Structural connectome quantifies tumour invasion and predicts survival in glioblastoma patients.

Glioblastoma is characterized by diffuse infiltration into the surrounding tissue along white matter tracts. Identifying the invisible tumour invasion beyond focal lesion promises more effective treatment, which remains a significant challenge. It is increasingly accepted that glioblastoma could widely affect brain structure and function, and further lead to reorganization of neural connectivity. Quantifying neural connectivity in glioblastoma may provide a valuable tool for identifying tumour invasion. Here we propose an approach to systematically identify tumour invasion by quantifying the structural connectome in glioblastoma patients. We first recruit two independent prospective glioblastoma cohorts: the discovery cohort with 117 patients and validation cohort with 42 patients. Next, we use diffusion MRI of healthy subjects to construct tractography templates indicating white matter connection pathways between brain regions. Next, we construct fractional anisotropy skeletons from diffusion MRI using an improved voxel projection approach based on the tract-based spatial statistics, where the strengths of white matter connection and brain regions are estimated. To quantify the disrupted connectome, we calculate the deviation of the connectome strengths of patients from that of the age-matched healthy controls. We then categorize the disruption into regional disruptions on the basis of the relative location of connectome to focal lesions. We also characterize the topological properties of the patient connectome based on the graph theory. Finally, we investigate the clinical, cognitive and prognostic significance of connectome metrics using Pearson correlation test, mediation test and survival models. Our results show that the connectome disruptions in glioblastoma patients are widespread in the normal-appearing brain beyond focal lesions, associated with lower preoperative performance (P < 0.001), impaired cognitive function (P < 0.001) and worse survival (overall survival: hazard ratio = 1.46, P = 0.049; progression-free survival: hazard ratio = 1.49, P = 0.019). Additionally, these distant disruptions mediate the effect on topological alterations of the connectome (mediation effect: clustering coefficient -0.017, P < 0.001, characteristic path length 0.17, P = 0.008). Further, the preserved connectome in the normal-appearing brain demonstrates evidence of connectivity reorganization, where the increased neural connectivity is associated with better overall survival (log-rank P = 0.005). In conclusion, our connectome approach could reveal and quantify the glioblastoma invasion distant from the focal lesion and invisible on the conventional MRI. The structural disruptions in the normal-appearing brain were associated with the topological alteration of the brain and could indicate treatment target. Our approach promises to aid more accurate patient stratification and more precise treatment planning.

Tumour treating fields in glioblastoma: is the treatment tolerable, effective, and practical in UK patients?

BACKGROUND: Tumour Treating Fields (TTF) in combination with standard therapy, prolongs survival in patients with glioblastoma (GBM). The aim of the current study was to assess the feasibility of integrating TTF into a standard UK neuro-oncology service with a focus on patient tolerability, compliance, and treatment delivery. METHODS: A prospective study was performed of UK patients with IDH 1 Wild Type, MGMT Unmethylated GBM treated with TTF, in conjunction with conventional therapy. Patient compliance data, device-specific tolerability questions, and an evaluation of disease progression and survival were collected. Monthly quality of life (QoL) questionnaires (EORTC QLQ-C30 with BN-20) examined the trend of global health, psychosocial function, and symptom progression. RESULTS: Nine patients were enrolled with a median age of 47 (seven males; two females). Overall, compliance with TTF was 89% (range 16-97%). Only one patient failed to comply with treatment. Patients tolerated the device with minimal side effects. Eight patients described mild to moderate skin irritation, whilst all patients were keen to recommend the device to other patients (100%). Most patients found the weight and size of the device to be its biggest drawback (72%). Progression-free survival was 5.5 months and median overall survival was 14.9 months. CONCLUSIONS: TTF was well-tolerated amongst a small cohort of UK patients, who were able to comply with treatment without any significant complication. QoL questionnaires showed no sustained deterioration in global health, physical and emotional function until the final months of life when the disease burden was greatest.

Local alkylating chemotherapy applied immediately after 5-ALA guided resection of glioblastoma does not provide additional benefit.

