209 research outputs found

    Prediction of the outcome of preoperative chemotherapy in breast cancer using DNA probes that provide information on both complete and incomplete responses

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    <p>Abstract</p> <p>Background</p> <p>DNA microarray technology has emerged as a major tool for exploring cancer biology and solving clinical issues. Predicting a patient's response to chemotherapy is one such issue; successful prediction would make it possible to give patients the most appropriate chemotherapy regimen. Patient response can be classified as either a pathologic complete response (PCR) or residual disease (NoPCR), and these strongly correlate with patient outcome. Microarrays can be used as multigenic predictors of patient response, but probe selection remains problematic. In this study, each probe set was considered as an elementary predictor of the response and was ranked on its ability to predict a high number of PCR and NoPCR cases in a ratio similar to that seen in the learning set. We defined a valuation function that assigned high values to probe sets according to how different the expression of the genes was and to how closely the relative proportions of PCR and NoPCR predictions to the proportions observed in the learning set was. Multigenic predictors were designed by selecting probe sets highly ranked in their predictions and tested using several validation sets.</p> <p>Results</p> <p>Our method defined three types of probe sets: 71% were mono-informative probe sets (59% predicted only NoPCR, and 12% predicted only PCR), 25% were bi-informative, and 4% were non-informative. Using a valuation function to rank the probe sets allowed us to select those that correctly predicted the response of a high number of patient cases in the training set and that predicted a PCR/NoPCR ratio for validation sets that was similar to that of the whole learning set. Based on DLDA and the nearest centroid method, bi-informative probes proved more successful predictors than probes selected using a t test.</p> <p>Conclusion</p> <p>Prediction of the response to breast cancer preoperative chemotherapy was significantly improved by selecting DNA probe sets that were successful in predicting outcomes for the entire learning set, both in terms of accurately predicting a high number of cases and in correctly predicting the ratio of PCR to NoPCR cases.</p

    A Blueprint for the Problem Formulation Phase of EPA-Type Ecological Risk Assessments for 316(b) Determinations

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    The difference between management objectives focused on sustainability of fish populations and the indigenous aquatic community, and a management objective focused on minimizing entrainment and impingement losses accounts for much of the ongoing controversy surrounding §316(b). We describe the EPA’s ecological risk assessment framework and recommend that this framework be used to more effectively address differences in management objectives and structure §316(b) determinations. We provide a blueprint for the problem formulation phase of EPA-type ecological risk assessments for cooling-water intake structures (CWIS) at existing power plant facilities. Our management objectives, assessment endpoints, conceptual model, and generic analysis plan apply to all existing facilities. However, adapting the problem formulation process for a specific facility requires consideration of the permitting agency’s guidelines and level of regulatory concern, as well as site-specific ecological and technical differences. The facility-specific problem formulation phase is designed around the hierarchy of biolo gical levels of organization in the generic conceptual model and the sequence of cause-effect events and risk hypotheses represented by this model. Problem formulation is designed to be flexible in that it can be tailored for facilities where §316(b) regulatory concern is low or high. For some facilities, we anticipate that the assessment can be completed based on consideration of susceptibility alone. At the other extreme, a high level of regulatory concern combined with the availability of extensive information and consideration of costly CWIS mitigation options may result in the ecological risk assessment relying on analyses at all levels. Decisions on whether to extend the ecological risk assessment to additional levels should be based on whether regulatory or generator concerns merit additional analyses and whether available information is adequate to support such analyses. In making these decisions, the functional dependence between levels of analysis must be considered in making the transition to the analysis phase and risk estimation component of the ecological risk assessment. Regardless of how the generic analysis plan is modified to develop a facility-specific analysis plan, the resulting plan should be viewed as a tool for comparing representative species and alternative CWIS options by focusing on relative changes (i.e., proportional or percent changes) in various measures. The analysis plan is specifically designed to encourage consideration of multiple lines of evidence and to characterize uncertainties in each line of evidence. Multiple lines of evidence from different levels of analysis, obtained using both prospective and retrospective techniques, provide a broader perspective on the magnitude of potential effects and associated uncertainties and risks. The implications of the EPA’s recent (April 2002) proposed regulations for existing facilities on the applicability of this blueprint are briefly considered

