Validation of Analytic Methods for Biomarkers Used in Drug Development

The role of biomarkers in drug discovery and development has gained precedence over the years. As biomarkers become integrated into drug development and clinical trials, quality assurance and in particular assay validation becomes essential with the need to establish standardized guidelines for analytical methods used in biomarker measurements. New biomarkers can revolutionize both the development and use of therapeutics, but is contingent upon the establishment of a concrete validation process that addresses technology integration and method validation as well as regulatory pathways for efficient biomarker development. This perspective focuses on the general principles of the biomarker validation process with an emphasis on assay validation and the collaborative efforts undertaken by various sectors to promote the standardization of this procedure for efficient biomarker development

Cancer screening in France: subjects’ and physicians’ attitudes

International audienceOBJECTIVE: Since screening for cancer has been advocated, funded, and promoted in France, it is important to evaluate the attitudes of subjects in the general population and general practitioners (GPs) toward cancer screening strategies. METHODS: EDIFICE is a nationwide opinion poll that was carried out by telephone among a representative sample of 1,504 subjects living in France and aged between 40 and 75 years and among a representative sample of 600 GPs. The questionnaire administered to subjects queried about previous screening for cancer. RESULTS: Ninety-three percent of women stated that they had undergone at least one mammography. Although rated "A" recommendation-strongly recommended-by the US Preventive Services Task Force, screening for colorectal cancer received less attention than prostate cancer screening which is rated "I"-insufficient evidence-(reported screening rates of 25% and 36%, respectively). Six percent of subjects stated that they had undergone lung cancer screening. GPs' attitudes toward cancer screening showed similar inconsistencies. CONCLUSIONS: It thus appears that understanding of cancer screening practices in the French general population does not match scientific evidence. To a lesser extent, this also holds for GPs

Soluble Isoforms of Vascular Endothelial Growth Factor Are Predictors of Response to Sunitinib in Metastatic Renal Cell Carcinomas

Angiogenesis is the target of several agents in the treatment of malignancies, including renal cell carcinoma (RCC). There is a real need for surrogate biomarkers that can predict selection of patients who may benefit from antiangiogenic therapies, prediction of disease outcome and which may improve the knowledge regarding mechanism of action of these treatments. Tyrosine kinase inhibitors (TKI) have proven efficacy in metastatic RCC (mRCC). However, the molecular mechanisms underlying the clinical response to these drugs remain unclear.The present study aimed to identify molecular biomarkers associated with the response to sunitinib, a Tyrosine kinase inhibitor. To evaluate this relationship, primary tumors from 23 metastatic RCC patients treated by sunitinib were analyzed for a panel of 16 biomarkers involved in tumor pathways targeted by sunitinib, using real-time quantitative reverse-transcriptase PCR. Nine of the 23 patients (39%) responded to sunitinib. Among transcripts analyzed, only the levels of vascular endothelial growth factor (VEGF) soluble isoforms (VEGF(121) and VEGF(165)) were associated with the response to sunitinib (P = 0.04 for both). Furthermore, the ratio of VEGF soluble isoforms (VEGF(121)/VEGF(165)) was significantly associated with prognosis (P = 0.02).This preliminary study provides a promising tool that might help in the management of metastatic RCC, and could be extended to other tumors treated by TKI

Impact of organised programs on colorectal cancer screening

<p>Abstract</p> <p>Purpose</p> <p>Colorectal cancer (CRC) screening has been shown to decrease CRC mortality. Organised mass screening programs are being implemented in France. Its perception in the general population and by general practitioners is not well known.</p> <p>Methods</p> <p>Two nationwide observational telephone surveys were conducted in early 2005. First among a representative sample of subjects living in France and aged between 50 and 74 years that covered both geographical departments with and without implemented screening services. Second among General Practionners (Gps). Descriptive and multiple logistic regression was carried out.</p> <p>Results</p> <p>Twenty-five percent of the persons(N = 1509) reported having undergone at least one CRC screening, 18% of the 600 interviewed GPs reported recommending a screening test for CRC systematically to their patients aged 50–74 years. The odds ratio (OR) of having undergone a screening test using FOBT was 3.91 (95% CI: 2.49–6.16) for those living in organised departments (referent group living in departments without organised screening), almost twice as high as impact educational level (OR = 2.03; 95% CI: 1.19–3.47).</p> <p>Conclusion</p> <p>CRC screening is improved in geographical departments where it is organised by health authorities. In France, an organised screening programs decrease inequalities for CRC screening.</p

Multifunctional Compounds for Activation of the p53‐Y220C Mutant in Cancer

The p53 protein plays a major role in cancer prevention, and over 50&thinsp;% of cancer diagnoses can be attributed to p53 malfunction. The common p53 mutation Y220C causes local protein unfolding, aggregation, and can result in a loss of Zn in the DNA‐binding domain. Structural analysis has shown that this mutant creates a surface site that can be stabilized using small molecules, and herein a multifunctional approach to restore function to p53‐Y220C is reported. A series of compounds has been designed that contain iodinated phenols aimed for interaction and stabilization of the p53‐Y220C surface cavity, and Zn‐binding fragments for metallochaperone activity. Their Zn‐binding affinity was characterized using spectroscopic methods and demonstrate the ability of compounds L4 and L5 to increase intracellular levels of Zn2+ in a p53‐Y220C‐mutant cell line. The in vitro cytotoxicity of our compounds was initially screened by the National Cancer Institute (NCI‐60), followed by testing in three stomach cancer cell lines with varying p53 status’, including AGS (WTp53), MKN1 (V143A), and NUGC3 (Y220C). Our most promising ligand, L5, is nearly 3‐fold more cytotoxic than cisplatin in a large number of cell lines. The impressive cytotoxicity of L5 is further maintained in a NUGC3 3D spheroid model. L5 also induces Y220C‐specific apoptosis in a cleaved caspase‐3 assay, reduces levels of unfolded mutant p53, and recovers p53 transcriptional function in the NUGC3 cell line. These results show that these multifunctional scaffolds have the potential to restore wild‐type function in mutant p53‐Y220C

