A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4.

Malignant brain tumors, known as H3K27-altered diffuse midline glioma (DMG) and H3G34-mutant diffuse hemispheric glioma (DHG), can affect individuals of all ages and are classified as CNS WHO grade 4. We comprehensively characterized 390 H3F3A-mutant diffuse gliomas (201 females, 189 males) arising in pediatric patients (under 20 years old) and adults (20 years and older) evaluated by the CGP program at Foundation Medicine between 2013 and 2020. We assessed information from pathology reports, histopathology review, and clinical data. The cohort included 304 H3K27M-mutant DMG (156 females, 148 males) and 86 H3G34-mutant DHG (45 females, 41 males). Median patient age was 20 years (1-74 years). The frequency of H3K27M-mutant DMG was similar in both pediatric and adult patients in our cohort-48.6% of the patients were over 20 years old, 31.5% over 30, and 18% over 40 at initial diagnosis. FGFR1 hotspot point mutations (N546K and K656E) were exclusively identified in H3K27M-mutant DMG tumors (64/304, 21%; p = 0.0001); these tend to occur in older patients (median age: 32.5 years) and mainly arose in the diencephalon. H3K27M-mutant DMG had higher rates of mutations in NF1 (31.0 vs 8.1%; p = 0.0001) and PIK3CA/PIK3R1 (27.9% vs 15.1%; p = 0.016) compared to H3G34-mutant DHG. However, H3G34-mutant DHG had higher rates of targetable alterations in cell-cycle pathway genes (CDK4 and CDK6 amplification; CDKN2A/B deletion) (27.0 vs 9.0%). Potentially targetable PDGFRA alterations were identified in ~ 20% of both H3G34-mutant DHG and H3K27M-mutant DMG. Overall, in the present study H3K27M-mutant DMG occurred at similar rates in both adult and patient patients. Through our analysis, we were able to identify molecular features characteristic of DMG and DHG. By identifying the recurrent co-mutations including actionable FGFR1 point mutations found in nearly one-third of H3K27M-mutant DMG in young adults, our findings can inform clinical translational studies, patient diagnosis, and clinical trial design.

Comparison of Automatic Segmentation Algorithms for the Subthalamic Nucleus.

INTRODUCTION: Various automatic segmentation algorithms for the subthalamic nucleus (STN) have been published recently. However, most of the available software tools are not approved for clinical use. OBJECTIVE: The aim of this study is to evaluate a clinically available automatic segmentation tool of the navigation planning software Brainlab Elements (BL-E) by comparing the output to manual segmentation and a nonclinically approved research method using the DISTAL atlas (DA) and the Horn electrophysiological atlas (HEA). METHODS: Preoperative MRI data of 30 patients with idiopathic Parkinson's disease were used, resulting in 60 STN segmentations. The segmentations were created manually by two clinical experts. Automatic segmentations of the STN were obtained from BL-E and Advanced Normalization Tools using DA and HEA. Differences between manual and automatic segmentations were quantified by Dice and Jaccard coefficient, target overlap, and false negative/positive value (FNV/FPV) measurements. Statistical differences between similarity measures were assessed using the Wilcoxon signed-rank test with continuity correction, and comparison with interrater results was performed using the Mann-Whitney U test. RESULTS: For manual segmentation, the mean size of the segmented STN was 133 ± 24 mm3. The mean size of the STN was 121 ± 18 mm3 for BL-E, 162 ± 21 mm3 for DA, and 130 ± 17 mm3 for HEA. The Dice coefficient for the interrater comparison was 0.63 and 0.54 ± 0.12, 0.59 ± 0.13, and 0.52 ± 0.14 for BL-E, DA, and HEA, respectively. Significant differences between similarity measures were found for Dice and Jaccard coefficient, target overlap and FNV between BL-E and DA; and FPV between BL-E and HEA. However, none of the differences were significant compared to interrater variability. The analysis of the center of gravity of the segmentations revealed that the BL-E STN ROI was located more medially, superior and posterior compared to other segmentations. Regarding the target overlap for beta power within the STN ROI included with the HEA, the BL-E segmentation showed a significantly higher value compared to manual segmentation. CONCLUSION: Automatic image segmentation by means of the clinically approved software BL-E provides STN segmentations with similar accuracy like research tools, and differences are in the range of observed interrater variability. Further studies are required to investigate the clinical validity, for example, by comparing segmentation results of BL-E with electrophysiological data.

