Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Towards building a trustworthy pipeline integrating Neuroscience Gateway and Open Science Chain.

When the scientific dataset evolves or is reused in workflows creating derived datasets, the integrity of the dataset with its metadata information, including provenance, needs to be securely preserved while providing assurances that they are not accidentally or maliciously altered during the process. Providing a secure method to efficiently share and verify the data as well as metadata is essential for the reuse of the scientific data. The National Science Foundation (NSF) funded Open Science Chain (OSC) utilizes consortium blockchain to provide a cyberinfrastructure solution to maintain integrity of the provenance metadata for published datasets and provides a way to perform independent verification of the dataset while promoting reuse and reproducibility. The NSF- and National Institutes of Health (NIH)-funded Neuroscience Gateway (NSG) provides a freely available web portal that allows neuroscience researchers to execute computational data analysis pipeline on high performance computing resources. Combined, the OSC and NSG platforms form an efficient, integrated framework to automatically and securely preserve and verify the integrity of the artifacts used in research workflows while using the NSG platform. This paper presents the results of the first study that integrates OSC-NSG frameworks to track the provenance of neurophysiological signal data analysis to study brain network dynamics using the Neuro-Integrative Connectivity tool, which is deployed in the NSG platform. Database URL: https://www.opensciencechain.org.

Involvement of autoimmunity to REG, a regeneration factor, in patients with primary Sjögren's syndrome.

The regenerating gene (Reg) was isolated originally as a gene specifically over-expressed in regenerating pancreatic islets and constitute a growth factor family. Reg gene product (Reg) is important in the pathophysiology of various human inflammatory diseases. Recently, the possible involvement of human REG in the regeneration of salivary ductal epithelial cells of patients with primary Sjögren's syndrome (SS) was reported. However, the expression of the REG family genes in minor salivary glands (MSG) and the occurrence of anti-REG Iα autoantibodies in SS patients were obscured. In this study, we examined the expression of REG family genes in the MSG of SS and screened anti-REG Iα autoantibodies in SS. The mRNA levels of REG family genes in MSG were quantified using real-time reverse transcription-polymerase chain reaction (RT-PCR) and REG Iα expression in the MSG was analysed by immunohistochemistry. The mRNA level of REG Iα in the MSG of SS patients was significantly higher than that of control. REG Iα protein was expressed highly in SS ductal epithelial cells. Anti-REG Iα autoantibodies in the sera were found in 11% of SS. All the MSG in the anti-REG Iα autoantibody-positive group showed REG Iα expression, whereas only 40% showed REG Iα expression in the anti-REG Iα autoantibody-negative group. The anti-REG Iα autoantibody-positive group showed significantly lower saliva secretion and a higher ratio of grade 4 (by Rubin-Holt) in sialography. These data suggest strongly that autoimmunity to REG Iα might play a role in the degeneration of MSG ductal epithelial cells in primary SS.

Decreased mRNA expression of two FOXP3 isoforms in peripheral blood mononuclear cells from patients with rheumatoid arthritis and systemic lupus erythematosus.

Both the number and functional capacity of T-regulatory (Treg) cells are known to be decreased in various autoimmune diseases. FOXP3, an essential transcription factor for Treg cells, has three isoforms in humans, wild, and exon 2- and exon 2-exon 7-lacking, although their role in autoimmunity is not clearly understood. Here, we investigated the messenger RNA (mRNA) expression of the major wild and exon-2 isoforms in peripheral mononuclear cells by quantitative PCR methods in 56 subjects, consisting of 23 rheumatoid arthritis (RA) and 25 systemic lupus erythematosus (SLE) patients, and 8 healthy controls (HCs). Although mRNA expression of the two isoforms did not directly correlate with clinical disease activity, relative expression of both was significantly lower in SLE and RA patients than in HCs. Furthermore, we found a significant statistical correlation between the two isoforms, suggesting that they are similarly regulated. Decreased expression of these isoforms in RA and SLE may reflect Treg cell abnormalities in these autoimmune diseases.

