tumor specific 25% LC Flashcards
what is the only fda approved veterinary therapy that is adaptive and specific ?
xenogenic DNA vaccine
- oncept
Most common loss of heterozygosity ?
mutations in tumor suppressor genes - p53
examples of loss of heterozygosity mutations
p53
PTCH
BRAF (human melanoma)
loss of INK4a (familial cut melanoma)
common locations of melanoma
- digital, nail bed, foot padn- dog
- haired skin
- oral cavity
- GI tract
- eye,
- nasal cavity
- anal sac
- mucocutaneous junctions
Oral melanoma, should you remove unilateral LN vs both LN vs no literature to support removing LN ?
histologic examination of the LN is recommended either through excision of the major LNs of the head and neck or sentinel LN (SLN) mapping
Selective lymphadenectomy avoids the indiscriminate extirpation of multiple LNs and, because it is a less extensive surgical dissection, reduces the risk of postoperative complications
equine melanoma treated with doxorubicin response rate
25% CR
ORR 47%
location of metastatic melanomas
lymph nodes, lungs, liver, meniges, adrenal gland
most common oral malignancy in the dog and common locations
melanoma
gingiva, lips, tongue, and hard pal- ate
oral melanoma common breeds
goldens, scottish terriers, chow chows, poodles, dachshunds
differentials for oral tumors
melanoma, squamous cell carcinoma, fibrosarcoma, osteosarcoma, acanthomatous ameloblastoma, and peripheral odontogenic fibroma
melanoma ihc cocktail
PNL2, Melan A, S100, tyrosinase, vimentin
BRAF mutations are common in human UV induced melanoma are they common in dog oral melanoma
no but they do have downstream ERK constituative activation
melanoma- associated genes clustered in the areas related to what pathways and processes
focal adhesion and PI3K-Akt signaling pathways, extracellular matrix–receptor interactions, and protein digestion and absorption
a small subset of dogs with malignant melanoma have mutations in what gene at what exon
c-kit exon 11
biologic behavior of haired skin melanoma
benign
surgery is curative with clean margins
What kind of vaccine is the k9 melanoma vax ONCEPT?
Xenogenic plasmid with human tyrosinase
What are prognostic factors for digit/nailbed tumors?
High stage regardless histo
distant mets in melanoma
Tx and survival times for digit/nailbed SCC?
Dog with sx good 2yr 40% and subungal better with 2yr 75%,
Cat 73days-30wk
2.5 mths - 7.5 mths
Tx and survival for digit melanoma? stage 1
Amp MST 12 months 1yr survivial ~ 50%
2 yr survival 12%
sx+Vax MST 476 days (16mths)
digital melanoma metastasis at diagnosis
30 - 40 %
how do dogs with digital melanoma die from their disease
distant or local mets
What are some molecular pathways that are mutated/changed with melanoma?
C-erb2, c-myc, BRAF(human), VEGF, β catnenin
What are prognositic factors for skin melanoma?
Histology, mitotic, location, breed, DNA ploidy, proliferation, lymphatic invasion
What are prognostic factors for oral melanoma?
Mitotic, size, stage, mets, bone lysis, location
What is the survival time with oral melanoma based on stage treated with surgery ?
Stage 1 (<2 cm no mets)- 12 - 30 months,
stage 2 (2-4cm no mets)- 5 - 27 months,
stage 3- (>4 cm +/- LN mets) 5 - 7 months
Stage 4 (distant mets) 80 days
dogs with stage I oral melanoma treated with standardized therapies, including surgery, RT, and/or chemotherapy, have an MST of approximately
12-14 mths
dogs die of distant mets not local recurrence
stage 1 oral melanoms PFS
19 months
melanoma staging
TNM WHO staging
in melanoma what % of LN are metastatic that are normal in size? big in size?
LN metastasis is present in approximately 70% of dogs with lymphadenomegaly
mets in approximately 40% with normal sized LNs.
what is an advance novel staging modality that may show melanoma mets
gallium citrate scintigraphy
CT
surgical margins for cutaneous melanomas
1 cm and 1 fascial plane deep
malignant melanomas surgical margins
2-3 cm wide and one fascial plane deep - underlying bone resection encouraged
or follow with RT
oral melanoma prognosis without complete excision
65 days
Dogs with incomplete histologic excision are 3.6 times more likely to die of tumor-related causes compared with dogs with complete histologic excision
melanoma behind premolar 3 were how much more likely to cause death (as opposed to rostral tumors)
4.3 times more likely to cause tumor related death
mst oral melanoma no sx
65 days - 2 mths
How does the melanoma vaccine Oncept work?
Human tyrosinase expressed on melanocytes causes Ab & Tcell response, same species do not generate enough response but xenogenic overcomes self tolerance
dendritic
What is survival in CMM with vaccine?
Stage 2-3 locoregional control 569 days. (19 mths)
What is unique about melanoma and RT?
Melanoma low a/B so hypofractionated or course fx better than small dose/fx
Low α/β ratio, or increased sensitivity to large fraction size 5-9 gy ( more acute tox less late tox)
melanoma response to RT?
Yes, 80-94% respond overall
25 - 70% cr
20 - 70% PR
recent study 0% response, 73% stable
pfs with rt for canine melanomas
PFS 4-8 months
How does RT+carbo work for melanoma?
Carbo thought to sensitize but differing results on if it helps, more AE with combo
What are the most common eye tumors in cats and dogs?
Dog conjunctiva melanoma
Cat anterior uveal melanoma
What are risk factors for developing ocular tumors?
UV, trauma
What ocular tumor are blue-eyed dogs at risk for developing?
Spindle cell sarcoma
What ocular tumors have the highest metastatic rate?
cat uveal intraocular melanoma and orbital tumors
melanoma mets but very slowly
local recurrence rate after rt in microscopic dz setting (melanoma)
26%
local recurrence rate after rt in macroscopic dz setting (melanoma)
45%
MST for dogs treated with RT with melanomas
4.5 - 15 months
RT protocols for melanoma
8 Gy x 4 (32Gy)
6 Gy x 6 (36 Gy)
cats treated with rt with oral melanoma mst
146 d (~5 mo)
one complete response
two partial response
dog with t1 or t2 melanoma treated with carbo radiosensitization 6gy x 6
recurrence rate
tt mets
mst
15% recurrence
10.2 months till mets
mst 12 months
dogs with oral melanoma treated with surgery and carboplatin
pfs
mst
when rt added?
recurrence rate?
