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Background and Purpose Immune Cell Effector Associated Neurotoxicity Syndrome (ICANS) is common amongst patients receiving CD19 targeted Chimeric Antigen Receptor T-cell (CAR-T) therapy. The purpose of this study is to characterize the incidence of seizures and ictal-interictal continuum (IIC) abnormalities in patients with ICANS. Methods Retrospective review of consecutive patients treated with axicabtagene ciloleucel (axi-cel) for recurrent high-grade systemic lymphoma at Stanford Medical Center between 2/2016-6/2019. Electronic medical records (EMR) were reviewed for clinical features, treatment information, EEG data, CRS (cytokine release syndrome)/ICANS severity, and clinical outcomes. Results Fifty-six patients met inclusion criteria. 85.7% of patients developed CRS, and 58.9% developed ICANS. Twenty-eight patients had EEG monitoring, of whom 26 had ICANS. Median duration of EEG monitoring was 30 hours (range .5-126 hours). Four patients (7.1%) had seizures (1 patient had a clinical generalized seizure, 2 patients had clinical and nonconvulsive seizures, and 1 patient had an isolated non-convulsive seizure). Ictal-interictal continuum abnormalities were common, of which generalized periodic discharges (GPDs) with triphasic morphology and GPDs with epileptiform morphology were most frequently seen. Generalized periodic discharges with triphasic wave morphology were found across Grade 2-3 peak ICANS severity, however the majority (86%) of patients with epileptiform GPDs had Grade 3 peak ICANS severity. Conclusions Among patients receiving axi-cel, seizure occurred in 7.1% of the total cohort, representing 12% of patients with ICANS. Ictal-interictal continuum abnormalities are also seen in patients with ICANS, most commonly GPDs. 75% of patients with seizures had nonconvulsive seizures supporting the use of continuous video EEG monitoring in this population.

BackgroundData on lines of therapy (LOTs) for cancer treatment is important for clinical oncology research, but LOTs are not explicitly recorded in EHRs. We present an efficient approach for clinical data abstraction and a flexible algorithm to derive LOTs from EHR-based medication data on patients with glioblastoma (GBM).MethodsNon-clinicians were trained to abstract the diagnosis of GBM from EHRs, and their accuracy was compared to abstraction performed by clinicians. The resulting data was used to build a cohort of patients with confirmed GBM diagnosis. An algorithm was developed to derive LOTs using structured medication data, accounting for the addition and discontinuation of therapies and drug class. Descriptive statistics were calculated and time-to-next-treatment analysis was performed using the Kaplan-Meier method.ResultsTreating clinicians as the gold standard, non-clinicians abstracted GBM diagnosis with sensitivity 0.98, specificity 1.00, PPV 1.00, and NPV 0.90, suggesting that non-clinician abstraction of GBM diagnosis was comparable to clinician abstraction. Out of 693 patients with a confirmed diagnosis of GBM, 246 patients contained structured information about the types of medications received. Of those, 165 (67.1%) received a first-line therapy (1L) of temozolomide, and the median time-to-next-treatment from the start of 1L was 179 days.ConclusionsWe also developed a flexible, interpretable, and easy-to-implement algorithm to derive LOTs given EHR data on medication orders and administrations that can be used to create high-quality datasets for outcomes research. We also showed that the cost of chart abstraction can be reduced by training non-clinicians instead of clinicians.Importance of the studyThis study proposes an efficient and accurate method to extract unstructured data from electronic health records (EHRs) for cancer outcomes research. The study addresses the limitations of manual abstraction of unstructured clinical data and presents a reproducible, low-cost workflow for clinical data abstraction and a flexible algorithm to derive lines of therapy (LOTs) from EHR-based structured medication data. The LOT data was used to conduct a descriptive treatment pattern analysis and a time-to-next-treatment analysis to demonstrate how EHR-derived unstructured data can be transformed to answer diverse clinical research questions. The study also investigates the feasibility of training non-clinicians to perform abstraction of GBM data, demonstrating that with detailed explanations of clinical documentation, best practices for chart review, and quantitative evaluation of abstraction performance, similar data quality to abstraction performed by clinicians can be achieved. The findings of this study have important implications for improving cancer outcomes research and facilitating the analysis of EHR-derived treatment data.

Clinical Characteristics of patients imaged with [18F]DASA-23

Imaging of IC-2

Purpose:Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM.Experimental Design:[18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/μmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma.Results:In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood–brain barrier and was rapidly cleared. In patients with GBM, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [18F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation.Conclusions:We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy–induced normalization of aberrant cancer metabolism.

Purpose: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM. Experimental Design: [18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/μmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma. Results: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood–brain barrier and was rapidly cleared. In patients with GBM, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [18F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation. Conclusions: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy–induced normalization of aberrant cancer metabolism.

