Clinical effectiveness and safety of intraarticular administration of a 117m Tin radiocolloid (Synovetin OATM ) for treatment of early and intermediate grade osteoarthritis of the elbow in a dose finding study conducted in 44 dogs.

Osteoarthritis of the elbow joint secondary to elbow dysplasia is common in dogs. Intraarticular radionuclide injection is thought to suppress both synovitis and inflammatory pain mediators in the joint which are not directly addressed by current treatments. This dose-finding investigation was a longitudinal, prospective, experimental parallel group, post-test study with repeated measures. Forty-four dogs, with low to intermediate-grade osteoarthritis, received a single injection into their most clinically affected elbow joint and were randomized into three treatment cohorts; 37 MBq, 64.75 MBq, or 92.5 MBq (normalized to the body surface area of a 22 kg dog) of 117m Sn radiocolloid. Dogs were assessed monthly by owners, using the canine Brief Pain Inventory (cBPI), and at 1, 3, 6, 9, and 12 months intervals by investigators. Positive responses to treatment were observed by both owners and clinicians in all dose groups with the medium dose group having the highest and most durable response rate based on cBPI scores. The results of this study support the use of 117m Sn radiocolloid as a primary treatment of osteoarthritis in low to intermediate-grade osteoarthritis of the canine elbow.

Comparison of Two Stifle Exploratory Methods Using Mini-Arthrotomy for Diagnosis of Canine Medial Meniscal Pathology: An Ex Vivo Study.

OBJECTIVE: The main aim of this study was to compare the accuracy of stifle exploratory using either a stifle distractor (SD method) or a combination of Hohmann and Senn retractors (HS method) for diagnosing canine medial meniscal tears in cranial cruciate ligament-deficient stifles. STUDY DESIGN: Fifteen pairs of canine cadaveric pelvic limbs were used and cranial cruciate ligament were transected in all stifles. Paired limbs were then randomly assigned to one of five groups based on the tears created in the caudal pole of the medial meniscus: no tear, peripheral detachment, or a variation in three vertical longitudinal tears. A craniomedial mini-arthrotomy was performed by two observers and diagnosis of the medial meniscal status was made utilizing the HS and SD methods. Correct diagnosis of the meniscal tear was compared for both methods and observers. RESULTS: Correct diagnoses were made using the HS and SD methods in 24/30 and 24/30 cases for observer 1 respectively; and in 17/30 and 19/30 cases for observer 2 respectively. There was no significant difference in the correct diagnosis of meniscal tears within each observer between the two methods. CONCLUSION: Both HS and SD methods have equal accuracy for the diagnosis of canine medial meniscal pathology for a board-certified surgeon. Unassisted surgeons using the SD method for the evaluation of the medial meniscus are at no diagnostic disadvantage compared with assisted surgeons utilizing the HS method.

Accuracy of a drilling with a custom 3D printed guide or free-hand technique in canine experimental sacroiliac luxations.

OBJECTIVE: To improve the accuracy of drilling during the repair of sacroiliac luxations (SILs) with a 3D-printed patient-specific drill guide (3D-GDT) compared to free-hand drilling technique (FHDT). STUDY DESIGN: Blinded, randomized, prospective ex vivo study. SAMPLE POPULATION: Sixteen canine cadavers (20-25 kg). METHODS: Dorsal, bilateral SILs were created. Pelvic CT was performed pre- and post-drilling. The FHDT was drilled followed by 3D-GDT. CT and 3D measurements of craniocaudal and dorsoventral angles were compared between FHDT and 3D-GDT, as well as deviations of entry and exit points relative to optimal trajectory. RESULTS: Mean craniocaudal and dorsoventral angles for both CT- and 3D-measured 3D-GDT (CT 4.2 ± 3.9° and 3.9 ± 3.2°, respectively; 3D 5.1 ± 5.1° and 2.8 ± 2.3°, respectively p = .0006) were lower compared to FHDT (CT 11.8 ± 4.0°, p < .0001 and 8.9 ± 6.1°, p = .01; 3D 12.4 ± 5.9°, p = .0006 and 5.3 ± 5.24°, p = .05). Entry dorsoventral and end craniocaudal, dorsoventral, and 3D linear deviations were reduced with 3D-GDT. Sacral corridor disruption was present in 20% (3/15) for FHDT compared with 0% for 3D-GDT. CT and 3D analyses were in strong agreement (r = 0.77). CONCLUSION: Deviations of drill trajectories were minimized relative to optimal trajectories with 3D-GDT compared to FHDT in the dorsoventral and craniocaudal planes. CLINICAL SIGNIFICANCE: The use of 3D-GDT improves accuracy of sacral drilling compared with FHDT in canine cadavers. These results justify further evaluation in a clinical, prospective study.

