Recurrence, death, and secondary malignancy after ovarian conservation for young women with early-stage low-grade endometrial cancer.

OBJECTIVE: To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer. METHODS: This multicenter retrospective study examined women aged <50 with stage I grade 1-2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort n = 1196, and Japan cohort n = 495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy. RESULTS: During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (P = 0.020) whereas the rate was unchanged in the Japan cohort (6.3-8.7%, P = 0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188-3.663, P = 0.805), overall survival (HR not estimated, P = 0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603-5.295, P = 0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557-17.464, P = 0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349-37.554, P = 0.021), but was not associated with overall survival (HR not estimated, P = 0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9 years, and all cases were salvaged. CONCLUSION: Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.

The Impact of Biochemical Markers on Major Adverse Cardiovascular Events and Contralateral Carotid Artery Stenosis Progression Following Carotid Interventions.

BACKGROUD: To determine if elevated preintervention high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) levels associate with major adverse cardiovascular events (MACE) or disease progression after carotid revascularization. METHODS: We retrospectively examined patients receiving elective carotid endarterectomy (CEA) or carotid artery stenting (CAS) at our institution from 2007 to 2014. All included patients had preintervention hsCRP and BNP levels. Examined outcomes of interest included contralateral carotid disease progression (increased stenosis or need for revascularization) and MACE (composite of death, stroke, myocardial infarction, need for coronary artery bypass graft or percutaneous coronary intervention) at 3 years after procedure. The relationship between baseline hsCRP and BNP levels and time to event was examined by univariate and multivariate Cox proportional hazard regression analyses. RESULTS: A total of 248 patients were included in the analysis (mean age: 68 ± 10 years), with 14% receiving CAS and 86% CEA. A total of 61 patients (25%) had 1 or more MACE by 3 years. Elevated hsCRP (>3 mg/L) trended toward associating with MACE but failed to reach significance (hazard ratio [HR]: 1.6 [1.0-2.7], P = 0.07). Multivariate analysis found that elevated BNP (>100pg/mL, HR: 2.2 [1.3-3.7], P = 0.002) and diabetes mellitus (HR: 1.9 [1.2-3.2], P = 0.01) predicted MACE. Having elevated preprocedural levels of both hsCRP and BNP significantly increased patients' likelihood of experiencing MACE (HR: 3.4 [1.6-7.1], P = 0.001). About 175 patients received contralateral carotid imaging postprocedure and of those patients, 31 (18%) experienced stenosis progression and/or revascularization within 3 years. However, neither elevated hsCRP (HR: 1.2 [0.6-2.3], P = 0.68) nor BNP (HR: 1.1 [0.5-2.5], P = 0.88) associated with disease progression. CONCLUSIONS: BNP elevation at the time of carotid intervention is associated with MACE in long-term follow-up. hsCRP does not appear to correlate with either disease progression of the contralateral artery or MACE.

Biventricular metastatic invasion from cervical squamous cell carcinoma.

Metastasis to the heart has been previously described with primary lung and breast carcinoma, lymphoma, leukaemia, mesothelioma and melanoma. However, left-ventricular cardiac metastasis from primary cervical squamous cell carcinoma is poorly described. This report describes the clinical presentation of a patient with cardiac metastatic invasion from cervical cancer.

Paradoxical attenuation of ß2-AR function in airway smooth muscle by Gi-mediated counterregulation in transgenic mice overexpressing type 5 adenylyl cyclase.

The limiting component within the receptor-G protein-effector complex in airway smooth muscle (ASM) for ß(2)-adrenergic receptor (ß(2)-AR)-mediated relaxation is unknown. In cardiomyocytes, adenylyl cyclase (AC) is considered the "bottleneck" for ß-AR signaling, and gene therapy trials are underway to increase inotropy by increasing cardiac AC expression. We hypothesized that increasing AC in ASM would increase relaxation from ß-agonists, thereby providing a strategy for asthma therapy. Transgenic (TG) mice were generated with approximately two- to threefold overexpression of type 5 AC (AC5) in ASM. cAMP and airway relaxation in response to direct activation of AC by forskolin were increased in AC5-TG. Counter to our hypothesis, isoproterenol-mediated airway relaxation was significantly attenuated (∼50%) in AC5-TG, as was cAMP production, suggesting compensatory regulatory events limiting ß(2)-AR signaling when AC expression is increased. In contrast, acetylcholine-mediated contraction was preserved. G(αi) expression and ERK1/2 activation were markedly increased in AC5-TG (5- and 8-fold, respectively), and ß-AR expression was decreased by ∼40%. Other G proteins, G protein-coupled receptor kinases, and ß-arrestins were unaffected. ß-agonist-mediated airway relaxation of AC5-TG was normalized to that of nontransgenic mice by pertussis toxin, implicating ß(2)-AR coupling to the increased G(i) as a mechanism of depressed agonist-promoted relaxation in these mice. The decrease in ß(2)-AR may account for additional relaxation impairment, given that there is no enhancement over nontransgenic after pertussis toxin, despite AC5 overexpression. ERK1/2 inhibition had no effect on the phenotype. Thus perturbing the ratio of ß(2)-AR to AC in ASM by increasing AC fails to improve (and actually decreases) ß-agonist efficacy due to counterregulatory events.

Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction.

Bitter taste receptors (TAS2Rs) on the tongue probably evolved to evoke signals for avoiding ingestion of plant toxins. We found expression of TAS2Rs on human airway smooth muscle (ASM) and considered these to be avoidance receptors for inhalants that, when activated, lead to ASM contraction and bronchospasm. TAS2R agonists such as saccharin, chloroquine and denatonium evoked increased intracellular calcium ([Ca²(+)](i)) in ASM in a Gßγ-, phospholipase Cß (PLCß)- and inositol trisphosphate (IP3) receptor-dependent manner, which would be expected to evoke contraction. Paradoxically, bitter tastants caused relaxation of isolated ASM and dilation of airways that was threefold greater than that elicited by ß-adrenergic receptor agonists. The relaxation induced by TAS2Rs is associated with a localized [Ca²(+)](i) response at the cell membrane, which opens large-conductance Ca²(+)-activated K(+) (BK(Ca)) channels, leading to ASM membrane hyperpolarization. Inhaled bitter tastants decreased airway obstruction in a mouse model of asthma. Given the need for efficacious bronchodilators for treating obstructive lung diseases, this pathway can be exploited for therapy with the thousands of known synthetic and naturally occurring bitter tastants.