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Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients.

BACKGROUND Disparity in mental health care among cancer patients remains understudied. METHODS A large, retrospective, single tertiary-care institution cohort study was conducted based on deidentified electronic health record data of 54,852 adult cancer patients without prior mental health diagnosis (MHD) diagnosed at the University of California, San Francisco between January 2012 and September 2019. The exposure of interest was early-onset MHD with or without psychotropic medication (PM) within 12 months of cancer diagnosis and primary outcome was all-cause mortality. RESULTS There were 8.2% of patients who received a new MHD at a median of 197 days (interquartile range, 61-553) after incident cancer diagnosis; 31.0% received a PM prescription; and 3.7% a mental health-related visit (MHRV). There were 62.6% of patients who were non-Hispanic White (NHW), 10.8% were Asian, 9.8% were Hispanic, and 3.8% were Black. Compared with NHWs, minority cancer patients had reduced adjusted odds of MHDs, PM prescriptions, and MHRVs, particularly for generalized anxiety (Asian odds ratio [OR], 0.66, 95% CI, 0.55-0.78; Black OR, 0.60, 95% CI, 0.45-0.79; Hispanic OR, 0.72, 95% CI, 0.61-0.85) and selective serotonin-reuptake inhibitors (Asian OR, 0.43, 95% CI, 0.37-0.50; Black OR, 0.51, 95% CI, 0.40-0.61; Hispanic OR, 0.79, 95% CI, 0.70-0.89). New early MHD with PM was associated with elevated all-cause mortality (12-24 months: hazard ratio [HR], 1.43, 95% CI, 1.25-1.64) that waned by 24 to 36 months (HR, 1.18, 95% CI, 0.95-1.45). CONCLUSIONS New mental health diagnosis with PM was a marker of early mortality among cancer patients. Minority cancer patients were less likely to receive documentation of MHDs or treatment, which may represent missed opportunities to identify and treat cancer-related mental health conditions.

Meningiomas are the most common primary central nervous system neoplasm. Despite promising recent progress in elucidating the genomic landscape and underlying biology of these histologically, molecularly, and clinically diverse tumors, the mainstays of meningioma treatment remain maximal safe resection and radiation therapy. The aim of this review of meningioma radiotherapy is to provide a concise summary of the history, current evidence, and future for application of radiotherapy in meningioma treatment.

Purpose To perform a propensity-score matched analysis comparing stereotactic body radiation therapy (SBRT) boost and high-dose-rate (HDR) boost for localized prostate cancer. Methods and Materials A single-institution retrospective chart review was conducted of men treated with pelvic external beam radiation therapy (EBRT) and SBRT boost (21 Gy and 19 Gy in 2 fractions) to the prostate for prostate cancer. A cohort treated at the same institution with HDR brachytherapy boost (19 Gy in 2 fractions) was compared. Propensity-score (PS) matching and multivariable Cox regression were used for analysis. Outcomes were biochemical recurrence freedom (BCRF) and metastasis freedom (MF). Results One hundred thirty-one men were treated with SBRT boost and 101 with HDR boost with median follow-up of 73.4 and 186.0 months, respectively. In addition, 68.8% of men had high-risk and 26.0% had unfavorable-intermediate disease, and 94.3% received androgen deprivation therapy. Five- and 10-year unadjusted BCRF was 88.8% and 85.3% for SBRT and 91.8% and 74.6% for HDR boost (log-rank P = .3), and 5- and 10-year unadjusted MF was 91.7% and 84.3% for SBRT and 95.8% and 82.0% for HDR (log-rank P = .8). After adjusting for covariates, there was no statistically significant difference in BCRF (hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.37-1.79; P = .6) or MF (HR 1.07; 95% CI, 0.44-2.57; P = .9) between SBRT and HDR boost. Similarly, after PS matching, there was no statistically significant difference between SBRT and HDR (BCRF: HR 0.66, 0.27-1.62, P = .4; MF: HR 0.84, 0.31-2.26, P = .7). Grade 3+ genitourinary and gastrointestinal toxicity in the SBRT cohort were 4.6% and 1.5%, and 3.0% and 0.0% in the HDR cohorts (P = .4, Fisher exact test). Conclusions SBRT boost plus pelvic EBRT for prostate cancer resulted in similar BCRF and MF to HDR boost in this single institution, PS matched retrospective analysis. Toxicity was modest. Prospective evaluation of SBRT boost for the treatment of unfavorable-intermediate and high-risk prostate cancer is warranted.

Objective To report the safety and efficacy of magnetic resonance-guided focused ultrasound (MRgFUS) in the treatment of painful bone metastases through a systematic review and meta-analysis of pain scores before and after MRgFUS treatment and post-treatment adverse events. Materials and methods A comprehensive literature search of PubMed and Embase databases was performed for studies evaluating the efficacy and/or safety of MRgFUS. The mean difference of pain scores (10-point visual analogue scale or numerical rating scale) between baseline and 1-month/3-month pain scores was collected and analyzed in a pooled meta-analysis. Post-treatment adverse events based on the Common Terminology Criteria for Adverse Events (CTCAE) grading were recorded and the pooled prevalence was calculated. Results A total of 33 studies published between 2007 and 2019 were collected, resulting in a total sample size of 1082 patients. The majority of the studies were prospective with a reported follow-up period of 3 months. The pooled proportion of patients that achieved pain relief from MRgFUS (complete response or partial response [≥ 2-point improvement of pain score]) was 79% (95% CI 73–83%). The pooled 1-month and 3-month mean difference in pain score were − 3.8 (95% CI − 4.3; − 3.3) and − 4.4 (95% CI − 5.0; − 3.7), respectively. The overall rate of high-grade (CTCAE grade 3 or higher) and low-grade (CTCAE grade 2 or lower) MRgFUS-related adverse events were 0.9% and 5.9%, respectively. Conclusion MRgFUS is an effective procedure that is able to provide significant pain palliation for patients with symptomatic bone metastases with a favorable safety profile.

