PurposeTo develop a cerebrospinal fluid (CSF) miRNA diagnostic biomarker for glioblastoma.Experimental DesignGlioblastoma tissue and matched CSF from the same patient (obtained prior to tumor manipulation) were profiled by TaqMan OpenArray® Human MicroRNA Panel. CSF miRNA profiles from glioblastoma patients and controls were created from three discovery cohorts and confirmed in two validation cohorts.ResultsmiRNA profiles from clinical CSF correlated with those found in glioblastoma tissues. Comparison of CSF miRNA profiles between glioblastoma patients and non-brain tumor patients yielded a tumor “signature” consisting of nine miRNAs. The “signature” correlated with glioblastoma tumor volume (p=0.008). When prospectively applied to cisternal CSF, the sensitivity and specificity of the ‘signature’ for glioblastoma detection were 67% and 80%, respectively. For lumbar CSF, the sensitivity and specificity of the signature were 28% and 95%, respectively. Comparable results were obtained from analyses of CSF extracellular vesicles (EVs) and crude CSF.ConclusionWe report a CSF miRNA signature as a “liquid biopsy” diagnostic platform for glioblastoma.

Background The survival trends and the patterns of clinical practice pertaining to radiation therapy and surgical resection for WHO grade I, II, and III astrocytoma patients remain poorly characterized. Methods Using the Surveillance, Epidemiology and End Results (SEER) database, we identified 2497 grade I, 4113 grade II, and 2755 grade III astrocytomas during the period of 1999–2010. Time-trend analyses were performed for overall survival, radiation treatment (RT), and the extent of surgical resection (EOR). Results While overall survival of grade I astrocytoma patients remained unchanged during the study period, we observed improved overall survival for grade II and III astrocytoma patients (Tarone-Ware P < .05). The median survival increased from 44 to 57 months and from 15 to 24 months for grade II and III astrocytoma patients, respectively. The differences in survival remained significant after adjusting for pertinent variables including age, ethnicity, marital status, sex, tumor size, tumor location, EOR, and RT status. The pattern of clinical practice in terms of EOR for grade II and III astrocytoma patients did not change significantly during this study period. However, there was decreased RT utilization as treatment for grade II astrocytoma patients after 2005. Conclusion Results from the SEER database indicate that there were improvements in the overall survival of grade II and III astrocytoma patients over the past decade. Analysis of the clinical practice patterns identified potential opportunities for impacting the clinical course of these patients.

A fundamental aspect of human beings is that they learn. The process of learning and what is learned are impacted by a number of factors, both cognitive and social; that is, humans are boundedly rational. Cognitive and social limitations interact, making it difficult to reason about how to provide information to impact what humans know, believe, and do. Herein, we use a multi-agent dynamicnetwork simulation system, Construct, to conduct such reasoning. In particular, we ask, What media should be used to provide information to most impact what people know, believe, and do, given diverse social structures? All simulated agents are boundedly rational both at the cognitive and social level, and so are subject to factors such as literacy, education, and the breadth of their social network. We find that there is no one most effective intervention; rather, to be effective, messages and the media used to spread the message need to be selected for the population being addressed. Typically, a multimedia campaign is critical.

OBJECTIVE The available evidence suggests that the clinical benefits of extended resection are limited for chemosensitive tumors, such as primary CNS lymphoma. Oligodendroglioma is generally believed to be more sensitive to chemotherapy than astrocytoma of comparable grades. In this study the authors compare the survival benefit of gross-total resection (GTR) in patients with oligodendroglioma relative to patients with astrocytoma. METHODS Using the Surveillance, Epidemiology, and End Results (SEER) Program (1999-2010) database, the authors identified 2378 patients with WHO Grade II oligodendroglioma (O2 group) and 1028 patients with WHO Grade III oligodendroglioma (O3 group). Resection was defined as GTR, subtotal resection, biopsy only, or no resection. Kaplan-Meier and multivariate Cox regression survival analyses were used to assess survival with respect to extent of resection. RESULTS Cox multivariate analysis revealed that the hazard of dying from O2 and O3 was comparable between patients who underwent biopsy only and GTR (O2: hazard ratio [HR] 1.06, 95% confidence interval [CI] 0.73-1.53; O3: HR 1.18, 95% CI 0.80-1.72). A comprehensive search of the published literature identified 8 articles without compelling evidence that GTR is associated with improved overall survival in patients with oligodendroglioma. CONCLUSIONS This SEER-based analysis and review of the literature suggest that GTR is not associated with improved survival in patients with oligodendroglioma. This finding contrasts with the documented association between GTR and overall survival in anaplastic astrocytoma and glioblastoma. The authors suggest that this difference may reflect the sensitivity of oligodendroglioma to chemotherapy as compared with astrocytomas.

