"Curtain-fall" technique for cerebrospinal fluid leak prevention after removal of intradural drainage. Technical note: application in chronic subdural hematoma surgery.

OBJECTIVE: Chronic subdural hematoma (CSDH) is frequently met in neurosurgical practice and often need urgent surgical treatment in case of neurological deterioration. Different surgical approaches to evacuate CSDH are described in the literature. In our experience, an external drainage system is crucial in order to avoid recurrences. We recently encountered a case of subcutaneous CSF collection after drainage removal. Thus, we developed a simple surgical technique to prevent postoperative CSF leak after subdural drainage system removal. METHOD: We have developed a technique in which the periosteum is harvested during the surgery prior to the evacuation of the hemorrhage and fixed with sutures on the uncut dura mater opposite and laterally to the exit of the catheter exiting the dural hole caused by the passage of the Jackson-Pratt subdural drainage system. When the drainage catheter is removed, the flap, partially held by the sutures, falls over the hole avoiding CSF leakage. By using this technique, the small dural hole will be covered with the periosteum allowing for natural closure and wound healing hence preventing CSF leakage. RESULTS: This technique was successfully employed in 21 patients who didn't develop postoperative CSF leakage following CSDH evacuation and removal of subdural drainage system. CONCLUSION: In this technical note, we describe a safe dura closure technique that we developed to help reduce the risk of postoperative CSF leakage following subdural drainage removal, which can, however, also be applied in all surgeries in which a catheter is placed in the subdural space.

UBE2C: A pan-cancer diagnostic and prognostic biomarker revealed through bioinformatics analysis.

BACKGROUND: The diverse and complex attributes of cancer have made it a daunting challenge to overcome globally and remains to endanger human life. Detection of critical cancer-related gene alterations in solid tumor samples better defines patient diagnosis and prognosis, and indicates what targeted therapies must be administered to improve cancer patients' outcome. MATERIALS AND METHODS: To identify genes that have aberrant expression across different cancer types, differential expressed genes were detected within the TCGA datasets. Subsequently, the DEGs common to all pan cancers were determined. Furthermore, various methods were employed to gain genetic alterations, co-expression genes network and protein-protein interaction (PPI) network, pathway enrichment analysis of common genes. Finally, the gene regulatory network was constructed. RESULTS: Intersectional analysis identified UBE2C as a common DEG between all 28 types of studied cancers. Upregulated UBE2C expression was significantly correlated with OS and DFS of 10 and 9 types of cancer patients. Also, UBE2C can be a diagnostic factor in CESC, CHOL, GBM, and UCS with AUC = 100% and diagnose 19 cancer types with AUC ≥90%. A ceRNA network constructed including UBE2C, 41 TFs, 10 shared miRNAs, and 21 circRNAs and 128 lncRNAs. CONCLUSION: In summary, UBE2C can be a theranostic gene, which may serve as a reliable biomarker in diagnosing cancers, improving treatment responses and increasing the overall survival of cancer patients and can be a promising gene to be target by cancer drugs in the future.

Retrosigmoid Intradural Suprameatal Approach: 2-Dimensional Operative Video.

INDICATIONS CORRIDOR AND LIMITS OF EXPOSURE: The retrosigmoid intradural suprameatal approach is mostly indicated for tumors in the cerebellopontine angle extending toward the Meckel cave and supratentorial regions, most frequently meningiomas and schwannomas. This approach was first established by the senior author in 1982. ANATOMIC ESSENTIALS NEED FOR PREOPERATIVE PLANNING AND ASSESSMENT: Nervous structures: cranial nerves III to XII, cerebellum, and brainstem. Vascular structures: anterior inferior cerebellar artery, posterior inferior cerebellar artery, superior cerebellar artery, basilar artery, vertebral artery, transverse, sigmoid, and petrous sinus, petrosal vein/veins, basilar plexus, and the mastoid emissary vein. Bony structures: petrous bone with internal auditory canal, jugular foramen and suprameatal tubercle, petrous apex, dorsum sellae, and posterior clinoid process. Structures within the petrous bone: vestibule, semicircular canals, and jugular bulb. ESSENTIALS STEPS OF THE PROCEDURE: After a suboccipital retrosigmoid craniectomy in the semisitting position and debulking of the tumor mass in the cerebellopontine angle, extension is achieved by drilling suprameatal tubercle above cranial nerve VII and VIII toward the petrous apex. The extent of bone drilling is tailored for each patient. PITFALLS/AVOIDANCE OF COMPLICATIONS: Avoid damage to cranial nerves, arteries, and veins during drilling, dissection, and tumor removal or by retraction. VARIANTS AND INDICATIONS FOR THEIR USE: In case of extreme supratentorial extensions laterally and dorsally, the opening of the tentorium may be helpful. For inferior extensions toward the upper spinal canal, opening of the foramen magnum and hemilaminectomy of C1 may be necessary.The patient consented to the procedure and to the publication of his/her image. Institutional logo in title slide, © 2023, INI Hannover. Used with permission.

Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases ε and δ in glioma families.

Pathogenic germline variants in the DNA polymerase genes POLE and POLD1 cause polymerase proofreading-associated polyposis, a dominantly inherited disorder with increased risk of colorectal carcinomas and other tumors. POLE/POLD1 variants may result in high somatic mutation and neoantigen loads that confer susceptibility to immune checkpoint inhibitors (ICIs). To explore the role of POLE/POLD1 germline variants in glioma predisposition, whole-exome sequencing was applied to leukocyte DNA of glioma patients from 61 tumor families with at least one glioma case each. Rare heterozygous POLE/POLD1 missense variants predicted to be deleterious were identified in glioma patients from 10 (16%) families, co-segregating with the tumor phenotype in families with available DNA from several tumor patients. Glioblastoma patients carrying rare POLE variants had a mean overall survival of 21 months. Additionally, germline variants in POLD1, located at 19q13.33, were detected in 2/34 (6%) patients with 1p/19q-codeleted oligodendrogliomas, while POLE variants were identified in 2/4 (50%) glioblastoma patients with a spinal metastasis. In 13/15 (87%) gliomas from patients carrying POLE/POLD1 variants, features of defective polymerase proofreading, e.g. hypermutation, POLE/POLD1-associated mutational signatures, multinucleated cells, and increased intratumoral T cell response, were observed. In a CRISPR/Cas9-derived POLE-deficient LN-229 glioblastoma cell clone, a mutator phenotype and delayed S phase progression were detected compared to wildtype POLE cells. Our data provide evidence that rare POLE/POLD1 germline variants predispose to gliomas that may be susceptible to ICIs. Data compiled here suggest that glioma patients carrying POLE/POLD1 variants may be recognized by cutaneous manifestations, e.g. café-au-lait macules, and benefit from surveillance colonoscopy.

Dual Effects of Resveratrol on the Expression and Secretion of Angiogenic Factors.

Angiogenesis is an essential process in the growth, development, and transition of tumors from dormancy to proliferating state. Resveratrol (RSV), as a natural polyphenolic compound, is claimed to be effective in regulating angiogenesis. This study aimed to evaluate the impact of RSV onthe angiogenesis process in HUVECs (human umbilical vein endothelial cells) alone and co-cultured with Jurkat cells. The effects of RSV on HUVECs and Jurkat cell viability and apoptosis were measured by MTT and Annexin-V/PI methods. HUVECs were co-cultured with pre-treated Jurkat cells and incubated for 24 h, 48 h and 72 h. The angiogenesis process in HUVECs and Jurkat cells alone and in co-culture models was investigated by analyzing the expression of VEGF, VEGFR-2, and Interleukin-8 (IL-8) employing qPCR and ELISA. RSV at low concentration (40 µM) had no significant effects on apoptosis rate of HUVECs, but higher concentrations (80-160 µM) increased apoptosis in co-culture method and HUVECs alone. RSV significantly reduced VEGFR2 and IL-8 gene expression also, IL-8 protein concentration in HUVECs, but the effects of this drug in the HUVECs-Jurkats co-culture were different. Expression of VEGF in Jurkat cells increased following treatment with RSV. RSV had direct anti-angiogenic effects on HUVECs. Unexpectedly its indirect effects were not significant on HUVECs-Jurkats co-culture. Results of our study showed, RSV may be effective in anti-angiogenesis therapy, but in some situations, it may induce angiogenesis. So, appropriate concentrations should achieve to minimize the unpredicted effects of RSV.

