Distribution of the nt230(del4) MDR1 mutation in different ...



Expression of VEGFR and PDGFR-α/-β in 187 canine nasal carcinomas.Irina Gramer1*, Tim Scase2, Deepthi Chandry2, David Killick1, Mary Marrington1, Laura Blackwood11Small Animal Teaching Hospital, Leahurst Campus, University of Liverpool, Neston, CH64 7TE, United Kingdom2 Bridge Pathology Ltd., 637 Gloucester Road, Horfield, Bristol, BS7 0BJ, United Kingdom*Corresponding author. Tel.: +44 7860812849.E-mail address: gramer.irina@ (I. Gramer)IntroductionCanine nasal tumours account for approximately 1% of all neoplasms in dogs. Average age at presentation is 10 years, and medium to large breeds are more commonly affected ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-1488", "PMID" : "556613", "abstract" : "The records of 43 dogs with nasal tumors (1969- 1974) were evaluated in retrospect. The median age at diagnosis was 10 years. Most affected dogs were bloody nasal discharge, sneezing, and nasal bone deformities. A new method of obtaining tissure for cytologic and histologic evalution proved to be accurate in making a definitive diagnosis in 50% of the cases evaluated. Affected dogs were treated by surgery, surgery plus immunotherapy, or not at all. The results of those treated by surgery alone were no better than those not treated.", "author" : [ { "dropping-particle" : "", "family" : "MacEwen", "given" : "E G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Withrow", "given" : "S J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patnaik", "given" : "A K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American Veterinary Medical Association", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1977", "1", "1" ] ] }, "page" : "45-8", "title" : "Nasal tumors in the dog: retrospective evaluation of diagnosis, prognosis, and treatment.", "type" : "article-journal", "volume" : "170" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Patnaik", "given" : "A K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Am Anim Hosp Assoc", "id" : "ITEM-2", "issue" : "25", "issued" : { "date-parts" : [ [ "1989" ] ] }, "page" : "103-114", "title" : "Canine sinonasal neoplasms: Clinicopathological study of 285 cases", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(1,2)", "plainTextFormattedCitation" : "(1,2)", "previouslyFormattedCitation" : "(1,2)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(1,2). Intranasal carcinomas [adenocarcinoma, squamous cell carcinoma (SCC) and undifferentiated carcinoma] represent two-thirds of nasal neoplasms ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1053/j.ctsap.2005.12.016", "ISSN" : "1096-2867", "PMID" : "16711615", "abstract" : "Dogs and cats of our society have outgrown their status as merely pets and are now considered our close companions and even family members. This shift in their roles has led to pet owners seeking improved preventative medicine for their four-legged friends. Subsequently, dogs and cats are living longer lives than ever before and developing more old-age-related diseases. One of the most devastating diseases of older animals is cancer. Once a veterinarian has detected cancer in a pet, pet owners seek advice on their next course of action. This article is intended to provide concise information regarding the diagnosis and treatment of intranasal tumors of the dog and cat. This article outlines the forms of nasal tumors that are the most common, the recommended imaging and biopsy techniques to diagnose the tumor, and the most appropriate treatments of them.", "author" : [ { "dropping-particle" : "", "family" : "Malinowski", "given" : "Christine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical techniques in small animal practice", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2006", "5" ] ] }, "page" : "89-94", "title" : "Canine and feline nasal neoplasia.", "type" : "article-journal", "volume" : "21" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(3)", "plainTextFormattedCitation" : "(3)", "previouslyFormattedCitation" : "(3)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(3). Their biological behaviour is characterized by progressive local invasion and a generally low metastatic rate at the time of diagnosis, though metastases are evident in 40% to 50% of dogs at the time of death, with regional lymph nodes and lungs most commonly affected ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Patnaik", "given" : "A K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Am Anim Hosp Assoc", "id" : "ITEM-1", "issue" : "25", "issued" : { "date-parts" : [ [ "1989" ] ] }, "page" : "103-114", "title" : "Canine sinonasal neoplasms: Clinicopathological study of 285 cases", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(2)", "plainTextFormattedCitation" : "(2)", "previouslyFormattedCitation" : "(2)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(2). The presence of regional lymph node metastasis at diagnosis is associated with a poor outcome ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1058-8183", "PMID" : "10519313", "abstract" : "Improvements in survival of dogs with nasal tumors have been slow to develop throughout the past three decades. Despite multiple studies examining various radiation time-dose schema, the advancement of CT-based computerized treatment planning, and the evaluation of detailed staging systems, the optimal treatment regimen, and most important prognostic factors regarding survival remain unclear. In this study, data from four previous studies were combined with data from 44 additional dogs, and this population of 130 dogs was evaluated for factors which influenced survival. Twenty-one dogs were treated with orthovoltage at the University of Pennsylvania. One hundred nine dogs were treated with cobalt photons at North Carolina State University. Sixty-five of these 109 dogs had been previously described. Of the 44 dogs not previously described, 35 were treated with a shrinking field technique. Survival was determined from the medical record, or from information derived by telephone or mail survey. The univariate Cox regression model was used to examine for relationship between various patient, tumor, and treatment variables and survival. Significant relationships identified in the univariate analysis were further analyzed using the multivariate Cox regression model. Median survival of the 130 dogs was 8.9 months (95% C.I., 8-11 months). In the univariate analysis, the following variables were associated with decreased survival: 1) age >10 years old, 2) regional lymph node metastasis, 3) advanced tumor stage, 4) use of megavoltage radiation, 5) overall total dose >55 Gray, and 6) boost technique performed. In a multivariate analysis of 125 dogs with complete data for age, radiation type, and radiation dose, age (p < .001) and radiation type (p = .02) were identified as joint predictors of survival. After adjusting for age, the staging system lost prognostic significance (p = .06). In a subset of dogs that received cobalt radiation, after adjusting for age, dogs treated with a boost technique had decreased survival (p = .001). In general, local control of canine nasal tumors following aggressive radiation therapy is poor. Early diagnosis and selection of appropriate patients is warranted and palliative types of treatment should be considered in dogs with a poor chance of long term survival.", "author" : [ { "dropping-particle" : "", "family" : "LaDue", "given" : "T A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dodge", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Page", "given" : "R L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Price", "given" : "G S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hauck", "given" : "M L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thrall", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary radiology & ultrasound : the official journal of the American College of Veterinary Radiology and the International Veterinary Radiology Association", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "0", "1" ] ] }, "page" : "312-7", "title" : "Factors influencing survival after radiotherapy of nasal tumors in 130 dogs.", "type" : "article-journal", "volume" : "40" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(4)", "plainTextFormattedCitation" : "(4)", "previouslyFormattedCitation" : "(4)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(4).A median survival time (MST) of 95 days has been reported for nasal carcinomas if no treatment is pursued ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.2460/javma.229.3.401", "ISSN" : "0003-1488", "PMID" : "16881833", "abstract" : "OBJECTIVE: To evaluate factors associated with survival in dogs with nasal carcinomas that did not receive treatment or received only palliative treatment.\n\nDESIGN: Retrospective case series.\n\nANIMALS: 139 dogs with histologically confirmed nasal carcinomas.\n\nPROCEDURES: Medical records, computed tomography images, and biopsy specimens of nasal carcinomas were reviewed. Only dogs that were not treated with radiation, surgery, chemotherapy, or immunotherapy and that survived > or = 7 days from the date of diagnosis were included. The Kaplan-Meier method was used to estimate survival time. Factors potentially associated with survival were compared by use of log-rank and Wilcoxon rank sum tests. Multivariable survival analysis was performed by use of the Cox proportional hazards regression model.\n\nRESULTS: Overall median survival time was 95 days (95% confidence interval [CI], 73 to 113 days; range, 7 to 1,114 days). In dogs with epistaxis, the hazard of dying was 2.3 times that of dogs that did not have epistaxis. Median survival time of 107 dogs with epistaxis was 88 days (95% CI, 65 to 106 days) and that of 32 dogs without epistaxis was 224 days (95% CI, 54 to 467 days).\n\nCONCLUSIONS AND CLINICAL RELEVANCE: The prognosis of dogs with untreated nasal carcinomas is poor. Treatment strategies to improve outcome should be pursued.", "author" : [ { "dropping-particle" : "", "family" : "Rassnick", "given" : "Kenneth M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goldkamp", "given" : "Carrie E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb", "given" : "Hollis N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Scrivani", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Njaa", "given" : "Bradley L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gieger", "given" : "Tracy L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Turek", "given" : "Michelle M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McNiel", "given" : "Elizabeth A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Proulx", "given" : "David R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chun", "given" : "Ruthanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mauldin", "given" : "Glenna E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phillips", "given" : "Brenda S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kristal", "given" : "Orna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American Veterinary Medical Association", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2006", "8", "1" ] ] }, "page" : "401-6", "title" : "Evaluation of factors associated with survival in dogs with untreated nasal carcinomas: 139 cases (1993-2003).", "type" : "article-journal", "volume" : "229" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(5)", "plainTextFormattedCitation" : "(5)", "previouslyFormattedCitation" : "(5)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(5). The main goal of therapy is typically to control local disease and treatment is most often radiotherapy (RT) alone, although surgery (rhinotomy), alone or in combination with RT is also reported ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/vru.12246", "ISSN" : "1740-8261", "PMID" : "25703137", "abstract" : "Carcinomas represent two-thirds of canine nasosinal neoplasms. Although radiation therapy (RT) is the standard of care, the incidence of local recurrence following treatment is high. Cyclooxygenase-isoform-2 (COX-2) is expressed in 71-95% of canine nasal carcinomas and has been implicated in tumor growth and angiogenesis. Accordingly, COX-2 inhibition seems rational to improve outcome. Dogs with histologically confirmed, previously untreated nasal carcinomas were randomized to receive the combination of a selective COX-2 inhibitor (firocoxib) and palliative RT (Group 1) or RT and placebo (Group 2). Patients were regularly monitored with blood tests, urinalysis, and computed tomography. Pet owners were asked to complete monthly a quality-of-life questionnaire. Twenty-four dogs were prospectively enrolled. According to Adams modified system, there were five stage 1, five stage 2, three stage 3, and 11 stage 4 tumors. Two dogs had metastases to regional lymph nodes. Median progression-free interval and overall survival were 228 and 335 days in Group 1 (n = 12) and 234 and 244 days in Group 2 (n = 12). These differences were not statistically significant. The involvement of regional lymph nodes was significantly associated with progression-free interval and overall survival (P = 0.004). Quality of life was significantly improved in Group 1 (P = 0.008). In particular, a significant difference was observed for activity and appetite. Although not providing a significant enhancement of progression-free interval and overall survival, firocoxib in combination with RT is safe and improved life quality in dogs with nasal carcinomas.", "author" : [ { "dropping-particle" : "", "family" : "Cancedda", "given" : "Simona", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sabattini", "given" : "Silvia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bettini", "given" : "Giuliano", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leone", "given" : "Vito F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Laganga", "given" : "Paola", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rossi", "given" : "Federica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Terragni", "given" : "Rossella", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gnudi", "given" : "Giacomo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vignoli", "given" : "Massimo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary radiology & ultrasound : the official journal of the American College of Veterinary Radiology and the International Veterinary Radiology Association", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "0", "1" ] ] }, "page" : "335-43", "title" : "Combination of radiation therapy and firocoxib for the treatment of canine nasal carcinoma.", "type" : "article-journal", "volume" : "56" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1111/j.1476-5829.2010.00243.x", "ISSN" : "1476-5829", "PMID" : "21569199", "abstract" : "The expression of cyclooxygenase isoform 2 (COX-2) in canine nasal carcinomas has been well documented. COX-2 expression has proven to be a prognostic factor in several human tumours. The aims of this study were to assess the correlation between immunohistochemical COX-2 expression and prognosis using rhinoscopic biopsies from 42 dogs with nasal carcinomas treated with hypofractionated radiotherapy, and to establish a replicable COX-2 scoring system. Ninety per cent of sections evaluated were COX-2 positive with a mean score of 6.6 (median 8.0; range 0-12). Neither COX-2 expression nor tumour type had a significant correlation with survival. There are likely to be many as yet unidentified variants which contribute to length of survival in dogs with nasal carcinomas. Immunohistochemical COX-2 expression appears unlikely to be of prognostic significance for canine nasal carcinoma.", "author" : [ { "dropping-particle" : "", "family" : "Belshaw", "given" : "Z", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Constantio-Casas", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brearley", "given" : "M J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dunning", "given" : "M D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holmes", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dobson", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary and comparative oncology", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2011", "6" ] ] }, "page" : "141-8", "title" : "COX-2 expression and outcome in canine nasal carcinomas treated with hypofractionated radiotherapy.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISSN" : "0301-0724", "PMID" : "1230415", "abstract" : "This paper describes the surgical treatment of fourteen dogs with intranasal neoplasms. Affected dogs were from ten breeds and their average age was eight years. Clinical signs included unilateral nasal discharge epistaxis and sneezing; later there was deformity of the face and/or palate. Diagnosis of intra-nasal tumour was made by radiological examination and by exploratory rhinotomy. Surgical excision of the tumour mass was attempted in all cases. Histological examination of resected nasal tissue revealed five carcinomas, six sarcomas and three examples of benign polypoid hyperplasia of the nasal mucosa. The average post-operative survival time was 11 months with a range from two weeks to four years.", "author" : [ { "dropping-particle" : "", "family" : "Denny", "given" : "H R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gibbs", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kelly", "given" : "D F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Folia veterinaria Latina", "id" : "ITEM-3", "issue" : "4", "issued" : { "date-parts" : [ [ "0", "1" ] ] }, "page" : "527-48", "title" : "[The surgical treatment of intra-nasal tumours in the dog].", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(6\u20138)", "plainTextFormattedCitation" : "(6\u20138)", "previouslyFormattedCitation" : "(6\u20138)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(6–8). MSTs following surgery alone are approximately three to six months although the procedure is associated with a high rate of morbidity ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-1488", "PMID" : "556613", "abstract" : "The records of 43 dogs with nasal tumors (1969- 1974) were evaluated in retrospect. The median age at diagnosis was 10 years. Most affected dogs were bloody nasal discharge, sneezing, and nasal bone deformities. A new method of obtaining tissure for cytologic and histologic evalution proved to be accurate in making a definitive diagnosis in 50% of the cases evaluated. Affected dogs were treated by surgery, surgery plus immunotherapy, or not at all. The results of those treated by surgery alone were no better than those not treated.", "author" : [ { "dropping-particle" : "", "family" : "MacEwen", "given" : "E G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Withrow", "given" : "S J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patnaik", "given" : "A K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American Veterinary Medical Association", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1977", "1", "1" ] ] }, "page" : "45-8", "title" : "Nasal tumors in the dog: retrospective evaluation of diagnosis, prognosis, and treatment.", "type" : "article-journal", "volume" : "170" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(1)", "plainTextFormattedCitation" : "(1)", "previouslyFormattedCitation" : "(1)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(1). Reported MSTs with curative intent RT range between eight and 19.7 months, with one- and two-year survival rates of 43% to 68% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-1488", "PMID" : "8496103", "abstract" : "Seventy-seven dogs with malignant tumors of the nasal and paranasal cavities were treated by use of radiotherapy. The tumors included carcinomas (58) and sarcomas (19). Radiographic findings, including site of involvement and tumor extension, were the basis of clinical staging. Staging was performed according to the tumor, node, metastasis staging of the World Health Organization, and a modified staging scheme based on prognostic factors that seemed to correlate best with response to treatment. All irradiations were done with a telecobalt 60 unit. Fifty-six dogs were treated with irradiation alone, and 21 had partial tumor resection prior to radiotherapy. Treatment dose was 48 Gy (minimal tumor dose) administered on a Monday-Wednesday-Friday basis at 4 Gy/fraction over 4 weeks. The irradiation technique emphasized rostral field with a generous treatment volume. Duration of follow-up after irradiation ranged from 1 month to 61 months. The 1- and 2-year overall survival rates were 60.3% and 25%, respectively, and the 1- and 2-year relapse-free survival rates were 38.2% and 17.6%, respectively. Results of histologic examination and our modified staging scheme were significant (P = 0.02 and P = 0.04, respectively) prognostic factors of relapse-free survival. Conversely, tumor site, tumor extension, World Health Organization clinical stage, and cytoreductive surgery prior to irradiation did not affect the outcome of treatment. According to our modified staging scheme, dogs with stage-2- disease have a poorer prognosis than dogs with stage-1 disease, with a relative risk of relapse 2.3-fold higher. Dogs with carcinoma had a poorer prognosis than dogs with sarcoma (predominantly chondrosarcoma) with a relative risk of relapse 3.3-fold higher.