Bachata Rosa Flashcards
Mutation and overexpression of what gene is present in both human and canine LSA?
What other TSG was also recently evaluated and found to be abnormal in both human and canine B-LSA?
p53 - lower remission rate and ST
Mutated in 16% and overexpressed in 22% of dogs with high-grade LSA
Hypermethylation of DAPK CpG islands - 45% of B-cell LSA; negative PI for survival in both humans and dogs
DAPK involved in IFN-y mediated apoptosis
What is the most common immunophenotype and cytomorphologic sub-classification of LSA in Boxers?
85% T-cell lymphoma
TCR ab+, CD4+
Lymphoblastic high-grade
What is the MST of Boxers and Boxer mix breeds when treated with the LOPP chemotherapy protocol? Prognostic indicators found?
MST - 3m (99d)
Boxers 6x more likely to develop PD
Boxer breed = negative PI for PFI
What is Ritcher’s syndrome and the MST* in dogs?
CLL -> lymphoma
Characterized by the presence of pleomorphic immunoblasts
Poor tx response and prognosis
MST 41d
What are the identified prognostic factors in dogs with CD21+ LSA (2)?
Large cell size = shorter remission duration and ST (HR: 2.77x more likely to die and 1.75x more likely to develop PD); also more likely to have lymphadenopathy and thrombocytopenia
MST: large cell 5m vs medium 9m vs small NR
Low MHC class II = shorter remission duration and ST (HR: 2.87x more likely to die and 3.49x more likely to develop PD)
MST: low 4m vs high 10.5m
What is the PFS* and MST in dogs with LSA treated with CCNU as a first line therapy? ORR? CR and PR?
PFS: 40d
MST 3.5m (111d)
ORR 52%, CR 35%, PR 17%
What is the PFS, and MST of dogs with LSA when treated with doxo/pred vs doxo/pred/CTX?
Main findings on this study?
Addition of CTX did NOT result in statistical improvement of ORR, PFS, or MST. Study was underpowered, however.
Doxo/pred/placebo - PFS 5 to 6m, MST 6 to 10m
Doxo/pred/CTX - PFS 8m, MST 14m
CR, PFI, MST with single agent doxo/pred in dogs with LSA of unknown phenotype?
ORR, CR, PFI, MST for B-cell?
ORR and CR* for T-cell?
Unknown: CR 78% PFS 4-6m, MST 5-10m
B-cell: ORR 100%, CR 70 to 86%, PFS 5-6m, MST 6-10m
Only chemo completion prognostic for PFS and ST; no diff when compared to historic controls that included T cell
T-cell: ORR 50%, CR 17%
CR to CHOP for T-cell vs B-cell canine multicentric LSA?
T-cell 88% (ORR 95%, PFI 5m, MST 8m)* largest study with specifically multicentric T-cell (no GI); 15% alive at 1 yr and 5% at 2 yr
B-cell 85 or >%
MOPP for T-cell: ORR 98%, CR 78%, PFI 6.3m, MST 9m)
25% alive at 2.5yrs
Main findings of RNA-loaded CD40-activated B-cells in dogs with spontaneous lymphoma?
Used CD40L transfected K562 cells to generate functional CD40-B cells from the peripheral blood of humans and dogs
It was administered to dogs in remission after induction of chemotherapy
Goal: Induce functional tumor-specific T cells in cancer patients
- CD40 activated B cells are highly efficient antigen-presenting cells capable of priming naive T cells, boosting memory T-cell responses and breaking tolerance to tumor antigens
- The use of tumor RNA as the antigenic payload allows for gene transfer without viruses or vectors and permits MHC-independent, multiple-antigen targeting
RESULTED IN:
-Higher % of dogs achieving a durable 2nd remission and improved lymphoma specific ST in relapsed dogs after rescue therapy
-Induced functional, antigen-specific T cells from healthy dogs and dogs with lymphoma
DID NOT affect: initial response, TTP, or ST compared to dogs tx with chemo alone
What is the ORR, CR, and PFI in dogs with NAIVE lymphoma when treated with alternating rabacfosadine/doxorubicin?
How does immunophenotype affect ORR?
Prognostic indicators (2)?
ORR 84% (CR 68%, PR 16%)
PFI 6.5m, if CR 7.2m
Immunophenotype predicted ORR:
95% - B cell
25% - T-cell
Substage and phenotype were associated with PFI; longer for B-cell
What is the ORR, CR, and PFI in dogs with B-cell LSA when treated with rabacfosadine in the RESCUE setting?
How does the PFI change for dogs with a CR or any response?
ORR: 74% (CR 45%, PR 29%)
PFI: 3.5m, 7m if CR, 6m with any response
No difference between doses used
What % of dogs with lymphoma vs myeloma develop dermatologic AE when treated with Tanovea?
Lymphoma: 25-37%
Myeloma: 50%
What is the most common phenotype, overall PFS and MST in dogs with colorectal lymphoma?
Does local therapy improve outcome?
B-cell, high-grade
PFS 3.6yrs
MST: 4-5yrs
Addition of local therapy to chemotherapy DOES NOT improve outcome
ORR, CR, PR to chemotherapy in dogs with colorectal LSA?
100% ORR
95% CR
5% PR
Prognostic factors in dogs with colorectal LSA (2)?
Younger dogs (<7yrs) = longer PFS (NR) and dz-specific MST
Hematochezia/substage b = longer PFS (NR)
What is the most common intestinal location in cats with LGL?
Most common phenotype?
IHC used for granules?
What % is NK origin?
Jejunum
granzyme B+ for granules (seen on cytology but not H&E sections)
CD3+ CD8+, CD20-, TCR gene rearrangement - most common
CD103 (integrin) - 60%
10% are NK origin (CD57+) and negative for B and T cell markers; C
What % of cats with LGL experience clinical benefit and a response when treated with chemotherapy?
35% - clinical benefit
30% - ORR
What is the overall TTP and MST in cats with LGL when treated with chemotherapy? MST w/o chemo? What % survives >7m?
TTP 50d
MST 2m; CHOP 60d, CCNU 60-130d
MST w/o chemo 2w
7% >6m SR
CHOP/COP ORR 30%
CCNU/Elspar ORR 56%
Negative prognostic indicators in cats with LGL (4)? Positive (1)?
- Substage b
- Circulating neoplastic cells
- Lack of chemo administration
- Lack of chemo response
Positive: chemo administration
What are the negative (4) and positive (3) prognostic factors identified in cats with nasal LSA?
Negative:
- Anemia
- Cribriform plate lysis
- Total RT dose of <32Gy
- BW of <4kg
Positive:
- Achievement of a CR
- Total RT dose of >32Gy
- Apoptotic index and Ki67 >40%
What is the overall MST in dogs with intermediate to high vs low-grade nasal LSA? Most common phenotype?
B-cell
Intermediate to high - MST 12.5m
Low - MST 2.3yr
No statistical difference in MST, but chemo alone had lowest MST of 5m vs RT + chemo MST of 15m
Most common primary and metastatic* intramedullary spinal tumor in dogs? Location?
Primary - ependymoma (neuroepithelial)
Metastatic- HSA and LSA per Withrow
HSA and TCC new paper; 33% each
T3-L3
Most common secondary brain tumor in cats vs dogs?
Cats - LSA #1, pituitary #2
Dogs - HSA #1, pituitary #2, LSA #3
What is the most common secondary intra-ocular tumor in dogs and cats?
LSA
Up to what % of dogs with LSA have ocular involvement? Most common abnormality?
37%
Uveitis
What is the PFS and OST in dogs with primary intrao-ocular LSA? Phenotype? CS? What % can develop neuro signs?
B-cell; considered stage V
Uveitis, endophthalmitis (inflammation of the anterior chamber), and 2/5 had abnormalities in contralateral eye
PFS/OST 6m
100% in one study
What is the PFS and MST in dogs with conjunctival LSA? Prognosis? How does it present?
Good prognosis
Considered stage I
PFS 7.5m, MST 18m
All unilateral, 2/4 had a discrete mass
Some can be cutaneous epi T-cell LSA
Some can develop LN involvement later on
What is the ORR and PFS of DTIC when used as a rescue in dogs with LSA?
ORR 35%
PFS 40d, if CR 144d
What population has been identified as having a higher risk for LSA development in Australia?
Neutered dogs (males and females)
What breeds are at higher risk for LSA development in Europe (4)?
Dobies, Rotties, Boxers, BMD
In Europe, what type of LSA do Rotties, Boxers, and dog de Bordeaux, most commonly develop?
Rotties - B cell
Boxers Bordeaux - T cell
In Europe, although Labs are not predisposed to developing LSA, what type do they most commonly get?
High grade T cell
What is the difference between Goldens in the USA vs Europe when it comes to LSA?
Unlike USA, they are not predisposed to LSA or TZL
What % of DLBCL and T cell LSA over-express PD-L1? What has this been associated with?
50% DLBCL
0% T cell
Increased expression of PD1 and PD1L in TIL and chemotherapy resistant cell lines in both B and T cells
Dogs with LSA tend to have a higher serum concentrations of what 2 things when compared to healthy dogs?
Lactate
B-hydroxybutyrate
How does the GI microbiota differ in dogs with asymptomatic LSA vs healthy dogs?
Asymptomatic LSA dogs have lower GI microbial diversity and higher degree of dysbiosis vs healthy dogs
How is the agreement of digital slide assessment with flow cytometry vs that of traditional glass slide assessment?
Lower
An s-phase fraction of > than ___% is consistent with high grade LSA. Sensitivity and specificity? What is it strongly associated with?
> 3.15%
Sensitivity 98%
Specificity 100%
Ki67
A Ki-67 of > than ___% is consistent with high grade LSA. Sensitivity and specificity?
Ki67 > 12.2%
96% sensitive
100% specific
What is the ORR, PFS, and MST in dogs with DLBCL, substage a, when treated with CHOP chemotherapy?
ORR 100% (82% CR, 18% PR)
PFS 8.5m
MST 11.5m
What are some identified PF for achieving a PR vs CR in dogs with DLBCL, substage a, when treated with CHOP (3)?
Thrombocytopenia at dx
Greater age at dx
High serum globulin concentration
What are some identified PF for a shorter PFS in dogs with DLBCL, substage a, when treated with CHOP (4)?
Thrombocytopenia at dx
Greater age at dx
PR as best response
Increased neutrophil count
MST 93d or < in these dogs
What is the ORR, CR, PFI, and MST of UK dogs with centroblastic DLBCL when treated with CHOP chemotherapy?
ORR 94%, CR 75%
PFI 6m, MST 11m (10.7m)
What is an identified prognostic factor for achieving a CR vs a PR in UK dogs with centroblastic DLBCL when treated with CHOP?
Entire dogs more likely to achieve CR
What are some identified prognostic factor (2) for achieving a longer PFI in UK dogs with centroblastic DLBCL when treated with CHOP?
Absence of anemia at dx
Pre-treatment neutrophil:lymphocyte ratio <9.44
What are some identified prognostic factor (4) for achieving a longer ST in UK dogs with centroblastic DLBCL when treated with CHOP?
Lymphocyte:monocyte ratio >1.43
Neut:lymph ratio <11.44
Combination of induction and rescue therapy
Increased number of doxorubicin doses
Upregulation, phosphorylation, and nuclear localization of what 2 TF have been noted in lymphocytes from dogs with DLBCL vs those from healthy LN?
STAT3 and ERK1/2
What is the ORR in chemotherapy naive lymphoma patients when given VBL? Doses used?
7% PR at 2 mg/m2
60% PR at 2.5 mg/m2 - 80% developed neutropenia 1 week post
What is the ORR and DFI of VBL when used as a rescue agent in dogs with LSA? Dose used?
VBL at 2.6mg/m2
ORR 26% (CR 8%, PR 18%)
DFI 30d
6% grade III or IV neut
In dogs with B cell lymphoma tx with doxo + pred, what has been addociated with a longer PFS and MST?
Chemo protocol completion
ORR, CR, PFS/DFI, and MST in dogs with T-cell LSA treated with Morgan vs Brown LOPP? 2-yr SR?
Morgan:
ORR 94%, CR 83%, PR 11%
PFS 14.4m, MST 17m
54% 1-yr PFS, 29% 2-yr PFS
Brown:
ORR 97%, CR 90%, PR 7%
DFI 6m, MST 8m
39% 1-yr SR, 25% 2-yr SR
AE to Morgan vs Brown LOPP in dogs with T-cell LSA?
Morgan:
86% overall (higher)
51% myelosuppression; grade 3+ neut/thrombo in 80%
74% GI; only 13% grade 3+
23% overall hospitalized; 11% if not including post induction
40% required dose reductions
Brown:
42% overall
Only 18% required dose reduction
How do CSC behave in dogs with B and T cell LSA vs LN samples from a healthy dog?
% of tumour cells expressing CSC markers were significantly increased in dogs with BCL, compared with B cells from normal lymph nodes. Similar results in T-cell.
CSC flow cytometry markers in B vs T cell lymphoma?
B-cell: higher expression of CD117, CD90, CD34, Oct 3/4 vs normal B cells
T-cell: higher expression of Oct 3/4 and downregulation of CD90 vs normal T-cells
What is the ORR and T-cell RR, TTP, duration of response and AE of verdinexor (KPT-335) in dogs with T-cell LSA (naive and progressive)?
MTD?
ORR: 37%, T-cell 71%
TTP 30d
Response duration 18d
AE: 95% grade 1-2
anorexia 45%
weight loss 31%
vomiting 26%
Hepatopathy also reported
1.75mg/kg PO BID 2-3x per week
What is verdinexor?
Oral selective inhibitor of nuclear export (SINE) ; reversibly binds to XPO1, which is responsible for moving p53, p21, pRb, FOXO, NF-KB into the cytoplasm
Based on geographical location within the USA, which locations have the longest vs shortest PFS when treated with chemo?
North - 8m
South - 6m
West - 4m
Dogs with centroblastic polymorphic DLBCL have a higher chance of 2-yr survival if what 4 factors are present?
BW >10kg
Normocalcemia
No BM involvement
No steroids
MST of dogs with Burkitt’s LSA?
15d
When dogs with LSA are treated with LPP in the relapse setting, which ones are more likely to respond?
Those getting a higher procarb dose
In geriatric dogs (14 or>) with LSA treated with COP or CHOP, what is the ORR, CR, duration of response, MST, grade 3 AE?
Negative PI (1)?
Most common phenotype?
B-cell 95% CR Duration of response 6m MST 7m AE: 27% (similar to historic CHOP data)
NPI: Anemia shorter PFI
What are some negative prognostic indicators for PFI and MST in geriatric dogs with B-cell LSA?
PFI: shorter if anemia present
MST: shorter if BW 13kg or >
American Golden Retrievers are more likely to have TZL vs BCL in which geographic locations?
North East
East North Central regions
How its T-zone (clear cell) lymphoma characterized?
A variant of PTCL-NOS characterized by clonal expansion of T-cells that lack expression of CD45, a pan-leukocyte antigen, within the paracortex and medullary cords of LN resulting in compression of germinal centres. The cells are small to intermediate in size with very rare mitoses.
Phenotype: high MHC class II, low-moderate CD21+, CD5+, CD45- Not always CD21+ but high % can be +
What % of older Golden Retrievers without clinical TZL have peripheral circulating TZ cells compared to non-Goldens?
Goldens - 31%
Non-Goldens - 14%
What % of older Goldens without clinical TZL that have circulating TZ cells also have clonal TCR gamma gene rearrangement vs Goldens without TZ cells?
Golden’s WITH TZ cells and clonal TCR - 34%
Golden’s WITHOUT TZ cells and clonal TCR - 20%
In dogs with nodal marginal lymphoma, what % is substage b, what % has stage V dz, splenic, hepatic, and BM involvement?
Most common extranodal site?
Substage b - 34% Stage V dz - 100% Spleen - 97% Hepatic - 80% BM involvement - 60% Extranodal site - lungs
How is the neoplastic lymphoid population described in dogs with nodal MZL?
Medium-sized CD21+ and +/- CD70a+ lymphocytes
Low mitotic activity
Histopath: diffuse growth, loss of follicle architecture, thinning of capsule
What is the ORR, CR, PR, TTP and lymphoma-specific MST in dogs with nodal MZL when treated with CHOP? Overall outcome?
Poor outcome
ORR 100%, CR 80%, PR 20%
TTP 5m
MST 9m (260d)
Negative prognostic factors for ST in dogs with nodal MZL (2)?
