Efficacy of a Triticum vulgare Extract as a Treatment of Cervical Ectropion: A Prospective Observational Cohort Study.

OBJECTIVES: To assess the effectiveness of a topical treatment for cervical ectropion with vaginal ovules containing aqueous extract of Triticum vulgare. METHODS: Prospective observational cohort study conducted between November 2020 and November 2022 at the colposcopy clinics of 2 different hospitals. Sexually active patients with a colposcopic diagnosis of cervical ectropion, awaiting ablative procedure, were included in the study and prescribed medical therapy with vaginal T. vulgare ovules (group 1) or wait-and-see therapy (group 2). At both enrollment and 2-month follow-up, a symptomatologic evaluation recording the intensity of postcoital bleeding, leucorrhea, and dyspareunia was performed with a Visual Analog Scale (VAS) questionnaire, and a colposcopic examination was performed, calculating the size of the ectropion area. RESULTS: A total of 116 patients (58 in group 1 and 58 in group 2) were included. Topical treatment with vaginal ovules containing aqueous extract of T. vulgare for 2 months resulted in significant decrease of symptoms related to cervical ectropion and significant reduction of the size of the ectropion area. CONCLUSIONS: Our results support the efficacy of topical treatment with vaginal ovules containing aqueous extract of T. vulgare for symptomatic cervical ectropion; our study also suggests that expectant management, despite being widely practiced, seems to lead to a worsening of the natural history of ectropion.

Quality of life improvements in women with uterine fibroids treated with relugolix combination therapy during the LIBERTY long-term extension study: A descriptive subgroup analysis in women with anemia at baseline.

OBJECTIVE: To investigate the effects of 52 weeks of treatment with relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) on symptoms of uterine fibroids (UF) and quality of life (QoL) in women with heavy menstrual bleeding associated with UF and anemia (hemoglobin ≤10.5 g/dL) at baseline. METHODS: This post hoc analysis included women from the LIBERTY long-term extension study with anemia (hemoglobin concentration ≤10.5 g/dL) at pivotal study baseline and documented hemoglobin values at week 52 (anemia-evaluable population). Treatment responders: women achieving a menstrual blood loss volume of <80 mL and a ≥50% reduction over the last 35 days of treatment. Anemia responders were women achieving a hemoglobin increase of >2 g/dL from baseline to week 52. Least squares (LS) mean changes from baseline in uterine fibroid symptom (UFS)-QoL symptom severity, fatigue, and health-related QoL total (HR-QoL) and (sub)scale scores were calculated. RESULTS: In total, 115 women were included in the anemia-evaluable population. Of 39 anemia-evaluable women who received continuous treatment with relugolix combination therapy for 52 weeks, 34 (87.2%) met treatment responder criteria and 23 (59.0%) were anemia responders. LS mean hemoglobin concentration increased by 29.4% at week 52. LS mean UFS-QoL symptom severity and fatigue scores decreased by 38.5 and 31.9 points, respectively, and HR-QoL total score increased by 41.6 points. CONCLUSION: In women with UF and a high disease burden due to anemia, relugolix combination therapy substantially improved hemoglobin levels, decreased distress due to symptoms, especially fatigue, over 52 weeks.

Oocyte competence is comparable between progestin primed ovarian stimulation with Norethisterone acetate (NETA-PPOS) and GnRH-antagonist protocols: A matched case-control study in PGT-A cycles.

OBJECTIVE: To outline oocyte competence after progestin primed ovarian stimulation with Norethisterone acetate (NETA-PPOS) compared to conventional GnRH-antagonist protocol. STUDY DESIGN: Retrospective matched case-control study involving advanced-maternal-age women undergoing ICSI with PGT-A. 89 NETA-PPOS were matched with 178 control patients based on maternal age and ovarian reserve biomarkers. Both groups underwent recombinant-FSH OS with GnRH-agonist ovulation trigger and collected ≥1 MII. In the study group, NETA (10 mg/day) was administered orally starting from day2 of the menstrual cycle. Euploid blastocyst rate per cohort of metaphase-II oocytes (EBR per MII) was the primary outcome. All other embryological and clinical outcomes were reported. Gestational age, birthweight and length were also assessed. RESULTS: The EBR per MII was comparable among PPOS and control (13.9 % ± 19.3 % versus 13.3 % ± 17.9 %; the sample size allowed to exclude up to a 10 % difference). Blastocysts morphology and developmental rate were similar. No difference was reported for all clinical outcomes among the 61 and 107 vitrified-warmed euploid single blastocyst transfers respectively conducted. The cumulative live birth delivery rate per concluded cycles was also comparable (24.7 % versus 21.9 %). Neonatal outcomes were analogous. CONCLUSIONS: Oocyte competence after NETA-PPOS and standard OS is comparable. This evidence is reassuring and, because of its lower cost and possibly higher patients' compliance, supports PPOS administration whenever the patients are indicated to freeze-all (e.g., fertility preservation, PGT-A, oocyte donation). More data are required about follicle recruitment, oocyte yield, gestational and perinatal outcomes. Randomized-controlled-trials are advisable to confirm our evidence.

