Faculty Bibliography

Importance:New treatments are needed to improve the prognosis of patients with recurrent high-grade glioma. Objective:To compare overall survival for patients receiving tumor resection followed by vocimagene amiretrorepvec (Toca 511) with flucytosine (Toca FC) vs standard of care (SOC). Design, Setting, and Participants:A randomized, open-label phase 2/3 trial (TOCA 5) in 58 centers in the US, Canada, Israel, and South Korea, comparing posttumor resection treatment with Toca 511 followed by Toca FC vs a defined single choice of approved (SOC) therapies was conducted from November 30, 2015, to December 20, 2019. Patients received tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma. Interventions:Patients were randomized 1:1 to receive Toca 511/FC (n = 201) or SOC control (n = 202). For the Toca 511/FC group, patients received Toca 511 injected into the resection cavity wall at the time of surgery, followed by cycles of oral Toca FC 6 weeks after surgery. For the SOC control group, patients received investigators' choice of single therapy: lomustine, temozolomide, or bevacizumab. Main Outcomes and Measures:The primary outcome was overall survival (OS) in time from randomization date to death due to any cause. Secondary outcomes reported in this study included safety, durable response rate (DRR), duration of DRR, durable clinical benefit rate, OS and DRR by IDH1 variant status, and 12-month OS. Results:All 403 randomized patients (median [SD] age: 56 [11.46] years; 62.5% [252] men) were included in the efficacy analysis, and 400 patients were included in the safety analysis (3 patients on the SOC group did not receive resection). Final analysis included 271 deaths (141 deaths in the Toca 511/FC group and 130 deaths in the SOC control group). The median follow-up was 22.8 months. The median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (hazard ratio, 1.06; 95% CI 0.83, 1.35; P = .62). The secondary end points did not demonstrate statistically significant differences. The rates of adverse events were similar in the Toca 511/FC group and the SOC control group. Conclusions and Relevance:Among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or other efficacy end points. Trial Registration:ClinicalTrials.gov Identifier: NCT02414165.

PURPOSE/OBJECTIVE:Metastases should be considered in a patient with a cancer history and a sellar/suprasellar lesion, as this diagnosis can change the management strategy in such patients. Once the diagnosis is established, stereotactic radiosurgery (SRS) can be a safe and effective approach for these patients. METHODS:This case series describes five patients with pituitary metastases managed with GKRS at a single institution, taken from our prospective registry. All patients had SRS using the Gamma Knife Perfexion or Icon (Elekta), according to our standard institutional protocol. The optic nerves and chiasm were contoured, and the plan was adjusted to restrict dose to the optic apparatus as necessary. The tumor margin doses delivered were 11 Gy, 12 Gy, 14 Gy, 18 Gy (3 sessions of 6 Gy), and 12 Gy at the 50% isodose line. RESULTS:In this series, all sellar metastases were treated successfully with good radiographic and clinical response. The histology of the tumors included endometrial, gastrointestinal, and lung adenocarcinomas. Typically, histology is taken into consideration when choosing the treatment dose, along with size and location. In these patients, however, the dose used for the sellar metastases was chosen primarily for visual safety. This was typically lower than the dose for brain metastases in other locations. CONCLUSION/CONCLUSIONS:SRS provides an alternative treatment approach for sellar/suprasellar metastases with excellent local control, symptom improvement and maintenance of systemic therapy as desired. As such, CNS failure is rarely the proximate cause of demise in pituitary metastases provided that endocrinopathies are recognized and managed appropriately.

