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The brain has long been thought to lack a lymphatic drainage system. Recent studies, however, show the presence of a brain-wide paravascular system appropriately named the glymphatic system based on its similarity to the lymphatic system in function and its dependence on astroglial water flux. Besides the clearance of cerebrospinal fluid and interstitial fluid, the glymphatic system also facilitates the clearance of interstitial solutes such as amyloid-β and tau from the brain. As cerebrospinal fluid and interstitial fluid are cleared through the glymphatic system, eventually draining into the lymphatic vessels of the neck, this continuous fluid circuit offers a paradigm shift in osteopathic manipulative medicine. For instance, manipulation of the glymphatic-lymphatic continuum could be used to promote experimental initiatives for nonpharmacologic, noninvasive management of neurologic disorders. In the present review, the authors describe what is known about the glymphatic system and identify several osteopathic experimental strategies rooted in a mechanistic understanding of the glymphatic-lymphatic continuum.

Tumor protein 53 (p53) regulates fundamental pathways of cellular growth and differentiation. Aberrant p53 expression in glioblastoma multiforme, a terminal brain cancer, has been associated with worse patient outcomes and decreased chemosensitivity. Therefore, correctly identifying p53 status in glioblastoma is of great clinical significance. p53 immunohistochemistry is used to detect pathological presence of the TP53 gene product. Here, we examined the relationship between p53 immunoreactivity and TP53 mutation status by DNA Sanger sequencing in adult glioblastoma. Of 41 histologically confirmed samples, 27 (66%) were immunopositive for a p53 mutation via immunohistochemistry. Utilizing gene sequencing, we identified only eight samples (20%) with TP53 functional mutations and one sample with a silent mutation. Therefore, a ≥10% p53 immunohistochemistry threshold for predicting TP53 functional mutation status in glioma is insufficient. Implementing this ≥10% threshold, we demonstrated a remarkably low positive-predictive value (30%). Furthermore, the sensitivity and specificity with ≥10% p53 immunohistochemistry to predict TP53 functional mutation status were 100% and 42%, respectively. Our data suggests that unless reliable sequencing methodology is available for confirming TP53 status, raising the immunoreactivity threshold would increase positive and negative predictive values as well as the specificity without changing the sensitivity of the immunohistochemistry assay.

Glioblastoma is the most frequent primary brain tumor in adults, with a dismal prognosis despite aggressive resection, chemotherapeutics, and radiotherapy. Although understanding of the molecular pathogenesis of glioblastoma has progressed in recent years, therapeutic options have failed to significantly change overall survival or progression-free survival. Thus, researchers have begun to explore immunomodulation as a potential strategy to improve clinical outcomes. The application of oncolytic virotherapy as a novel biological to target pathogenic signaling in glioblastoma has brought new hope to the field of neuro-oncology. This class of immunotherapeutics combines selective cancer cell lysis prompted by virus induction while promoting a strong inflammatory antitumor response, thereby acting as an effective in situ tumor vaccine. Several investigators have reported the efficacy of experimental oncolytic viruses as demonstrated by improved long-term survival in cancer patients with advanced disease. Newcastle disease virus (NDV) is one of the most well-researched oncolytic viruses known to affect a multitude of human cancers, including glioblastoma. Preclinical in vitro and in vivo studies as well as human clinical trials have demonstrated that NDV exhibits oncolytic activity against glioblastoma, providing a promising avenue of potential treatment. Herein, the authors provide a detailed discussion on NDV as a mode of therapy for glioblastoma. They discuss the potential therapeutic pathways associated with NDV as demonstrated by in vitro and in vivo experiments as well as results from human trials. Moreover, they discuss current challenges, potential solutions, and future perspectives in utilizing NDV in the treatment of glioblastoma.

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