Endoscopic 5-Aminolevulinic Acid-Induced Fluorescence-Guided Intraparenchymal Brain Tumor Resection-Can the Endoscope Detect More Fluorescence Than the Microscope?

OBJECTIVES: Using a laboratory-based optical setup, we show that 5-aminolevulinic acid (5ALA) fluorescence is better detected using the endoscope than the microscope. Furthermore, we present our case series of fully endoscopic 5ALA-guided resection of intraparenchymal tumors. METHODS: A Zeiss Pentero microscope was compared with the Karl Storz Hopkins endoscope. The spectra and intensity of each blue light source were measured. Quantitative fluorescence detection thresholds were measured using a spectrometer. Subjective fluorescence detection thresholds were measured by 6 blinded neuro-oncology surgeons. Clinical data were prospectively collected for all consecutive cases of fully endoscopic 5ALA-guided resection of intraparenchymal tumors between 2012 and 2023. RESULTS: The intensity of blue light on the sample was greater for the endoscope than the microscope at working distances less than 20 mm. The quantitative fluorescence detection thresholds were lower for the endoscope than the microscope at both 30-/10-mm working distances. Fluorescence detection threshold was 0.65%-0.80% relative 4-dicyanomethylene-2-methyl-6-p-dimethylaminostyryl-4H-pyranthe concentration (3.20 × 10-7 to 3.94 × 10-7mol/dm-3) for the microscope, 0.40%-0.55% relative concentrations (1.97 × 10-7 to 2.71 × 10-7mol/dm-3) for the endoscope at 30 mm, and 0.15%-0.30% relative concentrations (7.40 × 10-8 to 1.48 × 10-7mol/dm-3) for the endoscope at 10 mm. In total, 49 5ALA endoscope-assisted brain tumor resections were carried out on 45 patients (mean age = 41 years, male = 28). Greater than 95% resection was achieved in 80% of cases and gross total resection in 42%. Gross total resection was achieved in 100% of tumors in noneloquent locations. There was 1 new neurologic deficit. CONCLUSIONS: The endoscope provides enhanced visualization/detection of 5ALA-induced fluorescence compared with the microscope. 5ALA endoscopic-assisted resection of intraparenchymal tumors is safe and feasible.

Supramaximal versus gross total resection in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, effect on overall and progression free survival: systematic review and meta-analysis.

PURPOSE: To synthesize the evidence on the impact on progression-free survival (PFS) and overall survival (OS) of supramaximal resection (SMR) over gross total resection (GTR) in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4 (Glioblastoma). METHODS: The PubMed, Scopus, Web of Science, Ovid and Cochrane databases were systematically searched (up to November 30, 2022). Studies reporting OS and PFS on adult humans with a suspected Glioblastoma, treated either with a SMR or GTR were included. Hazard ratios were estimated for each study and treatment effects were calculated through DerSimonian and Laird random effects models. RESULTS: The literature search yielded 14 studies published between 2013 and 2022, enrolling a total of 6779 patients. Analysis of the included studies reveals significantly better clinical outcomes favoring SMR over GTR in terms of PFS (HR 0.67; p = 0.0007), and OS (HR 0.7; p = 0.0001). CONCLUSION: Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, are aggressive tumors with a very short long-term OS. SMR is an effective therapeutic approach contributing to increased PFS and OS in patients with this catastrophic disease.

FUTURE-GB: functional and ultrasound-guided resection of glioblastoma - a two-stage randomised control trial.

INTRODUCTION: Surgery remains the mainstay for treatment of primary glioblastoma, followed by radiotherapy and chemotherapy. Current standard of care during surgery involves the intraoperative use of image-guidance and 5-aminolevulinic acid (5-ALA). There are multiple other surgical adjuncts available to the neuro-oncology surgeon. However, access to, and usage of these varies widely in UK practice, with limited evidence of their use. The aim of this trial is to investigate whether the addition of diffusion tensor imaging (DTI) and intraoperative ultrasound (iUS) to the standard of care surgery (intraoperative neuronavigation and 5-ALA) impacts on deterioration free survival (DFS). METHODS AND ANALYSIS: This is a two-stage, randomised control trial (RCT) consisting of an initial non-randomised cohort study based on the principles of the IDEAL (Idea, Development, Exploration, Assessment and Long-term follow-up) stage-IIb format, followed by a statistically powered randomised trial comparing the addition of DTI and iUS to the standard of care surgery. A total of 357 patients will be recruited for the RCT. The primary outcome is DFS, defined as the time to either 10-point deterioration in health-related quality of life scores from baseline, without subsequent reversal, progressive disease or death. ETHICS AND DISSEMINATION: The trial was registered in the Integrated Research Application System (Ref: 264482) and approved by a UK research and ethics committee (Ref: 20/LO/0840). Results will be published in a peer-reviewed journal. Further dissemination to participants, patient groups and the wider medical community will use a range of approaches to maximise impact. TRIAL REGISTRATION NUMBER: ISRCTN38834571.