(ABSTRACT TRUNCATED AT 250 WORDS)", "author" : [ { "dropping-particle" : "", "family" : "Th\u00e9on", "given" : "A P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Madewell", "given" : "B R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harb", "given" : "M F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dungworth", "given" : "D L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American Veterinary Medical Association", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "1993", "5", "1" ] ] }, "page" : "1469-75", "title" : "Megavoltage irradiation of neoplasms of the nasal and paranasal cavities in 77 dogs.", "type" : "article-journal", "volume" : "202" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0003-1488", "PMID" : "3654292", "abstract" : "The nasal cavity of 67 dogs with malignant nasal neoplasia was treated with radiation. Preirradiation surgical cytoreduction of the tumor was done in 41 dogs. Fifty dogs were irradiated by use of 10 fractions over 22 days, and 17 dogs were given a similar total dose in 5 fractions over 35 days. The range of survival times (0.5 to 42 months), median survival time (8.5 months), and 1- and 2-year survival rates (38% and 30%, respectively) were better than those expected for other methods of treatment. Serious complications were few (4%). Survival times for dogs were determined on the basis of histologic tumor type and on the basis of megavoltage (cobalt or linear accelerator) vs softer deep radiation (cesium or orthovoltage) treatment, with or without cytoreductive surgery. Survival times of 10 dogs given softer radiation without surgery were shorter than those of 14 dogs that were given softer radiation and had cytoreductive surgery. Survival times of dogs that were given softer radiation and had surgery were similar to those of dogs that were given megavoltage radiation only. Cytoreductive surgery did not improve survival times for dogs that were given megavoltage radiation. Median survival time for 38 dogs with adenocarcinoma was 12 months, compared with 6 months for 14 dogs with squamous cell or undifferentiated carcinoma. Median survival time for 16 dogs with a variety of sarcomas was 11.2 months. Survival times of dogs with adenocarcinoma or sarcoma were significantly better (P less than 0.02 or 0.03) than for dogs with squamous cell or undifferentiated carcinoma. Necropsies were performed on 27 of 58 dogs that died or were euthanatized.(ABSTRACT TRUNCATED AT 250 WORDS)", "author" : [ { "dropping-particle" : "", "family" : "Adams", "given" : "W M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Withrow", "given" : "S J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walshaw", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Turrell", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Evans", "given" : "S M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kurzman", "given" : "I D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American Veterinary Medical Association", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "1987", "8", "1" ] ] }, "page" : "311-5", "title" : "Radiotherapy of malignant nasal tumors in 67 dogs.", "type" : "article-journal", "volume" : "191" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISSN" : "0003-1488", "PMID" : "16190593", "abstract" : "OBJECTIVE: To compare long-term results of radiotherapy alone versus radiotherapy followed by exenteration of the nasal cavity in dogs with malignant intranasal neoplasia.\n\nDESIGN: Retrospective study.\n\nANIMALS: 53 dogs with malignant intranasal neoplasia.\n\nPROCEDURE: All dogs underwent radiotherapy consisting of administration of 10 fractions of 4.2 Gy each on consecutive weekdays. For dogs in the surgery group (n=13), follow-up computed tomography was performed, and dogs were scheduled for surgery if persistent or recurrent tumor was seen.\n\nRESULTS: Perioperative complications for dogs that underwent surgery included hemorrhage requiring transfusion (2 dogs) and subcutaneous emphysema (8). Rhinitis and osteomyelitis-osteonecrosis occurred significantly more frequently in dogs in the radiotherapy and surgery group (9 and 4 dogs, respectively) than in dogs in the radiotherapy-only group (4 and 3 dogs, respectively). Two- and 3-year survival rates were 44% and 24%, respectively, for dogs in the radiotherapy group and 69% and 58%, respectively, for dogs in the surgery group. Overall median survival time for dogs in the radiotherapy and surgery group (477 months) was significantly longer than time for dogs in the radiotherapy-only group (19.7 months).\n\nCONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that exenteration of the nasal cavity significantly prolongs survival time in dogs with intranasal neoplasia that have undergone radiotherapy. Exenteration after radiotherapy may increase the risk of chronic complications.", "author" : [ { "dropping-particle" : "", "family" : "Adams", "given" : "William M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bjorling", "given" : "Dale E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McAnulty", "given" : "Jonathan E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Green", "given" : "Eric M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forrest", "given" : "Lisa J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vail", "given" : "David M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American Veterinary Medical Association", "id" : "ITEM-3", "issue" : "6", "issued" : { "date-parts" : [ [ "2005", "9", "15" ] ] }, "page" : "936-41", "title" : "Outcome of accelerated radiotherapy alone or accelerated radiotherapy followed by exenteration of the nasal cavity in dogs with intranasal neoplasia: 53 cases (1990-2002).", "type" : "article-journal", "volume" : "227" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1111/jsap.12083", "ISSN" : "1748-5827", "PMID" : "23718867", "abstract" : "OBJECTIVES: To determine the computed tomographic stage of dogs with nasal tumours in a UK referral population, and whether stage, time to referral and treatment correlates with outcome.\n\nMETHODS: Retrospective review of clinical records and computed tomography scans of dogs with nasal tumours.\n\nRESULTS: Dogs (n=78) presented to a referral practice in the UK with suspected nasal tumours are presented with more late stage tumours than dogs in the USA and Japan. Length of time from initial presentation to referral did not correlate with tumour stage at diagnosis. Median survival times for radiotherapy-treated dogs in this population are equivalent to those previously reported for late stage nasal tumours.\n\nCLINICAL SIGNIFICANCE: Dogs with nasal tumours are presented late in the course of disease in the North West of England. Dogs with clinical signs consistent with a nasal tumour should have timely imaging and biopsy, in order to make prompt treatment decisions. Although survival times are comparable with previous reports and radiotherapy is a valid treatment option for dogs with late stage disease, better outcomes are likely to be achievable with earlier treatment.", "author" : [ { "dropping-particle" : "", "family" : "Mason", "given" : "S L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maddox", "given" : "T W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lillis", "given" : "S M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blackwood", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of small animal practice", "id" : "ITEM-4", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "7" ] ] }, "page" : "347-53", "title" : "Late presentation of canine nasal tumours in a UK referral hospital and treatment outcomes.", "type" : "article-journal", "volume" : "54" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(9\u201312)", "plainTextFormattedCitation" : "(9\u201312)", "previouslyFormattedCitation" : "(9\u201312)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(9–12). A combination of surgical debulking and adjuvant RT has not been proven to increase MSTs ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-1488", "PMID" : "556613", "abstract" : "The records of 43 dogs with nasal tumors (1969- 1974) were evaluated in retrospect. The median age at diagnosis was 10 years. Most affected dogs were bloody nasal discharge, sneezing, and nasal bone deformities. A new method of obtaining tissure for cytologic and histologic evalution proved to be accurate in making a definitive diagnosis in 50% of the cases evaluated. Affected dogs were treated by surgery, surgery plus immunotherapy, or not at all. The results of those treated by surgery alone were no better than those not treated.", "author" : [ { "dropping-particle" : "", "family" : "MacEwen", "given" : "E G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Withrow", "given" : "S J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patnaik", "given" : "A K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American Veterinary Medical Association", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1977", "1", "1" ] ] }, "page" : "45-8", "title" : "Nasal tumors in the dog: retrospective evaluation of diagnosis, prognosis, and treatment.", "type" : "article-journal", "volume" : "170" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(1)", "plainTextFormattedCitation" : "(1)", "previouslyFormattedCitation" : "(1)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(1). Combining RT with cyclooxygenase-2 (COX-2) inhibitors and chemotherapy has also been investigated, but no survival benefit (MST of 201 to 474 days) compared to RT alone was identified ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1476-5829.2010.00243.x", "ISSN" : "1476-5829", "PMID" : "21569199", "abstract" : "The expression of cyclooxygenase isoform 2 (COX-2) in canine nasal carcinomas has been well documented. COX-2 expression has proven to be a prognostic factor in several human tumours. The aims of this study were to assess the correlation between immunohistochemical COX-2 expression and prognosis using rhinoscopic biopsies from 42 dogs with nasal carcinomas treated with hypofractionated radiotherapy, and to establish a replicable COX-2 scoring system. Ninety per cent of sections evaluated were COX-2 positive with a mean score of 6.6 (median 8.0; range 0-12). Neither COX-2 expression nor tumour type had a significant correlation with survival. There are likely to be many as yet unidentified variants which contribute to length of survival in dogs with nasal carcinomas. Immunohistochemical COX-2 expression appears unlikely to be of prognostic significance for canine nasal carcinoma.", "author" : [ { "dropping-particle" : "", "family" : "Belshaw", "given" : "Z", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Constantio-Casas", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brearley", "given" : "M J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dunning", "given" : "M D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holmes", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dobson", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary and comparative oncology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2011", "6" ] ] }, "page" : "141-8", "title" : "COX-2 expression and outcome in canine nasal carcinomas treated with hypofractionated radiotherapy.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1111/vru.12246", "ISSN" : "1740-8261", "PMID" : "25703137", "abstract" : "Carcinomas represent two-thirds of canine nasosinal neoplasms. Although radiation therapy (RT) is the standard of care, the incidence of local recurrence following treatment is high. Cyclooxygenase-isoform-2 (COX-2) is expressed in 71-95% of canine nasal carcinomas and has been implicated in tumor growth and angiogenesis. Accordingly, COX-2 inhibition seems rational to improve outcome. Dogs with histologically confirmed, previously untreated nasal carcinomas were randomized to receive the combination of a selective COX-2 inhibitor (firocoxib) and palliative RT (Group 1) or RT and placebo (Group 2). Patients were regularly monitored with blood tests, urinalysis, and computed tomography. Pet owners were asked to complete monthly a quality-of-life questionnaire. Twenty-four dogs were prospectively enrolled. According to Adams modified system, there were five stage 1, five stage 2, three stage 3, and 11 stage 4 tumors. Two dogs had metastases to regional lymph nodes. Median progression-free interval and overall survival were 228 and 335 days in Group 1 (n = 12) and 234 and 244 days in Group 2 (n = 12). These differences were not statistically significant. The involvement of regional lymph nodes was significantly associated with progression-free interval and overall survival (P = 0.004). Quality of life was significantly improved in Group 1 (P = 0.008). In particular, a significant difference was observed for activity and appetite. Although not providing a significant enhancement of progression-free interval and overall survival, firocoxib in combination with RT is safe and improved life quality in dogs with nasal carcinomas.", "author" : [ { "dropping-particle" : "", "family" : "Cancedda", "given" : "Simona", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sabattini", "given" : "Silvia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bettini", "given" : "Giuliano", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leone", "given" : "Vito F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Laganga", "given" : "Paola", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rossi", "given" : "Federica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Terragni", "given" : "Rossella", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gnudi", "given" : "Giacomo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vignoli", "given" : "Massimo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary radiology & ultrasound : the official journal of the American College of Veterinary Radiology and the International Veterinary Radiology Association", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "0", "1" ] ] }, "page" : "335-43", "title" : "Combination of radiation therapy and firocoxib for the treatment of canine nasal carcinoma.", "type" : "article-journal", "volume" : "56" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISSN" : "1058-8183", "PMID" : "15605853", "abstract" : "The purpose of this study was to evaluate the combined use of radiation and a slow-release cisplatin chemotherapy formulation for treatment of malignant nasal tumors in dogs. In this retrospective analysis, 51 dogs were evaluated with respect to treatment toxicity, tumor type, stage of disease, cribriform plate involvement, and overall survival. In general, treatment was well tolerated. Mean and median survival as assessed by the Kaplan-Meier product limit method was 570 and 474 days, respectively. No other factors, including tumor type, stage of disease, or cribriform plate invasion had a significant impact on survival. In conclusion, a combination of slow release cisplatin chemotherapy and radiation for the treatment of canine nasal tumors is well tolerated. Results of this analysis warrant further study to elucidate possible other beneficial radiation potentiating drugs and dosing schedules.", "author" : [ { "dropping-particle" : "", "family" : "Lana", "given" : "Susan E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dernell", "given" : "William S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lafferty", "given" : "Mary H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Withrow", "given" : "Stephen J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "LaRue", "given" : "Susan M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary radiology & ultrasound : the official journal of the American College of Veterinary Radiology and the International Veterinary Radiology Association", "id" : "ITEM-3", "issue" : "6", "issued" : { "date-parts" : [ [ "0", "1" ] ] }, "page" : "577-81", "title" : "Use of radiation and a slow-release cisplatin formulation for treatment of canine nasal tumors.", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(6,7,13)", "plainTextFormattedCitation" : "(6,7,13)", "previouslyFormattedCitation" : "(6,7,13)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(6,7,13). Chemotherapy as a sole treatment is not routinely recommended, but is reported: one study showed some benefit for individual dogs with a clinical response rate of 27% using single-agent cisplatin treatment ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-1488", "PMID" : "1548172", "abstract" : "In 11 dogs with nasal adenocarcinoma, IV treatment with 2 to 8 cycles of cisplatin at a dosage of 60 mg/m2 of body surface, given at 3-week intervals, resulted in a survival time of 8 to 128 weeks (mean, 32.7 weeks; median, 20 weeks). Radiography revealed complete remission in 2 dogs and partial remission in 1 dog, for an overall response rate of 27%. Clinical problems such as nasal discharge (n = 11), sneezing (n = 6), and epistaxis (n = 4) resolved in 1 to 2 weeks in all dogs after beginning chemotherapy.", "author" : [ { "dropping-particle" : "", "family" : "Hahn", "given" : "K A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knapp", "given" : "D W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Richardson", "given" : "R C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matlock", "given" : "C L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American Veterinary Medical Association", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1992", "2", "1" ] ] }, "page" : "355-7", "title" : "Clinical response of nasal adenocarcinoma to cisplatin chemotherapy in 11 dogs.", "type" : "article-journal", "volume" : "200" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(14)", "plainTextFormattedCitation" : "(14)", "previouslyFormattedCitation" : "(14)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(14). Another small study reported an objective response rate of 75% with resolution of clinical signs in all patients using a combination treatment of chemotherapy with doxorubicin and carboplatin and the COX-2 inhibitor piroxicam ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0005-0423", "PMID" : "15977611", "abstract" : "OBJECTIVE: To determine the efficacy and toxicity of chemotherapy in the treatment of canine nasal tumours.\n\nDESIGN: Retrospective clinical study\n\nPROCEDURE: Eight dogs with histologically confirmed nasal tumours were staged by means of complete blood count, serum biochemical analysis, cytological analysis of fine needle aspirate of the regional lymph nodes, thoracic radiographs and computed tomography scan of the nasal cavity. All dogs were treated with alternating doses of doxorubicin, carboplatin and oral piroxicam. All dogs were monitored for side effects of chemotherapy and evaluated for response to treatment by computed tomography scan of the nasal cavity after the first four treatments.\n\nRESULTS: Complete remission was achieved in four dogs, partial remission occurred in two dogs and two had stable disease on the basis of computed tomography evaluation. There was resolution of clinical signs after one to two doses of chemotherapy in all dogs.