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Osimertinib is a third-generation, central nervous system-active, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) selective for EGFR-TKI sensitizing and T790M resistance mutations. This phase 1, open-label study (NCT02491944) investigated absolute bioavailability and pharmacokinetics (PK) of oral and intravenous (IV) osimertinib. Ten healthy subjects (21-61 years) received a single oral 80-mg dose concomitantly with a 100 μg (containing 1 μCi) IV microtracer dose of [ C]osimertinib. Oral and IV PK were determined simultaneously for osimertinib and its active metabolites, AZ5104 and AZ7550. High-performance liquid chromatography and accelerator mass spectrometry were used to characterize IV dose PK. Geometric mean absolute oral bioavailability of osimertinib was 69.8% (90% confidence interval, 66.7, 72.9). Oral osimertinib was slowly absorbed (median time to maximum plasma concentration [t ] 7.0 hours). Following t , plasma concentrations fell in an apparent monophasic manner. IV clearance and volume of distribution were 16.8 L/h and 1285 L, respectively. Arithmetic mean elimination half-life estimates were 59.7, 52.6, and 72.6 hours for osimertinib, AZ5104, and AZ7550, respectively (oral dosing), and 54.9, 68.4, and 99.7 hours for [ C]osimertinib, [ C]AZ5104, and [ C]AZ7550, respectively (IV dosing). Oral osimertinib was well absorbed. Simultaneous IV and oral PK analysis proved useful for complete understanding of osimertinib PK and showed that the first-pass effect was minimal for osimertinib.

Objectives: To determine the causes of death in patients with status epilepticus. To analyze the relative contributions of seizure etiology, seizure refractoriness, use of mechanical ventilation, anesthetic drugs for seizure control, and medical complications to in-hospital and 90-day mortality, hospital length of stay, and discharge disposition. Design: Retrospective cohort. Setting: Single-center neuroscience ICU. Participants: Patients with status epilepticus were identified by retrospective search of electronic database from January 1, 2011, to December 31, 2016. Interventions: Review of electronic medical records. Measurements and Main Results: Demographics, clinical characteristics, treatments, and outcomes were collected. Univariable and multivariable logistic regression analysis were used to determine whether the use of anesthetic drugs, mechanical ventilation, Status Epilepticus Severity Score, refractoriness of seizures, etiology of seizures, or medical complications were associated with in-hospital, 90-day mortality or discharge disposition. Among 244 patients with status epilepticus (mean age was 64 yr [interquartile range, 42–76], 55% male, median Status Epilepticus Severity Score 3 [interquartile range, 2–4]), 24 received anesthetic drug infusions for seizure control. In-hospital and 90-day mortality rates were 9.2% and 19.2%, respectively. Death was preceded by withdrawal of life-sustaining treatment in 19 patients (86.3%) and cardiac arrest in three (13.7%). Only Status Epilepticus Severity Score was associated with in-hospital and 90-day mortality, whereas the use of anesthetic drugs for seizure control, mechanical ventilation, medical complications, etiology, and refractoriness of seizures were not. Hospital length of stay was longer in patients with medical complications (p = 0.0091), refractory seizures (p = 0.0077), and in those who required anesthetic drugs for seizure control (p = 0.0035). Patients who had refractory seizures were less likely to be discharged home (odds ratio, 0.295; CI, 0.143–0.608; p = 0.0009). Conclusions: In this cohort, death primarily resulted from the underlying neurologic disease and withdrawal of life-sustaining treatment and not from our treatment choices. Use of anesthetic drugs, medical complications, and mechanical ventilation were not associated with in-hospital and 90-day mortality.

Objective• To externally validate currently available bladder cancer nomograms for prediction of all-cause survival (ACS), cancer-specific survival (CSS), other-cause mortality (OCM) and progression-free survival (PFS). Patients and Methods• Retrospective analysis of a prospectively maintained database of 282 patients who underwent robot-assisted radical cystectomy (RARC) at a single institution was performed.• The Bladder Cancer Research Consortium (BCRC), International Bladder Cancer Nomogram Consortium (IBCNC) and Lughezzani nomograms were used for external validation, and evaluation for accuracy at predicting oncological outcomes.• The 2-and 5-year oncological outcomes were compared, and nomogram performance was evaluated through measurement of the concordance (c-index) between nomogram-derived predicted oncological outcomes and observed oncological outcomes. Results• The median (range) patient age was 70 (36-90) years. At a mean follow-up of 20 months, local or distant disease recurrence developed in 30% of patients. With an overall mortality rate of 33%, 17% died from bladder cancer.• The actuarial 2-and 5-year PFS after RARC was 62% (95% confidence interval [CI] 54-68) and 55% (95% CI 46-63), respectively. • The actuarial 2-and 5-year ACS was 66% (95% CI [59][60][61][62][63][64][65][66][67][68][69][70][71][72] and 47% (95% CI 37-55), respectively, and the 2-and 5-year CSS was 81% (95% CI 74-86) and 67% (95% CI 57-76), respectively. Conclusions• Bladder cancer nomograms available from the current open RC literature adequately predict ACS, CSS and PFS after RARC.• However, prediction of advanced tumour stage and lymph node metastasis was modest and the Lughezzani nomogram failed to predict OCM.

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