Michael O. Childress

Clinical Trial of Vinblastine in Dogs with Transitional Cell Carcinoma of the Urinary Bladder

BACKGROUND Transitional cell carcinoma (TCC) of the urinary bladder of dogs can be a difficult cancer to treat, and effective therapies are limited. Vinblastine has been used in humans with TCC and has potent anti-proliferative effects against canine TCC cells in vitro. OBJECTIVES To determine the antitumor activity and toxicoses of vinblastine in dogs with urinary bladder TCC. ANIMALS Animals selected were 28 privately owned dogs that presented to the Purdue University Veterinary Teaching Hospital (PUVTH) with measurable, histologically confirmed TCC. METHODS Prospective clinical trial: The starting vinblastine dosage was 3.0 mg/m(2) i.v. every 2 weeks. Treatment continued until cancer progression or unacceptable toxicoses occurred. Complete evaluations (physical exam, complete blood count [CBC], serum biochemical profile, urinalysis, thoracic radiography, abdominal ultrasound [US]) were performed at 8-week intervals. Urinary tract US with bladder tumor mapping was performed monthly. Toxicoses were graded according to Veterinary Co-Operative Oncology Group (VCOG) criteria. RESULTS Tumor responses included 10 (36%) partial remission, 14 (50%) stable disease, and 4 (14%) progressive disease. The median progression free interval was 122 days (range, 28-399 days). The median survival time was 147 days (range, 28-476 days) from 1st vinblastine treatment to death and 299 days (range, 43-921 days) from diagnosis to death. The majority of dogs (27 of 28) did not have clinically relevant adverse effects. Seventeen of 28 (61%) dogs required dosage reductions because of neutropenia. CONCLUSION AND CLINICAL IMPORTANCE Vinblastine has antitumor activity against TCC in dogs and can be considered another treatment option for this cancer.

Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occurring cancer.

The purpose of this study was to assess the toxicoses and antitumor activity of metronomic chlorambucil at a dosage of 4 mg m(-2) daily in dogs with naturally occurring cancer. Thirty-six dogs were enrolled in the study. The protocol was well tolerated with no grade 3 or 4 toxicoses noted. Complete remission was achieved, and lasted over 35 weeks in three dogs (mast cell tumour, soft tissue sarcoma and thyroid carcinoma). Partial remission was noted in 1 dog with histiocytic sarcoma (39 weeks duration) for an overall remission rate of 11% (4 of 36). Stable disease was noted in 17 dogs (47%) with various other cancers. The median progression-free interval was 61 days, and the median survival time was 153 days. Chlorambucil given in a metronomic protocol showed antitumor activity in dogs with a variety of naturally occurring cancers.

Metronomic administration of chlorambucil for treatment of dogs with urinary bladder transitional cell carcinoma.

OBJECTIVE To determine the antitumor effects and toxicoses of metronomic oral administration of a low dose of chlorambucil in dogs with transitional cell carcinoma (TCC). DESIGN Prospective clinical trial. ANIMALS 31 client-owned dogs with TCC for which prior treatments had failed or owners had declined other treatments. Procedures-Chlorambucil (4 mg/m2, PO, q 24 h) was administered to dogs. Before and at scheduled times during treatment, evaluations of dogs included physical examination, CBC, serum biochemical analyses, urinalysis, thoracic and abdominal imaging including cystosonography for measurement of TCCs, and grading of toxicoses. RESULTS 29 of 31 dogs had failed prior TCC treatment. Of the 30 dogs with available data, 1 (3%) had partial remission (≥ 50% reduction in tumor volume), 20 (67%) had stable disease (< 50% change in tumor volume), and 9 (30%) had progressive disease (≥ 50% increase in tumor volume or development of additional tumors); 1 dog was lost to follow-up. The median progression-free interval (time from the start of chlorambucil treatment to the day progressive disease was detected) for the dogs was 119 days (range, 7 to 728 days). The median survival time of dogs from the time of the start of chlorambucil treatment was 221 days (range, 7 to 747 days). Few toxicoses were detected; chlorambucil administration was discontinued because of toxicoses in only 1 dog. CONCLUSIONS AND CLINICAL RELEVANCE Metronomic administration of chlorambucil was well tolerated, and 70% of dogs had partial remission or stable disease. Metronomic administration of chlorambucil may be a treatment option for dogs with TCC.

