Chuzhong Li

Assessment of endoscopic treatment for middle cranial fossa arachnoid cysts

BackgroundEndoscopic cystocisternotomy is one of three surgical methods used to treat middle cranial fossa arachnoid cysts. There is debate about which method is the best.ObjectiveThe aim of this study is to evaluate the effectiveness and safety of endoscopic cystocisternotomy for treatment of arachnoid cysts of the middle cranial fossa.MethodsThirty-two patients with arachnoid cysts of the middle cranial fossa who had undergone endoscopic cystocisternal fenestration between 2004 and 2009 were studied retrospectively. Data were obtained on clinical and neuroradiological presentation, indications to treat, surgical technique, complications, and the results of clinical and neuroradiological follow-up.ResultsAmong the 27 patients with symptoms before surgery, 8 had disappearance of symptoms and 17 had improvement of symptoms. The cyst was reduced in size or it completely disappeared in 24 (75%) patients. The incidence rate of complications was 18.8%.ConclusionsEndoscopic cystocisternal fenestration is an effective treatment for symptomatic arachnoid cysts of the middle cranial fossa and should be the initial surgical procedure.

Suprasellar cysts: clinical presentation, surgical indications, and optimal surgical treatment

BackgroundTo describe the clinical presentation of suprasellar cysts (SSCs) and surgical indications, and compare the treatment methods of endoscopic ventriculocystostomy (VC) and ventriculocystocisternotomy (VCC).MethodsWe retrospectively reviewed the records of 73 consecutive patients with SSC who were treated between June 2002 and September 2009. Twenty-two patients were treated with VC and 51 with VCC. Outcome was assessed by clinical examination and magnetic resonance imaging.ResultsThe patients were divided into five groups based on age at presentation: age less than 1 year (n = 6), 1-5 years (n = 36), 6-10 years (n = 15), 11-20 years (n = 11), and 21-53 years (n = 5). The main clinical presentations were macrocrania (100%), motor deficits (50%), and gaze disturbance (33.3%) in the age less than 1 year group; macrocrania (75%), motor deficits (63.9%), and gaze disturbance (27.8%) in the 1-5 years group; macrocrania (46.7%), symptoms of raised intracranial pressure (ICP) (40.0%), endocrine dysfunction (40%), and seizures (33.3%) in the 6-10 years group; symptoms of raised ICP (54.5%), endocrine dysfunction (54.5%), and reduced visual field or acuity (36.4%) in the 11-20 years group; and symptoms of raised ICP (80.0%) and reduced visual field or acuity (40.0%) in the 21-53 years group. The overall success rate of endoscopic fenestration was 90.4%. A Kaplan-Meier curve for long-term efficacy of the two treatment modalities showed better results for VCC than for VC (p = 0.008).ConclusionsDifferent age groups with SSCs have different main clinical presentations. VCC appears to be more efficacious than VC.

Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas.

BackgroundDopamine agonists (DAs) are the first-line treatment for prolactinomas, which account for 25–30% of functioning pituitary adenomas, and bromocriptine (BRC) is the only commercially available DAs in China. However, tumors are resistant to therapy in 5–18% of patients.MethodsThe exomes of six responsive prolactinomas and six resistant prolactinomas were analyzed by whole-exome sequencing.ResultsUsing stringent variant calling and filtering parameters, ten somatic variants that were mainly associated with DNA repair or protein metabolic processes were identified. New resistant variants were identified in multiple genes including PRDM2, PRG4, MUC4, DSPP, DPCR1, RP1L1, MX2, POTEF, C1orf170, and KRTAP10-3. The expression of these genes was then quantified by real-time reverse-transcription PCR (RT–qPCR) in 12 prolactinomas and 3 normal pituitary glands. The mRNA levels of PRDM2 were approximately five-fold lower in resistant prolactinomas than in responsive tumors (p < 0.05). PRDM2 protein levels were lower in resistant prolactinomas than in responsive tumors, as determined by Western blotting and immunohistochemical analysis (p < 0.05). Overexpression of PRDM2 upregulated dopamine receptor D2 (D2DR) and inhibited the phosphorylation of ERK1/2 in MMQ cells. PRDM2 showed a synergistic effect with BRC on the inhibition of prolactin (PRL) secretion and MMQ cell viability, and low PRDM2 expression was associated with tumor recurrence.ConclusionsPRDM2 downregulation may play a role in dopamine-agonist resistance and tumor recurrence in prolactinomas.

