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2: Surgical Methods and Perioperative Care > Chapter 25 Introduction to Oncologic Surgery for the General Surgeon > Flashcards

Chapter 25 Introduction to Oncologic Surgery for the General Surgeon Flashcards

1
Q

What are the 6 phenotypic characteristics of neoplastic cells, that result from genotypic changes,

A
  1. Self sufficiency in growth signals
  2. Insensitivity to anti-growth signals
  3. Tissue invasion and metastasis
  4. Limitless replicative potential
  5. Sustained angiogenesis
  6. Evasion of apoptosis
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2
Q

List the 4 ways in which proto-oncogenes can be activated (i.e. become oncogenes) (Proto-oncogenes = normal genes that become mutated to form oncogene).

Once transformed to oncogene, these behavine in a dominant manner over proto-oncogenes. List 5 key protin types that may be produced as a result of oncogenes

A
  • Chromosomal translocation
  • Gene amplification
  • Point mutation (may be induced by ionizing radiation, chemical carcinogens, or mutations in proto-oncogenes e.g. K-ras or c-kit (CD117)
  • Viral insertions
  1. Growth factors
  2. Grpwth factor receptors
  3. Cytoplasimic kinases/Ras (ras = GTPases that act in cell signalling. e.g. k-ras = epidermal growth factor receptor)
  4. Transcription factors
  5. Anti-apoptotic proteins
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3
Q

What si the definition of metronomic chemotherapy

A

Frequent low dose chemotherapy to prevent tumour angiogenesis ad minimise toxicities

Or frequent administration of chemotherapeutics at doses significantly below the maximally tolerated dose, with no prolonged drug free breaka

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4
Q

What are the four stages of the cell division cycle? What are key events in each phase?

What is the name of the protiens necessary for regulation and entry into cell cycle?

A

G1 –> S –> G2 –>M

G1: Restricition point = critical checkpoint

S: Synthesis/doubling of new DNA

G2: Checkpoint

M: Mitosis

G1 + S +G2 = interphase

Regulation proteins are called cyclin-dependent kinases (= important growth signals in progression of normal and neoplastic cells)

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5
Q

How much time is spent in G1 phase? And M phase?

A

Various phases of the entire cell cycle as depicted typically last 10 to 25 hours in animals.

Only 1 hour is spent in the M phase. The longest and most variable phase is G1, which can range from 4 to 24 hours.

Also depicted is regulation of the cell cycle, many elements of which are targets of gene and molecular therapy

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6
Q

What three words are used to describe the development from a normal cell to a malignant phenotype/carcinogenesis?

A

Initiation, promotion, progression

Initiation irreversible but does not necessarily cause neoplasia. Initiated cell exposed to a promoting agent –> tumour growth. Initiation + promotion –> benign lesions such as polyp/papilloma. Progression when tumour gains ability to invade and establish blood vessels and to metastasise.

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7
Q

List 5 categories of ‘carcinogens’ and give an example of each

A
  1. Heritable carcinogens e.g BRCA gene alterations in mammary carcinoma. Only two confirmed heritable forms of neoplasia in dogs: Osteosarcoma on Deerhounds and RCND (renal cyastadenocarcinoma and nodular dermatofibrosis in GSDs, autosomal dominant inheritance)
  2. Biologic carcinogens i.e. virus/bacteria/funghi e.g. FeLV, Spirocerca lupi (–> sarcomas), papilloma –> SCC
  3. Physical carcinogens e.g. asbestos –> mesothelioma, TPLO plate –> osteosarc, aluminium based adjuvant vaccine –> FISS
  4. UV light –> SCC (melanoma not linked in SA cf humans). UV light cause dimerization of pyrimidine bases of DNA (thymine and cytosine) –> basal cell damage
  5. Ionizing radiation i.e due to radiation, rare, odd reports exists.
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8
Q

What group does the growth factor receptor c-kit fall into?

A

Platelet Derived Growth Factor Receptors (PDGFRs)

C-kit usually needs stem cell factor (a ligand) to bind, before c-kit activated downstream activity resulting in cell proliferation. In neoplasia the c-kit receptor is consitutively active (i.e. doesnt need stem cell factor)

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9
Q

What is the name of the growth factor receptor that plays an important role in the high malignancy of osteosarcoma?

