The Big Picture in Better Understanding the Equine Foot.

The multiple topics summarized in this article and discussed in detail in this issue of VCNA are comprehensive and in-depth, exploring concepts and clinical experiences for state-of-the-art care of the equine foot. The research on the equine foot will translate to the clinical setting and with this the compassionate care of the horse.

Real-world performance of blood-based proteomic profiling in first-line immunotherapy treatment in advanced stage non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibition (ICI) therapy has improved patient outcomes in advanced non-small cell lung cancer (NSCLC), but better biomarkers are needed. A clinically validated, blood-based proteomic test, or host immune classifier (HIC), was assessed for its ability to predict ICI therapy outcomes in this real-world, prospectively designed, observational study. MATERIALS AND METHODS: The prospectively designed, observational registry study INSIGHT (Clinical Effectiveness Assessment of VeriStrat® Testing and Validation of Immunotherapy Tests in NSCLC Subjects) (NCT03289780) includes 35 US sites having enrolled over 3570 NSCLC patients at any stage and line of therapy. After enrolment and prior to therapy initiation, all patients are tested and designated HIC-Hot (HIC-H) or HIC-Cold (HIC-C). A prespecified interim analysis was performed after 1-year follow-up with the first 2000 enrolled patients. We report the overall survival (OS) of patients with advanced stage (IIIB and IV) NSCLC treated in the first-line (ICI-containing therapies n=284; all first-line therapies n=877), by treatment type and in HIC-defined subgroups. RESULTS: OS for HIC-H patients was longer than OS for HIC-C patients across treatment regimens, including ICI. For patients treated with all ICI regimens, median OS was not reached (95% CI 15.4 to undefined months) for HIC-H (n=196) vs 5.0 months (95% CI 2.9 to 6.4) for HIC-C patients (n=88); HR=0.38 (95% CI 0.27 to 0.53), p<0.0001. For ICI monotherapy, OS was 16.8 vs 2.8 months (HR=0.36 (95% CI 0.22 to 0.58), p<0.0001) and for ICI with chemotherapy OS was unreached vs 6.4 months (HR=0.41 (95% CI 0.26 to 0.67), p=0.0003). HIC results were independent of programmed death ligand 1 (PD-L1). In a subgroup with PD-L1 ≥50% and performance status 0-1, HIC stratified survival significantly for ICI monotherapy but not ICI with chemotherapy. CONCLUSION: Blood-based HIC proteomic testing provides clinically meaningful information for immunotherapy treatment decision in NSCLC independent of PD-L1. The data suggest that HIC-C patients should not be treated with ICI alone regardless of their PD-L1 expression.

Evaluation of Circulating Tumor DNA for Methylated BCAT1 and IKZF1 to Detect Recurrence of Stage II/Stage III Colorectal Cancer (CRC).

BACKGROUND: Most recurrences of early-stage colorectal cancer detected with current surveillance measures are widespread and incurable. Circulating tumor DNA (ctDNA) may facilitate earlier diagnosis of recurrent colorectal cancer and improve cancer-related outcomes. METHODS: Plasma from patients undergoing standard surveillance after definitive treatment for stage II/III colorectal cancer was assayed with COLVERA and carcinoembryonic antigen (CEA) at a single time point. Results were correlated with radiographic imaging. Assay performance, including sensitivity and specificity for recurrence, were compared. Impact of potentially confounding variables was also explored. RESULTS: 322 patients were included in the final analysis, and 27 recurrences were documented over a median follow-up period of 15 months. Sensitivity for recurrence was 63% [confidence interval (CI), 42.4-80.6] and 48% (CI, 28.7-68.1) for COLVERA and CEA (≥5 ng/mL), respectively (P = 0.046), while specificity was 91.5% (CI, 87.7-94.4) and 96.3% (CI, 93.4-98.1), respectively (P = 0.016). Smoking and age were independent predictors of CEA but not COLVERA positivity. CONCLUSIONS: COLVERA was more sensitive but less specific than CEA in detecting recurrent colorectal cancer. Short median follow-up may have been responsible for apparent false positives in COLVERA. Studies with serial sampling and longer follow-up are needed to assess whether earlier detection of colorectal cancer recurrence translates into clinical benefit. IMPACT: This prospective study showed that COLVERA (a two-gene ctDNA assay) was more sensitive for detection of recurrence in a cohort of patients undergoing surveillance after definitive therapy for stages II and III colorectal cancer.

