The Pluripotent Stem-Cell Marker Alkaline Phosphatase is Highly Expressed in Refractory Glioblastoma with DNA Hypomethylation.

Background: Hypomethylation of genomic DNA induces stem-cell properties in cancer cells and contributes to the treatment resistance of various malignancies. Objective: To examine the correlation between the methylation status of stem-cell-related genes and the treatment outcomes in patients with glioblastoma (GBM). Methods: The genome-wide DNA methylation status was determined using HumanMethylation450 BeadChips, and the methylation status was compared between a group of patients with good prognosis (survival > 4 yr) and a group with poor prognosis (survival < 1 yr). Immunohistochemistry for proteins translated from hypomethylated genes, including alkaline phosphatase (ALPL), CD133, and CD44, was performed in 70 GBMs and 60 oligodendroglial tumors. Results: The genomic DNA in refractory GBM was more hypomethylated than in GBM from patients with relatively long survival (P = .0111). Stem-cell-related genes including ALPL, CD133, and CD44 were also significantly hypomethylated. A validation study using immunohistochemistry showed that DNA hypomethylation was strongly correlated with high protein expression of ALPL, CD133, and CD44. GBM patients with short survival showed high expression of these stem-cell markers. Multivariate analysis confirmed that co-expression of ALPL + CD133 or ALPL + CD44 was a strong predictor of short survival. Anaplastic oligodendroglial tumors without isocitrate dehydrogenase 1 mutation were significantly correlated with high ALPL expression and poor survival. Conclusion: Accumulation of stem-cell properties due to aberrant DNA hypomethylation is associated with the refractory nature of GBM.

Robustness of the neurological prognostic score in brain metastasis patients treated with Gamma Knife radiosurgery.

OBJECTIVE The neurological prognostic score (NPS) was recently proposed as a means for predicting neurological outcomes, such as the preservation of neurological function and the prevention of neurological death, in brain metastasis patients treated with Gamma Knife radiosurgery (GKRS). NPS consists of 2 groups: Group A patients were expected to have better neurological outcomes, and Group B patients were expected to have poorer outcomes. NPS robustness was tested in various situations. METHODS In total, 3040 patients with brain metastases that were treated with GKRS were analyzed. The cumulative incidence of the loss of neurological function independence (i.e., neurological deterioration) was estimated using competing risk analysis, and NPS was compared between Groups A and B by employing Gray's model. NPS was tested to determine if it can be applied to 5 cancer categories-non-small cell lung cancer, small cell lung cancer, gastrointestinal tract cancer, breast cancer, and other cancers-as well as if it can be incorporated into the 5 major grading systems: recursive partitioning analysis (RPA), score index for stereotactic radiosurgery (SIR), basic score for brain metastases (BSBM), graded prognostic assessment (GPA), and modified-RPA (M-RPA). RESULTS There were 2263 patients in NPS Group A and 777 patients in Group B. Neurological deterioration was observed in 586 patients (19.2%). The cumulative incidences of neurological deterioration were 9.5% versus 21.0%, 14.1% versus 25.4%, and 17.6% versus 27.8% in NPS Groups A and B at 1, 2, and 5 years, respectively. Significant differences were detected between the NPS groups in all cancer categories. There were significant differences between NPS Groups A and B for all classes in terms of the BSBM, GPA, and M-RPA systems, but the differences failed to reach statistical significance in terms of RPA Class I and SIR Class 0 to 3. CONCLUSIONS The NPS was verified as being highly applicable to all cancer categories and almost all classes for the 5 grading systems in terms of neurological function independence. This NPS system appears to be quite robust in various situations for brain metastasis patients treated with GKRS.

Transforming growth factor-ß and stem cell markers are highly expressed around necrotic areas in glioblastoma.

Invasion into surrounding normal brain and resistance to genotoxic therapies are the main devastating aspects of glioblastoma (GBM). These biological features may be associated with the stem cell phenotype, which can be induced through a dedifferentiation process known as epithelial-mesenchymal transition (EMT). We show here that tumor cells around pseudopalisading necrotic areas in human GBM tissues highly express the most important EMT inducer, transforming growth factor (TGF-ß), concurrently with the EMT-related transcriptional factor, TWIST. In addition, the stem cell markers CD133 and alkaline phosphatase (ALPL) were also highly expressed around necrotic foci in GBM tissues. The high expression of TGF-ß around necrotic regions was significantly correlated with shorter progression-free survival and overall survival in patients with GBM. High expression of stem cell markers, ALPL, CD133, and CD44 was also correlated with poor outcomes. These results collectively support the hypothesis that tissue hypoxia induces the stem cell phenotype through TGF-ß-related EMT and contributes to the poor outcome of GBM patients.