High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer.

BACKGROUND: The Toll-like receptor (TLR) 4 signalling pathway has been shown to have oncogenic effects in vitro and in vivo. To demonstrate the role of TLR4 signalling in colon tumourigenesis, we examined the expression of TLR4 and myeloid differentiation factor 88 (MyD88) in colorectal cancer (CRC). METHODS: The expression of TLR4 and MyD88 in 108 CRC samples, 15 adenomas, and 15 normal mucosae was evaluated by immunohistochemistry, and the correlations between their immunoscores and clinicopathological variables, including disease-free survival (DFS) and overall survival (OS), were analysed. RESULTS: Compared with normal mucosae and adenomas, 20% cancers displayed high expression of TLR4, and 23% cancers showed high expression of MyD88. The high expression of TLR4 and MyD88 was significantly correlated with liver metastasis (P=0.0001, P=0.0054). In univariate analysis, the high expression of TLR4 was significantly associated with shorter OS (hazard ratio (HR): 2.17; 95% confidence interval (95% CI): 1.15-4.07; P=0.015). The high expression of MyD88 expression was significantly associated with poor DFS and OS (HR: 2.33; 95% CI: 1.31-4.13; P=0.0038 and HR: 3.03; 95% CI: 1.67-5.48; P=0.0002). The high combined expression of TLR4 and MyD88 was also significantly associated with poor DFS and OS (HR: 2.25; 95% CI: 1.27-3.99; P=0.0053 and HR: 2.97; 95% CI: 1.64-5.38; P=0.0003). Multivariate analysis showed that high expressions of TLR4 (OS: adjusted HR: 1.88; 95% CI: 0.99-3.55; P=0.0298) and MyD88 (DFS: adjusted HR: 1.93; 95% CI: 1.01-3.67; P=0.0441; OS: adjusted HR: 2.25; 95% CI: 1.17-4.33; P=0.0112) were independent prognostic factors of OS. Furthermore, high co-expression of TLR4/MyD88 was strongly associated with both poor DFS and OS. CONCLUSION: Our findings suggest that high expression of TLR4 and MyD88 is associated with liver metastasis and is an independent predictor of poor prognosis in patients with CRC.

Clinical course of abducens nerve palsy associated with skull base tumours.

BACKGROUND: The clinical course of abducens nerve palsy associated with skull base tumour is rarely reported. In this study, we examined the post-operative course of abducens nerve palsies associated with various skull base tumours. METHOD: Between January 2003 and December 2006, 240 patients with various skull base tumours underwent surgery at Kyushu University Hospital. Among them, nine patients presented with abducens nerve palsies (ten nerves) following surgery. The conditions included two pituitary adenomas, two trigeminal schwannomas and five meningiomas. We evaluated the function of the abducens nerves in these patients on admission, at discharge, and periodically in the outpatient clinic. FINDINGS: Four of the abducens nerve palsies already existed prior to surgery, and six of them developed post-operatively. In the four patients with pituitary adenomas and trigeminal schwannomas, all nerves were anatomically preserved and showed complete recovery of function within 6 months after surgery. In contrast, only two of the six palsies in patients with skull base meningiomas showed complete recovery. In three patients with petro-clival meningiomas, the abducens nerves were completely transected during surgery, and one was reconstructed using fibrin glue. This patient remarkably recovered from the abducens nerve palsy within 2 years. CONCLUSIONS: The abducens nerve palsies in pituitary adenomas and trigeminal schwannomas showed a better clinical course compared to those in skull base meningiomas. The abducens nerve palsies that occur with skull base meningiomas are less likely to recover. Nevertheless, it is important to preserve the nerves and to perform surgical repair if the nerve is transected.

Predicting TERT promoter mutation using MR images in patients with wild-type IDH1 glioblastoma.