Safety and Clinical Response Following a Repeat Intraarticular Injection of Tin-117m (117mSn) Colloid in Dogs with Elbow Osteoarthritis.

OBJECTIVE: To determine if a repeat intraarticular (IA) injection of a tin-117m colloid radiosynoviorthesis (RSO) agent can be safely given in the same joint 12 months after an initial injection for treatment of canine elbow osteoarthritis (OA), and to evaluate the pain reduction effect of the repeat injection. METHODS AND MATERIALS: Nine client owned dogs with grade 1 or 2 elbow OA were given an IA injection of tin-117m colloid in both elbows, one of which had been treated ≤12 months earlier with the same RSO device. Treatment safety was evaluated by joint fluid analysis at baseline (BL) and at 180 days after treatment, and by urinalysis, CBC, and serum chemistry analysis of diagnostic samples obtained at BL and 180 days. Radiographs, computed tomography, and MRI scans were obtained at BL and 180 days to determine if disease progression differed in elbows given one versus two injections. Clinical response to treatment was assessed subjectively by dog owner responses to the Canine Brief Pain Inventory (CBPI) survey at BL, 90 and 180 days, and objectively by investigator-conducted force plate (FP) analysis of dogs at BL, 90, and 180 days. RESULTS: All post-treatment urinalysis, CBC and clinical chemistry results were within normal ranges. Joint fluid analysis showed a significant (P=0.0411) reduction in the percentage of monocytes at 180 days, consistent with the tin-117m colloid mode of action of apoptosis of pro-inflammatory macrophages at the injection site. There was no significant difference in OA progression in elbows given one or two injections. The treatment success rate was 55.5% (5/9) on day 90 as determined either by CBPI responses or FP analysis, and 66.6% (6/9) on day 180 as determined by FP analysis. CONCLUSION: The tin-117m colloid can be safely given as a repeat injection 12 months after an initial injection, and can potentially provide a durable therapeutic response in dogs with elbow OA.

Treatment response in dogs with naturally occurring grade 3 elbow osteoarthritis following intra-articular injection of 117mSn (tin) colloid.

The radionuclide 117mSn (tin-117m) embedded in a homogeneous colloid is a novel radiosynoviorthesis (RSO) device for intra-articular (IA) administration to treat synovial inflammation and mitigate osteoarthritis (OA) in dogs. A study to evaluate tin-117m colloid treatment response in dogs with OA was conducted at two centers, the School of Veterinary Medicine at Louisiana State University, and at a referral practice in Houston, Texas. The tin-117m colloid was administered per-protocol to 14 client-owned dogs with radiographically confirmed, grade 3 OA in one or both elbow joints. Dog owners and attending clinicians assessed the level of pain at baseline (BL) and the post-treatment pain response at 90-day intervals for one year. Owners assessed treatment response according to a pain severity score (PSS) and a pain interference score (PIS) as defined by the Canine Brief Pain Inventory. Clinicians reported a lameness score using a 0-5 scale, from no lameness to continuous non-weight bearing lameness, when observing dogs at a walk and a trot. The rate of treatment success as determined by improved mean PSS and PIS scores reported by dog owners was >70% at all time points. Clinicians reported an improved mean pain score from BL at post-treatment Days 90 (p<0.05), 180, and 270. The dog owner and clinician assessments of treatment success were significantly correlated (p>0.05) at Day 90 and Day 180 time points. Results indicated that a single IA dose of tin-117m colloid provided a significant reduction in pain and lameness and improved functionality for up to a full year, with no adverse treatment related effects, in a high percentage of dogs with advanced, clinical OA of the elbow joint.

