Endoscopic Endonasal Reconstruction of Intraoperative Cerebrospinal Fluid Leak in Different Skull base Regions: Outcomes, Meningitis and Risk Factors.

OBJECTIVE: Various non-vascularized or vascularized techniques have been adopted in endoscopic endonasal surgery (EES) for repairing intraoperative cerebrospinal fluid (CSF) leaks after tumor resection. Vascularized nasoseptal flaps (VNSF), free nasoseptal grafts (FNSG), free turbinate grafts (FTG), fascia lata and mashed muscle (FLMM) are frequently used. Outcomes of those grafts applied in the defects of different regions need to be clarified. METHODS: The data from a series of 162 patients with skull base tumor who underwent EES that had intraoperative CSF leak between Jan 2012 and Jan 2021 were retrospectively analyzed. The regions included anterior skull base (ASB), sellar region, clivus and infratemporal fossa (ITF). Repair failure rate (RFR), meningitis rate and associated risk factors were assessed. RESULTS: In total, 172 reconstructions were performed in 162 patients for the four sites of the skull base. There were 7 cases (4.3%) that had postoperative CSF leaks, which required second repair. The RFR for ASB, sellar region, clivus, and ITF was 2.6%, 2.2%, 16.7%, and 0%, respectively. The clivus defect was an independent risk factor for repair failure (P<0.01). The postoperative meningitis rate was 5.6%. Repair failure was an independent risk factor for meningitis (P < 0.01). CONCLUSIONS: VNSF, FNSG, FTG, FLMM are reliable autologous materials for repairing the dural defects in different regions during EES. Clivus reconstruction remains a great challenge, which had a higher RFR and meningitis rate. Repair failure is significantly associated with postoperative meningitis.

Clinical Observation of Various Types of Idiopathic Hypertrophic Cranial Pachymeningitis.

BACKGROUND: To assist doctors in making better treatment decisions and improve patient prognosis, it is important to determine which therapy modalities are suitable for various forms of idiopathic hypertrophic cranial pachymeningitis (IHCP). METHODS: All cases were received from the hospital medical record system, and some follow-up information was gathered through telephone follow-up. RESULTS: A total of 26 patients, 14 men and 12 women, with ages ranging from 20 to 73 years and a mean of 47.42 years, were included in the research. Regular types were less likely to recur than irregular and nodular types, focal types were less likely to recur than diffuse types, and corticosteroid-refractory types were more likely to recur than corticosteroid-sensitive types. CONCLUSIONS: The extent and shape of the lesion and susceptibility to corticosteroids are potential factors that could influence recurrence. Futhermore, this paper also proposes the fibroblasts as a new therapeutic target which may improve the quality of prognostic survival of patients.

[Clinical analysis of the treatment of maxillary odontogenic cyst by nasal endoscope fenestration through nasal base].

Objective:To investigate the feasibility and clinical effect of the surgical approach and method of transnasal fenestration under nasal endoscope for the treatment of maxillary odontogenic cyst. Methods:The clinical data of 23 cases with maxillary odontogenic cysts treated by nasal endoscopy through nasal fenestration were retrospectively analyzed. All cases underwent nasal endoscopy and CT examination before the operation. The mucosal membrane of the parietal wall of the cyst was excised through fenestration of the nasal base. The cyst fluid was removed by decompression, and the bony opening of the nasal base was trimmed and enlarged to the edge of the cyst. The intraoperative and postoperative effects were observed. Results:All cases were well exposed under the direct vision of nasal endoscope. The top wall of the cyst was removed to maximize the communication between the cyst cavity and the nasal floor. There were no complications such as nasolacrimal duct injury, turbinate atrophy, necrosis, and facial numbness. All patients were followed up for 6-12 months, and the clinical symptoms gradually disappeared after surgery. The inferior turbinate was in good shape, the cyst cavity was smooth, the cyst wall was determined, and no cyst recurrence was observed. Conclusion:The treatment of odontogenic cyst of maxilla under nasal endoscope through nasal fenestration is convenient. It has less trauma, fewer complications and a satisfactory curative effect, which is worthy of clinical promotion.