Multidetector computed tomography angiography for assessment of in-stent restenosis: meta-analysis of diagnostic performance

<p>Abstract</p> <p>Background</p> <p>Multi-detector computed tomography angiography (MDCTA)of the coronary arteries after stenting has been evaluated in multiple studies.</p> <p>The purpose of this study was to perform a structured review and meta-analysis of the diagnostic performance of MDCTA for the detection of in-stent restenosis in the coronary arteries.</p> <p>Methods</p> <p>A Pubmed and manual search of the literature on in-stent restenosis (ISR) detected on MDCTA compared with conventional coronary angiography (CA) was performed. Bivariate summary receiver operating curve (SROC) analysis, with calculation of summary estimates was done on a stent and patient basis. In addition, the influence of study characteristics on diagnostic performance and number of non-assessable segments (NAP) was investigated with logistic meta-regression.</p> <p>Results</p> <p>Fourteen studies were included. On a stent basis, Pooled sensitivity and specificity were 0.82(0.72–0.89) and 0.91 (0.83–0.96). Pooled negative likelihood ratio and positive likelihood ratio were 0.20 (0.13–0.32) and 9.34 (4.68–18.62) respectively. The exclusion of non-assessable stents and the strut thickness of the stents had an influence on the diagnostic performance. The proportion of non-assessable stents was influenced by the number of detectors, stent diameter, strut thickness and the use of an edge-enhancing kernel.</p> <p>Conclusion</p> <p>The sensitivity of MDTCA for the detection of in-stent stenosis is insufficient to use this test to select patients for further invasive testing as with this strategy around 20% of the patients with in-stent stenosis would be missed. Further improvement of scanner technology is needed before it can be recommended as a triage instrument in practice. In addition, the number of non-assessable stents is also high.</p

ETUDE DE PHASE I/II DE LA COMBINAISON DE TIRAPAZAMINE A L'ASSOCIATION CISPLATINE-VINORELBINE CHEZ LES PATIENTS ATTEINTS DE CARCINOME BRONCHIQUE NON A PETITES CELLULES AVANCE

PARIS12-CRETEIL BU Médecine (940282101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Utilisation en période péri-opératoire et complications chirurgicales du Sunitinib

L objectif principal de cette étude était d évaluer les complications post-opératoires des patients ayant reçu du sunitinib durant la période péri opératoire dans le cadre du traitement d un adénocarcinome rénal métastatique. L objectif secondaire était d établir à partir des données obtenues et d une revue exhaustive de la littérature, des règles de prescription du sunitinib afin qu il s insère au mieux dans la stratégie de prise en charge des patients. Entre octobre 2005 et juin 2007, 52 patients d un age moyen de 57 ans qui recevaient du Sunitinib pour un cancer du rein métastatique ont été suivis. Les effets secondaires et complications ont été répertoriés suivant la classification NCI CTC. Parmi les 52 patients suivis, 9 (17%) ont été opérés dans les 90 jours qui précédaient l initiation ou qui suivaient la fin du traitement et il y a eu au total 11 événements chirurgicaux. Parmi ces patients opérés, 4 présentaient une toxicité cutanée au moins grade 2 liée au Sunitinib. Le délai moyen d interruption du sunitinib avant chirurgie était de 7,8 (0-54) jours et le délai de reprise était de 19,8 (0-55) jours. Sur l ensemble des 11 procédures réalisées il n y a eu que 2 complications, à chaque fois à type de nécrose cutanée. Ces nécroses sont survenues chez des patients présentant antérieurement une toxicité cutanée grade 3 au Sunitinib. En conclusion, le Sunitinib semble montrer une faible toxicité en période péri opératoire. Cependant, les patients qui présentent une toxicité cutanée antérieure à la chirurgie semblent plus à risque de développer un retard de cicatrisation sévère. En l absence de références dans la littérature et devant un rationnel physiopathologique fort nous recommandons pour l instant la prudence. Ainsi, le sunitinib devrait être arrêté durant les 10 jours qui précédent et qui suivent la chirurgie, Aux vues de ces résultats, ce délai devrait revu en cas de toxicité cutanée préexistante.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Optimisation du transfert du gène de la thymidine kinase dans des cellules malignes sous contrôle de promoteurs spécifiques

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

ETUDE DE PHASE I/II DE LA COMBINAISON DE TIRAPAZAMINE A L'ASSOCIATION CISPLATINE-VINORELBINE CHEZ LES PATIENTS ATTEINTS DE CARCINOME BRONCHIQUE NON A PETITES CELLULES AVANCE

PARIS12-CRETEIL BU Médecine (940282101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF