Volumetric tumor response assessment is inefficient without overt clinical benefit compared to conventional,manual veterinary response assessment in canine nasal tumors

Accurate assessment of tumor response to therapy is critical in guiding management of veterinary oncology patients and is most commonly performed using response evaluation criteria in solid tumors criteria. This process can be time consuming and have high intra‐ and interobserver variability. The primary aim of this serial measurements, secondary analysis study was to compare manual linear tumor response assessment to semi‐automated, contoured response assessment in canine nasal tumors. The secondary objective was to determine if tumor measurements or clinical characteristics, such as stage, would correlate to progression‐free interval. Three investigators evaluated paired CT scans of skulls of 22 dogs with nasal tumors obtained prior to and following radiation therapy. The automatically generated tumor volumes were not useful for canine nasal tumors in this study, characterized by poor intraobserver agreement between automatically generated contours and hand‐adjusted contours. The radiologist's manual linear method of determining response evaluation criteria in solid tumors categorization and tumor volume is significantly faster (P < .0001) but significantly underestimates nasal tumor volume (P < .05) when compared to a contour‐based method. Interobserver agreement was greater for volume determination using the contour‐based method when compared to response evaluation criteria in solid tumors categorization utilizing the same method. However, response evaluation criteria in solid tumors categorization and percentage volume change were strongly correlated, providing validity to response evaluation criteria in solid tumors as a rapid method of tumor response assessment for canine nasal tumors. No clinical characteristics or tumor measurements were significantly associated with progression‐free interval.     

Canine astrocytic tumors: a comparative review

Tumors of astrocytic lineage are among the most common primary brain neoplasms in people and dogs. Current understanding of the pathogenesis of astrocytic tumors is limited in dogs compared with humans. In dogs, critical biological data concerning the natural history of disease progression, tumor imaging features, and response to therapeutic intervention are lacking. This review outlines the clinical, genetic, immunologic, and histopathologic characteristics of astrocytic tumors in dogs with special focus on comparative neuro-oncology. Common problems associated with the diagnosis of these neoplasms are summarized. Traditional veterinary histologic typing and grading of astrocytic tumors must be updated and supplemented with molecular data so that future studies directed toward therapeutic intervention and outcome can be optimized.     

The potential of the combined use of targeted type I interferon pathway inhibitors and oncolytic viruses to treat sarcomas

Replicating oncolytic viruses (OVs) are appealing, new, FDA‐approved, therapeutic options for humans with head and neck cancers and melanomas. These treatments are not yet available for veterinary patients, but recent clinical trials have shown several OVs to be safe in dogs and cats. Specific viruses being used to treat sarcomas in dogs include modified canine adenovirus 2, myxoma virus, vesicular stomatitis virus and reovirus. In cats with vaccine‐associated sarcomas, poxviruses have been injected postoperatively and a reduced rate of tumour recurrence was documented. To date, the response rates of canine and feline patients to OV therapy have been variable (as they are in people). Optimal methods of OV administration and dosing schedules continue to be evaluated. One way to improve outcomes of OV therapy in veterinary patients may be to use OVs in combination with other immunomodulatory therapies. This review discusses the potential utility of concurrent therapy with an OV and an inhibitor of the type I interferon pathway.     

Response evaluation criteria for solid tumours in dogs (v1.0): a Veterinary Cooperative Oncology Group (VCOG) consensus document

In veterinary medical oncology, there is currently no standardized protocol for assessing response to therapy in solid tumours. The lack of such a formalized guideline makes it challenging to critically compare outcome measures across various treatment protocols. The Veterinary Cooperative Oncology Group (VCOG) membership consensus document presented here is based on the recommendations of a subcommittee of American College of Veterinary Internal Medicine (ACVIM) board‐certified veterinary oncologists. This consensus paper has used the human response evaluation criteria in solid tumours (RECIST v1.1) as a framework to establish standard procedures for response assessment in canine solid tumours that is meant to be easy to use, repeatable and applicable across a variety of clinical trial structures in veterinary oncology. It is hoped that this new canine RECIST (cRECIST v1.0) will be adopted within the veterinary oncology community and thereby facilitate the comparison of current and future treatment protocols used for companion animals with cancer.     