overall median PFS (259 days - 9 mth)
MST (440 days - 15mth)
- did not significantly change when RT was added to the treatment protocol
- proportion of dogs with local recurrence was lower in the RT group (27%) compared with dogs not treated with RT (67%)
malignant melanoma in oral and non oral sites treated with RT vs RT + temozolamide
ORR
TTP
MST
ORR not sig diff - 81-87%
TTP - 205 d (6.8 mo) with RT+ temo vs 110 (3.5 mo) with RT only
MST not stat sig - 192 d (6.4 mo) vs 402 d (13 mo)
rt and melanoma tumor size MST
size <5cm3 86 weeks- 22 mths
5-15 cm3 16 wks - 4 mths
> 15 cm3 21 wks - 5 mths
RT and melanoma and VEGF
dogs with higher plasma VEGF levels treated with hypofractionated protocols had a shorter time to treatment failure and a shorter MST
RR for gross melanomas treated with:
cisplatin/piroxicam
carbo
chemo in general
- 18%
- 28%
five retrospective studies investigating the role of chemotherapy in the adjuvant set- ting after either surgery or RT found no significant differences in outcomes with the addition of chemotherapy to the treatment protocol
result of oncept trials
(1) is safe
(2) leads to the development of antityrosinase antibodies and T cells (3) is potentially therapeutic
(4) is an attractive candidate for further evaluation in an adjuvant, minimal residual disease phase II setting for canine MM
stage 3 and 4 melanoma treated with masitinib
MST
AE
success
MST 119d - 4 mth
low grade ae in all dogs - anemia diarrhea and anorexia
not good as single agent
microRNA expression in
CMM
OMM
CMM - decreased in some and increased in others
OMM - downregualted
checkpoint expression in melanomas vs melanocytomas
PD1/PDL1 sig higher in melanoma
can endotracheal intubation cause seeding of OMM
Suspected Iatrogenic Seeding of Oral Melanoma Secondary to Endotracheal Intubation in a Dog
pleural effusion reportedly melanocytic
following incomplete mm removal in a dog
Correlation Between KIT Expression and c-Kit Mutations in 2 Subtypes of Canine Oral Melanocytic Neoplasm
No relationship between c-Kit mutations and KIT expression
This DOES NOT support the used of c-kit targeting therapies
tumor infiltrating lymphocytes in oral melanoma
longer survial associated with higher TIL scores and higher CD8+ lymphs
lower CD4+/CD25+/FoxP3+Tregs
tumor size as a predictor of lymphatic invasion in omm
tumors <6.5mm (<0.6 cm) had no lymphatic invasion with 100% sn
tumors >24.5 mm (>2.4 cm) had guarantee of lymphatic invasion of 100% sp
expression of cyclin D1, Ki67 in omm
Cyclin D1 was detected in 69%
Ki-67 was present in 88.5%
cyclin d1 may be a marker of prognosis
somatic focal amplification on chromocome 30 Canis Familiaris [CFA] associated with what type of melanoma
amelanotic omm
linked to poor prognosis
prognostic factors for omm
gingival location MUTLIPLE STUDIES, lymphadenomegally, tumor ulceration, >6 mf
Important draining LN in OMM according to Javma study
frequency of LN mets in a OMM
frequency of contralateral ln
37% LN in omm
MRLN 81% (18% of these did not have mand ln)
23% contralateral
Evaluation of prognostic impact of pre-treatment neutrophil to lymphocyte and lymphocyte to monocyte ratios in dogs with oral malignant melanoma treated with surgery and adjuvant CSPG4-antigen electrovaccination
No sig associated between leukocyte ratios and outcome
Evaluation of accuracy for 18F-FDG positron emission tomography and computed tomography for detection of lymph node metastasis in canine oral malignant melanoma
CT clinical grading sens 83%, spec 94%
PET techniques 100% sens but requires SUV (standard uptake value) standardization to be specific
Difference in outcome DFI and ost between curative intent vs marginal excision as a first treatment in dogs with oral malignant melanoma and the impact of adjuvant CSPG4-DNA electrovaccination
DFI sig shorter in dogs with marginal excision over curative intent (6 mths vs 8 th) but not sig. on OST
Chondroitin sulphate proteoglycan 4 [CSPG4]
cellular membrane Ag overexpressed in canine melanoma cells (57%)
early cell surface progression marker involved in tumor cell proliferation, migration and invasion
bone invasion impact on ost for omm
Dogs with bone invasion was sig shorter than without 397 d (13 mth) vs 1063 d (35 mth)
worse ost with high Ki67 and MC >4
pfs and ost in gross omm treated with 36gy
pfs 171 d - 6mth
ost 232 d - 8 mth
improved if low WHO stage (I/II) and irradiating subclinical disease
omm and phagocytic activity
Canine oral primary melanoma cells exhibit shift to mesenchymal phenotype and phagocytic behavior which may play a role in progression
CD146 expression on OMM
expressed on on primary melanoma cells
maybe be a prognostic marker
Long-term survival of dogs with stage 4 oral malignant melanoma treated with anti-canine PD-1 therapeutic antibody
pulmonary nodules regressed
local tumro control
2 dogs
what is the effect of FOXP3, CD3, and IDO on cutaneous melanomas
Increased risk of tumor related death with increased FoxP3 cells per HPF and CD3+ cells that were FoxP3+ surrounding the tumor, and IDO+/HPF
IDO+/HPF independent prognostic factor
metastatic rate of foot pad melanoma
55%
outcome of food pad melanoma treated with surgery +/- adjuvant therapy
PFI 101 d (3.5 mth)
MST 240 d (8 mth)
adjuvant therapy did not improve outcome
TIL in feline mnelanocytic tumorts
TIL increased with MC and cellular pleomorphism
TIL Inversely associated with positive melan A PNL2 staining cells
TIL may be associated with features of malignancy
nasal planum melanocytic tumors in cats predisposing factor
pigmentation
nasal planum melanocytic tumors in cats MST
265d (9 mth)
LN mets in one
short term remission acheived with rt
is circulating cell free dna in cats with diffuse iris melanoma useful
not a good markers even if mets
non ocular melanomas in cats prognostic factors
tumor site ( lips, oral, nasal, mucosa, nasal planum )
MC >4
intratumoral necrosis
grading of non ocular melanomas in cats
SN and SP of the scheme
high grade if aggressive location and one of these: mc>4, intratumoral necrosis present
high grade if other location and both MC>4 and necrosis
80% sensitivity, 92% specificity for predicting tumor related death
MST of non ocular melanomas in cats
MST high grade 90 days
MST low grade not reached
TIL and prognostic factors in canine melanoma
CD20+ TILS sig associated with MI, pleomorphism, and pigmentation as well as tumor related death, presence of mets/recurrence, shorter OST and DFI
high CD20 is neg prog indicator
pevonedistat is a selective NEDD8 activating enzyme (NAE) inhbitor. what is its affect on malignant melanoma cells
Pevonedistat sig reduced viability of cells in dose and time dependent manner.
Promotes apoptosis and inhibits growth through DNA re-replication and cell senescence
- Some cell lines resistant
- P21 levels increased in more sensitive lines
COX 2 expression in cutaneous melanomas
over expressed in 42% OF CMM
cox 2 expression in oral mm
over expressed in 34% of omm
Histone demethylase inhibitors may be a potential therapeutic strategy for OMM. may decrease resistance to what chemotherapeutics
platinum agents
JARID1B
histone demethylase that causes proliferation dormancy and decreases drug sensitivity
highly expressed in canine melanomas
Antitumour effects of Liporaxel (oral paclitaxel) for canine melanoma
Induced anti angiogenesis - CD31 antibody on ihc
Induced apoptosis - terminal deoxynucleotidyl transferase dUTP Nick End labeling assay (TUNEL)
Down regulated cyclin d1 and inhibited cell proliferation - western blot
what cbc findings might you see in a cat with an intestinal mast cell tumor
anemia from perforation
commonly have mastocytosis and eosinophils
when combining vinblastine and palladia for mast cell tumor treatment what is recommended in terms of dosing and why
1.6 mg/m2 vinb - 20% dose reduction from low end 50% dose reduction from high end
palladia 3.25 mg/kg (2.75 in a later paper)
neutropenia is DLT
What do mast cells contain?
Histamine, heparin, vasoactive amines, prostagladinD, proteolytic enzymes
What other disease in dog have mast cells in periphery?
Parvo, skin diz, trauma, other neoplasia
breeds commonly affected by MCT
mbd, boxer, Bos- ton terrier, English bulldog, pug, Labrador and golden retrievers, cocker spaniels, schnauzers, Staffordshire terriers, beagles, Rhode- sian ridgebacks, Weimaraners, and Chinese shar-pei
genes identified in Goldens with MCT
GNAI2 gene and multiple genes associated with hyaluronic acid synthesis may be risk factors for MCT development
how do MCT in young animals behave
can spontaneously regress
described in cats, pigs, horse, and humans
one report of multiple mct regressing in jack Russel
is there a cause of MCT
thought to be chronic inflammation or skin irritants
Chromosomal fragile site expression, a phenomenon thought to genetically predispose humans to develop certain tumors, was shown to be increased in boxer dogs with MCT
VEGFR2 activation and mct
vegf expression has bee shown in many mct
preliminary evidence that VEGFR2 activation may be associated with inferior post surgical outcomes
Which breeds have benign MCT?
boxer, pug, bulldog, goldens in one study
Which breeds have malignant MCT?
GR, mastiff, Shar-pei, rottweiler, Shih Tzu, frenchie, pit bull
Survival of gastric MCT?
