Indirect computed tomography lymphangiography with aqueous contrast for evaluation of sentinel lymph nodes in dogs with tumors of the head.

Sentinel lymph node evaluation is widely used in human medicine to evaluate the first lymph node(s) to which a tumor drains. Sentinel lymph node biopsy allows avoidance of extensive lymphadenectomies in cases where the sentinel lymph node is negative for metastasis, thereby reducing patient morbidity. It has been shown that regional lymph nodes are not always the sentinel lymph node, thus identification and sampling of sentinel lymph nodes allows for more accurate staging, which is critical for treatment and prognostication in dogs with cancer. The objective of this prospective, pilot study was to determine if indirect computed tomography (CT) lymphangiography with aqueous contrast agent would successfully allow identification of sentinel lymph nodes in dogs with masses on the head. Eighteen dogs underwent CT lymphangiography. The sentinel lymph node was successfully identified within 3 min of contrast injection in 16 dogs (89%). Compression of lymphatic vessels from endotracheal tube ties and/or the patient's own body weight delayed or prevented identification of sentinel lymph nodes in two dogs (11%). Computed tomography lymphangiography with aqueous contrast can be used successfully to rapidly identify sentinel lymph nodes in dogs with masses on the head.

Relationship between Small Animal Intern Rank and Performance at a University Teaching Hospital.

The purpose of this study was to determine if there is a relationship between selection committee rankings of internship applicants and the performance of small animal interns. The hypothesis was that there would be a relationship between selection committee rank order and intern performance; the more highly an application was ranked, the better the intern's performance scores would be. In 2007, the Department of Small Animal Medicine and Surgery instituted a standardized approach to its intern selection process both to streamline the process and to track its effectiveness. At the end of intern years 2010-2014, every faculty member in the department was provided an intern assessment form for that year's class. There was no relationship between an individual intern's final rank by the selection committee and his/her performance either as a percentile score or a Likert-type score (p=.25, R2=0.04; p=0.31, R2=0.03, respectively). Likewise, when interns were divided into the top and bottom quartile based on their final rank by the selection committee, there was no relationship between their rank and their performance as a percentile score (median rank 15 vs. 20; p=.14) or Likert-type score (median rank 14 vs. 19; p=.27). Institutions that use a similar intern selection method may need to reconsider the time and effort being expended for an outcome that does not predict performance. Alternatively, specific criteria more predictive of performance outcomes should be identified and employed in the internship selection process.

Alternating rabacfosadine and doxorubicin for treatment of naïve canine lymphoma.

The current standard of care treatment for canine lymphoma is a multi-agent, CHOP-based chemotherapy protocol. Single agent doxorubicin (DOX) is less burdensome; however, multi-agent chemotherapy protocols are often superior. The recently approved drug rabacfosadine (RAB, Tanovea) provides an attractive option for combination therapy with DOX, as both drugs demonstrate efficacy against lymphoma and possess different mechanisms of action. A previous study evaluating alternating RAB/DOX reported an overall response rate (ORR) of 84%, with a median progression-free survival time (PFS) of 194 days. The aim of this prospective trial was to evaluate the same protocol in an additional population of dogs. Fifty-nine dogs with treatment naïve lymphoma were enrolled. RAB (1.0 mg/kg IV) was alternated with DOX (30 mg/m2 IV) every 21 days for up to six total treatments (3 cycles). Response assessment and adverse event (AE) evaluation were performed every 21 days using VCOG criteria. The ORR was 93% (79% CR, 14% PR). The median time to maximal response was 21.5 days; median PFS was 199 days. T cell immunophenotype and lack of treatment response were predictive of inferior outcomes. AEs were mostly gastrointestinal. Six dogs developed presumed or confirmed pulmonary fibrosis; four were grade 5. One dog experienced grade 3 extravasation injury with RAB that resolved with supportive treatment. These data mirror those of the previously reported RAB/DOX study, and support the finding that alternating RAB/DOX is a reasonable treatment option for canine lymphoma.

Clinical, pathologic and molecular findings in 2 Rottweiler littermates with appendicular osteosarcoma.

