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Alteration of default mode network: association with executive dysfunction in frontal glioma patients

Xiaokang Zhang, Guobin Zhang, Yonggang Wang, Huawei Huang, Haoyi Li, Mingxiao Li, Chuanwei Yang, Ming Li, Hongyan Chen, Bin Jing, and Song Lin

OBJECTIVE

Patients with frontal gliomas often experience executive dysfunction (EF-D) before surgery, and the changes in brain plasticity underlying this effect remain obscure. In this study, the authors aimed to assess whole-brain structural and functional alterations by using structural MRI and resting-state functional MRI (rs-fMRI) in frontal glioma patients with or without EF-D.

METHODS

Fifty-seven patients with frontal gliomas were admitted prospectively to the authors’ institution and assigned to one of two groups: 1) the normal executive function (EF-N) group and 2) the EF-D group, based on patient results for the Trail Making Test, Part B and Stroop Color-Word Test, Part C. Twenty-nine baseline-matched healthy controls were also recruited. All participants underwent multimodal MRI examination. Cortical surface thickness, surface-based resting-state activity (fractional amplitude of low-frequency fluctuation [fALFF] and regional homogeneity [ReHo]), and edge-based network functional connectivity (FC) were measured with FreeSurfer and fMRIPrep. The correlation between altered MRI parameters and executive function (EF) was assessed using Pearson correlation and receiver operating characteristic (ROC) analysis.

RESULTS

Demographic characteristics (sex, age, and education level) and clinical characteristics (location, volume, grade of tumor, and preoperative epilepsy) were not significantly different between the groups, but the Karnofsky Performance Scale score was worse in the EF-D group. There was no significant difference in cortical surface thickness between the EF-D and EF-N groups. In both low-grade and high-grade glioma patients the fALFF value (permutation test + threshold-free cluster enhancement, p value after family-wise error correction < 0.05) and ReHo value (t-test, p < 0.001) of the left precuneus cortex in the EF-D group were greater than those in the EF-N group, which were negatively correlated with EF (p < 0.05) and enabled prediction of EF (area under the ROC curve 0.826 for fALFF and 0.855 for ReHo, p < 0.001). Compared with the EF-N group, the FCs between the default mode network (DMN) from DMN node to DMN node (DMN-DMN) and from the DMN to the central executive network (DMN-CEN) in the EF-D group were increased significantly (network-based statistics corrected p < 0.05) and negatively correlated with EF (Pearson correlation, p < 0.05).

CONCLUSIONS

Apart from local disruption, the abnormally activated DMN in the resting state is related to EF-D in frontal glioma patients. DMN activity should be considered during preoperative planning and postoperative neurorehabilitation for frontal glioma patients to preserve EF.

Clinical trial registration no.: NCT03087838 (ClinicalTrials.gov)

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Impact of a cell cycle and an extracellular matrix remodeling transcriptional signature on tumor progression and correlation with EZH2 expression in meningioma

Benedito Jamilson Araújo Pereira, Antonio Marcondes Lerario, Paula Rodrigues Sola, Talita de Sousa Laurentino, Dipika R. Mohan, Antonio Nogueira de Almeida, Paulo Henrique Pires de Aguiar, Wellingson da Silva Paiva, Alda Wakamatsu, Manoel Jacobsen Teixeira, Sueli Mieko Oba-Shinjo, and Suely Kazue Nagahashi Marie

OBJECTIVE

The authors searched for genetic and transcriptional signatures associated with tumor progression and recurrence in their cohort of patients with meningiomas, combining the analysis of targeted exome, NF2-LOH, transcriptome, and protein expressions.

METHODS

The authors included 91 patients who underwent resection of intracranial meningioma at their institution between June 2000 and November 2007. The search of somatic mutations was performed by Next Generation Sequencing through a customized panel and multiplex ligation-dependent probe amplification for NF2 loss of heterozygosity. The transcriptomic profile was analyzed by QuantSeq 3′ mRNA-Seq. The differentially expressed genes of interest were validated at the protein level analysis by immunohistochemistry.

RESULTS

The transcriptomic analysis identified an upregulated set of genes related to metabolism and cell cycle and downregulated genes related to immune response and extracellular matrix remodeling in grade 2 (atypical) meningiomas, with a significant difference in recurrent compared with nonrecurrent cases. EZH2 nuclear positivity associated with grade 2, particularly with recurrent tumors and EZH2 gene expression level, correlated positively with the expression of genes related to cell cycle and negatively to genes related to immune response and regulation of cell motility.