Paraneoplastic disorders in dogs with hematopoietic tumors

Often overlooked in the presence of neoplasia, PNDs constitute significant clinical entities in dogs with hematopoietic tumors. They may cause morbidity and mortality in such patients, with effects more severe than those caused by the associated tumor. Accurate clinical evaluation of these disorders is important in differential diagnosis and treatment, for failure to realize that cancer can produce many clinical signs similar to those of other diseases may lead to incorrect diagnosis and delayed therapy. Early recognition of the problem underlying the PND is essential to selecting the proper therapeutic approach and maximizing the patient's chances for remission and survival. The presence of these disorders may complicate or rule out the preferred therapy in some cases of hematopoietic neoplasia, because the addition of cytotoxic drugs may worsen the existing PND, predisposing the dog to a variety of complications. Appropriate management of the PND may be of more immediate importance than treatment of the tumor. The study and recognition of PNDs in dogs with hematopoietic tumors may be valuable for a number of reasons: to facilitate early diagnosis of the tumor, for the observed abnormalities may represent tumor cell markers; to allow assessment of premalignant states; to aid in the search for metastases; to help quantify and monitor response to therapy; to aid in the evaluation of tumor recurrence or progression; to aid in identifying specific pathophysiologic processes by which cancer produces systemic effects; and to provide insight into the study of malignant transformation. Recognition of PNDs is relevant to the diagnosis and treatment of many problems in veterinary cancer medicine. With increasing emphasis on diagnosis and treatment of canine hematopoietic tumors, PNDs will be recognized with greater frequency and will assume greater importance in the therapeutic management of those patients. Research in veterinary and human cancer medicine needs to be directed toward identifying more definitively those substances and pathways that are responsible for PNDs, because therapy directed toward arresting the specific pathophysiologic processes causing the PND may offer the best approach for successful management of cancer.     

OUTCOMES AND PROGNOSTIC FACTORS ASSOCIATED WITH CANINE SINONASAL TUMORS TREATED WITH CURATIVE INTENT CONE‐BASED STEREOTACTIC RADIOSURGERY (1999–2013)

Stereotactic radiosurgery (SRS) is a relatively new therapeutic option in veterinary oncology. The role of this modality has not been extensively evaluated for the use in canine nasal tumors. The objective of this retrospective, observational study was to describe the clinical outcome and prognostic factors associated with survival times in a sample of canine patients treated with SRS for sinonasal tumors. Fifty‐seven dogs with sinonasal tumors met inclusion criteria. Histologic diagnoses included sarcoma (SA) (n = 9), carcinoma (CA) (n = 40), osteosarcoma (OSA) (n = 7), and round cell (n = 1). Four of 57 cases were treated twice with SRS. For these, the median and mean doses delivered were 30Gy and 33Gy, respectively (range 18.75Gy–56Gy). Late effects occurred in 23 cases and ranged from grades I–III. The median overall survival time was 8.5 months. The median overall survival times in dogs with tumor type of CA, SA, and OSA were 10.4, 10.7, and 3.1 months, respectively. Dogs with the tumor type of OSA had shorter overall survival time than that in dogs with tumor type of CA and SA. Findings from this retrospective study indicated that SRS may be beneficial for canine patients with sinonasal tumors, however a controlled clinical trial would be needed to confirm this. Prospective studies are also needed to better define the role of SRS as palliative or curative, and to further investigate the risk of clinically significant toxicity.     

