A Phase I Study of Capivasertib in Combination With Abiraterone Acetate in Patients With Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Although androgen receptor-targeted agents prolong the lives of patients with metastatic prostate cancer, patients develop therapy resistance and most ultimately succumb to the disease. The PI3K/AKT/PTEN pathway has been associated with the development of resistance, raising the possibility that pathway inhibitors may produce a clinical benefit. This open-label phase Ib study examined the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of adding capivasertib - a potent, selective inhibitor of AKT1/2/3 - to approved abiraterone acetate therapy. METHODS: Twenty-seven patients with metastatic castration-resistant prostate cancer who had undergone at least 1 prior line of systemic therapy received abiraterone acetate 1000 mg (orally administered once daily), plus oral prednisone 5 mg (twice daily) with capivasertib 400 mg (orally, twice daily, with an intermittent schedule of 4 days on, 3 days off). RESULTS: No dose-limiting toxicity was observed. The most frequent adverse events (all grade) were diarrhea (30%), anemia (26%), asthenia (22%), and nausea (22%). The most frequent grade 3 or higher adverse events were acute kidney injury (19%), hyperglycemia (7%), rash (7%), abdominal pain (7%), and asthenia (7%). Capivasertib and abiraterone PK were consistent with previously reported results from monotherapy dosing. Nine participants (33%) showed a 20% or greater decrease in prostate-specific antigen during study treatment. CONCLUSION: The combination of capivasertib and abiraterone acetate had an acceptable tolerability profile consistent with the known profile of each agent. These data support further evaluation of capivasertib and abiraterone acetate in patients with advanced prostate cancer.

Receptor Tyrosine Kinase Fusions and BRAF Kinase Fusions are Rare but Actionable Resistance Mechanisms to EGFR Tyrosine Kinase Inhibitors.

INTRODUCTION: We analyzed a large set of EGFR-mutated (EGFR+) NSCLC to identify and characterize cases with co-occurring kinase fusions as potential resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs). METHODS: EGFR+ (del 19, L858R, G719X, S768I, L851Q) NSCLC clinical samples (formalin-fixed paraffin-embedded tumor and blood) were analyzed for the presence of receptor tyrosine kinase (RTK) and BRAF fusions. Treatment history and response were obtained from provided pathology reports and treating clinicians. RESULTS: Clinical samples from 3505 unique EGFR+ NSCLCs were identified from June 2012 to October 2017. A total of 31 EGFR+ cases had concurrent kinase fusions detected: 10 (32%) BRAF, 7 (23%) ALK receptor tyrosine kinase (ALK), 6 (19%) ret proto-oncogene (RET), 6 (19%) fibroblast growth factor receptor 3 (FGFR3), 1 (3.2%) EGFR, and 1 (3.2%) neurotrophic receptor tyrosine kinase 1 (NTRK1), including two novel fusions (SALL2-BRAF and PLEKHA7-ALK). Twenty-seven of 31 patients had either a known history of EGFR+ NSCLC diagnosis or prior treatment with an EGFR TKI before the fusion+ sample was collected. Twelve of the 27 patients had paired pre-treatment samples where the fusion was not present before treatment with an EGFR TKI. Multiple patients treated with combination therapy targeting EGFR and the acquired fusion had clinical benefit, including one patient with osimertinib resistance due to an acquired PLEKHA7-ALK fusion achieving a durable partial response with combination of full-dose osimertinib and alectinib. CONCLUSIONS: RTK and BRAF fusions are rare but potentially druggable resistance mechanisms to EGFR TKIs. Detection of RTK and BRAF fusions should be part of comprehensive profiling panels to determine resistance to EGFR TKIs and direct appropriate combination therapeutic strategies.

From uranothorites to coffinite: a solid solution route to the thermodynamic properties of USiO4.

Experiments on the solubility of intermediate members of the Th(1-x)U(x)SiO4 solid solution were carried out to determine the impact of Th-U substitutions on the thermodynamic properties of the solid solution and then allow extrapolation to the coffinite end member. The ion activity products in solutions equilibrated with Th(1-x)U(x)SiO4 (0 ≤ x ≤ 0.5) were determined by dissolution experiments conducted in 0.1 mol·L(-1) HCl under Ar atmosphere at several temperatures ranging from 298 to 346 K. For all experiments, dissolution was congruent, and a constant composition of the aqueous solution was reached after 50-200 days of dissolution. The solubility product of thorite was determined (log *K(S,ThSiO4) = -5.62 ± 0.08) whereas the solubility product of coffinite was estimated (log *K(S,USiO4) = -6.1 ± 0.2). The stoichiometric solubility product of Th(1-x)U(x)SiO4 reached a maximum value for x = 0.45 ± 0.05. In terms of the standard Gibbs free energy of dissolution, solid solutions dissolve more spontaneously than the end members. The standard Gibbs free energy associated with the formation of thorite, coffinite, and intermediate members of the series were then evaluated. The standard Gibbs free energies of formation were found to increase linearly with the uranium mole fraction. Our data at low temperature clearly show that uranothorite solid solutions with x > 0.26, thus coffinite, are less stable than the mixture of binary oxides, which is consistent with qualitative evidence from petrographic studies of uranium ore deposits.

Primary pulmonary carcinoid tumor with metastasis to endometrial polyp.

INTRODUCTION: A carcinoid tumor occurring in the endometrium has been documented in the literature, but there is no report in regard to carcinoid tumor metastasis to endometrium. PRESENTATION OF CASE: We report a case of a malignant carcinoid metastasis to an endometrial polyp. Patient underwent hysteroscopy, and polypectomy. The pathology demonstrated an endometrial polyp containing a 4 mm x 5 mm nodule of metastatic carcinoid tumor, consistent with metastasis from patient's known pulmonary carcinoid. The tumor was morphologically similar to the tumors of the right lung, with similar immune-profile. DISCUSSION: This patient presented with a suspicious pelvic ultrasound. Due to her age, the first priority was to exclude uterine cancer. The endometrial polyp, which was found, had a small focus of metastatic carcinoid tumor. To the best of our knowledge, this finding has not been previously recorded in the literature. Our patient also had a history of metastatic carcinoid tumor to breast. This finding is also very uncommon. CONCLUSION: This is the first case in the literature described a malignant carcinoid metastasis to an endometrial polyp.

The relationship between Facebook and the well-being of undergraduate college students.

We investigated how Facebook use and attitudes relate to self-esteem and college adjustment, and expected to find a positive relationship between Facebook and social adjustment, and a negative relationship between Facebook, self-esteem, and emotional adjustment. We examined these relationships in first-year and upper-class students and expected to find differences between the groups. Seventy undergraduate students completed Facebook measures (time, number of friends, emotional and social connection to Facebook), the Rosenberg Self-Esteem Scale, and the Student Adaptation to College Scale. First-year students had a stronger emotional connection to and spent more time on Facebook while they reported fewer friends than upper-class students did. The groups did not differ in the adjustment scores. The number of Facebook friends potentially hinders academic adjustment, and spending a lot of time on Facebook is related to low self-esteem. The number of Facebook friends was negatively associated with emotional and academic adjustment among first-year students but positively related to social adjustment and attachment to institution among upper-class students. The results suggest that the relationship becomes positive later in college life when students use Facebook effectively to connect socially with their peers. Lastly, the number of Facebook friends and not the time spent on Facebook predicted college adjustment, suggesting the value of studying further the notion of Facebook friends.