Obesity and depression are risk factors for future eating disorder-related attitudes and behaviors in women with polycystic ovary syndrome.

OBJECTIVE(S): To identify clinical predictors of future eating disorder symptoms in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective cohort study. SETTING: University center. PATIENT(S): One hundred sixty-four women with PCOS by the Rotterdam criteria. INTERVENTION(S): Participants were characterized at a baseline visit between 2006 and 2017. A questionnaire including the validated Eating Disorder Examination-Questionnaire (EDE-Q) was self-administered at follow-up. MAIN OUTCOME MEASURE(S): EDE-Q global score (0-6, higher scores indicate more severe symptoms). RESULT(S): One hundred sixty-four women completed the follow-up survey an average of 5.3 years after the baseline visit. Compared with a normative population, women with PCOS had higher EDE-Q global scores (2.3 vs. 1.5) and scored higher on all subscales. Within the PCOS cohort, the following baseline clinical characteristics were independently predictive of scoring in the highest EDE-Q global score tertile: body mass index, waist circumference, hyperandrogenemia, high sensitivity C-reactive protein, and depression scores. Obesity at baseline conferred a 6.9-fold increase in the odds of elevated EDE-Q score (adjusted odds ratio = 6.89; 95% confidence interval, 2.70, 17.62), while a positive depression screen conferred 3.6-fold increased odds (adjusted odds ratio = 3.58; 95% confidence interval, 1.74-7.35). Compared with white women, nonwhite women were at risk of higher EDE-Q scores. CONCLUSION(S): Women with PCOS are at risk of disordered eating attitudes and behaviors, which may interfere with attempts at lifestyle interventions. Clinicians should screen women with PCOS for eating disorder psychopathology, especially those with obesity or depression. An exclusive focus on weight loss may have unintended consequences.

Associations Between Anti-Mullerian Hormone and Cardiometabolic Health in Reproductive Age Women Are Explained by Body Mass Index.

CONTEXT: The relationship between reproductive and cardiometabolic aging is unclear. It is unknown if the relationship differs across different clinical populations. OBJECTIVE: To determine whether markers of ovarian reserve are associated with cardiometabolic risk in reproductive aged women with unexplained infertility (UI), polycystic ovary syndrome (PCOS), and regularly cycling women (OVA). DESIGN AND SETTING: Cross-sectional data from 8 US-based academic centers. PARTICIPANTS: Women aged 25-40 from 3 clinical populations: 870 with UI, 640 with PCOS, and 921 community-based OVA. MAIN OUTCOME MEASURES: Multivariable linear regression models were used to relate anti-mullerian hormone (AMH) and antral follicle count with cardiometabolic parameters including body mass index (BMI), waist circumference (WC), fasting glucose and insulin, homeostasis model assessment-insulin resistance (HOMA-IR), lipids, and C-reactive protein. RESULTS: In age and study site-adjusted models, AMH inversely related to BMI in the UI and OVA groups (P = 0.02 and P < 0.001). Among women with PCOS, AMH inversely related to BMI (P < 0.001), and also to WC (P < 0.001), fasting insulin (P < 0.01), HOMA-IR (P < 0.01), triglycerides (P = 0.04), and C-reactive protein (P < 0.001) and directly related to higher total (P = 0.02), low-density lipoprotein (P < 0.01), and high-density lipoprotein cholesterol (P < 0.01). In OVA, AMH also varied inversely with WC (P < 0.001), fasting insulin (P = 0.02), and HOMA-IR (P = 0.02). Adjustment for BMI eliminated associations in the OVA group but in PCOS, the relationship of AMH to total (P = 0.03) and low-density lipoprotein cholesterol (P = 0.003) remained. CONCLUSION: Associations observed between AMH and cardiometabolic indices are largely explained by BMI in women with and without PCOS. (J Clin Endocrinol Metab XX: 0-0, 2019).

Outcomes of screening mammography in women less than 40 prior to fertility treatment: a retrospective pilot study.

