Vaccine Associated Sarcoma Flashcards
Lawrence et al. 2012. Masitinib demonstrates anti-proliferative and pro-apoptotic actvity in primary and metastatic feline injection-site sarcoma cells
Dyssregulation of PDGFR may play a role in feline ISS
Masitinib is selective for the PDGFR signaling pathway
Results?
Drug concentation needed?
Inhibited cell growth and PDGFR phophorylation in 2 cell lines
Needed to be higher to inhibit growth than to modulate ligand-induced autophosphorylating of PDGFR
Lawrence et al. 2013. Changes in g-H2AX expression in irradiated feline sarcoma cells: an indicator of ds-DNA breaks
Determine if radiation-induced damage to ISS cells could be detected using DNA DSB detection kit
Results with irradiated cells?
Irradiated cells showed increase in ds-DNA breaks compared to control cells
DNA dammage can be detected using mouse anti-human mAB for g-H2AX
Rousset et al. 2013. Clinical and low-field MRI characteristics of injection site sarcoma in 19 cats
19 cats
Tumors appearance on MRI?
Minieralization?
Tumor volume?
Contrast enhancement?
Difference between excisional and incisional biopsy?
Hyperintense on T1W and T2W
Larger tumors more likely to have mineralization
Could not predict tumors free margins at definitive surgery
Moderate to marked contrast enhancement
Infiltrative margins and presence of T2W hyperintense zone were more prevalent following excisional biopsy while cavitation more prevalent with incisional biopsy
Ladlow et al. 2013. Injection site-associated sarcoma in the cat: treatment recommendations and results to date
Metastatic lung involvement?
Recurrence?
Age?
25%
Even with clean margins tumor recurrence occurs in 1/3
Younger cats with peak presentation 6-7 years and second peak 10-11 years
Travetti et al. 2013. CT characteristics of FSA - a histological subtype of feline ISS
Location of FSA?
Contrast enhancement?
How should the cat be positioned if tumor is intrascapular?
Most were interscapular (45%)
Strong, ring (42%), heterogenerous (36%), homogeneous (9%)
Per posr-contrast scan - Forelimbs positioned caudally along the body in addition to standard protocol with the forelimbs extended cranially
Dean et al. 2013. The incidence of feline injection site sarcoma in the UK
America - 1 case per 1,000-10,000
Incidence risk per year?
1/16,000-50,000 cats registered by practices, 1/10,000-20,000 consultations and 1/5,000-12,500 vaccination visits
Incidence of FISS in UK is very low
Nolan et al. 2013. Stereotactic body RT for the treatment of ISS in cats: 11 cases
Toxicity?
Later radiation toxicity?
Objective RR?
Median PFI?
MST?
Infrequent and limited to mid self-limiting dermatitis and colitis in 2 and 1 of 11 cats
None
8 of 11 cats (73%) - PR or CR determined by CT or PE
242 days (8 mo)
301 days (10 mo)
Canwardine et al. 2014. UK owner preference for treatment of feline ISS
208 respondents
How many would pursue surgery? Would not?
Not allow amputations?
Would not pursue surgery for interscapular, chest, or abdomen?
39%, 1% would not
forelimbs (20%), hindlimb (15%), tail (15%)
26, 32, 27% would not have surgical tx of interscapular, chest, or abdomen
Willing to travel 100 miles for RT or chemo (66% and 69%)
Current recommendations may not be appropriate for UK owners
Cantatore et al. 2014. Factors influencing would healing complications after wide excision of injections site sarcomas of the trucks of cats
Analyze factors influencing development of wound healing complication (WHC) undergoing wide excision of ISS
Main factor associated with risk of total and major WHC?
What were the significant prognostic factors for major WHC?
What influenced duration of surgery?
Surgical time
Pattern of reconstruction, CT dimesions, clinical dimention, weight and BCS
Excision pattern and tumor CT dimentions
Turek et al. 2014. Masitinib mesylate does not enhance sensitivity to radiation on 3 feline ISS cell lines under normal growth conditions
Masitinib was investigated as radiosensitizer in 3 cell lines
What induced reduction of clonogenic survival?
Survival from combined masitnib and RT vs. RT alone?
Radiation administered alone or in combination with masitinib induced dose-dependent reduction in clonogenic survival
Survival from combined masitnib and RT was not significantly different from RT alone
Masitinib does not enhance radiosensitivity
Hill et al. 2014. In vitro efficacy of doxorubicin and etoposide against feline ISS cell line
Cell death by single agent or combinations?
Cell cycle difference after treatment?