CONCLUSIONS

The authors identified modules of dysregulated genes in grade 2 meningiomas related to the activation of oxidative metabolism, cell division, cell motility due to extracellular remodeling, and immune evasion that were predictive of survival and exhibited significant correlations with EZH2 expression.

Open access

Conventionally fully fractionated Gamma Knife Icon re-irradiation of primary recurrent intracranial tumors: the first report indicating feasibility and safety

Michael Yan, Lori Holden, Jay Detsky, Chia-Lin Tseng, Hany Soliman, Sten Myrehaug, Zain Husain, Sunit Das, Collins Yeboah, Nir Lipsman, Mark Ruschin, and Arjun Sahgal

OBJECTIVE

With the incorporation of real-time image guidance on the Gamma Knife system allowing for mask-based immobilization (Gamma Knife Icon [GKI]), conventionally fully fractionated (1.8–3.0 Gy/day) GKI radiation can now be delivered to take advantage of an inherently minimal margin for delivery uncertainty, sharp dose falloff, and inhomogeneous dose distribution. This case series details the authors’ preliminary experience in re-irradiating 7 complex primary intracranial tumors, which were considered to have been previously maximally radiated and situated adjacent to critical organs at risk.

METHODS

The authors retrospectively reviewed all patients who received fractionated re-irradiation using GKI at the Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada, between 2016 and 2021. Patients with brain metastases, and those who received radiotherapy courses in 5 or fewer fractions, were excluded. All radiotherapy doses were converted to the equivalent total dose in 2-Gy fractions (EQD2), with the assumption of an α/β ratio of 2 for late normal tissue toxicity and 10 for the tumor.

RESULTS

A total of 7 patients were included in this case series. Three patients had recurrent meningiomas, as well as 1 patient each with ependymoma, intracranial sarcoma, pituitary macroadenoma, and papillary pineal tumor. Six patients had undergone prior linear accelerator–based conventional fractionated radiotherapy and 1 patient had undergone prior proton therapy. Patients were re-irradiated with a median (range) total dose of 50.4 (30–63.4) Gy delivered in a median (range) of 28 (10–38) fractions with GKI. The median (range) target volume was 6.58 (0.2–46.3) cm3. The median (range) cumulative mean EQD2 administered to the tumor was 121.1 (107.9–181.3) Gy, and the median (range) maximum point EQD2 administered to the brainstem, optic nerves, and optic chiasm were 91.6 (74.0–111.5) Gy, 58.9 (6.3–102.9) Gy, and 59.9 (36.7–127.3) Gy, respectively. At a median (range) follow-up of 15 (6–42) months, 6 of 7 patients were alive with 4 having locally controlled disease. Only 3 patients experienced treatment-related toxicities, which were self-limited.

CONCLUSIONS

Fractionated radiotherapy using GKI may be a safe and effective method for the re-irradiation of complex progressive primary intracranial tumors, where the aim is to minimize the potential for serious late effects.

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Molecular characteristics of incidental lower-grade glioma for treatment decision-making

Jeongman Park, Jeongmin Sim, Juwon Ahn, Yu Jin Kim, Sojung Hwang, Kyunggi Cho, Da-Young Chang, Jin-Hwa Jung, Ju Hyung Moon, KyoungSu Sung, and Jaejoon Lim

OBJECTIVE

Several limitations are associated with the early diagnosis and treatment of incidental lower-grade glioma (iLGG), and due to its unknown molecular features, its management is categorized as either the “wait-and-see” strategy or immediate treatment. Therefore, in this study the authors explored iLGG’s clinical and molecular landscape to improve its management.

METHODS

The authors retrospectively assessed the differences between the molecular and clinical characteristics of iLGG and symptomatic lower-grade glioma (sLGG) samples filtered based on symptom data corresponding to The Cancer Genome Atlas cohort with mutations. Thereafter, genomic and transcriptomic analysis was performed.

RESULTS

There was no significant difference between iLGG and sLGG with respect to mutation status; however, there was an increase in the interaction between major mutations in sLGG, depending on the histological subtype and the IDH1 mutation status. Furthermore, the IDH1 mutation characteristics corresponding to wild-type glioma were much more obvious in sLGG than in iLGG. Additionally, in sLGG, genes associated with malignancy, including cell proliferation–related, cell migration–related, epithelial-to-mesenchymal transition–related, and negative regulation of cell death–related genes, were significantly upregulated, and groups showing higher expression levels of these genes were associated with worse prognosis. Also, 8 of the 75 identified upregulated genes showed positive correlation with resistance to the drugs that are normally used for glioma treatment, including procarbazine, carmustine, vincristine, and temozolomide.

