Genomic analysis of aggressive ductal adenocarcinoma of the prostate.

BACKGROUND: Genomic profile analysis using next-generation sequencing can potentially elucidate the pathogenesis of rare cancers. Ductal adenocarcinoma, a rare subtype of prostate cancer, has an aggressive nature. This is the first study to analyze the genomic profile of ductal adenocarcinoma in an Asian population. METHODS: We identified 12 patients newly diagnosed with ductal adenocarcinoma of the prostate at two hospitals, and nine patients (75.0%) had the pure type. Genomic assessment was performed using either the PleSSision testing platform or FoundationOne CDx. RESULTS: At least one genomic alteration occurred in 11 patients (91.7%), and the most frequently mutated gene was tumor suppressor protein p53 (TP53), which was found in six cases (50.0%). Alterations characteristic of this cohort were found in four cases (33.3%) of retinoblastoma transcriptional corepressor 1 (RB1), which was only observed in the pure type. Compared to previous study results, the frequency of genetic alterations in the phosphoinositide 3-kinase (PI3K) pathway (n = 3; 25.0%) and Wnt-ß-catenin pathway (n = 5; 41.7%) was comparable, but no alterations in the DNA damage repair (DDR) pathway were observed. None of the patients presented high tumor mutation burden or microsatellite instability. CONCLUSIONS: We found that the Asian cohort with ductal adenocarcinoma had actionable alterations, and a high frequency of alterations in TP53 and RB1 reflected the aggressive nature of the tumor. Genetic analysis using next-generation sequencing is expected to help elucidate the pathogenesis of ductal adenocarcinoma.

Vasohibin-1 expression as a biomarker of aggressive nature in ductal adenocarcinoma of the prostate: a retrospective cohort study at two centres in Japan.

OBJECTIVES: Vasohibin-1 (VASH1) is an endogenous angiogenesis regulator expressed in activated vascular endothelial cells. We previously reported that high VASH1 expression is a predictor of progression in acinar adenocarcinoma of the prostate. In this study, we evaluated the characteristics of ductal adenocarcinoma of the prostate by comparing the level of VASH1 expression between ductal and acinar adenocarcinoma specimens. DESIGN AND SETTING: A retrospective cohort study at two centres in Japan. PARTICIPANTS: Among the 1495 patients who underwent radical prostatectomy or transurethral resection for the past 15 years, a total of 14 patients diagnosed with ductal adenocarcinoma and 20 patients diagnosed with acinar adenocarcinoma with a Gleason score of 4+4 were included. INTERVENTIONS: We immunohistochemically examined the CD34 expression as the microvessel density (MVD) and activated endothelial cells as the VASH1 density (vessels per mm2). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the association of MVD and VASH1 density between ductal and acinar adenocarcinoma, and the secondary outcome was their oncological outcomes. RESULTS: Nine patients (64.3%) with ductal adenocarcinoma were diagnosed at an advanced clinical stage, and five patients (35.7%) died from cancer during a median follow-up of 56.0 months. The VASH1 densities (mean±SD) in ductal and acinar adenocarcinoma were 45.1±18.5 vs 16.1±21.0 (p<0.001), respectively, while the MVD (mean±SD) in ductal and acinar adenocarcinoma were 65.3±21.9 vs 80.8±60.7 (p=0.666), respectively. The 5-year cancer-specific survival rates for high and low VASH1 expression were 70.0% and 100.0% (p=0.006), respectively. High VASH1 expression and a diagnosis of ductal adenocarcinoma were significant predictors of cancer-specific survival. CONCLUSIONS: Ductal adenocarcinoma was more aggressive and had higher VASH1 expression than acinar adenocarcinoma, although MVD was equivalent. These results indicate that VASH1 expression may serve as a novel biomarker for the aggressive nature of ductal adenocarcinoma.

Granulomatous-lymphocytic Interstitial Lung Disease Associated with Good's Syndrome That Responded to Immunoglobulin Therapy.