Surgical Conservative Management of a Retained Placenta after Angular Pregnancy, a Case Report and Literature Review.

Angular pregnancies are rare and difficult to diagnose. Evidence suggests they are associated with a higher risk of intrauterine growth restriction and abnormal third stage of labor due to a retained placenta. The lack of standardized AP diagnostic criteria impacts on their correct identification and makes the treatment of potential complications challenging. We present a case of the successful conservative surgical management of a retained placenta after a term AP also complicated by intrauterine growth restriction. Moreover, to identify the best evidence regarding AP diagnostic criteria and retained placenta therapeutic approaches, we have realized an expert literature review.

[The protocol of the Easy-Net prospective project to improve the appropriateness of caesarean section in Calabria Region.] / Il protocollo del progetto prospettico Easy-Net per migliorare l'appropriatezza del ricorso al taglio cesareo nella Regione Calabria.

Italy is one of the European Countries with the highest caesarean section (CS) rate and large regional and local variability. In 2021, Calabria Region ranked as the third Italian region for the highest CS rate (38.5%). Calabria Region has joined the "Easy-Net" network program of Ministry of Health (NET-2016-02364191) on the evaluation of audit & feedback (A&F) interventions (Easy-Net https://easy-net.info/). The Easy-Net project is coordinated by The Department of Epidemiology of the Lazio Regional Health Service, and led for the Calabria Region by the Pugliese-Ciaccio Hospital of Catanzaro, with the Italian Ministry of Health and the Italian National Institute of Health. This project aims to reduce CS rate in Calabria Region, through A&F strategy interventions to improve perinatal care quality and maternal and neonatal outcomes. The adopted multi-strategic approach involves the use of Robson's classification to improve the appropriateness of the CS indications, and the A&F activities to identify health professionals' training needs and offer training update. This article describes the protocol of the Easy-Net WP6 study, "Prospective audit and feedback approach: efficacy in improving healthcare practice and reducing the caesarean section rate" (NET-2016-02364191-6). The project is organized in five phases which envisage the pre-intervention data collection relating to indicators of interest and staff attitudes on CS indication and A&F strategy. The 12 months of A&F interventions will be followed by the post-intervention data collection and the evaluation of appropriateness indicators and determinants. A study aimed at women is also planned to detect opinions regarding the use of CS. The study protocol was approved by the Ethics Committee of the Pugliese Ciaccio Hospital.

LIBERTY randomized withdrawal study: relugolix combination therapy for heavy menstrual bleeding associated with uterine fibroids.

