Oncology Flashcards
1
Q
What is the staging system for canine lymphoma?
A
Stages I: single LN, II: multiple LNs, III: regional LNs, IV: liver and/or spleen, V: distant metastasis.
Substaging: a - systemically well. b - systemically unwell.
2
Q
Clinical staging system for feline LSA?
A
Stage I: single extranodal tumor or node. Primary intrathoracic tumor.
Stage 2: 2+ nodes on same side of diaphragm, single tumor with regional LN involvement, 2 tumors +/- LN on same side of diaphragm, resectable primary GI tumor (usually ICJ)
Stage 3: 2 single tumor on opp sides or above/below diaphragm, all primary resectable abdo tumors, all paraspinal/epidural tumors
Stage 4: 1-3 + liver/spleen involvment
Stage 5: 1-4 + CNS and/or BM involvement
3
Q
Canine multicentric lymphoma - treatment options?
A
- Multiagent - CHOP. Remission rate >90%, DFI 12 months. 4-6 week cycles.
- Single agent - doxorubicin (+ steroid).
4
Q
Chronic lymphocytic leukemia (CLL) - criteria for treatment?
A
Lymphocyte count >60K
Organomegaly (infiltrative disease)
Most common form - T cell, granular form.
5
Q
Compare & contrast clinical features between ALL & CLL?
A
Signalment - ALL young-middle aged 6yo, CLL older 10-12yo
Cells - ALL resemble blasts, from BM. CLL small mature Lc, from peripheral blood +/- BM; can develop blast crisis / large cell LSA.
Immunophenotype - ALL B cell >90%. CLL T cell > B cell > atypical (B+T)
Lab - ALL leukopenia/leukocytosis, cytopenias (myelophthisis). CLL marked lymphocytosis, hyperglob (B cell > IgM > hyperviscosity syndrome + fLC/BJ proteinuria)
Similar - splenomegaly 70%, hepatomegaly 50%, mild generalised lymphadenopathy.
ALL +/- CNS, bone pain (infiltration)
BM aspirate - ALL blasts 30%+, CLL small mature Lc 30%+ (N <5-10%)
Workup - ddx stage V LSA (generally worse lymphadenopathy), hyperCa
6
Q
CLL - treatment and prognostic factors?
A
Chlorambucil and prednisolone - long term.
2nd-line: cyclophosphamide instead of chlorambucil.
Refractory - as per ALL tx (CHOP, L-aspar, cytarabine)
Overall good prognosis
Negative - anemia, immunophenotype (B cell worse than T)
7
Q
Cell surface markers for vascular neoplasia
A
CD31
Vimentin (spindle cell)
Factor 8
8
Q
Cell cycle non-specific drugs?
A
Anti-tumor antibiotics (doxo, mitoxantrone)
9
Q
Cell cycle specific drugs?
A
Alkylating agents (vinc-)
10
Q
MDR-positive dogs - pathogenesis and considerations?
A
ABCB1 gene mutation (aka Multi Drug Resistance 1 gene) - deletion in 4 base pairs. Gene encodes for p-glycoprotein - affects drug efflux from cells. Most significant implication in epileptic control (often more refractory to conventional anti-epileptic drugs in Collies).
Overall <2% prevalence (UK, presumably Aus).
11
Q
ABCB1/MDR1 - which drugs?
A
Alkylating agents (vincristine, vinblastine, vinorelbine), paclitaxel.
NOT cyclophosphamide, CCNU, doxorubicin.
MDR1 positive - Dose reduction by 25% if heterozygote, 50% if homozygous.
12
Q
Chemotherapeutic drugs that cross the BBB
A
Lipophilic drugs:
Procarbazine
Alkylating agents - lomustine (CCNU), temozolomide
Cytarabine arabinoside (anti-metabolite)
13
Q
Multiple myeloma - diagnostic criteria (list 4)
A
1) Neoplastic plasma cells in the BM/tissues
2) Lytic bone lesions
3) Monoclonal gammopathy (serum)
4) Bence Jones proteinuria (urine fLC)
3 & 4 - presence of clonal Ig paraproteins produced by neoplastic cells (M-proteins) - can be complete Ig (IgM predominantly as large) or free light chains (fLC).
14
Q
Multiple myeloma - clinical manifestations & mechanisms?
A
Hyperviscosity syndrome
- Bleeding diathesis 40% (M component interferes with platelet aggregation & platelet factor 3 release, thrombocytopenia, abnormal fibrin polymerisation, functional decr Ca2+, absorption of minor clotting proteins)
Systemic hypertension - ocular TOD
Renal dysfunction (proteinuria, poor perfusion, neoplastic infiltrate)
Lameness/bone pain
Immunosuppression - 2’ infections (decreased functional Ig, myelopthisis)
Cytopenias (anemia, thrombocytopenia)
Hypercalcemia (D>C) - pdtn of osteoclastic-activating factors, bone infiltration
15
Q
Multiple myeloma - treatment?
A
Melphalan and prednisolone
Pamidronate (if osteolytic lesions)
Lomustine (CCNU) + hepatoprotectant
16
Q
Multiple myeloma - prognosis?
A
MST 540-930 days with PO chemotherapy
17
Q
Soft tissue sarcoma (STS) grading system?
A
Grade I & II: low grade
Grade III: high grade
Histologic grade is PROGNOSTIC
18
Q
Grading system for neutropenia?
A
Grade 1-4
19
Q
Cyclophosphamide MOA?
A
Alkylating agent
20
Q
Cyclophosphamide adverse effects and MOA?