CONCLUSIONS

The new insights regarding the different molecular features of iLGG and sLGG indicated that the immediate management of iLGG could result in better prognosis than the wait-and-see strategy.

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Evaluating risk of recurrence in patients with meningioma

Jeffrey I. Traylor, Aaron R. Plitt, William H. Hicks, Tabarak M. Mian, Bruce E. Mickey, and Samuel L. Barnett

OBJECTIVE

Meningioma prognostication and treatment continues to evolve with an increasing understanding of tumor biology. In this study, the authors aimed to test conventional predictors of meningioma recurrence, histopathology variables for which there exists some controversy (brain invasion), as well as a novel molecular-based location paradigm.

METHODS

This is a retrospective study of a consecutive series of patients with WHO grade I–III meningioma resected at The University of Texas Southwestern Medical Center between 1994 and 2015. Time to meningioma recurrence (i.e., recurrence-free survival [RFS]) was the primary endpoint measured. Kaplan-Meier curves were constructed and compared using log-rank tests. Cox univariate and multivariate analyses were performed to identify predictors of RFS.

RESULTS

A total of 703 consecutive patients with meningioma underwent resection at The University of Texas Southwestern Medical Center between the years 1994 and 2015. A total of 158 patients were excluded for insufficient follow-up (< 3 months). The median age of the cohort was 55 years (range 16–88 years) and 69.5% (n = 379) were female. The median follow-up was 48 months (range 3–289 months). There was not a significantly increased risk of recurrence in patients with evidence of brain invasion, in patients with otherwise WHO grade I meningioma (Cox univariate HR 0.92, 95% CI 0.44–1.91, p = 0.82, power 4.4%). Adjuvant radiosurgery to subtotally resected WHO grade I meningiomas did not prolong the time to recurrence (n = 52, Cox univariate HR 0.21, 95% CI 0.03–1.61, p = 0.13, power 71.6%). Location (midline skull base, lateral skull base, and paravenous) was significantly associated with RFS (p < 0.01, log-rank test). In patients with high-grade meningiomas (WHO grade II or III), location was predictive of RFS (p = 0.03, log-rank test), with paravenous meningiomas exhibiting the highest rates of recurrence. Location was not significant on multivariate analysis.

CONCLUSIONS

The data suggest that brain invasion does not increase the risk of recurrence in otherwise WHO grade I meningioma. Adjuvant radiosurgery to subtotally resected WHO grade I meningiomas did not prolong the time to recurrence. Location categorized by distinct molecular signatures did not predict RFS in a multivariate model. Larger studies are needed to confirm these findings.

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Use of thyroid transcription factor 1 and napsin A to predict local failure and survival after Gamma Knife radiosurgery in patients with brain metastases from lung adenocarcinoma

Haewon Roh, Sung Yong Lee, Jinhwan Lee, Soon-Young Hwang, and Jong Hyun Kim

OBJECTIVE

Stereotactic radiosurgery (SRS), combined with contemporary targeted therapies and immunotherapies, has improved the overall survival of patients with lung adenocarcinoma (ADC). Given that histological subtypes reflect prognosis in patients with primary ADC, it is important to integrate pathological biomarkers to predict clinical outcomes after SRS in patients with brain metastases from lung ADC. Therefore, the authors investigated the prognostic relevance of various biomarkers of primary lung ADC for clinical outcomes after SRS.

METHODS

A total of 95 patients with 136 brain metastases (1–4 oligometastases) who were treated with Gamma Knife radiosurgery between January 2017 and December 2020 were included. The Kaplan-Meier method and univariate and multivariate analyses using Cox proportional hazard regression models were used to identify prognostic factors for local control, survival, and distant brain control.

RESULTS

Multivariate analysis revealed thyroid transcription factor 1 as an independent prognostic factor for local control (HR 0.098, 95% CI 0.014–0.698, p = 0.0203) and napsin A as a significant predictor of overall survival after SRS (HR 0.080, 95% CI 0.017–0.386, p < 0.01). In a subset analysis of epidermal growth factor receptor (EGFR) mutation, patients with EGFR exon 19 mutations showed better distant brain control than those with EGFR exon 21 mutations (p < 0.01).

CONCLUSIONS

Pathological biomarkers of primary cancer should be considered to predict clinical outcomes after SRS in patients with lung ADC. Use of such biomarkers may help to provide personalized treatment to each patient, improving clinical outcomes after SRS.

