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The present study evaluated the correlation between fine-needle aspiration biopsy and routine histo-pathological examination in the diagnosis of spontaneous mammary gland tumours in cats. From the studied 120 neoplastic growths, cytological diagnosis was correct in 111 cases (92.5%), and incorrect in 9 (7.5%) patients. Out of all studied tumours, 3 false positive (2.5%) and 6 false negative (5%) results were found out. Among benign tumours, cytological diagnosis was correct in 17 cases (94.44 %). Only one false negative diagnosis was demonstrated (5.56% of all benign tumours). As to malignant tumours, cytological diagnosis was correct in 94 (92.15%), and incorrect in 8 patients (7.85%). For diagnostics of feline mammary neoplasms, the sensitivity of cytology was 95.23%, the specificity  75%, positive predictive value: 97.5% and negative predictive value: 60% compared to routine histopathology. The analysis with Cohen’s kappa test showed agreement of 99.17% (Cohen’s κ 0.96) between cytology and histopathology for benign and 94.17% (Cohen’s κ 0.75) for malignant mammary neoplasms.

The present study evaluated the correlation between fine-needle aspiration biopsy and routine histopathological examination in the diagnosis of spontaneous mammary gland tumours in cats. From the studied 120 neoplastic growths, cytological diagnosis was correct in 111 cases (92.5%), and incorrect in 9 (7.5%) patients. Out of all studied tumours, 3 false positive (2.5%) and 6 false negative (5%) results were found out. Among benign tumours, cytological diagnosis was correct in 17 cases (94.44 %). Only one false negative diagnosis was demonstrated (5.56% of all benign tumours). As to malignant tumours, cytological diagnosis was correct in 94 (92.15%), and incorrect in 8 patients (7.85%). For diagnostics of feline mammary neoplasms, the sensitivity of cytology was 95.23%, the specificity? 75%, positive predictive value: 97.5% and negative predictive value: 60% compared to routine histopathology. The analysis with Cohen's kappa test showed agreement of 99.17% (Cohen's = 0.96) between cytology and histopathology for benign and 94.17% (Cohen's = 0.75) for malignant mammary neoplasms. [ABSTRACT FROM AUTHOR]

Abstract Background Mammary tumor is one of the most common diseases of canine in pet clinics. Objectives This study investigates the distribution and expression of the tumor transcription factor GLI1 and the downstream proteins, Bmi1 and Sox2, in canine mammary tumors and paracancerous tissues. Methods Cancerous and paracancerous normal mammary tissues were detected using western blotting (WB), and immunohistochemistry. Results The results showed that the histopathology of different types in mammary tumors by microscopic observation. GLI1/Bmi1/Sox2 expression was significantly higher in canine mammary invasive carcinoma than in ductal carcinoma and adjacent normal mammary tissues (p < 0.01). The expression of GLI1 in invasive carcinoma tissues was significantly higher than Bmi1 and Sox2, while Sox2 expression in ductal carcinoma tissues was significantly higher than GLI1 and Bmi1 (p < 0.01). GLI1/Bmi1/Sox2 all showed positive reactions in both mammary tumor and adjacent normal mammary tissues with immunohistochemistry. GLI1 and Sox2 showed strong positive staining in the cytoplasm of invasive mammary carcinoma and ductal carcinoma cells, and weak positive staining in the nuclei. The positive Bmi1 reaction was mainly concentrated in the cytoplasm of invasive carcinoma and ductal carcinoma cells, while the positive reaction on the cell membrane was weak. Conclusions We speculate that GLI1 and related proteins play an important role in regulating the proliferation and differentiation of tumors. Therefore, it provides important reference for the pathogenesis and pathogenicity of canine mammary tumor.

The study was conducted to investigate the expression of SLIT2 gene in representative tissue samples of mammary tumours of female dogs (n=10) with the age between 5.0 and 16.5 years brought to Veterinary Clinical Complex, LUVAS, Hisar. Excisional biopsy was taken after surgery of these cases. Histopathological studies confirmed four cases of adenocarcinoma, three cases of benign mixed tumours and two of myoepithelioma and one case of adenoma. Amplification plots and dissociation curves of RT-qPCR were indicative of specific amplification of the canine SLIT 2 gene in all the samples. Further, amplification product of a 160 bp SLIT 2 gene and 120 bp β-actin gene in all the RT-qPCR tubes were visible by 2% agarose gel electrophoresis. Out of 10 tissue samples examined, transcript levels of SLIT 2 genes in all different samples ranged from 1.90 to 84.98. Conclusively, the expression of SLIT 2 genes increased in all canine malignant mammary gland tumours, thereby showing its association with tumour malignancy. [ABSTRACT FROM AUTHOR]

Background: Mammary tumor is one of the most common diseases of canine in pet clinics. Objectives: This study investigates the distribution and expression of the tumor transcription factor GLI1 and the downstream proteins, Bmi1 and Sox2, in canine mammary tumors and paracancerous tissues. Methods: Cancerous and paracancerous normal mammary tissues were detected using western blotting (WB), and immunohistochemistry. Results: The results showed that the histopathology of different types in mammary tumors by microscopic observation. GLI1/Bmi1/Sox2 expression was significantly higher in canine mammary invasive carcinoma than in ductal carcinoma and adjacent normal mammary tissues (p < 0.01). The expression of GLI1 in invasive carcinoma tissues was significantly higher than Bmi1 and Sox2, while Sox2 expression in ductal carcinoma tissues was significantly higher than GLI1 and Bmi1 (p < 0.01). GLI1/Bmi1/Sox2 all showed positive reactions in both mammary tumor and adjacent normal mammary tissues with immunohistochemistry. GLI1 and Sox2 showed strong positive staining in the cytoplasm of invasive mammary carcinoma and ductal carcinoma cells, and weak positive staining in the nuclei. The positive Bmi1 reaction was mainly concentrated in the cytoplasm of invasive carcinoma and ductal carcinoma cells, while the positive reaction on the cell membrane was weak. Conclusions: We speculate that GLI1 and related proteins play an important role in regulating the proliferation and differentiation of tumors. Therefore, it provides important reference for the pathogenesis and pathogenicity of canine mammary tumor. [ABSTRACT FROM AUTHOR]