\n\nCONCLUSIONS: This chemotherapy protocol was efficacious and well tolerated in this series of eight cases of canine nasal tumours.", "author" : [ { "dropping-particle" : "", "family" : "Langova", "given" : "V", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mutsaers", "given" : "A J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phillips", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Straw", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Australian veterinary journal", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2004", "11" ] ] }, "page" : "676-80", "title" : "Treatment of eight dogs with nasal tumours with alternating doses of doxorubicin and carboplatin in conjunction with oral piroxicam.", "type" : "article-journal", "volume" : "82" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(15)", "plainTextFormattedCitation" : "(15)", "previouslyFormattedCitation" : "(15)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(15). Tyrosine kinase inhibitors may offer an additional therapeutic approach: a recent study demonstrated a 71.4% response rate to toceranib phosphate in a small patient cohort with nasal carcinoma, in which the majority of patients received prior RTADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1476-5829.2011.00275.x", "ISSN" : "1476-5829", "PMID" : "22236194", "abstract" : "The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia\u00ae, Pfizer Animal Health, Madison, NJ, USA) in select solid tumours in dogs. Cases in which toceranib was used to treat dogs with apocrine gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma (OSA), thyroid carcinoma, head and neck carcinoma and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 AGASACA [8 partial response (PR), 20 stable disease (SD)], 11/23 OSAs (1 PR and 10 SD), 12/15 thyroid carcinomas (4 PR and 8 SD), 7/8 head and neck carcinomas [1 complete response (CR), 5 PR and 1 SD] and 5/7 (1 CR and 4 SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg kg(-1) , 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis and 47/63 (74.6%) were treated 4 months or longer. Although these data provide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumours, future prospective studies are necessary to define its true activity.", "author" : [ { "dropping-particle" : "", "family" : "London", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mathie", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stingle", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clifford", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haney", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klein", "given" : "M K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beaver", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vickery", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vail", "given" : "D M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hershey", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ettinger", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vaughan", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alvarez", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hillman", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kiselow", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thamm", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Higginbotham", "given" : "M L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gauthier", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krick", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phillips", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ladue", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jones", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bryan", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gill", "given" : "V", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Novasad", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fulton", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carreras", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McNeill", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Henry", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gillings", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary and comparative oncology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2012", "9" ] ] }, "page" : "194-205", "title" : "Preliminary evidence for biologic activity of toceranib phosphate (Palladia(\u00ae)) in solid tumours.", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(16)", "plainTextFormattedCitation" : "(16)", "previouslyFormattedCitation" : "(16)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(16). Despite most dogs experiencing a favourable clinical response to RT the long-term survival is poor, due to local recurrence. Understanding the molecular mechanisms associated with canine nasal carcinoma oncogenesis may provide additional targets for therapy. Studies have identified p53 accumulation in nasal adenocarcinomas ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0002-9645", "PMID" : "9256970", "abstract" : "OBJECTIVE: To determine prevalence of p53 tumor suppressor protein overexpression in spontaneously arising tumors of dogs, using the CM-1 polyclonal antibody and immunohistochemical methods. DESIGN AND SAMPLE POPULATION: Retrospective analysis was performed on archived, paraffin-embedded tumor tissue from dogs. A total of 226 tumors were evaluated, including tumors of epithelial, mesenchymal, and round cell origins.\n\nPROCEDURES: Overexpression of p53 was detected by indirect immunohistochemical methods, using the CM-1 rabbit anti-human p53 polyclonal primary antibody. Protein overexpression was determined by use of a grading system based on percentage of stained tumor nuclei.\n\nRESULTS: Nuclear overexpression of p53 was detected in most squamous cell carcinomas, nasal adenocarcinomas, and perianal gland adenocarcinomas. Hemangiopericytomas, transitional cell carcinomas, mammary adenocarcinomas, apocrine gland adenocarcinomas, intestinal adenocarcinomas, mast cell tumors, and cutaneous histiocytomas had low numbers of nuclei overexpressing p53. Remaining tumor types had intermediate p53 nuclear overexpression. Cytoplasmic staining was observed in some carcinomas, particularly intestinal adenocarcinomas.\n\nCONCLUSIONS: Overexpression of p53 is common in spontaneously arising neoplasms of dogs.\n\nCLINICAL RELEVANCE: Prospective determination of p53 status in some tumor types may be as clinically useful in determining prognosis and predicting survival times for dogs with cancer as it is for human beings with cancer.", "author" : [ { "dropping-particle" : "", "family" : "Gamblin", "given" : "R M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sagartz", "given" : "J E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Couto", "given" : "C G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of veterinary research", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "1997", "8" ] ] }, "page" : "857-63", "title" : "Overexpression of p53 tumor suppressor protein in spontaneously arising neoplasms of dogs.", "type" : "article-journal", "volume" : "58" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(17)", "plainTextFormattedCitation" : "(17)", "previouslyFormattedCitation" : "(17)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(17) and expression of cyclooxygenase-2 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1058-8183", "PMID" : "15200266", "abstract" : "Cyclooxygenase-2 (COX-2) is an enzyme upregulated in some human and animal tumors. Enzymatic products are associated with tumorigenic activities. Given the poor response of canine nasal tumors to radiation, we considered the possibility that some of this resistance may be associated with COX-2 expression. To test this, 21 formalin-fixed, paraffin-embedded, and archived biopsy samples from canine epithelial nasal tumors were analyzed for COX-2 expression using immunohistochemistry. The biopsies were collected from dogs prior to radiation therapy. COX-2 expression was present in 17 of 21 (81%) tumors. The expression was observed in several different tumor types, including nasal carcinomas, adenocarcinomas, and squamous cell carcinomas. Samples from five control dogs without nasal neoplasia were also analyzed for COX-2 staining. These specimens were characterized by varying degrees of lymphoplasmacytic rhinitis with scattered regions of COX-2 positive respiratory epithelial and stromal cells. Whether the intensity and distribution of COX-2 expression in nasal tumors can be used as a prognostic marker requires further investigation. A combination therapy of irradiation and a selective COX-2 inhibitor appears worthy of clinical investigation in the treatment of canine epithelial nasal tumors.", "author" : [ { "dropping-particle" : "", "family" : "Kleiter", "given" : "Miriami", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malarkey", "given" : "David E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ruslander", "given" : "David E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thrall", "given" : "Donald E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary radiology & ultrasound : the official journal of the American College of Veterinary Radiology and the International Veterinary Radiology Association", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "0", "1" ] ] }, "page" : "255-60", "title" : "Expression of cyclooxygenase-2 in canine epithelial nasal tumors.", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/jl.2007.03.022", "ISSN" : "1090-0233", "PMID" : "17517527", "abstract" : "Cyclooxygenase(COX)-2 expression was evaluated in 24 paraffin-embedded canine nasal carcinoma tissue samples by immunohistochemistry. Several different tumor types were represented, including carcinomas, adenocarcinomas and squamous cell carcinomas. COX-2 expression was identified in 17/24 cases (71%). The proportion of positive cells expressing COX-2 ranged from 10 to 95% and COX-2 expression was predominantly localized in the cytoplasm. Treatment with a COX-2 inhibitor should be investigated, along with the utilization of COX-2 expression as a prognostic marker.", "author" : [ { "dropping-particle" : "", "family" : "Impellizeri", "given" : "Joseph A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Esplin", "given" : "D Glen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary journal (London, England : 1997)", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2008", "6" ] ] }, "page" : "408-10", "title" : "Expression of cyclooxygenase-2 in canine nasal carcinomas.", "type" : "article-journal", "volume" : "176" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(18,19)", "plainTextFormattedCitation" : "(18,19)", "previouslyFormattedCitation" : "(18,19)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(18,19), peroxisome proliferator-activated receptor γ ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1439-0442.2007.00961.x", "ISSN" : "0931-184X", "PMID" : "17877580", "abstract" : "Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a ligand-activated transcriptional factor belonging to the steroid receptor superfamily. PPAR-gamma is expressed in multiple normal and neoplastic tissues, such as the breast, colon, lung, ovary and placenta. In addition to adipogenic and anti-inflammatory effects, PPAR-gamma activation has been shown to be anti-proliferative by its differentiation-promoting effect, suggesting that activation of PPAR-gamma may be useful in slowing or arresting the proliferation of de-differentiated tumour cells. In this study, we investigated the expression of PPAR-gamma in normal and neoplastic canine nasal epithelium. Twenty-five samples composed of five normal nasal epithelia and 20 canine nasal carcinomas, were immunohistochemically stained for PPAR-gamma. The specificity of the antibody was verified by Western Blot analysis. Confocal laser scanning microscopical investigation was also performed. In normal epithelium, the staining pattern was cytoplasmic and polarized at the cellular free edge. In carcinomas, the neoplastic cells showed mainly strong cytoplasmatic PPAR-gamma expression; moreover, perinuclear immunoreactivity was also detected and few neoplastic cells exhibited a nuclear positivity. Our results demonstrate different patterns of PPAR-gamma expression in normal canine nasal epithelium when compared with canine nasal carcinoma. The importance of this transcription factor in the pathophysiology of several different tumours has stimulated much research in this field and has opened new opportunities for the treatment of the tumours.", "author" : [ { "dropping-particle" : "", "family" : "Paciello", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Borzacchiello", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Varricchio", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Papparella", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of veterinary medicine. A, Physiology, pathology, clinical medicine", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2007", "10" ] ] }, "page" : "406-10", "title" : "Expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) in canine nasal carcinomas.", "type" : "article-journal", "volume" : "54" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(20)", "plainTextFormattedCitation" : "(20)", "previouslyFormattedCitation" : "(20)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(20) and either epithelial growth factor receptor (EGFR) or vascular endothelial growth factor receptor (VEGFR) in nasal carcinomas ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1476-5829.2009.00178.x", "ISSN" : "1476-5829", "PMID" : "19453364", "abstract" : "Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) signalling pathways play a role in carcinogenesis. Inhibition of EGF receptor (EGFR) and of VEGF is effective in increasing the radiation responsiveness of neoplastic cells both in vitro and in human trials. In this study, immunohistochemical evaluation was employed to determine and characterize the potential protein expression levels and patterns of EGFR and VEGF in a variety of canine malignant epithelial nasal tumours. Of 24 malignant canine nasal tumours, 13 (54.2%) were positive for EGFR staining and 22 (91.7%) were positive for VEGF staining. The intensity and percentage of immunohistochemically positive neoplastic cells for EGFR varied. These findings indicate that EGFR and VEGF proteins were present in some malignant epithelial nasal tumours in the dogs, and therefore, it may be beneficial to treat canine patients with tumours that overexpress EGFR and VEGF with specific inhibitors in conjunction with radiation.", "author" : [ { "dropping-particle" : "", "family" : "Shiomitsu", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "C L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malarkey", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pruitt", "given" : "A F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thrall", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary and comparative oncology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2009", "6" ] ] }, "page" : "106-14", "title" : "Expression of epidermal growth factor receptor and vascular endothelial growth factor in malignant canine epithelial nasal tumours.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(21)", "plainTextFormattedCitation" : "(21)", "previouslyFormattedCitation" : "(21)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(21).VEGFR has been shown to be responsible for vasculogenesis as well as angiogenesis. Stimulation of VEGFRs leads to endothelial proliferation, migration and survival ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/80430", "ISSN" : "1078-8956", "PMID" : "11017137", "author" : [ { "dropping-particle" : "", "family" : "Carmeliet", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature medicine", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2000", "10" ] ] }, "page" : "1102-3", "title" : "VEGF gene therapy: stimulating angiogenesis or angioma-genesis?", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(22)", "plainTextFormattedCitation" : "(22)", "previouslyFormattedCitation" : "(22)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(22). VEGF is closely related to the platelet-derived growth factor (PDGF) family and its receptor PDGFR has also been shown to be involved with angiogenesis. Signalling from these receptor tyrosine kinases (rTK) has the potential to produce a supportive microenvironment for neoplasms by providing vasculature and proliferative drive. These rTKs are expressed in a variety of canine neoplasms including mast cell tumours (MCT) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1158/1541-7786.MCR-08-0067", "ISSN" : "1541-7786", "PMID" : "18644978", "abstract" : "In the current study, we examined the types and frequency of KIT mutations in mast cell tumors from 191 dogs. Sequencing of reverse transcription-PCR products revealed alterations in 50 (26.2%) of the dogs. Most mutations were in exon 11 (n = 32), and of these, most were internal tandem duplications (n = 25) between residues 571 and 590. Within exon 11, there were two hotspots for mutations at codons 555-559 and 571-590. In addition, nine dogs had mutations in exon 8 and eight had mutations in exon 9. We selected the two most common mutants and two representative exon 11 mutants for further analysis. When expressed in Ba/F3 cells, they were constitutively tyrosine phosphorylated and induced growth factor-independent cell proliferation. AG1296, a tyrosine kinase inhibitor, dose dependently inhibited both the tyrosine phosphorylation of these mutants and their induction of growth factor-independent proliferation. This study shows that activating mutations in not only exon 11 but also exons 8 and 9 are common in canine mast cell tumors. These results also show that Ba/F3 cells can be used for the direct characterization of canine KIT mutants, eliminating the need to make equivalent mutations in the mouse or human genes.", "author" : [ { "dropping-particle" : "", "family" : "Letard", "given" : "S\u00e9bastien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yang", "given" : "Ying", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hanssens", "given" : "Katia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Palm\u00e9rini", "given" : "Fabienne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leventhal", "given" : "Phillip S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gu\u00e9ry", "given" : "St\u00e9phanie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moussy", "given" : "Alain", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kinet", "given" : "Jean-Pierre", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hermine", "given" : "Olivier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dubreuil", "given" : "Patrice", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular cancer research : MCR", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2008", "7" ] ] }, "page" : "1137-45", "title" : "Gain-of-function mutations in the extracellular domain of KIT are common in canine mast cell tumors.", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(23)", "plainTextFormattedCitation" : "(23)", "previouslyFormattedCitation" : "(23)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(23), anal sac adenocarcinomas (ASAC) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1476-5829.2011.00275.x", "ISSN" : "1476-5829", "PMID" : "22236194", "abstract" : "The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia\u00ae, Pfizer Animal Health, Madison, NJ, USA) in select solid tumours in dogs. Cases in which toceranib was used to treat dogs with apocrine gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma (OSA), thyroid carcinoma, head and neck carcinoma and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 AGASACA [8 partial response (PR), 20 stable disease (SD)], 11/23 OSAs (1 PR and 10 SD), 12/15 thyroid carcinomas (4 PR and 8 SD), 7/8 head and neck carcinomas [1 complete response (CR), 5 PR and 1 SD] and 5/7 (1 CR and 4 SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg kg(-1) , 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis and 47/63 (74.6%) were treated 4 months or longer. Although these data provide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumours, future prospective studies are necessary to define its true activity.", "author" : [ { "dropping-particle" : "", "family" : "London", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mathie", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stingle", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clifford", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haney", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klein", "given" : "M K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" 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(PDGFs) belong to a family of polypeptide growth factors that signal through cell surface tyrosine kinase receptors to stimulate growth, proliferation and differentiation. Platelet-derived growth factor