Treatment of myeloid neoplasia with doxorubicin and cytarabine in 11 dogs.

Myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) are primary myeloid neoplasms in dogs generally considered to have a poor outcome. In this study, we assessed toxicity, efficacy and outcome of concurrent administration of doxorubicin and cytarabine in 11 dogs with myeloid neoplasia. Bone marrow specimens were reviewed by three pathologists and classified as either MDS (n = 2), high grade MDS/early AML (MDS/AML; n = 4) or AML (n = 5). The median number of treatment cycles was 5 (range 1-9) and resolution of cytopenia was reported in 7 of 11 dogs including 2 dogs with MDS, 2 dogs with MDS/AML, and 3 dogs with AML. The median duration of remission in the seven responders was 344 days (range 109-1428) and the median overall survival for all dogs was 369 days. Adverse events consisted of predominantly low-grade gastrointestinal illness and myelosuppression. Three dogs developed grade V toxicity manifesting with heart failure (n = 2) at 369 and 1170 days after diagnosis and acute gastrointestinal side effects (n =1). Despite a limited sample size, these results suggest that a doxorubicin and cytarabine protocol may be considered as a therapeutic option in dogs with myeloid neoplasia. Protocol safety, in particular regarding myocardial toxicity, and efficacy should be further investigated.

Prognostic significance of the urokinase plasminogen activator system in tissue and serum of dogs with appendicular osteosarcoma.

Urokinase plasminogen activator (uPA) and its receptor uPAR promote cancer invasion and metastasis and are emerging therapeutic targets in both human and canine malignancies. While their clinical significance is well-characterized in multiple human tumor types, studies investigating their roles in osteosarcoma are lacking. The objectives of this study were to characterize serum and tissue uPA/uPAR expression in dogs with osteosarcoma and assess the prognostic significance. Serum samples and a tissue microarray of canine appendicular osteosarcoma were analyzed for uPA and uPAR expression by ELISA (n = 49) and immunohistochemistry (n = 38), respectively. Serum uPA activity was also measured by a chromogenic assay (n = 25). Survival analysis was performed by Kaplan-Meier survival analysis, log rank test, and Cox regression analysis. Serum uPA level was significantly higher in dogs with osteosarcoma than clinically healthy control dogs (median 1905 vs 1440 pg/ml, p = 0.008). The majority of canine osteosarcoma tissues expressed uPA (75.9%) or uPAR (77.6%), with 70.7% dual-positivity, indicating autocrine/paracrine activation of the pathway. Survival analysis revealed shorter progression free survival (PFS) in dogs with high serum uPA level in a discovery cohort (n = 29; median PFS 94 vs 266 days, p = 0.003) but not in a validation cohort (n = 23; median PFS 167 vs 490 days, p = 0.16). The difference was significant when both cohorts were combined (n = 49; median PFS 128 vs 266 days, p = 0.003). Serum uPAR and tissue uPA/uPAR levels were not prognostic. In Cox multivariate analysis, high serum uPA level and activity were both associated with poor prognosis, independent of serum ALP, tumor location, and peripheral lymphocyte/monocyte counts. These results indicate high utilization of the uPA pathway and association with disease progression in canine osteosarcoma. Further study involving prospective evaluation to confirm the prognostic significance is warranted. The high prevalence of tissue uPA and uPAR expression suggests the uPA system as a potential therapeutic target in canine osteosarcoma.

Evaluation of PD-1 and PD-L1 expression in canine urothelial carcinoma cell lines.

Urothelial carcinoma (UC) is the most common urinary tumor in dogs and despite combinational therapies, only modest improvements in survival have been achieved in recent years. Given the utility of monoclonal antibodies against PD-1 and PD-L1 in human UC, we evaluated the protein and mRNA expression in three established canine urothelial carcinoma cell lines. Flow cytometry and western blot analysis confirmed cell line expression of both molecules in varying degrees. Reverse transcription PCR (RT-PCR) documented mRNA expression in all three cell lines for both PD-1 and PD-L1. Fluorescence microscopy was consistent with strong PD-1 and PD-L1 expression in the canine cell lines and was in line with previous human literature. Importantly, the flow cytometry work described in this study revealed higher cell intrinsic PD-1 expression in these cell lines which may have implications for tumor behavior and potential treatment opportunities in the future. Further work is necessary to determine the expression patterns in canine UC and potential for benefit with immunotherapy directed against PD-1 and PD-L1.

