Chapter 20 - Mast Cell Tumors Flashcards
1
Q
What is the most common cutaneous tumor in dogs and second most common in cats?
A
MCT
BCT is the most common cutaneous tumor in cats
2
Q
Where are mast cells produced,from what lineage do they originate, and where do they mature?
A
Bone marrow, myeloid lineage, leave BM as immature MC and mature/differentiate at tissues
3
Q
MC differentiation (BMDMC) is dependent on what growth factor?
A
SCF
Essential for differentiation of CD34+ hematopoietic stem cells into mast cells
4
Q
What bioactive substances are present in MC granules? What can influence this?
A
Vasoactive substances: Heparin, histamine
Proteases:tryptase, chymase
CK: TNFa, IL-6
Chemokines: CCL2, CXCL1
Growth factors: VEGF, bFGF
Lipid mediators: Prostaglandin D2, leukotriene 4
Dependent on environment
5
Q
What proteases are preferentiallypresent in MC granules of the GI tract vs skin?
A
Skin: both chymase and tryptase
GI: mainly chymase
6
Q
What chemotherapy drug can cause MC degranulation?
A
Doxorubicin
7
Q
What stains can be used for staining cytoplasmic granules of mast cells when they are not identified with routine stains on both cytology and histopathology?
A
Gimesia or Wright (Romanowsky stains) and toulidine blue.
8
Q
What immunohistochemical markers can be used for mast cells?
Flow cytometry?
A
Positive for vimentin, tryptase and CD117 (KIT)
Other markers: chymase, MCP-1, IL-8
Flow cytometry:
100% CD117+, CD45+, CD44+
82.4% IgE+
Also CD11b+, CD18+, CD34-, CD25-
9
Q
Name normal important biologic functions of mast cells (4)
A
Innate system responses
Antiparasite activity
Reactions to insect and spider venoms
Wound healing
10
Q
Mast cells in dogs exhibithigh degree of sensitivity to which 3 chemical substances?
A
Polysorbate 80
Cremophor EL
Doxorubicin
11
Q
CBMMC can be modulated by what 3 things?
A
Cytokines
Steroids
NSAIDs
12
Q
MCT in dogs account for ___% to ___% of all cutaneous tumors.
A
16 to 21%
13
Q
Spontaneously regressing MCT have been described in which spp (4)?
A
Cats, pigs, horses, humans
14
Q
What is the most common signalment indogs with MCT?
Although most tumors occur in ____ breed dogs, what breeds are at increased risk for MCTs? Lots!
In the predisposed breeds, are they usually benign or malignant? What breed is the exception to this rule?
A
Older dogs; mean age of8 to 9 years
Mix breed dogs
Increased risk breeds: Brachycephalic breeds, Labradors, Goldens, Cocker Spaniels, Schnauzers, Staffies, Beagles, Rhodesians, Weimaraners, Shar Peis
Behave in a more benign fashion except in Shar Peis, in which they behave aggressively
15
Q
High risk of high grade tumor development was recently reported in dogs with which characteristics (3)?
The risk of MCT development was reported to be highest in what 2 breeds in descending order?
What was the relative risk in these breeds?
A
1 Parson Russel Terrier - RR 15
Older, intact, male dogs
16
Q
What breeds (2)of dogs are reported to develop low grade tumors?
What breeds (2) of dogs have a 2-3 fold increased risk of developing high grade tumors?
A
Pugs and Boxers
Rottweilers and Shih-tzus
17
Q
“Environmental” risk factors for MCT development (2)?
A
Chronic inflammation
Skin irritants
18
Q
Altered expression of which CDKIs have been identified in dogs with MCT (2)?
A
p21 and p27 (upregulation)
19
Q
What chromosomal copy number variations in dogs with MCT have been associated with a shorter ST (7)?
A
Loss of PTEN and FAS
Gains in MAPK3, WNT5B, FGF, FOXM1, RAD51
20
Q
A recent study identified that dogs with MCT have higher ___ and lower ___ when compared to healthy controls.
A
Higher ROS Lower BAP (biological antioxidant potential)
21
Q
What genetic alteration or epigenetic modification has been described in grade 3 canine MCTs?
A
Global hypomethylation
22
Q
What is c-kit?
A
c-kit is a gene that codes for the tyrosine kinase receptor, KIT
23
Q
On what cellsis the KIT receptor normally expressed?
Activation of this receptor by SCF induces what changes in the cell (physiologic and molecular) (4)?
Inhibition of KIT receptor results in what?
A
Hematopoietic stem cells, mast cells, melanocytes
- Differentiation of CD34+ hematopoietic stem cells into mast cells
- Kit dimerization
- Subsequent phosphorylation
- Generation of IC signaling cascadesthat promoteproliferation, differentiation, and maturation of normal mast cells
Inhibition results cBMMC apoptosis
24
Q
Mutations inthe c-kit gene are found in which exons of dogs with MCT?
Mutations inthis gene results in what?
C-kit gene mutations are reportedly present in ___% to ___% of intermediate and high grade MCT.
A
Extracellular domain: exons 8 and 9
Transmembrane domain: exon 10
Juxtamembrane domain; exons 11 and 12
SCF ligand-independent activation of KIT and loss of negative KIT regulation -> unregulated/constitutively activated KIT signal transduction
25 to 30%
25
Mutations in the c-kit gene are linked to what 3 negative clinical behaviors of MCT in dogs?
Increased risk recurrence
Increased risk for metastasis
Worse prognosis
26
Approximately ___ to ___% of dogs with MCT present with multiple tumors.
11 to 14%
27
Approximately ___% of cutaneous MCT occur on the trunk and perineal region, ___% on the limbs, and ___% on the head and neck.
50% on trunk and perineal region
40% on the limbs
10% on head and neck
28
A case series of dogs with primary GI MCT reported that ___% were alive ___ month after first hospital admission, and < ___% were alive ___ months post diagnosis.
What are the most common CS in dogs with primary GI MCT (3)?
40% alive 1m post first hospital admission
<10% alive at 6 months post diagnosis
Vomiting, diarrhea, melena
29
In dogs, a visceral form of MCT, often referred to as disseminated or systemic mastocytosis, has been documented.
This form of dz is usually preceded by what?
MCT effacement of what organs is commonly observed with this form of dz?
An aggressive primary lesion elsewhere
Abdominal LN, spleen, liver, bone marrow
Pleural and peritoneal neoplastic effusions have been documented
30
Undifferentiated canine cutaneous MCT, as opposed to differentiated MCT, can have what gross physical and clinical characteristics (4)?
What is their metastatic rate (range)?
Rapid growth
Ulceration
Cause considerable irritation
Can attain a large size
55-96%
31
A SQ form of MCT that is soft and fleshy is often diagnosed as what type of tumor?
