Introduction - The Neurology and Neurosurgery Interest Group



Evaluation of Intraoperative Surgical Adjuncts and Resection of Glioblastoma (GB) INCLUDEPICTURE "/var/folders/jz/q93pvf4d2j933j5r73cvwyp80000gn/T/com.microsoft.Word/WebArchiveCopyPasteTempFiles/2Q==" \* MERGEFORMATINET ELISAR-GB INCLUDEPICTURE "/var/folders/jz/q93pvf4d2j933j5r73cvwyp80000gn/T/com.microsoft.Word/WebArchiveCopyPasteTempFiles/2Q==" \* MERGEFORMATINET Protocol Preparation: NANSIG Neurosurgery Chair 2019-2020: Georgios Solomou, giorgossolomou@ NANSIG Research Lead 2019-2020 : Ali Gharooni, aag56@cam.ac.uk Contents TOC \o "1-3" \h \z \u 1.Introduction PAGEREF _Toc21100122 \h 31.1.Summary PAGEREF _Toc21100123 \h 31.2.Background PAGEREF _Toc21100124 \h 42.Methods PAGEREF _Toc21100125 \h 52.1.Study Aim PAGEREF _Toc21100126 \h 52.2.Study Design PAGEREF _Toc21100128 \h 52.3.Inclusion and exclusion criteria PAGEREF _Toc21100129 \h 62.4.Audit standards PAGEREF _Toc21100130 \h 62.5.Outcome measures PAGEREF _Toc21100131 \h 73.Data Collection PAGEREF _Toc21100132 \h 73.1.Local Registration and Data Governance PAGEREF _Toc21100136 \h 73.2.Data collection PAGEREF _Toc21100137 \h 73.4.Data Validation PAGEREF _Toc21100138 \h 83.5.Dataset PAGEREF _Toc21100139 \h 93.6.Data analysis PAGEREF _Toc21100140 \h 93.7.Project Timeline PAGEREF _Toc21100141 \h 93.8Authorship Eligibility PAGEREF _Toc21100142 \h 103.9Study Steering Committee PAGEREF _Toc21100143 \h 10References PAGEREF _Toc21100144 \h 12Appendix A – Required data fields. PAGEREF _Toc21100145 \h 14Appendix B – Neurosurgical centres and Local Data Collection Groups PAGEREF _Toc21100146 \h 17Introduction Summary BackgroundGlioblastoma is the most common and aggressive primary intrinsic brain tumour and despite optimal combinatorial operative and adjuvant therapies, it remains incurable with a median survival of 6.1 months and a 3.4% 5-year survival rate. Evidence suggests that gross total resection (GTR) of enhancing tumour improves survival and progression-free survival. The National Institute for Health and Care Excellence (NICE) in 2018 and the European Association of Neuro-Oncology (EANO) in 2017, recommend that neurosurgeons should consider using intraoperative adjuncts (intraoperative MRI (IoMRI), intraoperative ultrasound (IoUS), neuronavigation, electrophysiological stimulation) during surgery for high grade gliomas (HGG) including glioblastoma and 5-Aminolevulinic acid (5-ALA) to be used only if the tumour is deemed suitable for GTR as a baseline standard. Objectives The ELISAR-GB audit aims to evaluate the current service provision regarding the availability and usage of intraoperative surgical adjuncts for glioblastoma deemed suitable for resection and whether pre-operative surgical intent was achieved upon using the suggested (NICE 2018 and EANO 2017) intraoperative technologies. Methods We aim to conduct a national (UK), prospective audit and service evaluation, for a period of 4 months, between the 6th of January 2020 and 31st of April 2020. Local teams consisting of NANSIG and BNTRC collaborators will register the audit locally, obtain local approval if needed, identify eligible patients, collect and upload data on a secure online server. BackgroundGlia is a type of tissue that support the neurones in the brain and spinal cord. Tumours arising from these cells are called, gliomas. The categorisation of gliomas in the WHO classification 2016, has recently been updated and now incorporates both histological and molecular characteristics. In the United Kingdom it is estimated that there are 10,000 new cases of primary brain tumours. Gliomas are the most common morphological type of primary intrinsic brain tumour and account for<60% of the casesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"NICE","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"publisher":"NICE","title":"Context | Brain tumours (primary) and brain metastases in adults | Guidance | NICE","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"URL":"","accessed":{"date-parts":[["2019","3","23"]]},"author":[{"dropping-particle":"","family":"Cancer Research UK","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-2","issued":{"date-parts":[["0"]]},"title":"Brain, other CNS and intracranial tumours statistics | Cancer Research UK","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"^1,2","plainTextFormattedCitation":"1,2","previouslyFormattedCitation":"^1,2"},"properties":{"noteIndex":0},"schema":""}1,2. Of all primary brain tumours in adults, glioblastoma, a WHO grade IV glioma, is the most common. Glioblastoma are aggressiveADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/sj.bjc.6602321","ISSN":"0007-0920","PMID":"15655548","abstract":"Recently, cancer mortality has been compared to research spending by the National Cancer Research Institute (NCRI), whose research budget is approximately pound sterling 250 million. The analysis shows a mis-match between mortality and research spending. As well as crude mortality rates, other measures of cancer burden should be considered because they contribute additional information. 'Years of life lost' (YLL) summed over each individual dying after a diagnosis of cancer represents a population-based mortality indicator of the impact of that disease on society. Years of life lost divided by the number of deaths for each cancer site produces an additional statistic, the average years of life lost (AYLL), which is a measure of the burden of cancer to the individual patient. For 17 cancer sites where data are available, four tumour sites have a rather large difference in mortality, comparing YLL to crude mortality. Years of life lost shows the population burden from cancers of the ovary, cervix, and CNS to be rather larger than suggested by crude mortality, despite screening programmes for cervix cancer. Using YLL, the underprovision of funding for lung cancer research is similar to that reported using percentage mortality. Breast cancer and leukaemia receive a relatively higher research spend than the population burden of these cancers, and the spending on leukaemia is quite extreme. Prostate cancer has a low per cent YLL but attracts a moderate amount of research spending. The use of AYLL as an indicator of individual cancer burden considerably changes the ranking of the mortality from different tumours. The mean AYLL is 12.5 years. Prostate cancer has the lowest AYLL, only 6.1 years; brain tumour patients have the highest, at just over 20 years. Comparing AYLL to research spending suggests four 'Cinderella' cancer sites with high individual cancer burden but low research spending: CNS tumours, cervix and kidney cancers, and melanoma. Breast cancer and leukaemia have roughly average AYLL but a considerable excess of research spending. YLL emphasises the discrepancy between research spending and mortality, and may be helpful for decisions concerning research support. Average years of life lost measures the burden to individual patients and may be helpful where individuals' needs are relevant, such as palliative care. As well as crude mortality, more subtle and comprehensive calculations of mortality statistics would be useful in debates on research fun…","author":[{"dropping-particle":"","family":"Burnet","given":"N G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jefferies","given":"S J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benson","given":"R J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hunt","given":"D P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Treasure","given":"F P","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Cancer","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2005","1","11"]]},"page":"241-245","title":"Years of life lost (YLL) from cancer is an important measure of population burden — and should be considered when allocating research funds","type":"article-journal","volume":"92"},"uris":[""]}],"mendeley":{"formattedCitation":"³","plainTextFormattedCitation":"3","previouslyFormattedCitation":"³"},"properties":{"noteIndex":0},"schema":""}3 and incurable. Recent evidence suggests that there has been a significant increase in the incidence of glioblastoma from 1995 to 2015 with the age-standardised rate per 100,000-people more than doubling from 2.4 to 5.0ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1155/2018/7910754","ISSN":"1687-9805","abstract":"<p> <italic>Objective</italic> . To investigate detailed trends in malignant brain tumour incidence over a recent time period. <italic>Methods</italic> . UK Office of National Statistics (ONS) data covering 81,135 ICD10 C71 brain tumours diagnosed in England (1995–2015) were used to calculate incidence rates (ASR) per 100k person–years, age–standardised to the European Standard Population (ESP–2013). <italic>Results</italic> . We report a sustained and highly statistically significant ASR rise in glioblastoma multiforme (GBM) across all ages. The ASR for GBM more than doubled from 2.4 to 5.0, with annual case numbers rising from 983 to 2531. Overall, this rise is mostly hidden in the overall data by a reduced incidence of lower-grade tumours. <italic>Conclusions</italic> . The rise is of importance for clinical resources and brain tumour aetiology. The rise cannot be fully accounted for by promotion of lower–grade tumours, random chance or improvement in diagnostic techniques as it affects specific areas of the brain and only one type of brain tumour. Despite the large variation in case numbers by age, the percentage rise is similar across the age groups, which suggests widespread environmental or lifestyle factors may be responsible. This article reports incidence data trends and does not provide additional evidence for the role of any particular risk factor. </p>","author":[{"dropping-particle":"","family":"Philips","given":"Alasdair","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henshaw","given":"Denis L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lamburn","given":"Graham","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O’Carroll","given":"Michael J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Environmental and Public Health","id":"ITEM-1","issued":{"date-parts":[["2018","6","24"]]},"page":"1-10","publisher":"Hindawi","title":"Brain Tumours: Rise in Glioblastoma Multiforme Incidence in England 1995–2015 Suggests an Adverse Environmental or Lifestyle Factor","type":"article-journal","volume":"2018"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴","plainTextFormattedCitation":"4","previouslyFormattedCitation":"⁴"},"properties":{"noteIndex":0},"schema":""}4. Despite optimal operative and post-operative management, glioblastoma mortality rate remains significantly higher compared to other glioma subtypes. The five-year survival rate for glioblastoma is only 3.4%, compared to 27% for WHO grade-3 astrocytomasADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2019","3","23"]]},"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"Astrocytoma Prognosis | Brain Tumour Survival Rates","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵","plainTextFormattedCitation":"5","previouslyFormattedCitation":"⁵"},"properties":{"noteIndex":0},"schema":""}5 and 78% for oligodendrogliomasADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2019","3","23"]]},"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"Oligodendroglioma Prognosis | Brain Tumour Survival Rates","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6.The aim of the management of glioblastoma is to maintain each patient’s quality of life for as long as possible. The current gold standard management of gliomas includes a combination of