Abstract Background Mastectomy is the most common procedure for treatment of mammary tumours. Dogs undergoing mastectomy have a risk of developing surgical site infections (SSI) and other postoperative complications. However, potential risk factors associated with such complications have been sparsely investigated. Thus, the objective of this retrospective study was to determine the incidence of, and identify risk factors for, SSI and non-SSI postoperative complications after mastectomy performed without perioperative antimicrobial prophylaxis in privately owned otherwise clinically healthy dogs. Results Medical records were reviewed retrospectively for 135 client-owned female dogs, 10–35 kg in weight and three to 10 years of age, which had undergone mastectomy due to mammary tumours at three referral animal hospitals in Sweden over a 3-year period. Twelve (8.9%) dogs developed SSI, and 21 dogs (17.1%) dogs suffered a non-SSI postoperative complication. The incidence of SSI and all complications (SSI and non-SSI) were higher in dogs that had two to three (SSI: P = 0.036 and all complications: P = 0.0039) and four to five (SSI and all complications: P = 0.038) mammary glands excised, compared to dogs that had one mammary gland excised. The incidence of SSI was 1.7% (n = 1/60) in dogs that had one gland removed. The incidence of non-SSI postoperative complications was higher in dogs with a higher body weight (P = 0.02). Conclusions The incidence of SSI was lower than or similar to previously reported incidences of SSI in dog populations that have undergone tumour excisional surgery, despite the fact that dogs in the present study had not received perioperative antibiotics. Dogs that had two or more glands excised had an increased risk of developing SSI and non-SSI complications compared to dogs that had one gland excised. Furthermore, higher BW was associated with an increased risk of non-SSI complications. Results from the study indicate that routine use of perioperative antibiotics in tumour excisional surgery can be questioned, at least in single gland mastectomy in otherwise clinically healthy dogs.

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This study aims to evaluate the efficacy and side effects of low dose cyclophosphamide chemotherapy plus meloxicam as an adjuvant treatment, compared with high dose doxorubicin or surgery alone in cats with mammary carcinoma. Medical records of 228 female cats treated for mammary carcinoma between 2008 and 2018, were reviewed in eight veterinary institutions. Only cats with complete tumour staging and radical mastectomy were included in the study. One hundred and thirty-seven cats were divided into three treatment groups: group 1 (n = 80) cats treated with surgery, group 2 (n = 34) cats that had surgery and adjuvant treatment with doxorubicin, and group 3 (n = 23) cats with surgery and adjuvant treatment with low dose metronomic cyclophosphamide and meloxicam. The study endpoints were disease free interval (DFI) and overall survival (OS). Toxicity was evaluated according to the VCOGCTCAE criteria. The median DFI was 270, 226 and 372 days in groups 1, 2 and 3, respectively. The median OS was 338 (group 1), 421 (group 2) and 430 (group 3) days. The differences between groups were not significant (DFI P = .280 and OS P = .186). Toxicity was observed in 52.9% (n = 18) of cats in group 2 and 39.1% (n = 9) of cats in group 3, with mild to moderate intensity. Differences were not significant (P = .306). In conclusion, adjuvant chemotherapy treatment did not improve survival and the overall benefit remains unproven. Randomized prospective trials are necessary to clarify the effectiveness of adjuvant chemotherapy treatment for feline mammary carcinomas. [ABSTRACT FROM AUTHOR]

Blood leukocyte counts and respective derived ratios have been described as potential prognostic markers in several tumours in veterinary oncology. This study aimed to evaluate peripheral blood leukocyte subpopulations and neutrophil‐to‐lymphocyte ratio (NLR) as prognostic factors for feline mammary carcinomas (FMC). Medical records from cats diagnosed with FMC between 2017 to 2019 were reviewed. Cats were included if fully staged, classified as WHO stage I to III, and submitted to mastectomy. Cats were excluded if they had evidence of other diseases. Forty‐nine cats were included. The study endpoints were disease‐free interval (DFI) and tumour‐specific survival (TSS). The median DFI and TSS were 389 days and 528 days respectively. In the univariate analysis, higher values of total white blood cell count (WBC), neutrophil count (NEU) and NLR were identified as significant prognostic factors for both endpoints (P <.05). On the multivariate analysis, NLR remained an independent prognostic factor for TSS (P =.024). In the receiver operating characteristic curve analysis, the estimated cut‐off for WBC was 8.49 × 109/L (DFI and TSS); for NEU was 4.62 × 109/L (DFI) and 6.65 × 109/L (TSS) and for NLR was 2.46. These cut‐offs were significant prognostic factors for DFI and TSS (P <.05). NLR cut‐off remained an independent prognostic factor for both DFI (P =.032) and TSS (P =.043) in the multivariable analysis. Our results suggest that NLR, NEU, and WBC can be important non‐invasive presurgical prognostic markers, and that NLR is an independent prognostic marker for FMC. Prospective studies are warranted to validate its clinical use. [ABSTRACT FROM AUTHOR]

Background: Mastectomy is the most common procedure for treatment of mammary tumours. Dogs undergoing mastectomy have a risk of developing surgical site infections (SSI) and other postoperative complications. However, potential risk factors associated with such complications have been sparsely investigated. Thus, the objective of this retrospective study was to determine the incidence of, and identify risk factors for, SSI and non-SSI postoperative complications after mastectomy performed without perioperative antimicrobial prophylaxis in privately owned otherwise clinically healthy dogs. Results: Medical records were reviewed retrospectively for 135 client-owned female dogs, 10–35 kg in weight and three to 10 years of age, which had undergone mastectomy due to mammary tumours at three referral animal hospitals in Sweden over a 3-year period. Twelve (8.9%) dogs developed SSI, and 21 dogs (17.1%) dogs suffered a non-SSI postoperative complication. The incidence of SSI and all complications (SSI and non-SSI) were higher in dogs that had two to three (SSI: P = 0.036 and all complications: P = 0.0039) and four to five (SSI and all complications: P = 0.038) mammary glands excised, compared to dogs that had one mammary gland excised. The incidence of SSI was 1.7% (n = 1/60) in dogs that had one gland removed. The incidence of non-SSI postoperative complications was higher in dogs with a higher body weight (P = 0.02). Conclusions: The incidence of SSI was lower than or similar to previously reported incidences of SSI in dog populations that have undergone tumour excisional surgery, despite the fact that dogs in the present study had not received perioperative antibiotics. Dogs that had two or more glands excised had an increased risk of developing SSI and non-SSI complications compared to dogs that had one gland excised. Furthermore, higher BW was associated with an increased risk of non-SSI complications. Results from the study indicate that routine use of perioperative antibiotics in tumour excisional surgery can be questioned, at least in single gland mastectomy in otherwise clinically healthy dogs. [ABSTRACT FROM AUTHOR]

