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Admixture mapping of uterine fibroid size and number in African American women.
Bray MJ, Edwards TL, Wellons MF, Jones SH, Hartmann KE, Velez Edwards DR
(2017) Fertil Steril 108: 1034-1042.e26
MeSH Terms: Adult, African Americans, Biological Specimen Banks, Biomarkers, Tumor, Cross-Sectional Studies, Databases, Factual, Electronic Health Records, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heredity, Humans, Leiomyoma, Leiomyomatosis, Linear Models, Logistic Models, Middle Aged, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Tumor Burden, United States, Uterine Neoplasms
Show Abstract · Added February 21, 2019
OBJECTIVE - To evaluate the relationship between genetic ancestry and uterine fibroid characteristics.
DESIGN - Cross-sectional study.
SETTING - Not applicable.
PATIENT(S) - A total of 609 African American participants with image- or surgery-confirmed fibroids in a biorepository at Vanderbilt University electronic health record biorepository and the Coronary Artery Risk Development in Young Adults studies were included.
INTERVENTION(S) - None.
MAIN OUTCOME MEASURE(S) - Outcome measures include fibroid number (single vs. multiple), volume of largest fibroid, and largest fibroid dimension of all fibroid measurements.
RESULT(S) - Global ancestry meta-analyses revealed a significant inverse association between percentage of European ancestry and risk of multiple fibroids (odds ratio: 0.78; 95% confidence interval 0.66, 0.93; P=6.05 × 10). Local ancestry meta-analyses revealed five suggestive (P<4.80 × 10) admixture mapping peaks in 2q14.3-2q21.1, 3p14.2-3p14.1, 7q32.2-7q33, 10q21.1, 14q24.2-14q24.3, for number of fibroids and one suggestive admixture mapping peak (P<1.97 × 10) in 10q24.1-10q24.32 for volume of largest fibroid. Single variant association meta-analyses of the strongest associated region from admixture mapping of fibroid number (10q21.1) revealed a strong association at single nucleotide polymorphism variant rs12219990 (odds ratio: 0.41; 95% confidence interval 0.28, 0.60; P=3.82 × 10) that was significant after correction for multiple testing.
CONCLUSION(S) - Increasing African ancestry is associated with multiple fibroids but not with fibroid size. Local ancestry analyses identified several novel genomic regions not previously associated with fibroid number and increasing volume. Future studies are needed to explore the genetic impact that ancestry plays into the development of fibroid characteristics.
Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
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Leiomyomas in Pregnancy and Spontaneous Abortion: A Systematic Review and Meta-analysis.
Sundermann AC, Velez Edwards DR, Bray MJ, Jones SH, Latham SM, Hartmann KE
(2017) Obstet Gynecol 130: 1065-1072
MeSH Terms: Abortion, Habitual, Abortion, Spontaneous, Adult, Female, Humans, Leiomyoma, Pregnancy, Pregnancy Complications, Neoplastic, Risk Factors, Uterine Neoplasms
Show Abstract · Added February 21, 2019
OBJECTIVE - To systematically review studies reporting the risk of spontaneous abortion among pregnant women of typical reproductive potential with and without uterine leiomyomas.
DATA SOURCES - We searched PubMed, EMBASE, Web of Science, and ClinicalTrials.gov for publications from January 1970 to December 2016.
METHODS OF STUDY SELECTION - We excluded studies that did not use imaging to uniformly document leiomyoma status of all participants, did not have a comparison group without leiomyomas, or primarily included women seeking care for recurrent miscarriage, infertility care, or assisted reproductive technologies.
TABULATION, INTEGRATION, AND RESULTS - Two authors independently reviewed eligibility, extracted data, and assigned overall quality ratings based on predetermined criteria. Of 1,469 articles identified, nine were eligible. Five enrolled general obstetric populations and four included women undergoing amniocentesis. In five studies in general obstetric populations that included 21,829 pregnancies (1,394 women with leiomyomas and 20,435 without), only one adjusted for potential confounders. This meta-analysis revealed no increase in risk of spontaneous abortion among those with leiomyomas compared with those without (11.5% compared with 8.0%; risk ratio 1.16, 95% CI 0.80-1.52). When bias from confounding was estimated for nonadjusted studies, the aggregate calculated risk ratio was 0.83 (95% CI 0.68-0.98).
