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Cancer Stem Cells and the Microenvironment

∗ Disclaimer: Max S. Wicha has financial holdings and is a scientific adviser for OncoMed Pharmaceuticals, is a scientific adviser for Veristem, and has research support from Dompe. Accumulating evidence suggests that most if not all tumors are maintained by a subpopulation of cells that display stem cell properties including self-renewal and lineage differentiation. Cancer stem cells (CSC) have been isolated from a number of human…

Genetic Mouse Models of Cancer

The study of many different organisms has contributed to our understanding of cancer at the molecular, cellular, and organismal levels. Considerable effort is focused on the rational design and use of mouse models, including spatially and temporally controlled genetic modifications to recapitulate human cancers. Long before the development of genetically engineered animal models, research on mice, rats, rabbits, and chickens led to major discoveries directly related…

Animal Models: Flies, Fish, and Yeast

The molecular pathogenesis of human cancer is a complex process that often requires the cooperation of genetic mutations within many cellular pathways that ultimately lead to tumorigenesis. Simple model organisms with conserved genes and developmental pathways offer systems with which to dissect the role of individual genes and their contribution to the development of cancer in vivo. From single-celled yeasts to vertebrate fish such as the zebrafish,…

Environmental Carcinogenesis

Introduction to Cancer and the Environment Environment, Genetics, and Cancer Overall human cancer risk is determined by complex interactions between host genetics and environmental exposures. On exposure to a cancer-causing agent, a cascade of events is set into motion that converts normal cells into cancer cells. This process is referred to as carcinogenesis, and cancer-causing agents are referred to as carcinogens. Hundreds of confirmed and suspected…

Infectious Agents and Cancer

Overview of Cancer and Infectious Agents Infectious agents are second only to tobacco use as a potentially preventable cause of cancer in humans. Estimates vary between 15% and 30% as to the percentage of cancers worldwide that are associated with an infectious etiology. The burden is greater in the developing world, but the impact even in the United States and other developed countries is significant. Specific…

Epigenetics and Cancer

It has been known for decades that genetic alterations are a fundamental driving force in the initiation and progression of human cancers. It is also now apparent, through a more recent and growing body of work, that epigenetic changes may be equally important in tumor development. Epigenetics refers to heritable changes in gene expression in somatic cells that are determined by other than alterations in the…

DNA Repair Pathways and Human Cancer

Introduction DNA repair is central to the field of cancer biology, and it has important implications for cancer diagnosis and treatment. Cancer cells are often deficient in a normal DNA repair function, and this deficiency allows the tumor to develop genomic instability. With defective DNA repair, the tumor cell can break and reform chromosomes, generate new oncogenic fusion genes, disrupt tumor suppressor genes, amplify drug resistance…

Tumor Suppressor Genes

Introduction Over the past 40 years, efforts to understand the underlying rules that govern the transformation of somatic cells into their malignant counterparts have led to the identification of discrete alterations in genes and gene products that, in combination, are responsible for the characteristic hallmarks of cancer. Broadly speaking, cancer-associated genes can be classified into three groups: oncogenes, tumor suppressor genes, and genes responsible for maintaining…

Oncogenes and Signal Transduction

Signaling: An Overview Intercellular communication is critical to embryonic development, tissue differentiation, and systemic responses to wounds and infections. These complex signaling networks are in large part initiated by growth factors. Such factors can influence cell proliferation in positive or negative ways, as well as inducing a series of differentiated responses in appropriate target cells including survival, apoptosis, and differentiation. The interaction of a growth factor…

Cancer: A Genetic Disorder

Our understanding of the origins of cancer has changed dramatically over the past three decades, due in large part to the revolution in molecular biology that has altered the face of all biomedical research. Powerful experimental tools have been thrust into the hands of cancer biologists. These tools, including newly devised and implemented technologies that permit the interrogation of entire genomes, have made it possible to…