A

Met

(a hepatocyte growth factor receptor)

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10
Q

What broad phenotypic changes do Ras oncogenes lead to?

A

Production of membrane associated proteins.

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11
Q

What 5 oncoproteins (broadly speaking) engourage cell proliferation i.e. 5 potential anti-cancer target sites

A
  1. Growth Factors (e.g
  2. Growth Factor Receptors
  3. Cytoplasmic kinases/Ras
  4. Transcription Factors
  5. Anti-apoptotic proteins
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12
Q

Give an example of an apoptotic oncogene

A

Bcl-2

A prosurvival molecule that normally regulates entry of a cell into apoptosis. Often over-expressed in tumours.

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13
Q

List the two sub-categories of tumour supressor gene

A

Gatekeeper vs Care-taker

Gatekeeper: Inhibit growth, promote death

Care-taker: Ensure DNA repair while maintaining genetic stability

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14
Q
  • Give an example of a tumour supressor gene.
  • Which sub category of tumour supressor gene does it fall into?
  • Give an example of a neoplasia where p53 mutations are found
A
  • p53
  • An example of a gate-keeper gene (i.e. inhibit growth, promote death)
  • Lymphoma, mammary carcinoma, osteosarcoma (also prognostic in osteosarc; 81d MST with mutation, 256d without)

Caspases also pro-apoptotic

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15
Q
  • Give an example of a tumour tha follows orderly neoplastic progression.
  • What are cyto findings of dysplasia?
  • List 2 findings that differentiate carcinoma in situ from dysplasia
  • When does carcinoma in situ becme carcinoma
A
  • UV induced SCC, TCC of bladder
  • Dysplasia cytology: increased anisocytosis, anisokaryosis, mitotic figures, chromatin changes
  • Increased criteria of malignancy, abnormal cells occupy full thickness of epithelium (but not beyond basement membrane)
  • Carcinoma when invaded beyone basement mambrane
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16
Q

What are telomeres?

How much telomere is lost/division

How do tumor cells commonly differ from normal cells re telomere?

A

Nucleoprotein complexes (TTAGGG repeat sequence) ends of linear chromosomes, that play crucial role in ageing (inability of DNA polymerase to replicate lagging strand = end replication problem)

50-200 bp of telomeric DNA lost with each replication

Tumor cells express high levels of telomerase

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17
Q

Most canine cells do not express telomerase. What are the exceptions?

A

Stem cells, lens tissue, male germ line, activated lymphocytes

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18
Q

What morphologic changes occur with apoptosis?

How does this differ from cell necrosis

A

Apoptotic cells: membrane blebbing, cytoplasm contraction, nuclear condensation (active process - ie cell produces factors that leads to own death)

Necrotic cells: cellular swelling and rupture of membranes (passive process)

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19
Q

What are the three major routes of metastasis?

A

Haematogenous, lymphatic, direct spread

Carcinoma and round cell tumours via lymphatics, sarcoma via haematogenous (generally)

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20
Q

How close to a capillary bed do tumour cells need to be to survive (i.e. induce angiogenesis if too far)

A

Within 100 - 200 um

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21
Q

What alternative method is there for quick cell type assessment, aside from intra-op cytology?

A

Frozen histologic sections (takes about an hour)

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22
Q

Contrast enhanced US has been used to distinguish benign vs malignant tumourw in which organs?

A

Liver and spleen

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23
Q

What agent is used when performing nuclear scintigraphy for the following conditions:

  • Osteosarcoma
  • GFR determination
  • Functional thyroid tumours
  • Pancreatic insulinoma
A
  • Osteosarcoma: Technitium-99m hydromethylele diphosphate (8% had asymptomatic lesion elsewhere)
  • GFR determination: Technetium-99m diethyle-triamine-pentacetic acid
  • Functional thyroid tumours: Technetium-99m
  • Pancreatic insulinoma: Indium-111 pentetreotide
24
Q

What is a key difference re contrast agents for MRI vs CT

A

MRI contrast is non-iodinated

25
Q

What does PET and SPECT stands for (in context of imaging)

A

Positron emission tomography: Gives info re biologic processes e.g. glucose metabolism. Images can be fused with CT –> PET-CT

Single photon emission computed tomography: Uses gamma camera to makes crossectional reconstruction –> better lacalisation

26
Q

What is used in PET scans?