Molecular imaging of 1p/19q deletion in oligodendroglial tumours with 11C-methionine positron emission tomography.

OBJECTIVE: Chromosome 1p/19q deletion is an established prognostic and predictive marker in the WHO grade III oligodendroglial tumours (OT). To estimate the genetic status preoperatively, the authors investigated the correlation between the uptake of (11)C-methionine in positron emission tomography (PET) and the 1p/19q status in grades II and III OT. METHODS: We retrospectively reviewed 144 patients with gliomas who received (11)C-methionine PET. 66 cases with grades II-III oligodendrogliomas or oligoastrocytomas underwent fluorescence in situ hybridisation to determine the 1p/19q status. The tissue uptake of (11)C-methionine was expressed as the ratio of the maximum standardised uptake value (SUVmax) in tumour areas to the mean SUV (SUVmean) in the contralateral normal brain (tumour-to-normal tissue (T/N) ratio). RESULTS: The T/N ratio in (11)C-methionine PET was significantly higher in grade III OT than in grade II tumours. The mean T/N ratio of the grade II tumours without 1p/19q deletion was significantly higher than that of the grade II tumours with 1p/19q deletion (mean 2.67 vs 1.94, respectively; p=0.0457). In grade III tumours, the mean T/N ratio of the tumours without 1p/19q deletion was also significantly higher than that of the tumours with 1p/19q deletion (mean 4.83 vs 3.49, respectively; p=0.0261). The rate of IDH1 mutation was lower and the rate of contrast enhancement on MRIs was higher in the 1p/19q non-deleted OT than those with 1p/19q deletion, which may contribute to the high T/N ratio. CONCLUSIONS: Among suspected OT, (11)C-methionine PET may help us preoperatively discriminate tumours with and without 1p/19q deletion.

Intrinsic protective mechanisms of the neuron-glia network against glioma invasion.

Gliomas arising in the brain parenchyma infiltrate into the surrounding brain and break down established complex neuron-glia networks. However, mounting evidence suggests that initially the network microenvironment of the adult central nervous system (CNS) is innately non-permissive to glioma cell invasion. The main players are inhibitory molecules in CNS myelin, as well as proteoglycans associated with astrocytes. Neural stem cells, and neurons themselves, possess inhibitory functions against neighboring tumor cells. These mechanisms have evolved to protect the established neuron-glia network, which is necessary for brain function. Greater insight into the interaction between glioma cells and the surrounding neuron-glia network is crucial for developing new therapies for treating these devastating tumors while preserving the important and complex neural functions of patients.

Importance of Adult Dmbx1 in Long-Lasting Orexigenic Effect of Agouti-Related Peptide.

Dmbx1 is a brain-specific homeodomain transcription factor expressed primarily during embryogenesis, and its systemic disruption (Dmbx1(-/-)) in the ICR mouse strain resulted in leanness associated with impaired long-lasting orexigenic effect of agouti-related peptide (AgRP). Because spatial and temporal expression patterns of Dmbx1 change dramatically during embryogenesis, it remains unknown when and where Dmbx1 plays a critical role in energy homeostasis. In the present study, the physiological roles of Dmbx1 were examined by its conditional disruption (Dmbx1(loxP/loxP)) in the C57BL/6 mouse strain. Although Dmbx1 disruption in fetal brain resulted in neonatal lethality, its disruption by synapsin promoter-driven Cre recombinase, which eliminated Dmbx1 expression postnatally, exempted the mice (Syn-Cre;Dmbx1(loxP/loxP) mice) from lethality. Syn-Cre;Dmbx1(loxP/loxP) mice show mild leanness and impaired long-lasting orexigenic action of AgRP, demonstrating the physiological relevance of Dmbx1 in the adult. Visualization of Dmbx1-expressing neurons in adult brain using the mice harboring tamoxifen-inducible Cre recombinase in the Dmbx1 locus (Dmbx1(CreERT2/+) mice) revealed Dmbx1 expression in small numbers of neurons in restricted regions, including the lateral parabrachial nucleus (LPB). Notably, c-Fos expression in LPB was increased at 48 hours after AgRP administration in Dmbx1(loxP/loxP) mice but not in Syn-Cre;Dmbx1(loxP/loxP) mice. These c-Fos-positive neurons in LPB did not coincide with neurons expressing Dmbx1 or melanocortin 4 receptor but did coincide with those expressing calcitonin gene-related peptide. Accordingly, Dmbx1 in the adult LPB is required for the long-lasting orexigenic effect of AgRP via the neural circuitry involving calcitonin gene-related peptide neurons.

