Survival prediction of glioblastoma patients—are we there yet? A systematic review of prognostic modeling for glioblastoma and its clinical potential

Glioblastoma is associated with a poor prognosis. Even though survival statistics are well-described at the population level, it remains challenging to predict the prognosis of an individual patient despite the increasing number of prognostic models. The aim of this study is to systematically review the literature on prognostic modeling in glioblastoma patients. A systematic literature search was performed to identify all relevant studies that developed a prognostic model for predicting overall survival in glioblastoma patients following the PRISMA guidelines. Participants, type of input, algorithm type, validation, and testing procedures were reviewed per prognostic model. Among 595 citations, 27 studies were included for qualitative review. The included studies developed and evaluated a total of 59 models, of which only seven were externally validated in a different patient cohort. The predictive performance among these studies varied widely according to the AUC (0.58–0.98), accuracy (0.69–0.98), and C-index (0.66–0.70). Three studies deployed their model as an online prediction tool, all of which were based on a statistical algorithm. The increasing performance of survival prediction models will aid personalized clinical decision-making in glioblastoma patients. The scientific realm is gravitating towards the use of machine learning models developed on high-dimensional data, often with promising results. However, none of these models has been implemented into clinical care. To facilitate the clinical implementation of high-performing survival prediction models, future efforts should focus on harmonizing data acquisition methods, improving model interpretability, and externally validating these models in multicentered, prospective fashion.

     

Current perspectives of autologous stem cell transplantation for severe juvenile idiopathic arthritis

The majority of children with Juvenile Idiopathic Arthritis can nowadays be treated adequately. However despite the use of combinations of antirheumatic drugs, corticosteroids and the newer so called biologicals (blocking the TNF, Interleukin 1 or Interleukin 6 pathways) a proportion of children with arthritis remain resistant also to these therapies and suffer from a very severe, debilitating and potentially fatal disease. For such children autologous stem cell transplantation (ASCT) is successfully performed since 1997. Here we describe the long term outcome of the initial cohort of children with resistant Juvenile Idiopathic arthritis, treated with ASCT. The initial cohort of children was treated with a conditioning regimen containing Cyclophosphamide, anti thymocyte globulins and low dose Total Body irradiation. Overall favourable responses were seen, with a drug free remission rate of 50–55 %. In the more recent years late relapses were noted with lower percentages for drug free long term outcome. Special emphasis is given on 2 cases showing very late relapses, occurring after 7 and 9 years. The observed relapses are often less severe compared to the situation before SCT and can be treated successfully with conventional drugs in the majority of cases. More recently, ASCT was performed in 4 JIA children with a fludarabin containing regimen in stead of low dose TBI. With a 4 to 5 year follow up, these 4 patients are all in drug free full remission. Allogeneic transplant with an HLA matched family donor was reported in 2 JIA cases. Follow up of 1 and 3 year is sofar show clinical disease remission and tapering of medition. In conclusion, given the favourable long term outcome, SCT remains a valuable treatment option for children with drug resistant JIA.     

The effect of smoking on survival in lung carcinoma patients with brain metastasis: a systematic review and meta-analysis

The effects of smoking on survival in BM patients have yet to be reviewed and meta-analysed. However, previous studies have shown that smokers had a greater risk of dying from lung cancer compared to non-smokers. This meta-analysis, therefore, aimed to analyse the effects of cigarette smoking on overall survival (OS) and progression-free survival (PFS) in lung cancer BM patients. PubMed, Embase, Web of Science, Cochrane and Google Scholar were searched for comparative studies regarding the effects of smoking on incidence and survival in brain metastases patients up to December 2020. Three independent reviewers extracted overall survival (OS) and progression-free survival data (PFS). Random-effects models were used to pool multivariate-adjusted hazard ratios (HR). Out of 1890 studies, fifteen studies with a total of 2915 patients met our inclusion criteria. Amongst lung carcinoma BM patients, those who were smokers (ever or yes) had a worse overall survival (HR: 1.34, 95% CI 1.13, 1.60, I2: 72.1%, p-heterogeneity?<?0.001) than those who were non-smokers (never or no). A subgroup analysis showed the association to remain significant in the ever/never subgroup (HR: 1.34, 95% CI 1.11, 1.63) but not in the yes/no smoking subgroup (HR: 1.30, 95% CI 0.44, 3.88). This difference between the two subgroups was not statistically significant (p?=?0.91). Amongst lung carcinoma BM patients, smoking was associated with a worse OS and PFS. Future studies examining BMs should report survival data stratified by uniform smoking status definitions.

