HEMANGIOSARCOMA

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"This list is for information purposes only and the listing is not necessarily an endorsement by the Dachshund Club of America Health and Welfare Trust Fund.  This listing may facilitate obtaining a necropsy of  deceased dogs by professional pathologists for a reasonable fee, and to have tissue samples sent  by them to the Breen lab.  We suggest individuals enquire with their particular state accredited Animal Disease Diagnostic Laboratory to find out about fees, hours, and other information. "  





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Last November tragedy unexpectedly and fatally struck one of my dachshunds who apeared vital and healthy just a few hours earlier.  We woke up to find our funny, active,  Mischief  suddenly weak and lethargic.  She went into shock as she was driven to the emergency clinic,  and within hours died  in my husband's arms.  Once again hemangiosarcoma violently struck with a volcanic splenetic rupture and a tsunami of blood swamping her internal cavities. The veterinarians were not able to stabilize Mischief though they tried so hard.  As usual with this disease, symptoms were not evident at all before the sudden fatal nightmare. This time, though,  I wanted my deceased dog's tissues to be used for research.  I had little success contacting researchers because it was a weekend, till Diane McCormick and Christine Taylor put me in touch with Van Andel Laboratories and Dr. Roe Froman.  We were able to have a necropsy performed locally by a  veterinary pathologist at the NC State Veterinary Diagnostic Center that confirmed the diagnosis. Blood and tissue samples were sent by them to Van Andel as was their report.
Shortly thereafter I was able to reach the Breen Laboratories, part of another research collaborative  that has been working with a number of breed clubs concerning hemangiosarcoma for at least eight years.  ( They authored the article I published in the DCA Newsletter of   2008.) According to their instructions  I sent Breen Laboratories  the North Carolina Veterinary Laboratory necropsy report and  also blood samples collected by my dogs' primary veterinarian from Mischief's unaffected senior relatives.
Why, after involvement in dachshunds for more than a half century  am I so concerned with just one  specific type of cancer? Because it affects mid aged dogs without warning, and because there seems to be a complex genetic factor.  In golden retrievers the disease has now reached epidemic status. Hemangiosarcoma was once thought to affect only large breeds of dogs, but unfortunately we have found that is not the case.
Dachshunds, so far, mostly standards, are being diagnosed too.  We breeders and owners may be able to help researchers find an answer and help our dogs too.
Breen Laboratories collaborate to share its samples with all three research laboratories  that are studying different aspects of the disease so materials sent will go a long way.  Breen Laboratories is going to be the sole contact for Dachshunds for these three groups.
BREEN LAB contact information:
Telephone:  919-513-1466

Fax:  919-513-7301  marked for attention of Breen Lab
E-mail; info@breenlab.org
Who are these people anyway, and what are their credentials?
This work will be performed by Dr. Matthew Breen, Professor of Genomics at NC State and the Center for Comparative Medicine and Translational Research (CCMTR), and genetics researcher at the University of North Carolina's Lineberger Comprehensive Cancer Center; In addition to his activities at NCSU, Dr. Breen was a founder member and now serves on the Board of Directors of the Canine Comparative Oncology and Genomics Consortium Inc. The CCOGC is a national organization that serves to gather tumor tissues that may be used for the advancement of canine (and human) cancer research. He also serves on the Scientific Advisory Board of the Morris Animal Foundation and the National Canine Cancer Foundation.
Also:  Dr. Jaime Modiano, Professor of Oncology and Comparative Medicine with the University of Minnesota's College of Veterinary Medicine and Masonic Cancer Center;  His research program has had uninterrupted support from federal and private sources for 16 years, leading to co-authorship of more than 50 peer-reviewed scientific manuscripts, and ~200 abstracts, presentations, and book chapters focused on various aspects of immunology, cancer cell biology, the genetic basis of cancer and applications of gene therapy;
And Dr. Kerstin Lindblad-Toh, Director of the Vertebrate Genome Biology Program at the Broad Institute,  a Professor of Comparative Genomics at Uppsala University in Sweden. Kerstin Lindblad-To is a professor in comparative genomics at Uppsala University and the Scientific Director of Vertebrate Genome Biology at the Broad Institute. At the Broad Institute Kerstin is responsible for the Mammalian Genome Project to annotate the human genome for functional constraint as well as for a large number of vertebrate genome projects several of which emphasize the detection of selective sweeps. She also leads the dog disease-mapping group. Her group has developed several SNP chip that has been used to identify several canine disease genes.
Why request Dachshund samples?
It is not only golden retrievers that exhibit a higher level of predisposition to this cancer than the general domestic dog population. Other breeds are also affected by hemangiosarcoma.  In recognition Breen lab has been requesting samples from other breeds too.  These include Australian shepherds, German shepherd dogs, flat-coated retrievers and briards.
Recently it was brought to the  attention  of Breen Laboratories that there may be an increasing incidence within the dachshund population and so they have added the dachshund to the breeds studied.
As with all of their cancer samples they aim to make the process of submitting samples, at a distressing time for the owner, a relatively simple process.  With the help of liaison people from the Health committees of the parent breed clubs, they  now have a significant sample population that allows them to study this cancer in more detail.
They are of course immensely grateful to the owners, breeders, veterinarians and liaison folks without whom this would not be possible. In the Breen lab there is a dedicated member of staff whose role is to facilitate the process and ensure that it happens in as seamless a manner as is possible.  Every case is treated with care and confidentiality.
Lisa Warren of DCA's Health and Welfare Trust Fund has received permission from the Board for the fund to reimburse shipping costs for samples sent to Breen Laboratories. Van Andel's grant will presently pay for shipping costs for samples sent to them.
Samples are small, and can be sent to both organizations easily.  I have gladly consented to be the liaison between Breen and DCA so can inform potential donors of requirements  to send them  affected dog tissue and blood samples, and non affected dog blood samples.
Having personally experienced this with my own dogs I am available to anyone who wants to just talk to someone who understands.
Barbara Axel 

THE VAN ANDEL INSTITUTE is studying only naturally occurring tumors, so we need the assistance of owners with dogs who develop Hemangiosarcoma. We are requesting fresh (NOT in formalin) tumor samples when the dog has surgery, a biopsy or is euthanized. If your dog is scheduled for surgery, please contact VARI ahead of time so we can FedEx a tumor collection kit to your veterinarian.

You can contact the VAI at 616-234-5258.

You may also mail/email Dr. Nick Duesbery, Associate Professor, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503 at nick.duesbery@vai.org.

Consent forms and more information for veterinarians can be accessed and downloaded from Van Andel's website, www.vai.org/helpingdogs.

Hemangiosarcoma

 

Hemangiosarcoma is a malignant tumor of blood vessel cells. With the exception of the skin form, which can often be eliminated by surgery, a diagnosis of hemangiosarcoma is bad news. This tumor is associated with serious internal bleeding and rapid internal spread. Fortunately, it is not completely without therapy options and, as long as expectations are realistic, temporary remissions are possible.

 Hemangiosarcoma can theoretically arise from any tissue where there are blood vessels (which amounts to anywhere in the body) but there are three classical locations which account for most presentations: Skin and subcutaneous forms, Splenic forms, Heart-based forms

 The Skin Form

 The skin form of hemangiosarcoma are the best types to have as they are the most easily removed surgically and thus have the greatest potential for complete cure.

 The skin forms of hemangiosarcoma are classified as either dermal and subcutaneous (also called hypodermal.) The true skin form looks like a rosy red or even black growth on the skin. This form is associated with sun exposure and thus tends to form on non-haired or sparsely haired skin, such as on the abdomen, or on areas with white fur. Dogs with short white haired fur (such as Dalmatians and pit bull terriers) are predisposed to the development of this tumor. Approximately 1/3 of cases will spread internally in the malignant way we usually associate with cancer so it is important to remove such growths promptly.

 What To Know When a Skin Growth Biopsy Comes Back as Hemangiosarcoma. The biopsy report will indicate whether or not the growth was completely excised. If the tissue completely surrounding the growth is normal, this indicates that the growth has been removed completely and that it should not grow back.