In the present study, the concentration of decorin in canine normal and neoplastic mammary gland tissues was examined to understand the potential role of decorin in development and progression of canine mammary tumours. The homogenates of 48 mammary gland tumours (10 benign and 38 malignant) and 10 samples of normal canine mammary gland tissue were used in the study. The presence and quantification of decorin was examined in the homogenates using Western blot and specific canine ELISA. Western blotting confirmed the presence of decorin both in the normal mammary gland tissues and in the mammary gland tumours. The concentration of decorin was significantly higher (p <.05) in the benign tumours and non‐metastatic malignant tumours than in the normal mammary gland. The concentration of decorin was significantly lower (p <.05) in the malignant tumours with metastasis to regional lymph nodes compared with benign tumours and non‐metastatic malignant tumours. No significant differences were found in the level of decorin between the benign and the non‐metastatic malignant tumours. Both the histological type of malignant tumours and the histological grade did not significantly affect the concentration of decorin. These findings suggest that neoplastic transformation in the canine mammary gland leads to increase in the decorin protein synthesis. The reducing decorin concentration in canine malignant mammary tumours appears to facilitate the metastatic spread of these tumours. [ABSTRACT FROM AUTHOR]

The aims of this study were to investigate the potential association of arginine vasopressin type 2 receptor (AVPR2) in canine mammary tumours with expression of oestrogen receptors α (ORα) and β (ORβ) and clinicopathological features of the neoplasms. Twenty-six canine mammary tumour samples (11 benign, 15 malignant) were immunolabelled for AVPR2, ORα and ORβ antigens. Moderate to intense immunolabelling of AVPR2 antigen, found in all neoplasms, was not significantly associated with expression of ORα or ORβ antigens or with clinicopathological features. These findings indicate a potential role for AVPR2 in the development of canine mammary tumours and the use of AVPR2-selective vasopressin analogues as therapeutic options. Canine simple mammary carcinoma. Immunohistochemical AVPR2 labelling is observed in the cell membrane and cytoplasm of tumour epithelial cells (black arrow). Image 1 [ABSTRACT FROM AUTHOR]

Recent studies highlighted the role of autophagy as a cardinal regulatory system for homeostasis and cancer‐related signalling pathways. In this context, the deregulated expression of p62 – Sequestosome1 (p62/SQSTM1) – a protein acting both as an autophagy receptor and signalling hub, has been associated with tumour development and chronic inflammation. Multiple clinical studies test drugs targeting autophagy, and even more research is on the way to clinical trials. However, no comparative investigations have been carried out to identify adequate preclinical models to assess p62‐based medicine. In veterinary oncology the role of p62 in cancer‐related pathways has been largely ignored. We compared p62 sequences in multiple organisms and found that canine p62 significantly diverges from the humans and from other animals sequences. Then, we chart by immunohistochemistry the expression levels of p62 in canine mammary tumours. A total of 66 tumours and 10 non‐neoplastic mammary samples were examined. The expression of p62 was higher in normal tissue and adenomas than carcinomas, with lowest levels of p62 protein detected in high grade carcinomas. In all cases examined the tumour stroma appeared to be p62‐negative. Taken together our results would suggest that in dogs the association between p62 expression and cancer cells overturns that reported in human breast carcinoma, where p62 accumulates in malignant cells as compared to normal epithelium. Thus, at least in canine mammary tumours, p62 should be not considered a tumour‐rejection antigen for an anti‐cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Breast cancer is a major cause of death among human females across the globe. The anti-neoplastic agents or therapies used for the treatment of cancers can enhance longevity but are subsequently observed to deteriorate the quality of life due to the extensive side effects produced. Saussurea costus is a potential medicinal plant of the Himalayas with noticeable ethnopharmacological properties. The phytochemicals present in Saussurea costus are responsible for anti-carcinogenic potential and warranted nil or minimal side effects of Saussurea costus and directed to use this plant as a preventive or therapeutic drug candidate against cancers. The present study was planned to evaluate the anti-neoplastic activity of Saussurea costus root extract (SL) in rat mammary tumour model. The anti-neoplastic activity of SL root extract at 3 different doses (100, 250 and 500 mg/kg BW) for 18 weeks against 12-dimethylbenz (a) anthracene (DMBA)-induced mammary tumours in Sprague Dawley (SD) female rats was analyzed through serum biochemistry (ALT, AST, ALP, Total protein, Creatinine and BUN), oxidative stress parameters (Lipid peroxidation, Catalase and Reduced glutathione), pro-inflammatory cytokines (TNF-α and NF-κB), immunohistochemical markers (Ki-67, MMP-9 and VEGF), real-time PCR (PCNA, p53, bax, bcl-2 and caspase-3, genes) and molecular docking. Inhibition of tumour parameters, minimal alteration in the liver (ALT, AST and ALP) and kidney enzymes (Creatinine and BUN), decreased activity of MDA, elevated levels of GSH and catalase, reduction in the levels of pro-inflammatory cytokines i.e. TNF-α and NF-κB, reduced gross and histomorphological changes, declined expression of Ki-67, MMP-9 and VEGF in vivo rat model, mRNA expression of cancer-related genes and docking of dehydrocostus lactone and costunolide with NF-κB and TNF-α demonstrated the chemopreventive action of SL root extract. The in-vivo trial elucidates anti-neoplastic activity of Saussurea costus root extract as demonstrated through the reduction of biochemical indices, oxidative stress parameters, histological changes, pro-inflammatory cytokines (NF-κB and TNF-α), cellular proliferation (Ki-67), metastases (MMP-9) and neovascularization (VEGF) markers with highest anti-neoplastic effect of SL extract at the dose of 500 mg/kg body weight. Therefore, the present study signifies the need to use the active principles present in the root extract of Saussurea costus against breast cancer as a therapeutic regimen. [Display omitted] [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are membrane‐bound vesicles produced by cells, known to play a key role in cell‐to‐cell communication. They exert pleiotropic biological functions via the horizontal transfer of bioactive molecules (DNA, RNAs, proteins, and lipids) within the tumour microenvironment and throughout the body. In human cancer, EVs are known to interfere with pathways that lead to tumour progression and are used as novel cancer biomarkers. In veterinary medicine, very little is known on cancer‐derived EVs. In this study, we preliminarily characterized EVs in mammary gland cancer of dogs and cats. EVs were isolated by ultracentrifugation from canine (CYPp), feline (FMCp) and human (MCF7) mammary tumour cell lines. EVs were visualized by transmission electron microscopy (TEM), counted using nanoparticle tracking analysis (NTA) and characterized by immunogold (CD63 and Alix) and western blot (Alix and TSG101). Additionally, EV production by "donor" cells (palmtdTomato+) and uptake by "recipient" cells (GFP+) were assessed. EVs were successfully isolated from all 3 cell lines by ultracentrifugation. Membrane‐bound structures (50‐400 nm) were identified by TEM and were positive for both CD63 and Alix at immunogold. Western blot showed positivity of EVs to Alix and TSG101. NTA analysis detected EVs from cell culture media ranging from 1.67 to 2.56 × 102 as number of EVs/cell and from 80 to 600 nm in size. Confocal microscopy identified the presence of palmtdTomato+ EVs into the cytoplasm of GFP+ cells. This preliminary study identified and characterized canine and feline mammary tumour cell‐derived EVs, opening in veterinary medicine a new interesting unexplored field with several applications and limitless potential. [ABSTRACT FROM AUTHOR]