Purpose To identify clinical and imaging variables associated with symptomatic recurrence of osteoid osteomas (OOs) treated with computerized tomography (CT)–guided radiofrequency (RF) ablation. Materials and Methods Seventy-one patients treated with the use of CT-guided RF ablation for OO at a single institution from July 2005 to May 2018 were included in this retrospective cohort analysis. Clinical data, including patient age, sex, race, and clinical outcomes, were collected from institutional electronic health records and telephone follow-up. Imaging variables regarding tumor characteristics were gathered from imaging reports and a blinded review of preprocedural images by an experienced musculoskeletal radiologist. Logistic regression, Cox proportional hazards, and Kaplan-Meier analyses were used to identify variables that are significantly associated with symptomatic recurrence, which was defined as pain occurring > 2 weeks after RF ablation. Results Ten patients (14.1%) experienced symptomatic recurrence at a median of 21.5 months after RF ablation. Univariable logistic regression classified young age (≤ 13 years), female sex, maximum tumor length, and “eccentricity index” (EI) ≥ 3 as predictive variables significantly associated with symptomatic recurrence. Multivariable logistic regression identified female sex and EI ≥ 3 to be significant predictors for symptomatic recurrence. A multivariable proportional hazards Cox regression of time to recurrence revealed EI ≥ 3 to be the only significant predictor of symptomatic recurrence. Conclusions Female patients with OOs with an EI ≥ 3 have a greater risk of symptomatic recurrence following RF ablation. The EI is a useful tool to identify OOs with elongated 3-dimensional morphology, which may warrant more extensive ablation.

Background: Pancreatic cancer is the third leading cause of cancer-related death in the United States. Total serum cholesterol (TSC) may predict cancer risk, although its role independent of statins remains elusive. We examined the association between TSC and pancreatic cancer risk independent of statins. Methods: A nested case–control analysis was conducted among statin-naïve patients within The Health Improvement Network (THIN), a United Kingdom–based general practice database. Cases were >40 years old and diagnosed with pancreatic cancer after at least 6 months of follow-up. Controls were selected by incidence density sampling and matched by age, sex, practice site, and follow-up. Primary exposure was TSC (mmol/L) prior to index date. Conditional logistic regression estimated ORs for pancreatic cancer risk associated with TSC. Sensitivity analyses were conducted among nondiabetics. Results: Among 1,241 cases and 3,307 matched controls, an average 8% reduction was observed in pancreatic cancer risk per mmol/L increase in TSC [OR 0.92, 95% confidence interval (CI): 0.85–1.00; nondiabetics: OR 0.91, 95% CI: 0.83–0.99]. When TSC was measured at 12-month intervals prior to diagnosis, the OR between TSC and pancreatic cancer was 0.88 at 0 to 12 months (95% CI: 0.77–1.00; nondiabetics: OR 0.81, 95% CI: 0.68–0.96). No significant association was seen at subsequent discrete intervals before index date. Conclusions: TSC is a significant predictor of short-term risk for pancreatic cancer. This risk increase associated with lower TSC was independent of statins. Impact: TSC could serve as a biomarker for risk stratification, screening, and early diagnosis of pancreatic cancer in future clinical prediction models.

Our group observed the first case of synchronous gastric neuroendocrine tumor (NET) and duodenal gastrinoma with autoimmune chronic atrophic gastritis (CAG), in the absence of Helicobacter pylori infection. Demographic, clinical, endoscopic, and pathologic data were abstracted from the electronic medical record at Mount Sinai Hospital from 2013 to 2015. The patient's anonymity was carefully protected, and informed consent was obtained for publication of protected health information. A 53-year-old woman with hypertension presented to Mount Sinai Hospital in June 2013 for a second opinion for management of gastric and duodenal NETs. After evaluation by gastroenterology and surgery, repeat upper endoscopy with ultrasound and fine-needle aspiration revealed multiple diminutive type I gastric NETs and 2 duodenal NETs, against a background of autoimmune CAG, with biopsy pathology negative for H. pylori. She subsequently underwent a transduodenal resection of the duodenal NETs, confirming low-grade, gastrin-positive, stage T2 duodenal NET. On routine follow-up over the next 2 years, clinical, radiographic, and endoscopic surveillance revealed no recurrent or metastatic gastric or duodenal disease. This first report of synchronous duodenal gastrinoma and gastric NET in the setting of autoimmune CAG can broaden our understanding of gastric NET pathophysiology.

PURPOSE: During the COVID-19 surge months of March and April 2020, our New York multicenter health system experienced an influx of cases with COVID-19. We sought to study the impact of the surge period on patients with cancer prescribed radiation treatment (RT). METHODS: We reviewed our secure departmental quality assurance database for all patients who underwent RT planning simulations from March 6, 2020, through April 30, 2020. A priority level between 1 and 3 was prospectively assigned to each case based on faculty consensus to determine which patients required immediate RT. In May 2020, each faculty physician again retrospectively reviewed their patients from the database and provided additional commentary on how the COVID-19 pandemic had affected each patient's care. All statistics are descriptive. RESULTS: A total of 412 RT courses in 406 unique patients were simulated for linear accelerator–based external beam RT. The median age was 66 years. Treatment intent was curative in 70.6% and palliative in 29.4%. Of the 412 cases, 66.7% were priority 1, 25% priority 2, and 7.8% priority 3. Two hundred thirty-nine cases (58%) underwent standard-of-care diagnosis, workup, and treatment plan. Seventeen patients (4.1%) electively canceled their RT, and 17 others (4.1%) electively delayed RT start. Thirty-four (8.3%) were prescribed hypofractionation to shorten their RT course, and 22 (5.3%) had a change in modality. Incomplete or delayed workup was identified in 19 cases (4.6%). CONCLUSION: The COVID-19 pandemic surge resulted in 42% of our patients having a non–standard-of-care pathway. This outcome demonstrates a significant impact of the COVID-19 crisis on routine cancer care.

