MCT Flashcards
What bioactive substances to MC’s contain?
Heparin, histamine, TNF-alpha and proteases
What can MCs rapidly produce when stimulated?
Chymase, tryptase, cytokines (TNF alpha, IL6) chemokines (CCL2, CXCL1) VEGF, basic fibroblast growth factor, prostaglindin D2, leukotriene C4
What was found to be a risk factor for golden retrievers with MCT?
polymorphisms in the GNAI2 gene and multiple genes assoc with hyaluronic acid synthesis
Alterations in expression of what cyclin-dependent kinase inhibitors have been identified in a many canine MCTs?
p21 and p27
What is KIT normally expressed on?
Hematopoietic stem cells, melanocytes and MCs
What does KIT bind and what does this cause?
SCF binds KIT –> KIT dimerization –> phosphorylation –> intracellular signaling –> proliferation, differentiation and maturation of normal MCs
What is essential for the differentiation of mature MC from CD34+ stem cells?
SCF (stem cell factor)
The juxtamembrane domains of kit are
exon 11-12
The extracellular domains of KIT are
exon 8-9
What do KIT mutations cause?
SCF-independent activation of KIT –> unregulated KIT signal transduction
c-kit mutations are associated with ____% of canine intermediate and high grade MCTS
25-30%
CNVs ( copy number variation) have been associated with (high/low) MCTs
High
MCTs with kit mutations showed aberrant CNVs involving what genes?
p53 and rB pathways
What drug metabolism and cell cycle pathways have been shown to correlated with cure from surgery vs. death from MCT?
solute carrier transporter and UDP glucuronosyltransferase gene families
What four stress response proteins are significantly upregulated in high-grade MCT
HSPA9 PDIA3 TCP1A TCP1E
Over expression of what micro-RNA was associated with MCT metastasis?
micro-RNA-9
What percent of dogs present with multiple MCTs?
11-14%
What is the behavior of primary GI MCT in dogs?
Aggressive - 40% alive at 30d , <10% alive at 6mo
GI ulceration has been documented in ____% of dogs undergoing necropsy
35-83% (may be selecting for higher grade tumors because necropsy)
What does histamine released from MCT act on?
H2 receptors on parietal cells –> increased HCl
In addition to high plasma histamine concentrations, dogs with MCT can also have decreased plasma ____ levels
Gastrin - normally released by antral G cells in response to increased gastric HCl
What mediates the hypotensive effects in humans with MC diseases?
Prostaglandins in the D series
What is the most consistent and reliable prognostic factor for canine MCT?
Grade
What is the long term survival rate for well-diffentiated and intermediate grade MCT after complete surgical excision
well-differentiated 80-90% Intermediate 75%
What is the metastatic rate for undifferentiated MCT
range 55%-96%
What locations are associated with high grade/worse prognosis for canine MCT
subungual, oral, mucous membranes scrotal and preputial visceral or bone marrow = grave
Microvessel density has been associated with what in canine MCT
Higher grade, higher degree of invasiveness, worse prognosis
What is the Bostock Grading system for canine MCT
Same as patnaik except numbers reversed (i.e. high grade = grade 1 on bostock, low grade = grade 3 on Bostok)
What stain can determine the AgNOR score?
silver colloid staining
What markers of proliferation have been associated with biologic behavior of MCT? Which is the least consistent
Ki67, AgNOR, PCNA PCNA least consistent
What mitotic index cutoff is associated with MST in dogs with MCT?
MI <5 MST >5 3mo; <5 80mo
What are the three distinct ckit patterns
membrane, focal/stippled diffuse cytoplasmic
The presence of c-kit activating mutations has been associated with what in canine MCT?
higher rate of local recurrence, metastasis, death from disease
What percent of dogs with MCT on the muzzle present with regional LN mets?
50-60% but doesn’t mean worse prognosis MST w/ mets = 14mo
What is associated with a more aggressive behavior for canine SQ MCT
MI >4, infiltrative growth pattern, presence of multinucleation
What is the prognosis for dogs with conjunctival MCT?
Good - no dogs in the study looking at this died from the MCT
What IHC are MCTs positive for?
Vimentin, tryptase CD117 (KIT) +/- chymase, MCP-1 and IL-8
How does ultrasound or CT analysis of either MCT or STS change tumor margins planned at surgery?
Ultrasound upgraded tumor margins in 19%, CT upgraded margins in 65%
What other conditions can cause a peripheral mastocytosis (1-90MCs/uL)?
acute inflammatory disease (parvo), inflammatory skin disease, regenerative anemia, neoplasia other than MCT and trauma; may be more dramatic in other diseases than in MCT
What was the incidence of bone marrow involvement at the time of diagnosis in dogs with MCT?
2.8%
What was the incidence of bone marrow involvement and mastocytosis in dogs with visceral MCT?
Bone marrow 56% mastocytosis 37%
Adjuvant RT is associated with what 2-yr control rates for stage 0, low or intermediate grade MCT
85-95%
What is the general rate of recurrence for incompletely excised MCT? what may be associated in predicting likelihood of recurrence?
10-30%; proliferation indicies Ki67/PCNA
Is adjuvant steroid or antihistamine therapy beneficial for cases of intermediate MCT that have been excised or treated with RT?
Nope
What are the three distinct syndromes for feline MCT?
Cutaneous, splenic/visceral and intestinal
What % of cutaneous and splenic/visceral feline MCT had c-kit mutations? What exons were these primarily present in
exons 8/9
Which subtype of feline cutaneous MCT may spontaneously regress?
Histiocytic MCT (vs. mastocytic MCT)
The histiocytic form of cMCT is more likely to occur in what signalment cat?
