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.

Ten-year outcomes following laparoscopic and open abdominal radical hysterectomy for "low-risk" early-stage cervical cancer: A propensity-score based analysis.

OBJECTIVE: Accumulating evidence suggested the detrimental effects of adopting minimally invasive surgery in the management of early-stage cervical cancer. However, long-term evidence on the role of minimally invasive radical hysterectomy in "low-risk" patients exists. METHODS: This is multi-institutional retrospective study comparing minimally invasive and open radical hysterectomy in low-risk early-stage cervical cancer patients. A propensity-score matching algorithm (1:2) was used to allocate patients into the study groups. Kaplan-Meir model was used to estimate 10-year progression-free and overall survival. RESULTS: Charts of 224 "low-risk" patients were retrieved. Overall, 50 patients undergoing radical hysterectomy were matched with 100 patients undergoing open radical hysterectomy. Minimally invasive radical hysterectomy was associated with a longer median operative time (224 (range, 100-310) vs. 184 (range, 150-240) minutes; p < 0.001), lower estimated blood loss (10 (10-100) vs. 200 (100-1000) ml, p < 0.001), and shorter length of hospital stay (3.8 (3-6) vs. 5.1 (4-12); p < 0.001). Surgical approach did not influence the risk of having intra-operative (4% vs. 1%; p = 0.257) and 90-day severe (grade 3+) postoperative complication rates (4% vs. 8%; p = 0.497). Ten-year disease-free survival was similar between groups (94% vs. 95%; p = 0.812; HR:1.195; 95%CI:0.275, 5.18). Ten-year overall survival was similar between groups (98% vs. 96%; p = 0.995; HR:0.994; 95%CI:0.182, 5.424). CONCLUSIONS: Our study appears to support emerging evidence suggesting that, for low-risk patients, laparoscopic radical hysterectomy does not result in worse 10-year outcomes compared to the open approach. However, further research is needed and open abdominal radical hysterectomy remains the standard treatment for cervical cancer patients.

Mammary-like adenocarcinoma of the vulva: a rare case report with next generation sequencing.

Vulvar adenocarcinomas are rare tumors, representing approximately 5% of vulvar cancers. Mammary-like adenocarcinomas of the vulva (MLAV) are extremely rare, and their molecular features are poorly described in the scientific literature. We report a case of an 88-year-old woman affected by MLAV with comedo-like features, with a detailed description of the pathological, immunohistochemical and molecular features. Immunohistochemistry (IHC) showed strong staining for cytokeratin 7, GATA3, androgen receptor, GCFPD15, and weak staining for mammaglobin; no staining for Her-2 was found. The proliferation index (Ki-67) was 15%. Molecular testing detected a pathogenic mutation of the AKT1 gene, a likely pathogenic frameshift insertion of the JAK1 gene, and two likely pathogenic frameshift deletions of the KMT2C gene; in addition, two variants of unknown significance (VUS) involving the ARID1A and OR2T4 genes were detected. Finally, two CNVs of the BRCA1 gene were identified.

The role of surgery in platinum-resistant ovarian cancer: A call to the scientific community.

In the last decade, a growing attention has been focused on identifying effective therapeutic strategies also in the orphan clinical setting of women with platinum-resistant disease. In this context, secondary cytoreductive surgery (SCS) remains a potential approach only in women with platinum sensitive relapse, but experimental data have been published supporting the role of SCS also in patients with platinum-resistant recurrence. In particular, surgery is emerging as a potential option in specific subgroups of women, such as those patients with low-grade serous histology, or low-volume relapse with disease located in the so-called pharmacological sanctuaries. Furthermore, contrasting evidences have suggested a potential role in this clinical setting of SCS combined with intraperitoneal hyperthermic chemotherapy. In this complex scenario we review here the available evidences regarding the role surgery in ovarian cancer patients with platinum resistant disease, trying also to understand which patients may benefit from this challenging, experimental approach.

Nusinersen by subcutaneous intrathecal catheter for symptomatic spinal muscular atrophy patients with complex spine anatomy.