chemotherapy, radiotherapy and surgeryADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa043330","ISSN":"00284793","abstract":"BACKGROUND Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. METHODS Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. RESULTS A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. CONCLUSIONS The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity.","author":[{"dropping-particle":"","family":"Stupp","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mason","given":"Warren P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bent","given":"Martin J.","non-dropping-particle":"Van Den","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weller","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fisher","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taphoorn","given":"Martin J.B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Belanger","given":"Karl","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brandes","given":"Alba A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marosi","given":"Christine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bogdahn","given":"Ulrich","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Curschmann","given":"Jürgen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Janzer","given":"Robert C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ludwin","given":"Samuel K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gorlia","given":"Thierry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Allgeier","given":"Anouk","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lacombe","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cairncross","given":"J. Gregory","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eisenhauer","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mirimanoff","given":"René O.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issued":{"date-parts":[["2005"]]},"title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷","plainTextFormattedCitation":"7","previouslyFormattedCitation":"⁷"},"properties":{"noteIndex":0},"schema":""}7. Whilst complete or near-complete safe resection is very challenging due to the a risk of neurological morbidity, it can lead to increased overall survival and progression free survivalADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3171/2012.9.JNS12504","ISSN":"0022-3085","PMID":"23039151","abstract":"OBJECT Extent of resection (EOR) has been shown to be an important prognostic factor for survival in patients undergoing initial resection of glioblastoma (GBM), but the significance of EOR at repeat craniotomy for recurrence remains unclear. In this study the authors investigate the impact of EOR at initial and repeat resection of GBM on overall survival. METHODS Medical records were reviewed for all patients undergoing craniotomy for GBM at the University of California San Francisco Medical Center from January 1, 2005, through August 15, 2009. Patients who had a second craniotomy for pathologically confirmed recurrence following radiation and chemotherapy were evaluated. Volumetric EOR was measured and classified as gross-total resection (GTR, > 95% by volume) or subtotal resection (STR, ≤ 95% by volume) after independent radiological review. Overall survival was compared between groups using univariate and multivariate analysis accounting for known prognostic factors, including age, eloquent location, Karnofsky Performance Status (KPS), and adjuvant therapies. RESULTS Multiple resections were performed in 107 patients. Fifty-two patients had initial GTR, of whom 31 (60%) had GTR at recurrence, with a median survival of 20.4 months (standard error [SE] 1.0 months), and 21 (40%) had STR at recurrence, with a median survival of 18.4 months (SE 0.5 months) (difference not statistically significant). Initial STR was performed in 55 patients, of whom 26 (47%) had GTR at recurrence, with a median survival of 19.0 months (SE 1.2 months), and 29 (53%) had STR, with a median survival of 15.9 months (SE 1.2 months) (p = 0.004). A Cox proportional hazards model was constructed demonstrating that age (HR 1.03, p = 0.004), KPS score at recurrence (HR 2.4, p = 0.02), and EOR at repeat resection (HR 0.62, p = 0.02) were independent predictors of survival. Extent of initial resection was not a statistically significant factor (p = 0.13) when repeat EOR was included in the model, suggesting that GTR at second craniotomy could overcome the effect of an initial STR. CONCLUSIONS Extent of resection at recurrence is an important predictor of overall survival. If GTR is achieved at recurrence, overall survival is maximized regardless of initial EOR, suggesting that patients with initial STR may benefit from surgery with a GTR at recurrence.","author":[{"dropping-particle":"","family":"Bloch","given":"Orin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Han","given":"Seunggu J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cha","given":"Soonmee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sun","given":"Matthew Z.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aghi","given":"Manish K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McDermott","given":"Michael W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Mitchel S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parsa","given":"Andrew T.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Neurosurgery JNS","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2012","12"]]},"page":"1032-1038","title":"Impact of extent of resection for recurrent glioblastoma on overall survival","type":"article-journal","volume":"117"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.3171/2011.7.JNS10998","ISSN":"1933-0693","PMID":"21417701","abstract":"OBJECT The value of extent of resection (EOR) in improving survival in patients with glioblastoma multiforme (GBM) remains controversial. Specifically, it is unclear what proportion of contrast-enhancing tumor must be resected for a survival advantage and how much survival improves beyond this threshold. The authors attempt to define these values for the patient with newly diagnosed GBM in the modern neurosurgical era. METHODS The authors identified 500 consecutive newly diagnosed patients with supratentorial GBM treated at the University of California, San Francisco between 1997 and 2009. Clinical, radiographic, and outcome parameters were measured for each case, including MR imaging-based volumetric tumor analysis. RESULTS The patients had a median age of 60 years and presented with a median Karnofsky Performance Scale (KPS) score of 80. The mean clinical follow-up period was 15.3 months, and no patient was unaccounted for. All patients underwent resection followed by chemotherapy and radiation therapy. The median postoperative tumor volume was 2.3 cm(3), equating to a 96% EOR. The median overall survival was 12.2 months. Using Cox proportional hazards analysis, age, KPS score, and EOR were predictive of survival (p < 0.0001). A significant survival advantage was seen with as little as 78% EOR, and stepwise improvement in survival was evident even in the 95%-100% EOR range. A recursive partitioning analysis validated these findings and provided additional risk stratification parameters related to age, EOR, and tumor burden. CONCLUSIONS For patients with newly diagnosed GBMs, aggressive EOR equates to improvement in overall survival, even at the highest levels of resection. Interestingly, subtotal resections as low as 78% also correspond to a survival benefit.","author":[{"dropping-particle":"","family":"Sanai","given":"Nader","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Polley","given":"Mei-Yin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McDermott","given":"Michael W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parsa","given":"Andrew T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Mitchel S","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of neurosurgery","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2011","7"]]},"page":"3-8","title":"An extent of resection threshold for newly diagnosed glioblastomas.","type":"article-journal","volume":"115"},"uris":[""]}],"mendeley":{"formattedCitation":"^8,9","plainTextFormattedCitation":"8,9","previouslyFormattedCitation":"^8,9"},"properties":{"noteIndex":0},"schema":""}8,9. To increase complete safe resection margins and minimise post-operative neurological morbidity, adjuncts in neurosurgery have been introduced, such as IoMRI ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.23736/S0390-5616.16.03284-7","ISSN":"1827-1855","PMID":"26149222","abstract":"BACKGROUND In patients with a glioblastoma (GBM), few unselected data exists using actual standard adjuvant treatment and contemporary surgical techniques like iMRI. Aim of study is to assess impact of EoR and recurrent surgery on survival and outcome. METHODS We assessed a consecutive unselected series of 170 surgeries for GBM (2008-2014) applying intraoperative MRI (iMRI). All patients received adjuvant radio-chemo-therapy. Overall-survival (OS), progression free survival (PFS), complications and new permanent neurological deficits (nPND) were assessed. Uni- and multivariate-cox-regression-models were calculated. RESULTS Mean follow-up was 40mo. GTR was intended in 82% and achieved in 77% of these cases. A nPND was found in 7% of patients. In multivariate cox-regression, GTR (HR:0.6, P<0.024) and absence of MGMT methylation (HR:1.6, P<0.042) was significantly associated with PFS. We found no difference in PFS after primary surgery and recurrent surgery. Concerning OS, in multivariate assessment an un-methylated MGMT-promotor (HR2.0, P<0.01) and presence of a complication (HR1.7, P<0.06) were negative prognosticators. Only GTR was significantly beneficial for OS (HR0.4, P<0.028) compared to a failed GTR and a STR. Repeated surgery for recurrent disease was positively associated with OS (HR0.6, P<0.06). CONCLUSIONS Surgery in a contemporary setup using iMRI, brain mapping and modern adjuvant treatment, has a higher OS and lower complication rates as previously published. A maximum but safe resection should be the goal of surgery since a perioperative complication significantly decreases OS. Recurrent surgery has a beneficial effect on OS without an increase of complications.","author":[{"dropping-particle":"","family":"Coburger","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wirtz","given":"Christian R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"K?nig","given":"Ralph W","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of neurosurgical sciences","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2017","6"]]},"page":"233-244","title":"Impact of extent of resection and recurrent surgery on clinical outcome and overall survival in a consecutive series of 170 patients for glioblastoma in intraoperative high field magnetic resonance imaging.","type":"article-journal","volume":"61"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰","plainTextFormattedCitation":"10","previouslyFormattedCitation":"¹⁰"},"properties":{"noteIndex":0},"schema":""}10, IoUSADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.wneu.2016.05.007","ISSN":"18788750","PMID":"27178235","abstract":"BACKGROUND Image-guided surgery has become standard practice during surgical resection, using preoperative magnetic resonance imaging. Intraoperative ultrasound (IoUS) has attracted interest because of its perceived safety, portability, and real-time imaging. This report is a meta-analysis of intraoperative ultrasound in gliomas. METHODS Critical literature review and meta-analyses, using the MEDLINE/PubMed service. The