Shawn L. Hervey-Jumper

Endothelial Cells Create a Stem Cell Niche in Glioblastoma by Providing NOTCH Ligands That Nurture Self-Renewal of Cancer Stem-Like Cells

One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment.

Awake craniotomy to maximize glioma resection: methods and technical nuances over a 27-year period

OBJECT Awake craniotomy is currently a useful surgical approach to help identify and preserve functional areas during cortical and subcortical tumor resections. Methodologies have evolved over time to maximize patient safety and minimize morbidity using this technique. The goal of this study is to analyze a single surgeons experience and the evolving methodology of awake language and sensorimotor mapping for glioma surgery. METHODS The authors retrospectively studied patients undergoing awake brain tumor surgery between 1986 and 2014. Operations for the initial 248 patients (1986-1997) were completed at the University of Washington, and the subsequent surgeries in 611 patients (1997-2014) were completed at the University of California, San Francisco. Perioperative risk factors and complications were assessed using the latter 611 cases. RESULTS The median patient age was 42 years (range 13-84 years). Sixty percent of patients had Karnofsky Performance Status (KPS) scores of 90-100, and 40% had KPS scores less than 80. Fifty-five percent of patients underwent surgery for high-grade gliomas, 42% for low-grade gliomas, 1% for metastatic lesions, and 2% for other lesions (cortical dysplasia, encephalitis, necrosis, abscess, and hemangioma). The majority of patients were in American Society of Anesthesiologists (ASA) Class 1 or 2 (mild systemic disease); however, patients with severe systemic disease were not excluded from awake brain tumor surgery and represented 15% of study participants. Laryngeal mask airway was used in 8 patients (1%) and was most commonly used for large vascular tumors with more than 2 cm of mass effect. The most common sedation regimen was propofol plus remifentanil (54%); however, 42% of patients required an adjustment to the initial sedation regimen before skin incision due to patient intolerance. Mannitol was used in 54% of cases. Twelve percent of patients were active smokers at the time of surgery, which did not impact completion of the intraoperative mapping procedure. Stimulation-induced seizures occurred in 3% of patients and were rapidly terminated with ice-cold Ringers solution. Preoperative seizure history and tumor location were associated with an increased incidence of stimulation-induced seizures. Mapping was aborted in 3 cases (0.5%) due to intraoperative seizures (2 cases) and patient emotional intolerance (1 case). The overall perioperative complication rate was 10%. CONCLUSIONS Based on the current best practice described here and developed from multiple regimens used over a 27-year period, it is concluded that awake brain tumor surgery can be safely performed with extremely low complication and failure rates regardless of ASA classification; body mass index; smoking status; psychiatric or emotional history; seizure frequency and duration; and tumor site, size, and pathology.

Maximizing safe resection of low- and high-grade glioma.

Surgical resection plays a central role in the management of gliomas. In this study, we review the evidence in support of extent of resection to improve survival, symptom management, and time to malignant transformation in low- and high-grade gliomas, and summarize the findings from our literature search regarding the role of extent of resection and intraoperative practices to maximize safety. There is a growing body of evidence supporting improved overall survival, improved progression-free survival, and superior quality of life with greater extent of resection. Additionally, a better understanding of central nervous system plasticity allows for a staged approach to the surgical management of low- and intermediate-grade gliomas. A number of intraoperative techniques have been utilized to offer safer glioma surgery with greater extent of resection. Approaches such as awake brain tumor surgery can be safely performed with low failure rates and excellent long-term functional outcomes.

Reoperation for recurrent high-grade glioma: a current perspective of the literature.

Optimal treatment for recurrent high-grade glioma continues to evolve. Currently, however, there is no consensus in the literature on the role of reoperation in the management of these patients. In this analysis, we reviewed the literature to examine the role of reoperation in patients with World Health Organization grade III or IV recurrent gliomas, focusing on how reoperation affects outcome, perioperative complications, and quality of life. An extensive literature review was performed through the use of the PubMed and Ovid Medline databases for January 1980 through August 2013. A total 31 studies were included in the final analysis. Of the 31 studies with significant data from single or multiple institutions, 29 demonstrated a survival benefit or improved functional status after reoperation for recurrent high-grade glioma. Indications for reoperation included new focal neurological deficits, tumor mass effect, signs of elevated intracranial pressure, headaches, increased seizure frequency, and radiographic evidence of tumor progression. Age was not a contraindication to reoperation. Time interval of at least 6 months between operations and favorable performance status (Karnofsky Performance Status score ≥70) were important predictors of benefit from reoperation. Extent of resection at reoperation improved survival, even in patients with subtotal resection at initial operation. Careful patient selection such as avoiding those individuals with poor performance status and bevacizumab within 4 weeks of surgery is important. Although limited to retrospective analysis and patient selection bias, mounting evidence suggests a survival benefit in patients receiving a reoperation at the time of high-grade glioma recurrence.

