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Melanoma, with its diverse histopathologic characteristics, can mimic both benign nevi and neoplasms of various cell lineages. Immunohistochemistry (IHC) can play a vital role in melanoma diagnosis, particularly when the cell lineage is unclear on hematoxylin and eosin sections. Commonly utilized IHC stains for melanoma diagnosis include SOX10, Melan-A, and S100. A relatively novel stain, PReferentially expressed Antigen in MElanoma (PRAME), is also proving useful in accurate melanoma diagnosis. However, none of these stains are completely specific to melanocytes or melanoma, and misinterpretation can lead to incorrect diagnoses. This report presents a unique case of triple-negative breast carcinoma (TNBC) metastatic to the skin exhibiting histopathologic characteristics similar to melanoma, including positivity for SOX10 and PRAME. Our aim is to highlight TNBC metastatic to the skin as a potential diagnostic pitfall., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Abstract: Vulvar examination during procedures for cervical carcinoma screening (CCS) can be a valid chance for early diagnosis of vulvar diseases and precancerous lesions. With this aim an online questionnaire was sent to the members of the Italian Cervical Carcinoma Screening Group (GISCi) from either first level group (FLG, Pap/human papillomavirus test sampling) or second level group (SLG, colposcopy and treatments) to assess if and how vulvar examination was performed. 86% of FLG and 90.2% of SLG report performing vulvar examination prior to CCS procedures. 15% of SLG cannot manage basic vulvar diseases and they refer patients to specialized center. 54.3% underline lack of standardized protocol in case of vulvar disease detection. Despite most health care professionals report examining the vulva during CCS procedures, vulvar cancer early diagnosis is still challenging., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2024, ASCCP.)

