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Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies

The treatment of patients with hematologic malignancies has been revolutionized over the past decades as new therapeutic targets continue to be identified through cellular and molecular studies of these conditions. These investigations have spawned the discovery, clinical evaluation, and US Food and Drug Administration (FDA) approval of new mechanistic-based therapeutic agents. A surprising number of these agents have progressed rapidly from the discovery phase to validation,…

Conventional and Molecular Cytogenomic Basis of Hematologic Malignancies

Dedicated to the loving memory of Eta Najfeld, MD, a Holocaust survivor and an amazing mother . Over the past 66 years the cytogenetic analysis of hematologic malignancies has been an area of prolific growth. Chromosome studies and karyotype analysis provide information of both biologic and clinical significance. Refinements in cell culture methods and the application of chromosome banding techniques have advanced our understanding of disease-specific…

Progress in the Classification of Hematopoietic and Lymphoid Neoplasms: Clinical Implications

Defining and classifying tumors of the hematopoietic and lymphoid tissue accurately is critical for providing optimal treatment to patients with hematologic malignancies. Explicit definitions and terminologies are prerequisites for the precise classification of hematologic malignancies. A reproducible classification that is based on consensus definitions and terminologies is fundamentally essential for proper medical practice and the advancement of medical knowledge. Generally, such classifications should be based upon…

Epstein-Barr Virus and Associated Lymphoproliferative Conditions

The initial clinical descriptions of primary Epstein-Barr virus (EBV) infections are credited to Filatov and Pfeiffer at the end of the 19th century. Pfeiffer coined the term glandular fever , which described an illness consisting of fever, malaise, sore throat, and lymphadenopathy. In 1920, Sprunt and Evans introduced the term infectious mononucleosis (IM) to describe a series of patients with fatigue, fever, lymphadenopathy, and prominent mononuclear…

Lysosomal Storage Diseases, Focusing On Gaucher Disease: Perspectives And Principles

Lysosomal Storage Diseases Lysosomal storage diseases (LSDs) are genetic disorders caused by deficiencies in single lysosomal hydrolases. Deficiencies result in cellular and organ damage due to subsequent accumulation of a specific substrate for that particular enzyme, hence the term “storage” disease. However, the diverse role of the lysosome in cellular metabolism means that the pathological consequences of enzyme deficiency extend beyond substrate accumulation. Although individually rare,…

Pediatric and Adult Histiocytic Disorders

The histiocytic disorders comprise a broad grouping of hematologic and immunologic diseases united by aberrant function, differentiation, and/or proliferation of cells of the mononuclear phagocyte system. The term histiocyte historically referred to tissue phagocytes but now more precisely defines cells of the monocyte/macrophage lineage ( Fig. 53.1 ). The ontogeny of these cells and their role(s) in pathogenesis continue to be studied and refined. In the…

Congenital Disorders of Lymphocyte Function

Over 350 molecular defects that result in primary immune deficiency are known to date. Many of these gene defects have been identified in recent years with the advent of whole-exome and whole-genome sequencing. The study of patients with primary immune deficiencies has unraveled fundamental mechanisms that govern lymphocyte development and function. Importantly, characterization of the molecular basis of these diseases has revealed unanticipated heterogeneity of the…

Disorders of Phagocyte Function

Phagocytic leukocytes are an essential component of the innate immune system that has evolved to rapidly respond to the presence of invading bacteria, fungi, and parasites. This first line of host defense also includes natural killer (NK) lymphocytes, complement, and other plasma proteins. As reviewed in Chapter 28, Chapter 49 , phagocytes are responsible for ingesting, killing, and digesting pathogens. Granulocytic phagocytes (neutrophils and eosinophils) circulate…

Lymphocytosis, Lymphocytopenia, Hypergammaglobulinemia, and Hypogammaglobulinemia

Any discussion of quantitative abnormalities of lymphocytes and immunoglobulins is necessarily linked because the B-cell compartment is responsible for immunoglobulin production and the T-cell compartment helps to provide the stimulus. Nevertheless, clinicians are often consulted when a quantitative disorder of one or the other is recognized. Thus, although overlapping, the defects are presented separately. Quantitative Disorders of Lymphocytes The normal number and distribution of lymphocyte subtypes…

Neutrophilic Leukocytosis, Neutropenia, Monocytosis, and Monocytopenia

Abnormalities of leukocyte number are commonly encountered in medical practice. The clinical significance of leukocytosis or leukopenia varies from none at all to being an early clue to a life-threatening process, whether that is a primary hematologic or secondary reactive process. Potential causes of leukocytosis or leukopenia are myriad. This chapter considers disorders faced by adult practitioners in hospital and outpatient clinics where the predominant hematologic…