OBJECTIVE: There are currently no evidence-based guidelines regarding breast cancer screening in women under 40 prior to initiating assisted reproductive technology (ART). The prevalence of abnormal findings on screening mammography in this population is unknown. The purpose of this study was to describe screening mammography outcomes in women less than 40 years old, referred for the indication of pre-ART. MATERIALS, METHODS, PROCEDURES: This is a retrospective review of women less than 40 years old presenting for screening mammography prior to ART between January 2010 and March 2017. Clinical history, breast cancer risk factors, imaging and pathology results were gathered from the electronic medical record. RESULTS: The study included 80 women. Mean patient age was 37 years (range 34-39 years). Sixty-seven (84%) had negative or benign screening (BI-RADS 1 or 2) and 13 (16%) were recalled for diagnostic imaging (BI-RADS 0). Four of 13 (31%) recalled women were given BI-RADS 1 or 2 at diagnostic work-up, 4 (31%) were given a BI-RADS 3, and 5 (38%) were recommended for biopsy (BI-RADS 4). At patient request, 2 of 4 (50%) BI-RADS 3 cases underwent biopsy, for 7 total biopsies. Six (86%) biopsies yielded benign results and 1 (14%) yielded DCIS. Overall cancer yield was 1.3%. CONCLUSION: In women under 40 who plan to undergo ART, screening mammography may identify breast malignancies. This may be of particular importance given many breast cancers are hormone sensitive, and thus fertility treatments may affect tumor growth. Future, larger studies are needed.

A 2019 reproductive update from the Midwest Reproductive Symposium International.

"Mystery, Medicine, and the Magnificent Mile," the theme for the annual Midwest Reproductive Symposium International (MRSi) in Chicago, IL, captured the attention of reproductive professionals all over the world. Each year, the conference agenda encompasses emerging technologies in assisted reproduction, updates in the management of reproductive diseases, and common challenges encountered in clinical practice. The structure of the meeting, offering a mixture of lectures, panel discussions, and interactive workshops, creates a collaborative environment for physicians, geneticists, embryologists, nurses, mental health professionals, basic scientists, business administrative professionals, reproductive endocrinology and infertility fellows, and obstetrics and gynecology residents. The goal of the MRSi meeting is to provide all reproductive professionals the opportunity to exchange ideas, foster relationships, and deliver quality patient care. As the field continues to evolve, MRSi provides an exciting venue to uncover the mysteries of reproductive medicine with enthusiasm and collaboration.

Preconception serum lipids and lipophilic micronutrient levels are associated with live birth rates after IVF.

RESEARCH QUESTION: Is a mixture of preconception serum lipids and lipophilic micronutrients associated with clinical pregnancy and live births? DESIGN: In this prospective cohort study, blood serum was collected on the day of oocyte retrieval for 180 women undergoing IVF at an academic reproductive health centre. Concentrations of lipids (phospholipids, total cholesterol, high- and low-density lipoproteins, and triglycerides) and lipophilic micronutrients (α-, δ-, and γ-tocopherols, retinol, ß- and α-carotenes, ß-cryptoxanthin, lutein and lycopene) were determined using diagnostic reagent kits and high-performance liquid chromatography. Poisson regression was used with robust variance estimation to evaluate changes in Z-scores for the mixture of serum lipid and lipophilic micronutrient concentrations as predictors of embryo implantation, clinical pregnancy and live birth, adjusted for age, body mass index (BMI), race, smoking status, infertility diagnosis, ovarian stimulation protocol and other measured lipid and lipophilic micronutrient concentrations. RESULTS: Each SD higher serum triglyceride concentration was associated with a lower chance of live birth (RR 0.54; 95% CI 0.33 to 0.90) whereas a 1 SD higher serum α-tocopherol concentration, as part of a mixture of serum lipids and lipophilic micronutrients, was associated with a higher likelihood for a live birth (RR 1.61; 95% CI 1.11 to 2.36). Serum ß-carotene concentrations were associated with live birth in a non-linear fashion; low ß-carotene was associated with a lower chance of live birth and high ß-carotene with a higher chance of live birth. CONCLUSION: Although components of a mixture of lipids and lipophilic micronutrients were associated with live birth outcomes after IVF, a larger investigation is necessary to fully evaluate the potential clinical implications.

