Purpose Current Lynch syndrome (LS) prediction models quantify the risk to an individual of carrying a pathogenic germline mutation in three mismatch repair (MMR) genes: MLH1, MSH2, and MSH6. We developed a new prediction model, PREMM, that incorporates the genes PMS2 and EPCAM to provide comprehensive LS risk assessment. Patients and Methods PREMM was developed to predict the likelihood of a mutation in any of the LS genes by using polytomous logistic regression analysis of clinical and germline data from 18,734 individuals who were tested for all five genes. Predictors of mutation status included sex, age at genetic testing, and proband and family cancer histories. Discrimination was evaluated by the area under the receiver operating characteristic curve (AUC), and clinical impact was determined by decision curve analysis; comparisons were made to the existing PREMM model. External validation of PREMM was performed in a clinic-based cohort of 1,058 patients with colorectal cancer. Results Pathogenic mutations were detected in 1,000 (5%) of 18,734 patients in the development cohort; mutations included MLH1 (n = 306), MSH2 (n = 354), MSH6 (n = 177), PMS2 (n = 141), and EPCAM (n = 22). PREMM distinguished carriers from noncarriers with an AUC of 0.81 (95% CI, 0.79 to 0.82), and performance was similar in the validation cohort (AUC, 0.83; 95% CI, 0.75 to 0.92). Prediction was more difficult for PMS2 mutations (AUC, 0.64; 95% CI, 0.60 to 0.68) than for other genes. Performance characteristics of PREMM exceeded those of PREMM. Decision curve analysis supported germline LS testing for PREMM scores ≥ 2.5%. Conclusion PREMM provides comprehensive risk estimation of all five LS genes and supports LS genetic testing for individuals with scores ≥ 2.5%. At this threshold, PREMM provides performance that is superior to the existing PREMM model in the identification of carriers of LS, including those with weaker phenotypes and individuals unaffected by cancer.

CYP2B6-G516T polymorphisms significantly affect the CL/F rate of EFV in children. Changes in hepatic enzyme activity by age may need to be considered when evaluating the impact of genetic variants on antiretroviral pharmacokinetics in children.

Objective To assess the pharmacokinetic (PK), safety and efficacy of dolutegravir plus optimized background regimen (OBR) in HIV infected treatment-experienced adolescents. Methods Children ≥12 to < 18 years received dolutegravir weight-based fixed doses at ~1.0 mg/kg once daily in a Phase I/II multicenter open-label 48 week study. Intensive PK evaluation was done at steady state after dolutegravir was added to a failing regimen or started at the end of a treatment interruption. Safety and HIV RNA and CD4 cell count assessments were performed through Week 48. Results Twenty three adolescents, were enrolled and 22 (96%) completed the 48 week study visit. Median age and weight were 15 years and 52 kg, respectively. Median (IQR) baseline CD4+ cell count was 466 cells/µL (297, 771). Median (IQR) baseline HIV-1 RNA log10 was 4.3 log10 copies/mL (3.9, 4.6). Dolutegravir geometric mean AUC(0–24) and C24 were 46.0 µg.h/mL and 0.90 µg/mL, respectively, which were within the study targets based on adult PK ranges. Virologic success with an HIV RNA < 400 copies/mL was achieved in 74 % (95% CI: 52% to 90%) at Week 48. Additionally, 61% (95% CI: 39% to 80%) had an HIV RNA < 50 copies/mL at Week 48. Median (IQR) gain in CD4 cell count at Week 48 was 84 cells/µL (−81, 238). Dolutegravir was well tolerated, with no Grade 4 AEs, SAEs or discontinuations due to AEs. Conclusions Dolutegravir achieved target PK exposures in adolescents. Dolutegravir was safe and well tolerated, providing good virologic efficacy through Week 48.

NCT00485264.