and FISH. Array-CGH showed advantage in identification of cryptic imbalances and detection of clonal aberrations in population of non-dividing cancer cells and samples with poor chromosome morphology. The integration of microarray analysis into the cytogenetic diagnosis of hematologic malignancies has the potential to improve patient management by providing clinicians with additional disease specific and potentially clinically actionable genomic alterations. PMID:26299921

  9. Favorable outcomes in patients surviving 5 or more years after allogeneic hematopoietic stem cell transplantation for hematologic malignancies.

    PubMed

    Le, Robert Quan; Bevans, Margaret; Savani, Bipin N; Mitchell, Sandra A; Stringaris, Kate; Koklanaris, Eleftheria; Barrett, A John

    2010-08-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for some hematologic malignancies. As the overall number of survivors continues to increase, studies systematically examining outcomes in long-term survivors are needed. We studied the clinical and quality-of-life outcomes in HSCT recipients surviving 5 or more years from HSCT. Since 1993, 262 patients with hematologic malignancies received a T cell-depleted myeloablative HSCT from an HLA-identical sibling at a single center. Ninety-two survived beyond 5 years from HSCT (median follow-up 9.4 years, range: 5.1-15.3). Median age at transplantation was 35 years (range: 10-56). Twenty-two (24%) received a bone marrow transplant, and 70 (76%) received a peripheral blood HSCT. Of the 92 survivors, 60 completed quality-of-life measures. The main outcomes examined were chronic graft-versus-host-disease, disease relapse, survival, health-related quality-of-life (HRQL) (Functional Assessment of Cancer Therapy-General), physical and mental health (SF-36), and symptom experience (Rotterdam Symptom Checklist). Seventy-five (82%) of 92 survivors no longer required systemic immunosuppressive treatment. Four (4.3%) relapsed with leukemia at a median of 8.5 years (range: 6.2-14.0) after HSCT. Four (4.3%) died between 7.4 and 13.4 years post-HSCT (1 relapse, 1 lung cancer, 1 pneumonia, 1 brain hemorrhage). Most survivors beyond 5 years had an excellent performance status with no difference in physical and mental health and higher HRQL scores (P = .02) compared with population norms. Although physical and psychologic symptom distress was low, those with higher symptom distress experienced inferior HRQL. These results show that 5 or more years after T cell-depleted HSCT for hematologic malignancy most individuals survive disease free with an excellent performance status, preserved physical and psychological health, and excellent HRQL. PMID:20302959

  10. A Pound of Cure Requires An Ounce (or More) of Prevention: Survivorship and Complications of Therapy for Hematologic Malignancies.

    PubMed

    Luskin, Marlise R; Banerjee, Rahul; Del Percio, Sarah; Loren, Alison W

    2015-09-01

    Patients treated for a hematologic malignancy are at risk for treatment-related complications. As the goal of therapy is frequently curative, treatments are especially intensive and long-term toxicity is common. Chemotherapy and radiation are associated with increased risk for cardiac and pulmonary disease, endocrine disorders, infertility, sexual dysfunction, second cancers, and psychosocial distress. The risk for each complication is dictated by patient characteristics including age, co-morbidities, and genetic predispositions, as well as the specifics of therapy. Survivors of pediatric cancers and allogeneic hematopoietic stem cell transplantation have unique risks due to vulnerable age at time of toxic exposure and ongoing immune dysfunction, respectively. PMID:26162948

  11. Invasive fungal infections in patients with hematologic malignancies (aurora project): lights and shadows during 18-months surveillance.

    PubMed

    Montagna, Maria Teresa; De Giglio, Osvalda; Napoli, Christian; Lovero, Grazia; Caggiano, Giuseppina; Delia, Mario; Pastore, Domenico; Santoro, Nicola; Specchia, Giorgina

    2012-01-01

    The aim of this multicenter prospective study was to evaluate the incidence of invasive fungal infections (IFIs) in adult and pediatric patients with hematologic malignancies, involving nine nosocomial facilities in Southern Italy over a period of 18 months. Furthermore, results of an environmental microbial surveillance routinely carried out in some of the enrolled hospitals are reported. A total of 589 onco-hematological patients were enrolled and 27 IFIs were documented. The main infections were caused by yeasts, more than filamentous fungi (overall incidence of 2.7% and 1.9%, respectively). The yeasts were mainly represented by Candida spp. (87.5%), all isolated by blood cultures; C. parapsilosis was the most common species. Among mould infections, the most frequent site was the lung, with regard to aspergillosis (81.8%). In six of the 10 patients with suspected aspergillosis, the diagnosis was made by the detection of galactomannan and (1,3)-β-d-glucan antigens. The microbiological surveillance carried out on 156 air, 312 water and 312 surface samples revealed low environmental contamination: Alternaria alternata was the only fungus isolated from two surface samples. Our data, especially the low occurrence of filamentous fungi, suggest a particular local epidemiology. Further studies are needed to confirm this microbiological trend in onco-hematological patients in Southern Italy, the results of which might be helpful to improve the management of these patients. PMID:22312285

  12. Invasive Fungal Infections in Patients with Hematologic Malignancies (Aurora Project): Lights and Shadows During 18-Months Surveillance

    PubMed Central

    Montagna, Maria Teresa; De Giglio, Osvalda; Napoli, Christian; Lovero, Grazia; Caggiano, Giuseppina; Delia, Mario; Pastore, Domenico; Santoro, Nicola; Specchia, Giorgina

    2012-01-01

    The aim of this multicenter prospective study was to evaluate the incidence of invasive fungal infections (IFIs) in adult and pediatric patients with hematologic malignancies, involving nine nosocomial facilities in Southern Italy over a period of 18 months. Furthermore, results of an environmental microbial surveillance routinely carried out in some of the enrolled hospitals are reported. A total of 589 onco-hematological patients were enrolled and 27 IFIs were documented. The main infections were caused by yeasts, more than filamentous fungi (overall incidence of 2.7% and 1.9%, respectively). The yeasts were mainly represented by Candida spp. (87.5%), all isolated by blood cultures; C. parapsilosis was the most common species. Among mould infections, the most frequent site was the lung, with regard to aspergillosis (81.8%). In six of the 10 patients with suspected aspergillosis, the diagnosis was made by the detection of galactomannan and (1,3)-β-d-glucan antigens. The microbiological surveillance carried out on 156 air, 312 water and 312 surface samples revealed low environmental contamination: Alternaria alternata was the only fungus isolated from two surface samples. Our data, especially the low occurrence of filamentous fungi, suggest a particular local epidemiology. Further studies are needed to confirm this microbiological trend in onco-hematological patients in Southern Italy, the results of which might be helpful to improve the management of these patients. PMID:22312285

  13. Immunogenicity of a monovalent influenza A(H1N1)pdm09 vaccine in patients with hematological malignancies

    PubMed Central

    Ide, Yuichiro; Imamura, Yutaka; Ohfuji, Satoko; Fukushima, Wakaba; Ide, Saburo; Tsutsumi, Chiyo; Koga, Masahisa; Maeda, Kazuhiro; Hirota, Yoshio

    2014-01-01

    Patients with hematological malignancies have high risk for morbidity and mortality from influenza. This study was conducted to evaluate the immunogenicity and reactogenicity of an influenza A(H1N1)pdm09 vaccine among such subjects. Fifty subjects were vaccinated twice during the 2009–2010 season. The antibody response was expressed in terms of mean fold rise (MFR) of geometric mean titer, seroresponse proportion (sR), and seroprotection proportion (sP). The first vaccination induced only a small response, and additional antibody was acquired after the second dose (MFR 2.3 and 3.9, sR 32% and 54%, and sP 30% and 48% after the first and the second vaccination, respectively). Rituximab treatment showed an especially inhibitory effect (MFR 1.3, sR 9% and sP 0%). When analyzed using logistic regression models, only rituximab was found to have an independent effect; the adjusted odds ratio for sR was 0.09 (P = 0.05). Influenza vaccination of patients with hematological malignancies resulted in adepuate response, and the second vaccination induced additional antibody. It is therefore recommended to vaccinate this group twice. PMID:25424946

  14. miR-29s: a family of epi-miRNAs with therapeutic implications in hematologic malignancies

    PubMed Central

    Amodio, Nicola; Rossi, Marco; Raimondi, Lavinia; Pitari, Maria Rita; Botta, Cirino; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2015-01-01

    A wealth of studies has highlighted the biological complexity of hematologic malignancies and the role of dysregulated signal transduction pathways. Along with the crucial role of genetic abnormalities, epigenetic aberrations are nowadays emerging as relevant players in cancer development, and significant research efforts are currently focusing on mechanisms by which histone post-translational modifications, DNA methylation and noncoding RNAs contribute to the pathobiology of cancer. As a consequence, these studies have provided the rationale for the development of epigenetic drugs, such as histone deacetylase inhibitors and demethylating compounds, some of which are currently in advanced phase of pre-clinical investigation or in clinical trials. In addition, a more recent body of evidence indicates that microRNAs (miRNAs) might target effectors of the epigenetic machinery, which are aberrantly expressed or active in cancers, thus reverting those epigenetic abnormalities driving tumor initiation and progression. This review will focus on the broad epigenetic activity triggered by members of the miR-29 family, which underlines the potential of miR-29s as candidate epi-therapeutics for the treatment of hematologic malignancies. PMID:25968566

  15. Risk of solid tumors and hematological malignancy in persons with Turner and Klinefelter syndromes: A national cohort study.

    PubMed

    Ji, Jianguang; Zöller, Bengt; Sundquist, Jan; Sundquist, Kristina

    2016-08-15

    The risk of solid and hematological malignancy in patients with Turner syndrome, characterized by X chromosome monosomy in women, and Klinefelter syndrome, characterized with two and more X chromosomes in men, is not well established, but such evidence may have etiological implications on cancer development. We identified a total of 1,409 women with Turner syndrome and 1,085 men with Klinefelter syndrome from the Swedish Hospital Discharge and Outpatient Register. These individuals were further linked to the Swedish Cancer Register to examine the standardized incidence ratios (SIRs) of cancer using the general population without Turner and Klinefelter syndromes as reference. The overall risk of cancer was 1.34 for women with Turner syndrome; it was increased only for solid tumors. For a specific type of tumor, the risk of melanoma and central nervous system tumor was significantly increased. For persons with Klinefelter syndrome, the risk of solid tumors was decreased (SIR = 0.66), whereas the risk of hematological malignancy was increased (SIR = 2.72). Non-Hodgkin lymphoma and leukemia showed an increased SIR of 3.02 and 3.62, respectively. Our study supported the hypothesis that X chromosome plays an important role in the etiology of solid tumors. The underlying mechanisms for the increased incidence of non-Hodgkin lymphoma and leukemia in persons with Klinefelter syndrome need to be investigated further. PMID:27061708

  16. miR-29s: a family of epi-miRNAs with therapeutic implications in hematologic malignancies.

    PubMed

    Amodio, Nicola; Rossi, Marco; Raimondi, Lavinia; Pitari, Maria Rita; Botta, Cirino; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2015-05-30

    A wealth of studies has highlighted the biological complexity of hematologic malignancies and the role of dysregulated signal transduction pathways. Along with the crucial role of genetic abnormalities, epigenetic aberrations are nowadays emerging as relevant players in cancer development, and significant research efforts are currently focusing on mechanisms by which histone post-translational modifications, DNA methylation and noncoding RNAs contribute to the pathobiology of cancer. As a consequence, these studies have provided the rationale for the development of epigenetic drugs, such as histone deacetylase inhibitors and demethylating compounds, some of which are currently in advanced phase of pre-clinical investigation or in clinical trials. In addition, a more recent body of evidence indicates that microRNAs (miRNAs) might target effectors of the epigenetic machinery, which are aberrantly expressed or active in cancers, thus reverting those epigenetic abnormalities driving tumor initiation and progression. This review will focus on the broad epigenetic activity triggered by members of the miR-29 family, which underlines the potential of miR-29s as candidate epi-therapeutics for the treatment of hematologic malignancies. PMID:25968566

  17. Informal Financial Assistance for Patients With a Hematological Malignancy: Implications for Oncology Social Work Practice.

    PubMed

    McGrath, Pam

    2015-01-01

    The article presents original research findings on informal financial assistance for hematological patients; that is, the gifts from family, friends, and communities that help patients cope with the financial hardship associated with cancer. The qualitative study involved interviews with 45 hematology patients that were audio-recorded, transcribed, coded, and then thematically analyzed. The findings examine the differing perspectives that individuals and families bring to the notion of informal financial aid, provide examples of individuals who require and receive informal financial assistance, and conclude with descriptions of those who require informal financial assistance but it is not available. The implications of the findings for oncology social work practice are explored. PMID:26671243

  18. Inhibition of CXCR4 by LY2624587, a Fully Humanized Anti-CXCR4 Antibody Induces Apoptosis of Hematologic Malignancies

    PubMed Central

    Peng, Sheng-Bin; Zhang, Xiaoyi; Paul, Donald; Kays, Lisa M.; Ye, Ming; Vaillancourt, Peter; Dowless, Michele; Stancato, Louis F.; Stewart, Julie; Uhlik, Mark T.; Long, Haiyan; Chu, Shaoyou; Obungu, Victor H.

    2016-01-01

    SDF-1 and CXCR4 are a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. Overexpression of CXCR4 is a hallmark of many hematological malignancies including acute myeloid leukemia, chronic lymphocytic leukemia and non-Hodgkin’s lymphoma, and generally correlates with a poor prognosis. In this study, we developed a humanized anti-CXCR4 monoclonal antibody, LY2624587 as a potent CXCR4 antagonist that was advanced into clinical study for cancer. LY2624587 blocked SDF-1 binding to CXCR4 with an IC50 of 0.26 nM, and inhibited SDF-1-induced GTP binding with a Kb of 0.66 nM. In human lymphoma U937 and leukemia CCRF-CEM cells expressing endogenous CXCR4, LY2624587 inhibited SDF-1-induced cell migration with IC50 values of 3.7 and 0.26 nM, respectively. This antibody also inhibited CXCR4 and SDF-1 mediated cell signaling including activation of MAPK and AKT in tumor cells expressing CXCR4. Bifocal microscopic and flow cytometry analyses revealed that LY2624587 mediated receptor internalization and caused CXCR4 down-regulation on the cell surface. In human hematologic cancer cells, LY2624587 caused dose dependent apoptosis in vitro and in vivo. In mouse xenograft models developed with human leukemia and lymphoma cells expressing high levels of CXCR4, LY2624587 exhibited dose-dependent tumor growth inhibition and provided significant survival benefit in a disseminated lymphoma model. Collectively, we have demonstrated that CXCR4 inhibition by LY2624587 has the potential for the treatment of human hematological malignancies. PMID:26954567

  19. STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model

    PubMed Central

    Couronné, Lucile; Scourzic, Laurianne; Pilati, Camilla; Valle, Véronique Della; Duffourd, Yannis; Solary, Eric; Vainchenker, William; Merlio, Jean-Philippe; Beylot-Barry, Marie; Damm, Frederik; Stern, Marc-Henri; Gaulard, Philippe; Lamant, Laurence; Delabesse, Eric; Merle-Beral, Hélène; Nguyen-Khac, Florence; Fontenay, Michaëla; Tilly, Hervé; Bastard, Christian; Zucman-Rossi, Jessica; Bernard, Olivier A.; Mercher, Thomas

    2013-01-01

    STAT3 protein phosphorylation is a frequent event in various hematologic malignancies and solid tumors. Acquired STAT3 mutations have been recently identified in 40% of patients with T-cell large granular lymphocytic leukemia, a rare T-cell disorder. In this study, we investigated the mutational status of STAT3 in a large series of patients with lymphoid and myeloid diseases. STAT3 mutations were identified in 1.6% (4 of 258) of patients with T-cell neoplasms, in 2.5% (2 of 79) of patients with diffuse large B-cell lymphoma but in no other B-cell lymphoma patients (0 of 104) or patients with myeloid malignancies (0 of 96). Functional in vitro assays indicated that the STAT3Y640F mutation leads to a constitutive phosphorylation of the protein. STA21, a STAT3 small molecule inhibitor, inhibited the proliferation of two distinct STAT3 mutated cell lines. Using a mouse bone marrow transplantation assay, we observed that STAT3Y640F expression leads to the development of myeloproliferative neoplasms with expansion of either myeloid cells or megakaryocytes. Together, these data indicate that the STAT3Y640F mutation leads to constitutive activation of STAT3, induces malignant hematopoiesis in vivo, and may represent a novel therapeutic target in some lymphoid malignancies. PMID:23872306

  20. CC-486 (Oral Azacitidine) Bioequivalence Study in Patients With Solid Tumor or Hematologic Malignancies

    ClinicalTrials.gov

    2016-08-10

    Hematological Neoplasms; Non-Hodgkin's Lymphoma; Hodgkin's Lymphoma; Lymphoma; Multiple Myeloma; Acute Myeloid Leukemia; Leukemia; Myelodysplastic Syndromes; Neoplasms; Melanoma; Breast Cancer; Metastatic Breast Cancer; Non-Small Cell Lung Cancer; Small Cell Lung Cancer; Renal Cell Carcinoma; Glioblastoma Multiforme; Osteosarcoma; Sarcoma; Thyroid Cancer; Genitourinary

  1. T-Cell Depleted Allogeneic Stem Cell Transplantation for Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2015-10-05

    Acute Myelogenous Leukemia; Lymphoid Leukemia; Chronic Myelogenous Leukemia; Malignant Lymphoma; Hodgkin's Disease; Chronic Lymphocytic Leukemia; Myeloproliferative Disorder; Anemia, Aplastic; Myelodysplastic Syndromes

  2. TNF-related apoptosis-inducing ligand (TRAIL): a potential candidate for combined treatment of hematological malignancies.

    PubMed

    Secchiero, Paola; Vaccarezza, Mauro; Gonelli, Arianna; Zauli, Giorgio

    2004-01-01

    TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF gene superfamily, which induces apoptosis through engagement of death receptors. TRAIL is unusual as compared to the other cytokines of this family, as it interacts with a complex system of receptors consisting of two pro-apoptotic death receptors (TRAIL-R1 and TRAIL-R2) and three decoy receptors (TRAIL-R3, TRAIL-R4 and osteoprotegerin). Moreover, with respect to other members of the TNF superfamily, such as CD95L and TNF-alpha, TRAIL has generated great interest as a potential tumor-specific cancer therapeutic because as a stable soluble trimer it selectively induces apoptosis in many transformed cells but not in normal cells. Of note, TRAIL cytotoxicity is at least partially independent of the major systems involved in resistance to chemotherapy, such as p53 wild-type function and multidrug resistance (MDR) genes. Since one fundamental problem of most cancers is the development of multiple mechanisms of resistance, which progressively reduce or suppress the therapeutic efficacy of conventional chemotherapy, new therapeutic approaches that either restore the pro-apoptotic activity of chemotherapeutic drugs or by-pass the mechanisms of resistance are highly desirable. This review will focus on the potential of TRAIL for its application in the therapy of hematological malignancies, used either alone or in combination with chemotherapy. The scenario emerging from the literature is that the treatment and management of hematological malignancies will require the rational combination of TRAIL plus conventional or new drugs in a regimen that would optimize the anti-neoplastic activity in malignant cells resistant to chemotherapy through restoration of the pro-apoptotic activity of TRAIL. PMID:15579063

  3. Radiation Therapy and Late Mortality From Second Sarcoma, Carcinoma, and Hematological Malignancies After a Solid Cancer in Childhood

    SciTech Connect

    Tukenova, Markhaba; Guibout, Catherine; Hawkins, Mike; Quiniou, Eric; Mousannif, Abddedahir; Pacquement, Helene; Winter, David; Bridier, Andre; Lefkopoulos, Dimitri; Oberlin, Odile; Diallo, Ibrahima; Vathaire, Florent de

    2011-06-01

    Purpose: To compare patterns of long-term deaths due to secondary carcinomas, sarcomas, and hematological malignancies occurring after childhood cancer in a cohort of patients followed over a median of 28 years. Methods and Materials: The study included 4,230 patients treated at eight institutions, who were at least 5-year survivors of a first cancer, representing 105,670 person-years of observation. Complete clinical, chemotherapeutic, and radiotherapeutic data were recorded, and the integral radiation dose was estimated for 2,701 of the 2,948 patients who had received radiotherapy. The integral dose was estimated for the volume inside the beam edges. The causes of death obtained from death certificates were validated. Results: In total, 134 events were due to second malignant neoplasm(s) (SMN). We found that the standardized mortality ratio decreased with increasing follow-up for second carcinomas and sarcomas, whereas the absolute excess risk (AER) increased for a second carcinoma but decreased for second sarcomas. There was no clear variation in SMN and AER for hematological malignancies. We found a significant dose-response relationship between the radiation dose received and the mortality rate due to a second sarcoma and carcinoma. The risk of death due to carcinoma and sarcoma as SMN was 5.2-fold and 12.5-fold higher, respectively, in patients who had received a radiation dose exceeding 150 joules. Conclusions: Among patients who had received radiotherapy, only those having received the highest integral radiation dose actually had a higher risk of dying of a second carcinoma or sarcoma.

  4. Therapeutic Challenges of Hepatic Mucormycosis in Hematologic Malignancy: A Case Report and Review of the Literature

    PubMed Central

    Bernardo, Raffaele M.; Gurung, Ananta; Jain, Dhanpat; Malinis, Maricar F.

    2016-01-01

    Patient: Female, 58 Final Diagnosis: Hepatic mucormycosis Symptoms: Abdominal pain • fever Medication: Amphotericin • posaconazole Clinical Procedure: IR-guided aspiration Specialty: Infectious Diseases Objective: Rare disease Background: The clinical presentation of mucormycosis can vary widely based on various host factors. Among malignancy-and bone marrow transplant-associated infections, the lungs are the most common site of infection. Involvement of the gastrointestinal tract is less frequently encountered. The clinical presentation is often nonspecific, and cultures typically yield no growth, making the diagnosis challenging. Case Report: We present a case of isolated hepatic mucormycosis in the setting of neutropenic fever and abdominal pain following induction chemotherapy for the treatment of acute myeloid leukemia. The patient was treated with combination antifungal therapy with amphotericin and posaconazole without surgical resection, given the presence of multiple liver lesions. After a prolonged course of dual antifungal therapy, the size of her liver lesions improved. Unfortunately, her lymphoproliferative disorder proved fatal, following approximately 13 months of antifungal therapy. Conclusions: Among patient with mucormycosis, mortality remains high, especially in the setting of gastrointestinal involvement. Although surgical resection along with dual antifungal therapy can improve outcomes, the high mortality rate necessitates further investigation into improved diagnostic and treatment strategies including optimal antifungal therapy. PMID:27406045

  5. The Arg399Gln polymorphism in the XRCC1 gene is associated with increased risk of hematological malignancies.

    PubMed

    Du, Liang; Liu, Yuqi; Xue, Pei; Song, Chenxi; Shen, Jiani; He, Qing; Peng, Yuanling; Tong, Xiang; Tang, Lizhi; Zhang, Yonggang

    2015-06-01

    The associations between the Arg399Gln polymorphism in X-ray repair cross-complementing gene 1 (XRCC1) gene and the risk of hematological malignancies have been extensively investigated. However, the results were inconsistent. The objective of the current study is to investigate the association by meta-analysis. We searched PubMed database, Embase database, CNKI database, Wanfang database, and Weipu database, covering all studies until August 7, 2013. Statistical analysis was performed by using the Revman4.2 software and the Stata10.0 software. A total of 27 case-control studies concerning the Arg399Gln polymorphism were included from 26 articles. The results suggested that the Arg399Gln polymorphism was not associated with an increased/decreased risk of hematological malignancies in total analysis (OR = 1.15, 95 % confidence interval (CI) = 0.97-1.35, P = 0.10 for Arg/Gln + Gln/Gln vs. Arg/Arg). In the subgroup analysis by ethnicity and cancer types, significant association was found in Asians (OR = 1.35, 95 % CI = 1.04-1.75, P = 0.03) but not in Europeans (OR = 1.07, 95 % CI = 0.86-1.33, P = 0.56), and in leukemia (OR = 1.25, 95 % CI = 1.02-1.54, P = 0.03) but not in lymphoma (OR = 0.98, 95 % CI = 0.80-1.20, P = 0.84) or myeloma (OR = 1.13, 95 % CI = 0.23-5.69, P = 0.88). The current meta-analysis indicated that the Arg399Gln polymorphism in the XRCC1 gene might be a risk factor for hematological malignancies in Asians or for leukemia. In future, more large-scale case-control studies are needed to validate these results. PMID:25619474

  6. Early and late complications related to central venous catheters in hematological malignancies: a retrospective analysis of 1102 patients.

    PubMed

    Morano, Salvatore Giacomo; Coppola, Lorenzo; Latagliata, Roberto; Berneschi, Paola; Chistolini, Antonio; Micozzi, Alessandra; Girmenia, Corrado; Breccia, Massimo; Brunetti, Gregorio; Massaro, Fulvio; Rosa, Giovanni; Guerrisi, Pietro; Mandelli, Franco; Foà, Roberto; Alimena, Giuliana

    2014-01-01

    Several severe complications may be associated with the use of central venous catheters (CVC). We retrospectively evaluated on a large cohort of patients the incidence of CVC-related early and late complications. From 7/99 to 12/2005, 1102 CVC have been implanted at our Institution in 881 patients with hematological malignancies (142,202 total day number of implanted CVC). Early mechanic complications were 79 (7.2% - 0.55/1,000 days/CVC). Thirty-nine episodes of early infective complications (<1 week from CVC implant) occurred (3.5% - 0.3/1000 days/CVC): furthermore, 187 episodes of CVC-related sepsis (17% - 1.3/1000 days/CVC) were recorded. There were 29 episodes (2.6%) of symptomatic CVC-related thrombotic complications, with a median interval from CVC implant of 60 days (range 7 - 395). The rate of CVC withdrawal due to CVC-related complications was 26%. The incidence of CVC-related complications in our series is in the range reported in the literature notwithstanding cytopenia often coexisting in hematological patients. PMID:24678388

  7. Early and Late Complications Related to Central Venous Catheters in Hematological Malignancies: a Retrospective Analysis of 1102 Patients

    PubMed Central

    Morano, Salvatore Giacomo; Coppola, Lorenzo; Latagliata, Roberto; Berneschi, Paola; Chistolini, Antonio; Micozzi, Alessandra; Girmenia, Corrado; Breccia, Massimo; Brunetti, Gregorio; Massaro, Fulvio; Rosa, Giovanni; Guerrisi, Pietro; Mandelli, Franco; Foà, Roberto; Alimena, Giuliana

    2014-01-01

    Several severe complications may be associated with the use of central venous catheters (CVC). We retrospectively evaluated on a large cohort of patients the incidence of CVC-related early and late complications. From 7/99 to 12/2005, 1102 CVC have been implanted at our Institution in 881 patients with hematological malignancies (142,202 total day number of implanted CVC). Early mechanic complications were 79 (7.2% - 0.55/1,000 days/CVC). Thirty-nine episodes of early infective complications (<1 week from CVC implant) occurred (3.5% - 0.3/1000 days/CVC): furthermore, 187 episodes of CVC-related sepsis (17% - 1.3/1000 days/CVC) were recorded. There were 29 episodes (2.6%) of symptomatic CVC-related thrombotic complications, with a median interval from CVC implant of 60 days (range 7 – 395). The rate of CVC withdrawal due to CVC-related complications was 26%. The incidence of CVC-related complications in our series is in the range reported in the literature notwithstanding cytopenia often coexisting in hematological patients. PMID:24678388

  8. Diagnosis of Invasive Fungal Diseases in Hematological Malignancies: A Critical Review of Evidence and Turkish Expert Opinion (TEO-2)

    PubMed Central

    Arıkan Akdağlı, Sevtap; Azap, Alpay; Başaran Demirkazık, Figen; Ener, Beyza; Aşcıoğlu Hayran, Sibel; Özdemir Kumbasar, Özlem; Metan, Gökhan; Odabaşı, Zekaver; Uzun, Ömrüm; Akan, Hamdi

    2014-01-01

    One of the most problematic issues in hematological malignancies is the diagnosis of invasive fungal diseases. Especially, the difficulty of mycological diagnosis and the necessity of immediate intervention in molds have led to the adoption of “surrogate markers” that do not verify but rather strongly suggest fungal infection. The markers commonly used are galactomannan (GM), beta-glucan, and imaging methods. Although there are numerous studies on these diagnostic approaches, none of these markers serve as a support for the clinician, as is the case in human immunodeficiency virus (HIV) or cytomegalovirus (CMV) infections. This paper has been prepared to explain the diagnostic tests. As molecular tests have not been standardized and are not used routinely in the clinics, they will not be mentioned here. PMID:25541650

  9. ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies

    PubMed Central

    Ishizawa, Jo; Kojima, Kensuke; Chachad, Dhruv; Ruvolo, Peter; Ruvolo, Vivian; Jacamo, Rodrigo O.; Borthakur, Gautam; Mu, Hong; Zeng, Zhihong; Tabe, Yoko; Allen, Joshua E.; Wang, Zhiqiang; Ma, Wencai; Lee, Hans C.; Orlowski, Robert; Sarbassov, Dos D.; Lorenzi, Philip L.; Huang, Xuelin; Neelapu, Sattva S.; McDonnell, Timothy; Miranda, Roberto N.; Wang, Michael; Kantarjian, Hagop; Konopleva, Marina; Davis, R. Eric.; Andreeff, Michael

    2016-01-01

    The clinical challenge posed by p53 abnormalities in hematological malignancies requires therapeutic strategies other than standard genotoxic chemotherapies. ONC201 is a first-in-class small molecule that activates p53-independent apoptosis, has a benign safety profile, and is in early clinical trials. We found that ONC201 caused p53-independent apoptosis and cell cycle arrest in cell lines and in mantle cell lymphoma (MCL) and acute myeloid leukemia (AML) samples from patients; these included samples from patients with genetic abnormalities associated with poor prognosis or cells that had developed resistance to the nongenotoxic agents ibrutinib and bortezomib. Moreover, ONC201 caused apoptosis in stem and progenitor AML cells and abrogated the engraftment of leukemic stem cells in mice while sparing normal bone marrow cells. ONC201 caused changes in gene expression similar to those caused by the unfolded protein response (UPR) and integrated stress responses (ISRs), which increase the translation of the transcription factor ATF4 through an increase in the phosphorylation of the translation initiation factor eIF2α. However, unlike the UPR and ISR, the increase in ATF4 abundance in ONC201-treated hematopoietic cells promoted apoptosis and did not depend on increased phosphorylation of eIF2α. ONC201 also inhibited mammalian target of rapamycin complex 1 (mTORC1) signaling, likely through ATF4-mediated induction of the mTORC1 inhibitor DDIT4. Overexpression of BCL-2 protected against ONC201-induced apoptosis, and the combination of ONC201 and the BCL-2 antagonist ABT-199 synergistically increased apoptosis. Thus, our results suggest that by inducing an atypical ISR and p53-independent apoptosis, ONC201 has clinical potential in hematological malignancies. PMID:26884599

  10. ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies.

    PubMed

    Ishizawa, Jo; Kojima, Kensuke; Chachad, Dhruv; Ruvolo, Peter; Ruvolo, Vivian; Jacamo, Rodrigo O; Borthakur, Gautam; Mu, Hong; Zeng, Zhihong; Tabe, Yoko; Allen, Joshua E; Wang, Zhiqiang; Ma, Wencai; Lee, Hans C; Orlowski, Robert; Sarbassov, Dos D; Lorenzi, Philip L; Huang, Xuelin; Neelapu, Sattva S; McDonnell, Timothy; Miranda, Roberto N; Wang, Michael; Kantarjian, Hagop; Konopleva, Marina; Davis, R Eric; Andreeff, Michael

    2016-02-16

    The clinical challenge posed by p53 abnormalities in hematological malignancies requires therapeutic strategies other than standard genotoxic chemotherapies. ONC201 is a first-in-class small molecule that activates p53-independent apoptosis, has a benign safety profile, and is in early clinical trials. We found that ONC201 caused p53-independent apoptosis and cell cycle arrest in cell lines and in mantle cell lymphoma (MCL) and acute myeloid leukemia (AML) samples from patients; these included samples from patients with genetic abnormalities associated with poor prognosis or cells that had developed resistance to the nongenotoxic agents ibrutinib and bortezomib. Moreover, ONC201 caused apoptosis in stem and progenitor AML cells and abrogated the engraftment of leukemic stem cells in mice while sparing normal bone marrow cells. ONC201 caused changes in gene expression similar to those caused by the unfolded protein response (UPR) and integrated stress responses (ISRs), which increase the translation of the transcription factor ATF4 through an increase in the phosphorylation of the translation initiation factor eIF2α. However, unlike the UPR and ISR, the increase in ATF4 abundance in ONC201-treated hematopoietic cells promoted apoptosis and did not depend on increased phosphorylation of eIF2α. ONC201 also inhibited mammalian target of rapamycin complex 1 (mTORC1) signaling, likely through ATF4-mediated induction of the mTORC1 inhibitor DDIT4. Overexpression of BCL-2 protected against ONC201-induced apoptosis, and the combination of ONC201 and the BCL-2 antagonist ABT-199 synergistically increased apoptosis. Thus, our results suggest that by inducing an atypical ISR and p53-independent apoptosis, ONC201 has clinical potential in hematological malignancies. PMID:26884599

  11. Longitudinal Changes in Body Mass and Composition in Survivors of Childhood Hematologic Malignancies After Allogeneic Hematopoietic Stem-Cell Transplantation

    PubMed Central

    Inaba, Hiroto; Yang, Jie; Kaste, Sue C.; Hartford, Christine M.; Motosue, Megan S.; Chemaitilly, Wassim; Triplett, Brandon M.; Shook, David R.; Pui, Ching-Hon; Leung, Wing

    2012-01-01

    Purpose To measure longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation (HSCT). Patients and Methods Body mass index (BMI) was analyzed in 179 survivors by category (underweight, healthy-weight, overweight, and obese) and by z score. Fat and lean body mass measured by dual-energy x-ray absorptiometry was analyzed as z scores. Results Over a median 6.6 years of follow-up, BMI z scores diminished significantly (0.32 pre-HSCT v −0.60 at 10 years post-HSCT; P < .001). Mean z scores for fat mass stayed within population norms, but those for lean mass remained below normal levels and diminished significantly over time (P = .018). Pre-HSCT BMI category and/or z score were strongly predictive of post-HSCT BMI (P < .001) and of fat and lean mass z scores (both P < .001). Survivors with extensive chronic graft-versus-host disease were more likely than others to have low BMI (P = .004) and low lean mass (P < .001) post-HSCT. Older age at HSCT (P = .015) and T-cell–depleted graft (P = .018) were predictive of lower post-HSCT BMI. Female patients had higher body fat (P = .002) and lower lean mass (P = .013) z scores than male patients, and black patients had higher fat mass z scores than white patients (P = .026). Conclusion BMI declines significantly after allogeneic HSCT for childhood hematologic malignancies, reflecting primarily a substantial decrease in lean mass but not fat mass. Monitoring and preservation of BMI and lean mass are vital, especially in those with the identified risk factors. PMID:23032628

  12. Impact of hematopoietic chimerism at day +14 on engraftment after unrelated donor umbilical cord blood transplantation for hematologic malignancies

    PubMed Central

    Moscardó, Federico; Sanz, Jaime; Senent, Leonor; Cantero, Susana; de la Rubia, Javier; Montesinos, Pau; Planelles, Dolores; Lorenzo, Ignacio; Cervera, Jose; Palau, Javier; Sanz, Miguel A.; Sanz, Guillermo F.

    2009-01-01

    Background Cord blood transplant is a feasible treatment alternative for adult patients with hematologic malignancies lacking a suitable HLA-matched donor. However, the kinetics of myeloid recovery is slow, and primary graft failure cannot be detected easily early after transplantation. We investigated the impact of hematopoietic chimerism status from unselected marrow cells 14 days after transplantation on predicting engraftment after a cord blood transplant. Design and Methods Seventy-one adult patients with hematologic malignancies undergoing single-unit unrelated donor cord blood transplantation after a myeloablative conditioning regimen were included in the study. All patients received conditioning regimens based on busulfan, thiotepa and antithymocyte globulin. Chimerism status was assessed analyzing short tandem repeat polymorphisms. Results The cumulative incidence of myeloid engraftment at 1 month was significantly lower in patients with mixed chimerism than in those with complete donor chimerism (55% vs. 94%; p<0.0001). For patients achieving myeloid recovery, the median time of engraftment was 16 days when donor chimerism at day + 14 was higher than 90%, compared with 24 days when donor chimerism was below this level (p<0.001). A donor chimerism level of 65% was found to be the best cut-off point for predicting primary graft failure, with a sensitivity of 97% and a specificity of 80%. The incidence of primary graft failure was 67% for patients with less than 65% donor chimerism at day +14 as compared to only 2% for those with more than 65% donor chimerism (p<0.001). Patients with mixed chimerism also had a lower cumulative incidence of platelet engraftment than those with complete chimerism (62% vs. 89%; p=0.01). Conclusions Donor-recipient chimerism status at day +14 predicts engraftment after a single-unit cord blood transplant in adults. PMID:19483157

  13. Myelosuppression grading of chemotherapies for hematologic malignancies to facilitate communication between medical and dental staff: lessons from two cases experienced odontogenic septicemia

    PubMed Central

    2013-01-01

    Background Odontogenic diseases can be a risk factor for life-threatening infection in patients with hematologic malignancies during chemotherapy that induces myelosuppression of variable severity. Previous studies noted the necessity of the elimination of all odontogenic foci before hematopoietic stem cell transplantation. To enable planning for the adequate dental intervention, the oral medicine team must understand the general status of patient and the intensity of the chemotherapy, which is sometimes difficult to be fully appreciated by dental staff. Therefore, a simplified grading would facilitate the sharing of information between hematologists, dentists and oral hygienists. This study aimed to introduce our myelosuppression grading of chemotherapies for hematologic malignancies and analyze the timing of occurrence of severe odontogenic infection. Methods 37 patients having received various chemotherapies for hematologic malignancies were enrolled. The chemotherapy regimens were classified into four grades based on the persistency of myelosuppression induced by chemotherapy. Mild myelosuppressive chemotherapies were classified as grade A, moderate ones as grade B, severe ones as grade C, and chemotherapies that caused severe myelosuppression and persistent immunodeficiency (known as conditioning regimens for transplant) as grade D. The timing of occurrence of severe odontogenic infection was retrospectively investigated. Results Two patients (5.4%) had severe odontogenic infections after grade B or C chemotherapy. One occurred after extraction of non-salvageable teeth; the other resulted from advanced periodontitis in a tooth that could not be extracted because of thrombocytopenia. Both were de novo hematologic malignancy patients. During grade D chemotherapy, no patients had severe odontogenic infections. Conclusions The simplified grading introduced in this study is considered a useful tool for understanding the myelosuppressive state caused by chemotherapy

  14. Prolonged Subcutaneous Administration of 852A, a Novel Systemic Toll-like Receptor 7 Agonist, to Activate Innate Immune Responses in Patients with Advanced Hematologic Malignancies

    PubMed Central

    Weigel, Brenda J.; Cooley, Sarah; DeFor, Todd; Weisdorf, Daniel J.; Panoskaltsis-Mortari, Angela; Chen, Wei; Blazar, Bruce R.; Miller, Jeffrey S.

    2013-01-01

    The toll-like receptor (TLR) 7 agonist 852A, a small-molecule imidazoquinoline, stimulates plasmacytoid dendritic cells to produce multiple cytokines. We conducted a Phase II study of 852A in patients with recurrent hematologic malignancies. The primary objective was assessing the activity of 852A administered subcutaneously twice weekly for 12 weeks. Secondary objectives were assessing the safety of 852A and its ability to activate the immune system with prolonged dosing. Methods Patients with relapsed hematologic malignancies of any age with adequate organ function were eligible. Patients initiated dosing at 0.6 mg/m2 twice weekly and escalated by 0.2 mg/m2 after every 2 doses as tolerated to a target dose of 1.2 mg/m2. Patients with responses or stable disease were eligible for additional cycles. Results Seventeen patients (15 males) entered the study: 6 with AML, 5 ALL, 4 NHL, 1 Hodgkin’s lymphoma, and 1 multiple myeloma. The mean age was 41 years (12–71 years). The median number of prior chemotherapy regimens was 5 (range=1–14). Thirteen patients completed all 24 injections. Grade 3–4 toxicities included nausea, dyspnea, fever, myalgia, malaise, and cough. Responses included 1 complete response (ALL), 1 partial response (AML), 2 stable disease (AML and NHL), and 9 progressive disease. Conclusions This is the first in-human hematologic malignancy trial of a subcutaneously (SC) delivered TLR7 agonist using a prolonged dosing schedule. 852A was safely administered up to 1.2 mg/m2 twice weekly with evidence of sustained tolerability and clinical activity in hematologic malignancies. Systemic TLR agonists for the treatment of hematologic malignancies warrant further study. PMID:22718533

  15. Prospective trial finds nystatin mouthwash effective prophylaxis for pulmonary invasive fungal infections that originate in the throat of patients with hematologic malignancies.

    PubMed

    Hu, R; Jiang, X; Wu, Y

    2013-01-01

    We investigated the source of fungi in the lungs of patients with hematological malignancies who had invasive pulmonary fungal infections (IPFI). We also conducted a prospective study to evaluate the efficacy of different mouthwash solutions in preventing IPFI in patients with hematologic malignancies. In order to determine the source of fungi in the lungs of 30 patients with hematologic malignancies who had IPFI, we collected samples from sites with suspected fungal infection and used PCR and sequencing for pathogen identification. For the prospective study, we enrolled 158 patients with hematological malignancies who had IPFI and randomly assigned them to one of three mouthwash groups: 1% nystatin, 2.5% sodium bicarbonate, or normal saline. Fungal staining and incidence of IPFI, oral fungal infection, and intestinal fungal infection were evaluated. We showed that 96.7% of the fungi isolated from the throats and the lungs were identical; 76.9% of the fungi from the lungs and digestive tracts were identical and, 84.6 % of the fungi from the throats and digestive tract were identical. Patients using 1% nystatin had lower incidence of IPFI (1.6%) and fungal enteritis (1.6%) than those using sodium bicarbonate (16.3% and 14.3%) or normal saline (27.7% and 12.8%). All treatments had low incidences of oral fungal infections (0 to 4.3%). Our data showed that fungi originating from mouth and throat cause IPFI. We also showed that use of a prophylactic mouthwash containing 1% nystatin was effective in preventing IPFI in patients with hematological malignancies. PMID:23374002

  16. Adoptive Immunotherapy for Hematological Malignancies Using T Cells Gene-Modified to Express Tumor Antigen-Specific Receptors

    PubMed Central

    Fujiwara, Hiroshi

    2014-01-01

    Accumulating clinical evidence suggests that adoptive T-cell immunotherapy could be a promising option for control of cancer; evident examples include the graft-vs-leukemia effect mediated by donor lymphocyte infusion (DLI) and therapeutic infusion of ex vivo-expanded tumor-infiltrating lymphocytes (TIL) for melanoma. Currently, along with advances in synthetic immunology, gene-modified T cells retargeted to defined tumor antigens have been introduced as “cellular drugs”. As the functional properties of the adoptive immune response mediated by T lymphocytes are decisively regulated by their T-cell receptors (TCRs), transfer of genes encoding target antigen-specific receptors should enable polyclonal T cells to be uniformly redirected toward cancer cells. Clinically, anticancer adoptive immunotherapy using genetically engineered T cells has an impressive track record. Notable examples include the dramatic benefit of chimeric antigen receptor (CAR) gene-modified T cells redirected towards CD19 in patients with B-cell malignancy, and the encouraging results obtained with TCR gene-modified T cells redirected towards NY-ESO-1, a cancer-testis antigen, in patients with advanced melanoma and synovial cell sarcoma. This article overviews the current status of this treatment option, and discusses challenging issues that still restrain the full effectiveness of this strategy, especially in the context of hematological malignancy. PMID:25517545

  17. Nondestructive discrimination between normal and hematological malignancy cell lines using near-infrared Raman spectroscopy and multivariate analysis

    NASA Astrophysics Data System (ADS)

    Huang, Hao; Lin, Duo; Chen, Weiwei; Yu, Yun; Xu, Jijin; Liang, Zhen; Lin, Xi; Dong, Zhong; Shi, Hong

    2014-08-01

    An accurate understanding of biomolecular changes in living cells associated with malignant transformation is of paramount importance in early cancer detection. The aim of this study was to apply near-infrared Raman spectroscopy (RS) for differentiating cancer from normal cells. High-quality Raman spectra in the range of 450-1800 cm-1 can be obtained from 31 normal and 64 hematological malignancy cells including 43 CA46 and 21 U266 cells. There were significant differences in Raman spectra between normal and cancer groups, which suggests special changes in the percentage of biomolecules including lipid, nucleic acids and proteins in different cell lines. A diagnostic accuracy of 100% can be achieved by principal components analysis (PCA) combined with linear discriminant analysis (LDA) for classification between cancer and normal cell lines. This exploratory study demonstrates the potential application of the RS technique combined with PCA-LDA as a clinical cell-based biosensor for the noninvasive cancer detection and screening at the molecular level.

  18. Planes, Trains, and Automobiles: Perspectives on CAR T Cells and Other Cellular Therapies for Hematologic Malignancies.

    PubMed

    Gill, Saar

    2016-08-01

    Hematologic oncologists now have at their disposal (or a referral away) a myriad of new options to get from point A (a patient with relapsed or poor-risk disease) to point B (potential tumor eradication and long-term disease-free survival). In this perspective piece, we discuss the putative mechanisms of action and the relative strengths and weaknesses of currently available cellular therapy approaches. Notably, while many of these approaches have been published in high impact journals, with the exception of allogeneic stem cell transplantation and of checkpoint inhibitors (PD1/PDL1 or CTLA4 blockade), the published clinical trials have mostly been early phase, uncontrolled studies. Therefore, many of the new cellular therapy approaches have yet to demonstrate incontrovertible evidence of enhanced overall survival compared with controls. Nonetheless, the science behind these is sure to advance our understanding of cancer immunology and ultimately to bring us closer to our goal of curing cancer. PMID:27136938

  19. Short-Term Bisphosphonate Therapy Could Ameliorate Osteonecrosis: A Complication in Childhood Hematologic Malignancies

    PubMed Central

    Greggio, N. A.; Pillon, M.; Varotto, E.; Zanin, A.; Talenti, E.; Palozzo, A. C.; Calore, E.; Messina, C.

