Tai-Tong Wong

Identification of CD133-Positive Radioresistant Cells in Atypical Teratoid/ Rhabdoid Tumor

Atypical teratoid/rhabdoid tumor (AT/RT) is an extremely malignant neoplasm in the central nervous system (CNS) which occurs in infancy and childhood. Recent studies suggested that CD133 could be considered a marker for brain cancer stem-like cells (CSCs). However, the role of CD133 in AT/RT has never been investigated. Herein we report the isolation of CD133-positive cells (CD133+), found to have the potential to differentiate into three germ layer tissues, from tissues of nine AT/RT patients. The migration/invasion/malignancy and radioresistant capabilities of CD133+ were significantly augmented when compared to CD133−. The clinical data showed that the amount of CD133+ in AT/RTs correlated positively with the degree of resistance to radiation therapy. Using cDNA microarray analysis, the genotoxic–response profiles of CD133+ and CD133− irradiated with 10 Gy ionizing radiation (IR) were analyzed 0.5, 2, 6, 12 and 24 h post-IR. We then validated these microarray data and showed increased phosphorylation after IR of p-ATM, p-RAD17, and p-CHX2 as well as increased expression of BCL-2 protein in CD133+ compared to CD133−. Furthermore, we found that CD133+ can effectively resist IR with cisplatin- and/or TRAIL-induced apoptosis. Immunohistochemical analysis confirmed the up-regulated expression of p-ATM and BCL-2 proteins in IR-treated CD133+ xenotransgrafts in SCID mice but not in IR-treated CD133−. Importantly, the effect of IR in CD133+ transplanted mice can be significantly improved by a combination of BCL-2 siRNA with debromohymenialdisine, an inhibitor of checkpoint kinases. In sum, this is the first report indicating that CD133+ AT/RT cells demonstrate the characteristics of CSCs. The IR-resistant and anti-apoptotic properties in CD133+ may reflect the clinical refractory malignancy of AT/RTs and thus the activated p-ATM pathway and BCL-2 expression in CD133+ could be possible targets to improve future treatment of deadly diseases like AT/RT.

Atypical teratoid/rhabdoid tumor of the central nervous system: a comparative study with primitive neuroectodermal tumor/medulloblastoma

Abstract Eleven atypical teratoid/rhabdoid tumors (AT/¶RT) and 121 primitive neuroectodermal tumors/medulloblastomas (PNET/MB) were included in this study for evaluation of the histopathological features of AT/RT and comparison between AT/RT and PNET/MB. Histopathological studies of AT/RT showed that in addition to the commonly recognized components, i.e., rhabdoid cells, small (PNET/MB) cells, spindle cells and epithelial components, there was a previously unrecognized component, sickle-shaped embracing cells, which were present in all cases and could be useful as a histological marker of this tumor. Immunohistochemical studies showed divergent differentiation of the tumor cells and among the 16 antibodies studied, vimentin, neuron-specific enolase, epithelial membrane antigen and glial fibrillary acidic protein were most commonly reactive. The frequency of AT/RT expressed as a ratio of AT/RT to PNET/MB was 1 : 11 in general and increased to 1 : 3.8 among patients younger than 3 years old. The AT/RT patients were younger than those with PNET/MB and had a female predominance. The MIB-1 labeling index of AT/RT was significantly higher than that of PNET/MB (mean 63.9 vs 40.1), which correlated with a shorter survival in patients with AT/¶RT than those with PNET/MB (median survival time ¶15.4 months vs 156.4 months).

A clinicopathologic study of 81 patients with ependymomas and proposal of diagnostic criteria for anaplastic ependymoma.