AMG-232, a New Inhibitor of MDM-2, Enhance Doxorubicin Efficiency in Pre-B Acute Lymphoblastic Leukemia Cells.

Background: Doxorubicin (DOX)-induced cardiotoxicity appears to be a growing concern for extensive use in acute lymphoblastic leukemia (ALL). The new combination treatment strategies, therefore might be an effective way of decreasing its side effects as well as improving efficacy. AMG232 (KRT-232) is a potential MDM-2 inhibitor, increasing available p53 through disturbing p53-MDM-2 interaction. In this study, we examined the effects of AMG232 on DOX-induced apoptosis of NALM-6 cells. Methods: The anti-leukemic effects of Doxorubicin on NALM-6 cells, either alone or in combination with AMG232, were confirmed by MTT assay, Annexin/PI apoptosis assay, and cell cycle analysis. Expression of apoptosis and autophagy-related genes were further evaluated by Real time-PCR method. To investigate the effect of AMG232 on NALM-6 cells, the activation of p53, p21, MDM-2, cleaved Caspase-3 proteins was evaluated using western blot analysis. Results: The results showed that AMG232 inhibition of MDM-2 enhances Doxorubicin-induced apoptosis in NALM-6 cells through caspase-3 activation in a time and dose-dependent manner. Furthermore, co-treatment of AMG232 with Doxorubicin hampered the transition of NALM-6 cells from G1 phase through increasing p21 protein. In addition, this combination treatment led to enhanced expression of apoptosis and autophagy-related genes in ALL cell lines. Conclusion: The results declared that AMG232 as an MDM-2 inhibitor could be an effective approach to enhance antitumor effects of Doxorubicin on NALM-6 cells as well as an effective future treatment for ALL patients.

Differences in the MRI Signature and ADC Values of Diffuse Midline Gliomas with H3 K27M Mutation Compared to Midline Glioblastomas.

We conducted a two-center retrospective survey on standard MRI features including apparent diffusion coefficient mapping (ADC) of diffuse midline gliomas H3 K27M-mutant (DMG) compared to midline glioblastomas H3 K27M-wildtype (midGBM-H3wt). We identified 39 intracranial DMG and 18 midGBM-H3wt tumors. Samples were microscopically re-evaluated for microvascular proliferations and necrosis. Image analysis focused on location, peritumoral edema, degree of contrast enhancement and DWI features. Within DMG, MRI features between tumors with or without histomorphological GBM features were compared. DMG occurred in 15/39 samples from the thalamus (38%), in 23/39 samples from the brainstem (59%) and in 1/39 tumors involving primarily the cerebellum (2%). Edema was present in 3/39 DMG cases (8%) versus 78% in the control (midGBM-H3wt) group (p < 0.001). Contrast enhancement at the tumor rim was detected in 17/39 DMG (44%) versus 67% in control (p = 0.155), and necrosis in 24/39 (62%) versus 89% in control (p = 0.060). Strong contrast enhancement was observed in 15/39 DMG (38%) versus 56% in control (p = 0.262). Apparent diffusion coefficient (ADC) histogram analysis showed significantly higher skewness and kurtosis values in the DMG group compared to the controls (p = 0.0016/p = 0.002). Minimum relative ADC (rADC) values, as well as the 10th and 25th rADC-percentiles, were lower in DMGs with GBM features within the DMG group (p < 0.001/p = 0.012/p = 0.027). In conclusion, DMG cases exhibited markedly less edema than midGBM-H3wt, even if histomorphological malignancy was present. Histologically malignant DMGs and midGBM-H3wt more often displayed strong enhancement, as well as rim enhancement, than DMGs without histomorphological malignancy. DMGs showed higher skewness and kurtosis values on ADC-histogram analysis compared to midGBM-H3wt. Lower minimum rADC values in DMGs indicated malignant histomorphological features, likely representing a more complex tissue microstructure.

