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Advanced Pathophysiology Exam Review

Study Guide

Review how cancer cells work

Chapter 12 – Cancer Biology p. 346

(a) Several of the hallmarks/enablers are mostly genomic alterations that initiate and maintain development of cancer. These hallmarks include sustained proliferative signaling, evading growth suppression, genomic instability, and replicative immortality. (b) Cancerous cells characteristically express mutated or overexpressed proto- oncogenes, referred to as oncogenes, which are independent of normal regulatory mechanisms and signal uncontrolled proliferation. (c) Some oncogenes, such as RAS result from point mutations. (d) Oncogenes – can result from genetic translocations. The Philadelphia chromosome in chronic myeloid leukemia (CML) result from a translocation that creates a novel protein fusion of the BCR and ABL genes and expression of an unregulated promoter of cell growth. (e) Tumor-suppressor genes must be inactivated in cancer cells by mutations to each allele, one from each parent. (f) A common mutation in cancer cells is inactivation of the tumor-suppressor gene tumor protein p53 (TP53), which controls expression of many genes that repair DNA damage, suppression of cellular proliferation during genome (g) Cancer cells are immortal. (h) When they reach a critical age, cancer cells activate tolemerase to restore and maintain their telomeres, thereby allowing cancer cells to divide repeatedly or become immortal. (i) Like many normal adult tissues, cancers can contain rare stem cells that provide a source of immortal cells. To fully eradicate a cancer, it may be necessary to target the cancer stem cell. (j) Most of the genetic and epigenetic alterations that causes cancer occur within the somatic tissues during the lifetime of the individual. (k) Access to the vascular system is essential for tumor growth. (l) Stromal cells and cancer cells can secrete multiple factors, such as vascular endothelial growth factor (VEGF), that stimulate new blood vessel growth (called neovascularization or angiogenesis). (m)The successful cancer cell divides rapidly, with the consequent requirement for the building blocks of new cells; cancer cell division often occurs in hypoxic and acidic environment. Many cancer genes also encourage aerobic glycolysis and promote high glucose utilization of a cancer. (n) In cancer, defects in the intrinsic or extrinsic pathways, or both provide resistance to apoptotic cell death. (o) Metastasis is the major cause of cancer.

Review and understand terms such as, dysplasia, hypoplasia, atrophy, hyperplasia, necrosis, ischemia, and hypoxia Dysplasia – refers to abnormal changes in the size, shape, and organization of mature cells. Dysplasia is not considered a true adaptive process but is related to hyperplasia. Dysplasia are mostly found in epithelia. It is not cancer and may not progress to cancer. It may be reversible. Hypoplasia – underdevelopment of a tissue Metaplasia – the reversible replacement of one mature cell type (epithelial or mesenchymal) by another, sometimes less differentiated, cell type. Atrophy – The decrease or shrinkage in cellular size. If atrophy occurs in a sufficient number of an organ’s cell, the entire organ shrinks or becomes atrophic. Hyperplasia – An increase in the number of cells in an organ or tissue resulting from an increase rate of cellular division. Hyperplasia occurs as a response to injury that results when the injury has been severe and prolonged. Necrosis – common type of cell death with severe cell swelling and breakdown of organelles. Ischemia – Reduced blood supply and can induce inflammation. Ischemic injury is often caused by gradual narrowing of arteries (arteriosclerosis) and complete blockage by blood clots (thrombosis). Hypoxia – The lack of sufficient oxygen, is the single most common cause of cellular injury. Can result from a reduced amount of oxygen in the air, loss of hemoglobin or hemoglobin function, reduced production of RBCs, consequences of respiratory and cardiovascular system disease and poisoning of the oxidative enzymes (cytochromes) within the cells. The most common cause of hypoxia is ischemia. Understand cellular transportation, such as active transport, diffusion, osmosis Cellular transportation – Membrane transport proteins that span the lipid bilayer and provide private thoroughfares for select molecules. Membrane transport proteins occur in many forms and are present in all cell membranes, sometimes called mediated transport; allowing selective passage of Na+, but not K+ or K+ but not Na+. The two main classes of membrane transport proteins are transporter and channels. Transporter – A specific , allowing only those ions that fit the unique binding sites on the protein. A transporter undergoes conformational changes to enable membrane transport. Channel – when open, forms a pore across the lipid bilayer that allows ions and selective polar organic molecules to diffuse across the membrane. Transport by channel depends on the size and electrical charge of the molecule. Active transport – Large molecules that moved in and out of the cell via active transport; which require life, biologic activity and the cell’s expenditure of metabolic energy. Unlike passive transport, active

