Publications by authors named "Naoko Sasamoto"

21 Publications

  • Page 1 of 1

Common Analgesic Use for Menstrual Pain and Ovarian Cancer Risk.

Cancer Prev Res (Phila) 2021 Jul 9. Epub 2021 Jul 9.

Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Menstrual pain has been associated with increased ovarian cancer risk, presumably through increased inflammation, which is known to play a critical role in ovarian carcinogenesis. Analgesic medications are frequently used to treat menstrual pain, some of which lower ovarian cancer risk. In this study, we examined the association between analgesic use for menstrual pain during the premenopausal period and ovarian cancer risk among women with history of menstrual pain. We used data from the New England Case-Control Study, including 1,187 epithelial ovarian cancer cases and 1,225 population-based controls enrolled between 1998 and 2008 with detailed information on analgesic use for their menstrual pain. We used unconditional logistic regression to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between analgesic use (i.e., aspirin, ibuprofen, acetaminophen) for menstrual pain and ovarian cancer risk. We further conducted a stratified analysis by intensity of menstrual pain (mild/moderate, severe). Among women with menstrual pain during their 20s and 30s, ever use of analgesics for menstrual pain was not significantly associated with ovarian cancer risk. However, among women with severe menstrual pain, ever use of aspirin or acetaminophen for menstrual pain was inversely associated with risk (OR, 0.41; 95% CI, 0.18-0.94 and OR, 0.43; 95% CI, 0.21-0.88 compared with never users, respectively). No significant association was observed between analgesic use and ovarian cancer risk among women with mild/moderate menstrual pain ( ≤ 0.03). Our results suggest that use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer. PREVENTION RELEVANCE: This study investigates whether analgesic use specifically for menstrual pain during the premenopausal period influences ovarian cancer risk. Our results suggest use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer among women with severe menstrual pain.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0090DOI Listing
July 2021

Prospective Analyses of Lifestyle Factors Related to Energy Balance and Ovarian Cancer Risk by Infiltration of Tumor-Associated Macrophages.

Cancer Epidemiol Biomarkers Prev 2021 May 2;30(5):920-926. Epub 2021 Mar 2.

Division of Public Health Sciences, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Lifestyle factors related to energy balance have been associated with ovarian cancer risk and influence the tumor immune microenvironment, including tumor-associated macrophages (TAM). However, no studies have assessed whether these factors differentially impact ovarian cancer risk by TAM densities.

Methods: We conducted a prospective analysis in the Nurses' Health Studies to examine the associations of physical activity, sitting time, and a food-based empirical dietary inflammatory pattern (EDIP) score with invasive epithelial ovarian cancer risk by TAM density assessed by immunohistochemistry. We considered density of CD68 (marker of total TAMs) and CD163 (marker of pro-carcinogenic M2-type TAMs), and their ratios. We used multivariable Cox proportional hazards regression to calculate hazard ratios (HR) and 95% confidence intervals (CI) of exposures with risk of ovarian tumors with high versus low TAMs, including analyses stratified by body mass index.

Results: Analyses included 312 incident ovarian cancer cases with TAM measurements. Physical activity, sitting time, and EDIP score were not differentially associated with ovarian cancer risk by TAM densities ( > 0.05). Among overweight and obese women, higher EDIP score was associated with increased risk of CD163 low-density tumors (HR comparing extreme tertiles, 1.57; 95% CI, 0.88-2.80; = 0.01), but not CD163 high-density tumors (comparable HR, 1.16; 95% CI, 0.73-1.86; = 0.24), though this difference was not statistically significant ( = 0.22).

Conclusions: We did not observe differential associations between lifestyle factors and ovarian cancer risk by TAM densities.

Impact: Future investigations examining the interplay between other ovarian cancer risk factors and the tumor immune microenvironment may help provide insight into ovarian cancer etiology.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102357PMC
May 2021

Intrauterine device use and risk of ovarian cancer: Results from the New England Case-Control study and Nurses' Health Studies.

Int J Cancer 2021 Jul 17;149(1):75-83. Epub 2021 Mar 17.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.

