Endometrial carcinosarcoma.

Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements. The majority of endometrial carcinosarcomas are characterized by p53 abnormalities. The proportion of POLE and microsatellite instablity-high (MSI-H) is directly related to the epithelial component, being approximately 25% and 3% in endometrioid and non-endometrioid components.The management of non-metastatic disease is based on a multimodal approach with optimal surgery followed by (concomitant or sequential) chemotherapy and radiotherapy, even for early stages. Palliative chemotherapy is recommended in the metastatic or recurrent setting, with carboplatin/paclitaxel doublet being the first-line regimen. Although the introduction of immunotherapy plus/minus a tyrosine kinase inhibitor shifted the paradigm of treatment of patients with recurrent endometrial cancer, patients with endometrial carcinosarcoma were excluded from most studies evaluating single-agent immunotherapy or the combination. However, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of pembrolizumab and lenvatinib in endometrial cancer (all histotypes) after progression on chemotherapy and single-agent immunotherapy in MSI-H cancers. In the era of precision medicine, emerging knowledge on molecular endometrial carcinosarcoma is opening new promising therapeutic options for more personalized treatment. The present review outlines state-of-the-art knowledge and future directions for patients with endometrial carcinosarcoma.

Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial.

BACKGROUND: Few prospective studies have compared poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors to chemotherapy for the treatment of BRCA1-mutated or BRCA2-mutated ovarian carcinoma. We aimed to assess rucaparib versus platinum-based and non-platinum-based chemotherapy in this setting. METHODS: In this open-label, randomised, controlled, phase 3 study (ARIEL4), conducted in 64 hospitals and cancer centres across 12 countries (Brazil, Canada, Czech Republic, Hungary, Israel, Italy, Poland, Russia, Spain, Ukraine, the UK, and the USA), we recruited patients aged 18 years and older with BRCA1-mutated or BRCA2-mutated ovarian carcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had received two or more previous chemotherapy regimens. Eligible patients were randomly assigned (2:1), using an interactive response technology and block randomisation (block size of six) and stratified by progression-free interval after the most recent platinum-containing therapy, to oral rucaparib (600 mg twice daily) or chemotherapy (administered per institutional guidelines). Patients assigned to the chemotherapy group with platinum-resistant or partially platinum-sensitive disease were given paclitaxel (starting dose 60-80 mg/m2 on days 1, 8, and 15); those with fully platinum-sensitive disease received platinum-based chemotherapy (single-agent cisplatin or carboplatin, or platinum-doublet chemotherapy). Patients were treated in 21-day or 28-day cycles. The primary endpoint was investigator-assessed progression-free survival, assessed in the efficacy population (all randomly assigned patients with deleterious BRCA1 or BRCA2 mutations without reversion mutations), and then in the intention-to-treat population (all randomly assigned patients). Safety was assessed in all patients who received at least one dose of assigned study treatment. This study is registered with ClinicalTrials.gov, NCT02855944; enrolment is complete, and the study is ongoing. FINDINGS: Between March 1, 2017, and Sept 24, 2020, 930 patients were screened, of whom 349 eligible patients were randomly assigned to rucaparib (n=233) or chemotherapy (n=116). Median age was 58 years (IQR 52-64) and 332 (95%) patients were White. As of data cutoff (Sept 30, 2020), median follow-up was 25·0 months (IQR 13·8-32·5). In the efficacy population (220 patients in the rucaparib group; 105 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 7·3-9·1) in the rucaparib group versus 5·7 months (5·5-7·3) in the chemotherapy group (hazard ratio [HR] 0·64 [95% CI 0·49-0·84]; p=0·0010). In the intention-to-treat population (233 in the rucaparib group; 116 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 6·7-7·9) in the rucaparib group versus 5·7 months (5·5-6·7) in the chemotherapy group (HR 0·67 [95% CI 0·52-0·86]; p=0·0017). Most treatment-emergent adverse events were grade 1 or 2. The most common grade 3 or worse treatment-emergent adverse event was anaemia or decreased haemoglobin (in 52 [22%] of 232 patients in the rucaparib group vs six [5%] of 113 in the chemotherapy group). Serious treatment-emergent adverse events occurred in 62 (27%) patients in the rucaparib group versus 13 (12%) in the chemotherapy group; serious adverse events considered related to treatment by the investigator occurred in 32 (14%) patients in the rucaparib group and six (5%) in the chemotherapy group. Three deaths were considered to be potentially related to rucaparib (one due to cardiac disorder, one due to myelodysplastic syndrome, and one with an unconfirmed cause). INTERPRETATION: Results from the ARIEL4 study support rucaparib as an alternative treatment option to chemotherapy for patients with relapsed, BRCA1-mutated or BRCA2-mutated ovarian carcinoma. FUNDING: Clovis Oncology.

