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Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12 and CHLA-266). Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.

Due to the limited efficacy of chemotherapy, the applications of adjuvant irradiation play an important role for ependymoma treatment. However, in the young ages, the resistance of residual and recurrent tumor, and long-term intellectual sequelae remain the major obstacles of radiotherapy. Understanding the mechanism of therapeutic failure caused by radio-resistance is, therefore, crucial in ependymoma treatment. Here we retrospectively analyze clinic-pathological factors in 82 cases of ependymoma less than 20 years old and identify radio-resistant genes through gene expression microarray followed by qRT-PCR validation and immunohistochemistry staining. Thirty-one out of 82 (37.8%) patients are under 3-year-old. The 10 years PFS and OS are 38% and 60%. Gross-total resection is the single significant prognostic factor for longer 10 years PFS and OS in the multivariant analysis (p

Medulloblastoma (MB) is the most commonly occurring malignant pediatric brain tumor worldwide. However, a recent study found that the treatment outcomes in those with high-risk disease receiving conventional treatment were suboptimal. This study aimed to assess outcomes and treatment strategies for specific histologic subtypes of pediatric MB. A total of 114 pediatric patients (age

Subependymal giant cell astrocytoma is a benign brain tumor mostly associated with tuberous sclerosis complex. However, it may be misinterpreted as other high-grade brain tumors due to the presence of large tumor cells with conspicuous pleomorphism and occasional atypical features, such as tumor necrosis and endothelial proliferation. In this study, we first investigated thyroid transcription factor-1 (TTF-1) expression in a large series of subependymal giant cell astrocytomas and other histologic and locational mimics to validate the diagnostic utility of this marker. We then examined TTF-1 expression in non-neoplastic brain tissue to determine the cell origin of subependymal giant cell astrocytoma. Twenty-four subependymal giant cell astrocytoma specimens were subjected to tissue microarray construction. For comparison, a selection of tumors, including histologic mimics (21 gemistocytic astrocytomas and 24 gangliogliomas), tumors predominantly occurring at the ventricular system (50 ependymomas, 19 neurocytomas, and 7 subependymomas), and 134 astrocytomas (3 pleomorphic xanthoastrocytomas, 45 diffuse astrocytomas, 46 anaplastic astrocytomas, and 40 glioblastomas) were used. Immunohistochemical stain for TTF-1 was positive in all 24 subependymal giant cell astrocytomas, whereas negative in all astrocytomas, gangliogliomas, ependymomas, and subependymomas. Neurocytomas were positive for TTF-1 in 4/19 (21%) of cases using clone 8G7G3/1 and in 9/19 (47%) of cases using clone SPT24. In the three fetal brains that we examined, TTF-1 expression was seen in the medial ganglionic eminence, a transient fetal structure between the caudate nucleus and the thalami. There was no BRAFV600E mutation identified by direct sequencing in the 20 subependymal giant cell astrocytomas that we studied. In conclusion, TTF-1 is a useful marker in distinguishing subependymal giant cell astrocytoma from its mimics. Expression of TTF-1 in the fetal medial ganglionic eminence indicates that subependymal giant cell astrocytoma may originate from the progenitor cells in this region.

BACKGROUND In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). Part of our aim was to explore the clinical application for drug target identification and finding clues to genetic predisposition. METHODS In total, 52 frozen tumor tissues of childhood MBs were collected. RNA-Seq and DNA methylation array data were generated. Molecular subgrouping was performed. We selected 51 clinically relevant genes for somatic variant calling using RNA-Seq data. Correlated clinical findings to genetic predisposition were defined. Potential drug targets and genetic predispositions were explored. RESULTS Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Potential drug targets were detected in the pathways of DNA damage response. Five patients with relevant clinical findings to genetic predisposition clustered in SHH MBs. The corresponding somatic driver mutations involved TP53, MSH6, PTEN, PTCH1, and TERT promoter (suspicious). For validation, whole exome sequencing (WES) of blood and tumor tissue was used in 10 patients with SHH MBs in the cohort series. This study included the five patients with potential genetic predispositions. Four patients exhibited relevant germline mutations named as TP53, MSH6, PTEN, and SUFU. CONCLUSION The findings of this study provide valuable information for personalized care of childhood MB in our cohort series and in Taiwan.

Tumors with epicenter in the thalamus occur in about 4 % of pediatric brain tumors. The histological diagnosis is mainly gliomas. Among them, low-grade glioma (LGG) constituted of a significant entity of the tumors (Cuccia et al., Childs Nerv Syst 13:514–521, 1997; Puget et al., J Neurosurg 106:354–362, 2007; Bernstein et al., J Neurosurg 61:649–656, 1984; Bilginer et al., Childs Nerv Syst 30:1493–1498, 2014). Since Kelly’s report in 1989, >90 % resection of thalamic tumors were achieved in reported series (Ozek and Ture, Childs Nerv Syst 18:450–6, 2002; Villarejo et al., Childs Nerv Syst 10:111–114, 1994; Moshel et al., Neurosurgery 61:66–75, 2007; Albright, J Neurosurg 100(5 Suppl Pediatrics): 468–472, 2004; Kelly, Neurosurgery 25:185–195, 1989; Drake et al., Neurosurgery 29: 27–33, 1991). Sixty-nine cases of thalamic tumors in children were retrospectively reviewed. There were 25 cases of LGGs. We analyzed our experience and correlated it with reported series. Summing up of 4 reported series and the present series, there were 267 cases of thalamic tumors in children. Among these tumors, 107 (40.1 %) were LGGs and 91 (34.1 %) were low-grade astrocytomas (LGAs). In the present series, all of the 25 LGGs were LGAs that consisted of 11 pilocytic astrocytomas (PAs) and 14 diffuse astrocytomas (DAs). Six cases received biopsy sampling only. The remaining 19 cases received different degrees of surgical resection via several approaches. Radical (>90 %) resection was achieved better in PAs comparing with DAs. There was no operative mortality. Two patients had increased neurological deficits. In a mean follow-up period of 11.9 years, three patients died of tumor progression and one patient died of anaplastic change. The 5- and 10-year overall survival (OS) was 87.1 and 87.1 %, respectively. Thalamic LGGs are mainly LGAs and are indolent. The rate of >90 % resection was relatively low in the present series. By applying contemporary diagnostic MRI studies, surgical facilities, and appropriate approaches in selective cases, we may try maximum neuroprotective radical (>90 %) resection.

Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors affecting children, and outcomes have remained dismal, even with access to new multimodal therapies. In this study, we compared the miRNomes and transcriptomes of pediatric low- (pLGGs) and high-grade gliomas (pHGGs) using small RNA sequencing (smRNA-Seq) and gene expression microarray, respectively. Through integrated bioinformatics analyses and experimental validation, we identified miR-137 and miR-6500-3p as significantly downregulated in pHGGs. miR-137 or miR-6500-3p overexpression reduced cell proliferation in two pHGG cell lines, SF188 and UW479. CENPE, KIF14 and NCAPG levels were significantly higher in pHGGs than pLGGs, and were direct targets of miR-137 or miR-6500-3p. Furthermore, knockdown of CENPE, KIF14 or NCAPG combined with temozolomide treatment resulted in a combined suppressive effect on pHGG cell proliferation. In summary, our results identify novel mRNA/miRNA interactions that contribute to pediatric glioma malignancy and represent potential targets for the development of new therapeutic strategies.

In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). In this study, we aimed to identify a molecular-clinical correlation and somatic mutation for exploring risk-adapted treatment, drug targets, and potential genetic predisposition. In total, 52 frozen tumor tissues of childhood MBs were collected. RNA sequencing (RNA-Seq) and DNA methylation array data were generated. Molecular subgrouping and clinical correlation analysis were performed. An adjusted Heidelberg risk stratification scheme was defined for updated clinical risk stratification. We selected 51 genes for somatic variant calling using RNA-Seq data. Relevant clinical findings were defined. Potential drug targets and genetic predispositions were explored. Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Genetic backgrounds of metastasis at diagnosis and extent of tumor resection were observed. The adjusted Heidelberg scheme showed its applicability. Potential drug targets were detected in the pathways of DNA damage response. Among the 10 patients with SHH MBs analyzed using whole exome sequencing studies, five patients exhibited potential genetic predispositions and four patients had relevant germline mutations. The findings of this study provide valuable information for updated risk adapted treatment and personalized care of childhood MBs in our cohort series and in Taiwan.

Background IDH mutation is an important prognostic factor of diffuse astrocytomas. Although the majority of IDH mutations could be identified by immunohistochemical (IHC) stain for R132H-mutant IDH1, DNA sequencing would be required for IHC negative cases to determine their IDH mutation status. This approach is not cost-effective for tumors with low IDH mutation rates. Objective To investigate whether BCAT1 could be used as a surrogate marker for IDH mutations, because BCAT1 is an enzyme related to IDH genes. Methods A group of 120 anaplastic astrocytomas were immunostained for BCAT1, ATRX, and R132H-mutant IDH1. Staining results correlated with the results of DNA sequencing of IDH1/IDH2. Results DNA sequencing showed IDH1/2 mutations in 50.8% of cases of which 73.8% had IDH1 R132H mutation. Several IDH1 noncodon 132 mutations, ie, G97D, S122N, G123E, I130K, and G131S, which had uncertain prognostic significance, were identified. IHC stain for R132H-mutant IDH1 identified 93.3% of IDH1 R132H mutations and 70.5% of all IDH mutations. BCAT1 loss was seen in 65.8% of cases, its sensitivity to identify IDH mutations was 96.7%. The sensitivity reached 100% for IDH1 codon 132 and IDH2 codon 172 mutations. Conclusion Positive BCAT1 stain could be used to exclude diffuse gliomas with IDH1 codon 132 and IDH2 codon 172 mutations. Selecting cases with negative BCAT1 and R132H-mutant IDH1 staining for DNA sequencing of IDH1/2 genes could improve the cost-effectiveness of detecting IDH mutations particularly in tumors with low IDH mutation rates, and confine the need of 1p/19q assay in IDH-mutant tumors.

Intracranial germ-cell tumors (GCTs) represent 10–15% of all pediatric brain tumors in East Asia. There is a wide histopathological spectrum of intracranial GCTs. Germinomas and nongerminomatous GCTs are the two major classifications. It is difficult to distinguish different subtypes of intracranial GCTs based solely on imaging studies, however, some tumor markers, such as α-fetoprotein or β-human chorionic gonadotropin, are helpful for diagnosis. In this study we present the case of a 13-year-old girl with an intracranial mixed GCT containing a hepatocellular carcinoma and germinoma without a primary liver tumor. Based on this unique pathological diagnosis, a series of treatments were applied, including surgery for gross tumor removal, adjuvant radiotherapy, and chemotherapy. Long-term follow up indicates fair disease control.

Methylation-specific polymerase chain reaction (MSP) for the promoter methylation status of O(6)-methylguanine-DNA-methyltranferase (MGMT) gene theoretically provides a positive or negative result. However, the faint MSP product is difficult to interpret. The aim of this study was to evaluate the significance of faint MSP product in glioblastoma (GBM). Critical concentrations of methylated control DNA, i.e., 100, 1, 0.5 and 0 % were run parallel with 116 newly diagnosed GBMs in order to standardize the interpretation and to distinguish positive (+), equivocal (±), and negative (-; unmethylated) results. Cases with the faint MSP product and its intensity between those of 1 and 0.5 % DNA controls were considered equivocal (±). MGMT methylation quantifications were also determined by quantitative real-time MSP (qMSP) and pyrosequencing (PSQ), and protein expression was detected by immunohistochemistry. There were significant correlations between MSP and all the aforementioned studies. The concordance rates between the MSP+ and qMSP+ cases, as well as the MSP- and qMSP- cases were 100 %, and the MSP± cases comprised 76.5 % of qMSP+ cases and 23.5 % of qMSP- cases. PSQ study showed that heterogeneous methylation was more frequently encountered in the MSP± cases. Multivariate analyses disclosed that although the overall survival of the MSP± cases was indistinct from that of the MSP+ cases, its progression free survival was significantly worse and was indistinct from that of the MSP- cases. In conclusion, GBMs with faint MGMT MSP products should be distinguished from MSP+ cases as their behaviors were different.

Promoter methylation is the most significant mechanism to regulate O6-methylguanine-DNA-methyltransferase (MGMT) expression. Single-nucleotide polymorphisms (SNPs) in the MGMT promoter region may also play a role. The aim of this study was to evaluate the clinical significance of SNPs in the MGMT promoter region of glioblastoma. Genomic DNAs from 118 glioblastomas were collected for polymerase chain reaction (PCR) amplification. Sanger sequencing was used to sequence the MGMT promoter region to detect SNPs. The results were correlated with MGMT status and patient survival. Rs1625649 was the only polymorphic SNP located at the MGMT promoter region in 37.5% of glioblastomas. Homozygous rs1625649 (AA genotype) was correlated with a higher MGMT methylation level and a lower protein expression, but the result was not statistically significant. In patients with MGMT methylated glioblastoma, cases with homozygous rs1625649 (AA genotype) were significantly associated with a lack of MGMT protein expression and a better progression-free survival (PFS) than the cases with wild type rs1625649 (CC genotype) or heterozygous rs1625649 (CA genotype). The survival impact was significant in multivariate analyses. In conclusion, the MGMT promoter homozygous rs1625649 (AA genotype) was found to correlate with a better PFS in patients with MGMT methylated glioblastoma.

