Publications by authors named "Stephen L Rose"

38 Publications

A Revised Markov Model Evaluating Oophorectomy at the Time of Hysterectomy for Benign Indication: Age 65 Years Revisited.

Obstet Gynecol 2022 May 5;139(5):735-744. Epub 2022 Apr 5.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, UW Health Hospital and Clinics, and the Department of Statistics and the Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.

Objective: To perform an updated Markov modeling to assess the optimal age for bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign indication.

Methods: We performed a literature review that assessed hazard ratios (HRs) for mortality by disease, age, hysterectomy with or without BSO, and estrogen therapy use. Base mortality rates were derived from national vital statistics data. A Markov model from reported HRs predicted the proportion of the population staying alive to age 80 years by 1-year and 5-year age groups at time of surgery, from age 45 to 55 years. Those younger than age 50 years were modeled as either taking postoperative estrogen or not; those 50 and older were modeled as not receiving estrogen. Computations were performed with R 3.5.1, using Bayesian integration for HR uncertainty.

Results: Performing salpingo-oophorectomy before age 50 years for those not taking estrogen yields a lower survival proportion to age 80 years than hysterectomy alone before age 50 years (52.8% [Bayesian CI 40.7-59.7] vs 63.5% [Bayesian CI 62.2-64.9]). At or after age 50 years, there were similar proportions of those living to age 80 years with hysterectomy alone (66.4%, Bayesian CI 65.0-67.6) compared with concurrent salpingo-oophorectomy (66.9%, Bayesian CI 64.4-69.0). Importantly, those taking estrogen when salpingo-oophorectomy was performed before age 50 years had similar proportions of cardiovascular disease, stroke, and people living to age 80 years as those undergoing hysterectomy alone or those undergoing hysterectomy and salpingo-oophorectomy at age 50 years and older.

Conclusion: This updated Markov model argues for the consideration of concurrent salpingo-oophorectomy for patients who are undergoing hysterectomy at age 50 and older and suggests that initiating estrogen in those who need salpingo-oophorectomy before age 50 years mitigates increased mortality risk.
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http://dx.doi.org/10.1097/AOG.0000000000004732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9015029PMC
May 2022

False-Negative Rates of Breast Cancer Screening with and without Digital Breast Tomosynthesis.

Radiology 2021 02 1;298(2):296-305. Epub 2020 Dec 1.

From the Department of Diagnostic Radiology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06510 (M.A.D.); Advocate Lutheran General Hospital, Park Ridge, Ill (S.M.F., F.M.D.); Department of Radiology, University Hospitals of Cleveland Medical Center, Cleveland, Ohio (D.M.P.); Albert Einstein Healthcare Network, Philadelphia, Pa (D.S.C.); Invision Sally Jobe Breast Centers and Radiology Imaging Associates, Denver, Colo (L.D.B.); TOPS Comprehensive Breast Center, Houston, Tex (S.L.R.); Solis Women's Health, Dallas, Tex (S.L.R.); Radiology Associates of Hollywood and Memorial Healthcare System, Hollywood, Fla (M.K.H.); John C. Lincoln Breast Health and Research Center, Phoenix, Ariz (L.N.G.); and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (E.F.C.).

Background Screening with digital breast tomosynthesis (DBT) improves breast cancer detection and recall rates compared with those obtained with digital mammography (DM); however, the impact of DBT on patient survival has not been established. False-negative (FN) screening examinations can be a surrogate for long-term outcomes, such as breast cancer morbidity and mortality. Purpose To determine if screening with DBT is associated with lower FN rates, detection of cancers with more favorable prognoses, and improved performance outcomes versus DM. Materials and Methods This retrospective study involved 10 academic and community practices. DM screening examinations 1 year prior to DBT implementation and DBT screening examinations from the start date until June 30, 2013, were linked to cancers through June 30, 2014, with data collection in 2016 and analysis in 2018-2019. Cancers after FN examinations were characterized by presentation, either symptomatic or asymptomatic. FN rates, sensitivity, specificity, cancer detection and recall rates, positive predictive values, tumor size, histologic features, and receptor profile were compared. Results A total of 380 641 screening examinations were included. There were 183 989 DBT and 196 652 DM examinations. With DBT, rates trended lower for overall FN examinations (DBT, 0.6 per 1000 screens; DM, 0.7 per 1000 screens; = .20) and symptomatic FN examinations (DBT, 0.4 per 1000 screens; DM, 0.5 per 1000 screens; = .21). Asymptomatic FN rates trended higher in women with dense breasts (DBT, 0.14 per 1000 screens; DM: 0.07 per 1000 screens; = .07). With DBT, improved sensitivity (DBT, 89.8% [966 of 1076 cancers]; DM, 85.6% [789 of 922 cancers]; = .004) and specificity (DBT, 90.7% [165 830 of 182 913 examinations]; DM, 89.1% [174 480 of 195 730 examinations]; < .001) were observed. Overall, cancers identified with DBT were more frequently invasive ( < .001), had fewer positive lymph nodes ( = .04) and distant metastases ( = .01), and had lower odds of an FN finding of advanced cancer (odds ratio, 0.9 [95% CI: 0.5, 1.5]). Conclusion Screening with digital breast tomosynthesis improves sensitivity and specificity and reveals more invasive cancers with fewer nodal or distant metastases. © RSNA, 2020 See also the editorial by Schattner in this issue.
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http://dx.doi.org/10.1148/radiol.2020202858DOI Listing
February 2021

How we do it: Family leave at Rose Imaging Specialists, a large specialized breast imaging practice.

Clin Imaging 2020 10 18;66:137-138. Epub 2020 May 18.

Rose Imaging Specialists, PA, 616 Cypress Creek Parkway, Suite 460, Houston, TX 77090, United States of America.

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http://dx.doi.org/10.1016/j.clinimag.2020.05.004DOI Listing
October 2020

Recurrence Rates in Patients With Cervical Cancer Treated With Abdominal Versus Minimally Invasive Radical Hysterectomy: A Multi-Institutional Retrospective Review Study.

J Clin Oncol 2020 04 7;38(10):1030-1040. Epub 2020 Feb 7.

University of Wisconsin, Madison, WI.

Purpose: To compare the disease-free survival (DFS) between open and minimally invasive radical hysterectomies (RH) performed in academic medical institutions.

Methods: Retrospective multi-institutional review of patients undergoing RH for stage IA1 (with lymphovascular invasion), IA2, and IB1 squamous, adenocarcinoma, or adenosquamous carcinoma between January 1, 2010 and December 31, 2017.

