Visceral leiomyosarcoma is well described in dogs, but information about non-visceral locations a... more Visceral leiomyosarcoma is well described in dogs, but information about non-visceral locations and prevalence is lacking. The diagnosis of leiomyosarcoma is challenging without a gold standard, and often includes the use of immunohistochemical (IHC) stains. We used defined histopathologic patterns, histochemical staining, and IHC staining for smooth muscle actin (SMA), desmin, and laminin to characterize suspected non-visceral leiomyosarcoma in dogs at a single academic institution. In a retrospective search, we identified 24 dogs with a definitive or suspected histologic diagnosis of leiomyosarcoma in a non-visceral location. Histopathology results and clinical details were obtained. Biopsy sections were reviewed by a single pathologist using standardized histologic criteria, including light microscopic appearance, immunohistochemistry (more than two-thirds of neoplastic cells labeled with SMA and desmin or laminin), and histochemical staining (minimal-to-mild matrix deposition by...
Background: Doxorubicin (DOX) is one of the most effective chemotherapeutics for canine high-grad... more Background: Doxorubicin (DOX) is one of the most effective chemotherapeutics for canine high-grade lymphoma. In addition to dose-dependent chronic cardiotoxicity, DOX can trigger acute cardiac arrhythmias during drug infusion. Diphenhydramine premedication is commonly used, as histamine release is a proposed mechanism for DOX-associated arrhythmogenesis. Hypothesis/Objectives: The study objectives were to evaluate the incidence and severity of DOX infusion-related cardiac arrhythmias in dogs with high-grade lymphoma and evaluate the effect of diphenhydramine premedication on arrhythmia frequency and severity during and after DOX infusion. Animals: Twenty-two client-owned dogs with cytologically/histopathologically confirmed high-grade lymphoma were recruited, of which 19 were enrolled and 9 completed the study. Methods: Dogs were screened by echocardiogram and concurrent electrocardiogram for this randomized prospective crossover study. Group A received no premedication for DOX #1 and was premedicated with diphenhydramine for DOX #2; Group B received diphenhydramine with DOX #1 and no premedication for DOX #2. For both visits, Holter monitor data were collected for 1 h pre-DOX and 3 h post-DOX administration. Results: Nineteen dogs were enrolled and 9 dogs [Group A (5), Group B (4)] completed the protocol. There was no statistical difference between the DOX alone and DOX + diphenhydramine when evaluating the total number of ventricular premature complexes (VPCs, P = 0.34), change in VPCs/hour (P = 0.25), total number of atrial premature complexes (APCs, P = 0.5), change in APCs/hour (P = 0.06), or ventricular arrhythmia severity score (P > 0.99). Willcox et al. Diphenhydramine and Doxorubicin-Related Acute Arrhythmias Conclusions and clinical importance: This study demonstrates that in these dogs with rigorous pretreatment cardiovascular screening, DOX infusion did not induce significant arrhythmias. Furthermore, these data suggest that, with this screening approach, diphenhydramine may not alter the arrhythmia number or severity in canine DOX recipients.
Journal of the American Veterinary Medical Association
OBJECTIVE To describe the procedure of prostatic artery embolization (PAE) in dogs with prostatic... more OBJECTIVE To describe the procedure of prostatic artery embolization (PAE) in dogs with prostatic carcinoma and to evaluate the short-term outcome for treated dogs. ANIMALS 20 client-owned dogs with prostatic carcinomas between May 2014 and July 2017. PROCEDURES In this prospective cohort study, dogs with carcinoma of the prostate underwent PAE with fluoroscopic guidance. Before and after PAE, dogs underwent CT and ultrasonographic examinations of the prostate, and each owner completed a questionnaire about the dog's clinical signs. Results for before versus after PAE were compared. RESULTS Prostatic artery embolization was successfully performed in all 20 dogs. Tenesmus, stranguria, and lethargy were significantly less common 30 days after PAE (n = 2, 1, and 0 dogs, respectively), compared with before PAE (9, 10, and 6 dogs, respectively). Median prostatic volume was significantly less 30 days after PAE (14.8 cm3; range, 0.4 to 48.1 cm3; interquartile [25th to 75th percentile] ...