Complications can occur following a prolonged latency period after radiation therapy for cancer, and this is a growing concern because secondary tumors are potentially fatal. Few studies have examined secondary tumors in patients who received radiation therapy as children.This retrospective study examined 1697 pediatric patients with central nervous system tumors who received treatment at Taipei Veterans General Hospital from January 1, 1975, to December 31, 2013. Secondary tumors developed in 27 of 681 patients who received cranial irradiation. Overall survival was estimated using the Kaplan-Meier method, and the significance of differences was determined by the log-rank test.The overall cumulative incidence of secondary tumors at 25 years was 3.96%, and there were similar numbers of male patients (n = 16) and female patients (n = 11). The mean age at diagnosis was 8.8 years (range, 3-16.5 years), the median dose of cranial irradiation was 52.5 Gy (mean, 53.4 Gy), the mean latency period was 14.6 years (range, 2-33 years), and the mean age at diagnosis of a secondary tumor was 23.1 years. The secondary tumors were mainly meningiomas (n = 13), sarcomas (n = 7), and high-grade gliomas (n = 6), and the mean latency periods were 19.66, 8.00, and 10.83 years, respectively. The overall survival rate from these secondary tumors was significantly different (P .05). Age at irradiation of7 years and craniospinal irradiation significantly increased the risk of a secondary tumor (P .05). Secondary tumors developed in 11 of 128 patients (8.6%) with primary medulloblastomas, which was higher than the overall cumulative incidence.Clinicians should consider the increased risk of secondary tumors in long-term cancer survivors who received craniospinal irradiation as children. Using a selective dose de-escalation strategy or deferring radiation therapy for young patients at highest risk of secondary cancers should be studied.

The relationship between human cytomegalovirus (HCMV) and glioblastoma (GBM) has been debated for more than a decade. We investigated the presence of HCMV genes, RNA and protein in GBMs and their relationships with tumor progression. Results of quantitative PCR for HCMV UL73, nested PCR for HCMV UL144, in situ hybridization (ISH) for RNA transcript, and immunohistochemistry (IHC) for protein expression and their relationship to the prognosis of 116 patients with GBM were evaluated. Nine (7.8%) cases revealed a low concentration of HCMV UL73, and only 2 of the 9 (1.7%) cases showed consistent positivity on repeat PCR testing. HCMV UL144, ISH and IHC assays were all negative. The HCMV UL73 positive cases did not show significant difference in the clinicopathological characters including age, gender, Karnofsky performance status, extent of resection, bevacizumab treatment, isocitrate dehydrogenase 1 mutation, O6-methylguanine-DNA-methyltranferase status and Ki67 labeling index, and did not reveal prognostic significance. As only one HCMV gene was detected at low concentration in 7.8% of GBMs and there was no evidence of transcription, protein expression or prognostic impact, we cannot conclude a relationship between HCMV and GBM in Taiwanese patients.

Embryonal tumors of the central nervous system represent a highly malignant tumor group of medulloblastoma (MB), atypical teratoid/rhabdoid tumor (AT/RT) and primitive neuroectodermal tumor that frequently afflict children. AT/RT is often misdiagnosed as MB/primitive neuroectodermal tumor but with higher recurrence and lower survival rates. Pathogenesis of AT/RT is largely unknown. In this study, we report both the miRNome and transcriptome traits in AT/RT and MB by using small RNA sequencing and gene expression microarray analyses. Our findings demonstrate that the miR-221/222-encoded micro RNAs are abundantly expressed in AT/RT but not in MB, which contribute substantially to the malignancy of embryonal tumors. miR-221/222 targeted SUN2, a newly discovered tumor suppressor, directly to increase cell proliferation and tumor malignancy in vitro and in vivo. Immunohistochemistry against SUN2 in a tissue microarray of 33 AT/RT and 154 MB tumor specimens also detected less SUN2 protein in AT/RT. Collectively, this study uncovers a novel tumor suppressor, SUN2, plays a critical role in miR-221/222-mediated AT/RT malignancy as well as supports miR-221/222 and SUN2 represent new promising targets for more active therapies in AT/RT. In addition, our miRNome and transcriptome data also provide a roadmap for further embryonal tumor research.

We present a patient with an isolated primary central nervous system lymphoma (PCNSL) of the fourth ventricle. A 77-year-old man had a 1 week history of intermittent vertigo, nausea, vomiting, and progressively unsteady gait. CT scans of the brain showed a fourth ventricle tumor. MRI revealed a 2.5 cm dumbbell-shaped avidly-enhancing tumor in the fourth ventricle. Metastasis or high-grade glioma was suspected. The neuropathological findings were compatible with a diffuse large B-cell lymphoma. A slit lamp examination, bone marrow biopsy, and imaging studies for extracranial lesions were unremarkable. We suggest that PCNSL be listed in the differential diagnosis of fourth ventricle tumors with well-circumscribed margins and homogenous contrast enhancement.

Aims To identify an easily obtainable non-neoplastic tissue that can be used as control material for monitoring optimal Ki-67 immunohistochemical staining. Methods and results Various tissues, including tonsil (60), uterine cervix (31), breast skin (26), oesophagus (15), stomach (15), small intestine (15) and colon (16), were studied in the search for ideal control tissue. Tonsil surface epithelium is superior to other tissues because it displayed an easily recognized Ki-67 staining pattern including high positive (parabasal layer), low positive (intermediate layer) and negative (basal and superficial layers) zones. Moderate to weak staining of the majority of the intermediate cells could serve as a threshold for positive staining. Of the variables potentially affecting staining results that were tested, the pretreatment solution for antigen retrieval had the greatest impact, of which pH 9 EDTA was far better than pH 6 citrate solution. Conclusions Tonsil surface epithelium is a useful control for monitoring Ki-67 staining. Achieving optimal staining results could minimize variations in Ki-67 index due to differences in the staining methods used by different laboratories.

Currently, there are only a few reported cases of symptomatic or asymptomatic subpial (intramedullary) spinal lipoma, and therefore no guidelines are available to indicate surgery. These lesions are infrequently associated with spina bifida. Herein, we provide our experience in the neurosurgical intervention of compressive myeloradiculopathy for encephalocraniocutaneous lipomatosis (ECCL). The patient initially presented with bilateral upper hand paralysis, then regained muscle power after surgery and during 1 year of follow-up. We discuss the neurosurgical indications and intervention, imaging studies, other associated symptoms, and the pathogenesis of ECCL in an infant.

