Decrease of dysmenorrhoea with hormonal treatment is a marker of endometriosis severity.

RESEARCH QUESTION: Is a decrease in dysmenorrhoea after suppressive hormonal therapy a marker of the endometriosis phenotype and of greater disease severity? DESIGN: Retrospective observational cohort study conducted in a French university hospital, between January 2004 and December 2019. Non-pregnant women aged younger than 42 years, who tested for dysmenorrhoea relief after suppressive hormonal therapy before surgery, and who had histological confirmation of endometriosis, were included. The comparisons were carried out according to the results of the suppressive hormonal test. RESULTS: Of the 578 histologically proven endometriosis patients with preoperative pain symptoms, the rate of dysmenorrhoea decrease after suppressive hormonal therapy was 88.2% (n = 510). These patients had a higher incidence of deep infiltrating endometriosis (DIE) intestinal lesions (45.7% [233/510] versus 30.8% [21/68], P = 0.01) and an increased rate of multiple DIE lesions (two or more) (72.8% [287/394] versus 56.4% [22/39], P = 0.02). After multivariate analysis, decrease of dysmenorrhoea after suppressive hormonal therapy remained significantly associated with the severe DIE phenotype (adjusted OR 3.9, 95% CI 2.0 to 7.6, P < 0.001). CONCLUSION: In women with endometriosis, a decrease of dysmenorrhoea after suppressive hormonal therapy is associated with the DIE phenotype and is a marker of greater severity.

Magnetic resonance imaging presentation of diffuse and focal adenomyosis before and after pregnancy.

RESEARCH QUESTION: Is there a change in magnetic resonance imaging (MRI) criteria of diffuse and focal phenotypes of adenomyosis before and after pregnancy? DESIGN: A retrospective, monocentric, observational study in a single academic tertiary referral centre for endometriosis diagnosis and management. Women were followed for symptomatic adenomyosis, and without a prior history of surgery who give birth after 24+0 weeks. For each patient, pelvic MRI pre- and post-pregnancy was performed by two experienced radiologists with the same image acquisition protocol. Diffuse and focal adenomyosis MRI presentation were analysed before and after pregnancy. RESULTS: Between January 2010 and September 2020, of the 139 patients analysed, 96 (69.1%) had adenomyosis at MRI distributed as follow: 22 (15.8%) presented diffuse adenomyosis, 55 (39.6%) focal adenomyosis and 19 (13.7%) both phenotypes. The frequency of isolated diffuse adenomyosis on MRI was significantly lower before versus after pregnancy (n = 22 [15.8%] versus n = 41 [29.5%], P = 0.01). The frequency of isolated focal adenomyosis was significantly higher before pregnancy than after pregnancy (n = 55 [39.6%] versus n = 34 [24.5%], P = 0.01). The mean volume of all focal adenomyosis lesions on MRI decreased significantly after pregnancy, from 6.7 ± 2.5 mm3 to 6.4 ± 2.3 mm3, P = 0.01. CONCLUSION: The current data indicate that, based on MRI, there is an increase in diffuse adenomyosis and a decrease in focal adenomyosis after pregnancy.

Discovery and validation of a transcriptional signature identifying homologous recombination-deficient breast, endometrial and ovarian cancers.

BACKGROUND: Molecular alterations leading to homologous recombination deficiency (HRD) are heterogeneous. We aimed to identify a transcriptional profile shared by endometrial (UCEC), breast (BRCA) and ovarian (OV) cancers with HRD. METHODS: Genes differentially expressed with HRD genomic score (continuous gHRD score) in UCEC/BRCA/OV were identified using edgeR, and used to train a RNAseq score (ridge-regression model) predictive of the gHRD score (PanCanAtlas, N = 1684 samples). The RNAseq score was applied in independent gynaecological datasets (CARPEM/CPTAC/SCAN/TCGA, N = 4038 samples). Validations used ROC curves, linear regressions and Pearson correlations. Overall survival (OS) analyses used Kaplan-Meier curves and Cox models. RESULTS: In total, 656 genes were commonly up/downregulated with gHRD score in UCEC/BRCA/OV. Upregulated genes were enriched for nuclear/chromatin/DNA-repair processes, while downregulated genes for cytoskeleton (gene ontologies). The RNAseq score correlated with gHRD score in independent gynaecological cancers (R² = 0.4-0.7, Pearson correlation = 0.64-0.86, all P < 10-11), and was predictive of gHRD score >42 (RNAseq HRD profile; AUC = 0.95/0.92/0.78 in UCEC/BRCA/OV). RNAseq HRD profile was associated (i) with better OS in platinum-treated advanced TP53-mutated-UCEC (P < 0.001) and OV (P = 0.013), and (ii) with poorer OS (P < 0.001) and higher benefit of adjuvant chemotherapy in Stage I-III BRCA (interaction test, P < 0.001). CONCLUSIONS: UCEC/BRCA/OV with HRD-associated genomic scars share a common transcriptional profile. RNAseq signatures might be relevant for identifying HRD-gynaecological cancers, for prognostication and for therapeutic decision.

