Surface electromyography of the vastus lateralis and gluteus medius muscles in post-operative T3-L3 hemilaminectomy dogs: a prospective controlled observational study.

Objective: The objective of this study was to determine if surface electromyography (sEMG) demonstrates differences in muscle activation between normal and dogs recovering from spinal cord injury due to intervertebral disk extrusion. Animals: Two groups of client-owned small-breed chondrodysplastic-type dogs were tested. Group 1 consisted of seven ambulatory paraparetic dogs that had undergone a hemilaminectomy procedure in the T3-L3 region for intervertebral disk extrusion 1 month prior. Group 2 was made up of seven normal dogs that had no history of intervertebral disk disease or spinal surgery. Procedures: Each subject walked 10 feet on a nonslip surface for at least five gait cycles for the sEMG to capture muscle activation of the vastus lateralis and gluteus medius, bilaterally. Muscle activation was quantified as the total myoelectric output area under the curve, averaged across all gait cycles. Results: Muscle activation was significantly greater in the post-operative hemilaminectomy group (p = 0.012). There was a significant difference in muscle activation between each hindlimb in the post-operative hemilaminectomy group, but not in the normal group. The muscle activation was significantly lower on the side that underwent surgery compared to the opposite limb (p = 0.0034). Conclusion and clinical importance: Post-operative hemilaminectomy dogs have greater hindlimb muscle activation compared to normal dogs, which likely represents a lack of descending inhibition secondary to upper motor neuron syndrome. The side of surgery is correlated with decreased muscle activation. Surface EMG can be used to evaluate muscle activity in dogs recovering from spinal decompression surgery.

RNA aggregates harness the danger response for potent cancer immunotherapy.

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Telangiectatic osteosarcoma in four dogs: Cytologic, histopathologic, cytochemical, and immunohistochemical findings.

Telangiectatic osteosarcoma is a rare variant of osteosarcoma histologically and clinically similar to hemangiosarcoma (HSA). This case series describes the imaging and cytologic features of four histologically confirmed telangiectatic osteosarcomas, including the use of cytochemical stains. Alkaline phosphatase (ALP) was applied to Wright-Giemsa-stained cytology slides, and Factor VIII immunohistochemistry was evaluated. Cytologic characteristics included atypical mesenchymal cells with evidence of acute and chronic hemorrhage. Telangiectatic osteosarcoma cases had positive ALP cytochemical staining, while control HSA cases were negative. Factor VIII immunohistochemistry was negative in telangiectatic osteosarcoma and positive in HSA. Cytologic diagnosis of telangiectatic osteosarcoma with positive ALP cytochemical staining can help differentiate this neoplasm from HSA.

mRNA challenge predicts brain cancer immunogenicity and response to checkpoint inhibitors.

To prospectively determine whether brain tumors will respond to immune checkpoint inhibitors (ICIs), we developed a novel mRNA vaccine as a viral mimic to elucidate cytokine release from brain cancer cells in vitro. Our results indicate that cytokine signatures following mRNA challenge differ substantially from ICI responsive versus non-responsive murine tumors. These findings allow for creation of a diagnostic assay to quickly assess brain tumor immunogenicity, allowing for informed treatment with ICI or lack thereof in poorly immunogenic settings.

mRNA aggregates harness danger response for potent cancer immunotherapy.

Messenger RNA (mRNA) has emerged as a remarkable tool for COVID-19 prevention but its use for induction of therapeutic cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Herein, we develop a facile approach for substantially enhancing immunogenicity of tumor-derived mRNA in lipid-particle (LP) delivery systems. By using mRNA as a molecular bridge with ultrapure liposomes and foregoing helper lipids, we promote the formation of 'onion-like' multi-lamellar RNA-LP aggregates (LPA). Intravenous administration of RNA-LPAs mimics infectious emboli and elicits massive DC/T cell mobilization into lymphoid tissues provoking cancer immunogenicity and mediating rejection of both early and late-stage murine tumor models. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for toll-like receptor engagement, RNA-LPAs stimulate intracellular pathogen recognition receptors (RIG-I) and reprogram the TME thus enabling therapeutic T cell activity. RNA-LPAs were safe in acute/chronic murine GLP toxicology studies and immunologically active in client-owned canines with terminal gliomas. In an early phase first-in-human trial for patients with glioblastoma, we show that RNA-LPAs encoding for tumor-associated antigens elicit rapid induction of pro-inflammatory cytokines, mobilization/activation of monocytes and lymphocytes, and expansion of antigen-specific T cell immunity. These data support the use of RNA-LPAs as novel tools to elicit and sustain immune responses against poorly immunogenic tumors.

