John H. Rossmeisl, Jr.

• DVM, MS, DACVIM
• Professor at Virginia Tech

High-frequency irreversible electroporation (H-FIRE), a nonthermal brain tumor ablation therapeutic, generates a central tumor ablation zone while transiently disrupting the peritumoral blood–brain barrier (BBB). We hypothesized that bystander effects of H-FIRE tumor cell ablation, mediated by small tumor-derived extracellular vesicles (sTDEV), dis...

Objective Brain tumors represent some of the most treatment refractory cancers, and there is a clinical need for additional treatments for these tumors. Domesticated dogs are the only other mammalian species which commonly develop spontaneous brain tumors, making them an ideal model for investigating novel therapies. Histotripsy is a non-thermal ul...

Background To ameliorate anticipated or ongoing neurological deficits, dogs undergoing brain tumor irradiation often are prescribed lengthy courses of prednisone PO during and after radiotherapy (RT). This practice can contribute to unwanted corticosteroid‐associated morbidity and may be unnecessary. Objective Determine whether long‐term corticost...

Convection-enhanced delivery is an experimental method for glioblastoma treatment. This work evaluates the Convection-Enhanced Therapy Catheter System (CETCS) by subjecting it to several cadaveric fetal bovine and porcine brain tests that replicate the anticipated future clinical use of the device. CETCS includes a cannula containing six microneedl...

The objective of this research was to compare two previously described stereotactic brain biopsy (SBB) techniques, three-dimensional skull contoured guides (3D-SCGs) and neuronavigation with Brainsight, to a novel SBB technique using Brainsight combined with a 3D-printed headframe (BS3D-HF) to improve the workflow of SBB in dogs. This was a prospec...

The blood–brain barrier (BBB) limits the efficacy of treatments for malignant brain tumors, necessitating innovative approaches to breach the barrier. This study introduces burst sine wave electroporation (B-SWE) as a strategic modality for controlled BBB disruption without extensive tissue ablation and compares it against conventional pulsed squar...

Introduction: Histotripsy is a non-thermal focused ultrasound therapy in development for the non-invasive ablation of cancerous tumors. Intracranial histotripsy has been limited by significant pressure attenuation through the skull, requiring large, complex array transducers to overcome this effect. Objective: Recently, a biocompatible, polyolef...

Magnetic resonance imaging (MRI) is used pervasively in veterinary practice for the antemortem diagnosis of intracranial tumors. Here, we provide an illustrated summary of the published MRI features of primary and secondary intracranial tumors of dogs and cats, following PRISMA scoping review guidelines. The PubMed andWeb of Science databases were...

Background Neurofilament light chain (NfL) is a frequently used biomarker in humans for both diagnostic and therapeutic monitoring purposes in various neurologic diseases. Hypothesis/Objectives It was hypothesized that dogs with diagnosed structural epilepsy (SE) would have a significantly higher serum NfL concentrations compared to dogs with idio...

Although many interventions for acute spinal cord injury (SCI) appear promising in experimental models, translation directly from experimental animals to human patients is a large step that can be problematic. Acute SCI occurs frequently in companion dogs and may provide a model to ease translation. Recently, incision of the dura has been highlight...

Meningiomas are the most common feline primary brain tumours, and calvarial hyperostosis (CH) is frequently documented in association with this neoplastic entity. The clinical significance of and mechanisms driving the formation of CH in cats with meningiomas are poorly understood, although tumour invasion into the skull and tumour production of cy...

Introduction The presence of cancer in dogs was detected by Raman spectroscopy of urine samples and chemometric analysis of spectroscopic data. The procedure created a multimolecular spectral fingerprint with hundreds of features related directly to the chemical composition of the urine specimen. These were then used to detect the broad presence of...

Simple Summary Neurotropic oncolytic viruses have shown promise for the treatment of brain tumors, as they are naturally capable of entering the brain and selectively killing cancer cells. In this study, the safety, immunologic responses, and anti-tumor effects of intravenous administration of a genetically modified strain of neurotropic oncolytic...