Introduction: The standard surgical treatment for early-stage cervical cancer includes hysterectomy and bilateral oophorectomy along the removal of parametrial tissue to achieve surgical radicality. However, in recent years, the role of simple hysterectomy for cervical cancer with favorable prognostic characteristics has been re-evaluated. One of the challenges in early-stage cervical cancer is identifying predictive factors for neoplastic parametrial infiltration and lymph node metastases that cannot be detected during the preoperative assessment. We hypothesized that histological tumor growth patterns may be associated with these features and could thus be useful for the management of apparent early-stage cervical cancer., Method: We identified 3 different histological patterns: the comedo-like, the infiltrative, and the expansive. We analyzed a series of clinic-pathological characteristics to determine the association of eachpatternwith aggressive features. Furthermore, we estimated odd ratios (ORs) in univariate and multivariate analyses for parametrial infiltration and lymph node metastasis., Results: We found that comedo-like pattern is associated to advanced FIGO stages, larger tumor size, lymphovascular space invasion, deeper invasion depth, parametrium involvement, and lymph node metastases. By univariate analysis, comedo-like pattern was statistically associated with both parametrial involvement (OR: 19.3, CI 5.47-68.6, p-value = < 0.001) and lymph node metastases (OR: 4.98, CI 1.71-14.5, p-value = 0.003). By multivariate analysis, the association between comedo-like pattern and parametrial involvement was confirmed (OR: 8.76, CI 2.34-32.75, p-value = 0.01)., Conclusion: The specific growth pattern of cervical cancer, assessed in a conization specimen before hysterectomy, can be useful to tailor surgical radicality., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Isoprenyl cysteine carboxyl methyltransferase (ICMT) catalyzes the last step of the prenylation pathway. Previously, we found that high ICMT levels enhance tumorigenesis in vivo and that its expression is repressed by the p53 tumor suppressor. Based on evidence suggesting that some ICMT substrates affect invasive traits, we wondered if this enzyme may promote metastasis. In this work, we found that ICMT overexpression enhanced lung metastasis in vivo. Accordingly, ICMT overexpression also promoted cellular functions associated with aggressive phenotypes such as migration and invasion in vitro. Considering that some ICMT substrates are involved in the regulation of actin cytoskeleton, we hypothesized that actin-rich structures, associated with invasion and metastasis, may be affected. Our findings revealed that ICMT enhanced the formation of invadopodia. Additionally, by analyzing cancer patient databases, we found that ICMT is overexpressed in several tumor types. Furthermore, the concurrent expression of ICMT and CTTN, which encodes a crucial component of invadopodia, showed a significant correlation with clinical outcome. In summary, our work identifies ICMT overexpression as a relevant alteration in human cancer that promotes the development of metastatic tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Long-acting cabotegravir has been studied mainly in the stringent framework of clinical trials, which does not necessarily reflect the situation of people with HIV (PWH) in routine clinical settings. The present population pharmacokinetic analysis aims to build real-world reference percentile curves of cabotegravir concentrations, accounting for patient-related factors that may affect cabotegravir exposure. The second objective is to simulate whether dosing interval adjustments of cabotegravir could be considered in specific subpopulations. Overall, 238 PWH contributed to 1,038 cabotegravir levels (186 during the initial oral administration phase and 852 after intramuscular injection). Cabotegravir pharmacokinetics was best described using a one-compartment model with distinct first order-absorption for oral and intramuscular administrations, and identical volume and clearance. Our model showed almost 40% faster absorption and 30% higher clearance than previously reported, resulting in a time to steady-state of 8 months and an elimination half-life of 4.6 weeks for long-acting cabotegravir. Sex and body mass index significantly influenced absorption, and bodyweight affected clearance. Model-based simulations showed that cabotegravir trough concentrations in females were 25% lower 4 weeks after the intramuscular loading dose, but 42% higher during the late maintenance phase. Finally, simulations indicated that in females, despite significantly higher cabotegravir concentrations, longer intervals between injections may not consistently ensure levels above the 4-fold protein-adjusted 90% inhibitory target concentration., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Differentiated vulvar intraepithelial neoplasia (dVIN) is a high-risk preinvasive vulvar lesion and precursor of human papillomavirus-independent vulvar squamous cell carcinoma (VSCC). Due to its rarity, literature data on its malignant potential are scant. The aim of the study is to assess the risk of developing VSCC in patients surgically treated for dVIN not associated with VSCC (solitary dVIN) and the risk of VSCC recurrence in patients treated for dVIN associated with VSCC (dVIN-VSCC) at first diagnosis., Material and Methods: A historical cohort study was performed in a northern Italy referral center for vulvar neoplasms. All consecutive women surgically treated for histologically confirmed dVIN from 1994 to 2021 were collected. Primary outcome was cancer risk or recurrent cancer risk, secondary outcomes were risk factors associated with VSCC development or recurrence. Kaplan-Meier method and log-rank test were used to estimate cancer risk or recurrent cancer risk differences and uni- and multivariate Cox regression analyses to identify risk factors associated with VSCC development in solitary dVIN and recurrence of dVIN-VSCC., Results: Seventy-six patients with dVIN at preoperative biopsy were included: at excisional specimens 44 were solitary dVIN and 32 were dVIN-VSCC. The absolute risk of VSCC development after solitary dVIN treatment was 43.2% with median time to to VSCC diagnosis of 25.4 months (range 3.5-128.0 months). VSCC recurrence absolute risk in treated dVIN-VSCC patients was 31.3% with median time to VSCC recurrence of 52.9 months (range 6.5-94.8 months). At uni- and multivariate regression analyses, only compliant topical ultrapotent corticosteroid treatment after solitary dVIN excision showed an ability to prevent VSCC development. No protective effect by corticosteroid treatment was shown for VSCC recurrence in dVIN-VSCC patients. Smoking was associated with higher cancer recurrence risk in dVIN-VSCC patients on both uni- and multivariate regression analyses., Conclusions: Patients with dVIN have a high risk of developing both primary and recurring VSCC. Early recognition, long-term follow up, and compliant ultrapotent topical corticosteroid treatment are recommended., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Management of lymphoid malignancies requires substantial health system resources. Total national health expenditure might influence population-based lymphoid malignancy survival. We studied the long-term survival of patients with 12 lymphoid malignancy types and examined whether different levels of national health expenditure might explain differences in lymphoid malignancy prognosis between European countries and regions., Methods: For this observational, retrospective, population-based study, we analysed the EUROCARE-6 dataset of patients aged 15 or older diagnosed between 2001 and 2013 with one of 12 lymphoid malignancies defined according to International Classification of Disease for Oncology (third edition) and WHO classification, and followed up to 2014 (Jan 1, 2001-Dec 31, 2014). Countries were classified according to their mean total national health expenditure quartile in 2001-13. For each lymphoid malignancy, 5-year and 10-year age-standardised relative survival (ASRS) was calculated using the period approach. Generalised linear models indicated the effects of age at diagnosis, gender, and total national health expenditure on the relative excess risk of death (RER)., Findings: 82 cancer registries (61 regional and 21 national) from 27 European countries provided data eligible for 10-year survival estimates comprising 890 730 lymphoid malignancy cases diagnosed in 2001-13. Median follow-up time was 13 years (IQR 13-14). Of the 12 lymphoid malignancies, the 10-year ASRS in Europe was highest for hairy cell leukaemia (82·6% [95% CI 78·9-86·5) and Hodgkin lymphoma (79·3% [78·6-79·9]) and lowest for plasma cell neoplasms (29·5% [28·9-30·0]). RER increased with age at diagnosis, particularly from 55-64 years to 75 years or older, for all lymphoid malignancies. Women had higher ASRS than men for all lymphoid malignancies, except for precursor B, T, or natural killer cell, or not-otherwise specified lymphoblastic lymphoma or leukaemia. 10-year ASRS for each lymphoid malignancy was higher (and the RER lower) in countries in the highest national health expenditure quartile than in countries in the lowest quartile, with a decreasing pattern through quartiles for many lymphoid malignancies. 10-year ASRS for non-Hodgkin lymphoma, the most representative class for lymphoid malignancies based on the number of incident cases, was 59·3% (95% CI 58·7-60·0) in the first quartile, 57·6% (55·2-58·7) in the second quartile, 55·4% (54·3-56·5) in the third quartile, and 44·7% (43·6-45·8) in the fourth quartile; with reference to the European mean, the RER was 0·80 (95% CI 0·79-0·82) in the first, 0·91 (0·90-0·93) in the second, 0·94 (0·92-0·96) in the third, and 1·45 (1·42-1·48) in the fourth quartiles., Interpretation: Total national health expenditure is associated with geographical inequalities in lymphoid malignancy prognosis. Policy decisions on allocating economic resources and implementing evidence-based models of care are needed to reduce these differences., Funding: Italian Ministry of Health, European Commission, Estonian Research Council., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The choice of a refeeding strategy is essential in the inpatient treatment of Anorexia Nervosa (AN). Oral nutrition is usually the first choice, but enteral nutrition through the use of a Nasogastric Tube (NGT) often becomes necessary in hospitalized patients. The literature provides mixed results on the efficacy of this method in weight gain, and there is a scarcity of studies researching its psychological correlates. This study aims to analyze the effectiveness of oral versus enteral refeeding strategies in inpatients with AN, focusing on Body Mass Index (BMI) increase and treatment satisfaction, alongside assessing personality traits. We analyzed data from 241 inpatients, comparing a group of treated vs. non-treated individuals, balancing confounding factors using propensity score matching, and applied regression analysis to matched groups. The findings indicate that enteral therapy significantly enhances BMI without impacting treatment satisfaction, accounting for the therapeutic alliance. Personality traits showed no significant differences between patients undergoing oral or enteral refeeding. The study highlights the clinical efficacy of enteral feeding in weight gain, supporting its use in severe AN cases when oral refeeding is inadequate without adversely affecting patient satisfaction or being influenced by personality traits.

