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  • 1
    Keywords: GENOME ; ASSOCIATION ; AMPLIFICATION ; DNA methylation ; REGION ; ONCOGENE ; HYPERMETHYLATION ; N-MYC ; CANDIDATE TUMOR-SUPPRESSOR ; RASSF1A
    Abstract: OBJECTIVE: The CpG island methylator phenotype is strongly associated with poor survival in neuroblastomas. Neuroblastomas with the CpG island methylator phenotype include almost all neuroblastomas with MYCN amplification, and, even among neuroblastomas without MYCN amplification, have worse prognosis. At the same time, methylation of individual tumor-suppressor genes is also reported to be associated with poor survival. The purpose of this study was to compare the prognostic power of the CpG island methylator phenotype with that of methylation of individual genes. METHODS: Methylation-specific polymerase chain reaction was performed for five individual genes (CASP8, EMP3, HOXA9, NR1I2 and CD44) in 140 Japanese and 152 German neuroblastomas. Kaplan-Meier analysis and log-rank tests were conducted to compare the survival between groups defined by methylation status. RESULTS: Among the five individual genes, only CASP8 methylation had a significant association with poor overall survival both in Japanese (hazard ratio = 3.1; 95% confidence interval = 1.5-6.4; P = 0.002) and German (hazard ratio = 4.8; 95% confidence interval = 2.1-11; P = 0.0002) neuroblastomas. HOXA9 and NR1I2 methylation were associated with poor survival only in German neuroblastomas. On the other hand, the CpG island methylator phenotype had a strong and consistent association in Japanese (hazard ratio = 22; 95% confidence interval = 5.3-93; P = 1.5 x 10(-5)) and German (hazard ratio = 9.5; 95% confidence interval = 3.2-28; P = 4.7 x 10(-5)) neuroblastomas. CONCLUSION: The CpG island methylator phenotype is likely to have stronger prognostic power than methylation of individual genes in neuroblastomas.
    Type of Publication: Journal article published
    PubMed ID: 23619990
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  • 2
    Keywords: STAGE ; PROGRESSION ; AMPLIFICATION ; chemotherapy ; DELETIONS ; SPONTANEOUS REGRESSION ; PREDICTION ; pathology ; N-MYC ; EXPRESSION-BASED CLASSIFICATION
    Abstract: Purpose: To optimize neuroblastoma treatment stratification, we aimed at developing a novel risk estimation system by integrating gene expression-based classification and established prognostic markers. Material and Methods: Gene expression profiles were generated from 709 neuroblastoma specimens using customized 4x44K microarrays. Classification models were built using 75 tumors with contrasting courses of disease. Validation was performed in an independent test set (n=634) by Kaplan-Meier estimates and Cox regression analyses. Results: The best-performing classifier predicted patient outcome with an accuracy of 0.95 (sensitivity 0.93, specificity 0.97) in the validation cohort. The highest potential clinical value of this predictor was observed for current low-risk patients (LR: 5-year EFS 0.84+/-0.02 vs 0.29+/-0.10; 5-year OS 0.99+/-0.01vs 0.76+/-0.11; both p〈0.001) and intermediate-risk patients (IR: 5-year EFS 0.88+/-0.06 vs 0.41+/-0.10; 5-year OS 1.0 vs 0.70+/-0.09; both p〈0.001). In multivariate Cox regression models for LR/IR patients the classifier outperformed risk assessment of the current German trial NB2004 (EFS: HR 5.07, 95%-CI 3.20-8.02, OS: HR 25.54, 95%-CI 8.40-77.66; both p〈0.001). Based on these findings, we propose to integrate the classifier into a revised risk stratification system for LR/IR patients. According to this system, we identified novel subgroups with poor outcome (5-year EFS 0.19+/-0.08; 5-year OS 0.59+/-0.1), for whom we propose intensified treatment, and with beneficial outcome (5-year EFS 0.87+/-0.05; 5-year OS 1.0), who may benefit from treatment de-escalation. Conclusion: Combination of gene expression-based classification and established prognostic markers improves risk estimation of LR/IR neuroblastoma patients. We propose to implement our revised treatment stratification system in a prospective clinical trial.
