James Y. Chen

Adaptive Hypertext Navigation Based On User Goals and Context

Hypertext systems allow flexible access to topics of information, but this flexibility has disadvantages. Users often become lost or overwhelmed by choices. An adaptive hypertext system can overcome these disadvantages by recommending information to users based on their specific information needs and preferences. Simple associative matrices provide an effective way of capturing these user preferences. Because the matrices are easily updated, they support the kind of dynamic learning required in an adaptive system.HYPERFLEX, a prototype of an adaptive hypertext system that learns, is described. Informal studies with HYPERFLEX clarify the circumstances under which adaptive systems are likely to be useful, and suggest that HYPERFLEX can reduce time spent searching for information by up to 40%. Moreover, these benefits can be obtained with relatively little effort on the part of hypertext authors or users.The simple models underlying HYPERFLEXs performance may offer a general and useful alternative to more sophisticated modelling techniques. Conditions under which these models, and similar adaptation techniques, might be most useful are discussed.

YB-1 Bridges Neural Stem Cells and Brain Tumor–Initiating Cells via Its Roles in Differentiation and Cell Growth

The Y-box binding protein 1 (YB-1) is upregulated in many human malignancies including glioblastoma (GBM). It is also essential for normal brain development, suggesting that YB-1 is part of a neural stem cell (NSC) network. Here, we show that YB-1 was highly expressed in the subventricular zone (SVZ) of mouse fetal brain tissues but not in terminally differentiated primary astrocytes. Conversely, YB-1 knockout mice had reduced Sox-2, nestin, and musashi-1 expression in the SVZ. Although primary murine neurospheres were rich in YB-1, its expression was lost during glial differentiation. Glial tumors often express NSC markers and tend to loose the cellular control that governs differentiation; therefore, we addressed whether YB-1 served a similar role in cancer cells. YB-1, Sox-2, musashi-1, Bmi-1, and nestin are coordinately expressed in SF188 cells and 9/9 GBM patient-derived primary brain tumor-initiating cells (BTIC). Silencing YB-1 with siRNA attenuated the expression of these NSC markers, reduced neurosphere growth, and triggered differentiation via coordinate loss of GSK3-β. Furthermore, differentiation of BTIC with 1% serum or bone morphogenetic protein-4 suppressed YB-1 protein expression. Likewise, YB-1 expression was lost during differentiation of normal human NSCs. Consistent with these observations, YB-1 expression increased with tumor grade (n = 49 cases). YB-1 was also coexpressed with Bmi-1 (Spearmans 0.80, P > 0.001) and Sox-2 (Spearmans 0.66, P > 0.001) based on the analysis of 282 cases of high-grade gliomas. These proteins were highly expressed in 10/15 (67%) of GBM patients that subsequently relapsed. In conclusion, YB-1 correlatively expresses with NSC markers where it functions to promote cell growth and inhibit differentiation.

Polo‐Like Kinase 1 Inhibition Kills Glioblastoma Multiforme Brain Tumor Cells in Part Through Loss of SOX2 and Delays Tumor Progression in Mice

Glioblastoma multiforme (GBM) ranks among the deadliest types of cancer and given these new therapies are urgently needed. To identify molecular targets, we queried a microarray profiling 467 human GBMs and discovered that polo‐like kinase 1 (PLK1) was highly expressed in these tumors and that it clustered with the proliferative subtype. Patients with PLK1‐high tumors were more likely to die from their disease suggesting that current therapies are inactive against such tumors. This prompted us to examine its expression in brain tumor initiating cells (BTICs) given their association with treatment failure. BTICs isolated from patients expressed 110‐470 times more PLK1 than normal human astrocytes. Moreover, BTICs rely on PLK1 for survival because the PLK1 inhibitor BI2536 inhibited their growth in tumorsphere cultures. PLK1 inhibition suppressed growth, caused G2/M arrest, induced apoptosis, and reduced the expression of SOX2, a marker of neural stem cells, in SF188 cells. Consistent with SOX2 inhibition, the loss of PLK1 activity caused the cells to differentiate based on elevated levels of glial fibrillary acidic protein and changes in cellular morphology. We then knocked glial fibrillary acidic protein (GFAP) down SOX2 with siRNA and showed that it too inhibited cell growth and induced cell death. Likewise, in U251 cells, PLK1 inhibition suppressed cell growth, downregulated SOX2, and induced cell death. Furthermore, BI2536 delayed tumor growth of U251 cells in an orthotopic brain tumor model, demonstrating that the drug is active against GBM. In conclusion, PLK1 level is elevated in GBM and its inhibition restricts the growth of brain cancer cells. STEM CELLS2012;30:1064–1075