     

Disruption of structural and functional networks in long‐standing multiple sclerosis

Both gray matter atrophy and disruption of functional networks are important predictors for physical disability and cognitive impairment in multiple sclerosis (MS), yet their relationship is poorly understood. Graph theory provides a modality invariant framework to analyze patterns of gray matter morphology and functional coactivation. We investigated, how gray matter and functional networks were affected within the same MS sample and examined their interrelationship. Magnetic resonance imaging and magnetoencephalography (MEG) were performed in 102 MS patients and 42 healthy controls. Gray matter networks were computed at the group‐level based on cortical thickness correlations between 78 regions across subjects. MEG functional networks were computed at the subject level based on the phase‐lag index between time‐series of regions in source‐space. In MS patients, we found a more regular network organization for structural covariance networks and for functional networks in the theta band, whereas we found a more random network organization for functional networks in the alpha2 band. Correlation analysis revealed a positive association between covariation in thickness and functional connectivity in especially the theta band in MS patients, and these results could not be explained by simple regional gray matter thickness measurements. This study is a first multimodal graph analysis in a sample of MS patients, and our results suggest that a disruption of gray matter network topology is important to understand alterations in functional connectivity in MS as regional gray matter fails to take into account the inherent connectivity structure of the brain. Hum Brain Mapp 35:5946–5961, 2014. © 2014 Wiley Periodicals, Inc.     

Between‐hospital variation in rates of complications and decline of patient performance after glioblastoma surgery in the dutch Quality Registry Neuro Surgery

Journal of Neuro-Oncology - For decisions on glioblastoma surgery, the risk of complications and decline in performance is decisive. In this study, we determine the rate of complications and...     

Evidence-based dexamethasone dosing in malignant brain tumors: what do we really know?

Purpose

The present study aims to conduct a systematic review of literature reporting on the dose and dosing schedule of dexamethasone (DXM) in relation to clinical outcomes in malignant brain tumor patients, with particular attention to evidence-based practice.

Methods

A systematic search was performed in PubMed, Embase, Web of Science, Cochrane, Academic Search Premier, and PsycINFO to identify studies that reported edema volume reduction, symptomatic relief, adverse events and survival in relation to dexamethasone dose in glioma or brain metastasis (BM) patients.

Results

After screening 1812 studies, fifteen articles were included for qualitative review. Most studies reported a dose of 16 mg, mostly in a schedule of 4 mg four times a day. Due to heterogeneity of studies, it was not possible to perform quantitative meta-analysis. For BMs, best available evidence suggests that higher doses of DXM may give more adverse events, but may not necessarily result in better clinical condition. Some studies suggest that higher DXM doses are associated with shorter survival in the palliative setting. For glioma, DXM may lead to symptomatic improvement, yet no studies directly compare different doses. Results regarding edema reduction and survival in glioma patients are conflicting.

Conclusions

Evidence on the safety and efficacy of different DXM doses in malignant brain tumor patients is scarce and conflicting. Best available evidence suggests that low DXM doses may be noninferior to higher doses in certain circumstances, but more comparative research in this area is direly needed, especially in light of the increasing importance of immunotherapy for brain tumors.