INTRODUCTION/AIMS: Intrathecal administration of nusinersen is challenging in patients with spinal muscular atrophy (SMA) who have spine deformities or fusions. We prospectively studied the safety and efficacy of nusinersen administration via an indwelling subcutaneous intrathecal catheter (SIC) for SMA patients with advanced disease. METHODS: Seventeen participants commenced nusinersen therapy between 2.7 and 31.5 years of age and received 9 to 12 doses via SIC. Safety was assessed in all participants. A separate efficacy analysis comprised 11 nonambulatory, treatment-naive SMA patients (18.1 ± 6.8 years) with three SMN2 copies and complex spine anatomy. RESULTS: In the safety analysis, 14 treatment-related adverse events (AEs) occurred among 12 (71%) participants; all were related to the SIC and not nusinersen. Device-related AEs interfered with 2.5% of nusinersen doses. Four SICs (24%) required surgical revision due to mechanical malfunction with or without cerebrospinal fluid leak (n = 2), and one (6%) was removed due to Staphylococcus epidermidis meningitis. In the efficacy analysis, mean performance on the nine-hole peg test improved in dominant (15.9%, P = 0.012) and nondominant (19.0%, P = 0.008) hands and grip strength increased by 44.9% (P = 0.031). We observed no significant changes in motor scales, muscle force, pulmonary function, or SMA biomarkers. All participants in the efficacy cohort reported one or more subjective improvement(s) in endurance, purposeful hand use, arm strength, head control, and/or speech. DISCUSSION: For SMA patients with complex spine anatomy, the SIC allows for reliable outpatient administration of nusinersen that results in meaningful improvements in upper limb function, but introduces risks of technical malfunction and iatrogenic infection.

Lin28 reprograms inner ear glia to a neuronal fate.

Sensorineural hearing loss is irreversible and can be caused by loss of auditory neurons. Regeneration of neural cells from endogenous cells may offer a future tool to restore the auditory circuit and to enhance the performance of implantable hearing devices. Neurons and glial cells in the peripheral nervous system are closely related and originate from a common progenitor. Prior work in our lab indicated that in the early postnatal mouse inner ear, proteolipid protein 1 (Plp1) expressing glial cells could act as progenitor cells for neurons in vitro. Here, we used a transgenic mouse model to transiently overexpress Lin28, a neural stem cell regulator, in Plp1-positive glial cells. Lin28 promoted proliferation and conversion of auditory glial cells into neurons in vitro. To study the effects of Lin28 on endogenous glial cells after loss of auditory neurons in vivo, we produced a model of auditory neuropathy by selectively damaging auditory neurons with ouabain. After neural damage was confirmed by the auditory brainstem response, we briefly upregulated the Lin28 in Plp1-expressing inner ear glial cells. One month later, we analyzed the cochlea for neural marker expression by quantitative RT-PCR and immunohistochemistry. We found that transient Lin28 overexpression in Plp1-expressing glial cells induced expression of neural stem cell markers and subsequent conversion into neurons. This suggests the potential for inner ear glia to be converted into neurons as a regeneration therapy for neural replacement in auditory neuropathy.

Cross-sectional study on the quality of oral lichen planus videos on YouTube™.

BACKGROUND: YouTube™ is one of the most used platforms for patients looking for health-related information. The purpose of this cross-sectional study was to analyze the available information about oral lichen planus on YouTube™ and how users interact with it. METHODS: A YouTube™ search for oral lichen planus was performed, setting English UK (language) and United Kingdom (country). Two hundred and fifteen results were screened, and 36 videos met the inclusion criteria. Videos' quality was evaluated using the DISCERN and the Global Quality Scale tools, and by categorizing them through quality assessment, source, duration, views, likes, and dislikes of each video were noted. RESULTS: According to quality assessments, 55.6% of the videos were classified as useful, while the 35.1% were classified as misleading/dangerous. The DISCERN and GQS values were generally low (31.56 ± 10.38 and 2.33 ± 1.07, respectively); DISCERN and GQS were positively correlated with the video length and negatively correlate with the data of upload (p < 0.05). CONCLUSIONS: This study corroborates the results of others that a great number of health-related videos available on YouTube™ feature misleading or potentially dangerous information; although the quality seems to slightly improve over time, medical associations and researchers ought to plan strategies aimed at improving the quality of the information delivered through YouTube™ and other social media.

Comparison of perioperative outcomes between standard laparoscopic and robot-assisted approach in patients with rectosigmoid endometriosis.