BACKGROUND: In the pivotal LIBERTY 1 and 2 trials and long-term extension study, once-daily relugolix combination therapy (40 mg relugolix, 1 mg estradiol, 0.5 mg norethindrone acetate) reduced menstrual blood loss volume and pain among women with uterine fibroids. Relugolix combination therapy was well tolerated with preservation of bone mineral density through 52 weeks. OBJECTIVE: This study aimed to report the 2-year relugolix combination therapy efficacy and safety results of the phase 3 LIBERTY randomized withdrawal study. STUDY DESIGN: Women with uterine fibroid-associated heavy menstrual bleeding who completed the 24-week LIBERTY 1 or 2 trials, followed by the 28-week long-term extension study (up to 52 weeks total treatment), and who met the responder criteria (menstrual blood loss volume <80 mL and ≥50% reduction from pivotal study baseline at week 48 [week 24 of long-term extension]) were randomized in a 1:1 ratio to either blinded treatment with relugolix combination therapy or placebo for 52 weeks (total treatment period, 104 weeks). For women who had a relapse of heavy menstrual bleeding during the study (menstrual blood loss volume ≥80 mL), open-label relugolix combination therapy was offered. The primary endpoint was the proportion of women who maintained menstrual blood loss volume <80 mL through week 76 (week 24 of randomized withdrawal study). Secondary endpoints included time to menstrual blood loss volume ≥80 mL, proportion of women who maintained a menstrual blood loss volume of <80 mL through week 104 (over the 52-week randomized treatment period), the proportion of women who achieved or maintained amenorrhea at week 76 at the end of treatment, and the change in Uterine Fibroid Symptom-Quality of Life Bleeding and Pelvic Discomfort Scale and symptom severity scores. Analyses were performed for the modified intent-to-treat population, including all randomized women who received ≥1 dose of the study drug. RESULTS: Of the 229 randomized women (relugolix combination therapy, n=115; placebo, n=114), 228 received the study drug and 175 (76.7%) completed the randomized withdrawal study. Through week 76, 78.4% of women on relugolix combination therapy maintained menstrual blood loss volume <80 mL vs 15.1% in the placebo group (difference, 63.4%; 95% confidence interval, 52.9%-73.9%; P<.0001). At week 104, 69.8% of women on relugolix combination therapy maintained menstrual blood loss volume <80 mL vs 11.8% in the placebo group (difference, 58.0%; 95% confidence interval, 47.0%-69.1%; P<.0001). Through week 104, 88.3% of women on placebo relapsed with heavy menstrual bleeding (median time to relapse, 5.9 weeks). Among the 89 women in the placebo group who relapsed and received open-label rescue treatment, 87 women responded to relugolix combination therapy with a menstrual blood loss volume <80 mL. The proportion of women who achieved or maintained amenorrhea were 57.4% vs 13.3% at week 76 (difference, 44.1%; 95% confidence interval, 33.10%-55.1%; P<.0001) and 58.3% vs 10.6% at week 104 (difference, 47.6%; 95% confidence interval, 37.0%-58.3%; nominal P<.0001) for relugolix combination therapy and the placebo group, respectively. Relugolix combination therapy was generally well tolerated; no new safety signals were identified, and the adverse event profile over the second year was consistent with that reported through the first year of treatment. Bone mineral density remained stable in women who received relugolix combination therapy from week 52 to week 104. In women continuously treated with relugolix combination therapy up to 2 years, bone mineral density was generally preserved. CONCLUSION: After 2 years of treatment with relugolix combination therapy, there was evidence of durability of the effect in maintaining low menstrual blood loss volume in women with symptomatic uterine fibroids. Most women had return of heavy menstrual bleeding and associated symptoms after treatment cessation, which improved upon retreatment with relugolix combination therapy. Relugolix combination therapy was well tolerated, the adverse event profile remained consistent, and the mean bone mineral density was generally preserved through 2 years of treatment.

Relugolix combination therapy in European women with symptomatic uterine fibroids: a subgroup analysis from the randomized phase 3 LIBERTY pivotal trials.

OBJECTIVE: In the 24-week, phase 3 LIBERTY 1 (L1) and LIBERTY 2 (L2) trials, relugolix combination therapy (relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0.5 mg)) reduced uterine fibroid (UF)-associated symptoms. This post hoc analysis assessed safety and efficacy of relugolix-CT in European women from L1/L2. METHODS: Premenopausal women (aged 18-50 years) with UF-associated heavy menstrual bleeding (HMB) were randomized 1:1:1 in L1 (N = 388) and L2 (N = 382) to relugolix-CT or placebo for 24 weeks, or delayed relugolix-CT (relugolix 40 mg then relugolix-CT; 12 weeks each). Primary endpoint: proportion of responders (menstrual blood loss (MBL) <80 mL and reduction of ≥50% from baseline MBL volume) over the last 35 days of treatment. Secondary endpoints: MBL volume, amenorrhea, UF-associated pain, symptom severity, distress related to bleeding and pelvic discomfort, health-related quality of life (HRQoL). Safety endpoints included adverse event (AE) reporting and bone mineral density (BMD) assessment. RESULTS: In European women from L1/L2 (N = 124, 16%), a significantly greater proportion of treatment responders was observed with relugolix-CT vs. placebo (85.4% vs. 19.1%, respectively; nominal p < .0001). There were statistically significant improvements with relugolix-CT vs. placebo for several secondary endpoints: reduction in MBL volume, amenorrhea rate, proportion achieving mild-to-no pain, reduction in symptom severity and distress from bleeding and pelvic discomfort, and improvement in HRQoL. Incidence of AEs and percentage changes in BMD from baseline to week 24 were similar for relugolix-CT and placebo. CONCLUSIONS: In European women with UF and HMB, once-daily relugolix-CT vs. placebo improved UF-associated symptoms and preserved BMD.

A plain language summary of the long-term relugolix combination therapy study for uterine fibroids.

