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.

Regional improvements in lumbosacropelvic Hounsfield units following teriparatide treatment.

OBJECTIVE: Opportunistic Hounsfield unit (HU) determination from CT imaging has been increasingly used to estimate bone mineral density (BMD) in conjunction with assessments from dual energy x-ray absorptiometry (DXA). The authors sought to compare the effect of teriparatide on HUs across different regions in the pelvis, sacrum, and lumbar spine, as a surrogate measure for the effects of teriparatide on lumbosacropelvic instrumentation. METHODS: A single-institution retrospective review of patients who had been treated with at least 6 months of teriparatide was performed. All patients had at least baseline DXA as well as pre- and post-teriparatide CT imaging. HUs were measured in the pedicle, lamina, and vertebral body of the lumbar spine, in the sciatic notch, and at the S1 and S2 levels at three different points (ilium, sacral body, and sacral ala). RESULTS: Forty patients with an average age of 67 years underwent a mean of 20 months of teriparatide therapy. Mean HUs of the lumbar lamina, pedicles, and vertebral body were significantly different from each other before teriparatide treatment: 343 ± 114, 219 ± 89.2, and 111 ± 48.1, respectively (p < 0.001). Mean HUs at the S1 level for the ilium, sacral ala, and sacral body were also significantly different from each other: 124 ± 90.1, -10.7 ± 61.9, and 99.1 ± 72.1, respectively (p < 0.001). The mean HUs at the S2 level for the ilium and sacral body were not significantly different from each other, although the mean HU at the sacral ala (-11.9 ± 52.6) was significantly lower than those at the ilium and sacral body (p = 0.003 and 0.006, respectively). HU improvement occurred in most regions following teriparatide treatment. In the lumbar spine, the mean lamina HU increased from 343 to 400 (p < 0.001), the mean pedicle HU increased from 219 to 242 (p = 0.04), and the mean vertebral body HU increased from 111 to 134 (p < 0.001). There were also significant increases in the S1 sacral body (99.1 to 130, p < 0.05), S1 ilium (124 vs 165, p = 0.01), S1 sacral ala (-10.7 vs 3.68, p = 0.04), and S2 sacral body (168 vs 189, p < 0.05). CONCLUSIONS: There was significant regional variation in lumbar and sacropelvic HUs, with most regions significantly increasing following teriparatide treatment. The sacropelvic area had lower HU values than the lumbar spine, more regional variation, and a higher degree of correlation with BMD as measured on DXA. While teriparatide treatment resulted in HUs > 110 in the majority of the lumbosacral spine, the HUs in the sacral ala remained suggestive of severe osteoporosis, which may limit the effectiveness of fixation in this region.

Effective heat dissipation in an adiabatic near-field transducer for HAMR.

To achieve a feasible heat-assisted magnetic recording (HAMR) system, a near-field transducer (NFT) is necessary to strongly focus the optical field to a lateral region measuring tens of nanometres in size. An NFT must deliver sufficient power to the recording medium as well as maintain its structural integrity. The self-heating problem in the NFT causes materials failure that leads to the degradation of the hard disk drive performance. The literature reports NFT structures with physical sizes well below 1 micron which were found to be thermo-mechanically unstable at an elevated temperature. In this paper, we demonstrate an adiabatic NFT to address the central challenge of thermal engineering for a HAMR system. The NFT is formed by an isosceles triangular gold taper plasmonic waveguide with a length of 6 µm and a height of 50 nm. Our study shows that in the full optically and thermally optimized system, the NFT efficiently extracts the incident light from the waveguide core and can improve the shape of the heating source profile for data recording. The most important insight of the thermal performance is that the recording medium can be heated up to 866 K with an input power of 8.5 mW which is above the Curie temperature of the FePt film while maintaining the temperature in the NFT at 390 K without a heat spreader. A very good thermal efficiency of 5.91 is achieved also. The proposed structure is easily fabricated and can potentially reduce the NFT deformation at a high recording temperature making it suitable for practical HAMR application.

Optical and thermal analysis of the light-heat conversion process employing an antenna-based hybrid plasmonic waveguide for HAMR.

We investigate a tapered, hybrid plasmonic waveguide which has previously been proposed as an optically efficient near-field transducer (NFT), or component thereof, in several devices which aim to exploit nanofocused light. We numerically analyze how light is transported through the waveguide and ultimately focused via effective-mode coupling and taper optimization. Crucial dimensional parameters in this optimization process are identified that are not only necessary to achieve maximum optical throughput, but also optimum thermal performance with specific application towards heat-assisted magnetic recording (HAMR). It is shown that existing devices constructed on similar waveguides may benefit from a heat spreader to avoid deformation of the plasmonic element which we achieve with no cost to the optical efficiency. For HAMR, our design is able to surpass many industry requirements in regard to both optical and thermal efficiency using pertinent figure of merits like 8.5% optical efficiency.

Color Vision Impairment Differentiates Alzheimer Dementia From Dementia With Lewy Bodies.

