Role of Positron Emission Tomography in Imaging of Non-neurologic Disorders of the Head, Neck, and Teeth in Veterinary Medicine.

Positron Emission Tomography (PET) is an imaging technique that provides functional information, in addition to structural information obtained with computed tomography (CT). The most common application is cancer staging, using 18F-Fluorodeoxyglucose (18F-FDG), a radioactive analog of glucose. Although limited data are available in the veterinary literature, human studies have demonstrated benefit with the addition of PET both for assessment of the primary tumor and for detection of metastatic disease. 18F-FDG PET appears to be more accurate at detecting the margin of oral neoplasia, in particular for tumors arising from highly vascularized tissue, such as the lingual and laryngeal areas. 18F-FDG PET has a high sensitivity for the detection of lymph node metastasis, however the specificity is variable between studies. Tracers beyond 18F-FDG can also be used for oncology imaging. 18F-Fluoride (18F-NaF) is an excellent osseous tracer, useful in assessing bone involvement of primary tumors or osseous metastasis. Other specific tracers can be used to assess cell proliferation or hypoxia for tumor characterization. 18F-FDG is also an excellent tracer for detection of inflammation. Human studies have demonstrated its value for the assessment of periodontitis and dental implant infection. 18F-NaF has been used to assess disorders of the temporomandibular joint in the human literature, demonstrating good correlation with arthralgia and therapeutic outcome. Both 18F-NaF and 18F-FDG had good concordance with localization of cervical pain in people. PET will likely have a growing role in veterinary medicine not only for oncologic imaging but also for assessment of inflammation and pain

A systematic review of criteria used to report complications in soft tissue and oncologic surgical clinical research studies in dogs and cats.

ObjectiveTo evaluate reporting of surgical complications and other adverse events in clinical research articles describing soft tissue and oncologic surgery in dogs and cats.Study designSystematic literature review.SampleEnglish-language articles describing soft tissue and oncologic surgeries in client-owned dogs and cats published in peer-reviewed journals from 2013 to 2016.MethodsCAB, AGRICOLA, and MEDLINE databases were searched for eligible articles. Article characteristics relevant to complications were abstracted and summarized, including reported events, definitions, criteria used to classify events according to severity and time frame, and relevant citations.ResultsOne hundred fifty-one articles involving 10 522 animals were included. Canine retrospective case series of dogs predominated. Ninety-two percent of articles mentioned complications in study results, but only 7.3% defined the term complication. Articles commonly described complications according to time frame and severity, but terminology and classification criteria were highly variable, conflicting between studies, or not provided. Most (58%) reported complications could have been graded with a published veterinary adverse event classification scheme, although common intraoperative complications were notable exceptions.ConclusionDefinitions and criteria used to classify and report soft tissue and oncologic surgical complications are often absent, incomplete, or contradictory among studies.Clinical significanceLack of consistent terminology contributes to inadequate communication of important information about surgical complications. Standardization of terminology and consistency in severity scoring will improve comparative evaluation of clinical research results

Blood and tissue biomarker analysis in dogs with osteosarcoma treated with palliative radiation and intra-tumoral autologous natural killer cell transfer.

We have previously reported radiation-induced sensitization of canine osteosarcoma (OSA) to natural killer (NK) therapy, including results from a first-in-dog clinical trial. Here, we report correlative analyses of blood and tissue specimens for signals of immune activation in trial subjects. Among 10 dogs treated with palliative radiotherapy (RT) and intra-tumoral adoptive NK transfer, we performed ELISA on serum cytokines, flow cytometry for immune phenotype of PBMCs, and PCR on tumor tissue for immune-related gene expression. We then queried The Cancer Genome Atlas (TCGA) to evaluate the association of cytotoxic/immune-related gene expression with human sarcoma survival. Updated survival analysis revealed five 6-month survivors, including one dog who lived 17.9 months. Using feeder line co-culture for NK expansion, we observed maximal activation of dog NK cells on day 17-19 post isolation with near 100% expression of granzyme B and NKp46 and high cytotoxic function in the injected NK product. Among dogs on trial, we observed a trend for higher baseline serum IL-6 to predict worse lung metastasis-free and overall survival (P = 0.08). PCR analysis revealed low absolute gene expression of CD3, CD8, and NKG2D in untreated OSA. Among treated dogs, there was marked heterogeneity in the expression of immune-related genes pre- and post-treatment, but increases in CD3 and CD8 gene expression were higher among dogs that lived > 6 months compared to those who did not. Analysis of the TCGA confirmed significant differences in survival among human sarcoma patients with high and low expression of genes associated with greater immune activation and cytotoxicity (CD3e, CD8a, IFN-γ, perforin, and CD122/IL-2 receptor beta). Updated results from a first-in-dog clinical trial of palliative RT and autologous NK cell immunotherapy for OSA illustrate the translational relevance of companion dogs for novel cancer therapies. Similar to human studies, analyses of immune markers from canine serum, PBMCs, and tumor tissue are feasible and provide insight into potential biomarkers of response and resistance

Inhaled recombinant human IL-15 in dogs with naturally occurring pulmonary metastases from osteosarcoma or melanoma: a phase 1 study of clinical activity and correlates of response.

PurposeAlthough recombinant human interleukin-15 (rhIL-15) has generated much excitement as an immunotherapeutic agent for cancer, activity in human clinical trials has been modest to date, in part due to the risks of toxicity with significant dose escalation. Since pulmonary metastases are a major site of distant failure in human and dog cancers, we sought to investigate inhaled rhIL-15 in dogs with naturally occurring lung metastases from osteosarcoma (OSA) or melanoma. We hypothesized a favorable benefit/risk profile given the concentrated delivery to the lungs with decreased systemic exposure.Experimental designWe performed a phase I trial of inhaled rhIL-15 in dogs with gross pulmonary metastases using a traditional 3+3 cohort design. A starting dose of 10 µg twice daily × 14 days was used based on human, non-human primate, and murine studies. Safety, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) were the primary objectives, while response rates, progression-free and overall survival (OS), and pharmacokinetic and immune correlative analyses were secondary.ResultsFrom October 2018 to December 2020, we enrolled 21 dogs with 18 dogs reaching the 28-day response assessment to be evaluable. At dose level 5 (70 μg), we observed two DLTs, thereby establishing 50 µg twice daily × 14 days as the MTD and recommended phase 2 dose. Among 18 evaluable dogs, we observed one complete response >1 year, one partial response with resolution of multiple target lesions, and five stable disease for an overall clinical benefit rate of 39%. Plasma rhIL-15 quantitation revealed detectable and sustained rhIL-15 concentrations between 1-hour and 6 hour postnebulization. Decreased pretreatment lymphocyte counts were significantly associated with clinical benefit. Cytotoxicity assays of banked peripheral blood mononuclear cells revealed significant increases in peak cytotoxicity against canine melanoma and OSA targets that correlated with OS.ConclusionsIn this first-in-dog clinical trial of inhaled rhIL-15 in dogs with advanced metastatic disease, we observed promising clinical activity when administered as a monotherapy for only 14 days. These data have significant clinical and biological implications for both dogs and humans with refractory lung metastases and support exploration of combinatorial therapies using inhaled rhIL-15