Barbara E. Kitchell

Prognostic Markers for Canine Melanocytic Neoplasms: A Comparative Review of the Literature and Goals for Future Investigation

Many studies have evaluated various prognostic markers for canine melanocytic neoplasms either as primary or secondary goals; however, design, methodology, and statistical validation vary widely across these studies. The goal of this article was to evaluate and compare published canine melanocytic neoplasm studies in relation to the principals established in the Recommended Guidelines for the Conduct and Evaluation of Prognostic Studies in Veterinary Oncology. Based on this evaluation, we determined which parameters currently have the most statistically supported validity for prognostic use in canine melanocytic neoplasia. This information can also be used as part of evidence-based prospective evaluations of treatment regimens. Additionally, we highlight areas in which the current data are incomplete and that warrant further evaluation. This article represents an initiative of the American College of Veterinary Pathologists Oncology Committee and has been reviewed and endorsed by the World Small Animal Veterinary Association.

Recommended guidelines for the conduct and evaluation of prognostic studies in veterinary oncology.

There is an increasing need for more accurate prognostic and predictive markers in veterinary oncology because of an increasing number of treatment options, the increased financial costs associated with treatment, and the emotional stress experienced by owners in association with the disease and its treatment. Numerous studies have evaluated potential prognostic and predictive markers for veterinary neoplastic diseases, but there are no established guidelines or standards for the conduct and reporting of prognostic studies in veterinary medicine. This lack of standardization has made the evaluation and comparison of studies difficult. Most important, translating these results to clinical applications is problematic. To address this issue, the American College of Veterinary Pathologists Oncology Committee organized an initiative to establish guidelines for the conduct and reporting of prognostic studies in veterinary oncology. The goal of this initiative is to increase the quality and standardization of veterinary prognostic studies to facilitate independent evaluation, validation, comparison, and implementation of study results. This article represents a consensus statement on the conduct and reporting of prognostic studies in veterinary oncology from veterinary pathologists and oncologists from around the world. These guidelines should be considered a recommendation based on the current state of knowledge in the field, and they will need to be continually reevaluated and revised as the field of veterinary oncology continues to progress. As mentioned, these guidelines were developed through an initiative of the American College of Veterinary Pathologists Oncology Committee, and they have been reviewed and endorsed by the World Small Animal Veterinary Association.

Development of a survey instrument to assess health-related quality of life in small animal cancer patients treated with chemotherapy

OBJECTIVEnTo develop a quality of life (QOL) survey for use in a canine cancer chemotherapy setting, validate the instruments utility, identify key questions that facilitate client and clinician communication regarding decisions in patient care, and use human and veterinary QOL literature to develop a comprehensive yet simple proxy survey instrument.nnnDESIGNnSurvey.nnnANIMALSn29 canine chemotherapy patients.nnnPROCEDURESnPatients were evaluated by both owners and veterinarians at the time of initial visit to the clinic and at 3 and 6 weeks after the initiation of chemotherapy. This survey consisted of a longitudinal evaluation of QOL with 6 components addressing the animals QOL retrospectively, before onset of cancer; changes in the animals QOL since manifestation of disease; changes in the animals QOL with regard to treatment response; owners QOL and its impact on priorities in decision making; clinicians impression of the owners priorities and QOL; and clinicians impression of the dogs QOL.nnnRESULTSnMultiple regression analysis indicated 3 significant predictors of canine cancer patient QOL to be play behaviors, signs of illness, and canine happiness as perceived by owners.nnnCONCLUSIONS AND CLINICAL RELEVANCEnThe QOL instrument was easy to use and enhanced client perception of patient care and clinician concern. Owners enjoyed the opportunity to complete the survey. Since questions regarding play behaviors, clinical signs of disease, and canine happiness were significant indicators of changes in QOL, these should be included in future studies. Quality of life assessment may facilitate treatment decisions and assessment of canine patients undergoing chemotherapy.

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.

