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Glioblastoma (GBM) is the most malignant form of glioma and has a poor median survival time. Fibroblast activation protein alpha (FAP) is a dual-specificity serine protease that is strongly associated with the development and progression of human carcinomas. However, relatively little is known about the function of FAP and its potential as a therapeutic target in GBMs.In this study, we aimed to explore the role of FAP in GBM through a series of experiments and to evaluate the therapeutic effect of PT100, a small molecule inhibitor of FAP, on GBM.Increased FAP expression was associated with poor survival in glioma. In vitro, FAP knockdown inhibited the process of EMT and caused a decrease in the number of M2 macrophages. In vivo, PT100 was confirmed to suppress the progression of GBMs significantly.FAP could serve as a biomarker and novel therapeutic target for the treatment of GBM and that PT100 is a promising drug for the treatment of GBM.

Glioma is the primary malignant tumor in the central nervous system, which characteristics of high malignancy, mortality and recurrence rate. Due to its heterogeneity, drug resistance, blood-brain barrier and other factors, the current treatment of glioma is mainly surgery resection combined with traditional radiotherapy and chemotherapy, but the therapeutic effect is not satisfactory. Methyl-CpG binding protein 2 (MeCP2) is an epigenetic regulator that has been reported to regulate the initiation and progression of glioma. However, the underlying mechanism in glioma remain unclear. In our study, we indicated that MeCP2 was upregulated in glioma tissues and cell lines, and MeCP2 knockdown repressed the cell proliferation and epithelial-mesenchymal transition (EMT), but boosted cell apoptosis in glioma. Furthermore, MeCP2 knockdown attenuated in vivo glioma growth in mice model. Mechanistically, miR-138-5p was identified to observably hampered the expression of MeCP2 by target MeCP2, and then inactivated the Wnt/β-Catenin signaling pathway. In addition, the following rescue assays disclosed that miR-138-5p repressed the glioma malignant phenotype, and MeCP2 overexpression reversed the inhibitory effect of miR-138-5p upregulation. Consistently, overexpression of MeCP2 elevated glioma development, but inhibition of the Wnt/β-Catenin signaling pathway with XAV-939 rescued the facilitation effect by overexpressing miR-138-5p. Our results revealed that miR-138-5p/MeCP2/Wnt/β-Catenin signaling might be a new target axis for the glioma treatment strategy.

Background Myxofibrosarcoma (MFS), especially radiation-Induced MFS (RIMFS) in the head and neck, is an extremely rare malignant fibroblastic tumor. The diagnosis and treatment of MFS remain great challenges. In the present study, we presented one case of RIMFS. Combined with previous literature, the clinical features, essentials of diagnosis, and treatment modalities of MFS in the head and neck were reviewed to better understand this rare entity. Case presentation We reported a case of RIMFS under the left occipital scalp in a 20-year-old girl with a history of medulloblastoma surgery and radiotherapy in 2006. A total tumor resection was performed with preservation of the overlying scalp the underlying bone, and no adjuvant therapy was administered after the first operation. The postoperative pathological diagnosis was high-grade MFS. The tumor relapsed 6 months later, and then, a planned extensive resection with negative surgical margins was carried out, followed by radiotherapy. No relapse occurred in a 12-month postoperative follow-up. Conclusions Planned gross total resection (GTR) with negative margins is the reasonable choice and footstone of other treatments for MFS. Ill-defined infiltrated borders and the complicated structures make it a great trouble to achieve total resection of MFS in the head and neck, so adjuvant radiotherapy and chemotherapy seem more necessary for these lesions.

OBJECTIVEPrimary intracranial rhabdomyosarcoma (PIRMS) is rare, and the effects of the treatment strategy on overall survival (OS) are unclear. This study aimed to evaluate risk factors pertinent to OS and to propose an optimal treatment strategy.METHODSClinical data of patients with PIRMS treated at Beijing Tiantan Hospital and from the English-language literature between 1946 and 2018 were reviewed. A literature review was performed via Ovid, MEDLINE, Embase, PubMed, Web of Science, and Cochrane databases using the terms “rhabdomyosarcoma,” “intracranial,” “cerebral,” and “brain.” Previously published data were processed and used according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.RESULTSThere were 8 males (66.7%) and 4 females with PIRMS at our institution, with a mean age of 24.3 years. Gross-total resection was achieved in 4 patients (33.3%), and adjuvant radiation and chemotherapy were administered in 5 (45.5%) and 3 (27.3%) patients, respectively. After a mean follow-up period of 13.7 months, all patients developed local-regional recurrence and died of the disease. Twenty-nine cases (14 female and 15 male) were reported in the literature with a median age of 9.0 years. After a mean follow-up duration of 18.6 months, 13 patients (44.8%) developed recurrences, 7 patients (24.1%) had extracranial metastasis, and 14 patients (48.3%) died. In the pooled cases, adjuvant radiation (hazard ratio [HR] 0.089, 95% confidence interval [CI] 0.027–0.288, p < 0.001) and age < 10 years (HR 0.227, 95% CI 0.077–0.666, p = 0.007) were independent predictors of good local-regional progression-free survival (LR-PFS). Adjuvant radiation therapy (HR 0.301, 95% CI 0.110–0.828, p = 0.020) and age < 10 years (HR 0.359, 95% CI 0.131–0.983, p = 0.046) were significant predictors for favorable OS in the multivariate model.CONCLUSIONSDue to the rarity of the disease, a poor outcome of PIRMS was demonstrated based on the pooled cohort. Use of radiation was associated with improved outcomes and should be considered to improve OS/LR-PFS. Further study is required to identify the optimal treatment regimen.Systematic review no.: CRD42019121249 (crd.york.ac.uk/PROSPERO/)