PURPOSE: The purpose of this study was to identify magnetic resonance imaging (MRI) features that are associated with telomerase reverse transcriptase promoter mutation (TERTm) in glioblastoma. MATERIALS AND METHODS: A total of 112 patients with glioblastoma who had MRI at 1.5- or 3.0-T were retrospectively included. There were 43 patients with glioblastoma with wild-type TERT (TERTw) (22 men, 21 women; mean age, 47±25 [SD] years; age range: 3-84 years) and 69 patients with glioblastoma with TERTm (34 men, 35 women; mean age 64±11 [SD] years; age range, 41--85 years). The feature vectors consist of 11 input units for two clinical parameters (age and gender) and nine MRI characteristics (tumor location, subventricular extension, cortical extension, multiplicity, enhancing volume, necrosis volume, the percentage of necrosis volume, minimum apparent diffusion coefficient [ADC] and normalized ADC). First, the diagnostic performance using univariate and multivariate logistic regression analyses was evaluated. Second, the cross-validation of the support vector machine (SVM) was performed by using leave-one-out method with 43 TERTw and 69 TERTm to evaluate the diagnostic performance. In addition, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for the differentiation between TERTw and TERTm were compared between logistic regression analysis and SVM. RESULTS: With multivariate analysis, the percentage of necrosis volume and age were significantly greater in TERTm glioblastoma than in TERTw glioblastoma. SVM allowed discriminating between TERTw glioblastoma and TERTm glioblastoma with sensitivity, specificity, PPV, NPV, and accuracy of 85.7% [60/70; 95% confidence interval (CI): 75.3-92.9%], 54.8% (23/42; 95% CI: 38.7-70.2%), 75.9% (60/79; 95% CI: 69.1-81.7%), 69.7% (23/33; 95% CI: 54.9-81.3%) and 74.1% (83/112; 95% CI: 65.0-81.9%), respectively. CONCLUSION: The percentage of necrosis volume and age may surrogate for predicting TERT mutation status in glioblastoma.

Parafibromin tumor suppressor enhances cell growth in the cells expressing SV40 large T antigen.

Parafibromin (PF) is a 531-amino acid protein encoded by HRPT2, a putative tumor suppressor gene recently implicated in the autosomal-dominant hyperparathyroidism-jaw tumor familial cancer syndrome and sporadic parathyroid carcinoma. To investigate effects of PF's overexpression on cell proliferation, we performed assays in four different cell lines. The transient overexpression of PF inhibited cell growth in HEK293 and NIH3T3 cells, but enhanced cell growth in the SV40 large T antigen-expressing cell lines such as 293FT and COS7 cells. In 293FT cells, PF was found to interact with SV40 large T antigen and its overexpression promoted entry into the S phase, implying that the interaction enhanced progression through the cell cycle. The tumor suppressor protein PF acts as a positive regulator of cell growth similar to an oncoprotein in the presence of SV40 large T antigen.

Prevention of adoptively transferred diabetes in nonobese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes. A gene therapy model for autoimmune diabetes.

Four pancreatic islet-specific CD4+ helper T (Th) 1 (Th1) clones and two Th1 clones transduced with an SRalpha promoter-linked murine IL-10 (mIL-10) cDNA of 2.0-6.0 x 10(6) cells were adoptively transferred to nonobese diabetic (NOD) mice at age 8 d. Cyclophosphamide (CY) was administered at age 37 d (plus CY), and the incidence of diabetes and the histological grade of insulitis were examined at age 47 d. After the adoptive transfer of IL-10-transduced Th1 cells, polymerase chain reaction (PCR) and reverse-transcription (RT)-PCR detected the neo gene and the retrovirus vector-mediated IL-10 mRNA in situ in recipient islets, respectively. RT-PCR detected the decrease of IFN-gamma mRNA relative to IL-10 mRNA in IL-10-transduced Th1 clones in vitro and also in recipient islets. All four wild type Th1 clones plus CY induced the insulitis grade of 2.75 and diabetes in 66% of recipient NOD mice. IL-10-transduced two Th1 clones plus CY induced periinsulitis with the grade of 1.43 and diabetes in 8.0%. The 1:1 mixture of wild type Th1 cells and IL-10-transduced Th1 cells plus CY induced periinsulitis with the grade of 1.85 and diabetes in 20%. The suppression of diabetes through decreasing IFN-gamma mRNA by the tissue-specific delivery of IL-10 to pancreatic islets with IL-10-transduced Th1 cells affords us the starting basis to develop the gene therapy for autoimmune diabetes.