Radiological Features of IgG4-Related Disease in the Head, Neck, and Skull Base.

BACKGROUND: IgG4-related disease (IgG4-RD) is increasingly recognized as a multisystemic, chronic inflammatory process characterized by histologic fibrosis with IgG4-positive plasma cell infiltration. OBJECTIVES: The purpose of this study was to characterize the imaging features of patients diagnosed with IgG4-RD in the head and neck, especially the skull base. METHODS: Our study evaluated CT and MR imaging features of IgG4-RD in the head, neck, and skull base. Images from 15 patients were retrospectively evaluated for the location, signal intensity, morphology, size, boundary, and pre- and post-contrast MRI performances. RESULTS: The lesions presented as irregular shaped, localized masses, distributed in skull base regions; 93.3% of the lesions were isointensity in T1WI (14/15). A total of 80% of the lesions were iso-hypointense in T2WI (12/15); 60% of the lesions got homogeneous enhancement (9/15); and 46.7% of the patients had cranial nerves dysfunction (7/15). The most likely involved cranial nerve was trigeminal nerves (5/15); 60% of the patients had osteolytic bone destruction or sclerosis (9/15). CONCLUSION: Typical radiological features of IgG4-RD included T1 isointensity and T2 hypointensity, homogeneous and gradual enhancement pattern in MRI, easy cranial nerve invasion, dura involvement but the absence of brain edema, and the presence of bone remodeling without destruction, blurred lesion boundaries.

Associations of Endocan, FGF2, and PDGF Expression with Pituitary Neuroendocrine Tumor (PitNET) Invasiveness.

AIM: About 6-17% of pituitary neuroendocrine tumors (PitNETs) are invasive. Cavernous sinus invasion complicates neurosurgery, making total tumor resection impossible and leading to high recurrence postoperatively. This study detected Endocan, FGF2, and PDGF to examine the associations of these angiogenic factors with the invasiveness of PitNETs and to identify novel therapeutic targets in PitNETs. MATERIAL AND METHODS: Endocan mRNA amounts (qRT-PCR) in 29 human PitNET specimens obtained after surgery were assessed alongside clinical parameters (PitNET lineage, sex, age, and imaging data). In addition, qRT-PCR was used to determine the gene expression of other angiogenic markers (FGF-2 and PDGF). RESULTS: Endocan was positively associated with PitNET invasiveness. Endocan expressing specimens had elevated FGF2 amounts, and FGF2 and PDGF were negatively correlated. CONCLUSION: A complex but precise balance was found among Endocan, FGF2, and PDGF in pituitary tumorigenesis. High Endocan and FGF2 and low PDGF expression levels in invasive PitNETs show Endocan and FGF2 could be novel treatment targets in invasive PitNET.

Treatment of Recurrent Undifferentiated Pleomorphic Sarcoma of Infratemporal Fossa by Surgery Combined With Carbon Ion Radiotherapy: One Case Report.

We retrospectively analyzed the diagnosis and treatment process of one patient with recurrent undifferentiated pleomorphic sarcoma (UPS) of infratemporal fossa and made a definite diagnosis by combining the imaging and pathological examination results. After treatment failure with 2 cycles of chemotherapy and several surgeries, UPS was eventually treated by surgery + carbon ion radiotherapy, and MRI reexamination showed no relapse. Head and neck UPS is located deeply, easily recurs after operation, and difficult to be resected completely by surgery, with a gradually shortened interval of relapse over the number of surgeries, which becomes a treatment challenge. After the last surgery, the patient received carbon ion radiotherapy, with a good therapeutic effect, and no sign of relapse just before sending this article. Based on the above advantages, we have concluded that surgery + carbon ion radiotherapy is a new effective pathway to treat head and neck UPS.

Excision of Greater Superficial Petrosal Nerve Schwannoma Via a Pure Endoscopic Endonasal Approach.