Highly Specific Droplet-Digital PCR Detection of Universally Methylated Circulating Tumor DNA in Endometrial Carcinoma.

BACKGROUND: No circulating biomarker is available for endometrial carcinoma (EC). We aimed to identify DNA positions universally hypermethylated in EC, and to develop a digital droplet PCR (ddPCR) assay for detection of hypermethylated circulating tumor DNA (meth-ctDNA) in plasma from patients with EC. METHODS: DNA positions hypermethylated in EC, and without unspecific hypermethylation in tissue/cell types releasing circulating cell-free DNA in plasma, were identified in silico from TCGA/Gene Expression Omnibus (GEO) data. A methylation-specific ddPCR (meth-ddPCR) assay following bisulfite conversion of DNA extracted from plasma was optimized for detection of meth-ctDNA according to dMIQE guidelines. Performances were validated on a retrospective cohort (n = 78 tumors, n = 30 tumor-adjacent tissues), a prospective pilot cohort (n = 33 stage I-IV patients), and 55 patients/donors without cancer. RESULTS: Hypermethylation of zinc finger and SCAN domain containing 12 (ZSCAN12) and/or oxytocin (OXT) classified EC samples from multiple noncancer samples with high diagnostic specificity/sensitivity [>97%; area under the curve (AUC) = 0.99; TCGA/GEO tissues/blood samples]. These results were confirmed in the independent retrospective cohort (AUC = 0.99). Meth-ddPCR showed a high analytical specificity (limit of blank = 2) and sensitivity (absolute lower threshold of detection = 50 pgmethDNA/mLplasma). In the pilot cohort, meth-ctDNA was detected in pretreatment plasma samples from 9/11 and 5/20 patients with advanced and non-advanced EC, respectively. 2 of 9 patients had ctDNA detected after macroscopic complete surgery and experienced progression within 6 months. No healthy donors had any copy of hypermethylated DNA detected in plasma. CONCLUSIONS: Meth-ddPCR of ZSCAN12/OXT allows a highly specific and sensitive detection of ctDNA in plasma from patients with EC and appears promising for personalized approaches for these patients.

Potential competing risk of death in older high-risk endometrial carcinoma patients: Results from a multicentric retrospective cohort.

INTRODUCTION: Adjuvant therapeutic decisions in older endometrial carcinoma (EC) patients are challenged by a balance between more frequent aggressive EC and comorbidities. We assessed whether EC and comorbidities are competing or cumulative risks in older EC patients. METHODS: All consecutive patients treated for FIGO stage I-IV EC in two University Hospitals in Paris between 2010 and 2017 were retrospectively included. Patients were categorized as: <70 years (y), >70y without comorbidity (fit), and > 70y with a Charlson comorbidity index>3 (comorbid). Association between high-risk EC (2021-ESGO-ETRO-ESP) or comorbidity, and disease-specific-survival (DSS), was evaluated using Cox model (estimation of cause-specific hazard ratio (CSHR), and Fine-Gray model (subdistribution HR) to account for competing events (death unrelated with EC). RESULTS: Overall, 253 patients were included (median age = 67y, IQR[59-77], median follow-up = 61.5 months, [44.4-76.8]). Among them, 109 (43%) were categorized at high-risk (proportion independent of age), including 67 (26%) who had TP53-mutated tumors. Comorbidity and high-risk group were both associated with all-cause mortality (HR = 4.09, 95%CI[2.29; 7.32] and HR = 3.21, 95%CI [1.69; 6.09], respectively). By multivariate analysis, patients with high-risk EC exhibited poorer DSS, regardless of age/comorbidity (Adjusted-CSHR = 6.62, 95%CI[2.53;17.3]; adjusted-SHR = 6.62 95%CI[2.50;17.5]). Patients>70y-comorbid with high-risk EC had 5-years cumulative incidences of EC-related and EC-unrelated death of 29% and 19%, respectively. In patients <70y, 5-years cumulative incidence of EC-related and EC-unrelated death were 25% and < 1% (one event), respectively. CONCLUSION: High-risk EC patients are exposed to poorer DSS regardless of age/comorbidities, comorbidities and cancer being two cumulative rather than competing risks. Our results suggest that age/comorbidity alone should not lead to underestimate EC-specific survival.

Development and validation of a RNAseq signature for prognostic stratification in endometrial cancer.