Evidence‐Based Medicine: The Design and Interpretation of Noninferiority Clinical Trials in Veterinary Medicine

Noninferiority trials are clinical studies designed to demonstrate that an investigational drug is at least as effective as an established treatment within a predetermined margin. They are conducted, in part, because of ethical concerns of administering a placebo to veterinary patients when an established effective treatment exists. The use of noninferiority trial designs has become more common in veterinary medicine with the increasing number of established veterinary therapeutics and the desire to eliminate potential pain or distress in a placebo‐controlled study. Selecting the appropriate active control and an a priori noninferiority margin between the investigational and active control drug are unique and critical design factors for noninferiority studies. Without reliable historical knowledge of the disease response in the absence of treatment and of the response to the selected active control drug, proper design and interpretation of a noninferiority trial is not possible. Despite the appeal of conducting noninferiority trials to eliminate ethical concerns of placebo‐controlled studies, there are real limitations and possible ethical conundrums associated with noninferiority trials. The consequences of incorrect study conclusions because of poor noninferiority trial design need careful attention. Alternative trial designs to typical noninferiority studies exist, but these too have limitations and must also be carefully considered.     

FDG PET/CT IMAGING IN CANINE CANCER PATIENTS

2‐Deoxy‐2‐[¹⁸F]fluoro‐d ‐glucose positron emission tomography/computed tomography (FDG PET/CT) is becoming increasingly available as an imaging modality in veterinary medicine. The purpose of this study was to report semiquantitative standard uptake values (SUV) of malignant and nonmalignant tissues and organs in canine cancer patients. FDG PET/CT was performed in 14 dogs including, nine mesenchymal tumors, four carcinomas, and one incompletely excised mast cell tumor. A generally higher FDG uptake was observed in carcinomas relative to sarcomas. Maximum SUV of carcinomas ranged from 7.6 to 27.0, and for sarcomas from 2.0 to 10.6. The FDG SUV of several organs and tissues, including regional brain uptake is reported, to serve as a reference for future FDG PET studies in canine cancer patients. Several potential pitfalls have been recognized in interpretation of FDG PET images of human patients, a number of these were also observed in this study.     

Pulmonary thromboembolism

Objective – To review the pathophysiology, clinical signs, diagnosis, and treatment of pulmonary thromboembolism (PTE) in small animals. Data Sources – Human and veterinary clinical studies, reviews, texts, and recent research in canine and feline PTE diagnosis and thromboembolic therapeutics. Human Data Synthesis – In humans, clinical probability assessment and point‐of‐care D‐dimer‐based algorithms are widely used. Computed tomography pulmonary angiography is the gold standard for PTE diagnosis in humans. Echocardiography is increasingly used for bedside assessment of affected patients. In low‐risk human patients anticoagulants alone are recommended while patients with cardiogenic shock are treated with thrombolytics followed by anticoagulation. Veterinary Data Synthesis – PTE is associated with numerous predisposing conditions causing hypercoagulability, blood flow stasis, or endothelial injury. Identifying at‐risk patients is key to diagnosis in small animals. Thromboelastography provides a method for identifying hypercoagulable patients. Computed tomography pulmonary angiography may replace selective pulmonary angiography as the imaging technique of choice for PTE diagnosis. PTE therapy consists of supportive treatment combined with appropriate, individualized thromboembolic pharmacotherapy for acute treatment and chronic management. Thrombolytic therapy for PTE remains controversial but may be indicated in hemodynamically unstable acute PTE. Thromboprophylaxis in specific conditions is rational although evidence of efficacy is limited. Prognosis depends upon degree of cardiopulmonary compromise and patient response to therapy. Mortality rates in small animals are unknown. Conclusions – New diagnostic techniques and advances in therapy offer significant potential for improvements in the identification and treatment of PTE in small animals. Further study must be directed to validating new diagnostic modalities and evaluating therapeutic regimes.     

