Xuehua Ding

Clinical analysis of 103 elderly patients with pituitary adenomas: Transsphenoidal surgery and follow-up

Our objective was to study the single-center clinical diagnosis and surgical treatment of pituitary adenomas in elderly patients. A retrospective single-center study was performed on 103 patients aged 65 years and over with a diagnosis of pituitary adenoma and with a mean follow-up duration of 6.1+/-1.3 years. All cases were macroadenomas. The clinical course was dominated by visual disturbance and headache, and hypopituitarism was also not uncommon. Despite the majority of patients (81.6%) having coexisting medical conditions, transsphenoidal surgery (TSS) was performed and well tolerated in all patients. Before 2000, conventional post operative radiotherapy was performed in 32 patients with radiological evidence of tumor remnants. Long-term follow-up revealed no tumor regrowth. However, progressive hypopituitarism was found in a number of patients. After 2000, gamma knife surgery was used for selected cases with documented tumor regrowth. All the remnant tumors treated using this approach appeared to either stabilize or regress without side-effects during the study period. The findings of this analysis support the use of TSS as a feasible treatment for pituitary adenomas in elderly patients. Age alone is no longer considered a contra-indication for treatment with TSS. With appropriate perioperative management, the technique is associated with minimal morbidity and is tolerated well by patients regardless of age. Additional follow-up, especially neuroradiological follow-up is needed to monitor tumor recurrence. However, the indications for post operative radiotherapy should be better defined.

Manifestation, management and outcome of subclinical pituitary adenoma apoplexy

The objective of this study was to investigate the clinical features, diagnosis, treatment and outcomes of subclinical pituitary adenoma apoplexy (SPAA) in 185 consecutive patients between January 1990 and May 2007. Of the 185 patients, 133 (71.89%) underwent transsphenoidal tumor decompression and the remaining 52 patients (28.11%) underwent transcranial surgery. Preoperative and postoperative endocrinological hormone concentrations were measured in all patients. Pituitary imaging was obtained by CT scans or MRI. Follow-up outcomes were obtained from the records of outpatient visits and by telephone interviews. Visual disturbance, headache and pituitary function impairment improved significantly in all patients. Prolactinoma was the most frequent type of pituitary adenoma in our series (51.89%). SPAA usually occurred in patients with large or giant adenomas (85.95%). Postoperative follow-up ranged from 1 year to 17 years with a mean of 7.4+/-1.6 years. The tumor recurred in 23 patients, 18 of whom were treated with postoperative radiotherapy for either residual tumors (n=8) or recurrence (n=10). Long-term thyroid hormone replacement was necessary in eight patients and steroid hormone replacement in six patients. The incidence of SPAA is relatively high compared with that of acute pituitary apoplexy. The exact pathogenic mechanism of SPAA remains unknown. MRI is significantly better than CT scans for detection of SPAA. Transsphenoidal decompression is safe and effective. Surgical decompression should be performed as early as possible.

RIZ1: a potential tumor suppressor in glioma

BackgroundRetinoblastoma protein-interacting zinc-finger gene 1 (RIZ1) displays strong tumor suppressive activities, and its expression is often silenced in many types of human tumors. However, the relationship between RIZ1 expression and glioma prognosis remains unclear.MethodsThe dysregulation of RIZ1 was evaluated using real-time polymerase chain reaction, western blot, and immunohistochemical analysis of gliomas from 51 patients. Correlation analysis was performed to examine relationships between RIZ1 immunoreactivity, clinicopathological features, and patient prognosis. Also, human malignant glioma U87 and U251 cell lines were stably transduced with ectogenic RIZ1 using a lentiviral vector to investigate the effects of induced expression of RIZ1 on cell proliferation, cell cycle, and apoptosis.ResultsReal-time polymerase chain reaction and western blot analysis showed that RIZ1 was downregulated in high-grade gliomas compared with low-grade gliomas and normal brain tissue. Immunohistochemistry showed less RIZ1 labeling in high-grade gliomas than in low-grade gliomas. There was a negative correlation between RIZ1 and Ki-67 immunoreactivity. Clinicopathological evaluation revealed that RIZ1 expression was negatively correlated with tumor grade and patient age. Kaplan-Meier survival analysis showed a positive correlation between RIZ1 immunoreactivity level and progression-free and overall survival times. Multivariate analysis showed that high RIZ1 expression was an independent prognostic factor for patients with gliomas. Induced expression of RIZ1 in U87 and U251 cells reduced cell proliferation and increased apoptosis, and cell cycle analysis revealed that a majority of cells were arrested at G2-M. Moreover, transfection with a RIZ1 expression vector increased p53 and caspase-3 expression and decreased p-IKBα and p-AKT protein levels, suggesting that RIZ1 may stimulate p53-mediated apoptosis and inhibit p-IKBα and p-AKT signaling pathways.ConclusionsOur results suggest that high RIZ1 labeling is indicative of lower grades of gliomas and is associated with better progression-free and overall survival rates. Therefore, RIZ1 may be a promising therapeutic target for patients with gliomas.