Case of multifocal glioblastoma with four fusion transcripts of ALK, FGFR2, NTRK2, and NTRK3 genes stresses the need for tumor tissue multisampling for transcriptomic analysis.

Glioblastoma multiforme (GBM) is the most malignant brain tumor with patient mortality rate close to 100%, 5-yr survival rate of ∼5%, and a median survival of 14 mo. GBMs have notorious histomorphologic and molecular heterogeneities thus giving hope for development of future personalized therapies. We describe here a case of a 48-yr-old male patient with three-nodular GBM. To address the question of intratumoral molecular heterogeneity, a comparative analysis of gene expression was performed by using multiple samples collected from different tumor sites with the aid of intraoperative magnetic resonance imaging (MRI). Sixteen GBM biosamples from parietal, temporal, and temporo-polar localizations were collected from primary, recurrent, and second recurrent tumors and were obtained and investigated by RNA sequencing. Our investigations revealed that biosamples derived from different tumor sites differ in their gene expression profiles with classical or mesenchymal signatures associated with clinically distinct molecular subtypes of GBM found within the same tumor. The results also showed significant differences in the expression of genes specific for targeted therapeutics. Our investigations have enabled the identification of four novel fusion transcripts-KIF5C-NTRK3, AC016907.2-ALK, CNTNAP3-NTRK2, and ZNF135-FGFR2-each present in only one sample. We found no differences between untreated and recurrent stages in the expression levels of genes involved in fusion transcripts, suggesting the lack of association between fusion transcript and treatment response. In contrast, longitudinal changes in the expression of VEGF and MGMT genes were concordant with the tumor response to bevacizumab and temozolomide. Our study underscores the importance of integrating a multisampling approach and RNA sequencing and demonstrates the predictive merit of an integrated approach for differentiating genomic aberrations associated with untreated or post-treatment recurrent GBMs.

Diffuse midline gliomas, H3 K27M-mutant are associated with less peritumoral edema and contrast enhancement in comparison to glioblastomas, H3 K27M-wildtype of midline structures.

PURPOSE: The entity 'diffuse midline glioma, H3 K27M-mutant (DMG)' was introduced in the revised 4th edition of the 2016 WHO classification of brain tumors. However, there are only a few reports on magnetic resonance imaging (MRI) of these tumors. Thus, we conducted a retrospective survey focused on MRI features of DMG compared to midline glioblastomas H3 K27M-wildtype (mGBM-H3wt). METHODS: We identified 24 DMG cases and 19 mGBM-H3wt patients as controls. After being retrospectively evaluated for microscopic evidence of microvascular proliferations (MVP) and tumor necrosis by two experienced neuropathologists to identify the defining histological criteria of mGBM-H3wt, the samples were further analyzed by two experienced readers regarding imaging features such as shape, peritumoral edema and contrast enhancement. RESULTS: The DMG were found in the thalamus in 37.5% of cases (controls 63%), in the brainstem in 50% (vs. 32%) and spinal cord in 12.5% (vs. 5%). In MRI and considering MVP, DMG were found to be by far less likely to develop peritumoral edema (OR: 0.13; 95%-CL: 0.02-0.62) (p = 0.010). They, similarly, were associated with a significantly lower probability of developing strong contrast enhancement compared to mGBM-H3wt (OR: 0.10; 95%-CL: 0.02-0.47) (P = 0.003). CONCLUSION: Despite having highly variable imaging features, DMG exhibited markedly less edema and lower contrast enhancement in MRI compared to mGBM-H3wt. Of these features, the enhancement level was associated with evidence of MVP.

Rare germline variants in the E-cadherin gene CDH1 are associated with the risk of brain tumors of neuroepithelial and epithelial origin.

