Recurrence is a major complication of some meningiomas. Although there were many studies on biomarkers associated with higher grades or increased aggressiveness, few studies specifically examined ...longitudinal samples of primary meningiomas and recurrences from the same patients for molecular life history. We studied 99 primary and recurrent meningiomas from 42 patients by FISH for 22q, 1q, 1p, 3p, 5q, 6q, 10p, 10q, 14q, 18q, CDKN2A/B homozygous deletion, ALT (Alternative Lengthening of Telomere), TERT re‐arrangement, targeted sequencing and TERTp sequencing. Although NF2 mutation and 22q were well known to be aetiological events in meningiomas, we found that in these paired meningiomas, combining the two events resulted in an NF2/22q group (57 tumors from 25 patients) which were almost mutually exclusive with those cases without these two changes (42 tumors from 17 patients) for NF2/22q. No other molecular changes were totally unique to NF2/22q or non‐NF2/22q tumors. For molecular evolution, NF2/22q meningiomas had higher cytogenetic abnormalities than non‐NF2/22q meningiomas (p = 0.003). Most of the cytogenetic changes in NF2/22q meningiomas were present from the outset whereas for non‐NF2/22q meningiomas, cytogenetic events were uncommon in the primary tumors and most were acquired in recurrences. For non‐NF2/22q tumors, CDKN2A/B homozygous deletion, 1q gain, 18p loss, 3p loss, and ALT were preferentially found in recurrences. Mutations were largely conserved between primary and recurrent tumors. Phylogenetic trees showed 11/11 patients with multiple recurrent tumors had a conserved evolutionary pattern. We conclude that for molecular life history, NF2 and 22q should be regarded as a group. NF2/22q recurring meningiomas showed more cytogenetic abnormalities in the primary tumors, whereas non‐NF2/22q meningiomas showed CDKN2A/B deletion and other cytogenetic abnormalities and ALT at recurrences. Although chromosome 1p loss is a known poor prognostic marker in meningiomas, it was also associated with a shorter TBR (time between resection) in this cohort (p = 0.002).
Accumulating evidence suggests that microRNAs (miRNAs) are over‐ or under‐expressed in tumors, and abnormalities in miRNA expression may contribute to carcinogenesis. MiR‐383 was previously ...identified as one of the under‐expresssed miRNAs in medulloblastoma (MB) by miRNA expression profiling. Quantitative reverse transcription polymerase chain reaction (RT‐PCR)‐based miRNA assays showed an enrichment of miR‐383 in normal brain. Based on these data, we speculated that miR‐383 is important in MB pathogenesis. In this study, we demonstrated significant downregulation of miR‐383 in 23/29 (79%) MB samples and 7/7 (100%) MB cells lines. Ectopic expression of miR‐383 in MB cells led to suppression of cell growth, cell accumulation at sub‐G1 phase and alteration of apoptosis‐related proteins. By transcriptomic analysis and computational algorithms, we identified peroxiredoxin 3 (PRDX3) as a target gene of miR‐383. Luciferase reporter assay confirmed that miR‐383 negatively regulated PRDX3 by interaction between miR‐383 and complementary sequences in the 3′ UTR of PRDX3. MiR‐383 repressed PRDX3 at transcriptional and translational levels as revealed by quantitative RT‐PCR and Western blot analysis. Furthermore, depletion of PRDX3 by siRNAs resulted in similar effects as observed in miR‐383‐transfected cells. In conclusion, miR‐383 acts as a regulator controlling cell growth of MB, at least in part, through targeting PRDX3.
MicroRNA-199a (miRNA-199a) has been shown to have comprehensive functions and behave differently in different systems and diseases. It is encoded by two loci in the human genome, miR-199a-1 in ...chromosome 19 and miR-199a-2 in chromosome 1. Both loci give rise to the same miRNAs (miR-199a-5p and miR-199a-3p). The cause of the diverse action of the miRNA in different systems is not clear. However, it is likely due to different regulation of the two genomic loci and variable targets of the miRNA in different cells and tissues. Here we studied promoter methylation of miR-199a in testicular germ cell tumors (TGCTs) and glioblastomas (gliomas) and discovered that hypermethylation in TGCTs of both miR-199a-1 and -2 resulted in its reduced expression, while hypomethylation of miR-199a-2 but not -1 in gliomas may be related to its elevated expression. We also identified a common regulator, REST, which preferentially bound to the methylated promoters of both miR-199a-1 and miR-199a-2. The action of miR-199a is dependent on its downstream targets. We identified MAFB as a putative target of miRNA-199a-5p in TGCTs and confirmed that the tumor suppression activity of the microRNA is mediated by its target MAFB. By studying the mechanisms that control the expressions of miR-199a and its various downstream targets, we hope to use miR-199a as a model to understand the complexity of miRNA biology.
