High glucocorticoid receptor expression in the sarcomatous versus carcinomatous elements of Mullerian carcinosarcomas.

Glucocorticoid receptor can be associated with poor prognosis among a variety of solid tumors in the absence of other nuclear hormone receptors. Our objective was to characterize differences in glucocorticoid receptor (GR), estrogen receptor (ER), progesterone receptor (PR), and androgen receptor expression in the sarcomatous versus carcinomatous components of ovarian and uterine carcinosarcomas. Eighteen patients diagnosed with Mullerian carcinosarcoma between May 2009 and August 2014 were included. Nuclear receptor expression was evaluated by immunohistochemistry using whole tissue specimens. Receptor expression was quantified using the H-score. Mean H-scores were compared between the sarcomatous and carcinomatous components of tumors using Wilcoxon signed-rank tests. We found that GR expression was significantly higher in the sarcomatous components than in the carcinomatous components of the cancers (mean H score 144.4 vs 38.9, p = 0.002). Conversely, ER (3.1 vs 63.1, p = 0.002) and PR (1.7 vs 47.2, p < 0.0001) expression were significantly decreased in the sarcomatous component compared to the carcinomatous component. Androgen receptor expression was low overall (0 versus 2.8, p = 0.04). We hypothesize that GR-high, ER/PR-low expression is associated with epithelial to mesenchymal transition in the sarcomatous cells and may serve as a potential therapeutic target.

The evolving role of immune checkpoint inhibitors in the treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer for which chemotherapy had been the only active treatment option once metastatic disease developed. Immune checkpoint inhibitors (ICIs) are now available to treat patients with advanced TNBC who have programmed cell death ligand 1 (PD-L1)-positive tumors; these agents have been shown to improve clinical outcomes. Additionally, long-term disease control can be achieved in a subset of patients. Continued investigations of ICIs and optimal combinations with chemotherapy and targeted agents to enhance the immune response are ongoing, along with studies aimed at identifying the patients most likely to benefit. For early-stage TNBC, the data to date on administering ICI-based combination therapies in the neoadjuvant setting are compelling and suggest that the benefit from immunotherapy does not depend on PD-L1 expression. This review will discuss the clinical trial data on ICIs as monotherapy and in combination with chemotherapy in the treatment of patients with metastatic and early-stage TNBC.

Constitutively active ESR1 mutations in gynecologic malignancies and clinical response to estrogen-receptor directed therapies.

OBJECTIVE: Endocrine therapy is often considered as a treatment for hormone-responsive gynecologic malignancies. In breast cancer, activating mutations in the estrogen receptor (mutESR1) contribute to therapeutic resistance to endocrine therapy, especially aromatase inhibitors (AIs). The purpose of this study was to evaluate the frequency and clinical relevance of ESR1 genomic alterations in gynecologic malignancies. METHODS: DNA from FFPE tumor tissue obtained during routine clinical care for 9645 gynecologic malignancies (ovary, fallopian tube, uterus, cervix, vagina, vulvar, and placenta) was analyzed for all classes of genomic alterations (base substitutions (muts), insertions, deletions, rearrangements, and amplifications) in ESR1 by hybrid capture next generation sequencing. A subset of alterations was characterized in laboratory-based transcription assays for response to endocrine therapies. RESULTS: A total of 295 ESR1 genomic alterations were identified in 285 (3.0%) cases. mutESR1 were present in 86 (0.9%) cases and were more common in uterine compared to other cancers (2.0% vs <1%, respectively p < 0.001). mutESR1 were enriched in carcinomas with endometrioid versus serous histology (4.4% vs 0.2% respectively, p < 0.0001 in uterine and 3.5% vs 0.3% respectively, p = 0.0004 in ovarian carcinomas). In three of four patients with serial sampling, mutESR1 emerged under the selective pressure of AI therapy. Despite decreased potency of estrogen receptor (ER) antagonists in transcriptional assays, clinical benefit was observed following treatment with selective ER-targeted therapy, in one case lasting >48 months. CONCLUSIONS: While the prevalence of ESR1 mutations in gynecologic malignancies is low, there are significant clinical implications useful in guiding therapeutic approaches for these cancers.

Magnitudes of gluteus medius muscle activation during standing hip joint movements in spiral-diagonal patterns using elastic tubing resistance.

The aim of this study was to simultaneously quantify electromyographic (EMG) activation levels (% maximum voluntary isometric contraction [MVIC]) within the gluteus medius muscles on both moving and stance limbs across the performance of four proprioceptive neuromuscular facilitation (PNF) spiral-diagonal patterns in standing using resistance provided by elastic tubing. Differential EMG activity was recorded from the gluteus medius muscle of 26 healthy participants. EMG signals were collected with surface electrodes at a sampling frequency of 1000 Hz during three consecutive repetitions of each spiral-diagonal movement pattern. Significant differences existed among the four-spiral-diagonal movement patterns (F3,75 = 19.8; p < 0.001). The diagonal two flexion [D2F] pattern produced significantly more gluteus medius muscle recruitment (50 SD 29.3% MVIC) than any of the other three patterns and the diagonal one extension [D1E] (39 SD 37% MVIC) and diagonal two extension [D2E] (35 SD 29% MVIC) patterns generated more gluteus medius muscle recruitment than diagonal one flexion [D1F] (22 SD 21% MVIC). From a clinical efficiency standpoint, a fitness professional using the spiral-diagonal movement pattern of D2F and elastic tubing with an average peak tension of about 9% body mass may be able to concurrently strengthen the gluteus medius muscle on both stance and moving lower limbs.