Challenges in lower limb lymphoedema assessment based on limb volume change: Lessons learnt from the SENTIX prospective multicentre study.

BACKGROUND: Lower limb lymphoedema (LLL) is the most disabling adverse effect of surgical staging of pelvic lymph nodes. However, the lack of standardisation of volumetric LLL assessment hinders direct comparison between the studies and makes LLL reporting unreliable. The aim of our study is to report outcomes from a prospective trial that have implications for LLL assessment standardisation. METHODS: In the prospective international multicentre trial SENTIX, a group of 150 patients with stage IA1-IB2 cervical cancer treated by uterine surgery with bilateral sentinel lymph node biopsy was prospectively evaluated by objective LLL assessment, based on limb volume change (LVC) using circumferrential limb measurements and subjective patient-reported swelling. The assessments were conducted in six-month periods over 24 months post-surgery. RESULTS: Patient LVC substantially fluctuated in both positive and negative directions, which were comparable in frequency up to ±14% change. Thirty-eight patients experienced persistent LVC increase >10% classified as LLL, with nine months median time to onset. Some 34.2% of cases experienced onset later than one year after the surgery. Thirty-three patients (22%) experienced transient oedema characterised as LVC >10%, which resolved without intervention between two consequent follow-up visits. No significant correlation between LVC >10% and a patient-reported swelling was observed. CONCLUSIONS: Given that we observed comparable fluctuations of the the lower-limb volumes after surgical treatment of cervical cancer in both positive and negative direction up to ±14%, the diagnostic threshold for LLL diagnosis based on LVC should be increased to >15% LVC. The distinction of transient oedema from persistent LLL requires repeated measurements. Also, as one-third of LLL cases are diagnosed >1-year post-surgery, a sufficient follow-up duration needs to be ensured. Patient-reported swelling correlated poorly with LVC and should only be used as an adjunct to objective LLL assessment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02494063.

Clear cell carcinoma of the endometrium.

Clear cell endometrial carcinoma represents an uncommon and poorly understood entity. Data from molecular/genomic profiling highlighted the importance of various signatures in assessing the prognosis of endometrial cancer according to four classes of risk (POLE mutated, MMRd, NSMP, and p53 abnormal). Unfortunately, data specific to clear cell histological subtype endometrial cancer are lacking. More recently, data has emerged to suggest that most of the patients (more than 80%) with clear cell endometrial carcinoma are characterized by p53 abnormality or NSMP type. This classification has important therapeutic implications. Although it is an uncommon entity, clear cell endometrial cancer patients with POLE mutation seem characterized by a good prognosis. Chemotherapy is effective in patients with NSMP (especially in stage III and IV) and patients with p53 abnormal disease (all stages). While, preliminary data suggested that patients with MMRd are less likely to benefit from chemotherapy. The latter group appears to benefit much more from immune checkpoint inhibitors: recent data from clinical trials on pembrolizumab plus lenvatinib and nivolumab plus cabozantinib supported that immunotherapy plus tyrosine kinase inhibitors (TKI) would be the most appropriate treatment for recurrent non-endometrioid endometrial cancer (including clear cell carcinoma) after the failure of platinum-based chemotherapy. Moreover, ongoing clinical trials testing the anti-tumor activity of innovative products will clarify the better strategies for advanced/recurrent clear cell endometrial carcinoma. Further prospective evidence is urgently needed to better characterize clear cell endometrial carcinoma.

SUCCOR cone study: conization before radical hysterectomy.

OBJECTIVE: To evaluate disease-free survival of cervical conization prior to radical hysterectomy in patients with stage IB1 cervical cancer (International Federation of Gynecology and Obstetrics (FIGO) 2009). METHODS: A multicenter retrospective observational cohort study was conducted including patients from the Surgery in Cervical Cancer Comparing Different Surgical Aproaches in Stage IB1 Cervical Cancer (SUCCOR) database with FIGO 2009 IB1 cervical carcinoma treated with radical hysterectomy between January 1, 2013, and December 31, 2014. We used propensity score matching to minimize the potential allocation biases arising from the retrospective design. Patients who underwent conization but were similar for other measured characteristics were matched 1:1 to patients from the non-cone group using a caliper width ≤0.2 standard deviations of the logit odds of the estimated propensity score. RESULTS: We obtained a weighted cohort of 374 patients (187 patients with prior conization and 187 non-conization patients). We found a 65% reduction in the risk of relapse for patients who had cervical conization prior to radical hysterectomy (hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.16 to 0.75, p=0.007) and a 75% reduction in the risk of death for the same sample (HR 0.25, 95% CI 0.07 to 0.90, p=0.033). In addition, patients who underwent minimally invasive surgery without prior conization had a 5.63 times higher chance of relapse compared with those who had an open approach and previous conization (HR 5.63, 95% CI 1.64 to 19.3, p=0.006). Patients who underwent minimally invasive surgery with prior conization and those who underwent open surgery without prior conization showed no differences in relapse rates compared with those who underwent open surgery with prior cone biopsy (reference) (HR 1.94, 95% CI 0.49 to 7.76, p=0.349 and HR 2.94, 95% CI 0.80 to 10.86, p=0.106 respectively). CONCLUSIONS: In this retrospective study, patients undergoing cervical conization before radical hysterectomy had a significantly lower risk of relapse and death.

