Osteosarcoma Flashcards
What is reported incidence of OSA in Scottish deerhounds?
15%
Which is not a negative prognostic factor for appendicular OSA?
- proximal humerus
- High MI
- Dog > 40kg
- High CD8/Treg ratio
- Relative lymphocytosis and monocytosis
- High CD8/Treg ratio –> Dogs with low CD8/Treg ratio in the blood (n = 6) had a significantly
shorter survival time than dogs with high CD8/Treg ratio (n = 6)
What are the criteria for performing pulmonary metastasectomy?
- primary tumor in CR (preferred >300d)
- 1 or 2 nodules on plain CXR
- cancer only found in lung (negative bone scan)
- long doubling time (>30 days) with no new visible lesions
What region of bone significantly affected time to fracture following SRS (i.e. if this part of the bone was affected, more likely to fracture sooner)? (Kubicek 2016)
Subchondral bone involvement
If involved - median time to fracture was 4.2 months
If not involved - 16.3 months
(consider evaluating for subchondral bone involvement as part of case selection for SRS)
Name 5 (or more) genetic factors that may contribute to OSA.
- p53, Rb, PTEN mutations
- MET oncogene activation
- Increased IGF-1 signaling
- HER2 overexpression
- Aberrant mTOR signaling
- TrkA overexpression
- Telomerase expression
- Increased MMPs, RANKL, cathespin K
- Increased Erin, CXCR4 (chemotactic activity for lymphs)
- OSA1 in Scottish deerhounds
The reported incidence of OSA in Scottish Deerhounds is?
15%
What is the MST for rib OSA treated with surgery and chemo?
8 months
What is the MST for dogs with extra skeletal OSA treated with surgery alone?
1 month
Rank sites of metastasis from shortest to longest MST: lung, soft tissue, bone.
soft tissue < lung < bone
19d vs. 59d vs. 132d
What are 5 requirements for suitable candidates of limb-sparing surgery?
- OSA confined to leg
- Affects < 50% of bone
- Absence of pathologic fx
- <360 degree involvement of soft tissue
- Firm, definable ST mass vs. edematous lesion
T/F: There are reports of histologically confirmed OSA undergoing spontaneous regression.
True
What % of dogs undergoing a limb-spare develop an allograft infection?
40-47.5%
According to the largest study, how often does scintigraphy detect a secondary site of OSA?
7.8% of cases
Largest study was 399 cases; most suspect lesions were NOT sampled in this study (Jankowski VCO 2003)
What is the 1 year survival rate for mandibular OSA treated with surgery alone?
71%
Withrow, check new Selmic paper
What is the MST for maxillary OSA after maxillectomy?
5 months
What were the findings of the BAY 12-9566/doxorubicin study?
BAY 12-9566 = Oral MMP inhibitor
Combination did not improve MST
No change in MMP levels detected
What is the MST for dogs with stage 3 OSA? (Boston JAVMA 2006)
76 days (stage 3 = metastasis to any site; stage 1 = low grade tumors, stage 2 = high grade tumors)
What was the MST of dogs treated with amputation and L-MTP-PE?
222 days
77 days with placebo
What was the MST for dogs treated with amputation, cisplatin, and L-MTP-PE?
- 4 months
9. 8 months with just amputation and cisplatin
What were the results of the OncoLAR/carboplatin study?
Long-acting somatostatin
No improvement in MST compared to placebo
43% reduction in circulating IGF-1 levels
What % of dogs experience pain relief after pRT for appendicular OSA?
74-93% for 53-130d (1.8 - 4.3mo)
What side effect is seen with 153-Sm-EDTMP?
Myelosuppression.
radiopharmaceutical targeted to areas of increased osteoblastic activity (for pain relief)
What do urine Ntx concentrations reflect?
N-telopeptide
Marker of bone resorption (mobilized from bone by osteoclasts and subsequently excreted in urine)
(has been used in bisphosphonate studies)
What is the behavior of parosteal/juxtacortical OSA?
Less aggressive, slow-growing
Metastasis can occur
What % of dogs experience pain palliation with pamidronate vs. zoledronate? Duration?
28% vs. 50% for > 4 months
zoledronate has 100x greater anti-resorptive potency
What is the most common site of chondrosarcoma? MST?