list of references in each article was double-checked for any missing references. We included all studies that reported the use of ultrasound to guide glioma-surgery. The meta-analyses were conducted according to statistical heterogeneity between the studies using Open MetaAnalyst Software. If there was no heterogeneity, fixed effects model was used for meta-analysis; otherwise, a random effect model was used. Statistical heterogeneity was explored by χ(2) and inconsistency (I(2)) statistics; an I(2) value of 50% or more represented substantial heterogeneity. RESULTS A wide search yielded 19,109 studies that might be relevant, of which 4819 were ultrasound in neurosurgery; 756 studies used ultrasound in cranial surgery, of which 24 studies used intraoperative ultrasound to guide surgical resection and 74 studies used it to guide biopsy. Fifteen studies fulfilled our stringent inclusion criteria, giving a total of 739 patients. The estimated average gross total resection rate was 77%. Furthermore, the relationship between extent of surgical resection and study population was not linear. Gross total resection was more likely under IoUS when the lesion was solitary and subcortical, with no history of surgery or radiotherapy. IoUS image quality, sensitivity, specificity, and positive and negative predictive values deteriorated as surgical resection proceeded. CONCLUSION IoUS-guided surgical resection of gliomas is a useful tool for guiding the resection and for improving the extent of resection. IoUS can be used in conjunction with other complementary technologies that can improve anatomic orientation during surgery. Real-time imaging, improved image quality, small probe sizes, repeatability, portability, and relatively low cost make IoUS a realistic, cost-effective tool that complements any existing tools in any neurosurgical operating environment.","author":[{"dropping-particle":"","family":"Mahboob","given":"Syed","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McPhillips","given":"Rachael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Qiu","given":"Zhen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jiang","given":"Yun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meggs","given":"Carl","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schiavone","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Button","given":"Tim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Desmulliez","given":"Marc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Demore","given":"Christine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cochran","given":"Sandy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eljamel","given":"Sam","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"World Neurosurgery","id":"ITEM-1","issued":{"date-parts":[["2016","8"]]},"page":"255-263","title":"Intraoperative Ultrasound-Guided Resection of Gliomas: A Meta-Analysis and Review of the Literature","type":"article-journal","volume":"92"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹","plainTextFormattedCitation":"11","previouslyFormattedCitation":"¹¹"},"properties":{"noteIndex":0},"schema":""}11, fluorescence guided surgery (e.g. 5-ALA)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1470-2045(06)70665-9","ISSN":"14702045","PMID":"16648043","abstract":"BACKGROUND 5-Aminolevulinic acid is a non-fluorescent prodrug that leads to intracellular accumulation of fluorescent porphyrins in malignant gliomas-a finding that is under investigation for intraoperative identification and resection of these tumours. We aimed to assess the effect of fluorescence-guided resection with 5-aminolevulinic acid on surgical radicality, progression-free survival, overall survival, and morbidity. METHODS 322 patients aged 23-73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at as NCT00241670. FINDINGS Median follow-up was 35.4 months (95% CI 1.0-56.7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17-40], p<0.0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41.0% [32.8-49.2] vs 21.1% [14.0-28.2]; difference between groups 19.9% [9.1-30.7], p=0.0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery. INTERPRETATION Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma.","author":[{"dropping-particle":"","family":"Stummer","given":"Walter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pichlmeier","given":"Uwe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meinel","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wiestler","given":"Otmar Dieter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zanella","given":"Friedhelm","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reulen","given":"Hans-Jürgen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"ALA-Glioma Study Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet Oncology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2006","5"]]},"page":"392-401","title":"Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²","plainTextFormattedCitation":"12","previouslyFormattedCitation":"¹²"},"properties":{"noteIndex":0},"schema":""}12 and awake craniotomy with electrophysiological stimulation.Data from randomised controlled trials (RCTs) have shown favourable outcomes in using 5-ALAADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1470-2045(06)70665-9","ISSN":"14702045","PMID":"16648043","abstract":"BACKGROUND 5-Aminolevulinic acid is a non-fluorescent prodrug that leads to intracellular accumulation of fluorescent porphyrins in malignant gliomas-a finding that is under investigation for intraoperative identification and resection of these tumours. We aimed to assess the effect of fluorescence-guided resection with 5-aminolevulinic acid on surgical radicality, progression-free survival, overall survival, and morbidity. METHODS 322 patients aged 23-73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at as NCT00241670. FINDINGS Median follow-up was 35.4 months (95% CI 1.0-56.7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17-40], p<0.0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41.0% [32.8-49.2] vs 21.1% [14.0-28.2]; difference between groups 19.9% [9.1-30.7], p=0.0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery. INTERPRETATION Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma.","author":[{"dropping-particle":"","family":"Stummer","given":"Walter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pichlmeier","given":"Uwe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meinel","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wiestler","given":"Otmar Dieter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zanella","given":"Friedhelm","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reulen","given":"Hans-Jürgen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"ALA-Glioma Study Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet Oncology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2006","5"]]},"page":"392-401","title":"Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²","plainTextFormattedCitation":"12","previouslyFormattedCitation":"¹²"},"properties":{"noteIndex":0},"schema":""}12 and IoMRI in achieving complete safe resection vs standard microscopic resection, which was statistically significant (P<0.05)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1470-2045(11)70196-6","ISSN":"14702045","PMID":"21868284","abstract":"BACKGROUND Intraoperative MRI is increasingly used in neurosurgery, although there is little evidence for its use. We aimed to assess efficacy of intraoperative MRI guidance on extent of resection in patients with glioma. METHODS In our prospective, randomised, parallel-group trial, we enrolled adults (≥18 years) with contrast enhancing gliomas amenable to radiologically complete resection who presented to Goethe University (Frankfurt, Germany). We randomly assigned patients (1:1) with computer-generated blocks of four and a sealed-envelope design to undergo intraoperative MRI-guided surgery or conventional microsurgery (control group). Surgeons and patients were unmasked to treatment group allocation, but an independent neuroradiologist was masked during analysis of all preoperative and postoperative imaging data. The primary endpoint was rate of complete resections as established by early postoperative high-field MRI (1·5 T or 3·0 T). Analysis was done per protocol. This study is registered with , number NCT01394692. FINDINGS We enrolled 58 patients between Oct 1, 2007, and July 1, 2010. 24 (83%) of 29 patients randomly allocated to the intraoperative MRI group and 25 (86%) of 29 controls were eligible for analysis (four patients in each group had metastasis and one patient in the intraoperative MRI group withdrew consent after randomisation). More patients in the intraoperative MRI group had complete tumour resection (23 [96%] of 24 patients) than did in the control group (17 [68%] of 25, p=0·023). Postoperative rates of new neurological deficits did not differ between patients in the intraoperative MRI group (three [13%] of 24) and controls (two [8%] of 25, p=1·0). No patient for whom use of intraoperative MRI led to continued resection of residual tumour had neurological deterioration. One patient in the control group died before 6 months. INTERPRETATION Our study provides evidence for the use of intraoperative MRI guidance in glioma surgery: such imaging helps surgeons provide the optimum extent of resection. FUNDING None.","author":[{"dropping-particle":"","family":"Senft","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bink","given":"Andrea","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Franz","given":"Kea","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vatter","given":"Hartmut","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gasser","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seifert","given":"Volker","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet Oncology","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2011","10"]]},"page":"997-1003","title":"Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial","type":"article-journal","volume":"12"},"uris":[""]}],"mendeley":{"formattedCitation":"¹³","plainTextFormattedCitation":"13","previouslyFormattedCitation":"¹³"},"properties":{"noteIndex":0},"schema":""}13. Despite this, a recent Cochrane review found notable risks of bias in those studies highlighting uncertainty in our estimates of benefit with these adjunctsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/14651858.CD012788.pub2","ISSN":"14651858","PMID":"29355914","abstract":"BACKGROUND Extent of resection is considered to be a prognostic factor in neuro-oncology. Intraoperative imaging technologies are designed to help achieve this goal. It is not clear whether any of these sometimes very expensive tools (or their combination) should be recommended as standard care for people with brain tumours. We set out to determine if intraoperative imaging technology offers any advantage in terms of extent of resection over standard surgery and if any one technology was more effective than another. OBJECTIVES To establish the overall effectiveness and safety of intraoperative imaging technology in resection of glioma. To supplement this review of effects, we also wished to identify cost analyses and economic evaluations as part of a Brief Economic Commentary (BEC). SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 7, 2017), MEDLINE (1946 to June, week 4, 2017), and Embase (1980 to 2017, week 27). We searched the reference lists of all identified studies. We handsearched two journals, the Journal of Neuro-Oncology and Neuro-oncology, from 1991 to 2017, including all conference abstracts. We