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Esophageal adenocarcinoma risk in Barrett's esophagus (BE) is increased 30- to 125-fold versus the general population. Among all BE patients, however, neoplastic progression occurs only once per 200 patient-years. Molecular biomarkers are therefore needed to risk-stratify patients for more efficient surveillance endoscopy and to improve the early detection of progression. We therefore performed a retrospective, multicenter, double-blinded validation study of eight BE progression prediction methylation biomarkers. Progression or nonprogression were determined at 2 years (tier 1) and 4 years (tier 2). Methylation was assayed in 145 nonprogressors and 50 progressors using real-time quantitative methylation-specific PCR. Progressors were significantly older than nonprogressors (70.6 versus 62.5 years; P < 0.001). We evaluated a linear combination of the eight markers, using coefficients from a multivariate logistic regression analysis. Areas under the ROC curve (AUC) were high in the 2-year, 4-year, and combined data models (0.843, 0.829, and 0.840; P < 0.001, <0.001, and <0.001, respectively). In addition, even after rigorous overfitting correction, the incremental AUCs contributed by panels based on the 8 markers plus age versus age alone were substantial (Delta-AUC = 0.152, 0.114, and 0.118, respectively) in all 3 models. A methylation biomarker-based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia.
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PMID:A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett's esophagus. 1943 94

Alpha-fetoprotein (AFP) is a commonly used tumor marker in the detection of hepatocellular carcinoma (HCC), and its sensitivity and specificity is insufficient to detect HCC in all patient samples. Recently, the immunocomplexed forms of AFP (AFP-IgM) have been reported to be present in HCC patients. This study was aimed at developing a novel time-resolved immunofluorometric assay (TR-IFMA) for the simultaneous determination of AFP-IgM and AFP concentration in HCC. We constructed a double-label assay by using Sm3+-labeled mAb to human IgM antibody, Eu3+-labeled mAb to AFP, and immobilized another mAb to AFP on the solid phase. The performances of the assay were all found to be satisfactory. The validity of the novel assay was confirmed by the good correlation between the results obtained by TR-IFMA and commercial ELISA or electrochemiluminescence immunoassay. AFP-IgM and AFP were increased above the cutoffs in 65.25 and 45.76% of HCC, respectively. ROC analysis yielded the following area under the curve: AFP-IgM 0.774 (CI 95% 0.736-0.809), AFP 0.771 (CI 95% 0.733-0.860). The combined use of AFP-IgM and AFP increased the sensitivity of detection to 72.88% in patients with HCC. These data suggest that the use of a combination of two markers in clinical practice could increase the accuracy of HCC diagnosis.
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PMID:Simultaneous determination of alpha-fetoprotein immune complexes and alpha-fetoprotein concentration in hepatocellular carcinoma using dual-label time-resolved immunofluorometric assays. 1945 31

The data of preoperative diagnosis and morphological examination were compared for 144 patients with prostatic carcinoma T1-4N0-XM0 subjected to radical prostatectomy in 1997-2007. In assessment of prostatic capsule invasion, sensitivity of the rectal examination was 21.7%, specificity--89.8%, diagnostic efficacy--68.1%, PPV--50.0%, NPV--70.9%, AUC under ROC curve--0.558 +/- 0.053 (p = 0.348); sensitivity of transrectal ultrasonic investigation--21.7%, specificity--89.8%, diagnostic efficacy--68.8%, PPV--52.6%, NPV--71.2%, AUC under ROC curve--0.563 +/- 0.053 (p = 0.211). Factors of a poor prognosis of prostatic capsule invasion were PSA > 10 ng/ml (p = 0.028) and Gleason score > 7 (p = 0.052). Combined use of these two parameters raises quality of preoperative assessment of category T [sensitivity--80.0%, specificity--55.1%, diagnostic efficacy--56.3%, PPV--80.4%, NPV--44.9%, AUC under ROC curve--0.624 +/- 0.049 (p = 0.017)]. Sensitivity of clinical assessment of N category was 11.1% in 100% specificity, 94.4% diagnostic efficacy, 100% PPV, 94.4% NPV, 0.556 +/- 0.107 (p = 0.577) AUC under ROC curve. A single significant prognostic factor of pN+ category was PSA > 10 ng/ml (p = 0.014). Sensitivity of histological examination of biopsy material in relation to true Gleason's parameter (< 7 or > 7) was 59.4%, specificity 89.3%, diagnostic efficacy 82.6%, PPV 61.3%, NPV 88.5%, AUC under ROC curve 0.743 +/- 0.056 (p < 0.0001). Thus, combined use of a baseline PSA concentration with a borderline value > 10 ng/ml and biopsy Gleason score > 7 raises quality of preoperative evaluation of extraprostatic tumor extension and condition of regional lymph nodes.
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PMID:[Prognostic implications of preoperative diagnosis of clinically local and locally advanced prostatic cancer]. 1952 72

