Neoplastic diseases are typically diagnosed by biopsy and histopathological evaluation. The pathology report is key in determining prognosis, therapeutic decisions, and overall case management and therefore requires diagnostic accuracy, completeness, and clarity. Successful management relies on collaboration between clinical veterinarians, oncologists, and pathologists. To date there has been no standardized approach or guideline for the submission, trimming, margin evaluation, or reporting of neoplastic biopsy specimens in veterinary medicine. To address this issue, a committee consisting of veterinary pathologists and oncologists was established under the auspices of the American College of Veterinary Pathologists Oncology Committee. These consensus guidelines were subsequently reviewed and endorsed by a large international group of veterinary pathologists. These recommended guidelines are not mandated but rather exist to help clinicians and veterinary pathologists optimally handle neoplastic biopsy samples. Many of these guidelines represent the collective experience of the committee members and consensus group when assessing neoplastic lesions from veterinary patients but have not met the rigors of definitive scientific study and investigation. These questions of technique, analysis, and evaluation should be put through formal scrutiny in rigorous clinical studies in the near future so that more definitive guidelines can be derived.
The aim of this paper is to discuss and update criteria that can guide the diagnosis, prognosis and treatment of canine and feline mammary neoplasms. It was elaborated during the IV Mammary Pathology Meeting: Diagnosis, Prognosis and Treatment of the Canine and Feline Mammary Neoplasia, held on April 29th and 30th, 2019 in Belo Horizonte – MG, Brazil, sponsored by the Laboratory of Comparative Pathology of the Federal University of Minas Gerais (UFMG), with the support of the Brazilian Association of Veterinary Pathology (ABPV) and Brazilian Association of Veterinary Oncology (ABROVET). Academics from several regions of Brazil were present and contributed to this work.
Mammary neoplasms are described as the third most common type of feline tumor, after haematopoietic and skin tumors, and present a challenge for clinicians because the prognosis for feline mammary tumors ranges from guarded to poor. Thus, it is necessary to define new therapeutic approaches and establish more in-depth knowledge about this disease in felines. The main aspects of the diagnosis, prognosis and treatment of feline mammary neoplasia were discussed, aiming to standardize the criteria and to serve as a guide for pathologists and veterinary clinicians.
Mast cell tumor (MCT) is a frequent cutaneous neoplasm in dogs that is heterogeneous in clinical presentation and biological behavior, with a variable potential for recurrence and metastasis. Accurate prediction of clinical outcomes has been challenging. The study objective was to develop a system for classification of canine MCT according to the mortality risk based on individual assessment of clinical, histologic, immunohistochemical, and molecular features. The study included 149 dogs with a histologic diagnosis of cutaneous or subcutaneous MCT. By univariate analysis, MCT metastasis and related death was significantly associated with clinical stage ( P < .0001, r = -0.610), history of tumor recurrence ( P < .0001, r = -0.550), Patnaik ( P < .0001, r = -0.380) and Kiupel grades ( P < .0001, r = -0.500), predominant organization of neoplastic cells ( P < .0001, r = -0.452), mitotic count ( P < .0001, r = -0.325), Ki-67 labeling index ( P < .0001, r = -0.414), KITr pattern ( P = .02, r = 0.207), and c-KIT mutational status ( P < .0001, r = -0.356). By multivariate analysis with Cox proportional hazard model, only 2 features were independent predictors of overall survival: an amendment of the World Health Organization clinical staging system (hazard ratio [95% CI]: 1.824 [1.210-4.481]; P = .01) and a history of tumor recurrence (hazard ratio [95% CI]: 9.250 [2.158-23.268]; P < .001]. From these results, we propose an amendment of the WHO staging system, a method of risk analysis, and a suggested approach to clinical and laboratory evaluation of dogs with cutaneous MCT.
1 The e ects of phosphodiesterase (PDE)4 and TNF-a inhibition were assessed on the local and remote injuries following intestinal ischaemia and reperfusion (I/R) injury in rats. 2 The PDE4 inhibitor rolipram dose-dependently (1 ± 10 mg kg 71 ) suppressed the local (intestine) and remote (lung) increases in vascular permeability and neutrophil recruitment following mild I/R injury. SB207499 (ari¯o), a structurally-distinct PDE4 inhibitor, also suppressed the injuries following mild I/R injury.3 In a severe model of I/R injury, treatment with rolipram (10 mg kg 71 ) partially reversed the local and remote increases in vascular permeability, neutrophil recruitment, intestinal haemorrhage and intestinal LTB 4 concentrations. The anti-TNF-a anti-serum was more e ective than rolipram at inhibiting local and remote injuries and prevented the lethality associated with severe I/R. 4 Rolipram and anti-TNF-a prevented the increase in the concentrations of TNF-a in the lung and intestine, but rolipram only partially inhibited the elevation of this cytokine in serum. Rolipram had little e ect on the increases of IL-1û concentrations in lung and serum, whereas treatment with anti-TNF-a markedly increased the concentration of this cytokine. Concentrations of IL-10 rose signi®cantly in the lung and serum and these increases were blocked by rolipram or anti-TNF-a. 5 The capacity of PDE4 inhibitors to block the recruitment of neutrophils into tissues, the production of LTB 4 and of the pro-in¯ammatory cytokines TNF-a, IL-1û and IL-6 appear to underlie their anti-in¯ammatory e ects in our model of I/R injury. Overall, PDE4 inhibition was less e ective than inhibition of TNF-a for protection against I/R injury. British Journal of Pharmacology (2001) 134, 985 ± 994
1 The e ects of the long lasting and potent PAF receptor antagonist UK74505 were assessed on the local and remote injuries following ischaemia and reperfusion (I/R) of the superior mesenteric artery (SMA) in rats.2 In a severe model of ischaemia (120 min) and reperfusion (120) injury, in addition to the local and remote increases in vascular permeability and neutrophil accumulation, there was signi®cant tissue haemorrhage, blood neutropenia, systemic hypotension and elevated local and systemic TNFa levels. 3 Post-ischaemic treatment with the selectin blocker fucoidin (10 mg kg 71 ) prevented neutrophil accumulation in tissue and, in consequence, all the local and systemic injuries following severe I/R. 4 Treatment with an optimal dose of UK74505 (1 mg kg 71 ) also reversed local and remote neutrophil accumulation, increases in vascular permeability and intestinal haemorrhage. UK74505 partially inhibited blood neutropenia and reperfusion-induced hypotension. 5 Interestingly, both fucoidin and UK74505 prevented the local, but not systemic, increases of TNF-a levels following severe I/R injury, demonstrating an important role of migrating cells for the local production of TNF-a. However, the results do not support a role for PAF as an intermediate molecule in the production of systemic TNF-a. 6 The bene®cial e ects of UK74505 and other PAF receptor antagonists in models of I/R injury in animals and the safety of UK74505 use in man warrant further investigations of the use of this drug as preventive measure for I/R injury in humans.