Clinical characteristics and outcome in 15 dogs treated with transsphenoidal hypophysectomy for nonfunctional sellar masses.

OBJECTIVE: To characterize the clinical features, neurological examination findings, diagnostic imaging results, histopathological findings, and outcome following transsphenoidal hypophysectomy (TSH) in dogs with nonfunctional sellar masses (NFSM). STUDY DESIGN: Multi-institutional retrospective study. METHODS: Medical records of dogs that underwent TSH for a NFSM were reviewed for clinical signs, physical and neurological examination findings, diagnostic imaging results, endocrine testing, surgery reports, and outcome. Magnetic resonance (MR) imaging was rereviewed, and tumors were classified using the previously described system according to pituitary tumor extension and vascular involvement. Owners of dogs that survived to discharge were contacted. RESULTS: The majority of dogs presented for mentation change (12/15). The mean pituitary to brain ratio (P/B ratio) was 1.05 (0.6-1.4). Eight dogs had a tumor imaging classification of 5B. Eleven dogs were diagnosed with a nonfunctional pituitary adenoma (NFPA). Perioperative mortality was 33% (5/15). The median survival for all dogs was 232 days (0-1658). When dogs that did not survive to discharge were excluded, the median survival time was 708 days. Seven of 10 dogs that survived the perioperative period received adjunctive therapy. Owner assessment of outcome was excellent (6/7) to good (1/7). CONCLUSION: The common presenting complaint for dogs with large NFSM causing mass effect was mentation changes. Dogs with NFPA that survived to discharge and received adjunctive therapy had good to excellent outcomes. CLINICAL SIGNIFICANCE: Transsphenoidal debulking with adjunctive therapy can be considered for the treatment of NFSM causing clinical signs of mass effect in dogs. Successful long-term outcomes are possible.

Agreement and differentiation of intradural spinal cord lesions in dogs using magnetic resonance imaging.

BACKGROUND: Magnetic resonance imaging is the method of choice for diagnosing spinal cord neoplasia, but the accuracy of designating the relationship of a neoplasm to the meninges and agreement among observers is unknown. OBJECTIVES: To determine agreement among observers and accuracy of diagnosis compared with histology when diagnosing lesion location based on relationship to the meninges. ANIMALS: Magnetic resonance images from 53 dogs with intradural extramedullary and intramedullary spinal neoplasms and 17 dogs with degenerative myelopathy. METHODS: Six observers were supplied with 2 sets of 35 images at different time points and asked to designate lesion location. Agreement in each set was analyzed using kappa (κ) statistics. We tabulated total correct allocations and calculated sensitivity, specificity, and likelihood ratios for location designation from images compared with known histologic location for lesions confined to 1 location only. RESULTS: Agreement in the first set of images was moderate (κ = 0.51; 95% confidence interval [CI], 0.43-0.58) and in the second, substantial (κ = 0.69; 95% CI, 0.66-0.79). In the accuracy study, 180 (75%) of the 240 diagnostic calls were correct. Sensitivity and specificity were moderate to high for all compartments, except poor sensitivity was found for intradural extramedullary lesions. Positive likelihood ratios were high for intradural extramedullary lesions and degenerative myelopathy. CONCLUSIONS AND CLINICAL IMPORTANCE: Overall accuracy in diagnosis was reasonable, and positive diagnostic calls for intradural extramedullary lesions and negative calls for intramedullary lesions are likely to be helpful. Observers exhibited considerable disagreement in designation of lesions relationship to the meninges.

Presumptive fibrocartilaginous embolic myelopathy in a pot-bellied pig.

A case of presumptive fibrocartilaginous embolic myelopathy in a pet pot-bellied pig is described in this report. This case, which was associated with a previous trauma, highlighted the importance of advanced diagnostic imaging in pigs with clinical signs consistent with a myelopathy.

Myélopathie à la suite d'une embolie fibrino-cartilagineuse présumée chez un cochon vietnamien. Ce rapport décrit un cas de myélopathie à la suite d'une embolie fibrino-cartilagineuse présumée chez un cochon vietnamien. Ce cas, qui était associé avec un traumatisme antérieur, met en évidence l'importance de l'imagerie diagnostique avancée chez les porcs avec des signes cliniques compatibles avec une myélopathie.(Traduit par Dr Serge Messier).

Clinical features and short-term outcome of presumptive intracranial complications associated with otitis media/interna: a multi-center retrospective study of 19 cats (2009-2017).

