Quantitative ultrasound measurement of uterine contractility in adenomyotic vs. normal uteri: a multicenter prospective study.

OBJECTIVE: To evaluate uterine contractility in patients with adenomyosis compared with healthy controls using a quantitative two-dimensional transvaginal ultrasound (TVUS) speckle tracking method. DESIGN: A multicenter prospective observational study took place in three European centers between 2014 and 2023. SETTING: One university teaching hospital, 1 teaching hospital and 1 specialised clinic. PATIENTS: A total of 46 women with a sonographic or magnetic resonance imaging diagnosis of adenomyosis were included. 106 healthy controls without uterine pathologies were included. INTERVENTION: Four-minute TVUS recordings were performed and four uterine contractility features were extracted using a speckle tracking algorithm. MAIN OUTCOMES MEASURES: The extracted features were contraction frequency (contractions/min), amplitude, velocity (mm/s), and coordination. Women with adenomyosis were compared with healthy controls according to the phase of the menstrual cycle. RESULTS: Throughout the different phases of the menstrual cycle, trends of increased amplitude, decreased frequency and velocity, and reduced contraction coordination were seen in patients with adenomyosis compared with healthy controls. These were statistically significant in the late follicular phase, with a higher amplitude (0.087 ± 0.042 vs. 0.050 ± 0.018), lower frequency and velocity (1.49 ± 0.22 vs. 1.68 ± 0.25 contractions/min, and 0.65 ± 0.18 vs. 0.88 ± 0.29 mm/s, respectively), and reduced contraction coordination (0.34 ± 0.08 vs. 0.26 ± 0.17), in the late luteal phase, with higher amplitude (0.050 ± 0.022 vs. 0.035 ± 0.013), lower velocity (0.51 ± 0.11 vs. 0.65 ± 0.13 mm/s), and reduced contraction coordination (0.027 ± 0.06 vs. 0.18 ± 0.07), and in the midfollicular phase, with decreased frequency (1.48 ± 0.21 vs. 1.69 ± 0.16 contractions/min) in patients with adenomyosis compared with healthy controls. During menses, a higher pain score was significantly associated with lower frequency and velocity and higher contraction amplitude. Results remained significant after correcting for age, parity, and body mass index. CONCLUSION: Uterine contractility differs in patients with adenomyosis compared with healthy controls throughout the phases of the menstrual cycle. This suggests an etiologic mechanism for the infertility and dysmenorrhea seen in patients with adenomyosis. Moreover, it presents new potential therapeutic targets and diagnostic markers.

Endometriosis and dysbiosis: State of art.

Endometriosis is a complex and heterogeneous disease affecting approximately 10% of reproductive age women. The hypothesis that alterations in the microbiota are involved in the pathogenesis of endometriosis has been postulated. Possible explanations for the implications of dysbiosis in endometriosis include the Bacterial Contamination hypothesis and immune activation, cytokine-impaired gut function, altered estrogen metabolism and signaling. Thus, dysbiosis, disrupt normal immune function, leading to the elevation of proinflammatory cytokines, compromised immunosurveillance and altered immune cell profiles, all of which may contribute to the pathogenesis of endometriosis. The aim of this review is to summarize the available literature data about the relationship between microbiota and endometriosis.

Epidemiological and Immune Profile Analysis of Italian Subjects with Endometriosis and Multiple Sclerosis.

OBJECTIVE: To report for the first time an Italian epidemiological analysis of the prevalence of multiple sclerosis (MS) in patients with endometriosis (EMS), through the study of the endometriosis population of our referral center; to analyze the clinical profile and perform a laboratory analysis to examine the immune profile and the possible correlation to other autoimmune diseases of the enrolled patients. METHODS: We evaluated 1652 women registered with EMS in the University of Naples Federico II and retrospectively searched patients with a co-diagnosis of MS. Clinical features of both conditions were recorded. Serum autoantibody and immune profiles were analyzed. RESULTS: 9 out of 1652 patients presented a co-diagnosis of EMS and MS (9/1652 = 0.005%). Clinically, EMS and MS presented in mild forms. Hashimoto's thyroiditis was found in two patients (2/9). Even if not statistically significant, a trend of variation in CD4- CD8 T lymphocytes and of B cells were found. CONCLUSION: Our findings suggest an increased risk of MS in women with EMS. However, large-scale prospective studies are needed.

