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Onco Board Review 2 > MCT > Flashcards

MCT Flashcards

1
Q

What are the 3 KIT staining patterns?

A
  1. membrane-associated; 2. focal to stippled cytoplasmic staining with decreased membrane-associated staining; 3. diffuse cytoplasmic staining
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2
Q

Which KIT staining pattern is associated with increased rate of recurrence and decreased survival?

A

diffuse cytoplasmic staining (Kiupel 2004)

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3
Q

Neg prognostic factors for dogs with multiple cutaneous MCT w/surgery? (Mullins 2006)

A

incomplete excision, local recurrence, size > 3cm, CS at time of dx, adjuvant tx

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4
Q

Do dogs with multiple MCT have different survival time than those with single?

A

Nope. (Murphy 2006)

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5
Q

DFI for high-risk MCT tx with VBL/pred after sx +/- RT? How many alive at 3 yrs?

A

DFI 1305 days, OS not reached but 65% alive at 3 yrs. (Thamm 2008)

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6
Q

OS for dogs with grade III MCT tx with VBL/pred after sx +/- RT?

A

1374d (3.8yr) (Thamm 2008)

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7
Q

Does prophylactic nodal irradiation improve outcome for MCT?

A

Yes. (Thamm 2008)

But No per Poirier 2006

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8
Q

What three histopath features affect survival time for SQ MCT?

A

MI >4/10 hpf, infiltrative growth pattern, presence of multinucleation. (Thompson 2011)

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9
Q

In Thompson 2011, which factor for canine SQ MCT was strong predictor of survival, local recurrence, and mets in multivariable analysis?

A

MI > 4/10 hpf

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10
Q

What are the criteria for high grade in the Kiupel MCT grading scheme? (4 factors)

A
  1. MI 7/10 hpf
  2. 3 multinucleated (3 or more nuclei) cells in 10 hpf
  3. 3 bizarre nuclei in 10 hpf
  4. karyomegaly
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11
Q

What are the criteria for high grade in the Patnaik MCt grading scheme? (6 factors)

A
  1. extends into SQ and underlying tissue
  2. pleomorphic
  3. indented nuclei
  4. > 1 nucleoli
  5. 3-6 MI PER HPF (not per 10 hpf)
  6. areas of hemorrhage, necrosis, edema
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12
Q

What factors affect PFS for grade 3 MCT? (Hume 2011)

A

tumor size and LN status in multivariate analysis (tumor size, LN, MI in univariate)

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13
Q

What factors affect OS for grade 3 MCT? (Hume 2011)

A

LN status in multivariate analysis (LN status, local tumor control, LN treatment, and MI in univariate analysis)

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14
Q

What is OS for dogs with for dogs with positive cytologic mets to liver and/or spleen? (Book 2011)

A

100d (3.3mo) vs. 291d (9.7mo, if no mets on cyto)

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15
Q

What is FAP? How does it affect MCT prognosis? (Giuliano 2017)

A

Fibroblast activating protein - membrane serine protease expressed by activated fibroblasts, particularly tumor associated fibroblasts. Neg prognostic factor – correlated with high grade (both Patnaik and Kiupel), MI, and Ki67 expression.

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16
Q

What is TIMP-1? How does it affect MCT prognosis? (Pulz 2017)

A

TIMP-1 = a tissue inhibitor of metalloproteinases.

Pos prognostic factor - increased expression showed better post-surgical survival.

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17
Q

What are neg prognostic factors in dogs with stage IV de novo MCT? (Pizzoni 2018)

A

tumor diameter > 3cm, more than 2 metastatic sites, BM infiltration, lack of local control –> all multivariate analysis.
(Note: in this study, well known prog factors such as anatomic site, grade, and mutation status did NOT affect PFI and ST)

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18
Q

Is c-kit mutation status different in primary vs. metastatic MCT? (Marconato 2014)

A

Nope.