Lymphoplasmacyte-rich meningioma with the features of lasmocytoma was first described in 1971 [1]. In 1993, ymphoplasmacyte-rich meningioma was proposed as a variant f meningioma in the World Health Organization classification 2]. Since lymphoplasmacyte-rich meningioma has neoplastic and nflammatory features simultaneously, its biological behavior and rognosis are not so clearly understood. We report a case of ymphoplasmacyte-rich meningioma in a 60-year-old female who nderwent a subtotal surgical resection. However, the residual umor progressed on the suprasellar region one year after opertion, and we arranged Gamma-Knife radiosurgery (GKS) for er. Seven months after GKS, significant tumor shrinkage was oted without any adverse radiation effects (ARE). There is a diference in response to radiation between benign meningiomas nd lymphoplasmacyte-rich meningiomas. This interesting clinical ourse may help us understand more about this rare meningioma.

We evaluated the predictive value of O6-methylguanine-DNA methyltransferase (MGMT) protein expression and MGMT promoter methylation status in glioblastomas (GBM) treated with temozolomide (TMZ) in a Taiwan medical center. Protein expression by immunohistochemical analysis (IHC) and MGMT promoter methylation detected by methylation-specific polymerase chain reaction (MSP) were performed in a series of 107 newly diagnosed GBMs. We used endothelial cells as an internal reference for IHC staining because the staining intensities of the MGMT-expressing cells in different specimens varied considerably; a positive result was defined as the staining intensity of the majority of tumor cells similar to that of the adjacent endothelial cells. Immunostainings for microglial/endothelial markers were included as part of the MGMT IHC evaluation, and in cases that were difficult to interpret, double-labeling helped to clarify the nature of reactive cells. The MGMT protein expression was reversely associated with MGMT promoter methylation status in 83.7% of cases (MSP/IHC and MSP/IHC; Pearson r=-0.644, P

The O-methylguanine-DNA-methyltranferase (MGMT) status is a powerful predictor of response to temozolomide for newly diagnosed glioblastoma (GBM) patients, and it is commonly assessed by immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP), quantitative real-time MSP (qMSP), and/or pyrosequencing (PSQ). This study was to compare their predictive power of prognosis in 121 newly diagnosed GBM patients using multivariate Cox regression with bootstrapping. MGMT status tested by IHC, MSP, qMSP, or PSQ all showed significant correlation with the progression-free survival and overall survival of GBM patients. The predictive power of IHC for progression-free survival and overall survival was lower than those of the methylation assays, but their differences were not significant. Performing additional methylation assay, especially PSQ, could better predict the prognosis of patients with IHC- tumors. MGMT status tested by IHC, MSP, qMSP, or PSQ all showed prognostic significance. An additional MGMT methylation assay, of which PSQ appeared to be the best, could improve the predictive power for GBM patients with MGMT IHC- tumors.

Background: Magnetic resonance diffusion-weighted imaging (DWI) has been widely used clinically in imaging diagnosis of intracranial disorders. The purpose of current study was to present a quantitative method of direct measuring the DWI signal intensity of brain gliomas on the monitors of hospital picture archiving and communicating system (PACS) for grading gliomas. Methods: This study recruited 135 patients with treatment-naïve brain gliomas. Direct measurement of the signal intensity of selected tumoral regions of interest (ROIs) by DWI on the monitors of the hospital PACS was performed for all patients. From the measurements, we obtained three values, defined as DWIT (tumor), DWIN (the homologous normal-appearing area of the tumor ROI in the contralateral hemisphere), and DWIWM (normal-appearing white matter) in the contralateral frontal lobe. Two ratios, DWIT/WM and DWIT/N, were obtained for each tumoral ROI. The same method was used for apparent diffusion coefficient (ADC) ratios of the tumoral ROI. Fractional polynomial regression and the Mann–Whitney U test were applied to determine the correlation between tumor grading, MIB-1 labeling index, and DWI and ADC ratios. Logistic regression models and receiver operating characteristic curve analysis were used to establish diagnostic models. Measurements of intraobserver and interobserver agreement were also made at 1-month interval. Results: The DWI ratios correlated positively with tumor grade and MIB-1 value (p

Summary Objectives Most patients with Cushing’s disease (CD) respond to corticotrophin-releasing hormone (CRH) or desmopressin with increased corticotrophin (ACTH) and cortisol levels. Although the vasopressin receptor subtype located on normal corticotrophs is the V3 receptor (V3R), desmopressin is a selective V2 receptor (V2R) agonist and it is unclear whether corticotrophinomas exhibit aberrant V2R expression. Furthermore, no studies have determined the relationship between the in vivo response of CD patients to desmopressin and vasopressin receptor expression, or between the response to CRH and CRH receptor (CRHR) expression. Therefore, the aim of this study was to investigate the expression of vasopressin receptors (V1R, V2R, and V3R) and CRHR on corticotroph tumours and its possible relation to the in vivo response. Designs A prospective study of 29 patients with CD. Methods Patients underwent desmopressin and CRH stimulation tests before surgery. The expression of vasopressin receptors and CRHR on corticotrophinomas was determined by immunocytochemistry. Results Most of the corticotrophinomas exhibited abundant expression of V1R, V3R, and CRHR, whereas the expression of V2R varied greatly and was lower in macroadenomas than in microadenomas. Both the percentage increment of ACTH and net area under the curve (AUC) of ACTH in the desmopressin stimulation test were found to be correlated with tumour volume. After adjustment for tumour volume, a positive correlation was found between the percentage increment of ACTH and the degree of V2R expression, but not between that of V1R or V3R. No relationship between the level of expression of CRHR on tumour tissues and the percentage increment or netAUC of ACTH to CRH was observed in CD patients. Conclusions We concluded that V2R was expressed on corticotrophinomas and that the level of its expression correlated well with the ACTH response to desmopressin in CD patients, although abundant expression of V1R and V3R was also found in almost all corticotroph tumours. Further studies are needed to elucidate the role of these receptors in the pathogenesis of CD.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system tumor often misdiagnosed as some other type of pediatric embryonal tumor, such as medulloblastoma (MB). Distinguishing AT/RT from primitive neuroectodermal tumor/MB is of clinical significance, as the reported survival rate of patients with AT/RT is much lower than that of patients with average-risk primitive neuroectodermal tumor/MB. The diagnosis of AT/RT currently relies primarily on the morphologic assessment and immunostaining of a few known markers, such as the lack of INI1 protein expression. Immunohistochemical staining of INI1 is considered very sensitive and is highly specific for the detection of INI1 genetic defects. Genetic studies have shown that deletion or mutation of the INI1 gene, which is located on 22q11.2, occurs in AT/RT lesions. During our gene expression microarray analysis, we unexpectedly found a subgroup of AT/RT patients still expressing INI1 mRNA, even though INI1 proteins were negative by immunohistochemistry in those cases. Direct DNA sequencing showed no INI1 sequence alternation in 3 of 4 AT/RTs. Point mutation was found in only 1 allele of the fourth case, which would result in a frameshift mutation and generate a new INI1 protein with an extra 100-aa tail. Global array comparative genomic hybridization analysis confirmed no aberration around the INI1 gene at 22q11.2. It also extended our knowledge on the chromosomal aberration situations in our series. This study reveals that a novel yet unidentified posttranscriptional regulatory mechanism(s) for INI1 protein synthesis exists in AT/RT tumor cells.