Young, siamese (male depending on study); usually presents with multiple masses that may be ulcerated (head/neck usually)
What are the two types of mastocytic cMCT in cats?
Compact (50-90% of cases) vs. diffuse (anaplastic)
Systemic mastocytosis does/does not occur in healthy or ill-from something other than a MCT in cats
does not
What percent of cats may present with positive buffy coats? What form of MCT is this usually associated with?
43%, usually splenic/visceral
What IHC markers are feline MCT usually positive for
Vimentin, alpha-1 antitrypsin and KIT
What other organs are frequently affected by splenic/visceral MCT?
liver (90%), LN (73%), bone marrow (40%), lung (20%)
What is the survival for cats undergoing splenectomy for splenic/visceral MCT
12-19mo even with bone marrow involvement
What are the 3 MC related diseases in people?
Cutaneous mastocytosis (benign, young children, spontaneous regression systemic mastocytosis - 4 subtypes extracutaneous MCT
What KIT mutation is most common in people with MC disease
point mutation in exon 17 - induces ligand-independent activation; exons 8 and 11 also identified
Are KIT inhibitors (imatinib, nilotinib, dasatinib) effective for treatin human MC diseases?
Not usually - inhibiting phosphorylation of KIT on exon 17 is challenging
What percent of feline MCT are kit positive on IHC (Mallett Vet Path 2012)
69% cutaneous
35% splenic
33% GI
What was found to be correlated with worse outcome in cats with MCT? What was the strongest predictive variable? (Sabattini VetPath 2010)
Multiple lesions, pleomorphic phenotype, KIT score, MI and Ki67 indicies
MI strongest
Other than MCT, what other disease can cause mastocythemia in cats? (Piviani Vet Clin Path 2013)
LSA, HSA, CKD
For low grade MST with tumor free margins on histopath (radial), what margin cutoff is concerning for incomplete excision based on tangential sections? (Dores VCO 2018)
<10.9mm
What was the percent overall shrinkage for excised canine cMCT? (Upchurch AJVR 2018)
17.7%
Was the amount of shrinkage in normal skin or the cMCT larger for excised canine cMCT? When did most of the shrinkage occur?
Larger for grossly normal skin (24.42%) compared to tumor (4.45%); most occurred immediately after excision
What was the overall risk of metastasis for grade 3 MCT (Patanaik) vs. high grade (Kiupel) (Stefanello JAVMA 2015)
OR for Patanaik = 5.46
OR for Kiupel = 2.54
What was the rate of mets from MCT for grade 1 and 2 tumors compared to low grade tumors (Stefanello JAVMA 2015)
Patanaik: grade 1 (5.8%) grade 2 (16.5%)
Kiupel 14.9% low grade had mets
Expression of what IHC marker was expressed in canine MCT but not normal MC and had lower expression in high grade MCT than low grade MCT? (Meyer Vet Path 2012)
CD 25 (subunit of IL-2 receptor)
What is the rate of abberant KIT staining in horses?
12%
What was the agreement between 28 vet pathologists for grade 3 MCT vs grade 1/2 MCT? (Kiupel Vet Path 2011)
High grade 75%, grade I/2, < 64%
What are the crieteria for high grade MCT on the two-tier system? (Kiupel Vet Path 2011)
Any 1 of the following:
MI ≥ 7
3 or more multinucleated (3 or more) in 10hpf
3 or more bizarre nuclei/10hpf
Nuclear diameters of at least 10% vary by at least 2-fold
What was the prognosis for low vs. high grade MCT on the two tier system? (Kiupel Vet Path 2011)
<4mo for high grade
>2yrs for low grade
An HN score > 0 was associated with what size cutaneous MCT? (Ferrari VCO 2018)
>3cm
What percent of dogs with non-palpable or normal sized LN had LN mets when the LN was extirpated? (Ferrari VCO 2018)
Almost 1/2 (HN2 28%, HN3 21%)
What was the tumor specific survival (TSS) for dogs with grade II stage II MCT treated with surgical removal vs not of the metastatic LN? (Marconato VCO 2018)
TSS LN extirpation: 2213d
W/o: 360d
For dogs with grade 2 stage 2 MCT, the risk of tumor progression was ___ higher without LN removal and the risk of tumor related death was ____ higher without LN removal (Marconato VCO 2018)
5x, 3.5x
What prognostic factors were associated with tumor progression for dogs with grade 2 stage 2 MCT? (Marconato VCO 2018)
Age >9
Head/neck
lymphadenopathy
no LN extirpation
What prognostic factors were associated with tumor related death for stage 2 MCT (marconato VCO 2018)
Head/neck, high grade no LN extirpation
What was the overall expression of fibroblast activating protein in canine MCT? (Giuliano J Comp Path 2017)
90% - 16 low to intermediate, 14 high
What was fibroblast activating protein correlated with in canine MCT
FAP positiviely correlated with Patnaik and Kiupel grade, MI and Ki67 expression - FAP may be negative prog factor in MCT
What defines HN0 for MCT? (Weishaar J Comp Path 2014)
0-3 scattered or individual MC in sinues and/or arenchyma per 400x field
What defines HN1 for MCT? (Weishaar J Comp Path 2014)
> 3 individualized MC in sinuses and/or parenchyma in a minimum of 4 400x fields
What defines HN2 for MCT? (Weishaar J Comp Path 2014)
Aggregates (clusters) of MCs (≥3 assoc cells) or sinusoidal sheets of MCs
HN2 = early metastasis
What defines HN3 for MCT? (Weishaar J Comp Path 2014)
Disruption or effacement of normal nodal architecture by MCs
Overt metastasis
What was MST for HN0/HN1 MCT vs. HN2/3 MCT (Weishaar J Comp Path 2014)
HN0/1 = 1824d
HN2/3 = 804d
What percentage of canine MCT have TP53 mutations? Associated with grade? (Vozdova VetJ 2019)
15%; mutation not associated with grade
How did the average extracellular vesicle concentration compare in dogs with MCT vs. healthy dogs? (Simundic VCO 2019)
Higher in MCT dogs than in healthy dogs
What is ibrutinib and how does it work?