Appendicular osteosarcoma was diagnosed and treated in a pair of littermate Rottweiler dogs, resulting in distinctly different clinical outcomes despite similar therapy within the context of a prospective, randomized clinical trial (NCI-COTC021/022). Histopathology, immunohistochemistry, mRNA sequencing, and targeted DNA hotspot sequencing techniques were applied to both dogs' tumors to define factors that could underpin their differential response to treatment. We describe the comparison of their clinical, histologic and molecular features, as well as those from a companion cohort of Rottweiler dogs, providing new insight into potential prognostic biomarkers for canine osteosarcoma.

ALVAC-fIL2, a feline interleukin-2 immunomodulator, as a treatment for sarcoids in horses: A pilot study.

BACKGROUND: Sarcoid tumors are common in horses and may negatively impact the performance and value of the horse. No known treatment is reliably successful. HYPOTHESES/OBJECTIVES: To determine tolerability, overall response rate, time to response, and progression-free survival of horses with biopsy-confirmed or suspected sarcoids treated with ALVAC-fIL2. ANIMALS: Client-owned horses with measurable, presumed- or biopsy-confirmed sarcoid tumors. METHODS: Prospective pilot study. One milliliter of ALVAC-fIL2 was injected into 4 to 5 areas of the sarcoid(s) in each horse (week 0); this treatment was repeated in weeks 1, 3, and 7. Sarcoids were measured at each visit, and response to treatment was determined according to the Response Evaluation Criteria in Solid Tumors for dogs (v1.0). After the final treatment, horses were reassessed and sarcoids remeasured every 3 months until tumor progression or for a minimum of 1 year if progression was not documented. RESULTS: Fourteen horses were included. Tumor size decreased in 86% of the horses, and the median time to first response was 89 days (range, 34-406 days). Median time to best response was 211 days (range, 56-406 days), but 3 of the sarcoids still were decreasing in size at the time of final evaluation. The median progression-free interval was not reached. Adverse events were minimal and included transient focal inflammation in 2 horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Intratumoral injection of ALVAC-fIL2 has promise as a well-tolerated and effective, tissue-sparing treatment for horses with sarcoid tumors.

A prospective, multi-centre, Veterinary Radiation Therapy Oncology Group study reveals potential efficacy of toceranib phosphate (Palladia) as a primary or adjuvant agent in the treatment of canine nasal carcinoma.

Radiation is the standard of care for dogs with nasal tumours. The addition of another therapy that could improve outcome without increasing toxicity is attractive. Medical therapy that could offer better outcome than maximally tolerated dose chemotherapy when radiation therapy (RT) is not possible or is declined is also attractive. This article reports the findings from a prospective, multi-centre, non-randomized, Veterinary Radiation Therapy Oncology Group clinical trial designed to evaluate whether toceranib phosphate (toceranib) has primary activity and if the addition of toceranib to RT could positively impact outcome. Owner's discretion determined enrolment in toceranib alone or toceranib + RT arm. Historical controls for radiation alone were selected from patients treated with identical RT and imaging protocols. Responses were evaluated with pre-treatment and week-16 CT scans. RT total dose of 42 Gy was completed in 10 fractions. Sixty-three dogs enrolled from 10 study sites. Overall response rates (CR + PR) were significantly improved in the toceranib + RT (79.4%) and RT alone (68.9%) arms over toceranib alone (22%) (p = .011). Clinical benefit rates (CR + PR + SD) were significantly improved in the toceranib + RT arm over the RT alone arm at 97.3% and 79.2% respectively (p = .036). Treatment with toceranib alone, toceranib + RT and RT alone resulted in median survival times of 298, 615 and 368 days respectively, but were not statistically significantly different (p = .0502). Adverse events associated with toceranib administration did not potentiate the RT side effect profile. Toceranib appears to have primary activity against nasal carcinoma.

Predictors of outcome in dogs with subcutaneous or intramuscular hemangiosarcoma.