BACKGROUND: Despite recent advances in endometrial carcinoma (EC) molecular characterization, its prognostication remains challenging. We aimed to assess whether RNAseq could stratify EC patient prognosis beyond current classification systems. METHODS: A prognostic signature was identified using a LASSO-penalized Cox model trained on TCGA (N = 543 patients). A clinically applicable polyA-RNAseq-based work-flow was developed for validation of the signature in a cohort of stage I-IV patients treated in two Hospitals [2010-2017]. Model performances were evaluated using time-dependent ROC curves (prediction of disease-specific-survival (DSS)). The additional value of the RNAseq signature was evaluated by multivariable Cox model, adjusted on high-risk prognostic group (2021 ESGO-ESTRO-ESP guidelines: non-endometrioid histology or stage III-IVA orTP53-mutated molecular subgroup). RESULTS: Among 209 patients included in the external validation cohort, 61 (30%), 10 (5%), 52 (25%), and 82 (40%), had mismatch repair-deficient, POLE-mutated, TP53-mutated tumors, and tumors with no specific molecular profile, respectively. The 38-genes signature accurately predicted DSS (AUC = 0.80). Most disease-related deaths occurred in high-risk patients (5-years DSS = 78% (95% CI = [68%-89%]) versus 99% [97%-100%] in patients without high-risk). A composite classifier accounting for the TP53-mutated subgroup and the RNAseq signature identified three classes independently associated with DSS: RNAseq-good prognosis (reference, 5-years DSS = 99%), non-TP53 tumors but with RNAseq-poor prognosis (adjusted-hazard ratio (aHR) = 5.75, 95% CI[1.14-29.0]), and TP53-mutated subgroup (aHR = 5.64 [1.12-28.3]). The model accounting for the high-risk group and the composite classifier predicted DSS with AUC = 0.84, versus AUC = 0.76 without (p = 0.01). CONCLUSION: RNA-seq profiling can provide an additional prognostic information to established classification systems, and warrants validation for potential RNAseq-based therapeutic strategies in EC.

Genomics of Endometriosis: From Genome Wide Association Studies to Exome Sequencing.

This review aims at better understanding the genetics of endometriosis. Endometriosis is a frequent feminine disease, affecting up to 10% of women, and characterized by pain and infertility. In the most accepted hypothesis, endometriosis is caused by the implantation of uterine tissue at ectopic abdominal places, originating from retrograde menses. Despite the obvious genetic complexity of the disease, analysis of sibs has allowed heritability estimation of endometriosis at ~50%. From 2010, large Genome Wide Association Studies (GWAS), aimed at identifying the genes and loci underlying this genetic determinism. Some of these loci were confirmed in other populations and replication studies, some new loci were also found through meta-analyses using pooled samples. For two loci on chromosomes 1 (near CCD42) and chromosome 9 (near CDKN2A), functional explanations of the SNP (Single Nucleotide Polymorphism) effects have been more thoroughly studied. While a handful of chromosome regions and genes have clearly been identified and statistically demonstrated as at-risk for the disease, only a small part of the heritability is explained (missing heritability). Some attempts of exome sequencing started to identify additional genes from families or populations, but are still scarce. The solution may reside inside a combined effort: increasing the size of the GWAS designs, better categorize the clinical forms of the disease before analyzing genome-wide polymorphisms, and generalizing exome sequencing ventures. We try here to provide a vision of what we have and what we should obtain to completely elucidate the genetics of this complex disease.

[Endometriosis and adenomyosis]. / Endométriose et adénomyose.

Diffuse adenomyosis, focal adenomyosis, ovarian endometrioma, superficial endometriosis and deep infiltrating adenomyosis are all defined by the presence of an endometrioid tissue in an ectopic location that is at distance from the endometrium. Although frequently associated, these lesions represent different clinico-pathological entities that the pathologist should recognized. Herein, we review the clinical and pathological features of these entities, as well as related current physiopathological understandings and differential diagnoses that could be raised by some morphological variants. The statistical association between endometriosis and several ovarian tumors, mainly endometrioid and clear cell carcinomas and seromucinous borderline tumors is well established and we present some molecular and morphological features that support this transformation potential.

Identification of TP53 mutated group using a molecular and immunohistochemical classification of endometrial carcinoma to improve prognostic evaluation for adjuvant treatments.