CONCLUSION - Leiomyoma presence was not associated with increased risk of spontaneous abortion in an analysis of more than 20,000 pregnant women. Failure of prior studies to adjust for confounders may have led to the common clinical belief that leiomyomas are a risk factor for spontaneous abortion.
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A multi-stage genome-wide association study of uterine fibroids in African Americans.
Hellwege JN, Jeff JM, Wise LA, Gallagher CS, Wellons M, Hartmann KE, Jones SF, Torstenson ES, Dickinson S, Ruiz-Narváez EA, Rohland N, Allen A, Reich D, Tandon A, Pasaniuc B, Mancuso N, Im HK, Hinds DA, Palmer JR, Rosenberg L, Denny JC, Roden DM, Stewart EA, Morton CC, Kenny EE, Edwards TL, Velez Edwards DR
(2017) Hum Genet 136: 1363-1373
MeSH Terms: Adult, African Americans, Alleles, Cell Adhesion Molecules, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Guanine Nucleotide Exchange Factors, Humans, Leiomyoma, Middle Aged, Neoplasm Proteins, Risk Factors, Uterine Neoplasms
Show Abstract · Added March 14, 2018
Uterine fibroids are benign tumors of the uterus affecting up to 77% of women by menopause. They are the leading indication for hysterectomy, and account for $34 billion annually in the United States. Race/ethnicity and age are the strongest known risk factors. African American (AA) women have higher prevalence, earlier onset, and larger and more numerous fibroids than European American women. We conducted a multi-stage genome-wide association study (GWAS) of fibroid risk among AA women followed by in silico genetically predicted gene expression profiling of top hits. In Stage 1, cases and controls were confirmed by pelvic imaging, genotyped and imputed to 1000 Genomes. Stage 2 used self-reported fibroid and GWAS data from 23andMe, Inc. and the Black Women's Health Study. Associations with fibroid risk were modeled using logistic regression adjusted for principal components, followed by meta-analysis of results. We observed a significant association among 3399 AA cases and 4764 AA controls at rs739187 (risk-allele frequency = 0.27) in CYTH4 (OR (95% confidence interval) = 1.23 (1.16-1.30), p value = 7.82 × 10). Evaluation of the genetic association results with MetaXcan identified lower predicted gene expression of CYTH4 in thyroid tissue as significantly associated with fibroid risk (p value = 5.86 × 10). In this first multi-stage GWAS for fibroids among AA women, we identified a novel risk locus for fibroids within CYTH4 that impacts gene expression in thyroid and has potential biological relevance for fibroids.
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16 MeSH Terms
Integrated Molecular Characterization of Uterine Carcinosarcoma.
Cherniack AD, Shen H, Walter V, Stewart C, Murray BA, Bowlby R, Hu X, Ling S, Soslow RA, Broaddus RR, Zuna RE, Robertson G, Laird PW, Kucherlapati R, Mills GB, Cancer Genome Atlas Research Network, Weinstein JN, Zhang J, Akbani R, Levine DA
(2017) Cancer Cell 31: 411-423
MeSH Terms: Carcinosarcoma, DNA Copy Number Variations, Epithelial-Mesenchymal Transition, Female, Humans, Mutation, Uterine Neoplasms
Show Abstract · Added October 30, 2019
We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified.
Copyright © 2017 Elsevier Inc. All rights reserved.
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Incidence and mortality of gynaecological cancers: Secular trends in urban Shanghai, China over 40 years.