    2010-01-01

    Osteonecrosis (ON) is a critical complication in the treatment of childhood leukemia and lymphoma. It particularly affects survivors of acute lymphoblastic leukemia and non-Hodgkin lymphoma reflecting the cumulative exposure to glucocorticosteroid therapy. ON is often multiarticular and bilateral, specially affecting weight-bearing joints. A conventional approach suggests a surgical intervention even if pharmacological options have also recently been investigated. We reported two cases of long time steroid-treated patients who underwent Bone Marrow Transplantation (BMT) for hematological disease. Both patients developed femoral head osteonecrosis (ON) that was diagnosed by magnetic resonance imaging (MRI) and the ON was also accompanied with pain and a limp. Despite of the conventional strategies of therapy, we successfully started a short-term treatment with bisphosphonates in order to decrease the pain and the risk of fracture. PMID:20589085

  20. HLA-Haploidentical Bone Marrow Transplantation for Hematologic Malignancies Using Nonmyeloablative Conditioning and High-Dose, Posttransplantation Cyclophosphamide

    PubMed Central

    Luznik, Leo; O’Donnell, Paul V.; Symons, Heather J.; Chen, Allen R.; Leffell, M. Susan; Zahurak, Marianna; Gooley, Ted A.; Piantadosi, Steve; Kaup, Michele; Ambinder, Richard F.; Huff, Carol Ann; Matsui, William; Bolaños-Meade, Javier; Borrello, Ivan; Powell, Jonathan D.; Harrington, Elizabeth; Warnock, Sandy; Flowers, Mary; Brodsky, Robert A.; Sandmaier, Brenda M.; Storb, Rainer F.; Jones, Richard J.; Fuchs, Ephraim J.

    2008-01-01

    We evaluated the safety and efficacy of high-dose, posttransplantation cyclophosphamide (Cy) to prevent graft rejection and graft-versus-host disease (GVHD) after outpatient nonmyeloablative conditioning and T cell-replete bone marrow transplantation from partially HLA-mismatched (haploidentical) related donors. Patients with advanced hematologic malignancies (n = 67) or paroxysmal nocturnal hemoglobinuria (n = 1) received Cy 50 mg/kg i.v. on day 3 (n = 28) or on days 3 and 4 (n 5 40) after transplantation. The median times to neutrophil (>500/µL) and platelet recovery (>20,000/µL) were 15 and 24 days, respectively. Graft failure occurred in 9 of 66 (13%) evaluable patients, and was fatal in 1. The cumulative incidences of grades II–IV and grades III–IV acute (aGVHD) by day 200 were 34% and 6%, respectively. There was a trend toward a lower risk of extensive chronic GVHD (cGVHD) among recipients of 2 versus 1 dose of posttransplantation Cy (P = .05), the only difference between these groups. The cumulative incidences of nonrelapse mortality (NRM) and relapse at 1 year were 15% and 51%, respectively. Actuarial overall survival (OS) and event-free survival (EFS) at 2 years after transplantation were 36% and 26%, respectively. Patients with lymphoid malignancies had an improved EFS compared to those with myelogenous malignancies (P = .02). Nonmyeloablative HLA-haploidentical BMT with posttransplantation Cy is associated with acceptable rates of fatal graft failure and severe aGVHD or cGVHD. PMID:18489989

  1. Pharmacokinetics and Pharmacodynamics with Extended Dosing of CC-486 in Patients with Hematologic Malignancies

    PubMed Central

    Garcia-Manero, Guillermo; Cogle, Christopher R.; Gore, Steven D.; Hetzer, Joel; Kumar, Keshava; Skikne, Barry; MacBeth, Kyle J.

    2015-01-01

    CC-486 (oral azacitidine) is an epigenetic modifier in development for patients with myelodysplastic syndromes and acute myeloid leukemia. In part 1 of this two-part study, a 7-day CC-486 dosing schedule showed clinical activity, was generally well tolerated, and reduced DNA methylation. Extending dosing of CC-486 beyond 7 days would increase duration of azacitidine exposure. We hypothesized that extended dosing would therefore provide more sustained epigenetic activity. Reported here are the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of CC-486 extended dosing schedules in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML) from part 2 of this study. PK and/or PD data were available for 59 patients who were sequentially assigned to 1 of 4 extended CC-486 dosing schedules: 300mg once-daily or 200mg twice-daily for 14 or 21 days per 28-day cycle. Both 300mg once-daily schedules and the 200mg twice-daily 21-day schedule significantly (all P < .05) reduced global DNA methylation in whole blood at all measured time points (days 15, 22, and 28 of the treatment cycle), with sustained hypomethylation at cycle end compared with baseline. CC-486 exposures and reduced DNA methylation were significantly correlated. Patients who had a hematologic response had significantly greater methylation reductions than non-responding patients. These data demonstrate that extended dosing of CC-486 sustains epigenetic effects through the treatment cycle. Trial Registration ClinicalTrials.gov NCT00528983 PMID:26296092

  2. New Insight on Epidemiology and Management of Bacterial Bloodstream Infection in Patients with Hematological Malignancies

    PubMed Central

    Menzo, Sara Lo; la Martire, Giulia; Ceccarelli, Giancarlo; Venditti, Mario

    2015-01-01

    Bloodstream infections (BSI) are a significant cause of morbidity and mortality in onco-hematologic patients. The Gram-negative bacteria were the main responsible for the febrile neutropenia in the sixties; their impact declined due to the use of fluoroquinolone prophylaxis. This situation was followed by the gradual emergence of Gram-positive bacteria also following the increased use of intravascular devices and the introduction of new chemotherapeutic strategies. In the last decade, the Gram-negative etiology is raising again because of the emergence of resistant strains that make questionable the usefulness of current strategies for prophylaxis and empirical treatment. Gram-negative BSI attributable mortality is relevant, and the appropriate empirical treatment significantly improves the prognosis; on the other hand the adequate delayed treatment of Gram-positive BSI does not seem to have a high impact on survival. The clinician has to be aware of the epidemiology of his institution and colonizations of his patients to choose the most appropriate empiric therapy. In a setting of high endemicity of multidrug-resistant infections also the choice of targeted therapy can be a challenge, often requiring strategies based on off-label prescriptions and low grade evidence. In this review, we summarize the current evidence for the best targeted therapies for difficult to treat bacteria BSIs and future perspectives in this topic. We also provide a flow chart for a rational approach to the empirical treatment of febrile neutropenia in a multidrug resistant, high prevalence setting. PMID:26185609

  3. The Beginning of the Road for Non-Coding RNAs in Normal Hematopoiesis and Hematologic Malignancies

    PubMed Central

    Heuston, Elisabeth F.; Lemon, Kenya T.; Arceci, Robert J.

    2011-01-01

    The field of non-coding RNAs (ncRNAs) encompasses a wide array of RNA classes that are indispensible for the regulation of cellular activities. However, de-regulation of these ncRNAs can also play key roles in malignant transformation and cancer cell behavior. In this article we survey a select group of microRNAs and long ncRNAs that appear to contribute in keys ways to the development of acute and chronic leukemias, as well as contribute to their diagnosis, prognosis, and potentially, their treatment. PMID:22303388

  4. Hematological Practice in India.

    PubMed

    Das, Reena; Ahluwalia, Jasmina; Sachdeva, Man Updesh Singh

    2016-04-01

    This article provides a short summary of hematological practice in India. It focuses particularly on how the patterns of hematologic practice differ from those of countries in the West with particular respect to genetic hematological diseases and a wide range of malignant disorders of hemopoiesis. It also focuses on the difficulties of control and management of hematological disorders set against a background of a relatively poor country. PMID:27040963

  5. Gene-modified T-cell therapy using chimeric antigen receptors for pediatric hematologic malignancies.

    PubMed

    Nakazawa, Yozo

    2016-06-01

    Chimeric antigen receptor (CAR) is the generic name for synthetic T cell receptors redirected to tumor-associated antigens. Most CARs consist of an ectodomain (scFv or ligand), a hinge region, a transmembrane domain, and signaling endodomains derived from one or two co-stimulatory molecules (CD28, 4-1BB, etc) and from a CD3-ζ chain. CD19-targeted CAR T cell therapy has achieved major success in the treatment of B cell malignancies. CD19 CAR-T cells elicited complete remission in 70-90% of adult and pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). CD19 CAR T cell therapy from allogeneic donors including third party donors is a potential option for B-cell malignancies. CAR T cell therapies for myeloma, acute myeloid leukemia, and T-cell leukemia are still under development. Our group is currently preparing a phase I study of CD19 CAR T cell therapy in pediatric and young adult patients with ALL using a non-viral gene transfer method, the piggyBac-transposon system. PMID:27384848

  6. Long-term outcomes after allogeneic stem cell transplantation for children with hematological malignancies.

    PubMed

    Ferry, C; Gemayel, G; Rocha, V; Labopin, M; Esperou, H; Robin, M; de Latour, R P; Ribaud, P; Devergie, A; Leblanc, T; Gluckman, E; Baruchel, A; Socié, G

    2007-08-01

    We analyzed long-term outcomes and psycho-social aspects in 112 children with malignancies surviving 1 year after hematopoietic stem cell transplantation. At 10 years, overall survival was 75+/-5%, TRM 18+/-4% and relapse 14+/-3%; 10-year cumulative incidence of infections was 31+/-4%, cataract 44+/-4%, pulmonary dysfunction 20+/-4%, bone and joint complications 29+/-5%, hypothyroidism 36+/-4%, cardiac complications 11+/-3% and secondary malignancies 7+/-3%. Total body irradiation (TBI) was the most significant risk factor associated with cataract, pulmonary impairment, osteoarticular complications and hypothyroidism. Chronic graft-versus-host disease was associated with higher incidence of pulmonary dysfunction. The number of complications per patient increased with time. Half of the patients had psychological disturbance, 13 signs of depression and 16 a history of eating behavior disorders; 54% of patients with one or more long-term complications had psychological problems. Sixty-nine patients had learning difficulties and 36 achieved normal scholarship. With increased follow-up, development of late effects and of psycho-social disturbance are of major concern. While the use of single-dose TBI has now been abandoned, other risk factors are still of concern in the early 2000s. PMID:17530002

  7. Thyroid abnormalities in patients treated with lenalidomide for hematological malignancies: results of a retrospective case review.

    PubMed

    Figaro, M Kathleen; Clayton, Warren; Usoh, Chinenye; Brown, Kara; Kassim, Adetola; Lakhani, Vipul T; Jagasia, Shubhada

    2011-06-01

    Lenalidomide is an antiangiogenic drug associated with hypothyroidism. We describe a case-series of lenalidomide use in hematological cancers and the prevalence of thyroid abnormalities. We reviewed medical records of patients treated with lenalidomide at a single center form 2005 to 2010 and extracted demographic, clinical, and laboratory data. Of 170 patients with confirmed lenalidomide use (age 64.9 ± 15 years), 148 were treated for multiple myeloma and 6% had thyroid abnormalities attributable only to lenalidomide. In patients with a previous diagnosis of thyroid dysfunction, the addition of lenalidomide therapy was associated with a higher incidence of subsequent TFTF abnormality (17%) as compared to patients with no previous diagnosis of thyroid dysfunction (6%) (P=0.0001). Many patients (44%) with pre-existing disease and a change in thyroid function before or while on lenalidomide had no further follow-up of their thyroid abnormalities, Of 20 patients who did not undergo any thyroid function testing either before starting or while on lenalidomide for a median of 9.4 months (± 6.5), 35% developed new symptoms compatible with hypothyroidism, including worsened fating, constipation or cold intolerance. Symptoms of thyroid dysfunction overlap with side effects of lenalidomide. Thyroid hormone levels are not regularly evaluated in patients on lenalidomide. While on this treatment, thyroid abnormalities can occur in patients with no previous diagnoses and in patients with pre-existing abnormalities. Because symptoms of thyroid dysfunction could be alleviated by appropriate treatment, thyroid function should be evaluated during the course of lenalidomide to improve patients quality of life. PMID:21544854

  8. A randomized, double blind comparative study of prophylactic parenteral nutritional support with or without glutamine in autologous stem cell transplantation for hematological malignancies -- three years' follow-up.

    PubMed

    Sykorova, A; Horacek, J; Zak, P; Kmonicek, M; Bukac, J; Maly, J

    2005-01-01

    Forty-four adult autologous transplant patients with hematological malignancies were randomized to receive either prophylactic parenteral nutrition PN (P group), or PN given ad hoc (C group). In each group, they were further randomized to receive standard PN (B group), or PN with 0.5 g glutamine/kg as L-Ala-L-Gln (A group). The overall survival (OS), disease-free survival (DFS) and event-free survival (EFS) in groups C vs. P and A vs. B were compared during follow-up with median 38 months. The final outcome rates in C/P/A/B groups, respectively (OS 65/81/63/85%, EFS 45/53/33/65% and DFS 56/50/35/77%), were not significantly different, apart from A < B in DFS rate (p=0.03, Fisher's exact test). Also in survival analysis (logrank test), no significant difference between groups C and P was found but generally worse parameters were observed for A vs. B group: for DFS (p=0.04) and EFS (p=0.01) the difference was significant, and for OS (p=0.09) it was borderline. In the three years' follow-up, no clinically useful benefit of prophylactic PN in autologous transplant patients was proven. Also, glutamine supplementation was not helpful, and was even connected with apparently worse long-term outcome. PMID:16284692

  9. Beyond pancreatic cancer: irinotecan and gemcitabine in solid tumors and hematologic malignancies.

    PubMed

    Rocha Lima, C M; Urbanic, J J; Lal, A; Kneuper-Hall, R; Brunson, C Y; Green, M R

    2001-06-01

    Non-platinum combinations including gemcitabine and irinotecan (Gemzar; Eli Lilly and Company, Indianapolis, IN) for the management of a variety of malignancies have started to emerge. Gemcitabine and irinotecan are well-tolerated single agents, each with a broad spectrum of antitumor activity. Preclinical data suggests synergy for the two drugs when used in combination. A phase I trial has defined a well-tolerated combination regimen using both drugs on a day-1, -8 schedule every 3 weeks. Phase II data suggest activity for the combination in pancreatic cancer, and a phase III trial of the two-drug combination versus gemcitabine alone is underway in previously untreated pancreatic cancer patients. Other phase II trials evaluating the impact of this combination on a variety of other tumors, such as non-small cell lung, small cell lung, breast, colorectal, and non-Hodgkin's lymphoma, are either forthcoming or in progress. Semin Oncol 28 (suppl 10):34-43. PMID:11510032

  10. Maximizing anthracycline tolerability in hematologic malignancies: Treat to each heart's content.

    PubMed

    Oliveira, Guilherme H; Al-Kindi, Sadeer G; Caimi, Paolo F; Lazarus, Hillard M

    2016-05-01

    Anthracyclines are the cornerstone of therapy for a wide spectrum of malignancies and have improved patient survival. Concern for anthracycline-related cardiotoxicity often leads to dose reductions or use of second-line regimens, which may adversely impact survival. Development of cardiotoxicity depends on a combination of cumulative dose modulated by individual patient characteristics, which we have termed individual cardiotoxic threshold (ICT). Patients with cancer often have characteristics such as age, gender, genetic predisposition and preexisting cardiovascular disease that can potentiate cardiotoxicity. Specialty cardiovascular assessment, more sensitive monitoring technology, and timely interventions in selected patients can decrease cardiotoxicity and improve patient outcomes. Prophylaxis with cardioprotective agents and other strategies have shown promising results in randomized trials and may improve tolerance to anthracyclines. In this review we introduce the concept of ICT and critically analyze the evidence supporting existing strategies to modulate it and increase cardiovascular tolerability of anthracyclines. PMID:26578029

  11. Intravenous Busulfan-Based Myeloablative Conditioning Regimens Prior to Hematopoietic Cell Transplantation for Hematologic Malignancies.

    PubMed

    Pasquini, Marcelo C; Le-Rademacher, Jennifer; Zhu, Xiaochun; Artz, Andrew; DiPersio, John; Fernandez, Hugo F; Mineishi, Shin; Kamishohara, Masaru; Mehta, Jayesh; Nakamura, Yuki; Ratanatharathorn, Voravit; Sobecks, Ronald; Burkart, Jeanne; Bredeson, Christopher

    2016-08-01

    Busulfan (Bu)-containing regimens are commonly used in myeloablative conditioning regimens before allogeneic hematopoietic cell transplantation (HCT). Yet, there is considerable variability on how Bu is administered related to frequency (4 times a day [Q6] or daily [Q24]) and combinations with other chemotherapeutic agents (cyclophosphamide [Cy] or fludarabine [Flu]). We performed a prospective cohort study of recipients of Bu-based conditioning according to contemporary practices to compare different approaches (BuCy Q6, n = 495; BuFlu Q24, n = 331; BuCy Q24, n = 96; BuFlu Q6, n = 91) in patients with myeloid malignancies between 2009 and 2011. BuFlu Q24 recipients were more likely to be older and tended to have worse performance status and a higher comorbid burden. The cumulative incidences of hepatic veno-occlusive disease (P = .40), idiopathic pneumonia (P = .50), and seizures (P = .50) did not differ across groups. One-year HCT-related mortality ranged from 12% to 16% (P = .80), 3-year relapse incidence ranged from 32% to 36% (P = .80), and 3-year overall survival ranged from 51% to 58% (P = .20) across groups. This study demonstrates that HCT conditioning regimens using i.v. Bu Q6 or Q24 alone or in combination with Cy or Flu have similar outcomes in the myeloablative setting for treatment of myeloid malignancies. PMID:27154848

  12. The outcomes of family haploidentical hematopoietic stem cell transplantation in hematological malignancies are not associated with patient age

    PubMed Central

    Dong, Lujia; Wu, Tong; Gao, Zhi-Yong; Zhang, Mei-Jie; Kan, Fangyu; Spellman, Stephen R.; Tan, Xi-You; Zhao, Yan-Li; Wang, Jing-Bo; Lu, Dao-Pei; Miklos, David; Petersdorf, Effie; Fernandez-Vina, Marcelo; Lee, Stephanie J.

    2011-01-01

    Haploidentical hematopoietic cell transplantation (HCT) has been used to treat hematologic malignancies but it is unknown whether the procedure is more effective in adults or children. To address this question, we analyzed patients aged 1–65 years old receiving myeloablative conditioning regimens followed by family 2 to 3 antigen HLA-mismatched HCT and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR, n=137) or performed in Dao-Pei Hospital in Beijing, China (n=181). The Dao-Pei cohort had more acute and chronic GVHD, less relapse, lower transplant related mortality (TRM) and better leukemia-free survival (LFS) than the CIBMTR cohort. Overall survival (OS) and outcomes were similar between adults and children. In the CIBMTR cohort receiving ex vivo T cell depletion (TCD), adults had higher TRM (RR 2.71, 95% CI 1.29–5.69, p=0.008) and lower overall survival (RR 1.75, 95%CI 1.08–2.84, p=0.023) than children. In the CIBMTR subset that did not receive ex vivo TCD, relapse was lower in adults compared to children (RR 0.24, 95% CI 0.07–0.80, p=0.020) but TRM, LFS and OS were similar. We conclude that outcomes in adults and children are similar overall, although children have better survival than adults if ex vivo TCD is used. PMID:21193055

  13. Plasma concentration of itraconazole in patients receiving chemotherapy for hematological malignancies: the effect of famotidine on the absorption of itraconazole.

    PubMed

    Kanda, Y; Kami, M; Matsuyama, T; Mitani, K; Chiba, S; Yazaki, Y; Hirai, H

    1998-03-01

    Fungal infection is a serious complication in immunocompromised patients, especially those with neutropenia. Itraconazole (ITZ) is expected to be an effective prophylactic agent for fungal infection because it has more activity against Aspergillus species than fluconazole and it is less toxic than amphotericin-B. However, ITZ is available only as an oral capsule, the absorption of which is thought to depend on the presence of acid in the stomach. In this study, the effect of famotidine, an H2-blocker, on the absorption of ITZ was investigated. Patients undergoing chemotherapy for hematological malignancies were enrolled. To minimize the effect of famotidine, the time of ITZ intake was different from that of famotidine intake. The plasma concentrations of ITZ with or without taking famotidine were determined just before and 4 h after ITZ intake. Mean trough and peak concentrations of ITZ without famotidine were 332 ng/ml and 476 ng/ml, respectively. When famotidine was co-administered, the concentrations decreased to 204 ng/ml and 315 ng/ml, respectively. Statistical analyses revealed significant differences between trough concentrations in the presence and absence of famotidine (p = 0.008). There was also a clear tendency toward higher peak concentrations in the plasma concentrations with famotidine (p = 0.06). These findings suggest that famotidine decreases the plasma concentration of ITZ in patients undergoing chemotherapy. Close monitoring of the plasma concentration of ITZ and dose adjustment are required for efficient prophylaxis. PMID:9821410

  14. In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies.

    PubMed

    Farag, Sherif S; Srivastava, Shivani; Messina-Graham, Steven; Schwartz, Jennifer; Robertson, Michael J; Abonour, Rafat; Cornetta, Kenneth; Wood, Lisa; Secrest, Angie; Strother, R Matthew; Jones, David R; Broxmeyer, Hal E

    2013-04-01

    Delayed engraftment is a significant limitation of umbilical cord blood (UCB) transplantation due to low stem cell numbers. Inhibition of dipeptidyl peptidase (DPP)-4 enhanced engraftment in murine transplants. We evaluated the feasibility of systemic DPP-4 inhibition using sitagliptin to enhance engraftment of single-unit UCB grafts in adults with hematological malignancies. Twenty-four patients (21-58 years) received myeloablative conditioning, followed by sitagliptin 600 mg orally days -1 to +2, and single UCB grafts day 0. Seventeen receiving red cell-depleted (RCD) grafts, matched at 4 (n=10) or 5 (n=7) of 6 human leucocyte antigen (HLA) loci with median nucleated cell dose 3.6 (2.5-5.2)×10(7)/kg, engrafted at median of 21 (range, 13-50) days with cumulative incidence of 94% (95% confidence interval, 84%-100%) at 50 days. Plasma DDP-4 activity was reduced to 23%±7% within 2 h. Area under DPP-4 activity-time curve (AUCA) correlated with engraftment; 9 of 11 with AUCA <6,000 activity·h engrafted within ≤21 days, while all 6 with higher AUCA engrafted later (P=0.002). Seven patients receiving red cell replete grafts had 10-fold lower colony forming units after thawing compared with RCD grafts, with poor engraftment. Systemic DPP-4 inhibition was well tolerated and may enhance engraftment. Optimizing sitagliptin dosing to achieve more sustained DPP-4 inhibition may further improve outcome. PMID:23270493

  15. Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy

    PubMed Central

    Klein, John P.; Ruggeri, Annalisa; Spellman, Stephen; Lee, Stephanie J.; Anasetti, Claudio; Arcese, William; Barker, Juliet N.; Baxter-Lowe, Lee Ann; Brown, Maria; Fernandez-Vina, Marcelo A.; Freeman, John; He, Wensheng; Iori, Anna Paola; Horowitz, Mary M.; Locatelli, Franco; Marino, Susana; Maiers, Martin; Michel, Gerard; Sanz, Guillermo F.; Gluckman, Eliane; Rocha, Vanderson

    2014-01-01

    We studied the effect of allele-level matching at human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 in 1568 single umbilical cord blood (UCB) transplantations for hematologic malignancy. The primary end point was nonrelapse mortality (NRM). Only 7% of units were allele matched at HLA-A, -B, -C, and -DRB1; 15% were mismatched at 1, 26% at 2, 30% at 3, 16% at 4, and 5% at 5 alleles. In a subset, allele-level HLA match was assigned using imputation; concordance between HLA-match assignment and outcome correlation was confirmed between the actual and imputed HLA-match groups. Compared with HLA-matched units, neutrophil recovery was lower with mismatches at 3, 4, or 5, but not 1 or 2 alleles. NRM was higher with units mismatched at 1, 2, 3, 4, or 5 alleles compared with HLA-matched units. The observed effects are independent of cell dose and patient age. These data support allele-level HLA matching in the selection of single UCB units. PMID:24141369

  16. [A retrospective analysis of neurotoxicity induced by vinca alkaloids combined with azole anti-fungal agents in hematological malignancies].

    PubMed

    Osato, Yoichi; Yokoyama, Tomohisa; Saito, Yumiko; Kani, Rinako; Hayabe, Hiroko; Miyamatsu, Hironobu; Ohyashiki, Kazuma

    2011-10-01

    Vinca alkaloids (VA) are some of the key anti-tumor agents for patients with hematological malignancies, and various adverse events such as paralytic ileus, peripheral neuropathy, and constipation were now recognized as adverse VA effects. Furthermore, azole anti-fungal agents are known to enhance VA toxicity because they delay the metabolism and excretion of VA by inhibiting CYP3A4. However, their clinical relationship has not been clearly described. Therefore, we studied neurotoxicity as a possible adverse event associated with VA in patients treated with azole anti-fungal agents, retrospectively. In our study, 100 patients (479 episodes) who received VA in our department from August 2008 to December 2010 were analyzed. Adverse events attributed to the combined administration of vincristine (VCR) and azole anti-fungal agents were grade 3 paralytic ileuses in 8 patients (8 episodes), grade 3 or 4 constipation in 16 patients (16 episodes), and grade 3 peripheral neuropathy in 10 patients (16 episodes). In addition, we investigated whether temporal discontinuation of azole anti-fungal agents during VA treatment decreases the frequency of these adverse events, and detected that it is likely to help avoid neurotoxicities enhanced by itraconazole, such as severe constipation (p=0. 0308) and paralytic ileus (p=0. 0967). Our findings indicated that we should pay much more attention to these adverse events, and must select patients carefully when we administer azole anti-fungal agents to them while they are being treated with VA. PMID:21996963

  17. Identification of Novel HLA-A*24:02-Restricted Epitope Derived from a Homeobox Protein Expressed in Hematological Malignancies

    PubMed Central

    Matsushita, Maiko; Otsuka, Yohei; Tsutsumida, Naoya; Tanaka, Chiaki; Uchiumi, Akane; Ozawa, Koji; Suzuki, Takuma; Ichikawa, Daiju; Aburatani, Hiroyuki; Okamoto, Shinichiro; Kawakami, Yutaka; Hattori, Yutaka

    2016-01-01

    The homeobox protein, PEPP2 (RHOXF2), has been suggested as a cancer/testis (CT) antigen based on its expression pattern. However, the peptide epitope of PEPP2 that is recognized by cytotoxic T cells (CTLs) is unknown. In this study, we revealed that PEPP2 gene was highly expressed in myeloid leukemia cells and some other hematological malignancies. This gene was also expressed in leukemic stem-like cells. We next identified the first reported epitope peptide (PEPP2271-279). The CTLs induced by PEPP2271-279 recognized PEPP2-positive target cells in an HLA-A*24:02-restricted manner. We also found that a demethylating agent, 5-aza-2’-deoxycytidine, could enhance PEPP2 expression in leukemia cells but not in blood mononuclear cells from healthy donors. The cytotoxic activity of anti-PEPP2 CTL against leukemic cells treated with 5-aza-2’-deoxycytidine was higher than that directed against untreated cells. These results suggest a clinical rationale that combined treatment with this novel antigen-specific immunotherapy together with demethylating agents might be effective in therapy-resistant myeloid leukemia patients. PMID:26784514

  18. PCR-Restriction Enzyme Analysis for Detection of Candida DNA in Blood from Febrile Patients with Hematological Malignancies

    PubMed Central

    Morace, Giulia; Pagano, Livio; Sanguinetti, Maurizio; Posteraro, Brunella; Mele, Luca; Equitani, Francesco; D’Amore, Giuseppina; Leone, Giuseppe; Fadda, Giovanni

    1999-01-01

    Blood samples were drawn daily from 72 patients who had hematological malignancies, neutropenia, and fever and who had failed to respond to broad-spectrum antibiotics. Each sample was used for conventional fungal blood cultures and for detection and identification of Candida DNA by a PCR method with subsequent restriction enzyme analysis (REA) recently developed in our laboratory. The PCR method was able to detect five CFU of Candida spp. per ml of blood, and subsequent REA of the amplicons allowed the identification of the Candida species most commonly implicated in cases of candidiasis. Thirty-one patients were PCR-REA positive, and four of these patients were also culture positive. The ultimate diagnosis for 13 of these patients and 1 patient who was PCR-REA negative was disseminated candidiasis (confirmed by clinical data, multiple cultures, histology, autopsy, and/or ultrasonographic evidence of hepatosplenic candidiasis). The molecular method is significantly more sensitive than conventional fungal blood cultures and has a high negative predictive value (97.5%) for the development of disseminated candidiasis in neutropenic patients. PMID:10325339

  19. Effects of cytapheresis on cell cycle distribution of peripheral blood and bone marrow cells in some hematological malignancies.

    PubMed

    Kotelnikov, V M; Kasatkina, V V; Dultsina, S M; Sarytcheva, T G; Kalinin, N N; Kovaleva, L G; Poljanskaja, A M; Isajev, V G; Khoroshko, N D; Lishmanova, N G

    1987-01-01

    Feulgen-DNA cytophotometry and 3H-thymidine autoradiography were used to evaluate therapeutic cytapheresis effects on cell cycle distributions of peripheral blood leukemic cells in 15 acute leukemia, 5 CML and 8 CLL patients and of bone marrow erythroblasts in 18 PV patients. Both individual cytapheresis procedures and a long-term program of cytapheresis altered cell cycle distributions and biochemistry which may be summarized as follows: An increase in percentage of cells in S-phase (acute leukemia, CML); a decrease in the differences between values of S-cell number obtained by cytophotometry and autoradiography (acute leukemia, CML, PV); a decrease in some cases in enlarged fraction of cells in G2 (blast crisis of CML, PV); an activation of G0----G1 transition and an increase in the PAS-positive lymphocyte fraction in CLL patients. An apparent increase of blasts in S-phase was found after a pheresis in acute leukemia patients who responded to subsequent chemotherapy. In "nonresponders", a pheresis had no effect on cell cycle distributions. The results of the study demonstrate that despite the wide variability of individual responses, cytapheresis activates cell proliferation and metabolic processes in patients with hematological malignancies. PMID:3561020

  20. Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies.

    PubMed

    El-Serafi, I; Fares, M; Abedi-Valugerdi, M; Afsharian, P; Moshfegh, A; Terelius, Y; Potácová, Z; Hassan, M

    2015-10-01

    The role of cytochrome P450 2J2 (CYP2J2) in cyclophosphamide (Cy) bioactivation was investigated in patients, cells and microsomes. Gene expression analysis showed that CYP2J2 mRNA expression was significantly (P<0.01) higher in 20 patients with hematological malignancies compared with healthy controls. CYP2J2 expression showed significant upregulation (P<0.05) during Cy treatment before stem cell transplantation. Cy bioactivation was significantly correlated to CYP2J2 expression. Studies in HL-60 cells expressing CYP2J2 showed reduced cell viability when incubated with Cy (half maximal inhibitory concentration=3.6 mM). Inhibition of CYP2J2 using telmisartan reduced Cy bioactivation by 50% and improved cell survival. Cy incubated with recombinant CYP2J2 microsomes has resulted in apparent Km and Vmax values of 3.7-6.6 mM and 2.9-10.3 pmol/(min·pmol) CYP, respectively. This is the first study demonstrating that CYP2J2 is equally important to CYP2B6 in Cy metabolism. The heart, intestine and urinary bladder express high levels of CYP2J2; local Cy bioactivation may explain Cy-treatment-related toxicities in these organs. PMID:25601761

  1. Clinical Comparison of Non-Myeloablative Conditioning with Anti-Thymocyte Globulin and Fludarabine for Patients with Hematologic Malignancies

    PubMed Central

    Li, Qingshan; Meng, Fanyi; Zhou, Ming; Yu, Bizhen; Mo, Wenjian; Du, Qinghua; Jiang, Xuejie; Wei, Yaming

    2015-01-01

    Background The influence of different non-myeloablative conditioning regimens on clinical outcome remains undefined. Material/Methods We retrospectively analyzed the hematopoietic reconstitution, graft-versus-host disease (GVHD), and quality of life (QOL) in 56 patients with hematologic malignancies who underwent non-myeloablative stem cell transplantation (NST) with a conditioning regimen based on anti-thymocyte globulin (ATG), followed by donor lymphocyte infusion (n=24), or Fludarabine (FLU) (n=32). Hematopoietic stem cells were derived from low-resolution HLA-matched identical sibling donors. Results The blood type transformation and platelet reconstitution presented significantly earlier in the FLU group than the ATG group (P<0.05). Within 100 days post-transplantation, the incidence of grade I–IV acute GVHD was significantly lower in the ATG group than the FLU group (P<0.05). After 100 days post-transplant, extensive chronic GVHD (cGVHD) was more prevalent in the ATG group than the FLU group (P<0.05). There were lower cumulative risk of relapse and higher non-relapse-related mortality in the ATG group, but better QOL in the FLU group within 24 months, and no difference in 3-year disease-free survival (DFS) or overall survival (OS) between the 2 groups (P>0.05). Conclusions The FLU-based conditioning regimen improved hematopoietic reconstitution and decreased extensive cGVHD, but there was no difference in 3-year DFS or OS between the 2 groups. PMID:26238068

  2. Recommendations for Risk Categorization and Prophylaxis of Invasive Fungal Diseases in Hematological Malignancies: A Critical Review of Evidence and Expert Opinion (TEO-4)

    PubMed Central

    Boğa, Can; Bolaman, Zahit; Çağırgan, Seçkin; Karadoğan, İhsan; Özcan, Mehmet Ali; Özkalemkaş, Fahir; Saba, Rabin; Sönmez, Mehmet; Şenol, Esin; Akan, Hamdi; Akova, Murat

    2015-01-01

    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. PMID:26316478

  3. Therapeutic Challenges of Hepatic Mucormycosis in Hematologic Malignancy: A Case Report and Review of the Literature.

    PubMed

    Bernardo, Raffaele M; Gurung, Ananta; Jain, Dhanpat; Malinis, Maricar F

    2016-01-01

    BACKGROUND The clinical presentation of mucormycosis can vary widely based on various host factors. Among malignancy- and bone marrow transplant-associated infections, the lungs are the most common site of infection. Involvement of the gastrointestinal tract is less frequently encountered. The clinical presentation is often nonspecific, and cultures typically yield no growth, making the diagnosis challenging. CASE REPORT We present a case of isolated hepatic mucormycosis in the setting of neutropenic fever and abdominal pain following induction chemotherapy for the treatment of acute myeloid leukemia. The patient was treated with combination antifungal therapy with amphotericin and posaconazole without surgical resection, given the presence of multiple liver lesions. After a prolonged course of dual antifungal therapy, the size of her liver lesions improved. Unfortunately, her lymphoproliferative disorder proved fatal, following approximately 13 months of antifungal therapy. CONCLUSIONS Among patients with mucormycosis, mortality remains high, especially in the setting of gastrointestinal involvement. Although surgical resection along with dual antifungal therapy can improve outcomes, the high mortality rate necessitates further investigation into improved diagnostic and treatment strategies including optimal antifungal therapy. PMID:27406045

  4. Evolved Cellular Mechanisms to Respond to Genotoxic Insults: Implications for Radiation-Induced Hematologic Malignancies.

    PubMed

    Fleenor, Courtney J; Higa, Kelly; Weil, Michael M; DeGregori, James

    2015-10-01

    Human exposure to ionizing radiation is highly associated with adverse health effects, including reduced hematopoietic cell function and increased risk of carcinogenesis. The hematopoietic deficits manifest across blood cell types and persist for years after radiation exposure, suggesting a long-lived and multi-potent cellular reservoir for radiation-induced effects. As such, research has focused on identifying both the immediate and latent hematopoietic stem cell responses to radiation exposure. Radiation-associated effects on hematopoietic function and malignancy development have generally been attributed to the direct induction of mutations resulting from radiation-induced DNA damage. Other studies have illuminated the role of cellular programs that both limit and enhance radiation-induced tissue phenotypes and carcinogenesis. In this review, distinct but collaborative cellular responses to genotoxic insults are highlighted, with an emphasis on how these programmed responses impact hematopoietic cellular fitness and competition. These radiation-induced cellular programs include apoptosis, senescence and impaired self-renewal within the hematopoietic stem cell (HSC) pool. In the context of sporadic DNA damage to a cell, these cellular responses act in concert to restore tissue function and prevent selection for adaptive oncogenic mutations. But in the contexts of whole-tissue exposure or whole-body exposure to genotoxins, such as radiotherapy or chemotherapy, we propose that these programs can contribute to long-lasting tissue impairment and increased carcinogenesis. PMID:26414506

  5. Invasive fungal infection in patients receiving chemotherapy for hematological malignancy: a multicenter, prospective, observational study in China.

    PubMed

    Sun, Yuqian; Huang, He; Chen, Jing; Li, Jianyong; Ma, Jun; Li, Juan; Liang, Yingmin; Wang, Jianmin; Li, Yan; Yu, Kang; Hu, Jianda; Jin, Jie; Wang, Chun; Wu, Depei; Xiao, Yang; Huang, Xiaojun

    2015-02-01

    This stud y examined the epidemiology, risk factors, management, and outcome of invasive fungal infection (IFI) in patients receiving chemotherapy for hematological malignancy in China. IFI risk factors were analyzed using univariate analysis and multivariate logistic regression. In total, 4,192 patients receiving 4,889 chemotherapy courses were enrolled [mean age 40.7 years, 58.4% male, 16.9% children (<18 years)]. The most common hematological diseases were acute myeloid leukemia (AML, 28.5%), non-Hodgkin lymphoma (NHL, 26.3%), and acute lymphoblastic leukemia (ALL, 20.2%). Severe neutropenia (absolute neutrophil count [ANC] <500/mm(3)) occurred after one third (1,633/4,889, 33.4%) of chemotherapy courses. Incidence of proven/probable IFI was 2.1% per chemotherapy course and higher in patients with myelodysplastic syndrome (MDS, 4.94%), acute hyperleukocytic leukemia (AHL, 4.76%), AML (3.83%), or induction chemotherapy. Risk factors included ANC <500/mm(3) [odds ratio (OR) 3.60], AML or MDS (OR 1.97), induction chemotherapy (OR 2.58), previous IFI (OR 3.08), and being male (OR 1.74). Antifungal agents, prescribed in one quarter (1,211/4,889, 24.8%) of chemotherapy courses, included primary/secondary prophylaxis (n = 827, 16.9%) and/or treatment (n = 655, 13.4%; 86.9 % triazoles), which was empirical (84.3%), pre-emptive (8.6%), or targeted (7.1%). Overall mortality following each chemotherapy course (1.5%) increased in proven/probable (11.7%) and possible IFI (8.2%). In summary, IFI was more common in MDS, AHL, AML, or induction chemotherapy, and substantially increased mortality. Neutropenic patients receiving induction chemotherapy for AML or MDS and those with previous IFI were at particular risk. Antifungal prophylaxis showed an independent protective effect but was not commonly used, even in high-risk patients. By contrast, empiric antifungals were widely used. PMID:25293517

  6. T cell receptor gamma and delta rearrangements in hematologic malignancies. Relationship to lymphoid differentiation.

    PubMed Central

    Griesinger, F; Greenberg, J M; Kersey, J H

    1989-01-01

    We have studied recombinatorial events of the T cell receptor delta and gamma chain genes in hematopoietic malignancies and related these to normal stages of lymphoid differentiation. T cell receptor delta gene recombinatorial events were found in 91% of acute T cell lymphoblastic leukemia, 68% of non-T, non-B lymphoid precursor acute lymphoblastic leukemia (ALL) and 80% of mixed lineage acute leukemias. Mature B-lineage leukemias and acute nonlymphocytic leukemias retained the T-cell receptor delta gene in the germline configuration. The incidence of T cell receptor gamma and delta was particularly high in CD10+CD19+ non-T, non-B lymphoid precursor ALL. In lymphoid precursor ALL, T cell receptor delta was frequently rearranged while T cell receptor gamma was in the germline configuration. This suggests that TCR delta rearrangements may precede TCR gamma rearrangements in lymphoid ontogeny. In T-ALL, only concordant T cell receptor delta and gamma rearrangements were observed. Several distinct rearrangements were defined using a panel of restriction enzymes. Most of the rearrangements observed in T-ALL represented joining events of J delta 1 to upstream regions. In contrast, the majority of rearrangements in lymphoid precursor ALL most likely represented D-D or V-D rearrangements, which have been found to be early recombinatorial events of the TCR delta locus. We next analyzed TCR delta rearrangements in five CD3+TCR gamma/delta+ ALL and cell lines. One T-ALL, which demonstrated a different staining pattern with monoclonal antibodies against the products of the TCR gamma/delta genes than the PEER cell line, rearranges J delta 1 to a currently unidentified variable region. Images PMID:2547833

  7. Superior Serum Concentrations with Posaconazole Delayed-Release Tablets Compared to Suspension Formulation in Hematological Malignancies

    PubMed Central

    Caddell, Ryan; Shillingburg, Alexandra; Lu, Xiaoxiao; Wen, Sijin; Hamadani, Mehdi; Craig, Michael; Kanate, Abraham S.

    2015-01-01

    Posaconazole (PCZ), approved for prophylaxis against invasive fungal disease in high-risk patients, is commercially available orally as a suspension formulation (PCZ-susp) and as a delayed-release tablet (PCZ-tab). We evaluated the serum steady-state concentrations (Css) of PCZ stratified by the administered formulation for antifungal prophylaxis in patients with myeloid malignancies (n = 150). The primary outcome was the attainment rate of the target Css of ≥700 ng/ml. Secondary outcomes included toxicity assessment (hepatotoxicity and corrected QT [QTc] interval prolongation) and breakthrough fungal infections. Patients who received the PCZ-susp (n = 118) or PCZ-tab (n = 32) and had PCZ Css assessment after at least 7 days of therapy were eligible. The median Css in the PCZ-susp group was 390 ng/ml (range, 51 to 1,870 ng/ml; mean, 436 ng/ml) compared to 1,740 ng/ml (range, 662 to 3,350 ng/ml; mean, 1,781 ng/ml) in the PCZ-tab group (P < 0.0001). The percentages of patients achieving the target goal of ≥700 ng/ml were 17% versus 97%, respectively (P < 0.0001). Hepatotoxicity (grade 2 or higher) occurred in 1 patient in each group. QTc interval measurements were available for 32 patients in the PCZ-susp group and for 12 patients in the PCZ-tab group, and prolonged intervals of grade 2 or higher were noted in 9% (n = 3) and 17% (n = 2), respectively (P = 0.6). Breakthrough fungal infections in the PCZ-susp and PCZ-tab groups were 7% (n = 8) and 3% (n = 1), respectively (P = 0.68). We conclude that the use of PCZ-tab was associated with higher Css and with the probability of achieving therapeutic goals without worsening of adverse effects. PMID:25987632

  8. Epigenetic inactivation of the MIR129-2 in hematological malignancies

    PubMed Central

    2013-01-01

    GRANTA-519, inhibited cellular proliferation and enhanced cell death, with concomitant SOX4 mRNA downregulation. Conclusions MIR129-2 is a tumor suppressive microRNA frequently methylated in lymphoid but not myeloid malignancies, leading to reversible MIR129-2 silencing. In CLL, MIR129-2 methylation was associated with an inferior survival. In MM, MIR129-2 methylation might be acquired during progression from MGUS to symptomatic MM. In NHL, MIR129-2 methylation might collaborate with MIR124-1 and MIR203 methylation in lymphomagenesis. PMID:23406679

  9. Autoimmune cytopenias after umbilical cord blood transplantation in adults with hematological malignancies: a single-center experience.

    PubMed

    Sanz, J; Arango, M; Carpio, N; Montesinos, P; Moscardó, F; Martín, G; López, F; Jarque, I; Lorenzo, I; de la Rubia, J; Solves, P; Boluda, B; Salazar, C; Cañigral, C; Sanz, M A; Sanz, G F

    2014-08-01

    We describe incidence, clinical features, serological data, response to therapy and outcome of autoimmune cytopenias (ACs), including autoimmune hemolytic anemia (AIHA) and autoimmune thrombocytopenia (AIT) in a series of 281 consecutive adults with hematological malignancies that received single-unit umbilical cord blood transplantation (UCBT) at a single institution. AIHA was diagnosed in 15 patients at a median time of 181 days (range, 25-543), 12 of them had cold antibodies (IgM). The 3-year cumulative incidence (CI) of AIHA was 5.4% (CI 95% 2.7-8.1). Concomitant infections at the time of AIHA were present in 10 patients. Five out of nine patients that received corticosteroids achieved either a PR or a CR, whereas six out of eight patients that received rituximab responded. Four patients developed AIT giving a 3-year CI of 1.4% (CI 95% 0-2.8), concomitant infections were present in three of them. Multivariable analysis showed that development of chronic GVHD (relative risk (RR) 4; 95% CI 1.1-13.7; P=0.03) and diagnosis of CML (RR 4.3; 95% CI 1.5-12.7; P=0.008) were associated with an increased risk of AC. In conclusion, AIHA and AIT are relevant and clinically significant complications in UCBT recipients, especially among those that develop chronic GVHD. Response to therapy is sub-optimal, and rituximab should be considered as a therapeutic option, in this setting were most patients had cold AIHA and a serological profile similar to that seen in cold agglutinin disease. PMID:24887383

  10. Targeting STAT5 in Hematological Malignancies through Inhibition of the Bromodomain and Extra-Terminal (BET) Bromodomain Protein BRD2

    PubMed Central

    Liu, Suhu; Walker, Sarah R.; Nelson, Erik A.; Cerulli, Robert; Xiang, Michael; Toniolo, Patricia A.; Qi, Jun; Stone, Richard M.; Wadleigh, Martha; Bradner, James E.; Frank, David A.