What is this summary about? This is a summary of a research study (known as a clinical trial) called the LIBERTY extension study. The LIBERTY extension study is a long-term study looking at how well a medicine called relugolix combination therapy worked in reducing blood loss during menstrual periods in women with uterine fibroids with heavy menstrual periods. Women were included in the extension study if they finished the 24-week LIBERTY 1 or LIBERTY 2 studies. Heavy menstrual periods were considered to be menstrual blood loss of about one-third of a cup of blood (80 ml) per cycle for two cycles or about two-thirds of a cup of blood (160 ml) during one cycle. The LIBERTY extension study also looked at whether relugolix combination therapy was safe to take for up to 1 year. What were the results? Out of 770 total women with uterine fibroids with heavy menstrual bleeding who took part in the LIBERTY 1 and LIBERTY 2 studies, 476 took part in the LIBERTY extension study. From the start of the LIBERTY 1 and LIBERTY 2 studies through the end of the LIBERTY extension: 163 women took relugolix combination therapy for 52 weeks 149 women took relugolix alone for 12 weeks followed by relugolix combination therapy for 40 weeks 164 women took placebo for 24 weeks followed by relugolix combination therapy for 28 weeks The LIBERTY extension study showed that most women in all three treatment groups responded to relugolix combination therapy by having less bleeding during their menstrual periods, having improved anemia symptoms, and having stable bone mineral loss. Side effects were similar across treatment groups, and the most common side effects were headaches and hot flushes. What do the results mean? Women with uterine fibroids with heavy menstrual bleeding taking relugolix combination therapy may have fewer uterine fibroid bleeding symptoms for up to 1 year of treatment. Clinical Trial Registration: NCT03049735 (ClinicalTrials.gov) (LIBERTY 1) Clinical Trial Registration: NCT03103087 (ClinicalTrials.gov) (LIBERTY 2) Clinical Trial Registration: NCT03412890 (ClinicalTrials.gov) (LIBERTY extension study).

A plain language summary of the safety of relugolix combination therapy and improvement in symptoms in women with uterine fibroids from the LIBERTY 1 and LIBERTY 2 studies.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of research studies (known as clinical trials) called LIBERTY 1 and LIBERTY 2. The LIBERTY 1 and LIBERTY 2 studies looked at how well a medication called relugolix combination therapy worked to reduce heavy bleeding at the time of menstruation compared with placebo. The studies also looked at what side effects were reported in women with uterine fibroids and heavy menstrual bleeding. WHAT WERE THE RESULTS?: Researchers looked at 388 adult women in the LIBERTY 1 study and 382 adult women in the LIBERTY 2 study. All women had heavy menstrual bleeding with uterine fibroids before the start of the LIBERTY 1 and LIBERTY 2 studies. The women were given one of three treatments during the studies: relugolix combination therapy or placebo for 24 weeks, or delayed relugolix combination therapy (relugolix alone for the first 12 weeks, then relugolix combination therapy for the last 12 weeks of the studies). More women taking relugolix combination therapy in the LIBERTY 1 study (73%) and LIBERTY 2 study (71%) had menstrual blood loss of less than one-third of a cup (80 mL) and had reduction of at least 50% less blood loss during their last menstrual period after 24 weeks of taking the medicine compared with placebo (LIBERTY 1: 19% and LIBERTY 2: 15%). The women taking relugolix combination therapy also had less pain than those taking placebo. Side effects were similar across treatment groups. Headaches and hot flushes were the most common side effects. WHAT DO THE RESULTS MEAN?: More women with uterine fibroids taking relugolix combination therapy for 24 weeks were likely to have fewer uterine fibroid symptoms than women receiving placebo. Clinical Trial Registration: NCT03049735 (LIBERTY 1); NCT03103087 (LIBERTY 2).

[The EASY-NET research programme: background, structure, and methodology]. / Il programma di rete EASY-NET: razionale, struttura e metodologie.

This is the first contribution of a series of interventions describing the EASY-NET research program (Bando Ricerca Finalizzata 2016, funds 2014-2015; NET-2016-02364191). Here, the objective is to illustrate the background and the research question, the structure and organization, the methodologies and the expected results of the programme. The main theme is audit&feedback (A&F), a proven and widespread technique for improving the quality of health care. EASY-NET, funded by the Italian Ministry of Health and by the governments of the participating Italian Regions, starts its research activities in 2019 with the aim of evaluating the effectiveness of A&F in improving care for different clinical conditions in various organizational and legislative contexts. The research network involves seven Italian Regions, each conducting specific research activities described by as many work packages (WP): Lazio (the leading Region, coordinator of the research activities), Friuli Venezia Giulia, Piedmont, Lombardy, Emilia-Romagna, Calabria, and Sicily. The involved clinical areas include the management of chronic diseases, emergency care for acute conditions, surgery in the oncological area, the treatment of heart disease, obstetrics, and the use of caesarean section and post-acute rehabilitation. The involved settings concern the community, the hospital, the emergency room, and the rehabilitation facilities. Different experimental or quasi-experimental study designs are applied in each WP to achieve specific objectives of the specific clinical and organizational context. In all WPs, the process and outcome indicators are calculated on the basis of the Health Information Systems (HIS) and, in some cases, they are integrated with measures obtained from ad hoc data collections. The programme aims to contribute to the scientific evidence on A&F also exploring the obstacles and favourable factors for its effectiveness and to promote its implementation in the health service, with the ultimate aim of improving the access to healthcare and the health outcomes for citizens.