Triple-negative breast cancer (TNBC) remains an unmet need in medicine. Previously, we and others found that interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, EphA3 and EphB2 receptors are over-expressed in almost all patients with glioblastoma (GBM). We performed a first-of-a-kind Phase I clinical trial in dogs with spontaneous gliomas using a co...

Interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, EphA3 and EphB2 receptors are over-expressed collectively in almost all patients with glioblastoma (GBM), and also in spontaneous canine gliomas, the most faithful model of human disease. The four receptors are widely present in various compartments of GBM tumors, including tumor core, infiltrating...

Background Fibrocartilaginous embolic myelopathy (FCE) is a well‐documented condition in dogs although rarely reported in chondrodystrophic breeds. Genetic associations have not been defined. Objectives Define the association of the chondrodystrophy‐associated FGF4L2 retrogene with histopathologically confirmed cases of FCE. Animals Ninety‐eight...

Background In humans, the T2‐weighted (T2W)—fluid‐attenuated inversion recovery (FLAIR) mismatch sign (T2FMM) is a specific imaging biomarker for the isocitrate dehydrogenase 1 (IDH1)‐mutated, 1p/19q non‐codeleted low‐grade astrocytomas (LGA). The T2FMM is characterized by a homogeneous hyperintense T2W signal and a hypointense signal with a hyperi...

Background: Irreversible electroporation (IRE) has been previously investigated in preclinical trials as a treatment for intracranial malignancies. Here, we investigate next generation high-frequency irreversible electroporation (H-FIRE), as both a monotherapy and a combinatorial therapy, for the treatment of malignant gliomas. Methods: Hydrogel...

High-frequency irreversible electroporation (H-FIRE) is a nonthermal tumor ablation technology that kills cancer cells via pulsed electric fields. H-FIRE has been shown to precisely and nonthermally ablate brain tumors while transiently disrupting the peritumoral blood-brain barrier (BBB). The enhanced BBB permeability post-tumor ablation can be ex...

Cancer in companion animals remains the largest contributor to mortality, with cancer incidence increasing as companion animal longevity continues to improve. Chemotherapy, radio-therapy, and surgery are the main treatment modalities for cancer in veterinary medicine, but these therapies harbor significant limitations. As a result of the limitation...

This chapter reviews closed stereotactic brain biopsy procedures, in which a stereotactic headframe is affixed to the animal's head prior to the performance of a diagnostic imaging scan such that the target lesion can be precisely localized and referenced to the external headframe or fiducials. The most common diseases diagnosed by brain biopsy in...

The blood-brain barrier (BBB) presents a formidable obstacle to the effective delivery of systemically administered pharmacological agents to the brain, with ~5% of candidate drugs capable of effectively penetrating the BBB. A variety of biomaterials and therapeutic delivery devices have recently been developed that facilitate drug delivery to the...

Convection-enhanced delivery (CED) is a drug delivery technique used to deliver thera-peutics directly to the brain and is a continually evolving technique to treat glioblastoma. Early versions of CED have proven to result in inadequate drug volume dispersed (V d), increasing the likelihood of tumor recurrence. Fiber optic microneedle devices (FMDs...

Convection-enhanced delivery (CED) is a drug delivery technique used to deliver therapeutics directly to the brain and is a continually evolving technique to treat glioblastoma. Early versions of CED have proven to result in inadequate drug volume dispersed (Vd), increasing the likelihood of tumor recurrence. Fiber optic microneedle devices (FMDs)...

Magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) measures have been described as methods for quantifying spinal cord injury and predicting outcome in dogs with intervertebral disc herniation (IVDH); however, studies comparing methods for selecting regions of interest (ROIs) are currently lacking. The aims of this retrospective, metho...

Glioblastoma is the deadliest malignant brain tumor. Its location behind the blood-brain barrier (BBB) presents a therapeutic challenge by preventing effective delivery of most chemother-apeutics. H-FIRE is a novel tumor ablation method that transiently disrupts the BBB through currently unknown mechanisms. We hypothesized that H-FIRE mediated BBB...

