Adjuvant Sirolimus Does Not Improve Outcome in Pet Dogs Receiving Standard-of-Care Therapy for Appendicular Osteosarcoma: A Prospective, Randomized Trial of 324 Dogs.

PURPOSE: The mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression. PATIENTS AND METHODS: A total of 324 pet dogs diagnosed with treatment-naïve appendicular osteosarcoma were randomized into a two-arm, multicenter, parallel superiority trial whereby dogs received amputation of the affected limb, followed by adjuvant carboplatin chemotherapy ± oral sirolimus therapy. The primary outcome measure was disease-free interval (DFI), as assessed by serial physical and radiologic detection of emergent macroscopic metastases; secondary outcomes included overall 1- and 2-year survival rates, and sirolimus pharmacokinetic variables and their correlative relationship to adverse events and clinical outcomes. RESULTS: There was no significant difference in the median DFI or overall survival between the two arms of this trial; the median DFI and survival for standard-of-care (SOC; defined as amputation and carboplatin therapy) dogs was 180 days [95% confidence interval (CI), 144-237] and 282 days (95% CI, 224-383) and for SOC + sirolimus dogs, it was 204 days (95% CI, 157-217) and 280 days (95% CI, 252-332), respectively. CONCLUSIONS: In a population of pet dogs nongenomically segmented for predicted mTOR inhibition response, sequentially administered adjuvant sirolimus, although well tolerated when added to a backbone of therapy, did not extend DFI or survival in dogs with appendicular osteosarcoma.

Substitution of mitoxantrone for doxorubicin in a multidrug chemotherapeutic protocol for first-line treatment of dogs with multicentric intermediate- to large-cell lymphoma.

OBJECTIVE To evaluate effects of substituting mitoxantrone for doxorubicin in a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapeutic protocol for first-line treatment of dogs with multicentric intermediate- to large-cell lymphoma. DESIGN Retrospective cohort study. ANIMALS 44 dogs treated with cyclophosphamide, mitoxantrone, vincristine, and prednisone (CMOP) and 51 dogs treated with CHOP at 12 referral institutions. PROCEDURES Medical records were reviewed to determine response to treatment, progression-free survival time, and overall survival time. For dogs treated with CMOP, adverse events were also recorded. RESULTS All 44 (100%) dogs treated with CMOP and 37 of 38 (97.4%) dogs treated with CHOP had a complete or partial response. Median progression-free survival time for dogs treated with CMOP was 165 days (95% confidence interval [CI], 143 to 187 days), and median overall survival time was 234 days (95% CI, 165 to 303 days). For dogs treated with CHOP, median progression-free survival time was 208 days (95% CI, 122 to 294 days), and median overall survival time was 348 days (95% CI, 287 to 409 days). Progression-free and overall survival times were not significantly different between groups. Overall, 9 of the 44 (20%) dogs treated with CMOP had adverse events likely or probably related to mitoxantrone, but all of these adverse events were mild. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that mitoxantrone may be a reasonable substitution in a CHOP protocol for treatment of dogs with multicentric intermediate- to large-cell lymphoma when doxorubicin is contraindicated.

Outcome following cosmetic rostral nasal reconstruction after planectomy in 26 dogs.

OBJECTIVE: To report the outcome and owner satisfaction after planectomy for nasal planum neoplasia with cosmetic reconstruction with bilateral labial mucocutaneous rotation flaps in dogs. STUDY DESIGN: Multi-institutional, retrospective case series. ANIMALS: Twenty-six client-owned dogs. METHODS: Medical records were searched for dogs that had undergone the procedure. Signalment, diagnosis, surgery, complications, requirement for revision surgery, recurrence, and survival information were recorded. Owners were contacted by telephone about their dog's quality of life after the procedure and their satisfaction with their dog's outcome. RESULTS: Twenty-five dogs underwent radical planectomy, and 1 dog underwent resection of the nasal planum. Twenty-four dogs had a diagnosis of squamous cell carcinoma, 1 had a diagnosis of atypical adenocarcinoma, and 1 had a diagnosis of a mast cell tumor. Complications occurred in 19 (73%) dogs, with 9 dogs requiring revision surgery; 1 dog not surviving to discharge. Median survival time was 1542 days (range, 3-2010). Recurrence of the primary tumor was suspected in 2 (7.7%) dogs, both with narrow or incomplete excision. Among 11 owners interviewed, 10 were satisfied with their dog's appearance, and 8 reported they would consent to the procedure again. CONCLUSION: Dehiscence was common after this procedure, but local tumor control and survival times were excellent. Owner satisfaction was high, although preoperative client education is vital. CLINICAL SIGNIFICANCE: This technique should be considered as a viable option for dogs with nasal planum neoplasia given the high rate of recurrence with less aggressive treatment. Complications common following surgery, but do not persist long term and survival times were excellent.

