Effects of Strong Inhibition of Cytochrome P450 3A and UDP glucuronosyltransferase 1A9 and Strong Induction of Cytochrome P450 3A on the Pharmacokinetics, Safety, and Tolerability of Soticlestat: Two Drug-Drug Interaction Studies in Healthy Volunteers.

Two open-label, phase 1 studies (NCT05064449, NCT05098041) investigated the effects of cytochrome P450 (CYP) 3A inhibition (via itraconazole), UDP glucuronosyltransferase (UGT) 1A9 inhibition (via mefenamic acid), and CYP3A induction (via rifampin) on the pharmacokinetics of soticlestat and its metabolites M-I and M3. In period 1 of both studies, participants received a single dose of soticlestat 300 mg. In period 2, participants received itraconazole on days 1-11 and soticlestat 300 mg on day 5 (itraconazole/mefenamic acid study; part 1); mefenamic acid on days 1-7 and soticlestat 300 mg on day 2 (itraconazole/mefenamic acid study; part 2); or rifampin on days 1-13 and soticlestat 300 mg on day 11 (rifampin study). Twenty-eight healthy adults participated in the itraconazole/mefenamic acid study (14 per part) and 15 participated in the rifampin study (mean age, 38.1-40.7 years; male, 79-93%). For maximum observed concentration, the geometric mean ratios (GMRs) of soticlestat + itraconazole, mefenamic acid, or rifampin to soticlestat alone were 116.6%, 107.3%, and 13.2%, respectively, for soticlestat; 10.7%, 118.0%, and 266.1%, respectively, for M-I, and 104.6%, 88.2%, and 66.6%, respectively, for M3. For area under the curve from time 0 to infinity, the corresponding GMRs were 124.0%, 100.6%, and 16.4% for soticlestat; 13.3%, 117.0%, and 180.8% for M-I; and 120.3%, 92.6%, and 58.4% for M3. Soticlestat can be administered with strong CYP3A and UGT1A9 inhibitors, but not strong CYP3A inducers (except for antiseizure medications, which will be further evaluated in ongoing phase 3 studies). In both studies, all treatment-emergent adverse events were mild or moderate. SIGNIFICANCE STATEMENT: These drug-drug interaction studies improve our understanding of the potential changes that may arise in soticlestat exposure in patients being treated with CYP3A inhibitors, UGT1A9 inhibitors, or CYP3A inducers. The results build on findings from previously published soticlestat studies and provide important information to help guide clinical practice. Soticlestat has shown positive phase 2 results and is currently in phase 3 development for the treatment of seizures in patients with Dravet syndrome and Lennox-Gastaut syndrome.

Molecular classification of endometrial carcinoma on endometrial biopsy: an early prognostic value to guide personalized treatment.

OBJECTIVE: Molecular features are essential for estimating the risk of recurrence and impacting overall survival in patients with endometrial cancer. Additionally, the surgical procedure itself could be personalized based on the molecular characteristics of the tumor. This study aims to assess the feasibility of obtaining reliable molecular classification status from biopsy specimens collected during hysteroscopy to better modulate the appropriate surgical treatment. METHODS: This monocentric, retrospective, observational study was conducted on 106 patients who underwent a biopsy procedure followed by radical surgery for endometrial cancer, with concurrent molecular investigation. The molecular classification was determined through immunohistochemical staining for p53 and mismatch repair proteins, along with gene sequencing for POLE. RESULTS: Overall, 106 patients underwent molecular investigation, which was finally achieved on 99 patients (93.4%). Among these, the molecular analysis was conducted in 71 patients (67%) on the pre-operative endometrial biopsy and on the final uterine specimen in 28 patients (26.4%). Most of the endometrial biopsies were performed using Bettocchi hysteroscopy (66%). Molecular analysis was not possible in seven patients (6.6%), with six cases due to sample inadequacy and one case attributed to intra-mucosal carcinoma. The molecular results showed that the copy number low sub-group was the most common, and five cases of 'multiple classifiers' were observed in the low-risk category. CONCLUSION: Our experience in obtaining molecular information from biopsy samples underscores the feasibility and efficacy of this technique, even in small tissue samples. This capability helps define the prognostic group of patients, facilitates timely decision-making, and develops a personalized strategy for each patient.

Lidocaine spray vs mepivacaine local infiltration for suturing 1st/2nd grade perineal lacerations: a randomised controlled non-inferiority trial.