Prospective Clinical Evaluation of Intra-Articular Injection of Tin-117m (117mSn) Radiosynoviorthesis Agent for Management of Naturally Occurring Elbow Osteoarthritis in Dogs: A Pilot Study.

PURPOSE: To evaluate the clinical effects of an intra-articular injection of 117mSn-colloid for management of canine grade 1 or 2 elbow osteoarthritis (OA). PATIENTS AND METHODS: This was a prospective study in 23 dogs with grade 1 or 2 elbow OA. An orthopedic examination and elbow radiographs were performed to confirm the presence of OA. Dogs were randomly assigned to receive unilateral intra-articular (IA) injection of low-dose (LD: 1.0mCi, n =8), medium-dose (MD: 1.75mCi, n =6), or high-dose (HD: 2.5mCi, n =9) of 117mSn-colloid. The primary outcome measure was peak vertical force (PVF) from force-plate gait analysis and secondary outcome measures included the Canine Brief Pain Inventory score (CBPI) and elbow goniometry. The CBPI was evaluated at pretreatment and then monthly post treatment for 1 year, and goniometry and PVF were evaluated at pretreatment, and at 1, 3, 6, 9 and 12 months post treatment. RESULTS: PVF improved at 3, and 9 months compared to pretreatment values in the HD group. CBPI scores improved at most of the time points in all dose groups. There was no significant difference in elbow goniometry between treated and untreated elbows. There were no self-reports of any adverse effects of the injection by the owners and none were noted by the examining veterinarian at the time of regularly scheduled re-evaluations. CONCLUSION: 117mSn IA injection was free of any obvious adverse effects, improved CBPI scores, and increased weight bearing in limbs with elbow OA providing preliminary evidence that 117mSn may be beneficial in the management of elbow OA in dogs. Although 17mSn appeared to be effective for management of elbow OA in these dogs, this pilot study has inherent limitations; therefore, future studies with larger numbers and with placebo group are needed.

Effect of Sedation on the Neurological Examination of the Patellar and Withdrawal Reflexes in Healthy Dogs.

Introduction: Pain, temperament, fear, and anxiety can prevent safe and accurate evaluation of common neurologic reflexes in dogs. When sedation is used it is unknown how the neurological examination, and specifically patellar and withdrawal reflexes are affected, and, if present, how long any effect might last. The purpose of this study is to investigate the effect of sedation on the evaluation of select common limb spinal reflexes in healthy dogs. Material and Methods: Fourteen healthy dogs with normal neurologic exams were included. After placing joint landmarks, patellar reflex and pelvic and thoracic limb withdrawal reflexes were tested. Joint angles were measured, obtaining reflex angle endpoints, change in angle, and change in time to reflex completion. These measurements were recorded at different time points: prior to sedation (awake timepoint), 15 and 30 min following administration of standardized sedation protocol of dexmedetomidine and butorphanol, and 15 and 30 min following administration of a standardized reversal agent, atipamazole. Results: For patellar reflex, the stifle end angle increased from 91.5 to 108.55 degrees (p < 0.0001) 15 min following sedation, and remained increased at 104.5 degrees (p < 0.0001) 30 min following sedation. Stifle change in angle increased from 9.6 to 24.4 degrees (p < 0.0001) 15 min following sedation, and remained increased at 20.85 degrees (p < 0.0001) and 11 degrees (p = 0.012) at 30 min sedation and 15 min reversal. Tarsal joint in pelvic withdrawal and elbow in thoracic withdrawal reflexes did not differ in at any timepoint of sedation or reversal when compared with the awake timepoint, for end angle or change in angle. The increases in end angle and change in angle for patellar reflex generated a change in time for patellar reflex from 0.12 s (awake) to 0.129 s (15 min sedation) which was statistically significant (p = 0.041). Change in time did not differ for pelvic withdrawal or thoracic withdrawal. Discussion/Conclusions: Reflexes were elicited in all dogs under sedation. Sedation does not affect the evaluation of the withdrawal reflex on any limb but improves the visualization of the patellar reflex in this group of neurologically normal dogs.

