Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas

Background: Continuous administration of low doses of cyclophosphamide and standard doses of cyclooxygenase‐inhibiting drugs has been shown to suppress tumor angiogenesis, reverse immunosuppression, and deplete regulatory T cells in cancer models. Hypothesis: We hypothesized that continuous treatment with low‐dose cyclophosphamide and full‐dose piroxicam would delay tumor recurrence in dogs with soft tissue sarcomas (STS). Animals: Eighty‐five dogs with incompletely resected STS, 30 treated dogs, and 55 contemporary control dogs. Methods: Treatment outcomes in 85 dogs with incompletely resected STS were evaluated in a retrospective study. Dogs in the treatment group received continuously administered low‐dose cyclophosphamide (10 mg/m²) and standard dose piroxicam (0.3 mg/kg) therapy. Time to local tumor recurrence (disease‐free interval; DFI) was compared between the 30 treated dogs and 55 untreated control dogs matched for age and tumor site and grade. Results: DFI was significantly (P < .0001) prolonged for STS of all sites (trunk and extremity) in treated dogs compared with untreated control dogs. The DFI also was significantly longer in treated dogs when tumor site (trunk and extremity) was compared. Twelve treated dogs (40%) experienced mild toxicity (grade 1 and 2) at some point during treatment and 1 dog developed grade 4 cystitis. Every other day dosing was tolerated better than daily dosing. Conclusions: Metronomic therapy with cyclophosphamide and piroxicam was very effective in preventing tumor recurrence in dogs with incompletely resected STS. These findings suggest that further evaluation of this approach is warranted as adjuvant therapy in dogs with highly metastatic tumors such as osteosarcoma and melanoma.     

Unilateral phacoemulsification and intraocular lens implantation in a dachshund

A 1.5-year-old, spayed, female dachshund was presented with a cataract and lens-induced uveitis in the left eye. The cataract progressed from immature to hypermature in 4 months. Phacoemulsification and intraocular lens implantation was performed and the dog remains visual in the left eye 1 year post-surgery.     

c‐Kit Mutation and Localization Status as Response Predictors in Mast Cell Tumors in Dogs Treated with Prednisone and Toceranib or Vinblastine

Background

KIT inhibitors, such as toceranib (TOC), and vinblastine (VBL) have not been prospectively compared in the treatment of macroscopic mast cell tumors (MCTs). Also, it is unknown whether VBL or TOC is superior for treating MCT without c‐kit mutations.

Hypothesis/Objectives

To determine the value of KIT genotyping and localization in treatment decisions for dogs with macroscopic MCT. We hypothesized that c‐kit mutated MCT would have a better response to TOC than VBL.

Animals

Eighty‐eight client‐owned dogs with macroscopic MCT.

Methods

Prospective, randomized trial. Dogs were randomized to TOC (2.75 mg/kg EOD) or VBL (2.5 mg/m² weekly × 4 then EOW) by KIT localization and c‐kit mutation status using an adaptive randomization scheme.

Results

Sixty dogs were allocated to TOC and 28 to VBL. Of the dogs receiving TOC, 20% had c‐kit mutations, compared to 30% receiving VBL (P = 0.74). Overall response rates were 46% (TOC) and 30% (VBL) (odds ratio = 1.56 [0.62–3.92]; P = 0.28). Median progression‐free survival (PFS) for dogs receiving VBL was 78 days (7–1,521) and for TOC 95.5 (14–990); hazard ratio (HR) = 1.34 [0.72–2.50]; P = 0.36. Median overall survival (OS) was 241.5 days (10–1,521) for the VBL group and 159 (20–990) for the TOC group; HR = 0.80 ([0.45–1.41]; P = 0.44).

Conclusions and Clinical Importance

Neither PFS nor OS was significantly different between treatment groups. As the proportion of dogs with c‐kit mutations was not different between treatment groups in this population of dogs, c‐kit mutation status did not predict treatment response.     

Flow Cytometric Characterization and Clinical Outcome of CD4+ T‐Cell Lymphoma in Dogs: 67 Cases

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.

Objective

To test the hypothesis that canine CD4+ T‐cell lymphoma (TCL) is a homogeneous group of lymphomas with an aggressive clinical course.

Animals

Sixty‐seven dogs diagnosed with CD4+ TCL by flow cytometry and treated at 1 of 3 oncology referral clinics.

Methods

Retrospective multivariable analysis of outcome in canine CD4+ TCL including patient characteristics, treatment, and flow cytometric features.

Results

The majority of CD4+ TCL were CD45+, expressed low class II MHC, and exhibited an aggressive clinical course independent of treatment regimen (median survival, 159 days). Histologically, CD4+ TCL were classified as lymphoblastic or peripheral T cell. Size of the neoplastic lymphocytes had a modest effect on both PFI and survival in this group. A small number of CD4+ TCL were CD45− and class II MHC high, and exhibited an apparently more indolent clinical course (median survival not yet reached).

