V410 Exam II Flashcards
(234 cards)
1
Q
(L14) What is surgical oncology?
A
Surgical oncology is using surgery to diagnose and treat cancer. It incorporates cancer biology and behavior, diagnostic tools, therapeutic intent, and possible surgical outcomes.
2
Q
(L14) What is surgical dose?
A
Surgical dose, in the context of oncology, is how much surgery should be applied to treat a tumor. The extent of surgery depends on the tumor type, its stage, its location, the possibility of other treatments, concurrent disease, and owner preference.
3
Q
(L14, 24) What is the difference between a tumor’s grade and its stage?
A
A tumor’s grade describes the appearance of its cells on histopathology and is an indication of the tumor’s behavior. A tumor’s stage is the extent to which the cancer has spread throughout the body, locally or systemically.
4
Q
(L14) What are two methods that we use to determine what a mass is? What are the pros and cons of either?
A
With a mass, you can either take a fine needle aspirate or a biopsy. FNAs are fast, easy, cheap, and can indicate the cell of origin relatively quickly but they’re often not completely diagnostic. They’re good tool to guide additional diagnostics. A biopsy is more invasive, but is more likely to provide a solid diagnosis.
5
Q
(L14) Distinguish between an incisional and excisional biopsy.
A
A small piece of a tumor is submitted in an incisional biopsy. For an excisional biopsy, the entire mass is removed and submitted for review.
6
Q
(L14) When would an incisional biopsy be indicated?
A
You should do an incisional biopsy when the information will change the work-up and treatment plan. For example, an incisional biopsy would be for tumors in which the differentials could affect prognosis and treatment options, and you wouldn’t want to commit to surgical removal of the whole tumor without understanding the cancer’s behavior.
7
Q
(L14) What are three basic goals for an incisional biopsy?
A
- obtain a diagnostic sample 2. minimize local contamination of adjacent tissue 3. preserve as many treatment options as possible
8
Q
(L14) When would an excisional biopsy be indicated?
A
You may want to take an excsional biopsy when the information would not affect your treatment plan. In other words, excision is an option if the treatment plan wouldn’t change regardless of tumor type. Excision could also work if the tumor was in a location that allowed for complete removal or if incision would likely risk metastasis.
9
Q
(L14) Briefly describe the process of staging.
A
Staging a tumor is evaluating how much it’s spread throughout the body. Through imaging and sampling of various locations, we have to determine the tumor type and the extent to which it spread locally to adjacent tissue, regionally to lymph nodes, and diffusely to distal sites.
10
Q
(L15) What is the difference between a surgical margin and a histologic margins?
A
A surgical margin is what is measured during surgery from the incision site to the palpable edge of the tumor. A histologic margin is assessed under a microscope - it’s the distance from the cut edge of a biopsy to the closest tumor cell.
11
Q
(L15) When referring to surgery, what are lateral and deep margins?
A
The lateral margins of an incision include the normal tissue removed in all directions around the sides of a visible tumor. The deep margin is the amount of normal tissue removed beneath a tumor.
12
Q
(L15) What is a fascial plane?
A
A fascial plane is the interface between two tissue layers.
13
Q
(L15) Describe an intracapsular excision.
A
With an intracapsular excision, or debulking, a tumor’s pseudocapsule is left intact. Some material within the pseudocapsule is removed, often with visible tumor matter left in the patient.
14
Q
(L15) Describe some pros and cons to an intracapsular excision.
A
Pros: 1. temporary treatment for a tumor’s negative effects Cons: 1. not curative 2. benefits are temporary until tumor regrows 3. risks seeding tumor cells 4. can complicate future treatments or procedures
15
Q
(L15) Describe a marginal excision.
A
A marginal excision involves removal of a visible tumor with as little normal tissue taken as possible, leaving microscopic traces. Some normal tissue can be removed along with the tumor, but as long as one area of the excision is immediately adjacent to the tumor’s margin, the entire procedure can be considered marginal.
16
Q
(L15) Describe some pros and cons to a marginal excision.
A
Pros: 1. remove the entire visible tumor 2. limits the invasiveness of major surgery 3. can be palliative Cons: 1. often not curative, especially if microscopic tumor cells are left behind 2. can seed tumor cells 3. can provide false expectations about prognosis 4. can make future sampling or treatment more difficult
17
Q
(L15) Describe a wide excision.
A
A wide excision involves removing lots normal tissue in all directions around the mass with the tumor. The goal is to completely remove the mass, visible or microscopic.
18
Q
(L15) Describe some pros and cons to a wide excision.
A
Pros: 1. remove both visible and microscopic aspects to a tumor 2. prevent local recurrence 3. reduce the need for additional treatment 4. can be curative Cons: 1. very invasive 2. not all tumors are in locations that allow for wide margins 3. patient may require reconstructive surgery
19
Q
(L15) What are some general guidelines for the margins of a wide excision?
A
With a wide incision, the lateral margins should span 2-5 cm in all directions, or at least remove 1 fascial plane especially if the tumor is malignant. The fascial plane that acts the a deep margin should also be excised.
20
Q
(L15) Describe a radical excision.
A
With a radical excision, the whole tissue compartment that the tumor is on is removed too.
21
Q
(L15) Describe some pros and cons to a radical excision?
A
Pros: 1. Remove all visible and microscopic aspects of a tumor 2. prevent local recurrence 3. reduce the need for additional treatment 4. can be curative Cons: 1. invasive 2. not possible for all tumors based on their location 3. patient may require reconstructive surgery 4. can impair normal function depending on how much tissue is removed
22
Q
(L15) What are two ways a surgery incision can be closed up? Which situations would favor one over the other?
A
- Primary wound closure - the tumor is removed and the overlying tissue is stitched together; this closure is indicated in intracapsular or marginal surgeries, where there is often lots of excess overlying skin. 2. Reconstructive surgery - the tumor is removed and tissue from another location is resected to cover the incision; indicated in wide and radical excisions
23
Q
(L15) What are the three ways that histologic margins can be categorized?
A
- incomplete/dirty - tumors cells are present at the edge of the sample, suggesting that there may still be neoplastic cells in the patient 2. complete/clean - only normal cells are present at the edge of the sample in all areas 3. narrow - tumor cells are < 5 mm to the edge of the specimen in any area
24
Q
(L16) When would you want to use chemotherapy alone?
A
- when systemic cancers are highly chemosensitive e.g. round cell tumors 2. for palliative care to slow the progression of disease
25
(L16) What is adjuvant chemotherapy?
Adjuvant chemotherapy is the combined use of post-operative chemotherapeutics and surgery to cancers with a high risk of metastasis.
26
(L16) What is neoadjuvant chemotherapy?
In neoadjuvant protocols, chemotherapy is given pre-op to debulk a tumor and prevent the risk of metastasis. Debulking a tumor can also increase the efficacy of surgery.
27
(L16) What is concomitant chemotherapy?
In concomitant protocols, chemotherapy is given simultaneously with radiation therapy for a synergistic effect.
28
(L16, 18) What is metronomic chemotherapy?
In metronomic chemotherapy, chemo is given daily at very low doses. The goal is to target angiogenesis associated with neoplasia, impeding tumor growth.
29
(L16) What unique parameter, instead of body weight, is used to calculate chemotherapeutic dosing?
Body surface area (BSA)
30
(L16) Why would you want to use a single chemotherapeutic protocol versus a multi-drug one or vice versa?
With a single drug protocol, it's easy to quantify the drug's efficacy, but tumor resistance to the drug is more likely to develop. A multi-drug protocol minimizes the risk of tumor resistance and the use of multiple drugs can be synergistic. However, using several drugs together risks acute toxicity.
31
(L16) Most chemotherapeutic agents target...
...rapidly dividing cells.
32
(L16) Describe the MOA of alkylating agents.