INTRODUCTION: Molecular classification of endometrial carcinoma has been proposed to predict survival. However, its role in patient management remains to be determined. We aimed to identify whether a molecular and immunohistochemical classification of endometrial carcinoma could improve decision-making for adjuvant therapy. METHODS: All consecutive patients treated for endometrial carcinoma between 2010 and 2017 at Cochin University Hospital were included. Clinical risk of relapse was based on European Society for Medical Oncology-European Society of Gynaecological Oncology-European SocieTy for Radiotherapy & Oncology (ESMO-ESGO-ESTRO) consensus. The clinical event of interest was event-free survival. Formalin-fixed paraffin-embedded tissue samples were processed for histopathological analysis and DNA extraction. The nuclear expression of mismatch repair and TP53 proteins was analyzed by immunohistochemistry. Next-generation sequencing of a panel of 15 genes including TP53 and POLE was performed using Ampliseq panels on Ion Torrent PGM (ThermoFisher). Tumors were allocated into four molecular groups using a sequential method based on next-generation sequencing and immunohistochemistry data: (1) POLE/ultramutated-like; (2) MSI/hypermutated-like (mismatch repair-deficient); (3) TP53-mutated (without POLE mutations or mismatch repair deficiency); (4) not otherwise specified (the remaining tumors). RESULTS: 159 patients were included; 125 tumors were available for molecular characterization and distributed as follows: (1) POLE/ultramutated-like: n=4 (3%); (2) MSI/hypermutated-like: n=35 (30%); (3) TP53-mutated: n=30 (25%); and (4) not otherwise specified: n=49 (42%). Assessing the TP53 status by immunohistochemistry only rather than next-generation sequencing would have misclassified 6 tumors (5%). TP53-mutated tumors were associated with poor prognosis, independently of International Federation of Gynecology and Obstetrics (FIGO) stage and histological grade (Cox-based adjusted hazard ratio (aHR) 5.54, 95% CI 2.30 to 13.4), and independently of clinical risk of relapse (aHR 3.92, 95% CI 1.59 to 9.64). Among patients with FIGO stage I-II tumors, 6 (38%) TP53-mutated tumors had low/intermediate clinical risk of relapse and did not receive adjuvant chemotherapy or radiotherapy. CONCLUSION: Endometrial carcinoma molecular classification identified potentially under-treated patients with poor molecular prognosis despite being at low/intermediate clinical risk of relapse. Consideration of molecular classification in adjuvant therapeutic decisions should be evaluated in prospective trials.

Anterior Focal Adenomyosis and Bladder Deep Infiltrating Endometriosis: Is There a Link?

STUDY OBJECTIVE: To evaluate the association between bladder deep infiltrating endometriosis (DIE) and anterior focal adenomyosis of the outer myometrium (aFAOM) diagnosed by preoperative magnetic resonance imaging (MRI). DESIGN: An observational, cross-sectional study using prospectively collected data (Canadian Task Force classification II-2). SETTING: Single university tertiary referral center. PATIENTS: All nonpregnant women younger than 42 years who had undergone complete surgical exeresis of endometriotic lesions. For each patient a standardized questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding the surgery. Only women with preoperative standardized uterine MRI were retained for this study. INTERVENTIONS: Thirty-nine women with histologically proven bladder DIE and an available preoperative MRI were enrolled in the study. Patients were divided into 2 groups: women with aFAOM (aFAOM (+), n = 19) and women without aFAOM (aFAOM (-), n = 20). Both groups were compared for general characteristics, medical history, MRI findings, and disease severity. MEASUREMENTS AND MAIN RESULTS: Nineteen patients (48.7%) with bladder DIE had aFAOM at preoperative MRI. The rate of associated diffuse adenomyosis was similar in the 2 groups (63.2% [n = 12] vs 73.7% [n = 14]; p = .48). The rate of an associated ovarian endometrioma (OMA) was significantly lower in the aFAOM (+) group (10.5% [n = 2] vs 40.0% [n = 8]; p = .03). There were fewer associated intestinal DIE lesions in the aFAOM (+) group compared with the aFAOM (-) group (26.3% vs 75.0%; p = .02), with lower involvement of the pouch of Douglas (26.3% vs 70%; p < .01). Total American Society for Reproductive Medicine score was significantly lower in the aFAOM (+) group (13.8 ± 12.2 vs 62.2 ± 46.2; p < .01). CONCLUSION: aFAOM is present in only half of women with bladder DIE and appears to be associated with lower associated posterior DIE.

Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes.

