Approximately 12,000 glioblastomas are diagnosed annually in the United States. The median survival rate for this disease is 12 months, but individual survival rates can vary with patient-specific ...factors, including extent of surgical resection (EOR). The goal of our investigation is to develop a reliable strategy for personalized survival prediction and for quantifying the relationship between survival, EOR, and adjuvant chemoradiotherapy.
We used accelerated failure time (AFT) modeling using data from 721 newly diagnosed patients with glioblastoma (from 1993 to 2010) to model the factors affecting individualized survival after surgical resection, and we used the model to construct probabilistic, patient-specific tools for survival prediction. We validated this model with independent data from 109 patients from a second institution.
AFT modeling using age, Karnofsky performance score, EOR, and adjuvant chemoradiotherapy produced a continuous, nonlinear, multivariable survival model for glioblastoma. The median personalized predictive error was 4.37 months, representing a more than 20% improvement over current methods. Subsequent model-based calculations yield patient-specific predictions of the incremental effects of EOR and adjuvant therapy on survival.
Nonlinear, multivariable AFT modeling outperforms current methods for estimating individual survival after glioblastoma resection. The model produces personalized survival curves and quantifies the relationship between variables modulating patient-specific survival. This approach provides comprehensive, personalized, probabilistic, and clinically relevant information regarding the anticipated course of disease, the overall prognosis, and the patient-specific influence of EOR and adjuvant chemoradiotherapy. The continuous, nonlinear relationship identified between expected median survival and EOR argues against a surgical management strategy based on rigid EOR thresholds and instead provides the first explicit evidence supporting a maximum safe resection approach to glioblastoma surgery.
Abstract Radiation therapy forms one of the building blocks of the multi-disciplinary management of patients with brain tumors. Improved survival following radiation therapy may come with a cost, ...including the potential complication of radiation necrosis. Radiation necrosis impacts the quality of life in cancer survivors, and it is essential to detect and effectively treat this entity as early as possible. Significant progress in neuro-radiology and molecular pathology facilitate more straightforward diagnosis and characterization of cerebral radiation necrosis. Several therapeutic interventions, both medical and surgical, may halt the progression of radiation necrosis and diminish or abrogate its clinical manifestations, but there are still no definitive guidelines to follow explicitly that guide treatment of radiation necrosis. We discuss the pathobiology, clinical features, diagnosis, available treatment modalities, and outcomes in the management of patients with intracranial radiation necrosis that follows radiation used to treat brain tumors.
Iron is a tightly regulated micronutrient with no physiologic means of elimination and is necessary for cell division in normal tissue. Recent evidence suggests that dysregulation of iron regulatory ...proteins may play a role in cancer pathophysiology. We use public data from The Cancer Genome Atlas (TCGA) to study the association between survival and expression levels of 61 genes coding for iron regulatory proteins in patients with World Health Organization Grade II-III gliomas. Using a feature selection algorithm we identified a novel, optimized subset of eight iron regulatory genes (STEAP3, HFE, TMPRSS6, SFXN1, TFRC, UROS, SLC11A2, and STEAP4) whose differential expression defines two phenotypic groups with median survival differences of 52.3 months for patients with grade II gliomas (25.9 vs. 78.2 months, p< 10-3), 43.5 months for patients with grade III gliomas (43.9 vs. 87.4 months, p = 0.025), and 54.0 months when considering both grade II and III gliomas (79.9 vs. 25.9 months, p < 10-5).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hyperosmolar therapy is the principal medical management strategy for elevated intracranial pressure. Mannitol has been the primary hyperosmolar agent for nearly a century and remains the de facto ...gold standard for medical management of intracranial hypertension. Over the past 25 years, however, hypertonic saline (HTS) has become a progressively more common alternative to mannitol, and several recent studies have suggested its relative superiority. These findings have prompted calls for large-scale comparator trials of mannitol and HTS, but such trials would only be necessary if the designation of mannitol as the gold standard is appropriate and if current evidence suggests its therapeutic equipoise with HTS. Mounting evidence supporting HTS suggests that neither of these conditions is necessarily true and, instead, mandates reassessment of the actual gold-standard agent for hyperosmolar therapy. In the present article I make the case that current evidence supports HTS, not mannitol, as the better choice for gold-standard therapy for medical management of intracranial hypertension. This is accomplished first by examining the evidence on which the apparent designation of mannitol as the presumed gold-standard is based, then by reviewing the recent comparative efficacy data for HTS versus mannitol, and finally by discussing additional clinical considerations for appropriate designation of a gold-standard agent for hyperosmolar therapy. This assessment has important implications both for patient care and for clinical trial design.
