Management of Uterine Fibroids and Sarcomas: The Palermo Position Paper.

BACKGROUND: Uterine fibroids are benign monoclonal tumors originating from the smooth muscle cells of the myometrium, constituting the most prevalent pathology within the female genital tract. Uterine sarcomas, although rare, still represent a diagnostic challenge and should be managed in centers with adequate expertise in gynecological oncology. OBJECTIVES: This article is aimed to summarize and discuss cutting-edge elements about the diagnosis and management of uterine fibroids and sarcomas. METHODS: This paper is a report of the lectures presented in an expert meeting about uterine fibroids and sarcomas held in Palermo in February 2023. OUTCOME: Overall, the combination of novel molecular pathways may help combine biomarkers and expert ultrasound for the differential diagnosis of uterine fibroids and sarcomas. On the one hand, molecular and cellular maps of uterine fibroids and matched myometrium may enhance our understanding of tumor development compared to histologic analysis and whole tissue transcriptomics, and support the development of minimally invasive treatment strategies; on the other hand, ultrasound imaging allows in most of the cases a proper mapping the fibroids and to differentiate between benign and malignant lesions, which need appropriate management. CONCLUSIONS AND OUTLOOK: The choice of uterine fibroid management, including pharmacological approaches, surgical treatment, or other strategies, such as high-intensity focused ultrasound (HIFU), should be carefully considered, taking into account the characteristics of the patient and reproductive prognosis.

Cornual Pregnancy: Results of a Single-Center Retrospective Experience and Systematic Review on Reproductive Outcomes.

Background and Objectives: Cornual pregnancies (CPs) are rare forms of ectopic pregnancy. When abortion does not occur, it can be a life-threatening condition for the mother and can also impair future fertility. We present our experience in the diagnosis and management of CPs. A systematic review was also conducted to investigate the reproductive outcomes after treatment. Materials and Methods: Between January 2010 and December 2022, we performed a retrospective, cross-sectional, single-center, and descriptive data collection and analysis (ClinicalTrial ID: NCT06165770). The search for suitable articles published in English was carried out using the following databases (PROSPERO ID: CRD42023484909): MEDLINE, EMBASE, Global Health, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Cochrane Methodology Register), Health Technology Assessment Database, Web of Science, and search register such as ClinicalTrial. Only studies describing the impact of CP treatment on fertility were selected. Results: Two studies were included in the systematic review. Seventeen patients suffering from CPs were selected. In our series, a pelvic ultrasound allowed for the diagnosis of a cornual localization in 35.30% of cases. Thirteen women (76.47%) underwent immediate surgical management. The laparoscopic approach was the most used (76.92%), with a laparotomic conversion rate of 30%. Four patients (23.52%) received medical treatment with methotrexate. After treatment, two patients managed to achieve pregnancy. Conclusions: CP is a rare form of ectopic pregnancy that can quickly become life-threatening for the mother. Ultrasound does not lead to a precise diagnosis in all cases. In the absence of complications and emergencies, laparoscopy is an approach that could be considered valid. For selected asymptomatic patients, medical treatment may be a valid alternative. The data from the studies included in the systematic review, although demonstrating a superiority of medical treatment in terms of future pregnancies, are heterogeneous and do not allow us to reach a definitive conclusion.

A review of phase II and III drugs for the treatment and management of endometriosis.