transport occurs across only living membranes that have to drive the flow “uphill” by coupling it on energy source. Diffusion – The movement of a solute molecule from an area of greater solute concentration to an area of lesser solute concentration, this difference in concentration is known as a concentration gradient. According to the same principle, if the concentration of particles is greater on one side of a permeable membrane than on the other side the particle diffuse spontaneously from the area of greater concentration to the area of less concentration. Osmosis – the movement of water “down” a concentration gradient, that is, across a semipermeable membrane from a region of higher water concentration to a region of lower water concentration. For osmosis to occur, the membrane must be more permeable to water than to solutes and the concentration of solutes must be greater so that water moves more easily Osmosis is directly related to both hydrostatic pressure and solute concentration but not to particle size or weight. **Review immunity to include *active natural, active artificial, *passive natural, passive artificial**

1. Active vs. Passive Immunity a) Active immunity – active acquired immunity i) Active natural are antibodies or T-cells are produced after either a natural exposure to an antigen ii) Active artificial is after immunization iii) Is long lived b) Passive Immunity – passive acquired immunity i) Preformed antibodies of T-Lymphocytes are transferred from a donor to a recipient. ii) Passive natural (placenta to fetus) iii) Passive artificially via immunotherapy for a specific disease. iv) Is temporary or short lived because the donor’s antibodies are eventually destroyed. Review inflammation and how it impacts or affects disease in the body a) Inflammation is programmed to responds to cellular or tissue damage, whether the damage tissue is septic (contaminated with microorganisms) or sterile. b) Inflammation – an efficient local and systemic response is mobilized to limit the extent of damage. c) Innate immunity (natural or native immunity) – The natural epithelial barrier and inflammation confer innate resistance and protection. d) Adaptive immunity (acquired or specific immunity) – Inflammation associated with infection usually initiates an adaptive process that results in a long-term and very effective immunity to the infecting microorganism.
2. Second line of defense: pg. 194 a) Inflammatory response: a rapid initiation and interactive system of humoral (soluble in the blood) and cellular systems designed to limit the extent of the tissue damage and destroy contaminating infectious microorganisms, and initiate the adaptive immunity and begin the healing process.

b) Has three primary systemic changes associated with the acute inflammatory response are fever, leukocytosis (a transient increase in the level of circulating leukocytes), and plasma proteins synthesis ( increased levels of circulating plasma proteins). i) Cardinal signs: heat, swelling, pain, and loss of function ii) Vascular response (1) Increased vasodilation – Increased size of blood vessels)  increases blood flow to the injured site (2) Increased vascular permeability – blood vessels become porous and leakage of fluid out of the vessels (exudation) cause swelling (edema) at the site of injury. The increased blood flow and concentration of red cells at the site of inflammation cause locally increased redness and warmth. (3) WBC adhere to the inner walls of vessels of vessels and they migrate through enlarged junctions between the endothelial cells lining the vessels into the surrounding tissue. (4) Benefits of inflammation include: (a) Prevention of infection and further damage (b) Limitation and control of the inflammatory process through the influx of plasma protein systems (clotting system) to prevent the inflammatory response from spreading to areas of healthy tissue. (c) Interaction with components of the adaptive immune system to elicit a more specific response to contaminating pathogens through the influx of macrophages and lymphocytes. (d) Preparation of the area of injury for healing through the removal of bacterial products, dead cells, and other products of inflammation. (5) Inflammatory stages (Figure 7.5 – page 196) Cellular injury (arterioles dilate)Acute inflammation (a result of increased blood flow and leakage of plasma causing redness and warmth)  Chronic inflammation + Healing  Granuloma + Healing  Healing. c) Three key plasma protein systems are essential to an effective inflammatory response: complement system, clotting system, and the kinin system. i) Complement system - activation of the complement system produce several factors that can destroy pathogens directly and can activate or collaborate with other components of the innate and adaptive immune response ii) Clotting system – the clotting (coagulation) is a group of plasma proteins that when activated sequentially, forms a blood clot at an injured or inflamed site. iii) Kinin system – augments inflammation in several ways. Bradykinin causes dilation of blood vessels acts with prostaglandins to stimulate nerve endings and induce pain. i) Cellular Mediators of inflammation p. (1) Cellular receptors (a) Toll-like receptors (TLRs) (Table 7.2- pg 201 )– Expressed on the surface of many cells that have direct and early contact with potential pathogenic microorganisms. These include mucosal epithelial cells, mast cells,

