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.

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.

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.

Characteristics and outcomes of surgically staged multiple classifier endometrial cancer.

OBJECTIVE: The growing adoption of molecular and genomic characterization is changing the current landscape of treatment of endometrial cancer patients. Using the surrogate molecular classification, endometrial cancer patients can be classified in four subgroups: POLE mutated (POLEmut), MMRd/MSI-H, p53 abnormal (p53abn), and no specific mutational profile (NSMP). However, some patients can harbor two or more molecular features (defined as multiple classifier). Since the rarity of this occurrence, evidence regarding multiple classifiers is still limited. Here, we described characteristics and outcomes of multiple classifiers. METHODS: This is a multi-institutional retrospective study. Data of consecutive patients having 2 or more molecular features were collected. Survival was assessed using the Kaplan-Meier and Cox proportional hazard methods. RESULTS: Charts of 72 multiple classifiers were reviewed. Median (range) follow-up was 9.8 (1.2, 37.5) months. Overall, 31 (43%) patients had POLEmut. Patients with POLEmut-MMRd/MSI-H, POLEmut-p53abn, and POLEmut-MMRd/MSI-H-p53abn were 6 (8.3%), 20 (27.8%), and 5 (6.9%), respectively. Among those 31 patients, no recurrence occurred within a median follow-up of 10.5 months (only seven (22.6%) patients had at least 2-year follow-up). The remaining 41 (56.9%) patients were diagnosed with tumors harboring both p53 and MMRd/MSI-H. Among them, four (9.8%) recurrences occurred at a median follow-up time of 8.9 months. Adjuvant therapy (other than vaginal brachytherapy) was administered in 5/31 (16%) and 25/41 (61%) patients with and without POLEmut, respectively (p < 0.001). CONCLUSIONS: Multiple classifiers endometrial cancer with POLEmut are characterized by good prognosis even in case of presence of MMRd/MSI-H and/or p53abn. Additional studies with long-term follow-up are needed.

HPV-related lesions after hysterectomy for high-grade cervical intraepithelial neoplasia and early-stage cervical cancer: A focus on the potential role of vaccination.

OBJECTIVE: To date, no data supports the execution of vaccination after hysterectomy for high-grade cervical intraepithelial neoplasia (CIN2+) and early-stage cervical cancer. We aim to evaluate the potential effect of vaccination after hysterectomy for high-grade cervical intraepithelial neoplasia and early-stage cervical cancer. METHODS: This is a multi-center retrospective study evaluating data of women who develop lower genital tract dysplasia (including anal, vulvar and vaginal intra-epithelial neoplasia) after having hysterectomy for CIN2+ and FIGO stage IA1- IB1 cervical cancer. RESULTS: Overall, charts for 77 patients who developed lower genital tract dysplasia were collected. The study population included 62 (80.5%) and 15 (19.5%) patients with CIN2+ and early-stage cervical cancer, respectively. The median (range) time between hysterectomy and diagnosis of develop lower genital tract dysplasia was 38 (range, 14-62) months. HPV types covered by the nonavalent HPV vaccination would potentially cover 94.8% of the development of lower genital tract dysplasia. Restricting the analysis to the 18 patients with available HPV data at the time of hysterectomy, the beneficial effect of nonvalent vaccination was 89%. However, considering that patients with persistent HPV types (with the same HPV types at the time of hysterectomy and who developed lower genital tract dysplasia) would not benefit from vaccination, we estimated the potential protective effect of vaccination to be 67% (12 out of 18 patients; four patients had a persistent infection for the same HPV type(s)). CONCLUSIONS: Our retrospective analysis supported the adoption of HPV vaccination in patients having treatment for HPV-related disease. Even in the absence of the uterine cervix, HPV vaccination would protect against develop lower genital tract dysplasia. Further prospective studies have to confirm our preliminary research.

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.

