Comparative aspects and clinical outcomes of canine renal hemangiosarcoma

BACKGROUND: Hemangiosarcoma (HSA) is a common solid tumor of the spleen, heart, and skin of dogs. Renal HSA represents an uncommon anatomic variant, with little reported about its biologic behavior and clinical outcome. HYPOTHESIS: That renal HSA is associated with longer survival than other visceral forms of HSA. ANIMALS: 14 dogs with renal HSA. METHODS: Medical records from 1999 to 2004 were searched for dogs with histopathologically confirmed renal HSA, and data relevant to clinical signs, treatments, and outcomes were abstracted. RESULTS: Clinical signs were nonspecific, and the median duration of clinical signs before diagnosis was 60 days. Two dogs presented in cardiovascular collapse secondary to hemoperitoneum. Common hematologic and biochemical abnormalities were anemia (9/14), hematuria (7/14), and proteinuria (7/14). One dog had pulmonary metastasis at diagnosis. All dogs had evidence of a renal mass visualized by abdominal radiography (14/14), ultrasound (9/14), or both. All dogs underwent nephrectomy, and 4/14 dogs also received adjunctive chemotherapy. Median survival time of all dogs was 278 days (range 0-1,005 days), and dogs with hemoperitoneum had significantly shorter survival times than dogs without hemoperitoneum (62 days versus 286 days, P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: These results indicate that hemoperitoneum and distant metastasis at diagnosis appear to occur less frequently in dogs with renal HSA compared with other visceral forms of HSA. Furthermore, dogs with renal HSA have protracted disease progression, with improved 1-year survival rates and longer median survival time compared to dogs with splenic, cardiac, and retroperitoneal HSA.     

Efficacy and toxicity of a dose-intensified doxorubicin protocol in canine hemangiosarcoma

The purpose of this study was to evaluate the efficacy and toxicity of a single-agent, dose-intensified doxorubicin protocol in canine hemangiosarcoma (HSA). Canine HSA is a highly malignant tumor, and most affected dogs die within 6 months of diagnosis. Doxorubicin is the most, and possibly the only, effective chemotherapeutic drug for this malignancy, but it provides only moderate improvement in survival. On the basis of previous studies reporting similar survival in dogs treated with doxorubicin as a single agent and doxorubicin-based combination chemotherapy and the concept of summation dose intensity, a dose-intensified single-agent doxorubicin protocol was initiated. Twenty dogs with HSA were recruited to participate in this study. Workup and staging were performed according to standard practice. Chemotherapy was initiated within 3 weeks of surgery. Doxorubicin was scheduled to be administered at 30 mg/m2 i.v. every 2 weeks for a total of 5 treatments. The dogs were monitored for toxicity and signs of recurrence during and at regular intervals after chemotherapy. The protocol was tolerated well. No dogs were hospitalized because of adverse effects or developed clinical signs consistent with doxorubicin-induced cardiomyopathy. There was a significant difference in survival in dogs with stage I and I1 HSA compared with dogs with stage III HSA. with median survival times of 257, 210, and 107 days, respectively. These results are slightly better than the historical control with respect to toxicity and efficacy but are not statistically different from what is achieved with standard treatments. There was no association between dose intensity and outcome.     

Biological and molecular characterization of a canine hemangiosarcoma-derived cell line

Canine hemangiosarcoma (HSA) is a devastating disease. Investigation of novel therapies has been limited by the limited availability of canine HSA-derived cell lines. We report the development of a canine HSA-derived cell line, DEN-HSA, which recapitulates features of angiogenic endothelium. DEN-HSA cells were derived from a spontaneous HSA arising in the kidney of a dog. DEN-HSA displayed surface molecules distinctive of endothelial histogenesis, including factor VIII-related antigen, ICAM-1 and alpha(v)beta3 integrin. In vitro, DEN-HSA formed microvascular tube-like structures on Matrigel, and proliferated in response to a variety of angiogenic growth factors. The cells expressed mRNA and protein specific for bFGF and its receptors, and VEGF and its receptors, among others. DEN-HSA conditioned medium evoked a marked angiogenic response in a murine corneal pocket assay, indicating potent proangiogenic activity of substances secreted by this cell line. This research confirms the DEN-HSA cell line as endothelial in origin, suggests the presence of angiogenic growth factor autocrine loops, and offers the potential to utilize DEN-HSA cells for the study of novel therapies that modulate endothelial proliferation.     

Expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and its expected roles in the bovine endometrium during gestation

Extracellular matrix metalloproteinase inducer (EMMPRIN) and its induced matrix metalloproteinases (MMPs) play a crucial role in tissue remodeling during the peri-implantation period. However, the role of EMMPRIN in the bovine placenta is still unclear. We have postulated that EMMPRIN might play a regulatory role in trophoblastic cell functions during gestation by itself or through the regulation of MMP expression. In this study, EMMPRIN mRNA was detected in the bovine placentome and interplacentome throughout gestation, and its expression was significantly higher in the cotyledon during late gestation. In situ hybridization showed that EMMPRIN mRNA was expressed in the caruncular epithelium and the cotyledonary epithelium, including binucleate cells. Western blot analysis detected a band representing a protein of approximately 65 kDa in the caruncular and cotyledonary tissues, and the intensity of its expression was increased in both of these tissues during late gestation. The expression levels of MMP-2 and MMP-14 in the bovine placenta were higher during late gestation, as was observed for EMMPRIN. Therefore, EMMPRIN might regulate trophoblastic cell functions, especially those of binucleate cells, through MMP expression in the bovine placenta.     

Gene expressions of canine angiopoietin-1 and -2 in normal tissues and spontaneous tumours

The angiopoietin (Ang) family of proteins are central to the regulation of angiogenesis. The purposes of this study were to determine cDNA sequences of canine Ang-1 and Ang-2 and investigate their expressions in normal tissues and spontaneous tumours. The cDNA sequences of canine Ang-1 and Ang-2 were 1,494 and 1,488 bp, and the deduced amino acid sequences were 497 and 495 residues, respectively. The cDNA sequences of canine Ang-1 and Ang-2 showed high homology with those of the other mammalian species. Canine Ang-1 and Ang-2 mRNA were detectable in all 22 normal tissues and spontaneous tumours. Higher mRNA expression level of canine Ang-2 was demonstrated in mammary simple carcinomas, haemangiosarcoma and hepatocellular carcinoma in comparison with normal tissues.     

Influence of persistent canine distemper virus infection on expression of RECK, matrix-metalloproteinases and their inhibitors in a canine macrophage/monocytic tumour cell line (DH82)

A morbillivirus infection of tumour cells is known to exert oncolytic activity, but the mechanism of this inhibitory action has not been well defined. Matrix metalloproteinases (MMPs) are important enzymes degrading the extracellular matrix and are often upregulated in malignant neoplasms. Recent studies have demonstrated that RECK may potently suppress MMP-2 and -9 activity, thus inhibiting angiogenesis and metastasis. In this study, real time quantitative polymerase chain reaction (RT-qPCR) was used to determine the effect of persistent infection with canine distemper virus (CDV) infection on the expression of MMPs and their inhibitors (TIMPS) in a canine macrophage/monocytic tumour cell line (DH82). The activity of proMMP-2 and proMMP-9 was also verified zymographically. Following CDV infection, MMP-2, TIMP-1 and TIMP-2 were down-regulated, while RECK was upregulated. These findings suggest that CDV infection restores RECK expression in tumour cells and may interfere with the intracellular processing of MMPs and TIMPs, thus possibly influencing tumour cell behaviour beneficially for the host. However, this needs to be verified in in vivo studies.     

