Abstract
A total of five clinical/research abstracts were accepted for inclusion in the poster session during the AAFP’s 2020 virtual conference, held on October 3 & 4 and 24 & 25.
Nqo1-Targeted Therapy for Feline Oral Squamous Cell Carcinoma
Alycen P Lundberg, Matthew W Boudreau, Kimberly A Selting, Jonathan Samuelson, Anne M Barger, Paul J Hergenrother, Timothy M Fan
University of Illinois at Urbana-Champaign, Urbana, IL, USA
Email:
Oral squamous cell carcinoma (OSCC) is the most common oral tumor in cats and current therapies are largely ineffective, providing <10% 1-year survival. Thus, new and targeted therapies are desperately needed. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a detoxifying enzyme that we have found to be highly upregulated in OSCC. Additionally, it is targetable with the anticancer agent isobutyl-deoxynyboquinone (IB-DNQ). When NQO1 is in the presence of IB-DNQ it generates excessive reactive oxygen species (ROS), resulting in cancer cell death but sparing normal tissues. Our previous in vitro work has demonstrated the ability to upregulate NQO1 with radiation therapy (RT), as well as the cytotoxic effects of IB-DNQ alone and IB-DNQ in combination with RT. Additionally, we have characterized the in vivo pharmacokinetics and tolerability of IB-DNQ in healthy cats. We hypothesized that RT will increase NQO1 protein in vivo, thereby rendering tumors more susceptible to IB-DNQ and that IB-DNQ combined with RT for the treatment of naive pet cats with OSCC will be tolerable and will exhibit measurable tumor reductions.
A total of 32 cats with cytologically or histologically confirmed OSCC were enrolled into the clinical trial. A small pilot study included five patients that were first treated with single-agent IB-DNQ using various dosing intervals to determine the safety and efficacy of 1.0 mg/kg IV IB-DNQ. Following this, eight patients were evaluated to determine the ability to upregulate NQO1 in vivo by comparing biopsies 2 and 4 h following 8 Gy radiation and using immunohistochemistry (IHC) to assess NQO1 protein score. Nineteen patients were then scheduled to receive four weekly combinatory treatments consisting of 8 Gy radiation followed by IB-DNQ at 1.0 mg/kg IV. Pre- and post-treatment CT scans were performed for objective tumor measurements using response evaluation criteria in solid tumors (RECIST) scoring in 23 patients, and tumor NQO1 expression was assessed by IHC prior to treatment to correlate with response to therapy. Safety and tolerability were assessed with weekly hematologic and biochemical monitoring, as well as measurement of urine 8-OHdG, a marker of oxidative damage.
In the pilot study of five cats treated with single-agent IB-DNQ, all maintained stable disease (SD); one patient experienced a tumor reduction of 20%, indicating that IB-DNQ can be effective as a single agent in some patients. Of the 18 cats that had pre- and post-treatment CT scans and received RT and IB-DNQ, 16.6% achieved a partial remission and 77.7% achieved stable disease for an overall biologic response of 94.4%. Treatment was well tolerated in all cats, with no significant hematologic or biochemical toxicities, and responses correlated with NQO1 protein intensity. In cats that received post-RT biopsies, NQO1 protein expression increased following exposure to radiation, supporting the ability to upregulate protein expression in vivo.
Single-agent IB-DNQ is well tolerated and can reduce tumor volume in a tumor with high basal NQO1 levels. Combining IB-DNQ with RT is safe in pet cats with OSCC and demonstrates promising anticancer effects. RT has the ability to upregulate NQO1 protein in vivo in tumor-bearing cats, thereby making them more susceptible to IB-DNQ therapy. These findings warrant further exploration in a larger scale clinical trial that includes a control group.