BackgroundPrognostic markers for meningioma are needed to risk-stratify patients and guide postoperative surveillance and adjuvant therapy.ObjectiveTo identify a prognostic gene signature for meningioma recurrence and mortality after resection using targeted gene-expression analysis.MethodsTargeted gene-expression analysis was used to interrogate a discovery cohort of 96 meningiomas and an independent validation cohort of 56 meningiomas with comprehensive clinical follow-up data from separate institutions. Bioinformatic analysis was used to identify prognostic genes and generate a gene-signature risk score between 0 and 1 for local recurrence.ResultsWe identified a 36-gene signature of meningioma recurrence after resection that achieved an area under the curve of 0.86 in identifying tumors at risk for adverse clinical outcomes. The gene-signature risk score compared favorably to World Health Organization (WHO) grade in stratifying cases by local freedom from recurrence (LFFR, P

Radiation therapy is an option as a primary treatment for small meningiomas and for treatment of recurrences after surgery. The technology for delivery of treatment has advanced much in the last 15 years, and now image guidance and stereotactic methods are used for defining the target location. There are different forms of treatment that include protons and photons, both delivered using multiple beam paths converging on the target. Currently the most common form of treatment uses photon energy derived from a linear accelerator using intensity modulated techniques. Radiation delivered in multiple sessions, more than five, is termed fractionated treatment, whereas those using five or less have been referred to radiosurgery. This chapter outlines the usefulness of radiation in the management of meningioma.

OBJECTIVEThe goal of this study was to investigate the impact of adjuvant radiotherapy (RT) on local recurrence and overall survival in patients undergoing primary resection of atypical meningioma, and to identify predictive factors to inform patient selection for adjuvant RT.METHODSOne hundred eighty-two patients who underwent primary resection of atypical meningioma at a single institution between 1993 and 2014 were retrospectively identified. Patient, meningioma, and treatment data were extracted from the medical record and compared using the Kaplan-Meier method, log-rank tests, multivariate analysis (MVA) Cox proportional hazards models with relative risk (RR), and recursive partitioning analysis.RESULTSThe median patient age and imaging follow-up were 57 years (interquartile range [IQR] 45–67 years) and 4.4 years (IQR 1.8–7.5 years), respectively. Gross-total resection (GTR) was achieved in 114 cases (63%), and 42 patients (23%) received adjuvant RT. On MVA, prognostic factors for death from any cause included GTR (RR 0.4, 95% CI 0.1–0.9, p = 0.02) and MIB1 labeling index (LI) ≤ 7% (RR 0.4, 95% CI 0.1–0.9, p = 0.04). Prognostic factors on MVA for local progression included GTR (RR 0.2, 95% CI 0.1–0.5, p = 0.002), adjuvant RT (RR 0.2, 95% CI 0.1–0.4, p < 0.001), MIB1 LI ≤ 7% (RR 0.2, 95% CI 0.1–0.5, p < 0.001), and a remote history of prior cranial RT (RR 5.7, 95% CI 1.3–18.8, p = 0.03). After GTR, adjuvant RT (0 of 10 meningiomas recurred, p = 0.01) and MIB1 LI ≤ 7% (RR 0.1, 95% CI 0.003–0.3, p < 0.001) were predictive for local progression on MVA. After GTR, 2.2% of meningiomas with MIB1 LI ≤ 7% recurred (1 of 45), compared with 38% with MIB1 LI > 7% (13 of 34; p < 0.001). Recursive partitioning analysis confirmed the existence of a cohort of patients at high risk of local progression after GTR without adjuvant RT, with MIB1 LI > 7%, and evidence of brain or bone invasion. After subtotal resection, adjuvant RT (RR 0.2, 95% CI 0.04–0.7, p = 0.009) and ≤ 5 mitoses per 10 hpf (RR 0.1, 95% CI 0.03–0.4, p = 0.002) were predictive on MVA for local progression.CONCLUSIONSAdjuvant RT improves local control of atypical meningioma irrespective of extent of resection. Although independent validation is required, the authors’ results suggest that MIB1 LI, the number of mitoses per 10 hpf, and brain or bone invasion may be useful guides to the selection of patients who are most likely to benefit from adjuvant RT after resection of atypical meningioma.

Atypical menginomas demonstrate increased clinical aggressiveness characterized by recurrence and diminished survival. The optimal management of atypical meningioma in the recurrent setting is especially not well defined. To characterize outcomes following salvage treatment of recurrent atypical meningioma and to identify risk factors for further recurrence. Retrospective chart review was performed on 65 patients who underwent salvage treatment of atypical meningioma at a single institution. Data were analyzed using the Kaplan–Meier method and Cox proportional hazards modeling. Sixty-five patients with recurrent atypical meningioma and median imaging follow-up of 4.0 years (range 1.9–6.6 years) underwent 62 surgeries and 114 radiation treatments (RT) for salvage therapy. Salvage modality was surgery (21%), surgery/RT (25%), or RT alone (54%), associated with 2 year local freedom from recurrence (LFFR) of 36, 59, and 73%, respectively (P = 0.01). Twenty percent of patients experienced CTCAE grade ≥ 3 toxicity with salvage therapy. Thirty-nine percent of patients experienced ≥ 3 recurrences. The median disease-free survival intervals after first and second salvage treatments were 2.9 and 1.3 years, respectively. On univariate Cox analysis, prior subtotal resection, prior RT, tumor diameter > 2.5 cm, and multifocal local recurrence were associated with recurrence after salvage therapy. On multivariate logistic regression, only multifocal local recurrence was associated with further recurrence. Recurrent atypical meningioma is clinically and pathologically more aggressive than primary atypical meningioma, and the likelihood of durable local control with salvage therapy is lower. Future efforts should identify patients at risk of recurrence, and aggressive upfront treatment should be employed.