Uterine contractile activity in healthy women throughout the menstrual cycle measured using a novel quantitative two-dimensional transvaginal ultrasound speckle tracking method.

RESEARCH QUESTION: To explore normal uterine contractile function across the menstrual cycle using a novel quantitative ultrasound method. DESIGN: This multicentre prospective observational study took place in three European centres from 2014 to 2022. Uterine contraction frequency (contractions/minute), amplitude, direction (cervix-to-fundus, C2F; fundus-to-cervix; F2C), velocity and coordination were investigated. Features were extracted from transvaginal ultrasound recordings (TVUS) using speckle tracking. Premenopausal women ≥18 years of age, with normal, natural menstrual cycles were included. A normal cycle was defined as: regular (duration 28 ± 2 days), no dysmenorrhoea, no menometrorrhagia. Four-minute TVUS were performed during the menstrual phase, mid-follicular, late follicular phase, early luteal phase and/or late luteal phase. Of the 96 recordings available from 64 women, 70 were suitable for inclusion in the analysis. RESULTS: Contraction frequency (for the posterior wall) and velocity (for the anterior uterine wall in the F2C direction) were highest in the late follicular phase and lowest in the menstrual and late luteal phases (1.61 versus 1.31 and 1.35 contractions/min, P < 0.001 and 0.81 versus 0.67 and 0.62 mm/s, P < 0.001, respectively). No significant difference was found for contraction amplitude. Contraction coordination (simultaneous contraction of the anterior and posterior walls in the same direction) was least coordinated in the mid-follicular phase (P = 0.002). CONCLUSIONS: This is the first study to objectively measure uterine contraction features in healthy women during the natural menstrual cycle on TVUS. Likewise, it introduces contraction coordination as a specific feature of uterine peristalsis. Differences in uterine contractility across the menstrual cycle are confirmed, with highest activity seen in the late follicular phase, and lowest in the late luteal phase.

Hysteroscopy and Retained Products of Conception: An Update.

Retained products of conception (RPOC) can occur after early or mid-trimester pregnancy termination and also following vaginal or cesarean delivery. It is frequently associated with continuous vaginal bleeding, pelvic pain, and infection. Late complications include intrauterine adhesions formation and infertility. Conventionally, the management of RPOC has been with blind dilation and suction curettage (D and C); however, hysteroscopic resection of RPOC is a safe and efficient alternative. In this review, we analyze the current available evidence regarding the use of hysteroscopic surgery for the treatment of RPOC comparing outcomes and complications of both traditional curettage and hysteroscopic technique. Data search has been conducted using the following databases MEDLINE, EMBASE, Web of Sciences, Scopus, Clinical Trial. Gov., OVID, and Cochrane Library interrogate all articles related to hysteroscopy and the preserved product of conception, updated through September 2020.

Novel diagnostic approaches to intrauterine neoplasm in fertile age: sonography and hysteroscopy.

Endometrial carcinoma (EC) is the most common gynecological malignancy in the world. It is mostly detected in postmenopausal women, but it can also occur in women of fertile age who need fertility-sparing therapy. An early diagnosis is the main objective for the correct management of these patients, making it possible to use a fertility-sparing treatment approach without exposing the patients to the risk of cancer progression. In this review, we discuss the role of sonography and hysteroscopy in the detection of intrauterine neoplasm in women of childbearing age.

Gigantomastia During Pregnancy Due to Burkitt Lymphoma.