OBJECTIVE: To identify prognostic factors in a large group of dogs with subcutaneous or intramuscular hemangiosarcoma (HSA) or both. Design-Multi-institutional retrospective cohort study. Animals-71 dogs with subcutaneous or intramuscular HSA. PROCEDURES: Medical records of affected dogs were reviewed. The following factors were evaluated for an association with outcome: dog age and sex, clinical signs, anemia, thrombocytopenia, neutrophilia, tumor stage at diagnosis, achievement of complete excision, intramuscular involvement, presence of gross disease, tumor recurrence, and treatment. RESULTS: Of the 71 cases identified, 16 (29%) had intramuscular tumor involvement. For all dogs, median time to tumor progression and overall survival time (OST) were 116 and 172 days, respectively; 25% survived to 1 year. Univariate analysis identified presence of clinical signs or metastasis at diagnosis, dog age, tumor size, use of any surgery, and presence of gross disease as predictors of time to tumor progression and OST. There was no significant difference in survival time between dogs with respect to type of HSA. Multivariate analysis confirmed that adequate local tumor control, tumor diameter ≤ 4 cm, presence of metastasis at diagnosis, and presence of gross disease were significantly associated with OST. CONCLUSIONS AND CLINICAL RELEVANCE: Subcutaneous and intramuscular HSA remains a heterogeneous group of tumors that generally carries a poor prognosis. Adequate local control of smaller tumors with no associated clinical signs or metastasis may provide the best chance of long-term survival.

Hypocalcemia following surgical treatment of metastatic anal sac adenocarcinoma in a dog.

A 9 yr old neutered male mixed-breed dog was presented for an anal sac apocrine gland adenocarcinoma with regional nodal metastases. At presentation, ionized calcium was 1.91 mmol/L (NOVA Stat reference range, 1.1-1.3 mmol/L). Surgical excision of the primary tumor and metastatic lymph nodes was performed. Following surgery, symptomatic hypocalcemia was noted. Repeated ionized calcium measurements confirmed hypocalcemia, and hypercalcemia of malignancy panels suggested parathyroid gland suppression as the cause. The calcium normalized with parenteral calcium administration, but calcium later became elevated with tumor recurrence and an increase in the parathormone-related peptide. Disrupted calcium homeostasis is a potential complication following the treatment of long-standing humoral hypercalcemia of malignancy.

Retrospective evaluation of intranasal carcinomas in cats treated with external-beam radiotherapy: 42 cases.

BACKGROUND: Little is known regarding the comparative efficacy of various irradiation strategies used to treat intranasal carcinomas (INC) in cats. OBJECTIVES: Investigate outcomes and prognostic factors associated with survival for cats with INC. ANIMALS: Forty-two cats with INC that underwent radiotherapy (RT). METHODS: Single-arm retrospective study. Medical record review for cats with INC that underwent RT at 1 of 7 veterinary RT facilities. Irradiation protocols categorized as: definitive-intent fractionated RT (FRT), definitive-intent stereotactic RT (SRT), and palliative-intent RT (PRT). Median overall survival time (OST) and disease progression-free survival (PFS; documented by advanced transverse imaging, or recurrence of symptoms) were calculated. Associations between tumor stage, RT protocol/intent, and adjunctive treatment usage and outcome were calculated. RESULTS: Cats underwent SRT (N = 18), FRT (N = 8), and PRT (N = 16). In multivariate modeling, cats received definitive-intent treatment (DRT; FRT/SRT) had significantly longer median PFS (504 days, [95% confidence interval (CI): 428-580 days] vs PRT 198 days [95% CI: 62-334 days]; p = 0.006) and median OST [721 days (95% CI: 527-915 days) vs 284 days (95% CI: 0-570 days); p = 0.001]). Cats that underwent second DRT course at time of recurrence lived significantly longer than cats that received 1 RT course (either DRT or PRT [median OST 824 days (95% CI: 237-1410 days) vs 434 days (95% CI: 277-591 days); p = .028]). CONCLUSION: In cats with INC, DRT is associated with prolonged OST and PFS as compared to PRT. If tumor progression occurs, a second course of DRT should be considered.

Adjuvant Sirolimus Does Not Improve Outcome in Pet Dogs Receiving Standard-of-Care Therapy for Appendicular Osteosarcoma: A Prospective, Randomized Trial of 324 Dogs.