INTRODUCTION: Endometriosis is an estrogen-dependent disease that gives rise to pelvic pain and infertility. Although estroprogestins and progestins currently stand as the first-line treatments for this condition, demonstrating efficacy in two-thirds of patients, a significant portion of individuals experience only partial relief or symptom recurrence following the cessation of these therapies. The coexistence of superficial, deep endometriosis, and ovarian endometriomas, as three distinct phenotypes with unique pathogenetic and molecular characteristics, may elucidate the current heterogeneous biological response to available therapy. AREAS COVERED: The objective of this review is to furnish the reader with a comprehensive summary pertaining to phase II-III hormonal treatments for endometriosis. EXPERT OPINION: Ongoing research endeavors are directed toward the development of novel hormonal options for this benign yet debilitating disease. Among them, oral GnRH antagonists emerge as a noteworthy option, furnishing rapid therapeutic onset without an initial flare-up; these drugs facilitate partial or complete estrogen suppression, and promote prompt ovarian function recovery upon discontinuation, effectively surmounting the limitations associated with previously employed GnRH agonists. Limited evidence supports the use of selective estrogen and progesterone receptor modulators. Consequently, further extensive clinical research is imperative to garner a more profound understanding of innovative targets for novel hormonal options.

Tailoring radicality in diaphragmatic surgery for deep endometriosis: A matter of choice.

Diaphragmatic endometriosis (DpE) is a rare disease localization which represents an important clinical challenge. The main criticisms toward the proper DpE management consist of poor consensus on both surgical indications and the choice between different surgical techniques available to treat the disease. Furthermore, only weak recommendations are provided by current guidelines and surgical management is mostly based on surgeon's experience. As consequence, the lack of standardization about the surgical treatment led to the risk of under- or over-treatments in patients suffering from this form of endometriosis. The latest evidence-based data suggest to adopt a lesion-oriented surgical approach serving as a guide in daily surgical activities, in order to ensure a tailored radicality and reduce the rate of surgery-related complications. Diaphragmatic endometriosis surgery should be performed only by expert surgeons with an extensive oncogynecologic expertise since it represents a technically demanding procedure. A multidisciplinary approach is also mandatory in order to adequately select and treat these patients by minimizing the risk of additional morbidity.

Experimental and new investigational drugs for the treatment of uterine fibroids.

INTRODUCTION: Uterine fibroids, the most prevalent benign tumors among reproductive-age women, pose treatment challenges that range from surgical interventions to medical therapies for symptom control. Progestins and estroprogestins effectively manage uterine bleeding by suppressing dysfunctional endometrium over fibroids. While GnRH agonists represent a crucial milestone in symptom treatment, their prolonged use results in menopausal-like symptoms and irreversible bone mineral density loss. Advancements in understanding fibroid pathophysiology have prompted the exploration of new compounds to overcome current therapy limitations. AREAS COVERED: This manuscript offers an updated overview of investigational drugs for symptomatic uterine fibroids. EXPERT OPINION: Despite ulipristal acetate's well-established efficacy as a selective progesterone receptor modulator (SPRM) in fibroid treatment, its prescription has declined due to the rare but severe risk of liver damage. Oral GnRH antagonists, like elagolix, relugolix, and linzagolix, with their novel pharmacodynamic properties, are gaining traction in fibroid management, inducing a dose-dependent reduction in circulating sex hormone levels. Ongoing research on natural compounds, such as vitamin D and epigallocatechin gallate (EGCG), presents emerging options for treating uterine fibroids. This evolving landscape reflects the ongoing efforts to improve therapeutic outcomes for individuals with symptomatic uterine fibroids.

Impact of surgery for endometriosis on the outcomes of in vitro fertilization.

This narrative review aims to summarize available evidence on the IVF-associated outcomes after surgery for endometriosis. Only one retrospective study investigated if surgical treatment of superficial/peritoneal endometriosis may modify the outcomes of IVF; therefore, more data are needed to confirm the benefit of surgery for this type of disease for improving ART outcomes, and to be able to support it in routine practice. Solid evidence from several meta-analyses demonstrates that surgical treatment of endometriomas does not enhance the outcomes of IVF. In contrast, surgical treatment of ovarian endometriosis may lead to a reduction in ovarian reserve, especially in cases involving bilateral endometriomas or repeated surgical procedures. Some non-randomized studies have examined if surgical treatment on deep endometriosis may influence IVF outcomes. A systematic review with meta-analysis revealed that patients who underwent surgery before IVF exhibited significantly higher pregnancy rates per patient, pregnancy rates per cycle, and live birth rates per patient compared to those without prior surgery. However, the available data are insufficient to recommend surgical excision of deep endometriosis as the first-line treatment for asymptomatic patients to enhance IVF outcomes.

