"Epidemiologic study of Vaccine Specific Risk and Vaccination Protocols in the Incidence of Vaccine Associated Sarcomas in Cats."
This study focuses on some of the remaining controversial and unsolved issues arising from the association between administration of some vaccines and development of soft tissue sarcomas in cats. Six major collaborating centers in the United States and Canada will be involved in this, the most exhaustive vaccine associated sarcoma study ever undertaken. The investigators will compare cats that have sarcomas diagnosed at vaccine sites with cats in which basal cell tumor has been diagnosed histologically. This prospective case control study will examine the relationship between putative risk factors and the conditional probability of developing vaccine associated feline sarcomas, to measure relative risk and incidence.

The principal investigator is P. H. Kass, DVM, PhD, University of California Davis. Co investigators are M. J. Hendrick VMD, S. Lester, DVM, MVSc, D. G. Esplin,DVM, PhD, L. D. McGill DVM, PhD, M. Slater, DVM, PhD, and W. L. Spangler, DVM, PhD.

"Molecular Biomarkers of Vaccine Associated Feline Sarcomas."
This study is designed to achieve the following objectives:

1. Establish a comprehensive tissue bank and database at the University of Minnesota for future vaccine associated feline sarcomas related molecular and molecular epidemiologic analyses. The tissue bank will include not only primary sarcomas, subsequent tumors collected on follow up, and metastases, but also blood samples and biopsy specimens of the histologically normal margins at specified distances and orientations from the tumors.
2. Investigate whether patients with vaccine associated feline sarcomas harbor alterations in two potential molecular biomarkers: the p53 tumor suppressor gene and the c myc proto oncogene. These genes are known to serve important roles in the pathogenesis of soft tissue sarcomas in humans. Moreover, results of preliminary studies indicate a loss of heterozygosity at the p53 locus in vaccine associated feline sarcomas.
3. Test the hypothesis of multiple genetic alterations in vaccine associated feline sarcomas. All cases will be followed up for subsequent tumor growth in the region of the primary tumor. The presence of a p53 mutation in the primary tumor that is distinct from any p53 mutations detected in subsequent tumors will be considered as molecular evidence of multiple genetic alterations.
4. Categorize the types of p53 mutations detected in vaccine associated feline sarcomas for preliminary indications of "signature" mutations, which are likely to provide important clues on disease etiology.
5. Record clinical outcome and initiate studies on the prognostic importance of general or specific alterations in p53 and c myc from tumor and histologically normal tissues. Maps of the site of tumor development indicating locations of genetic alterations and subsequent tumors may help provide guidelines for reliable identification of disease free margins.

The principal investigator is S. Kanjilal, PhD (Biochem), PhD (Mol. Cell Biol.), University of Minnesota. Co investigators are J. S. Klausner, DVM, DACVIM, V. Kapur, BVSc, MSc, PhD, C. Khanna, DVM, PhD, DACVIM, and C. Wood, DVM.

"Molecular Biomarkers of Vaccine-Associated Feline Sarcoma: p53 Mutations and Drug Sensitivity."
During the first year of this study, alteration of the p53 tumor suppressor gene was identified as a major genetic event in the development of vaccine associated feline sarcoma (VAFS). During the next phase of the study the investigators will investigate the clinical relevance of p53 alterations in VAFS with particular emphasis on finding an explanation for the recurrent nature of the disease and studying the effect of p53 mutations on the response (in vitro) to therapeutic agents.

The principal investigator is S. Kanjilal, PhD (Biochem), PhD (Mol. Cell Biol.), University of Minnesota. Co investigators are J. S. Klausner, DVM, DACVIM, V. Kapur, BVSc, MSc, PhD, C. Khanna, DVM, PhD, DACVIM, and C. Wood, DVM.

"Molecular Biomarkers of Vaccine-Associated Feline Sarcoma: Characterization of a Genetic Predisposition."
The investigators are studying key molecular changes that occur during the development of vaccine-associated feline sarcomas, with the ultimate goal of improving strategies for disease prevention and management. Initial results indicate that there may be a heritable genetic component that makes some cats more prone to tumor development. In the next phase of study, the researchers will analyze specific breeds of cats in the US that may have this predisposition. The results of this investigation will hopefully enable informed decisions to be made regarding the breeding and care of cats with the susceptibility to developing vaccine-associated sarcomas.

