5-ALA fluorescence in randomly selected pediatric brain tumors assessed by spectroscopy and surgical microscope.

PURPOSE: Fluorescence-guided surgery applying 5-aminolevulinic acid (5-ALA) in high-grade gliomas is an established method in adults. In children, results have so far been ambiguous. The aim of this study was to investigate 5-ALA-induced fluorescence in pediatric brain tumors by using the surgical microscope and a spectroscopic hand-held probe. METHODS: Fourteen randomly selected children (age 4-17) with newly MRI-verified brain tumors were included. No selection was based on the suspected diagnosis prior to surgery. All patients received 5-ALA (20 mg /kg) either orally or via a gastric tube prior to surgery. Intratumoral fluorescence was detected with the microscope and the probe. Moreover, fluorescence in the skin of the forearm was measured. Histopathology samples revealed seven low-grade gliomas, four medulloblastomas, one diffuse intrinsic pontine glioma, one glioblastoma and one atypical meningioma. Blood samples were analyzed, and potential clinical side effects were monitored. RESULTS: Microscopically, vague fluorescence was visible in two patients. Intratumoral fluorescence could be detected in five patients with the probe, including the two patients with vague microscopic fluorescence. Three of the oldest children had PpIX fluorescence in the skin. Nine children did not show any fluorescence in the tumor or in the skin. No clinical side effects or laboratory adverse events were observed. CONCLUSION: Fluorescence could not be used to guide surgery in this study, neither with the surgical microscope nor with the hand-held probe. In nine children, no fluorescence was discerned and children with noticeable fluorescence were all older than nine years. 5-ALA was considered safe to apply in children.

Awake craniotomy in epilepsy surgery includes previously inoperable patients with preserved efficiency and safety.

Introduction: Whilst awake craniotomy has been widely used historically in epilepsy surgery, the safety and efficacy of this approach in epilepsy surgery has been sparsely investigated in controlled studies. The objective of this study is to investigate the safety and efficacy of awake resection in epilepsy surgery and focuses on the possibility to widen surgical indications with awake surgery. Methods: Fifteen patients operated with awake epilepsy surgery were compared to 30 matched controls undergoing conventional/asleep epilepsy surgery. The groups were compared with regard to neurological complications, seizure control and location of resection. Results: Regarding seizure control, 86% of patients in the awake group reached Engel grade 1-2 compared to 73% in the control group, operated with conventional/asleep surgery, not a statistically significant difference. Neither was there a statistical significant difference regarding postoperative neurological complications. However, there was a significant difference in location of the resection when comparing the two groups. Of the 15 patients operated with awake intraoperative mapping, four had previously been considered as non-operable by epilepsy surgery centres, due to vicinity to eloquent brain regions and predicted risk of post-operative neurological deficits. Discussion: The results show that awake epilepsy surgery yields similar level of seizure control when compared to conventional asleep surgery, with maintained safety in regard to neurological complications. Furthermore, the results indicate that awake craniotomy in epilepsy surgery is feasible and possible in patients otherwise regarded as inoperable with epileptigenic zone in proximity to eloquent brain structures.

Initial cognitive impairment predicts shorter survival of patients with glioblastoma.

OBJECTIVES: Seizures as presenting symptom of glioblastoma (GBM) are known to predict prolonged survival, whereas the clinical impact of other initial symptoms is less known. Our main objective was to evaluate the influence of different presenting symptoms on survival in a clinical setting. We also assessed lead times, tumour size and localization. METHODS: Medical records of 189 GBM patients were reviewed regarding the first medical appointment, presenting symptom/s, date of diagnostic radiology and survival. Tumour size, localization and treatment data were retrieved. Overall survival was calculated using Kaplan-Meier and Mann-Whitney U test. Cox regression was used for risk estimation. RESULTS: Cognitive impairment as the initial symptom was often misinterpreted in primary health care leading to a delayed diagnosis. Initial global symptoms (66% of all patients) were associated with reduced survival compared to no global symptoms (median 8.4 months vs. 12.6 months). Those with the most common cognitive dysfunctions: change of behaviour, memory impairment and/or disorientation had a reduced median survival to 6.4 months. In contrast, seizures (32%) were associated with longer survival (median 11.2 months vs. 8.3 months). Global symptoms were associated with larger tumours than seizures, but tumour size had no linear association with survival. The setting of the first medical appointment was evenly distributed between primary health care and emergency units. CONCLUSION: Patients with GBM presenting with cognitive symptoms are challenging to identify, have larger tumours and reduced survival. In contrast, epileptic seizures as the first symptom are associated with longer survival and smaller tumours.