Prospective molecular profiling of canine cancers provides a clinically relevant comparative model for evaluating personalized medicine (PMed) trials

Background Molecularly-guided trials (i.e. PMed) now seek to aid clinical decision-making by matching cancer targets with therapeutic options. Progress has been hampered by the lack of cancer models that account for individual-to-individual heterogeneity within and across cancer types. Naturally occurring cancers in pet animals are heterogeneous and thus provide an opportunity to answer questions about these PMed strategies and optimize translation to human patients. In order to realize this opportunity, it is now necessary to demonstrate the feasibility of conducting molecularly-guided analysis of tumors from dogs with naturally occurring cancer in a clinically relevant setting. Methodology A proof-of-concept study was conducted by the Comparative Oncology Trials Consortium (COTC) to determine if tumor collection, prospective molecular profiling, and PMed report generation within 1 week was feasible in dogs. Thirty-one dogs with cancers of varying histologies were enrolled. Twenty-four of 31 samples (77%) successfully met all predefined QA/QC criteria and were analyzed via Affymetrix gene expression profiling. A subsequent bioinformatics workflow transformed genomic data into a personalized drug report. Average turnaround from biopsy to report generation was 116 hours (4.8 days). Unsupervised clustering of canine tumor expression data clustered by cancer type, but supervised clustering of tumors based on the personalized drug report clustered by drug class rather than cancer type. Conclusions Collection and turnaround of high quality canine tumor samples, centralized pathology, analyte generation, array hybridization, and bioinformatic analyses matching gene expression to therapeutic options is achievable in a practical clinical window (<1 week). Clustering data show robust signatures by cancer type but also showed patient-to-patient heterogeneity in drug predictions. This lends further support to the inclusion of a heterogeneous population of dogs with cancer into the preclinical modeling of personalized medicine. Future comparative oncology studies optimizing the delivery of PMed strategies may aid cancer drug development.

Characterization and treatment of transitional cell carcinoma of the abdominal wall in dogs: 24 cases (1985-2010).

OBJECTIVE To determine uroplakin III expression, potential etiologic factors, biological behavior, and treatment response of transitional cell carcinoma (TCC) in the abdominal wall (ABWTCC) in dogs. DESIGN Retrospective case series. ANIMALS 24 dogs with TCC of the urinary tract that also had histopathologic confirmation of ABWTCC. PROCEDURES Medical records, histologic slides, radiographs, and ultrasonographic images of dogs with ABWTCC between July 1, 1985, and December 31, 2010, were reviewed. In available tissue specimens, immunohistochemistry was used to detect uroplakin III expression in the ABWTCC and in the primary tumor. RESULTS The ABWTCC lesions ranged from < 2 to > 20 cm in diameter. Uroplakin III was expressed in 19 of 20 primary tumors and 17 of 17 ABWTCCs. Transitional cell carcinoma in the abdominal wall developed significantly more often in dogs that had undergone cystotomy (18/177 [10.2%]) than in those that had not (6/367 [1.6%]). In 1 dog that had not undergone cystotomy, TCC had invaded through the urinary bladder wall and spread down the median ligament to the abdominal wall. None of 18 dogs that received anticancer drugs had remission of the ABWTCC once clinically detected; median survival time after ABWTCC detection was 57 days (range, 0 to 324 days). CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that ABWTCC is uncommon, but once TCC becomes established and clinically detectable in the abdominal wall, it carries a poor prognosis. It is crucial to minimize risk of TCC seeding at surgery. Percutaneous sampling of TCC should be avoided. Uroplakin III is commonly expressed in ABWTCC.

Results of biopsy via transurethral cystoscopy and cystotomy for diagnosis of transitional cell carcinoma of the urinary bladder and urethra in dogs: 92 cases (2003-2008)

OBJECTIVE To assess the diagnostic utility of transurethral cystoscopic biopsy in dogs with histologically confirmed transitional cell carcinoma (TCC) of the urinary bladder and urethra. DESIGN Retrospective case series. ANIMALS 92 dogs with histologically confirmed TCC. PROCEDURES Information on sex, breed, neuter status, body weight, tumor location, biopsy method, number of biopsy procedures, experience level of clinician performing biopsy, and quality of biopsy sample was obtained from medical records. The association of variables with likelihood of achieving a diagnostic-quality biopsy sample was evaluated by use of logistic regression. RESULTS If used as the initial biopsy method, cystoscopic biopsy samples were of diagnostic quality in 65% of male dogs and 96% of female dogs with histologically confirmed TCC. Cystoscopic biopsy samples were significantly more likely to be of diagnostic quality in female dogs than in male dogs. CONCLUSIONS AND CLINICAL RELEVANCE Cystoscopic biopsy is an effective method to obtain biopsy samples in dogs with TCC of the bladder and urethra. Cystoscopy is more likely to produce a diagnostic-quality biopsy sample in female dogs with TCC than in male dogs with TCC. Cystoscopy should be considered as a primary means of biopsy in male and female dogs with masses of the urinary bladder or urethra.