Multicenter imaging outcomes study of The Cancer Genome Atlas glioblastoma patient cohort: imaging predictors of overall and progression-free survival

BACKGROUND Despite an aggressive therapeutic approach, the prognosis for most patients with glioblastoma (GBM) remains poor. The aim of this study was to determine the significance of preoperative MRI variables, both quantitative and qualitative, with regard to overall and progression-free survival in GBM. METHODS We retrospectively identified 94 untreated GBM patients from the Cancer Imaging Archive who had pretreatment MRI and corresponding patient outcomes and clinical information in The Cancer Genome Atlas. Qualitative imaging assessments were based on the Visually Accessible Rembrandt Images feature-set criteria. Volumetric parameters were obtained of the specific tumor components: contrast enhancement, necrosis, and edema/invasion. Cox regression was used to assess prognostic and survival significance of each image. RESULTS Univariable Cox regression analysis demonstrated 10 imaging features and 2 clinical variables to be significantly associated with overall survival. Multivariable Cox regression analysis showed that tumor-enhancing volume (P = .03) and eloquent brain involvement (P < .001) were independent prognostic indicators of overall survival. In the multivariable Cox analysis of the volumetric features, the edema/invasion volume of more than 85 000 mm(3) and the proportion of enhancing tumor were significantly correlated with higher mortality (Ps = .004 and .003, respectively). CONCLUSIONS Preoperative MRI parameters have a significant prognostic role in predicting survival in patients with GBM, thus making them useful for patient stratification and endpoint biomarkers in clinical trials.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Posttreatment Follow-up Evaluation of Patients With Nonfunctioning Pituitary Adenomas.

BACKGROUND Nonfunctioning pituitary adenomas (NFPAs) are among the most common pituitary lesions and may present with hypopituitarism and/or hyperprolactinemia. OBJECTIVE To review the existing literature as it pertains to preoperative endocrine assessment in the workup for NFPAs. METHODS A systematic review methodology was utilized to identify and screen articles assessing the role and results of preoperative laboratory assessment in patients with NFPAs. The prevalence of individual pituitary hormonal axis deficiencies was reviewed. RESULTS Twenty-nine studies met inclusion criteria for analysis. No class I evidence was available, and all studies met criteria for class II evidence. Baseline serum laboratory assessment showed a prevalence of overall hypopituitarism in 37% to 85% of patients. The most common hormonal axis deficiency was growth hormone deficiency, prevalent in 61% to 100% of patients. The next most common deficit was hypogonadism, seen in 36% to 95% of patients. Adrenal insufficiency was diagnosed in 17% to 62% of patients. Finally, hypothyroidism was seen in 8% to 81% of patients. Hyperprolactinemia was seen in 25% to 65% of patients, with a mean level of 39 ng/mL and with a minority of patients exceeding a serum prolactin level of 200 ng/mL. No evidence supporting routine biomarker testing (eg, α-subunit or chromogranin A) or genetic testing in patients with sporadic NFPAs was available. CONCLUSION Despite a paucity of class I evidence, multiple retrospective studies have demonstrated a high prevalence of hypopituitarism in patients with NFPAs. Routine endocrine analysis of all anterior pituitary axes to assess for hypopituitarism is recommended, with prolactin and insulin-like growth factor 1 evaluation also valuable to assess for hypersecretion states that might not be clinically suspected. The full guidelines document for this chapter can be located at https://www.cns.org/guidelines/guidelines-management-patients-non-functioning-pituitary-adenomas/Chapter_3. ABBREVIATIONS GH, growth hormoneIGF-1, insulin-like growth factor 1NFPA, nonfunctioning pituitary adenoma.