neutrophils, macrophages, dendritic cells, and some subpopulations of lymphocytes. (b) Complement receptors - found on many cells of the innate and adaptive immune responses. Such as granulocytes, monocytes/macrophages, lymphocytes, mast cells, erythrocytes, and platelets. Under a variety of normal and disease-related condition, immune complexes of antibody, antigen, and complement form in the blood and removed by cells expressing surface complement receptors. (c) Scavenger receptors - primary expressed on macrophages and facilitate recognition and phagocytosis of bacterial pathogens as well as damaged cells and altered soluble lipoproteins and associated with vascular damage. Thus, macrophages though this receptor, can identify and removed old RBCs and cells undergoing apoptosis. Another important scavenger receptor is CD14 , which recognizes the complex of LPS and LPS-binding protein. LPS- binding protein is up-regulated during inflammation by the cytokines IL- and IL-1 and helps remove bacterial LPS (endotoxin) from the circulation. (d) NOD like receptors – are cytoplasmic receptors that recognize products of microbes and damaged cells. NOD-1 and NOD-2 are cytoplasmic and recognize fragments of peptidoglycans from intracellular bacteria and initiate production of proinflammatory mediators, such as tumor necrosis factor (TNF) and IL-6. (e) Cytokines p. 201 - may either be proinflammatory or anti-inflammatory, depending on whether they tend to induce or inhibit the inflammatory response. the majority of important cytokines are classified as interleukins or interferons. (i) Interleukins – Biochemical messengers produced predominantly by macrophages and lymphocytes. Their effects include the following:

1. Alteration of adhesion molecule expression on many types of cells
2. Attraction of leukocytes to a site of inflammation (chemotaxis)
3. Induction of proliferation and maturation of leukocytes in the bone marrow
4. General enhancement of suppression of inflammation
5. Mediation of development of the acquired immune response. (ii) Interferons p. 203– are members of a family of low-molecular weight proteins that primarily protect against viral infections and modulate the inflammatory response. (iii) Chemokines - are members of he a family of low-molecular weight peptides that function primarily to induce leukocyte chemotaxis. Chemokines can be synthesized by macrophages, fibroblasts, and endothelial cells in response to proinflammatory cytokines. can be stimulated to produce chemokines, in response to Macrophages proinflammatory cytokines; by recognition of either infectious microorganisms or a Beta-defensin.

Differentiated B cells becomes a plasma cell (a factory of antibody production) and can be found in the blood, secondary lymphoid organs (primarily in the spleen and lymph nodes). And some inflammatory sites. (iv) Mast cells are the first to respond bc of their location on the skin, GI, and resp tracts. P. 203 Review cellular immunity compared to humoral immunity a) Humoral and cell-mediated immunity i) Humoral Immunityl : Antibodies that circulates in the blood and secretions and defends against extracellular microbes found in those fluids and microbial toxins.

• called humoral immunity. (1) B -Cell clonal selection: The humoral Immune response (a) (b) Can be measured by “titer”, the higher the titer, indicates more antibodies. (c) B-Memory cells – during the clonal selection process, B cells differentiate into antibody producing plasma cells and into a set of long-lived memory cells. Memory cells remain inactive until subsequent exposure to the same antigen; upon reexposure these memory cells will differentiate rapidly into new plasma cells to produce larger amounts of antibody. ii) Cellular Immunity: Effector T-cells are found in the blood and in tissues and organs and defend against intracellular pathogens and cancer cells. T-cells may develop cytokines that stimulate the protective response of other leukocytes. (1) Clonal selection of other T-cell phenotypes is dependent on help by the Th cell phenotype. Other effector cells include Tc cells that attack and destroy cells expressing antigens of intracellular (endogenous) origins (virus-infected cells, cancer cells) T-regulatory cells (Treg cells) that limit (suppress) the immune response, and T-memory cells that provide a rapid cell-mediated immune reaction to repeated exposure to the same antigen (secondary immune response). Review stress and it’s impact on inflammation, disease, immunity p, 325 - Fib. 11. Stress activates the SNS to stimulate the release of catecholamines (epinephrine and norepinephrine) from the adrenal medulla into the bloodstream and never endings that innervate peripheral organs and tissues. Sympathetic system: Epinephrine
• Metabolic – causes transient hyperglycemia, decreases glucose uptake in the muscles and other organs and deceases insulin release from the pancreas.
• Cardiac – enhances myocardial contractility (inotropic effect), increases heart rate and increases venous return to the heart, all of which increase increases cardiac output and blood pressure.

