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In recent years, extracellular vesicles (EVs) have emerged as prominent mediators of the homeostasis, repair, and regeneration of musculoskeletal tissues including bone, skeletal muscle, and cartilage. Accordingly, the therapeutic potential of EVs for regenerative medicine applications has not gone unnoticed. The use of EVs for the treatment of musculoskeletal injury and disease in veterinary species is a nascent but rapidly expanding area of research. Recent studies in this area have demonstrated the safety and feasibility of EV products in dogs and horses. While early clinical responses to EV-based therapeutics in companion animals have been favorable, more rigorously designed, sufficiently powered, and placebo-controlled clinical trials are required to fully elucidate the clinical benefits and best-use scenarios for EV therapeutics in veterinary medicine. Additionally, clinical translation of EV-based therapeutics will require Good Manufacturing Practice–compliant methods to scale up and purify EV products. Despite these challenges, EVs hold great promise in the regenerative medicine landscape, particularly in the treatment of musculoskeletal injury and disease in companion animals.

Open access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To categorize histologic lesions affecting the tongue, determine the frequency with which they develop, and identify risk factors associated with their development in dogs.

Design—Retrospective case series.

Animals—1,196 dogs.

Procedures—Diagnostic reports of lingual biopsy specimens from dogs evaluated from January 1995 to October 2004 were reviewed.

Results—Neoplasia comprised 54% of lingual lesions. Malignant tumors accounted for 64% of lingual neoplasms and included melanoma, squamous cell carcinoma, hemangiosarcoma, and fibrosarcoma. Largebreed dogs, especially Chow Chows and Chinese Shar-Peis, were at increased risk for melanoma. Females of all breeds and Poodles, Labrador Retrievers, and Samoyeds were more likely to have squamous cell carcinomas. Hemangiosarcomas and fibrosarcomas were commonly diagnosed in Border Collies and Golden Retrievers, respectively. Benign neoplasms included squamous papilloma, plasma cell tumor, and granular cell tumor. Small-breed dogs, especially Cocker Spaniels, were at increased risk for plasma cell tumors. Glossitis accounted for 33% of diagnoses; in most cases, the inciting cause was not apparent. Whereas large-breed dogs were more likely to have lingual neoplasia, small-breed dogs were more likely to have glossitis. Calcinosis circumscripta accounted for 4% of lingual lesions and predominately affected young large-breed dogs. The remaining submissions consisted mostly of various degenerative or wound-associated lesions.

Conclusions and Clinical Relevance—The frequency of lingual lesions was not evenly distributed across breeds, sexes, or size classes of dogs. Veterinarians should be aware of the commonly reported lingual lesions in dogs so that prompt diagnosis and appropriate management can be initiated.

Restricted access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To determine the efficacy of primary re-excision alone for treatment of soft tissue sarcomas after recent incomplete resection, the frequency and clinical importance of detecting residual tumor in resected scars, and prognostic factors associated with the procedure.

Design—Retrospective case series.

Animals—41 dogs.

Procedures—Medical records of dogs that had undergone recent incomplete excision of a soft tissue sarcoma at a referring veterinary practice and subsequent re-excision of the scar at the Colorado State University Veterinary Medical Center were reviewed.Owners and referring veterinarians were contacted for follow-up information.Slides from re-excised specimens were reviewed.Dogs that underwent radiation therapy after the re-excision procedure were excluded.

Results—41 dogs met the inclusion criteria, and long-term follow-up information was available for 39 dogs.Median follow-up time was 816 days.Local recurrence of tumor developed in 6 of 39 (15%) dogs, and distant metastasis occurred in 4 of 39 (10%) dogs.Healthy tis sue margins of 0.5 to 3.5 cm were achieved at re-excision. Residual tumor was identified in 9 of 41 (22%) resected scars.No tumor-, patient-, or treatment-related variables were associated with local recurrence except for the presence of liposarcoma or fibrosarcoma or whether fine-needle aspiration had been performed prior to surgery.

Conclusions and Clinical Relevance—After incomplete resection of soft tissue sarcomas, resection of local tissue should be performed, even if excisable tissue margins appear narrow.A long-term favorable prognosis is achievable without radiation therapy or amputation. The presence of residual tumor in resected scar tissue should not be used to predict local recurrence.

Restricted access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To assess survival time in dogs that underwent treatment for stage III osteosarcoma and evaluate factors affecting survival.

Design—Retrospective case series.

Animals—90 dogs with stage III osteosarcoma.

Procedures—Records in the osteosarcoma database at the Animal Cancer Center at Colorado State University from 1985 to 2004 were searched for dogs with metastatic disease at the time of evaluation. Dogs were included in the study if they had metastasis to any site and if treatment was initiated. A Kaplan-Meier survival analysis was performed, and the influences of age, sex, breed, primary tumor site, metastatic sites, and treatment on outcome were analyzed via log-rank analysis.

