Wait-and-scan management in sporadic Koos grade 4 vestibular schwannomas: A longitudinal volumetric study.

Background: Volumetric natural history studies specifically on large vestibular schwannomas (VSs), commonly classified as Koos grade 4, are lacking. The aim of the current study is to present the volumetric tumor evolution in sporadic Koos grade 4 VSs and possible predictors for tumor growth. Methods: Volumetric tumor measurements and tumor evolution patterns from serial MRI studies were analyzed from selected consecutive patients with Koos grade 4 VS undergoing initial wait-and-scan management between January 2001 and July 2020. The significant volumetric threshold was defined as a change in volume of ≥10%. Results: Among 215 tumors with a median size (IQR) of 2.7 cm3 (1.8-4.2), 147 tumors (68%) demonstrated growth and 75 tumors (35%) demonstrated shrinkage during follow-up. Growth-free survival rates (95% CI) at 1, 2, 5, and 10 years were 55% (48-61), 36% (29-42), 29% (23-36), and 28% (21-34), respectively and did not significantly differ in tumors> 20 mm (Chi-square = .40; P-value = .53). Four tumor evolution patterns (% of total) were observed: continued growth (60); initial growth then shrinkage (7); continued shrinkage (27); and stability (5). Good hearing (adjusted HR 2.21, 95% CI 1.48-3.30; P < .001) and peritumoral edema (adjusted HR 2.22, 95% CI 1.18-4.13; P = .01) at diagnosis were significantly associated with an increased likelihood of growth. Conclusions: Koos grade 4 VSs show a wide variety in size and growth. Due to variable growth patterns, an initial wait-and-scan strategy with short scan intervals may be an acceptable option in selected tumors, if no significant clinical symptoms of mass effect that warrant treatment are present.

Regional healthy brain activity, glioma occurrence and symptomatology.

It is unclear why exactly gliomas show preferential occurrence in certain brain areas. Increased spiking activity around gliomas leads to faster tumour growth in animal models, while higher non-invasively measured brain activity is related to shorter survival in patients. However, it is unknown how regional intrinsic brain activity, as measured in healthy controls, relates to glioma occurrence. We first investigated whether gliomas occur more frequently in regions with intrinsically higher brain activity. Second, we explored whether intrinsic cortical activity at individual patients' tumour locations relates to tumour and patient characteristics. Across three cross-sectional cohorts, 413 patients were included. Individual tumour masks were created. Intrinsic regional brain activity was assessed through resting-state magnetoencephalography acquired in healthy controls and source-localized to 210 cortical brain regions. Brain activity was operationalized as: (i) broadband power; and (ii) offset of the aperiodic component of the power spectrum, which both reflect neuronal spiking of the underlying neuronal population. We additionally assessed (iii) the slope of the aperiodic component of the power spectrum, which is thought to reflect the neuronal excitation/inhibition ratio. First, correlation coefficients were calculated between group-level regional glioma occurrence, as obtained by concatenating tumour masks across patients, and group-averaged regional intrinsic brain activity. Second, intrinsic brain activity at specific tumour locations was calculated by overlaying patients' individual tumour masks with regional intrinsic brain activity of the controls and was associated with tumour and patient characteristics. As proposed, glioma preferentially occurred in brain regions characterized by higher intrinsic brain activity in controls as reflected by higher offset. Second, intrinsic brain activity at patients' individual tumour locations differed according to glioma subtype and performance status: the most malignant isocitrate dehydrogenase-wild-type glioblastoma patients had the lowest excitation/inhibition ratio at their individual tumour locations as compared to isocitrate dehydrogenase-mutant, 1p/19q-codeleted glioma patients, while a lower excitation/inhibition ratio related to poorer Karnofsky Performance Status, particularly in codeleted glioma patients. In conclusion, gliomas more frequently occur in cortical brain regions with intrinsically higher activity levels, suggesting that more active regions are more vulnerable to glioma development. Moreover, indices of healthy, intrinsic excitation/inhibition ratio at patients' individual tumour locations may capture both tumour biology and patients' performance status. These findings contribute to our understanding of the complex and bidirectional relationship between normal brain functioning and glioma growth, which is at the core of the relatively new field of 'cancer neuroscience'.

