Immunology/Oncology Flashcards
Chemotherapy
“the management of illness by chemical means”
– affects dividing cells through disruption of DNA replication and/or cell division
Exmaples of Innate immunity
chemical: stomach acid and saliva pH
physical barriers: skin, tracheal mucus, mucosal endothelial surfaces, tears, and some cells of the immune system such as natural killer and phagocytic cells
Cytokines and enzymes are also part of innate immunity
Adaptive immunity
what is it mediated by?
term used for the body’s response to specific antigens.
– mediated by lymphocytes
Antibodies
immune response tailored to each type of antigen
– immune cells can produce specific immune proteins against spefic antigens
– retain a memory of the antigen in preparation for future encounters
Cytokines
what are they secreted by? What is their purpose?
– immune cells communicate using cytokines
– hormone‐like molecules secreted by lymphocytes, macrophages, and endothelial cells.
– Cytokines kill viruses and bacteria, stimulate hematopoiesis, mediate inflammatory responses, and activate the complement system.
Immunity classifications
x5
- innate or natural,
- acquired,
- passive,
- non‐specific or specific,
- cellular or humoral
Acquired immunity
Type of cells and types of immunity components
develops following exposure to various antigens
– specialized lymphocytes to produce antibodies that are specific for a particular antigen
– specialized B and T lymphocytes are activated by specific antigens and produce cell clones that attack foreign proteins
– Two components: humoral immunity and cellular immunity
Humoral immunity
– major defense system against bacterial infections.
– the function of activated B lymphocytes, known as plasma cells, that produce immunoglobulins (antibodies) which in turn activate the complement system to attack and neutralize antigens
– antigen–antibody complex → activates B lymphocytes
– As a B lymphocyte becomes an activated B lymphocyte, it undergoes many mitotic divisions to make numerous clones of itself
Cellular immunity
3 types of cells involved
x3 examples of this immunity
– mediated by T lymphocytes and is responsible for delayed allergic reactions, transplant rejection, and defense against viruses and neoplastic mutations.
– T lymphocytes have specific antigen receptors unique for single antigens.
– cloned, activated T lymphocytes make up three distinct populations:
1. killer T lymphocytes,
1. helper T cells, and
1. suppressor T cells.
Celluar = “T” mobile
Passive immunity
– defined by the transfer of antibodies from one individual to another, such as through the ingestion of colostrum or through placental circulation
– give the infant some protective and transient immunity but can cause significant illness if they fail – for example, failure of passive transfer in foals
Anaphylaxis definition
linically severe and life‐threatening type I hypersensitivity reaction with an acute onset following antigen exposure.
– caused by exposure to drugs, vaccines, food substances, reptile venom, insect venom, incompatible blood products, contrast agents, or ingested foreign material
three‐part classification system for anaphylactic reactions
- immunological IgE mediated,
- immunological non‐IgE mediated (IgG)
- non‐immunological
Immunological IgE‐mediated reactions
most commonly caused by insect stings and bites, reptile envenomation, food antigens, and drugs
– IgE antibodies are produced that bind to high‐affinity sites on mast cells in the tissue and basophils in the circulating pool
Immunological non‐IgE‐mediated reactions
commonly caused by immunoglobulin transfusions, complement activation, autoimmune disease, and coagulation cascade activation
– allergic response is mediated by IgG and macrophages
– much more antibody and antigen than the IgE‐mediated pathway
– These reactions do not release histamine
Non‐immunological reactions
caused by drugs such as chemotherapeutic agents or opioid analgesics and independent physical factors such as cold, heat, or exertion
– basophils and mast cells degranulate without the involvement of immunoglobulins
Pathophysiology of anaphylactic reactions
early response is clinically occult or undetectable but if the patient is re‐exposed to the antigen, → cross‐linking of the antibody molecules causes changes in the plasma membranes of the cell that permit an influx of extracellular calcium
– releases various stored and rapidly synthesized mediator products, including histamine, platelet activating factor (PAF), and cytokines, that potentiate the clinical signs of an anaphylactic reaction.
Histamine
where is it stored?
stored in the granules of mast cells.
