Oncology Flashcards
What are the 8 hallmarks of cancer
- Sustained angiogenesisi
- Evading apoptosis
- Self sufficiency in growth signals
- Insesntitivity to anti-growth signals
- Tissue invasion and metastasis
- Limitless replicative potential
- Deregulating cellular metabolism
- Immune evasion
What is the role of oncogenes and tumor supressor genes?
- Overactive tumor promoting genes (oncogenes) - caused by mutation to proto-oncogene, required mutation in one allele (dominant)
- Loss of tumor supressor genes - requires loss of both alleles (recessive)
What is the role of P53
- Acts as a checkpoint gene to survey cellular DNA damage
- Stops cell division when significant DNA damage is detected
- Can trigger apoptosis
- Loss of P53 is most common genetic alteration in human cancers
What is epigenetics?
- Gene function alteratiosn without changes to the DNA
- Usually through changes in the regulatory elements (promotor or enhancer)
- Linked to environemntal and acquired cancer risks
What are telomeres
- Specialised DNA protein complexes which cap chromosome ends and maintain stability
- Tandem repeats of TTAGGG
- Telomeres shorten with each division
What is telomerase
- Telomerase is a reverse transcriptase which extends telomeres giving cells proliferative potential
- Cancer cells often have high telomerase levels
What are the 5 steps in the metastatic cascade?
- Cellular basement membrane invasion and migration
- Invasion of nearby vessels and lymphatics
- Survival in circulation
- Extravasation into new tissues
- Proliferation in new site
What is angiogenesis (in neoplasia) and what are some of the growth factors that contribute to it
- Formation of new blood vessels within the tumor micorenvironment
- Driven by: Hypoxia, VEGF (vascular endothelial growth factor), PDGF (platelet endothelial growth factor) and bFGF (basic fibroblast growth factor)
- Many cancer cells can induce angiogenesis in absence of hypoxia by upregulating stimulatory cytockines
What is the cancer stem cell hypothesis?
- This proposes there is a population of cells within tumors that account for the rapis recurrence of a cancer after initial response to therapy.
- These cells are: slowly dividing, self renewing, resistant to conventional treatment.
Chemotherapy is most effective against small tumor burdens - due to what biological factors?
As tumors grow:
- growth fraction decreases
- cell time increases
- heterogenicity increases (leading to spontaneous resistance)
- areas of poor drug perfusion develop
Important because:
- Chemotherapy follows fractional kill kinetics
- Resistance occurs through spontaneous mutation which is correlated with number of cell divisions
Name some alkylating agents and their broad mechanism of action
- Cyclophosphamide, chlorambucil, melphalan, lomustine (CCNU)
- Create cross-links in DNA causing strand breaks or DNA alkylation
Name some antitumor antibiotics (anthracyclines) and their broad mechanism of action
- Doxorubicin, epirubicin, mitoxantrone
- Intercalate DNA and interfere with topoisomerases
- Are substrates for the multidrug resistance (MDR) pump (risk of resistance)
Name some Mitotitc inhibitors and their broad mechanism of action
- block spindle assembly (vinca alkaloids - vinblastine, vincristine, vinorelbine)
- or spindle stability (paclitaxel)
Name some platinum agents and their broad mechanism of action
Cisplatin, carboplatin
Create DNA cross-links and strand breaking
Name some antimetabolite agents and their broad mechanism of action
- Rabacfosadine, gemcitabine, Cytosine arabinoside, methotrexate, 5FU
- Nuceloside analogues or DNA enzyme inhbitors
- Interfere with DNA synthesis
What are the aims of a combination chemotherapy protocol
- Target different tumor cellular metabolic pathways to overcome resistance
- Maintain effectiveness without compounding toxicity
- Avoidance of cross-resistance
What is the mechanism of action of radiotherapy
Damages DNA
- Photons cause direct ionisation (1/3)
- non-DNA ionisation causes free radicle ionisation (2/3)
- Cause strand breakage - DSB (double strand break) most effective for cell death
What are the 5 R’s in radiation biology
- Repair: Radiation induces more repairable breaks than non-repairable, fractionation takes advantage of this
- Redistribution: Fractionation allows cells to move between cycle phases of varying sensitivity
- Repopulation: Tumour cells can regenerate during treatment (a common cause of failure)
- Re-oxygenation: Fractionation improves oxygenation of hypoxic tumour areas, oxygenation of tissues improves effect of radiation
- Radiosensitivity: Different cells have different radiosensitivity
Which immune cells are responsible for direct tumor cell killing
CD 8+ and NK cells
What is the mechanism of action of toceranib
A multikinase inhibitor that acts on multiple receptor tyrosine kinases (RTKs)
* Direct action: inhibiting transmitting KIT signals with gain-of-function mutations.