INTRODUCTION: Robot-assisted laparoscopic surgery (RALS) has gained widespread application in several surgical specialties. Previous studies on the feasibility and safety of RALS vs standard laparoscopy (S-LPS) for rectosigmoid endometriosis are limited and reported conflicting data. This study aims to compare S-LPS and RALS in patients with rectosigmoid endometriosis in terms of perioperative surgical and clinical data. MATERIAL AND METHODS: This is a multicentric, observational, prospective cohort study including 44 patients affected by rectosigmoid endometriosis referred to two tertiary referral centers for endometriosis from September 2018 to September 2019. Patients were divided into two groups: 22 patients underwent S-LPS, and 22 underwent RALS. Our primary outcome was to compare operative time (from skin incision to suture) between the two groups. Secondary outcomes included: operative room time (patient entry into operative room and patient out), estimated blood loss, laparotomic conversion rate, length of hospital stay, perioperative complications, and evaluation of endometriosis-related symptoms at 12-month follow up. RESULTS: The two groups were comparable regarding preoperative and surgical data, except for higher rates of hysterectomies and bilateral uterosacral ligament removal procedures in the RALS group. Also after adjusting for these discrepancies, operative time was similar between S-LPS and RALS. Operative room time was statistically longer in the RALS group compared with that of S-LPS. No statistically significant difference was found concerning other study outcomes. Pain and bowel symptoms improved in both groups at 12-month follow up. CONCLUSIONS: If performed by expert teams, RALS provides similar perioperative outcomes compared with S-LPS in rectosigmoid endometriosis surgical treatment, except for longer operative room time.

Laparoscopic splenectomy both for primary cytoreductive surgery for advanced ovarian cancer and for secondary surgery for isolated spleen recurrence: feasibility and technique.

BACKGROUND: This study investigated the feasibility and safety of laparoscopic splenectomy conducted in the contexts of both laparoscopic secondary surgery for isolated recurrence in the spleen and primary laparoscopic cytoreductive surgery for advanced ovarian cancer. METHODS: We performed a perspective observational study including all consecutive patients with ovarian cancer who underwent laparoscopic splenectomy as part of primary cytoreductive procedures for advanced stage ovarian cancer or secondary surgery for isolated splenic recurrence between January 2016 and May 2020. RESULTS: We enrolled 13 consecutive patients, candidate to laparoscopic splenectomy as part of primary cytoreductive procedures for advanced stage ovarian cancer (6 patients) or secondary surgery for isolated splenic recurrence of platinum-sensitive ovarian cancer (7 patients). Median operative time (509 min [range, 200-845]) for primary cytoreductive surgery varied according to surgical complexity depending on the extensiveness of the disease. Median operative time for secondary surgery for isolated splenic metastasis was 253 min (90-380). Only 1 patient with isolated splenic recurrence required conversion to an open approach. No intraoperative complication occurred, and no intraoperative blood transfusions were required. Median hospital stay was 3 days (range, 2-5) for isolated recurrence and 9 days (7-18) for primary cytoreductive surgery. Complete tumor resection was achieved in all patients. Median time from surgery to adjuvant chemotherapy was 16 days (7-24). All six patients who underwent laparoscopic splenectomy during primary cytoreductive surgery remain alive, four of whom exhibit no evidence of disease (median follow-up 25 months [4-36]). Among patients who underwent laparoscopic splenectomy during secondary surgery for isolated splenic relapse, all patients are alive and only one had a central diaphragmatic relapse 2 years after surgery (median follow-up 17 months ([5-48 months]). CONCLUSIONS: The laparoscopic approach to splenectomy is feasible and safe both in patients undergoing primary cytoreductive surgery for advanced stage disease and those with isolated recurrence of ovarian cancer, without compromising survival and allowing early initiation of postoperative systemic chemotherapy.

Laparoscopic laterally extended endopelvic resection procedure for gynecological malignancies.

