Pituitary metastases: current practice in Japan.

OBJECT: With advancement of cancer treatment and development of neuroimaging techniques, contemporary clinical pictures of pituitary metastases (PMs) must have changed from past reports. The goal of this paper was to elucidate the clinical features of PMs and current clinical practice related to those lesions. In this retrospective study, questionnaires were sent to 87 physicians who had treated PMs in Japan. RESULTS: Between 1995 and 2010, 201 patients with PMs were treated by the participating physicians. The diagnosis of PM was histologically verified in 69 patients (34.3%). In the other 132 patients (65.7%), the PM was diagnosed by their physicians based on neuroimaging findings and clinical courses. The most frequent primary tumor was lung (36.8%), followed by breast (22.9%) and kidney (7.0%) cancer. The average interval between diagnosis of primary cancer and detection of PM was 2.8 ± 3.9 (SD) years. Major symptoms at diagnosis were visual disturbance in 30.3%, diabetes insipidus in 27.4%, fatigue in 25.4%, headache in 20.4%, and double vision in 17.4%. Major neuroimaging features were mass lesion in the pituitary stalk (63.3%), constriction of tumor at the diaphragmatic hiatus (44.7%), hypothalamic mass lesion (17.4%), and hyperintensity in the optic tract (11.4%). Surgical treatment was performed in 26.9% of patients, and 74.6% had radiation therapy; 80.0% of patients who underwent radiotherapy had stereotactic radiotherapy. The median survival time was 12.9 months in total. Contributing factors for good prognosis calculated by Cox proportional hazard analysis were younger age, late metastasis to the pituitary gland, smaller PM size, and radiation therapy. The Kaplan-Meier survival was significantly better in patients with breast cancer and renal cell cancer than in those with lung cancer. CONCLUSIONS: At the time of this writing, approximately 60% (120/201) of PMs had been treated by stereotactic radiation therapy in Japan. The median survival time was much longer than that reported in past series. To confirm the changes of clinical features and medical practice, a prospective and population-based survey is mandatory.

Improvement in treatment results of glioblastoma over the last three decades and beneficial factors.

BACKGROUND: The purpose of this study is to elucidate the trend of glioblastoma outcome and scrutinize the factors contributing to better outcome over three decades. METHODS: Survival time and the influencing factors were retrospectively analyzed in 223 newly diagnosed primary glioblastoma patients during 1980-2010. Appraised factors included age, sex, tumor site, year of surgery, extent of resections, use of surgery supporting system, Karnofsky Performance Status (KPS), chemotherapy, conventional external beam radiotherapy (EBRT), and CyberKnife stereotactic radiotherapy (CK-SRT) use. RESULTS: The median survival time (MST) in all patients was 13.6 months. The MSTs for 4 periods were 9.8 (1980-1990), 13.7 (1991-2000), 12.9 (2001-2005), and 15.8 months (2006-2010), respectively (p=0.0047). Total resection, subtotal resection, partial resection, and biopsy had MSTs of 31.8, 13.9, 11.4, and 7.0 months, respectively (p<0.0001). Regarding chemotherapy, MSTs of the temozolomide base group and nimustine hydrochloride (ACNU) base group were 16.9 and 14.6 months, respectively, whereas the MST of patients without chemotherapy was only 9.8 months (p<0.0001). The MSTs for 40-Gy EBRT plus CK-SRT and 60-Gy EBRT were 19.1 and 10.7 months, respectively (p<0.0001). But in sub-selected patients, treated during 2001-2010, whose resection rate was total resection or subtotal resection, EBRT was completed and postoperative KPS was greater than or equal to 70, the MST with and without CK-SRT was 26.6 and 18.3 months, respectively (p=0.1529). According to the Cox proportional hazards model, degree of resection, KPS, ACNU use, temozolomide use, bevacizumab use, EBRT dose, and CK-SRT use were good prognostic factors. Use of neuronavigation and use of intraoperative magnetic resonance imaging were related to higher resection rate, but not determined as prognostic factors. CONCLUSIONS: We observed a gradual improvement in glioblastoma outcome, presumably because of improvements in therapeutic modalities for surgery, anticancer agents, and radiation, but the efficacy of CK-SRT remains unclear.

Intraoperative continuous monitoring of facial motor evoked potentials in acoustic neuroma surgery.