Good's syndrome is associated with thymoma and acquired immunodeficiency. A 54-year-old man visited our hospital with a complaint of cough. Chest imaging revealed diffuse nodular shadows and anterior mediastinal mass. Hypogammaglobulinemia and a decreased B lymphocyte count were found by a laboratory evaluation. The lung nodules markedly regressed after immunoglobulin therapy. The mediastinal mass and remaining nodule were surgically resected and diagnosed as a type AB thymoma and a necrotizing epithelioid granuloma with T lymphocyte-dominant alveolitis, respectively. The overall appearances of these lesions were mostly in line with the spectrum of granulomatous-lymphocytic interstitial lung disease associated with Good's syndrome.

Induced expression of GINS complex is an essential step for reactivation of quiescent stem-like tumor cells within the peri-necrotic niche in human glioblastoma.

PURPOSE: Glioblastoma is still intractable despite the progress in therapies, and the intractability is attributable to a minor population of stem-like tumor cells. As a niche harboring quiescent stem-like tumor cells with potentially high tumorigenicity, we have specified an area around large ischemic necrosis, termed 'peri-necrotic niche', in glioblastoma. In this study, the behavior of tumor cells inside and outside the peri-necrotic niche was analyzed to find out molecules responsible for reactivation of quiescent stem-like tumor cells to proliferate outside the niche. METHODS: Expression of Ki-67 and GINS complex composed of SLD5, PSF1, PSF2 and PSF3 was analyzed by immunohistochemistry in human glioblastoma tissue samples. Proliferation assays, immunoblotting and siRNA experiments were performed using a glioblastoma cell line. RESULTS: Immunohistochemical analysis revealed quiescent and proliferative phenotypes of tumor cells inside and outside the niche, respectively, and the proliferation was spatially correlated with the expression of GINS components in tumor cells. To mimic the tissue microenvironment inside versus outside the niche, glioblastoma cells were cultured under hypoxic versus normoxic conditions, or without versus with serum. Quiescence and proliferation of tumor cells were reversibly determined by the microenvironment inside and outside the niche, respectively, and proliferative activities paralleled the expression levels of GINS components. Furthermore, the reactivation of proliferation after reoxygenation or serum replenishment was suppressed in quiescent tumor cells with PSF1 knockdown. CONCLUSIONS: These findings indicate the essential role of GINS complex in the switch between quiescence and proliferation of tumor cells inside and outside the peri-necrotic niche.

Invasive inflammatory fibroid polyp of the stomach: a case report and literature review.

BACKGROUND: Inflammatory fibroid polyps (IFPs) are rare mesenchymal lesions that affect the gastrointestinal tract. IFPs are generally considered benign, noninvasive lesions; however, we report a case of an invasive gastric IFP. To the best of our knowledge, this is only the second case report of an invasive gastric IFP. CASE PRESENTATION: A 62-year-old woman presented with complaints of epigastric pain and vomiting. Computed tomography showed a 27-mm, hyper-enhancing tumor in the prepyloric antrum. Upper endoscopy also showed a submucosal tumor causing subtotal obstruction of the gastric outlet. Because a gastrointestinal stromal tumor was suspected, distal gastrectomy was performed. Histopathological examination revealed spindle cell proliferation in the submucosal layer. The spindle cells had invaded the muscularis propria layer and extended to the subserosal layer. The tumor was finally diagnosed as an IFP based on immunohistochemical findings. No mutations were identified in the platelet-derived growth factor receptor alpha (PDGFRA) gene via molecular genetic analysis. DISCUSSION AND CONCLUSIONS: After the discovery that IFPs often harbor PDGFRA mutations, these growths have been considered neoplastic lesions rather than reactive lesions. Based on the present case, IFPs might be considered not only neoplastic but also potentially invasive lesions.

Air bronchogram in pleomorphic carcinoma of the lung is associated with favorable prognosis.

