IgA transcytosis and antigen recognition govern ovarian cancer immunity.

Most ovarian cancers are infiltrated by prognostically relevant activated T cells1-3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, 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.

Associations between common contraceptive use and circulating inflammatory biomarkers.

Ovarian cancer incidence has declined in recent decades, due in part to oral contraceptive (OC) use and tubal ligation. However, intrauterine device (IUD) use has increasingly replaced OC use. As ovarian cancer is an inflammation-related disease, we examined the association of OC use, IUD use, and tubal ligation with plasma levels of C-reactive protein (CRP), interleukin 6 (IL-6), and soluble tumor necrosis factor α receptor 2 (sTNFR2), in the Nurses' Health Study (NHS) and NHSII. After adjusting for reproductive, hormonal, and lifestyle factors, and mutual adjustment for other methods of contraception, there were no differences in inflammatory markers between ever and never use of each method. However, CRP levels decreased from an average 30.4% (-53.6, 4.4) with every 5 years since initial IUD use (P-trend=0.03), while CRP increased an average 9.9% (95% CI: 5.7, 14.3) with every 5 years of use of OC (P-trend<0.0001) as well as differences by BMI and menopausal status. Our results suggest IUD use and tubal ligation are not associated with higher circulating inflammatory markers long term, although long duration of OC use may increase generalized inflammation, which may in part explain why its protective effect wanes over time.

Plasma proteins and persistent postsurgical pelvic pain among adolescents and young adults with endometriosis.

BACKGROUND: Noninvasive biomarkers that predict surgical treatment response would inform personalized treatments and provide insight into potential biologic pathways underlying endometriosis-associated pain and symptom progression. OBJECTIVE: To use plasma proteins in relation to the persistence of pelvic pain following laparoscopic surgery in predominantly adolescents and young adults with endometriosis using a multiplex aptamer-based proteomics biomarker discovery platform. STUDY DESIGN: We conducted a prospective analysis including 142 participants with laparoscopically-confirmed endometriosis from the Women's Health Study: From Adolescence to Adulthood observational longitudinal cohort with study enrollment from 2012-2018. Biologic samples and patient data were collected with modified World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project tools. In blood collected before laparoscopic ablation or excision of endometriosis, we simultaneously measured 1305 plasma protein levels, including markers for immunity, angiogenesis, and inflammation, using SomaScan. Worsening or persistent postsurgical pelvic pain was defined as having newly developed, persistent (ie, stable), or worsening severity, frequency, or persistent life interference of dysmenorrhea or acyclic pelvic pain at 1-year postsurgery compared with presurgery. We calculated odds ratios and 95% confidence intervals using logistic regression adjusted for age, body mass index, fasting status, and hormone use at blood draw. We applied Ingenuity Pathway Analysis and STRING analysis to identify pathophysiologic pathways and protein interactions. RESULTS: The median age at blood draw was 17 years (interquartile range, 15-19 years), and most participants were White (90%). All had superficial peritoneal lesions only and were treated by excision or ablation. One-year postsurgery, pelvic pain worsened or persisted for 76 (54%) of these participants with endometriosis, whereas pelvic pain improved for 66 (46%). We identified 83 proteins associated with worsening or persistent pelvic pain 1-year postsurgery (nominal P<.05). Compared with those with improved pelvic pain 1-year postsurgery, those with worsening or persistent pelvic pain had higher plasma levels of CD63 antigen (odds ratio, 2.98 [95% confidence interval, 1.44-6.19]) and CD47 (odds ratio, 2.68 [95% confidence interval, 1.28-5.61]), but lower levels of Sonic Hedgehog protein (odds ratio, 0.55 [95% confidence interval, 0.36-0.84]) in presurgical blood. Pathways related to cell migration were up-regulated, and pathways related to angiogenesis were down-regulated in those with worsening or persistent postsurgical pelvic pain compared with those with improved pain. When we examined the change in protein levels from presurgery to postsurgery and its subsequent risk of worsening or persistent postsurgical pain at 1-year follow-up, we observed increasing levels of Sonic Hedgehog protein from presurgery to postsurgery was associated with a 4-fold increase in the risk of postsurgical pain (odds ratio [quartile 4 vs 1], 3.86 [1.04-14.33]). CONCLUSION: Using an aptamer-based proteomics platform, we identified plasma proteins and pathways associated with worsening or persistent pelvic pain postsurgical treatment of endometriosis among adolescents and young adults that may aid in risk stratification of individuals with endometriosis.

