HPV-YAP1 oncogenic alliance drives malignant transformation of fallopian tube epithelial cells.

High grade serous ovarian carcinoma (HGSOC) is the most common and aggressive ovarian malignancy. Accumulating evidence indicates that HGSOC may originate from human fallopian tube epithelial cells (FTECs), although the exact pathogen(s) and/or molecular mechanism underlying the malignant transformation of FTECs is unclear. Here we show that human papillomavirus (HPV), which could reach FTECs via retrograde menstruation or sperm-carrying, interacts with the yes-associated protein 1 (YAP1) to drive the malignant transformation of FTECs. HPV prevents FTECs from natural replicative and YAP1-induced senescence, thereby promoting YAP1-induced malignant transformation of FTECs. HPV also stimulates proliferation and drives metastasis of YAP1-transformed FTECs. YAP1, in turn, stimulates the expression of the putative HPV receptors and suppresses the innate immune system to facilitate HPV acquisition. These findings provide critical clues for developing new strategies to prevent and treat HGSOC.

ISGylation enhances dsRNA-induced interferon response and NFκB signaling in fallopian tube epithelial cells.

Heritable mutations in BRCA1 associate with increased risk of high-grade serous tubo-ovarian cancer. Nongenetic risk factors associated with this cancer, which arises from fallopian tube epithelial (FTE) cells, suggests a role for repetitive ovulation wherein FTE cells are exposed to inflammatory signaling molecules within follicular fluid. We previously reported increased NFκB and EGFR signaling in BRCA1-deficient primary FTE cells, with follicular fluid exposure further increasing abundance of interferon-stimulated gene (ISG) transcripts, including the ubiquitin-like protein ISG15 and other ISGylation pathway members. Both NFκB and type I interferon signaling are upregulated by stimulation of cGAS-STING or MDA5 and RIGI pattern recognition receptors. Since some pattern recognition receptors and their signal transduction pathway members are ISGylated, we tested the impact of ISG15 and ISGylation on interferon regulatory factor 3 (IRF3) and NFκB signaling through cGAS-STING or RIGI and MDA5 activation. Expression of ISG15 or UBA7, the E1-like ISG15-activating enzyme, in immortalized FTE cells was disrupted by CRISPR gene editing. Activation of IRF3 by RIGI or MDA5 but not cGAS-STING was attenuated by loss of either ISG15 or UBA7 and this was reflected by a similar effect on NFκB activation and downstream targets. Loss of ISGylation decreased levels of both MDA5 and RIGI, with knockdown of RIGI but not MDA5, decreasing IRF3 and NFκB activation in parental cells. These finding indicate that ISGylation enhances the ability of dsRNA to activate cytokine release and proinflammatory signaling. Further work to explore ISGylation as a target for prevention of high-grade serous tubo-ovarian cancer in BRCA1 mutation carriers is warranted.

Development and characterization of human fetal female reproductive tract organoids to understand Müllerian duct anomalies.

Müllerian ducts are paired tubular structures that give rise to most of the female reproductive organs. Any abnormalities in the development and differentiation of these ducts lead to anatomical defects in the female reproductive tract organs categorized as Müllerian duct anomalies. Due to the limited access to fetal tissues, little is understood of human reproductive tract development and the associated anomalies. Although organoids represent a powerful model to decipher human development and disease, such organoids from fetal reproductive organs are not available. Here, we developed organoids from human fetal fallopian tubes and uteri and compared them with their adult counterparts. Our results demonstrate that human fetal reproductive tract epithelia do not express some of the typical markers of adult reproductive tract epithelia. Furthermore, fetal organoids are grossly, histologically, and proteomically different from adult organoids. While external supplementation of WNT ligands or activators in culture medium is an absolute requirement for the adult reproductive tract organoids, fetal organoids are able to grow in WNT-deficient conditions. We also developed decellularized tissue scaffolds from adult human fallopian tubes and uteri. Transplantation of fetal organoids onto these scaffolds led to the regeneration of the adult fallopian tube and uterine epithelia. Importantly, suppression of Wnt signaling, which is altered in patients with Müllerian duct anomalies, inhibits the regenerative ability of human fetal organoids and causes severe anatomical defects in the mouse reproductive tract. Thus, our fetal organoids represent an important platform to study the underlying basis of human female reproductive tract development and diseases.

STK11 (LKB1) immunohistochemistry is a sensitive and specific marker for STK11 adnexal tumours.