 If one wants to be absolutely positive that no tumor spread has yet occurred, the following non-invasive (but not inexpensive) testing is necessary. Chest radiographs - hemangiosarcoma tends to spread to the lungs. Advanced tumor spread can be picked up with this simple test. (Spots of tumor spread must be 3cm in diameter to be large enough to be visible on a radiograph.)  Ultrasound of the belly - specifically the spleen. Even a small splenic hemangiosarcoma should be detectable with ultrasound.  Ultrasound of the heart - even a small heart-based hemangiosarcoma should be detectable with ultrasound.

Subcutaneous or Hypodermal Hemangiosarcoma

 The overlying skin is often totally normal on top of a subcutaneous hemangiosarcoma and often the surgeon is surprised to find a dark red blood growth under the skin when the tumor is removed.

 Since up to 60% of hypodermal hemangiosarcomas spread internally the above three tests to rule out tumor spread are more important. If no sign of tumor spread is found after chest radiographs have been taken and ultrasound of the heart and belly are clear, prognosis is substantially better than if secondary tumor is found; however, additional treatment with chemotherapy is recommended if cure is the goal. Surgery alone has been associated with a 172-day (approximately 6 months) median survival time.

 Hemangiosarcoma of the Spleen

 The spleen is a fairly deep-seated abdominal organ that tends to go unnoticed unless it develops a growth of unusual enlargement. Splenic growths have the unfortunate tendency to break open and bleed profusely regardless of whether they are benign or malignant. While a splenectomy (removal of the spleen) certainly ends the prospect of this type of life-threatening sudden bleed, splenic hemangiosarcoma is still a rapidly spreading malignancy.

 When a splenic mass is detected, it may not be possible to tell prior to splenectomy whether or not the mass is malignant or not (though certainly basic testing is performed in an attempt to determine this.)

Read about [ http://www.VeterinaryPartner.com ] /Content.plx?P=A&A=1394&S=<%= SpeciesID %>&EVetID=<%= EVetID %>splenectomy to review the details of splenic mass evaluation. Chemotherapy after removal of the splenic hemangiosarcoma is reviewed here so see the hemangiosarcoma link on the splenectomy page when you are ready to return for more information. 25% of dogs with splenic hemangiosarcoma also have a heart-based hemangiosarcoma.

Survival time with surgery alone is 19 to 65 days for splenic hemangiosarcoma.

Heart-Based Hemangiosarcoma

 Like the splenic hemangiosarcoma, the heart-based hemangiosarcoma tends to exert its life-threatening effects by bleeding.

The heart is enclosed in a sac called the pericardium. When the hemangiosarcoma bleeds, the blood fills up the pericardium until it is so full that the heart inside is under so much pressure that it has no room to fill with the blood it has to pump.

On chest radiographs the heart is globoid (spherical). In fact, the actual heart is of normal shape but all that can be seen on the radiograph is the large round heart shadow of the pericardium filled to capacity with blood. Ultrasound is needed to truly see the effusion.

 This condition, if allowed to progress, results in an emergency circulating collapse called a "pericardial tamponade" and can only be relieved by tapping the pericardium with a needle and withdrawing the excess fluid. 63% of heart-based hemangiosarcomas have evidence of tumor spread at the time of their discovery. Survival time for surgery alone (removing the pericardium and snipping off the heart-based hemangiosarcoma) is approximately 4 months. In a study presented in the Journal of the American Veterinary Medical Association in February 2005, 23 dogs with this type of tumor were studied. Of the dogs that had surgery, approximately half of them had some sort of post-operative complication, though most complications were minor and 87% survived and were released to go home from the hospital. Eight of these dogs received chemotherapy in addition to surgery and these individuals had much longer survival times (median survival of 175 days vs. 42 days for dogs who had surgery without chemotherapy).

 Chemotherapy is necessary to create a substantial improvement in survival time. The most current protocol involves injectable Adriamycin (Doxorubicin) every 3 weeks and oral cyclophosphamide at home for 3 days out of the week.

 Chemotherapy of Canine Hemangiosarcoma With Doxorubicin and Cyclophosphamide

J Vet Intern Med 7[6]:370-376 Nov/Dec'93 Clinical Study 29 Refs Karin U. Sorenmo CMV, K. Ann Jeglum VMD, and Stuart C. Helfand DVMDept. of Clinical Studies, VHUP, 3850 Spruce Street, Philadelphia, PA 19104.

Sixteen dogs with a histologic diagnosis of hemangiosarcoma were treated with surgery and doxorubicin/ cyclophosphamide. The patients' characteristics, i.e., age, size, and breed, were similar to those of previous studies. Historic controls for surgery alone were used to evaluate efficacy of the chemotherapy. The results show a trend of improved survival in dogs with localized disease (Stage I) receiving combination therapy. The median survival was 250 days, with a mean of 403 days. The survival times for dogs with stage I, II, and III disease was also improved with combination therapy, when compared to historical controls treated with surgery alone. The overall median survival was 202 days with a mean of 285 days. Toxicities included mild to moderate neutropenia (9 of 16) and clinical signs, such as lethargy, anorexia, vomiting, diarrhea, and fever (13 of 16). Three dogs had severe neutropenia requiring hospitalization and supportive care. One dog died from sepsis and related complications. Chemotherapy with doxorubicin and cyclophosphamide appears to improve survival with acceptable morbidity in patients with early stage disease. (Author Abstract)

Copyright 2008 - 2012 by the Veterinary Information Network, Inc. All rights reserved

(DYM received permission to reprint this article from Phyllis DeGioia, Editor, Veterinary Partner)

http://www.VeterinaryPartner.com/Content.plx?P=A&A=1449

A Clinical Trial for Canine Hemangiosarcoma

 

AKC Canine Health Foundation. September 2011.

By Jaime F. Modiano, V.M.D., Ph.D.1,2 and Daniel A. Vallera, Ph.D.2,3 University of Minnesota

1Department of Veterinary Clinical Sciences, College of Veterinary Medicine; 2Masonic Cancer Center;

3Department of Therapeutic Radiology

 Science is full of examples where success comes from unexpected sources. This one arose from a hallway conversation among five curious people. Sometime around 2008, a casual conversation was struck up by Dr.Antonella Borgatti, a recently recruited assistant clinical professor of oncology; Jill Schappa, then a second-year DVM student working on a summer project in the Modiano lab; Megan Duckett, an assistant scientist in the Modiano lab who was working with them; Dr. Jaime Modiano, Perlman Professor of Animal Oncology and director of the Animal Cancer Care and Research program; and Dr. Dan Vallera, a professor in the Department of Therapeutic Radiology. Borgatti was interested in developing targeted therapies for sarcomas. Schappa had developed an interest in specific aspects of canine hemangiosarcoma. Vallera, an expert in targeted immunotherapies, had developed a bispecific ligand-targeted toxin (BST), where two proteins (ligands) that bind receptors commonly found in human cancers and the blood vessels that feed them were linked to a lethal bacterial toxin. Together, they found a unifying link that moved them all in a new direction. Vallera had developed the concept so BSTs would home to tumors (like “smart bullets”), which express high levels of the targeted receptors. By homing to the tumors, the lethal payload would be delivered with high specificity, and most normal cells and tissues would remain unharmed. Vallera’s group also had shown that the approach was feasible in laboratory animal models. Borgatti and Schappa realized that this approach would uniquely be able to target sarcomas, which are notoriously difficult to treat and occur only rarely in people, but frequently in dogs. Evaluating the therapy in dogs could be a win-win situation, as we might find an effective therapy to treat these cancers in our trusted companions and help to develop the therapy to treat these rare diseases in humans.

 Laboratory testing ensued, with support for Schappa through a Howard Hughes Medical Institute and Burroughs Wellcome Foundation Fellowship. The results of her work were presented to the scientific community at a Keystone meeting in March 2011, where the results garnered the attention of Dr. Corrie Painter, founder and director of Angiosarcoma Awareness, Inc.

A new partnership began, where Angiosarcoma Awareness has agreed in principle to support a clinical trial to test the safety and efficacy of this therapeutic approach in dogs with hemangiosarcoma.