Cardiovascular effects of anaphylaxis
rapid‐onset, refractory hypovolemic and distributive shock due to increased vascular permeability and vasodilation that causes swift and significant fluid shifts from the intravascular to the extravascular compartment
K9 “shock organs”
Liver and GIT
– histamine release within the GIT into portal vein induces hepatic vasodilation and an increase in hepatic blood flow.
– results in hepatic congestion and decreased venous outflow, further compromising blood flow from the hepatic circulation into the rest of the GIT
– reduced gastrointestinal venous return affects cardiac output and contributes to a global state of hypotensive and distributive shock
– Alters endothelial membrane permeability in the intestines → organ edema, fluid loss, hemorrhagic enteritis (that can start within minutes to hours following antigen exposure)
→ further contributing to hypovolemic shock
Feline “shock organs”
lungs and respiratory tract
Effects of Epinephrine for Anaphylaxis
– increase peripheral vascular resistance, counteracting vasodilation, and has positive effects on both blood pressure and coronary perfusion
– may have mast cell stabilizing properties and act as a PAF antagonist. It may also relieve respiratory distress and address some elements of shock
Chemotherapy‐Associated Neutropenia
– neutropenia typically secondary to overwhelming infection, neoplasia, or the myelosuppressive effects of parvovirus or chemotherapy
– Neutropenia secondary to chemotherapy commonly occurs in the 5–10 days following administration, although this is dependent on the agent administered
– graded 1- 4
Grade 1 neutropenia
neutrophil count at nadir is between normal for their species and 1500/μL
Grade 2 neutropenia
grade 2 (moderate) neutropenia is present when the neutrophil count is between 1500/μL and 1000/μL.
– Prophylactic broad‐spectrum antibiotic coverage can be considered at this point,
– CBC should be checked prior to the next dose of chemotherapy with a target neutrophil count of >3000/μL.
Grade 3 neutropenia
grade 3 (marked) neutropenia have a neutrophil count between 1000/μL and 500/μL and have an increased risk of secondary illness
– Antibiotics should be continued or initiated in these patients to prevent sepsis.
– next dose of chemotherapy should not be administered without a CBC done with neutrophil count seen above 3000/μL,
– dose should be reduced by 25%.
– best treated as outpatients if care is required, since hospitalization increases their risk of acquired illness
Grade 4 neutropenia
– severe with neutrophil count below 500/μL.
– at significant risk of sepsis and other secondary illness, even if they have been receiving antibiotic therapy
Chemotherapy
Gastrointestinal toxicity
two main ways that chemotherapy can cause gastrointestinal signs: centrally mediated nausea and direct injury to the stem cells of the intestinal crypts.
Chemotherapy
Crypt cells
crypt cells of the intestines commonly affected by chemotherapy
–causes GI side effects
Tumor Lysis Syndrome definition
oncological emergency that occurs following the death of tumor cells due to chemotherapy, radiation therapy, or spontaneous lysis
– sequel to chemotherapeutic or radiation therapy of hematological (i.e. lymphoma, leukemia) and solid tumor malignancies, most commonly within 48 hours of the initial therapy
Tumor lysis syndrome diagnosis
separated into laboratory and clinical syndromes
– “Laboratory” tumor lysis syndrome is diagnosed based on derangements in uric acid, potassium, phosphorus, and calcium
– “clinical” tumor lysis syndrome is diagnosed when laboratory tumor lysis syndrome is present along with elevated creatinine, seizure, cardiac arrhythmias, or acute death
Oncology
ATLS is characterized by
hyperkalemia,
hyperphosphatemia
metabolic acidosis
PathPhys of Tumor Lysis Syndrome
After cancer cells die they rupture and release previously intracellular products into the circulation, primarily calcium, nucleic acids, phosphorus, and potassium
= hypocalcemia, hyperkalemia, and hyperphosphatemia; hyperkalemia results in bradycardia cardiac arrhythmia
– rapid release of cellular byproducts overwhelms the body’s ability to clear and recycle waste → AKI common result from calcium and phosphorus precipitation → Hypocalcemia commonly occurs secondary to hyperphosphatemia and acute kidney injury (AKI) is a common sequalae of ATLS.