Magnetic resonance imaging (MRI) demonstrates clear advantages over other imaging modalities in neurosurgery with its ability to delineate critical neurovascular structures and cancerous tissue in ...high‐resolution 3D anatomical roadmaps. However, its application has been limited to interventions performed based on static pre/post‐operative imaging, where errors accrue from stereotactic frame setup, image registration, and brain shift. To leverage the powerful intra‐operative functions of MRI, e.g., instrument tracking, monitoring of physiological changes and tissue temperature in MRI‐guided bilateral stereotactic neurosurgery, a multi‐stage robotic positioner is proposed. The system positions cannula/needle instruments using a lightweight (203 g) and compact (Ø97 × 81 mm) skull‐mounted structure that fits within most standard imaging head coils. With optimized design in soft robotics, the system operates in two stages: i) manual coarse adjustment performed interactively by the surgeon (workspace of ±30°), ii) automatic fine adjustment with precise (<0.2° orientation error), responsive (1.4 Hz bandwidth), and high‐resolution (0.058°) soft robotic positioning. Orientation locking provides sufficient transmission stiffness (4.07 N/mm) for instrument advancement. The system's clinical workflow and accuracy is validated with lab‐based (<0.8 mm) and MRI‐based testing on skull phantoms (<1.7 mm) and a cadaver subject (<2.2 mm). Custom‐made wireless omni‐directional tracking markers facilitated robot registration under MRI.
To leverage the intra‐operative functions of MRI, e.g., instrument tracking, monitoring of physiological changes and tissue temperature in MRI‐guided stereotactic neurosurgery, a robotic positioner is proposed in this study. The compact and skull‐mounted robot incorporates soft robotics and operates in manual and automatic stages. The system is validated by a cadaver trial. Custom‐made wireless MRI tracking markers are also discussed.
To follow the revision of the fourth edition of WHO classification and the recent progress on the management of diffuse gliomas, the joint guideline committee of Chinese Glioma Cooperative Group ...(CGCG), Society for Neuro‐Oncology of China (SNO-China) and Chinese Brain Cancer Association (CBCA) updated the clinical practice guideline. It provides recommendations for diagnostic and management decisions, and for limiting unnecessary treatments and cost. The recommendations focus on molecular and pathological diagnostics, and the main treatment modalities of surgery, radiotherapy, and chemotherapy. In this guideline, we also integrated the results of some clinical trials of immune therapies and target therapies, which we think are ongoing future directions. The guideline should serve as an application for all professionals involved in the management of patients with adult diffuse glioma and also a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in China and other countries.
•The guideline provides diagnostic and management recommendations for diffuse gliomas.•The guideline focuses on molecular diagnostics, and the main treatment modalities.•The guideline includes clinical trials of immune therapies and target therapies.•The guideline should serve as an application for all medical professionals.
Bone development is dynamically regulated by homeostasis, in which a balance between adipocytes and osteoblasts is maintained. Disruption of this differentiation balance leads to various bone-related ...metabolic diseases, including osteoporosis. In the present study, a primate-specific microRNA (miR-637) was found to be involved in the differentiation of human mesenchymal stem cells (hMSCs). Our preliminary data indicated that miR-637 suppressed the growth of hMSCs and induced S-phase arrest. Expression of miR-637 was increased during adipocyte differentiation (AD), whereas it was decreased during osteoblast differentiation (OS), which suggests miR-637 could act as a mediator of adipoosteogenic differentiation. Osterix (Osx), a significant transcription factor of osteoblasts, was shown to be a direct target of miR-637, which significantly enhanced AD and suppressed OS in hMSCs through direct suppression of Osx expression. Furthermore, miR-637 also significantly enhanced de novo adipogenesis in nude mice. In conclusion, our data indicated that the expression of miR-637 was indispensable for maintaining the balance of adipocytes and osteoblasts. Disruption of miR-637 expression patterns leads to irreversible damage to the balance of differentiation in bone marrow.
Neuroinflammation plays a critical role in the pathogenesis of subarachnoid hemorrhage (SAH). Microglia, as the resident immune cells, orchestrate neuroinflammation distinctly in neurological ...diseases with different polarization statuses. However, microglial polarizations in the neuroinflammatory responses after SAH are not fully understood. In this study, we investigated the dynamics of microglial reaction in an endovascular perforated SAH model. By using the Cx3cr1
GFP/GFP
Ccr2
RFP/RFP
transgenic mice, we found that the reactive immune cells were largely from resident microglia pool rather than infiltrating macrophages. Immunostaining and real-time PCR were employed to analyze the temporal microglial polarization and the resulting inflammatory responses. Our results showed that microglia accumulated immediately after SAH with a centrifugal spreading through the Cortex Adjacent to the Perforated Site (CAPS) to the remote motor cortex. Microglia polarized dynamically from M1 to M2 phenotype along with the morphological transformation from ramified to amoeboid shapes. The ramified microglia demonstrated the M1 property, which suggested the function-related microglial polarization occurred prior to morphological transformation after SAH. Bipolar-shaped microglia appeared as the intermediate and transitional status with the capacity of bidirectional polarization. The microglial polarization status is distinct in molecular inflammatory responses; M1-related pro-inflammation was predominant in the early phase and subsequently transited to the M2-related anti-inflammation. The systematic characterization of the dynamics of microglial polarization in this study contributes to the understanding of the origin of neuroinflammatory responses after SAH and provides key foundation for further investigations to develop target treatment.