Optimal histologic criteria for the classification of and grading of ependymomas, including their anaplastic forms, remain elusive. This is especially true because of the poor correlation of these criteria with clinical outcome. The aim of this study was to identify the histopathologic parameters that could distinguish different prognostic groups of patients with ependymomas. Eighty-one patients with ependymal tumors, including those originally diagnosed ependymomas, anaplastic ependymomas and myxopapillary ependymomas, were enrolled in this study. Thirteen histologic parameters, including hypercellularity, nuclear pleomorphism, mitoses, endothelial proliferation, necrosis, clear cell, thrombi, dystrophic calcification, psammoma bodies, bone, cartilage, Rosenthal fibers and MIB-1 labeling index (LI), were evaluated in each patient and correlated with clinical outcome. We assigned one score for each histopathologic parameter evaluated and used a stepwise selection method with entry model based on the significance of the log-rank statistic to formulate a scoring model. Four parameters were chosen in this process, including mitoses ≥ 4/10 hpf (1.7/mm2), hypercellularity, endothelial proliferation and necrosis. The sum of these four parameters (scores) was the histopathologic score of the tumor. The progression-free survival (PFS) and overall survival (OS) of patients with histopathologic scores 0 and 1 were significantly better than those with histopathologic scores 2, 3 and 4 (p < 0.001 and p = 0.005, respectively). Because of the latter finding, we proposed that anaplastic ependymoma could be diagnosed by the presence of any two of the aforementioned four parameters. Multivariate analyses including clinical and histopathologic variables showed that histopathologic score ≥ 2 and subtotal resection were the factors related to increased risk of recurrence, while histopathologic score ≥ 2 was the only factor related to overall survival. Based on the above findings, we concluded that histopathology is an important prognostic indicator for patients with ependymomas.

Magnetoencephalographic yield of interictal spikes in temporal lobe epilepsy: Comparison with scalp EEG recordings

To compare magnetoencephalography (MEG) with scalp electroencephalography (EEG) in the detection of interictal spikes in temporal lobe epilepsy (TLE), we simultaneously recorded MEG and scalp EEG with a whole-scalp neuromagnetometer in 46 TLE patients. We visually searched interictal spikes on MEG and EEG channels and classified them into three types according to their presentation on MEG alone (M-spikes), EEG alone (E-spikes), or concomitantly on both modalities (M/E-spikes). The M-spikes and M/E-spikes were localized with MEG equivalent current dipole modeling. We analyzed the relative contribution of MEG and EEG in the overall yield of spike detection and also compared M-spikes with M/E-spikes in terms of dipole locations and strengths. During the 30- to 40-min MEG recordings, interictal spikes were obtained in 36 (78.3%) of the 46 patients. Among the 36 patients, most spikes were M/E-spikes (68.3%), some were M-spikes (22.1%), and some were E-spikes (9.7%). In comparison with EEG, MEG gave better spike yield in patients with lateral TLE. Sources of M/E- and M-spikes were situated in the same anatomical regions, whereas the average dipole strength was larger for M/E- than M-spikes. In conclusion, some interictal spikes appeared selectively on either MEG or EEG channels in TLE patients although more spikes were simultaneously identified on both modalities. Thus, simultaneous MEG and EEG recordings help to enhance spike detection. Identification of M-spikes would offer important localization of irritative foci, especially in patients with lateral TLE.

Quality of Life and Life Satisfaction in Families After a Child Has Undergone Corpus Callosotomy

: Epilepsy is a chronic neurological condition which can have a detrimental effect on patients’quality of life (QOL). We evaluated the overall satisfaction with QOL and changes in QOL in 25 families with children who had undergone corpus callosotomy for severe epilepsy. The mean age of seizure onset was 3.4 years, and the mean period from seizure onset to operation was 5.2 years. Mean follow‐up was 19.3 months. Twenty of 22 patients had various degrees of mental retardation. Mean reduction in severity of seizure activity was 64%. Nineteen of 25 (76%) parents were satisfied with the surgical result. Eighteen of 25 parents (72%) described a good level of satisfaction with their families QOL after callosotomy. Reduction in severity of seizure activity was significantly correlated with how successful families considered the surgery to be and how satisfied they were with their QOL (r= 0.72 and 0.77, respectively). Life domains showing one greatest improvement after callosotomy included level of self‐care, family life, and school performance. Improvements in level of self‐care, family life, and school performance were associated with higher levels of life satisfaction (r= 0.69, 0.60, and 0.59, respectively). Hyperactivity, attention span, and social skills improved significantly in 11 patients after surgery. Callosotomy did not improve mental performance. We conclude that improved seizure control after callosotomy is also associated with improved QOL.