Pooled Assessment of Computed Tomography Interpretation by Vascular Neurologists in the STRokE DOC Telestroke Network

BACKGROUND AND PURPOSE The objective of this pooled analysis was to determine the level of agreement between central read and each of 2 groups (spoke radiologists and hub vascular neurologists) in interpreting head computed tomography (CT) scans of stroke patients presenting to telestroke network hospitals. METHODS The Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC and STRokE DOC-AZ TIME) trials were prospective, randomized, and outcome blinded comparing telemedicine and teleradiology with telephone-only consultations. In each trial, the CT scans of the subjects were interpreted by the hub vascular neurologist in the telemedicine arm and by the spoke radiologist in the telephone arm. We obtained a central read for each CT using adjudicating committees blinded to treatment arm and outcome. The data were pooled and the results reported for the entire population. Kappa statistics and exact agreement rates were used to assess interobserver agreement for radiographic contraindication to recombinant tissue plasminogen activator (rt-PA), presence of hemorrhage, tumor, hyperdense artery, acute stroke, prior stroke, and early ischemic changes. RESULTS Among 261 analyzed cases, the agreement with central read for the presence of radiological rt-PA contraindication was excellent for hub vascular neurologist (96.2%, κ = .81, 95% CI .64-.97), spoke radiologist report (94.7%, κ = .64, 95% CI .39-.88), and overall (95.4%, κ = .74, 95% CI .59-.88). For rt-PA-treated patients (N = 65), overall agreement was 98.5%, and vascular neurologist agreement with central read was 100%. CONCLUSIONS Both vascular neurologists and reports from spoke radiologists had excellent reliability in identifying radiologic rt-PA contraindications. These pooled findings demonstrate that telestroke evaluation of head CT scans for acute rt-PA assessments is reliable.

Enhancing magnetic resonance imaging tumor detection with fluorescence intensity and lifetime imaging

Early detection is important for many solid cancers but the images provided by ultrasound, magnetic resonance imaging (MRI), and computed tomography applied alone or together, are often not sufficient for decisive early screening ∕ diagnosis. We demonstrate that MRI augmented with fluorescence intensity (FI) substantially improves detection. Early stage murine pancreatic tumors that could not be identified by blinded, skilled observers using MRI alone, were easily identified with MRI along with FI images acquired with photomultiplier tube detection and offset laser scanning. Moreover, we show that fluorescence lifetime (FLT) imaging enables positive identification of the labeling fluorophore and discriminates it from surrounding tissue autofluorescence. Our data suggest combined-modality imaging with MRI, FI, and FLT can be used to screen and diagnose early tumors.

Web-Based Tools and Mobile Applications To Mitigate Burnout, Depression, and Suicidality Among Healthcare Students and Professionals: a Systematic Review

ObjectiveBeing a healthcare professional can be a uniquely rewarding calling. However, the demands of training and practice can lead to chronic distress and serious psychological, interpersonal, and personal health burdens. Although higher burnout, depression, and suicide rates have been reported in healthcare professionals, only a minority receive treatment. Concerns regarding confidentiality, stigma, potential career implications, and cost and time constraints are cited as key barriers. Web-based and mobile applications have been shown to mitigate stress, burnout, depression, and suicidal ideation among several populations and may circumvent these barriers. Here, we reviewed published data on such resources and selected a small sample that readily can be used by healthcare providers.MethodsWe searched PubMed for articles evaluating stress, burnout, depression, and suicide prevention or intervention for healthcare students or providers and identified five categories of programs with significant effectiveness: Cognitive Behavioral Therapy (online), meditation, mindfulness, breathing, and relaxation techniques. Using these categories, we searched for Web-based (through Google and beacon.anu.edu.au—a wellness resource website) and mobile applications (Apple and mobile.va.gov/appstore) for stress, burnout, depression, and suicide prevention and identified 36 resources to further evaluate based on relevance, applicability to healthcare providers (confidentiality, convenience, and cost), and the strength of findings supporting their effectiveness.ResultsWe selected seven resources under five general categories designed to foster wellness and reduce burnout, depression, and suicide risk among healthcare workers: breathing (Breath2Relax), meditation (Headspace, guided meditation audios), Web-based Cognitive Behavioral Therapy (MoodGYM, Stress Gym), and suicide prevention apps (Stay Alive, Virtual Hope Box).ConclusionsThis list serves as a starting point to enhance coping with stressors as a healthcare student or professional in order to help mitigate burnout, depression, and suicidality. The next steps include adapting digital health strategies to specifically fit the needs of healthcare providers, with the ultimate goal of facilitating in-person care when warranted.

