Interbody cages versus structural bone grafts in lumbar arthrodesis: a systematic review and meta-analysis.

OBJECTIVE: The role of interbodies in lumbar arthrodesis has been insufficiently supported by evidence, impacting clinical decision-making and occasionally insurance coverage. This study aimed to compare clinical and radiological outcomes between lumbar arthrodesis with a synthetic interbody spacer (cage) versus structural bone graft alone (autograft or allograft) in patients with degenerative spine disease. METHODS: A systematic review of the literature was performed to identify studies directly comparing outcomes of lumbar interbody arthrodesis with and without interbody cage use. The outcomes of individual studies were synthesized in meta-analyses using random-effects models. RESULTS: Twenty studies with 1508 patients (769 with an interbody cage and 739 without an interbody cage) were included. Interbody cage placement was associated with a significantly greater increase in disc height after surgery (4.0 mm vs 3.4 mm, p < 0.01). There was a significantly greater reduction of back pain (visual analog scale [VAS] score) in cases in which an interbody cage was used (5.4 vs 4.7, p = 0.03). Fusion rates were 5.5% higher in the cage group (96.3% vs 90.8%) and reached statistical significance (p = 0.03). No statistically significant differences were identified between the two groups regarding all-cause reoperation rates, complication rates, or improvement in Oswestry Disability Index score or leg pain (VAS score). CONCLUSIONS: These results suggest that implantation of an interbody cage is associated with higher rates of fusion, more effective maintenance of disc height, and greater improvement of back pain. This study underlines the clinical value of interbody cages in lumbar arthrodesis for patients with degenerative spine disease.

Bone morphogenetic protein in subaxial cervical arthrodesis: a meta-analysis of 5828 patients.

OBJECTIVE: Use of bone morphogenetic protein (BMP)-an osteoinductive agent commonly used in lumbar arthrodesis-is off-label for cervical arthrodesis. This study aimed to identify the effect of BMP use on clinical and radiological outcomes in instrumented cervical arthrodesis. METHODS: A comprehensive systematic review of the literature was performed to identify studies directly comparing outcomes between cervical arthrodeses with and without using BMP. Outcomes were analyzed separately for cases of anterior cervical discectomy and fusion (ACDF) and posterior cervical fusion (PCF). RESULTS: A total of 20 studies with 5828 patients (1948 with BMP and 3880 without BMP) were included. In the ACDF cases, BMP use was associated with higher fusion rates (98.9% vs 93.6%, risk difference [RD] 8%; risk ratio [RR] 1.12, p = 0.02), lower reoperation rates (2.2% vs 3.1%, RD 3%; RR 0.48, p = 0.04), and higher risk of dysphagia (24.7% vs 8.1%, RD 11%; RR 1.93, p = 0.02). No significant differences in the Neck Disability Index, neck pain, or arm pain scores were associated with the use of BMP. On subgroup meta-analysis of ACDF cases, older age (≥ 50 years) and higher BMP dose (≥ 0.9 mg/level) were associated with significantly higher fusion rates and relatively lower risk for dysphagia, whereas arthrodesis of fewer segments (< 2 levels) showed significantly higher dysphagia rates without a significant increase in fusion rates. In the PCF cases, the use of BMP was not associated with significant differences in fusion (p = 0.38) or reoperation (p = 0.61) rates but was associated with significantly higher blood loss during surgery (mean difference 146.7 ml, p ≤ 0.01). CONCLUSIONS: Use of BMP in ACDF offers higher rates of augmented fusion and lower rates of all-cause reoperation but with an increased risk of dysphagia. The benefit of fusion outweighs the risk of dysphagia with a higher BMP dose in older patients being operated on for < 2 levels. The use of BMP in PCF seems to have a less important effect on clinical and radiological outcomes.

Impact of preoperative spinal injections within 30 days of lumbar decompression on surgical outcomes: a matched institutional study.