Unique region of the minor capsid protein of human parvovirus B19 is exposed on the virion surface.

Capsids of the B19 parvovirus are composed of major (VP2; 58 kD) and minor (VP1; 83 kD) structural proteins. These proteins are identical except for a unique 226 amino acid region at the amino terminus of VP1. Previous immunization studies with recombinant empty capsids have demonstrated that the presence of VP1 was required to elicit virus-neutralizing antibody activity. However, to date, neutralizing epitopes have been identified only on VP2. Crystallographic studies of a related parvovirus (canine parvovirus) suggested the unique amino-terminal portion of VP1 assumed an internal position within the viral capsid. To determine the position of VP1 in both empty capsids and virions, we expressed a fusion protein containing the unique region of VP1. Antisera raised to this protein recognized recombinant empty capsids containing VP1 and VP2, but not those containing VP2 alone, in an enzyme-linked immunosorbent assay. The antisera immunoprecipitated both recombinant empty capsids and human plasma-derived virions, and agglutinated the latter as shown by immune electron microscopy. The sera contained potent neutralizing activity for virus infectivity in vitro. These data indicate that a portion of the amino terminus of VP1 is located on the virion surface, and that this region contains intrinsic neutralizing determinants. The external location of the VP1-specific tail may provide a site for engineered heterologous epitope presentation in novel recombinant vaccines.

Abrogation of autoimmune diabetes in nonobese diabetic mice and protection against effector lymphocytes by transgenic paracrine TGF-beta1.

Paracrine effect of transforming growth factor-beta1 (TGF-beta1) on autoimmune insulitis and diabetes was studied by transgenic production of the active form of porcine TGF-beta1 (pTGF-beta1) in pancreatic islet (islet) alpha cells in nonobese diabetic (NOD) mice under the control of rat glucagon promoter (RGP) (NOD-RGP-TGF-beta1). None of 27 NOD-RGP-TGF- beta1 mice developed diabetes by 45 wk of age, in contrast to 40 and 71% in male and female nontransgenic mice, respectively. None of the NOD-RGP-TGF-beta1 mice developed diabetes after cyclophosphamide (CY) administration. Adoptive transfer of splenocytes of NOD-RGP-TGF-beta1 mice to neonatal NOD mice did not transfer diabetes after CY administration. Adoptive transfer of three types of diabetogenic lymphocytes to NOD-RGP-TGF-beta1 and nontransgenic mice after CY administration led to the lower incidence of diabetes in NOD-RGP-TGF-beta1 mice versus that in nontransgenic mice: 29 vs. 77% for diabetogenic splenocytes, 25 vs. 75% for islet beta cell-specific Th1 clone cells, and 0 vs. 50% for islet beta cell-specific CD8(+) clone cells, respectively. Based on these, it is concluded that autoimmune diabetes in NOD mice is not a systemic disease and it can be completely prevented by the paracrine TGF-beta1 in the islet compartment through protection against CD4(+) and CD8(+) effector lymphocytes.

Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice.

