| 1. |
- Bandaru, Sashidar, et al.
(author)
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Filamin A increases aggressiveness of human neuroblastoma.
- 2022
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In: Neuro-oncology Advances. - : Oxford University Press (OUP). - 2632-2498. ; 4:1
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Journal article (peer-reviewed)abstract
- The actin-binding protein filamin A (FLNA) regulates oncogenic signal transduction important for tumor growth, but the role of FLNA in the progression of neuroblastoma (NB) has not been explored.We analyzed FLNA mRNA expression in the R2 NB-database and FLNA protein expression in human NB tumors. We then silenced FLNA expression in human SKNBE2 and IMR32 NB cells by lentiviral vector encoding shRNA FLNA and assayed the cells for proliferation, migration, colony, spheroid formation, and apoptosis. SKNBE2 xenografts expressing or lacking FLNA in BALB/c nude mice were analyzed by both routine histopathology and immunohistochemistry.We observed shorter patient survival with higher expression of FLNA mRNA than patients with lower FLNA mRNA expression, and high-risk NB tumors expressed higher FLNA levels. Overexpression of FLNA increased proliferation of SH-SY5 NB cells. NB cell lines transfected with siRNA FLNA proliferated and migrated less, expressed lower levels of phosphorylated AKT and ERK1/2, formed smaller colonies and spheroids, as well as increased apoptosis. After inoculation of SKNBE2 cells infected with lentivirus expressing shRNA FLNA, size of NB tumors and number of proliferating cells were decreased. Furthermore, we identified STAT3 as an interacting partner of FLNA. Silencing FLNA mRNA reduced levels of NF-κB, STAT3 and MYCN, and increased levels of p53 and cleaved caspase 3.Inhibition of FLNA impaired NB cell signaling and function and reduced NB tumor size in vivo, suggesting that drugs targeting either FLNA or its interaction with STAT3 may be useful in the treatment of NB.
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| 2. |
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| 3. |
- Corell, Alba, et al.
(author)
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Stemness and clinical features in relation to the subventricular zone in diffuse lower-grade glioma : an exploratory study
- 2022
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In: Neuro-Oncology Advances. - : Oxford University Press. - 2632-2498. ; 4:1
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Journal article (peer-reviewed)abstract
- Background The subventricular zone (SVZ) of the human brain is a site of adult stem cell proliferation and a microenvironment for neural stem cells (NSCs). It has been suggested that NSCs in the SVZ are potential cells of origin containing driver mutations of glioblastoma, but their role in the origin of diffuse lower-grade gliomas (dLGGs) is not much studied. Methods We included 188 patients >= 18 years with IDH-mutated dLGG (WHO grades 2-3) histologically diagnosed between 2007 and 2020. Tissue microarrays of tumor samples for patients between 2007 and 2016 were used for immunodetection of Nestin, SOX2, SOX9, KLF4, NANOG, CD133 cMYC, and Ki67. DNA methylation profile was used for stemness index (mDNAsi). Tumor contact with the SVZ was assessed and the distance was computed. Results Overall, 70.2% of the dLGG had SVZ contact. Tumors with SVZ contact were larger (102.4 vs 30.9 mL, P < .01), the patients were older (44.3 vs 40.4 years, P = .04) and more often had symptoms related to increased intracranial pressure (31.8% vs 7.1%, P < .01). The expression of SOX2, SOX9, Nestin, and Ki67 showed intersample variability, but no difference was found between tumors with or without SVZ contact, nor with the actual distance to the SVZ. mDNAsi was similar between groups (P = .42). Conclusions We found no statistical relationship between proximity with the SVZ and mDNAsi or expression of SOX2, SOX9, Nestin, and Ki67 in IDH-mutated dLGG. Our data suggest that the potential impact of SVZ on IDH-mutated dLGG is probably not associated with a more stemness-like tumor profile.
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| 5. |
- Fahlström, Andreas, et al.
(author)
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Multiple meningiomas : Epidemiology, management, and outcomes
- 2023
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In: Neuro-Oncology Advances. - : Oxford University Press (OUP). - 2632-2498. ; 5:SUPP1, s. I35-I48
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Journal article (peer-reviewed)abstract
- Meningiomas are the most common nonmalignant brain tumor in adults, with an increasing incidence of asymptomatic meningiomas diagnosed on more ubiquitous neuroimaging. A subset of meningioma patients bear 2 or more spatially separated synchronous or metachronous tumors termed "multiple meningiomas" (MM), reported to occur in only 1%-10% of patients, though recent data indicate higher incidence. MM constitute a distinct clinical entity, with unique etiologies including sporadic, familial and radiation-induced, and pose special management challenges. While the pathophysiology of MM is not established, theories include independent origin in disparate locations through unique genetic events, and the "monoclonal hypothesis" of a transformed neoplastic clone with subarachnoid seeding precipitating numerous distinct meningiomas. Patients with solitary meningiomas carry the risk of long-term neurological morbidity and mortality, as well as impaired health-related quality of life, despite being a generally benign and surgically curable tumor. For patients with MM, the situation is even less favorable. MM should be regarded as a chronic disease, and in many cases, the management goal is disease control, as cure is seldom possible. Multiple interventions and lifelong surveillance are sometimes necessary. We aim to review the MM literature and create a comprehensive overview, including an evidence-based management paradigm.