Evaluating performance of existing computational models in predicting CD8+ T cell pathogenic epitopes and cancer neoantigens.

T cell recognition of a cognate peptide-major histocompatibility complex (pMHC) presented on the surface of infected or malignant cells is of the utmost importance for mediating robust and long-term immune responses. Accurate predictions of cognate pMHC targets for T cell receptors would greatly facilitate identification of vaccine targets for both pathogenic diseases and personalized cancer immunotherapies. Predicting immunogenic peptides therefore has been at the center of intensive research for the past decades but has proven challenging. Although numerous models have been proposed, performance of these models has not been systematically evaluated and their success rate in predicting epitopes in the context of human pathology has not been measured and compared. In this study, we evaluated the performance of several publicly available models, in identifying immunogenic CD8+ T cell targets in the context of pathogens and cancers. We found that for predicting immunogenic peptides from an emerging virus such as severe acute respiratory syndrome coronavirus 2, none of the models perform substantially better than random or offer considerable improvement beyond HLA ligand prediction. We also observed suboptimal performance for predicting cancer neoantigens. Through investigation of potential factors associated with ill performance of models, we highlight several data- and model-associated issues. In particular, we observed that cross-HLA variation in the distribution of immunogenic and non-immunogenic peptides in the training data of the models seems to substantially confound the predictions. We additionally compared key parameters associated with immunogenicity between pathogenic peptides and cancer neoantigens and observed evidence for differences in the thresholds of binding affinity and stability, which suggested the need to modulate different features in identifying immunogenic pathogen versus cancer peptides. Overall, we demonstrate that accurate and reliable predictions of immunogenic CD8+ T cell targets remain unsolved; thus, we hope our work will guide users and model developers regarding potential pitfalls and unsettled questions in existing immunogenicity predictors.

Decitabine increases neoantigen and cancer testis antigen expression to enhance T-cell-mediated toxicity against glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Despite maximal treatment, median survival remains dismal at 14-24 months. Immunotherapies, such as checkpoint inhibition, have revolutionized management of some cancers but have little benefit for GBM patients. This is, in part, due to the low mutational and neoantigen burden in this immunogenically "cold" tumor. METHODS: U87MG and patient-derived cell lines were treated with 5-aza-2'-deoxycytidine (DAC) and underwent whole-exome and transcriptome sequencing. Cell lines were then subjected to cellular assays with neoantigen and cancer testis antigen (CTA) specific T cells. RESULTS: We demonstrate that DAC increases neoantigen and CTA mRNA expression through DNA hypomethylation. This results in increased neoantigen presentation by MHC class I in tumor cells, leading to increased neoantigen- and CTA-specific T-cell activation and killing of DAC-treated cancer cells. In addition, we show that patients have endogenous cancer-specific T cells in both tumor and blood, which show increased tumor-specific activation in the presence of DAC-treated cells. CONCLUSIONS: Our work shows that DAC increases GBM immunogenicity and consequent susceptibility to T-cell responses in vitro. Our results support a potential use of DAC as a sensitizing agent for immunotherapy.

Advances in the management of glioblastoma.

Glioblastoma (GB) is the most common and most malignant primary brain tumour in adults. Despite much effort, gold standard therapy has not changed since the introduction of adjuvant temozolomide in 2005 and prognosis remains poor. Despite this, there has been significant improvement in the surgical technology and technique, that has allowed for increased rates of safe maximal resection of the tumour. In addition, our increased knowledge of the biology of GB has revealed more potential targets, especially in the field of immunotherapy, which has been successful in revolutionising treatment of other cancers. We review the current best practice for the treatment of GB and explore some of the more recent advances in GB management from both a surgical and molecular therapeutic perspective.

Correction to: Primary gliosarcoma: epidemiology, clinical presentation, management, and survival.

This corrects the article DOI: 10.23736/S0390-5616.17.04077-2.

Primary gliosarcoma: epidemiology, clinical presentation, management, and survival.