To report the early experience using an automated chatbot (Chats)for patient-reported outcomes (PRO) and symptom self-managementinhead and neck cancer (HNC) patients undergoing radiation treatment (RT).Patients aged ≥ 18 yearsdiagnosed with HNC who were scheduled to begin RT were given the option to use Chats from June 2018 to June 2019. Enrolled patients received chat notifications two days before weekly on-treatment visitsand every 1-4 weeks after RT for an additional 4 months. After the first in-person follow-up visit, participants completed an electronic usability and satisfaction questionnaire.Of 95 patients who agreed to participate, 84 were eligible for analysis.Participantswere significantly younger than patients who declined participation (mean age 61.3 vs 68.3 years;p-value 0.001). Patient engagement with Chats was highest at 67% during the first month and declined over time (p-value = 0.004). Concordance between PRO and clinician-reported outcomes (CRO) was fair, ranging from 0.10 to 0.43 (Cohen κ statistics). The most commonly under-reported symptoms were salivary duct inflammation (53%), xerostomia (41%), and mucositis (37%). 89% (39 of 44) of patients who completed surveys found Chats easy to use, and 61% reported that Chats helped with symptom self-management and reduced the need to call the care team.These early results suggest that an interactive chatbot is feasible and provides support for HNC patients during and after RT. Chats identified discordance between PRO and CRO. Further study is required to measure benefits of Chats in a larger population.

IMPORTANCE: Owing to the proximity to critical neurologic structures, treatment options for brainstem metastases (BSM) are limited, and BSM growth can cause acute morbidity or death. Stereotactic radiosurgery (SRS) is the only local therapy for BSM, but efficacy and safety of this approach are incompletely understood because patients with BSM are excluded from most clinical trials. OBJECTIVE: To perform a systematic review and comparative meta-analysis of SRS studies for BSM in the context of prospective trials of SRS or molecular therapy for nonbrainstem brain metastases (BM). DATA SOURCES: A comprehensive search of Pubmed/MEDLINE and Embase was performed on December 6, 2019. STUDY SELECTION: English-language studies of SRS for BSM with at least 10 patients and reporting 1 or more outcomes of interest were included. Duplicate studies or studies with overlapping data sets were excluded. Studies were independently evaluated by 2 reviewers, and discrepancies were resolved by consensus. A total of 32 retrospective studies published between 1999 and 2019 were included in the analysis. DATA EXTRACTION AND SYNTHESIS: Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed to identify studies. Study quality was assessed using Methodological Index for Non-Randomized Studies criteria. Fixed and random-effects meta-analyses and meta-regressions were performed for the outcomes of interest. MAIN OUTCOMES AND MEASURES: Primary study outcomes included 1-year and 2-year local control and overall survival, objective response rate, symptom response rate, neurological death rate, and rate of grade 3 to 5 toxic effects as described in Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The 32 retrospective studies included in the analysis comprised 1446 patients with 1590 BSM that were treated with SRS (median [range] dose, 16 [11-39] Gy; median [range] fractions, 1 [1-13]). Local control at 1 year was 86% (95% CI, 83%-88%; I(2) = 38%) in 1410 patients across 31 studies, objective response rate was 59% (95% CI, 47%-71%; I(2) = 88%) in 642 patients across 17 studies, and symptom improvement was 55% (95% CI, 47%-63%; I(2) = 41%) in 323 patients across 13 studies. Deaths from BSM progression after SRS were rare (19 of 703 [2.7%] deaths across 19 studies), and the neurologic death rate in patients with BSM (24%; 95% CI, 19%-31%; I(2) = 62%) was equivalent to the neurologic death rate in patients with BM who were treated on prospective trials. The rate of treatment-related grade 3 to 5 toxic effects was 2.4% (95% CI, 1.5%-3.7%; I(2) = 33%) in 1421 patients across 31 studies. These results compared favorably to trials of targeted or immunotherapy for BM, which had a wide objective response rate range from 17% to 56%. CONCLUSIONS AND RELEVANCE: Results of this systematic review and meta-analysis show that SRS for BSM was associated with effectiveness and safety and was comparable to SRS for nonbrainstem BM, suggesting that patients with BSM should be eligible for clinical trials of SRS. In this analysis, patients treated with SRS for BSM rarely died from BSM progression and often experienced symptomatic improvement. Given the apparent safety and efficacy of SRS for BSM in the context of acute morbidity or death from BSM growth, consideration of SRS at the time of enrollment on emerging trials of targeted therapy for BM should be considered.

Conscious perception occurs within less than 1 s. To study events on this time scale we used direct electrical recordings from the human cerebral cortex during a conscious visual perception task. Faces were presented at individually titrated visual threshold for 9 subjects while measuring broadband 40–115 Hz gamma power in a total of 1621 intracranial electrodes widely distributed in both hemispheres. Surface maps and k-means clustering analysis showed initial activation of visual cortex for both perceived and non-perceived stimuli. However, only stimuli reported as perceived then elicited a forward-sweeping wave of activity throughout the cerebral cortex accompanied by large-scale network switching. Specifically, a monophasic wave of broadband gamma activation moves through bilateral association cortex at a rate of approximately 150 mm/s and eventually reenters visual cortex for perceived but not for non-perceived stimuli. Meanwhile, the default mode network and the initial visual cortex and higher association cortex networks are switched off for the duration of conscious stimulus processing. Based on these findings, we propose a new “switch-and-wave” model for the processing of consciously perceived stimuli. These findings are important for understanding normal conscious perception and may also shed light on its vulnerability to disruption by brain disorders.

BACKGROUND AND PURPOSE:Chordoid meningiomas are uncommon WHO grade II primary intracranial neoplasms that possess unique chordoid histology and follow an aggressive clinical course. Our aim was to assess the utility of qualitative MR imaging features and quantitative apparent diffusion coefficient values as distinguishing preoperative MR imaging metrics to identify and differentiate chordoid histology from other meningioma histologic subtypes. MATERIALS AND METHODS:Twenty-one patients with meningiomas with chordoid histology, which included both chordoid meningiomas (>50% chordoid histology) and meningiomas with focal chordoid histology (