Successful management of doxorubicin overdose and extravasation in a dog with lymphoma.

A dog was hospitalized after accidental overdose and extravasation of doxorubicin. With supportive care and dexrazoxane, systemic toxicity resolved by Day 9 and extravasation injury by Day 36. This case demonstrates that, with treatment, dogs can survive doxorubicin overdose and extravasation. The report also highlights the importance of checking the dose of chemotherapeutic agents and preventing extravasation.

Gestion réussie d'une surdose à la doxorubicine et de l'extravasation chez un chien atteint d'un lymphome. Un chien a été hospitalisé après une surdose accidentelle et l'extravasation de doxorubicine. Avec des soins de soutien et de la dexrazoxane, la toxicité systémique s'est résorbée au Jour 9 et la blessure d'extravasation au Jour 36. Ce cas démontre que, avec un traitement, les chiens peuvent survivre à une surdose de doxorubicine et à l'extravasation. Ce rapport souligne aussi l'importance de la vérification de la dose d'agents chimiothérapeutiques et de la prévention de l'extravasation.(Traduit par Isabelle Vallières).

Indirect computed tomography lymphangiography with aqueous contrast for evaluation of sentinel lymph nodes in dogs with tumors of the head.

Sentinel lymph node evaluation is widely used in human medicine to evaluate the first lymph node(s) to which a tumor drains. Sentinel lymph node biopsy allows avoidance of extensive lymphadenectomies in cases where the sentinel lymph node is negative for metastasis, thereby reducing patient morbidity. It has been shown that regional lymph nodes are not always the sentinel lymph node, thus identification and sampling of sentinel lymph nodes allows for more accurate staging, which is critical for treatment and prognostication in dogs with cancer. The objective of this prospective, pilot study was to determine if indirect computed tomography (CT) lymphangiography with aqueous contrast agent would successfully allow identification of sentinel lymph nodes in dogs with masses on the head. Eighteen dogs underwent CT lymphangiography. The sentinel lymph node was successfully identified within 3 min of contrast injection in 16 dogs (89%). Compression of lymphatic vessels from endotracheal tube ties and/or the patient's own body weight delayed or prevented identification of sentinel lymph nodes in two dogs (11%). Computed tomography lymphangiography with aqueous contrast can be used successfully to rapidly identify sentinel lymph nodes in dogs with masses on the head.

Canine spontaneous head and neck squamous cell carcinomas represent their human counterparts at the molecular level.

Spontaneous canine head and neck squamous cell carcinoma (HNSCC) represents an excellent model of human HNSCC but is greatly understudied. To better understand and utilize this valuable resource, we performed a pilot study that represents its first genome-wide characterization by investigating 12 canine HNSCC cases, of which 9 are oral, via high density array comparative genomic hybridization and RNA-seq. The analyses reveal that these canine cancers recapitulate many molecular features of human HNSCC. These include analogous genomic copy number abnormality landscapes and sequence mutation patterns, recurrent alteration of known HNSCC genes and pathways (e.g., cell cycle, PI3K/AKT signaling), and comparably extensive heterogeneity. Amplification or overexpression of protein kinase genes, matrix metalloproteinase genes, and epithelial-mesenchymal transition genes TWIST1 and SNAI1 are also prominent in these canine tumors. This pilot study, along with a rapidly growing body of literature on canine cancer, reemphasizes the potential value of spontaneous canine cancers in HNSCC basic and translational research.