Alkylating agents, like cyclophosphamide, add an alkyl group to DNA bases, compromising normal DNA structure. Abnormal DNA crosslinks can form, DNA stands can break, DNA synthesis may be impaired, and nucleotide bases may be mis-paired. As a result, they're cell cycle dependent, but not specific for any phase.
33
(L16) Describe the MOA of platinum drugs.
Platinum drugs like cisplatin and carboplatin add an alkyl group to DNA bases, compromising normal DNA structure. Abnormal DNA crosslinks can form, DNA strands can break, DNA synthesis is impaired, and nucleotide bases may be mis-paired. As a result, they're cell cycle dependent, but not specific for any phase.
34
(L16) Describe the MOA of vinca alklaloids.
Vinca alkaloids like vincristine and vinblastine target and destabilize microtubules. This prevents the formation of mitotic spindles and mitosis, leading to mitotic arrest. Thus, vinca alkaloids are M phase specific.
35
(L16) Describe the MOA of antitumor antibiotics.
Antitumor antibiotics like doxorubicin create free radicals that cause oxidative damage to DNA. These drug molecules can also physically obstruct proteins associated with DNA synthesis and inhibit topoisomerase. Thus, these drugs are both phase-specific and non-specific.
36
(L16) Describe the MOA of antimetabolites.
Antimetabolites like cytosine arabinoside act like false nucleotides. When inserted into DNA, they impair any further replication or transcription. Thus, they are S phase specific.
37
(L16) Describe the MOA of methotrexate.
Methotrexate is a folic acid inhibitor. Folic acid is important to the the synthesis of purines. Methotrexate, ultimately, has the same chemotherapeutic effect as antimetabolites.
38
(L16) Describe the MOA of L-asparaginase.
L-asparaginase is an enzyme that metabolizes asparagine. Some lymphomas are thought to be completely reliant on exogenous asparagine so Elspar can effectively starve them out. This drug is not specific to proliferating cells.
39
(L17) Why do we often see less negative side effects with chemotherapy in veterinary medicine compared to human medicine?
In human medicine, the goal is complete removal of the cancer to extend a person's lifetime, so there's a higher tolerance for side effects. In veterinary medicine, we administer the same drugs but at much lower doses, the administration schedule can be reduced or delayed with the onset of side effects, and we tend not to combine multiple drugs for a single administration. We're trading tumor response and cure rates for a better quality of life.
40
(L17) A majority of chemotherapy patients exhibit negative side effects. T/F?
False Only 20-25% of patients show side effects with chemotherapy.
41
(L17) What three organ systems are usually affected by chemotherapy toxicity?
The bone marrow GI The skin
42
(L17) What is the one chemotherapeutic that is bone marrow sparing?
L-asparaginase, which doesn't target rapidly dividing cells. Bone marrow cells are also thought to be able to synthesize their own asparagine.
43
(L17) What complications are we risking with neutropenia caused by chemotherapy? What is the cut off point we use to prevent complications?
With neutropenia, we risk our patients getting sepsis. Sepsis is most likely to occur when neutropenia dips below 1000 count/microliter of blood.
44
(L17) What kind of treatment options do we have to prevent sepsis associated with chemotherapy-induced neutropenia? How can we treat neutropenia?
We treat with antibiotics, especially those that target Gram (-) bacteria. Neutropenia spontaneously resolves within 2-4 days but there is a human product, Neupogen, that stimulates bone marrow proliferation.
45
(L17) How is vomiting induced by chemotherapy categorized?
1. Acute - mediated by the chemoreceptor trigger zone; common in people but rare in veterinary patients 2. Delayed - caused the sloughing of GI crypt cells; occurs 2-5 days after administration; very common in veterinary patients
46
(L17) What options do we have to treat vomiting caused by chemotherapy?
Usually, vomiting is self-limiting and resolves when a new population of GI cells replace the old ones. However, with more severe cases, we can prescribe anti-emetics and provide nutritional management.
47
(L17) Is dermatological toxicity associated with chemotherapy common in veterinary medicine? Why?
No, because most dogs and cats don't have continually growing fur. Their coat undergoes periods of quiescence, making them resistant to chemotherapeutics that target proliferating cells. The main exception are dog breeds with continually growing coats e.g. poodles.
48
(L17) What is sterile hemorrhage cystitis?
Sterile hemorrhage cystitis is caused by acrolein, an irritating metabolite of cyclophosphamide. Typically, this presents as lower urinary tract signs, hematuria, and a thickened bladder wall.
49
(L17) How do we reduce the side effects associated with cyclophosphamide?
The oral form of the drug is less likely to cause sterile hemorrhage cystitis than the IV form. We can also give the drug in the morning instead of at night to reduce the amount of time the bladder is exposed to acrolein. Other options include giving furosemide, offering lots of water, and accommodating for frequent urinations. To alleviate the cystitis, we can prescribe anti-inflammatories.
50
(L17) What are some potential side effects caused by CCNU, an alkylating agent?
CCNU is associated with elevated liver enzymes, though most cases don't show clinical signs of any liver damage. Only 3-6% of patients develop liver failure.
51
(L17) What are side effects associated with cisplatin and carboplatin?
Cisplatin is highly nephrotoxic and emetogenic. It's also highly toxic in cats. Carboplatin isn't nephrotoxic but it does impact the bone marrow.
52
(L17) What are some side effects associated with vincristine?
Vincristine rarely can cause paralytic GI ileus. More commonly, vincristine is a vesicant, causing a local reaction if it gets outside of a vein.
53
(L17) What are some side effects associated with doxorubicin?
Doxorubicin is cardiotoxic, contributing to ventricular arrhythmias acutely and DCM chronically in dogs. It's also a vesicant and can cause a hypersensitivity reaction through the release of histamine. In cats, doxorubicin is nephrotoxic.
54
(L17) 5-fluorouracil and rabacfosadine are antimetabolites. What are some side effects associated with either of these drugs?
5-FU is deadly in cats, causing ataxia, disorientation, and seizures. Rabacfosadine causes non-specific otitis and dermatitis and, rarely, pulmonary fibrosis.
55
(L18) What processes do receptor tyrosine kinase regulate?
They initiate signal transduction associated with cell growth and proliferation.
56
(L18) What is constitutive activation of a receptor tyrosine kinase?
The gene controlling the expression for a tyrosine kinase is an oncogene - when it's mutated, the protein product is always active. Even without a ligand bound to it, an constitutively activated RTK is dimerized and initiating cell signaling.
57
(L18) How do receptor tyrosine kinase inhibitors work?
They bind to ATP binding sites on the receptor and prevent the phosphorylation of the tyrosine residues.
58
(L18) What about the dosing and side effects of small molecule inhibitors makes them so different from standard chemotherapeutics?
Small molecule inhibitors have been found to be efficacious at doses below what they're labeled for, meaning that we can achieve maximal therapeutic effects with less of a risk for toxicity. Also they have a different side effect profile from standard chemotherapeutics - they're more likely to cause GI signs and lethargy than causing neutropenia and thrombocytopenia.
59
(L18) Describe how tumor cells can induce angiogenesis.
Tumor cells upregulate the expression of pro-angiogenic factors like VEG-F and PDGF, stimulating blood vessel growth. They also decrease the expression of angiogenic inhibitors e.g. endostatin.
60
(L18) What drugs may be used as part of a metronomic chemotherapy protocol?
1. COX-2 inhibitors - COX-2, in the conversion of arachodonic acid into PGE2, stimulates angiogenesis and cell proliferation 2. An oral chemotherapeutic e.g. CCNU, cyclophosphamide 3. A target chemotherpeutic e.g. Palladia
61
(L19) What kinds of effects do we expect with a metronomic protocol?
