Research of Canine Osteosarcoma & IBD Advance Treatment Options

While there is no cure for canine osteosarcoma or inflammatory bowel disease (IBD), researchers are focusing on promising new treatments. Recent advancements in treating osteosarcoma may spare limbs and extend life for dogs affected by this painful cancer. Likewise, genetic discovery of polymorphisms causing IBD in German Shepherd Dogs may lead to new treatments. Here are snapshots of the research.

Killing Cancer Cells

Osteosarcoma is a fast-spreading, painful cancer that affects about 9 percent of giant breeds and 1 percent of large breeds. Owners and veterinarians work together to provide the best treatment possible using surgery, chemotherapy, radiation therapy and medications for palliative care. Usually, amputation of the affected limb followed by chemotherapy is recommended to increase survival, but owners of giant breeds often are reluctant to amputate, particularly a forelimb, because it can make walking difficult and may compromise quality of life.

While the conventional therapies for treating osteosarcoma aim to increase survival, research veterinarians are investigating promising new treatments. These include a recombinant bacteria vaccine and a powerful limb-sparing stereotactic radiosurgery that kills tumor cells and spares healthy tissue.

Osteosarcoma mostly occurs in dogs over the age of 8, long after they have been bred, but dogs as young as 1 or 2 years old can develop the cancer. Since osteosarcoma generally occurs in the leg bones, lameness and difficulty going up and down stairs are the most common signs that owners notice.

The cancer arises from mutated cells that stop bone-matrix remodeling and the production of bone cells. A definitive diagnosis is made from a bone biopsy, but characteristic lesions on radiographs are a strong indicator of osteosarcoma. Tumors are depicted in radiography as a starburst pattern of needle-like fragments of bone. In 90 to 95 percent of dogs, osteosarcomas have micrometastasized at the time of diagnosis. Micrometatasis is not clinically evident on radiographs but will eventually lead to large meta­static tumors usually in the lungs or other bones.

Treatment of osteosarcoma is challenging partly because the cancer is likely to metastasize, or spread, especially to the lungs. Metastasis in the lungs usually is the ultimate cause of death for dogs with bone cancer.

It is not known definitely whether osteosarcoma is an inherited condition in dogs. Nicola Mason, B.Vet.Med., Ph.D., DACVIM, the Pamela Cole Chair in Companion Animal Medicine at the University of Pennsylvania School of Veterinary Medicine, says, "Large and giant breeds may be predisposed to osteosarcoma because of genetic influences, but other factors may also be involved. Rapidly proliferating cells tend to be more susceptible to cancer-forming events, therefore dogs whose bones grow rapidly, such as large and giant breeds, or dogs that experience bone trauma and damage that requires cellular proliferation for repair may be at higher risk for developing osteosarcoma.

"Chronic inflammation is known to be associated with the development of other cancers, although it is unknown whether persistent bone inflammation predisposes to bone cancer. Most likely the cause of osteosarcoma, like other tumors, is multifactorial, involving both genetic and as-yet unknown environmental factors that together can create the perfect situation for bone cancer to develop."

Alternative approaches to treating osteosarcoma are being investigated. Sarah Charney, D.V.M., DACVIM, DACVR, adjunct professor of radiation oncology at the University of Illinois College of Veterinary Medicine and staff radiation oncologist at Animal Specialty Center in Yonkers, N.Y., is part of a team that has pioneered a limb-sparing CyberKnife® radiosurgery technique for dogs where amputation is not possible or desired. Combined with chemotherapy, this radiosurgery, also known as stereotactic surgery, has a survival time that is similar to the standard of care with amputation and chemotherapy for good candidates. Unfortunately, not all dogs are good candidates. The viability of radiosurgery is best assessed by a CT (computed tomography) scan. The benefit of radiosurgery is that it saves the limb.

"With this procedure, a radiation oncologist uses a high-tech, image-guided and computerized robotic control system to deliver radiation with submillimeter accuracy," Charney explains. "The CyberKnife radiation beams are sculpted to conform tightly to complex masses and deliver multiple radiation beams from many points outside the dog's body to the targeted tumor. The beams kill tumor cells yet spare healthy tissue. When the beams converge on the tumor mass, they deliver high-energy, pinpointed radiation with astounding power."

Compared to conventional radiation therapy, the precision of CyberKnife radiosurgery allows higher doses of radiation to be delivered to the tumor while minimizing damage to healthy tissue. One to three treatments are the same as 15 to 20 treatments of conventional radiation. The benefits include fewer hospital visits, fewer anesthetic episodes and reduced stress. Treatment is based on how much bone destruction has occurred as seen on a CT scan.

Meanwhile, at the University of Pennsylvania, Mason is testing a recombinant Listeria monocytogenes tumor vaccine. "Our project focuses on finding and killing the cancer cells that amputation and chemotherapy overlook," she says. "This method uses the body's immune system to elicit anti-tumor immunity and prolong survival in dogs with cancer of their long bones."

To be eligible, dogs with osteosarcoma must have had a limb amputation and standard chemotherapy consisting of four doses of carboplatin. "If the dogs live for more than eight months following vaccination, which is greater than one year post-diagnosis, then we will have increased median survival and will consider that the vaccine is having some effect," Mason says.