• Vascular - Epinephrine dilates blood vessels of skeletal muscle, allowing for greater oxygenation.
• GI – Epinephrine mobilizes free fatty acids and cholesterol by stimulating lipolysis freeing triglycerides and fatty acids from fat store, and by inhibiting the degradation of circulating cholesterol to bile acids; aiding the metabolic actions of cortisol. Parasympathetic system:
• Has anti-inflammatory effects and opposes the sympathetic (catecholamine) responses, for example, by slowing the heart rate. Hypothalamic-Pituitary-Adrenal system p. 326, p. 326
• The hypothalamus secretes corticotropin-releasing hormone (CRH), which binds to specific receptors on anterior pituitary cells that in turn, produce adrenocorticotropic hormone (ACTH). ACTH then is transported through the blood to the adrenal glands. The adrenal glands then release cortisol. Cortisol circulates in the plasma which then stimulates glyconeogenesis (formation of glucose from non-carbohydrate sources) from amino acids or free fatty acids in the liver. Cortisol enhances the elevated of blood glucose level promoted by other hormones such as epinephrine, glucagon, and growth hormone. Cortisol also affects protein metabolism, it increases the rate of synthesis of proteins and RNA in the liver. The anabolic effect is counteracted by the catabolism of protein to increase levels of circulating amino acids (chronic exposure to cortisol can severely deplete protein stores in muscles, bone, connective tissue, and skin. Stress, illness, and coping p. 338
• Repetitive stressors are based on a person’s appraisal of a situation.
• Evidence also points to the emerging connection between early stressful life events and a range of chronic illness in later life. Children adversity increases the risk of developing CVD, type 2 DM, cancer, and number of somatic disorders.
• This complex interplay connecting stress, depression, and inflammation may be understood in the context that stress is known to upregulate proinflammatory cytokines. o One mechanism involving proinflammatory cytokines on major depression is the effects of Tumor Necrosis Factor alpha, IL-2 and IL 6 in breaking down tryptophan, the essential amino acid of serotonin synthesis. Overtime, stress-induce proinflammatory cytokines reduce serotonin degradation that together contribute to alterations in mood, emotion, and motivational states and the eventual onset of major depression. o The risk of stress induced inflammation and depression is oxidative stress, which potentially damages or shortens the telomeres and accelerates aging, and increases the

risk for cancer, CVD, DM, obesity, Alzheimer disease, and early death.

o The relationship between stress and CV health may be mediated by stress-induced changes in immune functions, which may potentiate proinflammatory processes and permit alterations leading to heart disease. o Toxic exposure of glucocorticoids and catecholamines that promote oxidation, inflammation, and telomere shortening also is link to depression, bipolar, and possibly anxiety disorders. (a) Glucocorticoids, stress, and the immune system: (i) In regards to stress and immunity, the adrenal glands release glucocorticoid (mainly cortisol) into the bloodstream; then this cortisol inhibits the initial inflammatory response by suppressing the activity of Th1 cells, resulting in a decrease in innate immunity as well as the proinflammatory response. Cortisol also affects the activity of the Th cell, resulting in the increase of adaptive immunity and the anti- inflammatory response. Immune responses are regulated by innate immunity, such as monocytes/macrophages, dendritic cells, other phagocytic cells, and Th1 and Th2 lymphocytes; all which secrete chemical messengers known as cytokines. These cytokines are the interferons, interleukins, and tumor necrosis factor, they control innate and adaptive immune responses Understand hypersensitivity reactions

2. Hypersensitivity p. 256, table 9.1 and 9. a) Is characterized by the immune mechanism i) Type 1 – seasonal allergies - environmental (a) IgE mediated (cells involved: mast cells) (b) Mediated Reactions – Allergy (ex: pollen allergies, seasonal allergies) (i) 1 st^ time – First Exposure: Sensitization (ii) 2 nd^ time – Subsequent exposure: allergic reaction ii) Type 2 – Blood transfusion, organ transplant, ABO (a) Binds to antigen on the cell surface (b) Tissue specific reactions (IgG, IgM) – (cells involved: Macrophages in tissues) (c) Induced cell malfunction (i) Tissue specific: Specific cell or tissue (tissue specific antigens) is the target of an immune response. iii) Type 3 – Glomerulonephritis, arthritis, vasculitis (a) Binds to the antigen in the blood and complexes are formed in circulation and is deposited into the tissue. (b) Immune complex mediated (antigen-antibody) – (cells involved: Neutrophils) ( IgG, IgM) (i) Causes release of neutrophil chemotactic factor (i.e., Arthritis, )

iv) Type 4 - Graft rejection, poison ivy, TB skin test, metals (jewelry) (a) No antibody involved (T-cell activated) (no Antibody) (i) Cytotoxic T-cells are stimulated (cells involved: Lymphocytes, macrophages).