Brainstem gliomas, accounting for only 2% of adult brain tumors, constitute 10% to 20% of central nervous system tumors in the pediatric group [3]. They are mainly located in the mesencephalon, the pons (including the cerebellar peduncles), and the medulla oblongata. In pediatric patients, a thorough neurological examination and magnetic resonance (MR) imaging are essential in the establishment of the diagnosis, treatment plans, and therapeutic approaches with or without biopsy [1, 12]. Some case series had proved the therapeutic effect of Gamma Knife radiosurgery (GKS) to brainstem gliomas [4, 8, 15]. For pediatric patients, however, long-term adverse effects caused by radiation injury are always the main concern. In this report, we reviewed our long-term follow-up experience of two pediatric cases with brainstem gliomas after GKS treatment.

BACKGROUND: Previous intracranial germinoma (IG) studies have investigated the effect of different radiotherapy (RT) volumes and the necessity for adjunctive chemotherapy, but there is currently no consensus on the best treatment for this tumor. METHODS: From January 1989 to December 2009, 80 IG patients (≤20 years old) were treated with various RT regimens. Of them, 14 patients had craniospinal irradiation (CSI) + primary boost (PB); 8 patients had whole-brain irradiation (WBI) + PB; 31 patients had whole ventricular irradiation (WVI) + PB; and 27 patients had focal RT only. Twenty-nine patients (36.2%) also received systemic chemotherapy (CHT). Survival was estimated by the Kaplan-Meier method and variables affecting survival were analyzed by the Cox proportional hazard model. RESULTS: Eleven patients (13.8%) developed local recurrence or dissemination after treatment, and 10 of these patients were in the focal RT group. The 5-year relapse-free survival (RFS) for the CSI, WBI, WVI, and focal RT patients were 100%, 85.7%, 100%, and 84.6%, respectively (P = .001). The 5-year overall survival (OS) for CSI, WBI, WVI, and focal RT patients was 100%, 83.3%, 100%, and 87.9%, respectively (P = .125). Focal irradiation (P = .02) and initial use of CHT (P = .021) were negatively associated with RFS. CONCLUSIONS: Focal RT plus CHT were associated with inferior control of IG and a higher incidence of CHT-related toxicities. Adjustment of the radiation volume to the whole ventricular system without CHT is sufficient for treatment of nondisseminated IGs, even with lower primary RT doses (

Capsular serotypes K1 and K2, the rmpA gene (a regulator of the mucoid phenotype) and aerobactin from Klebsiella pneumoniae have been identified as the major virulence factors for pyogenic liver abscesses with high morbidity, mortality and severe complications. The pathological mechanisms remain unclear. In this study, we compared liver immune responses and pathological changes in response to different serotypes of K. pneumoniae infections. A mouse model was used to investigate cytokine and chemokine production, histopathology findings, phagocytic uptake and mortality induced by serotypes K1 (magA(+), rmpA(+), aerobactin(+)), K2 (magA(-), rmpA(+), aerobactin(+)), K62 (magA(-), rmpA(-), aerobactin(-)) and an acapsulated isogenic K1 mutant (ΔK1, magA(+), rmpA(+), aerobactin(+)). K. pneumoniae serotypes K1 and K2 showed lower 50% lethal dose values and more phagocytic resistance to neutrophils than K62 and the ΔK1 mutant. In sequential liver samples, viable bacteria counts increased 3 h to 3 days after low-dose inoculation (10(1) colony-forming unit (cfu)) with K1 and K2, while K62 and ΔK1 cleared rapidly and became undetectable even with high-dose inoculation (∼2.9 × 10(5) cfu). Time-dependent increases in cytokines and chemokines, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-10, keratinocyte-derived chemokines and macrophage inflammatory protein-2, were observed in the serum and liver tissue of K1- and K2-infected mice, and severe disease progression manifesting as microabscesses was also identified. K62 and ΔK1 inoculation did not result in similar immune responses and histological changes. These findings illustrate the critical role of phagocytic resistance against innate immunological defense mechanisms as well as its contribution to the development of liver abscesses.

Metastasis of nasopharyngeal carcinoma (NPC) to the dura, an extremely rare condition, can be symptomatically silent and mistaken for a benign entity radiographically. Missed diagnosis can lead to serious consequences or prove immediately fatal. We report a woman with dural metastasis of NPC that mimicked a meningioma on radiography. Craniectomy with tumour resection was performed due to rapid progression from the onset of symptoms to disability. The patient was still alive two years after surgery. This case emphasises the need to keep in mind the possibility of dural metastasis of NPC in patients with abnormal imaging features. This would not only avoid wrong and optimistic diagnosis, but also allow for appropriate treatment in a timely manner. To our knowledge, this is the first report of metastasis of NPC to the dura. We provide detailed information on the neoplastic lesion, which masqueraded as a benign entity and caused potentially fatal consequences.

Aim To construct a prognostic model for recurrence-free survival (RFS), progression-free survival (PFS) and cancer-specific survival (CSS) for patients who have undergone transurethral resection of non-muscle-invasive (pTa/pT1) urinary bladder urothelial tumours. Methods 1366 patients who had undergone transurethral resection of primary non-muscle-invasive urothelial tumours (pTa, 891 patients; pT1, 475 patients) confined to the bladder were retrospectively studied. Tumours were classified according to the 2004 WHO/International Society of Urologic Pathology grading system. Kaplan–Meier and stepwise Cox regression models were applied, and 200 bootstrap resamples were used to generate survival estimates and 95% CIs. A nomogram was developed that incorporated significant variables predicting survival. Results RFS, PFS and CSS probabilities for non-muscle-invasive bladder urothelial tumours were calculated. Incorporating salient prognostic factors (tumour grade, pT stage, patient age, status of intravesical instillation), the model satisfactorily predicted PFS (concordance index=0.79) and CSS (concordance index=0.87). Conclusions Robust nomograms were created to predict PFS and CSS. These data provide an overall perspective of disease outcomes which may aid in developing individualised follow-up programmes.

