The role of tissue factor and tissue factor pathway inhibitor in health and disease states

Objective – To review the veterinary and human literature on the role of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in health and disease states.
Data Sources – Original research articles and scientific reviews from both human and veterinary literature were searched for relevance to TF and TFPI.
Human Data Synthesis – Interest in both TF and TFPI has grown widely over the last several years. The impact TF plays in coagulation, inflammation, angiogenesis, tumor metastasis, and cellular signaling has become apparent. Treatment with TFPI for severe sepsis has been examined and is still currently under investigation. Inhibition of the TF pathway is being studied as an aid in the treatment of neoplasia. The important physiologic and pathophysiologic role these molecules play has only begun to be understood.
Veterinary Data Synthesis – There is a paucity of publications that discuss the importance of TF and TFPI in veterinary medicine. An enhanced understanding of the TF pathway in human medicine, in experimental animal models treating sepsis with TFPI, and in animal models demonstrating the proangiogenic properties of TF provides relevance to veterinary medicine.
Conclusion – It is apparent that TF and TFPI are important in health and disease. An enhanced understanding of the physiologic and pathophysiologic roles of these factors provides better insight into coagulation, inflammation, angiogenesis, disseminated intravascular coagulation, and tumor metastasis. This greater understanding may provide for the development of therapeutics for sepsis, disseminated intravascular coagulation, and neoplasia.     

Surgical Management of Adrenal Tumors and Insulinomas in Ferrets

Domestic ferrets are popular pets and comprise a significant percentage of the caseload in many veterinary practices. This article describes the diagnosis and surgical techniques for treatment of 2 common endocrine disorders affecting ferrets, adrenal gland disease and pancreatic beta cell neoplasms. Although medical treatment options are used to reduce the severity of clinical signs associated with adrenal hyperplasia or neoplasia, surgical removal of the adrenal gland(s) is the treatment of choice. Clinical disease associated with pancreatic beta cell tumors includes hypoglycemia, and in many cases the tumor will metastasize early in the course of the disease. Although achieving a complete resolution of pancreatic beta cell neoplasia is unlikely, surgical removal of insulin-secreting tumors is recommended to temporarily alleviate the clinical syndrome and confirm the diagnosis.     

Ocular oncology

Neoplasia can affect all ocular tissues. The clinical appearance of ocular neoplasia can vary considerably depending on the specific tissue involved. Intraocular neoplasia may mimic or incite ocular inflammatory disease in addition to causing hyphema or secondary glaucoma. Intraocular neoplasms can be primary tumors or may be secondary to metastatic disease or systemic neoplasia. Primary neoplasms, metastatic tumors, tumors extending from adjacent structures, and systemic neoplasms can also affect the adnexal tissues. Many ophthalmic tumors are histologically benign but are locally invasive and, within the confined space of the eye or orbit, can produce significant tissue distortion. Certain ocular neoplasms, such as many canine eyelid tumors, are amenable to simple excision and can be adequately managed in general practice. The evaluation and treatment of other ophthalmic neoplasms, however, may require the additional equipment available only in larger specialty practices, such as computed tomography and radiation therapy. Early diagnosis of ocular neoplasia is an important aspect of successful management.     

Treatment of canine hemangiosarcoma: 2000 and beyond

Canine hemangiosarcoma (HSA) is an aggressive and malignant neoplasia with a grave prognosis. Surgery and chemotherapy have limited success in prolonging survival times and increasing quality of life in dogs with HSA. Advances in medical oncology are resulting in increased survival rates and a better quality of life for veterinary cancer patients. An understanding of mechanisms of metastasis has led to the development of new treatments designed to delay or inhibit tumor spread. Promising new treatment options include novel delivery systems (inhalation or intracavitary chemotherapy); use of immunomodulators such as liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine; antimetastatic agents such as inhibitors of angiogenesis (interferons, thalidomide), matrix metalloproteinase inhibitors, and minocycline; dietary modifications; and gene therapy. Inhibitors of angiogenesis seem to be safe and, unlike conventional chemotherapy, do not induce drug resistance. Although many of the newer approaches are still under development and review, the use of multimodality therapy incorporating innovative treatment modalities may offer the best therapeutic option for dogs affected with HSA.     

Canine mammary gland tumors.