SUCCOR quality: validation of ESGO quality indicators for surgical treatment of cervical cancer.

OBJECTIVE: To evaluate whether compliance with European Society of Gynaecological Oncology (ESGO) surgery quality indicators impacts disease-free survival in patients undergoing radical hysterectomy for cervical cancer. METHODS: In this retrospective cohort study, 15 ESGO quality indicators were assessed in the SUCCOR database (patients who underwent radical hysterectomy for International Federation of Gynecology and Obstetrics (FIGO) stage 2009 IB1, FIGO 2018 IB1, and IB2 cervical cancer between January 2013 and December 2014), and the final score ranged between 0 and 16 points. Centers with more than 13 points were classified as high-quality indicator compliance centers. We constructed a weighted cohort using inverse probability weighting to adjust for the variables. We compared disease-free survival and overall survival using Cox proportional hazards regression analysis in the weighted cohort. RESULTS: A total of 838 patients were included in the study. The mean number of quality indicators compliance in this cohort was 13.6 (SD 1.45). A total of 479 (57.2%) patients were operated on at high compliance centers and 359 (42.8%) patients at low compliance centers. High compliance centers performed more open surgeries (58.4% vs 36.7%, p<0.01). Women who were operated on at centers with high compliance with quality indicators had a significantly lower risk of relapse (HR=0.39; 95% CI 0.25 to 0.61; p<0.001). The association was reduced, but remained significant, after further adjustment for conization, surgical approach, and use of manipulator surgery (HR=0.48; 95% CI 0.30 to 0.75; p=0.001) and adjustment for adjuvant therapy (HR=0.47; 95% CI 0.30 to 0.74; p=0.001). Risk of death from disease was significantly lower in women operated on at centers with high adherence to quality indicators (HR=0.43; 95% CI 0.19 to 0.97; p=0.041). However, the association was not significant after adjustment for conization, surgical approach, use of manipulator surgery, and adjuvant therapy. CONCLUSIONS: Patients with early cervical cancer who underwent radical hysterectomy in centers with high compliance with ESGO quality indicators had a lower risk of recurrence and death.

Voiding recovery after radical parametrectomy in cervical cancer patients: An international prospective multicentre trial - SENTIX.

OBJECTIVE: Voiding dysfunctions represent a leading morbidity after radical hysterectomy performed in patients with early-stage cervical cancer. The aim of this study was to perform ad hoc analysis of factors influencing voiding recovery in SENTIX (SENTinel lymph node biopsy in cervIX cancer) trial. METHODS: The SENTIX trial (47 sites, 18 countries) is a prospective study on sentinel lymph node biopsy without pelvic lymphadenectomy in patients with early-stage cervical cancer. Overall, the data of 300 patients were analysed. Voiding recovery was defined as the number of days from surgery to bladder catheter/epicystostomy removal or to post-voiding urine residuum ≤50 mL. RESULTS: The median voiding recovery time was three days (5th-95th percentile: 0-21): 235 (78.3%) patients recovered in <7 days and 293 (97.7%) in <30 days. Only seven (2.3%) patients recovered after >30 days. In the multivariate analysis, only previous pregnancy (p = 0.033) and type of parametrectomy (p < 0.001) significantly influenced voiding recovery >7 days post-surgery. Type-B parametrectomy was associated with a higher risk of delayed voiding recovery than type-C1 (OR = 4.69; p = 0.023 vs. OR = 3.62; p = 0.052, respectively), followed by type-C2 (OR = 5.84; p = 0.011). Both previous pregnancy and type C2 parametrectomy independently prolonged time to voiding recovery by two days. CONCLUSIONS: Time to voiding recovery is significantly related to previous pregnancy and type of parametrectomy but it is not influenced by surgical approach (open vs minimally invasive), age, or BMI. Type B parametrectomy, without direct visualisation of nerves, was associated with longer recovery than nerve-sparing type C1. Importantly, voiding dysfunctions after radical surgery are temporary, and the majority of the patients recover in less than 30 days, including patients after C2 parametrectomy.