Plasma proteomic profiles of pain subtypes in adolescents and young adults with endometriosis.

STUDY QUESTION: What are the similarities and differences in the systemic proteomic profiles by endometriosis-associated pain subtypes among adolescents and young adults with endometriosis? SUMMARY ANSWER: Endometriosis-associated pain subtypes exhibited distinct plasma proteomic profiles. WHAT IS KNOWN ALREADY: Endometriosis patients, especially those diagnosed in adolescents and young adults, are often plagued by various pain symptoms. However, it is not clear what biological processes underlie this heterogeneity. STUDY DESIGN, SIZE, DURATION: We conducted a cross-sectional analysis using data and plasma samples from 142 adolescent or young adult participants of the Women's Health Study: From Adolescence to Adulthood cohort with laparoscopically confirmed endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured 1305 plasma protein levels by SomaScan. We classified self-reported endometriosis-associated pain into subtypes of dysmenorrhea, acyclic pelvic pain, life impacting pelvic pain, bladder pain, bowel pain, and widespread pain phenotype. We used logistic regression to calculate the odds ratios and 95% confidence intervals for differentially expressed proteins, adjusting for age, BMI, fasting status, and hormone use at blood draw. Ingenuity Pathway Analysis identified enriched biological pathways. MAIN RESULTS AND THE ROLE OF CHANCE: Our study population consisted mainly of adolescents and young adults (mean age at blood draw = 18 years), with nearly all (97%) scored as rASRM stage I/II at laparoscopic diagnosis of endometriosis, which is a common clinical presentation of endometriosis diagnosed at a younger age. Pain subtypes exhibited distinct plasma proteomic profiles. Multiple cell movement pathways were downregulated in cases with severe dysmenorrhea and life impacting pelvic pain compared to those without (P < 7.5×10-15). Endometriosis cases with acyclic pelvic pain had upregulation of immune cell adhesion pathways (P < 9.0×10-9), while those with bladder pain had upregulation of immune cell migration (P < 3.7×10-8) and those with bowel pain had downregulation (P < 6.5×10-7) of the immune cell migration pathways compared to those without. Having a wide-spread pain phenotype involved downregulation of multiple immune pathways (P < 8.0×10-10). LIMITATIONS, REASONS FOR CAUTION: Our study was limited by the lack of an independent validation cohort. We were also only able to explore any presence of a pain subtype and could not evaluate multiple combinations by pain subtypes. Further mechanistic studies are warranted to elucidate the differences in pathophysiology by endometriosis-pain subtype. WIDER IMPLICATIONS OF THE FINDINGS: The observed variation in plasma protein profiles by pain subtypes suggests different underlying molecular mechanisms, highlighting the need for potential consideration of pain subtypes for effectively treating endometriosis patients presenting with various pain symptoms. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Department of Defense W81XWH1910318 and the 2017 Boston Center for Endometriosis Trainee Award. Financial support for establishment of and data collection within the A2A cohort were provided by the J. Willard and Alice S. Marriott Foundation. N.S., A.F.V., S.A.M., and K.L.T. have received funding from the Marriott Family Foundation. C.B.S. is funded by an R35 MIRA Award from NIGMS (5R35GM142676). S.A.M. and K.L.T. are supported by NICHD R01HD094842. S.A.M. reports serving as an advisory board member for AbbVie and Roche, Field Chief Editor for Frontiers in Reproductive Health, personal fees from Abbott for roundtable participation; none of these are related to this study. Other authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

The relationship of lifetime history of depression on the ovarian tumor immune microenvironment.