Depression Over the Lifespan in a Population-Based Cohort of Women With Polycystic Ovary Syndrome: Longitudinal Analysis.

OBJECTIVE: To (i) determine whether women with polycystic ovary syndrome (PCOS) from a population-based cohort experience elevated depression symptoms and (ii) characterize the trajectory of symptoms over the lifespan. DESIGN: The association between PCOS and longitudinal depression scores was investigated among 1127 black and white women participating in Coronary Artery Risk Development in Young Adults study. PCOS was ascertained at baseline (ages 20 to 32) by U.S. National Institutes of Health (NIH) criteria, incorporating androgens and symptoms of oligomenorrhea and hirsutism. The Center for Epidemiologic Studies-Depression (CES-D) scale was repeated prospectively in 5-year intervals over 25 years. Mixed-effects models evaluated the association between depression scores and PCOS after adjustment for confounders and characterized the trajectory of scores. The impact of race was explored. RESULTS: Eighty-three of 1127 (7.4%) participants met NIH PCOS criteria. Of these, 33 (40%) were black and 50 (60%) were white. CES-D scores were higher among women with PCOS [coefficient (coef) 2.51; 95% CI 1.49, 3.54; P < 0.01] across the lifespan. Scores decreased across the lifespan in women with and without PCOS (coef -0.1 point per year; P < 0.001). Black women experienced higher depression burden than white women (coef 1.80; 95% CI 1.20, 2.41; P < 0.001); however, an interaction was not detected between PCOS and race (P = 0.68). CONCLUSIONS: Women with PCOS-NIH from a population-based cohort are at risk for higher depression scores across the lifespan. Depression scores decline over time in women with PCOS in a trajectory similar to that in women without PCOS. Racial differences in depression risk should be acknowledged clinically and further explored.

Improved diagnostic performance for the diagnosis of polycystic ovary syndrome using age-stratified criteria.

OBJECTIVE: To determine optimal criteria for polycystic ovary morphology. DESIGN: Cross-sectional study. SETTING: Multidisciplinary polycystic ovary syndrome (PCOS) clinic at a tertiary academic center. PATIENT(S): Subjects with PCOS were seen between 2006 and 2015 and met PCOS 1992 National Institutes of Health criteria. Controls were from the Ovarian Aging (OVA) study (2006-2011), a longitudinal study including healthy women with regular menstrual cycles. INTERVENTION(S): Clinical data collection. MAIN OUTCOME MEASURE(S): Follicle number per ovary (FNPO) and ovarian volume (OV). RESULT(S): A total of 245 subjects with PCOS and 756 OVA study subjects were included in the FNPO analysis and had a mean (± SD) FNPO of 22.6 ± 12.4 and 10 ± 5.3, respectively. Receiver operating characteristic curves were created for both FNPO and OV and analyzed across age group categories (25 to <30, 30 to <35, and 35 to <40 years). Youden's and minimum distance (d) were used to compare efficacies of FNPO and OV thresholds. The optimal threshold for distinguishing PCOS from OVA controls was FNPO > 13. There was a decreasing trend in FNPO threshold with increasing age group (>15, >14, and >12, respectively). A total of 297 PCOS subjects and 756 OVA study subjects were included in the OV analysis and had a mean maximum OV of 10 ± 5 cm3 and 6.5 ± 5 cm3, respectively. The overall threshold was OV > 6.75 cm3, with a trend toward decreasing OV with increase in age group (>8.5, >7, and >6.25 cm3, respectively). CONCLUSION(S): Our findings reflect that age-stratified thresholds demonstrate superior diagnostic performance, with an improved balance of sensitivity and specificity compared with a single threshold. We propose age-specific thresholds for better diagnostic performance.

Clinical course of depression symptoms and predictors of enduring depression risk in women with polycystic ovary syndrome: Results of a longitudinal study.