Parcellation of the Subthalamic Nucleus in Parkinson's Disease: A Retrospective Analysis of Atlas- and Diffusion-Based Methods.

BACKGROUND: Deep brain stimulation (DBS) is an established method of treatment for Parkinson's disease (PD). A stimulation sweet spot at the interface between the motor and associative clusters of the subthalamic nucleus (STN) has recently been postulated. The aim of this study was to analyze the available clustering methods for the STN and their correlation to outcome. METHODS: This is a retrospective analysis of a group of 20 patients implanted with a DBS device for PD. Atlas-based and diffusion tractography-based parcellation of the STN was performed. The distances of the electrode to the obtained clusters were compared to each other and to outcome parameters, which included levodopa equivalent dose (LED) reduction, Unified Parkinson's Disease Rating Scale (UPDRS)-III scores, and reduction in scores for items 32 and 36 of the UPDRS-IV. RESULTS: The implanted electrodes were located nearest to the motor clusters of the STN. The following significant associations with postoperative LED reduction were found: (1) distance of the electrode to the motor cluster in the Accolla and DISTAL atlases (p < 0.01) and (2) distance of the electrode to the supplementary motor area cluster (p = 0.02). There was no association with either the UPDRS-III or the UPDRS-IV score. CONCLUSIONS: The results of this study suggest the possibility that atlas-based clustering, as well as diffusion tractography-based parcellation, can be useful in estimating the stimulation target ("sweet spot") for STN-DBS in PD patients. Atlas-based as well as diffusion-based clustering might become a useful tool in DBS trajectory planning.

Radiographic assessment of contrast enhancement and T2/FLAIR mismatch sign in lower grade gliomas: correlation with molecular groups.

PURPOSE: With the updated World Health Organization (WHO) 2016 neuropathological diagnostic criteria, radiographic prognostic associations in lower-grade gliomas (LGG, WHO grade II and III) are undergoing re-evaluation. METHODS: We identified 316 LGG patients (151 grade II and 165 grade III) for a combined cohort from three independent databases. We analyzed the preoperative axial FLAIR, axial T2-weighted and post-gadolinium volumetric T1-weighted MR images. The molecular data collected included the status of IDH1/2, TP53, TERT promoter and ATRX mutations, in addition to 1p/19q co-deletions. In a subset of cases (n = 133), we assessed the "T2-FLAIR mismatch" sign. RESULTS: Gliomas were assigned to one of the three molecular groups: Group O (IDH-mutant, 1p/19q co-deleted oligodendrogliomas, n = 95), Group A (IDH-mutant, ATRX inactivated astrocytomas, n = 175) and Group G (IDH wild-type, GBM-like, n = 46). A contrast-enhancing tumor was seen in 98 patients (31%), most frequently in Group G (n = 28/45, 57%), when compared to Group A (n = 49/175, 28%) and Group O (n = 24/95, 25.3%) tumors (p = 0.008 and p = 0.0011, respectively). Consistent with previous reports, T2-FLAIR mismatch was preferentially found in Group A tumors (73.1%, 60 of 82), although its presence was not associated with survival, after controlling for molecular group. False positive mismatch sign was noted in 28.5% (12/42) Group O tumors, but none of the tumors in Group G. A combination of all three factors: age under 40 years at first diagnosis, a tumor size larger than 6 cm and T2-FLAIR mismatch was highly specific for IDH mutant astrocytoma (Group A). CONCLUSION: We identify radiographic correlates of molecular groups in lower-grade gliomas, which join clinical demographic features in defining the characteristic presentation of these tumors. Radiographic correlates of prognosis in LGG require re-evaluation within molecular group.

Clinical Validation of Quality Improvements Using the Six Sigma Concept: A Case Study for Deep Brain Stimulation in Parkinson's Disease.

