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
Amagai et al. Production of stem cell factor in canine mast cell tumors
SCF contributes to proliferation of mast cells in autocrine/paracrine manner
High SCF expression was observed in how many of 7 MCT?
5/7
Kry et al. Additional local therapy with primary re-excision or RT improves survival and local control after incomplete or close surgical excision of MCT in Dogs
MST for primary re-excision? RT?
Local recurrence in re-excision group, RT group, comparison group?
Chemotherapy and survival and local control?
2930 days (8 years), 2194 days (6 years)
13%, 8%, and 38%
Not associated with improved survival or local control
Recommend re-excision or RT with incomplete excision of MCT
Elders et al. 2014. Recombinant canine IgE Fc and IgE Fc-TRAIL fusion protein bind to neoplastic canine mast cells
Halsey et al. Development of an in vitro model of acquired resistance to toceranib phosphate in canine mast cell tumor
Chronic TOC exposure led to c-kit mRNA and protein overexpression
Minimal p-gp activity and no functional p-gp
Fenger et al. Overexpression of miR-9 in mast cells is associated with invasive behaivour and spontaneous metastasis
miR-9 is increased in high grade canine MCT compared to low grade tumors and normal canine bone marrow derived mast cells
miR-9 overexpression enhanced invasion but no effect on cell proliferation or apoptosis
Causes upregulation of CMA1 - protease involved in activation of MMP and matrix remodeling
Piviani et al. Significance of mastocytemia in cats
Incidence of mastocytemia in cats with visceral disease or cutaneous disease?
Most common in visceral MCT
67%
DeWitt et al. A Novel imaging system distinguishes neoplastic from normal tissue during resection of soft tissue sarcomas and mast cell tumors in dogs
A florescent imaging agent that is activated by proteases in vivo was given to dogs 4-6 or 24-26 hr before tumor resection
Imaging system correctly distinguished cancer from normal tissue in?
Sensitivity and specificity?
Toxicity?
92%
92% and 92%
53% facial erythema - responded to IV benadryl
Rich et al. p62/Sequestosome-I: Mapping Sites of Protein-Handling stress in canine cutaneous mast cell tumors
Significant association with tier-2 (Kiupel) with p62-nuclear immunoreactivity being associated with ____ grade, p62-cytoplasmic with ___ grade
low, high
Burton et al. Pulse-administered toceranib phosphate plus lomustine for treatment of unresectable MCT in dogs
Toceranib given on day 1, 3, 5 of 21-day cycle (2.75 mg/kg) and on day 3 at 50 mg/m2
DLT?
ORR?
PFS?
Variable associated with improved PFS?
Neutropenia
46%
53 days
response to tx, absence of metastasis, no previous chemotherapy
Pratschke et al. Evaluation of modified proportional margins approach for surgical resection of MCT in dogs: 40 cases (2008-2012)
Resected with lateral margins equivalent to the widest measured diameter of tumor and minimum depth of 1 fascial plane deep to the tumor
40 tumors were excised with clear margins and 7 with incomplete margins
Local recurrence was 2%
Schwab et al. Clinical outcome for MCTs of canine pinnae treated with surgical excision (2004-2008)
Local recurrence in 1 dog with grade 2 MCT and 7/8 dogs with grade 3 MCT
MST for grade 1 and 2?
MST for grade 3?
Not reached
10 months
Baginski et al. The prognostic value of LN metastasis with grade 2 MCT in dogs: 55 cases (2001-2010)
Difference in survival time between dogs with or without LN mets?
MST?
What was prognostic for survival?
Which dogs had greater survival?
Not significant
Not reached at 65.9 mo
Tumor location
Greater for dogs that had removal of their metastatic LN
Jackson et al. Evaluation of fixation time using Diff-Quik for staining canine mast cell tumor aspirates
Slides were stained in Diff-Quick at varying fixation times (5 sec, 30 sec, 1 min, 2 min)
No difference in staining quality
Risselada et al. Surgically planned versus histologically measured lateral tumor margins for resection of cutaneous and SQ MCT in dogs: 46 cases (2010-2013)
Surgically mapped lateral margins differed significantly from histologically reported margins in 4 quadrants
Mean histologic margins were __ to ___ smaller than surgical margins
Did BCS contribute to decrease in lateral margins?
