Hsin-I Ma

Nodal promotes growth and invasion in human gliomas.

Uncontrolled growth and diffused invasion are major causes of mortality in patients with malignant gliomas. Nodal has been shown to have a central role in the tumorigenic signaling pathways of malignant melanoma. In this study, we show that grade IV human glioma cell lines expressed different levels of Nodal, paralleled to the potential for cell invasiveness. Treatment of glioma cell lines with recombinant Nodal (rNodal) increased matrix metalloproteinase 2 (MMP-2) secretion and cell invasiveness. The ectopic expression of Nodal in GBM glioma cells that expressed Nodal at low level resulted in increased MMP-2 secretion, enhanced cell invasiveness, raised cell proliferation rates in vitro, increased tumor growth in vivo, and was associated with poor survival in a mice xenograft model. In contrast, the knockdown of Nodal expression in U87MG glioma cells with high Nodal expression level had reduced MMP-2 secretion, less cell invasiveness, lower tumor growth in vivo and longer lifespan in mice with U87MG/shNodal cell xenografts. In addition, Nodal knockdown promoted the reversion of malignant glioma cells toward a differentiated astrocytic phenotype. Furthermore, our data support the notion that Nodal may regulate glioma progression through the induction of the leukemia inhibitory factor (LIF) and Cripto-1 through activated Smad.

Celecoxib and radioresistant glioblastoma-derived CD133+ cells: improvement in radiotherapeutic effects. Laboratory investigation.

OBJECT Glioblastoma, the most common primary brain tumor, has a poor prognosis, even with aggressive resection and chemoradiotherapy. Recent studies indicate that CD133(+) cells play a key role in radioresistance and recurrence of glioblastoma. Cyclooxygenase-2 (COX-2), which converts arachidonic acid to prostaglandins, is over-expressed in a variety of tumors, including CD133(+) glioblastomas. The COX-2-derived prostaglandins promote neovascularization during tumor development, and conventional radiotherapy increases the proportion of CD133(+) cells rather than eradicating them. The aim of the present study was to investigate the role of celecoxib, a selective COX-2 inhibitor, in enhancing the therapeutic effects of radiation on CD133(+) glioblastomas. METHODS Cells positive for CD133 were isolated from glioblastoma specimens and characterized by flow cytometry, then treated with celecoxib and/or ionizing radiation (IR). Clonogenic assay, cell irradiation, cell cycle analysis, Western blot, and xenotransplantation were used to assess the effects of celecoxib alone, IR alone, and IR with celecoxib on CD133(+) and CD133(-) glioblastoma cells. Three separate xenotransplantation experiments were carried out using 310 severe combined immunodeficient (SCID) mice: 1) an initial tumorigenicity evaluation in which 3 different quantities of untreated CD133(-) cells or untreated or pretreated CD133(+) cells (5 treatment conditions) from 7 different tumors were injected into the striatum of 2 mice (210 mice total); 2) a tumor growth study (50 mice); and 3) a survival study (50 mice). For these last 2 studies the same 5 categories of cells were used as in the tumorigenicity (untreated CD133(-) cells, untreated or pretreated CD133(+) cells, with pretreatment consisting of celecoxib alone, IR alone, or IR and celecoxib), but only 1 cell source (Case 2) and quantity (5 × 10(4) cells) were used. RESULTS High levels of COX-2 protein were detected in the CD133(+) but not the CD133(-) glioblastoma cells. The authors further demonstrated that 30 μM celecoxib was able to effectively enhance the IR effect in inhibiting colony formation and increasing IR-mediated apoptosis in celecoxib-treated CD133(+) glioblastoma cells. Furthermore, reduction in radioresistance was correlated with the induction of G2/M arrest, which was partially mediated through the increase in the level of phosphorylated-cdc2. In vivo xenotransplant analysis further confirmed that CD133(+)-associated tumorigenicity was significantly suppressed by celecoxib treatment. Importantly, pretreatment of CD133(+) glioblastoma cells with a combination of celecoxib and IR before injection into the striatum of SCID mice resulted in a statistically significant reduction in tumor growth and a statistically significant increase in the mean survival rate of the mice. CONCLUSIONS Celecoxib combined with radiation plays a critical role in the suppression of growth of CD133(+) glioblastoma stemlike cells. Celecoxib is therefore a radiosensitizing drug for clinical application in glioblastoma.

