Analytic approaches to clinical validation of results from preclinical models of glioblastoma:A systematic review

INTRODUCTION: Analytic approaches to clinical validation of results from preclinical models are important in assessment of their relevance to human disease. This systematic review examined consistency in reporting of glioblastoma cohorts from The Cancer Genome Atlas (TCGA) or Chinese Glioma Genome Atlas (CGGA) and assessed whether studies included patient characteristics in their survival analyses. METHODS: We searched Embase and Medline on 02Feb21 for studies using preclinical models of glioblastoma published after Jan2008 that used data from TCGA or CGGA to validate the association between at least one molecular marker and overall survival in adult patients with glioblastoma. Main data items included cohort characteristics, statistical significance of the survival analysis, and model covariates. RESULTS: There were 58 eligible studies from 1,751 non-duplicate records investigating 126 individual molecular markers. In 14 studies published between 2017 and 2020 using TCGA RNA microarray data that should have the same cohort, the median number of patients was 464.5 (interquartile range 220.5–525). Of the 15 molecular markers that underwent more than one univariable or multivariable survival analyses, five had discrepancies between studies. Covariates used in the 17 studies that used multivariable survival analyses were age (76.5%), pre-operative functional status (35.3%), sex (29.4%) MGMT promoter methylation (29.4%), radiotherapy (23.5%), chemotherapy (17.6%), IDH mutation (17.6%) and extent of resection (5.9%). CONCLUSION: Preclinical glioblastoma studies that used TCGA for validation did not provide sufficient information about their cohort selection and there were inconsistent results. Transparency in reporting and the use of analytic approaches that adjust for clinical variables can improve the reproducibility between studies

Association of extent of resection and functional outcomes in diffuse low-grade glioma: systematic review & meta-analysis.

Background: Surgical resection offers survival benefits in patients with diffuse low-grade glioma (DLGG) but its association with functional outcomes is uncertain. This systematic review assessed functional outcomes associated with extent of resection (EoR) in adults with DLGG. Methods: We searched Medline, Embase and CENTRAL on the 19th of February 2021 for observational studies reporting functional outcomes after surgical resection for patients aged ≥ 18 years with a new diagnosis of supratentorial DLGG according to any World Health Organization classification of primary brain tumors. The Newcastle–Ottawa Scale (NOS) informed our risk of bias assessments. The proportion of patients returning to work within 12 months entered a random-effects meta-analysis. PROSPERO registration number CRD42021238387. Results: There were seven eligible moderate to high-quality (NOS > 6) observational studies identified from 1,183 records involving 234 patients with DLGG. Functional outcomes reported included neurocognition (n = 2 studies), performance status (n = 3), quality of life (QoL) (n = 1) and return to work (n = 6). The proportion of patients who returned to work within 12 months of surgery was 84% (95% confidence interval [CI] 50–96%, I-squared = 38%, 5 studies) for gross total resection, 66% (95% CI 14–96%, I2 = 57%, 5 studies) for subtotal resection, and 31% (95% CI 4–82%, I2 = 0%, 4 studies) for partial resection. There was insufficient data on other functional outcomes for quantitative synthesis. Conclusion: A higher proportion of DLGG patients returned to work following gross total resection compared with those who had a subtotal or partial resection. Further studies with standardized assessments can clarify the association between EoR and different functional outcomes

Does Drain Position and Duration Influence Outcomes in Patients Undergoing Burr-Hole Evacuation of Chronic Subdural Hematoma? Lessons from a UK Multicenter Prospective Cohort Study.

BACKGROUND: Drain insertion following chronic subdural hematoma (CSDH) evacuation improves patient outcomes. OBJECTIVE: To examine whether this is influenced by variation in drain location, positioning or duration of placement. METHODS: We performed a subgroup analysis of a previously reported multicenter, prospective cohort study of CSDH patients performed between May 2013 and January 2014. Data were analyzed relating drain location (subdural or subgaleal), position (through a frontal or parietal burr hole), and duration of insertion, to outcomes in patients aged >16 yr undergoing burr-hole drainage of primary CSDH. Primary outcomes comprised modified Rankin scale (mRS) at discharge and symptomatic recurrence requiring redrainage within 60 d. RESULTS: A total of 577 patients were analyzed. The recurrence rate of 6.7% (12/160) in the frontal subdural drain group was comparable to 8.8% (30/343) in the parietal subdural drain group. Only 44/577 (7.6%) patients underwent subgaleal drain insertion. Recurrence rates were comparable between subdural (7.7%; 41/533) and subgaleal (9.1%; 4/44) groups (P = .95). We found no significant differences in discharge mRS between these groups. Recurrence rates were comparable between patients with postoperative drainage for 1 or 2 d, 6.4% and 8.4%, respectively (P = .44). There was no significant difference in mRS scores between these 2 groups (P = .56). CONCLUSION: Drain insertion after CSDH drainage is important, but position (subgaleal or subdural) and duration did not appear to influence recurrence rate or clinical outcomes. Similarly, drain location did not influence recurrence rate nor outcomes where both parietal and frontal burr holes were made. Further prospective cohort studies or randomized controlled trials could provide further clarification

Drains result in greater reduction of subdural width and midline shift in burr hole evacuation of chronic subdural haematoma