Ultrasonography is a valuable tool for the evaluation of neoplastic lesions in the dog and there is a growing interest in the use of this technique for the stadiation of canine mammary tumours. An accurate assessment of small sized nodules facilitates the stadiation of the mammary lesions and helps the clinician in the choice of the most indicated surgical therapy. The aim of this study was to identify those ultrasound criteria that may be useful in discriminating between benign and malignant lesions of small size (diameter smaller than 2 cm). Sixty-two nodules, < 2 cm in larger diameter, belonging to thirty-five bitches presented between January 2012 and February 2014 were evaluated. Tumours were observed by conventional ultrasound and assessed for: shape (regular-irregular), limit (defined-ill-defined), margins (regular-irregular), echogenicity (hypoechoic-isoechoic-hyperecoic), echotexture (homogeneus-heterogeneus), presence of hyperecoic halo, distal acoustic enhancement or shadowing and surrounding tissue alterations. Among the alterations in surrounding tissues, the disruption of the glandular tissue and the increase in echogenicity of the peritumoral tissues were assessed. Thereafter, bitches were subjected to mastectomy and nodules were evaluated histologically. None of the ultasound criteria considered in the current study showed a statistically significant relation with malignancy, except for the presence of alterations in the tissue surrounding the nodules. According to our results, this characteristic may indicate malignancy, however its subjectivity may affect the applicability in clinical practice. In conclusions, conventional ultrasound in bitches had a limited ability in discriminating benign and malignant mammary gland neoplastic lesions of small size (diameter < 2 cm). [ABSTRACT FROM AUTHOR]

Mammary gland tumours are the most common neoplasia diagnosed in the female dog. These tumours occur spontaneously or naturally as in humans, 50% of which are commonly diagnosed as malignant. Metastasis to other tissues especially the lung is a common cause of death in these dogs. Treatment of canine mammary gland tumours (CMT) involves mainly surgical resection with wide margin followed by chemotherapy with cytotoxic drugs for those with lymph node and distant metastasis. With the dog continuously described as a very suitable and valuable large animal model of human breast cancer, it becomes very obvious that CMT can be a model to further understand the biology of cancer as well as screening for new therapeutic agents that could be used to treat human breast cancer and CMT more effectively. This review focuses on research work that has been done on CMT over the past years, describing the epidemiology, diagnostics and recent advances in therapy for CMT as well as discussing the significance of the dog CMT as spontaneous animal model for human breast cancer. [ABSTRACT FROM AUTHOR]

Mammary tumours are the second most frequent neoplasia in dogs, mainly affecting older female patients. Approximately 50% of the mammary tumours are malignant with high percentage of mortality if not treated in time. The aim of this study was to analyze the data of canine patients with mammary tumours, to evaluate the type of tumours, as well as the relationship between tumour incidence and dogs’ age, reproductive cycle and sterilization. The survey was used to retrieve the information in the period of two years from the patient data base of the University Veterinary Hospital at the Faculty of Veterinary medicine in Skopje. Patients included in this survey were subjected to routine clinical investigation and additional laboratory tests (cytological examination, x-rays imaging, CBC and biochemical profile, histopathology of the tumor samples). Aged female patients (12 – 13 years) are the most susceptible category for development of mammary tumours. The reproductive history showed that five of the patients with malignant mammary tumourshave never whelped and were not treated with any exogenous hormones. Malignant tumours (adenocarcinoma) were diagnosed in 90% of the patients. Three patients died due to lung metastasis. Late diagnosis is one of the major problems that results in lethal outcome due to lung metastases. Since ovarian steroids play an important role in the aetiology, the most effective prevention of mammary tumoursis elective ovariectomy of the bitch at an early age.