35% to 42%
No
Shoop et al. Prevalence and risk factors for mast cell tumors in dogs in England
What was the prevelance?
Highest breed prevelance?
Which breed showed greater odds of diagnosis?
Which breeds had reduced odds?
Association with diagnosis and sex?
0.27%
Boxer 1.95%, GR 1.39%, Weimerainer 0.85%
Boxer, Pug, Staforshire bull terrier compared with crosbred dogs
GSD, Border Collie, WHWT, Springer spaniel, Cocker spaniel
None
Grant et al. Clinical response of masitinib mesylate in the treatment of canine macroscopic MCT
39 dogs
Clinical response rate? CR and PR?
Median time to progression?
AEs?
MST?
82%, 38.5% and 43.6%
79 days
64% - Elevated ALT 23% and vomiting 15%
159 days
London et al. KTN0158, a Humanized Anti-Kit mAb, demonstrates biologic activity against normal and malignant canine mast cells
Blocked mast cell degranulation in vitro
In dogs, well tolerated and reduced cutaneous mast cell number in dose-dependent manner
Clinical benefit in 12 dogs?
5 PR and 7 SD regardless of kit mutation status and decreased kit phosphorylation was observed
O. Skor et al. Pretreatment leukocyte ratios and concentrations as predictors of outcome in dogs with cutaneous MCT
Relative eosinophil concentration (REC), NER, and LMR were prognostic in univariate analysis
REC and NER were independent predictors of survival in multiple analyses
Lowe et al. The treatment of canine MCT with electrochemotherapy with or without surgical excision
ECT can be applied succesfully in smaller MCT as alternative to surgery
Can be combined with surgery either intra-op or post-op for larger lesions without significant toxicity
Sanchez et al. Antihistiminic and cardiorespiratory effects of diphenhydramine hydrochloride in anesthesized dogs undergoing excision of mast cell tumors
Mean diastolic pressure was ___ in diphenhydramine vs. control group
Mean arterial BP was ___ in diphenhydramine vs. control group during surgical closure
IV administration of diphenhydramine prior to MCT excision had no clear clinical cardirespiratory benefits
Lower
Lower
Bavcar et al. Combination toceranib and lomustine shows frequent high grade toxicities when used for treatment of non-resectable or recurrent MCT in dogs: A European multicenter study
Results?
Objective RR?
Severe AEs occured in all dogs
50%
3 dogs died….
Dores et al. Comparison of histologic margin status in low-grade cutaneous and SQ canine MCT examined by radial and tangential sections
Low grade MCT, HFTM>0mm should not be considered completely excised particularly when HFTM <10.9 mm
Shaw et al. Diagnostic accuracy of pre-treatment biopsy for grading cutaneous MCT in dogs
Determine concordane of tumor grade between various biopsy techniques (wedge, punch, needle core) when compared with excisional biopsy
Overall concordance with Patnaik? Kiupel?
Accuracy with wedge, punch, needle core compared to excisional with Patnaik?
Accuracy with wedge, punch, needle core compared to excisional with Kiupel?
96% and 92%
92%, 100% and 100%
90%, 95%, 100%
Salvadori et al. Effects of electrochemotherapy with cisplatin and peritumoral IL-12 gene electrotranser on canine MCT: a histopathologic and immunohistochemical study
Induced a cellular response characterized by recruitement of T-lymphocytes and macrophages and fibrotic proliferation with reduction of microvessels
Pizzoni et al. Features and prognostic impact of distant metastases in 45 dogs with de novo stage IV cutaneous MCT: A prospective study
PFI and ST were independent prognostic factors, including?
Negative prognostic factors in multivaraite analysis?
Anatomic site, histological grade, mutational status
Tumor diameter > 3cm, 2 metastatic sites, bone marrow infiltration, and lack of tumor control at primary site
Milovancev et al. Shaved margin histopathology and imprint cytology for assessment of excision in canine MCT and STS
Positive margin detection for imprint cytology, radial section histopathology, shaved margin histopathology for MCT but not STS
Intermethod agreement was poor
21%, 9% and 3%
Moore et al. Spinal MCT in dogs: Imaging features and clinical outcome of 4 cases
4 dogs presented for paraspinal hyperesthesia and subacute progressive or acute myelopathy
CT and MRI lesions were extradural
1 dog was nromal 4 years after lomustine
1 recurred within 2 months following surgery despite vinblastine
2 cases were euthanized
Smith et al. Recurrence rates and clinical outcome for dogs with grade II MCT with low AgNOR count and Ki67 index treated with surgery alone
What % of dogs developed local or distant recurrence?