Investigation of the effects of storage with preservatives at room temperature or refrigeration without preservatives on urinalysis results for samples from healthy dogs.

OBJECTIVE: To compare urinalysis results for canine urine samples stored in preservative-containing tubes at room temperature (20°C to 25°C [68°F to 77°F]) or refrigerated at 4°C (39.2°F) in plain glass tubes with results for the same samples immediately after collection. SAMPLES: Urine samples from 20 healthy dogs. PROCEDURES: Urine samples (1/dog) were divided into 6 aliquots (3 in preservative-containing tubes and 3 in plain glass tubes). Preservative-containing tubes were stored at room temperature and plain glass tubes were refrigerated. Urinalysis was performed 0, 24, and 72 hours after collection. Results for both storage conditions were compared with results for a reference sample (the 0-hour [immediate post-collection] aliquot in a plain glass tube) by Spearman correlation analysis with pairwise tests for selected variables. RESULTS: Physical variables (urine color and turbidity with and without centrifugation) for both storage conditions had high (rs = 0.7 to 0.9) or very high (rs = 0.9 to 1.0) degrees of positive correlation with reference sample results at all time points, except for color at 24 hours. Similar results were found for all biochemical variables with storage up to 72 hours. For microscopic characteristics, correlation with reference sample results ranged from low or nonsignificant to very high under both storage conditions. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that if a delay in urinalysis is expected, use of the preservative-containing tubes evaluated in this study may be a viable option for sample storage. Further research is warranted to assess direct comparability of results to those of freshly collected samples and use of these tubes to store samples from dogs with conditions affecting the urinary tract.

Effect of sedation or general anesthesia on elbow goniometry and thoracic limb circumference measurements in dogs with naturally occurring elbow osteoarthritis.

OBJECTIVE: To evaluate the effect of sedation or general anesthesia (GA) on elbow goniometry and thoracic limb circumference (TLC) measurements in dogs with elbow osteoarthritis (OA). STUDY DESIGN: Prospective study. ANIMALS: Twenty-four client-owned dogs with radiographically confirmed elbow OA. METHODS: Elbow goniometry and TLC measurements were made before and after either sedation or GA by using a hand-held goniometer and spring tension measuring tape, respectively. Observers were not allowed to review their pre-sedation or pre-GA measurements at the time of obtaining measurements on dogs under sedation or GA. Mixed analysis of variance models were used to compare elbow goniometry and TLC measurements before and after sedation or GA. RESULTS: Eleven and thirteen dogs were included in the sedation and GA groups, respectively. Mean elbow flexion decreased by 5° and 3° and mean elbow extension increased by 6° and 2° under sedation and GA, respectively. Total range of motion increased by 11° under sedation and by 5° under GA. Each of these changes was statistically significant (P < .05) except elbow extension under GA (P = .129). Sedation and GA did not influence TLC measurements (P > .05). CONCLUSION: Sedation or GA led to slight and similar increase in elbow flexion and extension but did not influence TLC measurements in dogs with elbow OA. CLINICAL SIGNIFICANCE: Sedation or GA can cause slight alterations to goniometric measurements in canine elbows with OA. The protocols used in this study for sedation and GA seem interchangeably acceptable for goniometry and TLC measurements in dogs with elbow OA.

Validation of the oscillometric blood pressure monitor Vet20 SunTech in anesthetized healthy cats.