    2014-01-01

    The transcription factor signal transducer and activator of transcription 5 (STAT5) is constitutively activated in a wide range of leukemias and lymphomas, and drives the expression of genes necessary for proliferation, survival, and self-renewal. Thus, targeting STAT5 is an appealing therapeutic strategy for hematological malignancies. Given the importance of bromodomain-containing proteins in transcriptional regulation, we considered the hypothesis that a pharmacological bromodomain inhibitor could inhibit STAT5-dependent gene expression. We found that the small molecule bromodomain and extra-terminal (BET) bromodomain inhibitor JQ1 decreases STAT5-dependent (but not STAT3-dependent) transcription of both heterologous reporter genes and endogenous STAT5 target genes. JQ1 reduces STAT5 function in leukemia and lymphoma cells with constitutive STAT5 activation, or inducibly activated by cytokine stimulation. Among the BET bromodomain sub-family of proteins, it appears that BRD2 is the critical mediator for STAT5 activity. In experimental models of acute T cell lymphoblastic leukemias, where activated STAT5 contributes to leukemia cell survival, Brd2 knock-down or JQ1 treatment shows strong synergy with tyrosine kinase inhibitors in inducing leukemia cells apoptosis. By contrast, mononuclear cells isolated form umbilical cord blood, which is enriched in normal hematopoietic precursor cells, were unaffected by these combinations. These findings indicate a unique functional association between BRD2 and STAT5, and suggest that combinations of JQ1 and tyrosine kinase inhibitors may be an important rational strategy for treating leukemias and lymphomas driven by constitutive STAT5 activation. PMID:24435449

  11. Socioeconomic status, area remoteness, and survival from childhood leukemia: results from the Nationwide Registry for Childhood Hematological Malignancies in Greece.

    PubMed

    Sergentanis, Theodoros; Dessypris, Nick; Kanavidis, Prodromos; Skalkidis, Ilias; Baka, Margarita; Polychronopoulou, Sophia; Athanassiadou, Fani; Stiakaki, Eftichia; Frangandrea, Ioanna; Moschovi, Maria; Petridou, Eleni T

    2013-09-01

    The aim of the present nationwide Greek study is to assess whether survival from acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) is modified by socioeconomic status (SES) and area remoteness. Detailed precoded information derived from a personal interview conducted by specially trained health personnel with the child guardians was available for 883 ALL and 111 AML incident childhood cases registered in the Nationwide Registry for Childhood Hematological Malignancies during the period 1996-2010. Parental socioprofessional category was recorded on the basis of ISCO68 and ISCO88 codes; the exact traveling distance between residence and the treating hospital was ad hoc calculated. Multivariate Cox's proportional hazards models were applied to examine the mutually adjusted associations between survival and potential predictors. Children from a lower parental socioprofessional category experienced 40% worse survival (P=0.02) independent of age, sex, and ALL subtype, whereas those whose parents were married had better outcomes (rate ratio: 0.47, P=0.01). Urbanization of residence at diagnosis or 'residence to treating hospital' distance was not nominally associated with survival from ALL. By contrast, no noteworthy associations implicating SES were found for AML survival, probably because of the burden of the disease and small numbers. Lower SES indicators and a single-parenthood family milieu seem to be independently associated with unfavorable outcomes from childhood ALL. Area remoteness might not be a significant outcome predictor during recent years, following considerable improvements in the motorway infrastructures and care delivery patterns. This study may provide a valuable snapshot capturing the impact of socioeconomic covariates before the burst of the Greek financial crisis. PMID:23238585

  12. Linear Accelerator-Based Intensity-Modulated Total Marrow Irradiation Technique for Treatment of Hematologic Malignancies: A Dosimetric Feasibility Study

    SciTech Connect

    Yeginer, Mete; Roeske, John C.; Radosevich, James A.; Aydogan, Bulent

    2011-03-15

    Purpose: To investigate the dosimetric feasibility of linear accelerator-based intensity-modulated total marrow irradiation (IM-TMI) in patients with hematologic malignancies. Methods and Materials: Linear accelerator-based IM-TMI treatment planning was performed for 9 patients using the Eclipse treatment planning system. The planning target volume (PTV) consisted of all the bones in the body from the head to the mid-femur, except for the forearms and hands. Organs at risk (OAR) to be spared included the lungs, heart, liver, kidneys, brain, eyes, oral cavity, and bowel and were contoured by a physician on the axial computed tomography images. The three-isocenter technique previously developed by our group was used for treatment planning. We developed and used a common dose-volume objective method to reduce the planning time and planner subjectivity in the treatment planning process. Results: A 95% PTV coverage with the 99% of the prescribed dose of 12 Gy was achieved for all nine patients. The average dose reduction in OAR ranged from 19% for the lungs to 68% for the lenses. The common dose-volume objective method decreased the planning time by an average of 35% and reduced the inter- and intra- planner subjectivity. Conclusion: The results from the present study suggest that the linear accelerator-based IM-TMI technique is clinically feasible. We have demonstrated that linear accelerator-based IM-TMI plans with good PTV coverage and improved OAR sparing can be obtained within a clinically reasonable time using the common dose-volume objective method proposed in the present study.

  13. Investigating the presence of fungal agents in febrile neutropenic patients with hematological malignancies using different microbiological, serological, and molecular methods

    PubMed Central

    Sönmez, Ahu; Eksi, Fahriye; Pehlivan, Mustafa; Sahin, Handan Haydaroglu

    2015-01-01

    This study aimed to investigate fungal agents in febrile neutropenic patients with hematological malignancies. Direct microscopy and cultures were performed on clinical samples collected from febrile neutropenic episodes. The galactomannan (GM) antigen was tested using enzyme-linked immunosorbent assays, and Aspergillus fumigatus and Candida albicans deoxyribonucleic acid (DNA) assessed using real-time polymerase chain reaction (PCR) in consecutive serum samples. Of the 199 episodes investigated, 1.5% were classified as definite invasive aspergillosis (IA), 4.0% as IA with high probability, and 4.0% as IA with low probability. Additionally, candidaemia was detected in eight episodes (4.1%). The GM antigen was found negative for 86.4% of episodes, as one positive for 7.0% of episodes, as two or more consecutive positives for 5.5% of episodes, and as positive in any two serum samples in 1.0% of episodes. While no C. albicans DNA was detected in 98.5% of 199 ­episodes, one positive result was obtained in 1.0% of episodes, and two or more consecutive positives in 0.5% of episodes. A. fumigatus PCR results were found negative in 81.9% of episodes, as one positive in 16.1% of episodes, as positive in any two serum samples in 1.0% of episodes, and consecutively positive in 1.0% of episodes. GM antigen tests were found consecutively positive in all three patients diagnosed as having definite IA. These findings indicate that conventional, serological, and molecular methods should be used in combination to detect fungal agents in febrile neutropenic patients. PMID:26295293

  14. Hematology and pathology devices; reclassification of the automated differential cell counter. Final rule.

    PubMed

    2002-01-14

    The Food and Drug Administration (FDA) is reclassifying the automated differential cell counter (ADCC) from class III (premarket approval) into class II (special controls). FDA is also identifying the guidance document entitled "Class II Special Controls Guidance Document: Premarket Notifications for Automated Differential Cell Counters for Immature or Abnormal Blood Cells; Final Guidance for Industry and FDA" as the special control that the agency believes will reasonably ensure the safety and effectiveness of the device. This reclassification is being undertaken based on new information submitted in a reclassification petition from the International Society for Laboratory Hematology (ISLH), under the Federal Food, Drug, and Cosmetic Act (the act), as amended by the Safe Medical Devices Act of 1990 and the FDA Modernization Act of 1997. PMID:11800006

  15. Obesity and the Risk for a Hematological Malignancy: Leukemia, Lymphoma, or Myeloma

    PubMed Central

    2010-01-01

    The aggregate of epidemiological studies indicates a significantly elevated risk for cancer in people with a high body mass index (BMI); a “dose–response” effect exists with increasing risk as BMI increases from the normal to overweight to obese categories. Successful sustained weight loss decreases future risk. The relationship of being overweight to the risk for leukemia in the aggregate has been supported in several large cohort studies and two meta-analyses of cohort and case–control studies. One meta-analysis found an elevated risk for each of the four major subtypes of leukemia. A significant association between the risk for non-Hodgkin's lymphoma and elevated BMI was supported by a meta-analysis of 13 cohort and nine case–control studies. The risk for diffuse large B-cell lymphoma may be especially significant. A high BMI increases the risk for myeloma, as judged by a meta-analysis of 11 cohort and four case–control studies. The biological relationship of obesity to the risk for cancer (biological plausibility) is unresolved. The two major causal final pathways could be “inductive” or “selective.” The metabolic, endocrinologic, immunologic, and inflammatory-like changes resulting from obesity may increase the cell mutation rate, dysregulate gene function, disturb DNA repair, or induce epigenetic changes, favoring the induction of neoplastic transformation (inductive). Alternatively, obesity may create an environment in which pre-existing clones that are dormant are permitted (selected) to emerge. PMID:20930095

  16. Discontinuation of Systematic Surveillance and Contact Precautions for Vancomycin-Resistant Enterococcus (VRE) and Its Impact on the Incidence of VRE faecium Bacteremia in Patients with Hematologic Malignancies.

    PubMed

    Almyroudis, Nikolaos G; Osawa, Ryosuke; Samonis, George; Wetzler, M; Wang, Eunice S; McCarthy, Philip L; Segal, Brahm H

    2016-04-01

    OBJECTIVE To study the effect of discontinuation of systematic surveillance for vancomycin-resistant Enterococcus (VRE) and contact isolation of colonized patients on the incidence of VRE bacteremia SETTING A hematology-oncology unit with high prevalence of VRE colonization characterized by predominantly sporadic molecular epidemiology PARTICIPANTS Inpatients with hematologic malignancies and recipients of hematopoietic stem cell transplantation METHODS The incidence of VRE bacteremia was measured prospectively during 2 different 3-year time periods; the first during active VRE surveillance and contact precautions and the second after discontinuation of these policies. We assessed the collateral impact of this policy change on the incidence of bacteremia due to methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile infection even though we maintained contact precautions for these organisms. Incidence of infectious events was measured as number of events per 1,000 patients days per month. Time series analysis was used to evaluate trends. RESULTS The incidence of VRE bacteremia remained stable after discontinuation of VRE surveillance and contact precautions. The incidence of MRSA bacteremia and Clostridium difficile infection for which we continued contact precautions also remained stable. Aggregated antibiotic utilization and nursing hours per patient days were similar between the 2 study periods. CONCLUSION Active surveillance and contact precautions for VRE colonization did not appear to prevent VRE bacteremia in patients with hematologic malignancies and recipients of hematopoietic stem cell transplantation with high prevalence of VRE characterized by predominantly sporadic molecular epidemiology. Infect. Control Hosp. Epidemiol. 2016;37(4):398-403. PMID:26750087

  17. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia.

    PubMed

    Styczynski, J; Reusser, P; Einsele, H; de la Camara, R; Cordonnier, C; Ward, K N; Ljungman, P; Engelhard, D

    2009-05-01

    These guidelines on the management of HSV, VZV and EBV infection in patients with hematological malignancies and after SCT were prepared by the European Conference on Infections in Leukemia following a predefined methodology. A PubMed search was conducted using the appropriate key words to identify studies pertinent to management of HSV, VZV and EBV infections. References of relevant articles and abstracts from recent hematology and SCT scientific meetings were also reviewed. Prospective and retrospective studies identified from the data sources were evaluated, and all data deemed relevant were included in this analysis. The clinical and scientific background was described and discussed, and the quality of evidence and level of recommendation were graded according to the Centers for Disease Control criteria. PMID:19043458

  18. A phase I dose-escalation study of MSC1992371A, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies.

    PubMed

    Graux, Carlos; Sonet, Anne; Maertens, Johan; Duyster, Justus; Greiner, Jochen; Chalandon, Yves; Martinelli, Giovanni; Hess, Dagmar; Heim, Dominik; Giles, Francis J; Kelly, Kevin R; Gianella-Borradori, Athos; Longerey, Blandine; Asatiani, Ekaterine; Rejeb, Narmyn; Ottmann, Oliver G

    2013-09-01

    A phase I dose-escalation study of MSC1992371A, an oral aurora kinase inhibitor, was carried out in patients with hematologic malignancies. Patients received escalating doses either on days 1-3 and 8-10 (n=36) or on days 1-6 (n=39) of a 21-day cycle. The maximum tolerated doses were 37 and 28 mg/m(2)/day, respectively. Dose-limiting toxicities included severe neutropenia with infection and sepsis, mucositis/stomatitis, and diarrhea. Complete responses occurred in 3 patients. Four disease-specific expansion cohorts then received the dose and schedule dictated by the escalation phase but the study was prematurely discontinued due to hematologic and gastrointestinal toxicity at clinically effective doses. PMID:23746966

  19. The impact of oral herpes simplex virus infection and candidiasis on chemotherapy-induced oral mucositis among patients with hematological malignancies.

    PubMed

    Chen, Y-K; Hou, H-A; Chow, J-M; Chen, Y-C; Hsueh, P-R; Tien, H-F

    2011-06-01

    The aim of this study was to evaluate the influences of oral candidiasis and herpes simplex virus 1 (HSV-1) infections in chemotherapy-induced oral mucositis (OM). The medical records of 424 consecutive patients with hematological malignancies who had received chemotherapy at a medical center in Taiwan from January 2006 to November 2007 were retrospectively reviewed. The results of swab cultures of fungus and HSV-1 for OM were correlated with associated clinical features. Younger age, myeloid malignancies, and disease status other than complete remission before chemotherapy were significantly correlated with the development of OM. Risks of fever (p < 0.001) and bacteremia were higher in patients with OM. Among 467 episodes of OM with both swab cultures available, 221 were non-infection (47.3%) and 246 were related to either fungal infections, HSV-1 infections, or both (52.7%); of the 246 episodes, 102 were associated with fungal infections alone (21.8%), 98 with HSV-1 infections alone (21%), and 46 with both infections (9.9%). Patients who had received antifungal agents prior to OM occurrence tended to have HSV-1 infection (p < 0.001). Our results suggest that Candida albicans and HSV-1 play an important role in chemotherapy-induced OM in patients with hematological malignancies. PMID:21225303

  20. c-Src activation through a TrkA and c-Src interaction is essential for cell proliferation and hematological malignancies

    SciTech Connect

    Kim, Min Soo; Kim, Gyoung Mi; Choi, Yun-Jeong; Kim, Hye Joung; Kim, Yoo-Jin; Jin, Wook

    2013-11-15

    Highlights: •TrkA was mainly present in other types of leukemia including AML. •TrkA enhances the survival of leukemia by activation of PI3K/Akt pathway. •TrkA induced significant hematological malignancies by inducing PLK-1 and Twist-1. •TrkA acted as a key regulator of leukemogenesis and survival through c-Src activation. -- Abstract: Although the kinase receptor TrkA may play an important role in acute myeloid leukemia (AML), its involvement in other types of leukemia has not been reported. Furthermore, how it contributes to leukemogenesis is unknown. Here, we describe a molecular network that is important for TrkA function in leukemogenesis. We found that TrkA is frequently overexpressed in other types of leukemia such as acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) including AML. In addition, TrkA was overexpressed in patients with MDS or secondary AML evolving from MDS. TrkA induced significant hematological malignancies by inducing PLK-1 and Twist-1, and enhanced survival and proliferation of leukemia, which was correlated with activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway. Moreover, endogenous TrkA associated with c-Src complexes was detected in leukemia. Suppression of c-Src activation by TrkA resulted in markedly decreased expression of PLK-1 and Twist-1 via suppressed activation of Akt/mTOR cascades. These data suggest that TrkA plays a key role in leukemogenesis and reveal an unexpected physiological role for TrkA in the pathogenesis of leukemia. These data have important implications for understanding various hematological malignancies.

  1. Serum (1-3)-beta-D-glucan as a tool for diagnosis of Pneumocystis jirovecii pneumonia in patients with human immunodeficiency virus infection or hematological malignancy.

    PubMed

    Desmet, Stefanie; Van Wijngaerden, Eric; Maertens, Johan; Verhaegen, Jan; Verbeken, Eric; De Munter, Paul; Meersseman, Wouter; Van Meensel, Britt; Van Eldere, Johan; Lagrou, Katrien

    2009-12-01

    (1-3)-Beta-D-Glucan (BG) reactivity was tested in serum samples from 28 patients with human immunodeficiency virus infection or a hematological malignancy and Pneumocystis jirovecii pneumonia (PCP) and 28 control patients. The sensitivity and specificity of BG detection with the Fungitell assay for PCP were 100 and 96.4%, respectively, using a cutoff value of 100 pg/ml. Serum BG testing looks promising for the noninvasive diagnosis of PCP. Our data suggest that a higher cutoff value for the diagnosis of PCP than for the diagnosis of invasive aspergillosis or candidiasis could be used safely and will improve the specificity of the test. PMID:19846641

  2. Asia-Pacific Hematology Consortium Report on approach to multiple myeloma. Survey results from the 6th International Hematologic Malignancies Conference: Bridging the Gap 2015, Beijing, China.

    PubMed

    Lu, Jin; Hou, Jian; Liu, Kai-Yan; Parmar, Simrit; De La Fuente, Adolfo; Andersson, Börje; Yan, ChenHua; Zhou, Daobin; Tan, Daryl; Ritchie, David; Wu, Deipei; Shpall, Elizabeth; Laport, Ginna G; Li, JianYong; Hu, Jiong; Zhang, Lian Sheng; Wang, Michael; Malhotra, Pankaj; Jiang, Qian; Qin, Yazhen; Wong, Raymond; Champlin, Richard; Issaragrisil, Surapol; Iyer, Swaminathan; Mathews, Vikram; Wang, Yu; Hu, Yu; Xiao, Zhijian; Shao, Zonghong; Rosengarten, Rafael; Steuernagle, Jon; Xiao, Jun Huang; Orlowski, Robert; Chim, Chor Sang

    2016-07-01

    The Asia-Pacific Hematology Consortium (APHCON), in partnership with MDRingTM, a mobile global physician education network, has initiated a detailed longitudinal study of physician knowledge and practice preferences in the Asia-Pacific sphere. The first dataset comes from a series of surveys answered by delegates at the APHCON Bridging The Gap (BTG) conference in Beijing in January, 2015. In this report we present our findings regarding diagnosis and treatment of multiple myeloma (MM). We aim to create a conduit for physicians in this region to share their experiences with the rest of the world, to identify areas of consensus and best practices, and to highlight opportunities for improvement in communication, education and patient care. PMID:26887657

  3. Population-Based Analysis of Hematologic Malignancy Referrals to a Comprehensive Cancer Center, Referrals for Blood and Marrow Transplantation, and Participation in Clinical Trial, Survey, and Biospecimen Research by Race.

    PubMed

    Clay, Alyssa; Peoples, Brittany; Zhang, Yali; Moysich, Kirsten; Ross, Levi; McCarthy, Philip; Hahn, Theresa

    2015-08-01

    Racial and ethnic disparities have been reported in clinical trial/research participation, utilization of autologous and allogeneic blood and marrow transplantation (BMT), and availability of allogeneic donors. We performed a population-based cohort study to investigate adult hematologic malignancy referrals to a US tertiary cancer center, utilization of BMT, and participation in clinical trial, survey, and biospecimen research by race. US Census Data and the New York State Public Access Cancer Epidemiology Database identified the racial distribution of the general population and new hematologic malignancy cases in the primary catchment area. From 2005 to 2011, 1106 patients aged 18 to 75 years were referred for BMT consultation; although the rate of BMT among hematologic malignancy referrals did not differ by race, the reasons for not receiving a BMT did. Participation in biospecimen research did not vary by race; however, African Americans and other minorities were significantly less likely to participate in survey research than European Americans. Although rates of hematologic malignancy referrals and use of BMT for minorities appear to be low (<10%), they closely reflect the race distribution of all hematologic malignancy cases and the western New York population. African Americans are equally likely as other races to participate in biospecimen banking, but further study is needed to understand reasons for lower participation in survey research. PMID:25899454

  4. Hematology in Africa.

    PubMed

    Makani, Julie; Roberts, David J

    2016-04-01

    This review of hematology in Africa highlights areas of current practice and the immediate needs for development and clinical research. Acute hematological practice is dominated by anemia, sickle cell disease, and the need to provide a safe and rapidly available supply of blood. There is a growing need for specialist services for bleeding and coagulation, hematological malignancy, and palliative care. There are many areas of practice where straightforward measures could yield large gains in patient care. There is an urgent need for good clinical research to describe the epidemiology, natural history, and management of hematological diseases in Africa. PMID:27040965

  5. Phase 1/2 trial of total marrow and lymph node irradiation to augment reduced-intensity transplantation for advanced hematologic malignancies

    PubMed Central

    Wong, Jeffrey; Stein, Anthony; Qian, Dajun; Hitt, Debbie; Naeem, Hossameldin; Dagis, Andrew; Thomas, Sandra H.; Forman, Stephen

    2011-01-01

    This phase 1/2 study assessed the augmentation of reduced-intensity conditioning (RIC) with total marrow and lymph node irradiation (TMLI), for peripheral blood stem cell transplantation, in patients with advanced hematologic disease. The regimen consisted of fludarabine 25 mg/m2 per day for 5 days, melphalan 140 mg/m2 for one day, and TMLI radiation at 150 cGy/fraction in 8 fractions over 4 days. Eligible patients were over 50 years old and/or had compromised organ function. Median age of the 33 evaluable patients was 55.2 years. Eighteen events of nonhematologic grade III or higher toxicities occurred in 9 patients. Day 30 and day 100 mortalities were 3% and 15%, respectively. Patients achieved myeloid and platelet engraftment at a median of 14 days after transplantation. Long-term toxicities occurred in 2 patients: hypokalemia and tremor, both grade III, on days 370 and 361 after transplantation. Fourteen patients died, 7 of relapse-related causes and 7 of non–relapse-related causes. With a median follow-up for living patients of 14.7 months, 1-year overall survival, event-free survival, and non–relapse-related mortality were 75%, 65%, and 19%, respectively. Addition of TMLI to RIC is feasible and safe and could be offered to patients with advanced hematologic malignancies who might not otherwise be candidates for RIC. PMID:20876852

  6. Low usage rate of banked sibling cord blood units in hematopoietic stem cell transplantation for children with hematological malignancies: implications for directed cord blood banking policies.

    PubMed

    Goussetis, Evgenios; Peristeri, Ioulia; Kitra, Vasiliki; Papassavas, Andreas C; Theodosaki, Maria; Petrakou, Eftichia; Spiropoulos, Antonia; Paisiou, Anna; Soldatou, Alexandra; Stavropoulos-Giokas, Catherine; Graphakos, Stelios

    2011-02-15

    Directed sibling cord blood banking is indicated in women delivering healthy babies who already have a sibling with a disease that is potentially treatable with an allogeneic cord blood transplant. We evaluated the effectiveness of a national directed cord blood banking program in sibling HLA-identical stem cell transplantation for hematological malignancies and the factors influencing the usage rate of the stored cord blood units. Fifty families were enrolled from which, 48 cord blood units were successfully collected and 2 collections failed due to damaged cord/placenta at delivery. Among enrolled families 4 children needed transplantation; however, only one was successfully transplanted using the collected cord blood unit containing 2×10(7) nucleated cells/kg in conjunction with a small volume of bone marrow from the same HLA-identical donor. Two children received grafts from matched unrelated donors because their sibling cord blood was HLA-haploidentical, while the fourth one received bone marrow from his HLA-identical brother, since cord blood could not be collected due to damaged cord/placenta at delivery. With a median follow-up of 6 years (range, 2-12) for the 9 remaining HLA-matched cord blood units, none from the prospective recipients needed transplantation. The low utilization rate of sibling cord blood in the setting of hematopoietic stem cell transplantation for pediatric hematological malignant diseases necessitates the development of directed cord blood banking programs that limit long-term storage for banked cord blood units with low probability of usage such as non-HLA-identical or identical to patients who are in long-term complete remission. PMID:21095146

  7. Modeling Sitagliptin Effect on Dipeptidyl Peptidase 4 (DPP4) Activity in Adults with Hematological Malignancies After Umbilical Cord Blood (UCB) Hematopoietic Cell Transplant (HCT)

    PubMed Central

    de Mendizábal, Nieves Vélez; Strother, Robert M.; Farag, Sherif S.; Broxmeyer, Hal E.; Messina-Graham, Steven; Chitnis, Shripad D.; Bies, Robert R.

    2014-01-01

    Background and Objectives Dipeptidyl peptidase-4 (DPP4) inhibition is a potential strategy to increase the engraftment rate of hematopoietic stem/progenitor cells. A recent clinical trial using sitagliptin, a DPP4 inhibitor approved for type 2 diabetes mellitus, has shown to be a promising approach in adults with hematological malignancies after umbilical cord blood (UCB) hematopoietic cell transplant (HCT). Based on data from this clinical trial, a semi-mechanistic model was developed to simultaneously describe DPP4 activity after multiple doses of sitagliptin in subjects with hematological malignancies after a single-unit UCB HCT. Methods The clinical study included 24 patients that received myeloablative conditioning followed by 4 oral sitagliptin 600mg with single-unit UCB HCT. Using a nonlinear mixed effects approach, a semi-mechanistic pharmacokinetic/pharmacodynamic model was developed to describe DPP4 activity from this trial data using NONMEM 7.2. The model was used to drive Monte-Carlo simulations to probe various dosage schedules and the attendant DPP4 response. Results The disposition of sitagliptin in plasma was best described by a 2-compartment model. The relationship between sitagliptin concentration and DPP4 activity was best described by an indirect response model with a negative feedback loop. Simulations showed that twice a day or three times a day dosage schedules were superior to once daily schedule for maximal DPP4 inhibition at the lowest sitagliptin exposure. Conclusion This study provides the first pharmacokinetic/pharmacodynamic model of sitagliptin in the context of HCT, and provides a valuable tool for exploration of optimal dosing regimens, critical for improving time to engraftment in patients after UCB HCT. PMID:24142388

  8. Efficacy of Oral Cryotherapy on Oral Mucositis Prevention in Patients with Hematological Malignancies Undergoing Hematopoietic Stem Cell Transplantation: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Zhai, Ruiren; Zhao, Shasha; Luo, Lan; Li, Dandan; Zhao, Xiaoli; Wei, Huaping; Pang, Zhaoxia; Wang, Lili; Liu, Daihong; Wang, Quanshun; Gao, Chunji

    2015-01-01

    Objectives Controversy exists regarding whether oral cryotherapy can prevent oral mucositis (OM) in patients with hematological malignancies undergoing hematopoietic stem cell transplantation (HSCT). The aim of the present meta-analysis was to evaluate the efficacy of oral cryotherapy for OM prevention in patients with hematological malignancies undergoing HSCT. Methods PubMed and the Cochrane Library were searched through October 2014. Randomized controlled trials (RCTs) comparing the effect of oral cryotherapy with no treatment or with other interventions for OM in patients undergoing HSCT were included. The primary outcomes were the incidence, severity, and duration of OM. The secondary outcomes included length of analgesic use, total parenteral nutrition (TPN) use, and length of hospital stay. Results Seven RCTs involving eight articles analyzing 458 patients were included. Oral cryotherapy significantly decreased the incidence of severe OM (RR = 0.52, 95% CI = 0.27 to 0.99) and OM severity (SMD = -2.07, 95% CI = -3.90 to -0.25). In addition, the duration of TPN use and the length of hospitalization were markedly reduced (SMD = -0.56, 95% CI = -0.92 to -0.19; SMD = -0.44, 95% CI = -0.76 to -0.13; respectively). However, the pooled results were uncertain for the duration of OM and analgesic use (SMD = -0.13, 95% CI = -0.41 to 0.15; SMD = -1.15, 95% CI = -2.57 to 0.27; respectively). Conclusions Oral cryotherapy is a readily applicable and cost-effective prophylaxis for OM in patients undergoing HSCT. PMID:26024220

  9. Evaluation of Bloodstream Infections During Chemotherapy-Induced Febrile Neutropenia in Patients with Malignant Hematological Diseases: Single Center Experience.

    PubMed

    Piukovics, Klára; Terhes, Gabriella; Lázár, Andrea; Tímár, Flóra; Borbényi, Zita; Urbán, Edit

    2015-09-01

    From year to year, it is important to get an overview of the occurrence of causative agents in febrile neutropenic patients to determine the empiric treatment. Thus our aims were to evaluate a four-year period regarding the prevalence of bloodstream infections and the most important causative agents. During this period, 1,361 patients were treated in our hematology ward because of various hematological disorders. 812 febrile episodes were recorded in 469 patients. At that time, 3,714 blood culture (BC) bottles were sent for microbiological investigations, 759 of them gave positive signal. From the majority of positive blood culture bottles (67.1%), Gram-positive bacteria, mainly coagulase-negative staphylococci (CNS), were grown. Gram-negative bacteria were isolated from 32.9% of the positive blood culture bottles, in these cases the leading pathogen was Escherichia coli. The high prevalence of CNS was attributed to mainly contamination, while lower positivity rate for Gram-negative bacteria was associated with the use of broad-spectrum empiric antibiotic treatment. PMID:26495130

  10. Evaluation of Bloodstream Infections During Chemotherapy-Induced Febrile Neutropenia in Patients with Malignant Hematological Diseases: Single Center Experience

    PubMed Central

    Piukovics, Klára; Terhes, Gabriella; Lázár, Andrea; Tímár, Flóra; Borbényi, Zita; Urbán, Edit

    2015-01-01

    From year to year, it is important to get an overview of the occurrence of causative agents in febrile neutropenic patients to determine the empiric treatment. Thus our aims were to evaluate a four-year period regarding the prevalence of bloodstream infections and the most important causative agents. During this period, 1,361 patients were treated in our hematology ward because of various hematological disorders. 812 febrile episodes were recorded in 469 patients. At that time, 3,714 blood culture (BC) bottles were sent for microbiological investigations, 759 of them gave positive signal. From the majority of positive blood culture bottles (67.1%), Gram-positive bacteria, mainly coagulase-negative staphylococci (CNS), were grown. Gram-negative bacteria were isolated from 32.9% of the positive blood culture bottles, in these cases the leading pathogen was Escherichia coli. The high prevalence of CNS was attributed to mainly contamination, while lower positivity rate for Gram-negative bacteria was associated with the use of broad-spectrum empiric antibiotic treatment. PMID:26495130

  11. Application of iPS cells derived from congenital myelodysplastic syndrome for research of nomal hematopoesis and hematological malignancies.

    PubMed

    Nakajima, Hideaki

    2016-08-01

    Induced pluripotent stem cells (iPSCs) are not only a valuable resource for regenerative medicine, but also a promising tool for disease modeling and drug discovery. Patient-specific iPSCs harboring disease-specific mutations are extremely useful for investigating disease mechanisms and novel treatment approaches. In the field of hematology, attempts to establish iPSCs from tumor cells such as those of leukemia or myelodysplastic syndrome (MDS) were largely unsuccessful because proper reprogramming processes were hampered by their extensive genetic alterations. In contrast, congenital disorders caused by a single genetic mutation are ideal candidates for deriving iPSCs. We have been investigating the molecular mechanisms underlying leukemia and MDS by implementing iPSC technology. Familial platelet disorder (FPD) is a rare autosomal dominant disorder characterized by thrombocytopenia and a high propensity for developing acute leukemia, which is caused by heterozygous mutation of RUNX1. We have successfully established iPSCs from three distinct FPD pedigrees and examined the responsible defect during hematopoietic development. This system will serve as a novel unprecedented platform for prospectively studying hematologic disorders using human cells. PMID:27599428

  12. Detection of Aspergillus flavus and A. fumigatus in Bronchoalveolar Lavage Specimens of Hematopoietic Stem Cell Transplants and Hematological Malignancies Patients by Real-Time Polymerase Chain Reaction, Nested PCR and Mycological Assays

    PubMed Central

    Zarrinfar, Hossein; Mirhendi, Hossein; Fata, Abdolmajid; Khodadadi, Hossein; Kordbacheh, Parivash

    2015-01-01

    Background: Pulmonary aspergillosis (PA) is one of the most serious complications in immunocompromised patients, in particular among hematopoietic stem cell transplants (HSCT) and patients with hematological malignancies. Objectives: The current study aimed to evaluate the incidence of PA and utility of molecular methods in HSCT and patients with hematological malignancies, four methods including direct examination, culture, nested polymerase chain reaction (PCR) and real-time PCR were performed on bronchoalveolar lavage (BAL) specimens in Tehran, Iran. Patients and Methods: During 16 months, 46 BAL specimens were obtained from individuals with allogeneic HSCT (n = 18) and patients with hematological malignancies (n = 28). Direct wet mounts with 20% potassium hydroxide (KOH) and culture on mycological media were performed. The molecular detection of Aspergillus fumigatus and A. flavus was done by amplifying the conserved sequences of internal transcribed spacer 1 (ITS1) ribosomal DNA by nested-PCR and the β-tubulin gene by TaqMan real-time PCR. Results: Seven (15.2%) out of 46 specimens were positive in direct examination and showed branched septate hyphae; 11 (23.9%) had positive culture including eight (72.7%) A. flavus and three (27.3%) A. fumigatus; 22 (47.8%) had positive nested-PCR and eight (17.4%) had positive real-time PCR. The incidence of invasive pulmonary aspergillosis (IPA) in these patients included proven IPA in 1 (2.2%), probable IPA in 10 (21.7%), possible IPA in 19 (41.3%) and not IPA in 16 cases (34.8%). Conclusions: The incidence of IPA in allogeneic HSCT and patients with hematological malignancies was relatively high and A. flavus was the most common cause of PA. As molecular methods had higher sensitivity, it may be useful as screening methods in HSCT and patients with hematological malignancies, or to determine when empirical antifungal therapy can be withheld. PMID:25763133

  13. Medical Decision-Making Incapacity among Newly Diagnosed Older Patients with Hematological Malignancy Receiving First Line Chemotherapy: A Cross-Sectional Study of Patients and Physicians

    PubMed Central

    Sugano, Koji; Okuyama, Toru; Iida, Shinsuke; Komatsu, Hirokazu; Ishida, Takashi; Kusumoto, Shigeru; Uchida, Megumi; Nakaguchi, Tomohiro; Kubota, Yosuke; Ito, Yoshinori; Takahashi, Kazuhisa; Akechi, Tatsuo

    2015-01-01

    Background Decision-making capacity to provide informed consent regarding treatment is essential among cancer patients. The purpose of this study was to identify the frequency of decision-making incapacity among newly diagnosed older patients with hematological malignancy receiving first-line chemotherapy, to examine factors associated with incapacity and assess physicians’ perceptions of patients’ decision-making incapacity. Methods Consecutive patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were recruited. Decision-making capacity was assessed using the Structured Interview for Competency and Incompetency Assessment Testing and Ranking Inventory-Revised (SICIATRI-R). Cognitive impairment, depressive condition and other possible associated factors were also evaluated. Results Among 139 eligible patients registered for this study, 114 completed the survey. Of these, 28 (25%, 95% confidence interval [CI]: 17%-32%) were judged as having some extent of decision-making incompetency according to SICIATRI-R. Higher levels of cognitive impairment and increasing age were significantly associated with decision-making incapacity. Physicians experienced difficulty performing competency assessment (Cohen’s kappa -0.54). Conclusions Decision-making incapacity was found to be a common and under-recognized problem in older patients with cancer. Age and assessment of cognitive impairment may provide the opportunity to find patients that are at a high risk of showing decision-making incapacity. PMID:26296202

  14. Reduced Intensity Chemotherapy and Radiation Therapy Before Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2016-05-23

    Acute Myeloid Leukemia; Acute Myeloid Leukemia in Remission; Aplastic Anemia; Chronic Myelomonocytic Leukemia; Hodgkin Lymphoma; Indolent Non-Hodgkin Lymphoma; Malignant Neoplasm; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Plasma Cell Myeloma; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Ring Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts

  15. Analysis of baseline hepatitis B virus DNA levels in chronic hepatitis B patients with non-hematological malignancies prior to the initiation of cancer chemotherapy

    PubMed Central

    YOUNG, SHIH-HAO; WEI, TIEN-HSIN; LIN, CHUNG-CHI; CHU, CHI-JEN; LEE, FA-YAUH; YU, MAY-ING; LU, REI-HWA; CHANG, CHIAO-YU; YANG, PEI-LING; WANG, MEI-HUI; LIN, HAN-CHIEH

    2016-01-01

    Reactivation of hepatitis B virus (HBV) infection is common (~20–50%) during cancer chemotherapy. Baseline HBV replication status is an important risk factor for HBV reactivation. To date, data on the baseline HBV DNA level for chronic hepatitis B (CHB) patients prior to chemotherapy, particularly for non-hematological malignancies, are limited. A total of 105 consecutive CHB patients with solid tumors who received prophylactic antiviral therapy prior to chemotherapy from November, 2011 to December, 2014, were enrolled in this study. The patients' tumors included: Breast cancer (37.1%), lung cancer (18.1%), colon cancer (17.1%), head and neck cancer (10.5%), other gastrointestinal tract malignancies (8.6%), gynecological cancer (4.8%) and others (3.8%). The mean age of the enrolled patients was 55.2±1.1 years, 48 of the patients were male, 3 were hepatitis B e antigen-positive, and 26.7% had abnormal alanine aminotransferase (ALT) levels at baseline. The median HBV DNA level measured by quantitative polymerase chain reaction assay prior to chemotherapy was 3.30 log10 IU/ml and 49.5% of the enrolled patients had a baseline HBV DNA level >2,000 IU/ml. A wide range of HBV distribution was found: <20 IU/ml (15.2%), 20≤DNA<2,000 IU/ml (35.3%), 2,000≤DNA<20,000 IU/ml (26.6%), 20,000≤DNA<106 IU/ml (17.2%) and <106 IU/ml (5.7%). Age and baseline ALT level were not strongly associated with virological activity. The mean HBV DNA and the percentage of patients with HBV DNA >2,000 IU/ml were comparable between different cancer groups. Quantitative HBsAg level was a major determinant of baseline HBV DNA, and a significant correlation was noted between log10 hepatitis B surface antigen and log10 HBV DNA levels (γ=0.641, P<0.001). Our study demonstrated a wide distribution of baseline HBV DNA level among CHB patients diagnosed with non-hematological malignancies. Of note, approximately half of the patients (i.e., those with HBV DNA >2,000 IU/ml) had a higher risk of HBV

  16. Invasive fungal sinusitis in patients with hematological malignancy: 15 years experience in a single university hospital in Taiwan

    PubMed Central

    2011-01-01

    Background Risk factors and outcomes in hematological patients who acquire invasive fungal sinusitis (IFS) are infrequently reported in the modern medical era. Method A retrospective study of hospitalized patients with hematological disease was conducted at National Taiwan University Hospital between January 1995 and December 2009. Results Clinical characteristics and outcomes with their associated radiographic and microbiological findings were analyzed. Forty-six patients with IFS and 64 patients with chronic non-invasive sinusitis were enrolled as comparsion. IFS developed more commonly in patients with acute myeloid leukemia (AML) and with prolonged neutropenia (absolute neutrophil count less than 500/mm3 for more than 10 days) (p < 0.001). Aspergillus flavus was the most common pathogen isolated (44%). Serum Aspergillus galactomannan antigen was elevated in seven of eleven patients (64%) with IFS caused by aspergillosis but negative for all three patients with mucormycosis. Bony erosion and extra-sinus infiltration was found in 15 of 46 (33%) patients on imaging. Overall, 19 of 46 patients (41.3%) died within 6 weeks. Patients with disease subtype of AML (p = 0.044; Odds Ratio [OR], 5.84; 95% confidence interval [95% CI], 1.02-30.56) and refractory leukemia status (p = 0.05; OR, 4.27; 95% CI, 1.003-18.15) had worse prognosis. Multivariate analysis identified surgical debridement as an independent good prognostic factor (p = 0.047) in patients with IFS. Conclusions Patients of AML with prolonged neutropenia (> 10 days) had significantly higher risk of IFS. Early introduction of anti-fungal agent and aggressive surgical debridement potentially decrease morbidity and mortality in high risk patients with IFS. PMID:21939544

  17. Detection of antibodies to Candida albicans germ tubes for diagnosis and therapeutic monitoring of invasive candidiasis in patients with hematologic malignancies.

    PubMed Central

    García-Ruiz, J C; del Carmen Arilla, M; Regúlez, P; Quindós, G; Alvarez, A; Pontón, J

    1997-01-01

    We prospectively investigated the ability of detection of antibodies to Candida albicans germ tubes (CAGT) to diagnose invasive candidiasis in 95 consecutive admissions of 73 patients with hematologic disorders undergoing intensive chemotherapy. The episodes were divided into three groups according to clinical and microbiological diagnosis. Group 1 comprised eight admissions of eight patients with invasive candidiasis. Group 2 comprised 42 admissions of 34 patients without evidence of invasive candidiasis. Group 3 comprised the remaining 45 admissions of 37 patients with febrile episodes which were not diagnosed by microbiological culture. Antibodies to CAGT were detected in 87.5% of group 1 patients. Detection of antibodies to CAGT in patients with Candida fungemia was delayed somewhat relative to the time the blood culture was positive, but antibodies to CAGT were detected earlier than a diagnosis was made in patients with deep-tissue candidiasis. Sera from 2 admissions in group 2 and 12 admissions in group 3 revealed antibodies to CAGT. At a titer of > or = 1:20, detection of antibodies to CAGT had a sensitivity of 87.5%, specificity of 95.2%, positive predictive value of 77.8%, and negative predictive value of 97.6%. Antibodies to CAGT were usually detected before beginning of empiric antifungal therapy. Titers of antibodies to CAGT were maintained in most patients who died but declined and eventually disappeared in the patients who survived. Since antibodies to CAGT were detected in all patients with tissue-proven invasive candidiasis but negative by blood culture, detection of antibodies to CAGT complemented blood cultures for diagnosis and therapeutic monitoring of patients with hematologic malignancies and invasive candidiasis. PMID:9399535

  18. Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3)

    PubMed Central

    Skiada, Anna; Lanternier, Fanny; Groll, Andreas H.; Pagano, Livio; Zimmerli, Stephan; Herbrecht, Raoul; Lortholary, Olivier; Petrikkos, George L.

    2013-01-01

    Mucormycosis is an emerging cause of infectious morbidity and mortality in patients with hematologic malignancies. However, there are no recommendations to guide diagnosis and management. The European Conference on Infections in Leukemia assigned experts in hematology and infectious diseases to develop evidence-based recommendations for the diagnosis and treatment of mucormycosis. The guidelines were developed using the evidence criteria set forth by the American Infectious Diseases Society and the key recommendations are summarized here. In the absence of validated biomarkers, the diagnosis of mucormycosis relies on histology and/or detection of the organism by culture from involved sites with identification of the isolate at the species level (no grading). Antifungal chemotherapy, control of the underlying predisposing condition, and surgery are the cornerstones of management (level A II). Options for first-line chemotherapy of mucormycosis include liposomal amphotericin B and amphotericin B lipid complex (level B II). Posaconazole and combination therapy of liposomal amphotericin B or amphotericin B lipid complex with caspofungin are the options for second line-treatment (level B II). Surgery is recommended for rhinocerebral and skin and soft tissue disease (level A II). Reversal of underlying risk factors (diabetes control, reversal of neutropenia, discontinuation/taper of glucocorticosteroids, reduction of immunosuppressants, discontinuation of deferroxamine) is important in the treatment of mucormycosis (level A II). The duration of antifungal chemotherapy is not defined but guided by the resolution of all associated symptoms and findings (no grading). Maintenance therapy/secondary prophylaxis must be considered in persistently immunocompromised patients (no grading). PMID:22983580

  19. Antibody-targeted horseradish peroxidase associated with indole-3-acetic acid induces apoptosis in vitro in hematological malignancies.

    PubMed

    Dalmazzo, Leandro F F; Santana-Lemos, Bárbara A; Jácomo, Rafael H; Garcia, Aglair B; Rego, Eduardo M; da Fonseca, Luiz M; Falcão, Roberto P

    2011-05-01

    Indole-3-acetic acid (IAA), when oxidized by horseradish peroxidase (HRP), is transformed into cytotoxic molecules capable of inducing cell injury. The aim of this study was to test if, by targeting hematopoietic tumors with HRP-conjugated antibodies in association with IAA treatment, there is induction of apoptosis. We used two lineages of hematologic tumors: NB4, derived from acute promyelocytic leukemia (APL) and Granta-519 from mantle cell lymphoma (MCL). We also tested cells from 12 patients with acute myeloid leukemia (AML) and from 10 patients with chronic lymphocytic leukemia (CLL). HRP targeting was performed with anti-CD33 or anti-CD19 antibodies (depending on the origin of the cell), followed by incubation with goat anti-mouse antibody conjugated with HRP. Eight experimental groups were analyzed: control, HRP targeted, HRP targeted and incubated with 1, 5 and 10mM IAA, and cells not HRP targeted but incubated with 1, 5 and 10mM IAA. Apoptosis was analyzed by flow cytometry using annexin V-FITC and propidium iodide labeling. Results showed that apoptosis was dependent on the dose of IAA utilized, the duration of exposure to the prodrug and the origin of the neoplasia. Targeting HRP with antibodies was efficient in activating IAA and inducing apoptosis. PMID:21168913

  20. Late Toxicity of a Novel Allogeneic Stem Cell Transplant Using Single Fraction Total Body Irradiation for Hematologic Malignancies in Children

    PubMed Central

    Ngwube, Alexander I.; Shenoy, Shalini; Druley, Todd E.; Hayashi, Robert J.