The principal investigator is S. Kanjilal, PhD (Biochem), PhD (Mol. Cell Biol.), University of Minnesota. Co investigators are J. S. Klausner, DVM, DACVIM, V. Kapur, BVSc, MSc, PhD, C. Khanna, DVM, PhD, DACVIM, and C. Wood, DVM.

"Molecular Biomarkers of Vaccine-Associated Feline Sarcoma: Alterations in Gene Expression during Tumor Development."
The investigators are studying key molecular changes that occur during the development of vaccine-associated feline sarcomas, with the ultimate goal of improving strategies for disease prevention and management. Initial results indicate that there may be a heritable genetic component that makes some cats more prone to tumor development. In the next phase of study, the researchers analyzed specific breeds of cats in the US that may have this predisposition. The results of this investigation will hopefully enable informed decisions to be made regarding the breeding and care of cats with the susceptibility to developing vaccine-associated sarcomas. In this study, the researchers will investigate the entire set of genes that are differentially expressed during tumor development. A comprehensive understanding of these molecular changes will enhance the ability to prevent and treat the disease.

The principal investigator is S. Kanjilal, PhD (Biochem), PhD (Mol. Cell Biol.), University of Minnesota. Co investigators are J. S. Klausner, DVM, DACVIM, V. Kapur, BVSc, MSc, PhD

"Molecular Analysis of Platelet Derived Growth Factor (PDGF) and the Cellular Protooncogenes sis, fms, and jun in Feline Vaccine-Associated Sarcomas, and Evaluation of the Role of Local Lymphocytes in Tumorigenesis."
One theory of tumorigenesis is that neoplasia may occur when there is uncontrolled stimulation of altered receptors by growth factors that are overproduced by the cells bearing the receptors (autocrine stimulation). The investigators laboratory has, by immunohistochemistry, identified and localized growth factors [(PDGF), transforming growth factor- (TGF-), and epidermal growth factor (EGF)], their receptors (PDGFr and EGFr), and one protooncogene (c-jun/AP-1) in the cells of: normal feline skin/panniculus, wounded skin/panniculus, postvaccinal panniculitis, postvaccinal panniculitis with early malignant transformation, vaccine-associated (VA) sarcomas, and unrelated sarcomas and epithelial tumors. There was consistent strong staining of the VA sarcomas for PDGF and its receptor, EGF and its receptor, TGF-, and c-jun (AP-1), while staining of non-VA sarcomas was nonexistent or weak. There was also evidence that the lymphocytes that commonly surround VA sarcomas may play a role in the neoplastic transformation of local fibroblasts via overstimulation by secreted growth factors.

The principal investigator is Mattie J. Hendrick, VMD, University of Pennsylvania. Co- investigators are Andrei T. Tikhonenko, PhD, and Christopher A. Hunter, PhD.

"Papillomavirus, Herpesvirus, and Polyomavirus: Exploring the Etiology of Vaccine-Associated Feline Sarcomas."
This project involves investigating possible viral causes of vaccine associated feline sarcomas. Immunohistochemistry and PCR are being used to detect papillomavirus, herpes-virus, and polyomavirus in the vaccine-associated tumors. These three viruses have been linked with various tumors in cats or other species, including humans.

The principal investigator is M. L. Jackson, DVM, MVetSc, PhD, University of Saskatchewan. Co-investigators are B. Kidney, DVM, MVetSc, D. Haines, DVM, MPhil, PhD, J. Ellis, DVM, PhD.

"Evaluation of Mutagenicity of Feline Vaccines (excluding Rabies) Using the A_L Assay."
Vaccination of cats is associated with the development of aggressive cancers that respond poorly to treatment. Little is known about why these tumors develop. The investigators believe the vaccines cause mutations to normal feline cells, leading to tumors. This research uses an assay to evaluate whether the vaccines cause mutations in cells. This research could lead to selection of vaccines that are not likely to cause tumors, preventing vaccine-associated sarcomas from developing.

The principal investigator is S. M. LaRue, DVM, PhD, Colorado State University. Co-investigator is E. A. McNiel, DVM, MS.