Recent and current clinical trials in canine appendicular osteosarcoma.

Osteosarcoma (OSA) is an aggressive primary bone tumor in the domestic dog that most often occurs within the appendicular skeleton. Despite the use of adjuvant chemotherapy, most dogs succumb to metastatic disease within 1 year of diagnosis. To improve this outcome, substantial research is currently focused on investigating novel therapies. Herein, we review emerging treatments and clinical trials that, if proven efficacious, could revolutionize the standard of care for canine appendicular OSA. This article includes a critical perspective on the safety, efficacy, and limitations of select immunotherapy, virotherapy, radiotherapy, targeted therapy, and personalized medicine trials, all of which reflect similar investigations taking place in human oncology. These clinical trials represent a major evolution in the overall approach to therapy for dogs with appendicular OSA that could have significant implications for improving survival.

Essais cliniques récents et en cours sur l'ostéosarcome appendiculaire canin. L'ostéosarcome (OSA) est une tumeur osseuse primaire agressive chez le chien domestique qui se produit fréquemment dans le squelette appendiculaire. Malgré l'utilisation de chimiothérapie complémentaire, la majorité des chiens succombent aux métastases en dedans d'une année du diagnostic. Afin d'améliorer ce résultat, de la recherche substantielle est actuellement concentrée sur l'étude de thérapies nouvelles. À cet égard, nous révisons les traitements émergents et les essais cliniques qui, s'ils s'avèrent efficaces, pourraient révolutionner le standard de soins pour les OSA appendiculaires canins. Le présent article inclus une perspective critique de la sécurité, l'efficacité et les limitations d'un choix d'immunothérapie, de virothérapie, de radiothérapie, de thérapies ciblées et d'essais médicaux personnalisés, qui reflètent tous des investigations similaires effectuées en oncologie humaine. Ces essais cliniques représentent une évolution majeure dans l'approche globale à la thérapie de chiens avec OSA appendiculaire qui pourrait avoir des implications significatives pour améliorer la survie.(Traduit par Dr Serge Messier).

Clinical-dosimetric relationship between lacrimal gland dose and keratoconjunctivitis sicca in dogs with sinonasal tumors treated with radiation therapy.

BACKGROUND: Dogs with sinonasal tumor can develop keratoconjunctivitis sicca (KCS) after radiation therapy (RT). In humans, the incidence of xerophtalmia is associated with the mean radiation dose received by the ipsilateral lacrimal gland (LG). HYPOTHESIS/OBJECTIVES: The eyes receiving a higher mean LG dose are more likely to develop KCS. The aim of the study was to determine a starting threshold dose to use as dose constraint for intensity-modulated radiation therapy (IMRT). ANIMALS: Dogs with nasal tumors treated with RT between August 2013 and December 2016. METHODS: Case control retrospective study of dogs with sinonasal tumor treated with 42 Gray (Gy) in 10 fractions using IMRT. Dogs were included if development of KCS after RT was documented (cases) or adequate follow-up information with Schirmer tear test (STT) result for ≥6 months after RT was available (controls). Lacrimal glands were contoured and dose distribution was calculated using the original treatment plan to determine prescribed doses to LGs. RESULTS: Twenty-five dogs were treated with RT and 5 dogs (20%) developed KCS. Fifteen dogs met the inclusion criteria including 5 unilateral KCS and 10 control dogs, resulting in 5 KCS eyes and 25 control eyes. KCS developed at a median of 111 days (84-122) after 1st RT. The mean LG dose reached using a 4.2 Gy per fraction was 33.08 Gy (range: 23.75-42.33) for KCS eyes and 10.33 Gy (1.8-24.77) for control eyes (P < .001). The minimum LG mean dose for developing KCS was 23.75 Gy. No eyes that received a mean LG dose <20 Gy developed KCS versus 5/7 (71%) developed with >20 Gy. CONCLUSION AND CLINICAL IMPORTANCE: Contouring and applying a dose constraint on LGs should be performed when using IMRT in dogs with sinonasal tumors to reduce the risk of KCS.

Composite lymphoma of concurrent T zone lymphoma and large cell B cell lymphoma in a dog.