Gigantomastia is a rare complication of pregnancy usually associated with benign conditions and rarely with malignancies. This paper reports a non-Hodgkin lymphoma case associated with gigantomastia during pregnancy. The patient was a 30-year-old gravida one woman, with a history of rapidly enlarging right breast at 2 weeks prior to presentation. After the first diagnosis of benign gigantomastia, the continuous growth of the breast, despite the delivery and bromocriptine therapy, required further investigation of the case. The histological analysis revealed the presence of Burkitt lymphoma. Malignant causes of unilateral gigantomastia in pregnancy should be considered in the differential diagnosis of this condition.

Poly (ADP-ribose) polymerase (PARP) as target for the treatment of epithelial ovarian cancer: what to know.

INTRODUCTION: Poly (ADP-ribose) polymerase (PARP) inhibitors are being developed in maintenance and recurrence treatment settings of epithelial ovarian cancers (EOCs) with BRCA 1-2 gene mutation. PARP inhibitors are the first example of drugs targeting the loss of a gene suppressor: they block base-excision repair in the cancer cells, which have lost homologous recombination due to BRCA-mutation, resulting in loss of DNA repair and cell death, also known as synthetic lethality. AREAS COVERED: This article provides an overview of PARP inhibitors in OC treatment and also an extensive section on the combined strategies of PARP inhibitors, including approved as well as currently investigated drugs. It also offers a section on the use of predictive biomarkers for PARP inhibitors treatment. Ongoing trials, including novel combinations, are discussed. EXPERT OPINION: In recent years, there is increasing evidence that PARP inhibitor therapy can have life-long percussion in the treatment of EOC, even if some questions have to be solved yet, such as its use in combination therapy, the possibility to retreat with a PARP inhibitor, and finally how to overcome a resistance mechanism to this therapy. In this way, PARP inhibitors can obtain an important role in making a personalized therapeutic program in the case of first-line, neoadjuvant, platinum-sensitive, and resistant high-grade serous OC treatment.

Microbiome and PCOS: State-of-Art and Future Aspects.

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease. The hypothesis that alterations in the microbiome are involved in the genesis of PCOS has been postulated. Aim of this review is to summarize the available literature data about the relationship between microbiome and PCOS. A search on PubMed and Medline databases was performed from inception to November 20Most of evidence has focused on the connection of intestinal bacteria with sex hormones and insulin-resistance: while in the first case, a relationship with hyperandrogenism has been described, although it is still unclear, in the second one, chronic low-grade inflammation by activating the immune system, with increased production of proinflammatory cytokines which interfere with insulin receptor function, causing IR (Insulin Resistance)/hyperinsulinemia has been described, as well as the role of gastrointestinal hormones like Ghrelin and peptide YY (PYY), bile acids, interleukin-22 and Bacteroides vulgatus have been highlighted. The lower genital tract microbiome would be affected by changes in PCOS patients too. The therapeutic opportunities include probiotic, prebiotics and synbiotics, as well as fecal microbiota transplantation and the use of IL-22, to date only in animal models, as a possible future drug. Current evidence has shown the involvement of the gut microbiome in PCOS, seen how humanized mice receiving a fecal transplant from women with PCOS develop ovarian dysfunction, immune changes and insulin resistance and how it is capable of disrupting the secondary bile acid biosynthesis. A future therapeutic approach for PCOS may involve the human administration of IL-22 and bile acid glycodeoxycholic acid.

Hysteroscopic approach to uterine cervical canal stenosis.

Cervical stenosis is defined as an adhesion process of variable degree, producing narrowing, distortion, or complete obliteration of the cervix. Several techniques have been defined to access to the uterine cavity and nowadays hysteroscopy seems to be the best option. In this manuscript, we review all the hysteroscopic modalities to overcome a cervical stenosis and access to the uterine cavity.

Role of biomarkers for early detection of ovarian cancer recurrence.