And SPECT scans?

A

PET uses F-fluorodeoxyglucose or more recently [123I]

SPECT uses gamma-ray emitting radionucleotides

27
Q

What sie of lesion can be detected on rads vs CT

A

Rads 6mm, CT 1 mm

28
Q

How are three stages of splenic haemaniosarc classified?

A

Stage 1: localised

Stage 2: ruptured

Stage 3: metastatic disease

29
Q

What are the four ‘extents’ of solid tumour excisiton, re surgical ‘dose’

A

Intralesional (i.e. debulking), marginal, wide, radical (wide and radical considered curative intent)

30
Q

List broad recommended margins for the following:

Benign

STS or MCT

Carcinoma

Injection site sarcoma

Axial or appendicular skeleton tumour

A
  • Benign: 1cm
  • STS or MCT: 2-3 cm. 2cm recommended for grade 1 and 2 MCTs.
  • Carcinoma: 1cm (and usually ok in low grade MCT and STS)
  • Injection site sarcoma: 5cm and two fascial planes
  • Axial or appendicular skeleton tumour: 1-3cm healthy bone

N.B using metric/barrier hybrid classification (i.e. distance/anatomic barrier)

31
Q

Define radical excision

A

Removal of entire tissue compartment

32
Q

List the 4 management options for unplanned marginal resection

A
  1. No treatment
  2. Staging resection of wound (excison w <10mm margins
  3. Wide resection of wound
  4. Add radio/chemo
33
Q

Define marginal resection

A

Dissection just peripheral to pseudocapsule, in reactive zone

34
Q

Define wide excision

A

Excision of normal appearing tissue en bloc with gross tumour

35
Q

Define sentinel lymph node

List 5 methods for determining sentinel LN

A

LN in regional lymphatic field that tumour drains into first, before draining into other regional LNs

  1. Lymphoscintigraphy
  2. Peritumoral injection of new methylene blue
  3. Intra-op cytology
  4. Intra-op histo
  5. Mohs sectioning (= horizontal section assessing deep and lateral margins in one slide)
36
Q

Differentiate between the Halsted theory vs Cady-Fisher theory of lymph node spread

A

Halsted:

Spread progresses first to nearby LNs and subsequently to other organs

Cady-Fisher

Cancer is systemic disease, cancer cells assumed not to spread in an orderly manner. LNs not considerd barriers to further spread

37
Q

In what percentage of tumour excision + axial pattern flap, were margins reported to be incomplete?

A

39%.

i.e. consider margina assessment (i.e. intra-op cytology, frozen section histo or delayed closure following histo)

38
Q

List 5 techniques to improve margin assessment

A
  • Ink margins
  • Suture passed through all vertical layers
  • Pin to cardboard
  • Tumour bed samples
  • Mohs sectioning (= horizontal section assessing deep and lateral margins in one slide)
39
Q

Complete the table

A

N.B. Poorly differentiated tumours commonly lose expression of these markers

40
Q

What percentage tissue shrinkage occurs between tissue collection and microscopic assessment?

A

30-47%

41
Q

What us the recurrence rate for completely excised grade 2 MCTs vs incompletely excised MCTs?

A

11% recurrence in completely excised grade 2 MCTs

18-35% recurrence in incompletely excised grade 2 MCTs

42
Q

What is ki67

A

Proliferation antigen marker

43
Q

List 4 potential surgical benefits of neoadjuvant radiotherapy

And 2 disadvantages

A
  • Reduce surgical dose
  • Transforms inoperable tumour to operable
  • Reduce incidence of tumour seeding and local recurrence
  • Theoretical advantage as unimpared vascular supply tumour i.e more radiosensitive
  • Delayed wound healing
  • Higher rate of wound complications

NB neoadjuvant radiotherpay recommended in FISS

44
Q

What does cell cycle specific and non-cell cycle specific mean re chemotherapy?

A

Cell cycle specific: Those effective in synthesis (S) or mitosis (M) phase of cell cycle

Non-cell cycle specific: Capable of cytotoxicity at any phase of cell cycle

45
Q
  • How do alkylating agents work?
  • Cell cycle specific or non-cell cycle specific?
  • List two examples and of an alkylating agent and most common use of each
A
  • Alkylating agents work by inserting butyl alkyl groups onto DNA/RNA strands –> interference with DNA replication/RNA translation
  • Non-cell cycle specific

e.g.