STUDY QUESTION: What is the relationship between endometriosis phenotypes superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA), deep infiltrating endometriosis (DIE) and the adenomyosis appearance by magnetic resonance imaging (MRI)? SUMMARY ANSWER: Focal adenomyosis located in the outer myometrium (FAOM) was observed more frequently in women with endometriosis, and was significantly associated with the DIE phenotype. WHAT IS KNOWN ALREADY: An association between endometriosis and adenomyosis has been reported previously, although data regarding the association between MRI appearance of adenomyosis and the endometriosis phenotype are currently still lacking. STUDY DESIGN, SIZE, DURATION: This was an observational, cross-sectional study using data prospectively collected from non-pregnant patients who were between 18 and 42 years of age, and who underwent surgery for symptomatic benign gynecological conditions between January 2011 and December 2014. For each patient, a standardized questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding the surgery. Only women with preoperative standardized uterine MRIs were retained for this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Surgery was performed on 292 patients with signed consent and available preoperative MRIs. After a thorough surgical examination of the abdomino-pelvic cavity, 237 women with histologically proven endometriosis were allocated to the endometriosis group and 55 symptomatic women without evidence of endometriosis to the endometriosis free group. The existence of diffuse or FAOM was studied in both groups and according to surgical endometriosis phenotypes (SUP, OMA and DIE). MAIN RESULTS AND THE ROLE OF CHANCE: Adenomyosis was observed in 59.9% (n = 175) of the total sample population (n = 292). Based on MRI, the distribution of adenomyosis was as follows: isolated diffuse adenomyosis (53 patients; 18.2%), isolated FAOM (74 patients; 25.3%), associated diffuse and FAOM (48 patients; 16.4%). Diffuse adenomyosis (isolated and associated to FAOM) was observed in one-third of the patients regardless of whether they were endometriotic patients or endometriosis free women taken as controls (34.2% (81 cases) versus 36.4% (20 cases)); P = 0.764. Among endometriotic women, diffuse adenomyosis (isolated and associated to FAOM) failed to reach significant correlation with the endometriosis phenotypes (SUP, 20.0% (8 cases); OMA, 45.2% (14 cases) and DIE, 35.5% (59 cases); P = 0.068). In striking contrast, there was a significant increase in the frequency of FAOM in endometriosis-affected women than in controls (119 cases (50.2%) versus 5.4% (3 cases); P < 0.001). FAOM correlated with the endometriosis phenotypes, significantly with DIE (SUP, 7.5% (3 cases); OMA, 19.3% (6 cases) and DIE, 66.3% (110 cases); P < 0.001). LIMITATIONS, REASONS FOR CAUTION: There was a possible selection bias due to the specificity of the study design, as it only included surgical patients in a referral center that specializes in endometriosis surgery. Therefore, women referred to our center may have suffered from particularly severe forms of endometriosis. This could explain the high number of women with DIE (166/237-70%) in our study group. This referral bias for women with severe lesions may have amplified the difference in association of FAOM with the endometriosis-affected patients compared to women without endometriosis. Furthermore, according to inclusion criteria, women in the endometriosis free group were symptomatic women. This may introduce some bias as symptomatic women may be more prone to have associated adenomyosis that in turn could have been overrepresented in the endometriosis free group. Whether this selection could have introduced a bias in the relationship between endometriosis and adenomyosis remains unknown. WIDER IMPLICATIONS OF THE FINDINGS: This study opens the door to future epidemiological, clinical and mechanistic studies aimed at better characterizing diffuse and focal adenomyosis. Further studies are necessary to adequately determine if diffuse and focal adenomyosis are two separate entities that differ in terms of pathogenesis. STUDY FUNDING/COMPETING INTEREST(S): No funding supported this study. The authors have no conflict of interest to declare.

Clinicopathologic Characteristics of Endometrial Cancer in Lynch Syndrome: A French Multicenter Study.

BACKGROUND: Limited data exist on Lynch syndrome (LS)-related endometrial cancer (EC) features. Amsterdam criteria II, commonly used, have poor sensitivity for detection of LS, which is underdiagnosed. AIM: The aim of this study was to describe the clinical and pathological features of LS-related EC among mutation-proven patients. METHODS: We conducted a retrospective study from 1977 to 2013 in 5 hospitals. The inclusion criteria were patients who had a primary EC associated to LS proven by a germline mutation. We analyzed the clinical data and the pathology of the tumors. The patient management and the survival data were also collected. RESULTS: Forty-nine patients (15 MLH1, 20 MSH2, 13 MSH6, 1 PMS2) were included. The mean age at diagnosis was 49.7 (SD, 10.5) years. The median body mass index was 22.6 kg/m. In 81.4% of cases, EC was the first cancer of the LS spectrum to occur. Endometrioid adenocarcinoma accounted for 89.2% of the EC, the lower uterine segment was involved in 25% of cases, and a synchronous ovarian cancer was present in 21.6% of patients. The tumors were grade 3 in 19.3% of cases and FIGO (International Federation of Gynecology and Obstetrics) stage I in 66.6% of cases. With a median follow-up of 58 months, 3 patients with conservative management developed a recurrence, and no patient died of EC. CONCLUSIONS: The LS-associated EC is characterized by a young age at onset, a high prevalence of lower uterine segment involvement, and synchronous ovarian cancers. The prognosis of these cancers does not appear different from sporadic tumors.

A Real-Life Experience of Bevacizumab in Elderly Women With Advanced Ovarian Carcinoma.