The aim of our study was to identify threshold levels of DNA methylation predictive of the outcome to better define the risk group of stage 4 neuroblastic tumor patients. Quantitative pyrosequencing analysis was applied to a training set of 50 stage 4, high risk patients and to a validation cohort of 72 consecutive patients. Stage 4 patients at lower risk and ganglioneuroma patients were included as control groups. Predictive thresholds of methylation were identified by ROC curve analysis. The prognostic end points of the study were the overall and progression-free survival at 60 months. Data were analyzed with the Cox proportional hazard model. In a multivariate model the methylation threshold identified for the SFN gene (14.3.3sigma) distinguished the patients presenting favorable outcome from those with progressing disease, independently from all known predictors (Training set: Overall Survival HR 8.53, p = 0.001; Validation set: HR 4.07, p = 0.008). The level of methylation in the tumors of high-risk patients surviving more than 60 months was comparable to that of tumors derived from lower risk patients and to that of benign ganglioneuroma. Methylation above the threshold level was associated with reduced SFN expression in comparison with samples below the threshold. Quantitative methylation is a promising tool to predict survival in neuroblastic tumor patients. Our results lead to the hypothesis that a subset of patients considered at high risk-but displaying low levels of methylation-could be assigned at a lower risk group.
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PMID:Outcome prediction and risk assessment by quantitative pyrosequencing methylation analysis of the SFN gene in advanced stage, high-risk, neuroblastic tumor patients. 1962 86

The authors propose a spatiotemporal enhancement pattern (STEP) for comprehensive characterization of breast tumors in contrast-enhanced MR images. By viewing serial contrast-enhanced MR images as a single spatiotemporal image, they formulate the STEP as a combination of (1) dynamic enhancement and architectural features of a tumor, and (2) the spatial variations of pixelwise temporal enhancements. Although the latter has been widely used by radiologists for diagnostic purposes, it has rarely been employed for computer-aided diagnosis. This article presents two major contributions. First, the STEP features are introduced to capture temporal enhancement and its spatial variations. This is essentially carried out through the Fourier transformation and pharmacokinetic modeling of various temporal enhancement features, followed by the calculation of moment invariants and Gabor texture features. Second, for effectively extracting the STEP features from tumors, we develop a graph-cut based segmentation algorithm that aims at refining coarse manual segmentations of tumors. The STEP features are assessed through their diagnostic performance for differentiating between benign and malignant tumors using a linear classifier (along with a simple ranking-based feature selection) in a leave-one-out cross-validation setting. The experimental results for the proposed features exhibit superior performance, when compared to the existing approaches, with the area under the ROC curve approaching 0.97.
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PMID:STEP: spatiotemporal enhancement pattern for MR-based breast tumor diagnosis. 1967 18

New parameters that could be used as tumor markers for lung cancer would be valuable. Our aim was to analyze the fatty acid profiles of total lipids from erythrocytes and platelets from patients with advanced non-small cell lung cancer (NSCLC), chronic obstructive pulmonary disease (COPD) and asthma to reveal the fatty acids that could be used as NSCLC biomarkers. In our study, 50, 15 and 15 patients with advanced NSCLC, COPD and asthma and 50 healthy subjects were enrolled. Fatty acid profiles were investigated using gas chromatography/mass spectrometry followed by ROC (receiver operating characteristics) curves analysis to gain information about biomarkers. Sialic acid (SA) and cytokeratins were measured by the thiobarbituric acid and immunoradiometric methods respectively. Useful fatty acid markers were as follows: erythrocytes, 22:0 and linoleic acid (LA, 18:2n6); platelets, 16:0, 18:0, and LA. At the cutoff value to obtain maximum accuracy, the best biomarker was platelet LA, with higher diagnostic yields than the commonly used markers SA or cytokeratins (100%, 76%, 75% and 86% sensitivity, specificity, positive predictive value and accuracy, respectively). These findings suggest that platelet LA might be used as a biomarker of NSCLC in relation to different aspects of the disease process that now needs to be explored.
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PMID:Platelet linoleic acid is a potential biomarker of advanced non-small cell lung cancer. 1973 67