Treatment of canine leproid granuloma syndrome: preliminary findings in seven dogs

OBJECTIVE: To determine effective treatment strategies for patients with refractory canine leproid granuloma syndrome. DESIGN: Multi-institutional retrospective/prospective case series using client-owned dogs. PROCEDURE: Seven dogs (four Boxers, one Dobermann, one Bullmastiff and one Bullmastiff cross-bred; ages 3 to 11 years) with leproid granulomas were treated successfully using a variety of treatment regimens. These cases were recruited because: lesions were either widely distributed over the dog; progressive, despite routine therapy, or were associated with particularly disfiguring lesions. The treatment regimen evolved during the course of the clinical study. RESULTS: Combination therapy using rifampicin (5 to 15 mg/kg p.o., every 24 h) and clarithromycin (8 to 24 mg/kg p.o. daily; dose divided every 8 or every 12 h) was used most frequently and proved to be effective and free from side effects. Total daily doses of clarithromycin in excess of 14 mg/kg were considered optimal and long treatment courses, in the order of 1 to 3 months, were used. Combination therapy using rifampicin (25 mg/kg; that is, higher than the recommended dose) and clofazimine was effective in one case, but resulted in hepatotoxicity. A topical formulation of clofazimine in petroleum jelly was used as an adjunct to oral rifampicin and doxycycline in another patient treated successfully. CONCLUSION: Based on our evolving clinical experience, a combination of rifampicin (10 to 15 mg/kg p.o., every 24 h) and clarithromycin (15 to 25 mg/kg p.o. total daily dose; given divided every 8 to 12 h) is currently recommended for treating severe or refractory cases of canine leproid granuloma syndrome. Treatment should be continued (typically for 4 to 8 weeks) until lesions are substantially reduced in size and ideally until lesions have resolved completely. A topical formulation, containing clofazimine in petroleum jelly may be used as an adjunct to systemic drug therapy. Further work is required to determine the most cost effective treatment regimen for this condition.     

Treatment of canine mast cell tumours with prednisolone and radiotherapy

This retrospective study describes 35 dogs with non‐resectable, grade I–III mast cell tumours on the head or limb treated with prednisolone (40 mg m^?2 daily) for 10–14 days prior to radiotherapy (4 × 800 cGy fractions at 7‐day intervals) from a 4 MV linear accelerator. Prednisolone was continued at a reduced dose rate (20 mg m^?2) during radiotherapy and for 2 months or longer afterwards. Eighteen of 24 tumours (75%) decreased in size in response to prednisolone treatment. By 6–8 weeks following radiotherapy, 12 dogs had achieved a complete remission and 19 a partial response. Two tumours remained static and two progressed during the course of treatment. The overall response rate was 88.5%. With long‐term follow‐up, 11 dogs experienced local recurrence (n = 4), metastasis (n = 5) or both (n = 2). The median progression‐free interval was 1031 days (95% CI 277.44–1784.56, Kaplan–Meier), with 1‐ and 2‐year progression‐free rates of 60 and 52%, respectively. Tumour grade did not predict the prognosis for this group of dogs, but tumour location did affect the outcome. Dogs with tumours located on the limb survived longer than those with tumours on the head. The combination of prednisolone with radiotherapy appears to have a useful role in the management of measurable mast cell tumours sited on the head and distal extremities.     

Incidence of canine dysautonomia in Missouri,USA, between January 1996 and December 2000

A cross-sectional survey of 217 veterinary facilities in Missouri, USA, was conducted to gather information about the occurrence of canine dysautonomia between January 1996 and December 2000. The state was divided into seven geographic regions for sampling, and 40 veterinary facilities from each region were selected randomly by computer-generated numbers to receive the questionnaire. Veterinarians from 74% (95% CI: 69, 79) of clinics in the state that saw canine patients were aware of dysautonomia prior to receiving the survey, and 43 respondents from five of the seven sampled regions stated that dysautonomia had been diagnosed in their practices during the study period. Respondents had diagnosed 182 cases of dysautonomia, leading to an estimated statewide total of 609 (95% CI: 272, 946) cases over the 5 years. Regional incidence estimates ranged from 0 to 1.91 cases per 10,000 dog years at risk. Case-fatality risk was 92%.     

