2014-09-12

I am often asked by clients if there is a blood test that can tell if their apparently healthy pet has cancer. Obviously, “cancer” is a scary word, and many of the various diseases given that label are difficult to diagnose and treat. Many people have had personal experiences of a family member, human or non-human, developing cancer, and they are understandably looking for a way to identify such disease as early as possible, with the hope this will make it easy to control or even cure. Unfortunately, like most things in medicine, the reality is far more complex and uncertain than a simple blood test that will identify a hidden cancer in time to treat it.

Cancers differ in their basic biology and behavior, so each requires a different approach to diagnosis. Leukemia may show up as an abnormal number of white blood cells in a complete blood test, but breast cancer will not. High calcium levels have been associated with several cancers, but these range from lymphoma, a common white blood cell cancer spread throughout the body, to anal gland carcinoma, an uncommon tumor that shows up in that particular location only. The variety among cancers make any single test for most or all types very unlikely.

A Bit About Screening Tests

It is also important to understand a bit about the difference between testing for a disease when there is some symptom or other reason to suspect it is present (diagnosis) and testing for the presence of disease in apparently healthy patients (screening). The chances of getting the right answer from a specific test for a particular cancer are much higher when the patient has typical symptoms or other test results that suggest the presence of that cancer. All tests are imperfect, and all give false positive or negative results sometimes. If large numbers of healthy patients are tested, most of whom don’t have the disease, then a lot of the positive tests will turn out to be wrong, but most of the negatives will be true. This is the case even for very, very good tests.

The best way to illustrate this is—brace yourself—with a little math.

Say you have 10,000 people to test, none of whom have any symptoms or problems to suggest they have cancer. However, 200 of them have the cancer you are testing for (2%), while 9,800 do not. You have a test that is about as close to perfect as you can get–98% sensitive and 98% specific. That means that if you have 100 patients with the disease, 98 will test positive and 2 will test negative even though they have it (sensitivity). It also means that if you test 100 patients who don’t have the disease, 98 will test negative and 2 will test positive even though they don’t have it (specificity).

So we test all 10,000. Here are the results we will get:

True positive (test positive and have cancer)- 196

True negative (test negative and don’t have cancer)-9,604

False positive (test positive but don’t have cancer)-196

False negative (test negative but actually have cancer)-4

So we found most of the cases of cancer and we re-assured most of the healthy people. BUT, we also told 4 people with cancer that they were fine. And we told 196 healthy people they had a terrible disease. Did we do more good than harm?

Well, it depends on lots of other things. If early detection leads to more effective treatment and better survival, then at least the true positive patients will benefit. However, those we missed will think all is well and may ignore future symptoms or test results that might actually help them get treatment.

On the other hand, if early detection with this test doesn’t lead to better treatments and outcomes, then all we’ve done is give people bad news which they can’t do anything about even if it’s true. Screening doesn’t help anybody if there is nothing we can do about the disease at the point at which we detect it.

It is also likely that those who got a positive test will have to undergo uncomfortable and expensive testing and maybe even cancer treatment even if they don’t actually have cancer (which, remember, is almost 200 of our patients). We have actively harmed these folks with our test.

There has been a lot of controversy in human medicine recently about screening tests for cancer that were once widely recommended. PSA testing for prostate cancer, for example, turns out to cause a lot of harm. Positive test results often result in expensive and uncomfortable treatment with some serious side effects, and yet it appears not to reliably improve long-term outcomes. In other words, men who get tested will often suffer more harm from treatment without actually living any longer than men who did not get early detection with this test. While the test still has some appropriate uses, widespread screening of men with no symptoms of disease turns out not to be a very good idea. Similar concerns have led to changes in screening for breast cancer and to a growing recognition in human medicine that screening tests of apparently healthy people lead to significant overdiagnosis and harm in many cases.

The situation is a bit different in veterinary medicine. For one thing, there are few blood tests that have been tested at all for the ability to detect cancer before symptoms develop. And for most cancers, there is no research evidence that such early detection would allow us to better treat or even cure such cancers if we could find them. While it is often assumed that the earlier we detect cancer the more we can do about it, this has not been proven in dogs and cats and has actually turned out not to be surprisingly often in humans.

But My Vet Said There Was a Good Screening Test for Cancer

Unfortunately, there are still some veterinarians who will recommend, and sell you, cancer screening blood tests for your pets with a good deal more confidence in their benefits than is justified. A recent article, written by an alternative medicine practitioner I’ve written about before, makes strong claims for his ability to use a couple of blood tests, C-reactive protein, thymidine kinase, and Vitamin D3 levels, to detect cancer or precancerous conditions before your pet is sick and then treat them effectively.

A series of simple, new, inexpensive blood tests bundled into a diagnostic panel now allows doctors to detect cancer and other serious problems before they develop in your dog or cat…These new blood tests can determine your companion’s risk of developing this dreaded disease, and even detect it in its earliest stages.

While these new cancer tests are very helpful for determining the status of your animal’s health before he becomes ill, they are also helpful for monitoring dogs and cats that already have cancer. For those already diagnosed with the disease, monitoring [these] levels helps veterinarians make decisions about changing treatment and to predict when/if the cancer may return and when the animal may come out of remission.

This cancer testing is very cost effective. In our office, we charge under $200 for the entire three-test profile, making it very inexpensive considering the wealth of information we receive from it. Additionally, this profile is the easiest and least expensive way to screen dogs and cats for cancer and other serious inflammatory diseases. There are really no disadvantages to having this testing done.

These claims raise a number of important questions: 1. Can these tests really detect cancer before your pet has symptoms? 2. What should we do if we have a positive test result? 3. Does testing, and whatever we do next, help prevent illness or prolong health and life? 4. Can this testing do any harm?