Of, these dogs, how many developed local recurrence?
Ancillary therapies may not be necessary for patients with incompletely excised grade II MCT with low proliferation activity
27%
7% - 1 had complete and 5 had incomplete margins - the difference was not significant
Thompson et al. Receptor TK expression profiles in canine cutaneous and SQ MCT
What was predictive of decreased survival time, DFI, and increased metastatic rate?
Increased rate of local recurrence?
phosphorylated kit, VEGFR2, and Kit cellular localization
VEGFR2 and kit cytoplasmic labeling
Vargas et al. IHC expression of the pluripotency factor OCT4 in canine MCT
OCT4 is not a prognostic indicator for canine MCT
Foncesca-Alves et al. Ki67/KIT double IHC staining in cutaneous MCT from Boxer dogs
Double positivity was observed in?
Which animals had longer survival time?
29%
Ki67-/Kit+ than Ki67+/Kit+
Amagai et al. A point mutation in the extracellular domain promotes tumorigenesis of mast cells via ligand-independent autodimerization
Morimoto et al. Evaluation of the global DNA methylation in canine MCT samples by immunostaining of 5-methyl cytosine
Global DNA hypomethylation was predominant in?
Grade 3, high grade, less differentiated MCT
Arendt et al. Genome wide association study of golden retrievers identifies germ line risk factors predisposing to MCT
SNP in GNAI2 gene - truncated protein
Hyaluronidase genes were identified as risk factors
Bauer et al. IL-4 downregulates expression of the target receptor CD30 in neoplastic canine mast cells
CD30 is target in human mast cell neoplasms
Pulz et al. Increased expression of tissue inhibitor of MP-1 correlated with improved outcome in canine cutaneous MCT
What was associated with post-surgical survival and disease-related mortality?
Dogs with ___ TIMP-1 positivity were more prone to die?
TIMP-1
<22.9%
Giantin et al. Transcriptomic analysis identified up-regulation of a solute carrier and UDP glucoronyltransferases in dogs with aggressive cutaneous MCT
375 differentialy expressed genes (DEG)
Associated with drug metabolism and cell cycle pathways
Members of solute carrier protein (SCP) and UDP glucoronyltransferases (UGT) genes were dysregulated
Barra et al. Apoptotic intrinsic pathway proteins predict survival in canine cutaneous MCT
IHC of BAX, BCL-2, APAF-1 and caspace 9 and 3 were performed
High __ expression was associated with higher mortality rate and shorter survival
BCL2 and APAF offered additional prognostic information
BAX
Halsey et al. Expression of phosphorylated KIT in canine MCT
Expression of __ was significantly correlated with 2-tier grading scheme and c-kit mutation
MCT from 4 of 7 patients had PR to TOC - pKIT expression was assessed by IHC, ____ expression was noted after TOC
pKIT
Reduced pKIT expression
Guiliano et al. Expression of fibroblast activating protein and correlation with histological grade, MI, and ki67 expression in canine MCT
FAP is serine protease expressed by activated fibroblasts, particularly tumor related fibroblasts (TAF)
What % of MCT expressed FAP
FAP was correlated with Patnaik and Kiupel, MI, and Ki67 expression
High FAP could be a negative prognostic factor in canine MCT
90%
Jark et al. Genomic copy number variation associated with clinical outcome in canine cutaneous MCT
Regions of loss in PTEN and FAS and regions of gain in MAPK3, WNT5B, FGF, FOXM1, and RAD51 were detected in MCT with short survival times
Mochizuki et al. Genomic profiling canine MCT identifies DNA copy number aberrations associated with KIT mutations and high histological grade
KIT mutations were less frequent in Pugs tumors and strongly associated with high histological grade
Tumors with kit mutations showed CNA in p53 and RB pathways
Romanucci et al. HSP32 and HSP90 Immunoexpression in relation ot Kit pattern, grading, and mitotic count in canine cutaneous MCT
All cases had cytoplasmic staining of Hsp90
Relationship between Hsp90 or Hsp32 with KIT pattern, mitotic count and tumor grade?
