Canine MCT Flashcards by Bushra Zaidi

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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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%

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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

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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

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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

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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

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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%

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Elliot et al. 2016. Canine oral mucosal MCT

33 dogs with MCT

Incidence of metastasis?

Adequate local control had improved outcome

55%

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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%

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***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 cutaneo**us 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 1. 6 mg/m2 EOW 3. 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. T*he 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. C*omparison 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. 4% 6. 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)