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Disorders of Iron and Copper Metabolism, the Sideroblastic Anemias, and Lead Toxicity

Iron lacks the glitter of gold and the sparkle of silver but outshines both in biologic importance. This plebeian metal is vital to the function of a wide variety of critical enzymes, including catalases, aconitases, ribonucleotide reductase, peroxidases, and cytochromes, which exploit the flexible redox chemistry of iron to execute a number of chemical reactions essential for our survival ( Box 11-1 ). In addition, we…

Megaloblastic Anemia

The metabolism of folate and that of cobalamin are intimately intertwined, and deficiency of either vitamin can manifest as megaloblastic anemia. The two deficiencies must be rigorously differentiated and treated specifically because their causes, mechanisms, nonhematologic expressions, courses, and prognoses differ. This is as true in pediatric medicine as in adult and geriatric medicine, from which much of the existing hematologic information originated. Recent advances in…

Diagnostic Approach to the Anemic Patient

Introduction In this chapter we attempt to provide a useful guide to the rapid and accurate diagnosis of anemia in children and young adults. We do not dwell on each diagnosis because they are described in detail throughout the book. Though productive methods of differential diagnosis of anemia vary greatly with the age of the pediatric patient, the most valuable tools at all ages remain the…

Principles of Bone Marrow and Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) is an accepted treatment for a wide variety of diseases afflicting children, including hematologic malignancies, bone marrow failure syndromes, immunodeficiency disorders, congenital hematologic defects, and select solid tumors. HSCT generally involves a conditioning phase with administration of chemotherapy with or without radiation therapy followed by the infusion of autologous (self) or allogeneic (other) hematopoietic stem cells (HSCs). The conditioning damages the…

Inherited Bone Marrow Failure Syndromes

Inherited bone marrow failure syndromes (IBMFSs) are a diverse collection of genetic disorders associated with inadequate blood cell production. Bone marrow failure (BMF) may manifest as an isolated cytopenia (pure red cell aplasia, neutropenia, or thrombocytopenia) or as pancytopenia with the clinical picture of aplastic anemia. Table 7-1 summarizes the more common IBMFSs, the blood cell lineages affected, the genes mutated and their modes of inheritance,…

Acquired Aplastic Anemia and Pure Red Cell Aplasia

Acquired and congenital bone marrow failure syndromes are characterized by a reduction in the effective production of mature erythrocytes, granulocytes, and platelets by the bone marrow. Bone marrow failure leads to various peripheral blood cytopenias. In some conditions, only one or two cell lines may be affected. In others such as aplastic anemia the result is pancytopenia. In this chapter, we deal only with the acquired…

Hemostasis in the Newborn and Infant

Development of the human hemostatic system begins in utero and continues until well after birth. As a result, functional levels of many of the procoagulants, coagulation inhibitors, fibrinolytic components, and platelet-associated factors differ from those of older children and adults, with “adult” values often not reached until about 6 months of age. These unique aspects of fetal and neonatal coagulation were first fully documented in the…

Neonatal Jaundice and Disorders of Bilirubin Metabolism

Introduction * URL referenced in this chapter includes: Online Mendelian Inheritance in Man (OMIM), . Elevation of the serum bilirubin level is a common, if not universal, finding during the first week of life and has been reviewed elsewhere. This can be a transient phenomenon that will resolve spontaneously or can signify a serious or even potentially life-threatening condition. There are many causes of hyperbilirubinemia…

Immune Hemolytic Disease

Historical Aspects Whereas many serious complications of pregnancy were well known in antiquity, maternofetal blood group incompatibility was recognized more recently. Against the high perinatal mortality prevailing until the mid-twentieth century, deaths from hemolytic disease were of little statistical significance, even though about half of the affected babies died. In 1932 Diamond and coworkers deduced the connection between “congenital anemia,” icterus gravis, and hydrops fetalis, and…

The Neonatal Erythrocyte and Its Disorders

Introduction At no other time in the life of a patient is the physician confronted with as many diagnostic considerations in the interpretation of apparent disturbances of the erythrocyte as during the neonatal period. Neonatal erythrocytes are fundamentally different from those of older children and adults, varying in size, shape, globin composition, oxygen transport, membrane characteristics, cellular metabolism, and life span. Because of these differences, evaluation…