contacted neuro-oncologists, trial authors, and manufacturers regarding ongoing and unpublished trials. SELECTION CRITERIA Randomised controlled trials evaluating people of all ages with presumed new or recurrent glial tumours (of any location or histology) from clinical examination and imaging (computed tomography (CT) or magnetic resonance imaging (MRI), or both). Additional imaging modalities (e.g. positron emission tomography, magnetic resonance spectroscopy) were not mandatory. Interventions included intraoperative MRI (iMRI), fluorescence-guided surgery, ultrasound, and neuronavigation (with or without additional image processing, e.g. tractography). DATA COLLECTION AND ANALYSIS Two review authors independently assessed the search results for relevance, undertook critical appraisal according to known guidelines, and extracted data using a prespecified pro forma. MAIN RESULTS We identified four randomised controlled trials, using different intraoperative imaging technologies: iMRI (2 trials including 58 and 14 participants, respectively); fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) (1 trial, 322 participants); and neuronavigation (1 trial, 45 participants). We identified one ongoing trial assessing iMRI with a planned sample size of 304 participants for which results are expected to…","author":[{"dropping-particle":"","family":"Jenkinson","given":"Michael D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barone","given":"Damiano Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bryant","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vale","given":"Luke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bulbeck","given":"Helen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lawrie","given":"Theresa A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hart","given":"Michael G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watts","given":"Colin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cochrane Database of Systematic Reviews","id":"ITEM-1","issued":{"date-parts":[["2018","1","22"]]},"page":"CD012788","title":"Intraoperative imaging technology to maximise extent of resection for glioma","type":"article-journal","volume":"1"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁴","plainTextFormattedCitation":"14","previouslyFormattedCitation":"¹⁴"},"properties":{"noteIndex":0},"schema":""}14. Furthermore, whilst efficacy in trial conditions has been demonstrated, there is great variation in GTR in prospective and retrospective cohort studies ranging from 47.6 - 98.5%ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fonc.2019.00620","abstract":"Background: High-grade glioma (HGG) is associated with a dismal prognosis despite significant advances in adjuvant therapies, including chemotherapy, immunotherapy, and radiotherapy. Extent of resection continues to be the most important independent prognosticator of survival. This underlines the significance of increasing gross total resection (GTR) rates by using adjunctive intraoperative modalities to maximize resection with minimal neurological morbidity. 5-aminolevulinic acid (5-ALA) is the only US Food and Drug Administration-approved intraoperative optical agent used for fluorescence-guided surgical resection of gliomas. Despite several studies on the impact of intra-operative 5-ALA use on the extent of HGG resection, a clear picture of how such usage affects patient survival is still unavailable. Methods: A systematic review was conducted of all relevant studies assessing the GTR rate and survival outcomes [overall survival (OS) and progression-free survival (PFS)] in HGG. A meta-analysis of eligible studies was performed to assess the influence of 5-ALA-guided resection on improving GTR, OS, and PFS. GTR was defined as >95% resection. Results: Of 23 eligible studies, 19 reporting GTR rates were included in the meta-analysis. The pooled cohort had 998 patients with HGG, including 796 with newly diagnosed cases. The pooled GTR rate among patients with 5-ALA-guided resection was 76.8% (95% confidence interval, 69.1-82.9%). A comparative subgroup analysis of 5-ALA-guided vs. conventional surgery (controlling for within-study covariates) showed a 26% higher GTR rate in the 5-ALA subgroup (odds ratio, 3.8; P < 0.001). There were 11 studies eligible for survival outcome analysis, 4 of which reported PFS. The pooled mean difference in OS and PFS was 3 and 1 months, respectively, favoring 5-ALA vs. control (P < 0.001). Conclusions: This meta-analysis shows a significant increase in GTR rate with 5-ALA-guided surgical resection, with a higher weighted GTR rate (~76%) than the pivotal phase III study (~65%). Pooled analysis showed a small yet significant increase in survival measures associated with the use of 5-ALA. Despite the statistically significant results, the low level of evidence and heterogeneity across these studies make it difficult to conclusively report an independent association between 5-ALA use and survival outcomes in HGG. Additional randomized control studies are required to delineate the role of 5-ALA in survival outcomes in HGG.","author":[{"dropping-particle":"","family":"Gandhi","given":"Sirin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tayebi Meybodi","given":"Ali","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Belykh","given":"Evgenii","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cavallo","given":"Claudio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhao","given":"Xiaochun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Syed","given":"Masood Pasha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borba Moreira","given":"Leandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lawton","given":"Michael T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakaji","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Preul","given":"Mark C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Oncology","id":"ITEM-1","issued":{"date-parts":[["2019"]]},"title":"Survival Outcomes Among Patients With High-Grade Glioma Treated With 5-Aminolevulinic Acid–Guided Surgery: A Systematic Review and Meta-Analysis","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁵","plainTextFormattedCitation":"15","previouslyFormattedCitation":"¹⁵"},"properties":{"noteIndex":0},"schema":""}15. Further, IoUS has been utilised in neurosurgery since 1982ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3171/jns.1982.57.2.0157","ISSN":"0022-3085","PMID":"7086507","abstract":"<p content-type=\"fine-print\">? The authors' experience with the intraoperative use of real-time ultrasonography during 21 neurosurgical procedures is reported. These procedures include neoplasm surgery in 18 cases, treatment of an arteriovenous malformation in one case, and ventricular catheter placement for hydrocephalus in two cases. In each of the neoplasm cases, the tumors were imaged just as well through the intact dura as on the brain surface itself. There were no cases in which the pathology could not easily be identified. The use of portable intraoperative ultrasonography in sterile coverings has proven to be extremely useful in localizing small subcortical neoplasms, as well as locating the solid and cystic portions of deep lesions. It has assisted in guiding needles for both biopsy and aspiration. It has also accurately identified and guided Silastic catheters during their placement in the ventricular system in cases of hydrocephalus. The authors have found real-time ultrasonography to be an important new tool in the operating room and will continue to rely on its imaging ability during selected procedures in the future.</p>","author":[{"dropping-particle":"","family":"Chandler","given":"William F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Knake","given":"James E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGillicuddy","given":"John E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lillehei","given":"Kevin O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Silver","given":"Terry M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Neurosurgery","id":"ITEM-1","issue":"2","issued":{"date-parts":[["1982","8"]]},"page":"157-163","title":"Intraoperative use of real-time ultrasonography in neurosurgery","type":"article-journal","volume":"57"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁶","plainTextFormattedCitation":"16","previouslyFormattedCitation":"¹⁶"},"properties":{"noteIndex":0},"schema":""}16 and numerous enhancements to this adjunct have been introduced which has improved imaging qualityADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/jon.12382","ISSN":"1552-6569","PMID":"27541694","abstract":"Neurosurgery makes use of preoperative imaging to visualize pathology, inform surgical planning, and evaluate the safety of selected approaches. The utility of preoperative imaging for neuronavigation, however, is diminished by the well-characterized phenomenon of brain shift, in which the brain deforms intraoperatively as a result of craniotomy, swelling, gravity, tumor resection, cerebrospinal fluid (CSF) drainage, and many other factors. As such, there is a need for updated intraoperative information that accurately reflects intraoperative conditions. Since 1982, intraoperative ultrasound has allowed neurosurgeons to craft and update operative plans without ionizing radiation exposure or major workflow interruption. Continued evolution of ultrasound technology since its introduction has resulted in superior imaging quality, smaller probes, and more seamless integration with neuronavigation systems. Furthermore, the introduction of related imaging modalities, such as 3-dimensional ultrasound, contrast-enhanced ultrasound, high-frequency ultrasound, and ultrasound elastography, has dramatically expanded the options available to the neurosurgeon intraoperatively. In the context of these advances, we review the current state, potential, and challenges of intraoperative ultrasound for brain tumor resection. We begin by evaluating these ultrasound technologies and their relative advantages and disadvantages. We then review three specific applications of these ultrasound technologies to brain tumor resection: (1) intraoperative navigation, (2) assessment of extent of resection, and (3) brain shift monitoring and compensation. We conclude by identifying opportunities for future directions in the development of ultrasound technologies.","author":[{"dropping-particle":"","family":"Sastry","given":"Rahul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bi","given":"Wenya Linda","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pieper","given":"Steve","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frisken","given":"Sarah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kapur","given":"Tina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wells","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Golby","given":"Alexandra J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Golby","given":"Alexandra J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of neuroimaging : official journal of the American Society of Neuroimaging","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2017"]]},"page":"5-15","publisher":"NIH Public Access","title":"Applications of Ultrasound in the Resection of Brain Tumors.","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁷","plainTextFormattedCitation":"17","previouslyFormattedCitation":"¹⁷"},"properties":{"noteIndex":0},"schema":""}17. Whilst no RCT has been performed, various studies have demonstrated its utility in achieving GTR, with a recent meta-analysis showing the rate of GTR of HGG with IoUS to be 