Cushing's disease results from corticotroph adenomas of the pituitary that hypersecrete adrenocorticotropin (ACTH), leading to excess glucocorticoid and hypercortisolism. Mutations of the ...deubiquitinase gene USP8 occur in 35-62% of corticotroph adenomas. However, the major driver mutations in USP8 wild-type tumors remain elusive. Here, we report recurrent mutations in the deubiquitinase gene USP48 (predominantly encoding p.M415I or p.M415V; 21/91 subjects) and BRAF (encoding p.V600E; 15/91 subjects) in corticotroph adenomas with wild-type USP8. Similar to USP8 mutants, both USP48 and BRAF mutants enhance the promoter activity and transcription of the gene encoding proopiomelanocortin (POMC), which is the precursor of ACTH, providing a potential mechanism for ACTH overproduction in corticotroph adenomas. Moreover, primary corticotroph tumor cells harboring BRAF V600E are sensitive to the BRAF inhibitor vemurafenib. Our study thus contributes to the understanding of the molecular mechanism of the pathogenesis of corticotroph adenoma and informs therapeutic targets for this disease.
Introduction: TTFields plus Temozolomide (TTFields/TMZ) extended survival versus TMZ alone in newly diagnosed glioblastoma (GBM) patients in the EF-14 trial. We have reported a retrospective analysis ...of newly diagnosed Chinese GBM patients who received TTFields/TMZ treatment and TMZ treatment from August 2018 to May 2021 in Huashan hospital in Shanghai. Methods: Overall survival (OS) and progression-free survival (PFS) curves were constructed using the Kaplan−Meier method. A Cox proportional hazards regression model, propensity score matched data, and inverse probability of treatment weighting (IPTW) based on propensity score were used to assess the effect of TTFields and account for confounding factors. Results: In the preliminary analysis, the median PFS in TTFields/TMZ group was 16 months (95% CI, 9.6−24.6) versus 11 months (95% CI, 9−12) in TMZ group (p < 0.05). Median overall survival was 21.8 months (95% CI, 17.4-NA) with TTFields/TMZ versus 15 months (HR = 0.43; 95% CI, 13−18) with TMZ alone. The multivariate analysis identified surgery type, STUPP scheme, IDH status, and TTFields use as favorable prognostic factors. After PSM adjustment, the variate among the groups was similar, except that the methylation rate of MGMT promoter remained high in the TMZ group (12 v 32 months; p = 0.011). Upon IPTW Survival analysis, TTFields was associated with a significantly lower risk of death (HR = 0.19 in OS; 95% CI, 0.09−0.41) and progression (HR = 0.35; 95% CI 0.14−0.9) compared with TMZ group. Conclusion: In the final analysis of our single-center Chinese patients with glioblastoma, adding TTFields to temozolomide chemotherapy resulted in statistically significant improvement in PFS and OS.
Ependymoma typically has a better overall survival rate than most gliomas. Only a few comprehensive clinical studies have been published, but these are mostly from Western countries and use small ...sample sizes. Histopathological classification is not sufficient to show variable outcomes, and fails to show prognostic markers of the diverse outcomes; hence, it is essential to understand biological mechanisms. In this study, 176 ependymoma samples (World Health Organization grade II and III) were reviewed at Huashan Hospital. Both children and adults were included. We performed multifactorial analyses of clinical prognostic factors and the biomolecular marker expressions of nucleolin, epidermal growth factor receptor (EGFR) and caveolae-associated protein caveolin-1 by immunohistochemistry. We identified the probabilities of progression-free survival and overall survival using univariate and multivariate statistical methods. The participants were diagnosed with ependymomas between 2002 and 2010, including distributions of tumor locations in intracranial and extracranial regions. Nucleolin was overexpressed in 67 % of our samples, demonstrating a subgroup with poor outcome; particularly infratentorial and anaplastic ependymomas. There was no significant correlation between the expression of EGFR and caveolin-1 and clinical outcomes. Clinically, inferior prognosis was observed with regard to age (<18 years), intracranial location, high grade ependymomas, and incomplete resection. We found that nucleolin was an unfavorable prognostic predictor for ependymomas. Moreover, our findings show a subset of aggravating outcomes in high-grade and posterior fossa tumors.