Single agent and combination drug increased cell death significantly reduced the number of viable cells
Cells in G0/G1 were reduced and G2/M were increased after treatment
Combining doxorubicin and etoposide at the lower EC yielded comparable results to the EC50 of either drug alone in degree of cytoxocity, level of apoptosis, and % of cells in G2/M phase
Petznek et al. 2014. Murine xenograft model demonstrates significant radiosensitising effect of liposomal doxorubicin in a combination therapy for feline injection site sarcoma
Recurrence rate after surgery is 70%
Pretreatment with doxorubicin resulted in?
Results suggest?
Significant enhancement radiaition induced cell death - result was confirmed in in vivo
Results suggest use of cocomittant chemo-radiaiton therapy for adjuvant treatment of FISS
Wojcik et al. 2015. Enhancing anti-tumor efficacy of Doxorubicin by non-covalent conjugation to gold nanoparticles - in vitro studies of feline FSA cell lines
Colloid gold particle are promising to overcome multidrug resistance
What was observed with Au-GSH-Dox in 4 cell lines?
What was this correlated with?
Higher cytotoxic effect than that of free doxorubicin in 3 out of 4 cell lines
Correlated to the acitvity of glycoprotein P
Hartmann et al. 2015. Feline injection site sarcoma: ABCD guidelines on prevention and management
Metastatic rate?
What is a trigger for malignant transformation?
Injections of what drugs have been associated with sarcoma formation?
What is particularly linked to FISS?
Risk if lower with?
What kind of vaccines should be used?
10-28%
Chronic inflammatory reactions
Injections of long acting drugs (glucocorticoids)
Adjuvant vaccines that induce intense local inflammation
Modified live and recombinant vaccines
Non-adjuvanted, modified-live, recombinant vaccines
Nemanic et al. 2016. Microscopic evaluation of peritumoral lesions of feline ISS identified by MRI and CT
All cats received CT and MRI of FISS followed by wide surgical excision
A total of 87 prei-tumoral lesions were examined
How were the lesions categorized?
How many lesions were seen on both imaging modalities at same location?
Unique imaging characteristics were seen how frequently?
Neoplastic (20%), non-neoplastic (59%), equivoval (22%)
25 instances
5/17 (30%) neoplastic peritumoral lesions
Extensive overlap between imaging features of neoplastic and nonneoplastic lesions preclues definitive identification of neoplastic pretumoral FISS using CT or MRI
Bray et al. 2016. Neoadjuvant and adjuvant chemotherapy combined with anatomical resection of feline ISS: results in 21 cats
21 cats with primary or recurrent FISS received 3 cycles of neoadjuvant chemotherapy with epirubicin, then resection then another 3 cycles of chemotherapy
Median follow up time
How may developed local tumor recurrence?
MST?
1072 days (3 yr)
14% (3 cats) at 264, 664, and 1573 days after surgery
MST could not be calculated 80% were alive or were censored due to death from other causes
When compared to historical controls, superior rates of tumor free survival and DFI
Terry et al. 2016. Changes in the dimension and volume of feline injection-site sarcomas following formalin fixation as determined by use of the elllipsoid volume formula and 3D- CT softwares
Shrinkage of FISS following excision and formation fixation was small and may be less than that of grossly normal tissue
Tumor volume estimated by the ellipsoid formula was consistently less than that estimated by 3D-CT software and should not be used when accuracy of tumor volume is of concern
Porceletto et al. 2017. Feline Injection site sarcoma
Investigate IHC expression of MMP-2, MMP-9 (Gelatinases), and TIMP2 (inhibitor) as prognostic factors
Expression?
Difference b/w recurrent and non-recurrent group?
Useful as prognostic factors?
What could be evaluated as prognostic factors?
Variable expressed - factors play a role in tumor invasiveness
None
No
Size of tumor measure after formalin fixation with cutoff of 3.75 cm (accuracy 86%), mitotic count optimal cutoff 20/10 (accuracy 80%)
Terry et al. 2017. Quantification of surgical margin length changes after excision of feline injection site sarcomas - a pilot study
5 cats
When did the largest mean decrease occured in gross normal surgical margins (GNSM) occur?
Formaline fixation, trimming, and mounting on slide did it affect GNSM?
Mean histologic tumor free margin was decreased when?
Immediately after excision
No
In vivo GNSM and on slide GNSM
Significant decrease in surgical margin occur immediately after excision (prior to fixation).
Subgross evaluation of tumor free margins from on-slide GNSM to HTFM overstimates the actucal tumor free margins.
Ferrari et al. 2017. Clinical and CT tumor dimension assessments for planning wide excision of injection site sarcomas in cats: how strong is the agreement?
The discrepancy between clinical and CT measurement of dimension in resectable tumors has led to bias that affects surgical dose
53 cats
What did the CT measurements show compared to clinical dimensions? Increased with?