The genetic basis of brain tumor development is poorly understood. Here, leukocyte DNA of 21 patients from 15 families with ≥ 2 glioma cases each was analyzed by whole-genome or targeted sequencing. As a result, we identified two families with rare germline variants, p.(A592T) or p.(A817V), in the E-cadherin gene CDH1 that co-segregate with the tumor phenotype, consisting primarily of oligodendrogliomas, WHO grade II/III, IDH-mutant, 1p/19q-codeleted (ODs). Rare CDH1 variants, previously shown to predispose to gastric and breast cancer, were significantly overrepresented in these glioma families (13.3%) versus controls (1.7%). In 68 individuals from 28 gastric cancer families with pathogenic CDH1 germline variants, brain tumors, including a pituitary adenoma, were observed in three cases (4.4%), a significantly higher prevalence than in the general population (0.2%). Furthermore, rare CDH1 variants were identified in tumor DNA of 6/99 (6%) ODs. CDH1 expression was detected in undifferentiated and differentiating oligodendroglial cells isolated from rat brain. Functional studies using CRISPR/Cas9-mediated knock-in or stably transfected cell models demonstrated that the identified CDH1 germline variants affect cell membrane expression, cell migration and aggregation. E-cadherin ectodomain containing variant p.(A592T) had an increased intramolecular flexibility in a molecular dynamics simulation model. E-cadherin harboring intracellular variant p.(A817V) showed reduced ß-catenin binding resulting in increased cytosolic and nuclear ß-catenin levels reverted by treatment with the MAPK interacting serine/threonine kinase 1 inhibitor CGP 57380. Our data provide evidence for a role of deactivating CDH1 variants in the risk and tumorigenesis of neuroepithelial and epithelial brain tumors, particularly ODs, possibly via WNT/ß-catenin signaling.

Atypical Teratoid/Rhabdoid Tumor (AT/RT) With Molecular Features of Pleomorphic Xanthoastrocytoma.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system tumor predominantly occurring in infants that may also arise in older children and adults. Rare secondary AT/RT developing from other tumors such as pleomorphic xanthoastrocytoma (PXA) are on record, but AT/RT presenting with molecular features of PXA have not been described. Here, we report 3 malignant central nervous system tumors in children (10, 13, and 18 y old). All tumors were located in the temporal lobe. In 2 cases, there was no history of a low-grade precursor lesion; in 1 case anaplastic PXA had been diagnosed 3 months earlier. Histopathologically, all tumors were composed of RT cells and showed frank signs of malignancy as well as loss of nuclear SMARCB1/INI1 protein expression. Two cases displayed homozygous deletions of the SMARCB1 region while the third case showed an exon 7 mutation (c.849_850delGT; p.Met283Ilefs*77). Of note, DNA methylation profiles did not group with AT/RT or other tumor entities using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-distributed stochastic neighbor embedding analysis and hierarchical clustering analysis, however, all tumors clearly grouped with PXA. Genome-wide copy number analysis revealed homozygous CDNK2A/B deletions and gains of whole chromosome 7. BRAF V600E mutations could be demonstrated in all cases. In conclusion, the possibility of AT/RT with molecular features of PXA needs to be taken into account and warrants molecular characterization of AT/RT especially in older children. Since treatments targeting mutated BRAF are available, identification of such cases may also have therapeutic consequences.

Data-Driven Identification of the Regions of Interest for Fiber Tracking in Patients with Brain Tumors.

BACKGROUND: We investigated the added value of combining information from direction-encoded color (DEC) maps with high-resolution structural magnetic resonance imaging scans (T1-weighted images [T1WIs]) to improve the identification of regions of interest (ROIs) for fiber tracking during preoperative planning for patients with brain tumors. METHODS: The dataset included 42 patients with gliomas and 10 healthy subjects from the Human Connectome Project. For identification of the ROIs, we combined the structural information from high-resolution T1WIs and the directional information from DEC maps. To test our hypothesis, we examined the interrater and intrarater agreement. RESULTS: We identified specific ROIs to extract the main white matter bundles. The directional information from the DEC maps combined with the T1WIs (T1WI-DEC maps) had significantly facilitated ROI identification in patients with brain tumors, especially patients in whom the tracts had been displaced by the mass effect of the tumor. Fiber tracking using the combined T1WI-DEC maps showed significantly greater inter- and intrarater agreement compared with using either T1WI or DEC maps alone. CONCLUSION: Combining the information from diffusion-derived color-encoded maps with high-resolution anatomical details from structural imaging (T1WI-DEC map), especially in patients with brain tumors, could be useful for accurate identification of the ROIs.