Studies have yet to determine whether or not equol can explain the chemopreventive effect of soy. In the present study, a single oral dose of 5 mg 7,12-dimethylbenz(a)anthracene (DMBA) was administered to 120 rats. After ovariectomy, these rats were divided into eight different treatment groups: control group (CG); high isoflavone (HI); middle isoflavone (MI); low isoflavone (Li); high equol (HE); middle equol (ME); low equol (LE); and oestrogen group (EG). At week 24 after DMBA was administered, tumour incidences were 60% (9/15) in CG, 13.3% (2/15) in the MI group, 13.3% (2/15) in the Li group, 6.7% (1/15) in the LE group, and 73.3% (11/15) in EG. Isoflavone/equol groups exhibited significantly lower incidences of tumour and longer mean latent period compared with CG and EG. Thiobarbituric acid reactive substances were significantly decreased in the plasma of the rats in HI and MI groups as well as in equol treatment groups compared with CG. Moreover, RT-PCR and western blotting show that the mRNA and protein expression levels of ERα and ERβ were significantly higher in isoflavone/equol treatment groups than in CG. In conclusion, isoflavone/equol intake can significantly inhibit the development of post-menopausal mammary tumours by antioxidant activities and oestrogenic activities.

Exercise training is thought to play a protective role against cancer development and metastasis, either by reducing hormonal stimulation of hormone-dependent cancers or by reducing the permeability of vascular walls towards invading metastatic cells. The purpose of this work was to evaluate the role of long-term exercise training in the development and metastasis of breast cancer, in an immune-competent 1-methyl-1-nitrosourea (MNU) induced rat model. A single MNU dose was administered to Sprague-Dawley rats at 50 days of age and the rats were subjected to exercise training on a treadmill at 20 m/min, 60 min/day, 5 days/week for 35 weeks. Exercised animals developed slightly less (2.30 ± 1.42) tumours per animal than sedentary animals (2.55 ± 1.44) and did not develop any metastasis, while two pulmonary metastases were observed in the sedentary group. All primary neoplasms and their metastases were positive for oestrogen ( ER) α and progesterone ( PR) receptors, indicating high hormonal sensitivity. Interestingly, exercise training increased circulating oestrogen levels, thus suggesting that the mechanism might involve either or both of a protective hormone-independent effect and modulation of tumoural vascularization. [ABSTRACT FROM AUTHOR]

The relative roles of SULF1 and SULF2 enzymes in tumour growth are controversial, but short SULF1/SULF2 splice variants predominate in human mammary tumours despite their non-detectable levels in normal mammary tissue. Compared with the normal, the level of receptor tyrosine kinase (RTK) activity was markedly increased in triple-positive mammary tumours during later stages of tumour progression showing increased p-EGFR, p-FGFR1 and p-cMet activity in triple-positive but not in triple-negative tumours. The abundance of catalytically inactive short SULF1/SULF2 variants permits high levels of HS sulphation and thus growth driving RTK cell signalling in primary mammary tumours. Also observed in this study, however, was increased N-sulphation detected by antibody 10E4 indicating that not only 6-O sulphation but also N-sulphation may contribute to increased RTK cell signalling in mammary tumours. The levels of such increases in not only SULF1/SULF2 but also in pEGFR, pFGFR1, p-cMet and Smad1/5/8 signalling were further enhanced following lymph node metastasis. The over-expression of Sulf1 and Sulf2 variants in mammary tumour-derived MDA-MB231 and MCF7 cell lines by transfection further confirms Sulf1-/Sulf2-mediated differential modulation of growth. The short variants of both Sulf1 and Sulf2 promoted FGF2-induced MDA-MB231 and MCF7 in vitro growth while full-length Sulf1 inhibited growth supporting in vivo mammary tumour cell signalling patterns of growth. Since a number of mammary tumours become drug resistant to hormonal therapy, Sulf1/Sulf2 inhibition could be an alternative therapeutic approach to target such tumours by down-regulating RTK-mediated cell signalling. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women worldwide. Cancer metastases are responsible for the high mortality rate. A small but distinct subset of cells, cancer stem cells (CSCs), have the capacity to self-renew, initiate tumour formation, and develop metastases. The CSC content in human breast cancer correlates with the Hippo tumour suppressor signalling pathway. Specifically, the activity of YAP/TAZ, transcription co-activators of the Hippo pathway, sustains the self-renewal and tumour-initiation capacities of CSCs. Little is known about YAP/TAZ in canine and feline mammary tumours, which are very common tumours. The preliminary aim of the study was to investigate the expression of YAP/TAZ in canine and feline mammary tumours by Western blot and immunohistochemistry. Increased cytoplasmic and nuclear expression of YAP/TAZ was observed in all carcinomas compared to normal tissues, indicating neoplastic deregulation of the Hippo pathway. Nuclear expression significantly increased in grade III (high grade carcinomas) compared to grade I (low grade carcinomas) tumours, suggesting that YAP/TAZ play a role in the increased aggressiveness of these tumours. Moreover, different scoring systems for immunohistochemical analyses were compared and the H index and the Allred scores were the most significant. In conclusion, YAP/TAZ are expressed in aggressive canine and feline mammary tumours as reported in some human cancers. Further studies might better elucidate the role of the Hippo pathway in prognosis and as a target for new therapies. In addition, tumours in dogs and cats may be a useful model to study this pathway. [ABSTRACT FROM AUTHOR]

• Measurement of acoustic attenuation and speed in three fixed canine mammary tumours. • Five sample pieces sectioned from the three tumours and used in measurements. • Attenuation and speed were in the range of 1.95–3.45 dB/cm.MHz and 1568–1636 m/s respectively. • Variations in attenuation and speed observed between samples from the same tumour. • Higher attenuation and speed than normal tissue due to varied tumour morphology. Canine mammary tumours (CMTs) are the most common neoplasm appearing in female dogs and are considered the equivalent animal model of human breast cancer. However, in the literature, there is a gap for ultrasonic characterisation of these tumours. In this study, experimental measurements for acoustic attenuation and propagation speed of three surgically excised malignant CMTs were implemented. The three tumours were fixed in formaldehyde for up to 72 h and a total of five sample pieces were sectioned from the three tumours to account for the varied morphology observed along the tumours. The through-transmission and pulse-echo techniques were employed for experimental measurements of the acoustic attenuation and propagation speed. Acoustic propagation speed of the five samples as measured at 2.7 MHz was in the range of 1568–1636 m/s. Correspondingly, acoustic attenuation was in the range of 1.95–3.45 dB/cm.MHz. Variations in both speed and attenuation were observed between samples acquired from the same tumour. Present findings suggest that both acoustic attenuation and propagation speed of CMTs are higher than normal canine tissues due to increased heterogeneity and varied morphology visually observed between the tumour specimens and evidenced by histological examination. Nevertheless, experimental results could aid in enhancing the use of ultrasound in the diagnosis and treatment of CMTs as well as provide essential data for comparative oncology. [ABSTRACT FROM AUTHOR]