Impact of Toceranib/Piroxicam/Cyclophosphamide Maintenance Therapy on Outcome of Dogs with Appendicular Osteosarcoma following Amputation and Carboplatin Chemotherapy: A Multi-Institutional Study.

BACKGROUND: We hypothesized that the addition of toceranib to metronomic cyclophosphamide/piroxicam therapy would significantly improve disease-free interval (DFI) and overall survival (OS) in dogs with appendicular osteosarcoma (OSA) following amputation and carboplatin chemotherapy. METHODS AND FINDINGS: This was a randomized, prospective clinical trial in which dogs with OSA free of gross metastatic disease (n = 126) received carboplatin chemotherapy (4 doses) following amputation. On study entry, dogs were randomized to receive piroxicam/cyclophosphamide with or without toceranib (n = 63 each) after completing chemotherapy. Patient demographics were not significantly different between both groups. During or immediately following carboplatin chemotherapy, 32 dogs (n = 13 toceranib; n = 19 control) developed metastatic disease, and 13 dogs left the study due to other medical conditions or owner preference. Following carboplatin chemotherapy, 81 dogs (n = 46 toceranib; n = 35 control) received the metronomic treatment; 35 dogs (n = 20 toceranib; n = 15 control) developed metastatic disease during the maintenance therapy, and 26 dogs left the study due to other medical conditions or owner preference. Nine toceranib-treated and 11 control dogs completed the study without evidence of metastatic disease 1-year following amputation. Toceranib-treated dogs experienced more episodes of diarrhea, neutropenia and weight loss than control dogs, although these toxicities were low-grade and typically resolved with supportive care. More toceranib-treated dogs (n = 8) were removed from the study for therapy-associated adverse events compared to control dogs (n = 1). The median DFI for control and toceranib treated dogs was 215 and 233 days, respectively (p = 0.274); the median OS for control and toceranib treated dogs was 242 and 318 days, respectively (p = 0.08). The one year survival rate for control dogs was 35% compared to 38% for dogs receiving toceranib. CONCLUSIONS: The addition of toceranib to metronomic piroxicam/cyclophosphamide therapy following amputation and carboplatin chemotherapy did not improve median DFI, OS or the 1-year survival rate in dogs with OSA.

Molecular homology and difference between spontaneous canine mammary cancer and human breast cancer.

Spontaneously occurring canine mammary cancer represents an excellent model of human breast cancer, but is greatly understudied. To better use this valuable resource, we performed whole-genome sequencing, whole-exome sequencing, RNA-seq, and/or high-density arrays on twelve canine mammary cancer cases, including seven simple carcinomas and four complex carcinomas. Canine simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many of which faithfully recapitulate key features of human breast cancer. Canine complex carcinomas, which are characterized by proliferation of both luminal and myoepithelial cells and are rare in human breast cancer, seem to lack genomic abnormalities. Instead, these tumors have about 35 chromatin-modification genes downregulated and are abnormally enriched with active histone modification H4-acetylation, whereas aberrantly depleted with repressive histone modification H3K9me3. Our findings indicate the likelihood that canine simple carcinomas arise from genomic aberrations, whereas complex carcinomas originate from epigenomic alterations, reinforcing their unique value. Canine complex carcinomas offer an ideal system to study myoepithelial cells, the second major cell lineage of the mammary gland. Canine simple carcinomas, which faithfully represent human breast carcinomas at the molecular level, provide indispensable models for basic and translational breast cancer research.

Outcome for client-owned domestic rabbits undergoing limb amputation: 34 cases (2000-2009).