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| 6. |
- Guo, Min, et al.
(author)
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Identification of functionally distinct and interacting cancer cell subpopulations from glioblastoma with intratumoral genetic heterogeneity
- 2020
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In: Neuro-Oncology Advances. - : Oxford University Press. - 2632-2498. ; 2:1
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Journal article (peer-reviewed)abstract
- BackgroundGlioblastomas display a high level of intratumoral heterogeneity with regard to both genetic and histological features. Within single tumors, subclones have been shown to communicate with each other to affect overall tumor growth. The aim of this study was to broaden the understanding of interclonal communication in glioblastoma.MethodsWe have used the U-343 model, consisting of U-343 MG, U-343 MGa, U-343 MGa 31L, and U-343 MGa Cl2:6, a set of distinct glioblastoma cell lines that have been derived from the same tumor. We characterized these with regard to temozolomide sensitivity, protein secretome, gene expression, DNA copy number, and cancer cell phenotypic traits. Furthermore, we performed coculture and conditioned media-based experiments to model cell-to-cell signaling in a setting of intratumoral heterogeneity.ResultsTemozolomide treatment of a coculture composed of all 4 U-343 cell lines presents a tumor relapse model where the least sensitive population, U-343 MGa 31L, outlives the others. Interestingly, the U-343 cell lines were shown to have distinct gene expression signatures and phenotypes although they were derived from a single tumor. The DNA copy number analysis revealed both common and unique alterations, indicating the evolutionary relationship between the cells. Moreover, these cells were found to communicate and affect each other’s proliferation, both via contact-dependent and -independent interactions, where NOTCH1, TGFBI, and ADAMTS1 signaling effects were involved, respectively.ConclusionsThese results provide insight into how complex the signaling events may prove to be in a setting of intratumoral heterogeneity in glioblastoma and provide a map for future studies.
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| 7. |
- Juvvuna, Prasanna Kumar, et al.
(author)
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NBAT1/CASC15-003/USP36 control MYCN expression and its downstream pathway genes in neuroblastoma.
- 2021
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In: Neuro-oncology advances. - : Oxford University Press (OUP). - 2632-2498. ; 3:1
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Journal article (peer-reviewed)abstract
- MYCN has been an attractive therapeutic target in neuroblastoma considering the widespread amplification of the MYCN locus in neuroblastoma, and its established role in neuroblastoma development and progression. Thus, understanding neuroblastoma-specific control of MYCN expression at the transcriptional and post-transcriptional level would lead to identification of novel MYCN-dependent oncogenic pathways and potential therapeutic strategies.By performing loss- and gain-of-function experiments of the neuroblastoma hotspot locus 6p22.3 derived lncRNAs CASC15-003 and NBAT1, together with coimmunoprecipitation and immunoblotting of MYCN, we have shown that both lncRNAs post-translationally control the expression of MYCN through regulating a deubiquitinase enzyme USP36. USP36 oncogenic properties were investigated using cancer cell lines and in vivo models. RNA-seq analysis of loss-of-function experiments of CASC15-003/NBAT1/MYCN/USP36 and JQ1-treated neuroblastoma cells uncovered MYCN-dependent oncogenic pathways.We show that NBAT1/CASC15-003 control the stability of MYCN protein through their common interacting protein partner USP36. USP36 harbors oncogenic properties and its higher expression in neuroblastoma patients correlates with poor prognosis, and its downregulation significantly reduces tumor growth in neuroblastoma cell lines and xenograft models. Unbiased integration of RNA-seq data from CASC15-003, NBAT1, USP36, and MYCN knockdowns and neuroblastoma cells treated with MYCN inhibitor JQ1, identified genes that are jointly regulated by the NBAT1/CASC15-003/USP36/MYCN pathway. Functional experiments on one of the target genes, COL18A1, revealed its role in the NBAT1/CASC15-003-dependent cell adhesion feature in neuroblastoma cells.Our data show post-translational regulation of MYCN by NBAT1/CASC15-003/USP36, which represents a new regulatory layer in the complex multilayered gene regulatory network that controls MYCN expression.