A postoperative tumor-specific death prediction model for patients with endometrial cancer: a retrospective study.

Background: Endometrial cancer (EC) is an epithelial malignancy occurring in the endometrium, with a 5-year mortality rate of above 10%. However, there is currently a lack of studies exploring the potential of a predictive model of tumor-specific death after surgery in these patients. Methods: From January 2015 to December 2017, data related to 482 patients with EC admitted to the Dushu Lake Hospital Affiliated to Soochow University were analyzed. Patients were divided into death (n=62) and survival (n=420) groups according to whether tumor-specific death occurred at 5 years postoperatively or not. The clinical characteristics of the two groups were compared, and the risk factors for tumor-specific death in patients with EC 5 years after surgery were investigated by logistics regression analysis. A nomogram prediction model was established according to the relevant risk factors. Results: Tumor size, Ki-67 positive rate, Federation International of Gynecology and Obstetrics (FIGO) stage, and the rate of vascular tumor thrombus between the two groups (P<0.05) were found to be the statistically significant factors. Positive Ki-67, tumor size >3.35 cm, stage III, and vascular tumor thrombus were factors that influenced the tumor-specific death at 5 years after surgery (P<0.05). The predictive model obtained an area under the receiver operating characteristic (ROC) curves in the training and verification sets of 0.847 [95% confidence interval (CI): 0.779-0.916] and 0.886 (95% CI: 0.803-0.969), respectively. Conclusions: The nomogram prediction model, which was established in this study, was proved to be valuable in predicting tumor-specific death 5 years after the surgery in patients with EC.

Incretin Hormone Secretion in Women with Polycystic Ovary Syndrome: Roles of Obesity, Insulin Sensitivity and Treatment with Metformin and GLP-1s.

BACKGROUND: The purpose of this narrative review is to describe the mechanisms that are responsible for the development of infertility and PCOS, with a focus on the role of obesity, insulin sensitivity and treatment with metformin and GLP-1s. METHODS: The relevant publications were identified after systematic queries of the following sources: PubMed, Google Scholar, Web of Science, and publishers' databases, complemented by a cross-check of the reference lists. We used a combination of the search terms "polycystic ovary syndrome", "obesity" and "insulin resistance" with "metformin", "exenatide", "liraglutide", "semaglutide", "orlistat" and terms relevant to the topic of each paragraph (e.g., "pathophysiology", "metabolism", "infertility", "treatment"). RESULTS: All articles describing the mechanisms responsible for the development of infertility and PCOS, with a focus on the role of obesity, insulin sensitivity and treatment with metformin and GLP-1s, were considered for this review. CONCLUSIONS: The existing research on GLP-1 receptor agonists (GLP-1RAs) has not conclusively established a specific therapeutic use for these drugs. Additionally, the efficacy of the newer generation of GLP-1RAs, particularly in terms of dosage and duration of exposure, warrants more extensive research. Understanding the optimal dosing and treatment duration could significantly enhance the therapeutic use of GLP-1RAs in managing PCOS and its associated conditions.

Endometrioma surgery: Hit with your best shot (But know when to stop).

