Citations

Abstract Background: Nulliparity is an established endometrial cancer risk factor, but whether this association is related to infertility is unclear. Although there are many underlying causes of infertility, few studies have assessed risk relationships according to specific causes. Despite concerns that most treatments induce ovulation and that the endometrium is highly hormonally-responsive, previous studies have provided conflicting results on treatment associations. Methods: To address these issues, we conducted a pooled analysis of 8,151 cases and12,471 controls from 2 cohort and 12 case-control studies conducted in 1982 to 2009 (N. America, Europe, Australia, Asia). All studies provided self-reported infertility, causes and treatments, except for 1 study that relied on data from national registries. Study-specific exposures and covariate data were harmonized across studies. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusted for study, age, interview year, race, parity, oral contraceptive and menopausal hormone use, and body mass index. If data were not reported for a particular variable, that study was excluded from the variable-specific analysis. Results: Nulliparous women had an elevated endometrial cancer risk compared with parous women (adjusted OR=1.73; 95% CI: 1.58-1.90).Women with self-reported infertility also had an increased risk (adjusted OR=1.22; 95% CI: 1.13-1.32) compared with those without infertility issues, even after adjusting for parity; the strongest associations was seen among studies that defined infertility as unsuccessfully trying to conceive for 2+ years (adjusted OR=1.31; 95% CI: 1.07-1.60). Infertility was associated with similar risks among nulliparous (1.22; 1.10-1.48) and parous (1.22; 1.12-1.34) women, although there was no increased risk associated with infertility among those who had given birth to 3+ children. Two infertility causes associated with risk elevation were endometriosis (adjusted OR=2.08; 95% CI: 1.46-2.95 compared with women no infertility problems) and anovulation (adjusted OR=1.40; 95% CI: 1.16-1.70). Based on relatively small numbers, none of the individual treatments (in vitro fertilization, selective estrogen response modulators, gonatropins, progestins, estrogens) were substantially related to risk. Conclusion: Based on mainly self-reported infertility data, we found that parity and infertility independently contribute to endometrial cancer risk, with parity seemingly being the predominant risk predictor. Understanding residual endometrial cancer relationships related to causes of infertility and infertility treatment may benefit from documented medical information on causes of infertility and treatment parameters. Citation Format: Hannah P. Yang, Linda S. Cook, Elisabete Weiderpass, Hans-Olov Adami, Kristin E. Anderson, Hui Cai, James R. Cerhan, Tess Clendenen, Ashley S. Felix, Christine Friedenreich, Montserrat Garcia-Closas, Marc T. Goodman, Xiaolin Liang, Jolanta Lissowska, Lingeng Lu, Anthony M. Magliocco, Susan E. McCann, Kristen B. Moysich, Sara H. Olson, Malcolm C. Pike, Silvia Polidoro, Fulvio Ricceri, Harvey Risch, Carlotta Sacerdote, V. Wendy Setiawan, Xiao Ou Shu, Amanda B. Spurdle, Britton Trabert, Penelope M. Webb, Nicolas Wentzensen, Yong-Bing Xiang, Youming Xu, Herbert Yu, Anne Zeleniuch-Jacquotte, Louise A. Brinton. Infertility and risk of incident endometrial carcinoma: a pooled analysis from the Epidemiology of Endometrial Cancer Consortium. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2167. doi:10.1158/1538-7445.AM2014-2167

