Thomas P. Gregor

CD40-Activated B Cell Cancer Vaccine Improves Second Clinical Remission and Survival in Privately Owned Dogs with Non-Hodgkin's Lymphoma

Cell-based active immunotherapy for cancer is a promising novel strategy, with the first dendritic cell (DC) vaccine achieving regulatory approval for clinical use last year. Manufacturing remains arduous, especially for DC vaccines, and the prospect of using cell-based immunotherapy in the adjuvant setting or in combination with chemotherapy remains largely untested. Here, we used a comparative oncology approach to test the safety and potential efficacy of tumor RNA-loaded, CD40-activated B cells in privately owned dogs presenting with non-Hodgkins lymphoma (NHL), a clinical scenario that represents not only a major problem in veterinary medicine but also a bona fide spontaneous animal model for the human condition. When administered to NHL dogs in remission after induction chemotherapy, CD40-B cells electroporated ex vivo with autologous tumor RNA safely stimulated immunity in vivo. Although chemotherapy plus CD40-B vaccination did not improve time-to-progression or lymphoma-specific survival compared to dogs treated with chemotherapy alone, vaccination potentiated the effects of salvage therapy and improved the rate of durable second remissions as well as subsequent lymphoma-specific survival following salvage therapy. Several of these relapsed dogs are now long-term survivors and free of disease for more than a year. Overall, these clinical and immunological results suggest that cell-based CD40 cancer vaccination is safe and synergizes with chemotherapy to improve clinical outcome in canine NHL. More broadly, our findings underscore the unique value of clinical investigations in tumor-bearing companion animals.

Distraction index as a risk factor for osteoarthritis associated with hip dysplasia in four large dog breeds.

OBJECTIVE To determine if age, breed, gender, weight or distraction index (DI) influenced the risk of radiographic osteoarthritis (OA) of canine hip dysplasia (CHD) in four common dog breeds; the American bulldog, Bernese mountain dog, Newfoundland and standard poodle. MATERIALS AND METHODS This was a cross sectional prevalence study with 4349 dogs. Canine hips were evaluated using 3 radiographic projections: the hip-extended view, the compression view and the distraction view. The hip-extended view was examined for the presence of OA. The PennHIP distraction view was utilized to calculate the DI. For all breeds, a multiple logistic regression model incorporating age, weight, gender, and DI was created. For each breed, disease-susceptibility curves grouping dogs on the basis of age were constructed. Receiver-operating characteristic (ROC) curves were developed for each breed regardless of age. RESULTS For all breeds, DI was the most significant risk factor for the development of OA associated with CHD. Weight and age were also significant risk factors in all four breeds, but gender was not. CLINICAL SIGNIFICANCE Results from this study support previous findings, that irrespective of breed, the probability of radiographic OA increases with hip joint laxity as measured by the DI. Breed-specific differences in this relationship, however, warrant investigation of all breeds affected by CHD to determine inherent dependency of hip OA on joint laxity. Such findings guide veterinarians in helping dog breeders to make evidence-based breeding decisions and in informing dog owners to implement preventative treatments for CHD for dogs found to be at risk.

A longitudinal study of the influence of lifetime food restriction on development of osteoarthritis in the canine elbow.

OBJECTIVE To report the effects of age and lifetime calorie restriction on development and progression of osteoarthritis (OA) in elbow joints of Labrador retrievers. STUDY DESIGN Longitudinal cohort study. ANIMALS Labrador retriever dogs (n=48). METHODS Puppies from 7 litters were allotted to 2 groups of 24 dogs each. Diet-restricted (DR) dogs received 25% fewer calories than control-fed (CF) pair mates. Elbow radiographs were taken at 6 and 8 years of age and end of life (EOL). Gross and histopathologic evaluations for OA occurred at EOL. RESULTS There was no statistical difference in radiographic OA frequency between groups at any of the time points. Radiographic OA severity was greater for CF dogs at 6 years only (P<.05). There was no significant difference between feeding groups for histopathologic prevalence or severity of OA. Similarly, there were no differences in gross OA lesions between the groups (P>.05). Fragmented medial coronoid process, un-united anconeal process, and osteochondrosis were not present in any elbow. CONCLUSION No differences in prevalence or severity of radiographic and histopathologic elbow OA were found between feeding groups. Diet restriction resulted in a 1.8-year extension in median lifespan but no additional incremental worsening of elbow disease. Evaluation at time points <6 years may have revealed larger differences in OA prevalence and severity between the dietary groups. CLINICAL RELEVANCE These findings support calorie restriction as a clinical tool to slow progression of elbow OA.