Results of studies assessing intrauterine device (IUD) use and ovarian cancer risk are inconsistent. We examined the association between IUD use, including duration, type and timing of use, and ovarian cancer risk using three population-based studies. Data from the New England Case-Control Study (NEC) and two prospective cohort studies, the Nurses' Health Studies (NHS/NHSII), were included in the analysis. Information on IUD use was collected by in-person interview in NEC and by biennial questionnaire in NHS/NHSII. We used unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) in NEC and Cox regression to calculate hazard ratios (HR) and 95% CI in NHS/NHSII. We used meta-analysis to combine the NEC and the pooled NHS/NHSII results. Overall, IUD use was not associated with epithelial ovarian cancer risk (OR = 0.96, 95% CI: 0.81-1.14 in NEC; HR = 0.89, 95% CI: 0.69-1.15 in NHS/NHSII; combined RR = 0.94, 95% CI: 0.81-1.08). Among IUD users, older age at first use was associated with increased ovarian cancer risk (P-trend = .03). We did not observe significant associations by IUD type or duration of use. In conclusion, IUD use was not associated with ovarian cancer risk in our study.
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http://dx.doi.org/10.1002/ijc.33531DOI Listing
July 2021

IgA transcytosis and antigen recognition govern ovarian cancer immunity.

Nature 2021 Mar 3;591(7850):464-470. Epub 2021 Feb 3.

Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Most ovarian cancers are infiltrated by prognostically relevant activated T cells, yet exhibit low response rates to immune checkpoint inhibitors. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.
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http://dx.doi.org/10.1038/s41586-020-03144-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969354PMC
March 2021

Epidemiologic and biologic correlates of serum HE4 and CA125 in women from the National Health and Nutritional Survey (NHANES).

Gynecol Oncol 2021 Apr 24;161(1):282-290. Epub 2021 Jan 24.

Harvard Medical School, 260 Longwood Avenue, Boston, MA 02115, United States of America; Laboratory of Genital Tract Biology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA 02115, United States of America.

Objectives: In women with ovarian cancer, tumor features largely determine serum HE4 and CA125 levels, but non-tumor factors may also influence levels and be better understood by studying determinants in a well-characterized sample of women without cancer.

Methods: Serum HE4 and CA125 were measured in 2302 women from the 2001-2002 cohort of the National Heath and Nutritional Survey (NHANES). Publicly-available data on this cohort included demographic/reproductive variables, blood counts, and measurements of C-reactive protein (CRP), total homocysteine (tHcy), cotinine, and creatinine which were examined as predictors of HE4 and CA125 using multivariate models and correlational analyses.

Results: HE4 increased non-linearly by age and current smokers had higher HE4. CA125 was lower in postmenopausal women and non-whites and trended downward with increasing BMI. Current-users of oral contraceptives (OCs) had lower HE4 and CA125; and a downward trend for CA125 was seen with increasing OC use. Pregnant women had higher CA125 and nursing women higher HE4. HE4 and CA125 were positively correlated with neutrophils, monocytes, and the neutrophil-to-lymphocyte ratio and inversely correlated with lymphocytes and the lymphocyte-to-monocyte ratio. CRP was positively correlated with both HE4 and CA125 in postmenopausal women. Strong positive correlations existed for HE4 with both tHcy and creatinine.

Conclusions: Serum levels of HE4 and CA125 are influenced by several hormonal or environmental stimuli which affect non-cancerous tissues normally expressing HE4 or CA125. Cytokine co-expression in those tissues may, in turn, affect white cell counts and account for their correlation with HE4 or CA125 levels.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994188PMC
April 2021

Racial/ethnic differences in average CA125 and CA15.3 values and its correlates among postmenopausal women in the USA.

Cancer Causes Control 2021 Mar 18;32(3):299-309. Epub 2021 Jan 18.

Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, USA.

Purpose: Among healthy postmenopausal women, levels of CA125 and CA15.3 are influenced by demographic and reproductive factors, including race/ethnicity. In this study, we sought to examine the interaction between race/ethnicity and other correlates of these biomarkers and whether the racial differences observed are simply determined by other correlates with racial differences.

Methods: In archived sera from 946 postmenopausal women who participated in the 2001-2002 cycle of the National Health and Nutrition Examination Survey, we measured CA125 and CA15.3 and examined their associations with health survey and examination data available in this cohort. We used multivariable linear regression to examine the association between CA125 and CA15.3 and race/ethnicity. We then calculated geometric means of these markers by demographic and reproductive factors stratified by race/ethnicity and used likelihood ratio tests to evaluate heterogeneity.