Substage b
Elevated serum lactate dehydrogenase
What % of dogs with hypercalcemic LSA have mediastinal involvement?
43%
What % of dogs with multicentric T-cell LSA have mediastinal involvement?
54%
Mediastinal lymphoma is almost always exclusively T-cell and hypercalcemia is most commonly associated with this form of LSA.
What % of dogs with mediastinal lymphoma are hypercalcemic at diagnosis?
68%
Most common phenotype and cytomorphology in dogs with mediastinal LSA?
T-cell
Lymphoblastic high-grae
What % of dogs with mediastinal T-cell LSA are substage b? Most common clinical signs?
85% - substage b
71% - lethargy
Anorexia
PU/PD
What % of dogs with mediastinal T-cell LSA have pleural effusion at diagnosis?
45%
In dogs with mediastinal T-cell LSA, what is the ORR, CR, PFS, and OST when treated with CHOP chemotherapy?
ORR 93%, CR 70%
PFS 4.5m
OST 6m
PPI in dogs with mediastinal T-cell LSA when treated with CHOP?
CHOP chemo - improved PFS and OST
Lack of pleural effusion - improved OST
Is there a difference in outcome in dogs with relapsed multicentric lymphoma when treated with TMZ vs TMZ + doxorubicin? Overall MST?
No; overall MST 40d
TMZ alone: ORR 32%, TTP 15d, MST 40d
TMX/doxo: ORR 60%, TTP 19d, MST 60d
Most common LSA in CNS in dogs?
DLBCL; usually an extension vs primary
CSF analysis in dogs with CNA LSA is diagnostic in what % of cases?
~70%
Increased TNC from which 95-100% are atypical lymphocytes and increased TP
Overall MST in dogs with CNS LSA?
170d (5.6m)
Phenotype of epitheliotropic LSA in dogs?
CD8+
ORR, CR, remission duration if CR, and MST in dogs with CETCL treated with CCNU?
ORR 80%, CR 30%
CR duration 4.5m (132d)
MST 6m
Prognostic factors in dogs with CETCL?
Positive PI:
- Mucocutaneous or mucosal lesions vs cutaneous
- For cutaneous lesions, the use of chemo and the presence of solitary lesions
- For mucocutaneous, younger age and presence of solitary lesions
Sensitivity of a moth-eaten spleen in cats with LSA on AUS?
13% sensitive
85% specific
What is the ORR to Elspar in cats with LSA? How is it when compared to dogs?
30% ORR (CR 15%, PR 15%)
Shorter duration of response; <7d
Sensitivity and specificity of flow cytometry for LSA diagnosis in cats?
What needle gauge is preferred in order to provide a highly cellular sample?
92% sensitive
100% specific
21 gauge needle
What is the most common Hodgkin’s like lymphoma in cats? Presentation? Immunophenotype? Prognosis?
Lymphocyte-histiocytic (RS cell variant); usually small to medium sized lymphocytes and large histiocytic looking lymphocytes
Reactive CD3+ T cells in the background
Lymphohistiocytic cells positive for BLA 36 and CD79a -> B-cell
Lymphadenopathy of 1 or > enlarged LN in the head/neck region
Prognosis: usually excellent
W/sx - DFI 1yr
W/o tx - MST 7m-4yr ST
Can sometimes regress on its own and then come back
Can become aggressive
Usually cats older than 6 yrs
What is the ORR, CR*, DFI, and MST for cats with various anatomic forms of intermediate to high-grade LSA when treated with intraperitoneal L-COP? 1 and 2yr SR?
ORR 96%, CR 77%, PR 19% DFI 14m (421d) MST 13m (388d) 55% 1-yr SR 47% 2-yr SR
Which anatomic in cats with LSA location has the shortest DFI when treated with intraperitoneal L-COP?
GI 7.6m < Nasal 13m < Peripheral 14
Most common AE in cats with intermediate to high-grade LSA when treated with intraperitoneal L-COP?
Vomiting - 42%
Also anorexia and weight loss
Prognostic indicators in cats with intermediate to high-grade LSA when treated with intraperitoneal L-COP (2)?
Younger age = more favorable response
CR = long-term ST
Most common cause of febrile neutropenia in cats?
#1 CCNU #2 Vincristine
Most important PI in cats with GI LSA?
Response to therapy
ORR, PFS, MST in cats with intermediate to high grade LSA treated with DMAC in the rescue setting? AE?
26% clinical benefit (no CR)
PFS 14d
MST 17d
16% grade 4 neutropenia
What % of cats with GI LSA have concurrent IBD?
60%
When the human WHO classification system is applied to cats with alimentary LSA, what is the predominant form seen in the stomach, SI, mesenteric LN, and ileocecocolic junction, large intestine?
Stomach - DLBCL
SI - EATL type I (48%) and II (42%)
Mesenteric LN - T-cell
Ileocecocolic - DLBCL
Phenotype statistically associated with associated with location
When the human WHO classification system is applied to cats with alimentary LSA, what are the 3 most common forms of alimentary LSA in cats?
1 EATL type I - 41%; transmural T-cell LSA, large cells; extension into submucosa and muscularis propia
What are the 2 most common alimentary forms of LSA in cats when using the feline classification system?
Mucosal - usually low grade, small-cell, T cell
Transmural - usually high-grade, small (40%) or large (60%), B or T cell; LGL is a large cell subtype
What % of alimentary LSA in cats are T vs B cell? Which form of LSA is more common within the phenotypes?
T- cell: 80%, usually mucosal (80%)
B-cell: 20%, usually transmural (95%)
What % of cats with LGAL develop large cell GI LSA?
3.7%
Most common location for alimentary LSA in cats?
SI; rarely in stomach and LI
In cats with alimentary LSA, what immunophenotype is most commonly associated with solitary/multifocal vs diffuse dz?
T-cell diffuse
B-cell solitary or multifocal; multiple common
Most common locations for low grade alimentary LSA?
Jejunum and ileum
What % of cats with LGAL exhibit epitheliotropism?
40%
What has been recently noted in cats with LGAL and COX-2 expression (2)?
COX-2 protein expression is present in 1/3 of cats with LGAL, but no difference when compared to cats with IBD.
COX-2 mRNA levels are higher in cats with LGAL vs IBD or healthy cats
What are the 2 most common subtypes of transmural large-cell LSA in cats?
LGL - most common one*
DLBCL
Most common subtype of large-cell transmural alimentary LSA in cats?
Large granular LSA - 82%
Overexpression of ____ mRNA has been noted in cats with LGAL vs IBD.
MDR1
What % of cats with discrete intermediate to high grade LSA develop intestinal perforation post chemotherapy induction?
17% (20-90d post)
What is the most common complication in cats with alimentary LSA that undergo full thickness biopsies? Prognostic indicators for complications?
Transient hypo or anorexia - 11%
Other: hyperthermia, pancreatitis
NO dehisence!!
No identified prognostic variables
Low albumin NOT prognostic (as opposed to dogs <2.5)
Besides flow cytometry, what test has the best sensitivity and specificity for differentiating small cell GI LSA vs IBD?
PARR - 90% sensitive
Histopath - 99% specific
How has abdominal RT been combined with chemotherapy in treatment naive cats with abdominal or multicentric lymphoblastic/large cell lymphoma?
Response and outcome?
6 week CHOP chemo 2-week holiday 1.5Gy x 10d (M-F) 5/8 had durable remission of >266d (9m) Overall, well tolerated
2 cats relapsed
1 euthanized for unknown reasons
What is the MST in cats with different types of GI LSA when treated with abdominal RT in the rescue setting? Protocol? AE?
8Gy x 2d
MST 7m
Minimal RT SE, 1 cat had self-limiting loss of appetite
What % of cats with LGL have extra-intestinal involvement?
Three most common locations?
85%
LN>liver>spleen>kidneys>lungs>bone marrow
Epitheliotropism common
LGAL accounts for what % of feline alimentary LSA?
60-75%
Most common form
What % of cats with LSA have pulmonary involvement?
13%
In cats, to what forms of LSA is pulmonary LSA associated (3)?
Mediastinal
Alimentary
Multicentric
Most common pulmonary lesions in cats with LSA?
No gross lesions 56%
Masses 25%
Nodules 20%
Most frequent radiographic pulmonary pattern seen in cats with LSA and pulmonary involvement?
Peribronchial-vascular infiltrative pattern
Most common phenotype and subtype in cats with LSA and pulmonary involvement?
B cell (90%) DLBCL (60%)
What are the identified risk factors for feline intestinal carcinoma (3)?
Age (10-12 yrs)
Males
Siamese - 1.8x increased risk for intestinal neoplasia and 5x increased risk for ACA
What IHC markers are used for GISTs (5)? Most sensitive ones (2)?
CD117 - 95-100% DOG-1 CD34 VImentin SMA - 30% (usually negative)
CD117 and DOG1; will catch the ones negative for CD117
Discovered-on-GIST 1 (DOG1) is a Ca-dependent Cl channel involved in generation of slow waves from the interstitial cells of Cajal
Where are mutations in the c-kit gene located in dogs with GIST?
Exon 11 of juxtamembrane domain of KIT
Results in constitutive activation
Mutations: deletions, ITD, and point mutations
What techniques can be used to detect c-kit mutations in dogs with GIST (2) and which one is more likely to detect a mutation?
RT-PCR: 72.4% detected
Conventional PCR: 32.6%
What is the most common KIT staining pattern in dogs with GIST? Is it associated with c-kit mutation status?
Diffuse cytoplasmic - 70%
partial/focal stippled cytoplasmic - 30%
NOT associated with c-kit mutation status
Why can females develop perianal gland adenomas after being spayed? What is another reason?
Loss of estrogenic inhibition
Testosterone-secreting adrenal tumor
What are some negative prognostic indicators in dogs with AGASACA (10)?
Tumor size: > 9cm2 or >2.5cm LD
Any mets: LN and distant
Advanced clinical stage
Lack of sx
Lack of chemo
Tx with chemo alone
LN mets and extirpation
Tx with platinums (shorter DFI, another study showed it decreases risk of local recurrence)
Hypercalcemia (newer studies say its not)
Some histopath changes (see next index card)
What are some negative histopathologic PI in dogs with AGASACA (7)?
Decreased E-cadherin expression
Solid growth pattern
Moderate or marked peripheral infiltration
Necrosis
Lymphovascular invasion
Cellular pleomorphism
MI 8 or >
What is the TTP and MST in dogs with early stage (<3.2cm) AGASACA w/o mets when treated with sx alone?
Recurrence rate and later metastasis?
TTP 2.4yrs
MST 3.4 yrs
RR 20%
Mets in 26% at 1yr or later
What is the MST in dogs with AGASACA that develop local recurrence and are treated with a 2nd surgery?
Overall 2 yrs
After 2nd sx 9.5m
What is the TTP and MST in dogs with AGASACA when treated with sx and 4 doses of carboplatin? Did chemotherapy make a difference in ST?
TTP 13m
MST 2 yrs
Chemo did not make a difference
What is the MST in dogs with AGASACA when treated with sx and melphalan?
20m
What is the MST in dogs with AGASACA treated with sx, carboplatin, and hypofractionated RT?
19m
What is the PFI and MST in dogs with stage 3b AGASACA when treated with sx vs hypofractionated RT?
Sx - PFI 5.3m, MST 6m
RT - PFI 11.5m, MST 15m
IIIb - T any size, nodal mets >4.5cm (vs a, <4.5m)
Dog with AGASACA, no nodal metastasis, hypercalcemic – what is the best treatment?
Pamidronate and fluids, sx alone, sx and hypofractionated RT to the node bed, Sx and Palladia
How to treat?
What % of AGASACAs express PDGFRa and b? VEGFR2 cytoplasmic staining?
Alpha - 100%
Beta - 17 to 19.5%
VEGFR - 80%
What are late SE that can occur with adjuvant RT for AGASACAs? How can this be minimized?
Rectal stricture or perforation
Minimize by using <3Gy per fraction
A study evaluating an IMRT theoretical 3.8 Gy x 12 protocol for dogs with stage IIIb AGASACA determined that in almost half of the patients, there was a ___% risk of late spinal cord toxicity. There was ___% risk of ____ in 33% of patients.
5% or > of late spinal cord toxicity
> 15% risk of myelopathy in 33% of patients
In dogs with GIST treated with Palladia, what is the median PFI when used in the gross vs microscopic dz setting? Biological response rate in dogs with gross disease?
Biological response 71% (2 CR, 1 PR, 1 SD)
PFI in gross dz 2.3yrs (for responders)
PFI in microscopic 1.3yrs
Negative PI for a shorter PFI in dogs with GIST treated with Palladia?
Metastasis at dx
High mitotic index (<5, 5-10, >10)
What is the TTP and MST in cats with salivary gland carcinoma when treated with RT and +/- surgery? Negative PI (2)?
TTP: 5m
ST: 2-19m
Advanced clinical stage
Compared to dogs, cats have a higher metastatic rate and poorer long term prognosis
What is the most common exocrine pancreatic tumor in cats?
Metastatic rate at diagnosis?
Most common clinical signs at presentation?
Pancreatic adenocarcinoma
32% have mets at dx
Weight loss (68%), anorexia (53%), vomiting (41%), palpable abdominal mass (41%)
What paraneoplastic syndrome can be seen in cats with exocrine pancreatic carcinoma?
Alopecia
Acute, progressive, non-scarring, bilaterally symmetric; predominantly involves the limbs, but can include the ventrum, head, and trunk
What is the most common comorbidity in cats with pancreatic carcinoma?
Diabetes mellitus - 15%
Other:
Heart dz or murmur (21%)
Hyperthyroidism (18%)
Overall MST in cats with pancreatic carcinoma?
What is the MST in cats with pancreatic carcinoma treated with sx and chemo?
1-yr SR?
What type of surgery is performed?
Overall 3m
MST w/sx and chemo 5.5 to 10.5m
*10.5 if no mets
8.8% 1-yr SR
Complete pancreatectomy or Whipple’s procedure (pancreaticoduodenectomy)
Negative PI in cats with pancreatic carcinoma (3)?
Peritoneal effusion (30d)
Tx with NSAIDs alone (26d)
Lack of sx and/or chemo (improves ST, 165d)
MST <1m
What chemotherapy has been shown to have clinical benefit in cats with pancreatic carcinoma?
Gemcitabine - 82%
Most common gastric mass in lesser curvature/antrum of stomach in dogs? CS: GI bleed, high BUN.
Gastric ACA - #1 gastric tumor in dogs (80%)
Most common location: lesser curvature and antrum
Metastatic rate of gastric ACA in dogs? Locations?
70-80% metastatic rate
lymph nodes #1, liver #2, lungs #3
Gastric ACA in dogs are more common in what sex and breeds (2)?
Males
Belgian Shepherd and Rough-Coated Collie
Ulcers and bleeding can occur in ___% of dogs with gastric ACA. Because of this, what is a common CBC finding?
50%
Microcytic hypochromic anemia
What is the 2-week and 3-month SR in dogs with gastric neoplasia (benign and malignant) undergoing pylorectomy and gastroduodenostomy (Billroth 1)?
What % of dogs undergoing this surgery survive to discharge?
MST?
75% 2-week survival rate
60% 3-month survival rate
88% survived to discharge
MST 1-2m (generally <6m)
Billroth 1 - resection of pyloric antrum (pylorectomy) and gastroduodenal anastomosis (gastroduodenostomy)
Three most common complications in dogs with gastric neoplasia undergoing pylorectomy and gastroduodenostomy (Billroth 1)?
hypoalbuminemia (63%) anemia (58%) transfusion (33%) hypotension (17%) hypoglycemia (17%) aspiration pneumonia (13%) pancreatitis (13%) sepsis due to dehiscence (8%)
Negative PI (on univariate) in dogs with gastric neoplasia undergoing pylorectomy and gastroduodenostomy (Billroth 1) (2)?
Preoperative weight loss
Malignant cancer
Most common GIST location?
Cecum
Second most common gastric tumor in dogs? Location? Signalment?
LMA
Stomach cardia, grow into lumen, discrete, pedunculated
Always focal
Commonly seen in older dogs ~15yr; Beagles
According to CT findings in dogs with gastric tumors, what tumor is most likely associated with larger LN?
Gastric LSA
According to CT findings in dogs with gastric tumors, is LSA more likely to be segmental or diffuse?