receptors (PDGFRs) are also considered important targets for specific kinase inhibitors in the treatment of several human tumours. The aim of this study was to investigate the role of PDGF-A, PDGF-B, PDGFR-\u03b1 and PDGFR-\u03b2 in canine lymphoma by determining gene and protein expression in lymph nodes of dogs with diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), T-lymphoblastic lymphoma (T-LBL) and in healthy control dogs. One lymph node was also studied at the end of therapy in a subset of dogs in remission for DLBCL. In controls, PDGF-A, PDGFR-\u03b1 and PDGFR-\u03b2 mRNA levels were significantly higher than in DLBCLs, PTCLs and T-LBLs. However, PDGFR-\u03b1 and PDGFR-\u03b2 were minimally expressed by lymphocytes and plasma cells in normal lymph nodes as determined by immunohistochemistry, while neoplastic B and T cells showed the highest score (P <0.05). This discordant result may be compatible with the constitutive expression of these molecules by endothelial cells and fibroblasts in normal lymph nodes, thereby influencing gene expression results. Furthermore, these cells were not included in the immunohistochemical analysis. Similarly, dogs with DLBCL that were in remission at the end of therapy showed significantly higher gene expression of PDGFs and receptors than at the time of diagnosis and with an opposite trend to the protein assay. PDGF-B protein and mRNA were overexpressed in PTCLs and T-LBLs when compared with DLBCLs and controls (P <0.05). Additionally, there was a correlation between protein expression of PDGF-B and both PDGFRs in PTCLs and T-LBLs, suggesting an autocrine or paracrine loop in the aetiology of aggressive canine T-cell lymphomas. These data provide a rationale for the use of PDGFR antagonists in the therapy of aggressive T-cell lymphomas, but not in DLBCLs.", "author" : [ { "dropping-particle" : "", "family" : "Aric\u00f2", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Guadagnin", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ferraresso", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gelain", "given" : "M E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Iussich", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "R\u00fctgen", "given" : "B C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mazzariol", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marconato", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aresu", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of comparative pathology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2014", "11" ] ] }, "page" : "322-8", "title" : "Platelet-derived growth factors and receptors in Canine Lymphoma.", "type" : "article-journal", "volume" : "151" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(24)", "plainTextFormattedCitation" : "(24)", "previouslyFormattedCitation" : "(24)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(24) and nasal carcinomas ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1476-5829.2009.00178.x", "ISSN" : "1476-5829", "PMID" : "19453364", "abstract" : "Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) signalling pathways play a role in carcinogenesis. Inhibition of EGF receptor (EGFR) and of VEGF is effective in increasing the radiation responsiveness of neoplastic cells both in vitro and in human trials. In this study, immunohistochemical evaluation was employed to determine and characterize the potential protein expression levels and patterns of EGFR and VEGF in a variety of canine malignant epithelial nasal tumours. Of 24 malignant canine nasal tumours, 13 (54.2%) were positive for EGFR staining and 22 (91.7%) were positive for VEGF staining. The intensity and percentage of immunohistochemically positive neoplastic cells for EGFR varied. These findings indicate that EGFR and VEGF proteins were present in some malignant epithelial nasal tumours in the dogs, and therefore, it may be beneficial to treat canine patients with tumours that overexpress EGFR and VEGF with specific inhibitors in conjunction with radiation.", "author" : [ { "dropping-particle" : "", "family" : "Shiomitsu", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "C L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malarkey", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pruitt", "given" : "A F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thrall", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary and comparative oncology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2009", "6" ] ] }, "page" : "106-14", "title" : "Expression of epidermal growth factor receptor and vascular endothelial growth factor in malignant canine epithelial nasal tumours.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(21)", "plainTextFormattedCitation" : "(21)", "previouslyFormattedCitation" : "(21)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(21). In veterinary medicine there are currently two licensed tyrosine kinase inhibitors (TKIs), masitinib and toceranib phosphate. Masitinib has inhibitory activity against KIT, PDGF and the fibroblast growth factor 3 receptor ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0007258", "ISSN" : "1932-6203", "PMID" : "19789626", "abstract" : "BACKGROUND: The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT.\n\nMETHODOLOGY/PRINCIPAL FINDINGS: In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC(50)) of 200+/-40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC(50) of 150+/-80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant.\n\nCONCLUSIONS: Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicity.", "author" : [ { "dropping-particle" : "", "family" : "Dubreuil", "given" : "Patrice", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Letard", "given" : "S\u00e9bastien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ciufolini", "given" : "Marco", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gros", "given" : "Laurent", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Humbert", "given" : "Martine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cast\u00e9ran", "given" : "Nathalie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Borge", "given" : "Laurence", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hajem", "given" : "B\u00e9reng\u00e8re", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lermet", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sippl", "given" : "Wolfgang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Voisset", "given" : "Edwige", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Arock", "given" : "Michel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Auclair", "given" : "Christian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leventhal", "given" : "Phillip S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mansfield", "given" : "Colin D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moussy", "given" : "Alain", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hermine", "given" : "Olivier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2009", "1" ] ] }, "page" : "e7258", "title" : "Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT.", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(25)", "plainTextFormattedCitation" : "(25)", "previouslyFormattedCitation" : "(25)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(25), whereas toceranib phosphate targets KIT, VEGF and PDGF receptors ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1740-8261.2012.01925.x", "ISSN" : "1058-8183", "PMID" : "22360684", "abstract" : "Palladia(TM) (toceranib phosphate-Pfizer Animal Health) is a novel orally administered receptor tyrosine kinase inhibitor (TKI) approved for treatment of canine mast cell tumors. Receptor tyrosine kinase dysregulation leads to tumor growth, progression, and metastasis. Toceranib's targets include vascular endothelial growth factor receptor (VEGFR-2/Flk-1/KDR), platelet-derived growth factor receptor, and kit. Positron Emission Tomography/Computed Tomography (PET/CT) is used commonly to diagnose, prognosticate, and monitor response to antineoplastic therapy in human patients. In this study, serial PET/CT imaging with (18) F-fluorodeoxyglucose ((18) FDG) was used to assess response to toceranib therapy in dogs with measurable solid malignancies. Six tumor-bearing dogs underwent tumor assessment using both standard RECIST criteria and PET/CT prior to and at a median of 5 weeks postinitiation of toceranib treatment. Toceranib was prescribed initially at a target dose 3.25 mg/kg PO q48 h, with subsequent modifications based on observed toxicity. Treatment was continued in patients achieving stable disease with acceptable drug tolerance. One dog was maintained on drug despite dose modification due to toxicity; measurable clinical and image-based responses were seen after 10 weeks of therapy. All others had stable or progressive disease based on clinical restaging and PET/CT at first recheck. . Due to discordance with anatomic and metabolic imaging, further studies are needed to investigate the role of molecular imaging in assessment of drug response and identify other potential molecular targets of toceranib.", "author" : [ { "dropping-particle" : "", "family" : "Leblanc", "given" : "Amy K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Miller", "given" : "Ashley N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Galyon", "given" : "Gina D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moyers", "given" : "Tamberlyn D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Long", "given" : "Misty J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stuckey", "given" : "Alan C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wall", "given" : "Jonathan S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morandi", "given" : "Federica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary radiology & ultrasound : the official journal of the American College of Veterinary Radiology and the International Veterinary Radiology Association", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "0", "1" ] ] }, "page" : "348-57", "title" : "Preliminary evaluation of serial (18) FDG-PET/CT to assess response to toceranib phosphate therapy in canine cancer.", "type" : "article-journal", "volume" : "53" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(26)", "plainTextFormattedCitation" : "(26)", "previouslyFormattedCitation" : "(26)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(26). These TKIs were primarily developed for the inhibition of KIT signalling in canine MCTs, but they have been shown to have a spectrum of activity including ASACs, thyroid carcinomas, pulmonary carcinomas, nasal carcinomas and metastatic osteosarcomas ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1476-5829.2011.00275.x", "ISSN" : "1476-5829", "PMID" : "22236194", "abstract" : "The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia\u00ae, Pfizer Animal Health, Madison, NJ, USA) in select solid tumours in dogs. Cases in which toceranib was used to treat dogs with apocrine gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma (OSA), thyroid carcinoma, head and neck carcinoma and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 AGASACA [8 partial response (PR), 20 stable disease (SD)], 11/23 OSAs (1 PR and 10 SD), 12/15 thyroid carcinomas (4 PR and 8 SD), 7/8 head and neck carcinomas [1 complete response (CR), 5 PR and 1 SD] and 5/7 (1 CR and 4 SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg kg(-1) , 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis and 47/63 (74.6%) were treated 4 months or longer. Although these data provide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumours, future prospective studies are necessary to define its true activity.", "author" : [ { "dropping-particle" : "", "family" : "London", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mathie", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stingle", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clifford", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haney", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klein", "given" : "M K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" 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: "", "family" : "Henry", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gillings", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary and comparative oncology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2012", "9" ] ] }, "page" : "194-205", "title" : "Preliminary evidence for biologic activity of toceranib phosphate (Palladia(\u00ae)) in solid tumours.", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1158/1078-R-08-1860", "ISSN" : "1078-0432", "PMID" : "19470739", "abstract" : "PURPOSE: The purpose of this study was to determine the objective response rate (ORR) following treatment of canine mast cell tumors (MCT) with toceranib phosphate (Palladia, SU11654), a kinase inhibitor with both antitumor and antiangiogenic activity through inhibition of KIT, vascular endothelial growth factor receptor 2, and PDGFRbeta. Secondary objectives were to determine biological response rate, time to tumor progression, duration of objective response, health-related quality of life, and safety of Palladia.\n\nEXPERIMENTAL DESIGN: Dogs were randomized to receive oral Palladia 3.25 mg/kg or placebo every other day for 6 weeks in the blinded phase. Thereafter, eligible dogs received open-label Palladia.\n\nRESULTS: The blinded phase ORR in Palladia-treated dogs (n = 86) was 37.2% (7 complete response, 25 partial response) versus 7.9% (5 partial response) in placebo-treated dogs (n = 63; P = 0.0004). Of 58 dogs that received Palladia following placebo-escape, 41.4% (8 complete response, 16 partial response) experienced objective response. The ORR for all 145 dogs receiving Palladia was 42.8% (21 complete response, 41 partial response); among the 62 responders, the median duration of objective response and time to tumor progression was 12.0 weeks and 18.1 weeks, respectively. Palladia-treated responders scored higher on health-related quality of life versus Palladia-treated nonresponders (P = 0.030). There was no significant difference in the number of dogs with grade 3/4 (of 4) adverse events; adverse events were generally manageable with dose modification and/or supportive care.\n\nCONCLUSIONS: Palladia has biological activity against canine MCTs and can be administered on a continuous schedule without need for routine planned treatment breaks. This clinical trial further shows that spontaneous tumors in dogs are good models to evaluate therapeutic index of targeted therapeutics in a clinical setting.", "author" : [ { "dropping-particle" : "", "family" : "London", "given" : "Cheryl A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malpas", "given" : "Phyllis B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wood-Follis", "given" : "Stacey L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boucher", "given" : "Joseph F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rusk", "given" : "Anthony W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rosenberg", "given" : "Mona P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Henry", "given" : "Carolyn J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mitchener", "given" : "Kathy L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klein", "given" : "Mary K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hintermeister", "given" : "John G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bergman", "given" : "Philip J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Couto", "given" : "Guillermo C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mauldin", "given" : "Guy N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Michels", "given" : "Gina M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical cancer research : an official journal of the American Association for Cancer Research", "id" : "ITEM-2", "issue" : "11", "issued" : { "date-parts" : [ [ "2009", "6", "1" ] ] }, "page" : "3856-65", "title" : "Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision.", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1111/vco.12053", "ISSN" : "1476-5829", "PMID" : "23845124", "abstract" : "Masitinib mesylate is a tyrosine kinase inhibitor approved for the treatment of gross, non-metastatic grade II and III canine mast cell tumours (MCTs). This study evaluated the use of masitinib as a frontline and rescue agent for metastatic and non-metastatic canine MCTs. Identification of toxicities and prognostic factors in these dogs was of secondary interest. Twenty-six dogs were included in this study. The overall response rate to masitinib was 50%. The median survival time for dogs that responded to masitinib was 630\u2009days versus 137\u2009days for dogs that did not respond (P\u2009=\u20090.0033). Toxicity was recorded in 61.5% of treated dogs, but the majority of adverse events were mild and self-limiting. Response to masitinib, not tumour grade, stage or location, was the most significant prognostic factor for survival in dogs with MCTs.", "author" : [ { "dropping-particle" : "", "family" : "Smrkovski", "given" : "O A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Essick", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rohrbach", "given" : "B W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Legendre", "given" : "A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary and comparative oncology", "id" : "ITEM-3", "issued" : { "date-parts" : [ [ "2013", "7", "12" ] ] }, "title" : "Masitinib mesylate for metastatic and non-resectable canine cutaneous mast cell tumours.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(16,27,28)", "plainTextFormattedCitation" : "(16,27,28)", "previouslyFormattedCitation" : "(16,27,28)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(16,27,28).In this study we sought to characterise the expression of VEGFR, PDGFR-α and PDGFR-β in a large group of canine malignant intranasal carcinomas as a first step to a rational assessment of the potential efficacy of TKIs in this tumour type. Material and methodsPatient collective and tissue selectionThe database at Bridge Pathology Ltd. in Bristol, United Kingdom, was searched for canine intranasal carcinomas. Tissue samples had been sent by first opinion practices and referral clinics in the United Kingdom. In the database tissue samples of 272 dogs with intranasal carcinoma were diagnosed between 2009 and 2014. All tissue was fixed in 10% neutral buffered formalin and subsequently paraffin embedded. Characterization of tumour subtype of all 272 tissue samples was confirmed in haematoxylin and eosin-stained sections by one of the board-certified pathologists at Bridge Pathology Ltd. according to established criteria ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0042-9686", "PMID" : "1086156", "abstract" : "Tumours of the nasal cavity are rare in domestic animals, most cases occurring in the dog. Epithelial tumours are the most common type in carnivores (dogs and cats). In general, the same types of tumour occur in domestic animals as occur in man. There was no significant predisposition for breed in dogs, but in both dogs and cats far more males than females were affected. Metastases occurred only rarely.", "author" : [ { "dropping-particle" : "", "family" : "St\u00fcnzi", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hauser", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Bulletin of the World Health Organization", "id" : "ITEM-1", "issue" : "2-3", "issued" : { "date-parts" : [ [ "1976", "1" ] ] }, "page" : "257-63", "title" : "Tumours of the nasal cavity.", "type" : "article-journal", "volume" : "53" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(29)", "plainTextFormattedCitation" : "(29)", "previouslyFormattedCitation" : "(29)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(29). In all cases the original diagnosis was used. Eighty five samples were excluded for one or more of the following reasons: 1) the nasal carcinoma was associated with the nasal planum rather than intranasal, 2) no definitive diagnosis was achieved via histopathology alone and no immunohistochemistry was performed, 3) submitted sample volume was too small to perform further analysis. Therefore, a total of 187 archived tissue samples were included. Identification of tumour tissue and preparation of tissue microarraysFor all 187 tissue blocks the corresponding slides were reviewed to identify the tumour tissue and to separate it from areas of normal tissue, inflammation or necrosis. The identified tumour tissue was punched out using a disposable punch biopsy (Punch biopsy, 2mm, Kai Medical). Twenty punches (one of each tissue sample) were re-embedded in one paraffin tissue block (Leica EG 1160 paraffin embedding station) along with two internal positive controls (canine ASAC [PDGFR], canine granulomatous tissue, [VEGFR]) for which positive expression of VEGFR, PDGFR-α and PDGFR-β has already been described ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/1746-6148-8-67", "ISSN" : "1746-6148", "PMID" : "22630170", "abstract" : "BACKGROUND: Toceranib phosphate (Palladia) has a reported objective response rate of 25% in both canine apocrine gland anal sac adenocarcinoma (AGASACA) and thyroid carcinoma (TC), with stable disease occurring in an additional 50-60% of dogs. The basis for the observed responses to toceranib is not known. The purpose of this study was to evaluate AGASACA and TC samples for the expression and activation of VEGFR2, PDGFR\u03b1, PDGFR\u03b2, KIT and RET to assess whether dysregulation of these receptor tyrosine kinases (RTKs) may contribute to the biologic activity of toceranib.