"Evaluation of Mutagenicity of Feline Vaccines using A_L Assay: Year 2."
Little is known about the etiopathogenesis of vaccine-associated sarcomas, but the probability of tumor development seems higher when adjuvanted vaccines have been administered. The investigators hypothesize that adjuvanted vaccines currently in use are inherently mutagenic to mammalian cells as a result of oxidative damage to DNA. In the first year of their research, the investigators used an in vitro assay, called the A_L assay, to evaluate the toxicity and mutagenicity of some commonly used feline vaccines. Because adjuvanted vaccines were found to be more toxic and mutagenic than non-adjuvanted vaccines, the researchers plan to continue this line of investigation. They also hypothesize that cats that develop vaccine-associated sarcomas are more susceptible to oxidative damage than are other cats. This hypothesis will be investigated by comparing the anti-oxidant capacity of affected cats with that of unaffected cats.

The principal investigator is S. M. LaRue, DVM, PhD, Colorado State University. Co-investigator is E. A. McNiel, DVM, MS

"Evaluation of Mutagenicity of Feline Vaccines using A_L Assay: Year 3."
In the first year of their research, the investigators used an in vitro assay, called the A_L assay, to evaluate the toxicity and mutagenicity of some commonly used feline vaccines. Because adjuvanted vaccines were found to be more toxic and mutagenic than non-adjuvanted vaccines, the researchers continued this line of investigation into a second and third year. They also hypothesize that cats that develop vaccine-associated sarcomas are more susceptible to oxidative damage than are other cats. This hypothesis will be investigated by comparing the anti-oxidant capacity of affected cats with that of unaffected cats.

The principal investigator is E. A. McNiel, DVM, PhD, Colorado State University. Co-investigator is S. M. LaRue, DVM, PhD.

"Growth Factor Expression and Vaccine Associated Sarcoma Tumorigenicity"
This study will pursue the following specific aims:

1. Develop new feline sarcoma cell lines from cats with vaccine associated feline sarcomas and cats with sarcomas in sites unrelated to vaccine administration, such as the oral cavity or distal portions of the extremities.
2. Determine the gene expression of insulin like growth factor 1 (IGF 1), hepatocyte growth factor (HGF), and platelet derived growth factor (PDGF) in tumor tissue or cells grown in culture, and adjacent, non neoplastic tissue from cats with sarcomas.
3. Determine the level of gene expression of IGF 1 receptor, HGF receptor, and PDGF receptor on tumor cells.
4. Determine the functional (growth and invasion) importance of IGF 1, HGF, and PDGF on sarcoma cells growing in tissue culture.
5. Determine the tumorigenic and metastatic potential of feline sarcoma cells.

The principal investigator is E. G. MacEwen, VMD, University of Wisconsin Madison. Co investigator is R. Radinsky, PhD.

"Selective Inhibition of Platelet-Derived Growth Factor Receptor (PDGFR) Activity."
Research conducted in the investigators' laboratory has shown that vaccine-associated feline sarcomas express high levels of a growth factor receptor for platelet-derived growth factor (PDGF). The investigators have found that this growth factor stimulates cells to grow in tissue culture, indicating that it may be one of the dominant factors associated with this cancer. They plan to test a drug to inhibit activity of the PDGF receptor and determine if blocking the receptor inhibits tumor growth. In addition, they will express a mutant receptor in feline cancer cells and determine if this will help inhibit activation of the normal PDGF receptor. The results of this study will help determine if the PDGF receptor contributes to the growth and progression of this aggressive cancer.

The principal investigator is E. Gregory MacEwen, VMD, University of Wisconsin-Madison. Co-investigators are J. Carew, BS, and R. Radinsky, PhD. Upon the death of Dr. MacEwen, D. Vail, DVM, became the principal investigator.

"Defining the Role of the Oxidative DNA Lesion, 8-hydroxyguanine, in Vaccine-Associated Feline Sarcoma."
A basic principle of cancer is that it cannot occur without some interaction with the genetic material of the body DNA. The purpose of this project is to uncover the initial step in the causation of aggressive soft tissue cancers in cats that may be associated with routine administration of vaccines. Since vaccines often cause an inflammatory reaction at the site of injection, highly reactive oxygen-derived free radicals are generated locally that may in some way alter the DNA of certain cells. The investigators will vaccinate a group of cats with commercially available vaccines at three different sites, then determine the concentration of a DNA alteration known as 8-hydroxyguanine that develops at these sites. They will also study this alteration in client-owned cats that develop inflammatory reactions approximately 3 weeks after vaccination. It is hoped that this work will lead to the development of a test to help determine which vaccine components may be causing vaccine-associated sarcomas. Re-formulation of vaccines may then prevent development of these cancers.

