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Find video protocols related to scientific articles indexed in Pubmed.
Practice patterns of post-radical prostatectomy incontinence surgery in Ontario.
Can Urol Assoc J
PUBLISHED: 11-20-2014
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We assess the practice patterns of artificial urinary sphincter (AUS) and urethral sling insertion after radical prostatectomy (RP) from a large population-based cohort.
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Chromosomal Instability in Cell-Free DNA Is a Serum Biomarker for Prostate Cancer.
Clin. Chem.
PUBLISHED: 10-29-2014
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Genomic instability resulting in copy number variation is a hallmark of malignant transformation and may be identified through massive parallel sequencing. Tumor-specific cell free DNA (cfDNA) present in serum and plasma provides a real-time, easily accessible surrogate.
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RRAD Promotes EGFR-Mediated STAT3 Activation and Induces Temozolomide Resistance of Malignant Glioblastoma.
Mol. Cancer Ther.
PUBLISHED: 10-13-2014
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Glioblastoma multiforme (GBM) is an extremely aggressive brain cancer with a median survival of less than two years. GBM is characterized by abnormal activation of receptor tyrosine kinase and constitutively activated STAT3. Although EGFR phosphorylation and STAT3 activation are essential for the maintenance of GBM cancer stem cells, the molecular mechanism underlying endosome-mediated STAT3 activation is not fully understood at present. In the current study, we showed that GTP-binding protein RRAD (RAS associated with diabetes, RAD) physically associates with EGFR, and EEA1, enhancing the stability and endosome-associated nuclear translocation of EGFR. Functionally, RRAD contributes to the activation of STAT3 and expression of the stem cell factors, OCT4, NANOG, and SOX2, thereby enhancing self-renewing ability, tumor sphere formation, EMT, and in vivo tumorigenesis. Most importantly, RRAD contributes to poor survival in GBM patients. RRAD expression is correlated with temozolomide resistance, and conversely, depletion of RRAD leads to sensitization of highly temozolomide-resistant GBM cells. Our data collectively support a novel function of RRAD in STAT3 activation, and provide evidence that RRAD acts as a positive regulator in the EGFR signaling pathway. These results demonstrate a critical role for RRAD in GBM tumorigenesis, and provide a rationale for the development of pharmacological inhibitors of RRAD in GBM.
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Small cell neuroendocrine carcinoma of the endometrium: A clinicopathologic study of six cases.
Taiwan J Obstet Gynecol
PUBLISHED: 10-08-2014
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Primary small cell carcinoma of the endometrium is a rare disease that can only be diagnosed at an advanced stage, and thus has a poor prognosis. In this study, the clinicopathologic characteristics of endometrial small cell carcinoma are described and the survival outcomes are discussed.
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Nanoparticle-Mediated Binning and Profiling of Heterogeneous Circulating Tumor Cell Subpopulations.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 09-22-2014
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The analysis of circulating tumor cells (CTCs) is an important capability that may lead to new approaches for cancer management. CTC capture devices developed to date isolate a bulk population of CTCs and do not differentiate subpopulations that may have varying phenotypes with different levels of clinical relevance. Here, we present a new device for CTC spatial sorting and profiling that sequesters blood-borne tumor cells with different phenotypes into discrete spatial bins. Validation data are presented showing that cancer cell lines with varying surface expression generate different binning profiles within the device. Working with patient blood samples, we obtain profiles that elucidate the heterogeneity of CTC populations present in cancer patients and also report on the status of CTCs within the epithelial-to-mesenchymal transition (EMT).
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Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.
Lancet Oncol.
PUBLISHED: 08-19-2014
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Cilengitide is a selective ?v?3 and ?v?5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter.
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Laparoendoscopic single-site versus conventional laparoscopic-assisted vaginal hysterectomy for benign or pre-invasive uterine disease.
Surg Endosc
PUBLISHED: 08-09-2014
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The aim of this study was to compare the surgical outcomes of laparoendoscopic single-site (LESS) versus conventional laparoscopic-assisted vaginal hysterectomy (LAVH) in patients with benign or pre-invasive uterine disease.
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Reliability of tumour grade 1 and endometrioid cell type on preoperative endometrial biopsy.
J Obstet Gynaecol
PUBLISHED: 08-06-2014
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The aim of this study was to evaluate the reliability of using tumour grade and cell type on preoperative endometrial biopsy for the selection of patients for conservative hormone treatment. We retrospectively reviewed results of 643 patients with endometrial carcinoma for tumour grade and 817 for tumour cell type who underwent endometrial biopsy followed by surgery. Of the 357 patients with a grade 1 tumour on preoperative endometrial biopsy, 58 (16.2%) were upgraded based on a final pathology report from hysterectomy specimens. For grade 1, the preoperative endometrial biopsy showed a sensitivity of 80.4%, a specificity of 78.6%, a positive predictive value (PPV) of 83.8% and a negative predictive value (NPV) of 74.5%. Of the 672 patients with the endometrioid cell type on preoperative biopsy, 46 (5.6%) showed a different cell type on final pathology. For the endometrioid cell type, preoperative endometrial biopsy had a sensitivity of 91.3%, a specificity of 64.9%, a PPV of 93.2% and an NPV of 58.6%. This weak predictive value should be considered when selecting patients for conservative hormone treatment.
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Comparison of adenocarcinoma and adenosquamous carcinoma in patients with early-stage cervical cancer after radical surgery.
Gynecol. Oncol.
PUBLISHED: 06-26-2014
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To compare outcomes after radical hysterectomy in patients with stage IB1 adenocarcinoma (AdCa) and adenosquamous carcinoma (AdSCCa) of the uterine cervix.
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KML001, a telomere-targeting drug, sensitizes glioblastoma cells to temozolomide chemotherapy and radiotherapy through DNA damage and apoptosis.
Biomed Res Int
PUBLISHED: 06-26-2014
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Standard treatment for glioblastoma comprises surgical resection, chemotherapy with temozolomide, and radiotherapy. Nevertheless, majority of glioblastoma patients have recurrence from resistance to the cytotoxic conventional therapies. We examined combinational effects of KML001, an arsenic compound targeting telomeres of chromosomes with temozolomide or irradiation, in glioblastoma cell lines and xenograft models, to overcome the therapeutic limitation of chemoradiation therapy for glioblastoma. Although KML001 alone showed little effects on in vitro survival of glioblastoma cells, cell death by in vitro temozolomide treatment or irradiation was synergistically potentiated by combination with KML001. Since phosphorylated ?-H2AX, cleaved casepase-3, and cleaved PARP were dramatically increased by KML001, the synergistic effects would be mediated by increased DNA damage and subsequent tumor cell apoptosis. Combinatorial effects of KML001 were observed not only in chemo- and radiosensitive glioblastoma cell line, U87MG, but also in the resistant cell line, U251MG. In the U87MG glioblastoma xenograft models, KML001 did not have systemic toxicity but showed synergistic therapeutic effects in combination with temozolomide or irradiation to reduce tumor volumes significantly. These data indicated that KML001 could be a candidate sensitizer to potentiate therapeutic effects of conventional cytotoxic treatment for glioblastoma.