[Fifteen ways to optimize feedback.] / Quindici modi per ottimizzare il feedback.

This article proposes a series of insights that are drawn from the most up-to-date scientific literature and functional for an optimal implementation of Audit & Feedback (A&F). The focus is on the "feedback" component of the methodology. Some key issues of the feedback are the capability to address changes perceived as priorities for the recipients, recommend actions that bring real improvements, and allow the people to whom recommendations are addressed to manage them. Other suggestions concern how to share the data: it is important to provide feedback as soon as possible, multiple times, starting from individual rather than general data, and including comparisons able to promote the desired change. Other operational indications concern the most effective way to display the feedback, such as tightly linking the graphical representation and the summary message, presenting the feedback in multiple ways, and simplifying the message to minimize cognitive overload. Finally, some suggestions are about how to transmit feedback: tailor interventions according to the specific barriers of a given clinical-organizational context, provide short and easily understandable messages followed by more details, emphasize the credibility of information, increase motivation to change practice, and encourage participatory feedback construction rather than passive delivery. It also proposes an analysis of some of the challenges related to the design of A&F interventions translatable into improvements in practice starting from the context of the Easy-Net network program.

Quality of life with relugolix combination therapy for uterine fibroids: LIBERTY randomized trials.

BACKGROUND: Symptomatic uterine fibroids are burdensome to live with; they are associated with symptom-related distress, affect daily activities, and reduce health-related quality of life. The LIBERTY randomized clinical trials showed that oral relugolix combination therapy (40 mg relugolix, 1 mg estradiol, and 0.5 mg norethindrone acetate once daily) markedly improved fibroid-associated symptoms and conditions, including heavy menstrual bleeding, pain, and anemia, and was well-tolerated. OBJECTIVE: This study aimed to evaluate the effect of relugolix combination therapy on the symptom burden and health-related quality of life among women with uterine fibroids. STUDY DESIGN: Two replicate, multinational, double-blind, 24-week, randomized, placebo-controlled, phase 3 studies, LIBERTY 1 and LIBERTY 2, were conducted in premenopausal women with uterine fibroid-associated heavy menstrual bleeding (≥80 mL per cycle for 2 cycles or ≥160 mL during 1 cycle). The symptom burden and health-related quality of life were secondary endpoints and were assessed using the validated Uterine Fibroid Symptom and Quality of Life questionnaire, which the participants completed at baseline and at week 12 and 24 of treatment. For this secondary analysis, the pooled LIBERTY 1 and LIBERTY 2 data set was used. The Uterine Fibroid Symptom and Quality of Life questionnaire is made up of a Symptom Severity scale and a Health-Related Quality of Life scale, the latter of which includes 6 subscales focusing on the following aspects of daily life: concern, activities, energy or mood, control, self-consciousness, and sexual function. The Revised Activities subscale of the Health-Related Quality of Life scale addresses the impact of uterine fibroids on physical and social activities. Symptom burden was also assessed via the Bleeding and Pelvic Discomfort subscale, a patient-reported outcome measure derived from the Uterine Fibroid Symptom Severity scale that focuses on distress from key uterine fibroid symptoms, which was a key secondary endpoint. Least squares mean changes from baseline to week 24 in the Symptom Severity scale, Bleeding and Pelvic Discomfort subscale, overall Health-Related Quality of Life scale, and the respective subscales were compared between the relugolix combination therapy and placebo groups. Responder analyses of the proportion of women who experienced a clinically meaningful change from baseline to week 24 were conducted for the Bleeding and Pelvic Discomfort and the activity subscales. A stratified Cochran-Mantel-Haenszel test, adjusted for stratification factors (region [North America vs rest of world] and baseline menstrual blood loss volume), was used for treatment comparisons. RESULTS: Across both trials, 509 women were randomized to the relugolix combination therapy or placebo groups (April 2017-December 2018). Participants on relugolix combination therapy showed a statistically significant reduction in symptom severity (-33.5 vs -12.1; nominal P<.0001) and the Bleeding and Pelvic Discomfort subscale from baseline to week 24 when compared with those on placebo treatment (-48.4 vs -17.4; nominal P<.0001). Overall, the total Health-Related Quality of Life scores improved significantly from baseline to week 24 in the relugolix combination therapy group when compared with the placebo (+37.6 vs +13.1; nominal P<.0001). Responder analyses demonstrated that more women treated with relugolix combination therapy reported a clinically meaningful reduction in the Bleeding and Pelvic Discomfort subscale and an improvement in physical and social activities when compared with those treated with the placebo (nominal P<.0001). CONCLUSION: After 24 weeks of treatment with relugolix combination therapy, women with symptomatic uterine fibroids experienced substantial improvements in health-related quality of life with all subscales showing improvement, including emotional well-being, physical and social activities, and sexual function. In addition, women reported substantial reductions in the overall symptom burden and distress caused by key fibroid-associated symptoms.