Electronic health records represent a large data source for outcomes research, but the majority of EHR data is unstructured (e.g. free text of clinical notes) and not conducive to computational methods. While there are currently approaches to handle unstructured data, such as manual abstraction, structured proxy variables, and model-assisted abstraction, these methods are time-consuming, not scalable, and require clinical domain expertise. This paper aims to determine whether selective prediction, which gives a model the option to abstain from generating a prediction, can improve the accuracy and efficiency of unstructured clinical data abstraction. We trained selective prediction models to identify the presence of four distinct clinical variables in free-text pathology reports: primary cancer diagnosis of glioblastoma (GBM, n = 659), resection of rectal adenocarcinoma (RRA, n = 601), and two procedures for resection of rectal adenocarcinoma: abdominoperineal resection (APR, n = 601) and low anterior resection (LAR, n = 601). Data were manually abstracted from pathology reports and used to train L1-regularized logistic regression models using term-frequency-inverse-document-frequency features. Data points that the model was unable to predict with high certainty were manually abstracted. All four selective prediction models achieved a test-set sensitivity, specificity, positive predictive value, and negative predictive value above 0.91. The use of selective prediction led to sizable gains in automation (anywhere from 57% to 95% reduction in manual abstraction of charts across the four outcomes). For our GBM classifier, the selective prediction model saw improvements to sensitivity (0.94 to 0.96), specificity (0.79 to 0.96), PPV (0.89 to 0.98), and NPV (0.88 to 0.91) when compared to a non-selective classifier. Selective prediction using utility-based probability thresholds can facilitate unstructured data extraction by giving “easy” charts to a model and “hard” charts to human abstractors, thus increasing efficiency while maintaining or improving accuracy.

Background In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients. Methods Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months). Results Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed. Conclusions Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058.

A hybrid watermarking scheme based on Triangular Vertex Transform (TVT) and Contourlet coefficients for high robustness is implemented. During watermark embedding, the cover image is first decomposed using Contourlet Transform to obtain high frequency and low frequency coefficients. The lower frequency coefficients are applied with TVT. Then, the W coefficients obtained from TVT are again subdivided. The watermark bit is then embedded on the subdivided coefficients to obtain the watermarked image. Reverse operation is followed in the extraction phase. The performance of this algorithm is evaluated using embedding capacity, Normalized cross correlation (Ncc) and Peak Signal to Noise Ratio (PSNR) using standard test images. These evaluation results disclose the domination of proposed scheme over traditional schemes

Rationale: First-line therapy for high-grade gliomas (HGGs) includes maximal safe surgical resection. The extent of resection predicts overall survival, but current neuroimaging approaches lack tumor specificity. The epidermal growth factor receptor (EGFR) is a highly expressed HGG biomarker. We evaluated the safety and feasibility of an anti-EGFR antibody, panitumuab-IRDye800, at subtherapeutic doses as an imaging agent for HGG. Methods: Eleven patients with contrast-enhancing HGGs were systemically infused with panitumumab-IRDye800 at a low (50 mg) or high (100 mg) dose 1-5 days before surgery. Near-infrared fluorescence imaging was performed intraoperatively and ex vivo, to identify the optimal tumor-to-background ratio by comparing mean fluorescence intensities of tumor and histologically uninvolved tissue. Fluorescence was correlated with preoperative T1 contrast, tumor size, EGFR expression and other biomarkers. Results: No adverse events were attributed to panitumumab-IRDye800. Tumor fragments as small as 5 mg could be detected ex vivo and detection threshold was dose dependent. In tissue sections, panitumumab-IRDye800 was highly sensitive (95%) and specific (96%) for pathology confirmed tumor containing tissue. Cellular delivery of panitumumab-IRDye800 was correlated to EGFR overexpression and compromised blood-brain barrier in HGG, while normal brain tissue showed minimal fluorescence. Intraoperative fluorescence improved optical contrast in tumor tissue within and beyond the T1 contrast-enhancing margin, with contrast-to-noise ratios of 9.5 ± 2.1 and 3.6 ± 1.1, respectively. Conclusions: Panitumumab-IRDye800 provided excellent tumor contrast and was safe at both doses. Smaller fragments of tumor could be detected at the 100 mg dose and thus more suitable for intraoperative imaging.

Objective Immunotherapy for patients with melanoma with brain metastasis has significantly improved outcomes; however, it has also been characterized by potentially dangerous immune-related adverse events (IRAEs). Several reports have suggested that these reactions can precede improved treatment responses. For intracranial disease control, we sought to identify if such an association exists. Methods We conducted a retrospective chart review of patients with melanoma who underwent immunotherapy treatment after diagnosis of brain metastasis. The study cohort was then stratified into 2 groups based on their history of developing an IRAE that prompted discontinuation of that regimen. The primary outcome variable included intracranial progression-free survival (PFS). Kaplan-Meier and Cox proportional hazard analyses were used to evaluate survival and predictors of outcomes. Results Fifty-two patients met the inclusion criteria, 17 of whom experienced severe IRAEs that led to discontinuation of immunotherapy. Median intracranial PFS was 19.9 versus 10.5 months (P = 0.053) in patients who did and did not experience severe IRAEs prompting discontinuation, respectively. No additional outcome benefits were identified for systemic PFS or overall survival (mean, 33.1 months and 27.6 months, respectively). Multivariable analysis identified BRAF mutation status as a negative prognosticator of brain progression (P = 0.013; hazard ratio, 3.90). Initial treatment with BRAF inhibitor was also a negative predictor of all-cause mortality (P = 0.015; hazard ratio, 10.73). Conclusions Immune-related adverse events may signify an underlying immunogenic response that has intracranial disease control benefits. Despite their associated side effects, immunotherapies continue to show promising outcomes as a first-line agent for melanoma with brain metastasis.

