Randomized trial of cisplatin versus firocoxib versus cisplatin/firocoxib in dogs with transitional cell carcinoma of the urinary bladder.

BACKGROUND: Cisplatin combined with a nonselective cyclooxygenase (cox) inhibitor has potent antitumor activity against transitional cell carcinoma (TCC) in dogs, but this treatment is limited by renal toxicosis. Cox-2 is expressed in TCC, but only in limited sites within the kidney. A cox-2 inhibitor could enhance the antitumor activity of cisplatin with potentially fewer adverse effects on the kidney. HYPOTHESIS: Cisplatin/cox-2 inhibitor treatment will have greater antitumor activity but no more renal toxicosis than cisplatin alone in dogs with TCC. ANIMALS: Forty-four dogs with naturally occurring urinary bladder TCC. METHODS: Dogs were randomized to receive cisplatin (60 mg/m(2) IV q21d), firocoxib (5 mg/kg PO q24h), or the combination. Tumor measurements were determined before and at 6-week intervals during treatment. Renal function was monitored by serum creatinine concentration, iohexol clearance, and urine specific gravity. Toxicoses were graded according to Veterinary Co-Operative Oncology Group (VCOG) criteria. RESULTS: The remission rate with cisplatin/firocoxib (57%) was significantly (P = .021) higher than that with cisplatin alone (13%). Renal and gastrointestinal toxicoses were common in dogs receiving cisplatin, but there were no significant differences between dogs receiving cisplatin or cisplatin/firocoxib. Firocoxib alone induced partial remission or stable disease in 20 and 33% of dogs, respectively. CONCLUSIONS: Firocoxib significantly enhanced the antitumor activity of cisplatin resulting in partial remission in more than half of the cases. The toxicoses inherent to cisplatin, however, were noted in dogs receiving this combination. Firocoxib had antitumor effects as a single agent and can be considered a palliative treatment for dogs with TCC.

Carboplatin and piroxicam therapy in 31 dogs with transitional cell carcinoma of the urinary bladder.

Invasive transitional cell carcinoma (TCC) of the urinary bladder responds poorly to medical therapy. Combining platinum chemotherapy with a cyclooxygenase (cox) inhibitor has shown promise against canine TCC, where the disease closely mimics the human condition. A phase II clinical trial of carboplatin combined with the cox inhibitor, piroxicam, was performed in 31 dogs with naturally occurring, histopathologically confirmed, measurable TCC. Complete tumour staging was performed before and at 6-week intervals during therapy. Tumour responses in 29 dogs included 11 partial remissions, 13 stable disease and five progressive disease. Two of the 31 dogs were withdrawn prior to the re-staging of the tumour. Gastrointestinal toxicity was observed in 23 dogs. Hematologic toxicity was noted in 11 dogs. The median survival was 161 days from first carboplatin treatment to death. In conclusion, carboplatin/piroxicam induced remission in 40% of dogs providing evidence that a cox inhibitor enhances the antitumour activity of carboplatin. The frequent toxicity and limited survival, however, do not support the use of this specific protocol against TCC.

Cisplatin versus cisplatin combined with piroxicam in a canine model of human invasive urinary bladder cancer.

PURPOSE: More than 12,000 people are expected to die from invasive transitional cell carcinoma (TCC) of the urinary bladder each year in the United States, indicating that more effective therapy is needed. Drugs inhibiting cyclooxygenase (cox) have recently been found to have chemopreventive and antitumor activity and may potentiate the effects of chemotherapy. The purpose of this study was to determine whether cisplatin combined with the cox-inhibitor piroxicam would induce remission more frequently than cisplatin alone in a relevant animal model of human invasive TCC. METHODS: Pet dogs with naturally occurring, histopathologically confirmed, measurable TCC of the urinary bladder were randomized to receive cisplatin (60 mg/m2 i.v. every 21 days) or cisplatin (same dosage) combined with piroxicam (0.3 mg/kg orally every 24 h). Complete staging was performed prior to and at 6-week intervals during therapy. RESULTS: After eight dogs had been evaluated in each treatment group, a significant difference in remission rate was noted (Fisher's Exact test, P < 0.004). Tumor responses in the cisplatin/piroxicam group included two complete remissions (CR), four partial remissions (PR), two stable disease (SD), and no progressive disease (PD). Tumor responses to cisplatin alone in eight dogs were no CR, no PR, four SD, and four PD. Six additional dogs were treated with cisplatin/piroxicam, and in total 10 of 14 dogs had remission (two CR, eight PR). Renal toxicity of cisplatin/ piroxicam was frequent and dose limiting. CONCLUSIONS: Cisplatin/piroxicam induced remission more frequently than cisplatin alone in a canine model of human invasive TCC. Strategies to reduce renal toxicity need to be developed prior to evaluation of cisplatin/piroxicam in humans or general use of this treatment in pet dogs.

