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MRI conformational changes and dysmorphia associated with Chiari malformation

Clare provided the first description of this disease in the dog published in 2000 and came to realize quickly that this disorder was more than a simple cerebellar herniation and rather was an extremely complex malformation of the skull and cervical vertebrae linked to brachycephalic head and facial characteristics. Understanding the way these conformation changes impact nervous tissue compliance and cerebrospinal fluid channels is key to understanding the pathogenesis of syringomyelia.  Clare has  been primary, co-investigator or supervisor in over 20 projects on the morphometric changes associated with Chiari malformation and its association to syringomyelia.

Genetics of Chiari malformation and syringomyelia

Prof Clare Rusbridge and Dr Penny Knowler have had a collaboration with Dr Kibar’s group of the University of Montreal since 2005 with an aim of identifying genetic markers for canine CMSM and to translate the findings into genomic studies on humans. They established a large database of DNA linked to MRI findings and over the last decade have refined phenotypical analysis of affected dogs and their diagnostic MRI in parallel with advances in statistical genetic analysis. Dr Knowler’s doctoral thesis  investigated the MRI morphometric traits and interpretation of study results. They also coordinated DNA and RNA collection and confimed dogs’ phenotypes. Recently strong candidate genes for CM in dogs and humans and SM in dogs were identified. These can be directly correlated to MRI morphometric traits and clinical findings of neuropathic pain. The findings have impact on understanding of the osseous changes in CM and why some patients are painful. In collaboration with the Medical Imaging Group at the Â鶹ÊÓƵ (HeadSpace project) we are applying a machine learning approach to the significant MRI morphometric traits to establish a simple objective measure that could be applied to future genetic and other studies and develop a medical image analysis software that can be used to screen susceptible breeding dogs and be translated into human studies. Our work on this was presented at ECVN congress 2017 and 2022 and on both occasions awarded the best Neuroimaging presentations. 

Medical and surgical management of syringomyelia

Since Clare Rusbridge’s original description of the disease she has led the veterinary world on the treatment of this disease and I have written several book chapters and provided simple treatment algorithms. She conduction one of the only studies that assessed the long term outcome after surgery that included follow up MRI of affected dogs. In addition Clare has researched what MRI features are more likely to be associated with neuropathic pain and in collaboration with the Royal Veterinary College I have conducted clinical trials comparing drugs for management of neuropathic pain. 

Progressive myoclonic epilepsy (Lafora’s disease)

Clare Rusbridge is the chief veterinary collaborator for an ongoing project on Lafora disease (a polyglucasan storage disease). After diagnosing this rare progressive myoclonic epilepsy in a canine patient in 2001, she links with Dr. Berge Minassian to study the mutation causing the disease. With the support of the Miniature Wirehaired Dachshund club she established a nationwide program of DNA collection from affected dogs and their relatives to conduct a genome scan and characterization of the mutation. The successful outcome was the first description of a mutation causing canine epilepsy and the first example of a tandem repeat expansion outside of humans. This has led to better understanding of the disease in humans. In addition, a test for detection of affected and carrier dogs was established to enable a controlled breeding program in affected dog breeds. Soon we hope to establish a preventative treatment program that will be translated for human patients.  

My area of research is the objective measurement of the welfare of animals.  The aim is to maximise use of the AWAG tool reflecting the five domains of welfare. This quantifies welfare using a temporal approach and provides a visual representation of the animal’s quality of life which is easily understood and encourages communication about animal welfare. This will encourage teamwork, so those caring for animals can plan and intervene in a targeted and timely way, demonstrating to regulators, consumers and welfare groups that a proactive approach is being taken to improving, or preventing deterioration, of animal quality of life.

The next step is to integrate it with Precision Livestock Farming technology to generate big data on animal welfare to inform policy makers and drive improved attitudes and investment in this area, ensuring better animal welfare and public perception.

The majority of my research is clinical based at , a world-renowned centre for oncology, soft tissue surgery, interventional radiology and internal medicine.