Rapid intraoperative histology of unprocessed surgical specimens via fibre-laser-based stimulated Raman scattering microscopy

Conventional methods for intraoperative histopathologic diagnosis are labour- and time-intensive, and may delay decision-making during brain-tumour surgery. Stimulated Raman scattering (SRS) microscopy, a label-free optical process, has been shown to rapidly detect brain-tumour infiltration in fresh, unprocessed human tissues. Here, we demonstrate the first application of SRS microscopy in the operating room by using a portable fibre-laser-based microscope and unprocessed specimens from 101 neurosurgical patients. We also introduce an image-processing method – stimulated Raman histology (SRH) – which leverages SRS images to create virtual haematoxylin-and-eosin-stained slides, revealing essential diagnostic features. In a simulation of intraoperative pathologic consultation in 30 patients, we found a remarkable concordance of SRH and conventional histology for predicting diagnosis (Cohens kappa, κ > 0.89), with accuracy exceeding 92%. We also built and validated a multilayer perceptron based on quantified SRH image attributes that predicts brain-tumour subtype with 90% accuracy. Our findings provide insight into how SRH can now be used to improve the surgical care of brain tumour patients.

A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas

OBJECT There is evidence that 5-aminolevulinic acid (ALA) facilitates greater extent of resection and improves 6-month progression-free survival in patients with high-grade gliomas. But there remains a paucity of studies that have examined whether the intensity of ALA fluorescence correlates with tumor cellularity. Therefore, a Phase II clinical trial was undertaken to examine the correlation of intensity of ALA fluorescence with the degree of tumor cellularity. METHODS A single-center, prospective, single-arm, open-label Phase II clinical trial of ALA fluorescence-guided resection of high-grade gliomas (Grade III and IV) was held over a 43-month period (August 2010 to February 2014). ALA was administered at a dose of 20 mg/kg body weight. Intraoperative biopsies from resection cavities were collected. The biopsies were graded on a 4-point scale (0 to 3) based on ALA fluorescence intensity by the surgeon and independently based on tumor cellularity by a neuropathologist. The primary outcome of interest was the correlation of ALA fluorescence intensity to tumor cellularity. The secondary outcome of interest was ALA adverse events. Sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and Spearman correlation coefficients were calculated. RESULTS A total of 211 biopsies from 59 patients were included. Mean age was 53.3 years and 59.5% were male. The majority of biopsies were glioblastoma (GBM) (79.7%). Slightly more than half (52.5%) of all tumors were recurrent. ALA intensity of 3 correlated with presence of tumor 97.4% (PPV) of the time. However, absence of ALA fluorescence (intensity 0) correlated with the absence of tumor only 37.7% (NPV) of the time. For all tumor types, GBM, Grade III gliomas, and recurrent tumors, ALA intensity 3 correlated strongly with cellularity Grade 3; Spearman correlation coefficients (r) were 0.65, 0.66, 0.65, and 0.62, respectively. The specificity and PPV of ALA intensity 3 correlating with cellularity Grade 3 ranged from 95% to 100% and 86% to 100%, respectively. In biopsies without tumor (cellularity Grade 0), 35.4% still demonstrated ALA fluorescence. Of those biopsies, 90.9% contained abnormal brain tissue, characterized by reactive astrocytes, scattered atypical cells, or inflammation, and 8.1% had normal brain. In nonfluorescent (ALA intensity 0) biopsies, 62.3% had tumor cells present. The ALA-associated complication rate among the study cohort was 3.4%. CONCLUSIONS The PPV of utilizing the most robust ALA fluorescence intensity (lava-like orange) as a predictor of tumor presence is high. However, the NPV of utilizing the absence of fluorescence as an indicator of no tumor is poor. ALA intensity is a strong predictor for degree of tumor cellularity for the most fluorescent areas but less so for lower ALA intensities. Even in the absence of tumor cells, reactive changes may lead to ALA fluorescence.