BACKGROUND: Depression is associated with a higher ovarian cancer risk. Prior work suggests that depression can lead to systemic immune suppression, which could potentially alter the anti-tumor immune response. METHODS: We evaluated the association of pre-diagnosis depression with features of the anti-tumor immune response, including T and B cells and immunoglobulins, among women with ovarian tumor tissue collected in three studies, the Nurses' Health Study (NHS; n = 237), NHSII (n = 137) and New England Case-Control Study (NECC; n = 215). Women reporting depressive symptoms above a clinically relevant cut-point, antidepressant use, or physician diagnosis of depression at any time prior to diagnosis of ovarian cancer were considered to have pre-diagnosis depression. Multiplex immunofluorescence was performed on tumor tissue microarrays to measure immune cell infiltration. In pooled analyses, we estimated odds ratios (OR) and 95% confidence intervals (CI) for the positivity of tumor immune cells using a beta-binomial model comparing those with and without depression. We used Bonferroni corrections to adjust for multiple comparisons. RESULTS: We observed no statistically significant association between depression status and any immune markers at the Bonferroni corrected p-value of 0.0045; however, several immune markers were significant at a nominal p-value of 0.05. Specifically, there were increased odds of having recently activated cytotoxic (CD3+CD8+CD69+) and exhausted-like T cells (CD3+Lag3+) in tumors of women with vs. without depression (OR = 1.36, 95 %CI = 1.09-1.69 and OR = 1.24, 95 %CI = 1.01-1.53, respectively). Associations were comparable when considering high grade serous tumors only (comparable ORs = 1.33, 95 %CI = 1.05-1.69 and OR = 1.25, 95 %CI = 0.99-1.58, respectively). There were decreased odds of having tumor infiltrating plasma cells (CD138+) in women with vs. without depression (OR = 0.54, 95 %CI = 0.33-0.90), which was similar among high grade serous carcinomas, although not statistically significant. Depression was also related to decreased odds of having naïve and memory B cells (CD20+: OR = 0.54, 95 %CI = 0.30-0.98) and increased odds of IgG (OR = 1.22, 95 %CI = 0.97-1.53) in high grade serous carcinomas. CONCLUSION: Our results provide suggestive evidence that depression may influence ovarian cancer outcomes through changes in the tumor immune microenvironment, including increasing T cell activation and exhaustion and reducing antibody-producing B cells. Further studies with clinical measures of depression and larger samples are needed to confirm these results.

Stability and reproducibility of proteomic profiles in epidemiological studies: comparing the Olink and SOMAscan platforms.

Limited data exist on the performance of high-throughput proteomics profiling in epidemiological settings, including the impact of specimen collection and within-person variability over time. Thus, the Olink (972 proteins) and SOMAscan7Kv4.1 (7322 proteoforms of 6596 proteins) assays were utilized to measure protein concentrations in archived plasma samples from the Nurses' Health Studies and Health Professionals Follow-Up Study. Spearman's correlation coefficients (r) and intraclass correlation coefficients (ICCs) were used to assess agreement between (1) 42 triplicate samples processed immediately, 24-h or 48-h after blood collection from 14 participants; and (2) 80 plasma samples from 40 participants collected 1-year apart. When comparing samples processed immediately, 24-h, and 48-h later, 55% of assays had an ICC/r ≥ 0.75 and 87% had an ICC/r ≥ 0.40 in Olink compared to 44% with an ICC/r ≥ 0.75 and 72% with an ICC/r ≥ 0.40 in SOMAscan7K. For both platforms, >90% of the assays were stable (ICC/r ≥ 0.40) in samples collected 1-year apart. Among 817 proteins measured with both platforms, Spearman's correlations were high (r > 0.75) for 14.7% and poor (r < 0.40) for 44.8% of proteins. High-throughput proteomics profiling demonstrated reproducibility in archived plasma samples and stability after delayed processing in epidemiological studies, yet correlations between proteins measured with the Olink and SOMAscan7K platforms were highly variable.

Pre-diagnosis and post-diagnosis dietary patterns and survival in women with ovarian cancer.

BACKGROUND: Evidence is limited on inflammation-related dietary patterns and mortality in ovarian cancer survivors. METHODS: We examined the associations between pre- and post-diagnosis dietary patterns, including change in diet from before to after diagnosis, and mortality among 1003 ovarian cancer survivors in two prospective cohort studies. Dietary pattern scores for empirical dietary inflammatory pattern (EDIP) and Alternative Healthy Eating Index (AHEI) were calculated based on food frequency questionnaires. We used Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for ovarian cancer-specific and all-cause mortality. RESULTS: Pre-diagnosis EDIP score and AHEI were not associated with mortality. Among non-high grade serous cases, a higher post-diagnosis EDIP score was associated with increased risk of all-cause mortality (HR5th vs 1st quintile = 1.95, 95% CI = 1.04-3.67, p-trend = 0.06). Compared to survivors consuming a low EDIP score diet before and after diagnosis, high post-diagnosis EDIP was associated with increased risk of ovarian cancer specific mortality (pre-to-post diagnosis low/high, HR = 1.38, 95% CI = 0.99-1.92; high/high HR = 1.58, 95% CI = 1.09-2.30) and all-cause mortality (low/high HR = 1.44, 95% CI = 1.06-1.95; high/high HR = 1.55, 95% CI = 1.10-2.19). CONCLUSION: Consuming a more inflammatory dietary pattern post-diagnosis was associated with increased mortality in ovarian cancer survivors, suggesting limiting the inflammatory potential of diet post-diagnosis could lead to enhanced survivorship.