Greater superficial petrosal nerve (GSPN) schwannomas are an exceedingly rare nerve sheath tumor. The current literature search was conducted using Medline and Embase database by key search terms. Only 31 cases have been reported in the literature so far. Facial palsy, hearing loss, and xerophthalmia accounted for 48.4% (15), 41.9% (13), and 29% (9) of all cases, respectively. The middle cranial fossa approach was used in all previous reports. A retrospective review of 2 GSPN schwannomas patients treated by endoscopic endonasal approach (EEA) in our center was collected. Clinical records, including clinical features, pre- and postoperative images, surgery, and follow-up information, were reviewed. In all cases, clinical features including facial numbness and headache were found, with tinnitus in case 1, hearing loss, xerophthalmia in case 2. Imaging studies showed a solid mass that originated in the anterior of the petrous bone. Two patients were treated by EEA. Furthermore, no recurrence was found during the follow-up period (15-29 months) in both of the 2 cases after the operation. Complete resection of GSPN schwannomas can be achieved via the pure EEA. Endoscopic endonasal approach for radical removal of tumors is safe and feasible.

Retrospective assessment of at-risk myocardium in reperfused acute myocardial infarction patients using contrast-enhanced balanced steady-state free-precession cardiovascular magnetic resonance at 3T with SPECT validation.

BACKGROUND: Contrast-enhanced (CE) steady-state free precession (SSFP) CMR at 1.5T has been shown to be a valuable alternative to T2-based methods for the detection and quantifications of area-at-risk (AAR) in acute myocardial infarction (AMI) patients. However, CE-SSFP's capacity for assessment of AAR at 3T has not been investigated. We examined the clinical utility of CE-SSFP and T2-STIR for the retrospective assessment of AAR at 3T with single-photon-emission-computed tomography (SPECT) validation. MATERIALS AND METHODS: A total of 60 AMI patients (ST-elevation AMI, n = 44;  non-ST-elevation AMI, n = 16) were recruited into the CMR study between 3 and 7 days post revascularization. All patients underwent T2-STIR, CE-bSSFP and late-gadolinium-enhancement CMR. For validation, SPECT images were acquired in a subgroup of patients (n = 30). RESULTS: In 53 of 60 patients (88 %), T2-STIR was of diagnostic quality compared with 54 of 60 (90 %) with CE-SSFP. In a head-to-head per-slice comparison (n = 365), there was no difference in AAR quantified using T2-STIR and CE-SSFP (R2 = 0.92, p < 0.001; bias:-0.4 ± 0.8 cm2, p = 0.46). On a per-patient basis, there was good agreement between CE-SSFP (n = 29) and SPECT (R2 = 0.86, p < 0.001; bias: - 1.3 ± 7.8 %LV, p = 0.39) for AAR determination. T2-STIR also showed good agreement with SPECT for AAR measurement (R2 = 0.81, p < 0.001, bias: 0.5 ± 11.1 %LV, p = 0.81). There was also a strong agreement between CE-SSFP and T2-STIR with respect to the assessment of AAR on per-patient analysis (R2 = 0.84, p < 0.001, bias: - 2.1 ± 10.1 %LV, p = 0.31). CONCLUSIONS: At 3T, both CE-SSFP and T2-STIR can retrospectively quantify the at-risk myocardium with high accuracy.

Superior turbinate management and olfactory outcome after endoscopic endonasal transsphenoidal surgery for pituitary adenoma: a propensity score-matched cohort study.