Glucose and insulin response after intravenous and subcutaneous somatostatin administration in healthy horses.

Equine metabolic syndrome (EMS) is prevalent in the equine population, and somatostatin analogs might be useful for diagnosis and/or treatment of EMS in horses. The purpose of this study was to evaluate the glucose and insulin responses to subcutaneous and intravenous administration of somatostatin. Six healthy research horses were included in this prospective study. An initial pilot study was performed to assess several different doses (10-22 µg/kg [4.5-10 µg/lb]) in two horses, then a final dosage of 22 µg/kg (10 µg/lb) was administered to six horses IV and SQ in a two-period randomized cross-over study performed over a 3-month study period. Blood samples were collected for measurement of plasma insulin and glucose concentrations during a 24-hr study period. Both IV and SQ somatostatin resulted in decreased insulin and increased glucose concentrations. SQ somatostatin resulted in a longer clinical effect, with return to baseline insulin occurring at 1.5 hr postadministration, versus 45 min for IV. Both IV and SQ administration of somatostatin to normal horses resulted in decreased insulin and increased glucose concentrations, likely due to suppression of insulin secretion by somatostatin. A more prolonged effect was seen following SQ administration as compared to IV administration, and no adverse effects were noted at varying doses. This study provides additional information regarding the effect of somatostatin administration on insulin and glucose concentrations in clinically healthy horses.

Novel dry cryotherapy system for cooling the equine digit.

OBJECTIVES: Digital cryotherapy is commonly used for laminitis prophylaxis and treatment. Currently validated methods for distal limb cryotherapy involve wet application or compression technology. There is a need for a practical, affordable, dry cryotherapy method that effectively cools the digit. The objective of this study was to evaluate the hoof wall surface temperatures (HWSTs) achieved with a novel dry cryotherapy technology. DESIGN: Repeated-measures in vivo experimental study. SETTING: Experimental intervention at a single site. PARTICIPANTS: 6 systemically healthy horses (3 mares, 3 geldings). INTERVENTIONS: Cryotherapy was applied to six horses for eight hours with a commercially available rubber and rubber and welded fabricice boot, which extended proximally to include the foot and pastern. Reusable malleable cold therapy packs were secured against the foot and pastern with the three built-in hook-and-loop fastener panels. PRIMARY AND SECONDARY OUTCOME MEASURES: HWST and pastern surface temperature of the cryotherapy-treated limb, HWST of the control limb and ambient temperature were recorded every five minutes throughout the study period. RESULTS: Results were analysed with mixed-effects multivariable regression analysis. The HWST (median 11.1°C, interquartile range 8.6°C-14.7°C) in the cryotherapy-treated limb was significantly decreased compared with the control limb (median 29.7°C, interquartile range 28.9°C-30.4°C) (P≤0.001). Cryotherapy limb HWST reached a minimum of 6.75°C (median) with an interquartile range of 4.1°C-9.3°C. Minimum HWST was achieved 68 minutes after cryotherapy pack application. CONCLUSIONS: Dry application of cryotherapy significantly reduced HWST and reached minimums below the therapeutic target of 10°C. This cryotherapy method might offer an effective alternative for digital cooling.

Patient-reported neuropathy and taxane-associated symptoms in a phase 3 trial of nab-paclitaxel plus carboplatin versus solvent-based paclitaxel plus carboplatin for advanced non-small-cell lung cancer.