Results: Non-white race was associated with lower CA125, with Non-Hispanic Black women being associated with - 29.0% (95% CI - 42.5%, - 12.2%) difference and Mexican American women being associated with - 6.4% (95% CI - 18.1%, 6.9%) difference on average compared to Non-Hispanic White women. Associations between CA125 and age and parity varied by race/ethnicity. Non-Hispanic Black women were associated with higher CA15.3 compared to Non-Hispanic White women, with 17.3% (95% CI - 0.5%, 38.3%) differences on average. Associations between CA15.3 and age, number of births, and age at natural menopause varied by race/ethnicity.

Conclusions: Among postmenopausal women, Non-Hispanic Black women were associated with lower CA125 and higher CA15.3 levels compared to Non-Hispanic White women. Our results support that race/ethnicity should be considered when assigning thresholds for these biomarkers being tested for diagnostic or screening purposes.
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http://dx.doi.org/10.1007/s10552-020-01384-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887701PMC
March 2021

Evaluation of CA125 in relation to pain symptoms among adolescents and young adult women with and without surgically-confirmed endometriosis.

PLoS One 2020 24;15(8):e0238043. Epub 2020 Aug 24.

Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, Massachusetts, United States of America.

Endometriosis is a painful gynecologic disease affecting one in ten reproductive aged women worldwide. Few studies have correlated this symptomatology with biomarker levels among women with and without endometriosis, and no studies correlating pain with biomarker levels have been performed in young patient populations. The purpose of this study was to examine whether CA125 correlates with different types and severity of pain among adolescents and young women with and without endometriosis and assess its performance as an endometriosis biomarker among those presenting with dysmenorrhea in this young population. Reproductive-aged women with laparoscopically-confirmed endometriosis (n = 282) and controls (n = 293) who participated in The Women's Health Study: From Adolescence to Adulthood (A2A), a cohort of adolescents and young women enrolled from 2012-2018, were included in this cross-sectional analysis. Plasma CA125 values were measured using WERF EPHect compliant blood samples collected at enrollment. Average CA125 were calculated by self-reported pain type (i.e. dysmenorrhea, non-cyclic/general pelvic pain, dyspareunia), severity, and frequency in endometriosis cases and controls. Median age at blood draw was 24 years in controls and 17 years in cases, with 68% and 89% non-Hispanic white, respectively. Most endometriosis cases (95%) were rASRM stage I/II. Average CA125 values were 12.5 U/mL in controls and 12.1 U/mL in cases adjusted for age. CA125 did not differ by pain type, its severity, or frequency in endometriosis cases or controls. Among participants who reported dysmenorrhea, CA125 did not discriminate endometriosis cases from controls using cutoff of 35 U/mL (AUC = 0.51, 95%CI = 0.50-0.53). Among adolescents and young adult women, CA125 did not correlate with pain type. CA125 did not efficiently discriminate endometriosis cases from controls even when accounting for pain symptomatology. Average CA125 values were low in adolescents and young women in both endometriosis cases and controls, suggesting cautious interpretation may be needed when measuring CA125 in this population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238043PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444809PMC
October 2020

In utero and early life exposures in relation to endometriosis in adolescents and young adults.

Eur J Obstet Gynecol Reprod Biol 2020 Sep 15;252:393-398. Epub 2020 Jul 15.

Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA, 02115, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA; Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MA, 49503, USA.

Objective: Endometriosis is a common gynecologic disorder often associated with severe pelvic pain and infertility with few known modifiable risk factors. We investigated whether in utero and early life exposures are associated with surgically diagnosed endometriosis among adolescents and young adults.

Study Design: This case-control study, including 295 laparoscopically-confirmed endometriosis cases and 309 population-based controls aged <25 years, was conducted using data from The Women's Health Study: From Adolescence to Adulthood which enrolled participants from 2012 to 2018. Information on in utero and early life factors were collected using a modified WERF EPHect questionnaire at enrollment, including their mother's age at delivery, birthweight, gestation length, exposure to smoking in utero and secondhand smoke during childhood up to age 13, and if the participant was breastfed.

Results: Median age at enrollment was 17 years (range 12-24) in cases and 22 years (range 7-24) in controls, with 83 % and 68 % non-Hispanic whites, respectively. The majority of cases (95 %) were rASRM stage I or II at diagnostic surgery. Exposure to breastfeeding in early life was associated with lower odds of endometriosis diagnosis (OR = 0.39, 95 % CI = 0.21-0.74). Exposure to secondhand smoke during childhood due to maternal smoking was associated with increased odds of endometriosis diagnosis (OR = 2.70, 95 % CI = 1.11-6.60).