Combined Gemcitabine and Carboplatin Therapy for Carcinomas in Dogs

BACKGROUNDnResponse and adverse reactions to combined gemcitabine (GEM) and carboplatin (CARBO) therapy in dogs with carcinomas are not documented.nnnHYPOTHESISnGEM and CARBO are safe for the treatment of dogs with carcinomas.nnnANIMALSnThirty-seven dogs with histologically or cytologically confirmed carcinomas.nnnMETHODSnProspective clinical trial. Dogs were treated with GEM (2 mg/kg, 20-30-minute infusion IV) on Days 1 and 8 and 4 hours later, CARBO (10 mg/kg IV) on Day 1. The cycle was repeated on Day 22.nnnRESULTSnThirty-seven dogs (29 with measurable tumor) received a median of 2 cycles (range 0.5-6) for a total of 101 cycles administered. Twelve dogs (32%) developed neutropenia (3 Grade 3, and 5 Grade 4) and 9 (24%) thrombocytopenia (2 Grade 3, and 1 Grade 4). Dogs >20 kg were twice as likely to develop thrombocytopenia (P= .023). Twenty-seven dogs (73%) had evidence of gastrointestinal (GI) toxicosis, but most signs were of mild to moderate severity and self-limiting. One dog died of treatment-related complications. Overall tumor response rate was 13%. One dog with metastatic prostatic carcinoma achieved a complete remission and 1 dog with intestinal adenocarcinoma and 1 with tonsillar squamous cell carcinoma achieved partial remission. Twelve dogs achieved stable disease for a median of 72 days.nnnCONCLUSION AND CLINICAL IMPORTANCEnGEM and CARBO combination causes mild to moderate hematologic and GI toxicosis in dogs with carcinoma. Response rate in this study was modest, and optimization of dosing of this combination is required.

Use of a balloon-expandable metallic stent to relieve malignant urethral obstruction in a cat

CASE DESCRIPTIONnA 19-year-old neutered male domestic shorthair cat was evaluated because of signs of urinary tract obstruction.nnnCLINICAL FINDINGSnPhysical examination findings were consistent with urethral obstruction, and a mass could be palpated in the region of the bladder neck. Abdominal ultrasonography and thoracic radiography revealed a mass in the trigone of the urinary bladder and a solitary mass in the left caudal lung lobe. Cytologic examination of the urine sediment, samples obtained by means of traumatic urethral catheterization, and fine-needle aspirates of the bladder mass did not result in a diagnosis.nnnTREATMENT AND OUTCOMEnA balloon-expandable metallic stent was placed in the proximal portion of the urethra to relieve the malignant obstruction. After stent placement, the cat had signs of urinary incontinence and detrusor atony, both of which resolved with medical treatment. The cat was euthanized 1 month after stent placement because of progressive azotemia. Histologic examination of necropsy samples revealed grade III urothelial carcinoma and papillary pulmonary adenocarcinoma.nnnCLINICAL RELEVANCEnFindings suggested that stent placement may be a viable palliative treatment in cats with malignant urinary obstruction.

Malignant Lymphoma in African Lions (Panthera Leo)

Malignant lymphoma has become an increasingly recognized problem in African lions (Panthera leo). Eleven African lions (9 male and 2 female) with clinical signs and gross and microscopic lesions of malignant lymphoma were evaluated in this study. All animals were older adults, ranging in age from 14 to 19 years. Immunohistochemically, 10 of the 11 lions had T-cell lymphomas (CD3+, CD79a–), and 1 lion was diagnosed with a B-cell lymphoma (CD3–, CD79a+). The spleen appeared to be the primary site of neoplastic growth in all T-cell lymphomas, with involvement of the liver (6/11) and regional lymph nodes (5/11) also commonly observed. The B-cell lymphoma affected the peripheral lymph nodes, liver, and spleen. According to the current veterinary and human World Health Organization classification of hematopoietic neoplasms, T-cell lymphoma subtypes included peripheral T-cell lymphoma (4/11), precursor (acute) T-cell lymphoblastic lymphoma/leukemia (2/11), chronic T-cell lymphocytic lymphoma/leukemia (3/11), and T-zone lymphoma (1/11). The single B-cell lymphoma subtype was consistent with diffuse large B-cell lymphoma. Feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) testing by immunohistochemistry on sections of malignant lymphoma was negative for all 11 lions. One lion was seropositive for FeLV. In contrast to domestic and exotic cats, in which B-cell lymphomas are more common than T-cell lymphomas, African lions in this study had malignant lymphomas that were primarily of T-cell origin. Neither FeLV nor FIV, important causes of malignant lymphoma in domestic cats, seems to be significant in the pathogenesis of malignant lymphoma in African lions.

