Combining radiation therapy with zoledronate for the treatment of osteo-invasive feline oral squamous cell carcinoma.

Feline oral squamous cell carcinoma (FOSCC) is the most common oral tumour diagnosed in pet cats and carries a poor prognosis with <10% one-year survival despite multi-modal therapies. Tumours of the mandible or maxilla are frequently osteo-invasive and pain can result from osteolysis. Zoledronate is a bisphosphonate that inhibits osteoclasts and reduces bone resorption. Radiation therapy (RT) is used to treat FOSCC due to anti-cancer activity and ability to improve quality of life. We hypothesized RT can be safely combined with zoledronate, and that this combinatory therapy would be efficacious, well tolerated, and result in decreased bone resorption in cats with FOSCC. SCCF1 cell line was treated with zoledronate before, concurrently, or after RT, and clonogenic assays were performed to determine if an optimal dosing schedule would be identified. Nine cats with osteoinvasive FOSCC were recruited for treatment with 4 weekly doses of 8 Gy RT combined with zoledronate administered at the first and fourth treatments. Serial CT scans were performed to assess tumour response. Safety and tolerability were monitored with hematologic and biochemical parameters, and acute radiation effects were characterized. Serum c-telopeptide (CTx) and relative bone mineral density (rBMD) by dual -energy X-ray absorptiometry (DEXA) quantified bone resorption. In vitro studies showed no clear benefit to timing of zoledronate with RT, therefore all zoledronate was administered concurrently with RT in FOSCC patients. Based on tumour volume, 4/9 (44.4%) cats achieved partial remission, 4/9 (44.4%) stable disease and 1/9 (11.1%) had progressive disease. The combinatory therapy was well-tolerated based on biochemical measurements, and all patients experienced decreased serum CTx. Combining RT with zoledronate in tumour-bearing cats is safe, well-tolerated, results in a partial remission rate of up to 44%, and decreases serum CTx, a marker of bone resorption.

Mediastinal Fibrosarcoma in a Dog-Case Report.

This represents the first published case report of mediastinal fibrosarcoma in a dog. An 8-year-old male neutered mixed breed dog was presented for evaluation of lethargy and increased panting. Thoracic focused assessment with sonography for trauma revealed moderate pleural effusion. Thoracic radiograph findings were suggestive of a cranial mediastinal mass. Computed tomography revealed a mass within the right ventral aspect of the cranial mediastinum. On surgical exploration, a cranial mediastinal mass with an adhesion to the right cranial lung lobe was identified and removed en-bloc using a vessel sealant device and requiring a partial lung lobectomy. Histopathology results described the cranial mediastinal mass as fibrosarcoma with reactive mesothelial cells identified within the sternal lymph node. The patient was treated with systemic chemotherapy following surgical removal. To date, the dog has survived 223 days following diagnosis with recurrence noted 161 days following diagnosis and radiation therapy was initiated. Primary cranial mediastinal fibrosarcoma while a seemingly rare cause of thoracic pathology in dogs, should be considered in the differential diagnosis for a cranial mediastinal mass.

Outcome of dogs with bone marrow suppression secondary to Sertoli cell tumour.

Sertoli cell tumours are one of the most common canine testicular neoplasia. These tumours are significantly more likely to arise in cryptorchid dogs and are often functional, oestrogen-secreting tumours which can lead to fatal myelotoxicity. The goal of this study was to describe the outcome of dogs with oestrogen-induced bone marrow suppression secondary to Sertoli cell tumours in seven client-owned dogs. Medical records from April 1, 2011 through April 1, 2021 were reviewed to identify dogs that underwent surgical management of a Sertoli cell tumour with documented bone marrow suppression. Overall, 5/7 dogs required transfusion of blood products peri-operatively. Cases 1 and 6 received a transfusion of packed red blood cells (RBC) prior to surgery and case 5 required a transfusion of whole blood. Case 1 also required a transfusion of platelets before surgery. Post-operatively, cases 1 and 2 received packed RBC's and case 6 received two transfusions of whole blood. Case 3 required transfusions of both fresh frozen plasma and platelets post-operatively. All dogs survived to discharge and 6/7 dogs had documented improvement in haematopoietic values. Two dogs remained chronically thrombocytopenic. The median hospital stay was 4 days. One dog died within 4 weeks of surgery from worsening pancytopenia. Survival for greater than 1 year was documented in 4/7 dogs, and one dog was lost to follow-up 4 months post-operatively. One dog remained severely pancytopenic 4 weeks post-operatively and received oral lithium treatment. Improvements in all blood cell lines were observed within the 4 weeks and resolution of pancytopenia within 6 weeks. Historically, the prognosis for dogs with bone marrow suppression secondary to Sertoli cell tumours was guarded to poor. This report documented improved outcomes for dogs that underwent surgery, including one dog that received lithium chloride as treatment for Sertoli cell tumour-induced bone marrow suppression.