Syk Interacts with and Phosphorylates Nucleolin To Stabilize Bcl-xL mRNA and Promote Cell Survival

ABSTRACT The Syk protein tyrosine kinase, a well-characterized regulator of immune cell function, plays an increasingly recognized role in tumorigenesis as a promoter of cell survival in both hematological and nonhematological malignancies. We show here that the expression of Syk in MCF7 or MDA-MB-231 breast cancer cells or in DG75 B-lymphoma cells protects cells from apoptosis induced by oxidative or genotoxic stress by stabilizing the mRNA for Bcl-xL, an antiapoptotic protein. Syk binds robustly to nucleolin and phosphorylates it on tyrosine, enhancing its ability to bind the Bcl-xL mRNA. Consequently, reducing the level of nucleolin by RNA interference attenuates the ability of Syk to protect cells from stress-induced cell death.

Hematologic abnormalities in the small animal cancer patient.

Veterinarians will encounter hematologic abnormalities routinely while treating small animal cancer patients. Some of these abnormalities, such as monoclonal gammopathy, are relatively rare and highly associated with specific neoplasms. Thus, their detection should compel a search for underlying cancer. Other hematologic abnormalities, such as anemia or thrombocytopenia, are very common in cancer patients, and their identification should prompt clinicians to consider the different mechanisms by which they may have arisen and whether further diagnostic tests are needed to fully characterize their etiology. Although cancer-related hematologic abnormalities are frequently described in the veterinary literature, the incidence, prevalence, and clinical significance of these abnormalities are less well-defined. Anemia and coagulopathies are major causes of morbidity and mortality in human cancer patients, and may have a tremendous impact on disease progression and tumor response to antineoplastic therapy. It is plausible that the same is true for veterinary cancer patients, given the pathological and biological similarity between human and small animal tumors. Future studies should address the epidemiology and clinical significance of these, and perhaps other, hematologic abnormalities in order to determine whether therapeutic intervention to correct them may improve patient outcomes.

Consequences of intratumoral injection of a herbal preparation containing blood root (Sanguinaria canadensis) extract in two dogs

CASE DESCRIPTION 2 dogs were referred for surgical removal of cutaneous tumors that had previously been treated by intratumoral injection of a herbal preparation containing blood-root (Sanguinaria canadensis) extract. CLINICAL FINDINGS 11 days following injection of bloodroot extract into a small dermal tumor, dog 1 developed a large, soft, fluctuant cutaneous mass at the site of injection. Ultrasonographic evaluation of the mass revealed a fluid-filled central cavity with increased echogenicity of the surrounding subcutaneous tissues. Dog 2 had a small dermal tumor under the left mandible that had been treated in similar fashion. However, an exuberant reaction was not observed following injection of bloodroot extract in this dog. TREATMENT AND OUTCOME Both dogs underwent surgical excision of the cutaneous tumors. Histologic evaluation revealed severe necrosis and inflammation in the excised tissues from dog 1. This dog experienced postsurgical wound complications and had a prolonged postsurgical recovery. Similar, although less severe, histopathologic findings were apparent in the excised tissues from dog 2; this dog recovered without complications. CLINICAL RELEVANCE Various products containing bloodroot are marketed on the Internet for topical and parenteral treatment of cutaneous neoplasms in domestic animals. However, the antineoplastic properties, therapeutic efficacy, and adverse effects of these products are poorly described in the veterinary literature. Clinicians should be aware of the potential for harm caused by the use of these products.

Inter- and intra-rater reliability of calliper-based lymph node measurement in dogs with peripheral nodal lymphomas

The purpose of this study was to assess reliability of lymph node measurements between and within raters in dogs with nodal lymphomas. Three raters measured lymph nodes from 20 dogs twice prior to and once after administering chemotherapy. Sum tumour volume (TV) and sum longest diameter (LD) of all lymph nodes at each time point, and the percent change in measurements following chemotherapy, were calculated for each dog. Inter- and intra-rater reliability were assessed with the intraclass correlation coefficient (ICC). ICC for inter-rater sum TV and sum LD prior to chemotherapy were 0.86 and 0.80, respectively. ICC for inter-rater sum TV and sum LD after chemotherapy were 0.95 and 0.91, respectively. ICC for percent change in sum TV and sum LD were 0.96 and 0.94, respectively. ICC for intra-rater reliability ranged from 0.90 to 0.98 for each rater. Inter- and intra-rater reliability in measurements among the three raters was good to excellent.