Conclusions and Clinical Importance

Although the majority of CD4+ TCL in dogs had uniform clinical and flow cytometric features and an aggressive clinical course, a subset had a unique immunophenotype that predicts significantly longer survival. This finding strengthens the utility of flow cytometry to aid in the stratification of canine lymphoma.     

Improving benthic biodiversity assessments in turbid aquatic environments

1. Biodiversity in turbid aquatic environments is commonly assessed using extractive sampling methods that damage the seabed. Underwater cameras equipped with clear liquid optical chambers (CLOCs) for the assessment of seabed habitats and species are a non-extractive alternative and have been applied in turbid environments globally. A CLOC is a body of clear liquid positioned in front of a camera to reduce the scattering of light that would otherwise occur when passing through the turbid water it displaces. Here, we test and quantify the effectiveness of a CLOC for marine benthic biodiversity assessments over gradients of increasing turbidity.
2. The addition of a CLOC to a conventional benthic camera system significantly enhanced the quality of information gathered. Images acquired using the CLOC system consistently recorded statistically higher values of image quality (49% increase, based on the clarity of the image), seabed visible within the drop-down frame (34% increase), and European Nature Information System habitat level identification (49% increase). Furthermore, it was found that the ‘annotation success’ of taxa (classification of a specimen to family level or higher) was found to increase between individual experts in the presence of a CLOC. A reduced sampling effort was also identified when using a CLOC. Taxonomic richness increased by 27% when comparing the same number of image stills collected with and without the CLOC.
3. By reducing the limitations of underwater visibility previously attributed to underwater cameras, this concept extends the potential for use of non-destructive survey techniques and allows for future users to collect robust information of an area, making better informed management decisions.

     

The potential of using alternative pastures,forage crops and gibberellic acid to mitigate nitrous oxide emissions

Purpose

In grazed pastures, nitrous oxide (N₂O), a powerful greenhouse gas and an ozone depletion substance, is mostly emitted from animal excreta, particularly animal urine-N returned to the soil during grazing. We conducted a series of four field lysimeter and plot experiments to assess the potential of using gibberellic acid (GA) and/or alternative pastures or forage crops to mitigate N₂O emissions from outdoor dairy farming systems.

Materials and methods

Pasture and forage plants assessed in the experiments included Italian ryegrass (Lolium multiflorum L.), lucerne (Medicago sativa L.), diverse pastures (including plantain (Plantago lanceolata L.), chicory (Cichorium intybus L.), perennial ryegrass (Lolium perenne L.) and white clover (Trifolium repens L.)), fodder beet (Beta vulgaris L.), kale (Brassica oleracea L.), as well as the standard perennial ryegrass and white clover (RG/WC) pastures. N₂O was determined using a standard static chamber method in the field either on top of lysimeters or field plots.

Results and discussion

The results showed that the application of GA to urine-treated lysimeters with Italian ryegrass, lucerne or RG/WC pastures did not result in lower N₂O emissions. However, the use of diverse pastures which included plantain with a lower urine-N loading rate at about 500 kg N ha^?1 significantly decreased N₂O emissions by 46 % compared with standard RG/WC with a urine-N loading rate at 700 kg N ha^?1. However, when urine-N was applied at the same rates (at 500 or 700 kg N ha^?1), the N₂O emissions were similar between the diverse and the standard RG/WC pastures. This would indicate that it is the N-loading rate in the urine from the different pastures that determines the N₂O emissions from different pastures or forages, rather than the plants per se. The N₂O emissions from cow urine from fodder beet were 39 % lower than from kale with the same urine-N application rate (300 kg N ha^?1).

Conclusions

These results suggest that N₂O emissions can potentially be reduced by incorporating diverse pastures and fodder beet into the grazed pasture farm system. Further studies on possible mechanisms for the lower N₂O emissions from the different pastures or forages would be useful.

     

Antibody domain exchange is an immunological solution to carbohydrate cluster recognition

Human antibody 2G12 neutralizes a broad range of human immunodeficiency virus type 1 (HIV-1) isolates by binding an unusually dense cluster of carbohydrate moieties on the "silent" face of the gp120 envelope glycoprotein. Crystal structures of Fab 2G12 and its complexes with the disaccharide Manalpha1-2Man and with the oligosaccharide Man9GlcNAc2 revealed that two Fabs assemble into an interlocked VH domain-swapped dimer. Further biochemical, biophysical, and mutagenesis data strongly support a Fab-dimerized antibody as the prevalent form that recognizes gp120. The extraordinary configuration of this antibody provides an extended surface, with newly described binding sites, for multivalent interaction with a conserved cluster of oligomannose type sugars on the surface of gp120. The unique interdigitation of Fab domains within an antibody uncovers a previously unappreciated mechanism for high-affinity recognition of carbohydrate or other repeating epitopes on cell or microbial surfaces.