Nasal
MST with various tx (RT, rhinotomy + RT, rhinotomy alone) 580d
What is MST for rib chondrosarcoma with en bloc resection?
1080d
What is the overall MST for appendicular chondrosarcoma?
540d
Note Farese Vet Surg 2009 paper that says MST varies based on grade
What is a risk factor for osteochondromatosis in cats?
FeLV
T/F: Histologic grade is prognostic for survival in feline OSA.
True
What IHC marker would be useful to differentiate tealgiectatic OSA from primary HSA of bone?
vWF
Giuffrida VCO 2016 - 20% of tumors reclassified from tOS –> HSA
No sample with osteoid production was positive for vWF
How does overall survival for tOS compare to bone HSA with local therapy and systemic tx? (Giuffrida 2018)
tOS - 213d (7mo), HSA - 299d (10mo)
Both tumors were aggressive with high rates of mets.
What % of bone HSA occurred in the hindlimb? (Giuffrida 2018)
78%
What anatomic differences exist between implant associated OSA and naturally occurring OSA? (Burton 2015)
- Implant-associated more likely to involve diaphysis (vs metaphysic for naturally occurring)
- Pelvic limb more commonly affected with implant-associated neoplasia
What is the reported MST for cats with OSA treated with amputation alone?
24-44 months
What CT finding can be used to predict time to fracture following stereotactic RT for dogs with appendicular OSA? (Kubicek 2016)
Subchondral bone involvement - 4.2 months
No subchondral bone involvement - 16.3 months
(subchondral = near the joint, epiphysis)
What is the utility of abdominal ultrasound in staging canine OS? (Cesario Aus Vet J 2016)
In 3/6 cases, hepatic metastasis was identified without concurrent pulmonary metastasis
Also in Wallis JAAHA 2013 - 5% had another neoplasm
What is the prognostic significance of CT vs. rads for thoracic imaging in routine staging of canine OSA? (Oblak VCO 2015)
The prevalence of CT-detected pulmonary metastasis in dogs with negative thoracic radiographs was 14%
Pulmonary lesions seen on CT that were not seen on rads; ground glass lesions should be considered concerning for metastasis (equivocal ground glass progressed in 3/4 cases)
Did increased sensitivity with CT to detect metastases influence survival analysis? (Eberle 2010)
No. This study detected nodules in 28% of dogs (vs. 5% with rads), but whether nodules were present on CT did not influence survival.
Is KIT expressed in feline osteosarcoma? (Wolfesberger 2016)
No
Is KIT expressed in canine osteosarcoma? (Wolfesberger 2016)
Yes, expressed in 78% via IHC
majority (50%) showed 10-50% positivity
What changes are seen in monocyte phenotype and function in dogs with OSA? (Tuohy 2016)
Cell surface expression of multiple chemokine receptors is significantly down-regulated in peripheral blood monocytes of dogs with OSA.
- CCR2 and CXCR2 decreased.
- PGE2 and TNFa were increased in OSA monocyte culture compared to control.
How does CD8/Treg ratio affect OSA survival? (Biller 2010)
Lower CD8/Treg ratio associated with shorter survival time.
T/F: Enrofloxacin inhibits OSA cell survival in vitro through interaction with p53.
False.
York VCO 2016 - enrofloxacin enhances effects of chemo in canine OSA cells with mutant and wild-type p53
What are the 1, 2, and 3 year survival rates for dogs with HER2+ appendicular OSA treated with local control, carbo, and recombinant L. monocytegenes expressing chimeric human Her2/Neu? (Mason Clin Can Res 2016)
1yr: 77.8%
2yr: 67%
3yr: 56%
What was the ORR to ifosfamide in dogs with metastatic OSA? (Batshinski 2014)
ORR 11.8% (1 CR, 1 PR)
2 dogs hospitalized due to ifosfamide toxicosis (dose ranged from 375 to 425 mg/m2)
MST was 95d
B-catenin is frequently expressed in canine OSA. How does it affect DFI/MST? (Stein 2011)
It doesn’t change DFI/MST.