Tumor cells can contain up to four times the normal quantity of phosphorus
AKI from ATLS
– rapid release of cellular byproducts overwhelms the body’s ability to clear and recycle waste → AKI common result from calcium and phosphorus precipitation →
– Hypocalcemia commonly occurs secondary to hyperphosphatemia and acute kidney injury (AKI) is a common sequalae of ATLS.
Urate nephropathy
– results when the purines adenine and guanine are metabolized into xanthine that is then metabolized into uric acid
– calcium phosphate salts may be deposited in the renal tubules.
– Coupled with damage by other nephrotoxins and volume depletion, this can result in oliguric renal failure
Treatment: Tumor lysis syndrome
– IVF essential but cautiously in the face of renal oliguria or anuria
– 0.9% saline and diuretics used to promote calciuresis
– treatment for hyperkalemia if indicated
Antihyperuricemic therapy for tumor lysis syndrome
– goal to lower uric acid levels
– xanthine oxidase inhibitors such as allopurinol or febuxostat and the recombinant urate oxidase enzyme rasburicase
– Allopurinol prevents the conversion of hypoxanthine to xanthine and hence xanthine to uric acid; however, it has many potential adverse drug reactions
Paraneoplastic Syndromes definition
any systemic illness that is induced by neoplasia but occurs in a body system far from and unrelated to the primary tumor
– illness can be acutely more serious than the primary disease and can be the first indication of the primary neoplasia.
Most common paraneoplastic syndromes in dogs
– caused by the production of polypeptide hormones that lead to endocrine‐like effects such as hypercalcemia and hypoglycemia.
– others include: anemia, thrombocytopenia, fever, cachexia, cutaneous abnormalities, and neurological signs.
Paraneoplastic syndrome
Several types of anemia are associated with neoplasia
affects 30% of dogs with cancer
– may be related to chronic disease, blood loss, immune‐mediated hemolysis, chronic chemotherapy, or pure red cell aplasia
Paraneoplastic syndrome
Anemia of chronic disease
– most common abnormality and results from decreased iron availability, shortened erythrocyte life span, and decreased erythropoiesis.
– characterized as normocytic, normochromic, and non‐regenerative.
– Iron replacement therapy will enable hemoglobin synthesis, help correct the anemia, and replenish iron stores (along with treating source of chronic blood loss)
Paraneoplastic syndrome
Blood loss anemia
– observed with bleeding tumors (e.g. hemangiosarcoma) and is generally microcytic, hypochromic, and can be either regenerative or non‐regenerative.
Paraneoplastic syndrome
IMHA and ITP as paraneoplastic syndromes
Can be seen with which neoplasia?
can be seen with K9 lymphoma
– secondary to protein production by malignant lymphocytes that either bind to or mimic antigens on red blood cells or platelet membranes, resulting in immune‐mediated destruction of red blood cells
– thrombocytopenia can be caused by the production of antiplatelet antibodies by the tumor, and cross‐reactivity between tumor antigens and platelet antigens
Other paraneoplastic complete blood count abnormalities
eosinophilia, considered a marker for systemic or intestinal mast cell neoplasia
Paraneoplastic syndrome
Leukocytosis
– A leukocytosis without obvious infection or other inflammatory causes has been associated with lymphoma and with tumors of the lungs, gastrointestinal tract, and genitourinary system
– thought to be from cytokine production that enhances the production of granulocytes and their release from bone marrow into the peripheral blood
Chemistry abnormalities associated with paraneoplastic syndromes
– hypercalcemia and hypoglycemia
– Hypercalcemia of malignancy occurs secondary to tumor cell production of a parathyroid hormone‐related peptide (PTHrp) and is the most common metabolic emergency seen in veterinary patients with cancer.
