The Association of Fractal Dimension with Vascularity and Clinical Outcomes in Glioblastoma.

BACKGROUND: Growing evidence indicates fractal analysis (FA) has potential as a computational tool to assess tumor microvasculature in glioblastoma (GBM). As fractal parameters of microvasculature have shown to be reliable quantitative biomarkers in brain tumors, there has been similar success in measuring the architecture of tumor tissue using FA in other tumor types. However, evaluating fractal parameters of tissue structure in relation to the microvasculature has not yet been implemented in GBM. We aimed to assess the utility of this methodology in quantifying structural characteristics of GBM cytoarchitecture and vascularity by correlating fractal parameters with gene expression. METHODS: Formalin-fixed paraffin-embedded specimens were retrospectively collected from 43 patients following resection of a newly diagnosed GBM; 4 normal brain specimens were obtained from epilepsy surgeries as controls. Tumor samples were processed using FA employing a software-based box-counting method algorithm and custom messenger RNA expression assays. Fractal parameters were then correlated with clinical features, outcomes, and a panel of 92 genes associated with vascularity and angiogenesis. RESULTS: Statistical analysis demonstrated that fractal-based indices were not adequate parameters for distinction of GBM cytoarchitecture compared with normal brain specimens. Correlation analysis of our gene expression findings suggested that hematoxylin and eosin-based FA may have adequate sensitivity to detect associations with vascular gene expression. CONCLUSIONS: The combination of neuropathological assessment and histology does not provide optimized data for FA in GBM. However, an association between FA and gene expression in GBM of genes pertaining to cytoarchitecture and angiogenesis warrants further investigation.

Non-invasive in situ Visualization of the Murine Cranial Vasculature.

Understanding physiologic and pathologic central nervous system function depends on our ability to map the entire in situ cranial vasculature and neurovascular interfaces. To accomplish this, we developed a non-invasive workflow to visualize murine cranial vasculature via polymer casting of vessels, iterative sample processing and micro-computed tomography, and automatic deformable image registration, feature extraction, and visualization. This methodology is applicable to any tissue and allows rapid exploration of normal and altered pathologic states.

Tentorial venous anatomy of mice and humans.

We recently described a transtentorial venous system (TTVS), which to our knowledge was previously unknown, connecting venous drainage throughout the brain in humans. Prior to this finding, it was believed that the embryologic tentorial plexus regresses, resulting in a largely avascular tentorium. Our finding contradicted this understanding and necessitated further investigation into the development of the TTVS. Herein, we sought to investigate mice as a model to study the development of this system. First, using vascular casting and ex vivo micro-CT, we demonstrated that this TTVS is conserved in adult mice. Next, using high-resolution MRI, we identified the primitive tentorial venous plexus in the murine embryo at day 14.5. We also found that, at this embryologic stage, the tentorial plexus drains the choroid plexus. Finally, using vascular casting and micro-CT, we found that the TTVS is the dominant venous drainage in the early postnatal period (P8). Herein, we demonstrated that the TTVS is conserved between mice and humans, and we present a longitudinal study of its development. In addition, our findings establish mice as a translational model for further study of this system and its relationship to intracranial physiology.

Multimodal Atlas of the Murine Inner Ear: From Embryo to Adult.

The inner ear is a complex organ housed within the petrous bone of the skull. Its intimate relationship with the brain enables the transmission of auditory and vestibular signals via cranial nerves. Development of this structure from neural crest begins in utero and continues into early adulthood. However, the anatomy of the murine inner ear has only been well-characterized from early embryogenesis to post-natal day 6. Inner ear and skull base development continue into the post-natal period in mice and early adulthood in humans. Traditional methods used to evaluate the inner ear in animal models, such as histologic sectioning or paint-fill and corrosion, cannot visualize this complex anatomy in situ. Further, as the petrous bone ossifies in the postnatal period, these traditional techniques become increasingly difficult. Advances in modern imaging, including high resolution Micro-CT and MRI, now allow for 3D visualization of the in situ anatomy of organs such as the inner ear. Here, we present a longitudinal atlas of the murine inner ear using high resolution ex vivo Micro-CT and MRI.

Mannan-BAM, TLR Ligands, Anti-CD40 Antibody (MBTA) Vaccine Immunotherapy: A Review of Current Evidence and Applications in Glioblastoma.

The foundation of precision immunotherapy in oncology is rooted in computational biology and patient-derived sample sequencing to enrich for and target immunogenic epitopes. Discovery of these tumor-specific epitopes through tumor sequencing has revolutionized patient outcomes in many types of cancers that were previously untreatable. However, these therapeutic successes are far from universal, especially with cancers that carry high intratumoral heterogeneity such as glioblastoma (GBM). Herein, we present the technical aspects of Mannan-BAM, TLR Ligands, Anti-CD40 Antibody (MBTA) vaccine immunotherapy, an investigational therapeutic that potentially circumvents the need for in silico tumor-neoantigen enrichment. We then review the most promising GBM vaccination strategies to contextualize the MBTA vaccine. By reviewing current evidence using translational tumor models supporting MBTA vaccination, we evaluate the underlying principles that validate its clinical applicability. Finally, we showcase the translational potential of MBTA vaccination as a potential immunotherapy in GBM, along with established surgical and immunologic cancer treatment paradigms.

Applications for nitric oxide in halting proliferation of tumor cells.

Tumor resistance to cytotoxic therapeutics coupled with dose-limiting toxicity is a serious hurdle in the field of medical oncology. In the face of this obstacle, nitric oxide has emerged as a powerful adjuvant for the hypersensitization of tumors to more traditional chemo- and radio-therapeutics. Furthermore, emerging evidence indicates that nitric oxide donors have the potential to function independently in the clinical management of cancer. Herein, we discuss the role of nitric oxide in cancer and the potential for nitric oxide donors to support conventional therapeutics.