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Fractionated Gamma Knife Radiosurgery for Benign Perioptic Tumors: Outcomes of 38 Patients in a Single Institute.
Brain Tumor Res Treat
PUBLISHED: 06-10-2014
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This study was performed to evaluate the efficacy and safety of fractionated Gamma Knife radiosurgery (GKRS) for perioptic lesions.
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TopBP1 and Claspin contribute to the radioresistance of lung cancer brain metastases.
Mol. Cancer
PUBLISHED: 05-11-2014
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Radiation therapy is one of the most effective therapeutic tools for brain metastasis. However, it is inevitable that some cancer cells become resistant to radiation. This study is focused on the identification of genes associated with radioresistance in metastatic brain tumor from lung cancer and the functional examination of the selected genes with regards to altered sensitivity of cancer cells to radiation.
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Tpl2 induces castration resistant prostate cancer progression and metastasis.
Int. J. Cancer
PUBLISHED: 04-22-2014
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Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC.
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Laparotomy conversion rate of laparoscopic radical hysterectomy for early-stage cervical cancer in a consecutive series without case selection.
Ann. Surg. Oncol.
PUBLISHED: 04-21-2014
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To estimate the feasibility and conversion rate of laparoscopic radical hysterectomy (LRH) in early-stage cervical cancer.
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High-Throughput, Miniaturized Clonogenic Analysis of a Limiting Dilution Assay on a Micropillar/Microwell Chip with Brain Tumor Cells.
Small
PUBLISHED: 04-18-2014
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The limiting dilution assay (LDA) is a clonogenic drug efficacy test designed to determine a value for drug efficacy based on an all-or-none (positive or negative) response within replicates. It also attempts to calculate minimum cell numbers for cells to form colony in each drugged conditions, wherein a large value implies high drug efficacy (as a large number of extant cells are required to start a colony). However, traditional LDAs are time-consuming to set up, often requiring many replicates for statistical analysis, and manual colony identification under a microscope to determine a positive or negative response is tedious and is susceptible to human error. To address these issues, a high-throughput miniaturized LDA assay is developed using a micropillar/microwell chip platform using an automatic colony identification method. Three glioblastoma multiforme (GBM) brain tumor isolates (448T, 464T, and 775T) are used to test this new assay, using the c-Met kinase inhibitors SU11274 and PHA665752 as the target drugs. The results show that the minimum cell number of 775T is larger than that of the other two cell types (SU11274 and PHA665752) in both the sampled drugs, a result that is in good agreement with the results of previous conventional experiments using 96 well plates.
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Global transcriptome analysis of formalin-fixed prostate cancer specimens identifies biomarkers of disease recurrence.
Cancer Res.
PUBLISHED: 04-08-2014
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Prostate cancer remains the second leading cause of cancer death in American men and there is an unmet need for biomarkers to identify patients with aggressive disease. In an effort to identify biomarkers of recurrence, we performed global RNA sequencing on 106 formalin-fixed, paraffin-embedded prostatectomy samples from 100 patients at three independent sites, defining a 24-gene signature panel. The 24 genes in this panel function in cell-cycle progression, angiogenesis, hypoxia, apoptosis, PI3K signaling, steroid metabolism, translation, chromatin modification, and transcription. Sixteen genes have been associated with cancer, with five specifically associated with prostate cancer (BTG2, IGFBP3, SIRT1, MXI1, and FDPS). Validation was performed on an independent publicly available dataset of 140 patients, where the new signature panel outperformed markers published previously in terms of predicting biochemical recurrence. Our work also identified differences in gene expression between Gleason pattern 4 + 3 and 3 + 4 tumors, including several genes involved in the epithelial-to-mesenchymal transition and developmental pathways. Overall, this study defines a novel biomarker panel that has the potential to improve the clinical management of prostate cancer.
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Feasibility and Safety of Laparoscopic Surgery for Obese Korean Women with Endometrial Cancer: Long-Term Results at a Single Institution.
J. Korean Med. Sci.
PUBLISHED: 03-19-2014
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The purpose of this study was to evaluate the surgical feasibility of and survival outcome after laparoscopy in obese Korean women with endometrial cancer which has recently been increasing. We reviewed the medical records of the patients treated at our medical institution between 1999 and 2012. The patients were divided into three groups, non-obese (Body Mass Index [BMI]<25.0), overweight (BMI 25-27.99), and obese (BMI?28.0). These patient groups were compared in terms of their clinical characteristics, treatment methods, as well as surgical and survival outcomes. In total, 55 of the 278 eligible patients were obese women. There were no differences in the three groups in terms of the proportion of patients who underwent lymphadenectomy, their cancer stage, histologic type, type of adjuvant treatment administered, intra-, post-operative, and long-term complications, operative time, number of removed lymph nodes, blood loss, and duration of hospitalization (P=0.067, 0.435, 0.757, 0.739, 0.458, 0.173, 0.076, 0.124, 0.770, 0.739, and 0.831, respectively). The Disease-Free Survival (DFS) times were 139.1 vs. 121.6 vs. 135.5 months (P=0.313), and the Overall Survival (OS) times were 145.2 vs. 124.8 vs. 139.5 months (P=0.436) for each group, respectively. Obese women with endometrial cancer can, therefore, be as safely managed using laparoscopy as women with normal BMIs.
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Impact of body mass index on the prognosis of Korean women with endometrioid adenocarcinoma of the uterus: A cohort study.
Obstet Gynecol Sci
PUBLISHED: 03-15-2014
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To analyze how pretreatment body mass index relates to known endometrial cancer prognostic factors and how it impacts the disease-free survival and cause-specific survival of Korean women with endometrial cancer.
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Patterns of somatic alterations between matched primary and metastatic colorectal tumors characterized by whole-genome sequencing.
Genomics
PUBLISHED: 02-25-2014
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Colorectal cancer (CRC) patients have poor prognosis after formation of distant metastasis. Understanding the molecular mechanisms by which genetic changes facilitate metastasis is critical for the development of targeted therapeutic strategies aimed at controlling disease progression while minimizing toxic side effects. A comprehensive portrait of somatic alterations in CRC and the changes between primary and metastatic tumors has yet to be developed. We performed whole genome sequencing of two primary CRC tumors and their matched liver metastases. By comparing to matched germline DNA, we catalogued somatic alterations at multiple scales, including single nucleotide variations, small insertions and deletions, copy number aberrations and structural variations in both the primary and matched metastasis. We found that the majority of these somatic alterations are present in both sites. Despite the overall similarity, several de novo alterations in the metastases were predicted to be deleterious, in genes including FBXW7, DCLK1 and FAT2, which might contribute to the initiation and progression of distant metastasis. Through careful examination of the mutation prevalence among tumor cells at each site, we also proposed distinct clonal evolution patterns between primary and metastatic tumors in the two cases. These results suggest that somatic alterations may play an important role in driving the development of colorectal cancer metastasis and present challenges and opportunities when considering the choice of treatment.