AIMS: STK11 adnexal tumour is a rare, recently described malignant neoplasm that is associated with Peutz-Jeghers syndrome. [Correction added on 3 October 2024, after first online publication: 'ST11' in preceding sentence has been corrected to 'STK11' in this version.] It predominantly originates from the para-adnexal soft tissues and often shows secondary involvement of the fallopian tube and ovary. STK11 adnexal tumours have a broad differential diagnosis due to their variable morphology and non-specific immunoprofile, and diagnostic confirmation currently requires sequencing to identify an STK11 mutation. We investigate the diagnostic utility of STK11 (LKB1) immunohistochemistry (IHC) in a cohort of STK11 adnexal tumours and morphological mimics. METHODS AND RESULTS: IHC for STK11 was performed on 122 tumours, including 17 STK11 adnexal tumours and 105 morphological mimics (10 female adnexal tumours of Wolffian origin, 22 adult granulosa cell tumours, 10 juvenile granulosa cell tumours, four Sertoli-Leydig cell tumours, two Leydig cell tumours, one Sertoli cell tumour, one steroid cell tumour, four extra-ovarian sex cord-stromal tumours, 16 ovarian endometrioid carcinomas, eight tubo-ovarian high-grade serous carcinomas, five ovarian mesonephric-like adenocarcinomas, 14 ovarian carcinosarcomas, five peritoneal malignant mesotheliomas, two pelvic plexiform leiomyomata and one ovarian solid pseudopapillary tumour). All STK11 adnexal tumours showed complete loss of cytoplasmic staining for STK11. All other tumour types showed retained cytoplasmic staining, except for one endometrioid carcinoma with mucinous differentiation which showed complete loss of STK11 expression and a high-grade serous carcinoma with subclonal loss. CONCLUSIONS: STK11 is a highly sensitive and specific immunohistochemical marker for distinguishing STK11 adnexal tumour from its histological mimics, and can obviate the need for confirmatory molecular studies in the appropriate morphological context.

Human peritoneal fluid exerts ovulation- and nonovulation-sourced oncogenic activities on transforming fallopian tube epithelial cells.

Secretory cells in the fallopian tube fimbria epithelium (FTE) are regarded as the main cells of origin of ovarian high-grade serous carcinoma (HGSC). Ovulation is the main cause of FTE oncogenesis, which proceeds through a sequence of TP53 mutations, chromosomal instability due to Rb/cyclin E aberration, in situ carcinoma (STIC), and metastasis to the ovary and peritoneum (metastatic HGSC). Previously, we have identified multiple oncogenic activities of the ovulatory follicular fluid (FF), which exerts the full spectrum of transforming activity on FTE cells at different stages of transformation. After ovulation, the FF is transfused into the peritoneal fluid (PF), in which the FTE constantly bathes. We wondered whether PF exerts the same spectrum of oncogenic activities as done by FF and whether these activities are derived from FF. By using a panel of FTE cell lines with p53 mutation (FT282-V), p53/CCNE1 aberrations (FT282-CCNE1), and p53/Rb aberrations plus spontaneous transformation, and peritoneal metastasis (FEXT2), we analyzed the changes of different transformation phenotypes after treating with FF and PF collected before or after ovulation. Similar to effects exhibited by FF, we found that, to a lesser extent, PF promoted anchorage-independent growth (AIG), migration, anoikis resistance, and peritoneal attachment in transforming FTE cells. The more transformed cells were typically more affected. Among the transforming activities exhibited by PF treatment, AIG, Matrigel invasion, and peritoneal attachment growth were higher with luteal-phase PF treatment than with the proliferative-phase PF treatment, suggesting an ovulation source. In contrast, changes in anoikis resistance and migration activities were similar in response to treatment with PF collected before and after ovulation, suggesting an ovulation-independent source. The overall transforming activity of luteal-phase PF was verified in an i.p. co-injection xenograft mouse model. Co-injection of Luc-FEXT2 cells with either FF or luteal-phase PF supported early peritoneal implantation, whereas co-injection with follicular-phase PF did not. This study, for the first time, demonstrates that PF from ovulating women can promote different oncogenic phenotypes in FTE cells at different stages of malignant transformation. Most of these activities, other than anoikis resistance and cell migration, are sourced from ovulation.

Comprehensive next-generation sequencing identifies novel putative pathogenic or likely pathogenic germline variants in patients with concurrent tubo-ovarian and endometrial serous and endometrioid carcinomas or precursors.