Preventative measures for AE?
A
- Haemorrhagic cystitis (via renal excretion of its hepatic metabolite acrolein which is urotoxic - caustic to uroepithelium). Prevention - frusemide +/- pred concurrently, walk dog frequently after admin. TMS for UTI.
- Myelosuppression (neutropenia)
21
Q
Canine cutaneous epitheliotropic LSA - predilection sites and presentation?
A
Mucocutaneous junctions (perianal, perioral, conjunctiva, paw pads)
GI epithelium - different disease entity
22
Q
ICC/IHC markers - which?
B or T cell LSA
A
B cell - Pax5, CD79
T cell - CD4, CD8, CD3
Histiocytic sarcoma - Iba1 (macrophage origin)
23
Q
MCT - prognostic factors?
A
Grading: high grade/grade III MCTs with a high mitotic rate (>5/10hpf) and/or prominent anisokaryosis and/or giant cell formation may have a poor outcome as a result of a high rate of local and distant metastasis or inoperable recurrence.
24
Q
Oral SCC - dogs - prognostic indicators?
A
Tumor size
Tumor location (rostral more likely surgically resectable than caudal)
LN metastasis (uncommon, 10%) - good to do sentinel lymph node mapping
25
Hemangiosarcoma - staging system?
Stage I: Tumor confined to the spleen.
Stage II: Ruptured splenic tumor with or without regional lymph node involvement.
Stage III: Distant lymph node or other tissue metastases.
26
Canine HSA - common primary sites?
Spleen >> right atrium, cutaneous, SQ.
27
Canine HSA - prognostic factors?
Negative prognostic indicators -
Advanced stage - hemoperitoneum or splenic rupture.
Stage I tumors - MST >2yrs survival with sx alone, stage II & III - 6-10mths with sx alone.
Some forms of cutaneous/ subcutaneous HSA appear to have a lower metastatic potential and less aggressive biologic behavior.
28
Tigilanol tiglate (Stelfonta) - MOA and indications?
Intra-lesional injection for non-metastatic canine MCT.
Reported 75% with single injection, 87% with >1 injection.
Indications:
Non-metastatic subcutaneous mast cell tumors located at or distal to the elbow or the hock in dogs
Non-metastatic cutaneous mast cell tumors located all over the body
Tumors must be less than or equal to 10 cm3 in volume, and must be accessible to intratumoral injection
Do not exceed 5 mL per dog, regardless of tumor volume or body weight
The minimum dose of STELFONTA is 0.1 mL, regardless of tumor
Day 1: acute inflammatory response with swelling and erythema noted on the tumor margins and surrounding tissues.
Day 2: necrotic destruction --> blackening, shrinkage and thick discharge
See JVIM 2021 papers:
1) Jones et al. Recurrence-free interval 12 months after local treatment of mast cell tumors in dogs using intratumoral injection of tigilanol tiglate.
2) De Ridder et al. Randomized controlled clinical study evaluating the efficacy and safety of intratumoral treatment of canine mast cell tumors with tigilanol tiglate (EBC-46).
3) Reddell et al. Wound formation, wound size, and progression of wound healing after intratumoral treatment of mast cell tumors in dogs with tigilanol tiglate.
29
Bisphosphonates - MOA and indications?
Example drugs - pamidronate, zolendronate.
MOA: synthetic analogs of naturally occurring inorganic pyrophosphate compounds whose therapeutic effect inhibits osteoclasts, reducing pathologic bone resorption without inhibiting bone mineralization. Bind to hydroxyapatite particles in bone and are subsequently released and endocytosed during osteoclastic-mediated resorption, resulting in apoptosis of osteoclasts and inhibition of bone resorption.
Indications - hypercalcemia of malignancy, reduction of skeletal events in the management of bony metastases (humans)
Adverse effects - nephrotoxicity (4.5% for zolendronate in dogs in 1 study)
30
L-asparaginase - differences between native and pergylated (PEG) form?
Indications & disadvantages?
PEG L-aspar - prolonged circulation time --> requires less frequent administration. Pergylation also reduces immunogenicity of the enzyme
Rapid acting
Antibody development occurs quickly to enzyme, often after 1 injection - so limited efficacy with multiple injections
31
Modified Adam staging system for nasal tumors in dogs and cats?
Stage I - confined to 1 nasal passage, paranasal, and frontal sinus, no bone involvement.
Stage II - any bone involvement with no evidence of involvement of orbit, SQ/submucosal tissue.
Stage III - any involvement of the orbit and/or nasopharyngeal and/or SQ/submucosal tissues.
Stage IV - involvement of the cribriform plate/invasion of the brain
32
Doxorubicin adverse effects and MOA? Cats vs dogs?
1) Nephrotoxicity (cats)
2) Cardiotoxicity (dogs?): arrhythmias, DCM? Occurs via myocyte injury from generation of free radicals, which incorporate iron. Histo - loss of myofibrils, sarcoplasmic vacuolar degeneration, and decreasing number of myocytes.
3) Hypersensitivity
4) Extravasation injury
33
Methotrexate MOA, indications?
MOA: antifolate drug --> inhibits dihydrofolate reductase (DHFR) = key enzyme in folate synthesis. Folate is needed for production & maintenance of new cells, DNA replication (methyl donor for formation of thymidylate), RNA synthesis. Drug effects - folate accumulation in inactive form - depletes reduced folate substrates.