* Indirect action: controlling angiogenesis through PDGFR and VEGFR inhibition
* It induces regulatory T cell suppression.
What are 3 main targets of toceranib
KIT,
Vascular endothelial growth factor receptor 2 (VEGFR2),
Platelet-derived growth factor receptor (PDGFR) beta.
What are the main adverse effects of toceranib
- Gastrointestinal toxicosis,
- myelotoxicosis,
- musculoskeletal disorders,
- depigmentation
- hypertension
- hypothyroidism
Which tumors respond to the direct action of Toceranib
Mast cell tumors (MCTs) and gastrointestinal stromal tumors (GISTs).
What is the prevalence range of c-KIT mutations in canine MCTs
8-45%
Which tumor types respond better to Toceranib’s indirect actions
Epithelial malignancies
What are the two classifications of chemotherapy drugs regarding extravasation potential
“Irritants” and “Vesicants”
List four immediate management steps for any extravasation event
1) Stop drug administration immediately,
2) Apply gentle negative pressure to remove drug,
3) Remove the catheter gently,
4) Avoid occlusive bandaging
Name examples of irritant chemotherapy drugs.
Platinum drugs (carboplatin, cisplatin),
dacarbazine,
mitoxantrone,
What are the typical effects of irritant drug extravasation
Mild to moderate erythema, edema, and crusting causing discomfort
Name examples of mild vesicant chemotherapy drugs
Vinca alkaloids (vincristine, vinblastine, vinorelbine)
What compresses should be applied for mild vesicant extravasation?
Warm compresses for 15-20 minutes, every 6 hours, for 2-3 days
Name three examples of serious vesicant chemotherapy drugs
Anthracyclines (doxorubicin, epirubicin),
dactinomycin,
mechlorethamine
What compresses should be applied for serious vesicant extravasation?
Cold compresses for 15-20 minutes, every 6 hours, for 2-3 days (opposite to mild vesicants)
What specific antidote can be used for doxorubicin extravasation, and when must it be administered?
IV dexrazoxane (10× the doxorubicin dose) within 3 hours, repeated at 24 and 48 hours.
When do neutrophil nadirs typically occur post-chemotherapy treatment
5-10 days post-treatment
When do platelet nadirs typically occur post-chemotherapy treatment
7-14 days post-treatment
Which genetic mutation increases risk of chemotherapy-induced myelosuppression in certain breeds?
Mutations in the ABCB1-1delta (MDR-1) gene
Collies, Australian Shepherds, and related breeds
Which chemotherapy agents most commonly cause clinically significant neutropenia in dogs and cats?
Carboplatin, doxorubicin, CCNU, mitoxantrone, vinblastine, and vinorelbine.
Which chemotherapy agents commonly cause thrombocytopenia
Carboplatin, CCNU, dacarbazine, melphalan, dactinomycin, cytosine arabinoside, and doxorubicin.
Which class of agents may cause cumulative and irreversible thrombocytopenia with chronic use
Alkylating agents (CCNU, chlorambucil, melphalan).
Which dog breeds are most susceptible to chemotherapy-induced alopecia
Continuously-growing hair breeds: Maltese, Bichon Frisé, Poodles, certain Terrier breeds, Shih-Tzu, and Old English Sheepdog.
What chemotherapeutic agent causes focal dermatologic reaction in approximately 50% of dogs
RAB
What is the syndrome characterized by erythema, ulceration and alopecia that can occur with liposomal doxorubicin
Palmar-plantar erythrodysesthesia (“hand-foot syndrome”)
What vitamin can reduce the severity of liposomal doxorubicin skin lesions in dogs
Pyridoxine (vitamin B6)
How does chemotherapy induce vomiting via the chemoreceptor trigger zone (CTZ)
Via neurotransmitters such as serotonin and substance P binding to 5-HT3 and neurokinin 1 (NK1) receptors.