1. cytotoxic killing of vascular endothelial cells 2. increasing the expression of angiogenic inhibitors 3. targeting endothelial progenitor cells 4. NO direct tumor cell cytotoxicity
62
(L19) What is a paraneoplastic syndrome (PNS)?
A PNS describes effects caused by neoplasia distal to the tumor, generally caused by the release of small molecules.
63
(L19) What are two GI paraneoplastic syndromes? Briefly describe them.
1. Cachexia - relatively rare in veterinary medicine; associated with lots of tumor types; multifactorial causes but generally results from alterations to metabolism 2. GI ulceration - associated with MCTs where overproduction of histamines cause hyperacidity in the stomach; the ulcer may contribute to an elevated BUN and a chronic microcytic, hypochromic anemia
64
(L19) What are the two endocrine paraneoplastic syndromes? Briefly describe them.
1. Hypercalcemia - most associated with LSA and AGASACA; causes lethargy, anorexia, weight loss, impaired renal function, and muscle weakness among other signs 2. Hypoglycemia - associated with insulinomas (among others); caused by hyperinsulinemia; uncommon in dogs
65
(L19) What are hematologic paraneoplastic syndromes?
1. Hypergammaglobulinemia - associated with multiple myeloma, lymphoma, and leukemia; caused by excessive Ig production by plasma cells 2. Anemia - associated with lots of cancers and causes are varied 3. Erythrocytosis - associated with many tumor types; caused by an overproduction of EPO and HIF-1 4. Neutrophilic leukocytosis - associated with lymphoma; likely caused by overproduction of stem cell growth factors 5. Thrombocytopenia - associated with multiple tumor types; caused by under-production or over-consumption 6. Coagulopathies and DIC
66
(L19) What is a neurologic paraneoplastic syndrome? Briefly describe it.
1. Myasthenia gravis - associated with thymomas and OSA, among others; caused by immune-mediated destruction of nicotinic ACh receptors
67
(L19) Describe hypertrophic osteopathy.
Associated with primary and metastatic lung tumors, hypertrophic osteopathy is characterized by periosteal bone formation along the long bones. Patients often present with weakness and lameness.
68
(L19) Describe fever as a paraneoplastic syndrome.
Fever can be associated with multiple tumor types, but in general, it's caused by the overproduction of prostaglandins and cytokines.
69
(L19) What are some possible mechanisms underlying cutaneous paraneoplastic syndromes?
A tumor can directly cause a cutaneous lesion e.g when MCTs degranulate causing itching and erythema. Other lesions can arise from endocrine imbalances caused by the tumor e.g. feminization or by immune-mediated destruction.
70
(L20) Describe plesiotherapy and which type of cancer it's most effective on.
With plesiotherapy, radioactive strontium is used. Due to radioactive decay, electrons are ejected, but these elections only penetrate about 3 mm into tissue. So, plesiotherapy is used primarily on superficial lesions e.g. SCC on cats' noses.
71
(L20) Describe how radiation therapy with linear accelerators works.
Linear accelerators can shoot either high energy electrons or photons. Unlike other forms of radiation therapy, linear accelerators can be modulated so that only the target tumor gets the max dose, sparing the skin.
72
(L20) Distinguish between gross tumor volume, clinical target volume, and planning target volume.
GTV is the visible tumor volume, often evaluated by imaging. CTV takes into account the GTV and the possibility of any microscopic local invasion into adjacent. Similarly, PTV, in addition to incorporating CTV, also accounts for any potential patient movement and uncertainty about the machine's set up. For example, if we were targeting a heart base mass or a thoracic wall tumor, the PTV would cover a larger area to accommodate for patient movement.
73
(L20) Why can't we apply the same planning target volume to every patient receiving radiation therapy?
The higher the PTV, the more normal tissue we risk irradiating and not all tumors are in an anatomic location that we can risk missing.
74
(L20, 21) How does radiation therapy kill tumor cells?
Rarely, radiation directly induces DSBs in DNA structure. More commonly, radiation breaks water into free radicals that damage DNA.
75
(L20) In what unit is radiation therapy measured in?
Grays
76
(L20, 21) Is radiation therapy local or systemic treatment?
Local
77
(L20) What are the goals of radiation therapy?
1. getting a definitive cure 2. tumor management and palliative care
78
(L20) What are the four factors that affect radiocurability?
1. the size of the tumor 2. the radio-tolerance of nearby normal tissue 3. the tumor type 4. anatomy and species
79
(L20) How does a tumor's size affect curability with radiation therapy?
Radiation works best on a microscopic level. A large tumor decreases the likelihood of curing it with radiation.
80
(L20) How does normal tissues' tolerance for radiotherapy affect a tumor's curability?
We want to minimize toxic side effects so we never use the maximum dose possible with radiation. How much radiation a tumor is exposed to is dependent on how well the adjacent normal tissue can tolerate it.
81
(L20, 21) Rank various cancers (round cell, carcinoma, sarcoma, melanoma) in order from highest to lowest susceptibility to radiation
Round cell tumor \>\> Carcinoma \>\> Sarcoma \>\> Gliomas \>\> Melanomas
82
(L20) When could you use radiation therapy alone?
1. When the tumor type is especially susceptible to radiation e.g. round cell tumors 2. The tumor is in a location and species that is susceptible to radiation e.g. nasal SCC in cats 3. The tumor is surgically inaccessible
83
(L20) Surgery and radiation therapy work well together. Why?
Both treatments are good for treating localized tumors. Surgery is suited for clearing out the gross, visible tumor while radiation can clear out any microscopic remnants.
84
(L21) Cells in which cell phase are the most sensitive to radiation therapy? The most resistant?
Cells in G2 and M phases are the most sensitive. Cells in S phase are the most resistant, likely because DNA repair mechanisms are active.
85
(L21) Relate how mutations to genes like ATM and BRCA contribute to cancer and susceptibility to radiation.
ATM and BRCA are genes that regulate DNA repair mechanisms. When they're mutated, cells can accumulate mutations, possibly leading to cancer. However, cancer cells are more susceptible to radiation than normal cells for that exact reason - without DNA repair mechanisms, cancer cells are less likely to repair the DNA damage caused by radiation.
86
(L21) Are proliferative cells or quiescent cells more susceptible to radiation?
Proliferative cells
87
(L21) What is radiation fractionation? Why is it better than one big bolus of radiation?
Fractionation is the process of giving multiple small doses of radiation over several administrations. It allows for greater control of therapeutic effect while minimizing toxicity. The inter-administration periods allow normal tissue to recover from radiation damage.
88
(L21) Which tissues exhibit side effects early after radiation? How about late after radiation?
Skin and the GI tract are the first tissues to exhibit any signs of toxicity since they're composed of rapidly proliferating cells. Late responding tissues include the pleura and the spinal cord.
89
(L21) What are the 4 Rs? Briefly describe them.
1. Repair - normal tissues have better DNA repair mechanisms than cancer cells, making them less susceptible to radiation 2. Repopulation - fractionation allows normal tissue to recover from radiation therapy while still targeting tumors 3. Redistribution - radiation can debulk a tumor, stimulating quiescent tumor cells to become proliferative and making susceptible to radiation 4. Reoxygenation - reoxygenation makes tumor cells more susceptible to radiation
90
(L22) Tumor cells are basically modified self cells. How do immune cells recognize them?
Immune cells can bind to tumor-specific and tumor-associated antigens. Tumor-specific antigens are things expressed only by neoplastic cells, not normal tissue. These can include chimeric or fetal proteins from mutant genes. Tumor-associated antigens are expressed on both neoplastic and normal tissues, but in tumor cells, they're novel or abnormally expressed.
91
(L22) What is immunoediting?
Immunoediting is the process of immune cells recognizing and binding to tumor-associated antigens.