Bruton’s tyrosine kinase (BTK) inhibitor; blocks IgE dependent activation and histamine release in human basos and MCs
What was the effect of ibrutinib on MCT cell lines? (Gamperl VCO 2019)
Suppressed phosphorylation of BTK and downstream STAT5
Induced apoptosis in cells at higher doses
High levels of what apopototic intrinsic pathway proteins was associated with a higher mortality rate and shorter ST? (Barra VCO 2018)
BAX
BCL2 lower in high grade tumors
Higher APAF1 = lower risk of death
Mean plasma CK18 was/was not a predictor of development of GI tox from TOC in dogs (Kovac JVIM 2018)
was not
What Jak2 and Stat5 inhibitors had efficacy in MCT lines
**Both MCT lines had JAK2 and STAT5 detected**
Jak2: R763, TG101348, AZD1490, ruxolitinib
Stat5: pimozide, piceatannol
What STAT 5 inhibitor has synergistic effects with KIT-targeting drugs for treatment of canine MCT (in cell lines) (Keller VCO 2018
Pimozide
Immuno expression of HSP32 was highest or lowest in high grade MCT? What does this suggest? (Romanucci Vet Path 2017)
Highest, suggests loss of immunosiganling in poorly differentiated MCT
Dogs with cMCT with loss of genomic copy numbers of ____ and gain of copy numbers in ____ had shorter survival and worse prognosis (Jark, ResVetSci2017)
Loss: PTEN, FAS
Gain: MAPK2, WNT5B, FGF, FOXM1, RAD51
What c-KIT mutation was detected in a MCT from a dog with resistance to imatinib? Nakano Vet Immuno 2017
c.2006 C-T in exon 14
Mutant kit with both _____ and _____ mutations caused ligand independent phosphorylation that was not suppressed by _____. (Nakano Vet Immuno 2017)
c.1663-1671del on exon 11
c.2006 C-T
Imatinib
What was the first mechanism of imatinib resistance identified in a clinical case of canine MCT? (Nakano Vet Immuno 2017)
c.2006 C-T in exon 14
What was associated with decreased MST/DFI and increased met rate in dog SQ and cMCT? (Thompson Vet Path 2016)
Phosphorylated KIT, VEGFR2, KIT cellular localization
What was associated with an increased rate of local recurrence in dogs with SQ or cMCT? (Thompson Vet Path 2016)
Expression of VEGFR2 and KIT diffuse cytoplasmic staining
What was the KIT expression pattern for most equine MCTs (Ressel JCompPath 2015)
low grade with KIT pattern 1 and low proliferation (2/3)
What is the expression of COX-2 in MCT, HS and HSA? (Heller Vet Path 2005)
Not expressed
What was the rate of ITD mutations in exon 11 and 12 of c-kit in cMCT? (AJVR 2002)
Grade 1 8%
Grade 2 35%
Grade 3 35%
Describe the mismatch repair protein expression in K9 MCT (Munday Vet Path 2009)
All expressed MLH1, MSH2 and MSH6
No difference in old dogs or nonpredisposed breeds
What is p62/sequestosome-1
Stress-inducible “hub” protein found in all cell types
Shuttles b/w nucleus and cytoplasm
Regulates NFkB
What p62 patterns were associated with MCT tumor grade? (Rich Vet Path 2014)
P62 nuclear - 100% low grade
P62 cytoplasmic - 93% high grade
What was the rate of phosphorylated KIT in canine MCT treated with TOC or VBL? what was it associated with? (Thamm VCO 2019)
pKIT in 66%
Associated with aberrant KIT localization, high MI and high grade
On multivariate analysis, what predicted MST and PFI for dogs with cutaneous MCT treated with TOC or VBL (Thamm VCO 2019)
MST - phosphorylated kit
PFI - MI
What breeds were more likely to have high grade MCT vs. those that weren’t (Reynolds VCO 2019)
More likely: Sharpeis
Less: goldens, pug
What location of MCT was more likely to have a high grade MCT? (VCO 2019 Reynolds)
Inguinal
What was correlated with response to glucocorticoid therapy in dogs with MCT and what was the response rate?
PR 63.3%
no response: 36.7%
Lower stage of disease, lower grade, lower KITr expression and Ki67 score
What was the MST for dogs with stage IV cMCT? (Pizzoni 2018)
MST 110d.
