Fimepinostat Impairs NF-κB and PI3K/AKT Signaling and Enhances Gemcitabine Efficacy in H3.3K27M-Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine glioma (DIPG) is the most aggressive pediatric brain tumor, and the oncohistone H3.3K27M mutation is associated with significantly worse clinical outcomes. Despite extensive research efforts, effective approaches for treating DIPG are lacking. Through drug screening, we identified the combination of gemcitabine and fimepinostat as a potent therapeutic intervention for H3.3K27M DIPG. H3.3K27M facilitated gemcitabine-induced apoptosis in DIPG, and gemcitabine stabilized and activated p53, including increasing chromatin accessibility for p53 at apoptosis-related loci. Gemcitabine simultaneously induced a prosurvival program in DIPG through activation of RELB-mediated NF-κB signaling. Specifically, gemcitabine induced the transcription of long terminal repeat elements, activated cGAS-STING signaling, and stimulated noncanonical NF-κB signaling. A drug screen in gemcitabine-treated DIPG cells revealed that fimepinostat, a dual inhibitor of HDAC and PI3K, effectively suppressed the gemcitabine-induced NF-κB signaling in addition to blocking PI3K/AKT activation. Combination therapy comprising gemcitabine and fimepinostat elicited synergistic antitumor effects in vitro and in orthotopic H3.3K27M DIPG xenograft models. Collectively, p53 activation using gemcitabine and suppression of RELB-mediated NF-κB activation and PI3K/AKT signaling using fimepinostat is a potential therapeutic strategy for treating H3.3K27M DIPG. SIGNIFICANCE: Gemcitabine activates p53 and induces apoptosis to elicit antitumor effects in H3.3K27M DIPG, which can be enhanced by blocking NF-κB and PI3K/AKT signaling with fimepinostat, providing a synergistic combination therapy for DIPG.

A novel radiological classification of midbrain pilocytic astrocytomas and its implication for surgical management: a single-institution experience of 57 cases.

OBJECTIVE: Surgery for midbrain pilocytic astrocytoma (PA) remains a formidable challenge. To facilitate decision-making and achieve a better outcome in the management of patients with midbrain PA, the authors have proposed a novel radiological classification of midbrain PAs with long-term follow-up. METHODS: Fifty-seven midbrain PA patients who underwent surgery at Beijing Tiantan Hospital, Capital Medical University, from January 2008 to June 2021, were reviewed. Based on tumor location and the topological anatomical change identified on MRI, midbrain PAs were categorized into four types: crural (12/57, 21.1%), tegmental (25/57, 43.9%), aqueductal (5/57, 8.8%), and tectal (15/57, 26.3%) PAs. The relevant clinical, radiological, and pathological data; surgical procedures and results; and long-term outcomes were collected and analyzed. RESULTS: The 1-, 3-, and 5-year survival rates reached 98%, 96%, and 96%, respectively, with gross-total resection achieved in 66.7% of cases, followed by near-total resection in 17.5% cases. The clinical and radiological features, selection of surgical approaches, and long-term postoperative deficits were distinct among each type. Crural PAs were associated with younger age (median 9 years, IQR 5.0-12.8 years); the largest tumor volume (median 31.9 cm3, IQR 17.2-42.6 cm3); the lowest preoperative Karnofsky Performance Scale (KPS) score (median 65, IQR 50-70); the most frequent preoperative motor deficit (91.7%); a mixed solid-cystic component (75%); occupation of the crural cistern; elevation and rotation of the thalamus (medial and/or lateral); displacement of the anterior third ventricle, uncus, and anterior commissure; the most diverse surgical approaches; more frequent use of multimodality image-guided surgery (58.3%); and the most remarkable improvement in KPS score at long-term follow-up. Tegmental PAs were associated with adolescents and young adults (median age 21 years, IQR 8-33 years); tumor volume (median 13.9 cm3, IQR 9.5-20.5 cm3); a good preoperative KPS score (median 80, IQR 70-80); a mixed solid-cystic component (72%); occupation of the ambient cistern and cerebellomesencephalic fissure; a close relationship with the dorsal pons, superior cerebellar peduncle, and posterior inferior third ventricle; and a higher probability of permanent postoperative sensory deficits (40%). Aqueductal and tectal PAs were associated with small tumor volume (median 9.14 cm3, IQR 5.1-17.4 cm3 and median 11.84 cm3, IQR 5.7-18.3 cm3, respectively), a higher percentage of hydrocephalus (80% and 86.7%, respectively), and a straightforward selection of limited surgical approaches. CONCLUSIONS: A novel and comprehensive radiological classification of midbrain PAs was established, which will serve as a valuable tool in patient management and promote uniform communication and comparison across different studies and publications.