Background Academic medicine needs more diverse leadership from racial/ethnic minorities, women, people with disabilities, and LGBTQIA+ physicians. Longitudinal structural support programs that bring together underrepresented in medicine (UiM) and non-UiM trainees are one approach to build leadership and scholarship capacity in diversity, equity, and inclusion (DEI). Objective To describe the creation, satisfaction with, and feasibility of a Leadership Education in Advancing Diversity (LEAD) Program and evaluate scholars' changes in self-efficacy, intended and actual behavior change, and outputs in leadership and DEI scholarship. Methods In 2017, we created the LEAD Program, a 10-month longitudinal, single institution program that provides residents and fellows (“scholars”) across graduate medical education (GME) with leadership training and mentorship in creating DEI-focused scholarship. In the first 3 cohorts (2017–2020), we assessed scholars' self-efficacy, actual and planned behavior change, and program satisfaction using IRB-approved, de-identified retrospective pre-/post-surveys. We measured scholarship as the number of workshops presented and publications developed by the LEAD scholars. We used descriptive statistics and paired 2-tailed t tests to analyze the data. Results Seventy-five trainees completed LEAD; 99% (74 of 75) completed the retrospective pre-/post-surveys. There was statistically significant improvement in scholars' self-efficacy for all learning objectives. All trainees thought LEAD should continue. LEAD scholars have created workshops and presented at local, regional, and national conferences, as well published their findings. Scholars identified the greatest benefits as mentorship, developing friendships with UiM and ally peers outside of their subspecialty, and confidence in public speaking. Conclusions LEAD is an innovative, feasible GME-wide model to improve resident and fellow self-efficacy and behaviors in DEI scholarship and leadership.

Summary Background Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. Methods This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5–3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0–2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov , NCT02320058 . Findings Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7–36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2–35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2–67·2]) of 101 patients in cohort A and three (16·7% [3·6–41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3–63·5]) patients in cohort A and three (16·7% [3·6–41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7–64·1) and overall survival was 71·9% (61·8–79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6–40·5) and overall survival was 36·6% (14·0–59·8). The most common grade 3–4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). Interpretation The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. Funding Bristol Myers Squibb.

The Humanities section of the February 12 issue of Neurology® included an article titled “Lucky and the root doctor.” In this piece, the author describes his previous encounters with a black patient and his wife, and recounts dialogues in which the author is introduced to some of the patient's health beliefs, which differ widely from his own. Unfortunately, and perhaps unintentionally, the piece frames these interactions in the context of a highly problematic portrayal of race. Many Neurology readers reacted to the article, expressing concern over the negative racial overtones and calling for immediate corrective action. The article was quickly retracted, and a formal letter of apology and action plan was subsequently issued by the editor-in-chief of Neurology .1

It became an important issue to protect the ownership and prevent unauthorized access. A blind and reversible watermarking technique is introduced in this work. The watermark will be generated from the host image and owner identity. Gray Level Co-occurrence Matrix can be used for key generation. Contourlet Transform is used to partition the image into multiple sub-bands. Principal Component Analysis is used to identify the appropriate bands that can be used for embedding the watermark. For the extraction of watermark, secret key and ownership id are required. This technique ensures superior performance in contrast with other techniques while calculating Bit Error Rate and Peak Signal to Noise Ratio.

PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel positron emission tomography (PET) tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[(18)F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([(18)F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and GBM patients. EXPERIMENTAL DESIGN: [(18)F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/μmol and radiochemical purity >95%. We performed initial testing of [(18)F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next we produced [(18)F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers, and a pilot cohort of glioma patients. RESULTS: In mouse imaging studies, [(18)F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio (TBR) of 3.6 ± 0.5. In human volunteers, [(18)F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In GBM patients, [(18)F]DASA-23 successfully outlined tumors visible on contrast-enhanced magnetic resonance imaging (MRI). The uptake of [(18)F]DASA-23 was markedly elevated in GBMs compared to normal brain, and it identified a metabolic non-responder within 1-week of treatment initiation. CONCLUSION: We developed and translated [(18)F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [(18)F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.

Patients with primary or secondary central nervous system (CNS) malignancies benefit from utilization of palliative care (PC) in addition to other supportive services, such as home health and social work. Guidelines propose early initiation of PC for patients with advanced cancers. We analyzed a cohort of privately insured patients with malignant brain or spinal tumors derived from the Optum Clinformatics Datamart Database to investigate health disparities in access to and utilization of supportive services. We introduce a novel construct, “provider patient racial diversity index” (provider pRDI), which is a measure of the proportion of non-white minority patients a provider encounters to approximate a provider’s patient demographics and suggest a provider’s cultural sensitivity and exposure to diversity. Our analysis demonstrates low rates of PC, home health, and social work services among racial minority patients. Notably, Hispanic patients had low likelihood of engaging with all three categories of supportive services. However, patients who saw providers categorized into high provider pRDI (categories II and III) were increasingly more likely to interface with supportive care services and at an earlier point in their disease courses. This study suggests that prospective studies that examine potential interventions at the provider level, including diversity training, are needed.

Digital watermarking is an important method employed to conserve the copyright ownership of digital images. The watermarked image is transmitted and the owner of image can confirm ownership of the digital image by extracting the embedded watermark. Reversible watermarking provides more protection to the digital images. This is applicable for data authentication, copyright protection and medical field and so on. In this work, reversible watermarking using Adaptive Edge Sensing Interpolation (AESI) is proposed. The proposed method can improve the embedding capacity in digital images to nearly 2bpp (bits per pixel) and extract the cover image without any damage.