Results: Of 815 patients, open RH was performed in 255 cases (29.1%) and minimally invasive RH in 560 cases (70.9%). There were 19 (7.5%) recurrences in the open RH and 51 (9.1%) recurrences in the minimally invasive group ( = .43). Risk-adjusted analysis revealed that minimally invasive RH was independently associated with an increased hazard of recurrence (aHR, 1.88; 95% CI, 1.04 to 3.25). Other factors independently associated with an increased hazard of recurrence included tumor size, grade, and adjuvant radiation. Conization before surgery was associated with lower recurrence risk (aHR, 0.4; 95% CI, 0.23 to 0.71). There was no difference in OS in the unadjusted analysis (HR, 1.14; 95% CI, 0.61 to 2.11) or after risk adjustment (aHR, 1.01; 95% CI, 0.5 to 2.2). Of 264 patients with tumors ≤ 2 cm on final pathology (excluding those with no residual tumor on final pathology), 2/82 (2.4%) recurred in the open RH group and 16/182 (8.8%) in the minimally invasive RH group ( = .058). In propensity score matching analysis, 7/159 (4.4%) recurrences were noted in the open RH group and 18/156 (11.5%) in the minimally invasive RH group ( = .019). Survival analysis revealed an increased risk of recurrence in the minimally invasive group in propensity-matched cohort (HR, 2.83; 95% CI, 1.1 to 7.18).

Conclusion: In this retrospective series, patients undergoing minimally invasive radical hysterectomy, including those with tumor size ≤ 2 cm on final pathology, had inferior DFS but not overall survival in the entire cohort.
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http://dx.doi.org/10.1200/JCO.19.03012DOI Listing
April 2020

O-RADS US Risk Stratification and Management System: A Consensus Guideline from the ACR Ovarian-Adnexal Reporting and Data System Committee.

Radiology 2020 01 5;294(1):168-185. Epub 2019 Nov 5.

From the Department of Radiology and Radiological Sciences and Department of Obstetrics and Gynecology, Vanderbilt University College of Medicine, 1161 21st Ave S, #D3300, Nashville, Tenn 37232 (R.F.A.); Department of Obstetrics and Gynecology, University Hospitals KU Leuven, Leuven, Belgium (D.T.); Department of Radiology, University of California, San Francisco, San Francisco, Calif (L.M.S.); Department of Development and Regeneration, KU Leuven, Leuven, Belgium (W.F.); Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium (W.F.); Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Brookline, Mass (B.R.B.); Department of Radiology, NYU Langone Health, New York, NY (G.L.B.); Department of Obstetrics and Gynecology, Queen Charlotte's and Chelsea Hospital, Imperial College London, London, England (T.B.); Department of Radiology, Mayo Clinic, Rochester, Minn (D.L.B.); Department of Radiology, Center for Fetal Diagnosis and Treatment, Children's Hospital of Philadelphia, Philadelphia, Pa (B.G.C.); Department of Radiology, Brigham and Women's Hospital, Boston, Mass (M.C.F.); Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY (S.R.G.); Department of Radiology, Johns Hopkins University, School of Medicine, Baltimore, Md (U.M.H.); Department of Radiology, Einstein Medical Center, Philadelphia, Pa (M.M.H.); Department of Radiology and Radiological Sciences, Carell Children's Hospital at Vanderbilt, Nashville, Tenn (M.H.S.); Department of Radiology, McGill University Health Centre, Montreal, Canada (C.R.); Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wis (S.L.R.); Department of Obstetrics and Gynecology, University of Connecticut School of Medicine, Farmington, Conn (B.P.W.); Department of Obstetrics and Gynecology, Mt. Sinai Hospital, University of Toronto, Toronto, Canada (W.L.W.); and Department of Medical Imaging and Department of Obstetrics and Gynecology, University of Toronto, Sunnybrook Research Institute, Toronto, Canada (P.G.).

The Ovarian-Adnexal Reporting and Data System (O-RADS) US risk stratification and management system is designed to provide consistent interpretations, to decrease or eliminate ambiguity in US reports resulting in a higher probability of accuracy in assigning risk of malignancy to ovarian and other adnexal masses, and to provide a management recommendation for each risk category. It was developed by an international multidisciplinary committee sponsored by the American College of Radiology and applies the standardized reporting tool for US based on the 2018 published lexicon of the O-RADS US working group. For risk stratification, the O-RADS US system recommends six categories (O-RADS 0-5), incorporating the range of normal to high risk of malignancy. This unique system represents a collaboration between the pattern-based approach commonly used in North America and the widely used, European-based, algorithmic-style International Ovarian Tumor Analysis (IOTA) Assessment of Different Neoplasias in the Adnexa model system, a risk prediction model that has undergone successful prospective and external validation. The pattern approach relies on a subgroup of the most predictive descriptors in the lexicon based on a retrospective review of evidence prospectively obtained in the IOTA phase 1-3 prospective studies and other supporting studies that assist in differentiating management schemes in a variety of almost certainly benign lesions. With O-RADS US working group consensus, guidelines for management in the different risk categories are proposed. Both systems have been stratified to reach the same risk categories and management strategies regardless of which is initially used. At this time, O-RADS US is the only lexicon and classification system that encompasses all risk categories with their associated management schemes.
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http://dx.doi.org/10.1148/radiol.2019191150DOI Listing
January 2020

Longitudinal assessment of post-surgical physical activity in endometrial and ovarian cancer patients.

PLoS One 2019 16;14(10):e0223791. Epub 2019 Oct 16.

Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, United States of America.

Objective: Physical activity plays a key role in cancer survivorship. The purpose of this investigation was to (a) describe the post-surgical physical activity trajectories of endometrial (n = 65) and ovarian (n = 31) cancer patients and (b) identify clinical and demographic predictors of physical activity over time.

Methods: 96 participants wore an Actiwatch accelerometer for three days at each of three time points (one week, one month and four months) after surgical intervention for their endometrial or ovarian cancer diagnosis. Analyses were conducted using linear mixed effects regression modeling in SAS 9.4.

Results: For both tumor types, although physical activity levels increased with time after surgery, even at four months patients were performing only a small fraction of the 150 minutes of recommended weekly moderate to vigorous physical activity. At 1 week, subjects were completing on average 14 minutes/week (SD = 4) of moderate-to-vigorous physical activity, compared to 14 minutes/week (SD = 2) of moderate-to-vigorous physical activity at four months post-surgery (p < .05). Better self-rated health was associated with higher physical activity (p = 0.02) in endometrial cancer survivors only. BMI, age, surgery type and use of neoadjuvant chemotherapy were not associated with activity over time.