Substandard or disrespectful care during labour should be of serious concern for healthcare professionals, as it can affect one of the most important events in a woman's life. Substandard care refers to the use of interventions that are not considered best-practice, to the inadequate execution of interventions, to situations where best-practice interventions are withheld from patients, or there is lack of adequate informed consent. Disrespectful care refers to forms of verbal and non-verbal communication that affect patients' dignity, individuality, privacy, intimacy, or personal beliefs. There are many possible underlying causes for substandard and disrespectful care in labour, including difficulties in modifying behaviours, judgmental or paternalistic attitudes, personal interests and individualism, and a human tendency to make less arduous, less difficult, or less stressful clinical decisions. The term "obstetric violence" is used in some parts of the world to describe various forms of substandard and disrespectful care in labour, but suggests that it is mainly carried out by obstetricians and is a serious form of aggression, carried out with the intent to cause harm. We believe that this term should not be used, as it does not help to identify the underlying problem, its causes, or its correction. In addition, it is generally seen by obstetricians and other healthcare professionals as an unjust and offensive term, generating a defensive and less collaborative mindset. We reach out to all individuals and institutions sharing the common goal of improving women's experience during labour, to work together to address the underlying causes of substandard and disrespectful care, and to develop common strategies to deal with this problem, based on mutual comprehension, trust and respect., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Liver steatosis is the most common chronic liver disease and affects 10-24% of the general population. As the grade of disease can range from fat infiltration to steatohepatitis and cirrhosis, an early diagnosis is needed to set the most appropriate therapy. Innovative noninvasive radiological techniques have been developed through MRI and US. MRI-PDFF is the reference standard, but it is not so widely diffused due to its cost. For this reason, ultrasound tools have been validated to study liver parenchyma. The qualitative assessment of the brightness of liver parenchyma has now been supported by quantitative values of attenuation and scattering to make the analysis objective and reproducible. We aim to demonstrate the reliability of quantitative ultrasound in assessing liver fat and to confirm the inter-operator reliability in different respiratory phases. We enrolled 45 patients examined during normal breathing at rest, peak inspiration, peak expiration, and semi-sitting position. The highest inter-operator agreement in both attenuation and scattering parameters was achieved at peak inspiration and peak expiration, followed by semi-sitting position. In conclusion, this technology also allows to monitor uncompliant patients, as it grants high reliability and reproducibility in different body position and respiratory phases., (© 2024. The Author(s).)

The preconception period is a unique and opportunistic time in a woman's life when she is motivated to adopt healthy behaviors that will benefit her and her child, making this time period a critical "window of opportunity" to improve short- and long-term health. Improving preconception health can ultimately improve both fetal and maternal outcomes. Promoting health before conception has several beneficial effects, including an increase in seeking antenatal care and a reduction in neonatal mortality. Preconception health is a broad concept that encompasses the management of chronic diseases, including optimal nutrition, adequate consumption of folic acid, control of body weight, adoption of healthy lifestyles, and receipt of appropriate vaccinations. Use of the FIGO Preconception Checklist, which includes the key elements of optimal preconception care, will empower women and their healthcare providers to better prepare women and their families for pregnancy., (© 2024 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Background: Artificial Intelligence entails the application of computer algorithms to the huge and heterogeneous amount of morphodynamic data produced by Time-Lapse Technology. In this context, Machine Learning (ML) methods were developed in order to assist embryologists with automatized and objective predictive models able to standardize human embryo assessment. In this study, we aimed at developing a novel ML-based strategy to identify relevant patterns associated with the prediction of blastocyst development stage on day 5., Methods: We retrospectively analysed the morphokinetics of 575 embryos obtained from 80 women who underwent IVF at our Unit. Embryo morphokinetics was registered using the Geri plus® time-lapse system. Overall, 30 clinical, morphological and morphokinetic variables related to women and embryos were recorded and combined. Some embryos reached the expanded blastocyst stage on day 5 (BL Group, n = 210), some others did not (nBL Group, n = 365)., Results: The novel EmbryoMLSelection framework was developed following four-steps: Feature Selection, Rules Extraction, Rules Selection and Rules Evaluation. Six rules composed by a combination of 8 variables were finally selected, and provided a predictive power described by an AUC of 0.84 and an accuracy of 81%., Conclusions: We provided herein a new feature-signature able to identify with an high performance embryos with the best developmental competence to reach the expanded blastocyst stage on day 5. Clear and clinically relevant cut-offs were identified for each considered variable, providing an objective tool for early embryo developmental assessment., (© 2024. The Author(s).)

Objectives: To evaluate the efficacy of acupuncture in relieving symptoms (dysmenorrhea, dyspareunia, pelvic pain and dyschezia) intensity, improving functional disability, reducing the number of days per months of dysmenorrhea, the frequency and the efficacy of analgesic use in deep infiltrating endometriosis (DIE). The safety profile was also evaluated., Methods: The study sample was 34 patients with DIE; for 2 months (T-2, T-1) the women recorded diary notes on the numbers of days of menstruation, the presence, intensity, and disability related to dysmenorrhea, dyspareunia, pelvic pain, and dyschezia. They then received a total of 15 acupuncture treatments over 6 months (T1-T6; once a week for 12 weeks, then once a month for 3 months)., Results: Dysmenorrhea intensity was decreased during treatment. A decrease of at least 50% in number of days of dysmenorrhea, and a decrease in moderate-to-severe disability starting from T1 to T6 was recorded for 58.6% of patients. Dyspareunia intensity steadily decreased starting at T2; the percentage of women with moderate-to-severe disability declined from 73.3% at T-2, to 36.9% at T3, T4, and T5. A decrease in pelvic pain score was noted starting at T1; the percentage of disability decreased from 83.3% at T-2 to 33.3% at T3 and T6. The intensity of dyschezia decreased from T-2 to T3 and T4 and then increased slightly. Analgesic drug use was lower during treatment and its efficacy appeared to be greater., Conclusions: The limitations notwithstanding our study-findings show that acupuncture was safe and effective in reducing pain intensity and symptoms-related disability. Larger-scale studies are needed to compare acupuncture and pharmacotherapy for endometriosis-related pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Chiarle, Allais, Sinigaglia, Airola, Rolando, Bergandi, Micalef and Benedetto.)