Our lack of understanding of the immune microenvironment in canine osteosarcoma (cOSA) has limite... more Our lack of understanding of the immune microenvironment in canine osteosarcoma (cOSA) has limited the identification of potential immunotherapeutic targets. In particular, our ability to utilize readily available tissue from a dog's primary tumour to predict the type and extent of immune response in their pulmonary metastatic lesions is unknown. We, therefore, collected 21 matched pairs of primary tumours and pulmonary metastatic lesions from dogs with OSA and performed immunohistochemistry to quantify T-lymphocyte (CD3), FOXP3+ cell, B-lymphocyte (Pax-5), and CD204+ macrophage infiltration. We found that T-lymphocytes and FOXP3+ infiltrates in primary tumours positively correlated with that of metastatic lesions (ρ = 0.512, P = 0.038 and ρ = 0.698, P = 0.007, respectively), while a strong trend existed for CD204+ infiltrates (ρ = 0.404, P = 0.087). We also observed T- and B-lymphocytes, and CD204+ macrophages to be significantly higher in a dog's pulmonary metastasis compared to their primary tumour (P = 0.018, P = 0.018, P = 0.016, respectively), while FOXP3+ cells were only significantly higher in metastases when all primary tumour and metastasis lesions were compared without pairing (P = 0.036). Together, these findings suggest that the metastatic immune microenvironment may be influenced by that of the primary cOSA, and that primary tumour immune biomarkers could potentially be applied to predict immunotherapeutic responses in gross metastatic disease. We, therefore, provide a rationale for the treatment of cOSA pulmonary metastases with immunotherapeutics that enhance the anti-tumour activity of these immune cells, particularly in dogs with moderate to high immune cell infiltration in their primary tumours.
Background: A doxorubicin (DOX)-based chemotherapy protocol, CHOP, is the most effective treatmen... more Background: A doxorubicin (DOX)-based chemotherapy protocol, CHOP, is the most effective treatment for canine high-grade B-cell lymphoma; however, the cost and time requirements associated with this protocol are not feasible for many pet owners. An alternative treatment option is the use of DOX, the most effective drug, in combination with prednisone. Prior studies with single-agent DOX included dogs with T-cell lymphoma, a known negative prognostic factor, which may have resulted in shorter reported survival times than if dogs with B-cell lymphoma were analyzed separately. The purpose of this study was to evaluate the outcome of dogs with highgrade B-cell lymphoma when treated with DOX and prednisone with or without L-asparaginase (L-ASP). Identification of prognostic factors was of secondary interest. Results: Thirty-three dogs were included in the study; 31 dogs were evaluable for response with an overall response rate of 84%. The median progression free survival (PFS) and overall survival (OS) were 147 days and 182 days, respectively. The one-year survival fraction was 23%. No variable other than protocol completion was found to be significant for either PFS or OS including historical prognostic factors such as substage, thrombocytopenia, and body weight. Conclusions: Dogs with high-grade B-cell lymphoma treated with DOX and prednisone with or without L-ASP have similar response rates, PFS, and OS to prior studies that did not differentiate between lymphoma immunophenotype. This protocol is not a replacement for CHOP; however, it is an alternative if time and cost are factors, while providing therapeutic benefit greater than prednisone alone.
Journal of the American Veterinary Medical Association
Small Animals & Exotic M ore than 80% of all mammary gland masses in cats are malignant, and the ... more Small Animals & Exotic M ore than 80% of all mammary gland masses in cats are malignant, and the behavior of these tumors is characterized by local invasion into the vasculature and surrounding tissues and metastasis Association of surgical approach with complication rate, progression-free survival time, and disease-specific survival time in cats with mammary adenocarcinoma: 107 cases (1991-2014
Development of iniparib as an anti-cancer agent was hindered in part by lingering questions regar... more 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
Journal of veterinary internal medicine / American College of Veterinary Internal Medicine, 2016
Compounded lomustine is used commonly in veterinary patients. However, the potential variability ... more Compounded lomustine is used commonly in veterinary patients. However, the potential variability in these formulations is unknown and concern exists that compounded formulations of drugs may differ in potency from Food and Drug Administration (FDA)-approved products. The initial objective of this study was to evaluate the frequency and severity of neutropenia in dogs treated with compounded or FDA-approved formulations of lomustine. Subsequent analyses aimed to determine the potency of lomustine obtained from several compounding pharmacies. Thirty-seven dogs treated with FDA-approved or compounded lomustine. Dogs that received compounded or FDA-approved lomustine and had pretreatment and nadir CBCs performed were eligible for inclusion. Variables assessed included lomustine dose, neutrophil counts, and severity of neutropenia. Lomustine 5 mg capsules from 5 compounding sources were tested for potency using high-pressure liquid chromatography (HPLC) with ultraviolet (UV) detection. T...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 30, 2018
Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins w... more Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (Indotecan), LMP776 (Indimitecan) and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology and pharmacokinetics. Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics and target engagement were determined. The maximally tolerated doses (MTDs) were 17.5 mg/mfor LMP 776 and 100 mg/mfor LMP744; bone marrow toxicity was dose...
Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of... more Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy. The primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine. Forty-seven client-owned dogs with measurable MCT. Toceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone. The MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy. Combined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT.
Veterinary Clinics of North America: Small Animal Practice, 2014
Clinical trials for companion animals are becoming more common and more accessible to pet owners ... more Clinical trials for companion animals are becoming more common and more accessible to pet owners as veterinary oncologists seek to expand their knowledge of tumor biology in companion animal species and improve the way they diagnose and treat cancer for these animals. Many owners enroll their pets because they wish to participate in clinical cancer research that may ultimately benefit pets and people. Understanding the goals, benefits, and risks of clinical trials participation provides the knowledge needed by primary care veterinarians to counsel their clients as to whether clinical trial participation is a good choice for them and their pets.
Canine cutaneous T-cell lymphoma (CTCL) is an uncommon disease for which efficacious therapies ar... more Canine cutaneous T-cell lymphoma (CTCL) is an uncommon disease for which efficacious therapies are lacking. The novel anticancer nucleotide prodrug VDC-1101 (formerly known as GS-9219) has shown efficacy in dogs with multicentric lymphoma. One of the observed adverse effects with this drug was a skin change characterized by hair loss, erythema, and pruritus, implying delivery of VDC-1101 to the skin. The primary study objective was to identify the objective response rate (ORR) to VDC-1101 in canine CTCL; secondary objectives included characterization of progression-free survival (PFS) and adverse events (AEs). Twelve dogs with chemotherapy-naïve or relapsed, histologically and immunohistochemically confirmed CTCL. Dogs received VDC-1101 as a 30-minute IV infusion once every 21 days. Prednisone (1 mg/kg PO q48h) was administered concurrently. In 11 evaluable patients, responses included 1 complete response (CR), 4 partial responses (PR), 2 stable disease (SD), and 4 progressive disease for an ORR of 45% and biologic response rate (CR/PR/SD) of 64%. The median PFS was 37.5 days (26 to >399 days), which includes 1 durable and ongoing CR (>1 year). Gastrointestinal and hematologic AEs were mild; no dogs developed grade 3 or 4 AEs. Three dogs developed dermatopathies and 1 of these dogs was removed from the study as a result of this AE. VDC-1101 has activity against canine CTCL and could provide another treatment option in a disease process with a poor prognosis.
Dose intense CHOP protocols have been shown to improve outcome for people with non-Hodgkin's lymp... more Dose intense CHOP protocols have been shown to improve outcome for people with non-Hodgkin's lymphoma, but evaluation of dose intense CHOP protocols for canine lymphoma is currently limited. The hypothesis of this retrospective study was that a 15-week dose intense CHOP protocol would have shorter treatment duration with similar efficacy to other doxorubicin-based multidrug protocols. Thirty-one client owned dogs with multicentric lymphoma were treated with a 15-week CHOP chemotherapy protocol with an overall response rate of 100% and a median progression-free interval (PFI) of 140 days [95% confidence interval (CI) 91-335 days]. Dogs that had two or more treatment delays had significantly prolonged PFI and overall survival in multivariate analysis. Dose intensity did not correlate with patient outcome. Dogs experiencing multiple treatment delays secondary to adverse events may receive their individual maximally tolerated dose while dogs with no adverse events may be underdosed. Future studies should focus on individual patient dose optimization.