Related sites and information:

American Kennel Club Canine Health Foundation articles: http://www.akcchf.org/news-events/library/articles/

Angiosarcoma Awareness: http://angiosarcomaawareness.org/page1.php

University of Minnesota Clinical Investigation Center http://www.cvm.umn.edu/cic/

University of Minnesota Clinical Trial Contact information: http://www.cvm.umn.edu/cic/contact/home.html

NCRAOA www.ncraoa.com Education is the Key

(From research reported by the AKC Canine Health Foundation and reprinted in the NCRAOA February Newsletter.)

Jaime F. Modiano, VMD, PhD, Michelle G. Ritt, DVM, DACVIM, Matthew Breen, PhD, CBiol, MIBiol, and Tessa Breen, BSc (Hons), Dip GD, CMM

University of Minnesota, St. Paul, MN (JFM & MGR), and North Carolina State University (MB, TB)

In following article, we describe the current state of knowledge for canine hemangiosarcoma, including what it is, why it may happen, and how it can be managed. In addition, we present recent findings from our programs that promise to help us improve our ability to diagnose, treat, and prevent this disease.

The Natural History of Canine Hemangiosarcoma

Canine hemangiosarcoma is among the most challenging and mysterious diseases encountered in veterinary practice. It is an incurable tumor of cells that line blood vessels, called vascular endothelial cells. Hemangiosarcoma is relatively common in dogs; it is estimated that this type of cancer accounts for 5-7% of all tumors seen in dogs. Considering the lifetime risk of cancer for dogs is between 1 in 2 and 1 in 3, we can calculate that 1.5 to 2.5 million of the ~72 million pet dogs in the United States today will get hemangiosarcoma and succumb from it. Although dogs of any age and breed are susceptible to hemangiosarcoma, it occurs more commonly in dogs beyond middle age (older than 6 years), and in breeds such as Golden Retrievers, German Shepherd Dogs, Portuguese Water Dogs, Bernese Mountain Dogs, Flat Coated Retrievers, Boxers and Skye Terriers, among others. According to the Golden Retriever Health Study published in 2000, the estimated lifetime risk of hemangiosarcoma in this breed is 1 in 5, illustrating the magnitude of this problem.

Unlike other cancers, hemangiosarcoma is almost an exclusive disease of dogs. In people, a similar type of tumor (angiosarcoma) occurs only rarely in association with workplace exposure to vinyl chloride and polychlorinated biphenyls (PCBs), such as is found in rubber and tire plants. An even smaller fraction of women who receive high dose radiation therapy for cancer (usually breast cancer) can develop angiosarcoma of the skin. Yet, angiosarcomas account for much less than 1% of all tumors seen in people. Certain mutations are known to predispose laboratory mice to hemangiosarcoma, but whether these mutations contribute to the disease in dogs is not known. Benign tumors of vascular endothelial cells, called hemangiomas, arise in the skin of people and dogs that have extended exposure to sunlight. These tumors are distinct from hemangiosarcomas and angiosarcomas, and they are not life threatening.

In dogs, the common primary sites for hemangiosarcoma are the spleen, the right atrium of the heart, and the subcutis, which is the tissue beneath the skin. The pattern of growth for these tumors involves infiltration into normal tissues surrounding the tumor as well as distant spread (metastasis). The disease is indolent; in other words, it does not cause pain and the rate of growth in the early stages is relatively slow. Dogs harboring even large hemangiosarcomas may show no clinical signs or evidence that they have a life threatening disease. Generally, the tumor cells retain some normal aspects of behavior, so they try to make blood vessels. But these vessels are tortuous and malformed, and blood cells tend to pool in them and clot. The clots then prevent blood and nutrients from reaching tumor cells, in turn causing them to die. This creates small ruptures in the tumor through which blood may escape into the abdomen, heart sac, chest, or subcutaneous space. Depending on the amount of blood lost, affected dogs may show non-specific (constitutional) signs such as lethargy and weakness, but these are transient and resolve as dogs reabsorb the blood components and make new blood cells. The clinical signs are recurrent, but they also are subtle enough to go unnoticed for some time. Since hemangiosarcoma tends to metastasize aggressively to lungs, liver, intestines, and mesentery (the membranous connective tissue that supports the intestines), distant spread (either microscopic or macroscopic) has inevitably occurred once the disease is finally diagnosed. The eventual outcome for patients with this disease often follows the rupture of a large or rapidly growing tumor, which results in acute, severe hemorrhage, collapse, shock, and death.

What Causes Hemangiosarcoma

We do not precisely know what causes canine hemangiosarcoma. The observations that the disease occurs more commonly in dogs than in other animals, and that some breeds are at higher risk than others tell us that heritable factors must contribute to risk. Ultimately, the interactions of these heritable risk factors with the environment probably lead to the spectrum of mutations that give rise to the tumor. As a matter of brief review, it is important to understand that "cancer is a genetic disease, although it is not always heritable." Tumors arise when cells accumulate mutations that eliminate normal constraints of growth and genetic integrity. These mutations provide cells a selective growth advantage within their environment, essentially the same evolutionary phenomenon that we call natural selection, albeit on a microscopic scale. Most mutations arise because the enzymes that control cell division are not foolproof. About 1 mutation occurs for each one to ten million bases that are replicated when time a cell divides (genomic DNA in dogs consists of about 2.5 billion base pairs; in other words, when a cell divides, it must copy 2.5 billion bases and the inherent error rate of the DNA replication machinery will introduce between ~250 and 2,500 errors, or mutations, to the DNA of each daughter cell). Since some cells in the body divide continuously to replace others that die or are damaged (for example, blood cells, skin cells, and gut cells), mutations are pretty much introduced constantly into cells in the body. For this reason, we say the greatest risk factor for cancer is "being alive". As mentioned above in the example of humans that are at risk to develop angiosarcoma, mutations also can occur from exposure to environmental toxicants. Fortunately, most of these mutations are silent (they neither help nor hurt the cell or the organism), and the body has mechanisms to eliminate most cells that acquire deleterious mutations. A relatively new concept about how cancer happens invokes the theory that only "stem cells" can give rise to tumors, making the acquisition of mutations in somatic cells (any cell that is not a sperm or an egg) a lesser concern. This will be discussed in detail later in the article. For now, it is important to understand that simply carrying a mutation does not necessarily mean an individual will get cancer - it only means that his or her risk is elevated. The practical implication of this statement is that we will probably never eliminate cancer completely from our population (human or canine), but we can achieve a significant reduction in the number of cases as we learn more about how the disease happens and we work to diminish risk factors or detect the disease early enough to treat it before it becomes a life-threatening condition.

The news is not all bad. We have identified some of the fundamental properties of canine hemangiosarcoma, and it is possible one or more of these may prove to be an "Achilles heel" for the tumor. For example, most of these tumors make growth factors that they need to survive, or they "coerce" cells in their environment to do this for them. One of these growth factors is vascular endothelial growth factor-A or VEGF, which acts by binding specific receptors on the hemangiosarcoma cells. New drugs under development by various pharmaceutical companies are designed specifically to interfere with the signals transmitted by these receptors. The reliance of hemangiosarcoma cells on VEGF signals to survive should make them more sensitive than normal cells to these drugs. Several groups are working to bring these drugs into the clinic, but the process is slow because testing must be done in a careful, deliberate way to ensure the compounds are safe and effective. The rules for participation in clinical trials are stringent, but if you have a dog that is diagnosed with terminal hemangiosarcoma, your veterinarian may have information about trials for which he or she may be eligible. As we will detail below, our work and that of others continues to illuminate new avenues that we may be able to use to more effectively prevent, control, and treat this disease.

Treatment for Canine Hemangiosarcoma

Regrettably, the standard-of-care for this disease has not seen significant advancement over the past 20 or 30 years. There is presently no readily available, effective test for early diagnosis of hemangiosarcoma. Careful analysis of blood samples by experienced pathologists may hint at the presence of chronic hemorrhage and blood vessel abnormalities that are suggestive of hemangiosarcoma. However, this method is neither sensitive nor specific to confirm the diagnosis. Non-invasive imaging methods are useful aids to diagnose the disease. In particular, ultrasound is moderately specific, but it is not sensitive, and the tumor must be large enough to be grossly visible. In addition, biopsies are required for confirmation of imaging results. Repeated biopsies of tissues where the tumors may arise (without other evidence for the presence of a tumor) are of little use to provide early diagnosis, and considering the fact that there is some risk to these procedures, such an approach is practically and ethically unacceptable.

