Bouvier Health Foundation Education Series
Part 3: Additional Health Updates from the 2013 AKC Health Foundation’s National Parent Club Conference
In this edition of the Dirty Beard Quarterly, updates covering current studies in Cruciate Ligament Interventions and Cancer will be explored. These are areas of ever expanding science, so what is covered will only be a synopsis of recent research. It is hoped that the information presented will spark interest and encourage your further investigation.
Investigation of Cranial Cruciate Ligament Deficiency and Associated Surgical Interventions Using Computer Simulation, Gina Bertocci, PhD, PE University of Louisville
Cranial cruciate ligament (CrCL) deficiency affects the canine stifle (knee) and is one of the most common canine orthopedic injuries, having an economic impact of more than $1billion in the United States in 2003. CrCL deficiency has a prevalence of 2.55% across all breeds and is most prevalent in Newfoundlands (8.9%), Rottweilers (8.3%), and Labrador Retrievers (5.8%). Despite such high prevalence, CrCL deficiency is still poorly understood and is thought to be due to degradation and not the result of trauma. Surgical intervention is often employed to stabilize the CrCL-deficient stifle, but no single surgical procedure is conclusively supported to suggest long-term success, osteoarthritis prevention or superiority. Dr. Bertocci’s group has developed a canine pelvic limb 3D computer simulation model of walking to gain an improved understanding of stifle biomechanics, as well as factors that may predispose dogs to CrCL rupture. This model allows noninvasive visualization and analysis of stifle biomechanics, simulates the intact and CRCL-deficient stifle, and was utilized to investigate anatomical characteristics and biomechanical parameters, such as ligament stiffness and tibial plateau angle to gain an understanding of their role in producing CrCL deficiency.
Their company model was based on a healthy male Golden Retriever with no orthopedic or neurologic diseases. A pelvic limb computed tomography (CT) scan was conducted to obtain anatomical geometry, and gait was recorded using a motion capture system and force platform. The computer model was developed in computer-aided engineering software and included canine-specific bone geometry, ligaments, muscles and ground reaction forces. Model simulation of the stance phase of walking was used to evaluate loads placed on stifle ligaments, translation and rotation of the tibia relative to the femur, and contact forces between the femur and menisci in both the intact and deficient stifle.
Commonly employed surgical procedures – tibial plateau leveling osteotomy (TPLO), tibial tuberosity advancement (TTA), lateral femoro-tibial suture stabilization (LFTS) and TightRope stabilization (TR) were implemented in the model through collaboration with a veterinary orthopedic surgeon to evaluate the ability of procedures to restore normal, CrCL-intact stifle biomechanics. Ligament loads, along with translation and rotation of the tibia relative to the femur and meniscal loads were evaluated surgical procedures. Additionally, her team will be investigating parameters specific to each surgical procedure (e.g. suture tension, tibial plateau rotation angle, etc.) to further understand their influence on surgical efficacy.
Her team has also determined that the use of stifle orthoses (braces) offer an alternative to surgical intervention, especially in patients that are poor anesthesia candidates with significant co-morbidities, that are of advanced age or whose owners lack the financial means for more costly surgery. In partnership with a veterinary prosthetics and orthotics clinic they are characterizing stifle orthosis-using dogs. The team has also implemented a preliminary representation of a customized stifle orthosis in their computer model to investigate associated stifle biomechanics. Once this research is finalized, they will compare stifle biomechanics during gait in a CrCL-deficient stifle with and without an orthosis to a CRCL-intact stifle. Furthermore, the team will investigate stifle orthosis design and fit parameters (e.g. hinge type and strap tension), along with patient-specific parameters, using their computer model to understand their role in orthosis effectiveness.
Dr. Bertocci is a professor in the Bioengineering Department and holds the Endowed Chair position in Biomechanics at the University of Louisville. She is also the Director of the Injury Risk Assessment and Prevention Laboratory and Fellow of the American Institute for Medical and Biological Engineering. Funding from the AKC Canine Health Foundation has allowed Dr. Bertocci to combine her life-long passion for animals with her expertise in biomechanics to investigate orthopedic conditions affecting the canine stifle joint. She and her team have implemented various common surgical procedures used to stabilize the stifle following CrCL rupture into their computer model to investigate how effectively these procedures restore normal stifle biomechanics.
The Cytogenomic Landscape of Canine Cancer, Matthew Breen PhD C.Biol FSB North Carolina State University, College of Veterinary Medicine
Chromosome aberrations have been collated from assessment of over 62,000 human neoplasms, collectively representing approximately 75 different types of cancer. There is broad acceptance that the accurate identification of recurring chromosome abnormalities in malignant cells provides opportunities to increase the sophistication of diagnosis, sub-classification and prognosis of neoplastic disorders. In human medicine, the identity of cytogenetic aberrations has been shown to also assist in the localization of cancer-associated genes and even selection of the most appropriate therapeutic approach. The application of molecular cytogenetics to the analysis of human neoplasms has revolutionized the way in which we interrogate tumor cells for cytogenetic changes, whether they are numerical or structural in nature.
Veterinary medicine has provided a wealth of information about the clinical and pathological presentation of numerous cancers in animals, and while both dogs and cats are now the subject of intense molecular cytogenetic attention, it is the dog that has provided much of the insight to date. Despite millions of years of divergent evolution, the high degree of similarity between human and dog also extends to their genome sequences. It is well known that purebred dog breeds are associated with differing susceptibility to specific malignancies, suggesting that selected breeds of dog are inheriting ‘at risk’ alleles for very few genes, perhaps even a single gene, with a profound effect. These features, combined with the sophisticated genomic resources now available for the dog, have placed the dog in a position of high visibility as a model system for cancer research.