What were negative prognostic factors for dogs with stage IV cMCT? (Pizzoni VCO 2018)
>3cm, >2 metastatic sites, bone marrow involvement, lack of primary tumor control
Combining MI and Ki67 score with ____ showed improved accuracy of predicting death in dogs with cMCT (Berlato VCO 2018)
minichromosome maintenance protein 7 (MCM7)
What are ckit mutations associated with in cMCT in dogs? (Thamm VCO 2019)
higher grade, increased recurrence rate, decreased ST
May NOT be an independent factor
Are dogs getting RT + VBL/pred for MCT more likely to get neutropenic than dogs without RT? (Stiborova JSAP 2019)
No increased risk - RT group 18% risk, chemo alone 23%
What were the randomized groups for Weishaar’s ckit vbl/toc study? (JVIM 2018)
Prospective randomized tiral - 88 dogs
TOC (2.75mg/m2 EOD) or VBL (2.5mg/m2 weekly x4 then EOW)
Randomized by KIT localization and c-kit mutation status using an adaptive randomization scheme
For dogs treated with toceranib for MCTs in a randomized study (Weishaar), what percent had c-kit mutations and what was the ORR for these dogs? (JVIM 2018)
20% had kit mutations, ORR 46%
What was the mPFS and OST of dogs treated with toceranib in a randomized trial looking at the influence of c-kit mutations (Weishaar JVIM 2018)
mPFS 95.5d (14-990)
OST 159 (20-990)
What percentage of dogs had kit mutations in Weishaars toceranib vs. vbl study and what was the ORR rate to vbl? (JVIM 2018)
30% had kit mutations
ORR 30%
What was the mPFS and OST for dogs treated with vbl randomized by kit mutation status? (Weishaar JVIM 2018)
mPFS 78d (7-1521)
OST 241.5d (10-1521)
Did c-kit mutation status predict the response to toc vs. vbl? Also, were PFS or OS different between these groups? (Weishaar JVIM 2018)
No difference in treatment response (c-kit mutation status was no different between groups)
No difference in OS or PFS
What was the response rate for intralesional triamcinolone treatment for MCTs in dogs? (Case JAVMA 2018)
ORR 67% - 4/24 CRs, 12/24PRs
What was the response rate to a single dose of intralesional tiramcinolone for MCT in dogs? (JAVMA 2018)
1/5 CR, 3/5 PR, 1/5 SD
What were the characteristics for inclusion for the study examining triamcinolone intralesionally for MCT in dogs (Case JAVMA 2018)
MCT ≥0.5cm treated with at least 1 IL tx
What AEs were reported for dogs with MCT treated with at least one intralesional triamcinolone tx? (Case JAVMA 2018)
3 dogs AEs: 1 local bleeding and 2 suspected GI ulceration
What rapid dose escalation was used for treatment of dogs with MCT? How was it tolerated? (Serra Varlera, VetM&Sci 2016)
2.3, 2.6, 3, 3 then 3 EOW
70% tolerated 3mg/m2 q7d at d 14 and 21
How many dogs had a DLT and d/c treatment due to toxicity in the study looking at rapid VBL escalation for MCT? (Serra Varlera VetM&Sci 2016)
30% DLT
8% d/c
**2 dogs died from febrile neutropenia**
How was the combination of toc and CCNU tolerated when used for treatment of non-resectable or recurrent MCT? (Bavcar VetJ 2017)? What were the doses used?
Doses: Toc 2.7mg/kg EOD, CCNU 60mg/m2 q3wk)
Severe AEs in all dogs (10 dogs), all needed protocol changes
**3 dogs died or were euthanized**
What waws the ORR for dogs treated with a combination of toc and CCNU for non-resectable or recurrent MCTs? (Bavcar VetJ 2017)
ORR 50%; long term response (>1yr) in 2
What does Masitinib target?
c-kit
Possibly PDGF receptor alpha and beta; lyn and FGFR receptor 3; focal adhesion kinase pathway
What was the ORR for dogs with macroscopic MCT treated with masitinib (Grant, JSAP 2016)
ORR 82% (by RECIST, 61% by WHO)
43% CR, 39% PR
What was the TTP and MST for dogs treated with masitinib for macroscopic MCT? (Grant JSAP 2016)
TTP 79d (longer if in CR)
MST 5mo
What was the rate of AEs/what grade for dogs treated with masitinib for gross MCT (Grant JSAP 2016)
AEs in 64% (25% grade 3/4)
Most common = ALT and vomiting
What was the protocol for pulse toc + CCNU for unrescetable MCT (Burton, JVIM 2015)?
TOC d 1, 3 and 5 of 21 d. cycle (2.75mg/kg)
CCNU d 3 of each cycle at 50mg/m2
What was the ORR and mPFS for dogs treated with pulse TOC + CCNU for unrescetable MCT? (Burton 2015)
ORR 46%
mPFS 53d
What was the response rate to a dose of vinorelbine for dogs with MCT?
13% response (CR or PR)
83% SD
What was the protocol for alternating CCNU and high dose VBL for dogs with MCT? (Rassnick VCO 2010)
CCNU 70mg/m2 alt EOW with VBL 3.5mg/m2
What was the ORR for dogs treated with CCNU/high dose VBL for MCT? (Rassnick VCO 2010)?
ORR 65%
What was the median PFS for dogs treated adjuvantly with CCNU/high dose VBL for MCT? (Rassnick VCO 2010)
mPFS = 489d
What was the PFS for dogs with grade 3 MCT vs. metastatic grade II MCT treated with CCNU/high dose VBL? (Rassnick VCO 2016)?
Grade 3 190d
metastatic grade II 954d
What was the confirmed ORR (CORR) for dogs treated with water soluble micellar paclitaxel (Paccal Vet) for nonresectable grade 2 or 3 MCT? (Vail JVIM 2012)
CORR 7% (150mg/m2)
What was the outcome for dogs treated with adjuvant CCNU/pred for incompletely excised grade 2 MCT? (Hosoya JAAHA 2009)?