\n\nRESULTS: mRNA for VEGFR2, PDGFR\u03b1/\u03b2, KIT and RET was detected in all AGASACA samples. mRNA for VEGFR2, PDGFR\u03b1/\u03b2, and KIT was detected in all TC samples, while mRNA for RET was amplified in 10/15 samples. No phosphorylation of VEGFR2, PDGFR\u03b1/\u03b2, or KIT was observed on the arrays. However, phosphorylation of RET was detected in 54% of the primary AGASACA and 20% of TC. VEGFR2 was expressed in 19/24 primary and 6/10 metastatic AGASACA and 6/15 TC samples. KIT was present in 8/24 primary and 3/10 metastatic AGASACA and 9/15 TC samples. PDGFR\u03b1 expression was noted in all tumor samples. In contrast PDGFR\u03b2 expression was found in only a few tumor samples but was evident in the stroma of all tumor specimens.\n\nCONCLUSIONS: Known targets of toceranib are expressed in both AGASAC and TC. Given the observed expression of VEGFR and PDGFR\u03b1/\u03b2 and phosphorylation of RET, these RTKs merit investigation as to their roles in the biology of AGSACA and TC and their contribution to toceranib's activity.", "author" : [ { "dropping-particle" : "", "family" : "Urie", "given" : "Bridget K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Russell", "given" : "Duncan S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kisseberth", "given" : "William C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "London", "given" : "Cheryl A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC veterinary research", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2012", "1" ] ] }, "page" : "67", "title" : "Evaluation of expression and function of vascular endothelial growth factor receptor 2, platelet derived growth factor receptors-alpha and -beta, KIT, and RET in canine apocrine gland anal sac adenocarcinoma and thyroid carcinoma.", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.4236/ojvm.2012.24030", "ISSN" : "2165-3356", "abstract" : "Formation of new blood vessels is paramount for tumour growth and metastatic dissemination and vascular endothelial growth factor (VEGF) is one of the key regulators of this process. The purpose of this study was to evaluate the immunohistochemical expression of VEGF in 23 splenic hemangiosarcomas and 7 splenic hemangiomas in dogs. Blood tests performed previous to splenectomy were analysed for correlation with tumour VEGF expression. Results showed significantly higher VEGF expression in hemangiosarcomas than hemangiomas and lower hematocrit values and red cell count in dogs affected with malignant neoplasia (P < 0.05). These findings suggest the presence of high VEGF levels may be related to the malignant vascular proliferation seen in hemangiosarcomas.", "author" : [ { "dropping-particle" : "", "family" : "Gianotti Campos", "given" : "Andressa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alvares Duarte Bonini Campos", "given" : "Juliana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Soares Sanches", "given" : "Daniel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "L\u00facia Zaidan Dagli", "given" : "Maria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maria Matera", "given" : "Julia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Open Journal of Veterinary Medicine", "id" : "ITEM-2", "issue" : "04", "issued" : { "date-parts" : [ [ "2012", "12", "13" ] ] }, "language" : "en", "page" : "191-195", "publisher" : "Scientific Research Publishing", "title" : "Immunohistochemical Evaluation of Vascular Endothelial Growth Factor (VEGF) in Splenic Hemangiomas and Hemangiosarcomas in Dogs", "type" : "article-journal", "volume" : "02" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(30,31)", "plainTextFormattedCitation" : "(30,31)", "previouslyFormattedCitation" : "(30,31)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(30,31). Immunohistochemical staining for VEGFR, PDGFR-α and PDGFR-βAntibody optimization was performed using a commercially available antibody diluent (Envision FLEX antibody diluent, DAKO). A dilution of 1:100 was suitable for VEGFR and PDGFR-β and a dilution of 1:50 was chosen for PDGFR-α. The optimal dilution factor was chosen based on expression intensity and pattern by a board-certified pathologist (Tim Scase). For each antibody optimization two tissue blocks (canine ASAC for PDGFR; canine granulomatous tissue for VEGFR) were used. Per paraffin-embedded tissue block 3 μm sections were taken (Leica RM2235) and mounted on positively charged glass lysine slides (Superfrost Plus, Menzel). Two glass lysine slides were created per tissue block as an additional control during immunostaining. Sections were de-waxed and a heat mediated antigen retrieval was performed in a high (Tris/EDTA buffer, pH 9) pH solution (Envision FLEX Target Retrieval Solutions, DAKO) in a water bath (PT Link, DAKO) at 97°C for 30 minutes. Immunohistochemistry was performed using an automated immunohistochemical staining machine (DAKO Cytomation Autostainer Plus). Endogenous peroxidase activity was blocked by incubation in hydrogen peroxide solution for 30 minutes (EnVision FLEX Peroxidase-Blocking Reagent). The tissue sections were incubated with the diluted (Envision FLEX antibody diluent, DAKO) primary antibodies for 30 minutes at room temperature. Immunohistochemical staining was detected using a monoclonal mouse anti-human VEGFR (sc-393163 FLK-1 (D-8), Insight Biotechnology Ltd.) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0092-8674", "PMID" : "7681362", "abstract" : "Examination of flk-1 receptor tyrosine kinase mRNA expression by in situ hybridization analysis revealed specific association with endothelial cells at all stages of mouse development, including the blood islands in the yolk sac of day 8.5-10.5 embryos, in which the early progenitors of this lineage originate. flk-1 transcripts were abundant in proliferating endothelial cells of vascular sprouts and branching vessels of embryonic and early postnatal brain, but were drastically reduced in adult brain, where proliferation has ceased. Identification of the angiogenic mitogen, vascular endothelial growth factor (VEGF), as the high affinity ligand of Flk-1 and correlation of the temporal and spatial expression pattern of Flk-1 and VEGF suggest a major role of this ligand-receptor signaling system in vasculogenesis and angiogenesis.", "author" : [ { "dropping-particle" : "", "family" : "Millauer", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wizigmann-Voos", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schn\u00fcrch", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martinez", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "M\u00f8ller", "given" : "N P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Risau", "given" : "W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ullrich", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1993", "3", "26" ] ] }, "page" : "835-46", "title" : "High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis.", "type" : "article-journal", "volume" : "72" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(32)", "plainTextFormattedCitation" : "(32)", "previouslyFormattedCitation" : "(32)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(32), a polyclonal rabbit anti-human PDGFR-α (sc-431 PDGFR-alpha (951), Insight Biotechnology Ltd.) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0892-6638", "PMID" : "9737716", "abstract" : "Hypertension increases mechanical force on the arterial wall by as much as 30%, resulting in marked alterations in signal transductions and gene expression in vascular smooth muscle cells (VSMCs) that contribute to matrix protein synthesis, cell proliferation, and differentiation. How the mechanical stimuli are converted into a biological signal in cells has yet to be studied. We investigated the role of both cyclic strain and shear stresses in initiating the cellular signaling on cultured VSMCs and found that mechanical forces evoked activation of mitogen-activated protein kinases, followed by enhanced DNA binding activity of transcription factor AP-1. Physical forces rapidly induced phosphorylation of platelet-derived growth factor receptor (PDGFR) alpha, an activated state. When GRB2, an adapter protein, was immunoprecipitated from treated VSMCs followed by Western blot analysis with anti-phosphotyrosine, -PDGFR alpha, and -GRB2 antibodies, respectively, phosphotyrosine positive staining was observed on PDGFR alpha bands of the same blot in stretch-stressed VSMCs, supporting the mechanical stress-induced activation of PDGFR alpha. Conditioned medium from stretch-stressed VSMCs did not result in PDGFR alpha phosphorylation, and antibodies binding to all forms of PDGFs did not block stress-induced PDGFR alpha activation. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signaling pathways normally used by growth factors.", "author" : [ { "dropping-particle" : "", "family" : "Hu", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "B\u00f6ck", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wick", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Q", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "FASEB journal : official publication of the Federation of American Societies for Experimental Biology", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "1998", "9" ] ] }, "page" : "1135-42", "title" : "Activation of PDGF receptor alpha in vascular smooth muscle cells by mechanical stress.", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(33)", "plainTextFormattedCitation" : "(33)", "previouslyFormattedCitation" : "(33)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(33) and a polyclonal rabbit anti-human PDGFR-β antibody (sc-432 PDGFR-beta (958), Insight Biotechnology Ltd.) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1074/jbc.M109.076638", "ISSN" : "1083-351X", "PMID" : "20164181", "abstract" : "The fusion of TEL with platelet-derived growth factor receptor (PDGFR) beta (TPbeta) is found in a subset of patients with atypical myeloid neoplasms associated with eosinophilia and is the archetype of a larger group of hybrid receptors that are produced by rearrangements of PDGFR genes. TPbeta is activated by oligomerization mediated by the pointed domain of TEL/ETV6, leading to constitutive activation of the PDGFRbeta kinase domain. The receptor transmembrane (TM) domain is retained in TPbeta and in most of the described PDGFRbeta hybrids. Deletion of the TM domain (DeltaTM-TPbeta) strongly impaired the ability of TPbeta to sustain growth factor-independent cell proliferation. We confirmed that TPbeta resides in the cytosol, indicating that the PDGFRbeta TM domain does not act as a transmembrane domain in the context of the hybrid receptor but has a completely different function. The DeltaTM-TPbeta protein was expressed at a lower level because of increased degradation. It could form oligomers, was phosphorylated at a slightly higher level, co-immunoprecipitated with the p85 adaptor protein, but showed a much reduced capacity to activate STAT5 and ERK1/2 in Ba/F3 cells, compared with TPbeta. In an in vitro kinase assay, DeltaTM-TPbeta was more active than TPbeta and less sensitive to imatinib, a PDGFR inhibitor. In conclusion, we show that the TM domain is required for TPbeta-mediated signaling and proliferation, suggesting that the activation of the PDGFRbeta kinase domain is not enough for cell transformation.", "author" : [ { "dropping-particle" : "", "family" : "Toffalini", "given" : "Federica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hellberg", "given" : "Carina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Demoulin", "given" : "Jean-Baptiste", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of biological chemistry", "id" : "ITEM-1", "issue" : "16", "issued" : { "date-parts" : [ [ "2010", "4", "16" ] ] }, "page" : "12268-78", "title" : "Critical role of the platelet-derived growth factor receptor (PDGFR) beta transmembrane domain in the TEL-PDGFRbeta cytosolic oncoprotein.", "type" : "article-journal", "volume" : "285" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(34)", "plainTextFormattedCitation" : "(34)", "previouslyFormattedCitation" : "(34)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(34) which have been previously validated for use with formalin fixed canine tissue ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0950-9232", "PMID" : "2158038", "abstract" : "A new human gene encoding a receptor-type tyrosine kinase was isolated by a weak cross-hybridization with v-ros oncogene. A cDNA of about 7.7 kb carried a 4.2 kb open reading frame, and the predicted amino acid sequence of 1338 residues contained extracellular, transmembrane and tyrosine kinase domains. Although its extracellular domain is approximately 220 amino acids longer than those of the products of the fms family, i.e. c-fms, c-kit and platelet-derived growth factor receptor genes, the overall structure including cysteine motifs in its extracellular domain and a long peptide insertion in its tyrosine kinase domain indicates that this new gene is closely related to the fms family. Consequently, the gene was designated as flt (fms-like tyrosine kinase) gene. The expression of the flt gene was strongly suppressed in most of the tumor cell lines examined so far, whereas this mRNA was expressed in a variety of normal tissues of adult rat.", "author" : [ { "dropping-particle" : "", "family" : "Shibuya", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yamaguchi", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yamane", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ikeda", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tojo", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matsushime", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sato", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Oncogene", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1990", "4" ] ] }, "page" : "519-24", "title" : "Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0892-6638", "PMID" : "9737716", "abstract" : "Hypertension increases mechanical force on the arterial wall by as much as 30%, resulting in marked alterations in signal transductions and gene expression in vascular smooth muscle cells (VSMCs) that contribute to matrix protein synthesis, cell proliferation, and differentiation. How the mechanical stimuli are converted into a biological signal in cells has yet to be studied. We investigated the role of both cyclic strain and shear stresses in initiating the cellular signaling on cultured VSMCs and found that mechanical forces evoked activation of mitogen-activated protein kinases, followed by enhanced DNA binding activity of transcription factor AP-1. Physical forces rapidly induced phosphorylation of platelet-derived growth factor receptor (PDGFR) alpha, an activated state. When GRB2, an adapter protein, was immunoprecipitated from treated VSMCs followed by Western blot analysis with anti-phosphotyrosine, -PDGFR alpha, and -GRB2 antibodies, respectively, phosphotyrosine positive staining was observed on PDGFR alpha bands of the same blot in stretch-stressed VSMCs, supporting the mechanical stress-induced activation of PDGFR alpha. Conditioned medium from stretch-stressed VSMCs did not result in PDGFR alpha phosphorylation, and antibodies binding to all forms of PDGFs did not block stress-induced PDGFR alpha activation. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signaling pathways normally used by growth factors.", "author" : [ { "dropping-particle" : "", "family" : "Hu", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "B\u00f6ck", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wick", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Q", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "FASEB journal : official publication of the Federation of American Societies for Experimental Biology", "id" : "ITEM-2", "issue" : "12", "issued" : { "date-parts" : [ [ "1998", "9" ] ] }, "page" : "1135-42", "title" : "Activation of PDGF receptor alpha in vascular smooth muscle cells by mechanical stress.", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1111/j.1478-3231.2010.02342.x", "ISSN" : "1478-3231", "PMID" : "20846345", "abstract" : "BACKGROUND: The debate concerning the potential remodelling and/or reversibility of cirrhotic lesions and biliary fibrosis is still open.\n\nAIMS/METHODS: In this work, we have used the precision-cut liver slice (PCLS) model, which maintains cell-cell and cell-matrix interactions to study, by immunohistochemistry, the behaviour of the different fibrogenic cells, i.e. hepatic stellate cells (HSC) and portal fibroblasts, in cultured (for 1 week) PCLS derived from normal and fibrotic human livers.\n\nRESULTS: In normal liver, before and after culture, \u03b1-smooth muscle (SM) actin was present only in the vessel walls. Platelet-derived growth factor (PDGF) receptor-\u03b2 was expressed before and after culture by portal fibroblasts, and appeared after culture in HSC. Before culture, CD 34 was not expressed in parenchyma, but appeared after culture in sinusoidal endothelial cells. In cirrhotic lesions, before culture, \u03b1-SM actin, PDGF receptor-\u03b2 and Thy-1 were expressed in septa; after culture, \u03b1-SM actin expression disappeared but the expression of the PDGF receptor-\u03b2 and Thy-1 was maintained. In cholestatic liver specimens, \u03b1-SM actin, PDGF receptor-\u03b2 and Thy-1 expression, which was present before culture in enlarged portal areas, disappeared after culture, and apoptosis was detected. In the parenchyma of both cirrhotic and cholestatic livers, the expression of the PDGF receptor-\u03b2 and of CD 34, which was not observed before culture, was present in HSC and sinusoidal endothelial cells, respectively, after culture.