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To investigate the role of transforming growth factor β1 (TGF-β1), Smad3, and phospho-Smad3 (p-Smad3) in the invasion of somatotropinomas.In total, 45 somatotropinomas were obtained from patients who underwent surgery for the first time between 2011 and 2015 at Beijing Tiantan Hospital. The expression of TGF-β1, Smad3, and p-Smad3 was examined by western blot, quantitative reverse transcription polymerase chain reaction, and immunohistochemistry in somatotropinomas, and factors correlated with tumor invasion were analyzed.A total of 13 invasive somatotropinomas and 32 noninvasive somatotropinomas were enrolled in the study. TGF-β1 protein (P0.01) and mRNA (P0.01) levels were significantly less in the invasive somatotropinomas than noninvasive somatotropinomas. There was no significant difference in Smad3 protein level or Smad3 mRNA level between invasive somatotropinomas and noninvasive somatotropinomas. However, the p-Smad3 protein level was significantly less in the invasive somatotropinomas than noninvasive somatotropinomas (P0.01). Univariate analysis demonstrated that TGF-β1 (P0.01) and p-Smad3 scores (P0.01) were associated with invasion. In multivariate analysis, p-Smad3 scores remained a significantly independent predictor of invasion (odds ratio 0.897, 95% confidence interval 0.834-0.964, P0.05).Low expression of p-Smad3 is correlated with invasion of somatotropinomas.

Objective We aimed to characterize the expression of transforming growth factor-α (TGF-α) and Ki-67 and to assess the relationship between TGF-α and Ki-67 expression and prognostic factors in skull base chordoma. Methods We retrospectively analyzed the data from 46 patients with skull base chordoma. The follow-up duration ranged from 1 to 168 months (mean, 74.1). The survival data were statistically analyzed using the Kaplan-Meier method and multivariate Cox regression analysis. The expression of TGF-α and Ki-67 were detected by immunohistochemical staining of paraffin-embedded patient tissue specimens. Results The total resection (TR) group had longer overall survival compared with the non-TR group (P = 0.042). The TR group also had longer progression-free survival (PFS) than did the non-TR group (P = 0.046). The group with a high Ki-67 labeling index (Ki-67LI) had shorter overall survival than did the group with a low Ki-67LI (P = 0.039). Also, the group with a high Ki-67LI had significantly shorter PFS than did the group with a low Ki-67LI (P = 0.016). Moreover, the group with high TGF-α expression had significantly shorter PFS compared with the group with low TGF-α expression (P = 0.005). Conclusions Our results have shown that high levels of TGF-α and Ki-67 are associated with shorter PFS in patients with chordoma. We have confirmed the role of Ki-67 as a functional molecular marker of poor prognosis. We also identified TGF-α as a potential novel biomarker for predicting prognosis for patients with skull base chordoma.

Background Parasellar plasmacytomas are rare tumors arising from the sellar region that should be considered in the differential diagnosis of lesions involving the sella and clivus. Before surgical pathologic examination, parasellar plasmacytomas have often been misdiagnosed as invasive pituitary adenomas or chordomas owing to the similarity of the clinical presentation and imaging findings. Methods We retrospectively reviewed the data from 5 patients with parasellar plasmacytoma who underwent endonasal endoscopic tumor resection in Beijing Tiantan Hospital from January 2008 to January 2018. Their clinical symptoms, radiological features, and treatment modalities and outcomes were summarized. Results We enrolled a total of 5 patients (3 men and 2 women; median age at diagnosis, 54 years; range, 47–61) with parasellar plasmacytoma in the present clinical series. The presenting symptoms mainly included diplopia, headache, and blurred vision. All the patients had undergone endonasal endoscopic surgery combined with adjuvant therapy. After postoperative radiotherapy, complete remission was achieved within a median follow-up period of 41 months (range, 15–120). Conclusions The differential diagnosis of parasellar plasmacytoma with pituitary adenoma and chordoma should include a thorough endocrine workup, neurological examination, and radiological assessment. Our findings support radiotherapy as the main treatment of choice for parasellar plasmacytoma, given its typical feature of relatively high radiosensitivity. Tumor resection through the endonasal endoscopic approach combined with adjuvant radiotherapy could be the optimal initial treatment strategy in long-term control of the lesion and alleviation of neurological symptoms.

