Kim A. Selting

Response evaluation criteria for peripheral nodal lymphoma in dogs (v1.0)--a Veterinary Cooperative Oncology Group (VCOG) consensus document.

Standardized assessment of response to therapy for lymphoma in dogs is lacking, making critical comparisons of treatment protocols difficult. This Veterinary Cooperative Oncology Group (VCOG) consensus document, based on the recommendations of a subcommittee of ACVIM board-certified veterinary oncologists, was unanimously adopted at the 29th Annual Conference of the Veterinary Cancer Society (VCS) by the VCOG membership. It has integrated guidance from the response assessment criteria established for lymphoma in human patients using standards available in routine veterinary oncology practices that are simple, repeatable and consistently applicable. These guidelines are intended only for use in dogs, where peripheral lymphadenopathy represents the principal component of their disease and as such do not critically assess extranodal disease (e.g., primary cutaneous, central nervous system, gastrointestinal). It is hoped these guidelines will be widely adopted and serve to facilitate the comparison of current and future treatment protocols used in the therapy of dogs.

Outcomes of cats with oral tumors treated with mandibulectomy: 42 cases.

Medical records of 42 cats treated with mandibulectomy for oral neoplasia at eight institutions were reviewed to determine morbidity, progression-free interval, and survival time. Progression-free and survival rates at 1 and 2 years were 56% and 49%, and 60% and 57%, respectively. Cats with squamous cell carcinoma had significantly shorter survival than cats with fibrosarcoma or osteosarcoma. Seventy-two percent of cats were dysphagic or inappetent immediately postoperatively, and 12% never regained the ability to eat. Despite acute morbidity in 98% and long-term morbidity in 76% of cats, 83% of the 30 owners providing information were satisfied with the outcome of mandibulectomy.

Recent trends in feline intestinal neoplasia: an epidemiologic study of 1,129 cases in the veterinary medical database from 1964 to 2004.

A retrospective epidemiologic study evaluated 1,129 feline intestinal tumor patients via data entered into the Veterinary Medical Database (VMDB) from 1964 to 2004. Cases were analyzed by breed, age, yr of diagnosis, tumor type, and location. The VMDB incidence of all intestinal tumors reported during this 40 yr period was 0.4%, with small intestinal tumors predominating. The most common intestinal tumor was lymphoma, but the most common nonlymphoid tumor was adenocarcinoma. The Siamese breed and increasing age after 7 yr conferred an increased risk. Intact males and females appeared to have a decreased risk compared with neutered patients, but this may be explained by the age difference among these patients as older patients were more likely to be neutered. Prospective studies evaluating neuter status predilection and prognosis are warranted.

Cardiac troponin I in canine patients with lymphoma and osteosarcoma receiving doxorubicin: comparison with clinical heart disease in a retrospective analysis

The cumulative cardiotoxicity that occurs as a result of doxorubicin chemotherapy is irreversible and can affect both quality and quantity of life for the cancer patient. Cardiac troponin I (cTnI) is a sensitive and specific marker of cardiomyocyte death. The purpose of this retrospective study was to evaluate serum concentrations of cTnI in dogs with lymphoma or osteosarcoma given doxorubicin chemotherapy, and with known cardiac outcome, based on a minimum assessment by physical examination and thoracic radiography. Serum samples were also available for cTnI measurement from seven healthy dogs given intracoronary doxorubicin. Serial serum samples obtained before, during and after doxorubicin chemotherapy showed increased cTnI concentrations in some clinical patients following chemotherapy (P = 0.0083 compared to baseline), but this did not correlate with clinical signs of cardiomyopathy. In dogs that subsequently developed cardiomyopathy however, serum cTnI concentrations were elevated before clinical signs became evident (confirmed with echocardiography).

Cloning and expression of canine CD25 for validation of an anti-human CD25 antibody to compare T regulatory lymphocytes in healthy dogs and dogs with osteosarcoma.