BACKGROUND: Gliosarcomas are malignant tumors of the central nervous system. As a variant of glioblastomas (GBM), they are treated in a similar fashion. However, there is growing evidence to suggest that they may be a separate entity. METHODS: Due to the rarity of primary gliosarcomas (PGS), here we publish data from a single center spanning over 14 years, comprising possibly one of the biggest case series in the literature to our knowledge. RESULTS: The mean age at presentation was 59 years with male preponderance (1.75:1). The most common presenting symptoms were balance and mobility issues (61%), followed by headaches (50%) and visual problems (39%). Tumours were most likely to involve the frontal and parietal lobes (27% and 21% respectively). Patients under 50 had a significant survival advantage (50% versus 32%). All patients had surgery, 79% had adjuvant radiotherapy, with a further 21% also receiving chemotherapy. Median survival from surgery of patients diagnosed with PGS was 6.6 months. Median and one-year survival were significantly better for patients who received radiotherapy (14 months; 46% one year survival) and improved further with combined radio- and chemotherapy (30 months; 77%, one year survival). CONCLUSIONS: For patients of good functional status, adjuvant chemo-radiotherapy is warranted and should be offered as it confers a much-improved overall survival.

Management of aneurysmal subarachnoid haemorrhage 17 years after the ISAT trial: a survey of current practice in the UK and Ireland.

Introduction: In the last two decades and driven by the International Subarachnoid Aneurysm Trial (ISAT), the management of aneurysmal subarachnoid haemorrhage (aSAH) has undergone extensive change from predominantly neurosurgical (clipping) to predominantly neuroradiological (coiling) treatment. In 2013, the UK's national Confidential Enquiry into Patient Outcome and Death (NCEPOD) recommended aSAH to be definitively treated within 48h of ictus. The aim of this survey was to assess how this recommendation is being followed across the UK and Ireland 17 years after ISAT and 6 years after the NCEPOD.Methods: An online survey consisting of 9 questions was electronically distributed to neurosurgical consultants and trainees. Missing or ambivalent data was collected or verified by emailing consultant neurosurgeons to ensure the coverage of all 32 neurosurgical units in the UK and Ireland.Results: Only 9 (28%) of units provide 7 days a week interventional neuroradiology service, but all 32 (100%) units have established networks with other neuroradiology centres to provide aSAH treatment within 48h of ictus assuming no delays in patient transfer. For aSAH patients requiring neurosurgical clipping, 27 (84%) of units provide (locally or through networks) aneurysm repair within 48h of ictus, whereas 5 (16%) units may breach this recommendation by keeping the aSAH patients that present after 5PM on Fridays and delaying their clipping to the subsequent Monday.Conclusion: Assuming no delays in patient transfer, 32 (100%) neurosurgical centres in the UK and Ireland meet the <48h ictus-to-treatment target for endovascular coiling and 27 (84%) units for neurosurgical clipping of aSAH.

Nitric oxide modulates cardiomyocyte pH control through a biphasic effect on sodium/hydrogen exchanger-1.

AIMS: When activated, Na+/H+ exchanger-1 (NHE1) produces some of the largest ionic fluxes in the heart. NHE1-dependent H+ extrusion and Na+ entry strongly modulate cardiac physiology through the direct effects of pH on proteins and by influencing intracellular Ca2+ handling. To attain an appropriate level of activation, cardiac NHE1 must respond to myocyte-derived cues. Among physiologically important cues is nitric oxide (NO), which regulates a myriad of cardiac functions, but its actions on NHE1 are unclear. METHODS AND RESULTS: NHE1 activity was measured using pH-sensitive cSNARF1 fluorescence after acid-loading adult ventricular myocytes by an ammonium prepulse solution manoeuvre. NO signalling was manipulated by knockout of its major constitutive synthase nNOS, adenoviral nNOS gene delivery, nNOS inhibition, and application of NO-donors. NHE1 flux was found to be activated by low [NO], but inhibited at high [NO]. These responses involved cGMP-dependent signalling, rather than S-nitros(yl)ation. Stronger cGMP signals, that can inhibit phosphodiesterase enzymes, allowed [cAMP] to rise, as demonstrated by a FRET-based sensor. Inferring from the actions of membrane-permeant analogues, cGMP was determined to activate NHE1, whereas cAMP was inhibitory, which explains the biphasic regulation by NO. Activation of NHE1-dependent Na+ influx by low [NO] also increased the frequency of spontaneous Ca2+ waves, whereas high [NO] suppressed these aberrant forms of Ca2+ signalling. CONCLUSIONS: Physiological levels of NO stimulation increase NHE1 activity, which boosts pH control during acid-disturbances and results in Na+-driven cellular Ca2+ loading. These responses are positively inotropic but also increase the likelihood of aberrant Ca2+ signals, and hence arrhythmia. Stronger NO signals inhibit NHE1, leading to a reversal of the aforementioned effects, ostensibly as a potential cardioprotective intervention to curtail NHE1 overdrive.