12 nogs, non developed local recurrence or mets
2 dogs died from liver failure
What were the 1- and 2-yr PF rates for dogs treated with CCN/pred for incompletely excised grade 2 MCT? (Hosoya JAAHA 2009)
1yr 100%, 2yr 77% (n= 12 dogs)
What was the remission rate for dogs treated with oral calcitriol for MCT? (Malone VCO 2010)
40% (1 CR, 3 PR)
How was high dose calcitriol (DN101) tolerated for dogs with MCT? (Malone VCO 2010)
Poorly - majority needed d/c because of tox - hyperCa, GI, azotemia
What was the ORR for dogs treated with chlorambucil and pred for inoperable MCT? (Taylor JSAP 2009])
ORR 38%
What was the PFI for the dogs that responded to chlorambucil and pred for inoperable MCT? What was the MST for all dogs? (Taylor JSAP 2009)
PFI for 8 responders = 533d.
overall MST = 140d
What was the response rate to vinblasine + pred vs. pred alone for treatment of MCT? (Rungsipipat Comp Clin Path 2009)
Vibl 78.2% vs. 50% pred alone
What proliferative markers were shown to decrease after treatment (vbl and/or pred) for dogs with MCT? (Rungsipipat CompClinPath 2009)
AgNOR, PCNA, Ki67
What was the MST for dogs treated with vbl/pred vs. pred alone for MCT? (Rungsipipat Comp clin path 2009)?
MST vbl 101d, pred alone 175d
ORR and median duration of response for dogs with microscopic or macroscopic MCT treated with alternating CCNU/VBL q2wks (Cooper VCO 2009)
ORR 57%, median duration 52wks
PFST and OST for dogs with macroscopic MCT treated with alternating CCNU/VBL q2wks (Cooper VCO 2009)
PFST 30wks, OST 35wks
PFST and OST for dogs with microscopic MCT treated with alternating CCNU/VBL EOW (Cooper VCO 2009)
PFST 35wks, OST 48wks
What was the response rate to imatinib for dogs with MCT (Isotani JVIM 2008)
48% w/in 14d
All dogs with exon ____ mutations had a response to imatinib (Isotani, JVIM 2008)
exon 11
What was the response rate for dogs with grade II or III nonresectable MCT treated with 2mg/m2 or 3.5mg/m2 without prednisone? Rassnick JVIM 2008
VBL 2.0 = 12% pr for 77d
VBL 3.5 = 27% ORR
Rate of grade 4 neutropenia after treatement with 3.5mg/m2 vbl for dogs with unresectable grade II or III MCT? (Rassnick JVIM 2008)
46%
What was the 1- and 2-yr survival rate for dogs treated for nonrescetable grade 2 or 3 MCT with masitinib? What was the dose of masitinib used?
12.5mg/kg/d
1yr 62.1% vs 36% for placebo
2yr 39.8% vs 15%
**treatment significantly prolonged survival rates**
Median OST for dogs with nonrescetable grade II or III MCT treated with masitinib (Hahn AJVR 2010)
617d. vs. 322d for placebo
What was found to have high or poor predictive value for tumor control for dogs treated with masitinib for nonresectable grade II or III MCT? (Hahn AJVR 2010)
High predictive value: tumor control at 6mo
Poor predictive value: short-term tumor response (6wks)
What was the rate of recurrence and median time to recurrence for dogs treated with ECT with cisplat for MCT? (Spugnini JVIM 2011)
recurrence 16% (6/37)
median time to recurrence 1200d
What was the ORR for metastatic and non-metastatic MCT treated with Masitinib (Smrkovski VCO 2013)
50%
What was the MST for responders vs. nonresponders in dogs treated with Masitinib for metastatic and nonresectable MCT? (Smrkovski VCO 2013)
Responders 630d
Nonresponders 137d
What was the rate of AEs and what were they in dogs treated with Masitinib for nonresectable or metastatic MCT? (Smrkovski VCO 2013)
Toxicity in 61.5% - most mild and self-limiting
ALT, proteinuria, heme (neutropenia) GI
What was the RR for dogs treated with Masitinib as a first-line vs. rescue treatment for nonresectable or metastatic MCT? (Smrkovski VCO 2013)
First line RR 57%; rescue 25%
What was the most common side effect for dogs treated with 12.5mg/kg/day Masitinib for nonmetastatic recurrent or nonresectable grade 2 or 3 MCT? (Hahn JVIM 2008)
GI upset - grade I/II diarrhea or vomiting
What was the TTP for dogs with nonmetastatic recurrent or nonresectable grade 2 or 3 MCT treated with masitinib? How did it compare if it was first line therapy?