OBJECTIVE: This study aimed to assess the tolerance of bevacizumab (BEVA) among older ovarian cancer patients in daily clinical practice and identify a subpopulation of patients with a high risk of severe adverse effects. METHODS: Consecutive patients with a pathologically proven high-grade serous ovarian, tubal, or peritoneal carcinoma who received BEVA between January 2006 and June 2014 were included in a retrospective analysis. RESULTS: Among 86 BEVA-treated patients, 42 (48.8%) received concomitant chemotherapy, 26 (30%) had baseline arterial hypertension (HTN), and 33 (38.4%) were considered elderly (>70 years). Incidence of arterial, venous thromboembolism, hemorrhage, and bowel perforation were 2%, 8%, 12%, and 0%, respectively, and was not related to age. Incidence of severe (NCI-CTC v4 G3-4) HTN was significantly higher in elderly patients than in younger ones (39%; 95% confidence interval [CI], 22%-56% vs 17%; 95% CI, 7%-27%) (P = 0.017 by χ test) and in patients with baseline HTN (P < 0.05). Twenty-three percent of younger patients had baseline HTN compared with 42% of older ones (P = 0.052). Among patients without baseline HTN, older age was not associated with increased risk of severe HTN. However, incidence of severe HTN reached 71% (95% CI, 47%-95%) in older patients with baseline HTN. Exploratory analysis indicates that progression-free survival was similar in younger and older patients. CONCLUSIONS: Bevacizumab is feasible in patients older than 70 years with advanced ovarian carcinoma. More attention must be paid to elderly patients with baseline HTN.

Inhibin A and inhibin B producing ovarian fibrothecoma revealed by suppression of follicle stimulating hormone (FSH) in a post-menopausal woman: report of the first case.

In this report, we describe the first case ever reported in the literature, of an inhibin-A (INHA) and inhibin-B (INHB) producing fibrothecoma. A post-menopausal woman was referred to our unit because of follicle stimulating hormone (FSH) level below the reference interval for postmenopausal women. By contrast luteinizing hormone, hCG, and estradiol levels were within normal range. This discrepancy suggested the secretion of FSH inhibitory factors. INHB and INHA levels were markedly elevated for age, 475 pg/mL and 100 pg/mL, respectively. Ultrasonography and MRI showed a pelvic mass of indeterminate nature. Abnormal inhibin secretion is generally observed in granulosa cell tumors. In this case this etiology was unlikely because of low estradiol and AMH levels. Surgical exploration revealed a 10 cm mass of the left ovary proven histologically to be an ovarian fibrothecoma (OFT). After tumor removal, INHB and INHA levels decreased rapidly. Only three cases of OFT with an important secretion of INHB have been reported to date. INHA secretion has never been associated with OFT. There is a need to develop coupled hormone and imaging strategies to diagnose the source of INH secretion in case of FSH/LH discrepancy.

History of Uterine Surgery Is Not Associated With an Increased Severity of Bladder Deep Endometriosis.

STUDY OBJECTIVE: To analyze whether a history of uterine surgery correlates with disease severity in patients with bladder deep infiltrating endometriosis (DIE). DESIGN: This was an observational, cross-sectional study using data collected prospectively (Canadian Task Force classification II-2). SETTING: A single university tertiary referral center. PATIENTS: We included all nonpregnant women younger than age 42 years who had undergone complete surgical exeresis of endometriotic lesions. For each patient, a standardized questionnaire was completed during a face-to-face interview that was conducted by the surgeon in the month preceding the surgery. INTERVENTIONS: One hundred seven women with histologically proven bladder DIE were enrolled in this study. For the purpose of the study, the women were assigned to 2 groups before surgery: a study group that included women with a history of a scarred uterus (SU) (SU+, n = 16) and a control group that included women without SU (SU-, n = 99). Both groups were compared in terms of their general characteristics, medical histories, surgical findings, and the severity of the disease. MEASUREMENTS AND MAIN RESULTS: Patient age and body mass index were higher for the SU+ group as compared to the SU- group (37.9 ± 5.6 vs 32.2 ± 4.7, p < .01, and 24.7 ± 4.9 vs 21.9 ± 2.9, p = .03, respectively). Preoperative painful symptom scores did not differ between the 2 groups. No significant difference was observed in the rates of history for surgery for endometriosis (n = 11 [68.7%] vs n = 49 [53.8], p = .27). Comparison of the anatomic distribution of the lesions did not reveal a significant difference. The total American Society for Reproductive Medicine score did not differ between the groups (32.0 ± 34.4 vs 35.5 ± 34.5, p = .71). The incidence rate of isolated bladder DIE did not differ between the 2 study groups (n = 6 [37.5%] vs n = 40 [43.9%], p = .79). CONCLUSION: SU before surgery for endometriosis was observed in 14.9% of cases of bladder DIE; however, this was not related to an increased severity of the disease. This observational study hence does not appear to support the pathophysiologic hypothesis of a transmyometrial source for bladder DIE.

Increased serum cancer antigen-125 is a marker for severity of deep endometriosis.