[How to optimize Audit&Feedback: experience from the EASY-NET programme]. / Come rendere più efficace l'Audit&Feedback: riflessioni dal programma di rete EASY-NET.

This is the second of a series of papers dedicated to the EASY-NET research programme (NET-2016-02364191). The rationale, structure and methodologies are described in the previous contribution. Scientific literature demonstrated that Audit & Feedback (A&F) is an effective strategy for continuous quality improvement and its effectiveness varies considerably according to factors that are currently little known. Some recent publication pointed out, with the contribution of an international group of experts, 15 suggestions to optimize A&F and developed a tool to evaluate their application. This tool, called REFLECT-52, includes 52 items related to the 15 suggestions and organized into four categories relating to the "Nature of the desired action", to the "Nature of the data available for feedback", to the "Feedback Display" and to the "Intervention delivery". Then, the aim of this work was to evaluate the level of adherence of A&F interventions tested in EASY-NET to suggestions from the literature by using a slightly adapted version of the REFLECT-52 tool, in its original language. In EASY-NET, 14 A&F interventions with different characteristics and in different clinical and organizational contexts were tested in seven Italian regions, each of these was evaluated by the respective research groups. Overall, the level of adherence was high in three of the four categories analysed, with some difficulties reported regarding the nature of the data available for feedback. In fact, contrary to what the literature suggests, it was not possible to send repeated feedback for some interventions and, in some cases, the data available for feedback presented a delay longer than one year. In summary, this analysis has confirmed a high level of compliance of the interventions tested with the suggestions from the literature, but it has also allowed researchers to identify critical aspects that need to be addressed for the future development of these strategies.

Long-term Relugolix Combination Therapy for Symptomatic Uterine Leiomyomas.

OBJECTIVE: In the LIBERTY 1 and LIBERTY 2 placebo-controlled trials, once-daily relugolix combination therapy reduced menstrual blood loss volume and pain in women with heavy menstrual bleeding associated with uterine leiomyomas and was well tolerated, with preservation of bone mineral density (BMD) through 24 weeks. Here we report the long-term efficacy and safety of relugolix combination therapy treatment for up to 52 weeks. METHODS: Women with uterine leiomyoma-associated heavy menstrual bleeding who completed any treatment arm in either the LIBERTY 1 or LIBERTY 2 trial were eligible to enroll in a 28-week long-term extension study. All participants received once-daily relugolix combination therapy (40 mg relugolix, estradiol 1 mg, norethindrone acetate 0.5 mg) in the extension study. The primary efficacy endpoint was the proportion of women who achieved or maintained a menstrual blood loss volume of less than 80 mL and a 50% or greater reduction in menstrual blood loss volume from LIBERTY study baseline to the last 35 days of treatment (defined as responders ). Analyses were conducted for all three randomized treatment groups from pivotal studies. RESULTS: Overall, 477 women enrolled, 476 were treated, and 363 (76.1%) completed 52 weeks. Among patients treated with relugolix combination therapy through 52 weeks (n=163), sustained improvement in heavy menstrual bleeding was observed in 87.7% (responders). The least squares mean menstrual blood loss volume reduction was 89.9%, with 70.6% of patients achieving amenorrhea. At week 52, 59.0% of patients with anemia at baseline had improvements in hemoglobin concentration of greater than 2 g/dL. Distress due to uterine leiomyoma-associated symptoms measured by the BPD (Bleeding and Pelvic Discomfort) scale score was reduced by 51.3 points. Sustained reductions in uterine and uterine leiomyoma volume were observed. Bone mineral density was preserved through week 52. CONCLUSION: Improvements in heavy menstrual bleeding and anemia and reduction of uterine leiomyoma-associated symptom burden were sustained through up to 52 weeks of treatment with relugolix combination therapy in women with uterine leiomyomas. No new safety concerns were identified, and BMD was maintained. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT03049735; NCT03103087; NCT03412890. FUNDING SOURCE: Myovant Sciences GmbH.

Prasterone in the treatment of mild to moderate urge incontinence: an observational study.