Segmental 60%
Diffuse 40%
According to CT findings in dogs with gastric tumors, is ACA more likely to be segmental or diffuse?
50:50
What are the intraoperative and perioperative mortality rates in dogs with massive HCC undergoing sx?
intraoperative 4.8%
perioperative 8-12%
What is the perioperative mortality rate in cats with massive liver tumors undergoing sx?
22%
In cats with massive liver tumors undergoing sx, what % survives to hospital discharge and what % lives >40d?
78%
61% lived >40d (multiple liver tumors)
Complication rate in dogs and cats undergoing liver sx for massive tumor removal?
Most common complication?
Dogs - 30%
Cats - 22%
Hemorrhage; 17% of dogs and 44-61% of cats undergoing liver lobectomy need a blood transfusion
What are some identified prognostic factors in dogs undergoing sx for massive HCC (8)?
Surgical excision vs palliative care (MST >1460d vs 270d); non-surgical cases 15.4x more likely to die
Increased ALT and AST
Increased ALP to AST ratio
Increased ALT to AST ratio
Side of liver involvement; higher risk of intra-op complications for R-sided tumors, but no difference in ST
Lethargy or tachypnea at presentation
Experiencing an anesthetic complication
Requiring a blood transfusion associated with failure to survive to discharge
What are some prognostic factors in cats with liver tumors treated with sx (3)?
Abdominal effusion
Preoperative anemia
Need for transfusion
Shorter MST
What is the most common primary hepatobiliary tumor in cats overall?
Bile duct adenoma (biliary cystadenoma) - 52% of all liver tumors
How do bile duct adenoma (biliary cystadenoma) loos grossly? Sex predisposition? CS?
Cystic appearance
Even distribution between focal vs multifocal
Male
Typically asymptomatic until mass effect occurs
What is the most common primary malignant hepatobiliary tumor in cats? Metastatic rate and locations?
Bile duct carcinoma (cholangiocarcinoma)
67-80% metastatic rate; LN, lungs, carcinomatosis, etc
PNS alopecia reported (and with HCC)
What is the second most common malignant hepatocellular tumor in cats?
Hepatocellular carcinoma
Metastatic rate and MST with and w/o sx in cats with HCC?
Met rate - 0%
MST: w/o surgery 1.4yrs vs w/sx 2.4yrs
What are the most common chemistry abnormalities in cats with HCC (4)?
AST elevated in >90%
ALT and ALP elevated in >70%
Hyperbilirubinemia in >40%
What viruses are associated with HCC in humans?
Hepatitis B and C
Woodchuck: Woodchuck hepatitis virus
In dogs vs cats, are primary vs metastatic tumors more common?
Dogs - metastatic
Cats - primary (usually benign)
Recently, upregulation of ___ mRNA was noted in dogs with HCC.
MET
In dogs with concurrent splenic and hepatic masses, what % had malignancies in both organs?
Of those with concurrent malignant lesions, what % had the same malignancy?
Most common malignancy?
48% - malignant in both organs
93% - same in both organs
HSA - 77%
ORR of Palladia in dogs with non-resectable liver tumors?
50% (PR) in 3/6 dogs
What % of dogs with HCC develop tumor reduction post trans-catheter arterial embolization?
100%
What is an identified predisposition for intestinal tumors in both dogs and cats?
Male sex
Of dogs with inflammatory intestinal polyps that underwent a 2nd biopsy, what % developed adenoma and ACA?
36% adenoma
20% ACA
In the study of dogs that developed adenomas and carcinomas after an initial diagnosis of polyps, what was also noted?
Inactivation of APC gene
Accumulation of B-catenin in cytoplasm -> translocation to nucleus -> promotion of Wnt associated genes
Most common sited for GIST in dog?
Cecum #1
Colon
What drug is used in humans with GIST?
Imatinib (Gleevec)
Can rescue with Sunitinib when Imatinib fails
In dogs, what are the most common locations for intestinal lymphoma?
Equal distribution between stomach and SI (LI less likely)
What dog breeds are predisposed to developing intestinal T-cell LSA (7) according to a Japan study?
Shiba dogs, German shepherds, Cairn terriers, Boston terriers, Papillons, Pugs and Maltese
What is the most common phenotype for intestinal T cell lymphoma in Shiba dogs in Japan?
CD3+, granzyme B+
Regardless of small or large cell
What is the most common phenotype and lesion distribution in dogs with small cell intestinal LSA?
T-cell
Diffuse - 38%
Discrete/multifocal - 23%
What is the most common clinical sign in dogs with small cell T-cell intestinal lymphoma?
Diarrhea #1
Weight loss
What are the 3 most common US abnormalities in dogs with small cell T-cell intestinal lymphoma? What % of dogs have a normal AUS?
Abnormal wall layering - 54%
Hyperechoic mucosal striations - 54%
Thickened muscularis - 34%
Normal - 38%
Mild lymphadenopathy - 46%; only 1 had LSA confirmed
What % of dogs with with small cell T-cell intestinal LSA exhibit epitheliotropism?
60%
What is the overall MST and MST of chemotherapy treated dogs (14/17) with with small cell T-cell intestinal LSA?
Overall MST 9m
Chemo tx dogs MST 14-21m
Identified prognostic factors in dogs with small cell T-cell intestinal LSA (4)?
Anemia = shorter ST
Weight loss = shorter ST
Tx with steroids + alkylator = longer ST vs steroids alone
Response to therapy = longer ST
What is the ORR to chemotherapy in dogs with small cell T-cell intestinal LSA?
70%
What % of canine small cell T-cell intestinal LSA co-express CD20?
48%
2 common chemistry abnormalities in dogs with small cell T-cell intestinal LSA?
Hypocobalaminemia -71%
Hypoalbuminemia - 69%
Most common intestinal location in dogs with small cell T-cell intestinal LSA?
Duodenum
Histopathologic description of dogs with smal-cell T-cell intestinal LSA?
Lymphocytic infiltrates within the intestinal villous lamina propria and epithelium.
Infiltrates were often more pronounced in the villous tips
Most common phenotype in dogs with large-cell intestinal LSA?
T-cell
What % of dogs with large cell intestinal LSA have intestinal + LN involvement vs intestinal involvement alone?
Intestinal + LN 48% (94% had LSA confirmed on LN)
Intestinal alone 40%
MST in dogs with large cell intestinal LSA when treated with multiple therapies?
2-2.5m
Dogs tx with CCNU have a numerically longer MST, but not statistically significant
No differences in outcome based on tx
Most common AUS abnormalities in dogs with high-grade intestinal LSA (4)?
#1 Thickened intestinal wall with loss of layering #2 presence of ≥ 1 discrete mass #3 ulceration
What are some negative prognostic indicators in dogs with high-grade intestinal LSA (4)?
Diarrhea
Anorexia
Septic peritonitis
Dz outside of intestines alone
What are the 3 most common causes of hypercalcemia in cats?
#1 idiopathic #2 kidney disease #3 neoplasia
What % of hypercalcemic cats have cancer?
1/3 or 33%
What are the most common causes of hypercalcemia of malignancy in cats?
Lymphoma and SCC
PTHrp mediated
What % of cats vs dogs with MM are have hypercalcemia?
Cats: 10-25%
Dogs: 15-20%
What is the main MOA for hypercalcemia in dogs and cats with MM?
IL-1B (osteoclast activating factor)
Expected BW abnormalities in dogs with primary hyperparathyroidism?
iCa and Tca - high
PTHrp - zero
PTH - normal or high
Ph - low (if neoplastic too)
What non-neoplastic infectious dzs can cause a monoclonal gammopathy (8)?
Babesia Ehrlichiosis Leishmaniasis FIP Coccidioides Heartworm Bartonella henselae Strep zooepidemicus in cats Chronic pyoderma Amyloidosis
Clinical case of TCC with hypertrophic osteopathy. What to do next?
Tumor excision
Can consider anti-inflammatory steroids, NSAIDs and/or bisphosphonates
What % of tumor bearing dogs have thrombocytopenia prior to therapy?
36% prior to therapy
Highest with lymphoproliferative disorders - 58%
Thrombocytopenia is higher in dogs with which class of tumors?
Lymphoproliferative disorders - 58%
What % of dogs and cats with MM have thrombocytopenia?
Cats 50%
Dogs 33%
Most common cause of thrombocytopenia in cats?
Lymphoma
What % of dog with HSA have thrombocytopenia?
75-97%
DIC cause of consumptive thrombocytopenia in ___% of dogs with cancer.
40%
What % of dogs with HSA and cats with splenic MCT have an abnormal coagulation profile?
Cat splenic MCT = 90%
Dog HSA = 50%
What is the most common PNS in dogs and cats with LSA?
Non-regenerative anemia
Non-regenerative anemia can be present in what % of dogs and cats with MM?
Dogs: 70%
Cats: 50-65%
Anemia more common than thrombocytopenia in MM*
What is the most common cutaneous tumor in cats? Biologic behavior and metastatic rate?
Basal cell tumor - 23% overall
(10 to 26%)
Usually benign. A study of 97 feline BCT had 10% categorized as malignant based on stromal invasion, vascular invasion, necrosis, high MI, LN mets (1 cat); another study had 1 cat with pulmonary mets
What is the most common malignant ear canal tumor in dogs and cats?
Ceruminous gland adenocarcinoma
In dogs and cats, are malignant vs benign tumors of the ear canal more common?
Dogs - uncertain
Cats -malignant
What canine breeds are at increased risk for developing ear canal ceruminous gland ACA (2)?
Cocker Spaniels and GSD
How is the metastatic rate in dogs and cats with ear canal ceruminous gland ACA?
Low and uncommon, but increases over time
Dogs - LN 3.3%, lungs 8.5%
Cats - LN 9%, lungs 0%
What is the TOC in dogs and cats with ear canal ceruminous gland ACA? Why?
TECA and BO
Recurrence is lower vs LECA
What are negative prognostic factors in dogs with ear canal ceruminous gland ACA (1)?
Extension beyond ear canal (cartilage invasion)
MST 6m vs w/o (confined) 30m
What are negative prognostic factors in cats with ear canal ceruminous gland ACA (4)?
MI of ≥ 3 (MST 12m vs 180m)
Neurologic CS (MST 15.5m vs 1.5m)
Histology (ACA MST 49m vs SCC 3.8m)
Extension beyond ear canal/cartilage invasion (MST 4m vs w/o 22m)
What are negative prognostic factors in dogs with digital melanoma (8)?
- Mitotic index ≥ 3
- Ki67 index ≥ 15
- ≥ 20% nuclear atypia
- Distant mets
- Degree of pigmentation (scale 0-2, 2 is favorable)
- Junctional activity
- Level of infiltration/extension beyond dermis
- Ulceration
What % of dogs with digital melanoma have metastasis at presentation?
30-40%
Picture of cytology (SCC) lab with lysis of P3. What is the metastatic rate at diagnosis and later on?
What % has lysis on xrays?
At dx 9%
Later on 23%
80% have lysis on xrays
What are identified prognostic factors in dogs with oral melanoma (14)?
- Ki67 index ≥ 19.5% (shorter DFI and MST)
- MI ≥ 4/10 hpf
- ≥ 30% nuclear atypia
- Co-expression of PDGFR a/b (37%, shorter DFI and MST)
- Higher % of intratumoral Tregs
- Stage of dz
- Size of tumor
- Lymphatic invasion
- Distant mets
- Degree of pigmentation
- Female sex
- Adjuvant therapy
- Intralesional excision
- > 12yrs of age
What are the negative prognostic indicators identified in dogs with lip melanoma (7)?
- Mitotic index ≥ 4/10 hpf
- Ki67 index ≥ 19.5%
- ≥ 30% nuclear atypia
- Distant mets
- Degree of pigmentation
- Junctional activity
- Level of infiltration/deep with bone involvement
Cutaneous melanomas are often benign if they are not in a mucocutaneous location. What are the negative prognostic indicators for this location in dogs (8)?
- Ki67 index ≥ 15%
- MI ≥ 3/10 hpf
- ≥ 20% nuclear atypia
- Extension beyond dermis/level of infiltration (Breslow thickness: >0.75cm = risk of recurrence/mets, >0.95cm = unfavorable outcome)
- Ulceration
- Distant mets
- Lymphatic invasion
- Degree of pigmentation
What combination of IHC markers is the most sensitive and specific when trying to differentiate an amelanotic from a STS (3)?
What is the sensitivity and specificity of this combination?
What other markers (2) and what other histologic characteristic (1) can be used to help dx melanoma?
What markers are 100% specific, but have a low sensitivity (3)?
Melan A, PNL2, tyrosinase (TRP1/2): 93% sensitive and 100% specific
S-100, MITF: highly sensitive, but less specific (will also stain sarcomas)
Others: vimentin, NSE - positive for both
100% specific, but low sensitivity: HMB-45, tyrosinase, tyrosinase hydroxylase
Presence of junctional activity = proliferation of neoplastic cells at the dermoepithelial junction
NOT ALL WILL STAIN WITH MELAN A
What IHC marker can be used to differentiate a malignant melanoma from a melanocytoma and how does the expression of this marker differs between them?
RACK1 (receptor for activated C kinase 1)
Malignant melanomas stain homogeneously and benign ones heterogeneously
Correlates with cell and nuclear size
What 2 transcription factors haven been associated with increased risk of death in dogs with melanomas? Which one was of prognostic significance on multivariate analysis?
FOXP3, IDO (indoleamine 2,3-dioxygenase)
Increased risk of death associated with higher:
- # FOXP3/HPF
- % of FOXP3+ infiltrating lymphocytes
- # IDO+ cells/HPF
Only #IDO+ cells/HPF prognostic on multivariate
What is the overall MST and PFS in dogs with anal sac melanoma treated with a combination of therapies?
MST 3.5m (107d) PFS 3m (92.5d)
What ICC stain has been shown to be 100% sensitive and specific for the diagnosis of amelanotic melanoma? How does this differ when compared to routine cytology stains?
Melan A
Routine cytology: 67% sensitive, 86% specific
When evaluating histopathology LN samples in dogs with melanoma and trying to differentiate malignant melanocytes from melanophages, the addition of Melan A has been reported to change the final diagnosis in what % of samples?
47%
14 from metastatic to reactive
1 from reactive to metastatic
What is the reported range of complete agreement between cytology and histopathology for the diagnosis of metastatic LN in dogs with melanoma?
30- 50%
POOR
What are the reported ranges for ORR, CR, PR, and PFI, in dogs with OMM when treated with hypofractionated RT? Time to metastasis?
ORR 83-100%
CR 50-70%
PR 25-30%
Time to mets 310d
What is the reported overall PFS and MST in dogs with OMM when treated with RT?
1 and 2 yr SR?
PFS 5-8m
MST 4-12m (stage dependent)
1-yr SR 35-50%
2-yr SR 20%
What is the reported rec
OMM when treated with RT in the microscopic vs gross dz setting?
Microscopic 25%
Gross 45%
What is the MST for stage I, II, III, and IV oral MM in dogs when treated with RT and adjuvant sx or chemo? Any prognostic factors identified?
Stage I: 2yrs (758d)
Stage II: 9m (278d)
Stage III: 5.5m (163d)
Stage IV: 2.5m (80d)
Stage
What has been shown to affect prognosis in dogs with OMM treated with different forms of RT (6)? These dogs were also +/- treated with sx and chemo.
- Stage; stage I dz vs higher and stage III dz tx with orthovoltage (shorter MST)
- Tumor volume/size (>5cm3 shorter MST)
- Bone involvement (shorter TTP and MST)
- High VEGF (shorter TTP and MST)
- Location (rostral better)
- RT in the microscopic dz setting (better)
What % of dogs with OMM is reported to develop oronasal fistulas and bone necrosis when tx with RT?
5.4% oronasal fistula
7-8% bone necrosis
When combining chemotherapy with RT for the treatment of OMM, what drug has been shown to be effective and how did it affect prognosis?
Temozolamide: 60mg/m2 x 5 days then q1 month
RT: 6 Gy x 5
Dogs tx with TMZ had a longer TTP vs RT alone; 205d vs 110d
No difference in ORR or MST
Dogs with OMM of what tumor volume are more likely to achieve a CR and longer MST when treated with RT?
<5cm3
Dogs with OMM have elevated ____ plasma values when compared to normal dogs.
What are 2 ways this can affect prognosis in dogs when treated with RT?
VEGF; shorter TTP and MST
Expression of ___ by tumor infiltrating lymphocytes has been documented in dogs with OMM. In what other tumors has this been documented (5)?