"Do I want to know it all?" A qualitative study of glioma patients' perspectives on receiving information about their diagnosis and prognosis.

PURPOSE: Glioma patients have poor prognosis. The amount of detail of disease-related information patients wish to receive is not known. The aim of this study was to explore glioma patients' experiences and preferences regarding receiving information on diagnosis and prognosis. METHODS: Semi-structured interviews were performed with patients diagnosed with glioma. The interviews were analysed by qualitative content analysis without predefined categories by two independent coders. RESULTS: Ten women and 15 men, with newly diagnosed grade II-IV glioma, age 25-76 years, were interviewed. Participants' experience on diagnosis communication was either indirect, meaning they found out their diagnosis unintentionally, e.g., from their electronic health record (EHR) instead of from their doctor, this causing anxiety and feelings of abandonment, insufficiently tailored: lacking in many aspects or individualised and compassionate. Participants generally wanted to know "the truth" about diagnosis and prognosis, but what they meant varied; some desired full honest information to allow for autonomous choices, others preferred general information without details, and some wanted no bad news at all, only positive information. Participants disclosed vulnerability after receiving their diagnosis, being cast into the unknown. They expressed a need for better everyday practical information to help create some control. Supportive staff could reduce participants' distress. CONCLUSION: There is a need to further develop and implement individually tailored information to glioma patients, both in consultations and patient-accessed EHR systems, which should have safe guards for sensitive information. Not all patients want to know it all, one size does not fit all.

ABCB1 single-nucleotide variants and survival in patients with glioblastoma treated with radiotherapy concomitant with temozolomide.

Standard treatment for glioblastoma (GBM) patients is surgery and radiochemotherapy (RCT) with temozolomide (TMZ). TMZ is a substrate for ABCB1, a transmembrane drug transporter. It has been suggested that survival for GBM patients receiving TMZ is influenced by different single-nucleotide variants (SNV) of ABCB1. We therefore examined SNV:s of ABCB1, namely 1199G>A, 1236C>T, 2677G>T/A, and 3435C>T and correlated to survival for GBM patients receiving RCT. In a pilot cohort (97 patients) a significant correlation to survival was found for SNV 1199G>A, with median OS for variant G/G patients being 18.2 months versus 11.5 months for A/G (p = 0.012). We found no correlation to survival for the other SNV:s. We then expanded the cohort to 179 patients (expanded cohort) and also included a confirmatory cohort (49 patients) focusing on SNV 1199G>A. Median OS for G/G versus A/G plus A/A was 15.7 and 11.5 months, respectively (p = 0.085) for the expanded cohort and 13.8 versus 16.8 months (p = 0.19) for the confirmatory. In conclusion, in patients with GBM receiving RCT with TMZ, no correlation with survival was found for the SNV:s 1236C>T, 2677G>T/A, and 3435C>T of ABCB1. Although the SNV 1199G>A might have some impact, a clinically significant role could not be confirmed.

One-Insertion Stereotactic Brain Biopsy Using In Vivo Optical Guidance-A Case Study.