OBJECTIVES: The aim of this study was to compile an overview of the clinical features of intracranial complication of otitis media/interna (OMI) in cats managed across five veterinary referral hospitals. Of additional interest were culture results that could inform empirical antibiotic selection, as well as outcome with both medical and surgical management. METHODS: A retrospective medical record review was conducted at five veterinary referral practices to identify cats with a diagnosis of intracranial complication secondary to OMI between 2009 and 2017. Clinical features, diagnostic findings, treatment and outcome were recorded. RESULTS: At total of 19 cats were identified. Sixty-three percent had no previous history of ear infection. Otoscopic examination was normal in 47% of cases. The most common bacterial isolate was Pasteurella multocida, which was identified in 24% of cases. Outcome was successful for 83% of cats managed with ventral bulla osteotomy (VBO) and in 66% of cats managed without surgical intervention. CONCLUSIONS AND RELEVANCE: Clinical suspicion of intracranial complications of OMI should remain high in cats with central vestibular disease even if otoscopic examination is normal. Antibiotic selection should be based on a culture and sensitivity; however, initial antibiotic therapy should include broad-spectrum coverage with special consideration for P multocida. Cats with intracranial complications of OMI can have a good outcome with either surgical or medical management and prospective studies are needed to assess the role of VBO in enhancing recovery.

Personalized Tumor RNA Loaded Lipid-Nanoparticles Prime the Systemic and Intratumoral Milieu for Response to Cancer Immunotherapy.

Translation of nanoparticles (NPs) into human clinical trials for patients with refractory cancers has lagged due to unknown biologic reactivities of novel NP designs. To overcome these limitations, simple well-characterized mRNA lipid-NPs have been developed as cancer immunotherapeutic vaccines. While the preponderance of RNA lipid-NPs encoding for tumor-associated antigens or neoepitopes have been designed to target lymphoid organs, they remain encumbered by the profound intratumoral and systemic immunosuppression that may stymie an activated T cell response. Herein, we show that systemic localization of untargeted tumor RNA (derived from whole transcriptome) encapsulated in lipid-NPs, with excess positive charge, primes the peripheral and intratumoral milieu for response to immunotherapy. In immunologically resistant tumor models, these RNA-NPs activate the preponderance of systemic and intratumoral myeloid cells (characterized by coexpression of PD-L1 and CD86). Addition of immune checkpoint inhibitors (ICIs) (to animals primed with RNA-NPs) augments peripheral/intratumoral PD-1+CD8+ cells and mediates synergistic antitumor efficacy in settings where ICIs alone do not confer therapeutic benefit. These synergistic effects are mediated by type I interferon released from plasmacytoid dendritic cells (pDCs). In translational studies, personalized mRNA-NPs were safe and active in a client-owned canine with a spontaneous malignant glioma. In summary, we demonstrate widespread immune activation from tumor loaded RNA-NPs concomitant with inducible PD-L1 expression that can be therapeutically exploited. While immunotherapy remains effective for only a subset of cancer patients, combination therapy with systemic immunomodulating RNA-NPs may broaden its therapeutic potency.

Evaluation of surgical repair of humeral condylar fractures using self-compressing orthofix pins in 23 dogs.

OBJECTIVE: To report short- and long-term clinical and radiographic outcomes in dogs with humeral condylar fractures repaired using self-compressing Orthofix pins. STUDY DESIGN: Retrospective evaluation with solicited long-term clinical and radiographic evaluations. ANIMALS: Twenty-three dogs with humeral condylar fractures. METHODS: Medical records and radiographs were reviewed. Owners were asked to return dogs for long-term clinical and radiographic evaluation. RESULTS: Dogs were aged 1.5-26 months (mean+/-SD, 5.8+/-5.0 months) with 20 dogs weighing <5 kg (mean, 3.6+/-2.8 kg). Of 21 dogs with immediate post-operative radiographs, 10 had anatomic reduction with the rest having either a step and/or gap at the articular surface. Kirschner wire migration and implant loosening were the most common post-operative complications. All fractures with adequate follow-up radiographic evaluations achieved union. Twelve of 13 dogs returned for long-term evaluation (mean, 19.0+/-18.5 months) were either sound (10 dogs) or had subtle, weight-bearing lameness (2). Fourteen dogs had radiographs >/=75 days after surgery (mean, 18.7+/-18.3 months), 8 dogs (57%) had no radiographic evidence of osteoarthritis (OA; mean OA score, 0.8; median 0), and all dogs had good or excellent limb function. CONCLUSIONS: Self-compressing Orthofix pins are suitable implants for the stabilization of humeral condylar fractures in small breed dogs. Implants were convenient and simple to use and complications were easily resolved. Dogs consistently had good long-term clinical and radiographic outcomes with no or minimal lameness and OA. CLINICAL RELEVANCE: Self-compressing Orthofix pins should be considered for the repair of humeral condylar fractures in small breed dogs.