Evaluation of the relationship between Orthopedic Foundation for Animals' hip joint scores and PennHIP distraction index values in dogs

OBJECTIVE To compare 2 screening methods for detecting evidence of hip dysplasia (Orthopedic Foundation for Animals [OFA] and PennHIP) in dogs. DESIGN Diagnostic test evaluation study. Animals-439 dogs >or= 24 months of age that received routine hip joint screening from June 1987 through July 2008. PROCEDURES Dogs were sedated, and PennHIP radiography was performed (hip joint- extended [HE], compression, and distraction radiographic views). The HE radiographic view was submitted for OFA evaluation. A copy of the HE radiographic view plus the compression and distraction radiographic views were submitted for routine PennHIP evaluation, including quantification of hip joint laxity via the distraction index (DI). RESULTS 14% (60/439) of dogs had hip joints scored as excellent by OFA standards; however, 52% (31/60) of those had a DI >or= 0.30 (range, 0.14 to 0.61). Eighty-two percent of (183/223) dogs with OFA-rated good hip joints had a DI >or= 0.30 (range, 0.10 to 0.77), and 94% (79/84) of dogs with OFA-rated fair hip joints had a DI >or= 0.30 (range, 0.14 to 0.77). Of all dogs with fair to excellent hip joints by OFA standards, 80% (293/367) had a DI >or= 0.30. All dogs with OFA-rated borderline hip joints or mild, moderate, or severe hip dysplasia had a DI >or= 0.30 (range, 0.30 to 0.83). CONCLUSION AND CLINICAL RELEVANCE Dogs judged as phenotypically normal by the OFA harbored clinically important passive hip joint laxity as determined via distraction radiography. Results suggested that OFA scoring of HE radiographs underestimated susceptibility to osteoarthritis in dogs, which may impede progress in reducing or eliminating hip dysplasia through breeding.

The Effects of Lifetime Food Restriction on the Development of Osteoarthritis in the Canine Shoulder

OBJECTIVE To report effects of age and lifetime food restriction on development and progression of shoulder joint osteoarthritis (OA) in Labrador retriever dogs. STUDY DESIGN Longitudinal life-span, cohort study. ANIMALS Labrador retriever dogs (n=48). METHODS Littermates were paired (gender, weight) to make 24 pairs of genetically similar dogs. Each diet-restricted (DR) pair-mate was fed daily 75% of the same diet consumed by its control-fed (CF) pair-mate for life. Shoulders were evaluated radiographically at years 6, 8, and end of life (EOL). At EOL shoulders were evaluated grossly and by histopathology for OA. RESULTS Radiographic evidence of shoulder OA was identified in 78% of dogs. Severity of radiographic shoulder OA at 6 (P<.03) and 8 years (P<.02) was significantly lower among DR dogs compared with CF dogs. Pooled gross evaluation results revealed 40 of 46 dogs had cartilage erosion on the caudal aspect of the humeral head. By EOL, 91% of dogs had histopathologic changes consistent with OA. CONCLUSION There was a high overall prevalence of radiographic, gross, and histologic OA among dogs. Substantial disparity was found between radiographic evidence of OA (at EOL) and characteristic changes visible by gross and histologic examination. CLINICAL RELEVANCE Radiographic evaluation correlates poorly with severity of shoulder joint pathology. The benefits of DR on shoulder OA are consistent with the demonstrated effect of DR in delaying species- and strain-specific diseases of aging.

Prospective Clinical Trial to Compare Vincristine and Vinblastine in a COP‐Based Protocol for Lymphoma in Cats

BACKGROUND Current standard chemotherapy protocols for lymphoma in cats carry risks of gastrointestinal toxicity, which can decrease quality of life and complicate response assessment. Protocols with less gastrointestinal toxicity may improve treatment tolerance. HYPOTHESIS/OBJECTIVES The study purpose was to compare response rate, outcome, and toxicity between cats that received vincristine or vinblastine as part of combination chemotherapy for lymphoma. We hypothesized that vinblastine would have similar efficacy, but less gastrointestinal toxicity, compared with vincristine. ANIMALS Forty client-owned cats with confirmed diagnosis of lymphoma. METHODS Cats were randomized to 1 of 2 treatment arms and received weekly COP-based chemotherapy for 6 months or until disease progression. Response rate, progression-free survival (PFS), lymphoma-specific survival (LSS), and incidence and severity of gastrointestinal and hematologic toxicity were compared between arms. Arm cross-over occurred if specific gastrointestinal toxicity criteria were noted. RESULTS Cats in both arms had similar response rates, PFS, and LSS (48 versus 64 days, P = .87; 139 versus 136 days, P = .96). Cats that received vincristine were significantly more likely to switch arms based on gastrointestinal toxicity than cats that received vinblastine (44.4 versus 10.5%, P = .02). Lower baseline weight was significantly negatively associated with PFS and LSS (P = .01, P = .003, respectively). Baseline anemia was significantly negatively associated with LSS (P = .04). CONCLUSIONS AND CLINICAL IMPORTANCE Results suggest that vinblastine is a reasonable alternative to vincristine in the treatment of some cats with lymphoma. Baseline body weight remains a significant prognostic factor for cats with lymphoma.