Background Glioblastoma (GBM) treatment requires access to complex medical services, and the Patient Protection and Affordable Care Act (ACA) sought to expand access to health care, including complex oncologic care. Whether the implementation of the ACA was subsequently associated with changes in 1-year survival in GBM is not known. Methods A retrospective cohort study was performed using the Surveillance, Epidemiology, and End Results (SEER) database. We identified patients with the primary diagnosis of GBM between 2008 and 2016. A multivariable-adjusted Cox proportional hazards model was developed using patient and clinical characteristics to determine the main outcome: the 1-year cumulative probability of death by state expansion status. Results A total of 25 784 patients and 14 355 deaths at 1 year were identified and included in the analysis, 49.7% were older than 65 at diagnosis. Overall 1-year cumulative probability of death for GBM patients in non-expansion versus expansion states did not significantly worsen over the 2 time periods (2008–2010: hazard ratio [HR] 1.11, 95% confidence interval [CI] 1.04–1.19; 2014–2016: HR 1.18, 95% CI 1.09–1.27). In GBM patients younger than age 65 at diagnosis, there was a nonsignificant trend toward the poorer 1-year cumulative probability of death in non-expansion versus expansion states (2008–2010: HR 1.09, 95% CI 0.97–1.22; 2014–2016: HR 1.23, 95% CI 1.09–1.40). Conclusions No differences were found over time in survival for GBM patients in expansion versus non-expansion states. Further study may reveal whether GBM patients diagnosed younger than age 65 in expansion states experienced improvements in 1-year survival.

Academic neurology departments must confront the challenges of developing a diverse workforce, reducing inequity and discrimination within academia, and providing neurologic care for an increasingly diverse society. A neurology diversity officer should have a specific role and associated title within a neurology department as well as a mandate to focus their efforts on issues of equity, diversity, and inclusion that affect staff, trainees, and faculty. This role is expansive and works across departmental missions, but it has many challenges related to structural intolerance and cultural gaps. In this review, we describe the many challenges that diversity officers face and how they might confront them. We delineate the role and duties of the neurology diversity officer and provide a guide to departmental leaders on how to assess qualifications and evaluate progress. Finally, we describe the elements necessary for success. A neurology diversity officer should have the financial, administrative, and emotional support of leadership in order for them to carry out their mission and to truly have a positive influence.

As the variety of moveable electronic gadgets are increasing, property energy sources for these devices become indispensable. The chance to power these devices by energy harvested exploitation renewable sources ought to be found. Triboelectric generators are the most effective answer to reap energy from low-frequency mechanical motions. A lamb may be a energy harvest home device that converts external energy into electricity by a conjunction of contact electrification and electricity induction and this electricity is employed to power our electronic gadgets wirelessly by exploitation wireless module. These devices open brand new horizons for tactics to provide and store wasted energy from our surroundings and during a close to future to power wireless sensors, electronic gadgets and thereby comparison numerous TEG's for harvest home energy., {"references":["1.\tZhou Y., Apo D.J., Priya S. Dual-phase self-biased magneto- electric energy harvester. Appl. Phys. Lett. 103(19), 2013, Art. no. 192909.","2.\tGupta R., Tomar M., Rammohan S., et al. Multiferroic cantilever for power generation using dual functionality. Appl. Phys. Lett. 109(19), 2016, Art. no. 193901.","3.\tZheng L., et al. Silicon-based hybrid cell for harvesting solar energy and raindrop electrostatic energy. Nano Energy. 9, 291–300p, 2014.","4.\tChen et al. All-plastic-materials based self-charging power system composed of triboelectric nanogenerators and supercapacitors. Adv. Funct. Mater. 26(7), 1070–1076p, 2015.","5.\tKim M.K., Kim M.S., Jo S.E., Kim Y.J. Triboelectric – thermoelectric hybrid nanogenerator for harvesting frictional energy. Smart Mater. Struct. 25(12), 2016, Art. no. 125007.","6.\tHu Y., Yang J., Niu S., et al. Hybridizing triboelectrification and electromagnetic induction effects for high-efficient mechanical energy harvesting. ACS Nano. 8(7), 7442–7450p, 2014.","7.\tZhang C., Tang W., Han C., et al. Theoretical compare son, equivalent transformation, and conjunction operations of electromagnetic induction generator and triboelectric nanogenerator for harvesting mechanical energy. Adv. Mater. 26(22), 3580–3591p, 2014."]}

PD-1 Immunotherapy is integral in treating multiple cancers, but has been associated with neurological adverse events (nAEs). Our study was aimed at identifying the clinical spectrum of nAEs associated with pembrolizumab and nivolumab. We performed an IRB approved single-center retrospective cohort study on patients receiving either pembrolizumab or nivolumab. Patients that developed nAEs within 12 months of treatment were identified. Descriptive statistics were conducted, and differences between groups were analyzed by the Chi-square or t test method. In total, 649 patients were identified. Seventeen patients (2.6%) developed nAEs. Eight of those were on pembrolizumab and nine were on nivolumab. Average age was 62.1 years. Ten were males and 7 were females. Most patients had melanoma (6, 35.3%). Patients who developed nAEs more frequently had intracranial lesions at initiation of anti PD-1 therapy compared to those who did not develop nAEs (76.5% vs 27.8%; p-value

Background We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma (GBM). Methods We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3 + 3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events grades 3–5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis. Results From 2010 to 2015, thirty patients were enrolled. The median age was 66 years (range, 51–86 y). The median target volume was 60 cm3 (range, 14.7–137.3 cm3). DLT occurred in 2 patients: one for posttreatment cerebral edema and progressive disease at 3 weeks (grade 4, dose 40 Gy); another patient died 1.5 weeks following SRS from postoperative complications (grade 5, dose 40 Gy). Late grades 1–2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2–12.6 mo). No grades 3–5 ARE occurred. With a median follow-up of 13.8 months (range 1.7–64.4 mo), the median survival times were: progression-free survival, 8.2 months (95% CI: 4.6–10.5); overall survival, 14.8 months (95% CI: 10.9–19.9); O6-methylguanine-DNA methyltransferase hypermethylated, 19.9 months (95% CI: 10.5–33.5) versus 11.3 months (95% CI: 8.9–17.6) for no/unknown hypermethylation (P = 0.03), and 27.2 months (95% CI: 11.2–48.3) if late ARE occurred versus 11.7 months (95% CI: 8.9–17.6) for no ARE (P = 0.08). Conclusions The per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grades 1–2 and did not statistically impact survival.