71.9% (95% CI, 64%-79.7%)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.wneu.2016.05.007","ISSN":"18788750","PMID":"27178235","abstract":"BACKGROUND Image-guided surgery has become standard practice during surgical resection, using preoperative magnetic resonance imaging. Intraoperative ultrasound (IoUS) has attracted interest because of its perceived safety, portability, and real-time imaging. This report is a meta-analysis of intraoperative ultrasound in gliomas. METHODS Critical literature review and meta-analyses, using the MEDLINE/PubMed service. The list of references in each article was double-checked for any missing references. We included all studies that reported the use of ultrasound to guide glioma-surgery. The meta-analyses were conducted according to statistical heterogeneity between the studies using Open MetaAnalyst Software. If there was no heterogeneity, fixed effects model was used for meta-analysis; otherwise, a random effect model was used. Statistical heterogeneity was explored by χ(2) and inconsistency (I(2)) statistics; an I(2) value of 50% or more represented substantial heterogeneity. RESULTS A wide search yielded 19,109 studies that might be relevant, of which 4819 were ultrasound in neurosurgery; 756 studies used ultrasound in cranial surgery, of which 24 studies used intraoperative ultrasound to guide surgical resection and 74 studies used it to guide biopsy. Fifteen studies fulfilled our stringent inclusion criteria, giving a total of 739 patients. The estimated average gross total resection rate was 77%. Furthermore, the relationship between extent of surgical resection and study population was not linear. Gross total resection was more likely under IoUS when the lesion was solitary and subcortical, with no history of surgery or radiotherapy. IoUS image quality, sensitivity, specificity, and positive and negative predictive values deteriorated as surgical resection proceeded. CONCLUSION IoUS-guided surgical resection of gliomas is a useful tool for guiding the resection and for improving the extent of resection. IoUS can be used in conjunction with other complementary technologies that can improve anatomic orientation during surgery. Real-time imaging, improved image quality, small probe sizes, repeatability, portability, and relatively low cost make IoUS a realistic, cost-effective tool that complements any existing tools in any neurosurgical operating environment.","author":[{"dropping-particle":"","family":"Mahboob","given":"Syed","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McPhillips","given":"Rachael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Qiu","given":"Zhen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jiang","given":"Yun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meggs","given":"Carl","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schiavone","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Button","given":"Tim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Desmulliez","given":"Marc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Demore","given":"Christine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cochran","given":"Sandy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eljamel","given":"Sam","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"World Neurosurgery","id":"ITEM-1","issued":{"date-parts":[["2016","8"]]},"page":"255-263","title":"Intraoperative Ultrasound-Guided Resection of Gliomas: A Meta-Analysis and Review of the Literature","type":"article-journal","volume":"92"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹","plainTextFormattedCitation":"11","previouslyFormattedCitation":"¹¹"},"properties":{"noteIndex":0},"schema":""}11, similar to other intraoperative adjuncts presented. Furthermore, there is some evidence to suggest the synergistic effects of combining these adjuncts in achieving GTRADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.wneu.2011.02.005","ISSN":"18788750","PMID":"21839963","abstract":"OBJECTIVE To compare intraoperative magnetic resonance imaging (MRI)-guided resection with resection guided by 5-aminolevulinic acid (5-ALA)-induced fluorescence in patients with gliomas and to evaluate the impact of intraoperative MRI in glioma surgery. METHODS From January 2005 to February 2009, 33 patients with gliomas (6 with World Health Organization [WHO] grade II, 7 with WHO grade III, 20 with WHO grade IV) who underwent craniotomy with neuronavigation and received 5-ALA by the same neurosurgeon were investigated retrospectively. In 19 patients, operations were performed using a combination of 5-ALA with intraoperative 1.5-T MRI. All patients were subjected to postoperative 1.5-T MRI to confirm the extent of resection. RESULTS Of 33 patients with gliomas, 21 (4 with WHO grade III and 17 with WHO grade IV) were 5-ALA-induced fluorescence-positive (5-ALA (+)). Surgery with intraoperative MRI was performed in 10 of the 21 patients, and the average resection rate was 92.6%. The average resection rate of patients who underwent surgery without intraoperative MRI was 91.8%. 5-ALA-induced fluorescence was not detected in 12 patients (6 with WHO grade II, 3 with WHO grade III, and 3 with WHO grade IV) with gliomas. Surgery with intraoperative MRI was performed in 9 of 12 patients, and the average resection rate was 89.2%. The average resection rate of patients who underwent surgery without intraoperative MRI was 68.7%. Intraoperative MRI-guided tumor resection resulted in a better resection rate in patients with 5-ALA-induced fluorescence-negative (5-ALA (-)) gliomas than in patients with 5-ALA (+) gliomas (20.5% vs 0.8%). CONCLUSIONS Intraoperative MRI-guided resection is a powerful tool to treat 5-ALA (-) gliomas (mostly low grade), and 5-ALA is useful for high-grade gliomas. The combination of intraoperative MRI and 5-ALA has a synergistic effect in glioma surgery. Additionally, precise tumor grading in preoperative imaging studies can be difficult. Surgery for gliomas should be performed using both 5-ALA-induced fluorescence and intraoperative MRI-guided resection.","author":[{"dropping-particle":"","family":"Tsugu","given":"Atsushi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ishizaka","given":"Hideo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mizokami","given":"Yoshihito","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Osada","given":"Takahiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baba","given":"Tanefumi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoshiyama","given":"Michitsura","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nishiyama","given":"Jun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsumae","given":"Mitsunori","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"World Neurosurgery","id":"ITEM-1","issue":"1-2","issued":{"date-parts":[["2011","7"]]},"page":"120-127","title":"Impact of the Combination of 5-Aminolevulinic Acid–Induced Fluorescence with Intraoperative Magnetic Resonance Imaging–Guided Surgery for Glioma","type":"article-journal","volume":"76"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1227/NEU.0000000000000729","ISSN":"0148-396X","author":[{"dropping-particle":"","family":"Gessler","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Forster","given":"Marie-Thérèse","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Duetzmann","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mittelbronn","given":"Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hattingen","given":"Elke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Franz","given":"Kea","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seifert","given":"Volker","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Senft","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neurosurgery","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2015","7","1"]]},"page":"16-22","publisher":"Narnia","title":"Combination of Intraoperative Magnetic Resonance Imaging and Intraoperative Fluorescence to Enhance the Resection of Contrast Enhancing Gliomas","type":"article-journal","volume":"77"},"uris":[""]}],"mendeley":{"formattedCitation":"^18,19","plainTextFormattedCitation":"18,19","previouslyFormattedCitation":"^18,19"},"properties":{"noteIndex":0},"schema":""}18,19.In the context of the current evidence base, the NICE and EANO recommend the consideration of using intraoperative adjuncts during initial surgery for HGG including glioblastomaADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1470-2045(14)70011-7","ISSN":"1474-5488","PMID":"25079102","abstract":"This guideline provides recommendations for diagnostic and therapeutic procedures for patients with malignant gliomas. We differentiate evidence-based standards from reasonable options or non-evidence-based measures that should no longer be considered. The recommendations herein should provide a framework and assurance for the choice of diagnostic procedures and therapeutic measures and aim to reduce complications from unnecessary treatment and cost. The guideline contributes to a critical appreciation of concurrent drugs with a focus on the controlled use of anticonvulsants and steroids. It should serve as a guideline for all professionals involved in the diagnostics and care of glioma patients and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in Europe. Implementation of the recommendations summarised here will need interdisciplinary structures of care for patients with brain tumours and structured processes of diagnostic and therapeutic procedures.","author":[{"dropping-particle":"","family":"Weller","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bent","given":"Martin","non-dropping-particle":"van den","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hopkins","given":"Kirsten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tonn","given":"J?rg C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stupp","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Falini","given":"Andrea","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cohen-Jonathan-Moyal","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frappaz","given":"Didier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henriksson","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Balana","given":"Carmen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chinot","given":"Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ram","given":"Zvi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reifenberger","given":"Guido","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Soffietti","given":"Riccardo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wick","given":"Wolfgang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"European Association for Neuro-Oncology (EANO) Task Force on Malignant Glioma","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet. Oncology","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2014","8","1"]]},"page":"e395-403","publisher":"Elsevier","title":"EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma.","type":"article-journal","volume":"15"},"uris":[""]},{"id":"ITEM-2","itemData":{"author":[{"dropping-particle":"","family":"NICE","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-2","issued":{"date-parts":[["0"]]},"publisher":"NICE","title":"Context | Brain tumours (primary) and brain metastases in adults | Guidance | NICE","type":"article-journal"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/S1470-2045(17)30194-8","ISSN":"1470-2045","abstract":"The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas. The guideline is based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline. The recommendations