Immunohistochemical characterization of neuroendocrine differentiation of canine anal sac glandular tumours.

Histological features and expression of neuroendocrine markers were examined in 69 samples of canine anal sac glandular carcinomas (ASGCs). The tumours were classified into solid, rosette and tubular types and mixtures of these types. Tumour-associated death in dogs with solid tumours and mixed tumours with solid components was higher than in dogs with rosette and tubular type tumours. Chromogranin A immunoreactivity was observed in 28 of 69 samples (40.6%) irrespective of histological type and was localized to the marginal areas of the tumour nest and the basal areas of the tubular and rosette structures. Neuron-specific enolase immunoreactivity in neoplastic epithelial cells was observed in 32 cases (46.4%) and was less frequently observed in the tubular type (14.3%). Synaptophysin expression was present in 15.9% of cases and was least frequent in the tubular type. Twenty-one of the 69 samples expressed more than two neuroendocrine markers and were classified as carcinomas with neuroendocrine differentiation. There was no relationship between neuroendocrine differentiation and clinical outcome. These results suggest that some ASGCs have neuroendocrine differentiation regardless of histological pattern, but clinical outcome is more related to the histological pattern than to neuroendocrine differentiation.

Tumour endothelial marker-1 is expressed in canine Haemangiopericytomas.

The aim of this study was to characterize immunohistochemically 18 cases of canine haemangiopericytoma (CHP) using two new candidate markers for pericytes, tumour endothelial marker (TEM)-1 and new glue (NG)-2, as well as the conventional mesenchymal cellular markers, vimentin, α-smooth muscle actin (α-SMA), desmin and von Willebrand factor (vWF). Because pericytes may have the same origin as endothelial or smooth muscle cells or the same differentiation potential as myofibroblasts, 17 cases of leiomyosarcoma (LMS), 20 cases of haemangiosarcoma (HS) and three cases of myofibroblastic sarcoma (MFS) were also examined. Expression of TEM-1 by >10% of the neoplastic population was observed in 94.4% (17/18) of haemangiopericytomas, 23.5% (4/17) of LMSs, 30.0% (6/20) of HSs and 66.7% (2/3) of MFSs. NG-2 expression by >10% of the neoplastic population was observed in 16.7% (3/18) of haemangiopericytomas, 52.9% (9/17) of LMSs, 0% (0/20) of HSs and 33.3% (1/3) of MFSs. Vimentin was expressed by all of tumours. In haemangiopericytoma, the incidence of positive immunoreactivity in >10% of the neoplastic population was 5.6% (1/18) for both α-SMA and desmin and 0% (0/18) for vWF. Considering the phenotypic features of cells expressing TEM-1, CHPs are thought to originate from immature vascular mural cells sharing their phenotype with myofibroblasts. NG-2 expression may be a phenotype of smooth muscle cells rather than pericytes in dogs.

Gingival rhabdomyosarcoma accompanied by an immature myogenic population immunoreactive for α-smooth muscle actin in a dog.

A 3-year-old female shih tzu was presented with a white to dark red mass arising from the gingiva. Because of the rapid and invasive growth of the mass, the dog was humanely destroyed. Microscopically, round to polygonal anaplastic cells with strongly eosinophilic cytoplasm grew in an alveolar pattern separated by fibrous stroma. Mitotic figures were numerous. Multinucleated cells and 'strap cells' were observed, but cross striation and glycogen accumulation were absent. Immunohistochemically, the tumour cells were positive for vimentin, desmin, muscle-specific actin and MyoD1, and a small number of tumour cells were positive for α-smooth muscle actin (α-SMA). Based on the morphological and immunohistochemical features, the gingival mass was diagnosed as alveolar rhabdomyosarcoma accompanied by α-SMA-positive immature myogenic cells.

Pancreatic carcinosarcoma in a cat.

A 10-year-old female American shorthair cat was presented for evaluation of weight loss. An intra-abdominal mass was found on ultrasonography and laparotomy was performed. The mass was located in the left uterine horn and further masses were found in the pancreas, greater omentum and diaphragm. Microscopical examination revealed that the pancreatic mass had epithelial and mesenchymal components, which on immunohistochemistry expressed cytokeratin and vimentin, respectively. In addition, some spindle cells expressed vimentin and E-cadherin, which might suggest epithelial to mesenchymal transition. In contrast, the uterine, omental and diaphragmatic masses had only mesenchymal composition. The pancreatic lesion is proposed to be a primary carcinosarcoma with metastasis of only the mesenchymal component to distant sites. This the first report of pancreatic carcinosarcoma in a cat.

Low-grade myofibroblastic sarcoma of the maxillary region in a dog.