Liposomally formulated phospholipid-conjugated indocyanine green for intra-operative brain tumor detection and resection.

Some tumor-specific near-infrared (NIR) fluorescent dyes such as indocyanine green (ICG), IDRye800CW, and 5-aminolevulinic acid have been used clinically for detecting tumor margins or micro-cancer lesions. In this study, we evaluated the physicochemical properties of liposomally formulated phospholipid-conjugated ICG, denoted by LP-iDOPE, as a clinically translatable NIR imaging nanoparticle for brain tumors. We also confirmed its brain-tumor-specific biodistribution and its characteristics as the intra-operative NIR imaging nanoparticles for brain tumor surgery. These properties of LP-iDOPE may enable neurosurgeons to achieve more accurate identification and more complete resection of brain tumor.

Role of Evaluating MGMT Status and 1p36 Deletion in Radiosurgery-Induced Anaplastic Ependymoma That Rapidly and Completely Resolved by Temozolomide Alone: Case Report and Review of the Literature.

Stereotactic gamma knife surgery (GKS)-induced brain tumors are extremely rare, and no ependymal tumors induced by GKS have been reported. Therefore, little is known about their clinical, pathologic, and genetic features. In addition, a regimen of adjuvant chemotherapy for anaplastic ependymoma (AE) has not been established. A 77-year-old man presented with a gait disturbance and left-side cerebellar ataxia more than 19 years after GKS performed for a cerebellar arteriovenous malformation. Imaging studies demonstrated an enhancing mass in the irradiated field with signs of intraventricular dissemination. Surgical resection confirmed the diagnosis of AE. Temozolomide (TMZ) was administrated postoperatively because the methylated promoter region of O(6)-methylguanine-DNA methyltransferase (MGMT) and 1p36 deletion were observed. Surprisingly, images 16 days after TMZ initiation demonstrated a complete resolution of the residual tumor that was maintained after three cycles of TMZ. This first case report of GKS-induced AE emphasizes the importance of genetic evaluation of MGMT and chromosomal deletion of 1p36 that are not commonly performed in primary ependymal tumors. In addition, it is speculated that a GKS-induced tumor may have a different genetic background compared with the primary tumor because the pathogenesis of the tumors differed.

Life-Threatening Intracranial Hypotension after Skull Base Surgery with Lumbar Drainage.

Although lumbar drainage (LD) is widely used in skull base surgery (SBS), no cases with intracranial hypotension (IH) following LD-assisted SBS have been reported, and skull base surgeons lack awareness of this potentially life-threatening condition. We report two cases of IH after LD-assisted SBS, a spheno-orbital meningioma and an osteosarcoma in the orbit. Despite a minimal amount of cerebrospinal fluid (CSF) drainage and early LD removal, severe postural headache and even a deteriorating consciousness level were observed in the early postoperative course. Neuroimages demonstrated epidural fluid collections, severe midline shift, and tonsillar sag compatible with IH. Epidural blood patch (EBP) immediately and completely reversed the clinical and radiologic findings in both patients. IH should be included in the differential diagnosis of postural headache after LD-assisted SBS that can be managed successfully with EBP. Persistent leakage of CSF at the LD-inserted site leads to IH. Broad dural dissection and wide removal of bony structure may be involved in the midline shift. EBP should be performed soon after conservative management fails. Further reports will determine the risk factors for IH development following LD-assisted SBS.

IDH1 mutation is prognostic for diffuse astrocytoma but not low-grade oligodendrogliomas in patients not treated with early radiotherapy.