Isolation and characterization of tumor stem-like cells from human meningiomas

Recent advances in research have found that tumor stem-like cells are resistant to surgery, radiotherapy, and chemotherapy. Tumor stem-like cells play critical roles in tumor recurrence, angiogenesis, and invasion in malignant brain tumors. However, the identification of tumor stem-like cells in meningiomas has not been clarified. In this study, we identified the stem-like features of sphere-forming cells in human meningiomas. The results showed that meningioma stem-like cells possess the ability to form spheres in identical stem cell culture condition. These meningioma sphere cells (MgSCs) expressed progenitor cell marker, CD133, but not differentiated cell marker, epithelial membrane antigen (EMA) on immunofluorescence staining. Importantly, the mRNA expression of ABCG, and CD133 was higher in MgSCs than daughter meningioma adherent cells (MgACs). In addition, cells displayed chemotherapeutic resistance to vincristine more in MgSCs than MgACs. This phenomenon was also found in single cell form from dissociated spheres than MgACs. Moreover, MgSCs are more resistant to irradiation treatment than MgACs. Furthermore, MgSCs revealed high tumorigenicity in vivo following orthotopic inoculation into the brains of immunodeficient mice. The corresponding immunohistochemical (IHC) staining found that MgSCs are positive for EMA, vimentin, and CD133, consistent with IHC of primary human meningiomas. These findings have provided better understanding of meningioma cell biology and suggested that meningioma stem-like cells may serve as a novel target in therapeutic resistant meningiomas.

The association of osteopontin and LMX1A expression with World Health Organization grade in meningiomas and gliomas

Tsai W‐C, Lee H‐S, Lin C‐K, Chen A, Nieh S & Ma H‐I 
(2012) Histopathology 61, 844–856

Cortactin, Fascin and Survivin Expression Associated with Clinicopathological Parameters in Brain Gliosarcoma

Gliosarcoma is a very rare primary neoplasm of the central nervous system classified as a variant of glioblastoma. Cortactin, fascin and survivin have been found in several human cancers to play important roles in tumor progression, but the expression pattern of these biomarkers in gliosarcoma is unclear. Immunostaining for cortactin, fascin and survivin was assessed in 6 surgical specimens of brain gliosarcoma, and the relationship between the expression of these biomarkers and tumor size or clinical parameters were examined. Five of our six patients with gliosarcoma survived 3-17 months. One patient is still alive for more than 24 months. The mean immunostaining scores for cortactin were significantly higher in the gliomatous (score 236.6 +/- 45.4) and sarcomatous (score 233.3 +/- 51.4) components than in normal brain tissues (score 21.6 +/- 6.6). The mean cytoplasmic immunostaining scores for fascin and survivin were also significantly higher in the gliomatous and sarcomatous components than in normal brain tissues. In addition, survivin was also stained in the nucleus of tumor cells. Linear regression analysis showed that fascin score in the gliomatous component was significantly associated with tumor size (R = 0.69) and the fascin score in the sarcomatous component was significantly associated with patients age (R = 0.87). In addition, the survivin cytoplasmic scores in the gliomatous and sarcomatous components were inversely associated with tumor size. Our results demonstrated that over-expression of cortactin, fascin and survivin is associated with malignant transformation of brain gliosarcoma. Development of drugs that target cortactin, fascin and survivin expression may be therapeutic to patients with gliosarcoma.

Full-endoscopic interlaminar removal of chronic lumbar epidural hematoma after spinal manipulation.

Background: Spinal manipulation is widely used for low back pain treatments. Complications associated with spinal manipulation are seen. Lumbar epidural hematoma (EDH) is one of the complications reported in the literature. If lumbar chronic EDH symptoms are present, which are similar to those of a herniated nucleus pulposus, surgery may be considered if medical treatment fails. Percutaneous endoscopic discectomy utilizing an interlaminar approach can be successfully applied to those with herniated nucleus pulposus. We use the same technique to remove the lumbar chronic EDH, which is the first documented report in the related literature. Methods: We present a case with chronic lumbar EDH associated with spinal manipulation. Neurologic deficits were noted on physical examination. We arranged for a full-endoscopic interlaminar approach to remove the hematoma for the patient with the rigid endoscopy (Vertebris system; Richard Wolf, Knittlingen, Germany). Results: After surgery, the patients radiculopathy immediately began to disappear. Magnetic resonance imaging (MRI) follow-up 10 days after the surgery revealed no residual hematoma. No complications were noted during the outpatient department follow up. Conclusions: Lumbar EDH is a possible complication of spinal manipulation. Patient experiencing rapidly progressive neurologic deficit require early surgical evacuation, while conservative treatment may only be applied to those with mild symptoms. A percutaneous full-endoscopic interlaminar approach may be a viable alternative for the treatment of those with chronic EDH with progressive neurologic deficits.