Use of radiography, computed tomography and magnetic resonance imaging for evaluation of navicular syndrome in the horse.

Radiographic evaluation of navicular syndrome is problematic because of its inconsistent correlation with clinical signs. Scintigraphy often yields false positive and false negative results and diagnostic ultrasound is of limited value. Therefore, we assessed the use of computed tomography and magnetic resonance imaging in a horse with clinical and radiographic signs of navicular syndrome. Cadaver specimens were examined with spiral computed tomographic and high-field magnetic resonance scanners and images were correlated with pathologic findings. Radiographic changes consisted of bony remodeling, which included altered synovial fossae, increased medullary opacity, cyst formation and shape change. These osseous changes were more striking and more numerous on computed tomographic and magnetic resonance images. They were most clearly defined with computed tomography. Many osseous changes seen with computed tomography and magnetic resonance imaging were not radiographically evident. Histologically confirmed soft tissue alterations of the deep digital flexor tendon, impar ligament and marrow were identified with magnetic resonance imaging, but not with conventional radiography. Because of their multiplanar capability and tomographic nature, computed tomography and magnetic resonance imaging surpass conventional radiography for navicular imaging, facilitating earlier, more accurate diagnosis. Current advances in imaging technology should make these imaging modalities available to equine practitioners in the future.

An imposed oscillating electrical field improves the recovery of function in neurologically complete paraplegic dogs.

We show that an applied electric field in which the polarity is reversed every 15 minutes can improve the outcome from severe, acute spinal cord injury in dogs. This study utilized naturally injured, neurologically complete paraplegic dogs as a model for human spinal cord injury. The recovery of paraplegic dogs treated with oscillating electric field stimulation (OFS) (approximately 500 to 600 microV/mm; n = 20) was compared with that of sham-treated animals (n = 14). Active and sham stimulators were fabricated in West Lafayette, Indiana. They were coded, randomized, sterilized, and packaged in Warsaw, Indiana, and returned to Purdue University for blinded surgical implantation. The stimulators were of a previously unpublished design and meet the requirements for phase I human clinical testing. All dogs were treated within 18 days of the onset of paraplegia. During the experimental applications, all received the highest standard of conventional management, including surgical decompression, spinal stabilization (if required), and acute administration of methylprednisolone sodium succinate. A radiologic and neurologic examination was performed on every dog entering the study, the latter consisting of standard reflex testing, urologic tests, urodynamic testing, tests for deep and superficial pain appreciation, proprioceptive placing of the hind limbs, ambulation, and evoked potential testing. Dogs were evaluated before and after surgery and at 6 weeks and 6 months after surgery. A greater proportion of experimentally treated dogs than of sham-treated animals showed improvement in every category of functional evaluation at both the 6-week and 6-month recheck, with no reverse trend. Statistical significance was not reached in comparisons of some individual categories of functional evaluation between sham-treated and OFS-treated dogs (ambulation, proprioceptive placing); an early trend towards significance was shown in others (deep pain), and significance was reached in evaluations of superficial pain appreciation. An average of all individual scores for all categories of blinded behavioral evaluation (combined neurologic score) was used to compare group outcomes. At the 6-month recheck period, the combined neurologic score of OFS-treated dogs was significantly better than that of control dogs (p = 0.047; Mann-Whitney, two-tailed).

A technique for magnetic resonance imaging of equine cadaver specimens.

We tested an adaptation of a technique for performing magnetic resonance (MR) imaging of human cadaver limbs in the horse. The forelimbs from a normal horse were collected, frozen, and sealed with a paraffin-polymer combination prior to imaging with either a high- or midfield magnetic resonance scanner. Each forelimb was defrosted, scanned, and refrozen on two separate occasions. A five-point scale was used to evaluate the quality of each set of sagittal and transverse, T1-weighted images of each digit. There was no difference in image quality between first and second scans of either specimen (p > 0.05). We conclude that this technique allows investigators to bank tissue specimens for future magnetic resonance imaging without significant loss of image quality.