Summary Hypoxia-inducible factor (HIF)-1α plays important physiological roles, but is also of significance in carcinogenesis in man and animals. This study aimed to identify HIF-1α expression in malignant canine mammary tumours (CMTs) and to find correlations with other key factors by using immunohistochemistry (IHC). The histological classification, grading and evaluation of lymphatic invasion were achieved by examining sections stained by haematoxylin and eosin. Determination of molecular subtype, expression of HIF-1α, oestrogen receptor (OR), progesterone receptor (PR), human epidermal growth factor receptor (HER)-2, Ki67, vascular endothelial growth factor (VEGF) and E-cadherin was evaluated by IHC in 87 samples of malignant CMTs. HIF-1α expression correlated significantly with histological type, grade of cancer, negativity for OR and expression of Ki67 and VEGF. Lymphatic invasion, molecular subtype, PR, HER-2 and E-cadherin levels did not significantly correlate with HIF-1α expression. The results of this study imply that HIF-1α may potentially play a role in increased malignancy of CMTs, as it does in human breast cancer. [ABSTRACT FROM AUTHOR]

Endothelins and their receptors have been implicated in numerous diseases and have recently emerged as relevant players in a variety of malignancies. Tumours overexpress the Endothelin-1 (ET-1) and the Endothelin-A receptors (ETAR) and their interaction enhances tumour growth and metastasis by promoting tumour cell survival, proliferation and angiogenesis. In this study we have evaluated the expression of ET-1 and ETAR in 50 canine mammary tumours, compared to normal controls. Results demonstrated a progressive increase in ET-1 and ETAR expression from benign tumour to grade 1 and to grade 2 malignant mammary tumours with a decrease of expression in grade 3 carcinomas. Co-localization of ET-1 and ETAR was observed in benign mammary tumours and in G1 and G2 carcinomas, while absent in G3 carcinomas. Concluding, ET-1/ETAR can be considered reliable markers for evaluating malignancy of canine mammary tumours and could have importance for the development of specific anticancer therapies. [ABSTRACT FROM AUTHOR]

Strategies to prevent tumour burden-induced cardiac remodelling that might progress to heart failure are necessary to improve patients’ health outcomes and tolerability to cancer therapies. Exercise has been suggested as a measure to prevent cardiac damage; however, its effectiveness on regulating cardiac remodelling secondary to cancer was never addressed. Using an animal model of mammary tumorigenesis, we studied the impact of 35 weeks of endurance training on heart, focusing on the signalling pathways modulated by pro-inflammatory and wasting cytokines. The cardiac fibrosis and myofiber disorganization induced by tumour burden was paralleled by the increase of myostatin and TWEAK with the activation of signalling pathways involving Smad-3, NF-κB, TRAF-6 and atrogin-1. The activation of Akt/mTOR was observed in heart from rats with tumours, for which contributed the extracellular matrix. Endurance training prevented the increase of serum and cardiac TWEAK promoted by cancer, as well as the activation of NF-κB, TRAF6, atrogin-1 and p70S6K in heart. Data highlight the impact of exercise in the modulation of signalling pathways activated by wasting cytokines and the resulting outcomes on heart adaptation. Future studies focused on the cellular pathways underlying cardiac remodelling will assist in the development of exercise programs targeting cancer-related cardiac alterations. [ABSTRACT FROM AUTHOR]

Mammary tumours are the second most frequent neoplasia in dogs, mainly affecting older female patients. Approximately 50% of the mammary tumours are malignant with high percentage of mortality, if not treated in time. The aim of this study was to analyze the data of canine patients with mammary tumours, to evaluate the type of tumours, as well as the relationship between tumour incidence and dogs' age, reproductive cycle and sterilization. The survey was used to retrieve the information in the period of two years from the patient data base of the University Veterinary Hospital at the Faculty of veterinary medicine in Skopje. Patients included in this survey were subjected to routine clinical investigation and additional laboratory tests (cytological examination, x-rays imaging, CBC and biochemical profile, histopathology of the tumor samples). Aged female patients (12 - 13 years) are the most susceptible category for development of mammary tumours. The reproductive history showed that five of the patients with malignant mammary tumours have never whelped and were not treated with any exogenous hormones. Malignant tumours (adenocarcinoma) were diagnosed in 90% of the patients. Three patients died due to lung metastasis. Late diagnosis is one of the major problems that results in lethal outcome due to lung metastases. Since ovarian steroids play an important role in the aetiology, the most effective prevention of mammary tumours is elective ovariectomy of the bitch at an early age. [ABSTRACT FROM AUTHOR]

Giant hamartoma of the breast is an unusual clinico-pathologic entity that tends to be mistaken with other tumours. Its clinical diagnosis is extremely difficult and, despite of the radiologic improvements, most of them are suspected and confirmed only when all specimen is studied. Its differential diagnosis includes fibroadenoma, lipoma, phyllodes tumour and various carcinomas. We report 2 cases of giant hamartoma of the breast in middle age female patients, with surgical approach of the tumor by nipple-areola sparing mastectomy and correction of the resultant breast deformity by prosthetic reconstruction and other with excisional biopsy with mastopexy. [ABSTRACT FROM AUTHOR]