Enhancing Radiation with Zoledronate in Feline Oral Squamous Cell Carcinoma
Alycen P Lundberg, Christine T Hoang, Audry Bilhymer, Kimberly A Selting
University of Illinois at Urbana-Champaign, Veterinary Clinical Medicine, Urbana, IL, USA
Email:
Oral squamous cell carcinoma (OSCC) is the most common oral tumor diagnosed in pet cats and carries a very poor prognosis, with <10% 1-year survival despite multimodal therapies. An inability to control local disease often causes significant morbidity. Invasion of surrounding tissues causes severe pain, and difficulty eating, drinking and grooming. Tumors arising from the mandible or maxilla with bony involvement are common and cause a significant amount of pain, largely driven by osteolysis. Bisphosphonates are a class of drugs that inhibit osteoclastic activity, thereby decreasing osteolysis and bone destruction, and are commonly used in canine patients with bone tumors. Zoledronate (ZOL) is a bisphosphonate with a notable ability to reduce osteolysis, and also may play a role as an anticancer agent by reducing angiogenesis, a hallmark of cancer. Additionally, in vitro data support multiple mechanisms of radiosensitization. Radiation therapy (RT) plays an important role in treatment of feline OSCC owing to its anticancer activity and the ability to improve quality of life. With this, we hypothesized that the efficacy of RT can be enhanced in vitro with the addition of ZOL, and that combining radiation and ZOL for the treatment of pet cats will be well tolerated and will decrease bone lysis and invasion.
Three OSCC cell lines (SCCF1, SCCF2, SCCF3) were treated with RT and ZOL at various time intervals – ZOL administered 2 h pre-RT, immediately pre-RT and 2 h post-RT – to determine optimal cytotoxicity and clonogenicity using a sulforhodamine B (SRB) and clonogenic survival assay, respectively. Once the effect of timing was evaluated, nine pet cats with naturally occurring OSCC with bone involvement were recruited for treatment with four weekly doses of 8 Gy RT using a Cobalt-60 machine, with ZOL 0.2 mg/kg IV given at the first and fourth treatments. CT scans were performed on day 0 and day 50 to objectively assess tumor response both volumetrically and using the response evaluation criteria in solid tumors (RECIST) scoring. Tumor volume was determined using a treatment planning system for radiation therapy (Eclipse v15.6; Varian). Safety and tolerability were monitored with hematologic and biochemical assessment, and acute radiation adverse effects were characterized using Veterinary Radiation Therapy Oncology Group (VRTOG) criteria. Serum C-telopeptide (CTx), a marker of bone resorption, was assessed weekly and relative bone mineral density (rBMD) was assessed at days 0 and 50 using dual-energy x-ray absorptiometry (DEXA).
There was no clear effect of timing to guide ZOL administration based on in vitro data; therefore, ZOL was given immediately before radiation as is customary with traditional radiosensitizing agents. All nine patients received the four weekly treatments with two doses of ZOL given concurrently with the first and fourth RT treatments. Three of nine (33.3%) cats experienced a partial remission and six (66.6%) cats experienced stable disease based on RECIST criteria. No patients experienced progressive disease during the course of treatment, though decreased quality of life owing to lack of tumor shrinkage did occur in most cats after completion of the trial. Treatment was well tolerated in all cats, with no biochemical toxicity. There was a statistically significant change in calcium and phosphorus from day 0 to day 22; however, this was transient and normalized at day 50 and was not clinically relevant in the patients. Radiation side effects were limited to grade 1 acute and late toxicities, and confined to the skin, mucous membranes and eyes. Serum CTx over time demonstrated a decrease in bone resorption in all patients, and rBMD did not change from day 0 to day 50.
This pilot study shows that combining RT with ZOL in pet cats with OSCC is safe and well tolerated, and results in a decrease in bone resorption. This combinatory therapy should be considered in treating feline patients with OSCC and bone involvement.
Clinical, Ultrasonographic and Anatomopathological Characteristics of Axillary and Inguinal Lymph Nodes in Cats with Mammary Carcinomas
Silvana B Vidor1, Fabiola PS Mello2, Angelica C Bertagnolli3, Simone P Bianchi1, Maria-Eduarda Baier1, Fernanda Vieira Amorim da Costa4, Emerson A Contesini1
1Post-Graduate Program in Veterinary Science, Federal Rio Grande do Sul, Porto Alegre, RS, Brazil
2Veterinary Teaching Hospital, Federal Rio Grande do Sul, Porto Alegre, RS, Brazil
3Laboratory of Histopathology, Fundação Estadual de Pesquisa Agropecuária, Instituto de Pesquisas Veterinárias Desidério Finamor, Eldorado do Sul, RS, Brazil
4Department of Animal Medicine, Federal Rio Grande do Sul, Porto Alegre, RS, Brazil
Email:
The aim of this study was to compare ultrasonography with manual palpation for assessment of axillary and inguinal lymph nodes in cats with malignant mammary tumors.