Diagnosis, treatment and prognosis of otomastoiditis induced by Fusobacterium necrophorum: A retrospective multicentre cohort study.

OBJECTIVES: Otomastoiditis caused by the anaerobic Fusobacterium necrophorum (F. necrophorum) often induces severe complications, such as meningitis and sinus thrombosis. Early diagnosis is difficult, partly because little is known about specific early signs. Comprehensive research about clinically chosen antimicrobial therapy has not been done yet and prognostic information about otomastoiditis caused by F. necrophorum is scarce. More knowledge about this subject is required. METHODS: In this retrospective cohort study, we included all cases of otomastoiditis caused by F. necrophorum treated in two university medical centres in the Netherlands during the past 10 years. Data was gathered from patient records and analysed using independent sample T-tests and Chi2-tests. RESULTS: This study reveals that otomastoiditis caused by F. necrophorum potentially induces neurological sequelae. Thereby, 80% of all included patients (n = 16) needed readmission within six months due to recurrence or complications of otomastoiditis caused by F. necrophorum. Mean (range) of age, CRP and temperature were 4.5 years (0.9-29.3), 243 mg/L (113-423) and 40 °C (37-41). All patients were hospitalized and treated with antibiotics, mostly metronidazole (n = 13/16) and a ß -lactam (n = 15/16). Additional treatment contained low molecular weight heparin (83%, n = 10/12), dexamethasone (78%, n = 7/9) and/or surgery (80%, n = 12/16, whereof 9/12 mastoidectomy). CONCLUSIONS: Patients and/or their parents need to be informed about this potential unfortunate prognosis when otomastoiditis caused by F. necrophorum is diagnosed. To improve early diagnosis, otomastoiditis caused by F. necrophorum should be suspected and therefore immediately cultured when a) young children present with otomastoiditis, with b) high CRP values, and/or c) vomiting and decreased consciousness.

Understanding Global Brain Network Alterations in Glioma Patients.

Introduction: Glioma patients show increased global brain network clustering related to poorer cognition and epilepsy. However, it is unclear whether this increase is spatially widespread, localized in the (peri)tumor region only, or decreases with distance from the tumor. Materials and Methods: Weighted global and local brain network clustering was determined in 71 glioma patients and 53 controls by using magnetoencephalography. Tumor clustering was determined by averaging local clustering of regions overlapping with the tumor, and vice versa for non-tumor regions. Euclidean distance was determined from the tumor centroid to the centroids of other regions. Results: Patients showed higher global clustering compared with controls. Clustering of tumor and non-tumor regions did not differ, and local clustering was not associated with distance from the tumor. Post hoc analyses revealed that in the patient group, tumors were located more often in regions with higher clustering in controls, but it seemed that tumors of patients with high global clustering were located more often in regions with lower clustering in controls. Conclusions: Glioma patients show non-local network disturbances. Tumors of patients with high global clustering may have a preferred localization, namely regions with lower clustering in controls, suggesting that tumor localization relates to the extent of network disruption. Impact statement This work uses the innovative framework of network neuroscience to investigate functional connectivity patterns associated with brain tumors. Glioma (primary brain tumor) patients experience cognitive deficits and epileptic seizures, which have been related to brain network alterations. This study shows that glioma patients have a spatially widespread increase in global network clustering, which cannot be attributed to local effects of the tumor. Moreover, tumors occur more often in brain regions with higher network clustering in controls. This study emphasizes the global character of network alterations in glioma patients and suggests that preferred tumor locations are characterized by particular network profiles.

Postoperative oscillatory brain activity as an add-on prognostic marker in diffuse glioma.

