Canine MCT Flashcards
Strefezzi et al. 2012. The value of immunohistochemical expression of BAX in formulating a prognosis for canine cutaneous MCT
BAX expression in 24 canine MCT and relate to grade and prognostic value
BAX expression ___ with higher grade
Animals with high levels of BAX were ____ more likely to die from disease and had ___ post-surgical survival times
Increased
4.25x, shorter
BAX expression may be related to aggressiveness of MCT
Prada et al. 2012. Evaluation of COX-2 expression in canine MCT
Cox-2 expression in tumors?
Labelled cells ranged from isolated positive cells thorughout the tumor (8) to localized foci (3) or diffuse labeling >50% of cells (31)
Intensity ranged from weak (4), moderate (16), strong (22) and greatest at the margin of tumor
Intensity of Cox-2 between histological groups?
86%
Significantly different
No significant difference noted for percentage of Cox-2 positive cells and for immunoreactivity score
Cox-2 inhibitors may be of value in treatment of MCTs
Pakorny et al. 2012. MRI of canine MCTs
On T2-W, 7/9 MCT were hyperintense to muscle and 2/9 isointense
On T1-W, 8/9 isointense and 1/9 mildly hypointense
Metastatic LNs were larger than contralateral LNs
All LNs were isointense on T1-W and hyperintense on T2-W
All LNs were moderately to strongly contrast enhancing
4/5 metastatic and 2/7 normal LNs had heterogeneous enhancement patterns - not significant
Caristen et al. 2012. Multicenter prospective trial of hypofractionated RT, toceranib, and prednisone for measurable canine MCT
17 dogs with MCT
ORR? how may achieving CR and PR?
Median time to best response? Median PFI?
Overall MST?
Common toxicity?
76.4%, 58.8% and 17.6%
32 days (1 month), 361 days
Not reached
GI and hepatic
O’Connell et al. 2013. Evaluation of prognostic indicators in dogs with multiple, simultaneously occuring cutaneous MCT: 63 cases
On multivariable analysis, dogs with grade 3 MCTs had?
Dogs treated with vinblastine/lomustine?
MSTs were significantly ___ in dogs with one recored MCT on an extremity?
PFS and MST?
Shorter PFS (18.7 versus 2.2 months) and MST (24 vs. 3 months)
16x increased risk of dying
Longer
Not reached
Beralato et al. 2012. Evaluation of minichromosomes maintenance protein 7 as a prognostic marker in canine cutaneous MCT
Michrosome maintenance proteins (MCMs) are sensitive markers of cellular proliferation and predictors of survival in human malignancies
95 dogs included with 31 dying of MCTs
Cut off value for MCM-7?
MST for MCM-7<0.18?
MCM-7>0.18
In multivariable analysis, MCM7 was signifcantly associated with survival
0.18
Not reached at 3668
187 days
Rodriguez et al. 2012. Immunohistochemical evaluation of AKT protein activation in canine MCT
25 MCTs
Was AKT detected? Phosphorylated AKT?
Correlation between labeling and histologic grade?
Detected in all samples, 24/25 expressed phosphorylated form
None
Teng et al. 2012. Overexpression of P-gp, STAT3, p-STAT3 and KIT in spontaneous canine cutaneous MCT before and after prednisolone treatment
P-gp, STAT3, and KIT are involved in GC resistance
Overall objective response rate on prednisolone? Poorly differentiated or higher stage response rate?
Median time span to reach maximal tumor regression?
Expression of P-gp and STAT3 before treatment?
pSTAT3 and KIT expression post-treatment?
Prednisolone treatment that caused marked reduction was correlated with?
Cytoplasmic KIT staining pattern was correlated with?
51.8%, lower
14d, 22 (81.5%) reached maximal regression at 21d
Overexpressed
Reduced
pSTAT3
Lower response rate to prednisolone treatment
Giantin et al. 2012. Expression of MMP, tissue inhibitors of metalloproteinase and vascular endothelial GF in canine MCT
Expression of VEGF-A, MMP, TIMP mRNA with histological grade?