10% @ <6months
Are multiple cutaneous MCT worse or better? What stage?
Stage3, Don’t know if de novo but one study MST not reached
What are the metastatic rates with grade in MCT?
Grade1 <10%,
grd2 5-22%,
grd3 55-96%
What is the survival with mets to liver, spleen, abdominal Ln for MCT?
34 days
What is the metastatic rate of SQ MCT?
6%
Prognostic factors for MCT?
Grade, proliferation, size (own , ckit, location, stage(1vs. 3)
What is survival with MI in MCT?
MC <5 MST 70months 5.8 yrs
MC >5 MST 2 months regardless of grade
vs
MC < 7 MST >2 YEARS low grade
MC >7 MST < 4 mth high grade
What is survival with Grade 2 MCT Ki67 >1.8
1yr survival 43%
2yr survival 21%
What locations have been associated with decreased survival for mct?
Mucocutaneous, nailbed, inguinal/peringuinal
Is inguinal truly worse for mct location?
Not in one study but preputial/scrotal MST 4.2months
What is the survival of oral/perioral mct?
MST 52months that decrease to 14months if mets
What is the survival of muzzle mct?
what % have mets at dx
MST 30 months, with 46% with mets @dx
What % of pathologist agreed on grade 1-2 patnick MCT?
<64%
What characteristics are evaluated for 2-tier MCT grading?
Mc, bizarre nuclei, multinucleated cells, karomegaly
What is the % recurrence with incomplete margins mct ?
25-30% especially grade 2
What is the survival with 2-tier MCT grading?
Low >2yr
High 4months
What is the survival with grade3 sx alone?
MST 9months, recurrence 50-60%
What is rr of palladia with RT for gross MCT?
ORR 76.4%
MST not reached
what is rr of pred with rt for gross mct?
ORR 88.5%
PFS 1031days(34 mo. 2.8yr)
Survival times for grade3 MCT sx with vinblastin/pred?
MST 1374 days (45 mo, 3 yr), another not reached
What is the response with pred/vinblastine in gross MCT?
rr 47%
MST 154days
grd3 MST 134days
What is the % response with vincristine and vinorelbine with gross MCT?
Vinc 7%, vinorelbine 13%
What is the response with CCNU with MCT sx removed?
42%
What are the responses of mct with hydroxyurea and chlorambucil?
Hydroxy-28%,
Chloram-38%
What is the survival with bone marrow mets in MCT?
With CCNU MST 43 days, symptomatic ~30days
What is the MST with grade 3 met with mets?
194 day(6 mo) vs. 503 (16 mo) if no mets
What is the MST with grade3 mct with Ln mets and tx/
240 days (8 mo) with tx and 42d if no tx
What is the survival with SQ MCT?
With incomplete margins MST 1199days (~40 mo, ~3 yr)
What feline breed is associated with a better prognosis with MCT?
Siamese, usually younger and develop histiocytic form
Where is MCT diz located in cats?
More visceral, GI and generally do not have cutaneous lesion associated (unlike dogs)
What other disease cause circulating mast cells in cats?
None, generally just MCT; 50% splenic have in BM
What is the tx and survival for splenic MCT in cats?
splenectomy even if distant mets can do well MST 12-19months, chemo unknown
Tx and prognosis with cutaneous MCT in cats?
Surgery with smaller margins because most benign, Histiocytic “wait & see’
Tx and survival with GI MCT in cats?
Surgery need large margins, most succumb to diz quickly
less than 1 year
What is sclerosing GI MCT in cats?
New GI variant, 23/25 cats dead in 2 months
What are the different histologic forms of MCT in the cat?
Histiocytic (spontaneously resolves); Mastocytic-compact (benign),
Diffuse (anaplastic malignant)
Patnaik grading scheme
Gr 1 - 3
looking at depth of invasion, cellular atypic, granularity, nuclear feature, MC, and multi nucleation
Kiupel grading scheme
high or low
HIGH =
MC >7/10hpf ,
>3 cells with multi nucleation/10hpf ,
>3 bizarre nuclei/hpf ,
karyomegaly >10% of cells
MC <7 low grade
bostock mct grading scheme
opposite of patnaik
gr I = anaplastic undifferentiated - highly cellular irregular size and shaped of nuclei, frequent mitosis, few granules
gr ii = intermediate grade, closely packed cells with indistinct cell borders, lower n:c ratio compare to anaplastic, infrequent mitosis, more granules than anaplastic
grIII = clearly defined cell boundaries, well differentiated, spherical or oval nuclei, rare or absent mitosis, large deep staining granules
based on a consensus statement and a study comparing the 2 and 3 category mct grading schemes what recommendation can be made about staging low grade tumors
staging should be recommended regardless of grade to local LN but full staging may not be necessary for low grade tumors
15% of Kiupel low grade tumors had more aggressive behavior
based on mct consensus statement what is the preferred mct grading scheme
kiupel + Ki67 & AgNOR
- help you understand low grade tumors risk of local recurrence
WHO staging scheme of mct
0 = one tumor incompletely excised form the dermis identified histologically without regional ln involvement
a - without signs
b - with systemic signs
1 = one tumor confined to the dermis without regional LN involvement
a - without signs
b - with systemic signs
2 = one tumor confined to the dermis with regional ln involvement
a - without signs
b - with systemic signs
3 = multiple dermal tumors, large infiltrating tumors with or without regional Ln involvement
a - without signs
b - with systemic signs
4 = any tumor with distant metastasis including bone marrow
proposed staging from consensus
Stage I Single tumor, without regional lymph node involvement
Stage II Multiple tumors (≥3), without regional lymph node involvement
Stage III Single tumor, with regional lymph node involvement
Stage IV Large and infiltrative tumors, without delineation, or multiple
tumors (≥3), with regional lymph node involvement
Stage V Any tumor with distant metastasis, including bone marrow invasion
and the presence of mast cells in the peripheral blood
dog with multiple cutaneous tumors - what stage and how does it affect prognosis?
stage 3 for WHO or 4 on new staging
Several studies indicate that there is no difference in outcome between patients with a single cutaneous MCTs and those with multiple MCT
others have suggested an inferior outcome in dogs with multiple tumors
dog with dermal mct and regional Ln metastasis what stage and how does it affect prognosis ?
stage 2 for WHO and stage 3 for new scheme
In 3 studies, the presence of MCs in the regional LNs was a negative prognostic factor for disease-free interval (DFI) and survival
however
Other studies have shown that dogs with intermediately differentiated MCTs with LN metastasis may have a good prognosis if the affected LN is removed and adjuvant chemotherapy and/or RT is administered.
grade seems more impt for outcome
histologic grading scheme of mct metastatic lymph nodes
HN0 = not metastatic, None to rare (0-3), scattered, individualized mast cells in sinuses (subcapsular, paracortical or medullary) and/or parenchyma per field
HN1= Pre Metastatic, Greater than three individualized mast cells in sinuses (subcapsular, paracortical or medullary)
and/or parenchyma in a minimum of 4 fields
HN2 = early metastatic, Aggregates of mast cells (>3 associated cells) in sinuses (subcapsular, paracortical or medullary) and/or parenchymal, or sinusoidal sheets of mast cells
HN3 = overtly metastatic, Disruption or effacement of normal nodal architecture by discrete foci, nodules, sheets, or overt masses composed of mast cells
dfi and ST for HN0/1 tumors
DFI for those classified as HN0/1 was not reached
MST was 1,824 days = 5 yrs
The 2-year disease-free percentages and survival percentages were 90% for HN0/1
dfi and st for HN2/3 tumors
DFI was not reached
MST was 804 days = 27 mths
The 2-year disease-free percentages and survival percentages were 56% for HN2/3.