The preservation of facial nerve function is one of the primary objectives in acoustic neuroma surgery. We detail our method of continuous intraoperative facial motor evoked potential (MEP) monitoring and present criteria for the preservation of facial nerve function to avoid postoperative facial nerve palsy. Our study population was comprised of 15 patients who did not (group 1), and 20 who did (group 2) undergo facial MEP monitoring during surgery to remove acoustic neuromas. In group 2, we continuously stimulated the facial motor cortex at 5- or 10-s intervals throughout surgery. Electromyograms (EMGs) were recorded from the contralateral orbicularis oculi- and orbicularis oris muscles. Optimal anode and cathode placement was at the facial motor cortex and the vertex, respectively. Postoperative facial palsy occurred in 8 of the 15 group 1 patients; in 2 it improved to grade II at 6 months after the operation. Of the 20 group 2 patients, 7 suffered postoperative facial palsy. At 6 months after the operation, their facial nerve function was normal. At the end of the operation, the ratio of the amplitude of the supramaximal EMG to the amplitude at the dural opening was 39.6 % in patients with- and 94.3 % in patients without transient postoperative facial palsy. Continuous facial MEP monitoring not only alerts to surgical invasion of the facial nerves but also helps to predict postoperative facial nerve function. To preserve a minimum amplitude ratio of 50 %, even transient postoperative facial palsy must be avoided. MEP monitoring is an additional useful modality for facial nerve monitoring during acoustic neuroma surgery.

Transsphenoidal surgical treatment of pituitary adenomas in patients aged 80 years or older.

To know the clinical characteristics of pituitary adenomas in the elderly patients aged 80 years or older who were surgically treated. From 1995 through 2012, 907 patients underwent surgery for the pituitary adenomas at Kagoshima- and Hiroshima University hospitals in Japan. Ten (1.1%) patients were aged 80 years or older. We retrospectively assessed the clinical characteristics including preoperative comorbidities, manifestations, neuroimaging findings, and endocrinologic features of these ten patients. The subjects included eight males and two females. Their ages ranged from 80 to 86 with mean of 83.1 years. Of these, besides one case of growth hormone-producing adenoma, others were clinically nonfunctioning adenoma. Six patients had modest comorbidities such as hypertension, cardiovascular diseases, diabetes mellitus, or chronic kidney dysfunction, and all patients were classified into grade 2-3 on American Society of Anesthesiologists' Physical Status grading. Transsphenoidal surgery was performed in all due to visual disturbance in eight, diabetes mellitus as an intercurrent illness of acromegaly in one, and for the purpose of preventing visual disturbance in one patient who had an adenoma impinging optic chiasm but still had normal visual field. The surgeries provided sufficient decompression of the optic pathways and improved visual disorder in all. In an acromegalic male, his comorbidities considerably improved. No permanent surgical morbidity ensued. More than three axes of anterior pituitary hormones were preoperatively impaired in all, which were rarely recovered. Transsphenoidal surgery is safe and efficient treatment way for patients aged 80 years or older with pituitary adenomas with chiasmatic symptoms when the patients' general condition is well preserved and pituitary hormonal deficiency is adequately replaced.

Immunoreactivity of Wnt5a, Fzd2, Fzd6, and Ryk in glioblastoma: evaluative methodology for DAB chromogenic immunostaining.

The aim of this study was to determine the influence of Wnt5a and its receptors on the survival of glioblastoma patients and to determine reliable evaluation methods for immunohistochemistry. Diagnostic specimens from 41 histopathologically confirmed primary glioblastoma patients whose Gd-enhanced tumors had been totally removed were immunohistochemically stained for Wnt5a, Fzd2, Fzd6, and Ryk. The immunoreactivity was evaluated using the following methods: (A) grayscale optical density after color deconvolution, (B) percentage of stained cells, (C) density of stained cells, (D) staining amount (multiplication product of B and C), and (E) staining rank. The data sets of A to E were statistically evaluated by correlation matrix analysis and regression analysis. The influence of the expression of the markers on survival was analyzed using a proportional hazard model. The results of color deconvolution (A) were well correlated with the results of the staining rank (E). In the semiquantitative results (B, C, and D), the staining amount (D) tended to show a better correlation with results of color deconvolution (A). Among all data sets, color deconvolution (A) demonstrated the most preferable fit in a proportional hazard model, and the expression of Fzd2 and Fzd6 was associated with poor prognosis in glioblastoma patients.