VEGF-A and MMP mRNA increased and TIMP decreased with increasing grade
Schlieben et al. 2012. Differences in the proteome of high-grade versus low-grade canine cutaneous MCT
4 stress response proteins were significantly upregulated in high grade tumors - HSPA9, PDIA3, TCP1A, TCP1E
Proteins assciated with cell motility (WDR1, ACTR3, ANXA6) were increased or decreased (ANXA2, ACTB)
Transferrin was down-regulated - which is usually upregulated in neoplastic cells
Vascellari et al. 2013. Expression of Ki67, BCL-2, and COX-2 in canine cutaneous MCT: association with grading and prognosis
MI and Ki-67 was significantly associated with grading and survival
No association between BCL-2 protein expression and either grading system or health status was observed
BCL-2 mRNA was higher in grade 2 than grade 1 no differences were detected between low and high-grade MCT
Increased BCL-2 mRNA was associated with increased mortality rate
COX-2 detected in 78% of MCT - no assciation with tumor grade or health status
Klopfleisch et al. 2012. Transcriptome and proteome analysis of tyrosine kinase inhibitor treated canine MCT cells identifies potentially kit signaling-dependent genes
40% of genes increased mRNA expression - pro-proliferative pathways of B- and T-cell receptors, chemokine receptors, steroid hormone receptors and EPO- RAS and MAP kinase signaling
24 proteins has changed expression levels involved in gene transcription e.g. EIA3, EIA4, TARDBP, protein folding e.g. HSP90, UCHL3, PDIA2 and protection from oxidative stress, GSTT3, SELENBP1
Mackowiak et al. 2013. E-cadherin in canine MCT: decreased expression and altered subcellular localization in grade 3 tumors
Expression of E-cadherin in grade 3 MCT?
Decreased expression
Meyer et al. 2013. All subunits of the IL-2 receptor are expressed by canine cutaneous MCT
What % expressed both subunits of the IL-2R? IL2?
IL-2Rg and IL-2 expression in high grade tumors? IL-2 expression decreased in?
IL-2R may be more relevant for early MCT development and well-differentiated tumors
86%, 64%
Decreased, c-KIT mutated tumors
Costa Casagrande et al. 2015. The value of molecular expression of KIT and KIT ligand analysed using real time PCR and IHC as prognostic indicator for canine cutaneous MCT
KIT-I, KIT-II, and KIT-III staining patterns?
Tumor recurrence rates and tumor related deaths association with KIT staining patterns?
11%, 61.73%, and 27%
No association
Results suggest correlation between aberrant KIT localization and increased proliferative activity of MCTs
Takeuchi et al. 2013. Validation of the prognostic value of histopathological grading or c-kit mutation in canine cutaneous MCT: a retrospective cohort study
Dogs with Patnaick grade III MCT had significantly ___ OS and PFS compared to grade I or II
Difference between grade I and II and OS, PFS?
Kiupel high grade MCT had significantly ___ PFS and OS
Presence of internal tandem repeat-Exon11 was associated with?
Reduced
None
Shorter
Shorter PFS
Donnelly et al. 2015. Evaluation of histological grade and histologically tumor-free margins as predictors of local recurrence in completely excised canine MCT
Which tumors were more likely to recur?
29% had HTFM of <3mm - none recurred
Narrow <3mm histologic margins are likely adequate to prevent LR or low grade tumors
High grade tumors have significant risk of LR regardless of HFTM
High grade tgab low grade - 35% vs. 3.9%
Warland et al. 2013. Breed predisposition in canine MCT: a single center experience in the UK
Which breeds were predisposed to MCT development?
Which breeds were underrepresented?