This review identifies the current literature on the use of bevacizumab for cerebral radiation necrosis in patients with high-grade gliomas, summarizes the clinical course and complications following ...bevacizumab, and discusses the relative costs and benefits of this therapeutic option. A Medline search was conducted of all clinical studies before September 2012 investigating outcomes following use of bevacizumab therapy for radiation necrosis in patients with high-grade gliomas. Clinical and radiographic outcomes are reviewed. Seven studies reported a total of 30 patients with high-grade gliomas treated with bevacizumab for radiation necrosis. All patients demonstrated decreased radiographic volume of edema on T1 and T2 MRI sequences. Clinical outcomes were reported for 23 patients: 16 (70 %) had improvement in neurologic signs or symptoms, 5 (22 %) had mixed results, and 2 (9 %) remained neurologically unchanged. Complications were documented in 5 of 7 studies (18 of 29 patients, 62 %) and included deep vein thrombosis, pulmonary embolism, visual field worsening, worsening hemiplegia, pneumonia, seizure, and fatigue. Only one study evaluated quality of life measures and none evaluated cost or cost effectiveness. Data regarding the use of bevacizumab to treat radiation necrosis in patients with high-grade gliomas is limited and primarily class III evidence. While bevacizumab improves neurological symptoms and reduces radiographic volume of necrosis-associated cerebral edema, it comes at the expense of a high rate of potentially serious complications. Definitive evidence for the utility, cost-effectiveness, and overall efficacy of this management strategy is currently lacking and additional investigation is warranted.
Gene expression data is often assumed to be normally-distributed, but this assumption has not been tested rigorously. We investigate the distribution of expression data in human cancer genomes and ...study the implications of deviations from the normal distribution for translational molecular oncology research.
We conducted a central moments analysis of five cancer genomes and performed empiric distribution fitting to examine the true distribution of expression data both on the complete-experiment and on the individual-gene levels. We used a variety of parametric and nonparametric methods to test the effects of deviations from normality on gene calling, functional annotation, and prospective molecular classification using a sixth cancer genome.
Central moments analyses reveal statistically-significant deviations from normality in all of the analyzed cancer genomes. We observe as much as 37% variability in gene calling, 39% variability in functional annotation, and 30% variability in prospective, molecular tumor subclassification associated with this effect.
Cancer gene expression profiles are not normally-distributed, either on the complete-experiment or on the individual-gene level. Instead, they exhibit complex, heavy-tailed distributions characterized by statistically-significant skewness and kurtosis. The non-Gaussian distribution of this data affects identification of differentially-expressed genes, functional annotation, and prospective molecular classification. These effects may be reduced in some circumstances, although not completely eliminated, by using nonparametric analytics. This analysis highlights two unreliable assumptions of translational cancer gene expression analysis: that "small" departures from normality in the expression data distributions are analytically-insignificant and that "robust" gene-calling algorithms can fully compensate for these effects.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Introduction Comparative effectiveness research (CER) seeks to inform clinical decisions between alternate treatment strategies using data that reflects real patient populations and ...real-world clinical scenarios for the purpose of improving patient outcomes. There are multiple clinical situations where the unique characteristics of observational investigations can inform medical decision-making within the CER paradigm. Accordingly, it is critical for clinicians to appreciate the strengths and limitations of observational research, particularly as they apply to CER. Methods This review focuses on the role of observational research in CER. We discuss the concept of evidence hierarchies as they relate to observational research and CER, review the scope and nature of observational research, present the rationale for its inclusion in CER investigations, discuss potential sources of bias in observational investigations as well as strategies used to compensate for these biases, and discuss a framework to implement observational research in CER. Conclusions The CER paradigm recognizes the limitations of hierarchical models of evidence and favors application of a strength-of-evidence model. In this model, observational research fills gaps in randomized clinical trial data and is particularly valuable to investigate effectiveness, harms, prognosis, and infrequent outcomes as well as in circumstances where randomization is not possible and in studies of many surgical populations. Observational investigations must be designed with careful consideration of potential sources of bias and must incorporate strategies to control such bias prospectively, and their results must be reported in a uniform and transparent fashion. When these conditions can be achieved, observational research represents a valuable and critical component of modern CER.
The use of hyperosmolar agents for intracranial hypertension was introduced in the early 20th century and remains a mainstay of therapy for patients with cerebral edema. Both animal and human studies ...have demonstrated the efficacy of two hyperosmolar agents, mannitol and hypertonic saline, in reducing intracranial pressure via volume redistribution, plasma expansion, rheologic modifications, and anti-inflammatory effects. However, because of physician and institutional variation in therapeutic practices, lack of standardized protocols for initiation and administration of therapy, patient heterogeneity, and a paucity of randomized controlled trials have yielded little Class I evidence on which clinical decisions can be based, most current evidence regarding the use of hyperosmolar therapy is derived from retrospective analyses (Class III) and case series (Class IV). In this review, we summarize the available evidence regarding the use of hyperosmolar therapy with mannitol or hypertonic saline for the medical management of intracranial hypertension and present a comprehensive discussion of the evidence associated with various theoretical and practical concerns related to initiation, dosage, and monitoring of therapy.
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