Classification of Brainstem Gliomas Based on Tumor Microenvironment Status.

The inter-tumor heterogeneity of the tumor microenvironment (TME) and how it correlates with clinical profiles and biological characteristics in brainstem gliomas (BSGs) remain unknown, dampening the development of novel therapeutics against BSGs. The TME status was determined with a list of pan-cancer conserved gene expression signatures using a single-sample gene set enrichment analysis (ssGSEA) and was subsequently clustered via consensus clustering. BSGs exhibited a high inter-tumor TME heterogeneity and were classified into four clusters: "immune-enriched, fibrotic", "immune-enriched, non-fibrotic", "fibrotic", and "depleted". The "fibrotic" cluster had a higher proportion of diffuse intrinsic pontine gliomas (p = 0.041), and "PA-like" tumors were more likely to be "immune-enriched, fibrotic" (p = 0.044). The four TME clusters exhibited distinct overall survival (p < 0.001) and independently impacted BSG outcomes. A four-gene panel as well as a radiomics approach were constructed to identify the TME clusters and achieved high accuracy for determining the classification. Together, BSGs exhibited high inter-tumor heterogeneity in the TME and were classified into four clusters with distinct clinical outcomes and tumor biological properties. The TME classification was accurately identified using a four-gene panel that can potentially be examined with the immunohistochemical method and a non-invasive radiomics method, facilitating its clinical application.

B7H3-targeting chimeric antigen receptor modification enhances antitumor effect of Vγ9Vδ2 T cells in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. This study investigates the therapeutic potential of human Vγ9Vδ2 T cells in GBM treatment. The sensitivity of different glioma specimens to Vγ9Vδ2 T cell-mediated cytotoxicity is assessed using a patient-derived tumor cell clusters (PTCs) model. METHODS: The study evaluates the anti-tumor effect of Vγ9Vδ2 T cells in 26 glioma cases through the PTCs model. Protein expression of BTN2A1 and BTN3A1, along with gene expression related to lipid metabolism and glioma inflammatory response pathways, is analyzed in matched tumor tissue samples. Additionally, the study explores two strategies to re-sensitize tumors in the weak anti-tumor effect (WAT) group: utilizing a BTN3A1 agonistic antibody or employing bisphosphonates to inhibit farnesyl diphosphate synthase (FPPS). Furthermore, the study investigates the efficacy of genetically engineered Vγ9Vδ2 T cells expressing Car-B7H3 in targeting diverse GBM specimens. RESULTS: The results demonstrate that Vγ9Vδ2 T cells display a stronger anti-tumor effect (SAT) in six glioma cases, while showing a weaker effect (WAT) in twenty cases. The SAT group exhibits elevated protein expression of BTN2A1 and BTN3A1, accompanied by differential gene expression related to lipid metabolism and glioma inflammatory response pathways. Importantly, the study reveals that the WAT group GBM can enhance Vγ9Vδ2 T cell-mediated killing sensitivity by incorporating either a BTN3A1 agonistic antibody or bisphosphonates. Both approaches support TCR-BTN mediated tumor recognition, which is distinct from the conventional MHC-peptide recognition by αß T cells. Furthermore, the study explores an alternative strategy by genetically engineering Vγ9Vδ2 T cells with Car-B7H3, and both non-engineered and Car-B7H3 Vγ9Vδ2 T cells demonstrate promising efficacy in vivo, underscoring the versatile potential of Vγ9Vδ2 T cells for GBM treatment. CONCLUSIONS: Vγ9Vδ2 T cells demonstrate a robust anti-tumor effect in some glioma cases, while weaker in others. Elevated BTN2A1 and BTN3A1 expression correlates with improved response. WAT group tumors can be sensitized using a BTN3A1 agonistic antibody or bisphosphonates. Genetically engineered Vγ9Vδ2 T cells, i.e.,  Car-B7H3, show promising efficacy. These results together highlight the versatility of Vγ9Vδ2 T cells for GBM treatment.