Lipoma
32
Describe the phenomenom known as Darier's sign
Degranulation, erythema, and wheal formation in the tissue surrounding the MCT
Occurs after manipulation and degranulation
33
GI ulceration has been documented in ___% to ___% of dogs with MCT that undergo necropsy.
35 to 80%
34
On what receptor does histamine act? What does this result in?
H2 receptors on parietal cells -> increased HCl secretion and decreased gastrin secretion as a result of negative feedback
35
Measurement of plasma concentrations of what substance are reportedly high in dogs with MCT and may be useful in assessing disease progression?
Histamine
36
Dogs with MCT and high plasma histamine concentrations have decreased concentrations of what substance?
Gastrin
37
What clinical signs can be seen in patients due to MCT degranulation/aggressive dz?
Vomiting, diarrhea, fever, peripheral edema, collapse
38
What prostaglandin is most likely responsible for hypotension in dogs with MCT?
PGD2
39
What 14 prognostic factors have been identified in dogs with MCT?
```
Grade
Stage
Location
Cell proliferation rate
Growth rate
DNA ploidy
Microvessel density
Recurrence
Systemic signs
Age
Breed
Sex
Tumor size
c-kit mutation
```
40
How does grade affect prognosis?
Dogs with undifferentiated or high grade tumors typically die of their disease following local therapy alone, whereas those with well-differentiated tumors are usually cured with appropriate local therapy.
This is the MOST CONSISTENT AND RELIABLE prognostic factor
41
How does stage affect prognosis?
Stages 0 and 1, confined to the skin, without local LN or distant mets, have a better prognosis than higher-stage disease
42
What locations are associated with the likelihood of high-grade tumors and worse prognosis (3)?
What locations are associated with a grave prognosis (2)?
Better prognosis?
High-grade: Subungual (nailbed), oral, and other mucous membrane sites (oral cavity and perineum/perineal area)
Scrotal, preputial, inguinal - worse prognosis
Visceral or bone marrow - grave prognosis
SQ tumors - better prognosis; extended ST and low recurrence and metastatic rates
43
What are some factors used to evaluate cell proliferation in MCT?
How does cell proliferation rate affects prognosis?
MI
Relative frequency of AgNORs
% of PCNA
% Ki67 immunopositivity
Predictive of post surgical outcome
44
How does DNA ploidy affect prognosis (2)?
Aneuploid tumors -> higher stage dz and shorter MST
45
How does microvessel density affect survival? With what is increased MVD associated (3)?
Higher grade, higher degree of invasiveness, and worse prognosis
46
How does local recurrence post surgery affect prognosis?
Dogs may carry a more guarded prognosis
47
How does systemic clinical signs affect prognosis?
What are some clinical signs?
Clinical signs are most commonly associated with what location?
The presence of systemic illness may be associated with higher-stage dz
Vomiting, diarrhea, melena, widespread erythema, edema
Release of vasoactive substancesVisceral location
48
How does age affect prognosis?
Older dogs may have shorter median DFI when treated with RT than younger dogs
49
How does breed affect prognosis?
Boxers and other brachycephalic breeds tend to have low to intermediate grade MCT and a better prognosis
50
How does sex affect prognosis?
Male dogs have a shorter ST vs female dogs when treated with chemotherapy
51
How does growth rate affect prognosis?
Tumors present for a significant period of time (months to years) w/o significant changes are usually benign vs the opposite
52
How does tumor size affect prognosis?
Large tumors may be associated with a worse prognosis following surgical removal and/or RT
53
How does a c-kit mutation affect prognosis (3)?
The presence is associated with a worse prognosis; higher rate of local recurrence, metastasis, and death from dz
54
What is the most consistent and reliable factor for prognosis in dogs with MCT?
Histologic grade
55
Overall, ___% to ___% of dogs with well-differentiated (low-grade) tumors and ___% of dogs with intermediate grade tumors experience long-term survival following complete surgical excision.
80 to 90% of low grade
75% of intermediate
56
Overall, the metastatic rates for undifferentiated (high-grade) tumors ranges from ___ to ___%. Most of these dogs die within ___ year.
Undifferentiated tumor met rate: 55 to 96%
1 year
57
In what order do MCT usually metastasize?
Regional lymph nodes, spleen, liver
58
Use word document to review following charts: Relative frequency of canine MCT by histologic grade. ST of dogs with sx-treated MCT according to histologic grade
-
59
Describe the Patnaik grading system
Grade I - confined to superficial dermis, round and monomorphic cells arranged in rows or small groups, distinct cytoplasms and medium-sized granules, condensed chromatin, absent nucleoli, absent to minimal edema/necrosis, 0 mitotic figures/HPF
Grade II - infiltrate lower dermal, SQ tissues, or muscle, round to ovoid moderately pleomorphic cells arranged in groups with thin fibrovascular stroma, moderate to highly cellular, most have distinct cytoplasm with fine granules, but some may be indistinct and have large granules, indented nucleus, 1 nucleolus, some double nuclei, areas of diffuse edema/necrosis, rare MI 0-2/HPF
Grade III - replace SQ and deep tissues, round, ovoid, or spindle shaped pleomorphic cells that have indistinct cytoplasm granules, common bizarre and multinucleated cells, indented to round nucleus with 1 or > prominent nucleoli, arranged in closely packed sheets, common edema, hemorrhage, and necrosis, MI >2/HPF
60
Describe the two-tier Kiupel grading system
High grade:
7 or > mitoses/10hpf
3 or > mutinucleated (3 or > nuclei) cells/10hpf
3 or > bizarre nuclei/10hpf
Karyomegaly where at least 10% of cells vary by 2-fold
61
According to Patnaik studies, what % of dogs have low, intermediate, and high grade MCT?
Low grade 36%
Intermediate 43%
High grade 20%
MST not reached in these studies
62
Overall, what % of dogs with grade I, II, and III are reported to be alive 1 and 4 years post-surgical resection?
1 year post:
Grade I - 100% alive
Grade II - 92% alive
Grade III - 46% alive
4 years post:
Grade I - 93%
Grade II - 44%
Grade III - 6%
63
When using the Patnaik grading system, what % of dogs with low grade (grade I and II) tumors die from their disease due to inaccurate grading?
15 to 30%
64
In a series of 95 dogs evaluated by both the Patnaik and Kiupel grading systems, which system was better at predicting dogs that would die of their disease?
Although the gold standard has historically been the Patnaik system, the Kiupel system was better in this study
65
What is Ki67 and how has it been associated with MCT behavior (3)?
Nuclear protein that accurately correlates with cell proliferation.
Ki67 has been associated with grade and survival time
- Higher score in dogs that die from their dz vs those that survive
- Grade II tumors with a higher score have a shorter ST
- Difference in Ki67 score depending on grade
66
When evaluating the relationship between proliferation indices and grade II canine MCT using the Patnaik system, how has Ki67 been associated with ST (3)?