Primary intracranial fibrosarcoma (PIF) was a rare tumor with a high relapse rate and dismal survival rate. This study aimed to delineate the clinical characteristics of primary intracranial fibrosarcoma (PIF) and the risk factors for outcomes. We reviewed 15 PIF patients, who underwent surgical treatment at our institution from January 2009 to December 2018. Meanwhile, 36 cases from the prior literature between November 1962 and December 2019 were also retrieved and pooled to identify the risk factors. In our cohort, while cystic component (46.7%), perilesional edema (83.3%), and vascular flow void (66.7%) were commonly observed, no patient was accurately diagnosed. The 2-year relapse-free survival (RFS) and overall survival (OS) were 12.2% and 30.2%, respectively. Based on the pooled data, tumor size (p = 0.006), Ki-67 index (p = 0.004), and radiotherapy dose (p = 0.029) were prognostic factors for RFS in univariate analysis. In the univariate analysis, tumor size (p = 0.002), NGTR (p = 0.049), and high Ki-67 index (p = 0.019) were significant predictors for OS; and further multivariate analysis (n = 18) showed that large tumor size (≥ 5 cm; HR 14.613, p = 0.022) and high Ki-67 index (≥ 30%; HR 5.879, p = 0.020) were the independent risk factors for OS. Due to the rarity and nonspecific clinicoradiological features, the correct diagnosis of PIF before surgery was challenging. The outcomes of PIF were poor, and GTR plus radiotherapy (at least 60 Gy) might benefit to the outcomes and were recommended. Future study with a large cohort was needed to verify our findings.

Objective Chronic subdural hematomas (CSDHs) in young people are uncommon, rupture of arachnoid cysts (ACs) is one of the reasons for young patients. The detailed features of CSDHs associated with ACs remain poorly understood. The objective of this study is to analyze the characteristics of risks for the rupture of ACs with CSDH in Adults. Methods The CT scans of 1231 patients who were diagnosed as CSDH were reviewed between Jan 2009 and Jan 2019 in the Department of Neurotrauma in Beijing Tian Tan Hospital, Capital Medical University/China National Clinical Research Center for Neurological Diseases. The clinical features, treatments, and prognosis of 32 patients with ACs were analyzed. Results Ruptured ACs with CSDH were diagnosed in 32 patients in 1231 CSDH cases, which account for 2.60%. Headache was the commonest presenting symptom. According to the Takizawa' classification, there were 22 cases for Type A, 9 for Type B and 1 for Type C. Thinning or external convex of the calvarium was demonstrated in 17/32 cases (53.1%). Thirty-one patients were treated with burr hole irrigation. Favorable outcomes were achieved in all patients. Conclusions The presence of ACs should be taken into consideration in young and middle-aged patients with CSDH. For those patients were found ACs in conventional medical examination, especially those whose imaging examinations demonstrated thinning or external convex of the calvarium, it was crucial to remind them to avoid the occurrence of traumatic brain injury (TBI). Burr hole irrigation is still the preferred treatment for ruptured ACs with CSDH.

Background Pituitary adenomas are common brain tumors. Although transsphenoidal surgery are able to achieve extensive tumor removal, the rate of recurrence ranges from 5 to 20% depending on the different subtype. Further understanding of these tumors is needed to develop novel strategies to improve the prognosis of patients. But their metabolic characteristics are largely unknown. Methods We used metabolomic, transcriptomic, and proteomic approaches to systematically investigate eight subtypes of pituitary adenomas and normal pituitary glands. By blocking IDH2, we investigate IDH2 play an inhibitory role in GH tumor cell growth and tumor secretion. Results We found that all of the pituitary adenomas displayed downregulated glucose metabolism and glycolysis compared to normal tissues. Together with the differences in amino acids and fatty acids, we categorized these tumors into three clusters. We then re-established the reprogrammed metabolic flux in pituitary adenomas based on multiomic analyses. Take growth hormone-secreting pituitary adenomas as an example, we revealed that IDH2 is a key player in the reprogrammed metabolism of such tumors. By blocking IDH2, we confirmed that IDH2 is a potential target for the inhibition of tumor cell growth and tumor secretion. Conclusions Our study first uncovered the metabolic landscape of pituitary adenomas and demonstrated a possible way to inhibit tumor growth by regulating aberrant metabolism.

Chordoma, a malignant bone cancer, is highly resistant to conventional therapeutic approaches; this greatly limits radio- and chemotherapeutic options and disease management. In the present study, we investigated three patient-derived chordoma cell lines to elucidate the molecular mechanism of resistance to therapeutics. An in vitro high-throughput chemical screening assay and an in vivo xenograft model were used to identify novel chemosensitizers for chordoma. We found that patient-derived chordoma cell lines recapitulated disease phenotypes, which were highlighted by robust resistance to medical therapy manifested as lack of DNA damage accumulation. Mechanistically, the PARP DNA repair pathway was found to play a central role in this resistance. Chemical screening confirmed that PARP inhibitors could strikingly enhance temozolomide (TMZ) therapy in chordoma cells. Combining the FDA-approved PARP inhibitor, olaparib, with chemotherapeutics not only potentiated DNA damage accumulation, cell cycle arrest, and apoptosis in vitro but also suppressed chordoma xenograft expansion in vivo. We conclude that combining PARP inhibition with TMZ could be an effective therapeutic approach for the clinical management of chordoma. KEY MESSAGES: The PARP DNA repair pathway enhances chemoresistance in chordoma cells. Combining PARP inhibitors with genotoxic agents induces chordoma cell cytotoxicity. PARP inhibitor combining with temozolomide suppresses growth of chordoma in vivo.

