Good laboratory practices for molecular genetic testing for heritable diseases and conditions.

Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations, laboratory testing is categorized as waived (from routine regulatory oversight) or nonwaived based on the complexity of the tests; tests of moderate and high complexity are nonwaived tests. Laboratories that perform molecular genetic testing are subject to the general CLIA quality systems requirements for nonwaived testing and the CLIA personnel requirements for tests of high complexity. Although many laboratories that perform molecular genetic testing comply with applicable regulatory requirements and adhere to professional practice guidelines,specific guidelines for quality assurance are needed to ensure the quality of test performance. To enhance the oversight of genetic testing under the CLIA framework,CDC and the Centers for Medicare & Medicaid Services (CMS) have taken practical steps to address the quality management concerns in molecular genetic testing,including working with the Clinical Laboratory Improvement Advisory Committee (CLIAC). This report provides CLIAC recommendations for good laboratory practices for ensuring the quality of molecular genetic testing for heritable diseases and conditions. The recommended practices address the total testing process (including the preanalytic,analytic,and postanalytic phases),laboratory responsibilities regarding authorized persons,confidentiality of patient information,personnel competency,considerations before introducing molecular genetic testing or offering new molecular genetic tests,and the quality management system approach to molecular genetic testing. These recommendations are intended for laboratories that perform molecular genetic testing for heritable diseases and conditions and for medical and public health professionals who evaluate laboratory practices and policies to improve the quality of molecular genetic laboratory services. This report also is intended to be a resource for users of laboratory services to aid in their use of molecular genetic tests and test results in health assessment and care. Improvements in the quality and use of genetic laboratory services should improve the quality of health care and health outcomes for patients and families of patients.

Tyrosine kinase inhibitors potentiate the cytotoxicity of MDR-substrate anticancer agents independent of growth factor receptor status in lung cancer cell lines.

To investigate the interactions of Epidermal Growth Factor Receptor (EGFR)-inhibiting tyrosine kinase inhibitors (TKIs) on P-gp-mediated drug resistance, we tested three TKIs, lapatinib, gefitinib and erlotinib in direct ATPase assays and in Non-Small Cell Lung Cancer (NCSLC) cell lines with defined low levels of growth factor receptor expression. The three TKIs potentiated the action of known P-gp substrate cytotoxic drugs at therapeutically-relevant concentrations. However, more detailed analysis revealed that the interaction of lapatinib with P-gp was distinct from that of gefitinib and erlotinib, and was characterised by direct inhibition of the stimulated P-gp ATPase activity. Lapatinib proved the most potent P-gp modulator of the TKIs examined. Drug transport studies in the P-gp-over-expressing A549-Taxol cell line showed that lapatinib and erlotinib are capable of increasing docetaxel accumulation at clinically achievable concentrations. Combination studies with P-gp substrate chemotherapeutic agents, demonstrated that all three TKIs have significant potential to augment cytotoxic activity against P-gp-positive malignancies, however, interestingly, these agents also potentiated the toxicity of epirubicin in non-P-gp resistant parental cells. Our observations suggest that the combination of lapatinib with a taxane or anthracycline warrants clinical investigation in NSCLC to examine if beneficial or detrimental interactions may result.