Grade IV glioma is the most common and aggressive primary brain tumour. Gross total resection with 5-aminolevulinic acid (5-ALA) guided surgery combined with local chemotherapy (carmustine wafers) is an attractive treatment strategy in these patients. No previous studies have examined the benefit carmustine wafers in a treatment programme of 5-ALA guided resection followed by a temozolomide-based chemoradiotherapy protocol. The objective of this study was to examine the benefit of carmustine wafers on survival in patients undergoing 5-ALA guided resection. A retrospective cohort study of 260 patients who underwent 5-ALA resection of confirmed WHO 2007 Grade IV glioma between July 2009 and December 2014. Survival curves were calculated using the Kaplan-Meier method from surgery. The log-rank test was used to compare survival curves between groups. Cox regression was performed to identify variables predicting survival. A propensity score matched analysis was used to compare survival between patients who did and did not receive carmustine wafers while controlling for baseline characteristics. Propensity matched analysis showed no significant survival benefit of insertion of carmustine wafers over 5-ALA resection alone (HR 0.97 [0.68-1.26], p = 0.836). There was a trend to higher incidence of wound infection in those who received carmustine wafers (15.4 vs. 7.1%, p = 0.064). The Cox regression analysis showed that intraoperative residual fluorescent tumour and residual enhancing tumour on post-operative MRI were significantly predictive of reduced survival. Carmustine wafers have no added benefit following 5-ALA guided resection. Residual fluorescence and residual enhancing disease following resection have a negative impact on survival.

Vertebral osteomyelitis in adults: an update.

INTRODUCTION: The incidence of vertebral osteomyelitis is increasing, attributed to an ageing population with inherent co-morbidities and improved case ascertainment. SOURCES OF DATA: References were retrieved from the PubMed database using the terms 'vertebral osteomyelitis' and 'spondylodiscitis' between January 1, 2009 and April 30, 2014 published in English as checked in May 2014 (>1000 abstracts checked). AREAS OF AGREEMENT: Blood cultures and whole spine imaging with magnetic resonance imaging are essential investigations. Thorough debridement is the mainstay of surgical management, although placing metalwork in active infection is becoming increasingly common. AREAS OF CONTROVERSY: The extent of pursuing spinal biopsies to determine aetiology, antimicrobial choices and duration, monitoring the response to treatment, and surgical techniques and timing all vary widely in clinical practice with heterogeneous studies limiting comparisons. Surgery, rather than conservative approaches, is being proposed as the default management choice, because it can, in carefully selected patients, offer faster reduction in pain scores and improved quality of life. AREAS TIMELY FOR DEVELOPING RESEARCH: Further studies are needed to define the most effective technique for spinal biopsies to maximize determining aetiology. High-quality trials are required to provide an evidence base for both the medical and surgical management of vertebral osteomyelitis, including challenging medical management as the default option.

Community consultation in emergency neurosurgical research: lessons from a proposed trial for patients with chronic subdural haematomas.

INTRODUCTION: Chronic subdural haematoma (CSDH) is one of the most common neurosurgical disorders and is especially prevalent in old age. The subdural evacuating port system (SEPS) has emerged in the last few years as a minimally invasive alternative to the standard procedure of burr-hole evacuation. NHS practice is evidence-driven and evidence from high-quality clinical studies is required prior to implementation of any changes. In the UK, the National Research Ethics Service (NRES) advises community consultation prior to starting a clinical trial, where the patient is unlikely to have capacity to consent to enrolment in the trial. To prepare for a trial comparing minimally invasive (SEPS) versus burr-hole evacuation for evacuation of a CSDH, we have designed and undertaken a pre-protocol community consultation survey to examine potential patient participation. MATERIAL(S) AND METHODS: The study population consisted of patients, family members and carers/friends in neurosurgical clinic waiting rooms and wards at Addenbrooke's Hospital, Cambridge, who individually completed a questionnaire (n = 215). RESULTS: Most respondents were willing to participate in the proposed randomised clinical trial (77%; 165/215). Moreover, 80% (171/215) and 74% (159/215) were willing to allow their next of kin and an independent consultant neurosurgeon to give surrogate consent, respectively. CONCLUSION: The results of our pre-protocol community consultation showed that not only would most respondents be willing to participate in the proposed trial, but also would be happy for either next of kin or an independent consultant neurosurgeon to give surrogate consent if they lacked capacity to consent themselves. The advantages of this type of survey are twofold: they increase patient and public involvement in the research process and allow researchers to design study protocols that are acceptable to the community.