1. Examples: Acute graf t rejection, skin test for TB, contact allergic reactions, and some autoimmune diseases (b) Delayed v) All can be life threatening Alloimmunity - 255 Understand how the body compensate for anemia

• Anemia – the reduction on the total circulating red cell mass or a decrease in the quality or quantity of hemoglobin. o Anemias commonly result from ▪ Blood loss acute/chronic ▪ Impaired erythrocyte productions ▪ Increased erythrocyte destruction ▪ Combination of these factors
• Compensation generally involves the cardiovascular, respiratory, and hematologic systems
• Blood loss – Within 24 hours of blood loss, lost plasma is replaced by mobilizing water and electrolytes from tissues and interstitial spaces into the vascular system.
• Erythropoiesis – development of RBCs in the bone marrow.
• In conditions of tissue hypoxia, erythropoietin is secreted by the liver and primarily the peritubular cells of the kidney.
• The body responds to reduced oxygenation in blood in two ways: o 1) stimulation of chemoreceptors of the carotid body and aortic arch that signals the brain to increase oxygen intake through increased ventilation o 2)stimulation of receptors on the kidney peritubular cells to increase erythropoietin synthesis and release. Review and understand each of the anemias and how they would look on a CBC. Macrocytic-Normochromic Anemias
• Are also termed megaloblastic anemias.
• RBCs are unusually large.
• DNA synthesis is defective. Due to deficiencies in vitamin B 12 or folate.
• Pernicious anemia (most common example) Lacks intrinsic factor from the gastric parietal cells.

Pernicious anemia. Pernicious anemia is caused by inadequate or absent production of intrinsic factor (IF) by gastric parietal cells. Complete or partial removal of the stomach (gastrectomy) causes IF deficiency

• Required for vitamin B 12 absorption **Another Macrocytic-Normochromic Anemia
• Folate (folic acid) deficiency anemia** Is common in alcoholics and individuals with chronic malnourishment. Is associated with neural tube defects of the fetus. Clinical manifestations (specific) Severe scales/fissures of the lips/and corners of the mouth Stomatitis: Mouth inflammation Painful ulcerations of the buccal mucosa and tongue Dysphagia (difficulty swallowing), flatulence, and watery diarrhea Treatment Oral dose of folate is administered daily until normal blood levels are obtained. Life-long treatment is not necessary. - Normocytic- Normochromic Iron-deficiency anemia Most common type of anemia worldwide Highest risk: Older adults, women, infants, poverty
• Clinical manifestations (specific) Brittle, thin, coarsely ridged, and spoon-shaped (concave or koilonychia) nails Red, sore, painful tongue Angular stomatitis: Dryness and soreness in the corners of the mouth Become symptomatic: When hemoglobin (Hgb) 7 to 8 g/dl Causes of Iron-deficiency anemia
• Inadequate dietary intake
• Excessive blood loss
• Chronic parasite infestations
• Disorders of iron and heme metabolism
• Menorrhagia (excessive bleeding during menstruation)
• Use of medications that cause gastrointestinal bleeding (aspirin, nonsteroidal NSAIDs- (chronic GI bleeding-common)
• Surgical procedures that decrease stomach acidity, and absorption (e.g., gastric bypass)
• Eating disorders, such as pica (craving and eating nonnutritional substances such as dirt, chalk, and paper) - Aplastic anemia Pathophysiology Hypocellular bone marrow that has been replaced with fat due to autoimmune response Clinical manifestations (specific) Occasionally a brownish pigmentation of the skin Weakness along with fever and dyspnea with rapidly developing signs of hemorrhaging if platelets are affected Evaluation Bone marrow biopsy

Aplastic anemia. Aplastic anemia is the result of bone marrow suppression or failure caused by an autoimmune disease directed against the hematopoietic stem cells that produces pancytopenia.

• Aplastic anemia
  • Treatment Bone marrow transplantation Peripheral blood stem cell transplantation May receive radiation or chemotherapy before procedure Immunosuppression Antithymocyte globulin with cyclosporin Corticosteroidal medications Identification of high-risk individuals If not treated or identified, death occurs - Hemolytic anemia
• Two causes: Autoimmune hemolytic anemias Drug-induced hemolytic anemia Form of immune hemolytic anemia that is usually the result of an allergic reaction against foreign antigens Penicillin, cephalosporins (more than 90s%), hydrocortisone
• Anemia of chronic disease Mild-to-moderate anemia from decreased erythropoiesis Malaria, AIDS, rheumatoid arthritis, lupus erythematosus, hepatitis, renal failure, and malignancies Pathologic mechanisms Decreased erythrocyte lifespan Suppressed production of erythropoietin Ineffective response of bone marrow to erythropoietin (Remember: comes from kidney) Altered iron metabolism Failure to increase erythropoiesis in response to decreased numbers of erythrocytes Understand all the aspects of a CBC