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Malignancies that can cause hypercalcaemia
- lymphosarcoma,
- anal gland adenocarcinoma,
- carcinoma of the thyroid, prostate, or mammary glands,
- thymoma,
- bone neoplasia,
- multiple myeloma,
- leukemias
Paraneoplastic hypoglycemia
often associated with insulinoma and other tumors such as:
1. adenocarcinoma,
1. lymphoma,
1. hepatomas,
1. leiomyomas
1. leiomyosarcomas,
1. carcinomas,
although any tumor can induce hypoglycemia
mechanisms of paraneoplastic hypoglycemia
3 possible mechanisms
secretion of insulin‐like peptides,
– glucose consumption by tumor cells,
– and impaired or altered gluconeogenesis and glycogenolysis in the liver
ALKYLATING Chemo Agents
x5
- Chlorambucil (Leukeran)
- Cyclophosphamide (Cytoxan)
- Procarbazine
- Melphalan (Alkeran)
- Lomustine CCNU
ANTHRACYCLINES Chemo Agents
- Doxorubicin (Adriamycin)
- Mitoxantrone (Novantrone)
ANTIMETABOLITES Chemo Agents
x3
- 5-Fluorouracil (5-FU)
- Cytosine arabinoside (Cytarabine, Cytosar-U,)
- Gemcitabine (Gemzar)
ANTITUBULIN Chemo Agents
x2
- Vinblastine
- Vincristine
PLATINUM Chemo Drugs
x2
- Carboplatin
- Cisplatin
TYROSINE KINASE INHIBITORS
Toceranib (Palladia)
MISCELLANEOUS Chemo Agents
x3
- L-asparaginase (Elspar)
- Imiquimod 5% cream (Aldara)
- Prednisone/prednisolone
Chemo agents that can possibly cause Allergic reactions
L-asparaginase, etoposide, and doxorubicin, and taxanes such as paclitaxel may cause IgE-mediated type I hypersensitivity reactions.
Bone marrow toxicity
Myelosuppression is a common side effect of chemotherapy but can also occur secondary to cancer, either by myelophthisis or paraneoplastic immune-mediated processes.
How soon can you see myelosuppression after chemo?
neutrophil nadir varies somewhat depending on the chemotherapy agent administered but most often occurs around 7 to 10 days after treatment.
Cardiotoxicity
Doxorubicin may cause cardiotoxicity in dogs and the resulting disease is similar to dilated cardiomyopathy (DCM).
Hepatotoxicity
after which chemo?
Hepatoxicity secondary to CCNU (lomustine) administration is relatively common in dogs
– CCNU-induced hepatoxicity is rare in cats.
Neurologic toxicity
5-Fluorouracil (5-FU) is extremely neurotoxic in cats and should never be administered in any form; results in a fatal reaction that may include excitability, blindness, tremors, dysmetria, and death
– toxicities in dogs have been reported after ingestion of these topical creams.
– grand mal seizures, tremors, dyspnea, and vomiting
Pulmonary toxicity
– Respiratory complications of cancer are generally due to advanced staged metastatic disease
– there are rare reports of chemotherapy drugs causing pulmonary pathology
– Cisplatin can cause fatal pulmonary edema in cats and should not be administered to this species
– Bleomycin has been reported to cause intestinal pneumonia and pulmonary fibrosis, and case reports exist of pulmonary fibrosis secondary to alkylating agents such as CCNU
Tranfusion Medicine
Immune Complex Formation; Type III hypersensitivity
– formation and depositing of immune complexes in areas such as the glomeruli, endothelial cells, lymph nodes, and synovium,
– can lead to neutrophil migration, activation, and inflammation resulting in glomerulonephritis, vasculitis, lymphadenitis, and immune‐mediated arthritis within hours to weeks of exposure
– use of protein concentrates such as human serum albumin is suspected to cause type III hypersensitivity
acute type 1 hypersensitivity response
– allergica reaction to antigen
– range from life-threatening to mild reaction
– typically occur within 1 hr of exposure
– may be localized to cutaneous manifestations such as angioedema, erythema, urticaria, and pruritus. Gastrointestinal signs such as vomiting and diarrhea may be also seen with generalized or systemic allergic reactions
– recently recognized signs of canine anaphylaxis include elevated alanine transaminase and increased gallbladder wall thickness