BACKGROUND: The Six Sigma concept allows for the evaluation of quality changes after the implementation of new technical equipment or adjustment of perioperative procedures. Exemplarily, we applied this method for quality assessment in deep brain stimulation surgery (DBS) for Parkinson's disease. METHODS: The medical procedure and possible errors were registered. Then, 6 critical-to-quality characteristics regarding clinical outcome, surgical precision, and the surgical process were measured. The surgical procedure was then optimized in 2 steps, and its measurement, along with the analysis, was repeated twice. RESULTS: By optimizing perioperative settings, the operation time could be reduced, and the precision of the lead placement could be increased. Clinical outcome, as measured by improvement in UPDRS-III, IV, and reduction of medication could also be improved with smaller required stimulation voltage. With directional leads considerable reduction of medication was achieved in 97% of patients (σ-value 3.39) compared to 83.7% (σ-value 2.53) with nondirectional leads. CONCLUSION: This study shows that the Six Sigma concept is a suitable quality tool to analyze and improve treatment quality of complex medical procedures such as lead positioning in DBS surgery in clinical routine. Our results suggest that directional leads in subthalamic nucleus DBS may have a favorable impact on patients' outcome.

Somatosensory functional MRI tractography for individualized targeting of deep brain stimulation in patients with chronic pain after brachial plexus injury.

BACKGROUND: The optimal targets for deep brain stimulation (DBS) in patients with refractory chronic pain are not clearly defined. We applied sensory functional MRI (fMRI)- and diffusion tensor imaging (DTI)-based DBS in chronic pain patients into 3 different targets to ascertain the most beneficial individual stimulation site. METHODS: Three patients with incapacitating chronic pain underwent DBS into 3 targets (periventricular gray (PVG), ventroposterolateral thalamus (VPL), and posterior limb of the internal capsule according to fMRI and DTI (PLIC). The electrodes were externalized and double-blinded tested for several days. Finally, the two electrodes with the best pain reduction were kept for permanent stimulation. The patients were then followed up for 12 months. Outcome measures comprised the numerical rating scale (NRS), short-form McGill's score (SF-MPQ), and health-related quality of life (SF-36). RESULTS: Continuous pain (mean NRS 6.6) was reduced to NRS 3.6 after 12 months. Only with stimulation of the PLIC pain attacks, that occurred at least 3 times a week (mean NRS 9.6) resolved in 2 patients and improved in one patient concerning both intensity (NRS 5) and frequency (twice a month). The mean SF-MPQ decreased from 92.7 to 50. The health-related quality of life improved considerably. CONCLUSION: fMRI- and DTI-based DBS to the PLIC was the only target with a significant effect on pain attacks and seems to be the most promising target in chronic pain patients after brachial plexus injury. The combination with PVG or VPL can further improve patients' outcome especially in terms of reducing the continuous pain.

Enhancing tumor apparent diffusion coefficient histogram skewness stratifies the postoperative survival in recurrent glioblastoma multiforme patients undergoing salvage surgery.

Objective To determine the value of apparent diffusion coefficient (ADC) histogram parameters for the prediction of individual survival in patients undergoing surgery for recurrent glioblastoma (GBM) in a retrospective cohort study. Methods Thirty-one patients who underwent surgery for first recurrence of a known GBM between 2008 and 2012 were included. The following parameters were collected: age, sex, enhancing tumor size, mean ADC, median ADC, ADC skewness, ADC kurtosis and fifth percentile of the ADC histogram, initial progression free survival (PFS), extent of second resection and further adjuvant treatment. The association of these parameters with survival and PFS after second surgery was analyzed using log-rank test and Cox regression. Results Using log-rank test, ADC histogram skewness of the enhancing tumor was significantly associated with both survival (p = 0.001) and PFS after second surgery (p = 0.005). Further parameters associated with prolonged survival after second surgery were: gross total resection at second surgery (p = 0.026), tumor size (0.040) and third surgery (p = 0.003). In the multivariate Cox analysis, ADC histogram skewness was shown to be an independent prognostic factor for survival after second surgery. Conclusion ADC histogram skewness of the enhancing lesion, enhancing lesion size, third surgery, as well as gross total resection have been shown to be associated with survival following the second surgery. ADC histogram skewness was an independent prognostic factor for survival in the multivariate analysis.

Genetic characterization and mutational profiling of foramen magnum meningiomas: a multi-institutional study.