\n\nCONCLUSIONS: These results indicate that during remodelling of pathological tissues in cultured liver slices, the myofibroblastic cells derived from HSC or from portal fibroblasts show different behaviours, suggesting different mechanisms of activation/deactivation.", "author" : [ { "dropping-particle" : "", "family" : "Guyot", "given" : "Christelle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lepreux", "given" : "S\u00e9bastien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Combe", "given" : "Chantal", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sarrazy", "given" : "Vincent", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Billet", "given" : "Fabrice", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Balabaud", "given" : "Charles", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bioulac-Sage", "given" : "Paulette", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Desmouli\u00e8re", "given" : "Alexis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Liver international : official journal of the International Association for the Study of the Liver", "id" : "ITEM-3", "issue" : "10", "issued" : { "date-parts" : [ [ "2010", "11" ] ] }, "page" : "1529-40", "title" : "Fibrogenic cell phenotype modifications during remodelling of normal and pathological human liver in cultured slices.", "type" : "article-journal", "volume" : "30" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(33,35,36)", "plainTextFormattedCitation" : "(33,35,36)", "previouslyFormattedCitation" : "(33,35,36)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(33,35,36). Staining was developed with 3,3’-diaminobenzidine tetrahydrochloride (EnVision FLEX DAB+ Chromogen, DAKO) and counterstained with haematoxylin. Replacing the primary antibody with antibody dilution buffer acted as a negative controls. Immunohistochemical evaluation protocolImmunohistochemical evaluation was done via evaluation of staining intensity and percentage of rTK positive tumour cells. Staining intensity was graded as no immunostaining, weak immunostaining, moderate and intense immunostaining. Positivity of tumour cells was assessed in five separate fields at x40 magnification and the average of the five fields was given as percentage. Percentage positivity was graded as follows: 0%, 1–25%, 26-75% and 76-100%. Necrotic areas were avoided because inflammatory cells and stromal macrophages may express certain rTKs. Tumours were considered positive for rTK if at least a weak immunostaining was present in at least 1-25% of tumour cells. Immunohistochemical localization was defined as cytoplasmic, membranous, cytoplasmic-membranous, nuclear or stromal depending on the predominant (>50%) staining pattern (Table 1).This study obtained ethics approval by the Veterinary Research Ethics Committee (University of Liverpool, School of Veterinary Science, Neston, UK) with the reference number VREC319. ResultsSample demographicsTissue samples were available for immunohistochemistry from 187 dogs. In 69 cases a definitive diagnosis was achieved via evaluation of histopathological features alone; in 111 cases a carcinoma was diagnosed based on histopathological features alone but a further subclassification was not possible and in seven cases immunohistochemistry was performed to achieve a definitive diagnosis. In four cases the sex was not specified at submission. Of the remaining 183, 100 dogs were male (male entire, n=36; male neutered, n=64) and 83 were female (female entire=24; female spayed=59). The female to male ratio was 1:1.2. Forty-three different breeds were presented of which Golden and Labrador Retriever (n=38), cross breeds (n=34) and Border Collies (n=18) were the most common. The median age was 9.9 years (range 2-16 years). Information on clinical signs, duration of clinical signs, tumour involvement of other structures and regional or distant metastasis was variably recorded on the submission forms; it was therefore decided not to include this information in this study. Histopathological findings and immunohistochemistryOf the 187 carcinomas diagnosed 36 (19.3%) were transitional cell carcinomas (TCC), 23 (12.3%) were squamous cell carcinomas (SCCs), eight (4.3%) were poorly differentiated carcinomas (PCA) and nine (4.8%) were other carcinomas (OCAs); (adenocarcinomas (ACA), n=3; neuroendocrine carcinomas (NCA), n=3; tubulopapillary carcinomas (TCA), n=3) (Figure 1)). Fifty nine point three percent (n=111) of the OCAs could not be definitively classified using histopathological features alone. In seven (3.7%) of these, immunohistochemistry was performed to achieve a definitive diagnosis (OCAs, n=2; SCCs, n=1; NCAs, n=1; PCAs, n=3). In the remaining 104 cases, the final diagnosis was simply recorded as carcinoma. In 154 cases (82.3%) concurrent lymphocytic, plasmacytic and occasionally neutrophilic rhinitis was evident.VEGFR was expressed in 158 (84.5%) of cases including one NCA, two ACAs, three TCAs, seven PCAs, 19 SCCs, 30 TCCs and 96 OCAs (Table 2). A weak expression pattern was identified in 22 cases (11.8%), a moderate expression in 69 (36.9%) and an intense expression in 67 (35.8%) cases (Figure 2). In nine cases between 1-25% of tumour cells expressed VEGFR, whereas in 28 dogs 26-75% of tumour cells and in 121 dogs >76% of tumour cells expressed VEGFR (Table 2). The cytoplasmic-membranous expression pattern was predominant in 111 cases (70.9%) followed by cytoplasmic expression in 41 dogs (21.9%); membranous expression in five cases and nuclear expression in one case (Figure 2). PDGFR-α was detected in 133 (71.1%) of cases (Table 2). Amongst these, two NCAs and TCAs, six PCAs, 17 SCCs, 23 TCCs and 83 OCAs were identified; no PDGFR-α expression was evident in ACAs. A weak expression pattern was present in 77 cases (57.9%), a moderate expression in 55 of cases (41.3%) and an intense one in one (0.5%) patient. In ten cases between 1-25% of tumour cells expressed PDGFR-α, in 17 dogs 26-75% of tumour cells and in 106 dogs >76% of tumour cells expressed PDGFR-α (Table 2). ACAs did not express PDGFR-α. The predominant expression pattern was cytoplasmic in 117 cases (87.9%) followed by a cytoplasmic-membranous expression in 15 dogs (8.0%) and a membranous expression in one (0.5%) case (Figure 2). PDGFR-β was identified in 74 (39.6%) patients including one NCA, three TCAs and PCAs, 12 SCCs, 13 TCCs and 42 OCAs; none of the ACAs expressed PDGFR-β (Table 2). PDGFR-β showed a weak expression in 28 cases (15.0%), a moderate expression in 33 (17.6%) and an intense expression in 13 dogs (7.0%). In ten cases between 1-25% of tumour cells expressed PDGFR-β, whereas in 27 dogs 26-75% of tumour cells and in 37 dogs >76% of tumour cells expressed PDGFR-β (Table 2). ACAs did not express PDGFR-β either. The cytoplasmic expression pattern was most predominant in 47 patients (63.5%) followed by a cytoplasmic-membranous pattern in 26 (13.9%) and a membranous pattern in one (0.5%) case (Figure 1). Co-expression of rTKs was common with 70 dogs (37.2%) expressing two and 63 (33.5%) expressing all three rTKs; in 36 (19.1%) cases only one rTK was expressed. One hundred twenty five cases (94.0%) with PDGFR-α expression showed co-expression of VEGFR and 69 cases (93.2%) with PDGFR-β expression exhibited simultaneous expression of VEGFR. Stromal expression of VEGFR was seen in 16 (8.5%), PDGFR-α in 29 (15.5%) and PDGFR-β in 114 (60.9%) cases (Figure 2). DiscussionIt is well recognized that rTKs are important factors in the development of malignant neoplasms in veterinary medicine. This is currently best characterized in canine MCTs ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1053/j.tcam.2009.02.002", "ISSN" : "19389736", "PMID" : "19732728", "abstract" : "Substantial progress in the field of molecular biology has permitted the identification of key abnormalities in cancer cells involving cell proteins that regulate signal transduction, cell survival, and cell proliferation. Such abnormalities often involve a class of proteins called tyrosine kinases that act to phosphorylate other proteins in the cell, tightly regulating a variety of cellular processes. A variety of small molecule inhibitors that target specific tyrosine kinases (known as tyrosine kinase inhibitors [TKIs]) have now been approved for the treatment of human cancer, and it is likely many more will become available in the near future. In some instances these inhibitors have exhibited significant clinical efficacy, and it is likely their biologic activity will be further enhanced as combination regimens with standard treatment modalities are explored. Although TKIs have been used extensively in humans, their application to cancers in dogs and cats is relatively recent. The TKIs Palladia (toceranib), Kinavet (masitinib), and Gleevec (imatinib) have been successfully used in dogs, and more recently Gleevec in cats. This article will review the biology of tyrosine kinase dysfunction in human and animal cancers, and the application of specific TKIs to veterinary cancer patients.", "author" : [ { "dropping-particle" : "", "family" : "London", "given" : "Cheryl A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Topics in Companion Animal Medicine", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2009", "8" ] ] }, "page" : "106-112", "title" : "Tyrosine Kinase Inhibitors in Veterinary Medicine", "type" : "article-journal", "volume" : "24" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(37)", "plainTextFormattedCitation" : "(37)", "previouslyFormattedCitation" : "(37)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(37). After approval of TKIs for the treatment of canine MCTs, further studies have been conducted to evaluate their use in other solid tumours, e. g. canine ASACs ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1476-5829.2011.00275.x", "ISSN" : "1476-5829", "PMID" : "22236194", "abstract" : "The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia\u00ae, Pfizer Animal Health, Madison, NJ, USA) in select solid tumours in dogs. Cases in which toceranib was used to treat dogs with apocrine gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma (OSA), thyroid carcinoma, head and neck carcinoma and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 AGASACA [8 partial response (PR), 20 stable disease (SD)], 11/23 OSAs (1 PR and 10 SD), 12/15 thyroid carcinomas (4 PR and 8 SD), 7/8 head and neck carcinomas [1 complete response (CR), 5 PR and 1 SD] and 5/7 (1 CR and 4 SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg kg(-1) , 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis and 47/63 (74.6%) were treated 4 months or longer. Although these data provide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumours, future prospective studies are necessary to define its true activity.", "author" : [ { "dropping-particle" : "", "family" : "London", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mathie", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stingle", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clifford", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haney", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klein", "given" : "M K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beaver", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vickery", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vail", "given" : "D M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hershey", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ettinger", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vaughan", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alvarez", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hillman", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kiselow", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thamm", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Higginbotham", "given" : "M L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gauthier", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krick", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phillips", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ladue", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jones", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bryan", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gill", "given" : "V", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Novasad", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fulton", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carreras", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McNeill", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Henry", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gillings", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary and comparative oncology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2012", "9" ] ] }, "page" : "194-205", "title" : "Preliminary evidence for biologic activity of toceranib phosphate (Palladia(\u00ae)) in solid tumours.", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1186/1746-6148-9-190", "ISSN" : "1746-6148", "PMID" : "24079884", "abstract" : "BACKGROUND: The receptor kinase inhibitor toceranib phosphate (Palladia) was approved for use in dogs in 2009 using a dose of 3.25 mg/kg administered every other day. Preliminary data suggests that lower doses of toeceranib may be associated with a reduced adverse event profile while maintaining sufficient drug exposure to provide biologic activity. The purpose of this study was to determine the Cmax of toceranib in dogs with solid tumors receiving 2.5-2.75 mg/kg every other day and to document the adverse events associated with this dose rate. Secondary objectives included determination of plasma VEGF concentrations in treated dogs and response to therapy.\n\nRESULTS: Dogs with solid tumors were administered toceranib at an intended target dose ranging from 2.5-2.75 mg/kg every other day and plasma samples were obtained for analysis of toceranib and VEGF plasma concentrations on days 0, 7, 14 and 30 of the study at 6 and 8 hours post drug administration. Additionally, plasma samples were obtained at 0, 1, 2, 6, 8, and 12 hours from dogs on day 30 for confirmation of Cmax. Response to therapy was assessed using standard RECIST criteria and adverse events were characterized using the VCOG-CTCAE. Toceranib administered at doses between 2.4-2.9 mg/kg every other day resulted in an average 6-8 hr plasma concentration ranging from 100-120 ng/ml, well above the 40 ng/ml concentration associated with target inhibition. Plasma VEGF concentrations increased significantly over the 30 day treatment period indicating that VEGFR2 inhibition was likely achieved in the majority of dogs. The lower doses of toceranib used in this study were associated with a substantially reduced adverse event profile compared to the established label dose of 3.25 mg/kg EOD.\n\nCONCLUSIONS: Doses of toceranib ranging from 2.4-2.9 mg/kg every other day provide drug exposure considered sufficient for target inhibition while resulting in an adverse event profile substantially reduced from that associated with the label dose of toceranib. This lower dose range of toceranib should be considered for future use in dogs with cancer.", "author" : [ { "dropping-particle" : "", "family" : "Bernabe", "given" : "Luis Feo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Portela", "given" : "Roberta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nguyen", "given" : "Sandra", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kisseberth", "given" : "William C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pennell", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yancey", "given" : "Mark F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "London", "given" : "Cheryl A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC veterinary research", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2013", "1" ] ] }, "page" : "190", "title" : "Evaluation of the adverse event profile and pharmacodynamics of toceranib phosphate administered to dogs with solid tumors at doses below the maximum tolerated dose.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(16,38)", "plainTextFormattedCitation" : "(16,38)", "previouslyFormattedCitation" : "(16,38)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(16,38). Despite reported use of TKIs in nasal tumours, to date, molecular markers, particularly VEGFR, PDGFR-α and PDGFR-β, have not been evaluated in a large cohort of canine nasal carcinomas..We have attempted to characterize these tumours using tissue immunohistochemistry to determine the level strength and pattern of VEGFR, PDGFR-α and PDGFR-β expression, as they represent targets for toceranib phosphate as well as masitinib ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0007258", "ISSN" : "1932-6203", "PMID" : "19789626", "abstract" : "BACKGROUND: The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT.\n\nMETHODOLOGY/PRINCIPAL FINDINGS: In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC(50)) of 200+/-40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC(50) of 150+/-80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant.\n\nCONCLUSIONS: Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicity.", "author" : [ { "dropping-particle" : "", "family" : "Dubreuil", "given" : "Patrice", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Letard", "given" : "S\u00e9bastien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ciufolini", "given" : "Marco", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gros", "given" : "Laurent", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Humbert", "given" : "Martine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cast\u00e9ran", "given" : "Nathalie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Borge", "given" : "Laurence", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hajem", "given" : "B\u00e9reng\u00e8re", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lermet", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sippl", "given" : "Wolfgang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Voisset", "given" : "Edwige", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Arock", "given" : "Michel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Auclair", "given" : "Christian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leventhal", "given" : "Phillip S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mansfield", "given" : "Colin D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moussy", "given" : "Alain", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hermine", "given" : "Olivier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2009", "1" ] ] }, "page" : "e7258", "title" : "Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT.", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1111/j.1740-8261.2012.01925.x", "ISSN" : "1058-8183", "PMID" : "22360684", "abstract" : "Palladia(TM) (toceranib phosphate-Pfizer Animal Health) is a novel orally administered receptor tyrosine kinase inhibitor (TKI) approved for treatment of canine mast cell tumors. Receptor tyrosine kinase dysregulation leads to tumor growth, progression, and metastasis. Toceranib's targets include vascular endothelial growth factor receptor (VEGFR-2/Flk-1/KDR), platelet-derived growth factor receptor, and kit. Positron Emission Tomography/Computed Tomography (PET/CT) is used commonly to diagnose, prognosticate, and monitor response to antineoplastic therapy in human patients. In this study, serial PET/CT imaging with (18) F-fluorodeoxyglucose ((18) FDG) was used to assess response to toceranib therapy in dogs with measurable solid malignancies. Six tumor-bearing dogs underwent tumor assessment using both standard RECIST criteria and PET/CT prior to and at a median of 5 weeks postinitiation of toceranib treatment. Toceranib was prescribed initially at a target dose 3.25 mg/kg PO q48 h, with subsequent modifications based on observed toxicity. Treatment was continued in patients achieving stable disease with acceptable drug tolerance. One dog was maintained on drug despite dose modification due to toxicity; measurable clinical and image-based responses were seen after 10 weeks of therapy. All others had stable or progressive disease based on clinical restaging and PET/CT at first recheck. . Due to discordance with anatomic and metabolic imaging, further studies are needed to investigate the role of molecular imaging in assessment of drug response and identify other potential molecular targets of toceranib.", "author" : [ { "dropping-particle" : "", "family" : "Leblanc", "given" : "Amy K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Miller", "given" : "Ashley N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Galyon", "given" : "Gina D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moyers", "given" : "Tamberlyn D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Long", "given" : "Misty J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stuckey", "given" : "Alan C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wall", "given" : "Jonathan S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morandi", "given" : "Federica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary radiology & ultrasound : the official journal of the American College of Veterinary Radiology and the International Veterinary Radiology Association", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "0", "1" ] ] }, "page" : "348-57", "title" : "Preliminary evaluation of serial (18) FDG-PET/CT to assess response to toceranib phosphate therapy in canine cancer.", "type" : "article-journal", "volume" : "53" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(25,26)", "plainTextFormattedCitation" : "(25,26)", "previouslyFormattedCitation" : "(25,26)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(25,26). Seven different subtypes of canine intranasal carcinoma, OCA, ACA, PCA, SCC, TCC, NCA and TCA were evaluated. In this study, 84.5% of canine nasal carcinomas were positive for VEGFR staining, 71.1% for PDGFR-α and 39.6% for PDGFR-β.VEGFR expression was relatively intense with >76% of tumour cells expressing the rTK in the majority of dogs (in 121 of 187). This is also represented in the relatively high median expression score of 134.7. The predominant VEGFR expression pattern in this study was cytoplasmic-membranous (70.9%). This is an interesting finding as tyrosine kinases (TKs) move away from the membrane once they have been activated ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ceb.2007.02.010", "ISSN" : "0955-0674", "PMID" : "17306972", "abstract" : "Receptor tyrosine kinases (RTKs) are essential components of signal transduction pathways that mediate cell-to-cell communication. These single-pass transmembrane receptors, which bind polypeptide ligands - mainly growth factors - play key roles in processes such as cellular growth, differentiation, metabolism and motility. Recent progress has been achieved towards an understanding of the precise (and varied) mechanisms by which RTKs are activated by ligand binding and by which signals are propagated from the activated receptors to downstream targets in the cell.", "author" : [ { "dropping-particle" : "", "family" : "Hubbard", "given" : "Stevan R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Miller", "given" : "W Todd", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current opinion in cell biology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2007", "4" ] ] }, "page" : "117-23", "title" : "Receptor tyrosine kinases: mechanisms of activation and signaling.