BACKGROUND: Evolution of indolent to aggressive lymphoma has been described in dogs but is difficult to distinguish from the de novo development of a second, clonally distinct lymphoma. Differentiation of these scenarios can be aided by next generation sequencing (NGS)-based assessment of clonality of lymphocyte antigen receptor genes. CASE PRESENTATION: An 8-year-old male intact Mastiff presented with generalized lymphadenomegaly was diagnosed with nodal T zone lymphoma (TZL) based on cytology, histopathology, immunohistochemistry and flow cytometry. Thirteen months later, the dog re-presented with progressive lymphadenomegaly, and based on cytology and flow cytometry, a large B cell lymphoma (LBCL) was diagnosed. Sequencing-based clonality testing confirmed the de novo development of a LBCL and the persistence of a TZL. CONCLUSIONS: The occurrence of two distinct lymphoid neoplasms should be considered if patient features and tumor cytomorphology or immunophenotype differ among sequential samples. Sequencing-based clonality testing may provide conclusive evidence of two concurrent and distinct clonal lymphocyte populations, termed most appropriately "composite lymphoma".

Computed tomography measurements of intraocular structures of the feline eye.

Diagnostic imaging of the eye can be performed using ultrasonography, MRI or CT. This study describes the CT dimensions, volumes and radiodensities of presumed normal feline intraocular structures. Nineteen adult patients were included in this retrospective study. Fourteen males and five females were included, with domestic short hair (DSH) being the predominant breed. Length, volume and radiodensity values for the lens, anterior chamber, vitreous chamber and optic nerve were calculated as well as measurements of the optic nerve width. There was no significant correlation found on linear regression analysis comparing patient's body weight with the various ocular measurements. Measurements of the lens, globe and optic nerve had significant differences (P<0.05) noted between the sexes, with males having increased values. These results may be skewed due to the large majority of male patients in the study. There was a weak correlation found between age and right eye (OD) optic nerve width, with an increase in the optic nerve width noted with increasing age. The findings of this study are a first step in establishing CT reference values for feline intraocular structure measurements.

Preserved limb function following subtotal iliopsoas muscle and femoral nerve resection in a dog with low grade intramuscular chondrosarcoma.

A 9-year-old spayed female Labrador retriever dog was diagnosed with a grade 1 chondrosarcoma associated with the right iliopsoas muscle. A computed tomography scan of the patient revealed the mass to begin at the level of L5, continuing to the insertion of the iliopsoas muscle on the femur. Surgery was performed to remove the mass. The femoral nerve was encased within the mass and the nerve was transected and removed, along with the iliopsoas muscle, with minimal intraoperative complications. With regular physiotherapy, the patient was able to independently walk, run, and jump, with mild functional lameness after 6 months.

Fonction préservée des membres après une résection partielle du muscle ilio-psoas et du nerf fémoral chez un chien atteint d'un chondrosarcome intramusculaire de faible grade. Une chienne Labrador retriever stérilisée âgée de 9 ans a été diagnostiquée avec un chondrosarcome de grade 1 associé au muscle ilio-psoas droit. Une tomodensitométrie de la patiente a révélé une masse commençant au niveau de L5 et se poursuivant vers l'insertion de l'ilio-psoas sur le fémur. Une chirurgie a été réalisée pour enlever la masse. Le nerf fémoral était enveloppé par la masse et le nerf a été coupé et enlevé, ainsi que le muscle ilio-psoas, avec des complications peropératoires minimes. Grâce à de la physiothérapie régulière, après 6 mois le patient était capable de marcher, courir et sauter de façon indépendante, avec une légère boiterie fonctionnelle.(Traduit par Isabelle Vallières).

Evaluation of metronomic cyclophosphamide chemotherapy as maintenance treatment for dogs with appendicular osteosarcoma following limb amputation and carboplatin chemotherapy.