SE: rapidly proliferating cells most susceptible - neoplastic cells, BM, GI epithelium. Low doses - GI epithelial necrosis, myelosuppression. High doses - hepatocellular tox, nephrotox, CNS damage.
70% renal excretion.
Indications: OSA & LSA most common.
Tx for MTX tox (humans): leucovorin (folinic acid) = reduced active form of folate. Competes with MTX. Used as rescue therapy in high dose MTX therapy.
34
Which LNs can an oral melanoma or SCC metastasize to?
Mandibular, retropharyngeal. Can also go to contralateral LN.
35
What is the typical phenotype of CLL in cats?
CD4+ (T helper)
36
What is an example of a drug that could theoretically increase the risk of toxicity of some chemotherapeutics?
P-glycoprotein inhibiting medications can induce a risk similar to ABCB1 (MDR-1) mutants. E.g. ketoconazole, cyclosporine. Both drugs also inhibit cytochrome p450 metabolism —> thus can also increase vinblastine toxicity.
37
Protocols for which neoplasms may feature carboplatin?
What is its side effect profile?
OSA, UCC, AGASACA, Melanoma. Carcinomas in general.
Can be given intra-cavitary.
Platinum, like cisplatin - but not nephrotoxic and doesn't cause fatal pulmonary oedema (cisplatin - ‘splat’ cats).
SE: GI, myelosuppression (14-28 days in).
Suggest dose adjustment for cats with renal disease, as renal excretion of drug means with reduced GFR > increased risk of myelosuppression.
38
Tx for doxorubicin extra-vasation?
What is a cat-specific doxorubicin adverse effect?
Dexrazoxane.
Nephrotoxicity.
39
Cell surface receptors associated with malignant histiocytiosis?
CD11c & CD18
Haemophagocytic: CD11d, CD18
40
Cell surface markers for:
- T cell
- B cell
- Haematopoietic stem cells
- CD3, CD5; subtypes CD4 (T helper) & CD8 (cytotoxic T cell)
- CD21, CD22, CD 25 (if activated)
- CD34
41
Cytarabine
- MOA
- Indications
- AE
Converted intracellularly to aracytidine triphosphate —> competes with deoxycytidine triphosphate to inhibit DNA polymerase —> inhibits DNA synthesis. S-phase specific - blocks cell progress from G1 to S phase.
Drug is incorporated into DNA.
Adjunct tx for:
- Lymphoreticular neoplasia (especially CNS lymphoma) - as rescue agent (poorly effective as single agent, limited data on efficacy as multi agent).
- Myeloproliferative disease (leukemia)
- MUO (dogs/cats) - combo with GCS
AE
- Hematologic - neutropenia (35%), thrombocytopenia (12%) most common. Myelosuppression worse with IV vs SQ.
- GI signs (including oral ulceration), neurotoxicity, hepatotoxicity (increased ALT in 15%), lethargy, pyrexia
- Alopecia, delayed hair regrowth, calcinosis cutis at injection sites reported
- Infiltrative lung disease (case report) following CRI
NB: drug resistance can develop (several mechanisms)
42
Which chemo drugs are contraindicated in MDR 1 (ABCB1) mutant dogs? What aspect of the drug PK is implicated?
Vincristine, Vinblastine, Doxorubicin, Paclitaxel.
Reduced biliary excretion so increased risk of SE.
Rare report of neurotoxicity (vincristine).
43
Vinca alkaloids
- Which drugs
- MOA (part of cell cycle affected)
- Vincristine, vinblastine, vinorelbine
- Inhibit microtubule assembly - so inhibit M phase.
44
Cyclophosphamide
- Drug class
- SE
- Contraindications
Alkylating agent
SE:
- Sterile hemorrhagic cystitis (acrolein metabolite) - dogs not cats
- Myelosuppression
-GI upset
Contraindications:
- Caution with hepatic or renal impairment
- Caution in TCC breeds (Scottish terrier)
45
Melphalan
- Drug class
- MOA
- SE
Alkylating agent
Effects DNA and RNA - so affects resting cells. Does not require hepatic activation, excreted in the urine unchanged.
SE
- Myelosuppression - onset & recovery from leukopenia can be delayed
- GI signs
- Pulmonary infiltrates/fibrosis.
- Neurotoxicity
- Skin HS (reported in people), dogs - minor hair coat changes (shaggy, lack lustre coat). Breeds with continuous growing hair coats (Poodles etc) more likely to have significant alopecia
- Secondary malignancies (reported in people)
46
Lomustine
- Drug class
- MOA
- AE
- Contraindications
Alkylating agent
Non-cell cycle phase specific
Crosses BBB - good for CNS neoplasia.
SE
Myelosuppression (nadir @1-3 weeks)
Hepatotoxicity (LE increase in 29% dogs, 6% clinical) - prophylactic SAME (hepatoadvanced) proven to reduce risk of this
GI upset
Pulmonary infiltrates
Nephrotoxicity
47
What stain can be used to differentiate canine osteosarcoma from others?
ALKP stain
100% Sn & 89% Sp.
Caution - reactive bone can stain similar, read cyto first
48
What biochemical/metabolic derangements are noted with tumor lysis syndrome? Which tumors are risk factors for this?
- Acute lysis of tumour cells following chemotherapy. Release of intracellular products & metabolites >> hyperK, hyperphos (+ 2’ hypoCa), hyperuricemia (from nucleic acids)
- Most common tumors: hematologic malignancies (ALL, lymphoblastic leukemia, acute myeloid leukemia, lymphoma), also other bulky or rapidly growing tumors
- Pre-tx azotemia may be at increased risk
49
What paraneoplastic manifestations can occur with testicular neoplasia?