P. 932 Normocytic-normochromic anemia Caused by acute blood loss, mainly a loss of intravascular volume and the effects depend on the rate of hemorrhage that can lead to cardiovascular collapse, shock , and death. If acute blood loss is not severe, within 24 hrs of blood loss, lost plasma is replaced by mobilizing water and electrolytes from tissues and the interstitial spaces into the vascular system, causing hemodilution. If Blood loss is severe, ore immature cells -metamyelocytes and nucleated RBCs may enter the circulation, and kidneys are stimulated to produce erythropoietin due to the lack of oxygen in the blood, which then stimulates the bone marrow to make erythrocytes (reticulocytes). Megaloblastic Anemia (occurs in bone marrow) The cells are challenged to make DNA, however, RNA production process normally. The cells have slow-maturing nuclei but have normal maturing cytoplasm. Therefore, megaloblastic erythroid precursors how large before the larger nuclei become mature enough to signal division (causing the cell to be larger than normal). These defective erythrocytes die prematurely causing anemia. Prevalence: Due to lack of Vit. B12 – seen among the poor, elderly, and alcoholics. Pernicious anemia – seen with megaloblastic anemia. Principal disorder is the lack of Intrinsic Factor (IF), which is secreted by gastric parietal cells and complexes with Vit. B12 in the small intestine, in the ilium. Clinical manifestations – develops slowly, non-specific symptoms: infections, mood swings, and GI, cardiac, or kidney ailment. If Hgb 7-8g/dL, s/s of weakness, fatigue, paresthesias of feet/fingers, walking difficulty, loss of appetite, abdominal pains, atrophic glossitis. Microcytic-Hypochromic anemia

Characterized by abnormally small erythrocytes that contain unusually reduced amounts of hemoglobin. – Common nutritional disorder of micro-hypochromic anemia is iron deficiency anemia. Prevalence: Iron deficiency anemia. Causes: dietary deficiency, impaired absorption, and increased requirement, and chronic blood loss. Iron deficiency anemia – most common type of nutritional disorder. Common in the US with toddlers, adolescent girls, and women of childbearing age, and children, poverty, and infants drinking cow’s milk. Review non-Hodgkin’s vs Hodgkin’s Lymphoma Malignant Lymphomas

• Make up a diverse group of neoplasms that develop from the proliferation of malignant lymphocytes in the lymphoid system.
• Two major categories Hodgkin lymphoma Linked to EBV

Characteristics Hodgkin Non-Hodgkin Nodal involvement Localized to single axial group of nodes (e.g., cervical, mediastinal, para- aortic) Multiple peripheral nodes Extranodal involvement Rare Common Spread Orderly spread Noncontiguous Fever, night sweats, weight loss Common Uncommon Reed Sternberg cells Present Not present Extent of disease Often localized Rarely localized Hodgkin has better prognosis Hodgkin Lymphoma (HL) – p. 979,

• Hodgkin lymphoma. Reed-Sternberg (RS) cells are large, often binucleated or mononucleated and represent malignant transformed lymphocytes and diagnostic for Hodgkin lymphoma (HL). HL is characterized by its progression from one group of lymph nodes to another, the development of systemic symptoms, and the presence of Reed-Sternberg (RS) cells.
• Survival of this cell may be linked to infection with EBV.
• Clinical manifestations: Adenopathy, mediastinal mass, splenomegaly, abdominal mass.
• Symptoms: fever, weight loss, night sweats, prutitis.
• Laboratory findings: leukocytosis, thrombocytosis, eosinophilia, elevated ESR, elevated alkaline phosphatase, paraneoplastic syndrome.
• Types:
• Treatment
  • Nodular sclerosis (Lymphoma HL) - * most common type
  • Mixed cellularity HL
  • Lymphocytic rich classic HL
  • Lymphocyte depletion HL
  • Stage 1 or 2 – survival rate 90-95%; are candidates for chemotherapy, radiation therapy, or a combination of these treatment modalities