MRI T2 hypointensity of metastatic brain tumors from gastric and colonic cancers.

BACKGROUND: Metastatic brain tumors from gastric and colon cancers are frequently revealed by hypointensity on T2-weighted magnetic resonance images (MRIs). However, the reason for this T2 hypointensity has yet to be clarified. We hypothesize that it is due to collagen deposition within the tissues. METHODS: Seven metastatic brain tumors, from 3 gastric cancers and 4 colon cancers were investigated. The degree of hypointensity of these tumors in T2-weighted images was quantitatively assessed as the ratio of gray-scale densities of tumor to brain using ImageJ. The result was compared with the amount of collagen in the resected specimens, which was quantified by ImageJ analysis software, utilizing the colour deconvolution method following Azan-Mallory staining. The degree of hypointensity was also compared with the ratio of viable epithelial component area/whole tissue area. Additionally, collagen distribution was studied by immunohistochemical staining. RESULTS: There was a clear negative correlation between intensity in T2-weighted images of these metastatic tumors and the amount of collagen they contained (R (2) = 0.766). However, there was no significant correlation between the T2 intensity and the ratio of viable epithelial component. Immunohistochemical analysis revealed that collagen types I, III, VII, X, and XI were expressed in the epithelial components and types IV, V, and VI were expressed in the stromal areas of the metastatic tumors. Collagen deposition was observed not only in stromal fibrous areas, but also in cytoplasmic areas in these metastatic tumors. CONCLUSIONS: Hypointensity of metastatic brain tumors arising from gastric and colonic cancers may be due to the accumulation of collagen in the tissues.

Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma.

Although there is a relationship between DNA repair deficiency and temozolomide (TMZ) resistance in glioblastoma (GBM), it remains unclear which molecule is associated with GBM recurrence. We isolated three TMZ-resistant human GBM cell lines and examined the expression of O6-methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) components. We used immunohistochemical analysis to compare MutL homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2) and MGMT expression in primary and recurrent GBM specimens obtained from GBM patients during TMZ treatment. We found a reduction in MLH1 expression and a subsequent reduction in PMS2 protein levels in TMZ-resistant cells. Furthermore, MLH1 or PMS2 knockdown confered TMZ resistance. In recurrent GBM tumours, the expression of MLH1 and PMS2 was reduced when compared to primary tumours.

Immunohistochemical expression of thrombomodulin in vestibular schwannoma.

Many vestibular schwannomas (VS) manifest intratumoral microhemorrhages whose underlying mechanisms are not fully understood. Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes the thrombin-mediated formation of activated protein C that inhibits thrombus formation. We investigated the existence of TM in VS and its potential role in the development of microhemorrhages. We used immunohistochemical staining to study the expression of TM in tissues derived from 25 patients with VS. Hemosiderin deposition was examined by Berlin blue staining and compared with the expression of TM. Vascular endothelial cells in all 25 VS tissues expressed TM. The TM-positive vessel ratio, calculated by dividing the number of TM-positive by the number of CD34-positive lumens, was significantly higher in hemosiderin-laden than hemosiderin-negative tissues (0.71 ± 0.17 vs. 0.53 ± 0.31, p = 0.049, Mann-Whitney U test). Our findings suggest a close relationship between the expression of TM and microhemorrhage in VS.

Severe growth hormone deficiency is rare in surgically-cured acromegalics.

Growth hormone deficiency (GHD) in surgically-cured acromegalics has been reported to negatively affect their metabolic condition and quality of life (QOL). The incidence of GHD, its causes, and its effects on their physio-psychological condition remain to be examined in detail. We performed a retrospective study to investigate GH secretory function in surgically-cured acromegalics, prognostic factors of GHD, and its impact on QOL. The study population consisted of 72 acromegalics who were determined to be surgically cured according to the Cortina consensus criteria. We recorded the incidence of impaired GH secretory function based on the peak GH level during postoperative insulin tolerance test (ITT) which lowered their nadir blood sugar to under 50 mg/dL. Their QOL was evaluated by SF-36. In surgically-cured acromegalics, the incidence of severe GHD (peak GH during ITT ≦ 3.0 µg/L) was 12.5 % (9/72). The preoperative tumor size was significantly larger in patients with severe GHD than without severe GHD (21.9 ± 9.0 vs. 15.5 ± 7.1 mm, p = 0.017). The peak GH levels during postoperative ITT were statistically correlated with the physical but not the mental component summary of the SF-36 score. The incidence of GHD was 12.5 % in our surgically-cured acromegalics. As some QOL aspects are positively related with peak GH levels during postoperative ITT, efforts should be made to preserve pituitary function in acromegalic patients undergoing adenomectomy.