Abstract Breast cancer is the number one diagnosed cancer in women. Luminal breast cancers express steroid hormone receptors (SR) and these cases can be effectively treated with endocrine therapies that block estrogen receptor (ER) activity or estrogen synthesis. Unfortunately, at least 40% of women develop resistance to anti-estrogen treatments and progress to metastatic disease. One of the important transitions from hormone responsive (ER+/PR+ luminal A) to refractory (ER+ luminal B) disease involves the loss of progesterone receptor (PR) protein expression. However, data from large clinical trials showed that exposure to a synthetic progestin (MPA) and estrogen, but not estrogen alone, increased breast cancer incidence and tumor grade. These data, while somewhat controversial, implicate PR action in breast cancer development and progression. PR isoforms (A and B) are ligand-activated transcription factors, though they can be activated in the absence of progestin via signaling pathways commonly elicited downstream of growth factor receptors. We have shown that growth factor signaling (EGF or heregulin) through PR-B can initiate rapid proliferation and survival of breast cancer cells growing in soft-agar. PR-B is phosphorylated and hyperactived by mitogenic protein kinases, including MAPK, CDK2, and CK2. Notably, over-expression and activation of Aurora A kinase (downstream of MAPKs) is associated with invasive breast cancer and poor prognosis. We hypothesize that activation of protein kinases commonly overexpressed in breast cancer provide a context for aberrant PR activity, resulting in upregulation of Her2/erbB2 signaling, EMT, and increased expression of mammary stem-cell mediators (stemness). To model this process, we over-expressed oncogenic Raf1 in ER+/PR+ MCF-7 breast cancer cells. MCF-7-Raf1 cells exhibited constitutive activation of the MAPK pathway and upregulation of both ER and PR mRNA and protein relative to parental controls. Addition of progestin to MCF-7-Raf1 cells increased PR phosphorylation and soft agar growth that was blocked by MLN8237, an Aurora kinase inhibitor. Interestingly, passage of MCF-7-Raf1 cells as mouse xenografts (1GX) led to rapid tumor progression that was associated with increased Aurora A phosphorylation, loss of PR mRNA and protein, expression of epithelial-to-mesenchymal (EMT) markers, increased stemness, and tamoxifen resistance. These data suggest that Aurora A kinase and PR cross-talk may drive early breast cancer progression in response to growth promoting signals. Targeting this cross-talk with Aurora kinase inhibitors and anti-progestins, in conjunction with conventional estrogen-blocking therapies, may improve survival outcomes by preventing progression to endocrine failure. MCF-7-Raf1 and MCF-7-Raf-1 (1GX) cells may provide a useful model for the study of SR-loss during luminal A to luminal B transition. Citation Format: Katherine A. Leehy, Tarah M. Regan Anderson, Andrea R. Daniel, Antonino B. D'Assoro, Carol A. Lange. Aurora A kinase and progesterone receptor cross talk in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2107. doi:10.1158/1538-7445.AM2014-2107

Background— After left ventricular assist device (LVAD) placement for advanced heart failure, increased cerebral perfusion should result in improved cognitive function. However, stroke (a well-known LVAD complication) and subclinical cerebral ischemia may result in transient or permanent cognitive decline. We sought to describe the incidence and predictors of cognitive decline after LVAD using a valid, sensitive assessment tool. Methods and Results— Among 4419 patients in the Interagency Registry for Mechanically Assisted Circulatory Support who underwent LVAD implantation between May 2012 and December 2013, cognitive function was assessed in 1173 patients with the Trail Making B Test before LVAD and at 3, 6, and 12 months. The test detects several forms of cognitive impairment, including subclinical stroke. Cognitive decline was defined as a clinically important increase during follow-up using a moderate Cohen d effect size of 0.5×baseline SD (32 s). The cumulative incidence of cognitive decline in the year after LVAD implantation, treating death and transplantation as competing risks, was 29.2%. In adjusted analysis, older age (≥70 versus <50 years; hazard ratio, 2.24; 95% confidence interval 1.46–3.44; P trend <0.001) and destination therapy (hazard ratio, 1.42; 95% confidence interval, 1.05–1.92) were significantly associated with greater risk of cognitive decline. Conclusions— Cognitive decline occurs commonly in patients in the year after LVAD and is associated with older age and destination therapy. These results could have important implications for patient selection and improved communication of risks before LVAD implantation. Additional studies are needed to explore the association between cognitive decline and subsequent stroke, health status, and mortality in patients after LVAD.

Background/Aims: Depressive disorders (DEP) are often comorbid with other chronic conditions. Bidirectional associations between DEP and these conditions are poorly understood. In this study, we aimed to identify chronic conditions with the greatest influence on the DEP diagnosis. Methods: A validated electronic health record-based algorithm was applied to identify DEP patients receiving primary care at Mayo Clinic between 2000 and 2013. Cases were identified on the basis of having > 2 DEP-related ICD-9 diagnosis codes, > 1 antidepressant prescription, and > 3 mentions of in- or outpatient clinical notes for DEP. Controls were matched on birth year (± 2 years), sex and outpatient clinic visits at the same year. We ascertained 26 chronic condition categories, as defined by Chronic Conditions Data Warehouse, using the 5 years of medical records prior to the DEP diagnosis. For each age group at diagnosis (60 years), gradient boosting machine models were applied to estimate relative influence (RI) of the chronic conditions on the DEP diagnosis. Results: A total of 11,219 DEP cases were identified (median age at DEP diagnosis 44 years, 34% male and 89% white). The proportion of subjects with at least one co-occurring condition increased with older age and was higher in DEP cases compared to controls (9.5% vs. 6.9% for subjects 60 years). For subjects aged ≤ 45 years, diabetes mellitus (RI=19.6%) was identified as the most influential condition contributing to the risk of DEP, followed by asthma (RI=11.6%) and rheumatoid arthritis (RI=11.0%). For subjects aged 46–60 years, the most influential condition was rheumatoid arthritis (RI=13.2%) followed by diabetes mellitus (RI=12.9%). For subjects older than 60 years, dementia (RI=10.7%) and rheumatoid arthritis (RI=10.2%) showed similar relative contribution to the risk of DEP. Discussion: Among nonelderly adults who received primary care at Mayo Clinic (2000–2013), diabetes mellitus and rheumatoid arthritis were the strongest risk predictors for a diagnosis of depression among 26 chronic conditions considered. Our results suggest that certain chronic conditions may play a role in exacerbating, precipitating or increasing longitudinal risk of medically significant depression.

