Carlstrom, Lucas P.

Abstract Glioblastoma (GBM) is a rapidly fatal malignancy typically treated with radiation and temozolomide (TMZ), an alkylating chemotherapeutic. These cytotoxic therapies cause oxidative stress and DNA damage, yielding a senescent-like state of replicative arrest in surviving tumor cells. Unfortunately, recurrence is inevitable and may be driven by surviving tumor cells eventually escaping senescence. A growing number of so-called “senolytic” drugs have been recently identified that are defined by their ability to selectively eliminate senescent cells. A growing inventory of senolytic drugs is under consideration for several diseases associated with aging, inflammation, DNA damage, as well as cancer. Ablation of senescent tumor cells after radiation and chemotherapy could help mitigate recurrence by decreasing the burden of residual tumor cells at risk of recurrence. This strategy has not been previously explored for GBM. We evaluated a panel of 10 previously described senolytic drugs to determine whether any could exhibit selective activity against human GBM persisting after exposure to radiation or TMZ. Three of the 10 drugs have known activity against BCL-XL and preferentially induced apoptosis in radiated or TMZ-treated glioma. This senolytic activity was observed in 12 of 12 human GBM cell lines. Efficacy could not be replicated with BCL-2 inhibition or senolytic agents acting against other putative senolytic targets. Knockdown of BCL-XL decreased survival of radiated GBM cells, whereas knockdown of BCL-2 or BCL-W yielded no senolytic effect. Implications: These findings imply that molecularly heterogeneous GBM lines share selective senescence-induced BCL-XL dependency increase the significance and translational relevance of the senolytic therapy for latent glioma.

Abstract Introduction Skull base neuroanatomy is classically taught using surgical atlases. Although these texts are critical and rich resources for learning three-dimensional (3D) relationships between key structures, we believe they could be optimized and complemented with step-by-step anatomical dissections to fully meet the learning needs of trainees. Methods Six sides of three formalin-fixed latex-injected specimens were dissected under microscopic magnification. A far lateral craniotomy was performed by each of three neurosurgery resident/fellow at varying stages of training. The study objective was the completion and photodocumentation of the craniotomy to accompany a stepwise description of the exposure to provide a comprehensive, intelligible, and anatomically oriented resource for trainees at any level. Illustrative case examples were prepared to supplement approach dissections. Results The far lateral approach provides a wide and versatile corridor for posterior fossa operation, with access spanning the entire cerebellopontine angle (CPA), foramen magnum, and upper cervical region. Key Steps Include The study includes the following steps: positioning and skin incision, myocutaneous flap, placement of burr holes and sigmoid trough, fashioning of the craniotomy bone flap, bilateral C1 laminectomy, occipital condyle/jugular tubercle drilling, and dural opening. Conclusion Although more cumbersome than the retrosigmoid approach, a far lateral craniotomy offers unparalleled access to lesions centered lower or more medially in the CPA, as well as those with significant extension into the clival or foramen magnum regions. Dissection-based neuroanatomic guides to operative approaches provide a unique and rich resource for trainees to comprehend, prepare for, practice, and perform complex cranial operations, such as the far lateral craniotomy.

Abstract Introduction Although endonasal endoscopic approaches (EEA) to the orbit have been previously reported, a didactic resource for educating neurosurgery and otolaryngology trainees regarding the pertinent anatomy, techniques, and decision-making pearls is lacking. Methods Six sides of three formalin-fixed, color latex–injected cadaveric specimens were dissected using 4-mm 0- and 30-degree rigid endoscopes, as well as standard endoscopic equipment, and a high-speed surgical drill. The anatomical dissection was documented in stepwise three-dimensional (3D) endoscopic images. Following dissection, representative case applications were reviewed. Results EEA to the orbit provides excellent access to the medial and inferior orbital regions. Key steps include positioning and preoperative considerations, middle turbinate medialization, uncinate process and ethmoid bulla removal, complete ethmoidectomy, sphenoidotomy, maxillary antrostomy, lamina papyracea resection, orbital apex and optic canal decompression, orbital floor resection, periorbita opening, dissection of the extraconal fat, and final exposure of the orbit contents via the medial-inferior recti corridor. Conclusion EEA to the orbit is challenging, in particular for trainees unfamiliar with nasal and paranasal sinus anatomy. Operatively oriented neuroanatomy dissections are crucial didactic resources in preparation for practical endonasal applications in the operating room (OR). This approach provides optimal exposure to the inferior and medial orbit to treat a wide variety of pathologies. We describe a comprehensive step-by-step curriculum directed to any audience willing to master this endoscopic skull base approach.

Abstract The complex and dynamic system of fluid flow through the perivascular and interstitial spaces of the CNS has new-found implications for neurological diseases. CSF movement throughout the CNS parenchyma is more dynamic than could be explained via passive diffusion mechanisms alone. Indeed, a semistructured glial-lymphatic (glymphatic) system of astrocyte-supported extracellular perivascular channels serves to directionally channel extracellular fluid, clearing metabolites and peptides to optimize neurological function. Clinical studies of the glymphatic network have to date proven challenging, with most data gleaned from rodent models and post-mortem investigations. However, increasing evidence suggests that disordered glymphatic function contributes to the pathophysiology of CNS ageing, neurodegenerative disease and CNS injuries, as well as normal pressure hydrocephalus. Unlocking such pathophysiology could provide important avenues towards novel therapeutics. We here provide a multidisciplinary overview of glymphatics and critically review accumulating evidence regarding its structure, function and hypothesized relevance to neurological disease. We highlight emerging technologies of relevance to the longitudinal evaluation of glymphatic function in health and disease. Finally, we discuss the translational opportunities and challenges of studying glymphatic science.