Ki67 of >1.8 = shorter ST and an estimated MST of 395d vs <1.8 = longer ST, MST not estimable
≥ 93 Ki67 positive nuclei/1,000 tumor cells more likely to die form their disease
Ki67 of >0.01 associated with higher risk of death
67
What histologic stain can be used to determine the presence of argyrophilic nucleolar organizing regions (AgNORs)?
Silver colloid
68
In a study of dogs with cutaneous MCTs, ___ was more predictive of biologic behavior and post-surgical prognosis when compared to histologic grade.
No dogs with an AgNOR score of less than ___ died from tumor related causes.
AgNOR score
<1.7
69
What proliferation marker is the least reliable? Most reliable?
PCNA (proliferating cell nuclear antigen) - estimates proliferating fraction of cells in S phase
AgNOR - reflects proliferative capacity and speed; most reliable but hard to standardize
70
What is the only marker of proliferation that does not require special stains?
Mitotic index (number of mitosis/10 HPF); uses hematoxylin and eosin
71
Define mitotic index
Number of mitotic figures/10 HPF
72
A mitotic index of 5 has been used as a prognostic cut-off for Patnaik graded tumors.
Regardless of grade, what is the MST of dogs with MCT that have a MI of ≤5 vs those with a MI of >?
What is the MST of dogs with grade III MCT that have a MI of ≤5 vs those with a MI of >5?
Overall:
MI of ≤5 MST of 70 months
MI of >5 MST of 2 months
Grade III:
MI of ≤5 MST not reached
MI of >5 MST <2m
73
A study evaluating DNA ploidy using flow cytometry in dogs with MCT suggested what trends (2)?
Aneuploid tumors - shorter survival time and higher clinical stage vs diploid tumors
74
What KIT receptor staining patterns have been associated with a more negative prognosis?
- Diffuse cytoplasmic
- Focal perinuclear to stippled cytoplasmic w/dec membrane staining
Associated with increased recurrence and shorter ST
75
What negative prognostic factors have have been identified in dogs with c-kit gene mutations (3)?
Increased rate of local recurrence, metastasis, and death from dz
76
Studies have attempted to evaluate correlations between histologic grade and Ki67, PCNA, AgNOR, and c-kit immunohistochemical scoring. What significant correlations were demonstrated?
High Ki67, PCNA, AgNOR scores all positively correlated with tumor grade
No significant correlation for c-kit scoring and grade
77
Approximately ___ to ___% of dogs with MCT in the muzzle present with regional LN metastasis.
What is the MST of dogs with muzzle MCT that receive therapy and of those with regional LN metastasis?
What therapy modality may improve survival in these dogs? DFI?
What are 2 identified independent factors for survival?
50 to 60%
MST 30 months; if LN mets 14 months
Cytoreductive sx for primary tumor and RT to tumor and LN beds; DFI in these 1240d
Tumor grade - grade II lived longer than grade III
Presence of metastasis - 7.7x increased risk of death
78
The prognosis in dogs with SQ MCT is favorable.
What is the metastatic rate, recurrence rate, and negative prognostic indicators in dogs with SQ MCT?
What are the 2 and 5 year survival probabilities?
Met rate 4%
Recurrence rate 8%
2-yr survival probability 92%
5-yr survival probability 86%
Dec survival associated with a MI >4, infiltrative growth pattern, presence of multinucleation
79
Conjunctival MCT have a ___ prognosis. A study of 32 dogs showed that ___% were disease free at a median of ___ months post surgery. How many dogs died of MCT dz?
Good prognosis
47% dz free at 21.4m (~2yrs) post sx
No dogs died of MCT dz
80
Describe the older MCT staging system
0 - one tumor incompletely excised from the dermis w/o LN involvement
I - one tumor confined to the dermis w/o regional LN mets
II - one tumor confined to the dermis w/regional LN mets
III - multiple dermal tumors; large or infiltrating tumors, with or w/o regiona; LN mets
IV - any tumor with distant mets
These can be subclassified as 1. w/o systemic clinical signs or as 2. w/systemic clinical signss
81
What is the effect of LN mets on prognosis in dogs with MCT? On what does it depend?
Not clearly established. Can do well with therapy. Depends on the grade of the tumor and tx; if intermediate, good prognosis, if high grade, poor prognosis.
In one study, LN was mets negative prognostic factor for survival and DFI.
Another study - intermediate grade tumors w/LN mets tx with cytoreductive sx and RT to tumor site and LN achieved long-term survival.
Another study - intermediate grade tumors with LN mets tx with sx and chemo may have good prognosis.
82
What was the DFI in a study of dogs with grade II MCT and regional LN mets that were treated with cytoreductive sx of the primary tumor and RT of tumor site and LN involved?
Median DFI - 1,240 days (3.3 yrs)
83
What is the MST in dogs with visceral MCT? Metastatic sites to which locations negatively affect survival?
90 days
Liver, spleen; MST 30d
84
What gross tumor characteristics have been associated with a worse prognosis?
Tumor ulceration, eruthema, pruritus
85
Prior to surgical excision of a MCT, what staging tests are warranted?
Depends on whether it is amenable to surgical excision or not and if NPI are identified on PE.
If amenable and no negative prognostic indicators present, nothing else besides regional LN cytology is needed.
If negative prognostic indicators present or tumor not amenable to wide surgical excision, abdominal ultrasound +/- liver and spleen asp
86
In a study of 56 healthy beagles, what % of LN aspirates contained mast cells?
What was the mean number of mast cells per slide?
What cytologic feature may be concerning for metastasis?
24%
6.4 cells/slide
Usually single; clustering and aggregates more worrisome
87
When staging dogs with cutaneous MCT or STS, the extent of local invasion can be upgraded in ___% of the cases when using US and ___% when using CT.
19% with US
65% with CT
88
How many mast cells in the buffy coat is consistent with systemic mastocytosis?
Peripheral mastocytosis can be seen with which conditions?
1-90 mast cells/uL
They SHOULD NOT be in circulation in a normal dog
Can be seen with acute inflammatory dz, especially parvo, inflammatory skin dz, regenerative anemia, neoplasia other than MCT, trauma
Because of this, no longer a part of staging exams
89
In dogs with MCT, the incidence of BM infiltration at presentation ranges from ___ to ___%.
Overall reported BM infiltration is ___%.
At presentation 3 to 20%
Overall 4.5%
90
In dogs with visceral MCT, the buffy coat has mast cells in ___% of the cases and in BM aspirates, ___% of the cases.
40% - buffy coat
| 60% - bone marrow
91
What surgical margins are ideal to obtain in dogs with cutaneous MCT?
3 cm lateral margins 1 fascial plane deep - historical and recommended for high grade tumors
1-2cm lateral margins may be sufficient in small and low grade tumors
Modified proportional margins approach: lateral margins equal to the widest diameter of the tumor and 1 fascial plane deep
92
What is the overall recurrence of incompletely excised MCT post surgery?
20 to 30%
93
After excision or fixing a tumor with formalin, margins can shrink up to what % of cases (range)?