MST for poorly differentiated tumors with LN mets vs no LN mets
what happens to ST if you treat the LN
high grade Ln mets ST = 194 d = 6.5. mth
high grade NO LN mets ST = 503 d =17 mths
treatment of the LN improved MST (240 days = 8 mth) compared with those dogs whose LNs were not treated (42 days)
how does the biologic behavior of a mct affect outcome
recent rapid progression is a worse outcome
local tumor ulceration, erythema, or pruritus have worse prognosis
recurrence after surgery is a worse prognosis
** all shown in few studies - not definitive**
Comparison of histologic margin status in low-grade cutaneous and subcutaneous canine mast cell tumours examined by radial and tangential sections
Radial sections: 4 radial sections of 5 directions (cr, cd, d, v, and deep) to inked margins
Tangential sections: taken parallel to the ink edge covering great % of total margin surface area
Tangential sections detect sig. More incomplete surgical margins
** 23% are categorized as neg on radial that were pos on tangential sectioning**
Radial sections incorrectly called clean – 50% of margins
when to use radial versus tangential mct margins
Radial sections have 100% specificity of predicting negative tangential margins at a cut point of 10.9 mm
if margins <10.9 mm tangential sectioning should be used
Amount of skin shrinkage affecting tumor versus grossly normal marginal skin of dogs for cutaneous mast cell tumors excised with curative intent
17.7% shrinkage with tumor shrinkage (4.45%) < normal skin shrinkage (24.42%)
Equation created to estimate post excisional margins from pre excisional measurements for mct
18.4%
(pre- excisional margin = postformalin margin/0.244)
compared to intra op how much did the length of surgical margins decrease at each processing step?
for mct
for sts
Compared to intra op measurements the length of surgical margins decreased at each processing step by median of
- 3 mm post op, 5 mm post fix, and 8.8 mm on glass/HTFM for MCT
- 2.5 mm, 2 mm, and 5 mm for STS
Max reduction in the total length of margins was 29.6 mm for MCT and 24.2 mm for STS
prognostic factors for mct
grade
stage
location
Proliferation - MC, AgNOR, Ki67
growth rate
microvessel density
recurrence
systemic signs
age
breed
sex f>m
tumor size
c-kit mutation - worse
DNA copy number
how does micro vessel density affect prognosis for mct
increased MVD = higher grade, higher degree of invasiveness and worse prognosis
what is AgNOR
histo silver staining method to identify generation time - speed of cell cycle progression proliferation rate
low for G1 phase and high for S-G2 phase
what is Ki67
ihc method to identify growth fraction - actively dividing cells
seen during mitosis - during interphase the non-phosphorylated form of Ki-67 form complex with DNA - role in organization of nucleolar chromatin in proliferating cells
what is Ag67
AgNOR x Ki67
growth fraction and proliferation rate
MC < 7 ( low grade mct)
MST
risk of death
risk of new tumors
mst > 2 years
5% dogs died due to mct disease
20% developed new tumors
MC > 7 ( low grade mct)
MST
risk of death
risk of mets
MST ,4 mths
90% dogs died due to mct
70% developed mets
risk of recurrence based on grade
Gr I and II mct
Tumors measuring < 3.2 cm excised with microscopic lateral margins at least 1 cm and a deep margins at least 4 mm including a fascial layer did not recur
risk of recurrence based on grade
low grade mct
96% of tumors did not recur, even though 29% were excised with microscopic margins
of 3 mm or less
risk of recurrence based on grade
high grade mct
36% recur locally despite histologically tumor-free margins
how does AgNOR score affect outcome of mct
Average AgNORs per cell < 1.7: No dogs died due to MCT-associated disease
** Average AgNORs per cell > 2.25**: Significantly decreased survival
Average AgNORs per cell > 4: Significantly decreased survival:
– 66.7% of dogs died from MCT-associated disease – MST 4 mth
Low Ki67 index and recurrence rate of mct
ki67 <23 - 11% recurrence
high ki67 and recurrence rate of mct
ki67 >23
increased risk of recurrence and mets
Ag67 and mct recurrence
Ag67 >54 - significantly associated with an increase rate of mct recurrence, increased risk of MCT-related mortality and
metastasis
60% 1 year survival
low grade tumors Ag67 < 54 - 11% recurrence rate
low grade tumor Ag67 > 54 increased risk of recurrence
KIT pattern I - perimembranous
local rr
distant met rate
mortality
2.4% local rr
14.3% distant met rate
2.4% mortality rate
KIT pattern ii - focal stippled
local rr
distant met rate
mortality
14% local rr
31% distant met rate
25.6% mortality
KIT pattern III - diffuse cytoplasmic
local rr
distant met rate
mortality
23.1% local rr
38.5% rate of distant met
38.5% mortality
sig dec dfi and st compared to pattern 2
C kit exon 8 and mct tx
tend to be lower grade tumors
mutation in exon 8 of c-Kit are also expected to respond to TKIs
c kit exon 11 and mct tx
associated with higher grade - high rate of metastasis and mortality and recurrence
will respond to TKIs
SQ mct - MC
risk of recurrence
risk of death
MC>0 <4 compared to MC 0
5.59 times higher risk of local recurrence
3.72 time higher risk of death
MC>4 compared to MC 0
36 times higher rate of mct related death
130 times higher risk of local recurrence
increased risk of metastasis
SQ MCT – Infiltrative tumor, MC > 4
effect of multinucleation on mst
MST 140 days 4.6 mths vs MST 950 days 32 mths with no multi nucleation
SQ MCT and growth pattern
infiltrative tumors are more likely to recur locally, cause distant mets, and have distant mct development
in general, completely excised well-circumscribed SCMCTs are unlikely to recur
infiltrative SQ MCT time to recurrence
Incompletely excised SCMCTs with infiltrative pattern: 70 days
Completely excised SCMCTs with infiltrative pattern: 1,000 days (33 mo)
Incompletely excised well-circumscribed SCMCTs: 365 days
AgNor for SQ MCT
agnor >2.71 sig more likely to reoccur
ki67 for SQ mct
ki67 >21.8 high risk of mets
Ag67 for SQ mct
Ag67 >55 associated with increased risk of mct related mortality and metastasis
KIT pattern 3 SQ MCT
Increased odds of local recurrence and
developing metastasis compared to
pattern I
– Increased odds of local recurrence
compared patterns I and II
is c-kit associated with high or low grade mct
c-kit mutations appear to be associated with 25% to 30% of intermediate- and high-grade MCTs, and evidence suggests that they are linked to increased risk of local recurrence, metastasis, and a worse prognosis
mct are the most common cutaneous tumor of the dogs
16 - 21 %
what percent of dogs have multiple SQ or dermal mct
11- 14%
what is the distribution on the body of cmct
50% of cutaneous MCTs occur on the trunk and perineal region, 40% on the limbs, and 10% on the head and neck
dariers sign
erythema and wheal formation in surrounding tissues
what percent of dogs with mct have gi ulceration
35-83% of dogs that underwent necropsy
systemic signs of mct
vomiting, diarrhea, fever, peripheral edema, and rarely collapse.