Canine mammary tumours are highly heterogeneous in morphology and behaviour and successful clinical management requires robust prognostic factors. Histological grade, determined by the Nottingham nuclear pleomorphism scoring method, has been considered one of these factors. Despite the adoption of this method, it is unknown whether inter-observer agreement exists regarding the assessment of its parameters in canine mammary carcinomas (CMC). In this study, the agreement between two observers in scoring nuclear pleomorphism using the Nottingham method was evaluated in 89 cases of CMC. Histological evidence of vascular invasion and/or lymph node metastases (both early signs of tumour aggressiveness) was recorded. For 48 animals, two years of follow-up data were available. Nuclear pleomorphism was quantitatively assessed using a stereological method that allowed for an unbiased estimation of nuclear size and its variability by determining the volume-weighted mean nuclear volume (...v). Differences between the ...v estimations and nuclear pleomorphism scores were evaluated. Additionally, the prognostic significance of clinicopathological features including nuclear score and ...v was evaluated. A poor agreement between the two observers was obtained (κ value 0.46). Tumours scored as 1 and 2 presented similar ...v values and only tumours that scored 3 presented significantly higher estimates. The ...v value was not associated with vascular invasion and/or lymph node metastases, but was higher in tumours that progressed during follow-up. In multivariable analysis, only tumour size was an independent factor regarding evidence of aggressiveness and an optimal cut-off of 2.9 cm was defined. [ABSTRACT FROM AUTHOR]

Summary: NOTCH-1 is a transmembrane receptor protein. Ligand proteins expressed on the surface of neighbouring cells bind to the NOTCH-1 extracellular domain by juxtacrine signalling and release the NOTCH intracellular domain (NICD) to alter gene expression. Forty feline mammary lesions (34 malignant and six hyperplastic) were submitted for immunohistochemical analysis of NICD expression using an anti-feline NICD monoclonal antibody. Associations between NICD expression in carcinomas and morphological parameters, as well as overall survival (OS), were investigated. NICD nuclear expression was observed in hyperplastic lesions (100%) while cytoplasmic localization was evident in carcinomas (0% nuclear positive; 87.5% cytoplasmic positive; 12.5% negative). Cytoplasmic NICD localization was statistically associated with carcinomas, while nuclear labelling was associated with hyperplasia. No significant correlation between positive or negative NICD expression and OS or morphological parameters was detected. NOTCH-1 activation, immunohistochemically identified by the NICD active form, appears to play a role in feline mammary carcinoma biology as the majority of tumours express this protein. Nuclear localization is consistent with the established NICD metabolic intranuclear pathway while cytoplasmic accumulation suggests aberrant NOTCH-1 signalling typical of malignant tumour progression. [Copyright &y& Elsevier]

Highlights: [•] We produced post-menopausal mammary tumour model in ovariectomised rats using DMBA. [•] Isoflavone/equol treatment inhibited development of post-menopausal mammary tumours. [•] Antioxidant activity and changing oestrogen receptor expression maybe the mechanism. [Copyright &y& Elsevier]

Résumé: Objectifs: Les métastases intra-mammaires (MIM) des cancers d’origine extra-mammaire sont peu fréquentes. L’objectif de cette revue de littérature était d’actualiser les connaissances et d’expliciter les erreurs diagnostiques. Patients et méthodes: La revue de la littérature via PubMed a permis de sélectionner 54 articles parus en anglais entre 2003 et 2012. Résultats: Les mélanomes (138 cas, 29,8 %) étaient plus fréquemment à l’origine des 463 cas de MIM, suivis des cancers pulmonaires, gynécologiques, digestifs et hématologiques. Les MIM surviennent chez la femme (92,2 %) vers 50ans, de manière métachrone (84,2 %). Cliniquement, elles sont généralement rondes, indolores, sans rétraction cutanée et associées à des adénopathies (33 %). À l’imagerie, elles sont plus souvent uniques. Le diagnostic, parfois évoqué par l’étude morphologique de la tumeur, est confirmé par l’immuno-histochimie. Les métastases systémiques sont fréquentes, entraînant une survie courte. Discusssion: La prévalence des primitifs n’est pas responsable à elle seule de la fréquence des MIM, comme le montre les mélanomes. La théorie de ű la graine et du sol Ƈ de Paget peut l’expliquer, certaines cellules tumorales ne pouvant s’implanter que dans certains organes. La vascularisation du sein paraît être également un facteur important. Cliniquement, les MIM peuvent être confondues avec des tumeurs bénignes. Néanmoins, un antécédent de cancer et des lésions multiples doivent faire suspecter la malignité. À l’imagerie, les signes sont peu spécifiques. Les caractéristiques morphologiques ne permettent pas d’affirmer le diagnostic avec certitude. L’immuno-histochimie est fondamentale, comme la comparaison avec l’histologie de la tumeur primitive. La prise en charge est essentiellement palliative. [ABSTRACT FROM AUTHOR]

The proto-oncogene HER-2/neu (c-erbB-2) encodes a transmembrane receptor protein with tyrosinekinase activity. Previous studies have shown that HER-2 protein over-expression is present in canine mammary tumours, however, possible prognostic and predictive analogies between protein over-expression patterns in canine and human species are still controversial. Thirty-five canine mammary carcinomas, 11 mammary adenomas, and normal, hyperplastic or dysplastic tissues taken at the marginal area of the tumours were evaluated by immunohistochemistry (IHC) for HER-2 expression, using the Hercept Test® system scoring guidelines. HER-2 over-expression was detected in 3/11 adenomas and 10/35 carcinomas. Normal, hyperplastic and dysplastic mammary tissues were also found to be positive. The correlations between HER-2 expression and tumour histological grading, mitotic index, the presence of lymphatic invasion, and overall survival (OS) were evaluated. In carcinomas, HER-2 positive status only correlated with the mitotic index. A positive correlation was also found between HER-2 positive status and the presence of HER-2 over-expression in normal, hyperplastic or/and dysplastic mammary tissues surrounding the tumours. The percentage of HER-2 over-expressing tumours was similar to the percentage previously observed in canine benign and malignant mammary tumours. However an investigation regarding morphologically normal and hyperplastic or dysplastic tissues surrounding neoplastic lesions also showed HER-2 over-expression. In contrast with human mammary tumours, this study confirmed that in canine species, HER-2 over-expression does not identify a subgroup of tumours with a poor prognosis. In fact, we found HER-2 over-expression in morphologically non-neoplastic mammary tissues, surrounding hyperplastic and neoplastic lesions. [ABSTRACT FROM AUTHOR]