How does Wnt signaling differ between OSA populations with/without increased expression of ALP? (Piskun 2011)
No significant difference in β-catenin expression or activation between OSA populations differing in serum ALP concentration
What were the results of combining pamidronate with pRT and DOX in a double-blind placebo-controlled study? (Fan JVIM 2009)
Combination was safe but did not clearly improve pain alleviation (40% had durable analgesia).
Dogs with pamidronate did have decreased NTx excretion.
Most common locations for bone HSA? (Giuffrida Vet Surg 2018)
proximal tibia (22%), mid-tibia (19.5%), proximal femur (14.6%)
Most common locations for tOSA? (Giuffrida Vet Surg 2018)
proximal humerus (37.9%), distal radius (13.8%), distal femur (13.8%) Most tOSA were in the forelimb
Does infection after amputation improve survival? (Hans 2018)
No.
Does histologic grade correlate with outcome in canine osteosarcoma? (Schott 2018)
No, per this study.
What percentage of Wnt5a (for non-canonical Wnt pathway) is present in Canine OSA? What influence does this have on PFS and OS? (Szigetvari 2016)
54%
No impact on PFS or OS
What % of tumors were reclassified (typically from tOSA to HSA) based on factor-VIII/vWF? (Giuffrida VCO 2016)
approx 20% (exact amount was 17%)
If devoid of osteoid, most likely HSA
(6 tumors reclassified from tOSA to HSA)
What is a negative prognostic factor for ulnar osteosarcoma? (Sivacolundhu JAVMA 2013)
Telangiectatic (multivariate analysis)
What was the MST for telangiectatic ulnar OSA? (Sivacolundhu JAVMA 2013)
208 days (7 months)
What is the MST for dogs with LN metastasis from OSA?
57-59 days
In evaluating immune cell infiltration of Canine OSA, dogs with greater than 4.7% of ____ cells experienced a significantly longer DFI. (Withers 2018)
CD204+ macrophages
also noted that lower number of these cells were located in proximal humerus tumors
MST and duration of pain control for dogs with primary/metastatic vertebral OSA treated with SBRT? (Swift 2018)
MST 139d
period of pain control 77d
Did metronomic CTX improve survival following carbo in a retrospective study? (Matsuyama JVIM 2018)
No.
Also, 58% of dogs in the CTX group needed to stop due to SHC! (standard 15 mg/m2/day dosing)
MST for stage III OSA with no tx compared to with metastasectomy? (Turner 2017)
No tx: 49-57d (2 months)
Metastasectomy: 232d
Preceding DFI did not influence this (selected for dogs with DFI >275d prior to dx of stage III OSA.
What was the complication rate in dogs with SRT followed by surgical stabilization for primary bone tumors? (Boston 2017)
16/17 had complications and 15/17 (88%) were considered major
Concluded that complication rate was prohibitively high, most common was infection
What two therapies have been evaluated for potential to reduce pathologic fx risk following SBRT for canine OSA? (Curtis PLoS One 2017)
zoledronate and PTH
What is the approximate risk of pathologic fracture with SBRT for appendicular OSA? (quoted in Curtis PLoS One 2017)
~33%
What immune reaction did ADXS31-164 trigger to demonstrate that it broke tolerance? (Mason 2016)
antigen-specific IFNgamma against the intracellular domain of HER2/neu
How does scapular OSA compare to appendicular OSA re: DFI and MST? (Montinaro 2013)
Similar survival
Adjunctive chemotherapy improved prognosis, similar to appendicular OSA
What is the metastatic rate of OS affecting the head?
37% (Withrow)
T/F: Dogs that have elevated pre-op ALP that don’t return to normal within 40 days after surgery develop earlier metastasis.
True.
What % of Rottweilers carry constitutional mutation in c-met that may affect signaling of osteoblasts and OSA cells?
80% (Liao 2006)
What location is most suitable for limb spare?
Distal radius or ulna - because function following limb sparing and carpal arthrodesis is good.
What margins are taken in bone sparing surgery?
3-5 cm proximal to the proximal radiographic margin of the tumor
Extensor muscles attached to the tumor pseudo capsule are transected to maintain 2-3cm soft tissue margins
In two case series, what was the rate of allograft infection with limb sparing surgery?
40-47.5% (Withrow)
Is there a difference between q2 wks and q3 wks for doxorubicin to treat canine OS?
Yes, q2 wks for 5 treatments better per Withrow - 1yr survival was 50.5% and 2yr was 9.7%
How does L-MTP-PE work against cancer?
It is a lipophilic derivative of muramyl dipeptide (synthetic analog of a Mycobacterium cell wall component) –> augments canine alveolar macrophage tumoricidal properties. This is supported by enhanced cytotoxicity against OS cells in vitro.
What hormones have been implicated in development of OS?
GH and IGF-1
In humans, peak incidence of OS development occurs during adolescent growth spurt which is when these are circulating the most.
Administration of what drug resulted in 43% reduction of IGF-1 concentrations?
long-acting analog of somatostatin (OncoLAR); did not translate to improved DFI or survival
What is the MST for grade 1, 2, and 3 MLO?
G1 - 50 months, G2 - 22 months, G3 - 11 months
What is the metastatic rate for grade 1, 2, and 3 MLO?
78% Gr III, 60% Gr II, 30% Gr I
What is the recurrence rate for complete/incompletely excised MLO?
~25% complete excision, ~75% incomplete excision
In Kirpensteijn 2002, was histologic grade prognostic?
Yes. In the multivariate analysis, histologic grade III OS and elevated pretreatment plasma alkaline phosphatase (AP) levels were independent predictors of clinical outcome. (75% of the tumors graded were grade III).
Grade did not predict outcome in Schott 2018, so this is controversial.
Is TOC effective as single agent against metastatic OSA? What changes in VEGF and Tregs were noted? (Laver 2017)
Not effective.
Plasma VEGF significantly elevated in patients receiving TOC (surrogate biomarker for VEGFR inhibition), no changes Tregs.
What Wnt pathway protein was identified as a possible marker of OSA cell proliferation? (Rodrigues, Stein 2017)
Frizzled-6
No difference in ALP-differing populations
What was the MST for extraskeletal OSA with wide excision? (Duffy VCO)
90d
In a study comparing carbo x6 vs alternating carbo/dox, which showed longer DFI? (Skorupski 2016)
Carbo alone - 425d
vs. 135d
Do canine OSA line with differing serum ALP behave differently in vitro? (Holmes VCO)
No
No differences in proliferation, migration, invasion, or chemosensitivity
Are aurora kinase inhibitors effective against OSA? (Cannon 2015)
No.
They are serine/threonine protein kinases that play a role in mitosis.
Is ifosfamide effective against metastatic OSA? (Batchinski VCO 2012)
No, minimal activity observed.
Time to death after first dose was 95d. Well-tolerated.
How did accuracy of cytology compare to histo to diagnose canine bone lesions? (Sabattani JVIM 2017)
Accuracy of cyto was 83% and histo was 82.1% (so similar)
Did pamidronate impair carboplatin therapy for cOSA? (Kozicki)
No
Is obesity associated with adverse outcomes for cOSA and LSA? (Romano)
No
Are dogs in areas with water fluoridation more likely to develop OSA? (Rebhun)
No
Does total cholesterol have prognostic significance for OSA? (Leeper JSAP)
It may, according to this JSAP study.
Which bone tumor location is less likely to fracture? (Rubin JAVMA 2015)
Radius (probably because ulna stabilizes)
Was there a difference between amp and amp + chemo in small breed dogs (<15 kg) with appendicular OSA? (Amsellem 2014)
No, MST for amp alone was comparable to that for amp+chemo.
(there was numerical difference, though - amp alone was 257d and with chemo 415d; amp alone similar to amp+chemo for large breeds)
What happened when pamidronate was combined with pRT in Oblak 2012?
Pamidronate decreased survival.
What was the rate of metastasis for OSA of maxilla, mandible, calvarium? Recurrence? (Selmic 2014)
38.5% (not that staging at diagnosis was not standardized)
Recurrence was 51.3%
Messy study with lots of different variables.
What histologic features were associated with poor outcome for OSA? (Saam 2011)
intravascular invasion, MI >5 in 3 microscopic hpfs, grade III classification
What laboratory finding identified by Saam 2011 was associated with poor prognosis?
proteinuria
What happened when pamidronate was combined with pRT in Oblak 2012?