Reduced Hsp32 in grade III/high grade suggest?
Not observed
Poorly differentiated MCs
Krick et al. Investigating associations between proliferation indices, c-kit, and LN stage in canine MCT
What were significantly associated with stage?
Sensitivity and specificity of AgNOR?
Recurrent tumors and high AgNORs are associated with?
AgNORs/nucleus and recurrent tumors
93% and 27%
Stage II and grade II MCT - AgNOR cutoff value does not predict LN metastasis
Keller et al. The JAK2/STAT5 signaling pathway as potential therapeutic target in canine mastocytoma
Inhibitos of JAK2 and STAT5
Results with inhibitors?
Potential target in canine mastocytoma
inhibited proliferation and survival in these cells
Tamlin et al. Prevelance of exon 11 internal tandem duplication in c-kit protooncogene in Australian canine MCT
Prevalence?
Prevelance in Patnaick grade 3? Kiupel high grade?
Presence of ITD was not associayed with signalment, tumor anatomical location or tumor size
18%
55.6% and 50%
Stefanello et al. Comparison of 2- and 3-category histologic grading systems for predicting the presence of metastasis at the time of initial evaluation in dogs with cutaneous MCT: 386 cases (2009-2014)
Sabattini et al. Histologic grading of canine MCT: Is 2 better than 3?
Camus et al. 2016. Cytology criteria for mast cell tumor grading in dgos with evaluation of clinical outcome
The cytologic grading scheme that best correlated with histology classified as tumor as high grade?
Sensitivity and specificty?
Dogs with histologic and cytologic high grade MCTs were 39x and 25x more likely to die 2-year follow up period
Poor granulated or had 2 of the 4 features - mitotic figures, multinucleated cells, nuclear polymorphism, >50% anisokaryosis
88% and 94%
Hergt et al. Use of a 2-tier histologic grading system for canine cutaneous mast cell tumors on cytology specimens
Agreement between histologic and cytologic grading was achived in 133 cases - sensitivity and specificity
5 high grade tumor on histology were classified as low grade on cytology
87% and 97%
Weisharr et al. 2018. c-kit mutation and localization status as response predictors in MCT in dogs treated with Prednisone and toceranib or vinblastine
Dogs treated with TOC 2.75 mg/kg EOD or VBL 2.5 mg/m2 weekly x 4 then EOW
20% of TOC had kit mutations and 30% receiving VBL
RR to TOC and VBL?
Median PFS for TOC and VBL?
MST for for TOC and VBL?
46% and 30%
95.5 days and 78 days
159 (5 mo) and 241.5 days (8 mo)
Case et al. 2018. Safety and efficacy of intralesional triamcinolone administration for treatment of MCT in dogs: 23 cases (2005-2011)
RR?
Median time to progression?
67%
63 days
Griffin et al. 2018. Pilot study utilizing flourine-18 fluorodexoyglucose-positron emission tomography/CT for glycolytic phenotyping of canine MCT
Hypothesized enhanced glucose uptake would correlate with grade
Correlation between grade of MCT and SUVmax - unable to show that this is a better staging tool
Horta et al. 2018. Assessement of canine MCT mortality risk based on clinical, histologic, IHC, and molecular features
Joselevitch et al. 2018. Nanog expression and proliferation indices in canine cutaneous MCT
NANOG is a pluropotency factor expressed by normal and cancer stem cells
All samples were positive for NANOG but expression not correlated with Ki67 but no significant difference between grade, disease related mortality, or survival
Not reliable prognostic factor
Gregorio et al. 2017. High COX2 expression in canine MCT is associated with proliferation, angiogenesis, and decreased OS
COX-2 intensity but not COX-2 extension is associated with decreased OS and higher grade of malignancy
Cox-2 intesnity associated with higher ki67, higher MI, higher microvascularization density
No association was observed for COX-2 intensity and CD3 T-lymphocyte and macrophage infiltration by MAC-387 immunolabelling
Upchurch et al. 2018. Amount of skin affecting tumor versus gross normal marginal skin of dogs for cutaneous MCT excised with curative intent
Overall shrinkage?