OBJECTIVE: To [1] characterize depression symptoms over time and [2] test the hypothesis that adverse metabolic parameters would associate with risk of enduring depression risk in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective cohort study. SETTING: University center. PATIENT(S): One hundred sixty-three women with PCOS. INTERVENTION(S): The Beck Depression Inventory Fast Screen (BDI-FS) was self-administered at baseline and follow-up to identify depression risk, using a cutoff score >4. MAIN OUTCOME MEASURE(S): BDI-FS scores. RESULT(S): Median baseline age was 29.0 years, and median follow-up interval was 5.5 years. Fifty-nine of 163 women had positive depression screens at baseline (36%); 52 women (32%) screened positive at follow-up. Median change in BDI-II score was 0 (interquartile range, -2, 1) over the study period. Of the 59 women at risk for depression at baseline, 22 screened negative at follow-up (37%), while 37 women remained at risk (63%). Considering these 59 women with positive depression screens at baseline, higher body mass index (BMI) was associated with increased odds of enduring depression risk at follow-up (adjusted odds ratio = 1.09; 95% confidence interval, 1.00, 1.18), in a multivariate logistic regression model. Compared with women with normal body weight at baseline, obese women (BMI >30 kg/m2) had five-fold increased odds of enduring depression risk at follow-up (adjusted odds ratio = 5.07; 95% confidence interval, 1.07, 24.0). CONCLUSION(S): The prevalence of depression was relatively stable over time in a cohort of women with PCOS. Elevated BMI is a hallmark of enduring depression risk. These results may assist providers in developing targeted intervention strategies to reduce the prevalence of long-term depressive symptoms in women with PCOS.

Association among depression, symptom experience, and quality of life in polycystic ovary syndrome.

BACKGROUND: Clinical stigmata of polycystic ovary syndrome include hirsutism, obesity, menstrual disturbances, and infertility. These symptoms impair health-related quality of life. Depression is also common. The relationship among depression, symptom self-perception, and quality of life in polycystic ovary syndrome is poorly understood. OBJECTIVE: We sought to investigate the relationship between health-related quality of life and depression in women with polycystic ovary syndrome. STUDY DESIGN: We conducted a secondary analysis of a multicenter, randomized clinical trial (Pregnancy in Polycystic Ovary Syndrome II, NCT00719186) comparing clomiphene citrate vs letrozole in the treatment of infertility. Subjects included 732 women ages 18-40 years with polycystic ovary syndrome by modified Rotterdam criteria. The validated Polycystic Ovary Syndrome Health-Related Quality of Life survey was self-administered, assessing the following domains: emotions, body hair, body weight, menstrual problems, and infertility; scores range from 1-7, with lower numbers indicating poorer quality of life. Depression was evaluated via the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire. Quality-of-life scores were compared between depressed and nondepressed women. Multivariate linear regression models analyzed the association between depression and quality-of-life scores, controlling for age, body mass index, hirsutism score, and duration of infertility. RESULTS: In all, 64 women (8.4%) met criteria for depression. Depressed women reported reduced quality of life in all domains compared to nondepressed women: mood (3.1 vs 4.6, P < .001), body hair (3.5 vs 4.2, P = .002), weight (2.0 vs 3.5, P < .001), menstrual problems (3.3 vs 4.1, P < .001), and infertility (1.9 vs 3.0, P < .001). Global quality-of-life score was reduced in depressed women (2.8 vs 3.9, P < .001). Impairments in quality of life in depressed women persisted in all domains after controlling for objective parameters including age, body mass index, hirsutism score, and infertility duration. CONCLUSION: Depression is associated with reduced quality of life related to polycystic ovary syndrome symptoms. Disturbances in health-related quality of life in depressed women are not explained by objective measures including body mass index, hirsutism scores, and duration of infertility. Depression may color the experience of polycystic ovary syndrome symptoms and should be considered when there is significant discordance between subjective and objective measures in women with polycystic ovary syndrome.

Insulin resistance is associated with depression risk in polycystic ovary syndrome.