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19
Q

What is MST for grade 2/stage 2 MCT treated with sx + chemo vs. sx + RT + chemo?

A

Sx + chemo = 1103d (3yr)

Sx + RT + chemo = 2056d (5.6yr)

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20
Q

What is DFI and MST for grade 2/stage 2 MCT treated with ALT + VBL/CCNU/pred?

A 
DFI = 2120d (5.8yr)
MST = 1359d (3.7yr)
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21
Q

What was the % local recurrence for MCT dogs with incomplete close margins and the following tx (Kry 2012):

  1. re-excision
  2. RT
  3. no further tx
A
  1. 13%
  2. 8%
  3. 38%

Most were grade 2.

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22
Q

What was the MST for MCT dogs with incomplete close margins and the following tx (Kry 2012):

  1. re-excision
  2. RT
  3. no further tx
A
  1. 2930d (8yr)
  2. 2194d (6yr)
  3. 710d (2yr)

Most were grade 2.

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23
Q

What are the recommended surgical margins for MCT (Simpson 2004)?

A

2cm margins, 1 fascial plane deep
(100% were completely excised with 2cm margins)
However, more recent recommendations are 3cm and 1 fascial plane for high grade especially.

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24
Q

What stains are expected to be positive in agranular MCT?

A

CD117, avidin peroxidase, Kpl antibody
Also express CD18, CD45
(poor staining with H&E, toluidine blue, alcian blue, Giemsa –> these are better for well-differentiated)

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25
Q

What tumors have been shown to express PD-L1 (Shosu 2016)

A

frequently expressed in malignant melanoma, mammary gland tumor, MCT, and LSA
(less frequent in STS and HSA)

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26
Q

Where do the c-kit genetic mutations occur in canine MCT?

A

either juxtamembrane domain (exons 11 and 12) or extracellular domain (exons 8 and 9)

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27
Q

What cell cycle control mutations have been identified in MCT?

A

p21, p27, CDK inhibitor mutations

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28
Q

What is the prevalence of c-kit mutation in dog/cat grade 2/3 MCT that failed surgical resection or was unresectable?

A

dog - 26%, cat - 68%

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29
Q

What will c-kit analysis look like if mutation present?

A

All samples have wild-type gene spike, if mutated there will be a second spike.

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30
Q

What percent of MCT dogs had GI ulceration at necropsy?

A

35-83%

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31
Q

What was MST for high/low grade MCT on Kiupel scale?

A

high: 4 months, low: > 2 years

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32
Q

What was the agreement on grading using Patnaik scale (reported in Kiupel paper)?

A

Grade 3 - 75%; grade 1-2 - 63%

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33
Q

What was cytologic grading agreement with Patnaik/Kiupel (Camus 2016)?

A

62% agreement with Patnaik, 97% agreement with Kiupel

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34
Q

What was Sn/Sp of Camus 2016 MCT cytologic grading?

A

88% Sn/94% Sp

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35
Q

Dysregulation of what miRNA has been correlated with aggressive MCT phenotype and metastatic behavior?

A

miR-9 (Fenger 2014)

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36
Q

What are the markers of proliferation for MCT?

A

Ki67 - nuclear protein that correlates w/proliferation; AgNOR - nuclear organizer region correlating with cell division; PCNA - proliferating cell nuclear antigen; MI

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37
Q

How do VEGF and microvessel density (MVD) correlate with MCT grade?

A

higher VEGF and MVD correlate with grade 3 (Patruno 2009)

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38
Q

What % of oral/perioral MCT have RLN mets at dx? (Hillman 2010)

A

60%
MST w/LN mets: 14 mo
MST no mets: not reached

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39
Q

Are inguinal MCT more aggressive?

A

No (according to two studies) but if you separate preputial/scrotal those are more aggressive.

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40
Q

What was 5yr survival for SQ MCT? (Thompson 2011)

A

86% 5yr survival

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41
Q

What is prognosis for conjunctival MCT? (Fife 2011)

A

Good px, 60% were disease free at 21 months.