OBJECTIVE: Foramen magnum (FM) meningiomas pose significant surgical challenges and have high morbidity and mortality rates. This study aimed to investigate the distribution of clinically actionable mutations in FM meningiomas and identify clinical characteristics associated with specific mutational profiles. METHODS: The authors conducted targeted next-generation sequencing of 62 FM meningiomas from three international institutions, covering all relevant meningioma genes (AKT1, KLF4, NF2, POLR2A, PIK3CA, SMO, TERT promoter, and TRAF7). Patients with a radiation-induced meningioma or neurofibromatosis type 2 (NF2) were excluded from the study. Additionally, patient and tumor characteristics, including age, sex, radiological features, and tumor location, were retrospectively collected and evaluated. RESULTS: The study cohort consisted of 46 female and 16 male patients. Clinically significant driver mutations were detected in 58 patients (93.5%). The most commonly observed alteration was TRAF7 mutations (26, 41.9%), followed by AKT1E17K mutations (19, 30.6%). Both mutations were significantly associated with an anterolateral tumor location relative to the brainstem (p = 0.0078). NF2 mutations were present in 11 cases (17.7%) and were associated with posterior tumor location, in contrast to tumors with TRAF7 and AKT1E17K mutations. Other common mutations in FM meningiomas included POLR2A mutations (8, 12.9%; 6 POLR2AQ403K and 2 POLR2AH439_L440del), KLF4K409Q mutations (7, 11.3%), and PIK3CA mutations (4, 6.5%; 2 PIK3CAH1047R and 2 PIK3CAE545K). POLR2A and KLF4 mutations exclusively occurred in female patients and showed no significant association with specific tumor locations. All tumors harboring AKT1E17K and POLR2A mutations displayed meningothelial histology. Ten tumors exhibited intratumoral calcification, which was significantly more frequent in NF2-mutant compared with AKT1-mutant FM meningiomas (p = 0.047). CONCLUSIONS: These findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, volume, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.

Distant white-matter diffusion changes caused by tumor growth.

OBJECTIVES: Various reports have suggested that the involvement of normal-looking white matter with tumors is not limited to just signal abnormalities detectable on conventional imaging. Thus, the purpose of this study was to investigate the distant effects of glioblastomas and metastases on white matter using diffusion tensor imaging (DTI). MATERIALS AND METHODS: Data for 21 patients harboring a glioblastoma (n=12) or a metastasis (n=9) located at a distance of smaller or equal to 10mm from a DTI-based reconstruction of the pyramidal tract were analyzed, using regions of interest (ROIs) placed along the pyramidal tracts in the cerebral peduncle distant (>15 mm) from the tumor. RESULTS: For the whole study population, fractional anisotropy (FA) was significantly lower on the side ipsilateral to the tumor (P<0.001), a difference that was also observed in the glioblastoma and metastasis subgroups. The trace value was significantly higher on the ipsilateral side in the whole population and metastasis subgroup, but not in the glioblastoma subgroup. The decrease in FA and the trace value increase were significant in a subgroup of patients with motor deficits, but not in those without such deficits. CONCLUSION: Hemispheric glioblastomas and metastases located close to the pyramidal tract induce diffusion changes in the tract that are observable at a distance of greater than 15 mm from the tumor border in the absence of T2 signal changes. These changes are different in glioblastomas and metastases, and mechanisms other than Wallerian degeneration may be contributing to the observed changes.

Anatomy of the supraventricular portion of the pyramidal tract.

BACKGROUND: The anatomy and somatotopy of the pyramidal tract during its course in the internal capsule has recently been discussed by many publications. However, the reports on the anatomy of the clinically more important supraventricular portion of the tract are scarce. The objective of this study is to investigate the anatomy and somatotopy of the supraventricular portion of the pyramidal tract. METHODS: In 13 patients undergoing surgery with subcortical electric stimulation for tumors located in the supraventricular white matter close to the pyramidal tract (as depicted by diffusion tensor tracking [DTT]), the relationship between the position of the stimulation point and the motor response in the arm or leg was analyzed. Additionally, the somatotopic organization of the tract was studied using separate tracking of arm and leg fibers in 20 healthy hemispheres. Finally, the course of the tract was studied by dissecting 15 previously frozen human hemispheres. RESULTS: In most cases, subcortical stimulation during the resection of tumors located behind and in front of the pyramidal tract elicited leg and arm movement, respectively. This association of stimulation point position with motor response type was significant. A DTT study of the somatotopy demonstrated a varying degree of rotation of the leg and arm fibers from mediolateral to posteroanterior configuration. Anatomic dissections demonstrated a folding-fan like structure of the pyramidal tract with a similar rotation pattern. CONCLUSION: The pyramidal tract undergoes a large part of its rotation from mediolateral to posteroanterior configuration during its course in the supraventricular white matter, although interindividual differences exist.