Identifying Biomarkers of Spinal Muscular Atrophy for Further Development.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by bi-allelic, recessive mutations of the survival motor neuron 1 (SMN1) gene and reduced expression levels of the survival motor neuron (SMN) protein. Degeneration of alpha motor neurons in the spinal cord causes progressive skeletal muscle weakness. The wide range of disease severities, variable rates of decline, and heterogenous clinical responses to approved disease-modifying treatment remain poorly understood and limit the ability to optimize treatment for patients. Validation of a reliable biomarker(s) with the potential to support early diagnosis, inform disease prognosis and therapeutic suitability, and/or confirm response to treatment(s) represents a significant unmet need in SMA. OBJECTIVES: The SMA Multidisciplinary Biomarkers Working Group, comprising 11 experts in a variety of relevant fields, sought to determine the most promising candidate biomarker currently available, determine key knowledge gaps, and recommend next steps toward validating that biomarker for SMA. METHODS: The Working Group engaged in a modified Delphi process to answer questions about candidate SMA biomarkers. Members participated in six rounds of reiterative surveys that were designed to build upon previous discussions. RESULTS: The Working Group reached a consensus that neurofilament (NF) is the candidate biomarker best poised for further development. Several important knowledge gaps were identified, and the next steps toward filling these gaps were proposed. CONCLUSIONS: NF is a promising SMA biomarker with the potential for prognostic, predictive, and pharmacodynamic capabilities. The Working Group has identified needed information to continue efforts toward the validation of NF as a biomarker for SMA.

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.

Outcomes of High-Grade Cervical Dysplasia with Positive Margins and HPV Persistence after Cervical Conization.

The objective of this work is to assess the 5-year outcomes of patients undergoing conization for high-grade cervical lesions that simultaneously present as risk factors in the persistence of HPV infection and the positivity of surgical resection margins. This is a retrospective study evaluating patients undergoing conization for high-grade cervical lesions. All patients included had both positive surgical margins and experienced HPV persistence at 6 months. Associations were evaluated with Cox proportional hazard regression and summarized using hazard ratio (HR). The charts of 2966 patients undergoing conization were reviewed. Among the whole population, 163 (5.5%) patients met the inclusion criteria, being at high risk due to the presence of positive surgical margins and experiencing HPV persistence. Of 163 patients included, 17 (10.4%) patients developed a CIN2+ recurrence during the 5-year follow-up. Via univariate analyses, diagnosis of CIN3 instead of CIN2 (HR: 4.88 (95%CI: 1.10, 12.41); p = 0.035) and positive endocervical instead of ectocervical margins (HR: 6.44 (95%CI: 2.80, 9.65); p < 0.001) were associated with increased risk of persistence/recurrence. Via multivariate analyses, only positive endocervical instead of ectocervical margins (HR: 4.56 (95%CI: 1.23, 7.95); p = 0.021) were associated with worse outcomes. In this high-risk group, positive endocervical margins is the main risk factor predicting 5-year recurrence.

Management of Patients Diagnosed with Endometrial Cancer: Comparison of Guidelines.

Endometrial cancer is the most common gynecological malignancy in Europe and its management involves a variety of health professionals. In recent years, big discoveries were made concerning the management of patients diagnosed with endometrial cancer, particularly in the field of molecular biology and minimally invasive surgery. This requires the continuous updating of guidelines and protocols over the years. In this paper, we aim to summarize and compare common points and disparities among protocols for management of patients diagnosed with endometrial cancer by leading international gynecological oncological societies. We therefore systematically report the parallel among the guidelines based on the various steps patients with endometrial cancer usually undergo. The comparison between American and European protocols revealed some relevant disparities, in particular regarding surgical staging, molecular biology application as a prognostic tool and follow up regimens. This could possibly cause differences in interpreting and applying protocols in clinical practice in small centers, leading to a lack of adherence to guidelines or even prompting a confusing mix of them.

Hysterectomy alone vs. hysterectomy plus sentinel node mapping in endometrial cancer: Perioperative and long-term results from a propensity-score based study.

OBJECTIVE: To compare outcomes after hysterectomy and hysterectomy plus sentinel node mapping (SNM) in endometrial cancer (EC) patients. MATERIALS AND METHODS: This is a retrospective study, collecting data of EC patients treated between 2006 and 2016 in nine referral centers. RESULTS: The study population included 398 (69.5%) and 174 (30.5%) patients having hysterectomy and hysterectomy plus SNM. As the results of the adoption of a propensity-score matched analysis, we selected two homogeneous cohort of patients (150 having hysterectomy only vs. 150 having hysterectomy plus SNM). The SNM group had a longer operative time, but did not correlate with length of hospital stay and estimated blood loss. Overall severe complication rates were similar between groups (0.7% in the hysterectomy group vs. 1.3% in the hysterectomy plus SNM group; p = 0.561). No lymphatic-specific complication occurred. Overall, 12.6% of patients having SNM were diagnosed with disease harboring in their lymph nodes. Adjuvant therapy administration rate was similar between groups. Considering patients having SNM, 4% of patients received adjuvant therapy on the basis of nodal status alone; all the other patients received adjuvant therapy also on the basis of uterine risk factors. Five-year disease-free (p = 0.720) and overall (p = 0.632) survival was not influenced by surgical approach. CONCLUSIONS: Hysterectomy (with or without SNM) is a safe and effective method for managing EC patients. Potentially, these data support the omission of side specific lymphadenectomy in case of unsuccessful mapping. Further evidence is warranted in to confirm the role SNM in the era of molecular/genomic profiling.