The levels of expression of O6-methylguanine-DNA methyltransferase (MGMT) are relevant in predicting the response to the alkylating chemotherapy in patients affected by glioblastoma. MGMT promoter methylation and the published MGMT regulating microRNAs (miRNAs) do not completely explain the expression pattern of MGMT in clinical glioblastoma specimens. Here we used a genome-wide microarray-based approach to identify MGMT regulating miRNAs. Our screen unveiled three novel MGMT regulating miRNAs, miR-127-3p, miR-409-3p, and miR-124-3p, in addition to the previously identified miR-181d-5p. Transfection of these three novel miRNAs into the T98G glioblastoma cell line suppressed MGMT mRNA and protein expression. However, their MGMT- suppressive effects are 30–50% relative that seen with miR-181d-5p transfection. In silico analyses of The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) revealed that miR-181d-5p is the only miRNA that consistently exhibited inverse correlation with MGMT mRNA expression. However, statistical models incorporating both miR-181d-5p and miR-409-3p expression better predict MGMT expression relative to models involving either miRNA alone. Our results confirmed miR-181d-5p as the key MGMT-regulating miRNA. Other MGMT regulating miRNAs, including the miR-409-3p identified in this report, modify the effect of miR-181d-5p on MGMT expression. MGMT expression is, thus, regulated by cooperative interaction between key MGMT-regulating miRNAs.

Background The number of brain metastases (BM) plays an important role in the decision between stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT). Methods We analyzed the survival of 5750 SRS-treated BM patients as a function of BM number. Survival analyses were performed using Kaplan-Meier analysis as well as univariate and multivariate Cox proportional hazards models. Results BM patients were first categorized as those with 1, 2–4, and 5–10 BM based on the scheme proposed by Yamamoto et al (Lancet Oncology 2014). Median overall survival for patients with 1 BM was superior to those with 2–4 BMs (7.1 mo v. 6.4 mo, p=0.009), and survival of patients with 2–4 BMs did not differ from those with 5–10 BMs (6.4 mo v. 6.3 mo, p=0.170). The median survival of patients with >10 BMs was lower than those with 2–10 BMs (6.3 mo v. 5.5 mo, p=0.025). In a multivariate model that accounted for age, Karnofsky Performance Score (KPS), systemic disease status, tumor histology, and cumulative intracranial tumor volume (CITV), we observed a ~10% increase in hazard of death when comparing patients with 1 versus 2–10 BM (p<0.001) or 10 versus >10 BM (p<0.001). When BM number was modeled as a continuous variable rather than using the Yamamoto classification, we observed a step-wise 5% increase in the hazard of death for every increment of 5–6 BM (p<0.001). Conclusions The contribution of BM number to overall survival is modest, and should be considered as one of the many variables considered in the decision between SRS and WBRT.

"Academic genealogy" refers to the linking of scientists and scholars based on their dissertation supervisors. We propose that this concept can be applied to medical training and that this "medical academic genealogy" may influence the landscape of the peer-reviewed literature. We performed a comprehensive PubMed search to identify US authors who have contributed peer-reviewed articles on a neurosurgery topic that remains controversial: the value of maximal resection for high-grade gliomas (HGGs). Training information for each key author (defined as the first or last author of an article) was collected (eg, author's medical school, residency, and fellowship training). Authors were recursively linked to faculty mentors to form genealogies. Correlations between genealogy and publication result were examined. Our search identified 108 articles with 160 unique key authors. Authors who were members of 2 genealogies (14% of key authors) contributed to 38% of all articles. If an article contained an authorship contribution from the first genealogy, its results were more likely to support maximal resection (log odds ratio = 2.74, p < 0.028) relative to articles without such contribution. In contrast, if an article contained an authorship contribution from the second genealogy, it was less likely to support maximal resection (log odds ratio = -1.74, p < 0.026). We conclude that the literature on surgical resection for HGGs is influenced by medical academic genealogies, and that articles contributed by authors of select genealogies share common results. These findings have important implications for the interpretation of scientific literature, design of medical training, and health care policy.

AUC, area under the receiver-operating characteristic curveBM, brain metastasisCITV, cumulative intracranial tumor volumeds-GPA, disease-specific Graded Prognostic AssessmentGPA, Graded Prognostic AssessmentIDI, integrated discrimination improvementKHMGH, Katsuta Hospital Mito Gamma HouseKPS, Karnofsky Performance StatusNRI, net reclassification improvementROC, receiver-operating characteristic curveSRS, stereotactic radiosurgeryUCSD/SDGKC, University of California, San Diego/San Diego Gamma Knife Center.