Conclusions: Our findings suggest that physical activity levels are different for those with better self-rated health, but those individuals are still insufficiently active. This study adds new information describing the trajectories and variables that influence physical activity in gynecologic cancer survivors after surgery and highlights the need for health promotion interventions in this population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223791PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795433PMC
March 2020

Using simple radiologic measurements to anticipate surgical challenge in endometrial cancer: a prospective study.

Int J Gynecol Cancer 2019 01;29(1):102-107

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University Of Wisconsin - Madison, Madison, Wisconsin, USA

Objectives: To determine if linear measurements of adiposity from pre-operative imaging can improve anticipation of surgical difficulty among endometrial cancer patients.

Methods: Eighty patients with newly diagnosed endometrial cancer were enrolled. Routine pre-operative imaging (MRI or CT) was performed. Radiologic linear measurements of the following were obtained: anterior-to-posterior skin distance; anterior skin to anterior edge of L5 distance (total anterior); anterior peritoneum to anterior edge of L5 distance (visceral obesity); and posterior edge of L5 to posterior skin distance (total posterior). Surgeons completed questionnaires quantifying preoperative anticipated operative difficulty and postoperative reported operative difficulty. The primary objective was to assess for a correlation between linear measurements of visceral fat and reported operative difficulty.

Results: Seventy-nine patients had questionnaires completed, preoperative imaging obtained, and surgery performed. Univariate analysis showed all four linear measurements, body mass index, weight, and anticipated operative difficulty were associated with increased reported operative difficulty (P< 0.05). Multivariate analysis demonstrated that body mass index and linear measurements visceral obesity and total posterior were independently associated with increased reported operative difficulty (P< 0.05). Compared with body mass index, the visceral obesity measurement was more sensitive and specific for predicting increased reported operative difficulty (visceral obesity; sensitivity 54%, specificity 91 %; body mass index; sensitivity 38%, specificity 89%). A difficulty risk model combining body mass index, visceral obesity, and total posterior demonstrated better predictive performance than any individual preoperative variable.

Conclusions: Simple linear measurements of visceral fat obtained from preoperative imaging are more predictive than body mass index alone in anticipating surgeon-reported operative difficulty. These easily obtained measurements may assist in preoperative decision making in this challenging patient population.
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http://dx.doi.org/10.1136/ijgc-2018-000037DOI Listing
January 2019

Preoperative obstructive sleep apnea screening in gynecologic oncology patients.

Am J Obstet Gynecol 2018 08 22;219(2):174.e1-174.e8. Epub 2018 May 22.

Division of Gynecologic Oncology, University of Wisconsin-Madison, Madison, WI; Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI. Electronic address:

Background: Women with a gynecologic cancer tend to be older, obese, and postmenopausal, characteristics that are associated with an increased risk for obstructive sleep apnea. However, there is limited investigation regarding the condition's prevalence in this population or its impact on postoperative outcomes. In other surgical populations, patients with obstructive sleep apnea have been observed to be at increased risk for adverse postoperative events.

Objective: We sought to estimate the prevalence of obstructive sleep apnea among gynecologic oncology patients undergoing elective surgery and to investigate for a relationship between obstructive sleep apnea and postoperative outcomes.

Study Design: Patients referred to an academic gynecologic oncology practice were approached for enrollment in this prospective, observational study. Patients were considered eligible for study enrollment if they were scheduled for a nonemergent inpatient surgery and could provide informed consent. Enrolled patients were evaluated for a preexisting diagnosis of obstructive sleep apnea. Those without a prior diagnosis were screened using the validated, 4-item STOP questionnaire (ie, Snore loudly, daytime Tiredness, Observed apnea, elevated blood Pressure). All patients who screened positive for obstructive sleep apnea were referred for polysomnography. The primary outcome was the prevalence of women with obstructive sleep apnea or those who screened at high risk for the condition. Secondary outcomes examined the correlation between body mass index (kg/m) with obstructive sleep apnea and assessed for a relationship between obstructive sleep apnea and postoperative outcomes.

Results: Over a 22-month accrual period, 383 eligible patients were consecutively approached to participate in the study. A cohort of 260 patients were enrolled. A total of 33/260 patients (13%) were identified as having a previous diagnosis of obstructive sleep apnea. An additional 66/260 (25%) screened at risk for the condition using the STOP questionnaire. Of the patients who screened positive, 8/66 (12%) completed polysomnography, all of whom (8/8 [100%]) were found to have obstructive sleep apnea. The prevalence of previously diagnosed obstructive sleep apnea or screening at risk for the condition increased as body mass index increased (P < .001). Women with untreated obstructive sleep apnea and those who screened at risk for the condition were found to have an increased risk for postoperative hypoxemia (odds ratio, 3.5; 95% confidence interval, 1.8-4.7; P = .011) and delayed return of bowel function (odds ratio, 2.1; 95% confidence interval, 1.3-4.5; P = .009).

Conclusion: The prevalence of obstructive sleep apnea or screening at risk for the condition is high among women presenting for surgery with a gynecologic oncologist. Providers should consider evaluating a patient's risk for obstructive sleep apnea in the preoperative setting, especially when risk factors for the condition are present.
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http://dx.doi.org/10.1016/j.ajog.2018.05.012DOI Listing
August 2018

Tomosynthesis Impact on Breast Cancer Screening in Patients Younger Than 50 Years Old.

AJR Am J Roentgenol 2018 Jun 9;210(6):1401-1404. Epub 2018 Apr 9.

1 Solis Mammography, 15601 Dallas Pkwy, Ste 500, Addison, TX 75001.

Objective: The question of benefits versus harms of breast cancer screening for women younger than 50 years old has been the subject of debate. We investigate if the addition of tomosynthesis to mammography improves screening performance outcomes for women in this age group.

Materials And Methods: Screening performance for 59,921 patients (41,542 digital mammography and 18,379 tomosynthesis) younger than 50 years old was collected from a community-based screening network from January 1, 2015, to December 31, 2015. Patients were offered tomosynthesis if it was available. Parameters including recall, biopsy, and cancer detection rates were compared. Mixed effects regression analysis was used to estimate rates with screening modality, age, and density as fixed effects and screening site as a random effect. Rates for patients with dense breast tissue were also evaluated.

Results: Model adjusted rates per 1000 screenings with digital mammography were compared with digital mammography plus tomosynthesis, respectively: recall rate decreased from 117 to 108 (difference, -8.3; p = 0.003); biopsy rate increased from 13.5 to 16.6 (difference, 3.1; p = 0.003); and cancer detection rate increased from 1.9 to 2.6 (difference, 0.8; p = 0.060). Model adjusted rates for patients with dense breast tissue were: recall rate decreased from 135 to 132 (difference, -3.2; p = 0.44); biopsy rate increased from 16.0 to 20.5 (difference, 4.5; p = 0.004); and cancer detection rate increased from 2.1 to 3.5 (difference, 1.3; p = 0.03).