The outcome of liver transplantation (LT) for hepatocarcinoma (HCC) is strongly influenced by HCC staging, which is based on radiological examinations in a pre-LT setting; concordance between pre-LT radiological and definitive pathological staging remains controversial. To address this issue, we retrospectively analyzed our LT series to assess concordance between radiology and pathology and to explore the factors associated with poor concordance and outcomes. We included all LTs with an HCC diagnosis performed between 2013 and 2018. Concordance (Co group) was defined as a comparable tumor burden in preoperative imaging and post-transplant pathology; otherwise, non-concordance was diagnosed (nCo group). Concordance between radiology and pathology was observed in 32/134 patients (Co group, 24%). The number and diameter of the nodules were higher when nCo was diagnosed, as was the number of pre-LT treatments. Although concordance did not affect survival, more than three pre-LT treatments led to a lower disease-free survival. Patients who met the Milan Criteria (Milan-in patients) were more likely to receive ≥three prior treatments, leading to a lower survival in multi-treated Milan-in patients than in other Milan-in patients. In conclusion, the concordance rate between the pre-LT imaging and histopathological results was low in patients with a high number of nodules. Multiple bridging therapies reduce the accuracy of pre-LT imaging in predicting HCC stages and negatively affect outcomes after LT.

Objective: To evaluate a wide range of clinical and ultrasound characteristics of different uterine smooth muscle tumors to identify features capable of discriminating between these types., Methods: This was a retrospective, multicenter study that included 285 patients diagnosed with uterine smooth muscle tumors (50 leiomyosarcomas, 35 smooth muscle tumors of uncertain malignant potential, and 200 leiomyomas). The patients were divided into three groups based on the histological type of their tumors, and the groups were compared according to the variables collected., Results: Leiomyosarcomas were more common in older and post-menopausal women. Compared with leiomyomas, smooth muscle tumors of uncertain malignant potential and leiomyosarcomas had similar ultrasound features such as absence of normal myometrium, multilocular appearance, hyper-echogenicity in case of uniform echogenicity, absence of posterior shadows, echogenic areas, and hyperechoic rim. Leiomyosarcomas were larger, had more cystic areas, and were associated with a higher prevalence of pelvic free fluid. Smooth muscle tumors of uncertain malignant potential were characterized by a higher frequency of International Federation of Gynecology and Obstetrics (FIGO) type 6-7, the absence of internal shadows, and, in the case of cystic area, the presence of a regular internal wall. Tumor outline varied among the three histological types. A color score of 1 was typical of leiomyoma, a color score 2 was mainly observed in leiomyomas and smooth muscle tumors of uncertain malignant potential, a color score 3 did not differ among the tumors, while a color of score 4 was related to leiomyosarcomas. When combining color scores 3 and 4, leiomyosarcomas and smooth muscle tumors of uncertain malignant potential showed a high percentage of both circumferential and intra-lesional vascularization. A cooked appearance was not statistically different among the tumors., Conclusions: Based on our findings, specific ultrasonographic features as well as age and menopausal status are associated with different uterine smooth muscle tumor types. Integration of these data can help the pre-operative assessment of these lesions for proper management., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aimed to analyze the human papillomavirus (HPV) genotype distribution in a large cohort of high-grade vaginal intraepithelial neoplasia (VaIN) (vaginal HSIL, VaIN2/3) patients from two Italian referral centers. We included all patients with histologically confirmed VaIN2/3 from the Department of Surgical Sciences, Sant'Anna Hospital, University of Torino, Torino, Italy, and Ospedale Maggiore della Carità, Novara, Italy, between 2003 and 2022. After the histological evaluation of formalin-fixed paraffin-embedded samples, we performed HPV genotyping with VisionArray HPV Chip 1.0. We detected HPV DNA in 94.4% of VaIN2/3 (168/178), with HPV 16 as the most prevalent genotype, accounting for 51.8% of all infections, 41.2% of VaIN2 and 77.6% of VaIN3 cases. Other frequent genotypes were HPV 58 (8.3%, 10.9% of VaIN2 and 2.0% of VaIN3), HPV 73 (5.4%, 5.0% of VaIN2 and 6.1% of VaIN3), and HPV 31 (5.4%, 6.7% of VaIN2 and 2.0% of VaIN3). 73.2% of VaIN2/3 had a single HPV genotype infection and 26.8% a multiple infection (20.8% a double infection, 4.8% a triple infection, and 1.2% a quadruple infection). Single infection was more frequently present in VaIN3 than VaIN2 (81.6% vs. 69.8%). 69.1% of single infections and 73.3% of multiple infections had one or more genotypes covered by nine-valent HPV vaccine. HPV vaccination is expected to have a large impact on reducing the incidence of vaginal intraepithelial neoplasia., (© 2024 Wiley Periodicals LLC.)