Uterine serous carcinoma.

Serous endometrial cancer represents a relative rare entity accounting for about 10% of all diagnosed endometrial cancer, but it is responsible for 40% of endometrial cancer-related deaths. Patients with serous endometrial cancer are often diagnosed at earlier disease stage, but remain at higher risk of recurrence and poorer prognosis when compared stage-for-stage with endometrioid subtype endometrial cancer. Serous endometrial cancers are characterized by marked nuclear atypia and abnormal p53 staining in immunohistochemistry. The mainstay of treatment for newly diagnosed serous endometrial cancer includes a multi-modal therapy with surgery, chemotherapy and/or radiotherapy. Unfortunately, despite these efforts, survival outcomes still remain poor. Recently, The Cancer Genome Atlas (TCGA) Research Network classified all endometrial cancer types into four categories, of which, serous endometrial cancer mostly is found within the "copy number high" group. This group is characterized by the increased cell cycle deregulation (e.g., CCNE1, MYC, PPP2R1A, PIKCA, ERBB2 and CDKN2A) and TP53 mutations (90%). To date, the combination of pembrolizumab and lenvatinib is an effective treatment modality in second-line therapy, with a response rate of 50% in advanced/recurrent serous endometrial cancer. Owing to the unfavorable outcomes of serous endometrial cancer, clinical trials are a priority. At present, ongoing studies are testing novel combinations of various targeted and immunotherapeutic agents in newly diagnosed and advanced/recurrent endometrial cancer - an important strategy for serous endometrial cancer, whereby tumors are usually p53+ and pMMR, making response to PD-1 inhibitor monotherapy unlikely. Here, the rare tumor working group (including members from the European Society of Gynecologic Oncology (ESGO), Gynecologic Cancer Intergroup (GCIG), and Japanese Gynecologic Oncology Group (JGOG)), performed a narrative review reporting on the current landscape of serous endometrial cancer and focusing on standard and emerging therapeutic options for patients affected by this difficult disease.

Radical hysterectomy in early cervical cancer in Europe: characteristics, outcomes and evaluation of ESGO quality indicators.

INTRODUCTION: Comprehensive updated information on cervical cancer surgical treatment in Europe is scarce. OBJECTIVE: To evaluate baseline characteristics of women with early cervical cancer and to analyze the outcomes of the ESGO quality indicators after radical hysterectomy in the SUCCOR database. METHODS: The SUCCOR database consisted of 1272 patients who underwent radical hysterectomy for stage IB1 cervical cancer (FIGO 2009) between January 2013 and December 2014. After exclusion criteria, the final sample included 1156 patients. This study first described the clinical, surgical, pathological, and follow-up variables of this population and then analyzed the outcomes (disease-free survival and overall survival) after radical hysterectomy. Surgical-related ESGO quality indicators were assessed and the accomplishment of the stated recommendations was verified. RESULTS: The mean age of the patients was 47.1 years (SD 10.8), with a mean body mass index of 25.4 kg/m2 (SD 4.9). A total of 423 (36.6%) patients had a previous cone biopsy. Tumor size (clinical examination) <2 cm was observed in 667 (57.7%) patients. The most frequent histology type was squamous carcinoma (794 (68.7%) patients), and positive lymph nodes were found in 143 (12.4%) patients. A total of 633 (54.8%) patients were operated by open abdominal surgery. Intra-operative complications occurred in 108 (9.3%) patients, and post-operative complications during the first month occurred in 249 (21.5%) patients, with bladder dysfunction as the most frequent event (119 (10.3%) patients). Clavien-Dindo grade III or higher complication occurred in 56 (4.8%) patients. A total of 510 (44.1%) patients received adjuvant therapy. After a median follow-up of 58 months (range 0-84), the 5-year disease-free survival was 88.3%, and the overall survival was 94.9%. In our population, 10 of the 11 surgical-related quality indicators currently recommended by ESGO were fully fulfilled 5 years before its implementation. CONCLUSIONS: In this European cohort, the rate of adjuvant therapy after radical hysterectomy is higher than for most similar patients reported in the literature. The majority of centers were already following the European recommendations even 5 years prior to the ESGO quality indicator implementations.

Evaluation of zinc and copper levels in vaginal tissues and whole blood: correlation with age.