The relationship between abnormal cell proliferation and aberrant control of hormonal secretion is a fundamental and poorly understood issue in endocrine cell neoplasia. Transgenic mice with parathyroid-targeted overexpression of the cyclin D1 oncogene, modeling a gene rearrangement found in human tumors, were created to determine whether a primary defect in this cell-cycle regulator can cause an abnormal relationship between serum calcium and parathyroid hormone response, as is typical of human primary hyperparathyroidism. We also sought to develop an animal model of hyperparathyroidism and to examine directly cyclin D1's role in parathyroid tumorigenesis. Parathyroid hormone gene regulatory region--cyclin D1 (PTH--cyclin D1) mice not only developed abnormal parathyroid cell proliferation, but also developed chronic biochemical hyperparathyroidism with characteristic abnormalities in bone and, notably, a shift in the relationship between serum calcium and PTH. Thus, this animal model of human primary hyperparathyroidism provides direct experimental evidence that overexpression of the cyclin D1 oncogene can drive excessive parathyroid cell proliferation and that this proliferative defect need not occur solely as a downstream consequence of a defect in parathyroid hormone secretory control by serum calcium, as had been hypothesized. Instead, primary deregulation of cell-growth pathways can cause both the hypercellularity and abnormal control of hormonal secretion that are almost inevitably linked together in this common disorder.

Minimal subenhancer requirements for high-level polyomavirus DNA replication: a cell-specific synergy of PEA3 and PEA1 sites.

The cell-specific regulation of DNA replication has important implications for the molecular strategy of cellular gene control. Mouse polyomavirus (Py) DNA replication is examined as a model of cell-specific replication control. Using an FM3A-derived mouse cell line which expresses early viral proteins (FOP cells), we determined the minimal sequence requirements for viral DNA replication. FOP cells were observed to have much simpler enhancer requirements than 3T6 and many other cells and did not need a B enhancer for high levels of DNA replication. Using these cells, we show that the individual or tandem binding sites for several unrelated trans-acting factors which are generally subfunctional as transcriptional enhancers (simian virus 40 A core, TGTGGAATG; EBP20, TGTGGTTTT; PEA1 [an AP-1 analog], GTGACTAA; PEA2, GACCGCAG; and PEA3, AGGAAG) stimulated low levels of Py DNA replication. The ordered dimeric combination of PEA3 and PEA1 factor-binding sites, however, acted synergistically to stimulate viral DNA replication to high wild-type levels. This is in contrast to prior results in which much larger enhancer sequences were necessary for high-level viral DNA replication. PEA3/PEA1-stimulated DNA replication showed a distance and orientation independence relative to the origin, which disagrees with some but not other prior analyses of enhancer-dependent DNA replication. It therefore appears that trans-acting factor-binding sites (enhansons) can generally activate DNA replication and that the AP-1 family of sites may act synergistically with other associated trans-acting factors to strongly affect Py DNA replication in specific cells.

A case of hyperparathyroidism-jaw tumour syndrome found in the treatment of an ossifying fibroma in the maxillary bone.

Hyperparathyroidism-jaw tumour (HPT-JT) syndrome is characterized by parathyroid tumours as well as by ossifying fibromas of the mandible and maxilla, renal cysts, or Wilms' tumours. Recently, the gene responsible for HPT-JT syndrome has been identified as the HRPT2 tumour suppressor gene. In an 18-year-old male, a tumour in the maxilla was first diagnosed as an ossifying fibroma. During biochemical screening before surgery, the patient received a diagnosis of primary hyperparathyroidism. Neck computed tomography scanning showed a parathyroid tumour. Surgical excisions to remove the jaw tumour and parathyroid adenoma were performed. The postoperative course has been uneventful and a follow up at 2 years revealed no evidence of recurrence. The HRPT2 germline mutation of 39delC was detected in the proband, but not in his unaffected parents. These results suggested that the germline mutation occurred de novo.

Primary liver carcinoma and liver cirrhosis in atomic bomb survivors, Hiroshima and Nagasaki, 1961-75, with special reference to hepatitis B surface antigen.