Menopause marks the end of menstrual cyclicity and, depending on individual vulnerability, has several consequences related to gonadal steroid deprivation, especially if it is premature. Menopause may be more burdensome for some women than for others. Individual factors, such as personal history, socioeconomic status, ethnicity, and current health conditions, affect symptomatology and, thereby, the menopausal experience. In addition, some menopausal symptoms, such as severe hot flashes, sleep disorders, and depression, are markers of future health risks. Counseling is a fundamental part of health care in the peri- and postmenopause periods. It must include an assessment of the patient's symptoms, needs, desires, and risk profile to address the benefits and risks of menopausal hormone therapy (MHT) on an individual basis and promote a healthy lifestyle. Indeed, healthcare practitioners can and must protect the health and lives of mid-life women by increasing awareness of menopausal symptoms and ensuring healthcare options, especially MHT. The type and duration of MHT should be tailored based on the patient's history, menopausal age, physical characteristics, and current health status so that the benefits always outweigh the risks. This FIGO position paper focuses on the benefits and risks of MHT on health domains, target organs, and systems, and on systemic and vaginal MHT regimens, to provide indications that can be used in the clinical practice for menopausal counseling. Moreover, it offers insights into what FIGO considers the mainstay for the healthcare management of women in peri- and postmenopause, worldwide., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Objective: To determine the prognostic role of systemic inflammatory markers for Stage I epithelial ovarian cancer (EOC)., Materials and Methods: We performed a retrospective, single-center, observational study. We included patients with Stage I EOC cancer undergoing primary surgery between 1993 and 2016. Inflammatory markers were assessed by analyzing blood samples collected at initial diagnosis before EOC surgery. We evaluated these markers' association with disease-free survival (DFS) and cancer-specific survival (CSS)., Results: We included 176 women in our study. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) were related to both DFS and CSS in the univariate analysis. In the multivariate Cox analysis, adjuvant chemotherapy (hazard ratio [HR] 0.17, 95% confidence interval [CI] 0.04-0.71, P = 0.02) and SII ≥730 (HR 6.84, 95% CI 1.30-35.9, P = 0.023) were independent predictors of DFS, while FIGO Stage IB-IC (HR 7.91, 95% CI 1.04-59.8, P = 0.04), NLR ≥3 (HR 56.8, 95% CI 7.46-433, P < 0.001) and PLR ≥169 (HR 49.1 95% CI 11.1-217.8, P = 0.005) were independent predictors of CSS., Conclusions: Systemic inflammatory markers are easily obtainable from patients' routine blood analyses and may represent inexpensive and reproducible prognostic markers in early-stage EOC., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Objectives: The objective of this study is to investigate vulvovaginal disease (VVD) awareness in Italian obstetrics and gynecology (Ob/Gyn) residents., Materials and Methods: A 25-question survey on VVD basic knowledge (17 questions) and willingness to improve it (8 questions) was distributed through Ob/Gyn resident online group chats, from different Italian Universities in January 2023. A total number of 250 residents were invited to participate; 124 responses were obtained (response rate: 50%). Data were collected and analyzed using descriptive statistics through REDCap., Results: Overall, 87 of the 124 respondents (70%) fully completed the questionnaire and represented the study group. Residents were distributed among years of residency: 15% first year, 31% second year, 23% third year, 11% fourth year, and 20% fifth year. Most (60%) never attended a VVD clinic during residency, with an increasing percentage of attendance in later residency years (15% at first year vs 65% at fifth).Participants reported low knowledge of vulvar precancerous lesions and vulvoscopy but better knowledge of vaginitis, vulvar self-examination, and lichen sclerosus. Of the respondents, 50% were not satisfied with the education provided during residency, and more than 60% lacked confidence in managing VVD.All participants expressed a strong desire to improve their knowledge and skills, with 100% agreeing that every gynecologist should know the "basics" and 98% wanting to improve their knowledge through webinars (45%), lessons (34%), newsletters, and videos (19%)., Conclusion: Our findings indicate a significant need to improve VVD knowledge among Italian Ob/Gyn residents. Further efforts are necessary to provide information about VVD and comprehensive training programs in Italian Universities., Competing Interests: Disclosure statement: The authors have no conflicts of interest to declare and they received no financial support for the research, authorship, and/or publication of this article., (Copyright © 2023, ASCCP.)

Background: The efficacy and tolerability of long-acting cabotegravir and rilpivirine were demonstrated in Phase III trials. However, low concentrations combined with other risk factors have been associated with an increased risk of virologic failure. This study aims to verify whether drug concentrations measured in a real-world setting are consistent with those previously reported., Methods: SHCS-879 is a nationwide observational study within the Swiss HIV Cohort Study for the monitoring of people with HIV (PWH) on long-acting cabotegravir plus rilpivirine. Samples were collected from March 2022 to March 2023., Findings: Overall, 725 samples were obtained from 186 PWH. Our data show a large inter-individual variability in cabotegravir and rilpivirine concentrations, with some individuals exhibiting repeatedly low concentrations. Rilpivirine trough concentrations were consistent with those from Phase III trials, while cabotegravir concentrations were lower. The first concentrations quartile was only slightly above the target of 664 ng/mL. Exploratory statistical analyses found 35% (p < 0·01) lower cabotegravir trough in males compared to females. Overall, 172 PWH (92%) remained suppressed and three experienced virologic failures (1·6%), of those, two had sub-optimal drug exposure. No association was found between low trough levels and detectable viral load., Interpretation: Real-world cabotegravir concentrations are substantially lower than previously reported. However, these concentrations appear sufficient to ensure sustained virological suppression in almost every PWH. These reassuring data challenge the rather conservative thresholds adopted to date, which may raise unnecessary concerns. Yet, our study reveals that some PWH have repeatedly very low drug levels, for reasons that remain to be elucidated., Funding: This work was funded by the Swiss National Science Foundation, grant number N ◦ 324730&#95;192449. This study received no support from pharmaceutical industries. This study was performed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #201369), by SHCS project #879, and by the SHCS research foundation. The SHCS data were gathered by the Five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers)., Competing Interests: M.C. reports grants and payment for expert testimony from Gilead, MSD and ViiV, and support for attending meetings from Gilead, paid to his institution outside of the submitted work. D.B. has received honoraria for advisory board from the companies Gilead, MSD, and ViiV, and support for attending meetings from ViiV and Gilead. H.F.G. has received unrestricted research grants from Gilead Sciences; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences, Johnson and Johnson, Janssen, Novartis, and ViiV Healthcare; and grants from the Swiss National Science Foundation, the Yvonne Jacob Foundation, from National Institutes of Health and unrestricted research grants from Gilead Sciences. B.S. reports support for travel grants and advisory boards from Gilead Sciences and ViiV, paid to his institution outside of the submitted work. The institution of H.F. received educational grants from ViiV, MSD, AbbVie, Gilead, and Sandoz paid to the institution. M.S. reports advisory board paid to his institution by Gilead, MSD, ViiV, Moderna and Pfizer. The institution of A.R. received grants from Gilead; support for attending meetings from Gilead and Pfizer; and advisory boards from MSD and Moderna. C.M. has received speaker honoraria from ViiV, MSD, and Gilead unrelated to this work. C.D.B. received travel grant for congress participation from Gilead. The institution of E.B. received grants from the Swiss National Science Foundation; grants from MSD; support for attending meetings from Gilead, MSD, ViiV and Pfizer; and advisory boards from Gilead, MSD, ViiV, Pfizer, Moderna, AstraZeneca, Abbvie and Lilly. The institution of P.S. received honoraria for advisory board and support for attending meetings from ViiV and Gilead. The other authors declare no conflict of interest., (© 2023 The Author(s).)