Fetal Growth and Neonatal Outcomes in Pregestational Diabetes Mellitus in a Population with a High Prevalence of Diabetes.

The aim of this retrospective study, conducted in an Italian tertiary care hospital, was to evaluate maternal-fetal and neonatal clinical outcomes in a group of patients with pregestational diabetes mellitus (PGDM), such as diabetes mellitus type 1 (DM1), diabetes mellitus type 2 (DM2), and maturity onset diabetes of the young (MODY). Overall, 174 pregnant women, nulliparous and multiparous, with a single pregnancy were enrolled. Data on pregnancy, childbirth, and newborns were collected from medical records. The selected patients were divided into two groups: the PGDM group (42 with DM1, 14 with DM2, and 2 with MODY), and the control group (116 patients with a negative pathological history of diabetes mellitus). We reported an incidence of preterm delivery of 55.2% in the PGDM group, including 59.5% of those with DM1 and 42.9% of those with DM2, vs. 6% in the controls. Fetal growth disorders, such as intrauterine growth retardation, small for gestational age, and fetal macrosomia were found in 19% and 3.6% in the case and control groups, respectively. A relationship between DM2 and gestational hypertension was found.

Native tissue repair (NTR) versus transvaginal mesh interventions for the treatment of anterior vaginal prolapse: Systematic review and meta-analysis.

The aim of the present systematic review and meta-analysis was to compare native tissue repair (NTR) against transvaginal mesh augmentation for the repair of anterior vaginal prolapse. A total of 2289 articles were found but only 27 (24.8 %) were included in the review. Guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) were followed to guide the process of the systematic review and meta-analysis. The quality of the observational studies was evaluated according to the Scottish Intercollegiate Guidelines Network, whereas the quality of randomized control trials (RCT) was assessed by the Cochrane risk-of-bias scale. The mesh repair intervention was associated with a higher anatomical cure rate in comparison with NTR repair when the follow-up was ≤24 months [pooled risk difference (95 % CI): -0.18 % (-0.22 %; 0.13 %); p-value: <0.0001; I2: 36.0 %]. Studies reporting anatomical failure had similar findings [pooled risk difference (95 % CI): 0.17 % (0.01 %; 0.33 %); p-value: 0.03; I2: 88.6 %]. No differences in the risk of re-operation were observed between NTR repair and mesh augmentation. Pooled risk differences in the incidence of post-surgical and late complications were higher for the mesh repair intervention [-0.05 % (95 % CI: -0.10 %; 0.00 %) p-value: 0.05; I2: 68.3 %] [-0.05 % (95 % CI: -0.14 %; 0.03 %) p-value: 0.25; I2: 82.0 %]. Women who underwent mesh repair reported greater satisfaction than women who underwent NTR [pooled risk difference (95 % CI): -0.07 % (-0.16 %; 0.02 %); p-value: 0.15; I2: 65.3 %]. In conclusion, mesh repair surgery had higher anatomical cure and satisfaction rates, with no differences in re-operation rate, but had higher post-surgical and late complications in comparison with NTR.

Reproductive and pregnancy outcomes of fertility-sparing treatments for early-stage endometrial cancer or atypical hyperplasia: A systematic review and meta-analysis.