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Outcome of conventional treatment and prognostic factor in elderly glioblastoma patients.
Acta Neurochir (Wien)
PUBLISHED: 01-30-2014
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Glioblastoma (GBM) is the most life-threatening primary brain tumour. Especially in elderly patients, a poorer outcome is noticeable. Until now, the effectiveness of the conventional active treatment has been controversial. The purpose of this study is to find the optimal treatment for elderly patients with newly diagnosed GBM.
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Efficacy of postoperative radiotherapy for high grade meningiomas.
J. Neurooncol.
PUBLISHED: 01-29-2014
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The necessity of postoperative radiotherapy (PORT) for meningiomas remains contentious. Here, the role of PORT in patients who underwent surgical resection for WHO grade II and III meningiomas was assessed. The record of 114 patients with WHO grade II (n = 72) and III (n = 42) meningiomas treated at Samsung Medical Center between March 1995 and April 2013 were reviewed and classified according to the extent of surgical resection and implementation of PORT. Median follow-up was 55.9 months. Simpson grade (SG) I, II, III, and IV resections were achieved in 29, 56, 9 and 20 patients, respectively. The 5-year local control (LC) and overall survival rate was 65.8 and 84.2 %, respectively. Thirty patients (26.3 %) developed local failure and five patients (4.4 %) developed distant metastases. The extent of surgical resection (SG I-II vs. III-IV) was influenced by tumor location (orbital and skull base lesions vs. others, p = 0.001) and the surgeons' experience (>10 operations, p = 0.044). Extent of surgical resection was also associated with local failure, overall progression, and overall survival (p = 0.001, p < 0.001, and p < 0.001, respectively). PORT improved LC in patients with incomplete surgical resection (SG III-IV, p = 0.049). Complete resection (SG I-II) is an important prognostic factor for LC and survival, and the extent of surgical resection (SG I-II vs. III-IV) is influenced by tumor location. PORT could improve the LC in WHO grade II-III meningioma patients who underwent incomplete surgical resection (SG III-IV).
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Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study.
Lancet Oncol.
PUBLISHED: 01-17-2014
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Studies of complications resulting from surgery or radiotherapy for prostate cancer have mainly focused on incontinence and erectile dysfunction. We aimed to assess other important complications associated with these treatments for prostate cancer.
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Long-term outcomes after fertility-sparing laparoscopic radical trachelectomy in young women with early-stage cervical cancer: an Asan Gynecologic Cancer Group (AGCG) study.
J Surg Oncol
PUBLISHED: 01-08-2014
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To evaluate the long-term outcomes and risk factors for recurrence after fertility-sparing laparoscopic radical trachelectomy (LRT) in young women with early-stage cervical cancer.
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Targeting the epithelial to mesenchymal transition in glioblastoma: the emerging role of MET signaling.
Onco Targets Ther
PUBLISHED: 01-01-2014
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Glioblastoma multiforme (GBM) is the most common human primary brain malignancy and has a dismal prognosis. Aggressive treatments using maximal surgical resection, radiotherapy, and temozolomide result in median survival of only 14.6 months in patients with GBM. Numerous clinical approaches using small molecule inhibitors have shown disappointing results because of the genetic heterogeneity of GBM. The epithelial to mesenchymal transition (EMT) is a crucial biological process occurring in the early development stages of many species. However, cancer cells often obtain the ability to invade and metastasize through the EMT, which triggers the scattering of cells. The hepatocyte growth factor (HGF)/MET signaling pathway is indicative of the EMT during both embryogenesis and the invasive growth of tumors, because HGF potently induces mesenchymal transition in epithelial-driven cells. Activation of MET signaling or co-overexpression of HGF and MET frequently represents aggressive growth and poor prognosis of various cancers, including GBM. Thus, efforts to treat cancers by inhibiting MET signaling using neutralizing antibodies or small molecule inhibitors have progressed during the last decade. In this review, we discuss HGF/MET signaling in the development of diseases, including cancers, as well as updates on MET inhibition therapy.
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Human kallikrein-2 gene and protein expression predicts prostate cancer at repeat biopsy.
Springerplus
PUBLISHED: 01-01-2014
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The human kallikrein-2 (hK2) protein and two single nucleotide polymorphism (SNPs) (rs2664155, rs198977) of the gene are associated with prostate cancer risk. We examined whether hK2 protein and gene SNPs predict prostate cancer at the time of repeat biopsy.
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Translational validation of personalized treatment strategy based on genetic characteristics of glioblastoma.
PLoS ONE
PUBLISHED: 01-01-2014
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Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. The Cancer Genome Atlas (TCGA) Research Network has been established the comprehensive genomic abnormalities of GBM, which sub-classified GBMs into 4 different molecular subtypes. The molecular subtypes could be utilized to develop personalized treatment strategy for each subtype. We applied a classifying method, NTP (Nearest Template Prediction) method to determine molecular subtype of each GBM patient and corresponding orthotopic xenograft animal model. The models were derived from GBM cells dissociated from patient's surgical sample. Specific drug candidates for each subtype were selected using an integrated pharmacological network database (PharmDB), which link drugs with subtype specific genes. Treatment effects of the drug candidates were determined by in vitro limiting dilution assay using patient-derived GBM cells primarily cultured from orthotopic xenograft tumors. The consistent identification of molecular subtype by the NTP method was validated using TCGA database. When subtypes were determined by the NTP method, orthotopic xenograft animal models faithfully maintained the molecular subtypes of parental tumors. Subtype specific drugs not only showed significant inhibition effects on the in vitro clonogenicity of patient-derived GBM cells but also synergistically reversed temozolomide resistance of MGMT-unmethylated patient-derived GBM cells. However, inhibitory effects on the clonogenicity were not totally subtype-specific. Personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs, although more sophisticated classifying techniques and subtype specific drugs need to be further elucidated.
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Analysis and comparison of somatic mutations in paired primary and recurrent epithelial ovarian cancer samples.