Can these Tests Really Detect Cancer Before My Pet Gets Sick?

The short answer is, we don’t know. It is important to remember that none of these tests is routinely used or recommended for cancer screening of healthy people or animals by doctors or organizations specializing in cancer detection and treatment. This kind of screening is not a widely accepted practice. Nevertheless, there is research evidence looking at the possible value of these tests for cancer screening. I will offer a brief summary of the evidence and try to answer our four questions.

Thymidine kinase (TK1)- This is a substance which is produced by dividing cells. Since cancer cells typically divide more rapidly than healthy cells, it tends to be produced in greater amounts when there are cancer cells present. This is particularly true for cancers of blood cells, such as lymphoma and leukemia. TK1 it is less consistently elevated in patients with other kinds of tumors. To a lesser extent, elevated TK1 levels have also been associated with viral infections and inflammatory conditions as well as cancer.

There is a lot of evidence to suggest that TK1 levels are higher in dogs with known cancer than in healthy dogs, especially when the cancer is lymphoma or leukemia. Most studies compare health animals with those already diagnosed with cancer by other methods, and they usually find higher TK1 levels in the cancer group. These are not, however, animals with occult cancer, that is cancer that hasn’t caused any symptoms or been diagnosed yet. Whether TK1 levels are consistently higher in dogs who have cancer but not symptoms hasn’t been clearly demonstrated. The TK1 levels of healthy dogs, dogs with cancer, and dogs with other diseases overlap quite a bit. There are even some studies in which as many as half of the dogs with known lymphoma had normal TK1 levels. So there are certainly not clear absolute differences to distinguish these groups.

While it has some potential, TK1 testing is not clearly a useful diagnostic or monitoring tool for dogs with most cancers, much less a screening tool for dogs who might or might not have cancer. As usual, there is even less data related to cats, though there are some suggesting TK1 might behave similarly in this species.

C-Reactive Protein (CRP)-

CRP is a protein associated with inflammation. Inflammation can be caused by many different things, such as infection, autoimmune disease, and of course cancer. CRP is quite sensitive to inflammation, but it does nothing to help distinguish the cause. In dogs, CRP is elevated in at least some kinds of cancer, and the values are generally higher than in dogs without cancer. However, there is significant overlap between these groups, so some dogs with cancer will have normal CRP and some without will have elevated CRP. Interestingly, dogs with lymphoma who are in remission (no illness or detectable tumor but microscopic cancer still present somewhere) generally have lower CRP than dogs with active lymphoma. This means CRP could possibly be used to test for relapse of this cancer. However, dogs in remission are just like dogs without symptoms of cancer who we would be using a test like this to screen, so these data suggest we wouldn’t be able to find lymphomas with this test if there were no symptoms or obvious tumors.

Vitamin D-

Vitamin D, like all vitamins, has a number of essential functions in the body. It has been well known for decades how much vitamin D people (and dogs and cats) require to prevent symptoms of Vitamin D deficiency disease. However, it has been a bit of a fad for a while now to claim that even higher levels would have protective effects against a variety of diseases, including cancer.

This is based largely on a few studies which found that people with certain disease, including some kinds of cancer, tend to have lower Vitamin D levels than healthy people. However, additional research has failed to demonstrate that low levels cause these diseases or that supplements prevent them. People who are sick may have low Vitamin D levels as a symptom of their illness rather than as part of its cause. For the most part, testing for Vitamin D and supplementing to prevent cancer is not recommended in humans unless there are specific reasons to believe an individual patient is at risk for low Vitamin D levels (in other words, routine screening is not recommended).

There is not good evidence to suggest that subclinical Vitamin D deficiency is a real problem in dogs or cats either, or that supplementation beyond the levels currently used in commercial diets is of any benefit.

Veterinary Diagnosic Institute Cancer Tests-

Despite the fact that these tests are not used as general cancer screening aids in humans, and the lack of strong evidence to show they can reliably predict cancer in dogs and cats, there is a company selling these tests as a tool for cancer screening, as well as for cancer diagnosis and monitoring response to therapy. Apart from the general information for each test I’ve already discussed, the company has produced one clinical study to evaluate its screening test.

Selting KA, Sharp CR, Ringold R, Knouse J. Serum thymidine kinase 1 and C-reactive protein as biomarkers for screening clinically healthy dogs for occult disease. Vet Comp Oncol. 2013 Jul 16. doi: 10.1111/vco.12052. [Epub ahead of print]

This study involved collecting blood from about 360 dogs (German shepherds and golden retrievers) to test for CRP and TK1 and then following them for 6 months or more to see which developed cancer or died of some other disease. The dogs were not evaluated by a veterinarian as part of the study, and most health information was obtained from questionnaires completed by owners. This raises the possibility that some dogs may not have been properly classified or diagnosed, which might change the results and conclusions significantly.

As expected, over the short course of the study the incidence of cancer was pretty low, about 3%. This means 11 dogs developed some kind of cancer. Because CRP is not very specific for cancer but simply detects any inflammation, it was not used by itself to predict cancer development. However, the TK1 test tends to be more specific for cancer but not as sensitive as the CRP, so the authors looked at both the TK1 by itself and the combination of the two tests (called the neoplasia index or NI) to predict cancer development.

Sensitivity and specificity of a diagnostic test are always in opposition to one another. The more sensitive a test is (that is, the more actual cases of disease it finds), the less specific it is (that is, the more healthy patients will test positive for a disease they don’t have). This is true for any test, and the balance between the two numbers is related to what value of the test one uses as a cutoff. In this study, the authors followed the common practice of  analyzing their data with a variety of cutoffs to try and find the best balance between sensitivity and specificity for the test.

