Changcun Pan

The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults

Brainstem and thalamic gliomas are rare, and they are poorly understood in adults. Genetic aberrations that occur in these tumors are still unknown. In this study, we investigated whether thalamic gliomas have different genetic aberrations and clinical outcomes compared with brainstem gliomas in adults. Forty-three glioma samples were selected, including 28 brainstem and 15 thalamic gliomas. The frequency of the K27M mutation in adult midline gliomas was 58.1%. High-grade gliomas in the thalamus were statistically significantly more numerous than brainstem gliomas. Patients with K27M mutant brainstem gliomas had a significantly shorter overall survival than patients with wild-type tumors (P = .020) by Cox regression after adjustment for other independent risk factors. However, there was no statistical tendency toward a poorer overall survival in thalamic gliomas containing the K27M mutation compared with wild-type tumors. The presence of the K27M mutation significantly corresponded with mutations in TP53 in thalamic gliomas. Interestingly, the K27M mutation was mutually exclusive with mutations in IDH1, which was detected only in brainstem gliomas. The microarray data identified 86 differentially expressed genes between brainstem and thalamic gliomas with the K27M mutation. The cyclin-dependent kinase 6 (CDK6) gene, which plays an important role in cancer pathways, was found to be differentially expressed between brainstem and thalamic gliomas with K27M mutations. Although the K27M mutation was frequently observed in adult brainstem and thalamic gliomas, this mutation tended to be associated with a poorer prognosis in brainstem gliomas but not in thalamic gliomas. Brainstem gliomas may present different genetic aberrations from thalamic gliomas. These differences may provide guidance for therapeutic decisions for the treatment of adult brainstem and thalamic gliomas, which may have different molecular targets.

Upregulation of p-Smad2 contributes to FAT10-induced oncogenic activities in glioma

The human leukocyte antigen f-associated transcript 10 (FAT10) has a similar structure and function with ubiquitin, which efficiently mediate proteasome degradation in an ubiquitin-independent manner. FAT10 expression is upregulated in many tumor tissues and plays a vital role in cell cycle regulation and tumor genesis. However, its role in glioma has not been illuminated. The aim of this study was to evaluate the prognostic value of FAT10 and investigate its functional roles in glioma. The expression of FAT10 in glioma patient samples was examined using quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry methods. Glioma cell lines with either FAT10 overexpression or knockdown were created. The effect of FAT10 on glioma cell migration and invasion was investigated using these cells. In the present study, we had shown that FAT10 was elevated significantly in glioma samples and correlated with tumor pathological grade. FAT10 high-expression glioma is associated with a poor clinical prognosis. Overexpression of FAT10 promoted proliferation, invasion, migration, and sphere formation of glioma cells, whereas downregulation of FAT10 had an opposite effect. Overexpression of FAT10 also promoted the growth of glioma cells in vivo. Moreover, FAT10 enhanced the phosphorylation of Smad2, which contributes to FAT10-induced oncogenic activities in glioma. In conclusion, these findings indicate that FAT10 is a critical regulator potential therapeutic target of glioma.

Patient-derived DIPG cells preserve stem-like characteristics and generate orthotopic tumors

Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor, with a median survival of less than one year. Due to enormous difficulties in the acquisition of DIPG specimens and the sophisticated technique required to perform brainstem orthotopic injection, only a handful of DIPG pre-clinical models are available. In this study, we successfully established eight patient-derived DIPG cell lines, mostly derived from treatment-naïve surgery or biopsy specimens. These patient-derived cell lines can be stably passaged in serum-free neural stem cell media and displayed distinct morphologies, growth rates and chromosome abnormalities. In addition, these cells retained genomic hallmarks identical to original human DIPG tumors. Notably, expression of several neural stem cell lineage markers was observed in DIPG cell lines. Moreover, three out of eight cell lines can form orthotopic tumors in mouse brainstem by stereotactic injection and these tumors faithfully represented the characteristics of human DIPG by magnetic resonance imaging (MRI) and histopathological staining. Taken together, we established DIPG pre-clinical models resembling human DIPG and they provided a valuable resource for future biological and therapeutic studies.Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor, with a median survival of less than one year. Due to enormous difficulties in the acquisition of DIPG specimens and the sophisticated technique required to perform brainstem orthotopic injection, only a handful of DIPG pre-clinical models are available. In this study, we successfully established eight patient-derived DIPG cell lines, mostly derived from treatment-naïve surgery or biopsy specimens. These patient-derived cell lines can be stably passaged in serum-free neural stem cell media and displayed distinct morphologies, growth rates and chromosome abnormalities. In addition, these cells retained genomic hallmarks identical to original human DIPG tumors. Notably, expression of several neural stem cell lineage markers was observed in DIPG cell lines. Moreover, three out of eight cell lines can form orthotopic tumors in mouse brainstem by stereotactic injection and these tumors faithfully represented the characteristics of human DIPG by magnetic resonance imaging (MRI) and histopathological staining. Taken together, we established DIPG pre-clinical models resembling human DIPG and they provided a valuable resource for future biological and therapeutic studies.