  • Cyclophosphamide: mainstay of lymphoma treatment
  • Lomustine: Primary agent for histiocytic sarcoma or MCT, rescue agent for lymphoma
46
Q

What is the main complication of cyclophosphamide and how can risk be reduced?

A

Sterile haemorrhagic cystits. Give with frusemide

47
Q
  • How do microtubule inhibitors work?
  • Cell cycle specific or non-cell cycle specific?
  • List 3 examples and their most common uses
A
  • Microtubule inhibitors affect spindle apparatus during mitosis.
  • (Therefore) Cell-cycle specific
  • Vincrinstine: Lymphoma (“O” of CHOP (O=Oncovin))
  • Vinblastine: MCT (+- lomustine)
  • Vinorelbine: 1st choice for primary lung tumour (in humans, pulmonary tissue achieves x300 level found in serum)
48
Q
  • How do anthracyclines work?
  • Cell cycle specific or non-cell cycle specific?
  • List an example, common uses, most common complication
A
  • Anthracyclines have multiple MoA inc topoisomerase inhibition, DNA intercalation, formation of iron free radicals –> DNA damage
  • Non cell cycle specific
  • Doxorubicin. Lymphoma, haemagiosarc, high-grade STS, high grade carcinoma, osteosarc.
  • Complication = Dilative cardiomyopathy like damage occurs after cumulative doses of 180-240 mg/m2. Severe vesicant with extravasation

N.B. in cats –> renal insufficiency, myelosupression, GI toxicity

49
Q
  • How do platinum agentswork?
  • Cell cycle specific or non-cell cycle specific?
  • List an example, common uses, most common complication
A
  • Cause covalent binding of DNA strands –> restricts DNA and therfore protein synthesis.
  • Non-cell cycle specific
  • Carboplatin, Osteosarc (singe agent or in combo with doxo). Nephrotoxic
50
Q

Why can’t cisplatin be used in cats??

A

Cisplatin causes fatal pulmonary oedema in cats.

51
Q

How do bisphosphonates work (n.b. not chemotherapeutic per se)

Name two exampes

A

Bisphosphonates inhibit osteoclast activity -> supression of bone resorbtion

Pamidronate, zoledronate (better)

52
Q

What is the bone marrow nadir of most chemotherapeutics?

Which drug is the exception and when is its nadir?

Below which neutrophil and which platelet numbers should chemo be delayed?

A

7 days

Except carboplatin. Carboplatin nadir 10-14 days

Delay if neutrophils < 1,500 cells/uL or platelets <50,000 cells/uL

If occurs delay by 5-7d. If severe reduce chemo dose by 20%

53
Q

How do tyrosine kinase inhibitors work?

List an example

A

Target ATP binding site of membrane and cytoplasmic tyrosine kinases that are crucial for phosphorylation.

Toceranib. Only appropriate in grade 3 or high stge MCTs.

54
Q

HOw does MDR-1 gene mutation affect chemo agents?

A

Among the most common acquired mechanisms of resistance is a mutation in the canine multidrug-resistance gene (MDR-1). The MDR gene expresses p-glycoprotein, a transmembrane protein in the family of ATP-dependent binding cassette transporters.32 The normal role of this transporter protein is to protect the body against xenobiotic toxins.

It is normally found in the blood-brain barrier, renal proximal tubules, and intestinal epithelial cells, and it actively removes xenobiotic toxins from these critical organ systems by pumping the drugs out of the cells. MDR substrates include chemotherapeutics derived from natural substrates such as the vinca alkaloids, which are derived from the periwinkle plant, and anthracyclines such as doxorubicin, which was developed as an extract from Streptomyces.

This is also the reason why herding breeds such as Collies, Shelties, and Australian Cattle Dogs have increased sensitivity to drugs such as ivermectin and to chemotherapy drugs such as vincristine and doxorubicin. These breeds have an increased likelihood of an MDR-1 gene mutation that results in nonfunctional p-glycoprotein, making them more likely to experience complications with these chemotherapeutics

55
Q
A

2: Surgical Methods and Perioperative Care (11 decks)

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