In the case of cancer screening for apparently healthy patients, there are dangers to both a low sensitivity and a low specificity. If the test is very sensitive but not very specific, then it will indicate a lot of healthy animals have cancer when they don’t. Apart from the worry this creates for their owners, there will be a lot of expensive, and sometimes uncomfortable or even dangerous, follow-up testing and possibly even unnecessary treatment for a disease that isn’t there. This is the danger of overdiagnosis.

On the other hand, if a test is very specific but not very sensitive, a lot of animals with cancer will show up as healthy on the test. This is a problem if early detection and treatment could lead to a better outcome, though as I mentioned earlier this has not generally been demonstrated for dogs and cats with cancer.

For TK1 alone, the best sensitivity achieved was 100%, meaning all dogs that developed cancer later had an abnormal test at that particular cutoff. However, when that level was used, the specificity was 0, meaning that everybody would test positive whether they had cancer or not. At the other end, the best specificity achieved was 98%, but at this level sensitivity was only 27%. Between these extremes, it was possible to get one or the other value around 80% with the opposite value about 70%. This is not a very good compromise for a test intended to be used in a population with a very low rate of cancer because there will be a lot of patients misclassified with regard to a very serious disease.

The authors expected, of course, the TK1 to be pretty specific (good at ruling out cases that don’t have cancer) but not very sensitive. This is why they combined it with the more sensitive CRP to try and improve the overall sensitivity without losing too much specificity. This combined neoplasia index had an optimal balance of sensitivity and specificity at 82% sensitivity and 91% specificity. In the case of a cancer screening test, it is probably better to favor specificity so you don’t do unnecessary tests and treatments on healthy animals. A lower sensitivity will miss some true cases of disease, but it isn’t clear yet that finding these cases earlier improves their outcome, and of course they will eventually develop symptoms that will lead to a diagnosis.

In the case of a screening test, which is intended to be used on a population which is mostly healthy and disease is rare (about 3% in this study, for example), there are a couple of numbers more useful than specificity and sensitivity. These are the positive predictive value (PPV) and the negative predictive value (NPV). The PPV is, essentially, the percentage of positive tests that are correct, that is the patient actually has the cancer the test says they have. The PPV for this test in this study was 22.5%. That means that when a patient has a positive test, only about 22% of the time is there actually a cancer there. That leads us to  the second question….

What Should I Do if my Pet Has a Positive Test?

The veterinarian promoting this test offers some hint of how he responds to positive results.

In my practice, animals with increased TK levels are supplemented with specific herbal remedies (Healthy Qi, CA Support, etc.) to support their immune systems. The blood is retested one month later. If TK levels are back to normal, no further testing is needed for four months. If TK levels continue to increase, then we must search further for the reason why it’s increasing. A persistent elevation of TK levels predicts the likelihood of cancer developing over the next six months.

So this doctor recommends responding to a positive test with the use of unproven, and untested, herbal products from the pre-scientific system of myths and metaphors known as Traditional Chinese Veterinary Medicine (TCVM). Given the implausible and unvalidated methods used in this system, the risks of untested and unregulated herbal supplements, and the fact that the concept of “boosting the immune system” is itself nonsense, this is certainly not a useful response. Of course, the plan proposed here also ignores the fact that values such as these vary with time for many reasons, and the fact that they might decrease when such remedies are used does not, of course actually mean the remedies are responsible, though that is undoubtedly the implication here.

I would like to be able to say that this approach is only that of this individual “holistic” veterinarian, and it does not necessarily imply that VDI has a similarly dubious and evidence-poor approach to the use of their products. However, among the informational materials VDI offers vets to help understand how to use this test is an article, entitled The Holistic View, by this same doctor. Clearly, the company is willing to endorse such dubious practices in the interest of marketing its products.

Simply following TK1 levels over time, if one chooses to measure them, may be a more reasonable strategy. Persistent elevations or increases over time are more likely to be meaningful than individual values. But instituting dubious treatment in response to an elevation is not rational. Neither is an extensive diagnostic workup looking for cancer. While the risks of diagnostic imaging, such as chest x-rays and abdominal ultrasounds, are low, these tests do have costs, they can find irrelevant abnormalities which would lead to unnecessary further testing and treatment, and they can generate false reassurance when they fail to find an abnormality. Effective use of such tests requires establishing a reasonable clinical index of suspicion which can help guide interpretation of the results and further actions.

This author makes similar recommendations for responding to elevated CRP levels, including the use of supplements of unproven or questionable value without a specific diagnosis or clear clinical purpose for making use of them.

In animals with elevated CRP or Hpt levels, specific nutritional supplements (antioxidants, fatty acids, etc.) are administered to reduce harmful inflammatory proteins. Diseases know to be associated with inflammation, such as dental disease, arthritis, and allergies, are diagnosed and treated appropriately to reduce inflammation in the body. The blood is retested in one month and CRP/Hpt levels should have returned to normal. If they haven’t, further investigation is undertaken.

And finally, the author makes a number of strong claims about the prevalence of Vitamin D deficiency and the need for supplementation that are not supported by real evidence or accepted by veterinary nutrition specialists.

While pet food is formulated with enough vitamin D3 to prevent deficiency disease (rickets), the levels are too low for maximum health. Testing shows most dogs have blood levels considered insufficient for optimal health, and would benefit from supplementation. Once the vitamin D3 test results are available, supplementation is given with the goal of shooting for a blood level of 100 mg/ml (in studies, animals with cancers tended to have vitamin D3 blood levels lower than 100.) Additional testing is done to confirm if the prescribed amount of vitamin D3, typically given once daily with food, is enough to reach the recommended blood level.