Objective The present study was conducted to evaluate the levels of Cdk2, cyclin E, p21, and p27 in growth hormone adenomas (GHPAs) and analyze their association with clinicopathologic features. Methods We collected 46 GHPA specimens and clinical materials from March 2012 to December 2015 at Beijing Tiantan Hospital. We analyzed the expression of Cdk2, cyclin E, p21, and p27 using immunohistochemistry, quantitative real-time polymerase chain reaction, Western blot, and methylation-specific polymerase chain reaction and sequencing. Results The levels of cyclin E and Cdk2 were much greater in the invasive group than in the noninvasive group (P 50%. Statistically significant differences were found in 4 CpG sites between the invasive and noninvasive specimens (P Conclusions Overexpression of cyclin E/Cdk2 and loss of p27 appears to be associated with a poor prognosis and might play a role in the treatment of GHPAs in the future.

Objective To explore molecular markers of radiosensitivity and prognostic factors in patients with clival chordomas. Methods Retrospective review was performed of 35 patients. Mean follow-up interval was 66.37 months (range, 29–106 months). Kaplan-Meier method was used for survival analysis. Immunohistochemical staining was used to detect expression levels of extracellular signal-regulated kinase (ERK) and 15-hydroxyprostaglandin dehydrogenase (HPGD). Results Total resection was achieved in 12 cases, subtotal resection was achieved in 12 cases, and partial resection was achieved in 11 cases. Radiation-sensitive group comprised 17 cases, and radiation-resistant (RR) group comprised 18 cases. Five-year progression-free survival (PFS) rates in total resection and nontotal resection groups were 46.3% and 10.1%, respectively (P = 0.005). Mean H-scores of ERK in radiation-resistant and radiation-sensitive groups were 110.38 and 82.98, respectively (P = 0.043). Mean H-scores of HPGD in radiation-resistant and radiation-sensitive groups were 178.62 and 203.47, respectively (P = 0.031). Mean PFS in low ERK expression group (58.61 months) was significantly longer than mean PFS in high ERK expression group (24.94 months) (P = 0.022). Mean PFS in high HPGD expression group (39.54 months) was significantly longer than mean PFS in low HPGD expression group (9.5 months) (P = 0.013). Conclusions Radical resection with protection of important structures is the most effective treatment of clival chordomas. High HPGD expression and low ERK expression were associated with radiation sensitivity and better prognosis. HPGD and ERK can be used as biomarkers to predict prognosis and guide treatment.

Objective Transnasal endoscopic skull base surgery (SBS) presents a major challenge for inexperienced neurosurgeons because of the complicated anatomic structures, 2-dimensional endoscopic view, limited operative field, and required skills. We designed a personalized multimaterial and multicolor three-dimensional (3D)-printed SBS simulation to reproduce the complex anatomy of the skull base. The fidelity and feasibility for anatomic education and surgical training were assessed. Methods Two-dimensional computer tomography and magnetic resonance images were collected from a 42-year-old healthy male volunteer. After 3D modeling and spatial alignment, personalized SBS simulations were produced using a multimaterial 3D printer. The fidelity of the models was assessed by 3 experienced neurosurgeons, and the effects for anatomic education and surgical training were evaluated by 10 resident trainees. Both evaluations were based on 5-point Likert questionnaires. Results The mean scores for fidelity of tissue structure ranged from 3.7 to 4.7, and scores for aid in anatomic education and surgical training ranged from 3.5 to 4.9. Conclusion The 3D-printed SBS simulation is a practical, economical, high-fidelity model. It has great potential for anatomic education and operative training in transnasal endoscopic surgery.

Objective To identify biomarkers key to invasiveness of the 3 subtypes of nonfunctioning pituitary adenomas (NFPAs) and provide a guidance for therapeutic decision making and identification of potential adjuvant drugs. Methods Fifty NFPA tumor tissues obtained from transsphenoidal surgery were used in the study. Three invasive NFPAs and 4 noninvasive NFPAs were used for gene expression microarray analyses. In addition, there are 5 invasive NFPAs and 4 noninvasive NFPAs used for proteomic analyses. Invasive-related biomarkers were identified by bioinformatics analysis by integrating the transcriptomics and proteomics data sets. All 3 subtypes of NFPAs (null cell adenomas, oncocytomas, and gonadotroph adenomas) were used to validate differentially expressed candidate biomarkers by means of quantitative real-time reverse transcription polymerase chain reaction and Western blot. The level of EZR was downregulated in pituitary adenoma cell line GH3 to investigate the invasive effect of EZR on GH3 cells by using the RNA interference technique. Results Eight genes involved in the invasion function were found by bioinformatics analysis, and the EZR gene was identified as a novel invasive-related biomarker in the 3 subtypes of NFPAs. The expression level of EZR was found higher in terms of invasiveness than the noninvasive ones of the 3 subtypes of NFPAs. Moreover, the knockdown of EZR inhibited the invasion of GH3 cells in vitro. Conclusions EZR is a novel biomarker in terms of invasion among the 3 subtypes of NFPAs, and it is a promising guide for therapeutic decision making as well.