During 1961-75, 128 cases of primary liver carcinoma (PLC) in the Radiation Effects Research Foundation life-span study extended sample and 301 cases of liver cirrhosis in the pathology study sample were observed. The presence of hepatitis B surface antigen (HBsAg) was assessed in all of the cases with the use of orcein and aldehyde fuchsin stains and was confirmed by the immunofluorescence technique. The incidence of PLC was two times higher in Nagasaki than in Hiroshima, which was statistically significant, but little difference was noted in the prevalence of cirrhosis in the two cities. Findings that might possibly explain the higher PLC incidence in Nagasaki were 1) the 2.3 times higher presence in Nagasaki than in Hiroshima of HBsAg in the livers of subjects without liver disease and 2) the two times higher prevalence in Nagasaki than in Hiroshima of cirrhosis with PLC. We believe that the higher incidence of PLC in Nagasaki is attributable to hepatitis B virus infection, although other factors (e.g., immunologic competence affected by radiation) cannot be excluded. In both cities, a suggestive relationship of radiation dose to cirrhosis prevalence, but not to PCL prevalence, was noted. To clarify possible radiation effects on cirrhosis prevalence, further follow-up of the populations of these two cities is necessary.

Frequent overexpression of the cyclin D1 oncogene in invasive lobular carcinoma of the breast.

Invasive lobular carcinoma comprises approximately 10% of human mammary cancers, yet little is known about the molecular basis of this carcinoma. Because cyclin D1 plays a role in the pathogenesis of breast carcinomas of the ductal type, we hypothesized that this confirmed oncogene might also participate in the development of lobular carcinomas. We sought to determine the frequency of cyclin D1 protein overexpression in invasive lobular carcinoma, to investigate the cause of the protein accumulation, and to identify the effects of high levels of the protein on the regulation of the cell cycle. The study group comprises 27 indisputable cases of invasive lobular carcinoma showing varying degrees of cytological atypia. Immunohistochemical staining using well-characterized monoclonal and polyclonal antibodies disclosed cyclin D1 protein in the majority of the invasive lobular carcinoma cells in 80% of the tumors. In marked contrast, only rare cells of the noninvasive component (lobular carcinoma in situ) in the same tissue sections showed positive staining. Southern blotting of nine cases did not reveal evidence of cyclin D1 gene amplification. Immunohistochemical staining for Ki-67, a protein present in all dividing cells, showed that most cells positive for cyclin D1 did not stain for Ki-67. We conclude that the vast majority of invasive lobular carcinomas show overexpression of cyclin D1 protein. The absence of cyclin D1 protein expression in the noninvasive cells suggests that the molecule plays a role in the progression to the invasive form of lobular carcinoma. In contrast to the ductal types of breast cancer, cyclin D1 gene amplification does not seem to cause the cyclin D1 protein overexpression in lobular cancers. The lack of correlation between cyclin D1 and Ki-67 expression suggests that the cyclin D1 oncogene acts through mechanisms other than simple acceleration of the cell cycle clock in this subtype of human breast carcinoma.

Role of p53 mutations in endocrine tumorigenesis: mutation detection by polymerase chain reaction-single strand conformation polymorphism.

To elucidate the molecular basis for endocrine tumorigenesis, p53 mutations in human endocrine tumors were analyzed by using polymerase chain reaction-single strand conformation polymorphism. Exons 5 through 10 of the p53 gene were studied in genomic DNAs from 134 primary endocrine tumors and 6 human endocrine cancer-derived cell lines. Mutations were detected and identified in 4 endocrine tumors, including one parathyroid adenoma and three thyroid carcinoma cell lines. The sites of these mutations were in exons 5 (codon 151 and 152) and 7 (codon 248 and 255). In all of three tumor cell lines, but not in a parathyroid adenoma, the normal allele encoding the p53 gene was lost. However, p53 mutations were not found in any other endocrine tumors or cell lines. Based upon these results, we concluded that the p53 gene may play a role in the tumorigenesis of a limited number of parathyroid adenoma and thyroid cancers, and that the p53 mutation with an allelic loss of the p53 gene is an important factor in malignant tumorigenesis of the thyroid gland.