BACKGROUND: Zinc and copper are essential trace elements and play a crucial role in the homeostasis of connective tissues. In this study, we aimed to define zinc and copper levels in the vaginal tissue and establish whether a correlation exists between the zinc and copper levels either or both in whole blood or vaginal tissue samples and whether the finding correlates with the age of the patient or at least with her menopausal status. METHODS: We collected whole blood and vaginal tissue samples from 32 women and measured their zinc and copper levels by inductively coupled plasma optical emission spectrometry. We have performed Student's t test to evaluate the differences in the mean levels of trace elements and multiple regression to evaluate the association between vaginal tissue zinc/copper levels and age, menopausal status, number of vaginal deliveries, and zinc/copper blood levels. RESULTS: Zinc levels were significantly higher in both the vaginal tissues and whole blood samples than copper levels (p < 0.01). In the vaginal tissue samples, a strong positive correlation could be detected between zinc and copper levels (r = 0.82, p < 0.01). In the vaginal tissue, a negative correlation was found for zinc and copper levels with the age of women (r = - 0.27, p = 0.04 and r = - 0.56, p < 0.01). Multiple linear regression model (age, menopausal status, vaginal delivery and copper/zinc blood levels) showed that only age remained a significant predictor for zinc and copper vaginal tissues levels (p = 0.03, 95% CI - 2.28 to - 0.06; p = 0.004, 95% CI - 1.76 to - 0.34). CONCLUSIONS: Zinc and copper levels in the vaginal tissue decline with age. Out of the examined variables (age, menopausal status, vaginal delivery, and copper/zinc levels), only age is a significant predictor of vaginal zinc/copper levels.

Analysis of nationwide reflection of rising cesarean section rate in neonatal outcomes of Hungary.

AIM: The authors investigated the effect of rising cesarean rates on maternal and perinatal mortality and in neonatal morbidity in Hungary. METHODS: The authors searched the validated Hungarian National Health database of neonatal discharge records for ICD-10 codes: P0590 (growth restriction); P2010 (fetal hypoxia in labor); P2090 (intrauterine hypoxia); P2200 (respiratory distress syndrome); P2390 (congenital pneumonia); P2400 (meconium aspiration); P2850 (respiratory insufficiency); P3990 (neonatal infection); P9130 (cerebral irritability) and P9141 (cerebral depression) collected between 2006 and 2015. County-specific number of deliveries, perinatal deaths, and data on the route of delivery from the national database were also collected. Controlling for regional disparities with Human Development Index was also performed. Logistic regression analysis was performed to identify determinants of early neonatal mortality. RESULTS: While cesarean section-rate rose from 28.6% to 38.2% perinatal mortality stayed within the range between 7.8‰ and 6.1‰. Early (0-6 days) neonatal mortality (NMR) of the whole country in 2006 was 2.8‰ and showed a significant decrease over the years to reach 1.7‰ in 2015. The rate of most neonatal morbidities decreased significantly. Controlled regression analysis proved that cesarean rates negatively influenced neonatal mortality rates. CONCLUSION: The rise of the cesarean section rate in Hungary between 2006 and 2015 was associated with a detectable reduction of perinatal mortality and morbidity; however, the proportion of improvement in neonatal morbidity is far less than the increment in cesarean rate.

SUCCOR study: an international European cohort observational study comparing minimally invasive surgery versus open abdominal radical hysterectomy in patients with stage IB1 cervical cancer.

BACKGROUND: Minimally invasive surgery in cervical cancer has demonstrated in recent publications worse outcomes than open surgery. The primary objective of the SUCCOR study, a European, multicenter, retrospective, observational cohort study was to evaluate disease-free survival in patients with stage IB1 (FIGO 2009) cervical cancer undergoing open vs minimally invasive radical hysterectomy. As a secondary objective, we aimed to investigate the association between protective surgical maneuvers and the risk of relapse. METHODS: We obtained data from 1272 patients that underwent a radical hysterectomy by open or minimally invasive surgery for stage IB1 cervical cancer (FIGO 2009) from January 2013 to December 2014. After applying all the inclusion-exclusion criteria, we used an inverse probability weighting to construct a weighted cohort of 693 patients to compare outcomes (minimally invasive surgery vs open). The first endpoint compared disease-free survival at 4.5 years in both groups. Secondary endpoints compared overall survival among groups and the impact of the use of a uterine manipulator and protective closure of the colpotomy over the tumor in the minimally invasive surgery group. RESULTS: Mean age was 48.3 years (range; 23-83) while the mean BMI was 25.7 kg/m2 (range; 15-49). The risk of recurrence for patients who underwent minimally invasive surgery was twice as high as that in the open surgery group (HR, 2.07; 95% CI, 1.35 to 3.15; P=0.001). Similarly, the risk of death was 2.42-times higher than in the open surgery group (HR, 2.45; 95% CI, 1.30 to 4.60, P=0.005). Patients that underwent minimally invasive surgery using a uterine manipulator had a 2.76-times higher hazard of relapse (HR, 2.76; 95% CI, 1.75 to 4.33; P<0.001) and those without the use of a uterine manipulator had similar disease-free-survival to the open surgery group (HR, 1.58; 95% CI, 0.79 to 3.15; P=0.20). Moreover, patients that underwent minimally invasive surgery with protective vaginal closure had similar rates of relapse to those who underwent open surgery (HR, 0.63; 95% CI, 0.15 to 2.59; P<0.52). CONCLUSIONS: Minimally invasive surgery in cervical cancer increased the risk of relapse and death compared with open surgery. In this study, avoiding the uterine manipulator and using maneuvers to avoid tumor spread at the time of colpotomy in minimally invasive surgery was associated with similar outcomes to open surgery. Further prospective studies are warranted.