BACKGROUND: Endometrial serous carcinoma (ESC) and tubo-ovarian high-grade serous carcinoma (HGSC) are characterized by late-stage presentation and high mortality. Current guidelines for prevention recommend risk-reducing salpingo-oophorectomy (RRSO) in patients with hereditary mutations in cancer susceptibility genes. However, HGSC displays extensive genetic heterogeneity with alterations in 168 genes identified in TCGA study, but current germline testing panels are often limited to the handful of recurrently mutated genes, leaving families with rare hereditary gene mutations potentially at-risk. OBJECTIVE: To determine if there are rare germline mutations that may aid in early identification of more patients at-risk for ESC and/or HGSC by evaluating patients with concurrent ESC, HGSC or precursor lesions, and endometrial atypical hyperplasia (CAH) or low-grade endometrial endometrioid adenocarcinoma (LGEEA). METHODS: We performed targeted next-generation sequencing using TSO 500, a 523 gene panel, on formalin-fixed paraffin-embedded tumor and matched benign non-tumor tissue blocks from 5 patients with concurrent ESC, HGSC or precursor lesions, and CAH or LGEEA. RESULTS: We identified germline pathogenic, likely pathogenic or uncertain significance variants in cancer susceptibility genes in 4 of 5 patients - affected genes included GLI1, PIK3R1, FOXP1, FANCD2, INPP4B and H3F3C. Notably, none of these genes were included in the commercially available germline testing panels initially used to evaluate the patients at the time of their diagnoses. CONCLUSION: Comprehensive germline testing of patients with concurrent LGEEA or CAH and ESC, HGSC or precursor lesions may aid in early identification of relatives at-risk for cancer who may be candidates for RRSO with hysterectomy.

Trends in ovarian, fallopian tube, and primary peritoneal cancer incidence, mortality, and survival: A 15-year population-based analysis.

OBJECTIVE: To characterize trends in ovarian, fallopian tube, and primary peritoneal cancer incidence and incidence-based mortality based on histology and site of origin. METHODS: We obtained age-adjusted incidence and incidence-based mortality for patients with ovarian, fallopian tube, and primary peritoneal cancer from 2000 to 2019 from the US SEER 17 database. Joinpoint 4.9.1.0 was used to characterize log-linear time trends. RESULTS: The incidence and incidence-based mortality of all cancers trended down during the study period. The incidence of epithelial cancers decreased from 2004 to 2019 (AAPC -1.2%, p < 0.001), including that of high-grade (2006-2019: APC -1.2%, p < 0.05) and low-grade (2003-2019: APC -2.4%, p < 0.05) epithelial cancers. There was no change in incidence or incidence-based mortality for ovarian stromal and germ cell cancers. CONCLUSION: There has been a decrease in the incidence and incidence-based mortality of ovarian, fallopian tube, and primary peritoneal cancer, primarily due to reductions in advanced stage epithelial cancers originating in the ovary, fallopian tube, or peritoneum.

The karyometric signature is altered in fallopian tubes with serous tubal intraepithelial carcinoma.

OBJECTIVE: Recent evidence suggests that the fimbriated end of the fallopian tube harbors the precursor cells for many high-grade ovarian cancers, opening the door for development of better screening methods that directly assess the fallopian tube in women at risk for malignancy. Previously we have shown that the karyometric signature is abnormal in the fallopian tube epithelium in women at hereditary risk of ovarian cancer. In this study, we sought to determine whether the karyometric signature in serous tubal intraepithelial carcinoma (STIC) is significantly different from normal, and whether an abnormal karyometric signature can be detected in histologically normal tubal epithelial cells adjacent to STIC lesions. METHODS: The karyometric signature was measured in epithelial cells from the proximal and fimbriated portion of the fallopian tube in fallopian tube specimens removed from women at: 1) average risk for ovarian cancer undergoing surgery for benign gynecologic indications (n = 37), 2) hereditary risk of ovarian cancer (germline BRCA alterations) undergoing risk-reducing surgery (n = 44), and 3) diagnosed with fimbrial STICs (n = 17). RESULTS: The karyometric signature in tubes with fimbrial STICs differed from that of tubes with benign histology. The degree of karyometric alteration increased with increasing proximity to fimbrial STICs, ranging from moderate in the proximal portion of the tube, to greatest in both normal appearing fimbrial cells near STICs as well as in fimbrial STIC lesions. CONCLUSION: These data demonstrate an abnormal karyometric signature in STICs that may extend beyond the STIC, potentially providing an opportunity for early detection of fallopian tube neoplasia.

Does the choice of platinum doublet matter? A study to evaluate the impact of platinum doublet choice for treatment of platinum-sensitive ovarian cancer recurrence on the development of future PARP inhibitor and platinum resistance.