The National Consensus Group recommends that all women with tumors larger than 1 cm be offered chemotherapy regardless of tumor histology of lymph node status. This recommendation is to ensure that everyone at risk for failing, even though the risk may be low in women with relatively small tumors and favorable histology, has a choice and receives the benefit of adjuvant chemotherapy. This type of treatment recommendation may also be made in dogs based on recognized, well-accepted prognostic factors such as tumor size, stage, type, and histologic differentiation. Based on the limited clinical information available in veterinary medicine, the drugs that are effective in human breast cancer, such as cyclophosphamide, 5-fluorouracil, and doxorubicin, may also have a role in the treatment of malignant mammary gland tumors in dogs. Randomized prospective studies are needed, however, to evaluate the efficacy of chemotherapy in dogs with high-risk mammary gland tumors and to determine which drugs and protocols are the most efficacious. Until such studies are performed, the treatment of canine mammary gland tumors will be based on the individual oncologist's understanding of tumor biology, experience, interpretation of the available studies, and a little bit of gut-feeling. Table 2 is a proposal for treatment guidelines for malignant canine mammary gland tumors according to established prognostic factors, results from published veterinary studies, and current recommendations for breast cancer treatment in women.     

INVITED REVIEW—NEUROIMAGING RESPONSE ASSESSMENT CRITERIA FOR BRAIN TUMORS IN VETERINARY PATIENTS

The evaluation of therapeutic response using cross‐sectional imaging techniques, particularly gadolinium‐enhanced MRI, is an integral part of the clinical management of brain tumors in veterinary patients. Spontaneous canine brain tumors are increasingly recognized and utilized as a translational model for the study of human brain tumors. However, no standardized neuroimaging response assessment criteria have been formulated for use in veterinary clinical trials. Previous studies have found that the pathophysiologic features inherent to brain tumors and the surrounding brain complicate the use of the response evaluation criteria in solid tumors (RECIST) assessment system. Objectives of this review are to describe strengths and limitations of published imaging‐based brain tumor response criteria and propose a system for use in veterinary patients. The widely used human Macdonald and response assessment in neuro‐oncology (RANO) criteria are reviewed and described as to how they can be applied to veterinary brain tumors. Discussion points will include current challenges associated with the interpretation of brain tumor therapeutic responses such as imaging pseudophenomena and treatment‐induced necrosis, and how advancements in perfusion imaging, positron emission tomography, and magnetic resonance spectroscopy have shown promise in differentiating tumor progression from therapy‐induced changes. Finally, although objective endpoints such as MR imaging and survival estimates will likely continue to comprise the foundations for outcome measures in veterinary brain tumor clinical trials, we propose that in order to provide a more relevant therapeutic response metric for veterinary patients, composite response systems should be formulated and validated that combine imaging and clinical assessment criteria.     

Laboratory abnormalities in patients with cancer

In this problem-oriented review of abnormalities associated with cancer, we have emphasized distinctive diagnostic points related to pathogenesis for each condition and outlined how the approach to management is determined by pathogenesis. For abnormalities of the complete blood count, it is important to distinguish between abnormalities directly related to marrow malignancy and abnormalities associated with extramarrow malignancy. Hemopoietic tumors consist of developmentally deficient blood cells produced by a clonal population of malignant stem cells. Tumors infiltrating marrow cause overcrowding in the limited marrow microenviroment. Extramarrow malignancies cause blood abnormalities, but the potential for normal marrow function is present. Abnormalities of blood cells secondary to therapy are usually clearly identified by consideration of clinical history. The initial differential diagnosis for hypercalcemia is malignancy. An aggressive diagnostic approach may be needed to identify the neoplasm, and therapy should incorporate measures to prevent renal failure. Hypoproteinemia and hyperproteinemia may be caused by neoplasia. Monoclonal gammopathies should be identified and may be associated with hyperviscosity syndrome. Hypoglycemia in the adult animal is most frequently caused by insulin-secreting tumors, but it has also been associated with hepatic and other tumors. Increased blood urea nitrogen, creatinine, lipase, amylase, and liver enzyme activities may also be caused by malignancy. Inadequate urine concentrating ability may be caused by hypercalcemia or malignancy-associated renal insufficiency. Hematuria in older animals is suggestive of urinary tract neoplasia. Exfoliated tumor cells may be identified in the urine sediment of these patients.     