Introduction: Convection-enhanced delivery (CED) has been extensively studied for drug delivery to the brain due to its inherent ability to bypass the blood-brain barrier. Unfortunately, CED has also been shown to inadequately distribute therapeutic agents over a large enough targeted tissue volume to be clinically beneficial. In this study, we exp...

Three juvenile dogs presented with an acute onset of paraspinal hyperesthesia and/or neurologic deficits. These dogs underwent anesthesia for MRI and additional diagnostics. The thoracolumbar MRI in Dog 1 revealed an accumulation of T2-weighted (T2W) hyperintense, T1-weighted (T1W) iso- to hyperintense, contrast enhancing extradural material. The d...

Background Brain tumor therapeutic responses can be quantified from magnetic resonance images (MRI) using 1‐ (1D) and 2‐dimensional (2D) linear and volumetric methods, but few studies in dogs compare these techniques. Hypotheses Linear methods will be obtained faster, but have less agreement than volumetric measurements. Therapeutic response agree...

Background Seizures in the early postoperative period after intracranial surgery may affect outcome in dogs. Objectives To determine the incidence of early postoperative seizures (EPS) in dogs with brain tumors, identify specific risk factors for EPS, and determine if EPS affects outcome. Animals Eighty‐eight dogs that underwent 125 intracranial...

The treatment of CNS disorders suffers from the inability to deliver large therapeutic agents to the brain parenchyma due to protection from the blood-brain barrier (BBB). Herein, we investigated high-frequency pulsed electric field (HF-PEF) therapy of various pulse widths and interphase delays for BBB disruption while selectively minimizing cell a...

Background Orthostatic tremor (OT) is a rare movement disorder characterized by high‐frequency (>12 Hz) involuntary, rhythmic, sinusoidal movements affecting predominantly the limbs while standing. Objective To describe the signalment, presenting complaints, phenotype, diagnostic findings, treatment, and outcome of a large sample of dogs with OT....

The fiberoptic microneedle device (FMD) is a fused-silica microcatheter capable of co-delivery of fluids and light that has been developed for convection-enhanced delivery and photothermal treatments of glioblastoma. Here we investigate the biocompatibility of FMD fragments chronically implanted in the rat brain in the context of evaluating potenti...

In veterinary medicine, irreversible electroporation (IRE) applications have been evaluated in several early phase clinical trials evaluating the safety and feasibility of treatment of solid tumors located within different organ systems. These clinical trials support the use of IRE as a safe and effective alternative treatment option for tumors tha...

Improved therapeutics for malignant brain tumors are urgently needed. High-frequency irreversible electroporation (H-FIRE) is a minimally invasive, nonthermal tissue ablation technique, which utilizes high-frequency, bipolar electric pulses to precisely kill tumor cells. The mechanisms of H-FIRE-induced tumor cell death and potential for cellular r...

New therapeutic strategies are direly needed in the fight against cancer. Over the last decade, several tumor ablation strategies have emerged as stand-alone or combination therapies. Histotripsy is the first completely non-invasive, non-thermal, and non-ionizing tumor ablation method. Histotripsy can produce consistent and rapid ablations, even ne...

Background: High-grade meningioma is an aggressive type of brain cancer that is often recalcitrant to surgery and radiotherapy, leading to poor overall survival. Currently, there are no FDA-approved drugs for meningioma, highlighting the need for new therapeutic options, but development is challenging due to the lack of predictive preclinical mode...

Objective Design 3D printed skull contoured brain biopsy guides (3D‐SCGs) from computed tomography (CT) or T1‐weighted magnetic resonance imaging (T1W MRI). Study Design Feasibility study. Sample Population Five beagle dog cadavers and two client‐owned dogs with brain tumors. Methods Helical CT and T1W MRI were performed on cadavers. Planned tar...

Dissemination of glioma in humans can occur as leptomeningeal nodules, diffuse leptomeningeal lesions, or ependymal lesions. Cerebrospinal fluid (CSF) drop metastasis of glioma is not well-recognized in dogs. Ten dogs with at least two anatomically distinct and histologically confirmed foci of glioma were included in this study. The 10 dogs underwe...