The options for therapy of canine hemangiosarcoma are limited, largely because the disease is not diagnosed until the late stages. The standard consists of surgery to shrink or remove the primary tumor, when possible, followed by intensive chemotherapy. In some cases, surgery is not feasible, or it can be impractical or inappropriate (for example, if there is evidence of extensive metastatic spread to sites beyond the primary tumor). Median survival for dogs treated with surgery alone is approximately 90 days, and that is extended to approximately 180 days by the addition of chemotherapy using one of several protocols available. Because the goal for chemotherapy in pet dogs is to extend life with good quality, toxicity is generally not a major issue of concern, and when it occurs it is most often managed without much difficulty.

There is no other therapy that has been proven to be effective to manage or control hemangiosarcoma. As we will mention below, the cells that give rise to this disease originate in the bone marrow. We do not yet know when (or why) they localize to the organ where the disease will arise, but this means that prophylactic splenectomy (removing the spleen to prevent the development of the disease) is unlikely to have any benefit, since in the absence of a spleen, the transformed cell (or cells) can simply go to another organ. Also, the spleen is not simply a "window dressing" organ, and even though dogs can function without a spleen, they will have reduced ability to adapt or respond to a variety of conditions.

Several alternative and complementary approaches (diet, herbs, mystical energy, etc.) have recently become popular as people try to find treatments for canine hemangiosarcoma. This usually follows extensive publicity (such as from Internet chat groups) after a dog receives these treatments and survives longer than anticipated, leading proponents to advertise this as success and evidence that their approach is curative for hemangiosarcoma. The danger of attributing curative power to treatment approaches after an anecdotal response cannot be overstated. There is no reported case where one of these therapies has been consistently successful (or even as good as the standard of care) after it has been tested without bias to try to replicate the anecdotal response. In fact, sometimes such treatments can actually interfere with - or increase the toxicity of chemotherapy drugs. We know that when some tumors are caught early enough, surgery alone, surgery plus chemotherapy, and in some cases no treatment at all can lead to extended survival. In rare instances, the behavior of the tumor itself is such that disease progression is extremely slow and dogs can survive for an extended period regardless of the therapy used. This means that a small proportion of dogs diagnosed with hemangiosarcoma will live 2, 3, 4 years and longer even without aggressive management. Therefore, it is essential for families who have dogs that are diagnosed with cancer to recognize two things. One is that veterinarians would not willingly hold back effective therapies for any disease. Our job and our responsibility are to improve the health and well being of dogs and their families, and all of us would welcome an effective and non-toxic cure for this disease. The other is that there is no shortage of predators on the Internet and elsewhere who benefit from the desperation people feel when they know a beloved family member will probably die from a serious, incurable disease (please visithttp://www.quackwatch.org/00AboutQuackwatch/altseek.html if you want to read more about "miracle cures" for cancer advertised in the lay press and on the Internet).

Hope for the Future

The unwavering support of the dog-loving community has already made a difference in our understanding of canine hemangiosarcoma. To end this article, we will highlight new information that makes us optimistic about our chances to win the battle against this disease. Here, we wish to note our gratitude for the support that our group and our collaborators have collectively received from dog clubs and owners alike, both financial and by making samples available for ongoing studies.

Development of a Test for Early Detection. As we mentioned above, one way to improve our success treating hemangiosarcoma is by detecting the disease early. Previous work from our group showed there are unique patterns of protein expression that can help distinguish hemangiosarcoma cells from normal blood vessel lining cells, even within the tumor. We also knew that most tumors shed some cells into the circulation. We reasoned, then, that we could take advantage of this to develop a test to look for tumor cells in the circulation, providing a minimally invasive, accurate diagnostic test for hemangiosarcoma. In many ways, this is similar to the proverbial search for a needle in a haystack. The tumor cells are so infrequent that they cannot be detected in routine blood tests, nor are they easy to enrich. To accomplish our goal, we needed to use a robust technology called flow cytometry. For this, cells are "tagged" with fluorescent molecules that identify their lineage of origin and then cells are run through an instrument (the flow

cytometer) that combines sophisticated optics, fluidics and software that make it capable of analyzing tens of thousands or hundreds of thousands of cells in a matter of minutes. With financial support from the Portuguese Water Dog Foundation, Inc., the Portuguese Water Dog Club of America, and Idexx Laboratories, we were able to show proof of principle for this test. The work was published in the July 2006 issue of the journal Experimental Hematology. Idexx Laboratories has licensed the technology from the University of Colorado. As of the writing of this article, the test is in the final stages of optimization and transfer to Idexx for final testing. Several questions remain to be answered before the test can be offered commercially, not the least of which are cost analysis and market research to ensure that the final product is not only diagnostically useful, but also affordable for veterinarians and pet owners.

A planned future use for this test is its application to detect the presence of hemangiosarcoma in dogs at risk before the tumor poses a clinical hazard. As is true for other tumors, early detection is likely to offer the highest probability of successful treatment outcomes. There is, however, an important caveat. The presence of hemangiosarcoma cells in the circulation does not tell us where in the body the tumor is likely to develop, as tumors in the spleen, liver, heart, and skin all produce positive results in this test. Therefore, we have initiated several studies with support from the AKC Canine Health Foundation, the National Canine Cancer Foundation, and others, to develop novel treatment strategies for hemangiosarcoma that are independent of the site of origin (these are still in the earliest stages of laboratory development). Only then will we be able to ethically and judiciously use early detection to improve outcomes for dogs affected with this disease.

Is Hemangiosarcoma a Disease of Stem Cells? A lot of attention has been focused recently on stem cells and their potential use to cure a wide variety of diseases. The "dark side" of stem cells is that these may be the only cells that can give rise to tumors. It is very important to note here that this is not a reason to avoid or abandon research on the therapeutic promise of stem cells, as there is no practical, documented evidence that the possibility to develop cancer is any higher in laboratory animals or patients that receive stem cell transplants.

Until recently, the dominant theory for the origin of cancer assumed that all cells possess an equal capacity for self-renewal; that is, the capacity to make a new identical cell that retains all the properties of the mother cell, and that proliferation of cancer cells was a random process driven entirely by selection of mutations that increased the fitness of a cell in a particular environment. A competing theory now exists whose main concept is that self-renewal is limited to a small population of "cancer stem cells." These cells possess the two features that define "stemness": (1) self-renewal and (2) multipotency (the capacity to make new cells that can differentiate into more than one type or lineage). In other words, a very small number of self-renewing cells in a tumor generate large numbers of progeny that make up the bulk of the tumor (or tumors). The existence of "cancer stem cells" is now well documented; they have unique properties of gene and protein expression, and the initial transformation seems to involve a relatively small number of mutations. The accumulation of additional mutations determines the extent to which the progeny from these cells will differentiate, variably resulting in distinct clinical entities such as high-grade, aggressive tumors and low-grade, indolent tumors.

This model of cancer explains why multicellular animals like a dog, with trillions of cells in their bodies, can survive to reproductive age without developing cancer, as the capacity for tumor formation is limited to perhaps a few hundred "stem cells", dramatically reducing the probability that any cell with cancer-causing potential will accumulate the set of mutations needed to develop the disease. Still, the high incidence of cancer among older individuals reinforces the notion that even with a limited number of susceptible stem cells, the probability to develop cancer over a long life is quite high. With regard to canine hemangiosarcoma, recent data from our lab support the idea that this is a disease of stem cells, the first such evidence for a canine tumor. Current work is focused on characterizing these stem cells, as their unique properties may provide opportunities to develop highly targeted, non-toxic therapies to effectively treat this disease.