OBJECTIVE: The authors sought to determine how the temporal proximity of lumbar epidural spinal injection prior to surgery impacts clinical outcomes (e.g., 30-day readmission, postoperative complications, CSF leak) in patients undergoing lumbar decompression without fusion. METHODS: The authors queried their institutional registry to identify patients who underwent elective lumbar decompression for spondylotic pathology between January 2019 and March 2022 at multiple centers within the same hospital network. Patients were divided into groups based on the time between their surgical date and the most recent preoperative spinal injection: group 1, patients with duration < 1 month; group 2, 1-3 months; and group 3, no spinal injection within 3 months. Primary outcomes of interest were the length of hospital stay, postoperative complications, rate of intraoperative CSF leak, and rates of reoperation and hospital readmission. For patients in groups 1 and 2, the authors also recorded the number of injections within 12 months prior to surgery to better understand the effect of multiple recent injections. The independent Student t-test and Pearson's chi-square test were mainly performed for univariate analyses of the continuous and categorical variables, respectively. RESULTS: A total of 121 and 283 patients received a spinal injection at < 1 month and 1-3 months prior to surgery, respectively, and were separately matched in a 3:1 ratio with 2562 patients with no history of preoperative spinal injection within 3 months before surgery. Among the matched cohorts, patients who received spinal injections < 1 month before lumbar decompression had significantly higher risks of 30-day complication (7.4% vs 0.8%, OR 9.6, p < 0.001), 30-day readmission (5.8% vs 2.2%, OR 3.5, p = 0.049), and 90-day readmission (9.1% vs 2.8%, OR 3.5, p = 0.003) than patients with no history of spinal injection. However, compared with patients with no history of spinal injection, the patients who received spinal injections 1-3 months before surgery were not at higher risk for postoperative complications or readmission. The CSF leak rates were significantly different between the three patient cohorts (10.7% vs 6.7% vs 4.9% for the < 1 month, 1-3 months, and no injection cohorts, respectively; p = 0.02). CONCLUSIONS: Lumbar decompression within 1 month of preoperative spinal injection was associated with higher risks of readmission and postoperative complications, including CSF leak. However, with the exception of CSF leak, these risks were no longer observed when spinal injection occurred 1-3 months prior to lumbar decompression.

The association between bone mineral density and proximal junctional kyphosis in adult spinal deformity: a systematic review and meta-analysis.

OBJECTIVE: Proximal junctional kyphosis (PJK) is a complication of surgical management for adult spinal deformity (ASD) with a multifactorial etiology. Many risk factors are controversial, and their relative importance is not fully understood. The authors aimed to elucidate the association between bone mineral density (BMD) and PJK. METHODS: A systematic literature search was performed using PubMed and Web of Science keywords of "Proximal Junctional Kyphosis [MeSH] OR Proximal Junctional Failure [MeSH]" AND "Bone Mineral Density [MeSH] OR Hounsfield Units [MeSH] OR DEXA [MeSH]" set to the date range of January 2002 to July 2022. Studies required a minimum of 10 patients and 12 months of follow-up. Articles were included if they were in the English language and presented a primary retrospective cohort that included a comparison of patients with and without PJK, as well as a radiographic biomarker for BMD, such as Hounsfield units (HU) or T-score. RESULTS: A total of 18 unique studies with 2185 patients who underwent ASD surgery were identified. Of these, 537 patients (24.6%) developed PJK. Eight studies provided T-scores that were amenable to comparison, which found that patients who developed PJK were found to have lower BMD T-scores by a mean of -0.69 (95% CI -0.88 to -0.50; I2 = 63.9%, p < 0.001). The HU at the UIV among patients with the PJK group (n = 101) compared with the non-PJK group (n = 156) was found to be significantly lower (mean difference -32.35, 95% CI -46.05 to -18.65; I2 = 28.7%, p < 0.001). CONCLUSIONS: This meta-analysis suggests that low preoperative BMD as measured by T-score and a diagnosis of osteoporosis were associated with higher postoperative PJK. Additionally, lower HU on CT at the UIV were found to be significant risk factors for postoperative PJK as well. These findings suggest that more attention to preoperative BMD is a risk factor for PJK among ASD patients is warranted.

Operative Treatment of Bertolotti Syndrome: Resection Versus Fusion.