With the exception of solar-induced dermal hemangiosarcoma (HSA), the biologic behaviour of canin... more With the exception of solar-induced dermal hemangiosarcoma (HSA), the biologic behaviour of canine HSA is characterised by rapid tumour growth, a high metastatic rate and short survival times. Outcome of dogs with HSA of the tongue has not been previously reported. The purpose of this study was to assess outcome and prognostic factors in dogs with lingual HSA. Clinical data was collected retrospectively and histopathology was reviewed for 20 dogs. Median progression free survival was 524 days and the median overall survival time was 553 days. All dogs had low or intermediate grade tumours; most tumours were small and located on the ventral surface of the tongue. Prognostic factors significantly associated with increased survival included small tumour size and absence of clinical signs of an oral mass at the time of diagnosis. Dogs with HSA confined to the tongue may have a better prognosis compared with HSA in other organs.
Low-dose, continuous (metronomic) chemotherapy improves tumor control by inhibiting tumor angioge... more Low-dose, continuous (metronomic) chemotherapy improves tumor control by inhibiting tumor angiogenesis and suppressing regulatory T cells (Treg) in mice and humans. The effects of metronomic chemotherapy on Treg and tumor angiogenesis in dogs has not been investigated previously. To determine whether metronomic cyclophosphamide (CYC) therapy decreases Treg or exhibits antiangiogenic activity or both in dogs with soft tissue sarcoma (STS). We hypothesized that Treg numbers would be increased in dogs with STS and that continuous dosing of CYC would decrease Treg in a dose-dependent manner, as well as exhibit antiangiogenic activity. Eleven client-owned dogs with grade I or II STS. Twenty-one healthy dogs were used as controls. Prospective, open, clinical trial. Dogs with STS were enrolled in 2 dose cohorts and administered CYC at 12.5 or 15 mg/m(2) p.o. once daily for 28 days. Whole blood and tumor biopsy specimens were obtained on days 0, 14, and 28 to assess changes in T lymphocyte subsets by flow cytometry and tumor microvessel density (MVD), respectively. Administration of CYC at 12.5 mg/m(2)/d significantly decreased the number of Treg from days 0 to 28, but there was no change in the percentage of Treg or tumor MVD. In dogs that received CYC at 15.0 mg/m(2)/d, both the number and percent of Treg as well as tumor MVD were significantly decreased over 28 days. CYC administered at 15 mg/m(2)/d should be used in further studies examining the antitumor properties of low-dose CYC in dogs.
Many chemotherapy protocols have been reported for treatment of canine appendicular osteosarcoma ... more Many chemotherapy protocols have been reported for treatment of canine appendicular osteosarcoma (OSA), but outcome comparisons in a single population are lacking. To evaluate the effects of protocol and dose intensity (DI) on treatment outcomes for carboplatin and doxorubicin-based chemotherapy protocols. Four hundred and seventy dogs with appendicular OSA. A retrospective cohort study was performed comprising consecutive dogs treated (1997-2012) with amputation followed by 1 of 5 chemotherapy protocols: carboplatin 300 mg/m(2) IV q21d for 4 or 6 cycles (CARBO6), doxorubicin 30 mg/m(2) IV q14d or q21d for 5 cycles, and alternating carboplatin 300 mg/m(2) IV and doxorubicin 30 mg/m(2) IV q21d for 3 cycles. Adverse events (AE) and DI were evaluated. Kaplan-Meier survival curves and Cox proportional hazards regression were used to compare disease-free interval (DFI) and survival time (ST) among protocols. The overall median DFI and ST were 291 days and 284 days, respectively. A lower proportion of dogs prescribed CARBO6 experienced AEs compared to other protocols (48.4% versus 60.8-75.8%; P = .001). DI was not associated with development of metastases or death. After adjustment for baseline characteristics and prognostic factors, none of the protocols provided a significant reduction in risk of development of metastases or death. Although choice of protocol did not result in significant differences in DFI or ST, the CARBO6 protocol resulted in a lower proportion of dogs experiencing AEs, which could be advantageous in maintaining high quality of life during treatment. DI was not a prognostic indicator in this study.
Background: Canine T-cell lymphoma (TCL) is conventionally considered an aggressive disease, but ... more Background: Canine T-cell lymphoma (TCL) is conventionally considered an aggressive disease, but some forms are histologically and clinically indolent. CD4 TCL is reported to be the most common subtype of TCL. We assessed flow cytometric characteristics, histologic features when available, and clinical outcomes of CD4+ TCL to determine if flow cytometry can be used to subclassify this group of lymphomas.