Primary malignant melanoma in the pineal region treated without chemotherapy.

BACKGROUND: Primary pineal malignant melanomas are uncommon intracranial tumor. Here we discuss and review a case of primary pineal malignant melanoma over its feature of imaging studies, pathological findings, and management. CASE DESCRIPTION: A 49-year-old woman receiving renal dialysis underwent computed tomography due to a 4-month history of tinnitus and hearing disturbance. A high-density 35-mm diameter tumor was detected in the pineal region; there was obstructive hydrocephalus. The tumor was heterogeneously hyperintense on T1-weighted magnetic resonance images, iso- and low-mixed intense on T2-weighted images with hemorrhagic components, and very low-intense on T2(*) images. A tumor was subtotally removed via the occipital transtentorial approach. Histologically, it consisted of densely proliferated spindle-shaped or polygonal cells with rich cytoplasmic melanin. The neoplastic cells manifested cellular pleomorphism, nuclear atypia, and mitosis (3/10 high-power fields) and were immunopositive for HMB45, Melan-A, and S100 protein. The MIB-1 index was 17.4%. Whole-body 18-fluoro-deoxyglucose positron emission tomography did not demonstrate any sites with hyper uptake. Examination of the skin and mucosa identified no lesions suggestive of melanoma. She underwent treatment with the whole brain and extended local boost irradiation. Chemotherapy was not delivered due to renal failure. Follow-up imaging studies showed no recurrence or distant lesions 56 weeks after surgery. CONCLUSION: We report a rare case of primary pineal malignant melanoma with prolonged survival of more than 56 weeks after subtotal tumor resection followed by whole-brain and extended local irradiation without chemotherapy. Radiotherapy without chemotherapy might be sufficient for the treatment of this tumor.

TLR4, IL-6, IL-18, MyD88 and HMGB1 are highly expressed in intracranial inflammatory lesions and the IgG4/IgG ratio correlates with TLR4 and IL-6.

We determined distribution of plasma cells and IgG4/IgG index and factors associated with the index in intracranial inflammatory lesions. Specimens of nine patients were analyzed immunohistochemically using antibodies against CD45, CD68, CD3, CD4, CD8, CD20, CD138, lambda chain, kappa chain, IgG, IgG4, IL-1α, IL-6, IL-18, toll-like receptor (TLR) 2, TLR4, high-mobility group box 1 (HMGB1), tumor necrosis factor-alpha (TNF-α), myeloid differentiation factor 88 (MyD88), and anaplastic lymphoma kinase (ALK). The relationship between all the factors was assessed using Spearman's rank correlation coefficient (ρ). Negative ALK staining was observed in all the patients. Plasma cells were detected in eight patients with varying degrees. The highest number of neutrophils, but no plasma cells, was observed in a patient with the shortest history of inflammation. IgG4/IgG index was independent of the number of plasma cells. The index was relatively highly correlated with IL-6 (ρ = 0.7271) and TLR4 expression (ρ = 0.7246). IL-6 expression was highly correlated with TLR4 expression (ρ = 0.8042). IL-18 was maximally expressed in all the patients. TLR4 expression was strong, but TRL2 expression was weak. Positive HMGB1 staining was observed in all the patients, predominantly in the nuclei, but also in the cytoplasm in four patients. The cytoplasmic expression strongly correlated with IL-1α expression (ρ = 0.9583). The cytoplasmic colocalization of HMGB1 and IL-1α was histologically confirmed in cells with collapsing nuclei by the double-staining method. The IgG4/IgG indexes varied case by case. IL-6 and TLR4 expressions may influence IgG4/IgG index. The nuclei of cells with both IL-1α and HMGB1 expressions in the cytoplasm collapse in the cell death stage. The cooperative high expression of TLR4, IL-6, IL-18, MyD88 and HMGB1 suggest their critical roles in the inflammation circuit.