INTRODUCTION: Progression-free survival (PFS) in glioma patients varies widely, even when stratifying for known predictors (i.e. age, molecular tumor subtype, presence of epilepsy, tumor grade and Karnofsky performance status). Neuronal activity has been shown to accelerate tumor growth in an animal model, suggesting that brain activity may be valuable as a PFS predictor. We investigated whether postoperative oscillatory brain activity, assessed by resting-state magnetoencephalography is of additional value when predicting PFS in glioma patients. METHODS: We included 27 patients with grade II-IV gliomas. Each patient's oscillatory brain activity was estimated by calculating broadband power (0.5-48 Hz) in 56 epochs of 3.27 s and averaged over 78 cortical regions of the Automated Anatomical Labeling atlas. Cox proportional hazard analysis was performed to test the predictive value of broadband power towards PFS, adjusting for known predictors by backward elimination. RESULTS: Higher broadband power predicted shorter PFS after adjusting for known prognostic factors (n = 27; HR 2.56 (95% confidence interval (CI) 1.15-5.70); p = 0.022). Post-hoc univariate analysis showed that higher broadband power also predicted shorter overall survival (OS; n = 38; HR 1.88 (95% CI 1.00-3.54); p = 0.038). CONCLUSIONS: Our findings suggest that postoperative broadband power is of additional value in predicting PFS beyond already known predictors.

Understanding cognitive functioning in glioma patients: The relevance of IDH-mutation status and functional connectivity.

INTRODUCTION: Cognitive deficits occur frequently in diffuse glioma patients, but are limitedly understood. An important marker for survival in these patients is isocitrate dehydrogenase (IDH) mutation (IDH-mut). Patients with IDH-mut glioma have a better prognosis but more often suffer from epilepsy than patients with IDH-wildtype (IDH-wt) glioma, who are generally older and more often have cognitive deficits. We investigated whether global brain functional connectivity differs between patients with IDH-mut and IDH-wt glioma, and whether this measure reflects variations in cognitive functioning in these subpopulations beyond the associated differences in age and presence of epilepsy. METHODS: We recorded magnetoencephalography and tested cognitive functioning in 54 diffuse glioma patients (31 IDH-mut, 23 IDH-wt). Global functional connectivity between 78 atlas regions spanning the entire cortex was calculated in two frequency bands (theta and alpha). Group differences in global functional connectivity were tested, as was their association with cognitive functioning, controlling for age, education, and presence of epilepsy. RESULTS: Patients with IDH-wt glioma had lower functional connectivity in the alpha band than patients with IDH-mut glioma (p = 0.040, corrected for age and presence of epilepsy). Lower alpha band functional connectivity was associated with poorer cognitive performance (p < 0.034), corrected for age, education, and presence of epilepsy. CONCLUSION: Global functional connectivity is lower in patients with IDH-wt diffuse glioma compared to patients with IDH-mut diffuse glioma. Moreover, having lower functional alpha connectivity relates to poorer cognitive performance in patients with diffuse glioma, regardless of age, education, and presence of epilepsy.

Oscillatory brain activity associates with neuroligin-3 expression and predicts progression free survival in patients with diffuse glioma.

INTRODUCTION: Diffuse gliomas have local and global effects on neurophysiological brain functioning, which are often seen as 'passive' consequences of the tumor. However, seminal preclinical work has shown a prominent role for neuronal activity in glioma growth: mediated by neuroligin-3 (NLGN3), increased neuronal activity causes faster glioma growth. It is unclear whether the same holds true in patients. Here, we investigate whether lower levels of oscillatory brain activity relate to lower NLGN3 expression and predict longer progression free survival (PFS) in diffuse glioma patients. METHODS: Twenty-four newly diagnosed patients with diffuse glioma underwent magnetoencephalography and subsequent tumor resection. Oscillatory brain activity was approximated by calculating broadband power (0.5-48 Hz) of the magnetoencephalography. NLGN3 expression in glioma tissue was semi-quantitatively assessed by immunohistochemistry. Peritumor and global oscillatory brain activity was then compared between different levels of NLGN3 expression with Kruskal-Wallis tests. Cox proportional hazards analyses were performed to estimate the predictive value of oscillatory brain activity for PFS. RESULTS: Patients with low expression of NLGN3 had lower levels of global oscillatory brain activity than patients with higher NLGN3 expression (P < 0.001). Moreover, lower peritumor (hazard ratio 2.17, P = 0.008) and global oscillatory brain activity (hazard ratio 2.10, P = 0.008) predicted longer PFS. CONCLUSIONS: Lower levels of peritumor and global oscillatory brain activity are related to lower NLGN3 expression and longer PFS, corroborating preclinical research. This study highlights the important interplay between macroscopically measured brain activity and glioma progression, and may lead to new therapeutic interventions in diffuse glioma patients.