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COL1A2 inhibition suppresses glioblastoma cell proliferation and invasion

Yi Wang, Maki Sakaguchi, Hemragul Sabit, Sho Tamai, Toshiya Ichinose, Shingo Tanaka, Masashi Kinoshita, Yasuo Uchida, Sumio Ohtsuki, and Mitsutoshi Nakada

OBJECTIVE

An extracellular matrix such as collagen is an essential component of the tumor microenvironment. Collagen alpha-2(I) chain (COL1A2) is a chain of type I collagen whose triple helix comprises two alpha-1 chains and one alpha-2 chain. The authors’ proteomics data showed that COL1A2 is significantly higher in the blood of patients with glioblastoma (GBM) compared with healthy controls. COL1A2 has many different functions in various types of cancers. However, the functions of COL1A2 in GBM are poorly understood. In this study, the authors analyzed the functions of COL1A2 and its signaling pathways in GBM.

METHODS

Surgical specimens and GBM cell lines (T98, U87, and U251) were used. The expression level of COL1A2 was examined using GBM tissues and normal brain tissues by quantitative real-time polymerase chain reaction. The clinical significance of these levels was evaluated using Kaplan-Meier analysis. Small interfering RNA (siRNA) and small hairpin RNA of COL1A2 were transfected into GBM cell lines to investigate the function of COL1A2 in vitro and in vivo. Flow cytometry was introduced to analyze the alteration of cell cycles. Western blot and immunohistochemistry were performed to analyze the underlying mechanisms.

RESULTS

The expression level of COL1A2 was upregulated in GBM compared with normal brain tissues. A higher expression of COL1A2 was correlated with poor progression-free survival and overall survival. COL1A2 inhibition significantly suppressed cell proliferation in vitro and in vivo, likely due to G1 arrest. The invasion ability was notably deteriorated by inhibiting COL1A2. Cyclin D1, cyclin-dependent kinase 1, and cyclin-dependent kinase 4, which are involved in the cell cycle, were all downregulated after blockade of COL1A2 in vitro and in vivo. Phosphoinositide 3-kinase inhibitor reduced the expression of COL1A2. Although downregulation of COL1A2 decreased the protein kinase B (Akt) phosphorylation, Akt activator can phosphorylate Akt in siRNA-treated cells. This finding suggests that Akt phosphorylation is partially dependent on COL1A2.

CONCLUSIONS

COL1A2 plays an important role in driving GBM progression. COL1A2 inhibition attenuated GBM proliferation by promoting cell cycle arrest, indicating that COL1A2 could be a promising therapeutic target for GBM treatment.

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Impact of radiotherapy delay following biopsy for patients with unresected glioblastoma

Sarah Gao, Lan Jin, Jennifer Moliterno, Zachary A. Corbin, Ranjit S. Bindra, Joseph N. Contessa, James B. Yu, and Henry S. Park

OBJECTIVE

Because of the aggressive nature of glioblastoma, patients with unresected disease are encouraged to begin radiotherapy within approximately 1 month after craniotomy. The aim of this study was to investigate the potential association between time interval from biopsy to radiotherapy with overall survival in patients with unresected glioblastoma.

METHODS

Patients with unresected glioblastoma diagnosed between 2010 and 2014 who received adjuvant radiotherapy and concurrent chemotherapy were identified in the National Cancer Database. Demographic and clinical data were compared using chi-square and Wilcoxon rank-sum tests. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards regression modeling.

RESULTS

Among 3456 patients with unresected glioblastoma, initiation of radiotherapy within 3 weeks of biopsy was associated with a higher hazard of death compared with later initiation of radiotherapy. After excluding patients who received radiotherapy within 3 weeks of biopsy to minimize the effects of confounders associated with short time intervals from biopsy to radiotherapy, the median interval from biopsy to radiotherapy was 32 days (IQR 27–39 days). Overall, 1782 (66.82%) patients started radiotherapy within 5 weeks of biopsy, and 885 (33.18%) patients started radiotherapy beyond 5 weeks of biopsy. On multivariable analysis, there was no significant difference in overall survival between these two groups (HR 0.96, 95% CI 0.88–1.50; p = 0.374).

CONCLUSIONS

In patients with unresected glioblastoma, a longer time interval from biopsy to radiotherapy does not appear to be associated with worse overall survival. However, external validation of these findings is necessary given that selection bias is a significant limitation of this study.