Endoscopy in Temporal Lobe Glioma and Metastasis Resection: Is There a Role?

BACKGROUND: Surgical access to the temporal lobe is complex with many eloquent white fiber tracts, requiring careful preoperative surgical planning. Many microsurgical approaches to the temporal lobes are described, each with their own disadvantages. The adoption of the endoscope in neurosurgery has increased the options available when treating these difficult access tumors. We present our experience of a novel, minimally invasive, endoscopic approach to resect temporal lobe tumors. METHODS: All patients undergoing endoscopic temporal lobe tumor resection between December 1, 2011 and December 1, 2017, with a single surgeon, were included. Tumors were resected through a minicraniotomy using a high-definition rigid endoscope with a 0- and 30-degree viewing angle. Bimanual resection was performed using standard microsurgical technique. RESULTS: There were 45 patients (22 men and 23 women) with a mean age of 53 years. There were 23 (51%) glioblastoma multiforme, 11 (24%) metastases, 7 (16%) astrocytoma, 3 (7%) anaplastic astrocytoma, and 1 (2%) World Health Organization grade I glioneuronal tumor. In 82.2% of cases (37/45), >95% resection was achieved and 42.2% (19/45) of patients achieving gross total resection. CONCLUSIONS: The endoscope has a role in temporal lobe intraparenchymal tumor surgery, especially in 3 illustrative scenarios: 1) medial temporal, parahippocampal-gyrus low-grade nonenhancing gliomas, 2) subcortical high-grade glioma and metastases medial to the sagittal stratum, and 3) recurrent gliomas with cystic resection cavity. The endoscope offers a safe and useful adjunct to the surgeons' armamentarium in brain tumor surgery. A minimally invasive approach also reduces surgical morbidity and length of stay.

Complications following intracranial pressure monitoring in children: a 6-year single-center experience.

OBJECTIVE Intracranial pressure (ICP) monitoring is an important tool in the neurosurgeon's armamentarium and is used for a wide range of indications. There are many different ICP monitors available, of which fiber-optic intraparenchymal devices are very popular. Here, the authors document their experience performing ICP monitoring from 2005 to 2015 and specifically complication rates following insertion of the Microsensor ICP monitor. METHODS A retrospective case series review of all patients who underwent ICP monitoring over a 10-year period from 2005 to 2015 was performed. RESULTS There were 385 separate operations with an overall complication rate of 8.3% (32 of 385 cases). Hardware failure occurred in 4.2% of cases, the CSF leakage rate was 3.6%, the postoperative hemorrhage rate was 0.5%, and there was 1 case of infection (0.3% of cases). Only patients with hardware problems required further surgery as a result of their complications, and no patient had any permanent morbidity or mortality from the procedure. Younger patients (p = 0.001) and patients with pathologically high ICP (13% of patients with high ICP vs 6.5% of patients with normal ICP; p = 0.04) were significantly more likely to have complications. There was no significant difference in the complication rates between general neurosurgical patients and craniofacial patients (7.6% vs 8.8%, respectively; p = 0.67). CONCLUSIONS Intraparenchymal ICP monitoring is a safe procedure associated with low complications and morbidity in the pediatric craniofacial and neurosurgical population and should be offered to appropriate patients to assess ICP with the reassurance of the safety record reported in this study.

Residual enhancing disease after surgery for glioblastoma: evaluation of practice in the United Kingdom.

BACKGROUND: A growing body of clinical data highlights the prognostic importance of achieving gross total resection (GTR) in patients with glioblastoma. The aim of this study was to determine nationwide practice and attitudes towards achieving GTR and dealing with residual enhancing disease. METHODS: The study was in 2 parts: an electronic questionnaire sent to United Kingdom neuro-oncology surgeons to assess surgical practice followed by a 3-month prospective, multicenter observational study of current neurosurgical oncology practice. RESULTS: Twenty-seven surgeons representing 22 neurosurgical units completed the questionnaire. Prospective data were collected for 113 patients from 15 neurosurgical units. GTR was deemed to be achieved at time of surgery in 82% (91/111) of cases, but in only 45% (36/80) on postoperative MRI. Residual enhancing disease was deemed operable in 16.3% (13/80) of cases, however, no patient underwent early repeat surgery for residual enhancing disease. The most commonly cited reason (38.5%, 5/13) was perceived lack of clinical benefit. CONCLUSION: There is a subset of patients for whom GTR is thought possible, but not achieved at surgery. For these patients, early repeat resection may improve overall survival. Further prospective surgical research is required to better define the prognostic implications of GTR for residual enhancing disease and examine the potential benefit of this early re-intervention.