92
(L22) Describe how the innate and adaptive immune system interplay to eliminate tumor cells.
Innate system cells, are involved in the general recognition of TAAs and releasing cytokines to initiate an immune response. Namely dendritic cells recognize, bind to, and present tumor-associated antigens to cytotoxic CD8 T lymphocytes. CD4 T lymphocytes release cytokines that also recruit more cytotoxic T cells.
93
(L22) Describe some mechanisms that would allow a tumor cell to escape our immune system
1. the depletion of cytotoxic T cells 2. the loss of of helper T cells 3. infiltration of the tumor by protective regulatory T cells or the production of cytokines that attract regulatory T cells 4. overexpression of PD-L1 on neoplastic cells 5. recruitment of immunosuppressive myeloid-derived suppressor cells 6. downregulation of MHC class 1 receptors
94
(L22) What are biologic response modifiers? How could they be anti-tumor?
These are essentially vaccines that carry attenuated bacteria or bacterial components to stimulate the innate immune system. The goal is to have the stimulated innate immune system recruit adaptive immune cells. Examples: BCG vaccine and liposomal muramyl tripeptide
95
(L22) What are cytokines therapies? How are they anti-tumor?
Cytokine therapies, often involving IL-2, are meant to stimulate an immune response.
96
(L22) Imiquimod is an immunological adjuvant. How is it anti-tumor?
Imiquimod is a topical toll-like receptor agonist. It's meant to stimulate dendritic cells and T cells.
97
(L22) How would blocking PD-1/PD-L1 interactions be anti-tumor?
PD-1 is a receptor expressed on activated CD8 T cells and binds to PD-L1 antigens on targets like tumor cells. However, this interaction inhibits the T cell's cytotoxic effects, sparing the tumor cell. Inhibiting this interaction would lead to tumor cell apoptosis.
98
(L22) How do DNA vaccines work?
DNA vaccines are foreign DNA encoding specific antigens that are uptaken by cells when administered. These foreign antigens can then stimulate an adaptive immune response. Examples: Oncept, a vaccine with human tyrosinase, to treat canine melanomas; murine CD20 vaccines to treat canine lymphoma
99
(L23) Describe three ways in which a cell can develop resistance to apoptosis. (Apoptosis is regulated cell death, so think mutations to normal regulatory processes)
1. Mutations to checkpoint proteins - Tumor suppressor genes like p53 regulate key checkpoints in the cell cycle and mutations to these genes allow abnormal cells to continue cycling. 2. Mutations to the intrinsic apoptotic pathway - Over-expression of Bcl-2 inhibits the release of cytochrome c from the mitochondria and the activation of caspases. 3. Mutations to the extrinsic apoptotic pathway - Mutations to T cell receptors prevents the binding of cytotoxic T cells.
100
(L23) Differentiate between intrinsic and extrinsic tumor resistance.
Intrinsic resistance is conferred by genetics or epigenetics. They're inherent byproducts of the mutations a tumor cell population has accrued. Extrinsic resistance involves the tumor's acquisition of resistance to a specific treatment. Any chemotherapy would kill the cells susceptible to it, leaving behind resistant cells. These resistant cells then repopulate, and the resulting tumor will now be resistant to that chemotherapeutic.
101
(L23) What are three intrinsic mechanisms that would make a cell more or less resistant to radiation therapy?
1. Proliferative cells are more susceptible to radiation than quiescent ones. 2. Cells with impaired DNA repair systems are more susceptible to radiation. 3. Hypoxic cells are more resistant to radiation.
102
(L23) What are some mechanisms in which a tumor cell can develop drug resistance?
1. Reduced uptake - the tumor downregulates the expression of transporters on the cell surface 2. Increased efflux - the tumor overexpresses transporters that pump a drug out of cells 3. Increased metabolism - the tumor upregulates the expression of enzymes that metabolize a drug
103
(L23) How do MDR1 transporters contribute to multi-drug resistance?
MDR1 transporters are ATP-driven protein pumps that can remove antitumor antibiotics, vinca alkaloids, and kinase inhibitors from inside the cell. Normally, these pumps are meant to remove chloride from excretory cells, but their over-expression contributes to drug resistance.
104
(L23) How cancer-associated fibroblasts promote neoplasia?
Cancer-associated fibroblasts express and produce collagenases, cytokines, and angiogenic stimulators. The collagenases digest the normal ECM and allow for the tumor to grow locally. The cytokines and angiogenic factors promote tumor growth and vascularization and inhibit apoptosis.
105
(L23) What kinds of immune cells contribute to neoplasia?
If a tumor cell can survive the acute immune response, it can co-opt chronic M2 macrophages, or tumor-associated macrophages, to continue growing. Normally, M2 macrophages produce angiogenic factors, block apoptosis, and downregulate the immune system as part of a healing process , but these functions foster tumor growth. The recruitment of of regulatory T cells also inhibits any other potential immune response against the tumor cells.
106
(L23) How does a tumor's extracellular matrix promote tumor survival?
The ECM formed creates very high interstitial pressure within the tumor. So even if a tumor is vascularized, drugs and immune cells in vessels have to exit against a high pressure gradient, rendering them ineffective.
107
(L23) Describe how the cells near the center of a tumor are more resistant to chemotherapy than cells near the surface.
Cells near the surface of a tumor are oxygenated and well-vascularized. The interstitial pressure there is also almost normal, which facilitates chemotherapy efficacy. In contrast, near the tumor's core, cells are hypoxic to anoxic, the interstitial pressure is high, the pH is altered, and there are little to no blood vessels. All of these factors decrease chemotherapeutic efficacy.
108
(L23) Why are hypoxic cells more resistant to therapy than oxygenated cells?
Without oxygen, radiation and chemotherapeutics, which act through the formation of free radicals, are less effective. Additionally, hypoxic cells release hypoxia-induced factors (HIFs) which are anti-apoptotic, stimulate proliferation, and are angiogenic. HIFs have also been shown to increase the accumulation of mutations and stimulate metastasis.
109
(L24) What diagnostic tool do we use to assign a tumor's grade?
Histopathology
110
(L24) Why do we stage?
A tumor's stage impacts prognosis, which can affect what treatments are available.
111
(L24) What kinds of tools do we have to evaluate the size of a primary tumor?
1. the physical exam 2. basic and advanced imaging 3. nuclear scintigraphy
112
(L24) What kinds of tools we do have to evaluate if there is systemic metastasis?
Based on the location of the metastasis, we have: 1. the physical exam 2. basic and advanced imaging 3. auscultation of the lungs 4. evaluating the size, shape, and consistency of LNs 5. FNA and biopsy 6. Bloodwork
113
(L24) What are the advantages and limitations of thoracic radiographs as as a diagnostic tool for cancer?
They're good for evaluating the thoracic cage for hilar lymphadenopathy or pulmonary metastasis. They also allow for evaluation of the heart and other thoracic structures. However, the technique impacts the diagnostic potential of x-rays and they're much less sensitive than advanced imaging at detecting pulmonary nodules.
114
(L24) What are the advantages and limitations of CT as a diagnostic tool for cancer?
CT provides good reproducible bone and spatial detail. There's also tissue settings and the contrasts that can further reveal more information. However, CTs are expensive and require heavy sedation or anesthesia.
115
(L24) What are some advantages and limitations of nuclear scintigraphy as a diagnostic tool for cancer?
Nuclear scintigraphy is a good scan for primary and metastatic bone tumors and thyroid tumors. However, it provides poor spatial detail for soft tissues.
116
(L24) What are the advantages and limitations of ultrasound as a diagnostic tool for cancer?
Ultrasound is minimally invasive, relatively inexpensive, doesn't necessitate anesthesia, and provides real-time imaging. However, it's very user-dependent and there are structures, especially in the pelvis, that are hard to ultrasound.