OBJECTIVES: The use of a platinum doublet for the treatment of platinum-sensitive epithelial ovarian cancer (EOC) recurrence is well established. The impact of the non­platinum chemotherapy used as part of a platinum doublet on PARP inhibitor (PARPi) and platinum sensitivity it not known. We aimed to describe oncologic outcomes in cases of recurrent EOC receiving PARPi as maintenance therapy based on preceding platinum doublet. METHODS: Retrospective study of patients with platinum-sensitive recurrent ovarian, fallopian tube or primary peritoneal cancer treated with platinum doublet followed by maintenance PARPi from 1/1/2015 and 1/1/2022. Comparisons were made between patients receiving carboplatin + pegylated liposomal doxorubicin (CD) versus other platinum doublets (OPDs). Descriptive statistics, Kaplan-Meier and univariate survival analyses were performed. RESULTS: 100 patients received PARPi maintenance following a platinum doublet chemotherapy regimen for platinum-sensitive recurrence. 25/100 (25%) received CD and 75/100 (75%) received OPDs. Comparing CD and OPDs, median progression-free survival was 8 versus 7 months (p = 0.26), median time to platinum resistance was 15 versus 13 months (p = 0.54), median OS was 64 versus 90 months (p = 0.28), and median OS from starting PARPi was 25 versus 26 months (p = 0.90), respectively. CONCLUSIONS: Using pegylated liposomal doxorubicin as part of a platinum doublet preceding maintenance PARPi for platinum-sensitive recurrence does not seem to hasten PARPi resistance or platinum resistance compared to OPDs. Although there was a non-significant trend towards increased OS among patients who received a platinum doublet other than CD prior to PARPi, the OS from PARPi start was similar between groups. Given the retrospective nature of this study and small study population, further research is needed to evaluate if the choice of platinum doublet preceding PARPi maintenance impacts PARPi resistance, platinum resistance and survival.

Diagnosis and management of isolated serous tubal intraepithelial carcinoma: A qualitative focus group study.

OBJECTIVE: A Serous Tubal Intraepithelial Carcinoma (STIC) without concomitant invasive carcinoma is occasionally identified and associated with a high risk of subsequent peritoneal carcinomatosis. Management needs optimisation. This study explores professionals' opinions and clinical practices regarding the diagnosis, counselling, treatment and follow-up of isolated STIC to facilitate clinical decision making and optimise the direction of future research. A secondary aim is to assess international clinical guidelines. DESIGN: Focus group study. SETTING: Four online sessions. POPULATION: International panel (n = 12 countries) of gynaecologists, gynaecologic oncologists, pathologists and medical oncologists (n = 49). METHODS: A semi-structured interview guide was used. Two independent researchers analysed transcripts by open and axial coding. Results were organised in domains. Relevant (inter)national guidelines were screened for recommendations regarding isolated STIC. MAIN OUTCOME MEASURES: Professionals' opinions and clinical practices regarding isolated STIC management. RESULTS: Regarding pathology, most professionals identified the SEE-FIM protocol as standard of care for high-risk patients, whereas variation exists in the histopathological examination of fallopian tubes in the general population. Confirmation of STIC diagnosis by a specialised pathologist was recommended. Regarding work-up and follow-up after STIC diagnosis, there was variety and discordance. Data on outcomes is limited. As for treatment, chemotherapy and PARP inhibitors were not recommended by most. Eleven guidelines provided limited recommendations. CONCLUSIONS: We identified recommendations and highlighted knowledge gaps in the diagnosis and management of isolated STIC. Moreover, recommendations in clinical guidelines are limited. There is an agreed need for international collaboration for the prospective registration of isolated STIC.

Systematic review and network meta-analysis of hydrosalpinx treatment before in vitro fertilization.