TTP 188d overall
if first line TTP 253d (vs 75d for placebo)
What was the protocol for dogs treated with single-agent hydroxyurea for MCT? (Rassnick VCO 2010)
60mg/kg PO q24 x14 then 30mg/kg PO q24
What was the response rate for dogs treated with single-agent hydroxyurea for MCT? (Rassnick VCO 2010)
28%
What were the AEs for single agent hydroxyurea for treatment of dogs with MCT (Rassnick VCO 2010)
Primary AE = anemia (median drop in HCT 10%)
Neutropenia, thrombocytopenia
What was the PFS for dogs treated with VBL/CTX/pred for measureable disease vs. incomplete excision or high risk of mets (Camps-Palau VCO 2007)
Measurable: 74d
Incomplete or high risk of mets 865d
Did hypotonic water as adjuvant therapy for incompletely excised MCT affect survival time or rate of local recurrence (Brocks Vet Surg 2008 - mentioned in new withrow chapter)
Nope - not recommended for use
What % of MCT were not diagnosed with rapid stain compared with Giemsa? How about LN mets? (Sabattini VCO 2018)
5% of MCT - majority high grade tumors
7-18% of nodal mets
Did cytologic grading accuracy differ between aqueous stains vs. Giemsa? (Sabattini VCO 2018)
Nope - 85% accuracy
What was the CT appearance of the liver in 5 dogs with confirmed cytologic mets from MCT? (Hughes VRU 2018)
4/5 normal - CT not good for detecting liver mets
What CT finding were significantly associated with MCT mets in the spleen? (Hughes VRU 2018)
Heterogenous or nodular spleen
Was FDG-PET-CT better for staging MCT in dogs compared to traditional methods? Anything associated with high grade? (Griffin VRU 2018)
Nope
Higher median SUVmax correlated with high grade (5.63, range 3.92-23.73) vs low grade (2.7, 1.8-5.7)
What was the diagnostic accuracy for pre-treatment bx of cMCT in dogs? (Shaw, VCO 2017)
Overall agreement 96% on Patnaik, 92% on Kiupel; lowest for wedge bx
If bx of cMCT did not match the overall grade after surgical removal, did bx over or underestimate grade? (Shaw VCO 2017)
Under
What was significantly associated with stage 2 grade 2 MCT? (Krick JAAHA 2017)
AgNORs/nucleus (OR 2.8)
Recurrent tumors(OR 8.8)
What was the sensitivity and specificity of AgNORs/cell in predicting stage of canine MCT? What was the cutoff value? ( Krick JAAHA 2017)
AgNORs/cell ≥1.87
sensitivity 93.3
specificity 27.4%
What was the AgNOR cutoff value that reliably predicted LN metastasis for canine MCT? (Krick JAAHA 2017)
Trick question - cutoff NOT determined
What were the cytologic characterisitics used to grade cMCT cytologically for dogs? (Scarpa VCO 2016)
number of mitoses
multinucleated cells
bizarre nuclei
presence of karyomegaly
What was the accuracy, sensitivity and specificity for cytologic grading of canine cMCT? (Scarpa VCO 2016)
Accuracy 94%
Sensitivity 84.6%
Specificity 97.3%
What criteria classified a MCT as high grade based on cytology (Camus VetPath 2016)
Poorly granular
OR at least two of the following:
Mitotic figures, nuclear pleomorphism, binucleated or multinucleated cells, >50% anisokaryosis
What was the sensitivity and specificity of the Camus cyto grading scheme compared to histopathology (Vet Path 2016)
88% sensitivity
94% specificity
What was the overall agreement, sensitivity, specificity and kappa score for two teir cyto grading for MCT? (Hergt VetClinPath 2016)
Agreement in 113 cases, 87% sens; 97 spec; kappa 0.853
Of the 8 cases that disagreed between cyto and histo grading for MCT, how many were cyto low/histo high vs cyto high/histo low? (Hergt Vet Clin Path 2016)
5 low on cyto, high on histo
3 high on cyto, low on histo
What percentage of c-kit mutations matched between primary and metastatic lesions for MCT? (Marconato 2014)
100%
What were the MR imaging characteristics of MCT **exam committee**
T2: 7/9 = hyperintense to mm, 2/9 iso
T1: 8/9 isointense, 1 iso
All strongly contrast enhancing (homogenous 5, heterogenous 4)
Incidence of bone marrow mets from MCT at diagnosis vs. in overall study? (Enicott VCO 2007)
At dx: 2.8%
All: 4.5%
Survival for dogs with liver/spleen mets from MCT compared to w/o? (Stefanello JVIM 2009)
34d vs. 733d
What breeds are predisposed to get maculopapular cutaneous mastocytosis? Ngo JFMS 2019
Sphynx, Devon Rex
What were the three types of feline maculopapular cutaneous mastocytosis described? (Ngo JFMS 2019)
Polymorphic
Monomorphic
Pigmented
Stem cell factor was expressed in what percent of feline cutaneous MCT? Where in tumor was this expressed and what other markers were/were not associated with it?(Sakurai J Comp Path 2018)
43% (10/23) expressed at margins of feline cMCT
8/10 co-expressed Kit, not near Ki-67 expressing cells
What was the MST for cats with GI MCT? (Barrett VCO 2018)
531 d.
What was associated with a prolonged survival times in cats with gastrointestinal MCT? (Barrett VCO 2018)
Treatment - chemo (CCNU/chlorambucil most commonly), sx+chemo, steroids + sx, steroids alone
What was found to significantly prolong survival in cats with splenic MCT? (Evans VCO 2017)
Splenectomy - 856d vs. 342d w/o
What was the survival time for cats terated with chemo alone vs. supportive care for cats with splenic MCT? (Evans VCO 2017)
Chemo alone 244d, supportive care 365d
What was the survival time for cats treated with splenectomy vs. splenectomy + surgery for splenic MCT? (Evans VCO 2017)
Splenectomy: 856d, +chemo: 853d.
Role of chemo for treatment = unknown
What was the overall clinical benefit for cats treated with TOC for MCT (various locations) (Berger JFMS 2017)
80%
86% cutaneous
80% visceral
76% GI involvement
Median duration of treatment for cats with clinical benefit from TOC for MCT? (Berger JFMS 2017)
36wks for cutanoues, 48 for visceral and 23 for GI
What was the median dose/schedule for cats treated with TOC for MCT? (Berger JFMS 2017)
2.5mg/kg PO 3 days/wk
What was the rate of AEs for cats treated with TOC for MCT? (Berger JFMS 2017)
60% rate of AE, jaority low-grade GI or heme
What was the rate of KIT expression for feline intestinal MCT? (Sabattini JFMS 2016
overall 12/17 70.5%
membranous (33%), focal paranuclear (33%), diffuse cytoplasmic (13%)
What KIT staining pattern was associated with less differentiated intestinal MCT in cats? (Sabattini JFMS 2016)
Diffuse cytoplasmic
What breed of cats is overrepresented for feline cMCT? (Melville FJMS 2015)
Siamese, Burmese, Russian Blue, Ragdoll
What was the most common location for cMCT in young vs. older cats? (Melville JFMS 2015)
Young: head
Older: trunk
What was or was not associated with survival time in cats with cMCT? (Melville JFMS 2015)?