Diffusion MRI-based connectomics features improve the noninvasive prediction of H3K27M mutation in brainstem gliomas.

PURPOSE: To establish an individualized predictive model to identify patients with brainstem gliomas (BSGs) at high risk of H3K27M mutation, with the inclusion of brain structural connectivity analysis based on diffusion MRI (dMRI). MATERIALS AND METHODS: A primary cohort of 133 patients with BSGs (80 H3K27M-mutant) were retrospectively included. All patients underwent preoperative conventional MRI and dMRI. Tumor radiomics features were extracted from conventional MRI, while two kinds of global connectomics features were extracted from dMRI. A machine learning-based individualized H3K27M mutation prediction model combining radiomics and connectomics features was generated with a nested cross validation strategy. Relief algorithm and SVM method were used in each outer LOOCV loop to select the most robust and discriminative features. Additionally, two predictive signatures were established using the LASSO method, and simplified logistic models were built using multivariable logistic regression analysis. An independent cohort of 27 patients was used to validate the best model. RESULTS: 35 tumor-related radiomics features, 51 topological properties of brain structural connectivity networks, and 11 microstructural measures along white matter tracts were selected to construct a machine learning-based H3K27M mutation prediction model, which achieved an AUC of 0.9136 in the independent validation set. Radiomics- and connectomics-based signatures were generated and simplified combined logistic model was built, upon which derived nomograph achieved an AUC of 0.8827 in the validation cohort. CONCLUSION: dMRI is valuable in predicting H3K27M mutation in BSGs, and connectomics analysis is a promising approach. Combining multiple MRI sequences and clinical features, the established models have good performance.

A multimodal imaging-based classification for pediatric diffuse intrinsic pontine gliomas.

OBJECT: Pediatric diffuse intrinsic pontine glioma (DIPG) is a radiologically heterogeneous disease entity, here we aim to establish a multimodal imaging-based radiological classification and evaluate the outcome of different treatment strategies under this classification frame. METHODS: This retrospective study included 103 children diagnosed with DIPGs between January 2015 and August 2018 in Beijing Tiantan Hospital (Beijing, China). Multimodal radiological characteristics, including conventional magnetic resonance imaging (MRI), diffuse tensor imaging/diffuse tensor tractography (DTI/DTT), and positron emission tomography (PET) were reviewed to construct the classification. The outcome of different treatment strategies was compared in each DIPG subgroup using Kaplan-Meier method (log-rank test) to determine the optimal treatment for specific DIPGs. RESULTS: Four radiological DIPG types were identified: Type A ("homocentric", n=13), Type B ("ventral", n=41), Type C ("eccentric", n=37), and Type D ("dorsal", n=12). Their treatment modalities were grouped as observation (43.7%), cytoreductive surgery (CRS) plus radiotherapy (RT) (24.3%), RT alone (11.7%), and CRS alone (20.4%). CRS+RT mainly fell into type C (29.7%), followed by type B1 (21.9%) and type D (50%). Overall, CRS+RT exhibited a potential survival advantage compared to RT alone, which was more pronounced in specific type, but this did not reach statistical significance, due to limited sample size and unbalanced distribution. CONCLUSION: We proposed a multimodality imaging-based radiological classification for pediatric DIPG, which was useful for selecting optimal treatment strategies, especially for identifying candidates who may benefit from CRS plus RT. This classification opened a window into image-guided integrated treatment for pediatric DIPG.

Role of neuronavigation in the surgical management of brainstem gliomas.