Tended to be larger than clinical dimensions and this increased with increasing tumor size
Pierro et al. 2017. Anti-proliferative effect of metformin on a feline injection site sarcoma cell line independent of Mtor inhibition
Metformin is oral hypoglycemic drug that inhibits cancer cell proliferation via upregulation of AMPK (AMP activated protein kinase) and possibly inhibition of mTOR
Feline ISS cell line were treated with metformin at varied concentrations
What was observed?
Mechanism of cell death?
Was there inhibition of mTOR?
Dose dependent decrease in cell viability
Apoptosis or necrosis
No inhibition of mTOR or phosphorylated mTOR
Metformin causes cell death by apoptosis or necrosis but does not appear to be mediated by mTOR inhibition
Maxwell et al. 2017. In vitro chemosensitivity of feline injection site-associated sarcoma cell lines to carboplatin
What was the effect of carboplatin on FISS cell viability?
Caused dose-dependent and time-dependent effects on cell viability
Local tumor control might be achived by implantation of Cl-CSH beads immediately following radical or marginal excision of the primary tumor or by implantation without tumor resection
Longo et al. 2017. Dynamic tomographic studies of interscapular feline ISS: essential or useless practice?
Tumor volume estimates were compared between the ellipsoid and the semi-automated segmentation methods - 2 observers
How may invaded the adjacent muscular structures from 84 cats? How many muscles infiltrated?
Between the extended and flexed position the average estimated number of infiltrated muscles, was there agreement?
How were the higher tumor volumes detected?
Tumors with small volumes showed?
59/84 (70%), 15 muscles
Yes, 1.9 (extended) and 1.84 (flexed) and 1.89 extended and 1.85 flexed
Ellipsoid method
Slightly decreased muscle infiltrastion
Marked difference in the recorded distance between the skeletal structures and the neoplasm in the 2 different positions were established
Muller et al. 2017. Curative intent radical en bloc resection using a minimum or a 3 cm margin in feline ISS: a retrospective analysis of 131 cases
Treated with 3 cm lateral margins (chest and abdominal wall) and 2 fascial planes (interscapular tumors)
Median DFI and ST?
Who was more likely to die?
RR and DFI for the different tumor locations?
Local tumor recurrence rate?
Who was more likely to get tumor recurrence?
Which tumor bed bodies were associated with lower RR?
21 and 24 months
Patients operated for recurrent tumors than de novo tumors
Comparable
38%
Recurrent tumors (RR 55.5% vs 33.3%)
Free to tumor cells were associated with lower RR compared to those with tumor cells (3.5% vs. 76%)
Holtermann et al. 2017. The tyrosine kinase inhibitor toceranib in feline injection site sarcoma: efficacy and side effects
18 cats with unresectable FISS were treated at 3.25 mg/kg EOD
Response?
No clinical response :(
Benton et al. 2017. Gold nanoparticles enahnce radiation sensitization and suppress colony formation ina feline injection site sarcoma cell line, in vitro
Assess effects of gold nanoparticles (AuNP) on ISS cytotoxicity and colony formation as standalone or combination with RT
What was the effect of AuNP of cell proliferation?
Viability and cell cycle of ISS?
Results when AuNP and RT were combined?
Significantly decreased cell proliferation
Not significantly altered
Decreased colony formation compared to RT alone
Carneiro et el. 2018. Feline injection site sarcoma: Immunohistochemical characteristics
Analyzed for vimentin, cytokeratin, desmin, S100, viral leukemia virus, COS-2, c-KIT
Desmin?
Vimentin?
S-100 protein?
c-KIT?
COX-2
FeLV viral particles?
81% negative
100% positive
95.2% positive
19% positive
- 9% positive
- 9% positive
Rossi et al. 2018. Comparison of definitive intent finely fractionated and palliative intent coarsely fractionated radiotherapy as adjuvent treatment of feline microscopic injection site sarcoma
Sx then treat with one of the RT protocol
59 cats: 38 finely fractionated protocol (48-52.8 Gy over 4 weeks) and 21 coarsely fractionated group (36 Gy over 3 weeks in 6 fractions)
PFI between the 2 groups?
Overall PFI?
When only first-occurence cases were included, median PFI?
In cats that underwent multiple surgeries, PFI?
Not different
2000 days
longer in finely fractionated compared with coarsely fractionated (1430 vs. 540 days)
No difference between protocol (233 vs. 395 days)
Cats with primarily occuring ISS benefit from finely fractionated RT
Graf et al. 2018. Feline injection site sarcomas: Data from Switzerland 2009-2014
Marked decrease in incidence of FSA and occured after non-adjuvanted FeLV virus was introduced
Alum adjuvanted vaccines are involved in genesis of FISS
Abdelmageed et al. 2018. Feline vaccine sarcomagenesis: Is there an inflammation independent role for aluminum?