PRIMARY IRRADIATION OF CANINE INTRACRANIAL MASSES

Twenty-nine dogs received primary radiation therapy for intracranial lesions and clinical signs suggestive of neoplasia. Presumptive diagnosis and tumor categorization was based on computed tomographic or magnetic resonance images. Meningioma was the most likely tumor type in 22 dogs and glioma or choroid plexus tumors were tentatively identified in 4 and 3 dogs, respectively. Cobalt-60 radiation was delivered in 3 Gy fractions on a daily, Monday-through-Friday basis for a total dose of 48 Gy (16 fractions) in 28 dogs; one dog received 54 Gy. Two of 29 dogs died during treatment of signs suggestive of progressive tumor growth but were included in the overall evaluation of response to treatment. Median overall survival was 250 days (range 21-804). Mild acute radiation effects on normal tissue developed and did not influence outcome in any dog. Late radiation effects could not be evaluated in this study. No significant predictive indicators were identified from the clinical or imaging data. Radiation therapy is superior to medical treatment of brain tumors in dogs with steroids, is useful for tumors that are not currently operable and may be preferable to surgical resection in dogs if the mass appears infiltrative. However, 22/29 (76%) dogs died of recurrent progressive neuropathy suggestive of tumor regrowth or progression. Thus, alternative methods for delivery of radiation to dogs with brain tumors or novel combinations of therapy should continue to undergo evaluation.     

INITIAL EVALUATION OF SAFETY OF WIDE‐FIELD IRRADIATION IN THE TREATMENT OF HEMATOPOIETIC NEOPLASIA IN THE CAT

Localized radiation therapy is well tolerated in cats with confined tumors; however, the use of wide‐field radiation therapy to treat disseminated neoplasia has not been evaluated systematically in this species. Wide‐field external beam radiation therapy, which we define as irradiation of cranial or caudal halves of the body either individually or sequentially, was undertaken as an experimental option to treat cats with either chemotherapy‐refractory or naïve hematopoietic neoplasia considered to have a poor prognosis. Fifteen cats with hematopoietic malignancies received wide‐field external beam radiation therapy between 2003 and 2006. Cats received 8 Gy delivered in 4 Gy fractions with ⁶⁰Co photons. Treatment‐related toxicity was scored according to criteria established by the Veterinary Cooperative Oncology Group. Animals without preexisting abnormalities on hemograms exhibited no or mild (Grade 1 or 2) hematopoietic toxicity. Although most cats (14 of 15) had preexisting gastrointestinal (GI) signs, these signs were stable (29%) or improved (42%) following irradiation. Worsening GI signs following irradiation occurred transiently in two cats and in association with progressive disease in two others. No pulmonary, renal, hepatic, or dermatologic toxicities were detected. In summary, wide‐field external beam radiation therapy can be administered safely to, and may provide therapeutic benefit for, cats with disseminated hematopoietic neoplasia.     

Clinical indications and applications of radiotherapy and hyperthermia in veterinary oncology

The response of dogs and cats with neoplasia to radiation therapy has improved significantly during the past 10 years. This has largely been due to more aggressive radiation therapy treatment schedules, more accurate planning, and refinement of clinical indications. Sufficient numbers of dogs and cats irradiated with curative intent have not been accumulated to yet define the full impact of more aggressive therapy. However, many tumors will likely remain resistant to irradiation because of concomitant normal tissue injury that must be minimized. Systematic investigation of combination therapy (surgery, radiation, chemotherapy, and hyperthermia) should succeed in reducing local tissue side effects and increased local tumor control. A comprehensive approach to tumor management begins with decisions thoughtful of optimal treatment for suspected malignant tumors even at the time of initial examination and client counseling. An incisional biopsy provides essential information to determine the therapeutic course and should be considered prior to initial excision. More aggressive treatment, of even small tumors, early in the clinical course will lead to prolonged tumor control. Radiation therapy should be considered fundamental in the comprehensive treatment plan of many solid tumors.     

Moh’s micrographic surgery for the management of a periocular mast cell tumor in a dog

A 3‐year‐old neutered male boxer dog presented with a 6‐month history of a waxing and waning mass of the left dorsotemporal eyelid margin. Cytology and biopsy confirmed a diagnosis of mast cell neoplasia. Systemic staging of the dog failed to reveal any evidence of metastatic neoplasia. Owing to the location of the tumor within the eyelid margin and the wide surgical margins recommended for excision of mast cell tumors, Mohs micrographic surgery (MMS) was chosen for its potential to conserve tissues while providing intraoperative confirmation the tumor was completely excised. Utilizing MMS horizontal sectioning technique, 100% of the surgical margins were assessed prior to closure of the surgical wound. This represents the first time a comprehensive MMS protocol was used in a veterinary patient under general anesthesia.     

