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1.
Eur J Gastroenterol Hepatol ; 28(2): 164-72, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26560750

ABSTRACT

BACKGROUND AND AIMS: In many countries, current treatment for patients with chronic hepatitis C involves a combination of peginterferon and ribavirin, associated with a protease inhibitor for hepatitis C virus genotype 1. More recent and efficient less toxic antiviral treatments are now available for some patients. Thus, the decision to treat or to wait is challenging. The aims of this study were to: (a) estimate the proportion of treated patients, (b) evaluate the reasons for this decision, and (c) examine the patients' points-of-view in treatment decision. METHODS: This was a prospective study conducted at three French referral centers between March and June 2013. Epidemiological and virological data, reasons for treatment or nontreatment, and data on the doctors' and patients' choices were collected. RESULTS: A total of 255 patients were analyzed. Only 52.6% of patients with fibrosis of 2 or higher were treated. Treatment uptake was reduced in the following groups: previously treated patients, those with poor tolerance during prior treatment, those with heavy alcohol consumption, and those with hepatocellular carcinoma. Of the cirrhotic patients, 55% were not treated: 51.1% had a contraindication, 22.2% had a previous nonresponse. When treatment was refused by the patient, fear of side effects and professional problems were the most frequently cited reasons (90 and 40%, respectively). CONCLUSION: Patients were treated primarily according to consensus guidelines. However, only 45% of cirrhotic patients were treated. In 7.6% of the cases, the patient refused therapy. This study enabled us to measure the importance of patient choice in medical decision-making. Well-informed patients expected not only more efficient but also well-tolerated therapy.


Subject(s)
Antiviral Agents/therapeutic use , Decision Support Techniques , Hepatitis C, Chronic/drug therapy , Protease Inhibitors/therapeutic use , Time-to-Treatment , Antiviral Agents/adverse effects , Female , France/epidemiology , Guideline Adherence , Health Knowledge, Attitudes, Practice , Hepatitis C, Chronic/diagnosis , Hepatitis C, Chronic/epidemiology , Humans , Male , Middle Aged , Patient Education as Topic , Patient Participation , Patient Preference , Patient Selection , Practice Guidelines as Topic , Practice Patterns, Physicians' , Prospective Studies , Protease Inhibitors/adverse effects , Severity of Illness Index , Time Factors , Treatment Outcome , Treatment Refusal
2.
Eur Urol ; 58(1): 96-104, 2010 Jul.
Article in English | MEDLINE | ID: mdl-19674832

ABSTRACT

BACKGROUND: Accumulating evidence suggests that DNA methylation markers could serve as sensitive and specific cancer biomarkers. OBJECTIVE: To determine whether a panel of methylated genes would have the potential to identify primary bladder cancer (BCa) in voided urine samples. DESIGN, SETTING, AND PARTICIPANTS: A pharmacologic unmasking reexpression analysis in BCa cell lines was initially undertaken to unveil candidate methylated genes, which were then evaluated in methylation-specific polymerase chain reaction (MSP) assays performed on DNA extracted from noncancerous and cancerous bladder tissues. The most frequently methylated genes in cancerous tissues, with 100% specificity, were retained for subsequent MSP analysis in DNA extracted from urine samples to build and validate a panel of potential methylated gene markers. Urine samples were prospectively collected at three urologic centres from patients with histologically proven BCa and processed for use in real-time MSP and cytologic analysis. Patients with nonmalignant urologic disorders were included as controls. MEASUREMENTS: A urine sample was classified as valid when > or = 10 copies of the gene encoding ß-actin were measured in the urine sediment genomic DNA. Sensitivity, specificity, and predictive values of the MSP and cytology tests were assessed and compared. RESULTS AND LIMITATIONS: MSP assays performed on 466 of the 496 (94%) valid urine samples identified two genes, TWIST1 and NID2, that were frequently methylated in urine samples collected from BCa patients, including those with early-stage and low-grade disease. The sensitivity of this two-gene panel (90%) was significantly better than that of cytology (48%), with comparable specificity (93% and 96%, respectively). The positive predictive value and negative predictive value of the two-gene panel was 86% and 95%, respectively. CONCLUSIONS: Detection of the methylated TWIST1 and NID2 genes in urine sediments using MSP provides a highly (> or = 90%) sensitive and specific, noninvasive approach for detecting primary BCa. TRIAL REGISTRATION: BlCa-001 study - EudraCt 2006-003303-40.