    2015-01-01

    Single fraction total body irradiation (SFTBI) as part of a myeloablative preparative regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for hematopoietic malignancies was shown to have similar survival compared with fractionated total body irradiation (FTBI)-containing regimens, with less acute toxicity. The objective of this study was to determine long-term toxicity >2 years following SFTBI-based HSCT. Twenty-one patients were evaluated at a median follow-up of 6.8 years. Thyroid dysfunction was found in 21% of patients, 1 of whom (5.2%) was symptomatic; 23% had gonadal failure; 50% of patients with growth potential had linear growth disturbance; 27% had mild to moderate pulmonary disease; and 25% had cataracts. Intelligence quotient was stable. cGVHD was present in 28%, and 4 patients (19%) were on immune suppression 2 years posttransplant. Overall survival subsequent to 2 years posttransplant was 76% in this cohort of patients. No secondary malignancies were observed. In conclusion, the toxicities of SFTBI occurred at similar or reduced frequency compared with FTBI. SFTBI should be considered for patients who may benefit from a radiation-containing HSCT preparative regimen. PMID:25333837

  1. Effect of HLA-Matching Recipients to Donor Noninherited Maternal Antigens on Outcomes after Mismatched Umbilical Cord Blood Transplantation for Hematologic Malignancy

    PubMed Central

    Rocha, Vanderson; Spellman, Stephen; Zhang, Mei-Jie; Ruggeri, Annalisa; Purtill, Duncan; Brady, Colleen; Baxter-Lowe, Lee Ann; Baudoux, Etienne; Bergamaschi, Paola; Chow, Robert; Freed, Brian; Koegler, Gesine; Kurtzberg, Joanne; Larghero, Jerome; Lecchi, Lucilla; Nagler, Arnon; Navarrette, Cristina; Prasad, Vinod; Pouthier, Fabienne; Price, Thomas; Ratanatharathorn, Voravit; van Rood, Jon J.; Horowitz, Mary M.; Gluckman, Eliane; Eapen, Mary

    2013-01-01

    Transplantation-related mortality (TRM) is high after HLA-mismatched umbilical cord blood (UCB) transplantation (UCBT). In utero, exposure to noninherited maternal antigen (NIMA) is recognized by the fetus, which induces Tregulator cells to that haplotype. It is plausible that UCBTs in which recipients are matched to donor NIMAs may alleviate some of the excess mortality associated with this treatment. To explore this concept, we used marginal matched-pair Cox regression analysis to compare outcomes in 48 NIMA-matched UCBTs (ie, the NIMA of the donor UCB unit matched to the patient) and in 116 non–NIMA-matched UCBTs. All patients had a hematologic malignancy and received a single UCB unit. Cases and controls were matched on age, disease, disease status, transplantation-conditioning regimen, HLA match, and infused cell dose. TRM was lower after NIMA-matched UCBTs compared with NIMA-mismatched UCBTs (relative risk, 0.48; P=.05; 18% versus 32% at 5 years posttransplantation). Consequently, overall survival was higher after NIMA-matched UCBT. The 5-year probability of overall survival was 55% after NIMA-matched UCBTs versus 38% after NIMA-mismatched UCBTs (P=.04). When faced with the choice of multiple HLA-mismatched UCB units containing adequate cell doses, selecting an NIMA-matched UCB unit may improve survival after mismatched UCBT. PMID:22814031

  2. Effect of HLA-matching recipients to donor noninherited maternal antigens on outcomes after mismatched umbilical cord blood transplantation for hematologic malignancy.

    PubMed

    Rocha, Vanderson; Spellman, Stephen; Zhang, Mei-Jie; Ruggeri, Annalisa; Purtill, Duncan; Brady, Colleen; Baxter-Lowe, Lee Ann; Baudoux, Etienne; Bergamaschi, Paola; Chow, Robert; Freed, Brian; Koegler, Gesine; Kurtzberg, Joanne; Larghero, Jerome; Lecchi, Lucilla; Nagler, Arnon; Navarrette, Cristina; Prasad, Vinod; Pouthier, Fabienne; Price, Thomas; Ratanatharathorn, Voravit; van Rood, Jon J; Horowitz, Mary M; Gluckman, Eliane; Eapen, Mary

    2012-12-01

    Transplantation-related mortality (TRM) is high after HLA-mismatched umbilical cord blood (UCB) transplantation (UCBT). In utero, exposure to noninherited maternal antigen (NIMA) is recognized by the fetus, which induces T regulator cells to that haplotype. It is plausible that UCBTs in which recipients are matched to donor NIMAs may alleviate some of the excess mortality associated with this treatment. To explore this concept, we used marginal matched-pair Cox regression analysis to compare outcomes in 48 NIMA-matched UCBTs (ie, the NIMA of the donor UCB unit matched to the patient) and in 116 non-NIMA-matched UCBTs. All patients had a hematologic malignancy and received a single UCB unit. Cases and controls were matched on age, disease, disease status, transplantation-conditioning regimen, HLA match, and infused cell dose. TRM was lower after NIMA-matched UCBTs compared with NIMA-mismatched UCBTs (relative risk, 0.48; P = .05; 18% versus 32% at 5 years posttransplantation). Consequently, overall survival was higher after NIMA-matched UCBT. The 5-year probability of overall survival was 55% after NIMA-matched UCBTs versus 38% after NIMA-mismatched UCBTs (P = .04). When faced with the choice of multiple HLA-mismatched UCB units containing adequate cell doses, selecting an NIMA-matched UCB unit may improve survival after mismatched UCBT. PMID:22814031

  3. High serum levels of extracellular vesicles expressing malignancy-related markers are released in patients with various types of hematological neoplastic disorders.

    PubMed

    Caivano, Antonella; Laurenzana, Ilaria; De Luca, Luciana; La Rocca, Francesco; Simeon, Vittorio; Trino, Stefania; D'Auria, Fiorella; Traficante, Antonio; Maietti, Maddalena; Izzo, Tiziana; D'Arena, Giovanni; Mansueto, Giovanna; Pietrantuono, Giuseppe; Laurenti, Luca; Musto, Pellegrino; Del Vecchio, Luigi

    2015-12-01

    Many cell types release extracellular vesicles (EVs), including exosomes, microvesicles (MVs), and apoptotic bodies, which play a role in physiology and diseases. Presence and phenotype of circulating EVs in hematological malignancies (HMs) remain largely unexplored.The aim of this study was to characterize EVs in peripheral blood of HM patients compared to healthy subjects (controls). We isolated serum EVs from patients with chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), Waldenstrom's macroglobulinemia (WM), Hodgkin's lymphoma (HL), multiple myeloma (MM), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDS), and controls. EVs were isolated from serum of peripheral blood by ultracentrifuge steps and analyzed by flow cytometry to define count, size, and immunophenotype. MV levels were significantly elevated in WM, HL, MM, AML, and some MPNs and, though at a lesser degree, in CLL and NHL as compared to healthy controls. HL, MM, and MPNs generated a population of MVs characterized by lower size (below 0.3 μm) when compared to controls. MVs from patients specifically expressed tumor-related antigens, such as CD19 in B cell neoplasms, CD38 in MM, CD13 in myeloid tumors, and CD30 in HL. Both total and antigen-specific count of MVs significantly correlated with different HM clinical features such as Rai stage in CLL, International Prognostic Scoring System in WM, International Staging System in MM, and clinical stage in HL. MVs may represent a novel biomarker in HMs. PMID:26156801

  4. Inosine Triphosphate Pyrophosphohydrolase (ITPA) polymorphic sequence variants in adult hematological malignancy patients and possible association with mitochondrial DNA defects

    PubMed Central

    2013-01-01

    Background Inosine triphosphate pyrophosphohydrolase (ITPase) is a ‘house-cleaning’ enzyme that degrades non-canonical (‘rogue’) nucleotides. Complete deficiency is fatal in knockout mice, but a mutant polymorphism resulting in low enzyme activity with an accumulation of ITP and other non-canonical nucleotides, appears benign in humans. We hypothesised that reduced ITPase activity may cause acquired mitochondrial DNA (mtDNA) defects. Furthermore, we investigated whether accumulating mtDNA defects may then be a risk factor for cell transformation, in adult haematological malignancy (AHM). Methods DNA was extracted from peripheral blood and bone marrow samples. Microarray-based sequencing of mtDNA was performed on 13 AHM patients confirmed as carrying the ITPA 94C>A mutation causing low ITPase activity, and 4 AHM patients with wildtype ITPA. The frequencies of ITPA 94C>A and IVS2+21A>C polymorphisms were studied from 85 available AHM patients. Results ITPA 94C>A was associated with a significant increase in total heteroplasmic/homoplasmic mtDNA mutations (p<0.009) compared with wildtype ITPA, following exclusion of haplogroup variants. This suggested that low ITPase activity may induce mitochondrial abnormalities. Compared to the normal population, frequencies for the 94C>A and IVS2+21A>C mutant alleles among the AHM patients were higher for myelodyplastic syndrome (MDS) - but below significance; were approximately equivalent for chronic lymphoblastic leukemia; and were lower for acute myeloid leukemia. Conclusions This study invokes a new paradigm for the evolution of MDS, where nucleotide imbalances produced by defects in ‘house-cleaning’ genes may induce mitochondrial dysfunction, compromising cell integrity. It supports recent studies which point towards an important role for ITPase in cellular surveillance of rogue nucleotides. PMID:23547827

  5. xCELLigence system for real-time label-free monitoring of growth and viability of cell lines from hematological malignancies

    PubMed Central

    Martinez-Serra, Jordi; Gutierrez, Antonio; Muñoz-Capó, Saúl; Navarro-Palou, María; Ros, Teresa; Amat, Juan Carlos; Lopez, Bernardo; Marcus, Toni F; Fueyo, Laura; Suquia, Angela G; Gines, Jordi; Rubio, Francisco; Ramos, Rafael; Besalduch, Joan

    2014-01-01

    The xCELLigence system is a new technological approach that allows the real-time cell analysis of adherent tumor cells. To date, xCELLigence has not been able to monitor the growth or cytotoxicity of nonadherent cells derived from hematological malignancies. The basis of its technology relies on the use of culture plates with gold microelectrodes located in their base. We have adapted the methodology described by others to xCELLigence, based on the pre-coating of the cell culture surface with specific substrates, some of which are known to facilitate cell adhesion in the extracellular matrix. Pre-coating of the culture plates with fibronectin, compared to laminin, collagen, or gelatin, significantly induced the adhesion of most of the leukemia/lymphoma cells assayed (Jurkat, L1236, KMH2, and K562). With a fibronectin substrate, nonadherent cells deposited in a monolayer configuration, and consequently, the cell growth and viability were robustly monitored. We further demonstrate the feasibility of xCELLigence for the real-time monitoring of the cytotoxic properties of several antineoplastic agents. In order to validate this technology, the data obtained through real-time cell analysis was compared with that obtained from using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. This provides an excellent label-free tool for the screening of drug efficacy in nonadherent cells and discriminates optimal time points for further molecular analysis of cellular events associated with treatments, reducing both time and costs. PMID:24959085

  6. [Tandem transplantation with peripheral autologous hematopoietic blood stem cells in treatment of oncologic and hematologic malignancies. Initial results of the Donauspital, Vienna].

    PubMed

    Ruckser, R; Kier, P; Sebesta, C; Kittl, E; Kurz, M; Selleny, S; Höniger, S; Scherz, M; Habertheuer, K H; Zelenka, P

    1995-01-01

    10 patients were subjected to tandem transplantation for breast cancer (n = 3), ovarian cancer (n = 2) and multiple myeloma (n = 5), at the Second Department of Medicine, Donauspital, Vienna. The breast cancer patients were in stages 2 and 3, respectively, at diagnosis and entered complete remission thereafter. 2 of them developed lymph node metastasis and additional local recurrence, the 3rd patient presented with distant metastasis. The 2 patients with ovarian cancer were in stages Figo III and IV, respectively, at the time of diagnosis, and showed minimal residual disease at second-look-operation. 5 patients with multiple myeloma were in stage 3 pretransplant. Peripheral stem cells were obtained after either high-dose cyclophosphamide or FEC induction and application of cytokines. In 4 patients, tandem transplantation has been completed. 1 patient with multiple myeloma, who had received total body irradiation in combination with chemotherapy for the 2nd transplant, succumbed from idiopathic interstitial pneumonia. No severe clinical complications were observed in all other patients. All patients with solid tumors entered complete remission after the 1st transplantation. 3 of them completed tandem transplantation. Of these, 2 remain in continuous complete remission, the 3rd patient relapsed in lymph nodes day 485. In patients who received only 1 course of high dose chemotherapy with stem cell transplantation, relapses occurred on days 29 and 75, respectively. All patients with multiple myeloma entered only partial remission. We conclude that supralethal chemotherapy with peripheral blood stem cell support is a safe procedure that may at least induce prolonged remissions in solid tumors and hematologic malignancies.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7762251

  7. Chimerism-based pre-emptive immunotherapy with fast withdrawal of immunosuppression and donor lymphocyte infusions after allogeneic stem cell transplantation for pediatric hematologic malignancies.

    PubMed

    Horn, Biljana; Petrovic, Aleksandra; Wahlstrom, Justin; Dvorak, Christopher C; Kong, Denice; Hwang, Jimmy; Expose-Spencer, Jueleah; Gates, Michael; Cowan, Morton J

    2015-04-01

    The presence of increasing host chimerism or persistent mixed chimerism (MC) after hematopoietic stem cell transplantation for leukemia in children is a predictor of relapse. To reduce the risk of relapse, we prospectively studied post-transplantation chimerism-based immunotherapy (IT) using fast withdrawal of immunosuppression (FWI) and donor lymphocyte infusions (DLI) in children with early post-transplantation MC. Forty-three children with hematologic malignancies at 2 institutions were enrolled prospectively in this study from 2009 until 2012 and were followed for a mean of 42 (SD, 10) months. Twelve patients (28%) were assigned to the observation arm based on the presence of graft-versus-host disease (GVHD) or full donor chimerism (FDC), and 5 (12%) sustained early events and could not undergo intervention. Twenty-six (60%) patients with MC were assigned to IT with FWI, which started at a median of 49 days (range, 35 to 85 days) after transplantation. Fourteen patients proceeded to DLI after FWI. Toxicities of treatment included GVHD, which developed in 19% of patients undergoing intervention, with 1 of 26 (4%) dying from GVHD and 1 (4%) still requiring therapy for chronic GVHD 21 months after DLI. Patients with MC undergoing IT had similar 2-year event-free survival (EFS) (73%; 95% confidence interval (CI), 55% to 91%) compared with patients who achieved FDC spontaneously (83%; 95% CI, 62% to 100%); however, because 50% of all relapses in the IT occurred later than 2 years after transplantation, the EFS declined to 55% (95% CI, 34% to 76%) at 42 (SD, 11) months. There were no late relapses in the observation group. EFS in the entire cohort was 58% (95% CI, 42% to 73%) at 42 (SD, 11) months after transplantation. Evidence of disease before transplantation remained a significant predictor of relapse, whereas development of chronic GVHD was protective against relapse. PMID:25644958

  8. A Phase I Study of the First-in-Class Anti-Mitochondrial Metabolism Agent, CPI-613, in Patients with Advanced Hematologic Malignancies

    PubMed Central

    Pardee, Timothy S.; Lee, King; Luddy, John; Maturo, Claudia; Rodriguez, Robert; Isom, Scott; Miller, Lance D.; Stadelman, Kristin M.; Levitan, Denise; Hurd, David; Ellis, Leslie R.; Harrelson, Robin; Manuel, Megan; Dralle, Sarah; Lyerly, Susan; Powell, Bayard L

    2014-01-01

    Purpose The lipoate derivative CPI-613 is a first-in-class agent that targets mitochondrial metabolism. This study determined the effects of CPI-613 on mitochondrial function and defined the maximally tolerated dose (MTD), pharmacokinetics (PKs), and safety in patients with relapsed or refractory hematologic malignancies. Experimental Design Human leukemia cell lines were exposed to CPI-613 and mitochondrial function was assayed. A phase I trial was conducted in which CPI-613 was given as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days. Results CPI-613 inhibited mitochondrial respiration of human leukemia cells consistent with the proposed mechanism of action. In the phase I trial, 26 patients were enrolled. CPI-613 was well tolerated with no marrow suppression observed. When the infusion time was shortened to 1 hour renal failure occurred in 2 patients. At 3780 mg/m2, there were 2 dose-limiting toxicities (DLTs). At a dose of 2940 mg/m2 over 2 hours, no DLTs were observed, establishing this as the MTD. Renal failure occurred in a total of 4 patients and resolved in all but 1, who chose hospice care. CPI-613 has a triphasic elimination with an alpha half-life of ~1.34 hours. Of 21 evaluable, heavily pretreated, patients, 4 achieved an objective response and 2 achieved prolonged stabilization of disease for a clinical benefit rate of 29%. Following drug exposure, gene expression profiles of peripheral blood mononuclear cells from responders demonstrated immune activation. Conclusion CPI-613 inhibits mitochondrial function and demonstrates activity in a heavily pretreated cohort of patients. PMID:25165100

  9. AMG 319 Lymphoid Malignancy FIH

    ClinicalTrials.gov

    2016-01-20

    Cancer; Chronic Lymphocytic Leukemia; Diffuse Large Cell Lymphoma; Hematologic Malignancies; Hematology; Leukemia; Low Grade Lymphoma; Lymphoma; Mantle Cell Lymphoma; Non-Hodgkin's Lymphoma; Oncology; Oncology Patients; T Cell Lymphoma; Tumors

  10. A Prospective Study of {sup 18}FDG-PET With CT Coregistration for Radiation Treatment Planning of Lymphomas and Other Hematologic Malignancies

    SciTech Connect

    Terezakis, Stephanie A.; Schöder, Heiko; Kowalski, Alexander; McCann, Patrick; Lim, Remy; Turlakov, Alla; Gonen, Mithat; Barker, Chris; Goenka, Anuj; Lovie, Shona; Yahalom, Joachim

    2014-06-01

    Purpose: This prospective single-institution study examined the impact of positron emission tomography (PET) with the use of 2-[{sup 18}F] fluoro-2-deoxyglucose and computed tomography (CT) scan radiation treatment planning (TP) on target volume definition in lymphoma. Methods and Materials: 118 patients underwent PET/CT TP during June 2007 to May 2009. Gross tumor volume (GTV) was contoured on CT-only and PET/CT studies by radiation oncologists (ROs) and nuclear medicine physicians (NMPs) for 95 patients with positive PET scans. Treatment plans and dose-volume histograms were generated for CT-only and PET/CT for 95 evaluable sites. Paired t test statistics and Pearson correlation coefficients were used for analysis. Results: 70 (74%) patients had non-Hodgkin lymphoma, 10 (11%) had Hodgkin lymphoma, 12 (10%) had plasma-cell neoplasm, and 3 (3%) had other hematologic malignancies. Forty-three (45%) presented with relapsed/refractory disease. Forty-five (47%) received no prior chemotherapy. The addition of PET increased GTV as defined by ROs in 38 patients (median, 27%; range, 5%-70%) and decreased GTV in 41 (median, 39.5%; range, 5%-80%). The addition of PET increased GTV as defined by NMPs in 27 patients (median, 26.5%; range, 5%-95%) and decreased GTV in 52 (median, 70%; range, 5%-99%). The intraobserver correlation between CT-GTV and PET-GTV was higher for ROs than for NMPs (0.94, P<.01 vs 0.89, P<.01). On the basis of Bland-Altman plots, the PET-GTVs defined by ROs were larger than those defined by NMPs. On evaluation of clinical TPs, only 4 (4%) patients had inadequate target coverage (D95 <95%) of the PET-GTV defined by NMPs. Conclusions: Significant differences between the RO and NMP volumes were identified when PET was coregistered to CT for radiation planning. Despite this, the PET-GTV defined by ROs and NMPs received acceptable prescription dose in nearly all patients. However, given the potential for a marginal miss, consultation with an experienced PET

  11. Reduced-intensity conditioning regimen using low-dose total body irradiation before allogeneic transplant for hematologic malignancies: Experience from the European Group for Blood and Marrow Transplantation

    SciTech Connect

    Belkacemi, Yazid . E-mail: y-belkacemi@o-lambret.fr; Labopin, Myriam; Hennequin, Christophe; Hoffstetter, Sylvette; Mungai, Raffaello; Wygoda, Marc; Lundell, Marie; Finke, Jurgen; Aktinson, Chris; Lorchel, Frederic; Durdux, Catherine; Basara, Nadezda

    2007-02-01

    Purpose: The high rate of toxicity is the limitation of myelobalative regimens before allogeneic transplantation. A reduced intensity regimen can allow engraftment of stem cells and subsequent transfer of immune cells for the induction of a graft-vs.-tumor reaction. Methods and Materials: The data from 130 patients (80 males and 50 females) treated between 1998 and 2003 for various hematologic malignancies were analyzed. The median patient age was 50 years (range, 3-72 years). Allogeneic transplantation using peripheral blood or bone marrow, or both, was performed in 104 (82%), 22 (17%), and 4 (3%) patients, respectively, from HLA identical sibling donors (n = 93, 72%), matched unrelated donors (n = 23, 18%), mismatched related donors (4%), or mismatched unrelated donors (6%). Total body irradiation (TBI) at a dose of 2 Gy delivered in one fraction was given to 101 patients (78%), and a total dose of 4-6 Gy was given in 29 (22%) patients. The median dose rate was 14.3 cGy/min (range, 6-16.4). Results: After a median follow-up period of 20 months (range, 1-62 months), engraftment was obtained in 122 patients (94%). Acute graft-vs.-host disease of Grade 2 or worse was observed in 37% of patients. Multivariate analysis showed three favorable independent factors for event-free survival: HLA identical sibling donor (p < 0.0001; relative risk [RR], 0.15), complete remission (p < 0.0001; RR, 3.08), and female donor to male patient (p = 0.006; RR 2.43). For relapse, the two favorable prognostic factors were complete remission (p < 0.0001, RR 0.11) and HLA identical sibling donor (p = 0.0007; RR 3.59). Conclusions: In this multicenter study, we confirmed high rates of engraftment and chimerism after the reduced intensity regimen. Our results are comparable to those previously reported. Radiation parameters seem to have no impact on outcome. However, the lack of a statistically significant difference in terms of dose rate may have been due, in part, to the small population

  12. Comparison of the hematological profile of elite road cyclists during the 2010 and 2012 GiroBio ten-day stage races and relationships with final ranking.

    PubMed

    Lombardi, Giovanni; Lanteri, Patrizia; Fiorella, Pier Luigi; Simonetto, Luigi; Impellizzeri, Franco M; Bonifazi, Marco; Banfi, Giuseppe; Locatelli, Massimo

    2013-01-01

    Cycling stage races are strenuous endurance events during which exercise-induced variations in hematological parameters are consistently observed. However, specific literature on such changes is scarce and published data have been derived from small samples of athletes. The aims of this study were: (1) to determine the hematological response to middle-term strenuous endurance; and (2) to determine whether a relationship exists between the athlete-specific hematological profile and final placement in a cycling stage race. The study population was male professional cyclists (n = 253) competing in the 2010 (n = 144) and 2012 (n = 109) GiroBio 10-day stage races. Blood draws taken before the start of the race, at mid-race, and at end-race were performed in strict compliance with academic and anti-doping pre-analytical warnings. Blood chemistry included white blood cell, red blood cell, hemoglobin concentration, hematocrit, mean corpuscular volume (MCV), mean hemoglobin content (MCH), mean corpuscular hemoglobin content (MCHC), platelets, and reticulocyte relative and absolute counts. Compared to baseline values, erythrocyte, hemoglobin, hematocrit, MCHC, platelet and reticulocyte counts were all consistently lower at mid-race, but returned to normal by race-end, while leukocytes were increased in the final phase. MCV increased during both events. MCH increased in the first part to then return to baseline in the 2012 race. The calculated OFF-score consistently decreased in the first half of the race before increasing, but remained lower than the baseline value. The trends of variation in hematological parameters were substantially similar in both events. There was an inverse, albeit weak, relationship between placement and erythrocyte, platelet, hemoglobin, hematocrit and OFF-score values in the 2010, but not in the 2012 race. In conclusion, the data confirm that, in this large series of elite road cyclists, the strenuous effort a rider sustains during a

  13. Decreased complement mediated binding of antibody//sup 3/-dsDNA immune complexes to the red blood cells of patients with systemic lupus erythematosus, rheumatoid arthritis, and hematologic malignancies

    SciTech Connect

    Taylor, R.P.; Horgan, C.; Buschbacher, R.; Brunner, C.M.; Hess, C.E.; O'Brien, W.M.; Wanebo, H.J.

    1983-06-01

    The complement mediated binding of prepared antibody//sup 3/H-dsDNA immune complexes to the red blood cells obtained from a number of patient populations has been investigated. Patients with solid tumors have binding activity similar to that seen in a normal group of individuals. However, a significant fraction of patients with systemic lupus erythematosus, rheumatoid arthritis, and hematologic malignancies have lowered binding activity compared with normal subjects. Quantitative studies indicate the lowered activity probably arises due to a decrease in complement receptors on the respective red blood cells. The potential importance and implications of these findings are briefly discussed.

  14. DCB - Cancer Immunology, Hematology, and Etiology Research

    Cancer.gov

    Part of NCI’s Division of Cancer Biology’s research portfolio, studies supported include the characterization of basic mechanisms relevant to anti-tumor immune responses and hematologic malignancies.

  15. Reptile Hematology.

    PubMed

    Sykes, John M; Klaphake, Eric

    2015-09-01

    The basic principles of hematology used in mammalian medicine can be applied to reptiles. The appearances of the blood cells are significantly different from those seen in most mammals, and vary with taxa and staining method used. Many causes for abnormalities of the reptilian hemogram are similar to those for mammals, although additional factors such as venipuncture site, season, hibernation status, captivity status, and environmental factors can also affect values, making interpretation of hematologic results challenging. Values in an individual should be compared with reference ranges specific to that species, gender, and environmental conditions when available. PMID:26297412

  16. Chronic myelogenous leukemia-like hematological malignancy with t(8;22) in a 26-year-old pregnant woman: A case report

    PubMed Central

    QIN, YOU-WEN; YANG, YI-NING; BAI, PING; WANG, CHUN

    2016-01-01

    t(8;22)(p11;q11) is a rare but recurrent genetic alteration in various hematological disorders. Patients with t(8;22)(p11;q11) may be misdiagnosed with chronic myelogenous leukemia (CML), due to the similar clinical features. Thus, the current study presents a patient with t(8;22)(p11;q11) who was previously misdiagnosed with CML in the chronic phase. The current patient was a 26-year-old woman who was 4-weeks pregnant and in whom an increased white blood cell count (4.0×1010/l) was found upon physical examination. The patient had no history of hematological disease. Although cytogenetics showed a normal karyotype and no breakpoint cluster region/Abelson murine leukemia viral oncogene homolog 1 (BCR/ABL) fusion gene was detected by reverse transcription-polymerase chain reaction, a diagnosis of chronic myelogenous leukemia (CML) was initially made according to the clinical and morphological features. Another 6 weeks later, t(8;22)(p11;q11) rearrangement was present in 9 out of 10 analyzed metaphases. Fluorescence in situ hybridization and reverse transcription-polymerase chain reaction indicated a negative result for the BCR/ABL fusion, but gave a positive result for the BCR-fibroblast growth factor receptor 1 fusion. A hematological diagnosis of atypical CML was again formed. PMID:27313753

  17. NCI First International Workshop on the Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Cell Transplantation: Report from the Committee on Prevention of Relapse Following Allogeneic Cell Transplantation for Hematological Malignancies

    PubMed Central

    Alyea, Edwin P.; DeAngelo, Daniel J.; Moldrem, Jeffrey; Pagel, John M.; Przepiorka, Donna; Riddell, Stan; Sadelin, Michel; Young, James W.; Giralt, Sergio; Bishop, Michael

    2011-01-01

    Prevention of relapse after allogeneic hematopoietic stem cell transplantation is the most likely approach to improve survival of patients treated for hematologic malignancies. Herein we review the limits of currently available transplant therapies and the innovative strategies being developed to overcome resistance to therapy or to fill therapeutic modalities not currently available. These novel strategies include nonimmunologic therapies, such as targeted preparative regimens and posttransplant drug therapy, as well as immunologic interventions, including graft engineering, donor lymphocyte infusions, T cell engineering, vaccination and dendritic cell-based approaches. Several aspects of the biology of the malignant cells as well as the host have been identified that obviate success of even these newer strategies. To maximize the potential for success, we recommend pursuing research to develop additional targeted therapies to be used in the preparative regimen or as maintenance post-transplant, better characterize the T-cell and dendritic cells subsets involved in graft-versus-host disease and the graft-versus-leukemia/tumor effect, identify strategies for timing immunologic or nonimmunologic therapies to eliminate the noncycling cancer stem cell, identify more targets for immunotherapies, develop new vaccines that will not be limited by HLA, and develop methods to identify population at very high risk for relapse in order to accelerate clinical development and avoid toxicity in patients not at risk for relapse. PMID:20580849

  18. Haploidentical stem cell transplantation after a reduced-intensity conditioning regimen for the treatment of advanced hematologic malignancies: posttransplantation CD8-depleted donor lymphocyte infusions contribute to improve T-cell recovery.

    PubMed

    Dodero, Anna; Carniti, Cristiana; Raganato, Anna; Vendramin, Antonio; Farina, Lucia; Spina, Francesco; Carlo-Stella, Carmelo; Di Terlizzi, Simona; Milanesi, Marco; Longoni, Paolo; Gandola, Lorenza; Lombardo, Claudia; Corradini, Paolo

    2009-05-01

    Haploidentical hematopoietic stem cell transplantation provides an option for patients with advanced hematologic malignancies lacking a compatible donor. In this prospective phase 1/2 trial, we evaluated the role of reduced-intensity conditioning (RIC) followed by early add-backs of CD8-depleted donor lymphocyte infusions (DLIs). The RIC regimen consisted of thiotepa, fludarabine, cyclophosphamide, and 2 Gy total body irradiation. Twenty-eight patients with advanced lymphoproliferative diseases (n = 24) or acute myeloid leukemia (n = 4) were enrolled. Ex vivo and in vivo T-cell depletion was carried out by CD34(+) cell selection and alemtuzumab treatment. The 2-year cumulative incidence of nonrelapse mortality was 26% and the 2-year overall survival (OS) was 44%, with a better outcome for patients with chemosensitive disease (OS, 75%). Overall, 54 CD8-depleted DLIs were administered to 23 patients (82%) at 3 different dose levels without loss of engraftment or acute toxicities. Overall, 6 of 23 patients (26%) developed grade II-IV graft-versus-host disease, mainly at dose level 2. In conclusion, our RIC regimen allowed a stable engraftment with a rather low nonrelapse mortality in poor-risk patients; OS is encouraging with some long-term remissions in lymphoid malignancies. CD8-depleted DLIs are feasible and promote the immune reconstitution. PMID:19211934

  19. Hematologic complications of pregnancy.

    PubMed

    Townsley, Danielle M

    2013-07-01

    Pregnancy induces a number of physiologic changes that affect the hematologic indices, either directly or indirectly. Recognizing and treating hematologic disorders that occur during pregnancy is difficult owing to the paucity of evidence available to guide consultants. This review discusses specifically the diagnosis and management of benign hematologic disorders occurring during pregnancy. Anemia secondary to iron deficiency is the most frequent hematologic complication and is easily treated with oral iron formulations; however, care must be taken not to miss other causes of anemia, such as sickle cell disease. Thrombocytopenia is also a common reason for consulting the hematologist, and distinguishing gestational thrombocytopenia from immune thrombocytopenia (ITP), preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), or thrombotic thrombocytopenic purpura (TTP) is essential since the treatment differs widely. Occasionally the management of mother and infant involves the expeditious recognition of neonatal alloimmune thrombocytopenia (NAIT), a condition that is responsible for severe life-threatening bleeding of the newborn. Additionally, inherited and acquired bleeding disorders affect pregnant women disproportionately and often require careful monitoring of coagulation parameters to prevent bleeding in the puerperium. Finally, venous thromboembolism (VTE) during pregnancy is still largely responsible for mortality during pregnancy, and the diagnosis, treatment options and guidelines for prevention of VTE during pregnancy are explored. PMID:23953339

  20. Hematologic Complications of Pregnancy

    PubMed Central

    Townsley, Danielle M.

    2013-01-01

    Pregnancy induces a number of physiologic changes that affect the hematologic indices, either directly or indirectly. Recognizing and treating hematologic disorders that occur during pregnancy is difficult owing to the paucity of evidence available to guide consultants. This paper specifically reviews the diagnosis and management of benign hematologic disorders occurring during pregnancy. Anemia secondary to iron deficiency is the most frequent hematologic complication and is easily treated with oral iron formulations,; however care must be taken not to miss other causes of anemia, such as sickle cell disease. Thrombocytopenia is also a common reason for consulting the hematologist and distinguishing gestational thrombocytopenia from immune thrombocytopenia (ITP), preeclampsia, HELLP syndrome, or thrombotic thrombocytopenic purpura (TTP) is essential since the treatment differs widely. Occasionally the management of mother and infant involves the expeditious recognition of neonatal alloimmune thrombocytopenia (NAIT), a condition that is responsible for severe life-threatening bleeding of the newborn. Additionally, inherited and acquired bleeding disorders affect pregnant women disproportionately and often require careful monitoring of coagulation parameters in order to prevent bleeding in the puerperium. Finally, venous thromboembolism (VTE) during pregnancy is still largely responsible for mortality during pregnancy and the diagnosis, treatment options and guidelines for prevention of VTE during pregnancy are explored. PMID:23953339

  1. Chimerism Analysis of Cell-Free DNA in Patients Treated with Hematopoietic Stem Cell Transplantation May Predict Early Relapse in Patients with Hematologic Malignancies

    PubMed Central

    Aljurf, Mahmoud; Abalkhail, Hala; Alseraihy, Amal; Mohamed, Said Y.; Ayas, Mouhab; Alsharif, Fahad; Alzahrani, Hazza; Al-Jefri, Abdullah; Aldawsari, Ghuzayel; Al-Ahmari, Ali; Belgaumi, Asim F.; Walter, Claudia Ulrike; El-Solh, Hassan; Rasheed, Walid; Albitar, Maher

    2016-01-01

    Background. We studied DNA chimerism in cell-free DNA (cfDNA) in patients treated with HSCT. Methods. Chimerism analysis was performed on CD3+ cells, polymorphonuclear (PMN) cells, and cfDNA using 16 small tandem repeat loci. The resulting labeled PCR-products were size-fractionated and quantified. Results. Analyzing samples from 191 patients treated with HSCT for nonneoplastic hematologic disorders demonstrated that the cfDNA chimerism is comparable to that seen in PMN cells. Analyzing leukemia patients (N = 126) showed that, of 84 patients with 100% donor DNA in PMN, 16 (19%) had evidence of clinical relapse and >10% recipient DNA in the plasma. Additional 16 patients of the 84 (19%) showed >10% recipient DNA in plasma, but without evidence of relapse. Eight patients had mixed chimerism in granulocytes, lymphocytes, and plasma, but three of these patients had >10% recipient DNA in plasma compared to PMN cells and these three patients had clinical evidence of relapse. The remaining 34 patients showed 100% donor DNA in both PMN and lymphocytes, but cfDNA showed various levels of chimerism. Of these patients 14 (41%) showed laboratory or clinical evidence of relapse and all had >10% recipient DNA in cfDNA. Conclusion. Monitoring patients after HSCT using cfDNA might be more reliable than cellular DNA in predicting early relapse. PMID:27006832

  2. Hematological Problems of Pregnancy

    PubMed Central

    Ballem, P.J.

    1988-01-01

    Hematologic complications are relatively common in pregnancy. Furthermore, many chronic hematologic disorders require special surveillance and intervention in pregnancy. In this brief review, the author discusses common nutritional anemias in pregnancy. She reviews the disorders of hemoglobin synthesis and the need for early genetic counselling and prenatal diagnosis, as well as the special requirements and problems affected patients encounter in pregnancy. An overview of the frequent causes of thrombocytopenia in pregnancy is given and an approach suggested to the management of both the mother and the fetus. An approach is also presented to the management of women at risk for thrombosis in pregnancy, a particularly vexing and controversial problem. The risks of the various forms of anticoagulation are reviewed. Finally, a brief review of obstetrical hemorrhage is presented along with some guidelines useful in its management. PMID:21253125

  3. Choice of Unmanipulated T Cell Replete Graft for Haploidentical Stem Cell Transplant and Posttransplant Cyclophosphamide in Hematologic Malignancies in Adults: Peripheral Blood or Bone Marrow—Review of Published Literature

    PubMed Central

    Farhan, Shatha; Peres, Edward; Janakiraman, Nalini

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (SCT) is often the only curative option for many patients with malignant and benign hematological stem cell disorders. However, some issues are still of concern regarding finding a donor like shrinking family sizes in many societies, underrepresentation of the ethnic minorities in the registries, genetic variability for some races, and significant delays in obtaining stem cells after starting the search. So there is a considerable need to develop alternate donor stem cell sources. The rapid and near universal availability of the haploidentical donor is an advantage of the haploidentical SCT and an opportunity that is being explored currently in many centers especially using T cell replete graft and posttransplant cyclophosphamide. This is probably because it does not require expertise in graft manipulation and because of the lower costs. However, there are still lots of unanswered questions, like the effect of use of bone marrow versus peripheral blood as the source of stem cells on graft-versus-host disease, graft versus tumor, overall survival, immune reconstitution, and quality of life. Here we review the available publications on bone marrow and peripheral blood experience in the haploidentical SCT setting. PMID:27118973

  4. Fludarabine Phosphate and Total-Body Radiation Followed by Donor Peripheral Blood Stem Cell Transplant and Immunosuppression in Treating Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2015-12-01

    -cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; Waldenström Macroglobulinemia

  5. Eosinophilic pustular folliculitis associated with hematological disorders: A report of two cases and review of Japanese literature.

    PubMed

    Takamura, Saori; Teraki, Yuichi

    2016-04-01

    Eosinophilic pustular folliculitis (EPF) occurs in patients with hematological disorders. However, clinical information about hematological disorder-associated EPF is scarce. We report two cases of EPF associated with mantle cell lymphoma and reviewed the available published work on Japanese cases. We identified a total of 23 Japanese cases, including the two cases reported here, who had hematological disorder-associated EPF. Fourteen cases were associated with treatment for hematological malignancies (transplantation-related EPF) and nine cases were associated with hematological malignancies themselves (hematological malignancy-related EPF). Although the skin eruption was clinically indistinguishable between the two subtypes, transplantation-related EPF occurred on the face and trunk of young and middle-aged men and women, whereas hematological malignancy-related EPF occurred mostly on the face of older men. Peripheral blood eosinophilia was more frequently observed in transplantation-related EPF. These observations suggest variations among patients with EPF associated with hematological disorders. PMID:26362415

  6. Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing αβ+T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies.

    PubMed

    Muccio, Letizia; Bertaina, Alice; Falco, Michela; Pende, Daniela; Meazza, Raffaella; Lopez-Botet, Miguel; Moretta, Lorenzo; Locatelli, Franco; Moretta, Alessandro; Della Chiesa, Mariella

    2016-03-01

    We analyzed the impact of human cytomegalovirus infection on the development of natural killer cells in 27 pediatric patients affected by hematological malignancies, who had received a HLA-haploidentical hematopoietic stem cell transplantation, depleted of both α/β+ T cells and B cells. In line with previous studies in adult recipients of umbilical cord blood transplantation, we found that human cytomegalovirus reactivation accelerated the emergence of mature natural killer cells. Thus, most children displayed a progressive expansion of a memory-like natural killer cell subset expressing NKG2C, a putative receptor for human cytomegalovirus, and CD57, a marker of terminal natural killer cell differentiation. NKG2C(+)CD57(+) natural killer cells were detectable by month 3 following hematopoietic stem cell transplantation and expanded until at least month 12. These cells were characterized by high killer Ig-like receptors (KIRs) and leukocyte inhibitory receptor 1 (LIR-1) and low Siglec-7, NKG2A and Interleukin-18Rα expression, killed tumor targets and responded to cells expressing HLA-E (a NKG2C ligand). In addition, they were poor Interferon-γ producers in response to Interleukin-12 and Interleukin-18. The impaired response to these cytokines, together with their highly differentiated profile, may reflect their skewing toward an adaptive condition specialized in controlling human cytomegalovirus. In conclusion, in pediatric patients receiving a type of allograft different from umbilical cord blood transplantation, human cytomegalovirus also induced memory-like natural killer cells, possibly contributing to controlling infections and reinforcing anti-leukemia effects. PMID:26659918

  7. Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing αβ+T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies

    PubMed Central

    Muccio, Letizia; Bertaina, Alice; Falco, Michela; Pende, Daniela; Meazza, Raffaella; Lopez-Botet, Miguel; Moretta, Lorenzo; Locatelli, Franco; Moretta, Alessandro; Chiesa, Mariella Della

    2016-01-01

    We analyzed the impact of human cytomegalovirus infection on the development of natural killer cells in 27 pediatric patients affected by hematological malignancies, who had received a HLA-haploidentical hematopoietic stem cell transplantation, depleted of both α/β+ T cells and B cells. In line with previous studies in adult recipients of umbilical cord blood transplantation, we found that human cytomegalovirus reactivation accelerated the emergence of mature natural killer cells. Thus, most children displayed a progressive expansion of a memory-like natural killer cell subset expressing NKG2C, a putative receptor for human cytomegalovirus, and CD57, a marker of terminal natural killer cell differentiation. NKG2C+CD57+ natural killer cells were detectable by month 3 following hematopoietic stem cell transplantation and expanded until at least month 12. These cells were characterized by high killer Ig-like receptors (KIRs) and leukocyte inhibitory receptor 1 (LIR-1) and low Siglec-7, NKG2A and Interleukin-18Rα expression, killed tumor targets and responded to cells expressing HLA-E (a NKG2C ligand). In addition, they were poor Interferon-γ producers in response to Interleukin-12 and Interleukin-18. The impaired response to these cytokines, together with their highly differentiated profile, may reflect their skewing toward an adaptive condition specialized in controlling human cytomegalovirus. In conclusion, in pediatric patients receiving a type of allograft different from umbilical cord blood transplantation, human cytomegalovirus also induced memory-like natural killer cells, possibly contributing to controlling infections and reinforcing anti-leukemia effects. PMID:26659918

  8. Zebrafish in hematology: sushi or science?

    PubMed Central

    Carradice, Duncan

    2008-01-01

    After a decade of the “modern era” of zebrafish hematology research, what have been their major contributions to hematology and what challenges does the model face? This review argues that, in hematology, zebrafish have demonstrated their suitability, are proving their utility, have supplied timely and novel discoveries, and are poised for further significant contributions. It presents an overview of the anatomy, physiology, and genetics of zebrafish hematopoiesis underpinning their use in hematology research. Whereas reverse genetic techniques enable functional studies of particular genes of interest, forward genetics remains zebrafish's particular strength. Mutants with diverse and interesting hematopoietic defects are emerging from multiple genetic screens. Some mutants model hereditary blood diseases, occasionally leading to disease genes first; others provide insights into developmental hematology. Models of malignant hematologic disorders provide tools for drug-target and pharmaceutics discovery. Numerous transgenic zebrafish with fluorescently marked blood cells enable live-cell imaging of inflammatory responses and host-pathogen interactions previously inaccessible to direct observation in vivo, revealing unexpected aspects of leukocyte behavior. Zebrafish disease models almost uniquely provide a basis for efficient whole animal chemical library screens for new therapeutics. Despite some limitations and challenges, their successes and discovery potential mean that zebrafish are here to stay in hematology research. PMID:18182572

  9. Mycophenolate Mofetil and Cyclosporine in Reducing Graft-Versus-Host Disease in Patients With Hematologic Malignancies or Metastatic Kidney Cancer Undergoing Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-03-01

    /Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Renal Cell Cancer; T-cell Large Granular Lymphocyte Leukemia; Type 1 Papillary Renal Cell Carcinoma; Type 2 Papillary Renal Cell Carcinoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; Waldenström Macroglobulinemia

  10. Artificial intelligence in hematology.

    PubMed

    Zini, Gina

    2005-10-01

    Artificial intelligence (AI) is a computer based science which aims to simulate human brain faculties using a computational system. A brief history of this new science goes from the creation of the first artificial neuron in 1943 to the first artificial neural network application to genetic algorithms. The potential for a similar technology in medicine has immediately been identified by scientists and researchers. The possibility to store and process all medical knowledge has made this technology very attractive to assist or even surpass clinicians in reaching a diagnosis. Applications of AI in medicine include devices applied to clinical diagnosis in neurology and cardiopulmonary diseases, as well as the use of expert or knowledge-based systems in routine clinical use for diagnosis, therapeutic management and for prognostic evaluation. Biological applications include genome sequencing or DNA gene expression microarrays, modeling gene networks, analysis and clustering of gene expression data, pattern recognition in DNA and proteins, protein structure prediction. In the field of hematology the first devices based on AI have been applied to the routine laboratory data management. New tools concern the differential diagnosis in specific diseases such as anemias, thalassemias and leukemias, based on neural networks trained with data from peripheral blood analysis. A revolution in cancer diagnosis, including the diagnosis of hematological malignancies, has been the introduction of the first microarray based and bioinformatic approach for molecular diagnosis: a systematic approach based on the monitoring of simultaneous expression of thousands of genes using DNA microarray, independently of previous biological knowledge, analysed using AI devices. Using gene profiling, the traditional diagnostic pathways move from clinical to molecular based diagnostic systems. PMID:16203606

  11. The European Hematology Association Roadmap for European Hematology Research: a consensus document

    PubMed Central

    Engert, Andreas; Balduini, Carlo; Brand, Anneke; Coiffier, Bertrand; Cordonnier, Catherine; Döhner, Hartmut; de Wit, Thom Duyvené; Eichinger, Sabine; Fibbe, Willem; Green, Tony; de Haas, Fleur; Iolascon, Achille; Jaffredo, Thierry; Rodeghiero, Francesco; Salles, Gilles; Schuringa, Jan Jacob

    2016-01-01

    The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. PMID:26819058

  12. The European Hematology Association Roadmap for European Hematology Research: a consensus document.

    PubMed

    Engert, Andreas; Balduini, Carlo; Brand, Anneke; Coiffier, Bertrand; Cordonnier, Catherine; Döhner, Hartmut; de Wit, Thom Duyvené; Eichinger, Sabine; Fibbe, Willem; Green, Tony; de Haas, Fleur; Iolascon, Achille; Jaffredo, Thierry; Rodeghiero, Francesco; Salles, Gilles; Schuringa, Jan Jacob

    2016-02-01

    The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap.The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders.The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. PMID:26819058

  13. Hematologic Disorders: Anemia.

    PubMed

    Baltierra, David; Harper, Tiffany; Jones, Matthew Page; Nau, Konrad C

    2015-06-01

    Anemia occurs in up to 25% of the US population. Normal hemoglobin levels vary by race, sex, and age. Classification of anemia by mean corpuscular volume guides the differential diagnosis and evaluation. Iron studies, reticulocyte count, the red blood cell distribution width index, and blood test results are used to make the diagnosis. Iron deficiency anemia is the most common microcytic anemia and is managed with iron therapy. Parenteral iron is available when the oral route cannot be used. Patients who do not benefit from therapy should be evaluated for adherence, malabsorption, occult bleeding, systemic disease, or less common inherited disorders. A source of gastrointestinal bleeding is found in 60% to 70% of patients with iron deficiency anemia who are referred for endoscopy. Normocytic anemia has a broad differential, including nutritional deficiencies, blood loss, renal disease, malignancy (solid tumors or hematologic cancer), rheumatologic disorders, endocrine disorders, and other systemic diseases. Macrocytic anemias are seen with vitamin B12 and folate deficiency, alcohol use, thyroid disease, hydroxyurea, antiretroviral drugs, myelodysplastic syndromes, and myeloma. Oral vitamin B12 is underused, and can be as effective as intramuscular vitamin B12 in managing anemia due to vitamin B12 deficiency. PMID:26080453

  14. Filgrastim-Stimulated Bone Marrow Compared with Filgrastim-Mobilized Peripheral Blood in Myeloablative Sibling Allografting for Patients with Hematologic Malignancies: A Randomized Canadian Blood and Marrow Transplant Group Study.