117
(L24) What are some advantages and limitations of MRI as a diagnostic tool for cancer?
MRI provides really good detail for soft tissues, especially the brain and CNS and there are contrast options that can differentiate edema from hemorrhage. It's limited by it's need for anesthesia and cost.
118
(L14) What is surgical oncology?
Surgical oncology is using surgery to diagnose and treat cancer. It incorporates cancer biology and behavior, diagnostic tools, therapeutic intent, and possible surgical outcomes.
119
(L14) What is surgical dose?
Surgical dose, in the context of oncology, is how much surgery should be applied to treat a tumor. The extent of surgery depends on the tumor type, its stage, its location, the possibility of other treatments, concurrent disease, and owner preference.
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(L14, 24) What is the difference between a tumor's grade and its stage?
A tumor's grade describes the appearance of its cells on histopathology and is an indication of the tumor's behavior. A tumor's stage is the extent to which the cancer has spread throughout the body, locally or systemically.
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(L14) What are two methods that we use to determine what a mass is? What are the pros and cons of either?
With a mass, you can either take a fine needle aspirate or a biopsy. FNAs are fast, easy, cheap, and can indicate the cell of origin relatively quickly but they're often not completely diagnostic. They're good tool to guide additional diagnostics. A biopsy is more invasive, but is more likely to provide a solid diagnosis.
122
(L14) Distinguish between an incisional and excisional biopsy.
A small piece of a tumor is submitted in an incisional biopsy. For an excisional biopsy, the entire mass is removed and submitted for review.
123
(L14) When would an incisional biopsy be indicated?
You should do an incisional biopsy when the information will change the work-up and treatment plan. For example, an incisional biopsy would be for tumors in which the differentials could affect prognosis and treatment options, and you wouldn't want to commit to surgical removal of the whole tumor without understanding the cancer's behavior.
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(L14) What are three basic goals for an incisional biopsy?
1. obtain a diagnostic sample 2. minimize local contamination of adjacent tissue 3. preserve as many treatment options as possible
125
(L14) When would an excisional biopsy be indicated?
You may want to take an excsional biopsy when the information would not affect your treatment plan. In other words, excision is an option if the treatment plan wouldn't change regardless of tumor type. Excision could also work if the tumor was in a location that allowed for complete removal or if incision would likely risk metastasis.
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(L14) Briefly describe the process of staging.
Staging a tumor is evaluating how much it's spread throughout the body. Through imaging and sampling of various locations, we have to determine the tumor type and the extent to which it spread locally to adjacent tissue, regionally to lymph nodes, and diffusely to distal sites.
127
(L15) What is the difference between a surgical margin and a histologic margins?
A surgical margin is what is measured during surgery from the incision site to the palpable edge of the tumor. A histologic margin is assessed under a microscope - it's the distance from the cut edge of a biopsy to the closest tumor cell.
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(L15) When referring to surgery, what are lateral and deep margins?
The lateral margins of an incision include the normal tissue removed in all directions around the sides of a visible tumor. The deep margin is the amount of normal tissue removed beneath a tumor.
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(L15) What is a fascial plane?
A fascial plane is the interface between two tissue layers.
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(L15) Describe an intracapsular excision.
With an intracapsular excision, or debulking, a tumor's pseudocapsule is left intact. Some material within the pseudocapsule is removed, often with visible tumor matter left in the patient.
131
(L15) Describe some pros and cons to an intracapsular excision.
Pros: 1. temporary treatment for a tumor's negative effects Cons: 1. not curative 2. benefits are temporary until tumor regrows 3. risks seeding tumor cells 4. can complicate future treatments or procedures
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(L15) Describe a marginal excision.
A marginal excision involves removal of a visible tumor with as little normal tissue taken as possible, leaving microscopic traces. Some normal tissue can be removed along with the tumor, but as long as one area of the excision is immediately adjacent to the tumor's margin, the entire procedure can be considered marginal.
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(L15) Describe some pros and cons to a marginal excision.
Pros: 1. remove the entire visible tumor 2. limits the invasiveness of major surgery 3. can be palliative Cons: 1. often not curative, especially if microscopic tumor cells are left behind 2. can seed tumor cells 3. can provide false expectations about prognosis 4. can make future sampling or treatment more difficult
134
(L15) Describe a wide excision.
A wide excision involves removing lots normal tissue in all directions around the mass with the tumor. The goal is to completely remove the mass, visible or microscopic.
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(L15) Describe some pros and cons to a wide excision.
Pros: 1. remove both visible and microscopic aspects to a tumor 2. prevent local recurrence 3. reduce the need for additional treatment 4. can be curative Cons: 1. very invasive 2. not all tumors are in locations that allow for wide margins 3. patient may require reconstructive surgery
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(L15) What are some general guidelines for the margins of a wide excision?
With a wide incision, the lateral margins should span 2-5 cm in all directions, or at least remove 1 fascial plane especially if the tumor is malignant. The fascial plane that acts the a deep margin should also be excised.
137
(L15) Describe a radical excision
With a radical excision, the whole tissue compartment that the tumor is on is removed too.
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(L15) Describe some pros and cons to a radical excision?
Pros: 1. Remove all visible and microscopic aspects of a tumor 2. prevent local recurrence 3. reduce the need for additional treatment 4. can be curative Cons: 1. invasive 2. not possible for all tumors based on their location 3. patient may require reconstructive surgery 4. can impair normal function depending on how much tissue is removed
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(L15) What are two ways a surgery incision can be closed up? Which situations would favor one over the other?
1. Primary wound closure - the tumor is removed and the overlying tissue is stitched together; this closure is indicated in intracapsular or marginal surgeries, where there is often lots of excess overlying skin. 2. Reconstructive surgery - the tumor is removed and tissue from another location is resected to cover the incision; indicated in wide and radical excisions
140
(L15) What are the three ways that histologic margins can be categorized?
1. incomplete/dirty - tumors cells are present at the edge of the sample, suggesting that there may still be neoplastic cells in the patient 2. complete/clean - only normal cells are present at the edge of the sample in all areas 3. narrow - tumor cells are \< 5 mm to the edge of the specimen in any area
141
(L16) When would you want to use chemotherapy alone?
1. when systemic cancers are highly chemosensitive e.g. round cell tumors 2. for palliative care to slow the progression of disease
142
(L16) What is adjuvant chemotherapy?
Adjuvant chemotherapy is the combined use of post-operative chemotherapeutics and surgery to cancers with a high risk of metastasis.
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(L16) What is neoadjuvant chemotherapy?
In neoadjuvant protocols, chemotherapy is given pre-op to debulk a tumor and prevent the risk of metastasis. Debulking a tumor can also increase the efficacy of surgery.
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(L16) What is concomitant chemotherapy?
In concomitant protocols, chemotherapy is given simultaneously with radiation therapy for a synergistic effect.
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(L16, 18) What is metronomic chemotherapy?
In metronomic chemotherapy, chemo is given daily at very low doses. The goal is to target angiogenesis associated with neoplasia, impeding tumor growth.
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(L16) What unique parameter, instead of body weight, is used to calculate chemotherapeutic dosing?
Body surface area (BSA)
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(L16) Why would you want to use a single chemotherapeutic protocol versus a multi-drug one or vice versa?
With a single drug protocol, it's easy to quantify the drug's efficacy, but tumor resistance to the drug is more likely to develop. A multi-drug protocol minimizes the risk of tumor resistance and the use of multiple drugs can be synergistic. However, using several drugs together risks acute toxicity.
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(L16) Most chemotherapeutic agents target...
Rapidly dividing cells.
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(L16) Describe the MOA of alkylating agents.
Alkylating agents, like cyclophosphamide, add an alkyl group to DNA bases, compromising normal DNA structure. Abnormal DNA crosslinks can form, DNA stands can break, DNA synthesis may be impaired, and nucleotide bases may be mis-paired. As a result, they're cell cycle dependent, but not specific for any phase.