Subject(s)
Biomarkers, Tumor/genetics , Cell Adhesion Molecules/genetics , DNA Methylation , DNA, Neoplasm/urine , Nuclear Proteins/genetics , Twist-Related Protein 1/genetics , Urinary Bladder Neoplasms/diagnosis , Actins/genetics , Actins/urine , Adult , Aged , Aged, 80 and over , Calcium-Binding Proteins , Cell Line, Tumor , Female , Humans , Male , Middle Aged , Neoplasm Staging , Polymerase Chain Reaction , Prospective Studies , Sensitivity and Specificity , Urinary Bladder Neoplasms/urine
3.
J Mol Diagn ; 10(4): 332-7, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18556773

ABSTRACT

Epigenetic silencing of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) by promoter methylation predicts successful alkylating agent therapy, such as with temozolomide, in glioblastoma patients. Stratified therapy assignment of patients in prospective clinical trials according to tumor MGMT status requires a standardized diagnostic test, suitable for high-throughput analysis of small amounts of formalin-fixed, paraffin-embedded tumor tissue. A direct, real-time methylation-specific PCR (MSP) assay was developed to determine methylation status of the MGMT gene promoter. Assay specificity was obtained by selective amplification of methylated DNA sequences of sodium bisulfite-modified DNA. The copy number of the methylated MGMT promoter, normalized to the beta-actin gene, provides a quantitative test result. We analyzed 134 clinical glioma samples, comparing the new test with the previously validated nested gel-based MSP assay, which yields a binary readout. A cut-off value for the MGMT methylation status was suggested by fitting a bimodal normal mixture model to the real-time results, supporting the hypothesis that there are two distinct populations within the test samples. Comparison of the tests showed high concordance of the results (82/91 [90%]; Cohen's kappa = 0.80; 95% confidence interval, 0.82-0.95). The direct, real-time MSP assay was highly reproducible (Pearson correlation 0.996) and showed valid test results for 93% (125/134) of samples compared with 75% (94/125) for the nested, gel-based MSP assay. This high-throughput test provides an important pharmacogenomic tool for individualized management of alkylating agent chemotherapy.


Subject(s)
DNA Methylation , Glioma/diagnosis , O(6)-Methylguanine-DNA Methyltransferase/genetics , Polymerase Chain Reaction/methods , Promoter Regions, Genetic/genetics , Glioma/genetics , Humans , Reproducibility of Results , Sensitivity and Specificity
4.
Am J Pathol ; 160(1): 113-22, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11786405

ABSTRACT

Local cellular immune defects have been described in several tumors including human papillomavirus (HPV)-associated cervical cancer. This observation suggests the potential therapeutic benefit of immune manipulations that restore cellular immunity. Here, we evaluated the ability of bispecific monoclonal antibodies (bimAbs) to redirect T cells against keratinocytes transformed in vitro by HPV in an autologous three-dimensional culture model (organotypic cultures). The epidermal growth factor receptor (EGFR) was chosen as target for an anti-CD3/anti-EGFR bimAb because it is overexpressed in many malignant epithelial lesions and only weakly expressed in the basal layers of normal squamous epithelium. Interestingly, in organotypic cultures, the pattern of expression of EGFR was similar to that observed in vivo. The ability of T cells retargeted by CD3/EGFR bimAb to lyse HPV-transformed cell lines was confirmed in monolayer cultures. In autologous organotypic cultures, an increase in apoptotic HPV(+) keratinocytes and a significant decrease in the thickness of HPV(+) organotypic cultures were observed when activated lymphocytes and bimAbs were added to the cultures, whereas organotypic cultures of normal keratinocytes were not significantly affected. These data were similar to those obtained in the allogeneic model. These results suggest the potential usefulness of CD3-EGFR bimAb-retargeted lymphocytes in immunotherapeutic protocols for malignant epithelial lesions.


Subject(s)
Antibodies, Monoclonal/pharmacology , CD3 Complex/immunology , ErbB Receptors/immunology , Keratinocytes/immunology , Lymphocytes/drug effects , Lymphocytes/physiology , Uterine Cervical Neoplasms/immunology , Antibodies, Monoclonal/immunology , Antibody Specificity , Cytotoxicity, Immunologic , ErbB Receptors/metabolism , Female , Humans , Keratinocytes/metabolism , Keratinocytes/virology , Organ Culture Techniques , Papillomaviridae/isolation & purification , Tumor Cells, Cultured , Uterine Cervical Neoplasms/pathology
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