STUDY OBJECTIVE: To determine whether cancer antigen-125 (CA-125) levels are increased in women with endometriosis, especially in those with endometriomas (OMAs), deep infiltrating lesions (DIE), and superficial endometriosis (SUP) compared with controls without endometriosis in a large cohort of operated women. DESIGN: Cross-sectional study (Canadian Task Force classification II-2). SETTING: Tertiary-care university hospital. PATIENTS: Four hundred six women with histologically proven endometriosis and 279 women without endometriosis. INTERVENTIONS: Surgical examination of the abdomino-pelvic cavity. MEASUREMENTS AND MAIN RESULTS: Preoperative serum CA-125 antigen levels were evaluated by electrochemoluminescence immunoassay in women with endometriosis and controls. Correlations between serum CA-125 levels and clinical and anatomical characteristics of disease severity were examined. Women with endometriosis displayed higher mean serum CA-125 levels compared with disease-free controls (50.1 ± 62.4 U/mL vs 22.5 ± 25.2 U/mL; p ≤ .001). CA-125 levels were significantly increased in women with OMA (60.8 ± 63.5 U/mL) and DIE (55.2 ± 68.7 U/mL) compared with women with SUP (23.2 ± 24.5 U/mL) and controls (22.5 ± 25.2 U/mL). There was no difference in CA-125 levels between patients with SUP and controls and between patients with OMA and DIE. CA-125 serum levels were correlated with DIE severity: the mean number of DIE lesions and worst DIE lesion. CONCLUSION: Serum CA-125 levels were significantly increased in women with severe forms of endometriosis, OMA, and DIE lesions. In addition, elevated serum Ca-125 levels were associated with more severe and extended DIE lesions. In women with superficial peritoneal lesions, CA-125 levels were not different from women without endometriosis.

Measurement of hs-CRP is irrelevant to diagnose and stage endometriosis: prospective study of 834 patients.

OBJECTIVE: The pathogenesis of endometriosis is associated with an inflammatory process. Here, we assessed if the levels of high-sensitivity C-reactive protein (hs-CRP) in serum could constitute an effective method for detecting systemic inflammation during endometriosis. STUDY DESIGN: This was a prospective, laboratory-based study, which was carried out in a tertiary care university hospital. Patients with histologically proven endometriosis (n = 370) and unaffected women (n = 464) were enrolled from January 2005 through December 2009. We performed complete surgical excision of endometriotic lesions with pathological analysis. In addition, hs-CRP levels were determined through a particle-enhanced immunoturbidimetric method. The hs-CRP levels were measured in both controls and women with endometriosis according to the established surgical classifications of endometriosis: superficial peritoneal endometriosis, endometrioma, and deep infiltration endometriosis. Also, hs-CRP levels were evaluated according to hormonal treatment and menstrual cycle. RESULTS: The hs-CRP serum levels did not statistically differ between women with endometriosis and controls (median in ng/mL [range]: 0.82 [0.04-42.89] vs 0.9 [0.03-43.73], respectively; P = .599). Moreover, subgroup analysis revealed no difference among superficial peritoneal endometriosis, endometrioma, deep infiltration endometriosis, and controls: 0.8 (0.15-13.35), 0.81 (0.04-38.82), 0.83 (0.09-42.89), and 0.9 (0.03-43.73), respectively; P = .872. Furthermore, no effect was observed regarding hormonal treatment or menstrual cycle. CONCLUSION: Although endometriosis is an inflammatory disease, we failed to identify any systemic changes in hs-CRP serum levels. Therefore, hs-CRP analysis appears to be irrelevant to the diagnosis and staging of endometriosis.

Radiation Proctitis in Patients With Locally Advanced Cervical Cancer Treated by Chemoradiation: Analysis and Predictive Factors From a Retrospective Cohort.

OBJECTIVES: Radiation proctitis is a misunderstanding complication of chemoradiation in locally advanced cervical cancer. The objective of our study is to provide a detailed description and analysis of predictive factors associated with radiation proctitis in a retrospective cohort of patients treated by chemoradiation for locally advanced cervical cancer. METHODS: All patients treated by exclusive chemoradiation or chemoradiation followed by brachytherapy for locally advanced cervical cancer from 2011 to 2017 were included in the study. A bivariate analysis was conducted to establish correlations between the occurrence of radiation proctitis and various clinical and technical variables. RESULTS: A total of 128 patients were included in the study. The mean dose (SD) to the planning target volume was 47.1 Gy (6.2). Fifty-nine (46.1%) patients underwent brachytherapy. Sixteen patients (12.5%) developed radiation proctitis, grade 2 or higher in 12 patients (9.3%). In univariate analysis, anticoagulant or antiplatelet treatments ( P =0.039), older age ( P =0.049), rectal volume irradiated at 40 Gy ( P =0.01) and 30 Gy ( P =0.037) were significantly associated with the occurrence of a grade ≥2 radiation proctitis. The delivered dose to 2 cm 3 of rectum (D2cm 3 ) showed a potential association with the occurrence of radiation proctitis of all grades ( P =0.064). CONCLUSIONS: This study highlights clinical and technical factors that should be considered in assessing the risk of radiation proctitis. These results contribute to a better understanding of this complication.