Ovarian endometriomas (OEs) are commonly detected by ultrasound in individuals affected by endometriosis. Although surgery was widely regarded in the past as the gold standard for treating OEs, especially in the case of large cysts, the surgical management of OEs remains debated. Firstly, OEs often represent the "tip of the iceberg" of underlying deep endometriosis, and this should be considered when treating OEs to ameliorate patients' pain for focusing on the surgical objectives and providing better patient counseling. In the context of fertility care, OEs may have a detrimental effect on ovarian reserve through structural alterations, inflammatory responses, and oocyte reserve depletion. Conversely, the surgical approach may exacerbate the decline within the same ovarian reserve. While evidence suggests no improvement in in-vitro fertilization (IVF) outcomes following OE surgery, further studies are needed to understand the impact of OE surgery on spontaneous fertility. Therefore, optimal management of OEs is based on individual patient and fertility characteristics such as the woman's age, length of infertility, results of ovarian reserve tests, and surgical background. Among the available surgical approaches, cystectomy appears advantageous in terms of reduced recurrence rates, and traditionally, bipolar coagulation has been used to achieve hemostasis following this approach. Driven by concerns about the negative impact on ovarian reserve, alternative methods to obtain hemostasis include suturing the cyst bed, and novel methodologies such as CO2 laser and plasma energy have emerged as viable surgical options for OEs. In instances where sonographic OE features are non-reassuring, surgery should be contemplated to obtain tissue for histological diagnosis and rule out eventual ovarian malignancy.

Perception about benefits and risks related to combined hormonal contraceptives use in women with Lynch syndrome.

OBJECTIVE: Lynch syndrome (LS) is a hereditary condition associated with an increased risk of colorectal and endometrial cancer. This study aimed to assess the knowledge, attitudes, and beliefs of women with LS regarding combined hormonal contraceptive (CHC) use compared to a control group of healthy women. METHODS: Pre-menopausal women with LS (n = 43) and an age-matched control group of healthy women (n = 128) participated in this prospective, cross-sectional study (NCT05909410). Participants completed an electronic questionnaire evaluating perceptions of CHC use and its impact on various cancers, medical conditions, and symptoms. Statistical analysis compared responses between the two groups, with reported p-values. RESULTS: Women with LS were less likely to use CHCs compared to the control group (p = 0.03) and had a more negative perception of CHCs' impact on colorectal cancer (p = 0.023) and endometrial cancer (p = 0.028). Limited knowledge was observed in both groups regarding the protective effects of CHCs against colorectal and ovarian cancer. Perceptions of CHC use and its impact on symptoms and chronic diseases did not significantly differ between the groups (p > 0.05). CHC use was not associated with greater awareness of the protective effect against colorectal (p = 0.89) and endometrial cancer (p = 0.47), but it was associated with a desire for contraception (OR 21.25; 95% CI 1.16 to 388.21; p = 0.039). CONCLUSION: This study highlights contrasting perceptions of CHCs and their implications in oncology between women with LS and healthy women. Tailored counselling and support strategies are crucial for empowering women with LS to make informed decisions about their gynaecologic health.

This study illuminates divergent perceptions of combined hormonal contraceptives and their oncological implications between women with Lynch syndrome and healthy women.Tailored counseling and supportive strategies are essential for empowering women with Lynch syndrome to make informed decisions regarding their gynecologic health.

Frozen Section of Placental Membranes and Umbilical Cord: A Valid Diagnostic Tool for Early-Onset Neonatal Sepsis Management.

Early-onset neonatal sepsis (EONS), a serious infection in newborns within 3 days, is challenging to diagnose. The current methods often lack accuracy, leading to unnecessary antibiotics or delayed treatment. This study investigates the role of the frozen section examination of placental membranes and umbilical cord (FSMU) to improve EONS diagnosis in the daily lab practice. This retrospective study reviewed data from 59 neonates with EONS risk factors who underwent FSMU according to our institutional protocol. Concordance between the FSMU and the Final Pathological Report (FPR) was assessed. The FSMU demonstrated a high concordance (Kappa = 0.88) for funisitis diagnosis, with excellent accuracy (98.3%). A moderate concordance was observed for chorioamnionitis stage and grade. The FSMU shows promise as a rapid and accurate tool for diagnosing EONS, particularly for funisitis. This study suggests that the FSMU could be a valuable tool for EONS diagnosis, enabling a more judicious antibiotic use and potentially improving outcomes for newborns.

Ultrasonographic characterization of parametrial endometriosis: a prospective study.