Conclusions: Among adolescents and young adults, our data suggest exposures to breastfeeding in early life and secondhand smoke during childhood may be associated with endometriosis risk, providing insight into etiologic pathways to be explored in this young population.
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http://dx.doi.org/10.1016/j.ejogrb.2020.07.014DOI Listing
September 2020

Peripheral Blood Leukocyte Telomere Length and Endometriosis.

Reprod Sci 2020 10 23;27(10):1951-1959. Epub 2020 Jun 23.

Department of Obstetrics and Gynecology, Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.

Endometriosis is a common gynecologic disease defined by the presence of endometrial-like tissue outside the uterine cavity. While its etiology is largely unknown, accumulating evidence suggests that inflammation plays a major role. Our objective was to investigate the association between peripheral blood leukocyte telomere length (LTL) and endometriosis using data from two large population-based studies, the New England Case-Control Study (NEC; n = 877) and the National Health and Nutrition Examination Survey (NHANES; n = 2268). NEC control participants were identified through a combination of random digit dialing, drivers' license lists, and town resident lists. In NHANES, selection algorithms were used to identify a nationally representative sample. Blood samples and demographic, reproductive, and health-related information were available from both data sources. Endometriosis was defined as self-reported of physician-diagnosed endometriosis. LTL was measured using quantitative polymerase chain reaction. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the association between LTL and endometriosis. Shorter LTL was associated with greater odds of history of endometriosis. In NEC, women with the shortest LTL tertile compared with the longest had a 2.5-fold greater odds of endometriosis (OR = 2.56, 95% CI = 1.16-5.63; p value, test for linear trend = 0.02). The association was stronger among women who usually experienced moderate or severe menstrual pain (OR  = 3.50, 95% CI = 1.12-10.97). In NHANES, the data suggested a similar but attenuated association (OR = 1.29, 95% CI = 0.85-1.96). The observed associations in NEC suggest that shorter LTL may be associated with greater odds of endometriosis. A better understanding of how LTL influences endometriosis risk could elucidate novel disease pathophysiology.
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http://dx.doi.org/10.1007/s43032-020-00214-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483746PMC
October 2020

Association Between Breastfeeding and Ovarian Cancer Risk.

JAMA Oncol 2020 06 11;6(6):e200421. Epub 2020 Jun 11.

Women's Cancer Research Center, Magee-Womens Research Institute, Hillman Cancer Center, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Importance: Breastfeeding has been associated with a reduced risk of epithelial ovarian cancer in multiple studies, but others showed no association. Whether risk reduction extends beyond that provided by pregnancy alone or differs by histotype is unclear. Furthermore, the observed associations between duration and timing of breastfeeding with ovarian cancer risk have been inconsistent.

Objective: To determine the association between breastfeeding (ie, ever/never, duration, timing) and ovarian cancer risk overall and by histotype.

Design, Setting, And Participants: A pooled analysis of parous women with ovarian cancer and controls from 13 case-control studies participating in the Ovarian Cancer Association Consortium was performed. Odds ratios (ORs) and 95% CIs of the overall association were calculated using multivariable logistic regression and polytomous logistic regression for histotype-specific associations. All data were collected from individual sites from November 1989 to December 2009, and analysis took place from September 2017 to July 2019.

Exposures: Data on breastfeeding history, including duration per child breastfed, age at first and last breastfeeding, and years since last breastfeeding were collected by questionnaire or interview and was harmonized across studies.

Main Outcomes And Measures: Diagnosis of epithelial ovarian cancer.

Results: A total of 9973 women with ovarian cancer (mean [SD] age, 57.4 [11.1] years) and 13 843 controls (mean [SD] age, 56.4 [11.7] years) were included. Breastfeeding was associated with a 24% lower risk of invasive ovarian cancer (odds ratio [OR], 0.76; 95% CI, 0.71-0.80). Independent of parity, ever having breastfed was associated with reduction in risk of all invasive ovarian cancers, particularly high-grade serous and endometrioid cancers. For a single breastfeeding episode, mean breastfeeding duration of 1 to 3 months was associated with 18% lower risk (OR, 0.82; 95% CI, 0.76-0.88), and breastfeeding for 12 or more months was associated with a 34% lower risk (OR, 0.66; 95% CI, 0.58-0.75). More recent breastfeeding was associated with a reduction in risk (OR, 0.56; 95% CI, 0.47-0.66 for <10 years) that persisted for decades (OR, 0.83; 95% CI, 0.77-0.90 for ≥30 years; P for trend = .02).