Introduction Nous avions precedemment rapporte l’efficacite et la tolerance de NIVO + IPI chez des patients (pts) atteints d’un melanome et presentant des metastases cerebrales (MBM) non traitees et asymptomatiques, de l’etude CheckMate 204. Nous presentons ici la premiere analyse de NIVO + IPI chez des patients atteints de MBM symptomatiques, ainsi que des donnees mises a jour dans la cohorte de pts presentant des MBM asymptomatiques. Materiel et methodes Dans cet essai de phase II, des patients presentant ≥ 1 MBM mesurable, non irradiee et de 0,5 a 3,0 cm ont ete inclus dans 2 cohortes : – ceux ne presentant aucun symptome neurologique et ne recevant pas de traitement par corticosteroides (asymptomatiques ; cohorte A) ; – ceux presentant des symptomes neurologiques, qu’ils recoivent ou non un traitement par corticosteroides (symptomatiques ; cohorte B). Dans les deux cohortes, les pts ont recu NIVO 1 mg/kg + IPI 3 mg/kg toutes les 3 semaines × 4, puis NIVO 3 mg/kg toutes les 2 semaines jusqu’a progression ou toxicite. Le critere d’evaluation principal etait le taux de benefice clinique intracrânien (CBR ; proportion de patients avec une reponse complete [CR] + reponse partielle [PR] + maladie stable [SD] ≥ 6 mois). A la date limite clinique du 1er mai 2018, tous les patients traites (101 dans la cohorte A et 18 dans la cohorte B) avaient ete suivis pendant ∼6 mois ou plus. Resultats Dans cette analyse actualisee de la cohorte A (suivi median de 20,6 mois), le CBR etait de 58,4 % (voir Tableau 1 ). Dans la cohorte B, les patients ont recu une mediane de 1 dose de NIVO + IPI, et 2 patients sur 18 (11 %) ont recu les 4 doses. Apres un suivi median de 5,2 mois dans la cohorte B, le taux de reponse objective intracrânienne etait de 16,7 % et le CBR de 22,2 %. Des evenements indesirables de grade 3/4 ont ete observes chez 54,5 % des patients de la cohorte A et chez 55,6 % de ceux de la cohorte B (6,9 % et 16,7 % touchant le systeme nerveux, respectivement), avec 1 deces lie au traitement dans la cohorte A (myocardite immuno-induite). Conclusion Chez les patients atteints de MBM asymptomatiques, ces resultats actualises montrent un taux eleve de reponses intracrâniennes durables, ce qui conforte NIVO + IPI en tant que traitement de premiere intention dans cette population. Une activite anti-tumorale intracrânienne a ete observee avec NIVO + IPI chez les patients atteints de MBM symptomatiques, mais des etudes supplementaires sont necessaires pour comprendre les mecanismes biologiques de la resistance a l’immunotherapie et pour ameliorer les traitements dans cette population difficile.

Introduction Gliosarcomas are clinically aggressive tumors, histologically distinct from glioblastoma. Data regarding the impact of extent of resection and post-operative adjuvant therapy on gliosarcoma outcomes are limited. Methods Patients with histologically-confirmed gliosarcoma diagnosed between 1999 and 2019 were identified. Clinical, molecular, and radiographic data were assembled based on historical records. Comparisons of categorical variables used Pearson’s Chi-square and Fisher’s exact test while continuous values were compared using the Wilcoxon signed-rank test. Survival comparisons were assessed using Kaplan-Meier statistics and Cox regressions. Results Seventy-one gliosarcoma patients were identified. Secondary gliosarcoma was not associated with worse survival when compared to recurrent primary gliosarcoma (median survival 9.8 [3.8 to 21.0] months vs 7.6 [1.0 to 35.7], p = 0.7493). On multivariable analysis, receipt of temozolomide (HR = 0.02, 95% CI 0.001 to 0.21) and achievement of gross total resection (GTR; HR = 0.13, 95% CI 0.02 to 0.77) were independently prognostic for improved progression-free survival (PFS) while only receipt of temozolomide was independently associated with extended overall survival (OS) (HR = 0.03, 95% CI 0.001 to 0.89). In patients receiving surgical resection followed by radiotherapy and concomitant temozolomide, achievement of GTR was significantly associated with improved PFS (median 32.97 [7.1 to 79.6] months vs 5.45 [1.8 to 26.3], p = 0.0092) and OS (median 56.73 months [7.8 to 104.5] vs 14.83 [3.8 to 29.1], p = 0.0252). Conclusion Multimodal therapy is associated with improved survival in gliosarcoma. Even in patients receiving aggressive post-operative multimodal management, total surgical removal of macroscopic disease remains important for optimal outcomes.