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| 8. |
- Krynina, Olha, et al.
(author)
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The potential of liquid biopsy for detection of the KIAA1549-BRAF fusion in circulating tumor DNA from children with pilocytic astrocytoma
- 2024
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In: Neuro-Oncology Advances. - : Oxford University Press. - 2632-2498. ; 6:1
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Journal article (peer-reviewed)abstract
- BackgroundLow-grade gliomas (LGGs) represent children’s most prevalent central nervous system tumor, necessitating molecular profiling to diagnose and determine the most suitable treatment. Developing highly sensitive screening techniques for liquid biopsy samples is particularly beneficial, as it enables the early detection and molecular characterization of tumors with minimally invasive samples.MethodsWe examined CSF and plasma samples from patients with pilocytic astrocytoma (PA) using custom multiplexed droplet digital polymerase chain reaction (ddPCR) assays based on whole genome sequencing data. These assays included a screening test to analyze BRAF duplication and a targeted assay for the detection of patient-specific KIAA1549::BRAF fusion junction sequences or single nucleotide variants.ResultsOur findings revealed that 5 out of 13 individual cerebrospinal fluid (CSF) samples tested positive for circulating tumor DNA (ctDNA). Among these cases, 3 exhibited the KIAA1549::BRAF fusion, which was detected through copy number variation (CNV) analysis (n = 1) or a fusion-specific probe (n = 2), while 1 case each displayed the BRAF V600E mutation and the FGFR1 N577K mutation. Additionally, a quantitative analysis of cell-free DNA (cfDNA) concentrations in PA CSF samples showed that most cases had low cfDNA levels, below the limit of detection of our assay (<1.9 ng).ConclusionsWhile CNV analysis of CSF samples from LGGs still has some limitations, it has the potential to serve as a valuable complementary tool. Furthermore, it can also be multiplexed with other aberrations, for example, to the BRAF V600 test, to provide important insights into the molecular characteristics of LGGs.
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| 9. |
- Ljungqvist, Johan, et al.
(author)
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Clinical experiences and learning curves from robot-assisted neurosurgical biopsies with Stealth Autoguide™
- 2024
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In: NEURO-ONCOLOGY ADVANCES. - 2632-2498. ; 6:1
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Journal article (peer-reviewed)abstract
- Background Biopsies of intracranial lesions are a cornerstone in the diagnosis of unresectable tumors to guide neurooncological treatment; however, the procedure is also associated with risks. The results from the cranial robot guidance system Stealth Autoguide (TM) were studied after introduction at a neurosurgical department. Primary aims include the presentation of clinical and radiological data, accuracy of radiological diagnosis, learning curves of the new technology, diagnostic yield, and precision. The secondary aim was to study complications.Methods Retrospective data inclusion was performed on patients >= 18 years undergoing biopsy with Stealth Autoguide (TM) due to suspected brain tumors in the first 3 years after the introduction of the technique. Data regarding clinical characteristics, intraoperative variables, pathological diagnosis, and complications were recorded. Analyses of learning curves were performed.Results A total of 79 procedures were performed on 78 patients with a mean age of 62 years (SD 12.7, range 23-82), 30.8% were female. Tumors were often multifocal (63.3%) and supratentorial (89.9%). The diagnostic yield was 87.3%. The first-hand radiological diagnosis was correct in 62.0%. A slight decrease in operation time was observed, although not significant. The surgeon contributed to 12% of the variability.Conclusions Robot-assisted biopsies with Stealth Autoguide (TM) seem to be comparable, with regards to complications, to frame-based and other frameless neurosurgical biopsies. Learning curves demonstrated no statistical differences in time of surgery and only 12% surgeon-related variation (ie, variation caused by the change of performing surgeon), suggesting a successful implementation of this technical adjunct. Neurosurgeons will sometimes biopsy a tumor to officially diagnose it if it is too risky to remove with surgery. Biopsies are typically performed by the surgeon without the use of robots. In this study, the authors wanted to describe their experience with robot-assisted brain tumor biopsies. To do this, they reviewed the medical records of patients who had brain tumor biopsies done with a commercial robot. Their results showed that 78 patients had a robot-assisted brain tumor biopsy at their hospital. A diagnosis was achievable for 87% of these patients. The time taken for surgery did not seem to change much over the study period, and the surgeon only accounted for a small portion of the differences in the length of surgery. Although 41% of patients had some bleeding at the site of biopsy, the bleedings were most often small and rarely caused problems for the patient.
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| 10. |
- Strand, Per Sveino, et al.
(author)
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Growth dynamics of untreated meningiomas.