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(L16) Describe the MOA of platinum drugs.
Platinum drugs like cisplatin and carboplatin add an alkyl group to DNA bases, compromising normal DNA structure. Abnormal DNA crosslinks can form, DNA strands can break, DNA synthesis is impaired, and nucleotide bases may be mis-paired. As a result, they're cell cycle dependent, but not specific for any phase.
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(L16) Describe the MOA of vinca alklaloids.
Vinca alkaloids like vincristine and vinblastine target and destabilize microtubules. This prevents the formation of mitotic spindles and mitosis, leading to mitotic arrest. Thus, vinca alkaloids are M phase specific.
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(L16) Describe the MOA of antitumor antibiotics.
Antitumor antibiotics like doxorubicin create free radicals that cause oxidative damage to DNA. These drug molecules can also physically obstruct proteins associated with DNA synthesis and inhibit topoisomerase. Thus, these drugs are both phase-specific and non-specific.
153
(L16) Describe the MOA of antimetabolites.
Antimetabolites like cytosine arabinoside act like false nucleotides. When inserted into DNA, they impair any further replication or transcription. Thus, they are S phase specific.
154
(L16) Describe the MOA of methotrexate.
Methotrexate is a folic acid inhibitor. Folic acid is important to the the synthesis of purines. Methotrexate, ultimately, has the same chemotherapeutic effect as antimetabolites.
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(L16) Describe the MOA of L-asparaginase.
L-asparaginase is an enzyme that metabolizes asparagine. Some lymphomas are thought to be completely reliant on exogenous asparagine so Elspar can effectively starve them out. This drug is not specific to proliferating cells.
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(L17) Why do we often see less negative side effects with chemotherapy in veterinary medicine compared to human medicine?
In human medicine, the goal is complete removal of the cancer to extend a person's lifetime, so there's a higher tolerance for side effects. In veterinary medicine, we administer the same drugs but at much lower doses, the administration schedule can be reduced or delayed with the onset of side effects, and we tend not to combine multiple drugs for a single administration. We're trading tumor response and cure rates for a better quality of life.
157
(L17) A majority of chemotherapy patients exhibit negative side effects. T/F?
False Only 20-25% of patients show side effects with chemotherapy.
158
(L17) What three organ systems are usually affected by chemotherapy toxicity?
The bone marrow GI The skin
159
(L17) What is the one chemotherapeutic that is bone marrow sparing?
L-asparaginase, which doesn't target rapidly dividing cells. Bone marrow cells are also thought to be able to synthesize their own asparagine.
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(L17) What complications are we risking with neutropenia caused by chemotherapy? What is the cut off point we use to prevent complications?
With neutropenia, we risk our patients getting sepsis. Sepsis is most likely to occur when neutropenia dips below 1000 count/microliter of blood.
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(L17) What kind of treatment options do we have to prevent sepsis associated with chemotherapy-induced neutropenia? How can we treat neutropenia?
We treat with antibiotics, especially those that target Gram (-) bacteria. Neutropenia spontaneously resolves within 2-4 days but there is a human product, Neupogen, that stimulates bone marrow proliferation.
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(L17) How is vomiting induced by chemotherapy categorized?
1. Acute - mediated by the chemoreceptor trigger zone; common in people but rare in veterinary patients 2. Delayed - caused the sloughing of GI crypt cells; occurs 2-5 days after administration; very common in veterinary patients
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(L17) What options do we have to treat vomiting caused by chemotherapy?
Usually, vomiting is self-limiting and resolves when a new population of GI cells replace the old ones. However, with more severe cases, we can prescribe anti-emetics and provide nutritional management.
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(L17) Is dermatological toxicity associated with chemotherapy common in veterinary medicine? Why?
No, because most dogs and cats don't have continually growing fur. Their coat undergoes periods of quiescence, making them resistant to chemotherapeutics that target proliferating cells. The main exception are dog breeds with continually growing coats e.g. poodles.
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(L17) What is sterile hemorrhage cystitis?
Sterile hemorrhage cystitis is caused by acrolein, an irritating metabolite of cyclophosphamide. Typically, this presents as lower urinary tract signs, hematuria, and a thickened bladder wall.
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(L17) How do we reduce the side effects associated with cyclophosphamide?
The oral form of the drug is less likely to cause sterile hemorrhage cystitis than the IV form. We can also give the drug in the morning instead of at night to reduce the amount of time the bladder is exposed to acrolein. Other options include giving furosemide, offering lots of water, and accomodating for frequent urinations. To alleviate the cystitis, we can prescribe anti-inflammatories.
167
(L17) What are some potential side effects caused by CCNU, an alkylating agent?
CCNU is associated with elevated liver enzymes, though most cases don't show clinical signs of any liver damage. Only 3-6% of patients develop liver failure.
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(L17) What are side effects associated with cisplatin and carboplatin?
Cisplatin is highly nephrotoxic and emetogenic. It's also highly toxic in cats. Carboplatin isn't nephrotoxic but it does impact the bone marrow.
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(L17) What are some side effects associated with vincristine?
Vincristine rarely can cause paralytic GI ileus. More commonly, vincristine is a vesicant, causing a local reaction if it gets outside of a vein.
170
(L17) What are some side effects associated with doxorubicin?
Doxorubicin is cardiotoxic, contributing to ventricular arrhythmias acutely and DCM chronically in dogs. It's also a vesicant and can cause a hypersensitivity reaction through the release of histamine. In cats, doxorubicin is nephrotoxic.
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(L17) 5-fluorouracil and rabacfosadine are antimetabolites. What are some side effects associated with either of these drugs?
5-FU is deadly in cats, causing ataxia, disorientation, and seizures. Rabacfosadine causes non-specific otitis and dermatitis and, rarely, pulmonary fibrosis.
172
(L18) What processes do receptor tyrosine kinase regulate?
They initiate signal transduction associated with cell growth and proliferation.
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(L18) What is constitutive activation of a receptor tyrosine kinase?
The gene controlling the expression for a tyrosine kinase is an oncogene - when it's mutated, the protein product is always active. Even without a ligand bound to it, an constitutively activated RTK is dimerized and initiating cell signaling.
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(L18) How do receptor tyrosine kinase inhibitors work?
They bind to ATP binding sites on the receptor and prevent the phosphorylation of the tyrosine residues.
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(L18) What about the dosing and side effects of small molecule inhibitors makes them so different from standard chemotherapeutics?
Small molecule inhibitors have been found to be efficacious at doses below what they're labeled for, meaning that we can achieve maximal therapeutic effects with less of a risk for toxicity. Also they have a different side effect profile from standard chemotherapeutics - they're more likely to cause GI signs and lethargy than causing neutropenia and thrombocytopenia.
176
(L18) Describe how tumor cells can induce angiogenesis.
Tumor cells upregulate the expression of pro-angiogenic factors like VEG-F and PDGF, stimulating blood vessel growth. They also decrease the expression of angiogenic inhibitors e.g. endostatin.
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(L18) What drugs may be used as part of a metronomic chemotherapy protocol?
1. COX-2 inhibitors - COX-2, in the conversion of arachodonic acid into PGE2, stimulates angiogenesis and cell proliferation 2. An oral chemotherapeutic e.g. CCNU, cyclophosphamide 3. A target chemotherpeutic e.g. Palladia
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(L18) What kinds of effects do we expect with a metronomic protocol?
1. cytotoxic killing of vascular endothelial cells 2. increasing the expression of angiogenic inhibitors 3. targeting endothelial progenitor cells 4. NO direct tumor cell cytotoxicity
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(L19) What is a paraneoplastic syndrome (PNS)?