OBJECTIVES We developed 1-((2-fluoro-6-(fluoro-[18F])phenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) as a novel radiopharmaceutical to measure pyruvate kinase M2 levels by positron emission tomography (PET). PKM2 catalyzes the final step in glycolysis, the key process of tumor metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in the healthy brain, making it an important biomarker of cancer glycolytic re-programming. Here, we report the first evaluation of [18F]DASA-23 in human healthy volunteers and subjects with low-grade (LGG) and high-grade glioma (HGG). METHODS [18F]DASA-23 was synthesized under GMP conditions. Brain [18F]DASA-23 PET/MRI scans (3T) were performed in human healthy volunteers (n=5) and subjects with LGG (n=3) and HGG (n=2). The PET imaging duration was 60 min and standardized uptake value (SUV) calculations were performed on the 30–60 min summed images. The maximum SUV in the tumor (TumorSUVmax) and contralateral white matter (WMSUVmax) were calculated. RESULTS [18F]DASA-23 specific activity was 2961±873 mCi/µmol (n=10) with radiochemical purity >95%, injected mass of 1.8±0.7 mcg, and dose of 0.3±0.02 mcg per kg body weight. In healthy volunteers, [18F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared through the bladder and also showed uptake in the gallbladder, liver, and intestines over time. [18F]DASA-23 was found to be intact in plasma up to 10 min post-injection and 75% intact at 30 min post-injection. In subjects with glioma, TumorSUVmax was significantly greater in HGG (2.2±0.4, n=2) compared to LGG (0.8±0.3m n=3), p=0.02. In this early human series, the normalized ratio of TumorSUVmax/WMSUVmax was not significantly different between subjects with HGG (2.0±0.6) and LGG (1.0±0.4), p=0.1. CONCLUSION [18F]DASA-23 is a promising new imaging agent for the non-invasive delineation of LGG and HGG based on aberrantly expressed PKM2. An ongoing study is evaluating the utility of this agent in additional patients with intracranial malignancies (NCT03539731).

Purpose: For brain metastases, surgical resection with postoperative stereotactic radiosurgery is an emerging standard of care. Postoperative cavity stereotactic radiosurgery is associated with a specific, underrecognized pattern of intracranial recurrence, herein termed nodular leptomeningeal disease (nLMD), which is distinct from classical leptomeningeal disease. We hypothesized that there is poor consensus regarding the definition of LMD, and that a formal, self-guided training module will improve interrater reliability (IRR) and validity in diagnosing LMD. Methods and Materials: Twenty-two physicians at 16 institutions, including 15 physicians with central nervous system expertise, completed a 2-phase survey that included magnetic resonance imaging and treatment information for 30 patients. In the ``pretraining{''} phase, physicians labeled cases using 3 patterns of recurrence commonly reported in prospective studies: local recurrence (LR), distant parenchymal recurrence (DR), and LMD. After a self-directed training module, participating physicians completed the ``posttraining{''} phase and relabeled the 30 cases using the 4 following labels: LR, DR, classical leptomeningeal disease, and nLMD. Results: IRR increased 34\% after training (Fleiss' Kappa K = 0.41 to K = 0.55, P < .001). IRR increased most among non-central nervous system specialists (+58\%, P < .001). Before training, IRR was lowest for LMD (K = 0.33). After training, IRR increased across all recurrence subgroups and increased most for LMD (+67\%). After training, >= 27\% of cases initially labeled LR or DR were later recognized as nLMD. Conclusions: This study highlights the large degree of inconsistency among clinicians in recognizing nLMD. Our findings demonstrate that a brief self-guided training module distinguishing nLMD can significantly improve IRR across all patterns of recurrence, and particularly in nLMD. To optimize outcomes reporting, prospective trials in brain metastases should incorporate central imaging review and investigator training. (C) 2019 Elsevier Inc. All rights reserved.

Here we review a variety of preclinical studies and a first-in-human clinical trial of newly diagnosed glioblastoma (GBM) patients that have investigated the significance of the influx of tumor associated macrophages (TAMs) into tumors after irradiation. We summarize the effects on the response of the tumors and normal tissues to radiation of various agents that either reduce the influx of TAMs into tumors after radiation or change their M1/M2 polarization. The studies show that following irradiation there is an accumulation of bone marrow derived TAMs in the irradiated tumors. These TAMs stimulate the resumption of blood flow in the irradiated tumors thereby promoting recurrence of the tumors. A key mechanism for this accumulation of TAMs is driven by the SDF-1/CXCR4 chemokine pathway though other pathways could also be involved for some tumors. Blocking this pathway to prevent the TAM accumulation in the tumors both enhances tumor response to radiation and protects irradiated tissues. A clinical trial in which the CXCR4 antagonist plerixafor was added to standard therapy of glioblastoma validated the preclinical findings by demonstrating i) reduced blood flow in the irradiated site, and ii) significantly improved tumor local control compared to GBM patients not treated with plerixafor. We conclude that macrophage exclusion after radiation therapy (MERT) is an effective way both to enhance the tumor response to radiation and to protect the irradiated normal tissues. Further clinical trials are warranted.