OBJECTIVE: To study the ultrasonographic diagnostic accuracy and characteristics of parametrial endometriosis comprehensively. DESIGN: This prospective study enrolled patients with suspected deep endometriosis (DE) scheduled for laparoscopic surgical treatment. Preoperative ultrasonographic examinations were performed following the International Deep Endometriosis Analysis criteria. This study aimed to evaluate the presence of parametrial endometriosis and its ultrasonographic characteristics, using surgical diagnosis as the reference standard. Additionally, indirect signs of DE and concomitant DE nodules associated with parametrial involvement were identified, assessing their predictive significance in the anterior, lateral, and posterior parametrial areas. SETTING: Referral institution for endometriosis. PATIENTS: Patients with suspected DE scheduled for surgical treatment. INTERVENTIONS: Standardized preoperative ultrasonographic examination. MAIN OUTCOME MEASURES: The diagnostic accuracy of transvaginal ultrasound in identifying parametrial endometriosis, including sensitivity and specificity, and the ultrasonographic characteristics of parametrial nodules, prevalence in distinct parametrial areas, and associations with indirect DE signs and concomitant DE nodules. RESULTS: Surgical confirmation of parametrial nodules was observed in 105 of 545 patients (left, 18.5; right, 17.0%). Transvaginal ultrasound demonstrated a sensitivity of 77.1% (95% confidence interval, 68.0%-84.8%) and specificity of 99.1% (95% confidence interval, 67.7%-99.8%). Parametrial nodules typically exhibited characteristics such as a mild hypoechoic appearance (83.6%), starry morphology (74.7%), irregular margins (70.2%), and low vascularization. The posterior parametrial region was the most common location (52.2%), followed by the lateral (41.0%) and anterior (6.8%) parametrial regions. Concomitant DE nodules in the rectum (63.5%) and infiltrating the rectovaginal septum (56.5%) were significantly more prevalent in patients with parametrial involvement. Indirect DE signs, such as the ovaries fixed to the uterine wall (71.8%) and the absence of a posterior sliding sign (51.8%), were also more common in women with parametrial nodules. Hydronephrosis, although relatively uncommon in patients with parametrial involvement (8.2%), was largely detected in lateral parametrial nodules (70.0%). CONCLUSIONS: This study represents a systematic ultrasonographic characterization of parametrial endometriosis. Specifically, it comprehensively assesses the diagnostic accuracy of transvaginal ultrasound in identifying parametrial involvement within a sizable cohort of patients with preoperative suspicion of DE. CLINICAL TRIAL REGISTRATION NUMBER: NCT06017531.

"From the tip to the deep of the iceberg": Parametrial involvement in endometriosis.

Deep endometriosis (DE) can be localized in the parametrium, a complex bilateral anatomical structure, sometimes necessitating intricate surgical intervention due to the potential involvement of autonomic nerves, uterine artery, and ureter. If endometriotic ovarian cysts have been considered metaphorically representative of "the tip of the iceberg" concerning concealed DE lesions, it is reasonable to assert that parametrial lesions should be construed as the most profound region of this iceberg. Also, based on a subdual clinical presentation, a comprehensive diagnostic parametrial evaluation becomes imperative to strategize optimal management for patients with suspected DE. Recently, the ULTRAPARAMETRENDO studies aimed to evaluate the role of transvaginal ultrasound for parametrial endometriosis, showing distinctive features, such as a mild hypoechoic appearance, starry morphology, irregular margins, and limited vascularization. The impact of medical therapy on parametrial lesions has not been described in the current literature, primarily due to the lack of adequate detection at imaging. The extension of DE into the parametrium poses significant challenges during the surgical approach, thereby increasing the risk of intra- and postoperative complications, mainly if performed by centers with low expertise and following multiple surgical procedures where parametrial involvement has gone unrecognized. Over time, the principles of nerve-sparing surgery have been incorporated into the surgical DE treatment to minimize iatrogenic damage and potentially reduce the risk of functional complications.