Background— Implanting centers often require the identification of a dedicated caregiver before destination therapy left ventricular assist device (DT LVAD) implantation; however, the caregiver experience surrounding this difficult decision is relatively unexplored. Methods and Results— From October 2012 through July 2013, we conducted semistructured, in-depth interviews with caregivers of patients considering DT LVAD. Data were analyzed using a mixed inductive and deductive approach. We interviewed 17 caregivers: 10 caregivers of patients living with DT LVAD, 6 caregivers of patients who had died with DT LVAD, and 1 caregiver of a patient who had declined DT LVAD. The themes identified, which could also be considered dialectical tensions, are broadly interpreted under 3 domains mapping to decision context, process, and outcome: (1) the stark decision context, with tension between hope and reality; (2) the challenging decision process, with tension between wanting loved ones to live and wanting to respect loved ones’ wishes; and (3) the downstream decision outcome, with tension between gratitude and burden. Conclusions— Decision-making surrounding DT LVAD should incorporate decision support for patients and caregivers. This should include a focus on caregiver burden and the predictable tensions that caregivers experience.

Modulation of mitochondrial respiratory chain, dehydrogenase, and nucleotide-metabolizing enzyme activities is fundamental to cellular protection. Here, we demonstrate that the potassium channel opener diazoxide, within its cardioprotective concentration range, modulated the activity of flavin adenine dinucleotide-dependent succinate dehydrogenase with an IC50of 32 μM and reduced the rate of succinate-supported generation of reactive oxygen species (ROS) in heart mitochondria. 5-Hydroxydecanoic fatty acid circumvented diazoxide-inhibited succinate dehydrogenase-driven electron flow, indicating a metabolism-dependent supply of redox equivalents to the respiratory chain. In perfused rat hearts, diazoxide diminished the generation of malondialdehyde, a marker of oxidative stress, which, however, increased on diazoxide washout. This effect of diazoxide mimicked ischemic preconditioning and was associated with reduced oxidative damage on ischemia-reperfusion. Diazoxide reduced cellular and mitochondrial ATPase activities, along with nucleotide degradation, contributing to preservation of myocardial ATP levels during ischemia. Thus, by targeting nucleotide-requiring enzymes, particularly mitochondrial succinate dehydrogenase and cellular ATPases, diazoxide reduces ROS generation and nucleotide degradation, resulting in preservation of myocardial energetics under stress.

The failing ventricular myocardium is characterized by reduction of high-energy phosphates and reduced activity of the phosphotransfer enzymes creatine kinase (CK) and adenylate kinase (AK), which are responsible for transfer of high-energy phosphoryls from sites of production to sites of utilization, thereby compromising excitation-contraction coupling. In humans with chronic atrial fibrillation (AF) unassociated with congestive heart failure (CHF), impairment of atrial myofibrillar energetics linked to oxidative modification of myofibrillar CK has been observed. However, the bioenergetic status of the failing atrial myocardium and its potential contribution to atrial electrical instability in CHF have not been determined. Dogs with ( n = 6) and without ( n = 6) rapid pacing-induced CHF underwent echocardiography (conscious) and electrophysiological (under anesthesia) studies. CHF dogs had more pronounced mitral regurgitation, higher atrial pressure, larger atrial area, and increased atrial fibrosis. An enhanced propensity to sustain AF was observed in CHF, despite significant increases in atrial effective refractory period and wavelength. Profound deficits in atrial bioenergetics were present with reduced activities of the phosphotransfer enzymes CK and AK, depletion of high-energy phosphates (ATP and creatine phosphate), and reduction of cellular energetic potential (ATP-to-ADP and creatine phosphate-to-Cr ratios). AF duration correlated with left atrial area ( r = 0.73, P = 0.01) and inversely with atrial ATP concentration ( r = −0.75, P = 0.005), CK activity ( r = −0.57, P = 0.054), and AK activity ( r = −0.64, P = 0.02). Atrial levels of malondialdehyde, a marker of oxidative stress, were significantly increased in CHF. Myocardial bioenergetic deficits are a conserved feature of dysfunctional atrial and ventricular myocardium in CHF and may constitute a component of the substrate for AF in CHF.