OBJECTIVE: Dementia with Lewy bodies (DLB) is frequently misdiagnosed for Alzheimer dementia (AD), especially in its earlier stages. We characterized color vision impairment (CVI) in patients with DLB versus patients with AD to determine its usefulness in improving accuracy of early diagnosis. METHODS: We retrospectively reviewed charts of patients with AD, DLB, and patients with mild cognitive impairment suspected to be in the prodromal phase of DLB (pro-DLB) or prodromal phase of AD (pro-AD). All patients underwent an online 15-hue color vision arrangement test. RESULTS: Fifty-two patients were included in this study with a median age of 77 years, of which 44% were female. No significant differences in gender, age, or Montreal Cognitive Assessment existed among patients with AD (n = 15), pro-AD (n = 5), pro-DLB (n = 8), and DLB (n = 24). Of the 52 patients, 4 (2 AD, 1 DLB, and 1 pro-AD) had CVI history from a young age and were excluded from final analyses. New-onset CVI prevalence differed significantly based on diagnosis: patients with pro-AD (20%), patients with AD (15%), patients with pro-DLB (38%), and patients with DLB (78%, P < .001). In a stepwise multivariate logistic regression analysis to determine factors associated with CVI, "diagnosis type" as a binary variable (DLB or pro-DLB vs AD or pro-AD) was the only variable retained in the model (odds ratio = 9.8 [95% CI: 2.3-42.1], P < .001). CONCLUSIONS: Color vision impairment in patients with DLB showed a prevalence similar to the core features of DLB (∼80%) and can be supportive to a diagnosis of DLB versus AD. Pending prospective confirmation of our findings, simple online color vision testing could be incorporated into multivariate diagnostic tools to possibly improve accuracy of early diagnosis of DLB.

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.

Adaptation to antiangiogenic therapy in neurological tumors.

Because tumors require a vascular supply for their survival and growth, angiogenesis is considered an important therapeutic target in most human cancers including cancer of the central nervous system. Antiangiogenic therapy has focused on inhibitors of the vascular endothelial growth factor (VEGF) signaling pathway. VEGF pathway-targeted drugs have shown therapeutic efficacy in several CNS tumors and have been tried most frequently in glioblastoma. These therapies, however, have been less effective than anticipated as some patients do not respond to therapy and some receive only modest benefit. Underlying this suboptimal response are multiple mechanisms of drug resistance involving changes in both tumor cells and their microenvironment. In this review, we discuss the multiple proposed mechanisms by which neurological tumors evolve to become resistant to antiangiogenic therapies. A better understanding of these mechanisms, their context, and their interplay will likely facilitate improvements in pharmacological strategies for the targeted treatment of neurological tumors.

Update on the management of recurrent Cushing's disease.

After transsphenoidal surgery, Cushing's disease (CD) shows excellent long-term remission rates, but it may recur and pose a therapeutic challenge. Findings in recent published reports on the treatment of recurrent adrenocorticotropic hormone (ACTH)-secreting tumors suggest that repeat resection, radiation-based therapies such as Gamma Knife surgery and proton-beam radiosurgery, pharmacotherapy, and bilateral adrenalectomy all have important roles in the treatment of recurrent CD. Each of these interventions has inherent risks and benefits that should be presented to the patient during counseling on retreatment options. Radiation-based therapies increasingly appear to have efficacies similar to those of repeat resection in achieving biochemical remission and tumor control. In addition, an expanding retinue of medication-based therapies, several of which are currently being evaluated in clinical trials, has shown some promise as tertiary adjunctive therapies. Lastly, bilateral adrenalectomy may offer durable control of refractory recurrent CD. An increasing number of published studies with long-term patient outcomes highlight the evolving treatment patterns in the management of recurrent CD.

World War II, tantalum, and the evolution of modern cranioplasty technique.

Cranioplasty is a unique procedure with a rich history. Since ancient times, a diverse array of materials from coconut shells to gold plates has been used for the repair of cranial defects. More recently, World War II greatly increased the demand for cranioplasty procedures and renewed interest in the search for a suitable synthetic material for cranioprostheses. Experimental evidence revealed that tantalum was biologically inert to acid and oxidative stresses. In fact, the observation that tantalum did not absorb acid resulted in the metal being named after Tantalus, the Greek mythological figure who was condemned to a pool of water in the Underworld that would recede when he tried to take a drink. In clinical use, malleability facilitated a single-stage cosmetic repair of cranial defects. Tantalum became the preferred cranioplasty material for more than 1000 procedures performed during World War II. In fact, its use was rapidly adopted in the civilian population. During World War II and the heyday of tantalum cranioplasty, there was a rapid evolution in prosthesis implantation and fixation techniques significantly shaping how cranioplasties are performed today. Several years after the war, acrylic emerged as the cranioplasty material of choice. It had several clear advantages over its metallic counterparts. Titanium, which was less radiopaque and had a more optimal thermal conductivity profile (less thermally conductive), eventually supplanted tantalum as the most common metallic cranioplasty material. While tantalum cranioplasty was popular for only a decade, it represented a significant breakthrough in synthetic cranioplasty. The experiences of wartime neurosurgeons with tantalum cranioplasty played a pivotal role in the evolution of modern cranioplasty techniques and ultimately led to a heightened understanding of the necessary attributes of an ideal synthetic cranioplasty material. Indeed, the history of tantalum cranioplasty serves as a model for innovative thinking and adaptive technology development.