Conclusions And Relevance: Breastfeeding is associated with a significant decrease in risk of ovarian cancer overall and for the high-grade serous subtype, the most lethal type of ovarian cancer. The findings suggest that breastfeeding is a potentially modifiable factor that may lower risk of ovarian cancer independent of pregnancy alone.
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http://dx.doi.org/10.1001/jamaoncol.2020.0421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118668PMC
June 2020

Adverse Pregnancy Outcomes in Endometriosis - Myths and Realities.

Curr Obstet Gynecol Rep 2020 Mar 30;9(1):27-35. Epub 2020 Jan 30.

Department of Epidemiology, Harvard T.H. Chan School of Public Health.

Purpose Of Review: There is increasing interest in the long-term health and comorbid conditions associated with endometriosis for both women and neonates. The purpose of this review was to synthesize and discuss the current state of the literature investigating endometriosis and risk of adverse pregnancy outcomes.

Recent Findings: Methodologic considerations for studying endometriosis and adverse pregnancy outcomes include complexities regarding the comparison population, endometriosis definition, sample size, residual confounding, and interactions. The current research on endometriosis and adverse pregnancy outcomes should be interpreted cautiously. To date, evidence suggests that endometriosis may be associated with higher risk of ectopic pregnancy, placenta previa, preterm birth, and cesarean section. While an association with miscarriage and stillbirth has been consistently observed, the relative risk was small.

Summary: Pregnant women with endometriosis may be at higher risk for certain adverse pregnancy outcomes and may therefore benefit from additional monitoring. However, additional research is needed to confirm these associations and should focus on ensuring studies have internal and external validity, as well as, investigate the potential for differences in endometriosis phenotypes. Moreover, future research should focus on understanding potential mechanisms of association and better understanding how early interventions, through increased monitoring or screening during pregnancy, may improve outcomes.
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http://dx.doi.org/10.1007/s13669-020-00281-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188856PMC
March 2020

Development and validation of circulating CA125 prediction models in postmenopausal women.

J Ovarian Res 2019 Nov 26;12(1):116. Epub 2019 Nov 26.

CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Background: Cancer Antigen 125 (CA125) is currently the best available ovarian cancer screening biomarker. However, CA125 has been limited by low sensitivity and specificity in part due to normal variation between individuals. Personal characteristics that influence CA125 could be used to improve its performance as screening biomarker.

Methods: We developed and validated linear and dichotomous (≥35 U/mL) circulating CA125 prediction models in postmenopausal women without ovarian cancer who participated in one of five large population-based studies: Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n = 861), the Nurses' Health Studies (NHS/NHSII, n = 81), and the New England Case Control Study (NEC, n = 923). The prediction models were developed using stepwise regression in PLCO and validated in EPIC, NHS/NHSII and NEC.

Result: The linear CA125 prediction model, which included age, race, body mass index (BMI), smoking status and duration, parity, hysterectomy, age at menopause, and duration of hormone therapy (HT), explained 5% of the total variance of CA125. The correlation between measured and predicted CA125 was comparable in PLCO testing dataset (r = 0.18) and external validation datasets (r = 0.14). The dichotomous CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, time since menopause, and duration of HT with AUC of 0.64 in PLCO and 0.80 in validation dataset.

Conclusions: The linear prediction model explained a small portion of the total variability of CA125, suggesting the need to identify novel predictors of CA125. The dichotomous prediction model showed moderate discriminatory performance which validated well in independent dataset. Our dichotomous model could be valuable in identifying healthy women who may have elevated CA125 levels, which may contribute to reducing false positive tests using CA125 as screening biomarker.
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http://dx.doi.org/10.1186/s13048-019-0591-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878636PMC
November 2019

Investigation of factors associated with ABCB5-positive limbal stem cell isolation yields from human donors.

Ocul Surf 2020 01 24;18(1):114-120. Epub 2019 Oct 24.

Department of Medicine, VA Boston Healthcare System, Boston, MA, United States; Division of Genetics, Brigham and Women's Hospital, Boston, MA, United States; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Electronic address:

Purpose: To identify factors associated with isolation yields of ATP-binding cassette (ABC) superfamily member B5 (ABCB5)-positive limbal stem cells (LSCs) from human cadaveric donor eyes.