BRAF V600E mutation is a significant prognosticator of the tumour regrowth rate in brainstem gangliogliomas

BRAF V600E mutations are progression factors in paediatric low-grade gliomas. Furthermore, a high percentage of paediatric brainstem gangliogliomas have BRAF V600E mutations. However, their clinical significance, including possible connections between the biomarkers and gangliogliomas clinical features, especially a brainstem counterpart, is unclear. To identify potential molecular features predictive of brainstem gangliogliomas clinical outcomes, a retrospective cohort of 28 World Health Organization (WHO) grade I brainstem gangliogliomas was analysed for BRAF V600E, IDH1 R132H, and IDH2 R172K mutations, TERT C228T/C250T promoter mutation, H3F3A K27M mutation and MGMT methylation. The volume of tumours was calculated accurately by using 3D Slicer software. The clinical data of these patients were retrospectively analysed. In tumours with BRAF V600E mutations, the tumour regrowth rate was significantly faster than that of the wild type group (p=0.001). Moreover, the BRAF V600E mutant group had shorter progression-free survival (PFS) compared with wild type (p=0.012). On multivariate analysis, no factor was found to be an independent prognostic factor; however, tumours with faster regrowth rates had a strong trend towards an increased risk for shorter PFS (HR=1.027, p=0.056). No statistical analysis could be performed to evaluate factors affecting overall survival (OS). These data suggest that BRAF V600E can predict the regrowth rate of brainstem gangliogliomas after microsurgery, and a BRAF V600E-targeted therapeutic may be a promising early intervention measure for patients who harbour BRAF V600E mutation after microsurgery.

An Automatic Preoperative Path-Planning Algorithm for Neurosurgery Using Combined MRI and DTI

Background: The structure of brainstem is very complex, and the surgical path planning for surgical navigation system can reduce the damage of the important tissue. We proposed an automatic preoperative path planning method based on combined magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) for determining optimal surgical paths in brain stem tumor surgery. Methods: First, we register the DTI into the MRI by comprehensive considering three type’s information of trace, fractional anisotropy and relative anisotropy to achieve more accurate DTI location information. After that, the optimal solution model of the preoperative path which computes a cost function associated with each point on the outer brain boundary and instrument entry path, is constructed by the gravitational repulsion model and spline interpolation using the segmented model of brainstem and fiber bundle. Furthermore, the preoperative path can be achieved automatically by optimizing the solution of the cost function, and the results are evaluated by comparing the cost of a particular path associated with each critical structure, as well as the total number of examining all the cross-sectional images orthogonal to this path. Results: Our method could complete automatic preoperative path planning and avoid important tissue damage with less cross-sectional images orthogonal to the planning path.