Low-field magnetic resonance imaging of early subchondral cyst-like lesions in induced cranial cruciate ligament deficient dogs.

Six healthy adult male mongrel dogs underwent cranial cruciate ligament transection in the left stifle. Survey radiography of both stifles and low-field (0.064 T) MRI of the left stifle were performed preoperatively and at 2, 6, and 12 weeks postoperatively. Focal changes in signal intensity were seen with MRI in the subchondral bone of the medial tibial condyle at 2 and 6 weeks postoperatively. At 12 weeks postoperative, a cyst-like lesion was detected using MRI in the subchondral bone of the medial tibial condyle in 4 of 6 dogs and a less defined lesion at this site in the remaining 2 dogs. The cyst-like lesion was spherical in shape and showed typical characteristics of fluid with low signal intensity on T1-weighted images, high signal intensity on T2-weighted images and high signal intensity on inversion recovery images. The lesion was seen in the subchondral bone of the caudal medial and/or middle region of the tibial plateau slightly cranial to the insertion of the caudal cruciate ligament. No subchondral cysts were seen in the tibia on radiographs. Histopathologically, the tibia was characterized by a loose myxomatous phase of early subchondral cyst formation.

A prospective clinical trial comparing metrizamide and iohexol for equine myelography.

A prospective clinical trial comparing adverse postmyelographic effects and myelographic quality of metrizamide and iohexol was conducted. Using a predetermined, randomized assignment, 24 horses exhibiting neurologic signs were administered either metrizamide (180 mgl/ml) or iohexol (180 mgl/ml) via cerebellomedullary puncture. Each horse was evaluated postmyelographically for adverse effects. Myelographic quality was assessed by a numerical scoring method. Adverse effects were observed more frequently with metrizamide (21) compared with iohexol (6) myelography (p < 0.05). Seizures, intensification of preexisting neurologic signs and prolonged anesthetic recovery were the most common complications after myelography. There was no difference in myelographic quality (p > 0.05). We conclude that iohexol is safer than metrizamide for equine myelography and that quality myelograms can be obtained with either contrast medium.

Therapeutic administration of a selective inhibitor of nitric oxide synthase does not ameliorate the chronic inflammation and tissue damage associated with adjuvant-induced arthritis in rats.

Up-regulation of the inducible isoform of nitric oxide synthase (iNOS) was determined during the development of adjuvant-induced arthritis in the rat. iNOS enzymatic activity, measured in spleen tissue, appeared and increased coincidentally with the appearance and degree of paw swelling and joint destruction in this arthritis model, when measured on days 0 through 21 subsequent to inoculation of the rats with adjuvant. The increase in enzymatic activity was paralleled by an increase in the plasma nitrite/nitrate (NOx) level and the appearance of immunoreactive iNOS, as measured by Western immunoblot, in the spleens of these rats. Prophylactic administration of N-iminoethyl-L-lysine (L-NIL) completely abolished iNOS activity (plasma NOx elevation) and effectively reduced both the swelling and radiographic changes in the joint tissues of the noninjected paw measured on day 21. However, therapeutic administration of L-NIL beginning on day 14 had no effect on the inflammatory or arthritic changes measured on day 21, even though plasma NOx levels were reduced to that of the naive controls. These results suggest that iNOS may be involved with the initial stages of the immune response to adjuvant injection, but its product, NO, does not mediate the chronic inflammation and joint destruction which occur during the later phase in this model.

Periosteal new bone formation in a canine neuropathic model of osteoarthritis.

OBJECTIVE: To characterize, for the first time, periosteal new bone formation in a well-established canine model of accelerated osteoarthritis (OA) with features of neuropathic arthropathy. METHODS: Seven dogs underwent left L4-S1 dorsal root ganglionectomy (DRG), followed 3 weeks later by transection of the anterior cruciate ligament of the ipsilateral knee (ACLT). Eight weeks thereafter, a postmortem examination was performed to assess the severity of cartilage changes of OA and the formation of new bone on the distal femur and proximal tibia in the cruciate-deficient limb. RESULTS: As described previously, extensive full-thickness ulceration of the articular cartilage was present in the unstable knee of every dog. The femoral shaft immediately proximal to the condyles in the unstable limb was consistently wider (mean +/- SD diameter 22.4 +/- 2.2 mm) than that in the contralateral limb (19.9 +/- 1.3 mm; P = 0.01). Xeroradiography and histologic examination of the distal femur revealed extensive formation of woven bone on the periosteal surfaces of the medial, lateral, and anterior aspects of the femoral shaft in the OA limb of every dog. These bony changes were not seen in radiographs of dogs that underwent DRG with the cruciate ligament left intact (n = 8) or of neurologically intact dogs that underwent ACLT (n = 7) and were examined 24 weeks after surgery. CONCLUSION: Formation of new periosteal bone on the distal femur and tibia is a feature of this model of accelerated OA that is not seen in the conventional ACLT model of OA in the neurologically intact dog. This observation suggests that interruption of sensory input from the limb may affect the regulation of osteogenesis in the mechanically unstable joint.