BACKGROUND: Perineal lacerations are a very common complication of post-partum. Usually, the repair of 1st and 2nd-grade lacerations is performed after the administration of local anesthesia. Despite the great relevance of the problem, there are only a few studies about the best choice of local anesthetic to use during suturing. We performed a randomised controlled trial to evaluate the efficacy and safety of the use of a local anesthetic spray during the suturing of perineal lacerations in the post-partum. METHODS: We compared the spray with the standard technique, which involves the infiltration of lacerated tissues, using the NRS scale. 136 eligible women who had given birth at University Hospital of Udine were enrolled and randomly assigned to receive nebulization of Lidocaine hydrochloride 10% spray (experimental group) or subcutaneous/submucosal infiltration of mepivacaine hydrochloride (control group) during suturing of perineal laceration. RESULTS: The lacerations included 84 1st-grade perineal traumas (61.7%) and 52 2nd-grade perineal traumas (38.2%). All the procedures were successfully completed without severe complications or serious adverse reactions. There were no statistically significant differences between the two groups in terms of blood losses or total procedure time. Moreover, there were no statistically significant differences in terms of NRS to none of the intervals considered. Regarding the application of the spray in the B group, in 36 cases (52.9%) it was necessary to improve the number of puffs previously supposed to be sufficient (5 puffs). Just in 3 cases, an additional injection was necessary (4.4%). CONCLUSIONS: Our study demonstrates that lidocaine spray alone can be used as a first line of local anesthetic during the closure of I-II-grade perineal lacerations, as it has comparable efficacy to mepivacaine infiltration. TRIAL REGISTRATION: The trial was recorded on https://clinicaltrials.gov . Identification number: NCT05201313. First registration date: 21/01/2022. Unique Protocol ID: 0042698/P/GEN/ARCS.

Use of etonogestrel subcutaneous implant in Sardinia, Italy: women's compliance and satisfaction.

PURPOSE OF THE ARTICLE: The main aim of the study was to analyze the population of women who used etonogestrel implant, the reason that led them to this type of contraception, and the degree of compliance with it. Materials and methods: We carried out a retrospective study on women who had etonogestrel subcutaneous implant placed (n°47) over a 6-year period (2015-2021). We submitted the women a series of questions by telephone questionnaire (range 10-72 months after placements, mean 40 months) that investigated the comorbidities and side effects related to etonogestrel implant. MATERIALS AND METHODS: We carried out a retrospective study on women who had etonogestrel subcutaneous implant placed (n°47) over a 6-year period (2015-2021). We submitted the women a series of questions by telephone questionnaire (range 10-72 months after placements, mean 40 months) that investigated the comorbidities and side effects related to etonogestrel implant. RESULTS: The average age of placement of etonogestrel implant was 33.8 ± 3.45 years. As regards level of education, 16/47 (34%) of the women had a university degree, 21/47 (44%) had a high school diploma and 10/47 (21%) had a secondary school diploma. The 12/47 (25%) of the women were, at the time of the counselling, unemployed and only 8% did not use in the past contraceptive methods other than etonogestrel implant. The 92% of women choose etonogestrel implant because it offered safe, comfortable and long-lasting contraception. Among the main side effects evaluated, we reported spotting in 24 out of 47 (51%), headache in 4 out of 47 (8.5%). The 85% of the women recommended etonogestrel implant to their friends as a contraceptive method, with an approval rating for the implant, expressed a rating from 1 to 10 with the mean that was 7.79, the median 8. CONCLUSIONS: Our results are of interest because they derive from a region of Italy in which the Long acting reversible contraception (LARC) is strongly underused. Etonogestrel implant was a safe and effective, long-acting, reversible hormonal contraception (LARC) and majority of women recommended the etonogestrel implant to their friends as a contraceptive method.

Etonogestrel implant is a safe and effective, long-acting, reversible hormonal contraception (LARC). The majority of women in our study choose the etonogestrel implant for its characteristics; among the main side effects evaluated we reported spotting and headache. The majority of women recommended the etonogestrel implant to their friends as a contraceptive method.

Possible Effect of Polycystic Ovary Syndrome (PCOS) on Cardiovascular Disease (CVD): An Update.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women during the fertile period. Women with PCOS have an increased risk of developing major cardiovascular risk factors during the fertile period: obesity, impaired glucose tolerance, diabetes mellitus, dyslipidemia, and metabolic syndrome. The possible effect of PCOS on cardiovascular disease (CVD) has been reported in different studies, but the results are not clear for several reasons. Indeed, most of the studies analyzed a cohort of fertile women who, given their relatively young age, have a low frequency of cardiovascular diseases. In addition, longitudinal studies have a short follow-up period, insufficient to draw firm conclusions on this topic. Finally, pharmacological treatment is limited by the lack of specific drugs available to specifically treat PCOS. In this review, we report on studies that analyzed the possible effect of PCOS on the most common CVD (hypertension, arterial stiffness, atherosclerosis, and cardiovascular event) and available drugs used to reduce CVD in PCOS women.

Modulation of adipose-derived stem cell behavior by prostate pathology-associated plasma: insights from in vitro exposure.