CD10 is an important cell marker in the diagnosis of acute lymphoblastic leukaemia and of breast myoepithelial (ME) cells in humans. The objective of this study was to assess the value of CD10 as a marker of canine ME cells using immunohistochemistry on routinely processed normal, dysplastic and neoplastic mammary tissue. Five different CD10 positive cell types were identified on the basis of cell morphology, pattern of immunoreactivity, and on the co-expression of additional cell lineage-specific markers. Type 1 cells were typical fusiform cells with a ME cell phenotype (calponin- and cytokeratin [CK] 14-positive, CK8/18-negative). Type 2 cells were typical or atypical polyhedral cells with a luminal epithelial (LE) cell phenotype (calponin- and CK14-negative, CK8/18-positive). Type 3 cells had a type 1 phenotype with variable morphology, and type 4 were atypical neoplastic cells with a mixed ME/LE phenotype. Type 5 cells were typical fusiform cells with a stromal phenotype. Type 1 cells were considered normal ME cells and were found in all sample types; type 2 cells were considered normal or neoplastic LE cells and were also found in all sample types; types 3 and 4 cells were restricted to tumour samples and to malignant turnouts, respectively, and type 5 cells were found in all sample types, although predominantly in neoplastic tissue. The findings indicate that the CD10 antigen is a sensitive (although not specific) marker of canine ME cells in normal, dysplastic and neoplastic mammary tissue. Differences in the distribution and staining intensity of CD10-positive cells suggest a number of potential roles for this protein in the pathogenesis of canine mammary neoplasia. [ABSTRACT FROM AUTHOR]

Abstract: Leptin and its receptor (ObR) expression were investigated by immunohistochemistry in normal, hyperplastic and neoplastic canine mammary tissues and related to clinical-pathological features. Leptin expression was detected in healthy mammary tissues, adenosis and in benign mammary tumours and was lower in ductal hyperplasias and malignant tumours. A high percentage of ObR-positive cells were present in adenosis, benign tumours and in complex carcinomas, while ObR expression was lower in healthy mammary tissues, in ductal hyperplasias and in a large part of invasive mammary carcinomas. Our data demonstrated that cancer cells expressed at low level leptin and ObR in canine mammary tumours with a more aggressive behaviour, as well as in lymph node metastases. Consequently, leptin and ObR expressions in this species resulted to be not associated with a reduced overall survival. [Copyright &y& Elsevier]

For several years, veterinary oncologists have been struggling with the prognosis of mammary tumours in dogs and cats. Translation of tumour characteristics into prognostic information is an invaluable tool for the use of the most appropriate therapies, as well as for planning innovative therapeutic trials. Moreover, canine and feline spontaneous mammary gland tumours are good models for the study of human breast cancer. Collecting and interpreting information regarding the prognosis of canine and feline mammary tumours is difficult due to the fact that different methods have been applied to study various components and characteristics. This review identifies some of the challenges of prognostic studies of spontaneous canine and feline mammary tumours and suggests standardized procedures to overcome these challenges and facilitate reproducibility and assessment of results. [ABSTRACT FROM AUTHOR]

Abstract: Immunohistochemical detection of Cyclooxygenase (Cox)-1 and -2 enzymes in canine mammary tumours (CMT) has recently been described. However, the prognostic value of their expression needs to be established. The aim of this study was to investigate Cox (-1 and -2) prognostic value in malignant CMT by evaluating its correlation with clinicopathological parameters (tumour size, histological type, necrosis, lymph node metastasis) and with Disease Free Survival (DFS) and Overall Survival (OS). Twenty seven female dogs with malignant tumours were included. Cox-2 expression was associated with lymph node metastasis at surgery time, development of distant metastasis during follow-up (p =0.038), DFS (p =0.03) and OS (p =0.04). Multivariate survival analysis showed that Cox-2 did not retain its significance as an independent prognostic factor. For Cox-1 expression, no statistically significant association was observed. Present study suggests the usefulness of testing Cox-2 specific inhibitors as part of an adjuvant therapy in female dogs with malignant mammary neoplasias. [Copyright &y& Elsevier]

Summary: Inflammatory mammary carcinoma (IMC) is the most aggressive type of mammary tumour in the dog and has been proposed as a model for human inflammatory breast cancer. The aim of this study was to investigate angiogenesis in canine IMC by immunohistochemical assessment of the expression of vascular endothelial growth factor (VEGF). Tissues from 19 cases of IMC were compared with tissues from 27 cases of invasive mammary carcinoma without inflammation (non-IMC). Immunohistochemical expression of oestrogen receptor (ER), progesterone receptor (PR) and HER-2 receptor was also assessed. VEGF was strongly expressed in all IMCs and the percentage of VEGF-immunoreactive tumour cells was significantly higher in IMC than in non-IMC (P =0.02). There was no difference in HER-2 receptor expression between IMC and non-IMC, and no IMC expressed ER or PR. These results suggest that VEGF may contribute to the high angiogenic phenotype of canine IMC and that this expression may underlie the tendency towards local and systemic metastasis of these tumours. [Copyright &y& Elsevier]

Interferons (IFNs) are naturally produced cytokines with multiple important biological functions. The activity of recombinant feline IFN-ω (rFeIFN-ω) alone and in combination with chemotherapeutic drugs was tested on canine and feline mammary carcinoma cell lines (REM134 and CAT-MT) and putative tumour-initiating cells (TIC) derived from these cell lines by sphere assay. Viability was measured by chemoluminescence and a one-way analysis of variance and Student's t-tests were used for statistical analysis. rFeIFN-ω showed in vitro antitumour activity on feline and canine mammary carcinoma cells and putative TICs with a dose-dependent and target cell-specific action. Putative TICs were more resistant to the action of rFeIFN-ω compared with daughter REM134 and CAT-MT cells. REM134 cells and TICs were more sensitive to rFeIFN-ω compared with the feline counterparts. An additive effect was noticed between rFeIFN-ω and conventional anticancer drugs, in particular following co-culture of cells with anthracycline drugs. The results suggest that rFeIFN-ω warrants further investigation as a therapeutic adjunct in feline and canine mammary tumours. [ABSTRACT FROM AUTHOR]