The development of stereotaxy can be dated back 100 years. However, most stereotactic neurosurgery still relies on the workflow established about half a century ago. With the arrival of ...computer-assisted navigation, numerous studies to improve the neurosurgical technique have been reported, leading to frameless and magnetic resonance imaging (MRI)-guided/verified techniques. Frameless stereotaxy has been proved to be comparable to frame-based stereotaxy in accuracy, diagnostic yield, morbidity, and mortality. The incorporation of intraoperative MRI guidance in frameless techniques is considered an appealing method that could simplify workflow by reducing coregistration errors in different imaging modalities, conducting general anesthesia, and monitoring the surgical progress. In light of this situation, manually operated platforms have emerged for MRI-guided frameless procedures. However, these procedures could still be complicated and time-consuming because of the intensive manual operation required. To further simplify the procedure and enhance accuracy, robotics was introduced. Robots have superior capabilities over humans in certain tasks, especially those that are limited by space, accuracy demanding, intensive, and tedious. Clinical benefits have been shown in the recent surge of robot-assisted surgical interventions. We review the state-of-the-art intraoperative MRI-guided robotic platforms for stereotactic neurosurgery. To improve the surgical workflow and achieve greater clinical penetration, 3 key enabling techniques are proposed with emphasis on their current status, limitations, and future trends.
•Vision and advantages of the new stereotactic neurosurgical workflow with real-time MRI-guided robot-assisted approach.•Three key enabling technologies are proposed: nonrigid image registration, MR-based tracking, and MRI-compatible actuation.•Nonrigid image registration compensates for the image discrepancies resulting from brain deformation and MRI distortion.•MR-based tracking unit provides real-time positional feedback with high resolution, low latency, and high sampling.•MR-safe hydraulic actuator can offer precise manipulation and maintain high MRI quality during robot operation.
Cognitive deficits are common after aneurysmal subarachnoid haemorrhage (aSAH), and clinical evaluation is important for their management. Our hypothesis was that the Montreal Cognitive Assessment ...(MoCa) is superior to the Mini-Mental State Examination (MMSE) in screening for cognitive domain deficit in aSAH patients.
We carried out a prospective observational and diagnostic accuracy study on Hong Kong aSAH patients aged 21 to 75 years who had been admitted within 96 hours of ictus. The domain-specific neuropsychological assessment battery, the MoCA and MMSE were administered 2-4 weeks and 1 year after ictus. A cognitive domain deficit was defined as a cognitive domain z score <-1.65 (below the fifth percentile). Cognitive impairment was defined as two or more cognitive domain deficits. The study is registered at ClinicalTrials.gov of the US National Institutes of Health (NCT01038193).
Both the MoCA and the MMSE were successful in differentiating between patients with and without cognitive domain deficits and cognitive impairment at both assessment periods. At 1 year post-ictus, the MoCA produced higher area under the curve scores for cognitive impairment than the MMSE (MoCA, 0.92; 95% CI, 0.83 to 0.97 versus MMSE, 0.77; 95% CI, 0.66 to 0.83, p = 0.009).
Cognitive domain deficits and cognitive impairment in patients with aSAH can be screened with the MoCA in both the subacute and chronic phases.
Radiotherapy-induced glioblastomas (RIGB) are a well-known late and rare complication of brain irradiation. Yet the clinical, radiological and molecular characteristics of these tumors are not well ...characterized.
This was a retrospective multicentre study that analysed adult patients with newly diagnosed glioblastoma over a 10-year period. Patients with RIGB were identified according to Cahan's criteria for radiation-induced tumors. A case-control analysis was performed to compare known prognostic factors for overall survival (OS) with an independent cohort of IDH-1 wildtype de novo glioblastomas treated with standard temozolomide chemoradiotherapy. Survival analysis was performed by Cox proportional hazards regression.
A total of 590 adult patients were diagnosed with glioblastoma. 19 patients (3%) had RIGB. The mean age of patients upon diagnosis was 48 years ± 15. The mean latency duration from radiotherapy to RIGB was 14 years ± 8. The mean total dose was 58Gy ± 10. One-third of patients (37%, 7/19) had nasopharyngeal cancer and a fifth (21%, 4/19) had primary intracranial germinoma. Compared to a cohort of 146 de novo glioblastoma patients, RIGB patients had a shorter median OS of 4.8 months versus 19.2 months (p-value: <.001). Over a third of RIGBs involved the cerebellum (37%, 7/19) and was higher than the control group (4%, 6/146; p-value: <.001). A fifth of RIGBs (21%, 3/19) were pMGMT methylated which was significantly fewer than the control group (49%, 71/146; p-value: .01). For RIGB patients (32%, 6/19) treated with re-irradiation, the one-year survival rate was 67% and only 8% for those without such treatment (p-value: .007).
The propensity for RIGBs to develop in the cerebellum and to be pMGMT unmethylated may contribute to their poorer prognosis. When possible re-irradiation may offer a survival benefit. Nasopharyngeal cancer and germinomas accounted for the majority of original malignancies reflecting their prevalence among Southern Chinese.
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