To verify prognostic significance of the 2004 World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading systems, we retrospectively studied the tumors of 1,515 patients who underwent transurethral resection of primary non–muscle-invasive urothelial tumors (pTa, 1,006 patients; pT1, 509 patients) confined to the bladder. Cases were classified according to the 2004 WHO/ISUP systems as 212 cases of papillary urothelial neoplasm of low malignant potential (PUNLMP), 706 low-grade papillary urothelial carcinomas (LPUCs), and 597 high-grade papillary urothelial carcinomas (HPUCs). PUNLMP showed the statistically significantly lowest recurrence cumulative incidence compared with the other tumor types. There were significant differences and trends for higher progression and cancer-specific mortality cumulative incidence in the following order: PUNLMP, LPUC, pTa HPUC, and pT1 HPUC. No differences of progression and cancer-specific mortality cumulative incidence were found between pTa and pT1 LPUC. Our study validates the usefulness of the 2004 WHO/ISUP system to classify urothelial tumors into prognostically distinct categories that would contribute to the design of therapeutic and monitoring strategies for patients with non–muscle-invasive bladder urothelial tumors.

Background This report analyzed a research project supported nationwide expert consultation of anatomic pathology in Taiwan. Methods The data were collected from the requisitions and consultation reports of 2,686 cases in this project from 2003 to 2006. The number of cases, tissue origin, additional special stains, turnaround time (TAT), concordance, discordance, referring pathologists, and consultants were analyzed. Results Skin, hematopoietic system, and bone and soft tissue were the most common (48.3%) specimens sent for consultation. The tentative diagnosis and consultation diagnosis were discordant in 1,074 (64.3%) cases. Major discrepancy was seen in 205 (12.3%) cases, of which 66.8% were changed from malignant to benign, 21.0% were changed from benign to malignant, whereas 12.2% were changed from one category of malignancy to another. Additional special stains were performed on 38.7% of cases and hematology specimen was the most frequent. The mean TAT was 3.4 days. Pathologists working in institutes having fewer pathologists sent more cases for consultation. The opinion of the estimated annual consultation rate from the pathologists in Taiwan was 0.7%. Conclusions This program was beneficial simply by helping the referring pathologists in the workup and diagnosis. This result made the entire program a reasonable quality improvement program. J. Surg. Oncol. 2010; 101:430–435. © 2010 Wiley-Liss, Inc.

Purpose: Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. In a previous study, we showed that GNMT acts as a susceptibility gene for hepatocellular carcinoma. Here, we report on our efforts to characterize the haplotypes, loss of heterozygosity (LOH), and expression levels of the GNMT in prostate cancer. Experimental Design: Peripheral blood mononuclear cell DNA collected from 326 prostate cancer patients and 327 age-matched controls was used to determine GNMT haplotypes. Luciferase reporter constructs were used to compare the promoter activity of different GNMT haplotypes. GNMT LOH rates in tumorous specimens were investigated via a comparison with peripheral blood mononuclear cell genotypes. Immunohistochemical staining was used to analyze GNMT expression in tissue specimens collected from 5 normal individuals, 33 benign prostatic hyperplasia patients, and 45 prostate cancer patients. Results: Three major GNMT haplotypes were identified in 92% of the participants: A, 16GAs/DEL/C (58%); B, 10GAs/INS/C (19.9%); and C, 10GAs/INS/T (14.5%). Haplotype C carriers had significantly lower risk for prostate cancer compared with individuals with haplotype A (odds ratio, 0.68; 95% confidence interval, 0.48-0.95). Results from a phenotypic analysis showed that haplotype C exhibited the highest promoter activity (P < 0.05, ANOVA test). In addition, 36.4% (8 of 22) of the prostatic tumor tissues had LOH of the GNMT gene. Immunohistochemical staining results showed abundant GNMT expression in normal prostatic and benign prostatic hyperplasia tissues, whereas it was diminished in 82.2% (37 of 45) of the prostate cancer tissues. Conclusions: Our findings suggest that GNMT is a tumor susceptibility gene for prostate cancer.

Mixed germ cell tumors with non-germ cell malignant components rarely occur in the anterior mediastinum. We report a case of a 34-year-old man who presented with an anterior mediastinum mass. Mixed germ cell tumor was initially diagnosed based on the pathologic findings of germinoma on thoracoscopic biopsy and clinical findings of elevated serum alpha-fetoprotein and beta-human chorionic gonadotropin. The patient received preoperative chemotherapy and subsequent complete resection of the residual tumor. Pathologic examination of the excised specimen showed predominantly malignant ganglioneuroma and small residual foci of teratoma. To our knowledge, this is the first reported case of a malignant ganglioneuroma arising from mediastinal mixed germ cell tumor.

Medulloblastoma (MB) is a type of malignant tumor arising only in the cerebellum that was first defined by Cushing and Bailey in 1920s. In this review paper, we trace the evolution of risk stratification and the correlated changing concept of management in the past years. Outcome analysis of the hospital series of the Taipei Veterans General Hospital, Cheng Hsin General Hospital, and Taipei Medical University Hospital was performed to correlate prognostic indicators with reported studies. The purpose is to provide clues for age-specific and risk-adjusted optimal, effective, but beneficial and protective treatment strategies of these tumors in children.

ObjectThe authors report the long-term treatment results of Gamma Knife surgery (GKS) for patients with low-grade astrocytomas who underwent surgery at a single institution.MethodsA series of 21 patients (median age 20 years) with 25 intracranial low-grade astrocytomas (World Health Organization Grades I and II) were treated with GKS between 1993 and 2003. Among them, four underwent GKS as a primary treatment. Two underwent GKS as a treatment boost after radiotherapy. In the other 15 patients, GKS was performed as an adjuvant or salvage treatment for residual/recurrent tumors after the patients had undergone craniotomy. Tumor volumes ranged from 0.2 to 13.3 ml (median 2.4 ml). Prescription margin doses ranged from 8 to 18 Gy (median 14.5 Gy). Radiation volumes were 1.3 to 21.6 ml (median 3.6 ml). Patients underwent regular follow up, with neurological evaluation and magnetic resonance imaging studies obtained at 6-month intervals.One patient was lost to follow-up. The clinical follow-up time was 5 to 144 months (median 67 months). Complete tumor remission was seen in three patients. The 10-year progression-free patient survival rate after GKS was 65%. Tumor progression was found in six patients of whom five received further salvage treatment. All the tumor progression occurred within the GKS-treated volumes. Mild-to-moderate adverse radiation effects (AREs) were found in eight patients. Both of the patients who had undergone GKS as a treatment boost after radiotherapy developed AREs, but with good shrinkage of tumors.Conclusions Gamma Knife surgery provides durable long-term local tumor control with acceptable toxicity for some patients with highly selected low-grade astrocytomas.