Manual palpation during clinical staging may not be adequate to appreciate masses within lymph nodes, owing to their small size. Therefore, it was hypothesized that ultrasound examination can be more efficient for diagnosis of metastasis, as has previously been reported for dogs and humans.
This prospective study of female cats with malignant mammary tumors treated at the Universidade Federal do Rio Grande do Sul Veterinary Teaching Hospital, Brazil, took place between January 2017 and December 2018. One examiner (SBV) manually palpated the cats’ axillary and inguinal lymph nodes during physical examination. Another investigator (FPSM) carried out lymph node imaging using a Mylab 40 device (Esaote Healthcare do Brasil) with a 7.5–12 MHz linear transducer. Lymph nodes were considered metastatic if a minimum of three of the following ultrasonographic features were present: irregular borders, heterogeneous textures, a hypoechoic appearance, a hyperechoic appearance with no acoustic shadow, lack of nodal hilum and increased blood flow. Other characteristics were recorded: long axis measurements, short/long axis ratios and the resistive index (RI). Histologic assessments were subsequently performed on the tumors and lymph nodes. The inter-rater reliability between the histopathology, ultrasonography and palpation evaluations was expressed using the Cohen Kappa coefficient (IBM SPSS v.22 software). Pearson’s chi-square was used to analyze the association between lymph node metastasis and tumor characteristics (eg, location, ulceration, attachment to underlying tissues) and histopathology (eg, necrosis, lymphatic invasion, delimited area).
In 23 patients, 41 instances of malignant neoplasm were histologically identified. The most common types were cribriform (11, 27%), tubulopapillary (9, 22%) and tubular (2, 5%) carcinomas. Five (22%) patients presented with metastasis to the axillary lymph nodes, seven (30%) to the inguinal nodes and one (4%) to both locations. Lymph node metastasis was associated with tumor ulceration (P = 0.011), attachment to underlying tissues (P = 0.014), lack of delimited area (P = 0.002) and lymphatic invasion (P <0.001). It was possible to perform lymph node ultrasonography on 16 patients (n = 16). Of 32 lymph nodes, 10 tested positive (see table). The histopathology showed strong reliability (κ = 0.805, P <0.001) with ultrasonographic findings and reasonable reliability with manual palpation (κ = 0.393, P = 0.020).
Ultrasonography can improve lymph node assessment during the clinical staging of mammary tumors in cats. Further studies on the characteristics of metastatic lymph nodes are needed.
Safety Evaluation of Low-Dose Meloxicam with Toceranib Phosphate (Palladia) In Cancer-Bearing Cats: A Phase I Dose-Finding Study
Samuel J Keepman, MacKenzie A Pellin
University of Wisconsin Veterinary Medical Teaching Hospital, Madison, WI, USA
Email:
Toceranib phosphate (Palladia; Zoetis) is a receptor tyrosine kinase inhibitor that has demonstrated activity against several feline cancers. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly utilized in protocols targeting canine and human cancers as supportive medications to mitigate pain, for direct anticancer properties via COX-2 inhibition or to treat other chronic inflammatory conditions commonly seen in aged, cancer-bearing populations. NSAIDs are infrequently utilized in feline patients due to concern for renal compromise. Recent studies, however, have demonstrated that cats may tolerate low doses of meloxicam without evidence of kidney injury. The objective of our study was primarily to determine the maximum tolerated dose and adverse event profile of combined toceranib and meloxicam in cancer-bearing cats. Secondary objectives were to assess the anticancer efficacy of the drug combination, as well as the impact upon quality of life and analgesia.
Cats with cancers that do not involve the kidneys were eligible for the study. The 3-month trial assumed a conventional 3 + 3 cohort design. Palladia was administered q48h at a target dose of 2.5–2.75 mg/kg PO. Meloxicam was administered at a starting dose of 0.01 mg/kg PO on the opposite days to Palladia, and was then incrementally escalated up to 0.02 mg/kg PO q24h in subsequent cohorts pending acceptable dose-limiting toxicities. Bloodwork, urine dipstick, urine specific gravity, blood pressure, tumor measurements (if possible), Glasgow pain score and client-completed quality of life surveys were recorded every 2–4 weeks.