OBJECTIVE: To evaluate a veterinary-specific oscillometric noninvasive blood pressure (NIBP) system according to the guidelines of the American College of Veterinary Internal Medicine (ACVIM) Consensus Statement. STUDY DESIGN: Prospective clinical study. ANIMALS: A total of 33 client-owned cats (20 females and 13 males). METHODS: Cats were premedicated with methadone (0.3 mg kg-1) and alfaxalone (2 mg kg-1) intramuscularly. After 15 minutes anesthesia was induced with isoflurane (3%) in 100% oxygen by facemask while breathing spontaneously. A 22 gauge catheter was placed in the median caudal artery and systolic (SAP), diastolic (DAP) and mean (MAP) arterial pressures were measured. NIBP measurements were collected by placing the cuff (40% of limb circumference) on the right or left antebrachium. The agreement between the two methods was evaluated with the Bland-Altman methods, and the oscillometric NIBP device was evaluated using the ACVIM guidelines for validation of devices. RESULTS: Data from 30 of the 33 cats were analyzed. Five paired measurements were taken from each cat, totaling 150 paired measurements. Mean bias (limits of agreements) for SAP, DAP and MAP were 2.7 (-22.7 to 28.1), 0.9 (-22.3 to 24.2) and 1.3 (-20.4 to 23.0). The oscillometric NIBP passed all validation criteria, except correlation which was <0.9 for SAP, DAP and MAP. CONCLUSIONS AND CLINICAL RELEVANCE: The Vet20 did not meet all validation criteria by the ACVIM. However, all criteria except correlation were met.

Influence of orthopedic examination on lameness scores and interobserver and intraobserver agreement in dogs with naturally occurring elbow osteoarthritis.

OBJECTIVE: To determine the influence of orthopedic examination on numerical rating score (NRS) and visual analog score (VAS) when scoring lameness in dogs with elbow osteoarthritis (OA) and to evaluate interobserver and intraobserver agreement in NRS and VAS on the basis of video-graphic gait analysis. DESIGN: Prospective blinded study. ANIMALS: Eighteen client-owned dogs with radiographically confirmed elbow OA. METHODS: Videos were obtained for all dogs at a walk and at a trot both prior to and immediately after orthopedic examination. All videos were randomly sequenced. Six observers, unaware of the timing of the video, independently assigned both NRS and VAS twice, with at least a 2-week interval. Scores were evaluated with mixed analysis of variance, and the agreement among observers was accessed by intraclass correlation coefficient (ICC). RESULTS: No difference was detected between NRS and VAS at walk or at trot before and after orthopedic examination. Numeric rating score and VAS at walk were lower than those at trot before an orthopedic examination by scores of 0.17 (P = .0018) and 3.54 (P = .0019), respectively. The ICC for both scores for all observers was >0.9. CONCLUSION: An orthopedic examination did not exacerbate the NRS and the VAS for dogs with elbow OA. Interobserver and intraobserver agreement was high for both lameness scores. CLINICAL SIGNIFICANCE: Lameness may be scored after gait evaluation in dogs with elbow OA irrespective of the timing of a comprehensive orthopedic examination.

Titanium-Alloy Anchoring System as a Suitable Method of Extracapsular Repair.

Objective: To characterize the effect of a titanium-alloy anchoring system (TAS) on the motion of the cranial cruciate ligament (CrCL) deficient stifle. To compare the motion with the TAS to that of the CrCL-intact and CrCL-deficient stifle. Study Design: Each canine pelvic limb was mounted in a loading jig under 30% body weight. Motion data was collected using an electromagnetic tracking system at stifle angles of 125°, 135°, and 145° with the CrCL-intact, CrCL-deficient and the TAS applied. Results: Total translation of the CrCL-deficient stifle following the TAS was reduced, but remained greater than the CrCL-intact stifle at angles of 125°, 135°, and 145°. Internal rotation of the TAS groups was greater than the CrCL-intact group at 145°, but not 125° and 135°. Varus motion of the TAS group was decreased compared to the CrCL-deficient group, but increased compared to the CrCL-intact group at angles of 125°, 135°, and 145°. Conclusion: Total translation and internal rotation of the CrCL-deficient stifle following the TAS differed from that of the CrCL-intact stifle. However, the TAS reduced total translation and internal rotation of the tibia relative to the femur in the CrCL-deficient stifle to levels that may yield clinically acceptable results.