Lymphoma in cats treated with a weekly cyclophosphamide-, vincristine-, and prednisone- based protocol: 114 cases (1998-2008)

OBJECTIVE To evaluate the clinical response rate, progression-free survival time, overall survival time, and possible prognostic factors associated with a cyclophosphamide-, vincristine-, and prednisone (COP)-based chemotherapy protocol in cats with lymphoma. DESIGN Retrospective case series. ANIMALS 114 cats with lymphoma. PROCEDURES Medical records of cats receiving a weekly COP-based chemotherapy protocol from 1998 to 2008 at the Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania were evaluated for information regarding signalment, anatomic site of involvement, cell morphology, treatment, and outcome. Retroviral status, baseline weight, substage, anatomic location, dose delays, dose reductions, and response to treatment were evaluated for prognostic importance. RESULTS The majority of cases (94 [82.4%]) were substage b, and the most common anatomic site was the gastrointestinal tract (57 [50%]). Clinical response rate after the first chemotherapy cycle was 47.4%. Response to treatment was significantly associated with progression-free survival time and overall survival time, whereas substage was significantly associated with progression-free survival time. The median progression-free survival time and overall survival time were 65.5 and 108 days, respectively. Compared with nonresponders, responders had significantly longer median progression-free survival time (364 vs 31 days) and median overall survival time (591 vs 73 days). CONCLUSIONS AND CLINICAL RELEVANCE Clinical response after 1 cycle of COP-based chemotherapy was predictive for progression-free survival time and overall survival time in cats with lymphoma; therefore, response after 1 cycle of chemotherapy could be used to guide decisions about further treatment. No new prognostic factors were identified.

Un-United Medial Epicondyle of the Humerus: Radiographic Prevalence and Association with Elbow Osteoarthritis in a Cohort of Labrador Retrievers

OBJECTIVE To longitudinally characterize the radiographic appearance of un-united medial epicondyle (UME) of the humerus, evaluate UME association with osteoarthritis (OA) and consider its relevance to the elbow dysplasia complex. STUDY DESIGN Longitudinal cohort study. ANIMALS Labrador retrievers (n=48) from 7 litters. METHODS Forty-eight same-sex littermates were paired for this lifetime feeding study. One of each pair was control-fed; the pair mate was fed 25% less than the control each day. Elbows of 46 surviving dogs were radiographed at ages 6 and 8 years, and/or at end-of-life (EOL). Elbow histopathology was done EOL, although UME lesions were not evaluated histologically. RESULTS Seven dogs (15%) had UME, representing 5 litters; 4 were control-fed, 3 diet-restricted. Six (86%) dogs had unilateral lesions; 1 was bilateral. UME was evident on craniocaudal (CrCd) radiographic projections by 8 years in all dogs. UME was detected in only 1 elbow by mediolateral radiographic projection. Elbow OA frequency in UME affected dogs was not significantly different from the remaining study population. Histopathologic lesions were bilateral in dogs with unilateral UME. CONCLUSIONS UME may be more common than previously thought. Most cases were unilateral and diet restriction had no effect on frequency. The CrCd view was critical for diagnosis. Elbow OA was not directly associated with UME. CLINICAL RELEVANCE Infrequent diagnosis of UME could result from infrequent radiography and use of only the flexed lateral radiographic projection required by the Orthopedic Foundation for Animals for elbow screening. Like hip evaluations, screening for UME should be continued for life, until genetics are better understood. Lack of association between UME and elbow OA suggests that UME is not likely a component of elbow dysplasia.

Effects of osteoarthritis on radiographic measures of laxity and congruence in hip joints of Labrador Retrievers

OBJECTIVE- To determine effects of hip joint osteoarthritis on radiographic measures of hip joint laxity and congruence. DESIGN- Longitudinal study. ANIMALS- 40 Labrador Retrievers. PROCEDURES- Dogs were assigned to 2 groups based on radiographic evidence of osteoarthritis. Dogs in the osteoarthritis group were free of osteoarthritis at initial radiographic evaluation (t(1)) and developed osteoarthritis by a subsequent radiographic evaluation (t(2)). Dogs in the nonosteoarthritis group had no radiographic osteoarthritis at either evaluation. Hip joint laxity was quantified by use of the distraction index (DI) from a distraction radiographic view and use of the Norberg angle (NA) from a ventrodorsal hip-extended radiographic view. The compression index (CI) from a compression radiographic view was used as a measure of joint congruence (concentricity). RESULTS- Hip joint laxity (NA or DI) did not change over time in the nonosteoarthritis group. Mean hip joint laxity (NA and DI) for the osteoarthritis group was greater at t(1) than for the nonosteoarthritis group. With the onset of osteoarthritis, mean NA decreased significantly and mean CI increased significantly, but mean DI remained unchanged. CONCLUSIONS AND CLINICAL RELEVANCE- No radiographic evidence for compensatory hip joint tightening associated with osteoarthritis was detected. Hip-extended radiography revealed that hip joints got looser with osteoarthritis and NA decreased. Hip joint laxity (DI) on distraction radiographs was unchanged by the onset of osteoarthritis and remained constant in the osteoarthritis and nonosteoarthritis groups at both evaluations. However, the CI increased with osteoarthritis, as reflected in nonzero indices (incongruence). The CI may be a valid marker for early hip joint osteoarthritis.