30% grade 1, 55% grade 2, 15% grade 3 - all tx with surgery and most had incomplete margins

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42
Q

What is WHO staging scheme for MCT?

A 
0 - 1 tumor incompletely excised
1 - 1 tumor w/out RLN
2 - 1 tumor in dermis with RLN
3 - multiple tumors or large/infiltrating tumor w/ or w/out RLN (the multiple tumors part is controversial)
4 - any tumor with distant mets
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43
Q

Should you sample ultrasonographically normal liver/spleen? Justify answer with literature.

A

Yes per:

  • Stefanello 2009 - majority of dogs with infiltration and normal appearing liver/spleen
  • Book 2011 - infiltration MST was 100 days, no infiltration was 290 days; cytology agreement with AUS - 63% spleen, 71% liver
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44
Q

What is rate of BM infiltration in canine cutaneous MCT?

A

3% initial staging, 5% overall

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45
Q

In Pizzoni VCO 2018, what was % BM infiltration for stage IV dogs?

A

20%! (and only 11% of dogs with BM infiltration had circulating mast cells)

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46
Q

What was MST for stage IV MCT in Pizzoni 2018?

A

110 days

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47
Q

What is electrochemotherapy? What was recurrence rate after electrochemotherapy with cisplatin for MCT (Spugnini 2011)?

A

Tumor bed infusion with cisplatin and then electrical pulses. 16% recurrence rate in Spugnini study; median time to recurrence was 3 years.

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48
Q

What was CR rate for electrochemotherapy with IL-12 gene electrotransfer? (Cemazar VCO 2017)

A

72%
(78% of patients had detectable serum IFN-gamma and/or IL-12)

Interleukin 12 (IL-12) is produced by activated antigen-presenting cells (dendritic cells, macrophages). It promotes the development of Th1 responses and is a powerful inducer of IFNγ production by T and NK cells.

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49
Q

What is MCT RR to VBL/CCNU? (Cooper 2009)

A

60% - 1yr duration

65% of patients in study had macroscopic dz but grade unknown.

50
Q

What is PFS for macroscopic and microscopic MCT treated with VBL/CTX/pred? (Camps-Palau 2007)

A

macroscopic PFS 74 days (2.5mo)
microscopic PFS 865 days (2.4yr)
(grade?)

51
Q

What receptors are inhibited by Palladia?

A

KIT, VEGFR2, PDGFRbeta

52
Q

What was the RR for macroscopic MCT to Palladia? (London 2009)

A

40%

vs. 8% placebo

53
Q

What was duration of response for macroscopic MCT to Palladia? PFS? (London 2009)

A

response - 3 months

PFS - 4.5 months

54
Q

What % of MCT had KIT mutation? (London 2009)

A

20-40%

55
Q

What did London 2009 report as likelihood for MCT with c-kit mutation to respond to Palladia?

A

2x more likely to respond vs. wild-type c-kit
(68% vs. 37%)
This has NOT necessarily been corroborated by other studies (see Weishaar 2018)

56
Q

What is MST for MCT tx with masitinib - c-kit mutated vs. wild-type? (Hahn 2008)

A

c-kit mutation: MST not reached
normal c-kit: 253d (8.4mo)
(recurrent or nonresectable tumors evaluated)

57
Q

What was overall PFS for MCT tx with masitinib (Hahn 2008)?

A

PFS 118d (4mo); first-line therapy PFS 253 days (8.4mo)

58
Q

Overall RR of MCT to masitinib? (Smrkovski 2013)

A

50%

Although Grant 2016 reported 82.1% response rate

59
Q

Does imatinib have efficacy against canine MCT? (Isotani 2008)

A

Yes - objective responses in both c-kit mutant and wild-type.
No PK studies have been done in dogs, though.