Despite accumulating knowledge regarding molecular backgrounds, the optimal management strategy for low-grade gliomas remains controversial. One reason is the marked heterogeneity in the clinical course. To establish an accurate subclassification of low-grade gliomas, we retrospectively evaluated isocitrate dehydrogenase-1 (IDH1) mutation in clinical specimens of diffuse astrocytomas (DA) and oligodendroglial tumors separately. No patients were treated with early radiotherapy, and modified PCV chemotherapy was used for postoperative residual tumors or recurrence in oligodendroglial tumors. Immunohistochemical evaluation of IDH status, p53 status, O(6)-methylguanine methyltransferase expression, and the MIB-1 index were performed. The 1p and 19q status was analyzed with fluorescence in situ hybridization. Ninety-four patients were followed for a median period of 8.5 years. For DAs, p53 was prognostic for progression- free survival (PFS) and IDH1 was significant for overall survival (OS) with multivariate analysis. In contrast, for oligodendroglial tumors, none of the parameters was significant for PFS or OS. Thus, the significance of IDH1 mutation is not clear in oligodendroglial tumors that are homogeneously indolent and chemosensitive. In contrast, DAs are heterogeneous tumors including some potentially malignant tumors that can be predicted by examining the IDH1 mutation status.

Stereotactic radiosurgery in combination with up-front high-dose methotrexate as a first-line treatment for newly diagnosed primary central nervous system lymphoma.

The efficacy of stereotactic radiosurgery (SRS) instead of whole brain radiotherapy (WBRT) following high-dose methotrexate (HD-MTX) for primary central nervous system lymphoma (PCNSL) is unclear. To clarify whether SRS in combination with up-front HD-MTX supplements the effect of HD-MTX in remaining or refractory lesions after initial HD-MTX treatment. The authors conducted a retrospective review for newly diagnosed PCNSL patients who underwent SRS after HD-MTX as a first-line treatment. The local control (LC), the progression-free survival (PFS), the recurrence patterns, the salvage treatments, the overall survival (OS), the Karnofsky Performance Status (KPS), the activities of daily living (ADL) were analyzed as well as radiosurgical parameters. Twenty patients underwent SRS for 51 lesions with the median volume of 0.45 cm(3). The median age at SRS was 67 (range 37-82). The median KPS at SRS was 90. The LC rate at 2 years was 86.0 %, the median PFS after SRS was 17 months, necessitating additional SRS and chemotherapy. The median OS was 52 months. No significant side effects related to SRS were observed. During follow-up period, the good ADL preservation was achieved for 13 months from SRS. Patients with KPS ≥ 90 at SRS demonstrated longer ADL preservation (32 months from SRS). SRS following up-front HD-MTX without WBRT provided excellent LC, acceptable OS and the long ADL preservation period. These benefits may be more emphasized especially in patients with good KPS, but should be validated in a large patient population.

Identification of stroke-associated-antigens via screening of recombinant proteins from the human expression cDNA library (SEREX).

BACKGROUND: Because circulating antibodies against a variety of antigens have been detected in patients with coronary heart disease, carotid atherosclerosis and those who have suffered a stroke, it is suspected that immune response may be one of the mechanisms of atherogenesis The objective of this study is to identify novel antibodies in ischemic stroke patients by screening the expressed recombinant proteins using a human cDNA library (SEREX). METHODS: To identify the candidate antigens, cDNA library was screened by SEREX using plasma from ten patients with ischemic stroke. Subsequently, via ELISA using recombinant proteins and synthetic peptides, the serum antibody levels were measured in two independent patient/healthy donor (HD) cohorts (142 and 78 in the 2nd screening and a validation cohort, respectively). RESULTS: The initial screening resulted in the identification of six candidate antigens. Of these antigens, replication protein A2 (RPA2) was determined to be the antigen associated with stroke (P < 0.05) by ELISA with 2nd screening and validation cohort. Multifactorial logistic regression analysis showed that the increased levels of the RPA2 antibodies (RPA2-Abs) associated with stroke independent of other risk factors for stroke (P < 0.05). Receiver operating curve analysis demonstrated that the area under the curve from ELISA using GST fusion RPA2 and synthetic peptides (bRPA2-132) were 0.867 (95% CI: 0.798-0.936) and 0.971 (95% CI: 0.940-1.00), respectively. If the cut-off value of the bRPA2-132-Ab level was determined to be 0.334, the sensitivity and specificity of the antibody level as the diagnostic marker for stroke were 0.323 (95% CI: 0.209-0.453) and 1.00 (95% CI: 0.713-1.00), respectively. CONCLUSIONS: SEREX identified RPA2 as the antigen associated with ischemic stroke and serum auto-antibodies against RPA2 elevates in stroke patients. RPA2-Abs could become a biomarker for the evaluation of ischemic stroke at risk.