Background : The management of early breast cancer (BC) needs supervision and skill maintenance, and should be performed by specialists working as a team in multidisciplinary breast units. This approach aims to improve the long-term survival and quality of life of patients with BC. Methods : This was a prospective observational study including patients newly diagnosed with operable BC. The study encompassed the pre-surgical phase, throughout the diagnostic and surgical workout, and included post-therapeutic master multidisciplinary team meetings (MTMs) sessions, between 2019 and 2022. Results : We enrolled 280 patients with BC from eight breast units. The Senonetwork indicators regarding diagnosis, waiting time, loco-regional treatment, and adjuvant therapy were collected for each patient discussed. Conclusions : Overall, the majority of quality indicators were respected among breast units. The most critical issue referred to timing indicators: more than 30 days from MTM to surgery, more than 42 days from diagnosis to surgery, and more than 60 days from the first screening mammogram to surgery for many patients. Some aspects of the histopathological diagnosis of intraductal BC also need to be improved. Furthermore, other critical issues in our study regarded some aesthetical indicators, demonstrating low interest in these essential quality indicators.

Purpose: To evaluate the risk of recurrence of severe placenta-mediated pregnancy complications and compare the efficacy of two different anti-thrombotic regimens in women with a history of late fetal loss without thrombophilia., Patients and Methods: We performed a 10-year retrospective observational study (2008-2018) analyzing a cohort of 128 women who suffered from pregnancy fetal loss (>20 weeks of gestational age) with histological evidence of placental infarction. All the women tested negative for congenital and/or acquired thrombophilia. In their subsequent pregnancies, 55 received prophylaxis with acetylsalicylic acid (ASA) only and 73 received ASA plus low molecular weight heparin (LMWH)., Results: Overall, one-third of all pregnancies (31%) had adverse outcomes related to placental dysfunction: pre-term births (25% <37 weeks, 5.6% <34 weeks), newborns with birth weight <2500 g (17%), and newborns small for gestational age (5%). The prevalence of placental abruption, early and/or severe preeclampsia, and fetal loss >20 weeks were 6%, 5%, and 4% respectively. We found a risk reduction for combination therapy (ASA plus LMWH) compared with ASA alone for delivery <34 weeks (RR 0.11, 95% CI: 0.01-0.95 p  = 0.045) and a trend for the prevention of early/severe preeclampsia (RR 0.14, 95% CI: 0.01-1.18, p  = 0.0715), while no statistically significant difference was observed for composite outcomes (RR 0.51, 95%CI: 0.22-1.19, p  = 0.1242). An absolute risk reduction of 5.31% was observed for the ASA plus LMWH group. Multivariate analysis confirmed a risk reduction for delivery <34 weeks (RR 0.32, 95% CI 0.16-0.96 p  = 0.041)., Conclusion: In our study population, the risk of recurrence of placenta-mediated pregnancy complications is substantial, even in the absence of maternal thrombophilic conditions. A reduction of the risk of delivery <34 weeks was detected in the ASA plus LMWH group.

Objectives: We investigated the attitudes to change the frequency of menstrual bleeding by using combined hormonal contraception (CHC). Personality characteristics were also explored., Methods: We conducted a cross-sectional study in two university hospitals in northern Italy. Current, past and never CHC users ( n  = 545; age 18-44 years) completed a self-administered semi-structured questionnaire and the Ten-Item Personality Inventory (TIPI)., Results: Forty-five percent of responders ( n  = 301) would prefer to change their bleeding frequency by using CHC. A flexible regimen was the preferred choice ( n  = 80; 33%) followed by extended regimens to bleed every 3 months ( n  = 54; 22%) or to never bleed ( n  = 43; 18%). The main positive reasons were to avoid dysmenorrhea (43%) and have more freedom in sexual (36%) and active (35%) life, whereas the main reason for a negative attitude was 'menstrual rhythm is natural' (59%). Age had a significant influence on women's willingness to change menstrual frequency by using CHC [>39 years (57%), 30-39 years (31%) and <30 years (46%)] (χ 2 : 9.1; p  = 0.01). Never users significantly reported a more negative attitude (71%) in comparison with past (51%) and current users (49%) (χ 2 : 18.7; p  = 0.001). Personality traits played a role, with higher scores of openness ( p  = 0.005) and extraversion ( p  = 0.001) in women with a positive attitude., Conclusions: Almost half of our study sample reported a preference for changing their menstrual pattern by using CHC. Flexibility was the preferred choice across age and use of CHC. Personality characteristics (openness and extroversion) might influence attitudes toward CHC-induced menstrual bleeding changes.