Oestrogen production (also progesterone, corticosteroids)
Most commonly seen with Sertoli cell tumors (70% intraabdominal testes, less in scrotal & inguinal testes), rare with seminomas & Leydig cell tumors. Related to excessive E2 production.
**- Feminization syndrome **
- **BM hypoplasia with myelosuppressio**n > thrombocytopenia, anemia >, granulocytopenia), hemorrhage)
- Symmetrical and squamous metaplasia of the prostate resulting in cystic benign prostatic hyperplasia
- Gynecomastia and galactorrhea
- Attractiveness to other males
- Atrophy of non-neoplastic testicle due to negative feedback of E2 on HP axis etc.
50
What % of dogs with splenic HSA have right atrial involvement?
Up to 25%
51
What are potential benefits for hypofractionated external beam RT in canine HSA?
- Palliation for non-resectable SQ or IM HSA - high response rate but not necessarily increase survival.
- Cardiac HSA - reduce frequency of tamponade
52
Which 3 angiogenic factors were found to be increased in blood & effusions of HSA dogs, with overexpression of receptors in tumor tissues?
VCNA review
VEGF, PDGF & endothelin-1
53
What is collagen XXVII peptide? What is its diagnostic & prognostic utility for canine HSA?
Mullin VCNA 2019 review
Protein breakdown product, related to invasive & angiogenic processes.
Higher serum [ ] in HSA dogs esp with large metastatic burdens.
Also decreased levels after sx resection, and subsequent increases with tumor recurrence.
54
For the following treatments, what is the drug MOA when used in dogs with HSA?
1. Thalidomide
2. Ifosfamide
Ifosfamide = alkylating agent. Can be single agent or combo with doxo alternating. Give with saline & mesna (hemorrhagic cystitis risk)
Thaliomide: influences expression of several angiogenesis genes, including VEGF, fibroblast growth factor (β -FGF) and hepatocyte growth factor (HGF). Immomodulatory + pro-inflammatory
Trialled as maintenance tx for HSA.
55
What paraneoplastic signs occur in dogs with thymoma and how often?
What flow cytometry findings are encountered with neoplastic thymic lymphocytes?
2/3 cases.
**- MG 40%, megaO & aspiration pneumonia 40%**
- Exfoliative dermatitis, erythema multiforme
- HyperCa
- T-cell lymphocytosis
- Anemia
- Polymyositis
Thymic lymphocytes are CD4+CD8+ (T cells). Vs peripheral Lc (<2% CD4+CD8+)
56
Which of the following are positive prognostic factors with thymoma in dogs & cats?
- Age
- Tumor invasiveness
- Significant lymphocytic infiltrate
- Mitotic index
- Cystic thymomas (cats)
Only cystic thymomas in cats & significant lymphocytic infiltrate.
57
What infectious organism has been reported with canine transmissible veneral tumor (TVT) cells?
Leishmania spp.
58
What markers may be useful to differentiate HSA from other neoplasms?
- FVIII/vWF - differentiate from lymphangiosarcoma
- CD34 - haematopoietic stem cell marker. Some evidence that HSA may arise from these cells.
59
What markers may be useful to diagnose histiocytic sarcoma?
**CD204** - macrophages (macrophage scavenger receptor)
CD11c - dendritic cells - HS (vs histiocytoma Ecad+)
**CD11d** - splenic red pulp Mp - **hemophagocytic HS**
**CD18** - leukocyte adhesion molecule, binds to CD11. Incr expression in Mp & granulocytes
60
Which breed is overrepresented with periarticular HS?
What IHC markers may be useful to differentiate PAHS from other joint tumors?
Flat coated retrievers
61
How may bisphosphonates be useful in the treatment of histiocytic sarcoma in dogs?
E.g. liposomal clodronate - ability to deplete macrophages & potential to increase effectiveness of cytotoxic chemotherapy (increase cell uptake of drug). Induce apoptosis in HS cell lines. (NB also trialled for canine refractory IMHA - reduces EV hemolysis by apoptosis of Mp)
Zoledronate - significantly increases doxo uptake by malignant histiocytic cells & significantly increased cell killing in-vitro
62
What are mechanisms of hypoglycemia as a paraneoplastic syndrome, and commonly associated tumors?
- Excessive insulin pdtn (insulinomas), IGF-I & II, somatomedins (extra-pancreatic tumours)
- Expression of insulin receptors or glucose utilisation by neoplastic cells
- Decreased hepatic glycogenolysis and/or gluconeogenesis
- Binding of insulin by M proteins (multiple myeloma)
63
Treatment options for insulinoma?
Surgical excision (partial pancreatectomy) - complications DM, pancreatitis, hypoglycemia (atrophied normal beta cells)
Medical management
- Frequent feeds, complex CHO & fibre, high fat
- Glucocorticoids (incr hepatic gluconeogenesis & glycogenolysis, stimulate glucagon, inhibit insulin pdtn > inhibit tissue glucose uptake)
- Diazoxide (benzothiadiazide diuretic; inhibits insulin secretion & glucose utilization by peripheral tissues, stimulates hepatic gluconeogenesis & glycogenolysis; inhibits closure of ATP-dependent K+ channels in pancreatic beta cells > inhibits opening of voltage-gated Ca2+ channels, Ca2+ influx > decr exocytosis of insulin vesicles)
70% response rate.