Genetic polymorphisms of DNMT3L involved in hypermethylation of chromosomal ends are associated with greater risk of developing ovarian endometriosis.

Endometrioma is a common ovarian cyst associated with pain and infertility, but its pathogenesis remains enigmatic. Demonstration of the subtelomeric location of hypermethylation in endometrioma has been reported by genome-wide profiling of methylated promoters. Recently, rs113593938, a polymorphism in the DNA methyltransferase 3-like (DNMT3L) gene has been associated with subtelomeric hypomethylation. We investigated the association between endometrioma and rs113593938, rs8129776, rs7354779, and rs2276248, which were chosen for thoroughly covering the locus of interest. We enrolled 127 patients with histologically proved endometrioma and no associated deep endometriotic lesions and 317 healthy subjects for a case-control genetic association study. Genotyping was performed after PCR amplification of the region encompassing the polymorphisms, restriction enzyme digestion, and detection of fragments on an agarose gel. Differences in genotype and allele distributions between cases and controls were tested for each polymorphism separately using the χ(2) test. The rs8129776 was significantly associated with endometrioma (P = 0.003). Haplotype analysis showed a higher risk for the patients carrying the ACCC+T haplotypes for rs8129776, rs7354779, rs113593938, and rs2276248 (odds ratio, 7.15; 95% CI, 2.63 to 19.44). We report, for the first time to our knowledge, the association of DNMT3L genetic variants and endometrioma; DNMT3L expression itself was not modified. Our study constitutes a first milestone toward a plausible role of DNMT3L in the establishment of specific DNA methylation patterns in endometrioma.

Profibrotic interleukin-33 is correlated with uterine leiomyoma tumour burden.

STUDY QUESTION: Are interleukin-33 (IL-33) serum levels higher in women with uterine leiomyoma compared with controls without leiomyoma? SUMMARY ANSWER: Serum IL-33 is elevated in women with uterine leiomyoma and correlated with features of uterine leiomyoma tumour burden, namely fibroid number, size and weight. WHAT IS KNOWN ALREADY: Uterine leiomyomas are the most common benign tumours in premenopausal women associated with major tissue fibrosis. IL-33 is a cytokine involved in fibrotic disorders. The potential role of IL-33 in leiomyoma has not been reported before. STUDY DESIGN, SIZE, DURATION: This is a prospective laboratory study conducted in a tertiary-care university hospital between January 2005 and December 2010. We investigated non-pregnant, 42-year-old patients (n = 151) during surgery for a benign gynaecological condition. PARTICIPANTS/MATERIALS, SETTING, METHODS: After complete surgical exploration of the abdominopelvic cavity, 59 women with histologically proved uterine leiomyoma and 92 leiomyoma-free control women were enrolled. Women with endometriosis or past history of ovarian malignancy and borderline tumours were not included. The control group included women with benign ovarian cysts, paratubal cysts or tubal defects without any evidence of uterine leiomyoma. For each patient, a structured questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding surgery. Serum samples were obtained in the month preceding the surgical procedures according to the menstrual phase or hormonal therapy. IL-33 was measured in sera by enzyme-linked immunosorbent assay, and correlation of IL-33 concentration with the extent and severity of the disease was investigated. MAIN RESULTS AND THE ROLE OF CHANCE: IL-33 was detected in 32 (54.2%) women with leiomyoma and 18 (19.6%) controls (P < 0.001). Serum IL-33 was higher in women with leiomyoma (median, 140.1 pg/ml; range, 7.5-2247.7) than in controls (median, 27.8 pg/ml; range, 7.5-71.6; P = 0.002). We found positive correlations between serum IL-33 concentration and leiomyoma features, such as fibroid weight (r = 0.630; P = 0.001) and size (r = 0.511; P = 0.018) and the number of fibroids (r = 0.503; P = 0.003). LIMITATIONS, REASONS FOR CAUTION: There was a possible selection bias due to inclusion of only surgical patients. Therefore our control group consisted of women who underwent surgery for benign gynaecological conditions. This may lead to biases stemming from the fact that certain of these conditions, such as tubal infertility or ovarian cysts, might be associated with altered serum IL-33 levels. WIDER IMPLICATIONS OF THE FINDINGS: We demonstrate for the first time that elevated serum IL-33 levels are associated with the existence of uterine leiomyoma. However, even if an association does not constitute proof of cause and effect, investigating the mechanisms that underlie fibrogenesis associated with leiomyomas is a step towards understanding this enigmatic disease. This study opens the doors to future, more mechanistics studies to establish the exact role of IL-33 in uterine leiomyomas pathogenesis. STUDY FUNDING/COMPETING INTEREST(S): No funding, no conflict of interest.