risk of surgery to mct
life-threatening hypotensive events during surgery - prostaglandins in the D series secreted by tumor cells
Coagulation abnormalities and localized excessive bleeding
Metastatic rates for undifferentiated MCT
range from 55% to 96%, and most dogs with these tumors die of their disease within 1 year
how does anatomic location affect dermal mct
perigenital, perioral, mucocutaneous junction - higher grade, higher, met potential, and shorter survival
response to pred alone for cmct
20% ORR
4% cr
16% pr
what stain do you add to cyto to reveal granules in mct
wright giemsa or toluene blue
may still be agranular
ihc for mct
vimentin - , CD117 (KIT) +, chymase +, tryptase +, mcp-1+/- , IL8 +/-1
what can cause mastocytosis in the Buffy coat
acute inflammatory disease (in particular parvoviral infections), inflammatory skin disease, regenerative anemias, neoplasia other than MCT, and trauma
One study revealed that peripheral mastocytosis is actually more likely to occur and may be more dramatic in dogs with diseases other than MCT - dont perform anymore
incidence of BM infiltration of cMCT at dx
incidence of bone marrow infiltration at initial staging was only 2.8%
involvement of bone marrow or peripheral blood in the absence of disease in regional LN or abdominal organs is unlikely and the routine performance of bone marrow aspirates for clinical staging has fallen out of favor
incidence of BM infiltration of visceral MCT at dx
56% of bone marrow aspirates reveal MC dissemination
response of cmct to vincristine
ORR 7% - PR only
response of cmct to CCNU
ORR 44%
6% CR
38% PR
response duration 79d
response of cmct to vinblastine/pred
ORR 43%-47%
CR 4-33%
PR 13- 39%
response duration 154 days - not reached
response of cmct to vinb/pre/cytoxan
ORR 63%
CR 18%
PR 45%
response duration 73 days
response of cmct to COP-HU
ORR 59%
23% CR
35% PR
response 53 d duration
response of cmct to CVP
ORR 57-64%
24-29% CR
32-35% PR
duration: 141d CR, 66d PR
1 year in another study
response of cmct to hydroxyurea
ORR 28%
4% cr 24% pr
response duration 46 days
response of cmct to pred/chlorambucil
ORR 38%
PR 46%
CR 14%
duration 533
response of cmct to palladia
ORR 43-63%
PR 28-46%
CR 14-17%
duration 3 months - not reached
response of cmct to masitinib (kinavet)
ORR 55-82%
PR 29 - 44%
CR 26-38%
duration not reached
response of cmct to palladia and ccnu
orr 46%
pr 36%
cr 10%
response of cmct to palladia and vinb
orr 71%
pr 57%
cr 14%
on multivariate analysis which prognostic factors were significant
clinical stage, history of tumor recurrence, Patnaik and Kiupel grades, predominant organization of neoplastic cells, mitotic count, Ki-67 labeling index , KITr pattern, and c-KIT mutational status
new amended clinical staging system and tumor recurrence
all were significant on univariate analysis
will c-kit mutation status predict response to treatment?
c‐kit mutation status did not predict treatment response
Palladia - 20% had Ckit - 46% RR
Vinb - 30% had ckit - 30% RR
PFS - 78 d VBL and 95.5d Palladia
OST - 241.5 d VBL and 159 Palladia
PFS and OST were not significant
palladia, RT, and pred response of gross MCT, mst , pfi
24Gy in 3 or 4 fractions
ORR 76.4%,
CR 58.8%,
PR 17.6%
Median PFI 316 days(10 mo), MST not reached
if a dog has high grade tumor should you remove draining lymph node
TTP
MST
time to progression is sig short in dogs without lymphadenectomy (150 days) compared to the other dogs (229 days)
MST was also shorter in dogs that did not undergo lymphadenectomy (250 days) compared to dogs that underwent lymphadenectomy (371 days)
On multivariable analysis, lack of lymphadenectomy was associated with higher risk of overall tumor progression, nodal progression and tumor-related death,
what size mct tumor has been shown to have increased risk of recurrence
3 cm or >
should you remove the local lymph nodes of mct regardless of staging
lack of immediate lymphadenectomy was associated with a higher risk for tumor progression
No significant difference in survival time
metastatic rate of mucosal MCT
> 50%
where do mct metastasize to in the cns
intramedullary
dose limiting toxicity of palladia and vinb combo
neutropenia
should you give palladia with vinb for mct
AG says no - 50% reduction in dose intensity compared to single agent
71% rr and enhanced myelosuppression suggest additive or synergistic activity
prognostic factors for SQ tumors
MC >4, multi nucleation, absent granules, multiple mct
what is the sn and sp of cytologic grading scheme
88% sn
94% sp
prognostic factors for feline cMCT
MC >5 — MC >2 in another study
incomplete surgical resection - sig effects PFS
cytoplasmic KIT stain - sig effects OST
visceral location
poor differentiation
prognostic indicators in cats undergoing splenectomy for splenic mct
Administration of a blood product, metastasis to a regional lymph node, and evidence of either concurrent or historical neoplasia were negatively associated with survival
Response to chemotherapy was associated with an improved median survival time
ST in cat with mct with splenectomy
mst 390 days in one study
Splenectomy vs not (MST 856 vs 342d)
role of chemotherapy is unknown
feline intestinal mast cell tumor prognostic factors
degree of differentiation, MC >2,
outcome of treatment of feline GI mct
chemo alone
sx and chemo
steroids alone
sx and steroids
chemo alone - MST 541d
sx and chemo - MST 396d
steroids alone - MST 55d
sx and steroids - 340d
no significant difference to survival time between treatment groups
Any treatment improved survival times
palladia use in cats for mct
clinical benefit
rr
AE
CB 80% visceral 86% cutaneous 76% gi
RR 70%
60% experienced adverse events with 87% defined as low Grade 1 or 2
ckit mutation and prognosis for feline splenic mct
No correlation was observed between c-Kit mutations and tumour differentiation, mitotic activity or survival
how frequently was kit staining in feline
cMCT
splenic MCT
GI MCT
69% of cutaneous MCTs,
35% of splenic MCTs,
33% of GI MCTs were positive for KIT
superficial RT for cutaneous mct
limited case series
3 patients had cr
low grade tox
what stain and sectioning technique was shown to have a 98% accuracy for identifying metastatic mct LN
evaluation of the first longitudinal section and an additional step section = 100% accuracy
200um step parallel to the first section
recommend metachromatic stain such as toludine blue
what is the detection rate of sentinel ln mapping with CT lymphangiography
90% detection rate
9% failure rate
based on CT lymphangiography how many tumors changed stage or treatemtn recommendation
40% of tumors had a change of stage or tx recommendation by using the snl not the lrln
sentinel ln mapping with CT lymphangiography showed was disagreement with loco regional LN
27-32 % of sentinel LN were not the regional ln
does the combination of RT with vinblastine cause and hematologic toxicity ?
does not increase the risk of neutropenia
Mast cell tumours in dogs less than 12 months of age - prognosis
great - all alive at >1000 days despite 4 being high grade and 12 with mets
Salivary miR-21 as a biomarker for mct
High in dogs with MCT compared to healthy group
Recurrent gene mutations detected in canine mast cell tumours
Prevalence of GNB1 mutation 17.3% (similar to prevalence of KIT alterations)
GNB1 mutations did not affect survival negatively and tended toward positive
pre op neoadjuvant vinblastine-prednisolone
use
complication rate
success of complete margins
recurrence rate
can be used for unresectable mct or to improve margins
16.7% wound dehiscence
complete excision 47%
local recurrence 21% - not influenced by completeness of excision or response to vinb
Lymph node metastasis in feline cutaneous low-grade mast cell tumours
59% had early or overtly metastatic LN despite low grade
ST gastrointestinal mct feline
one study showed st 531 d
sx, chemo, pred all aided st
metastatic rate of mct to spleen/liver
overall met rate 10.7 %
10.2% to spleen
6.3% to the liver
5.9% to both
if mct mets not identified in the spleen will it be found in the liver?