BACKGROUND:Petrous face meningiomas (PFMs) are challenging tumors because of their proximity to the cranial nerves, brainstem, and critical vasculature. The objective of this study is to present surgical outcomes and support an anatomic classification for PFM based on clinical presentation. METHODS:A retrospective chart review was performed, and 51 PFMs were identified. Tumors were classified by location along the petrous face into anterior, middle, and posterior. Presentation and outcomes were analyzed with logistic regression. RESULTS:The median follow-up was 31.6 months. Tumors were World Health Organization grade I (n= 50), with 1 World Health Organization grade II tumor. Location was anterior (22%), middle (14%), posterior (53%), and overlapping (12%). Median tumor diameter was 3.0 cm (range, 0.8-6.2 cm). Anterior location was associated with facial pain/numbness on presentation (P < 0.0001), middle location with hearing loss/vestibular dysfunction (P= 0.0035), and posterior with hydrocephalus (P= 0.0190), headache (P=0.0039), and vertigo (P= 0.0265). Extent of resection was gross total (63%), near total (14%), and subtotal (25%). The observed radiographic recurrence rate was 15%. Mean progression-free survival after diagnosis was 9.1 years with 2-year, 5-year, and 10-year progression-free survival of 91.8%, 78.6%, and 62.9%, respectively. The complication rate was 27%. Age, location, and approach were not associated with complications. CONCLUSIONS:PFMs present with distinct clinical syndromes based on their location along the petrous face: anterior with trigeminal symptoms, middle with auditory/vestibular symptoms, and posterior with symptoms of mass effect/hydrocephalous. Surgical resection is associated with excellent long-term survival and a low rate of recurrence, which can be managed with radiotherapy.

Author(s): Gennatas, Efstathios D; Wu, Ashley; Braunstein, Steve E; Morin, Olivier; Chen, William C; Magill, Stephen T; Gopinath, Chetna; Villaneueva-Meyer, Javier E; Perry, Arie; McDermott, Michael W; Solberg, Timothy D; Valdes, Gilmer; Raleigh, David R | Abstract: BackgroundMeningiomas are stratified according to tumor grade and extent of resection, often in isolation of other clinical variables. Here, we use machine learning (ML) to integrate demographic, clinical, radiographic and pathologic data to develop predictive models for meningioma outcomes.Methods and findingsWe developed a comprehensive database containing information from 235 patients who underwent surgery for 257 meningiomas at a single institution from 1990 to 2015. The median follow-up was 4.3 years, and resection specimens were re-evaluated according to current diagnostic criteria, revealing 128 WHO grade I, 104 grade II and 25 grade III meningiomas. A series of ML algorithms were trained and tuned by nested resampling to create models based on preoperative features, conventional postoperative features, or both. We compared different algorithms' accuracy as well as the unique insights they offered into the data. Machine learning models restricted to preoperative information, such as patient demographics and radiographic features, had similar accuracy for predicting local failure (AUC = 0.74) or overall survival (AUC = 0.68) as models based on meningioma grade and extent of resection (AUC = 0.73 and AUC = 0.72, respectively). Integrated models incorporating all available demographic, clinical, radiographic and pathologic data provided the most accurate estimates (AUC = 0.78 and AUC = 0.74, respectively). From these models, we developed decision trees and nomograms to estimate the risks of local failure or overall survival for meningioma patients.ConclusionsClinical information has been historically underutilized in the prediction of meningioma outcomes. Predictive models trained on preoperative clinical data perform comparably to conventional models trained on meningioma grade and extent of resection. Combination of all available information can help stratify meningioma patients more accurately.

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/β1 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/β1 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/β1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and β1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/β1 complex to maintain the high-affinity β1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/β1 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 β1 integrin, creating a complex with much greater affinity for fibronectin (FN) than α5β1. 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/β1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.

The aim of this study was to explore the association of body mass index (BMI), waist circumference (WC), and BMI and WC changes over time with cognitive decline in a nationally representative sample.A total of 5239 participants (≥65 years) were followed for 3 years as part of the National Health and Aging Trends Study. Cox proportional hazard regression was applied to model the risk of cognitive decline.BMI, after adjusting for WC and main confounders, was associated with reduced risk of cognitive decline (hazard ratio [HR] 0.97 for each unit BMI increase, 0.95-0.99). After stratifying by gender and age, this effect remained significant among females and young elders ≤80 years. A BMI decrease and WC increase10% over the study period were associated with increased risk of cognitive decline (HR 1.98, 1.16-3.38; HR 1.30, 1.04-1.62, respectively).In the elderly individuals, lean mass, as measured by BMI adjusted for WC, was associated with reduced risk of cognitive decline. Loss of lean mass and gain of fat mass, as measured by WC adjusted for BMI, were associated with elevated risk of cognitive decline.

Driving is an important part of everyday life for most adults, and restrictions on driving can place a significant burden on individuals diagnosed with epilepsy. Although sensorimotor deficits during seizures may impair driving, decreased level of consciousness often has a more global effect on patients' ability to respond appropriately to the environment. Better understanding of the mechanisms underlying alteration of consciousness in epilepsy is important for decision-making by people with epilepsy, their physicians, and regulators in regard to the question of fitness to drive. Retrospective cohort and cross-sectional studies based on surveys or crash records can provide valuable information about driving in epilepsy. However, prospective objective testing of ictal driving ability during different types of seizures is needed to more fully understand the role of impaired consciousness and other deficits in disrupting driving. Driving simulators adapted for use in the epilepsy video-EEG monitoring unit may be well suited to provide both ictal and interictal data in patients with epilepsy. Objective information about impaired driving in specific types of epilepsy and seizures can provide better informed recommendations regarding fitness to drive, potentially improving the quality of life of people living with epilepsy.