OBJECTIVE: To compare the outcomes of joint resection versus fusion in patients who undergo operative treatment for Bertolotti syndrome. METHODS: A chart review identified patients with Bertolotti syndrome who underwent operative treatment, consisting of either Bertolotti joint decompression/resection or fusion across the abnormal transitional lumbosacral vertebrae. Patients with other symptomatic operative spinal disease were excluded. RESULTS: Twenty-seven patients (9 men, 18 women) were identified for inclusion in the study with an average age of 40 ± 16 years, body mass index of 27 ± 5, and follow-up of 39 ± 48 months. Most patients presented with back pain (74%) or leg pain (48%) for an average duration of 61 ± 54 months. Nineteen (70%) presented with a Castellvi subtype 2a Bertolotti joint with computed tomography as the most common method for radiographic diagnosis (56%). When comparing long-term pain improvement (>12 months) after fusion (n = 9) versus joint resection (n = 18), more fusion patients reported improvement in their pain (78%) compared to joint resection (28%, P = 0.037). There was not a statistically significant difference in the short-term pain improvement (<6 months) between the fusion (100%) and resection (78%) patients (P = 0.27). There was no statistically significant difference between the two groups in terms of age, sex, body mass index, presenting symptoms, symptom duration, Bertolotti injection response, follow up, Castellvi subtype, and complications. CONCLUSIONS: Patients with Bertolotti syndrome who underwent surgical fusion across the transitional lumbosacral vertebrae had a higher rate of long-term pain improvement compared to patients who had resection of the abnormal pseudoarticulation.

Association of Maximal Extent of Resection of Contrast-Enhanced and Non-Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma.

Importance: Per the World Health Organization 2016 integrative classification, newly diagnosed glioblastomas are separated into isocitrate dehydrogenase gene 1 or 2 (IDH)-wild-type and IDH-mutant subtypes, with median patient survival of 1.2 and 3.6 years, respectively. Although maximal resection of contrast-enhanced (CE) tumor is associated with longer survival, the prognostic importance of maximal resection within molecular subgroups and the potential importance of resection of non-contrast-enhanced (NCE) disease is poorly understood. Objective: To assess the association of resection of CE and NCE tumors in conjunction with molecular and clinical information to develop a new road map for cytoreductive surgery. Design, Setting, and Participants: This retrospective, multicenter cohort study included a development cohort from the University of California, San Francisco (761 patients diagnosed from January 1, 1997, through December 31, 2017, with 9.6 years of follow-up) and validation cohorts from the Mayo Clinic (107 patients diagnosed from January 1, 2004, through December 31, 2014, with 5.7 years of follow-up) and the Ohio Brain Tumor Study (99 patients with data collected from January 1, 2008, through December 31, 2011, with a median follow-up of 10.9 months). Image accessors were blinded to patient groupings. Eligible patients underwent surgical resection for newly diagnosed glioblastoma and had available survival, molecular, and clinical data and preoperative and postoperative magnetic resonance images. Data were analyzed from November 15, 2018, to March 15, 2019. Main Outcomes and Measures: Overall survival. Results: Among the 761 patients included in the development cohort (468 [61.5%] men; median age, 60 [interquartile range, 51.6-67.7] years), younger patients with IDH-wild-type tumors and aggressive resection of CE and NCE tumors had survival similar to that of patients with IDH-mutant tumors (median overall survival [OS], 37.3 [95% CI, 31.6-70.7] months). Younger patients with IDH-wild-type tumors and reduction of CE tumor but residual NCE tumors fared worse (median OS, 16.5 [95% CI, 14.7-18.3] months). Older patients with IDH-wild-type tumors benefited from reduction of CE tumor (median OS, 12.4 [95% CI, 11.4-14.0] months). The results were validated in the 2 external cohorts. The association between aggressive CE and NCE in patients with IDH-wild-type tumors was not attenuated by the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. Conclusions and Relevance: This study confirms an association between maximal resection of CE tumor and OS in patients with glioblastoma across all subgroups. In addition, maximal resection of NCE tumor was associated with longer OS in younger patients, regardless of IDH status, and among patients with IDH-wild-type glioblastoma regardless of the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. These conclusions may help reassess surgical strategies for individual patients with newly diagnosed glioblastoma.

From bench to bedside: trends in National Institutes of Health funding for neurosurgeons from 1991 to 2015.