Methods: Whole eye globes were obtained from the Saving Sight eye bank, Kansas City, MO and the CorneaGen eye bank, Seattle, WA. ABCB5-positive LSCs were sorted by flow cytometry upon anti-ABCB5 monoclonal antibody staining within one week after donor death. The yields of live limbal epithelial cells in their entirety and of isolated pure ABCB5-positive LSC subsets were correlated with variables contained in the eye donors' medical information.

Results: The mean isolation yield of live limbal epithelial cells and ABCB5-positive LSCs per donor eye was (340,000 ± 160,000 and 2,608 ± 1,842 respectively, mean ± SD). Stepwise regression analysis showed that cardiac disease-related death was the strongest negative predictor of the ABCB5-positive LSC isolation yield (p = 0.01). While we observed a trend for an age-related decline in the yield of ABCB5-positive LSCs, a statistically significant association could not be established (2% decrease/year, p = 0.11). Additionally, despite a trend for decreased isolation yields of total live limbal epithelial cells isolated from single donors with a longer time between death and tissue processing (p = 0.04), this did not affect the yields of purified ABCB5-positive LSC, which was independent of increasing time between death and tissue processing (p = 0.50).

Conclusions: Our study identifies cardiac disease-related death as a donor variable significantly associated with lower ABCB5-positive LSC isolation yields.
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http://dx.doi.org/10.1016/j.jtos.2019.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840156PMC
January 2020

Endometriosis and Risk of Adverse Pregnancy Outcomes.

Obstet Gynecol 2019 09;134(3):527-536

Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona; the Channing Division of Network Medicine, the Department of Obstetrics, Gynecology, and Reproductive Biology, the Division of Preventive Medicine, and the Division of Women's Health, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Department of Nutrition and the Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; the MRC Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland; and the Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, East Lansing, Michigan.

Objective: To investigate the relationship between endometriosis and adverse pregnancy outcomes.

Methods: Women between ages 25 and 42 years in 1989 (n=116,429) reported detailed information on pregnancies and reproductive health at baseline and every 2 years thereafter in the Nurses' Health Study II, a cohort study. In 2009, they completed a detailed, pregnancy-focused questionnaire. A total of 196,722 pregnancies were reported. Adverse pregnancy outcomes included spontaneous abortion, ectopic pregnancy, stillbirth, gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (preeclampsia or gestational hypertension), preterm birth, and low birth weight. We estimated the relative risks (RRs) and 95% CIs of adverse pregnancy outcomes comparing pregnancies in women with and without a history of laparoscopically confirmed endometriosis using multivariable log-binomial regression, with generalized estimating equations to account for multiple pregnancies per woman.

Results: Endometriosis was associated with a greater risk of pregnancy loss (spontaneous abortion: RR 1.40, 95% CI 1.31-1.49; ectopic pregnancy: RR 1.46, 95% CI 1.19-1.80). Endometriosis was also associated with a greater risk of GDM (RR 1.35, 95% CI 1.11-1.63) and hypertensive disorders of pregnancy (RR 1.30, 95% CI 1.16-1.45).

Conclusions: We observed an association between laparoscopically confirmed endometriosis and several adverse pregnancy outcomes. Future research should focus on the potential biological pathways underlying these relationships to inform screening or preventive interventions.
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http://dx.doi.org/10.1097/AOG.0000000000003410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922084PMC
September 2019

Predicting Circulating CA125 Levels among Healthy Premenopausal Women.

Cancer Epidemiol Biomarkers Prev 2019 06 4;28(6):1076-1085. Epub 2019 Apr 4.

Public Health Direction and Biodonostia Research Institute and Ciberesp, Basque Regional Health Department, San Sebastian, Spain.

Background: Cancer antigen 125 (CA125) is the most promising ovarian cancer screening biomarker to date. Multiple studies reported CA125 levels vary by personal characteristics, which could inform personalized CA125 thresholds. However, this has not been well described in premenopausal women.

Methods: We evaluated predictors of CA125 levels among 815 premenopausal women from the New England Case Control Study (NEC). We developed linear and dichotomous (≥35 U/mL) CA125 prediction models and externally validated an abridged model restricting to available predictors among 473 premenopausal women in the European Prospective Investigation into Cancer and Nutrition Study (EPIC).