Circulating proteomic profiles associated with endometriosis in adolescents and young adults.

STUDY QUESTION: What are the systemic molecular profiles of endometriosis diagnosed in adolescents and young adults? SUMMARY ANSWER: Significant enrichment and increased activation of proteins related to angiogenesis and cell migration pathways were observed in endometriosis cases compared to controls (P-value < 2.4 × 10-8). WHAT IS KNOWN ALREADY: Little is known about the pathophysiology of adolescent endometriosis despite the fact that over 50% of adults with endometriosis report onset of severe pelvic pain during adolescence. STUDY DESIGN, SIZE, DURATION: A cross-sectional analysis using data on 142 laparoscopically confirmed endometriosis cases and 74 controls from the observational longitudinal cohort of Women's Health Study: From Adolescence to Adulthood (A2A). PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured 1305 plasma protein levels using the validated, multiplex aptamer-based proteomics discovery platform, SOMAscan. We calculated odds ratios and 95% CIs using logistic regression adjusting for age, BMI, fasting status and hormone use at blood draw for differentially expressed proteins (P < 0.05). Ingenuity Pathway Analysis and STRING analysis were performed to identify biological pathways and protein interactions. We also examined proteins and pathways associated with superficial peritoneal lesion colors (i.e. red, vascularized, white, blue/black, brown). MAIN RESULTS AND THE ROLE OF CHANCE: Average age at blood draw was 18 years for endometriosis cases and 22 years for controls. We identified 63 proteins associated with endometriosis with type-I error set at 0.05, and absolute fold change >1.2, revealing significant enrichment of dysregulated proteins in biological pathways associated with endometriosis. Increased activation of pathways related to angiogenesis and cell migration was observed in plasma from endometriosis cases compared to controls (P-value < 2.4 × 10-8). Furthermore, when we examined proteins and pathways associated with lesion colors, vascularized lesions were associated with upregulation of pathways related to immune cell migration/activation and inflammation, whereas white, blue/black and brown lesions were associated with downregulation of these pathways. LIMITATIONS, REASONS FOR CAUTION: Validation of our results in independent datasets and mechanistic studies are warranted to further our understanding of the pathophysiological characteristics of this common but understudied patient population. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this was the first study to comprehensively examine circulating proteins in predominantly adolescents and young adult women with and without endometriosis. Results from this study provide novel biological insight that will build toward further research to elucidate endometriosis pathophysiology during the earlier course of the disease trajectory. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Department of Defense (W81XWH1910318) and the 2017 Boston Center for Endometriosis Trainee Award. Financial support for establishment of and data collection within the A2A cohort were provided by the J. Willard and Alice S. Marriott Foundation. N.S., A.F.V., S.A.M., K.L.T. have received funding from Marriott Family Foundation. S.A.M. and K.L.T. are supported by NICHD (R01 HD94842). S.A.M. serves as an advisory board member for AbbVie and Roche; neither are related to this study. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

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

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.

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

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

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.