Gradual declination of IGF-1 over a year after transsphenoidal adenomectomy of GH producing pituitary adenomas.

To know the longitudinal shift of blood IGF-1 of cured acromegaly, we conducted retrospective survey of changes in blood IGF-1 over two years, which has not been previously investigated. Blood IGF-1 levels were measured for longer than 2 years after TSS in 37 patients whose nadir GH during postoperative oral glucose tolerance test (OGTt) was under 1 ng/mL. Blood IGF-1 very gradually declined after three months; 230.6 (mean) ng/mL at 3-12 months, 202.3 ng/mL at 12-24 months, and 198.6 ng/mL at 24-36 months. Their SD values, calculated based on standard IGF-1 values of age- and sex-matched Japanese population, also slowly decreased after three months; 1.69 (mean) at 3-12 months, 1.23 at 12-24 months, and 1.12 at 24-36 months. Very slow decrease of the IGF-1 levels continued beyond the first several months and even the first year after TSS. The declination of values is greater than that associated with aging. This declination may be at least partially a reflection of the slow decrease and late normalization of GH secretion.

Identification of CD133+ cells in pituitary adenomas.

Stem-like cells in tumors are capable of self-renewal and pluri-differentiation; they are thought to play important roles in tumor initiation and maintenance. Stem-like cells in malignant glioma express CD133. We examined samples from human pituitary adenoma, a generally benign neoplasm, for CD133 expression using routine immunohistochemical and biochemical methods. Our study of 70 pituitary adenomas (clinically nonfunctioning adenomas and growth hormone-, prolactin-, adrenocorticotropic hormone-, and thyroid-stimulating hormone-producing adenomas) showed that 18 (25.7%) expressed CD133. This rate was higher in clinically nonfunctioning (33.3%) than functioning adenomas (12.0%) (p = 0.085). Real-time PCR assay revealed the expression of CD133 mRNA in samples immunohistochemically positive for CD133. Neither the patient age and gender, nor the tumor size or postoperative recurrence rate correlated with CD133 positivity. CD133+ cells ubiquitously coexpressed CD34, nestin, and VEGFR2 (KDL1). S-100 and GFAP were not coexpressed with CD133. Chromogranin A, Pit-1, SF-1, and NeuroD1 were immune-negative, indicating that CD133+ cells did not have the potential to differentiate into functional endocrine cells. Our data suggest that the expression of CD133 in pituitary adenomas is related to immature endothelial progenitor cells that may play a role in the neovascularization of pituitary adenomas. Further studies are needed to elucidate the significance of CD133+ cells with respect to neovascularization and their sustainable growth in pituitary adenomas.

Role of sonic hedgehog signaling in migration of cell lines established from CD133-positive malignant glioma cells.

The sonic hedgehog (SHH) signaling pathway is essential for normal development and embryogenic morphogenesis. In malignant neoplasms its inappropriate activation correlates with tumorigenesis, proliferation, and migration. However, the role of SHH in infiltrative growth of glioblastoma remains to be elucidated. CD133 is a marker of tumor stem cells in glioblastoma, which are thought to play important roles in tumorigenesis, drug resistance, and tumor recurrence. We investigated the role of the SHH signaling pathway in migration of glioblastoma cell lines derived from CD133-positive cells. Two cell lines, GBM1 and GBM2, were established from CD133-positive cells sorted on an automagnetic cell separator from dispersed human glioblastoma cells. Both cell lines exhibited sphere-like growth in serum-free medium containing growth factor. Expression of patched (PTCH)-, a receptor of SHH, of smoothened (SMO)-, a 7 transmembrane receptor, and of GLI1- and GLI2, PTCH cascade signal proteins, was evaluated by reverse-transcription polymerase chain reaction (RT-PCR). The effects of recombinant SHH in the medium, and of knockdown of SMO-, GLI1- or GLI2 messenger RNA (mRNA) on the migratory ability of neoplastic cells were evaluated by scratch assays. RT-PCR revealed the presence of PTCH-, SMO-, GLI1-, and GLI2 mRNA in these cells. Their migratory ability was significantly enhanced (P < 0.05) by addition of recombinant SHH to the medium. Knockdown of SMO-, GLI1- or GLI2 mRNA resulted in significant decrease in the mobility of the neoplastic cells. Our study suggests that the SHH pathway plays an important role in the migratory ability of cells derived from CD133-positive human glioblastoma cells.