Skull base meningiomas represent approximately 25% of all meningiomas, nearly 20% of which are atypical or anaplastic. To date, effective medical treatments for meningiomas are still lacking. Genetic aberrations (TRAF7, KLF4, AKT1, and SMO) and the effects of genetic aberrations on the expression of inhibitory immune checkpoint molecules (PD-L1, IDO, and TDO2) in skull base meningiomas are still unclear. Genetic alterations in the four genes were identified in 92 skull base meningiomas by Sanger sequencing. The expression differences in immune checkpoints between mutant and wild-type (WT) tumors were determined by immunohistochemistry (IHC) and Western blot (WB). The four mutations were not concurrently detected in the patients with skull base meningiomas. Among the tumors from the KLF4-mutated group, almost half were petroclival meningiomas. KLF4- and TRAF7-mutated tumors were predominantly secretory meningiomas. SMO-mutated tumors exhibited higher calcification, and half of these tumors were observed in the brain midline. Receiver operating characteristic curve analysis indicated that tumor volume can predict KLF4 and TRAF7 mutation status with high sensitivity and specificity, respectively. The IHC and WB analyses indicated that PD-L1, IDO, and TDO2 levels in tumors with TRAF7 mutations were significantly higher than those in WT tumors. Meanwhile, there was a significant difference in TDO2 between tumors with AKT1 mutations and WT tumors. Specifically, TRAF7 mutations could play a key role in skull base meningiomas by regulating the expression of inhibitory immune checkpoints and thus suppressing immune responses. Checkpoint inhibitors may be potential strategies for targeted immunotherapies of these mutant meningiomas.

We sought to clarify the expression characteristics and prognostic significance of transforming growth factor (TGF)-β3 in cranial meningiomas.We analyzed the expression of TGF-β3 at the mRNA level in 38 frozen meningioma samples. Clinical data collection, follow-up, correlations, and survival analyses were performed.World Health Organization (WHO) grade I meningiomas showed an average expression level of 2.55, which was higher than that of WHO grade II (average of 1.50) and WHO grade III (average of 0.21) (Kruskal-Wallis test, P = 0.008). For meningiomas with a history of surgery, the mean TGF-β3 expression level was 0.71, much lower than that of primary meningiomas with a mean value of 2.55 (Mann-Whitney U-test, P = 0.008). According to the Kaplan-Meier analysis and univariate Cox analysis, WHO grade (P = 0.001), history of surgery (P0.001), tumor volume (P = 0.045), preoperative Karnofsky Performance Status (P = 0.001), peritumoral brain edema (P = 0.039), postoperative radiotherapy (P = 0.001), degree of resection (P = 0.039), and TGF-β3 expression (P = 0.038) were prognostic factors for tumor recurrence. In addition, WHO grade (P0.001), history of surgery (P0.001), preoperative Karnofsky Performance Status (P = 0.002), peritumoral brain edema (P = 0.006), postoperative radiotherapy (P = 0.007), bone invasion (P = 0.03), and TGF-β3 expression (P = 0.041) were prognostic factors for mortality.TGF-β3 expression levels gradually declined with the increase of WHO grade and were lower in recurrent meningiomas than in primary meningiomas. Besides, low TGF-β3 expression was found to predict tumor recurrence and mortality in meningiomas based on univariate analysis.

BACKGROUND Intravenous and inhalational anesthesia might have different associations with long-term outcome in cancer patients, with reports of adverse effects of inhalation anesthesia. However, the effects of anesthesia in patients with high-grade glioma (HGG) are not known. METHODS This study investigated 154 patients who received propofol and 140 patients who received sevoflurane for maintenance of anesthesia during HGG tumor resection. The primary outcomes were progression-free survival and overall survival. RESULTS Median progression-free survival was 10 months (interquartile range [IQR], 6 to 18) versus 11 months (IQR 6 to 20; P=0.674), and median overall survival was 18 months (IQR, 11 to 39) versus 18 months (IQR, 10 to 44; P=0.759) in patients maintained with propofol and sevoflurane, respectively. Higher preoperative Karnofsky performance status and postoperative chemotherapy were associated with a reduced hazard of tumor progression or death, whereas higher age-adjusted Charlson comorbidity index and longer duration of anesthesia were associated with an increased hazard of progression or death. World Health Organization tumor classification IV and incomplete tumor resection were associated with an increased hazard of tumor progression but not death. Anesthesia maintenance with sevoflurane increased the risk of death in patients with Karnofsky performance status

BACKGROUND Mannitol is widely used to reduce brain tissue swelling and improve brain relaxation during neurosurgery. However, the optimal dosage for patients with midline shift undergoing supratentorial tumor resection remains unclear. METHODS In this randomized, controlled double-blinded study, 204 patients with preoperative midline shift who underwent elective supratentorial brain tumor surgery were equally allocated to receive placebo or 0.7, 1.0, or 1.4 g/kg mannitol infusion. The primary outcome was the proportion of satisfactory brain relaxation. RESULTS Demographics and baseline characteristics were similar among the 4 groups. Trend analysis showed that mannitol infusion increased satisfactory brain relaxation (P