What is the mechanism of action of crofelemer in treating chemotherapy-induced diarrhea?
It inhibits secretion of chloride ions and water by GI epithelial cells.
Which chemotherapy drug is primarily associated with cardiac toxicosis?
Doxorubicin
At what cumulative dose does the risk of doxorubicin cardiac toxicity significantly increase?
> 180 mg/m²
What agent can be co-administered to reduce the risk of doxorubicin cardiotoxicity
Dexrazoxane (an iron chelator).
Which chemotherapy drug is notably hepatotoxic in dogs, causing increased ALT in up to 86% of treated animals?
Lomustine (CCNU)
What is the nature of CCNU-induced liver damage?
Cumulative and often irreversible damage,
with acute liver failure rarely occurring after a single treatment
Name two hepatoprotectants that may reduce the severity of chemotherapy-induced liver damage
S-adenosylmethionine and silybin
Which chemotherapy drugs require dose adjustments with pre-existing liver disease due to biliary excretion
Vinca alkaloids and doxorubicin
What neurologic effect can vincristine cause
Ileus due to neurotoxic effect on enteric motor function
Why is 5-fluorouracil contraindicated in cats
It can be neurotoxic and is fatal to cats
Which chemotherapy drugs are known nephrotoxicants
Cisplatin (dogs),
ifosfamide (dogs & cats),
streptozotocin (dogs)
Which chemotherapy drugs can cause Sterile Hemorrhagic Cystitis (SHC)
Cyclophosphamide and ifosfamide
What metabolite causes direct bladder irritation leading to SHC
Acrolein, an inactive metabolite
What drug is administered concurrently with high-dose cyclophosphamide to reduce the risk of SHC
Furosemide
Why is cisplatin contraindicated in cats
It causes fatal pulmonary edema when administered IV to cats
Which drug has been associated with diabetes in approximately 40% of cases
Streptozotocin (toxic to pancreatic beta cells)
Used for treatment of insulinoma
What unusual side effects have been associated with toceranib phosphate
Pancreatitis and lameness
Which drugs have been associated with pulmonary fibrosis
Bleomycin, high-dose CCNU in cats, and RAB
Which chemotherapy drug can cause true IgE-mediated hypersensitivity reaction
L-asparaginase
What measures can reduce the risk of hypersensitivity reactions with L-asparaginase
Administer SC or IM instead of IV, or premedicate with diphenhydramine
What causes anaphylactoid reactions with rapid IV administration of doxorubicin
Histamine release from mast cells (not true IgE-mediated hypersensitivity)
Melphalan
- Alkylating agent (Nitrogen mustard)
- DNA cross linking
- Myelosupression
Cyclophosphamide
- Alkylating agent (Nitrogen mustard)
- DNA cross-linking (prodrug)
- Neutropenia, sterile haemorrhagic cystitis
Ifosfamide
- Alkylating agent (Nitrogen mustard)
- DNA cross-linking (prodrug)
- nephrotoxicity, myelosuppression, sterile haemorrhagic cystitis
Chlorambucil
- Alkylating agent (Nitrogen mustard)
- DNA alkylation
- Myelosupression
Lomustine (CCNU)
- Alkylating agent (nitrosoureas)
- DNA Alkylation
- Myelosuppression, cumulative hepatotoxicity
Streptozotocin
- Alkylating agent (nitrosoureas)
- DNA alkylation
- GI toxicity and myelosupression, beta cell toxicity
Dacarbazine
- Alkylating agent
- DNA methylation
- Gi toxicity, myelosuppression
Procarbazine
- Alkylating agent
- DNA methylation
- Gi toxicity and myelosuppression
Mechlorethamine
- Alkylating agent (Nitrogen mustard)
- DNA cross linking
- Vesicant, myelosuppression, GI toxicity
Doxorubicin
- Antitumour antibiotic
- DNA intercalation, topoisomerase II inhibition
- Cumulative cardiotoxicity, vesicant, myelosuppression, GI toxicity
Mitoxantrone
- Antitumour antibiotic
- DNA intercalation, topoisomerase II inhibition
- myelosuppression
Actinomycin D
- Antitumour antibiotic
- DNA intercalation, RNA/protein synthesis inhibition
- Vesicant, GI toxicity and myelosuppression
Cytosine Arabinoside
- Antimetabolite
- DNA polymerase inhibition
- Myelosuppression, GI toxicity
Methotrexate
- Antimetabolite
- Dihydrofolate reductase inhibition
- Myelosuppression, GI toxicity