Adipose-derived stem cells (ADSCs) are promising in regenerative medicine. Their proliferation, survival and activation are influenced by specific signals within their microenvironment, also known as niche. The stem cell niche is regulated by complex interactions between multiple cell types. When transplanted in a specific area, ADSCs can secrete several immunomodulatory factors. At the same time, a tumor microenvironment can influence stem cell behavior, modulating proliferation and their ability to differentiate into a specific phenotype. Whitin this context, we exposed ADSCs to plasma samples derived from human patients diagnosed with prostate cancer (PC), or precancerous lesions (PL), or benign prostatic hyperplasia (BPH) for 4, 7 or 10 days. We then analyzed the expression of main stemness-related markers and cell-cycle regulators. We also measured cytokine production and polyamine secretion in culture medium and evaluated cell morphology and collagen production by confocal microscopy. The results obtained from this study show significant changes in the morphology of ADSCs exposed to plasma samples, especially in the presence of prostate cancer plasma, suggesting important implications in the use of ADSCs for the development of new treatments and application in regenerative medicine.

Ergonomics in the operating room and surgical training: a survey on the Italian scenario.

Introduction: Surgical-related injuries are frequent, in fact the reported percentage of musculoskeletal disorders in surgeons is between 47% and 87%. These conditions are caused by long periods of standing, incorrect postures, repeated movements, little rest between operations, the lack of integrated operator rooms, the correct number and arrangement of monitors and the use of non-ergonomic instruments. This survey aims to assess the Italian overview both highlighting how prevalent surgical-related injury is in our surgeons and whether there is an operating room ergonomics education program in Italian surgical specialty schools. Methods: An anonymous questionnaire was designed through SurveyMonkey© web application. This survey was composed of 3 different sections concerning the general characteristics of the participants, their surgical background and any training performed, and any injuries or ailments related to the surgical activity. The survey was carried out in the period 1th of December 2022 and the 6th of February 2023. Results: At the close of our survey, 300 responses were collected. Among the participants, the two most represented specialties were Gynecology and Obstetrics (42.3%) and General Surgery (39.7%) and surgeons were mainly employed in the Northern regions of Italy (54.8%). Analyzing the participants' background, 61.7% of the respondents had laparoscopic training during their training and only 53.1% had a pelvic trainer during their residency. In accordance with 98.7% of the respondents, during surgery we have the feeling of being in an uncomfortable position that causes discomfort or muscle pain, and regarding the frequency of these discomforts, the majority of our study population experiences these problems monthly (46.2%), while in 29.6% it is experienced weekly, 12.1% annually and finally 12.1% daily. The surgical approach that is most correlated with these disorders is laparoscopy (62.7%) while the one that causes the least discomfort is robotic surgery (1.4%). These discomforts cause 43.9% of our population to take a break or do short exercises to reduce pain during surgery, and the body areas most affected are the back (61.6%), neck (40.6%) and shoulders (37.8%). Conclusion: Despite this, our survey allows us to highlight some now-known gaps present in the surgical training program of our schools and the lack of protection toward our surgeons during their long career.

Sentinel node mapping in high-intermediate and high-risk endometrial cancer: Analysis of 5-year oncologic outcomes.

OBJECTIVE: To assess 5-year oncologic outcomes of apparent early-stage high-intermediate and high-risk endometrial cancer undergoing sentinel node mapping versus systematic lymphadenectomy. METHODS: This is a multi-institutional retrospective, propensity-matched study evaluating data of high-intermediate and high-risk endometrial cancer (according to ESGO/ESTRO/ESP guidelines) undergoing sentinel node mapping versus systematic pelvic lymphadenectomy (with and without para-aortic lymphadenectomy). Survival outcomes were assessed using Kaplan-Meier and Cox proportional hazard methods. RESULTS: Overall, the charts of 242 patients with high-intermediate and high-risk endometrial cancer were retrieved. Data on 73 (30.1%) patients undergoing hysterectomy plus sentinel node mapping were analyzed. Forty-two (57.5%) and 31 (42.5%) patients were classified in the high-intermediate and high-risk groups, respectively. Unilateral sentinel node mapping was achieved in all patients. Bilateral mapping was achieved in 67 (91.7%) patients. Three (4.1%) patients had site-specific lymphadenectomy (two pelvic areas only and one pelvic plus para-aortic area), while adjunctive nodal dissection was omitted in the hemipelvis of the other three (4.1%) patients. Sentinel nodes were detected in the para-aortic area in eight (10.9%) patients. Twenty-four (32.8%) patients were diagnosed with nodal disease. A propensity-score matching was used to compare the aforementioned group of patients undergoing sentinel node mapping with a group of patients undergoing lymphadenectomy. Seventy patient pairs were selected (70 having sentinel node mapping vs. 70 having lymphadenectomy). Patients undergoing sentinel node mapping experienced similar 5-year disease-free survival (HR: 1.233; 95%CI: 0.6217 to 2.444; p = 0.547, log-rank test) and 5-year overall survival (HR: 1.505; 95%CI: 0.6752 to 3.355; p = 0.256, log-rank test) than patients undergoing lymphadenectomy. CONCLUSIONS: Sentinel node mapping does not negatively impact 5-year outcomes of high-intermediate and high-risk endometrial cancer. Further prospective studies are warranted.