Ovarian cancer is frequently diagnosed at an advanced stage and a fraction of these patients fail to respond to primary therapy and relapses in 70% of cases. On account of the high recurrence probability and the poor outcomes after recurrence, there is an urgent need to predict progression as early as possible and thus found the strategies to detect and prevent a recurrence. Considering that biomarkers have contributed to the management of ovarian cancer by distinguishing benign and malignant pelvic masses and monitoring response to treatment, in this review, we aim to discuss the latest evidence reported in the literature about the use of biomarkers to detect OC recurrence. In detail, we summarized all the evidence of the most quoted biomarkers like HE4, osteopontin, mesothelin (MSLN), Folate receptor α (FOLR1), paraneoplastic antigens, miRNA, cancer stem cells (CSCs) and a combination of them to evaluate their role as prognostic biomarkers for ovarian cancer recurrence.

Current and experimental drug therapy for the treatment of polycystic ovarian syndrome.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 8-13% of reproductive-age women. Irregular periods, hirsutism, or infertility are the most common clinical presentations of patients affected by PCOS. This syndrome is also linked to metabolic abnormalities such as type 2 diabetes, insulin resistance and obesity. The optimal therapeutic approach is still unknown. AREAS COVERED: This narrative review offers an overview of the literature on current and experimental pharmacological options for treating PCOS and highlights ongoing clinical trials. Several electronic databases were searched and current research registers were analyzed to the present year. The papers selected for this review were critically analyzed, and all data available were summarized, organized, and explored to derive key information. EXPERT OPINION: The main goal of PCOS treatment is to obtain a metabolic and hormonal balance. Optimal PCOS therapy should be direct to the reproductive abnormalities and the entire spectrum of endocrine and metabolic complications that appear to have a long-term negative impact on PCOS patient health, as in post-menopausal period. The discovery of new mechanisms in PCOS pathogenesis will offer the possibility of testing new drug classes.

Advances in therapeutic vaccines for treating human papillomavirus-related cervical intraepithelial neoplasia.

AIM: Human papillomavirus (HPV) is the etiologic agent of the majority of cervical intraepithelial lesions (CIN) and cervical cancers. While prophylactic HPV vaccines prevent infections from the main high-risk HPV types associated with cervical cancer, alternative nonsurgical and nonablative therapeutics to treat HPV infection and preinvasive HPV diseases have been experimentally investigated. Therapeutic vaccines are an emerging investigational strategy. This review aims to introduce the results of the main clinical trials on the use of therapeutic vaccines for treating HPV infection and -related CIN, reporting the ongoing studies on this field. METHODS: Data research was conducted using MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID and Cochrane Library querying for all articles related to therapeutic vaccines for the treatment of HPV-related CIN. Selection criteria included randomized clinical trials, nonrandomized controlled studies and review articles. RESULTS: Preliminary data are available on the evaluation of therapeutic vaccines for treating cervical HPV infections and CIN. Despite having in vitro demonstrated to obtain humoral and cytotoxic responses, therapeutic vaccines have not yet clinically demonstrated consistent success; moreover, each class of therapeutic vaccines has advantages and limitations. Early clinical data are available in the literature for these compounds, except for MVA E2, which reached the phase III clinical trial status, obtaining positive clinical outcomes. CONCLUSION: Despite promising results, to date many obstacles are still present before hypothesize an introduction in the clinical practice within the next years. Further studies will draw a definitive conclusion on the role of therapeutic vaccines in this setting.

Advances in paclitaxel combinations for treating cervical cancer.

INTRODUCTION: Cervical cancer is the fourth common cancer in women worldwide. While, in the past, locally advanced stage disease was treated by pelvic radiotherapy, nowadays the National Cancer Institute strongly recommends chemoradiation protocols. Weekly cisplatin was previously the standard of care in this setting; however, the low response rate and the short median progression-free survival (PFS) of patients have led researchers to investigate combinatory regimens. AREA COVERED: This article is based on literature searches up until April 2019, with current trial registers also analyzed. All data available on this topic has been summarized in this narrative review. EXPERT OPINION: In recent years, it has been demonstrated that cisplatin-based doublets, and in particular, cisplatin plus paclitaxel, are superior to cisplatin as a monotherapy in terms of response rate and progression-free survival of patients with advanced cervical cancer. This double regime combined with bevacizumab is also considered the first-line option for metastatic or recurrent disease. Dose-dense paclitaxel in neo-adjuvant chemotherapy combinations is a promising option in patients with locally advanced cervical cancer. Exploration of novel biological therapies and in vitro combinations based on the use of paclitaxel is warranted.