What Are the Breed-Specific Risk Factors for Canine Hemangiosarcoma? We mentioned previously that hemangiosarcoma is a rather common cancer in certain breeds, including Golden Retrievers, German Shepherd Dogs, and Portuguese Water Dogs. This tells us that heritability contributes to risk, and so it may be possible to reduce the incidence by eliminating the highest risk alleles from the population. Moreover, if risk factors responsible for the disease are unique among breeds, we might have to consider the possibility that various new therapy approaches will have to be developed to effectively treat this disease in different breeds of dogs. To date, we have taken several approaches to identify how heritable factors influence hemangiosarcoma risk. One approach, developed largely in collaboration with Dr. Elaine Ostrander at the National Human Genome Research Institute of the National Institutes of Health and Dr. Kerstin Lindblad-Toh at the Broad Institute of MIT and Harvard, seeks to map risk alleles in Portuguese Water Dogs, Golden Retrievers, and German Shepherds using resources made available by the recent completion of the Canine Genome Project. We continue to collect samples for these projects, and we would be extremely grateful to owners who wished to participate by contributing blood and pedigree information from healthy (aged) dogs and from affected dogs. Information for participation is available at http://www.modianolab.org/studyInfo/studyInfo_index.shtml. A second approach, developed largely in collaboration with Dr. Matthew Breen, seeks to determine breed specific abnormalities that are detectable in tumors obtained from dogs of different breeds. We have made significant progress on this project, and have new data showing that, indeed, tumors from dogs of one specific breed are functionally and genetically more similar to each other than they are to tumors from dogs of other breeds. We are extremely excited about this information, as it will, for the first time, provide tangible evidence that heritable risk factors are a contributor to the development of canine cancer. More importantly, these results are the first step in our long-term goal to develop strategies for prevention and treatment that address specific causes underlying the biology of canine hemangiosarcoma.

In conclusion, hemangiosarcoma remains a devastating, untreatable disease of dogs. However, ongoing work in our laboratories and elsewhere is rapidly increasing our understanding of this disease, providing hope that we will achieve our goals to reduce its incidence and control its impact on dogs and their human families within our lifetime.

Reprinted with permission from the AKC Canine Health Foundation: www.akcchf.org

 


The Dachshund Club of America Health and Welfare Trust Fund thanks the author, Rhonda Hovan, for permission to print this excerpt from the Golden Retriever Club of America website's article "Ask The Health and Genetics Committee: Hemangiosarcoma FAQ's


Does it ever happen that the spleen is removed due to HSA, and the dog is cured? Does the disease always metastasize? Is it ever recommended to remove an “at risk” dog’s spleen to prevent HSA?
Though one hesitates to use absolute words like “never” and “always” to describe biological processes, in this case, it is very nearly certain that removing a spleen with an HSA tumor will not cure the disease. Further, removing a healthy spleen will not prevent this disease. Let’s examine the disease process in greater detail to understand why.
Many people are aware that in humans, it is estimated that a breast cancer usually has been growing for an average of 8-10 years before the tumor reaches a size where it can be detected. Likewise, current theories in visceral hemangiosarcoma (and other cancers) estimate that the first mutant cells become cancerous several years before the tumor reaches detectable size (Etzioni et al, 2003; Wulfkuhle et al, 2003; Laird, 2003). Because the cancerous hemangiosarcoma cells may arise in any blood vessel in the body, they have ready access to circulating blood and can migrate freely through the body in the blood stream.
At some point a primary tumor site develops, and this is typically in a highly vascular organ such as the spleen, liver, or heart. In some malignant tumors, factors associated with the primary tumor actually suppress the growth of tumors that originate from cancer cells that have escaped into the blood from the primary tumor (O'Reilly et al., 1994). So although malignant cells from the primary tumor have nearly always spread elsewhere in the body, they may temporarily remain dormant while the primary tumor is growing. However, removal of the primary tumor isessential to prevent additional shedding of malignant cells, and to prevent problems associated with tumor enlargement and rupture. Unfortunately, in model systems, removal of some primary tumors can actually increase the growth rate of metastases because removing the tumor also removes the source of the factors that suppress the growth of secondary tumors (Barbour and Coventry, 2003; Ouatas et al, 2003). Thus, it is extremely likely that visceral HSA will have spread before the primary tumor is detected and it is even possible that removal of the primary tumor will actually increase the growth rate of HSA in the distant (metastatic) sites.
In addition, although a large proportion of primary HSA tumors occur in the spleen, there is only limited evidence that the original mutation to cancerous cells occurs in the spleen. Since the spleen functions as a filter to remove abnormal blood cells from circulation, a likely scenario is that hemangiosarcoma cells originating elsewhere are captured by the spleen, and then develop into the primary tumor. It is unlikely that removal of the spleen would prevent HSA, because the primary tumor can develop in alternate sites such as the liver or right atrium of the heart (obviously not candidates for prophylactic organ removal). Further, the spleen functions to aid the body to fight infections, and is certainly not a “disposable” organ that can be removed with no consequence to the dog.
At the 2000 National, a seminar was presented on HSA. Someone asked if there was any way to detect hemangiosarcoma with regular ultrasounds. The answer was that even twice- yearly ultrasounds might not catch rapidly spreading cancers, because they could develop in a dog’s body and kill it within as short a stretch as six months. In response to this, a breeder shared that they had ultrasounded a Golden in late August, showing a normal heart. Then in mid-December, there was a lesion visible on the heart, which was confirmed as hemangiosarcoma. The dog died in late January. The earlier ultrasound showed a splenic mass, but the pathology report indicated a benign hematoma, not hemangiosarcoma. What use is ultrasounding when the cancer spreads and kills so quickly anyway?
As discussed above, current research indicates that by the time a tumor is large enough to be detected on ultrasound, the disease has existed for some time, and metastasis has already occurred. Even monthly ultrasounds would not “catch” HSA prior to metastasis.
However, periodic ultrasounds might discover a primary HSA tumor prior to rupture, permitting removal of the tumor before it has spread its contents into the abdominal cavity (which may contribute to additional metastasis). This may add several months to the dog’s survival time, and of course, will prevent sudden collapse and death due to tumor rupture. However, approximately one-half of splenic tumors are benign, and these generally cannot be distinguished from HSA without surgery (Clifford et al, 2004). Thus, the potential benefit of discovering an HSA tumor prior to rupture, must be balanced against the possibility of surgery for a benign tumor. There are reasons that removing a benign tumor may also be of benefit, but we have found no studies comparing the risk and benefits of surgery for benign splenic masses. As always, the attending veterinarian is in the best position to make recommendations for the most appropriate health care and diagnostic procedures for the individual dog.

 

 

Reviewed and updated 2011

Posted by the Bichon Frise Club of America

 

Hemangiosarcoma, also known as malignant hemangiothelioma or angiosarcoma, is a very aggressive, high-grade soft tissue cancer of vascular tissue with the skin, heart and spleen the most common areas affected. Dermal (skin) hemangiosarcomas are less aggressive than visceral tumors with lower metastatic potential and longer survival times. Visceral (internal) tumors are highly malignant tumors with a poor prognosis. This highly malignant cancer originates in the lining of the blood vessels, spreads rapidly, causing tumors almost anywhere in the body. Insidiously, it attempts to build its own blood vessel network, making blood-blister-like formations which disrupt normal organ function. A common form of cancer in dogs, hemangiosarcoma affects mostly older, large breed dogs although all dogs, including young, can be affected. Males tend to have a higher rate of diagnosis than females, with German Shepherds, Portuguese Water Dogs and Golden Retrievers more affected than other breeds. Because hemangiosarcoma occurs more commonly in dogs than other animals and is more frequent in some breeds, inheritable-risk-factors with environmental factors probably lead to the range of possible mutations at the genetic level that gives rise to the tumor. This cancer has not been reported in large numbers in Bichons, although it has occurred.

 

Dermal (skin) hemangiosarcoma often appears as a rosy red or purple to black growth on the skin, which may be raised. Associated with sun exposure, this form of tumor tends to appear on non-haired or sparsely haired areas like the abdomen. Dogs with short white-haired fur (such as Dalmatians, Whippetts, Italian Greyhounds, Bull terriers) are prone to this tumor development. Although solar-induced canine dermal hemangiosarcomas generally do not have as aggressive biologic behavior as visceral tumors and can be controlled with topical chemotherapy as needed, numerous lesions may continue to appear over a period of several years. Because 30% of all dogs with dermal hemangiosarcoma develop metastatic disease, it is important to remove the growths promptly.