We correlated serial brain MRIs with neuropathological findings in a 16-year-old female whose autopsy was consistent with Wernicke's encephalopathy (WE). Diffusion-weighted imaging, diffusion coefficients mapping and neuropathology findings were suggested vasogenic edema in the periaqueductal and peri-the-fourth ventricular areas. This is the first documented case report to make this direct comparison. The characteristic WE changes in the mammillary body was also correlated with the findings of MRI with contrast enhancement. Bilateral cortical lesions revealed by MRI were atypical and rare in WE and were not evidenced by pathological changes.

Background Conjunctival biopsy is considered to be a simple, safe and specific diagnostic procedure for sarcoidosis. This study was designed to determine the value of this procedure in Taiwan. Methods This study was conducted from December 2003 to April 2005 at the uveitis clinic of Taipei Veterans General Hospital. Blind sampling was conducted, obtaining a biopsy sample measuring 1 cm long by 3 mm wide from both lower fornices. A positive result was defined as the presence of non-caseating granuloma when other granuloma-forming processes had been excluded. Results Twenty-nine patients (7 men, 22 women) were enrolled. Mean age at diagnosis was 47.8 ± 12.4 years. The most common initial symptom was eye-related problems in 19 (65.5%) patients. Of 58 biopsies, 15 (25.9%) specimens in 11 (37.9%) patients proved to be positive. Four patients experienced bilateral involvement; 7 patients had unilateral involvement. No prominent conjunctival nodules or follicles were noted. Gender, age, presence of uveitis, initial symptoms, and chest condition comparisons revealed no association between positive and negative conjunctival biopsies. Conclusion Blind and bilateral conjunctival biopsy, due to its ease, safety and specificity, could be the first biopsy in patients with clinical or chest X-ray abnormalities suggesting sarcoidosis. None of our patients with positive biopsy had nodular lesions.

Purpose: To assess outcomes and prognostic factors in radiotherapy of pediatric central nervous system atypical teratoid/rhabdoid tumor (AT/RT). Methods and Materials: Seventeen patients with central nervous system AT/RT were retrospectively reviewed after curative radiotherapy as primary or adjuvant therapy between January 1990 and December 2003. Overall and failure-free survival rates were calculated using the Kaplan–Meier method. The log–rank method was used to compare the effects of dosage (>50 Gy or ≤50 Gy) and treatment duration (>45 days or ≤45 days). Multivariate analysis was performed for prognostic factors. Results: Median overall survival and failure-free survival were 17 and 11 months, respectively. The 3 longest-surviving patients were older, underwent gross tumor removal, and completed both craniospinal and focal boost irradiation. Multivariate analysis revealed a significant relationship between the following: overall survival and performance status ( p = 0.019), failure-free survival and total irradiation dose ( p = 0.037), time interval between surgery and radiotherapy initiation ( p = 0.031), and time interval between surgery and radiotherapy end point ( p = 0.047). Conclusion: Radiotherapy is crucial in the treatment of AT/RT. We recommend initiating radiotherapy immediately postoperatively and before systemic chemotherapy in pediatric patients ≥3 years of age.

Summary Positron emission tomography (PET) allows examination of a variety of physiological parameter, including blood flow, glucose, amino acid and oxygen metabolism. However, correlation of PET scan findings and the degree of malignancy of intracerebral tumors continues to be controversial. Nine patients with primarily diagnosed intraparenchymal brain tumors were included in this study. We performed 11 C-methionine-PET (met-PET) prior to surgical treatment and the differential absorption ratio (DAR) was calculated. All patients underwent open or stereotactic surgery and specimens for pathological diagnosis were obtained. The biological activity of each tumor was determined by calculation of the proliferation index from MIB-1 immunohistochemistry. The DAR of met-PET for individual tumors correlated with the histological diagnosis and degree of malignancy and this was further confirmed by good correlation with the MIB-1 proliferation index. We conclude that met-PET may be a reliable and effective preoperative evaluation to determine the type and malignancy of intraparenchymal brain lesions.

Object. The authors conducted a study to determine the optimal radiation dose for vestibular schwannoma (VS) and to examine the histopathology in cases of treatment failure for better understanding of the effects of irradiation. Methods. A retrospective study was performed of 195 patients with VS; there were 113 female and 82 male patients whose mean age was 51 years (range 11–82 years). Seventy-two patients (37%) had undergone partial or total excision of their tumor prior to gamma knife surgery (GKS). The mean tumor volume was 4.1 cm3 (range 0.04–23.1 cm3). Multiisocenter dose planning placed a prescription dose of 11 to 18.2 Gy on the 50 to 94% isodose located at the tumor margin. Clinical and magnetic resonance (MR) imaging follow-up evaluations were performed every 6 months. A loss of central enhancement was demonstrated on MR imaging in 69.5% of the patients. At the latest MR imaging assessment decreased or stable tumor volume was demonstrated in 93.6% of the patients. During a median follow-up period of 31 months resection was avoided in 96.8% of cases. Uncontrolled tumor swelling was noted in five patients at 3.5, 17, 24, 33, and 62 months after GKS, respectively. Twelve of 20 patients retained serviceable hearing. Two patients experienced a temporary facial palsy. Two patients developed a new trigeminal neuralgia. There was no treatment-related death. Histopathological examination of specimens in three cases (one at 62 months after GKS) revealed a long-lasting radiation effect on vessels inside the tumor. Conclusions. Radiosurgery had a long-term radiation effect on VSs for up to 5 years. A margin 12-Gy dose with homogeneous distribution is effective in preventing tumor progression, while posing no serious threat to normal cranial nerve function.

One of the fundamental aspects of nitric oxide (NO) is the regulation of the inflammatory processes involved in neuronal apoptosis. Expressions of NO and NO synthase (NOS) are considered to be involved in brain tissue injuries and brain tumors. The purpose of our study was to investigate the roles of NO and inducible-form NOS (iNOS) in the pathogenesis of brain tumors. NO levels in the cerebrospinal fluid (CSF) of 36 brain tumor patients were detected utilizing the NO-chemiluminescence method. Deparaffinized tissue sections were immunostained for the presence of antibodies against iNOS and for apoptosis using the TUNEL stain. The results were compared with 10 control patients (with epilepsy and hydrocephalus). Higher levels of NO and iNOS activities may induce immune responses and neurotoxicities. This preliminary study revealed elevated NO and NOS activities with an increased amount of apoptotic processes in brain tumor tissues, which may indicate the possible roles of NO in the formation of brain tumors.