Coronavirus disease 2019 (COVID-19) is associated with a high inflammatory burden that can induce severe respiratory disease among other complications; vascular and neurological damage has emerged as a key threat to COVID-19 patients. Risk of severe infection and mortality increases with age, male sex, and comorbidities including cardiovascular disease, hypertension, obesity, diabetes, and chronic pulmonary disease. We review clinical and neuroradiological findings in five patients with COVID-19 who suffered severe neurological disease and illustrate the pathological findings in a 7-year-old boy with COVID-19-induced encephalopathy whose brain tissue sample showed angiocentric mixed mononuclear inflammatory infiltrate. We summarize the structural and functional properties of the virus including the molecular processes that govern the binding to its membrane receptors and cellular entry. In addition, we review clinical and experimental evidence in patients and animal models that suggests coronaviruses enter into the central nervous system (CNS), either via the olfactory bulb or through hematogenous spread. We discuss suspected pathophysiological mechanisms including direct cellular infection and associated recruitment of immune cells and neurovirulence, at least in part, mediated by cytokine secretion. Moreover, contributing to the vascular and neurological injury, coagulopathic disorders play an important pathogenic role. We survey the molecular events that contribute to the thrombotic microangiopathy. We describe the neurological complications associated with COVID-19 with a focus on the potential mechanisms of neurovascular injury. Our thesis is that following infection, three main pathophysiological processes-inflammation, thrombosis, and vascular injury-are responsible for the neurological damage and diverse pathology seen in COVID-19 patients.

Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific 'GBM-on-a-Chip' microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-β1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.

The concept of thermal therapy toward the treatment of brain tumors has gained traction in recent years. Traditionally, thermal therapy has been subdivided into hyperthermia, with mild elevation of temperature in treated tissue above the physiologic baseline; and thermal ablation, where even higher temperatures are achieved. The recent surge in interest has been driven by the use of novel thermal ablation technologies, including laser interstitial thermal therapy (LITT), that are implemented in brain tumor treatment. Here, we review previous scientific literature on the biologic effects of thermal therapy on brain tumors, with an emphasis on glioblastoma (GBM), an aggressive brain malignancy. In addition, we present in vitro evidence from our laboratory that even moderate elevations in temperature achieved in the penumbra around laser-ablated coagulum may also produce GBM cell death. While much remains to be elucidated in terms of the biology of thermal therapy, we propose that it is a welcome addition to the neuro-oncology armamentarium, in particular with regard to GBM, which is generally resistant to current chemoradiotherapeutic regimens.

OBJECTIVE:Although a growing body of data support the functional connectivity between the precuneus and the medial temporal lobe during states of resting consciousness as well as during a diverse array of higher-order functions, direct structural evidence on this subcortical circuitry is scarce. Here, the authors investigate the very existence, anatomical consistency, morphology, and spatial relationships of the cingulum bundle V (CB-V), a fiber tract that has been reported to reside close to the inferior arm of the cingulum (CingI). METHODS:Fifteen normal, formalin-fixed cerebral hemispheres from adults were treated with Klingler's method and subsequently investigated through the fiber microdissection technique in a medial to lateral direction. RESULTS:A distinct group of fibers is invariably identified in the subcortical territory of the posteromedial cortex, connecting the precuneus and the medial temporal lobe. This tract follows the trajectory of the parietooccipital sulcus in a close spatial relationship with the CingI and the sledge runner fasciculus. It extends inferiorly to the parahippocampal place area and retrosplenial complex area, followed by a lateral curve to terminate toward the fusiform face area (Brodmann area [BA] 37) and lateral piriform area (BA35). Taking into account the aforementioned subcortical architecture, the CB-V allegedly participates as a major subcortical stream within the default mode network, possibly subserving the transfer of multimodal cues relevant to visuospatial, facial, and mnemonic information to the precuneal hub. Although robust clinical evidence on the functional role of this stream is lacking, the modern neurosurgeon should be aware of this tract when manipulating cerebral areas en route to lesions residing in or around the ventricular trigone. CONCLUSIONS:Through the fiber microdissection technique, the authors were able to provide original, direct structural evidence on the existence, morphology, axonal connectivity, and correlative anatomy of what proved to be a discrete white matter pathway, previously described as the CB-V, connecting the precuneus and medial temporal lobe.