INTRODUCTION: nab-Paclitaxel (nab-P) is approved, in the United States, in combination with carboplatin for the first-line treatment of advanced non-small-cell lung cancer, based on a randomized phase 3 trial of nab-P plus carboplatin (nab-P/C) versus solvent-based paclitaxel plus carboplatin (sb-P/C). This trial revealed a higher overall response rate (33% versus 25%; p = 0.005) and longer, but not statistically significant, overall and progression-free survival for nab-P/C versus sb-P/C. In addition, nab-P/C demonstrated lower rates of grade 3 or higher peripheral neuropathy, myalgia, arthralgia, and neutropenia but higher rates of anemia and thrombocytopenia. This report analyzes patient and physician assessment of symptoms within this trial. METHODS: Patients completed the taxane subscale of the Functional Assessment of Cancer Therapy questionnaire, which focuses on taxane toxicity, including peripheral neuropathy and neurotoxicity. Mean baseline scores and changes from baseline are reported. Physicians also graded the severity of neuropathy at each patient visit using National Cancer Institute Common Toxicity Criteria. RESULTS: Patients receiving nab-P/C reported significantly less worsening of peripheral neuropathy (p < 0.001), pain (p < 0.001), and hearing loss (p = 0.002). Patient-reported edema was similar between the two treatment arms. In agreement with patient-reported symptoms, the results of a per-treatment cycle physician assessment of peripheral neuropathy also favored nab-P/C over sb-P/C (p < 0.001). CONCLUSION: In this trial of patients receiving first-line treatment for advanced non-small-cell lung cancer, nab-P/C was associated with statistically and clinically significant reductions in patient-reported neuropathy, neuropathic pain in the hands and feet, and hearing loss compared with sb-P/C.

Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death.

We hypothesized that the high early death rate (EDR) due to bleeding in acute promyelocytic leukemia (APL) is in part attributable to delays in all- trans retinoic acid (ATRA). We conducted a retrospective analysis of the timing of ATRA administration. 204 consecutive patients with newly diagnosed APL between 1992 and 2009 were identified. The EDR was 11%. 44% of early deaths occurred in the first week. Hemorrhage accounted for 61% of early deaths. ATRA was ordered the day APL was suspected in 31% of patients. Delays in ATRA administration led to increases in the percentage of early deaths from hemorrhage.

Evaluation of oral administration of firocoxib for the management of musculoskeletal pain and lameness associated with osteoarthritis in horses.

OBJECTIVE: To generate data on the effects of firocoxib administration to horses with osteoarthritis. ANIMALS: Client-owned horses with signs of lameness and joint pain associated with osteoarthritis. PROCEDURES: Firocoxib was administered as an oral paste (0.1 mg/kg, q 24 h) for 14 days. Assessments were performed on day 0 (baseline) and days 7 and 14. RESULTS: 390 of 429 horses from 80 sites in 25 states met the criteria for analysis. Quarter Horse and Thoroughbred were the 2 most commonly represented breeds, comprising half of the study population. Signs of musculoskeletal pain or lameness attributed to osteoarthritis were diagnosed in a single joint in 197 (197/390 [50.5%]) horses and in multiple joints in 193 (193/390 [49.5%]) horses. In those with involvement of a single joint, the tarsus was the most frequently affected joint (79/197 [40.1 %]). Among the 390 horses with complete lameness data, improvement was reported in approximately 80% by day 14. Investigators rated 307 (78.7%) horses as improved, whereas owners or handlers rated 316 (81.0%) horses as improved at the termination of the study. Horses treated with firocoxib paste had significant improvement in lameness scores from baseline values. Improvement was most rapid within the first 7 days after starting treatment and continued, albeit at a slower rate, through treatment day 14. CONCLUSIONS AND CLINICAL RELEVANCE: Firocoxib significantly improved lameness scores throughout the 14-day period with few adverse effects. Firocoxib can be a safe cyclooxygenase-2-specific NSAID for the treatment of musculoskeletal pain and lameness associated with osteoarthritis.

Prognostic indicators of poor outcome in horses with laminitis at a tertiary care hospital.

This retrospective study investigated the factors associated with a poor outcome (death by euthanasia or from other causes) in horses treated for laminitis at a tertiary care hospital. Cases (n = 247) were defined as patients with laminitis that were euthanized or that died of other causes during hospitalization. Controls (n = 344) were patients with laminitis that survived to be discharged from the hospital. In the final multivariate analysis, the factors significantly associated with an increased risk for death and their respective odds ratios (OR) were as follows: Thoroughbred (OR = 1.57); racehorse (OR = 1.76); treatment with flunixin meglumine (OR = 1.76); vascular pathology (OR = 2.12); distal displacement of the third phalanx (OR = 2.68); pneumonia (OR = 2.87); and lameness of Obel grade II (OR = 2.99), grade III (OR = 9.63), or grade IV (OR = 20.48). The use of glue-on shoes significantly reduced the risk for death (OR = 0.36).

