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Molecularly-guided trials (i.e. PMed) now seek to aid clinical decision-making by matching cancer targets with therapeutic options. Progress has been hampered by the lack of cancer models that account for individual-to-individual heterogeneity within and across cancer types. Naturally occurring cancers in pet animals are heterogeneous and thus provide an opportunity to answer questions about these PMed strategies and optimize translation to human patients. In order to realize this opportunity, it is now necessary to demonstrate the feasibility of conducting molecularly-guided analysis of tumors from dogs with naturally occurring cancer in a clinically relevant setting. A proof-of-concept study was conducted by the Comparative Oncology Trials Consortium (COTC) to determine if tumor collection, prospective molecular profiling, and PMed report generation within 1 week was feasible in dogs. Thirty-one dogs with cancers of varying histologies were enrolled. Twenty-four of 31 samples (77%) successfully met all predefined QA/QC criteria and were analyzed via Affymetrix gene expression profiling. A subsequent bioinformatics workflow transformed genomic data into a personalized drug report. Average turnaround from biopsy to report generation was 116 hours (4.8 days). Unsupervised clustering of canine tumor expression data clustered by cancer type, but supervised clustering of tumors based on the personalized drug report clustered by drug class rather than cancer type. Collection and turnaround of high quality canine tumor samples, centralized pathology, analyte generation, array hybridization, and bioinformatic analyses matching gene expression to therapeutic options is achievable in a practical clinical window (<1 week). Clustering data show robust signatures by cancer type but also showed patient-to-patient heterogeneity in drug predictions. This lends further support to the inclusion of a heterogeneous population of dogs with cancer into the preclinical modeling of personalized medicine. Future comparative oncology studies optimizing the delivery of PMed strategies may aid cancer drug development.

Eight cats with locally advanced, oral squamous cell carcinoma (SCC) were treated with a combination of gemcitabine and palliative radiotherapy. Low-dose gemcitabine was administered twice weekly (25 mg/m2) in conjunction with megavoltage radiation in 6 Gray (Gy) fractions for a total dose of 36 Gy. Responses included two complete and four partial responses, and two cats had no response to therapy. Median duration of remission was 42.5 days (range, 11 to 85 days). Median survival time was 111.5 days (range, 11 to 234 days). This data suggests that a combination of low-dose gemcitabine and palliative radiation therapy may be tolerable for cats with oral SCC and may cause a therapeutic benefit.

Twenty cats with spontaneously arising tumors received oral lomustine at a dose range of 32 to 59 mg/m 2 every 21 days. Due to biohazard concerns associated with lomustine capsule reformulation, a standardized 10-mg capsule dosage was used for all cats regardless of body weight. Severe hematological toxicity was infrequent, with the incidence of either grade III or IV neutropenia and thrombocytopenia being 4.1% and 1.0%, respectively. Cats receiving higher cumulative doses of lomustine trended toward a greater likelihood for progressive neutropenia ( P =0.07). Two cats with lymphoma, two cats with fibrosarcoma, and one cat with multiple myeloma achieved a measurable partial response to lomustine therapy. Cats treated with higher dosages of lomustine trended toward statistically significant higher response rates ( P =0.07).

A 15-yr-old, male lesser Madagascar hedgehog tenrec (Echinops telfairi) presented with a mass caudal to the right ear. Cytology suggested a sarcoma. Surgical removal was attempted. Histology was consistent with a soft tissue sarcoma. The mass recurred within 331 days post operation. Radiation therapy was initiated. Computed tomography was used for staging in conjunction with three-dimensional computerized treatment planning software to permit accurate lesion localization and to optimize normal tissue sparing. A total dose of 6,480 cGy was administered in 24 fractions over 46 days. Transient hind limb paresis developed during the course of the radiation therapy, but resolved after 7 days with prednisone treatment. Minimal acute radiation toxicity was observed. The mass responded with at least a 90% reduction in volume following radiation treatment. The animal survived 266 days from the initiation of treatment. On necropsy, a small mass and granulation tissue were found at the site of the initial neoplasm, indicating good regional control of the tumor; however, extensive metastases to the spleen and liver were present. Immunohistochemically, the original, recurrent, and metastatic populations were strongly positive for HMB 45 and weakly positive for S-100, and the final diagnosis was metastatic amelanotic melanoma.

Chlorambucil is an alkylating agent commonly used in veterinary oncology for conditions including lymphoma. Chlorambucil neurotoxicity has been well recognized in human patients. Onsets of central nervous system signs, such as myoclonus, tremors, muscular twitching, agitation, and tonic-clonic seizures, have been reported in humans and laboratory animals treated with chlorambucil. This case of a cat with intestinal lymphoma represents the first veterinary patient reported to have chlorambucil-induced neurotoxicity. Neurotoxicity should be considered a potential side effect of chlorambucil therapy in veterinary patients.

Abstract Malignant melanoma (MM) is a life-threatening disease characterized by a highly aggressive biologic behavior in both humans and dogs. Despite improvements in diagnosis and patient care, most deaths from MM are due to metastases that are resistant to conventional treatment modalities. To ultimately reduce the mortality associated with metastatic disease, it is necessary to better define the fundamental molecular mechanisms of malignant tumor progression. The progression of disease is a consequence of the complex interactions between malignantly transformed cells and host factors. Characterization of the stages of tumor progression and the changes occurring in highly malignant cells is important for the development of effective treatment regimens. The dys-regulated molecular mechanisms of transformed melanocytes are presently being characterized. In this review, we summarize the current understanding of the molecular phases in the progression of MM, which include genetic instability, dysregulated proliferation of melanocytes, increased invasion and metastasis, and angiogenesis.