Leukotriene inhibition in small animal medicine

Leukotrienes are important mediators of inflammatory and allergic conditions in people and are suspected to play an important role in tumorigenesis and tumor growth of several different tumor types. Based on this, researchers are making great progress in identifying novel pharmacologic targets for several human diseases. Leukotriene inhibition has resulted in therapeutic benefit in clinical trials involving people with osteoarthritis, allergic asthma, and atopic dermatitis. Despite this progress and the possibility that leukotriene inhibition may also play an important therapeutic role in veterinary patients, parallel advances have not yet been made in veterinary medicine. This article summarizes leukotriene function and synthesis. It also reviews the published literature regarding potential therapeutic applications of leukotriene inhibition in both human and veterinary medicine, focusing primarily on osteoarthritis, NSAID induced gastrointestinal mucosal damage, allergic asthma, atopic dermatitis, and cancer.     

Conformity and controversies in the diagnosis,staging and follow‐up evaluation of canine nodal lymphoma: a systematic review of the last 15 years of published literature

Diagnostic methods used in the initial and post‐treatment evaluation of canine lymphoma are heterogeneous and can vary within countries and institutions. Accurate reporting of clinical stage and response assessment is crucial in determining the treatment efficacy and predicting prognosis. This study comprises a systematic review of all available canine multicentric lymphoma studies published over 15 years. Data concerning diagnosis, clinical stage evaluation and response assessment procedures were extracted and compared. Sixty‐three studies met the eligibility criteria. Fifty‐five (87.3%) studies were non‐randomized prospective or retrospective studies. The survey results also expose variations in diagnostic criteria and treatment response assessment in canine multicentric lymphoma. Variations in staging procedures performed and recorded led to an unquantifiable heterogeneity among patients in and between studies, making it difficult to compare treatment efficacies. Awareness of this inconsistency of procedure and reporting may help in the design of future clinical trials.     

Acute lung injury and acute respiratory distress syndromes in veterinary medicine: consensus definitions: The Dorothy Russell Havemeyer Working Group on ALI and ARDS in Veterinary Medicine

Background: As veterinary medicine has become more sophisticated, with greater numbers of veterinary patients receiving intensive care, more patients with an acute respiratory distress (ARDS)‐like syndrome have been recognized. Methods: A consensus definition meeting was held for the purpose of developing veterinary‐specific definitions for acute lung injury (ALI) and ARDS. Results/conclusions: Three clinically based definitions for acute lung injury and acute respiratory distress‐like syndromes occurring in veterinary patients were described. Neonatal equine respiratory distress syndrome (NERDS) was defined separately due to the specific requirement for primary developmental surfactant dysfunction and lack of an inflammatory component. Five diagnostic criteria categories were established for Veterinary ALI/ARDS (Vet ALI/ARDS) with 4 required and a fifth highly recommended criteria. A strong consensus was reached that onset of respiratory distress must have been acute and that known risk factors must be present. Additional criteria included evidence of pulmonary capillary leak with no evidence of increased pulmonary capillary pressure, evidence of inefficient gas exchange and, finally, evidence of inflammation. Some features of ALI/ARDS in the neonatal horse were recognized as unique, therefore, equine neonatal ALI/ARDS (EqNALI/EqNARDS) was similarly defined but with a graded gas exchange inefficiency table to allow for normal developmental changes in gas exchange. Use of these definitions in planning prospective studies of these problems in veterinary patients should allow for more direct comparisons of studies and clinical trials, with a larger goal of improving outcome in veterinary patients.     

Intra‐operative imaging of surgical margins of canine soft tissue sarcoma using optical coherence tomography