- Octreotide (somatostatin analogue) - inhibits insulin, glucagon, GH
- Streptozotocin (cytotoxic tx): selective destruction of pancreatic B-cells, only taken up by GLUT-2 & not other transporters.
64
Clinical response of dogs with multicentric LSA to conventional CHOP chemotherapy?
How does the clinical response & remission time for a reinduction protocol compare with that of an induction CHOP protocol in these dogs?
80-95% remission, MST 10-12 months; 20-25% dogs alive at 2 years.
Similar clinical response but 50% remission time with re-induction
65
Strong negative prognostic factors for canine LSA?
WHO clinical substage b (CSx at presentation)
Histopath grade (high bad)
HyperCa, mediastinal lymphadenopathy - likely reflect T-cell LSA
Significant BM infiltration
Anatomic location (Leukemia, diffuse cutaneous & alimentary, hepatosplenic forms bad)
Anemia
Immunophenotype (T cell bad)
Flow cytometry characteristics of peripheral blood
Prolonged steroid pre-tx (shortens response duration)
66
What is rituximab? Indications?
Canine anti-canine CD20 monoclonal antibody.
B cell LSA (CD20 = B cell antigen)
67
Briefly describe the MOA & AE of the following novel treatments for canine LSA:
- RV-1001
- Verdinexor (KPT-335)
- Rabacfosadine succinate (Tanovea-CA1)**
**RV-1001**: phosphatidylinositol 3-kinase delta iso-form (PI3Kd) inhibitor. PI3K = intracellular kinase that is a key signalling node in many forms of cancer, PI3K pathway dysregulation is present in canine LSA. AE: GI, hepatobiliary.
**KPT-335**: inhibitor of exportin-1 protein (XPO-1), which is responsible for the binding & nuclear export of a large variety of important tumor suppressor genes. Clinical trials in B & T cell canine LSA.
**Rabacfosadine**: double prodrug of guanine nucleotide analog (PMEG), inhibits DNA synthesis > S phase arrest & apoptosis of LSA cells. AE: GI, hematologic, cumulative dermatopathy, rarely idiosyncratic delayed pulmonary fibrosis. Not MDR substrate, doesn't cross BBB. *Similar ORR 84% as combo with doxo cf conventional CHOP for B cell LSA, some efficacy vs cutaneous T cell LSA. Reduced efficacy with T cell immunophenotype & pre-tx*
68
T-zone LSA
- Disease characteristics
- What flow cytometry characteristics enable diagnosis without biopsy/cytology necessarily?
- Predisposed breed?
- Type of peripheral T-cell LSA with indolent disease course
- T cells lack CD45 antigen. Common - express CD21, lymphocytosis
- GRs (40% cases)
69
What negative prognostic factors can be identified for canine B cell LSA based on flow cytometry?
What flow cytometry findings can be observed for canine multicentric T-cell LSA? What 2 clin path findings is this disease associated with?
Predisposed breeds?
Large-sized lymphocytes, low MHC class II expression (B cells express CD21)
Aggressive clinical course (MST 159d)
HyperCa, mediastinal mass
Boxers, GRs
70
What is pegylated doxorubicin, and what are its advantages over the conventional formulation?
Decreased risk of cardiotoxicity & greater cytotoxicity for some neoplastic cell types
71
What are the 3 forms of cutaneous T cell LSA in dogs?
1. Mycosis fungoides (MF) - mushroom-like appearance of skin tumors
2. Pagetoid reticulosis (PR) – localised vs generalised form
3. Sézary syndrome - progressive form of MF, during which patients become leukemic & neoplastic lymphocytes are found in peripheral blood. Extremely rare in dogs.
72
What are some treatments for cutaneous T cell LSA in dogs?
CCNU = 1st line (1 small study though)
Safflower oil, oral retinoids, pegylated doxorubicin, rabacfosadine, total skin electron beam therapy
73
List some key differences between cutaneous lymphocytosis (CL) & epitheliotrophic T cell LSA (CTCL)?
CL = indolent disease, typically spontaneously regress or slow progression (small # progress to LSA). Cats > dogs, usually pruritic.
CD3, CD5, CD18 expression. Tx chlorambucil, CCNU.
CTCL = aggressive disease, poor px MST 6mths (dogs+cats). Pruritus (dogs > cats). CD8+ expression 80-90%.
74
What cell type is TVT a malignant proliferation of? Treatment options for TVT & response?
Histiocytes.
Single agent vincristine 90-95% CR + prolonged response. DOX for refractory cases. +/- adjunct RT. Sx for localised lesions (30-75% recurrence)
Some tumors spontaneously regress.
75
What is the utility of the CADET histiocytic malignancy (HM) assay and what is its Sn/Sp?
Assay evaluates effusions, cytology or biopsy samples for copy number aberrations consistent with those found in HS > reduction in copy # consistent with HS. Sn/Sp 78/95%.
76
Describe how the following can be useful for the diagnosis and/or monitoring of TCC/UC in dogs:
- IHC (which marker)
- CADET BRAF
IHC with uroplakin III (UPIII) = transmembrane protein expressed in superficial transitional epithelial cells in the UT, expressed in >90% of canine TCCs.
BRAF detects a single mutation in exon 15 of the canine BRAF gene in urine/bx. Mutation involves 1 AA change (from valine to glutamic acid) in the BRAF protein in tumor cells > increased kinase activity that signals cells to proliferate > tumor development.
- High Sp >99% (mutation is absent in non-neoplastic bladder tissues e.g. inflammatory disease, polyps).
- Sn 85% (15% UC/TCC dogs lack mutation)
- Assay measures fractional abundance of BRAF mutation.