    Evaluation of a 30-gene paclitaxel, fluorouracil, doxorubicin and cyclophosphamide chemotherapy response predictor in a multicenter randomized trial in breast cancer

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    PurposeWe examined in a prospective, randomized, international clinical trial the performance of a previously defined 30-gene predictor (DLDA-30) of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil, doxorubicin, cyclophosphamide (T/FAC) chemotherapy, and assessed if DLDA-30 also predicts increased sensitivity to FAC-only chemotherapy. We compared the pCR rates after T/FAC versus FAC×6 preoperative chemotherapy. We also performed an exploratory analysis to identify novel candidate genes that differentially predict response in the two treatment arms.Experimental Design273 patients were randomly assigned to receive either weekly paclitaxel × 12 followed by FAC × 4 (T/FAC, n=138), or FAC × 6 (n=135) neoadjuvant chemotherapy. All patients underwent a pretreatment FNA biopsy of the tumor for gene expression profiling and treatment response prediction.ResultsThe pCR rates were 19% and 9% in the T/FAC and FAC arms, respectively (p<0.05). In the T/FAC arm, the positive predictive value (PPV) of the genomic predictor was 38% (95%CI:21–56%), the negative predictive value (NPV) 88% (CI:77–95%) and the AUC 0.711. In the FAC arm, the PPV was 9% (CI:1–29%) and the AUC 0.584. This suggests that the genomic predictor may have regimen-specificity. Its performance was similar to a clinical variable-based predictor nomogram.ConclusionsGene expression profiling for prospective response prediction was feasible in this international trial. The 30-gene predictor can identify patients with greater than average sensitivity to T/FAC chemotherapy. However, it captured molecular equivalents of clinical phenotype. Next generation predictive markers will need to be developed separately for different molecular subsets of breast cancers

    Does the use of the 2009 FIGO classification of endometrial cancer impact on indications of the sentinel node biopsy?

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    <p>Abstract</p> <p>Background</p> <p>Lymphadenectomy is debated in early stages endometrial cancer. Moreover, a new FIGO classification of endometrial cancer, merging stages IA and IB has been recently published. Therefore, the aims of the present study was to evaluate the relevance of the sentinel node (SN) procedure in women with endometrial cancer and to discuss whether the use of the 2009 FIGO classification could modify the indications for SN procedure.</p> <p>Methods</p> <p>Eighty-five patients with endometrial cancer underwent the SN procedure followed by pelvic lymphadenectomy. SNs were detected with a dual or single labelling method in 74 and 11 cases, respectively. All SNs were analysed by both H&E staining and immunohistochemistry. Presumed stage before surgery was assessed for all patients based on MR imaging features using the 1988 FIGO classification and the 2009 FIGO classification.</p> <p>Results</p> <p>An SN was detected in 88.2% of cases (75/85 women). Among the fourteen patients with lymph node metastases one-half were detected by serial sectioning and immunohistochemical analysis. There were no false negative case. Using the 1988 FIGO classification and the 2009 FIGO classification, the correlation between preoperative MRI staging and final histology was moderate with Kappa = 0.24 and Kappa = 0.45, respectively. None of the patients with grade 1 endometrioid carcinoma on biopsy and IA 2009 FIGO stage on MR imaging exhibited positive SN. In patients with grade 2-3 endometrioid carcinoma and stage IA on MR imaging, the rate of positive SN reached 16.6% with an incidence of micrometastases of 50%.</p> <p>Conclusions</p> <p>The present study suggests that sentinel node biopsy is an adequate technique to evaluate lymph node status. The use of the 2009 FIGO classification increases the accuracy of MR imaging to stage patients with early stages of endometrial cancer and contributes to clarify the indication of SN biopsy according to tumour grade and histological type.</p
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