PLoS ONE
PUBLISHED: 01-01-2014
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The TP53 mutations have been proved to be predominated in ovarian cancer in a study from The Cancer Genome Atlas (TCGA). However, the molecular characteristics of recurrent ovarian cancers following initial treatment have been poorly estimated. This study was to investigate the pattern of somatic point mutations in matched paired samples of primary and recurrent epithelial ovarian cancers, using the OncoMap mutation detection protocol. We have adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. OncoMap v.4.4 was used to evaluate genomic DNA isolated from a set of 92 formalin-fixed, paraffin-embedded (FFPE) tumors, consisting of matched paired samples of initially diagnosed and recurrent tumors from 46 epithelial ovarian cancer (EOC) patients. Mutations were observed in 33.7% of the samples, with 29.3% of these samples having a single mutation and the remaining 4.3% having two or more mutations. Among the 41 genes analyzed, 35 mutations were found in four genes, namely, CDKN2A (2.2%), KRAS (6.5%), MLH1 (8.2%) and TP53 (20.7%). TP53 was the most frequently mutated gene, but there was no correlation between the presence of mutation in any gene and clinical prognosis. Furthermore, somatic mutations did not differ between primary and recurrent ovarian carcinomas. Every mutation present in recurrent samples was detected in the corresponding primary sample. In conclusion, these OncoMap data of Korean EOC samples provide that somatic mutations were found in CDKN2A, KRAS, MLH1, and TP53. No differences in mutational status between primary and recurrent samples were detected. To understand the biology of tumor recurrence in epithelial ovarian cancer, more studies are necessary, including epigenetic modifications or additional mutations in other genes.
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NTRK1 fusion in glioblastoma multiforme.
PLoS ONE
PUBLISHED: 01-01-2014
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Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor, yet with no targeted therapy with substantial survival benefit. Recent studies on solid tumors showed that fusion genes often play driver roles and are promising targets for pharmaceutical intervention. To survey potential fusion genes in GBMs, we analysed RNA-Seq data from 162 GBM patients available through The Cancer Genome Atlas (TCGA), and found that 3' exons of neurotrophic tyrosine kinase receptor type 1 (NTRK1, encoding TrkA) are fused to 5' exons of the genes that are highly expressed in neuronal tissues, neurofascin (NFASC) and brevican (BCAN). The fusions preserved both the transmembrane and kinase domains of NTRK1 in frame. NTRK1 is a mediator of the pro-survival signaling of nerve growth factor (NGF) and is a known oncogene, found commonly altered in human cancer. While GBMs largely lacked NTRK1 expression, the fusion-positive GBMs expressed fusion transcripts in high abundance, and showed elevated NTRK1-pathway activity. Lentiviral transduction of the NFASC-NTRK1 fusion gene in NIH 3T3 cells increased proliferation in vitro, colony formation in soft agar, and tumor formation in mice, suggesting the possibility that the fusion contributed to the initiation or maintenance of the fusion-positive GBMs, and therefore may be a rational drug target.
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Genetically-engineered Human Neural Stem Cells with Rabbit Carboxyl Esterase Can Target CNS Lymphoma.
Anticancer Res.
PUBLISHED: 12-11-2013
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Despite advances in its treatment, CNS lymphoma remains a devastating disease. Taking advantage of the tumour-tropic properties of neural stem cells (NSCs) is a novel therapeutic strategy. To apply this strategy to the treatment of CNS lymphoma, we investigated the role of NSCs expressing carboxyl esterase (HB1.F3.CE), which activates irinotecan.
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High-Throughput Screening (HTS) of Anticancer Drug Efficacy on a Micropillar/Microwell Chip Platform.
Anal. Chem.
PUBLISHED: 12-02-2013
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Contemporary cancer therapy refers to treatment based on genetic abnormalities found in patients tumor. However, this approach is faced with numerous challenges, including tumor heterogeneity and molecular evolution, insufficient tumor samples available along with genetic information linking to clinical outcomes, lack of therapeutic drugs containing pharmacogenomic information, and technical limitations of rapid drug efficacy tests with insufficient quantities of primary cancer cells from patients. To address these problems and improve clinical outcomes of current personalized gene-targeted cancer therapy, we have developed a micropillar/microwell chip platform, which is ideally suited for encapsulating primary cancer cells in nanoscale spots of hydrogels on the chip, generating efficacy data with various drugs, eventually allowing for a comparison of the in vitro data obtained from the chip with clinical data as well as gene expression data. As a proof of concept in this study, we have encapsulated a U251 brain cancer cell line and three primary brain cancer cells from patients (448T, 464T, and 775T) in 30 nL droplets of alginate and then tested the therapeutic efficacy of 24 anticancer drugs by measuring their dose responses. As a result, the IC50 values of 24 anticancer drugs obtained from the brain cancer cells clearly showed patient cell-specific efficacy, some of which were well-correlated with their oncogene overexpression (c-Met and FGFR1) as well as the in vivo previous results of the mouse xenograft model with the three primary brain cancer cells.
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Preoperative fluorine 18 fluorodeoxyglucose tumoral uptake ratio between upper and lower abdomen in primary advanced-stage ovarian cancer.
Int. J. Gynecol. Cancer
PUBLISHED: 11-22-2013
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The objective of this study was to assess whether the ratio of upper abdomen (UA) to lower abdomen (LA) (relative to the umbilicus) standardized fluorine 18 fluorodeoxyglucose uptake, as measured by preoperative positron emission tomography and computed tomography, is predictive of recurrence, survival, and suboptimal cytoreduction (residual tumor >1.0 cm) in advanced-stage ovarian cancer (AOC).
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Colorectal cancer patient-derived xenografted tumors maintain characteristic features of the original tumors.
J. Surg. Res.
PUBLISHED: 10-11-2013
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Despite significant improvements in colon cancer outcomes over the past few decades, preclinical development of more effective therapeutic strategies is still limited by the availability of clinically relevant animal models. To meet those clinical unmet needs, we generated a well-characterized in vivo preclinical platform for colorectal cancer using fresh surgical samples.
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Alpha-smooth muscle actin (ACTA2) is required for metastatic potential of human lung adenocarcinoma.
Clin. Cancer Res.
PUBLISHED: 08-30-2013
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Metastatic relapse of primary lung cancer leads to therapeutic resistance and unfavorable clinical prognosis; therefore, identification of key molecules associated with metastatic conversion has significant clinical implications. We previously identified a link between early brain metastasis of lung adenocarcinoma and amplification of the ?-smooth muscle actin (ACTA2) gene. The aim of present study was to investigate the prognostic and functional significance of ACTA2 expression in cancer cells for the metastatic potential of lung adenocarcinomas.
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Tpl2 kinase impacts tumor growth and metastasis of clear cell renal cell carcinoma.
Mol. Cancer Res.