OBJECTIVE: To report the pregnancy outcomes of women with prior endometrial cancer and endometrial hyperplasia managed with fertility-sparing treatments. METHODS: Medline and Embase databases were searched. Inclusion criteria were studies reporting the pregnancy outcomes of women who had undergone fertility-sparing treatments for endometrial hyperplasia or early endometrioid endometrial cancer. Outcomes explored were pregnancy, miscarriage and livebirth rates according to the type of progestin treatment used. Subgroup analyses according to the type of diagnostic follow-up were also performed. Meta-analyses of proportions using a random effects model were used to combine data. RESULTS: Twenty-nine studies (1036 women) were included, and 82.8% [95% confidence interval (CI) 72.3-91.2] of women achieved complete remission. Pregnancy rates were 56.3% (95% CI 41.6-70.5) with megestrol (MA) or medroxyprogesterone acetate (MPA), 63.1% (95% CI 37.0-85.6) with levonorgestrel-releasing intrauterine device (LNG-IUD), 57.9% (95% CI 37.7-76.8) with MA or MPA and metformin, 59.8% (95% CI 48.3-70.7) with MPA and LNG-IUD, 15.4% (95% CI 4.3-42.2) with gonadotropin-releasing hormone analogue (GnRHa) combined with LNG-IUD or letrozole, and 40.7% (95% CI 24.5-59.3) with LNG-IUD and GnRHa. Miscarriage rates were 17.4% (95% CI 12.2-23.4), 14.3% (95% CI 6.4-24.7), 57.9% (95% CI 37.7-76.8), 26.9% (95% CI 14.6-39.3), 100% (95% CI 34.0-100) and 18.2% (95% CI 5.1-47.7), respectively, and livebirth rates were 68.8% (95% CI 56.0-80.3), 80.8% (95% CI 69.5-90.0), 69.9% (95% CI 56.1-82.0), 25.97 (95% CI 14.6-39.3), 0% (95% CI 0-66.0) and 81.8% (95% CI 52.3-94.8), respectively. Finally, stratifying the analysis considering the endometrial sampling method alone, the pregnancy rate was 68.6% (95% CI 51.2-83.6; 10 studies, I2 = 83.5%) in women who underwent hysteroscopy and 60.5% (95% CI 53.4-67.5; 13 studies, I2 = 39.8%) in women managed with dilatation and curettage biopsy; the miscarriage and livebirth rates were 13.2% (95% CI 8.0-19.5; I2 = 0%) and 81.2% (95% CI 67.4-91.8; I2 = 67.3%), respectively, for hysteroscopy, and 25.2% (95% CI 17.8-33.3; I2 = 15.5%) and 67.5% (95% CI 58.8-75.5; I2 = 0%), respectively, for dilatation and curettage biopsy. CONCLUSION: Fertility-sparing treatment in women with endometrial cancer or hyperplasia is associated with an overall good response to therapy, good chance of achieving pregnancy and a good livebirth rate. Diagnostic follow-up with hysteroscopy was associated with a higher pregnancy rate, although this requires confirmation in adequately powered randomized trials.

Development of a Nomogram Predicting the Risk of Persistence/Recurrence of Cervical Dysplasia.

Background: Cervical dysplasia persistence/recurrence has a great impact on women's health and quality of life. In this study, we investigated whether a prognostic nomogram may improve risk assessment after primary conization. Methods: This is a retrospective multi-institutional study based on charts of consecutive patients undergoing conization between 1 January 2010 and 31 December 2014. A nomogram assessing the importance of different variables was built. A cohort of patients treated between 1 January 2015 and 30 June 2016 was used to validate the nomogram. Results: A total of 2966 patients undergoing primary conization were analyzed. The median (range) patient age was 40 (18-89) years. At 5-year of follow-up, 6% of patients (175/2966) had developed a persistent/recurrent cervical dysplasia. Median (range) recurrence-free survival was 18 (5-52) months. Diagnosis of CIN3, presence of HR-HPV types, positive endocervical margins, HPV persistence, and the omission of HPV vaccination after conization increased significantly and independently of the risk of developing cervical dysplasia persistence/recurrence. A nomogram weighting the impact of all variables was built with a C-Index of 0.809. A dataset of 549 patients was used to validate the nomogram, with a C-index of 0.809. Conclusions: The present nomogram represents a useful tool for counseling women about their risk of persistence/recurrence after primary conization. HPV vaccination after conization is associated with a reduced risk of CIN2+.

Sentinel Lymph Node Biopsy in Surgical Staging for High-Risk Groups of Endometrial Carcinoma Patients.