"We hope in the future to test whether this vaccine is effective in dogs that have not had amputations. This technology could be applied to other cancers, such as canine mammary cancer," she says. "It also may help people. Pediatric oncologists are watching our trial closely. This bacteria-based vaccine could possibly stimulate an immune response in children with osteosarcoma."

While Cyberknife radiosurgery and the L. monocytogenes vaccine provide a glimpse of future treatment possibilities for osteosarcoma, owners of dogs diagnosed with the cancer today continue to struggle to determine the best treatment that will extend longevity for their individual dog.

Genetics May Aid IBD Treatments

When a dog experiences idiopathic diarrhea and vomiting, veterinarians may suspect canine inflammatory bowel disease. The chronic gastrointestinal condition occurs more commonly in middle-aged large-breed dogs. Since it cannot be cured, veterinarians manage IBD using medications to address the signs.

Efforts to learn more about IBD in German Shepherd Dogs led to the recent discovery of polymorphisms in the TLR4 and TLR5 genes. The research was supported by the Morris Animal Foundation and the American German Shepherd Dog Charitable Foundation (AGSDCF).

Lead investigator Karin Allenspach, Dr.med.vet., Ph.D., head of the Clinical Investigation Center at The Royal Veterinary College of the University of London, says, "It appears German Shepherd Dogs with chronic enteropa­thies have a distinctly different micro­biome from healthy dogs, as well as from other breeds with IBD. This includes overrepresentation of certain traditionally labeled 'beneficial' bacteria in the duodenum, specifically sequences of the order of Lactobacilalles.

"We've made great progress to identify genetic predispositions underlying IBD in German Shepherd Dogs. We continue to analyze whether the mutation of an immune system protein is linked to the intestinal inflammation associated with IBD. If so, new treatments potentially could be developed. We also have identified antibodies specific for E. coli flagellin in dogs with IBD that are not present in unaffected dogs. This could lead to the development of a noninvasive diagnostic test for IBD."

While diarrhea and vomiting are the most common signs of IBD, the disorder also may cause anorexia or loss of appetite, weight loss, and blood or mucous in the stool. With loss of appetite, a dog becomes lethargic and loses condition and coat. Signs are persistent, and by the time a veterinarian examines a dog with IBD, overall health condition may be poor.

"The clinician faced with a potential case of IBD usually performs an extensive workup to exclude extra gastrointestinal causes as well as treatable disorders, such as pancreatic diseases, chronic parasitic or bacterial infections, and tumors," Allenspach says. An accurate diagnosis may require an endoscopic biopsy of the GI tract. A veterinarian looks for lesions caused by lymphoplasma cellular inflammation in the mucous layer of the GI tract. These can be seen in about half of cases.

"The intestinal lining is composed of cells with proteins on the surface," says Allenspach. "Some of the proteins are receptors that recognize microbes. If that protein is not functioning properly, it will tell the immune system to develop inflammation against the normal bacteria in the intestines, causing the diarrhea and vomiting that are characteristic of the disease."

After a tentative diagnosis of IBD is determined, the gold standard approach to treatment is a food trial with an elimination diet containing a novel or hydrolyzed protein. This is based on theories that IBD is caused by an allergic reaction or hypersensitivity to dietary antigens. If a food trial does not reduce signs of IBD, antibiotic treatment is tried for several weeks, followed by immunosuppressant and anti-inflammatory treatments.

Lymphocytic plasmacytic IBD is the most common. It is due to an excess of two kinds of white blood cells, lymphocytes and plasma cells. Lymphocytes are responsible for much of the body's immune protection, and plasma cells are a mature type of lymphocyte. This type sometimes responds well to a four- to five-week course of antibiotics, such as metronidazole or tylosin. "These antibiotics probably are effective because they change the gut microflora," Allenspach explains.

If antibiotics fail, the next step is anti-inflammatories, such as steroids, and immunosuppressants, which help eliminate intestinal inflammation. "Steroids can have significant side effects," says Allenspach, who is researching alternative medications. Cyclosporine, a drug used in humans to prevent organ transplant rejection, has shown excellent results without the side effects associated with steroid use, excessive thirst, urination and gastrointestinal ulcers, she says.

The second most common form of IBD, eosinophilic gastritis or gastro­enteritis, refers to the type of inflammation found in biopsies of the GI tract. This type of IBD is more severe. Biopsies show a high number of white blood cells called eosinophils that are often linked to allergic responses and parasitic infestations.

As breeders try to understand whether they should breed dogs with IBD, veterinary experts also grapple with the question. "It is too early to say that dogs with the mutation should be excluded from the breeding pool," Allenspach says. "It is probable that many dogs carry the mutation, but not all of them will get IBD. It is unlikely that one mutation is the single cause of the disease. There are environmental factors and probably other genetic factors that we haven't found yet."

In most breeds, the cause of IBD is likely not strictly genetic or environmental, Allenspach says. Affected dogs within a breed probably share one or more genetic mutations, but the presence of the mutation alone does not mean the dog will develop IBD.

"If the environmental triggers were known, they could be avoided so possibly a dog carrying the mutation would never develop the disease," says Allenspach. "This is an area needing to be studied. At this point, we really don't know."

Meanwhile, Allenspach advises breeders not to link every dog or every breed in the same category. "My belief is that there are different triggers in different breeds and thus different responses to treatment among the breeds as well as among different dogs," she says.  

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