A Prospective Study of Longitudinal Risks of Cognitive Deficit for People Undergoing Glioblastoma Surgery Using a Tablet Computer Cognition Testing Battery: Towards Personalized Understanding of Risks to Cognitive Function.

Glioblastoma and the surgery to remove it pose high risks to the cognitive function of patients. Little reliable data exist about these risks, especially postoperatively before radiotherapy. We hypothesized that cognitive deficit risks detected before surgery will be exacerbated by surgery in patients with glioblastoma undergoing maximal treatment regimens. We used longitudinal electronic cognitive testing perioperatively to perform a prospective, longitudinal, observational study of 49 participants with glioblastoma undergoing surgery. Before surgery (A1), the participant risk of deficit in 5/6 cognitive domains was increased compared to normative data. Of these, the risks to Attention (OR = 31.19), Memory (OR = 97.38), and Perception (OR = 213.75) were markedly increased. These risks significantly increased in the early period after surgery (A2) when patients were discharged home or seen in the clinic to discuss histology results. For participants tested at 4-6 weeks after surgery (A3) before starting radiotherapy, there was evidence of risk reduction towards A1. The observed risks of cognitive deficit were independent of patient-specific, tumour-specific, and surgery-specific co-variates. These results reveal a timeframe of natural recovery in the first 4-6 weeks after surgery based on personalized deficit profiles for each participant. Future research in this period could investigate personalized rehabilitation tools to aid the recovery process found.

Memory recovery in relation to default mode network impairment and neurite density during brain tumor treatment.

OBJECTIVE: The aim of this study was to test brain tumor interactions with brain networks, thereby identifying protective features and risk factors for memory recovery after resection. METHODS: Seventeen patients with diffuse nonenhancing glioma (ages 22-56 years) underwent longitudinal MRI before and after surgery, and during a 12-month recovery period (47 MRI scans in total after exclusion). After each scanning session, a battery of memory tests was performed using a tablet-based screening tool, including free verbal memory, overall verbal memory, episodic memory, orientation, forward digit span, and backward digit span. Using structural MRI and neurite orientation dispersion and density imaging (NODDI) derived from diffusion-weighted images, the authors estimated lesion overlap and neurite density, respectively, with brain networks derived from normative data in healthy participants (somatomotor, dorsal attention, ventral attention, frontoparietal, and default mode network [DMN]). Linear mixed-effect models (LMMs) that regressed out the effect of age, gender, tumor grade, type of treatment, total lesion volume, and total neurite density were used to test the potential longitudinal associations between imaging markers and memory recovery. RESULTS: Memory recovery was not significantly associated with either the tumor location based on traditional lobe classification or the type of treatment received by patients (i.e., surgery alone or surgery with adjuvant chemoradiotherapy). Nonlocal effects of tumors were evident on neurite density, which was reduced not only within the tumor but also beyond the tumor boundary. In contrast, high preoperative neurite density outside the tumor but within the DMN was associated with better memory recovery (LMM, p value after false discovery rate correction [Pfdr] < 10-3). Furthermore, postoperative and follow-up neurite density within the DMN and frontoparietal network were also associated with memory recovery (LMM, Pfdr = 0.014 and Pfdr = 0.001, respectively). Preoperative tumor and postoperative lesion overlap with the DMN showed a significant negative association with memory recovery (LMM, Pfdr = 0.002 and Pfdr < 10-4, respectively). CONCLUSIONS: Imaging biomarkers of cognitive recovery and decline can be identified using NODDI and resting-state networks. Brain tumors and their corresponding treatment affecting brain networks that are fundamental for memory functioning such as the DMN can have a major impact on patients' memory recovery.

A systematic review of cognitive function in patients with glioblastoma undergoing surgery.