Vertical transmission of methicillin-resistant Staphylococcus aureus at delivery and its clinical impact: An observational, prospective cohort study.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) infection has a significant clinical impact on both pregnant women and neonates. The aim of this study was to assess accurately the vertical transmission rate of MRSA and its clinical impacts on both pregnant mothers and neonates. MATERIAL AND METHODS: We conducted a prospective observational cohort study of 898 pregnant women who were admitted to our department and 905 neonates from August 2016 to December 2017. MRSA was cultured from nasal and vaginal samples taken from the mothers at enrollment and from nasal and umbilical surface swabs taken from neonates at the time of delivery. We examined the vertical transmission rate of MRSA in mother-neonate pairs. We used multivariable logistic regression to identify risk factors for maternal MRSA colonization and maternal/neonatal adverse outcomes associated with maternal MRSA colonization. RESULTS: The prevalence of maternal MRSA colonization was 6.1% (55 of 898) at enrollment. The independent risk factors were multiparity and occupation (healthcare provider) (odds ratio [OR] 2.35, 95% confidence interval [CI] 1.25-4.42 and OR 2.58, 95% CI 1.39-4.79, respectively). The prevalence of neonatal MRSA colonization at birth was 12.7% (7 of 55 mother-neonate pairs) in the maternal MRSA-positive group, whereas it was only 0.12% (one of 843 pairs) in the maternal MRSA-negative group (OR 121, 95% CI 14.6-1000). When maternal vaginal samples were MRSA-positive, vertical transmission was observed in four of nine cases (44.4%) in this study. Skin and soft tissue infections developed more frequently in neonates in the maternal MRSA-positive group than in the MRSA-negative group (OR 7.47, 95% CI 2.50-22.3). CONCLUSIONS: The prevalence of MRSA in pregnant women was approximately 6%. Vertical transmission caused by maternal vaginal MRSA colonization was observed in four of nine cases (44.4%). Although our study includes a limited number of maternal MRSA positive cases, the vertical transmission of MRSA may occur in up to 44% of neonates of mothers with vaginal MRSA colonization. Maternal MRSA colonization may be associated with increased development of skin and soft tissue infections in neonates via vertical transmission.

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

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.

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

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.

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

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.

The Cancer Spectrum Theory.

SUMMARY: Biological characteristics of tumors are heterogeneous, forming spectra in terms of several factors such as age at onset, anatomic spatial localization, tumor subtyping, and the degree of tumor aggressiveness (encompassing a neoplastic property spectrum). Instead of blindly using dichotomized approaches, the application of the multicategorical and continuous analysis approaches to detailed cancer spectrum data can contribute to a better understanding of the etiology of cancer, ultimately leading to effective prevention and precision oncology. We provide examples of cancer spectra and emphasize the importance of integrating the cancer spectrum theory into large-scale population cancer research.

Plasma microRNA expression in adolescents and young adults with endometriosis: the importance of hormone use.

Introduction: Prior studies have investigated the diagnostic potential of microRNA (miRNA) expression profiles for endometriosis. However, the vast majority of previous studies have only included adult women. Therefore, we sought to investigate differential expression of miRNAs among adolescents and young adults with endometriosis. Methods: The Women's Health Study: from Adolescence to Adulthood (A2A) is an ongoing WERF EPHect compliant longitudinal cohort. Our analysis included 64 patients with surgically-confirmed endometriosis (96% rASRM stage I/II) and 118 females never diagnosed with endometriosis frequency matched on age (median = 21 years) and hormone use at blood draw. MicroRNA measurement was separated into discovery (10 cases and 10 controls) and internal replication (54 cases and 108 controls) phases. The levels of 754 plasma miRNAs were assayed in the discovery phase using PCR with rigorous internal control measures, with the relative expression of miRNA among cases vs. controls calculated using the 2-ΔΔCt method. miRNAs that were significant in univariate analyses stratified by hormone use were included in the internal replication phase. The internal replication phase was split 2:1 into a training and testing set and utilized FirePlex miRNA assay to assess 63 miRNAs in neural network analyses. The testing set of the validation phase was utilized to calculate the area under the curve (AUC) of the best fit models from the training set including hormone use as a covariate. Results: In the discovery phase, 49 miRNAs were differentially expressed between endometriosis cases and controls. The associations of the 49 miRNAs differed by hormone use at the time of blood draw. Neural network analysis in the testing set of the internal replication phase determined a final model comprising 5 miRNAs (miR-542-3p, let-7b-3p, miR-548i, miR-769-5p, miR-30c-1-3p), yielding AUC = 0.77 (95% CI: 0.67-0.87, p < 0.001). Sensitivity in the testing dataset improved (83.3% vs. 72.2%) while the specificity decreased (58.3% vs. 72.2%) compared to the training set. Conclusion: The results suggest that miR-542-3p, let-7b-3p, miR-548i, miR-769-5p, miR-30c-1-3p may be dysregulated among adolescent and young adults with endometriosis. Hormone use was a significant modifier of miRNA dysregulation and should be considered rigorously in miRNA diagnostic studies.

Subgroups of pelvic pain are differentially associated with endometriosis and inflammatory comorbidities: a latent class analysis.