No standard treatment protocol to guide the management of the primary central nervous system atypical teratoid rhabdoid tumors (ATRTs). To evaluate the efficacy of GTR (gross total resection), RT (radiotherapy), CCMT (conventional chemotherapy), or intensified chemotherapy (ICMT) and verify the optimal treatment strategy. A total of 501 cases (18 cases from our center and 483 cases from published literature) were eligible for analysis. Clinical characteristics were reviewed, and overall survival (OS) of each combined treatment modality was compared. These prior publication data were processed according to PRISMA guidelines. This study included 265 (52.9%) males and 216 (43.1%) females. The median age of the cohort was 2.2 years with 295 (58.9%) cases younger than 3 years. GTR was achieved in 217 (43.3%) patients. Initial adjuvant CCMT, CCMT plus intrathecal chemotherapy (ITCMT), CCMT plus high-dose chemotherapy (HDCMT), and CCMT plus ITCMT and HDCMT were administered in 228 (45.5%), 78 (15.6%), 55 (11.0%), and 24 (4.8%) patients, respectively. Radiotherapy (RT) was prescribed in 266 (53.1%) patients. Fewer patients younger than 3 years old received RT (21.9% vs 33.0%, p

BackgroundMyxofibrosarcoma (MFS) is a rare malignant fibroblastic tumor that primarily occurred in proximal extremities of older people. However, MFS, especially radiation-Induced MFS is extremely rare in the head and neck. Local recurrence is very common, the diagnosis and treatment of MFS is always a great challenge. We presented one case of radiation-induced MFS, combined with previous literature, the clinical features, essentials of diagnosis and treatment modalities of MFS in head and neck were reviewed to better understand this rare entity.Case presentationHere, we reported a case of radiation-Induced MFS under left occipital scalp in a 20-year-old girl with a history of medulloblastoma surgery and radiotherapy in 2006. A total tumor resection was performed with preservation of the overlying scalp the underlying bone, and no adjuvant therapy was administered after surgery. Post-operative pathological diagnosis was high-grade MFS. Unfortunately, the tumor relapsed six month later. Then a planned extensive resection was carried out, followed by radiotherapy. In addition, intra-operative frozen section was sent to confirm negative surgical margin. No relapse occurred in 12-month postoperative follow-up.ConclusionsPlanned gross total resection (GTR) with negative margins is the reasonable choice and footstone of other treatments for MFS. Ill-defined infiltrated borders and the complicated structures make it a great trouble to achieve total resection of MFS in the head and neck. Therefore, adjuvant radiotherapy and chemotherapy seem more necessary for these lesions. Further studies are needed to confirm the efficacy of radio-chemotherapy for head and neck MFS.

Background The use of cranial fixation devices in neurosurgery is very common, which is considered to be an important auxiliary method for many craniotomies. However, previous studies have reported complications of using cranial fixation devices, including brain tissue, nerve and blood vessel damage, scalp laceration, subcutaneous hematoma, etc. Some of the complications are serious and even potentially fatal, and the causes of which may be related to the incorrect use of cranial fixation devices. Although there are no serious complications in our review, the cause of that needs to be further summarized and analyzed, as so to minimize the serious consequences caused by the cranial fixation device slippage and ensure the safety of the patients’ surgical procedure. Case presentation In our recent work, we have continuously found three cases of unstable cranial fixation devices, which make us to analyze the possible factors and summarize experience combined with the review of other senior neurosurgeons (more than 3 years of working experience) from different departments of neurosurgery. Conclusions Based on our recent incidents of unstable cranial fixation and the experience of investigating and analyzing senior doctors from different neurosurgery centers, we summarized experience to minimize the risk of unstable cranial fixation. We tried a variety of options, including a safe anatomical location for cranial fixation, teamwork, and communication with anesthesiologists and itinerant nurses, to ensure the stability of the patient’s cranial fixation devices. The data obtained in this survey has great limitations, including the doctor’s personal prejudice and dependence on anecdotal memories. Therefore, the data should be interpreted with caution. However, there are still some modes that can help to better understand the use of safe cranial fixation. Based on the above research and analysis, we have made recommendations that may help neurosurgeons to avoid preventable complications

BACKGROUND The use of cerebral fixation devices in neurosurgery is very common, which is considered to be an important auxiliary method for many craniotomies. However, previous studies have reported complications of using cerebral fixation devices. Some of the complications are serious and even potentially fatal, and the causes of which may be related to incorrect use of cranial fixation devices. Although there are no serious complications, the cause of that needs to be further summarized and analyzed, as so to minimize the serious consequences caused by the cerebral fixation devices slippage and ensure the safety of the patients’ surgical procedure.METHODS In our recent work, we have continuously found three cases of unstable cerebral fixation devices, which allowed us to analysis the possible factors and summarize experience combined with the review of other senior neurosurgeons from different departments of neurosurgery.RESULTS Based on our recent unstable cranial fixation incidents and the experience of investigating and analyzing senior doctors from different neurosurgery centers, we conducted experience analysis and summary to minimize the risk of unstable cranial fixation pins. We tried a variety of options, including a safe anatomical location for cranial fixation, teamwork and communication with anesthesiologists and itinerant nurses to ensure the stability of the patient’s cerebral fixation devices.CONCLUSIONS The data obtained in this survey has great limitations, including the doctor’s personal prejudice and dependence on anecdotal memories. Therefore, the data should be interpreted with caution. Despite these limitations, there are still some modes that can help to better understand the use of safe skull fixation. Based on the above research and analysis, we have made recommendations that may help avoid preventable complications