Pamidronate decreased survival.
What is the 1 yr survival rate for carbo post amputation?
35.4%
PKC (protein kinase C) inhibitors affect ___ activation, which may play a role in OSA metastasis. (Hona, Khanna 2011)
Ezrin
MST for OSA dog with LN mets? (Hillers 2005)
59d
What is the telomerase status for a majority of Canine OSA tumors?
Positive (73% in Kow JVIM 2008)
Rate of p53 mutations in OSA? How does this affect survival? (Kirpensteijn Veg Surg 2008)
40.7%
Decreased survival
Distal radius vs. proximal humerus survival in Schott 2017?
Distal radius 488d
Proximal humerus 208d
What site were Rotties more likely to have metastasis? (7% in McNeill VCO 2017)
Brain
MST for OSA dog with LN mets? (Hillers 2005)
59d
Five factors for OSA grading? (Kirpensteijn 2002)
pleomorphism, mitoses (<10, 10-20, >21), tumor matrix, tumor cells, necrosis
What dog was over-represented in Amsellem’s small breed OSA study?
Miniature schnauzer
What information did pretreatment, platelet-corrected VEGF provide for OSA? (Thamm 2008)
serum VEGF levels correlated significantly with survival
- VEGF above median (upper 50%) = DFI 145 days
- VEGF below median (lower 50%) = DFI 356 days
Dogs with a higher percentage of CD204+ macrophages experienced significantly longer or shorter DFI? (Withers 2019, ePub 2018)
Longer
They also noted that there were fewer CD204+ macrophages in proximal humerus OSA
_____ decreases CXRC4 expression in canine osteosarcoma by 27.7% in cells and 40% in OSA primary tumor. (Byrum JVIM 2016)
zoledronate
CXCR4 - has been explored as a target for metastases in solid tumors (cell migration and homing); zoledronate reduced expression via proteasome degradation and decreased prenylation
What was unusual about the metastatic pattern in dogs treated with zoledronate? (Byrum JVIM 2016)
Metastases found in unusual locations like LN, nervous, and cutaneous tissues; disproportionate number of cases also had visceral involvement.
Importance: Zoledronate can alter CXCR4 expression and functionality in OS cells, and consequent perturbations in CXCR4 intracellular signaling cascades might influence patterns of metastases.
What was the dose limiting structure for SBRT for vertebral OSA? (Swift 2017)
spinal cord
most patients died before late effects
In paper evaluating cortical allograft vs. endoprosthesis for limb-spare, what improved outcome? (Liptak 2006)
Infection - 685d (23 months) vs. 289d (9.6 months)
Infection rate was 55-60%
What were the main findings with using PET CT to identify metastatic lesions and treating with SBRT? (Selmic 2017)
PET-CT facilitated finding metastases, SBRT improved neurologic signs
What was found regarding EGFR and OSA? (Selvarajah 2012)
75% of primary tumors and lung mets stained for EGFR
- higher than normal bone and estrapulmonary metastatic sites
How does EGFR correlate with prognosis in OSA?
Worse prognosis
What does erlotinib inhibit? What was the impact on OSA cells? (Mantovani BMC Vet Res 2016)
EGFR
activity as a single agent against cells and may enhance radiosensitization
What % of OSA cell line and OSA tissue samples showed HER2 overexpression? (Flint 2004)
86% - cell lines
40% - tissue samples
What was the rate of pathologic fracture in dogs with appendicular primary bone neoplasia treated with medical management only? (Rubin 2015)
38%
identified at necropsy
Which is FALSE regarding monocyte phenotype and function in canine osteosarcoma?
a. CCR2 and CXCR2 are significantly downregulated in dogs with OSA.
b. PGE2 and TNFa are significantly decreased in dogs with OSA.
c. Peripheral blood monocytes exhibit significantly decreased chemotaxis in dogs with OSA.
d. CD14 expression is high and CD16 expression is low on the monocytes of dogs with OSA that have a relative monocytosis.
b. PGE2 and TNFa are significant decreased in dogs with OSA
Tuohy 2016 - PGE2 and TNFa are higher in OSA dogs
Fan 2008 - majority of primary tumor expressed CXCR2 but minority of metastasis express CXCR2