Knockdown of CDK6 enhances glioma sensitivity to chemotherapy

Chemotherapy is widely used for the treatment of glioma. Given the high resistance of brain neoplasm tissues to chemotherapy, it is important to find new methods to improve the effects of chemotherapy. However, the molecular mechanisms underlying glioma resistance to chemotherapy are largely unknown. Here, we demonstrate that CDK6, a cell cycle regulator, is significantly upregulated in glioma cells, and the increasing expression of CDK6 correlates well with the grades of glioma malignancy. Using shRNA-mediated CDK6 knockdown, we found that the proliferation and survival of tumor cells were dramatically inhibited. Moreover, CDK6 knockdown in the U251 glioma cell line caused significant increase in the apoptosis of U251 cells treated with temozolomide (TMZ). Furthermore, CDK6 knockdown reduced the expression level of drug resistance genes such as MRP and MDR. These data indicate that CDK6 is an important mediator of glioma resistance to chemotherapy. Our findings provide a new strategy for the development of chemotherapy sensitizer.

ADAM10 promotes pituitary adenoma cell migration by regulating cleavage of CD44 and L1.

ADAM10 is a metalloproteinase that regulates invasiveness in many tumors. Here, we found that ADAM10 expression correlates with the invasiveness of pituitary adenomas and contributes to invasion by cleaving L1 and CD44. In high-grade pituitary adenoma patients, ADAM10 expression levels were found to be elevated compared with low-grade pituitary adenomas. In a phorbol 12-myristate 13-acetate (PMA)-stimulated pituitary adenoma cell line, AtT-20 cells, we found that the cleavage of L1 was correspondingly enhanced with the increased interaction between Src and Shc. Increases in PMA-induced L1 cleavage and the phosphorylation of residue 418 of Src (418Src) were promoted by overexpression of ADAM10. Inversely, knockdown of Adam10 suppressed PMA-induced L1 cleavage and the phosphorylation of Src, which was blocked by the Src inhibitor PP2 and the MEK inhibitor PD98059. On the other hand, calcium flux activation in AtT-20 cells resulted in increased CD44 cleavage, with reduction of the interaction between calmodulin and ADAM10. The induction of enhanced CD44 cleavage by calcium flux activation was inhibited by knockdown of Adam10. In addition, Adam10 knockdown repressed AtT-20 cell migration, which was reversed by CD44EXT (CD44 ectodomain cleavage). Collectively, these data indicated that ADAM10 facilitated cell migration through modulation of CD44 and L1 cleavage.

High bone sialoprotein (BSP) expression correlates with increased tumor grade and predicts a poorer prognosis of high-grade glioma patients.

Objectives To investigate the expression and prognostic value of bone sialoprotein (BSP) in glioma patients. Methods We determined the expression of BSP using real-time RT-PCR and immunohistochemistry in tissue microarrays containing 15 normal brain and 270 glioma samples. Cumulative survival was calculated by the Kaplan-Meier method and analyzed by the log-rank test. Univariate and multivariate analyses were performed by the stepwise forward Cox regression model. Results Both BSP mRNA and protein levels were significantly elevated in high-grade glioma tissues compared with those of normal brain and low-grade glioma tissues, and BSP expression positively correlated with tumor grade (P<0.001). Univariate and multivariate analysis showed high BSP expression was an independent prognostic factor for a shorter progression-free survival (PFS) and overall survival (OS) in both grade III and grade IV glioma patients [hazard ratio (HR) = 2.549 and 3.154 for grade III glioma, and HR = 1.637 and 1.574 for grade IV glioma, respectively]. Patients with low BSP expression had a significantly longer median OS and PFS than those with high BSP expression. Small extent of resection and lineage of astrocyte served as independent risk factors of both shorter PFS and OS in grade III glioma patients; GBM patients without O6-methylguanine (O6-meG) DNA methyltransferase (MGMT) methylation and Karnofsky performance score (KPS) less than 70 points were related to poor prognosis. Lack of radiotherapy related to shorter OS but not affect PFS in both grade III and grade IV glioma patients. Conclusion High BSP expression occurs in a significant subset of high-grade glioma patients and predicts a poorer outcome. The study identifies a potentially useful molecular marker for the categorization and targeted therapy of gliomas.

High cytoplasmic FOXO1 and pFOXO1 expression in astrocytomas are associated with worse surgical outcome.