The Effect of Vaginal Microablative Fractional CO2 Laser Treatment on Vaginal Cytology.

BACKGROUND AND OBJECTIVES: Most recently vaginal laser treatment was introduced as a new option for women with genitourinary syndrome of menopause, vaginal dryness. Our objective was to assess the effects of intravaginal CO2 laser treatment on vaginal cytology. STUDY DESIGN/MATERIALS AND METHODS: Fifty-two women with symptoms of vaginal dryness were enrolled and underwent vaginal laser treatment using a fractional CO2 laser. Patients received three vaginal laser treatments 4 weeks apart. Vaginal cytology was obtained before the first treatment and 4 weeks after each additional treatment. Vaginal dryness was assessed by using a Visual Analog Scale (VAS). RESULTS: Out of the 52 women enrolled, 34 were in menopause. Postmenopausal women had significantly lower vaginal maturation values (VMV) compared with premenopausal women at the baseline visit (mean ± standard deviation [SD], 42 ± 23 vs. 68 ± 13, P < 0.01). The vaginal dryness VAS was higher (worse) in postmenopausal women compared with premenopausal cases (mean ± SD, 5.7 ± 4 vs. 2.4 ± 3, P < 0.01). The VMV did not change significantly over time after vaginal laser treatment. However vaginal dryness VAS improved significantly after each treatment. Both in the premenopausal and postmenopausal groups, vaginal dryness scores improved significantly from baseline after the three treatments (postmenopausal 5.7 ± 4 vs. 1.6 ± 2.5, P < 0.01 and premenopausal 2.4 ± 3 vs. 0.2 ± 0.5, P < 0.01). Those patients who had improvement in VMV had significantly better (lower) dryness VAS compared with those women without an improvement in VMV after the three treatments (mean ± SD, 0.3 ± 0.8 vs. 1.6 ± 2.6, P = 0.04). CONCLUSIONS: Vaginal dryness VAS improved significantly in a cohort of premenopausal and postmenopausal women undergoing vaginal CO2 laser treatment despite no significant change in vaginal cytology. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.

The Effect of Fractional CO2 Laser Treatment on the Symptoms of Pelvic Floor Dysfunctions: Pelvic Floor Distress Inventory-20 Questionnaire.

BACKGROUND AND OBJECTIVES: To assess the improvement on pelvic floor distress (PFD)-related urogenital symptoms using validated questionnaires after intravaginal CO2 laser treatment. STUDY DESIGN/MATERIALS AND METHODS: Forty postmenopausal women with genitourinary symptoms of menopause (GSM) were enrolled into this prospective cohort study and underwent vaginal laser treatment using MonaLisa Touch® fractional CO 2 laser system. Patients received three vaginal laser treatments with 360° probe 4 weeks apart. A three-component Pelvic Floor Distress Inventory (PFDI-20) validated questionnaire was filled out by each patient before each session and 4 weeks after the final treatment. Wilcoxon rank sum test was used to compare the before and after treatment scores. RESULTS: Pelvic Organ Prolapse Distress Inventory (POPDI-6) scores were not significantly different after the first treatment compared with baseline (mean ± standard deviation [SD], 21 ± 18 vs. 17 ± 15, P = 0.44). However, each subsequent treatment resulted in further, statistically significant improvement in symptom scores (14 ± 15, P = 0.03 and 13 ± 13, P = 0.01, after the second and third treatments, respectively). Similarly, Urinary Distress Inventory (UDI-6) scores were not significantly different after the first laser treatment (mean ± SD, 36 ± 25 vs. 29 ± 23, P = 0.36). After the second and third treatments there were significant improvement in the standardized scores (24 ± 20, P = 0.03 and 22 ± 21, P = 0.01). Colorectal-Anal Distress Inventory (CRADI-8) scores did not change significantly after three laser treatments. CONCLUSIONS: Three sessions of microablative fractional CO2 vaginal laser treatment significantly improves patient reported urinary and pelvic organ prolapse symptoms. Lasers Surg. Med. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Suprapubic pressure facilitates the procedure of office hysteroscopy: A randomized controlled trial.