The updated VCOG‐CTCAE v2 guidelines contain several important updates and additions since the last update (v1.1) was released in 2011 and published within Veterinary and Comparative Oncology in 2016. As the Veterinary Cooperative Oncology Group (VCOG) is no longer an active entity, the original authors and contributors to the VCOG‐CTCAE v1.0 and v...

OBJECTIVE Treatment of CNS disorders suffer from the inability to deliver large therapeutic agents to the brain parenchyma due to protection from the blood-brain barrier (BBB). High-frequency electroporation (HFE) employs a series of high voltage pulsed electric fields to disrupt the BBB and/or ablate tumor tissue while sparring proteinaceous struc...

Glioblastoma (GBM) complexity and heterogeneity requires treatment that addresses those pathobiological features. We have been developing selective cytotoxic agents able to target at the same time several GBM-associated factors. The chosen targets are responsible for the disease progression and/or recurrence as well as for resistance to the existin...

The interleukin 13 receptor alpha 2 (IL13RA2) and ephrin type-A receptor 2 (EPHA2) receptors are attractive therapeutic targets, being expressed in ~90% of canine and human gliomas, and absent in normal brain. Clinical trials using an earlier generation IL-13 based cytotoxin showed encouraging clinical effects in human glioma, but met with technica...

Standard treatment for glioblastoma is non-curative and only partially effective. Convection enhanced delivery (CED) was developed as an alternative approach for effective loco-regional delivery of drug via a small catheter inserted into the diseased brain. However, previous CED clinical trials revealed the need for improved catheters for controlle...

Background Quantitative magnetic resonance imaging (QMRI) techniques of magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) provide microstructural information about the spinal cord. Objective Compare neurologic grades using the modified Frankel scale with MTR and DTI measurements in dogs with thoracolumbar intervertebral disk he...

Background Stereotactic brain biopsy (SBB) allows for histopathologic diagnosis of brain tumors. Adverse events (AE) occur in 5 to 29% of dogs after SBB, but risk factors associated with developing AE are poorly described. Objective Identify clinicopathologic, diagnostic imaging, or procedural variables that are associated with AE in dogs after SB...

Background Treatment for glioblastoma (GBM) remains an unmet need in medicine. Novel therapies that address GBM complexity and heterogeneity in particular are warranted. To this end, we target four tumor-associated receptors at a time that span virtually all of the GBM microenvironment including bulk tumor cells, infiltrating tumor cells, neovascul...

Background: The interleukin 13 receptor alpha 2 (IL13RA2) and ephrin type-A receptor 2 (EPHA2) receptors are attractive therapeutic targets, being expressed in ~90% of canine and human gliomas, and absent in normal brain. Clinical trials using an earlier generation IL-13 based cytotoxin showed encouraging clinical effects in human glioma, but met...

In veterinary medicine, quality of life (QOL) assessment instruments, which are important components of the holistic evaluation of treatment success, have largely not included organ-specific concerns that may be broadly relevant to caregivers of dogs with intracranial disease. The objective of this study was to identify core questionnaire items and...

BACKGROUND: The interleukin 13 receptor alpha 2 (IL13RA2) and ephrin type-A receptor 2 (EPHA2) receptors are attractive therapeutic targets, being expressed in ~90% of canine and human gliomas, and absent in normal brain. Clinical trials using an earlier generation IL-13 based cytotoxin showed encouraging clinical effects in human glioma, but met w...

Background Intracranial hypertension (ICH) is often presumptively diagnosed based on clinical or imaging findings. Clinical or imaging surrogates of ICH are not usually validated with reference standard direct intracranial pressure (dICP) recordings. Hypotheses Dogs with brain magnetic resonance imaging (MRI) or clinical features of presumed ICH w...

Background Seizures are a common presenting sign in dogs with brain tumors. Hypothesis/Objectives To investigate the effect of radiotherapy on freedom from brain tumor‐associated seizures and survival time in dogs. Animals Thirty‐two client‐owned dogs with brain tumor‐associated seizures; 18 received medical treatment and radiotherapy, 14 receive...

