RESUMEN
As the most common and deadly of primary brain tumors, malignant gliomas have earned their place within one of the most multifaceted and heavily-funded realms of medical research. Numerous avenues of pre-clinical investigation continue to provide valuable insight, but modeling the complex evolution and behavior of these tumors within a host under simulated circumstances may pose challenges to extrapolation of data. Remarkably, certain breeds of pet dogs spontaneously and sporadically develop high grade gliomas that follow similar incidence, treatment, and outcome patterns as their human glioma counterparts. The most malignant of these tumors have been refractory to limited treatment options despite aggressive treatment; outcomes are dismal with median survivals of just over 1 year in humans and 2 months in dogs. Novel treatments are greatly needed and combination therapies appear to hold promise. This clinical protocol, a dose-escalating phase I study in dogs with sporadic malignant glioma, represents a first in comparative oncology and combination immunotherapy. The trial will evaluate M032, an Interleukin-12 expressing Herpes Simplex virus, alone and combined with a checkpoint inhibitor, Indoximod. Extensive pre-clinical work has demonstrated safety of intracranial M032 administration in mice and non-human primates. M032 is currently being tested in humans with high-grade malignant gliomas. Thus, in a novel fashion, both canine and human trials will proceed concurrently allowing a direct "head-to-head" comparison of safety and efficacy. We expect this viral oncolytic therapy to be as safe as it is in human patients and M032 to (a) infect and kill glioma cells, producing a virus and tumor cell antigen-rich debris field; (b) provide an adjuvant effect due to liberation of viral DNA, which is rich in unmethylated CpG sequences that "toggle" TLR-9 receptors; and (c) express IL-12 locally, stimulating induction of TH1 lymphocytes. The resultant immune-mediated anti-viral responses should, through cross-epitope spreading, translate into a strong response to tumor antigens. The ability to compare human and dog responses in real time affords the most stringent test of suitability of the dog as an informative model of human brain tumors. Subsequent studies will allow canine trials to properly inform the design of human trials.
RESUMEN
OBJECTIVE: Overlapping surgery, a long-standing practice within academic neurosurgery centers nationwide, has recently come under scrutiny from the government and media as potentially harmful to patients. Therefore, the objective of this systematic review and meta-analysis is to determine the safety of overlapping neurosurgical procedures. METHODS: The authors performed a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A review of PubMed and Medline databases was undertaken with the search phrase "overlapping surgery AND neurosurgery AND outcomes." Data regarding patient demographics, type of neurosurgical procedure, outcomes, and complications were extracted from each study. The principle summary measure was odds ratio (OR) of the association of overlapping versus non-overlapping surgery with outcomes. RESULTS: The literature search yielded a total of 36 studies, of which 5 studies met inclusion criteria and were included in this study. These studies included a total of 25,764 patients undergoing neurosurgical procedures. Overlapping surgery was associated with an increased likelihood of being discharged home (OR, 1.32; 95% confidence interval [CI], 1.20-1.44; P < 0.001) and a reduced 30-day unexpected return to the operating room (OR, 0.79; 95% CI, 0.72-0.87; P < 0.001). Overlapping surgery did not significantly affect OR of length of surgery, 30-day mortality, or 30-day readmission. CONCLUSIONS: Overlapping neurosurgical procedures were not associated with worse patient outcomes. In addition, prospective studies are needed to assess the safety overlapping procedures.