Gemcitibine
- Antimetabolite
- Nucleoside analogue, inhibits DNA synthesis
- Myelosuppression
5-Fluorouracil
- Antimetabolite
- Uracil analogue, Thymidylate synthetase inhibition, inhibits DNA synthesis
- Myelosupression, GI toxicity
- **Contraindicated in cats **
Rabacfosadine
- Antimetabolite
- Nucleotide analogue
- GI toxicity, **idiosyncratic pulmonary fibrosis, dermatologic **
Paclitaxel
- Antimicrotubule agent (taxane)
- Causes abnormal organization of spindle microtubules and mitotic arrest
- Hypersensitivity reactions, myelosuppression
Vincristine, vinblastine, vinorelbine
- Antimicrotubule agent (vinca alkaloid)
- Microtubule assembly inhibition - metaphase arrest
- Vincristine - Peripheral neurotoxicity, GI ileus, vesicant
- Myelosupression, vesicant
Carboplatin and Cisplatin
- Platinum agents
- DNA cross linking
- Carboplatin - myelosuppression
- Cisplatin - nephrotoxicity, GI toxicity, contraindicated in cats
Hydroxyurea
- Ribonucleotide reductase inhibition, depletion of deoxyribonucleotide
- myeleosupression, onycholysis
L-asparaginase
- Asparagine depletion and inhibition of protein synthesis
- Hypersensitivity reactions
Toceranib, masitinib, imatinib
- Tyrosine kinase inhibitors
- RTK inhibition (KIT, VEGFR2, PDGFR)
- GI toxicity, hyporexia, proteinuria/PLN, hypertension, hepatotoxicity
Which chemotherapeutics target the S phase
Antimetabolites,
alkylating agents,
cross-linking agents,
topoisomerase inhibitors
Which chemotherapeutics target the M phase
Antimicrotubule agents
Which tumor type is most commonly associated with gastrointestinal ulceration
What is the mechanism
- Mast cell tumours
- Hyperhistaminemia stimulating gastric acid secretion
Which cytokines mediate cancer cachexia?
TNF-α, IL-1, and IL-6
Which canine tumors are commonly associated with hypercalcemia of malignancy?
T-cell lymphoma and anal sac apocrine gland adenocarcinoma
Which feline tumors are associated with hypercalcemia of malignancy?
Lymphoma, squamous cell carcinoma (SCC), and multiple myeloma
What are three tumor types associated with hypoglycemia?
What molecule typically mediates this
Insulinoma, hepatocellular tumors, and smooth muscle tumors
IGF-2
Which tumor is most commonly associated with hyperestrogenism?
What are the clinical sigs
- Sertoli cell tumors (especially in cryptorchid testes)
- Feminisation and BM toxicity
How common is anemia in dogs/cats with lymphoma?
Very common, reported in 30-58% of cases
How common is thrombocytopenia in dogs with cancer before treatment?
Present in 13-36% of dogs
Which neoplasm is associated with hyperglobulinemia?
Multiple myeloma
Which tumor types are associated with erythrocytosis
Renal tumors
What tumor is associated with nodular dermatofibrosis, and in which breed?
Renal cystadenocarcinomas, mostly in German shepherds
What type of tumor is associated with superficial necrolytic dermatitis?
Glucagon-secreting tumors
What tumor types are associated with feline paraneoplastic alopecia?
Pancreatic and biliary carcinomas
What tumor is associated with exfoliative dermatitis in cats?
Thymoma
Which tumor is most commonly associated with myasthenia gravis?
Thymoma
Which tumor types are associated with hypertrophic osteopathy?
Primary or metastatic lung tumors
What is the most common histopathological diagnosis in dogs with lymphoma
Diffuse large B cell lymphoma (DLBCL) - 50% cases
Which subclassification of lymphoma is most liekly to cause paraneoplastic hypercalcemia
T cell
Which dogs show a higher breed prevalacance for B cell lymphoma
Basset Hound, Cocker Spaniel, Border Collie, Doberman Pinscher
Which dogs show a higher breed prevalacance for T cell lymphoma
Boxer, Shih Tzu, Cavalier King Charles Spaniel, Airedale
Which breed are over represented in Indolent T-zone Lymphoma (TZL)
Golden retreiver ~40% cases
What proportion of dogs with Indolent T zone lymphoma (TZL) have a concurrent blood lymphcytosis
50%
Which anatomical location for lymphoma is more likely to have an associated paraneoplastic hypercalcemia?