Background: Knot security of half-knot (H) sequences varies with rotation, but half-knots risk destabilisation., Objectives: To investigate the rotation of half-hitch (S) sequences on knot security., Materials and Methods: The loop and knot security of symmetrical and asymmetrical sliding and blocking half-hitch sequences was measured using a tensiometer., Results: Loop security of symmetrical sliding half-hitch sequences is much higher than asymmetrical sequences, increasing from 6+2 to 21+2 and from 27+6 to 48+5 Newton (N) for 2 and 4 half-hitches respectively (both P<0.0001). Symmetrical sliding sequences are more compact and remain in the same plane, squeezing the passive thread, while asymmetrical sequences rotate loosely around the passive end. Blocking sequences are superior when asymmetrical since changing the passive end acts like changing rotation, transforming the asymmetrical sliding into a symmetrical blocking half-hitch on the new passive thread. The knot security of 2 sliding and 1 blocking half-hitch doubles from 52+3 to 98+2 N for the worst (asymmetric sliding and symmetric blocking, SSaSsb) or best rotation sequences (SSsSab). Adding a second asymmetric blocking half-hitch (Sab) increases security further to 105+3 N. The overall knot security of four-throw, correctly rotated, half-hitch (SSsSabSab) or half-knot (H2H1sH1s, H2H2a and H2H2s) sequences is similar for four suture diameters., Conclusion: Rotation affects the security of half-hitch sequences, which should be symmetrical when sliding, and asymmetrical when blocking., What Is New?: Half-hitch sequences are clinically superior to half-knot sequences. They do not risk destabilisation, and loop security improves approximation of tissues under traction, permitting tight knots.

Human papillomavirus (HPV) encompasses a group of viruses that infect the skin and mucous membranes. In the presence of certain factors, persistent infection with high-risk HPVs can trigger a process of neoplastic transformation. Imiquimod is a topical agent that acts as a Toll-like receptor 7/8 agonist, stimulating the innate and adaptive immune system to exert antitumor and antiviral effects. It has been approved for the treatment of various skin conditions, however, its efficacy and safety in the management of HPV-related-neoplasms of the lower genital tract, such as vulvar, vaginal, and cervical neoplasia, are still under investigation. This review summarizes the current evidence on the use of imiquimod for the treatment of HPV-induced lesions of the female lower genital tract, focusing on its indications, mechanisms of action, outcomes, and predictors of response., (© 2023 Wiley Periodicals LLC.)

Importance: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary node staging of patients with early breast cancer (BC), but its necessity can be questioned since surgery for examination of axillary nodes is not performed with curative intent., Objective: To determine whether the omission of axillary surgery is noninferior to SLNB in patients with small BC and a negative result on preoperative axillary lymph node ultrasonography., Design, Setting, and Participants: The SOUND (Sentinel Node vs Observation After Axillary Ultra-Sound) trial was a prospective noninferiority phase 3 randomized clinical trial conducted in Italy, Switzerland, Spain, and Chile. A total of 1463 women of any age with BC up to 2 cm and a negative preoperative axillary ultrasonography result were enrolled and randomized between February 6, 2012, and June 30, 2017. Of those, 1405 were included in the intention-to-treat analysis. Data were analyzed from October 10, 2022, to January 13, 2023., Intervention: Eligible patients were randomized on a 1:1 ratio to receive SLNB (SLNB group) or no axillary surgery (no axillary surgery group)., Main Outcomes and Measures: The primary end point of the study was distant disease-free survival (DDFS) at 5 years, analyzed as intention to treat. Secondary end points were the cumulative incidence of distant recurrences, the cumulative incidence of axillary recurrences, DFS, overall survival (OS), and the adjuvant treatment recommendations., Results: Among 1405 women (median [IQR] age, 60 [52-68] years) included in the intention-to-treat analysis, 708 were randomized to the SLNB group, and 697 were randomized to the no axillary surgery group. Overall, the median (IQR) tumor size was 1.1 (0.8-1.5) cm, and 1234 patients (87.8%) had estrogen receptor-positive ERBB2 (formerly HER2 or HER2/neu), nonoverexpressing BC. In the SLNB group, 97 patients (13.7%) had positive axillary nodes. The median (IQR) follow-up for disease assessment was 5.7 (5.0-6.8) years in the SLNB group and 5.7 (5.0-6.6) years in the no axillary surgery group. Five-year distant DDFS was 97.7% in the SLNB group and 98.0% in the no axillary surgery group (log-rank P = .67; hazard ratio, 0.84; 90% CI, 0.45-1.54; noninferiority P = .02). A total of 12 (1.7%) locoregional relapses, 13 (1.8%) distant metastases, and 21 (3.0%) deaths were observed in the SLNB group, and 11 (1.6%) locoregional relapses, 14 (2.0%) distant metastases, and 18 (2.6%) deaths were observed in the no axillary surgery group., Conclusions and Relevance: In this randomized clinical trial, omission of axillary surgery was noninferior to SLNB in patients with small BC and a negative result on ultrasonography of the axillary lymph nodes. These results suggest that patients with these features can be safely spared any axillary surgery whenever the lack of pathological information does not affect the postoperative treatment plan., Trial Registration: ClinicalTrials.gov Identifier: NCT02167490.

Background: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection., Methods: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4-10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected., Results: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level., Conclusions: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

The loop and knot securities of two polyfilament and two monofilament sutures of four diameters (3.0, 2.0, 0, 1) were evaluated with a tensiometer for four four-throw knots, known to be secure with a 2.0 polyfilament suture. Loop security of Monocryl 1 is low, being 14.7 ± 3.0 Newton (N) for a three-throw half-knot (H3) and 15.4 ± 2.4 N and 28.3 ± 10 N for two (SSs) and four (SSsSsSs) symmetrical sliding half-hitches. This is lower than 18, 24, and 46 N for similar knots with Vicryl. Polyfilament sutures have excellent knot security for all four diameters. Occasionally, some slide open with slightly lower knot security, especially for larger diameters, although this is not clinically problematic. Knot security of monofilament sutures was unpredictable for all four knots, especially for larger diameters, resulting in many clinically insecure knots. A secure monofilament knot requires a six-throw knot with two symmetrical sliding half-hitches or two symmetrical half-knots secured with four asymmetric blocking half-hitches. In conclusion, with polyfilament sutures, four- or five-throw half-knot or half-hitch sequences result in secure knots. For monofilament sutures, loop and knot security is much less, half-knot combinations should be avoided, and secure knots require six-throw knots with four asymmetric blocking half-hitches.