The purpose of this paper is to demonstrate that voxels with inhomogeneously broadened water resonances, as revealed by high spectral and spatial resolution (HiSS) MRI, correlate with underlying tumor pathology findings, and thus carry diagnostically useful information. Thirty-four women with mammographically suspicious breast lesions were imaged at 1.5 T, using high-resolution echo-planar spectroscopic imaging. Fourier component images (FCIs) of the off-peak spectral signal were generated, and clusters of voxels with significant inhomogeneous broadening (broadened clusters) were identified and correlated to biopsy results. Inhomogeneously broadened clusters were found significantly more frequently in malignant than in benign lesions. A larger percentage of broadened cluster voxels were found inside the malignant versus benign lesions. The high statistical significance for separation of benign and malignant lesions was robust over a large range of post-processing parameters, with a maximum ROC area under curve of 0.83. In the human breast, an inhomogeneously broadened water resonance can serve as a correlate marker for malignancy and is likely to reflect the underlying anatomy or physiology.
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PMID:Fourier component imaging of water resonance in the human breast provides markers for malignancy. 1974 Dec 76

Matrix metalloproteases (MMPs) are endopeptidases involved in tumor cell invasion. Childhood acute lymphoblastic leukemia (ALL) is characterized by its capacity to infiltrate different organs. We analyzed the expression of MMP-2, -9, -14 and TIMP-1 and -2 in a prospective study on 86 children with newly diagnosed ALL (73 B- and 13 T-lineage) and 9 children at relapse with B-ALL. Membrane-bound and intracytoplasmic MMPs and TIMPs were analyzed by flow cytometry, and secreted MMPs were quantified by ELISA. In patients at relapse, MMP-14 was present in a greater proportion of the B-ALL cell population than at diagnosis. In patients with peripheral infiltration, intracytoplasmic MMP-9 was significantly higher than in patients without infiltration. ROC curve and Kaplan-Meier curve analysis showed that a high secretion of MMP-9 (>2450 pg/ml/10(6) cells) was associated with a lower overall survival rate, suggesting that the secretion of MMP-9 is an independent prognostic factor in childhood B-ALL.
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PMID:In vitro secretion of matrix metalloprotease 9 is a prognostic marker in childhood acute lymphoblastic leukemia. 1974 69

Resistance to radio and chemotherapy is one of the major drawbacks in the progression of head and neck squamous cell cancer (HNSCC) patients, evidencing the importance of finding optimum molecular prognosis markers to develop personalized treatment schedules. TGF-beta effector TAK1 activity has been related to a greater aggressiveness in several types of cancer (Kondo et al. 1998; Edlund et al. 2003; Kaur et al. 2005) and, although there has been described no significant implication of TAK1 in HNSCC development, we have further examined the role of its mRNA expression as a marker of prognosis in HNSCC. Fifty-nine advanced HNSCC patients were recruited for the study. The tumor expression of TAK1 mRNA was analyzed with RT-PCR using Taqman technology and its relationship with the clinical outcome of the patients studied. TAK1 mRNA expression was lower in patients that relapsed than in those that did not, but the difference was only significant between the patients that showed response to treatment (p < 0.001). ROC curve analyses pointed a 0.5 expression ratio TAK1/B2M value as an optimum cut-off point for relapse and response. Our data suggest the TAK1 mRNA analysis by Taqman RT-PCR can predict the risk of relapse in HNSCC patients.
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PMID:TAK1 mRNA expression in the tumor tissue of locally advanced head and neck cancer patients. 1978 75

Several tools for predicting the likelihood of non-sentinel lymph node (non-SLN) involvement in SLN positive breast cancer patients have been created so far.The aim of our study was to create and validate different nomograms for predicting the likelihood of non-SLN involvement that would be applicable in different institutions and that would also include the results of the preoperative US examination of the axilla. From January 2000 to January 2009, 534 breast cancer patients underwent axillary lymph node dissection (ALND) due to metastatic SLN at our institution. Using logistic regression results three nomograms differing in the inclusion of the results of intraoperative examination of SLN were created. The nomograms were validated using bootstrap methods. In all three nomograms, US examination of the axilla was a powerful independent variable. Other variables included(different in different nomograms) were tumor size, lymphovascular invasion, metastasis size in SLN, number of negative and number of positive SLNs. Mean absolute error and mean area under the ROC curve equals to 0.016 and 0.77 for the first, 0.023 and 0.75 for the second and 0.014 and 0.79 for the third nomogram. Three nomograms for predicting the likelihood of non-SLN metastases including the results of the preoperative US examination of the axilla were created at our institution. They differ in the inclusion of the results of intraoperative examination of SLNs and are thus applicable in different institutions. The validation results seem promising and omission of completion ALND might be considered in patients with the probability of having non-SLN metastases of 10% or less.
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PMID:Ljubljana nomograms for predicting the likelihood of non-sentinel lymph node metastases in breast cancer patients with a positive sentinel lymph node. 1978 49


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