Results—Median survival time was 76 days, with a range of 0 to 1,583 days. No significant differences in survival times on the basis of age, sex, breed, or primary site were observed. Breeds and primary tumor sites were typical of those usually associated with osteosarcoma in dogs. Dogs treated palliatively with radiation therapy and chemotherapy had a significantly longer survival time (130 days) than dogs in all other treatment groups. Dogs treated with surgery alone had a significantly shorter survival time (3 days) than dogs treated with surgery and chemotherapy (78 days). Dogs with bone metastases had a longer survival time than dogs with soft tissue metastases.

Conclusions and Clinical Relevance—Treatment of dogs with stage III osteosarcoma can result in various survival times. Dogs with metastasis to bone and dogs that were treated palliatively with radiation and chemotherapy had the longest survival times.

Restricted access
in Journal of the American Veterinary Medical Association

Abstract

OBJECTIVE To determine survival times of selected dogs with metastatic (stage III) osteosarcoma, whether disease-free interval (DFI) was associated with survival time after diagnosis of stage III disease (ie, stage III survival time), and whether a survival benefit of metastasectomy existed.

DESIGN Retrospective case series with nested cohort study.

ANIMALS 194 client-owned dogs treated for histologically confirmed appendicular osteosarcoma from 1997 through 2009.

PROCEDURES Dogs were included if they had stage I or II osteosarcoma at the time of initial evaluation, had amputation of the affected appendage and ≥ 1 dose of chemotherapy afterward, and developed metastasis within the follow-up period or prior to death. Data collected from the medical records included signalment, primary tumor location, clinical and laboratory findings, whether metastasectomy was performed, and outcome. Various factors were examined for associations with outcome.

RESULTS Dogs that received no treatment for the metastasis had a median survival time between 49 and 57 days after diagnosis of stage III osteosarcoma. Duration of the preceding DFI had no association with this period. Metastasectomy alone was associated with a longer median stage III survival time (232 days) than no metastasectomy (49 days). Among all dogs identified as qualifying for pulmonary metastasectomy on the basis of < 3 pulmonary nodules visible on thoracic radiographs and a DFI > 275 days (n = 21), a survival advantage was also identified for those that actually received pulmonary metastasectomy (6).

CONCLUSIONS AND CLINICAL RELEVANCE Preceding DFI had no influence on survival time of dogs with stage III osteosarcoma. Metastasectomy was associated with an increase in survival time for selected dogs.

Restricted access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To evaluate the outcome in terms of progression-free interval (PFI) and overall survival time (ST) after curative-intent resection of oral melanoma in dogs.

Design—Retrospective case series.

Animals—70 client-owned dogs.

Procedures—An electronic medical record search and review was performed for dogs that underwent curative-intent resection of oral melanoma (May 1, 1998, to December 31, 2011). Information gathered included signalment, oral location of tumor, staging results, type of surgery, type of adjuvant therapy, findings on histologic evaluation, and outcome.

Results—36 (51.4%), 16 (22.9%), 13 (18.6%), and 1 (1.4%) of 70 dogs had tumors classified as stage I, II, III, and IV, respectively; tumor stage could not be determined for 4 (5.7%) dogs because of the lack of tumor size information. Fifty-one (72.9%) dogs had tumors completely excised. Twenty-nine (41.4%) dogs received adjuvant therapy. Median PFI and ST were 508 and 723 days, respectively. Thirty-two (45.7%) dogs had disease progression. Significant associations with PFI or ST were found for administration of adjuvant therapy, presence of metastatic disease at the time of diagnosis, higher tumor stage (III or IV), increased tumor size (> 3 cm), and sexually intact female dogs. Administration of adjuvant treatment was associated with a 130% increased hazard (hazard ratio, 2.3; 95% confidence interval [CI], 1.0 to 5.0) of disease progression; the presence of metastases at the time of diagnosis was associated with a 281% increased hazard (hazard ratio, 3.8; 95% CI, 1.5 to 9.6) of death.

Conclusions and Clinical Relevance—Results indicated that dogs with oral melanoma can have a long PFI and ST after resection with wide margins.

Restricted access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To evaluate the efficacy and toxicity of an alternating carboplatin and doxorubicin chemotherapy protocol in dogs with putative microscopic metastases after amputation for appendicular osteosarcoma and assess patient-, tumor-, and treatment-related factors for associations with prognosis.

Design—Retrospective case series.

Animals—50 client-owned dogs.

Procedures—Records of dogs that underwent amputation for appendicular osteosarcoma and received an alternating carboplatin and doxorubicin chemotherapy protocol were reviewed. Dogs had full staging and were free of detectable metastases prior to chemotherapy. Data on disease-free interval (DFI), survival time, and toxicoses were retrieved from medical records and owner or referring veterinarian communications.

Results—Median DFI was 202 days. Median survival time was 258 days. Twenty-nine (58%) dogs completed the protocol as planned, and the rest were withdrawn typically because of metastases or toxicoses. Grade 3 or 4 myelosuppression was reported in 9 of 50 (18%) dogs and grade 3 or 4 gastrointestinal toxicosis in 6 of 50 (12%) dogs. There were no chemotherapy-related fatalities. Univariate factors associated with significant improvement in DFI included tumor location (radius), receiving doxorubicin as the first drug, starting chemotherapy more than 14 days after amputation, and no rib lesions on preamputation bone scans. Multivariate factors associated with a significant improvement in survival time were tumor location (radius) and completing chemotherapy.