Comparison of the VIDAS and IMMULITE‐2000 methods for cortisol measurement in canine serum

Background: Serum cortisol concentration is often measured in dogs for the diagnosis and monitoring of adrenal disease. An enzyme‐linked fluorescent assay (VIDAS method) on the MiniVidas analyzer has been validated for the measurement of cortisol concentration in human serum and could have applications for canine samples. Objective: The aim of this study was to compare canine cortisol results obtained using the VIDAS method with those obtained using the IMMULITE‐2000 immunoassay, which has previously been validated for canine serum. Methods: The concentration of cortisol in 40 canine serum samples was determined concurrently with the VIDAS and IMMULITE methods, the latter as the reference method. Pearson's correlation coefficient, linear, and Deming regression analyses and Bland–Altman analysis were used to compare the 2 methods. Acceptability of the new method was judged using a medical decision chart (MEDx chart). Results: Cortisol concentrations obtained with the IMMULITE method ranged from 23.1 to 1380 nmol/L. Correlation (r=.977) and simple linear regression (slope=1.0722, confidence interval [CI] 0.996–1.148; intercept=?4.799, CI ?42.838 to 33.240) revealed no proportional or constant error. Based on Deming regression and a Bland–Altman plot the 2 methods gave comparable results. The MEDx chart indicated that performance of the new method was good at decision limits of 40, 132, and 480 nmol/L. Conclusion: Results of the VIDAS method were comparable to those of the IMMULITE‐2000 reference method such that the VIDAS may be used as an alternative assay to evaluate serum cortisol concentration in dogs for the diagnosis of adrenal disease.     

The Treatment of Acute Glaucoma in Dogs and Cats

Objective: Glaucoma is an optic nerve disease that may result in rapid loss of vision. Early detection of acute glaucoma and aggressive treatment is important to preserve vision. Continued treatment is indicated in chronic glaucoma to alleviate discomfort associated with chronic elevated intraocular pressure.
Etiology: In primary glaucoma, an abnormal iridocorneal angle results in obstruction to outflow of aqueous humor. In secondary glaucoma, an otherwise normal iridocorneal angle is obstructed by abnormalities such as a luxated lens, neovascular membranes or inflammatory material.
Diagnosis: The diagnosis is made by a combination of clinical signs such as corneal edema, mydriasis, decreased vision, episcleral hyperemia, and confirmed by measuring an elevation in intraocular pressure. Complete ophthalmic examination, knowledge of breed predisposition to various ocular diseases and gonioscopy will aid in distinguishing between primary and secondary glaucoma
Therapy: Aggressive medical management is important in acute glaucoma. Surgical procedures are often indicated after initial emergency medical treatment of acute glaucoma. Chronic, painful blind eyes are best treated with one of various surgical procedures.
Prognosis: The prognosis for maintaining vision or regaining temporarily lost vision in acute glaucoma is related to numerous factors including time between onset of clinical signs and appropriate treatment, etiology of the glaucoma, initial response to therapy and client compliance.     

Feline conjunctival hemangioma and hemangiosarcoma: a retrospective evaluation of eight cases (1993-2004)