Improved efficiency of patient admission with electronic health records in neurosurgery.

BACKGROUND: Electronic health records (EHRs) may be controversial but they have the potential to improve patient care. We investigated whether the introduction of an electronic template-based admission form for the collection of information about the patient's medical history and neurological and clinical state at admission in the neurosurgical unit might have an impact on the quality of documentation in a discharge record and the amount of time taken to produce this documentation. METHOD: A new digital template-based admission form (EHR) was developed and assessed with QNOTE, an assessment tool of medical notes with standardised criteria and the possibility to benchmark the quality of documentations. This was compared to 30 prior paper-based handwritten documentations (HWD) regarding the utilisation of these medical notes for dictation of medical discharge records. RESULTS: Implementation of the EHR significantly improved the quality of patient admission documentation with a QNOTE mean grand score of 87 ± 22 (p < 0.0001) compared to prior HWD with 44 ± 30. The mean documentation time for HWD was 8.1 min ± 4.1 min and the dictation time for discharge records was 10.6 min ± 3.5 min. After implementation of EHR, the documentation time increased slightly to 9.6 min ± 2.3 min (n.s.), while the time for dictation of discharge records was reduced to 5.1 min ± 1.2 min (p < 0.0001). There was a clear correlation between a higher quality of documentation and a higher needed documentation time as well as higher quality of documentation and lower dictation times of discharge records. CONCLUSION: Implementation of the EHR improved the quality of patient admission documentation and reduced the dictation time of discharge records. IMPLICATIONS: It is crucial to involve stakeholders and users of EHRs in a timely manner during the stage of development and implementation phase to ensure optimal results and better usability.

Identification of the large descending tracts using diffusion tensor imaging in Chiari III malformation.

INTRODUCTION: The paper focuses on the use of diffusion tensor imaging (DTI) in the evaluation of one case of Chiari III malformation. CASE REPORT: In the case discussed, DTI was used to delineate the position of large descending tracts within the malformation and the reconstructed images were used to plan the surgical procedure. DISCUSSION: The clinical and imaging findings, the technical aspects of the DTI fiber tract reconstruction and the outcome are summarized.

Exome sequencing identifies frequent genomic loss of TET1 in IDH-wild-type glioblastoma.

Glioblastoma (GBM) is the most common and malignant brain tumor in adults. Genomic and epigenomic alterations of multiple cancer-driving genes are frequent in GBM. To identify molecular alterations associated with epigenetic aberrations, we performed whole exome sequencing-based analysis of DNA copy number variations in 55 adult patients with IDH-wild-type GBM. Beside mutations in common GBM driver genes such as TERTp (76%), TP53 (22%) and PTEN (20%), 67% of patients were affected by amplifications of genes associated with RTK/Rb/p53 cell signaling, including EGFR (45%), CDK4 (13%), and MDM2/4 (both 7%). The minimal deleted region at chromosome 10 was detected at the DNA demethylase TET1 (93%), mainly due to a loss-of-heterozygosity of complete chromosome 10 (53%) or by a mono-allelic microdeletion at 10q21.3 (7%). In addition, bi-allelic TET1 deletions, detected in 18 patients (33%), frequently co-occurred with EGFR amplification and were associated with low levels of TET1 mRNA expression, pointing at loss of TET1 activity. Bi-allelic TET1 loss was not associated with global concentrations of 5-hydroxymethylcytosine, indicating a site-specific effect of TET1 for DNA (de)methylation. Focal amplification of EGFR positively correlated with overall mutational burden, tumor size, and poor long-term survival. Bi-allelic TET1 loss was not an independent prognostic factor, but significantly associated with poor survival in patients with concomitant EGFR amplification. Rates of genomic TET1 deletion were significantly lower in a cohort of IDH1-mutated patients. Despite the relevance of TET1 for DNA demethylation and as potential therapeutic target, a frequent genomic loss of TET1 has not previously been reported in GBM.

Validity of primary motor area localization with fMRI versus electric cortical stimulation: a comparative study.