low likelihood in liver if not in the spleen
nef spleen ctyo has 99% ppv
what has been associated with splenic mct metastasis in dogs
tumor size and systemic signs
Τhe Effect of Opioid Administration on Cytologic and Histopathologic Diagnosis of Canine Cutaneous Mast Cell Tumors Treated by Surgical Excision
administration of morphine or butorphanol as part of the preanesthetic medication for surgical removal of canine cutaneous mast cell tumors does not influence histopathologic and cytologic grading of MCTs
Inclusion of fibroblasts and collagen fibrils in the cytologic grading of canine cutaneous mast cell tumors
higher fibroblasts and/or collagen fibrils were associated with increased survival and low grade
Wound formation, wound size, and progression of wound healing after intratumoral treatment of mast cell tumors in dogs with tigilanol tiglate
Maximal wound formation day 7 in 89% of dogs
Wounds left to heal by second intention
Time to heal was 28 - 42 days
wound formation correlates with effectiveness
response rate of tigilanol tiglate
75% CR by 28 days with not recurrence in 93% by 84 days
88% CR after two treatments
recurrence of mct after stelfonta
12 months
metastasis with high grade mct location
LN mets 96%, spleen 67%, liver 59%, bone marrow 41%, kidneys 33%, heart 29%, lung uncommon 18%
met rate of inguinal mct
40%
met rate of multiple mct nodules
47%
cyto grading overall accuracy
94%
sig associated with mst and tumor related death
wound healing complication for marginal mct vs sts
29% for mct
31% for sts
is it safe to use chemo post operatively after mct removal
Postop chemo </=30d associated with increased odds of incisional complications
steroids was not
surgical margins for low grade mct
Conservative lateral margins <2cm for small tumors okay
>2 cm <3cm margins for larger tumors are okay for low grade MCT
Outcomes of adjunctive radiation therapy for the treatment of mast cell tumors in dogs and assessment of toxicity
No SC MCT recurred after radiation therapy and only 7% of dogs with SCMCT were reported to have died of their disease
RR similar between radiation type 526 day
supports sue of rt after narrow or incomplete excision
use of prophylactic LN irradiation in dogs with high grade mct
pfs
Treating the locoregional lymph nodes with radiation and/or surgery significantly improves outcome in dogs with high-grade mast cell tumors
Prophylactic LN radiation pfs >2381d (6yr) vs 197d (6.5 mo)
Phosphorylated KIT as a predictor of outcome in canine mast cell tumors treated with toceranib phosphate or vinblastine
Pkit was associated with aberrant kit localization, high mc, and high grade
Pkit was the only independent predictive factor for ost in multivariate
MC was the only independent predictive factor for PFI
does adjuvant medical therapy provide benefit to dogs with low grade mct
no
mst high grade mct
1046 d (34 mo)
80% 1 year survival
73% 2 year survival
local recurrence of high grade mct
18.4%
regional LN mets of high grade mct
12%
development of new mct of high grade mct
30%
negative prognostic factors for high grade mct
high mc and tumor diameter
Tumor location, margins, and use of chemo did not affect MST
is nanog associated with proliferation
not in mct
Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib effect on mast cells
suppress IgE-dependent histamine release in primary MCT and may exert anti-proliferative effects
Factors affecting prognosis in canine subcutaneous mast cell tumors
LN mets - mst 552d (17 mo) v 1722 d (4.5 yr)
local recurrence - mst 551d (17 mo) vs 1722d (4.5 yr)
infiltrative - 268d (9 mo) vs not reached
Grade II Subcutaneous Mast Cell Tumors Treated with Surgery Alone
outcome
neg prog factor
PFS 1474d(4 yr), DFI not reached, OST not reached
AgNOR neg prog factor
use of ultrasound as a predictor of liver or spleen mct mets
US poor predictor of metastasis with sens 67%, spec 68%, PPV 21%, NPV 94% in the spleen
Worse in the liver 29% sens, 93% spec, PPV 56%, NPV 82%
effect of spleen and liver mets on top and mst
TTP for no mets not reached, early mets 305d, mets 69d
MST for no mets not reached, early mets 322d, and mets 81 d
stage 4 mc tumors prognostic factors
tumor diameter >3 cm, more than 2 metastatic sites, bone marrow infiltration, and lack of tumor control at the primary site were confirmed to be negative prognostic factors by multivariate analysis
local tumor control predict a better outcome
anatomic location of the primary tumor, histo-pathological grade, mutational status, type of treatment and onset of treatment-related toxicity were not significantly associated with either PFI or ST
mst of stage iv mct
110d (3-4 mo)
how does BAX expression affect outcome of mct
BAX expression was associated with higher mortality rate and shorter survival.
BCL2 expression was significantly lower in high grade MCTs
deregulation of the intrinsic apoptotic pathway is present in cutaneous mct
mastocytosis vs multiple distant mets - which is worse fo mct
mastocytosis worse prognosis
one met is better than multiple
dogs with mastocytosis does anything affect survival
chemo increased survival
CVP better than palladia
ost 119d (~4mo)
does pre surgical mct biopsy grading predict post surgical grading
yes
96% concordance with patniak
92% concordance with kiupel
Wedge 92% accurate, punch and needle core 100%
Discordant results underestimated the grade of the tumor but are sufficient
mct on the pinna was is th most likely SNL
superficial cervical in 94.4% of cases
prognosis of mct on the pinna
Median TTP 270 days (9mo) and TSS 370 days (12 mo)
only high grade was associated with decreased survival
lysyl oxidase (LOX) enzyme expression in cMCT associated with grade
Cytoplasmic +LOX sig. Higher in high grade tumors
when is marginal mct excision acceptable for tumor control
Marginal excision of low- to intermediate-grade MCTs is an acceptable approach if followed by treatment with RT - no gross disease
two-year control rates of 85% to 95%
what species exhibits mast cell erythrophagocytosis
cats
what breed of cat is more likely to develop cmct
siamese
behavior of compact mastocytic feline mct
less commonly metastasize
anaplastic mastocytic feline mct behavior and histo
anaplastic tumors may have a high MI, marked cellular and nuclear pleomorphism, and infiltration into the subcutaneous tissues.
reported to behave in a more malignant manner with metastasis to LNs and the abdomen - new study shows most are benign
most common site of cmct in cats
head and neck esp pinna
common misdiagnosis for histocytic feline mct
granulomatous nodular panniculitis or deep dermatitis
mast cells may comprise on 20% of the cells with lymphoid aggregates and eos
may not have granules
ihc feline mct
vimentin, α-1 antitrypsin, and KIT
prognostic factors for cMCT in cats
high MI appear to be at greatest risk for local recurrence and metastasis,
proposed MC 5
RR of strontium 90
98% control rate - mst >3 yr
RR feline cMCT to ccnu
50% ORR
50-60mg/m2
response duration 25 to 727 days (24 mo)
most common intestinal mct location
SI > colonic
prognostic factors for intestinal mct
histologic differentiation, MC >2
c-kit was not prognostic
what is the rate of metastasis of osa to the local lymph node
<10% - 4.4% at the time of amputation
what site of osa is least likely to fracture
distal radius
what is the mst of a dog with axial osa who has mandibulectomy
> 2 year
how does the addition of pamidronate to RT affect canine osa outcome
unlikely to change survival but improves chance of pain control
prognostic factors for survival for osa
Increased weight
humerus location
stage - ln mets
grade,
monocytosis,
leukocytosis,
ALP,
low CD8/Treg
mod to high p53 staining
Telangiectatic (for ulnar OSA)
# of nodules on CT - but not whether or not there are nodules
strong cox2 staining
prognostic factors for DFI for osa
humerus location
stage (LN mets)
monocytosis,
leukocytosis,
ALP
veg<50% shorter dfi
criteria for limb sparing sx for osa
<50% bone involved, no fx, one limb, <360 degree ST involved,
radius/ulna best;
no local chemo treatment or RT
Contraindications 🡪 >50% bone involvement, location
outcome and complications of limb spare surgery for osa
High infection 40-50%,
recurrence 20-60% with incomplete and more likely to met;
Do as good as amp+chemo; 80% good limb function
osa t regs
low CD8: t reg ratio sig shorter ST than high ratio
what is the most likely tumor to cause HO
OSA, TCC
greyhound with lytic lesion in the ulna on bx it looks like tOSA. what is the next step?
request IHC FVIII/vWF.
amputation etc
what is the effect of palladia on OSA
not benefit as a single agent
What are risk factors for OSA?
Neutered rottweilers,
RT,
unrepaired fx,
metal implants,
chronic osteomyelitis,
age,
weight bearing bones,
hereditary
Do pulm nodule seen on ct change prognosis for osa if not seen on cxr
no change in ST
what distinguishes tOSA from HSA
FVIII/vWF
cells lining blood-filled spaces demonstrated positive FVIII-RAg/vWF immunoreactivity were HSA
what percent of appendicular HSA are miscatergorized as tOSA without the use of IHC
20%
what cancer has mutations in STAT3 and p53
OSA
What effect does ZOL have on expression of chemokine receptors in OSA?
zol reduced CXCR4 expression by 40% within the primary tumor
What is true of radiosensitivity and repair of sublethal RT-induced damage in OSA?