PURPOSE: The mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression. PATIENTS AND METHODS: A total of 324 pet dogs diagnosed with treatment-naïve appendicular osteosarcoma were randomized into a two-arm, multicenter, parallel superiority trial whereby dogs received amputation of the affected limb, followed by adjuvant carboplatin chemotherapy ± oral sirolimus therapy. The primary outcome measure was disease-free interval (DFI), as assessed by serial physical and radiologic detection of emergent macroscopic metastases; secondary outcomes included overall 1- and 2-year survival rates, and sirolimus pharmacokinetic variables and their correlative relationship to adverse events and clinical outcomes. RESULTS: There was no significant difference in the median DFI or overall survival between the two arms of this trial; the median DFI and survival for standard-of-care (SOC; defined as amputation and carboplatin therapy) dogs was 180 days [95% confidence interval (CI), 144-237] and 282 days (95% CI, 224-383) and for SOC + sirolimus dogs, it was 204 days (95% CI, 157-217) and 280 days (95% CI, 252-332), respectively. CONCLUSIONS: In a population of pet dogs nongenomically segmented for predicted mTOR inhibition response, sequentially administered adjuvant sirolimus, although well tolerated when added to a backbone of therapy, did not extend DFI or survival in dogs with appendicular osteosarcoma.

Rabacfosadine for naïve canine intermediate to large cell lymphoma: Efficacy and adverse event profile across three prospective clinical trials.

While current lymphoma therapies induce remission in most dogs, drug-resistant relapse is common, creating a need for novel agents. Rabacfosadine (RAB), a double prodrug of the acyclic nucleotide phosphonate 9-(2-phosphonylmethoxyethel) guanine (PMEG), preferentially targets lymphoma cells with reduced systemic toxicity compared with PMEG. Previous studies evaluating RAB administered every 21 days have suggested efficacy in both naïve and relapsed subjects; however, no large studies of RAB as a single agent have been reported in previously untreated dogs with intermediate to large cell lymphoma. The purpose of this study was to evaluate the safety and efficacy of RAB in dogs with previously untreated (excluding corticosteroids) lymphoma. Sixty-three dogs received up to five RAB treatments every 21 days (16 at 0.82 mg/kg and 47 at 1.0 mg/kg) as a 30 minutes intravenous infusion, with (n = 23) or without (n = 40) concurrent corticosteroids. Response assessment and adverse event (Ae) evaluation were performed every 21 days via Veterinary Cooperative Oncology Group (VCOG) criteria. The overall response rate was 87% (52% CR, 35% PR). The overall median progression free interval was 122 days (199 for CR, 89 for PR and 153 days for all responders). T-cell immunophenotype and corticosteroid pre-treatment were predictive of inferior outcomes on multivariate analysis. AEs were most commonly of gastrointestinal origin (hyporexia/diarrhoea) and generally resolved with supportive treatment and/or dosage adjustment. Three dogs experienced VCOG-CTCAE grade 5 delayed pulmonary fibrosis. In conclusion, RAB administered every 3 weeks is generally well tolerated and demonstrates substantial antitumour activity in dogs with previously untreated intermediate to large cell lymphoma.

Insulin-like growth factor-I receptor signaling blockade combined with radiation.

Signaling through the insulin-like growth factor-I receptor (IGF-IR) is implicated in cellular proliferation, apoptosis, carcinogenesis, metastasis, and resistance to cytotoxic cancer therapies. Targeted disruption of IGF-IR signaling combined with cytotoxic therapy may therefore yield improved anticancer efficacy over conventional treatments alone. In this study, a fully human anti-IGF-IR monoclonal antibody A12 (ImClone Systems, Inc., New York, NY) is examined as an adjunct to radiation therapy. IGF-IR expression is shown for a diverse cohort of cell lines, whereas targeted IGF-IR blockade by A12 inhibits IGF-IR phosphorylation and activation of the downstream effectors Akt and mitogen-activated protein kinase. Anchorage-dependent proliferation and xenograft growth is inhibited by A12 in a dose-dependent manner, particularly for non-small cell lung cancer lines. Clonogenic radiation survival of H226 and H460 cells grown under anchorage-dependent conditions is impaired by A12, demonstrating a radiation dose-enhancing effect for IGF-IR blockade. Postradiation anchorage-independent colony formation is inhibited by A12 in A549 and H460 cells. In the H460 xenograft model, combining A12 and radiation significantly enhances antitumor efficacy compared with either modality alone. These effects may be mediated by promotion of radiation-induced, double-stranded DNA damage and apoptosis as observed in cell culture. In summary, these results validate IGF-IR signal transduction blockade as a promising strategy to improve radiation therapy efficacy in human tumors, forming a basis for future clinical trials.