OBJECTIVES: To compare different methods to treat hydrosalpinx, based on both ablative and non-ablative approaches, in infertile patients before undergoing IVF-ET. METHODS: Systematic review and network meta-analysis (NMA) of comparisons between different treatments of hydrosalpinx in infertile patients undergoing IVF. DATA SOURCES: structured searches in common citation databases. Study inclusion criteria: peer-reviewed randomized trials (RCT) or cohort studies comparing effects of salpingectomy, laparoscopic proximal tubal occlusion (LTO), insertion of intratubal device (ITD), sclerotherapy, ultrasound-guided aspiration and no treatment, on live birth, ongoing pregnancy, clinical pregnancy as main outcomes, considering also miscarriage, ectopic pregnancy and complications as secondary outcomes. Principal NMA included RCT, and aggregated NMA of RCT and observational studies was carried out. Pooled effects have been estimated by Odds Ratio (OR) and its 95% confidence interval (CI) for direct and indirect-mixed comparisons, derived from random-effects models. Imprecision and heterogeneity of NMA estimations was assessed by comparison of its 95% CI with predefined intervals for clinically relevant size of effect (OR <0.9 or >1.1). Surface under the cumulative ranking curve (SUCRA) were used to predict treatment rankings for each outcome. RESULTS: Nine RCT were included in main analysis, plus 17 additional observational studies in additional analysis. NMA of RCT did not identify significant differences in the effect of compared treatments on live birth rate, and LTO was the option with the highest value of SUCRA (0.92, mean rank: 1.2). Salpingectomy and US-aspiration associated to a significant increase of ongoing pregnancy rate compared to no treatment, according to NMA results (NMA OR: 4.35; 95% CI: 1.7, 11.14 and 2.8; 95% CI: 1.03, 7.58 respectively). Salpingectomy had the highest SUCRA value (0.88, mean rank: 1.4). NMA estimated significant increase of clinical pregnancy rate for salpingectomy compared with no treatment (NMA OR: 2.24; 95% CI: 1.3, 3.86) as well as for LTO versus no treatment (NMA OR: 2.55; 95% CI: 1.2, 5.41). Both comparisons were affected by a high grade of heterogeneity. For clinical pregnancy, LTO was the intervention with highest SUCRA (0.85; mean rank: 1.6). Regarding secondary outcomes, feasible NMA estimates did not support significant differences between treatments effects. According to aggregated NMA including randomized and observational studies, sclerotherapy showed significant beneficial effects on live birth rate compared to no treatment (NMA (OR: 4.6; 95% CI: 1.21, 17.46). Compared with untreated patients, the aggregated NMA estimates a higher ongoing pregnancy rate in patients treated with salpingectomy (NMA OR: 3.35; 95% CI: 2.12, 5.12), US-aspiration (NMA OR: 2.16; 95% CI: 1.28, 3.65) and LTO (NMA OR: 2.46; 95% CI: 1.11, 5.43). Salpingectomy and LTO produced a higher beneficial effect compared to ITD, based on both direct and indirect comparisons. Salpingectomy obtained the highest SUCRA value in rank of effects on ongoing pregnancy (0.94; mean rank: 1.2). NMA found significant effects on clinical pregnancy for comparisons between the different active management procedures compared with no treatments, with the exception of ITD insertion. LTO had more increasing effect on clinical pregnancy rate compared with US-aspiration (NMA OR: 2.04; 95% CI: 1.05, 3.97), while for the rest of the comparisons between procedures no significant differences were identified. NMA ranked LTO as the treatment with a highest SUCRA value (0.91; mean rank: 1.5). NMA prediction models identified LTO as best intervention to reduce miscarriage (SUCRA value: 0.84; mean rank: 1.8), as sclerotherapy as safer option in terms of ovarian response to IVF stimulation. CONCLUSIONS: The present NMA fails to support the effectiveness of any option to treat hydrosalpinx before IVF in order to improve live birth rates, although the beneficial effect of salpingectomy and US aspirations on ongoing pregnancy rates and of both salpingectomy and LTO on clinical pregnancy rates emerges from our analysis, which reinforces current recommendations. Based on the aggregated analyses, sclerotherapy could be a promising alternative to conventional laparoscopic techniques, combined with a favorable safety profile. This article is protected by copyright. All rights reserved.

Impact of gated FDG PET/CT on the staging of patients with suspected or proven newly diagnosed advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer: results from a non-randomized, phase II clinical trial.

OBJECTIVE: Imaging for staging ovarian cancer is important to determine the extent of disease. The primary objective of this study was to compare gated 18F-fluorodeoxyglucose positron emission tomography coupled with computed tomography (FDG PET/CT) and standard CT scan with intravenous contrast to diagnose thoracic involvement in patients with advanced ovarian cancer prior to treatment. The secondary objective was to estimate changes in the International Federation of Gynecology and Obstetrics (FIGO) stage and clinical management resulting from gated PET/CT. METHODS: The IMAGE trial is a non-randomized phase II clinical trial comparing standard CT scanning with gated PET/CT in diagnosing thoracic involvement in a non-selected group of patients with suspected ovarian cancer on a contrast CT scan. Three sets of PET images were obtained comprising an ungated 2 min whole body image, a static 7.5 min image of the upper abdomen and thorax, and a gated end-expiratory image over the upper abdomen and thorax. Images were evaluated for specificity, sensitivity, diagnostic accuracy, and the proportion of patients with changes in FIGO stage and subsequent clinical management was compared between imaging techniques. RESULTS: A total of 84 patients were enrolled based on a standard CT scan, 67 of whom were eligible for gated PET/CT scans. Diagnostic accuracy with gated PET/CT was more than 80% for lesions in lung, liver, extra-abdominal sites, and pleura, but less than 50% for extra-abdominal lymph nodes. Compared with CT scan at baseline, 46% of patients who had 7.5 min gated PET/CT had disease upstaged from stage III to IV, and 8% had disease downstaged from stage IV to III. However, this led to a change of management in only 5% of patients. CONCLUSIONS: Gated PET/CT enables upstaging; however, in our institution it altered clinical management only in a minority of patients. TRIAL REGISTRATION NUMBER: NCT02258165.