Connectomic profile and clinical phenotype in newly diagnosed glioma patients.

Gliomas are primary brain tumors, originating from the glial cells in the brain. In contrast to the more traditional view of glioma as a localized disease, it is becoming clear that global brain functioning is impacted, even with respect to functional communication between brain regions remote from the tumor itself. However, a thorough investigation of glioma-related functional connectomic profiles is lacking. Therefore, we constructed functional brain networks using functional MR scans of 71 glioma patients and 19 matched healthy controls using the automated anatomical labelling (AAL) atlas and interregional Pearson correlation coefficients. The frequency distributions across connectivity values were calculated to depict overall connectomic profiles and quantitative features of these distributions (full-width half maximum (FWHM), peak position, peak height) were calculated. Next, we investigated the spatial distribution of the connectomic profile. We defined hub locations based on the literature and determined connectivity (1) between hubs, (2) between hubs and non-hubs, and (3) between non-hubs. Results show that patients had broader and flatter connectivity distributions compared to controls. Spatially, glioma patients particularly showed increased connectivity between non-hubs and hubs. Furthermore, connectivity distributions and hub-non-hub connectivity differed within the patient group according to tumor grade, while relating to Karnofsky performance status and progression-free survival. In conclusion, newly diagnosed glioma patients have globally altered functional connectomic profiles, which mainly affect hub connectivity and relate to clinical phenotypes. These findings underscore the promise of using connectomics as a future biomarker in this patient population.

Neural network alterations underlie cognitive deficits in brain tumor patients.

PURPOSE OF REVIEW: Brain tumor patients suffer from cognitive deficits, regardless of tumor grade or location. Deficits have a general character, falling in the domains of attention, working memory, information processing speed, and executive functioning. This review explores a new, brain network-based view of these deficits in brain tumor patients. RECENT FINDINGS: Network theory has evolved within the fields of mathematics and sociology and has resulted in its application to many complex systems, such as social networks, traffic flow networks, and biological protein networks. In the brain, a network can be constructed by assessing either functional or anatomical connections between brain areas, and subsequently extracting their overarching network patterns. Important brain network features are local specialization, operationalized by local clustering, and global integration or path length. Widespread disturbances in network topology are found in brain tumor patients, which relate to their cognitive problems. Furthermore, changes in network topology in response to oncological interventions, particularly tumor resection, go hand in hand with cognitive outcome. SUMMARY: Cognitive deficits in brain tumor patients are reflected in whole-brain network disturbances. Possible future clinical use of these findings mostly concerns prognostics and tailoring treatment strategies.

Functional differences in emotion processing during adolescence and early adulthood.

Adolescence is a transitional period between childhood and adulthood and is characterized by emotional instability. Underlying this behavior may be an imbalance between the limbic subcortical areas and the prefrontal cortex. Here, we investigated differences in these regions during adolescence and young adulthood. Fifty subjects aged 10 to 24 viewed and rated neutral, negative, and positive pictures (IAPS: International Affective Picture System), while being scanned with functional MRI. Only those trials in which there was a match between the subject's response and the IAPS rating were included in the analyses. Task performance (matching accuracy, reaction times) did not differ across age. Activity in the amygdala and hippocampus decreased with age when processing emotional salient stimuli versus neutral stimuli. In contrast, activation in the ventrolateral prefrontal cortex increased with age. Importantly, we show for the first time that these age-related changes are paralleled by an increase in functional coupling of the amygdala and hippocampus with the orbitofrontal cortex and ventrolateral prefrontal cortex. These findings are in line with the general notion that brain development from childhood to adulthood is characterized by a gradual increase in frontal control over subcortical regions. Understanding these developmental changes is important as these may underlie typical adolescent behavior.