BACKGROUND: Stereotactic neurosurgical brain biopsies are afflicted with risks of inconclusive results and hemorrhage. Such complications can necessitate repeated trajectories and prolong surgical time. OBJECTIVE: To develop and introduce a 1-insertion stereotactic biopsy kit with direct intraoperative optical feedback and to evaluate its applicability in 3 clinical cases. METHODS: An in-house forward-looking probe with optical fibers was designed to fit the outer cannula of a side-cutting biopsy kit. A small aperture was made at the tip of the outer cannula and the edges aligned with the optical probe inside. Stereotactic biopsies were performed using the Leksell Stereotactic System. Optical signals were measured in millimeter steps along the preplanned trajectory during the insertion. At the region with the highest 5-aminolevulinic acid (5-ALA)-induced fluorescence, the probe was replaced by the inner cannula, and tissue samples were taken. The waiting time for pathology diagnosis was noted. RESULTS: Measurements took 5 to 10 minutes, and the surgeon received direct visual feedback of intraoperative 5-ALA fluorescence, microcirculation, and tissue gray-whiteness. The 5-ALA fluorescence corroborated with the pathological findings which had waiting times of 45, 50, and 75 minutes. Because only 1 trajectory was required and the patient could be prepared for the end of surgery immediately after sampling, this shortened the total surgical time. CONCLUSION: A 1-insertion stereotactic biopsy procedure with real-time optical guidance has been presented and successfully evaluated in 3 clinical cases. The method can be modified for frameless navigation and thus has great potential to improve safety and diagnostic yield for both frameless and frame-based neurosurgical biopsy procedures.

[Neurosurgery still pivotal in the diagnostics and treatment of brain tumor patients]. / Neurokirurgin alltjämt kärnan i behandlingen av hjärntumörer.

Treatment of adult patients with brain tumors is a multi-disciplinary effort involving several medical disciplines: neurosurgery, oncology, neurology, neuropathology, neuroradiology, and rehabilitation medicine. While the brain tumor field has gone through vast diagnostical changes during the last decade, the hopes of similar achievements in the systemic treatment of these patients with new methods have so far not been fulfilled. As such, neurosurgery still has a pivotal role in the diagnostics and treatment of brain tumor patients. Improved preoperative evaluation of the tumor and adjacent anatomical and functional brain areas, together with advanced microsurgical techniques, intraoperative mapping and monitoring, as well as new minimally invasive techniques, makes brain tumor surgery safer. Indeed, it is now possible to safely operate patients previously considered to have too unfavorable risk-benefit ratio. This article aims at presenting an overview of current neurosurgical treatments of brain tumors.

The sex-dependent role of the androgen receptor in glioblastoma: results of molecular analyses.

We sought to analyse the androgen receptor (AR) in glioblastoma (GBM) due to the location of the AR gene on chromosome X, often reported with shorter survival and higher prevalence of GBM among males. Copy number (CN) and mRNA expression of AR were tested with droplet digital PCR in 91 fresh-frozen GBM samples and 170 formalin-fixed, paraffin-embedded samples collected at Linköping University Hospital. The fresh-frozen cohort was also subjected to pyrosequencing methylation analysis of 17 CpG sites in the AR promoter. Additionally, the gene expression of AR was analysed in the fresh-frozen cohort and The Cancer Genome Atlas (TCGA) cohort of isocitrate dehydrogenase wild-type primary GBM (135 females and 219 males). The association of AR expression and overall survival (OS) was tested with Kaplan-Meier log rank analysis after dichotomisation by maximally selected rank statistics. We found that AR CN alterations were more common in female GBM. AR gene expression correlated with methylation levels of different CpG sites in males and females but there was no difference in expression between sexes. Survival analysis of TCGA cohort revealed the opposite effect of AR overexpression on OS of males and females, with high AR expression correlating with shorter OS in females and longer OS in males. Additional gene set enrichment analysis showed that AR expression correlated with DNA repair response, especially in the male group. In summary, we found that high AR gene expression in GBM exhibits sex-dependent effects on patient survival, which, for males, is linked to DNA repair response.

A new microsurgical instrument--a suction tube combined with a microdissector.

A microsurgical suction tube with an attached ball probe has been developed. It functions as a microdissector when the ball probe is in its extended position, creating a larger working field than an ordinary sucker. When the ball probe is in the repose position, it does not interfere with the suction capacity, and the suction tube serves as a regular sucker. By adding the properties of the microdissector to the suction tube, dissection of exquisitely fine and subtle structures, including arachnoidal membranes, is facilitated. The ball probe is easily dismantled from the suction tube and the whole instrument conveniently cleaned.