Morphometric measurements to predict meniscal size in skeletally mature dogs for meniscal transplantation.

OBJECTIVE: To determine a relationship between morphometric measurements (MM) and meniscal dimensions (MD) in the dog. STUDY DESIGN: Cadaveric study. ANIMALS: Eighteen mixed-breed canine cadavers (22.35 ± 4.06 kg); 36 each of medial and lateral menisci. METHODS: The following MM were obtained in duplicate: height at scapula, withers, pelvis, rump, and greater trochanter; chest circumference; pelvic circumference; length from occiput to the base of the tail; hock to stifle length (HS); body weight; body condition score; and body fat percentage (BF%). Stifles were disarticulated, and digital photographs of in situ menisci were used to obtain meniscal measurements in duplicate. Morphometric parameters were compared with MD via Pearson correlation (r). A correlation of r ≥ 0.65 was considered strong. RESULTS: The strongest correlation was noted between HS and MD, with r = 0.85 for lateral meniscal width, r = 0.77 for medial meniscal length, and r = 0.76 for medial meniscal width. Lateral meniscal length had the strongest correlation with height at rump (HRu) (r = 0.73). Body weight correlated strongly with meniscal width and fairly with meniscal length. Body condition score and BF% correlated weakly with MD. CONCLUSION: Hock to stifle length was an easily obtainable variable and was proportional to MD. CLINICAL SIGNIFICANCE: Hock to stifle length may be considered by tissue banks and veterinary surgeons as a quick and cost effective screening tool for appropriate meniscal sizing in dogs.

Extracorporeal shock wave therapy improves short-term limb use after canine tibial plateau leveling osteotomy.

OBJECTIVE: To determine the influence of postoperative extracorporeal shock wave therapy (ESWT) on hind limb use after tibial plateau leveling osteotomy (TPLO). STUDY DESIGN: Randomized, prospective clinical trial. ANIMALS: Sixteen client-owned dogs, 2 to 10 years old weighing 18 to 75 kg. METHODS: Dogs were randomly assigned to treatment cohorts, TPLO with ESWT (ESWT, n = 9) or TPLO without ESWT (control, n = 7). Treatment consisted of 1000 pulses at 0.15 mJ/mm2 immediately and 2 weeks after surgery. Subjective pain, stifle goniometry, stifle circumference, peak vertical force (PVF) and vertical impulse (VI) were measured before surgery, prior to ESWT, and 2 and 8 weeks after surgery. Measures were compared between treatments at each time point and among time points for each treatment (P < .05). RESULTS: The PVF (5.5 ± 1.0 N/kg, mean ± SD) and VI (0.67 ± 0.14 N-s/kg) of surgically treated limbs in the ESWT cohort were higher 8 weeks after surgery compared with preoperative (3.8 ± 1.1 N/kg, P < .0001 and 0.47 ± 0.21 N-s/kg, P = .0012, respectively) values. In the control cohort, PVF (2.9 ± 1.3 N/kg, P = .0001) and VI (0.33 ± 0.20 N-s/kg, P = .0003) 2 weeks after surgery and VI (0.42 ± 0.2 N-s/kg, P = .0012) 8 weeks after surgery were lower (4.59 ± 2.33 N/kg and 0.592 ± 0.35 N-s/kg, respectively) than before surgery. Other parameters did not differ between groups. CONCLUSION: Weight bearing increased faster after TPLO in dogs treated with postoperative ESWT. CLINICAL SIGNIFICANCE: This study provides evidence to consider adjunct ESWT after TPLO.

Effect of tibial rotation on the tibial plateau angle measurement in dogs: An ex vivo study.