A PNS describes effects caused by neoplasia distal to the tumor, generally caused by the release of small molecules.
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(L19) What are two GI paraneoplastic syndromes? Briefly describe them.
1. Cachexia - relatively rare in veterinary medicine; associated with lots of tumor types; multifactorial causes but generally results from alterations to metabolism 2. GI ulceration - associated with MCTs where overproduction of histamines cause hyperacidity in the stomach; the ulcer may contribute to an elevated BUN and a chronic microcytic, hypochromic anemia
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(L19) What are the two endocrine paraneoplastic syndromes? Briefly describe them.
1. Hypercalcemia - most associated with LSA and AGASACA; causes lethargy, anorexia, weight loss, impaired renal function, and muscle weakness among other signs 2. Hypoglycemia - associated with insulinomas (among others); caused by hyperinsulinemia; uncommon in dogs
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(L19) What are hematologic paraneoplastic syndromes?
1. Hypergammaglobulinemia - associated with multiple myeloma, lymphoma, and leukemia; caused by excessive Ig production by plasma cells 2. Anemia - associated with lots of cancers and causes are varied 3. Erythrocytosis - associated with many tumor types; caused by an overproduction of EPO and HIF-1 4. Neutrophilic leukocytosis - associated with lymphoma; likely caused by overproduction of stem cell growth factors 5. Thrombocytopenia - associated with multiple tumor types; caused by under-production or over-consumption 6. Coagulopathies and DIC
183
(L19) What is a neurologic paraneoplastic syndrome? Briefly describe it.
Myasthenia gravis - associated with thymomas and OSA, among others; caused by immune-mediated destruction of nicotinic ACh receptors
184
(L19) Describe hypertrophic osteopathy.
Associated with primary and metastatic lung tumors, hypertrophic osteopathy is characterized by periosteal bone formation along the long bones. Patients often present with weakness and lameness.
185
(L19) Describe fever as a paraneoplastic syndrome.
Fever can be associated with multiple tumor types, but in general, it's caused by the overproduction of prostaglandins and cytokines.
186
(L19) What are some possible mechanisms underlying cutaneous paraneoplastic syndromes?
A tumor can directly cause a cutaneous lesion e.g when MCTs degranulate causing itching and erythema. Other lesions can arise from endocrine imbalances caused by the tumor e.g. feminization or by immune-mediated destruction.
187
(L20) Describe plesiotherapy and which type of cancer it's most effective on.
With plesiotherapy, radioactive strontium is used. Due to radioactive decay, electrons are ejected, but these elections only penetrate about 3 mm into tissue. So, plesiotherapy is used primarily on superficial lesions e.g. SCC on cats' noses.
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(L20) Describe how radiation therapy with linear accelerators works.
Linear accelerators can shoot either high energy electrons or photons. Unlike other forms of radiation therapy, linear accelerators can be modulated so that only the target tumor gets the max dose, sparing the skin.
189
(L20) Distinguish between gross tumor volume, clinical target volume, and planning target volume.
GTV is the visible tumor volume, often evaluated by imaging. CTV takes into account the GTV and the possibility of any microscopic local invasion into adjacent. Similarly, PTV, in addition to incorporating CTV, also accounts for any potential patient movement and uncertainty about the machine's set up. For example, if we were targeting a heart base mass or a thoracic wall tumor, the PTV would cover a larger area to accommodate for patient movement.
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(L20) Why can't we apply the same planning target volume to every patient receiving radiation therapy?
The higher the PTV, the more normal tissue we risk irradiating and not all tumors are in an anatomic location that we can risk missing.
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(L20, 21) How does radiation therapy kill tumor cells?
Rarely, radiation directly induces DSBs in DNA structure. More commonly, radiation breaks water into free radicals that damage DNA.
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(L20, 21) In what unit is radiation therapy measured in?
Grays
193
(L20, 21) Is radiation therapy local or systemic treatment?
Local
194
(L20) What are the goals of radiation therapy?
1. getting a definitive cure 2. tumor management and palliative care
195
(L20) What are the four factors that affect radiocurability?
1. the size of the tumor 2. the radio-tolerance of nearby normal tissue 3. the tumor type 4. anatomy and species
196
(L20) How does a tumor's size affect curability with radiation therapy?
Radiation works best on a microscopic level. A large tumor decreases the likelihood of curing it with radiation.
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(L20) How does normal tissues' tolerance for radiotherapy affect a tumor's curability?
We want to minimize toxic side effects so we never use the maximum dose possible with radiation. How much radiation a tumor is exposed to is dependent on how well the adjacent normal tissue can tolerate it.
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(L20, 21) Rank various cancers (round cell, carcinoma, sarcoma, melanoma) in order from highest to lowest susceptibility to radiation
Round cell tumor \>\> Carcinoma \>\> Sarcoma \>\> Gliomas \>\> Melanomas
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(L20) When could you use radiation therapy alone?
1. When the tumor type is especially susceptible to radiation e.g. round cell tumors 2. The tumor is in a location and species that is susceptible to radiation e.g. nasal SCC in cats 3. The tumor is surgically inaccessible
200
(L20) Surgery and radiation therapy work well together. Why?
Both treatments are good for treating localized tumors. Surgery is suited for clearing out the gross, visible tumor while radiation can clear out any microscopic remnants.
201
(L21) Cells in which cell phase are the most sensitive to radiation therapy? The most resistant?
Cells in G2 and M phases are the most sensitive. Cells in S phase are the most resistant, likely because DNA repair mechanisms are active.
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(L21) Relate how mutations to genes like ATM and BRCA contribute to cancer and susceptibility to radiation.
ATM and BRCA are genes that regulate DNA repair mechanisms. When they're mutated, cells can accumulate mutations, possibly leading to cancer. However, cancer cells are more susceptible to radiation than normal cells for that exact reason - without DNA repair mechanisms, cancer cells are less likely to repair the DNA damage caused by radiation.
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(L21) Are proliferative cells or quiescent cells more susceptible to radiation?
Proliferative cells
204
(L21) What is radiation fractionation? Why is it better than one big bolus of radiation?
Fractionation is the process of giving multiple small doses of radiation over several administrations. It allows for greater control of therapeutic effect while minimizing toxicity. The inter-administration periods allow normal tissue to recover from radiation damage.
205
(L21) Which tissues exhibit side effects early after radiation? How about late after radiation?
Skin and the GI tract are the first tissues to exhibit any signs of toxicity since they're composed of rapidly proliferating cells. Late responding tissues include the pleura and the spinal cord.
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(L21) What are the 4 Rs? Briefly describe them.
1. Repair - normal tissues have better DNA repair mechanisms than cancer cells, making them less susceptible to radiation 2. Repopulation - fractionation allows normal tissue to recover from radiation therapy while still targeting tumors 3. Redistribution - radiation can debulk a tumor, stimulating quiescent tumor cells to become proliferative and making susceptible to radiation 4. Reoxygenation - reoxygenation makes tumor cells more susceptible to radiation
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(L22) Tumor cells are basically modified self cells. How do immune cells recognize them?
Immune cells can bind to tumor-specific and tumor-associated antigens. Tumor-specific antigens are things expressed only by neoplastic cells, not normal tissue. These can include chimeric or fetal proteins from mutant genes. Tumor-associated antigens are expressed on both neoplastic and normal tissues, but in tumor cells, they're novel or abnormally expressed.
208
(L22) What is immunoediting?
Immunoediting is the process of immune cells recognizing and binding to tumor-associated antigens.
209
(L22) Describe how the innate and adaptive immune system interplay to eliminate tumor cells.
Innate system cells, are involved in the general recognition of TAAs and releasing cytokines to initiate an immune response. (L22) (L22) Namely dendritic cells recognize, bind to, and present tumor-associated antigens to cytotoxic CD8 T lymphocytes. CD4 T lymphocytes release cytokines that also recruit more cytotoxic T cells.