Visceral leiomyosarcoma is well described in dogs, but information about non-visceral locations a... more Visceral leiomyosarcoma is well described in dogs, but information about non-visceral locations and prevalence is lacking. The diagnosis of leiomyosarcoma is challenging without a gold standard, and often includes the use of immunohistochemical (IHC) stains. We used defined histopathologic patterns, histochemical staining, and IHC staining for smooth muscle actin (SMA), desmin, and laminin to characterize suspected non-visceral leiomyosarcoma in dogs at a single academic institution. In a retrospective search, we identified 24 dogs with a definitive or suspected histologic diagnosis of leiomyosarcoma in a non-visceral location. Histopathology results and clinical details were obtained. Biopsy sections were reviewed by a single pathologist using standardized histologic criteria, including light microscopic appearance, immunohistochemistry (more than two-thirds of neoplastic cells labeled with SMA and desmin or laminin), and histochemical staining (minimal-to-mild matrix deposition by...
Background: Doxorubicin (DOX) is one of the most effective chemotherapeutics for canine high-grad... more Background: Doxorubicin (DOX) is one of the most effective chemotherapeutics for canine high-grade lymphoma. In addition to dose-dependent chronic cardiotoxicity, DOX can trigger acute cardiac arrhythmias during drug infusion. Diphenhydramine premedication is commonly used, as histamine release is a proposed mechanism for DOX-associated arrhythmogenesis. Hypothesis/Objectives: The study objectives were to evaluate the incidence and severity of DOX infusion-related cardiac arrhythmias in dogs with high-grade lymphoma and evaluate the effect of diphenhydramine premedication on arrhythmia frequency and severity during and after DOX infusion. Animals: Twenty-two client-owned dogs with cytologically/histopathologically confirmed high-grade lymphoma were recruited, of which 19 were enrolled and 9 completed the study. Methods: Dogs were screened by echocardiogram and concurrent electrocardiogram for this randomized prospective crossover study. Group A received no premedication for DOX #1 and was premedicated with diphenhydramine for DOX #2; Group B received diphenhydramine with DOX #1 and no premedication for DOX #2. For both visits, Holter monitor data were collected for 1 h pre-DOX and 3 h post-DOX administration. Results: Nineteen dogs were enrolled and 9 dogs [Group A (5), Group B (4)] completed the protocol. There was no statistical difference between the DOX alone and DOX + diphenhydramine when evaluating the total number of ventricular premature complexes (VPCs, P = 0.34), change in VPCs/hour (P = 0.25), total number of atrial premature complexes (APCs, P = 0.5), change in APCs/hour (P = 0.06), or ventricular arrhythmia severity score (P > 0.99). Willcox et al. Diphenhydramine and Doxorubicin-Related Acute Arrhythmias Conclusions and clinical importance: This study demonstrates that in these dogs with rigorous pretreatment cardiovascular screening, DOX infusion did not induce significant arrhythmias. Furthermore, these data suggest that, with this screening approach, diphenhydramine may not alter the arrhythmia number or severity in canine DOX recipients.
Journal of the American Veterinary Medical Association
OBJECTIVE To describe the procedure of prostatic artery embolization (PAE) in dogs with prostatic... more OBJECTIVE To describe the procedure of prostatic artery embolization (PAE) in dogs with prostatic carcinoma and to evaluate the short-term outcome for treated dogs. ANIMALS 20 client-owned dogs with prostatic carcinomas between May 2014 and July 2017. PROCEDURES In this prospective cohort study, dogs with carcinoma of the prostate underwent PAE with fluoroscopic guidance. Before and after PAE, dogs underwent CT and ultrasonographic examinations of the prostate, and each owner completed a questionnaire about the dog's clinical signs. Results for before versus after PAE were compared. RESULTS Prostatic artery embolization was successfully performed in all 20 dogs. Tenesmus, stranguria, and lethargy were significantly less common 30 days after PAE (n = 2, 1, and 0 dogs, respectively), compared with before PAE (9, 10, and 6 dogs, respectively). Median prostatic volume was significantly less 30 days after PAE (14.8 cm3; range, 0.4 to 48.1 cm3; interquartile [25th to 75th percentile] ...