Corrigenda: Residual enhancing disease after surgery for glioblastoma: evaluation of practice in the United Kingdom.

[This corrects the article DOI: 10.1093/nop/npx023.][This corrects the article DOI: 10.1093/nop/npx023.].

The British Neurosurgical Trainee Research Collaborative: Five years on.

Since its inception in 2012, the British Neurosurgical Trainee Research Collaborative (BNTRC) has established itself as a robust example of a trainee-led research collaborative. This article summarises the work of the collaborative over its first 5 years of existence, outlining the structure, its research projects, impact and future directions.

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

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

Selective 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in Gliomas.

Malignant gliomas are locally invasive tumors that offer a poor prognosis. Evidence shows that complete resection of the tumor at the time of surgery confers a significant improvement in overall survival. In recent years, 5- aminolevulinic acid (ALA)-induced fluorescence has been used by neurosurgeons to good effect in increasing the rate of complete resection. Despite the considerable interest in the use of 5-ALA in fluorescence-guided neurosurgery, the mechanisms behind the accumulation of Protoporphyrin IX (PpIX) in neoplastic tissue are unclear. In this review, we summarize the evidence in the literature on the mechanisms underlying the selective production of PpIX with a specific focus on gliomas.

Fast Track Recovery Program After Endoscopic and Awake Intraparenchymal Brain Tumor Surgery.

BACKGROUND: There is an increasing drive to deliver a more efficient, cost-effective service leading to shorter stays in hospital. The advent of endoscopic and awake tumor surgery has reduced the morbidity associated with brain tumor resection, allowing patients to mobilize and be discharged earlier. Here, we present the outcomes from a single neurosurgical center in the United Kingdom on a fast track recovery program. METHODS: All consecutive patients undergoing elective endoscopic (n = 65) or awake (n = 10) tumor resection over a 3-year period between 1 December 2011 and 31 January 2015, under a single surgeon, were recruited. Data regarding their length of stay and outcomes were prospectively collated and analyzed. RESULTS: 66.7% of patients could be discharged safely within 1 postoperative day. Of the patients who stayed longer, 76% had a prolonged stay because of either social reasons or failing occupational therapy assessments. Only 6 cases (24%) of prolonged hospital admission were for medical reasons. Patients discharged within 1 day were no more likely to develop postoperative complications compared with those staying for longer (18% vs. 28%; odds ratio, 0.56; 95% confidence interval, 0.18-1.75; P = 0.21). The readmission rates were identical in both groups (16%). The only factor significantly affecting length of stay was World Health Organization performance score, both pre- and postoperative. CONCLUSIONS: An early discharge after endoscopic and awake craniotomy tumor resection is both safe and feasible for most patients and is not associated with increased postoperative morbidity. We recommend that all patients who have good baseline function be offered short stay surgery.

Yield and complications of frame-based and frameless stereotactic brain biopsy--the value of intra-operative histological analysis.

OBJECTIVES: Image-guided brain biopsy is an established method to obtain histopathological diagnosis and guide management for cerebral lesions. The study aimed to establish negative biopsy and symptomatic haemorrhage rates at a single centre, and to assess the influence of factors such as lesion location, final pathology and the use of intra-operative smears. METHODS: A retrospective analysis of all frame-based and frameless stereotactic biopsies carried out over 57 months from July 2006 to March 2011. RESULTS: A total of 351 biopsies were undertaken, 256 frame-based (73%) and 95 frameless (27%). Mean age was 57 years (range 18-87). Negative biopsy rate was 5.1%. There was a significantly greater negative biopsy rate in deep brain biopsies (p = 0.011) and in the cerebellum (p < 0.001). Intra-operative smear significantly reduced negative biopsy rates from 11.1% to 3.7% (p = 0.011). If repeat smear was requested, yet not provided, then the negative biopsy rate was 57.1% (p = 0.0085). The overall symptomatic haemorrhage rate was 3.7%. There was a significant increase in haemorrhage rate in deep versus superficial biopsies (p = 0.023) and a significantly greater haemorrhage rate in lymphoma biopsies (p = 0.015). There was no significant increase in haemorrhage rate in high-grade compared with low-grade tumour biopsies. Mortality rates at 7 and 30 days post-operatively were 0.6% and 1.7%, respectively, with mortality after 7 days unrelated to biopsy. CONCLUSION: We advocate intra-operative histopathological analysis to decrease negative biopsy rates and advise increased caution when undertaking biopsies of deep lesions or suspected lymphoma cases due to the potentially increased risk of haemorrhage.