As pets, our dogs (and thus their genomes) are exposed to the same environmental influences as ourselves. The combination of pathophysiological and genetic similarities shared between human and dog led to our hypothesis that canine tumors would contain the natural variety of chromosome aberrations that are observed in the corresponding human cancers, a feature not evident with induced tumors in rodents. We have shown our hypothesis to be valid, by demonstrating that there are considerable cytogenomic changes shared by numerous forms of cancer that affect both human and dog. Research teams are investigating cytogenomic changes evident in a variety of the leading cancers in dogs, including lymphoma, leukemia, osteosarcoma, histiocytic neoplasia, urogenital carcinoma, intracranial malignancies, hemangiosarcoma and melanoma. Of broader significance our data also reveal that several of the changes conserved between human and dog also extend to other animals with similar cancers. Researchers are now aligning cytogenomic data from comparable cancers in multiple species to identify the genes likely to be of greatest significance to the malignant process. Identification of these genes is key to developing new ways to halt the cancer process and extend both duration and quality of like of patients.
Dr. Breen is a member of the NCSU Center for Comparative Medicine and Translational Research (CCMTR) and the Cancer Genetics Program at the University of North Carolina’s Lineberger Comprehensive Cancer Center. Dr. Breen was a charter member, and now serves on the Board of Directors, of the Canine Comparative Oncology and Genomics Consortium (CCOGC), a 501(c)(3) not-for-profit organization established to promote the role of the dog in comparative biomedical research. He is also a major collaborator with Drs. Kerstin Lindblad-Toh and Jaime F. Modiano, and together these researchers have led to the discovery of heritable traits that account for risk in work on canine hemangiosarcoma.
The ongoing efforts of these & countless other researchers cannot continue without the support of the canine fancy. Not only are financial contributions necessary, through organizations, such as the Bouvier Health Foundation & the AKC Canine Health Foundation, but something as simple as a DNA blood draw done on your Bouvier companion at the St Louis Specialty will provide needed samples for these research teams to conduct valuable studies to further the lives of our magnificent breed. Please visit modianolab.org and/or breenlab.org to read more about how you can participate in clinical trials and support this important research.
Please Note: there has been some confusion regarding the DNA samples we submit for our dogs. The cheek-swab sample that is sent to the American Kennel Club is ONLY used to establish a DNA Profile Number and ultimately used to verify lineage. The blood draw/cheek-swab procedures to be conducted at the St. Louis Specialty are submitted to Canine Health Information Center (CHIC), who maintains the DNA Repository – the Repository is jointly sponsored by the AKC/CHF and the OFA. The valuable purpose of these samples is to provide research teams with Canine DNA that meet a specific study protocol. Because of its value to researchers, it’s recommended, whenever possible, that the CHIC Repository blood draws be conducted on full litters and litter-parents. Please visit the following websites for more information – www.caninehealthinfo. ) org (CHIC DNA Repository) &/or www.akc.org/dna/certify. cfm (AKC DNA Profile Program)
Canine Hemangiosarcoma: How Much Do We Really Know and When Will We Find a Cure, Jaime F. Modiano, VMD, PhD University of Minnesota
Hemangiosarcoma is a common and lethal cancer of dogs. Some breeds have a higher risk to develop the disease and it can occur at any age. Not much has changed since the disease was first described in the 1960s. The most significant therapeutic gains were the introduction of surgery in the 1970s and the introduction of chemotherapy in the 1980s. Since then, most practical gains have been incremental, improving the safety and tolerability of chemotherapy.
The cause of the disease is unknown. Until recently, it was generally accepted that the tumors arise from endothelial (blood vessel lining) cells. Researchers first proposed that this tumor might originate from bone marrow derived cells in 2006. Since then, researchers have expanded this line of investigation to document that the tumor cells can differentiate along various lineages, including myeloid (white blood cells), adipose (fat cells), and vascular (blood vessel forming cells). The ongoing work of the research teams seek to define the interactions between the tumor cells and their microenvironment that determine which lineage predominates, and that provide a safe niche for tumor growth and progression. We believe that disrupting this niche will delay or prevent metastatic spread, and more importantly, protect tumor sites from hemorrhage, which is the most common lethal event in this disease.
Researchers are implementing a comprehensive approach to beat canine hemangiosarcoma. This includes development of new therapies to help dogs that develop the disease today, as well as new methods for prevention and control that will reduce the number of dogs that will develop hemangiosarcoma in the future. A better understanding of the disease has allowed researchers to make significant gains on both fronts of the battle against this aggressive tumor. The progress has not gone unnoticed, allowing us to establish new collaborations that will similarly help human patients with angiosarcoma.
To help in this research, the fancy of ALL breeds can spread the word about these ongoing efforts, contribute samples, and support agencies such as the AKC Canine Health Foundation that fund this work. This will sustain our capabilities to drive innovation, to stay at the forefront of cancer prevention and treatment, and to recruit new talented faculty and students that will bring and implement new ideas.
Dr. Modiano joined the College of Veterinary Mediine, School of Medicine, and masonic Cancer Center at the University of Minnesota in 2007, where he continues his research program as Alvin and June Perlman Endowed Professor of Oncology and Comparative medicine and Director of the Animal Cancer Care and Research Program. He has also served as Director for Cancer Immunology and Immunotherapy for the Donald Monk Cancer Research Foundation; he is a partner at Veterinary Research Associates, LLC, a company focused on development and implementation of diagnostics for veterinary medicine and a founder/scientist at ApopLogic Pharmaceuticals, Inc, a biotechnology company focused on development of cancer therapeutics.