Anatomy and Physiology of Hematopoiesis

This chapter offers a review of the anatomy and physiology of normal hematopoiesis that is intended to provide a basis for understanding the marrow failure syndromes described at length in the following chapter. In this chapter we briefly discuss the phylogeny of hematopoiesis and describe marrow anatomy and the egress of recognizable hematopoietic cells from the marrow into the peripheral blood. A more detailed analysis then…

Molecular Pathology

One of the primary challenges in the clinical management of cancer patients is to establish the correct diagnosis. For over a century, the primary means of diagnosis has been tumor microscopy, an approach that can readily distinguish benign from malignant conditions, but falls short on providing the additional detail needed to guide modern therapies. As a result, a number of technologies have been developed and are…

Cancer Chemoprevention

Chemoprevention is the use of pharmacologic interventions to reduce the risk of cancer or to treat or reduce the risk of intraepithelial neoplasia (IEN ) developing into cancer. As a noninvasive lesion representing an often pathologically discernable intermediate state between normal and malignant tissue, IEN has a substantial cancer risk. The molecular biology of preinvasive carcinogenesis and drug interventions was substantially advanced by translational research of…

Hematopoietic Growth Factors and Cytokines

Growth factors regulate the essential cellular process of proliferation and differentiation. Overproduction of growth factors is a common feature of tumor cells, stimulating unregulated proliferation of themselves in an autocrine fashion, and of adjacent cells in a paracrine fashion. More specifically, hematopoietic growth factor is a common term for the family of glycoproteins that regulate proliferation and differentiation of hematopoietic cells. Cytokines are a subtype of…

Heat Shock Protein 90 and the Proteasome : Housekeeping Proteins That Are Also Molecular Targets for Cancer Therapy

Introduction Cancer is a disease of genetic instability. Although only a few specific alterations seem to be required for generation of the malignant phenotype, at least in colon carcinoma there are approximately 10,000 estimated mutations at time of diagnosis. The genetic plasticity of cancer cells allows them to frequently escape the precise molecular targeting of a single signaling node or pathway, making them ultimately nonresponsive to…

RNA as a Therapeutic Molecule

Acknowledgments CM Croce is supported by Program Project Grants from the National Cancer Institute. GA Calin is the Alan M. Gewirtz Leukemia & Lymphoma Society Scholar. He is also supported as a Fellow at the University of Texas MD Anderson Research Trust, as a University of Texas System Regents Research Scholar, and by the NIH/NCI, the DoD, and the CLL Global Research Foundation. We thank Maitri…

Gene Therapy and Oncolytic Viruses

Introduction Genetic alterations are the driving force behind cancer development and progression. It follows that cancer could potentially be treated by correcting these alterations using gene therapy or by agents that kill cells by mechanisms based on these genetic alterations. Approaches of these kinds have a number of potential advantages. Vectors and viruses can be engineered in countless ways to achieve specificity and potency ( Table…

Interferons

Acknowledgment This chapter is revised and updated from the same chapter in the prior edition of Molecular Basis of Cancer. That chapter was written by the author together with R. Silverman and G. Sen of the Cleveland Clinic, whose prior contributions provided important elements of this update. Introduction Interferons (IFNs) comprise a family of secreted α-helical cytokines induced in response to specific extracellular biomolecules through stimulation…

Cancer Immunotherapy with Vaccines and Checkpoint Blockade

Therapeutic vaccination for cancer continues to be a major approach to the overall immunotherapy of cancer. Historically, interest in cancer immunology stemmed from the perceived potential activity of the immune system as a weapon against cancer cells. In fact, the term magic bullet, commonly used to describe many visions of cancer therapy, was coined by Paul Ehrlich in the late 1800s in reference to antibodies targeting…

Cancer and the Cellular Immune Response

Introduction Key features of the immune system are its abilities to distinguish self from nonself, to recognize and respond to a myriad of foreign molecules (antigens) with exquisite specificity, to remember previously encountered antigens and quickly mobilize an expanded response, and to scan the entire body continuously for antigens. These properties make the immune system ideal for defending the host against developing and recurrent cancers and…