MIRRORS: a prospective cohort study assessing the feasibility of robotic interval debulking surgery for advanced-stage ovarian cancer.

OBJECTIVE: To establish the feasibility and safety of robotic interval debulking surgery following the MIRRORS protocol (robot-assisted laparoscopic assessment prior to robotic or open surgery) in women with advanced-stage ovarian cancer. MIRRORS is the first of three planned trials: MIRRORS, MIRRORS-RCT (pilot), and MIRRORS-RCT. METHODS: The participants were patients with stage IIIc-IVb epithelial ovarian cancer undergoing neo-adjuvant chemotherapy, suitable for interval debulking surgery with a pelvic mass ≤8 cm. The intervention was robot-assisted laparoscopic assessment prior to robotic or open interval debulking surgery (MIRRORS protocol). The primary outcome was feasibility of recruitment, and the secondary outcomes were quality of life (EORTC QLQC30/OV28, HADS questionnaires), pain, surgical complications, complete cytoreduction rate (%), conversion to open surgery (%), and overall and progression-free survival at 1 year. RESULTS: Overall, 95.8% (23/24) of patients who were eligible were recruited. Median age was 68 years (range 53-83). All patients had high grade serous histology and were BRCA negative. In total, 56.5% were stage IV, 43.5% were stage III, 87.0% had a partial response, while 13.0% had stable disease by RECIST 1.1. Median peritoneal cancer index was 24 (range 6-38). Following MIRRORS protocol, 87.0% (20/23) underwent robotic interval debulking surgery, and 13.0% (3/23) had open surgery. All patients achieved R<1 (robotic R0=47.4%, open R0=0%). No patients had conversion to open. Median estimated blood loss was 50 mL for robotic (range 20-500 mL), 2026 mL for open (range 2000-2800 mL) (p=0.001). Median intensive care length of stay was 0 days for robotic (range 0-8) and 3 days (range 3-13) for MIRRORS Open (p=0.012). The median length of stay was 1.5 days for robotic (range 1-17), 6 days for open (range 5-41) (p=0.012). The time to chemotherapy was as follows 18.5 days for robotic (range 13-28), 25 days for open (range 22-28) (p=0.139). CONCLUSIONS: Robotic interval debulking surgery appears safe and feasible for experienced robotic surgeons in patients with a pelvic mass ≤8 cm. A randomized controlled trial (MIRRORS-RCT) will determine whether MIRRORS protocol has non-inferior survival (overall and progression-free) compared with open interval debulking surgery.

Factors Influencing the Visualization of Fallopian Tubes in Hysterosalpingo-Contrast Sonography (HyCoSy)-The Value of Multimodal HyCoSy in Visualizing the Fallopian Tubes.

BACKGROUND: Four-dimensional hysterosalpingo-contrast sonography (4D-HyCoSy) can non-invasively evaluate the patency of the fallopian tubes and is increasingly used in clinical practice. However, some factors may lead to false-positive diagnoses. This study aims to analyze the factors affecting clear imaging of the fallopian tubes in 4D-HyCoSy and explore methods to improve the quality of fallopian tube imaging. METHODS: A total of 118 patients were enrolled in this retrospective study. After injecting the SonoVue into the uterine cavity, three modes of HyCoSy were completed in sequence: 4D-HyCoSy, 2D-HyCoSy, and second harmonic imaging (SHI). Participants were divided into two groups: the easy visualization group (fallopian tubes could be visualized using only 4D-HyCoSy) and the difficult visualization group (a multimodal combination was required for visualization). The position of the uterus, the relationship between the ovaries and the uterus, endometrial thickness, time of catheterization in the uterine cavity, presence or absence of lesions in the uterine cavity, whether intestinal gas covers the fallopian tubes and the imaging effect of different modes on the fallopian tubes was analyzed, to determine the key factors affecting the clear imaging of the fallopian tubes. RESULTS: The positional relationship between the ovary and the uterus (OR = 4.711, 95% CI: 1.322-19.77, P = 0.023), the positioning of the uterus (OR = 3.843, 95% CI: 1.129-15.26, P = 0.04), endometrial thickness (OR = 3.985, 95% CI: 1.168-15.99, P = 0.036), and the duration of intrauterine catheter placement (OR = 3.547, 95% CI: 1.042-13.52, P = 0.05) were independent factors that affecting difficulty in visualizing the fallopian tubes. CONCLUSION: Uterine position, the positional relationship between the ovary and the uterus, endometrial thickness, and the time of catheter insertion are factors that affect visualizing the fallopian tubes during 4D-HyCoSy. The combination of multimodal imaging, especially the combination of 4D-HyCoSy with SHI mode, can help improve the quality of fallopian tube visualization.