Optical coherence tomography (OCT) is a rapid non‐invasive imaging technique that has shown high sensitivity for intra‐operative surgical margin assessment in human breast cancer clinical trials. This promising technology has not been evaluated in veterinary medicine. The objective of this study was to correlate normal and abnormal histological features with OCT images for surgical margins from excised canine soft tissue sarcoma (STS) and to establish image evaluation criteria for identifying positive surgical margins. Fourteen client‐owned dogs underwent surgical resection of a STS and OCT imaging of 2 to 4 areas of interest on the resected specimen were performed. Following imaging these areas were marked with surgical ink and trimmed for histopathology evaluation. Results showed that different tissue types had distinct characteristic appearances on OCT imaging. Adipose tissue exhibited a relatively low scattering and a honey‐comb texture pattern. Skeletal muscle and sarcoma tissue were both dense and highly scattering. While sarcoma tissue was highly scattering, it did not have organized recognizable structure in contrast to muscle which showed clear fibre alignment patterns. In this investigation, we showed different tissue types had different and characteristic scattering and image texture appearances on OCT, which closely correlate with low‐power histology images. Given the differentiation between tissue types the results support that OCT could be used to identify positive surgical margins immediately following resection of STS. Further research is needed to assess the diagnostic accuracy of this method for surgical margin assessment.     

Spinal cord injury in small animals 2. Current and future options for therapy.

Although there can be substantial spontaneous improvements in functional status after a spinal cord injury, therapeutic intervention is desirable in many patients to improve the degree of recovery. At present only decompressive surgery and the neuroprotective drug methylprednisolone sodium succinate are effective and in widespread clinical use. There are limitations to the efficacy of these therapies in some clinical cases and they cannot restore satisfactory functional status to all patients. Many drugs have been investigated experimentally to assess their potential to preserve injured tissue and promote functional recovery in clinically relevant settings, and several of them would be suitable for assessment in future veterinary clinical trials. In addition, experimental techniques designed to mould the response of the CNS to injury, by the promotion of axonal regeneration across the lesion and the encouragement of local sprouting of undamaged axons, have recently been successful, suggesting that effective therapy for even very severe spinal cord injury may soon be available.     

Thromboembolic therapies in dogs and cats: an evidence-based approach.

In veterinary medicine, we are forced to make use of less than ideal "evidence," such as extrapolation from experimental studies in dogs and cats without naturally occurring diseases and from clinical trials in other species (particularly human clinical trials), as well as limited information gained from veterinary clinical experience, small clinical trials, case studies, and anecdotal reports. In this article, specific treatment recommendations are made for each of the common thromboembolic conditions seen in dogs and cats. These recommendations are made with the important caveat that, to date, such suggested therapeutic approaches are based on limited evidence.     

Responsiveness and validity of the SCORFAD, an extent and severity scale for feline hypersensitivity dermatitis

Background – Hypersensitivity (allergic) dermatitis (HD) is commonly seen in cats, causing pruritus and various patterns of skin lesions, including at least one of the following: head and neck excoriations, self‐induced alopecia, eosinophilic plaques and miliary dermatitis. Few studies have evaluated the efficacy of therapeutic interventions for feline HD, and although various scales have been considered, none has been formally validated for the assessment of disease severity and its response to therapy. Objective – To design and validate a novel scale (SCORing Feline Allergic Dermatitis; SCORFAD) to assess the value of different criteria used as outcome measures for the treatment of feline HD and to set minimal thresholds for defining the clinical success of tested interventions. Animals – One hundred client‐owned cats. Methods – The SCORFAD scale was designed to include the four most frequently identified lesion types in feline HD (eosinophilic plaque, head and neck excoriations, self‐induced alopecia and miliary dermatitis) across 10 body regions. The extent and severity of each lesion type were graded prior to inclusion and after 3 and 6 weeks in a clinical study to compare the efficacy of two doses of ciclosporin with placebo. Results – The SCORFAD scale was found to exhibit satisfactory content, construct, criterion and sensitivity to change. The percentage reduction in SCORFAD from baseline was determined to be the most valid assessment of clinical response. Inter‐ and intra‐observer reliability was not assessed. Conclusions and clinical importance – The SCORFAD scale is proposed for use as a validated tool for the assessment of disease severity and response to therapeutic interventions in clinical trials for feline HD.     