OBJECTIVE To determine the effectiveness of metronomic cyclophosphamide (MC) chemotherapy (primary treatment of interest) with adjuvant meloxicam administration as maintenance treatment for dogs with appendicular osteosarcoma following limb amputation and carboplatin chemotherapy. DESIGN Retrospective case series with nested cohort study. ANIMALS 39 dogs with a histologic diagnosis of appendicular osteosarcoma that underwent limb amputation and completed carboplatin chemotherapy from January 2011 through December 2015. PROCEDURES Dogs were grouped by whether carboplatin chemotherapy had been followed with or without MC chemotherapy (15 mg/m2, PO, q 24 h) and meloxicam (0.1 mg/kg [0.045 mg/lb], PO, q 24 h). The Breslow rank test was used to assess whether MC chemotherapy was associated with overall survival time (OST) and disease progression-free time (PFT) after limb amputation. RESULTS 19 dogs received carboplatin and MC chemotherapy, and 20 dogs received only carboplatin chemotherapy. No differences were identified between these groups regarding age, reproductive status, body weight, serum alkaline phosphatase activity, tumor location, or histologic grade or subtype of osteosarcoma. Median duration of MC chemotherapy for dogs in the carboplatin-MC group was 94 days (range, 7 to 586 days); this treatment was discontinued for 11 (58%) dogs when cystitis developed. Overall, 11 (28%) dogs survived to the time of analysis, for a median follow-up period of 450 days (range, 204 to 1,400 days). No difference in median PFT or OST was identified between the 2 groups. CONCLUSIONS AND CLINICAL RELEVANCE Maintenance MC chemotherapy following limb amputation and completed carboplatin chemotherapy was associated with no increase in PFT or OST in dogs with appendicular osteosarcoma. Cystitis was common in MC-treated dogs, and prophylactic treatment such as furosemide administration could be considered to reduce the incidence of cystitis in such dogs.

Correlation Between Body Weight and Mitoxantrone-Associated Neutropenia in Dogs.

Thirty-seven dogs with histologically or cytologically confirmed malignant tumors treated with single-agent mitoxantrone at 5 mg/m2 were evaluated in a retrospective study assessing the correlation between body weight and neutropenia associated with a single dose of mitoxantrone in dogs. Overall, eight dogs (21%) experienced grade 3 neutropenia and five dogs (14%) experienced grade 4 neutropenia on day 7 following mitoxantrone chemotherapy. Dogs ≤10 kg body weight were significantly more likely to develop grade 3 or 4 neutropenia (5.8 relative risk; 95% confidence interval, 2.6-12.9; P < .0001) than dogs >10 kg. Dogs ≤15 kg body weight were significantly more likely to develop grade 3 or 4 neutropenia (8.1 relative risk; 95% confidence interval, 2.1-31.3; P < .0001) than dogs >15 kg. Of the 13 patients who developed grade 3 or 4 neutropenia, 6 (46%) were hospitalized for clinical signs related to neutropenia. Based on the severity of neutropenia and the resulting hospitalization seen in dogs ≤10 kg, a dose reduction could be considered for the initial dose of mitoxantrone, and clinicians should be aware of the increased risk of neutropenia in patients 10.1 to ≤15 kg.

Retrospective evaluation of toceranib (Palladia) treatment for canine metastatic appendicular osteosarcoma.

This retrospective study evaluated the outcomes of dogs with macroscopic pulmonary metastasis of appendicular osteosarcoma (OSA) treated with toceranib. Medical records of 20 dogs with macroscopic pulmonary metastasis of OSA that received toceranib were reviewed. The median dose and duration of toceranib administration were 2.52 mg/kg (range: 2.12 to 2.72 mg/kg) and 60 days (range: 17 to 231 days). The median progression free survival (PFS) and overall survival (OS) were 36 days (range: 17 to 231 days) and 90 days (range: 17 to 433 days), respectively. The clinical benefit rate was 10% (2/20; 1 partial response and 1 stable disease). The longest length of initial pulmonary nodules had significant impact on both PFS (P = 0.01) and OS (P = 0.02). The prognosis for dogs with metastatic OSA was poor with only 10% of dogs showing clinical benefit from toceranib. These results suggest that toceranib may not improve outcome in dogs with macroscopic pulmonary metastasis of OSA.