FOXO1 is at a convergence point of receptor tyrosine kinase (RTK) signaling, which is one of the three core pathways implicated in glioblastoma. It was recently shown that FOXO1 can effectively induce glioma cell death and inhibit tumor growth through cell cycle arrest and apoptosis. We therefore evaluated FOXO1 and pFOXO1 protein expression in 181 primary astrocytoma samples and 16 normal brain samples. Astrocytoma samples expressed higher cytoplasmic FOXO1 and pFOXO1 than normal brain samples. Nuclear pFOXO1 level was significantly higher than nuclear FOXO1 in astrocytomas. High cytoplasmic FOXO1 expression was associated with older onset age (P = 0.001) and higher WHO grade (P = 0.001). The trend was also observed between cytoplasmic pFOXO1 expression and WHO grade although not significant. Univariate survival analysis showed that both high cytoplasmic FOXO1 and pFOXO1 expression indicated a significantly shorter median overall survival and progression-free survival. Multivariate survival analysis revealed cytoplasmic FOXO1 expression, cytoplasmic pFOXO1 expression, WHO grade, gender, extent of resection and radiotherapy to be independent prognostic factors for overall survival and progression-free survival. Thus, our data suggested that cytoplasmic FOXO1 and pFOXO1 expression may serve as valuable prognostic variables in astrocytomas and may have significant implications for the development and application of targeted therapy.

Effects of hypoxia inducible factor-1α on apoptotic inhibition and glucocorticoid receptor downregulation by dexamethasone in AtT-20 cells.

BackgroundHypoxia inducible factor-1α (HIF-1α) is the central transcriptional regulator of hypoxic responses during the progression of pituitary adenomas. Although previous immunohistochemical studies revealed that HIF-1α is expressed in adreno-cortico-tropic-hormone (ACTH) pituitary adenomas, the role of HIF-1α remains unclear.MethodsAtT-20 cells were incubated under hypoxic conditions (1 % O2) for 12 h. HIF-1α mRNA and protein expression levels were measured by real-time PCR and western blotting, respectively. BrdU was used to determine the effects of hypoxia on cell viability. AtT-20 cells were transfected with siRNA targeting HIF-1α, followed by hypoxia (1 % O2) for 12 h. Apoptosis was determined by annexin V-FITC flow cytometry and Tdt-mediated dUTP nick end-labelling (TUNEL) assay. In addition, we examined interactions between HIF-1α, glucocorticoid receptor (GR), and dexamethasone under both normoxic and hypoxic conditions.ResultsHypoxia triggered the time-dependent proliferation of AtT-20 cells in association with increased HIF-1α mRNA and protein levels. However, the viability of AtT-20 cells decreased greatly when they were first transfected with HIF-1α-siRNA and then exposed to hypoxia. According to flow cytometry (annexin V-FITC and PI staining) and TUNEL analyses, a greater percentage of cells were apoptotic when transfected with HIF-1α siRNA and subsequently cultured under hypoxic conditions compared to those in the normoxia and mock groups. After AtT-20 cells were cultured in 1 % O2 and then treated with dexamethasone, HIF-1α levels significantly increased or decreased in normoxic or hypoxic conditions, respectively. Dexamethasone suppressed GR expression to a higher degree in hypoxic than normoxic conditions. Downregulation of GR by dexamethasone was greatly prevented in cells that were transfected with HIF-1α siRNA.ConclusionsThese findings strongly suggest that HIF-1α exerts an antiapoptotic role and participates in the downregulation of GR by dexamethasone in hypoxic AtT-20 cells.

Surgery for Primary Filum Terminale Ependymomas: Outcome and Prognostic Factors

Primary filum terminale ependymoma (PFTE) is a unique type of ependymomas and locates on extramedullary site. However, the clinical features and prognostic factors of PFTE are still unknown due to its rarity.

The Krause approach: MRI measurements in the Chinese population

We undertook this study to provide anatomical guidance for preoperative positioning for surgery in the pineal region. The anatomical differences between different ages and sexes were obtained by measuring relevant anatomical parameters on imaging of the infratentorial supracerebellar approach (the Krause approach). MRI of 262 healthy Chinese patients were included (232 adults, 30 children). The depth of the infratentorial supracerebellar approach, the angle between the tentorium cerebelli (the approach orientation) and the glabella-external occipital protuberance line, and the angle between the tentorium cerebelli and the dorsum sellae-external occipital protuberance line were measured and analyzed. In adults, the angle between the infratentorial supracerebellar approach and the glabella-external occipital protuberance line was 35.7° ± 6.3° (mean ± standard deviation [SD]), greater than the same angle in children, 29.3° ± 5.0° (p<0.01). In adults, the angle (mean ± SD) between the approach orientation and the dorsum sellae-external occipital protuberance line was 36.2° ± 5.0°, greater than the same angle in children, 30.7° ± 4.5° (p<0.01). The depth of the Krause approach (mean ± SD) was 51.30 mm ± 4.66 mm in men and 47.58 mm ± 4.29 mm in women (p<0.01), while in children the approach depth was 50.47 mm ± 2.62 mm, with no statistical difference between children and adults (p>0.05). For surgery using the Krause approach in adults, the inclination angle of the tentorium cerebelli and the depth provided by the median sagittal MRI are instructive for preoperative head positioning and intraoperative management. The angle between the approach orientation and the easily observed glabella-external occipital protuberance line can be used to achieve appropriate preoperative positioning and reduce the surgical risk.