BACKGROUND: Pleomorphic carcinoma (PC) of the lung is a rare histological type of lung carcinoma. The association between computed tomography (CT) findings and histology with outcome remains unclear. We examined the relationships between CT features and histopathologic findings, and evaluated the impact of CT features and other clinicopathologic factors on survival. METHODS: Thirty-five consecutive patients with PC of the lung who underwent surgery between October 2010 and December 2015 were enrolled in this study. The 35 tumors were classified with or without air bronchogram in the tumors, and with or without intratumoral ground glass opacity (GGO) on CT. RESULTS: Air bronchogram and GGO were detected in 12 (34.3%) and 5 (14.3%) tumors, respectively. Multivariate analysis revealed that air bronchogram was significantly associated with the presence of adenocarcinoma components with lepidic growth patterns (P = 0.005), and predominance of adenocarcinomas (P = 0.026). GGO was significantly associated with the presence of adenocarcinoma component with lepidic growth pattern (P = 0.010). Air bronchogram was an independent favorable prognostic factor for overall survival, whereas GGO did not have a significant effect on survival. CONCLUSION: Air bronchogram observed in PCs of the lung is strongly related with histological components of the tumor and favorable outcome.

A surgical strategy using a fusion image constructed from 11C-methionine PET, 18F-FDG-PET and MRI for glioma with no or minimum contrast enhancement.

The objective of this study was to investigate the distribution of 11C-methionine (MET) and F-18 fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) imaging and the hyperintense area in T2 weighted imaging (T2WI) in glioma with no or poor gadolinium enhancement in magnetic resonance imaging (GdMRI). Cases were also analyzed pathologically. We prospectively investigated 16 patients with non- or minimally enhancing (< 10% volume) glioma. All patients underwent MET-PET and FDG-PET scans preoperatively. After delineating the tumor based on MET uptake, integrated 3D images from FDG-PET and MRI (GdMRI, T2WI or FLAIR) were generated and the final resection plane was planned. This resection plane was determined intraoperatively using the navigation-guided fencepost method. The delineation obtained by MET-PET imaging was larger than that with GdMRI in all cases with an enhanced effect. In contrast, the T2WI-abnormal signal area (T2WI+) tended to be larger than the MET uptake area (MET+). Tumor resection was > 95% in the non-eloquent area in 4/5 cases (80%), whereas 10 of 11 cases (90.9%) had partial resection in the eloquent area. In a case including the language area, 92% resection was achieved based on the MET-uptake area, in contrast to T2WI-based partial resection (65%), because the T2WI+/MET- area defined the language area. Pathological findings showed that the T2WI+/MET+ area is glioma, whereas 6 of 9 T2WI+/MET- lesions included normal tissues. Tissue from T2W1+/MET+/FDG+/GdMRI+ lesions gave an accurate diagnosis of grade in six cases. Non- or minimally enhancing gliomas were classified as having a MET uptake area that totally or partially overlapped with the T2WI hyperintense area. Resection planning with or without a metabolically active area in non- or minimally enhancing gliomas may be useful for accurate diagnosis, malignancy grading, and particularly for eloquent area although further study is needed to analyze the T2WI+/MET- area.

A primary extradural malignant rhabdoid tumor at the craniovertebral junction in a 3-year-old boy.

INTRODUCTION: Malignant rhabdoid tumor (MRT) is a highly aggressive childhood neoplasm and mainly presents in kidney and brain. We report the case of a patient with extrarenal extracranial MRT in the craniovertebral junction (CVJ). CASE REPORT: A 3-year-old boy presented with tetraparesis that had rapidly developed for 2 weeks. The tumor was located in the ventral side of the C1 and C2 extradural space and had invaded the lower clivus. The symptom recovered after subtotal resection of the tumor through a lateral approach with removal of bilateral lateral masses at C1 and instrumental occipital-C2 posterior fusion. Definite histological diagnosis of the extradural tumor was difficult; however, a metastatic lesion in the rib showed a proliferation of INI1/SMARCB1-negative spindle and rhabdoid cells, indicating the tumor was MRT. Stereotactic CyberKnife radiotherapy with a marginal dose of 26 Gy contributed to control of local regrowth of the tumor before histopathological confirmation and induction of chemotherapy with ifosfamide, cisplatin, and etoposide. The patient survived for 29 months without local recurrence of the tumor and with independent activity, however then died of multiple metastases. CONCLUSION: Treatment strategies for MRT in the CVJ should include an optimal surgical approach for reduction of tumor volume and stabilization of the spine, followed by high dose chemotherapy. Stereotactic radiotherapy may be useful for local control.