Extrinsic Nonimmune Hemolytic Anemias

By definition, extrinsic causes of hemolysis are abnormalities in the environment in which the red blood cells (RBCs), usually normal themselves, circulate. These abnormalities can be acute or chronic in nature. They can arise from congenital lesions but usually result from acquired insults. Inherited anomalies of glucose-6-phosphate dehydrogenase (G6PD) deficiency, which reduces the RBCs’ ability to deal with oxidative stressors, can leave RBCs more vulnerable to…

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is a rare autoimmune disease caused by autoimmune-mediated destruction of red blood cells (RBCs) by autoantibodies with various properties and target specificities. Exact laboratory diagnosis may sometimes be difficult; therefore, experienced diagnostic reference centers play an important role. The disease can be primary (idiopathic) or caused by an underlying condition (secondary), including systemic autoimmune diseases, infections, primary immunodeficiencies, drugs, or neoplasms (mostly…

Red Blood Cell Membrane Disorders

Characterization of the structure and function of red blood cell (RBC) membrane proteins and their genes ( Fig. 46.1 ) has led to considerable advances in our understanding of the molecular pathology of membrane-associated disorders, including the definition and characterization of mutations of membrane proteins as a well-defined cause of hereditary hemolytic disease. Likewise, knowledge of the molecular mechanisms underlying changes in RBC deformability, structural integrity,…

Red Blood Cell Enzymopathies

Red blood cells (RBCs) are highly specialized cells with the sole function of delivering oxygen to the tissues. During oxygen delivery, a highly destructive reactive oxygen species (ROS)—such as superoxide—is generated from a small fraction of the oxygen released from hemoglobin. ROS oxidizes hydroxylated sulfur groups (SH), leading to profound alterations in protein structures. This is most marked by the transformation of the hemoglobin present in…

Hemoglobin Variants Associated With Hemolytic Anemia, Altered Oxygen Affinity, and Methemoglobinemias

Hemoglobinopathies are inherited diseases caused primarily by mutations affecting the globin genes. Nearly 1000 mutations are known to alter the structure, expression, or developmental regulation of individual globin genes and the hemoglobins that they encode. Of these, only a few produce clinical disease. Many are highly instructive for students of gene structure, function, and regulation, but further consideration of most is not warranted in a clinically…

Clinical Aspects of Sickle Cell Disease

Hemoglobinopathies are the most common genetic diseases in humans. In sickle cell disease (SCD), a single nucleotide substitution (GTG for GAG, rs334 ) in the sixth codon of the β-globin gene produces an abnormal sickle hemoglobin (HbS). Due to a change in the convention for numbering amino acid residues in the human β-hemoglobin chain, the HbS mutation becomes E7V rather than E6V and the current numbering…

Pathobiology of Sickle Cell Disease

Since it was recognized as the “first molecular disease,” sickle cell anemia (HbSS) caused by homozygosity for the mutant sickle beta-globin gene has provided the classic paradigm for single-gene disorders. Predominant clinical features include hemolytic anemia, episodic painful vasoocclusive events, an inflammatory vasculopathy, chronic organ deterioration, and a foreshortened life span. The genesis of clinical HbSS is complicated, and an understanding of its pathophysiology integrates concepts…

Thalassemia Syndromes

The thalassemia syndromes are a heterogeneous group of inherited anemias which result from defects in the synthesis of one or more of the globin chain subunits of the hemoglobin (Hb) tetramer. The basic defect, decreased or absent production of a globin subunit, results in an imbalance between globins produced as a result of expression of genes from the alpha-globin gene cluster on chromosome 16, and those…

Megaloblastic Anemias

The term megaloblastic anemia is used to describe a group of disorders characterized by a distinct morphologic pattern in hematopoietic cells. A common feature is a defect in deoxyribonucleic acid (DNA) synthesis, with lesser alterations in ribonucleic acid (RNA) and protein synthesis, leading to a state of unbalanced cell growth and impaired cell division. Most megaloblastic cells are not resting but vainly engaged in attempting to…

Heme Biosynthesis and Its Disorders: Porphyrias and Sideroblastic Anemias

The porphyrias and the sideroblastic anemias are metabolic disorders that involve defects in heme biosynthesis. Most forms of porphyria are inherited in a Mendelian autosomal dominant pattern, but some types are recessive, and others are acquired through exposure to porphyrinogenic drugs and chemicals. A linked group of diseases, the porphyrinurias, are not porphyrias but have in common alterations of heme biosynthesis following exposure to various toxins.…