Identifying preoperative language tracts and predicting postoperative functional recovery using HARDI q-ball fiber tractography in patients with gliomas

OBJECT Diffusion MRI has uniquely enabled in vivo delineation of white matter tracts, which has been applied to the segmentation of eloquent pathways for intraoperative mapping. The last decade has also seen the development from earlier diffusion tensor models to higher-order models, which take advantage of high angular resolution diffusion-weighted imaging (HARDI) techniques. However, these advanced methods have not been widely implemented for routine preoperative and intraoperative mapping. The authors report on the application of residual bootstrap q-ball fiber tracking for routine mapping of potentially functional language pathways, the development of a system for rating tract injury to evaluate the impact on clinically assessed language function, and initial results predicting long-term language deficits following glioma resection. METHODS The authors have developed methods for the segmentation of 8 putative language pathways including dorsal phonological pathways and ventral semantic streams using residual bootstrap q-ball fiber tracking. Furthermore, they have implemented clinically feasible preoperative acquisition and processing of HARDI data to delineate these pathways for neurosurgical application. They have also developed a rating scale based on the altered fiber tract density to estimate the degree of pathway injury, applying these ratings to a subset of 35 patients with pre- and postoperative fiber tracking. The relationships between specific pathways and clinical language deficits were assessed to determine which pathways are predictive of long-term language deficits following surgery. RESULTS This tracking methodology has been routinely implemented for preoperative mapping in patients with brain gliomas who have undergone awake brain tumor resection at the University of California, San Francisco (more than 300 patients to date). In this particular study the authors investigated the white matter structure status and language correlation in a subcohort of 35 subjects both pre- and postsurgery. The rating scales developed for fiber pathway damage were found to be highly reproducible and provided significant correlations with language performance. Preservation of the left arcuate fasciculus (AF) and the temporoparietal component of the superior longitudinal fasciculus (SLF-tp) was consistent in all patients without language deficits (p < 0.001) at the long-term follow-up. Furthermore, in patients with short-term language deficits, the AF and/or SLF-tp were affected, and damage to these 2 pathways was predictive of a long-term language deficit (p = 0.005). CONCLUSIONS The authors demonstrated the successful application of q-ball tracking in presurgical planning for language pathways in brain tumor patients and in assessing white matter tract integrity postoperatively to predict long-term language dysfunction. These initial results predicting long-term language deficits following tumor resection indicate that postoperative injury to dorsal language pathways may be prognostic for long-term clinical language deficits. Study results suggest the importance of dorsal stream tract preservation to reduce language deficits in patients undergoing glioma resection, as well as the potential prognostic value of assessing postoperative injury to dorsal language pathways to predict long-term clinical language deficits.

Impact of multimodal intraoperative monitoring during correction of symptomatic cervical or cervicothoracic kyphosis: Clinical article

OBJECT surgical correction of symptomatic cervical or cervicothoracic kyphosis involves the potential for significant neurological complications. Intraoperative monitoring has been shown to reduce the risk of neurological injury in scoliosis surgery, but it has not been well evaluated during surgery for cervical or cervicothoracic kyphosis. In this article, the authors review a cohort of patients who underwent kyphosis correction with multimodal intraoperative monitoring (MIOM). METHODS twenty-nine patients were included in the study. Preoperative and postoperative Cobb angles were measured to determine the extent of correction. Multimodal intraoperative monitoring consisted of somatosensory evoked potentials, transcranial motor evoked potentials (tMEPs), and electromyography activity. Sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs) were assessed for each monitoring modality. RESULTS the mean patient age was 58.0 years, and 20 patients were female. The mean pre- and postoperative sagittal Cobb angles were 41.3° and 7.3°, respectively. A total of 8 intraoperative monitoring alerts were observed. Transcranial MEPs yielded a sensitivity of 75%, specificity of 84%, PPV of 43%, and NPV of 95%. Somatosensory evoked potentials had a sensitivity of 25%, specificity of 96%, PPV of 50%, and NPV of 88%. Electromyography resulted in a sensitivity of 0%, specificity of 93%, PPV of 0%, and NPV of 96%. Changes in tMEPs led to successful intervention in 2 cases. There was 1 case in which a C-8 palsy occurred without any changes in MIOM. CONCLUSIONS in contrast to sensitivity and PPV, specificity and NPV were generally high in all 3 monitoring modalities. Both false-positive and false-negative results occurred. Transcranial MEP monitoring was the most useful modality and appeared to allow successful intervention in certain cases. Larger, prospective comparative studies are necessary to determine whether MIOM truly decreases the rate of neurological complications and is therefore worth the added economic cost and intraoperative time.