OBJECTIVE: Neurosurgeons play an important role in advancing medicine through research, the funding of which is historically linked to the National Institutes of Health (NIH). The authors defined variables associated with neurosurgical NIH funding, prevalence of funded topics by neurosurgical subspecialty, and temporal trends in NIH neurosurgical funding. METHODS: The authors conducted a retrospective review of NIH-funded American Association of Neurological Surgeons members using NIH RePORTER (http://report.nih.gov/) for the years 1991-2015. RESULTS: The authors followed 6515 neurosurgeons from 1991 to 2015, including 6107 (94%) non-MD-PhD physicians and 408 (6%) MD-PhDs. NIH grants were awarded to 393 (6%) neurosurgeons, with 23.2% of all first-time grants awarded to the top 5 funded institutions. The average total funded grant-years per funded neurosurgeon was 12.5 (range 1-85 grant-years). A higher percentage of MD-PhDs were NIH funded than MDs (22% [n = 91] vs 5% [n = 297], p < 0.0001). The most common grants awarded were R01 (128, 33%), K08 (69, 18%), F32 (60, 15%), M01 (50, 13%), and R21 (39, 10%). F32 and K08 recipients were 9-fold (18% vs 2%, p < 0.001) and 19-fold (38% vs 2%, p < 0.001) more likely to procure an R01 and procured R01 funding earlier in their careers (F32: 7 vs 12 years after residency, p = 0.03; K08: 9 vs 12 years, p = 0.01). Each year, the number of neurosurgeons with active grants linearly increased by 2.2 (R2 = 0.81, p < 0.001), whereas the number of total active grants run by neurosurgeons increased at nearly twice the rate (4.0 grants/year) (R2 = 0.91, p < 0.001). Of NIH-funded neurosurgical grants, 33 (9%) transitioned to funded clinical trial(s). Funded neurosurgical subspecialties included neuro-oncology (33%), functional/epilepsy (32%), cerebrovascular (17%), trauma (10%), and spine (6%). Finally, the authors modeled trends in the number of active training grants and found a linear increase in active R01s (R2 = 0.95, p < 0.001); however, both F32 (R2 = 0.36, p = 0.01) and K08 (R2 = 0.67, p < 0.001) funding had a significant parabolic rise and fall centered around 2003. CONCLUSIONS: The authors observed an upward trend in R01s awarded to neurosurgeons during the last quarter century. However, their findings of decreased K08 and F32 training grant funding to neurosurgeons and the impact of these training grants on the ultimate success and time to success for neurosurgeons seeking R01 funding suggests that this upward trend in R01 funding for neurosurgeons will be difficult to maintain. The authors' work underscores the importance of continued selection and mentorship of neurosurgeons capable of impacting patient care through research, including the MD-PhDs, who are noted to be more represented among NIH-funded neurosurgeons.

Connectivity of the human insula: A cortico-cortical evoked potential (CCEP) study.

OBJECTIVE: The human insula is increasingly being implicated as a multimodal functional network hub involved in a large variety of complex functions. Due to its inconspicuous location and highly vascular anatomy, it has historically been difficult to study. Cortico-cortical evoked potentials (CCEPs), utilize low frequency stimulation to map cerebral networks. They were used to study connections of the human insula. METHODS: CCEP data was acquired from each sub-region of the dominant and non-dominant insula in 30 patients who underwent stereo-EEG. Connectivity strength to the various cortical regions was obtained via a measure of root mean square (RMS), calculated from each gyrus of the insula and ranked into weighted means. RESULTS: The results of all cumulative CCEP responses for each individual gyrus were represented by circro plots. Forty-nine individual CCEP pairs were stimulated across all the gyri from the right and left insula. In brief, the left insula contributed more greatly to language areas. Sensory function, pain, saliency processing and vestibular function were more heavily implicated from the right insula. Connections to the primary auditory cortex arose from both insula regions. Both posterior insula regions showed significant contralateral connectivity. Ipsilateral mesial temporal connections were seen from both insula regions. In visual function, we further report the novel finding of a direct connection between the right posterior insula and left visual cortex. SIGNIFICANCE: The insula is a major multi-modal network hub with the cerebral cortex having major roles in language, sensation, auditory, visual, limbic and vestibular functions as well as saliency processing. In temporal lobe epilepsy surgery failure, the insula may be implicated as an extra temporal cause, due to the strong mesial temporal connectivity findings.

Growth hormone and prolactin-staining tumors causing acromegaly: a retrospective review of clinical presentations and surgical outcomes.