Fibrosarcoma adjacent to the site of microchip implantation in a cat.

A 14-year-old spayed female domestic shorthair cat presented with an interscapular mass. A computed tomography scan, biopsy, and histological examination revealed a fibrosarcoma adjacent to a pet identification microchip. Because the cat was previously vaccinated at this site, it is not possible to establish definitive causation of the fibrosarcoma, but this is the first report of a tumor in the vicinity of a microchip in a cat. Microchip-associated tumors have been reported in rodents and dogs. Veterinarians should be aware that because inflammation may predispose felines to tumor formation, separation and observation of vaccination and implantation sites are indicated. Adherence to American Association of Feline Practitioners (AAFP) vaccination guidelines and monitoring of microchip implantation sites are recommended.

Combination chemotherapy with L-asparaginase, lomustine, and prednisone for relapsed or refractory canine lymphoma.

BACKGROUND: Canine lymphoma (LSA) is responsive to initial treatment, however, it then becomes resistant to drugs in the initial protocol. New rescue protocols are needed. HYPOTHESIS: A combination of L-asparaginase, lomustine, and prednisone will be well tolerated and efficacious as a rescue therapy for dogs with LSA. ANIMALS: Thirty-one client owned dogs with cytologically confirmed multicentric LSA who were refractory or whose disease had relapsed after a CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone)-based chemotherapy protocol. METHODS: Prospective clinical trial. Lomustine (target dose, 70 mg/m2) was administered orally at 3-week intervals for a total of 5 doses or until disease progression. L-asparaginase (400 U/kg) was administered subcutaneously concurrently with the first 2 lomustine treatments. Prednisone was administered at a tapering dose for the duration of the protocol. RESULTS: Overall response rate for dogs treated with this protocol was 87% (27/31), with 52% (16/31) of dogs achieving a complete response. Median time to response was 21 days. Median time to progression was 63 days (111 days for dogs achieving a complete response and 42 days for dogs achieving a partial response). There were no significant differences in response rates and times to progression between dogs who had received L-asparaginase before beginning this rescue protocol and those who had not. Toxicoses were mild and self-limiting in 29 of 31 cases. CONCLUSIONS AND CLINICAL IMPORTANCE: This is a well-tolerated rescue therapy for relapsing LSA in dogs. Response rates and remission durations compare favorably to other rescue protocols. Therefore, this protocol is a viable rescue option.

Mammary gland tumors in male dogs.

BACKGROUND: Reports of mammary-gland tumors in male dogs are lacking. OBJECTIVE: To describe the clinical characteristics of mammary-gland tumors in male dogs. ANIMALS: Eight male dogs diagnosed with mammary-gland tumors. METHODS: Retrospective study. Medical databases from 3 institutions were searched. Medical records were abstracted, and owners and referring veterinarians contacted for follow-up information. Tissues were reviewed for histologic type, and immunohistochemical staining for estrogen and progesterone receptors (ER, PR) was performed. RESULTS: Eight dogs with histologically confirmed mammary-gland tumors were included in this retrospective study. Median age at diagnosis was 11.5 years. Four dogs were sexually intact; 4 were neutered. All were purebred. Mammary-gland tumors were incidental findings in 7 of 8 dogs. All dogs were treated with only surgical excision. All but 1 dog had benign epithelial tumors. The dog with the malignant tumor was the only dog to develop possible local recurrence but de novo tumor development cannot be excluded. No dog had evidence of metastatic disease at diagnosis. Based on institutional population data, it was determined that female dogs are 62 times more likely to develop mammary-gland tumors than male dogs (P < .001). Estrogen-receptor expression was strong in the majority of tumors; progesterone-receptor expression, although present in all tumors, was less intense. CONCLUSIONS/CLINICAL IMPORTANCE: This study suggests that mammary-gland tumors in male dogs are rare, usually benign, and surgery alone can provide long-term control in most dogs.

