Patient specific implants for amputation prostheses: design, manufacture and analysis.

OBJECTIVES: To design, manufacture and analyze custom implants with functional gradation in macrostructure for attachment of amputation prostheses. METHODS: The external shape of the implant was designed by extracting geometrical data of canine cadavers from computed tomography (CT) scans to suit the bone cavity. Three generations of implant designs were developed and were optimized with the help of fit/fill and mechanical performance of implant-cadaver bone assembly using CT analysis and compression testing, respectively. A final optimized, custom Ti6Al4V alloy amputation implant, with approximately 25% porosity in the proximal region and approximately zero percent porosity in the distal region, was fabricated using Laser Engineered Net Shaping (LENS™)--a laser based additive manufacturing technology. RESULTS: The proposed design changes in the second generation designs, in terms of refining thresholds, increased the average fill of the bone cavity from 58% to 83%. Addition of a flange between the stem and the head in the second generation designs resulted in more than a seven-fold increase in the compressive load carrying capacity of the assembly. Application of LENS™ in the fabrication of present custom fit Ti6Al4V alloy implants enabled incorporation of 20 to 30% porosity in the proximal region and one to two percent residual porosity in the distal portion of the implant. CLINICAL SIGNIFICANCE: Patient specific prostheses having direct connection to the skeletal structure can potentially aid in problems related to load transfer and proprioception in amputees. Furthermore, application of LENS™ in the fabrication of custom implants can be faster to incorporate site specific porosity and gradients for improving long-term stability.

Lung tumor development and spontaneous regression in lambs coinfected with Jaagsiekte sheep retrovirus and ovine lentivirus.

Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring and experimentally inducible lung cancer of sheep caused by Jaagsiekte sheep retrovirus (JSRV). The first aim of this study was to monitor the development of OPA with minimally invasive, real-time observations of animals experimentally infected with JSRV as well as ovine lentivirus (maedi-visna virus). Worldwide, simultaneous infection of sheep with these 2 retroviruses is a common occurrence, naturally and experimentally; consequently, the lung tumor homogenates used as inocula contained both viruses. Following inoculation, computed tomography was used to detect tumor nodules early, before the onset of clinical signs, and to monitor tumor advancement. However, not only was OPA disease progression observed, but the apparent spontaneous regression of OPA was witnessed. In fact, regression was more common than progression following JSRV inoculation of neonatal lambs. Immune responses were detected, particularly involving CD3(+) T cells and the production of antibodies against JSRV that may mediate the spontaneous regression of JSRV-induced OPA. The second aim of this study was to determine whether OPA tumors harbor genetic alterations similar to those found in human lung adenocarcinoma. No mutations were found in the tyrosine kinase domain of the epidermal growth factor receptor, KRAS codons 12 and 13, or the DNA-binding domain of p53 in tumor DNA from naturally occurring and experimentally-induced OPA cases. Overall, the genetic profile combined with the disease development data provides further important characterization of OPA and describes, for the first time, spontaneous regression of OPA tumors in experimentally infected sheep.

A review of sentinel lymph node evaluation and the need for its incorporation into veterinary oncology.

Being the first lymph node or nodes to which many primary tumours reliably drain, the disease status of the sentinel lymph node/s (SLN) is important in the prediction of survival. SLN identification and biopsy are critical in the staging of human cancers. The status of the SLN helps determine prognosis and shape treatment plans. SLN evaluation is currently not routinely performed in veterinary oncology, not even at specialty oncology practices. Given the prognostic importance of lymph node involvement in tumours such as mammary gland carcinoma, osteosarcoma, synovial cell sarcoma and mast cell tumours, SLN evaluation should be incorporated into routine clinical practice so as to improve our clinical assessment of veterinary oncologic patients.

Intra-operative cisplatin for the treatment of canine extremity soft tissue sarcomas.

Nineteen dogs with histologically confirmed soft tissue sarcomas of the extremities were treated with a combination of marginal surgery and intra-operative chemotherapy in the form of cisplatin in a biodegradable implant delivery system (Atrigel; Atrix Laboratories, Fort Collins, Co, USA). None of the dogs had evidence of metastasis at time of treatment. The median dose of cisplatin was 52.1 mg/m(2) (mean 55.4 mg/m(2), range 18.5-108.6 mg/m(2)). Wound complications were noted in 16 dogs (84.2%). Median follow-up time was 874 days (mean 777 days, range 125-1463 days). Nine dogs (47.3%) were alive at the time of analysis. Local recurrence occurred in three dogs (16.6%). The time to recurrence was 214, 264 and 874 days.