    PubMed

    Couban, Stephen; Aljurf, Mahmoud; Lachance, Sylvie; Walker, Irwin; Toze, Cynthia; Rubinger, Morel; Lipton, Jeffrey H; Lee, Stephanie J; Szer, Richard; Doocey, R; Lewis, Ian D; Huebsch, Lothar; Howson-Jan, Kang; Lalancette, Michel; Almohareb, Fahad; Chaudhri, Nadeem; Ivison, Sabine; Broady, Raewyn; Levings, Megan; Fairclough, Diane; Devins, Gerald; Szwajcer, David; Foley, Ronan; Smith, Clayton; Panzarella, Tony; Kerr, Holly; Kariminia, Amina; Schultz, Kirk R

    2016-08-01

    In adult hematopoietic cell transplantation (HCT), filgrastim-mobilized peripheral blood (G-PB) has largely replaced unstimulated marrow for allografting. Although the use of G-PB results in faster hematopoietic recovery, it is also associated with more chronic graft-versus-host disease (cGVHD). A potential alternative allograft is filgrastim-stimulated marrow (G-BM), which we hypothesized may be associated with prompt hematopoietic recovery but with less cGVHD. We conducted a phase 3, open-label, multicenter randomized trial of 230 adults with hematologic malignancies receiving allografts from siblings after myeloablative conditioning to compare G-PB with G-BM. The primary endpoint was time to treatment failure, defined as a composite of extensive cGVHD, relapse/disease progression, and death. With a median follow-up of 36 months (range, 9.6 to 48), comparing G-BM with G-PB, there was no difference between the 2 arms with respect to the primary outcome of this study (hazard ratio [HR], .91; 95% confidence interval [CI], .68 to 1.22; P = .52). However, the cumulative incidence of overall cGVHD was lower with G-BM (HR, .66; 95% CI, .46 to .95; P = .007) and there was no difference in the risk of relapse or progression (P = .35). The median times to neutrophil recovery (P = .0004) and platelet recovery (P = .012) were 3 days shorter for recipients allocated to G-PB compared with those allocated to G-BM, but there were no differences in secondary engraftment-related outcomes, such as time to first hospital discharge (P = .17). In addition, there were no graft failures in either arm. This trial demonstrates that, compared with G-PB, the use of G-BM allografts leads to a significantly lower rate of overall cGVHD without a loss of the graft-versus-tumor effect and comparable overall survival. Our findings suggest that further study of this type of allograft is warranted. PMID:27154847

  15. Distinct Inflammatory Mediator Patterns Characterize Infectious and Sterile Systemic Inflammation in Febrile Neutropenic Hematology Patients

    PubMed Central

    Wennerås, Christine; Hagberg, Lars; Andersson, Rune; Hynsjö, Lars; Lindahl, Anders; Okroj, Marcin; Blom, Anna M.; Johansson, Peter; Andreasson, Björn; Gottfries, Johan; Wold, Agnes E.

    2014-01-01

    Background Invasive infections and sterile tissue damage can both give rise to systemic inflammation with fever and production of inflammatory mediators. This makes it difficult to diagnose infections in patients who are already inflamed, e.g. due to cell and tissue damage. For example, fever in patients with hematological malignancies may depend on infection, lysis of malignant cells, and/or chemotherapy-induced mucosal damage. We hypothesized that it would be possible to distinguish patterns of inflammatory mediators characterizing infectious and non-infectious causes of inflammation, respectively. Analysis of a broad range of parameters using a multivariate method of pattern recognition was done for this purpose. Methods In this prospective study, febrile (>38°C) neutropenic patients (n = 42) with hematologic malignancies were classified as having or not having a microbiologically defined infection by an infectious disease specialist. In parallel, blood was analyzed for 116 biomarkers, and 23 clinical variables were recorded for each patient. Using O-PLS (orthogonal projection to latent structures), a model was constructed based on these 139 variables that could separate the infected from the non-infected patients. Non-discriminatory variables were discarded until a final model was reached. Finally, the capacity of this model to accurately classify a validation set of febrile neutropenic patients (n = 10) as infected or non-infected was tested. Results A model that could segregate infected from non-infected patients was achieved based on discrete differences in the levels of 40 variables. These variables included acute phase proteins, cytokines, measures of coagulation, metabolism, organ stress and iron turn-over. The model correctly identified the infectious status of nine out of ten subsequently recruited febrile neutropenic hematology patients. Conclusions It is possible to separate patients with infectious inflammation from those with sterile

  16. American Society of Hematology

    MedlinePlus

    Main Navigation Account Navigation Main Content American Society of Hematology ASH Store ASH Job Center ASH Apps Share Your Idea Donate My Account Search Show Main Menu + About Awards Membership ASH ...

  17. Microarrays in hematology.

    PubMed

    Walker, Josef; Flower, Darren; Rigley, Kevin

    2002-01-01

    Microarrays are fast becoming routine tools for the high-throughput analysis of gene expression in a wide range of biologic systems, including hematology. Although a number of approaches can be taken when implementing microarray-based studies, all are capable of providing important insights into biologic function. Although some technical issues have not been resolved, microarrays will continue to make a significant impact on hematologically important research. PMID:11753074

  18. Rheumatic manifestations of hematologic disorders.

    PubMed

    Aviña-Zubieta, J A; Galindo-Rodriguez, G; Lavalle, C

    1998-01-01

    A review of the literature during the past year on rheumatic manifestations in hematologic diseases supports the idea that 80% of the hemorrhage in hemophilia occurs within the joints, with knees, elbows, and ankles being the most affected joints in adults. In contrast, the ankle is the target joint in children. Septic arthritis in hemophilic patients is becoming more important due to the advent of HIV infection. Radioactive synoviorthesis in hemarthrosis has the same rate of success as surgical synovectomy, but with far lower costs. A new study documents the association of arthritis and vasculitis in patients with myelodysplasic syndromes and lymphoproliferative disorders. An increased incidence of scoliosis in patients with beta-thalassemia has been noted. Finally, the effects of bone marrow transplantation in patients with previous autoimmune diseases is reviewed. Progression of rheumatoid arthritis after bone marrow transplantation is documented in a patient with 13 years of follow-up. Hematologic disorders in rheumatic diseases are not the topic of this review. PMID:9448995

  19. THE DIFFERENTIAL ALGORITHM BETWEEN RHEUMATOLOGIC AND MALIGN DISEASES

    PubMed Central

    Këpuska, Arbnore Batalli; Spahiju, Lidvana; Bejiq, Ramush; Manqestena, Rufadije; Stavileci, Valbona; Ibraimi, Zana

    2016-01-01

    Objective: The aim of this study is to determine the differential algorithm between rheumatism and malignant diseases. For every pediatrician, to be warned when attending joint pain and child arthralgia and prevent and treat within time malignant diseases. Methods: Our case presented in Pediatric Clinic, was referred by Regional Hospital of Ferizaj with suspected diagnose of Febris Rheumatica and Arthralgia. The main complaint was joint pain. Initially the patient was admitted at Cardiology and Rheumatology department. Then after examinations was referred to Hemato-Oncology department. Hospitalized during the period from 12.12.2014 to 18.01.2015. Results: Bone marrow biopsy as terminal diagnostic tool reviled severe malignant hematologic disease, which was masked by clinical and lab findings as Febris Rheumatica. Conclusion: Arthralgia as one of child’s often complain, should have a special attention paid to, as it might be a warning sign for a lot of diseases. Steroid treatment should not be used before final diagnose of the disease and before rolling out hematologic etiology with peripheral blood smear. PMID:27147926

  20. Hematologic manifestations of Helicobacter pylori infection

    PubMed Central

    Campuzano-Maya, Germán

    2014-01-01

    Helicobacter pylori (H. pylori) is the most common infection in humans, with a marked disparity between developed and developing countries. Although H. pylori infections are asymptomatic in most infected individuals, they are intimately related to malignant gastric conditions such as gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma and to benign diseases such as gastritis and duodenal and gastric peptic ulcers. Since it was learned that bacteria could colonize the gastric mucosa, there have been reports in the medical literature of over 50 extragastric manifestations involving a variety medical areas of specialization. These areas include cardiology, dermatology, endocrinology, gynecology and obstetrics, hematology, pneumology, odontology, ophthalmology, otorhinolaryngology and pediatrics, and they encompass conditions with a range of clear evidence between the H. pylori infection and development of the disease. This literature review covers extragastric manifestations of H. pylori infection in the hematology field. It focuses on conditions that are included in international consensus and management guides for H. pylori infection, specifically iron deficiency, vitamin B12 (cobalamin) deficiency, immune thrombocytopenia, and MALT lymphoma. In addition, there is discussion of other conditions that are not included in international consensus and management guides on H. pylori, including auto-immune neutropenia, antiphospholipid syndrome, plasma cell dyscrasias, and other hematologic diseases. PMID:25278680

  1. Hematology and immunology studies

    NASA Technical Reports Server (NTRS)

    Kimzey, S. L.; Fischer, C. L.; Johnson, P. C.; Ritzmann, S. E.; Mengel, C. E.

    1975-01-01

    The hematology and immunology program conducted in support of the Apollo missions was designed to acquire specific laboratory data relative to the assessment of the health status of the astronauts prior to their commitment to space flight. A second objective was to detect and identify any alterations in the normal functions of the immunohematologic systems which could be attributed to space flight exposure, and to evaluate the significance of these changes relative to man's continuing participation in space flight missions. Specific changes observed during the Gemini Program formed the basis for the major portion of the hematology-immunology test schedule. Additional measurements were included when their contribution to the overall interpretation of the flight data base became apparent.

  2. Drug-Induced Hematologic Syndromes

    PubMed Central

    Mintzer, David M.; Billet, Shira N.; Chmielewski, Lauren

    2009-01-01

    Objective. Drugs can induce almost the entire spectrum of hematologic disorders, affecting white cells, red cells, platelets, and the coagulation system. This paper aims to emphasize the broad range of drug-induced hematological syndromes and to highlight some of the newer drugs and syndromes. Methods. Medline literature on drug-induced hematologic syndromes was reviewed. Most reports and reviews focus on individual drugs or cytopenias. Results. Drug-induced syndromes include hemolytic anemias, methemoglobinemia, red cell aplasia, sideroblastic anemia, megaloblastic anemia, polycythemia, aplastic anemia, leukocytosis, neutropenia, eosinophilia, immune thrombocytopenia, microangiopathic syndromes, hypercoagulability, hypoprothrombinemia, circulating anticoagulants, myelodysplasia, and acute leukemia. Some of the classic drugs known to cause hematologic abnormalities have been replaced by newer drugs, including biologics, accompanied by their own syndromes and unintended side effects. Conclusions. Drugs can induce toxicities spanning many hematologic syndromes, mediated by a variety of mechanisms. Physicians need to be alert to the potential for iatrogenic drug-induced hematologic complications. PMID:19960059

  3. A hostel for the hostile: the bone marrow niche in hematologic neoplasms

    PubMed Central

    Krause, Daniela S.; Scadden, David T.

    2015-01-01

    Our understanding of the biology of the normal hematopoietic stem cell niche has increased steadily due to improved murine models and sophisticated imaging tools. Less well understood, but of growing interest, is the interaction between cells in the bone marrow during the initiation, maintenance and treatment of hematologic neoplasms. This review summarizes the emerging concepts of the normal and leukemic hematopoietic bone marrow niche. Furthermore, it reviews current models of how the microenvironment of the bone marrow may contribute to or be modified by leukemogenesis. Finally, it provides the rationale for a “two-pronged” approach, directly targeting cancer cells themselves while also targeting the bone microenvironment to make it inhospitable to malignant cells and, ultimately, eradicating cancer stem-like cells. PMID:26521296

  4. Hematologic and oncologic complications in the critically ill child.

    PubMed Central

    McIntosh, S.

    1984-01-01

    Admission of a patient to an intensive care unit for management of direct consequences of a hematologic or oncologic disease is occasionally necessary. Such problems included exchange transfusion, sepsis, compression of vital structures by malignant tumor, metabolic derangements, leukostasis, post-operative care, major sickling episodes in vital organs, and disseminated coagulopathy. More often, however, hematologic complications arise in the child critically ill from other causes, such as trauma or infections. The first two sections of this review address blood transfusion and hemostasis, topics likely to have wide application in the care of critically ill children. The last portion discusses problems unique to patients with sickling or malignant disease. Images FIG. 3 FIG. 4 FIG. 5 FIG. 6 PMID:6382836

  5. Microscale functional cytomics for studying hematologic cancers

    PubMed Central

    Young, Edmond W. K.; Pak, Chorom; Kahl, Brad S.; Yang, David T.; Callander, Natalie S.; Miyamoto, Shigeki

    2012-01-01

    An important problem in translational cancer research is our limited ability to functionally characterize behaviors of primary patient cancer cells and associated stromal cell types, and relate mechanistic understanding to therapy selection. Functional analyses of primary samples face at least 3 major challenges: limited availability of primary samples for testing, paucity of functional information extracted from samples, and lack of functional methods accessible to many researchers. We developed a microscale cell culture platform that overcomes these limitations, especially for hematologic cancers. A key feature of the platform is the ability to compartmentalize small populations of adherent and nonadherent cells in controlled microenvironments that can better reflect physiological conditions and enable cell-cell interaction studies. Custom image analysis was developed to measure cell viability and protein subcellular localizations in single cells to provide insights into heterogeneity of cellular responses. We validated our platform by assessing viability and nuclear translocations of NF-κB and STAT3 in multiple myeloma cells exposed to different conditions, including cocultured bone marrow stromal cells. We further assessed its utility by analyzing NF-κB activation in a primary chronic lymphocytic leukemia patient sample. Our platform can be applied to myriad biological questions, enabling high-content functional cytomics of primary hematologic malignancies. PMID:22262772

  6. Malignant melanoma slide review project: Patients from non-Kaiser hospitals in the San Francisco Bay Area. Final report

    SciTech Connect

    Reynolds, P.

    1993-01-05

    This project was initiated, in response to concerns that the observed excess of malignant melanoma among employees of Lawrence Livermore National Laboratory (LLNL) might reflect the incidence of disease diagnostically different than that observed in the general population. LLNL sponsored a slide review project, inviting leading dermatopathology experts to independently evaluate pathology slides from LLNL employees diagnosed with melanoma and those from a matched sample of Bay Area melanoma patients who did not work at the LLNL. The study objectives were to: Identify all 1969--1984 newly diagnosed cases of malignant melanoma among LLNL employees resident in the San Francisco-Oakland Metropolitan Statistical Area, and diagnosed at facilities other than Kaiser Permanente; identify a comparison series of melanoma cases also diagnosed between 1969--1984 in non-Kaiser facilities, and matched as closely as possible to the LLNL case series by gender, race, age at diagnosis, year of diagnosis, and hospital of diagnosis; obtain pathology slides for the identified (LLNL) case and (non-LLNL) comparison patients for review by the LLNL-invited panel of dermatopathology experts; and to compare the pathologic characteristics of the case and comparison melanoma patients, as recorded by the dermatopathology panel.

  7. Aluminum toxicity. Hematological effects.

    PubMed

    Mahieu, S; del Carmen Contini, M; Gonzalez, M; Millen, N; Elias, M M

    2000-01-01

    Sequential effects of intoxication with aluminum hydroxide (Al) (80 mg/Kg body weight, i.p., three times a week), were studied on rats from weaning and up to 28 weeks. The study was carried out on hematological and iron metabolism-related parameters on peripheral blood, at the end of the 1st, 2nd, 3rd, 4th, 5th and 6th months of exposure. As it was described that hematotoxic effects of Al are mainly seen together with high levels of uremia, renal function was measured at the same periods. The animals treated developed a microcytosis and was accompanied by a decrease in mean corpuscular hemoglobin (MCH). Significantly lower red blood cell counts (RBC million/microl) were found in rats treated during the 1st month. These values matched those obtained for control rats during the 2nd month. From the 3rd month onwards, a significant increase was observed as compared to control groups, and the following values were obtained by the 6th month: (T) 10.0 +/- 0.3 versus (C) 8.7 +/- 0.2 (million/microl). Both MCH and mean corpuscular volume (MCV) were found to be significantly lower in groups treated from the 2nd month. At the end of the 6th month the following values were found: MCH (T) 13.3 +/- 0.1 versus (C) 16.9 +/- 0.3 (pg); MCV (T) 42.1 +/- 0.7 versus (C) 51.8 +/- 0.9 (fl). Al was found responsible for lower serum iron concentration levels and in the percentage of transferrin saturation. Thus, although microcytic anemia constitutes an evidence of chronic aluminum exposure, prolonged exposure could lead to a recovery of hematocrit and hemoglobin concentration values with an increase in red cell number. Nevertheless, both microcytosis and the decrease of MCH would persist. These modifications took place without changes being observed in the renal function during the observation period. PMID:10643868

  8. Cytology of canine malignant histiocytosis.

    PubMed

    Brown, Diane E.; Thrall, Mary Anna; Getzy, David M.; Weiser, M. Glade; Ogilvie, Gregory K.

    1994-01-01

    Cytologic features of bone marrow, tissue, and abdominal fluid in seven cases of malignant histiocytosis in dogs are described, and histopathology, hematology, and serum biochemistry of the cases are reviewed. Diagnosis of malignant histiocytosis was confirmed by tissue morphology and immunohistochemistry; neoplastic cells in all cases had positive immunoreactivity to lysozyme. This stain can be used to definitively establish the diagnosis of malignant histiocytosis on cytology specimens as well as tissue sections. Cytologic findings included numerous pleomorphic, large, discrete mononuclear cells with abundant, lightly basophilic, vacuolated, granular cytoplasm. Nuclei were round to oval to reniform with marked anisocytosis and anisokaryosis; nucleoli were prominent. Mitotic figures, often bizarre, were occasionally seen. Multinucleated giant cells and phagocytosis of erythrocytes and leukocytes were prominent features in cytologic preparations in four cases. Four dogs were anemic, five dogs were thrombocytopenic, and three dogs were hypercalcemic. Breeds affected included Doberman Pinscher (1), Golden Retriever (2), Flat Coated Retriever (3), and mixed-breed dog (1). PMID:12666013

  9. Malignancy after renal transplantation.

    PubMed

    Zeier, Martin; Hartschuh, Wolfgang; Wiesel, Manfred; Lehnert, Thomas; Ritz, Eberhard

    2002-01-01

    Malignancy following renal transplantation is an important medical problem during the long-term follow-up. The overall incidence of malignancy at this time is 3 to 5 times higher than in the general population. The most common malignancies are lymphoproliferative disorders (early after transplantation) and skin carcinomas (late after transplantation). The type of malignancy is different in various countries and dependent on genetic and environmental factors. Another important confounder for risk of malignancy after renal transplantation is the type of immunosuppression. Previous use of cytotoxic drugs (eg, cyclophosphamide) or a history of analgesic abuse are additional risk factors. Malignancy may even be transplanted by the graft. Previous cancer treatment in a uremic patient on the transplant waiting list is of great importance in relation to waiting time and postmalignancy screening. Finally, every dialysis patient on the waiting list should undergo a regular screening program before and after renal transplantation to detect a potentially malignant tumor in an early stage. In addition to specific oncological treatment, managing a malignancy after renal transplantation should include modification of immunosuppression. PMID:11774131

  10. Non-Ablative Allo HSCT For Hematologic Malignancies or SAA

    ClinicalTrials.gov

    2011-12-07

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Precancerous/Nonmalignant Condition; Small Intestine Cancer

  11. Stem Cell Transplantation as Immunotherapy for Hematologic Malignancies

    ClinicalTrials.gov

    2009-01-28

    Leukemia; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Chronic Myeloid Leukemia; Juvenile Myelomonocytic Leukemia; Myelodysplastic Syndrome; Paroxysmal Nocturnal Hemoglobinuria; Hodgkin's Lymphoma; Non-Hodgkin Lymphoma

  12. Haploidentical Stem Cell Transplant for Treatment Refractory Hematological Malignancies

    ClinicalTrials.gov

    2009-02-12

    Acute Lymphoblastic Leukemia (ALL); Acute Myeloid Leukemia (AML); Secondary AML; Myelodysplastic Syndrome (MDS); Secondary MDS; Chronic Myeloid Leukemia; Juvenile Myelomonocytic Leukemia (JMML); Paroxysmal Nocturnal Hemoglobinuria (PNH); Lymphoma, Non-Hodgkin; Hodgkin Disease

  13. Study of MLN8237 in Patients With Advanced Hematological Malignancies

    ClinicalTrials.gov

    2015-12-17

    B-cell Follicular Lymphoma; B-cell Marginal Zone Lymphoma; Diffuse Large B-cell Lymphoma; B-cell Mantle Cell Lymphoma; B-cell Small Lymphocytic Lymphoma (SLL); B-Cell Chronic Lymphocytic Leukemia (B-CLL); Multiple Myeloma; Waldenstrom's Macroglobulinemia; Noncutaneous Peripheral T-cell Lymphoma Not Otherwise Specified (PTCL-NOS); Angioimmunoblastic T-cell Lymphoma (AITL); Anaplastic Large Cell Lymphoma; Enteropathy Associated T-cell Lymphoma (EATCL); NK Lymphoma (NKL)

  14. Improved radioimmunotherapy of hematologic malignancies. Progress report, 1988--1991

    SciTech Connect

    Press, O.W.; Barofsky, D.F.

    1991-12-31

    This progress report describes accomplishments under four headings, namely: The study of the relative rates of metabolic degradation of radiolabeled monoclonal antibodies (MAb) targeting tumor associated antigens; Effects of lysosomotropic amines, carboxylic ionophores, and thioamides on the retention of radiolabeled MAbs by tumor cells; Subcellular site of radioimmunoconjugate degradation and the sizes of fragments generated by intracellular metabolism of radiolabeled antibodies; and Patterns of metabolic degradation of radioimmunoconjugates made with different techniques and with different radionuclides.

  15. Rasburicase and Allopurinol in Treating Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2015-05-28

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; de Novo Myelodysplastic Syndromes; Noncontiguous Stage II Adult Burkitt Lymphoma; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Stage I Adult Burkitt Lymphoma; Stage III Adult Burkitt Lymphoma; Stage IV Adult Burkitt Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  16. Haploidentical Stem Cell Transplantation for Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2009-01-28

    Leukemia, Acute Lymphocytic (ALL); Leukemia, Myeloid, Acute(AML); Leukemia, Myeloid, Chronic(CML); Juvenile Myelomonocytic Leukemia(JMML); Hemoglobinuria, Paroxysmal Nocturnal (PNH); Lymphoma, Non-Hodgkin (NHL); Myelodysplastic Syndrome (MDS)

  17. Measuring symptoms as a critical component of drug development and evaluation in hematological diseases

    PubMed Central

    Williams, Loretta A; Yucel, Emre; Cortes, Jorge E; Cleeland, Charles S

    2014-01-01

    With the rapid development of new therapies for patients with hematological malignancies, there is an increasing need for patient report of symptom status during all phases of drug testing. The patient’s perspective on new treatments reflects treatment tolerability as well as symptom benefit, and may assist patients and clinicians in choosing treatments. Inclusion of patient-reported outcomes, more common in solid-tumor than hematological trials, provides early information about symptoms to guide decisions about appropriate dosing and supportive care needs. We provide a historical overview of the use of patient-reported outcomes and symptom assessment in solid-tumor and hematological drug development, and offer recommendations about methodological issues in the monitoring of symptoms in the drug development process in hematological clinical trials. PMID:24910769

  18. Myeloid Sarcoma: An Unusual Case of Mediastinal Mass and Malignant Pleural Effusion with Review of Literature.

    PubMed

    Sahu, Kamal Kant; Tyagi, Ruchita; Law, Arjun Datt; Khadwal, Alka; Prakash, Gaurav; Rajwanshi, Arvind; Varma, Subhash Chander; Malhotra, Pankaj

    2015-12-01

    Myeloid sarcoma is an extramedullary tumor seen most commonly in patients with acute myeloid leukemia and less frequently in chronic myeloid leukemia, myelodysplastic syndrome and rarely, in an isolated form without any other underlying malignancy. Malignant pleural effusion in hematological malignancies is rare when compared with solid tumors. We present an unusual case of myeloid sarcoma in which a mediastinal mass with pleural effusion was the initial presentation. A 27 year old gentleman presented with complaints of fever, chest pain and swelling in the anterior chest wall for 6 months. Examination revealed a lump measuring 5 × 5 cm on the left side of the chest wall. Hematological evaluation showed hemoglobin-14.2 g/dL, platelet count-233 × 10(9)/L, TLC-117 × 10(6)/L with normal differential counts. Contrast enhanced computerised tomography (CECT) confirmed the presence of a soft tissue mass in the superior mediastinum abutting against the chest wall. Core biopsy was suggestive of myeloid sarcoma and immunohistochemistry was positive for myeloperoxidase and negative for CD3, CD 20 and CD 23. Pleural fluid analysis showed the presence of malignant cells. Bone marrow examination did not show an excess of blasts. A final diagnosis of extramedullary myeloid sarcoma with malignant pleural effusion was made. The patient was given induction chemotherapy (3 + 7 regimen) with daunorubicin and cytosine arabinoside. Repeat CECT done on day 28 showed complete resolution of pleural effusion and significant reduction in the size of mediastinal mass. The patient has successfully completed three cycles of consolidation therapy following which there has been complete resolution of the mass. He remains asymptomatic on close follow up. PMID:26306072

  19. Malignancies and thalassemia: a review of the literature.

    PubMed

    Zanella, Sara; Garani, Maria Chiara; Borgna-Pignatti, Caterina

    2016-03-01

    Thalassemia is a genetic hematologic disease, characterized by a defect in hemoglobin chain synthesis. Because of safe transfusions and effective chelation therapy, survival of affected patients has significantly improved in the last few decades. However new complications are appearing. Among them are hepatocellular carcinoma and other forms of cancer, particularly hematologic malignancies. The present review focuses on the frequency of cancer in thalassemia patients and on possible predisposing factors. PMID:26916208

  20. Fish hematology and associated disorders.

    PubMed

    Grant, Krystan R

    2015-01-01

    Fish health is a growing concern as pets, education, and aquaculture evolves. For the veterinary staff, fish handling, diagnostics, medicine, and surgery may require specialized training and equipment in comparison with terrestrial and arboreal animals, simply because of their aquatic nature and diversity. Fish hematology is one diagnostic tool that may not require additional equipment, may be inexpensive, and provide useful information in guiding treatment options. Challenges involving hematology may include handling and restraint, venipuncture, evaluation, and interpretation. In this article, strategies for these challenges are discussed for teleost (bony fish) and elasmobranch (cartilaginous fish) fish types. PMID:25421028

  1. Fish Hematology and Associated Disorders.

    PubMed

    Grant, Krystan R

    2015-09-01

    Fish health is a growing concern as pets, education, and aquaculture evolves. For the veterinary staff, fish handling, diagnostics, medicine, and surgery may require specialized training and equipment in comparison with terrestrial and arboreal animals, simply because of their aquatic nature and diversity. Fish hematology is one diagnostic tool that may not require additional equipment, may be inexpensive, and provide useful information in guiding treatment options. Challenges involving hematology may include handling and restraint, venipuncture, evaluation, and interpretation. In this article, strategies for these challenges are discussed for teleost (bony fish) and elasmobranch (cartilaginous fish) fish types. PMID:26297413

  2. Will targeting PI3K/Akt/mTOR signaling work in hematopoietic malignancies?

    PubMed Central

    Gao, Yanan; Yuan, Chase Y.

    2016-01-01

    The constitutive activation of phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway has been demonstrated to be critical in clinical cancer patients as well as in laboratory cancer models including hematological malignancies. Great efforts have been made to develop inhibitors targeting this pathway in hematological malignancies but so far the efficacies of these inhibitors were not as good as expected. By analyzing existing literatures and datasets available, we found that mutations of genes in the pathway only constitute a very small subset of hematological malignancies. Deep understanding of the function of gene, the pathway and/or its regulators, and the cellular response to inhibitors, may help us design better drugs targeting the hematological malignancies. PMID:27583254

  3. 42 CFR 493.941 - Hematology (including routine hematology and coagulation).

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 5 2013-10-01 2013-10-01 false Hematology (including routine hematology and coagulation). 493.941 Section 493.941 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF....941 Hematology (including routine hematology and coagulation). (a) Program content and frequency...

  4. 42 CFR 493.941 - Hematology (including routine hematology and coagulation).

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 5 2011-10-01 2011-10-01 false Hematology (including routine hematology and coagulation). 493.941 Section 493.941 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF....941 Hematology (including routine hematology and coagulation). (a) Program content and frequency...

  5. 42 CFR 493.941 - Hematology (including routine hematology and coagulation).

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 5 2012-10-01 2012-10-01 false Hematology (including routine hematology and coagulation). 493.941 Section 493.941 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF....941 Hematology (including routine hematology and coagulation). (a) Program content and frequency...

  6. 42 CFR 493.941 - Hematology (including routine hematology and coagulation).

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Hematology (including routine hematology and coagulation). 493.941 Section 493.941 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF....941 Hematology (including routine hematology and coagulation). (a) Program content and frequency...

  7. 42 CFR 493.849 - Condition: Hematology.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Condition: Hematology. 493.849 Section 493.849 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... These Tests § 493.849 Condition: Hematology. The specialty of hematology, for the purpose of...

  8. 42 CFR 493.1215 - Condition: Hematology.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Condition: Hematology. 493.1215 Section 493.1215 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES....1215 Condition: Hematology. If the laboratory provides services in the specialty of Hematology,...

  9. Transfusion Considerations in Pediatric Hematology and Oncology Patients.

    PubMed

    Bercovitz, Rachel S; Josephson, Cassandra D

    2016-06-01

    Pediatric patients with malignancies or benign hematologic diseases are a heterogeneous group with complicated underlying pathophysiologies leading to their requirements for transfusion therapy. Common practice among pediatric hematologists, oncologists, and transplant physicians is to transfuse stable patients red cells to maintain a hemoglobin greater than 7 or 8 g/dL and transfuse platelets to maintain a count greater than 10,000 or 20,000 platelets/μL. This review compiles data from myriad studies performed in pediatric patients to give readers the knowledge needed to make an informed choice when considering different management strategies for the transfusion of red blood cells, platelets, plasma, and granulocytes. PMID:27113005

  10. TNF-α, a good or bad factor in hematological diseases?

    PubMed Central

    Tian, Tian; Wang, Min

    2014-01-01

    Tumor necrosis factor-alpha (TNF-α) is a highly pleiotropic cytokine involved in a spectrum of physiological processes that control inflammation, anti-tumor responses and homeostasis through two receptors, TNF-R1 and TNF-R2. In general, TNF-R1 mediates cytotoxicity, resistance to infection and stimulation of NF-κB. By contrast, TNF-R2 has been implicated in proliferation of T-cell line, thymocytes and human mononuclear cells. Hematological malignancies are the types of cancer that affect normal hematopoiesis, have a speedy development, high lethal rate and until now still have no effective treatment. Several studies have shown that inflammatory cytokines play an important role in the onset and progress of these diseases. In this review, we summarize the recent studies and evaluate the positive or negative role of TNF-α in some hematological malignancies or diseases with a malignant tendency.

  11. Haploidentical Stem Cell Transplantation in Adult Haematological Malignancies.

    PubMed

    Parmesar, Kevon; Raj, Kavita

    2016-01-01

    Haematopoietic stem cell transplantation is a well-established treatment option for both hematological malignancies and nonmalignant conditions such as aplastic anemia and haemoglobinopathies. For those patients lacking a suitable matched sibling or matched unrelated donor, haploidentical donors are an alternative expedient donor pool. Historically, haploidentical transplantation led to high rates of graft rejection and GVHD. Strategies to circumvent these issues include T cell depletion and management of complications thereof or T replete transplants with GVHD prophylaxis. This review is an overview of these strategies and contemporaneous outcomes for hematological malignancies in adult haploidentical stem cell transplant recipients. PMID:27313619

  12. Haploidentical Stem Cell Transplantation in Adult Haematological Malignancies

    PubMed Central

    Parmesar, Kevon; Raj, Kavita

    2016-01-01

    Haematopoietic stem cell transplantation is a well-established treatment option for both hematological malignancies and nonmalignant conditions such as aplastic anemia and haemoglobinopathies. For those patients lacking a suitable matched sibling or matched unrelated donor, haploidentical donors are an alternative expedient donor pool. Historically, haploidentical transplantation led to high rates of graft rejection and GVHD. Strategies to circumvent these issues include T cell depletion and management of complications thereof or T replete transplants with GVHD prophylaxis. This review is an overview of these strategies and contemporaneous outcomes for hematological malignancies in adult haploidentical stem cell transplant recipients. PMID:27313619

  13. Radioimmunotherapy of malignancies

    SciTech Connect

    Reilly, R.M. )

    1991-05-01

    The critical issues in radioimmunotherapy are highlighted, and novel ways of improving the therapeutic indexes of radioimmunotherapeutic agents are outlined. The use of radioactively labeled monoclonal antibodies to treat malignant tumors has been investigated in animals and humans. Radionuclides suitable for labeling antibodies for such use include iodine 125, iodine 131, yttrium 90, rhenium 188, and copper 67. Radiobiological factors to be considered in radioimmunotherapy include the size and density of the tumor and the ability of a radiolabeled antibody to penetrate the tumor nodule. The dose of radiation required to destroy a tumor varies; however, the whole-body dose must not exceed 200 rads to avoid irreversible toxicity to the bone marrow. Despite the theoretical inadequacy of radiation doses to tumors indicated by conventional dosimetry, responses have been observed in animals and humans. More reliable and accurate dosimetric methods are under development. The induction of human antimouse antibodies can alter the pharmacokinetics of radiolabeled antibodies. Improving the therapeutic index of radioimmunotherapeutic agents may be achieved through regional therapy, administering a secondary antibody to improve clearance, combining radioimmunotherapy with external-beam irradiation, using an avidin-biotin conjugate system to deliver the radiolabeled antibodies, and addressing the problem of tumor antigen heterogeneity. Researchers are working to reduce or eliminate the clinical problems associated with radioimmunotherapy. Hematologic malignancies, such as lymphomas, are more likely than solid tumors to respond satisfactorily. 110 refs.

  14. MicroRNA-155 and Its Role in Malignant Hematopoiesis

    PubMed Central

    Ranganath, Prajnya

    2015-01-01

    MicroRNA-155 (miR-155) is a multifunctional molecule involved in both normal and malignant hematopoiesis. It has been found to be involved in the pathogenesis of many different hematological malignancies with either an oncogenic or a tumor-repressor effect, depending on the nature of the cell and the type of malignancy. In particular, it has been strongly implicated in the causation of diffuse large B-cell lymphomas. This review focuses on the molecular interactions of miR-155, its oncogenic mechanisms, and its potential as an effective therapeutic target for the associated malignancies. PMID:26523117

  15. Hematologic manifestations of celiac disease

    PubMed Central

    Halfdanarson, Thorvardur R.; Litzow, Mark R.; Murray, Joseph A.

    2007-01-01

    Celiac disease is a common systemic disorder that can have multiple hematologic manifestations. Patients with celiac disease may present to hematologists for evaluation of various hematologic problems prior to receiving a diagnosis of celiac disease. Anemia secondary to malabsorption of iron, folic acid, and/or vitamin B12 is a common complication of celiac disease and many patients have anemia at the time of diagnosis. Celiac disease may also be associated with thrombocytosis, thrombocytopenia, leukopenia, venous thromboembolism, hyposplenism, and IgA deficiency. Patients with celiac disease are at increased risk of being diagnosed with lymphoma, especially of the T-cell type. The risk is highest for enteropathy-type T-cell lymphoma (ETL) and B-cell lymphoma of the gut, but extraintestinal lymphomas can also be seen. ETL is an aggressive disease with poor prognosis, but strict adherence to a gluten-free diet may prevent its occurrence. PMID:16973955

  16. Caregivers' insights on the dying trajectory in hematology oncology.

    PubMed

    McGrath, P

    2001-10-01

    It is increasingly acknowledged in the research literature that palliative care is not offered to patients with a hematologic malignancy. The evidence indicates that patients are not dying at home or in the comfort of the hospice setting but are more likely to end up in the high-tech care of an intensive care unit. The holistic, compassionate care of the hospice/palliative care philosophy is not routinely made available to either these patients or the families who care for them. However, little is known about what the end-of-life experience is for such patients and their families and how they are managing to negotiate their dying experience in a system that is designed to cure not to palliate. In particular, there is a dearth of information on what happens to the caregivers during what is characteristically a prolonged and difficult period of sustained caring within the high-tech system. This discussion presents findings from recent research that is beginning to document the experience of the dying trajectory for patients from these diagnostic groups and their families. The hope and expectation from such research is that the information will make a contribution to building multidisciplinary plans of care for hematologic malignancies during the dying trajectory, to ensure that patients and their families are appropriately referred to the palliative system or, at least, are given sensitive palliative care within the curative system. PMID:11605712

  17. TET proteins and 5-methylcytosine oxidation in hematological cancers

    PubMed Central

    An, Jungeun; Pastor, William A.; Ko, Myunggon; Rao, Anjana

    2015-01-01

    Summary DNA methylation has pivotal regulatory roles in mammalian development, retrotransposon silencing, genomic imprinting and X-chromosome inactivation. Cancer cells display highly dysregulated DNA methylation profiles characterized by global hypomethylation in conjunction with hypermethylation of promoter CpG islands (CGIs) that presumably lead to genome instability and aberrant expression of tumor suppressor genes or oncogenes. The recent discovery of Ten-Eleven-Translocation (TET) family dioxygenases that oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) in DNA has led to profound progress in understanding the mechanism underlying DNA demethylation. Among the three TET genes, TET2 recurrently undergoes inactivating mutations in a wide range of myeloid and lymphoid malignancies. TET2 functions as a bona fide tumor suppressor particularly in the pathogenesis of myeloid malignancies resembling chronic myelomoncytic leukemia (CMML) and myelodysplastic syndromes (MDS) in human. Here we review diverse functions of TET proteins and the novel epigenetic marks that they generate in DNA methylation/demethylation dynamics and normal and malignant hematopoietic differentiation. The impact of TET2 inactivation in hematopoiesis and various mechanisms modulating the expression or activity of TET proteins are also discussed. Furthermore, we also present evidence that TET2 and TET3 collaborate to suppress aberrant hematopoiesis and hematopoietic transformation. A detailed understanding of the normal and pathological functions of TET proteins may provide new avenues to develop novel epigenetic therapies for treating hematological malignancies. PMID:25510268

  18. Serum thrombopoietin level in various hematological diseases.

    PubMed

    Usuki, K; Tahara, T; Iki, S; Endo, M; Osawa, M; Kitazume, K; Kato, T; Miyazaki, H; Urabe, A

    1996-09-01

    To investigate the pathophysiological role of thrombopoietin (TPO) in thrombopoiesis, we measured its serum levels in 15 healthy individuals, 84 patients with various hematological diseases and 2 patients with liver cirrhosis using an enzyme immunoassay procedure. The TPO level was 0.84 +/- 0.40 f mol/ml in normal individuals. TPO levels were considerably elevated in patients with myelosuppression after intensification chemotherapy of acute leukemia in complete remission (postchemotherapy group; n = 18; 18.46 +/- 9.70 f mol/ml). When the data of normal individuals and the postchemotherapy group were combined, TPO levels were inversely correlated with the platelet count in this combined group. We compared these data of normal individuals and the postchemotherapy group with various hematological disease states. In aplastic anemia (n = 13; 16.03 +/- 9.44 f mol/ml), acute lymphoblastic leukemia (n = 5; 10.36 +/- 5.57 f mol/ml), malignant lymphoma (n = 6; 2.79 +/- 2.27 f mol/ml), multiple myeloma (n = 3; 3.34 +/- 0.20 f mol/ml) and chronic lymphocytic leukemia (n = 2; 1.71 +/- 3.91 f mol/ml), the relationship of serum TPO levels and platelet counts was almost the same as in the combined group with normal individuals and the postchemotherapy group. However, the TPO levels were slightly higher in myeloproliferative disorders (n = 12; 1.99 +/- 1.47 f mol/ml) and lower in acute myelogenous leukemia (n = 8; 2.27 +/- 1.25 f mol/ml), hypoplastic leukemia (n = 3; 2.76 +/- 2.23 f mol/ml), myelodysplastic syndrome (n = 2; 0.42 +/- 0.60 f mol/ml), liver cirrhosis (n = 2; 1.50 +/- 0.92 f mol/ml) and idiopathic thrombocytopenic purpura (n = 12; 2.08 +/- 1.41 f mol/ml), when compared to the regression line for the combined group with normal individuals and postchemotherapy group. These findings suggest that TPO might play an important role in regulation of the platelet count in normal and pathological conditions. PMID:8888496

  19. Association of thyroid diseases with primary extra-thyroidal malignancies in women: results of a cross-sectional study of 6,386 patients.

    PubMed

    Prinzi, Natalie; Sorrenti, Salvatore; Baldini, Enke; De Vito, Corrado; Tuccilli, Chiara; Catania, Antonio; Coccaro, Carmela; Bianchini, Marta; Nesca, Angela; Grani, Giorgio; Mocini, Renzo; De Antoni, Enrico; D'Armiento, Massimino; Ulisse, Salvatore

    2015-01-01

    We here analyzed the prevalence of extra-thyroidal malignancies (EM) in 6,386 female patients affected by different thyroid disease (TD). At first, an age-matched analysis of EM in all patients was performed. We then evaluated EM prevalence in four TD diagnostic categories: non-nodular TD (n = 2,159); solitary nodule (n = 905); multinodular TD (n = 2,871); differentiated thyroid cancers (n = 451). Finally, patients were grouped based on the absence (n = 3,820) or presence of anti-thyroglobulin (TgAb) and/or anti-thyroperoxidase (TPOAb) (n = 2,369), or anti-Thyroid Stmulating Hormone (TSH) receptor autoantibodies (n = 197). A total of 673 EM were recorded. EM prevalence in TD patients was higher compared to the general population (Odds Ratio, OR 3.21) and the most frequent EM was breast cancer (OR 3.94), followed by colorectal (OR 2.18), melanoma (OR 6.71), hematological (OR 8.57), uterus (OR 2.52), kidney (OR 3.40) and ovary (OR 2.62) neoplasms. Age-matched analysis demonstrated that the risk of EM was maximal at age 0-44 yr (OR 11.28), remaining lower, but significantly higher that in the general population, in the 45-59 and 60-74 year age range. Breast and hematological malignancies showed an increased OR in all TD, while other cancers associated with specific TD. An increased OR for melanoma, breast and hematological malignancies was observed in both TPOAb and/or TgAb autoantibody negative and positive patients, while colorectal, uterus, kidney and ovary cancers showed an increased OR only in thyroid autoantibody negative patients. In conclusions, women affected by both benign and malignant TD, especially at a younger age and in absence of thyroid autoimmunity, have an increased risk of developing primary EM, thus requiring a careful follow-up and surveillance. PMID:25826596

  20. The bone marrow stroma in hematological neoplasms—a guilty bystander

    PubMed Central

    Tripodo, Claudio; Sangaletti, Sabina; Piccaluga, Pier P.; Prakash, Sonam; Franco, Giovanni; Borrello, Ivan; Orazi, Attilio; Colombo, Mario P.; Pileri, Stefano A.

    2013-01-01

    In the setting of hematological neoplasms, changes in the bone marrow (BM) stroma might arise from pressure exerted by the neoplastic clone in shaping a supportive microenvironment, or from chronic perturbation of the BM homeostasis. Under such conditions, alterations in the composition of the BM stroma can be profound, and could emerge as relevant prognostic factors. In this Review, we delineate the multifaceted contribution of the BM stroma to the pathobiology of several hematological neoplasms, and discuss the impact of stromal modifications on the natural course of these diseases. Specifically, we highlight the involvement of BM stromal components in lymphoid and myeloid malignancies, and present the most relevant processes responsible for remodeling the BM stroma. The role of bystander BM stromal elements in the setting of hematological neoplasms is discussed, strengthening the rationale for treatment strategies that target the BM stroma. PMID:21448151

  1. Malignant mesothelioma

    PubMed Central

    Moore, Alastair J; Parker, Robert J; Wiggins, John

    2008-01-01

    Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10–20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational "environmental" exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis. PMID:19099560

  2. Clinical hematology of rodent species.

    PubMed

    Pilny, Anthony A

    2008-09-01

    Pet rodents, such as rats, guinea pigs, and chinchillas, differ from more traditional companion animal species in many aspects of their hematologic parameters. Animals within this order have much diversity in size, anatomy, methods of restraint, and blood collection technique. Appropriate sample collection is often the most challenging aspect of the diagnostic protocol, and inappropriate restraint may cause a stress response that interferes with blood test results. For many of these patients, sedation is required and can also affect results as well. In most cases, however, obtaining a standard database is necessary and very possible when providing medical care for this popular group of pets. PMID:18675732

  3. Genome-wide association studies for hematological traits in Chinese Sutai pigs

    PubMed Central

    2014-01-01

    Background It has been shown that hematological traits are strongly associated with the metabolism and the immune system in domestic pig. However, little is known about the genetic architecture of hematological traits. To identify quantitative trait loci (QTL) controlling hematological traits, we performed single marker Genome-wide association studies (GWAS) and haplotype analysis for 15 hematological traits in 495 Chinese Sutai pigs. Results We identified 161 significant SNPs including 44 genome-wide significant SNPs associated with 11 hematological traits by single marker GWAS. Most of them were located on SSC2. Meanwhile, we detected 499 significant SNPs containing 154 genome-wide significant SNPs associated with 9 hematological traits by haplotype analysis. Most of the identified loci were located on SSC7 and SSC9. Conclusions We detected 4 SNPs with pleiotropic effects on SSC2 by single marker GWAS and (or) on SSC7 by haplotype analysis. Furthermore, through checking the gene functional annotations, positions and their expression variation, we finally selected 7 genes as potential candidates. Specially, we found that three genes (TRIM58, TRIM26 and TRIM21) of them originated from the same gene family and executed similar function of innate and adaptive immune. The findings will contribute to dissection the immune gene network, further identification of causative mutations underlying the identified QTLs and providing insights into the molecular basis of hematological trait in domestic pig. PMID:24674592

  4. Multiscale Modeling of Hematologic Disorders

    SciTech Connect

    Fedosov, Dmitry A.; Pivkin, Igor; Pan, Wenxiao; Dao, Ming; Caswell, Bruce; Karniadakis, George E.