The vidian canal: radiological features in Japanese population and clinical implications.

The vidian canal (VC), a bony tunnel in which the vidian artery and nerve pass, has been widely known as an important landmark to identify the anterior genu of the petrous carotid artery (AGPCA) especially during lateral extended endoscopic endonasal approachs (LEEEAs). The objectives of this study in the Japanese population are to describe the radiological anatomic features and relationships between VC and its surrounding structures, and discuss the clinical implications. We studied 231 high-resolution computed tomography (CT) scans with a slice thickness of 0.5 mm. All the patients had known sellar or parasellar pathologies but without any involvement of VC. The following VC-related parameters were examined: its length, relationship to AGPCA, course from the pterygopalatine fossa to the carotid canal, its position relative to the medial pterygoid plate and pneumatization pattern of the sphenoid sinus. Mean length of VC is 14.6 mm. There is more tendency of straight-running VC compared to other populations. VC locates infero-lateral to AGPCA in all the cases. The protrusion of VC and the paraclival carotid artery to the sphenoid sinus, as well as well-pneumatization of the sinus is also observed more frequently in almost a half of the population. Surgeons who perform LEEEAs in Japanese patients must know these anatomical features. The characteristics particular to Japanese populations may facilitate better identification of VC and exposure to AGPCA intraoperatively.

Pulsed Laser-induced Liquid Jet System for Treatment of Sellar and Parasellar Tumors: Safety Evaluation.

OBJECTIVE: The pulsed laser-induced liquid jet (LILJ) system is an emerging surgical instrument intended to assist both maximal removal of the lesion and functional maintenance through preservation of fine vessels and minimal damage to the surrounding tissue. The system ejects the minimum required amount of pulsed water through a handy bayonet-shaped catheter. We have already shown a significant increase in removal rate, in addition to a noteworthy reduction of intraoperative blood loss and procedure time in the treatment of large pituitary and skull base tumors in a single-institution series. The present study evaluated the safety of the system in multiple institutions. METHODS: The study included 46 patients, 29 men and 17 women (mean age: 59.1 years) who underwent microsurgical/endoscopic resection of lesions in or in the vicinity of the pituitary fossa through the transsphenoidal approach between October 2011 and June 2012 at six institutions. The histologic diagnoses were pituitary adenoma (31 cases), meningioma (4), craniopharyngioma (3), cavernous angioma (2), and Rathke cyst cleft (1). Lesion volume ranged from 2.0 to 30.4 cm³ (mean: 3.7 cm³). Cavernous sinus invasion was observed in 11 cases and suprasellar extension in 29 cases. RESULTS: Preservation of intralesional arteries (diameter: 150 µm) was achieved in all situations in > 80% of cases. Intended surgical steps were achieved except for some restrictions in motion due to the use of an optical quartz fiber. No complications occurred directly related to the use of the device. CONCLUSIONS: The LILJ system can be used for safe removal of lesions in or in the vicinity of the pituitary fossa.

A new grading system focusing on neurological outcomes for brain metastases treated with stereotactic radiosurgery: the modified Basic Score for Brain Metastases.