Optical Brain Biopsy with a Fluorescence and Vessel Tracing Probe.

BACKGROUND: Accurate stereotactic biopsies of brain tumors are imperative for diagnosis and tailoring of the therapy. Repetitive needle insertions enhance risks of brain lesioning, hemorrhage, and complications due to prolonged procedure. OBJECTIVE: To investigate clinical benefits of a combined 5-aminolaevulinic acid (5-ALA) fluorescence and laser Doppler flowmetry system for the detection of malignant brain tumor and blood vessels in stereotactic biopsies. METHODS: Planning of targets and trajectories was followed by optical measurements in 20 patients, using the Leksell Stereotactic System and a manual insertion device. Fluorescence spectra, microvascular blood flow, and tissue grayness were recorded each millimeter along the paths. Biopsies were taken at preplanned positions. The diagnoses were compared with the fluorescence signals. The recordings were plotted against measurement positions and compared. Sites indicating a risk of hemorrhage were counted as well as the time for the procedures. RESULTS: Signals were recorded along 28 trajectories, and 78 biopsies were collected. The final diagnosis showed 17 glioblastomas, 2 lymphomas, and 1 astrocytoma grade III. Fluorescence was seen along 23 of the paths with 4 having the peak of 5-ALA fluorescence 3 mm or more from the precalculated target. There was increased microcirculation in 40 of 905 measured positions. The measurement time for each trajectory was 5 to 10 min. CONCLUSION: The probe provided direct feedback of increased blood flow along the trajectory and of malignant tissue in the vicinity of the target. The method can increase the precision and the safety of the biopsy procedure and reduce time.

Case Report: Subtherapeutic Vancomycin and Meropenem Concentrations due to Augmented Renal Clearance in a Patient With Intracranial Infection Caused by Streptococcus intermedius.

Streptococcus intermedius occasionally causes brain abscesses that can be life-threatening, requiring prompt antibiotic and neurosurgical treatment. The source is often dental, and it may spread to the eye or the brain parenchyma. We report the case of a 34-year-old man with signs of apical periodontitis, endophthalmitis, and multiple brain abscesses caused by Streptococcus intermedius. Initial treatment with meropenem and vancomycin was unsuccessful due to subtherapeutic concentrations, despite recommended dosages. Adequate concentrations could be reached only after increasing the dose of meropenem to 16 g/day and vancomycin to 1.5 g × 4. The patient exhibited high creatinine clearance consistent with augmented renal clearance, although iohexol and cystatin C clearances were normal. Plasma free vancomycin clearance followed that of creatinine. A one-day dose of trimethoprim-sulfamethoxazole led to an increase in serum creatinine and a decrease in both creatinine and urea clearances. These results indicate that increased tubular secretion of the drugs was the cause of suboptimal antibiotic treatment. The patient eventually recovered, but his left eye needed enucleation. Our case illustrates that augmented renal clearance can jeopardize the treatment of serious bacterial infections and that high doses of antibiotics are needed to achieve therapeutic concentrations in such cases. The mechanisms for regulation of kidney tubular transporters of creatinine, urea, vancomycin, and meropenem in critically ill patients are discussed.

Deletions on Chromosome Y and Downregulation of the SRY Gene in Tumor Tissue Are Associated with Worse Survival of Glioblastoma Patients.