Artifacts and technical errors presented as part of the 1996 ACVR oral certification examination.

Cases used for the examination consisted of various imaging artifacts and technical errors. The candidate was expected to name or identify the problem and discuss its cause and prevention. For the purpose of completeness, the scope and detail given here is in excess of that needed to pass the examination. Unless the problem was obvious, the examiner pointed out the problem to be discussed.

Diagnosis of canine hyperadrenocorticism.

Diagnosis of canine hyperadrenocorticism can only be made when a suspicion of the disorder persists after completion of a thorough history and physical examination. The first diagnostic testing steps include a complete blood count, serum biochemical tests, and urinalysis with urine culture. Radiography or ultrasonography may also be necessary, depending on physical findings. Screening tests are next applied to support or exclude the clinical diagnosis of hyperadrenocorticism. After the diagnosis has been made, discrimination tests are applied to determine whether the cause is pituitary or adrenal. The limitations of screening tests, particularly in the presence of nonadrenal diseases, cannot be overemphasized. We recommend that neither screening tests nor discrimination tests for hyperadrenocorticism be used in dogs with concurrent nonadrenal disease.

Phase II clinical trial of carboplatin in canine transitional cell carcinoma of the urinary bladder.

Fourteen dogs with histologically-confirmed transitional cell carcinoma (TCC) of the urinary bladder were treated with 300 mg/m2 carboplatin every 3 weeks. Response to therapy was assessed with abdominal radiography, double contrast cystography, urinary bladder ultrasonography and thoracic radiography before therapy and at 6-week intervals during therapy. Dogs were monitored for hematologic toxicity with a CBC and platelet count performed immediately before and 10 to 14 days after carboplatin treatment. Tumor responses included progressive disease in 11 dogs and stable disease in 1 dog. Two dogs were euthanized due to carboplatin toxicity before assessment of tumor response. Toxicity included thrombocytopenia with or without neutropenia in 7 dogs and gastrointestinal toxicity in 6 dogs. Carboplatin therapy was not beneficial in the treatment of TCC in the 14 dogs in this study.

Cisplatin treatment of transitional cell carcinoma of the urinary bladder in dogs: 18 cases (1983-1993).

OBJECTIVE: To determine whether cisplatin administered at a dosage of 60 mg/m2 of body surface area, IV, every 21 days, would induce remission of transitional cell carcinoma of the urinary bladder in dogs. DESIGN: Retrospective analysis of medical records. ANIMALS: 18 dogs with histologically confirmed transitional cell carcinoma of the urinary bladder. PROCEDURE: Clinical staging was performed by means of physical examination, contrast cystography or ultrasonography, and thoracic radiography prior to and 42 days after the initiation of cisplatin treatment. Dogs with clinical signs of tumor progression were reevaluated earlier than 42 days in some instances. Complete remission (CR) was defined as complete resolution of measurable tumor. Partial remission (PR) was defined as a > or = 50% reduction in tumor volume without development of new tumors. Stable disease was defined as < 50% change in tumor volume at 42 days without development of new lesions. Progressive disease (PD) was defined as > or = 50% increase in tumor volume or development of new tumors at any time. Dogs were reevaluated at 42-day intervals until they had a CR, developed PD, or developed unacceptable adverse effects. RESULTS: Three dogs had a PR, 4 had stable disease, and 9 had PD. Tumor response could not be assessed in 2 dogs: 1 dog developed grand mal seizures 3 hours after the first dose of cisplatin was given and was euthanatized; the other dog continued to have clinical signs of urinary tract obstruction and was euthanatized 8 days after the first dose of cisplatin. Four dogs developed renal azotemia that was suspected to be secondary to cisplatin nephrotoxicity. CLINICAL IMPLICATIONS: The cisplatin dosage was higher than that reported in studies of dogs with transitional cell carcinoma of the bladder. Even with this higher dosage, none of the dogs had a CR, and only 3 of 18 had a PR. A more effective, less toxic treatment for transitional cell carcinoma in dogs is needed.