Survivorship

The individual with a newly diagnosed hematologic malignancy begins a journey with the urgent goal to cure the malignancy. That goal can be met for an ever-increasing number of these individuals, and hematopoietic cell transplant (HCT) plays an important role in cure or disease management for life prolongation. The journey is intense. It might look like the following. Clinical Scenario John is a 43-year-old gentleman who…

Symptom Management and Palliative Care in Hematologic Malignancies

Introduction Patients with hematologic malignancies experience complex physical and psychosocial symptoms, affecting their quality of life (QOL). Patients may undergo specific high-risk procedures such as hematopoietic cell transplantations (HCTs) and chimeric antigen receptor T-cell (CAR-T-cell) therapies, which further predispose them to toxicities. Therefore it is imperative to screen individuals for risk factors with additional physical and psychologic interventions before initiating treatments. The intensity of symptoms and…

Miscellaneous Complications of Chimeric Antigen Receptor T-Cell Therapy

Hemophagocytic Lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life-threatening complication of autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, reported in 1% to 3.5% of patients with relapsed or refractory (r/r) large B-cell lymphoma (LBCL). In the ZUMA-1 trial, only one of the 108 patients treated with axicabtagene ciloleucel (axi-cel) developed HLH, resulting in patient’s death, while no cases of HLH were reported in…

Neurologic Complications of Chimeric Antigen Receptor Therapy

Epidemiology and Pathogenesis Beginning in 2017, there has been a steady increase in use of U.S. Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T-cell products for refractory relapsed hematologic tumors. Various host factors like disease burden, pretreatment inflammation, and pretreatment endothelial activation have been reported to predict the neurotoxicity. Conditioning regimen affects the toxicity, with 60 Cy/125 Flu preconditioning seeming to achieve maximum effect…

Cytokine Release Syndrome Following CD19 Directed Chimeric Antigen Receptor T-Cell Therapy

Introduction T-cells genetically engineered to express a chimeric antigen receptor (CAR) that targets a specific tumor antigen have become a major clinical tool to treat several high-risk hematologic malignancies. Since the development of the first CAR T-cell in 1989, remarkable progress has been made in this burgeoning field and to date, autologous CAR T-cell products have been approved by the U.S. Food and Drug Administration (FDA)…

Miscellaneous Complications of Hematopoietic Cellular Transplantation

Introduction Advancements in hematopoietic cell transplantation (HCT) have been associated with expanding indications and eligibility, alternative donor options, and improvement in overall survival (OS). Yet, HCT for hematologic malignancies are still associated with the potential for significant toxicities that may be influenced by the primary diagnosis, prior treatment history (including but not limited to prior HCT and/or immunotherapies), comorbid conditions, and/or preparative regimen and/or donor source.…

Graft-Versus-Host Disease

Introduction Graft-versus-host disease (GVHD) is the leading cause of nonrelapse mortality (NRM) beyond day 100 in recipients of human leukocyte antigen (HLA)-matched sibling donor (MSD) hematopoietic cell transplantation (HCT), and the second leading cause of NRM in recipients of HLA-matched unrelated donor (MUD). The incidence of grade II–IV acute GVHD is about 25% to 50%, grade III–IV acute GVHD about 5% to 20%, chronic GVHD about…

Graft Failure After Hematopoietic Cell Transplantation

Introduction and Historical Perspective The first hematopoietic cell transplantation (HCT) was performed in 1956 and demonstrated neutrophil recovery and transient donor cell engraftment, as documented by red cell engraftment. However, in these original transplants only two of the six reported patients had transient evidence of donor cell engraftment. From 1958 to 1968, a total of 203 patients underwent allogeneic bone marrow (BM) transplant, and the results…

Management of Infections in Stem Cell Transplant Recipients

Infections are a frequent cause of morbidity and mortality in recipients of hematopoietic cell transplant (HCT). Multiple studies have documented a significant and progressive improvement in outcomes of recipients of HCT over the last two decades because of a decline in nonrelapse mortality, including deaths attributed directly or indirectly to infections. Advances in infection diagnosis and management are the topic of this chapter. Infections are different…