Conclusion: Tomosynthesis in a community setting resulted in decreased recall rates for patients younger than 50 years old. For the subgroup of women with dense breast tissue, cancer detection rates also increased.
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http://dx.doi.org/10.2214/AJR.17.18839DOI Listing
June 2018

Aldehyde dehydrogenase 1A1 (ALDH1A1) expression by immunohistochemistry is associated with chemo-refractoriness in patients with high-grade ovarian serous carcinoma.

Hum Pathol 2018 03 26;73:1-6. Epub 2017 Aug 26.

Department of Pathology, University of Wisconsin Hospital and Clinics, Madison, WI 53792. Electronic address:

Aldehyde dehydrogenase-1A1 (ALDH1A1), CD133, CD44, and CD24 have been reported as cancer stem cell markers in ovarian cancers. The goal of our study was to assess the prognostic significance of these markers in patients with advanced serous ovarian cancer. Formalin-fixed, paraffin-embedded tissues from 347 ovarian cancers were used to construct a microarray. Immunohistochemical studies for ALDH1A1, CD133, CD44, and CD24 were performed and scored semiquantitatively by 2 pathologists based on intensity and percent of positive immunoreactive cells. Immunohistochemistry was compared to clinical parameters and survival. Of the 347 cases, early stage disease, nonserous tumors, cases with incomplete therapy, and cores with no tumor were excluded. Immunohistochemistry was interpretable in 124 of the 136 stage III and IV ovarian serous carcinoma. ALDH1A1, CD24, and CD44 were variably detected in both tumor and stromal cells, and immunoreactivity in tumor was stronger than in stromal cells. CD133 immunoreactivity was not quantified due to nonspecific staining in tumor and stroma. Statistical analyses using χ and Student t test revealed that ALDH1A1-positive (n=53) carcinoma were 3 times more likely to demonstrate platinum refractoriness than ALDH1A1-negative (n=71) tumors (17% vs. 6%, respectively; p=.04); however, neither progression free nor overall survival was influenced by ALDH1A1 status in this cohort. The expression of CD44 and CD24 had no clinicopathological associations in the present study. Our study supports that ALDH1A1 expression is associated with poor response to platinum-based therapy in patients with high-grade ovarian serous carcinoma. Further study of this relationship is needed to understand how this could impact clinical care.
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http://dx.doi.org/10.1016/j.humpath.2017.06.025DOI Listing
March 2018

The impact of physician burnout on clinical and academic productivity of gynecologic oncologists: A decision analysis.

Gynecol Oncol 2017 09 24;146(3):642-646. Epub 2017 Jun 24.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL, United States.

Objective: Physician burnout is associated with mental illness, alcohol abuse, and job dissatisfaction. Our objective was to estimate the impact of burnout on productivity of gynecologic oncologists during the first half of their career.

Methods: A decision model evaluated the impact of burnout on total relative value (RVU) production during the first 15years of practice for gynecologic oncologists entering the workforce from 2011 to 2015. The SGO practice survey provided physician demographics and mean annual RVUs. Published data were used to estimate probability of burnout for male and female gynecologic oncologists, and the impact of depression, alcohol abuse, and early retirement. Academic productivity was defined as annual PubMed publications since finishing fellowship.

Results: Without burnout, RVU production for the cohort of 250 gynecologic oncologists was 26.2 million (M) RVUs over 15years. With burnout, RVU production decreased by 1.6 M (5.9% decrease). Disproportionate rates of burnout among females resulted in 1.1 M lost RVUs for females vs. 488 K for males. Academic production without burnout was estimated at 9277 publications for the cohort. Burnout resulted in 1383 estimated fewer publications over 15years (14.9%).

Conclusions: The impact of burnout on clinical and academic productivity is substantial across all specialties. As health care systems struggle with human resource shortages, this study highlights the need for effective burnout prevention and wellness programs for gynecologic oncologists. Unless significant resources are designated to wellness programs, burnout will increasingly affect the care of our patients and the advancement of our field.
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http://dx.doi.org/10.1016/j.ygyno.2017.06.026DOI Listing
September 2017

Effect of age on breast cancer screening using tomosynthesis in combination with digital mammography.

Breast Cancer Res Treat 2017 Aug 18;164(3):659-666. Epub 2017 May 18.

, Tetonia, ID, USA.

Purpose: To determine the effect of tomosynthesis imaging as a function of age for breast cancer screening.

Methods: Screening performance metrics from 13 institutions were examined for 12 months prior to introduction of tomosynthesis (period 1) and compared to those after introduction of tomosynthesis (period 2, range 3-22 months). Screening metrics for women ages 40-49, 50-59, 60-69, and 70+ , included rates per 1000 screens for recalls, biopsies, cancers, and invasive cancers detected.

Results: Performance parameters were compared for women screened with digital mammography alone (n = 278,908) and digital mammography + tomosynthesis (n = 173,414). Addition of tomosynthesis to digital mammography produced significant reductions in recall rates for all age groups and significant increases in cancer detection rates for women 40-69. Largest recall rate reduction with tomosynthesis was for women 40-49, decreasing from 137 (95% CI 117-156) to 115 (95% CI 95-135); difference, -22 (95% CI -26 to -18; P < .001). Simultaneous increase in invasive cancer detection rate for women 40-49 from 1.6 (95% CI 1.2-1.9) to 2.7 (95% CI 2.2-3.1) with tomosynthesis (difference, 1.1; 95% CI 0.6-1.6; P < .001) was observed.

Conclusions: Addition of tomosynthesis to digital mammography increased invasive cancer detection rates for women 40-69 and decreased recall rates for all age groups with largest performance gains seen in women 40-49. The similar performance seen with tomosynthesis screening for women in their 40s compared to digital mammography for women in their 50s argues strongly for commencement of mammography screening at age 40 using tomosynthesis.
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http://dx.doi.org/10.1007/s10549-017-4299-0DOI Listing
August 2017

Biopsychosocial predictors of pain among women recovering from surgery for endometrial cancer.

Gynecol Oncol 2016 Feb 10;140(2):301-6. Epub 2015 Sep 10.

Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States; Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States. Electronic address:

Objective: This study investigated post-surgical changes in pain among endometrial cancer patients, as well as the extent to which emotional distress and inflammatory and regulatory cytokine levels were associated with pain.

