Identifying the need to refine the potential patient risk factors for niraparib-induced thrombocytopenia.

OBJECTIVE: Niraparib is a poly (ADP-ribose) polymerase inhibitor (PARP) approved for use in maintenance therapy for ovarian cancer that is associated with the unpredictable grade 3/4 thrombocytopenia. This study was conducted to refine patient dosing recommendations for niraparib based upon clinical practice observations of grade 3/4 thrombocytopenia. METHODS AND MATERIALS: Six patient cases were reviewed to identify similarities in patient factors. An in vitro study was conducted using healthy volunteer blood spiked with Niraparib concentrations ranging from 0 ng/mL to 5000 ng/mL. Manual platelet counts were evaluated at different time intervals for each concentration and compared to untreated controls. Data was then analyzed based on percent change in platelet count versus untreated control for each concentration/time point. RESULTS: In three patients with body weight > 80 kg and platelet count >200 × 109/L, decreased creatinine clearance (CrCl) <60 mL/min was identified as potential signal. An additional three patients with weights below 77 kg and/or baseline platelet counts <150 × 109/L were re-evaluated, and it was observed that all had decreased CrCl of <60 mL/min. Albumin <3.5 g/dL was also observed in some patients with thrombocytopenia. The in vitro study, observed a direct concentration-dependent relationship between niraparib and thrombocytopenia. CONCLUSION: The data suggests that renal insufficiency and hypoalbuminemia may be associated with the development of niraparib-induced thrombocytopenia. Moreover, the preliminary in vitro studies also demonstrated a concentration-dependent relationship between niraparib and direct toxicity to platelets.

Using Simulation to Define the Learning Curve for the Digital Cervical Examination.

INTRODUCTION: To assess how skill in the digital cervical examination is acquired in medical students. METHODS: In a longitudinal study, medical students completed 200 simulated cervical examinations. We performed regressions of each student's cumulative accuracy using the linear, power, and sigmoidal models to determine best fit. We also constructed multilevel models to determine the influence of dilation and effacement on accuracy and to determine whether the starting level and rate of learning varied between individuals. To assess skill decay, we assessed accuracy at 1, 2, and 5 months after training. We defined the amount of sustained accuracy needed to achieve competence using cumulative summation analyses and determined the amount of practice needed to reach this level of skill. RESULTS: Twenty-five medical students participated. The median (interquartile range) of cumulative accuracy at the end of the study was 69% (65-78) for dilation and 80% (76-91) for effacement. The sigmoidal model had the best fit. All students achieved competence during the study. The multilevel models showed that accuracy decreased with higher dilation and lower effacement and found that starting level and rate of learning varied between individuals. Maximal accuracy in both dilation and effacement was seen after 150 repetitions. Accuracy of the medical students persisted for 1 month for dilation and 2 months for effacement. The average±SD number of repetitions needed to achieve competence was 89±46 (range 35-195) for dilation and 48±38 (range 11-174) for effacement. DISCUSSION: Based on the variability in skill between individuals and the rate of skill acquisition and decay, we feel that a competence-based rather than time-based approach is most appropriate, that trainee performance should be monitored both during and after training, and that 150 repetitions, or more, should be included in any digital cervical examination simulation regimen.