PD-L1
Also in OSA, HSA, MCT, CMT, prostatic ACA
A mutation in the KIT gene has been detected in exon ___ in ___% of dogs with MM.
All samples with a mutation were KIT+ on IHC, but what was the difference in staining?
How does the mutation affect prognosis?
Exon 11, C -> T mutation
10% of dogs with MM
Strongly positive in 56%
Weakly positive in 44%
Significantly associated with dz recurrence
How does the Oncept melanoma vaccine work?
In what % of dogs is a cell-mediated immune response produced?
Encodes human tyrosinase gene, which is inserted into pING plasmid vector.
Plasmid vector contains cytomegalovirus promoter, kanamycin resistance selection marker, and a CpG sequence (which signals through TLR9).
Tumor Ag is taken up by DCs -> presented via MHC class II (less commonly, class I) -> incites cell-mediated immune response in ~1/3 of dogs -> production of Ag-specific IFN-y T-cells
CpG sequences also augment TH1 response
What is the overall MST in dogs with stage I-III OMM and either adequate or inadequate locoregional control when treated with all available xenogenic vaccines?
Adequate locoregional control > 3yrs
Inadequate locoregional control 18m
In vitro, high-dose of what substance have induced apoptosis in melanoma cell lines? How does it induce apoptosis?
High-dose ascorbate
activation of Bax?
What is the overall metastatic rate in cats with malignant melanoma (excluding ocular)?
30.7%
What extra-ocular malignant melanoma site in cats has the shortest MST vs the longest when treated with multiple therapies?
Oral MST 4
Cutaneous MST 6
Auricular MST not reached
What are 2 identified prognostic indicators in cats with MM and how do they affect prognosis?
Amelanotic melanoma - negative prognosis
Surgical therapy - longer MST
What % of cats treated with the Oncept vaccine develop adverse events? Is the incidence higher or lower in dogs?
12% - pain on administration, brief muscle fasciculation, transient inappetence, depression, nausea, mild increase in pigmentation at injection site
Incidence of AE higher in dogs
How are SCC categorized according to their degree of invasiveness?
In situ
Superficial (<2mm deep)
Infiltrative
ORR, recurrence rate, and ST in cats with IN SITU nasal planum SCC in situ when treated with Strontium?
ORR 100%
RR 0%
ST > 3000d
ORR, PR, CR, recurrence rate, PFI, and OST in cats with SUPERFICIAL nasal planum SCC when treated with Strontium?
What % developed new lesions at a different location?
ORR 98% (CR 88%, PR 10%)
RR 20% at median time of 308d only in cats with T1+, but no in situ
ST > 3000d; better for those with a CR vs PR
New lesions 33%
ORR, CR, RR in cats with all degrees of invasive nasal planum SCC when treated with strontium?
ORR 100% (CR 87%, PR 13% )
RR 13% - only in the 2 cats that had a PR which also had T2 dz at 81 and 141d
A study in cats with all degrees of invasive nasal planum SCC evaluated the use of fractionated vs single dose strontium.
Was there a difference on ORR, DFI, or MST between the tx groups?
Positive prognostic factors identified? (4)
No difference in ORR or MST, but DFI of cats tx with fractionated protocol significantly longer
ORR 96%, CR 74%, PR 22%,
RR 17% at median of 251d
DFI 780d
OST 1040d
PF: CR = longer ST No comorbidities = longer ST Early stage dz (T1-2) = longer ST Fractionated protocol = longer DFI
What % of dogs with nasal SCC that undergo nasal planectomy with bilateral labial mucocutaneous rotational flap experience complications?
Most common complications (2)?
What % required revision surgery?
Clean margins were obtain in what % of dogs?
Pulmonary metastatic rate?
73% overall complication rate
Complications:
50% dehiscence
20% narrowing of nasal orifice
35% revision surgery
88% obtained clean margins
18% pulmonary mets at ~1 yr post diagnosis
Most common clinical signs in dogs with nasosinal tumors?
Others?
What clinical signs could make you be more concerned about neoplasia vs non-neoplasia?
Unilateral epistaxis and/or mucopurulent discharge of 2 to 3 months duration
Other: facial deformity, sneezing, unwillingness to open mouth, dyspnea or stertorous breathing, exophthalmos, ocular discharge (due to mechanical obstruction of nasolacrimal duct)
Facial deformity, stridor -> cancer
Systemic clinical signs -> non-neoplastic
What clinical sign in dogs with nasosinal dz is significantly noted to be more common with neoplasia, foreign bodies, and nasal mycosis?
What about with cancer specifically?
Pure or mixed hemorrhagic discharge
Stridor, facial deformity (can happen with fungal and angiomatous proliferation too)
What staging system for dogs with nasosinal neoplasia have been associated with prognostic significance when RT is used?
Adams
Modified Adams
Describe the modified Adams staging system
Stage I - confined to one nasal passage, paranasal sinus, or frontal sinus, with NO bone involvement beyond turbinates
Stage II - ANY bone involvement beyond turbinates, BUT NO evidence of orbit/subcutaneous/submucosal mass
Stage III - involvement of orbit and/or nasopharyngeal, subcutaneous, or submucosal mass
Stage IV - cribriform plate lysis
How has the modified Adams’ staging system been associated with prognosis in dogs with nasosinal tumors that are treated with RT?
Dogs with stage IV dz based on CT images have shorter DFI and ST when treated with definitive RT
What is the MST and DFI of dogs with stage I vs stage IV dz when treated with definitive RT?
Stage I - DFS 6.5m, MST 24m
Stage IV - DFS 4m, MST 7m
What is the overall MST of dogs with untreated nasal carcinomas?
3m (95d)
What is the MST in dogs with untreated nasal carcinoma that have epistaxis vs in dogs w/o?
Epistaxis - 3m (88d)
Without - 7.5m (224d)
What is the MST of dogs with nasal tumors when tx with definitive RT alone?
1-yr and 2-yr survival rates?
What % of carcinomas experience tumor volume reduction compared to sarcomas?
7 to 20 months
1-yr survival rate 40-70%
2-yr survival rate 10-45%
Carcinomas - 70%
Sarcomas - 20%
What RT boost technique were recently published in dogs with nasal tumors when treated with IMRT with the goal of administering a higher dose and decreasing side effects and what was the outcome?
Boost technique: GTV receives a higher dose (20% in the study) while maintaining same CTV
Ocular changes were negligible
33% developed VRTOG grade 3 mucositis
Late AE not evaluated
Median PFI and ST not reached
What is the MST in dogs with nasal tumors when treated with palliative RT?
What % of dogs have improvement of clinical signs?
Median duration of response?
MST 5 to 10months
65-100% improvement of CS
Duration of response: 4 to 10m
What are some identified positive (2) and negative (5) prognostic factors in dogs with nasal tumors when tx with palliative RT?
Positive for complete resolution of CS:
- Adams stage I dz
- CS present for >90d
Negative PF:
- CS present for <90 days prior to dx associated with higher risk of relapse
- Adams stage IV dz - MST ~4.8m
- Age of <10yrs
- Non-dolichocephalic breeds
- Dyspnea
What are some acute SE from definitive RT and how long do they take to resolve?
Oral mucositis, KCS, blepharitis, rhinitis, skin desquamation
Within 2-8 weeks after tx
What are some late SE from definitive RT?
When do they usually develop?
Cataracts, corneal keratitis, corneal atrophy, KCS, uveitis, retinal hemorrhage and degeneration, neuronal tissue SE (brain necrosis causing neuro changes or seizures, optic nerve degeneration), skin fibrosis.
Months to years after therapy; irreversible
What arethe most common and clinically relevant late effects in dogs with nasal tumors treated with RT?
Ocular changes - usually occur 6 to 9 months after RT
KCS, cataract formation, blindness
What is the overall MST and PFS in dogs with nasal tumors when treated with SRT (3 papers)?
MST specifically for carcinoma, sarcoma, and OSA?
Overall MST 8.5- 19.5m
PFS 1yr
Sarcoma - 10.7m
Carcinoma - 10.4m
OSA - 3m (significantly shorter ST)
What is the overall response or clinical response rate in dogs with nasal tumors when treated with SRT?
95-100%
What % of dogs with nasal tumors treated with SRT develop acute and late side effects?
What % of dogs are euthanized due to late AE?
Acute 23-32%
Late 17-40%; highest with SRS single fraction (fistulas, osteonecrosis, seizures)
7% mortality rate
What is the 1 and 2 yr SR in dogs with nasal tumors treated with SRT?
1 yr - 70%
2 yr 40%
In dogs with nasal tumors treated with SRS, what has been associated with increased acute AE?
GTV > 50cm3
When gemcitabine is used as a radiosensitizer in dogs and cats with nasosinal carcinoma that are treated with RT, what % requires dose reductions?
Cats 50%
Dogs 80%
Neutropenia or local acute tissue damage
What is the MOA for gemcitabine when used as a radiosensitizer?
Inhibits RNR -> depletion of dNTPs -> inhibition of DNA polymerase and decreased DNA repair
Results in inhibition of sublethal damage repair; most evident in mismatch repair-deficient cells
Most pronounced if administered 24-60 hours prior to RT
What is the MOA for cisplatin when used as a radiosensitizer?
Covalently binds to purine DNA bases, causing adducts, and causing dsDNA breaks; decreases ability of tumor cells to repair DNA damage caused by ionizing RT; inhibition of non-homologous end-joining
Exposure to RT causes single and double strand DNA breaks
Although cisplatin does not increase the number of DSB, having an adduct near a DSB results in complete abolition of NHEJ repair
The presence of unrepaired ds breaks results in cell death
What patients are at risk for development of benign osteocartilaginous tumors?
What are these composed of and where do they arise from?
Young px with active osteochondral ossification sites
Tumors that grow from the cartilaginous rings and are composed of cancellous bone capped by cartilage; they grow at the same speed as the rest of the skeleton
May reflect a malfunction of osteogenesis rather than true cancer and are benign
Young px also at risk of oncocytoma development
What are oncocytes?
Epithelial cellscharacterized by an excessive number of mitochondria, resulting in an abundant acidophilic and granular cytoplasm.
Can be benign or malignant
What are rhabdomyomas?
Benign tumor of skeletal muscle
Can be large, minimally invasive, and do not metastasize
How can rhabdomyomas be differentiated from oncocytomas?
Transmission electron microscopy and IHC
Appear THE SAME with light microscopy
- 3 laryngeal tumors dx initially diagnosed as oncocytomas by light microscopy were dx as rhabdomyomas after ultrastructural and immunocytochemical examination
- Rhabdomyomas are different from oncocytomas, but require electron microscopy or IHC to be differentiated from oncocytomas because they appear identical on light microscopy
- Same thing for rhabdomyosarcoma, diagnostic features of skeletal muscle differentiation may not be evident at the light microscope level and may only be recognized by IHC or transmission electron microscopy. TEM is the gold standard in both humans and dogs, but it cannot differentiate between the subtypes.
The majority of laryngeal tumors in dogs are malignant and very locally invasive, except which one?
Rhabdomyoma
Can be large but are minimally invasive and do not metastasize
Most common primary lung tumor in dogs and cats? Humans?
Dogs - bronchoalveolar carcinoma 85%
Cats - adenocarcinoma 60-70%
Humans - small cell carcinoma 25% and non-small cell 85%
What % of dogs with pulmonary carcinoma have evidence of local vascular or lymphatic invasion and what is the distant metastatic rate?
Local vascular or lymphatic invasion - 70%
Distant - 25%
Anaplastic CA >90%, SCC >50%
What is the metastatic rate in cats with pulmonary carcinoma?
Overall 75% (LN 30%, intrathoracic 30%, extrathoracic 15%)
88% of cats with digital carcinoma have metastasis from a primary pulmonary carcinoma; MST 1m with digital amputation alone; not recommended as other lesions cn pop up
How can you confirm pulmonary metastasis on a digital lesion?
IHC with TTF-1 and the presence of ciliated epithelial cells (thyroid transcription factor 1)
Prognostic factors in dogs with pulmonary carcinoma (8)?
CS at diagnosis Tumor size >100cm3 TNM stage (>T1N0M0) LN involvement Involvement of entire lung lobe Gross dz post-operatively Histologic type (papillary has best prognosis vs. SCC and undifferentiated Ca) Histologic grade (well differentiated best progn)
Prognostic factors in cats with pulmonary carcinoma (8)?
CS at diagnosis (dyspnea, especially) TNM stage (>T1N0M0) LN enlargement Pulmonary metastasis Histologic type Histologic grade Degree of differentiation Pleural effusion
MST in dogs with T1, T2, T3, N0, and N1 pulmonary carcinoma when tx with surgery? Statistically, which one has the best ST?
T1 (solitary): 12-26m T2 (multiple): 2.5-7m T3 (invasive into adjacent tissue): 23d-3m N0: 6-15m N1: 1 to 2m
T1N0M0 tumors of papillary type MST 18.5m (555d) vs 72d for others
MST in dogs with pulmonary ACA vs SCC vs papillary* adenocarcinoma when treated with sx?
Papillary - 18.5m
ACA - 19m
SCC - 8m
All other tumor types 2.4m
What is the MST in cats with well-differentiated bronchogenic carcinoma when treated with sx?
23-24m
Some studies say shorter ST
What are the surgical approaches for lung lobectomies?
What approach is required for removal of lesions in multiple lobes?
What approach is associated with higher morbidity?
Lateral (intercostal) thoracotomy and median sternotomy
Median sternotomy needed for multiple
Median sternotomy - more likely to have increased fluid production from chest tube, hypoxia, prolonged hospital stay
For hilar LN biopsies - easier to perform via lateral thoracotomy
What is the TTP and MST in dogs with advanced pulmonary carcinoma when treated with sx vs metronomic chemotherapy with CTX, thalidomide and piroxicam vs no therapy?
Main findings?
Metronomic chemotherapy:
TTP 5.7m
MST 4.6m
Surgery:
TTP 3m
MST 3m
No therapy:
TTP 20d
MST 2m
Significantly longer TTP and MST with MC vs sx and MTD groups.
Breeds predisposed to develop pulmonary histiocytic sarcoma (2)?
Pembrook Welsh Corgis, Min Schnauzers
When compared to other pulmonary tumors, what imaging characteristics do pulmonary HS have in dogs (3)?
- Significantly larger
- Right middle (43%) and left cranial (38%) most common locations
- More likely to invade entire lobe
What % of dogs with localized HS have the pulmonary form?
31%
What is the overall PFI and MST of dogs with pulmonary HS?
PFS 7m
MST 4.5-8m
What is the PFS and MST of dogs with pulmonary HS treated with CCNU chemo alone?
PFS 3m
MST 4m
What is the PFS and MST of dog with pulmonary HS treated with surgery and CCNU?
PFS 9m
MST 12.5m
What prognostic factors (3) in dogs with pulmonary HS negatively affect PFI and MST?
Clinical signs - PFS only
Intrathoracic mets - PFS & MST
Tx with sx alone
Tumor size NOT prognostic
ORR of dogs with pulmonary HS to chemotherapy?
44%
In Norway, what breeds are at increased risk for developing testicular tumors? Which ones?
Shelties and Collies have a 5x increased
Shelties - majority (80%) are Sertoli
Collies - majority (70%) mixed Sertoli/seminoma
Norweigan elkhounds - 2x increased risk of seminoma
What breeds (3) most commonly get seminomas?
German Shepherds
Belgian Malinois
Norweigan elkhounds (2x increased risk)
With what frequency do the different types of testicular tumors occur in dogs within the USA?
Equal frequency
What testicular tumor most commonly secretes estrogen?
Sertoli
50% produce estrogen and signs of feminization; 17% if scrotal
What testicular tumor is most likely to cause feminization signs? Is it affected by location?
How can estrogen be measured?
Sertoli (>50% if cryptorchid and 15% if scrotal)
Estraidol 17-B - usually higher when compared to normal dogs; not all dogs have elevated estraidol
Testosterone/estraidol ratio - usually lower; feminization signs occur secondary to disruptions in this ratio, may be better
What are the clinical signs associated with feminization syndrome?
Bilateral symmetric alopecia, cutaneous hyperpigmentation, thinning of skin, galactorrhea, gynecomastia, atrophy of prepuce, atrophy of contralateral testicle, squamous prostatic metaplasia, bone marrow suppression
What effects can hyperestrogenism have on the bone marrow?