Biomechanical characteristics of allogeneic cortical bone pins designed for fracture fixation.

The biomechanical characteristics of 1.2 mm diameter allogeneic cortical bone pins harvested from the canine tibia were evaluated and compared to 1.1 mm diameter stainless steel pins and 1.3 mm diameter polydioxanone (PDS) pins using impact testing and four-point bending. The biomechanical performance of allogeneic cortical bone pins using impact testing was uniform with no significant differences between sites, side, and gender. In four-point bending, cortical bone pins harvested from the left tibia (204.8 +/- 77.4 N/mm) were significantly stiffer than the right tibia (123.7 +/- 54.4 N/mm, P = 0.0001). The site of bone pin harvest also had a significant effect on stiffness, but this was dependent on interactions with gender and side. Site C in male dogs had the highest mean stiffness in the left tibia (224.4 +/- 40.4 N/mm), but lowest stiffness in the right tibia (84.9 +/- 24.2 N/mm). Site A in female dogs had the highest mean stiffness in the left tibia (344.9 +/- 117.4 N/mm), but lowest stiffness in the right tibia (60.8 +/- 3.7 N/mm). The raw and adjusted bending properties of 1.2 mm cortical bone pins were significantly better than 1.3 mm PDS pins, but significantly worse than 1.1 mm stainless steel pins (P < 0.0001). In conclusion, cortical bone pins may be suitable as an implant for fracture fixation based on initial biomechanical comparison to stainless steel and PDS pins used in clinical practice.

Cranial mediastinal carcinomas in nine dogs.

Nine dogs were diagnosed with cranial mediastinal carcinomas. Based on histological and immunohistochemical analysis, four dogs were diagnosed with ectopic follicular cell thyroid carcinomas, one dog with ectopic medullary cell thyroid carcinoma, two dogs with neuroendocrine carcinomas and two dogs with anaplastic carcinomas. Clinical signs and physical examination findings were associated with a space-occupying mass, although one dog was diagnosed with functional hyperthyroidism. Surgical resection was attempted in eight dogs. The cranial mediastinal mass was invasive either into the heart or into the cranial vena cava in three dogs. Resection was complete in six dogs and unresectable in two dogs. All dogs survived surgery, but four dogs developed pulmonary thromboembolism and two dogs died of respiratory complications postoperatively. Adjunctive therapies included pre-operative radiation therapy (n=1) and postoperative chemotherapy (n=3). Three dogs had metastasis at the time of diagnosis, but none developed metastasis following surgery. The overall median survival time was 243 days. Local invasion, pleural effusion and metastasis did not have a negative impact on survival time in this small case series.

Curative-intent radiation therapy as a treatment modality for appendicular and axial osteosarcoma: a preliminary retrospective evaluation of 14 dogs with the disease.

Canine osteosarcoma is a common bone malignancy associated with aggressive local disease and rapid metastasis. Current local therapeutic modalities do not provide curative-intent options for dogs with significant orthopaedic or neurologic disease, dogs which are denied amputation or dogs with non-resectable lesions. The goals of this retrospective study included the evaluation of local control, survival, and time to the development of metastases in 14 dogs treated with curative-intent radiation therapy and chemotherapy. Median local disease control was 202 days (79-777). Median survival was 209 days (79-781). Median time to metastasis was 314 days (7-645). No significant correlation was found between the outcome and pre-treatment alkaline phosphatase levels, radiographic appearance, tumour site, radiation dose or chemotherapeutics administered. In these dogs, full-course radiation therapy in conjunction with chemotherapy was not found to yield equivalent results to the standard of care options.

Survival analysis of one versus two treatments of local delivery cisplatin in a biodegradable polymer for canine osteosarcoma.

The purpose of this study was to evaluate one versus two doses of local delivery cisplatin in a biodegradable polymer (OPLA-Pt) for the treatment of osteosarcoma (OSA) after amputation in dogs. Medical records were reviewed retrospectively, and 105 dogs were included in the study; 39% of dogs received one treatment (surgical implantation) of OPLA-Pt and 61% of dogs received two treatments of OPLA-Pt after amputation. Administration of two doses of OPLA-Pt did not have a significant effect on disease-free interval or survival time compared to one dose. The anatomic site of the tumour was identified as a prognostic factor, and dogs with proximal humeral OSA had the shortest disease-free interval and survival times. There was no advantage to giving a second dose of local delivery cisplatin following amputation for the treatment of OSA in dogs.