Loss of the same alleles of HRAS1 and D11S151 in two independent pancreatic cancers from a patient with multiple endocrine neoplasia type 1.

The DNAs from two independent pancreatic cancers (tumors 1 and 2) in a patient with multiple endocrine neoplasia type 1 were analyzed. No amplification or gross rearrangement of 19 protooncogenes was observed. However, Southern blot analysis using polymorphic DNA probes revealed loss of heterozygosity at loci on chromosome 11p in both tumors. In tumor 1, an extensive region including the HRAS1, PTH, CALCA, and D11S151 loci was deleted, while in tumor 2 loss of heterozygosity was limited at the HRAS1 and D11S151 loci. Because loss of heterozygosity at other chromosomal loci in the two tumors was quite rare, loss of genes on 11p might be nonrandom. It is noteworthy that the same allele at the HRAS1 locus and also the same allele at the D11S151 locus were lost in the two independent tumors. These results suggest that loss of genes at the HRAS1 and/or D11S151 loci plays an important role unmasking the remaining sequences probably having a recessive mutation.

[Hemiarch replacement and concomitant valve repair for proximal aortic aneurysm accompanying bicuspid aortic valve with mild regurgitation].

A 64-year-old man who had proximal aortic aneurysm and bicuspid aortic valve with mild regurgitation underwent hemiarch replacement and concomitant valve repair under selective cerebral perfusion and deep hypothermic circulatory arrest. Valve repair technique consisted of leaflet plication according to Schaefers and subcommissural annular plication. No homologous transfusion was required, and the patient was extubated 5.5 hours after surgery. The repaired valve showed trivial regurgitation and no stenosis, and remained stable 22 months after surgery. Schaefers' technique of aortic leaflet plication is simple and reproducible, and is therefore recommendable for such cases.

MR Imaging-Based Analysis of Glioblastoma Multiforme: Estimation of IDH1 Mutation Status.

BACKGROUND AND PURPOSE: Glioblastoma multiforme is highly aggressive and the most common type of primary malignant brain tumor in adults. Imaging biomarkers may provide prognostic information for patients with this condition. Patients with glioma with isocitrate dehydrogenase 1 (IDH1) mutations have a better clinical outcome than those without such mutations. Our purpose was to investigate whether the IDH1 mutation status in glioblastoma multiforme can be predicted by using MR imaging. MATERIALS AND METHODS: We retrospectively studied 55 patients with glioblastoma multiforme with wild type IDH1 and 11 patients with mutant IDH1. Absolute tumor blood flow and relative tumor blood flow within the enhancing portion of each tumor were measured by using arterial spin-labeling data. In addition, the maximum necrosis area, the percentage of cross-sectional necrosis area inside the enhancing lesions, and the minimum and mean apparent diffusion coefficients were obtained from contrast-enhanced T1-weighted images and diffusion-weighted imaging data. Each of the 6 parameters was compared between patients with wild type IDH1 and mutant IDH1 by using the Mann-Whitney U test. The performance in discriminating between the 2 entities was evaluated by using receiver operating characteristic analysis. RESULTS: Absolute tumor blood flow, relative tumor blood flow, necrosis area, and percentage of cross-sectional necrosis area inside the enhancing lesion were significantly higher in patients with wild type IDH1 than in those with mutant IDH1 (P < .05 each). In contrast, no significant difference was found in the ADC(minimum) and ADC(mean). The area under the curve for absolute tumor blood flow, relative tumor blood flow, percentage of cross-sectional necrosis area inside the enhancing lesion, and necrosis area were 0.850, 0.873, 0.739, and 0.772, respectively. CONCLUSIONS: Tumor blood flow and necrosis area calculated from MR imaging are useful for predicting the IDH1 mutation status.