BACKGROUND: Biological causes of sex disparity seen in the prevalence of cancer, including glioblastoma (GBM), remain poorly understood. One of the considered aspects is the involvement of the sex chromosomes, especially loss of chromosome Y (LOY). METHODS: Tumors from 105 isocitrate dehydrogenase (IDH) wild type male GBM patients were tested with droplet digital PCR for copy number changes of ten genes on chromosome Y. Decreased gene expression, a proxy of gene loss, was then analyzed in 225 IDH wild type GBM derived from TCGA and overall survival in both cohorts was tested with Kaplan-Meier log-rank analysis and maximally selected rank statistics for cut-off determination. RESULTS: LOY was associated with significantly shorter overall survival (7 vs. 14.6 months, p = 0.0016), and among investigated individual genes survival correlated most prominently with loss of the sex-determining region Y gene (SRY) (10.8 vs. 14.8 months, p = 0.0031). Gene set enrichment analysis revealed that epidermal growth factor receptor, platelet-derived growth factor receptor, and MYC proto-oncogene signaling pathways are associated with low SRY expression. CONCLUSION: Our data show that deletions and reduced gene expression of chromosome Y genes, especially SRY, are associated with reduced survival of male GBM patients and connected to major susceptibility pathways of gliomagenesis.

Variations in the management of diffuse low-grade gliomas-A Scandinavian multicenter study.

BACKGROUND: Early extensive surgery is a cornerstone in treatment of diffuse low-grade gliomas (DLGGs), and an additional survival benefit has been demonstrated from early radiochemotherapy in selected "high-risk" patients. Still, there are a number of controversies related to DLGG management. The objective of this multicenter population-based cohort study was to explore potential variations in diagnostic work-up and treatment between treating centers in 2 Scandinavian countries with similar public health care systems. METHODS: Patients screened for inclusion underwent primary surgery of a histopathologically verified diffuse WHO grade II glioma in the time period 2012 through 2017. Clinical and radiological data were collected from medical records and locally conducted research projects, whereupon differences between countries and inter-hospital variations were explored. RESULTS: A total of 642 patients were included (male:female ratio 1:4), and annual age-standardized incidence rates were 0.9 and 0.8 per 100 000 in Norway and Sweden, respectively. Considerable inter-hospital variations were observed in preoperative work-up, tumor diagnostics, surgical strategies, techniques for intraoperative guidance, as well as choice and timing of adjuvant therapy. CONCLUSIONS: Despite geographical population-based case selection, similar health care organizations, and existing guidelines, there were considerable variations in DLGG management. While some can be attributed to differences in clinical implementation of current scientific knowledge, some of the observed inter-hospital variations reflect controversies related to diagnostics and treatment. Quantification of these disparities renders possible identification of treatment patterns associated with better or worse outcomes and may thus represent a step toward more uniform evidence-based care.

Experiences of awake surgery in non-tumoural epilepsy in eloquent localizations.

BACKGROUND: Whilst modern awake intraoperative mapping has been widely accepted and implemented in the last decades in neuro-oncology, sparse reports have been published on the safety and efficiency of this approach in epilepsy surgery. METHOD: This article reports four cases with different locations of epileptogenic zones as examples of possible safe and efficient resections. RESULT: The results of the resections on seizure control were Engel 1 (no disabling seizures) in all cases and no patient experienced significant neurological deficits. DISCUSSION: The discussion focuses on aspects of the future of epilepsy surgery in a hodotopical paradigm.

Neurosurgical patterns of care for diffuse low-grade gliomas in Sweden between 2005 and 2015.

BACKGROUND: In the last decade, increasing evidence has evolved for early and maximal safe resection of diffuse low-grade gliomas (LGGs) regarding survival. However, changes in clinical practice are known to occur slowly and we do not know if the scientific evidence has yet resulted in changes in neurosurgical patterns of care. METHODS: The Swedish Brain Tumor Registry was used to identify all patients with a first-time histopathological diagnosis of LGG between 2005 and 2015. For analysis of surgical treatment patterns, we subdivided assessed time periods into 2005-2008, 2009-2012, and 2013-2015. Population-based data on patient and disease characteristics, surgical management, and outcomes were extracted. RESULTS: A total of 548 patients with diffuse World Health Organization grade II gliomas were identified: 142 diagnosed during 2005-2008, 244 during 2009-2012, and 162 during 2013-2015. Resection as opposed to biopsy was performed in 64.3% during 2005-2008, 74.2% during 2009-2012, and 74.1% during 2013-2015 (P = .08). There was no difference among the 3 periods regarding overall survival (P = .11). However, post hoc analysis of data from the 4 (out of 6) centers that covered all 3 time periods demonstrated a resection rate of 64.3% during 2005-2008, 77.4% during 2009-2012, and 75.4% during 2013-2015 (P = .02) and longer survival of patients diagnosed 2009 and onward (P = .04). CONCLUSION: In this nationwide, population-based study we observed a shift over time in favor of LGG resection. Further, a positive correlation between the more active surgical strategy and longer survival is shown, although no causality can be claimed because of possible confounding factors.