A subcutaneous tumour was identified in the maxillary region of a 14-year-old mixed breed dog. This tumour had grown rapidly over 2 weeks. Microscopically, the tumour had ill-defined borders and was composed of bundles and whorls of atypical spindle cells accompanied by abundant collagen fibres. Immunohistochemically, neoplastic cells were immunoreactive for vimentin, α-smooth muscle actin and calponin and negative for S100 protein, von Willebrand factor, desmin and smoothelin. These results suggested that the neoplastic cells were derived from myofibroblasts and that the tumour was a low-grade myofibroblastic sarcoma.

Spermatocytic seminoma with neuroectodermal differentiation and sertoli cell tumor in a dog.

Two distinct nodules developed in a cryptorchid testis of an 8-year-old male West Highland White Terrier. One nodule was a Sertoli cell tumor. The other was a spermatocytic seminoma with focal primitive neuroectodermal differentiation: formation of Homer-Wright rosettes and perivascular pseudorosettes, with immunoreactivity for S-100 protein, neuron-specific enolase, synaptophysin, neurofilament-68 kDa, microtubule-associated protein 2, and vimentin. The dog was alive and healthy 2 years after castration.

Fifty-two week chronic toxicity of enzymatically decomposed rutin in Wistar rats.

The chronic toxicity of enzymatically decomposed rutin, which consists mainly of isoquercitrin, was evaluated in male and female Wistar rats with dietary administration at concentrations of 0%, 0.04%, 0.2%, 1% and 5% for 52 weeks. No toxicological findings were found in the mortality, body weights, food consumption, hematology, clinical biochemistry or organ weights in either sex. Obvious clinical signs were chromaturia that could be attributed to the color of test substance in the 5% groups of both sexes. Coloration of the urine collected over 24h in the 1% and 5% groups of both sexes was noted. Increased daily urinary calcium excretion was observed in the 5% groups of both sexes and an increase in urinary calcium concentration was observed in the male 5% group. On histopathological examination, incidences of mineralization, inflammatory cell debris, inflammatory cell infiltration and/or transitional cell hyperplasia in the renal pelvis were increased in the 5% male group, whereas treated females showed no apparent difference in these incidences. Based on the above findings, the no observed adverse effect level (NOAEL) was estimated to be 1% in both sexes (542.4 mg/kg body weight/day for males and 674.0mg/kg body--weight/day for females).

Prostate cancer screening strategies with re-screening interval determined by individual baseline prostate-specific antigen values are cost-effective.

AIMS: To determine whether prostate cancer screening strategies with re-screening interval determined by individual baseline prostate-specific antigen values are cost-effective. METHODS: Based on the results of an actual contemporary screening program, we established Markov decision analytic models of prostate cancer screening with personalized re-screening interval strategies using cutoff baseline PSA levels for biennial screening as well as a model of uniformly annual or biennial screening. These strategies were compared in terms of cumulative incidence of early cancer and cost-effectiveness. RESULTS: Early cancer detection rates were similar among all strategies. Personalized strategies were more cost-effective compared to uniform screening strategies. If all participants with negative PSA results uniformly omit annual screening, it would be more costly but less effective (dominated). Contrary, annual screening for all participants would cost too much. These results were robust throughout sensitivity analysis incorporating every assumption in the models. CONCLUSIONS: This study adds important evidence that personalized rescreening strategies based on individual baseline PSA have advantages of cost-effectiveness against conventional uniform strategies.

Chronic toxicity and carcinogenicity of dietary administered ammonium sulfate in F344 rats.

Chronic toxicity and carcinogenicity studies of ammonium sulfate, used as a food additive in fermentation, were performed in male and female Fisher 344 rats at dietary concentrations of 0%, 0.1%, 0.6% and 3.0% in a 52-week toxicity study and 0%, 1.5% and 3.0% in a 104-week carcinogenicity study. Treatment with ammonium sulfate caused significant increase in kidney and/or liver weights in males and females of the 3.0% diet group, but no effects were found on survival rate, body weights, and hematological, serum biochemical or histopathological parameters at any dose levels in the chronic toxicity study. Regarding carcinogenicity, ammonium sulfate did not exert any significant influence on the incidences of tumors in any of the organs and tissues examined. It was concluded that the no observed adverse effect level of ammonium sulfate was the 0.6% diet, which is equivalent to 256 and 284 mg/kg b.w./day in males and females, respectively, and the compound is non-carcinogenic under the conditions of the study.

A histological study of the cardiac conduction system in a heifer with complete atrioventricular block.

A case of complete atrioventricular (AV) block of congenital origin in a 16-month-old Holstein heifer was studied histologically with serial sectioning of the cardiac conduction system. The heart was enlarged and showed moderate dilatation of the left and right ventricles. Histologically, the abnormally placed and poorly formed AV bundle was observed in association with abnormality in the tricuspid extension of the central fibrous body, suggesting that the pathological state of the AV bundle had been responsible for the complete AV block. This type of anatomical fault in the AV bundle is considered to be part of an embryological, developmental malformation of the central fibrous body.