OBJECTIVE: Acromegaly results in disfiguring growth and numerous medical complications. This disease is typically caused by growth hormone (GH)-secreting pituitary adenomas, which are treated first by resection, followed by radiation and/or medical therapy if needed. A subset of acromegalics have dual-staining pituitary adenomas (DSPAs), which stain for GH and prolactin. Presentations and treatment outcomes for acromegalics with DSPAs are not well understood. METHODS: The authors retrospectively reviewed the records of more than 5 years of pituitary adenomas resected at their institution. Data were collected on variables related to clinical presentation, tumor pathology, radiological size, and disease recurrence. The Fisher's exact test, ANOVA, Student t-test, chi-square test, and Cox proportional hazards and multiple logistic regression were used to measure statistical significance. RESULTS: Of 593 patients with pituitary adenoma, 91 presented with acromegaly. Of these 91 patients, 69 (76%) had tumors that stained for GH only (single-staining somatotrophic adenomas [SSAs]), while 22 (24%) had tumors that stained for GH and prolactin (DSPAs). Patients with DSPAs were more likely to present with decreased libido (p = 0.012), signs of acromegalic growth (p = 0.0001), hyperhidrosis (p = 0.0001), and headaches (p = 0.043) than patients with SSAs. DSPAs presented with significantly higher serum prolactin (60.7 vs 10.0 µg/L, p = 0.0002) and insulin-like growth factor-1 (IGF-1) (803.6 vs 480.0 ng/ml, p = 0.0001), and were more likely to have IGF-1 levels > 650 ng/ml (n = 13 [81.3%] vs n = 6 [21.4%], p = 0.0001) than patients with SSAs despite similar sizes (1.8 vs 1.7 cm, p = 0.5). Patients with DSPAs under 35 years of age were more likely to have a recurrence (n = 4 [50.0%] vs n = 3 [11.1%], p = 0.01) than patients with SSAs under the age of 35. DSPA patients were less likely to achieve remission with surgery than SSA patients (n = 2 [20%] vs n = 19 [68%], p = 0.01). Univariate analysis identified single-staining tumors (p = 0.02), gross-total resection (p = 0.02), and tumor diameter (p = 0.05) as predictors of surgical remission. Multiple logistic regression demonstrated that SSAs (p = 0.04) were independently associated with surgical remission of acromegaly. Kaplan-Meier analysis revealed that DSPAs had more time until disease remission (p = 0.033). CONCLUSIONS: Acromegalics with tumors that stain for prolactin and GH, which represented almost a quarter of acromegalics in this cohort, had more aggressive clinical presentations and postoperative outcomes than SSAs. Prolactin staining provides useful information for acromegalics undergoing pituitary surgery.

Postoperative Delirium in Glioblastoma Patients: Risk Factors and Prognostic Implications.

BACKGROUND: Delirium is a postoperative neurological morbidity in glioblastoma whose risk factors, incidence, and prognostic implications remain undefined. OBJECTIVE: To develop an algorithm using preoperative factors to predict postoperative delirium. METHODS: Retrospective analysis of 554 consecutive patients (mean age = 61.5 yr; 42% female) undergoing first glioblastoma procedure at our institution 2005 to 2011. RESULTS: Postoperative delirium occurred in 7% of patients (n = 38). Patients undergoing biopsy (10%; n = 54) did not experience delirium. In patients undergoing resection (n = 500), multivariate logistic regression identified 5 factors independently predicting postoperative delirium: age, chronic pulmonary disease, psychiatric history, bihemispheric tumors, and tumor size. We developed a score function entitled "GRAD" (Glioblastoma Risk Assessment for Delirium) to stratify patients into risk categories by assigning point(s) to each preoperative factor based on the relative magnitude of its regression coefficient. Point totals were summed for each patient: patients with 0 to 2 (n = 227) and 3 to 7 (n = 221) points were designated as low and high risk with postoperative delirium rates of 2% vs 15%, respectively (chi-square; P < .001), with the model validated using a separate patient cohort. Postoperative delirium lengthened hospital stays (P < .001), decreased likelihood of discharge home (P < .001), and was independently associated with decreased survival (4.5 vs 13.4 mo; hazard ratio = 1.9 [1.2-2.8]) in multivariate analysis. CONCLUSION: We developed a model to predict development of postoperative delirium using 2 tumor-specific (bihemispheric tumors and tumor size) and 3 patient-specific (age, psychiatric history, and chronic pulmonary disease) factors. High-risk patients and their families should be counseled preoperatively, and this risk could be considered in the choice of biopsy vs resection, and resection patients should be monitored closely postoperatively.

A cross-sectional study of neurosurgical department chairs in the United States.