PUBLISHED: 08-27-2013
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Due to the innate high metastatic ability of renal cell carcinoma (RCC), many patients with RCC experience local or systemic relapses after surgical resection. A deeper understanding of the molecular pathogenesis underlying advanced RCC is essential for novel innovative therapeutics. Tumor progression locus 2 (Tpl2), upregulated in various tumor types, has been reported to be associated with oncogenesis and metastatic progression via activation of the MAPK signaling pathway. Herein, the relevance of Tpl2 in tumor growth and metastasis of RCC is explored. Inspection of The Cancer Genome Atlas (TCGA) indicated that Tpl2 overexpression was significantly related to the presence of metastases and poor outcome in clear cell RCC (ccRCC), which is the most aggressive subtype of RCC. Moreover, expression of Tpl2 and CXCR4 showed a positive correlation in ccRCC patients. Depletion of Tpl2 by RNAi or activity by a Tpl2 kinase inhibitor in human ccRCC cells remarkably suppressed MAPK pathways and impaired in vitro cell proliferation, clonogenicity, anoikis resistance, migration, and invasion capabilities. Similarly, orthotopic xenograft growth and lung metastasis were significantly inhibited by Tpl2 silencing. Furthermore, Tpl2 knockdown reduced CXCL12-directed chemotaxis and chemoinvasion accompanied with impaired downstream signaling, indicating potential involvement of Tpl2 in CXCR4-mediated metastasis. Taken together, these data indicate that Tpl2 kinase is associated with and contributes to disease progression of ccRCC. Implications: Tpl2 kinase activity has prognostic and therapeutic targeting potential in aggressive clear cell renal cell carcinoma.
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Prognostic factors and outcomes in endometrial stromal sarcoma with the 2009 FIGO staging system: A multicenter review of 114 cases.
Gynecol. Oncol.
PUBLISHED: 08-16-2013
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To assess prognostic factors associated with disease-related survival in endometrial stromal sarcoma (ESS) using the 2009 FIGO staging system.
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Clinical significance of tumor volume in endometrial cancer: a Japan-Korea cooperative study.
Gynecol. Oncol.
PUBLISHED: 06-29-2013
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The aim of this study was to elucidate the significance of tumor volume as a risk factor for predicting lymph node metastasis.
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Gamma knife radiosurgery for brain metastases from breast cancer.
J Korean Neurosurg Soc
PUBLISHED: 06-26-2013
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The authors conducted a retrospective cohort study to determine prognostic factors and treatment outcomes of brain metastases (BM) from breast cancer (BC) after Gamma Knife radiosurgery (GKS).
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A practical scoring system to determine whether to proceed with surgical resection in recurrent glioblastoma.
Neuro-oncology
PUBLISHED: 06-25-2013
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To determine the benefit of surgical management in recurrent glioblastoma, we analyzed a series of patients with recurrent glioblastoma who had undergone surgery, and we devised a new scale to predict their survival.
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Chemical inhibition of prometastatic lysyl-tRNA synthetase-laminin receptor interaction.
Nat. Chem. Biol.
PUBLISHED: 06-18-2013
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Lysyl-tRNA synthetase (KRS), a protein synthesis enzyme in the cytosol, relocates to the plasma membrane after a laminin signal and stabilizes a 67-kDa laminin receptor (67LR) that is implicated in cancer metastasis; however, its potential as an antimetastatic therapeutic target has not been explored. We found that the small compound BC-K-YH16899, which binds KRS, impinged on the interaction of KRS with 67LR and suppressed metastasis in three different mouse models. The compound inhibited the KRS-67LR interaction in two ways. First, it directly blocked the association between KRS and 67LR. Second, it suppressed the dynamic movement of the N-terminal extension of KRS and reduced membrane localization of KRS. However, it did not affect the catalytic activity of KRS. Our results suggest that specific modulation of a cancer-related KRS-67LR interaction may offer a way to control metastasis while avoiding the toxicities associated with inhibition of the normal functions of KRS.
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Use of complex surgical procedures, patterns of tumor spread, and CA-125 predicts a risk of incomplete cytoreduction: a Korean Gynecologic Oncology Group study (KGOG-3022).
Gynecol. Oncol.
PUBLISHED: 06-18-2013
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We aimed to develop a risk model to predict a risk of suboptimal cytoreduction in primary surgery of ovarian cancer.
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Hormonal therapy for women with stage IA endometrial cancer of all grades.
Obstet Gynecol
PUBLISHED: 06-08-2013
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To estimate the oncologic and pregnancy outcomes after oral progestin treatment of women of reproductive age with stage IA endometrial adenocarcinoma with stage IA, grade 1 differentiation with superficial myometrial invasion or stage IA, grade 2-3 differentiation with or without superficial myometrial invasion.
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Individualized prediction of overall survival after postoperative radiation therapy in patients with early-stage cervical cancer: a Korean Radiation Oncology Group study (KROG 13-03).
Int. J. Radiat. Oncol. Biol. Phys.
PUBLISHED: 05-03-2013
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A nomogram is a predictive statistical model that generates the continuous probability of a clinical event such as death or recurrence. The aim of the study was to construct a nomogram to predict 5-year overall survival after postoperative radiation therapy for stage IB to IIA cervical cancer.
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Gene silencing of c-Met leads to brain metastasis inhibitory effects.
Clin. Exp. Metastasis
PUBLISHED: 04-09-2013
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An unfortunate consequence of improvements in the treatments of advanced primary cancers is the concurrent increase of metastatic brain tumors. Despite of unfavorable clinical prognosis, radiation therapy is still the only viable treatment option for brain metastases. Expression of c-Met induces cell migration and invasion in many cancers, which are indispensable steps for metastasis. Accordingly, we examined the effects of gene silencing of c-Met on brain metastasis to evaluate the possibility of c-Met as a potential target. MDA-MB-435 cells were transfected with c-Met targeting short hairpin RNAs (shRNAs). Effects of c-Met shRNAs on the expression of epithelial mesenchymal transition (EMT) related proteins, in vitro migration, and in vivo brain metastasis were examined. Expression of mesenchymal markers and in vitro migration of MDA-MB-435 cells were significantly inhibited by introduction of c-Met shRNAs. When c-Met-silenced MDA-MB-435 cells were stereotactically implanted into the brains of immune-compromised mice or injected into the right internal carotid arteries, c-Met-silenced MDA-MB-435 cells produced significantly smaller tumor masses or survival time was significantly prolonged, respectively, compared with MDA-MB-435 cells transfected with control shRNA. The data reveal the novel function of c-Met in the process of brain metastasis and its potential as a preventive and/or therapeutic target in this disease.
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Vaginal cuff dehiscence after hysterectomy.
Int J Gynaecol Obstet
PUBLISHED: 03-28-2013
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To determine the incidence of vaginal cuff dehiscence (VCD) among women undergoing hysterectomy according to clinico-surgical factors including surgical route, and to describe patient characteristics associated with VCD.
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Laparoscopic versus open radical hysterectomy in patients with stage IB2 and IIA2 cervical cancer.