Recent avenues of research include:

Ex vivo work on autologous blood transfusions with assistance from a Cell Saver. This work was funded by BSAVA Petsavers and resulted in two publications;

• Galliano A, Kalmukov IA, Godolphin J, Ferreira R, Norgate DJ, Bacon NJ. Intraoperative cell salvaging: ex vivo evaluation of two swab-washing methods. Am J Vet Res. 2022 Jul 30;83(10):ajvr.22.03.0061. doi: 10.2460/ajvr.22.03.0061
• Kalmukov IA, Galliano A, Godolphin J, Ferreira R, Cardoso I, Norgate DJ, Bacon NJ. Ex vivo evaluation of a novel cell salvage device to recover canine erythrocytes. Vet Surg. 2022 Nov;51(8):1223-1230. doi: 10.1111/vsu.13875

Collaboration with the Department of Comparative Biomedical Sciences has also resulted in several manuscripts about the use of machine-learning in veterinary oncology

• Rai T, Morisi A, Bacci B, Bacon NJ, Dark MJ, Aboellail T, Thomas SA, Bober M, La Ragione R, Wells K. Deep learning for necrosis detection using canine perivascular wall tumour whole slide images. Sci Rep. 2022 Jun 23;12(1):10634. doi: 10.1038/s41598-022-13928-1
• Morisi A, Rai T, Bacon NJ, Thomas SA, Bober M, Wells K, Dark MJ, Aboellail T, Bacci B, La Ragione RM. Detection of Necrosis in Digitised Whole-Slide Images for Better Grading of Canine Soft-Tissue Sarcomas Using Machine-Learning. Vet Sci. 2023 Jan 8;10(1):45. doi: 10.3390/vetsci10010045
• Rai, A. Morisi, B. Bacci, N. J. Bacon, S. A. Thomas, R. M. La Ragione, M. Bober, K. Wells, An investigation of aggregated transfer learning for classification in digital pathology. Proc. SPIE 10956, Medical Imaging 2019: Digital Pathology, 109560U (18 March 2019);
• Taranpreet Rai, A Morisi, B Bacci, NJ Bacon, SA Thomas, RM La Ragione, M Bober, K Wells., Can ImageNet feature maps be applied to small histopathological datasets for the classification of breast cancer metastatic tissue in whole slide images?., Medical Imaging 2019: Digital Pathology 10956, 109560V

I have mentored several oncologic projects in the past 5 years (2017-2022) using clinical material and follow-up from AURA Veterinary. Many are multi-institutional collaborations, often with international links. Successful publications include;