Our lack of understanding of the immune microenvironment in canine osteosarcoma (cOSA) has limite... more Our lack of understanding of the immune microenvironment in canine osteosarcoma (cOSA) has limited the identification of potential immunotherapeutic targets. In particular, our ability to utilize readily available tissue from a dog's primary tumour to predict the type and extent of immune response in their pulmonary metastatic lesions is unknown. We, therefore, collected 21 matched pairs of primary tumours and pulmonary metastatic lesions from dogs with OSA and performed immunohistochemistry to quantify T-lymphocyte (CD3), FOXP3+ cell, B-lymphocyte (Pax-5), and CD204+ macrophage infiltration. We found that T-lymphocytes and FOXP3+ infiltrates in primary tumours positively correlated with that of metastatic lesions (ρ = 0.512, P = 0.038 and ρ = 0.698, P = 0.007, respectively), while a strong trend existed for CD204+ infiltrates (ρ = 0.404, P = 0.087). We also observed T- and B-lymphocytes, and CD204+ macrophages to be significantly higher in a dog's pulmonary metastasis compared to their primary tumour (P = 0.018, P = 0.018, P = 0.016, respectively), while FOXP3+ cells were only significantly higher in metastases when all primary tumour and metastasis lesions were compared without pairing (P = 0.036). Together, these findings suggest that the metastatic immune microenvironment may be influenced by that of the primary cOSA, and that primary tumour immune biomarkers could potentially be applied to predict immunotherapeutic responses in gross metastatic disease. We, therefore, provide a rationale for the treatment of cOSA pulmonary metastases with immunotherapeutics that enhance the anti-tumour activity of these immune cells, particularly in dogs with moderate to high immune cell infiltration in their primary tumours.
Background: A doxorubicin (DOX)-based chemotherapy protocol, CHOP, is the most effective treatmen... more Background: A doxorubicin (DOX)-based chemotherapy protocol, CHOP, is the most effective treatment for canine high-grade B-cell lymphoma; however, the cost and time requirements associated with this protocol are not feasible for many pet owners. An alternative treatment option is the use of DOX, the most effective drug, in combination with prednisone. Prior studies with single-agent DOX included dogs with T-cell lymphoma, a known negative prognostic factor, which may have resulted in shorter reported survival times than if dogs with B-cell lymphoma were analyzed separately. The purpose of this study was to evaluate the outcome of dogs with highgrade B-cell lymphoma when treated with DOX and prednisone with or without L-asparaginase (L-ASP). Identification of prognostic factors was of secondary interest. Results: Thirty-three dogs were included in the study; 31 dogs were evaluable for response with an overall response rate of 84%. The median progression free survival (PFS) and overall survival (OS) were 147 days and 182 days, respectively. The one-year survival fraction was 23%. No variable other than protocol completion was found to be significant for either PFS or OS including historical prognostic factors such as substage, thrombocytopenia, and body weight. Conclusions: Dogs with high-grade B-cell lymphoma treated with DOX and prednisone with or without L-ASP have similar response rates, PFS, and OS to prior studies that did not differentiate between lymphoma immunophenotype. This protocol is not a replacement for CHOP; however, it is an alternative if time and cost are factors, while providing therapeutic benefit greater than prednisone alone.
Journal of the American Veterinary Medical Association
Small Animals & Exotic M ore than 80% of all mammary gland masses in cats are malignant, and the ... more Small Animals & Exotic M ore than 80% of all mammary gland masses in cats are malignant, and the behavior of these tumors is characterized by local invasion into the vasculature and surrounding tissues and metastasis Association of surgical approach with complication rate, progression-free survival time, and disease-specific survival time in cats with mammary adenocarcinoma: 107 cases (1991-2014
Development of iniparib as an anti-cancer agent was hindered in part by lingering questions regar... more 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
Journal of veterinary internal medicine / American College of Veterinary Internal Medicine, 2016
Compounded lomustine is used commonly in veterinary patients. However, the potential variability ... more Compounded lomustine is used commonly in veterinary patients. However, the potential variability in these formulations is unknown and concern exists that compounded formulations of drugs may differ in potency from Food and Drug Administration (FDA)-approved products. The initial objective of this study was to evaluate the frequency and severity of neutropenia in dogs treated with compounded or FDA-approved formulations of lomustine. Subsequent analyses aimed to determine the potency of lomustine obtained from several compounding pharmacies. Thirty-seven dogs treated with FDA-approved or compounded lomustine. Dogs that received compounded or FDA-approved lomustine and had pretreatment and nadir CBCs performed were eligible for inclusion. Variables assessed included lomustine dose, neutrophil counts, and severity of neutropenia. Lomustine 5 mg capsules from 5 compounding sources were tested for potency using high-pressure liquid chromatography (HPLC) with ultraviolet (UV) detection. T...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 30, 2018
Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins w... more Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (Indotecan), LMP776 (Indimitecan) and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology and pharmacokinetics. Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics and target engagement were determined. The maximally tolerated doses (MTDs) were 17.5 mg/mfor LMP 776 and 100 mg/mfor LMP744; bone marrow toxicity was dose...
Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of... more Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy. The primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine. Forty-seven client-owned dogs with measurable MCT. Toceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone. The MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy. Combined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT.
Veterinary Clinics of North America: Small Animal Practice, 2014
Clinical trials for companion animals are becoming more common and more accessible to pet owners ... more Clinical trials for companion animals are becoming more common and more accessible to pet owners as veterinary oncologists seek to expand their knowledge of tumor biology in companion animal species and improve the way they diagnose and treat cancer for these animals. Many owners enroll their pets because they wish to participate in clinical cancer research that may ultimately benefit pets and people. Understanding the goals, benefits, and risks of clinical trials participation provides the knowledge needed by primary care veterinarians to counsel their clients as to whether clinical trial participation is a good choice for them and their pets.
Canine cutaneous T-cell lymphoma (CTCL) is an uncommon disease for which efficacious therapies ar... more Canine cutaneous T-cell lymphoma (CTCL) is an uncommon disease for which efficacious therapies are lacking. The novel anticancer nucleotide prodrug VDC-1101 (formerly known as GS-9219) has shown efficacy in dogs with multicentric lymphoma. One of the observed adverse effects with this drug was a skin change characterized by hair loss, erythema, and pruritus, implying delivery of VDC-1101 to the skin. The primary study objective was to identify the objective response rate (ORR) to VDC-1101 in canine CTCL; secondary objectives included characterization of progression-free survival (PFS) and adverse events (AEs). Twelve dogs with chemotherapy-naïve or relapsed, histologically and immunohistochemically confirmed CTCL. Dogs received VDC-1101 as a 30-minute IV infusion once every 21 days. Prednisone (1 mg/kg PO q48h) was administered concurrently. In 11 evaluable patients, responses included 1 complete response (CR), 4 partial responses (PR), 2 stable disease (SD), and 4 progressive disease for an ORR of 45% and biologic response rate (CR/PR/SD) of 64%. The median PFS was 37.5 days (26 to >399 days), which includes 1 durable and ongoing CR (>1 year). Gastrointestinal and hematologic AEs were mild; no dogs developed grade 3 or 4 AEs. Three dogs developed dermatopathies and 1 of these dogs was removed from the study as a result of this AE. VDC-1101 has activity against canine CTCL and could provide another treatment option in a disease process with a poor prognosis.
Dose intense CHOP protocols have been shown to improve outcome for people with non-Hodgkin's lymp... more Dose intense CHOP protocols have been shown to improve outcome for people with non-Hodgkin's lymphoma, but evaluation of dose intense CHOP protocols for canine lymphoma is currently limited. The hypothesis of this retrospective study was that a 15-week dose intense CHOP protocol would have shorter treatment duration with similar efficacy to other doxorubicin-based multidrug protocols. Thirty-one client owned dogs with multicentric lymphoma were treated with a 15-week CHOP chemotherapy protocol with an overall response rate of 100% and a median progression-free interval (PFI) of 140 days [95% confidence interval (CI) 91-335 days]. Dogs that had two or more treatment delays had significantly prolonged PFI and overall survival in multivariate analysis. Dose intensity did not correlate with patient outcome. Dogs experiencing multiple treatment delays secondary to adverse events may receive their individual maximally tolerated dose while dogs with no adverse events may be underdosed. Future studies should focus on individual patient dose optimization.