- Indications: screening high risk breeds (early/preclinical dz), monitoring tx response (mutant load), monitoring tumor recurrence, detecting mets (pleural/ peritoneal effusions)
77
What newer treatment may be benefical as a single-agent protocol for the treatment of BRAF-positive dogs with UC/TCC? What is the reported clinical response rate & AE?
Vermurafenib = selective BRAF inhibitor.
PR 39%, SD 55%, PD 6%. Highest remission rate reported with single agent tx. Median PFI 152d, MST 204d.
AE: GI signs, cutaneous masses, myelosuppression not observed.
78
In which breed are renal cystadenocarcinomas observed? What is the causal gene mutation, mode of inheritance and associated clinical manifestations?
GSDs
BHD gene
autosomal dominant
Nodular dermatofibrosis, uterine leiomyomas
79
Indications for administration of the following?
- Mesna
- Dexrazoxane
Chemoprotectants.
Mesna - reduces risk of cystitis associated
with ifosfamide & cyclophosphamide by binding to toxic metabolites in urine.
Dexrazoxane - protects against doxorubicin-associated chronic
cardiotoxicosis & reduces severity
of doxo-associated extravasation injury
when used soon thereafter.
80
What are the characteristics of acute vs late radiation side effects?
Acute radiation toxicity: reversible, self-limiting, during/soon after RT, confined to radiated area. Targets rapidly dividing cells (epithelium, mucosa, tumor). Typically heal 2-4 weeks with supportive care.
- Late: >6 months post-RT. Targets slowly-proliferating or non-renewing tissues (heart, lung, kidneys, nerve, bone, muscle). Progressive and irreparable d/t fibrosis, vascular damage, necrosis, loss of stem cells.
- Osteoradionecrosis, secondary tumor formation may occur if long term survival (>3-5yrs) following RT
- Greater fraction size > greater probability of late toxicity
- Overall dose also affects risk of developing late RT effects
81
What is the cytokine implicated in late dermatological radiation side effects?
TGF-beta
82
Which forms of SCC in dogs are highly metastatic?
Tonsillar, lingual
83
List 3 paraneoplastic syndromes that may be observed with GI smooth muscle tumors or GIST?
1. Hypoglycaemia (production of insulin-like growth factor II-like peptide)
2. Erythrocytosis (pdtn of EPO-like molecule)
3. 2’ nephrogenic DI
84
Which IHC markers are useful to differentiate between GI smooth muscle vs stromal tumors?
GIST - **c-KIT (CD117)+** , **DOG-1+** (stains interstitial cells of Cajal > peristalsis, more Sp vs cKIT)
Leiomyoma/sarcoma - usually express SMA, c-KIT negative
(Smooth muscle markers = vimentin, desmin, alpha smooth muscle actin (SMA); neurogenic markers = S100, NSF, synaptophysin)
85
Negative prognostic factors for MCT?
1. High histo grade
2. MI ( cutaneous/SQ)
86
Toceranib
- MOA
- AE
Small molecule TKI; inhibits TK activity of several split receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor-2 (VEGFR2), platelet-derived growth factor receptor-beta (PDGFR-beta) & KIT (stem cell growth factor receptor).
Anti-angiogenic effects (VEGFR2 & PDGFR-b activity). May reduce immunosuppressive Tregs in peripheral blood. Induce cell cycle apoptosis in c-KIT expressing tumor cells.
AE - GI, proteinuria (20-25%), SHT (37-45% develop SBP >160mmHg), azotemia, hyperphos, pancreatitis, cytopenias, hypoalb, incr ALT, muscle cramp, TE dz, nephrotic syndrome reported
- Cats - GI, myelosuppression, azotemia, hepatopathy, alopecia
87
Discuss prognostic factors for canine MCT?
1. KIT protein localisation (Patterns II - loss of peri-membranous labelling along with focal or stippled cytoplasmic labelling, & III - cytoplasmic; assoc with incr local recurrence & shorter survival)
2. Activating mutation in exons 11 of c-KIT (more common in high grade MCTs ~20%) - assoc with mets, incr local recurrence & shorter survival)
3. High histo grade
4. Clinical stage
5. Substage b (systemically ill)
88
What mutation does 20-40% of MCTs express? What treatment implications may this have?
Cytoplasmic (c-KIT) mutation - TK receptor --> uncontrolled signaling. c-KIT+ MCTs are 2x as likely to respond to TKIs (response rate 69% vs 37% w/o)
89
Combined assessment of which 2 cell proliferation markers provide the most accurate prognostic info for canine cutaneous MCTs?
Name 1 other cell proliferation marker commonly used & discuss limitations for its use.
**Argyrophilic nucleolus organizer regions (AgNORs)** - nuclear proteins visualised by silver stains. Large # & small size correlate with increased speed of cell cycle progression. **Marker of cell proliferation**.
**Ki67 ** - nuclear protein that labels all cycling cells but cannot be detected in resting cells. Marker of **growth fraction.**
- 23+ Ki-67+ cells/grid area assoc with shorter survival & incr mortality.
Combo agNORxKi-67 score >54 = incr risk of MCT-related mortality & mets.
MC index - identifies cells in M phase of cell cycle. Poor Sn (low MC doesn't indicate benign biological behaviour)
90
What histo features/markers for canine cutaneous MCTs are useful for indicating likelihood of recurrence following surgical excision?
High-grade + MCTs with mutation in exon 11 of c-Kit - high likelihood (up to 40%) of local recurrence despite clean surgical margins.