While there is certainly evidence that dogs with cancers, and other diseases, often have lower levels of Vitamin D than healthy dogs, as in humans it has not yet been clearly shown that the low levels increase the risk of developing disease or that supplementation prevents it. The specific number this author recommends as a target comes from a single study of dogs with a particular kind of cancer. And Vitamin D supplementation has risks as well, so recommending it based on inadequate data is not appropriate or helpful.

When screening tests of unproven value is recommended, and all abnormal results are taken as an indication to prescribe (i.e. sell) supplements that also have unclear value, it is difficult not to see profit as a significant motive in the marketing of this test. And while I don’t doubt this individual believes he is finding, and then treating or preventing cancer with this approach, this does not eliminate the potential influence of the obvious profit potential in this approach, nor excuse the lack of concern for the very weak evidence behind the practice.

A more evidence-based answer to the question of how to respond to a positive test result simply isn’t available, which is one of the major reasons why this sort of testing is not widely recommended. Until it is clear that the test consistently identifies real disease at a stage where it is both otherwise undetectable and can be more effectively treated, the testing and the diagnostic or therapeutic followup is based on little more than speculation or intuition, not sound, science-based medicine. This is also the answer to our third question….

Will Testing & the Followup Prevent Illness or Prolong Life?

The answer, unfortunately, is no one knows. The current evidence suggests some of these tests could lead to more effective detection and treatment of some cancers. However, as I mentioned earlier, this has not yet been proven to actually be true for humans or veterinary patients. The majority of promising ideas in medicine fail to fulfil their promise, which is why thorough scientific research is vital. Leaping on the bandwagon too early might occasionally work out well, but the odds are far better that it will lead to taking useless or even harmful actions that later evidence clearly shows we would be better off not having taken. If this particular testing strategy does turn out to work well for at least some patients, the folks promoting it will naturally look like prescient geniuses. If, as is more likely, it turns out to be less useful than hoped or even worthless or harmful, most people will probably not notice as we will likely move right on to the next promising idea. But a careful review of medical history suggests that we could make much better decisions, for ourselves and our pets, if we waited until the evidence was a lot stronger. After all, we are talking about testing healthy animals with no signs of disease! How much should we really put them through in an effort to prevent diseases they may not get using a test and therapies we don’t know actually work? Let’s not forget our last question…

Can These Tests Do Any Harm?

As I’ve already mentioned, overdiagnosis is a real, and serious, risk. The data shows that the PPV for this test, the proportion of positive results that are actually true, is quite low. So we are going to identify a lot of animals as having a disease they don’t have. If we put these animals through a lot of expensive diagnostic tests or, even worse, subject them to untested treatments as suggested by some proponents of this screening test, then we will generate a great deal of unnecessary stress for pets and their owners and unnecessary expense for some clients, and we may even harm some of the pets we are trying to help.

Of course, we will certainly detect at least some animals who actually do have cancer. Isn’t this a good thing, and doesn’t this balance the possible expense and harm we might do? Unfortunately, we don’t really know the answer to this either. Since we can’t be sure that detecting these cases earlier actually helps them, there is no way to balance that against the costs and risks of the testing.

Bottom Line

Screening tests, which try to identify hidden disease in apparently healthy animals, can sometimes be beneficial. If these tests are sufficiently accurate, and if we have truly useful treatments to offer the cases we find, then we can use such screening to reduce disease and suffering. However, at the moment there is no such screening blood test for cancer in dogs and cats.

The specific tests suggested here, thymidine kinase, C-reactive protein, and Vitamin D, do have some potential value in testing for cancer and monitoring cancer treatment. The evidence, however, is very preliminary and does not clearly tell us that these tests, alone or in combination, are sufficiently accurate to find most hidden cancers and not misidentify too many healthy animals as having cancer. Much more research needs to be done before these tests can be recommended as part of soundly scientific and evidence-based medicine.

And there is little evidence that if we had such a test we could actually help the pets with cancer we identified live longer or healthier lives. In addition to working on developing good screening tests for cancer in dogs and cats, we will need to find out which treatments, if any, can help these pets to live longer and stay healthier once we find them. Given unproven herbal remedies and supplements to these animals, even if the tests showing they have hidden disease are correct, does not benefit them and may do harm.

It is natural to want a clear, simply way to reassure ourselves our pets are healthy, and to want effective treatments to give them if we find they have cancer even though they appear healthy. However, taking the best care possible of our animal companions does not mean subjecting them to testing which is unreliable and therapies which aren’t proven to be safe and effective. Good preventative health care means scientific, evidence-based healthcare, not chasing after comforting promises without real evidence.

The best strategy for preventing disease in our pets is to feed them nutritionally complete diets, maintain them at a healthy, lean body condition, keep up with appropriate preventative care for infectious diseases and parasites, and provide them with appropriate socialization and training, physical and mental exercise, and love. While less dramatic in some ways that blood tests, supplements, and other kinds of constant tinkering with their physiology, this is still the best preventative health care we can give our pets.

Bibliography

There are many basic science articles investigating TK!, CRP, and Vitamin D in dogs and cats (mostly dogs). This is intended as a sample of the literature to illustrate the state of the existing evidence. There have not yet been systematic reviews of these tests and compounds for companion animals, but plenty of other studies are indexed on PubMed.

1. Vet J. 2013 Sep;197(3):854-60. doi: 10.1016/j.tvjl.2013.05.036. Epub 2013 Jul 4.

High levels of inactive thymidine kinase 1 polypeptide detected in sera from dogs

with solid tumours by immunoaffinity methods: implications for in vitro

diagnostics.