Amount of shrinkage with gross visible tumor (4.45%) was less than within the surrounding normal skin (24%)
Most shrinkage occured when?
18%
Right after excision
Russell et al. 2017. Characterizing microcopial invasion patterns in canine MCT and STS
Invasion in both circumferential and deep directions was greated in?
In MCT group, ___ invasion was greater than ___ invasion
2 variables associated with incomplete MCT excision?
MCT vs. STS
circumferential than deep invsion
intraoperative grossly normal circumferantial margin size and assymetry invasion index
Marconato et al. Therapeutic impact of regional lymphadenectomy in canine stage II cutaneous MCT
The risk of developing local, nodal, distant relapse was higher in ___ group
Risk of tumor progression and tumor related death were 5.47 and 3.6x higher in ___ group
Regional lymphadenectomy may have therapeutic value and improve prognosis in dogs with stage II MCT
LNS - LN sampling
LNS vs. LND (LN dissection)
Berlato et al. 2018. Comparison of minichromosome maintenance protein 7, Ki67 and MI in the prognosis of intermediate Patnaik grade cutaneous MCT in dogs
Sabarrini et al. 2018. Comparison between May-Grunwald-Giemsa and rapid cytological stains in FNA of canine MCT
How many of primary MCT were hypogranular with aqeous rapid stain (RS)
Accuracy in cytological grading assessment (85%) did not differ between RS and MGG
How many metastatic LNs were hypogranular with RS?
Use of RS is discouraged for search of nodal metastases
18%
46%
Ferrari et al. 2018. The impact of extirpation of non-palpable/normal sized regional LN on staging of canine cutaneous MCT
33 (35%) were HN0, 14 (15%) were HN1, 26 (28%) were HN2 and 20 (21%) were HN3
The presence of positive (HN>0) RLN was associated with cMCT larger than 3 cm
Blackwood et al. 2017. Acute RT toxicity in 57 dogs with gross and microscopic MCT
57 dogs - 28 gross disease and 29 microscopic disease
No difference in toxicity between gross and microscopic disease
Variable associated with increased toxicity?
Use of prednisolone prior to radiotherapy
Scarpa et al. 2012. Use of histologic margin evaluation to predict recurrence of cutaneous malignant tumors in dogs and cats after surgical excision
60 surgically excised tumors - 20 STS, 20 MCT, 20 carcinomas
Surgical margins clean 48%, close in 18%, and infiltrated in 33%
Recurrence rates for animals that had infiltrated tumors or close margins were higher than with clean margins
Margin classification was predictor of RFI (recurrence free interval)
Accuracy of method to predict recurrence was 95% carcinomas, 87% STS, 76% MCT
Evan et al. 2018. Treatment outcomes and prognostic factors of feline splenic mast cell tumors: A multi-institutional retrospective study of 64 cases
Splenectomy (A n=20), splenectomy and chemotherapy (B, n=20), chemotherapy alone (C, n=15), or supportive care (D, n=9)
Median tumor specific survival (MTSS) for A, B, C, D
Splenectomy prolongs survival in cats with MCT. Role of chemotherapy is unknown.
A = 856 (2.3 y)
B = 853 (2.3 y)
C = 244 (8 mo)
D = 365 (1 y)
Ho et al. 2018. Retrospective study of more than 9000 feline cutaneous tumors in UK: 2006-2013
Prevelence of masses on the skin?
Prevalence of non-malignant and malignant?
4 most common tumors?
- 4%
- 6% and 52.7%
Basal cell tumors, FSA, SCC, MCT
Dobromylskyj et al. Evaluation of minichromosome maintenance protein 7 and c-kit as prognostic markers in feline cutaneous MCT
71 feline cutaneous MCT
What factors were associated with survival times?
MI and kit labeling pattern, while MCM-7 (proliferation marker) and KIT reactivity score were not
Melville et al. 2015. Feline cutaneous mast cell tumors: a UK based study comparing signalment and histological features with long term outcomes
Second most common skin tumors in cats
How many died from MCT?
Median age?