BM suppression/hypoplasia: may be irreversible
Transient increase in granulopoiesis with peripheral neutrophilia followed by progressive neutropenia, thrombocytopenia, and nonregenerative anemia
Which testicular tumor can sometimes be associated with perianal gland hyperplasia?
Interstitial cell tumor
What % of dogs with a testicular tumor have a contralateral testicular tumor or a primary tumor elsewhere?
50%
Therefore, COMPLETE STAGING is recommended
What % of dogs with prostatic carcinoma have COX-2 expression vs normal prostate?
75-88% express COX-2 (vs 0% normal prostate tissue)
Dogs with prostatic carcinoma have an improved ST when treated with what?
NSAID; MST 7m vs 0.7m if no nsaid
A 2018 study NSAID MST 1.7m
Piroxicam or carprofen
What % of dogs with prostatic carcinoma have a BRAF mutation?
85%
What is the benefit of systemic chemo for prostatic carcinomas?
Unclear
What is an identified risk factors for prostatic carcinoma development in dogs?
Castration; OR 2.3:4.3
Also tend to develop more aggressive tumors
What % of dogs with prostatic carcinoma have metastasis at the time of diagnosis and at the time of death?
40% at diagnosis; SLLN most commonly
80% at death
What % of canine prostatic carcinoma develops metastatic disease to bone? Most common site? Mediated by (3)?
22 to 42%
Lumbar vertebrae and pelvis
May be mediated by TGF-B, PTH-rP, endothelin
More commonly osteoproductive, but can also be osteolytic
Skeletal metastasis most commonly OSTEOBLASTIC in nature
Unlike humans, in dogs with prostatic carcinoma, downregulation or hypermethylation of what gene has not been detected?
Like humans, dogs exhibit loss of ___ and gain of ___.
APC gene
Loss of NKX3.1
Gain of c-MYC
When compared to BPH, dogs with prostatic carcinoma have increased nuclear expression of what 2 things?
Survivin
Sox9 (stem cell marker)
What % of dogs with prostatic carcinoma have a concurrent UTI?
33-36%
Mineralization in the canine prostate can be due to what?
In intact dogs - prostatitis, BPH, cysts
In neutered dogs - 100% PPV for neoplasia
Prostatectomy should be considered in which dogs?
Dogs with early stage dz and no capsular involvement
What % of dogs undergoing total prostatectomy develop major complications, transient incontinence, and permanent incontinence?
Major complications - 16%: dehiscence, uroabdomen, prepubic herniation
60% transient - resolved within 4 weeks
35% permanent incontinence
In the VSSO study where dogs were treated with prostatectomy, did the addition of chemotherapy prolong ST?
No
What is the DFI and MST in dogs with prostatic carcinoma when treated with prostatectomy, NSAIDs, and chemo?
Negative PI in the VSSO study (1)?
DFI 3m (2.7m)
MST 8m (7.7m)
1-yr SR 32% and 2-yr SR 12%
Histologic extracapsular extension MST 4.6m
Overall clinical response rate and MST of dogs with TCC and prostate involvement when treated with chemo and an NSAID?
Clinical response 33%
MST 3.5m
Negative PI in dogs with prostatic carcinoma when treated with chemo + NSAID? (4)
- Intact male status - shorter MST
- Presence of CS - shorter MST
- Metastasis to sites other than lungs - shorter MST
- Tx with NSAIDs alone (TTP/MST 1.7m vs addition of chemo 3.5m)
Survival time of dogs with prostatic lymphoma? How does it usually present? US characteristics? Most common phenotype? Breed?
Mean ST 2m; 2 dogs tx with chemo survived for 1 and 10m
56% had LN involvement and all appeared to have multicentric intra-abdominal dz
US: hypoechoic lesions, ABSENCE of mineralization
T-cell most common
1/2 were Labs
How can you use PCR to diagnose a TVT?
TVT cells all share a c-myc oncogene rearrangement - a long interspersed nuclear element (LINE-1) is present 5’ to the first exon
LINE-1 can disrupt transcriptional regulation of downstream genes, potentially initiating oncogenic activity
LINE-c-myc sequence is used to confirm a diagnosis with PCR
How does the karyotype change in dogs with TVT?
Highly conserved karyotypic changes
Normal dogs have 78 chromosomes and all but 2 are acrocentric (the 2 sex chromosomes)
TVT cells have a rearranged karyotype consisting of 57-59 chromosomes, including 15-17 submetacentric (resulting from fusion) chromosomes and 40-42 acrocentric chromosomes
TVT cells are aneuploid but exhibit stable and similar karyotypes in samples from different regions
How does TVT influence the immune system?
TVT cells downregulate MHC class I B2 microglobulin and MHC class II expression; this occurs secondary to TGF-B1 production by the tumor and allows for immune system evasion and decreased NK cell activity
Tumor infiltrating lymphocytes produce IFN-y, which promotes MHC expression and counteracts TGF-B1 actions from tumor cells; TIL then secrete IL-6 which is synergistic with IFN-y -> MHC expression and NK function is restored, allowing for tumor regression
This occurs during P phase, but expression of IL-6 triggers R phase
Why do females develop hepatoid gland adenomas when spayed?
They lose estrogenic inhibition
What is the most common intraocular tumor in cats?
Anterior uveal melanoma
What is the metastatic rate of anterior uveal melanomas in cats? Locations?
50%
Lungs or liver
When do anterior uveal melanomas metastasize in cats?
1 to 3 years post enucleation
How do anterior uveal melanomas progress in cats?
Slowly progressive over months to years : iridial hyperpigmentation -> glaucoma
What are identified prognostic risks for metastasis in cats with anterior uveal melanomas (4)?
More common with high MI
Larger tumors
Tumor invasion into ciliary body stroma
Invasion into scleral venous plexus
What are prognostic factors for ST identified in cats with anterior uveal melanomas (4)?
Tumor confined to iris stroma and trabecular meshwork = longer ST, decreased MR
Enucleation after invasion to ciliary body (but NOT sclera) = MST 5 yrs
Enucleation after scleral invasion = MST 1.5yrs
Glaucoma
What can increase the risk of SCC development in cats (4)?
Flea collars 5x
Canned tuna 4.7x
Canned food 3x
Household smoke 2.5x
The risk of tonsillar SCC is ___x higher in dogs living in urban
10x
What oral tumors are known to be responsive to RT (3)?
Melanoma
Canine oral SCC
Acanthomatous ameloblastoma
What oral tumors are considered to be RT resistant (2)?
Feline SCC
Fibrosarcoma
Canine papillary oral SCC:
- Age of dogs?
- Most common location?
- What % have T2 or T3 dz at diagnosis?
- Overexpression of what protein?
- Met rate?
- Therapy, prognosis, and MST?
- Histopathology?
Very young dogs; 2-5m; 1 study 75% >6yrs
70% rostral; arise from gingiva of dentate jaws
92% are advanced T2-T3 at dx; seem large and invasive
p53
Complete excision or reduction + RT: all dz-free at >4yr
0% metastatic rate
Excellent prognosis
Histopath:
-Exophytic superficial papillary portion that lacks criteria of malignancy and can be confused with papilloma
- Deep invasive portion extends into gingival stroma or bone can be confused with SCC or ameloblastoma
- Papillomavirus has not been detected
What was recently published about intratumoral T cells in cats with oral SCC (3)?
- CD3+ T cell infiltrates in 92% of samples
- T-regs within the neoplastic epithelium and stroma in 60%
- Increased total frequency of circulating Tregs compared to healthy controls (but proportion of T regs compared to other lymphocytes unchanged)
As opposed to high COX2 expression in dogs with oral SCC, what % of oral SCC in cats express COX2?
18% - therefore COX2 likely not beneficial
What is the significance of MVD and EGFR expression in cats with oral SCC?
High MVD = shorter MST
EGFR expression inversely related to ST
MVD is higher in which location in cats with oral SCC?
Higher in TONGUE vs mandibular and maxillary regions
What negative prognostic factors (3) have been identified in cats with oral SCC when treated with SRT? How do they affect prognosis?
Higher MVD, more keratinized SCC, male sex = shorter PFI and ST
Negative PI in cats with oral SCC (8)?
Anorexia at dx
Location:
- Tonsillar/cheek - improved prognosis with accelerated RT/carbo (mean ST 725d vs other locations)
- Mandible with sx -improved
Complete response to accelerated RT/carbo (MST 375d)
Male cats
High bmi-1% expression (protein involved in self-renewal)
High MVD
High EGFR (inversely related to ST)
More keratinized SCC
Palladia ORR/biological response and MST in cats with SCC? Prognostic indicators? Toxicity %?
ORR 57% (biological response rate)
MST 4m
NPI: Anorexia at dx
17% had AE (grade 1-2GI, 1 grade 4 ALT)
Fatty acid synthase is over expressed in humans and cats with what type of cancer? What medication has been shown to reduce cell viability in vitro?
SCC
Orlistat - FASN inhibitor
Recently, ___ was shown to decrease canine SCC cell growth in vitro in tumors that over-expressed ___.
YM 155 (a survivin inhibitor) Survivin
With surgery for oral melanomas, the disease is usually controlled in ___% of the cases.
75%
What factors affect prognosis in dogs with oral melanoma when treated with sx (3)?
Tumor size: <2cm vs >2cm
Stage - mets vs no mets
Ability of the first sx to achieve local control
Sensitivity of CT for identifying metastatic LN in px with oral tumors?
Poor
10-12%
What % of dogs and cats with facial/oral tumors have metastasis to the mandibular LN vs other regional LN?
When retropharyngeal LN metastasis is present, what LNs are also ALWAYS involved according to one study?
What % has ipsilateral vs contralateral metastasis?
55%
Mandibular LN
Ipsilateral 90%
Contralateral 60%
What is the MST in dogs with oral MM when treated with sx alone for stage I-III dz?
I: 17-18m (PFI 19m)
II: 5-6m
III: 3m
What is the most common intra-operative complication in dogs with oral tumors undergoing a partial maxillectomy?
Intraoperative bleeding - 53%
43% required blood transfusion
Complications like IO bleeding and requirement of a blood transfusion in dogs with oral tumors undergoing a partial maxillectomy are significantly associated with what 4 things?
- tumor size
- location (caudal)
- maxillectomy type (complete, caudal, and if involving orbit)
- surgical approach (dorsolateral combined with intraoral)
What are the 3 most common short-term complications in dogs with oral tumors undergoing a partial maxillectomy?
Lip trauma 13%
Dehiscence and fistula 11%
Most common post-op complications in dogs with oral tumors undergoing a partial maxillectomy (3)?
Minor epistaxis
Facial swelling
Difficulty eating
What % of dogs and cats with tonsillar SCC have systemic dz at diagnosis?
What % of dogs develop LN and pulmonary mets?
90%
70% LN
10-20% pulmonary mets at diagnosis
What % of dogs with tonsillar SCC have bilateral dz as per CT?
50%
Canine tonsillar SCC and surgery?
Rarely curative and if performed, it should be bilateral due to high % of dogs with bilateral dz
Control rate with radiation therapy alone and 1-yr SR in dogs with tonsillar SCC?
Can this be improved?
75% control rate
<10% 1-yr survival
Yes; with chemotherapy - improved RR and ST
Overall MST of dogs with tonsillar SCC treated with sx, RT, and/or chemotherapy?
6m
Significantly improved ST
Negative PI in dogs with tonsillar SCC (3)?
Anorexia
Lethargy
Lack of RT/chemo
Urban environments are associated with increased risk of what types of cancer in urban dogs?
Canine LSA
Tonsillar SCC
Nasal tumors in dolicocephalic breeds
Recent literature suggest an improved overall MST for oral FSA in dogs of what?
8m to 2 years
Likely due to improved sx technique
Overall MST, recurrence rate, and 1-yr SR of dogs with oral FSA treated with surgery alone?
What is prognostic (1)?
MST 10-12m
RR 30-50%
1-yr SR of 20-50%
MST lower with conservative vs aggressive sx; MST 300d vs 526 days
DFI and MST of incompletely excised oral FSA in dogs?
DFI 13m
MST 19m
50% of maxillary tumors incompletely excised
MST of dogs with oral FSA when tx with RT alone?
What is prognostic (1)?
MST 7m
Definitive RT longer PFS vs palliative; PFS 470d vs 170d
PFI, MST, recurrence rate, and 1-yr PFS in dogs with oral FSA when treated with sx and adjuvant RT?
What is prognostic (1)?
PFI 10m
MST 18-26m (1.5 to 2.2yrs)
24-32% recurrence
1-yr PFS of 76%
Tumor size: T1 and T2 improved PFS and ST vs T3
Prognostic factors in dogs with oral FSA (7)?
Strongest predictor of survival?
- Location: mandibular shorter PFS and MST vs maxillary
- Size: MST not reached for T1 vs T2 and T3
- Grade
- Tx with any type of RT longer PFS and MST, but definitive RT protocol better than palliative
- Type of sx performed: no sx vs conservative vs aggressive
- Complete sx excision vs incomplete
- Sx + RT longer PFS and ST = STRONGEST
Most common lingual tumor in dogs and cats?
SCC
Possible predilection of lingual T-zone lingual lymphoma has been noted in what breed?
Golden Retriever
How does lingual T-zone lymphoma look grossly?
Multifocal to coalescing, raised, red, nodular mases
RARELY ulcerated
What % of dogs with lingual T zone lymphoma have concurrent lymphadenopathy and lymphocytosis?
70% lymphadenopathy
60% lymphocytosis
Most common immunophenotype of lingual T zone lymphoma?
CD8+ (majority)
CD45-
Lack epitheliotropism
Expand within superficial submucosa and are separated from the dermis
CR and SD responses in dogs with lingual T zone lymphoma to any treatment?
CR 60%
SD 30%
10/12 still alive 27 to 893d post diagnosis
What is the 4th most common tumor in the oral cavity of dogs?
OSA
Overall, what % of canine OSA is oral or maxillofacial?
12%
What % of axial canine OSA involves the mandible vs the maxilla?
Mandible 27%
Maxilla 16-22%
What is the overall metastatic rate of dogs with oral/maxillofacial OSA?
What % of dogs have mets at diagnosis?
Is the rate higher for the mandible or maxilla and if so, what is the metastatic rate?
Time to metastasis?
35-40% overall
6% at diagnosis
58% mandibular
17-20 months
What type of OSA is most commonly seen in the mandible vs maxilla?
Mandible - osteoblastic
Maxilla - osteoclastic
Compare recurrence, metastasis, cause of death, and ST in dogs with mandibular vs maxillary OSA.
Maxillary - higher RR, local dz most common cause of death, no mets reported, shorter MST
Mandibular - lower RR, metastasis most common cause of death in 35%, 58% met rate, longer MST
What is the MST, recurrence rate, MFI, metastatic rate, and 1-yr SR in dogs with MANDIBULAR OSA tx with maxillectomy and +/- chemo? Most common cause of death?
MST 17.5m RR 15-45% MFI 20m Metastatic rate 58% 1-yr SR 35-70%
Prognostic factors in dogs with mandibular OSA for metastasis and ST (2)?
- Grade: II/III tumors 2.4x increased risk of mets and shorter MST
- Lack of adjuvant chemotherapy 2.6x increased risk of mets and shorter MST
Overall, shorter MFI and MST
What OSA location in the canine head is most likely to recur after sx?
Calvarium
MST 11m
Identified prognostic indicators in dogs with OSA of the head? Positive (4) and negative (5)
Positive:
- mandibular location
- smaller body weight
- grade I
- pure-bred dogs
Negative:
- Incomplete surgical margins
- Grade II/III tumors
- Lack of adjuvant chemo post op
- Every 1,000-cell increase in monocyte count associated with a 76% increased hazard of death
- MI >40 on univariate
Tx of choice for canine MLO?
Sx; poor responses to RT and chemo
Overall RR and RR for grade I, II, and III MLO in dogs?
What is it dependent on (2)?
Overall 47-58%
I - 30%
II - 50% (47%)
III - 80% (78%)
Grade and margins
DFI in dogs with completely vs incompletely excised MLO?
Complete - 3.6 yrs
Incomplete - 11m
Overall metastatic rate and in grade I, II, and III in dogs with MLO?
Incompletely vs completely excised tumors?
Time to metastasis?
What is it dependent on (2)?
Overall 60% to lungs
I - 30%
II - 60%
III - 80% (78%)
Complete - 25%
Incomplete - 75%
Late in dz
Grade and margins dependent
Slow growing tumor so can consider metastasectomy (>12m survival)
Overall MST and MST in grade I, II, and III MLO in dogs?