Objective: NeuroNavigation (NN) is a widely used intraoperative imaging guidance technique in neurosurgical operations; however, its value in brainstem glioma (BSG) surgery is inadequately reported and lacks objective proof. This study aims to investigate the applicational value of NN in BSG surgery. Method: A retrospective analysis was performed on 155 patients with brainstem gliomas who received craniotomy from May 2019 to January 2022 at Beijing Tiantan Hospital. Eighty-four (54.2%) patients received surgery with NN. Preoperative and postoperative cranial nerve dysfunctions, muscle strength, and Karnofsky (KPS) were evaluated. Patients' radiological features, tumor volume, and extent of resection (EOR) were obtained from conventional MRI data. Patients' follow-up data were also collected. Comparative analyses on these variables were made between the NN group and the non-NN group. Result: The usage of NN is independently related to a higher EOR in diffuse intrinsic pontine glioma (DIPG) (p=0.005) and non-DIPG group (p<0.001). It was observed that fewer patients in the NN group suffered from deterioration of KPS (p=0.032) and cranial nerve function (p=0.017) in non-DIPG group, and deterioration of muscle strength (p=0.040) and cranial nerve function (p=0.038) in DIPG group. Moreover, the usage of NN is an independent protective factor for the deterioration of KPS (p=0.04) and cranial nerve function (p=0.026) in non-DIPG patients and the deterioration of muscle strength (p=0.009) in DIPG patients. Furthermore, higher EOR subgroups were found to be independently related to better prognoses in DIPG patients (p=0.008). Conclusion: NN has significant value in BSG surgery. With the assistance of NN, BSG surgery achieved higher EOR without deteriorating patients' functions. In addition, DIPG patients may benefit from the appropriate increase of EOR.

Clinical, pathological, and radiological features of 80 pediatric diffuse intrinsic pontine gliomas: A single-institute study.

Objective: Diffuse intrinsic pontine gliomas (DIPGs) are rare but devastating diseases. This retrospective cross-sectional study aimed to investigate the clinical, radiological, and pathological features of DIPGs. Materials and methods: The clinical data of 80 pediatric DIPGs under clinical treatment in Beijing Tiantan Hospital from July 2013 to July 2019 were retrospectively collected and studied. A follow-up evaluation was performed. Results: This study included 48 men and 32 women. The most common symptoms were cranial nerve palsy (50.0%, 40/80 patients) and limb weakness (41.2%, 33/80 patients). Among the 80 patients, 24 cases were clinically diagnosed, 56 cases were pathologically verified, and 45 cases were tested for H3K27 alteration status, with 34 H3K27 alteration cases confirmed. Radiological results indicated that enhancement was common (65.0%, 52/80 patients). Cho/Cr was of predictive value for H3K27 alteration status (P = 0.012, cutoff value = 2.38, AUC = 0.801). Open cranial surgery followed by further chemotherapy and radiotherapy was beneficial for patients' overall survival. Cox regression analysis indicated H3K27 alteration to be the independent prognostic influencing factor for DIPGs in this series (P = 0.002). Conclusion: DIPGs displayed a wide spectrum of clinical and imaging features. Surgery-suitable patients could benefit from postoperative comprehensive therapy for a better overall survival. H3K27 alteration was the independent prognostic influencing factor for DIPGs.

11C-methionine PET imaging characteristics in children with diffuse intrinsic pontine gliomas and relationship to survival and H3 K27M mutation status.

PURPOSE: This study aimed to describe 11C-methionine (11C-MET) PET imaging characteristics in patients with paediatric diffuse intrinsic pontine glioma (DIPG) and correlate them with survival and H3 K27M mutation status. METHODS: We retrospectively analysed 98 children newly diagnosed with DIPG who underwent 11C-MET PET. PET imaging characteristics evaluated included uptake intensity, uniformity, metabolic tumour volume (MTV), and total lesion methionine uptake (TLMU). The maximum, mean, and peak of the tumour-to-background ratio (TBR), calculated as the corresponding standardised uptake values (SUV) divided by the mean reference value, were also recorded. The associations between the PET imaging characteristics and clinical outcomes in terms of progression-free survival (PFS) and overall survival (OS) and H3 K27M mutation status were assessed, respectively. RESULTS: In univariate analysis, imaging characteristics significantly associated with shorter PFS and OS included a higher uniformity grade, higher TBRs, larger MTV, and higher TLMU. In multivariate analysis, larger MTV at diagnosis, shorter symptom duration, and no treatment were significantly correlated with shorter PFS and OS. The PET imaging features were not correlated with H3 K27M mutation status. CONCLUSION: Although several imaging features were significantly associated with PFS and OS, only MTV, indicating the size of the active tumour, was identified as a strong independent prognostic factor.

White matter alterations in pediatric brainstem glioma: An national brain tumor registry of China study.