This study was designed to assess the efficacy of a matrix metalloproteinase inhibitor in prolonging posttreatment survival for dogs with appendicular osteosarcoma after treatment with amputation and doxorubicin chemotherapy.BACKGROUNDThis study was designed to assess the efficacy of a matrix metalloproteinase inhibitor in prolonging posttreatment survival for dogs with appendicular osteosarcoma after treatment with amputation and doxorubicin chemotherapy.Survival will be prolonged in dogs receiving BAY 12-9566.HYPOTHESISSurvival will be prolonged in dogs receiving BAY 12-9566.The study included 303 dogs with appendicular osteosarcoma.ANIMALSThe study included 303 dogs with appendicular osteosarcoma.Dogs were treated with doxorubicin (30 mg/m2) every 2 weeks for 5 treatments starting 2 weeks after amputation. Dogs were randomly allocated to receive a novel nonpeptidic biphenyl inhibitor of matrix metalloproteinases (MMPs, BAY 12-9566; 4-[4-4-(chlorophenyl)phenyl]-4-oxo-2S-(phenylthiomethyl) butanoic acid) or placebo after doxorubicin chemotherapy.METHODSDogs were treated with doxorubicin (30 mg/m2) every 2 weeks for 5 treatments starting 2 weeks after amputation. Dogs were randomly allocated to receive a novel nonpeptidic biphenyl inhibitor of matrix metalloproteinases (MMPs, BAY 12-9566; 4-[4-4-(chlorophenyl)phenyl]-4-oxo-2S-(phenylthiomethyl) butanoic acid) or placebo after doxorubicin chemotherapy.Median survival for all 303 dogs was 8 months; and 1-year, 2-year, and 3-year survival rates were 35%, 17%, and 9%, respectively. Treatment with BAY 12-9566 did not influence survival. Multivariate analysis revealed that increasing age (P = .004), increasing weight (P = .006), high serum alkaline phosphatase (ALP) (P = .012) and high bone ALP (P < .001) were independently associated with shorter median survival times. Additional analyses on available data indicated that as the number of mitotic figures in the biopsy increased (P = .013), and as plasma active MMP-2 concentrations increased (P = .027), the risk of dying increased.RESULTSMedian survival for all 303 dogs was 8 months; and 1-year, 2-year, and 3-year survival rates were 35%, 17%, and 9%, respectively. Treatment with BAY 12-9566 did not influence survival. Multivariate analysis revealed that increasing age (P = .004), increasing weight (P = .006), high serum alkaline phosphatase (ALP) (P = .012) and high bone ALP (P < .001) were independently associated with shorter median survival times. Additional analyses on available data indicated that as the number of mitotic figures in the biopsy increased (P = .013), and as plasma active MMP-2 concentrations increased (P = .027), the risk of dying increased.Doxorubicin is an effective adjuvant to amputation in prolonging survival for dogs with appendicular osteosarcoma.CONCLUSIONS AND CLINICAL IMPORTANCEDoxorubicin is an effective adjuvant to amputation in prolonging survival for dogs with appendicular osteosarcoma.

This study was undertaken to determine whether Haemobartonella felis (Mycoplasma haemofelis), the causative bacterial agent of feline infectious anemia, infects nondomestic cats. Routine complete blood count and polymerase chain reaction (PCR) were performed to detect the gene for 16S ribosomal RNA for the organism. Sixty-four blood samples were collected from 54 nondomestic cats, including tigers (Panthera tigris), cheetahs (Acinonyx jubatus), lions (P. leo), mountain lions (Felis concolor), snow leopards (P. unica), and a jaguar (P. onca). Some cats were sampled on two or three different dates. Two tigers were positive for H. felis by PCR analysis. As previously described in domestic cats, the parasitemia appears to be intermittent in nondomestic cats.

Molecularly-guided trials (i.e. PMed) now seek to aid clinical decision-making by matching cancer targets with therapeutic options. Progress has been hampered by the lack of cancer models that account for individual-to-individual heterogeneity within and across cancer types. Naturally occurring cancers in pet animals are heterogeneous and thus provide an opportunity to answer questions about these PMed strategies and optimize translation to human patients. In order to realize this opportunity, it is now necessary to demonstrate the feasibility of conducting molecularly-guided analysis of tumors from dogs with naturally occurring cancer in a clinically relevant setting. A proof-of-concept study was conducted by the Comparative Oncology Trials Consortium (COTC) to determine if tumor collection, prospective molecular profiling, and PMed report generation within 1 week was feasible in dogs. Thirty-one dogs with cancers of varying histologies were enrolled. Twenty-four of 31 samples (77%) successfully met all predefined QA/QC criteria and were analyzed via Affymetrix gene expression profiling. A subsequent bioinformatics workflow transformed genomic data into a personalized drug report. Average turnaround from biopsy to report generation was 116 hours (4.8 days). Unsupervised clustering of canine tumor expression data clustered by cancer type, but supervised clustering of tumors based on the personalized drug report clustered by drug class rather than cancer type. Collection and turnaround of high quality canine tumor samples, centralized pathology, analyte generation, array hybridization, and bioinformatic analyses matching gene expression to therapeutic options is achievable in a practical clinical window (<1 week). Clustering data show robust signatures by cancer type but also showed patient-to-patient heterogeneity in drug predictions. This lends further support to the inclusion of a heterogeneous population of dogs with cancer into the preclinical modeling of personalized medicine. Future comparative oncology studies optimizing the delivery of PMed strategies may aid cancer drug development.