focus on pathological and radiological diagnostics, and the main treatment modalities of surgery, radiotherapy, and pharmacotherapy. In this guideline we have also integrated the results from contemporary clinical trials that have changed clinical practice. The guideline aims to provide guidance for diagnostic and management decisions, while limiting unnecessary treatments and costs. The recommendations are a resource for professionals involved in the management of patients with glioma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.","author":[{"dropping-particle":"","family":"Weller","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bent","given":"Martin","non-dropping-particle":"van den","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tonn","given":"J?rg C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stupp","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Preusser","given":"Matthias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cohen-Jonathan-Moyal","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henriksson","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Le","family":"Rhun","given":"Emilie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Balana","given":"Carmen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chinot","given":"Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bendszus","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reijneveld","given":"Jaap C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dhermain","given":"Frederick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"French","given":"Pim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marosi","given":"Christine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watts","given":"Colin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oberg","given":"Ingela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pilkington","given":"Geoffrey","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baumert","given":"Brigitta G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taphoorn","given":"Martin J B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hegi","given":"Monika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Westphal","given":"Manfred","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reifenberger","given":"Guido","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Soffietti","given":"Riccardo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wick","given":"Wolfgang","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet Oncology","id":"ITEM-3","issue":"6","issued":{"date-parts":[["2017","6","1"]]},"page":"e315-e329","publisher":"Elsevier","title":"European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas","type":"article-journal","volume":"18"},"uris":[""]}],"mendeley":{"formattedCitation":"^1,20,21","plainTextFormattedCitation":"1,20,21","previouslyFormattedCitation":"^1,20,21"},"properties":{"noteIndex":0},"schema":""}1,20,21. Since July 2018, NICE has specifically recommended that HGG, which are amenable to total surgical resection should be offered 5-ALA, whilst other forms of adjuncts (i.e. IoMRI, IoUS, awake craniotomy) should be ‘considered’.In addition, in 2017 the EANO reflected on the increasing evidence that having no residual enhancing disease after operation of glioblastoma is related to improved survival. Therefore, suggesting that if agreed to be feasible, surgery for glioblastoma should be complete resection of enhanced disease or GTR. Thus, in this audit, GTR is defined as no residual enhancing disease on T1-weighted MRI with contrastADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1470-2045(06)70665-9","ISSN":"14702045","PMID":"16648043","abstract":"BACKGROUND 5-Aminolevulinic acid is a non-fluorescent prodrug that leads to intracellular accumulation of fluorescent porphyrins in malignant gliomas-a finding that is under investigation for intraoperative identification and resection of these tumours. We aimed to assess the effect of fluorescence-guided resection with 5-aminolevulinic acid on surgical radicality, progression-free survival, overall survival, and morbidity. METHODS 322 patients aged 23-73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at as NCT00241670. FINDINGS Median follow-up was 35.4 months (95% CI 1.0-56.7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17-40], p<0.0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41.0% [32.8-49.2] vs 21.1% [14.0-28.2]; difference between groups 19.9% [9.1-30.7], p=0.0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery. INTERPRETATION Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma.","author":[{"dropping-particle":"","family":"Stummer","given":"Walter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pichlmeier","given":"Uwe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meinel","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wiestler","given":"Otmar Dieter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zanella","given":"Friedhelm","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reulen","given":"Hans-Jürgen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"ALA-Glioma Study Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet Oncology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2006","5"]]},"page":"392-401","title":"Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²","plainTextFormattedCitation":"12","previouslyFormattedCitation":"¹²"},"properties":{"noteIndex":0},"schema":""}12 i.e. close to >90% resection of enhancing tumour. To assess the extent of resection, NICE recommends the use of post-operative T1-weighted MRI within 72hrs post-operatively1. Prior to the NICE guidelines 2018 updateADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"NICE","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"publisher":"NICE","title":"Context | Brain tumours (primary) and brain metastases in adults | Guidance | NICE","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"¹","plainTextFormattedCitation":"1","previouslyFormattedCitation":"¹"},"properties":{"noteIndex":0},"schema":""}1, a British Neurosurgical Trainee Research Collaborative study (BNTRC) by Ma et al, 2017, reported that only 44% of surgeons had routine access to 5-ALA and it was used in only 15.9% of potential cases. Since then no audit was conducted to re-evaluate these findings and the impact of the new guidelines. The study also showed that post-operative MRI was performed within 72hrs in only 70.8% of cases, and that GTR was achieved in only 55%. The rate of GTR was statistically significantly better only when all adjuncts were taken into account suggesting “the use of surgical adjuncts to increase GTR rates”. Notably, despite the accumulation of evidence, Ma et al discuss that variation in surgical practice was representative of the lack of consensus on best practiceADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/nop/npx023","ISSN":"2054-2577","author":[{"dropping-particle":"","family":"Ma","given":"Ruichong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chari","given":"Aswin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brennan","given":"Paul M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alalade","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Anderson","given":"Ian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Solth","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marcus","given":"Hani J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watts","given":"Colin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolias","given":"Angelos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sinha","given":"Rohit","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O’Neill","given":"Kevin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Paine","given":"Heidi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rasul","given":"Fahid","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ashkan","given":"Keyoumars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Corns","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jenkinson","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kitchen","given":"Neil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holliman","given":"Damian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Glancz","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aly","given":"Ahmed","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Stuart","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Plaha","given":"Puneet","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dyson","given":"Edward","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Toescu","given":"Sebastian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haliasos","given":"Nick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ghosh","given":"Arnab","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McKintosh","given":"Edward","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rominiyi","given":"Olamide","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jellinek","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gallagher","given":"Mat","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jones","given":"Tim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wykes","given":"Victoria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grundy","given":"Paul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haq","given":"Imran","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brydon","given":"Howard","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuro-Oncology Practice","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2018","5","10"]]},"page":"74-81","publisher":"Narnia","title":"Residual enhancing disease after surgery for glioblastoma: evaluation of practice in the United Kingdom","type":"article-journal","volume":"5"},"uris":[""]}],"mendeley":{"formattedCitation":"²²","plainTextFormattedCitation":"22","previouslyFormattedCitation":"²²"},"properties":{"noteIndex":0},"schema":""}22. This was compounded by variation in the availability of each technology across centres, surgeon training in each technology, and the perceived time needed to use these adjuncts within an operation. Further, one unit showed that use of IoMRI added 105 minutes to an operation, and when the patient was awake it added another two hours to the operating timeADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.wnsx.2019.100022","ISSN":"25901397","abstract":"Background: Despite the most recent surgical aids and tools, surgical removal of infiltrating brain tumors remains a challenge. Unclear margins, edematous areas, and infiltrative behavior are the main causes for failing gross total removals. Also, excessive resection of peri-tumoral tissue often carries risks of damaging the nearby functioning cortical and subcortical structures with an unacceptable decrease in patient's quality of life and postoperative functional status, and the risk of making patients not eligible to adjuvant treatments. Awake surgery and intraoperative magnetic resonance imaging (ioMRI) are among the most effective aids in preventing damage to functional brain while maximizing the extent of resection. Methods: We present our series of 46 patients operated on at Southmead Hospital (North Bristol NHS Trust) in between July 2014 and February 2017 using ioMRI plus or minus awake surgery. Setting, patient features, indications, type and size of tumors, surgical times, extent of resection, morbidity, and survival are analyzed and discussed. Results: Overall, ioMRI check led to a +43% resections in Group 1 and +58% in Group 2. In grade 2 tumors, GTR was 46% in Group 1 and 55% in Group 2 (41% in