The rapamycin-derivative RAD001 (everolimus) inhibits cell viability and interacts with the Akt-mTOR-p70S6K pathway in human medullary thyroid carcinoma cells.

Over-expression of the proto-oncogene Akt/PKB has been demonstrated in some neuroendocrine tumor models. Akt may activate downstream proteins such as mTOR and p70S6K, inducing tumor proliferation. The rapamycin-derivative RAD001, everolimus, interacts with this pathway by antagonizing mTOR, but its effects on neuroendocrine tumors are largely unknown. We explored the mechanism of action of RAD001 on cell proliferation, hormonal secretion and on Akt/mTOR/p70S6K pathway activation, in a human medullary thyroid carcinoma (MTC) cell-line (TT) and in cells derived from human MTCs. Treatment with RAD001 significantly inhibited cell viability in a dose- and time-dependent fashion, and diminished phosphorylation of Akt downstream targets, mTOR and p70S6K, in both TT cell-line and cultured human MTCs. Akt phosphorylation was not affected by RAD001. RAD001 induced cell-cycle arrest in the G(0)/G(1) phase in TT cells, but had no effect on apoptosis. Moreover, RAD001 did not affect calcitonin and carcinoembryonic antigen secretion in TT cells and in human MTCs. RAD001 seems to have potent anti-proliferative effect in human MTC cells, which suggest that clinical trials of this agent are of considerable interest

Patients' Perceptions of Omitted Examinations and Tests: A Qualitative Analysis

OBJECTIVES: To understand the nature of patients' expectations for parts of the physical examination and for diagnostic testing and the meaning patients ascribe to their desires. DESIGN: Qualitative inquiry based on patient interviews and focused on perceived diagnostic omissions as “critical incidents.” SETTING: Three general internal medicine practices (21 practitioners) in one mid-sized northern California city. PATIENTS: Of 687 patients visiting these practice sites and completing a detailed questionnaire, 125 reported one or more omissions of care and 90 completed an in-depth telephone interview. This study focuses on the 56 patients interviewed who did not receive desired components of the physical examination or diagnostic tests. MEASUREMENTS: Qualitative analysis of key themes underlying patients' unmet expectations for examinations and tests, as derived from verbatim transcripts of the 56 interviews. MAIN RESULTS: The 56 patients perceived a total of 113 investigative omissions falling into four broad categories: physical examination (47 omissions), conventional tests (43), high-cost tests (10), and unspecified investigations (13). Patients considered omitted investigations to have value along both pragmatic and symbolic dimensions. Diagnostic maneuvers had pragmatic value when they were seen to advance the technical aims of diagnosis, prognosis, or therapy. They had symbolic value when their underlying purpose was to enrich the patient-physician relationship. Patients in this study were often uncomfortable with clinical uncertainty, distrusted empiric therapy, endorsed early detection, and frequently interpreted failure to examine or test as failure to care. CONCLUSIONS: When patients express disappointment at failing to receive tests or examinations, they may actually be expressing concerns about the basis of their illness, the rationale for therapy, or the physician-patient relationship