OBJECTIVE: To test the hypothesis that insulin resistance is associated with depression risk in polycystic ovary syndrome (PCOS). DESIGN: Secondary analysis of data from a multicenter randomized trial. SETTING: Multicenter university-based clinical practices. PATIENT(S): Seven hundred thirty-eight women with PCOS by modified Rotterdam criteria seeking pregnancy enrolled in a randomized clinical trial comparing clomiphene citrate versus letrozole. INTERVENTION(S): The Primary Care Evaluation of Mental Disorders Patient Health Questionnaire was self-administered to identify depression using a validated algorithm at enrollment. Demographic and anthropometric data were collected, and serum assays were performed. Insulin resistance was estimated using the homeostatic model of insulin resistance (HOMA-IR), with a cutoff of >2.2 considered abnormal. MAIN OUTCOME MEASURE(S): Demographic, endocrine, and metabolic parameters associated with depression. RESULT(S): In a univariate logistic regression analysis, elevated HOMA-IR was associated with 2.3-fold increased odds of depression (odds ratio [OR] = 2.32; 95% confidence interval [CI], 1.28-4.21). This association remained significant after controlling for age and body mass index (adjusted OR [aOR] = 2.23; 95% CI, 1.11-4.46) and in a model including additional potential confounders (aOR = 2.03; 95% CI, 1.00-4.16). CONCLUSION(S): Insulin resistance has a strong and independent association with depression in PCOS and may serve as a physiologic mediator. Our findings corroborate a growing body of evidence linking insulin resistance to depressed mood. The association between insulin resistance and depressed mood warrants further investigation to elucidate mechanisms and identify potential therapeutic targets.

To freeze or not to freeze: decision regret and satisfaction following elective oocyte cryopreservation.

OBJECTIVE: To characterize the degree of decision regret following elective oocyte cryopreservation (EOC) for social indications, and identify factors associated with regret. DESIGN: Retrospective cohort survey study. SETTING: Academic center. PATIENTS: Two hundred one women who underwent EOC for fertility preservation between 2012 and 2016. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Decision Regret Scale (DRS) score, from 0-100, with a cut-off >25 indicative of moderate to severe regret; and attitudes regarding decision satisfaction. RESULTS: Median DRS score was 0 (interquartile range 0-15) and the mean was 10 (range 0-90). Thirty-three women (16%) experienced moderate to severe decision regret. Factors associated with decision regret included: number of eggs frozen, perceived adequacy of information prior to EOC, adequacy of emotional support during EOC, and patient-estimated probability of achieving a live birth using their banked eggs. In a multivariate logistic model, increased perceived adequacy of information (adjusted odds ratio 0.63, 95% confidence interval 0.42-0.97) and patient-estimated probability of achieving a live birth (adjusted odds ratio 0.80, 95% confidence interval 0.67-0.96) were associated with reduced odds of regret. One hundred sixty-seven women (88%) reported increased control over reproductive planning following EOC. One hundred eighty-three (89%) affirmed they will be happy they froze eggs, even if they never use them. CONCLUSIONS: The risk of decision regret following EOC is non-negligible. Low number of mature oocytes cryopreserved is a risk factor for increased regret, while perceptions of adequate information and emotional support, and increased patient-estimates of achieving a live birth using banked eggs are associated with reduced risk of regret.

Antimüllerian hormone levels and antral follicle counts are not reduced compared with community controls in patients with rigorously defined unexplained infertility.

OBJECTIVE: To test the hypothesis that women with unexplained infertility demonstrate evidence of diminished ovarian reserve when compared with a population of community controls. DESIGN: Cross-sectional study. SETTING: Multicenter university-based clinical practices. PATIENT(S): Study participants included 277 healthy, normo-ovulatory female partners with rigorously defined unexplained infertility randomly selected from a multicenter trial (Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation). Controls included 226 healthy, normo-ovulatory women not seeking treatment for fertility from a community-based cohort (Ovarian Aging study). INTERVENTION(S): Serum antimüllerian hormone (AMH) assay at a central laboratory, FSH, fasting serum metabolic testing, transvaginal ultrasonography for antral follicle counts (AFCs), anthropometric measurements. MAIN OUTCOME MEASURE(S): Average AMH, AFC, and AMH/AFC were compared between infertile and control women by age. Analyses of covariance compared these outcomes while controlling for confounders, including age, race, body mass index, smoking history, and study site. RESULT(S): In our models, AMH, AFC, and AMH/AFC ovarian reserve indices did not differ between infertile women and community-based controls, after controlling for age, race, body mass index, smoking history, and study site. CONCLUSION(S): Currently utilized predictors of ovarian reserve do not discriminate women with rigorously defined unexplained infertility from healthy community-based women of similar demographic characteristics. Contrary to our hypothesis, among women with FSH in the normal range (≤12 IU/L), women with unexplained infertility did not show evidence of decreased ovarian reserve as measured by AMH and AFC. Ovarian reserve markers in isolation may not serve as predictors of future fertility.