Basigin can be a therapeutic target to restore the retinal vascular barrier function in the mouse model of diabetic retinopathy.

Despite the advance in medical technology, diabetic retinopathy (DR) is still an intractable disease which leads to the damage of retinal cells and finally the visual loss. Impairment of retinal vascular barrier triggered by an admixture of multiple inflammatory cytokines is a core of pathophysiology of DR. Therefore, the molecules involved commonly in multiple cytokines-induced impairment of vascular barrier would be the targets of curative treatment of DR. Here, we demonstrate that basigin, a transmembrane molecule expressed in neural barrier-forming endothelial cells, is the molecule essential for vascular barrier impairment which is shared by various triggers including VEGF, TNFα and IL-1ß. In vitro data with neural microvascular endothelial cells indicated that stimulation with cytokines decreases the levels of claudin-5 in cell membranes and consequently impairs the barrier function in a manner dependent on the interaction of claudin-5 with basigin and caveolin-1. In addition, the increased vascular permeability in retinas of streptozotocin-induced diabetic mice was shown to be clearly normalized by intravitreous injection of siRNAs specific for basigin. This study has highlighted basigin as a common essential molecule for various stimuli-induced impairment of retinal vascular barrier, which can be a target for strategies to establish a curative treatment of DR.

Significant antitumor response of disseminated glioblastoma to bevacizumab resulting in long-term clinical remission in a patient with encephalocraniocutaneous lipomatosis: A case report.

The prognosis of recurrent and disseminated glioblastoma is very poor. Bevacizumab is an effective established therapy for recurrent glioblastoma following treatment with radiotherapy plus temozolomide. However, the efficacy of bevacizumab is limited to prolonging progression-free survival, without significant prolongation of the overall survival. We herein report a case of glioblastoma in a 32-year-old female patient with encephalocraniocutaneous lipomatosis (ECCL) that had disseminated following surgical resection and subsequent treatment with temozolomide and radiation therapy. The disseminated tumors disappeared completely after five courses of bevacizumab therapy. Surprisingly, the patient has remained in clinical remission for >2.5 years after dissemination by continuing this therapy. To the best of our knowledge, this is the first case of long-time clinical remission following glioblastoma dissemination and treatment with bevacizumab. In the present case, bevacizumab exerted an atypically strong antitumor effect against disseminated glioblastoma after multidisciplinary treatments had already been applied. Moreover, this is the first report of ECCL associated with a malignant brain tumor.

Stroma-poor Warthin's tumor with significant oncocytic hyperplasia: case presentation and considerations regarding its histogenesis.