ABSTRACT: Chronic pelvic pain is heterogeneous with potentially clinically informative subgroups. We aimed to identify subgroups of pelvic pain based on symptom patterns and investigate their associations with inflammatory and chronic pain-related comorbidities. Latent class analysis (LCA) identified subgroups of participants (n = 1255) from the Adolescence to Adulthood (A2A) cohort. Six participant characteristics were included in the LCA: severity, frequency, and impact on daily activities of both menstruation-associated (cyclic) and non-menstruation-associated (acyclic) pelvic pain. Three-step LCA quantified associations between LC subgroups, demographic and clinical variables, and 18 comorbidities (10 with prevalence ≥10%). Five subgroups were identified: none or minimal (23%), moderate cyclic only (28%), severe cyclic only (20%), moderate or severe acyclic plus moderate cyclic (9%), and severe acyclic plus severe cyclic (21%). Endometriosis prevalence within these 5 LCA-pelvic pain-defined subgroups ranged in size from 4% in "none or minimal pelvic pain" to 24%, 72%, 70%, and 94%, respectively, in the 4 pain subgroups, with statistically significant odds of membership only for the latter 3 subgroups. Migraines were associated with significant odds of membership in all 4 pelvic pain subgroups relative to those with no pelvic pain (adjusted odds ratios = 2.92-7.78), whereas back, joint, or leg pain each had significantly greater odds of membership in the latter 3 subgroups. Asthma or allergies had three times the odds of membership in the most severe pain group. Subgroups with elevated levels of cyclic or acyclic pain are associated with greater frequency of chronic overlapping pain conditions, suggesting an important role for central inflammatory and immunological mechanisms.

Early Detection of Ovarian Cancer.

The risk of death from ovarian cancer is highly associated with the clinical stage at diagnosis. Efforts to implement screening for ovarian cancer have been largely unsuccessful, due to the low prevalence of the disease in the general population and the heterogeneity of the various cancer types that fall under the ovarian cancer designation. A practical test for early detection will require both high sensitivity and high specificity to balance reducing the number of cancer deaths with minimizing surgical interventions for false positive screens. The technology must be cost-effective to deliver at scale, widely accessible, and relatively noninvasive. Most importantly, a successful early detection test must be effective not only at diagnosing ovarian cancer but also in reducing ovarian cancer deaths. Stepwise or multimodal approaches among the various areas under investigation will likely be required to make early detection a reality.

Visualized peritoneal fluid variation in adolescents and young adults with endometriosis: is there more to it?

Background: Peritoneal fluid is a medium for endometriosis-associated biomarker discovery from which the local peritoneal environment and pathophysiologic pathways are often inferred. Therefore, we evaluated the associations between peritoneal fluid color and volume at time of endometriosis-related laparoscopic surgery with patient characteristics, endometriosis type and lesion location in adolescents and young adults with endometriosis. Methods: We conducted a cross-sectional analysis among 545 patients undergoing surgery for endometriosis who enrolled in the Women's Health Study: from Adolescence to Adulthood cohort study. Patient characteristics, surgically visualized endometriosis phenotypes, and gross characteristics of peritoneal fluid were collected in compliance with World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project (EPHect) tools. Chi-square or Fisher's exact tests were applied to test for differences across categories. Results: Most of the patients were adolescents or young adults (86% age <25 years) of white race (89%), with only superficial peritoneal lesions and rASRM stage = I/II observed at surgery (both 95%). We observed variation in peritoneal fluid color across different menstrual cycle phases at time of surgery (p = 0.006). Among those who were cycling at time of surgery, endometriosis patients with red peritoneal fluid were most likely to be in the proliferative phase (49%) compared to the secretory phase (27%), while those with yellow or orange peritoneal fluid were most likely to be in the secretory phase (57% and 86% respectively). Yellow color was significantly less common in those taking combined oral contraceptives but much more common with progesterone only formulation exposure (p = 0.002). Peritoneal fluid volume did not differ by cycle phase but was more likely to be low (≤6 ml) for those exposed to hormones at time of surgery (p = 0.01). Those with acyclic pelvic pain were less likely to have red peritoneal fluid (p = 0.001) but had greater volume (p = 0.02) compared to those without. Conclusion: Our findings highlight the importance of accounting for menstrual cycle phase and hormonal exposures when designing research using peritoneal fluid samples and inferring from biomarker results intended to advance our understanding of endometriosis and associated symptom pathophysiology.