Results: The final linear CA125 prediction model included age, race, tubal ligation, endometriosis, menstrual phase at blood draw, and fibroids, which explained 7% of the total variance of CA125. The correlation between observed and predicted CA125 levels based on the abridged model (including age, race, and menstrual phase at blood draw) had similar correlation coefficients in NEC ( = 0.22) and in EPIC ( = 0.22). The dichotomous CA125 prediction model included age, tubal ligation, endometriosis, prior personal cancer diagnosis, family history of ovarian cancer, number of miscarriages, menstrual phase at blood draw, and smoking status with AUC of 0.83. The abridged dichotomous model (including age, number of miscarriages, menstrual phase at blood draw, and smoking status) showed similar AUCs in NEC (0.73) and in EPIC (0.78).

Conclusions: We identified a combination of factors associated with CA125 levels in premenopausal women.

Impact: Our model could be valuable in identifying healthy women likely to have elevated CA125 and consequently improve its specificity for ovarian cancer screening.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548604PMC
June 2019

Transumbilical extraction of 151-300-g myomas without morcellator versus conventional laparoscopic myomectomy with power morcellator.

Gynecol Minim Invasive Ther 2017 Oct-Dec;6(4):162-166. Epub 2017 Jul 8.

Department of Obstetrics and Gynecology, Minoh City Hospital, Osaka, Japan.

Study Objective: The aim of this study was to compare the surgical outcomes, particularly the specimen retrieval time, between two methods of laparoscopic myomectomy: transumbilical retrieval of the myoma without a morcellator and conventional retrieval of the myoma using a power morcellator via the left lower quadrant.

Design: Retrospective study.

Setting: Public hospital.

Patients: Seventy-four women undergoing laparoscopic myomectomy.

Interventions: Laparoscopic myomectomy followed by myoma retrieval via transumbilical extraction or electric motorized morcellator extraction.

Measurements And Main Results: Seventy-four patients undergoing laparoscopic myomectomy followed by myoma retrieval via transumbilical extraction or electric motorized morcellator extraction were studied. Significant differences were observed in the average weight of the retrieved myomas between the transumbilical and morcellator groups (141.0 vs. 262.8 g, respectively; p < 0.001). Therefore, we chose 27 patients whose total specimen weight was 151-300 g; 13 patients were in the transumbilical extraction group and 14 were in the electric motorized morcellator group. No significant differences were observed in patient characteristics between the two groups. The operative time, blood loss volume, and myoma retrieval time were similar between the two groups.

Conclusion: Laparoscopic myomectomy with transumbilical extraction for myoma retrieval is a feasible method for specimens weighing up to 300 g.
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http://dx.doi.org/10.1016/j.gmit.2017.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135198PMC
July 2017

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer.

Clin Cancer Res 2018 03 20;24(6):1389-1401. Epub 2017 Dec 20.

Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy and , decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease. Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951622PMC
March 2018

Postoperative administration of dienogest for suppressing recurrence of disease and relieving pain in subjects with ovarian endometriomas.

Gynecol Endocrinol 2016 Aug 18;32(8):646-649. Epub 2016 Feb 18.

b Department of Obstetrics and Gynecology , Osaka University Graduate School of Medicine , Osaka , Japan , and.

To assess the effect of dienogest on recurrence of ovarian endometriomas and severity of pain after laparoscopic surgery, a retrospective study of 81 patients was performed at three institutions in Osaka, Japan. Patients had a six-month minimum follow-up after laparoscopic surgery for ovarian endometriomas performed between June 2012 and August 2014. Patients who chose to receive 2 mg dienogest daily and those who were managed expectantly postoperatively were included. Recurrence was defined as the presence of endometriomas of more than 2 cm. A visual analog scale (VAS) was used to score the intensity of pelvic pain. The cumulative recurrence rate and absolute VAS score changes between the baseline and at 6, 12, 18 and 24 months after the start of administration were evaluated in both groups. The recurrence rate was 16.5% and 24.0% in the expectant management group at 12 and 24 months, respectively. No recurrences occurred in the dienogest treatment group. The rate of VAS score reduction was significantly higher in the dienogest than in the expectant management group. Dienogest is effective on the recurrence of ovarian endometrioma and relieving pelvic pain after laparoscopic surgery.
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http://dx.doi.org/10.3109/09513590.2016.1147547DOI Listing
August 2016

Assessment of age-specific safety of laparoscopic surgery in elderly patients with ovarian tumors.

J Obstet Gynaecol Res 2016 Mar 2;42(3):297-301. Epub 2015 Dec 2.