Background: Previous studies have identified alterations in structural connectivity of patients with glioma. However, white matter (WM) integrity measured by diffusion kurtosis imaging (DKI) in pediatric patients with brainstem glioma (BSG) was lack of study. Here, the alterations in WM of patients with BSG were assessed through DKI analyses. Materials and methods: This study involved 100 patients with BSG from the National Brain Tumor Registry of China (NBTRC) and 50 age- and sex-matched healthy controls from social recruitment. WM tracts were segmented and reconstructed using U-Net and probabilistic bundle-specific tracking. Next, automatic fiber quantitative (AFQ) analyses of WM tracts were performed using tractometry module embedded in TractSeg. Results: WM quantitative analysis identified alterations in DKI-derived values in patients with BSG compared with healthy controls. WM abnormalities were detected in the projection fibers involved in the brainstem, including corticospinal tract (CST), superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP) and inferior cerebellar peduncle (ICP). Significant WM alterations were also identified in commissural fibers and association fibers, which were away from tumor location. Statistical analyses indicated the severity of WM abnormality was statistically correlated with the preoperative Karnofsky Performance Scale (KPS) and symptom duration of patients respectively. Conclusion: The results of this study indicated the widely distributed WM alterations in patients with BSG. DKI-derived quantitative assessment may provide additional information and insight into comprehensively understanding the neuropathological mechanisms of brainstem glioma.

Functionalized Macrophage Exosomes with Panobinostat and PPM1D-siRNA for Diffuse Intrinsic Pontine Gliomas Therapy.

Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain tumor. Mutation of p53-induced protein phosphatase 1 (PPM1D) in DIPG cells promotes tumor cell proliferation, and inhibition of PPM1D expression in DIPG cells with PPM1D mutation effectively reduces the proliferation activity of tumor cells. Panobinostat effectively kills DIPG tumor cells, but its systemic toxicity and low blood-brain barrier (BBB) permeability limits its application. In this paper, a nano drug delivery system based on functionalized macrophage exosomes with panobinostat and PPM1D-siRNA for targeted therapy of DIPG with PPM1D mutation is prepared. The nano drug delivery system has higher drug delivery efficiency and better therapeutic effect than free drugs. In vivo and in vitro experimental results show that the nano drug delivery system can deliver panobinostat and siRNA across the BBB and achieve a targeted killing effect of DIPG tumor cells, resulting in the prolonged survival of orthotopic DIPG mice. This study provides new ideas for the delivery of small molecule drugs and gene drugs for DIPG therapy.

Adult diffuse intrinsic pontine glioma: clinical, radiological, pathological, molecular features, and treatments of 96 patients.

OBJECTIVE: Unlike its pediatric counterpart, adult diffuse intrinsic pontine glioma (DIPG) remains largely unelucidated. In this study, the authors examined the clinical, radiological, pathological, molecular, and clinical aspects of 96 adult DIPGs. METHODS: The National Brain Tumor Registry of China (April 2013-December 2019) was used to collect data on radiologically diagnosed adult DIPG patients. Survival analysis was conducted using Kaplan-Meier curves and univariate and multivariate Cox regression. The chi-square test/Wilcoxon rank-sum test and multivariable logistic regression were used to examine the clinical and radiological characteristics of patients with long-term survival (LTS). Interaction analyses between clinical factors were also conducted. RESULTS: The median age at symptom onset was 33.5 years, and the median duration of symptoms was 4.5 months. The frequencies of H3K27M and IDH1 mutations were 37.2% and 26.5%, respectively. All adult DIPG patients had a median overall survival (OS) of 19.5 months, with 1-, 2-, and 3-year survival rates of 67.0%, 42.8%, and 36.0%, respectively. The median OS of 40 patients who did not undergo treatment was 13.4 months. Patients with H3K27M-mutant tumors had a poorer prognosis than those with IDH-mutant tumors (p < 0.001) and H3K27M(-)/IDH-wild-type tumors (p = 0.002), with a median OS of 11.4 months. The median OSs of patients with H3K27M-mutant tumors who received treatment and those who did not were 13.8 months and 7.5 months, respectively (p = 0.016). Among patients with and without a pathological diagnosis, H3K27M mutation (p < 0.001) and contrast enhancement on MRI (p = 0.003), respectively, imparted a worse prognosis. Treatments were the predictive factor for patients with H3K27M-mutant tumors (p = 0.038), whereas contrast enhancement on MRI was the prognostic factor for the H3K27M(-) group (p = 0.038). In addition, H3K27M mutation and treatment were significant predictors for patients with symptom duration ≤ 4 months (H3K27M, p = 0.020; treatment, p = 0.014) and tumors with no contrast enhancement (H3K27M, p = 0.003; treatment, p = 0.042). Patients with LTS were less likely to have cranial nerve palsy (p = 0.002) and contrast enhancement on MRI at diagnosis (p = 0.022). CONCLUSIONS: It is recommended that all adult DIPG patients undergo genomic testing for H3K27M and IDH mutations. Despite the low prevalence, additional study is needed to better characterize the efficacy of various treatment modalities in adults with DIPG.