Background: Central neurocytoma is a rare intracranial tumor. Due to the limited number of reported cases, the treatment strategy for central neurocytomas, especially large central neurocytomas, remains controversial. This paper discusses our clinical experience in the treatment of large central neurocytomas.Methods: A retrospective analysis of 29 patients with intraventricular central neurocytomas diagnosed and treated by the same surgeon between April 2012 and September 2019 at the Neurosurgery Departments of Beijing Tiantan Hospital and Hainan General Hospital was performed. The clinical characteristics, treatment plans and prognoses of these patients were reviewed.Results: Among the 29 patients, the average age of onset was 31.93 (17-61) years, and the average maximum tumor diameter was 54.17 ± 15.62 mm. Twenty-three patients (79.3%) had an average maximum diameter greater than 50 mm. Twenty-seven patients (93.1%) underwent transcortical tumor resection. Twenty-seven patients (93.1%) underwent gross total tumor resection. Five patients (17.2%) received radiotherapy after the first operation, and 3 patients (10.3%) had tumor recurrence. None of the patients died.Conclusions: Surgical resection via transcortical fistulotomy is a reliable approach for removal of large central neurocytomas in the ventricle. Patients should be closely observed postoperatively, and MRI of the head should be performed regularly. If a tumor shows progression, then radiotherapy should be considered.

Background Central neurocytoma is a rare intracranial tumor. Due to the limited number of reported cases in the past, there is still controversy about the treatment strategy for central neurocytoma, especially large central neurocytomas occupying bilateral ventricles. This paper will discuss our clinical experience in the treatment of large central neurocytoma. Methods A retrospective analysis of 29 patients with intraventricular central neurocytoma diagnosed and treated by the same surgeon between April 2012 and September 2019 at the Neurosurgery Departments of Beijing Tiantan Hospital and Hainan General Hospital was performed. The clinical characteristics, treatment plan and prognosis of these patients were discussed. Results Among the 29 patients, the average age of onset was 31.93 (17-61) years, and the average maximum tumor diameter was 54.17 ± 15.62 mm. Among them, 23 patients (79.3%) had an average maximum diameter greater than 5 cm. Twenty-seven patients (93.1%) underwent transcortical tumor resection. Twenty-seven patients (93.1%) achieved gross total tumor resection. Five patients (17.2%) received radiotherapy after the first operation, and 3 patients (10.3%) had tumor recurrence. None of the patients died. Conclusion Operation is the basis of the treatment of central neurocytoma. It is possible for patients to be cured by total resection of the tumor and protection of normal ventricular structure. Transcortical fistulotomy is a reliable approach for the removal of large central neurocytomas in the ventricle. Patients should be closely observed post-operation, and MRI of the head should be rechecked regularly. If tumor progression occurs, then radiotherapy should be considered.

Objectives Limited data regarding intracranial mesenchymal chondrosarcoma (MCS) are available. The goal of this study was to report the clinical characteristics, challenges in management, and poor outcomes of intracranial MCS. Methods Clinical data for 16 patients with MCS were reviewed retrospectively to evaluate their clinical characteristics, management, and outcomes. Results This study included 11 male and 5 female patients with a mean age of 22.9 ± 14.4 years. The most common presentations were headache (n = 10; 62.5%), followed by cranial deficits (n = 7; 43.6%). The radiologic spectrum for MCS was broad, and only 18.8% (3/16) of MCSs were correctly diagnosed preoperatively. Aggressive resection (including subtotal resection and gross total resection) and partial resection was performed in 62.5% (10/16) and 37.50% (6/16) of patients. With a median follow-up of 34 months (range, 10–78 months), 5 patients (31.3%) died and 8 patients (50%) developed tumor recurrence. The 1-, 3-, and 5-year rates of progression-free survival and overall survival were 86%, 53%, and 42% and 93%, 70%, and 56%, respectively. Although the differences were not significantly different, aggressive resection and the use of radiotherapy tended to improve the prognosis of the patients. Conclusions Clinical characteristics of MCS are variable. The current management of intracranial MCS referring to conventional chondrosarcoma could not yield satisfactory outcomes. Further study is needed to identify the optimal treatments.

Objective To investigate 10 candidate single nucleotide polymorphisms (SNPs) in 5 genes (CASP8, XRCC1, WRN, NF2, and BRIP1) to confirm the association between the 5 genes and the meningioma risk in a Chinese population. Methods We examined 10 candidate SNPs in 5 genes (CASP8, XRCC1, WRN, NF2, and BRIP1) to confirm the association between the 5 genes and the meningioma risk and tumor-related phenotype in 433 individuals, including 215 patients with meningioma and 218 controls. Results The polymorphisms rs4968451T>G in BRIP1 were significantly associated with the risk of meningioma (TT vs. TG vs. GG additive, P = 0.005; TT+TG vs. GG dominant, P = 0.015; TT/GT+GG recessive, P = 0.034). The significant association was found only in females for BRIP1 rs4968451T>G (TT+TG vs. GG dominant, P = 0.001; TT/GT+GG recessive, P = 0.044). We observed no significant association between genotypes and the meningioma risk for the other 9 SNPs. Through genotype-phenotype analysis, the genotype of BRIP1 rs4968451T>G was also strongly associated with tumor-related phenotypes, including the tumor grade and tumor subtypes. BRIP1 rs4968451T>G was associated with markedly grade I meningioma risk (TT+TG vs. GG dominant, P = 0.008; TT/GT+GG recessive, P = 0.020). In addition, BRIP1 rs4968451T>G was associated with markedly meningothelial and transitional meningioma risk. Furthermore, the genotype of CAPS8, XRCC1, and NF2 was associated with different subtype of meningioma risk. Conclusions This study indicated a role for BRIP1 gene variations in meningioma and may be informative for future genetic or biological studies of meningioma. These findings will assist in further understanding the genetic cause for meningiomas and guide more effective biological interventions to facilitate meningiomas.