Abstract BACKGROUND: Breast cancer affects thousands of women each year. Epithelial to Mesenchymal transition (EMT) has been associated with increased metastatic potential of cancer cells as well as resistance to chemotherapy. Predicatively, presence of EMT leads to worse prognosis in patients with breast cancer. We have recently showed that Aurora-A plays a key role in development of EMT and increased ability of breast cancer cells for self renewal. Therefore we hypothesized that inhibition of Aurora-A in breast cancer cells will lead to increased sensitivity to chemotherapy. RESULTS: Increased Aurora-A expression, as assessed by IHC staining, in patients with locally advanced disease was associated with worse prognosis. We show that in ER+ cell line, MCF7, activating MAPK pathway through overexpression of Raf1 leads to increase in Aurora-A activity. These cells have decreased sensitivity to treatment with paclitaxel when compared to untransfected cells in MTT assays. This effect is even more exacerbated with over-expression of Aurora-A. The sensitivity to paclitaxel was restored with inhibition of Aurora-A by specific inhibitor, Alisertib. This was further explored in triple negative (MDA-MB-231) or Her-2/neu expressing (SUM149) cell lines. These cells express higher levels of Aurora-A. Inhibition of Aurora-A activity in combination with paclitaxel was superior when compared to either therapy alone. Similar effect was seen with use of anthracyclines. Inhibition of Aurora-A resulted in decreased SMAD5 expression as well as decreased Akt phosphorylation. Current studies are looking at a role of Aurora-A in activating SMAD5 and its role in resistance to chemotherapy. In vivo experiments evaluating combination therapies in breast cancer animal model are ongoing. CONCLUSIONS: Inhibition of Aurora-A by a specific inhibitor, MLN8237, resulted in decreased SMAD5 expression and increased effectiveness of chemotherapeutic agents in breast cancer cells. These results contribute to better understanding of signaling pathways involved in resistance of breast cancer cells to chemotherapy. This knowledge could be very useful in developing more effective treatments for breast cancer patients in neo-adjuvant, adjuvant and metastatic settings. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-07.

Activation Sequence During Atrial PacingIntroductionIn patients with intraatrial conduction delay and sinus node (SN) dysfunction, pacing Bachmann's bundle (BBR) and coronary sinus ostium (CSO) has been suggested to achieve atrial resynchronization with potential beneficial impact on atrial fibrillation and diastolic heart failure. Clinical studies have not shown superiority of one approach.Methods and ResultsWe studied electrical activation sequence in an open‐chest acute canine model of normal atrial function in 8 mongrel dogs under general anesthesia. Bipolar plunge electrodes were distributed over the surface of the atria during unifocal pacing, and intracardiac activation sequence was observed. SN pacing resulted in near‐simultaneous activation at midline sites (BBR and CSO); the left atrium (LA) was activated by anterior and posterior wavefronts simultaneously propagating septally to laterally and meeting at the low‐lateral perimitral LA. Right atrial appendage (RAA) pacing created intra‐RA conduction delay and delayed onset of LA activation. Pacing from RAA, CSO, and BBR resulted in nonsimultaneous activation at midline sites and produced an anteroposterior gradient of LA activation. This phenomenon was seen to the greatest degree with midline pacing and shifted the site of latest activation away from the low‐lateral perimitral LA in all pacing configurations except SN pacing.ConclusionPacing‐induced intra‐LA activation dispersion is enhanced with midline atrial pacing, and secondarily shifts the site of latest activation away from the lateral mitral annulus. Measuring atrial activation times to the low‐lateral perimitral LA can underestimate the degree of atrial dyssynchrony and be misinterpreted as atrial synchrony. Establishing clinical impact requires evaluation of human data.