OBJECTIVE: To assess the effects of prasterone compared with hyaluronic acid on symptoms of mild to moderate urinary urgency in women with genitourinary syndrome of menopause. METHODS: This is an observational prospective cohort study. A total of 58 postmenopausal women were enrolled (from December 2019 to May 2021). Overactive Bladder Screener questionnaire, Patient Global Impression of Improvement questionnaire, International Consultation on Incontinence Questionnaire-Short Form, and International Quality of Life questionnaire were used. RESULTS: Fifty-eight women, 29 (50%) and 29 (50%), were treated with prasterone and hyaluronic acid for 12 weeks, respectively. At the end of the study, 26 (89.7%) versus 3 (10.3%) women reported an improvement (Patient Global Impression of Improvement score ≤3) of the symptoms in the prasterone versus hyaluronic acid group. According to the International Consultation on Incontinence Questionnaire-Short Form, no statistically significant difference was recorded before treatment between the prasterone and hyaluronic acid groups (median, 12 [6-12] vs 11 [8-12]; P = 0.8). Conversely, a statistically significant difference was recorded after treatment between the two groups (median, 8 [5-11] vs 10 [8-11]; P = 0.03). According to the International Quality of Life, a statistically significantly lower median score was recorded in the prasterone compared with the hyaluronic acid group, before (73 [interquartile range {IQR}, 55-81] vs 89 [IQR, 67-94]; P < 0.01) and after (78 [IQR, 65-86] vs 87 [IQR, 72-99]; P = 0.04) treatment. CONCLUSIONS: The current observational study supports the hypothesis that prasterone might improve the severity of urinary urge incontinence in this set of women. However, these results need to be confirmed in further studies with a controlled design and a larger population.

Relugolix Combination Therapy for Uterine Leiomyoma-Associated Pain in the LIBERTY Randomized Trials.

OBJECTIVE: To assess the effect of once-daily relugolix combination therapy (relugolix-CT: relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg) compared with placebo on moderate-to-severe pain in women with uterine leiomyomas and heavy menstrual bleeding. METHODS: Two replicate, multinational, double-blind, 24-week, randomized, phase 3 studies (LIBERTY 1 and 2) were conducted in premenopausal women with uterine leiomyoma-associated heavy menstrual bleeding (80 mL or greater per cycle for two cycles or 160 mL or greater during one cycle). A predefined secondary objective was to determine the effect of relugolix-CT on moderate-to-severe uterine leiomyoma-associated pain in the pain subpopulation (women with maximum pain scores of 4 or higher on the 0-10 numerical rating scale at baseline, with pain score reporting compliance of 80% (ie, 28 days or more over the last 35 days of treatment). This key secondary endpoint was defined as the proportion of women achieving minimal-to-no uterine leiomyoma-associated pain (maximum numerical rating scale score 1 or lower) at week 24; menstrual and nonmenstrual pain were evaluated in prespecified secondary analyses. Treatment comparisons were performed in the pooled LIBERTY 1 and 2 pain subpopulation using the Cochran-Mantel-Haenszel test stratified by baseline menstrual blood loss volume. RESULTS: Across both trials, 509 women were randomized to relugolix-CT or placebo (April 2017-December 2018). Of these, 277 (54.4%) met pain subpopulation requirements. With relugolix-CT, 45.2% (95% CI 36.4-54.3) of women achieved minimal-to-no pain compared with 13.9% (95% CI 8.8-20.5) with placebo (nominal P<.001). The proportions of women with minimal-to-no pain during menstrual days and during nonmenstrual days were significantly higher with relugolix-CT (65.0% [95% CI 55.6-73.5] and 44.6% [95% CI 32.3-57.5], respectively) compared with placebo (19.3% [95% CI 13.2-26.7], nominal P<.001, and 21.6% [95% CI 12.9-32.7], nominal P=.004, respectively). CONCLUSION: Over 24 weeks, relugolix-CT significantly reduced moderate-to-severe uterine leiomyoma-associated pain with a more pronounced effect on menstrual pain. These data support that relugolix-CT had clinically meaningful effects on women's experience of uterine leiomyoma-associated pain. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: LIBERTY 1, NCT03049735; LIBERTY 2, NCT03103087. FUNDING SOURCE: Myovant Sciences GmbH.

Successful Vaginal Delivery after Induction of Labour in a Patient Treated for Non-Hodgkin's Lymphoma of the Cervix: A Case Report and Literature Review.

OBJECTIVE: Primary non-Hodgkin's lymphomas of the cervix are rare; they represent about 1% of all cases. There are no available guidelines regarding the safest mode of delivery after treatment and resolution of a cervical lymphoma. Case Report. We report the first case of a successful vaginal delivery after induction of labour in a woman recovered from a primary large B-cell lymphoma of the cervix and a literature review. CONCLUSION: In carefully selected patients with fully treated non-Hodgkin's lymphoma of the cervix with no residual disease, induction of labour via prostaglandins pessary may be a safe option if indicated.