Huang Z, Zheng Y, Wen W, Wu C, Bao P, Wang C, Zhong W, Gao YT, Jin F, Xiang YB, Shu XO, Beeghly-Fadiel A
(2016) Eur J Cancer 63: 1-10
MeSH Terms: Adult, Age Factors, Aged, Aged, 80 and over, China, Female, Humans, Incidence, Middle Aged, Mortality, Ovarian Neoplasms, Urban Population, Uterine Cervical Neoplasms, Uterine Neoplasms, Young Adult
Show Abstract · Added April 18, 2017
AIM - Appraisal of cancer trends is essential for future cancer control, but relevant studies in China are scarce due to a lack of long-term data. With 40-years of cancer registry data, we sought to evaluate secular time trends in incidence and mortality of gynaecological cancers in an urban Chinese population.
MATERIALS AND METHODS - Data on incidence and mortality of invasive cervical, uterine and ovarian cancer were collected by the Shanghai Cancer Registry. Age-standardised incidence and mortality rates were calculated for women aged 20-84 in urban Shanghai between 1973 and 2012. Age-period-cohort Poisson regression models were used to evaluate age, period and cohort effects. Overall linear trends, interpreted as the estimated annual percentage change (EAPC), were derived from the net drift in age-drift models.
RESULTS - Overall, cervical cancer incidence and mortality substantially decreased (EAPC = -4.5% and -5.5%, respectively); however, an upward trend was apparent among younger women (age <60). Uterine cancer incidence increased slightly (EAPC = 1.8%), while mortality decreased over time (EAPC = -2.4%). Ovarian cancer incidence and mortality both increased, although the increase in incidence (EAPC = 1.8%) was larger than mortality (EAPC = 0.6%). While cohort effects were most evident for cervical cancer incidence and mortality, significant age, period, and cohort effects were found for all three gynaecological cancers evaluated.
CONCLUSIONS - These secular trends in incidence and mortality of gynaecological cancers in Shanghai likely reflect changing risk factor profiles and improved cancer prognosis over time, and suggest new priorities and call for additional efforts for gynaecological cancer prevention and control for women in China.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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15 MeSH Terms
The Relationship between Total Fibroid Burden and First Trimester Bleeding and Pain.
Michels KA, Hartmann KE, Archer KR, Ye F, Edwards DR
(2016) Paediatr Perinat Epidemiol 30: 115-23
MeSH Terms: Adolescent, Adult, African Americans, European Continental Ancestry Group, Female, Humans, Pain, Pregnancy, Pregnancy Complications, Cardiovascular, Pregnancy Complications, Neoplastic, Pregnancy Trimester, First, Prospective Studies, United States, Uterine Hemorrhage, Uterine Neoplasms, Young Adult
Show Abstract · Added February 22, 2016
BACKGROUND - Few studies comment on the association between fibroids and symptoms among pregnant women. These studies generally are retrospective and do not to assess the influence of number of tumours or their volume on risk of symptoms.
METHODS - Right from the Start is a prospective cohort that enrolled pregnant women from the southeastern USA between 2000 and 2012. In the first trimester, all participants had standardised ultrasounds to determine the presence or absence of fibroids. Symptoms were queried in a telephone survey. We used polytomous logistic regression to model odds of bleeding, pain, or both symptoms in relation to increasing total fibroid number and volume among white and black women.
RESULTS - Among 4509 participants, the prevalence of fibroids was 11%. Among those reporting symptoms (70%), 11% reported only bleeding, 59% reported only pain, and 30% reported both symptoms. After adjusting for age, race, parity, hypertension, smoking, alcohol use, and study site, increasing number of fibroids was associated with pain [odds ratio (OR) 1.16, 95% confidence interval (CI) 1.00, 1.33] and both symptoms [OR 1.25, 95% CI 1.08, 1.45] but not with bleeding among all women. Fibroid volume was not associated with symptoms among black women, but white women with the smallest fibroid volumes were more likely to report both symptoms than those without fibroids [OR 1.79, 95% CI 1.17, 2.72].
CONCLUSIONS - Very large tumours are not requisite for experiencing symptoms, as small fibroids and increasing number of tumours are associated with pain and both symptoms.
© 2015 John Wiley & Sons Ltd.
