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      Immunohistochemical Expression of Potential Therapeutic Targets in Canine Thyroid Carcinoma

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          Abstract

          Background

          Thyroid carcinoma is a common endocrine tumor in the dog. Local invasive growth frequently precludes surgical excision and, in up to 38% of dogs, the tumor has already metastasized by the time of diagnosis. Therefore, it is important to investigate new treatment modalities that may be useful for the large number of dogs with inoperable tumors or metastatic disease.

          Hypothesis/Objectives

          To investigate the immunohistochemical expression of potential therapeutic targets in canine thyroid tumors.

          Animals

          74 dogs with thyroid neoplasia.

          Methods

          Immunohistochemistry was performed for thyroglobulin, calcitonin, vascular endothelial growth factor ( VEGF), p53, cycloxygenase‐2 (cox‐2), and P‐glycoprotein (P‐gp).

          Results

          Fifty‐four (73%) tumors were classified as follicular cell thyroid carcinomas ( FTCs) and 20 (27%) as medullary thyroid carcinomas ( MTCs). Eighty percent of FTCs and all MTCs had a high percentage (76–100%) of neoplastic cells immunopositive for VEGF. Thirteen percent of FTCs and 50% of MTCs expressed cox‐2. Seven percent of FTCs and 70% of MTCs expressed P‐gp. No tumor was immunopositive for p53 expression. Expression of VEGF ( P = .034), cox‐2 ( P = .013), and P‐gp ( P < .001) was significantly higher in MTCs compared to FTCs.

          Conclusions and Clinical Importance

          VEGF is a potential therapeutic target in both FTC and MTC in dogs. Cox‐2 and P‐gp may be useful molecular targets in canine MTC.

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          Most cited references27

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          Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland.

          The p53 gene was analyzed in tumor specimens obtained from 52 patients with various types of carcinoma of the thyroid gland by a combined molecular and immunocytochemical approach. The histologic types included 37 well-differentiated papillary and follicular carcinomas, 8 poorly differentiated, and 7 undifferentiated carcinomas. The p53 gene was shown to be unaffected in all differentiated tumors by single-strand conformation polymorphism analysis. However, in two out of eight (25%) of poorly differentiated carcinomas and five out of seven (71%) undifferentiated carcinomas, p53 mutations were identified and subsequently characterized by DNA sequencing. One undifferentiated carcinoma displayed two areas with varying degrees of differentiation. The comparative analysis of the p53 gene, in both the more and the less differentiated area of this tumor, clearly showed that the p53 mutation was confined to the latter component of the tumor specimen. These results indicate that mutations of the p53 gene are associated with the most aggressive histologic types of thyroid tumors, such as the undifferentiated carcinoma and, to a certain extent, the poorly differentiated carcinoma, and that the alterations of this gene represent a late genetic event in human thyroid carcinogenesis.
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            Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner.

            Naturally occurring regulatory T (T(R)) cells suppress autoreactive T cells whereas adaptive T(R) cells, induced in the periphery, play an important role in chronic viral diseases and cancer. Several studies indicate that cyclooxygenase (COX) inhibitors prevent cancer development of colon adenomas and delay disease progression in patients with colorectal cancer (CRC). We have shown that adaptive T(R) cells express COX-2 and produce PGE(2) that suppress effector T cells in a manner that is reversed by COX-inhibitors. Here we demonstrate that CRC patients have elevated levels of PGE(2) in peripheral blood, and CRC tissue samples and draining lymph nodes display increased numbers of FOXP3+ T(R) cells. Depletion of T(R) cells from PBMC enhanced anti-tumor T-cell responses to peptides from carcinoembryonic antigen. Furthermore, the COX inhibitor indomethacin and the PKA type I antagonist Rp-8-Br-cAMPS significantly improved the anti-tumor immune activity. We suggest that adaptive T(R) cells contribute to an immunosuppressive microenvironment in CRC and inhibit effector T cells by a COX-2-PGE(2)-dependent mechanism and thereby facilitate tumor growth. Therapeutic strategies targeting T(R) cells and the PGE(2)-cAMP pathway may be interesting to pursue to enhance anti-tumor immune activity in CRC patients.
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              Piroxicam therapy in 34 dogs with transitional cell carcinoma of the urinary bladder.