Library Preparation for Small RNA Transcriptome Sequencing in Patients Affected by Cerebral Cavernous Malformations.

Small RNA sequencing by Illumina's Next Generation technology has revolutionized the transcriptome analysis by facilitating massive parallel sequencing of RNA molecules at low cost. Illumina's Next Generation RNA sequencing is ideal for profiling small RNA (microRNAs, snoRNAs, and piRNAs) libraries in the identification of novel biomarkers for better clinical diagnosis. This method offers significant advantages when compared to microarray analysis with the ability to identify novel transcripts, higher sensitivity, specificity, and detection of rare and low-abundance transcripts. Small RNAs, including microRNAs and snoRNAs, belong to the class of small non-coding RNAs with 50-200 nucleotides in length and are involved in post-transcriptional regulation of gene expression. Executing Illumina's Next Generation Sequencing technology, we have recently deciphered microRNAs and snoRNAs expressed in cerebral cavernous malformations (CCMs). Small RNA library preparation is a prerequisite step prior to RNA sequencing for the identification of microRNAs and snoRNAs. Here, we describe stepwise small RNA library preparation starting from total RNA isolated from CCMs patient until library validation using the Illumina® TruSeq® Small RNA Sample preparation kit. We believe this method will shed light into the functional identification of other novel small non-coding RNAs in CCMs that awaits discovery.

Transformation of Hematopoietic Stem and Progenitor Cells by Leukemia Extracellular Vesicles: A Step Toward Leukemogenesis.

Regulation of hematopoietic stem and progenitor cells (HSPCs) self-renewal, expansion, and differentiation is an inevitable process for normal hematopoiesis in the bone marrow (BM) niche, where leukemia cells are born, proliferate and occupy the microenvironment. External mediators such as extracellular vesicles (EVs) shed from leukemia cells, are one of the most important cell to cell communicators, and leading to phenotype and genotype modification and subsequently, fate of the cell. This review highlights recent evidences about the possible roles of leukemia derived-EVs on maintenance, proliferation, and death of HSPCs in a same microenvironment as leukemia cells. In addition, it focuses on mechanisms involved in the transformation of BM niche in favor of leukemia microenvironment remodeling by leukemia derived-EVs.

The Fluctuations of Blood Oxygen Level-Dependent Signals as a Method of Brain Tumor Characterization: A Preliminary Report.

OBJECTIVE: In this study we present the nature and characteristic of the fluctuation of blood oxygen level-dependent (BOLD) signals measured from brain tumors. METHODS: Supratentorial astrocytomas, which were neither operated nor previously managed with chemotherapy or radiotherapy, were segmented, and the time series of the BOLD signal fluctuations were extracted. The mean (across patients) power spectra were plotted for the different World Health Organization tumor grades. One-way analysis of variance (ANOVA) was performed to identify significant differences between the power spectra of different tumor grades. Results were considered significant at P < 0.05. RESULTS: A total of 58 patients were included in the study. This group of patients included 1 patient with grade I glioma; 15 with grade II; 12 with grade III; and 30 with grade IV. The power spectra of the tumor time series were individually inspected, and all tumors exhibited high peaks at the lower frequency signals, but these were more pronounced in high-grade tumors. ANOVA showed a significant difference in power spectra between groups (P = 0.000). Post hoc analysis with Bonferroni correction showed a significant difference between grade II and grade III (P = 0.012) and grade IV (P = 0.000). There was no significant power spectra difference between grade III and IV tumors (P = 1). CONCLUSIONS: The power spectra of BOLD signals from tumor tissue showed fluctuations in the low-frequency signals and were significantly correlated with tumor grade. These signals could have a misleading effect when analyzing resting state functional magnetic resonance imaging and could be also viewed as a potential method of tumor characterization.

Inter-Network Functional Connectivity Changes in Patients With Brain Tumors: A Resting-State Functional Magnetic Resonance Imaging Study.