AIM: To minimize the experienced pain during office hysteroscopy, a number of technical approaches and maneuvers are used. The aim of the study was to assess the effect of suprapubic pressure (SuPuP) applied during hysteroscopy. The impact of this maneuver on experienced pain (assessed by visual analog scale [VAS]) and duration of passage through the cervical canal was measured and compared to a reference group with no SuPuP. METHODS: Hysteroscopy was performed in study subjects as part of their infertility work-up. Patients were randomized into two groups as part of a controlled trial. In group 1, SuPuP was applied while inserting the scope; in group 2, SuPuP was not applied. Pain experienced during the procedure was measured on a 0-10 VAS. Duration of passage through the cervical canal was measured by analyzing the video of the procedure. The effect of SuPuP was estimated by testing for between-groups differences in these outcomes. RESULTS: The number of patients included the study was 60. Mean (SD) VAS score was 3.40 (1.276) in group 1 compared to 3.33 (0.802) in group 2 (P = 0.809). Mean (SD) time of passage through the cervical canal in group 1 was 30.5 (18.37) seconds compared to 43.0 (24.51) seconds in group 2 (P = 0.029). CONCLUSION: Applying suprapubic pressure could facilitate the procedure by significantly shortening the duration of the passage through the cervical canal, but significantly not reduces the pain experienced during hysteroscopy. Further studies are to be undertaken to investigate the advantages of suprapubic pressure during office hysteroscopy.

Circulating miRNA Profiling in Plasma Samples of Ovarian Cancer Patients.

Ovarian cancer is one of the most common cancer types in women characterized by a high mortality rate due to lack of early diagnosis. Circulating miRNAs besides being important regulators of cancer development could be potential biomarkers to aid diagnosis. We performed the circulating miRNA expression analysis in plasma samples obtained from ovarian cancer patients stratified into FIGO I, FIGO III, and FIGO IV stages and from healthy females using the NanoString quantitative assay. Forty-five miRNAs were differentially expressed, out of these 17 miRNAs showed significantly different expression between controls and patients, 28 were expressed only in patients, among them 19 were expressed only in FIGO I patients. Differentially expressed miRNAs were ranked by the network-based analysis to assess their importance. Target genes of the differentially expressed miRNAs were identified then functional annotation of the target genes by the GO and KEGG-based enrichment analysis was carried out. A general and an ovary-specific protein-protein interaction network was constructed from target genes. Results of our network and the functional enrichment analysis suggest that besides HSP90AA1, MYC, SP1, BRCA1, RB1, CFTR, STAT3, E2F1, ERBB2, EZH2, and MET genes, additional genes which are enriched in cell cycle regulation, FOXO, TP53, PI-3AKT, AMPK, TGFß, ERBB signaling pathways and in the regulation of gene expression, proliferation, cellular response to hypoxia, and negative regulation of the apoptotic process, the GO terms have central importance in ovarian cancer development. The aberrantly expressed miRNAs might be considered as potential biomarkers for the diagnosis of ovarian cancer after validation of these results in a larger cohort of ovarian cancer patients.

Aberrant Methylation Status of Tumour Suppressor Genes in Ovarian Cancer Tissue and Paired Plasma Samples.

Ovarian cancer is a highly heterogeneous disease and its formation is affected by many epidemiological factors. It has typical lack of early signs and symptoms, and almost 70% of ovarian cancers are diagnosed in advanced stages. Robust, early and non-invasive ovarian cancer diagnosis will certainly be beneficial. Herein we analysed the regulatory sequence methylation profiles of the RASSF1, PTEN, CDH1 and PAX1 tumour suppressor genes by pyrosequencing in healthy, benign and malignant ovarian tissues, and corresponding plasma samples. We recorded statistically significant higher methylation levels (p < 0.05) in the CDH1 and PAX1 genes in malignant tissues than in controls (39.06 ± 18.78 versus 24.22 ± 6.93; 13.55 ± 10.65 versus 5.73 ± 2.19). Higher values in the CDH1 gene were also found in plasma samples (22.25 ± 14.13 versus 46.42 ± 20.91). A similar methylation pattern with positive correlation between plasma and benign lesions was noted in the CDH1 gene (r = 0.886, p = 0.019) and malignant lesions in the PAX1 gene (r = 0.771, p < 0.001). The random forest algorithm combining methylation indices of all four genes and age determined 0.932 AUC (area under the receiver operating characteristic (ROC) curve) prediction power in the model classifying malignant lesions and controls. Our study results indicate the effects of methylation changes in ovarian cancer development and suggest that the CDH1 gene is a potential candidate for non-invasive diagnosis of ovarian cancer.