OBJECT: The Basic Score for Brain Metastases (BSBM) proposed by Lorenzoni and colleagues is one of the best grading systems for predicting survival periods after stereotactic radiosurgery (SRS) for brain metastases. However, it includes no brain factors and cannot predict neurological outcomes, such as preservation of neurological function and prevention of neurological death. Herein, the authors propose a modified BSBM, adding 4 brain factors to the original BSBM, enabling prediction of neurological outcomes, as well as of overall survival, in patients undergoing SRS. METHODS: To serve as neurological prognostic scores (NPSs), the authors scored 4 significant brain factors for both preservation of neurological function (qualitative survival) and prevention of neurological death (neurological survival) as 0 or 1 as described in the following: > 10 brain tumors = 0 or ≤ 10 = 1, total tumor volume > 15 cm(3) = 0 or ≤ 15 cm(3) = 1, MRI findings of localized meningeal dissemination (yes = 0 or no = 1), and neurological symptoms (yes = 0 or no = 1). According to the sum of NPSs, patients were classified into 2 subgroups: Subgroup A with a total NPS of 3 or 4 and Subgroup B with an NPS of 0, 1, or 2. The authors defined the modified BSBM according to the NPS subgroup classification applied to the original BSBM groups. The validity of this modified BSBM in 2838 consecutive patients with brain metastases treated with SRS was verified. RESULTS: Patients included 1868 with cancer of the lung (including 1604 with non-small cell lung cancer), 355 of the gastrointestinal tract, 305 of the breast, 176 of the urogenital tract, and 134 with other cancers. Subgroup A had 2089 patients and Subgroup B 749. Median overall survival times were 2.6 months in BSBM 0 (382 patients), 5.7 in BSBM 1 (1143), 11.4 in BSBM 2 (1011) and 21.7 in BSBM 3 (302), and pairwise differences between the BSBM groups were statistically significant (all p < 0.0001). One-year qualitative survival rates were 64.6% (modified BSBM 0A, 204 patients), 45.0% (0B, 178), 82.5% (1A, 825), 63.3% (1B, 318), 86.4% (2A, 792), 73.7% (2B, 219), 91.4% (3A, 268), and 73.5% (3B, 34). One-year neurological survival rates were 82.6% (0A), 52.4% (0B), 90.5% (1A), 78.1% (1B), 91.1% (2A), 83.2% (2B), 93.9% (3A), and 76.3% (3B), where A and B identify the subgroup. Statistically significant differences in both qualitative and neurological survivals between Subgroups A and B were detected in all BSBM groups. CONCLUSIONS: The authors' new index, the modified BSBM, was found to be excellent for predicting neurological outcomes, independently of life expectancy, in SRS-treated patients with brain metastases.

Risk factors in chronic subdural hematoma: comparison of irrigation with artificial cerebrospinal fluid and normal saline in a cohort analysis.

BACKGROUND: Chronic subdural hematoma (CSDH) is known to have a substantial recurrence rate. Artificial cerebrospinal fluid (ACF) is an effective irrigation solution in general open craniotomy and endoneurosurgery, but no evidence of its use in burr-hole surgery exists. OBJECTIVE: To identify the potential of ACF irrigation to prevent CSDH recurrence. More specifically, to investigate the perioperative and intraoperative prognostic factors, and to identify controllable ones. METHODS: To examine various prognostic factors, 120 consecutive patients with unilateral CSDH treated with burr-hole drainage between September 2007 and March 2013 were analyzed. Intraoperative irrigation was performed with one of two irrigation solutions: normal saline (NS; n = 60) or ACF (n = 60). All patients were followed-up for at least 6 months postoperatively. We also examined the morphological alternations of the hematoma outer membranes after incubation with different solutions. RESULTS: Eleven patients (9.2%) had recurrence. Nine patients (15%) required additional surgery in the NS group, whereas only 2 patients (3.3%) in the ACF group required additional surgery. Among preoperative and intraoperative data, age (<80 years old, P = .044), thrombocyte (>22.0, P = .037), laterality (right, P = .03), and irrigation solution (ACF, P = .027) were related to smaller recurrence rates by log-rank tests. Only the type of irrigation solution used significantly correlated with recurrence in favor of ACF in both Cox proportional hazards (relative hazard: 0.20, 95% confidence interval (CI): 0.04-0.99; P = .049) and logistic regression models (odds ratio, 0.17, 95% CI: 0.03-0.92; P = .04) using these factors. Histological examinations of the hematoma membranes showed that the membranes incubated with NS were loose and infiltrated by inflammatory cells compared with those incubated with ACF. CONCLUSION: Irrigation with ACF decreased the rate of CSDH recurrence.

Circulating anti-filamin C autoantibody as a potential serum biomarker for low-grade gliomas.