Oviductal motile cilia are essential for oocyte pickup but dispensable for sperm and embryo transport.

Mammalian oviducts play an essential role in female fertility by picking up ovulated oocytes and transporting and nurturing gametes (sperm/oocytes) and early embryos. However, the relative contributions to these functions from various cell types within the oviduct remain controversial. The oviduct in mice deficient in two microRNA (miRNA) clusters (miR-34b/c and miR-449) lacks cilia, thus allowing us to define the physiological role of oviductal motile cilia. Here, we report that the infundibulum without functional motile cilia failed to pick up the ovulated oocytes. In the absence of functional motile cilia, sperm could still reach the ampulla region, and early embryos managed to migrate to the uterus, but the efficiency was reduced. Further transcriptomic analyses revealed that the five messenger ribonucleic acids (mRNAs) encoded by miR-34b/c and miR-449 function to stabilize a large number of mRNAs involved in cilium organization and assembly and that Tubb4b was one of their target genes. Our data demonstrate that motile cilia in the infundibulum are essential for oocyte pickup and thus, female fertility, whereas motile cilia in other parts of the oviduct facilitate gamete and embryo transport but are not absolutely required for female fertility.

Primary fallopian tube cancer followed by primary breast cancer in RAD51C mutation carrier treated with niraparib as first line maintenance therapy: a case report.

Given the rarity of RAD51C mutations, the risk and treatment of metachronous breast cancer after the diagnosis of ovarian cancer in RAD51C mutation carriers is not clear, especially for those who have received PARPi treatment. We report the case of a 65-year-old woman diagnosed with stage IIIC high-grade serous primary fallopian tube cancer. The patient had no family history of breast or ovarian cancer. The patient received three cycles of neoadjuvant chemotherapy with paclitaxel and carboplatin and achieved a complete response. After interval debulking surgery, the patient received three cycles of adjuvant chemotherapy. Collection and extraction of saliva DNA for next-generation sequencing identified a RAD51C mutation c.838-2 A > G. The patient received niraparib as front-line maintenance treatment. After 36 months of niraparib treatment, the patient had grade II invasive ductal carcinoma of the left breast that was positive for estrogen receptor (90%) and Ki-67 (30%) and negative for progesterone receptor and human epidermal growth factor receptor 2. Computed tomography revealed the absence of distant metastases. Modified radical mastectomy and axillary lymph node dissection were then performed. The final pathological report of the breast showed a 1.8 cm Bloom-Richardson grade II invasive ductal carcinoma in the left breast with axillary lymph node metastasis (1/21). Finally, the breast cancer was stage IIA, pT1cN1M0. The metachronous breast cancer in this case may be the first report of second primary cancer in fallopian tube cancer patient harboring a RAD51C mutation during niraparib treatment. Further studies are required to determine optimal treatment.

Giving birth after fertility-sparing treatment for primary leiomyosarcoma of the fallopian tube.

Primary leiomyosarcoma of the fallopian tube (PLFT) is an extremely rare gynecological malignancy that has only been described in case reports. Fertility-sparing treatment for PLFT has not been reported previously. A 24-year-old nulligravida woman was diagnosed with stage IC1 PLFT in the right fallopian tube after experiencing right lower quadrant pain for 2 weeks. She underwent laparoscopic right salpingectomy to preserve fertility followed by adjuvant chemotherapy with gemcitabine/docetaxel. She subsequently became pregnant spontaneously, delivering a term baby 27 months after treatment. This appears to be the only report of the use of fertility-preserving treatment for PLFT. The success of the treatment provides valuable information on the preservation of fertility in young women with PLFT.

Colo-salpingeal fistula: a rare gynecologic manifestation of diverticular disease.