 

The overlying skin on top of a hypodermal (under the skin) hemangiosarcoma is often totally normal. When the tumor is removed, a dark red blood growth is found. Because 60% of hypodermal hemangiosarcomas spread internally, it is important to run further tests, chest x-rays, ultrasound of the abdomen, and ultrasound of the heart to determine if the cancer has spread.

 

Visceral (internal) hemangiosarcoma accounts for 2% of all reported malignancies and up to 5% of all noncutaneous tumors in dogs. Although these numbers seem small, the impact is significant since this form of cancer kills. The spleen and right atrium of the heart are the most common sites of occurrence of visceral hemangiosarcoma. The spleen is seated deeply within the abdomen and tends to go unnoticed unless it develops a growth of unusual size. Because the spleen is especially vascular, any growth, regardless of whether it is benign or malignant, has a tendency to break open and bleed profusely. If the splenic tumor is found early and is not too large, a splenectomy (removal of the spleen) may be preformed. Although a splenectomy certainly protects from this life-threatening sudden bleed, splenic hemangiosarcoma is still a rapidly spreading malignancy. 25% of dogs with splenic hemangiosarcoma also have a heart-based hemangiosarcoma.

 

Like the splenic hemangiosarcoma, the heart-based hemangiosarcoma tends to exert its life-threatening effects by bleeding. The heart is enclosed in a sac called the "pericardium." When the hemangiosarcoma bleeds, the blood fills up the pericardium creating so much pressure that the heart can no longer function. If allowed to progress, results are a circulatory collapse called a "pericardial tamponade" and can only be relieved by withdrawing the excess fluid from within the pericardium. At the time the heart-based hemangiosarcoma is discovered, 63% have evidence of metastatic tumor.

 

The most common blood disorder associated with hemangiosarcoma tumor is disseminated intravascular coagulation (DIC), blood clotting that occurs inappropriately inside the blood vessels. This process uses up all the blood clotting elements rapidly. Dogs with this condition usually have platelet deficiencies, increased blood clotting times, decreased fibrin content in the blood and an increase in fibrin degradation products. This is the cause of death in most dogs affected with hemangiosarcoma. Bleeding disorders associated with hemangiosarcoma are sometimes confused with immune-mediated hemolytic anemia because the type of anemia caused by the two conditions is very similar and early clinical signs are often very similar. Also, due to the thrombocytopenia (platelet deficiency), immune-mediated thrombocytopenia may be suspected.

 

Visceral hemangiosarcomas leave little warning they are present prior to causing severe clinical signs of disease. A common estimate of the average time from discovery of the tumor until death occurs is six to eight weeks, but death occurs more rapidly than this in some cases. Visible bleeding, usually in the form of nosebleeds, and signs associated with blood loss, such as tiring easily, episodes of unexplained weakness, pallor to the mucus membranes of the mouth and eyes, increased respiratory rates, abdominal swelling and depression are the most common presenting signs for hemangiosarcoma. A few dogs just suddenly die with no clinical signs having been noted. A large splenic hemangiosarcoma can be found on physical exam. Heart-based hemangiosarcoma is hard to find on physical exam and can be missed on x-rays. If bloody fluid is aspirated from the abdomen, hemangiosarcoma is suspected. Sometimes hundreds of small tumors are spread throughout the body, and surgical exploration or an autopsy are the only ways to identify the problem.

 

Hemangiosarcoma is primarily treated with a combination of surgery and chemotherapy and some radiation. The drug of choice is Doxorubicin and Cyclophosphamide. Surgical removal alone is often not very rewarding. Because of the high risk of metastasis, the average survival time without chemotherapy is one to two months, with less than 10% of these dogs living a year. With surgical removal and accompanying chemotherapy, the average survival time increases to five to seven months. However, 90% of theses dogs still do not survive more than a year after initial treatment. Skin-based hemangiosarcoma appears less likely to be metastatic when initially diagnosed, and surgical removal of the skin-based tumors can be curative. However, chemotherapy is often recommended in addition to surgery.

 

In summary, hemangiosarcoma tumors cause significant bleeding extra-vascular (outside the blood vessels) and clotting intra-vascular (within the blood vessels) and spread early; survival times are usually short. Surgery is helpful to prevent massive blood loss, but rarely affords a cure. Chemotherapy can be helpful, but even with aggressive treatment survival beyond one year is extremely rare. Only superficial skin tumors allow long-term survival with surgery alone, although recurrence is likely. Recently, some fundamental properties of canine hemangiosarcoma, unique patterns of protein expression, have been identified that may lead to the development of new chemotherapy drugs in association with early detection to increase survival time. In addition, recent data from the Modiano Lab supports the idea that the disease is of stem cells, the first such evidence for a canine tumor. Work there is focusing on characterizing these stem cells, as their unique properties may lead to highly targeted, non-toxic therapies to effectively treat this disease. Because hemangiosarcoma is rare in humans little research funds have been allocated toward this disease thus improvements in early detection and treatment is slow.

 

Heritability contributes to the risk of developing hemangiosarcoma so it may be possible to reduce the incidence by removing the highest risk alleles from the population. Research by Dr. Elaine Ostrander and Dr. Kerstin Lindblad-toh seek to map risk alleles in Portuguese Water Dogs, Golden Retrievers, and German Shepherds using resources made available by the recent completion of the Canine Genome Project.

 

Dr. Matthew Breen seeks to determine breed specific abnormalities that are detectable in tumors obtained from dogs of different breeds. Data from this project shows that tumors from dogs of one specific breed are functionally and genetically more similar to each other than they are to tumors from dogs of other breeds. This will provide tangible evidence that heritable risk factors are a contributor to the development of canine cancer.

 

American Kennel Club/Canine Health Foundation has fifteen grants dedicated to work on finding cause and treatment for canine hemangiosarcoma.

 

Jaime F. Modiano, VMD, PhD, Michelle G. Ritt, DVM, DACVIM, Matthew Breen, PhD, Cbiol, MIBiol, and Tessa Breen, BSc (Hons), Dip GD, CMM, University of Minnesota, St. Paul, MN (JFM & MGR), and North Carolina State University (MB TB), "Canine Hemangiosarcoma - The Road From Despair to Hope", Discoveries American Kennel Club Canine Health Foundation, Issue 24, Winter 2007, pp 3, 5, 8, 9

 

 