Methods: Women (N=71) who underwent surgery for endometrial cancer completed questionnaires assessing pain intensity and interference, depression, and anxiety at 1week, 4weeks, and 16weeks post-surgery. Participants also provided a blood sample for the analysis of a panel of 7 cytokines at the same time points.

Results: Participants showed significant declines in pain intensity and pain interference from 1week to 4weeks post-surgery, after which pain remained stable. After adjusting for time since surgery, surgery type, adjuvant therapy, disease stage, age, and BMI, mixed-effects linear regression models indicated that greater depression and anxiety were associated with both greater pain intensity and interference. Higher levels of circulating IL-6 were also correlated with greater pain intensity, but not interference. Fixed-effects linear regression models indicated that temporal variation in depression, anxiety, and IL-6 within individual patients was associated with corresponding changes in pain. Pain symptoms were maximal when anxiety, depression, and IL-6 were highest. No other cytokines were associated with changes in pain.

Conclusion: These findings indicate that depression, anxiety, and IL-6 may exacerbate pain during the recovery period following surgery for a gynecologic malignancy. Targeting these psychological processes and the proinflammatory cytokine IL-6 in women with more severe and persistent pain may help to reduce suffering and improve post-surgical recovery.
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http://dx.doi.org/10.1016/j.ygyno.2015.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724440PMC
February 2016

Circadian actigraphic rest-activity rhythms following surgery for endometrial cancer: A prospective, longitudinal study.

Gynecol Oncol 2015 Jun 21;137(3):448-55. Epub 2015 Apr 21.

Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.

Objective: To investigate (1) circadian rest-activity rhythm disturbances among endometrial cancer patients as they recover from surgery in comparison to a historical reference group of women with no cancer history and (2) health- and treatment-related predictors of dysregulated rest-activity rhythms in endometrial cancer patients.

Methods: 60 endometrial cancer patients participated in a prospective, longitudinal study with actigraphic assessment at 1week, 1month, and 4months post-surgery. 60 women without cancer from an epidemiological sample completed one actigraphic assessment, acting as a reference group.

Results: On average, results revealed initial significant rest-activity dysregulation at 1week and 1month post-surgery for the endometrial cancer group and then significant recovery in rest-activity patterns at 4months post-surgery. Similarly, the cancer group had significantly more impaired rhythms than the reference group at 1week post-surgery, but demonstrated comparable rhythms by 4months post-surgery. Among the health- and treatment-related variables examined, obesity and receipt of more invasive surgery were found to predict more impaired rhythms at all time points.

Conclusion(s): The current study highlights significant disturbances in rest-activity patterns for endometrial cancer patients initially during surgical recovery followed by improvement in these patterns by 4months post-surgery; however, obese patients and those having more invasive surgery demonstrated more impaired rest-activity patterns throughout the 4-month recovery period. Further research is warranted to understand how more impaired rest-activity patterns relate to health and quality of life outcomes.
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http://dx.doi.org/10.1016/j.ygyno.2015.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452033PMC
June 2015

Symptom management of gynecologic cancers: refocusing on the forest.

Gynecol Oncol 2015 Mar;136(3):413-4

Division of Gynecologic Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ygyno.2015.01.555DOI Listing
March 2015

Frailty index predicts severe complications in gynecologic oncology patients.

Gynecol Oncol 2015 Apr 17;137(1):98-101. Epub 2015 Jan 17.

Division of Gynecologic Oncology, University of Wisconsin, Madison, WI, United States.

Objective: The purpose of this study was to quantify the predictive value of frailty index on 30-day Clavien class IV (requiring critical care support) and class V (30-day mortality) complications after gynecologic cancer surgery.

Methods: Patients included in the National Surgical Quality Improvement Program (NSQIP) 2008-2011 had a final diagnosis of gynecologic malignancy. Modified frailty index (mFI) was calculated with 11 variables. Higher mFI scores indicated more severe comorbidities. Logistic regression was used to control for known predictors of complications.

Results: Of the total 6551 patients, 188 (2.9%) of the patients experienced a Clavien IV/V complication. 2958 patients had a score of 0 (45.2%), 2405 patients had a score of 1 (36.7%), 985 patients had a score of 2 (15%), 162 patients had a score of 3 (2.5%) and 41 patients had a score≥4 (0.6%). The rates of Clavien IV/V complications were 2%, 2.7%, 4.4%, 7.4% and 24.4% for mFI scores of 0, 1, 2, 3 and ≥4, respectively (p<0.001). Variables found to be significant for predicting Clavien IV and V complications on logistic regression modeling were preoperative albumin<3g/dL (OR=6.5), operative time (OR=1.003 per min increase), non-laparoscopic surgery (OR=3.3), and frailty index (OR score 0=reference, score 1=1.26, score 2=1.9, score 3=2.33 and score≥4=12.5). Taking the two preoperative factors of albumin and mFI allowed for greater precision in identifying women who are at higher risk for requiring ICU care (>10% risk).

Conclusions: Modified frailty index (mFI) is predictive of the need for critical care support and 30-day mortality after surgery for gynecologic cancer.
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http://dx.doi.org/10.1016/j.ygyno.2015.01.532DOI Listing
April 2015

Reply: To PMID 24949539.

Am J Obstet Gynecol 2015 May 18;212(5):688. Epub 2014 Dec 18.

University of Wisconsin, Gynecologic Oncology, 600 Highland Ave. H4/676 Madison, WI 53717.

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http://dx.doi.org/10.1016/j.ajog.2014.12.023DOI Listing
May 2015

A reader study comparing prospective tomosynthesis interpretations with retrospective readings of the corresponding FFDM examinations.

Acad Radiol 2014 Sep;21(9):1204-10

TOPS Comprehensive Breast Center, 17030 Red Oak Dr, Houston, TX 77090.

Rationale And Objectives: To compare performance of prospective interpretations of clinical tomosynthesis (digital breast tomosynthesis [DBT]) plus full-field digital mammography (FFDM) examinations with retrospective readings of the corresponding FFDM examinations alone.

Methods And Materials: Seven Mammography Quality Standard Act-qualified radiologists retrospectively interpreted 10,878 FFDM examinations that had been interpreted by other radiologists during prospective clinical interpretations of DBT plus FFDM. The radiologists were blinded to the Breast Imaging Reporting and Data System (BIRADS) category given during the clinical interpretations and the verified outcome by follow-up and/or any diagnostic workup that may have followed. Ratings (BIRADS 0, 1, or 2) were recorded. Group performance levels in terms of recall rates and attributable cancer detection rates were compared to the prospective clinical interpretations of the same examinations (DBT plus FFDM) using McNemar test (two sided/tailed) with significance level of .05.