OBJECTIVE: Measuring functional connectivity (FC) and resting state networks (RSNs) using resting state functional magnetic resonance imaging is a method of preoperative planning in patients with brain tumors. However, the baseline FC and RSNs are altered in patients with brain tumors. In this study, we examined changes in inter-network FC in patients with brain tumors. METHODS: We performed region of interest (ROI) analysis of FC in 34 patients with supratentorial gliomas and 14 healthy subjects. We performed bivariate correlation analyses at the level of each subject. Resulting correlations were Fischer Z-transformed. The used nodes included 132 ROIs from the automated anatomical labeling atlas in addition to 32 ROIs representing the different functional brain networks. We investigated second-level effects by contrasting dummy encoded covariates representing the effects of group membership on functional connectivity. The significant 2-sided P value with corrected false discovery rate was set to 0.05. We set the t contrast between the group of patients with brain tumors and the group of healthy subjects to detect the effects of tumors on inter-network connectivity. RESULTS: Overall, the inter-network FC was significantly higher in patients with brain tumors compared with healthy subjects. The anterior and posterior cerebellar networks, as well as the supratentorial network, showed significantly higher connectivity in patients with brain tumors than in healthy subjects. CONCLUSION: Although brain tumors affect the FC and RSNs, the current study showed higher baseline inter-network connectivity in patients with brain tumors, which could indicate an intrinsic neural compensatory mechanism.

Intraoperative Resting-State Functional Connectivity and Resting-State Networks in Patients with Intracerebral Lesions: Detectability and Variations Between Sessions.

OBJECTIVE: To evaluate the functional connectivity (FC) and resting-state networks (RSNs) in patients under anesthesia operated for resection of intracerebral lesions. METHODS: We performed intraoperative resting-state functional magnetic resonance imaging (irs-fMRI) in 24 patients under anesthesia before and after lesion resection. Correlation matrices were established for each session (a total 48 of sessions). We analyzed the changes in overall FC and in FC of the healthy and operated hemispheres between the first and second sessions. We tested the correlation between changes in FC and clinical outcomes and the duration, rate, and total dosage of anesthesia. We also performed a group analysis to detect topographic changes in RSNs in patients under anesthesia. A single-subject analysis was performed to detect clinically relevant RSNs in each patient. RESULTS: FC decreased significantly in the second session, as did interhemispheric connectivity. The decrease in the pathological hemisphere was significant and significantly greater than the decrease in the intrahemispheric connectivity of the healthy hemisphere. The change in FC was not correlated with clinical outcome or with the duration, rate, or dosage of anesthesia. Group analysis showed topographic changes in RSNs, especially in high-level networks such as default mode and salience networks. Identification of clinically relevant networks was also possible. CONCLUSIONS: FC and RSNs could be identified under anesthesia and used for extended brain mapping. Further studies are needed to optimize the depth of hypnosis to stabilize FC between sessions.

Elderly Patients with Frontobasal and Suprasellar Meningiomas: Safety and Efficacy of Tumor Removal via Frontolateral Approach.

OBJECTIVE: Many neurosurgeons prefer conservative treatments in the elderly because of higher rates of mortality and morbidity after surgery. We aim to evaluate safety and efficacy of surgery in elderly patients with frontobasal and suprasellar meningiomas with a simple operative procedure, the frontolateral approach. METHODS: Retrospective analysis was made in consecutive patients with meningiomas operated via frontolateral approach. They were divided into 2 groups: elderly group (age ≥ 65 years) and young group (age < 65 years). Multivariate logistic regression analysis was performed for postoperative complications and Karnofsky Performance Scale score (KPS). RESULTS: The study comprises 128 patients operated over a 19-year period, of which 35 patients were in the elderly group and 93 patients were in the young group. More elderly patients presented with American Society of Anesthesiology (ASA) class II and III (57.1% vs. 43%). Gross resection was achieved in 31 cases in the elderly and 85 cases in young group (88.6% vs. 90.3%, P = 0.17). Postoperative KPS in both groups was improved (85.7% vs. 91.4%, P = 0.18). One death occurred in elderly group (2.9%, P = 0.27). Approach-related and medical morbidity in the elderly group was slightly higher than in the young group without significant difference (respectively, 11.4% and 14.3% vs. 9.7% and 8.6%, P = 0.18). Multivariate logistic regression showed increasing age was not associated with approach-related morbidity (odds ratio [OR]: 1.39, P = 0.53), medical morbidity (OR: 1.94, P = 0.88), and improvement of KPS (OR: 0.32, P = 0.25). CONCLUSIONS: Frontobasal and suprasellar meningiomas in elderly patients can be treated surgically with acceptably low morbidity and mortality rates via the frontolateral approach. Preoperative KPS score ≤60 and ASA classification ≥III predict an unfavorable postoperative outcome.