60
Q

What is MTD of VBL when combined with EOD toceranib? (Robat 2012)

A

1.6 mg/m2

BUT toceranib was at 3.25 mg/kg EOD in this study

61
Q

What was ORR of toceranib combined with hypofractionated RT for MCT? (Carlsten 2012)

A

ORR 76.4% (58.8% CR and 17.6% PR)

62
Q

What was MST of toceranib combined with hypofractionated RT for MCT? (Carlsten 2012)

A

MST not reached, median follow-up 374d, median PFI 316d (10.5mo)

63
Q

What is RR to hydroxyurea for MCT? (Rassnick 2010)

A

28%

64
Q

In cats with splenic MCT, what is MST with splenectomy vs. no surgery? (Evans 2017)

A 
Splenectomy 856d (2.3yr), no surgery 342d (0.9yr)
Role of chemo remains unknown
65
Q

What was % benefit to Palladia for cats with MCT amd median duration of benefit? (Berger 2017)

A

80%; median duration 36 weeks (9 months)

50 cats with cutaneous (22), splenic/hepatic/visceral (10), GI (17), other (1)

66
Q

ORR to CCNU in cats with MCT? Duration of response? Dose? Toxicity? (Rassnick 2008)

A

ORR 50% (median duration 168d - 5.6mo)
Dose 50-60 mg/m2
Toxicity neutropenia, thrombocytopenia

67
Q

What % of nodes palpate normal but have MCT mets? (Ferrari 2018)

A

50%
This increased to 65% if you included pre-metastatic status (HN1)
Justifies prophylactic nodal removal or sampling at a minimum - they did not compare to cyto in this study.

68
Q

Prognosis of intramuscular MCT?

A

Favorable according to Robinson 2017. All 6 dogs that had had surgery were alive at follow-up with a minimum elapsed time of 7 months; 3 had adjunct chemo.

69
Q

ORR of chlorambucil and pred for MCT? (Taylor 2009)

A

38% but this is a crap study.

70
Q

Criteria for the MCT RNL metastasis classification system? (Weishaar 2014)

A

HN0 - none to rare mast cells (non-metastatic)
HN1 - more than 3 mast cells in 4hpf (pre-metastatic)
HN2 - aggregates (early metastasis)
HN3 - disruption or effacement of normal nodal architecture (over metastasis)

71
Q

MST for HN0/1 vs. HN2/3?

A

HN0/1 = 1824 days (5yr)
HN2/3 = 804 days (2.2yr)
High grade more likely to met (duh).

72
Q

What % of MCT were changed to incomplete margins using tangential sectioning instead of radial? (Dores 2018)

A

Low grade MCT 23% change in tumor free margin status with radial to tangential

73
Q

In evaluating histologically tumor free margins, what margin prevented recurrence of high grade tumors? (Donnelly 2015)

A

No “safe” margin was identified, no association between HTFM and LR. 36% recurred.

74
Q

In Donnelly 2015, what % of low grade MCT had histologic margins less than 3 mm and how many recurred?

A

29% had <3mm, none recurred.

Only 3.9% low grade MCT recurred total in this study.

75
Q

What was RR of macroscopic MCT to toceranib vs. VBL in a prospective study? (Weishaar 2018)

A

46% TOC, 30% VBL

76
Q

What was MST and PFS of macroscopic MCT to toceranib vs. VBL in a prospective study? (Weishaar 2018)

A

VBL - MST 241.5d (8mo); PFS was 78d (2.6mo)

TOC - 159d (5.3mo); PFS was 95.5d (3.2mo)

77
Q

Did c-kit mutation predict treatment response to TOC or VBL in recent prospective study? (Weishaar 2018)

A

Nope.

78
Q

Did kit cytoplastmic staining affect prognosis in cats? What MI cut-off was prognostic? (Sabattani 2013)

A

Yes - risk factors associated with survival were MI >5/10hpf and cytoplastmic kit staining. In 67% of cats, multiple nodules from same cat had different mutational status.