What is it dependent on (2)?
Overall 21m
I - 50m
II - 22m
III - 11m
Location and grade dependent
What is the MST in dogs with MLO of the mandible vs other locations?
Mandibular MST 4yrs
Other: 1.5yr (590d)
What are the 2 types of feline epulides?
Fibromatous - 60%
Giant cell epulis - 30%
How does GCE differentiate from fibromatous epulis in cats?
Significantly different and more aggressive behavior
In dogs, these behave like fibromatous epulis and rarely recur post sx
Which IHC markers can be used for GCE and what cell origin are they suggestive of?
IHC suggestive of osteoclastic origin
POS for: vimentin, TRAP, RANK
NEG for: SMA, MIB-1, factor VIII
In dogs, these behave like fibromatous epulis and rarely recur post sx
What % of AA invades bone?
80-100%
What is the most common site for AA in dogs?
Rostral mandible
What dog breeds are predisposed to developing AA?
Shetland and Old English sheep dogs
What 2 proteins are over-expressed in dogs with AA?
MMP9
TIMP1
MST and recurrence rate for MANDIBULAR AA treated with mandibulectomy? 1yr SR?
MST not reached; >28-64m
0-3% recurrence
98-100% 1-yr SR
MST and recurrence rate for MAXILLARY AA treated with maxillectomy? 1yr SR?
MST not reached; >26-30m
0-11% recurrence
71-100% 1-yr SR
When hypofractionated RT is used to treat AA, what is the 3-yr PFS?
Recurrence rate?
Complications (2)?
80% 3-yr SR
8-18% recurrence; 8x higher risk in T3 tumors
Transformation in 5-18%
Bone necrosis 6%
Response rate of IL bleomycin in dogs with AA?
100% CR for > 1 yr in 4 dogs
What is the MST in dogs with incompletely excised non-tonsillar SCC that do not receive adjuvant therapy vs those that receive RT post operatively?
Protocol used?
Sx alone - 6m
Sx + RT - 5.6yrs
8-9 Gy x 4 (weekly)
(In the case of FSA, did not improve outcome)
Compared to other oral tumors in dogs, what tumor is most likely to be incompletely excised after maxillectomy?
FSA
50% incompletely excised
Why can’t imatinib and masitinib be used in dogs with oral FSA?
In vitro, cell death requires doses unable to be achieved clinically
Effects potentiated by doxorubicin.
What things are evaluated when determining the grade of a ST?
Degree of differentiation: normal M tissue [1], specific histo type [2], undifferentiated [3]
Mitosis: 0-9 [1], 10-19 [2], 20 or > [3]
Necrosis: none [1], 50% [2], >50% [3]
Grade I: cum score of 4 or <
Grade II: cum score of 5-6
Grade III: cum score of 7 or >
LOOK AT GRADE TABLE!!
What are 2 stains that will help confirm a peripheral nerve sheath tumor?
S-100 - derived from cells of neural crest origin normally present in cells derived from the neural crest (Schwann cells, and melanocytes), chondrocytes, adipocytes, myoepithelial cells, macrophages, Langerhans cells, dendritic cells, and keratinocytes. Some FSA +.
Vimentin - protein expressed in mesenchymal cells (all sarcomas positive)
What is the difference in histology between lipomas and liposarcomas?
Lipomas have INDISINCT nuclei and cytoplasm resembling normal fat.
Liposarcomas are characterized by increased cellularity, DISTINCT nuclei, and abundant cytoplasm with one or more droplets of fat.
Where are intermuscular lipomas usually located?
Caudal thigh of dogs between the semitendinosus and semimembranosus
What is the most common complication seen with removal of intermuscular lipomas?
Seroma formation if a penrose drain is not used
What are infiltrative lipomas?
Uncommon tumors composed of well-differentiated adipose cells without evidence of anaplasia.
Cannot be differentiated from simple lipomas.
Considered benign and do not metastasize.
Commonly invade adjacent muscle, fascia, nerve, myocardium, joint capsule, and even bone.
Aggressive treatment such as amputation may be needed.
What is a diagnostic challenge seen when using CT to evaluate infiltrative lipomas?
It cannot be distinguished from normal fat and DO NOT contrast enhance. They are, however, more likely to have an irregular shape.
Liposarcomas, however, DO contrast enhance
What are liposarcomas?
Malignant tumors arising from adipoblasts
They are locally invasive
They DO CONTRAST ENHANCE!!
What is the metastatic potential of liposarcomas and what are the most common sites they metastasize to?
Low to moderate
Lungs, liver, spleen, and bone
Metastasis in dogs with liposarcoma is more commonly associated with which histologic subtype?
Pleomorphic
Most common liposarcoma histologic subtype to metastasize to extrapulmonary soft tissue structures?
Myxoid
Is the prognosis in dogs with liposarcomas affected by the histologic subtype?
No
What is the MST for liposarcomas with wide resection, marginal resection, and incisional biopsy?
MST 1200 days - wide surgical resection
MST 650 days - marginal resection
MST 180 - incisional biopsy
CT characteristics of liposarcomas?
77% contained focal areas of fat attenuation
81% heterogeneous internal attenuation
38% lacked clearly defined capsule and were locally infiltrative
23% had foci of mineralization
More likely to be heterogeneous, have a soft tissue component with irregular conglomerate appearance, mineralized, and have regional lymphadenopathy
How are rhabdomyosarcomas diagnosed?
Transmission electron microscopy
IHC
TEM is the gold standard in both humans and dogs, but it cannot differentiate between the subtypes.
What are the IHC stains and criteria used to diagnose rhabdomyosarcomas? What are some skeletal muscle specific markers?
At least 1 muscle specific marker and absence of smooth muscle markers is needed
Src-actin Myosin - mature SKM Myoglobin -mature SKM Myogenin - embryological nuclear TF MyoD - embryological nuclear TF
ALL are vimentin and desmin positive, but these lack specificity
How do lymphangiosarcomas look histologically and with what tumor can it be confused?
What IHC (2)markers can be used to clear up confusion?
They resemble normal endothelial cells.
May be confused with HSA because of the vascular channels, however, RBC are not seen within channels.
Lymphatic and endothelial cells - both positive for factor VIII-RA and CD31
Lymphatic endothelial cells: PROX-1, LYVE -1
What are dermal hemangiomas and HSA associated with?
UV light exposure in short-haired dogs with poorly pigmented skin
How are canine cutaneous HSA staged? What are the stages?
According to depth of involvement
Stage I - confined to dermis
Stage II - extending into SQ tissues (hypodermal)
Stage III - involving underlying muscle(hypodermal)
What is the treament of choice fore cutaneous HSA?
Wide surgical excision +/- doxo (if stage II or III)
What is the ORR of doxorubicin for cutaneous HSA in the gross dz setting? Median duration of response?
ORR 40%
50d
What is the MST in dogs with stage I, II, and III dermal HSA when treated with surgery?
Stage I: 780 days (2yrs)
Stage II-III: 5.5 to 10m (170-300d)
What is the metastatic rate for stage I, II, and III dermal HSA in dogs?
Stage I: 30%
Stage II-III: 60%
What is the locoregional recurrence rate in dogs with cutaneous HSA tx with sx? Most common in which breeds?
77%; pre-disposed breeds w/ventral location/multiple tumors
50-80% in cats
Prognostic factors in dogs with dermal (no SQ invasion) HSA?
Predisposed breeds = longer MST
Ventral abdomen location = longer MST
Solar changes = longer MST
Mets or hemoabdomen = shorter MST
In dogs with SQ and IM HSAs treated with surgery, +/- radiation therapy,and doxorubicin, what is the median DFI and MST?
SQ - DFI/MST > 4yrs
IM - DFI/MST 9m
What are the 2 different types of synoviocytes?
Type A - phagocytic and resemble macrophages
Type B - fibroblastic; produce glycosaminoglycan
From what type of synoviocytes do synovial cell sarcomas arise?
What about histiocytic sarcomas?
What is the exception?
Synovial cell sarcomas - Type B (fibroblastic)
Histiocytic sarcoma - Type A (phagocytic macrophage resemblance)
Periarticular histiocytic sarcoma - arises from dendritic cells; cannot use CD18 to differentiate between DC and type A macrophages
What immmunohistochemical cell marker, utilized to dx histiocytic sarcomas, cannot differentiate between macrophages (type A synoviocytes)and dendritic antigen presenting cells?
CD18
IHC markers to differentiate between synovial cell sarcoma, histiocytic sarcoma, and malignant fibrous histiocytoma?
SCS: vimentin+, pancytokeratin +/- (small population)
Histiocytic sarcoma: vimentin+, CD18+
Malignant fibrous histiocytoma: vimentin+, SMA+
What is the metastatic potential of synovial cell sarcomas?
What are the most common metastatic sites?
Moderate to high (higher risk vs STS)
Regional LN, lungs
Up to ___ % of dogs with synovial cell sarcomas have evidence of metastasis at the time of diagnosis and ___ % by the time of euthanasia.
30% - diagnosis
55% - euthanasia
What is the typical signalment for synovial cell sarcomas in dogs? Common anatomic locations?
Large breeds
Flat-coated and Golden retrievers
No sex predilection
Larger joints - stifle, elbow, shoulder
Most common presenting complaint in dogs with synovial cell sarcomas?
Lameness
What are some radiographic features of synovial cell sarcomas in dogs?
How are these be different from OSA?
How do these differ in cats?
Periarticular soft tissue swelling, bone invasion manifested as ill-defined periosteal reaction and/or multifocal punctate osteolyitic lesions, can involve sites on either side of the joint.
Cats - bone involvement is rare in cats
What is the treatment of choice? Why?
Limb amputation
Local recurrence is common and MST is better (850d vs 450 if marginal resection)
Forequarter amputation, hemipelvectomy or coxofemoral diasrticulation - as much as possible
Prognostic factors in dogs with synovial cell sarcomas (4)?
Stage/presence of metastasis
Histologic grade
Extent of surgical treatment
Pancytokeratin +
What is the MST in dogs with synovial cell sarcoma with metastasis vs without?
W/o mets >36m
With mets <6m
What is the MST in dogs with synovial cell sarcoma when treated with amputation vs marginal resection?
Amputation - 30m
Marginal resection - 15m
What is the MST for the different grades of canine synovial cell sarcoma?
> 48m - grade I
36m - grade II
7m - grade III
What is the MST and metastatic rate for dogs with synovial sarcoma, myxoma, histiocytic sarcoma, and other types of synovial tumors?
Synovial - MST 32m, MR 30-55%
Myxoma - MST 30m, MR 0%
Histiocytic sarcoma - MST 5m, MR 90%
Other types - MST 3.5m, MR 100%
For surgery alone…
Recurrence rate for grade I, II, and III STS after marginal/incomplete resection in dogs?
Median time to recurrence and metastasis?
MST?
Grade I - 7%
Grade II - 35%
Grade III - 75%
1yr to recurrence and mets
4yrs
How does adjuvant RT delay time to recurrence in dogs with incompletely excised STS?
Control rates at 1 and 2 yr?
MST?
Time to recurrence >700d
80-95% controlled at 1yr
70-90% controlled at 2 yr
6yrs
What is the 3-year PFS and 3-year local failure free* probability for 3 years in dogs with incompletely/marginally excised STS when treated with hypofractionated RT?
Local recurrence rate? Time to recurrence?
Acute AE?
MST?
3-year PFS probability: 24%
3-year local failure free probability: 73%
21% recurrence rate at a median of 9m
AE: 65% required treatment (dermatitis, mucostitis)
MST not reached
Protocol: 6-8Gy/weekly for a total of 24-32Gy using electrons
Incompletely excised STS in a dog, what to do next?
A 2nd surgery is ALWAYS the best choice
For low grade (I-II) - active surveillance or staging sx (scar with 0.5-1cm margins)
High grade - sx if possible, if not RT (cumulative doses of >50Gy rec for better control) or metronomic chemo
Consider adjuvant chemo for high-grade tumors, those with high met rate, presence of mets
How do Tregs and MVD change in dogs with incompletely excised STS after metronomic chemotherapy? Doses?
A 15.0mg/m2/day dose resulted in decreased # and % Tregs along with decreased tumor MVD
A 12.5mg/m2/day decreased Treg # only; no change in % Tregs or MVD
What is the median DFI in dogs with incompletely excised STS treated with metronomic chemotherapy vs those not treated?
DFI > 410d in treated dogs vs 210
How does MC affect prognosis in dogs with STS?
Prolongs disease free interval time
What is the overall % of agreement between pathologists for tumor grade in pre-treatment biopsies vs excisional biopsies in dogs with STS?
What % of pre-treatment biopsies underestimate the grade vs overestimate it?
60% agreement
30% underestimate
12% overestimate
No statistical difference in accuracy between various techniques (punch, needle core, wedge)
Histologic subtype agreed for 89% of cases
What is the sensitivity and specificity of pre-treatment biopsies for high grade STS in dogs?
95% specific
33% sensitive
-You can believe a high grade result, but not a low grade
What is the sensitivity of LN aspirates for sarcoma in dogs?
67%
Mutation or loss of which gene/protein has been associated to cats with injection site sarcomas?
Most common mechanism by which it occurs?
How does this affect prognosis?
p53
LOH most common
Rapid tumor recurrence and reduced overall survival
p53 mutations have been identified in ___ to ___% of cats with VAS.
What type of p53 staining pattern is negatively associated with prognosis?
60 to 80%
Cytoplasmic staining in 44%; shorter time to recurrence and ST
Although Withrow states that FeLV has not been detected in ISS, a newer study found viral particles in ___% of the cases
43%
Mor than ___% of FISS are COX-2 positive.
> 56%
In cats with FIIS, COX2 expression is highest vs lowest in what situations?
High - in tumors with greatest inflammatory infiltrates
Lowest - in grade 3 tumors vs 1 and 2
*One study found no association between COX2 and grade
c-kit expression is present in what % of FIIS?
19-26%
Answer the following questions for cats with ISS treated surgically with 5cm lateral margins and 2 fascial planes deep.
Completely excised in what %?
Local tumor recurrence in what %?
Major complications in what %?
What was the overall MST?
97% complete excision rate
14% recurrence rate
11% major complications; dehiscence in interscapular tumors most common
11% metastatic rate
MST 907 days (2.4 yrs)
CCNU ORR, CR, PR, median PFS, and duration of response in cats with ISS?
ORR 25% (1CR, 6PR)
PFS 2m (60d)
Duration of response 2.5m (80d)
What % FSA in cats are virally induced? How does this affect prognosis?
2%
Poor prognosis
Feline sarcoma virus
Results from the rare recombination of FeLV DNA provirus and feline proto-oncogenes, resulting in a hybrid.
FeLV incorporates into feline’s DNA near a proto-oncogene and takes up the proto-oncogene into the FeLV provirus -> formation of FSV occurs.
In the process, part of FeLV GAG gene, most of the envelope gene, and all of the pole genes are lost.
The loss of these vital components makes FeSV dependent on FeLV as a helper virus for replication.
Recombination results in transformation of fibroblasts and production of fibrosarcomas.
Cats with FeSV always test positive for FeLV
Natural transmission between cats does not occur
FOCMA and FSV
FOCMA = protein found on the surface of FeLV and FeLV-induced neoplasms but not on non-neoplastic feline cells. It is detected serologically when cells expressing it react to immunoglobulins produced in cats that have regressed FeSV-induced FSA or FeLV infection.
Some cats are capable of rejecting transformed cells and producing FOCMA antibodies. This is important in the experimental response of cats to FeSV because FOCMA Ab administration has been associated with tumor regression and failure to develop tumors. Cats that fail to develop FOCMA die quickly of fast-growing sarcomas.
Ab to FOCMA van protect against neoplastic and myeloproliferative disease.
Some FeLV vaccines contain FOCMA and elicit an anti-FOCMA response. The importance of this in preventing dz in vaccinates is unknown.
What is the biologic behavior of FSV?
Rrapid growth with doubling times as short as 12-72 hours.
Lesions typically occur at sites of previous bite wounds.
Met rate 30% to lungs or other organs.
Chemo and RT have been used and although RT is usually combined with sx in the case of solitary tumors, recurrence both within the RT field or outside is common
The vaccine associated feline sarcoma task force recommends treatment for masses after vaccination based on what?