Boxers, Labrador Retriever, GR, Stafordshire Bull Terriers
English springer spaniel, GSD, WHWT, CKCS
Gentilini et al. 2015. The use of COLD-PCR, DHPLC and GeneScanning for the highly sensitive detection of c-KIT somatic mutations in canine MCT
Convetional PCR/sequencing showed sensitivity of 50-20%
All novel methods had higher sensitivity allowed reaching as low as 2.5-1.2% of the mutated DNA
Lejeune et al. 2015. Aggressive local therapy combined with systemic chemotherapy provides long term control in grade II stage 2 canine MCT: 21 cases (1999-2012)
Treated with local therapy and systemic chemotherapy (pred, CCNU, VBL)
Median survival for all dogs?
Median DFI?
Dogs treated with surgery and chemo had ____ survival than those with surgery, RT, chemo
___ patients had local recurrence in RT field
1359 days (3.7 years)
2120 days (5.8 years)
shorter
2
Shiomitsu et al. 2016. The radiosensitizing effect of the aurora kinase inhibitors, ENMD-2076, on canine MCT in vitro
ENMD-2076 is aurora kinase inhibitor that has multi-targert TKI properties
mRNA and protein expression of aurora-A and aurora B were evaluated
____ seen in cells treated and affected cell cyle in the ___ phase
Radiosensitization was seen after 3Gy and 6Gy exposured with ENMD-2076 for 48 hr
Expression of __ was increased and was highest 24h post irradiation in cells without ENMD-2076 treatment
Dose-dependent cytotoxicity, G2/M phase
caspace-3
Usefulness of treating with aurora kinase inhibitors alone or in connjunction with RT
Clarke et al. 2014. Histologic characteristics and KIT staining pattern of equine cutaneous MCT
What breed was over-represented?
Most tumors were ___ differentiated and __ mitotic rates
Abberant KIT staining pattern?
KIT staining pattern and histologic features were not associated with poor outcome
Arabians
Well-differentiated, low mitotic rates (96%)
Uncommon 12%
Elliot et al. 2016. Canine oral mucosal MCT
33 dogs with MCT
Incidence of metastasis?
Adequate local control had improved outcome
55%
Scarpa et al. 2016. Cytological grading of canine cutaneous MCT
Number of mitoses, multinucleated cells, bizarre nuclei and presence of karyomegaly
The parameters were significantly different between histologically low-grade and high grade tumors
Accuracy? Sensitivity? Specificity?
How many high grade MCT were not detected?
94%, 85%, 97%
4%
Giantin et al. 2014. Global gene expression of canine cutaneous MCT: could molecular profilinf be useful for sybtype classification and prognostication
Significant association was found between mRNA expression and MCT-related mortality for FOXM1, GSN, FEN1, and KPNA2
Barbosa et al. 2014. Reproducibility of nuclear morphometry parameters from cytologic smears of canine cutaneous MCT-intra and interobserver utility
No significant effects were detected for observer, time, and interaction observer-time
Nuclear morphometric analysis using cytologic smears is reproducible method for grading MCT
Miller et al. 2016. A retrospetive review of treatment and response of high-risk MCT in dogs
94 dogs with high metastatic risk MCT
Treated with cytotoxic chemo or TKI masitinib, in gross disease or as an adjunct to surgical resection of primary tumor
MST for patients receiving surgery? No surgery
Patients with surgically excised Patnaik gtrade II and high Ki67 in absence of metastatic disease treated with VBL/pred showed significantly _____ survival than those treated with masitinib (MST?)
278 days (9 months) vs. 91 days (3 months)
MST 1946 days (5.3 years), 369 days (1 year)
van Lelyyeld et al. 2015. Comparison between Ki67 index and mitotic index for predicting outcome in canine MCT
Correlation between ki67 index and mitotix index was moderate, while agreement was poor
A high ki67 was?