In today's world waste is becoming a most vital issue that has to be properly taken care. The inadequate waste collection, transport, disposal and treatment is becoming a major environmental challenge in India. The management of waste has attained the highest importance in this era, the volume of waste generated is increasing day to day life. In most of the communities across the world, people are showing negative attitude towards the waste management even though they are well aware of the consequences of improper solid waste management. Although the municipalities are taking care of the waste management system, they too face many challenges regarding proper treatment of waste due to lack of infrastructure that has been not yet provided by the government. The challenges and barriers of waste management are significant and so are the opportunities. The future is becoming mobile nowadays, the developing new era will be carved by mobile development and digital evolution. Even though new innovations and technologies are arising they still are not being benefited by us due to lack of waste treatment plants. Mobile products and applications are becoming worthy for organisations, stakeholders and common people. Using these applications waste management can effectively done. Aim of this project is to develop a sustainable waste management app emphasizing on recycling, energy generation, effective disposal s and waste prevention Rahul Jayan | Ranjana. A | Reena Thomas | Renin Joy "Trash Go Waste" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-3 | Issue-4 , June 2019, URL: https://www.ijtsrd.com/papers/ijtsrd23209.pdf

Objective: A qualitative study of PwMS who had clinically significant levels of anxiety was conducted to gain a richer perspective on their experience. The objective was to explore PwMS’ experiences of anxiety and their perspectives on causes and outcomes. Design: Twenty in-depth, semi-structured interviews were conducted with PwMS consecutively recruited from the Neurology Department of a NHS University Hospital. Sixteen had a relapsing-remitting course, three had a secondary progressive course and one person had primary progressive multiple sclerosis (MS). Interviews were recorded, transcribed and analysed using inductive thematic analysis. Results: Although participants thought different factors had initially triggered their anxiety, being given the diagnosis of MS appeared to be the most significant factor for many participants. Difficulties in the workplace and in relationships, particularly related to perceived dependence on others were also important themes. A wide range of emotional responses and negative thinking patterns were associated with anxiety; this suggested the presence of comorbid depression. Participants were able to acknowledge the positive and negative coping strategies that impacted on their anxiety. Conclusion: This review confirms that anxiety can have many negative implications for PwMS and suggests that early detection and intervention are necessary in order to improve patient’s well-being.

2543 Background: BPM31510 is an ubidecarenone-lipid conjugate nanodispersion in clinical development for advanced malignancies, including high grade glioma (HGG). BPM31510’s anti-cancer effect is mediated by induction of mitochondrial superoxide and activation of cell death in glioblastoma models. Herein, we present preliminary pharmaco-kinetic and dynamic data, and survival from a phase I study of BPM31510 + Vitamin K in HGG with progression after bevacizumab (BEV). Methods: This was an open-label phase I study of BPM31510 continuous infusion with Vitamin K (10mg IM qweek) using a mTPI design, starting at 110mg/kg 2X/week, allowing 2 dose escalations & 1 de-escalation. Patients had received ChemoRT and were in recurrence after BEV. Results: Of 12 patients treated with BPM31510, 9 completed the 28-day DLT period. 2 patients came off study for progressive disease; 1 patient after asymptomatic hemorrhage into tumor bed (G1). 10 patients had primary GB, 2 had AA. Median age was 54.5yo (27-67) and KPS 70 (60-90). On Day 1 of BPM31510, a dose dependent increase in Cmax was observed; Tmax values were similar for all doses. AUC was linear with dose escalation. For all doses, Day 4 Cmax values were higher compared to Day 1. In contrast there was variable decrease in Tmax (table). Of evaluable patients, 4 patients received the highest dose 171mg/kg, where a single patient experienced DLT: G3 AST & ALT. The most common grade 1/2 AEs were elevated AST, rash, and fatigue, each occurring in 4 patients. The mOS for 9 eligible/evaluable patients was 128 days (95% CI: 48-209) while PFS was 34 days (95% CI of mean 8.9). Two patients are currently alive >12 months. Conclusions: BPM31510 + vitamin K demonstrated a safe profile to maximum dose of 171mg/kg twice/week with potential therapeutic utility in treatment-refractory HGG patients. Multi-omic molecular profiles characterizing AE and response to be reported from the study will be investigated for next phase of clinical development. Clinical trial information: NCT03020602 . [Table: see text]

PURPOSE: To investigate ferumoxytol-enhanced MRI as a noninvasive imaging biomarker of macrophages in adults with high-grade gliomas. MATERIALS AND METHODS: In this prospective study, adults with high-grade gliomas were enrolled between July 2015 and July 2017. Each participant was administered intravenous ferumoxytol (5 mg/kg) and underwent 3.0-T MRI 24 hours later. Two sites in each tumor were selected for intraoperative sampling on the basis of the degree of ferumoxytol-induced signal change. Susceptibility and the relaxation rates R2* (1/T2*) and R2 (1/T2) were obtained by region-of-interest analysis by using the respective postprocessed maps. Each sample was stained with Prussian blue, CD68, CD163, and glial fibrillary acidic protein. Pearson correlation and linear mixed models were performed to assess the relationship between imaging measurements and number of 400× magnification high-power fields with iron-containing macrophages. RESULTS: Ten adults (four male participants [mean age, 65 years ± 9 {standard deviation}; age range, 57–74 years] and six female participants [mean age, 53 years ± 12 years; age range, 32–65 years]; mean age of all participants, 58 years ± 12 [age range, 32–74 years]) with high-grade gliomas were included. Significant positive correlations were found between susceptibility, R2*, and R2’ and the number of high-power fields with CD163-positive (r range, 0.64–0.71; P < .01) and CD68-positive (r range, 0.55–0.57; P value range, .01–.02) iron-containing macrophages. No significant correlation was found between R2 and CD163-positive (r = 0.33; P = .16) and CD68-positive (r = 0.24; P = .32) iron-containing macrophages. Similar significance results were obtained with linear mixed models. At histopathologic analysis, iron particles were found only in macrophages; none was found in glial fibrillary acidic protein–positive tumor cells. CONCLUSION: MRI measurements of susceptibility, R2*, and R2’ (R2* – R2) obtained after ferumoxytol administration correlate with iron-containing macrophage concentration, and this shows their potential as quantitative imaging markers of macrophages in malignant gliomas. © RSNA, 2018 Online supplemental material is available for this article.

BackgroundBrain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases.MethodsIn this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response.ResultsAmong 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases.ConclusionsNivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).

Radiogenomics mapping noninvasively determines important relationships between the molecular genotype and imaging phenotype of various tumors, allowing advances in both clinical care and cancer research. While early work has shown its technical feasibility, here we extend radiogenomic mapping to a locoregional level that can account for the molecular heterogeneity of tumors. To achieve this, our data processing pipeline relies on three main steps: 1) the use of multi-omics data fusion to generate a set of 100 interpretable gene modules, 2) the use of patch-based image analysis (specifically of contrast-enhanced T1-weighted weighted MR images) combined with Generalized Linear Models (GLM) to establish potential links between module expressions and local MR signal, and 3) the use of expression heatmaps based on GLMs decision values to explore visualization of tumor molecular heterogeneity. The performance of the proposed approach was evaluated using a leave-one-patient-out crossvalidation method as well as a separate validation data set. The top performing models were based on a small set of 20 features and yielded Area Under the receiver operating characteristic Curve (AUC) above 0.65 on the validation cohort for eight modules. Next, we demonstrate the clinical and biological interpretation of four modules using molecular expression heatmaps superimposed on clinical radiographic images, showing the potential for assessing tumor molecular heterogeneity and the utility of this method for precision treatment in clinical decision making and imaging surveillance.

Extraneural metastatic disease of glioma is rare and poses unique therapeutic challenges. Increasingly, the ability to sequence genetic alterations in tumors has allowed for the identification of common oncogenic signatures such as the activating BRAFV600E mutation and may be useful in therapeutic decision making. We report two patients with widespread aggressive gliomas whose tumors were found to express the BRAFV600E mutation and then responded robustly albeit transiently when exposed to vemurafenib. Although both patients succumbed to their disease, our results suggest that targeting BRAF might be appropriate for patients with aggressive gliomas that express this mutation.

Following the introduction of the Patient Self-Determination Act of 1990, the Veterans Health Administration developed its own advance medical directive (AMD) policy, which most recently states that documentation is mandatory for all hospital patients in all settings. The object of this study was to assess the effectiveness of AMD documentation at a local Veterans Affairs Medical Center. AMD documentation was compared among three inpatient services: surgery, medicine, and psychiatry. Retrospective in nature, 594 inpatient cases were compared. Results revealed that, overall, the rate of AMD documentation was 37.7%. AMD documentation on surgery was statistically more frequent (45.6%) than for either medicine (33.2%) or psychiatry (34.5%). The difference between the numbers of days to AMD documentation for all three services was not statistically significant. While there was no statistically significant difference across gender, Caucasians had AMDs documented more frequently than African Americans (p.001). Logistic regression reveals that social worker and physician intervention, not patient-specific variables, are the primary predictors of AMD incidence. Policy makers may need to consider the realities of hospital care, especially in emergency settings, and be more specific in the steps of implementation of the policy in the evenings, weekends, and holidays. True adherence to policy implementation may require hospital administrators to increase staff and educational efforts so that the concept of AMD communication and documentation is completely explained to all staff and patients. Policy should include an electronic record reminder that is renewed every 3 years and provisions for accommodating patients who arrive on weekends and holidays, with special awareness of the particular communication needs of minority groups. The study conclusions are that further inquiry is needed to understand these policy nuances to enable the Veterans Affairs Administration to improve its policies and performance in this important aspect of healthcare.

Purpose We report a longitudinal assessment of health-related quality of life (HRQOL) in patients with glioblastoma (GBM) treated on a prospective dose escalation trial of 5-fraction stereotactic radiosurgery (25-40 Gy in 5 fractions) with concurrent and adjuvant temozolomide. Methods HRQOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 (QLQ-C30) general, the EORTC quality of life questionnaire-brain cancer specific module (QLQ-BN20), and the M.D. Anderson Symptom Inventory–Brain Tumor (MDASI-BT). Questionnaires were completed at baseline and at every follow-up visit after completion of radiosurgery. Changes from baseline for 9 predefined HRQOL measures (global quality of life, physical functioning, social functioning, emotional functioning, motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty) were calculated at every time point. Results With a median follow-up time of 10.4 months (range, 0.4-52 months), 139 total HRQOL questionnaires were completed by the 30 patients on trial. Compliance with HRQOL assessment was 76% at 12 months. Communication deficit significantly worsened over time, with a decline of 1.7 points per month ( P =.008). No significant changes over time were detected in the other 8 scales of our primary analysis, including global quality of life. Although 8 patients (27%) experienced adverse radiation effects (ARE) on this dose escalation trial, it was not associated with a statistically significant decline in any of the primary HRQOL scales. Disease progression was associated with communication deficit, with patients experiencing an average worsening of 13.9 points per month after progression compared with 0.7 points per month before progression ( P =.01). Conclusion On this 5-fraction dose escalation protocol for newly diagnosed GBM, overall HRQOL remained stable and appears similar to historical controls of 30 fractions of radiation therapy. Tumor recurrence was associated with worsening communication deficit, and ARE did not correlate with a decline in HRQOL.