Although Warthin's tumor is one of the common tumors of the salivary glands, Warthin's tumors with a prominent component of nodular oncocytic hyperplasia reminiscent of oncocytoma are rare. Here we report such a tumor, measuring 3 cm in diameter, found in the parotid gland of an 81-year-old man. Histologically, approximately 70% of the mass was a component of nodular oncocytic proliferation, and the remaining portion was a component of conventional Warthin's tumor. We performed immunohistochemical analysis to explore what factors determined the morphogenesis of the two components in the single mass. Cytokeratin (CK) 5÷6-positive tumor cells, which represent basal cells, were aligned in a layer in the conventional Warthin's tumor component, whereas they were localized around blood vessels in the nodular oncocytic hyperplasia component. Immunostaining for CD34 showed that capillaries were sparsely present beneath the bilayered epithelia in the former component, while blood vessels resembling sinusoids separated the trabeculae of the tumor cells in the latter component. Ki-67 labeling index was slightly higher in the latter component. Double immunostaining for CK5÷6 and Ki-67 revealed that most of Ki-67-positive proliferating tumor cells were CK5÷6-positive, suggesting that CK5÷6-positive population contained proliferative progenitor cells of the tumor. These findings imply that the regional difference in the distribution pattern and proliferative activity of CK5÷6-positive putative progenitor cells along with the difference in the pattern of vascular network occurred during the tumorigenic process of the tumor and determined one region to become conventional Warthin's tumor morphology and the other to become nodular oncocytic hyperplasia.

Metastatic cerebellar tumor of papillary thyroid carcinoma mimicking cerebellar hemangioblastoma.

INTRODUCTION: Well-differentiated papillary thyroid carcinoma generally (PTC) have a favorable prognosis. This metastasis is rare in the central nervous system. Brain metastasis has a relatively poor prognosis. We present a rare case of cerebellar metastasis, one that mimics a solid type cerebellar hemangioblastoma and because of which it was very hard to reach accurate preoperative diagnosis. Accurate diagnosis was challenging because of the similar imaging and histopathological findings for these two tumors. CASE DESCRIPTION: A brain lesion was detected by routine medical checkup of the brain with MRI in a 49-year-old woman 2 years after thyroidectomy for well-differentiated PTC. Gadolinium-enhanced MRI showed a homogeneous prominently enhanced lesion with surrounding enhanced dilated vessels in the left cerebellar hemisphere. Digital subtraction angiography showed a strongly stained lesion fed by the peripheral branch of the left posterior inferior cerebellar artery with drainage into the inferior vermian vein, revealing arteriovenous shunting. The most like likely preoperative diagnosis was felt to be that of a solid cerebellar hemangioblastoma. Gross total resection of the tumor was achieved by bilateral suboccipital craniotomy, and intraoperative pathological analysis suggested hemangioblastoma. Histopathological findings showed proliferation of vacuolated sheeted tumor cells with clear and eosinophilic cytoplasm and numerous thin-walled microvessels, consistent with hemangioblastoma. However, the final diagnosis was brain metastasis of the follicular variant of PTC due to a partial thyroid follicle-like pattern including eosinophilic fluid pathologically and positive TTF-1 immunostaining. DISCUSSION AND EVALUATION: Since presented rare case of cerebellar metastasis of PTC was very similar to solid type cerebellar hemangioblastoma on imaging and histopathological findings, accurate diagnosis was challenging. Moreover, it is extremely rare for a cerebellar metastasis to occur as an initial distant metastasis of PTC, and hemangioblastoma is the most common primary cerebellar neoplasm in adults. This epidemiological data was also one of the reason of difficulty to reach preoperative accurate diagnosis. CONCLUSIONS: To the best of our knowledge, there are no other reports of challenging diagnosis case of these two tumors in the literature. Brain metastasis of a well-differentiated PTC could be a relatively poor prognostic factor, and accurate diagnosis and suitable surgical therapy or radiotherapy are needed.

Tumour resistance in induced pluripotent stem cells derived from naked mole-rats.

The naked mole-rat (NMR, Heterocephalus glaber), which is the longest-lived rodent species, exhibits extraordinary resistance to cancer. Here we report that NMR somatic cells exhibit a unique tumour-suppressor response to reprogramming induction. In this study, we generate NMR-induced pluripotent stem cells (NMR-iPSCs) and find that NMR-iPSCs do not exhibit teratoma-forming tumorigenicity due to the species-specific activation of tumour-suppressor alternative reading frame (ARF) and a disruption mutation of the oncogene ES cell-expressed Ras (ERAS). The forced expression of Arf in mouse iPSCs markedly reduces tumorigenicity. Furthermore, we identify an NMR-specific tumour-suppression phenotype-ARF suppression-induced senescence (ASIS)-that may protect iPSCs and somatic cells from ARF suppression and, as a consequence, tumorigenicity. Thus, NMR-specific ARF regulation and the disruption of ERAS regulate tumour resistance in NMR-iPSCs. Our findings obtained from studies of NMR-iPSCs provide new insight into the mechanisms of tumorigenicity in iPSCs and cancer resistance in the NMR.