Chiari I malformation is the herniation of cerebellar tonsils below the level of the foramen magnum due to congenital or acquired pathologies. Acquired Chiari I malformation (ACM) may occur secondary to space-occupying lesions (SOLs), such as intracranial tumors due to elevated intracranial pressure (ICP), and can be accompanied by syringomyelia. ACM and syringomyelia have been shown to resolve after resection of the SOL, without the need for adjuvant posterior fossa decompression. The vast majority of SOLs leading to ACM have been reported in the posterior fossa, thus exerting a direct mass effect on the cerebellum. Supratentorial SOLs leading to ACM are much less frequent but, when present, are most commonly parieto-occipital. We report a rare case of a large anterior left frontal, parasagittal meningioma causing ACM and syringomyelia. These findings resolved following the resection of the meningioma, with no further surgical intervention. Our case demonstrates that ACM can occur secondary to an anterior supratentorial mass and further supports the idea that decompression of the posterior fossa is not required for the resolution of intracranial tumor-associated ACM and syringomyelia.

The transsphenoidal corridor for pituitary adenoma surgery was established as early as 1906 by Schloffer and was subsequently refined by Cushing throughout the early 20thcentury [1]. The use of intraoperative magnetic resonance imaging (iMRI) in endoscopic endonasal transsphenoidal resections, however, is a relatively contemporary addition to the surgical treatment of pituitary tumors. The morbidity of these cases has decreased over the years in light of advances in intraoperative navigation as well as improvements in endoscope dynamics and surgical instruments. Despite such improvements, a substantial number of patients require repeat surgeries or subsequent radiotherapy for residual and/or recurrent disease. This can be largely attributed to cavernous sinus invasion or suprasellar extension, which pose technical challenges to achieving gross total resections (GTRs). The rate of GTR for pituitary tumors cited in the literature varies from 59-88%.[2-3] The advantage of iMRI is that it provides the surgeon with immediate feedback regarding their progress and ability to safely achieve GTR which, in pituitary surgery, is critical for long term cure. Additionally, although there is concern for increased risk of postoperative endocrine dysfunction, Zhibin et al prove that this is not necessarily the case. In their series, 133 patients who underwent iMRI had higher rates of GTR and did not have a significant difference in postoperative hypopituitarism. [4] This study includes a combined retrospective and prospective comparative analysis of 238 patients who underwent transsphenoidal resection of a pituitary tumor from January 2013 until May 2019. All patients were operated on by one of four experienced neurosurgeons and one of three experienced otolaryngologists. There were 203 patients who did not undergo iMRI and 25 patients who did. A 3 tesla MRI magnet was used in all cases. All intraoperative images were read and interpreted by a senior neuroradiologist at our institution. Amongst the two groups, there was no statistically significant difference in patient age (p = 0.488), tumor size (microadenoma versus macroadenoma, p = 0.878), and primary versus recurrent tumor (p = 0.837). The use of iMRI did not yield a decrease in the length of stay (4.84 days in the no iMRI group and 5 in the iMRI group, p = 0.777). There were zero cases of a return to the OR for residual tumor in the intraoperative MRI group versus the non-MRI group. However, this did not reach statistical significance. This study did not yield a statistically significant difference in GTR (p = 0.75), near total resection (NTR, p = 0.167), or subtotal resection (p = 0.083). This is likely secondary to a low sample size and therefore power in the iMRI group. Finally, there was no significant difference in the number of patients requiring postoperative DDAVP (p = 0.099) or hydrocortisone (p = 0.873) after discharge. Preliminary results reveal a potential benefit of iMRI use to assess for residual disease which can be addressed immediately during the initial operation, thus decreasing the need for re-operations. Furthermore, the ability to correlate intraoperative findings with an intraoperative structure may lead to more precise identification and preservation of normal gland, which can possibly decrease the incidence of postoperative endocrine dysfunction