Pituitary adenoma (PA) is one of the most common intracranial neoplasms. Several genetic predisposing factors for PA have been identified, but they account for a small portion of cases. In this ...study, we sought to identify the PA genetic risk factors by focusing on causative mutations for PAs. Among the 4 affected and 17 asymptomatic members from one family with familial PA, whole-exome sequencing identified cosegregation of the PA phenotype with the heterozygous missense mutation c.4136G>T (p.Arg1379Leu) in cadherin-related 23 (CDH23). This mutation causes an amino acid substitution in the calcium-binding motif of the extracellular cadherin (EC) domains of CDH23 and is predicted to impair cell-cell adhesion. Genomic screening in a total of 12 families with familial PA (20 individuals), 125 individuals with sporadic PA, and 260 control individuals showed that 33% of the families with familial PA (4/12) and 12% of individuals with sporadic PA (15/125) harbored functional CDH23 variants. In contrast, 0.8% of the healthy control individuals (2/260) carried functional CDH23 variants. Gene-based analysis also revealed a significant association between CDH23 genotype and PA (p = 5.54 × 10−7). Moreover, PA individuals who did not harbor functional CDH23 variants displayed tumors that were larger in size (p = 0.005) and more invasive (p < 0.001). Therefore, mutations in CDH23 are linked with familial and sporadic PA and could play important roles in the pathogenesis of PA.
Intraoperative ultrasonography is widely used in neurosurgery for the management of intracerebral hematoma and brain tumor. However, the clinical value of this method in the surgery of cerebral ...arteriovenous malformations (AVMs) has not been reported. In this study, the application of intraoperative ultrasonography for AVM surgery was evaluated prospectively.
This prospective clinical study comprised 41 patients who underwent microsurgical resection of cerebral AVMs at our institute. After routine craniotomy, ultrasonographic imaging with color Doppler ultrasonography and real-time contrast-enhanced ultrasonographic angiography if necessary were applied as navigated images on the monitor during the operation.
Ultrasonographic imaging made it easier to understand the vascular architecture during the operation. Color Doppler flow imaging clearly delineated the shape and margin of the AVMs. Intraoperative real-time contrast-enhanced ultrasonographic angiography enabled the surgeons to categorically identify AVM feeders both on the surface and deep in the tissue.
Microneurosurgery with intraoperative ultrasonographic image guidance was a safe, effective, and reliable method for identifying the afferent and efferent vessels and for confirming the complete resection of AVMs. These benefits of image-guided microsurgery were mostly apparent for deep-seated AVMs that were not visible on the surface of the brain.
This study aimed to generate mutant mice containing the Acvrl1 gene flanked with LoxP sequences to allow conditional deletion of Acvrl1 by the LoxP/Cre system. Such mice may facilitate the ...development of brain arteriovenous malformation (BAVM) models.
The CRISPR/Cas9 technique was used to edit Acvrl1. Two single guide RNAs (sgRNAs) with recognition sites on intron 3 and 8 and a donor vector that was homologous with the targeted gene and contained two LoxP sequences were designed and constructed. The in vitro-synthesized sgRNA, Cas9 mRNA and donor vectors were injected into mouse zygotes, which were then transferred into pseudopregnant mice. Neonatal mutant mice were identified by genotyping and sequencing.
Two mice with a floxed Acvrl1 allele were generated at a success rate of 8.7%. The target mice, which were healthy and fertile, were obtained through interbreeding.
CRISPR/Cas9 is a reliable gene-editing tool, and is able to efficiently modify Acvrl1 and create the target mice.
•This study is to generate mutant mice containing the Alk1 gene flanked with LoxP sequences to allow the conditional deletion of Alk1 by the LoxP/Cre system.•CRISPR/Cas9 technique was used to edit Alk1.•CRISPR/Cas9 technique was able to efficiently modify Alk1 and create the target mice.
Abstract Background Intraoperative ultrasound is widely used in neurosurgery for the management of intracerebral hematoma and brain tumor. However, the clinical value of this method in the surgery of ...cerebral arteriovenous malformations (AVMs) has not been reported. In this study, the application of intraoperative ultrasound for AVMs surgery was evaluated prospectively. Methods This prospective clinical study comprised of 41 patients who underwent microsurgical resection of cerebral AVMs at our institute. After routine craniotomy, ultrasound imaging with color Doppler ultrasonography and real-time contrast-enhanced ultrasound angiography if necessary were applied as navigated images on the monitor during the operation. Results Ultrasound image made it easier to understand the vascular architecture during the operation. Color Doppler flow image clearly delineated the shape and margin of the AVMs. Intraoperative real-time contrast-enhanced ultrasound angiography enabled the surgeons to categorically identify AVM feeders both on the surface and deep in the tissue. Conclusions Microneurosurgery with intraoperative ultrasound image guidance was a safe, effective and reliable method for identifying the afferent and efferent vessels and for confirming the complete resection of AVMs. These benefits of image-guided microsurgery were mostly apparent for deep-seated AVMs that were not visible on the surface of the brain.
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