OBJECTIVE: To describe morbidity, function, outcome, and owner satisfaction associated with limb amputation in domestic rabbits. DESIGN: Retrospective case series. ANIMALS: 34 client-owned domestic rabbits. PROCEDURES: Medical records of domestic rabbits undergoing limb amputation for any cause between 2000 and 2009 were reviewed. The Kaplan-Meier method was used to estimate survival rate and median survival time, and variables were analyzed for relationship to risk of morbidity resulting in euthanasia and to outcome (survival vs nonsurvival [death or euthanasia]). Owners were interviewed to determine satisfaction with outcome of the procedure. RESULTS: 28 rabbits underwent pelvic limb amputation, and 6 underwent thoracic limb amputation. At the last follow-up, 18 rabbits were dead, 9 were alive, and 7 were lost to follow-up. Median overall survival time was 720 days (range, 4 to 3,250 days). Acute and delayed or chronic complications were observed in 22 of 34 and 19 of 32 rabbits, respectively, most commonly difficulty ambulating, hygiene issues, and pododermatitis (cutaneous ulcers at the hock). Six rabbits were euthanized because of complications at a median of 104 days (range, 4 to 399 days) after surgery. Risk of morbidity resulting in euthanasia increased with heavier body weight and concurrent disease affecting ambulation at the time of amputation. Weight, age, and pododermatitis at the time of amputation were significantly negatively associated with survival time. Thirty-one (91%) owners were satisfied with the outcome. CONCLUSIONS AND CLINICAL RELEVANCE: Although limb amputation was tolerated by most rabbits and most owners were satisfied, complications resulted in death in 6 of 34 (18%) rabbits, and 19 of 32 (59%) developed chronic complications. Amputation in heavy rabbits or those with concurrent pododermatitis, musculoskeletal disease, or neurologic disease should be considered carefully. Because of the small sample size and retrospective nature of this study, results should be interpreted as exploratory and hypothesis generating.

Dexrazoxane treatment of doxorubicin extravasation injury in four dogs.

CASE DESCRIPTION: 4 dogs were treated with dexrazoxane for known or suspected doxorubicin extravasation. Records were retrospectively reviewed. Doses and number of doses of dexrazoxane were variable. Dexrazoxane was administered within 2 hours after known extravasation in 3 dogs and 48 hours after suspected extravasation in 1 dog. Additional medical treatments included tissue cooling in all dogs, topically administered dimethyl sulfoxide ointment in 3, and orally administered piroxicam in 1. CLINICAL FINDINGS: Mild erythema and edema at the extravasation site developed within 1 to 6 days after extravasation in the 3 dogs that received dexrazoxane within 2 hours after extravasation. Extensive tissue necrosis occurred in the dog treated 48 hours after suspected extravasation. TREATMENT AND OUTCOME: Only the dog with severe tissue necrosis required surgical intervention. Lesions in the other 3 dogs resolved with medical management alone. All dogs survived the event. CLINICAL RELEVANCE: To date, use of dexrazoxane in the management of doxorubicin extravasation has not been reported in dogs. Treatment was successful in 3 of 4 patients. The most effective dosage and timing of administration are unknown; however, there is evidence to suggest that administration within 6 hours after the event is warranted. Further studies are needed to confirm efficacy and to optimize use of this drug in the prevention and treatment of anthracycline extravasation injury in veterinary patients.

Evaluation of factors associated with second remission in dogs with lymphoma undergoing retreatment with a cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy protocol: 95 cases (2000-2007).

OBJECTIVE: To evaluate factors associated with second remission in dogs with lymphoma retreated with a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) protocol after relapse following initial treatment with a first-line 6-month CHOP protocol. DESIGN: Retrospective case series. ANIMALS: 95 dogs with lymphoma. PROCEDURES: Medical records were reviewed. Remission duration was estimated by use of the Kaplan-Meier method. Factors potentially associated with prognosis were examined. RESULTS: Median remission duration after the first-line CHOP protocol was 289 days (range, 150 to 1,457 days). Overall, 78% (95% confidence interval [CI], 69% to 86%) of dogs achieved a complete remission following retreatment, with a median second remission duration of 159 days (95% CI, 126 to 212 days). Duration of time off chemotherapy was associated with likelihood of response to retreatment; median time off chemotherapy was 140 days for dogs that achieved a complete remission after retreatment and 84 days for dogs that failed to respond to retreatment. Second remission duration was associated with remission duration after initial chemotherapy; median second remission duration for dogs with initial remission duration ≥ 289 days was 214 days (95% CI, 168 to 491 days), compared with 98 days (95% CI, 70 to 144 days) for dogs with initial remission duration < 289 days. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggested that retreatment with the CHOP protocol can be effective in dogs with lymphoma that successfully complete an initial 6-month CHOP protocol.