ɑ/β low = higher dose/less fractionation indicated
Upregulated p53 in OSA increased radiosensitivity
Surviving cell fractions at 2 Gy: 0.6
what tumors express PD-L1
o Melanoma
o OSA
o Mammary
o Prostatic adenocarcinoma
o TCC
o HSA
What is the relationship between Wnt and β-catenin in K9 OSA?
Moderate-high expression of β-catenin associated with development of mets
- No relationship with with DFI and OST
- No mutation in exon 3
Why are carboplatin and gemcitabine synergistic/what results when given together?
both cause dec dna synthesis (induces cell cycle arrest and apoptosis). gemcitabine decreases DNA repair via dec ribonucleotide reductase - NER which is how carbo adducts are repaired
What cytokines have been used in vet med therapy?
IFNy-mostly FeLV cats FISS-tolerated
IL2 inhaled in OSA mets was tolerated
Which is more aggressive OSA mandible or maxilla?
Maxilla MST 5-10months recurrence 83-100%
mandible 15-18months
mst for mandibular osa with surgery
does chemo work?
MST 525d (17.5 mo)
mst chemo 1023d (35 mo) - not stat sig but on multivariate analysis not having chemo was significant as was histologic grade
met rate of mandibular osa
58% developed mets
What is the survival of skull OSA?
Complete resection >1503days - 50 mths vs.
128d - 4 mths with incomplete
What is survival with sx for multi lobular osteochondrosarcoma?
800-1332 ( 2- 4 yrs) complete resection vs. 330 days incomplete
What is recurrence by grade of mlo?
Grade3 78% MST 11 months,
Grd2 47-60% MST 22 months,
Grd1 30% MST 50 months
what is the time to metastasis in MLO
426-522 days
so can do pulmonary metatestecomy
Which site in dogs is affected more with OSA? Cats?
dogs - Appendincular, forelimbs 2x as hindlimbs;
Cats appendicular 2x as axial, hindlimbs are most common
Describe location and survival time for dog OSA?
- I think these are all sx and chemo
Distal carpus/tarsus MST 466days; 15mth
Rib 8months
Scapula 246days; 8 mth
Mandible 70% 1yr survival;
Maxilla 5months;
spine 4months,
extraskeletal 5months;
Skull 204days 7 mth
ST of rib osa
sx alone
sx and chemo
sx alone - 3 mo
sx and chemo - 8 mo
What is the risk of mets and associated survival for OSA?
15% @ dx lung mets-MST 59days;
4.4% Ln-MST 59days;
7.8% bone mets-MST 132days - 4 mths
What are genetic and molecular mutations that affect OSA?
P53, Rb, HGF/MET, IGF, GH, PTEN, MMP2&9, ckit, PDGF, RANKL, ezrin, COX2, VEGF, STAT3, Wnt, integrin, survivin, RON
What is the survival for amputation alone for OSA?
135-168days
4.5 -5.5 mths
What is the survival for cats with OSA?
Amputation MST 22-44 months,
No chemo needed
What is the survival with RT+chemo for OSA?
209 days - 7 mths
Skull MST 265days - 9 mths
What is the response for palliative RT in OSA?
74-93% respond,
takes 11-21days,
last for 56-130days ( up to 4 mths)
What is the general response/survival with amp+chemo for osa?
MST 9-12months with variety of tx-cisplatin, carbo, dox, alternating carbo/dox or cis/dox
What other chemo drugs have been used as inhalants or oral?
Satraplatin-659days (6dogs) oral,
Dox & paclitaxel inhalant-fibrosis;
Gemcitabine-not good;
Palladia lung mets 1PR 43.5% stable
What impact do bisphosphantes have on OSA?
Palliative 28% responded >4months, RT+dox+pam-bloodwork better but owner did not notice;
Another RT+chemo+pam-the RT+pam group did the worst 69days
What type of OSA is less aggressive?
Parosteal or juxtacorticol
What is the most common site for chondrosarcoma in the dog? and MST
Nasal cavity
MST 210-580 days (7-19 mo) various tx
What is different between dog and cat Multiple cartilagenous exostosis MCE?
Cat - skeletally mature, rare on long bones, virally induced, aggressive behavior poor prog
Occurs AFTER skeletal maturity in cats (v. dogs which resolve at the time of skeletal maturity)
FeLV positive
What tumors have kit mutations?
MCT, FISS, OSA, interstitial/Leydig, RCC, thyroid, melanoma, AGASACA, AML, HS & HSA(?)
ALP and osa
No significant difference in cell proliferation, migration, invasion, or chemo Sn btwn cell lines assoc w normal and increased ALP serum conc
in vitro study
rate of pathologic fracture of osa
common location
38% - 40%
femur most commonly affected (57.1%), followed by tibia (52.9% one study showed tibia more), humerus (37%), radius (20%), ulna.
what type of surgery for rib osa
en bloc - 1 rib cr and cd
samarium given to dogs with osa
- benefit?
32 dogs w appendicular – 63% had improvement in lameness within 2 weeks of 1st dose, 25% had no change, and 12% had worsening
o Overall MST 100 d
o No sig difference in MST of 134 d for historical cohort that underwent amp alone
Samarium for MLO
benefit?
No clinically important AEs w Sm-EDTMP documented
▪ 20% had subjective improvement
▪ MST 144 d
Periosteal osa
arising from inner periosteum, appears radiographically aggressive and is also biologically intermediate like intramedullary OSA
pfi 461 d ost 555d
Parosteal OSA
arises from outter periosteum, appears radiographically LESS aggressive and is also biologically LESS aggressive
pfi 350 d - ost not reached
Prognostic factors of appendicular chondrosarcoma w surgery
tumor grade - survival
mst for rib chondrosarcomas based on grade
Grade 1 - >2723 d, 7yr
Grade 2 - 853 d, ~2yr
Grade 3 - >3820 d
found the paper this is correct
MST for dogs with rib chondrosarcoma was not reached (mean 1301 days) and survival was significantly greater than all other types of rib tumors
duration and RR with “boom boom” RT 2 x 10 gy
93% subjective improvement in pain within 14 days
duration of response 80 days (2.5 mo)
MST and met rate for appendicular chondrosarcoma in dogs for each tumor grade
o Grade 1 – 0% pulmonary mets, MST 6 yr
o Grade 2 – 31% mets, MST 2.7 yr
o Grade 3 – 50% met, MST 9 mo
rate of path fracture following RT to osa
36% - same as no rt
developed fx 24-250 d following rt
AE seen with RT to OSA
gr 1 skin tox most common SE
Carboplatin v. carbo/doxo for OSA
Dogs receiving carbo alone had sig longer DFI (425 d 14 mths v. 135 d 4.5 mth) than dogs receiving alternating carbo/doxo
Tox similar btwn groups
criteria for osa metastectomy
Primary tumor in CR – preferably for long relapse-free interval (>300 d)
One or two nodules on plain CXR
Cancer only found in lung (neg bone scan)
Long doubling time (>30 d) w no new visible lesions w/in this time
ost and mst after metastectomy isa
ost 487 d (16 mo)
MST after metastectomy was 176 d - 232 d (6-7mth) following development of stage III dz, sig improved from no metastectomy (49 d after stage III dz)
mst of ulnar telangiectatic osa
MST 208 d (7 mo) (compared to 463 d (15 mo) for other histo subtypes in ulna)
expression of PD-L1, HVEM, and B7H3 in osa cell lines versus mets
higher expression in mets
poss biomarker
Evaluation of microwave ablation for local treatment of dogs with distal radial osteosarcoma
pilot study
tumor necrosis varied btw 30 - 90%
no immediate complications
Percutaneous microwave ablation of solitary presumptive pulmonary metastases in two dogs with appendicular osteosarcoma
one pneumothorax
it is possible
Lateral manus translation for limb-sparing surgery in 18 dogs with distal radial osteosarcoma in dogs
dfi
mst
complication
Complications - infection, biomechanical, local recurrence
DFI 219d (7mo)
MST 370d (1 yr)
Effect of surgical site infection on survival after limb amputation in the curative-intent treatment of canine appendicular osteosarcoma
DFI 236 days - 7 m
OST 283 days - 9 m
DFI and MST did not differ between groups - SSI vs not
most common location of appendicular hsa
tibia
78% of hsa tumors were in the hind limb
ost with chemo and amp for appendicular hsa
9 months - more aggressive treatment = better outcome
ost with chemo and amp for tOSA
7 months
Outcome and Metastatic Behavior of Canine Sinonasal Osteosarcoma
30% metastatic rate with median time to metastasis 458 days, mets more common to LN then lungs
Medium time to local progression was 335 days
OST 410 days
Prognostic value of fluorine18 flourodeoxyglucose positron emission tomography/computed tomography in dogs with appendicular osteosarcoma
Maximum standard uptake value SUV of the primary tumor was significantly negatively associated with the OS
Ost SUV >7.4 = 254 d - 8 mth
Ost SUV < 7.4 = 680 d - 23 mth
Role of Periostin Expression in Canine Osteosarcoma Biology
Periostin mRNA and protein expression upregulated >40 fold in canine OSA compared to normal bone
Not associated with time to metastasis
Associated with pro-tumorigenic pathways including WNT, EM transitions, and angiogenesis
Autologous cancer cell vaccination, adoptive T-cell transfer, and interleukin-2 administration in dogs with osteosarcoma
- toxicity
- dfi
- mst
low grade toxicity with premeds
DFI 213 d (7.7mo)
MST 415 d (13 mo) 5 dogs lived >730d (2 yr)
where is an abnormal met location that can be the first location deteted in osa?