J Surg Oncol
PUBLISHED: 03-26-2013
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To compare survival and surgical outcomes of laparoscopic (LRH) and open radical hysterectomy (ORH) in patients with stage IB2 and IIA2 cervical cancer.
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Fertility-sparing surgery for young women with early-stage epithelial ovarian cancer.
Gynecol. Obstet. Invest.
PUBLISHED: 03-20-2013
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To discuss the latest findings on oncologic and reproductive outcomes of fertility-sparing surgery in epithelial ovarian cancer (EOC) and to suggest proper indications for this treatment.
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Risk of seizure and its clinical implication in the patients with cerebral metastasis from lung cancer.
Acta Neurochir (Wien)
PUBLISHED: 03-18-2013
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The prevalence, risk factors, and clinical implication of seizure development were investigated in patients with metastatic brain tumors.
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Increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy.
J. Urol.
PUBLISHED: 02-12-2013
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Transrectal ultrasound guided prostate biopsy is widely used to confirm the diagnosis of prostate cancer. The technique has been associated with significant morbidity in a small proportion of patients.
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Radiosensitization of brain metastasis by targeting c-MET.
Lab. Invest.
PUBLISHED: 02-04-2013
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Radiotherapy is the most widely used therapeutic modality in brain metastasis; however, it only provides palliation due to inevitable tumor recurrence. Resistance of tumor cells to ionizing radiation is a major cause of treatment failure. A critical unmet need in oncology is to develop rationale driven approaches that can enhance the efficacy of radiotherapy against metastatic tumor. Utilizing in vivo orthotopic primary tumor and brain metastasis models that recapitulate clinical situation of the patients with metastatic breast cancer, we investigated a molecular mechanism through which metastatic tumor cells acquire resistance to radiation. Recent studies have demonstrated that the hepatocyte growth factor (HGF)-c-Met pathway is essential for the pathologic development and progression of many human cancers such as proliferation, invasion and resistance to anticancer therapies. In this study, c-Met signaling activity as well as total c-Met expression was significantly upregulated in both breast cancer cell lines irradiated in vitro and ex vivo radio-resistant cells derived from breast cancer brain metastatic xenografts. To interrogate the role of c-Met signaling in radioresistance of brain metastasis, we evaluated the effects on tumor cell viability, clonogenicity, sensitivity to radiation, and in vitro/in vivo tumor growth after targeting c-Met by small-hairpin RNA (shRNA) or small-molecule kinase inhibitor (PF-2341066). Although c-Met silencing or radiation alone demonstrated a modest decrease in clonogenic growth of parental breast cancers and brain metastatic derivatives, combination of two modalities showed synergistic antitumor effects resulting in significant prolongation of overall survival in tumor-bearing mice. Taken together, optimizing c-Met targeting in combination with radiation is critical to enhance the effectiveness of radiotherapy in the treatments of brain metastasis.
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Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells.
Cancer Cell
PUBLISHED: 02-02-2013
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Glioblastoma multiforme (GBM) displays cellular hierarchies harboring a subpopulation of stem-like cells (GSCs). Enhancer of Zeste Homolog 2 (EZH2), the lysine methyltransferase of Polycomb repressive complex 2, mediates transcriptional repression of prodifferentiation genes in both normal and neoplastic stem cells. An oncogenic role of EZH2 as a transcriptional silencer is well established; however, additional functions of EZH2 are incompletely understood. Here, we show that EZH2 binds to and methylates STAT3, leading to enhanced STAT3 activity by increased tyrosine phosphorylation of STAT3. The EZH2-STAT3 interaction preferentially occurs in GSCs relative to non-stem bulk tumor cells, and it requires a specific phosphorylation of EZH2. Inhibition of EZH2 reverses the silencing of Polycomb target genes and diminishes STAT3 activity, suggesting therapeutic strategies.
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Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors.
J Thorac Oncol
PUBLISHED: 01-19-2013
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The incidence of leptomeningeal carcinomatosis (LC) has increased in patients with metastatic non-small-cell lung cancer (NSCLC) because of recent improvements in survival. The clinical features and prognostic factors of LC in NSCLC patients, however, have not been well identified. The aim of this study was to identify the clinical features and prognostic factors of NSCLC patients with LC.
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Patient-specific orthotopic glioblastoma xenograft models recapitulate the histopathology and biology of human glioblastomas in situ.
Cell Rep
PUBLISHED: 01-17-2013
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Frequent discrepancies between preclinical and clinical results of anticancer agents demand a reliable translational platform that can precisely recapitulate the biology of human cancers. Another critical unmet need is the ability to predict therapeutic responses for individual patients. Toward this goal, we have established a library of orthotopic glioblastoma (GBM) xenograft models using surgical samples of GBM patients. These patient-specific GBM xenograft tumors recapitulate histopathological properties and maintain genomic characteristics of parental GBMs in situ. Furthermore, in vivo irradiation, chemotherapy, and targeted therapy of these xenograft tumors mimic the treatment response of parental GBMs. We also found that establishment of orthotopic xenograft models portends poor prognosis of GBM patients and identified the gene signatures and pathways signatures associated with the clinical aggressiveness of GBMs. Together, the patient-specific orthotopic GBM xenograft library represent the preclinically and clinically valuable "patient tumors phenocopy" that represents molecular and functional heterogeneity of GBMs.
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Adenosine potentiates the therapeutic effects of neural stem cells expressing cytosine deaminase against metastatic brain tumors.
Oncol. Rep.
PUBLISHED: 01-07-2013
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Tumor-tropic properties of neural stem cells (NSCs) provide a novel approach with which to deliver targeting therapeutic genes to brain tumors. Previously, we developed a therapeutic strategy against metastatic brain tumors using a human NSC line (F3) expressing cytosine deaminase (F3.CD). F3.CD converts systemically administered 5-fluorocytosine (5-FC), a blood-brain barrier permeable nontoxic prodrug, into the anticancer agent 5-fluorouracil (5-FU). In this study, we potentiated a therapeutic strategy of treatment with nucleosides in order to chemically facilitate the endogenous conversion of 5-FU to its toxic metabolite 5-FU ribonucleoside (5-FUR). In vitro, 5-FUR showed superior cytotoxic activity against MDA-MB-435 cancer cells when compared to 5-FU. Although adenosine had little cytotoxic activity, the addition of adenosine significantly potentiated the in vitro cytotoxicity of 5-FU. When MDA-MB?435 cells were co-cultured with F3.CD cells, F3.CD cells and 5-FC inhibited the growth of MDA-MB-435 cells more significantly in the presence of adenosine. Facilitated 5-FUR production by F3.CD was confirmed by an HPLC analysis of the conditioned media derived from F3.CD cells treated with 5-FC and adenosine. In vivo systemic adenosine treatment also significantly potentiated the therapeutic effects of F3.CD cells and 5-FC in an MDA-MB-435 metastatic brain tumor model. Simple adenosine addition improved the antitumor activity of the NSCs carrying the therapeutic gene. Our results demonstrated an increased therapeutic potential, and thereby, clinical applicability of NSC-based gene therapy.