Dioxin and endometriosis: a new possible relation based on epigenetic theory.

Endometriosis is a chronic disease characterized by the growth of endometrial-like glands and stroma outside the uterine cavity. Nowadays, the exact etiology of endometriosis is unclear and the interaction between a variety of environmental physical and chemical compounds may potentially promote the disease in women with an individual susceptibility. The first demonstration of a relation between an environmental factor and endometriosis was obtained with the chronic dietary exposure of a primate colony to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Besides the well-known dioxin's pathway of action, several papers are focusing on the role of epigenetic mechanisms, a way through which the genome responds to the environment and can lead to permanent changes in gene expression until affecting the phenotypes or cause disease. In this review, we focus on the possible role of dioxin epigenetics modification in endometriosis.

Is there a Relationship Between Vitamin D and Endometriosis? An Overview of the Literature.

BACKGROUND: Vitamin D is involved in the physiological functions of several tissues, however, its deficiency may contribute to the development of various disorders. Recent research has been focusing on the role of vitamin D in the pathogenesis of endometriosis based on the evidence of the presence of vitamin D receptor and the enzymes required for vitamin D synthesis in the ectopic endometrium. Endometriosis, defined as the presence of endometrial glands and stroma in ectopic locations, is considered an estrogen-dependent disease and Vitamin D seems to have a role in modulation of the inflammatory state and proliferation of endometriotic cells. OBJECTIVE: This study aimed to review the available literature regarding the relationship between vitamin D and endometriosis as well as the effects of vitamin D supplementation. METHODS: A search on PubMed database has been performed. RESULTS: The relationship between endometriosis and Vitamin D has been analyzed through the evaluation of vitamin D serum level, the polymorphism of vitamin D receptor and the role of vitamin D-binding protein in patient with endometriosis. The possible role of Vitamin D in the endometriosis therapy has also been investigated, in particular, the effect of vitamin D on pain relief, on endometriotic lesion in vitro and in rat models and in addition to a future target immunotherapy. CONCLUSION: Although promising, the data analyzed are not sufficient to evidence a cause-effect relationship between VD status and endometriosis, therefore further studies are needed in order to better clarify the association between vitamin D and endometriosis, especially in the context of the possibility of new treatment options.

Unraveling a difficult diagnosis: the tricks for early recognition of ovarian cancer.

Epithelial ovarian cancer (EOC) is the predominant type of ovarian cancer (OC). The 5-year survival of patients has improved over the last three decades, although the overall cure rate of OC if about 30%. Despite high response rates after initial chemotherapy, most patients with advanced ovarian cancer ultimately develop the recurrent disease because of resistance to chemotherapy. A proper early diagnosis and treatment of patients with ovarian cancer are urgently needed. Nowadays the diagnosis is performed by means of clinical symptoms and signs, often indicators of a disease already at an advanced stage, tumor markers (CA125 and HE4), transvaginal ultrasonography and imaging, very useful in distinguishing adnexal masses. Understand the nature of an adnexal mass is the primary point to begin the diagnosis of OC. Validated different model to approach and characterize adnexal pathology preoperatively are described, such as the International Ovarian Tumor Analysis (IOTA) and the Assessment of Different NEoplasias in the AdneXa (ADNEX) model. New tumor markers, such as PRSS8, FOLR1, KLK6/7, GSTT1, and miRNAs, are getting ahead and are worth noting for early detection of ovarian cancer. Despite the development of numerous ultrasound models for the diagnosis of adnexal masses and the analysis of different tumor markers, the early diagnosis of ovarian cancer is still difficult to practice. Moreover, identifying genetic risk alleles, such as germline BRCA1 and BRCA2 mutations, for ovarian cancer has had a significant impact on disease prevention strategies.