Ultrasonographic features of 10 metastatic lymph nodes
At the time of writing, 17 cats had been enrolled in the study. The maximum tolerated dose of meloxicam when combined with Palladia at that point was not yet reached, but was at least 0.01 mg/kg q24h (or 0.02 mg/kg q48h). The most common adverse events noted were weight loss and anorexia. Grade 3 weight loss was noted in three cats. No cats needed to be withdrawn due to adverse events from the drug combination. Eight cats were withdrawn early due to disease progression (n = 5), sudden death (n = 1) or difficulty administering medications (n = 2). Quality of life and Glasgow pain scores improved or remained stable for cats whose disease did not progress. One cat had a partial response for 83 days before being lost to follow-up, while the remaining cats had stable disease for a median time of 61 days before study withdrawal or until the date of last follow-up.
Preliminary data indicate that low-dose meloxicam combined with Palladia is safe and well tolerated in cancer-bearing cats. No renal adverse events were observed. Quality of life and pain were stable to improved in the majority of cats that received the drug combination; worsening scores in the remaining cats were likely due to disease progression, difficulty administering medications or comorbidities. Anticancer efficacy of the drug combination cannot be definitively evaluated with the current data. Continued patient recruitment is needed to determine the maximum tolerated dose of meloxicam. The results of our study will be used to guide further phase II/III clinical trials.
Value of Technology With Regard To Client Satisfaction, Weight Loss Rate and Behaviors in a Multiple-Cat Weight Management Program
Kenneth J Lambrecht1, Barr N Hadar2, Zvonimir Poljak2, Theresa M Bernardo2
1West Towne Veterinary Center, Pets Reducing for Rescues, Madison, WI, USA
2Ontario Veterinary College, Guelph, Ontario, Canada
Email:
The purpose of this study was to see if a pet health technology ecosystem (PHTE) is an effective tool in a weight management program (WMP) in multiple-cat households. Obesity prevalence in cats is 60% and shows no sign of slowing. The average cat household in the USA has 1.8 cats. The major challenges faced by cat owners in a WMP are accurately measuring food, preventing food stealing and obtaining accurate weights.
A 12-week WMP of indoor-only two- to three-cat households managed by US and Canadian veterinarians were randomized to a technology group (with PHTE) or traditional group (standard of care without the ecosystem). Both groups received Hill’s Metabolic Rx weight loss diet and were instructed to feed three times a day. The Pet Nutrition Alliance calculator was used to recommend caloric intake for a target of 1% body weight (BW) loss per week and a food scale provided to mark a measuring cup amount for the traditional group. Monthly veterinary clinic weighins were recommended. BW, food intake, behaviors and device notes were recorded by pet owners. The technology group received a PHTE consisting of a digital BW scale, smart feeder, activity monitor and webcam, the components of which were based on a pilot study we performed in November/ December 2018. Health-related quality of life (HRQoL) was measured at various time points using the validated online tool, Vetmetrica. Veterinary and pet owner feedback was collected through a pre- and post-WMP survey and owner diaries. Approval was obtained by Ontario Veterinary College for animal use and research ethics, and from pet owners for presentation and publication.
Fifteen of the 45 enrolled cats completed the study; nine in the traditional group and six in the technology group. Fifty-six percent (5/9) of cats in the traditional group and 100% (6/6) of cats in the technology group lost weight. The average weekly weight loss percentage was significantly higher (P = 0.036) in the technology group (0.70%) compared with the traditional group (0.18%). Results indicate an overall high satisfaction with the PHTE as part of a technology-enhanced feline WMP. Pet owners found the smart feeder was a very valuable addition to the WMP, followed by the digital BW scale. Technology-group cats had an average trend toward grazing feeding patterns (more frequent, smaller, longer meals) and decreased daily activity counts throughout the WMP.
Cats in multiple-cat households lost more weight using technology than with traditional methods. HRQoL metrics improved throughout the weight loss program. The evolution of smart feeders to record feeding behaviors related to weight management may provide useful observations in the future. Ideally there would have been intervention groups for each component (feeder, BW scale, activity monitor, webcam) to distinguish the effects of each individual device. This was not done owing to time and resource limitations. These findings may support the effectiveness of a PHTE for multiple-cat household weight management with the digital BW scale and smart feeder as the preferred components.