17 to 30%
94
What is recommended prior to surgery for tumors that are not amenable to wide surgical resection, such as distal extremities?
Biopsy to determine how best tx needed
95
When RT is used as primary therapy in dogs wtih MCT, doses between 40 to 50Gy result in 1-year control rates of approximately ___%
50%
96
Best therapy combo to achieve local control for dogs with MCT that are not amenable to wide surgical resection? Second option?
Surgery and RT #1
Surgery and chemo #2 - if RT not available or unaffordable
97
When surgery is combined with RT to achieve stage 0 disease in dogs with incompletely excised low to intermediate grade tumors, 2-year control rates of ___ to ___% can be achieved.
85 to 95%
98
What is the response rate of single agent prednisone in dogs with intermediate and high grade MCT?
ORR, CR, PR? Dose used?
Range of duration of response?
1mg/kg daily pred dose
ORR 20 to 75%
CR 4%
PR 16-60%
In 5 dogs: range 3 to 7.5m and 1 dog >28 mo
99
A recent study found that response to corticosteroids was dependent on what 5 things?
Expression of glucocorticoid receptor - low expression low response (and viceversa), and lower stage, grade, pattern of KIT expression and KI67
100
According to recent studies, are single-agent or multi-agent protocols better in dogs with measurable MCT?
What protocol has been shown to provide the best response?
ORR, CR, PR with this protocol?
Median response duration?
MST if CR vs PR?
For the most part, how is the response to bulky MCT when treated with chemo?
Multi agent CCNU/VBL
ORR 64%, CR 30%, PR 35%
Median response duration 7m
MST if CR 140d vs 66d if PR
Short-lived
101
What is the ORR in dogs with measurable MCT treated with vincristine?
ORR 7% (2 dogs had a PR)
102
What is the ORR, CR, PR, and median PFI (response duration) in dogs with measurable MCT treated with vinblastine?
MTD?
What % developed grade 4 neutropenia?
```
ORR 12 to 27%
PR 12 to 23%
CR 0 to 4%
Response duration: 20 to 80d
MTD 3.5 mg/m2
45% develop a grade 4 neutropenia
```
103
What is the ORR, CR, PR, and median response duration in dogs with measurable MCT treated with lomustine?
ORR 45%
CR 6%
PR 38%
Responde duration 80d
104
What is the ORR, CR, PR, and median PFI (response duration) in dogs with measurable MCT treated with prednisone and vinblastine?
MST when used post-operatively for high risk MCT? 1 and 2-year DFI?
```
Measurable dz:
ORR 50%
CR 33%
PR 13%
PFI 154d (5m)
```
```
Post operatively:
MST 1374 (~4yrs)
70% 1 and 2yr dz free intervals
```
105
What is the ORR, CR, PR, and median PFI (response duration) in dogs with measurable MCT treated with predinsone, cyclophosphamide, and vinblastine?
PFS and MST for high-risk MCT in the post-operative setting?
Gross dz: ORR 63%, CR 45%, PR 18%, PFI 74d
Post op setting: PFS 2.4yrs, MST >5.7yr
106
What is the ORR, CR, PR, and median PFI (response duration) in dogs with measurable MCT treated with COP-HU?
ORR 60%, CR 23%, PR 35%
| PFI 50d
107
What is the ORR, CR, PR, and median PFI (response duration) in dogs with measurable MCT treated with prednisone, vinblastine, and CCNU?
ORR 57-64%
CR 24-29%
PR 32-35%
PFI 3-7m
108
What is the PFI and MST in dogs with high-risk MCT when treated with prednisone, vinblastine, and CCNU in the post-operative setting (microscopic dz)?
PFI 9m
| MST 12m
109
What is the ORR, CR, PR, and median PFI (response duration) in dogs with measurable MCT treated with BCC/hCG? (Bacillus Calmette-Guerin/human chorionic gonadotropin)
ORR 30%, CR 15%, PR 15%
| PFI not reached
110
What is the ORR, CR, PR, and median PFI (response duration) in dogs with measurable MCT treated with calcitriol?
ORR 40%
CR 10%
PR 30%
PFI 74-90d
111
What is the ORR, CR, PR, and median PFI (response duration) in dogs with measurable MCT treated with hydroxyurea?
ORR 28%, CR 4%, PR 24%
| PFI 46d for PR
112
What is the ORR, CR, PR, and median PFI (response duration) in dogs with measurable MCT treated with prednisone and chlorambucil?
```
ORR 38%, CR 14%, PR 24%
PFI 533d (18m)
```
113
What 2 veterinary TKI's have been approved by the FDA?Limited studies have been performed with which human TKI?
Toceranib (Palladia) and masitinib (Kinavet)
Imatinib (Gleevec)
114
A multicenter, placebo-controlled, double-blind, randomized study was performed in 145 dogs with recurrent or metastatic intermediate or high-grade MCT treated with Palladia (SU11654).
What was the ORR, CR, PR, median duration of response, and median time to tumor progression?
Including dogs with SD, what was the overall biologic activity?
Most common AE?
```
ORR 43%, OBA: 60%
CR 15%
PR 28%
Median duration of response 3m
Median time to tumor progression 4.5m
GI upset
```
115
In the previously mentioned study, ___% of dogs with c-kit mutation vs ___ % of dogs without it responded to Palladia.
70% of dogs with mutation
| 37% of dogs without it
116
What is the labeled Palladia dose?
Equivalent antitumor activity and decreased AE can been seen with what dose?
Minimum dose Palladia recommends?
3. 25mg/kg PO EOD
2. 5 to 2.75 PO EOD or MWF
Min 2.2mg/kg
117
A double-blind, randomized, placebo-controlled, phase III clinical trial of dogs with nonmetastatic, recurrent or nonresectable, grade II or III MCT treated with masitinib was performed.
Population: Combination of tx naive and previously treated dogs.
What was the overall TTP?
TTP when used as a first-line therapy? In dogs harboring KIT mutation vs in those w/o mutation?
Overall TTP 120 d (4mo)
TTP in tx naive 250 d (8.4mo)
TTP in tx naive w/mutation NR (better than w/o mutation)
TTP in tx naive w/o mutation 250d (8.4m)
*Other studies show response does not depend on mutation status*
118
What is the 12 and 24 month survival rates in dogs with non-resectable or recurrent, non-metastatic, grade II or III MCT, when treated with masitinib?
CR at 24 months were present in ___% of dogs.
MST for masitinib treated dogs? Significant when compared to placebo?
What association was made in this study?
This was a placebo-controlled study as well.
1-yr 60% alive
2-yr 40% alive
10%
MST 620d (not statistically significant from placebo dogs)
Good control at 6m had a high PPV for control at 2 years, with a sensitivity of 76% and specificity of 88%.
119
Masitinib in dogs with MCT that are grade II-III, measurable, metastatic and non-metastatic MCT, treatment naive and as a rescue agent.
