Faculty Bibliography

High-grade glioma (HGG), a deadly primary brain malignancy, manifests radioresistance mediated by cell-intrinsic and microenvironmental mechanisms. High levels of the cytokine transforming growth factor-beta (TGF-beta) in HGG promote radioresistance by enforcing an effective DNA damage response and supporting glioma stem cell self-renewal. Our analysis of HGG TCGA data and immunohistochemical staining of phosphorylated Smad2, which is the main transducer of canonical TGF-beta signaling, indicated variable levels of TGF-beta pathway activation across HGG tumors. These data suggest that evaluating the putative benefit of inhibiting TGF-beta during radiotherapy requires personalized screening. Thus, we used explant cultures of seven HGG specimens as a rapid, patient-specific ex vivo platform to test the hypothesis that LY364947, a small molecule inhibitor of the TGF-beta type I receptor, acts as a radiosensitizer in HGG. Immunofluorescence detection and image analysis of gamma-H2AX foci, a marker of cellular recognition of radiation-induced DNA damage, and Sox2, a stem cell marker that increases post-radiation, indicated that LY364947 blocked these radiation responses in five of seven specimens. Collectively, our findings suggest that TGF-beta signaling increases radioresistance in most, but not all, HGGs. We propose that short-term culture of HGG explants provides a flexible and rapid platform for screening context-dependent efficacy of radiosensitizing agents in patient-specific fashion. This time- and cost-effective approach could be used to personalize treatment plans in HGG patients.

PURPOSE: To pool data across multiple institutions internationally and report on the cumulative experience of brainstem stereotactic radiosurgery (SRS). METHODS AND MATERIALS: Data on patients with brainstem metastases treated with SRS were collected through the International Gamma Knife Research Foundation. Clinical, radiographic, and dosimetric characteristics were compared for factors prognostic for local control (LC) and overall survival (OS) using univariate and multivariate analyses. RESULTS: Of 547 patients with 596 brainstem metastases treated with SRS, treatment of 7.4% of tumors resulted in severe SRS-induced toxicity (grade >/=3, increased odds with increasing tumor volume, margin dose, and whole-brain irradiation). Local control at 12 months after SRS was 81.8% and was improved with increasing margin dose and maximum dose. Overall survival at 12 months after SRS was 32.7% and impacted by age, gender, number of metastases, tumor histology, and performance score. CONCLUSIONS: Our study provides additional evidence that SRS has become an option for patients with brainstem metastases, with an excellent benefit-to-risk ratio in the hands of experienced clinicians. Prior whole-brain irradiation increases the risk of severe toxicity in brainstem metastasis patients undergoing SRS.

Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1alpha (Hif1alpha)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.

A craniotomy over the superior cerebellar convexity for approaches to this region typically involves a small infratentorial craniotomy and then drilling down of the bone to expose some portion of the transverse/sigmoid sinuses. The authors describe the anatomy of the region and the method for a two-part paramedian occipital and suboccipital craniotomy (supra and infratentorial) that may have time-saving, safety, and cosmetic advantages. For this technique, a supratentorial craniotomy is used to expose the transverse sinus from above, and subsequently, dissection across the sinus over the cerebellar convexity can be done under direct vision. The two bone pieces are joined on the inner table side while plates for fixation above the superior nuchal line can be counter-sunk to avoid post-operative pain from the prominence of screws. There is no need for cranioplasty materials since there is no burring down of bone for adequate exposure of the transverse sinus. The technique has been used by two senior surgeons over the years convincing them of the speed, safety, and utility of the technique. Here, the authors present a single example of the technique.

The neural mechanisms that support working memory (WM) depend on persistent neural activity. Within topographically organized maps of space in dorsal parietal cortex, spatially selective neural activity persists during WM for location. However, to date the necessity of these topographic subregions of human parietal cortex for WM remain unknown. To test the causal relationship of these areas to WM, we compared the performance of patients with lesions to topographically organized parietal cortex to controls on a memory-guided saccade (MGS) task as well as a visually-guided saccade (VGS) task. The MGS task allowed us to measure WM precision continuously with great sensitivity, while the VGS task allowed us to control for any deficits in general spatial or visuomotor processing. Compared to controls, patients generated memory-guided saccades that were significantly slower and less accurate, while visually-guided saccades were unaffected. These results provide key missing evidence for the causal role of topographic areas in human parietal cortex for WM, as well as the neural mechanisms supporting WM.