Midkine expression in high grade gliomas: Correlation of this novel marker with proliferation and survival in human gliomas

Background: High-grade primary glioma have poor prognosis and predictive biomarkers is very important. Midkine (MDK), a heparin-binding growth factor, is important in regulating carcinogenesis, cell proliferation, mitogenesis, and angiogenesis. This study aimed to identify over-expression of MDK in gliomas and correlate this with clinical outcomes. The authors put forward their hypothesis correlating proliferation and poor survival with over-expression of this novel protein. Methods: Two datasets from Gene Expression Omnibus (GEO) included human data of 100 and 180 patients, respectively. The MDK expression, World Health Organization (WHO) pathological grade, sex, age, and survival time were identified for statistical analysis. Results: A search of the GEO profile revealed that MDK expression level was statistically greater in the WHO grade IV compared with grade II (P = 0.002), in grades III and IV compared with nontumor control (P = 0.044 and P < 0.001, respectively) after adjustments using the Bonferroni method. By the Kaplan-Meier survival curve, the high MDK expression group had poorer survival outcome (2.38-fold hazard, 95% confidence interval: 1.22-4.63) than the low MDK expression group after adjustments for WHO grade and age. Conclusions: Taken together, there is a positive correlation between MDK expression and WHO grading of human gliomas. Moreover, MDK over-expression is significant correlated to poor survival outcome in high-grade, suggesting that MDK may be an important therapeutic target.

Occipital interhemispheric approach without excision of tentorium for the tumor in the medial temporal region: technical note

BACKGROUND An occipital interhemispheric approach for the lesions in the middle part of the medial temporal region has been reported. However, this approach usually requires the excision of the tentorium to provide satisfactory exposure. In this case, we used this approach without the excision of the tentorium to remove the parahippocampal gyrus tumor, which was located superolateral to tentorial edge in the middle part of the medial temporal region. CASE DESCRIPTION A 22-year-old man who had seizures for 3 years presented with a tumor in the right parahippocampal gyrus. The tumor was successfully removed by the occipital interhemispheric approach without the excision of the tentorium. The postoperative course was uneventful. CONCLUSIONS An occipital interhemispheric approach without the excision of tentorium is a feasible and safe approach for parahippocampal tumors superolateral to tentorial edge, even in a case where the tumor is deeply located in the middle part of medial temporal region.

Quantitative analysis of anatomical relationship between cavernous segment internal carotid artery and pituitary macroadenoma

Abstract Cavernous segment internal carotid artery (CSICA) injury during endoscopic transsphenoidal surgery for pituitary tumor is rare but fatal. The aim of this study is to investigate anatomical relationship between pituitary macroadenoma and corresponding CSICA using quantitative means with a sense to improve safety of surgery. In this retrospective study, a total of 98 patients with nonfunctioning pituitary macroadenomas undergoing endoscopic transsphenoidal surgeries were enrolled from 2005 to 2014. Intercarotid distances between bilateral CSICAs were measured in the 4 coronal levels, namely optic strut, convexity of carotid prominence, median sella turcica, and dorsum sellae. Parasellar extension was graded and recorded by Knosp–Steiner classification. Our findings indicated a linear relationship between size of pituitary macroadenoma and intercarotid distance over CSICA. The correlation was absent in pituitary macroadenoma with Knosp–Steiner grade 4 parasellar extension. Bigger pituitary macroadenoma makes more lateral deviation of CSICA. While facing larger tumor, sufficient bony graft is indicated for increasing surgical field, working area and operative safety.

Image analysis of open-door laminoplasty for cervical spondylotic myelopathy: Comparing the influence of cord morphology and spine alignment

OBJECTIVES Previous studies have identified the factors affecting the surgical outcome of cervical spondylotic myelopathy (CSM) following laminoplasty. Nonetheless, the effect of these factors remains controversial. It is unknown about the association between pre-operative cervical spinal cord morphology and post-operative imaging result following laminoplasty. The goal of this study is to analyze the impact of pre-operative cervical spinal cord morphology on post-operative imaging in patients with CSM. METHODS Twenty-six patients with CSM undergoing open-door laminoplasty were classified according to pre-operative cervical spine bony alignment and cervical spinal cord morphology, and the results were evaluated in terms of post-operative spinal cord posterior drift, and post-operative expansion of the antero-posterior dura diameter. RESULTS By the result of study, pre-operative spinal cord morphology was an effective classification in predicting surgical outcome - patients with anterior convexity type, description of cervical spinal cord morphology, had more spinal cord posterior migration than those with neutral or posterior convexity type after open-door laminoplasty. Otherwise, the interesting finding was that cervical spine Cobbs angle had an impact on post-operative spinal cord posterior drift in patients with neutral or posterior convexity type spinal cord morphology - the degree of kyphosis was inversely proportional to the distance of post-operative spinal cord posterior drift, but not in the anterior convexity type. CONCLUSIONS These findings supported that pre-operative cervical spinal cord morphology may be used as screening for patients undergoing laminoplasty. Patients having neutral or posterior convexity type spinal cord morphology accompanied with kyphotic deformity were not suitable candidates for laminoplasty.