Vigorous exercise is associated with superior metabolic profiles in polycystic ovary syndrome independent of total exercise expenditure.

OBJECTIVE: To characterize metabolic features of women with polycystic ovary syndrome (PCOS) by exercise behavior and determine relative health benefits of different exercise intensities. DESIGN: Cross-sectional study. SETTING: Tertiary academic institution. PATIENT(S): Three hundred and twenty-six women aged 14-52 years-old with PCOS by Rotterdam criteria examined between 2006 and 2013. INTERVENTION(S): International Physical Activity Questionnaire (IPAQ) administered to classify patients into three groups based on Department of Health and Human Services (DHHS) Guidelines of vigorous, moderate, and inactive, along with physical examination and serum testing. MAIN OUTCOME MEASURE(S): Blood pressure, body mass index (BMI), waist circumference, fasting lipids, fasting glucose and insulin, 2-hour 75-gram oral glucose tolerance, homeostatic model assessment of insulin resistance (HOMA-IR). RESULT(S): The DHHS guidelines for adequate physical activity were met by 182 (56%) women. Compared with moderate exercisers and inactive women, the vigorous exercisers had lower BMI and lower HOMA-IR; higher levels of high-density lipoprotein cholesterol and sex hormone-binding globulin; and a reduced prevalence of the metabolic syndrome. In a multivariate logistic regression analysis controlling for age, BMI, and total energy expenditure, every hour of vigorous exercise reduced a patient's odds of metabolic syndrome by 22% (odds ratio 0.78; 95% confidence interval, 0.62, 0.99). CONCLUSION(S): Women with PCOS who met DHHS guidelines for exercise demonstrated superior metabolic health parameters. Vigorous but not moderate activity is associated with reduced odds of the metabolic syndrome, independent of age, BMI, and total energy expenditure. PCOS patients should be encouraged to meet activity guidelines via vigorous physical activity.

Putative role for insulin resistance in depression risk in polycystic ovary syndrome.

OBJECTIVE: To evaluate whether insulin resistance is associated with depression risk in women with polycystic ovary syndrome (PCOS), independent of other factors, including body mass index (BMI). DESIGN: Cross-sectional. SETTING: Tertiary university center. PATIENT(S): A total of 301 women, aged 14-52 years, with PCOS by Rotterdam criteria, consecutively examined between 2006 and 2013. INTERVENTION(S): Complete history and physical examinations, including endovaginal ultrasounds, dermatologic assessments, completion of Beck Depression Inventory Fast Screen (BDI-FS), and serum testing. MAIN OUTCOME MEASURE(S): Scores >4 on BDI-FS indicated a positive screen for depression. Scores were further subdivided into mild (5-8), moderate (9-12), and severe (>12) depression risk. Insulin resistance was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). RESULT(S): A total of 131 women (44%) were at risk for depression, determined by positive BDI-FS screening. These patients had higher BMI (32.3 vs. 28.5), and elevated insulin resistance, assessed by HOMA-IR (5.2 vs. 2.6), compared with patients with negative depression screening. In a stratified analysis by BMI category, obese women with positive depression screens had elevated HOMA-IR, compared with obese women with normal BDI-FS scores (7.4 vs. 4.1). In a multivariate logistic regression analysis, HOMA-IR was independently related to the odds of depression risk after controlling for age, ethnicity, BMI, and exercise (odds ratio: 1.07). CONCLUSION(S): Depression is common in PCOS. After controlling for confounders in multivariate regression analyses, we found HOMA-IR to be significantly associated with depression risk. Our data suggest a complex interplay among insulin resistance, obesity, and depression in PCOS, warranting additional investigation. Mental health assessment is indicated in comprehensive care of patients with PCOS.