Évaluation rétrospective du traitement avec tocéranib (Palladia) pour l'ostéosarcome appendiculaire métastatique canin. Cette étude rétrospective a évalué les résultats des chiens souffrant de métastase pulmonaire macroscopique de l'ostéosarcome appendiculaire (OSE) traité avec tocéranib. Les dossiers médicaux de 20 chiens atteints de métastase pulmonaire macroscopique d'OSE qui ont reçu tocéranib ont été évalués. La dose médiane et la durée de l'administration de tocéranib étaient de 2,52 mg/kg (étendue de 2,12 à 2,72 mg/kg) et de 60 jours (étendue de 17 à 231 jours). La progression de survie libre (PSL) médiane et la survie totale (ST) étaient de 36 jours (étendue de 17 à 231 jours) et de 90 jours (étendue de 17 à 433 jours), respectivement. Le taux de bienfaits cliniques étaient de 10 % (2/20; 1 réponse partielle et 1 maladie stable). Le plus long intervalle avant l'apparition des nodules pulmonaires initiaux avait un impact important sur la PSL (P = 0,01) et la ST (P = 0,02). Le pronostic pour les chiens atteints d'OSE métastatique était mauvais et seulement 10 % des chiens ont manifesté des bienfaits cliniques lors de l'usage de tocéranib. Ces résultats suggèrent que le tocéranib pourraient ne pas améliorer les résultats cliniques chez les chiens souffrant de métastase pulmonaire macroscopique causée par OSE.(Traduit par Isabelle Vallières).

Adjuvant Doxorubicin with or without Metronomic Cyclophosphamide for Canine Splenic Hemangiosarcoma.

This retrospective study investigated the outcome of 33 dogs with splenic hemangiosarcoma treated with surgery followed by adjuvant dose-intensified doxorubicin (DOX) with or without low-dose metronomic cyclophosphamide (LDM-C) maintenance therapy. Among the 33 dogs, 18 dogs received LDM-C. Clinical stage was available for all dogs (5 stage I, 18 stage II, and 10 stage III). Nine dogs had macroscopic, and 24 dogs had microscopic disease at the start of DOX treatment. Median progression-free survival (PFS) and overall survival were 125 and 133 days, respectively. Clinical stage and tumor burden (microscopic versus macroscopic) at the start of chemotherapy was prognostic for PFS. No significant difference was observed in PFS or overall survival for the addition of LDM-C after a completed DOX protocol (P = .563 and P = .148, respectively). Based on the results of this retrospective study, the addition of LDM-C therapy as a maintenance regimen following a completed protocol of DOX adjuvant treatment of canine hemangiosarcoma may not improve outcome.

Evaluation of toxicity of a chronic alternate day metronomic cyclophosphamide chemotherapy protocol in dogs with naturally occurring cancer.

Sterile hemorrhagic cystitis (SHC) is an important complication of cyclophosphamide chemotherapy in dogs as it is reported in up to 23% of cases with various protocols. The current study reports toxicities of a protocol of metronomic cyclophosphamide, and identifies risk factors for development of adverse effects. A retrospective cohort study of dogs treated with metronomic cyclophosphamide at an intended dose of 25 mg/m2 every other day was conducted. Fifty dogs were included with a median length of treatment of 90 days (range: 1 to 1305 days). Treatment was discontinued in 22 dogs (44%) due to adverse effects; 16 dogs (32%) developed SHC after a median time of 127.5 days (range: 54 to 1305 days). Higher cumulative dose was significantly associated with a higher risk of SHC development (P = 0.048). Therefore, close monitoring and/or prophylactic treatments should be considered for patients receiving chronic metronomic cyclophosphamide therapy.

Évaluation de la toxicité du protocole de chimiothérapie prolongée à la cyclophosphamide métronomique tous les deux jours chez les chiens atteints d'un cancer acquis naturellement. La cystite hémorragique stérile (CHS) est une complication importante de la chimiothérapie à la cyclophosphamide chez les chiens car elle est signalée dans jusqu'à 23 % des cas avec divers protocoles. L'étude actuelle signale les toxicités d'un protocole de cyclophosphamide métronomique et identifie les facteurs de risque pour le développement d'effets indésirables. Une étude rétrospective auprès d'une cohorte de chiens traités à l'aide de la cyclosphamide métronomique à une dose prévue de 25 mg/m2 tous les deux jours a été réalisée. Cinquante chiens ont été inclus avec une durée moyenne de traitement de 90 jours (fourchette : de 1 à 1305 jours). Le traitement a été discontinué chez 22 chiens (44 %) en raison des effets indésirables; 16 chiens (32 %) ont développé la CHS après une durée moyenne de 127,5 jours (fourchette : de 54 à 1305 jours). Une dose cumulative supérieure était significativement associée à un risque supérieur de développer la CHS (P = 0,048). Par conséquent, une surveillance étroite et/ou des traitements prophylactiques devraient être considérés pour les patients recevant une thérapie prolongée à la cyclophosphamide métronomique.(Traduit par Isabelle Vallières).