79
Q

What is MST of GI MCT in cats? (Barrett 2018)

A

531d (1.5yr)
26% of cats actually died from a different cause. GI MCT may be better prognosis than previously reported).
Surgery and medical tx (including pred) both associated with prolonged survival. May need no more than pred.

80
Q

In Weishaar 2018 multivariate analysis, what factors affected PFS? OS?

A

PFS - grade and KIT localization

OS - KIT localization

81
Q

Ki67 as prognosticator - cut-off? (Vascellari 2012)

A

10.6

>10/6 – 8x higher risk of mortality

82
Q

Response of MCT to glucocorticoids? (Horta 2018)

A

63% PR, no CR

83
Q

Multivariate analysis of glucocorticoids and MCT - response to GCs correlates with what? (Horta 2018)

A

tumor recurrence/related death, clinical stage, MI

84
Q

What % of MCT located on muzzle present with RLN mets? What is MST for RLN mets?

A

50-60%, 14 months

85
Q

T/F: The presence of c-kit activating mutation is associated with higher rate of local recurrence, metastasis, and death from MCT.

A

True

86
Q

What % of incompletely excised low/intermediate grade MCT recur?

A

20-30%

87
Q

Which is/are not neg prog factor(s) for MCT?

  1. diploid tumor
  2. high Ki67
  3. male dog
  4. systemic signs
  5. Shar Pei breed
A

diploid tumor and male dog

88
Q

Incidence of BM involvement in MCT for cutaneous? visceral?

A

cutaneous - 2.8%, visceral 56% (different than recent study)

89
Q

What % of treated vs. placebo dogs were alive at 2yrs in masitinib study?

A

40% vs. 15%

90
Q

RR with VBL/TOC?

A

71%

91
Q

What exons are feline cKIT mutations located on?

A

8 and 9

92
Q

What surgical margins are recommended for feline GI MCT?

A

5-10cm

93
Q

What were prognostic factors for feline splenic MCT according to Evans 2018? According to historical data?

A

Evans - none were significant.

Historically - anorexia, significant weight loss, male gender

94
Q

What 5 features of canine MCT histopath correlated with worse outcome? (Sabattini 2010)

A

multiplicity of lesions, pleomorphic phenotype, KIT score, mitotic indices, Ki67 indices

95
Q

Ki67 cutoff that predicts MCT grade and survival?

A

1.8 (Maglennon VCO 2008)

96
Q

Turnover of ____ appears to play an important role in canine MCT pathogenesis. (Arendt PLoS Genetics 2015)

A

hyaluronan

97
Q

Does imatinib have clinically activity against MCT in dogs? (Isotani JVIM 2008)

A

Yes, dose at 10 mg/kg daily. Authors recommended checking for exon 11 mutation within c-kit.

98
Q

In Schultheiss 2011, there was no recurrence of tumors with >/= ___ mm lateral and >/= ___ mm deep margins. (this was only MCT)

A

10mm lateral

4mm deep

99
Q

In Scarpa 2012 (evaluation of histologic margins of multiple tumor types), what conclusion was made about follow-up? (This included MCT, STS, and carcinomas)

A

Should follow for at least 2 years, late tumor recurrence was noted in this study.

100
Q

Do ferret MCTs express KIT?

A

Yes, 100% showed expression. 1/3 showed KIT pattern 1 and the remaining KIT pattern III. (Vilalta Journal of Comp Path 2016)

101
Q

What two features were significantly associated with survival in evaluation of feline GI MCT? (Sabattini 2016)

A

tumor degree of differentiation and MI > 2

cytoplasmic KIT pattern was associated with lesser differentiation

102
Q

What is the ORR to pred and VBL in macroscopic MCT? (Thamm/Vail 2008)

A

47%

103
Q 
What is the response rate of measurable MCT to the following:
CCNU
Calcitriol
Hydroxyurea
Chlorambucil/pred
A

CCNU - 44% (source?)
Calcitriol - 40%
Chlorambucil/pred - 38% (bad study)
Hydroxyurea - 28% (bad study)

104
Q

Where were the majority of feline c-kit mutations identified? Were these mutations correlated with biologic behavior? (Sabattini 2013)

A

exon 9 - 71%
(exon 8, 19%; exon 9, 71%; exon 11, 10%)
Not correlated with behavior

105
Q

What is the typical behavior of a canine conjunctival MCT?