    Type of Publication: Journal article published
    PubMed ID: 25231397
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  • 3
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; CLASSIFICATION ; DIAGNOSIS ; INFORMATION ; SYSTEM ; COHORT ; DISEASE ; RISK ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; validation ; PATIENT ; prognosis ; SEQUENCE ; SEQUENCES ; IDENTIFICATION ; AMPLIFICATION ; gene expression ; MICROARRAY DATA ; microarrays ; DESIGN ; NUMBER ; CANCER-PATIENTS ; PREDICTION ; SELECTION ; CANCER PATIENTS ; neuroblastoma ; ONCOLOGY ; GENE-EXPRESSION PROFILES ; development ; prospective ; RISK STRATIFICATION ; outcome ; SIGNATURES ; EXPRESSION SIGNATURES ; STRATIFICATION
    Abstract: Purpose: Reliable prognostic stratification remains a challenge for cancer patients, especially for diseases with variable clinical course such as neuroblastoma. Although numerous studies have shown that outcome might be predicted using gene expression signatures, independent cross-platform validation is often lacking. Experimental Design: Using eight independent studies comprising 933 neuroblastoma patients, a prognostic gene expression classifier was developed, trained, tested, and validated. The classifier was established based on reanalysis of four published studies with updated clinical information, reannotation of the probe sequences, common risk definition for training cases, and a single method for gene selection (prediction analysis of microarray) and classification (correlation analysis). Results: Based on 250 training samples from four published microarray data sets, a correlation signature was built using 42 robust prognostic genes. The resulting classifier was validated on 351 patients from four independent and unpublished data sets and on 129 remaining test samples from the published studies. Patients with divergent outcome in the total cohort, as well as in the different risk groups, were accurately classified (log-rank P 〈 0.001 for overall and progression-free survival in the four independent data sets). Moreover, the 42-gene classifier was shown to be an independent predictor for survival (odds ratio, 〉5). Conclusion: The strength of this 42-gene classifier is its small number of genes and its cross-platform validity in which it outperforms other published prognostic signatures. The robustness and accuracy of the classifier enables prospective assessment of neuroblastoma patient outcome. Most importantly, this gene selection procedure might be an example for development and validation of robust gene expression signatures in other cancer entities. Clin Cancer Res; 16(5); 1532-41. (C)2010 AACR
    Type of Publication: Journal article published
    PubMed ID: 20179214
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  • 4
    ISSN: 0300-9629
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1435-232X
    Keywords: Key words Chromosome 9q ; DA41 ; DAN ; FISH ; Ubiquitin-like protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract DA41 was previously identified as one of the DAN-binding proteins, via a yeast-based two-hybrid screening strategy. In the present study, we cloned a human homolog of DA41 cDNA. Structural analysis revealed that human DA41 cDNA consisted of 2,861 nucleotides in length and encoded a protein of 589 amino acids, with a predicted molecular mass of 62.4 kDa. Human DA41 exhibited an 86% amino acid sequence identity to rat DA41, indicating the evolutionarily conserved structure and function of DA41. A database search for DA41-related protein(s) identified mouse PLIC-1, PLIC-2, frog XDRP1, and yeast DSK2. DA41 and each DA41-related protein contain a ubiquitin-like domain in their amino-terminal regions. DA41 was expressed ubiquitously in adult human tissues, with relatively higher levels in pituitary gland, adrenal gland, kidney, thymus, and placenta. Fluorescence in situ hybridization (FISH) revealed that DA41 was mapped to human chromosome 9q21.2–q21.3, a position overlapping the candidate tumor suppressor locus for bladder cancer.
    Type of Medium: Electronic Resource
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  • 6
    Publication Date: 2018-12-01
    Description: Background: The density of tumor-infiltrating lymphocytes has been reported to reflect the antitumor immune status, and many reports have shown that tumor-infiltrating CD8 + and total T-lymphocytes may be strong prognostic biomarkers in colorectal cancer. We previously reported that the density of tumor-infiltrating immune cells in hematoxylin and eosin (H&E)-stained sections may be an easily available prognostic biomarker. However, it remains unclear whether the density of tumor-infiltrating immune cells in H&E-stained sections accurately reflects the antitumor immune status. Patients and Methods: A total of 308 patients who underwent curative resection for stage II/III colorectal cancer were enrolled. The density of both tumor-infiltrating immune cells in H&E-stained sections and tumor-infiltrating lymphocyte subsets was assessed by immunohistochemistry. Results: The density of tumor-infiltrating immune cells in H&E-stained sections was significantly and positively correlated with that of tumor-infiltrating CD4 + /CD8 + /total T-lymphocytes. Conclusion: The density of tumor-infiltrating immune cells in H&E-stained sections may be a reasonable immunological biomarker.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 7
    Publication Date: 2018-03-30