Prostate-specific membrane antigen expression in tumor-associated vasculature of breast cancers.

Prostate-specific membrane antigen (PSMA) has been found to be expressed in the tumor-associated neovasculature of multiple solid tumor types including breast cancers. However, thus far, the number of cases studied from some tumor types has been limited. In this study, we set out to assess PSMA expression in the tumor-associated vasculature associated with invasive breast carcinomas in a sizable cohort of patients. One hundred and six patients with AJCC stage 0-IV breast cancer were identified. Ninety-two of these patients had primary breast cancer [invasive breast carcinoma with or without co-existing ductal carcinoma in situ (DCIS) (74) or DCIS alone (18)]. In addition, 14 patients with breast cancer metastases to the brain were identified. Immunohistochemical staining for PSMA and CD31 was performed on parallel representative tumor sections in each case. Tumor-associated vascular endothelial cell PSMA immunoreactivity was semi-quantitatively assessed based on two parameters: overall percent of endothelial positivity and staining intensity. PSMA expression for tumor-associated vascular endothelial cells was scored 0 if there was no detectable PSMA expression, 1 if PSMA staining was detectable in 5-50%, and 2 if PSMA expression was positive in >50% of microvessels. CD 31 staining was concurrently reviewed to confirm the presence of vasculature in each case. Tumor-associated vasculature was PSMA-positive in 68/92 (74%) of primary breast cancers and in 14/14 (100%) of breast cancers metastatic to brain. PSMA was not detected in normal breast tissue or carcinoma cells. All but 2 cases (98%) showed absence of PSMA expression in normal breast tissue-associated vasculature. The 10-year overall survival was 88.7% (95% CI = 80.0%, 93.8%) in patients without brain metastases. When overall survival (OS) was stratified based on PSMA score group, patients with PSMA scores of 0, 1, and 2 had 10-year OS of 95.8%, 96.0%, and 79.7%, respectively (p = 0.12). When PSMA scores of 0 and 1 were compared with 2, there was a statistically significant difference in OS (96.0% vs 79.7%, respectively, p = 0.05). Patients with a PSMA score of 2 had a significantly higher median tumor size compared with patients in the lower PSMA score groups (p = 0.04). Patients with higher nuclear grade were more likely to have a PSMA score of 2 compared with patients with lower nuclear grade (p < 0.0001). Patients with a PSMA score of 2 had a significantly higher median Ki-67 proliferation index compared with patients in the lower PSMA score groups (p < 0.0001). Patients with estrogen receptor (ER)-negative tumors were more likely to have a PSMA score of 2 compared with patients with ER-positive tumors (p < 0.0001). Patients with progesterone receptor (PR)-negative tumors were more likely to have a PSMA score of 2 compared with patients with PR-positive tumors (p = 0.03). No significant association was observed between PSMA score group status and lymph node involvement (p = 0.95). Too little variability was present in Human epidermal growth factor receptor-2 (Her2/neu) amplified tumors to correlate with PSMA score group status. To date, this is the first detailed assessment of PSMA expression in the tumor-associated vasculature of primary and metastatic breast carcinomas. Further studies are needed to evaluate whether PSMA has diagnostic and/or potential therapeutic value.

Assessment of pain as a sequela in patients treated with intracavitary brachytherapy accelerated partial breast irradiation (IBAPBI): preliminary results of a prospective study.