Results: During the prospective clinical interpretations of DBT plus FFDM, 588 cases were recalled (588 of 10,878, 5.41%) compared to 888 cases recalled (888 of 10,878, 8.16%) during the FFDM-alone retrospective interpretations (absolute difference, 35%; P<.0001). There were 59 and 38 suspicious abnormalities later verified as cancers detected during the DBT plus FFDM and the FFDM-alone interpretations, respectively (absolute increase, 55%; P<.0001). Invasive cancer detections were 48 and 29, respectively (absolute increase, 66%; P<.0001).

Conclusions: The combination of DBT plus FFDM for screening asymptomatic women resulted in a significant reduction in recall rates and a simultaneous increase in cancer detection rates when compared to retrospective interpretations of corresponding FFDM examinations alone.
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http://dx.doi.org/10.1016/j.acra.2014.04.008DOI Listing
September 2014

Breast cancer screening using tomosynthesis in combination with digital mammography.

JAMA 2014 Jun;311(24):2499-507

Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Importance: Mammography plays a key role in early breast cancer detection. Single-institution studies have shown that adding tomosynthesis to mammography increases cancer detection and reduces false-positive results.

Objective: To determine if mammography combined with tomosynthesis is associated with better performance of breast screening programs in the United States.

Design, Setting, And Participants: Retrospective analysis of screening performance metrics from 13 academic and nonacademic breast centers using mixed models adjusting for site as a random effect.

Exposures: Period 1: digital mammography screening examinations 1 year before tomosynthesis implementation (start dates ranged from March 2010 to October 2011 through the date of tomosynthesis implementation); period 2: digital mammography plus tomosynthesis examinations from initiation of tomosynthesis screening (March 2011 to October 2012) through December 31, 2012.

Main Outcomes And Measures: Recall rate for additional imaging, cancer detection rate, and positive predictive values for recall and for biopsy.

Results: A total of 454,850 examinations (n=281,187 digital mammography; n=173,663 digital mammography + tomosynthesis) were evaluated. With digital mammography, 29,726 patients were recalled and 5056 biopsies resulted in cancer diagnosis in 1207 patients (n=815 invasive; n=392 in situ). With digital mammography + tomosynthesis, 15,541 patients were recalled and 3285 biopsies resulted in cancer diagnosis in 950 patients (n=707 invasive; n=243 in situ). Model-adjusted rates per 1000 screens were as follows: for recall rate, 107 (95% CI, 89-124) with digital mammography vs 91 (95% CI, 73-108) with digital mammography + tomosynthesis; difference, -16 (95% CI, -18 to -14; P < .001); for biopsies, 18.1 (95% CI, 15.4-20.8) with digital mammography vs 19.3 (95% CI, 16.6-22.1) with digital mammography + tomosynthesis; difference, 1.3 (95% CI, 0.4-2.1; P = .004); for cancer detection, 4.2 (95% CI, 3.8-4.7) with digital mammography vs 5.4 (95% CI, 4.9-6.0) with digital mammography + tomosynthesis; difference, 1.2 (95% CI, 0.8-1.6; P < .001); and for invasive cancer detection, 2.9 (95% CI, 2.5-3.2) with digital mammography vs 4.1 (95% CI, 3.7-4.5) with digital mammography + tomosynthesis; difference, 1.2 (95% CI, 0.8-1.6; P < .001). The in situ cancer detection rate was 1.4 (95% CI, 1.2-1.6) per 1000 screens with both methods. Adding tomosynthesis was associated with an increase in the positive predictive value for recall from 4.3% to 6.4% (difference, 2.1%; 95% CI, 1.7%-2.5%; P < .001) and for biopsy from 24.2% to 29.2% (difference, 5.0%; 95% CI, 3.0%-7.0%; P < .001).

Conclusions And Relevance: Addition of tomosynthesis to digital mammography was associated with a decrease in recall rate and an increase in cancer detection rate. Further studies are needed to assess the relationship to clinical outcomes.
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http://dx.doi.org/10.1001/jama.2014.6095DOI Listing
June 2014

Preoperative hypoalbuminemia is an independent predictor of poor perioperative outcomes in women undergoing open surgery for gynecologic malignancies.

Gynecol Oncol 2013 Nov 17;131(2):416-22. Epub 2013 Aug 17.

University of Wisconsin, Department of Gynecologic Oncology, Madison, WI, USA. Electronic address:

Objective: To quantify the impact of preoperative hypoalbuminemia on 30-day mortality and morbidity after gynecologic cancer surgery.

Methods: Patients included in the National Surgical Quality Improvement Program (NSQIP) dataset who underwent any non-emergent surgery for gynecologic malignancy between 1/1/2008 and 12/31/2010 were identified. Analysis was conducted with albumin both as a dichotomous variable (<3.5 g/dl was defined as low albumin) and as a continuous variable to determine a clinically relevant cut-off value.

Results: Of the total 3171 patients identified, 2110 had preoperative albumin levels available for analysis. In addition, 279 (13.3%) of these patients had low albumin levels. According to multivariate analysis, the low albumin group had significantly higher odds of developing one or more post-operative complications (OR-2,CI: 1.47-2.73, p<0.0001), three or more complications (OR-4.1,CI: 2.31-7.1, p<0.0001), surgical complications (OR-2.39,CI: 1.59-3.58, p<0.0001), thromboembolic complications (OR-2.59,CI: 1.33-5.06, p<0.0001), pulmonary complications (OR-4.06,CI: 2.05-8.03, p<0.0001), or infectious complications (OR-1.84,CI: 1.26-2.69, p<0.0001) and a higher 30-day mortality (OR-6.52,CI: 2.51-16.95, p<0.0001). Upon subgroup analysis, this difference was not found in patients undergoing laparoscopic surgery. In patients undergoing open surgery, the probability of experiencing one or more post-operative complications increased linearly with the decrease in albumin level; however, the probability of patients experiencing three or more complications and 30-day mortality increased sharply as soon as the albumin level decreased below 3g/dl.

Conclusion: Preoperative albumin levels <3g/dL identify a population of patients at a very high-risk of experiencing perioperative morbidity and 30-day mortality after open surgery.
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http://dx.doi.org/10.1016/j.ygyno.2013.08.011DOI Listing
November 2013

Implementation of breast tomosynthesis in a routine screening practice: an observational study.

AJR Am J Roentgenol 2013 Jun;200(6):1401-8

TOPS Comprehensive Breast Center, 17030 Red Oak Dr, Houston, TX 77090, USA.

Objective: Digital mammography combined with tomosynthesis is gaining clinical acceptance, but data are limited that show its impact in the clinical environment. We assessed the changes in performance measures, if any, after the introduction of tomosynthesis systems into our clinical practice.