YM500: a small RNA sequencing (smRNA-seq) database for microRNA research

MicroRNAs (miRNAs) are small RNAs ∼22 nt in length that are involved in the regulation of a variety of physiological and pathological processes. Advances in high-throughput small RNA sequencing (smRNA-seq), one of the next-generation sequencing applications, have reshaped the miRNA research landscape. In this study, we established an integrative database, the YM500 (http://ngs.ym.edu.tw/ym500/), containing analysis pipelines and analysis results for 609 human and mice smRNA-seq results, including public data from the Gene Expression Omnibus (GEO) and some private sources. YM500 collects analysis results for miRNA quantification, for isomiR identification (incl. RNA editing), for arm switching discovery, and, more importantly, for novel miRNA predictions. Wetlab validation on >100 miRNAs confirmed high correlation between miRNA profiling and RT-qPCR results (R = 0.84). This database allows researchers to search these four different types of analysis results via our interactive web interface. YM500 allows researchers to define the criteria of isomiRs, and also integrates the information of dbSNP to help researchers distinguish isomiRs from SNPs. A user-friendly interface is provided to integrate miRNA-related information and existing evidence from hundreds of sequencing datasets. The identified novel miRNAs and isomiRs hold the potential for both basic research and biotech applications.

DriverDB: an exome sequencing database for cancer driver gene identification

Exome sequencing (exome-seq) has aided in the discovery of a huge amount of mutations in cancers, yet challenges remain in converting oncogenomics data into information that is interpretable and accessible for clinical care. We constructed DriverDB (http://ngs.ym.edu.tw/driverdb/), a database which incorporates 6079 cases of exome-seq data, annotation databases (such as dbSNP, 1000 Genome and Cosmic) and published bioinformatics algorithms dedicated to driver gene/mutation identification. We provide two points of view, ‘Cancer’ and ‘Gene’, to help researchers to visualize the relationships between cancers and driver genes/mutations. The ‘Cancer’ section summarizes the calculated results of driver genes by eight computational methods for a specific cancer type/dataset and provides three levels of biological interpretation for realization of the relationships between driver genes. The ‘Gene’ section is designed to visualize the mutation information of a driver gene in five different aspects. Moreover, a ‘Meta-Analysis’ function is provided so researchers may identify driver genes in customer-defined samples. The novel driver genes/mutations identified hold potential for both basic research and biotech applications.

Change in treatment strategy for intracranial germinoma: Long-term follow-up experience at a single institute

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.

Optimal Treatment for Intracranial Germinoma: Can We Lower Radiation Dose Without Chemotherapy?

PURPOSE To review the effectiveness of reduced-dose and restricted-volume radiation-only therapy in the treatment of intracranial germinoma and to assess the feasibility of reducing or eliminating the use of chemotherapy. METHODS AND MATERIALS Between January 1996 and March 2007, a retrospective analysis was performed that included 38 patients who received either reduced radiation alone (30 Gy for 26 patients) or reduced radiation with chemotherapy (n = 12 patients). All 38 patients received extended focal (including whole-ventricle) irradiation and were followed up until February 2008. Overall survival (OS) and relapse-free survival (RFS) rates were calculated. Variables associated with survival were evaluated by univariate Cox proportional hazards regression. RESULTS Median follow-up was 62.4 months (range, 10.1-142.5 months). The total 5-year OS rate was 93.7%. The 5-year OS and RFS rates for patients receiving radiation only were 100% and 96.2%, respectively. The rates for those receiving radiation plus chemotherapy were 83.3 % and 91.7%, respectively (not statistically significant). No predictive factor was significantly associated with the OS or RFS rate. Chemotherapy had no significant effect on survival but was associated with a higher incidence of treatment-related toxicity. CONCLUSIONS A further decrease in the radiation dose to 30 Gy with whole-ventricle irradiation is sufficient to treat selected patients with intracranial germinoma. Wide-field irradiation or chemotherapy should be avoided as these methods are unnecessary. Thus, reduction of the radiation dose to 30 Gy may be feasible, even without chemotherapy.

Choroid plexus tumors in childhood

Choroid plexus tumors are rare and account for only 2.3% (8/352) of primary childhood intracranial neoplasms in our series. Most of our patients were under 2 years of age. The tumors had a predilection for the lateral ventricle. Calcification was found in half of these tumors, and ossification was seen in 1 case. Histological features of malignancy including invasion, loss of differentiation, and severe nuclear pleomorphism pointed to a poor prognosis. Such features were found in 2 cases. Neither a large number of mitoses nor necrosis was a constant feature in cases of malignancy. Transthyretin, a marker for choroid plexus tumors, was positive in all cases. However, negative S-100 or positive carcinoembryonic antigen was not necessarily associated with a more aggressive histological pattern. All the papillomas could be totally resected without recurrence, and all the patients with carcinoma died within a few months.