Relationship between cytokeratin staining patterns and clinico-pathological features in somatotropinomae.

OBJECTIVE: Somatotropinomae are classified as densely and sparsely granulated adenomae, which typically exhibit a perinuclear pattern (PP) and a dot pattern (DP) in cytokeratin (CK) immunostaining respectively. Some exhibit a mixed pattern (MP). We studied the relationship between these somatotropinoma subtypes and their clinico-pathological features. METHODS: The study population consisted of 141 Japanese acromegalic patients. We evaluated their clinical presentation and their response to provocation tests with TRH and LHRH and to suppression (octreotide) test. Tumour tissues were subjected to immunostaining for CAM-5.2, MIB-1, CD34, E-cadherin (CDH1) and p53 (TP53). In 43 cases (30 non-DP and 13 DP), we analysed gsp mutations (constitutively activating mutations of the G(s)α protein that is encoded by GNAS gene). RESULTS: The 141 adenomae were categorised into three subtypes based on their CK staining patterns; 30 (21.3%) exhibited DP, 83 (58.9%) exhibited PP, and 28 (19.9%) exhibited MP. Compared with the other subtypes, DP adenomae were significantly larger, and their E-cadherin expression and response to TRH, LHRH and octreotide challenge were lower. The postoperative cure rate tended to be lower in DP adenomae. gsp mutations were detected in 25 of 43 cases examined (58.1%); 20 of the 30 non-DP (66.7%) and 5 of the 13 DP tumours (38.5%) were affected by the mutation. CONCLUSION: DP somatotropinomae exhibit characteristic features. Compared with the non-DP subtypes, DP adenomae manifested a larger tumour size, a lower incidence of abnormal responses to TRH and LHRH challenge, a poor response to octreotide test and a lower expression of E-cadherin. gsp mutation was not exclusive for non-DP somatotropinomae.

Xanthogranuloma in the suprasellar region.

A 26-year-old man presented with a xanthogranuloma located exclusively in the suprasellar region manifesting as general fatigue, bitemporal hemianopsia, and polyuria. Endocrinological examination disclosed severe hypopituitarism. Magnetic resonance imaging demonstrated a clearly defined suprasellar mass that was heterogeneously enhanced after gadolinium administration and was markedly hypointense on T(2)-weighted images. The tumor was subtotally removed under a preoperative diagnosis of craniopharyngioma. Histological examination found fibrous tissue with abundant cholesterol clefts, multinucleated giant cells, and hemosiderin deposits, but no epithelial cells. Xanthogranulomas of the sellar region are reported to be predominantly located in the sella turcica, but should be included in the differential diagnosis even in cases of suprasellar mass lesions.

Treatment of elderly acromegalics.

We assessed the incidence of elderly patients in Japanese acromegalics and the characteristics of their clinical presentation. We also evaluated the safety and efficacy of transsphenoidal surgery (TSS) in this patient group. During the 28-year period from 1980 to 2007 we treated 290 patients with acromegaly at our hospitals. Of these, 9 (3.1%) were elderly, i.e. 70 years old or older. They comprised 0.7% of acromegalics treated during the first- and 4.5% of patients with acromegaly treated during the 2nd 14-year period. Before treatment, all manifested abnormal glucose tolerance; 6 had diabetes mellitus (DM), 6 presented with hypertension, and 2 had cardiovascular disease, malignant neoplasms, or hyperlipidemia. Of the 7 elderly acromegalics who underwent TSS none manifested surgical morbidity or new pituitary hormone deficiencies. Postoperatively, the nadir growth hormone (GH) level at the oral glucose tolerance test (OGTT) was under 1.0 ng/mL in 5 patients, insulin-like growth factor (IGF-1) levels normalized in 4. Glucose tolerance improved in all operated patients. Only 1 of 6 patients with preoperatively diagnosed DM continued to manifest DM post-treatment, anti-hypertensive drugs could be tapered in 3 of patients with preoperative hypertension. In conclusion, we found that there was a high incidence of abnormal glucose tolerance and hypertension in elderly acromegalics, that surgical treatment was effective and safe in this population, and that it was useful for the control of co-morbidities.