3-2-1 rule
If mass is still evident 3 months after vaccination
If the mass is larger than 2cm in diameter
If the mass increases in size 1 month after vaccination
VAFS Task Force recommends what minimal margins? Problem with this? Best margin recommendations?
Minimal: 2cm lateral and 2cm deep
Problem: <50% completely excised
5cm lateral and 2 fascial planes deep
Task Force BULLSHIT; studies to determine if recommendations made a difference
- Implementation of of task force changed tumor locations
- Significant decrease in interscapular and lateral thoracic wall tumors
- Significant increase in tumors of the right thoracic limb (but not left), the R/L pelvic limbs, abdominal wall
- # tumors cranial to the diaphragm decreased and # of tumors caudal to it increased
What are risk factors for the development of TCC in dogs (7)? What has been found to help reduce the risk?
Older generation flea/tick control products Lawn chemicals (ex. 2,4-D) Female sex Obesity in females Cyclophosphamide exposure Neutered status Breeds
Scottish Terriers that ate vegetables at least 3 times per week had reduced risk (OR 0.3). Carrots were most commonly used. Green leafy veggies or yellow orange veggies. NOT cruciferous.
Overweight females exposed to flea products 28x risk vs normal weight males w/o exposure
What breeds are at increased risk for TCC development (8)?
Scotties (OR 18-21) Eskimo dogs (OR 6.5) Shelties (OR 6) Westies (OR 5.8) Keeshonds (OR 4.2) Samoyed (OR 3.4) Beagle (OR 3) Dalmatian (OR 2.4)
Scottish Terriers that ate vegetables at least 3 times per week had reduced risk (OR 0.3). Carrots were most commonly used. Green leafy veggies or yellow orange veggies. NOT cruciferus
Ses Shel Wee Kee Sam Begged Dan
In dogs with renal cell carcinoma, what is the overall MST and MST post nephrectomy*?
1 and 2 year survival rates?
Time to recurrence or metastasis?
MST 480-530*d
1-yr SR 45%
2-yr SR 25%
- 5m
* use of adjuvant therapy did not improve prognosis, but 6 dogs with distant mets were treated with chemo and had an MST of 14m*
What are the negative prognostic factors for ST identified in dogs with renal cell carcinoma (10)?
Age <6yrs
Hematuria
Cachexia
Metastasis at dx (MST 4.5m vs 18m)
Clear cell subtype (MST 3m)
Histologic vascular invasion
Fuhrman nuclear grade (grade IV MST 3m, grade III MST 1yr, grade II MST 3yr)
14-3-3o IHC protein expression; 38% of RCC; associated with poorly differentiated tubular subtype and MI of >30
High COX-2 expression; present in 76%; MST 14m vs 40m
**MI (>30 MST 4-6m [HR 12], 10-30 MST 15m, <10 MST 3.2yrs)
What is Sanguer sequencing?
Gold standard for detecting a single nucleotide substitution, but requires a 10-20% fraction of mutated allele for reliable detection - therefore low sensitivity leading to false negatives. Can be used in tissue or urine.
BRAF mutations are present in what % of dogs with urothelial and prostatic carcinoma? Overall?
Overall - 80% (20% do NOT posses the mutation)
Urothelial - 67%
Prostatic - 80%
Describe the BRAF mutation in dogs with urogenital TCC. What is the equivalent mutation in humans?
BRAF gene in chromosome 16, exon 15, codon 450 or 595
Results in a T -> A transversion that causes aa substitution of valine for glutamic acid
Leads to constitutive activation of the MAPK pathway
Humans, V600E, chromosome 7
SOMATIC mutation
Sensitivity and specificity of Sanger sequencing and ddPCR for detecting BRAF mutations in tissue and urine samples from dogs with TCC?
Sanger sensitivity:
Tissue - 71% (67% UC, 78% PC)
Urine - 61% UC, 100% PC
ddPCR sensitivity:
Tissue: 79% (75% UC, 85% PC)
Urine: 85% (83% UC, 100% PC)
BOTH are 100% specific! ddPCR more sensitive than Sanger for both tissue and urine
Advantages of ddPCR over Sanger for BRAF mutation detection?
ddPCR much more sensitive; able to detect mutation when present at levels as low as 0.005% (1 in 10,000 alleles)
Sanger requires a 10-20% fraction of mutated allele for reliable detection - therefore low sensitivity leading to false negatives.
What BRAF inhibitor is used in human patients with melanoma?
Vemurafenib
BRAF mutation present in >90%
What % of dogs with TCC experience relief of UO with urethral stent placement?
98-100%
What % of dogs with TCC experience incontinence, UTIs, stranguria, and re-obstruction after urethral stent placement? Median time to re-obstruction?
Incontinence 37-64% (males more common); severe in 26% (equal sex)
UTI 35%
Re-obstruction 22% at median of 3m
Stranguria 5%
What is the MST in dogs with TCC when treated with urethral stent?
What has been shown to prolong the MST in these dogs (2)? MST?
MST 20d to 2.5m (therefore mostly palliative)
Tx with an NSAID for >4 weeks prior to stent
Chemotherapy post stent
MST 8m
Most common cause of re-obstruction in dogs with urethral stents?
100% due to PD
10% due to intraluminal PD
90% due to PD cranial or caudal to stent
Duration of stranguria in dogs with urethral stents is significantly associated with what?
Degree of incontinence post stent placement
Longer stranguria duration = increased risk of severe incontinence; 1.7x increased risk for every 2 weeks duration
ORR and MST of piroxicam when used as a single agent in dogs with urogenital carcinoma?
ORR - 18% (6% CR, 12% PR, 53% SD)
MST 6m
*non COX selective
ORR, PFS, and MST of deracoxib when used as a single agent in dogs with urogenital carcinoma?
ORR 17% (PR 17%, SD 71%)
PFI 4.5m
MST 10.7m
GI toxicity in 19%
*COX 2 selective inhibitor
ORR, PFS, and MST of firocoxib when used as a single agent in dogs with urogenital carcinoma?
ORR: 20% (20% PR, 33% SD)
PFI 3.5m
MST 5m
COX-2 selective*
Identified prognostic factors in dogs with TCC (6)?
- TNM stage
- Tumor location: urethral (worse prognosis) and prostatic involvement
- Dogs receiving 3+ chemo drugs had a longer MST compared to those receiving 1-2 chemo drugs
- Daily piroxicam had a longer PFS and MST
- Sx - trigonal location shorter MST, improved MST when combined with doxo and piroxicam
- AUS findings: dogs with wall involvement, heterogenous mass, and trigone location - shorter MST
What factors are associated with a higher TNM stage in dogs with TCC (3)?
young age (increased risk of nodal mets)
prostate involvement (increased risk of distant mets)
higher T stage (increased risk of nodal and distant mets).
Dogs with TCC and higher # of ___ have an improved MST.
Granzyme B+ TIL
CTL and NK are granzyme B+
DFI unaffected
___ overexpression is documented in 56% of TCC.
Treatment with what TKI results in cell cycle arrest and decreased cell growth of all TCC lines in vitro?
HER-2
Iapatinib - TKI of HER2, EGFR
What is the MST in dogs with TCC according to the different TNM stages?
T1-2: 7m T3: 4m N0: 8m N1: 1.5-2m M0: 7m M1: 3.5m
What is the diagnostic yield of US-guided kidney FNAs in dogs and cats?
Sensitivity and specificity for neoplasia?
70% (dogs 72%, cats 68%)
Dog: 80% sensitive and 90% specific for cancer; highest for LSA
Cat: 100% sensitive and specific for neoplasia
Expression of what 2 IHC markers by the majority of canine RCC suggests they arise from the distal convoluted tubule of the kidney?
Cytokeratin
VImentin
What IHC markers are used to diagnosed RCC in cats (4)?
CK7, CK20, KIT, CD10
What is the MST in px with brain tumors treated with palliative care?
Is there a location that may do better with palliative care?
6d to 4m; generally 2m
Supratentorial/forebrain tumors 6m
Cats <1m
What are some positive prognostic indicators overall in dogs and cats with primary brain tumors (6)?
Solitary lesions (some w/ multiple meningiomas do well)
Limited neurologic dysfunction
Normal CSF analysis
Tumor type
Supratentorial/forebrain location
Tx with RT or sx/RT combo
What are some negative prognostic indicators overall in dogs and cats with primary brain tumors (6)?
Multiple lesions
Neurologic CS
Palliative care
Infratentorial/caudal brain lesions
High VEGF
High PCNA index
What is the MST in dogs with meningioma when tx with sx, HU/pred, conventional RT, SRT, and sx/RT combination?
Hypofractionated RT with VMAT for intracranial and spinal M?
Sx: 7-10m
Hydroxyurea/pred: 7m
Conventional RT: 12-27m (gen 12m/351d)
SRT: 17-19m
Hypofractionatd RT with VMAT: 66% ORR 2 yrs post; 2-yr SR 74%, MST not reached
Sx + RT: 17m
What % of dogs with intracranial meningioma treated with SRT experience AE? Suspect cause? Tx?
30-35%
Subacute demyelination
Most responsive to steroids
What is the mortality rate in dogs with intracranial meningioma treated with SRT?
What was found to be predictive of death during the first 6m post therapy?
10%
Volume of normal brain receiving 100% of SRT dose was predictive of death during first 6m
Ideally <1cc of normal brain tissue should receive 100% of isodose
Meningioma-specific negative prognostic factors in dogs (6)?
Histotype (anaplastic = worse; psammomatous, meningothelial, and transitional better)
High VEGF expression
High PCNA index (shorter PFS),
Longer MST with HU vs pred alone (7m vs 3.5m)
Infratentorial location and high gradient index = shorter ST post SRT
Volume of normal brain receiving 100% of SRT dose was predictive of death during first 6m
What are the 1 and 2 yr SR in dogs with intracranial meningiomas treated with SRT?
1-yr 60-65%
2-yr 24-33%
What is the MST in dogs with glioma when treated with sx (craniotomy), chemotherapy, conventional RT and SRS/VMAT +/- TMZ?
Sx: 6m
CCNU chemotherapy:
- glioma 4.5m
- astrocytome 3-8m
Conventional RT: 7-9m
SRS VMAT, +/- TMX: 13-14m
What is the 1yr-SR of dogs with glioma when treated with sx vs SRT?
Sx 1-yr SR: 25%, 2-yr 6%
SRS 1-yr SR: 60-90%
Glioma-specific positive PI in dogs (5)?
Extra-axial longer ST vs intra-axial
Ratio between target and brain volume <5% increased ST
Normal mentation at dx increased ST
CCNU longer ST vs palliative (35d)
Tumor volume <5%
What is the MST in cats with intracranial meningioma when treated with sx and RT?
% of neurologic improvement with RT?
Sx: 2-3yrs
RT: 17m (combo of tumors); 96% improvement
What is the recurrence rate in cats with intracranial meningioma when tx with sx?
20%
What % of dogs with intracranial meningiomas tx with sx survive to discharge?
92%
8% overall mortality rate
What is the intraoperative and postoperative complication rate in dogs with intracranial meningiomas when treated with surgery?
Intraop 10%
Postop 45%
What is the most common intraoperative complication in dogs with meningiomas treated with surgery?
Hemorrhage
What % of dogs with intracranial meningiomas tx with surgery experience neurologic vs non-neurologic postoperative complications?
45% transient neurologic deterioration
18% non-neurologic; aspiration pneumonia
Which intracranial tumor commonly has a contrast enhancing rim on MRI? Why?
Glioma
Correlates with necrotic or cystic areas; not specific for G, seen best on T2 images
How do canine gliomas look on MRI?
Arise from intra-axial tissue and move outwards; infiltrative (as opposed to displacing tissue)
Often lacks distinct margins
Ring enhancement; seen best on T2
Hyperintense on T2W
Hypo to isointense on T1W
How do canine meningiomas look on MRI?
Arise from periphery of brain and pushes brain inwards
Broad base with extra-axial attachment -> dural or meningeal tail
Distinct tumor margins
Uniformly contrast-enhancing
25% have a cystic component
Hyperintense on T2W
Hypo to isointense on T1W
Most tumors are hyperintense on what MRI setting?
T2W
What is the relationship between gliomas and c-kit?
Gliomas - all negative for c-kit and COX-2 in one study
c-kit expressed on vasculature of high grade gliomas
3 high grade tumors had intramural vascular expression of c-kit
This suggests kit inhibitors may provide an anti-angiogenic effect in high grade gliomas
In humans, expression of c-kit and COX is associated with a poor prognosis
What is the most common primary intradural spinal cord tumor in dogs?
Meningioma
What is the most common location for spinal meningiomas in dogs?
C1-C4
100% intradural and usually extramedullary
MST of dogs with spinal meningioma when treated?
17m (500d)
Most common metastatic intramedullary spinal cord tumor and location in dogs?
HSA and TCC
T3-L3
Withrow says HSA and LSA, but recent literature says what above
Most common extradural spinal cord tumor in both dogs and cats?
OSA
Most common primary spinal cord tumor in dogs vs cats and location?
Dogs - meningioma; cervical
Cats - LSA; thoracolumbar or lumbosacral
Primary>metastatic
Most common metastatic brain tumors in dogs and cats?
Cats - LSA #1, pituitary #2
Dogs - HSA #1, pituitary carcinoma #2, LSA #3
Most common phenotype of canine CNS lymphoma?
DLBCL >50%
What % of canine CNS lymphoma infiltrates the pituitary?
> 70%
Most common clinical signs in dogs with CNS lymphoma (2)?
Weakness, ataxia
MST in dogs with CNS lymphoma when treated with multiple therapies?
6m (171d)
The majority of gliomas in dogs are what grade?
High grade - 94%
Invasive and resistant to therapy
What is the most sensitive IHC stain for anaplastic oligodendryomas? What other tumor is also positive?
Olig; most sensitive, but astros also +
Others: SOX10, PDGFRa, NG2, GFAP
Astrocytomas
When RT is being pursued as a treatment modality, what is recommended for planning purposes? Why?
Combination of CT and MRI
GTV measured on MRI typically 25% larger than CT
If MRI not available, recommend using CT GTV + additional margin of 0.3cm to avoid geographic miss for 3D-CRT
What % of dogs with brain tumors experience shrinkage 3m after SRT?
60%
Clinical response to RT in dogs with brain meningiomas?
80%
Clinical benefit of SRS in dogs with meningioma?
60%
In dogs with primary or metastatic vertebral OSA when treated with SRT, what is the MST, and % that experienced improved pain control and neurologic score?
MST 4.5m
83% improved pain control
44% improved neuro score
Splenic fibrohistiocytic nodules is a term no longer used and has been reclassified to other dzs, with the most common ones being stromal sarcomas, HS, and complex nodular hyperplasia.
What is the MST of splenic stromal sarcomas and splenic HS?
Stromal splenic sarcoma - 16m
Splenic HS - 2.4m
SFHN represents a heterogeneous group of diseases and the authors propose this term should no longer be used.
Splenic fibrohistiocytic nodules (SFHN) were previously classified as grades 1-3 based on what?
What were the MSTs for the grade and what was prognostic (2)?
% lymphocytic infiltrate
PI:
Lymphoid:fibrohistiocytic ratio
Grade
Grade 3 significantly shorter MST (113 days) compared to grades 1 and 2 (MST not reached; mean 1,118 days)
What % of plasma cells should be present in a normal bone marrow?
What % of plasma cells in the bone marrow is suggestive of MM in dogs and cats?
< 5%
> 20% is abnormal
Can consider abnormal >10% in cats as they may not have extensive bone marrow involvement, so also consider cell morphology and visceral organ infiltration as they can be more commonly affected or of equal importance
What BM finding is a prognostic factor in cats with multiple myeloma?
Plasma cell morphology
- well-differentiated (< 15% blasts)
- intermediate (15-49% blasts)
- poorly differentiated (>50% blasts)
~80% of cats exhibit abnormal plasma cell morphology
What are the negative prognostic factors identified in dogs with MM (5)?
Hypercalcemia
Bence Jones (light chain) proteinuria
Extensive bone lysis
Presence of renal dz = shorter PFI and MST
High neutrophil to lymphocyte ratio >4.28 = shorter PFI and MST
In a newer study, hypercalcemia and bone lysis were not prognostic
What is the historic ORR, CR, median time to response, and MST in dogs with MM treated with melphalan?
92% ORR, 43% CR
MST 540d
A study evaluating pulse-dosed vs daily administered melphalan in dogs with MM was performed. ORR? Prognostic factors identified (2)? Which ones were not of prognostic significance (2)?
