Veterinarians have recently noticed an increase in sarcomas appearing
in cats at body sites commonly used for vaccine administration. The
Vaccine-Associated Feline Sarcoma Task Force (VAFSTF) has been formed
to address this emerging feline health issue (see the Journal of the
American Veterinary Medical Association, Vol. 210, No. 3, pp. 310-311).

The task force met in November to review research proposals and
designate the recipients of support. Available financial resources permitted the
funding of four projects for the upcoming year; other studies were
approved but are awaiting additional funds. Parties interested in
supporting studies to examine the epidemiology, etiology, and treatment
of these rare but aggressive tumors should contact Dr. Robin Starr,
VAFSTF Chairperson, American Animal Hospital Association, PO Box
150899, Denver, CO, 80215.

The VAFSTF would like to thank the following donors for their generous
support of this year's studies:

American Animal Hospital Association Foundation - $50,000
Fort Dodge Animal Health - $25,000
American Association of Feline Practitioners - $25,000
Cornell Feline Health Center - $10,000
Veterinary Cancer Society - $5,000
Synbiotics Corporation - $2,500
Intervet Inc. - $10,000 pledged

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 regarding the association between the
administration of some vaccines and the development of soft-tissue sarcomas in cats.
The investigators will compare cats with sarcomas diagnosed at vaccine
sites with cats having a histologic diagnosis of basal cell tumor.
This prospective case-control study will examine the relationship between
putative risk factors and the conditional probability of development of
vaccine-associated feline sarcomas (VAFS), thus seeking to measure
relative risk and incidence. This multicenter study will involve six
major collaborating centers in the United States and Canada, and will
be the most exhaustive vaccine-associated sarcoma study ever undertaken.

Some questions to be addressed include:

1. Is the risk associated with the use of non-adjuvanted
vaccines equivalent to that of adjuvanted vaccines?
2. Is the risk associated with the use of attenuated vaccines
equivalent to that of inactivated vaccines?
3. Within antigen classes, is there homogeneity of risk?
4. Do other factors, for example, injections administered at the
same location over the cat's lifetime, re-use of syringes, or mixing of
vaccines in the same syringe have any effect on sarcoma incidence?

Principle investigator: P. H. Kass, DVM, PhD
Co-investigators: M. J. Hendrick, VMD; S. Lester, DVM, MVSc; D. G.
Esplin, DVM, PhD; L. D. McGill, DVM, PhD; M. Slater, DVM, PhD; W. L. Spangler, DVM, PhD.


Molecular Biomarkers of Vaccine-Associated Feline Sarcomas.

One of the features of vaccine-associated feline
sarcomas is either the presence or the subsequent development of
multiple synchronous tumors at the vaccination site or at the margins of
previous excisions. The specific reasons for regrowth of tumors at the
vaccination site are unknown. It is possible that the multiple tumors
represent field cancerization at the vaccination site. During field
cancerization, distinct genetic alterations occur in numerous cells
throughout the exposed area or "field" (in this case, the vaccination
site). Some of these cells undergo clonal expansion and the tissue
becomes predisposed to growth of multiple primary tumors and
premalignant lesions. The importance of determining the occurrence of field
cancerization lies in the fact that the risk of developing cancer in
the affected area remains high for several years, requiring extended
follow-up and repeated surgical intervention. The prognosis for such
patients is often poor. Therefore, it is important to develop molecular
biomarkers for defining disease-free margins and predicting clinical outcomes.

The study is designed to achieve the following objectives:

1. Establish a comprehensive tissue bank and database at the
University of Minnesota for future VAFS-related molecular and molecular
epidemiologic analyses. The tissue bank will not only include primary
sarcomas, subsequent tumors collected on follow-up, and metastases (if
any), but also blood samples, and biopsies of the histologically normal
margins taken at specified distances and orientations from the tumors.

2. Investigate if patients with VAFS harbor alterations in two
potential molecular biomarkers: the p53 tumor suppressor gene and the c-myc
proto-oncogene. These genes are known to play 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 VAFS.

3. Test the hypothesis of field cancerization in VAFS. 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 field cancerization.