Mitotic index (>5)
Ki67 showed significant survival difference within the MI <2 but not if >2
High mitotic index predicted death but many dogs with low index also died
Sensitive (85%) but poorly specific (58%)
Poorly sensitive (32%) and highly specific (96%)
Ressel et al. 2015. Equine cutaneous MCT exhibit variable differentiation, proliferation activity and KIT expression
Large proportion of tumors were multinodular or diffuse dermal infiltrates of mast cells with mild anisokaryosis, low proliferative rate and sdominanance of KIT pattern I - well differentiated CMCT
1/3 had infiltrative growth, moderate to marked anisokaryosis and high degree of proliferation - poorly differentiated and KIT II and III pattern
Zorzan et al. 2015. Mutational hotspot of TET2, IDH1, SRSF2, SF3B1, KRAS, and NRAS from human systemic mastocytosis are not conserved in canine MCT
No mutations were found in TET2
Cemazar et al. 2017. Efficacy and safety of electrochemotherapy combined with preitumoral IL-12 gene electrotransfer of canine MCT
Response rate?
IL-12 gene electrotransfer resulted in __% of patients with detectable serum ___ and ___
72%
78%, IFN-g and IL-12
Mochizuki et al. 2017. Association of breed and histopathological grade in canine MCT
High grade tumor increase with ___ and __ and __ dogs have increased odds of developing high grade tumor
Breed associated with low/intermediate grade
advancing age, male and intact dogs
Pug
Barker et al. 2016. Survey of UK-based veterinary surgeons options on the use of surgery and chemotherapy in the treatment of canine high-grade MCT, splenic HSA, and appendicular OSA
Respondents recommend chemotherapy for HGMCT, SHA, and AOS?
Appropriate chemotherapy protocol was not know by __ for HGMCT, SHA, and AOS?
For those not recommending chemotherapy __ did not believe chemo to be efficacious for these tumors
90, 40, 57%
25, 51, 36%
29, 64, 65
Macfarlane et al. 2016. Use of neutrophil to lymphocyte ratio for predicting histopathological grade of canine mast cell tumors
62 cases with gross MCT (14 high grade, 49 low grade)
Median NLR was different between high- and low grade MCT at different locations
Multivariable model identified increasing NLR and age to be associated with increased risk of high-grade MCT
Mutz et al. 2017. Cytologic comparison of the percentage of mast cells in LN aspirate samples from clinicaly normal dogs vs. dogs with allergic dermatologic disease and dogs with cutaneous MCT
Group 1 - healthy dogs
Group 2 - ADD
Group 3 - MCT on head and limbs
Percentage of mast cells: 0% for 1, 0.05% for 2, and 0.4% for 3
Group 3 - 16 LNs were normal in size and 6 of these had evidence of metastasis
7 LNs were enlarged and 5 had evidence of metastasis
Milovancev et al. 2018. Reductions in margin lenght after excision of grade II MCT and grade I and II STS in dogs
All processing steps resulted in ____ among MCT samples except between ____ vs. ____, and for STS except between
significant reductions, postfixation vs. subgross; ex-vivo vs. postfixation and subgross vs. HTFM
Moirano et al. 2018. Association of prognostic features and treatment on survival time of dogs with systemic mastocytosis: A retropsective analysis of 40 dogs
Dog with metastatic disease confined to distant LN lived ___ than those with circulating mast cells in blood
Metastatic disease in more than 2 sites had ___ prognosis than disease in single location
Administration of chemo over prednisone alone, with combination of lomustine, VBL and pred ___ survival over TKI, toceranib
longer
worse
prolonging
Marconato et al. 2014. Concordance of c-kit mutational status in matched primary and metastatic cutaneous canine MCT at baseline
21 dogs with metastatic MCT
Concordance of mutational status in 21 primary and matched metastatic MCT was __%?
Primary and secondary tumor can be used for c-kit testing
100%
Schlieben et al. 2013. Tandem duplication of kit Exon 11 influences the proteome of canine MCT
15 differentially expressed proteins were identified in mutated MCTs
Involves in cytoskeleton structure and cell motility (ACTR2, ACTB, and CAPPA1), cell signaling (ARHGDIA) and lipid metabolism (ALOX15 and ACSBG4), or are serum proteins
The KIT mutation changes the proteome of affected cells with major affect on the composition of cytoskeletal proteome and cell motility proteins.