Fluorescein-Guided Surgery for Pediatric Brainstem Gliomas: Preliminary Study and Technical Notes

Introduction Brainstem gliomas (BsG) account for 10 to 15% of pediatric brain tumors. Surgery is the preferred treatment for focal and exophytic lesions. Sodium fluorescein has been proven safe and effective in resection of malignant brain tumors. Objective The objective was to o analyze the safety and effectiveness of this approach, to evaluate intraoperative fluorescein imaging, and to measure the safety of chosen dose for pediatric patients. Methods Twelve cases were enrolled between March 2014 and September 2016 in Beijing Tiantan Hospital. All of the patients received 2.5 mg/kg of sodium fluorescein before opening the dura; the intraoperative fluorescence enhancement was observed, and the degree of satisfaction and consistency with the neuronavigation were evaluated. Results With a mean age of 7.5 years, there were eight cases located within the pontine, three in the medullary oblongata, and one in the tectal plate. Histological results were astrocytoma, glioblastoma, oligodendroglioma, and pilocytic astrocytoma. Under the fluorescein module of the microscope, the tumors were recognizable enough to help surgeons to discriminate the lesion from non‐fluorescent tissue, with a consistency of 83% with the neuronavigation. Total removal was accomplished in nine cases, while the mean percentage of resection of the other cases was 93.7%. The Karnofsky performance score (KPS) showed no significant differences between pre‐operation and discharge, but there was a difference between pre‐operation and 6‐month follow‐up. Conclusion The fluorescein‐guided surgery is useful for demarcating the tumor margin and works well with other navigation and monitoring devices. A safe dose of sodium fluorescein (2.5 mg/kg) was proven effective for children.

A machine learning-based prediction model of H3K27M mutations in brainstem gliomas using conventional MRI and clinical features

BACKGROUND H3K27M is the most frequent mutation in brainstem gliomas (BSGs), and it has great significance in the differential diagnosis, prognostic prediction and treatment strategy selection of BSGs. There has been a lack of reliable noninvasive methods capable of accurately predicting H3K27M mutations in BSGs. METHODS A total of 151 patients with newly diagnosed BSGs were included in this retrospective study. The H3K27M mutation status was obtained by whole-exome, whole-genome or Sangers sequencing. A total of 1697 features, including 6 clinical parameters and 1691 imaging features, were extracted from pre- and post-contrast T1-weighted and T2-weighted images. Using a random forest algorithm, 36 selected MR image features were integrated with 3 selected clinical features to generate a model that was predictive of H3K27M mutations. Additionally, a simplified prediction model comprising the Karnofsky Performance Status (KPS) at diagnosis, symptom duration at diagnosis and edge sharpness on T2 was established for practical clinical utility using the least squares estimation method. RESULTS H3K27M mutation was an independent prognostic factor that conferred a worse prognosis (p = 0.01, hazard ratio = 3.0, 95% confidence interval [CI], 1.57-5.74). The machine learning-based model achieved an accuracy of 84.44% (area under the curve [AUC] = 0.8298) in the test cohort. The simplified model achieved an AUC of 0.7839 in the test cohort. CONCLUSIONS Using conventional MRI and clinical features, we established a machine learning-based model with high accuracy and a simplified model with improved clinical utility to predict H3K27M mutations in BSGs.

Prognostic indicators of adult medullary gliomas after microsurgical treatment - A retrospective analysis of 54 patients.

Due to the low incidence of medullary gliomas, the special location, and the function of the gliomas in the medulla oblongata, microsurgical treatment is still challenging for neurosurgeons. The aim of this study was to observe the effect of microsurgical treatment of adult medullary gliomas and to explore the prognostic factors after treatment. The clinical data from 54 patients with adult medullary gliomas who received microsurgical treatment at Beijing Tiantan Hospital (China) from April 2008 to April 2014 was retrospectively analyzed. The factors affecting their prognosis were analyzed with log-rank univariate analysis. The factors that affected prognosis included age, gender, duration of preoperative symptoms, Karnofsky Performance Scale (KPS) score, World Health Organization (WHO) grade, extent of tumor resection, and postoperative complications. Those with statistical significance in the univariate analysis were entered into a multivariate Cox regression analysis. WHO grading showed 7 cases of grade I, 30 cases of grade II, 14 cases of grade III, and 3 cases of grade IV tumors. Univariable analysis showed that postoperative nasogastric feeding (P=0.031), WHO pathological grade (P=0.018), extent of resection (P=0.016), and preoperative involvement of ≥3 cranial nerves (CNs) (P=0.014) affected overall survival. The WHO pathological grade of the tumor was an independent risk factor for prognosis. In conclusion, the WHO pathological grade of the tumor was an important prognostic indicator.