Was associated: MI
Was not associated: number of tumors
What percent of cats died from cMCT? (Melville FJMS 2015)
17.4%
What was the overall MST for cats treated with splenectomy for splenic MCT? (Kraus JAAHA 2015)
390d.
What were negative prognostic factors for cats undergoing splenectomy for splenic MCT? (Kraus JAAHA 2015)
Admin of blood product, mets to regional LN, concurrent or historic neoplasia
What was associated with improved survival time for cats treated with splenectomy for splenic MCT? (Kraus JAAHA 2015)
Response to chemo
What was the dose of CCNU given to cats for treatment of MCT? (Rassnick JAVMA 2008)
50-60mg/m2
What was the ORR and median response duration to CCNU for feline MCT? (Rassnick JAVMA 2008)
ORR 50%, median duration 168d
What were the primary toxicities associated with CCNU given to cats with MCT? (Rassnick 2008(
Neutropenia and thrombocytopenia
What were the predominant staining patterns for feline MCT (Rodriguez-Carino VetPath 2009)
diffuse cytoplasmic (8/19) and membranous (7/19)
Atypical feline MCT typically have which KIT pattern? (Rodriguez0Carubi Vet Path 2009)
diffuse cytoplasmic
What was the rate of metastasis (and hwere was it) for felline intestinal sclerosing MCT (Halsey, VCO 2010)
66%, LN and hepatic
What was the outcome for feline intestinal sclerosis MCT? (Halsey VCO 2010)
23/25 died/euth w/in 2 mo
What four TKIs were tested in felline MCT with systemic mastocytosis with what exon internal tandem duplication? (Hadzijusufovic Vet Immuno/Immunopath 2009)
imatinib, midostaurin, nilotinib, and dasatinib
Exon 8
What were the results of the 4 TKI’s tested on feline MCT in vitro? (Hadzijusufovic Vet Immuno and immunopath 2009)
All four showed dose-dependent growth inhibition, growth inhibition associated with morph signs of apoptosis
What was the rate of metastasis for oral mucosal MCT in dogs? (Elliot VCO 2016)
55% at time of diagnosis
What was prognostic for dogs with oral mucosal MCT (Elliot VCO 2016)
Nodal mets (w/ = MST 276d vs. not reach if not)
MI >5 MST 120 vs. not reached if <5
Inadequate local control (OST 242 vs. not reached)
**site not prognostic - lip, gingiva, other**
Dogs with high grade/grade II MCT did better with vinblastine/pred compared to ______? (Miller VCO 2014)
Masitinib (369d) vs. vbl/pred 1946d
What was associated with outcome for dogs with MCT on the pinna that were treated surgically? (Schwab JAAHA 2014)
Grade - MST grade 1-2 not reached
MST of grade3 = 10mo
What was the affect of LN mets on dogs with grade 2 MCT treated with surgery to remove the primary tumor +/- LN? (baginski JAAHA 2014)
No difference in survival time, but dogs that had metastatic LN removed did to better than those that did not
What was the MST for high-risk MCT treated with adjuvant vbl/pred? (Thamm 2006)
Grade II MST not reached
Grade III MST 1374d
In canine MCT, a Ki67 index cutoff value of ____ was correlated with aggressive behavior
> 1.8% = more likely to be aggressive (lower 1- 2- and 3-yr survivals)
What prognostic factors are associated with SQ MCT? (Thompson Vet Path 2011)
MI >4 strongly predictive of mortality
others - infiltrative growth pattern, presence of multinucleation
What was the MST for SQ MST with an MI > 4 + other poor prognostic factors (infiltrative growth, multinuc) vs. those with an MI >4 w/o other poor prognostic factors (Thompson vet path 2011)
W/ other poor = mst 140d
w/o = mst 950d
What KIT and IHC proliferation indicies were associated with tumor regrowth or metastasis for canine SQ MCT? (Thompson Vet Path 2011)
Recur: AgNOR >2.71
Recur or met: MI >4, Ki67 >21.8 Ag67 (AgNOR x Ki67) > 55, cytoplasmic kit localization
Increased ____ and ____ were significantly associated with decreased survival and increased local mets for canine SQ MCT (Webster Vet Path 2007)
Ki67 > 23
Ag67 (AgNOR x Ki67) >54
SQ MCT with aberrant KIT localization or c-kit mutations were associated with ____ (Webster Vet Path 2007)
increased cellular proliferation
What was the MST for dogs with multiple cutaneous MCTs (Mullins JAVMA 2006)
MST not reached
2-5yr survival 85%
What was the rate of metastasis for dogs with multiple cutaneous MCTs (Mullins JAVMA 2006)
15%
What was prognostic for DFI in dogs with multiple cutaneous MCTs? (Mullins JAVMA 2006)
Clinical signs at time of dx
What factors were prognostic for DFI and OS in dogs with MCT treated with VBL/pred (Webster BMC 2008)
Grade 3, c-kit mutation, increased cytoplasmic KIT, increased Ki67 and AgNOR
Bcl-2 expression was higher in what grade MCT and was associated with what? (Vascellari Vet Path 2013)
Higher in grade 2 than 1 (but not different in high vs. low)
increased Bcl-2 associated with increased mortality
____% of cutaneous MCT were positive for IHC for PGE2 and VEGF and ____ grade MCT had higher PGE2 than grade ______. (Amorim VCO 2010
100% expressed both; grade II and III had higher PGE2 than grade I
A mitotic index of ____ was found to be prognostic in 148 dogs with cutaneous MCT (Romansik Vet Path 2007)