Maternal and perinatal complications according to maternal age: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the risk levels for maternal and perinatal complications at > 40, > 45 and > 50 years old compared with younger controls. METHODS: Electronic databases were searched from their inception until March 2021. We included studies reporting pregnancy outcome in pregnant women aged 40, 45, and 50 years or older compared with controls at the time of delivery. Case reports and case series were excluded. The primary outcome was the incidence of stillbirth. Meta-analysis was performed using the random effects model of DerSimonian and Laird, to produce summary treatment effects in terms of relative risk (RR) with 95% confidence interval (CI). Heterogeneity was measured using I2 (Higgins I2 ). Subgroup analyses in women older than 45 years and in those older than 50 years were performed. RESULTS: Twenty-seven studies, including 31 090 631 women, were included in the meta-analysis. The overall quality of the included studies was moderate to high. Most of the included studies were retrospective cohort studies (21/27), four were population-based studies, and two were cross-sectional studies. Women aged ≥40 years had significantly higher risk of stillbirth (RR 2.16, 95% CI 1.86-2.51), perinatal mortality, intrauterine growth restriction, neonatal death, admission to neonatal intensive care unit, pre-eclampsia, preterm delivery, cesarean delivery, and maternal mortality compared with women younger than 40 years old (RR 3.18, 95% CI 1.68-5.98). The increased risks for maternal mortality were 42.76 and 11.60 for women older than 50 years and for those older than 45 years, respectively, whereas those for stillbirth were 3.72 and 2.32. The risk of stillbirth and cesarean delivery was significantly higher in women >45 years compared with those aged 40-45 years, and in those aged >50 years compared with those aged 45-50 years. The risk of maternal mortality was significantly higher in women aged >50 years compared with those aged 40-45 (RR 60.40, 95% CI 13.28-274.74). CONCLUSION: The risk of stillbirth, cesarean delivery, and maternal mortality increases with advancing maternal age. The risk ratios for maternal mortality were 3.18, 11.60, and 42.76 in women older than 40, older than 45, and older than 50 years, respectively. These data should be used when women with advanced maternal age are counseled regarding their risk in pregnancy. SYSTEMATIC REVIEW REGISTRATION: The review was registered with the PROSPERO International Prospective Register of Systematic Reviews (registration No.: CRD42020208788).

Awareness of gestational diabetes mellitus foetal-maternal risks: an Italian cohort study on pregnant women.

BACKGROUND: Gestational diabetes mellitus (GDM) incidence is increasing worldwide. It represents a major risk factor for adverse foetal-maternal outcomes. Awareness among women in regard to GDM-related risks (in particular foetus ones) has been proven to have an impact on compliance with recommendations. Therefore we aimed to evaluate the efficacy of our post-diagnosis counselling, that informs affected women of the GDM related risks for complications, in determining an adequate level of understanding. METHOD: This is a cohort study involving 400 women undergoing the 24-28 weeks 75 g oral glucose tolerance test. Two hundred women diagnosed with GDM received the post-diagnosis counselling (treatment group) and two hundred women diagnosed without did not receive any counselling (control group). Both populations were surveyed with a 5 question questionnaire regarding their awareness about GDM foetal-maternal related risks. Their level of education about GDM foetal-maternal related risks, estimated according to the number of correct answers, was scored as: primary (score 0-1), secondary (score 2-3) or tertiary (score 4-5). RESULTS: Most of the women in the treatment group after receiving the post-diagnosis counselling have demonstrated a secondary level of education 132/200 (66%). Their mean level of awareness was higher in comparison to the control group 2.6 ± 1.8 (SD) versus 2.14 ± 1.8 (SD) p value = 0.012. In particular, they've demonstrated to be more aware of the risks for the foetus to become macrosomic (p = 0.004) or to die in utero (p = 0.0001). A high level of education and to have had previous pregnancies positively affected correct answers. CONCLUSIONS: Our post-diagnosis counselling has played a role in improving women awareness about GDM foetal-maternal related risks. Future study will explore the impact of women's level of awareness on glycaemic control.

Incidental diagnosis of a pancreatic adenocarcinoma in a woman affected by gestational diabetes mellitus: case report and literature review.

Pancreatic cancer is rarely diagnosed during pregnancy; it usually manifests with symptoms such as epigastric pain, vomiting, weight loss, and jaundice, rarely mimicking the hemolysis, elevated liver enzymes, and low platelet count syndrome. It has been postulated that there exists a correlation between the diagnosis of gestational diabetes mellitus and the occurrence of pancreatic cancer later in life. We conducted an expert literature review of the 31 available documented pancreatic cancer cases that were diagnosed during pregnancy. We also report pancreatic adenocarcinoma incidentally suspected in an asymptomatic woman affected by gestational diabetes mellitus; the woman was undergoing a fetal growth scan.