Tolerability of gemcitabine and carboplatin doublet therapy in cats with carcinomas.

BACKGROUNDnThis study was performed to determine the toxicity of gemcitabine-carboplatin doublet therapy in cats with carcinomas.nnnHYPOTHESISnGemcitabine and carboplatin are safe in tumor-bearing cats.nnnANIMALSnTwenty cats with spontaneously occurring carcinomas.nnnMETHODSnA cohort of 6 cats received gemcitabine (2 mg/kg IV) on days 1, 8, and 15 and carboplatin (10 mg/kg IV) immediately after gemcitabine on day 1 of a 21-day cycle. A 2nd cohort of 14 cats received carboplatin 4 hours after gemcitabine on day 1 and gemcitabine on day 8 but not day 15. The cycles were repeated every 21 days.nnnRESULTSnCats in the 1st cohort received a median of 3.75 cycles per animal (range, 1-6). Two cats (33.3%) developed grade 3 or 4 neutropenia, 1 (16.7%) grade 4 thrombocytopenia, and 1 (16.7%) grade 3 gastrointestinal toxicity. Gemcitabine dose reductions and treatment delays occurred in 1 and 4 cats, respectively. Cats in the 2nd cohort received a median of 2 cycles per animal (range, 0.5-10). Two cats (14.3%) had grade 3 or 4 neutropenia and 1 (7.1%) had grade 3 and 4 gastrointestinal toxicity. One cat required gemcitabine dose reduction and 6 had treatment delays. In the 2nd cohort, of 11 cats with measurable tumors, there was 1 complete response (pancreatic carcinoma) and 1 partial response (squamous cell carcinoma, receiving concurrent nonsteroidal anti-inflammatory drugs).nnnCONCLUSIONS AND CLINICAL IMPORTANCEnGemcitabine-carboplatin combination appears moderately well tolerated in tumor-bearing cats. Minimal patient benefit suggests that alternative schedules or combinations of gemcitabine with other agents should be explored.

Pharmacologic Inhibition of MEK Signaling Prevents Growth of Canine Hemangiosarcoma

Angiosarcoma is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As a model for human angiosarcoma, we studied primary cells and tumorgrafts derived from canine hemangiosarcoma (HSA), which is also an endothelial malignancy with similar presentation and histology. Primary cells isolated from HSA showed constitutive extracellular signal–regulated kinase (ERK) activation. The mitogen-activated protein/extracellular signal–regulated kinase (MEK) inhibitor CI-1040 reduced ERK activation and the viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro. HSA-derived primary cells were also sensitive to sorafenib, an inhibitor of B-Raf and multireceptor tyrosine kinases. In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts. Sorafenib decreased tumor size in both in vivo models, although cardiac tumorgrafts were more sensitive. In human angiosarcoma, we noted that 50% of tumors stained positively for phosphorylated ERK1/2 and that the expression of several MEK-responsive transcription factors was upregulated. Our data showed that MEK signaling is essential for the growth of HSA in vitro and in vivo and provided evidence that the same pathways are activated in human angiosarcoma. This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human angiosarcoma, and it highlights the use of spontaneous canine cancers as a model of human disease. Mol Cancer Ther; 12(9); 1701–14. ©2013 AACR.

TREATMENT OF MALIGNANT LYMPHOMA IN AN AFRICAN LION (PANTHERA LEO)

Abstract A 14 yr-old male, vasectomized African lion (Panthera leo) exhibited mild weight loss despite adequate appetite. Splenomegaly was diagnosed on physical examination. On the basis of hematology and clinical pathology, malignant lymphoma with chronic lymphocytic leukemia was diagnosed. Abdominal exploratory surgery and splenectomy were performed. Histologic examination and immunohistochemistry confirmed a small cell peripheral T-cell lymphoma. Initial treatments consisted of doxorubicin and prednisone, with later addition of lomustine. The lion remained in clinical remission at 2 mo, 6 mo, and 12 mo postchemotherapy physical examinations. The lion survived 504 days from initial diagnosis. At necropsy, the only lesions consistent with lymphoma were localized epitheliotrophic infiltrates of small neoplastic T lymphocytes within the nasopharyngeal epithelium and the underlying submucosa observed on microscopic examination.