What is the ORR? CR and PR?
MST for responders vs non-responders?
Most important prognostic factor for survival?
Median time to maximal tumor response?
This is 2 studies that report response rates combined*
ORR 50 to 80%
CR 40%, PR 43%
MST in responders 160- 630d vs 140d in non-responders
Response to therapy
Median time to max tumor response 1m
Median time to progression 80d, longer for px with a CR
120
What is the labeled dose for masitinib?
Approved for treatment of what type of MCT?
12.5mg/kg PO SID
Labeled for gross, non-metastatic, grade II or III MCT
121
In a study of 21 dogs with measurable MCT treated with imatinib, what was the ORR? Responses were seen within what period of time?
50%
| 2 weeks
122
Are there any PK studies of imatinib in vet med?
No, so there is not an establised dose
123
A phase I clinical trial evaluated the use of combined VBL and Palladia for dogs with measurable MCT.
What was the maximum tolerated dose of VBL? This resulted in a VBL dose intensity reduction of ___%.
What was the dose limiting toxicity? What was the protocol used?
Objective/biologic response rate?
1.6mg/m2; VBL reduced by 50%
Additive myelosuppression, neutropenia; due to overlapping dose limiting toxicities
VBL every other week + Palladia every other day
70%
124
Tx of non-resectable or measurable MCT with prednisone, Palladia, and hypofractionated RT has been evaluated in dogs.
What is the ORR, CR, PR, PFI, and MST? PFI was significantly shorter in what dogs?
What was the median time to best response?
1-year ST and dz free survival?
What % required a drug holiday, dose reductions, and developed RT SE?
ORR 76.4%, CR 58.8%, PR 17.6% on an intent to tx basis
PFI 316 days; significantly shorter dogs with c-kit mutation (188d)
Median time to best response 30 days
MST not reached with a median follow up time of 374d
70% 1-yr ST and 45% dz free at 1-yr
Holiday 87%
Reduction 53%
RT SE 50% grade I acute effects; no grade 2 or 3
Toceranib was administered for 1 week before initiating RT. RT consisted of 24 Gy delivered once weekly in 3 to 4 fractions.
125
What antacid may be more effective in dogs with bulky MCT?
Omperazole
126
What are the 3 syndromes in which MCTs occur in cats?
Cutaneous
Splenic/visceral
Intestinal
127
What % of cats with cutaneous and splenic/visceral MCT have c-kit mutations?
___% are located in exon ___ and ___% are located in exon ___.
Both mutated exons encode which domain of KIT receptor?
Do KIT mutations appear to affect prognosis in cats with MCT? MST
65 to 70%
Exon 8 - 45 to 75%
Exon 9 - 20 to 25%
5th immunoglobulin domain of KIT
Majority ITD and cytoplasmic ezpression
No; 780d (specifically splenic)
128
The granules in feline MCT stain blue with ___ and purple with ___.
Feline mast cells have phagocytic activity and can eat what type of cells?
Blue - Gimesia
Purple - toulidine blue
RBC
129
MCT represent the ___ most common cutaneous tumor in cats, accounting for approximately ___% of cutaneous tumors in this spp in the USA. In United Kingdom, they account for ___%
2nd
20% - USA
8% - United Kingdom
130
Approximately what % of cats have multiple MCT?
20%
131
Superficial ulceration is present in what % of cases?
How do they usually look?
25%
Raised, firm, well-circumscribed, hairless, often white. Occassionally can have a plaque-like appearance.
132
What are the two different histologic types of feline cutaneous MCT?
Which one is more common?
1. Mastocytic -> compact (well differentiated) and diffuse (anaplastic)
Compact/well differentiated: homogeneous cords and nests of slightly atypical mast cells with basophilic round nuclei, ample eosinophilic cytoplasm, and distict cell borders. Eosinophils are conspicuous in only 1/2 of cases.
Diffuse/anaplastic: less discrete, infiltrated into SQ, large nuclei (>50% cell diameter), 2-3 mitosis/hpf, marked anisocytosis, mononuclear and multinucleated giant cells, eosinophils more commonly observed
2. Histiocytic -> morphologic features of of histiocytic mast cells; sheets of histiocyte like cells with equivocal cytoplasmic granularity, accompanied by randomly scattered lymphoid aggregates and eosinophils, granules lacking in some reports, other reports granules readily demonstrable
Compact MCT most commonly seen; 50-90%
133
What histologic type of feline cutaneous MCT may regress on its own?
Over what period of time?
Histiocytic
Over 4m to 2yrs
134
Compact MCT represent ___ to ___% of all cases of cutaneous MCT in cats.
50 to 90%
135
What feline breed is predisposed to develop both types of cutaneous MCT?
What are other other predisposed breeds (3)?
Siamese
Other: Ragdoll, Russian Blue, Burmese
136
The histiocytic form of MCT primarily occurs in cats younger than what age?
<4 years
137
Although recent studies have failed to prove this, what sex has been documented to be at increased risk for MCT development?
Male sex
138
What form of mastocytic (cutaneous) MCT may be associated with a worse prognosis?
Diffuse/anaplastic
Well differentiated/compact tumors tend to behave in a benign fashion and metastasis is uncommon
139
What are the most common locations for cutaneous MCT in cats?
Head and neck
Followed by trunk, limbs, other
140
Where in the head do they commonly occur?
Pinnae near the base of the ear
141
How do histiocytic MCT typically present?
Multiple, nonpruritic, firm, hairless, pink and sometimes ulcerated
142
In cats with histiocytic MCT, mast cells on cytology may only comprise ___% of the cells present, with the majority of cells being sheets of ___ that lack cytoplasmioc granules.
20%
histiocytes
143
One study found that ___% of cats with multiple cutaneous mast cell tumors also had mast cell dz where else (2)?
7%
| Spleen and LN7
144
One study demonstrated that ___% of cats with MCT had mast cells on buffy coat examination. The majority of cats had what form of MCT?
43%
Splenic/visceral
145
Most cutaneous MCT behave in what fashion?
Benign
146
Feline MCT are positive for what IHC stains (3)?
vimentin, a-1 antitrypsin, KIT
147
Although the histologic grading system described for feline MCT has provided no prognostic information in several series and is not used, what is the most important histopathologic characteristic that may be related to a greater risk of local recurrence and metastasis, and is therefore considered the strongest prognostic indicator.?
High MI
148
What is the definitive treatment in cats with cutaneous MCT?
Surgery
149
What is the recurrence rate in cats with surgically excised cutaneous MCT?
0 to 25%
150
In a study of 23 cats with MCT of the eyelids, local tumor control with surgery alone was achieved in ___% of the cases.
The rest of the cats were treated with a combination of RT and cryotherapy.
The overall MST was ___ .