Association between pelvic organ prolapse types and levator-urethra gap as measured by 3D transperineal ultrasound.

OBJECTIVES: To evaluate the association between pelvic organ prolapse (POP) types and levator-urethra gap (LUG) as measured by 3-dimensional transperineal tomographic ultrasound. METHODS: A retrospective study was carried out on 98 women with symptomatic POP. Three-dimensional transperineal tomographic ultrasound images and POP quantification coordinates were reviewed. Each vaginal compartment was staged for the degree of prolapse, and total number of involved compartments identified. LUG was measured on 3-dimensional tomographic sonograms as the distance between the center of the urethra and the levator insertion bilaterally. Based on prior studies, an abnormal LUG of 25 mm or greater indicated levator avulsion. The LUG and the presence or absence of unilateral/bilateral avulsions was analyzed with reference to the clinical diagnosis of prolapse (single versus multicompartment, and mild [stage II] versus severe [stage III-IV]). Generalized logit models were used to evaluate the association between avulsion and prolapse type and stage. RESULTS: The LUG was substantially larger in women with multicompartment compared to single-compartment POP (28.9 ± 4.1 mm versus 22.7 ± 4.1 mm, P < .01). Similarly, LUG was substantially larger in women with severe (stage III-IV) compared to mild (stage II) POP (28.8 ± 4.7 mm versus 23.3 ± 4.5 mm, P < .01). Women with severe prolapse were 32 times more likely than women with mild prolapse to have bilateral levator avulsion. Those with POP involving all 3 vaginal compartments were 76 times more likely than single-compartment POP to have bilateral levator avulsions. CONCLUSIONS: Bilateral levator ani avulsion as diagnosed by LUG measurements of 25 mm or greater at rest is associated with multicompartment, severe prolapse.

The Effects of Heat Exposure on Vaginal Smooth Muscle Cells: Elastin and Collagen Production.

AIMS: To evaluate smooth muscle cells (SMCs) proliferation and elastin and collagen production after heat exposure (65°C). METHODS: Samples were taken from the anterior vaginal wall, SMCs were cultured, and heated to 65°C for 30 and 60 s. Cell proliferation was assessed; tropoelastin and collagen production was measured. RESULTS: Heat does not affect SMC proliferation at 65°C neither at 30 nor at 60 s. Surface-deposited elastin level was significantly increased after heat exposure (mean ± SD, 30 s 155 ± 5% of control [p < 0.01] and 60 s 516 ± 40% of control [p < 0.01]). Tropoelastin levels in the culture media were significantly lower after 60 s of heat exposure (mean ± SD, 30 s 102 ± 5% of control [p = ns] and 60 s 70 ± 2% of control [p = 0.04]). Significant increase in surface-deposited collagen production was found (mean ± SD, 30 s 170 ± 6% of control [p < 0.01] and 60 s 123 ± 6% of control [p < 0.01]), but no such elevation was measured in the media after heat exposure (mean ± SD, 30 s 120 ± 20% of control [p = ns] and 60 s 100 ± 20% of control [p = ns]). CONCLUSION: When SMCs are exposed to heat there is significant elevation in collagen and elastin production. Changes in the composition of the extracellular matrix after heat exposure may contribute to vaginal wall remodeling.

[Efficacy of the percutaneous tibial nerve stimulation in the treatment of lower urinary tract symptoms]. / A percutan nervus tibialis stimuláció szerepe egyes kismedencei kórképek kezelésében.

Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive, safe and well-tolerated neuromodulation technique for the lower urinary tract dysfunctions. PTNS delivers neuromodulation to the pelvic floor through the S2-4 junction of the sacral nerve plexus via the route of the posterior tibial nerve. Using the fine needle electrode insertion above the ankle, the tibial nerve is accessed, which connected to the stimulator. To date despite of its excessive clinical use, PTNS mechanism of action still remains unclear. The technique seems to be an efficacious and safe treatment for overactive bladder syndrome (OAB). It could be recommended according to the Urinary Incontinence Guideline of the European Association of Urology in women who did not have adequate improvement or could not tolerate anti-muscarinic therapy. The success rate is comparable to sacral nerve stimulation in OAB patients. PTNS has been used for fecal incontinence since 2003, however, many of the published studies are of poor quality. PTNS has also been shown to have positive effects on chronic pelvic pain, when the usual therapeutic steps did not result in satisfactory improvement. No major complications are reported in the literature, following PTNS treatment. Orv Hetil. 2018; 159(43): 1735-1740.