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(39)", "plainTextFormattedCitation" : "(39)", "previouslyFormattedCitation" : "(39)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(39). A similar staining pattern has already been demonstrated for KIT in canine MCTs and was associated with their grade. Diffuse cytoplasmic staining was associated with higher grade MCTs whereas low grade tumours more commonly had membranous staining ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1155/2014/787498", "ISSN" : "2090-8113", "PMID" : "24701365", "abstract" : "Canine cutaneous mast cell tumors (MCT) are the lethal skin tumors. The biological behavior of the MCT cells is quite varied and unpredictable. Almost MCT dogs usually require a rapid diagnosis and therapy. However, MCT diagnosis and prognosis are still dependent on histopathology which is rather inconvenient, time-consuming, painful, and harmful for some cases. Indeed, MCT can be easily accessible using fine-needle aspiration (FNA). In this study, our biopsy specimens were classified as low- and high-grade MCT based on the novel 2-tier histopathologic grading system. We have demonstrated the usage of fine-needle aspirated MCT cells (FNA-MCT cells) from these specimens as a primary cell source to study the distribution of CD117-immunocytochemistry (CD117-ICC) staining patterns and the frequency of internal tandem duplication- (ITD-) mutant exon-11 of c-kit. The result has substantially shown that there were three staining patterns identified in the cells. Only paranuclear pattern was significantly increased in the cells from high-grade MCT. Altogether, the ITD-mutant exon-11 was also detectable only in these cells. Therefore, the result has supported our hypothesis that there was an increased opportunity to observe a higher CD117-ICC staining pattern and exon-11 mutation in high-grade MCT; even these two parameters may not precisely indicate a histopathological grade.", "author" : [ { "dropping-particle" : "", "family" : "Sailasuta", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ketpun", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Piyaviriyakul", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Theerawatanasirikul", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Theewasutrakul", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rungsipipat", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary medicine international", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "1" ] ] }, "page" : "787498", "title" : "The Relevance of CD117-Immunocytochemistry Staining Patterns to Mutational Exon-11 in c-kit Detected by PCR from Fine-Needle Aspirated Canine Mast Cell Tumor Cells.", "type" : "article-journal", "volume" : "2014" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(40)", "plainTextFormattedCitation" : "(40)", "previouslyFormattedCitation" : "(40)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(40). The expression pattern of VEGFR may therefore suggest activation of this TK and thus might be a relevant consideration in predicting a nasal carcinoma’s biological behaviour. In previous reports of canine oral melanoma and canine mammary tumours, a predominant cytoplasmic pattern was similarly demonstrated ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1476-5829.2007.00130.x", "ISSN" : "1476-5829", "PMID" : "19754779", "abstract" : "Serum, plasma and tissue expression of vascular endothelial growth factor (VEGF) was measured in 20 dogs previously diagnosed histologically with oral melanoma. The concentrations of VEGF in serum and plasma were significantly higher in dogs with melanoma than in a control population (P <or= 0.002). Concentrations of VEGF in the serum and plasma of dogs with melanoma were highly correlated (r = 0.867). Ninety-five per cent of melanoma tissues expressed VEGF. Two staining patterns were detected: diffuse and granular cytoplasmic staining. High blood concentrations of VEGF were correlated to a shorter survival time in dogs receiving definitive therapy (P = 0.002). Survival times were significantly longer in dogs receiving definitive therapy versus palliative therapy (median 496 versus 97 days, P = 0.007). Blood concentrations of VEGF were associated with stage (P < 0.05). Dogs with oral melanoma have increased serum, plasma and tissue concentrations of VEGF. Increased expression of VEGF may be a reasonable target for future therapy of canine oral melanoma.", "author" : [ { "dropping-particle" : "", "family" : "Taylor", "given" : "K H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "A N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Higginbotham", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schwartz", "given" : "D D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carpenter", "given" : "D M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whitley", "given" : "E M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary and comparative oncology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2007", "12" ] ] }, "page" : "208-18", "title" : "Expression of vascular endothelial growth factor in canine oral malignant melanoma.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.jcpa.2010.04.006", "ISSN" : "1532-3129", "PMID" : "20570280", "abstract" : "The histopathological and clinical aspects of canine mammary tumours (CMTs) have been widely studied, but the variation in the biological behaviour of these neoplasms hampers the identification of prognostic factors. Sustained angiogenesis has been suggested to be one of the most important factors underlying tumour growth and invasion. This process involves the action of several growth factors including vascular endothelial growth factor (VEGF). The present study characterizes the relationship between immunohistochemical expression of VEGF and gross (e.g. size and tissue fixation) and microscopical (e.g. type, growth, necrosis, lymphoid infiltration, lymph node metastasis, histological grade and proliferation index) features of CMTs. Forty-eight benign and 64 malignant CMTs were evaluated. Statistical analysis failed to show a significant relationship between VEGF expression and the pathological features, suggesting that VEGF expression occurs in both benign and malignant tumours and is independent of histological type, proliferation, tissue invasion or local metastatic capacity.", "author" : [ { "dropping-particle" : "", "family" : "Santos", "given" : "A A F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oliveira", "given" : "J T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lopes", "given" : "C C C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Amorim", "given" : "I F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vicente", "given" : "C M F B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "G\u00e4rtner", "given" : "F R M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matos", "given" : "A J F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of comparative pathology", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2010", "11" ] ] }, "page" : "268-75", "title" : "Immunohistochemical expression of vascular endothelial growth factor in canine mammary tumours.", "type" : "article-journal", "volume" : "143" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(41,42)", "plainTextFormattedCitation" : "(41,42)", "previouslyFormattedCitation" : "(41,42)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(41,42). Another study demonstrated a nuclear staining pattern (two cases), which was observed in only one case in this study ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1476-5829.2009.00178.x", "ISSN" : "1476-5829", "PMID" : "19453364", "abstract" : "Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) signalling pathways play a role in carcinogenesis. Inhibition of EGF receptor (EGFR) and of VEGF is effective in increasing the radiation responsiveness of neoplastic cells both in vitro and in human trials. In this study, immunohistochemical evaluation was employed to determine and characterize the potential protein expression levels and patterns of EGFR and VEGF in a variety of canine malignant epithelial nasal tumours. Of 24 malignant canine nasal tumours, 13 (54.2%) were positive for EGFR staining and 22 (91.7%) were positive for VEGF staining. The intensity and percentage of immunohistochemically positive neoplastic cells for EGFR varied. These findings indicate that EGFR and VEGF proteins were present in some malignant epithelial nasal tumours in the dogs, and therefore, it may be beneficial to treat canine patients with tumours that overexpress EGFR and VEGF with specific inhibitors in conjunction with radiation.", "author" : [ { "dropping-particle" : "", "family" : "Shiomitsu", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "C L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malarkey", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pruitt", "given" : "A F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thrall", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary and comparative oncology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2009", "6" ] ] }, "page" : "106-14", "title" : "Expression of epidermal growth factor receptor and vascular endothelial growth factor in malignant canine epithelial nasal tumours.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(21)", "plainTextFormattedCitation" : "(21)", "previouslyFormattedCitation" : "(21)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(21). Nuclear staining may represent aberrant mislocalization of VEGFR but its relationship to tumour behaviour is unclear. Given the strong expression of VEGFR in canine nasal carcinomas, this rTK may play some role in the development or progression of this cancer and may therefore give possible indication for the use of TKIs. Considering that RT currently plays an important role in the treatment of canine intranasal carcinomas, the concurrent use of TKIs could be considered to enhance the effect of irradiation, leading to improved outcomes. As abnormal tumour vessel morphology contributes to intratumoral hypoxia stimulating angiogenesis via VEGFR, TKIs may normalize tumour blood vessels leading to improved tissue oxygenation and thereby increased sensitivity to radiotherapy ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1152/physrev.00038.2010", "ISSN" : "1522-1210", "PMID" : "21742796", "abstract" : "New vessel formation (angiogenesis) is an essential physiological process for embryologic development, normal growth, and tissue repair. Angiogenesis is tightly regulated at the molecular level. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks of cancer. The imbalance of pro- and anti-angiogenic signaling within tumors creates an abnormal vascular network that is characterized by dilated, tortuous, and hyperpermeable vessels. The physiological consequences of these vascular abnormalities include temporal and spatial heterogeneity in tumor blood flow and oxygenation and increased tumor interstitial fluid pressure. These abnormalities and the resultant microenvironment fuel tumor progression, and also lead to a reduction in the efficacy of chemotherapy, radiotherapy, and immunotherapy. With the discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis, efforts have focused on novel therapeutics aimed at inhibiting VEGF activity, with the goal of regressing tumors by starvation. Unfortunately, clinical trials of anti-VEGF monotherapy in patients with solid tumors have been largely negative. Intriguingly, the combination of anti-VEGF therapy with conventional chemotherapy has improved survival in cancer patients compared with chemotherapy alone. These seemingly paradoxical results could be explained by a \"normalization\" of the tumor vasculature by anti-VEGF therapy. Preclinical studies have shown that anti-VEGF therapy changes tumor vasculature towards a more \"mature\" or \"normal\" phenotype. This \"vascular normalization\" is characterized by attenuation of hyperpermeability, increased vascular pericyte coverage, a more normal basement membrane, and a resultant reduction in tumor hypoxia and interstitial fluid pressure. These in turn can lead to an improvement in the metabolic profile of the tumor microenvironment, the delivery and efficacy of exogenously administered therapeutics, the efficacy of radiotherapy and of effector immune cells, and a reduction in number of metastatic cells shed by tumors into circulation in mice. These findings are consistent with data from clinical trials of anti-VEGF agents in patients with various solid tumors. More recently, genetic and pharmacological approaches have begun to unravel some other key regulators of vascular normalization such as proteins that regulate tissue oxygen sensing (PHD2) and vessel maturation (PDGFR\u03b2, RGS5, Ang1/2, TGF-\u03b2). Here, \u2026", "author" : [ { "dropping-particle" : "", "family" : "Goel", "given" : "Shom", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Duda", "given" : "Dan G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Lei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Munn", "given" : "Lance L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boucher", "given" : "Yves", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fukumura", "given" : "Dai", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jain", "given" : "Rakesh K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Physiological reviews", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "7" ] ] }, "page" : "1071-121", "title" : "Normalization of the vasculature for treatment of cancer and other diseases.", "type" : "article-journal", "volume" : "91" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1177/1947601911423654", "ISSN" : "1947-6027", "PMID" : "22866203", "abstract" : "The vascular network delivers oxygen (O(2)) and nutrients to all cells within the body. It is therefore not surprising that O(2) availability serves as a primary regulator of this complex organ. Most transcriptional responses to low O(2) are mediated by hypoxia-inducible factors (HIFs), highly conserved transcription factors that control the expression of numerous angiogenic, metabolic, and cell cycle genes. Accordingly, the HIF pathway is currently viewed as a master regulator of angiogenesis. HIF modulation could provide therapeutic benefit for a wide array of pathologies, including cancer, ischemic heart disease, peripheral artery disease, wound healing, and neovascular eye diseases. Hypoxia promotes vessel growth by upregulating multiple pro-angiogenic pathways that mediate key aspects of endothelial, stromal, and vascular support cell biology. Interestingly, recent studies show that hypoxia influences additional aspects of angiogenesis, including vessel patterning, maturation, and function. Through extensive research, the integral role of hypoxia and HIF signaling in human disease is becoming increasingly clear. Consequently, a thorough understanding of how hypoxia regulates angiogenesis through an ever-expanding number of pathways in multiple cell types will be essential for the identification of new therapeutic targets and modalities.", "author" : [ { "dropping-particle" : "", "family" : "Krock", "given" : "Bryan L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Skuli", "given" : "Nicolas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Simon", "given" : "M Celeste", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Genes & cancer", "id" : "ITEM-2", "issue" : "12", "issued" : { "date-parts" : [ [ "2011", "12" ] ] }, "page" : "1117-33", "title" : "Hypoxia-induced angiogenesis: good and evil.", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISSN" : "0890-9091", "PMID" : "15934498", "abstract" : "Angiogenesis is an essential step in the growth and spread of solid tumors--the cause of more than 85% of cancer mortality. Inhibiting angiogenesis would therefore seem to be a reasonable approach to prevent or treat cancer. However, tumor angiogenesis differs from normal angiogenesis in that the resulting vessels are tortuous, irregularly shaped, and hyperpermeable. These abnormalities result in irregular blood flow and high interstitial fluid pressure within the tumor, which can impair the delivery of oxygen (a known radiation sensitizer) and drugs to the tumor. Emerging evidence suggests that antiangiogenic therapy can prune some tumor vessels and normalize the structure and function of the rest, thereby improving drug delivery and normalizing the tumor microenvironment. This normalization effect may underlie the therapeutic benefit of combined antiangiogenic and cytotoxic therapies. This paper reviews current and emerging concepts of the mechanism of action of antiangiogenic therapies and discusses the implications of these mechanisms for their optimal clinical use.", "author" : [ { "dropping-particle" : "", "family" : "Jain", "given" : "Rakesh K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Oncology (Williston Park, N.Y.)", "id" : "ITEM-3", "issue" : "4 Suppl 3", "issued" : { "date-parts" : [ [ "2005", "4" ] ] }, "page" : "7-16", "title" : "Antiangiogenic therapy for cancer: current and emerging concepts.