    2012-01-28

    Parasitic infectious diseases and other hereditary hematologic disorders are often associated with major changes in the shape and viscoelastic properties of red blood cells (RBCs). Such changes can disrupt blood flow and even brain perfusion, as in the case of cerebral malaria. Modeling of these hematologic disorders requires a seamless multiscale approach, where blood cells and blood flow in the entire arterial tree are represented accurately using physiologically consistent parameters. In this chapter, we present a computational methodology based on dissipative particle dynamics (DPD) which models RBCs as well as whole blood in health and disease. DPD is a Lagrangian method that can be derived from systematic coarse-graining of molecular dynamics but can scale efficiently up to small arteries and can also be used to model RBCs down to spectrin level. To this end, we present two complementary mathematical models for RBCs and describe a systematic procedure on extracting the relevant input parameters from optical tweezers and microfluidic experiments for single RBCs. We then use these validated RBC models to predict the behavior of whole healthy blood and compare with experimental results. The same procedure is applied to modeling malaria, and results for infected single RBCs and whole blood are presented.

  5. Common hematological disorders in children.

    PubMed

    Bansal, Deepak; Totadri, Sidharth

    2014-01-01

    It is common for primary care physicians to be faced with children with hematological disorders in everyday practice. The article seeks to provide realistic information for the first-contact physician in handling common hematological diseases in children. Practical step-wise approach to understanding and investigating anemia and bleeding disorders is illustrated. Requirement of iron in normal children and management of iron deficiency anemia (IDA) and thalassemia is explained. The gold standard for IDA continues to be ferrous sulphate which has good bioavailability and is inexpensive. There is emerging concept of delayed clamping of umbilical cord at birth, particularly in regions with widespread IDA, to augment iron stores in infancy. Typical case scenarios of children with immune thrombocytopenia (ITP) and hemophilia are provided to facilitate the understanding of management in day to day practice. The vital role of the medical practitioner in shared care of patients with acute lymphoblastic leukemia and febrile neutropenia is emphasized. A risk based treatment algorithm for febrile neutropenia is provided. PMID:23934100

  6. Nitrogen dioxide effects on progression of mouse lymphoma, a blood cell malignancy. Final report, 17 July 1986-16 April 1988

    SciTech Connect

    Richters, A.

    1988-03-08

    Earlier studies employing the injection of cancer cells into mice indicated that nitrogen dioxide facilitated the spread and establishment of cancer. The study was initiated to verify that finding, using an animal model that has more similarities to human cancer. The model used was a strain of mouse (AKR/cum) that develops a spontaneous blood-cell malignancy. The results of the study showed that the malignancy tended to develop later and spread less extensively while the percentage of specific T-lymphocytes was reduced in mice exposed to 0.25-ppm nitrogen dioxide when compared to mice held in clean air. Mortality due to cancer in the exposed mice was also reduced. The investigators noted that the result is consistent with exposure causing impairment of immune cells, the T-lymphocytes that participate in the malignancy. These results suggest that, at least in the strain of mouse studied, ambient levels of nitrogen dioxide may affect the immune system.

  7. 42 CFR 493.851 - Standard; Hematology.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 5 2013-10-01 2013-10-01 false Standard; Hematology. 493.851 Section 493.851... (CONTINUED) STANDARDS AND CERTIFICATION LABORATORY REQUIREMENTS Participation in Proficiency Testing for... These Tests § 493.851 Standard; Hematology. (a) Failure to attain a score of at least 80 percent...

  8. Hematology of infancy and childhood: Third edition

    SciTech Connect

    Nathan, D.G.; Oski, F.A.

    1987-01-01

    These two volumes consist of 14 sections, each containing several chapters. The section titles are: History, Neonatal Hematology, Bone Marrow Failure, Disorders of Erythrocyte Production, Hemolytic Anemias, Disorders of Hemoglobin, The Phagocyte System, The Immune System, Oncology, Storage Disease, Coagulation, Genetics, Transfusion Therapy, and Hematologic Manifestations of Systemic Diseases.

  9. Non-Hodgkin's Malignant Lymphoma with Aggressive Development

    PubMed Central

    DANCIU, Cezara Elisabeta; HEROIU (CATALOIU), Adriana-Daniela; POPESCU, Cristian Radu

    2014-01-01

    Non-Hodgkin's malignant lymphoma is a hematologic malignant disease which usually responds to the polychemotherapy. We present a clinical case report of a 50 years old patient who develops an aggressive type of lymphoma. Patient develops a nodal Non-Hodgkin's malignant lymphoma who present at hospital admission as a huge tumor at the right side of the neck. Any type of treatment was a failure, the patient having a particularly aggressive form of lymphoma, resistant to all three chemotherapy regimens tested. Death occurs quickly, about one year after diagnosis and initiation of therapy. PMID:25553129

  10. The Role of Histone Acetyltransferases in Normal and Malignant Hematopoiesis

    PubMed Central

    Sun, Xiao-Jian; Man, Na; Tan, Yurong; Nimer, Stephen D.; Wang, Lan

    2015-01-01

    Histone, and non-histone, protein acetylation plays an important role in a variety of cellular events, including the normal and abnormal development of blood cells, by changing the epigenetic status of chromatin and regulating non-histone protein function. Histone acetyltransferases (HATs), which are the enzymes responsible for histone and non-histone protein acetylation, contain p300/CBP, MYST, and GNAT family members. HATs are not only protein modifiers and epigenetic factors but also critical regulators of cell development and carcinogenesis. Here, we will review the function of HATs such as p300/CBP, Tip60, MOZ/MORF, and GCN5/PCAF in normal hematopoiesis and the pathogenesis of hematological malignancies. The inhibitors that have been developed to target HATs will also be reviewed here. Understanding the roles of HATs in normal/malignant hematopoiesis will provide the potential therapeutic targets for the hematological malignancies. PMID:26075180

  11. The Role of Histone Acetyltransferases in Normal and Malignant Hematopoiesis.

    PubMed

    Sun, Xiao-Jian; Man, Na; Tan, Yurong; Nimer, Stephen D; Wang, Lan

    2015-01-01

    Histone, and non-histone, protein acetylation plays an important role in a variety of cellular events, including the normal and abnormal development of blood cells, by changing the epigenetic status of chromatin and regulating non-histone protein function. Histone acetyltransferases (HATs), which are the enzymes responsible for histone and non-histone protein acetylation, contain p300/CBP, MYST, and GNAT family members. HATs are not only protein modifiers and epigenetic factors but also critical regulators of cell development and carcinogenesis. Here, we will review the function of HATs such as p300/CBP, Tip60, MOZ/MORF, and GCN5/PCAF in normal hematopoiesis and the pathogenesis of hematological malignancies. The inhibitors that have been developed to target HATs will also be reviewed here. Understanding the roles of HATs in normal/malignant hematopoiesis will provide the potential therapeutic targets for the hematological malignancies. PMID:26075180

  12. Hematologic toxicity of immunosuppressive treatment.

    PubMed

    Danesi, R; Del Tacca, M

    2004-04-01

    The administration of immunosuppressive agents may be associated with the occurrence of hematologic toxicity, such as anemia, due to bone marrow suppression or hemolysis, leukopenia, and thrombocytopenia. The administration of azathioprine and mycophenolate mofetil is more frequently associated with bone marrow suppression, while hemolytic-uremic syndrome may occur after administration of cyclosporine, tacrolimus, or muromonab (OKT3) and may be associated with the loss of the allograft. Moreover, microangiopathic hemolytic anemia and thrombocytopenia are rare, but potentially severe, complications of immunosuppressive treatment with tacrolimus and cyclosporine; they are characterized by intravascular hemolysis due to mechanical destruction of red cells as a result of pathological changes in small blood vessels. Viral infections (cytomegalovirus), administration of antiviral agents (gancyclovir), inhibitors of angiotensin-converting enzyme and angiotensin II receptor antagonists, antibacterial agents (sulfamethoxazole and trimethoprim), and allopurinol may aggravate bone marrow suppression, particularly when administered with agents that interfere with purine biosynthesis, including azathioprine and mycophenolate mofetil. PMID:15110637

  13. Skylab experiment results: Hematology studies

    NASA Technical Reports Server (NTRS)

    Kimzey, S. L.; Ritzmann, S. E.; Mengel, C. E.; Fischer, C. L.

    1975-01-01

    Studies were conducted to evaluate specific aspects of man's immunologic and hematologic systems that might be altered by or respond to the space flight environment. Biochemical functions investigated included cytogenetic damage to blood cells, immune resistance to disease, regulation of plasma and red cell volumes, metabolic processes of the red blood cell, and physicochemical aspects of red blood cell function. Measurements of hematocrit value showed significant fluctuations postflight, reflecting observed changes in red cell mass and plasma volume. The capacity of lymphocytes to respond to an in vitro mitogenic challenge was repressed postflight, and appeared to be related to mission duration. Most other deviations from earth function in these systems were minor or transient.

  14. GATA-related hematologic disorders.

    PubMed

    Shimizu, Ritsuko; Yamamoto, Masayuki

    2016-08-01

    The transcription factors GATA1 and GATA2 are fundamental regulators of hematopoiesis and have overlapping expression profiles. GATA2 is expressed in hematopoietic stem cells and early erythroid-megakaryocytic progenitors and activates a certain set of early-phase genes, including the GATA2 gene itself. GATA2 also initiates GATA1 gene expression. In contrast, GATA1 is expressed in relatively mature erythroid progenitors and facilitates the expression of genes associated with differentiation, including the GATA1 gene itself; however, GATA1 represses the expression of GATA2. Switching the GATA factors from GATA2 to GATA1 appears to be one of the key regulatory mechanisms underlying erythroid differentiation. Loss-of-function analyses using mice in vivo have indicated that GATA2 and GATA1 are functionally nonredundant and that neither can compensate for the absence of the other. However, transgenic expression of GATA2 under the transcriptional regulation of the Gata1 gene rescues lethal dyserythropoiesis in GATA1-deficient mice, illustrating that the dynamic expression profiles of these GATA factors are critically important for the maintenance of hematopoietic homeostasis. Analysis of naturally occurring leukemias in GATA1-knockdown mice revealed that leukemic stem cells undergo functional alterations in response to exposure to chemotherapeutic agents. This mechanism may also underlie the aggravating features of relapsing leukemias. Recent hematologic analyses have suggested that disturbances in the balance of the GATA factors are associated with specific types of hematopoietic disorders. Here, we describe GATA1- and GATA2-related hematologic diseases, focusing on the regulation of GATA factor gene expression. PMID:27235756

  15. Panobinostat (LBH589): a potent pan-deacetylase inhibitor with promising activity against hematologic and solid tumors.

    PubMed

    Prince, H Miles; Bishton, Mark J; Johnstone, Ricky W

    2009-06-01

    The deacetylase inhibitors are a structurally diverse class of targeted antineoplastic agents that have demonstrated in vitro and in vivo preclinical activity in a wide range of malignancies. Based on this preclinical activity, several deacetylase inhibitors have undergone rapid clinical development in recent years. Among these, the deacetylase inhibitor panobinostat is one of the most widely studied, with extensive pharmacokinetic, pharmacodynamic and dose-finding data available across a wide variety of hematologic and solid tumors. Furthermore, panobinostat has demonstrated favorable clinical activity against various hematologic malignancies, most notably lymphomas and myeloid malignancies in Phase I and II studies. In this article, we discuss the preclinical data on panobinostat and emerging data from Phase I and II studies in cancer patients. PMID:19519200

  16. Risk of Non-hematologic Cancer in Individuals with High Count Monoclonal B-Cell Lymphocytosis (MBL)

    PubMed Central

    Solomon, Benjamin M.; Chaffee, Kari G.; Moreira, Jonathan; Schwager, Susan M.; Cerhan, James R.; Call, Timothy G.; Kay, Neil E.; Slager, Susan L.; Shanafelt, Tait D.

    2015-01-01

    It is unknown whether individuals with monoclonal B-cell lymphocytosis (MBL) are at risk for adverse outcomes associated with chronic lymphocytic leukemia (CLL), such as the risk of non-hematologic cancer. We identified all locally-residing individuals diagnosed with high count MBL at Mayo Clinic between 1999 and 2009 and compared their rates of non-hematologic cancer to that of patients with CLL and two control cohorts: general medicine patients and patients who underwent clinical evaluation with flow cytometry but who had no hematologic malignancy. After excluding individuals with prior cancers, there were 107 high count MBL cases, 132 CLL cases, 589 clinic controls, and 482 flow cytometry controls. With 4.6 years median follow-up, 14 (13%) individuals with high count MBL, 21 (4%) clinic controls (comparison MBL p<0.0001), 18 (4%) flow controls (comparison MBL p=0.0001), and 16 (12%) CLL patients (comparison MBL p=0.82) developed non-hematologic cancer. On multivariable Cox regression analysis, individuals with high count MBL had higher risk of non-hematologic cancer than flow controls (HR=2.36; p=0.04) and borderline higher risk than clinic controls (HR=2.00; p=0.07). Patients with high count MBL appear to be at increased risk for non-hematologic cancer, further reinforcing that high count MBL has a distinct clinical phenotype despite low risk of progression to CLL. PMID:26310541

  17. Risk of non-hematologic cancer in individuals with high-count monoclonal B-cell lymphocytosis.

    PubMed

    Solomon, B M; Chaffee, K G; Moreira, J; Schwager, S M; Cerhan, J R; Call, T G; Kay, N E; Slager, S L; Shanafelt, T D

    2016-02-01

    It is unknown whether individuals with monoclonal B-cell lymphocytosis (MBL) are at risk for adverse outcomes associated with chronic lymphocytic leukemia (CLL), such as the risk of non-hematologic cancer. We identified all locally residing individuals diagnosed with high-count MBL at Mayo Clinic between 1999 and 2009 and compared their rates of non-hematologic cancer with that of patients with CLL and two control cohorts: general medicine patients and patients who underwent clinical evaluation with flow cytometry but who had no hematologic malignancy. After excluding individuals with prior cancers, there were 107 high-count MBL cases, 132 CLL cases, 589 clinic controls and 482 flow cytometry controls. With 4.6 years median follow-up, 14 (13%) individuals with high-count MBL, 21 (4%) clinic controls (comparison MBL P<0.0001), 18 (4%) flow controls (comparison MBL P=0.0001) and 16 (12%) CLL patients (comparison MBL P=0.82) developed non-hematologic cancer. On multivariable Cox regression analysis, individuals with high-count MBL had higher risk of non-hematologic cancer compared with flow controls (hazard ratio (HR)=2.36; P=0.04) and borderline higher risk compared with clinic controls (HR=2.00; P=0.07). Patients with high-count MBL appear to be at increased risk for non-hematologic cancer, further reinforcing that high-count MBL has a distinct clinical phenotype despite low risk of progression to CLL. PMID:26310541

  18. Second primary malignancies among patients with myeloma-related-diseases in the KMF database.

    PubMed

    Kosugi, Satoru; Shibayama, Hirohiko; Nakatani, Eiji; Kida, Toru; Ohta, Kensuke; Kaneko, Hidemi; Yagi, Hideo; Tanaka, Hirokazu; Fuchida, Shin-Ichi; Nakaya, Aya; Kobayashi, Masayuki; Kuroda, Junya; Kamitsuji, Yuri; Uoshima, Nobuhiko; Adachi, Yoko; Tsudo, Mitsuru; Shimazaki, Chihiro; Nomura, Shosaku; Hino, Masayuki; Matsumura, Itaru; Taniwaki, Masashi; Kanakura, Yuzuru; Takaori-Kondo, Akifumi

    2016-07-01

    The incidence of second primary malignancies (SPMs) in Japanese patients with myeloma or myeloma-related diseases was studied by using the Kansai Myeloma Forum (KMF) database registered from November 2012 to March 2015. We studied 1,571 cases. Hematologic malignancies were documented in 10 patients, and solid tumors in 36 during this period. The cumulative 5-year incidence was estimated to be 1.0% for hematological malignancies and 3.7% for solid tumors. In the patients with smoldering myeloma or MGUS without treatment, solid tumors but not hematologic malignancies developed, though the cumulative incidence of each malignancy did not differ significantly from that in patients receiving treatment. Although statistical analysis showed that treatment with melphalan, bortezomib, lenalidomide, or thalidomide had no effect on the occurrence of hematological malignancies, lenalidomide administration was more frequent in the patients with solid tumors. To evaluate the SPMs in myeloma or myeloma-related diseases more accurately, accumulation of a larger number of patients and longer observation are needed. PMID:27498726

  19. American Society of Pediatric Hematology/Oncology

    MedlinePlus

    ... 2016 Engage with ASPHO and benefit from the Society’s professional development, education, and networking resources! Read More » ... Career Center Mentoring Funding Compensation Survey © The American Society of Pediatric Hematology/Oncology 8735 W. Higgins Road, ...

  20. Common hematologic problems in the newborn nursery.

    PubMed

    Watchko, Jon F

    2015-04-01

    "Common red blood cell disorders encountered in the normal newborn nursery include hemolytic disease of the newborn and resultant hyperbilirubinemia, anemia, and polycythemia. A less frequent clinically relevant hematologic issue in newborns to be covered herein is thrombocytopenia." PMID:25836711

  1. Hematologic responses to hypobaric hyperoxia.

    NASA Technical Reports Server (NTRS)

    Larkin, E. C.; Adams, J. D.; Williams, W. T.; Duncan, D. M.

    1972-01-01

    Study of the effects of hypoxia, activity, and G forces on human hematopoiesis in an attempt to elucidate these phenomena more precisely. Eight subjects were exposed to an atmosphere of 100% O2 at 258 mm Hg for 30 days, and thereafter immediately exposed to transverse G forces, simulating the Gemini flights' reentry profile. All subjects displayed a significant continuous decline in red cell mass during the exposure period, as measured by the carbon monoxide-dilution method. The Cr51 method also indicated a decline in red blood corpuscle mass. The decrease in red cell mass was due to suppression of erythropoiesis and to hemolysis. After exposure to hyperoxia, all subjects exhibited elevated plasma hemoglobin levels, decreased reticulocyte counts, and decreased red cell survivals. CO production rates and urine erythropoietin levels were unchanged. Two hours after termination of exposure to hyperoxia, all subjects exhibited increased reticulocyte counts which were sustained for longer than two weeks. The progressive decrease in red cell mass was promptly arrested on return to ground level atmospheres. Within 116 days after exposure to hyperoxia, the hematologic parameters of all eight subjects had returned to control levels.

  2. Invasive Aspergillosis in Hematological Patients.

    PubMed

    Kimura, Shun-Ichi

    2016-01-01

    Invasive aspergillosis (IA) is still one of the leading causes of morbidity and mortality in hematological patients, although its outcome has been improving. Prolonged and profound neutropenia in patients receiving intensive chemotherapy for acute leukemia and stem cell transplantation is a major risk factor for IA. Allogeneic stem cell transplant recipients with graft-versus-host disease and corticosteroid use are also at high risk. Management in a protective environment with high efficiency particular air (HEPA) filter is generally recommended to prevent aspergillosis in patients with prolonged and profound neutropenia. Antifungal prophylaxis against Aspergillus species should be considered in patients with past history of aspergillosis or colonization of Aspergillus species, at facilities with high incidence of IA and those without a protective environment. Early diagnosis and prompt antifungal treatment is important to improve outcome. Imaging studies such as computed tomography and biomarkers such as galactomannan antigen and β-D-glucan are useful for early diagnosis. Empirical antifungal treatment based on persistent or recurrent fever during neutropenia despite broad-spectrum antibiotic therapy is generally recommended in high-risk patients. Alternatively, a preemptive treatment strategy has recently been proposed in the context of progress in the early diagnosis of IA based on the results of imaging studies and biomarkers. Voriconazole is recommended for initial therapy for IA. Liposomal amphotericin B is considered as alternative initial therapy. Combination antifungal therapy of echinocandin with voriconazole or liposomal amphotericin B could be a choice for refractory cases. PMID:27251320

  3. A “Bone Marrow Score” for Predicting Hematological Disease in Immunocompetent Patients With Fevers of Unknown Origin

    PubMed Central

    Wang, Hao-Yuan; Yang, Ching-Fen; Chiou, Tzeon-Jye; Yang, Sheng-Hsiang; Gau, Jyh-Pyng; Yu, Yuan-Bin; Liu, Chun-Yu; Liu, Jin-Hwang; Chen, Po-Min; Hsu, Hui-Chi; Fung, Chang-Phone; Tzeng, Cheng-Hwai; Hsiao, Liang-Tsai

    2014-01-01

    Abstract Delayed diagnosis of hematological malignancies in immunocompetent patients with fever of unknown origin (FUO) remains an exhausting challenge for non-hematologist physicians. This retrospective cohort study aimed to establish a scoring system, “bone marrow (BM) score”, to identify FUO patients who require early bone marrow biopsy (BMB) to diagnose hematological disease. Two cohorts, comprising 85 (training) and 20 (validation) eligible immunocompetent patients, with FUOs diagnosed between January 1, 2006 and July 31, 2013, underwent BMBs and were enrolled in the study. Demographic, laboratory, imaging, diagnostic, and outcome data were collected and retrospectively analyzed. Factors associated with hematological etiologies diagnosed using BMBs in the training cohort were identified and scored according to the relative hazards. These were further validated using the validation cohort. For the training cohort, 29 of 85 (34.1%) patients had hematological etiologies diagnosed using BMB. Seven factors significantly predicted the diagnostic yield of hematological diseases in the BM and were scored, with the 6 points for leucoerythroblastic changes in peripheral blood smears, 5.5 for elevated ferritin level (>1000 ng/mL), 4 for splenomegaly, 2 for thrombocytopenia, 1.5 for each of elevated lactate dehydrogenase levels and anemia, and 1 for neutropenia. When the cut-off value of the scoring system was set to 6, its sensitivity and specificity to diagnose hematological diseases in the BM of immunocompetent FUO patients were 93% and 58%, respectively. For the validation cohort, 7 of 20 (35%) patients had hematological disease, and all had BM scores higher than the cut-off, with the sensitivity and specificity at 100% and 77%, respectively. As immunocompetent FUO patients with hematological disease have poor prognoses, the “BM score” is valuable for non-hematologist physicians to identify immunocompetent FUO patients requiring early BMB. PMID:25501092

  4. Malignant thymoma.

    PubMed

    Wang, L S; Huang, M H; Lin, T S; Huang, B S; Chien, K Y

    1992-07-15

    Sixty-one patients underwent operations for malignant thymomas between 1961 and 1989. Twenty-three patients had associated myasthenia gravis (MG), an incidence of 37.7%. Upon being admitted to the hospital, the patients' most common symptoms included chest pain, MG, cough, and dyspnea. Only 7 of 61 (11.5%) patients had no symptom. Tumor staging of 58 patients with invasive thymomas was performed according to Masaoka classification. The patients were classified as follows: Stage II disease, 5; Stage III, 41; Stage IVa, 8; and Stage IVb, 4. In addition, thymic carcinoma was present in three patients. The series had a resection rate of 55.7%. The incidence of operative complications was 16.3%. Only one patient died of myocardial infarction; the incidence of operative mortality was 1.6%. The patients with MG had a higher rate of resection (69.6%) and a higher incidence of complete thymectomy (14 of 23 patients; 60.9%). Mixed lymphoepithelial tumors and epithelial cell predominant tumors were the most frequent histologic patterns (45.9% and 34.4%, respectively). Fifty-two patients had postoperative radiation therapy, and 10 patients had chemotherapy. The overall cumulative survival rates in the series were 59% and 34% at 5 and 10 years, respectively. The results demonstrated that the factors affecting the prognosis may include resectability, postoperative irradiation or chemotherapy, MG, and tumor staging. The influence of histologic variation on survival rates could not be clearly defined in the series. Surgical resection, particularly complete thymectomy, followed by irradiation is the primary option of therapeutic management for malignant thymoma. PMID:1617594

  5. Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers.

    PubMed

    Cottini, Francesca; Hideshima, Teru; Xu, Chunxiao; Sattler, Martin; Dori, Martina; Agnelli, Luca; ten Hacken, Elisa; Bertilaccio, Maria Teresa; Antonini, Elena; Neri, Antonino; Ponzoni, Maurilio; Marcatti, Magda; Richardson, Paul G; Carrasco, Ruben; Kimmelman, Alec C; Wong, Kwok-Kin; Caligaris-Cappio, Federico; Blandino, Giovanni; Kuehl, W Michael; Anderson, Kenneth C; Tonon, Giovanni

    2014-06-01

    Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine-threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels. PMID:24813251

  6. Pleiotropic roles of Notch signaling in normal, malignant, and developmental hematopoiesis in the human

    PubMed Central

    Kushwah, Rahul; Guezguez, Borhane; Lee, Jung Bok; Hopkins, Claudia I; Bhatia, Mickie

    2014-01-01

    The Notch signaling pathway is evolutionarily conserved across species and plays an important role in regulating cell differentiation, proliferation, and survival. It has been implicated in several different hematopoietic processes including early hematopoietic development as well as adult hematological malignancies in humans. This review focuses on recent developments in understanding the role of Notch signaling in the human hematopoietic system with an emphasis on hematopoietic initiation from human pluripotent stem cells and regulation within the bone marrow. Based on recent insights, we summarize potential strategies for treatment of human hematological malignancies toward the concept of targeting Notch signaling for fate regulation. PMID:25252682

  7. Malignant hyperpyrexia

    PubMed Central

    Isaacs, Hyam; Barlow, M. B.

    1973-01-01

    The history, clinical presentation, and management of malignant hyperpyrexia are presented. The aetiology seems to be associated with some inherited abnormality which affects the movement and binding of calcium ions in the sarcoplasmic reticulum, sarcoplasm, and mitochondria. Whether this is a primary muscular defect or secondary to some trophic neural influence is yet to be established. The subjects carrying the abnormal trait show evidence of a myopathy which is subclinical in most instances and revealed only by estimation of serum CPK or biopsy. In some families where the myopathy is clinically obvious there may be, in addition, a variety of musculoskeletal abnormalities. A plea is made for routine monitoring of temperature during anaesthesia and for procainamide or procaine to be readily available in all operating theatres. A history of anaesthetic deaths in a family calls for special care, and, if the serum CPK is elevated, suxamethonium and halothane are to be avoided. Families with orthopaedic and muscular abnormalities are at increased risk and should have estimation of serum CPK before surgery. As a bonus of this study it is suggested that serum CPK estimations be used to screen pigs for selective breeding and so eliminate the disease, which causes soft exudative pork. Images PMID:4708457

  8. The emerging importance of ribosomal dysfunction in the pathogenesis of hematologic disorders.

    PubMed

    Raiser, David M; Narla, Anupama; Ebert, Benjamin L

    2014-03-01

    More than a decade has passed since the initial identification of ribosomal protein gene mutations in patients with Diamond-Blackfan anemia (DBA), a hematologic disorder that became the founding member of a class of diseases known as ribosomopathies. In these diseases, genetic abnormalities that result in defective ribosome biogenesis cause strikingly tissue-specific phenotypes in patients, specifically bone marrow failure, craniofacial abnormalities and skeletal defects. Several animal models and numerous in vitro studies have demonstrated that the p53 pathway is central to the ribosomopathy phenotype. Additionally, there is mounting evidence of a link between the dysregulation of components of the translational machinery and the pathology of various malignancies. The importance of the role of ribosomal dysfunction in the pathogenesis of hematologic disorders is becoming clearer, and elucidation of the underlying mechanisms could have broad implications for both basic cellular biology and clinical intervention strategies. PMID:23863123

  9. Immunotherapy of hematological cancers: PD-1 blockade for the treatment of Hodgkin's lymphoma

    PubMed Central

    Kroemer, Guido; Galluzzi, Lorenzo

    2015-01-01

    The blockade of immunological checkpoints has been successfully employed for the treatment of various solid neoplasms including melanoma, mesothelioma, non-small cell lung carcinoma, and renal cell carcinoma. A recent study indicates that the vast majority of patients with advanced, heavily pretreated Hodgkin's lymphoma (HL) also respond to a monoclonal antibody targeting programmed cell death 1 (PDCD1, best known as PD-1). Thus, checkpoint blockers may soon become part of our therapeutic armamentarium against hematological tumors. This would be particularly important as it would spare (at least some) patients the deleterious toxic effects of combinatorial chemotherapies and bone marrow transplantation. We anticipate that the realm of immunotherapy will eventually conquer vast portions of the territory that now belongs to hematological malignancies. PMID:26155425

  10. Prognostic factors for mortality with fungal blood stream infections in patients with hematological and non-hematological malignancies

    PubMed Central

    Salih, Zena; Cavet, Jim; Dennis, Mike; Somervaille, Tim; Bloor, Adrian; Kulkarni, Samar

    2013-01-01

    Background: This single center retrospective analysis was undertaken to identify the incidence, clinical impact, and prognostic factors for mortality associated with fungal blood stream infections (BSI) in cancer patients. Materials and Methods: One hundred and twenty four patients had 169 episodes of fungal BSI. Incidence has not changed over a 10 year period but non albicans candida species are the predominant fungal isolates. Mortality with fungal BSI was significantly higher than that with other microbial agents. Risk of mortality was associated with renal dysfunction and Candida albicans as the isolate. Type of chemotherapy, patient characteristics, and neutrophil count did not influence the mortality following fungal BSI. Conclusion: Fungal BSI is rare and the incidence has not changed in this hospital. Mortality associated with fungal BSI is high. Risk score at the time of developing fungal BSI has prognostic potential to identify patients with higher risk of mortality associated with fungal BSI. PMID:24455639

  11. Differences in attitudes and beliefs toward end-of-life care between hematologic and solid tumor oncology specialists

    PubMed Central

    Hui, D.; Bansal, S.; Park, M.; Reddy, A.; Cortes, J.; Fossella, F.; Bruera, E.

    2015-01-01

    Background Patients with hematologic malignancies often receive aggressive care at the end-of-life. To better understand the end-of-life decision-making process among oncology specialists, we compared the cancer treatment recommendations, and attitudes and beliefs toward palliative care between hematologic and solid tumor specialists. Patients and methods We randomly surveyed 120 hematologic and 120 solid tumor oncology specialists at our institution. Respondents completed a survey examining various aspects of end-of-life care, including palliative systemic therapy using standardized case vignettes and palliative care proficiency. Results Of 240 clinicians, 182 (76%) clinicians responded. Compared with solid tumor specialists, hematologic specialists were more likely to favor prescribing systemic therapy with moderate toxicity and no survival benefit for patients with Eastern Cooperative Oncology Group (ECOG) performance status 4 and an expected survival of 1 month (median preference 4 versus 1, in which 1 = strong against treatment and 7 = strongly recommend treatment, P < 0.0001). This decision was highly polarized. Hematologic specialists felt less comfortable discussing death and dying (72% versus 88%, P = 0.007) and hospice referrals (81% versus 93%, P = 0.02), and were more likely to feel a sense of failure with disease progression (46% versus 31%, P = 0.04). On multivariate analysis, hematologic specialty [odds ratio (OR) 2.77, P = 0.002] and comfort level with prescribing treatment to ECOG 4 patients (OR 3.79, P = 0.02) were associated with the decision to treat in the last month of life. Conclusions We found significant differences in attitudes and beliefs toward end-of-life care between hematologic and solid tumor specialists, and identified opportunities to standardize end-of-life care. PMID:26041765

  12. 21 CFR 864.8625 - Hematology quality control mixture.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Hematology quality control mixture. 864.8625 Section 864.8625 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Reagents § 864.8625...

  13. 21 CFR 864.8625 - Hematology quality control mixture.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Hematology quality control mixture. 864.8625 Section 864.8625 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Reagents § 864.8625...

  14. 21 CFR 864.8625 - Hematology quality control mixture.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Hematology quality control mixture. 864.8625 Section 864.8625 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Reagents § 864.8625...

  15. 21 CFR 864.8625 - Hematology quality control mixture.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Hematology quality control mixture. 864.8625 Section 864.8625 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Reagents § 864.8625...

  16. 21 CFR 864.8625 - Hematology quality control mixture.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Hematology quality control mixture. 864.8625 Section 864.8625 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Reagents § 864.8625...

  17. Allo HSCT Using RIC for Hematological Diseases

    ClinicalTrials.gov

    2016-01-20

    Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Plasma Cell Leukemia; Myelodysplastic Syndromes; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; B-Cell Lymphoma; Follicular Lymphoma; Lymphoplasmacytic Lymphoma; Mantle-Cell Lymphoma; Prolymphocytic Leukemia; Lymphoblastic Lymphoma; Burkitt's Lymphoma; Non-Hodgkin's Lymphoma; Multiple Myeloma; Myeloproliferative Syndromes; Hematological Diseases

  18. A hematologic survey of captive waterfowl

    USGS Publications Warehouse

    Shave, H.J.; Howard, V.

    1976-01-01

    Hematologic parameters were studied in giant Canada geese (Branta canadensis maxima), mallard ducks (Anas platyrhynchos platyrhynchos) and various species of diving ducks at seasonal intervals throughout the year. Highest values for packed cell volume, hemoglobin content and erythrocyte counts were found in the winter and pre-nesting periods. Mean corpuscular volume and mean corpuscular hemoglobin varied inversely with these values.

  19. Imaging Manifestations of Hematologic Diseases with Renal and Perinephric Involvement.

    PubMed

    Purysko, Andrei S; Westphalen, Antonio C; Remer, Erick M; Coppa, Christopher P; Leão Filho, Hilton M; Herts, Brian R

    2016-01-01

    The kidneys and perinephric tissues can be affected by a variety of hematologic disorders, which usually occur in the setting of multisystem involvement. In many of these disorders, imaging is used to evaluate the extent of disease, guide biopsy, and/or monitor disease activity and patient response to therapy. Lymphoma, leukemia, and multiple myeloma commonly manifest as multiple parenchymal or perinephric lesions. Erdheim-Chester disease and Rosai-Dorfman disease, rare forms of multisystemic histiocytosis, are often identified as perinephric and periureteral masses. Renal abnormalities depicted at imaging in patients with sickle cell disease include renal enlargement, papillary necrosis, and renal medullary carcinoma. Sickle cell disease, along with other causes of intravascular hemolysis, can also lead to hemosiderosis of the renal cortex. Thrombosis of renal veins is sometimes seen in patients with coagulation disorders but more often occurs in association with certain malignancies and nephrotic syndrome. Immunoglobulin G4-related sclerosing disease is another multisystem process that often produces focal renal lesions, seen along with involvement of more characteristic organs such as the pancreas. Perinephric lesions with calcifications should raise the possibility of secondary amyloidosis, especially in patients with a history of lymphoma and multiple myeloma. Although the imaging patterns of renal and perinephric involvement are usually not specific for a single entity, and the same entity can manifest with different or overlapping patterns, familiarity with these patterns and key clinical and histopathologic features may help to narrow the differential diagnosis and determine the next step of care. (©)RSNA, 2016. PMID:27257766

  20. Malignant teratoma (image)

    MedlinePlus

    A malignant teratoma is a type of cancer consisting of cysts that contain one or more of the three primary embryonic germ layers: ectoderm, mesoderm, and endoderm. Because malignant teratomas have usually spread by the time of diagnosis, ...

  1. From Melanocyte to Metastatic Malignant Melanoma

    PubMed Central

    Bandarchi, Bizhan; Ma, Linglei; Navab, Roya; Seth, Arun; Rasty, Golnar

    2010-01-01

    Malignant melanoma is one of the most aggressive malignancies in human and is responsible for almost 60% of lethal skin tumors. Its incidence has been increasing in white population in the past two decades. There is a complex interaction of environmental (exogenous) and endogenous, including genetic, risk factors in developing malignant melanoma. 8–12% of familial melanomas occur in a familial setting related to mutation of the CDKN2A gene that encodes p16. The aim of this is to briefly review the microanatomy and physiology of the melanocytes, epidemiology, risk factors, clinical presentation, historical classification and histopathology and, more in details, the most recent discoveries in biology and genetics of malignant melanoma. At the end, the final version of 2009 AJCC malignant melanoma staging and classification is presented. PMID:20936153

  2. Pediatric Salivary Gland Malignancies.

    PubMed

    Ord, Robert A; Carlson, Eric R

    2016-02-01

    Pediatric malignant salivary gland tumors are extremely rare. The percentage of malignant tumors is higher than that seen in adults, although the outcomes in terms of survival are better in pediatric patients. The mainstay of treatment is surgical excision with negative margins. This article reviews current concepts in demographics, etiology, management, and outcomes of malignant salivary tumors in children. PMID:26614703

  3. Imaging of Spinal Manifestations of Hematological Disorders.

    PubMed

    Pawha, Puneet S; Chokshi, Falgun H

    2016-08-01

    Imaging manifestations of hematological diseases and their potential complications are broad, and there may be significant overlap in features of various disease processes. Knowledge of appropriate choice of imaging test, pertinent imaging patterns, and pathophysiology of disease can help the reader increase specificity in the diagnosis and treatment of the patient. Most importantly, we encourage readers of this review to engage their radiologists during the diagnostic, treatment, and management phases of care delivery. PMID:27444004

  4. Combined loss of Tet1 and Tet2 promotes B-cell, but not myeloid malignancies in mice

    PubMed Central

    Zhao, Zhigang; Chen, Li; Dawlaty, Meelad M.; Pan, Feng; Weeks, Ophelia; Zhou, Yuan; Cao, Zeng; Shi, Hui; Wang, Jiapeng; Lin, Li; Chen, Shi; Yuan, Weiping; Qin, Zhaohui; Ni, Hongyu; Nimer, Stephen D.; Yang, Feng-Chun; Jaenisch, Rudolf; Jin, Peng; Xu, Mingjiang

    2016-01-01

    Summary TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2−/− HSC/HPCs showed overlapping and unique 5hmC and 5mC profiles, and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed-onset of myeloid malignancies compared to Tet2−/− mice, and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1/2 individually and together via communication in the pathogenesis of hematological malignancies. PMID:26586431

  5. DNA methylation in normal and malignant hematopoiesis.

    PubMed

    Celik, Hamza; Kramer, Ashley; Challen, Grant A

    2016-06-01

    The study of DNA methylation has been a rapidly expanding field since its dawn in the 1960s. DNA methylation is an epigenetic modification that plays a crucial role in guiding the differentiation of stem cells to their destined lineage, and in maintaining tissue homeostasis. Moreover, aberrant DNA methylation has been well characterized as a significant contributing factor in the pathogenesis of a variety of cancers. Hematopoiesis is a process that is uniquely susceptible to epigenetic changes due to the small pool of actively cycling stem cells that give rise to the entire mature immune-hematopoietic system. Mutations in DNA methyltransferase enzymes have been shown to be initiating events in the development of hematological malignancies such as acute myeloid leukemia and, therefore, have become targets for improved diagnostics and therapy. The spatial and temporal regulation of DNA methylation in the hematopoietic developmental hierarchy is critical to hematopoietic homeostasis. An improved understanding of the roles that DNA methylation plays in normal and malignant hematopoiesis will have a significant impact on the future of regenerative stem cell therapy and clinical treatment of hematopoietic malignancies. This review aims to highlight current developments in the field and prioritize future research directions. PMID:26943352

  6. Segmental neurofibromatosis and malignancy.

    PubMed

    Dang, Julie D; Cohen, Philip R

    2010-01-01

    Segmental neurofibromatosis is an uncommon variant of neurofibromatosis type I characterized by neurofibromas and/or café-au-lait macules localized to one sector of the body. Although patients with neurofibromatosis type I have an associated increased risk of certain malignancies, malignancy has only occasionally been reported in patients with segmental neurofibromatosis. The published reports of patients with segmental neurofibromatosis who developed malignancy were reviewed and the characteristics of these patients and their cancers were summarized. Ten individuals (6 women and 4 men) with segmental neurofibromatosis and malignancy have been reported. The malignancies include malignant peripheral nerve sheath tumor (3), malignant melanoma (2), breast cancer (1), colon cancer (1), gastric cancer (1), lung cancer (1), and Hodgkin lymphoma (1). The most common malignancies in patients with segmental neurofibromatosis are derived from neural crest cells: malignant peripheral nerve sheath tumor and malignant melanoma. The incidence of malignancy in patients with segmental neurofibromatosis may approach that of patients with neurofibromatosis type I. PMID:21137621

  7. RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS

    PubMed Central

    Cottini, Francesca; Hideshima, Teru; Xu, Chunxiao; Sattler, Martin; Dori, Martina; Agnelli, Luca; Hacken, Elisa ten; Bertilaccio, Maria Teresa; Antonini, Elena; Neri, Antonino; Ponzoni, Maurilio; Marcatti, Magda; Richardson, Paul G.; Carrasco, Ruben; Kimmelman, Alec C.; Wong, Kwok-Kin; Caligaris-Cappio, Federico; Blandino, Giovanni; Kuehl, W. Michael; Anderson, Kenneth C.; Tonon, Giovanni

    2014-01-01

    Oncogene–induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53–independent, pro-apoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway co–activator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1–induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine–threonine kinase, STK4. Importantly, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a novel synthetic–lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels. PMID:24813251

  8. Verification and quality control of routine hematology analyzers.

    PubMed

    Vis, J Y; Huisman, A

    2016-05-01

    Verification of hematology analyzers (automated blood cell counters) is mandatory before new hematology analyzers may be used in routine clinical care. The verification process consists of several items which comprise among others: precision, accuracy, comparability, carryover, background and linearity throughout the expected range of results. Yet, which standard should be met or which verification limit be used is at the discretion of the laboratory specialist. This paper offers practical guidance on verification and quality control of automated hematology analyzers and provides an expert opinion on the performance standard that should be met by the contemporary generation of hematology analyzers. Therefore (i) the state-of-the-art performance of hematology analyzers for complete blood count parameters is summarized, (ii) considerations, challenges, and pitfalls concerning the development of a verification plan are discussed, (iii) guidance is given regarding the establishment of reference intervals, and (iv) different methods on quality control of hematology analyzers are reviewed. PMID:27161194

  9. Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation

    PubMed Central

    Mayle, Allison; Yang, Liubin; Rodriguez, Benjamin; Zhou, Ting; Chang, Edmund; Curry, Choladda V.; Challen, Grant A.; Li, Wei; Wheeler, David; Rebel, Vivienne I.

    2015-01-01

    DNA methyltransferase 3A (DNMT3A) is mutated in hematologic malignancies affecting myeloid, mixed, and lymphoid lineages, and these mutations are associated with poor prognosis. Past studies in mice revealed Dnmt3a-knockout (KO) hematopoietic stem cells (HSCs) had increased self-renewal, but no leukemia was observed. Here, all lethally irradiated mice transplanted with Dnmt3a-deleted HSCs died within 1 year. Animals were diagnosed with a spectrum of malignancies similar to those seen in patients with DNMT3A mutations, including myelodysplastic syndrome, acute myeloid leukemia, primary myelofibrosis, and T- and B-cell acute lymphocytic leukemia. In some cases, acquired malignancies exhibited secondary mutations similar to those identified in patients. Loss of Dnmt3a led to disturbed methylation patterns that were distinct in lymphoid and myeloid disease, suggesting lineage-specific methylation aberrations promoted by Dnmt3a loss. Global hypomethylation was observed in all of the malignancies, but lymphoid malignancies also exhibited hypermethylation, particularly at promoter regions. This mouse model underscores the important role of Dnmt3a in normal hematopoietic development and demonstrates that Dnmt3a loss of function confers a preleukemic phenotype on murine HSCs. This model may serve as a tool to study DNMT3A mutation-associated malignancies and for developing targeted strategies for eliminating preleukemic cells for prevention and treatment of hematologic malignancies in the future. PMID:25416277

  10. [Triclonal gammopathy and malignant immunoproliferative syndrome].

    PubMed

    Grosbois, B; Jégo, P; de Rosa, H; Ruelland, A; Lancien, G; Gallou, G; Leblay, R

    1997-01-01

    Three distinct monoclonal gammopathies were identified in the serum of a 79 year-old man. In 1972 he presented with Waldenström's macroglobulinemia IgM Kappa. Twenty years later multiple myeloma was diagnoses. Serum protein electrophoresis performed at this time showed three monoclonal bands. Immunofixation identified these bands as monoclonal IgM kappa, IgG kappa and IgA kappa. Twenty-six cases of triclonal gammopathies were previously reported. Sixteen cases were associated with malignant immuno-proliferative diseases (non-hodgkin lymphoma, Waldenström's macroglobulinemia, multiple myeloma); five cases with non-hematologic diseases; three cases were of undetermined significance. The origin of three distinct monoclonal proteins may derive from three unrelated clones or alternatively from a single clone in which an isotype switch has occurred. PMID:9247046

  11. Hematology of healthy Florida manatees (Trichechus manatus)

    USGS Publications Warehouse

    Harvey, J.W.; Harr, K.E.; Murphy, D.; Walsh, M.T.; Nolan, E.C.; Bonde, R.K.; Pate, M.G.; Deutsch, C.J.; Edwards, H.H.; Clapp, W.L.

    2009-01-01

    Background: Hematologic analysis is an important tool in evaluating the general health status of free-ranging manatees and in the diagnosis and monitoring of rehabilitating animals. Objectives: The purpose of this study was to evaluate diagnostically important hematologic analytes in healthy manatees (Trichechus manatus) and to assess variations with respect to location (free ranging vs captive), age class (small calves, large calves, subadults, and adults), and gender. Methods: Blood was collected from 55 free-ranging and 63 captive healthy manatees. Most analytes were measured using a CELL-DYN 3500R; automated reticulocytes were measured with an ADVIA 120. Standard manual methods were used for differential leukocyte counts, reticulocyte and Heinz body counts, and plasma protein and fibrinogen concentrations. Results: Rouleaux, slight polychromasia, stomatocytosis, and low numbers of schistocytes and nucleated RBCs (NRBCs) were seen often in stained blood films. Manual reticulocyte counts were higher than automated reticulocyte counts. Heinz bodies were present in erythrocytes of most manatees. Compared with free-ranging manatees, captive animals had slightly lower MCV, MCH, and eosinophil counts and slightly higher heterophil and NRBC counts, and fibrinogen concentration. Total leukocyte, heterophil, and monocyte counts tended to be lower in adults than in younger animals. Small calves tended to have higher reticulocyte counts and NRBC counts than older animals. Conclusions: Hematologic findings were generally similar between captive and free-ranging manatees. Higher manual reticulocyte counts suggest the ADVIA detects only reticulocytes containing large amounts of RNA. Higher reticulocyte and NRBC counts in young calves probably reflect an increased rate of erythropoiesis compared with older animals. ?? 2009 American Society for Veterinary Clinical Pathology.