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16 MeSH Terms
Enhancing uterine fibroid research through utilization of biorepositories linked to electronic medical record data.
Feingold-Link L, Edwards TL, Jones S, Hartmann KE, Velez Edwards DR
(2014) J Womens Health (Larchmt) 23: 1027-32
MeSH Terms: Adolescent, Adult, African Continental Ancestry Group, Age Factors, Aged, Algorithms, Case-Control Studies, Electronic Health Records, Female, Humans, Leiomyoma, Magnetic Resonance Imaging, Middle Aged, Pelvic Pain, Phenotype, Predictive Value of Tests, Retrospective Studies, Risk Factors, Tomography, X-Ray Computed, Ultrasonography, Uterine Neoplasms
Show Abstract · Added February 12, 2015
BACKGROUND - Uterine leiomyomata (fibroids) affect up to 77% of women by menopause and account for $9.4 billion in yearly healthcare costs. Most studies rely on self-reported diagnosis, which may result in misclassification of controls since as many as 50% of cases are asymptomatic and thus undiagnosed. Our objective was to evaluate the performance and accuracy of a fibroid phenotyping algorithm constructed from electronic medical record (EMR) data, limiting to subjects with pelvic imaging.
METHODS - Our study population includes women from a clinical population at Vanderbilt University Medical Center (2008-2012). Analyses were restricted to women 18 years and older with at least one fibroid diagnosis confirmed by imaging for cases or at least two separate pelvic imaging procedures without a diagnosis for controls. We randomly reviewed 218 records to evaluate the accuracy of our algorithm and assess the indications for pelvic imaging. Participant characteristics and indications for imaging were compared between cases and controls in unadjusted and adjusted logistic regression analyses.
RESULTS - Our algorithm had a positive predictive value of 96% and negative predictive value of 98%. Increasing age (odds ratio=1.05, 95% confidence interval 1.03-1.08) and Black race (odds ratio=2.15, 95% confidence interval 1.18-3.94) were identified as risk factors for fibroids. The most common indications for imaging in both cases and controls were pain, bleeding, and reproductive factors, and the most common imaging modality was a pelvic ultrasound.
CONCLUSIONS - These data suggest that using biorepositories linked to EMR data is a feasible way to identify populations of imaged women that facilitate investigations of fibroid risk factors.
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21 MeSH Terms
Differential vimentin expression in ovarian and uterine corpus endometrioid adenocarcinomas: diagnostic utility in distinguishing double primaries from metastatic tumors.
Desouki MM, Kallas SJ, Khabele D, Crispens MA, Hameed O, Fadare O
(2014) Int J Gynecol Pathol 33: 274-81
MeSH Terms: Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Carcinoma, Endometrioid, Diagnosis, Differential, Female, Humans, Immunohistochemistry, Middle Aged, Neoplasm Grading, Neoplasm Metastasis, Neoplasm Staging, Neoplasms, Multiple Primary, Ovarian Neoplasms, Predictive Value of Tests, Sensitivity and Specificity, Uterine Neoplasms, Vimentin
Show Abstract · Added May 19, 2014
This study aimed to assess the diagnostic value of vimentin expression in differentiating endometrioid adenocarcinoma of primary uterine corpus and ovarian origin. Immunohistochemical analyses for the expression of vimentin in tumoral epithelial cells were performed on 149 endometrioid adenocarcinomas wherein the primary sites were not in question, including whole tissue sections of 27 carcinomas of uterine corpus origin (and no synchronous ovarian tumor), 7 carcinomas of ovarian origin (and no synchronous uterine corpus tumor) and a tissue microarray (TMA) containing 91 primary uterine corpus and 24 primary ovarian carcinomas. We also assessed 15 cases that synchronously involved the uterine corpus and ovary, 15 cases of metastasis to organs/tissues other than uterine corpus or ovary as well as 7 lymph node metastases. Vimentin was negative in 97% (30/31) of primary ovarian carcinomas. In contrast, 82% (97/118) of primary uterine corpus carcinomas were vimentin-positive. Vimentin expression was discordant in 53% of synchronous tumors. The sensitivity and specificity of negative vimentin staining in predicting an ovarian primary were 97% and 82%, respectively, whereas parallel values for positive vimentin staining in predicting a primary uterine tumor were 82% and 97%, respectively. The pattern of vimentin expression in all cases was maintained in their respective regional lymph nodes and distant metastases. In conclusion, ovarian and uterine corpus endometrioid adenocarcinomas have different patterns of vimentin expression. If validated in larger and/or different data sets, these findings may have diagnostic value in distinguishing metastatic lesions from double primary tumors involving both sites.