Oncocytomas represent a subset of benign pituitary adenomas that are characterized by significant mitochondrial hyperplasia. Mitochondria are key organelles for energy generation and metabolic intermediate production for biosynthesis in tumour cells, so understanding the mechanism underlying mitochondrial biogenesis and its impact on cellular metabolism in oncocytoma is vital. Here, we studied surgically resected pituitary oncocytomas by using multi-omic analyses. Whole-exome sequencing did not reveal any nuclear mutations, but identified several somatic mutations of mitochondrial DNA, and dysfunctional respiratory complex I. Metabolomic analysis suggested that oxidative phosphorylation was reduced within individual mitochondria, and that there was no reciprocal increase in glycolytic activity. Interestingly, we found a reduction in the cellular lactate level and reduced expression of lactate dehydrogenase A (LDHA), which contributed to mitochondrial biogenesis in an in vitro cell model. It is of note that the hypoxia-response signalling pathway was not upregulated in pituitary oncocytomas, thereby failing to enhance glycolysis. Proteomic analysis showed that 14-3-3η was exclusively overexpressed in oncocytomas, and that 14-3-3η was capable of inhibiting glycolysis, leading to mitochondrial biogenesis in the presence of rotenone. In particular, 14-3-3η inhibited LDHA by direct interaction in the setting of complex I dysfunction, highlighting the role of 14-3-3η overexpression and inefficient oxidative phosphorylation in oncocytoma mitochondrial biogenesis. These findings deepen our understanding of the metabolic changes that occur within oncocytomas, and shine a light on the mechanism of mitochondrial biogenesis, providing a novel perspective on metabolic adaptation in tumour cells. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Objective Primary intracranial angioleiomyoma is a rare and distinct neoplasm. Only 29 cases have been reported previously, and we aimed to investigate the clinical and radiopathologic features of these lesions. Methods Medical records and radiographs of 8 patients (7 male and 1 female; mean age: 48.7 years) at our institution were reviewed retrospectively. Patient follow-up and a literature review were performed. Results The most common preoperative symptom was a visual defect (n = 2), followed by diplopia (n = 1) and abducens paralysis (n = 1). Three patients were asymptomatic. The parasellar area (particularly the cavernous sinus) was the predilection site (n = 4; 50.0%). Radiographically, all lesions were solid without cystic degeneration. All lesions appeared with T1 hypointensity and T2 hyperintensity, and they were gradually heterogeneously enhanced after the administration of gadolinium. Complete resection was achieved in 7 patients (87.5%) without recurrence after 26.8 months of follow-up. Mitosis was rarely observed, and the Ki-67 labeling index was less than 1%; pathologically, the cavernous type was the most common. Conclusions Primary intracranial angioleiomyomas were prevalent in middle-aged men, and they usually involved the cavernous sinus and were frequently pathologically identified as the cavernous type. Preoperative symptoms varied depending on lesion location. The preoperative diagnosis of primary intracranial angioleiomyomas is difficult without pathology. Digital subtraction angiography and preoperative embolization are useful for differential diagnosis and surgery. Given the indolent biology of these tumors, a favorable outcome can be achieved using total resection without recurrence. A larger sample size with long-term follow-up is needed to verify our findings.

Objective Intracranial and intraspinal clear cell meningiomas (CCMs) are rarely reported because of their extremely low incidence, and the current understanding of CCM is poor. The purpose of this study was to analyze the incidence and the clinical, radiologic, pathologic, and prognostic features of intracranial and intraspinal CCMs. Methods Among 14,310 cases of intracranial and intraspinal meningiomas that were surgically treated between 2006 and 2016 at Beijing Tian Tan Hospital, 56 were chosen for analysis and retrospectively reviewed. To determine which parameters were associated with longer progression-free survival (PFS) and overall survival (OS), statistical analysis was performed. Results CCMs accounted for approximately 0.39% of all intracranial and intraspinal meningiomas. Patients with CCM had a mean age of 32.3 years and there was a female predilection (20 males and 36 females). Gross total resection was achieved in 35 cases, and subtotal resection was achieved in 21 cases. All patients were followed up for 10–206 months after surgery. Twenty-six patients experienced tumor recurrence, and the median PFS was 48.0 months. The 1-year, 3-year, and 5-year PFS was 87.5%, 59.8%, and 41.8%, respectively. Twelve patients died of tumor recurrence, and the median OS was not available. The 1-year, 3-year, and 5-year OS was 98.2%, 91.3%, and 65.8%, respectively. Univariate analysis showed that total tumor removal was significantly associated with a better prognosis. Multivariate analysis confirmed only Simpson grade III and IV resection as an independent risk factor for shorter PFS. Radiotherapy mildly improved PFS after both gross total resection and subtotal resection, showing no significant difference because of the small sample size and short follow-up duration. Conclusions CCM is a rare subtype of World Health Organization grade II meningioma. CCM typically involves young patients and shows a female predilection and high recurrence rate. When possible, total resection is the primary and most suitable treatment for CCM. For patients with primary tumors, radiotherapy is recommended after the initial operation regardless of the extent of resection. For patients with disease recurrence, secondary surgery combined with radiotherapy might serve as an effective treatment.