Objective We sought to compare the prognosis of clival chordomas with different dural penetration and establish the relationship between dural penetration and platelet-derived growth factor receptor (PDGFR)-β signaling pathway. Methods Tumors in Type I (33 cases) showed limited dural penetration, while those in Type II (34 cases) had more serious dural penetration. Cox multivariate regression analysis was used to analyze risk factors affecting survival. Kaplan-Meier analysis measured overall survival (OS) and progression-free survival (PFS). To determine the relationship between dural penetration and PDGFR-β signaling, expression of PDGFR-β, Akt, mammalian target of rapamycin (mTOR), and phosphatase and tensin homolog (PTEN) expression was compared using immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and Western blotting. Results Total resection was achieved in 9 cases in Type I and 11 in Type II. There were significant correlations between OS and dural penetration (P = 0.032) and age (P = 0.034). PFS correlated significantly with dural penetration (P = 0.022), gender (P = 0.001), and degree of resection (P = 0.001). Mean OS in Type I was significantly longer than in Type II (P = 0.046). Patients aged

Background The ventriculoscopic approach has been considered to be more safe and effective in the treatment of hydrocephalus, arachnoid cysts and intraventricular lesions in neurosurgery. We found that intraoperative bleeding-related complications have the greatest impact on ventriculoscopic surgery. Until now, few studies fully discussed this complication. Methods Patients who underwent ventriculoscopic surgery between May 2011 and December 2012 at Beijing Tiantan Hospital were analyzed. Results A total of 126 patients were enrolled in the study. Intraoperative hemorrhage was observed in 75 cases (59.5%). Intraoperative hemorrhage classification of patients was as follows: stage I (n = 62); stage II (n = 11); stage III (n = 2). We found that there was no significant difference in complication rate and rate of symptom improvement between the patients who had hemorrhage and the patients who did not ( P Conclusions Intraoperative hemorrhage in ventriculoscopic surgery should be paid more attention. Generally, a skilled neurosurgeon can address hemorrhage with a low complication rate. Consequently, the ventriculoscopic approach is safe and effective in the treatment of specified brain ventricular disease.

This study was undertaken primarily to research transforming growth factor β1 (TGF-β1) and Wnt inhibitory factor 1 (WIF1) for the prediction of nonfunctioning pituitary adenoma (NFPAs) invasion and recurrence of tumor samples and the relations between quantitatively determined markers and clinical characters.We studied 104 patients, including 59 patients without recurrence and 45 patients with recurrence (9 patients with one surgery and 36 patients operated twice, both tumors being studied). All tissues were immunostained for TGF-β1 and WIF1 using tissue microarrays and confirmed with real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot.We found that invasion, TGF-β1, and WIF1 were significantly associated with recurrence and that age was associated with low expression of TGF-β1 and WIF1 (P0.001). There were no statistically significant differences in the expression of the 2 proteins between the noninvasive and the invasive groups. The expression of TGF-β1 and WIF1 in primary tumors in the recurrence group was lower than in the nonrecurrence group (P0.001). In the 36 paired primary or recurrent tumors, the expression of TGF-β1 and WIF1 in recurrent tumors was higher than the expression of primary tumors, which was confirmed with qRT-PCR and Western blot. Therefore, TGF-β1 and WIF1 seem to be related to recurrence or progression of pituitary adenomas.The expression of TGF-β1 and WIF1 in NFPAs correlated with cell proliferation and recurrence potential. They may be good markers of progressive behavior in NFPAs; however, the biologic mechanism needs further study.