    Description: Background: Chemotherapy with trastuzumab, pertuzumab and docetaxel (TPD regimen) is now strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER)2-positive breast cancer. In this study, we analyzed the expression of HER 1–4 proteins, and investigated whether or not their expression was predictive of the response of advanced HER2-positive breast cancer to chemotherapy with the TPD regimen. Patients and Methods: The study consisted of 29 cases in which TPD regimen chemotherapy was carried out from September 2013 to November 2015. The expression levels of estrogen receptor (ER), progesterone receptor (PgR), Ki67, HER1, HER2, HER3 and HER4 were evaluated using immunostaining employing needle biopsy specimens. Results: The overall response rate (ORR) was significantly higher in the HER3-positive group than in the HER3-negative group (p=0.002). In prognostic analysis, the HER3-positive group showed a significant progression-free survival extension over the HER3-negative group (p=0.042, log-rank). In univariate analysis, objective response (p=0.004, hazard ratio(HR)=0.123) and positive HER3 expression (p=0.023, HR=0.279) significantly contributed to extension of progression-free survival interval. Conclusion: HER3 expression may be a useful factor for predicting the response of HER2-positive breast cancer to chemotherapy with the TPD regimen.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 8
    Publication Date: 2018-05-31
    Description: Background/Aim: The clinical significance of postoperative neutrophil lymphocyte ratio (NLR) remains unclear. The aim of this study was to examine the impact of postoperative NLR on prediction for postoperative recurrence of gastric cancer. Patients and Methods: A retrospective analysis was performed on data from 170 patients with Stage II/III gastric cancer who underwent surgery followed by adjuvant chemotherapy using S-1 between 2006 and 2015. Postoperative NLR was calculated every 6 months and the data at the time of recurrence or last survival were used for analysis. Results: Postoperative NLR was associated with Prognostic nutritional index (PNI) and modified Glasgow Prognostic Score (mGPS). In multivariate analysis, we found that elevated CA19-9, CEA and NLR were independent predictive markers. The patients with low values of both NLR and CEA after surgery had the most favorable prognosis. Conclusion: The postoperative NLR might be one of the surrogate markers for recurrence after curative surgery for patients with Stage II/III gastric cancer.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 9
    Publication Date: 2018-05-01
    Description: Background/Aim: Several proteins involved in immune regulation and the relationship among these, the tumor microenvironment, and clinical outcomes of eribulin treatment were evaluated in advanced or metastatic breast cancer patients. Patients and Methods: This retrospective cohort study comprised 52 eribulin-treated locally advanced or metastatic breast cancer patients. Cancer tissue samples were obtained before and after treatment in 10 patients. Immunohistochemistry was performed to determine programmed death (PD)-1, CD8, and forkhead box P3 (FOXP3) expression by stromal tumor-infiltrating lymphocytes, and PD-ligand (L1) and PD-L2 expression by cancer cells. Results: Of the 10 patients, 5 were responders (partial response) and 5 were non-responders (stable disease, 2; progressive disease, 3) to eribulin. PD-1, PD-L2, and FOXP3 expression became negative in 5 patients, PD-L1 expression became negative in 6 patients, and CD8 expression became positive in 3 patients after treatment. The response to eribulin was significantly associated with PD-L1 and FOXP3 negative conversion (p=0.024 and 0.004, respectively). The change in E-cadherin expression (positive or negative) was also correlated with the changes in PD-L1 and FOXP3 (p=0.024 and 0.004, respectively). Kaplan–Meier analysis with log-rank tests revealed that progression-free survival and time-to-treatment failure were significantly longer in patients with PD-L1 and FOXP3 negative conversion (p=0.012 and 0.001; p=0.049 and 0.018, respectively). Conclusion: The efficacy of eribulin may be attributed to its biological effects on the immune system (reduction of PD-L1 and FOXP3 expression) through epithelial–mesenchymal transition suppression, and vascular remodeling and improvement of the tumor microenvironment.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 10
    Publication Date: 2018-03-30
    Description: Background: miR-96 is reported to inhibit reversion cysteine-rich Kazal motif (RECK), which is associated with tumor invasion, in solid cancer types (e.g. breast cancer, non-small cell lung cancer, esophageal cancer). The purpose of this study is to clarify whether miR-96 is similarly associated with tumor invasion in colorectal cancer. Materials and Methods: We performed western blotting to investigate the expression of RECK when miR-96 mimics or inhibitors were transferred into HCT-116 colorectal cancer cells. The RECK mRNA level was assessed by a reverse transcription polymerase chain reaction. An invasion assay was used to evaluate tumor invasion. Results: The expression of RECK was inhibited by the transfection of miR-96 mimics. RECK mRNA level was reduced by miR-96 mimics and increased by miR-96 inhibitor. In the invasion assay, miR-96 mimics were shown to promote tumor invasion. Conclusion: miR-96 may be associated with tumor invasion through inhibition of RECK expression in colorectal cancer.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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