Pneumonectomy: four case studies and a comparative review.

Pneumonectomy is the resection of all lung lobes in either the left or right lung field. The surgical technique and postoperative results of pneumonectomy for clinical disease have not been reported in companion animals. Pneumonectomy was performed in three dogs and one cat to treat pulmonary or pleural disease, and the postoperative outcome compared with the complications and results reported in the human literature. One dog died immediately postoperatively due to suspected respiratory insufficiency and the remaining three animals survived the perioperative period. Postoperative complications were reported in two animals. Cardiac complications occurred in the cat, with perioperative arrhythmias and progressive congestive heart failure. Gastrointestinal complications were diagnosed in one dog, with mediastinal shift and oesophageal dysfunction. Left- and right-sided pneumonectomy is feasible in companion animals, and the postoperative outcome and complications encountered in this series were similar to those reported in humans.

Haemangiosarcoma of the urinary bladder in a dog.

Haemangiosarcoma of the urinary bladder is reported in a dog. The bladder mass was detected incidentally during physical examination. Partial cystectomy with unilateral ureteroneocystostomy were performed to remove the tumour en bloc. Necrosis of the urinary bladder was diagnosed 10 days postoperatively and the dog was euthanased.

Pulmonary metastatectomy in the management of four dogs with hypertrophic osteopathy.

The efficacy and outcome of pulmonary metastatectomy in the management of hypertrophic osteopathy (HO) secondary to metastatic osteosarcoma was retrospectively evaluated in four dogs. Metastatectomy was performed by subpleural enucleation, partial lung lobectomy or complete lung lobectomy through either a median sternotomy or thoracoscopically. Perioperative morbidity was minimal. Clinical signs associated with HO resolved within 24 h of pulmonary metastatectomy in all dogs. Durable remission of symptomatic HO was achieved in all dogs (range, 50-294 days), although recurrence of HO was noted in one dog, 246 days post metastatectomy due to metastasis to the lungs and chest wall. Pulmonary metastatectomy resulted in a rapid and prolonged resolution of HO, and the clinical benefits of metastatectomy potentially exceed the morbidity associated with the surgical procedure.

Surgical treatment of right-sided renal lymphoma with invasion of the caudal vena cava.

An eight-year-old, male castrated basset hound presenting with a three-month history of lethargy was examined. Diagnostic tests including radiography and ultrasonography showed a right-sided renal mass. A 99mTc diethylenetriamine penta-acetic acid scan demonstrated that this kidney was non-functional. At surgery, invasion of the caudal vena cava was found, and the renal segment of the vena cava and the right kidney were resected. The left renal vein was anastomosed to the more proximal vena cava using a polytetrafluoroethylene graft, and the dog recovered well. Two days postsurgery, the dog suffered an acute episode of aspiration pneumonia and was euthanased. The renal mass was diagnosed as lymphoma on histopathology.

Nuclear scanning with 99mTc-HDP for the initial evaluation of osseous metastasis in canine osteosarcoma.

The purpose of this retrospective analysis was to evaluate the use of nuclear scintigraphy in determining the rate of secondary sites of osseous malignancy at initial presentation in dogs with osteosarcoma. Radiographs of suspicious secondary lesions were reviewed and placed into four separate categories: benign lesions; no lesion seen on radiographs; subtle radiographic changes suggestive of, but not conclusive for, metastasis; and metastatic lesions highly suspected on radiographs. Three hundred and ninety-nine dogs were evaluated by technetium nuclear scanning for suspected osteosarcoma. Three hundred and twenty-six of 399 dogs (82%) had only one apparent site on the nuclear scan, whereas 72 dogs (18%) had more than one suspicious site on the nuclear scans. Highly suspected secondary metastatic lesions were detected by nuclear scans in 7.8% of cases. Although interpretation of nuclear scans is subjective, this study showed a 7.8% chance of detecting unsuspected osseous metastasis with nuclear scans in canine osteosarcoma patients on initial presentation.

Spontaneous regression of osteosarcoma in four dogs.