Background: The transcochlear approach extends the anterior exposure afforded by the translabyrinthine technique. Although this wider exposure allows improved access to cranial nerves and the brainstem with less retraction on the cerebellum, the classical description involving facial nerve transposition often results in permanent facial paresis. This study discusses the role of the transcochlear approach in resection of cerebellopontine angle tumors including patient selection, surgical technique, and outcomes. Study Design: Retrospective review. Methods: This is a retrospective review conducted at a single academic institution. Cases performed by our skull base team (neurotologist and neurosurgeon) between 2000 and 2015 were reviewed. All cases utilizing the transcochlear approach were included. Factors including tumor size, completeness of resection, facial nerve function, post-operative complications, and length of stay were analyzed. Results: Fourteen cases were included. All of these patients had pre-operative severe hearing loss except for two in which surgery was performed urgently in the setting of hydrocephalus and brainstem compression. Eight out of 14 patients had pre-operative facial paresis. Tumor size ranged from 2.2-7 cm in greatest dimension (mean = 4.56 cm). All patients underwent a transcochlear approach to and removal of tumor with blind sac of the external auditory canal. In addition, 3 patients underwent an immediate facial nerve to hypoglossal anastomosis. Post-operatively, patients remained in the hospital for 3-5 days (mean = 4). Of the patients who started out with normal facial nerve function (n = 6), 3 recovered to House-Brackmann scores II or greater. There were no reported CSF leaks requiring hospitalization and 1 abdominal hematoma from fat graft harvest. There was a single mortality reported in the peri-operative period; however, on autopsy the cause of death was unrelated to the surgery itself or any subsequent intracranial event. Conclusions: As in other surgical approaches destructive to the labyrinth, patients were selected with consideration of their pre-operative hearing status and/or their candidacy for hearing preservation surgery. Patients with pre-operative facial nerve paralysis and hearing loss were deemed particularly appropriate candidates for the transcochlear technique given the additional exposure and the lack of added morbidity. In these cases the surgeon also has the option to perform dynamic facial nerve reanimation at the time of tumor resection

Background: Salvage surgery for progressive symptoms or recurrent growth of vestibular schwannoma (VS) after stereotactic radiosurgery (SRS) is uncommon. It has been reported to be more difficult, the same or easier than expected compared with microsurgical resection (MS) of treatment-naive VS, with variable facial nerve outcomes. We conducted a matched cohort analysis to evaluate facial nerve outcomes for patients undergoing MS for progressive symptoms or recurrent growth of VS after SRS compared with MS for treatment-naive VS. Methods: We evaluated the records of 365 non-NF2 VS patients treated with MS from 2001 to 2014. All patients who had postoperative notes were considered to have "adequate follow-up" and included in the study. Nine patients underwent resection for VS after prior SRS (MS-POST SRS) with no prior intervention, 7 of which had adequate follow-up, and 331 patients that underwent MS for treatment naive VS (MS-NO SRS), 317 of which had adequate follow-up. From this dataset, we created propensity score matched cohorts to retrospectively compare facial nerve preservation and clinical outcomes. The propensity score model incorporated age at surgery, tumor size, and pre-operative HB grade, and cases were matched at a ratio of 4:1 MS-NO SRS to MS-POST SRS cases. Results: The MS-POST SRS (n = 7) and MS-NO SRS (n = 28) groups differed only in preoperative hearing status (p < 0.01). Preoperative HB grades were similar between MS-POST SRS and MS-NO SRS groups (p>0.3). The average time-to-intervention after SRS in the MS-POST SRS group was 44.4 months. The indication for MS after SRS was symptom progression with tumor growth in 4 cases, and only tumor growth in the remaining 3. Postoperatively, 3 cases in the MS-POST SRS group demonstrated improvement in HB grade and none became worse whereas 3 of 28 cases in the MS-NO SRS group demonstrated improvement and 12 cases had decrement in HB grade relative to baseline (p < 0.05). There was no significant difference in the extent of resection with both cohorts (MS-POST SRS and MS-NO SRS) attaining gross total resection in 85.7% of cases. Subsequent intervention was not required for any case in the MS-POST SRS group and 2 cases in the MS-NO SRS group, although this difference was not significant. Both cases requiring subsequent intervention in the MS-POST SRS group were gross total resections via the translabyrinthine approach, with subsequent intervention required at 62 and 48 months. There were no significant differences in the complication rate for individual complications or the overall complication rate between cohorts. Conclusions: At a center with high clinical volume, microsurgical resection of VS after prior SRS was associated with good postoperative facial nerve preservation and low morbidity, comparable to those observed in resection of treatment-naive VS. In addition there were similar outcomes in terms of extent of resection between the two groups. The good outcomes reported here may reflect a confluence of factors which include patient selection, the experience of the attending surgeons, the use of more contemporary SRS dosing protocols during initial treatment for these patients, and divergent goals of therapy between cohorts