Expression of estrogen receptor α and growth factors in human prolactinoma and its correlation with clinical features and gender

Background: Many studies demonstrate that growth factors play an important role in the pathogenesis of prolactinoma induced by estrogen. The effects of estrogen are mainly mediated through its nuclear receptor (ERα); however, expression of ERα and growth factors in prolactinoma and healthy pituitary and their relationship remain obscure. Aim: To obtain new insights regarding the expression differences of these factors and their relationship and to investigate the correlation between gender and clinical features in patients with prolactinoma. Subjects and methods: A total of 21 human prolactinomas and 6 healthy human pituitaries were examined for mRNA expression of ERα, basic fibroblast growth factor (bFGF), transforming growth factor α (TGFα), TGFβ1, TGFβ3, and TGFβ receptor type II (TGFβRII) by means of real-time PCR. Patient clinical data was also analyzed. Results: Both PRL level and tumor volume of the male patient group were higher than that of the female patient group. There was a significant correlation between PRL level and tumor volume in the total patient group. Expression of ERα, bFGF, TGFα, and TGFβ3 mRNA levels of the patient group were significantly different from that of the control group. A significant correlation between ERα mRNA levels and PRL levels, tumor volume, TGFβ1 mRNA levels in the total patient group were found. Conclusions: PRL level and tumor volume have a significant difference between genders in prolactinoma patients. ERα and some growth factors may be involved in the tumorigenesis of prolactinoma. ERα could potentially be an effective therapy target for treating prolactinoma.

Reversal of multidrug resistance by magnetic chitosan-Fe3O4 nanoparticle-encapsulated MDR1 siRNA in glioblastoma cell line

Abstract Objective: To investigate the reversal effects of MDR1 gene on multidrug resistance in the glioblastoma cell line BT325 by magnetic chitosan-Fe3O4 nanoparticle-encapsulated MDR1 siRNA. Methods: The shRNA expression vector was constructed and the recombinant plasmids were cloned. Magnetic chitosan-Fe3O4 nanoparticles were prepared and the encapsulation rate was determined. After transfection, the BT325 cells were cultured to assay the transfection efficiency. The changing of MDR1 mRNA level and P-gp protein was evaluated. And the sensitivity to different chemotherapeutic drugs was assessed in BT325-siRNA transfected cell and untransfected cell by IC50 values. Results: The MDR1 RNAi plasmid was successfully designed and preparation. The encapsulation efficiency of the magnetic chitosan-Fe3O4 nanoparticle was 98–99%. The transfection efficiency of the siRNA-nanoparticles in BT325 cells was 70–80%. And the MDR1 mRNA levels were downregulated by reverse transcription (RT)-PCR assay. Furthermore, the results of P-gp protein expression decreased on immunocytochemical assay, Western blot and flow cytometry compared with control group. The IC50 values of DOX and VCR were decreased between the transfected cell and normal BT325 cell. Conclusion: After targeted transfection of the glioblastoma cell line with magnetic chitosan-Fe3O4 nanoparticle-encapsulated MDR1 siRNA, the expression of MDR1 at both the mRNA and protein level decreased, which increased sensitivity to chemotherapy in vitro. It might provide a basis for investigation of the mechanism involved in multidrug resistance in glioma.

The role of FSCN1 in migration and invasion of pituitary adenomas.

The prediction of invasion or malignant behavior in PAs remains challenging. FSCN1, an actin-bundling protein, is associated with increased risk of mortality and metastasis in various cancer types. The objective of the study was to evaluate the expression of FSCN1 in 312 PAs cases, and to analyze its association with clinicopathologic features and invasion of PAs, thus serving as a promoter of cancer invasion. In non-function PAs (NFPA), FSCN1 nuclear-positive cases were 53/97 in the invasive group (IPA), and 21/115 in the noninvasive group (nIPA) (ⅹ(2) = 30.65, p = 0.004). FSCN1 cytoplasm-positive cases were 36/97 in IPA, and 8/107 in nIPA (ⅹ(2) = 29.09, p = 0.000). In growth hormone adenomas (GHomas), FSCN1 nuclear-positive were 10/13 in IPA, and 3/37 in nIPA (ⅹ(2) = 23.67, p = 0.000). FSCN1 cytoplasm-positive were 8/13 in IPA, and 2/37 in nIPA (Table 3 ⅹ(2) = 18.94, p = 0.000). Overall, a significant difference was found between FSCN1 expression and tumor size (ⅹ(2) = 46.21, p = 0.000), not age (ⅹ(2) = 2.09, p = 0.148). In the high FSCN1 expression group, 27/137 cases (19.7%) had tumor recurrence, and 10/175 cases (5.7%) in low FSCN1 level (ⅹ(2) = 14.40 p = 0.000). Reduction of FSCN1 suppressed the invasion level of GH3 cells through transwells test. In addition, reduction of FSCN1 can obviously down-regulate the level of Notch1 and DLL3. Our data may help in deciding whether FSCN1 can be a predictor for invasion and recurrence of PAs.

Integrative proteomics and transcriptomics revealed that activation of the IL-6R/JAK2/STAT3/MMP9 signaling pathway is correlated with invasion of pituitary null cell adenomas

Non-functioning pituitary adenomas (NFPAs) are a highly heterogeneous group, but few studies have explored the invasion mechanism of specific subtypes of NFPAs. The objective of this study was to investigate the differential molecular expression patterns and the critical biological signaling pathways involved in the invasion of pituitary null cell adenomas (PNCAs) through integrative proteomics and transcriptomics. A total of 1160 genes and 283 proteins were found to be differentially expressed in invasive and non-invasive PNCAs. The differentially expressed molecules related to invasion were enriched in 15 canonical signaling pathways, 15 clusters of diseases or biological functions and 5 upstream molecules. Among them, the majority of the differentially expressed molecules were found to be involved in transport of molecule, migration of cells and cell movement. Notably, IL-6 was a significantly activated upstream regulator, and the IL6R/JAK2/STAT3 cascade was found to play a critical role in acute phase response signaling, which was the most significant canonical signaling pathway. Furthermore, we validated the overexpression of IL-6R, JAK2, STAT3, p-STAT3 and MMP9 in invasive PNCAs. Our data suggest that overactivation of the IL-6R/JAK2/STAT3/MMP9 pathway is critical for the invasion of PNCAs.