Aluminum hydroxide preparation in CHO cells?
Which cells were sensitive?
Cytotoxic and mutagenis in CHO cells in vitro
Cells deficient in DNA ds breaks than ss break - Al is associated with ds breaks
Hsueh et al. 2019. Role of nuclear factor-kappa B in feline injection site sarcoma
Nuclear expression of NF-κB p65 was detected in ____% of FISS cases and not correlated with tumor grading, sex, and age.
The NF-κB inhibitor, DHMEQ, was able to prevent nuclear translocation of NF-κB p65, inhibit cell proliferation, migration, and colonization in dosage-dependent manners, and induce cell apoptosis in these primary FISS cells.
Conclusions: High expression rate of nuclear NF-κB p65 in FISS cases and dose-dependent inhibitory effects on the growth of FISS primary cells treated with NF-κB inhibitor suggested that NF-κB might be a potential molecular therapeutic target for FISS.
83.3%
Wei et al 2019. Elucidating the transcriptional program of feline injection-site sarcoma using a cross-species mRNA-sequencing approach
Background: Feline injection-site sarcoma (FISS), an aggressive iatrogenic subcutaneous malignancy, is challenging to manage clinically and little is known about the molecular basis of its pathogenesis. Tumor transcriptome profiling has proved valuable for gaining insights into the molecular basis of cancers and for identifying new therapeutic targets. Here, we report the first study of the FISS transcriptome and the first cross-species comparison of the FISS transcriptome with those of anatomically similar soft-tissue sarcomas in dogs and humans.
Methods: Using high-throughput short-read paired-end sequencing, we comparatively profiled FISS tumors vs. normal tissue samples as well as cultured FISS-derived cell lines vs. skin-derived fibroblasts. We analyzed the mRNA-seq data to compare cancer/normal gene expression level, identify biological processes and molecular pathways that are associated with the pathogenesis of FISS, and identify multimegabase genomic regions of potential somatic copy number alteration (SCNA) in FISS. We additionally conducted cross-species analyses to compare the transcriptome of FISS to those of soft-tissue sarcomas in dogs and humans, at the level of cancer/normal gene expression ratios.
Results: We found: (1) substantial differential expression biases in feline orthologs of human oncogenes and tumor suppressor genes suggesting conserved functions in FISS; (2) a genomic region with recurrent SCNA in human sarcomas that is syntenic to a feline genomic region of probable SCNA in FISS; and (3) significant overlap of the pattern of transcriptional alterations in FISS with the patterns of transcriptional alterations in soft-tissue sarcomas in humans and in dogs. We demonstrated that a protein, BarH-like homeobox 1 (BARX1), has increased expression in FISS cells at the protein level. We identified 11 drugs and four target proteins as potential new therapies for FISS, and validated that one of them (GSK-1059615) inhibits growth of FISS-derived cells in vitro.
Conclusions: (1) Window-based analysis of mRNA-seq data can uncover SCNAs. (2) The transcriptome of FISS-derived cells is highly consistent with that of FISS tumors. (3) FISS is highly similar to soft-tissue sarcomas in dogs and humans, at the level of gene expression. This work underscores the potential utility of comparative oncology in improving understanding and treatment of FISS.
Fleming et al. 2019. CT angiography and MRI imaging features do not predict the tumor type and grade of feline injection site sarcoma
Computed tomographic angiography (CTA) and magnetic resonance imaging (MRI) have been described as methods for preoperative surgical planning in cats with feline injection site sarcomas (FISS), however, few published studies have compared these modalities. The objective of this retrospective, secondary analysis study was to determine if imaging features of FISS on CTA and MRI are predictive of neoplastic peritumoral projections. Archived data from a previous prospective study were retrieved for 10 cats with FISS. All cats had been evaluated in a single anesthetic episode with MRI and dual phase CT (CTA) imaging followed by surgical removal. Histopathological grading and targeted histopathology of imaging-identified peritumoral projections were performed. Two observers evaluated the CTA and MRI studies for FISS shape, margination, size, enhancement pattern, postcontrast uniformity, pre- and postcontrast margination, the number of muscles involved, mass mineralization, and bone lysis. Metal was present in the imaging field of three of 10 cats, resulting in one nondiagnostic MRI.
Peritumoral projections were detected in all cats with both imaging modalities, and most were benign. At least one neoplastic peritumoral projection was detected in six cats using MRI, five cats using CTA, and three cats with both modalities. Higher grade FISS were larger than low grade using MRI, and FISS were larger using MRI. Other FISS imaging features using MRI and CTA were similar. Findings supported use of either MRI or CTA for detecting neoplastic peritumoral projections in cats with FISS. Authors recommend CTA for cats with known metallic objects in the scan field.