ORR 86%
MST 930d
Prognostic factors:
Renal dz (MST 330d)
Neutrophil to lymphocyte ratio of >4.28 (MST 330d)
Not of significance:
Hypercalcemia
Lytic lesions
What is the ORR, CR, median time to response, and MST in cats with MM when treated with melphalan? DLT?
ORR 70%
CR 30%
Time to response 4.5m
MST 8.5m (not SS diff from CTX)
DLT: neutropenia; d/c in 63%
What is the ORR, CR, median time to response, and MST in cats with MM when treated with melphalan? DLT?
ORR 83%
CR 50%
Time to response 45d
MST 13m (not SS diff from melphalan)
Toxicity common but mild, none required d/c
Authors recommend as first line therapy*
What is the ORR and CR in cats with MM treated with chlorambucil?
ORR/CR 50%
According to Withrow, what is the ORR and MST in cats with MM when treated with melphalan or COP? Compared to Europe study?
ORR 60%
Most die within 4m
Occasional long-term survivors >1yr
Europe study: 9.5m
What % of cats with MM have hyperglobulinemia at dx? Monoclonal vs biclonal?
88% (most common BW abnormality in 1 study)
80% monoclonal
20% biclonal
Biclonal gammopathies cats>dogs
Most common M component in cats vs dogs with MM?
Cats: IgG (more common in some studies)
Dogs: IgG or IgA
What is referred to as the M component in patients with MM?
The presence of a malignant clonal protein (M-protein or M-spike) reflecting production of a single Ig
What % of cats with MM exhibit Bence Jones proteinuria?
50%
What chemistry abnormality in cats with MM is inversely correlated to globulin levels?
Cholesterol
Hypocholesterolemia in 70% of cases
What would be the expected levels of EPO and blood oxygen in px with polycythemia vera vs PNS polycythemia?
PV: low or low-normal EPO and normal blood O2
PNS: increased EPO, normal O2
What has to be done in order to dx polycythemia vera?
Rule out everything else
Increased activity of what signaling pathway has been identified in neoplastic canine HSA cell lines vs normal endothelial cells?
NOTCH; necessary for maintenance of stem-cell properties
Inhibition via y-secretase inhibitors suppresed cell growth
What red blood cell morphology has been associated with HSA (2)?
Shistocytes - seen with microangiopathic hemolysis
Acanthocytes - 10% of dogs with them have HSA
Dogs with splenic masses that weigh more than ___kg are more likely to have HSA.
> 27.8kg
When comparing the site and cause of spontaneous hemoabdomen, dogs weighing < ___kg were more likely to be bleeding from which organ vs dogs weighing > than ___kg.
Bleeding from which organ was most commonly associated with HSA?
< 20kg liver
> 20kg spleen
Spleen
Although there is no difference in cytology of pericardial effusion in dogs with HSA vs other tumors, dogs with HSA have elevated levels of what when compared to dogs with idiopathic effusions?
Troponin I
If > 0.25 ng/mL more likely to be cardiac HSA
What IHC stains can be requested to dx HSA?
Von Willebrand factor (factor VIII-related antigen
CD31/PECAM)
Other markers that could be used:
- CD117 (KIT)
- Claudin 5
- VEGFA and its receptor Flk-1 - no difference when compared to non-neoplastic endothelial cells
- Ang 2 - may be useful
- Tie 2 - less reliable
Why is an IHC panel more useful to dx HSA vs any marker on its own?
Poorly differentiated tumors may not express vWF
CD31 is not a consistent marker as cross labeling can occur with other tumors (AGASACA, nodular hyperplasia, mammary Ca, plasmacytoma, RCC, cutaneous histiocytoma)
What % of dogs undergoing laparoscopy for splenic HSA have to convert to open laparotomy?
What was significantly associated with conversion?
27%
Heavier body weight
Splenic mass, BCS, were NOT
What was recently shown to decrease MST when given concurrently with doxorubicin in dogs with splenic HSA?
Concurrent doxo and metronomic chemo with CTX = shorter MST
When used in a metronomic fashion combined with CTX and piroxicam, what drug has been shown to improve TTM and MST in dogs with HSA post splenectomy and doxo completion?
Thalidomide
TTM and MST not reached
CTX alone has not been shown to increase anything after doxo
What is the MST in dogs with HSA treated with single agent thalidomide post splenectomy?
Prognostic indicators?
1-yr SR?
MST 6m (172d)
PI: Stage II dz longer MST vs stage III (40d)
33% 1-yr SR (vs usual 10% 1-yr SR)
What has been demonstrated when Palladia is administered to dogs with stage I or II splenic HSA after doxorubicin (q2w) chemotherapy completion?
What % of dogs receiving Palladia developed mets?
No improvement in ANYTHING over doxorubicin alone. Same numbers as with everything else.
Overall DFI 140
Palladia DFI 160
Overall MST 170
Palladia MST 170
~5.6m
80%
What chemotherapy drug has been shown to inhibit HSA cell migration and induce apoptosis in vitro?
Paclitaxel
What 2 chemical compounds have been shown to enhance cell kill when combined with doxorubicin vs doxo alone in cell lines?
Tetrathiomolybdate - Cu binding agent that may reduce resistance
Resveratrol - naturally occurring polyphenolic compound in red wine; induces autophagy via activation of MAPK
What is allogenic LDC vaccination for dogs with HSA?
In what did it result?
AE?
Cationic liposome and DNA complex, which is an immune stimulant added to vaccines, combined with pooled cells from 2 HSA cell lines.
8 doses were administered along with doxorubicin chemo
Vaccine elicited strong humoral immune response to a control antigen and most dogs also mounted an Ab response against canine HSA cell lines
DFI 3m
MST 6m
20% GI AE; diarrhea and anorexia most common
How does Yunnan Baiyao work for HSA (3)?
Increased activity of caspases 3 and 7
Increased clot strength on TEG
Improved DFI in dogs with HSA
Identified negative prognostic factors in dogs with splenic HSA?
Sx alone Stage (I vs II-III) Mets at dx MI (<11 MST 10m, 11-20 MST 7m, >21 4m) Administration of allogenic blood products
Cutaneous HSA most common signalment, location, and predisposed breeds (9)?
Light pigmented dogs with thin coats
Ventral abdomen and preputial region most common location
Breeds: Whippets, Salukis, bloodhounds, beagles, white bulldogs, English pointers, Staffies, Italian greyhound Dalmatian
Histopathology consistent with UV-associated solar dermatosis is detected in what % of dogs with skin HSA?
70%
How is the location distribution of HSA in cats?
Equally distributed between visceral and cutaneous forms
In cats with visceral HSA, what % has multifocal disease at sx?
Most common locations?
77% multifocal disease
Liver 35% Small intestine 31% Large intestine 31% Abdominal LN 31% Mesentery 27% Spleen 23%
With which form of HSA is the metastatic rate higher in cats?
Visceral (vs cutaneous/SQ)
What % of cats with visceral HSA have pulmonary mets at diagnosis vs extrathoracic mets?
33% pulmonary at dx
60% extrathoracic mets
When compared to dogs, how does cutaneous/SQ HSA behave in cats? Major concern with it?
Behaves similar to other STS
Local recurrence in; 60-80%
Cutaneous - MST not reached
SQ - MST 384d (12.8m)
Negative PI in cats with HSA (3)?
SQ location (vs cutaneous)
Visceral form (poor progn and high met rate)
MI>3 (MST 2m)
Incomplete tumor excision (MST 9m)
MST of cats with visceral HSA?
2.5m
MST of dogs with cardiac/pericardial mesothelioma when treated with a pericardiectomy?
10-15m; can be less, not a lot out there, usually palliative; IC chemotherapy can be beneficial
“Grossly”, how does mesothelioma look?
Cytologically, how do mesothelial cells look?
Histologically, what are the 3 ways they can be classified and which one is most commonly seen?
Diffuse nodular masses that cover the surface of body cavities (depends on histo type)
Similar to epithelial cells; CANNOT be diagnosed cytologically
Epithelial, mesenchymal, biphasic (combination)
Epithelial most common
What can cause an increase in proliferation of mesothelial cells?
Any sort of inflammation
What variant of the mesenchymal form of mesothelioma can be seen in male or German Shepherd dogs?
Sclerosing: resembles a sarcoma
Causes restriction
What is the metastatic rate of mesothelioma?
True metastasis is rare.
Fluid accumulation results in exfoliation and implantation of cells, which results in seeding and multiple tumor formation.
What is a CT finding that can be seen in px with mesothelioma?
Pleural thickening
How can you rule out mesothelioma in a px with pericardial effusion?
Normal fibronectin concentration; usually increased with MSA
Local penetration of IC chemotherapy?
2-3mm; consider debulking sx for large masses before IC
Overall MST of dogs with malignant thoracic effusions?
MST with IC carbo or mitoxantrone vs no tx?
Prognostic factors for response to therapy?
Overall 4-12m
11m w/chemo
<1m if no therapy
Tx dogs live longer than w/o tx
NO PI identified; presence of effusion, thoracic disease, chemotherapy drug used, or metastasis did not affect MST
Infiltration of thymomas by which cell is positively correlated with improved survival in both dogs and cats?
Lymphocytes
What is the most common form of thymomas in cats and how does int influence prognosis?
Cystic; better prognosis
Metastatic rate of cystic thymoma in cats?
20%
How can you differentiate lymphoma vs thymoma using flow cytometry?
Thymoma - >10% of lymphocytes co-express CD4+ and CD8+
Lymphoma - <2% co-express
Carcinoma <1% co-expression and samples usually have a low lymphocyte count (<40%)
Negative prognostic factors in dogs with thymoma (6)?
Presence of another tumor at dx; MST 282 vs 586d
Lack of sx excision; MST 76 vs 635d
Masaoka stage III+ MST 224 vs 1045d
Presence of PNS (MG or hypercalcemia)
Incomplete margins
Tx with adjuvant chemo and/or RT
PNS did not influence outcome in a study
What % of dogs with thymoma have a polyclonal PCR result?
92%
How do thymomas differentiate from lymphomas when contrast-enhanced CT are performed?
Thymomas - more likely to have heterogenous contrast enhancement
LSA - more likely to be homogeneous
What is the ORR in dogs and cats with thymoma treated with adaptive RT (3Gy x 12)?
What is the % of regression per day?
GTV and PTV shrunk by how much?
100%; all achieved a PR
5% regression/day
GTV and PTV 30%
Why replanning may help protect organs at risk
Tasmanian facial tumor immune regulation, differences from TVT, metastatic rate, IHC, prognosis
Tumor highly conserved, as TVT
They downregulate expression of MHC genes, but NOT through upregulation of TGF-B1 as TVT
Downregulation of MHC can be restored by treating with IFN-y
Metastatic rate 65% to LN, lungs, kidneys
It is a PNST of Schuwann cell origin, so IHC positive for:
S-100, vimentin, periaxin
Periaxin 100% sensitive and the most specific marker
No response to chemo
Most die within 6 months of infection
Prognostic factors for <1m survival in dogs with HS (4)?
Anemia
Thrombocytopenia Hypoalbuminemia
Palliative therapy (12-40d)
Biomarkers for HS in BMD (3)?
High ferritin (not necessarily outside the reference range) - early in dz/asymptomatic
Lower total WBC count - early in dz/asymptomatic
High MCP-1 (monocyte chemoattractant protein); it is a chemokine produced by DCs and macrophages; serves to recruit mononuclear cells from the marrow to sites of inflammation
What is the most reliable IHC marker for HS?
CD204
Class A macrophage scavenger receptor, expressed on normal tissue macrophages.
HS samples and normal macrophages will be CD204+.
Lymphoid neoplasms, sarcomas, and cutaneous histiocytomas (Langerhans origin) will be CD204-.
50/50 HS samples were positive, including EHS
What dog breed is most commonly associated with pulmonary HS?
Min Schnauzer; OR 4.8 for HS
What breeds are predisposed to developing HS (6)?
Flat coated retreivers (OR 34) Bernese Mountain dog (OR 15) Sharpeis (OR 16) Miniature Schnauzers (OR 4.8) Golden retreiver (OR 3.9) Rottweilers
What IHC markers are used for feline progressive histiocytosis (7)?
Positive for: CD1a, CD1c, CD11b, CD18, MHC II +/-, E-cadherin
87% express PDGFR-b (of FPH and HS)
Almost all cats surviving > 300d had high PDGFR-b expression
What is feline progressive histiocytosis? Most common locations?
Initially occurs in skin and progresses over time to involve multiple organs (LN, lungs, abdominal viscera)
Multiple firm, haired or hairless, dermal papules or nodules, that can coalesce into plaques and become ulcerated
Head, feet, legs
Unresponsive to steroids, effective medical tx not available; can consider removal of solitary masses, but development of more is expected
Disease progresses over months to years (median 13.4m)
What are the most common TSG mutations in BMD and FCR with HS?
CDKN2A/B deletions - 63%
PTEN deletions - 40%
RB1 - FCR 2x more likely to have deletions vs BMD
TP53 - FCR 2x more likely to have gain of function mutations vs BMD
BMD with HS have a higher prevalence of a gain of function mutation in what gene, compared to other breeds?
PTPN11 gene - exon 3
BMD with HS had a higher prevalence of this mutation (37%) compared to other breeds with HS (9%)
Identified risk factors in BMD vs FCR
BMD:
- 225x higher risk of HS
- 17x more likely to die from tumor causes
- 2x as likely as FCR to develop disseminated dz
- FCR 7x more likely than BMD to have localized dz
- Prev orthopedic dz increases risk of HS in BMD, but risk is lower in those receiving medications for >6m
What proteinases are expressed at the invasive front of HS and are produced by TAMS (4)?
MMP 2, 9, 14
TIMP 1
Metastatic rate at dx of pulmonary HS?
16% pulmonary
46% intrathoracic
Common MRI findings (4) in dogs with CNS HS?
Diffuse enhancement of meninges
Forebrain most common location
Solitary extra-axial mass with moderate to marked CE
Iso or hypointense on T2 (vs meningioma, hyperintense)
Negative prognostic factors on multivariate analysis for dogs with histiocytic sarcoma (4)? On univariate (1)?
Multivariate:
- Thrombocytopenia
- Disseminated dz
- Palliative therapy
- Concurrent use of steroids
Univariate:
-Elevated survivin levels- also associated with chemoresistance
ORR of epirubicin in dogs with HS (alternating with CCNU, singe agent, rescue)?
Rescue-specific ORR?
Overall TTP and MST?
What % required dose reductions? DLT?
ORR 29%
Rescue specific ORR 19%
TTP 2m
MST 6m
30% due to GI toxicity primarily
Marker for erythrophagocytic HS?
CD11d (macrophages from the splenic red pulp and BM)
Blood work abnormalities that can be seen with EHS (4)?
MST?
Regenerative anemia - 94%
Hypoalbuminemia - 94%
Thrombocytopenia - 88%
Hypocholesterolemia - 70%
days to 1-2m
Describe the Philadelphia and Raleigh chromosomes
Philadelphia
- BCR-abl 9 ->22 translocation
- Chrom 9 encodes abl gene for a TKR involved in growth and differentiation
- Chrom 22 encodes bcr gene
- Abl gene moves close to the bcr gene (9->22 translocation) and a new fusion gene bcr-abl is formed; this allows for constitutive activation of the abl tyrosine kinase, which promotes CML; present in 90% of CML cases and occasionally AML and ALL
Raleigh:
BCR-ABL translocation affects chromosomes 9 and 26
Canine ALL phenotype?
Typically B-cell
CD34+, CD21+, CD3-, CD4-, CD8-
<10% T-cell: CD3+, CD4-, CD8-, CD21-
Canine AML phenotype?
CD45+, CD34+, CD11b+, CD11c+, CD14+, MPO+, CD4+ (+/- )
Granulocytes can sometimes express CD4 so it may be CD4+
Strong ALP (none in LSA or CLL); weak on some ALL
Negative for B and T cell markers; 30% can express them
Canine CLL phenotypes? Which one is more common?
T-cell: CD8+ with large granular morphology . MOST COMMON.
MST 930d
B-cell: CD21+, CD34-
SMALL BREED DOGS/Bulldogs
MST 480d
What is different about Bulldogs and CLL?
Increased risk of CLL
Median age of 6 yrs
Low MHC class II and CD25 expression
Higher % of hyperglobulinemia