Spontaneous regression of primary malignant bone tumors is rare but has been reported in the human literature. To the authors' knowledge, spontaneous regression of primary bone tumors in dogs or cats has not been reported. Osteosarcoma (OSA) is the most common primary bone tumor in humans, and it has been reported that the incidence of OSA is 40 to 50 times greater in dogs than humans. In this report, high-grade OSA was diagnosed in biopsy specimens obtained from 4 dogs that subsequently underwent spontaneous regression without tumor-specific treatment. Osteosarcoma in dogs has characteristics similar to that of OSA in humans.

Effect of gas-plasma sterilization on the osteoinductive capacity of demineralized bone matrix.

The current study evaluated the effect of low-temperature hydrogen peroxide gas plasma sterilization on the osteoinductive capability of human demineralized bone matrix using a rat model. Twelve athymic rats received three separate implants consisting of steam-sterilized demineralized bone matrix (negative control), sterile-harvest demineralized bone matrix (positive control), and gas-plasma-sterilized demineralized bone matrix. A demineralized bone matrix pellet from each sterilization group was placed individually into one of three separate soft tissue pockets created in the epaxial musculature of each rat. All 12 rats were euthanized 9 weeks after implantation. Each implantation site was removed along with 0.5-cm normal tissue around the implant. Histologic examination was done on each implant site to determine the presence or absence of new bone, cartilage, or bone marrow elements. All 12 sterile harvest demineralized bone matrix sites histologically contained new bone elements, whereas none of the negative control or gas plasma sterilized demineralized bone matrix sites contained any of these same elements. The results of this study indicate that demineralized bone matrix sterilized with low-temperature, gas-plasma sterilization loses its osteoinductive capacity in a manner similar to that of steam-sterilized demineralized bone matrix, making low-temperature, gas- plasma sterilization unsuitable as a method of secondary sterilization of demineralized bone matrix.

Accuracy of radiography, nuclear scintigraphy, and histopathology for determining the proximal extent of distal radius osteosarcoma in dogs.

OBJECTIVE: To compare the accuracy of radiography, nuclear scintigraphy, and histopathology for determining the proximal extent of distal radius osteosarcoma in dogs. STUDY DESIGN: Retrospective clinical study. SAMPLE POPULATION: Twenty client-owned dogs taken to Colorado State University with osteosarcoma of the distal radius. METHODS: Medical records of 20 dogs with confirmed osteosarcoma that underwent a limb-salvage procedure were reviewed. Measurements were performed directly from the lateral view of each radius, from both the scintigram and the radiograph, to determine the length of the radius and the distance from the proximal extent of the tumor to the distal radiographic or scintographic extent of the radius. The ratio of distal radial involvement to total radius length was calculated. A similar ratio was also determined using the macroslide, which included the entire portion of bone that was excised during the limb-salvage procedure. All 3 methods of measurement were compared. RESULTS: Nuclear scintigraphy significantly overestimated tumor length when compared with macroslide specimen measurements. Radiography also overestimated tumor length, but these results were not significantly different from macroslide specimen measurements. CONCLUSIONS: Both radiography and nuclear scintigraphy overestimate the extent of distal radius osteosarcoma in dogs when compared with histopathologic macroslides of the same lesions. Nuclear scintigraphy overestimated tumor extent to a larger degree than did radiography. CLINICAL RELEVANCE: Although radiography is a more accurate method of measurement of the extent of distal radius osteosarcoma, because nuclear scintigraphy overestimates tumor length to a greater degree, scintigraphy may provide a larger margin of safety for determining the site of proximal osteotomy during a limb-salvage procedure. However, caution should be taken when utilizing scintigraphy, because this method may overestimate length of radius involved to such an extent as to cause the surgeon to believe that a patient is not a suitable limb-salvage candidate.

Clinical outcome of dogs with grade-II mast cell tumors treated with surgery alone: 55 cases (1996-1999).