BACKGROUND: Functional magnetic resonance imaging (fMRI) is a widely used method for research and visualization of the brain function. However, its clinical use is still limited. Our objective was to study fMRI reliability in localizing the primary hand motor cortex (M1) under pathological conditions caused by the proximity of a brain tumour. The results were then compared with standard technique of cortical function mapping-electric cortical stimulation (ECS). METHOD: We compared M1 areas localized with the fMRI and ECS in 18 patients with brain tumours in fronto-parietal regions. The 1.5 T blood oxygenation-level dependent (BOLD) fMRI was performed preoperatively using a motor task involving rhythmic touching of the thumb consecutively with other fingers on the same hand contralateral to the affected hemisphere. Each individual fMRI result was displayed at the P < 0.05 significance level corrected for family wise error (more conservative approach) or at the P < 0.001 level uncorrected (less conservative approach) and projected on the T1-weighted image used for neuronavigation. FINDINGS: In 12 patients (66.6%) we found full agreement between the fMRI and ECS. In 3 patients (16.6%) the overlap was only partial, with one ECS testing position on motor response found outside the BOLD signal cluster. In another 3 cases (16.6%) there was a discrepancy between the two methods. The fMRI sensitivity for localizing the ECS reactive M1 cortex was 71%. The fMRI/ECS consistency was within a 5-mm range in 77% of the testing positions used for ECS which complies with the inherent accuracy of the navigation system. CONCLUSIONS: Because the overlap between the two methods never exceeded 10-mm, we found that the fMRI method correctly guided the ECS to the M1 cortex in 83% of patients. Infiltrative growth of the tumour and collateral oedema were the reasons for the BOLD signal suppression in three patients. Our results support using ECS as a more reliable tool for M1 cortical mapping than fMRI.

Olfactory bulb volume changes associated with trans-sphenoidal pituitary surgery.

OBJECTIVE: The trans-sphenoidal approach is most frequently used for pituitary adenoma (PA) enucleation. However, effects of this surgery on neighboring structures have received little attention so far. In particular, no investigations on olfactory bulb (OB) anatomy after trans-sphenoidal surgery have been reported. Because impairment of olfaction has been shown in small groups following trans-sphenoidal surgery we hypothesized that the transnasal approach is likely to alter OB volume which is associated with changes of olfactory function. METHODS: The study comprised 33 patients with pituitary adenoma (14 women and 19 men, mean age 50 years). Comprehensive assessment of olfactory function was conducted with the "Sniffin' Sticks" test kit. Based on magnetic resonance imaging scans OBs were measured before and approximately one year after trans-sphenoidal PA enucleation. RESULTS: Owing to postoperative non-compliance and MRI artifacts partly due to drill friction complete evaluation of "Sniffin' Sticks" in term of obtaining the TDI score was possible pre- and postoperatively in 21 patients whereas OB volumes were available in 32 patients. Approximately one year after surgery olfactory function was not significantly different from baseline. However, left- and right-sided OB volume in patients treated via trans-sphenoidal surgery decreased (p = 0.001). The side of the surgical approach did not affect OB volume in a side-specific manner. Changes in odor threshold were significantly correlated to changes in right-sided OB volume (r = 0.45, p = 0.024). CONCLUSION: Overall olfactory performance one year after surgery was not significantly different from baseline. However, changes in OB volume are associated with changes in olfactory performance and OB volumes decreased in patients.

TERT Promoter Mutation Detection in Cell-Free Tumor-Derived DNA in Patients with IDH Wild-Type Glioblastomas: A Pilot Prospective Study.