OBJECTIVE: To determine the effect of tibial rotation on radiographic tibial plateau angle (TPA) measurement in normal and cranial cruciate ligament (CrCL)-deficient stifles. STUDY DESIGN: Cadaveric study. SAMPLE POPULATION: Five pairs of canine cadaver hind limbs with no stifle osteoarthritis. METHODS: Mediolateral radiographs of each specimen were obtained at 0°, 10°, 20°, and 30° of internal and external rotation of the tibia with both intact and transected CrCL. Two Kirschner wires were placed at the cranial and caudal landmarks of the tibial plateau, and the 0° views were imaged again, representing the anatomic TPA. Five observers measured the TPA twice on all images. Measurements were compared by using a mixed-model ANOVA. Intraobserver and interobserver variability were evaluated by using the coefficient of variation. RESULTS: Tibial plateau angle did not differ among the anatomic, CrCL-intact, and CrCL-deficient 0° views or between the CrCL-intact and CrCL-deficient views at the various tibial rotations. The only difference detected was between CrCL-intact stifles radiographed at 0° and external rotation (range, 1.16°-1.6°; P = .016, P = .001, and P < .001). Tibial rotation, CrCL transection, and their interaction all failed to influence intraobserver and interobserver variability (P > .05). CONCLUSION: In CrCL-deficient stifles, tibial rotation of up to 30° internally and externally did not result in clinically relevant changes in TPA measurements. CLINICAL SIGNIFICANCE: The TPA can be successfully measured with up to 30° of internal and external tibial rotation in CrCL-deficient stifles with no osteoarthritic changes.

Feline histoplasmosis: a retrospective study of 22 cases (1986-2009).

Twenty-two cases of feline histoplasmosis seen at the Virginia-Maryland Regional College of Veterinary Medicine Teaching Hospital between 1986 and 2009 were reviewed. The median age of affected cats was 9 yr (mean, 8.8 yr). Female domestic shorthairs were more commonly affected. The clinical presentation of most cases was nonspecific. The most common presenting complaints included weakness, lymphadenopathy, weight loss, and anorexia. Less frequent clinical signs included vomiting, diarrhea, blindness, and lameness. Less than half of the cats had clinical evidence of pulmonary disease on admission. Anemia and hypoalbuminemia were common laboratory abnormalities. An interstitial pattern was the most common radiographic pattern observed with pulmonary disease. Diagnosis was based on identification of the organism on cytology or histopathology. Fifteen of the 22 cats were treated, and itraconazole was the most common antifungal agent prescribed. Median duration of the antifungal treatment was 5 mo for cats that survived to discharge. Overall survival at time of discharge for cats in this study was 55%.

Reversing tumor immune suppression with intratumoral IL-12: activation of tumor-associated T effector/memory cells, induction of T suppressor apoptosis, and infiltration of CD8+ T effectors.

A single intratumoral injection of IL-12 and GM-CSF-loaded slow-release microspheres induces T cell-dependent eradication of established primary and metastatic tumors in a murine lung tumor model. To determine how the delivery of cytokines directly to the microenvironment of a tumor nodule induces local and systemic antitumor T cell activity, we characterized therapy-induced phenotypic and functional changes in tumor-infiltrating T cell populations. Analysis of pretherapy tumors demonstrated that advanced primary tumors were infiltrated by CD4+ and CD8+ T cells with an effector/memory phenotype and CD4+CD25+Foxp3+ T suppressor cells. Tumor-associated effector memory CD8+ T cells displayed impaired cytotoxic function, whereas CD4+CD25+Foxp3+ cells effectively inhibited T cell proliferation demonstrating functional integrity. IL-12/GM-CSF treatment promoted a rapid up-regulation of CD43 and CD69 on CD8+ effector/memory T cells, augmented their ability to produce IFN-gamma, and restored granzyme B expression. Importantly, treatment also induced a concomitant and progressive loss of T suppressors from the tumor. Further analysis established that activation of pre-existing effector memory T cells was short-lived and that both the effector/memory and the suppressor T cells became apoptotic within 4 days of treatment. Apoptotic death of pre-existing effector/memory and suppressor T cells was followed by infiltration of the tumor with activated, nonapoptotic CD8+ effector T lymphocytes on day 7 posttherapy. Both CD8+ T cell activation and T suppressor cell purge were mediated primarily by IL-12 and required IFN-gamma. This study provides important insight into how local IL-12 therapy alters the immunosuppressive tumor milieu to one that is immunologically active, ultimately resulting in tumor regression.