Citations

ObjectiveTo evaluate the long‐term outcomes and potential predictors of treatment failure after robotic sacrocolpopexy.MethodsWe identified 70 consecutive patients from 2002 to 2012 with symptomatic post‐hysterectomy vaginal vault prolapse that underwent robotic sacrocolpopexy. Multiple clinical and surgical variables were evaluated for potential association with treatment failure, which was defined as any repeat operation for recurrent prolapse or mesh‐related complications.ResultsThe median age at surgery was 67 years (interquartile range 59–74 years) and median follow up was 72 months (interquartile range 39–114 months). Overall, six out of 70 patients (8.6%) underwent a total of six secondary surgeries, including four for recurrent prolapse (two anterior repairs, one posterior repair, one apical) and two mesh complications. No patient‐related factors were associated with the risk of repeat surgery: age (P = 0.45), diabetes mellitus (P = 0.24), tobacco use (P = 0.61) or prior prolapse surgery (P = 0.1) on univariate analysis. Freedom from repeat prolapse surgery or surgery for mesh complication was 98% at 1 year, 95% at 3 years and 90% at 6 years. At last follow up, 80% of patients reported that they would or probably would recommend robotic sacrocolpopexy to a family member or friend.ConclusionsRobotic sacrocolpopexy is associated with excellent long‐term outcomes. Recognition of long‐term success is important for preoperative patient counseling.

Abstract The t(8;21) chromosomal translocation produces AML1-ETO, an oncogenic fusion protein that compromises the function of AML1, a transcription factor critical for the myeloid cell differentiation. The differentiation arrest and self-renewal phenotypes of cells expressing AML1-ETO have been chiefly studied at the single gene level. In order to understand how the genome-wide occupancy of AML1-ETO and associated co-regulators contributes to the leukemic properties of Kasumi-1 cells, a model system for human t(8;21) leukemia, chromatin immunoprecipitation-sequencing (ChIP-seq) experiments were employed. Genome-wide DNA binding profiles for AML1 and AML1-ETO in Kasumi-1 cells showed that both proteins were enriched at introns and distal upstream regulatory regions, the latter implying that distal elements are likely important for target gene regulation. Importantly, A substantial fraction of AML1/AML1-ETO-p300 co-localization occurs near transcriptional start sites (TSSs) in promoter regions associated with transcriptionally active loci, as indicated by an observed enrichment of the H3K4me3 histone modification. A significant discovery of the current study is the co-localization of AML1/AML1-ETO with N-CoR on regions that are primarily distal to TSSs. Analyses of both gene expression data and gene ontology suggest that the AML1/AML1-ETO co-localization with N-CoR, more so than with p300, is associated with the leukemic phenotype of Kasumi-1 cells. De novo motif discovery reveals that PU.1 motifs are over-represented in regions co-occupied by AML1-ETO and N-CoR compared to other AML1-ETO bound regions. Our findings establish a novel and predominant AML leukemia signature characterized by occupancy of the AML1-ETO/N-CoR complex at genomic regions enriched in motifs for myeloid differentiation factors. We propose that this property is critical for maintenance of the leukemic phenotype. Citation Format: Daniel J. Trombly, Troy W. Whitfield, Srivatsan Padmanabhan, Jonathan A. Gordon, Jane B. Lian, Andre J. van Wijnen, Sayyed K. Zaidi, Janet L. Stein, Gary S. Stein. Co-occupancy of AML1-ETO and N-CoR defines a dominant phenotypic signature in leukemic cells. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B28.