Purpose: We conducted a pilot study to assess the feasibility and the potential implications of detecting TERT promoter (TERTp)-mutant cell-free tumor-derived DNA (tDNA) in the cerebrospinal fluid (CSF) and plasma of glioblastoma patients.Experimental Design: Matched CSF and plasma samples were collected in 60 patients with glial tumors. The CSF collection was obtained during surgery, before any surgical manipulation of the tumor. The extracted tDNA and corresponding tumor DNA samples were analyzed for TERTp and isocitrate dehydrogenase (IDH) hotspot mutations. In addition, the variant allele frequency (VAF) of TERTp mutation in the CSF-tDNA was correlated with tumor features and patients' outcome.Results: Thirty-eight patients had TERTp-mutant/IDH wild-type glioblastomas. The matched TERTp mutation in the CSF-tDNA was successfully detected with 100% specificity (95% CI, 87.6-100%) and 92.1% sensitivity (95% CI, 78.6-98.3%) (n = 35/38). In contrast, the sensitivity in the plasma-tDNA was far lower [n = 3/38, 7.9% (95% CI, 1.6-21.4%)]. We concordantly observed a longer overall survival of patients with low VAF in the CSF-tDNA when compared with patients with high VAF, irrespective of using the lower quartile VAF [11.45%; 14.0 mo. (95% confidence interval, CI, 10.3-17.6) vs. 8.6 mo. (95% CI, 4.1-13.2), P = 0.035], the lower third VAF [13%; 15.4 mo. (95% CI, 11.6-19.2) vs. 8.3 mo. (95% CI, 2.3-14.4), P = 0.008], or the median VAF [20.3%; 14.0 mo. (95% CI, 9.2-18.7) vs. 8.6 mo. (95% CI, 7.5-9.8), P = 0.062] to dichotomize the patients.Conclusions: This pilot study highlights the value of CSF-tDNA for an accurate and reliable detection of TERTp mutations. Furthermore, our findings suggest that high TERTp mutation VAF levels in the CSF-tDNA may represent a suitable predictor of poor survival in glioblastoma patients. Further studies are needed to complement the findings of our exploratory analysis. Clin Cancer Res; 24(21); 5282-91. ©2018 AACR.

Probabilistic Tractography of the Cranial Nerves in Vestibular Schwannoma.

OBJECTIVE: Multiple recent studies have reported on diffusion tensor-based fiber tracking of cranial nerves in vestibular schwannoma, with conflicting results as to the accuracy of the method and the occurrence of cochlear nerve depiction. Probabilistic nontensor-based tractography might offer advantages in terms of better extraction of directional information from the underlying data in cranial nerves, which are of subvoxel size. METHODS: Twenty-one patients with large vestibular schwannomas were recruited. The probabilistic tracking was run preoperatively and the position of the potential depictions of the facial and cochlear nerves was estimated postoperatively by 3 independent observers in a blinded fashion. The true position of the nerve was determined intraoperatively by the surgeon. Thereafter, the imaging-based estimated position was compared with the intraoperatively determined position. Tumor size, cystic appearance, and postoperative House-Brackmann score were analyzed with regard to the accuracy of the depiction of the nerves. RESULTS: The probabilistic tracking showed a connection that correlated to the position of the facial nerve in 81% of the cases and to the position of the cochlear nerve in 33% of the cases. Altogether, the resulting depiction did not correspond to the intraoperative position of any of the nerves in 3 cases. CONCLUSIONS: In a majority of cases, the position of the facial nerve, but not of the cochlear nerve, could be estimated by evaluation of the probabilistic tracking results. However, false depictions not corresponding to any nerve do occur and cannot be discerned as such from the image only.

Comparison of probabilistic and deterministic fiber tracking of cranial nerves.

OBJECTIVE The depiction of cranial nerves (CNs) using diffusion tensor imaging (DTI) is of great interest in skull base tumor surgery and DTI used with deterministic tracking methods has been reported previously. However, there are still no good methods usable for the elimination of noise from the resulting depictions. The authors have hypothesized that probabilistic tracking could lead to more accurate results, because it more efficiently extracts information from the underlying data. Moreover, the authors have adapted a previously described technique for noise elimination using gradual threshold increases to probabilistic tracking. To evaluate the utility of this new approach, a comparison is provided with this work between the gradual threshold increase method in probabilistic and deterministic tracking of CNs. METHODS Both tracking methods were used to depict CNs II, III, V, and the VII+VIII bundle. Depiction of 240 CNs was attempted with each of the above methods in 30 healthy subjects, which were obtained from 2 public databases: the Kirby repository (KR) and Human Connectome Project (HCP). Elimination of erroneous fibers was attempted by gradually increasing the respective thresholds (fractional anisotropy [FA] and probabilistic index of connectivity [PICo]). The results were compared with predefined ground truth images based on corresponding anatomical scans. Two label overlap measures (false-positive error and Dice similarity coefficient) were used to evaluate the success of both methods in depicting the CN. Moreover, the differences between these parameters obtained from the KR and HCP (with higher angular resolution) databases were evaluated. Additionally, visualization of 10 CNs in 5 clinical cases was attempted with both methods and evaluated by comparing the depictions with intraoperative findings. RESULTS Maximum Dice similarity coefficients were significantly higher with probabilistic tracking (p < 0.001; Wilcoxon signed-rank test). The false-positive error of the last obtained depiction was also significantly lower in probabilistic than in deterministic tracking (p < 0.001). The HCP data yielded significantly better results in terms of the Dice coefficient in probabilistic tracking (p < 0.001, Mann-Whitney U-test) and in deterministic tracking (p = 0.02). The false-positive errors were smaller in HCP data in deterministic tracking (p < 0.001) and showed a strong trend toward significance in probabilistic tracking (p = 0.06). In the clinical cases, the probabilistic method visualized 7 of 10 attempted CNs accurately, compared with 3 correct depictions with deterministic tracking. CONCLUSIONS High angular resolution DTI scans are preferable for the DTI-based depiction of the cranial nerves. Probabilistic tracking with a gradual PICo threshold increase is more effective for this task than the previously described deterministic tracking with a gradual FA threshold increase and might represent a method that is useful for depicting cranial nerves with DTI since it eliminates the erroneous fibers without manual intervention.