There was no consensus regarding the treatment of intracranial chondrosarcoma (CSA). The study aimed to evaluate the adverse factors for progression-free survival (PFS) and overall survival (OS) and to propose a treatment strategy for CSA.The clinical chart and radiographic data of 106 consecutive cases (mesenchymal and conventional CSA in 18 and 88 patients, respectively) of surgically treated CSAs were retrospectively reviewed.Gross total resection was achieved in 43 patients (40.6%), and adjuvant radiotherapy was administered in 45 patients. After a mean follow-up duration of 47.8 months, 38 patients (37.3%) experienced recurrence. PFS and disease-specific OS at 5 years was 57.7% and 74.4%. Independent adverse factors for PFS were previous surgery (hazard ratio [HR] 2.261; P = 0.028), increased lesion size (HR, 1.298; P = 0.026), extent of surgical resection (HR, 3.226; P0.001), malignant pathology (HR, 2.018; P = 0.003), and postoperative radiotherapy (HR, 3.246; P = 0.001). The stereotactic radiosurgery subgroup presented best 5-year PFS of 88.9%, and a linear accelerator prolonged the mean PFS time (57.0 months) compared with no radiation (38.1 months). In the incomplete resection subgroup (n = 63), radiotherapy significantly benefited tumor control (HR, 2.101; P = 0.016). Extent of surgical resection (HR, 1.797; P = 0.026) and malignant disease (HR, 1.717; P = 0.030) were associated with OS.Intracranial CSAs were not completely amendable by surgery alone. Gross total resection as far as possible plus radiation were necessary for mesenchymal CSA and conventional CSA with active growth or residual tumor. Stereotactic radiosurgery was an alternative if proton therapy was unavailable. A future study with a large cohort is required to verify our findings.

Objective An intradural extramedullary bronchogenic cyst (IEBC) is a congenital malformation and an extremely rare type of endodermal cyst. This study aims to report the clinical and radiologic characteristics and surgical outcomes of IEBCs and to review the available literature. Methods The medical records of 6 patients (3 female) with pathologically confirmed bronchogenic cysts involving the spinal cord between 2009 and 2016 were retrospectively reviewed, and follow-up evaluations were performed. Results Of the 6 symptomatic lesions, 4 were located in the cervical vertebra, 1 at the lumbar vertebra, and the remaining 1 at the craniocervical junction. Radiographs showed signals similar to cerebral spinal fluid on all magnetic resonance imaging sequences without contrast enhancement. Total resection was achieved in 3 patients. Histopathology revealed simple and pseudostratified respiratory epithelium with benign subepithelial mucous glands and fat components neighboring the cyst. After a mean follow-up duration of 49.2 months, 2 asymptomatic residual lesions regrew after nontotal resection. In previous literature including 19 cases, most IEBCs (84.2%) tended to be homogeneous and well demarcated on radiologic images, and 85.7% were not contrast enhancing. Cervical or upper thoracic segments were predilection sites with intradural extramedullary localization. The majority of IEBCs had similar benign histological features. The recurrence rate was 15.4% after nontotal resection but nil after total resection. Conclusions IEBCs displayed an indolent course, and the most effective management with positive outcomes was total resection. Nontotal resection, cystic fenestration, and biopsy, which were associated with recurrence, should be avoided.

Background Standard therapy for chordoma consists of surgical resection followed by high-dose irradiation. Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine phosphatase involved in signal transduction, cell cycle progression, cell differentiation, and DNA repair. LB100 is a small-molecule inhibitor of PP2A designed to sensitize cancer cells to DNA damage from irradiation and chemotherapy. A recently completed phase I trial of LB100 in solid tumors demonstrated its safety. Here, we show the therapeutic potential of LB100 in chordoma. Methods Three patient-derived chordoma cell lines were used: U-CH1, JHC7, and UM-Chor1. Cell proliferation was determined with LB100 alone and in combination with irradiation. Cell cycle progression was assessed by flow cytometry. Quantitative γ-H2AX immunofluorescence and immunoblot evaluated the effect of LB100 on radiation-induced DNA damage. Ultrastructural evidence for nuclear damage was investigated using Raman imaging and transmission electron microscopy. A xenograft model was established to determine potential clinical utility of adding LB100 to irradiation. Results PP2A inhibition in concert with irradiation demonstrated in vitro growth inhibition. The combination of LB100 and radiation also induced accumulation at the G2/M phase of the cell cycle, the stage most sensitive to radiation-induced damage. LB100 enhanced radiation-induced DNA double-strand breaks. Animals implanted with chordoma cells and treated with the combination of LB100 and radiation demonstrated tumor growth delay. Conclusions Combining LB100 and radiation enhanced DNA damage-induced cell death and delayed tumor growth in an animal model of chordoma. PP2A inhibition by LB100 treatment may improve the effectiveness of radiation therapy for chordoma.