Prospective evaluation of clinically relevant type B hyperlactatemia in dogs with cancer

Background: Cancer is considered a cause of type B hyperlactatemia in dogs. However, studies evaluating cancer as a cause of clinically relevant type B hyperlactatemia (>2.5 mmol/L) are lacking. Cancer cells have a higher lactate production because of increased aerobic glycolysis, known as the “Warburg effect.” The mechanisms through which aerobic glycolysis occurs are not well elucidated, but neoplasia may cause type B hyperlactatemia via this process. Objectives: To determine if malignant tumors of dogs are associated with clinically relevant type B hyperlactatemia (>2.5 mmol/L). Animals: Thirty‐seven client‐owned dogs with malignant tumors: 22 with hematopoietic and 15 with solid tumors. Methods: Histology was used to confirm the diagnosis (cytology was considered adequate for diagnosis of lymphoma). Confounding conditions associated with hyperlactatemia were excluded. Lactate measurements were immediately performed on free‐flow jugular whole blood samples using the LactatePro analyzer. Results: All dogs had lactate concentrations <2.5 mmol/L. Mean blood lactate concentration was 1.09 mmol/L. Mean blood lactate concentrations for solid and hematopoietic tumors were 0.95 and 1.19 mmol/L, respectively. Dogs with lymphoma (n = 18) had a mean blood lactate concentration of 1.15 mmol/L. Conclusions: Malignant tumors were not considered a cause of clinically relevant type B hyperlactatemia. Therefore, cancer‐related type B hyperlactatemia in dogs is uncommon, and hyperlactatemia should prompt careful investigation for causes other than cancer.     

Derivation of feline vaccine-associated fibrosarcoma cell line and its growth on chick embryo chorioallantoic membrane – a new in vivo model for veterinary oncological studies

Feline vaccine associated fibrosarcomas are the second most common skin tumor in cats. Methods of treatment are: surgery, chemotherapy and radiotherapy. Nevertheless, the usage of cytostatics in feline vaccine associated sarcoma therapy is limited due to their adverse side effects, high toxicity and low biodistribution after i.v. injection. Therefore, much research on new therapeutic drugs is being conducted. In human medicine, the chick embryo chorioallantoic membrane (CAM) model is used as a cheap and easy to perform assay to assess new drug effectiveness in cancer treatment. Various human cell lines have different tumors growth on CAM. In veterinary medicine such model has not been described yet. In the present article derivation of feline vaccine associated fibrosarcoma cell line and its growth on CAM is described. The cell line and the tumor grown were confirmed by histopathological and immunohistochemical examination. As far as we believe, this is the first attempt to create such model, which may be used for further in vivo studies in veterinary oncology.     

Clinical techniques in small animal molecular oncology

The diagnosis, staging, and treatment of tumors in veterinary as well as human oncology have traditionally incorporated elements of anatomic extent of neoplasia through various clinical and pathologic methods. These clinicopathological methods have been the basis for the development of the tumor, node, and metastasis and grading systems, which have translated into clinically significant advances over the last 20 to 30 years. Unfortunately, there continues to be significant limitations to this system when prognostication and therapeutic decisions need to be made specific to a patient. For example, completely resected and cleanly staged phenotypically identical grade II mast cell tumors in dogs can have opposing clinical outcomes. In addition, dogs or cats with identical stage and grade lymphoma can have significantly divergent responses to the same multi-agent chemotherapy protocol. Numerous nonanatomic neoplastic molecular prognostic factors have been recently identified and have the potential to improve on the presently available tumor, node, and metastasis- and grading-based systems. To date in human oncology, single nonanatomic factors have only occasionally translated into efficient and independent prognostic factors, which speaks to the heterogeneity of cancer. Therefore, the use of panels of factors have been encouraged that will allow for the development of a molecular prognostic index, which can then be used in concert with presently available systems. This review will summarize how to best utilize presently available tumor, node, and metastasis- and grading-based systems, and incorporate newly available molecular prognostic factors.     

II. Parameters to Monitor in the Trauma Patient – The Ideal.

Patient monitoring devices may be considered as extensions of the veterinary clinician's senses. Many of the parameters outlined above have been used for years, without the term “monitor” being used. In this report, several patient monitoring methods have been discussed, and their advantages weighed. It is hoped that judicious use of some of these monitoring methods may aid the veterinary clinician in diagnosis and treatment of his trauma patients.     