Kiran Kumar J(1), Sharif H, Westberg S, von Euler H, Eriksson S.

Determination of serum thymidine kinase 1 (STK1) activity has been used as a

proliferation marker for neoplastic diseases in both human and veterinary

medicine. The purpose of this study was to determine STK1 activity and enzyme

levels in different dog tumours. Serum samples from three dogs with leukaemia,

five with lymphoma, 21 with solid tumours and 18 healthy dogs were analyzed for

STK1 activity, using an optimized [(3)H]-deoxythymidine (dThd) phosphorylation

assay, and for STK1 protein levels using an immunoaffinity/western blot assay.

STK1 activity in dogs with haematological tumours was significantly higher than

in the solid tumour and healthy dog groups (mean ± standard deviation [SD] = 65 ±

79, 1.1 ± 0.5, and 1.0 ± 0.4 pmol/min/mL, respectively). Serum samples were

analyzed after immunoaffinity isolation by western blot and the TK1 26 kDa band

intensities quantified revealing that concentrations were significantly higher in

dogs with haematological tumours and solid tumours compared to healthy dogs (mean

± SD=33 ± 12, 30 ± 13, and 10 ± 5 ng/mL, respectively). Pre-incubation with the

reducing agent dithioerythritol (DTE) showed a decrease in STK1 activity and

protein levels in most samples, but an increase of about 20% in sera from healthy

dogs and from those with haematological malignancies. Compared to animals with

solid tumours, the specific STK1 activity (nmol [(3)H]-deoxythymidine

monophosphate (dTMP)/min/mg of TK1 protein of 26 kDa) was 30-fold higher in

haematological malignancies and 2.5-fold higher in healthy dogs, respectively.

The results demonstrate that there is a large fraction of inactive TK1 protein,

particularly in sera from dogs with solid tumours. The findings are important in

the use of STK1 as a biomarker.

2. Vet Comp Oncol. 2013 Jul 16. doi: 10.1111/vco.12052. [Epub ahead of print]

Serum thymidine kinase 1 and C-reactive protein as biomarkers for screening

clinically healthy dogs for occult disease.

Selting KA(1), Sharp CR, Ringold R, Knouse J.

Thymidine kinase (TK1) is a biomarker that correlates well with diagnosis and

prognosis in certain canine cancers. Canine C-reactive protein (cCRP) is a widely

accepted marker of inflammation correlated with increased risk and severity of

various diseases. We evaluated serum TK1 and cCRP concentrations in apparently

healthy dogs (n?=?360). All dogs were followed up for a minimum of 6?months by

health questionnaire. All dogs with cancer were identified using a proprietary

dual-biomarker algorithm [termed Neoplasia Index (NI)]. Specificity of positive

NI is 0.91 and high positive is 0.98. All-cause mortality was 20% in dogs with

elevated cCRP and 3% in dogs with low cCRP. The performance of serum TK1 and cCRP

as tools for screening for occult cancer is improved when evaluated together.

Serum TK1 and cCRP (unified in the NI) are useful in the screening of occult

canine cancer. cCRP is useful in screening for other serious diseases.

3. Vet Comp Oncol. 2013 Mar;11(1):1-13. doi: 10.1111/j.1476-5829.2011.00296.x. Epub

2011 Dec 8.

Thymidine kinase assay in canine lymphoma.

Elliott JW(1), Cripps P, Blackwood L.

The aim of the study was to evaluate if thymidine kinase (TK) correlated with

duration of first remission (DFR) or survival in dogs with lymphoma and if

initial TK levels correlated with stage and substage; and also to assess if TK

level at diagnosis correlated with immunophenotype. TK was assayed in 73 dogs

with treatment naïve lymphoma, then again after treatment; 47% had an initial TK

above the reference interval. Dogs with B-cell lymphoma had higher initial TK

activities than dogs with T-cell lymphoma. TK levels were not higher in dogs with

higher stage disease and TK activity prior to treatment was not associated with

DFR or survival. Where TK was elevated at diagnosis, it fell into the reference

range during remission. TK was normal in 53% dogs at diagnosis, which is higher

than previously reported. Further studies are warranted to assess the utility of

TK in dogs with lymphoma.

4. J Feline Med Surg. 2013 Feb;15(2):142-7. doi: 10.1177/1098612X12463928. Epub 2012

Oct 17.

Serum thymidine kinase activity in clinically healthy and diseased cats: a

potential biomarker for lymphoma.

Taylor SS(1), Dodkin S, Papasouliotis K, Evans H, Graham PA, Belshaw Z, Westberg

S, von Euler HP.

The thymidine kinases are enzymes that convert deoxythymidine to deoxythymidine

monophosphate and have a function in DNA synthesis. Rapidly proliferating cells

will have higher levels of thymidine kinase. Serum thymidine kinase activity

(sTK) is a useful tumour marker in humans and dogs, with utility as a prognostic

indicator in lymphoma. In the current study serum samples were collected from 49

clinically healthy cats, 33 with lymphoma, 55 with inflammatory disease and 34

with non-haematopoietic neoplasia (NHPN). sTK was measured using a radioenzyme

assay and a reference interval (1.96 × SD) was established from the clinically

healthy cats (<5.5 U/l). Mean sTK activity for healthy cats was 2.2 U/l (range

0.8-8.4, ± SD 1.7). Mean sTK activity for cats with lymphoma was 17.5 U/l (range

1.0-100.0 SD ± 27.4). Mean sTK activity for cats with NHPN was 4.2 U/l (range

1.0-45.0, SD ± 8.6). Mean sTK activity for the inflammatory group was 3.4 U/l

(range 1.0-19.6, SD 3.9). Cats with lymphoma had significantly higher sTK

activity than healthy cats or cats with inflammatory disease (P <0.0001) and cats

with NHPN (P <0.0002). sTK activity is a potentially useful biomarker for feline

lymphoma and further study is required to assess its utility as a prognostic

indicator.