Characterization of the STK11 splicing variant as a normal splicing isomer in a patient with Peutz-Jeghers syndrome harboring genomic deletion of the STK11 gene.

We report a STK11 splicing variant comprising a 131-bp insertion that is derived from intron 1, which has previously been reported to possess potent pathogenicity. The same variant was detected in a Peutz-Jeghers syndrome patient harboring a genomic deletion in the vicinity of exon 1 of the STK11 gene, which indicated that this variant was derived from the wild-type allele. We also found the same variant in other normal subjects. This variant corresponds to the predicted transcript variant of STK11 (XM_011528209), which is derived from the genomic sequence of Chr19 (NT_011295.12). Therefore, we concluded that the splicing variant was not pathogenic.

Histological Characterization of the Tumorigenic "Peri-Necrotic Niche" Harboring Quiescent Stem-Like Tumor Cells in Glioblastoma.

BACKGROUND: Characterization of the niches for stem-like tumor cells is important to understand and control the behavior of glioblastomas. Cell-cycle quiescence might be a common mechanism underlying the long-term maintenance of stem-cell function in normal and neoplastic stem cells, and our previous study demonstrated that quiescence induced by hypoxia-inducible factor (HIF)-1α is associated with a high long-term repopulation capacity of hematopoietic stem cells. Based on this, we examined human astrocytoma tissues for HIF-1α-regulated quiescent stem-like tumor cells as a candidate for long-term tumorigenic cells and characterized their niche histologically. METHODS: Multi-color immunohistochemistry was used to visualize HIF-1α-expressing (HIF-1α+) quiescent stem-like tumor cells and their niche in astrocytoma (WHO grade II-IV) tissues. This niche was modeled using spheroids of cultured glioblastoma cells and its contribution to tumorigenicity was evaluated by sphere formation assay. RESULTS: A small subpopulation of HIF-1α+ quiescent stem-like tumor cells was found in glioblastomas but not in lower-grade astrocytomas. These cells were concentrated in the zone between large ischemic necroses and blood vessels and were closer to the necrotic tissues than to the blood vessels, which suggested that a moderately hypoxic microenvironment is their niche. We successfully modeled this niche containing cells of HIF-1α+ quiescent stem-like phenotype by incubating glioblastoma cell spheroids under an appropriately hypoxic condition, and the emergence of HIF-1α+ quiescent stem-like cells was shown to be associated with an enhanced sphere-forming activity. CONCLUSIONS: These data suggest that the "peri-necrotic niche" harboring HIF-1α+ quiescent stem-like cells confers a higher tumorigenic potential on glioblastoma cells and therefore may be a therapeutic target to control the behavior of glioblastomas.

IgG4-related disease manifesting the gastric wall thickening.

IgG4-related disease (IgG4-RD) is a recently designated disease entity and its full picture has not yet been elucidated. Here, we report an unusual case of a patient with gastric wall thickening secondary to IgG4-RD. A 68-year-old male visited our hospital with itchy skin lesions and an episode of organizing pneumonia. On the suspicion of malignancy-associated skin lesions, computed tomography (CT) was performed. The CT revealed prominent thickening of the gastric wall. Due to the possibility of malignancy, the patient underwent distal gastrectomy. Histopathological examination showed fibrosis of the submucosa and prominent thickening of the muscularis propria. Most of infiltrating cells were IgG4-positive plasma cells. Post-operative blood test revealed significantly high serum levels of total IgG and IgG4. Based on these histological features, the patient was given a definitive diagnosis of IgG4-RD. Further accumulation of cases like the present case that develop IgG4-RD with rare manifestations would lead to the elucidation of pathogenesis.