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.

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.

A generalized "cut and projection" algorithm for the generation of quasiperiodic plasmonic concentrators for high efficiency ultra-thin film photovoltaics.

This report will present a generalized two-dimensional quasiperiodic (QP) tiling algorithm based on de Bruijn's "cut and projection" method for use in plasmonic concentrator (PC) / photovoltaic hybrid devices to produce wide-angle, polarization-insensitive, and broadband light absorption enhancement. This algorithm can be employed with any PC consisting of point-like scattering objects, and can be fine-tuned to achieve a high spatial density of points and high orders of local and long-range rotational symmetry. Simulations and experimental data demonstrate this enhancement in ultra-thin layers of organic photovoltaic materials resting on metallic films etched with arrays of shallow sub-wavelength nanoholes. These devices work by coupling the incident light to surface plasmon polariton (SPP) modes that propagate along the dielectric / metal interface. This effectively increases the scale of light-matter interaction, and can also result in constructive interference between propagating SPP waves. By comparing PCs made with random, periodic, and QP arrangements, it is clear that QP is superior in intensifying the local fields and enhancing absorption in the active layer.

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.

Lower Hounsfield Units at the Upper Instrumented Vertebrae are Significantly Associated With Proximal Junctional Kyphosis and Failure Near the Thoracolumbar Junction.

BACKGROUND: Low bone mineral density (BMD) on dual energy x-ray absorptiometry (DXA) is likely a risk factor for proximal junctional kyphosis (PJK) and proximal junctional failure (PJF). However, prior instrumentation and degenerative changes can preclude a lumbar BMD measurement. Hounsfield units (HU) represent an alternative method to estimate BMD via targeted measurements at the intended operative levels. OBJECTIVE: To determine if patients with lower HU at the upper instrumented vertebrae (UIV) and vertebral body superior to the UIV (UIV + 1) are at greater risk for PJK and PJF. METHODS: A retrospective chart review identified patients at least 50 yr of age who underwent instrumented lumbar fusion with pelvic fixation, a UIV from T10 to L2, and a preoperative computed tomography (CT) encompassing the UIV. HU were measured at the UIV, UIV + 1, and the L3-L4 vertebral bodies. RESULTS: A total of 150 patients (80 women and 70 men) were included with an average age of 66 yr and average follow-up of 32 mo. Multivariable logistic regression analysis with an area under the curve (AUC) of 0.89 demonstrated HU at the UIV/UIV + 1 as the only independent predictor of PJK/PJF with an odds ratio of 0.94 (P-value = .031) for a change in a single HU. Patients with HU at UIV/UIV + 1 of <110 (n = 35), 110 to 160 (n = 73), and >160 (n = 42) had a rate of PJK/PJF of 63%, 27%, and 12%, respectively (P-value < .001). CONCLUSION: Patients with lower HU at the UIV and UIV + 1 were significantly associated with PJK and PJF, with an optimal cutoff of 122 HU that maximizes sensitivity and specificity.

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.

Clinical and Imaging Characteristics Associated with Color Vision Impairment in Lewy Body Disease.

BACKGROUND: Color vision impairment (CVI) has been reported in dementia with Lewy bodies (DLB) and prodromal Lewy body disease (pro-LBD). OBJECTIVE: In order to better characterize the diagnostic value of CVI testing, we compared the prevalence of CVI in patients with with Lewy body disease compared to Alzheimer's disease (AD), and we examined clinical and imaging characteristics associated with CVI in patients with DLB and suspected pro-LBD. METHODS: We retrospectively reviewed medical records, dopamine transporter (DaT-SPECT) imaging, and volumetric MRI from patients with AD, DLB, and suspected pro-LBD who underwent an online Farnsworth D-15 color vision test. RESULTS: 111 patients (62 DLB, 25 pro-LBD, and 24 AD) were included with a median age of 75 years. Newly diagnosed CVI was present in 67% of patients with DLB, 44% of patients with pro-LBD, and 18% of patients with AD. In patients with DLB, CVI was associated with lower Montreal Cognitive Assessment (MoCA) scores and lower sub-scores in visuospatial/executive function, naming, and language. In a multivariable logistic regression model, a diagnosis of DLB or pro-LBD compared to AD, and a lower composite MoCA score in visuospatial/executive function, naming, and language were associated with CVI controlling for age and gender. Among 17 DLB patients who underwent volumetric MRI, patients with CVI (n = 9) demonstrated lower normative volumetric percentiles in the right transverse superior temporal lobe. CONCLUSION: We provide further evidence that CVI can help differentiate DLB from AD, and we suggest that CVI may be an indicator of cognitive decline and disease progression in DLB.

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.