BACKGROUND: Patients with glioblastoma (GB) are more likely to suffer cognitive deficits with poor quality of life as compared with lower-grade glioma patient groups, for whom cognition research is plentiful. The objective of this systematic review is to evaluate the cognitive function of patients with GB before and after surgery. METHODS: This review was prospectively registered with PROSPERO. PubMed and EMBASE searches were performed, most recently March 15, 2018. Inclusion criteria were adult patients, histologically confirmed GB, and cognitive tests conducted before and/or after surgery. Screening and data extraction were carried out independently by 2 authors. RESULTS: A total of 512 abstracts were screened. Nineteen studies were included with 902 participants, of whom only 423 had histologically confirmed GB. Only 11 studies tested cognitive function both before and after surgery. A total of 114 different cognitive tests were used. The most common test was used in only 9 studies; 82 tests were used only once. Follow-up time ranged from 1 week to 16 months with extremely high dropout rates. Eighteen of 19 studies reported cognitive deficits in their samples, with prevalence ranging from 22% to 100% (median 64%, interquartile range 42%). Only 1/11 longitudinal studies reported normal cognitive function, 3/11 reported initial deficits with improvement after surgery, 3/11 reported static deficits, and 4/11 reported deterioration. CONCLUSION: There is a consistently high risk of cognitive deficit for patients with GB undergoing surgery. The included studies showed marked heterogeneity in study design, case-mix of included diagnoses, and the type and timing of cognitive tests used. We highlight considerations for the design of future studies to avoid such bias.

Semi-automated construction of patient individualised clinical target volumes for radiotherapy treatment of glioblastoma utilising diffusion tensor decomposition maps.

OBJECTIVES: Glioblastoma multiforme (GBM) is a highly infiltrative primary brain tumour with an aggressive clinical course. Diffusion tensor imaging (DT-MRI or DTI) is a recently developed technique capable of visualising subclinical tumour spread into adjacent brain tissue. Tensor decomposition through p and q maps can be used for planning of treatment. Our objective was to develop a tool to automate the segmentation of DTI decomposed p and q maps in GBM patients in order to inform construction of radiotherapy target volumes. METHODS: Chan-Vese level set model is applied to segment the p map using the q map as its initial starting point. The reason of choosing this model is because of the robustness of this model on either conventional MRI or only DTI. The method was applied on a data set consisting of 50 patients having their gross tumour volume delineated on their q map and Chan-Vese level set model uses these superimposed masks to incorporate the infiltrative edges. RESULTS: The expansion of tumour boundary from q map to p map is clearly visible in all cases and the Dice coefficient (DC) showed a mean similarity of 74% across all 50 patients between the manually segmented ground truth p map and the level set automatic segmentation. CONCLUSION: Automated segmentation of the tumour infiltration boundary using DTI and tensor decomposition is possible using Chan-Vese level set methods to expand q map to p map. We have provided initial validation of this technique against manual contours performed by experienced clinicians. ADVANCES IN KNOWLEDGE: This novel automated technique to generate p maps has the potential to individualise radiation treatment volumes and act as a decision support tool for the treating oncologist.

Glioblastoma surgery related emotion recognition deficits are associated with right cerebral hemisphere tract changes.

Patients with glioblastoma face abysmal overall survival, cognitive deficits, poor quality of life and limitations to social participation; partly attributable to surgery. Emotion recognition deficits mediated by pathophysiological mechanisms in the right inferior fronto-occipital fasciculus and right inferior longitudinal fasciculus have been demonstrated in traumatic brain injury and dementia, with negative associations for social participation. We hypothesize similar mechanisms occur in patients undergoing resection surgery for glioblastoma. Here, we apply tract-based spatial statistics using a combination of automated image registration methods alongside cognitive testing before and after surgery. In this prospective, longitudinal, observational study of 15 patients, surgery is associated with an increase in emotion recognition deficits (P = 0.009) and this is correlated with decreases in fractional anisotropy in the inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation and uncinate fasciculus; all in the right hemisphere (P = 0.014). Methodologically, the combination of registration steps used demonstrate that tract-based spatial statistics can be applied in the context of large, scan distorting lesions such as glioblastoma. These results can inform clinical consultations with patients undergoing surgery, support consideration for social cognition rehabilitation and are consistent with theoretical mechanisms that implicate these tracts in emotion recognition deficits across different diseases.