First aid for the laminitic foot: therapeutic and mechanical support.

The goals of mechanical treatment during the acute phase of laminitis are to preserve the lamellar interface by reducing the forces that are compromising its integrity and to make the horse more comfortable. Early decision making is important in managing acute laminitis. This article helps the practitioner to identify some of the commonly used and accepted methods of protecting the laminitic foot. The materials available and the theories behind their use are also described. The laminitic foot needs to be understood before determining methods for its support. Most treatment options involve shifting the weight-bearing forces from compromised areas of the foot (ie, the lamellar interface) to areas more capable of supporting the patient's weight, remembering that the sum of the forces should remain the same. The many treatment options available allow for flexibility and effective management and permit each modality to be combined in infinite ways for hoof support. The goal of therapy is to support the foot and stop the progression of the disease to the chronic phase.

Home care for horses with chronic laminitis.

Home care for horses with chronic laminitis has been discussed rarely in the veterinary literature even though, at any given time, most of us have at least 1 chronic laminitis case in our care that is being managed at home by the owner. Almost all of our knowledge on this aspect of laminitis treatment has been gleaned through experience, by individually working through the medical, ethical, financial, and emotional challenges these cases can present. Much has already been presented on the medical management of the laminitic horse and on strategies for trimming and shoeing the laminitic foot. This article focuses on the other challenges so often faced when directing the home care of a horse with chronic laminitis.

Gene expression in the lamellar dermis-epidermis during the developmental phase of carbohydrate overload-induced laminitis in the horse.

OBJECTIVE: Gene expression in the lamellar dermis and epidermis was compared between healthy horses and horses in the developmental phase of carbohydrate overload-induced laminitis, in order to better understand the local biochemical and cellular events involved in the pathogenesis of laminitis. ANIMALS: Six healthy adult horses, with no history or clinical evidence of laminitis. PROCEDURES: Horses were randomly divided into two groups: control (n=3) and laminitis (n=3). Control horses received no treatment and were humanely euthanatized at the same time as the laminitis group. Horses in the laminitis group were given oligofructose (10g/kg bwt by nasogastric tube) and humanely euthanatized 24-30h later, before any clinical signs of laminitis were apparent. Sections of lamellar dermis and epidermis were harvested from the dorsal hoof wall of each horse immediately after death and cryopreserved until analysis. A bovine microarray chip, comprising approximately 15,000 genes, was used to compare gene expression between laminitis and control groups. RESULTS: A total of 155 genes were up-regulated in the laminitis group. No genes were down-regulated. Genes coding for the production of pro-inflammatory biochemical or cellular processes and those involved in protein degradation/turnover predominated. Several regulatory or anti-inflammatory genes were also up-regulated. CONCLUSIONS AND CLINICAL RELEVANCE: Generation of inflammatory mediators within the lamellar tissues occurred before the development of substantial dermal-epidermal separation, inflammatory infiltrate, or vascular changes, and before the horses began showing signs of foot pain. While further studies are needed, early and targeted anti-inflammatory therapy may halt or prevent the development of laminitis in at-risk individuals.

Risk factors for development of acute laminitis in horses during hospitalization: 73 cases (1997-2004).

OBJECTIVE: To identify risk factors for development of acute laminitis in horses during hospitalization for illness or injury. DESIGN: Retrospective case-control study. ANIMALS: 73 horses that developed laminitis (case horses) and 146 horses that did not develop laminitis (control horses) during hospitalization. PROCEDURES: Case and control horses were matched in a 2:1 ratio by the date on which each horse was evaluated. Potential risk factors investigated included age, breed, and sex; highest and lowest values recorded during hospitalization for fibrinogen concentration, WBC count, PCV, and total solids concentration; and comorbid disease states, including pneumonia, endotoxemia, diarrhea, medically treated colic, surgically treated colic, pituitary adenoma, retained placenta or metritis, forelimb lameness, hind limb lameness, acute renal failure, and vascular abnormalities. A univariate screening of all potential risk factors was performed to determine which variables should be selected for further analysis. All factors found to be associated with development of laminitis were included in a multivariate conditional logistic regression model. RESULTS: Development of laminitis was marginally associated with lowest and highest fibrinogen concentrations, highest PCV, and lowest total solids concentration and significantly associated with pneumonia, endotoxemia, diarrhea, abdominal surgery for colic, and vascular abnormalities. In the multivariate analysis, only endotoxemia was significantly associated with laminitis. CONCLUSIONS AND CLINICAL RELEVANCE: Endotoxemia is an important risk factor for development of acute laminitis in horses during hospitalization for medical or surgical conditions. Early recognition of endotoxemia, or the potential for it to develop in certain disease states, and initiation of treatment directed at endotoxemia or its consequences may help prevent laminitis in horses during hospitalization.