INTRODUCTION: Diverticulitis can be complicated by fistulas between the colon and neighboring structures, which predispose to significant morbidity and mortality. Fistulas involving the female urogenital tract often present with urogynecologic symptoms, such as vaginal discharge or recurrent urinary tract infections. While colo-vaginal fistulas, a more common variant, often present with vaginal flatulence, colo-salpingeal fistulas are exceedingly rare and have not been reported with this symptomatology. We describe a case of colo-saplingeal fistula presenting with vaginal flatulence, requiring multidisciplinary collaboration for diagnosis and management. CASE: A 63-year-old woman presented with vaginal flatulence in the setting of persistent diverticulitis. Computed tomography (CT) scan revealed sigmoid diverticulitis, a submucosal abscess abutting the uterus, and air within the endometrial cavity, raising suspicion for a colo-uterine fistula. Following transient symptomatic relief with medical management and antibiotics, recurrence of symptoms prompted surgical intervention. Laparoscopic exploration allowed diagnosis of the colo-salpingeal fistula. Sigmoid colectomy and left salpingo-oophorectomy were performed with a minimally invasive surgical approach, resulting in an uncomplicated recovery with remission of symptoms. DISCUSSION: This rare case highlights novel gynecologic symptoms for a colo-salpingeal fistula, contrasted with reported presentations through a comprehensive literature review. This case underscores the importance of recognizing gynecologic symptoms related to diverticular disease, which may be subtle, but provide important considerations for prognosis and treatment. A multidisciplinary approach to care from diagnosis through surgery allowed for successful recognition and minimally invasive treatment of this anomalous condition before further complications could arise. Ultimately, surgical approaches to diverticulitis-associated gynecologic fistulas should be individualized.

IFTT in children and adolescents-single-center experience and systematic review of literature.

PURPOSE: Isolated fallopian tube torsion (IFTT) is defined by rotation of the fallopian tube around itself without involving the ipsilateral ovary. It is a rare cause of acute lower abdominal pain in (adolescent) girls, but is commonly overlooked. Due to its rarity, literature is still scarce. Currently there is no generally accepted management and treatment. METHODS: A retrospective analysis of all IFTT cases treated in our institution was performed. In addition, a systematic literature research on pediatric IFTT was carried out on Medline/ PubMed database according to PRISMA principles using predefined search terms and inclusion criteria. Patient characteristics regarding age, clinical symptoms, diagnostic methods, treatment, and follow-up were analyzed. RESULTS: Three of our patients and fifty-nine reports totaling one hundred seventy girls were included in the analysis. Mean age was 13.0 years. Left tube was slightly more often affected (52.9%). Abdominal pain was present in 99.4% of cases accompanied with nausea in 57.1%. In only 16.4%, correct preoperative diagnosis was made. Salpingectomy was the most common treatment in 111 (66.9%) cases, 55 (33.1%) patients were treated with detorsion of the tube (organ-sparing management). Girls with symptoms longer than 1 day had a significant higher rate of salpingectomy (95% CI, P = 0.0323). CONCLUSION: When IFTT is suspected, emergency laparoscopy should be performed to possibly preserve future reproductive potential. In case of detorsion and reinstated blood supply, organ-preserving management should be performed with simultaneous addressment of concomitant pathology if possible. Sufficient long-term follow-up must be assured to get significant results to introduce guidelines for children and adolescents.

Dysregulation of TMEM16A impairs oviductal transport of embryos.

Ectopic pregnancy is an acute abdominalgia in obstetrics and gynecology, especially in fallopian tubal pregnancy. The ion channel protein transmembrane protein 16A (TMEM16A) is widely distributed in various tissues, even in the oviduct. In this study, we showed that TMEM16A was expressed in the human fallopian tube and was upregulated in patients with tubal pregnancy. By measuring isolated fallopian tube tissues, we found that TMEM16A was involved in regulating not only the contraction of muscle strips but also the beat frequency of cilia. In addition, pharmacological activation or inhibition of TMEM16A could lead to retention of embryos in oviducts. Moreover, the embryos in oviducts were delayed in development and some of them had malformations and deletions. The total number of embryos in the oviducts and uterus was significantly less than that of the control group. Furthermore, we detected changes in the level of m6A methylation, where the relevant writers and readers were reduced in tubal tissues from tubal pregnancies. In m6A mRNA methylation, writers catalyze the addition of methyl groups to cytosine residues and readers bind to the methyl groups and affect gene translation. In human fallopian tube epithelial cell line FTE187, we found that interference with methyltransferase 3 (METTL3) expression increased TMEM16A, suggesting that TMEM16A might be regulated by m6A methylation. In general, our study revealed a novel regulatory point for embryo transport and development, introducing a new role for the diagnosis and treatment of tubal pregnancy.NEW & NOTEWORTHY The ion channel protein TMEM16A is expressed in the epithelium and smooth muscle of the human fallopian tube and is upregulated in patients with tubal pregnancy. TMEM16A is involved in regulating the smooth muscle contraction and the cilia beating. Dysregulated TMEM16A may result in embryo retention in the oviduct and delayed early embryo development. Our study reveals a new regulatory point for embryo transport and development.