Direct access through the sinuses and nasopharyngeal mucosa in the endoscopic endonasal approach (EEA) raises concern for a contaminated operative environment and subsequent infection. The reported rate of meningitis in endoscopic endonasal skull base surgery in the literature ranges from 0.7 to 3.0% [1, 2]. The only factor identified as being independently associated with meningitis in a statistically significant manner is cerebrospinal fluid (CSF) leak [1-5]. However, many centers performing high volume of EEAs use postoperative antibiotic coverage independent of the presence intraoperative or postoperative CSF leak. Furthermore, while meningitis remains a severe concern, most centers use postoperative gram-positive coverage to prevent toxic shock syndrome caused by Staphylococcus aureus infection in the setting of prolonged nasal packing. There are currently a multitude of approaches regarding perioperative antibiotic coverage in EEAs [1-4]. Given the lack of consensus in the literature and our experience regarding the benefit of discontinuation of prolonged prophylactic antibiotics throughout the breadth of neurosurgical procedures, we sought to analyze the need for postoperative antibiotics in EEAs further. As such, we performed a prospective analysis compared with a retrospective cohort to delineate whether discontinuation of postoperative antibiotics leads to a change in the rate of postoperative infections. The retrospective cohort consisted of patients who underwent an EEA from January 1, 2013 to May 31, 2019. These patients all received postoperative antibiotics while nasal packing was in place (median 7 days). Starting on April 1, 2019 until August 1, 2019, we discontinued postoperative antibiotic use. Patients from this group made up the prospective cohort. The retrospective cohort had 315 patients (66% pituitary macroadenomas vs. 7% microadenomas, 4% meningiomas, 4% craniopharyngiomas, 4% chordomas, and 15% others) while the prospective group had 23 patients (57% pituitary macroadenomas, 30% craniopharyngiomas, 8% meningiomas/chordomas, and 5% others). The primary endpoint was rate of postoperative infections and specifically, meningitis and multidrug resistant organism (MDRO) infections. There was no statistically significant difference in the use of nasal packing (p = 0.085), intraoperative CSF leak (p = 0.133), and postoperative CSF leak (p = 0.507) between the two groups. There was also no significant difference in the number of patients with positive preoperative MSSA and MRSA nasal swabs (p = 0.622). There was a significant decrease in the number of patients discharged with antibiotics (55.1% in the retrospective and 4.5% in the prospective group, p = 0.000). The number of patients with positive blood cultures (p = 0.701) and positive urine cultures (p = 0.691) did not differ significantly between the two groups. Finally, there was no statistically significant difference in postoperative CSF infections (p = 0.34) or MDRO infections (0.786) between the two groups. We describe promising preliminary results that demonstrate that discontinuation of postoperative antibiotics in EEAs do not lead to a statistically significant increase in the rate of postoperative CSF or MDRO infections. The previous algorithm for postoperative antibiotic coverage in our center, like many centers, called for gram-positive coverage, which may have contributed to the overall preponderance of gram-negative meningitis cases in this cohort

Background/UNASSIGNED:Glioma is a family of primary brain malignancies with limited treatment options and in need of novel therapies. We previously demonstrated that the adhesion G protein-coupled receptor GPR133 (ADGRD1) is necessary for tumor growth in adult glioblastoma, the most advanced malignancy within the glioma family. However, the expression pattern of GPR133 in other types of adult glioma is unknown. Methods/UNASSIGNED:We used immunohistochemistry in tumor specimens and non-neoplastic cadaveric brain tissue to profile GPR133 expression in adult gliomas. Results/UNASSIGNED:We show that GPR133 expression increases as a function of WHO grade and peaks in glioblastoma, where all tumors ubiquitously express it. Importantly, GPR133 is expressed within the tumor bulk, as well as in the brain-infiltrating tumor margin. Furthermore, GPR133 is expressed in both isocitrate dehydrogenase (IDH) wild-type and mutant gliomas, albeit at higher levels in IDH wild-type tumors. Conclusion/UNASSIGNED:The fact that GPR133 is absent from non-neoplastic brain tissue but de novo expressed in glioma suggests that it may be exploited therapeutically.