5. Vet Comp Oncol. 2012 Dec;10(4):292-302. doi: 10.1111/j.1476-5829.2011.00298.x.

Epub 2011 Oct 20.

Elevated serum thymidine kinase activity in canine splenic hemangiosarcoma*.

Thamm DH(1), Kamstock DA, Sharp CR, Johnson SI, Mazzaferro E, Herold LV, Barnes

SM, Winkler K, Selting KA.

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.

6. Int J Oncol. 2009 Feb;34(2):505-10.

Monitoring therapy in canine malignant lymphoma and leukemia with serum thymidine

kinase 1 activity–evaluation of a new, fully automated non-radiometric assay.

Von Euler HP(1), Rivera P, Aronsson AC, Bengtsson C, Hansson LO, Eriksson SK.

Thymidine kinase 1 (TK), which is involved in the synthesis of DNA precursors, is

only expressed in S-G2 cells. Serum TK levels correlate to the proliferative

activity of tumor disease. Determinations of TK levels have so far relied on

radio enzyme assay (REA) and experimental ELISA methods, which have limited the

clinical use of this biomarker, although recent studies in dogs with malignant

lymphoma (ML) demonstrate its wide potential. A non-radiometric method based on a

competitive immunoassay with specific anti-3′-azido-deoxythymidine monophosphate

(AZTMP) antibodies has been further developed into the fully automated Liaison TK

assay (DiaSorin). Sera from healthy dogs (n=30), and dogs with leukemia (LEUK)

(n=35), ML (n=84), non-hematological tumors (n=50), and inflammatory disease

(n=14) were tested using both methods. Lymphoma and LEUK samples were available

before and during chemotherapy. The coefficients of variation for the Liaison TK

assay in this study were 6.3 and 3.4% (low/high TK, respectively), and the

correlation between TK REA (X) and the Liaison TK assay (Y) was y=0.9203x+1.3854

(R2=0.9501). The TK1 levels measured during chemotherapy gave very clear

differences between dogs in complete remission and dogs out of remission. A

Tukey-Kramer analysis showed that all LEUKs and MLs out of remission differed

significantly from the other groups. The Liaison TK assay showed high precision,

high sensitivity and a good correlation to the TK REA. The Liaison TK assay

provides valuable clinical information in the treatment and management of canine

LEUK and ML, with a potential to be further validated in human trials.

7. 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(1), Einarsson R, Olsson U, Lagerstedt AS, Eriksson S.

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.

8. J Vet Intern Med. 2004 Sep-Oct;18(5):595-6.

Serum thymidine kinase activity: an alternative to histologic markers of cellular

proliferation in canine lymphoma.

Madewell BR.

Thymidine kinase (TK) is a cellular enzyme which is involved in a ‘salvage

pathway’ of DNA synthesis. It is activated in the G1/S phase of the cell cycle,

and its activity has been shown to correlate with the proliferative activity of

tumor cells…. Clinical studies have reported high serum TK concentrations in a

variety of neoplasias. The majority of these studies concerned hematological

malignancies. TK seems to be a useful marker in non-Hodgkin’s lymphoma, where it

correlates with clinical staging and provides marked prognostic information on

(progression-free) survival.

PMID: 15515571  [PubMed - indexed for MEDLINE]

9. J Vet Med Sci. 1997 Oct;59(10):957-60.

Plasma thymidine kinase activity in dogs with lymphoma and leukemia.

Nakamura N(1), Momoi Y, Watari T, Yoshino T, Tsujimoto H, Hasegawa A.

Plasma thymidine kinase (TK) activity was evaluated as a plasma marker for canine

lymphoma and leukemia. A tentative “cut-off” value was set at 6.0 U/l as the

upper level of plasma TK based on the mean + 2SD of plasma TK activity in 13

clinically healthy dogs. The levels of plasma TK activity in all of the 20 dogs

with lymphoma and leukemia were higher than the cut-off value, whereas those in

dogs with lymphoma decreased in parallel with the reduction of the tumor mass

after chemotherapy. These findings suggested that estimation of plasma TK

activity can be used as a plasma marker for lymphoma and leukemia in the dog.

10. Vet Comp Oncol. 2014 Jul 8. doi: 10.1111/vco.12101. [Epub ahead of print]

Serum 25-hydroxyvitamin D concentrations in dogs – correlation with health and

cancer risk.

Selting KA(1), Sharp CR, Ringold R, Thamm DH, Backus R.

25-hydroxyvitamin D (25(OH)D) is important in bone health as well as many

diseases including cancer. Supplementation may increase responsiveness of cancer

cells to chemotherapy. Serum 25(OH)D, intact parathyroid hormone (iPTH) and

canine C-reactive protein (c-CRP) were measured in healthy dogs and dogs with

haemoabdomen. Regression analysis determined optimal 25(OH)D concentrations. In

healthy dogs (n = 282), mean iPTH concentrations correlated inversely (r(2) =

0.88, P < 0.001) to 25(OH)D concentrations. Variation in both iPTH and c-CRP

plateaued at 25(OH)D concentrations of 100-120 ng mL(-1) . Haemoabdomen dogs (n =

63, 43 malignant and 20 benign) had 25(OH)D concentrations ranging from 19.4 to

>150 ng mL(-1) . Relative risk of cancer increased with decreasing 25(OH)D

concentrations [RR = 3.9 for 25(OH)D below 40 ng mL(-1) (P = 0.0001)]. Serum

25(OH)D concentrations in dogs vary widely, and are influenced by dietary VitD

content. Serum vitD measurement can identify dogs for which supplementation may

improve health and response to cancer therapy.