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(L22) Describe some mechanisms that would allow a tumor cell to escape our immune system.
1. the depletion of cytotoxic T cells 2. the loss of of helper T cells 3. infiltration of the tumor by protective regulatory T cells or the production of cytokines that attract regulatory T cells 4. overexpression of PD-L1 on neoplastic cells 5. recruitment of immunosuppressive myeloid-derived suppressor cells 6. downregulation of MHC class 1 receptors
211
(L22) What are biologic response modifiers? How could they be anti-tumor?
These are essentially vaccines that carry attenuated bacteria or bacterial components to stimulate the innate immune system. The goal is to have the stimulated innate immune system recruit adaptive immune cells. Examples: BCG vaccine and liposomal muramyl tripeptide.
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(L22) What are cytokines therapies? How are they anti-tumor?
Cytokine therapies, often involving IL-2, are meant to stimulate an immune response.
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(L22) Imiquimod is an immunological adjuvant. How is it anti-tumor?
Imiquimod is a topical toll-like receptor agonist. It's meant to stimulate dendritic cells and T cells.
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(L22) How would blocking PD-1/PD-L1 interactions be anti-tumor?
PD-1 is a receptor expressed on activated CD8 T cells and binds to PD-L1 antigens on targets like tumor cells. However, this interaction inhibits the T cell's cytotoxic effects, sparing the tumor cell. Inhibiting this interaction would lead to tumor cell apoptosis.
215
(L22) How do DNA vaccines work?
DNA vaccines are foreign DNA encoding specific antigens that are uptaken by cells when administered. These foreign antigens can then stimulate an adaptive immune response. Examples: Oncept, a vaccine with human tyrosinase, to treat canine melanomas; murine CD20 vaccines to treat canine lymphoma
216
(L23) Describe three ways in which a cell can develop resistance to apoptosis.
(Apoptosis is regulated cell death, so think mutations to normal regulatory processes) 1. Mutations to checkpoint proteins - Tumor suppressor genes like p53 regulate key checkpoints in the cell cycle and mutations to these genes allow abnormal cells to continue cycling. 2. Mutations to the intrinsic apoptotic pathway - Over-expression of Bcl-2 inhibits the release of cytochrome c from the mitochondria and the activation of caspases. 3. Mutations to the extrinsic apoptotic pathway - Mutations to T cell receptors prevents the binding of cytotoxic T cells.
217
(L23) Differentiate between intrinsic and extrinsic tumor resistance.
Intrinsic resistance is conferred by genetics or epigenetics. They're inherent byproducts of the mutations a tumor cell population has accrued. Extrinsic resistance involves the tumor's acquisition of resistance to a specific treatment. Any chemotherapy would kill the cells susceptible to it, leaving behind resistant cells. These resistant cells then repopulate, and the resulting tumor will now be resistant to that chemotherapeutic.
218
(L23) What are three intrinsic mechanisms that would make a cell more or less resistant to radiation therapy?
1. Proliferative cells are more susceptible to radiation than quiescent ones. 2. Cells with impaired DNA repair systems are more susceptible to radiation. 3. Hypoxic cells are more resistant to radiation.
219
(L23) What are some mechanisms in which a tumor cell can develop drug resistance?
1. Reduced uptake - the tumor downregulates the expression of transporters on the cell surface 2. Increased efflux - the tumor overexpresses transporters that pump a drug out of cells 3. Increased metabolism - the tumor upregulates the expression of enzymes that metabolize a drug
220
(L23) How do MDR1 transporters contribute to multi-drug resistance?
MDR1 transporters are ATP-driven protein pumps that can remove antitumor antibiotics, vinca alkaloids, and kinase inhibitors from inside the cell. Normally, these pumps are meant to remove chloride from excretory cells, but their over-expression contributes to drug resistance.
221
(L23) How cancer-associated fibroblasts promote neoplasia?
Cancer-associated fibroblasts express and produce collagenases, cytokines, and angiogenic stimulators. The collagenases digest the normal ECM and allow for the tumor to grow locally. The cytokines and angiogenic factors promote tumor growth and vascularization and inhibit apoptosis.
222
(L23) What kinds of immune cells contribute to neoplasia?
If a tumor cell can survive the acute immune response, it can co-opt chronic M2 macrophages, or tumor-associated macrophages, to continue growing. Normally, M2 macrophages produce angiogenic factors, block apoptosis, and downregulate the immune system as part of a healing process , but these functions foster tumor growth. The recruitment of of regulatory T cells also inhibits any other potential immune response against the tumor cells.
223
(L23) How does a tumor's extracellular matrix promote tumor survival?
The ECM formed creates very high interstitial pressure within the tumor. So even if a tumor is vascularized, drugs and immune cells in vessels have to exit against a high pressure gradient, rendering them ineffective.
224
(L23) Describe how the cells near the center of a tumor are more resistant to chemotherapy than cells near the surface.
Cells near the surface of a tumor are oxygenated and well-vascularized. The interstitial pressure there is also almost normal, which facilitates chemotherapy efficacy. In contrast, near the tumor's core, cells are hypoxic to anoxic, the interstitial pressure is high, the pH is altered, and there are little to no blood vessels. All of these factors decrease chemotherapeutic efficacy.
225
(L23) Why are hypoxic cells more resistant to therapy than oxygenated cells?
Without oxygen, radiation and chemotherapeutics, which act through the formation of free radicals, are less effective. Additionally, hypoxic cells release hypoxia-induced factors (HIFs) which are anti-apoptotic, stimulate proliferation, and are angiogenic. HIFs have also been shown to increase the accumulation of mutations and stimulate metastasis.
226
(L24) What diagnostic tool do we use to assign a tumor's grade?
Histopathology
227
(L24) Why do we stage?
A tumor's stage impacts prognosis, which can affect what treatments are available.
228
(L24) What kinds of tools do we have to evaluate the size of a primary tumor?
1. the physical exam 2. basic and advanced imaging 3. nuclear scintigraphy
229
(L24) What kinds of tools we do have to evaluate if there is systemic metastasis?
Based on the location of the metastasis, we have: 1. the physical exam 2. basic and advanced imaging 3. auscultation of the lungs 4. evaluating the size, shape, and consistency of LNs 5. FNA and biopsy 6. Bloodwork
230
(L24) What are the advantages and limitations of thoracic radiographs as as a diagnostic tool for cancer?
They're good for evaluating the thoracic cage for hilar lymphadenopathy or pulmonary metastasis. They also allow for evaluation of the heart and other thoracic structures. However, the technique impacts the diagnostic potential of x-rays and they're much less sensitive than advanced imaging at detecting pulmonary nodules.
231
(L24) What are the advantages and limitations of CT as a diagnostic tool for cancer?
CT provides good reproducible bone and spatial detail. There's also tissue settings and the contrasts that can further reveal more information. However, CTs are expensive and require heavy sedation or anesthesia.
232
(L24) What are some advantages and limitations of nuclear scintigraphy as a diagnostic tool for cancer?
Nuclear scintigraphy is a good scan for primary and metastatic bone tumors and thyroid tumors. However, it provides poor spatial detail for soft tissues.
233
(L24) What are the advantages and limitations of ultrasound as a diagnostic tool for cancer?
Ultrasound is minimally invasive, relatively inexpensive, doesn't necessitate anesthesia, and provides real-time imaging. However, it's very user-dependent and there are structures, especially in the pelvis, that are hard to ultrasound.
234
(L24) What are some advantages and limitations of MRI as a diagnostic tool for cancer?
MRI provides really good detail for soft tissues, especially the brain and CNS and there are contrast options that can differentiate edema from hemorrhage. It's limited by its need for anesthesia and cost.