Endometriosis and sexual disorders: the effect of surgical and medical treatment, a multicentre cross-sectional study.

Background: Sexual health is a major concern in women with endometriosis, however only a few controlled studies have examined this with validated instruments. The effect of hormonal treatments on sexual function in endometriosis is also an underrated topic. The aim of this study was to investigate sexual function of patients with endometriosis by a specific tool to better evaluate their sexual function (including different domains), and the influence of hormonal treatment or surgery on these parameters. Methods: An observational, cross-sectional, multicentre study was conducted in a group (n=194) of sexually active, women aged 25-45 years old, with surgical or ultrasonographic diagnosis of endometriosis, referred to the Endometriosis Center of Careggi University Hospital or Negrar di Valpolicella. Sexual function was assessed by administering the Female Sexual Function Index (FSFI), which assesses the domains of desire, arousal, lubrication, orgasm, satisfaction and pain. FSFI scores were compared to those of a control group (n=58) and according to the treatment received by patients with endometriosis. Results: Ovarian endometriosis was present in 50 patients (25.8%), deep infiltrating endometriosis in 65 patients (33.5%) and both in 79 patients (40.7%). Adenomyosis coexisted in 102 patients (52.6%). Women with endometriosis reported a mean total FSFI score of 18.3 [4.2-25.8] (< 26.55), indicating female sexual dysfunction (FSD) in all patients. At multivariate analysis, after adjusting for confounders (BMI and hormonal therapy), women with endometriosis presented significantly lower scores than controls in all the FSFI (p<0.001). Patients with endometriosis under hormonal treatments (n=124; 64%), regardless of the type, had significantly lower scores in all FSFI subscales and total score, even after adjusting for confounders-age, BMI and history of surgery. Conclusions: Patients with endometriosis are at risk for FSD, encompassing not only dyspareunia, but all domains of sexual function. Hormonal treatments do not result in improvement in sexual symptoms.

"Things Have Changed"-Laparoscopic Cytoreduction for Advanced and Recurrent Ovarian Cancer: The Experience of a Referral Center on 108 Patients.

OBJECTIVE: To report the feasibility of laparoscopic cytoreduction surgery for primary and recurrent ovarian cancer in a select group of patients. METHODS: A retrospective analysis was conducted on a cohort of patients with FIGO stage IIIA-IV advanced ovarian cancer who underwent laparoscopic primary debulking surgery (PDS), interval debulking surgery (IDS), or secondary debulking surgery (SDS) between June 2008 and January 2020. The primary endpoint was achieving optimal cytoreduction, defined as residual tumor less than 1 cm. Secondary endpoints included evaluating surgical complications and long-term survival, assessed at three-month intervals during the initial two years and then every six months. RESULTS: This study included a total of 108 patients, among whom, 40 underwent PDS, 44 underwent IDS, and 24 underwent SDS. Optimal cytoreduction rates were found to be 95.0%, 97.7%, and 95.8% for the PDS, ISD, and SDS groups, respectively. Early postoperative complications (<30 days from surgery) occurred in 19.2% of cases, with 7.4% of these cases requiring reintervention. One patient died following postoperative respiratory failure. Late postoperative complications (<30 days from surgery) occurred in 9.3% of cases, and they required surgical reintervention only in one case. After laparoscopic optimal cytoreduction with a median follow-up time of 25 months, the overall recurrence rates were 45.7%, 38.5%, and 39.3% for PDS, ISD, and SDS, respectively. The three-year overall survival rates were 84%, 66%, and 63%, respectively, while the three-year disease-free survival rates were 48%, 51%, and 71%, respectively. CONCLUSIONS: Laparoscopic cytoreduction surgery is feasible for advanced ovarian cancer in carefully selected patients, resulting in high rates of optimal cytoreduction, satisfactory peri-operative morbidity, and encouraging survival outcomes. Future studies should focus on establishing standardized selection criteria and conducting well-designed investigations to further refine patient selection and evaluate long-term outcomes.