BACKGROUND: Surgical management of the superior turbinate (ST) is required to access the sella in endoscopic endonasal transsphenoidal surgery (EETS) for pituitary adenoma. Two common ST management techniques include partial resection of the ST (PRST) and intentional lateralization of the ST (ILST). Given the concentrated distribution of the olfactory nerve fibers on the medial surface of the ST, in this study we aimed to ascertain whether PRST worsens the objective olfactory outcome when compared with ILST. METHODS: A retrospective, propensity score-matched cohort study was performed at a tertiary referral center. A total of 232 adult patients undergoing EETS for pituitary adenoma were analyzed. The threshold test (STT) and the 12-item identification test (SIT-12) from "Sniffin' Sticks" were administered for separate nostrils preoperatively and 6 months postoperatively. RESULTS: Of 232 patients, 109 had right-sided PRST and 123 received right-sided ILST. Propensity score matching-controlling for olfactory-related confounding factors, including gender, age, medical comorbidities, surgical technique, and preoperative olfaction-resulted in 74 matched pairs. When comparing the 6-month postoperative olfactory performance of the right nostril, the STT score was significantly lower in the PRST group than the ILST group (p = 0.036, η2 for effect size estimate = 0.030), but the SIT-12 scores were similar in the 2 groups (p = 0.325). Overall, the olfactory outcomes for the right nostril did not qualitatively differ between the PRST and ILST groups (p = 0.401). CONCLUSION: Despite its association with threshold impairment, PRST in EETS does not seem to carry an additional risk of postoperative olfactory dysfunction.

Inhibition Of Glycogen Synthase Kinase 3 Beta Suppresses The Growth And Survival Of Skull Base Chordoma Cells By Downregulating Brachyury Expression.

PURPOSE: Chordomas are locally aggressive tumors arising from notochordal remnants. Brachyury, a protein coded by T-gene, is crucial for chordoma cell proliferation. The aim of this study was to evaluate the effects of glycogen synthase kinase 3 beta (GSK3ß) activity on brachyury expression and on the growth and survival of skull base chordoma cells. PATIENTS AND METHODS: In this study, 16 paraffin-embedded specimens of primary skull base chordomas were analyzed for the expression of phosphorylated GSK3ß and brachyury using immunohistochemistry. The UM-Chor1 cell line derived from a clival chordoma was treated with AR-A014418 (AR), an inhibitor of GSK3ß, and brachyury expression was analyzed by qRT-PCR and Western blotting. The possible mechanism by which brachyury regulates the Wnt/ß-catenin signaling pathway was investigated by immunocytochemistry. The effects of AR on cell proliferation as well as sensitivity to chemotherapeutic drugs were also examined. RESULTS: The results suggested that phosphorylated GSK3ß and brachyury were upregulated in chordoma tissues. The GSK3ß inhibitor (AR) decreased brachyury expression and suppressed the growth and survival of the chordoma cells, possibly via regulation of the Wnt/ß-catenin signaling pathway. Moreover, AR increased the sensitivity of chordoma cells to chemotherapeutic drugs in vitro. CONCLUSION: This study provides evidence for the clinical development of the GSK3ß inhibitor (AR-A014418) as a potential chemotherapeutic adjuvant for the treatment of chordoma.

Direct Transcavernous Sinus Approach for Endoscopic Endonasal Resection of Intracavernous Sinus Tumors.

OBJECTIVE: Because of its vascular supply and neurovascular contents, the cavernous sinus (CS) is a challenging area to dissect in the setting of skull base tumors with intracavernous extension or invasion. In the present study, we report the clinical outcomes of 14 patients with tumors with CS invasion that were surgically treated using a direct transcavernous sinus approach for endoscopic endonasal resection of their intracavernous sinus tumors. METHODS: Fourteen patients had undergone surgery using a direct endoscopic endonasal transcavernous sinus approach. The pathologic entities included Knosp grade 3-4 pituitary adenomas (n = 8), meningioma (n = 3), squamous cell carcinoma (n = 2), and chondrosarcoma (n = 1). The indications, surgical technique, and outcomes are discussed. RESULTS: Gross total resection was achieved in 11 patients (78.6%). All patients experienced resolution or improvement of symptoms. One patient experienced a transient oculomotor nerve palsy, which had resolved within 2 months postoperatively. No other complications occurred. For those tumors that had been grossly resected, no recurrence developed in any patient (mean follow-up, 40.4 ± 24.8 months; range 10-84). CONCLUSIONS: Depending on the space created by intracavernous sinus tumors, use of the transanterior wall for the CS approach in endoscopic endonasal surgery could adequately treat most patients in our case series. This approach provided good visualization of the CS and can be used to treat tumors with favorable outcomes and a low incidence of complications in appropriately evaluated patients.