Department of Obstetrics and Gynecology, Minoh City Hospital, Minoh, Japan.

Aim: We assessed the age-specific safety of laparoscopic surgery in elderly patients with ovarian tumors.

Material And Methods: We performed a retrospective analysis of 55 elderly patients treated by laparoscopic salpingo-oophorectomy under the diagnosis of an ovarian tumor between January 2009 and December 2014. We divided patients into three groups: "young-elderly" (aged 65-74), "old-elderly" (aged 75-84), and "super-elderly" (aged 85-105) and assessed clinical characteristics, surgical results and postoperative course. Statistical significance of categorical variables was examined by the Student's t-test, Mann-Whitney U test, or Fisher's exact test. Multiple regression analysis was used for multivariate analysis.

Results: Of a total of 55 patients who underwent laparoscopic surgery, there were 36 patients in the young-elderly group, 17 in the old-elderly group, and two in the super-elderly group. Statistical analysis was performed between the young-elderly and the old-elderly groups because of the small number in the super-elderly group. More frequent comorbidities were found in the patients in the old-elderly than in the young-elderly group (Fisher's exact test, P = 0.007). There were no significant differences in operative time, estimated blood loss and postoperative hospital stay between the young-elderly and old-elderly groups. Intraoperative complications only occurred in the young-elderly group. Postoperative complications occurred in all groups.

Conclusions: Although patients in the old-elderly group had a significantly higher risk for surgery, they had equivalent surgical results to the young-elderly group for laparoscopic salpingo-oophorectomy.
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http://dx.doi.org/10.1111/jog.12889DOI Listing
March 2016

Endometrial adenocarcinoma arising in a Turner's syndrome patient with spontaneous menstruation: a case report.

J Reprod Med 2014 Mar-Apr;59(3-4):177-80

Background: Women with Turner's syndrome exhibit anovulation, and the majority do not spontaneously menstruate. We present an unusual case of endometrial adenocarcinoma developing in a Turner's syndrome patient who was exhibiting spontaneous menstruation while not receiving regular hormone therapy.

Case: The patient's karyotype from blood lymphocytes was a mosaic of 45,XO/ 46,XX. Menarche and sexual development were normal. Her menstrual cycle had been regular for one year, but then became noticeably irregular. At age 26 she was referred to our hospital after bleeding for almost 1 year. An endometrial adenocarcinoma was detected during performance of diagnostic endometrial curettage. A total abdominal hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy was conducted. The final histological diagnosis was endometrial adenocarcinoma, Grade 1, pT1a N0 M0. Fluorescence in situ hybridization analysis of the right and left ovaries revealed a mosaic karyotype of 45,XO/ CONCLUSION: Previous reports regarding Turner's syndrome detected spontaneous menstruation in only 16% of patients; however, spontaneous menstruation was observed in 8 of 10 (80%) Turner's syndrome cases that developed endometrial carcinoma without receiving regular hormone therapy (p < 0.0001). Hormone therapy may be indicated for an irregular menstrual cycle in Turner's syndrome patients.
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May 2014

Fetal and neonatal anemia associated with anti-Jr(a) : a case report showing a poorly hemolytic mechanism.

J Obstet Gynaecol Res 2011 Aug 12;37(8):1132-6. Epub 2011 Apr 12.

Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.

Although recently published case reports suggest the significance of Jr(a) alloimmunization in the obstetric setting, the involved mechanism still remains unclear. Here we report a case of severe fetal and neonatal anemia associated with anti-Jr(a) alloimmunization, which was successfully managed using Doppler assessment of peak systolic velocity of the fetal middle cerebral artery (MCA-PSV). A Japanese woman with anti-Jr(a) (titer 1024) was referred to our department at 20 weeks' gestation. As fetal MCA-PSV exceeded 1.5 multiple of median, labor was induced and a female neonate of 1998 g was delivered vaginally at 33 weeks and 5 days of gestation. The infant's hematocrit and hemoglobin levels were 25.4% and 82 g/L, respectively, but her total bilirubin level (15 µmol/L; 0.9 mg/dL) and reticulocyte counts (4.5%) were low. During the course, the infant showed no apparent signs of hemolysis. Jr(a) alloimmunization should be recognized as a possible cause of fetal anemia with no direct hemolytic process.
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http://dx.doi.org/10.1111/j.1447-0756.2010.01477.xDOI Listing
August 2011
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