11. Vet Parasitol. 2014 Jun 16;203(1-2):153-9. doi: 10.1016/j.vetpar.2014.02.001.

Epub 2014 Feb 25.

Serum acute phase protein concentrations in dogs with spirocercosis and their

association with esophageal neoplasia – a prospective cohort study.

Nivy R(1), Caldin M(2), Lavy E(1), Shaabon K(1), Segev G(1), Aroch I(3).

Spirocerca lupi, the dog esophageal worm, typically induces formation of

esophageal nodules, which may transform to sarcoma. Ante mortem discrimination

between benign and malignant esophageal masses is challenging. Serum acute phase

proteins (APPs) are utilized in diagnosis and prognosis of various canine

diseases as markers of inflammation. This study characterized serum APPs

concentrations in dogs with benign and malignant esophageal spirocercosis and

evaluated their accuracy in differentiating benign from malignant lesions.

Seventy-eight client-owned dogs with esophageal spirocercosis were included.

Serum C-reactive protein (CRP), haptoglobin, serum-amyloid A (SAA) and albumin

concentrations were measured upon diagnosis and follow-up visits, and compared

with healthy dogs, and between malignant and benign cases. Haptoglobin, CRP and

SAA concentrations were higher, and albumin concentration was lower (P<0.001 for

all) in infected dogs compared to healthy controls. Dogs with suspected neoplasia

had significantly higher CRP (P=0.011), haptoglobin (P=0.008) and SAA (P=0.05),

and lower albumin (P=0.012) concentrations compared to dogs with benign

esophageal nodules. APPs moderately discriminated between suspected malignant and

benign esophageal disease. None of the dogs with suspected neoplasia had

concurrent normal concentrations of all APPs. The present results indicate that

canine spirocercosis is characterized by an acute phase reaction, both at

presentation and during treatment. When concentrations of all four APPs are

within reference range, esophageal malignancy is highly unlikely. Although

concentrations of all positive APPs were significantly higher in suspected

neoplastic cases compared to benign ones, moderate discriminatory power limits

their clinical use. Neither APP was useful to monitor response to treatment.

12. Vet Rec. 2012 Jun 23;170(25):648. doi: 10.1136/vr.100401. Epub 2012 Jun 1.

Acute phase protein levels in dogs with mast cell tumours and sarcomas.

Chase D(1), McLauchlan G, Eckersall PD, Pratschke J, Parkin T, Pratschke K.

The acute phase proteins (APP) form part of a non-specific host response to

inflammation. They may be induced by a range of different causes, including

infection, inflammation, cancer and trauma. As they form part of the earliest

response to such insults, they have potential for early identification of

disease. In people, APP levels have been shown to correlate both with the extent

of disease and also the prognosis in several forms of neoplasia, including

prostate, oesophageal and colorectal cancer. As such, they can be used as

prognostic and monitoring tools. To date, similar studies in veterinary patients

have been limited, largely retrospective in nature and many are non-specific for

tumour type. The purpose of this study was to evaluate a panel of four APPs in

dogs with naturally occurring mast cell tumours (MCTs) and sarcomas to identify

in the first instance whether increased levels of individual APPs, or

identifiable combinations of APPs, was linked with the presence of disease. In

the patients with MCTs, C-reactive protein (CRP) and a-1 acid glycoprotein levels

increased, with a concurrent drop in serum amyloid A levels. In the sarcoma

patients, CRP, a-1 acid glycoprotein and haptoglobin were increased. These

findings suggest that specific solid tumour types in dogs may be associated with

specific changes in APP profiles.

13. Vet Clin Pathol. 2009 Sep;38(3):348-52. doi: 10.1111/j.1939-165X.2009.00139.x.

Epub 2009 Apr 16.

Evaluation of serum haptoglobin and C-reactive protein in dogs with mammary

tumors.

Planellas M(1), Bassols A, Siracusa C, Saco Y, Giménez M, Pato R, Pastor J.

Author information:

(1)Department of Animal Medicine and Surgery, Universitat Autonoma de Barcelona,

Barcelona, Spain. marta.planellas@uab.cat

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.

PMID: 19392756  [PubMed - indexed for MEDLINE]

14. J Vet Intern Med. 2007 Nov-Dec;21(6):1231-6.

Serum C-reactive protein concentration as an indicator of remission status in

dogs with multicentric lymphoma.

Nielsen L(1), Toft N, Eckersall PD, Mellor DJ, Morris JS.

BACKGROUND: The acute-phase protein C-reactive protein (CRP) is used as a

diagnostic and prognostic marker in humans with various neoplasias, including

non-Hodgkin’s lymphoma.

OBJECTIVE: To evaluate if CRP could be used to detect different remission states

in dogs with lymphoma.

ANIMALS: Twenty-two dogs with untreated multicentric lymphoma.

METHODS: Prospective observational study. Blood samples were collected at the

time of diagnosis, before each chemotherapy session, and at follow-up visits,

resulting in 287 serum samples.