Funder: University of EdinburghAbstract: Background: Drain insertion following chronic subdural haematoma (CSDH) evacuation reduces recurrence and improves outcomes. The mechanism of this improvement is uncertain. We assessed whether drains result in improved postoperative imaging, and which radiological factors are associated with recurrence and functional outcome. Methods: A multi-centre, prospective cohort study of CSDH patients was performed between May 2013 and January 2014. Patients aged > 16 years undergoing burr hole evacuation of primary CSDH with pre- and postoperative imaging were included in this subgroup analysis. Baseline and clinical details were collected. Pre- and postoperative maximal subdural width and midline shift (MLS) along with clot density were recorded. Primary outcomes comprised mRS at discharge and symptomatic recurrence requiring re-drainage. Comparisons were made using multiple logistic regression. Results: Three hundred nineteen patients were identified for inclusion. Two hundred seventy-two of 319 (85%) patients underwent drain insertion at the time of surgery versus 45/319 (14%) who did not. Twenty-nine of 272 patients who underwent drain insertion experienced recurrence (10.9%) versus 9 of 45 patients without drain insertion (20.5%; p = 0.07). Overall change in median subdural width was significantly greater in the drain versus ‘no drain’ groups (11 mm versus 6 mm, p < 0.01). Overall change in median midline shift (MLS) was also significantly greater in the drain group (4 mm versus 3 mm, p < 0.01). On multivariate analysis, change in maximal width and MLS were significant predictors of recurrence, although only the former remained a significant predictor for functional outcome. Conclusions: The use of subdural drains results in significantly improved postoperative imaging in burr hole evacuation of CSDH, thus providing radiological corroboration for their recommended use

Prospective, multicentre study of external ventricular drainage-related infections in the UK and Ireland.

OBJECTIVES: External ventricular drain (EVD) insertion is a common neurosurgical procedure. EVD-related infection (ERI) is a major complication that can lead to morbidity and mortality. In this study, we aimed to establish a national ERI rate in the UK and Ireland and determine key factors influencing the infection risk. METHODS: A prospective multicentre cohort study of EVD insertions in 21 neurosurgical units was performed over 6 months. The primary outcome measure was 30-day ERI. A Cox regression model was used for multivariate analysis to calculate HR. RESULTS: A total of 495 EVD catheters were inserted into 452 patients with EVDs remaining in situ for 4700 days (median 8 days; IQR 4-13). Of the catheters inserted, 188 (38%) were antibiotic-impregnated, 161 (32.5%) were plain and 146 (29.5%) were silver-bearing. A total of 46 ERIs occurred giving an infection risk of 9.3%. Cox regression analysis demonstrated that factors independently associated with increased infection risk included duration of EVD placement for ≥8 days (HR=2.47 (1.12-5.45); p=0.03), regular sampling (daily sampling (HR=4.73 (1.28-17.42), p=0.02) and alternate day sampling (HR=5.28 (2.25-12.38); p<0.01). There was no association between catheter type or tunnelling distance and ERI. CONCLUSIONS: In the UK and Ireland, the ERI rate was 9.3% during the study period. The study demonstrated that EVDs left in situ for ≥8 days and those sampled more frequently were associated with a higher risk of infection. Importantly, the study showed no significant difference in ERI risk between different catheter types

Translational health data science for improving population-level survival of people with glioblastoma

Glioblastoma is the most common malignant primary brain tumour with poor survival of under one year. The current standard of care treatment offers modest survival benefits, and treatment options for patients with glioblastoma have not changed since 2005. Incomplete understanding of glioblastoma tumour biology presents challenges in drug development for glioblastoma, but inefficiencies resulting from suboptimal methodology may also contribute to the lack of effective treatment. Systematic evaluation of translational studies and analyses of population-based data can optimise research strategy to improve survival for all patients with glioblastoma. This thesis aims to apply epidemiological and health data science approaches to glioblastoma research data for improving translational research and population-level survival. The first chapter of the thesis discusses epidemiological and clinical aspects of glioblastoma in the context of all brain tumours and outlines the challenges and opportunities for research. Chapter 2 defines the problem by summarising the longer-term (≥2 years) survival of people diagnosed with glioblastoma in a systematic review and meta-analysis of 63 population-based cohort studies. The next chapter (Chapter 3) examines how changes in diagnostic practice can affect brain tumour incidences and how this may explain population-level survival described in the previous chapter. The following two chapters (Chapters 4 and 5) are systematic reviews that evaluated reporting standards, consistencies and analytic approaches of preclinical glioblastoma studies to identify methodological limitations precluding clinical translation. Chapter 6 is a cohort study of 414 consecutive patients with glioblastoma in Southeast Scotland that investigated how well clinical trial findings apply to real-world clinical cohorts concerning the modification of treatment effect of chemotherapy by a molecular marker. Chapter 7 presents a matched cohort study comparing the risks of cardiovascular events between brain tumour patients and the general population in Wales. The final chapter summarises the findings presented in this thesis and discusses their implications for future research. The programme of work in this thesis emphasises the need for transparency and consistency in translational glioblastoma research, and it demonstrates the value of routine healthcare data to understand population-level survival for people with glioblastoma