Gingival osteogenic melanoma in two dogs.

Osteogenic melanoma is a rare variant of metaplastic malignant melanoma in human medicine and appears to be a similarly rare variant in dogs. Two dogs with oral malignant melanoma with neoplastic bone formation are reported in this study. Both tumors were characterized by malignant melanocytes that transitioned into neoplastic bone at the deep margins of the neoplasm. Immunohistochemical analysis revealed S100- and Melan-A-positive neoplastic cells adjacent to, and occasionally embedded within, an osteoid and chondroblastic matrix. Scattered clusters of neoplastic cells were also positive for osteocalcin. The findings indicate that in dogs, as in humans, neoplastic melanocytes have metaplastic potential and can be osteogenic.

Tolerance doses of cutaneous and mucosal tissues in ring-necked parakeets (Psittacula krameri) for external beam megavoltage radiation.

Currently used dosages for external-beam megavoltage radiation therapy in birds have been extrapolated from mammalian patients and often appear to provide inadequate doses of radiation for effective tumor control. To determine the tolerance doses of cutaneous and mucosal tissues of normal birds in order to provide more effective radiation treatment for tumors that have been shown to be radiation responsive in other species, ingluvial mucosa and the skin over the ingluvies of 9 ring-necked parakeets (Psittacula krameri) were irradiated in 4-Gy fractions to a total dose of either 48, 60, or 72 Gy using an isocentric cobalt-60 teletherapy unit. Minimal radiation-induced epidermal changes were present in the high-dose group histologically. Neither dose-related acute nor chronic radiation effects could be detected in any group grossly in cutaneous or mucosal tissue over a 9-month period. Radiation doses of 72 Gy in 4-Gy fractions were well tolerated in the small number of ring-necked parakeets in this initial tolerance dose study.

Fibrosarcoma adjacent to the site of microchip implantation in a cat.

A 14-year-old spayed female domestic shorthair cat presented with an interscapular mass. A computed tomography scan, biopsy, and histological examination revealed a fibrosarcoma adjacent to a pet identification microchip. Because the cat was previously vaccinated at this site, it is not possible to establish definitive causation of the fibrosarcoma, but this is the first report of a tumor in the vicinity of a microchip in a cat. Microchip-associated tumors have been reported in rodents and dogs. Veterinarians should be aware that because inflammation may predispose felines to tumor formation, separation and observation of vaccination and implantation sites are indicated. Adherence to American Association of Feline Practitioners (AAFP) vaccination guidelines and monitoring of microchip implantation sites are recommended.

Outcomes of cats with oral tumors treated with mandibulectomy: 42 cases.

Medical records of 42 cats treated with mandibulectomy for oral neoplasia at eight institutions were reviewed to determine morbidity, progression-free interval, and survival time. Progression-free and survival rates at 1 and 2 years were 56% and 49%, and 60% and 57%, respectively. Cats with squamous cell carcinoma had significantly shorter survival than cats with fibrosarcoma or osteosarcoma. Seventy-two percent of cats were dysphagic or inappetent immediately postoperatively, and 12% never regained the ability to eat. Despite acute morbidity in 98% and long-term morbidity in 76% of cats, 83% of the 30 owners providing information were satisfied with the outcome of mandibulectomy.

Phase I trial and pharmacokinetic analysis of ifosfamide in cats with sarcomas.