QuestionCystic fibrosis (CF) is characterised by the accumulation of viscous adherent mucus in the lungs. While several hypotheses invoke a direct relationship with cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction (i.e. acidic airway surface liquid (ASL) pH, low bicarbonate (HCO3−) concentration, airway dehydration), the dominant biochemical alteration of CF mucus remains unknown.Materials/methodsWe characterised a novel cell line (CFTR-KO Calu3 cells) and the responses of human bronchial epithelial (HBE) cells from subjects with G551D or F508del mutations to ivacaftor and elexacaftor-tezacaftor-ivacaftor. A spectrum of assays such as short-circuit currents, quantitative PCR, ASL pH, Western blotting, light scattering/refractometry (size-exclusion chromatography with inline multi-angle light scattering), scanning electron microscopy, percentage solids and particle tracking were performed to determine the impact of CFTR function on mucus properties.ResultsLoss of CFTR function in Calu3 cells resulted in ASL pH acidification and mucus hyperconcentration (dehydration). Modulation of CFTR in CF HBE cells did not affect ASL pH or mucin mRNA expression, but decreased mucus concentration, relaxed mucus network ultrastructure and improved mucus transport. In contrast with modulator-treated cells, a large fraction of airway mucins remained attached to naïve CF cells following short apical washes, as revealed by the use of reducing agents to remove residual mucus from the cell surfaces. Extended hydration, but not buffers alkalised with sodium hydroxide or HCO3−, normalised mucus recovery to modulator-treated cell levels.ConclusionThese results indicate that airway dehydration, not acidic pH and/or low [HCO3−], is responsible for abnormal mucus properties in CF airways and CFTR modulation predominantly restores normal mucin entanglement.

Objectives Poly(ADP-ribose) polymerase (PARP), calpain, and nuclear factor-κB (NF-κB) are reported to participate in inflammatory reactions in pathologic conditions and are involved in traumatic brain injury. The objective of this study was to investigate whether PARP participates in inflammation related to calpain and NF-κB in a mouse model of controlled cortical impact (CCI). Methods PJ34 (10 mg/kg), a selective PARP inhibitor, was administered intraperitoneally 5 minutes and 8 hours after experimental CCI. We then performed a histopathologic analysis, and we measured calpain activity and protein levels in all animals. The cytosolic, mitochondria, and nuclear fractions were prepared and used to determine the levels of PARP, calpastatin, NF-κB p65, inhibitory-κB-α, tumor necrosis factor-α, interleukin-1β, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2. We then measured blood–brain barrier disruption using electron microscopy at 6 and 24 hours after CCI. Results Treatment with PJ34 markedly reduced the extent of both cerebral contusion and edema, improved neurologic scores, and attenuated blood–brain barrier damage resulting from CCI. Our data showed that the cytosolic and nuclear fractions of calpain and NF-κB were up-regulated in the injured cortex and that these changes were reversed by PJ34. Moreover, PJ34 significantly enhanced the calpastatin and inhibitory-κB levels and decreased the levels of inflammatory mediators. Conclusions PARP inhibition by PJ34 suppresses the overactivation of calpain and the production of inflammatory factors that are caused by NF-κB activation and attenuates neuronal cell death in a mouse model of CCI.

Retinol dehydrogenase-10 (RDH10) is a member of the short-chain dehydrogenase/reductase family, which plays an important role in retinoic acid (RA) synthesis. Here, we show that RDH10 is highly expressed in human gliomas, and its expression correlates with tumor grade and patient survival times. In vitro, lentivirus-mediated shRNA knockdown of RDH10 suppressed glioma cell proliferation, survival, and invasiveness and cell cycle progression. In vivo, RDH10 knockdown reduced glioma growth in nude mice. Microarray analysis revealed that RDH10 silencing reduces expression of TNFRSF12A (Fn14), TNFSF12 (TWEAK), TRAF3, IKBKB (IKK-β), and BMPR2, while it increases expression of TRAF1, NFKBIA (IκBα), NFKBIE (IκBε), and TNFAIP3. This suggests that RDH10 promotes glioma cell proliferation and survival by regulating the TWEAK-NF-κB axis, and that it could potentially serve as a novel target for human glioma treatment.

// Hongwei Cheng 1,* , Xiang Mao 1,2,5,* , Zonggang Hou 3,5,* , Jian Xu 2 , Shuyu Hao 3,5 , Huan Li 3,5 and Baiyun Liu 2,3,4,5 1 Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China 2 Neurotrauma Laboratory, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 3 Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China 4 Nerve Injury and Repair Center of Beijing Institute for Brain Disorders, Beijing, China 5 China National Clinical Research Center for Neurological Diseases, Beijing, China * These authors contributed equally to this work Correspondence to: Baiyun Liu, email: // Keywords : cerebral perfusion pressure, regional cerebral blood flow, intracranial pressure, contrast-enhanced ultrasound, Pathology Section Received : July 31, 2017 Accepted : September 22, 2017 Published : October 11, 2017 Abstract To discuss the relationship between the regional cerebral blood flow (rCBF) and cerebral perfusion pressure (CPP) and the effect of CPP on rCBF in different spaces in an experimental animal model. As the ICP increased, the CPP and rCBF (A × β value measured by CEU) decreased to varying degrees. The rCBF 1 and rCBF 2 were well correlated with the CPP. At the same CPP, rCBF 1 decreased significantly than the level of rCBF 2 (p < 0.01). Six healthy cross-breed dogs, both males and females, weighing 18.3 ± 1.6 kg, were selected to establish models of increased intracranial pressure (ICP) via the installation of an epidural latex sacculus. The calculated CPP was in accordance with the ICP through the formula CPP = MAP - ICP, and contrast-enhanced ultrasound (CEU) was used to instantly measure the rCBF 1 and 2 cm around the sacculus edge. The relationship between rCBF 1 cm (rCBF 1 ) and 2 cm (rCBF 2 ) around the sacculus edge and the CPP was analyzed. As the ICP increased, the CPP and rCBF both decreased. The rCBF and the CPP had a linear relationship, but the perfusion pressure did not necessarily determine all parts of the rCBF. The rCBF was different in different spaces: the farther away from the injured site, the smaller the effect on the rCBF.