Imaging features and classification of peritumoral edema in vestibular schwannoma.

BACKGROUND: Peritumoral edema (PTE) is rarely present in patients with vestibular schwannomas (VS). We studied the correlation between radiological tumor characteristics and the presence of edema, describe its magnetic resonance imaging features and classify the different edema patterns. METHODS: We analysed 605 consecutive patients treated for VS at our Institute. PTE was found in 30 patients, studied on fluid attenuated inversion recovery sequences and categorised as involving the brachium pontis, cerebellum and/or brainstem. Tumor volume, shape, surface, internal structure and axis of growth were evaluated and compared to a matched series of 30 patients without PTE. RESULTS: In our population of patients, 5% showed PTE. Edema involved the brachium pontis in 22 cases (88%), cerebellum in 15 (60%) and brainstem in 3 (12%). PTE was classified as mild (one region involved), moderate (two regions) and severe (three regions). Edema was present not only perpendicular to the major tumor growth axis but also parallel to it (91%). The difference between the two groups in regards to tumor shape and surface was not significant. We found no correlation between tumor and edema volumes. CONCLUSIONS: VS can cause PTE, but its incidence is less frequent than in skull base meningiomas. PTE involves most frequently the brachium pontis, followed by the cerebellum and brainstem. Its occurrence correlates with tumor size but not with other radiological VS features. PTE is not always located perpendicular to the major axis of tumor growth, which indicated that the compressive theory proposed for meningiomas is not plausible explanation for its manifestation.

Transcriptome-wide Profiling of Cerebral Cavernous Malformations Patients Reveal Important Long noncoding RNA molecular signatures.

Cerebral cavernous malformations (CCMs) are low-flow vascular malformations in the brain associated with recurrent hemorrhage and seizures. The current treatment of CCMs relies solely on surgical intervention. Henceforth, alternative non-invasive therapies are urgently needed to help prevent subsequent hemorrhagic episodes. Long non-coding RNAs (lncRNAs) belong to the class of non-coding RNAs and are known to regulate gene transcription and involved in chromatin remodeling via various mechanism. Despite accumulating evidence demonstrating the role of lncRNAs in cerebrovascular disorders, their identification in CCMs pathology remains unknown. The objective of the current study was to identify lncRNAs associated with CCMs pathogenesis using patient cohorts having 10 CCM patients and 4 controls from brain. Executing next generation sequencing, we performed whole transcriptome sequencing (RNA-seq) analysis and identified 1,967 lncRNAs and 4,928 protein coding genes (PCGs) to be differentially expressed in CCMs patients. Among these, we selected top 6 differentially expressed lncRNAs each having significant correlative expression with more than 100 differentially expressed PCGs. The differential expression status of the top lncRNAs, SMIM25 and LBX2-AS1 in CCMs was further confirmed by qRT-PCR analysis. Additionally, gene set enrichment analysis of correlated PCGs revealed critical pathways related to vascular signaling and important biological processes relevant to CCMs pathophysiology. Here, by transcriptome-wide approach we demonstrate that lncRNAs are prevalent in CCMs disease and are likely to play critical roles in regulating important signaling pathways involved in the disease progression. We believe, that detailed future investigations on this set of identified lncRNAs can provide useful insights into the biology and, ultimately, contribute in preventing this debilitating disease.