MONITORING THE TRAUMA PATIENT

Patient monitoring devices may be considered as extensions of the veterinary clinician's senses. Many of the parameters outlined above have been used for years, without the term “monitor” being used. In this report, several patient monitoring methods have been discussed, and their advantages weighed. It is hoped that judicious use of some of these monitoring methods may aid the veterinary clinician in diagnosis and treatment of his trauma patients.     

Secondary Intracranial Neoplasia in the Dog: 177 Cases (1986–2003)

Background: This study investigates the frequency, location, and clinical findings associated with 177 secondary brain tumors in dogs.
Hypothesis: Secondary intracranial neoplasia is more common than primary intracranial neoplasia in dogs during the time period studied, and hemangiosarcoma (HSA) is the most common secondary intracranial tumor.
Animals: One hundred and seventy-seven client-owned dogs presented to the Matthew J. Ryan Veterinary Hospital between 1986 and 2003.
Methods: Medical records were searched for a diagnosis of intracranial neoplasia in dogs who underwent complete postmortem examination. Of these dogs, those with a diagnosis of primary intracranial neoplasia were excluded.
Results: Of the 177 secondary brain tumors, 51 (29%) were HSAs, 44 (25%) were pituitary tumors, 21 (12%) were lymphosarcomas, and 21 (12%) were metastatic carcinomas. The average age at diagnosis was 9.6 ± 3.0 years. Most tumors were located in the cerebrum, and a mentation change was the most common presenting clinical sign. On postmortem examination, the same tumor that was in the brain was also present in the lung in 84 cases (47%), in the kidney in 62 cases (35%), and in the heart in 55 cases (31%).
Conclusions and Clinical Importance: Secondary intracranial neoplasia in dogs was more common than primary intracranial neoplasia during the time period studied. Many of these dogs had related disease in other body systems that was apparent on diagnostic tests such as thoracic radiography.     

Urologic disorders of the geriatric dog

Disorders of the urinary system are common in geriatric dogs. Common urinary disorders that are seen in older dogs include chronic renal failure, urinary incontinence, bladder tumors, and prostate problems. Therapy for chronic renal failure is aimed at both slowing the progression of the disease and ameliorating the signs of uremia. Therapeutic recommendations for the conservative medical management of chronic renal failure include reducing dietary protein, moderately reducing salt intake, maintaining normal serum phosphorus levels, providing free access to water, avoiding stress, supplementing water soluble vitamins, using anabolic steroids to treat the anemia of chronic renal failure, treating acidosis, and controlling hypocalcemia. Urinary incontinence can often be controlled or eliminated. The appropriate approach to management of this disorder is to identify and remove specific causes. Common causes of urinary incontinence are urethral incompetence, urinary tract infection, and polyuria and polydypsia. Bladder tumors are, fortunately, not a common tumor of dogs, but are more common in geriatric dogs than in the young. The most common bladder tumor is the transitional cell carcinoma. Therapy for this tumor is usually palliative because of its malignant nature and because it is usually located in the neck of the bladder. Its location in the bladder often makes it impossible to resect the tumor completely without removing the entire bladder and diverting the ureters. New chemotherapeutic modalities are being evaluated that may increase life expectancy after diagnosis and, therefore, improve prognosis. Prostate disease is also seen in older dogs. Types of prostate abnormalities seen in dogs include prostatic hyperplasia, cysts, abscesses, acute and chronic infection, and neoplasia. The institution of proper therapy requires an accurate diagnosis; neutering is often recommended as a part of therapy regardless of the type of prostatic disease present.     

The use of erythropoietin.

EPO is a hematopoietic growth factor produced in the kidney that stimulates erythropoiesis. It effectively treats hypoproliferative anemia associated with CRF, improving quality of life in these patients. Other uses that are poorly characterized in veterinary medicine include treatment of cancer patients on chemotherapy, hematologic disorders, and anemic FeLV-infected cats as well as preoperative conditioning for elective surgeries that may involve significant blood loss. Careful monitoring of therapy is necessary for optimal results. Several complications are associated with rHuEPO therapy. The production of anti-rHuEPO antibodies is the most significant and can be a life-threatening event. Alternatives to human EPO are being sought to provide beneficial effects while avoiding antibody formation.