Intratumoral Heterogeneity of Glioblastoma Infiltration Revealed by Joint Histogram Analysis of Diffusion Tensor Imaging.

BACKGROUND: Glioblastoma is a heterogeneous disease characterized by its infiltrative growth, rendering complete resection impossible. Diffusion tensor imaging (DTI) shows potential in detecting tumor infiltration by reflecting microstructure disruption. OBJECTIVE: To explore the heterogeneity of glioblastoma infiltration using joint histogram analysis of DTI, to investigate the incremental prognostic value of infiltrative patterns over clinical factors, and to identify specific subregions for targeted therapy. METHODS: A total of 115 primary glioblastoma patients were prospectively recruited for surgery and preoperative magnetic resonance imaging. The joint histograms of decomposed anisotropic and isotropic components of DTI were constructed in both contrast-enhancing and nonenhancing tumor regions. Patient survival was analyzed with joint histogram features and relevant clinical factors. The incremental prognostic values of histogram features were assessed using receiver operating characteristic curve analysis. The correlation between the proportion of diffusion patterns and tumor progression rate was tested using Pearson correlation. RESULTS: We found that joint histogram features were associated with patient survival and improved survival model performance. Specifically, the proportion of nonenhancing tumor subregion with decreased isotropic diffusion and increased anisotropic diffusion was correlated with tumor progression rate (P = .010, r = 0.35), affected progression-free survival (hazard ratio = 1.08, P < .001), and overall survival (hazard ratio = 1.36, P < .001) in multivariate models. CONCLUSION: Joint histogram features of DTI showed incremental prognostic values over clinical factors for glioblastoma patients. The nonenhancing tumor subregion with decreased isotropic diffusion and increased anisotropic diffusion may indicate a more infiltrative habitat and potential treatment target.

Characterizing tumor invasiveness of glioblastoma using multiparametric magnetic resonance imaging.

OBJECTIVE: The objective of this study was to characterize the abnormalities revealed by diffusion tensor imaging (DTI) using MR spectroscopy (MRS) and perfusion imaging, and to evaluate the prognostic value of a proposed quantitative measure of tumor invasiveness by combining contrast-enhancing (CE) and DTI abnormalities in patients with glioblastoma. METHODS: Eighty-four patients with glioblastoma were recruited preoperatively. DTI was decomposed into isotropic (p) and anisotropic (q) components. The relative cerebral blood volume (rCBV) was calculated from the dynamic susceptibility contrast imaging. Values of N-acetylaspartate, myoinositol, choline (Cho), lactate (Lac), and glutamate + glutamine (Glx) were measured from multivoxel MRS and normalized as ratios to creatine (Cr). Tumor regions of interest (ROIs) were manually segmented from the CE T1-weighted (CE-ROI) and DTI-q (q-ROI) maps. Perfusion and metabolic characteristics of these ROIs were measured and compared. The relative invasiveness coefficient (RIC) was calculated as a ratio of the characteristic radii of CE-ROI and q-ROI. The prognostic significance of RIC was tested using Kaplan-Meier and multivariate Cox regression analyses. RESULTS: The Cho/Cr, Lac/Cr, and Glx/Cr in q-ROI were significantly higher than CE-ROI (p = 0.004, p = 0.005, and p = 0.007, respectively). CE-ROI had significantly higher rCBV values than q-ROI (p < 0.001). A higher RIC was associated with worse survival in a multivariate overall survival (OS) model (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.06-1.85, p = 0.016) and progression-free survival (PFS) model (HR 1.55, 95% CI 1.16-2.07, p = 0.003). An RIC cutoff value of 0.89 significantly predicted shorter OS (median 384 vs 605 days, p = 0.002) and PFS (median 244 vs 406 days, p = 0.001). CONCLUSIONS: DTI-q abnormalities displayed higher tumor load and hypoxic signatures compared with CE abnormalities, whereas CE regions potentially represented the tumor proliferation edge. Integrating the extents of invasion visualized by DTI-q and CE images into clinical practice may lead to improved treatment efficacy.