Intracranial EEG (icEEG) provides a critical road map for epilepsy surgery but it has become increasingly difficult to interpret as technology has allowed the number of icEEG channels to grow. Borrowing methods from neuroimaging, we aimed to simplify data analysis and increase consistency between reviewers by using 3D surface projections of intracranial EEG poweR (3D-SPIER). We analyzed 139 seizures from 48 intractable epilepsy patients (28 temporal and 20 extratemporal) who had icEEG recordings, epilepsy surgery, and at least one year of post-surgical follow-up. We coregistered and plotted icEEG β frequency band signal power over time onto MRI-based surface renderings for each patient, to create color 3D-SPIER movies. Two independent reviewers interpreted the icEEG data using visual analysis vs. 3D-SPIER, blinded to any clinical information. Overall agreement rates between 3D-SPIER and icEEG visual analysis or surgery were about 90% for side of seizure onset, 80% for lobe, and just under 80% for sublobar localization. These agreement rates were improved when flexible thresholds or frequency ranges were allowed for 3D-SPIER, especially for sublobar localization. Interestingly, agreement was better for patients with good surgical outcome than for patients with poor outcome. Localization using 3D-SPIER was measurably faster and considered qualitatively easier to interpret than visual analysis. These findings suggest that 3D-SPIER could be an improved diagnostic method for presurgical seizure localization in patients with intractable epilepsy and may also be useful for mapping normal brain function.

The objective of this study was to identify underlying mechanisms affecting smoking cessation among smokers taking t'ai chi classes. Smokers from t'ai chi classes had attributed t'ai chi practice as the primary reason for quitting smoking.Two (2) students from the community college population who had taken a t'ai chi class completed an open-ended questionnaire, to identify possible variables involved in motivations for smoking cessation. An Internet search identified a third student from a university program who had posted observations of how t'ai chi affected her efforts at smoking cessation. The three written responses were evaluated for correlating comments, to identify possible theoretical aspects of why t'ai chi would impact smoking cessation. All three identified increased awareness of smoking habits due to t'ai chi as the primary reason for quitting smoking. A review of literature was conducted to clarify the role of enhanced awareness as a mediator in modifying destructive behavior and addiction. Results from an unpublished study of a t'ai chi smoking cessation program were utilized as supporting data.Two (2) primary areas of behavior modification focusing on the role of enhanced self-awareness are identified from the review of literature: Mindfulness Meditation (MM), and traditional Zen practice. Zen and MM are identified as readily adaptable to using t'ai chi as a form of moving meditation for dealing with addiction.T'ai chi, as a more dynamic form of meditation, can be an effective method for enhancing mindfulness and awareness for breaking cycles of addiction and habit. Possible effects on physical cravings were also identified. As a novel and unusual form of mind/body exercise, t'ai chi may be a particularly appealing adjunct to smoking cessation programs, particularly in light of the many ancillary health benefits of t'ai chi.

Background Risk factors for pre- and postoperative seizures in supratentorial meningiomas are understudied compared to other brain tumors. Objective To report seizure frequency and identify factors associated with pre- and postoperative seizures in a large single-center population study of patients undergoing resection of supratentorial meningioma. Methods Retrospective chart review of 1033 subjects undergoing resection of supratentorial meningioma at the author's institution (1991-2014). Multivariate regression was used to identify variables significantly associated with pre- and postoperative seizures. Results Preoperative seizures occurred in 234 (22.7%) subjects. At 5 years postoperative, probability of seizure freedom was 89.9% among subjects without preoperative seizures and 62.2% with preoperative seizures. Multivariate analysis identified the following predictors of preoperative seizures: presence of ≥1 cm peritumoral edema (odds ratio [OR]: 4.45, 2.55-8.50), nonskull base tumor location (OR: 2.13, 1.26-3.67), greater age (OR per unit increase: 1.03, 1.01-1.05), while presenting symptom of headache (OR: 0.50, 0.29-0.84) or cranial nerve deficit (OR: 0.36, 0.17-0.71) decreased odds of preoperative seizures. Postoperative seizures after discharge were associated with preoperative seizures (OR: 5.70, 2.57-13.13), in-hospital seizure (OR: 4.31, 1.28-13.67), and among patients without preoperative seizure, occurrence of medical or surgical complications (OR 3.39, 1.09-9.48). Perioperative anti-epileptic drug use was not associated with decreased incidence of postoperative seizures. Conclusions Nonskull base supratentorial meningiomas with surrounding edema have the highest risk for preoperative seizure. Long-term follow-up showing persistent seizures in meningioma patients with preoperative seizures raises the possibility that these patients may benefit from electrocorticographic mapping of adjacent cortex and resection of noneloquent, epileptically active cortex.

Purpose We report a case of lung carcinoma developing in the location of a migrated prostate brachytherapy seed. Methods and Materials A 57-year-old male nonsmoker was originally diagnosed with prostate adenocarcinoma Group IIB in October 1999. Treatment was completed at an outside local hospital and consisted of hormone suppression, pelvic external beam radiation, and transperineal interstitial permanent prostate brachytherapy with loose iodine-125 seeds. Results The treatment was unremarkable for any complications, and immediate postimplant evaluation did not reveal any loose seeds. The patient remained clinically without evidence of disease and was asymptomatic until an isolated episode of hematuria in December 2009. Radiographic evaluation noted an incidental right lower lobe lung mass with a 4-mm hyperdensity slightly off-center. Biopsy confirmed Stage IB limited-stage small-cell lung cancer, and he underwent thoracic radiation with concurrent systemic chemotherapy. The mass remained mildly avid on a positron emission tomographic scan after treatment, and he underwent surgical evaluation with final pathology demonstrating no residual tumor but a metal rod-like implant consistent with a migrated radioactive brachytherapy seed. Conclusions To our knowledge, this is the first case of a long-term adverse sequela seen in the location of a migrated brachytherapy seed. Although reported incidence of pulmonary seed emboli remains low with little measurable consequence on pulmonary function, we must appreciate that a theoretical risk for secondary malignancy remains not only locally within the periprostatic region but also at any site of seed migration.