control group). In grade 3 tumors, GTR was 57% in Group 1 and 66% in Group 2 (30% in control group). In Grade 4 tumors, GTR was 63% in Group 1, 66% in Group 2 (36% in control group). In terms of theatre occupation, the use of ioMRI added 1/2 operative session; the addition of awake surgery implied the use of another 1/2 operative session. Morbidity did not differ among the groups, with low incidence of permanent post-operative deficits (<5%). Group 2 OS was statistically longer when compared to the control group. Conclusions: Using ioMRI together with awake surgery is demanding for the anesthetic team, staff nurses, and for the patient. Nevertheless, low morbidity, greater total resections rates, and longer survival suggest its use is effective in making more approachable gliomas of all grades that we would consider “complex” due to their intrinsic features or locations.","author":[{"dropping-particle":"","family":"Pichierri","given":"Angelo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bradley","given":"Marcus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iyer","given":"Venkat","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"World Neurosurgery: X","id":"ITEM-1","issued":{"date-parts":[["2019"]]},"title":"Intraoperative Magnetic Resonance Imaging–Guided Glioma Resections in Awake or Asleep Settings and Feasibility in the Context of a Public Health System","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"²³","plainTextFormattedCitation":"23","previouslyFormattedCitation":"²³"},"properties":{"noteIndex":0},"schema":""}23. Since the implementation of the new NICE 2018 and EANO 2017 guidelines, no further evaluation of service provision was conducted.In light of this rationale, the Neurology and Neurosurgery Student Interest Group (NANSIG) in collaboration with the British Neurosurgical Trainee Research Collaborative (BNTRC), propose to audit the current service provision regarding the availability and the usage of intraoperative surgical adjuncts for glioblastoma deemed suitable for resection.MethodsStudy Aim To prospectively audit the availability and usage of surgical adjuncts in the UK for glioblastoma according to the NICE and EANO guidelines: 5-ALA, intraoperative MRI, intraoperative US, awake craniotomy, neurophysiology and tractography. To evaluate whether GTR was planned and achieved in each case.Study DesignTo prospectively collect national data from all centres offering neurosurgical oncology service in the UK, for a period of four months comparing current practise to current guidance and to assess preoperative resection intent using combination of adjuncts suggested by NICE. Cases to be collected will include those patients with a diagnosis of suspected HGG including glioblastoma (grade IV) on MRI scan who are deemed suitable for resection (GTR or not) by the operating surgeon/consultant. Inclusion and exclusion criteriaInclusion:All Patients with first diagnosis of suspected glioblastoma/HGG on MRI:Aged 18 years and aboveReceiving neurosurgical intervention with intention to achieve complete resection or subtotal resection (debulk) of enhancing component on post-operative T1-weighted MRI with contrast, as decided by the operating surgeonSupratentorial tumoursExclusion:Emergency/unplanned procedures No MRI data available (i.e. MRI contraindicated in patient)Infratentorial tumoursBiopsy surgeryPrior operative or non-operative management of index glioma Previous diagnosis and treatment (operative or adjuvant) of primary or secondary brain tumourAudit standardsThe audit criteria are based on current NICE guidance and the EANO recommendations and are the following:Patients deemed suitable for GTR of HGG including glioblastoma should be offered 5-ALA (100%)Patients deemed suitable for surgical resection (GTR or debulk) of a glioblastoma should be considered to be offered any of the following intraoperative adjuncts: IoMRIIoUSTractographyAwake craniotomyInvolvement of other specialists (e.g. physiotherapist)Post-operative MRI should occur within 72hr (100%) Surgery for glioblastoma should aim for GTR when deemed feasible Outcome measuresPrimary outcomes:Percentage of centres offering the surgical adjuncts as per NICE guidelinesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"NICE","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"publisher":"NICE","title":"Context | Brain tumours (primary) and brain metastases in adults | Guidance | NICE","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"¹","plainTextFormattedCitation":"1","previouslyFormattedCitation":"¹"},"properties":{"noteIndex":0},"schema":""}1 1.2.36-1.2.42Percentage of resections of glioblastoma where each or combination of intraoperative surgical adjuncts suggested by NICE were usedPercentage of patients that underwent resection who have had MRI within 72hours post-operatively Percentage of patients with glioblastoma intended to have GTR that have RED with each combination of adjuncts on post-operative MRISecondary outcomesPercentage of patients with glioblastoma intended to have GTR that have RED based on location, eloquence and molecular characteristics Percentage of glioblastoma with successful uptake of 5ALA (5ALA +ve)Resource use in terms of operation length, requirement for level 2 or 3 critical care beds, length of inpatient stay, place of dischargeChange in neurological function or adverse effects with each combination of surgical adjunctsOverall survival/PFS in two yearsData CollectionLocal Registration and Data GovernanceThe project should be registered as a clinical audit with each local audit department. Caldicott Guardian approval and local supervising consultant neurosurgeon approval should be in place if necessary, prior to data collection. Data collectionNo identifiable patient information will be stored or uploaded. If collaborators wish to use the paper copies of the collection proforma, these must be stored securely at the centre and destroyed using confidential waste disposal once the data have been uploaded. Each Neurosurgical centre will have a local collaborative team formed by the NANSIG university representative, a neurosurgical trainee/registrar, a local consultant and additional medical students/Junior doctors. Data will be collected by the team over a period of four months from January 6th to 31st of April 2020. The NANSIG university representative will be responsible for data entry on the online database. All eligible cases should be included. Data collection fields are outlined in Appendix A. Some of the data will require some expertise in radiological imaging interpretation, (i.e. tumour location) and if not clear from neuroradiology report, should be referred to the neurosurgical trainee and reviewed by the consultant neurosurgeon. In cases where further advice is needed the local team can decide whether the advice of a local neuroradiologist is needed.Data is collected locally and submitted to an online secure central database – Castor24. Any locally collected data must be stored in a secure locked room on-site, or on a password protected NHS hospital site as per local research and audit department policy. Sources of data for case ascertainment can include local hospital online portals, theatre logbook/lists, neuro-oncology MDT lists and pathology departments. Once a case is identified, useful sources of data will include pre-operative and post-operative notes, patient clinical notes, pathology reports and radiological scans. The operating surgeon must clearly state prior to data collection their intention regarding extent of resection i.e. GTR Or subtotal resection (STR), either during the MDT or otherwise. Data ValidationData validation will be performed in two centres in the UK. Data validators should be trainees/registrars/junior doctors not involved in the initial data collection. The validator will select a single 1-month study period at a local centre to validate and will take place after completion of data collection. The validator will send a summary of how many records were reviewed and error rates to the study management group. There are two components of validation:Case ascertainment Validators will independently identify all patients eligible for inclusion over the one-month study period. The target for data ascertainment is >95%.Data accuracy Validators will independently collect data for five key data fields relating to operative and 5 for non-operative measures. The selection of fields will only be made available to validators. Conflicts with the data originally submitted by the relevant local team will be resolved by discussion between the validator and local team. The target for accuracy of collected data is >98%.The outcome of data validation (case ascertainment and data accuracy) and error rates will not affect the inclusion of data in the pooled analysis.Data accuracy will be determined for the data fields for selected cases. The target for data accuracy is >95%. DatasetData domains that relate to patient, tumour, surgical adjunct and post-operative period will be collected. No patient identifiable confidential information collected will be submitted onto Castor. No information in additional to routinely collected clinical information will be collected. All patients will have a unique Castor ID number traceable to the identifiable patient information only through securely stored forms physically on NHS sites or on password-protected NHS computers and servers. A full list of data fields is provided in appendix A. Data will be stored on a secure server using the Castor platform. If data collectors upload data on an Excel sheet or proforma it should be stored on an NHS trust computer or locked room that is only accessible by a student or doctor registered with the NHS trust. Errors in data entry will be resolved with local data collection teams prior to any analysis. Data analysisAnalysis will be performed on anonymised data. Data will be analysed using descriptive statistics on participant characteristics and outcomes as outlined in appendix using an appropriate software such as SPSS or R. Project TimelineData collection will start on Monday 6st of January 2020 and is to include data until Thursday 31st of April 2020. Below is a chart outlining the study timeline:Apr-Sept2019OctNovDecJan 2020FebMarAprMayJuneJulyAugSeptOctNovProtocol development and approvalLocal team sign upLocal project registrationData collection periodData submission deadlineData cleaning and validationStatistical AnalysisPreparing Manuscript(s)Publication and presentation back to local departments Authorship EligibilityThe contribution to all participants who are NANSIG local representatives, medical students and junior doctors will be recognised with PubMed citable collaborator-status authorship under the group entitled “NANSIG collaborators”. PubMed citable collaborator-status authorship will also be given in recognition of the supporting trainees and local supervising consultant neurosurgeons, under the group :BNTRC”Fully named authors must satisfied the International Committee of Medical Journal Editors’ conditions for authorship as follows: (i) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (ii)Drafting the work or revising it critically for important intellectual content; AND (iii)Final approval of the version to be published; AND (iv) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Study Steering Committee NANSIG: Georgios Solomou, Ali Gharooni, Danyal Zaman Khan, Melissa Gough BNTRC: Mr Dan Fountain, Mr Rory J Piper, Mr Michael Tin Chung Poon, Mr Angelos G KoliasConsultants: Prof. Colin Watts, Prof. Keymouras Ashkan, Mr. Stephen Price, Mr. Puneet Plaha, Mr. Michael