The present study was conducted to evaluate the levels of Cdk2, cyclin E, p21, and p27 in growth hormone adenomas (GHPAs) and analyze their association with clinicopathologic features.We collected 46 GHPA specimens and clinical materials from March 2012 to December 2015 at Beijing Tiantan Hospital. We analyzed the expression of Cdk2, cyclin E, p21, and p27 using immunohistochemistry, quantitative real-time polymerase chain reaction, Western blot, and methylation-specific polymerase chain reaction and sequencing.The levels of cyclin E and Cdk2 were much greater in the invasive group than in the noninvasive group (P0.05). Significant differences were found between cyclin E and p21 and tumor size (P0.05) and between cyclin E expression and invasion (P0.05). Tumors were more likely to require whole resection in patients with low cyclin E expression (P0.05). The high-level p27 group had better progression-free survival than did the low-level p27 group (P0.01). Quantitative real-time polymerase chain reaction and Western blot analysis revealed a similar trend for Cdk2, cyclin E, p21, and p27 protein levels in growth hormone specimens (P0.01). An average of 33 CpG sites per sample were analyzed using matrix-assisted laser desorption ionization time-of-flight mass array, and in 7 of the 33 CpG sites, the methylation levels of p27 were50%. Statistically significant differences were found in 4 CpG sites between the invasive and noninvasive specimens (P0.01).Overexpression of cyclin E/Cdk2 and loss of p27 appears to be associated with a poor prognosis and might play a role in the treatment of GHPAs in the future.

The invasion and recurrence of clinical nonfunctioning pituitary adenomas (NFA) often lead to surgical treatment failure. Circular RNAs (circRNAs) are a novel class of RNAs whose 3' and 5' ends are joined together and have been shown to play important roles in cancer development. Until now, the roles of circRNAs have remained unclear in invasive and recurrent NFA.We detected and summarized the circRNA expression pattern in 75 NFA tissues from 10 noninvasive cases and 65 invasive cases and 9 pairs of NFA tumor tissues from 9 recurrent cases by circRNA microarrays. Accordingly, functional enrichment analysis and pathway analysis were performed and the circRNA-microRNA (miRNA) network was generated by bioinformatic analysis tools. Five new invasive NFA samples and 5 noninvasive NFA samples were collected to measure the microarray results.A total of 570 dysregulated circRNAs (invasive tumor vs. noninvasive tumor) and 10 upregulated circRNAs (recurrent tumor tissue vs. first surgery tumor tissue) were identified based on the situation (fold change2; P0.05). The parental genes of the dysregulated circRNAs in the comparison between invasion tumor and noninvasion tumor were found to be enriched in some cell adhesion signaling pathways such as Focal adhesion, Hippo signaling pathway, PI3K-Akt signaling pathway, and Adherens junction. The circRNA-miRNA network showed that the dysregulated circRNA may function as miRNA sponges.This is the first study to conduct and comprehensively analyze the circRNA expression profile in invasive and recurrent NFA. Our finding will provide evidence for the significance of circRNAs in NFA diagnosis, prognosis, and clinical treatment.

Objective Down-regulation of mothers against decapentaplegic homolog 3 (Smad3) results in the formation of tumors both in vivo and in vitro. However, little is known about the effect of Smad3 on adrenocorticotropic hormone-secreting pituitary adenomas (ACTH-PAs). Our objective was to study the expression and effect of Smad3 in ACTH-PAs and its possible mechanisms. Methods Smad3, COOH-terminally phosphorylated mothers against decapentaplegic homolog 3 (pSmad3), and mothers against decapentaplegic homolog 2 proteins (Smad2) were detected in samples from 5 normal anterior pituitaries and 18 ACTH-PAs by Western blot and immunohistochemical analysis. Then, Smad3 expression was up-regulated by Smad3-CMV plasmid or down-regulated by small interfering RNA in ACTH tumor cells (AtT-20) in vitro. Cell proliferation, apoptosis, ACTH level, and pSmad3, B-cell lymphoma/lewkmia-2 (BCL-2), and pro-opiomelanocortin (POMC) protein expression in the AtT-20 cells were measured to investigate the antitumor effects of Smad3. Results Reduced expression of Smad3 and pSmad3 but unchanged Smad2 levels were found in ACTH-PAs compared with normal pituitaries. In vitro, the overexpression of Smad3 inhibited cell proliferation, promoted cell apoptosis, and decreased ACTH secretion; in contrast, Smad3 knockdown increased cell proliferation and decreased cell apoptosis but had no significant effect on ACTH secretion. At the same time, overexpression of Smad3 increased pSmad3 but inhibited BCL-2 and POMC protein expression. On the contrary, underexpression of Smad3 inhibited pSmad3 but promoted BCL-2 and POMC protein expression. Conclusions Smad3 is underexpressed in ACTH-PAs. Reversing the expression of Smad3 in AtT-20 cells could suppress cell growth, promote tumor apoptosis, and decrease ACTH secretion. Tumor suppression was possibly mediated by the promotion of pSmad3 and the reduction of BCL-2 and POMC expression.