Conversely low grade + low AgNOR x Ki67 index - low risk (<10%) of local recurrence regardless of surgical margins.
91
3 presentations of feline MCT?
What is the treatment for feline splenic MCT?
Cutaneous, visceral, intestinal
Splenectomy - MCT 12-19mths
92
What is the role of heat shock protein HSP90? What treatment implications may it have for dogs with MCTs (and possibly other solid tumors)?
Responsible for folding multiple proteins (esp oncogenes e.g. KIT, MET, BRAF, AKT)
HSP90 inhibitors may be useful (block protein folding > protein degradation & tumor cell death). STA-1474 showed good activity in dogs with MCT (clinical trial).
93
What is sentinel LN mapping & its utility in identifying metastatic disease?
What are methods used for SLN mapping?
2019 VCNA review
SLN = concept based on theory that metastasis occurs in an orderly progression within the lymphatic system with tumor cells draining into a specific lymph node (SLN) in a regional lymphatic field before draining into other regional LNs.
SLN has an important role as a filter and barrier for disseminating tumor cells. So status of SLN reflectsstatus of the entire regional lymphatic bed - probability that a non-SLN is positive for mets when SLN is free of tumor = <0.1%.
**Lymphoscintigraphy (using 99mTn)** - used in dogs; contrast-enhanced US, ; peritumoral injection of blue dye (slow, over 24hrs) or indocyanine green. Intra-op cytology, histopathology, or one-step nucleic acid amplification.
94
List some tumor ablation techniques & tumor types that these techniques have been trialled.
Ethanol ablation - for PT/thyroid tumors (not useful for hyperT cats)
Radiofrequency ablation - PT/thyroid tumors, pulmonary (> pneumothorax), prostatic
Laser ablation - Nd-YAG 1064nm, CO2 diode. UCC (though high risk of seeding & urethral perf). Spirocera lupi-oesophageal sarcoma
Microwave ablation - adv: can ablate larger tumors, faster. Liver, renal tumors, pulmonary mets
High frequency US ablation
95
List some tumor ablation techniques & tumor types that these techniques have been trialled.
Ethanol ablation - for PT/thyroid tumors (not useful for hyperT cats)
Radiofrequency ablation - PT/thyroid tumors, pulmonary (> pneumothorax), prostatic
Laser ablation - Nd-YAG 1064nm, CO2 diode. UCC (though high risk of seeding & urethral perf). Spirocera lupi-oesophageal sarcoma
Microwave ablation - adv: can ablate larger tumors, faster. Liver, renal tumors, pulmonary mets
High frequency US ablation - extracorporeal (superficial/benign tumorsnot surrounded by bone/air e.g. uterine), transrectal (prostate), interstitial (biliary, oesophageal), percutaneous (deeper tumors).
Cryoablation - tumors of the head (nasal ACA, maxillary tumors)
Energy based ablation - not really used in vet med yet. Reports - CNS glioma, distal limb sarcoma.
96
What is the principle & diagnostic utility of PET/CT? What radiopharmaceutical is used most commonly in vet med?
What factors can interfere with image interpretation?
VCNA review
Nuclear medicine that uses radiopharmaceutical (positron emitters = positively charged particles aka beta+ particles).
**F-18 FDG** (2-deoxy-2-18F-fluorodeoxyglucose) used most commonly
- Glucose analogue labelled to F-18 --> I/C uptake by glucose transporters --> phosphorylated > transported into mitochondria & stored as glycogen or converted to ATP > remains trapped within cells.
- PET/CT maps whole body glucose metabolism -detects **hypermetabolic areas (high FDG uptake) **- tumor cells use more glucose than normal cells. Measure SUVmax (standardized uptake value).
- Useful for dx, monitor tx response, dz recurrence
- Used most commonly for OSA (also others)
- Other indications: PUO workup, unknown cause of lameness
Factors:
- False + (highly metabolic tissues e.g. brain, cardiac, salivary glands - FDG excreted in saliva)
- FNAs 1-2d pre-procedure (local tissue inflammation)
- Hyperglycemia (uncontrolled DM) - postpone procedure, as high serum glucose competes with F-18 FDG for I/C uptake
- Metallic implants/hyperattenuating structures (appear hypermetabolic)
- Detects lesions >5-8mm
97
What does the Oncept vaccine contain and what is its indication?
Xenogenic DNA vaccine - contains DNA encoding the gene for the human melanocyte protein tyrosinase (I/C glycoprotein needed for melanin pdtn & overexpressed in most melanocytic tumors). Vax triggers immune response which X-reacts with the dog's tyrosinase protein.
For stage 2-3 malignant melanoma (labelled for dogs, but safe for use in cats).
AE: depigmentation (immune response against normal melanocytes)
NB: amelanotic melanomas have less tyrosinase but vax still useful to prevent mets.
98
What gene mutation may occur in tumor cells of malignant melanoma in dogs, and how may this impact additional diagnostic and/or treatment considerations?
Exon 11 KIT gene mutations (similar to MCT - TK receptor)
Consider c-KIT testing (PCR), tx with TKIs (palladia) esp for dogs with advanced stage dz and/or lack of response to Oncept vax.
99
What parameters are assessed for grading of soft tissue sarcomas?
Differentiation (well vs undifferentiated), mitosis (0-9, 10-19,>20), necrosis (none, <50%, >50%). Each parameter scored 1-3. Grade 1 score /=7
100
Feline injection site sarcomas are immunoreactive to which growth factors, and which one was most strongly expressed? Which proto-oncogene has also been implicated in FISS development?