BACKGROUND: Glioma is the most common primary malignant central nervous system tumor in adult, and is usually not curable due to its invasive nature. Establishment of serum biomarkers for glioma would be beneficial both for early diagnosis and adequate therapeutic intervention. Filamins are an actin cross-linker and filamin C (FLNC), normally restricted in muscle tissues, offers many signaling molecules an essential communication fields. Recently, filamins have been considered important for tumorigenesis in cancers. METHODS: We searched for novel glioma-associated antigens by serological identification of antigens utilizing recombinant cDNA expression cloning (SEREX), and found FLNC as a candidate protein. Tissue expressions of FLNC (both in normal and tumor tissues) were examined by immunohistochemistry and quantitative RT-PCR analyses. Serum anti-FLNC autoantibody level was measured by ELISA in normal volunteers and in the patients with various grade gliomas. RESULTS: FLNC was expressed in glioma tissues and its level got higher as tumor grade advanced. Anti-FLNC autoantibody was also detected in the serum of glioma patients, but its levels were inversely correlated with the tissue expression. Serum anti-FLNC autoantibody level was significantly higher in low-grade glioma patients than in high-grade glioma patients or in normal volunteers, which was confirmed in an independent validation set of patients' sera. The autoantibody levels in the patients with meningioma or cerebral infarction were at the same level of normal volunteers, and they were significantly lower than that of low-grade gliomas. Total IgG and anti-glutatione S-transferase (GST) antibody level were not altered among the patient groups, which suggest that the autoantibody response was specific for FLNC. CONCLUSIONS: The present results suggest that serum anti-FLNC autoantibody can be a potential serum biomarker for early diagnosis of low-grade gliomas while it needs a large-scale clinical study.

Postnatal development of Blake's pouch cyst: a case report and new insight for its pathogenesis.

Blake's pouch cyst (BPC), a rare cystic malformation in the posterior fossa, is believed to be caused by the congenital expansion of the posterior membranous area that normally regresses during embryogenesis. However, due to the wide spectrum of the onset pattern and age of patients, the natural history and the pathogenesis are poorly understood. The authors describe the case of a girl who admitted with headache and right abducens nerve paresis at the age of 3 years and 10 months. Magnetic resonance (MR) imaging demonstrated a tetraventricular hydrocephalus, an open aqueduct, and a posterior fossa cyst compatible with BPC. Multiple tumors were also noticed in the ventricular wall. Tumor biopsy and an endoscopic third ventriculostomy were performed. Intraoperative observation confirmed the BPC, and pathological diagnosis was pilomyxoid astrocytoma. In retrospect, MR imaging was performed twice in the past, at the age of 8 months and again at 22 months, and no anomaly was detected, suggesting that Blake's pouch was once regressed. Therefore, a BPC in this patient was certainly developed after her second or third year of life. The ventricular tumors may influence the cerebrospinal fluid (CSF) absorption, which triggered the re-expansion of BPC from the possible remnant of Blake's pouch. This is a rare but important report providing evidence that in addition to the classic congenital BPC in which the remnant of Blake's pouch remains persistent, there could be postnatal or secondary BPC, which develops after birth. Possible mechanisms include that the remnant of Blake's pouch, which originally disappears, may re-expand postnatally in association with unknown trigger or a change in CSF dynamics or absorption.

Changes in cortical microvasculature during misery perfusion measured by two-photon laser scanning microscopy.

This study aimed to examine the cortical microvessel diameter response to hypercapnia in misery perfusion using two-photon laser scanning microscopy (TPLSM). We evaluated whether the vascular response to hypercapnia could represent the cerebrovascular reserve. Cerebral blood flow (CBF) during normocapnia and hypercapnia was measured by laser-Doppler flowmetry through cranial windows in awake C57/BL6 mice before and at 1, 7, 14, and 28 days after unilateral common carotid artery occlusion (UCCAO). Diameters of the cortical microvessels during normocapnia and hypercapnia were also measured by TPLSM. Cerebral blood flow and the vascular response to hypercapnia were decreased after UCCAO. Before UCCAO, vasodilation during hypercapnia was found primarily in arterioles (22.9%±3.5%). At 14 days after UCCAO, arterioles, capillaries, and venules were autoregulatorily dilated by 79.5%±19.7%, 57.2%±32.3%, and 32.0%±10.8%, respectively. At the same time, the diameter response to hypercapnia in arterioles was significantly decreased to 1.9%±1.5%. A significant negative correlation was observed between autoregulatory vasodilation and the diameter response to hypercapnia in arterioles. Our findings indicate that arterioles play main roles in both autoregulatory vasodilation and hypercapnic vasodilation, and that the vascular response to hypercapnia can be used to estimate the cerebrovascular reserve.