The principal investigator is J. McHugh Law, DVM, PhD, DACVP, North Carolina State University. Co-investigators are M. Hauck and S. Price.

"Lymphoid Aggregates in Feline Vaccine-Associated Sarcoma."
The purpose of this research is to better understand what role, if any, the feline immune response has in vaccine associated sarcoma development. Surface proteins (phenotypic markers) and chemical messengers (cytokines) produced by cells of the immune system at tumor sites will be measured and compared with surface markers and quantities of cytokines detected at normal vaccine sites and at inflammatory sites induced by a foreign body. The effect of the combination of cytokines from each of these sites on normal feline fibroblasts in culture will be observed. Results of this study should provide information on how the cellular and cell factors in the tumor environment differs from the environment at normal vaccine sites thus providing information on which factors contribute to the growth and/or maintenance of tumor cells in affected cats.

The principal investigator is R. D. Schultz, Ph.D. Co-principal investigator is E. E. Carroll, DVM, PhD.

"Comparable Efficacy of Doxorubicin Versus Stealth Liposomal Doxorubicin in Cats with Vaccine Associated Sarcomas: a Multicenter Randomized Clinical Trial."
Cats with vaccine associated sarcomas experience unacceptably high recurrence rates following surgical excision and low response rates to standard chemotherapeutic approaches instituted in an adjuvant or primary setting. Although radiation therapy may be a viable option for vaccine associated feline sarcomas, availability makes this modality unrealistic for many patients. Several institutions recommend doxorubicin adjuvant or primary chemotherapy for the management of these tumors. However, only anecdotal evidence exists regarding efficacy of this approach.

The dose limiting adverse reactions of doxorubicin include myelosuppression, cardiotoxicity, and, in the feline species in particular, anorexia. Recently, various liposome formulations have been used as doxorubicin carrier systems to reduce toxicity. A commercially available doxorubicin entrapped stealth liposome formulation (Doxil, Sequus Pharmaceuticals Inc, Menlo Park, California) has proven to be effective in enhancing tumoricidal effects, compared with free doxorubicin in a various tumor models, and to decrease systemic toxicosis. A dose escalation trial is under way to determine the maximally tolerated dose of Doxil in cats. Preliminary results suggest that cats can safely receive at least 40 percent more doxorubicin when it is delivered in this encapsulated form. In a phase I clinical trial, a 36 percent response rate (partial or complete) to Doxil has been observed in cats with advanced, unresectable vaccine associated feline sarcomas. Fifty six percent of these responding cats have experienced a reduction of at least 50 percent in tumor volume.

The purpose of this study is to evaluate the comparable efficacy of doxorubicin versus stealth liposomal doxorubicin in cats with VAFS.

The principal investigator is D. M. Vail, DVM, University of Wisconsin Madison. Co investigators are P. A. Ciekot, R. Chun, J. E. Obradovich, M. O'Brien, R. M. Fred III, and K. A. Jeglum.

"Comparison of Tumor Response to Radiation Therapy Alone with Radiotherapy Plus an Adjuvant Hemoglobin-Based Oxygen Carrier Radiotherapy Sensitizer, and Follow-up Assessment after Surgery and Chemotherapy."
Although some data suggests that vaccine associated sarcomas respond poorly to surgical excision, radio- and chemotherapy, this has not been prospectively studied. Efficacy of radiation therapy may be limited by tumor hypoxia that has been attributed to reduced tumor diffusion, decreased tumor perfusion, or increased tumor oxygen consumption. However, when tumor oxygen content is increased, enhancement of cell kill after radiotherapy occurs. Thus, a novel and promising approach to improve treatment efficacy would include concomitant administration of an oxygen-carrying agent to act as a sensitizer of radiotherapy.