Daily drained CSF volume is a predictor for shunt dependence - A retrospective study.

OBJECTIVES: Acute hydrocephalus ensues from various intracranial processes and is usually treated using external ventricular drainage (EVD). After the acute phase, a clamp trial is usually performed to identify patients requiring permanent CSF shunting. The aim of our study was to identify simple and clinically accessible factors that can help predict the result of the EVD clamp trial. METHODS: 86 patients were selected for this retrospective analysis. Average CSF drained volume over 3 days given a constant EVD pressure level of 15 cm H2O and other clinical and laboratory parameters were statistically compared with the result of an EVD clamp trial. RESULTS: The univariate analysis identified significant differences between the groups of patients who failed or passed the EVD clamp trial for the mean daily drained volume over 3 days (Mann-Whitney U-test, p<0.01). In the multivariate logistic regression, the average daily CSF output over 3 days was also significant (p=0.02), no other significant factors could be identified. Using hierarchical clustering, the best threshold daily value for EVD clamp trial failure was found at 130 ml (mean daily drained CSF volume) with the sensitivity of 64.5% and specificity of 83.6% (chi-square 20.6, p<0.01). CONCLUSION: We have identified a simple, clinically available factor for identifying patients who are likely to fail the EVD clamp trial.

Evaluation of diffusion-tensor imaging-based global search and tractography for tumor surgery close to the language system.

Pre-operative planning and intra-operative guidance in neurosurgery require detailed information about the location of functional areas and their anatomo-functional connectivity. In particular, regarding the language system, post-operative deficits such as aphasia can be avoided. By combining functional magnetic resonance imaging and diffusion tensor imaging, the connectivity between functional areas can be reconstructed by tractography techniques that need to cope with limitations such as limited resolution and low anisotropic diffusion close to functional areas. Tumors pose particular challenges because of edema, displacement effects on brain tissue and infiltration of white matter. Under these conditions, standard fiber tracking methods reconstruct pathways of insufficient quality. Therefore, robust global or probabilistic approaches are required. In this study, two commonly used standard fiber tracking algorithms, streamline propagation and tensor deflection, were compared with a previously published global search, Gibbs tracking and a connection-oriented probabilistic tractography approach. All methods were applied to reconstruct neuronal pathways of the language system of patients undergoing brain tumor surgery, and control subjects. Connections between Broca and Wernicke areas via the arcuate fasciculus (AF) and the inferior fronto-occipital fasciculus (IFOF) were validated by a clinical expert to ensure anatomical feasibility, and compared using distance- and diffusion-based similarity metrics to evaluate their agreement on pathway locations. For both patients and controls, a strong agreement between all methods was observed regarding the location of the AF. In case of the IFOF however, standard fiber tracking and Gibbs tracking predominantly identified the inferior longitudinal fasciculus that plays a secondary role in semantic language processing. In contrast, global search resolved connections in almost every case via the IFOF which could be confirmed by probabilistic fiber tracking. The results show that regarding the language system, our global search is superior to clinically applied conventional fiber tracking strategies with results similar to time-consuming global or probabilistic approaches.