With the exception of solar-induced dermal hemangiosarcoma (HSA), the biologic behaviour of canin... more With the exception of solar-induced dermal hemangiosarcoma (HSA), the biologic behaviour of canine HSA is characterised by rapid tumour growth, a high metastatic rate and short survival times. Outcome of dogs with HSA of the tongue has not been previously reported. The purpose of this study was to assess outcome and prognostic factors in dogs with lingual HSA. Clinical data was collected retrospectively and histopathology was reviewed for 20 dogs. Median progression free survival was 524 days and the median overall survival time was 553 days. All dogs had low or intermediate grade tumours; most tumours were small and located on the ventral surface of the tongue. Prognostic factors significantly associated with increased survival included small tumour size and absence of clinical signs of an oral mass at the time of diagnosis. Dogs with HSA confined to the tongue may have a better prognosis compared with HSA in other organs.
Low-dose, continuous (metronomic) chemotherapy improves tumor control by inhibiting tumor angioge... more Low-dose, continuous (metronomic) chemotherapy improves tumor control by inhibiting tumor angiogenesis and suppressing regulatory T cells (Treg) in mice and humans. The effects of metronomic chemotherapy on Treg and tumor angiogenesis in dogs has not been investigated previously. To determine whether metronomic cyclophosphamide (CYC) therapy decreases Treg or exhibits antiangiogenic activity or both in dogs with soft tissue sarcoma (STS). We hypothesized that Treg numbers would be increased in dogs with STS and that continuous dosing of CYC would decrease Treg in a dose-dependent manner, as well as exhibit antiangiogenic activity. Eleven client-owned dogs with grade I or II STS. Twenty-one healthy dogs were used as controls. Prospective, open, clinical trial. Dogs with STS were enrolled in 2 dose cohorts and administered CYC at 12.5 or 15 mg/m(2) p.o. once daily for 28 days. Whole blood and tumor biopsy specimens were obtained on days 0, 14, and 28 to assess changes in T lymphocyte subsets by flow cytometry and tumor microvessel density (MVD), respectively. Administration of CYC at 12.5 mg/m(2)/d significantly decreased the number of Treg from days 0 to 28, but there was no change in the percentage of Treg or tumor MVD. In dogs that received CYC at 15.0 mg/m(2)/d, both the number and percent of Treg as well as tumor MVD were significantly decreased over 28 days. CYC administered at 15 mg/m(2)/d should be used in further studies examining the antitumor properties of low-dose CYC in dogs.
Many chemotherapy protocols have been reported for treatment of canine appendicular osteosarcoma ... more Many chemotherapy protocols have been reported for treatment of canine appendicular osteosarcoma (OSA), but outcome comparisons in a single population are lacking. To evaluate the effects of protocol and dose intensity (DI) on treatment outcomes for carboplatin and doxorubicin-based chemotherapy protocols. Four hundred and seventy dogs with appendicular OSA. A retrospective cohort study was performed comprising consecutive dogs treated (1997-2012) with amputation followed by 1 of 5 chemotherapy protocols: carboplatin 300 mg/m(2) IV q21d for 4 or 6 cycles (CARBO6), doxorubicin 30 mg/m(2) IV q14d or q21d for 5 cycles, and alternating carboplatin 300 mg/m(2) IV and doxorubicin 30 mg/m(2) IV q21d for 3 cycles. Adverse events (AE) and DI were evaluated. Kaplan-Meier survival curves and Cox proportional hazards regression were used to compare disease-free interval (DFI) and survival time (ST) among protocols. The overall median DFI and ST were 291 days and 284 days, respectively. A lower proportion of dogs prescribed CARBO6 experienced AEs compared to other protocols (48.4% versus 60.8-75.8%; P = .001). DI was not associated with development of metastases or death. After adjustment for baseline characteristics and prognostic factors, none of the protocols provided a significant reduction in risk of development of metastases or death. Although choice of protocol did not result in significant differences in DFI or ST, the CARBO6 protocol resulted in a lower proportion of dogs experiencing AEs, which could be advantageous in maintaining high quality of life during treatment. DI was not a prognostic indicator in this study.
Background: Canine T-cell lymphoma (TCL) is conventionally considered an aggressive disease, but ... more Background: Canine T-cell lymphoma (TCL) is conventionally considered an aggressive disease, but some forms are histologically and clinically indolent. CD4 TCL is reported to be the most common subtype of TCL. We assessed flow cytometric characteristics, histologic features when available, and clinical outcomes of CD4+ TCL to determine if flow cytometry can be used to subclassify this group of lymphomas.
Uploads
Papers by Jenna Burton