Experimental osteoarthritis in dogs: a comparison of the Pond-Nuki and medial arthrotomy methods.

Lesions induced by transecting the cranial cruciate ligament in two surgical models of osteoarthritis (OA) in mature, male, cross-bred dogs were compared by using an established grading system and alternatives. Previously, we relied on evaluations of lesions in articular cartilage on femurs alone. No statistically significant differences were found between grades for lesions in cartilage when either treated or control joints were compared by surgical method. Because the Pond-Nuki method yielded statistically significant differences between grades for lesions affecting treated and control femurs or tibias, and for some parameters indicative of synovitis, we preferred this method of surgery. Although by using the medial arthrotomy method of surgery, we were able to destabilize the joint in a more consistent manner, significant differences between treated and control joints were found for lesions on tibias, but not femurs, a frequent site for OA in humans. Suggestions are made for enhancing the surgical models and for a more holistic approach to evaluating joints morphologically.

Use of extracorporeal shock wave lithotripsy for treatment of nephrolithiasis and ureterolithiasis in five dogs.

The safety and efficacy of extracorporeal shock wave lithotripsy in 5 dogs with nephrolithiasis and ureterolithiasis was assessed. Three dogs had bilateral nephrolithiasis, 1 had bilateral nephrolithiasis and unilateral ureterolithiasis, and 1 had unilateral nephrolithiasis and unilateral ureterolithiasis. A first-generation lithotriptor was used for all treatments. None of the dogs developed clinically important complications during or after treatment, except for 1 dog treated for bilateral nephrolithiasis that developed transient ureterolithiasis. Renal function was unchanged in all dogs following treatment. Clinical signs resolved in all dogs. Extracorporeal shock wave lithotripsy appears to be a safe and effective means of treating nephrolithiasis and ureterolithiasis in dogs and appears to cause less renal parenchymal damage and renal function loss than does nephrotomy.

Plasma and cerebrospinal fluid concentrations of 4-aminopyridine following intravenous injection and metered intrathecal delivery in canines.

Potassium channel blockade by 4-aminopyridine (4-AP) has been shown to initiate modest levels of functional recovery in spinal-injured dogs and people following intravenous administration; however, the relevant central nervous system (CNS) concentration mediating these effects is not known. We have determined the concentrations of 4-aminopyridine in plasma and cerebrospinal fluid following intravenous administration (0.5 mg/kg) in large (> 22 kg) dogs, using liquid column chromatography. Plasma levels are initially high (> 1 microgram/mL) and fall rapidly to levels less than 100 ng/mL by about 2 h postinjection. A characteristic secondary peak in plasma 4-AP is observed at about 1 h postinjection. Corresponding concentrations of 4-AP in CSF were relatively stable for nearly 2 h, never exceeding (as a mean) 50 ng/mL within the first 2 h postinjection. We suggest behavioral recovery in clinical cases of spinal cord injury in both dogs and humans is mediated by such low (< 50 ng/mL) concentrations of 4-AP bathing the lesion. Since the adverse side effects that accompany IV administration of the drug limit its potential clinical usefulness, we have evaluated the feasibility of an alternate route of administration, continuous metered delivery of 4-AP into the spinal cord's subarachnoid space. This is accomplished by using a surgically implantable pump and delivery catheter. The pump itself can be interrogated, and is fully programmable, by noninvasive telemetry. Intrathecal delivery rates of between 1 and 60 micrograms of 4-AP per hour never produced detectable levels of the drug in plasma or cervically sampled CSF in dogs independent of the amount or duration of infusion (hours to days). The levels of 4-AP in lumbar samples of CSF near the lumbar delivery site suggest a very steep gradient of the drug, with local concentrations easily reaching 1 microgram/mL or higher (10- to 20-fold higher than can be safely produced by IV administration). The most frequent adverse reaction to intrathecal 4-AP delivery was a mild hindlimb tremor, fully reversible following reduction in the rate of drug delivery or termination of delivery. This route of drug administration relative to clinical spinal cord injury is discussed.