HypothesisWe hypothesize that adjuvant radiation and chemotherapy improve the clinical benefit from treatment of advanced-stage endometrial adenocarcinoma.MethodsWe conducted a retrospective review of 125 patient with stage III or IVA endometrial adenocarcinoma who received adjuvant chemotherapy (n = 60) or chemoradiation (n = 65). Primary end points were rate of clinical benefit (ie, the percentage of patients who were alive and disease-free for at least 6 months after the last day of adjuvant treatment) and progression-free and overall survival.ResultsThe addition of radiation to chemotherapy improved the rate of clinical benefit from 55% to 77%. Differences in clinical benefit were attributed to a reduction in the number of pelvic relapses after chemoradiation. There were no substantial differences in the rate of extrapelvic relapse events seen between the chemotherapy alone and chemoradiation groups. Patients receiving radiation had prolonged median progression-free survival (36 vs 17 months in chemotherapy alone) and median overall survival (70 vs 64 months in chemotherapy alone).ConclusionsThe addition of radiation to chemotherapy improved the clinical benefit of patients with stage III or IVA endometrial adenocarcinoma. A clinical trial powered to evaluate clinical benefit and survival outcomes of chemotherapy and radiation is under way.

Received: June 10, 2010 , Accepted: July 29, 2010 , Published: August 8, 2010 // The glioblastoma genome displays remarkable chromosomal aberrations, which harbor critical glioblastoma-specific genes contributing to several oncogenetic pathways. To identify glioblastoma-targeted genes, we completed a multifaceted genome-wide analysis to characterize the most significant aberrations of DNA content occurring in glioblastomas. We performed copy number analysis of 111 glioblastomas by Digital Karyotyping and Illumina BeadChip assays and validated our findings using data from the TCGA (The Cancer Genome Atlas) glioblastoma project. From this study, we identified recurrent focal copy number alterations in 1p36.23 and 4p16.3. Expression analyses of genes located in the two regions revealed genes which are dysregulated in glioblastomas. Specifically, we identify EGFR negative regulator, ERRFI1, within the minimal region of deletion in 1p36.23. In glioblastoma cells with a focal deletion of the ERRFI1 locus, restoration of ERRFI1 expression slowed cell migration. Furthermore, we demonstrate that TACC3, an Aurora-A kinase substrate, on 4p16.3, displays gain of copy number, is overexpressed in a glioma-grade-specific pattern, and correlates with Aurora kinase overexpression in glioblastomas. Our multifaceted genomic evaluation of glioblastoma establishes ERRFI1 as a potential candidate tumor suppressor gene and TACC3 as a potential oncogene, and provides insight on targets for oncogenic pathway-based therapy.

Background Pathologic diagnosis and therapeutic interventions on the small bowel have been difficult and challenging for gastroenterologists. In the last few years, significant advances have been made in this direction. New diagnostic and therapeutic modalities for visualizing the small bowel have been introduced. Furthermore, increased indications for small-bowel imaging and therapeutics have been recognized. However, the currently available methods have limitations, and development of newer, rapid, minimally invasive, safe, and readily available techniques is needed. Objective Our purpose was to evaluate the safety and efficacy of a novel method of spiral enteroscopy using a specialized overtube (Endo-Ease Discovery SB) with a pediatric colonoscope (PCF-140L). Design Case series. Setting Two international tertiary referral centers. Patients Twenty-seven adult patients with obscure GI bleeding were enrolled in this study. Intervention Spiral enteroscopy with the Endo-Ease Discovery SB overtube and a pediatric colonoscope. Main Outcome Measurements Depth of insertion, time of procedure, and complications. Results Average depth of insertion was 176 cm (range 80-340 cm) from ligament of Treitz, and average time of procedure was 36.5 minutes (range 90-65 minutes). Eleven patients had minor complications, which included minimal mucosal trauma and sore throat. Limitations Small number of patients with a case series study design. Conclusions Preliminary data suggest that use of Endo-Ease Discovery SB overtube for enteroscopy is a safe and effective technique for visualization of the small bowel.

Evaluation of behavioral impairment during epileptic seizures is critical for medical decision making, including accurate diagnosis, recommendations for driving, and presurgical evaluation. We investigated the quality of behavioral testing during inpatient video-electroencephalography (EEG) monitoring at an established epilepsy center, and introduce a technical innovation that may improve clinical care. We retrospectively reviewed video-EEG data from 152 seizures in 33 adult or pediatric patients admitted for video-EEG monitoring. Behavioral testing with questions or commands was performed in only 50% of seizures ictally, 73% of seizures postictally, and 80% with either ictal or postictal testing combined. Furthermore, the questions or commands were highly inconsistent and were performed by nonmedical personnel in about one fourth of cases. In an effort to improve this situation we developed and here introduce Automatic Responsiveness Testing in Epilepsy (ARTiE), a series of video-recorded behavioral tasks automatically triggered to play in the patient's room by computerized seizure detection. In initial technical testing using prerecorded or live video-EEG data we found that ARTiE is initiated reliably by automatic seizure detection. With additional clinical testing we hope that ARTiE will succeed in providing comprehensive and reliable behavioral evaluation during seizures for people with epilepsy to greatly improve their clinical care.

The incidence of gastric neuroendocrine tumors (NETs) has increased tenfold since the 1970s. Our aim was to describe the clinicopathologic profile, management, and outcomes of type I gastric NETs at The Mount Sinai Hospital. From existing databases of the Mount Sinai Division of Gastrointestinal Pathology and the Carcinoid Cancer Foundation, we identified 56 patients with type I gastric NETs seen at The Mount Sinai Hospital from 1993 to 2012. We generated a comprehensive dataset encompassing demographic, clinical, endoscopic, and pathologic factors. Survival information was determined from medical records and the Social Security Death Index. Tumor–node–metastasis staging was conducted, and tumors were graded based on mitotic counts and Ki67 index. Median NET size was 3.0 mm; 55.8 % displayed multifocal disease. Stages I, II, III, and IV disease were observed in 83.8, 10.8, 5.4, and 0 %, respectively. Tumors were either low (69.7 %) or intermediate (30.3 %) grade. Furthermore, 3.6 % of patients developed gastric dysplasia, and 5.5 % had gastric adenocarcinoma. Patients underwent endoscopy every 15 months, while 28.6 % underwent polypectomy, 32.7 % somatostatin therapy, and 46.4 % surgical resection. 5- and 10-year disease-specific survival was 100 %. Most patients received annual endoscopic surveillance, with a minority undergoing surgical resection, though outcomes remained excellent independent of therapeutic approach. We identified a very low but real rate of loco-regional spread, despite the generally indolent behavior of type I gastric NETs. Several patients demonstrated concurrent dysplasia or adenocarcinoma, underscoring the efficacy of regular endoscopic management not only for gastric NETs, but also for dysplasia and adenocarcinoma.