Abstract Background: CA125 is elevated in 80% of ovarian cancer cases and has proven utility in assessing response to therapy and prognosis. Unfortunately, CA125 is elevated in a variety of benign conditions and only in 50% of early stage ovarian cancers, resulting in a sensitivity and specificity unacceptable for population-based screening. Therefore, understanding factors that influence CA125 at presentation could provide important insights for interpreting CA125 values. Methods: Using pre-treatment CA125 and detailed epidemiologic data from 12 studies participating in the Ovarian Cancer Association Consortium (OCAC), we evaluated factors previously reported to influence CA125 levels, including age, race, oral contraceptive use, parity, tubal ligation, endometriosis, body mass index (BMI), personal history of breast cancer, or a family history of breast or ovarian cancer. We used linear regression to estimate the association between each variable and CA125 probit scores, which we used to standardize values between studies. Secondary analyses included adjustment for histologic subtype. We also estimated the associations within each study using log-transformed CA125 as the outcome and estimated summary measures using random effects meta-analyses. Results: Of the 4417 cases included in the analysis, 2918 (66%) were serous, 227 (5%) were mucinous, 484 (11%) were endometrioid, and 258 (6%) were clear cell carcinomas. Median CA125 values varied between studies with a high of 831 U/mL and a low of 271 U/mL. We observed no association between race, oral contraceptive use, tubal ligation, endometriosis, prior breast cancer, and family history of breast cancer and pre-treatment CA125. However, we observed increased pre-treatment CA125 levels with older age (>70 vs. < 50, p=0.03), parity (p=0.01), number of children (p=0.02), obesity (BMI>30 vs. 21-25, p=0.03), and family history of ovarian cancer (p=0.05). Results were similar but attenuated when we calculated summary estimates of the association using meta-analysis of study specific estimates of the association with log-transformed CA125 rather than probit scores. Age and BMI remained predictive of pre-treatment CA125 values after adjustment for histologic subtype. Our data are limited by between site variability in CA125 assays; therefore, validation of these findings is needed with adjustment for type of assay used or in a study population in which all cases had pre-treatment CA125 values measured with the same assay. Conclusions: Despite these limitations, results from this analysis of over 4000 ovarian cancer cases suggest that age and body size may influence pre-treatment CA125 values. Citation Format: KL Terry, A Babic, BY Karlan, MT Goodman, D Lambrechts, F Heitz, K Matsuo, I McNeish, T Pejovic, S Kruger Kjaer, PM Webb, E Hogdall, EL Goode, DW Cramer, for the Ovarian Cancer Association Consortium. Epidemiologic predictors of pre-treatment CA125 in women with ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS13.

Abstract Estrogen receptor (ER) β is highly expressed in normal breast epithelium and a putative tumor suppressor. Atypical hyperplasia substantially increases breast cancer risk, but identification of biomarkers to further improve risk stratification is needed. We evaluated ERβ expression in breast tissues from women with atypical hyperplasia and association with subsequent breast cancer risk. ERβ expression was examined by immunohistochemistry in a well-characterized 171-women cohort with atypical hyperplasia diagnosed 1967–1991. Nuclear ERβ percent and intensity was scored in the atypia and adjacent normal lobules. An ERβ sum score (percent + intensity) was calculated and grouped as low, moderate, or high. Competing risks regression was used to assess associations of ERβ expression with breast cancer risk. After 15-year median follow-up, 36 women developed breast cancer. ERβ expression was lower in atypia lobules in than normal lobules, by percent staining and intensity (both P < 0.001). Higher ERβ expression in the atypia or normal lobules, evaluated by percent staining, intensity or sum score, decreased the risk of subsequent breast cancer by 2-fold (P = 0.04) and 2.5-fold (P = 0.006). High normal lobule ERβ expression conferred the strongest protective effect in premenopausal women: the 20-year cumulative incidence of breast cancer was 0% for women younger than 45 years with high versus 31% for low–moderate ERβ expression (P = 0.0008). High ERβ expression was associated with a significantly decreased risk of breast cancer in women with atypical hyperplasia. These data suggest that ERβ may be a useful biomarker for risk stratification and a novel therapeutic target for breast cancer risk reduction. Cancer Prev Res; 8(11); 1084–92. ©2015 AACR.

Glycosylphosphatidylinositol (GPI)-anchored proteins are resistant to solubilization with Triton X-100 at 4 °C, and they can be recovered in Triton-insoluble membranes (TIMs) that float to a characteristic buoyant density. Because the GPI structure itself has been shown to target GPI-anchored proteins to TIMs, we investigated the association of GPI-anchor intermediates with TIMs. GPI-anchor biosynthesis involves a pathway of some 10 steps that take place in the endoplasmic reticulum (ER). These intermediates include glucosaminyl-acylphosphatidylinositol [GlcN-(acyl)PI] and later mannosylated GPIs, denoted H6, H7 and H8, that are present not only in the ER but also in other cell compartments, including the plasma membrane. At least two-thirds of the GlcN-(acyl)PI in HeLa D cells and mannosylated GPIs in K562 cells were found in TIMs. Although previous reports have considered TIMs to be derived primarily from the plasma membrane, we recovered TIMs from subcellular fractions enriched in ER membranes. The ER marker calnexin and GPI-anchored proteins as well as N-acetylglucosaminyl-phosphatidylinositol and mannosylated GPIs were present in ER-TIMs. Interestingly, GlcN-PI and H7 were less enriched in ER-TIM than the other GPIs, suggesting that ER-TIMs might reflect a compartmentalization of the GPI-anchor biosynthetic pathway in the ER.