Pulmonary fibrosis is characterized by chronic inflammation and excessive collagen deposition. Neutrophils are thought to be involved in the pathogenesis of lung fibrosis. We hypothesized that CXCR2-mediated neutrophil recruitment is essential for the cascade of events leading to bleomycin-induced pulmonary fibrosis. CXCL1/KC was detected as early as 6 hours after bleomycin instillation and returned to basal levels after Day 8. Neutrophils were detected in bronchoalveolar lavage and interstitium from 12 hours and peaked at Day 8 after instillation. Treatment with the CXCR2 receptor antagonist, DF2162, reduced airway neutrophil transmigration but led to an increase of neutrophils in lung parenchyma. There was a significant reduction in IL-13, IL-10, CCL5/RANTES, and active transforming growth factor (TGF)-beta(1) levels, but not on IFN-gamma and total TGF-beta(1,) and enhanced granulocyte macrophage-colony-stimulating factor production in DF2162-treated animals. Notably, treatment with the CXCR2 antagonist led to an improvement of the lung pathology and reduced collagen deposition. Using a therapeutic schedule, DF2162 administered from Days 8 to 16 after bleomycin reduced pulmonary fibrosis and levels of active TGF-beta(1) and IL-13. DF2162 treatment reduced bleomycin-induced expression of von Willebrand Factor, a marker of angiogenesis, in the lung. In vitro, DF2162 reduced the angiogenic activity of IL-8 on human umbilical vein endothelial cells. In conclusion, we show that CXCR2 plays an important role in mediating fibrosis after bleomycin instillation. The compound blocks angiogenesis and the production of pro-angiogenic cytokines, and decreases IL-8-induced endothelial cell activation. An effect on neutrophils does not appear to account for the major effects of the blockade of CXCR2 in the system.
In areas where schistosomiasis is endemic, a negative correlation is observed between atopy and helminth infection, associated with a low prevalence of asthma. We investigated whether Schistosoma mansoni infection or injection of parasite eggs can modulate airway allergic inflammation in mice, examining the mechanisms of such regulation. We infected BALB/c mice with 30 S. mansoni cercariae or intraperitoneally injected 2,500 schistosome eggs, and experimental asthma was induced by ovalbumin (OVA). The number of eosinophils in bronchoalveolar lavage fluid was higher in the asthmatic group than in asthmatic mice infected with S. mansoni or treated with parasite eggs. Reduced Th2 cytokine production, characterized by lower levels of interleukin-4 (IL-4), IL-5, and immunoglobulin E, was observed in both S. mansoni-treated groups compared to the asthmatic group. There was a reduction in the number of inflammatory cells in lungs of S. mansoni-infected and egg-treated mice, demonstrating that both S. mansoni infection and the egg treatment modulated the lung inflammatory response to OVA. Only allergic animals that were treated with parasite eggs had increased numbers of CD4 ؉ CD25 ؉ Foxp3 ؉ T cells and increased levels of IL-10 and decreased production of CCL2, CCL3, and CCL5 in the lungs compared to the asthmatic group. Neutralization of IL-10 receptor or depletion of CD25 ؉ T cells in vivo confirmed the critical role of CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells in experimental asthma modulation independent of IL-10.The prevalence of allergic diseases such as asthma has increased markedly over the past few decades (5). The immune response to allergens is characterized by eosinophilic inflammation of the airways, airway hyperreactivity, and immunoglobulin E (IgE) production by B cells (39). The immune etiology of asthma is complex. Genetic and immunological analyses of atopic individuals have revealed that Th2 cytokines are usually associated with allergies (23, 25). Furthermore, Th2 cells which produce interleukin-4 (IL-4), IL-5, and IL-13 mediate the inflammatory reaction in the lung. Production of IL-5 increases differentiation, recruitment, and survival of eosinophils and therefore plays an important role in the development of pulmonary eosinophilia during allergic disorders (26). Moreover, IL-13 is important for IgE production, mucus hyperplasia, and eosinophilia (34). The levels of these cytokines are higher in allergic patients and play a direct role in the inflammatory response.It has been suggested that people in developing countries suffer less from allergic disease than those who live in industrialized countries because the former are frequently exposed to bacteria and helminth infections associated with poverty and lack of basic sanitary conditions (21). Both helminth infections and allergic diseases are associated with Th2 cytokines and high levels of IgE and eosinophilia. Though they appear to have similar immune responses, a negative correlation between helminth infection and allergic disease has been obse...
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