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1016/r.2004.10.011", "ISSN" : "1535-6108", "PMID" : "15607960", "abstract" : "The recent landmark Phase III clinical trial with a VEGF-specific antibody suggests that antiangiogenic therapy must be combined with cytotoxic therapy for the treatment of solid tumors. However, there are no guidelines for optimal scheduling of these therapies. Here we show that VEGFR2 blockade creates a \"normalization window\"--a period during which combined radiation therapy gives the best outcome. This window is characterized by an increase in tumor oxygenation, which is known to enhance radiation response. During the normalization window, but not before or after it, VEGFR2 blockade increases pericyte coverage of brain tumor vessels via upregulation of Ang1 and degrades their pathologically thick basement membrane via MMP activation.", "author" : [ { "dropping-particle" : "", "family" : "Winkler", "given" : "Frank", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Kozin", "given" : "Sergey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tong", "given" : "Ricky T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chae", "given" : "Sung-Suk", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Booth", "given" : "Michael F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garkavtsev", "given" : "Igor", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Lei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hicklin", "given" : "Daniel J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fukumura", "given" : "Dai", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tomaso", "given" : "Emmanuelle", "non-dropping-particle" : "di", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Munn", "given" : "Lance L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jain", "given" : "Rakesh K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer cell", "id" : "ITEM-4", "issue" : "6", "issued" : { "date-parts" : [ [ "2004", "12" ] ] }, "page" : "553-63", "title" : "Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases.", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(43\u201346)", "plainTextFormattedCitation" : "(43\u201346)", "previouslyFormattedCitation" : "(43\u201346)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(43–46). Although there is currently no data on radiosensitization in canine intranasal carcinomas, inhibition of VEGFR in combination with RT has shown promise in treatment improvement in human clinical trials ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0008-5472", "PMID" : "11289107", "abstract" : "Certain refractory neoplasms, such as glioblastoma multiforme (GBM) and melanoma, demonstrate a resistant tumor phenotype in vivo. We observed that these refractory tumor models (GBM and melanoma) contain blood vessels that are relatively resistant to radiotherapy. To determine whether the vascular endothelial growth factor receptor-2 (Flk-1/KDR) may be a therapeutic target to improve the effects of radiotherapy, we used the soluble extracellular component of Flk-1 (ExFlk), which blocks vascular endothelial growth factor binding to Flk-1 receptor expressed on the tumor endothelium. Both sFlk-1 and the Flk-1-specifc inhibitor SU5416 eliminated the resistance phenotype in GBM and melanoma microvasculature as determined by both the vascular window and Doppler blood flow methods. Human microendothelial cells and human umbilical vein endothelial cells showed minimal radiation-induced apoptosis. The Flk-1 antagonists sFlk-1 and SU5416 reverted these cell models to apoptosis-prone phenotype. Flk-1 antagonists also reverted GBM and melanoma tumor models to radiation-sensitive phenotype after treatment with 3 Gy. These findings demonstrate that the tumor microenvironment including the survival of tumor-associated endothelial cells contributes to tumor blood vessel resistance to therapy.", "author" : [ { "dropping-particle" : "", "family" : "Geng", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Donnelly", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McMahon", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lin", "given" : "P C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sierra-Rivera", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oshinka", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hallahan", "given" : "D E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer research", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2001", "3", "15" ] ] }, "page" : "2413-9", "title" : "Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy.", "type" : "article-journal", "volume" : "61" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1158/1535-7163.MCT-06-0508", "ISSN" : "1535-7163", "PMID" : "17308057", "abstract" : "AZD2171 is a highly potent, orally active inhibitor of vascular endothelial growth factor receptor signaling. The potential for AZD2171 to enhance the antitumor effects of radiotherapy was investigated in lung (Calu-6) and colon (LoVo) human tumor xenograft models. Combined treatment resulted in a significantly enhanced growth delay compared with either modality alone. The enhancement was independent of whether chronic once daily AZD2171 treatment was given 2 h prior to each radiation fraction (2 Gy daily for 3 or 5 consecutive days), and daily thereafter, or commenced immediately following the course of radiotherapy. Histologic assessments revealed that 5 days of radiation (2 Gy) or AZD2171 (3 or 6 mg/kg/d) reduced vessel density and perfusion. Concomitant AZD2171 and radiation enhanced this effect and produced a significant increase in tumor hypoxia. Concomitant AZD2171 (6 mg/kg/d) was also found to reduce tumor growth significantly during the course of radiotherapy (5 x 2 Gy). However, the extent and duration of tumor regression observed postradiotherapy was similar to sequentially treated tumors, suggesting that preirradiated tumors were sensitized to AZD2171 treatment. An enhanced antivascular effect of administering AZD2171 postradiotherapy was observed in real-time in Calu-6 tumors grown in dorsal window chambers. Collectively, these data support the clinical development of AZD2171 in combination with radiotherapy.", "author" : [ { "dropping-particle" : "", "family" : "Williams", "given" : "Kaye J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Telfer", "given" : "Brian A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shannon", "given" : "Aoife M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Babur", "given" : "Muhammad", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stratford", "given" : "Ian J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wedge", "given" : "Stephen R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular cancer therapeutics", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2007", "2", "1" ] ] }, "page" : "599-606", "title" : "Combining radiotherapy with AZD2171, a potent inhibitor of vascular endothelial growth factor signaling: pathophysiologic effects and therapeutic benefit.", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(47,48)", "plainTextFormattedCitation" : "(47,48)", "previouslyFormattedCitation" : "(47,48)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(47,48). PDGFR-α expression was relatively weak to moderate with >76% of tumour cells expressing the rTK in the majority of dogs (n=106). This is also reflected in the relatively lower median expression score of 97.8 compared to VEGFR expression. PDGFR-β expression was also relatively weak to moderate compared to PDGFR-α with 26-75% (n=27) and >76% of tumour cells (n=37) expressing the rTK. This is again reflected in the relatively lower median expression score of 54.6 compared to VEGFR expression. The predominant PDGFR expression pattern in the current study was cytoplasmic (PDGFR-α, 87.9%; PDGFR-β, 63.5%) as already reported in previous studies with canine vascular tumours ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/vco.12035", "ISSN" : "1476-5829", "PMID" : "23611531", "abstract" : "We examined whether mutation of the platelet-derived growth factor receptor protein tyrosine kinase (PDGFR)-\u03b1 and PDGFR-\u03b2 genes contributes to their overexpression in canine vascular tumours. Genomic sequences of trans- or juxtamembrane regions of PDGFR-\u03b1 and PDGFR-\u03b2 were analysed with immunohistochemical staining and polymerase chain reaction-direct sequencing using DNA from paraffin-embedded neoplastic tissues of 27 hemangiosarcomas (HSAs) and 20 hemangiomas (HAs). Immunohistochemically, 75% of the HA cases were positive for PDGFR-\u03b1 and almost most of the HA cases were negative for PDGFR-\u03b2. Of the HSA cases, 55.6% were negative for PDGFR-\u03b1 and 63% were strongly positive for PDGFR-\u03b2. Among the HA cases, 1 missense mutation was detected in PDGFR-\u03b1 exon 18 and 1 in PDGFR-\u03b2 exon 17. Two HSA cases had missense mutations in exon 14 and 1 in exon 17 of PDGFR-\u03b2. Thus, genomic mutation of trans- or juxtamembrane regions of PDGFRs was not the main mechanism driving the activation of receptors in HSA and HA.", "author" : [ { "dropping-particle" : "", "family" : "Abou Asa", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mori", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maruo", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Khater", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "El-Sawak", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Abd El-Aziz", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yanai", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sakai", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Veterinary and comparative oncology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013", "4", "24" ] ] }, "title" : "Analysis of genomic mutation and immunohistochemistry of platelet-derived growth factor receptors in canine vascular tumours.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(49)", "plainTextFormattedCitation" : "(49)", "previouslyFormattedCitation" : "(49)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(49). Interestingly, this study also demonstrated a strong stromal expression for both PDGFRs (PDGFR-α in 15.5%; PDGFR-β in 60.9%) as compared to VEGFR (8.5%). This has already been previously described in human breast cancer ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.2353/ajpath.2009.081030", "ISSN" : "1525-2191", "PMID" : "19498003", "abstract" : "This study systematically analyzes platelet-derived growth factor (PDGF) receptor expression in six types of common tumors as well as examines associations between PDGF beta-receptor status and clinicopathological characteristics in breast cancer. PDGF receptor expression was determined by immunohistochemistry on tumor tissue microarrays. Breast tumor data were combined with prognostic factors and related to outcome endpoints. PDGF alpha- and beta-receptors were independently expressed, at variable frequencies, in the tumor stroma of all tested tumor types. There was a significant association between PDGF beta-receptor expression on fibroblasts and perivascular cells in individual colon and prostate tumors. In breast cancer, high stromal PDGF beta-receptor expression was significantly associated with high histopathological grade, estrogen receptor negativity, and high HER2 expression. High stromal PDGF beta-receptor expression was correlated with significantly shorter recurrence-free and breast cancer-specific survival. The prognostic significance of stromal PDGF beta-receptor expression was particularly prominent in tumors from premenopausal women. Stromal PDGF alpha- and beta-receptor expression is a common, but variable and independent, property of solid tumors. In breast cancer, stromal PDGF beta-receptor expression significantly correlates with less favorable clinicopathological parameters and shorter survival. These findings highlight the prognostic significance of stromal markers and should be considered in ongoing clinical development of PDGF receptor inhibitors.", "author" : [ { "dropping-particle" : "", "family" : "Paulsson", "given" : "Janna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sj\u00f6blom", "given" : "Tobias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Micke", "given" : "Patrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pont\u00e9n", "given" : "Fredrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Landberg", "given" : "G\u00f6ran", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heldin", "given" : "Carl-Henrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bergh", "given" : "Jonas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brennan", "given" : "Donal J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jirstr\u00f6m", "given" : "Karin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ostman", "given" : "Arne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The American journal of pathology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2009", "7" ] ] }, "page" : "334-41", "title" : "Prognostic significance of stromal platelet-derived growth factor beta-receptor expression in human breast cancer.", "type" : "article-journal", "volume" : "175" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(50)", "plainTextFormattedCitation" : "(50)", "previouslyFormattedCitation" : "(50)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(50). While VEGFR exerts important cellular functions, such as driving angiogenesis in tumour development, through a predominant cytoplasmic expression in tumur cells (following TK activation), PDGFRs may play a more important control function in the tumour’s microenvironment – hence its strong stromal expression. The tumour microenvironment is involved with increased vessel function and can thereby also lead to increased tumor growth ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cytogfr.2004.03.002", "ISSN" : "1359-6101", "PMID" : "15207817", "abstract" : "PDGFs and their cognate tyrosine kinase alpha- and beta-receptors are involved in multiple tumor-associated processes including autocrine growth stimulation of tumor cells, stimulation of tumor angiogenesis and recruitment and regulation of tumor fibroblasts. The recent development of clinically useful PDGF antagonists, like STI571/Glivec, has increased the interest in PDGF receptors as cancer drug targets. Autocrine PDGF receptor signaling occurs in certain malignancies characterized by mutational activation of PDGF or PDGF receptors, for instance, dermatofibrosaracoma protuberans, gastrointestinal stromal tumors, and hypereosinophilic syndrome. The roles of PDGF in regulation of tumor angiogenesis and tumor fibroblasts are more general, and probably occur in most common solid tumors. Concerning tumor angiogenesis recent studies have predominantly focused on the importance of PDGF receptor signaling for tumor pericyte recruitment. PDGF receptors in the tumor stroma have also attracted attention as interesting drug targets because of their function as regulators of tumor interstitial fluid pressure, tumor transvascular transport and tumor drug uptake. In summary, the improved understanding of the role of PDGF signaling in tumor biology, and the introduction of PDGF antagonists, has set the stage for a continued development of PDGF antagonists as novel cancer drugs.", "author" : [ { "dropping-particle" : "", "family" : "Ostman", "given" : "Arne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cytokine & growth factor reviews", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2004", "8" ] ] }, "page" : "275-86", "title" : "PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma.", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(51)", "plainTextFormattedCitation" : "(51)", "previouslyFormattedCitation" : "(51)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(51). Inhibition of PDGFRs may therefore lead to alterations in the tumour microenvironment (stromal expression) as well as at tumour cells (cytoplasmic expression). Targeting stromal tissue has been documented in human solid tumours ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1200/JCO.2009.21.8487", "ISSN" : "1527-7755", "PMID" : "19738123", "abstract" : "PURPOSE: This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics, and maximum-tolerated dose (MTD) of an oral platelet-derived growth factor receptor inhibitor, CP-868,596.\n\nPATIENTS AND METHODS: Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups.\n\nRESULTS: Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased gamma-glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months).\n\nCONCLUSION: CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted.", "author" : [ { "dropping-particle" : "", "family" : "Lewis", "given" : "Nancy L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lewis", "given" : "Lionel D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eder", "given" : "Joseph P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reddy", "given" : "Nandi J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Guo", "given" : "Feng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pierce", "given" : "Kristen J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Olszanski", "given" : "Anthony J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cohen", "given" : "Roger B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "id" : "ITEM-1", "issue" : "31", "issued" : { "date-parts" : [ [ "2009", "11", "1" ] ] }, "page" : "5262-9", "title" : "Phase I study of the safety, tolerability, and pharmacokinetics of oral CP-868,596, a highly specific platelet-derived growth factor receptor tyrosine kinase inhibitor in patients with advanced cancers.", "type" : "article-journal", "volume" : "27" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(52)", "plainTextFormattedCitation" : "(52)", "previouslyFormattedCitation" : "(52)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(52). This study had some limitations including possible heterogeneity withinof individual tumours and microarray small sample size within the microarray. In addition, only one sample per tumour was assessed; as these samples were small and an individual sample may not have reflected heterogenous rTK expression. However, the large number of individual tumour samples should give sufficient power to limit this particular limitation across tumour populations. However, for individual patients, tumour heterogeneity could be very important as it could limit the effectiveness of a particular targetted therapy chosen on the basis of a small sample. If only a small subpopulation of tumour/stroma cells express the target, then a significant treatment response is less likely. We were also unalble to correlateion of expression with tumour subtype, because of the high percentage of carcinomas without further sub classification and the small numbers of specified subgroups.. In the current study, expression of the three evaluated rTKs was predominantly intense with >76% of tumour cells expressing VEGFR, PDGFR-α and PDGFR-β. Interestingly, none of the ACAs in this study expressed PDGFRs, but they exhibited a predominantly intense VEGFR expression with >76% of tumour cells expressing the rTK. In summary, we can state that the majority of canine intranasal carcinoma subtypes expressed at least one rTK intensely in >76% of tumour cells. We therefore conclude that further investigation of the clinical utility of TKI treatment for canine intranasal carcinomas with with TKIs is clearly warranted in the future and investigation of the clinical utility of these agents (e. g. toceranib phosphate, masitinib) in dogs with intranasal carcinomas should be pursued. Conflict of interest statementProf. Laura Blackwood, was a member of the ACEE panel funded by Pfizer (2009-2012).ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. MacEwen EG, Withrow SJ, Patnaik AK. 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Table 1: rTK scoring protocolStaining intensity Parameter on x20 magnificationPositive tumour cellsParameter on x40 magnificationStaining localizationParameter on x40 magnificationno staining0%cytoplasmweak1-25%membranousmoderate26-75%cytoplasm-membranousintense76-100%nuclearTable2: rTK expression in 187 canine nasal carcinomasExpression of rTKExpression (patient no.)CA(n=111)ACA(n=3)PCA(n=8)TCC(n=36)SCC(n=23)NCA(n=3)TCA(n=3)VEGFRExpression (total)9627301913Intensityimmunostainingweak14003401moderate3923131200intense430414312Positivity tumour cells1-25%400210226-75%1813330076-100%7414251511PDGFR-αExpression (total)8306231722Intensityimmunostainingweak5005111320moderate320112402intense1000000Positivity tumour cells1-25%700120026-75%1200311076-100%6406191412PDGFR-βExpression (total)4203131213Intensityimmunostainingweak 15006601moderate24024300intense3013312Positivity tumour cells1-25%701110026-75%1601351176-100%19019602Figure 1: Histopathological features nasal carcinomasFigure 2 with pictures a-c demonstrates the different histopathological features of canine nasal carcinomas. Picture a shows a transitional cell carcinoma which is in general a poorly differentiated neoplasm of the nasal surface epithelium. The tumour cells are closely packed and do not form intercellular bridges. Tumour cells are polyhedric and often arranged in solid sheets (here) or cords. Picture b demonstrates a squamous cell carcinoma of the non-keratinizing subtype with small pseudolumina containing eosinophilic material. Tumour cells form solid islets with intercellular bridges. Picture c shows a poorly differentiated carcinoma with small round to pleomorphic cells. Tumour cells do not resemble features of glandular or squamous differentiation. Abundant mitotic figures and areas of necrosis indicate a high degree of malignancy.Figure 2: Expression of VEGFR, PDGFR-α and PDGFR-βThe expression pattern of VEGFR, PDGFR-α and PDGFR-β in different subtypes of canine nasal carcinomas are depicted in pictures a-i. Picture a and b show an adenocarcinoma, picture c, d and f demonstrate a poorly differentiated carcinoma whereas pictures e and g-i show carcinomas.a-c VEGFR immunostaining: a-b - moderate to intense staining with cytoplasmic-membranous expression pattern, c - intense membranous and nuclear pattern;d-f PDGFR-α immunostaining: d - weak cytoplasmic expression pattern, e - moderate to intense cytoplasmic-membranous expression pattern, f - intense cytoplasmic-membranous expression pattern;g-i PDGFR-β immunostaining: g - no staining, h - stromal staining, i - weak to moderate cytoplasmic-membranous expression pattern ................
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