Surgical management and clinical outcomes of cerebellar liponeurocytomas-a report of seven cases and a pooled analysis of individual patient data.

Cerebellar liponeurocytomas (CLPNs) are very rare, with very few studies on this disease. Their treatment protocol also remains unclear. To better understand the disease, we reviewed the clinical features and outcomes, and proposed a treatment protocol based on previously reported cases as well as cases from our institute. The clinical data were obtained from seven patients with pathologically confirmed CLPNs, who underwent surgical treatment at our institute between November 2011 and June 2021. We also reviewed the relevant literature and 75 patients with CLPNs were identified between September 1993 and June 2021. Risk factors for progression-free survival (PFS) were evaluated in the pooled cohort. Our cohort included four males and three females, with a mean age of 43.9 ± 14.5 years (range: 29-64 years). CLPNs were located in the lateral ventricle in three cases and in the cerebellum in four cases. All seven cases achieved gross total resection (GTR) and radiotherapy was administered to two cases. After a mean follow-up of 44.9 ± 44.4 months, all patients remained well, with no recurrence or death. Among the 75 patients reported in the literature, 35 were males and 40 were females, with a mean age of 46.2 ± 13.6 years (range: 6-77 years). Biopsy, GTR, and non-GTR were achieved in one (1.3%), 50 (66.7%), and 24 (32%) patients, respectively. Radiotherapy was administered to 16 cases and chemotherapy was administered to only one case. After a mean follow-up of 47.5 ± 51.5 months, three patients died and tumor recurrence occurred in 17 patients. Multivariate Cox analysis revealed that non-GTR predicted a poor PFS (p = 0.020), and postoperative radiotherapy could not prolong PFS (p = 0.708). Kaplan-Meier analysis also showed that GTR was significantly associated with longer PFS (p = 0.008), and postoperative radiotherapy could not prolong PFS (p = 0.707). PFS rates at 1, 5, 10 years were 92.7%, 78.0%, 23.8% respectively. CLPNs are very rare brain tumors. Although they have favorable clinical prognosis, the recurrence is relatively high. GTR should be the first choice for treatment and close follow-up is necessary. Postoperative radiotherapy could not improve PFS in this study. A larger cohort is needed to verify our findings.

The role of diffusion tensor imaging and tractography in the surgical management of brainstem gliomas.