To assess pain rates and relationship to radiation-induced fibrosis (RIF) in patients treated with intracavitary brachytherapy accelerated partial breast irradiation (IBAPBI). Thirty-nine patients treated with IBAPBI were assessed prospectively for development of pain pretreatment, 1 month post-IBAPBI, and every 6 months thereafter. A qualitative subjective Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) questionnaire assessed pain. Use of pain medications was assessed as "no", "sometimes", or "regularly". A quantitative objective validated pressure threshold (PTH) measured pain in the site of IBAPBI breast (index) and its mirror-image in the nonirradiated breast (control). A validated tissue compliance meter (TCM) quantitatively assessed RIF in the index and control breasts at all time points. Mean ΔPTH(kg) and ΔTCM(mm) values reflected mean difference between the index and control breasts. Median follow-up is 44 months (range 5-59 months). According to LENT-SOMA, pain occurred in 89% at 1 and 24 months, 67% at 30 months, 30% at 36 months, 29% at 40 months, and 20% at 48 months. No patient used pain medication "regularly" but the use "sometimes" decreased over time: 61% at 1 month, 42% at 18 and 24 months, 13% at 36 months, and 10% at 40 months. Mean ΔPTH values, compared to Δ0 kg at baseline, peaked in absolute value by 1 month to -1.36 kg (p < 0.0001), persisted after 18 months at -0.99 kg (p < 0.0001) and 24 months at -0.73 kg (p < 0.0001), and returned to nearly baseline by 40 months at -0.11 kg (p < 0.57). Mean ΔPTH and ΔTCM correlated significantly with subjective patient reports of pain at each time point (p < 0.0001). To date, this is the first report to prospectively assess pain employing quantitative and qualitative inventories in patients treated with IBAPBI. Pain is experienced in the majority of patients experienced pain within the first 2 years, sometimes requiring a medication, and though subsides, it may persist 4 years after IBAPBI.

Transforming growth factor ß-1 (TGF-ß1) is a serum biomarker of radiation induced fibrosis in patients treated with intracavitary accelerated partial breast irradiation: preliminary results of a prospective study.

PURPOSE: To examine a relationship between serum transforming growth factor ß -1 (TGF-ß1) values and radiation-induced fibrosis (RIF). METHODS AND MATERIALS: We conducted a prospective analysis of the development of RIF in 39 women with American Joint Committee on Cancer stage 0-I breast cancer treated with lumpectomy and accelerated partial breast irradiation via intracavitary brachytherapy (IBAPBI). An enzyme-linked immunoassay (Quantikine, R&D, Minneapolis, MN) was used to measure serum TGF-ß1 before surgery, before IBAPBI, and during IBAPBI. Blood samples for TGF-ß1 were also collected from 15 healthy, nontreated women (controls). The previously validated tissue compliance meter (TCM) was used to objectively assess RIF. RESULTS: The median time to follow-up for 39 patients was 44 months (range, 5-59 months). RIF was graded by the TCM scale as 0, 1, 2, and 3 in 5 of 20 patients (25%), 6 of 20 patients (30%), 5 of 20 patients (25%), and 4 of 20 patients (20%), respectively. The mean serum TGF-ß1 values were significantly higher in patients before surgery than in disease-free controls, as follows: all cancer patients (30,201 ± 5889 pg/mL, P=.02); patients with any type of RIF (32,273 ± 5016 pg/mL, P<.0001); and women with moderate to severe RIF (34,462 ± 4713 pg/mL, P<0.0001). Patients with moderate to severe RIF had significantly elevated TGF-ß1 levels when compared with those with none to mild RIF before surgery (P=.0014) during IBAPBI (P≤0001), and the elevation persisted at 6 months (P≤.001), 12 months (P≤.001), 18 months (P≤.001), and 24 months (P=.12). A receiver operating characteristic (ROC) curve of TGF-ß1 values predicting moderate to severe RIF was generated with an area under the curve (AUC)ROC of 0.867 (95% confidence interval 0.700-1.000). The TGF-ß1 threshold cutoff was determined to be 31,000 pg/mL, with associated sensitivity and specificity of 77.8% and 90.0%, respectively. CONCLUSIONS: TGF-ß1 levels correlate with the development of moderate to severe RIF. The pre-IBAPBI mean TGF-ß1 levels can serve as an early biomarker for the development of moderate to severe RIF after IBAPBI.