OBJECTIVE: To determine the maximally tolerated dose (MTD) and dose-limiting toxicosis (DLT) of ifosfamide in tumor-bearing cats. ANIMALS: 38 cats with resected, recurrent, or metastatic sarcomas. PROCEDURE: The starting dosage of ifosfamide was 400 mg/m(2) of body surface area, IV, and dosages were increased by 50 to 100 mg/m(2) in cohorts of 3 cats. To protect against urotoxicosis, mesna was administered at a dosage equal to 20% of the calculated ifosfamide dosage. Diuresis with saline (0.9% NaCl) solution before and after administration of ifosfamide was used to minimize nephrotoxicosis. Samples for pharmacokinetic analysis were obtained after the MTD was reached. RESULTS: 38 cats were entered into this phase I study and were administered a single dose of ifosfamide at various dosages. The MTD was 1,000 mg/m(2), and neutropenia was the DLT. Seven of 8 episodes of neutropenia were on day 7 after treatment, and 1 cat developed severe neutropenia on day 5. Adverse effects on the gastrointestinal tract were generally mild and self-limiting, the most common of which was nausea during ifosfamide infusion. One cat had signs consistent with a drug-induced hypersensitivity reaction. There were no episodes of hemorrhagic cystitis or nephrotoxicosis. Correlations between pharmacokinetic variables and ifosfamide-associated toxicoses were not found. Preliminary evidence of antitumor activity was observed in 6 of 27 cats with measurable tumors. CONCLUSIONS AND CLINICAL RELEVANCE: The dosage of ifosfamide recommended to treat tumor-bearing cats is 900 mg/m(2) every 3 weeks. This dosage should be used in phase II clinical trials.

Variation among pathologists in histologic grading of canine cutaneous mast cell tumors.

Ten veterinary pathologists at 1 veterinary institution independently assigned histologic grades to the same 60 canine cutaneous mast cell tumors (MCTs). There was significant variation among pathologists in grading the MCTs (P < 0.001). The probability of assigning a low grade was significantly higher for the pathologists in this study who use a published reference for histologic grading of canine cutaneous MCTs that allows subcutaneous MCTs or MCTs with mitotic figures to be included in the low-grade category (P < 0.0001 and P < 0.0001, respectively).

Outcome of dogs with mast cell tumors in the inguinal or perineal region versus other cutaneous locations: 124 cases (1990-2001).

OBJECTIVE: To compare clinical outcome of dogs with cutaneous mast cell tumors (MCTs) in the inguinal or perineal region with outcome for dogs with MCTs in other cutaneous locations. DESIGN: Retrospective study. ANIMALS: 37 dogs with MCTs in the inguinal or perineal region and 87 dogs with MCTs in other cutaneous locations. PROCEDURE: Information obtained from the medical records included sex, breed, age, histologic grade of all tumors, number and location of all tumors, tumor size (ie, diameter of the tumor), completeness of surgical excision, treatments administered in addition to surgery, and outcome. In all dogs, the primary treatment consisted of surgical excision. RESULTS: Disease-free interval and survival time for dogs with MCTs in the inguinal or perineal region were not significantly different from values for dogs with MCTs in other cutaneous locations. Dogs with incompletely excised tumors, dogs with grade III tumors, and dogs that received systemic treatment were 2, 2.5, and 4 times as likely, respectively, to have a relapse. Factors significantly associated with a shorter survival time were age > 8 years, metastatic disease at the time of initial diagnosis, and tumor relapse. CONCLUSIONS AND CLINICAL RELEVANCE: Results of the present study suggest that dogs with MCTs in the inguinal or perineal region do not have a worse prognosis in regard to disease-free interval or survival time than do dogs with MCTs in other cutaneous locations. Treatment recommendations for dogs with cutaneous MCTs should be based on confirmed predictors of biological behavior, such as histologic grade and clinical stage.

Iridium-192 interstitial brachytherapy as adjunctive treatment for canine cutaneous mast cell tumors.

Eleven dogs with cutaneous mast cell tumors (MCTs) were treated with surgery and iridium-192 ((192)Ir) interstitial brachytherapy. Minimum tumor doses ranged from 47.2 to 63.3 Gy. Treated tumors were classified as grade II (n=7) or III (n=4). Five dogs had recurrences with a median progression-free interval of 1391 days, and six dogs had no recurrence at a median follow-up time of 942 days. Acute adverse effects were well tolerated, and late effects were mild. One dog developed a second tumor of a different cell type in the radiation treatment field.