4. Categorize the types of p53 mutations detected in VAFS for
preliminary indications of "signature" mutations. Such mutations are likely to
provide important clues on disease etiology.

5. Record clinical outcome and initiate studies on the
prognostic significance 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 in providing guidelines for reliable identification of
disease-free margins.

Principal investigator: S. Kanjilal, PhD.
Co-investigators: J. S. Klausner, DVM, DACVIM; V. Kapur, BVSc, MSc, PhD;
C. Khanna, DVM, PhD, DACVIM; C. Wood, DVM.


Growth Factor Expression and Vaccine-Associated Sarcoma Tumorgenicity.

The molecular events leading to the development of vaccine-associated feline sarcomas is
unknown. However, there is accumulating evidence that the activation of genetically-altered
growth factor signaling pathways contributes to the development and progression
of many forms of cancer. The major goal of this study is to provide
direct evidence that autocrine/paracrine growth factors and their
receptors regulate or influence neoplastically-transformed mesenchymal
cells and play an important role in the formation of vaccine-associated
feline sarcomas. Overexpression of growth factor receptors in cancer
cells may provide an important target for therapeutic intervention; it is
hoped that the results of this study will guide in the designing of effective therapeutic strategies.

This study will pursue the following specific aims:

1. Develop new feline sarcoma cell lines from cats with VAFS and
those from non-vaccine sites such as the oral cavity or distal 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) significance of
IGF-1, HGF, and PDGF on sarcoma cells growing in tissue culture.

5. Determine the tumorigenic and metastatic potential of feline
sarcomas cells.

Principal investigator: E. G. MacEwen, VMD.
Co-investigator: R. Radinsky, PhD.

Comparable Efficacy of Doxorubicin Versus Stealth Liposomal
Doxorubicin in Cats with Vaccine-Associated Sarcomas:
A Multicenter Randomized Clinical Trial
Vaccine-associated feline sarcomas

(VAFS) are associated with unacceptably high recurrence rates following
surgical excision and relatively low response rates to standard
chemotherapeutic approaches instituted in either an adjuvant or primary
setting. While radiation therapy may be a viable option for VAFS,
availability makes this modality unrealistic for a significant proportion
of patients. Several institutions are presently recommending
doxorubicin adjuvant or primary chemotherapy for the management of these tumors.
However, only anecdotal evidence exists regarding efficacy of this approach.
The dose limiting toxicities of doxorubicin includes myelosuppression,
cardiotoxicity, and in the feline species in particular, anorexia.
Recently, various liposome formulations have been utilized as
doxorubicin drug carrier systems to reduce toxicity. A commercially available
doxorubicin-entrapped stealth liposome formulation (Doxilr, Sequus
Pharmaceuticals Inc., Menlo Park, CA) has proven to be effective in
enhancing tumoricidal effects when compared to free doxorubicin in a
variety of tumor models, and to decrease systemic toxicity. A dose
escalation trial is currently underway to determine the maximally
tolerated dose of Doxil in cats. Preliminary results suggest that cats
can safely receive at least 40% more doxorubicin when it is delivered
in this encapsulated form; even higher dosage rates may be possible. In a
phase I clinical trial, a 36% response rate (partial or complete) to
Doxil has been observed in cats with advanced, unresectable VAFS.
Fifty-six percent of these responding cats have achieved at least a 50%
reduction in tumor volume.

The purpose of this study is to prospectively evaluate, in the context
of a randomized multicenter clinical trial, the comparable efficacy of
doxorubicin versus stealth liposomal doxorubicin in cats with VAFS in
two settings:

1. Adjuvant therapy in cats with microscopic disease subsequent
to cytoreductive surgery.

2. Primary therapy in cats with measurable macroscopic disease.

Principal investigator: D. M. Vail, DVM, MS, DACVIM
Co-investigators: P. A. Ciekot; R. Chun; J. E. Obradovich; M. O'Brien;
R. M. Fred III; K. A. Jeglum.

Dr. James R. Richards
Education/Communication Subgroup Chair, VAFSTF
Director, Cornell Feline Health Center
Cornell University College of Veterinary Medicine
Ithaca, New York 14853

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