Use of intravenous lidocaine to prevent reperfusion injury and subsequent multiple organ dysfunction syndrome

Objective: The objective of this article is to review the human and veterinary literature and provide evidence for the potential beneficial effects of intravenous (IV) lidocaine hydrochloride in preventing post‐ischemic–reperfusion injury, the systemic inflammatory response syndrome (SIRS), and subsequent multiple organ dysfunction syndrome (MODS). Human data synthesis: Lidocaine is a local anesthetic and antiarrhythmic agent that has been used for years in human and veterinary medicine for the treatment of ventricular dysrhythmias associated with blunt cardiac trauma, myocardial ischemia, and cardiac surgery. More recently, the drug has been touted as a scavenger of reactive oxygen species (ROS), and has been used to prevent reperfusion dysrhythmias after treatment of myocardial infarction, cross‐clamping of the aorta, and in trauma medicine. Veterinary data synthesis: Although no clinical experiments with prophylactic intravenous lidocaine exist in veterinary medicine, there is a large body of evidence from experimental animals that support the use of lidocaine as a Na⁺/Ca²⁺ channel blocker, superoxide and hydroxyl radical scavenger, inflammatory modulator, and potent inhibitor of granulocyte functions. Lidocaine is being used in some clinical situations in an attempt to prevent the SIRS in veterinary trauma patients. ^a,b, ^a,b Conclusions: A large body of experimental evidence exists supporting the use of lidocaine as an anti‐oxidant and inflammatory modulator useful in preventing reperfusion injury. With the lack of cost‐effective and safe treatments for reperfusion injury in veterinary and human trauma medicine, the use of IV lidocaine to prevent the ensuing inflammatory response and MODS makes it an attractive addition to existing treatments. Therefore, it is essential that prospective clinical trials involving lidocaine as a treatment for prevention of reperfusion injury be performed in companion animals to demonstrate its safety and efficacy.     

Liposome‐encapsulated chemotherapy: Current evidence for its use in companion animals

Cytotoxic drugs encapsulated into liposomes were originally designed to increase the anticancer response, while minimizing off‐target adverse effects. The first liposomal chemotherapeutic drug was approved for use in humans more than 20 years ago, and the first publication regarding its use in a canine cancer patient was published shortly thereafter. Regardless, no general application for liposomal cytotoxic drugs has been established in veterinary oncology till now. Due to the popularity of canines as experimental models for pharmacokinetic analyses and toxicity studies, multiple publications exist describing various liposomal drugs in healthy dogs. Also, some evidence for its use in veterinary cancer patients exists, especially in canine lymphoma, canine splenic hemangiosarcoma and feline soft tissue sarcoma, however, the results have not been overwhelming. Reasons for this may be related to inherent issues with the enhanced permeability and retention effect, the tumour phenomenon which liposomal drugs exploit. This effect seems very heterogeneously distributed in the tumour. Also, it is potentially not as ubiquitously occurring as once thought, and it may prove important to select patients for liposomal therapy on an individual, non‐histology‐oriented, basis. Concurrently, new developments with active‐release modified liposomes in experimental models and humans will likely be relevant for veterinary patients as well, and holds the potential to improve the therapeutic response. It, however, does not resolve the other challenges that liposomal chemotherapy faces, and more work still needs to be done to determine which veterinary patients may benefit the most from liposomal chemotherapy.     

Use of biochemical markers of bone metabolism in veterinary medicine

Effective, non-invasive bone assessment methods for screening, diagnosis and follow-up of the skeleton are more and more requested in veterinary medicine. In contrast to clinical parameters, invasive methods and imaging techniques, indices of bone turnover is a tool for bone metabolism evaluation of the whole skeleton. Biochemical bone markers therefore provide a more real-time assessment of the bone status with simple blood- or urine-analysis. This article surveys currently available biochemical marker of bone metabolism used in veterinary medicine. Additionally, information is provided about physiological and pathological, as well as therapeutic variations of biochemical bone marker concentrations in various species.