Solamargine inhibits proliferation and promotes apoptosis of CM-319 human chordoma cells through suppression of notch pathway.

BACKGROUND: Solamargine (SM), which represents a natural steroid alkaloid glycoside compound and a cytotoxic agent, has been proved to enhance the sensitivity of lung cancer cells to tumor necrosis factors (TNFs). In this study, we aimed to investigate the roles and mechanisms of SM in chordoma. METHODS: Cell viability, proliferation, apoptosis and cell cycle were measured by cell counting Kit-8 (CCK-8) assay, 5(6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling and flow cytometry (FCM), respectively. Western blot and quantitative real-time reverse transcription PCR (qRT-PCR) assays were performed to detect the expressions of related mRNAs and proteins. RESULTS: The results revealed that SM distinctly suppressed the proliferation of CM-319 cells. SM significantly induced the CM-319 cells apoptosis through up-regulating the expression levels of Caspase-3/8/9. The cell cycle of CM-319 cells was blocked by SM in G1 phase. Moreover, SM could significantly suppress the Notch pathway in CM-319 cells. CONCLUSIONS: In conclusion, SM suppressed the proliferation and enhanced the apoptosis ability of CM-319 cells via suppressing the Notch pathway. The results suggested that SM might be a novel therapeutic agent and supported the utilization of SM in chordoma.

Up-regulation of the IRX2 gene predicts poor prognosis in nasopharyngeal carcinoma.

Aberrant expression of the IRX2 gene contributes to the oncogenesis and progression of various cancers. In this study, we analyzed the clinical significance and the prognostic value of mRNA expression level of the IRX2 gene in nasopharyngeal carcinoma (NPC) patients, with the goal to find a novel prognostic biomarker for NPC. Tissue samples were collected prior to treatment from 71 NPC patients for the detection of mRNA expression level of a total of 31503 genes, with high throughput screening of the mRNA expression profile. The Kaplan-Meier curves and log-rank test were used for univariate analyses to determine if the mRNA expression level of IRX2 and other 31502 genes, as well as clinical characteristics were of prognostic value for overall survival (OS), distant metastasis-free survival (DMFS) and disease-free survival (DFS). Regularized Cox regression was performed to test the contribution of prognostic factors to OS, DMFS, and DFS of NPC patients. The Cox proportional hazard model was used to test the independence of prognostic effect of IRX2 and other clinical features. The receiver operator characteristic curve was drawn and the area under the curve (AUC) was calculated to evaluate the predictive power of IRX2 gene. Univariate analyses showed a higher mRNA expression level of the IRX2 gene correlated with shorter OS (P = 0.001), DMFS (P = 0.003), and DFS (P = 0.007). Regularized Cox regression and Cox proportional hazard model analyses further showed that ahigher mRNA expression level of the IRX2 gene in the primary NPC was an independent prognostic factor for OS (Coxnet beta = 0.03, Cox proportion hazard model P = 0.038), DMFS (Coxnet beta = 0.018, Cox proportion hazard model P = 0.01) and DFS (Coxnet beta = 0.008, Cox proportion hazard model P = 0.029). The AUC showed that the mRNA expression level of the IRX2 gene is a significant predictor for predicting the OS (AUC value = 0.7105) and DMFS (AUC value = 0.7027) of NPC patients. Our results demonstrated that the IRX2 gene may be a novel independent unfavorable prognostic factor for NPC patients.

Endoscopic Approach to Remove Intra-extracranial Tumors in Various Skull Base Regions: 10-year Experience of a Single Center.