Thyroid lesions and dioxin accumulation in the livers of jungle crows (Corvus macrorhynchos) in urban and suburban Tokyo.

Wild jungle crows (Corvus macrorhynchos) captured from three different areas of Tokyo were examined to evaluate environmental contamination of dioxins. In addition to the pathologic examination of their whole body, accumulation of dioxins, mRNA expression of the aryl hydrocarbon receptor (AhR), and pentoxyresorufin-O-depenthylase (PROD) activity in the liver were determined. Marked histopathologic changes were observed in the thyroid glands, especially in the crows from the urban downtown area. Levels of dioxins and their toxic equivalents (TEQs) and AhR mRNA expression in the livers of the crows from the urban area were higher than those from the suburban area. There was a high correlation between the levels of TEQs and PROD activity. The results of the present study demonstrated that jungle crows possess AhR-mediated toxicologic pathways similar to those of mammals and suggest the possibility that the thyroidal changes observed in the adult crows from the urban areas are one of the toxic manifestations resulting from exposure to dioxins and other environmental chemicals.

Development of pericardial mesothelioma in golden retrievers with a long-term history of idiopathic haemorrhagic pericardial effusion.

This report describes the development of pericardial mesothelioma in five golden retrievers with a long-term history of idiopathic haemorrhagic pericardial effusion (IHPE). These five dogs were treated with repeated pericardiocentesis for recurrent episodes of pericardial fluid accumulation; other than IHPE, all potential causes of this fluid accumulation were ruled out by the results of diagnostic imaging and cytology and bacterial or fungal culture of fluid obtained during pericardiocentesis. In three dogs that eventually underwent pericardiectomy, neoplastic lesions were not detected in any organs or tissues within the thoracic cavity during the surgical procedure, and the surgical biopsies were consistent with IHPE. In one of the three dogs, however, cytology of recurrent thoracic effusion revealed clusters of neoplastic mesothelial cells from 1 month after surgical intervention until death. The clinical course of the disease ranged from 30 to 54 months between the first visit and death, and on post-mortem examination pericardial mesothelioma was diagnosed in all five dogs. The clinical observations, together with the breed and age of the affected animals, suggested that the five dogs initially suffered from IHPE, which was then followed by the development of pericardial mesothelioma. It is possible that IHPE is associated with the development of pericardial mesothelioma in golden retrievers through a chronic inflammatory process.

Evaluation of the toxicity of enzymatically decomposed rutin with 13-weeks dietary administration to Wistar rats.

The subchronic toxicity of enzymatically decomposed rutin, which consists mainly of isoquercitrin, was investigated in male and female Wistar rats with dietary administration at concentrations of 0, 0.2, 1 and 5% for 13 weeks. No mortality or abnormal clinical signs were observed throughout the experimental period in any groups. Body weight gain was reduced from week 10 to the end of the experiment in the 5% dosed males as compared to the 0% controls. Decreased erythrocytic parameters, i.e. red blood cell count, hemoglobin concentration and hematocrit, and significantly lowered serum triglyceride levels were also detected in the 5% males. Organ weight measurement, macro and microscopic observation revealed no test substance-related toxicological changes. Based on the above findings, no-observed-adverse-effect levels (NOAELs) for male and female rats were estimated to be 1 and 5%, respectively, translating into 539 and 3227 mg/kg b.w./day.

Smooth muscle hamartoma of the abomasum in a calf.

This report describes a case of smooth muscle hamartoma of the abomasum in a 6-month-old steer humanely killed because of severe pneumonia. At necropsy, marked thickening of the abomasal wall in the area of the pylorus was found. On cut section, the thickness of the submucosal layer, extending from the submucosa to the muscularis propria, was seen to be increased to 3 cm. The upper (i.e., nearest to the gut lumen) half of the sectioned thickening was composed mainly of adipose-like tissue and the lower half mainly of muscle-like tissue. Histologically, the submucosal layer was composed of fibroadipose tissue, within which were embedded, to varying degrees, numerous well-defined, haphazardly oriented, thin to thick bundles of smooth muscle fibres. This appears to be the first report of smooth muscle hamartoma of the stomach or abomasum in animals, including man.

Sequential analysis of testicular lesions and serum hormone levels in rats treated with a Psoralea corylifolia extract.