T regulatory cells (Tregs) are a unique subset of T helper cells that serve to modify/inhibit effector cells of the immune system and thus are essential to prevent autoimmunity. Overzealous Treg activity may contribute to impaired immune responses to cancer. Tregs can be phenotypically identified by proteins expressed on the cell surface (CD4 and CD25) and inside the cell (forkhead box3 (FoxP3)), although in dogs, no anti-canine CD25 antibody exists. We hypothesized that a mouse anti-human CD25 antibody definitively recognizes the canine protein and can be used to identify Tregs in dogs. We describe cloning and transfection of the canine CD25 gene into human HeLa cells with subsequent expression of the canine protein on the cell surface detected using an anti-human CD25 antibody in a flow cytometric assay. Validation of this antibody was used to identify CD4+CD25+FoxP3+ Tregs in 39 healthy dogs and 16 dogs with osteosarcoma (OSA). Results were expressed in five different ways and showed significantly fewer %CD4+CD25+ T lymphocytes expressing FoxP3 in blood of older dogs (>/=7 years) compared with the other two age groups (<2 and 2-6 years) (p<0.001) and fewer %CD4+CD25+FoxP3+ Tregs in the tumor draining lymph nodes of OSA patients compared to the unrelated lymph node (p=0.049). However, there was no significant difference in % Tregs in the peripheral blood or lymph nodes between the control dogs and those with OSA. While the CD25 antibody can be successfully used in a flow cytometric assay to identify Tregs, this study does not support clinical utility of phenotypic recognition of Tregs in dogs with OSA.

Retrospective evaluation of adjunctive doxorubicin for the treatment of feline mammary gland adenocarcinoma: 67 cases.

Medical records for 67 cats with histologically confirmed mammary gland adenocarcinomas treated with adjunctive doxorubicin from June 1994 through December 2002 were reviewed. Data were examined to evaluate factors influencing disease-free interval (DFI) and survival time. The Kaplan-Meier median survival time of cats that received surgery and doxorubicin was 448 days. The Kaplan-Meier median DFI was 255 days. Significant univariate prognostic factors for DFI included histological subtype, completion of initial chemotherapy, development of metastatic disease, and location of metastatic disease. Significant univariate prognostic factors for survival included tumor volume, the development of metastatic disease, and location of metastatic disease.

Safety evaluation of combination vinblastine and toceranib phosphate (Palladia®) in dogs: a phase I dose‐finding study

Combining drugs with known single-agent activity that lack overlapping dose-limiting toxicities (DLT) and exert antitumour activity through different mechanisms could improve clinical outcome. As toceranib and vinblastine meet these requisites, a phase I trial was performed in combination in dogs with mast cell tumours. The DLT for the simultaneous combination was neutropenia and the maximally tolerated dose was vinblastine (1.6 mg m(-2) every other week) concurrent with toceranib (3.25 mg kg(-1) PO, every other day). This represents greater than a 50% reduction in dose intensity for vinblastine (compared with single-agent use) and as such does not support this combination based on current drug combination paradigms. Although a strict adherence to dose paradigms speaks against the combination, evidence of significant activity (71% objective response) and enhanced myelosuppression suggest additive or synergistic activity. A prospective randomized evaluation comparing this combination with standard single-agent treatments would seem prudent to interrogate this potential.

Feasibility and Safety of Targeted Cisplatin Delivery to a Select Lung Lobe in Dogs via the AeroProbe® Intracorporeal Nebulization Catheter