Weishaar et al. 2014. Correlation of nodal mast cells with clinical outcome in dogs with mast cell tumor and a proposed classification system for the evaluation of node metastasis
Different histologic patterns of node-associated mast cells correlate with clinical outcome in dogs
Berlato et al. Comparison of mitotic index and Ki67 index in the prognostication of canine cutaneous MCT
95 dogs
Multivariable analysis, risk of dying due to MCT was ____ in dogs with increased Ki67 (HR 3.0) index or increased mitotic index (HR 2.7)
Mitotic index and Ki67 index were able to differentiate MCTs with worse prognosis
Similar
Worley et al. Incorporation of sentinel LN mapping in dogs with MCT: 20 consecutive procedures
20 MCT in 19 dogs were excised with SLN mapping
__ dogs had SLNs different from closest node
12 dogs had metastasis in extirpated SLN, 7 occured in MCT with MI<5
No correlation was noted between patient stage and c-kit protooncogene
Anatomic sampling of LNs in dogs does not reflect which LNs are receiving the draining tumor lymph
8 dogs
Takanosu et al. Sensitive detection of the c-kit c.1430G>T mutation by mutant-specific polymerase chain reaction in feline mast cell tumors
c.1430G>T in c-kit exon 9 was detected in 15.7% of samples by mutation-specific PCR but only in 7.1% by PCR-restriction fragment lenght polymorphism (RFLP)
Finotello et al. Redox status evaluation in dogs affected by MCT
23 dogs with MCT and 10 healthy dogs
At baseline, dogs with MCT had ____ d-ROMS (reactive oxygen metabolites-derived compounds) and ___ BAP (biological antioxidant potential)
Difference in a-tocopherol?
higher, lower
No significant difference
Warland et al. The utility of staging in canine MCT
220 dogs with MCT were staged with LN palpation/cytology, CXRs, and AUS
___% had metastasis to local LN, __ had distant metastasis
Development of distant metastasis in absence of LN metastasis?
Pulmonary metastasis?
Utility of further staging was low and CXRs not useful in staging MCT
30%, 7%
None
None
Robat et al. Safety evaluation of combination vinblastine and toceranib in dogs: phase I dose-finding study
DLT for combination?
MTD for vinblastine?
MTD for palladia?
Objective response?
Neutropenia
- 6 mg/m2 EOW
- 25 mg/kg PO EOD
50% reduction in vinblastine does not support combination
71% objective response and enhanced myelosuppression suggest synergistic activity
Chon et al. Safety evaluation of combination toceranib and piroxicam in tumor bearing dogs (excluding mast cell tumors): a phase I dose finding study
Combination of toceranib at 3.25 mg/kg EOD and piroxicam 0.3 mg/kg/day was safe
Meyer et al. 2012. CD25 is expressed by canine cutaneous MCT but not by cutaneous connective tissue mast cells
Grade 1 had strong expression of CD25 while grade 3 had decreased levels
CD25 may play a role in early MCT development and may be stimulatory factor for grade I MCT, while grade 3 MCT seem less dependent on CD25
Mallett et al. 2012. Immunohistochemical characterization of feline MCT
What % of cutaneous MCT, splenic MCT, GI MCT have histamine immunoreactivity?
Seratonin immunoreacticity?
Positive for kit - cutaneous, splenic, GI?
Heterogeneity of MCT based on location
20%, 18%, 53%
3 GI and 1 cutaneous MCT
69%, 35%, 33%
Sabbatini et al. 2013. Prognostic significance of kit receptor tyrosine kinase dysregulation in feline cutaneous MCT
24 cats with primary cutaneous MCT
Risk factors affecting survival?
Increased mitotic activity was associated with?
c-kit mutations were how frequent? Influence on prognosis?
67% had different mutatioon in different nodules
mitoses>5 per 10 hpf and cytoplasmic c-kit labeling
kit cytoplasmic expression
56% (exon 8 19%, exon 9 71%, exon 11 10%) - not related to protein expression and no influence on prognosis