___% of cats developed metastasis to the ___.
83% adequate local control with sx alone
945 days (2.5 yrs)
4% to the skin (1 cat)
151
Metastatic rate in cats with cutaneous MCT ranges from ___ to ___%.
Tumors that metastasize are more likely to be what histologic type?
0-22%
Anaplastic
152
For what type of feline cutaneous MCT is the "wait and see" approach appropriate?
Histiocytic form in young cats with multiple tumors as they can regress on their own
153
What is the local control rate in incompletely excised feline cutaneous MCT that are treated strontium-90? MST?
98%
MST >3 years
154
Feline MCT may be less reponsive to what drug, commonly used in dogs?
In what form of cutaneous MCT is the response equiocal?
Prednisone
Histiocytic
155
What is the ORR, CR, and PR to CCNU in cats with cutaneous MCT?
ORR 50%
CR 10%
PR 40%
156
What other drugs have been used in cats with cutaneous MCT?
Palladia, VBL, chlorambucil
157
What is the overall clinical benefit of Palladia seen in cats with mast cell neoplasia (all locations)?
What % of cats develop AE? What % is considered grade 4 or 5?
80%
AE - 60%, 15% grade 4 or 5
Mostly elevated ALT/ALP
158
What is the RR and median duration of response in cats with cutaneous, splenic/hepatic (visceral), and GI MCT when treated with Palladia?
What is the overall median duration of response in cats exhibiting clinical benefit? For each of these forms?
Cutaneous - 86%; 36 weeks (9 mo)
Visceral - 80%; 48 weeks (12 mo)
GI - 80%; 23 weeks (6 mo)
Overall median duration of response 7.5m
159
What TKI have been evaluated in cats with MCT?
Toceranib, masitinib, imatinib
160
What is the most common spleen neoplasia seen in cats?
MCT
161
MCT accounted for ___% of splenic dz in cats from pathologic submissions iun a series of 455 specimens.
15%
162
Necropsy data on 30 cats with visceral/splenic MCT revealed dissemination or involvement of the following organs: ___% liver, ___% visceral LN, ___% bone marrow___%, lungs, ___% to intestines
```
90% liver
73% visceral LN
40% bone marrow
20% lungs
17% intestines
```
163
Up to ___% of cats with splenic/visceral MCT have peritoneal and pleural effusions rich in mast cells and eosinophils and ___ to ___% have circulating mast cells.
1/3 of cases have pleural and peritoneal effusion
| 40 to 100% circulating mast cells
164
In a report of 43 cats with splenic/visceral MCT, ___% had bone marrow involvement and ___% had an abnormal coagulation profile.
23% BM involvement
90% abnormal coagulation profile
Not clinically significant
165
What CBC abnormality is a common findings in cats with splenic/visceral MCT?
Anemia
166
What is the TOC for splenic MCT, despite involvement of other organs?
Splenectomy
167
What two forms of splenic MCT exist?
Diffuse/smooth form
| Nodular form
168
The majority of older studies report a MST of ___ to ___% in cats with splenic MCT when treated with splenectomy, despite BM involvement and peripheral mastocytosis.
More recent studies report a MST range post splenectomy of what?
The lowest MST reported is ___.
12 -19 months
13-28m
4.4 months
169
What are negative prognostic indicators in cats with splenic/visceral MCT whent treated with splenectomy (9)?
```
Anorexia
Significant weight loss
Male gender
Poor response to chemo
Blood transfusion
LN metastasis
Concurrent neoplasia
Chemo
Not having a splenectomy
```
170
What may happen with peripheral mastocytosis post splenectomy in cats with MCT?
May not completely resolve, but significantly decreases over time
171
What test should be performed routinely to monitor cats with splenic MCT and peripheral mastocytosis once splenectomy is performed?
Buffy coat evaluation; may indicate dz progression if it increases
172
What is the third most common primary intestinal tumor in cats?
```
MCT
#1 lymphoma
#2 adenocarcinoma
```
173
Cats within what age are at risk for intestinal MCT?
Older cats
174
What are common clinical signs in cats with intestinal MCT?
Vomiting #1, diarrhea, anorexia, palpable intestinal mass
175
What are the most common intestinal locations for feline MCT?
Small intestine, equally divided between duodenum, jejunum, and ileum. Recent study suggests diffuse more common.
176
Colonic MCT are reported in < ___% of feline intestinal MCT.
<15%
177
Metastasis with feline intestinal MCT is ___ (common or uncommon), with metastasis to the LN and liver present in ___% of cases in one study, describing a form of intestinal MCT known as ____.
Common;
65%
Sclerosing MCT - subvariant?
178
Cats with intestinal MCT usually have a ___ prognosis.
Poor
179
Increased cirulating numbers of what type of WBC can be seen in cats with intestinal MCT?
Eosinophilia
Peripheral mastocytosis rare unlike visceral
180
What is the treatment of choice for cats with intestinal MCT? Margins?
Surgery, 5 to 10cm margins because the tumor typically extends histologically well beyond gross dz
181
MST of cats with intestinal MCT? Approximately ___% die or are euthanized at this point.
A recent study reported an improved overall MST of ___, but ___ if metastasis was present.
< 2-3 months, 90%
Recent study overall MST 17.7 months, but 13.2 if mets present
182
What chemotherapy drugs have been use with reported response rates in cats with intestinal MCT?
Palladia, lomustine, chlorambucil
183
What are the KIT tyrosine kinase receptor domains and which are the exons that code for each domain?
Extracellular domain - exons 1-9
Transmembrane domain - exon 10
Intracellular domain - exons 11-21
184
The intracellular KIT domain is further divided into which 2 domains? Which exons code for these domains?
Juxtamembrane domain - exons 11 and 12; exert negative regulation
Cytoplasmic TK domain - ATP binding site exon 13 and phosphotransferase exon 17
185
How are mutation in the c-kit gene in dogs characterized in primary tumors versus metastatic tumors?
Mutation status is similar, suggesting metastatic lesions may not necessarily acquire new mutations
186
How are ITD of the c-kit gene characterized in dogs with multiple cutaneous MCT?
They can vary within multiple tumors in the same individual
ITD = duplication of exons within the same gene
187
Expression of phosphorylated KIT (measured with IHC) in canine MCT has been shown to correlate with what grading system?
2-tier grading system by Kiupel
Associated with increased risk of mets, shorter DFI, and shorter MST
188
Besides exon mutations, what other abnormalities have been noted in the KIT receptor in dogs with MCT?
Aberrant cytoplasmic localization
Associated with increased risk of recurrence, mets, shorter DFI, and shorter MST
189
Approximately what % of dogs with low grade MCT will develop additional MCTs?
20%
190
What is the % of agreement on grade between pathologists when using the Patnaik and Kiupel grading systems for dogs with MCT?
Patnaik - 62%
| Kiupel - 97%
191
When reclassifying Patnaik intermediate grade tumors using the Kiupel system, what % are considered low and high grade tumors?