OBJECTIVE: Diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) have the ability to noninvasively visualize changes in white matter tracts, as well as their relationships with lesions and other structures. DTI/DTT has been increasingly used to improve the safety and results of surgical treatment for lesions in eloquent areas, such as brainstem cavernous malformations. This study aimed to investigate the application value of DTI/DTT in brainstem glioma surgery and to validate the spatial accuracy of reconstructed corticospinal tracts (CSTs). METHODS: A retrospective analysis was performed on 54 patients with brainstem gliomas who had undergone surgery from January 2016 to December 2018 at Beijing Tiantan Hospital. All patients underwent preoperative DTI and tumor resection with the assistance of DTT-merged neuronavigation and electrophysiological monitoring. Preoperative conventional MRI and DTI data were collected, and the muscle strength and modified Rankin Scale (mRS) score before and after surgery were measured. The surgical plan was created with the assistance of DTI/DTT findings. The accuracy of DTI/DTT was validated by performing direct subcortical stimulation (DsCS) intraoperatively. Multiple linear regression was used to investigate the relationship between quantitative parameters of DTI/DTT (such as the CST score and tumor-to-CST distance [TCD]) and postoperative muscle strength and mRS scores. RESULTS: Among the 54 patients, 6 had normal bilateral CSTs, 12 patients had unilateral CST impairments, and 36 had bilateral CSTs involved. The most common changes in the CSTs were deformation (n = 29), followed by deviation (n = 28) and interruption (n = 27). The surgical approach was changed in 18 cases (33.3%) after accounting for the DTI/DTT results. Among 55 CSTs on which DsCS was performed, 46 (83.6%) were validated as spatially accurate by DsCS. The CST score and TCD were significantly correlated with postoperative muscle strength (r = -0.395, p < 0.001, and r = 0.275, p = 0.004, respectively) and postoperative mRS score (r = 0.430, p = 0.001, and r = -0.329, p = 0.015, respectively). The CST score was independently linearly associated with postoperative muscle strength (t = -2.461, p = 0.016) and the postoperative mRS score (t = 2.052, p = 0.046). CONCLUSIONS: DTI/DTT is a valuable tool in the surgical management of brainstem gliomas. With good accuracy, it can help optimize surgical planning, guide tumor resection, and predict the postoperative muscle strength and postoperative quality of life of patients.

Trans-lamina terminalis suprategmental approach for ventral midbrain lesions: Technical note.

Surgical resection of lesions located in the ventral midbrain is challenging. Few approaches and safe entry zones (SEZs) have been proposed and used to remove this type of lesion, and each has its limitations. Using two illustrating cases, the authors describe a trans-lamina terminalis suprategmental approach for removing ventral midbrain lesions. This approach provides a straight surgical trajectory with sparse neurovascular structures and can be performed with a standard pterional or subfrontal craniotomy. It may be the ideal approach for ventromedial midbrain lesions extending towards the third ventricle.

Surgical treatment and prognosis of focal brainstem gliomas in children: A 7 year single center experience.

This study aims to describe the role of open surgical treatment for focal brainstem gliomas (FBSGs) with the assistance of multimodal neuronavigation and intraoperative neurophysiological monitoring (IOM) in children to investigate the efficacy of microsurgical treatment in pediatric FBSGs. Also the prognostic factors related to the overall survival (OS) of FBSGs to describe the patient and tumor characteristics relevant to prognosis/outcome were focused on. Clinical data of 63 pediatric patients below 16 years of age with FBSGs admitted to the Neurosurgical Unit of Beijing Tiantan Hospital from January 2012 to December 2018 were retrospectively analyzed. All patients underwent initial surgical treatment, followed by magnetic resonance diffusion tensor imaging (DTI), neuronavigation and IOM. Gross or near total resection (GTR or NTR) was achieved in 57/63 (90.5%) cases, and subtotal resection (STR) was achieved in 6/63 (9.5%) cases. Postoperative adjuvant therapy was received by 27/63 (42.9%) cases. Postoperative pathological examination revealed that 36/63 (57.1%) cases had grade I gliomas, 22/63 (34.9%) had grade II, and 5/63 (8.0%) had grade III-IV gliomas according to the WHO classification. The mean Karnofsky score preoperatively was 60, and at the time of follow-up was 90. Consecutively, 6 cases demonstrated disease progression, and 5 of these were deceased. The OS in all patients was 81.2% at 5 years. Histological grade (P < .001) and age at diagnosis (P = .023) showed significant association with prolonged OS. Multimodal neuronavigation and IOM allow very precise intracranial surgery, contributing to a maximally safe resection that might decrease the postoperative disability and mortality rate. This study also showed that pediatric FBSGs were mostly low-grade tumors with excellent surgical outcomes. Consequently, it is suggested that microsurgery can be used to treat FBSGs in children in order to provide better prognosis and survival outcomes.

The integrated genomic and epigenomic landscape of brainstem glioma.

Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies. We perform a comprehensive study incorporating epigenetic and genomic analyses on a large cohort of brainstem gliomas, including Diffuse Intrinsic Pontine Gliomas. Here we report, from DNA methylation data, distinct clusters termed H3-Pons, H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles. The majority of tumors within H3-Pons and-H3-Medulla harbors H3F3A mutations but shows distinct methylation patterns that correlate with anatomical localization within the pons or medulla, respectively. Clinical data show significantly different overall survival between these clusters, and pathway analysis demonstrates different oncogenic mechanisms in these samples. Our findings indicate that the integration of genetic and epigenetic data can facilitate better understanding of brainstem gliomagenesis and classification, and guide future studies for the development of novel treatments for this disease.

Potent anti-tumor efficacy of palbociclib in treatment-naïve H3.3K27M-mutant diffuse intrinsic pontine glioma.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain cancer without cure. Seeking therapeutic strategies is still a major challenge in DIPG research. Previous study has shown that dysregulation of G1/S cell cycle checkpoint was common in DIPG and this dysregulation is even more enriched in the H3.3K27 M mutant subgroup. Here we assess potential anti-tumor efficacy of palbociclib, a specific and cytostatic inhibitor of CDK4/6, on high grade H3.3-K27 M-mutant DIPGs in vitro and in vivo. METHODS: We established patient-derived cell lines from treatment-naïve specimens. All the lines have H3.3K27 M mutation. We used a range of biological in vitro assays to assess the effect of palbociclib on growth of DIPGs. Palbociclib activity was also assayed in vivo against three independent DIPG orthotropic xenografts model. FINDINGS: Dysregulation of G1/S cell cycle checkpoint is enriched in these DIPGs. Then, we showed that depletion of CDK4 or CDK6 inhibits DIPG cells growth and blocks G1/S transition. Furthermore, palbociclib effectively repressed DIPG growth in vitro. Transcriptome analysis showed that palbociclib not only blocks G1/S transition, it also blocks other oncogenic targets such as MYC. Finally, palbociclib activity was assayed in vivo against DIPG orthotropic xenografts to demonstrate the high efficiency of blocking tumor growth. INTERPRETATION: Our findings thus revealed that palbociclib could be the therapeutic strategy for treatment-naïve DIPG with H3.3K27 M mutation. FUND: Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support, Beijing Municipal Natural Science Foundation, Ministry of Science and Technology of China, and National Natural Science Foundation of China.

Identification of survival­associated key genes and long non­coding RNAs in glioblastoma multiforme by weighted gene co­expression network analysis.

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumour. However, the causes of GBM are not clear, and the prognosis remains poor. The aim of the present study was to elucidate the key coding genes and long non­coding RNAs (lncRNAs) associated with the survival time of GBM patients by obtaining the RNA expression profiles from the Chinese Glioma Genome Atlas database and conducting weighted gene co­expression network analysis. Modules associated with overall survival (OS) were identified, and Gene Ontology and pathway enrichment analyses were performed. The hub genes of these modules were validated via survival analysis, while the biological functions of crucial lncRNAs were also analysed in the publicly available data. The results identified a survival­associated module with 195 key genes. Among them, 33 key genes were demonstrated to be associated with OS, and the majority of these were involved in extracellular matrix­associated and tyrosine kinase receptor signalling pathways. Furthermore, LOC541471 was identified as an OS­associated lncRNA, and was reported to be involved in the oxidative phosphorylation of GBM with pleckstrin­2. These findings may significantly enhance our understanding on the aetiology and underlying molecular events of GBM, while the identified candidate genes may serve as novel prognostic markers and potential therapeutic targets for GBM.

Diffuse Intrinsic Pontine Gliomas Exhibit Cell Biological and Molecular Signatures of Fetal Hindbrain-Derived Neural Progenitor Cells.

Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumor-related death among children. Until now, there is still a lack of effective therapy with prolonged overall survival for this disease. A typical strategy for preclinical cancer research is to find out the molecular differences between tumor tissue and para-tumor normal tissue, in order to identify potential therapeutic targets. Unfortunately, it is impossible to obtain normal tissue for DIPG because of the vital functions of the pons. Here we report the human fetal hindbrain-derived neural progenitor cells (pontine progenitor cells, PPCs) as normal control cells for DIPG. The PPCs not only harbored similar cell biological and molecular signatures as DIPG glioma stem cells, but also had the potential to be immortalized by the DIPG-specific mutation H3K27M in vitro. These findings provide researchers with a candidate normal control and a potential medicine carrier for preclinical research on DIPG.