Sporadic gliomas in companion dogs provide a window on the interaction between tumorigenic mechanisms and host environment. We compared the molecular profiles of canine gliomas with those of human pediatric and adult gliomas to characterize evolutionarily conserved mammalian mutational processes in gliomagenesis. Employing whole-genome, exome, tran...

Primary brain tumors are among the deadliest cancers that remain highly incurable. A need exists for new approaches to tumor therapy that can circumvent the blood brain barrier (BBB), target highly resistant tumors and cancer stem-like cells (CSCs) as well create an anti-cancer immunomodulatory environment. Successful treatments may also require a...

Background Histiocytic sarcoma affecting the central nervous system (CNS HS) in dogs may present as primary or disseminated disease, often characterized by inflammation. Prognosis is poor, and imaging differentiation from other CNS tumors can be problematic. Objective To characterize the clinicopathological inflammatory features, breed predisposit...

Treatment of intracranial disorders suffers from the inability to accumulate therapeutic drug concentrations due to protection from the blood–brain barrier (BBB). Electroporation-based therapies have demonstrated the capability of permeating the BBB, but knowledge of the longevity of BBB disruption (BBBD) is limited. In this study, we quantify the...

A heterogeneous and infiltrating tumor like glioblastoma (GBM) cannot be effectively treated with a single-targeted therapy. Hence, targeting several GBM-associated factors that are responsible for the disease progression and/or recurrence at once is a way to address the issue of tumor heterogeneity. Building on a Phase I clinical trial of a cytoto...

Diffuse gliomas are the commonest of malignant brain tumors with high-grade tumors carrying dismal prognosis. Preclinical models have proven themselves as poor predictors of clinical efficacy, attributed to the lack of a comparable tumor microenvironment. Comparative genomics of canine and human gliomas provide an attractive alternative modality to...

In the dog, primary intracranial neoplasia represents ~2–5% of all cancers and is especially common in certain breeds including English and French bulldogs and Boxers. The most common types of primary intracranial cancer in the dog are meningioma, glioma, and choroid plexus tumors, generally occurring in middle aged to older dogs. Much work has rec...

Clinical translation of novel therapeutics that improve the survival and quality of life of patients with neurological disease remains a challenge, with many investigational drug and device candidates failing in advanced stage clinical trials. Naturally occurring inherited and acquired neurological diseases, such as epilepsy, inborn errors of metab...

Background The intranasal (IN) route for rapid drug administration in patients with brain disorders, including status epilepticus, has been investigated. Status epilepticus is an emergency, and the IN route offers a valuable alternative to other routes, especially when these fail. Objectives To compare IN versus IV midazolam (MDZ) at the same dosa...

Granulomas can “mimic” gliomas on magnetic resonance imaging (MRI) in human patients. The goal of this retrospective study was to report canine brain granulomas that were consistent with glioma based upon MRI, report their histologic diagnosis, and identify MRI criteria that might be useful to distinguish granuloma from glioma. Ten granulomas, init...

Intramedullary signal change (ISC) is a non-specific finding that is frequently observed on magnetic resonance imaging (MRI) examinations of the canine spinal cord. ISC can represent a variety of primary pathological processes such as neoplasms or myelitides or secondary changes such as edema, cysts, gliosis, or myelomalacia. An unusual phenotype of...

Sporadic gliomas in companion dogs provide a window on the interaction between tumorigenic mechanisms and host environment. We compared the molecular profiles of canine gliomas with those of human pediatric and adult gliomas to characterize evolutionarily conserved mammalian mutational processes in gliomagenesis. Employing whole genome-, exome-, tr...

Vertebral osteosarcoma (OSA) is the most common primary vertebral tumor in dogs, however studies examining the survival time after surgical decompression of these tumors are limited. There is also limited information regarding the benefit of adjunctive treatments such as radiation therapy or chemotherapy in these patients. The goal of this study wa...

Background: Despite promising treatments for breast cancer, mortality rates remain high and treatments for metastatic disease are limited. High-frequency irreversible electroporation (H-FIRE) is a novel tumor ablation technique that utilizes high-frequency bipolar electric pulses to destabilize cancer cell membranes and induce cell death. However,...