Background The postoperative ventricular adhesion after resection of central nervous system tumors can obstruct physiologic cerebrospinal fluid (CSF) circulation and cause temporal horn entrapment. The surgical goal is to restore physiologic flow of CSF. The authors reviewed their database to report their experience with endoscopic fenestration for treating entrapped temporal horn caused by atrial adhesions. All endoscopic operations performed from February 2015 to December 2016 were reviewed. Case Description Three patients developed temporal horn entrapment after tumor resection. Fenestration was successful in all patients, with a subsequent stomy of the septum pellucidum. Follow-up magnetic resonance imaging 1 year later showed a patent reduction of the entrapped horn. Conclusions Endoscopic fenestration is an option in the treatment of entrapped temporal horns. However, more experience is required to recommend it as the treatment of choice.

Skull base chordomas are clinically malignant because of the difficulty of total removal and the high recurrence rate. Because the disease-free survival after surgery is currently unpredictable, there is a need for new parameters, obtained from histologic analyses of the resection specimen, that allows a risk stratification of patients with chordoma.In recent years, electron microscopic diagnoses were introduced into the clinical practice for the diagnosis of chordoma in our department. Clinical outcomes and electron microscopic features were retrospectively reviewed in the study. The electron micrograph shows that clival chordoma can be divided into cell-dense type (CDT) and matrix-rich type (MRT). Of all the patients with chordoma, complete data from 27 patients were obtained. There were 12 patients in the CDT group and 15 patients in the MRT group. The paraffin-embedded tissue samples were stained with Ki-67 antibody. The prognostic values of electron microscopic classification were compared between the 2 groups.There were no statistical differences in the gender (P = 0.704) and age distribution (P = 0.243) between the 2 groups. There was also no statistical difference concerning the constitution of primitive tumors and recurrent tumors between the 2 groups (P = 0.706). The CDT group had a higher mortality rate than the MRT group (P = 0.037). The tumors in the CDT group were prone to recurrence and the need for reoperation within 1 year after surgery, which is statistically different from that in the MRT group (P0.001). Chordoma tumors of 23 patients (85.2%) stained positive for Ki-67. CDT chordomas had a higher Ki-67 proliferation index than the MRT chordomas (P = 0.013).The present study demonstrates the utility of the ultrastructural features in the prognostic outcome of patients with chordoma. According to the ultrastructures of chordomas, they can be divided into CDT and MRT. CDT chordoma cells have a more aggressive proliferative ability. Patients with CDT have a poor prognostic factor in clival chordoma, which has a higher risk of recurrence and a shorter survival.

Objective To review the literature and analyze the efficacy and safety of 3 surgical methods (neuroendoscopic fenestration, microsurgical fenestration, and cystoperitoneal shunting) for middle cranial fossa arachnoid cysts (MCFACs). Methods We searched MEDLINE, PubMed, and Cochrane Central electronic databases and collected studies of patients with MCFACs treated with 1 of 3 surgical methods. Eligible studies reported the rate of clinical symptoms improvement (RCSI), rate of cyst reduction (RCR), rate of total complications (RTC), rate of short-term complications (RSTC), rate of long-term complications (RLTC), and other parameters. Results Eighteen studies met the criteria. MCFACs were divided into 3 groups on the basis of surgical method: RCSI in group I (237 patients, neuroendoscopic fenestration) was 90% (95% confidence interval [CI]: 83%–95%); RCR: 76% (95% CI: 67%–84%); RTC: 28% (95% CI: 22%–34%); RSTC: 23% (95% CI: 17%–30%); and RLTC: 6% (95% CI: 3%–11%). RCSI in group II (144 patients, microsurgical fenestration) was 87% (95% CI: 75%–96%); RCR: 87% (95% CI: 70%–97%); RTC: 49% (95% CI: 30%–68%); RSTC: 44% (95% CI: 21%–68%); RLTC: 3% (95% CI: 0%–12%). RCSI in group III (93 patients, cystoperitoneal shunting) was 93% (95% CI: 66%–99%); RCR: 93% (95% CI: 66%–99%); RTC: 20% (95% CI: 5%–42%); RSTC: 10% (95% CI: 0%–31%); RLTC: 15% (95% CI: 9%–23%). RLTC differed significantly between the 3 groups (P = 0.005); RTC and RSTC between group I and group II (P = 0.002). Conclusions All 3 surgical methods are effective for MCFACs, but considering safety, neuroendoscopic fenestration may be the best initial procedure.