<5 MST 70mo
>5 MST 2mo
What was the PFS and OST for dogs with grade 3 MCT (Hume JAAHA 2011)
PFS 133d, OS 257
Mix of treatments (21/32 had adequate local control)
What was prognostic for PFS and MST for dogs with grade 3 MCT treated with a variety of treaments (Hume JAAHA 2011)
PFS: tumor size (>3cm), LN status
MST: treatment of LN mets (240d. vs 89d)
What was the overall rate of recurrence and rate of developing a new MCT for dogs with incompletely excised grade 2 cMCT? (Seguin JVIM 2006)
Recurrence 23.3%
39.3% developed another MCT
Dogs presenting with metastatic disease from MCT benefited from what treatment? (Miller VCO 2016)
surgery to remove the pimary + chemo - MST 278d vs. 91d w/o surgery
Which KIT staining pattern was associated with local MCT recurrence and shorter survival? (Kupel Vet Path 2004)
Diffuse cytoplasmic
Tumor suppressor in lung cancer 1 (TSLC1) had what relationship with Ki67 and tumor grade for MCTs? (Taylor VCO 2010)
TSLC1 inversely correlated with tumor grade and Ki67
Lower TSLC1 in intermediate MCT = more likely to die from MCT related disease
What signalment dog had increased overall risk of developing MCT? (White, JAAHA 2011)
Spayed females (OR 4.11)
Boxers (6.09)
Large (2.1) and giant (5.44) breeds
For dogs with MCT on the head treated with RT, where was the highs grade toxicity? (Blackwood VCO 2018)
Mucosa or nasal planum
What was associated with an increased frequency of grade 2 or 3 RT toxicityf at 1st recheck for dogs treated with RT for MCT? (Blackwood 2018)
increased frequency in patients using prednisolone prior to RT
What was the RT/Palladia protocol for hypofx RT + TOC for gross MCT in dogs? (Carlsten JVIM 2012)
Toc 1 week prior to RT
RT 24Gy in 3-4fx
What was th ORR for dogs treated with hypofx RT + TOC for gross disease MCT? (Carlsten JVIM 2012)
ORR 76.4%
CR 58.8%
PR 17.6%
**higher response rate than Palladia as single agent**
What was the median time to best response for dogs treated with hypofx RT + TOC for gross disease MCT (JVIM 2012 Carlsten)
32d
What was the median PFI and MST for dogs with gross disease MCT treated with hypofx RT + TOC? (Carlsten JVIM 2012)
mPFI 316d, MST not reached
What was the rate of tumor recurrence for incompletely excised grade II MCT treated with cobalt RT? What effect did prophylactic nodal irradiation have? (Poirier JAAHA 2006)
Rate of recurrence 6.7%
No difference in mets when dogs had or didn’t have prophy. RT to LN
What was the clinical benefit to treatment with diphenhydramine in dogs undergoing excision of MCT? (Sanchez JAVMA 2017)
None found - histamine higher during max tumor manipulation and surgery prep in diphenhydramine group; higher in control for surgical dissection
How did histological margins compare to surgical margins measured in dogs with MCT? (Risselada JAVMA 2015)
histo 35-42% smaller than lateral surgical margins
BCS did not influence this
Did a low AgNOR and Ki67 score for grade II MCT surgically removed influence rate of recurrence? (Smith VCO 2015)
Sort of - only 7% rate of recurrence for dogs, no difference in complete vs. incomplete margins
Authors conclusion - second surgery may not be necessary for incomplete sx in grade II MCT with low Ki67/AgNOR scores
What was the MST for dogs with incompletely exicsed MCT treated with a second surgery vs. RT vs. no additional therapy? (Kry Vet Surg 2014)
Recut: 2930d
RT 2194d
No additional therapy: 710d (significantly shorter)
T/F: adjunctive chemo was associated with improved survival or local control in dogs with narrow or incompletely excised MCT (Kry Vet Surg 2014)
False - no benefit found
No MCT recurrence of mets after surgery were found for dogs with what histologic margins (for any grade MCT) (Schultheiss JAVMA 2011)
Lateral margins >10mm, deep margins >4mm
What was the rate of achieving histo clean margins for dogs having MCT (SQ or dermal) removed with modified proportional margins? How many had local recurrence? (Pratschke JAVMA 2013)
85% complete, 15% incomplete
Local recurrence suspected in 1 dog (2%)
What was the rate of complete excision and local recurrence for dogs with grade 1 or 2 MCT treated with 2cm lateral and 1 fascial plane deep margins? (Fulcher JAVMA 2006)
91% completely excised, no local recurrence
What was the response rate to neoadjuvant pred prior to surger for MCT? What was the difference between dosing strategies for pred? (Stanclift JAVMA 2008)
70% response rate
No difference in size reduction b/w 1mg/kg and 2.2mg/kg
What is tigilanol tiglate and how does it work (Miller Frontiers in Vet Science 2019)
Novel diterpene ester from Fontainea picrosperma seed
Modifies cell signaling processes and induces rapid hemorrhagic necrosis and activates protein kinase C
Mainly targets tumor vasculature
What was found to be the best dosing for tiglanol tiglate in dogs with MCT (Miller Frontiers in Vet Science 2019)
Highest concentration used (1mg/ml) - 90% CT, majority AEs grade 1 (80%), rest grade II