Sex or neuter predilection?
Breeds predisposed?
Common location in older and younger cats?
What was associated with survival time?
17.4%
11 years
None
Pedigree breeds - Siamese, Burmese, Russian Blue, Ragdoll
Trunk in older and head in younger
Mitotic index but not histological type
Kraus et al. Outcome and Prognostic Indicators in Cats undergoing splenectomy for splenic mast cell tumors
36 cats with splenic MCT undergoing splenectomy
MST?
What factors were negatively associayed with survival?
What was associated with improved survival time?
390 days
Blood products, metastasis to regional LN, evidence of concurrent or historical neoplasia
Response to chemotherapy
Sabattini et al. 2016. Feline intestinal MCT: clinicopathologic characterisation and KIT mutation analysis
10 tumors in SI, 2 in ileocaecocolic junction, 5 large intestine
Survival times 5-538 days
6 well differentiated, 6 moderately differentiated, 3 poorly differentiated
Poorly differentiated - deposition of collagen, higher mitotic and ki67 index compared to more differentiated tumors
On survival analysis, tumor degree of differentiation and mitotic index >2 were associated with decreased survival time
Kit pattern - membranous (33%), focal paranuclear (33%), diffuse cytoplasmic (13%)
Cytoplasmic kit was associated with lesser differentiation
Harper et al. 2017. Toxicity and response in cats with neoplasia treated with toceranib phosphate
MCT or malignant epithelial tumors - 14 cats
Toxicity?
Overall biological response rate?
Response in MCT?
Duration of response?
10/14 - mild myelosuppression or GI effects, 2 had severe hepatoxicity, 1 died from CHF - unknown if related to palladia
57%
Partial or complete response
3 months
None of the SCC achieved a response
Barrett et al. Outcome following treatment of feline GI MCT (FGIMCT)
31 cats with FGIMCT
Mean age?
Metastatic sites?
Therapies: chemo alone (15), surgery and chemo (7), steroids alone (6), surgery and steroids (3)
Most commonly used chemo drugs?
MST?
Treatments associated with prolonged survival?
Treatment other than prednisolone may not be necessary in some cats.
12.9 y
Abdominal LNs (10), abdominal viscera (4), both (2)
Lomustine (15) and chlorambucil (12)
531 days (1.5 y)
Surgery and medial treatments (including prednisolone)
Berger et al. 2018. Restrospective evaluation of toceranib phosphate use in cats with mast cell neoplasia
50 cats with cutaneous (n=22), splenic/hepatic (visceral) (n=10), GI (n=17), or other (n=1) mast cell neoplasia
Clinical benefit? - cutaneous, visceral, GI
Majority of cats received glucocorticoids during toceranib treatment
Median duration of CB for cutaneous, visceral, GI?
Dosage: 2.5 mg/kg 3x/week
AEs?
80% - 86% cutaneous, 80% visceral, 76% GI
36 weeks, 48 weeks, 23 weeks
60% - grade 1 or 2 GI or hematological events
Sakuri et al. 2018. Expression of stem cell factor in feline MCT
23 samples of feline MCT
SCF expression?
Location of SCF-positive tumor cells in cutaneous MCT?
Expression of kit in the SCF positive tumors?
Ki67-positive tumor cells?
10 cutaneous MCT and a case of splenic mastocytosis
Located at the margins
8/10 cutaneous - kit-positive cells were located near the SCF-positive cells
Not found near the SCF-positive cells
SCF-autocrine/paracrine mechanism are involved in the expansion of cutaneous MCT, but not in tumor proliferation
Sabattini et al. 2018. Grading Cutaneous MCT in Cats
Group 1 - cats alive with no MCT-related disease 1000 days from surgery
Group 2 - cats developing histologically confirmed metastatic or cutaneous disseminated disease
High grade - >5 mitotic figures abd atleast 2 criteria - tumor diameter >1.5 cm, irregular nuclear shape, and nucleolar prominence/chromatin clusters
24% of high grade MCT had reduced survival time (349 days) compared to low grade tumor - MST not reached
Further studies are warranted
Elbahi et al. Histiocytic-like atypical mast cell tumors in Horses
1-2cm in diameter and localized to the eyes (one eyelid, 2 conjunctiva)