- 2024
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In: Neuro-oncology advances. - 2632-2498. ; 6:1
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Journal article (peer-reviewed)abstract
- Knowledge about meningioma growth characteristics is needed for developing biologically rational follow-up routines. In this study of untreated meningiomas followed with repeated magnetic resonance imaging (MRI) scans, we studied growth dynamics and explored potential factors associated with tumor growth.In a single-center cohort study, we included 235 adult patients with radiologically suspected intracranial meningioma and at least 3 MRI scans during follow-up. Tumors were segmented using an automatic algorithm from contrast-enhanced T1 series, and, if needed, manually corrected. Potential meningioma growth curves were statistically compared: linear, exponential, linear radial, or Gompertzian. Factors associated with growth were explored.In 235 patients, 1394 MRI scans were carried out in the median 5-year observational period. Of the models tested, a Gompertzian growth curve best described growth dynamics of meningiomas on group level. 59% of the tumors grew, 27% remained stable, and 14% shrunk. Only 13 patients (5%) underwent surgery during the observational period and were excluded after surgery. Tumor size at the time of diagnosis, multifocality, and length of follow-up were associated with tumor growth, whereas age, sex, presence of peritumoral edema, and hyperintense T2-signal were not significant factors.Untreated meningiomas follow a Gompertzian growth curve, indicating that increasing and potentially doubling subsequent follow-up intervals between MRIs seems biologically reasonable, instead of fixed time intervals. Tumor size at diagnosis is the strongest predictor of future growth, indicating a potential for longer follow-up intervals for smaller tumors. Although most untreated meningiomas grow, few require surgery.
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| 11. |
- Werlenius, Katja, et al.
(author)
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A randomized phase II trial of efficacy and safety of the immunotherapy ALECSAT as an adjunct to radiotherapy and temozolomide for newly diagnosed glioblastoma.
- 2021
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In: Neuro-oncology advances. - : Oxford University Press (OUP). - 2632-2498. ; 3:1
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Journal article (peer-reviewed)abstract
- There is an urgent need for effective treatments against glioblastoma (GBM). In this trial, we investigated the efficacy and safety of an adoptive cell-based immunotherapy.Patients with newly diagnosed GBM were recruited at 4 study sites in Sweden. The patients were randomized 1:2 to receive either radiotherapy (RT), 60 Gy/30 fractions, with concomitant and adjuvant temozolomide (TMZ) only, or RT and TMZ with the addition of Autologous Lymphoid Effector Cells Specific Against Tumor (ALECSAT) in an open-label phase II trial. The primary endpoint was investigator-assessed progression-free survival (PFS). The secondary endpoints were survival and safety of ALECSAT.Sixty-two patients were randomized to either standard of care (SOC) with RT and TMZ alone (n = 22) or SOC with ALECSAT (n = 40). Median age was 57 years (range 38-69), 95% of the patients were in good performance status (WHO 0-1). There was no significant difference between the study arms (SOC vs ALECSAT + SOC) in PFS (7.9 vs 7.8 months; hazard ratio [HR] 1.28; 95% confidence interval [CI] 0.70-2.36; P = .42) or in median overall survival (OS) (18.3 vs 19.2 months; HR 1.16, 95% CI 0.58-2.31; P = .67). The treatment groups were balanced in terms of serious adverse events (52.4% vs 52.5%), but adverse events ≥grade 3 were more common in the experimental arm (81.0% vs 92.5%).Addition of ALECSAT immunotherapy to standard treatment with radiochemotherapy was well tolerated but did not improve PFS or OS for patients with newly diagnosed GBM.
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| 12. |
- Wu, Wendy Yi-Ying, et al.
(author)
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Prediagnostic biomarkers for early detection of glioma : using case-control studies from cohorts as study approach
- 2022
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In: Neuro-Oncology Advances. - : Oxford University Press. - 2632-2498. ; 4, s. II73-II80
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Journal article (peer-reviewed)abstract
- Background: Understanding the trajectory and development of disease is important and the knowledge can be used to find novel targets for therapy and new diagnostic tools for early diagnosis.Methods: Large cohorts from different parts of the world are unique assets for research as they have systematically collected plasma and DNA over long-time periods in healthy individuals, sometimes even with repeated samples. Over time, the population in the cohort are diagnosed with many different diseases, including brain tumors.Results: Recent studies have detected genetic variants that are associated with increased risk of glioblastoma and lower grade gliomas specifically. The impact for genetic markers to predict disease in a healthy population has been deemed low, and a relevant question is if the genetic variants for glioma are associated with risk of disease or partly consist of genes associated to survival. Both metabolite and protein spectra are currently being explored for early detection of cancer.Conclusions: We here present a focused review of studies of genetic variants, metabolomics, and proteomics studied in prediagnostic glioma samples and discuss their potential in early diagnostics.
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