Conclusions and Clinical Relevance—Alternating administration of carboplatin and doxorubicin resulted in DFI and survival time similar to those reported for single-agent protocols. Clients should be counseled regarding the likelihood of toxicoses. Relevance of sequence and timing of starting chemotherapy should be further evaluated.

Restricted access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To document effects of cisplatin on regenerate bone formation during the distraction and consolidation phases of bone transport osteogenesis.

Animals—10 skeletally mature hounds.

Procedure—Bone transport osteogenesis was performed to reconstruct a 3-cm defect in the radius of each dog. Five dogs were randomly selected to receive cisplatin (70 mg/m2, IV, q 21 d for 4 cycles), and 5 were administered saline (0.9% NaCl) solution. Bone mineral density was measured by use of dual-energy x-ray absorptiometry (DEXA) on days 24, 55, and 90 after surgery. Dogs were euthanatized 90 days after surgery. Histomorphometry was performed on nondecalcified sections of regenerate bone. Bone mineral density and histomorphometric indices of newly formed bone were compared between groups.

Results—Densitometric differences in regenerate bone mineral density were not detected between groups at any time period. Cisplatin-treated dogs had decreased mineralized bone volume, decreased percentage of woven bone volume, decreased percentage of osteoblast-covered bone, increased porosity, and increased percentage of osteoblast-covered surfaces, compared with values for control dogs. Lamellar bone volume and osteoid volume did not differ significantly between groups.

Conclusions and Clinical Relevance—Regenerate bone will form and remodel during administration of cisplatin. Results of histomorphometric analysis suggest that bone formation and resorption may be uncoupled in cisplatin-treated regenerate bone as a result of increased osteoclast activity or delayed secondary bone formation during remodeling. These histomorphometric differences were modest in magnitude and did not result in clinically observable complications or decreased bone mineral density as measured by use of DEXA. (Am J Vet Res 2002;63:703–711)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine whether sustained release of transforming growth factor (TGF)-β1 from a gelatin hydrogel would enhance bone regeneration in critical-sized long-bone defects and overcome inhibitory effects of preoperative irradiation.

Animals—24 adult New Zealand White rabbits.

Procedure—Rabbits were allocated to 2 groups. Twelve rabbits received localized megavoltage radiation to the right ulna by use of a cobalt 60 teletherapy unit, and 12 rabbits received no irradiation. Then, a 1.5-cm defect was aseptically created in the right ulna of each rabbit. Gelatin hydrogel that contained 5 µg of adsorbed recombinant-human (rh) TGF-β1 was placed in the defect of 12 rabbits (6 irradiated and 6 nonirradiated), and the other 12 rabbits received hydrogel without rhTGF-β1. Rabbits were euthanatized 10 weeks after surgery. New bone formation within the defect was analyzed by use of nondecalcified histomorphometric methods. A 1-way ANOVA was used to compare differences among groups.

Results—New bone formation within the defect was significantly greater in TGF-β1–treated rabbits than in rabbits treated with hydrogel carrier alone. Local delivery of rhTGF-β1 via a hydrogel carrier in irradiated defects resulted in amounts of bone formation similar to those for nonirradiated defects treated by use of rhTGF-β1.

Conclusions and Clinical Relevance—Local delivery of TGF-β1 by use of a hydrogel carrier appears to have therapeutic potential for enhancing bone formation in animals after radiation treatments.

Impact for Human Medicine—This technique may be of value for treating human patients at risk for delayed bone healing because of prior radiation therapy. (Am J Vet Res 2005;66:1039–1045)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To describe outcomes for small-breed dogs with appendicular osteosarcoma.

Design—Multi-institutional retrospective case series.

Animals—51 small-breed dogs.

Procedures—Records from participating Veterinary Society of Surgical Oncology members were searched for dogs that weighed ≤ 15 kg (33 lb) with a histologic diagnosis of appendicular osteosarcoma. The Kaplan-Meier method was used to determine median survival times (MSTs), and Cox regression was performed to identify variables associated with survival time.

Results—Tumors were most commonly located on the humerus (n = 15) and femur (14). Of the 51 study dogs, 9 were treated nonsurgically, 16 underwent amputation of the affected limb only, and 26 underwent curative-intent treatment, with MSTs of 112, 257, and 415 days, respectively. The MST did not differ significantly between dogs in the amputation-only and curative-intent groups. For dogs in the nonsurgical group, MST decreased significantly as the tumor histologic score increased. For dogs in the amputation-only group, MST decreased as body weight increased.

Conclusions and Clinical Relevance—For the small-breed dogs with appendicular osteosarcoma of the present study, tumor histologic grade and mitotic index were subjectively lower and MST following amputation of the affected limb without adjuvant chemotherapy was longer, compared with those for similarly affected larger dogs. Results indicated no significant advantage in MST for dogs that underwent curative-intent treatment versus dogs that underwent amputation only, and further investigation of the importance of adjuvant chemotherapy is warranted.

Restricted access
in Journal of the American Veterinary Medical Association