OBJECTIVES: Pelvic side wall infiltration by gynecological malignancies has been considered for a long time an absolute contraindication to curative resection. The development of the laterally extended endopelvic resection (LEER) has challenged this surgical paradigm. Although the LEER has been standardized in open surgery, only small studies have been published about its endoscopic feasibility. The objective of this study is to analyze the safety of LEER in patients with gynecological malignancies involving the pelvic side wall. METHODS: We retrospectively evaluated a consecutive series of patients who underwent a laparoscopically modified LEER between July 2014 and November 2018. This indicated gynecological tumors involving the pelvic sidewall and surgeries were conducted in two Italian institutions. All patients underwent pre-operative CT scan or PET to evaluate for distant metastases. Patients without suspicioun of distant metastasis underwent pelvic MRI and examination under anesthesia to establish the resectability of the disease and concomitant diagnostic laparoscopy to exclude intraperitoneal dissemination. All women with disease-free interval <6 months, and/or performance status >2 ECOG were excluded. Type of resection was defined based on the status of the pathologic margins: R0, microscopically negative (free margin <5 mm); R1, microscopically positive; and R2, macroscopically (grossly) positive. Disease-free survival was calculated from the date of primary surgery to the time of recurrence. Overall survival was defined as the time from primary surgery to death. RESULTS: Overall, 39 patients underwent a laparoscopic LEER and 18 (46.2%) patients were eligible for a laparoscopic approach. Laparoscopic LEER was performed as primary treatment for newly diagnosed tumors in eight patients (44.4%), and for recurrences in the other 10 patients (55.6%). No laparotomic conversions were registered. R0 resection was achieved with negative margins in all patients. The median operative time was 415 min (range, 285-615), median estimated blood loss was 285 mL (range, 100-600), and the median length of hospital stay was 10 days (range; 4-22). Only four patients (22.2%) needed blood intraoperative transfusion. In seven patients (38.9%), post-operative admission to intensive care unit was required. There were three (16.7%) intraoperative complications, all managed laparoscopically. In total there were six (33.3%) major postoperative complications: three patients (16.7%) experienced moderate hydronephrosis with normal renal function, which required temporary placement of nephrostomy; one patient (5.6%) had permanent urinary retention; and two patients (11.1%) had a reoperation, one for post-operative hemoperitoneum and another for complete vaginal cuff dehiscence. DISCUSSION: Laparoscopic LEER can be safely performed by experienced laparoscopic surgeons, in carefully selected patients with gynecological malignancies involving the lateral pelvic side wall, even for those in which a bladder and rectum sparing surgery appears possible. Further larger prospective trials are needed to evaluate the oncological and the long-term functional outcomes.

Incidence, predictors and clinical outcome of pancreatic fistula in patients receiving splenectomy for advanced or recurrent ovarian cancer: a large multicentric experience.

PURPOSE: To evaluate the incidence, predictors and clinical outcome of pancreatic fistulas in patients receiving splenectomy during cytoreductive surgery for advanced or recurrent ovarian cancer. METHODS: Data of women who underwent splenectomy during cytoreduction for advanced or recurrent ovarian cancer from December 2012 to May 2018 were retrospectively retrieved from the oncological databases of five institutions. Surgical, post-operative and follow-up data were analysed. RESULTS: Overall, 260 patients were included in the study. Pancreatic resection was performed in 45 (17.6%) women, 23 of whom received capsule resection alone, while 22 required tail resection. Hyperthermic intraperitoneal chemotherapy (HIPEC) was administered in 28 (10.8%) patients. In the overall population, a pancreatic fistula was detected in 32 (12.3%) patients, and pancreatic resection (p-value = 0.033) and HIPEC administration (p-value = 0.039) were associated with fistula development. In multivariate analysis, HIPEC (OR = 2.573; p-value = 0.058) was confirmed as a risk factor for fistula development in women receiving splenectomy alone, while concomitant cholecystectomy (OR = 2.680; p-value = 0.012) was identified as the only independent predictor of the occurrence of pancreatic fistulas in those receiving additional distal pancreatectomy. Although the median length of hospital stay was higher in women with pancreatic leakage (p-value = 0.008), the median time from surgery to adjuvant treatment was not significantly increased. CONCLUSION: HIPEC was identified as a risk factor for pancreatic fistulas in patients who underwent splenectomy alone, while concomitant cholecystectomy was the only independent predictor of fistula in those receiving additional pancreatectomy. The development of pancreatic leakage was not associated with increased post-operative mortality or delay in the initiation of chemotherapy.

Feasibility and safety of laparoscopic approach in obese patients with endometriosis: a multivariable regression analysis.

PURPOSE: To evaluate the feasibility and safety of laparoscopic excision of endometriotic lesions in obese women. METHODS: Retrospective analysis of prospectively collected data involving consecutive women scheduled for complete laparoscopic removal of macroscopic endometriotic lesions between January 2012 and November 2018. Operative time, laparotomic conversion rates, complication rates, and length of hospital stay were recorded. RESULTS: One thousand two hundred thirty women were enrolled and divided into two main groups, according to the World Health Organization classification of obesity, obese (body mass index ≥ 30 kg/m2) and non-obese (body mass index < 30 kg/m2). During the study period, 91 (7.4% of overall study cohort) obese women underwent surgery. At univariate analyses, significant differences between the two groups were found in terms of age, rates of severe endometriosis, American Society of Anesthesiologists physical status classification ≥ III, and different surgical procedures. Significant differences in terms of median operative time [125 (interquartile range (IQR) 85-165) in obese group vs 110 min (IQR 75-155) in non-obese group, P = 0.04] were observed. There were no significant differences between the obese and non-obese groups with respect to the other variables of interest. After adjusted multivariable regression models for potential confounders, difference in operating time (coefficient of 13.389; 95% CI 1.716, 25.060) was still found to be significant. CONCLUSION: In our tertiary care referral center, laparoscopic removal of endometriosis is feasible and safe, except for a slight increase of operative time and conversion rate.