OBJECTIVEThe position of neurosurgery department chair undergoes constant evolution as the health care landscape changes. The authors' aim in this paper was to characterize career attributes of neurosurgery department chairs in order to define temporal trends in qualities being sought in neurosurgical leaders. Specifically, they investigated the hypothesis that increased qualifications in the form of additional advanced degrees and research acumen are becoming more common in recently hired chairs, possibly related to the increased complexity of their role.METHODSThe authors performed a retrospective study in which they collected data on 105 neurosurgeons who were neurosurgery department chairs as of December 31, 2016, at accredited academic institutions with a neurosurgery residency program in the United States. Descriptive data on the career of neurosurgery chairs, such as the residency program attended, primary subspecialty focus, and age at which they accepted their position as chair, were collected.RESULTSThe median age and number of years in practice postresidency of neurosurgery chairs on acceptance of the position were 47 years (range 36-63 years) and 14 years (range 6-33 years), respectively, and 87% (n = 91) were first-time chairs. The median duration that chairs had been holding their positions as of December 31, 2016, was 10 years (range 1-34 years). The most common subspecialties were vascular (35%) and tumor/skull base (27%), although the tendency to hire from these specialties diminished over time (p = 0.02). More recently hired chairs were more likely to be older (p = 0.02), have more publications (p = 0.007), and have higher h-indices (p < 0.001) at the time of hire. Prior to being named chair, 13% (n = 14) had a PhD, 4% (n = 4) had an MBA, and 23% (n = 24) were awarded a National Institutes of Health R01 grant, tendencies that were stable over time (p = 0.09-0.23), although when additional degrees were analyzed as a binary variable, chairs hired in 2010 or after were more likely to have an MBA and/or PhD versus those hired before 2010 (26% vs 10%, p = 0.04). The 3 most common residency programs attended by the neurosurgery chairs were Massachusetts General Hospital (n = 8, 8%), University of California, San Francisco (n = 8, 8%), and University of Michigan (n = 6, 6%). Most chairs (n = 63, 61%) attended residency at the institution and/or were staff at the institution before they were named chair, a tendency that persisted over time (p = 0.86).CONCLUSIONSMost neurosurgery department chairs matriculated into the position before the age of 50 years and, despite selection processes usually involving a national search, most chairs had a previous affiliation with the department, a phenomenon that has been relatively stable over time. In recent years, a large increase has occurred in the proportion of chairs with additional advanced degrees and more extensive research experience, underscoring how neurosurgical leadership has come to require scientific skills and the ability to procure grants, as well as the financial skills needed to navigate the ever-changing financial health care landscape.

Developing an Algorithm for Optimizing Care of Elderly Patients With Glioblastoma.

BACKGROUND: Elderly patients with glioblastoma have an especially poor prognosis; optimizing their medical and surgical care remains of paramount importance. OBJECTIVE: To investigate patient and treatment characteristics of elderly vs nonelderly patients and develop an algorithm to predict elderly patients' survival. METHODS: Retrospective analysis of 554 patients (mean age = 60.8; 42.0% female) undergoing first glioblastoma resection or biopsy at our institution (2005-2011). RESULTS: Of the 554 patients, 218 (39%) were elderly (≥65 yr). Compared with nonelderly, elderly patients were more likely to receive biopsy only (26% vs 16%), have ≥1 medical comorbidity (40% vs 20%), and develop postresection morbidity (eg, seizure, delirium; 25% vs 14%), and were less likely to receive temozolomide (TMZ) (78% vs 90%) and gross total resection (31% vs 45%). To predict benefit of resection in elderly patients (n = 161), we identified 5 factors known in the preoperative period that predicted survival in a multivariate analysis. We then assigned points to each (1 point: Charlson comorbidity score >0, subtotal resection, tumor >3 cm; 2 points: preoperative weakness, Charlson comorbidity score >1, tumor >5 cm, age >75 yr; 4 points: age >85 yr). Having 3 to 5 points (n = 78, 56%) was associated with decreased survival compared to 0 to 2 points (n = 41, 29%, 8.5 vs 16.9 mo; P = .001) and increased survival compared to 6 to 9 points (n = 20, 14%, 8.5 vs 4.5 mo; P < .001). Patients with 6 to 9 points did not survive significantly longer than elderly patients receiving biopsy only (n = 57, 4.5 vs 2.7 mo; P = .58). CONCLUSION: Further optimization of the medical and surgical care of elderly glioblastoma patients may be achieved by providing more beneficial therapies while avoiding unnecessary resection in those not likely to receive benefit from this intervention.