Materials And Methods: In this observational study, we used verified practice- and outcome-related databases to compute and compare recall rates, biopsy rates, cancer detection rates, and positive predictive values for six radiologists who interpreted screening mammography studies without (n = 13,856) and with (n = 9499) the use of tomosynthesis. Two-sided analyses (significance declared at p < 0.05) accounting for reader variability, age of participants, and whether the examination in question was a baseline were performed.

Results: For the group as a whole, the introduction and routine use of tomosynthesis resulted in significant observed changes in recall rates from 8.7% to 5.5% (p < 0.001), nonsignificant changes in biopsy rates from 15.2 to 13.5 per 1000 screenings (p = 0.59), and cancer detection rates from 4.0 to 5.4 per 1000 screenings (p = 0.18). The invasive cancer detection rate increased from 2.8 to 4.3 per 1000 screening examinations (p = 0.07). The positive predictive value for recalls increased from 4.7% to 10.1% (p < 0.001).

Conclusion: The introduction of breast tomosynthesis into our practice was associated with a significant reduction in recall rates and a simultaneous increase in breast cancer detection rates.
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http://dx.doi.org/10.2214/AJR.12.9672DOI Listing
June 2013

The use of humor in patients with recurrent ovarian cancer: a phenomenological study.

Int J Gynecol Cancer 2013 May;23(4):775-9

Department of Obstetrics and Gynecology, The University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.

Objective: Humor has been shown to decrease the use of pain medicine, improve mood, and decrease stress. However, the timing and setting for using humor can be perceived differently depending on the patient and the context. Our objective was to better understand how patients with recurrent ovarian cancer experience humor to gain insight into the feasibility of using humor as a therapeutic adjunct.

Methods: We conducted structured patient interviews with women being treated for recurrent ovarian cancer. The phenomenological method of Colaizzi was used to gain an in-depth understanding of how women with recurrent ovarian cancer use and view humor in relation to their diagnosis.

Results: Most patients used humor to cope with cancer and felt that humor alleviated their anxiety. The use of humor by physicians and nurses was perceived as appropriate and positive. A previous relationship with a physician was often felt necessary before the use of humor. Humor was often perceived not only in traditional jokes but was also found in humorous anecdotes from the caregiver's life outside of medicine.

Conclusions: This study revealed that humor is an often used coping mechanism for women with recurrent ovarian cancer and subjectively helps alleviate anxiety. The use of humor by physicians was found to be universally perceived as appropriate and positive. The waiting area seems to be a place where humorous experiences would be welcomed. These findings provide additional insight into the role that humor plays in the lives of patients with recurrent ovarian cancer.
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http://dx.doi.org/10.1097/IGC.0b013e31828addd5DOI Listing
May 2013

The role of appendectomy for mucinous ovarian neoplasms.

Am J Obstet Gynecol 2013 Jan 16;208(1):46.e1-4. Epub 2012 Oct 16.

Department of Obstetrics and Gynecology, University of Wisconsin Hospital and Clinics, Madison, WI, USA.

Objective: To determine how frequently the appendix harbors pathology in women having surgery for mucinous neoplasms of the ovary and assess the associated morbidity.

Study Design: A retrospective chart review of patients operated on at our institution with the diagnosis of a mucinous neoplasm of the ovary or appendix.

Results: A total of 327 cases were identified. Of the 309 women with mucinous ovarian neoplasms, 197 (64%) were benign, 68 (22%) low malignancy potential, and 44 (14%) were invasive. Of 155 appendectomies performed, only 1 metastatic low grade mucinous appendiceal tumor was found, but this appendix was grossly abnormal. There was no association between wound complications and appendectomy.

Conclusion: When a grossly normal appendix is removed during surgery for a mucinous ovarian neoplasm without evidence of pseudomyxoma peritonei, no primary or metastatic mucinous appendiceal tumors are found.
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http://dx.doi.org/10.1016/j.ajog.2012.10.863DOI Listing
January 2013

Phase II trial of nab-paclitaxel in the treatment of recurrent or persistent advanced cervix cancer: A gynecologic oncology group study.

Gynecol Oncol 2012 Dec 14;127(3):451-5. Epub 2012 Sep 14.

The University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.

Background: Metastatic and recurrent, platinum resistant cervix cancer has an extremely poor prognosis. The Gynecologic Oncology Group has studied >20 cytotoxic drugs or drug combinations in the second-line, phase II setting of advanced, drug resistant cervix cancer.

Methods: Nanoparticle, albumin-bound paclitaxel (nab-paclitaxel) was administered at 125 mg/m(2) IV over 30 minutes on days 1, 8 and 15 of each 28 day cycle to 37 women with metastatic or recurrent cervix cancer that had progressed or relapsed following first-line cytotoxic drug treatment. A flexible, 2-stage accrual design that allowed stopping early for lack of treatment activity was utilized. Because of slow patient accrual, the second stage was not completed.

Results: Of 37 patients enrolled, 2 were ineligible due to no prior cytotoxic chemotherapy, which left 35 eligible patients evaluable for response and tolerability. All of the eligible patients had 1 prior chemotherapy regimen and 27 of them had prior radiation therapy with concomitant cisplatin. The median number of nab-paclitaxel cycles were 4 (range 1-15). Ten (28.6%; CI 14.6%-46.3%) of the 35 patients had a partial response and another 15 patients (42.9%) had stable disease. The median progression-free and overall survival were 5.0 and 9.4 months, respectively. The only NCI CTCAE grade 4 event was neutropenia in 2 patients (5.7%) which resolved following dose reduction. Grade 3 neurotoxicity was reported in 1 (2.9%) patient and resolved to grade 2 following dose discontinuation.

Conclusions: Nab-paclitaxel has considerable activity and moderate toxicity in the treatment of drug resistant, metastatic and recurrent cervix cancer.
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http://dx.doi.org/10.1016/j.ygyno.2012.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459779PMC
December 2012

What is the optimal venous thromboembolism prophylaxis for gynecological oncology patients with CNS metastases?

Gynecol Oncol 2011 Nov 31;123(2):409-10. Epub 2011 Jul 31.

Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison WI, USA.

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http://dx.doi.org/10.1016/j.ygyno.2011.06.032DOI Listing
November 2011

Xanthohumol decreases Notch1 expression and cell growth by cell cycle arrest and induction of apoptosis in epithelial ovarian cancer cell lines.

Gynecol Oncol 2011 Aug 26;122(2):396-401. Epub 2011 May 26.

Department of Obstetrics and Gynecology, The University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.

