Glioblastoma Multiforme: Clinical Findings, Magnetic Resonance Imaging, and Pathology in Five Dogs

Lipsitz, David; Higgins, Robert; Kortz, Gregg D.; Dickinson, Peter J.; Bollen, Andrew W.; Naydan, Diane K.; Lecouteur, Richard A

doi:10.1354/vp.40-6-659

Cited by 129 publications

(138 citation statements)

References 25 publications

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“…Veterinary trials with toceranib and masitinib have shown benefit in several cancers but have not been reported for brain tumors. Documented overexpression of VEGF, VEGF receptors, and PDGFR alpha in some canine brain tumors108, 109, 110, 111, 112, 113, 114, 115, 116 may justify trials with these or similar small molecules in defined patients.…”

Section: Novel Therapiesmentioning

confidence: 99%

Advances in Diagnostic and Treatment Modalities for Intracranial Tumors

Dickinson

2014

Veterinary Internal Medicne

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Intracranial neoplasia is a common clinical condition in domestic companion animals, particularly in dogs. Application of advances in standard diagnostic and therapeutic modalities together with a broad interest in the development of novel translational therapeutic strategies in dogs has resulted in clinically relevant improvements in outcome for many canine patients. This review highlights the status of current diagnostic and therapeutic approaches to intracranial neoplasia and areas of novel treatment currently in development.

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Section: Novel Therapiesmentioning

confidence: 99%

Advances in Diagnostic and Treatment Modalities for Intracranial Tumors

Dickinson

2014

Veterinary Internal Medicne

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“…In addition, there is a high correlation of neuroimaging features observed with magnetic resonance imaging scans in canine and human GBM, which is used as a diagnostic tool for canine GBM. Peritumoral edema is a consistent finding in both human and canine GBM (30,35).…”

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confidence: 82%

“…Canine GBMs are histopathologically indistinguishable from human GBMs (30). Both are highly infiltrative, contain areas of intratumoral necrosis, pseudopalisading, hemorrhage, cellular pleomorphism, nuclear atypia, abnormal mitosis, and endothelial proliferation (34).…”

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confidence: 99%

Adenoviral-Mediated Gene Transferinto the Canine Brain in Vivo

et al. 2007

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NIH Public Access Author ManuscriptNeurosurgery. Author manuscript; available in PMC 2007 November 27. Published in final edited form as:Neurosurgery. 2007 January ; 60(1): 167-178. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript transgenes elicited immune-mediated long-term survival in a syngeneic intracranial GBM model in rodents. However, the lack of a large GBM animal model makes it difficult to predict the outcome of therapies in humans. Dogs develop spontaneous GBM that closely resemble the human disease; therefore, they constitute an excellent large animal model. We assayed the transduction efficiency of adenoviral vectors (Ads) encoding β-galactosidase (βGal), TK, and Flt3L in J3T dog GBM cells in vitro and in the dog brain in vivo. METHODS:J3T cells were infected with Ads (30 plaque-forming units/cell; 72 h) encoding βGal (Ad-βGal), TK (Ad-TK), or Flt3L (Ad-Flt3L). We determined transgene expression by immunocytochemistry, βGal activity, Flt3L enzyme-linked immunosorbent assay, and TK-induced cell death. Ads were also injected intracranially into the parietal cortex of healthy dogs. We determined cell-type specific transgene expression and immune cell infiltration.RESULTS: Adenoviral-mediated gene transfer of HSV1-TK, Flt3L, and βGal was detected in dog glioma cells in vitro (45% transduction efficiency) and in the dog brain in vivo (10-mm 2 area transduced surrounding each injection site). T cells and macrophages/activated microglia infiltrated the injection sites. Importantly, no adverse clinical or neuropathological side effects were observed. CONCLUSION:We demonstrate effective adenoviral-mediated gene transfer into the brain of dogs in vivo and support the use of these vectors to develop an efficacy trial for canine GBM as a prelude to human trials. KeywordsAdenovirus; Dog; Flt3L; Ganciclovir; Gene therapy; Glioblastoma; HSV1-TK Glioblastoma multiforme (GBM), the most common type of primary brain tumor in adults, is an aggressive and locally invasive tumor. Survival of patients affected by GBM has remained virtually unchanged during the past decades (6−12 mo after diagnosis) despite advances in surgery, radiation, and chemotherapy (8,12,16,24,27,37). Considering the poor prognosis of patients with high-grade glioma, novel therapeutic approaches are needed. Gene therapies are currently being developed and implemented in rodent preclinical models and in clinical trials (2,13,(21)(22)(23)26,38). However, the lack of a large animal model of GBM makes it difficult to predict the outcome of preclinical therapies when translated directly from small rodent brains to those of human patients.Promising results in preclinical rodent experiments have led to human clinical trials, some of which showed therapeutic efficacy (13,26,40,50). Nevertheless, the lack of a preclinical model that closely mimics the human condition and neuroanatomy, in addition to host immune responses to the gene therapy vectors, has hampered the clinical implementation of novel therapies. The small size of the r...