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Fatal Ifosfamide-induced metabolic encephalopathy in patients with recurrent epithelial ovarian cancer: report of two cases.
Cancer Res Treat
PUBLISHED: 12-27-2011
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Central nervous system (CNS) toxicity has been reported in approximately 10-30% of patients receiving intravenous infusions of ifosfamide. Encephalopathy is a rare but serious CNS adverse reaction in these patients, and although usually transient and reversible, may cause persistent neurological dysfunction or death. Clinical features range from fatigue and confusion to coma and death. Although methylene blue can be used to treat ifosfamide-induced neurotoxicity, including encephalopathy, its mechanism of action remains poorly defined. We describe here two patients with recurrent epithelial ovarian cancer who experienced fatal encephalopathy following ifosfamide/mesna treatment.
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The expression of DNA damage checkpoint proteins and prognostic implication in metastatic brain tumors.
Oncol. Res.
PUBLISHED: 12-18-2011
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The most important therapeutic tool in brain metastasis is radiation therapy. However, resistance to radiation is a possible cause of recurrence or treatment failure. Recently, DNA damage checkpoint signaling pathway activation after irradiation has received increasing attention. The association between the expression levels and survival outcome was evaluated to find possible therapeutic targets in brain metastasis. Radiosensitivity of human non-small cell lung cancer cell lines was determined by checking their viability after treatment with varying doses of ionizing radiation (IR). The expression of DNA checkpoint proteins was analyzed by Western blots and immunohistochemistry. On the basis of the clinical data for the patients, the association between the expression of the components and patients survival was investigated. The expression levels of TopBP1 and phosphorylated Chk1 (P-Chk1) protein were higher in radioresistant lung cancer cell lines compared to radiosensitive cell lines. We previously assessed radiation survival of lung cancer cell lines after treating them with Chk1 inhibitor, AZD7762. AZD7762 significantly sensitized both radioresistant and radiosensitive cells to IR. We also observed a strong inverse relationship between progression-free survival (PFS) and expression level of P-Chk1 and TopBP1. This study, which is the first clinical report that connects DNA damage checkpoints and prognosis of brain metastasis, supports these two proteins to be promising targets for overcoming the radioresistance in brain metastasis.
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Radiation therapy is a treatment to be considered for recurrent epithelial ovarian cancer after chemotherapy.
Tumori
PUBLISHED: 12-14-2011
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Radiation therapy provides a safe and effective alternative treatment option for recurrent epithelial ovarian cancer, although it has not been a treatment of choice. We evaluated the efficacy and toxicity of radiation therapy for recurrent epithelial ovarian cancer after chemotherapy according to the disease status.
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Paratubal serous borderline tumor.
J Gynecol Oncol
PUBLISHED: 12-05-2011
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Although paratubal cysts are well-characterized incidental findings, paratubal serous borderline tumors are very rare, with only one case report in the literature. We describe here a 27-year-old, nulliparous, married woman with a paratubal serous borderline tumor. The patient presented with a huge pelvic mass accompanied by flank pain and underwent paratubal cystectomy and fertility-sparing surgical staging procedures. Thirteen months after surgery, she delivered a healthy baby at term. She is well, without evidence of disease, 20 months after surgery. Because paratubal serous borderline tumors are very rare, their optimal management must be extrapolated from their ovarian counterparts.
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In vivo specific delivery of c-Met siRNA to glioblastoma using cationic solid lipid nanoparticles.
Bioconjug. Chem.
PUBLISHED: 11-28-2011
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RNA interference is a powerful strategy that inhibits gene expression through specific mRNA degradation. In vivo, however, the application of small interfering RNAs (siRNAs) is severely limited by their instability and their poor delivery into target cells and tissues. This is especially true with glioblastomas (GBMs), the most frequent and malignant form of brain tumor, that has limited treatment options due to the largely impenetrable blood-brain barrier. Here, cationic solid lipid nanoparticles (SLN), reconstituted from natural components of protein-free low-density lipoprotein, was conjugated to PEGylated c-Met siRNA. The c-Met siRNA-PEG/SLN complex efficiently down-regulated c-Met expression level, as well as decreased cell proliferation in U-87MG in vitro. In orthotopic U-87MG xenograft tumor model, intravenous administration of the complex significantly inhibited c-Met expression at the tumor tissue and suppressed tumor growth without showing any systemic toxicity in mice. Use of Cy5.5 conjugated SLN revealed enhanced accumulation of the siRNA-PEG/SLN complexes specifically in the brain tumor. Our data demonstrates the feasibility of using siRNA-PEG/SLN complexes as a potential carrier of therapeutic siRNAs for the systemic treatment of GBM in the clinic.
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Wnt activation is implicated in glioblastoma radioresistance.
Lab. Invest.
PUBLISHED: 11-14-2011
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Glioblastoma (GBM) patients have dismal median survival even with the most rigorous treatments currently available. Radiotherapy is the most effective non-surgical therapy for GBM patients; however, patients succumb due to tumor recurrence within a year. To develop a curative therapeutic approach, we need to better understand the underlying molecular mechanism of radiation resistance in GBM. Towards this goal, we developed an in vivo orthotopic GBM model system that mimics the radiation response of human GBM, using both established-GBM cell line and patient-derived freshly dissociated GBM specimen. In-vivo ionizing radiation (IR) treatment prolonged the survival of mice with intracranical tumor derived from U373MG, but failed to prevent tumor recurrence. U373MG and GBM578 cells isolated after in-vivo IR (U373-IR and 578-IR) were more clonogenic and enriched with stem cell-like characteristics, compared with mock-treated control tumor cells. Transcriptomic analyses and quantitative real-time reverse-transcription PCR analyses using these matched GBM cells before and after radiation treatment revealed that Wnt pathways were preferentially activated in post-IR GBM cells. U373-IR cells and 578-IR were enriched with cells positive for both active ?-catenin (ABC) and Sox2 population, and this subpopulation was further increased after additional in-vitro radiation treatment, suggesting that radiation resistance of GBM is mediated due, in part, to the activation of stem cell-associated pathways including Wnt. Finally, pharmacological and siRNA inhibition of Wnt pathway significantly decreased the survival and clonogenicity of GBM cells and reduced their ABC(+)/Sox2(+) population. Together, these data suggest that Wnt activation is a molecular mechanism to confer GBM radioresistance and an important therapeutic target.
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Mutated IDH1 is a favorable prognostic factor for type 2 gliomatosis cerebri.
Brain Pathol.