Background Stereotactic brain biopsy (SBB) is a technique that allows for definitive diagnosis of brain lesions. Little information is available regarding the diagnostic utility of SBB in dogs with intracranial diseases. Objective To investigate the diagnostic accuracy (DA) of SBB in dogs with brain tumors. Animals Thirty‐one client‐owned dogs th...

The present invention relates to the field of optical imaging and therapeutics. More particularly, embodiments of the present invention provide minimally-invasive Fiberoptic Microneedle Devices (FMDs) for light-based therapeutics, which physically penetrate tissue and deliver light directly into the target area below the skin surface. Embodiments o...

Malignant gliomas are incurable tumors and canine spontaneous gliomas are the closest model to human disease. In our Phase I canine clinical trial we are delivering a cocktail targeting IL-13RA2 and EphA2 receptors containing modified bacterial cytotoxins using convection enhanced delivery (CED). Dogs with forebrain gliomas demonstrating IL-13RA2 a...

Glioblastoma is a heterogeneous tumor for which all single-targeted agents failed. Being that a cytotoxic cocktail targeting IL-13RA2 and EphA2 receptors is effective in the treatment of spontaneous gliomas in dogs, we have been further pursuing molecular resection by targeting four tumor-specific/associated receptors at once: IL-13RA2, EphA2, EphA...

Sporadic glioma occurs in companion dogs at frequencies comparable to humans. Genomic characterization of canine glioma has a distinct merit, in that age distribution at the time of diagnosis implies a pediatric disease while the animals are in the adult stage of life. This creates an opportunity to compare relative timing of driver events to that...

In dogs diagnosed with solid tumors, regional lymph node involvement or evidence of distant metastasis can predict worse prognoses and significantly decreased survival. Lymph node size alone has been shown to be insufficient as a predictor for the accurate clinical staging of some canine neoplasia. However, certain regional lymph nodes (including t...

High-frequency irreversible electroporation is a nonthermal method of tissue ablation that uses bursts of 0.5-to 2.0-microsecond bipolar electric pulses to permeabilize cell membranes and induce cell death. High-frequency irreversible electroporation has potential advantages for use in neurosurgery, including the ability to deliver pulses without i...

Sporadic glioma occurs in companion dogs at frequencies comparable to humans, despite differences in environmental exposures and age at time of diagnosis. Despite advances in molecular and phenotypic characterization of adult gliomas, accurate prognostication and curative treatment modalities are often limited by lack of animal translational models...

A variety of inflammatory conditions of unknown cause (meningoencephalomyelitis of unknown etiology—MUE) and neoplastic diseases can affect the central nervous system (CNS) of dogs. MUE can mimic intracranial neoplasia both clinically, radiologically and even in some cases, histologically. Serum immunosignature protein microarray assays have been u...

The National Cancer Institute Comparative Brain Tumor Consortium, Patient Outcomes Working Group, propose a consensus document in support of standardized magnetic resonance imaging protocols for canine brain tumor clinical trials. The intent of this manuscript is to address the widely acknowledged need to ensure canine brain tumor imaging protocols...

Glioma is a unique neoplastic disease that develops exclusively in the central nervous system (CNS) and rarely metastasizes to other tissues. This feature strongly implicates the tumor-host CNS microenvironment in gliomagenesis and tumor progression. We investigated the differences and similarities in glioma biology as conveyed by transcriptomic pa...

High-frequency irreversible electroporation is a nonthermal method of tissue ablation that uses bursts of 0.5- to 2.0-microsecond bipolar electric pulses to permeabilize cell membranes and induce cell death. High-frequency irreversible electroporation has potential advantages for use in neurosurgery, including the ability to deliver pulses without...

While magnetic resonance imaging (MRI) is the gold-standard imaging modality for diagnosis of intracranial neoplasia, computed tomography (CT) remains commonly used for diagnosis and therapeutic planning in veterinary medicine. Despite the routine use of both imaging modalities, comparison of CT and MRI has not been described in the canine patient....