The principal investigator is Ann E. Hohenhaus, DVM, DACVIM, The Bobst Hospital and Caspary Research Institute of the Animal Medical Center, New York, New York.

"The Utility of Contrast-Enhanced Computed Tomography in the Evaluation and Treatment of Cats with Vaccine-Associated Fibrosarcoma."
The purpose of this study is to determine the utility of performing CT scans in the evaluation of cats with vaccine associated sarcomas. The CT findings will be evaluated in conjunction with the biopsy results to:

1. Further characterize feline sarcomas
2. Identify potential prognostic factors
3. Guide treatment decisions

The majority of cats with vaccine-associated sarcomas are currently undergoing at least one surgery prior to referral for radiation therapy. By further defining the role of tumor staging prior to the initial definitive surgery, it may be possible to improve local control and prolong overall survival in cats with vaccine associated sarcomas.

The principal investigator is M. C. McEntee, DVM, DACVIM, DAVR, University of California at Davis. Co-investigator is V. F. Samii, DVM, DACVR.

"Towards a Novel Therapy of Vaccine-Associated Feline Sarcomas: Reoviral Oncolysis."
Vaccine associated feline sarcomas (VAFS), like many other tumors, are likely to have activated oncogenes. Expression or activation of one such oncogene called Ras may make them susceptible to killing by an otherwise innocuous virus called a reovirus. The purpose of this study is to determine if VAFSs have activated Ras, which may make them candidates for novel therapy using reovirus.

The principal investigator is J. A. Ellis, DVM, PhD. Co-investigators are B. Kidney, DVM, MVSc, D. Haines, DVM, MPhil, PhD, M. Jackson, DVM, MVSc, PhD.

"Phase II Evaluation of Ifsofamide in Cats with Spontaneously-Occurring Soft Tissue Sarcoma."
Complete surgical removal of sarcomas is extremely difficult since they are poorly defined and spread easily. Even in combination with radiation, the cure rate is low. Ifosfamide is one of the few chemotherapy agents that have proven effective against sarcomas in humans. The investigators will evaluate ifsofamide in cats to determine the activity against feline sarcomas. If successful, this chemotherapy agent could make a major advance in the treatment of sarcomas in cats.

The principal investigator is K. Rassnick, DVM, DACVIM, Cornell University. Co-investigators are R. L. Page and M. C. McEntee DVM, DACVIM, DAVR.

"Molecular Fingerprinting of Vaccine Associated Feline Sarcoma Evolution."
The aim of this project is to identify genetic loci and/or genes altered during the process of tumor development following vaccination in cats. The genetic map thus generated can help in identifying molecular markers useful in diagnosis and prognosis. Furthermore, the molecular markers elucidated may provide targets for effective treatment by chemo- and bio-therapeutic approaches with antidotes, or by gene therapy.

The principal investigator is V. S. Venkatraj, B.V. Sc., Ph.D., FACMG. Co-investigators are K. Rogers, B. Weeks, E. Collisson, J. Womack, M. Hanneman, and M. Longnecker.

"Investigation into the Use of Telomerase as a Therapeutic Target in Feline Vaccine-Associated Sarcoma."
The aims of the project are to study telomerase inhibition using the technique of RNA interference and to develop delivery systems for this approach which can be applied clinically and to study targeting of a radiosensitizing gene to vaccine-associated sarcomas based on telomerase expression.

Principal investigator is D. J. Argyle, B.V.M.S., Ph.D., M.R.C.V.S. Co-investigator is M. Turek, D.A.C.V.I.M., D.A.C.V.R., D.V.M.

"Evaluation of the Duration and Diameter of Post-vaccinal Masses in Cats Receiving Rabies and Feline Leukemia Virus Vaccines: a Practitioner Based Study."
Granuloma formation following the administration of adjuvanted vaccines may be confused with tumors that develop at these injection sites. This study will evaluate the frequency, magnitude and duration of post-vaccinal granuloma (nodules) frequently produced by these adjuvanted vaccines. The injections sites following the administration of five adjuvanted feline vaccines - three rabies and two feline leukemia vaccines - will be evaluated for three months following their administration.

The principal investigator is D. W. Macy, D.V.M., M.S., D.A.C.V.I.M.. Co-investigator is J. C. Whittemore, D.V.M.

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