• Stage 3 – survival rate 80-85%
• Stage 4 – survival rate 75%
• Survival rate is related to white count, if high >15,000 (poor) or a low Hgb <10.5 (poor) , low lymphocyte <600, and male.
• Cure for HL can be achieved in 75% of cases with current therapies.
• Combined treatment with radiation therapy and chemotherapy
• High-dose chemotherapy with bone marrow or stem cell transplantation
• Monoclonal antibodies
• Nonmyeloablative allogeneic stem cell transplantation Non-Hodgkin Lymphoma (NHL)
• Result from genetic
• A heterogeneous group of neoplasms arising from lymphoid tissue, with varied biologic and clinical features.
• Dependent on the type (B cell or T cell), tumor stage
• Histologic status (low, intermediate, high grade), symptoms, age, and any co-morbidities o Intermediate -high grade are aggressive – presents with high fever and night sweats, weight loss.
• NHL – has been reclassified in the WHO/REAL scheme into o 1 ) B-cell neoplasms – includes a variety of lymphomas including myelomas that originate from B-cells at various stages of differentiation. o T-cell and NK cell neoplasms – includes lymphomas that originate from either T- cells or NK cells. o These cancers are differentiated from HL by lack of RS cells and other cellular changes not characteristic of HL. Clinical Manifestations:
• Localized or generalized lymphadenopathy, cervical, axillary, inguinal, and femoral changes are the most commonly affected sites, swelling is painless and the nodes have enlarged and transformed over a period of months or years.
• Treatment
• Biopsy is primary for diagnosis
• Success of treatment is dependent on: type of lymphoma, stage, type of cell, involvement of organs, age, severity of the body’s reaction to the disease.
• Chemotherapy or radiation
• Combination of chemotherapy and radiation
• Monoclonal antibody: Rituximab
• Radioimmunotherapy: Combination of radiation therapy with monoclonal antibody therapy
• Survival: Extended periods but less than the survival rate for Hodgkin lymphoma
• 1 yr – 77%
• 5 yrs – 59%
• 10 yrs – 42%

Review acute vs chronic leukemia

4. Commonly has fever associated with hypermetabolism. Fever usually is present as a result of two causes: (1) infection associated with the decrease in functional neutrophils and (2) hypermetabolism associated with the ongoing rapid growth and destruction of leukemic cells. - ALL (Acute lymphoblastic leukemia) o 75-80% of childhood leukemias o Is composed of immature B (pre-B) or (pre -T) cells called lymphoblasts. o Many of the chromosomal abnormalities documental in ALL cause dysregulation of the expression and function of transcription factor required for normal B-cell and T-cell development o 1/3 of children have platelet count <20, o Organs involved: Renal failure, Extramedullary invasion, 10% have CNS involvement - AML (Acute myeloid leukemia) o 20-25% of childhood leukemias o Translocation of the long arms of chromosomes 9 and 22 (aka Philadelphia chromosomes) occurs in more than 97% of CML o Is caused by acquired oncogenic mutations that impair differentiation, resulting in the accumulation of immature myeloid blasts in the marrow and other organs. o Epigenetic alterations are frequent in AML and have a central role. o ½ platelet count of <50,000, DIC is common Clinical manifestations - Pallor, fatigue, petechiae, purpura, bleeding, and fever, hgb < Understand the pathophysiology of heart failure and how it may present in a patient Heart Failure - Lef t Heart Failure (CHF) - Systolic heart failure – reduced ejection fraction (HFrEF) - <40% - Diastolic heart failure – preserved ejection fraction Can occur individually or together Systolic Heart Failure - Inability of the heart to generate adequate cardiac output to perfuse tissues - Causes release of many hormones/mediators: - Catecholamines - RAAS: Angiotensin II and aldosterone

P STT P R Review the basics of an EKG

• Arginine vasopressin (antidiuretic hormone)
• Natriuretic peptides
• Inflammatory cytokines: Endothelial hormones, tumor necrosis factor- alpha (TNF-α) and interleukin 6 (IL-6)
• Myocyte calcium transport Insulin resistance and diabetes Systolic Heart Failure … See Diagram ** Right Heart Failure - Is the inability of the right ventricle to provide adequate blood flow into the pulmonary circulation.
• Can result from an increase in left ventricular filling pressure that is reflected back into the pulmonary circulation.
• Can result from diffuse hypoxic pulmonary disease.
• Treatment: Is the same as left heart failure. See Diagram *** R vs. L Heart Failure Characteristics Left Heart Failure Right Heart Failure Edema Pulmonary Peripheral Clinical manifestations Dyspnea, orthopnea, cough of frothy sputum Jugular venous distension and hepatosplenomegaly Pathophysiologic processes Inability of the heart to generate adequate cardiac output to perfuse vital tissues Inability of the heart to provide adequate blood flow into the pulmo circulation at a normal central venous pressure p. 1029

