Melanoma Flashcards by Megan S

What are the four IHC markers in the melanoma cocktail? What else can be used?

PNL2, melan-A, TRP-1, TRP-2

Also S-100

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What is the sensitivity and specificity of the melanoma cocktail?

Sn >90%, Sp 100%

Smedley Vet Path 2011

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T/F: BRAF mutations are common in canine melanoma.

False

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Name two pathways that are constitutively activated in melanoma and can be effectively targeted in vitro?

MAPK and PI3K/AKT
(Fowles 2013)
- rapamycin inhibits PI3K/AKT

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In canine oral melanoma, which proliferation index (IHC) predicts behavior and what is the significant level?

Ki67 value of >19.5
Sn 87.1%/Sp 85.4% at predicting death/euthanasia by 1yr post-dx
(Bergin Vet Path 2011)

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For oral and cutaneous melanoma in dogs, what are the MI cut-offs?

Oral >/= 4/10 hpf

Cutaneous >/= 3/10 hpf

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What is the approximate MST for stage 1 oral melanoma tx with surgery?

Withrow - 17-18mo
Boston - 20mo
Tuohy - 24mo

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What is the approximate MST for stage 2 or 3 melanoma tx with surgery alone?

Withrow - stage 2 = 5-6mo, stage 3 = 3mo

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What is the approx. recurrence rate for melanoma tx with matxillectomy and mandibulectomy?

Maxillectomy - 48%

Mandibulectomy - 22%

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What is the likelihood of dying from disease with incomplete margins?

3.6x more likely to die

caudal tumor 4.3x more likely

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What is the RR of melanoma to RT? PFS?

82-94%
PFS 5-8 mo
(for feline - 3/5 cats (60% RR) in Farrelly paper)

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What is MST for oral melanoma tx with RT alone?

7-10mo depending on study

2015 Kawabe JAVMA:

stage 1: 2yrs
stage 2: 9mo
stage 3: 5mo
stage 4: 2.7mo

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What is the likelihood of tumor progression/recurrence after RT for oral melanoma? (adjuvant vs. RT alone)

microscopic - 26%

macroscopic - 45%

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What is the RR to platinum chemo for canine melanoma?

18-28%

Boria/cisplatin = 18%, Rassnick/carbo = 28%

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What proportion of dogs develop humoral immune response to xenogeneic tyrosinase vaccination? Horses?

Dogs - 1/3 (3 out of 9)

Horses - 100% (5/5 in Lembcke Equine Vet Sci 2012)

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How does PDGFR impact prognosis in canine melanoma? (Lussich VCO 2016)

PDGFRa and B receptor co-expression and Ki67 values >19.5 were both associated with worse prognosis

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What adjuvant therapy may improve time to progression in dogs with oral melanoma after RT? (Cancedda VCO 2014)

temozolomide

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What % of dogs have AE to melanoma vaccine? (Sarbu 2015)

11% - grade 1-2 pain, muscle fasciculation, nausea/inappetence, pigmentation at injection site

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Two prognostic factors for feline non-ocular melanoma? (Luna 2000, Chamel 2016)

Amelanotic vs. pigmented

surgical vs. nonsurgical tx

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Describe stage 3 oral melanoma.

Tumor >4cm and/or RLN involvement, no distant metastasis (that would be stage 4).

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Stage 1 melanoma treated appropriately has reported MST of?

12-19 months

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What % of dogs with OMM have LN mets with normal palpation?

40%

70% when nodes are big

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Why are hypofractionated RT protocols more effective in OMM?

Low alpha:beta ratio

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What is the %CR of OMM to RT?

51-69%

PR 25-31%

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What is the significance of c-kit expression in melanoma? (Newman Vet Path 2012)

Loss of c-kit common in neoplastic tumors; potential for prognostic indicators c-kit was strong and diffuse in all dermal melanomas

What was the incidence of BM and GI toxicity in dogs with various tumors treated with dRT and concurrent carbo?