BACKGROUND: In endometrial carcinoma (EC) patients, sentinel lymph node (SLN) biopsy has shown the potential to reduce post-operative morbidity and long-term complications, and to improve the detection of low-volume metastasis through ultrastaging. However, while it has shown high sensitivity and feasibility in low-risk EC patient groups, its role in high-risk groups is still unclear. AIM: To assess the role of SLN biopsy through the cervical injection of indocyanine green (ICG) in high-risk groups of early-stage EC patients. MATERIALS AND METHODS: Seven electronic databases were searched from their inception to February 2021 for studies that allowed data extraction about detection rate and accuracy of SLN biopsy through the cervical injection of ICG in high-risk groups of early-stage EC patients. We calculated pooled sensitivity, false negative (FN) rate, detection rate of SLN per hemipelvis (DRh), detection rate of SLN per patients (DRp), and bilateral detection rate of SLN (DRb), with 95% confidence interval (CI). RESULTS: Five observational cohort studies (three prospective and two retrospective) assessing 578 high risk EC patients were included. SLN biopsy sensitivity in detecting EC metastasis was 0.90 (95% CI: 0.03-0.95). FN rate was 2.8% (95% CI: 0.6-11.6%). DRh was 88.4% (95% CI: 86-90.5%), DRp was 96.6% (95% CI: 94.7-97.8%), and DRb was 80% (95% CI: 75.4-83.9). CONCLUSION: SLN biopsy through ICG cervical injection may be routinely adopted instead of systematic pelvic and para-aortic lymphadenectomy in surgical staging for high-risk groups of early-stage EC patients, as well as in low-risk groups.

Prevalence of HPV Infection and p16INK4a Overexpression in Surgically Treated Laryngeal Squamous Cell Carcinoma.

Background: The mucosal high-risk (HR) human papillomavirus (HPV) is associated with oropharyngeal carcinogenesis. Aims of this study were to evaluate the prevalence of HR-HPV infection in laryngeal squamous cell carcinoma (LSCC) from different subsites, and the clinico-biological meaning of p16 overexpression. Methods: Ninety-seven LSCCs submitted to primary surgery (n = 75) or to post-irradiation salvage laryngectomy (n = 22) were evaluated for HR-HPV DNA and RNA using Luminex-based assays. p16 immunohistochemistry was performed. Results: HR-HPV DNA from HPV16 was detected in seven cases (8.75%), without significant differences between supraglottic and glottic lesions. HPV RNA was never detected. p16 overexpression correlated with HR-HPV DNA, but the kappa agreement score was poor. HPV DNA showed no impact on prognosis. p16 overexpression was associated with a better survival (OS, RFS) in primarily operated cases, while an inverse association with OS was observed in the salvage surgery group. Conclusions: HR-HPV infection appears to have a marginal role in LSCC independent of the anatomical subsite. p16 expression is deregulated in LSCC independent of HPV but displays a prognostic role in patients submitted to primary surgery. The negative predictive role of p16 overexpression in patients undergoing salvage surgery deserves more investigations for validation and elucidation of its clinical relevance.

Correlation of Leptin, Proinflammatory Cytokines and Oxidative Stress with Tumor Size and Disease Stage of Endometrioid (Type I) Endometrial Cancer and Review of the Underlying Mechanisms.

Endometrioid endometrial cancer is associated with increased BMI and obesity through multiple pathogenetic mechanisms involving hyperestrogenism, hyperinsulinemia, altered adipokine secretion, inflammation, and oxidative stress. In the present study, we aimed to investigate the correlation between BMI, leptin, the proinflammatory cytokines IL-6 and TNFα, reactive oxygen species (ROS), and the traditional prognostic factors T, G, N and M status among type I endometrioid and type II endometrial cancer patients. We enrolled 305 consecutive endometrial cancer patients prospectively. We found that BMI, leptin, and IL-6 significantly correlated with T status, N status, and M status among endometrioid type I endometrial cancer patients. Among type II endometrial cancer patients, BMI and leptin did not correlate with any of the prognostic parameters, whereas there was a positive correlation between IL-6 and the presence of distant metastases. In the multivariate regression analysis, BMI, leptin, and IL-6 were independent predictive variables of T, N, and M status in endometrioid type I endometrial cancer patients. Our study demonstrates that weight gain, adiposity-related adipokines, inflammation, and oxidative stress correlate with the prognostic factors of endometrioid endometrial cancer. Knowledge of the role of obesity-related biological pathways and mediators in the pathogenesis and prognosis of endometrioid endometrial malignancies may offer new perspectives on combined therapeutic strategies that have not been explored to date, both in the advanced disease and in the adjuvant setting.

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.