skin/SQ
dog with appendicular osa - skin nodules noted to be mets - what is the pulmonary metastatic rate ?
85% to lungs
5% to the bone
dog with appendicular osa - skin nodules noted to be mets. what is the prognosis after identification of mets
grave <2 mths
Survival with surgery and chemo 94 d or chemo alone 64d no treatment 11d
Adverse events and outcomes in dogs with appendicular osteosarcoma treated with limb amputation and a single subcutaneous infusion of carboplatin
7% hospitalization rate for GI AE from chemo
NOT RECOMMENDED d/t low survival
MST 196d - 6/5 mth
Evaluation of metronomic cyclophosphamide chemotherapy as maintenance treatment for dogs with appendicular osteosarcoma following limb amputation and carboplatin chemotherapy
No benefit
58% developed cystitis
does Auranofin improve overall survival when combined with standard of care in a pilot study involving dogs with osteosarcoma
yes - translational study
survival times ranging between 806 and 1525 days in males
Timing of adjuvant chemotherapy after limb amputation and effect on outcome in dogs with appendicular osteosarcoma without distant metastases
TTP longer for dogs who received chemo </= 5 days of amp 375 d vs >5d 202d
OST longer too 445d 14.8 mth vs >5d 239d 8 mths survival
what RT protocol + chemo for osa has better survival times
ST longer in dogs receiving SRT+chemo 350d - 11 mth vs fxRT + chemo 147d - 5 mth
any RT was better than none as long as baseline pain scores were low and RT dose high
what were prognostic factors for survival with isa when Rt was given with chemo
low baseline pain score
high rt dose
pain and rt dose did not impact survival in dogs who did not receive chemo
Safety evaluation of the canine osteosarcoma vaccine, live Listeria vector
AE generally mild and self limiting: nausea, lethargy, fever
8% developed Listeria + abscesses (3 at amp site, 1 septic stifle, 1 bacterial cystitis, 1 lung masses)
what is the osa vaccine
vax targeting the dominant immune epitopes of HER2 was developed using a highly attenuated recombinant Listeria monocytogenes
resulted in improved OST in 18 dogs receiving amp, platinum chemo (956d (31 mo) vs historic control receiving standard of care tx 423d (14 mo))
Outcome and prognosis for canine appendicular osteosarcoma treated with stereotactic body radiation 2021 study
84% max lameness improvement at 3 weeks for a median of 6 mo duration
41% fracture rate with 21% have amp after treatment; dogs with salvage amp had sig longer OST 346 - 11.5 mths vs 202 days - 7 mth
No difference in survival with 15 dogs who had mets
MST 233 days - 8 mth
primary osteosarcoma of the digits, metacarpal and metatarsal bones
pfi
ost
pfi 377d - 12.5mth
st 687 - 23 mths
Chemo, lymphocyte and monocyte count no sig. effect
how does perioperative pain control affect outcome in dogs with osa
Dogs treated with high intensity perioperative pain (NSAID, bupivcane locally) had a higher probability of survival than those not treated 378 d 12.5 vs 252d - 8 mths
how does macrophage and lymphocyte infiltration affect outcome in canine osa
increased macrophages may be protective
lymphocyte infiltration did not correlate with outcome
how to circulating tumor cells affect survival and metastasis in osa
dogs that had mets had a spike in CTCs 1 month before and had a shorter mst 10x more likely to die
Feasibility and safety of whole lung irradiation in the treatment of canine appendicular osteosarcoma
Well tolerated only mild hematopoietic toxicity, pneumonitis, pulmonary fibrosis
success of whole lung irradiation in the treatment of canine appendicular osteosarcoma
no change in dfi
osa limb salvage surgery and secondary amp
how many needed it
reason
st after amp
84% of dogs with limb spare did not need to undergo secondary amputation
Reasons - local recurrence and surgical site infection
Dogs live 205 days beyond 2nd amp
amputation and ssi improved survival
can you remove ilium only if it has osa
Iliectomy can be considered for a mass confined to the ilium when preservation of the limb is desired.
recurrence occured but not mets
outcome of srt for mlo
10 gy x 3 f
well tolerated but remission was shortlived
st of dogs with vertebral osa after palliative sx alone or combine wiht chemo and rt
sx alone - 42 days
sx and chemo - 82 days
only one dog treated wiht sx and rt - 101 d
6 dogs treated with all 3 - mst 261 d
Nanoparticle hyperthermia and monocytes
Nanoparticle hyperthermia may increase in vitro monocyte chemotaxis
may aid with anti-tumore immunity
Effects of the potassium-sparing diuretic amiloride on chemotherapy response in canine osteosarcoma cells
Amiloride strongly synergized with doxorubicin in combination treatment and exhibited additive or antagonistic effects with carboplatin in canine OSA cells.
Combination treatment with doxorubicin significantly upregulated p53-mitochondrial signaling to activate apoptosis and downregulate Akt phosphorylation
does propranolol or carvedilol affect osa cell viability
Prolonged exposure to propranolol and carvedilol significantly decreased the surviving fraction of canine osteosarcoma cells after 3Gy radiation
how do platinum drugs enter the cell
via CTR1
what is one mechanism of platinum resistance
Atox1 aggregates platinum agents preventing then from forming DNA adducts
ATOX1 antioxidant 1 copper chaperone
copper chaperones and osa response to carbo
Inhibition of copper chaperones (DC-AC50 smi of Atox1 and CCS) sensitizes human and canine osteosarcoma cells to carboplatin chemotherapy
selective inhibitor of nuclear export (SINE) verdinexor (laserdia) exhibits biologic activity against canine osteosarcoma cell lines
- how
SINE prevents tumor suppressor proteins from leaving the nucleus thereby allowing to carry out normal functions and kill cancer cells
Canine OS cell lines and primary OS subset cells have increase XPO1 compared to osteoblasts
All cells lines had dose dep. Growth inhibition with verdinexor
Verdinexor + doxo synergistic potent cell inhibition im 3 lines
hedgehog pathway and osa cell lines
hedgehog/smoothened is activated in canine OSA cell lines and cyclopamine suppresses OSA survival via inhibition of SMO → possible signaling pathway may be druggable target
S. aureus. infection affects osa
- how
downregulates TGF-β and heightens the inflammatory signature in human and canine macrophages to counteract osteosarcoma-induced immune suppression