21% grade 3-4 neutropenia; 20% grade 3-4 thrombocytopenia | 10% grade 3-5 GI tox

T/F: Carbo reduces the proportion of dogs with OMM that die of metastasis?

False

T/F: Dogs with higher plasma VEGF treated with RT have shorter time to tx failure and shorter MST.

True (Taylor VCO 2007)

What 4 criteria must be met to diagnose a radiation-induced tumor?

1. develops in previously irradiated site 2. adequate time has passed (> 1 year) 3. Pre-irradiation revealed normal bone 4. Histologic dx of a second, different malignant tumor confirmed

What are the most common RT-induced tumors?

sarcomas

What two negative prognostic factors were identified in dogs with digital melanoma tx with the vaccine?

1. advanced stage dz | 2. increased time from digit amp to starting vaccine

Is the Wnt B-catenin pathway activated in oral melanoma?

Is the Wnt B-catenin pathway activated in cutaneous melanoma?

Yes

What is the biologic activity of Palladia against canine melanoma? (London 2003)

54%

What was the 1 year survival rate for dogs with digital melanoma treated with a murine tyrosinase DNA vaccine?

63% | MST = 476d

What were the effects of an anti-PD-L1 antibody in vitro? What were effects in 7 dogs with OMM and 2 with undifferentiated sarcoma? (Maekawa 2017)

in vitro - increased cytokine production and proliferation of dog mononuclear cells OMM - objective response in 1 dog Sarc - objective response in 1 dog

What is prognostic in non-ocular melanoma in cats? (Chamel 2016)

amelanotic associated with worse prognosis

What is IQGAP1? Is it expressed in human and/or canine melanoma? (Lee PLoS One 2017)

It is a signaling scaffold that regulates oncogenic ERK1/2 MAPK signaling in human Ras and Raf driven cancers Yes, expressed in both human and canine melanoma.

What is bosutinib? How did it affect melanoma cells?

SRC inhibitor | Caspase-independent apoptosis

In a study by Grimes et al in 2017, what was the conclusion regarding agreement between cyto and histo for LN metastasis and association with survival?

Poor agreement, no association with survival.

What was PFS and MST in dogs with malignant anal sac melanoma, regardless of tx? (Vinayak 2017)

``` PFS 92.5d (3mo) MST 107d (3.6mo) ```

What is Oncept vaccine licensed for?

Stage II-III OMM with adequate local control

How does Pgp expression differ between oral and cutaneous melanoma? (Finotello 2016)

100% expressed in OMM, 66.6% expressed in cutaneous | Could be a reason for chemo resistance

What does binding of PD-L1 to PD-1 cause?

When PD-L1 binds PD-1 on T cells --> negatively regulates activation signals from T cell receptor --> results in inhibition of effector function of cytotoxic T cells

What cancers express PD-L1? (Maekawa PLoS One 2016)

melanoma, OSA, cHSA, MCT, mammary ACA, prostate ACA

In a study by Skinner et al (2016), what % of dogs with malignancies of the head had LN mets?

45%

In a study by Skinner et al (2016), what % of the dogs with metastasis had mets to the contralateral node?

62% (92% had ipsilateral mets)

In a study by Skinner et al (2016), what % of the dogs OMM had mets to all four lymph centers?

4 of the 13 (30%) | Based on this study, recommend extirpation of all four LN with head/neck tumors, especially OMM.

How did 2 year survival of OMM with CSPG4-antigen electrovaccination compare to surgery alone?

30.4% vs. 5.3%

What % of dogs with stage II-III melanoma die within 1 year of surgery?

70-75%

What pattern of PDGFR expression is associated with worse prognosis?

PDGFR-alpha and beta co-expression.

What % of cats had AE to melanoma vaccine?

29%; all were mild

Is IL-12 pro-inflammatory or anti-inflammatory? How does it work?

Pro-inflammatory cytokine. Mediates Th1 response and cytotoxic T-cell activation.

What is NHS-IL12? (Paoloni PLoS One 2015)

antibody that targets necrotic tumor regions linked to IL-12

What two markers in the serum increased after NH-IL12 administration? Did any of the dogs respond? (Paoloni PLoS One 2015)