D Jenkinson, Miss Kathrin Whitehouse RolesProject Leads: Georgios Solomou & Ali Gharooni Protocol preparation: Georgios Solomou, Ali GharooniData collection Team: Ali Gharooni, Melissa GoughManuscript Preparation Lead & Corresponding author: Georgios SolomouBNTRC Coordination: NANSIG Chair (Georgios Solomou) Senior advisor committee: Prof. Colin Watts – Honorary Consultant Neurosurgeon and Professor in Neurosurgery, University Hospitals BirminghamProf. Keyoumars Ashkan – Professor of Neurosurgery and Consultant Neurosurgeon, King’s College Hospital NHS Trust Mr. Stephen Price – Honorary Consultant Neurosurgeon and Clinician Scientist,?Cambridge?University Hospitals Trust Mr. Puneet Plaha – Consultant Neurosurgeon, Oxford University Hospitals NHS TrustMr. Michael D Jenkinson – Honorary Consultant Neurosurgeon and Senior Clinical Lecturer in Neurosurgery, University Hospitals Liverpool (SBNS Academic Chair) Miss Kathrin Whitehouse – Senior Fellow in Neurosurgery, Southampton University HospitalsMr. Angelos G Kolias - Clinical Lecturer in Neurosurgery, Cambridge University Hospitals Trust & the University of Cambridge Mr Michael Tin Chung Poon – Cancer Research UK Clinical PhD Fellow, University of Edinburgh Mr. Rory J Piper – Academic Clinical Fellow in Neurosurgery, Oxford University Hospitals NHS Trust (BNTRC 2019-2020 Chair) Mr. Dan Fountain – Academic Clinical Fellow in Neurosurgery, Salford Royal NHS Foundation Trust ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. NICE. Context | Brain tumours (primary) and brain metastases in adults | Guidance | NICE. [cited 2019 Mar 23]; Available from: . Cancer Research UK. Brain, other CNS and intracranial tumours statistics | Cancer Research UK [Internet]. [cited 2019 Mar 23]. Available from: . Burnet NG, Jefferies SJ, Benson RJ, Hunt DP, Treasure FP. Years of life lost (YLL) from cancer is an important measure of population burden—and should be considered when allocating research funds. British journal of cancer. 2005 Jan;92(2):241.4. Philips A, Henshaw DL, Lamburn G, O’Carroll MJ. Brain tumours: rise in Glioblastoma Multiforme incidence in England 1995–2015 suggests an adverse environmental or lifestyle factor. Journal of environmental and public health. 2018;2018.5. Astrocytoma Prognosis | Brain Tumour Survival Rates [Internet]. [cited 2019 Mar 23]. Available from: . Oligodendroglioma Prognosis | Brain Tumour Survival Rates [Internet]. [cited 2019 Mar 23]. Available from: . Stupp R, Mason WP, Van Den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England Journal of Medicine. 2005 Mar 10;352(10):987-96. 8. Bloch O, Han SJ, Cha S, Sun MZ, Aghi MK, McDermott MW, Berger MS, Parsa AT. Impact of extent of resection for recurrent glioblastoma on overall survival. Journal of neurosurgery. 2012 Dec 1;117(6):1032-8.9. Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. Journal of neurosurgery. 2011 Jul 1;115(1):3-8.10. Coburger J, Wirtz CR, Koenig RW. Impact of extent of resection and recurrent surgery on clinical outcome and overall survival in a consecutive series of 170 patients for glioblastoma in intraoperative high field magnetic resonance imaging. Journal of neurosurgical sciences. 2017 Jun;61(3):233-44.11. Mahboob S, McPhillips R, Qiu Z, Jiang Y, Meggs C, Schiavone G, Button T, Desmulliez M, Demore C, Cochran S, Eljamel S. Intraoperative ultrasound-guided resection of gliomas: a meta-analysis and review of the literature. World neurosurgery. 2016 Aug 1;92:255-63.12. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. The lancet oncology. 2006 May 1;7(5):392-401.13. SSenft C, Bink A, Franz K, Vatter H, Gasser T, Seifert V. Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial. The lancet oncology. 2011 Oct 1;12(11):997-1003.14. J Jenkinson MD, Barone DG, Bryant A, Vale L, Bulbeck H, Lawrie TA, Hart MG, Watts C. Intraoperative imaging technology to maximise extent of resection for glioma. Cochrane Database of Systematic Reviews. 2018(1).15. Gandhi S, Tayebi Meybodi A, Belykh E, Cavallo C, Zhao X, Pasha SM, Borba Moreira L, Lawton M, Nakaji P, Preul M. Survival outcomes among patients with high-grade glioma treated with 5-aminolevulinic acid–guided surgery: a systematic review and meta-analysis. Frontiers in oncology. 2019;9:620. 16. Chandler WF, Knake JE, McGillicuddy JE, Lillehei KO, Silver TM. Intraoperative use of real-time ultrasonography in neurosurgery. Journal of neurosurgery. 1982 Aug 1;57(2):157-63.17. Sastry R, Bi WL, Pieper S, Frisken S, Kapur T, Wells III W, Golby AJ. Applications of ultrasound in the resection of brain tumors. Journal of Neuroimaging. 2017 Jan;27(1):5-15.18. TTsugu A, Ishizaka H, Mizokami Y, Osada T, Baba T, Yoshiyama M, Nishiyama J, Matsumae M. Impact of the combination of 5-aminolevulinic acid–induced fluorescence with intraoperative magnetic resonance imaging–guided surgery for glioma. World neurosurgery. 2011 Jul 1;76(1-2):120-7.19. Gessler F, Forster MT, Duetzmann S, Mittelbronn M, Hattingen E, Franz K, Seifert V, Senft C. Combination of intraoperative magnetic resonance imaging and intraoperative fluorescence to enhance the resection of contrast enhancing gliomas. Neurosurgery. 2015 Mar 23;77(1):16-22.20. Weller M, van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A, Cohen-Jonathan-Moyal E, Frappaz D, Henriksson R, Balana C, Chinot O. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. The lancet oncology. 2014 Aug 1;15(9):e395-403.21. Weller M, Van Den Bent M, Tonn JC, Stupp R, Preusser M, Cohen-Jonathan-Moyal E, Henriksson R, Le Rhun E, Balana C, Chinot O, Bendszus M. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. The lancet oncology. 2017 Jun 1;18(6):e315-29.22. Ma R, Chari A, Brennan PM, Alalade A, Anderson I, Solth A, Marcus HJ, Watts C. Residual enhancing disease after surgery for glioblastoma: evaluation of practice in the United Kingdom. Neuro-Oncology Practice. 2017 Sep 27;5(2):74-81.23. Pichierri A, Bradley M, Iyer V. Intraoperative Magnetic Resonance Imaging–Guided Glioma Resections in Awake or Asleep Settings and Feasibility in the Context of a Public Health System. World neurosurgery: X. 2019 Jul 1;3:100022.24. Castor Electronic Data Capture 2019 [Available from: . Appendix A – Required data fields. Pre-operative data DoBDd/mm/yyyyGenderMale, FemaleSite of tumour (tick >1 if applicable)Right frontal, Right Temporal, Right Parietal, Right OccipitalLeft Frontal, Left Temporal, Left Parietal, Left Occipital, InsulaEloquent*Yes, NoIf yes to the above then please tick which function (please tick all that apply)Motor, sensory, language, vision, other (please specify)WHO Performance status– Prior to surgery0, 1, 2, 3, 4 or 5Was there a contrast enhancement on the pre-operative T1W MRI with contrast? Yes, NoRegarding surgical adjuncts, please tick which of the following are available at your centre (select all that apply)5ALA, Neuronavigation, intraoperative MRI, intraoperative US, awake craniotomy, Direct Electrical Stimulation/neurophysiology, tractography, other (Please specify)Was tractography done as part of the pre-operative planning? Yes, NoIs this suitable for complete resection (GTR), according to the MDT and the operating surgeon?Yes, NoIf no to above (n.10) then why?To preserve neurological function, other (please specify)Operative data Date of operationDd/mm/yyyyPlease tick, Surgical adjunct used (select all that apply)5-ALA, Neuronavigation, Intraoperative MRI, Intraoperative US, Direct Electrical Stimulation/neurophysiology, awake craniotomy, endoscopic assisted craniotomy, Other i.e. merging IoUS with neuronavigation (Please specify)In awake craniotomy group, please tick other specialists involved (select all that apply) Neuropsychologists, Speech and Language Therapists, Psychiatrists, physiotherapists other (Please specify)In 5-ALA group, was there a visible red/pink fluorescence during surgery?Yes, NoIf yes (for n.15), was the visible fluorescence completed resected during the operation?Yes, NoIn IoMRI group, tick settings used (select all that apply) 1.5T,3T, T1, T2, Flair, T1c, DWI, otherIn IoMRI group, is a 1-room or 2-room solution used?1 room2 roomIn IoMRI group, was there further resection of the tumour after the MRI was performed?Yes, noDuration of operation (Hrs)1-2,2-3,3-4,4-5,5-6,6-7,7-8,8-9,9-10 >10Post-operative dataGBM histologically confirmed? Yes, No, other (please specify) Molecular characterisationIDH mutant, IDH wildtype , IDH NOS (unknown), other (Please specify eg MGMT) MRI done within 72 hours?Yes, NoIf no, why not?Patient unwell, patient died, MRI department issues, other**Was Gross total Resection achieved as seen in the 72-hour contrast enhance T1-weighted MRI? Yes, NoIf no, why not? To preserve neurological function,Other (Please specify)Adverse Events Yes, NoIf yes to adverse effects then tick from optionsInfection, Stroke, Seizure, CSF leak, Haematoma, other [Please describe]Post-operative deficitYes, NoIf yes to post-operative deficit, then tick from the options (please tick all that apply)Motor, sensory, language, vision, cognition, other (Please describe)WHO performance status – on discharge?0, 1, 2, 3, 4 or 5Date of dischargeDd/mm/yyyyPlace of dischargePatient’s usual home, to friends/relatives, care facility (eg nursing home, hospice), community hospital, local acute hospital, died, (other)* Areas that are responsible for sensory, motor (premotor, supplementary motor, primary motor) and language (Broca’s & Wernicke’s) functions of the brain found during intraoperative cortical stimulation or functional imaging during surgery** In our audit, GTR is defined as NO residual enhancing disease (RED) of contrast enhanced tumour as seen on T1-weighted, contrast-enhanced MRI within 72hours post operatively as judged/seen by the neuroradiologist and the neurosurgeon i.e. complete resection. The neuroradiologist and the neurosurgeon will have to reach an agreement. Appendix B – Neurosurgical centres and Local Data Collection GroupsNeurosurgical CentreMedical SchoolNANSIG CollaboratorsAberdeen Royal Infirmary University of Aberdeen Addenbrookes University of Cambridge Beaumont HospitalRoyal College of Surgeons in IrelandCharing Cross Hospital Imperial College London Cork University HospitalUniversity College CorkDerriford Hospital Plymouth University Essex Neurological Centre Bart’s and The LondonHull Royal Infirmary University of Hull James Cook University Hospital University of Durham John Radcliffe Hospital University of Oxford King’s College HospitalKing’s College LondonLeeds General Infirmary University of Leeds Ninewells Hospital University of Dundee QMC University Hospital University of Nottingham Royal Hallamshire Hospital University of Sheffield Royal London Hospital Bart’s and The LondonRoyal Preston Hospital University of Central Lancashire Royal Stoke, North Midlands Keele University Royal Victoria Hospital Queen’s University BelfastRoyal Victoria Infirmary Newcastle University Salford Royal Hospital University of Manchester Southampton General Hospital University of Southampton Southern General Hospital University of Glasgow Southmead Hospital University of Bristol St Bartholemew’s and Royal London Hospital Bart’s and The LondonSt George’s Hospital St George’s University of London The National Hospital for Neurology and Neurosurgery University College London The Princess Royal Hospital University of Brighton The Queen Elizabeth Hospital University of BirminghamThe Walton Centre Liverpool University/University of Central Lancashire University Hospital of Wales Cardiff University Walsgrave Hospital University of Warwick Western General Hospital University of Edinburgh ................
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