In order to clarify pathogenetic targets for the testicular toxicity of a extract of Psoralea corylifolia (P. corylifolia), F344 rats were fed diet containing 3% P. corylifolia extract for up to 12 weeks and subjected to hormone assays and histopathological examination on the testis and epididymis at weeks 1, 2, 4, 8 and 12 (Exp 1). Similar analyses were performed on 1, 3, 7 and 14 days after a single gavage administration of the P. corylifolia extract at a dose of 10 g/kg b.w. (Exp 2). In Exp 1, increase in the numbers of degenerated and exfoliated germ cells and loss of elongated spermatids beyond steps 7 or 8 were initially observed in the seminiferous tubules at week 1, followed by more pronounced degeneration of germ cells with depletion of post-meiotic populations from week 2. The tubular degeneration was associated with Leydig cell atrophy and persistent reduction of serum testosterone and FSH levels throughout the treatment period and a slight reduction of serum LH in later stages. In Exp 2, reduction of serum testosterone and FSH levels preceded degeneration of germ cells in stage VII and VIII tubules at 3 and 7 days after the administration. The results suggest that rapid androgen deprivation reflecting direct interference with Leydig cell function and simultaneous disturbance of the pituitary-testicular axis play pivotal roles in P. corylifolia extract-induced germ cell injury in seminiferous tubules.

Transgenic tumor models for carcinogen identification: the heterozygous Trp53-deficient and RasH2 mouse lines.

Genetically altered mouse models (GAMM) for human cancers have been critical to the investigation and characterization of oncogene and tumor suppressor gene expression and function and the associated cancer phenotype. Similarly, several of the mouse models with defined genetic alterations have shown promise for identification of potential human carcinogens and investigation of mechanisms of carcinogen-gene interactions and tumorigenesis. In particular, both the B6.129N5-Trp53 mouse, heterozygous for a p53 null allele, and the CB6F1-RasH2 mouse, hemizygous for the human H-ras transgene, have been extensively investigated. Using 26-week exposure protocols at or approaching the maximum tolerated dose, the summary results to date indicate the potential for GAMM to identify and, possibly, classify chemicals of potential risk to humans using short-term carcinogenicity experiments. This IWGT session focused on: (1) the development of recommendations for genetic/molecular characterization required in animals, tissues, and tumors before and after treatment for identification of presumptive human carcinogens based on the current state of knowledge, (2) identification of data gaps in our current state of knowledge, and (3) development of recommendations for research strategies for further development of our knowledge base of these particular models. By optimization of protocols and identification of significant outcomes and responses to chemical exposure in appropriate short-term mechanism-based genetically altered rodent models, strategies for prevention and intervention may be developed and employed to the benefit of public health.

Primary malignant mixed mesenchymal tumour of the heart in a dog.

A case of primary malignant mixed mesenchymal tumour of the heart in an 8-year-old golden retriever is described. The cardiac tumour, measuring 2.5 x 3 x 5 cm, was located in the posterior part of the atrial septum, extending into the surrounding region. Histologically, the tumour was composed of multiple mesenchymal elements of fibrosarcoma, rhabdomyosarcoma, liposarcoma and chondrosarcoma. No previous reports of such a tumour occurring in the heart of the dog were found in the literature.

Myocardial hamartoma of the right atrium in a dog.

A myocardial hamartoma of the right atrium is described in an 8-year-old dog that died from pneumonia. At necropsy, a firm, mottled, dark-brown right atrial appendage, of normal shape but slightly enlarged, was found incidentally. On section, the right atrial appendage was composed of a grey-tan, solid mass. Histological features of the mass were as follows: the component cells were mature cardiac muscle cells; the mass contained all of the components of the normal heart wall (i.e., epicardium, myocardium and endocardium), but the arrangement of the component tissues was disorganized; growth of the mass was non-invasive, and continuity of the component cells with adjacent normal myocardial cells was evident, suggesting a congenital origin. This appears to be the first report of congenital myocardial hamartoma in any animal other than man.

Iron lactate induction of pancreatic and endometrial proliferative lesions and a lack of increased tumors in a 104-week carcinogenicity study in F344 rats.

Iron lactate has been used as a food additive for iron supplementation. The present study was conducted to determine whether it might have carcinogenic potential. A total of 150 male and 150 female Fischer 344 rats were divided into three groups and fed basal diet containing 0, 1 or 2% of iron lactate for 104 weeks. No iron lactate-induced tumors were observed in any groups, although the incidences of pancreatic acinar cell and endometrial gland hyperplasias were increased in males and females, respectively, in the 2% group. Thus our in vivo animal data indicate that iron lactate lacks carcinogenicity in male and female F344 rats. However, estrogenic effects might be concluded based on the data for endometrial lesions. In a second experiment, an estrogen responsive rat pituitary tumor cell line, MtT/Se, and a human breast cancer cell line, MCF-7, were therefore employed to examine the estrogenic potential of iron lactate with regard to receptor binding affinity and ERE-reporter gene activation. Results in both cases were negative. Further investigations are needed to elucidate the mechanisms of induction of pancreatic and endometrial proliferative lesions by iron lactate.