BACKGROUND: Some problems have been found in the usually adopted combined approach for the removal of intra-extracranial tumors in skull base. Herein, we described a pure endoscopic transnasal or transoral approach (ETA) for the removal of intra-extracranial tumors in various skull base regions. METHODS: Retrospectively, clinical data, major surgical complications, pre- and postoperative images, and follow-up information of a series of 85 patients with intra-extracranial tumors in various skull base regions who were treated by surgery via ETA in our skull base center during the past 10 years were reviewed and analyzed. RESULTS: Gross total tumor removal was achieved in 80/85 cases (94.1%) in this study. All 37 cases with tumors in anterior skull base and all 14 cases with tumors in jugular foramen received total tumor removal. Thirteen and three cases with tumors in clivus received total and subtotal tumor removal, respectively. Total and subtotal tumor removal was performed for 16 cases and 2 cases in lateral skull base, respectively. The complications in this study included: cerebrospinal fluid leakage (n = 3), meningitis (n = 3), and new cranial nerve deficits (n = 3; recovered in 3 months after surgery). In the follow-up period of 40-151 months (median: 77 months), seven patients (8.8%) out of the 80 cases of total tumor removal experienced recurrence. CONCLUSIONS: Complete resection of intra-extracranial growing tumors in various skull base regions can be achieved via the pure ETA in one stage in selected cases. Surgical procedure for radical removal of tumors is feasible and safe.

The PI3K inhibitor GDC-0941 enhances radiosensitization and reduces chemoresistance to temozolomide in GBM cell lines.

Glioblastoma multiforme (GBM) is among the most lethal of all human tumors. It is the most frequently occurring malignant primary brain tumor in adults. The current standard of care (SOC) for GBM is initial surgical resection followed by treatment with a combination of temozolomide (TMZ) and ionizing radiation (IR). However, GBM has a dismal prognosis, and survivors have compromised quality of life owing to the adverse effects of radiation. GBM is characterized by overt activity of the phosphoinositide 3-kinase (PI3K) signaling pathway. GDC-0941 is a highly specific PI3K inhibitor with promising anti-tumor activity in human solid tumors. It is being evaluated in Phase II clinical trials for the treatment of breast and non-squamous cell lung cancer. We hypothesized that GDC-0941 may act as an antitumor agent and potentiate the effects of TMZ and IR. In this study, GDC-0941 alone induced cytotoxicity and pro-apoptotic effects. Moreover, combined with the standard GBM therapy (TMZ and IR), it suppressed cell viability, showed enhanced pro-apoptotic effects, augmented autophagy response, and attenuated migratory/invasive capacity in three glioma cell lines. Protein microarray analyses showed that treatment with TMZ+GDC-0941+IR induced higher levels of p53 and glycogen synthase kinase 3-beta (GSK3-ß) expression in SHG44GBM cells than those induced by other treatments. This was verified in all cell lines by western blot analysis. Furthermore, the combination of TMZ and GDC-0941 with or without IR reduced the levels of p-AKT and O6-methylguanine DNA methyltransferase (MGMT) in T98G cells. The results of this study suggest that the combination of TMZ, IR, and GDC-0941 is a promising choice for future treatments of GBM.

miR-219-5p inhibits proliferation and clonogenicity in chordoma cells and is associated with tumor recurrence.

Chordoma is a rare malignant bone tumor that is usually localized to the skull base, vertebral column and sacrum. The transcription factor brachyury, which is encoded by the T gene, has a critical role in the development and progression of chordoma, although the mechanisms underlying brachyury regulation remain unclear. The aim of the current study was to identify and characterize microRNAs (miRs) that regulate brachyury expression in chordoma. MicroRNAs that target brachyury were predicted using miRanda and TargetScan. Using reverse transcription-quantitative polymerase chain reaction, miR-219-5p was shown to be significantly downregulated in chordoma tissues and the U-CH2 chordoma cell lines. A dual-luciferase reporter assay was used to validate the inhibitory effect of miR-219-5p on brachyury mRNA expression. The expression level of brachyury was downregulated in U-CH2 cells following transfection with miR-219-5p mimics and upregulated following transfection with the miR-219-5p inhibitor. The effects of miR-219-5p on the proliferation and clonogenicity of chordoma cells were assessed using cell counting kit-8, EdU and clone formation assays. These in vitro results indicated that miR-219-5p may have an important role in regulating the cell proliferation and clonogenicity of human chordoma cells, potentially by targeting brachyury. Furthermore, the associations between the expression levels of miR-219-5p and various clinicopathological factors were analyzed, and miR-219-5p expression was shown to correlate with tumor extent and recurrence. These results suggested that miR-219-5p functions as a tumor suppressor in chordoma and, therefore, that miR-219-50 may be a potential target for therapeutic intervention.