  12. Hematological Practice in Hong Kong and China.

    PubMed

    Kwong, Yok-Lam; Ha, Shau-Yin; Chan, Vivian

    2016-04-01

    Thalassemias and hemophilias are the most important inherited hematological diseases in Hong Kong and China. Prenatal diagnosis has significantly decreased the burden of these diseases. For thalassemia major, adequate transfusion and iron chelation therapy have dramatically improved patient outlook. Hematopoietic stem cell transplantation is curative for thalassemia major and is increasingly adopted. The efficacy of arsenic trioxide in acute promyelocytic leukemia (APL) was discovered in China. An oral formulation of arsenic trioxide was developed in Hong Kong for newly diagnosed and relapsed APL patients. With combination chemotherapy containing non-P-glycoprotein-dependent drugs and L-asparaginase, durable remission can be achieved in the most patients. PMID:27040964

  13. Hematological Disorders Following Exposure to Insecticides

    PubMed Central

    Mastromatteo, Ernest

    1964-01-01

    The medical literature dealing with hematological disorders following exposure to insecticides (chiefly chlorinated hydrocarbons and organic phosphorus compounds) is briefly reviewed. The development of blood dyscrasias as a consequence of exposure to insecticides is considered unlikely. Reported cases are few in number and often involve persons with little contact with these materials. It is often impossible to prove (or to disprove) a cause-and-effect relation in the individual case. Pointers which may be of assistance in evaluating this relationship are described. Purpura as a result of allergic vascular changes after exposure to insecticides is also discussed. PMID:14145471

  14. Nanopharmacology in translational hematology and oncology

    PubMed Central

    Tomuleasa, Ciprian; Braicu, Cornelia; Irimie, Alexandra; Craciun, Lucian; Berindan-Neagoe, Ioana

    2014-01-01

    Nanoparticles have displayed considerable promise for safely delivering therapeutic agents with miscellaneous therapeutic properties. Current progress in nanotechnology has put forward, in the last few years, several therapeutic strategies that could be integrated into clinical use by using constructs for molecular diagnosis, disease detection, cytostatic drug delivery, and nanoscale immunotherapy. In the hope of bringing the concept of nanopharmacology toward a viable and feasible clinical reality in a cancer center, the present report attempts to present the grounds for the use of cell-free nanoscale structures for molecular therapy in experimental hematology and oncology. PMID:25092977

  15. Malignant Vagal Paraganglioma.

    PubMed

    Hamersley, Erin R S; Barrows, Amy; Perez, Angel; Schroeder, Ashley; Castle, James T

    2016-06-01

    Paragangliomas are rare, typically benign neuroendocrine tumors that represent a small portion of head and neck tumors. A small percentage of these are known to have malignant potential. They arise from the carotid body, jugular bulb or vagus nerves. There is limited literature discussing the management of malignant vagal paragangliomas. We present a case of a 25 year old female with a left malignant vagal paraganglioma. The following case presentation will describe the presentation, classic radiologic findings, and management of a malignant vagal paraganglioma along with a review of the literature. PMID:25712400

  16. The Mediating Role of Mental Adjustment in the Relationship between Perceived Stress and Depressive Symptoms in Hematological Cancer Patients: A Cross-Sectional Study

    PubMed Central

    Li, Yingchun; Yang, Ying; Zhang, Rong; Yao, Kun; Liu, Zhuogang

    2015-01-01

    Background Depression is a particularly common psychological disorder that affects cancer patients. Diagnosed with hematological malignancies constitute a serious unpredictable and uncontrollable medical stress situation and patients are susceptible to suffer from depressive symptoms. The aims of the study were to explore the correlation between perceived stress and depressive symptoms in patients with hematological malignancies, and assess the mediating role of mental adjustment between these variables. Methods A single center, cross-sectional study was performed by convenience sampling between July 2013 and April 2014 in a hospital of China. The Center for Epidemiologic Studies Depression Scale, Perceived Stress Scale, and Mini-Mental Adjustment Scale, as well as questions about demographic and clinical factors was distributed to 300 hematological cancer patients. Completed questionnaires were received from 227 inpatients. Results The results showed that perceived stress was positively correlated with depressive symptoms. The mental adjustment significantly mediated the relationship between perceived stress and depressive symptoms. Conclusions Among hematological cancer patients perceived stress may be a risk factor for depressive symptoms, whereas positive coping style might be protective against depressive symptoms. Results showed that medical managers could support the development of mental adjustment in the patients to alleviate psychological disorders. PMID:26587991

  17. Hematologic effects and complications of snake envenoming.

    PubMed

    Berling, Ingrid; Isbister, Geoffrey K

    2015-04-01

    Hematologic abnormalities are the most common effects of snake envenoming globally. Venom-induced consumption coagulopathy (VICC) is the commonest and most important. Other hematologic abnormalities are an anticoagulant coagulopathy and thrombotic microangiopathy. Venom-induced consumption coagulopathy is a venom-induced activation of the clotting pathway by procoagulant toxins, resulting in clotting factor consumption and coagulopathy. The type of procoagulant toxin differs between snakes and can activate prothrombin, factor X, and factor V or consume fibrinogen. The most useful investigation in VICC is a prothrombin time/international normalized ratio. The d-dimer may assist in early diagnosis, but fibrinogen levels often add little in the clinical setting. Bedside investigations would be ideal, but point-of-care testing international normalized ratio and whole blood clotting tests have been shown to be unreliable in VICC. The major complication of VICC is hemorrhage, including intracranial hemorrhage which is often fatal. The role of antivenom in VICC is controversial and may only be beneficial for some types of snakes including Echis spp where the duration of abnormal clotting is reduced from more than a week to 24 to 48 hours. In contrast, antivenom does not appear to speed the recovery of VICC in Australian snake envenoming. Other treatments for VICC include factor replacement, observation and prevention of trauma, and heparin. An Australian study showed that fresh-frozen plasma speeds recovery of VICC, but early use may increase consumption. There is no evidence to support heparin. PMID:25556574

  18. Splenectomy in hematologic disorders. The ever-changing indications.

    PubMed Central

    Wilhelm, M C; Jones, R E; McGehee, R; Mitchener, J S; Sandusky, W R; Hess, C E

    1988-01-01

    A comparison between a series of splenectomies performed at the University of Virginia Medical Center for hematologic disorders between 1946 and 1962 (Series I) and 1963 and 1982 (Series II) is presented. Four hundred splenectomies (20 per year) were performed between 1963 and 1982 compared with 94 (5.5 per year) between 1946 and 1962. Also noted in Series II was a sharp decline in the number performed each year between 1974 and 1983. The major factor responsible for these observations was the evolution of the staging laparotomy for malignant lymphomas, particularly Hodgkin's disease, and the decline in the average annual incidence of staging laparotomies since 1974. Staging laparotomy currently is rarely done for non-Hodgkin's lymphomas. Also contributing to the changes noted was an increase in the total number but subsequent fall in the annual incidence of splenectomy for hereditary spherocytosis, idiopathic hypersplenism, and myeloproliferative disorders in Series II. The average number of splenectomies for idiopathic thrombocytopenic purpura increased from 1.1 per year in Series I to 3.6 per year in Series II; the annual incidence during the study period of Series II, however, remained constant. The total number of splenectomies for hairy cell leukemia and Felty's syndrome increased from zero in Series I to 12 and 17, respectively, in Series II, whereas the number of miscellaneous reasons dropped from 29 (1.7 per year) in Series I to 15 (0.75 per year) in Series II. The mortality rate in Series I was 6.3% compared with 4.0% in Series II. No deaths occurred in Series II after 1979. Indications for splenectomy in Series II were for diagnostic purposes in 3.2%, therapeutic in 56.5%, staging in 39.5%, and restaging in 0.8%. Accessory spleens were found in 49 (12.5%) in Series II. PMID:3377568

  19. Principles of analytical validation of next-generation sequencing based mutational analysis for hematologic neoplasms in a CLIA-certified laboratory.

    PubMed

    Kanagal-Shamanna, Rashmi; Singh, Rajesh R; Routbort, Mark J; Patel, Keyur P; Medeiros, L Jeffrey; Luthra, Rajyalakshmi

    2016-04-01

    Targeted therapy based on mutational profiles is the current standard of practice for the management of patients with hematologic malignancies. Next-generation sequencing (NGS)- based analysis has been adopted by clinical laboratories for high-throughput mutational profiling of myeloid and lymphoid neoplasms. The technology is fairly novel and complex, hence both validation and test implementation in a CLIA-certified laboratory differ substantially from traditional sequencing platforms. Recently, organizations such as the American College of Medical Genetics, Centers for Disease Control and Prevention and College of American Pathologists have published principles and guidelines for NGS test development to ensure standardization of testing across institutions. Summarized here are the recommendations from these organizations as they pertain to targeted NGS-based testing of hematologic malignancies ('liquid tumors'), with particular emphasis on myeloid neoplasms. PMID:26765348

  20. Clinical, hematological and biochemical alterations in olive flounder, Paralichthys olivaceus following experimental infection by Vibrio scophthalmi

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hematological analysis can provide key values for monitoring fish health conditions. There is no information available on hematological changes of olive flounder following infection by Vibrio scophthalmi. In this study, hematological and biochemical alterations were determined for olive flounder inf...

  1. Investigational Immunotherapeutics for B-Cell Malignancies

    PubMed Central

    Quintás-Cardama, Alfonso; Wierda, William; O'Brien, Susan

    2010-01-01

    The use of rituximab-based chemoimmunotherapy regimens has remarkably improved the response rates, long-term outcomes, and quality of life of patients with B-cell malignancies. However, a substantial number of patients exhibit either primary or acquired resistance to rituximab, which suggests that novel immunotherapeutics with distinct mechanisms of action are necessary. A series of monoclonal antibodies with specificity against different surface antigens expressed on malignant B cells (eg, CD22, CD23, CD40, CD70) and novel immunotherapeutics (eg, bispecific monoclonal antibodies, small-modular immunopharmaceuticals, T-cell engagers) are currently in clinical or final preclinical stages of development. Although these agents offer reason for optimism, considerable challenges lie ahead in establishing their real clinical value, as well as in integrating them into current therapeutic algorithms for patients with B-cell malignancies. This review describes some of the most promising investigational immunotherapeutics for the treatment of B-cell malignancies. PMID:20048186

  2. 78 FR 69324 - Revised Medical Criteria for Evaluating Hematological Disorders

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-19

    ... hematological disorders. For example: \\1\\ (50 FR 50068) \\2\\ We published some revisions to the hematological body system on April 24, 2002, and November 15, 2004. See 67 FR 20018 and 69 FR 67017 (corrected at 70 FR 15227). These revisions were not comprehensive; they addressed only specific listings. The...

  3. Hematological profile of sickle cell disease from South Gujarat, India.

    PubMed

    Rao, Sanjeev Shyam; Goyal, Jagdish Prasad; Raghunath, S V; Shah, Vijay B

    2012-05-10

    The aim of this study was to determine hematological profile of sickle cell disease (SCD) from Surat, South Gujarat, India. This prospective cross-sectional study was conducted in the Department of Pediatrics and Sickle Cell Anemia Laboratory, Faculty of Pathology, Government Medical College, Surat, India, between July 2009 and December 2010. Patients included in this study were in their steady state for a long period of time without any symptoms related to SCD or other diseases which could affect the hematological parameters. Venous blood of all patients was collected in ethylenediaminetetraacetic acid and hematological indices were measured. Thirty-three subjects homozygous in all were studied for their hematological parameters for sickle cell anemia. Moderate to severe anemia, low mean cell volume and high foetal hemoglobin dominate the hematological profile of SCD children. PMID:22826798

  4. Hematological profile of sickle cell disease from South Gujarat, India

    PubMed Central

    Rao, Sanjeev Shyam; Goyal, Jagdish Prasad; Raghunath, S.V.; Shah, Vijay B.

    2012-01-01

    The aim of this study was to determine hematological profile of sickle cell disease (SCD) from Surat, South Gujarat, India. This prospective cross-sectional study was conducted in the Department of Pediatrics and Sickle Cell Anemia Laboratory, Faculty of Pathology, Government Medical College, Surat, India, between July 2009 and December 2010. Patients included in this study were in their steady state for a long period of time without any symptoms related to SCD or other diseases which could affect the hematological parameters. Venous blood of all patients was collected in ethylenediaminetetraacetic acid and hematological indices were measured. Thirty-three subjects homozygous in all were studied for their hematological parameters for sickle cell anemia. Moderate to severe anemia, low mean cell volume and high foetal hemoglobin dominate the hematological profile of SCD children. PMID:22826798

  5. Primary malignant melanoma

    PubMed Central

    Mısır, A. Ferhat; Durmuşlar, Mustafa C.; Zerener, Tamer; Gün, Banu D.

    2016-01-01

    Malignant melanomas (MM) of the oral cavity are extremely rare, accounting for 0.2% to 8.0% of all malignant melanomas. Malignant melanomas is more frequently seen at the level of the hard palate and gingiva. Early diagnosis and treatment are important for reducing morbidity. Malignant melanoma cells stain positively with antibodies to human melanoma black 45, S-100 protein, and vimentin; therefore, immunohistochemistry can play an important role in evaluating the depth of invasion and the location of metastases. A 76-year-old man developed an oral malignant melanoma, which was originally diagnosed as a bluish reactive denture hyperplasia caused by an ill-fitting lower denture. The tumor was removed surgically, and histopathological examination revealed a nodular-type MM. There was no evidence of recurrence over a 4-year follow-up period. PMID:27052289

  6. Molecular biology of malignant gliomas.

    PubMed

    Belda-Iniesta, Cristóbal; de Castro Carpeño, Javier; Casado Sáenz, Enrique; Cejas Guerrero, Paloma; Perona, Rosario; González Barón, Manuel

    2006-09-01

    Gliomas are the most common primary brain tumours. In keeping with the degree of aggressiveness, gliomas are divided into four grades, with different biological behaviour. Furthermore, as different gliomas share a predominant histological appearance, the final classification includes both, histological features and degree of malignancy. For example, gliomas of astrocytic origin (astrocytomas) are classified into pilocytic astrocytoma (grade I), astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (GMB) (grade IV). Tumors derived from oligodendrocytes include grade II (oliogodendrogliomas) and grade III neoplasms (oligoastrocytoma). Each subtype has a specific prognosis that dictates the clinical management. In this regard, a patient diagnosed with an oligodendroglioma totally removed has 10-15 years of potential survival. On the opposite site, patients carrying a glioblastoma multiforme usually die within the first year after the diagnosis is made. Therefore, different approaches are needed in each case. Obviously, prognosis and biological behaviour of malignant gliomas are closely related and supported by the different molecular background that possesses each type of glioma. Furthermore, the ability that allows several low-grade gliomas to progress into more aggressive tumors has allowed cancer researchers to elucidate several pathways implicated in molecular biology of these devastating tumors. In this review, we describe classical pathways involved in human malignant gliomas with special focus with recent advances, such as glioma stem-like cells and expression patterns from microarray studies. PMID:17005465

  7. Systemic Sclerosis and Malignancy: A Review of Current Data

    PubMed Central

    Zeineddine, Nabil; Khoury, Lara El; Mosak, Joseph

    2016-01-01

    Systemic sclerosis (SSc) is associated with increased risk of malignancy. The organ systems most commonly affected are the lungs, the breasts and the hematological system. Risk factors predisposing a SSc patient for development of malignancy are not well defined, and the pathogenic basis of the association is yet to be explained. The incidence of malignancies in SSc patients is variable from one report to another, but most importantly, questions regarding the role of immunosuppressive therapies and the effect of autoantibodies have weak or sometimes contradictory answers in most of the currently available literature and physicians have no available guidelines to screen their SSc patients for malignancies. The lack of a concretely defined high-risk profile and the absence of malignancy screening guidelines tailored for SSc patients raise the importance of the need for more studies on the association of SSc and cancer and should incite rheumatology colleges to develop specific recommendations for the clinician to follow while approaching patients with SSc. PMID:27540435

  8. Hypercalcemia of Malignancy: An Update on Pathogenesis and Management

    PubMed Central

    Mirrakhimov, Aibek E.

    2015-01-01

    Hypercalcemia of malignancy is a common finding typically found in patients with advanced stage cancers. We aimed to provide an updated review on the etiology, pathogenesis, clinical presentation, and management of malignancy-related hypercalcemia. We searched PubMed/Medline, Scopus, Embase, and Web of Science for original articles, case reports, and case series articles focused on hypercalcemia of malignancy published from 1950 to December 2014. Hypercalcemia of malignancy usually presents with markedly elevated calcium levels and therefore, usually severely symptomatic. Several major mechanisms are responsible for the development of hypercalcemia of malignancy including parathyroid hormone-related peptide-mediated humoral hypercalcemia, osteolytic metastases-related hypercalcemia, 1,25 Vitamin D-mediated hypercalcemia, and parathyroid hormone-mediated hypercalcemia in patients with parathyroid carcinoma and extra parathyroid cancers. Diagnosis should include the history and physical examination as well as measurement of the above mediators of hypercalcemia. Management includes hydration, calcitonin, bisphosphonates, denosumab, and in certain patients, prednisone and cinacalcet. Patients with advanced underlying kidney disease and refractory severe hypercalcemia should be considered for hemodialysis. Hematology or oncology and palliative care specialists should be involved early to guide the options of cancer targeted therapies and help the patients and their closed ones with the discussion of comfort-oriented care. PMID:26713296

  9. Drugs Approved for Malignant Mesothelioma

    MedlinePlus

    ... Professionals Questions to Ask about Your Treatment Research Drugs Approved for Malignant Mesothelioma This page lists cancer ... in malignant mesothelioma that are not listed here. Drugs Approved for Malignant Mesothelioma Alimta (Pemetrexed Disodium) Pemetrexed ...

  10. The molecular basis of myeloid malignancies

    PubMed Central

    KITAMURA, Toshio; INOUE, Daichi; OKOCHI-WATANABE, Naoko; KATO, Naoko; KOMENO, Yukiko; LU, Yang; ENOMOTO, Yutaka; DOKI, Noriko; UCHIDA, Tomoyuki; KAGIYAMA, Yuki; TOGAMI, Katsuhiro; KAWABATA, Kimihito C.; NAGASE, Reina; HORIKAWA, Sayuri; HAYASHI, Yasutaka; SAIKA, Makoto; FUKUYAMA, Tomofusa; IZAWA, Kumi; OKI, Toshihiko; NAKAHARA, Fumio; KITAURA, Jiro

    2014-01-01

    Myeloid malignancies consist of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasm (MPN). The latter two diseases have preleukemic features and frequently evolve to AML. As with solid tumors, multiple mutations are required for leukemogenesis. A decade ago, these gene alterations were subdivided into two categories: class I mutations stimulating cell growth or inhibiting apoptosis; and class II mutations that hamper differentiation of hematopoietic cells. In mouse models, class I mutations such as the Bcr-Abl fusion kinase induce MPN by themselves and some class II mutations such as Runx1 mutations induce MDS. Combinations of class I and class II mutations induce AML in a variety of mouse models. Thus, it was postulated that hematopoietic cells whose differentiation is blocked by class II mutations would autonomously proliferate with class I mutations leading to the development of leukemia. Recent progress in high-speed sequencing has enabled efficient identification of novel mutations in a variety of molecules including epigenetic factors, splicing factors, signaling molecules and proteins in the cohesin complex; most of these are not categorized as either class I or class II mutations. The functional consequences of these mutations are now being extensively investigated. In this article, we will review the molecular basis of hematological malignancies, focusing on mouse models and the interfaces between these models and clinical findings, and revisit the classical class I/II hypothesis. PMID:25504228

  11. Protein kinase inhibitors against malignant lymphoma

    PubMed Central

    D’Cruz, Osmond J; Uckun, Fatih M

    2013-01-01

    Introduction Tyrosine kinases (TKs) are intimately involved in multiple signal transduction pathways regulating survival, activation, proliferation and differentiation of lymphoid cells. Deregulation or overexpression of specific oncogenic TKs is implicated in maintaining the malignant phenotype in B-lineage lymphoid malignancies. Several novel targeted TK inhibitors (TKIs) have recently emerged as active in the treatment of relapsed or refractory B-cell lymphomas that inhibit critical signaling pathways, promote apoptotic mechanisms or modulate the tumor microenvironment. Areas covered In this review, the authors summarize the clinical outcomes of newer TKIs in various B-cell lymphomas from published and ongoing clinical studies and abstracts from major cancer and hematology conferences. Expert opinion Multiple clinical trials have demonstrated that robust antitumor activity can be obtained with TKIs directed toward specific oncogenic TKs that are genetically deregulated in various subtypes of B-cell lymphomas. Clinical success of targeting TKIs is dependent upon on identifying reliable molecular and clinical markers associated with select cohorts of patients. Further understanding of the signaling pathways should stimulate the identification of novel molecular targets and expand the development of new therapeutic options and individualized therapies. PMID:23496343

  12. Hematologic consequences of exposure to ionizing radiation.

    PubMed

    Dainiak, Nicholas

    2002-06-01

    From the early 1900s, it has been known that ionizing radiation (IR) impairs hematopoiesis through a variety of mechanisms. IR exposure directly damages hematopoietic stem cells and alters the capacity of bone marrow stromal elements to support and/or maintain hematopoiesis in vivo and in vitro. Exposure to IR induces dose-dependent declines in circulating hematopoietic cells not only through reduced bone marrow production, but also by redistribution and apoptosis of mature formed elements of the blood. Recently, the importance of using lymphocyte depletion kinetics to provide a "crude" dose estimate has been emphasized, particularly in rapid assessment of large numbers of individuals who may be exposed to IR through acts of terrorism or by accident. A practical strategy to estimate radiation dose and triage victims based upon clinical symptomatology is presented. An explosion of knowledge has occurred regarding molecular and cellular pathways that trigger and mediate hematologic responses to IR. In addition to damaging DNA, IR alters gene expression and transcription, and interferes with intracellular and intercellular signaling pathways. The clinical expression of these disturbances may be the development of leukemia, the most significant hematologic complication of IR exposure among survivors of the atomic bomb detonations over Japan. Those at greatest risk for leukemia are individuals exposed during childhood. The association of leukemia with chronic, low-dose-rate exposure from nuclear power plant accidents and/or nuclear device testing has been more difficult to establish, due in part to lack of precision and sensitivity of methods to assess doses that approach background radiation dose. Nevertheless, multiple myeloma may be associated with chronic exposure, particularly in those exposed at older ages. PMID:12063018

  13. Analysis of non-clonal chromosome abnormalities observed in hematologic malignancies among Southwest Oncology Group patients

    SciTech Connect

    McConnell, T.S.; Dobin, S.M.

    1994-09-01

    From 1987-1994, the Southwest Oncology Group Cytogenetics Committee reviewed 1571 studies in 590 adult patient cases with ALL, AML, CML or CLL. These were analyzed for the presence of clinically important non-clonal abnormalities (NCA). Abnormalities were defined as non-clonal if one metaphase had a structural abnormality or an extra chromosome. Chromosome loss was not analyzed due to the possibility of random loss. In 72 cases (12%) comprising 136 studies, at least one NCA was observed. In 21 of these cases (29%), NCAs consisted of obvious clonal evolution or instability, and thus were not included in the analysis. At least one structural NCA was observed in which the abnormality differed from the mainline in 36 (50%) patients. Seventeen of the 36 cases had a normal mode. Nineteen of the 36 patients had an abnormal or normal/abnormal mode. At least one numerical NCA was found in 15 cases (21%). Fifteen cases (21%) contained at least one marker chromosome. Several cases involved NCA in more than one of the above divisions. NCAs could be classified into several categories: (1){open_quotes}the clone to come{close_quotes}, (2) evolving clones which then disappeared, (3) NCAs with putative clinical importance that never became clonal, (4) NCAs during remission identical to the preceding clonal abnormality, (5) NCAs which indicated clonal evolution or instability. Examples include one metaphase with t(9;22) or del(20q) or inv(16) or +8 which either preceded or followed clonal findings of the same aberration. Such findings should be communicated to the clinician.

  14. Improved radioimmunotherapy of hematologic malignancies. Progress report, November 1, 1993--October 31, 1994

    SciTech Connect

    Press, O.W.

    1994-08-04

    This report summaries progress made during the time interval between November 1, 1993 and October 31, 1994 and briefly describes studies on the metabolism of antibodies targeting B cell antigens, retention of labeled antibodies by human B cell lymphocytes, and tissue distribution of Chloramine T and tyramine cellobiose labeled antibodies in mice harboring a human erythroleukemia tumor transplant.

  15. Donor T Cells After Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2016-07-20

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

  16. Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2016-07-15

    Acute Biphenotypic Leukemia; Acute Erythroid Leukemia in Remission; Acute Leukemia in Remission; Acute Megakaryoblastic Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; Acute Myeloid Leukemia With FLT3/ITD Mutation; Acute Myeloid Leukemia With Inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1; Acute Myeloid Leukemia With Inv(3)(q21q26.2); RPN1-EVI1; Acute Myeloid Leukemia With Multilineage Dysplasia; Acute Myeloid Leukemia With t(6;9)(p23;q34); DEK-NUP214; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Complete Remission; B Acute Lymphoblastic Leukemia With t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1); B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1; Burkitt Lymphoma; Childhood Acute Lymphoblastic Leukemia in Complete Remission; DS Stage II Plasma Cell Myeloma; DS Stage III Plasma Cell Myeloma; Myelodysplastic Syndrome; Recurrent Anaplastic Large Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma; Secondary Acute Myeloid Leukemia; T Lymphoblastic Lymphoma

  17. Bioengineering targeted nanodrugs for hematologic malignancies: An innovation in pediatric oncology

    NASA Astrophysics Data System (ADS)

    Krishnan, Vinu

    Chemotherapy for pediatric cancers employs combinations of highly toxic drugs. This has achieved 5-year survival rates exceeding 90% in children treated for leukemia -- the most prominent form of pediatric cancer. However, delayed onset of harmful side effects in more than 60% of survivors result in death or low quality of life post therapy. This is primarily due to the non-specific effect of drugs on healthy dividing cells in a growing child. Nanomedicine has advanced tremendously to improve adult cancer therapy, but as yet has had minimal impact in pediatric oncology. There is a pressing need for innovative therapeutic strategies that can reduce life-threatening side effects caused by conventional chemotherapy in the clinic. Targeting chemotherapeutic agents specifically to leukemia cells may alleviate treatment-related toxicity in children. The research objective of this dissertation is to bioengineer and advance preclinically a novel nanotherapeutic approach that can specifically target and deliver drugs into leukemic cells. Dexamethasone (Dex) is one of the most commonly used chemotherapeutic drugs in treating pediatric leukemia. For the first part in this study, we encapsulated Dex in polymeric NPs and validated its anti-leukemic potential in vitro and in vivo. NPs with an average diameter of 110 nm were assembled from an amphiphilic block copolymer of poly(ethylene glycol) (PEG) and poly-caprolactone (PCL) bearing pendant cyclic ketals (ECT2). The blank NPs were nontoxic to cultured cells in vitro and to mice in vivo. Encapsulation of Dex into the NPs (Dex-NP) did not compromise the bioactivity of the drug. Dex-NPs induced glucocorticoid phosphorylation and showed cytotoxicity similar to free drug when treated with leukemic cells. Studies using NPs labeled with fluorescent dyes revealed leukemic cell surface binding and internalization. In vivo biodistribution studies showed NP accumulation in the liver and spleen with subsequent clearance of particles with time. In a preclinical model of leukemia, Dex-NPs significantly improved the quality of life and survival of mice compared to the group treated with free Dex. In the second section, we demonstrate, that doxorubicin (DOX, an anthracycline commonly used in pediatric leukemia therapy) when encapsulated within 80 nm sized NPs and modified with targeting ligands against CD19 (a B-lymbhoblast antigen, CD19-DOX-NPs) can be delivered in a CD19-specific manner to leukemic cells. The CD19-DOX-NPs were internalized via receptor-mediated endocytosis and imparted cytotoxicity in a CD19-dependent manner in CD19 positive (CD19+) leukemic cells. Leukemic mice treated with CD19-DOX-NPs survived significantly longer and manifested a higher degree of agility indicating reduced apparent systemic toxicity during treatment compared to mice treated with free DOX. This study for the first time shows the efficacy of polymeric NPs to target and deliver chemotherapeutic drugs in pediatric oncology and suggests that targeted nanotherapy can potentially improve the therapeutic efficacy of conventional chemotherapy and reduce treatment-related side effects in children.

  18. 78 FR 5186 - Clinical Flow Cytometry in Hematologic Malignancies; Public Workshop; Request for Comments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-24

    ... (77 FR 76051, December 26, 2012). An FDA workshop for acute lymphocytic leukemia (ALL) MRD was held... malfunctions, injuries and deaths related to the use of such reagents to the FDA (62 FR 62260, November 21..., 2013 (77 FR 76050, December 26, 2012). Dated: January 17, 2013. Leslie Kux, Assistant Commissioner...

  19. Ascorbic acid serum levels are reduced in patients with hematological malignancies

    PubMed Central

    Huijskens, Mirelle J.A.J.; Wodzig, Will K.W.H.; Walczak, Mateusz; Germeraad, Wilfred T.V.; Bos, Gerard M.J.

    2016-01-01

    In this paper we demonstrate that patients treated with chemotherapy and/or hematopoietic stem cell transplantation (HSCT) have highly significant reduced serum ascorbic acid (AA) levels compared to healthy controls. We recently observed in in vitro experiments that growth of both T and NK cells from hematopoietic stem cells is positively influenced by AA. It might be of clinical relevance to study the function and recovery of immune cells after intensive treatment, its correlation to AA serum levels and the possible effect of AA supplementation. PMID:27014565

  20. Sirolimus and Mycophenolate Mofetil in Preventing GVHD in Patients With Hematologic Malignancies Undergoing HSCT

    ClinicalTrials.gov

    2016-06-14

    Adult Hodgkin Lymphoma; Adult Myelodysplastic Syndrome; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Hodgkin Lymphoma; Childhood Myelodysplastic Syndrome; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Myelofibrosis; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Non-Hodgkin Lymphoma

  1. A Phase 1 Dose Escalation Study of TAK-901 in Subjects With Advanced Hematologic Malignancies

    ClinicalTrials.gov

    2013-07-01

    Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Chronic Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Multiple Myeloma; Waldenstrom's Macroglobulinemia; Myelodysplastic Syndrome; Philadelphia Chromosome-negative CML; Myeloid Metaplasia; Myelofibrosis; Advanced Polycythemia; Non-Hodgkins Lymphoma

  2. Ipilimumab or Nivolumab in Treating Patients With Relapsed Hematologic Malignancies After Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-08-24

    Myeloproliferative Neoplasm; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Hodgkin Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Plasma Cell Myeloma

  3. Outcomes of Hematological Malignancies after Unrelated Donor Hematopoietic-Cell Transplantation According to Place of Residence

    PubMed Central

    Loberiza, Fausto R; Lee, Stephanie J; Klein, John P; Hassebroek, Anna; Dehn, Jason G; Frangoul, Haydar A; Hahn, Theresa; Hale, Gregory; Lazarus, Hillard M; LeMaistre, Charles F; Maziarz, Richard T; Rizzo, J Douglas; Majhail, Navneet S

    2009-01-01

    Studies suggest that patients who live in rural areas may have worse clinical outcomes compared with patients living in urban areas. We studied whether place of residence (rural vs. urban) is associated with clinical outcomes of patients with leukemia or myelodysplastic syndrome who received an unrelated donor hematopoietic-cell transplantation (HCT). Patients’ residential ZIP code at the time of transplant was used to determine rural or urban designation based on the Rural Urban Commuting Codes. The study included 6140 patients reported to the Center for International Blood and Marrow Transplant Research from 121 US HCT centers: 1179 (19%) came from rural areas while 4961 (81%) came from urban areas. Rural and urban patients were similar in patient-, disease- and transplant-related characteristics aside from household income and distance travelled to HCT center. After adjusting for income and other significant patient, disease and transplant-related variables, the risk of overall mortality between patients residing in rural and urban areas were not statistically significant (relative risk 1.01, 95% confidence intervals 0.93–1.10, p=0.74). Similar outcomes were noted for transplant-related mortality, disease-free survival and relapse. Patient’s income, derived from US Census and based on their residential ZIP code, was independently associated with outcomes. In summary, our study showed no differences in the clinical outcomes of patients from rural or urban areas after unrelated donor HCT. PMID:19879951

  4. Study Evaluating AMD3100 for Transplantation of Sibling Donor Stem Cells in Patients With Hematological Malignancies

    ClinicalTrials.gov

    2013-08-09

    Leukemia, Myeloid, Acute; Leukemia, Myelogenous, Chronic; Leukemia, Lymphoblastic, Acute; Lymphocytic Leukemia, Chronic; Myelodysplastic Syndromes; Multiple Myeloma; Lymphoma, Non-Hodgkin; Hodgkin Disease

  5. A Two-Step Approach to Reduced Intensity Bone Marrow Transplant for Patients With Hematological Malignancies

    ClinicalTrials.gov

    2016-08-17

    Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Aplastic Anemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Essential Thrombocythemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Juvenile Myelomonocytic Leukemia; Mastocytosis; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Anemia; Refractory Anemia With Ringed Sideroblasts; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Waldenström Macroglobulinemia

  6. Donor Umbilical Cord Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2015-12-18

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Erythroleukemia (M6a); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Pure Erythroid Leukemia (M6b); B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Burkitt Lymphoma; Childhood Acute Erythroleukemia (M6); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Juvenile Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Secondary Myelofibrosis; Splenic Marginal Zone Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; Waldenstrom Macroglobulinemia

  7. Deferasirox in Treating Iron Overload Caused By Blood Transfusions in Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2014-12-09

    Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Langerhans Cell Histiocytosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Mast Cell Leukemia; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Myeloid/NK-cell Acute Leukemia; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Anemia; Refractory Multiple Myeloma; Secondary Acute Myeloid Leukemia; Secondary Myelofibrosis; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Testicular Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Waldenstrom Macroglobulinemia

  8. Methoxyamine and Fludarabine Phosphate in Treating Patients With Relapsed or Refractory Hematologic Malignancies

    ClinicalTrials.gov

    2015-08-12

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage III Chronic Lymphocytic Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

  9. Vaccine Therapy in Preventing Cytomegalovirus Infection in Patients With Hematological Malignancies Undergoing Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-05-27

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Promyelocytic Leukemia (M3); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Nodular Lymphocyte Predominant Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; B-cell Adult Acute Lymphoblastic Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cytomegalovirus Infection; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Isolated Plasmacytoma of Bone; Monoclonal Gammopathy of Undetermined Significance; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Central Nervous System Hodgkin Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Primary Myelofibrosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Multiple Myeloma; Stage I Small Lymphocytic Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cu

  10. Self-Regulatory Fatigue, Quality of Life, Health Behaviors, and Coping in Patients with Hematologic Malignancies

    PubMed Central

    Ehlers, Shawna L.; Patten, Christi A.; Gastineau, Dennis A.

    2015-01-01

    Background Self-regulatory fatigue may play an important role in a complex medical illness. Purpose Examine associations between self-regulatory fatigue, quality of life, and health behaviors in patients pre- (N=213) and 1-year post-hematopoietic stem cell transplantation (HSCT; N=140). Associations between self-regulatory fatigue and coping strategies pre-HSCT were also examined. Method Pre- and 1-year post-HSCT data collection. Hierarchical linear regression modeling. Results Higher self-regulatory fatigue pre-HSCT associated with lower overall, physical, social, emotional, and functional quality of life pre- (p’s<.001) and 1-year post-HSCT (p’s<.01); lower physical activity pre-HSCT (p<.02) and post-HSCT (p<.03) and less healthy nutritional intake post-HSCT (p<.01); changes (i.e., decrease) in quality of life and healthy nutrition over the follow-up year; and use of avoidance coping strategies pre-HSCT (p’s<.001). Conclusion This is the first study to show self-regulatory fatigue pre-HSCT relating to decreased quality of life and health behaviors, and predicting changes in these variables 1-year post-HSCT. PMID:24802991

  11. Mismatched Family Member Donor Transplantation for Children and Young Adults With High Risk Hematological Malignancies

    ClinicalTrials.gov

    2016-05-03

    Leukemia, Acute Lymphocytic (ALL); Leukemia, Myeloid, Acute(AML); Leukemia, Myeloid, Chronic(CML); Juvenile Myelomonocytic Leukemia (JMML); Hemoglobinuria, Paroxysmal Nocturnal (PNH); Hodgkin Lymphoma; Lymphoma, Non-Hodgkin (NHL); Myelodysplastic Syndrome (MDS)

  12. 3-AP and High-Dose Cytarabine in Treating Patients With Advanced Hematologic Malignancies

    ClinicalTrials.gov

    2013-01-23

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia

  13. Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy.

    PubMed

    Ammann, Eric M; Jones, Michael P; Link, Brian K; Carnahan, Ryan M; Winiecki, Scott K; Torner, James C; McDowell, Bradley D; Fireman, Bruce H; Chrischilles, Elizabeth A

    2016-01-14

    In patients with hypogammaglobulinemia secondary to chronic lymphocytic leukemia (CLL) or multiple myeloma (MM), intravenous immune globulin (IVIg) may be administered to reduce the risk of infection. Since 2013, IVIg products have carried a boxed safety warning about the risk of thromboembolic events (TEEs), with TEEs reported in 0.5% to 15% of patients treated with IVIg. In this retrospective cohort study of older patients with CLL or MM identified from the Surveillance, Epidemiology, and End Results-Medicare Linked Database, we assessed rates of clinically serious TEEs in 2724 new users of IVIg and a propensity-matched comparison group of 8035 nonusers. For the primary end point, arterial TEE, we observed a transient increased risk of TEE during the day of an IVIg infusion and the day afterward (hazard ration = 3.40; 95% confidence interval [CI]: 1.25, 9.25); this risk declined over the remainder of the 30-day treatment cycle. When considered in terms of absolute risk averaged over a 1-year treatment period, the increase in risk attributable to IVIg was estimated to be 0.7% (95% CI: -0.2%, 2.0%) compared with a baseline risk of 1.8% for the arterial TEE end point. A statistically nonsignificant risk increase of 0.3% (95% CI: -0.4%, 1.5%) compared with a baseline risk of 1.1% was observed for the venous TEE end point. Further research is needed to establish the generalizability of these results to patients receiving higher doses of IVIg for other indications. PMID:26443622

  14. Safety and Tolerability of HSC835 in Patients With Hematological Malignancies

    ClinicalTrials.gov

    2016-02-02

    Acute Myelocytic Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome; Chronic Lymphocytic Leukemia; Marginal Zone Lymphoma; Follicular Lymphomas; Large-cell Lymphoma; Lymphoblastic Lymphoma; Burkitt's Lymphoma; High Grade Lymphomas; Mantle-cell Lymphoma; Lymphoplasmacytic Lymphoma

  15. Immunological recovery in 48 patients following syngeneic marrow transplantation for hematological malignancy. [/sup 60/Co

    SciTech Connect

    Whiterspoon R.P.; Kopecky, K.; Storb, R.F.

    1982-02-01

    Immunological function of 48 syngeneic transplant patients prepared with 120 mg of cyclophosphamide per kg and 9.2 to 12.0 Gy (920 to 1000 rad) total body irradiation was compared with that of 153 allogeneic recipients. Lymphocyte counts and T cell numbers in syngeneic recipients were low during the first post-transplant month but higher than those of allogeneic recipients. Serum immunoglobulin levels in syngeneic recipients were normal by completion of the first post-transplantation month and were higher than allogeneic recipients at that time. Total hemolytic complement (CH/sub 50/) and third (C3) and fourth (C4) components were normal throughout the post-transplantation course in both groups of patients. Antibody production to primary injection of bacteriophage THETAX174 (Phage) was low in both syngeneic and allogeneic recipients during the first post-transplantation month and rose gradually thereafter. Some syngeneic recipients failed to produce normal amounts of IgG in their secondary response to phage. Antibody production after primary and secondary injection of keyhole limpet hemocyanin or pneumococcal polysaccharide was lower than normal early after grafting and rose later, comparable to that seen in allogeneic recipients. We conclude that immunological recovery in syngeneic recipients is very similar to recovery in allogeneic recipients except in the first month postgrafting where twins are slightly better than allogeneic recipients for lymphocyte and immunoglobulin levels. Other mechanisms than those listed here must play an important role in protecting the syngeneic marrow graft recipient from opportunistic infection. (JMT)

  16. Vorinostat, Tacrolimus, and Methotrexate in Preventing GVHD After Stem Cell Transplant in Patients With Hematological Malignancies

    ClinicalTrials.gov

    2015-10-13

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Graft Versus Host Disease; Intraocular Lymphoma; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Post-transplant Lymphoproliferative Disorder; Primary Central Nervous System Hodgkin Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Ringed Sideroblasts; Refractory Chronic Lymphocytic Leukemia; Refractory Cytopenia With Multilineage Dysplasia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Central Nervous System Hodgkin Lymphoma; Secondary Central Nervous System Non-Hodgkin Lymphoma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell L

  17. Repeat Transplantation for Relapsed or Refractory Hematologic Malignancies Following Prior Transplantation

    ClinicalTrials.gov

    2016-05-03

    Acute Lymphoblastic Leukemia (ALL); Acute Myeloid Leukemia (AML); Myeloid Sarcoma; Chronic Myelogenous Leukemia (CML); Juvenile Myelomonocytic Leukemia (JMML); Myelodysplastic Syndrome (MDS); Non-Hodgkin Lymphoma (NHL)

  18. Altered expression of p53 and MDM2 proteins in hematological malignancies.

    PubMed

    Koníková, E; Kusenda, J

    2003-01-01

    In order to define the possible role of the MDM2 gene in the pathogenesis of human leukemia, the expression of MDM2 protein was examined in samples of fixed-permeabilized peripheral blood (PB) or bone marrow (BM) cells of leukemic patients by using flow cytometry. The present study showed, that normal PB and BM cells expressed low levels of MDM2. Overexpression of this protein was more frequently found in leukemic cells, namely in samples of patients with advanced, than those in incipient clinical stage of disease at examination. Of the 34 leukemias tested in our laboratory 24 (70%) showed abnormal expression of the MDM2 protein. This include 8/12 (66%) ALL, 10/13 (76%) B-CLL, and 6/9 (66%) AML. Since MDM2 and p53 are functionally related and overexpression of MDM2 can abrogate wild (wt)-p53 tumor suppressive function, we examined simultaneously with MDM2 protein expression also the expression of both wt-p53 and mutant (mt)-p53 with two MoAbs (Ab5 and Pab240). As measured by flow cytometry only a small part of the observed wt-p53 protein was in true wt-conformation (Ab5+), while most was in mt-conformation (Pab240+), which could mean, that most of the p53 protein in the cells was not functional, as in its usual role as a suppressor of the cell cycle. The MDM2 positive cases were negative for p53 (Pab240-) in hematopoietic cells of patients with B- and T-ALL at diagnosis and in relapsed disease. Samples of patients in remission with immunophenotype of normal cells were p53 and MDM2 negative. The expression of Ki67 antigen a nuclear protein associated with cell proliferation was used to verify the proliferative activity of the leukemic cells. Results of the two-color flow cytometric assay, which allows better definition of pathologic cell populations and nuclear fluorescence data for p53, MDM2 or Ki67 on a population of cells expressing only a given surface blast marker, confirmed their coexpression in the same cell. Our preliminary results supported the view that the expression of p53 is very probably involved in the regulation of leukemic hematopoiesis and that the inhibition of p53 expression could modulate the proliferation of leukemic cells. It appears, that MDM2 overexpression, which may be p53-dependent, or also p53-independent plays an important role in leukemogenesis and/or disease progression. PMID:12687276

  19. Cryoglobulinemia as an Initial Manifestation of Underlying Hematological Malignancy: A Rare Occurrence in India

    PubMed Central

    Kumar, Narender; Das, Reena; Chandra, Dinesh; Malhotra, Pankaj

    2014-01-01

    Cryoglobulinemias rarely been reported from India even though associated conditions such as hepatitis C infection, rheumatoid arthritis and plasma cell dyscrasias, etc., are common occurrences. In many regions of the country, temperatures in winter can be conducive to the precipitation of cryoglobulins, yet epidemiology of the disease suggests that it is a common condition in the west. We encountered a 68-year-old-male patient who presented with a history of headache off and on along with hepatosplenomegaly. The rare occurrence of cryoglobulinemia in our setting can delay the diagnosis, as happened in our case, since the index of suspicion of clinicians and laboratory personnel is low. We are reporting this case because of the rarity and protean clinical manifestations of cryoglobulinemia. PMID:25328341

  20. Neoplastic meningitis resulting from hematological malignancies: pharmacokinetic considerations and maximizing outcome

    PubMed Central

    Grewal, Jai; Saria, Marlon; Grewal, Harpreet K; Kesari, Santosh

    2012-01-01

    Neoplastic meningitis, also known as leptomeningeal metastases, is a complication of various types of cancer that occurs when tumor cells enter the cerebrospinal fluid (CSF), travel along CSF pathways and grow. Treatment options include drug delivery directly into the CNS or systemic administration for targeted action in the CNS. CNS drug delivery is limited by the blood–brain barrier and the blood–CSF barrier. It may be possible to partially overcome this by using high-dose systemic therapy; however, this is done at the possible expense of increased systemic toxicity. Intra-CSF drug delivery bypasses the blood–brain barrier and allows direct access of the chemotherapeutic agent to the CSF. Because neoplastic meningitis occurs in an increasingly large percentage of all cancer patients, it is imperative to optimize drug delivery to the CSF and meninges. Both the pharmacokinetic profile of the chemotherapeutic agent and the site of administration influence therapeutic efficacy. Achieving prolonged therapeutic cytotoxic drug concentrations and even distribution in the CSF will improve efficacy. In this article we summarize data on the efficacy, safety and outcome of high-dose systemic and intra-CSF treatments. PMID:22396850

  1. Central Nervous System Disease in Hematological Malignancies: Historical Perspective and Practical Applications

    PubMed Central

    Pui, Ching-Hon; Thiel, Eckhard

    2009-01-01

    Acute lymphoblastic leukemia (ALL) 5-year survival rates are approaching 90% in children and 50% in adults who are receiving contemporary risk-directed treatment protocols. Current efforts focus not only on further improving cure rate but also on patient quality of life. Hence, all protocols decrease or limit the use of cranial irradiation as central nervous system (CNS)-directed therapy, even in patients with high-risk presenting features, such as the presence of leukemia cells in the cerebrospinal fluid (even resulting from traumatic lumbar puncture), adverse genetic features, T-cell immunophenotype, and a large leukemia-cell burden. Current strategies for CNS-directed therapy involve effective systemic chemotherapy (eg, dexamethasone, high-dose methotrexate, intensive asparaginase, ifosfamide) and early intensification and optimization of intrathecal therapy. Options under investigation for the treatment of relapsed or refractory CNS leukemia in ALL patients include thiotepa and intrathecal liposomal cytarabine. CNS involvement in non-Hodgkin’s lymphoma (NHL) is associated with young age, advanced stage, number of extranodal sites, elevated lactate dehydrogenase, and International Prognostic Index score. Refractory CNS lymphoma in patients with NHL carries a poor prognosis, with a median survival of 2 to 6 months; the most promising treatment, autologous stem cell transplant, can extend median survival from 10 to 26 months. CNS prophylaxis is required during the initial treatment of NHL subtypes that carry a high risk of CNS relapse, such as B-cell ALL, Burkitt’s lymphoma, and lymphoblastic lymphoma. The use of CNS prophylaxis in the treatment of diffuse large B-cell lymphoma is controversial because of the low risk of CNS relapse (~5%) in this population. In this article, we review current and past practice of intrathecal therapy in ALL and NHL and the risk-models that aim to identify predictors of CNS relapse in NHL. PMID:19660680

  2. Malignant melanoma maxilla

    PubMed Central

    Devi, Seema; Sinha, Richi; Singh, Rakesh Kumar

    2015-01-01

    A malignant melanoma is a highly lethal melanocytic neoplasm. A neoplasm usually affects the skin. Malignant melanomas in the head and neck region are rare, accounting for less than 1% of all melanomas. Malignant melanoma of the nose and paranasal sinuses is an aggressive disease typically presenting at an advanced stage, with a 5-year survival rate ranging 20-30%. Melanomas are tumors arising from melanocytes, which are neuroectodermally derived cells located in the basal layers of the skin. This is a case report of a 35-year-old male, who presented with very aggressive disease and developed liver metastasis. PMID:26668467

  3. Procaine in Malignant Hyperpyrexia

    PubMed Central

    Moulds, R. F. W.; Denborough, M. A.