Epithelioid/rhabdoid glioblastoma: a highly aggressive subtype of glioblastoma.

Epithelioid glioblastoma (GBM) and rhabdoid GBM are rare variants that are morphologically similar, but there is no consensus on the characteristics of each disease. These tumors have aggressive features of early recurrence and leptomeningeal dissemination and tend to develop in younger patients compared to typical GBM. The prognosis is normally worse than typical GBM, even with intensive chemoradiotherapy after surgical resection. Thus, accurate diagnosis and effective therapy for epithelioid/rhabdoid GBM are required. Four consecutive patients aged 16-48 years were diagnosed with epithelioid/rhabdoid GBM by pathological and immunohistochemical analysis at Yamaguchi University Hospital from 2006 to 2012. Two of these patients had relatively long-term survival (19 and 23 months after diagnosis). Two cases had a BRAF V600E mutation, whereas no ATRX mutation was present in any cases. All patients suffered leptomeningeal and/or spinal dissemination that worsened their prognosis. These results illustrate the need for a new therapeutic approach, such as molecular targeted drug therapy like BRAF inhibition, in addition to standard chemoradiotherapy for typical GBM.

ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function.

Neural vascular barrier is essential for the life of multicellular organisms, and its impairment by tissue hypoxia is known to be a central of pathophysiology accelerating the progression of various intractable neural diseases. Therefore, the molecules involved in hypoxia-induced impairment of vascular barrier can be the targets to establish new therapies for intractable diseases. Here, we demonstrate that a disintegrin and metalloproteinases (ADAMs) 12 and 17 expressed in endothelial cells are the molecules responsible for the impairment of neural vascular barrier by hypoxia. Brain microvascular endothelial cells in vitro lost their barrier properties immediately after hypoxic stimulation through diminished localization of claudin-5, a tight junction molecule, on cell membranes. Hypoxic disappearance of claudin-5 from cell membranes and the consequent loss of barrier properties were completely suppressed by inhibition of the metalloproteinase activity which was found to be attributed to ADAM12 and ADAM17. Inhibition of either ADAM12 or ADAM17 was sufficient to rescue the in vivo neural vasculature under hypoxia from the loss of barrier function. This is the first report to specify the molecules which are responsible for hypoxia-induced impairment of neural vascular barrier and furthermore can be the targets of new therapeutic strategies for intractable neural diseases.

Genetic characterization of skull base chondrosarcomas.

OBJECT: Although chondrosarcomas rarely arise in the skull base, chondrosarcomas and chordomas are the 2 major malignant bone neoplasms occurring at this location. The distinction of these 2 tumors is important, but this distinction is occasionally problematic because of radiological and histological overlap. Unlike chordoma and extracranial chondrosarcoma, no case series presenting a whole-genome analysis of skull base chondrosarcomas (SBCSs) has been reported. The goal of this study is to clarify the genetic characteristics of SBCSs and contrast them with those of chordomas. METHODS: The authors analyzed 7 SBCS specimens for chromosomal copy number alterations (CNAs) using comparative genomic hybridization (CGH). They also examined IDH1 and IDH2 mutations and brachyury expression. RESULTS: In CGH analyses, the authors detected CNAs in 6 of the 7 cases, including chromosomal gains of 8q21.1, 19, 2q22-q32, 5qcen-q14, 8q21-q22, and 15qcen-q14. Mutation of IDH1 was found with a high frequency (5 of 7 cases, 71.4%), of which R132S was most frequently mutated. No IDH2 mutations were found, and immunohistochemical staining for brachyury was negative in all cases. CONCLUSIONS: To the best of the authors' knowledge, this is the first whole-genome study of an SBSC case series. Their findings suggest that these tumors are molecularly consistent with a subset of conventional central chondrosarcomas and different from skull base chordomas.