PUBLISHED: 11-14-2011
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The prognostic significance of IDH1 mutations has been demonstrated in gliomas. It is unclear whether IDH1 mutation is also a prognostic factor in gliomatosis cerebri (GC). Primary GCs can be grouped into type 1 GCs, which have the classical diffuse growth pattern without mass formation, and type 2 GCs, which form neoplastic masses in addition to classic diffuse lesions. In this study, the prognostic relevance of IDH1/2 mutations in 74 GCs (43 type 1 and 31 type 2) was evaluated. We detected 33 (44.6%) IDH1 mutations, including R132H and R132S, by bidirectional Sanger sequencing. No mutations were detected in IDH2. The percentage of 2-year overall survival for wild-type IDH1 patients was 46 vs. 72% for patients with IDH1-mutated tumors. Mutations of IDH1 were strongly correlated with both increased overall survival (OS) and progression-free survival (PFS) in patients with type 2 GCs, and IDH1 mutations were also an independent prognostic factor predicting increased OS and PFS in type 2 GC patients in multivariate analysis. However, IDH1 mutations did not correlate with survival outcomes in patients with type 1 GCs. Finally, the subgroup of GC, which has IDH1 wild-type and additional solid component showed the worst prognosis.
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EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction.
Cancer Res.
PUBLISHED: 10-05-2011
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Aberrant activation of receptor tyrosine kinases (RTK) is causally linked to the pathobiological traits of glioblastoma and genesis of glioma stem-like cells (GSC), but the underlying mechanism is still unknown. Here, we show that epidermal growth factor receptor (EGFR) signaling regulates the proliferation, angiogenesis, and acquisition of GSC characteristics by inducing inhibitor of differentiation 3 (ID3) and ID3-regulated cytokines [GRO1 and interleukins (IL)-6 and 8] induction. We found that EGFR-mediated ID3 expression was regulated by Smad5, which was directly phosphorylated by AKT. Furthermore, ID3 alone imparted GSC features to primary astrocytes derived from Ink4a/Arf-deficient mouse, and EGFR-ID3-IL-6 signaling axis gave rise to tumor cell heterogeneity. Conversely, EGFR inhibitors suppressed EGFR-AKT-Smad5-driven induction of ID3, which led to a decrease in the tumorsphere forming ability of GSCs and U87MG cells that possess an active mutant EGFR, EGFRvIII, without obvious cytotoxic effects. However, these cells seemed to regain colonogenic ability after removal of the EGFR inhibitors. Together, the results delineate a novel integrative molecular mechanism in which the RTK-ID signaling pathway governs genesis and maintenance of GBM histopathologic features, such as GSCs-based tumor initiation, progression, and angiogenesis.
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Optimal debulking surgery followed by paclitaxel/platinum chemotherapy is very effective in treating ovarian carcinosarcomas: a single center experience.
Gynecol. Obstet. Invest.
PUBLISHED: 09-27-2011
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There have been only a few reports on the survival and management of patients with ovarian carcinosarcomas. We evaluated the clinical characteristics, outcomes and prognostic factors of ovarian carcinosarcomas.
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Recognition of parametrial invasion, an important landmark when treating cervical cancer.
Gynecol. Oncol.
PUBLISHED: 09-19-2011
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Histological assessment of parametrial invasion in uterine cervical cancer is often subjective due to the parametrium being a loosely defined structure without apparent definitive landmarks. This study defines a precise and consistent histological landmark for the parametrium.
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Surgical staging and adjuvant chemotherapy in the management of patients with adult granulosa cell tumors of the ovary.
Gynecol. Oncol.
PUBLISHED: 09-09-2011
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To analyze the role of surgical staging and adjuvant chemotherapy in patients with adult type granulosa cell tumor (GCT) of the ovary.
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Free radicals enzymatically triggered by Clonorchis sinensis excretory-secretory products cause NF-?B-mediated inflammation in human cholangiocarcinoma cells.
Int. J. Parasitol.
PUBLISHED: 09-08-2011
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Chronic clonorchiasis, caused by direct and continuous contact with Clonorchis sinensis worms and their excretory-secretory products, is associated with hepatobiliary damage, inflammation, periductal fibrosis and even development of cholangiocarcinoma. Our previous report revealed that intracellular reactive oxygen species were generated in C. sinensis excretory-secretory product-treated human cholangiocarcinoma cells; however, their endogenous sources and pathophysiological roles in host cells were not determined. In the present study, we found that treatment of human cholangiocarcinoma cells with excretory-secretory products triggered increases in free radicals via a time-dependent activation of NADPH oxidase, xanthine oxidase and inducible nitric oxide synthase. This increase in free radicals substantially promoted the degradation of cytosolic I?B-?, nuclear translocation of nuclear factor-?B subunits (RelA and p50), and increased ?B consensus DNA-binding activity. Excretory-secretory product-induced nuclear factor-?B activation was markedly attenuated by preincubation with specific inhibitors of each free radical-producing enzyme or the antioxidant, N-acetylcysteine. Moreover, excretory-secretory products induced an increase in the mRNA and protein expression of the proinflammatory cytokines, IL-1? and IL-6, in an nuclear factor-?B-dependent manner, indicating that enzymatic production of free radicals in ESP-treated cells participates in nuclear factor-?B-mediated inflammation. These findings provide new insights into the pathophysiological role of C. sinensis excretory-secretory products in host chronic inflammatory processes, which are initial events in hepatobiliary diseases.
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HDR monotherapy for man with radiotherapy contraindications and prostate cancer.
Can J Urol
PUBLISHED: 08-23-2011
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There is debate about the optimal management of high risk localized prostate cancer. Initial options include surgery or radiation combined with androgen deprivation therapy. We describe a case of a patient with contraindications to radiotherapy who was managed with high dose rate (HDR) brachytherapy as his sole treatment. A medically operable patient presented with a T2c N0 M0 Gleason 9 adenocarcinoma with an initial PSA of 19.9 ng/mL. Previously, he had severe ulcerative colitis managed with pancolectomy and a neorectum fashioned from ileum anastomosed behind his prostate. After a negative extended lymph node dissection, a HDR brachytherapy implant of 35 Gy in 5 fractions over 3 days was delivered. No androgen deprivation therapy was used. The treatment was extremely well tolerated in the short and long term with no significant bowel or bladder side effects observed in follow up. After 7 years, his PSA was 0.04 ng/mL. The excellent long-term biochemical control and minimal radiation toxicity observed in this patient suggests that HDR monotherapy may be a safe and effective alternative for high risk prostate cancer patients in whom EBRT is contraindicated.
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Prospective multi-institutional study evaluating the performance of prostate cancer risk calculators.
J. Clin. Oncol.
PUBLISHED: 06-20-2011
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Prostate cancer risk calculators incorporate many factors to evaluate an individuals risk for prostate cancer. We validated two common North American-based, prostate cancer risk calculators.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.