Expression of cyclooxygenase-1 and -2 in naturally occurring squamous cell carcinomas in horses.

OBJECTIVE: To assess expression of cyclooxygenase (COX)-1 and -2 in naturally occurring squamous cell carcinomas (SCCs) and the analogous normal tissues in horses. SAMPLE POPULATION: Tissue samples collected from 3 conjunctival, 2 vulvar, 4 preputial, and 5 penile SCCs during surgical excision in 14 horses and from corresponding body regions (conjunctiva [n = 5 horses], vulva [2], prepuce [3], and penis [3]) in 5 horses euthanized for reasons unrelated to neoplasia. PROCEDURES: Tissue samples were snap frozen in liquid nitrogen and stored at -80 degrees C until analysis. Protein was extracted from the frozen tissues, and western blot analyses were performed. Nonneoplastic and abnormal tissues from each body region were run on the same blot, and blots were run in triplicate. Molecular-weight markers and COX-1 and 2 ovine standards (positive control samples) were run concurrently on the gels; negative control samples were not used. RESULTS: All tissues, including the nonneoplastic and SCC tissues, expressed both COX-1 and -2 proteins. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the expression of COX proteins in both nonneoplastic and SCC-affected tissues in horses is markedly different from that in other species. The reason for the potential benefit of COX-2 inhibitors in horses and other species is unknown. Further research needs to be performed to evaluate the efficacy of COX-2 inhibitors as cancer treatments in horses. Investigation of the mechanisms of tumor development in horses should be performed to increase understanding of this disease and ascertain how the mechanisms differ from those in other animals.

Vancomycin for the treatment of methicillin-resistant staphylococcal and enterococcal infections in 15 horses.

We retrospectively reviewed the cases of 15 foals and adult horses in which vancomycin was used, alone or in combination with an aminoglycoside, to treat methicillin-resistant staphylococcal and enterococcal infections. Signalment, presenting complaint, history (including history of treatment for the current complaint), results of bacterial culture and antimicrobial susceptibility testing, treatment, and outcome were reviewed. The average vancomycin dosage was 7.5 mg/kg q8h, administered by intravenous infusion over 30 min. The infection resolved in all 7 horses with soft tissue infections and in 6 of the 8 horses with infections involving a bone or a joint, or both. No adverse effects of vancomycin therapy were noted. Although the number of cases is small, our findings suggest that vancomycin, alone or in combination with an aminoglycoside, is safe and effective for the treatment of resistant staphylococcal and enterococcal infections in horses and foals. However, owing to the importance of staphylococci and enterococci in human medicine and the problems with emerging resistance, we recommend that the use of vancomycin in horses be limited to cases in which culture and susceptibility results clearly indicate that this agent is likely to be effective and in which there is no reasonable alternative.

Tracing axons of peripheral nerves in rats: a potential technique to study the equine recurrent laryngeal nerve.

To study the fascicular anatomy of peripheral nerves, three different groups of retrograde axonal tracers were evaluated: fluorophores, horseradish peroxidase conjugated to subunit B of cholera toxin (CT-HRP), and adeno-associated virus (AAV). The hindlimb nerves in rats served as a model to identify the most efficient tracer in regard to labeling axons within peripheral nerves. The rat's tibial and common peroneal nerves were injected with the different tracers and the sciatic nerve was subsequently examined for evidence of labeled axons. The CT-HRP clearly provided the best results in this rat model. Subsequently, CT-HRP was injected into the recurrent laryngeal nerve (RLN) of two horses in order to identify the location and distribution pattern of the RLN axons within the course of the cervical vagus nerve trunk. No labeling could be observed in either of the two horses.