The role of TGF-β/Smad signaling in dopamine agonist-resistant prolactinomas.

BACKGROUND Prolactinomas are the most common secretory pituitary adenomas. The first line of treatment involves dopamine agonists (DAs); however, a subset of patients is resistant to such therapy. Recent studies suggest that dopamine can up-regulate TGF-β1 synthesis in rat pituitary lactotrophs whereas estradiol down-regulates TGF-β1. To date, the role of TGF-β/Smad signaling in DAs-resistant prolactinomas has not been explored. METHODS High-content screening (HCS) techniques, qRT-PCR, Western blot, immunofluorescence and ELISA, were performed to determine the role of TGF-β/Smad signaling in DAs-resistant prolactinomas. RESULTS We reported a significant down-regulation of TGF-β/Smad signaling cascade in DAs-resistant prolactinomas compared to normal human anterior pituitaries. Following treatment with TGF-β1, the dopamine agonist, bromocriptine, and the estrogen antagonist (ER), fulvestrant in GH3 cells, we found that TGF-β1 and fulvestrant caused significant cytotoxicity in a dose- and time-dependent manner and activated Smad3 was detected following exposure to TGF-β1 and fulvestrant. In addition, treating GH3 cells with fulvestrant increased active TGF-β1 levels and decreased PRL levels in a dose-dependent manner. CONCLUSION TGF-β/Smad signaling pathway may play an important role in DA-resistant prolactinomas and has the potential to be a viable target for the diagnosis and treatment of prolactinomas, particularly in patients who are resistant to DAs.

Overexpression of the cell adhesion molecule claudin-9 is associated with invasion in pituitary oncocytomas

Pituitary oncocytoma is a subtype of nonfunctioning pituitary adenomas with the potential to be locally invasive. Currently, surgery is the most effective treatment, whereas functional pituitary adenomas can be treated by drugs. We analyzed the invasiveness of pituitary oncocytomas to identify biomarkers that may be useful for guiding future therapeutic decision making. To identify important biomarkers of pituitary oncocytomas, 20 oncocytomas that were negative for hormone-specific immunostaining were confirmed by anti-mitochondria antibody immunostaining and electron microscopy. Our clinical phenotype data showed a prominent male predilection (85%). These tumors were classified as invasive or noninvasive based on preoperative magnetic resonance imaging, intraoperative records, and pathology slide. We observed significantly different expression profiles between pituitary oncocytomas (n = 3) and normal pituitary glands (n = 3). A total of 1937 genes were differentially expressed between the pituitary oncocytomas and normal pituitary glands. Among these 1937 genes, 954 were up-regulated and 983 were down-regulated in pituitary oncocytomas. The most significantly altered gene, claudin-9 (CLDN9), was further confirmed by quantitative real-time polymerase chain reaction, Western blot, and immunohistochemical staining in 10 invasive pituitary oncocytoma samples and 10 noninvasive pituitary oncocytoma samples. High levels of CLDN9 were found in the pituitary oncocytomas, whereas low levels were detected in normal pituitary glands. In addition, the CLDN9 expression level was higher in invasive oncocytomas compared with noninvasive oncocytomas. Bioinformatics Gene Ontology analysis was performed to better understand the critical role of CLDN9 in the development and progression of oncocytomas. Consequently, CLDN9 may be an important biomarker for invasive pituitary oncocytomas.

Identification of Differentially Expressed Genes in Pituitary Adenomas by Integrating Analysis of Microarray Data

Pituitary adenomas, monoclonal in origin, are the most common intracranial neoplasms. Altered gene expression as well as somatic mutations is detected frequently in pituitary adenomas. The purpose of this study was to detect differentially expressed genes (DEGs) and biological processes during tumor formation of pituitary adenomas. We performed an integrated analysis of publicly available GEO datasets of pituitary adenomas to identify DEGs between pituitary adenomas and normal control (NC) tissues. Gene function analysis including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) networks analysis was conducted to interpret the biological role of those DEGs. In this study we detected 3994 DEGs (2043 upregulated and 1951 downregulated) in pituitary adenoma through an integrated analysis of 5 different microarray datasets. Gene function analysis revealed that the functions of those DEGs were highly correlated with the development of pituitary adenoma. This integrated analysis of microarray data identified some genes and pathways associated with pituitary adenoma, which may help to understand the pathology underlying pituitary adenoma and contribute to the successful identification of therapeutic targets for pituitary adenoma.