OBJECTIVE: To determine outcome for dogs with grade-II mast cell tumors treated with surgery alone. DESIGN: Retrospective study. ANIMALS: 55 dogs. PROCEDURES: Medical records were examined, and signalment; location and size of tumor; staging status; dates of local recurrence, metastasis, death, or last follow-up examination; status of surgical margins; previous surgery; postoperative complications; and cause of death were recorded. Follow-up information was obtained via reexamination or telephone conversations with owners or referring veterinarians. Univariate analysis was performed to identify prognostic factors. RESULTS: 60 tumors in 55 dogs were included. Median follow-up time was 540 days. Three (5%) mast cell tumors recurred locally; median time to local recurrence was 62 days. Six (11%) dogs developed another mast cell tumor at a different cutaneous location; median time to a different location was 240 days. Three (5%) dogs developed metastases; median time to metastasis was 158 days. Fourteen dogs died; 3 deaths were related to mast cell tumor, and 7 were unrelated. The relationship with mast cell tumor was not known for 4. Median survival times were 151, 841, and 827 days, respectively, for these 3 groups. Forty-six (84%) dogs were free of mast cell tumors during the study period. A reliable prognostic factor could not be identified. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that additional local treatment may not be required after complete excision of grade-II mast cell tumors and that most dogs do not require systemic treatment.

Treatment with a combination of doxorubicin, surgery, and radiation versus surgery and radiation alone for cats with vaccine-associated sarcomas: 25 cases (1995-2000).

OBJECTIVE: To compare use of doxorubicin, surgery, and radiation versus surgery and radiation alone for treatment of cats with vaccine-associated sarcoma. DESIGN: Retrospective study. ANIMALS: 25 cats with vaccine-associated sarcomas. PROCEDURE: Time to first recurrence and survival time were compared between the 2 treatment groups. The number of surgeries (1 or > 1) were compared with respect to time to first recurrence and survival time. RESULTS: Median time to first recurrence was 661 days for the group that received doxorubicin, surgery, and radiation. Median time to first recurrence has not yet been attained for the group treated with surgery and radiation alone. Median survival time was 674 days for the group treated with doxorubicin, surgery, and radiation and 842 days for the group treated with surgery and radiation alone. For time to first recurrence and survival time, significant differences were not detected between cats that had 1 surgery and those that had > 1 surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Significant differences between the 2 treatment groups were not detected. The efficacy of doxorubicin in the treatment of vaccine-associated sarcomas is uncertain.

Outcome following treatment of vertebral tumors in 20 dogs (1986-1995).

Twenty dogs with histopathologically confirmed primary (n=15) or metastatic (n=5) osteosarcoma (n=14) or fibrosarcoma (n=6) of the vertebral column were treated with surgery (n=4), radiation therapy and chemotherapy (n=6), surgery and chemotherapy (n=2), or surgery, radiation, and chemotherapy (n=8). All dogs died due to their disease; 15 died due to local failure, and five died due to nonvertebral metastasis. Overall median survival time was 135 days, with a range of 15 to 600 days. Of the factors evaluated, only postoperative neurological status had a significant influence on outcome by multivariate analysis. This study supports the overall guarded prognosis for dogs with vertebral neoplasia. Better combinations of surgery, chemotherapy, and radiation therapy remain to be defined for this difficult subset of animal cancer.

Identification of matrix metalloproteinases in canine neoplastic tissue.

OBJECTIVE: To identify matrix metalloproteinases (MMP) 2 and 9 in canine tumor tissue and to compare the amount of activity to that in unaffected stromal tissue. ANIMALS: 30 dogs with spontaneously developing, high-grade osteosarcoma. PROCEDURE: Tumor and nearby stromal tissue (muscle) were obtained at the time of surgery. Specimens were homogenized, and supernatants were assayed, using gelatin zymography. Human derived standards were run concurrently. Densitometry was done to obtain a semiquantitative arbitrary unit value for each specimen. The amount of activity in tumor tissue was compared with the amount in stromal tissue. RESULTS: Gelatinolytic bands were observed from the analysis of all tumor tissues and in most stromal tissues. These bands migrated in the same molecular weight area as the human MMP 2 and 9 standards. Gelatinolytic activity could be quenched by the addition of 50 mM EDTA and 1 microg of synthetic tissue inhibitor of metalloproteinase (TIMP) 2 per 100 ml. There was significantly more gelatinolytic activity in tumor tissue than in stromal tissue. CONCLUSIONS AND CLINICAL RELEVANCE: MMP 2 and 9 are detectable in canine neoplastic tissue. Matrix metalloproteinases activity in tumor tissue is higher than in unaffected stromal tissue, indicating that canine MMP may be involved in the pathogenesis of tumor growth and metastasis.