``` IL-10 and CD8+ increased in serum. 2 dogs (out of 18) responded (was not primary endpoint for the study) ```

What are the prognostic factors for survival post curative-intent surgery for OMM? (Tuohy 2014)

administration of adjuvant therapy; presence of mets at dx; higher stage (III or IV); tumor size >3cm; intact female dogs (note that admin of adjuvant therapy associated with 130% risk of dz progression - prob gave adjuvant therapy to worse cases)

What was the median PFI and MST for curative-intent surgery for canine OMM? (Tuohy 2014)

``` PFI 508d (1.4y) MST 723d (2y) ```

What is the role of miR-203 in human and canine melanoma? (Noguchi 2016)

tumor-suppressive miRNA

What are cancer stem cell markers (used to identify CSCs in OMM in Guth 2014)?

CD133, CD34, CD44, CD24, Oct3/4 | This study found that CSCs were rare in cancer cell lines in comparison to tumor samples

What were poor prognostic indicators in Boston et al 2014 (evaluating adjuvant therapy in 151 OMM cases)?

tumor size, patient age, intralesional excision (vs. marginal, wide, or radical)

Did Boston et al 2014 identify survival benefit for adjuvant therapy with canine OMM?

No -- no post op-tx MST was 335d, with post-op tx MST was 352d (small sample sizes)

Does maropitant have anti-tumor effect in melanoma xenograft models? (Borrego 2016, Vail)

No; did have effect in cell lines but likely off-target | Study failed to ID cell line or xenograft that has NK-1R mRNA or protein (neurokinin-1 receptor)

Four genes with increased expression in metastasizing uveal melanoma (Malho 2013)

HTR2B, FXR1, LTA4H, CDH1

What proteasome inhibitor inhibits growth of canine melanoma cells in vitro and in vivo? (Ito K 2013)

bortezomib | growth inhibition may be secondary to suppression of NFkB pathway

Levels of ___ and ___ were decreased in K9 OMM xenograft models when treated with CTX + piroxicam. (Choisunirachon VCO 2015)

MVD and VEGF

Is the Wnt/B-catenin pathway activated in canine OMM? (Chon 2013)

No (rare)

Does expression of tyrosinase correlate with pigmentation in dogs? Horses? (Phillips 2012)

No for both

Is c-kit expression a positive or negative prognostic indicator in canine mucosal melanoma? (Newman 2012)

positive (loss of expression correlated with decreased survival)

What is p21/Waf-1?

Universal CDK inhibitor - loss of function permits cell growth. May have a role in melanoma cells (TLM-1).

What tumor suppressors May play a role in malignant melanoma?

p53, p21/waf-1, p16/ink-4a

What does the Oncept vaccine encode for?

The Oncept vaccine uses xenogeneic DNA plasmids that contain the gene encoding human tyrosinase (huTyr)

What is the MST after enucleation for feline uveal melanoma that has invaded into the ciliary body and sclera?

1.5 yrs

T/F: Enucleation improves MST in cats with malignant uveal melanoma?

False

What is the metastatic rate of feline malignant melanoma of the anterior uveal?

55-66%

What % of canine intraocular melanomas are benign?

78%

What is the most common malignant tumor of the canine conjunctiva?

melanoma

T/F: Most feline eyelid tumors are malignant?

True

What were results with L-MTP-PE and melanoma? (Withrow)

stage I oral melanoma that received L-MTP-PE had increased survival over placebo dogs

What is the 1 year survival rate for dogs with digital melanoma?

42-57%