Cross-activating c-Met/ß1 integrin complex drives metastasis and invasive resistance in cancer.

The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/ß1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/ß1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/ß1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and ß1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/ß1 complex to maintain the high-affinity ß1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/ß1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced α5 integrin from ß1 integrin, creating a complex with much greater affinity for fibronectin (FN) than α5ß1. Thus, tumor cells adapt to microenvironmental stressors induced by metastases or bevacizumab by coopting receptors, which normally promote both cell migration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/ß1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.

Improved Survival with Decreased Wait Time to Surgery in Glioblastoma Patients Presenting with Seizure.

BACKGROUND: Preoperative seizure is reported to confer favorable prognosis in glioblastoma patients, but studies to date have not investigated how broadly applicable seizure is as a prognostic factor. OBJECTIVE: To investigate if prompter surgical intervention affects the relationship between preoperative seizure and prognosis in glioblastoma patients, focusing on the development of tumor growth and/or additional preoperative symptoms after seizure. METHODS: Retrospective analysis of 443 patients (mean age = 60.2; 60% male) undergoing first glioblastoma resection at our institution (2005-2011). RESULTS: Preoperative seizure(s) occurred in 28% of patients (n = 124), of which 63 (51%) had only seizure at presentation. Patients experiencing seizure as their only preoperative symptom ("seizure-only"; n = 45) survived over twice as long as patients who presented with seizure and then later developed additional preoperative symptoms (n = 18; "other symptoms postseizure"; 26.8 vs 10.2 months, P < .001) and patients without preoperative seizure ("no seizure"; 26.8 vs 13.1 months, P < .001). Multivariate stepwise analysis revealed preoperative seizures only (hazard ratio 0.54 [0.37-0.75]; P < .001) to be independently associated with increased survival. Longer wait time from presentation (ie, diagnostic magnetic resonance imaging) to surgery was a risk factor for developing additional symptoms. Eleven "other symptoms postseizure" patients (69%) vs 6 of the "seizure-only" patients (15%) had wait times >45 days (P < .001). CONCLUSION: Seizure as the only preoperative symptom independently improved survival, however, when patients developed additional preoperative symptoms, typically due to surgical delay, no prognostic benefit was observed. Prompt diagnosis and neurosurgical intervention is warranted in patients with seizures without other preoperative symptoms to preserve their favorable prognosis.

GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance.

Clinical trials revealed limited response duration of glioblastomas to VEGF-neutralizing antibody bevacizumab. Thriving in the devascularized microenvironment occurring after antiangiogenic therapy requires tumor cell adaptation to decreased glucose, with 50% less glucose identified in bevacizumab-treated xenografts. Compared with bevacizumab-responsive xenograft cells, resistant cells exhibited increased glucose uptake, glycolysis, 13C NMR pyruvate to lactate conversion, and survival in low glucose. Glucose transporter 3 (GLUT3) was upregulated in bevacizumab-resistant versus sensitive xenografts and patient specimens in a HIF-1α-dependent manner. Resistant versus sensitive cell mitochondria in oxidative phosphorylation-selective conditions produced less ATP. Despite unchanged mitochondrial numbers, normoxic resistant cells had lower mitochondrial membrane potential than sensitive cells, confirming poorer mitochondrial health, but avoided the mitochondrial dysfunction of hypoxic sensitive cells. Thin-layer chromatography revealed increased triglycerides in bevacizumab-resistant versus sensitive xenografts, a change driven by mitochondrial stress. A glycogen synthase kinase-3ß inhibitor suppressing GLUT3 transcription caused greater cell death in bevacizumab-resistant than -responsive cells. Overexpressing GLUT3 in tumor cells recapitulated bevacizumab-resistant cell features: survival and proliferation in low glucose, increased glycolysis, impaired oxidative phosphorylation, and rapid in vivo proliferation only slowed by bevacizumab to that of untreated bevacizumab-responsive tumors. Targeting GLUT3 or the increased glycolysis reliance in resistant tumors could unlock the potential of antiangiogenic treatments.

Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies.

Glioblastoma is the most common malignant brain tumor, and it carries an extremely poor prognosis. Attempts to develop targeted therapies have been hindered because the blood-brain barrier prevents many drugs from reaching tumors cells. Furthermore, systemic toxicity of drugs often limits their therapeutic potential. A number of alternative methods of delivery have been developed, one of which is convection-enhanced delivery (CED), the focus of this review. The authors describe CED as a therapeutic measure and review preclinical studies and the most prominent clinical trials of CED in the treatment of glioblastoma. The utilization of this technique for the delivery of a variety of agents is covered, and its shortcomings and challenges are discussed in detail.