Utilizing feline oral squamous cell carcinoma patients to develop NQO1-targeted therapy.

Developing effective therapies for the treatment of advanced head-and-neck squamous cell carcinoma (HNSCC) remains a major challenge, and there is a limited landscape of effective targeted therapies on the horizon. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a 2-electron reductase that is overexpressed in HNSCC and presents as a promising target for the treatment of HNSCC. Current NQO1-targeted drugs are hindered by their poor oxidative tolerability in human patients, underscoring a need for better preclinical screening for oxidative toxicities for NQO1-bioactivated small molecules. Herein, we describe our work to include felines and feline oral squamous cell carcinoma (FOSCC) patients in the preclinical assessment process to prioritize lead compounds with increased tolerability and efficacy prior to full human translation. Specifically, our data demonstrate that IB-DNQ, an NQO1-targeted small molecule, is well-tolerated in FOSCC patients and shows promising initial efficacy against FOSCC tumors in proof-of-concept single agent and radiotherapy combination cohorts. Furthermore, FOSCC tumors are amenable to evaluating a variety of target-inducible couplet hypotheses, evidenced herein with modulation of NQO1 levels with palliative radiotherapy. The use of felines and their naturally-occurring tumors provide an intriguing, often underutilized tool for preclinical drug development for NQO1-targeted approaches and has broader applications for the evaluation of other anticancer strategies.

Surgical excision of a feline orbital lacrimal gland adenocarcinoma with adjunctive cryotherapy and carboplatin-impregnated bead implantation.

The purpose of this report was to discuss the diagnosis, treatment, and outcome of a cat with an orbital lacrimal gland adenocarcinoma. A 14.5-year-old spayed female domestic shorthair cat was evaluated for a firm swelling at the left dorsotemporal orbital rim. The orbital mass was excised with preservation of the globe, and adjunctive cryotherapy was performed. A definitive diagnosis of lacrimal gland adenocarcinoma was obtained after histopathologic evaluation and histochemical staining with periodic acid-Schiff and mucicarmine. Thirteen months postoperatively, tumor regrowth occurred with a much larger osteolytic lesion, and a second surgery was performed consisting of tumor excision with implantation of carboplatin-impregnated calcium sulfate hemihydrate beads. The cat has remained free of recurrence 11 months after the second surgery (26 months after initial diagnosis and surgery). A feline orbital lacrimal gland adenocarcinoma was successfully managed utilizing globe-preserving surgical excision with adjunctive cryotherapy and subsequent carboplatin-impregnated bead implantation. Orbital lacrimal gland adenocarcinoma in cats may not be as aggressive as other forms of periocular, head, and neck adenocarcinomas.

Pharmacokinetics and derivation of an anticancer dosing regimen for the novel anti-cancer agent isobutyl-deoxynyboquinone (IB-DNQ), a NQO1 bioactivatable molecule, in the domestic felid species.

Isobutyl-deoxynyboquinone (IB-DNQ) is a selective substrate for NAD(P)H:quinone oxidoreductase (NQO1), an enzyme overexpressed in many solid tumors. Following activation by NQO1, IB-DNQ participates in a catalytic futile reduction/reoxidation cycle with consequent toxic reactive oxygen species generation within the tumor microenvironment. To elucidate the potential of IB-DNQ to serve as a novel anticancer agent, in vitro studies coupled with in vivo pharmacokinetic and toxicologic investigations in the domestic felid species were conducted to investigate the tractability of IB-DNQ as a translationally applicable anticancer agent. First, using feline oral squamous cell carcinoma (OSCC) as a comparative cancer model, expressions of NQO1 were characterized in not only human, but also feline OSCC tissue microarrays. Second, IB-DNQ mediated cytotoxicity in three immortalized feline OSCC cell lines were studied under dose-dependent and sequential exposure conditions. Third, the feasibility of administering IB-DNQ at doses predicted to achieve cytotoxic plasma concentrations and biologically relevant durations of exposure were investigated through pharmacokinetic and tolerability studies in healthy research felines. Intravenous administration of IB-DNQ at 1.0-2.0 mg/kg achieved peak plasma concentrations and durations of exposure reaching or exceeding predicted in vitro cytotoxic concentrations. Clinical adverse side effects including ptyalism and tachypnea exhibited during and post-IV infusion of IB-DNQ were transient and tolerable. Additionally, IB-DNQ administration did not produce acute or delayed-onset unacceptable hematologic, non-hematologic, or off-target oxidative toxicities. Collectively, the findings reported here within provide important safety and pharmacokinetic data to support the continued development of IB-DNQ as a novel anticancer strategy for NQO1 expressing cancers.