Role of Extracellular Vesicles in Epithelial Ovarian Cancer: A Systematic Review.

Extracellular vesicles (EVs) are a heterogeneous group of cell-derived submicron vesicles released under physiological or pathological conditions. EVs mediate the cellular crosstalk, thus contributing to defining the tumor microenvironment, including in epithelial ovarian cancer (EOC). The available literature investigating the role of EVs in EOC has been reviewed following PRISMA guidelines, focusing on the role of EVs in early disease diagnosis, metastatic spread, and the development of chemoresistance in EOC. Data were identified from searches of Medline, Current Contents, PubMed, and from references in relevant articles from 2010 to 1 April 2020. The research yielded 194 results. Of these, a total of 36 papers, 9 reviews, and 27 original types of research were retained and analyzed. The literature findings demonstrate that a panel of EV-derived circulating miRNAs may be useful for early diagnosis of EOC. Furthermore, it appears clear that EVs are involved in mediating two crucial processes for metastatic and chemoresistance development: the epithelial-mesenchymal transition, and tumor escape from the immune system response. Further studies, more focused on in vivo evidence, are urgently needed to clarify the role of EV assessment in the clinical management of EOC patients.

Pathologic response to neoadjuvant chemotherapy in advanced ovarian cancer: utility of a scoring system to predict outcomes.

BACKGROUND: Growing evidence supports the role of neoadjuvant chemotherapy in patients with advanced epithelial ovarian cancer. Currently, there is no shared histopathologic scoring system to assess pathologic response in the specimens obtained at interval surgery after neoadjuvant chemotherapy This review aims to summarize the literature on pathologic response, focusing on proposed scoring systems. METHODS: The systematic review was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, focusing on the definition of pathologic response, its prognostic value, possible predictors, and future implications. Eighteen manuscripts focusing on pathologic response in epithelial ovarian cancer were selected for analysis. RESULTS: Overall, eight histopathologic scoring systems to evaluate pathologic response have been proposed. There are currently no available markers (serum, radiological, genomic) to select which patients could achieve the highest benefit from neoadjuvant chemotherapy experiencing a complete pathologic response. A three-tier scoring system (CRS) based on omental assessment and which classifies the response to neoadjuvant chemotherapy has been validated in external cohorts of epithelial ovarian cancer. This scoring system demonstrated adequate interobserver reproducibility. Data is limited on the pathologic complete response rate changes according to chemotherapy regimen. CONCLUSIONS: A histopathologic scoring system endowed with prognostic value could be helpful in personalizing the treatment decision in patients with epithelial ovarian cancer.

Systematic Review of Cytoreductive Surgery and Bevacizumab-Containing Chemotherapy in Advanced Ovarian Cancer: Focus on Safety.

BACKGROUND: Initial experiences reported increased surgical morbidities in patients receiving cytoreductive surgery for colorectal cancer after bevacizumab-containing chemotherapy; however, more recent literature suggests a favorable toxicity profile in patients with advanced ovarian cancer (AOC). With the aim of providing a more objective point of view on this controversial issue, we present here a systematic literature review. METHODS: Systematic revision of the available literature was conducted using the PubMed, MEDLINE, and EMBASE electronic databases. All studies reporting safety data regarding cytoreductive surgery performed before or after bevacizumab-containing chemotherapy have been analyzed for the purposes of this study. The study has been prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Forty-eight studies were retrieved from the electronic databases, with 23 (47.9%) being excluded due to an unsatisfactory study design. Among the remaining 25 manuscripts, 16 did not report data regarding surgical morbidities after cytoreductive surgery, therefore only 9 studies were included in the final analysis. Overall, 198 AOC patients received bevacizumab-containing neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) in the context of five studies, among whom 21 women experienced grade 3/4 postoperative complications (10.6%), which appears to be in line with data reported in patients receiving IDS after carboplatin-paclitaxel NACT. Results from phase I-II clinical trials, and dataset analysis from GOG-0218, did not observe an increased incidence of complications in AOC patients receiving bevacizumab-containing adjuvant chemotherapy after cytoreductive surgery. CONCLUSIONS: The incorporation of bevacizumab into first-line chemotherapy was not associated with increased morbidities before and after cytoreductive surgery in women with AOC.