 Early Cancer Detection Tests: Do They Work?
We are all familiar with recommendations from physicians and other health advocacy groups for various kinds of cancer screening tests, such as mammograms to detect breast cancer, colonoscopies to detect and prevent colon cancer, Pap smears to detect and prevent cervical cancer, and PSA tests to detect prostate cancer. What all of these tests have in common is the theme that early detection saves lives. We also know that in people, cancers for which there are no good methods of early detection such as ovarian cancer and pancreatic cancer are often so advanced at the time of diagnosis that cure rates are low.
With that as context, it’s completely understandable that we would be eager to embrace technologies that offer early cancer detection for our dogs. Our natural expectation is that the earlier cancer is diagnosed, the better chance our dogs will have for a cure or improved prognosis. And of course, this is especially on the minds of owners of breeds at highest risk for cancer1.
Therefore, the recent announcement of a new cancer detection blood test2 intended for use as “a wellness screen for the apparently healthy dog prior to the onset of visible signs” has raised a great deal of interest among dog owners. The most immediate question seems to be, “Does it really work?” While some of this discussion will be specific to this particular test, the general considerations can guide evaluation of other tests marketed for similar purposes.
Veterinary Diagnostic Institute’s (VDI) INCaSe test uses measurements of thymidine kinase-1 (TK1) and C-reactive protein (CRP) in an undisclosed algorithmic formula to provide a result that is claimed to inform the owner with a high degree of accuracy that the dog is either at “increased risk for neoplasia or other disorder” (Positive); has a high probability of “active malignant disease” (High Positive); or at “low risk of major neoplastic disease in the next several months” (Negative). First we’re going to discuss a little bit of the science behind this test (don’t worry, just a few paragraphs!), and then we’ll examine how “early cancer detection” screening as it currently stands impacts dogs and their owners.
Thymidine kinase-1 is an enzyme that is present in dividing cells, and since cancers by definition include uncontrolled cell division, it has long been known in humans that TK1 levels increase in the presence of cancer. The most dramatic rise is in hematologic (blood) malignancies, and the primary use for TK1 assays in humans is in monitoring remission in non-Hodgkin lymphoma. Note that it is not used as a screening test for early detection of disease in apparently healthy people, and we'll get back to that point in a minute.
A few small peer-reviewed (meeting accepted scientific standards) studies have validated that a rise in TK1 also occurs in dogs with lymphomai (LSA), and one recent study showed that TK1 rises in dogs with hemangiosarcomaii (HSA). All of these studies compared TK1 values in dogs
1 However, although the risk is even higher in some breeds, 50% of all dogs over the age of 10 get cancer.
2 INCaSe canine cancer screen (Initial Notification Cancer Screen), Veterinary Diagnostics Institute
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with either LSA or HSA to normal dogs, and none of these studies included C-reactive protein testing (as does VDI’s INCaSe test). CRP is a general measure of inflammation, and while it is not specific to cancer, elevated CRP has been associated with several kinds of cancer in people. Evidence is beginning to accumulate that CRP may also be elevated in dogs with several kinds of cancer
iii iv, but high CRP can also be caused by infection, some autoimmune diseases, and many chronic diseases. Likewise, TK1 can also rise for reasons other than cancer, such as viral infections and wound healing after trauma and surgery.
While some abstracts have been provided in the endnotes for those who want more details, what all of this means is that there is definitely some scientific support for the claim that TK1 and CRP levels are often elevated in dogs that have certain kinds of cancer, primarily lymphoma and hemangiosarcoma. What it does not mean, however, is that there is scientific evidence indicating that TK1 and CRP levels are elevated in “apparently healthy” dogs prior to the onset of other signs of cancer (a group that VDI targets for its INCaSe test). As of this writing (February 2012), there are no published peer-reviewed studies that have examined this question.
However, the study reported in Abstract i measured TK1 levels in dogs with lymphoma that had been treated with chemotherapy and were in remission. Investigators found that high TK1 levels at the time of diagnosis generally returned to normal during remission, and then rose significantly by three weeks prior to relapse. They concluded from this study that TK1 could be used to predict recurrence of disease several weeks prior to clinical signs, and this is very similar to the way that TK1 testing is used in monitoring people with non-Hodgkin lymphoma.
Although there are no peer-reviewed data to support this next supposition, for the sake of discussion let's just say that an “early cancer detection test” might be able to predict LSA or HSA in a healthy dog in advance of clinical signs. Or maybe some owners will just be interested in trying a test out of curiosity. So let's examine a couple of likely scenarios of what might happen if the result comes back “positive” on a well-dog screening test.
In the first scenario, the owner of course is worried and upset, and sets forth on a mission to find cancer. It is very likely that the owner will want further testing to be done, which may include ultrasounds, radiographs, blood panels, and maybe even an MRI. And at the end of all that, the owner has spent quite a bit of money and nothing was found. Without a specific disease to treat, the owner then just worries and waits for cancer to show itself clinically, and nothing useful was gained. A good case could be made that it would have been better not to have done a screening test, and instead of wasting resources chasing a diagnosis that wasn’t yet detectable, wait until cancer becomes clinically evident (if it ever does – some results will be false positives). Those resources could then be spent on treating the dog if that is the owner’s choice.
In an alternate scenario, prompted by a positive “early cancer detection test,” an abdominal ultrasound does indeed find a splenic mass. Although the test cannot tell for certain whether the mass is hemangiosarcoma or perhaps a benign hematoma, let's go with the worst case and say it's HSA and the dog has a splenectomy. Has anything been gained for dogs in which a tumor is discovered as a result of a positive screening test? Well, providing that the tumor is in an operable site, it's true that the dog will not suddenly collapse and die unexpectedly, and that is
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certainly important to the very small percentage of owners whose dogs will fit this circumstance. Sadly, however, the deadly course of the disease will not have changed, because early detection has never been shown to improve outcome with regard to ability to achieve remission, duration of remission, or overall survival time in either lymphoma or hemangiosarcoma.
Further, if, for example, TK1 values can only predict disease a few weeks in advance of clinical signs (as research indicates to be the case in detecting lymphoma remissions) – and since HSA is an extremely rapidly developing disease -- there is probably only a very narrow slice of time in which the above scenario will apply. And indeed, VDI’s own interpretation of a Negative result on their test states that the dog is at “low risk of major neoplastic disease in the next several months,” which appears to acknowledge that there is only a short window of time during which test results might be meaningful.
Reframing the Question
So where does this leave us? Unfortunately, for the vast majority of owners whose dog receives a positive result on an “early cancer detection test,” there will be nothing whatsoever that they can do to improve their dog's outcome based on having had the test. For this reason, some scientists who have developed other methods of early detection -- as well as many clinical general veterinarians and oncologists -- consider it questionable to promote or offer these kinds of cancer predictive tests. And let's come back to the case with humans, in which much more is known about TK1 testing. TK1 testing in humans is not used as a widespread or even targeted (to high-risk populations) screening test to predict lymphoma. Why? For the same reason -- it does not improve outcome.
In discussing a test marketed by another company (OncoPet Diagnostics, Inc.3) for the early detection of cancer in dogs, board certified veterinary oncologist Dr. Timothy Rocha noted in an online article, “It’s made by a company that is out to make a profit so, of course, they want as many people to use their product as possible. The problem arises when people who love their pets feel the need to go on a ‘cancer hunt,’ subjecting their animals to a lot of unnecessary diagnostic testing that can actually stress your pet and cost owners thousands of dollars. Owners
3 OncoPet Diagnostic Inc Disclaimers, excerpted below, certainly raise some concern with this test also:
• The OncoPet RECAF™ test has NOT been approved by the U.S. Food and Drug Administration, the U.S. Department of Agriculture, or any other regulatory organization in any country for use in the diagnosis of cancer in any species
