AM CVn binaries consist of a WD accreting from a hydrogen-deficient star (or WD) companion (Warner, 1995;Solheim, 2010). In their formation history (Fig. 1.6 and Section 1.3.1.1), AM CVns form after at least one CE phase of their progenitor system. The current RLO is initiated, due to orbital damping caused by GW radiation, at orbital periods of typically 5−20 min (depending on the nature and the temperature of the companion star), and the mass-transfer rate is determined

BackgroundBrain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access.MethodsPatients with Her-2+ metastatic breast cancer either with at least one 1-cm diameter brain metastasis or without brain metastases underwent dynamic carbon-11 radiolabelled lapatinib ([11C]lapatinib)-PET. Less than 20 μg of [11C]lapatinib was administered before and after 8 days of oral lapatinib (1,500 mg once daily). Radial arterial blood sampling was performed throughout the 90-min scan. The contribution of blood volume activity to the tissue signal was excluded to calculate lapatinib uptake in normal brain and metastases. Partitioning of radioactivity between plasma and tissue (V T) was calculated and the tissue concentration of lapatinib derived. Plasma lapatinib levels were measured and adverse events noted.ResultsSix patients (three with brain metastases) were recruited. About 80% plasma radioactivity corresponded to intact [11C]lapatinib after 60 min. PET signal in the brain corresponded to circulating radioactivity levels, with no [11C]lapatinib uptake observed in normal brain tissue. In contrast, radioactivity uptake in cranial metastases was significantly higher (p = 0.002) than that could be accounted by circulating radioactivity levels, consistent with [11C]lapatinib uptake in brain metastases. There was no difference in lapatinib uptake between the baseline and day 8 scans, suggesting no effect of increased drug access by inhibition of the drug efflux proteins by therapeutic doses of lapatinib.ConclusionsIncreased lapatinib uptake was observed in brain metastases but not in normal brain.Trial registrationClinicalTrials.gov: NCT01290354

No abstract

Treatment with molecularly-targeted therapy has revolutionized cancer care, including BRAF/MEKtargeted melanoma therapy. However responses are heterogenous and frequently not long-lasting. Novel strategies to target resistance are needed. We studied a cohort of patients with resectable metastatic melanoma treated with neoadjuvant BRAF/MEK-targeted therapy (n=52) and noted a strong sexual dimorphism in response to treatment, with female patients demonstrating signi cantly higher rates of a major pathologic response (MPR) (p=0.0001). RNA sequencing of tumors demonstrated enrichment of androgen-related genes in those failing to achieve MPR. Pre-clinical studies validated these ndings, with signi cantly increased tumor growth in male vs female mice treated with BRAF/MEK inhibitors (BRAF/MEKi) (p=0.0005). Androgen receptor (AR) expression was upregulated in tumors of BRAF/MEKitreated mice, and modulation of AR signaling via AR-blockade or castration was associated with signi cantly slower tumor growth (p=0.0001 and p=0.00004, respectively). Together, these results have important implications in the context of treatment with BRAF/MEKi-targeted therapy.

No abstract