     

Minimum spanning tree analysis of the human connectome

One of the challenges of brain network analysis is to directly compare network organization between subjects, irrespective of the number or strength of connections. In this study, we used minimum spanning tree (MST; a unique, acyclic subnetwork with a fixed number of connections) analysis to characterize the human brain network to create an empirical reference network. Such a reference network could be used as a null model of connections that form the backbone structure of the human brain. We analyzed the MST in three diffusion‐weighted imaging datasets of healthy adults. The MST of the group mean connectivity matrix was used as the empirical null‐model. The MST of individual subjects matched this reference MST for a mean 58%–88% of connections, depending on the analysis pipeline. Hub nodes in the MST matched with previously reported locations of hub regions, including the so‐called rich club nodes (a subset of high‐degree, highly interconnected nodes). Although most brain network studies have focused primarily on cortical connections, cortical–subcortical connections were consistently present in the MST across subjects. Brain network efficiency was higher when these connections were included in the analysis, suggesting that these tracts may be utilized as the major neural communication routes. Finally, we confirmed that MST characteristics index the effects of brain aging. We conclude that the MST provides an elegant and straightforward approach to analyze structural brain networks, and to test network topological features of individual subjects in comparison to empirical null models.     

The combined use of steroids and immune checkpoint inhibitors in brain metastasis patients: a systematic review and meta-analysis

BackgroundImmune checkpoint inhibitors (ICI) have been a breakthrough for selected cancer patients, including those with brain metastases (BMs). Likewise, steroids have been an integral component of symptomatic management of BM patients. However, clinical evidence on the interaction between ICI and steroids in BM patients is conflicting and has not adequately been summarized thus far. Hence, the aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI.MethodsA systematic literature search was performed. Pooled effect estimates were calculated using random-effects models across included studies.ResultsAfter screening 1145 abstracts, 15 observational studies were included. Fourteen studies reported sufficient data for meta-analysis, comprising 1102 BM patients of which 32.1% received steroids. In the steroid group, median OS ranged from 2.9 to 10.2 months. In the nonsteroid group, median OS ranged from 4.9 to 25.1 months. Pooled results demonstrated significantly worse OS (HR = 1.84, 95% CI 1.22-2.77) and systemic progression-free survival (PFS; HR = 2.00, 95% CI 1.37-2.91) in the steroid group. Stratified analysis showed a consistent effect across the melanoma subgroup; not in the lung cancer subgroup. No significant association was shown between steroid use and intracranial PFS (HR = 1.31, 95% CI 0.42-4.07).ConclusionsAdministration of steroids was associated with significantly worse OS and PFS in BM patients receiving ICI. Further research on dose, timing, and duration of steroids is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI.     

Bone marrow stromal cells for repair of the spinal cord: towards clinical application

Stem cells have been recognized and intensively studied for their potential use in restorative approaches for degenerative diseases and traumatic injuries. In the central nervous system (CNS), stem cell-based strategies have been proposed to replace lost neurons in degenerative diseases such as Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (Lou Gehrig's disease), or to replace lost oligodendrocytes in demyelinating diseases such as multiple sclerosis. Stem cells have also been implicated in repair of the adult spinal cord. An impact to the spinal cord results in immediate damage to tissue including blood vessels, causing loss of neurons, astrocytes, and oligodendrocytes. In time, more tissue nearby or away from the injury site is lost due to secondary injury. In case of relatively minor damage to the cord some return of function can be observed, but in most cases the neurological loss is permanent. This review will focus on in vitro and in vivo studies on the use of bone marrow stromal cells (BMSCs), a heterogeneous cell population that includes mesenchymal stem cells, for repair of the spinal cord in experimental injury models and their potential for human application. To optimally benefit from BMSCs for repair of the spinal cord it is imperative to develop in vitro techniques that will generate the desired cell type and/or a large enough number for in vivo transplantation approaches. We will also assess the potential and possible pitfalls for use of BMSCs in humans and ongoing clinical trials.