Quality of Life in Women After Pelvic Exenteration for Gynecological Malignancies: A Multicentric Study.

OBJECTIVES: This retrospective, multicentric study investigates quality-of-life issues and emotional distress in gynecological cancer survivors submitted to pelvic exenteration (PE). METHODS: The Global Health Status scale of European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30; the EORTC QLQ-CX24 (CX24), and EORTC QLQ-OV28 questionnaires were administered at least 12 months from surgery only in women with no evidence of further recurrence after PE. Statistical analysis was performed by the analysis of variance (for repeated measures. RESULTS: Ninety-six subjects affected by gynecological malignancies receiving PE were enrolled in the study. Anterior PE was performed in 47 patients (49%), posterior PE was performed in 29 cases (30.2%), and total PE performed in 20 women (20.8%). In 38 cases (39.6%), a definitive colostomy was performed. Urinary diversion with continent pouch was created in 11 patients. (11.5%), whereas in the remaining cases, a noncontinent pouch was reconstructed. Patients showed a significant discomfort in attitude to disease (71.5 ± 4.7), body image (48.9 ± 6.4), financial difficulties (56.2 ± 5.8), gastrointestinal symptoms (constipation, 47.8 ± 5.1; diarrhea, 62.4 ± 6.6; appetite loss, 43.6 ± 6.7), insomnia (64.5 ± 6.6), Global Health Status (64.6 ± 3.8), physical functioning (65.8 ± 4.6), role functioning (58.8 ± 5.8), and emotional functioning (67.4 ± 4.2). A higher number of ostomies (hazard rate [HR], 7.613; P = 0.012), the creation of a noncontinent bladder (HR, 8.230; P = 0.009), and of definitive colostomy (HR, 8.516; P = 0.008) emerged as independent predictors of poorer Global Health Status scores. Older age (HR, 11.235; P = 0.003), vaginal/vulvar cancer (HR, 7.369; P = 0.013), total/posterior PE (HR, 7.393; P = 0.013), higher number of ostomies (HR, 7.613; P = 0.012), the creation of a noncontinent bladder (HR, 8.230; P = 0.009), and of definitive colostomy (HR, 8.516; P = 0.008) emerged as independent predictors of lower body image levels. CONCLUSIONS: Long-term psycho-oncological support is strongly recommended. The reduction of ostomies seems the most effective way to improve patients' quality of life.

Tumor Size, an Additional Risk Factor of Local Recurrence in Low-Risk Endometrial Cancer: A Large Multicentric Retrospective Study.

OBJECTIVE: The identification of patients with endometrial cancer (EC) at higher risk for relapse is critical to individualize and better tailor postoperative treatment. No evidence is available regarding the possible association between tumor size (TS) and the risk of local recurrence. The purpose of this study was to analyze the correlation between TS and risk/type of recurrence in EC patients, stratified according to the new European Society of Medical Oncology-European Society of Gynecological Oncology-European Society for Radiotherapy and Oncology classification. METHODS: Data of patients with histologically proven EC who received primary surgical treatment between November 1999 and June 2015 were retrospectively retrieved from 5 institutions. Optimal TS cutoff was calculated using a receiver operating characteristic curve. Site of recurrence as a function of TS and groups of risk were analyzed. Local recurrence-free survival, recurrence-free survival, and overall survival were calculated using the Kaplan-Meier method. RESULTS: Data of 1166 patients were analyzed. Among them, 514 (44.1%) had low-risk EC, 174 (14.9%) had intermediate risk EC, 173 (14.8%) had high-intermediate risk EC, and 305 (26.2%) had high-risk EC. A total of 134 (11.5%) women had recurrence: 47 (4%) of them had local relapse, 30 (2.6%) had locoregional relapse, and 57 (4.9%) had distant relapse. Tumor size 25 mm or greater emerged as the threshold for the prediction of a higher rate of local recurrence (P < 0.0001, hazard ratio = 18.2, P = 0.005) and a lower local recurrence-free survival and recurrence-free survival (P < 0.0001) only in patients with low-risk EC. There was no statistically significant correlation between TS and recurrence in the other risk groups. CONCLUSIONS: In this very large series, tumor size emerges as an independent prognostic factor of local recurrence in women with low-risk EC and could be a valuable additional criterion to personalize the treatment approach to these patients.