84-86% low grade
| 14-17% high grade
192
When using the Kiupel grading system in dogs with MCT, what are the 1-year SR for low and high grade tumors?
94% low grade
| 46% high grade
193
The Kiupel grading system is independently associated with what 3 prognostic factors?
Time to metastasis/LN metastasis
PFS
OST
194
When using the Kiupel system, what is the MST of dogs with low and high grade tumors?
Low MST > 2 years
| High MST < 4m
195
When using the Kiupel system, what % of dogs with low and high grade tumors die from their disease?
Dogs with high grade tumors are how many times more likely to die from their dz when compared to low grade tumors?
Low - 5%
| High - 90%, 50x more likely to die
196
When using the Kiupel system, what % of dogs with low grade tumors have evidence of metastatic disease at diagnosis?
15-20%
197
When using the Kiupel system, what % of dogs with high grade tumors develop metastasis?
70%
198
When evaluating the relationship between proliferation indices and grade II MCT using the Patnaik system, which markers have been associated with grade and survival time?
Ki67 > 1.8
| AgNOR > 1.8
199
What is the reported sensitivity and specificity of Ki67 when > 1.8 for MCT related death?
Sensitivity 87%
| Specificity 58%
200
Although histologic grade is the most consistent prognostic indicator in dogs with MCT, what proliferation marker was shown to be be a better prognostic than grade in one study?
AgNOR
201
An AgNOR score of ___ or more has been associated with the presence of ___ in intermediate grade MCT.
AgNOR score of 1.87 or > associated with the presence of LN metastasis
202
What is the sensitivity and specificity of an AgNOR score of 1.87 or > for the presence of LN metastasis?
Sensitivity 93%
| Specificity 27%
203
An AgNOR x Ki67 product score of > than ___ has been associated with increased risk of what 2 things?
>54
| Increased risk of metastasis and eath
204
What % of dogs with an AgNOR score of >54 die within 1 year?
60%
205
Dogs with an AgNOR score of >54 that lack ITD in exon 11 have been reported to have a better ORR to ___ than ___ (2 chemo drugs).
Vinblastine than Palladia
206
What is the reported sensitivity and specificity of a MI >5 for predicting tumor-related death in dogs with MCT?
Sensitivity 32%
| Specificity 96%
207
What is the reported sensitivity and specificity of a MI ≥2 for predicting tumor-related death in dogs with MCT?
A MI of >2 was associated with what prognostic factor on multivariate analysis?
Sensitivity 76%
Specificity 80%
Shorter ST in dogs with cutaneous and SQ MCT
208
In Patnaik intermediate/grade II tumors, which of the following is the most sensitive and specific proliferation marker for predicting MCT related death?
a. MI >5
b. Ki67 >0.018
c. MCM7 >0.18
Most sensitive MCM7 - 83%
Most specific MI >5 - 99%
MCM& = minichromosome maintenance protein 7, one of the 6 MCMs involved in DNA replication, the MCM complex is activated by CDK and involved in S phase
209
Dogs with a high Ki67/MCM7 combination have an increased risk of ___ to die from MCT-related causes.
28x
210
What locations have been associated with a good or favorable prognosis vs a poor prognosis in dogs with MCT?
Good and favorable: SQ, conjunctiva, oral mucocutaneous and perioral, grade I and II pina
More guarded/poor: preputial, scrotal, oral mucosa, BM, visceral, inguinal, grade III pinna
211
Increased VEGFR expression in canine MCT can affect prognosis in which ways (4)?
Increased risk of recurrence, mets, shorter DFI, and shorter MST
212
ITD in c-kit activating mutations most commonly occur in which exon?
Exon 11
213
ITD in exon 11 occur in ___ to ___% of all canine MCT and ___ to___% of grade II and III tumors.
How do mutations in this exon increase the risk of local recurrence, systemic metastasis, and death?
20 to 30% of all canine MCT
30 to 50% of grade II to III tumors
5x risk of local recurrence
6x risk of systemic metastasis
15x risk of death
214
ITD in exon 8 and 9 occur in < than ___ % of all canine MCT.
<5%
215
Dogs with mutations in what exon have a better prognosis?
Exon 8
216
Presence of an eosinophilia of more than ___% and a neutrophil to eosinophil ratio of ≤ ___ are associated with a longer PFI and ST in dogs with MCT.
>4%
| ≤25
217
MCT on which locations are most likely to metastasize to regional LN and distantly?
Head
218
What is the MST of dogs with oral mucocutaneous and perioral (muzzle) MCT? Metastatic rate? Negative PI?
MST 52m
Metastatic rate 60%
NPI: presence of mets
Cutaneous, mucocutaneous, or mucosal locations were not associated with survival time
219
What is the MST of grade I, II, and III pinnae MCT in dogs when treated with multiple therapy modalities?
What grade had the highest recurrence rate?
Grade I and II - MST not reached
Grade III - MST 10m
Grade III - 88% recurrence rate
220
Describe the new MCT staging system
I - single tumor w/o LN involvement
II - 3 or more tumors w/o LN involvement
III - single tumor with regional LN involvement
IV - large and infiltrative tumors or ≥ 3 with regional LN inv
V - distant mets including mast cells in the periphery
221
A Ki67 of > than ___% was recently associated with a higher mortality rate in dogs with cutaneous and SQ MCT.
5.6%
222
What % of dogs with MCT have nodal metastasis at diagnosis (range)? Distant?
20 to 30% nodal mets
6.8% distant mets
223
What % of dogs developed distant mets in the absence of regional nodal mets?
What % of dogs with distant mets have evidence of regional nodal mets?
0%
100%
224
What is the % of disagreement between cytology and histopath when evaluating a LN for evidence of metastasis?
20% disagreement
225
The presence of trafficking mast cells can increase with what 2 things?
Infection
| Ulceration
226
Some evidence suggests that intermediate grade tumors with ___ metastasis may have a better prognosis than ___ tumors.
LN mets
| High grade tumors
227
What are some negative prognostic indicators for PFS identified in dogs with systemic mastocytosis? For MST?
For PFS:
Tumor diameter >3cm
2+ metastatic sites
Measurable primary tumor at dx
For MST:
Lack of local control
BM infiltration
228
What is the MST in dogs with MCT and BM involvement?
35 to 43d
229
What is the most recently reported MST in dogs with systemic mastocytosis?
ORR to chemotherapy?
110d
47% ORR
230
What is the overall concordance between pre-surgical and post surgical biopsies in dogs with MCT when using the Patnaik and Kiupel systems?
Which pre-surgical biopsy technique was less accurate?
Patnaik 96%
Kiupel 92%
Wedge bx less accurate (92%) when compared to punch or core
231
Recurrence rate of K9 grade 2 completely and incompletely excised tumors?
Completely - 5 to 10%
| Incompletely - 7%
232
Recurrence rate of K9 grade 3 tumors despite wide margins?