Vaccine-associated feline sarcoma: current perspectives.

Feline injection site sarcomas (FISS; also known as vaccine-associated sarcomas) have been recognized for >20 years. Although uncommon, these tumors are iatrogenic, and vaccination against rabies and feline leukemia virus is perhaps the most common inciting cause. The exact etiopathogenesis is unknown, but it is widely accepted that inflammation induced by vaccines or other injections likely plays a critical role in tumor development. Injection site sarcomas are extremely locally invasive. Multimodal therapy, incorporating combinations of surgery, radiation therapy, and sometimes chemotherapy or immunotherapy, is recommended. However, tumor recurrences are common even with aggressive treatment, and many cats with FISS ultimately succumb to this devastating disease. While vaccination protocols play an important role in the management and control of infectious disease, veterinarians must be diligent in following established vaccination guidelines to minimize individual patient risk of FISS development. Early tumor detection and client education are also vital in the successful treatment of FISS.

Eosinophilic leukemia in three African pygmy hedgehogs ( Atelerix albiventris) and validation of Luna stain.

Neoplasia is usually encountered in the African pygmy hedgehog at a mean age of 3.5 y, and malignancy is common. Myelogenous leukemias are rarely reported in hedgehogs. We describe 3 cases of eosinophilic leukemia in adult, middle-aged (mean age: 2.3 y) hedgehogs, for which prognosis appears grave. In 1 case, attempted treatment was unsuccessful, and in all 3 cases, the disease course was rapid and all died soon after diagnosis. Blood smear evaluation, along with complete blood count, was critical in making the diagnosis in all cases. Luna stain was validated and used to better visualize eosinophils in cytologic and histologic sections. Electron microscopy confirmed the presence of specific granules in hedgehog eosinophils.

A Comparative Oncology Study of Iniparib Defines Its Pharmacokinetic Profile and Biological Activity in a Naturally-Occurring Canine Cancer Model.

Development of iniparib as an anti-cancer agent was hindered in part by lingering questions regarding its mechanism of action, the activity of its metabolites, and their potential accumulation in tumors. Due to strong similarities in metabolism of iniparib between humans and dogs, a veterinary clinical trial in pet dogs with spontaneous cancers was designed to answer specific questions pertaining to pharmacokinetic exposures and tolerability of iniparib. Dogs were treated with iniparib alone and in combination with carboplatin chemotherapy. Iniparib doses ranged between 10-70 mg/kg intravenously (IV). Plasma, tumor and normal tissue samples were collected before and at various time points scheduled after exposure for pharmacokinetic and biologic analysis. The primary endpoints included characterization of dose-limiting toxicities (DLT) and determination of the drug exposures that could be achieved in both normal and tumor tissues. Nineteen dogs were treated. DLT included fever, anorexia, diarrhea, neutropenia, and thrombocytopenia; most effects were attributable to carboplatin based on the timing of adverse event onset. The maximum tolerated dose (MTD) of iniparib was not identified. Moderate to high variability in plasma exposure was noted for iniparib and all metabolites between animals. When quantifiable, iniparib and metabolite plasma:tumor ratios were < 0.088 and <1.7, respectively. In this study, iniparib was well tolerated as a single agent and in combination with carboplatin over a range of doses. However, clinically relevant concentrations of the parent drug and selected metabolites were not detectable in canine tumor tissues at any studied dose, thus eliminating expectations for clinical responses in dogs or humans. Negative clinical trials in humans, and the uncertainties of its mechanism of action, ultimately led to the decision to stop clinical development of the drug. Nevertheless, the questions that can be asked and answered within the comparative oncology approach are evident from this successfully executed comparative clinical trial and exemplify the value of such studies in drug development.