Mediastinal
What is the WHO staging for lymphoma
- Stage I: Single lymph node
- Stage II: Multiple lymph nodes in a regional area (same side of diaphragm)
- Stage III: Generalized lymphadenopathy
- Stage IV: Liver and/or spleen involvement (± lymph node involvement)
- Stage V: Any other anatomic site, including bone marrow and blood
- Substage a: Without clinical signs of disease
- Substage b: With clinical signs of disease
What are the cluster of differentiation T cell markers?
CD3, CD5, CD4, CD8
What are the cluster of differentiation B cell markers?
CD20, CD21, CD79a
What is the pan-leucocyte marker
CD45
What is the leucocyte pre-cursor marker (immature lymphoid/myeloid cells)
CD34
Expression of MHCII is typically high or low in peripheral T cell lymphoma in dogs
Low
FeLV is strongly associated with which neoplastic diseases
Large cell lymphoma (usually T cell) and Leukaemia
FIV infected cats are more likely to develop which type of lymphoma
approx 5x more likely to develop lymphoma
typically B cell in extranodal sites
FeLV associated lymphoma is most likely foudn in which anatomical locations
Mediastinal lymphoma most common, followed by multicentric, spinal, renal, or ocular
GI and nasal not usually FeLV associated
What anatomical location is most common in cats and what are the 3 types
Gatrointestinal
* Mucosal T cell lymphoma (EATCL Type II): small/intermediate lymphocytes in LP
* Transmural T cell lymphoma (EATCL Type I): large granular lymphocytes
* Diffuse large B cell lymphoma (DLBCL)
What are some prognostic indicators for cats with lymphoma
- Response to treatment
- FeLV positivity - strong negative factor
- Large granular lymphoma - aggressive variant
What are some prognostic indicators for dogs with lymphoma
- Immunophenotype: T-cell (except TZL) worse than B-cell
- Clinical substage: b worse than a
- Hypercalcemia: negative factor
- GI involvement: negative factor
What are the CD features of most chronic lymphocytic leukemias (CLL) in dogs?
- At least 75% are CD8+ CD45+ T-cell in origin
- CD21+ B-cell CLL is the next most common subtype
What are the CD features of most chronic lymphocytic leukemias (CLL) in cats?
- Almost all cases are CD4+ cell in origin
Is CLL in cats associated with FeLV/FIV?
No
What characterises acute lymphoblastic leukemia (ALL)
- proliferation of immature lymphoblasts in BM
- Diagnosis based on >20% blasts in peripheral blood or BM
What CD marker typically distinguishes acute leukemia from lymphoma?
What proportion of dogs with ALL are negative for this marker?
CD34+
25% dogs with ALL are CD34-
Is ALL in cats associated with FeLV or FIV
FeLV
What characterises Myelodysplastic syndrome?
- Cytopenias in multiple cell lines
- Bone marrow usually normocellular to hypercellular with dysplastic changes
- Increased blasts but <20% of nucleated cells
What characterises multiple myeloma
Arises from single clone of plasma cells producing excess immunoglobulin (can be whole Ig moelcule or molecular portion)
What are some of the characteristic clinical findings with multiple myeloma
- Other cytopenias (anaemia, thrombocytopenia and sometimes neutropenia)
- Bone lesion with dicrete osteolytic painful areas (vertebrae, ribs, pelvis, long bones)
- Coagulation and bleeding disorders
- Excess light chains (bence jones proteins) can cause renal damage
What are the diagnostic criteria for multiple myeloma
Need>/=2
* BM plasmacytosis (>20%)
* Serum monoclonal gammopathy
* Osteolytic lesions
* Bence-Jones proteinuria
What is BRAF
a gene and associated protein that helps control cell growth
What is the BRAF mutation and what disease can it help identify
- Specific mutation detected is called BRAF V595E
- More than 80% of dogs with transitional cell carcinoma (TCC) have this BRAF V595E mutation
What is the sensitivity and specificity of BRAF
Testing has >85% sensitivity with 100% specificity when used on free-catch urine samples