Delivery of drugs by airway can minimize systemic toxicity and maximize local drug concentrations. Most cancers metastasize to the lungs. Our purpose was to determine platinum concentrations in the lung after targeted delivery of cisplatin (CDDP) with an intracorporeal nebulizing catheter (INC), and to determine the safety of escalating doses of inhaled CDDP. In anesthetized and mechanically ventilated healthy dogs, the INC (AeroProbe) was introduced via flexible bronchoscope into the right caudal lung lobe (RCLL) and CDDP (10 mg/m2) administered. Tissue and serum platinum concentrations were compared to those after an equivalent intravenous dose of CDDP (n = 3 dogs/group). In three additional dogs, pharmacokinetics were performed after inhaled and intravenous CDDP. Increasing dosages of inhaled CDDP (10, 15, 20, and 30 mg/m2) were then administered every 2 weeks. Dogs were sacrificed for postmortem examination at week 10. One additional dog was treated with a single dose of 30 mg/m2 and sacrificed 2 weeks later. Immediately following a single inhaled dose, mean CDDP levels were 44 times greater in the RCLL than in most other tissues and 15.6 times lower in the serum compared to intravenous dosing. Pharmacokinetic comparison showed that the AUC0-24h was similar (p = 0.72), but maximum serum concentration was fivefold lower after inhalation than intravenous delivery (p = 0.02). Escalating doses of inhaled CDDP (cumulative 75 mg/m2) produced no significant clinical or hematological effects, but there was radiographic and histologic evidence of severe pneumonitis with mild to moderate fibrosis confined to the RCLL. Radiographic and histologic changes were similar in the single, high-dose dog. Targeted inhaled CDDP achieved high concentrations in the treated lobe, with lower peak serum levels than after intravenous administration. Escalating doses of inhaled CDDP produced focal pneumonitis and fibrosis in the treated lung lobe with minimal clinical and hematologic effects. Targeted inhaled chemotherapy could be a promising method of treatment for primary and secondary lung tumors.

Gum arabic-coated radioactive gold nanoparticles cause no short-term local or systemic toxicity in the clinically relevant canine model of prostate cancer

Introduction Gum arabic-coated radioactive gold nanoparticles (GA-198AuNPs) offer several advantages over traditional brachytherapy in the treatment of prostate cancer, including homogenous dose distribution and higher dose-rate irradiation. Our objective was to determine the short-term safety profile of GA-198AuNPs injected intralesionally. We proposed that a single treatment of GA-198AuNPs would be safe with minimal-to-no evidence of systemic or local toxicity. Methods Nine dogs with spontaneously occurring prostatic cancer were treated. Injections were performed with ultrasound or computerized tomography guidance. Complete blood counts, chemistry panels, and urinalyses were performed at weekly intervals for 1 month and imaging was repeated 4 weeks postinjection. Planar scintigraphic images were obtained within 30 minutes of injection. Results No statistically significant difference was found in any hematologic or biochemical parameter studied, nor was any evidence of tumor swelling or abscessation found in eight dogs with repeat imaging; one dog died secondary to urethral obstruction 12 days following injection. At 30 minutes postinjection, an average of 53% of injected dose in seven dogs was retained in the prostate, with loss of remaining activity in the bladder and urethra; no systemic uptake was detected. Conclusion GA-198AuNP therapy had no short-term toxicity in the treatment of prostatic cancer. While therapeutic agent was found in the prostate immediately following injection, some loss of agent was detected in the bladder and urethra. Localization of radioactivity within the prostate was lower than anticipated and likely due to normal vestigial prostatic ducts. Therefore, further study of retention, dosimetry, long-term toxicity, and efficacy of this treatment is warranted prior to Phase I trials in men.

Serum 25-hydroxyvitamin D concentrations in dogs – correlation with health and cancer risk†

25-hydroxyvitamin D (25(OH)D) is important in bone health as well as many diseases including cancer. Supplementation may increase responsiveness of cancer cells to chemotherapy. Serum 25(OH)D, intact parathyroid hormone (iPTH) and canine C-reactive protein (c-CRP) were measured in healthy dogs and dogs with haemoabdomen. Regression analysis determined optimal 25(OH)D concentrations. In healthy dogs (n = 282), mean iPTH concentrations correlated inversely (r(2) = 0.88, P < 0.001) to 25(OH)D concentrations. Variation in both iPTH and c-CRP plateaued at 25(OH)D concentrations of 100-120 ng mL(-1) . Haemoabdomen dogs (n = 63, 43 malignant and 20 benign) had 25(OH)D concentrations ranging from 19.4 to >150 ng mL(-1) . Relative risk of cancer increased with decreasing 25(OH)D concentrations [RR = 3.9 for 25(OH)D below 40 ng mL(-1) (P = 0.0001)]. Serum 25(OH)D concentrations in dogs vary widely, and are influenced by dietary VitD content. Serum vitD measurement can identify dogs for which supplementation may improve health and response to cancer therapy.