[Involvement of MAPK signal transduction pathways in regulating the expression of glucocorticoid receptor isoforms in nasal polyp epithelia in vitro].

OBJECTIVE: To explore the upstream signal transduction mechanism responsible for the decrease of the ratio of the two glucocorticoid receptor (GR) subunits (GRα and GRß) in nasal polyp in vitro. METHODS: The GRα/GRß decrease cell model was established by lipopolysaccharide (LPS)-induced human nasal epithelia (HNE) of nasal polyp in vitro. Changes in the protein and mRNA expression of GRα, GRß and the key enzymes in the p38MAPK, ERK and JNK signal pathways were measured, respectively, before and after being induced with different doses of LPS and specific inhibitors of p38MAPK, JNK and ERK. SPSS 16.0 software (Analysis of variance, ANOVA) was used to analyze the data. RESULTS: With the LPS induction, the GRα/GRß ratio declined in both a time-dependent manner and a concentration-dependent manner in HNE, which demonstrated the successful establishment of a GRα/GRß decrease model in vitro. After cultured HNE were induced with the same set of LPS, the p38MAPK, ERK and JNK signal pathways were also activated. The mRNA expression of p38MAPK and JNK in each LPS-induced group (17.14 ± 1.50, 22.34 ± 2.78, 30.12 ± 1.07; 2.51 ± 0.13, 3.79 ± 0.67, 4.41 ± 0.83; 25.62 ± 1.77, 31.33 ± 1.97, 37.25 ± 2.46) was significantly higher than that (7.39 ± 0.31, 2.04 ± 0.34, 2.38 ± 0.35) in the control group (χ² value was 15.347, 18.331, 14.671, all P < 0.01). Either a specific inhibitor (SB203580) of the p38MAPK pathway or a specific inhibitor (SP600125) of the JNK pathway increased the GRα/GRß ratio at the meantime of inhibiting their pathways. SB203580 exhibited a much stronger increase effect on GRα/GRß ratio than SP600125. The specific inhibitors (PD98059) of ERK had no influence on the expression of GR isoforms. CONCLUSIONS: The above results demonstrated that the decrease of GRα/GRß ratio in HNE induced by LPS in vitro is mediated through the p38MAPK and JNK signal pathways. It is possible to improve the treatment effect of GC resistance in nasal polyp by targeting these specific signal pathways.

Overexpression of the BMP4/SMAD signaling pathway in skull base chordomas is associated with poor prognosis.

Chordomas are rare, locally invasive tumors with characteristic expression of the T-box transcription factor Brachyury. Little is yet known of the molecular events involved in the development of these tumors. Bone morphogenesis protein 4 (BMP4) signaling, which acts upstream of Brachyury in embryonic development, has been implicated in carcinogenesis in multiple malignancies. To explore the role of the canonical BMP4/SMAD signaling pathway in the pathogenesis of chordoma, we investigated, in 40 skull base chordomas, the expression of three major components of the signaling axis: BMP4, phospho-SMAD5 and SMAD4. Immunostaining revealed positive expression in 70%, 52.5% and 90% of cases, respectively. Eighteen (45%) of patients exhibited concurrent positive expression of these markers, which we defined as "high" expression of the BMP4/SMAD signaling pathway. Interestingly, when we compared the pattern of expression with clinicopathological parameters, we found that high expression of the pathway was more often observed in larger tumors (≥ 4 cm) than smaller ones (P = 0.010), and correlated significantly with dural invasion (P = 0.024). The Kaplan-Meier log-rank test showed that the 5-year overall survival rate for patients with high expression of the pathway was significantly lower than those with low expression (71.4% vs. 90.2%, P = 0.010). In conclusion, our results demonstrate for the first time that overexpression of the BMP4/SMAD signaling pathway could predict poor clinical outcome in skull base chordomas, suggesting activation of this pathway is involved in chordoma pathogenesis.