Patients cured of acromegaly do not experience improvement of their skull deformities.

PURPOSE: Acromegaly is a rare disease that is associated with many co-morbidities. This condition also causes progressive deformity of the skull which includes frontal bossing and cranial thickening. Surgical and/or medical management can cure this condition in many patients, but it is not understood if patients cured of acromegaly experience regression of their skull deformities. METHODS: We performed a retrospective analysis on patients treated at our dedicated pituitary center from 2009 to 2014. We looked at all MRI images taken during the treatment of these patients and recorded measurements on eight skull dimensions. We then analyzed these measurements for changes over time. RESULTS: 29 patients underwent curative treatment for acromegaly within our timeframe. The mean age for this population was 45.0 years old (range 19-70) and 55.2 % (n = 16) were female. All of these patients were treated with a transsphenoidal resection for a somatotropic pituitary adenoma. 9 (31.1%) of these patients required further medical therapy to be cured. We found statically significant variation in the coronal width of the sella turcica after therapy, which is likely attributable to changes from transsphenoidal surgery. None of the other dimensions had significant variation over time after cure. CONCLUSION: Patients cured of acromegaly should not expect natural regression of their skull deformities. Our study suggests that both frontal bossing and cranial thickening do not return to normal after cure.

Frontal Sinus Morphometry in Relation to Surgically Relevant Landmarks in the United States Population.

BACKGROUND: Knowledge of frontal sinus morphometry is important in bifrontal, pterional, orbitozygomatic, and supraorbital craniotomies. Inadvertent frontal sinus violation can lead to infection, cerebrospinal fluid fistula, and mucocele formation. In particular, knowledge of anatomy in relation to surgically relevant landmarks can help surgeons perform these procedures more precisely and safely. We performed a descriptive radiographic analysis to better understand variations in frontal sinus anatomy. METHODS: Using 3-dimensional reconstructive software, we analyzed 162 normal cranial computerized tomographic angiograms (from 80 men and 82 women). A line between the supraorbital notches (SONs) was used as a horizontal reference line (HRL). We recorded the maximum sinus height and width from the HRL and midline, respectively. In addition, sinus width was measured in relation to the SON at 0, 1, and 2 cm above the HRL. RESULTS: The mean maximal sinus height from the HRL was 1.8 cm. The mean maximum sinus width was 2.6 cm (right and left) from midline and 0.46 cm (right) and 0.49 cm (left) from the SON. Less than 11% of sinuses were lateral to the SON at 2.0 cm above the HRL and <6% of sinuses were >1.5 cm lateral to the SON at 1.0 cm above the HRL. CONCLUSIONS: Planned surgical corridors >1.5 cm lateral to the SON and/or >3.0 cm above the HRL are most likely to avoid the frontal sinus based on our radiographic measurements of normal sinus anatomy. Careful radiographic study and appropriate planning for more medial and/or inferior corridors is suggested.

Cortico-cortical evoked potentials for sites of early versus late seizure spread in stereoelectroencephalography.

Cortico-cortical evoked potentials offer the possibility of understanding connectivity within seizure networks to improve diagnosis and more accurately identify candidates for seizure surgery. We sought to determine if cortico-cortical evoked potentials and post-stimulation oscillatory changes differ for sites of EARLY versus LATE ictal spread. 37 patients undergoing stereoelectroencephalography were tested using a cortico-cortical evoked potential paradigm. All electrodes were classified according to the speed of ictal spread. EARLY spread sites were matched to a LATE spread site equidistant from the onset zone. Root-mean-square was used to quantify evoked responses and post-stimulation gamma band power and coherence were extracted and compared. Sites of EARLY spread exhibited significantly greater evoked responses after stimulation across all patients (t(36)=2.973, p=0.004). Stimulation elicited enhanced gamma band activity at EARLY spread sites (t(36)=2.61, p=0.03, FDR corrected); this gamma band oscillation was highly coherent with the onset zone. Cortico-cortical evoked potentials and post-stimulation changes in gamma band activity differ between sites of EARLY versus LATE ictal spread. The oscillatory changes can help visualize connectivity within the seizure network.