SUMMARY Objective: Secondary generalization of seizures has devastating consequences for patient safety and quality of life. The aim of this intracranial electroencephalography (icEEG) study was to investigate the differences in onset and propagation patterns of temporal lobe seizures that remained focal versus those with secondary generalization, in order to better understand the mechanism of secondary generalization. Methods: A total of 39 seizures were analyzed in nine patients who met the following criteria: (1) icEEG-video monitoring with at least one secondarily generalized tonic– clonic seizure (GTCS), (2) pathologically proven hippocampal sclerosis, and (3) no seizures for at least 1 year after anteromedial temporal lobe resection. Seizures were classified as focal or secondary generalized by behavioral analysis of video. Onset and propagation patterns were compared by analysis of icEEG. Results: We obtained data from 22 focal seizures without generalization (FS), and 17 GTCS. Seizure-onset patterns did not differ between FS and GTCS, but there were differences in later propagation. All seizures started with low voltage fast activity, except for seven seizures in one patient (six FS, one GTCS), which started with sharply contoured theta activity. Fifteen of 39 seizures started from the hippocampus, and 24 seizures (including six seizures in a patient without hippocampal contacts) started from other medial temporal lobe areas. We observed involvement or more prominent activation of the posterior-lateral temporal regions in GTCS prior to propagation to the other cortical regions, versus FS, which had no involvement or less prominent activation of the posterior lateral temporal cortex. Occipital contacts were not involved at the time of clinical secondary generalization. Significance: The posterior-lateral temporal cortex may serve as an important “gateway” controlling propagation of medial temporal lobe seizures to other cortical regions. Identifying the mechanisms of secondary generalization of focal seizures could lead to improved treatments to confine seizure spread.

Many anterolateral craniovertebral junction (CVJ) tumors can safely be resected using a simple posterolateral approach given the surgical corridor provided by brainstem shift. We sought to study how increasing anterolateral CVJ lesion size affects exposure in the posterolateral and far lateral approaches. Six cadaveric heads were used. A posterolateral approach was performed on one side and a far lateral with one-third condyle resection on the other side. Clival and brainstem exposure and surgical freedom were measured. A balloon catheter was used to simulate 10, 15, and 20mm anterolateral mass lesions. Mean clival exposure was significantly greater with the far lateral approach (197.4 versus [vs] 135.0 mm(2), p=0.03) with no balloon, but this difference disappeared with lesion sizes of 10 mm (246.8 vs 237.9 mm(2), p=0.79), 15 mm (306.7 vs 262.4 mm(2), p=0.25), and 20 mm (360.0 vs 332.7 mm(2), p=0.64). Mean brainstem exposure was significantly greater with the far lateral approach for 0 mm (127.8 vs 65.8 mm(2), p

Purpose Administering adjuvant chemotherapy before breast radiotherapy decreases the risk of systemic recurrence, but delays in radiotherapy could yield higher local failure. We assessed the feasibility and efficacy of placing radiotherapy earlier in the breast-conserving treatment course for lymph node–positive breast cancer. Methods and Materials Between June 2000 and December 2004, 44 women with node-positive Stage II and III breast cancer were entered into this trial. Breast-conserving surgery and 4 cycles of doxorubicin (60 mg/m 2 )/cyclophosphamide (600 mg/m 2 ) were followed by 4 cycles of paclitaxel (175 mg/m 2 ) delivered every 3 weeks. Radiotherapy was concurrent with the first 2 cycles of paclitaxel. The breast received 39.6 Gy in 22 fractions with a tumor bed boost of 14 Gy in 7 fractions. Regional lymphatics were included when indicated. Functional lung volume was assessed by use of the diffusing capacity for carbon monoxide as a proxy. Breast cosmesis was evaluated with the Harvard criteria. Results The 5-year actuarial rate of disease-free survival is 88%, and overall survival is 93%. There have been no local failures. Median follow-up is 75 months. No cases of radiation pneumonitis developed. There was no significant change in the diffusing capacity for carbon monoxide either immediately after radiotherapy ( p = 0.51) or with extended follow-up ( p = 0.63). Volume of irradiated breast tissue correlated with acute cosmesis, and acute Grade 3 skin toxicity developed in 2 patients. Late cosmesis was not adversely affected. Conclusions Concurrent paclitaxel chemotherapy and radiotherapy after breast-conserving surgery shortened total treatment time, provided excellent local control, and was well tolerated.

Glioblastoma multiforme (GBM) is one of the deadliest tumors afflicting humans, and the mechanisms of its onset and progression remain largely undefined. Our attempts to elucidate its molecular pathogenesis through DNA copy-number analysis by genome-wide digital karyotyping and single nucleotide polymorphism arrays identified a dramatic focal amplification on chromosome 1q32 in 4 of 57 GBM tumors. Quantitative real-time PCR measurements revealed that HDMX is the most commonly amplified and overexpressed gene in the 1q32 locus. Further genetic screening of 284 low- and high-grade gliomas revealed that HDMX amplifications occur solely in pediatric and adult GBMs and that they are mutually exclusive of TP53 mutations and MDM2 amplifications. Here, we demonstrate that HDMX regulates p53 to promote GBM growth and attenuates tumor response to chemotherapy. In GBM cells, HDMX overexpression inhibits p53-mediated transcriptional activation of p21, releases cells from G0 to G1 phase, and enhances cellular proliferation. HDMX overexpression does not affect the expression of PUMA and BAX proapoptotic genes. While in GBM cells treated with the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), HDMX appears to stabilize p53 and promote phosphorylation of the DNA double-stranded break repair protein H2AX, up-regulate the DNA repair gene VPX, stimulate DNA repair, and confer resistance to BCNU. In summary, HDMX exhibits bona fide oncogenic properties and offers a promising molecular target for GBM therapeutic intervention.