Q R S Intervals PR: 0.12 – 0.20 sec (a measure of time from the onset of atrial activation to the onset of ventricular activation) QRS: under 0.10 sec (represents the sum of all ventricular muscle cell depolarizations; usually 0.06 to 0.20 seconds) ST: the entire ventricular myocardium is depolarized QT: under 0.38 sec (sometimes called the electrical systole of the ventricles, it lasts about 0. seconds, but it varies.) Review valvular disorders in the heart ▪ Tricuspid atresia – no communication between the RA and RV. A common cyanotic heart defect. Causes exertional dyspnea, tachypnea and hypoxemia. Leads to polycythemia and clubbing. ▪ Aortic stenosis (AS) – a narrowing of the aortic outflow tract. Valvular stenosis is caused by malformation or fusion of the cusps – it is the most common type of AS. Limit exercise. Can lead to pulmonary vascular congestion and result in MI. ▪ Pulmonary stenosis (PS) – the narrowing of the pulmonary outflow tract; may be in the form of abnormal thickening of the valve leaflets or narrowing of the arterial (supravalvular) or ventricular (subvalvular) side of the valve. ▪ Pulmonary Atresia – severe form of PS and involves complete fusion of the commissures and narrowing the main PA, allowing no blood to flow out of the RV to the PA. Pulmonary blood flow to the lungs is now depended on a PDA. For survival a VSD or ASD / PFO is needed. ▪ Valvular dysfunction (p. 1092 Table 33.6)

• Valvular stenosis – valve orifice is constricted and narrowed, impeding forward flow of blood and increasing the workload of the cardiac chamber proximal to the diseased valve.
• Valvular regurgitation – the lave leaflets or cusps fail to shut completely permitting blood flow to continue when the valve is supposed to be closed. Review the genetics of conditions such as Cystic Fibrosis, marfan’s syndrome, Tay-Sachs disease, Down syndrome

Cystic Fibrosis – 1380 – An autosomal recessive disease that results from defective epithelial chloride ion transport; CF gene is located on Chromosome 7. The most common variant is called F508delCFTR, a protein is an activated chloride channel present on the surface of many types of epithelial cells, including those lining airways, bile ducts, the pancreas, sweat ducts, paranasal sinuses, ad the vas deferens. A disease of the exocrine glands that involves multiple organ systems but primarily the gastrointestinal and respiratory systems. Prognosis is mainly determined by the degree of pulmonary involvement with death caused by a combination of respiratory failure and cor pulmonale. Marfan’s syndrome – 1094 – Aortic or mitral regurgitation, aortic aneurysm, Mitral valve prolapse, often associated with inherited connective tissue disorder, thought to result from a genetic or environmental disruption of valvular development during the 5 th^ or 6 th^ week of gestation. Tay-sachs disease – 630 - Autosomal recessive, mutation of the HEXA gene (chromosome 15), lysosome storage disorder. Caused by a deficiency of hexosaminidase (an enzyme that degrades fatty acids within nerve cell lysosomes), an enzyme, which results in accumulation of a material that damages the brain. Onset of this disease is from 4-6 months old. Major neurologic features: FTT, blindness, seizures, progressive paralysis, usually death by age 4. Down syndrome – 144, 1120 – The karyotype of Down syndrome consists of 47 chromosomes and shows trisomy 21. Commonly has AVSD, VSD. Facial appearance is distinctive, a low nasal bridge, epicanthal folds, protruding tongue, a flat, low-set ears. Poor muscle tone (hypotonia) and short stature. Congenital heart defects after about 1/3 to ½ of live births, reduced ability to fight respiratory tract infections, and susceptibility to leukemia. Understand the flight or fight concept p. 323 a) Stress- encompasses both physiologic and psychologic ideas b) General adaptation syndrome (GAS), triad of syndrome of manifestations (1) The alarm stage or reaction with is the CNS (central nervous system) is aroused and the body’s defenses are mobilized (i.e. “fight or flight”) (2) The stage of resistance or adaptation during which mobilization contributes to “fight or flight”. (3) The stage of exhaustion where continuous stress causes the progressive breakdown of compensatory mechanisms (acquired adaptations) and homeostasis). Exhaustion marks the onset of certain diseases (diseases of adaptation). c) Initially one becomes alarmed by a stressor that activates the hypothalamus and SNS. The resistance or adaptation phase begins with the actions of the hormones cortisol, norepinephrine, and epinephrine. Exhaust (aka allostatic overload) occurs if the stress continues and adaptation is not successful, ultimately causing impairment of the immune response, heart failure, and kidney failure, leading to death.

2. Stress response (Table 11.1 – p. 328) Brain: Hypothalamus connected to the pituitary gland stimulated by the (Sympathetic Nervous System) SNS, releases the hormone Corticotrophin Releasing Factor (CRF) , CRF activates the pituitary gland, to release the adrenocorticotropic hormone (ACTH), which alerts the adrenal glands, adrenal glands are located on top of each kidney, ACTH from

pituitary activates the adrenal cortex to release cortisol, at the same time, neurons in the hypothalamus signal the epinephrine, adrenaline, norepinephrine, and noradrenaline, these hormones push the body into hyper alertness.