MIB-1 labeling index has been used as a complementary method to differentiate better and worse prognostic groups of astrocytic tumors. However, its reproducibility has been doubted because of the interlaboratory and interobserver variability. We studied the interobserver reproducibility of four manual counting methods of MIB-1 labeling index, including direct counting, area fraction, line intersection with a graticule, and line intersection without a graticule to estimate the total number of the cells. Using line intersection estimate, either with or without a graticule, yielded a worse result. Those MIB-1 labeling indices of astrocytomas were overlapping with those of anaplastic astrocytomas and glioblastomas. Besides, the intraclass correlation coefficient was smaller, and the coefficient of variation was greater than that attained when using a graticule and counting the total number of cells either directly or by area-fraction estimate. The level of interobserver agreement using an MIB-1 labeling index cutoff value of 11.0 was moderate to substantial when applying the line-intersection estimate, and it was almost perfect when applying the direct counting or the area-fraction estimate. The interobserver reproducibility and agreement of MIB-1 labeling index in astrocytic tumors were different depending on the counting methods. Direct counting with a graticule yielded the best result. Before establishing reference standards for staining and counting, the reproducibility of MIB-1 labeling index should be verified.

Neurogenic tumor of the lung is very uncommon. To the best of our knowledge, endobronchial schwannoma complicated by massive hemoptysis in a patient with neurofibromatosis 2 has not been reported previously. We report a case of endobronchial schwannoma complicated by massive hemoptysis in an 18-year-old man with neurofibromatosis 2. The diagnosis of neurofibromatosis 2 was established by demonstration of bilateral vestibular schwannomas on magnetic resonance imaging of the brain and pathologic examination of the resected brain tumors. Massive hemoptysis developed after surgical removal of the brain tumors in this patient. Bronchoscopy was done immediately after the first episode of hemoptysis and a tumor protruding from the orifice of the right lower lobe bronchus was found. Despite 2 additional bronchoscopies to stop bleeding and ameliorate airway obstruction in the consecutive 2 days, hemoptysis recurred rapidly and caused profound oxygen desaturation. The patient was subjected to right lower lobectomy and endobronchial schwannoma was evidenced pathologically.

Although there are criteria for interpretation of the staining results for Her-2/neu in the DAKO HercepTest, the determination of staining intensity and percentage of complete membrane staining is subjective. We studied 46 cases of invasive breast carcinoma to evaluate interobserver reproducibility among 5 pathologists. Complete agreement was achieved in 22 (48%) of 46 cases. Generalized kappa values indicated substantial agreement (0.80). Discrepancies between negative (0, 1+) and positive (2+, 3+) results occurred in 2 cases (kappa = 0.96). One was because of a tangential cut of the basal part of the tumor that mimicked complete membranous staining, and the other was a borderline case that revealed focal (5%-15%) complete membranous staining. Distinguishing weakly (2+) from strongly (3+) positive results showed agreement in only 13 (59%) of 22 positive cases (kappa = 0.38). If more than 50% of tumor cells revealing strong complete membrane staining were regarded as strongly positive, agreement would be improved (kappa = 0.78). While there was a high percentage (70%-80%) of negative cases during routine evaluation, the good interobserver agreement and high negative predictive value made immunohistochemical analysis an effective screening test to exclude negative cases.

BACKGROUND Although various histopathologic features have been associated with aggressive behavior or recurrence of meningiomas, there is little agreement about which features are the most important and in what combination. The objective of this study was to formulate diagnostic criteria for atypical meningioma. METHODS Eighty-three patients with meningiomas who underwent macroscopic total resection and had been followed until they developed recurrent disease or for at least 10 years were studied. Thirteen histopathologic parameters that related to recurrence of the tumor were evaluated in each patient. All possible combinations of histologic parameters that were related significantly to recurrence were used to formulate scoring models. The model that included the fewest parameters and that could distinguish tumor recurrence best within 10 years was chosen as the final model. RESULTS The final model included three parameters: loss of architecture, mitoses ≥ 1.5/mm2, and necrosis. Of the 52 tumors with a score < 2 (0 or 1 of the 3 parameters), all except 1 tumor did not recur within 10 years, and they were all considered benign meningiomas. Of the 31 tumors with a score ≥ 2 (2 or 3 of the 3 parameters), 94% recurred within 10 years (76% recurred within 5 years), and they were considered atypical meningiomas. The estimated 5-year and 10-year recurrence rates for the benign meningiomas were 0.0% and 1.9%, respectively, for benign meningiomas and 71.0% and 93.5%, respectively, for atypical meningiomas (P < 0.001). The estimated 5-year and 10-year mortality rates also were significantly different (0.0% and 0.0% vs. 22.1% and 26.7%, respectively; P < 0.001). The MIB-1 labeling index (LI) for the entire group studied ranged from 0.4 to 33.5 (mean LI, 8.4). Fifty-two tumors with an LI of < 10 did not recur within 10 years. Of the 31 tumors with an LI ≥ 10, 97% recurred (71% within 5 years). CONCLUSIONS Histopathology and MIB-1 LI were able to predict clinical outcomes of patients with meningioma. The authors propose that atypical meningioma may be diagnosed when two of the following three criteria are present: loss of architecture, mitoses ≥ 1.5/mm2, and necrosis. Cancer 2002;94:1538–47. © 2002 American Cancer Society. DOI 10.1002/cncr.10351

This study aimed to evaluate the treatment of intracranial nongerminomatous germ cell tumors (NGGCT) and to identify the prognostic factors for survival. Thirty-nine patients with nondisseminated NGGCTs, excluding those with pure mature teratomas, were treated between January 1985 and December 2010. Twenty-four patients received gross total or partial removal, 11 had excision biopsies, and 4 had no surgery. Radiotherapy was given postoperatively or definitively with a median tumor bed dose of 54 Gy (range 30–54) with or without craniospinal irradiation. All patients received ten cycles of adjuvant chemotherapy, vinblastine, bleomycin, etoposide, and cisplatin after radiotherapy, except for one with mixed anaplastic astrocytoma component who received oral temozolomide. Survival and prognostic factors were estimated by the Kaplan–Meier method and log-rank tests, respectively. After a median follow-up of 77.7 months (range 14–336), the 6-year overall survival (OS) and progression-free survival (PFS) were 74.4 and 79.5 %, respectively. Inferior PFS was associated with lesions in the suprasellar region (p = 0.017), poor pathological features (p = 0.048), and with poor image (p