Consecutive histological changes in an astroblastoma that disseminated to the spinal cord after repeated intracranial recurrences: a case report.

A 17-year-old male patient underwent surgery five times (four consecutive intracranial tumor removal surgeries and a final spinal tumor removal surgery). After the third surgery, this case was reported as a low-grade astroblastoma that is characterized by perivascular pseudorosettes consisting of elongated tumor cells arranged around the blood vessels. However, the fourth and fifth surgical specimens demonstrated very interesting histological changes in the astroblastoma. Through the course of relapses, the constituent cells of the astroblastic perivascular rosettes became smaller and rounder, and a multilayered cell arrangement was observed. The nucleus-to-cytoplasm ratio increased, and the compact intervascular cells ultimately lost glial fibrillary acidic protein (GFAP) expression. These undifferentiated cells showed high MIB-1 indices and an increased olig2 index. On the other hand, the cells in all the surgical specimens were positive for certain neuronal markers such as NSE, TUJ1, and nestin. Some astroblastomas may be more immature than the usual astrocytes; however, it is necessary to study more cases to confirm this.

Changes in tissue factor and the effects of tissue factor pathway inhibitor on transient focal cerebral ischemia in rats.

INTRODUCTION: To determine the contribution of tissue factor (TF) to focal cerebral ischemia/reperfusion injury, we investigated the changes in TF in rat brains with transient focal cerebral ischemia and also assessed the effect of TF pathway inhibitor (TFPI). MATERIALS AND METHODS: Spontaneous hypertensive rats were subjected to 90-min of middle cerebral artery occlusion (MCAO) and then were reperfused for up to 24 h. Immediately after MCAO, recombinant human TFPI (rhTFPI) (50 or 20 microg/kg/min) was administered by means of a continuous intravenous injection for 4.5 h. RESULTS AND CONCLUSIONS: TF immunoreactivity decreased or scattered in the ischemic area after reperfusion, however, an increased TF expression was observed in the microvasculature with the surrounding brain parenchyma and it peaked at 3 to 6 h, which coincided with the start of fibrin formation. On the other hand, total TF protein in ischemic area continued to exist and did not remarkably change until 24 h after reperfusion. At 24 h after reperfusion, the total infarct volume in the group treated with 50 microg/kg/min rhTFPI was significantly smaller than that in the controls (saline). Western blotting and immunohistochemical studies showed that rhTFPI treatment resulted in a decrease of fibrin in the ischemic brains and microvasculature. TF-mediated microvascular thrombosis is thus considered to contribute to focal cerebral ischemia/reperfusion injury. The continuous infusion of rhTFPI until a peak of TF-mediated microvascular thrombosis therefore attenuates the infarct volume by reducing fibrin deposition in the cerebral microcirculation.

The neurofibromatosis type 1 gene product neurofibromin enhances cell motility by regulating actin filament dynamics via the Rho-ROCK-LIMK2-cofilin pathway.

Neurofibromin is a neurofibromatosis type 1 (NF1) tumor suppressor gene product with a domain that acts as a GTPase-activating protein and functions, in part, as a negative regulator of Ras. Loss of neurofibromin expression in NF1 patients is associated with elevated Ras activity and increased cell proliferation, predisposing to a variety of tumors of the peripheral and central nervous systems. We show here, using the small interfering RNA (siRNA) technique, that neurofibromin dynamically regulates actin cytoskeletal reorganization, followed by enhanced cell motility and gross cell aggregation in Matrigel matrix. NF1 siRNA induces characteristic morphological changes, such as excessive actin stress fiber formation, with elevated negative phosphorylation levels of cofilin, which regulates actin cytoskeletal reorganization by depolymerizing and severing actin filaments. We found that the elevated phosphorylation of cofilin in neurofibromin-depleted cells is promoted by activation of a Rho-ROCK-LIMK2 pathway, which requires Ras activation but is not transduced through three major Ras-mediated downstream pathways via Raf, phosphatidylinositol 3-kinase, and RalGEF. In addition, the exogenous expression of the NF1-GTPase-activating protein-related domain suppressed the NF1 siRNA-induced phenotypes. Neurofibromin was demonstrated to play a significant role in the machinery regulating cell proliferation and in actin cytoskeletal reorganization, which affects cell motility and adhesion. These findings may explain, in part, the mechanism of multiple neurofibroma formation in NF1 patients.