Surgical assessment of the insula. Part 1: surgical anatomy and morphometric analysis of the transsylvian and transcortical approaches to the insula.

OBJECTIVE Transcortical and transsylvian corridors have been previously described as the main surgical approaches to the insula, but there is insufficient evidence to support one approach versus the other. The authors performed a cadaveric comparative study regarding insular exposure, surgical window and freedom, between the transcortical and transsylvian approaches (with and without cutting superficial sylvian bridging veins). Surgical anatomy and skull surface reference points to the different insular regions are also described. METHODS Sixteen cadaveric specimens were embalmed with a customized formula to enhance neurosurgical simulation. Two different blocks were defined in the study: first, transsylvian without (TS) and with the superficial sylvian bridging veins cut (TSVC) and transcortical (TC) approaches to the insula were simulated in all (16) specimens. Insular surface exposure, surgical window and surgical freedom were calculated for each procedure and related to the Berger-Sanai insular glioma classification (Zones I-IV) in 10 specimens. Second, the venous drainage pattern and anatomical landmarks considered critical for surgical planning were studied in all specimens. RESULTS In the insular Zone I (anterior-superior), the TC approach provided the best insular exposure compared with both TS and TSVC. The surgical window obtained with the TC approach was also larger than that obtained with the TS. The TC approach provided 137% more surgical freedom than the TS approach. Only the TC corridor provided complete insular exposure. In Zone II (posterior-superior), results depended on the degree of opercular resection. Without resection of the precentral gyrus in the operculum, insula exposure, surgical windows and surgical freedom were equivalent. If the opercular cortex was resected, the insula exposure and surgical freedom obtained through the TC approach was greater to that of the other groups. In Zone III (posterior-inferior), the TC approach provided better surgical exposure than the TS, yet similar to the TSVC. The TC approach provided the best insular exposure, surgical window, and surgical freedom if components of Heschls gyrus were resected. In Zone IV (anterior-inferior), the TC corridor provided better exposure than both the TS and the TSVC. The surgical window was equivalent. Surgical freedom provided by the TC was greater than the TS approach. This zone was completely exposed only with the TC approach. A dominant anterior venous drainage was found in 87% of the specimens. In this group, 50% of the specimens had good alternative venous drainage. The sylvian fissure corresponded to the superior segment of the squamosal suture in 14 of 16 specimens. The foramen of Monro was 1.9 cm anterior and 4.42 cm superior to the external acoustic meatus. The M2 branch over the central sulcus of the insula became the precentral M4 (rolandic) artery in all specimens. CONCLUSIONS Overall, the TC approach to the insula provided better insula exposure and surgical freedom compared with the TS and the TSVC. Cortical and subcortical mapping is critical during the TC approach to the posterior zones (II and III), as the facial motor and somatosensory functions (Zone II) and language areas (Zone III) may be involved. The evidence provided in this study may help the neurosurgeon when approaching insular gliomas to achieve a greater extent of tumor resection via an optimal exposure.

Advances in the Surgical Management of Low-Grade Glioma

Over the past 2 decades, extent of resection has emerged as a significant prognostic factor in patients with low-grade gliomas (LGGs). Greater extent of resection has been shown to improve overall survival, progression-free survival, and time to malignant transformation. The operative goal in most LGG cases is to maximize extent of resection, while avoiding postoperative neurologic deficits. Several advanced surgical techniques have been developed in an attempt to better achieve maximal safe resection. Intraoperative magnetic resonance imaging, fluorescence-guided surgery, intraoperative functional pathway mapping, and neuronavigation are some of the most commonly used techniques with multiple studies to support their efficacy in glioma surgery. By using these techniques either alone or in combination, patients harboring LGGs have a better prognosis with less surgical morbidity following tumor resection.