A

Benign

106
Q

How did micellar paclitaxel compare to CCNU for MCT? (Vail 2012)

A

CORR (confirmed ORR) was 7% for paclitaxel and 1% for CCNU

107
Q

How did hepatotoxicity with micellar paclitaxel compare to CCNU? (Vail 2012)

A

CCNU - 33%

paclitaxel - 2%

108
Q

What was the response rate of MCT to Vinorelbine? Toxicity? (Grant 2008)

A

13% response
54% neutropenia, 46% GI dox
(dose 1 tx at 15 mg/m2)

109
Q

What are the response rates of MCT to the following?

  • Chlorambucil/pred
  • Lomustine
  • VBL/pred
  • VBL/CCNU
  • VBL/CCNU/pred
  • Palladia
  • Masitinib
  • VBL/Palladia
A
  • Chlorambucil/pred: 38%
  • Lomustine: 42%
  • VBL/pred: 47%
  • VBL/CCNU: 57%
  • VBL/CCNU/pred: 65%
  • Palladia: 42%
  • Masitinib: 50% (82% ORR in Grant 2016, 2/3 had pred)
  • VBL/Palladia: 71%
110
Q

What does masitinib target?

A

c-kit, PDGFRa/B, lyn, FGFR receptor 3, focal adhesion kinase pathway

111
Q

What was the accuracy of using margins to predict MCT recurrence? STS? Carcinoma? (Scarpa 2012)

A

MCT - 76%
STS - 87%
Carcinoma - 94%

112
Q

What is the dose of masitinib? (Hahn 2010)

A

12.5 m/kg

113
Q

What was the confirmed ORR, biologic response rate, and 5 week PFS in dogs with grade 2 or 3 MCT treated with Paccal Vet? (Vail JVIM 2012)

A

CORR: 7%, BORR: 23%, 6 week PFS: 68%

114
Q

Which KIT exon is most commonly mutated in canine MCT?

A

exon 11

115
Q

What are the four members of the ErbB family of RTKs?

A
  1. ErbB-1 (aka EGFR/HER1)
  2. ErbB-2 (aka HER2/neu)
  3. ErbB-3 (aka HER3)
  4. ErbB-4 (aka HER4)
116
Q

What is the MOA of gefitinib and erlotinib?

A

bind to ATP-binding pocket of INTRAcellular kinase domain of EGFR - prevents autophosphorylation and downstream signaling

117
Q

What are MOR to EGFR inhibitors?

A
  1. secondary mutation of EGFR that prevents drug binding

2. activation of downstream signals (i.e. amplification of Met)

118
Q

What is the MOA of cetuximab and panitumumab? What is the molecular predictor of response of these in colorectal cancer?

A
  • Bind to extracellular domain of EGFR, inhibits activation and receptor dimerization
  • absence of K-RAS mutation
119
Q

What % of dogs with macroscopic MCT have elevated histamine?

A

75%

120
Q

What does electrochemotherapy do to cell membranes? (Lowe 2016)

A

temporary permeabilization and increased porosity

121
Q

T/F: Dogs with MCT that were treated with electrochemotherapy intra-operatively had the longest DFA, as compared to dogs treated in gross disease setting or post-operatively. (Lowe 2016)

A

True

122
Q

What are the most commonly used agents for electrochemotherapy in canine MCT?

A

bleomycin, cisplatin

Onco Board Review 2 (20 decks)

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