    1972-01-01

    The caffeine contracture of normal human muscle, which has been used as a model for malignant hyperpyrexia, is greatly potentiated by halothane. Prior administration of procaine markedly reduces the halothane-potentiated caffeine contracture, and procaine given at the height of the contracture induces relaxation. Lignocaine, on the other hand, produces a variable response and sometimes increases the contracture. The muscle from a patient with an inherited susceptibility to malignant hyperpyrexia contracted spontaneously with halothane alone, and this contracture was reversed by procaine. These experiments support the therapeutic use of procaine in malignant hyperpyrexia. PMID:4642792

  4. Value of Nerve Biopsy in Patients With Latent Malignant Hemopathy and Peripheral Neuropathy

    PubMed Central

    Duchesne, Mathilde; Mathis, Stéphane; Corcia, Philippe; Richard, Laurence; Ghorab, Karima; Jaccard, Arnaud; Magy, Laurent; Vallat, Jean-Michel

    2015-01-01

    Abstract Hematological malignancies include several diseases that may affect the peripheral nervous system (PNS) through various mechanisms. A common and challenging situation is represented by the occurrence of an active peripheral neuropathy in a patient with a supposed inactive hematological disorder. We report clinical, electrophysiological, biological, and pathological data of 8 patients with latent malignant hemopathies (most were considered in remission): B-cell chronic lymphocytic leukemia in 3 patients, B-cell lymphoma in 1 patient, low-grade non-Hodgkin's lymphoma in 1 patient, Waldenström's macroglobulinemia in 1 patient, smoldering multiple myeloma in 1 patient, and monoclonal gammopathy of undetermined significance in 1 patient. In all these cases, the nerve biopsy (NB) helped to diagnose the hematological relapse or detect a pathological mechanism linked to the hematological disorder: epineurial lymphocytic infiltration in 5 patients (including one with antimyelin-associated glycoprotein antibodies), cryoglobulin deposits in 1 patient, chronic inflammatory demyelinating polyneuropathy in 1 patient, and necrotizing vasculitis in 1 patient. In each case, pathological findings were crucial to select the adequate treatment, leading to an improvement in the neurological and biological manifestations. These observations illustrate the value of NB and the need for active collaboration between neurologists and hematologists in such cases. PMID:25621682

  5. Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies.

    PubMed

    Lewinsohn, Maya; Brown, Anna L; Weinel, Luke M; Phung, Connie; Rafidi, George; Lee, Ming K; Schreiber, Andreas W; Feng, Jinghua; Babic, Milena; Chong, Chan-Eng; Lee, Young; Yong, Agnes; Suthers, Graeme K; Poplawski, Nicola; Altree, Meryl; Phillips, Kerry; Jaensch, Louise; Fine, Miriam; D'Andrea, Richard J; Lewis, Ian D; Medeiros, Bruno C; Pollyea, Daniel A; King, Mary-Claire; Walsh, Tom; Keel, Siobán; Shimamura, Akiko; Godley, Lucy A; Hahn, Christopher N; Churpek, Jane E; Scott, Hamish S

    2016-02-25

    Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical. PMID:26712909

  6. Nurses’ Health Study Contributions on the Epidemiology of Less Common Cancers: Endometrial, Ovarian, Pancreatic, and Hematologic

    PubMed Central

    Barnard, Mollie E.; Bertrand, Kimberly A.; Bao, Ying; Crous-Bou, Marta; Wolpin, Brian M.; De Vivo, Immaculata; Tworoger, Shelley S.

    2016-01-01

    Objectives. To review the contributions of the Nurses’ Health Study (NHS) to epidemiologic knowledge of endometrial, ovarian, pancreatic, and hematologic cancers. Methods. We reviewed selected NHS publications from 1976 to 2016, including publications from consortia and other pooled studies. Results. NHS studies on less common cancers have identified novel risk factors, such as a reduced risk of endometrial cancer in women of advanced age at last birth, and have clarified or prospectively confirmed previously reported associations, including an inverse association between tubal ligation and ovarian cancer. Through biomarker research, the NHS has furthered understanding of the pathogenesis of rare cancers, such as the role of altered metabolism in pancreatic cancer risk and survival. NHS investigations have also demonstrated the importance of the timing of exposure, such as the finding of a positive association of early life body fatness, but not of usual adult body mass index, with non-Hodgkin lymphoma risk. Conclusions. Evidence from the NHS has informed prevention strategies and contributed to improved survival from less common but often lethal malignancies, including endometrial, ovarian, pancreatic, and hematologic cancers. PMID:27459458

  7. Therapeutic radiation and the potential risk of second malignancies.

    PubMed

    Kamran, Sophia C; Berrington de Gonzalez, Amy; Ng, Andrea; Haas-Kogan, Daphne; Viswanathan, Akila N

    2016-06-15

    Radiation has long been associated with carcinogenesis. Nevertheless, it is an important part of multimodality therapy for many malignancies. It is critical to assess the risk of secondary malignant neoplasms (SMNs) after radiation treatment. The authors reviewed the literature with a focus on radiation and associated SMNs for primary hematologic, breast, gynecologic, and pediatric tumors. Radiation appeared to increase the risk of SMN in all of these; however, this risk was found to be associated with age, hormonal influences, chemotherapy use, environmental influences, genetic predisposition, infection, and immunosuppression. The risk also appears to be altered with modern radiotherapy techniques. Practitioners of all specialties who treat cancer survivors in follow-up should be aware of this potential risk. Cancer 2016;122:1809-21. © 2016 American Cancer Society. PMID:26950597

  8. Transfusions for anemia in adult and pediatric patients with malignancies.

    PubMed

    Shah, Neil; Andrews, Jennifer; Goodnough, Lawrence Tim

    2015-09-01

    Anemia is present in over two-thirds of patients with malignant hematological disorders. The etiology of anemia predominates from ineffective erythropoiesis from marrow infiltration, cytokine related suppression, erythropoietin suppression, and vitamin deficiency; ineffective erythropoiesis is further exacerbated by accelerated clearance due to antibody mediated hemolysis and thrombotic microangiopathy. As the anemia is chronic in nature, symptoms are generally well tolerated and often non-specific. Transfusion of red blood cells (RBCs) is a balance between providing benefit for patients while avoiding risks of transfusion. Conservative/restrictive RBC transfusion practices have shown equivalent patient outcomes compared to liberal transfusion practices, and meta-analysis has shown improved in-hospital mortality, reduced cardiac events, re-bleeding, and bacterial infections. The implications for a lower threshold for transfusion in patients with malignancies are therefore increasingly being scrutinized. Alternative management strategies for anemia with IV iron and erythropoietin stimulating agents (ESAs) should be considered in the appropriate settings. PMID:25796130

  9. Nelarabine in the Treatment of Refractory T-Cell Malignancies

    PubMed Central

    Roecker, Andrew M.; Stockert, Amy; Kisor, David F.

    2010-01-01

    Nelarabine is a nucleoside analog indicated for the treatment of adult and pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) that is refractory or has relapsed after treatment with at least two chemotherapy regimens. After being first synthesized in the late 1970s and receiving FDA approval in 2005, the appropriate use of nelarabine for refractory hematologic malignancies is still being elucidated. Nelarabine is the prodrug of 9-β-D-arabinofuranosylguanine (ara-G) which when phosphorylated intracellularly to ara-G triphosphate (ara-GTP), preferentially accumulates in cancerous T-cells. Dose-dependent toxicities, including neurotoxicity and myelosuppression, have been documented and may, in turn, limit the ability to appropriately treat the diagnosed malignancy. This article will summarize the pharmacologic properties of nelarabine and will address the current place in therapy nelarabine holds based upon the results of the available clinical trials to date. PMID:21151585

  10. Profile of pacritinib and its potential in the treatment of hematologic disorders

    PubMed Central

    Hatzimichael, Eleftheria; Tsolas, Evangelos; Briasoulis, Evangelos

    2014-01-01

    Pacritinib (previously known as SB-1518) is an innovative selective inhibitor of Janus kinase 2 and FMS-related tyrosine kinase 3 providing potential in the treatment of hematological malignancies such as myeloproliferative neoplasias, acute myeloid leukemia, and various lymphomas. Pacritinib has potent antiproliferative activity in Janus kinase 2 and/or FMS-related tyrosine kinase 3 activity-dependent cell lines and an ability to promote apoptosis and inhibit the signal transducers and activators of transcription (STAT) pathway. Pharmacokinetic studies have indicated a good per os bioavailability and favorable kinetic parameters. To date, promising results have been produced in five completed early-phase clinical trials in which pacritinib has been studied. Pacritinib displayed interesting activity and an acceptable safety profile, with mild to moderate gastrointestinal disorders being its most common adverse effects. PMID:25170285

  11. Cancer stem-like cells: the dark knights of clinical hematology and oncology.

    PubMed

    Frinc, Ioana; Muresan, Mihai-Stefan; Zaharie, Florin; Petrov, Ljubomir; Irimie, Alexandra; Berce, Cristian; Berindan-Neagoe, Ioana; Tomuleasa, Ciprian

    2014-01-01

    According to recent epidemiological studies, malignant diseases represent the second cause of mortality worldwide and metastasis is the main cause of morbidity and mortality in most cancers. Even if the concept of "cancer stem cells" (CSCs) was anticipated by the genius of Rudolph Virchow, the father of modern pathology, more than 150 years ago, it is only in last few years that that scientists have begun to develop strategies aimed at inhibiting CSCs at a molecular level, the only way cancer can truly be attacked, by crossing the border between histology and molecular biology. The current concise review aims at emphasizing the main characteristics of tumor initiating cells, bridging the basic science to clinical hematology and oncology. PMID:24965388

  12. Panuveal malignant mesenchymoma.

    PubMed

    Pe'er, J; Neudorfer, M; Ron, N; Anteby, I; Lazar, M; Rosenmann, E

    1995-09-01

    Intraocular malignant mesenchymal tumors are very rare, and only a few case reports of such primary and metastatic tumors have been reported. We report a case of a malignant mesenchymoma involving the entire uveal tract. A 21-year-old woman presented with a tumor on the whole iris of the right eye, which caused intractable glaucoma. Upon enucleation of the eye, a very anaplastic tumor was found to occupy the whole uveal tract; its features were compatible with a tumor of mesenchymal origin, including rhabdomyosarcomatous and liposarcomatous characteristics. Choroidal osteoma was a coincidental finding. The histologic findings of the tumor were of two types of malignant mesenchymal tumors, and therefore the diagnosis of malignant mesenchymoma was made. This is to our knowledge the first tumor of its kind to be reported intraocularly. PMID:7668945

  13. [Rheumatoid arthritis and malignancy].

    PubMed

    Kameda, Tomohiro; Dobashi, Hiroaki

    2016-06-01

    Rheumatoid arthritis (RA) is associated with excess mortality. Especially, malignancy is a major cause of mortality. According to previous reports, the overall incidence of malignancies in RA patients has been reported to be comparable or slightly higher than that in general population. The increased incidence of malignant lymphoma and lung cancer has been reported to be consistent in most studies. The use of some csDMARD was also reported as risk factors for malignancy. Recently, MTX associated lymphoproliferative disorder(MTX-LPD) is one of the important complications in RA treatment. We revealed the mean MTX dose was demonstrated to be an independent risk factor regarding MTX-LPD onset in RA patients. This data suggest that the treatment with higher MTX dose promotes LPD onset in Japanese RA patients. PMID:27311195

  14. Gynecologic malignancy in pregnancy

    PubMed Central

    Ji, Yong Il

    2013-01-01

    Gynecologic malignancy during pregnancy is a stressful problem. For the diagnosis and treatment of malignancy during pregnancy, a multidisciplinary approach is needed. Patients should be advised about the benefits and risk of treatment. When selecting a treatment for malignancy during pregnancy, the physiologic changes that occur with the pregnancy should be considered. Various diagnostic procedures that do not harm the fetus can be used. Laparoscopic surgery or laparotomy may be safely performed. The staging approach and treatment should be standard. Systemic chemotherapy during the first trimester should be delayed if possible. Radiation therapy should preferably start postpartum. Although delivery should be delayed preferably until after 35 weeks of gestation, termination of pregnancy may be considered when immediate treatment is required. Subsequent pregnancies do not increase the risk of malignancy recurrence. PMID:24328018

  15. Chemoembolization of hepatic malignancy.

    PubMed

    Gonsalves, Carin F; Brown, Daniel B

    2009-01-01

    Treatment of primary and secondary hepatic malignancies with transarterial chemoembolization represents an essential component of interventional oncology. This article discusses patient selection, procedure technique, results, and complications associated with transarterial chemoembolization. PMID:18668189

  16. Anemia in the elderly: a public health crisis in hematology.

    PubMed

    Guralnik, Jack M; Ershler, William B; Schrier, Stanley L; Picozzi, Vincent J

    2005-01-01

    Over 3 million people in the United States aged 65 years and older are anemic. This condition is associated with significant functional impairment and, perhaps, increased mortality. In March 2004, the American Society of Hematology (in conjunction with the National Institute of Aging) convened a "blue ribbon" panel of twenty physicians who are experts on various aspects of this topic. This paper highlights important consensus concepts resulting from that meeting. In particular, four areas of thought are shared. First, the epidemiology of anemia in the elderly is reviewed, including its definition, its expression in different racial groups, and its wide-ranging manifestations. Second, the pathophysiology of anemia in the elderly is reviewed as pertains to three general etiological categories (nutritional, chronic diseases, and so-called "unexplained" anemias). Particular emphasis is given to pathophysiologic mechanisms of anemia that are potentially unique to this age group. Third, a practical approach to the diagnosis and management of anemia for this patient population for the practicing hematologist is provided. Finally, the public health implications of anemia in the elderly for key stakeholder constituencies will be discussed in the oral presentation. PMID:16304431

  17. Effect of Combined Fluoroquinolone and Azole Use on QT Prolongation in Hematology Patients

    PubMed Central

    Wilson, John W.; Estes, Lynn L.

    2013-01-01

    QTc prolongation is a risk factor for development of torsades de pointes (TdP). Combination therapy with fluoroquinolones and azoles is used in patients with hematologic malignancies for prophylaxis and treatment of infection. Both drug classes are implicated as risk factors for QTc prolongation. The cumulative effect on and incidence of QTc prolongation for this combination have not been previously described. A retrospective chart review was performed with hospitalized inpatients from 1 September 2008 to 31 January 2010 comparing QTc interval data from electrocardiogram (ECG) assessment at baseline and after the initiation of combination therapy. Ninety-four patients were eligible for inclusion. The majority, 88 patients (93.6%), received quinolone therapy with levofloxacin. Fifty-three patients (56.4%) received voriconazole; 40 (42.6%) received fluconazole. The overall mean QTc change from baseline was 6.1 (95% confidence interval [CI], 0.2 to 11.9) ms. Twenty-one (22.3%) of the studied patients had clinically significant changes in the QTc while receiving combination fluoroquinolone-azole therapy. Statistically significant risk factors for clinically significant changes in QTc were hypokalemia (P = 0.03) and a left-ventricular ejection fraction of <55% (P = 0.02). Low magnesium (P = 0.11), exposure to 2 or more drugs with the potential to prolong the QTc interval (P = 0.17), and female sex (P = 0.21) trended toward significance. Combination therapy with fluoroquinolone and azole antifungals is associated with increased QTc from baseline in hospitalized patients with hematologic malignancies. One in five patients had a clinically significant change in the QTc, warranting close monitoring and risk factor modification to prevent the possibility of further QTc prolongation and risk of TdP. PMID:23229485

  18. The Malignant Protein Puzzle.

    PubMed

    Walker, Lary C; Jucker, Mathias

    2016-01-01

    When most people hear the words malignant and brain, cancer immediately comes to mind. But our authors argue that proteins can be malignant too, and can spread harmfully through the brain in neurodegenerative diseases that include Alzheimer's, Parkinson's, CTE, and ALS. Studying how proteins such as PrP, amyloid beta, tau, and others aggregate and spread, and kill brain cells, represents a crucial new frontier in neuroscience. PMID:27408676

  19. Sorafenib Tosylate in Treating Patients With Malignant Mesothelioma.

    ClinicalTrials.gov

    2013-06-04

    Epithelial Mesothelioma; Recurrent Malignant Mesothelioma; Sarcomatous Mesothelioma; Stage IA Malignant Mesothelioma; Stage IB Malignant Mesothelioma; Stage II Malignant Mesothelioma; Stage III Malignant Mesothelioma; Stage IV Malignant Mesothelioma

  20. Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies.

    PubMed

    Matthews, Geoffrey M; Mehdipour, Parinaz; Cluse, Leonie A; Falkenberg, Katrina J; Wang, Eric; Roth, Mareike; Santoro, Fabio; Vidacs, Eva; Stanley, Kym; House, Colin M; Rusche, James R; Vakoc, Christopher R; Zuber, Johannes; Minucci, Saverio; Johnstone, Ricky W

    2015-11-19

    Histone deacetylase (HDAC) inhibitors (HDACis) have demonstrated activity in hematological and solid malignancies. Vorinostat, romidepsin, belinostat, and panobinostat are Food and Drug Administration-approved for hematological malignancies and inhibit class II and/or class I HDACs, including HDAC1, 2, 3, and 6. We combined genetic and pharmacological approaches to investigate whether suppression of individual or multiple Hdacs phenocopied broad-acting HDACis in 3 genetically distinct leukemias and lymphomas. Individual Hdacs were depleted in murine acute myeloid leukemias (MLL-AF9;Nras(G12D); PML-RARα acute promyelocytic leukemia [APL] cells) and Eµ-Myc lymphoma in vitro and in vivo. Strikingly, Hdac3-depleted cells were selected against in competitive assays for all 3 tumor types. Decreased proliferation following Hdac3 knockdown was not prevented by BCL-2 overexpression, caspase inhibition, or knockout of Cdkn1a in Eµ-Myc lymphoma, and depletion of Hdac3 in vivo significantly reduced tumor burden. Interestingly, APL cells depleted of Hdac3 demonstrated a more differentiated phenotype. Consistent with these genetic studies, the HDAC3 inhibitor RGFP966 reduced proliferation of Eµ-Myc lymphoma and induced differentiation in APL. Genetic codepletion of Hdac1 with Hdac2 was pro-apoptotic in Eµ-Myc lymphoma in vitro and in vivo and was phenocopied by the HDAC1/2-specific agent RGFP233. This study demonstrates the importance of HDAC3 for the proliferation of leukemia and lymphoma cells, suggesting that HDAC3-selective inhibitors could prove useful for the treatment of hematological malignancies. Moreover, our results demonstrate that codepletion of Hdac1 with Hdac2 mediates a robust pro-apoptotic response. Our integrated genetic and pharmacological approach provides important insights into the individual or combinations of HDACs that could be prioritized for targeting in a range of hematological malignancies. PMID:26447190

  1. Malignant Tourette syndrome.

    PubMed

    Cheung, Min-Yuen Cynthia; Shahed, Joohi; Jankovic, Joseph

    2007-09-15

    The aim of this work was to draw attention to potentially life-threatening symptoms associated with Tourette syndrome (TS) and to explore their relationship to TS comorbidities. Medical records of all patients with TS evaluated at our Movement Disorders Clinic between July 2003 and July 2006 were reviewed. Data on patients with malignant TS, defined as >or=2 emergency room (ER) visits or >or=1 hospitalizations for TS symptoms or its associated behavioral comorbidities, were entered into a dataset and analyzed. Five illustrative cases are described. Of 333 TS patients evaluated during the 3-year period, 17 (5.1%) met the criteria for malignant TS. Hospital admission or ER visits were for tic-related injuries, self-injurious behavior (SIB), uncontrollable violence and temper, and suicidal ideation/attempts. Compared with patients with nonmalignant TS, those with malignant TS were significantly more likely to have a personal history of obsessive compulsive behavior/disorder (OCB/OCD), complex phonic tics, coprolalia, copropraxia, SIB, mood disorder, suicidal ideation, and poor response to medications. Although TS is rarely a disabling disorder, about 5% of patients referred to a specialty clinic have life-threatening symptoms. Malignant TS is associated with greater severity of motor symptoms and the presence of >or=2 behavioral comorbidities. OCD/OCB in particular may play a central role in malignant TS; obsessive compulsive qualities were associated with life-threatening tics, SIB, and suicidal ideation. Malignant TS is more refractory to medical treatment than nonmalignant TS. PMID:17566119

  2. Whole Pelvic Intensity-modulated Radiotherapy for Gynecological Malignancies: A Review of the Literature

    PubMed Central

    Hymel, Rockne; Jones, Guy C.; Simone, Charles B.

    2015-01-01

    Radiation therapy has long played a major role in the treatment of gynecological malignancies. There is increasing interest in the utility of intensity-modulated radiotherapy (IMRT) and its application to treat gynecological malignancies. Herein, we review the state-of-the-art use of IMRT for gynecological malignancies and report how it is being used alone as well as in combination with chemotherapy in both the adjuvant and definitive settings. Based on dosimetric and clinical evidence, IMRT can reduce gastrointestinal, genitourinary, and hematological toxicities compared with 3D conformal radiotherapy for gynecologic malignancies. We discuss how these attributes of IMRT may lead to improvements in disease outcomes by allowing for dose escalation of radiation therapy, intensification of chemotherapy, and limiting toxicity-related treatment breaks. Currently accruing trials investigating pelvic IMRT for cervical and endometrial cancers are discussed. PMID:25600840

  3. Common emergencies in cancer medicine: hematologic and gastrointestinal syndromes.

    PubMed Central

    Thomas, C. R.; Carter, I. K.; Leslie, W. T.; Sutton, F.

    1992-01-01

    A myriad of both primary and secondary hematologic and gastrointestinal system-related clinical problems may exist in the cancer patient. This review outlines a standard approach to the prompt diagnosis and therapeutic intervention for these clinical issues. PMID:1602515

  4. Assessing Safety of Pneumatic Tube System (PTS) for Patients with Very Low Hematologic Parameters

    PubMed Central

    Koroglu, Mustafa; Erkurt, Mehmet Ali; Kuku, Irfan; Kaya, Emin; Berber, Ilhami; Nizam, Ilknur; Yagar, Yavuz; Kayis, Seyit Ali

    2016-01-01

    Background Preventive interventions save lives during the process of chemotherapy for hematologic malignancies, when a hematology laboratory can ensure accurate results. The use of a pneumatic tube system (PTS) is associated with measurement errors and unnecessary transfusions. The aim of this study was to evaluate pre-analytical errors associated with transportation method (PTS versus hand-delivered) and to investigate whether there are unnecessary transfusion events in pancytopenia leukemia patients with very low hematological parameters. Material/Methods A total of 140 paired blood collections were performed for hemogram and biochemistry assays. Paired EDTA and serum gel blood samples were collected from 58 cases with acute leukemia on different days. For each pair, one sample was hand-delivered by a courier (Group 1) while the other sample was transported through a PTS (Group 2). Results The hand-delivered method showed that some platelet transfusions were unnecessary for different thrombocyte cut-off values. Calculated unnecessary platelet (PLT) transfusion ratios when using PTS (PLT <30×103/μL, 16.3%; PLT <25×103/μL, 16.4%; PLT <20×103/μL, 80.3%; PLT <15×103/μL, 48.6%; and PLT <10×103/μL, 150.0%) were found to be statistically significant (p=0.002, p=0.046, p<0.000, p=0.028, and p<0.000, respectively). In contrast, for RBC transfusion ratios, although the ratios were high in Group 2, we found no significant difference between the two groups; (HGB <8.0 g/dL, 23.3%; HGB <9.0 g/dL, 25.0%, HGB<10.0 g/dL, 19.3%) and (p=0.002, p=0.085, p<0.160, and p=0.235, respectively). Conclusions Although our results cannot be universally applied, physicians should be careful, skeptical, and suspicious of transfusion decisions in hematology clinics and consider potential analytical and pre-analytical errors in cases of severe cytopenia when using PTS. PMID:27097101

  5. Hematology of the Domestic Ferret (Mustela putorius furo).

    PubMed

    Smith, Stephen A; Zimmerman, Kurt; Moore, David M

    2015-09-01

    Pet ferrets are presented to veterinary clinics for routine care and treatment of clinical diseases and female reproductive problems. In addition to obtaining clinical history, additional diagnostic testing may be required, including hematological assessments. This article describes common blood collection methods, including venipuncture sites, volume of blood that can be safely collected, and handling of the blood. Hematological parameters for normal ferrets are provided along with a description of the morphology of ferret leukocytes to assist in performing a differential count. PMID:26297407

  6. Connective tissue: Vascular and hematological (blood) support

    PubMed Central

    Calvino, Nick

    2003-01-01

    Abstract Connective Tissue (CT) is a ubiquitous component of all major tissues and structures of the body (50% of all body protein is CT), including that of the blood, vascular, muscle, tendon, ligament, fascia, bone, joint, IVD's (intervertebral discs) and skin. Because of its ubiquitous nature, CT is an often overlooked component of any essential nutritional program that may address the structure, and/or function of these tissues. The central role of CT in the health of a virtually all cells, tissues, organs, and organ systems, is discussed. General nutritional CT support strategies, as well as specific CT support strategies that focus on blood, vascular, structural system (eg, muscles, tendons, ligaments, fascia, bone, and joints), integument (skin) and inflammatory and immune mediation will be discussed here and will deal with connective tissue dynamics and dysfunction. An overview of the current scientific understanding and possible options for naturally enhancing the structure and function of CT through the application of these concepts will be discussed in this article, with specific attention on the vascular and hematological systems. PMID:19674592

  7. Hyperhemolysis Syndrome without Underlying Hematologic Disease

    PubMed Central

    Eberly, Lauren Anne; Osman, Diaa; Collins, Nathaniel Perryman

    2015-01-01

    Introduction. Hyperhemolysis is characterized by a life-threatening hemolytic transfusion reaction, with hemoglobin (Hb) and hematocrit (Hct) dropping markedly lower than before transfusion. This phenomenon, commonly described in sickle cell disease, is a rare occurrence in patients without hemoglobinopathies. Case Report. A 55-year-old male presented to the hospital after a motorcycle crash and received 10 units of cross-matched blood for active bleeding. The patient was blood group O, with a negative antibody screen. Ten days later, he represented complaining of dyspnea and was found to have a hematocrit of 12%. The direct antiglobulin test was positive for anti-immunoglobin G and complement. Indirect antiglobulin test was positive for anti-Jka alloantibodies. The presence of Jka antigen was revealed in one unit of previously transfused blood; patient's RBCs were negative for the Jka antigen. Laboratory data demonstrated findings consistent with DHTR, as well as reticulopenia and elevated ferritin levels. He continued to show signs of active hemolysis, requiring a total of 4 subsequent units of pRBCs. Each transfusion precipitated a drop in Hb and Hct to levels lower than before transfusion; once transfusions were held, the patient slowly recovered. Discussion. Hyperhemolysis in the setting of a DHTR can occur in patients without hematologic disease. PMID:25785210

  8. Erythrocyte and platelet proteomics in hematological disorders.

    PubMed

    Chakrabarti, Abhijit; Halder, Suchismita; Karmakar, Shilpita

    2016-04-01

    Erythrocytes undergo ineffective erythropoesis, hemolysis, and premature eryptosis in sickle cell disease and thalassemia. Abnormal hemoglobin variants associated with hemoglobinopathy lead to vesiculation, membrane instability, and loss of membrane asymmetry with exposal of phosphatidylserine. This potentiates thrombin generation resulting in activation of the coagulation cascade responsible for subclinical phenotypes. Platelet activation also results in the release of microparticles, which express and transfer functional receptors from platelet membrane, playing key roles in vascular reactivity and activation of intracellular signaling pathways. Over the last decade, proteomics had proven to be an important field of research in studies of blood and blood diseases. Blood cells and its fluidic components have been proven to be easy systems for studying differential expressions of proteins in hematological diseases encompassing hemoglobinopathies, different types of anemias, myeloproliferative disorders, and coagulopathies. Proteomic studies of erythrocytes and platelets reported from several groups have highlighted various factors that intersect the signaling networks in these anucleate systems. In this review, we have elaborated on the current scenario of anucleate blood cell proteomes in normal and diseased individuals and the cross-talk between the two major constituent cell types of circulating blood. PMID:26611378

  9. Five hematologic tests and treatments to question.

    PubMed

    Hicks, Lisa K; Bering, Harriet; Carson, Kenneth R; Haynes, Adam E; Kleinerman, Judith; Kukreti, Vishal; Ma, Alice; Mueller, Brigitta U; O'Brien, Sarah H; Panepinto, Julie A; Pasquini, Marcelo C; Rajasekhar, Anita; Sarode, Ravi; Wood, William A

    2014-12-01

    Choosing Wisely® is a medical stewardship initiative led by the American Board of Internal Medicine Foundation in collaboration with professional medical societies in the United States. The American Society of Hematology (ASH) released its first Choosing Wisely® list in 2013. Using the same evidence-based methodology as in 2013, ASH has identified 5 additional tests and treatments that should be questioned by clinicians and patients under specific, indicated circumstances. The ASH 2014 Choosing Wisely® recommendations include: (1) do not anticoagulate for more than 3 months in patients experiencing a first venous thromboembolic event in the setting of major, transient risk factors for venous thromboembolism; (2) do not routinely transfuse for chronic anemia or uncomplicated pain crises in patients with sickle cell disease; (3) do not perform baseline or surveillance computed tomography scans in patients with asymptomatic, early-stage chronic lymphocytic leukemia; (4) do not test or treat for heparin-induced thrombocytopenia if the clinical pretest probability of heparin-induced thrombocytopenia is low; and (5) do not treat patients with immune thrombocytopenia unless they are bleeding or have very low platelet counts. PMID:25696917

  10. Five hematologic tests and treatments to question.

    PubMed

    Hicks, Lisa K; Bering, Harriet; Carson, Kenneth R; Haynes, Adam E; Kleinerman, Judith; Kukreti, Vishal; Ma, Alice; Mueller, Brigitta U; O'Brien, Sarah H; Panepinto, Julie A; Pasquini, Marcelo C; Rajasekhar, Anita; Sarode, Ravi; Wood, William A

    2014-12-01

    Choosing Wisely(®) is a medical stewardship initiative led by the American Board of Internal Medicine Foundation in collaboration with professional medical societies in the United States. The American Society of Hematology (ASH) released its first Choosing Wisely(®) list in 2013. Using the same evidence-based methodology as in 2013, ASH has identified 5 additional tests and treatments that should be questioned by clinicians and patients under specific, indicated circumstances. The ASH 2014 Choosing Wisely(®) recommendations include: (1) do not anticoagulate for more than 3 months in patients experiencing a first venous thromboembolic event in the setting of major, transient risk factors for venous thromboembolism; (2) do not routinely transfuse for chronic anemia or uncomplicated pain crises in patients with sickle cell disease; (3) do not perform baseline or surveillance computed tomography scans in patients with asymptomatic, early-stage chronic lymphocytic leukemia; (4) do not test or treat for heparin-induced thrombocytopenia if the clinical pretest probability of heparin-induced thrombocytopenia is low; and (5) do not treat patients with immune thrombocytopenia unless they are bleeding or have very low platelet counts. PMID:25472968

  11. Parvovirus-B19 and hematologic disorders.

    PubMed

    Yetgin, Sevgi; Aytaç Elmas, Selin

    2010-12-01

    Parvovirus-B19 (PV-B19) is a member of Parvoviridae, which is one of the smallest DNA viruses. PV-B19-associated diseases usually serve as a good representation of the balance of virus, host response and the immune system. The diseases manifested with PV-B19 are erythema infectiosum, which is common in children, hydrops fetalis, transient pure red cell aplasia in patients with chronic hemolytic anemia, arthralgia - mostly observed in women, and chronic pure red cell aplasia in immunocompromised individuals. Cytopenia (bicytopenia, monocytopenia or pancytopenia) may also accompany the diseases mentioned above. On the other hand, there are many diseases, including neurologic, vasculitic, hepatic, rheumatoid, nephritic, autoimmune, myocardial, and others in which the mechanisms of the diseases are not clear, which may be associated with PV-B19. The virus may manifest with unexpected and unexplained clinical pictures and lead to misdiagnosis. Therefore, hematologic disorders in any unestablished clinical diagnosis should be investigated for PV-B19 infection. However, serologic examination for PV-B19 diagnosis is not sufficient in immunocompromised status. The virus can be determined with polymerase chain reaction (PCR) in the serum or tissue samples. Supportive therapy, blood transfusion and immunoglobulin are the conventional therapeutic interventions for PV-B19 today. Vaccination studies are under examination. PMID:27263735

  12. Hematological and hemorheological effects of air pollution

    SciTech Connect

    Baskurt, O.K.; Levi, E.; Caglayan, S.; Dikmenoglu, N.; Kutman, M.N. )

    1990-07-01

    Selected hematological parameters and erythrocyte deformability indexes for 16 young male military students were compared before and after a period of exposure to heavy pollution. These students lived in Ankara, which has a serious air pollution problem. The mean sulfur dioxide levels measured at a station proximal to the campus where the students lived were 188 micrograms/m3 and 201 micrograms/m3 during first and second measurements, respectively. During the period between the two measurements, the mean sulfur dioxide level was 292 micrograms/m3. Significant erythropoiesis was indicated by increased erythrocyte counts and hemoglobin and hematocrit levels. Methemoglobin percentage was increased to 2.37 +/- 0.49% (mean +/- standard error) from 0.51 +/- 0.23%. Sulfhemoglobinemia was present in six subjects after the period of pollution, but it was not present in any student prior to this period. Significant increases in erythrocyte deformability indexes were observed after the period of pollution, i.e., from 1.13 +/- 0.01 to 1.21 +/0 0.02, implying that erythrocytes were less flexible, which might impair tissue perfusion.

  13. Simulants of Malignant Melanoma

    PubMed Central

    Piérard-Franchimont, Claudine; Delvenne, Philippe

    2015-01-01

    During the recent period, dermoscopy has yielded improvement in the early disclosure of various atypical melanocytic neoplasms (AMN) of the skin. Beyond this clinical procedure, AMN histopathology remains mandatory for establishing their precise diagnosis. Of note, panels of experts in AMN merely report moderate agreement in various puzzling cases. Divergences in opinion and misdiagnosis are likely increased when histopathological criteria are not fine-tuned and when facing a diversity of AMN types. Furthermore, some AMN have been differently named in the literature including atypical Spitz tumor, metastasizing Spitz tumor, borderline and intermediate melanocytic tumor, malignant Spitz nevus, pigmented epithelioid melanocytoma or animal-type melanoma. Some acronyms have been further suggested such as MELTUMP (after melanocytic tumor of uncertain malignant potential) and STUMP (after Spitzoid melanocytic tumor of uncertain malignant potential). In this review, such AMN at the exclusion of cutaneous malignant melanoma (MM) variants, are grouped under the tentative broad heading skin melanocytoma. Such set of AMN frequently follows an indolent course, although they exhibit atypical and sometimes worrisome patterns or cytological atypia. Rare cases of skin melanocytomas progress to loco regional clusters of lesions (agminate melanocytomas), and even to regional lymph nodes. At times, the distinction between a skin melanocytoma and MM remains puzzling. However, multipronged immunohistochemistry and emerging molecular biology help profiling any malignancy risk if present. PMID:26779311

  14. Potentially malignant oral lesions: clinicopathological correlations.

    PubMed

    Maia, Haline Cunha de Medeiros; Pinto, Najara Alcântara Sampaio; Pereira, Joabe Dos Santos; Medeiros, Ana Miryam Costa de; Silveira, Éricka Janine Dantas da; Miguel, Márcia Cristina da Costa

    2016-03-01

    Objective To determine the incidence of potentially malignant oral lesions, and evaluate and correlate their clinical and pathological aspects. Methods The sample consisted of cases clinically diagnosed as oral leukoplakia, oral erythroplakia, erythroleukoplakia, actinic cheilitis, and oral lichen planus treated at a diagnostic center, between May 2012 and July 2013. Statistical tests were conducted adopting a significance level of 5% (p≤0.05). Results Out of 340 patients, 106 (31.2%) had potentially malignant oral lesions; and 61 of these (17.9%) were submitted to biopsy. Actinic cheilitis was the most frequent lesion (37.5%) and the lower lip was the most affected site (49.6%). Among 106 patients in the sample, 48 (45.3%) reported nicotine consumption, 35 (33%) reported alcohol intake and 34 (32.1%) sun exposure while working. When clinical and histopathological diagnoses were compared, oral erythroplakia and atypical ulcer were the lesions that exhibited greater compatibility (100% each). Conclusion In most cases, clinical and histopathological diagnoses were compatible. An association between the occurrence of erythroplakia, leukoplakia and erythroleukoplakia with smoking was observed. Similarly, an association between actinic cheilitis and sun exposure was noted. Erythroleukoplakia presented the highest malignancy grade in this study. Finally, dental surgeons should draw special attention to diagnosis of potentially malignant oral lesions, choose the best management, and control the lesions to avoid their malignant transformation. PMID:27074232

  15. Ophthalmic Manifestations of Hematopoietic Malignancy.

    PubMed

    Yoshida-Hata, Natsuyo; Katai, Naomichi; Oshitari, Toshiyuki

    2016-01-01

    Purpose. To report the ocular findings in patients with hematopoietic malignancy with optic nerve involvement and abducens nerve palsy. Methods. The medical records of all cases of hematopoietic cancer with ophthalmic involvements seen in the Department of Ophthalmology of the National Center for Global Health and Medicine between 2009 and 2014 were reviewed. Results. Eight patients with hematopoietic cancer with optic nerve invasion or abducens nerve palsy were studied. The primary diseases were 3 cases of multiple myeloma, 1 case of acute lymphocytic leukemia, 1 case of follicular lymphoma, and 3 cases of AIDS-related lymphoma. Six cases had optic nerve invasion, 2 cases had abducens nerve palsy, and 1 case had optic nerve invasion of both eyes. The median visual acuity of eyes with optic nerve invasion was 0.885 logarithm of the minimum angle of resolution (logMAR) units. The final visual acuity of eyes with optic nerve invasion was 1.25 logMAR units, and that of those with sixth-nerve palsy was -0.1 logMAR units. Six cases died during the five-year follow-up period. An ophthalmic involvement in patients with hematopoietic cancer, especially AIDS-related lymphoma, was associated with poor prognosis. Conclusion. Because ophthalmic involvement in patients with hematopoietic malignancy has a poor prognosis, an early diagnosis of the cancers by the ophthalmologic findings by ophthalmologists could improve the prognosis. PMID:27375913

  16. Ophthalmic Manifestations of Hematopoietic Malignancy

    PubMed Central

    2016-01-01

    Purpose. To report the ocular findings in patients with hematopoietic malignancy with optic nerve involvement and abducens nerve palsy. Methods. The medical records of all cases of hematopoietic cancer with ophthalmic involvements seen in the Department of Ophthalmology of the National Center for Global Health and Medicine between 2009 and 2014 were reviewed. Results. Eight patients with hematopoietic cancer with optic nerve invasion or abducens nerve palsy were studied. The primary diseases were 3 cases of multiple myeloma, 1 case of acute lymphocytic leukemia, 1 case of follicular lymphoma, and 3 cases of AIDS-related lymphoma. Six cases had optic nerve invasion, 2 cases had abducens nerve palsy, and 1 case had optic nerve invasion of both eyes. The median visual acuity of eyes with optic nerve invasion was 0.885 logarithm of the minimum angle of resolution (logMAR) units. The final visual acuity of eyes with optic nerve invasion was 1.25 logMAR units, and that of those with sixth-nerve palsy was −0.1 logMAR units. Six cases died during the five-year follow-up period. An ophthalmic involvement in patients with hematopoietic cancer, especially AIDS-related lymphoma, was associated with poor prognosis. Conclusion. Because ophthalmic involvement in patients with hematopoietic malignancy has a poor prognosis, an early diagnosis of the cancers by the ophthalmologic findings by ophthalmologists could improve the prognosis. PMID:27375913

  17. Short- and long-term outcomes in onco-hematological patients admitted to the intensive care unit with classic factors of poor prognosis

    PubMed Central

    Faucher, Etienne; Cour, Martin; Jahandiez, Vincent; Grateau, Adeline; Baudry, Thomas; Hernu, Romain; Simon, Marie; Robert, Jean-michel; Michallet, Mauricette; Argaud, Laurent

    2016-01-01

    Although the overall mortality of patients admitted to intensive care units (ICU) with hematological malignancy has decreased over the years, some groups of patients still have low survival rates. We performed a monocentric retrospective study including all patients with hematological malignancy in a ten-year period, to identify factors related to the outcome for the whole cohort and for patients with allogeneic hematopoietic stem cell transplantation (HSCT), neutropenia, or those requiring invasive mechanical ventilation (IMV). A total of 418 patients with acute leukemia (n=239; 57%), myeloma (n=69; 17%), and lymphoma (n=53; 13%) were studied. Day-28 and 1-year mortality were 49% and 72%, respectively. The type of disease was not associated with outcome. The disease status was independentlty associated with 1-year mortality only. Independent predictors of day-28 mortality were IMV, renal replacement therapy (RRT), and performance status. For allogeneic HSCT recipients (n=116), neutropenic patients (n=124) and patients requiring IMV (n=196), day-28 and 1-year mortality were 52%, 54%, 74% and 81%, 78%, 87%, respectively. Multivariate analysis showed that IMV and RRT for allogeneic HSCT recipients, performance status and IMV for neutropenic patients, and RRT for patients requiring IMV were independently associated with short-term mortality (p<0.05). These results suggest that IMV is the strongest predictor of mortality in hematological patients admitted to ICUs, whereas allogeneic HSCT and neutropenia do not worsen their short-term outcome. PMID:26968953

  18. Total sternectomy for malignant disease.

    PubMed

    París, F; Blasco, E; Tarazona, V; Pastor, J; Zarza, A G; Padilla, J

    1980-09-01

    From 1972 to 1978, six total sternectomies for malignant disease of the sternum were carried out. The clinical data are summarized and the surgical technique is described. After sternectomy, the area of chest wall resection was repaired by suturing a sheet of silicone rubber to the edges of the defect and chest wall stability was assured by using one or two stainless steel struts. Finally the defect was covered with methylmethacrylate prepared and applied inthe operative field. The prosthetic material was shaped until curing by polymerization was complete. We discuss the advantages of this type of reconstruction, the technical details, the use of antibiotics, the surgical drainage, and the need for biopsy prior to carrying out a total sternectomy. PMID:7412352

  19. Malignant Catarrhal Fever

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Malignant catarrhal fever (MCF) is a frequently fatal viral disease of ruminant species, particularly cattle, bison, and deer. Clinical signs vary between species. Two major epidemiologic types of MCF exist, and are defined by the ruminant species that serve as natural reservoir hosts for infection...

  20. [Malignant peritoneal mesothelioma].

    PubMed

    Scripcariu, V; Dajbog, Elena; Lefter, L; Ferariu, D; Pricop, Adriana; Grigoraş, M; Dragomir, Cr

    2006-01-01

    Mesothelioma is a neoplasm originating from the mesothelial surface lining cells of the serous human cavities. It may involve the pleura, less frequently the peritoneum rarely, the pericardium, the tunica vaginalis testis and ovarian epithelium. Asbestos has been widely used in industry. A causal relationship between asbestos exposure and pleural, peritoneal and pericardial malign mesothelioma was suggested, the risk of cancer being correlated to cumulate exposure. Studies from National Cancer Institute, USA, show that the malignant mesothelioma is a rare and aggressive asbestos related malignancy. The symptomatology is insidious and poses difficult problems in diagnosis and treatment. This paper presents the case of a 59 year old patient with malignant peritoneal mesothelioma who worked almost 40 years as an electrician, exposed to asbestos fibers. He was hospitalized for important weight loss, abdominal pain and tiredness being diagnosed after imaging tests with a giant tumor, localized at the abdominal upper level, which seems to originate from the spleen's superior pole. During surgery we discovered a tumor with cystic parts, intense vascularized, which turn to be adherent in the upper side to the lower face of the left midriff cupola, to the spleen superior pole and 1/3 middle level of the great gastric curve. It was performed surgical ablation of the tumor, splenectomy with favorable postoperative evolution, the patient being now under chemotherapy treatment. PMID:17283842