Platelet derived growth factor (PDGF) - strongest, epidermal growth factor (EGF) & transforming growth factor-β (TGF-β).
NB: FeLV and the feline sarcoma virus are NOT involved.
C-jun (encodes translational protein AP-1)
101
Treatment recommendations for STS?
Wide sx resection (3cm lateral margins, 1 fascial plane deep) + resect bx tracts/fixed areas.
If clean margins: grade I-II - routine FU q3-6mths, grade III - adjunct chemo with DOX
If incomplete margins: adjuvant RT or wide sx resection of scar (preferred) - FU depends on whether subsequent margins are clean + grade (see top)
102
Predilection sites for OSA?
Treatment options for canine vs feline OSA?
Metaphyses of the distal radius, distal femur, and proximal humerus (away from the elbow and toward the knee)
Cats - amputation alone can be curative/prolonged MST. Adjuvant chemotherapy not indicated/recc as low metastatic rate & amputation alone is effective
103
Predilection sites for OSA?
Treatment options for canine vs feline OSA?
Metaphyses of the distal radius, distal femur, and proximal humerus (away from the elbow and toward the knee)
Cats - amputation alone can be curative/prolonged MST (<2yrs). Adjuvant chemotherapy not indicated/recc as low metastatic rate & amputation alone is effective
104
What are 2 negative prognostic indicators for canine appendicular OSA based on a meta-analysis?
Serum ALKP
Proximal humeral osteosarcoma
105
What are the advantages of electrochemotherapy? List the most common 2 drugs which are administered with ECT and 2 indications?
Adv:
- Electroporation increases transmembrane mvt & cell uptake) of some chemotherapy drugs --> promotes drug efficacy
- Allows use of lipophobic drugs with narrow therapeutic
indices to obtain high response rates (eg cisplatin in cats)
- Can be administered repeatedly in cases of recurrence
Dogs - melanoma, MCT
106
What paraneoplastic syndrome can occur with polycythemia vera?
Hypoglycemia (increased RBC mass and secondary glucose depletion)
107
Multiple myeloma in cats - key differences vs dogs?
Increased M component - mostly IgA (vs IgM/IgG/IgA dogs), extramedullary extension (FNA spleen/liver may have good dx yield), BM plasmacytosis less common, increased LE, proteinuria > common
108
Negative prognostics factors for MM?
- BJ proteinuria
- Hypercalcemia
- Extensive osteolytic lesions
- Renal disease (AKI)
- Increased neutrophil-to-lymphocyte ratio (NLR): may reflect a decreased antitumor immune response by Lc + concurrent protumor activity by Np (IL-6)
109
What components are assessed in serum/urine protein electrophoresis? DDx for monoclonal gammopathy?
Alpha = acute phase proteins
Beta = fibrinogen, complement etc; also Ig (A, M, G)
Gamma globulin = Ig (A, M, G)
DDx: neoplasia - plasma cell neoplasia e.g. MM, extramedullary plasmacytoma; also B cell lymphoma, or B cell CLL
Infectious - rickettsial dz (ehrlichiosis - IgG, lyme disease, leishmania), FIV, FIP
110
What are negative prognostic indicators for feline mammary carcinomas?
What interventions improve survival?
Neg px:
- Tumor size (>3cm MST 6mths vs >3yrs for tumors <2cm)
- Lymphovascular invasion
- LN mets (death within 9mths of dx)
- High histo grade
- Higher Ki-67, AgNOR (cell proliferation markers)
- HER2 protein expression
Improve survival:
- Chain mastectomy (vs conservative sx)
- Sx + adjuvant chemo (doxo + cyclophosphamide + NSAID).MST 1998d vs 414d for sx alone
111
Meningiomas in dogs vs cats: key differences?
Dogs - 1/3 malignant (cats mostly benign)
Sx removal - less predictable if sx resectable for dogs - some don't recc sx removal in dogs if not planning to pursue adjunct RT.
112
Meningiomas in dogs vs cats: key differences?
Dogs - 1/3 malignant (cats mostly benign)
Sx removal - less predictable if sx resectable for dogs - some don't recc sx removal in dogs if not planning to pursue adjunct RT.
Chemo - unknown role/benefit in dogs. Hydroxyurea, CCNU trialled. RT improves MST vs med/sx alone.
Cats - sx alone > MST 2yrs
113
Spinal tumors: which are most common in cats vs dogs?
Dogs: meningioma (Boxers, younger dogs)> HSA, MNSTs. Nephroblastoma (GR, GSD). Large breeds, 9-10yo.
Cats: LSA (young cats, FeLV+, TL spine, 85% multiple extraneural locations esp BM, kidneys, liver, skeletal muscle, spleen) > OSA (>8yo)
114
Which phases of the cell cycle are resistant vs susceptible to radiation therapy?
S (DNA synthesis, 6-8hrs) - radioresistant.
G2 (RNA & protein synthesis, 2hrs): radiosensitive.
115
Which vaccines are associated with feline injection site sarcomas, and what are the key clinical characteristics?
1 – 2 – 3 RULE
- Still growing 1 month post vax
- >2cm in size
- Persists for ≥3 mths post vax
Associated vax – FeLV, Rabies (aluminum adjuvant)
Histopath - needle-like crystalline material, multinucleate giant cells, glycogen, intratumoral endocytosed RBCs & Hb crystals, infiltrating WBCs incl macrophages, neutrophils, lymphocytes
