The androgen receptor (AR) signaling pathway is a major therapeutic target in the treatment of prostate cancer. The AR functions as a ligand-activated transcription factor in the presence of the cognate hormone ligands testosterone and dihydrotestosterone (DHT). We have characterized a highly conserved sequence at the C-terminal end of helix 10/11 in the ligand-binding domain (LBD), which is prone to receptor point mutations in prostate cancer. This sequence includes threonine 877 that is involved in hydrogen bonding to the D ring of the steroid molecule and leads to promiscuous ligand activation of the AR when mutated to alanine or serine. A second mutation in this region, H874Y, also results in a receptor protein that has broadened ligand-binding specificity, but retains an affinity for DHT (K(d) = 0.77 nm) similar to that of the wild-type receptor. The structure of the mutant LBD, expressed in Escherichia coli, is not dramatically altered compared with the wild-type AR-LBD in the presence of DHT, but shows a modestly increased sensitivity to protease digestion in the absence of hormone. This mutant AR showed wild-type AR-LBD/N-terminal domain interactions, but significantly enhanced binding and transactivation activity with all three members of the p160 family of coactivator proteins. Together, these phenotypic changes are likely to confer a selective advantage for tumor cells in a low androgen environment resulting from hormone therapy.

BackgroundDespite the benefits to early palliative care in the treatment of terminal illness, barriers to timely hospice referrals exist. Physicians who are more comfortable having end-of-life (EOL) conversations are more likely to refer to hospice. However, very little is known about what factors influence comfort with EOL care.MethodsAn anonymous survey was sent to all the residents and fellows at a single institution. Self-reported education, experience and comfort with EOL care was assessed. Using multivariate logistic regression analysis, variables that influenced comfort with EOL conversations were analyzed.ResultsMost residents (88.1%) reported little to no classroom training on EOL care during residency. EOL conversations during residency were frequent (50.6% reported > 10) and mostly unsupervised (61.9%). In contrast, EOL conversations during medical school were infrequent (3.7% reported >10) and mostly supervised (78.6%). Most (54.3%) reported little to no classroom training on EOL care during medical school. Physicians that reported receiving education on EOL conversations during residency and those who had frequent EOL conversations during residency had significantly higher comfort levels having EOL conversations (p = 0.017 and p = 0.003, respectively). Likewise, residents that felt adequately prepared to have EOL conversations when graduating from medical school were more likely to feel comfortable (p = 0.030).ConclusionsMost residents had inadequate education in EOL conversation skills during medical school and residency. Despite the lack of training, EOL conversations during residency are common and often unsupervised. Those who reported more classroom training during residency on EOL skills had greater comfort with EOL conversations. Training programs should provide palliative care education to all physicians during residency and fellowship, especially for those specialties that are most likely to encounter patients with advanced terminal disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12909-016-0819-6) contains supplementary material, which is available to authorized users.

The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies.

RCTs published in major oncology journals do not consistently report essential therapeutic details necessary for translation of the trial findings to clinical practice. Potential solutions to improve reporting include modification of submission guidelines, use of online appendices, and providing open access to trial protocols.

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