Guidelines: Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Posttreatment Follow-up Evaluation of Patients With Nonfunctioning Pituitary Adenomas.

BACKGROUND Nonfunctioning pituitary adenomas (NFPAs) are the most frequent pituitary tumors. Due to the lack of hormonal hypersecretion, posttreatment follow-up evaluation of NFPAs is challenging. OBJECTIVE To create evidence-based guidelines in an attempt to formulate guidance for posttreatment follow-up in a consistent, rigorous, and cost-effective way. METHODS An extensive literature search was performed. Only clinical articles describing postoperative follow-up of adult patients with NFPAs were included. To ascertain the class of evidence for the posttreatment follow-ups, the authors used the Clinical Assessment evidence-based classification. RESULTS Twenty-three studies met the inclusion criteria with respect to answering the questions on the posttreatment radiologic, endocrinologic, and ophthalmologic follow-up. Through this search, the authors formulated evidence-based guidelines for radiologic, endocrinologic, and ophthalmologic follow-up after surgical and/or radiation treatment. CONCLUSION Long-term radiologic, endocrinologic, and ophthalmologic surveillance monitoring after surgical and/or radiation therapy treatment of NFPAs to evaluate for tumor recurrence or regrowth, as well as pituitary and visual status, is recommended. There is insufficient evidence to make a recommendation on the duration of time of surveillance and its frequency. It is recommended that the first radiologic study to evaluate the extent of resection of the NFPA be performed ≥3 months after surgical intervention. The full guidelines document for this chapter can be located at https://www.cns.org/guidelines/guidelines-management-patients-non-functioning-pituitary-adenomas/Chapter_8. ABBREVIATION NFPA, nonfunctioning pituitary adenoma.

Visual Determination of Conjugate Eye Deviation on Computed Tomography Scan Predicts Diagnosis of Stroke Code Patients

BACKGROUND Head computed tomography (CT) is critical for stroke code evaluations and often happens prior to completion of the neurological exam. Eye deviation on neuroimaging (DeyeCOM sign) has utility for predicting stroke diagnosis and correlates with National Institutes of Health Stroke Scale (NIHSS) gaze score. We further assessed the utility of the DeyeCOM sign, without complex caliper-based eye deviation calculations, but simply with a visual determination method. METHODS Patients with initial head CT and final diagnosis from an institutional review board-approved consecutive prospective registry of stroke codes at the University of California, San Diego, were included. Five stroke specialists and 1 neuroradiologist reviewed each CT. DeyeCOM+ patients were compared to DeyeCOM- patients (baseline characteristics, diagnosis, and NIHSS gaze score). Kappa statistics compared stroke specialists to neuroradiologist reads, and visual determination to caliper measurement of DeyeCOM sign. RESULTS Of 181 patients, 46 were DeyeCOM+. Ischemic stroke was more commonly diagnosed in DeyeCOM+ patients compared to other diagnoses (P = .039). DeyeCOM+ patients were more likely to have an NIHSS gaze score of 1 or higher (P = .006). The NIHSS score of DeyeCOM+ stroke versus DeyeCOM- stroke patients was 8.3 ± 6.0 versus 6.7 ± 8.0 (P = .065). Functional outcomes were similar (P = .59). Stroke specialists had excellent agreement with the neuroradiologist (Κ = .89). Visual inspection had excellent agreement with the caliper method (Κ = .88). CONCLUSIONS Using a time-sensitive visual determination of gaze deviation on imaging was predictive of ischemic stroke diagnosis and presence of NIHSS gaze score, and was consistent with the more complex caliper method. This study furthers the clinical utility of the DeyeCOM sign for predicting ischemic strokes.