              Thirty-four dogs with histopathologically confirmed, measurable, nonresectable transitional cell carcinoma of the urinary bladder were treated with piroxicam (0.3 mg/kg PO sid) and were evaluated for tumor response and drug toxicity. Dogs were evaluated at the Purdue University Veterinary Teaching Hospital by means of physical examination, thoracic and abdominal radiography, cystography, complete blood count, serum biochemistry profile, and urinalysis. In selected cases, prostaglandin E2 (PGE2) concentrations in plasma and in supernatants of stimulated monocytes, and natural killer cell activity were quantified. Dogs were evaluated before therapy and at 28 and 56 days after initiation of therapy. Dogs with stable disease or remission at 56 days remained on the study and were evaluated at 1 to 2 months intervals. Tumor responses were 2 complete remissions, 4 partial remissions, 18 stable diseases, and 10 progressive diseases. The median survival of all dogs was 181 days (range, 28 to 720+ days), with 2 dogs still alive. Piroxicam toxicity consisted of gastrointestinal irritation in 6 dogs and renal papillary necrosis (detected at necropsy) in 2 dogs. Monocyte production of PGE2 appeared to decrease with therapy in dogs whose tumors were decreasing in size, and increased in dogs with tumor progression. A consistent pattern in natural killer cell activity was not observed. In vitro cytotoxicity assays against 4 canine tumor cell lines revealed no direct antitumor effects of piroxicam. In summary, antitumor activity, which was not likely the result of a direct cytotoxic effect, was observed in dogs with transitional cell carcinoma of the bladder treated with piroxicam.
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                Author and article information

                Journal
                J Vet Intern Med
                J. Vet. Intern. Med
                10.1111/(ISSN)1939-1676
                JVIM
                Journal of Veterinary Internal Medicine
                John Wiley and Sons Inc. (Hoboken )
                0891-6640
                1939-1676
                24 February 2014
                Mar-Apr 2014
                : 28
                : 2 ( doiID: 10.1111/jvim.2014.28.issue-2 )
                : 564-570
                Affiliations
                [ 1 ] Department of Medicine and Clinical Biology of Small Animals Faculty of Veterinary MedicineGhent University MerelbekeBelgium
                [ 2 ] Department of Pathology, Bacteriology and Poultry DiseasesFaculty of Veterinary Medicine Ghent University MerelbekeBelgium
                [ 3 ] Department of Clinical Sciences of Companion AnimalsFaculty of Veterinary Medicine Utrecht University UtrechtThe Netherlands
                [ 4 ] Department of Comparative Physiology and BiometricsFaculty of Veterinary Medicine Ghent University MerelbekeBelgium
                Author notes
                [*] [* ]Corresponding author: Miguel Campos, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, Merelbeke 9820, Belgium; e‐mail: miguel.campos@ 123456ugent.be .
                Article
                JVIM12330
                10.1111/jvim.12330
                4857974
                24612088
                f315bcc9-1781-407e-921f-b9412836f262
                Copyright © 2014 by the American College of Veterinary Internal Medicine
                History
                : 17 September 2013
                : 05 December 2013
                : 16 January 2014
                Page count
                Pages: 7
                Funding
                Funded by: ECVIM‐CA Clinical Studies Fund
                Funded by: Ghent University
                Award ID: 01J02510
                Categories
                Original Article
                Standard Articles
                Custom metadata
                2.0
                jvim12330
                March/April 2014
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.8.8 mode:remove_FC converted:25.04.2016

                Veterinary medicine
                cyclooxygenase‐2,p53,p‐glycoprotein,vegf
                Veterinary medicine
                cyclooxygenase‐2, p53, p‐glycoprotein, vegf

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