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Contralateral subfrontal approach for tuberculum sellae meningioma: techniques and clinical outcomes

Yeong Jin Kim, Kyung-Sub Moon, Woo-Youl Jang, Tae-Young Jung, In-Young Kim, and Shin Jung

OBJECTIVE

Tuberculum sellae meningiomas (TSMs) present a burdensome surgical challenge because of their adjacency to vital neurovascular structures. The contralateral subfrontal approach provides an outstanding corridor for removing a TSM with an excellent visual outcome and limited complications. The authors present their long-term surgical experience in treating TSMs via the contralateral subfrontal approach and discuss patient selection, surgical techniques, and clinical outcomes.

METHODS

Between 2005 and 2021, the authors used the contralateral subfrontal approach in 74 consecutive patients presenting with TSMs. The surgical decision-making process and surgical techniques are described, and the clinical outcomes were retrospectively analyzed.

RESULTS

The mean patient age was 54.4 years, with a female predominance (n = 61, 82%). Preoperatively, 61 patients (82%) had vision symptoms and 73 (99%) had optic canal invasion by tumor. Gross-total resection was achieved in almost all patients (n = 70, 95%). The visual function improvement and stabilization rate was 91% (67/74). Eight patients (11%) showed a worsening of visual function on the less-compromised (approach-side) optic nerve. There was no occurrence of cerebrospinal fluid leakage. Four patients (5%) experienced recurrences after the initial operation (mean follow-up duration 63 months). There were no deaths in this study.

CONCLUSIONS

The contralateral subfrontal approach provides a high chance of complete tumor removal and visual improvement with limited complications and recurrences, especially when the tumor is in a unilateral or midline location causing unilateral visual symptoms or bilateral asymmetrical visual symptoms, regardless of tumor size or encasement of major vessels. With the appropriate patient selection, surgical technique, and familiarity with surrounding neurovascular structures, this approach is reliable for TSM surgery.

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Intraoperative confocal laser endomicroscopy: prospective in vivo feasibility study of a clinical-grade system for brain tumors

Irakliy Abramov, Marian T. Park, Evgenii Belykh, Alexander B. Dru, Yuan Xu, Timothy C. Gooldy, Lea Scherschinski, S. Harrison Farber, Andrew S. Little, Randall W. Porter, Kris A. Smith, Michael T. Lawton, Jennifer M. Eschbacher, and Mark C. Preul

OBJECTIVE

The authors evaluated the feasibility of using the first clinical-grade confocal laser endomicroscopy (CLE) system using fluorescein sodium for intraoperative in vivo imaging of brain tumors.

METHODS

A CLE system cleared by the FDA was used in 30 prospectively enrolled patients with 31 brain tumors (13 gliomas, 5 meningiomas, 6 other primary tumors, 3 metastases, and 4 reactive brain tissue). A neuropathologist classified CLE images as interpretable or noninterpretable. Images were compared with corresponding frozen and permanent histology sections, with image correlation to biopsy location using neuronavigation. The specificities and sensitivities of CLE images and frozen sections were calculated using permanent histological sections as the standard for comparison. A recently developed surgical telepathology software platform was used in 11 cases to provide real-time intraoperative consultation with a neuropathologist.

RESULTS

Overall, 10,713 CLE images from 335 regions of interest were acquired. The mean duration of the use of the CLE system was 7 minutes (range 3–18 minutes). Interpretable CLE images were obtained in all cases. The first interpretable image was acquired within a mean of 6 (SD 10) images and within the first 5 (SD 13) seconds of imaging; 4896 images (46%) were interpretable. Interpretable image acquisition was positively correlated with study progression, number of cases per surgeon, cumulative length of CLE time, and CLE time per case (p ≤ 0.01). The diagnostic accuracy, sensitivity, and specificity of CLE compared with frozen sections were 94%, 94%, and 100%, respectively, and the diagnostic accuracy, sensitivity, and specificity of CLE compared with permanent histological sections were 92%, 90%, and 94%, respectively. No difference was observed between lesion types for the time to first interpretable image (p = 0.35). Deeply located lesions were associated with a higher percentage of interpretable images than superficial lesions (p = 0.02). The study met the primary end points, confirming the safety and feasibility and acquisition of noninvasive digital biopsies in all cases. The study met the secondary end points for the duration of CLE use necessary to obtain interpretable images. A neuropathologist could interpret the CLE images in 29 (97%) of 30 cases.

CONCLUSIONS

The clinical-grade CLE system allows in vivo, intraoperative, high-resolution cellular visualization of tissue microstructure and identification of lesional tissue patterns in real time, without the need for tissue preparation.