• Some normal animals may test positive for cancer (false positives) and some animals with cancer may test negative using the OncoPet RECAF™ test (false negatives). Depending on the type of cancer, the number of false negatives can be as high as 25% (75% sensitivity) and the number of false positives among normal dogs can be as high as 10% (90% specificity). It should be kept in mind that these figures are calculated from experiments done on the most common types of cancers in companion animals and therefore they may be different for other types of cancers for which sensitivity values might not have been assessed yet. Some acute inflammatory lesions produce very high levels of circulating RECAF™ and therefore samples from animals suspected of having an inflammatory process or infection should not be sent for testing.
• The calculation of the positive/negative cutoff value and the sensitivity and specificity of the test are estimated from a relatively small number of samples and might not reflect the values obtained from a larger number of samples
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want to do what is best for their animals, but this type of testing doesn’t always amount to a positive for your dog.”
Now, all that said, there may indeed be a more useful way to apply TK1 testing, and this is beginning to find its way into oncology practices. TK1 levels may be monitored during remission in dogs that have been treated with chemotherapy for lymphoma, following the model of a similar use in humans. Levels that remain high or become high during remission may indicate the need for more frequent follow-up intervals, so that rescue protocols can be initiated at the first sign of relapse. There is also some evidence to suggest that high TK1 levels prior to therapy correspond to significantly shorter survival time (Abstract i). However, for a number of reasons, it does not appear that this is currently in widespread use to predict response to therapy or duration of remission.
In summary, owners must decide for themselves and in consultation with their veterinarian whether any of the early cancer detection tests make sense for their dog in their individual circumstances. But as one considers the science behind and the value of tests marketed for the early detection of cancer, the initial question of “Does it really work?” should perhaps be reframed into the more relevant “Will it benefit my dog?”
By Rhonda Hovan
Research Facilitator, Golden Retriever Club of America
Correspondence to: rhondahovan@aol.com
Abstracts
i J Vet Intern Med. 2004 Sep-Oct;18(5):696-702.
Serum thymidine kinase activity in dogs with malignant lymphoma: a potent marker for prognosis and monitoring the disease.
von Euler H, Einarsson R, Olsson U, Lagerstedt AS, Eriksson S.
Source
Faculty of Veterinary Medicine and Animal Science, Department of Small Animal Clinical Sciences, Swedish University of Agricultural Sciences (SLU), S-750 07 Uppsala, Sweden. henrik.von.euler@kirmed.slu.se
Abstract
Serum thymidine kinase (sTK) activity was evaluated as a tumor marker for canine malignant lymphoma (ML). The objective was to investigate if sTK, as in humans, could be used as a prognostic marker for survival time in dogs with ML and if sTK could identify early signs of progression of disease in treated dogs. Serum samples from 52 dogs with ML were tested for initial TK activity. Samples from 21 normal dogs and 25 dogs with nonhematologic neoplasms were used for comparison. Forty-four dogs with ML were treated. Serum TK activity was measured in treated dogs before each treatment and every 4 weeks thereafter until relapse. Dogs with ML had 2-180 times higher TK activity (TK 5-900 U/L) than normal dogs (TK <7 U/L) based on the mean + 2 standard deviations. In the group of other neoplasms, only 2 dogs had a moderate increase (6.4 and 7.5 U/L) compared with the controls. Mean sTK activities in the dogs with ML that had gone into complete remission (CR) were not significantly different from activities in healthy controls (P = .68). Mean sTK at least 3 weeks before and at the time of relapse was significantly higher than activity measured at CR (P < .0001). Dogs with ML that initially had sTK >30 U/L had significantly shorter survival times (P < .0001). Furthermore, sTK activity reflected the clinical staging of ML. Measuring sTK can be used as a powerful objective tumor marker for prognosis and for predicting relapse before recurrence of clinically detectable disease in dogs with ML undergoing chemotherapy.
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ii Vet Comp Oncol. 2011 Oct 20. doi: 10.1111/j.1476-5829.2011.00298.x. [Epub ahead of print]
Elevated serum thymidine kinase activity in canine splenic hemangiosarcoma(*).
Thamm DH, Kamstock DA, Sharp CR, Johnson SI, Mazzaferro E, Herold LV, Barnes SM, Winkler K, Selting KA.
Source
Animal Cancer Center, Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA Tufts University, North Grafton, MA, USA Emergency Animal Hospital of NW Austin, Austin, TX, USA Wheat Ridge Veterinary Specialists, Wheat Ridge, CO, USA Dove Lewis Emergency Animal Hospital, Portland, OR, USA Animal Emergency Critical Care, The LifeCentre, Leesburg, VA, USA Georgia Veterinary Specialists, Atlanta, GA, USA University of Missouri, Columbia, MO, USA.
Abstract
Thymidine kinase 1 (TK1) is a soluble biomarker associated with DNA synthesis. This prospective study evaluated serum TK1 activity in dogs presenting with hemoabdomen and a splenic mass. An ELISA using azidothymidine as a substrate was used to evaluate TK1 activity. Sixty-two dogs with hemoabdomen and 15 normal controls were studied. Serum TK1 activity was significantly higher in dogs with hemangiosarcoma (HSA) than in normal dogs (mean ± SEM = 17.0 ± 5.0 and 2.01 ± 0.6, respectively), but not dogs with benign disease (mean ± SEM = 10.0 ± 3.3). Using a cut-off of 6.55 U/L, TK activity demonstrated a sensitivity of 0.52, specificity of 0.93, positive predictive value of 0.94 and negative predictive value of 0.48 for distinguishing HSA versus normal. When interval thresholds of <1.55 and >7.95 U/L were used together, diagnostic utility was increased. Serum TK1 evaluation may help to discriminate between benign disease and HSA in dogs with hemoabdomen and a splenic mass.
iii Vet Clin Pathol. 2009 Sep;38(3):348-52. Epub 2009 Apr 16.
Evaluation of serum haptoglobin and C-reactive protein in dogs with mammary tumors.
Planellas M, Bassols A, Siracusa C, Saco Y, Giménez M, Pato R, Pastor J.
Source
Department of Animal Medicine and Surgery, Universitat Autonoma de Barcelona, Barcelona, Spain. marta.planellas@uab.cat
Abstract
BACKGROUND:
In veterinary medicine, there is increasing interest in measuring acute phase proteins as a tool in the diagnosis and monitoring of neoplastic diseases. Although mammary neoplasms are the most common type of cancer in dogs, acute phase proteins have not been extensively evaluated in dogs with mammary tumors.
OBJECTIVES:
The aim of this study was to evaluate serum haptoglobin (Hp) and C-reactive protein (CRP) concentrations in the dogs with mammary tumors and assess their potential association with malignancy.
METHODS:
A retrospective study of dogs with mammary tumors was performed. Serum concentrations of CRP and Hp were determined in healthy control dogs (n=20) and dogs with mammary tumors before surgery (n=41). Mammary tumors were grouped as carcinomas (n=24), fibrosarcoma (n=1), malignant mixed tumors (n=7), benign mixed tumors (n=6), and adenomas (n=3). CRP and Hp concentrations were compared in dogs with different tumor types and were also compared based on tumor size, lymph node infiltration, skin ulceration, fixation to underlying tissue, and time between tumor identification and removal.
RESULTS:
Hp concentration was significantly (P<.043) higher in dogs with mammary tumors (median 2.03 g/L, range 0.09-2.94 g/L) compared with controls (1.38 g/L, range 0.08-3.00 g/L), but the range of values overlapped considerably. CRP concentration was higher in dogs with carcinomas (4.70 mg/L, range 0.63-128.96 mg/L) vs controls (2.11 mg/L, range 0.25-6.57 mg/L) (P=.0008) and in dogs with ulcerated skin (14.8 mg/L, range 5.7-128.9 mg/L, n=3) compared with those without ulceration (2.4 mg/L, range 0.11-30.3 mg/L, n=38) (P=.048).
CONCLUSIONS:
Serum Hp and CRP do not appear to have value in diagnosing or predicting malignancy of mammary tumors in dogs. Higher CRP concentrations in dogs with mammary carcinoma suggest a role for inflammation in this tumor type.
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iv Vet J. 2007 Jul;174(1):188-92. Epub 2006 Aug 9.
Changes in C-reactive protein and haptoglobin in dogs with lymphatic neoplasia.
Mischke R, Waterston M, Eckersall PD.
Source
Small Animal Clinic, Hannover School of Veterinary Medicine, Hannover, Germany. reinhard.mischke@tiho-hannover.de
Abstract
Acute phase proteins (APP) are regarded as a useful diagnostic tool in humans with lymphomas, leukaemias and multiple myeloma. C-reactive protein (CRP) and haptoglobin concentrations were measured in dogs with malignant multicentric (high grade) lymphoma (n=16), acute lymphoblastic leukaemia (ALL) (n=11), chronic lymphocytic leukaemia (CLL) (n=7) and multiple myeloma (n=8). Twenty-five healthy dogs served as controls. Measurements of the CRP plasma concentration were performed using a commercial ELISA and haptoglobin was measured with an assay based on its haemoglobin binding capacity. Global group comparisons using Kruskal-Wallis-test revealed significant group differences for both APPs (P<0.0001). Median CRP concentrations were increased in all groups with neoplastic lymphatic disorders (lymphoma: 37.2mg/L, ALL: 47.8mg/L, CLL: 35.5mg/L, myeloma: 17.6mg/L) compared to controls (1.67mg/L; P<0.001). Compared to the healthy controls (median=0.59g/L), haptoglobin was especially increased in dogs with ALL (6.8g/L, P<0.0001) followed by dogs with malignant lymphoma (3.8g/L, P<0.0001), CLL (3.2g/L, P=0.0008), and multiple myeloma (3.0g/L, P=0.0163). For both APPs, a wide range of values was found in all patient groups. The results indicate that particularly severe and acute lymphatic neoplasia, such as high grade lymphoma and ALL, cause significant acute phase reactions in dogs and must be included in the differential diagnoses of increased blood levels of these APPs.