• David John Brewer, Michael Macfarlane, Erin O’Connell, Nicholas J Bacon, Toxicity of zoledronic acid after intravenous administration: A retrospective study of 95 dogs, J Vet Intern Med 2022 Jan;36(1):253-258.  doi: 10.1111/jvim.16335
• Villedieu EJ, Petite AF, Godolphin JD, Bacon NJ. Prevalence of pulmonary nodules suggestive of metastasis at presentation in dogs with cutaneous or subcutaneous soft tissue sarcoma. J Am Vet Med Assoc. 2021 Jan 15;258(2):179-185. doi: 10.2460/javma.258.2.179
• Homer LM, Bacon NJ. Hemipelvectomy to treat sarcoma of the proximal portion of the femur in a rabbit. J Am Vet Med Assoc. 2021 Jan 15;258(2):192-196. doi: 10.2460/javma.258.2.192
• Ying Wu, Yu-Mei Chang, Gerry Polton, Anneliese J Stell, Balazs Szladovits, Michael Macfarlane, Laureen M Peters, Simon L Priestnall, Nicholas J Bacon, Kelvin Kow, Sarah Stewart, Eshita Sharma, Michelle R Goulart, John Gribben, Dong Xia, Oliver A Garden, Gene Expression Profiling of B Cell Lymphoma in Dogs Reveals Dichotomous Metabolic Signatures Distinguished by Oxidative Phosphorylation, Front Oncol. 2020 Mar 6;10:307.  doi: 10.3389/fonc.2020.00307
• Sarah E Boston, Lucinda L van Stee, Nicholas J Bacon, David Szentimrey, Barbara M Kirby, Sebastiaan van Nimwegen 2 , Vincent A Wavreille , Outcomes of eight cats with oral neoplasia treated with radical mandibulectomy, Vet Surg. 2020 Jan;49(1):222-232.  doi: 10.1111/vsu.13341
• D’Aout C, Renfrew H, Dobromylskyj M, Bacon N, Herrmann A, Taylor SS. Intranasal proliferative fibro-osseous dysplasia in a domestic longhair cat. JFMS Open Rep. 2020 Jun 10;6(1):2055116920917839. doi: 10.1177/2055116920917839
• Amsellem PM, Cavanaugh RP, Chou PY, Bacon NJ, Schallberger SP, Farese JP, Kuntz CA, Liptak JM, Culp WTN, Robat CS, Powers BE. Apocrine gland anal sac adenocarcinoma in cats: 30 cases (1994-2015). J Am Vet Med Assoc. 2019 Mar 15;254(6):716-722. doi: 10.2460/javma.254.6.716
• Carlos H de Mello Souza, Nicholas Bacon, Sarah Boston, Victoria Randall, Vincent Wavreille, Owen Skinner, Ventral mandibulectomy for removal of oral tumours in the dog: Surgical technique and results in 19 cases, Vet Comp Oncol. 2019 Sep;17(3):271-275.  doi: 10.1111/vco.12472
• Galliano, A., Belmudes, A. and Bacon, N.J. (2019), Cholecystocutaneous fistula and associated cholelithiasis in an eight-year-old dachshund. Vet Rec Case Rep, 7: e000786.
• P Beer, A Pozzi, C Rohrer Bley, N Bacon, N S Pfammatter, C Venzin , The role of sentinel lymph node mapping in small animal veterinary medicine: A comparison with current approaches in human medicine, Vet Comp Oncol. 2018 Jun;16(2):178-187.  doi: 10.1111/vco.12372
• Michelle A Giuffrida, Debra A Kamstock, Laura E Selmic, William Pass, Anna Szivek, Michael B Mison, Sarah E Boston, Leslie E Fox, Cecilia Robat, Janet A Grimes, Karl C Maritato, Nicholas J Bacon. Primary appendicular hemangiosarcoma and telangiectatic osteosarcoma in 70 dogs: A Veterinary Society of Surgical Oncology retrospective study, Vet Surg. 2018 Aug;47(6):774-783.  doi: 10.1111/vsu.12926
• Giuffrida MA, Bacon NJ, Kamstock DA. Use of routine histopathology and factor VIII-related antigen/von Willebrand factor immunohistochemistry to differentiate primary hemangiosarcoma of bone from telangiectatic osteosarcoma in 54 dogs. Vet Comp Oncol. 2017 Dec;15(4):1232-1239. doi: 10.1111/vco.12259
• Kelsey KL, Kubicek LN, Bacon NJ, Torres T, Robertson SA. Neuromuscular blockade and inspiratory breath hold during stereotactic body radiation therapy for treatment of heart base tumors in four dogs. J Am Vet Med Assoc. 2017 Jan 15;250(2):199-204. doi: 10.2460/javma.250.2.199
• Talbott JL, Boston SE, Milner RJ, Lejeune A, Souza CH, Kow K, Bacon NJ, Hernandez JA. Retrospective Evaluation of Whole Body Computed Tomography for Tumor Staging in Dogs with Primary Appendicular Osteosarcoma. Vet Surg. 2017 Jan;46(1):75-80. doi: 10.1111/vsu.12579
• Boston SE, Vinayak A, Lu X, Larue S, Bacon NJ, Bleedorn JA, Souza CHM, Ehrhart NP. Outcome and complications in dogs with appendicular primary bone tumors treated with stereotactic radiotherapy and concurrent surgical stabilization. Vet Surg. 2017 Aug;46(6):829-837. doi: 10.1111/vsu.12669