The purpose of this retrospective study was to evaluate feline primary conjunctival vascular tumors of endothelial origin. Eight cases (six hemangiomas, two hemangiosarcomas) from a collection of 3460 feline submissions between 1993 and 2004 were evaluated using routine hematoxylin and eosin (H&E). Signalment, location, size, duration, epithelial pigmentation, margins, adjuvant therapy, outdoor activity, and geographic location, comparing ultraviolet (UV) radiation levels by state, were recorded. Follow-up information was available for five cases. In this study, the average age was 10.6 years, with neutered males over-represented. The Domestic Short-haired cat was most commonly affected. The most common anatomic site was the nictitating membrane, with the left eye preferentially affected. The average size and duration, prior to presentation, was 7.5 mm and 4.4 months, respectively. Seven of eight cases were devoid of epithelial pigmentation in nonaffected areas and the majority of cases were from states with high annual UV-light exposure. Only cases of hemangiosarcoma underwent surgical re-excisions following incomplete excision; however, no further recurrences were reported. No cases evaluated had evidence of metastatic disease at the time of excision. Surgical excision alone may be curative. However, recurrence is possible. These tumors demonstrate similar predilection sites and involvement of nonpigmented epithelium, as is true in canine cases, which may relate to risk factors as well.     

Canine conjunctival hemangioma and hemangiosarcoma: a retrospective evaluation of 108 cases (1989-2004)

Canine conjunctival tumors of vascular endothelial origin are common, although under-reported. The purpose of this study was to evaluate the epidemiology of and potential risk factors for these tumors. This study evaluated 108 cases (70 hemangiomas, 38 hemangiosarcomas) from 8300 canine submissions between 1989 and 2004. Signalment, location, pigmentation, size, duration, diagnosis, margins, ancillary therapy, and geographic location were recorded. Follow-up information was available for 49 cases. Each case was matched with two unaffected controls and compared using logistic regression analysis. Average age upon presentation was 8.6 years; there was no sex predilection. Risk of conjunctival tumors was statistically different among breed groups (P = 0.0010), demonstrating a propensity to occur in groups likely to have increased outdoor activity. Primary involvement occurred within nonpigmented epithelium along the leading edge of the nictitating membrane (41/108) and temporal bulbar conjunctiva (33/108). The etiology remains unknown; however, the strong site predilection, involvement of nonpigmented epithelium, and development within specific breed classes strongly suggest ultraviolet (UV) light as a significant risk factor. In a full-logistic model including breed, gender, age, and UV exposure, UV was not a statistically significant variable (P = 0.1215). In a reduced-model including UV only, significance was approached (P = 0.0696) and posthoc contrast demonstrated a significant linear trend with increasing UV exposure (P = 0.0147). In separate analysis of risks associated with hemangiosarcoma, compared with hemangioma, breed was not significant while increasing UV exposure was significant (P = 0.0381). Early surgical therapy is recommended and may be curative; however, recurrence is possible and more likely with hemangiosarcomas (11/20).     

Treatment of canine generalized demodicosis associated with hyperadrenocorticism with spot-on moxidectin and imidacloprid

Background

Canine generalized demodicosis associated with hyperadrenocorticism is often problematic and might be intractable. The aim of this study was to report the efficacy of a weekly application of spot-on moxidectin/imidacloprid in dogs with hyperadrenocorticism and secondary generalized demodicosis.

Methods

Dogs with hyperadrenocorticism and secondary generalized demodicosis were included. The condition of hyperadrenocorticism was treated and stabilized with trilostane before and throughout the study period in all dogs.

Results

Average total live adult mite counts before treatment and after four, eight and 12 weeks of spot-on moxidectin/imidacloprid (2.5/10 mg/kg) applications were 20.1 ± 6.3 (range, 13–33), 0.5 ± 0.7 (range, 0–2; 6/11 were negative), 0.2 ± 0.4 (range, 0–1; 9/11 were negative), 0.2 ± 0.4 (range, 0–1; 9/11 were negative) and 0.1 ± 0.3 (range, 0–1; 10/11 were negative) respectively; this difference was significant (P < 0.001). Ten of 11 dogs (90.1%) achieved clinical remission, as demonstrated by the absence of demodectic mites at any life stage at monthly scrapings for eight consecutive weeks, and maintained remission throughout the 12-month follow-up period.

Conclusion

The weekly application of spot-on moxidectin/imidacloprid appeared to be effective and safe against generalized adult onset canine demodicosis associated with hyperadrenocorticism.