Lung diseases such as emphysema, interstitial fibrosis, and pulmonary vascular diseases cause significant morbidity and mortality, but despite substantial mechanistic understanding, clinical management options for them are limited, with lung transplantation being implemented at end stages. However, limited donor lung availability, graft rejection, and long-term problems after transplantation are major hurdles to lung transplantation being a panacea. Bioengineering the lung is an exciting and emerging solution that has the ultimate aim of generating lung tissues and organs for transplantation. In this article we capture and review the current state of the art in lung bioengineering, from the multimodal approaches, to creating anatomically appropriate lung scaffolds that can be recellularized to eventually yield functioning, transplant-ready lungs. Strategies for decellularizing mammalian lungs to create scaffolds with native extracellular matrix components vs. de novo generation of scaffolds using biocompatible materials are discussed. Strengths vs. limitations of recellularization using different cell types of various pluripotency such as embryonic, mesenchymal, and induced pluripotent stem cells are highlighted. Current hurdles to guide future research toward achieving the clinical goal of transplantation of a bioengineered lung are discussed.

1.A family of structurally related but genetically distinct natriuretic peptides exist which include atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) of myocardial cell origin and C-type natriuretic peptide (CNP) of endothelial and renal epithelial cell origin. All three exert actions via cGMP, with ANP and BNP functioning via the natriuretic peptide A receptor and CNP via the natriuretic peptide B receptor. 2.Circulating and urinary natriuretic peptides were determined in response to acute intravascular volume overload (AVO). Additionally, their functional role in cardiorenal regulation during AVO was investigated by utilizing the natriuretic peptide receptor antagonist HS-142-1. Control (n = 5) and study dogs (HS-142-1, n = 9) underwent AVO with normal saline equal to 10% of body weight over 1 ;h. Both groups demonstrated similar significant increases in right atrial pressure, pulmonary capillary wedge pressure, pulmonary artery pressure and cardiac output. Circulating ANP paralleled increases in right atrial pressure and pulmonary capillary wedge pressure, with no changes in plasma BNP or CNP. At peak AVO, urinary CNP excretion was increased compared with baseline (7.0±4.2 versus 62±8.0 ;pg/min, P< 0.05). 3.In the HS-142-1-treated group, plasma cGMP was decreased compared with the control group (9.6±1.1 to 5.0±1.2 ;pmol/ml, P< 0.05). A significant attenuation of natriuresis (566±91 versus 1241±198 ;μEq/min, P< 0.05) and diuresis (4.8±0.7 versus 10.1±2.0 ;ml/min, P< 0.05) was also observed at peak AVO in the HS-142-1 treated group. 4.These findings support differential and selective responses of the three natriuretic peptides to AVO, in which plasma ANP and urinary CNP are markers for AVO. Secondly, these studies confirm the role of ANP and CNP but not BNP in the natriuretic and diuretic response to acute volume overload.

Summary Objective Epilepsy surgery is the most effective treatment for select patients with drug‐resistant epilepsy. In this article, we aim to provide an accurate understanding of the current epidemiologic characteristics of this intervention, as this knowledge is critical for guiding educational, academic, and resource priorities. Methods We profile the practice of epilepsy surgery between 1991 and 2011 in nine major epilepsy surgery centers in the United States, Germany, and Australia. Clinical, imaging, surgical, and histopathologic data were derived from the surgical databases at various centers. Results Although five of the centers performed their highest number of surgeries for mesial temporal sclerosis ( MTS ) in 1991, and three had their highest number of MTS surgeries in 2001, only one center achieved its peak number of MTS surgeries in 2011. The most productive year for MTS surgeries varied then by center; overall, the nine centers surveyed performed 48% (95% confidence interval [CI] −27.3% to −67.4%) fewer such surgeries in 2011 compared to either 1991 or 2001, whichever was higher. There was a parallel increase in the performance of surgery for nonlesional epilepsy. Further analysis of 5/9 centers showed a yearly increase of 0.6 ± 0.07% in the performance of invasive electroencephalography ( EEG ) without subsequent resections. Overall, although MTS was the main surgical substrate in 1991 and 2001 (proportion of total surgeries in study centers ranging from 33.3% to 70.2%); it occupied only 33.6% of all resections in 2011 in the context of an overall stable total surgical volume. Significance These findings highlight the major aspects of the evolution of epilepsy surgery across the past two decades in a sample of well‐established epilepsy surgery centers, and the critical current challenges of this treatment option in addressing complex epilepsy cases requiring detailed evaluations. Possible causes and implications of these findings are discussed.