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“…Previously, canine gliomas have been shown to contain common alterations observed in human gliomas, including EGFR expression and amplification, VEGF expression and aberrant p53 overexpression and gene mutation. [12][13][14] Of note, IDH1 and IDH2 are highly conserved between dog and human, with 96.9 and 96.4% identity at the protein level, respectively (HomoloGene). The arginines mutated in human gliomas are also conserved between these species, with canine IDH1 R132 corresponding to human IDH1 R132 and canine IDH2 R238 corresponding to human IDH2 R172.…”

Section: Dear Editormentioning

confidence: 99%

Evidence linking CD44‐positive cells and gemcitabine resistance in pancreatic cancer cells: need for further substantiation

Hagmann

Jesnowski

Löhr

2010

Intl Journal of Cancer

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Human diffuse and anaplastic astrocytomas, well-differentiated and anaplastic oligodendrogliomas and secondary glioblastomas frequently (>70%) contain somatic mutations of the R132 codon of the cytoplasmic NADPþ-dependent isocitrate dehydrogenase (IDH1) or the corresponding R172 codon in its homolog, IDH2. [1][2][3][4][5] Other gliomas, such as primary glioblastomas, contain IDH1 R132 mutations more rarely. 2,4,[6][7][8] Less frequent IDH1 R132 mutations have also been identified in acute myeloid leukemia, 9 prostate cancer 8 and colorectal cancer. 10 IDH1 R132 and IDH2 R172 are conserved in all known species and are important for the enzymatic function of the encoded proteins, 2,4,11 but the significance of these changes in cancer is not fully clear.Canines develop oligodendrogliomas and astrocytomas that resemble the human versions of these tumors. Previously, canine gliomas have been shown to contain common alterations observed in human gliomas, including EGFR expression and amplification, VEGF expression and aberrant p53 overexpression and gene mutation. [12][13][14] Of note, IDH1 and IDH2 are highly conserved between dog and human, with 96.9 and 96.4% identity at the protein level, respectively (HomoloGene). The arginines mutated in human gliomas are also conserved between these species, with canine IDH1 R132 corresponding to human IDH1 R132 and canine IDH2 R238 corresponding to human IDH2 R172. The conservation of some genetic mechanisms of gliomagenesis in dogs, the conserved nature of the IDH genes between human and dog and the high frequency of IDH gene mutations in some human glioma subtypes led us to test whether canine gliomas contain IDH gene mutations.IDH status was determined for 25 formalin-fixed, paraffin-embedded (FFPE) samples from 25 brain tumors that developed spontaneously. Canine glioma types analyzed included 8 oligodendrogliomas, 4 anaplastic oligodendrogliomas, 3 astrocytomas, 3 anaplastic astrocytomas and 2 glioblastomas, all of which have been shown to contain IDH gene mutations in humans, as well as 1 gliomatosis cerebri. Three meningiomas and 1 anaplastic ependymoma were also analyzed. Genomic DNA was isolated using a microtome and the QIAamp DNA FFPE tissue kit (Qiagen, Valencia, CA). H&E slides were created from sections derived from paraffin sections flanking the material used for DNA extraction, and a neuropathologist confirmed the presence of tumor on all slides. Three samples contained 30-50% tumor on both slides, 5 samples contained 50-70% tumor on both slides and all other slides contained 70-100% tumor on both slides. For the 8 samples with less than 70% tumor tissue identified on either slide, DNA was also isolated from scrapings of the tumor area to analyze pure tumor tissue. PCR and sequencing primers were designed using Primer 3 (http://wwwgenome.wi.mit.edu/cgibin/primer/primer3_www.cgi) and synthesized by integrated DNA technologies (Coralville, IA). Primers were designed to amplify a 202 bp region surrounding the canine IDH1 R132 and a 212 bp region surrounding the ca...

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Glioblastoma Multiforme: Clinical Findings, Magnetic Resonance Imaging, and Pathology in Five Dogs

Cited by 129 publications

References 25 publications

Advances in Diagnostic and Treatment Modalities for Intracranial Tumors

Advances in Diagnostic and Treatment Modalities for Intracranial Tumors

Adenoviral-Mediated Gene Transferinto the Canine Brain in Vivo

Evidence linking CD44‐positive cells and gemcitabine resistance in pancreatic cancer cells: need for further substantiation

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