Assessment of genetic and non-genetic risk factors for venous thromboembolism in glioblastoma - The predictive significance of B blood group.

INTRODUCTION: Venous thromboembolism (VTE) is a common problem among patients with glioblastoma multiforme (GBM) and with some other cancers. Here, we evaluated genetic and non-genetic potential risk factors for VTE among GBM patients. MATERIALS AND METHODS: A cohort of 139 patients treated with concomitant radiotherapy and temozolomide were included in the study. Next generation sequencing and genotyping approaches were applied to assess genetic risk factors in the haemostatic system. Clinical data including surgery, reoperation as well as blood group and patient information such as age and gender were available from patient records. Logistic regression analysis was performed to asses VTE risk. RESULTS: In the study 47 patients (34%) were diagnosed for VTE during the course of their disease. When genetic and non-genetic potential risk factors were evaluated, only B blood group was found to be significantly associated with VTE incidence (odds ratio [OR] = 6.91; confidence interval [CI] = 2.19-24.14; P = 0.001). In contrast, A and O blood groups did not correlate with VTE risk. Frontal lobe tumor location also seemed to slightly increase VTE risk compared to other brain sites (OR = 3.14; CI = 1.1-10.7) although the significance level was at borderline (P = 0.05). Current study identified B blood group as the component in non-O blood groups that is responsible for increased VTE risk. CONCLUSION: In conclusion, these results suggest for the first time that B blood group is predictive for VTE incidence among patients with glioblastoma, information that may be potentially valuable when selecting GBM patients who are at risk for VTE for anticoagulant prophylaxis.

5-ALA fluorescence and laser Doppler flowmetry for guidance in a stereotactic brain tumor biopsy.

A fiber optic probe was developed for guidance during stereotactic brain biopsy procedures to target tumor tissue and reduce the risk of hemorrhage. The probe was connected to a setup for the measurement of 5-aminolevulinic acid (5-ALA) induced fluorescence and microvascular blood flow. Along three stereotactic trajectories, fluorescence (n = 109) and laser Doppler flowmetry (LDF) (n = 144) measurements were done in millimeter increments. The recorded signals were compared to histopathology and radiology images. The median ratio of protoporphyrin IX (PpIX) fluorescence and autofluorescence (AF) in the tumor was considerably higher than the marginal zone (17.3 vs 0.9). The blood flow showed two high spots (3%) in total. The proposed setup allows simultaneous and real-time detection of tumor tissue and microvascular blood flow for tracking the vessels.

[Awake craniotomy for brain tumours]. / Vakenkirurgi vid låggradiga gliom rekommenderas - Goda resultat av 7 års erfarenheter i Linköping.

Awake craniotomy for brain tumours  Awake neurosurgery is a useful method in lesions near eloquent brain areas, particularly low-grade gliomas.The aim is to maximise tumour resection and preserve neurological function. We performed 40 primary awake surgeries and 8 residual surgeries. Patients were operated awake throughout the procedure or with a laryngeal mask and general anaesthesia during the opening stage and then awake during intracerebral surgery. Language and motor function were mapped with direct cortical stimulation, motor evoked potential and standardised neurological testing. Radiologically, complete resection was achieved in 18 out of 40 patients in the primary surgeries. Full neurological recovery at three months was observed in 29 patients. Of the 11 patients with persisting neurological deficits at three months, symptoms were present preoperatively in 9 patients. We conclude that awake surgery, combined with intraoperative neurophysiological methods, is a safe method to improve treatment for low-grade gliomas.

TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma.

Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNP's, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.