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19 MeSH Terms
Uterine neoplasms, version 1.2014.
Koh WJ, Greer BE, Abu-Rustum NR, Apte SM, Campos SM, Chan J, Cho KR, Cohn D, Crispens MA, Dupont N, Eifel PJ, Fader AN, Fisher CM, Gaffney DK, George S, Han E, Huh WK, Lurain JR, Martin L, Mutch D, Remmenga SW, Reynolds RK, Small W, Teng N, Tillmanns T, Valea FA, McMillian N, Hughes M
(2014) J Natl Compr Canc Netw 12: 248-80
MeSH Terms: Female, Humans, Uterine Neoplasms
Show Abstract · Added March 10, 2014
Adenocarcinoma of the endometrium (also known as endometrial cancer or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. An estimated 49,560 new uterine cancer cases will occur in 2013, with 8190 deaths resulting from the disease. Uterine sarcomas (stromal/mesenchymal tumors) are uncommon malignancies, accounting for approximately 3% of all uterine cancers. The NCCN Guidelines for Uterine Neoplasms describe malignant epithelial carcinomas and uterine sarcomas; each of these major categories contains specific histologic groups that require different management. This excerpt of these guidelines focuses on early-stage disease.
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3 MeSH Terms
Uterine leiomyomata and cesarean birth risk: a prospective cohort with standardized imaging.
Michels KA, Velez Edwards DR, Baird DD, Savitz DA, Hartmann KE
(2014) Ann Epidemiol 24: 122-6
MeSH Terms: Adult, Body Mass Index, Cesarean Section, Confidence Intervals, Female, Humans, Labor, Obstetric, Leiomyoma, North Carolina, Obstetric Labor Complications, Predictive Value of Tests, Pregnancy, Pregnancy Complications, Neoplastic, Prevalence, Prospective Studies, Risk Factors, Tennessee, Texas, Ultrasonography, Prenatal, Uterine Neoplasms
Show Abstract · Added March 5, 2014
PURPOSE - To determine if women with leiomyomata detected using uniform ultrasound methods are at increased risk of cesarean birth, without regard to indication.
METHODS - Women were enrolled in Right from the Start (2000-2010), a prospective pregnancy cohort. Leiomyomata were counted, categorized, and measured during first trimester ultrasounds. Women provided information about demographics and reproductive history during first trimester interviews. Route of delivery was extracted from medical records or vital records, if the former were unavailable. Generalized estimating equations were used to calculate risk ratios (RR) and 95% confidence intervals (CIs) for the risk of cesarean birth by leiomyoma presence and characteristics.
RESULTS - Among 2635 women, the prevalences of leiomyomata and cesarean birth were 11.2% and 29.8%, respectively. Women with leiomyomata, compared with those without, had a 27% increase in cesarean risk (RR, 1.27; CI, 1.17-1.37). The association was weaker following adjustment for maternal body mass index and age (adjusted risk ratio [ARR], 1.11; CI, 1.02-1.20). The adjusted risk was elevated for women with a single leiomyoma 3 cm or more in diameter (ARR, 1.22; CI, 1.14-1.32) and women with the largest total leiomyoma volumes (ARR, 1.59; CI, 1.44-1.76).
CONCLUSIONS - Women with leiomyomata were at increased risk for cesarean birth particularly, those with larger tumor volumes.
Copyright © 2014 Elsevier Inc. All rights reserved.
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20 MeSH Terms