Objective: Notch1 signaling is active in ovarian cancer and is a promising pathway for new therapies in ovarian cancer. We have previously detected high Notch1 expression in ovarian tumors. Xanthohumol has been shown to inhibit cancer cell growth and invasion, including Kaposi's sarcoma, which also highly expresses Notch1. We hypothesized that the Notch1 signaling pathway is targeted by xanthohumol leading to decreased ovarian cancer cell growth.

Methods: SKOV3 and OVCAR3 cells were utilized. MTT growth assays were conducted following treatment with xanthohumol. Quantitative RT-PCR and Western blot analyses were conducted to assess Notch1 down-regulation. Luciferase reporter assays were performed to assess functional down-regulation of Notch1. Cell cycle analysis was performed by flow cytometry.

Results: Significant growth inhibition and down-regulation of Notch1 transcription and protein expression were found following xanthohumol treatment. In addition, xanthohumol increased Hes6 transcription and decreased Hes1 transcription, known downstream targets of Notch 1. These observations were associated with cell cycle inhibition as demonstrated by an increase in p21 expression and S and G2/M cell cycle arrest confirmed by an increase in phosphorylated cdc2. Furthermore, an increase in the apoptotic markers, cleaved caspase-3 and cleaved PARP were observed.

Conclusion: Xanthohumol was a potent inhibitor of ovarian cancer cell growth, and our results suggest that xanthohumol may be influencing the Notch1 pathway. These findings suggest that xanthohumol could be useful as a therapeutic agent in ovarian cancer.
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http://dx.doi.org/10.1016/j.ygyno.2011.04.027DOI Listing
August 2011

Where once there was color.

Authors:
Stephen L Rose

Obstet Gynecol 2011 Jan;117(1):143-144

From the University of Wisconsin, Madison, Wisconsin.

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http://dx.doi.org/10.1097/AOG.0b013e318202addfDOI Listing
January 2011

Notch 1 signaling is active in ovarian cancer.

Gynecol Oncol 2010 Apr 8;117(1):130-3. Epub 2010 Jan 8.

The Department of Obstetrics and Gynecology, The University of Wisconsin, Madison, WI 53792, USA.

OBJECTIVE.: Despite advances in chemotherapy and radical surgery, most advanced stage ovarian cancer patients die from their disease, highlighting the need for the development of novel treatment strategies. The Notch signaling pathway plays an important role in cellular differentiation, proliferation and apoptosis. We hypothesized that the active form of Notch 1, the Notch 1 intracellular domain (NICD), would be overexpressed in ovarian cancer cells and that depletion of NICD would lead to growth reduction. METHODS.: Following institutional review board approval, NICD expression was analyzed in human ovarian cancer specimens as well as the ovarian cancer cell lines OVCAR3, SKOV3, and CaOV3. In addition, the effects of Notch 1 depletion on ovarian cancer cell growth were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) growth assay for 6 days following transfection with siRNA against Notch 1. RESULTS.: Western blot analysis revealed abundant NICD expression in all 3 ovarian cancer cell lines, as well as in 16 of 21 (76%) human ovarian cancer samples. Following treatment with Notch 1 siRNA, expression of NICD was greatly reduced in all three cell lines. Furthermore, this depletion of NICD was associated with significant growth inhibition of all three ovarian cancer cell lines. CONCLUSIONS.: NICD was frequently expressed in ovarian cancer cell lines and human ovarian cancer specimens. Importantly, depletion of Notch 1 led to growth inhibition of ovarian cancer cells. These findings support the hypothesis that Notch 1 plays a role in ovarian cancer proliferation, encouraging the investigation of this pathway as a therapeutic target.
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http://dx.doi.org/10.1016/j.ygyno.2009.12.003DOI Listing
April 2010

Notch signaling pathway in ovarian cancer.

Authors:
Stephen L Rose

Int J Gynecol Cancer 2009 May;19(4):564-6

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.

The literature is replete with reports of the paradoxical role of Notch signaling in human cancer. Notch appears to act as both an oncogene and a tumor suppressor gene depending on the cellular context. This review focuses on the nascent knowledge of Notch signaling in ovarian cancer. Despite advances in chemotherapy and radical surgery, ovarian cancer remains the most deadly gynecologic malignancy. Therapeutic improvements are necessary to enhance outcomes of patients with ovarian cancer. I will review the evidence for Notch activation in ovarian cancer and potential strategies for Notch inactivation as targeted treatment of ovarian cancer.
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http://dx.doi.org/10.1111/IGC.0b013e3181a12ed2DOI Listing
May 2009

DNA methylation changes in ovarian cancer are cumulative with disease progression and identify tumor stage.

BMC Med Genomics 2008 Sep 30;1:47. Epub 2008 Sep 30.

Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson AZ 85724 USA.

Background: Hypermethylation of promoter CpG islands with associated loss of gene expression, and hypomethylation of CpG-rich repetitive elements that may destabilize the genome are common events in most, if not all, epithelial cancers.

Methods: The methylation of 6,502 CpG-rich sequences spanning the genome was analyzed in 137 ovarian samples (ten normal, 23 low malignant potential, 18 stage I, 16 stage II, 54 stage III, and 16 stage IV) ranging from normal tissue through to stage IV cancer using a sequence-validated human CpG island microarray. The microarray contained 5' promoter-associated CpG islands as well as CpG-rich satellite and Alu repetitive elements.

Results: Results showed a progressive de-evolution of normal CpG methylation patterns with disease progression; 659 CpG islands showed significant loss or gain of methylation. Satellite and Alu sequences were primarily associated with loss of methylation, while promoter CpG islands composed the majority of sequences with gains in methylation. Since the majority of ovarian tumors are late stage when diagnosed, we tested whether DNA methylation profiles could differentiate between normal and low malignant potential (LMP) compared to stage III ovarian samples. We developed a class predictor consisting of three CpG-rich sequences that was 100% sensitive and 89% specific when used to predict an independent set of normal and LMP samples versus stage III samples. Bisulfite sequencing confirmed the NKX-2-3 promoter CpG island was hypermethylated with disease progression. In addition, 5-aza-2'-deoxycytidine treatment of the ES2 and OVCAR ovarian cancer cell lines re-expressed NKX-2-3. Finally, we merged our CpG methylation results with previously published ovarian expression microarray data and identified correlated expression changes.

Conclusion: Our results show that changes in CpG methylation are cumulative with ovarian cancer progression in a sequence-type dependent manner, and that CpG island microarrays can rapidly discover novel genes affected by CpG methylation in clinical samples of ovarian cancer.
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http://dx.doi.org/10.1186/1755-8794-1-47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2566571PMC
September 2008
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