RESULTS: Before therapy, a statistically significant majority of the dogs (P =

.0019) had CRP concentrations above the reference range (68%, 15/22). After

achieving complete remission 90% (18/20) of the dogs had CRP concentrations

within the reference range, and the difference in values before and after

treatment was statistically significant (P < .001). CRP concentrations of dogs in

complete remission (median, 1.91; range, 0.2-103) were significantly different (P

= .031) from those of dogs with partial remission (median, 2.48; range, 0-89),

stable disease (median, 1.77; range, 1.03-42.65), or progressive disease (median,

8.7; range, 0-82.5). There was profound variation of CRP measurements within each

dog.

CONCLUSIONS: CRP is useful in determining complete remission status after

treatment with cytotoxic drugs. However, the individual variation between dogs

means CRP concentration is not sufficiently different in other remission states

to permit its use in monitoring progression of the disease. Greater reliability

in determining remission status might be achieved by combining CRP concentration

with other serum markers.

15. 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(1), Waterston M, Eckersall PD.

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.

16. J Am Vet Med Assoc. 2007 Feb 15;230(4):522-6.

Serum C-reactive protein concentrations in dogs with multicentric lymphoma

undergoing chemotherapy.

Merlo A(1), Rezende BC, Franchini ML, Simões DM, Lucas SR.

OBJECTIVE: To determine whether serum C-reactive protein (CRP) concentration is

high in dogs with multicentric lymphoma, whether CRP concentration changes in

response to chemotherapy, and whether CRP concentration can be used as a marker

for relapse in dogs with multicentric lymphoma.

DESIGN: Cohort study.

ANIMALS: 20 dogs with multicentric lymphoma and 8 healthy control dogs undergoing

chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) or with

vincristine, cyclophosphamide, methotrexate, and L-asparaginase (VCMA) and 20

other healthy dogs.

PROCEDURES: Serum CRP concentration was measured weekly during the first month of

chemotherapy and then at 3-week intervals until relapse in dogs with multicentric

lymphoma, weekly for 16 weeks in healthy dogs undergoing chemotherapy, and once

in the healthy dogs not undergoing chemotherapy.

RESULTS: For both groups of dogs with lymphoma, mean serum CRP concentration

during week 1 (prior to treatment) was significantly higher than mean

concentrations following induction of chemotherapy and at the time of relapse.

Mean serum CRP concentration in the healthy dogs undergoing chemotherapy was not

significantly different at any time from mean concentration for the healthy dogs

not undergoing chemotherapy. No significant differences were observed between

dogs treated with CVP and dogs treated with VCMA.

CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that serum CRP concentration

is high in dogs with multicentric lymphoma but that serum CRP concentration is

not a useful marker for relapse and that chemotherapy itself does not affect

serum CRP concentration.

19. J Vet Intern Med. 2005 Nov-Dec;19(6):865-70.

Preliminary studies of serum acute-phase protein concentrations in hematologic

and neoplastic diseases of the dog.

Tecles F(1), Spiranelli E, Bonfanti U, Cerón JJ, Paltrinieri S.

Serum concentrations of acute-phase proteins (APPs): haptoglobin (Hp),

ceruloplasmin (Cp), serum amyloid A (SAA), and C-reactive protein (CRP) were

determined in healthy dogs (n = 15) and dogs with different diseases grouped as

acute inflammation (I, n = 12), hematologic neoplasias (HT, including leukemia

and lymphoma, n = 16), nonhematologic neoplasias (NHT, including epithelial,

mesenchymal, and mixed, n = 20), and autoimmune hemolytic anemia (AIHA, n = 8).

SAA and CRP were analyzed using commercially available enzyme-linked

immunosorbent assay (ELISA) kits, and Hp and Cp were measured using colorimetric

methods, all previously validated for use in dogs. Increased concentrations of

all APPs were observed in all groups of diseased dogs, but statistical

significance only was observed with Hp (I, P < .001; HT, P < .05), Cp (I, P <

.05; AIHA, P < .01), and CRP (I, P < .001; HT, P < .001; AIHA, CRP P < .05). High

variability in individual APPs within each group of diseases was found with no

significant differences between leukemia and lymphoma as well as among different

types of neoplasia. The AIHA group had smaller increases in Hp, SAA, and CRP but

higher concentrations of Cp. When follow-up of individual cases was possible, a

decrease in APPs generally was found in cases with favorable outcome. The results

of this study suggest that neoplasia and hematologic diseases such as AIHA should

be considered as possible causes of mild increases in APPs in dogs. Measurement

of APPs may be helpful to assess clinical evolution and monitor treatment of

these processes.

20. Biochem Biophys Res Commun. 2003 Jan 31;301(1):212-7.

The canine mast cell activation via CRP.

Fujimoto T(1), Sato Y, Sasaki N, Teshima R, Hanaoka K, Kitani S.

We report here canine mastocytoma-derived cell (CMMC) activation via two

pentraxin, limulus- and human-CRP. Mast cell chemotaxis was measured by Boyden’s

blindwell chamber. To confirm that the cell migration was chemotactic,

“checkerboard” analysis was performed. We used Fura-2 to investigate CRP-mediated

cytosolic calcium elevation. To examine whether CRP-induced stimulation is

mediated through G-proteins, CMMC were incubated with pertussis toxin (PTx)

before use in chemotaxis assay and Ca(2+) mobilization. CMMC migration in

response to CRP was both chemokinetic and chemotactic. Limulus-CRP induced a

transient Ca(2+)-mobilization dose-dependently. Preincubation of the cells with

PTx inhibited CRP chemotaxis and Ca(2+)-mobilization, suggesting that G-proteins

of the Gi-class are involved in the chemotaxis. We suggest that CRP may

participate in the migration of mast cells to inflamed tissues during an

acute-phase response. CRP-mediated recruitment of mast cells might play an

important role in hypersensitivity and inflammatory processes.

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