40%
233
Primary K9 MCT that measure > ___cm are more likely to have a palpably normal regional LN that contains either pre-metastatic or metastatic dz.
>3cm
234
In dogs, What % of palpably normal LN are classified as HN3 once excised?
22%
235
Compared to dogs with residual disease, those undergoing surgical excision of the metastatic LN have a lower risk of developing what (3)?
Development of local, nodal, or distant relapse
236
Compared to dogs with residual disease, those that do not undergo surgical excision of a metastatic LN have an increased risk of ___ for tumor progression and ___ for death.
5. 5x for tumor progression
| 3. 5 for death
237
Dogs undergoing re-excision or irradiation of their incompletely excised MCT experience longer ___ and ___ compared to those that don't.
Dogs receiving which treatment modality resulted in lower RR?
Longer TTR and MST
RT (8% vs 38% if no tx)
238
In dogs with high risk MCTs (grade 3 or grade 2 w/mets, what is the overall PFS and MST?
PFS - 130d (4m)
MST - 260 to 300d (8.6m to 10m)
239
What are some positive and negative PI identified in dogs with high risk MCTs (grade 3 or grade 2 w/mets)?
Negative: metastasis, no tx of the metastatic LN, chemo in the gross dz setting, no adjuvant chemo
Positive: no metastasis, removal of the tumor and metastatic LN, chemo in the microscopic dz setting, combination therapy
240
Although no significant difference in acute AE severity or frequency has been noted when comparing RT in the gross and macroscopic dz setting in dogs with MCT, pretreatment with what medication was associated with an increased frequency of grade 2 toxicity?
Prednisone
241
What is the MOA of prednisone in MCT?
Inhibits proliferation and induces tumor apoptosis in vitro
| Decreases peritumoral edema and inflammation
242
What is the ORR and TTP in dogs with MCT when treated with intralesional triamcinolone (combined with other therapies like chemo and RT?
ORR 67%
| TTP 60d
243
A recent study evaluated the tolerability of "rapid vinblastine dose escalation" in dogs with high risk MCT (30 dogs with microscopic disease and 4 with macroscopic disease).
How was the protocol schedule? What % required dose reductions? What % developed mild GI toxicity? What % developed febrile grade 4 neutropenia?
First month: day 0 at 2.3mg/m2, day 7 at 2.6mg/m2, day 14 at 3mg/m2, day 21 at 3mg/m2. Thereafter, 3mg/m2 every other day.
26% required dose reductions
30% mild GI toxicity
12% febrile grade 4 neutropenia
244
What is the MST in dogs with Patnaik grade II tumors that have a Ki67 of >1.8 and no evidence of metastatic disease when treated with VBL vs masitinib in the post operative setting?
MST 1946d for vinblastine
MST 370 for masitinib
245
In a recent study of dogs with MCT, response to Palladia or VBL was not affected by which factor?
Presence of c-kit mutation
246
When Palladia (EOD) is combined with CCNU for the treatment of MCT in dogs, what % of dogs developed unacceptable AE? How many were euthanized due to AE?
What was the ORR and PFI?
Dose of Palladia and CCNU used?
Palladia 2.75mg/m2 EOD and CCNU at 60mg/m2 q3w
100% unacceptable AE, 30% euthanized (panc, GI tox)
ORR 50%
PFI 2.9m (86d)
247
When Palladia (EOD) is combined with CCNU for the treatment of MCT in dogs, what % of dogs developed neutropenia?
What was the ORR, PFI, and MST?
Dose of Palladia and CCNU used?
```
Palladia at 2.75mg/m2 on days 1, 3, 5
CCNU at 60mg/m2 q3 weeks
ORR 46% (10% CR, 36% PR)
PFI 50d
OST 130d
DLT: neutropenia, 83% developed it
```
248
What % of dogs devevlop AE while on masitinib? What % develops grade 3 AE?
What are the 2 most commonly reported AE? Most severe? Other AE?
64% develop AE, 26% are grade III
Most common AE:
GI adverse events (vomiting and diarrhea) - mostly Elevated ALT
Most severe AE: proteinuria - 7%
```
Other AE:
Mild myelosuppression
Protein losing nephropathy leading to edema
Increased BUN/creat
Hemolytic anemia
```
249
What is inhibited by Palladia, Masitinib, and Imatinib?
Palladia - KIT, PDGFR a/b, VEGFR1, CSF1, Ret, Flt3
Masitinib - KIT, PDGFR a/b, Lyn, FGFR3, focal adhesion kinase pathway
Imatinib - KIT, PDGFR a/b, BCR-Abl
250
Resistance to Palladia in dogs can potentially arise from what?
Secondary point mutations in the juxtamembrane and tyrosine kinase KIT domains
251
ECT and and bleomycin for incompletely excised MCT in dogs can result in local control in ___% of cases. With cisplatin?
85% - bleomycin
65% - cisplatin
252
Has the timing of ECT and surgery in dogs with MCT been associated with prognosis?
Post-operative ECT results in improved DFI and MST compared to ECT alone, intra-op ECT, and ECT for recurrence
253
In dogs, ECT and peritumoral ___ gene electrotransfer can result in an ORR of ___%, CR in ___%, and PR in ___%.
CR likely to be achieved in all tumors measuring less than ___.
After therapy, what changes can be observed in serum (2) and biopsy of tumor (2)?
IL-12
ORR 83%, CR 72%, PR 11%
<2cm3
Serum: increased IFN-y and IL-12
Biopsy: decreased MVD, preivascular lymphocyte infiltration
ECT protocol: ECT with cisplatin or bleomycin, followed by human IL-12 plasmid peritumorally, 2nd electric pulse
254
JAK2 inhibitors (RJ63, pimozide, ruxolitinib) have been shown to decrease expression of ___ in K9 MCT lines.
STAT5 -> induction of apoptosis
255
CD30 mAb (brentuximab) has caused what effects in K9 MCT lines?
Inhibition of growth and apoptosis
256
What kinase inhibitors have been shown to inhibit MCT death during G2/M cell cycle phase and can therefore potentially act as a radiosensitizer in K9 MCT?
Aurora kinase inhibitors (ENMD-2076)
They are serine/threonine kinases that regulate cell cycle and mitotic spindle assembly
257
What are 2 prognositc indicators identified in cats with intestinal MCT? What are they associated with?
Tumor degree of differentiation
MI >2
Decreased survival time
258
Although ___% of cats with intestinal MCT express KIT, how many mutations were identified?
70% - membranous and focal paranuclear most common
| No mutations identified
259
KIT mutations in humans with mast cell disease are most common in which exon?
17
260
What is the proposed grading scheme for high-grade MCT in cats?
MI >5/10hpf and at least two of the following:
- Tumor diameter >1.5cm
- Irregular nuclear shape
- Nucleolar prominence/chromatin clusters
261
When it comes to KIT and feline MCT, what is a negative prognostic indicator?
Cytoplasmic expression