Alteration of metabolism in cancer cells is a central aspect of the mechanisms that sustain aggressive traits. Aldo-keto reductase 1 B1 (AKR1B1) catalyzes the reduction of several aldehydes to alcohols consuming NADPH. Nevertheless, the ability of AKR1B1 to reduce different substrates renders difficult to comprehensively ascertain its biological role. Recent evidence has implicated AKR1B1 in cancer; however, the mechanisms underlying its pro-oncogenic function remain largely unknown. In this work, we report that AKR1B1 expression is controlled by the p53 tumor suppressor. We found that breast cancer patients bearing wild-type TP53 have reduced AKR1B1 expression. In cancer cell lines, p53 reduced AKR1B1 mRNA and protein levels and repressed promoter activity in luciferase assays. Furthermore, chromatin immunoprecipitation assays indicated that p53 is recruited to the AKR1B1 promoter. We also observed that AKR1B1 overexpression promoted metastasis in the 4T1 orthotopic model of triple-negative breast cancer. Proteomic analysis of 4T1 cells overexpressing AKR1B1 showed that AKR1B1 exerts a marked effect on proteins related to metabolism, with a particular impact on mitochondrial function. This work provides novel insights on the link between the p53 pathway and metabolism in cancer cells and contributes to characterizing the alterations associated to the pathologic role of AKR1B1., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Di Benedetto, Borini Etichetti, Cocordano, Cantoia, Arel Zalazar, Bicciato, Menacho-Márquez, Rosano and Girardini.)

The term Headache Disorders (HD) refers to a number of nervous system pathologies characterised by recurrent headaches. Despite the serious impact HD have on the health system, society, and the economy, these are an underestimated, underdiagnosed, and, hence, undertreated phenomenon. Triptans are the first-line therapy for the acute treatment of moderate to severe migraine but their utilization is still inadequate, perhaps also because in Italy no triptan can be bought without a medical prescription. In this article, the data from a 2016-2017 study has been further analysed with the aim of evaluating any associations between the use of triptans and the other series of variables identified in the questionnaire. This further analysis has been connected to the role that community pharmacies could play on this issue. The questionnaire was administered to 4,424 pharmacy users by 610 purposely trained pharmacists working in 514 pharmacies. The survey was carried out in 19 of the 20 Italian regions. The data shows that only 25% of patients suffering from HDs are prescribed triptans. Older patients, those with definite migraines, and those with a chronic disorder resort more frequently to this class of pharmaceuticals, as do those patients in care at a specialist headache centre. The multivariable analysis also confirmed these results. Our study, which performed a direct detection, in real life, on patients requesting pharmacological treatment for a migraine headache, therefore confirmed the need to investigate the reasons behind the low use and prescription of triptans in the Italian population. Moreover, any future studies should take advantage of community pharmacies, plan actions that would allow a series of evaluations over time of the requirements of migraineurs, and establish a process to put these patients under the care of the pharmacy to ensure adherence to therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Baratta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Vulvar lichen sclerosus is a chronic inflammatory disease involving vulvar skin. The risk of developing invasive vulvar cancer for women with LS is reported in the literature, but the risk of extra-vulvar tumors has been under-investigated. This multicentric study aims to estimate the risk of developing cancers in a cohort of women with a diagnosis of vulvar lichen sclerosus., Methods: A cohort of women diagnosed with and treated for vulvar lichen sclerosus in three Italian gynecological and dermatological clinics (Turin, Florence, and Ferrara) was retrospectively reviewed. Patient data were linked to cancer registries of the respective regions. The risk of subsequent cancer was estimated by dividing the number of observed and expected cases by the standardized incidence ratio., Results: Among 3414 women with a diagnosis of vulvar lichen sclerosus corresponding to 38,210 person-years of follow-up (mean 11.2 years) we identified 229 cancers (excluding skin cancers and tumors present at the time of diagnosis). We found an increased risk of vulvar cancer (standardized incidence ratio = 17.4; 95 % CL 13.4-22.7), vaginal cancer (standardized incidence ratio = 2.7; 95 % CL 0.32-9.771), and oropharyngeal cancer (standardized incidence ratio = 2.5; 95 % CL 1.1-5.0), and a reduced risk of other gynecological tumors (cervical, endometrial, ovarian) and breast cancer., Conclusions: Patients with vulvar lichen sclerosus should undergo annual gynecological check-up with careful evaluation of the vulva and vagina. The increased risk of oropharyngeal cancer also suggests the need to investigate oropharyngeal cavity symptoms and lesions in patients with vulvar lichen sclerosus., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Recurrent pregnancy loss (RPL) refers to two or more miscarriages before 20 weeks gestation. Its prevalence is 1-2%; its pathogenesis remains unexplained in more than 50% of cases, in which the cause is thought to be abnormal immune activity during placentation leading to a lack of pregnancy-induced immune tolerance. It is unknown whether immune activity is deranged in the endometrium of women with RPL. We studied the gene expression and the quantitative tissue protein levels of three immune checkpoints (CD276, which enhances cytotoxic T-cell activity, cytotoxic T-lymphocyte-associated antigen-4 [CTL-4], which reduces Th1 cytokine production, and lymphocyte activation gene-3 [LAG-3], which shows suppressive activity on Tregs and CD4+ T-cells) in endometrial samples from 27 women with unexplained RPL and in 29 women with dysfunctional uterine bleeding and previous uneventful pregnancies as controls. RNA isolation, real-time PCR, protein isolation, and ELISA were performed. CD276 gene expression and protein tissue levels were significantly lower in the endometrium of the RPL group than in the controls, whereas both CTL-4 and LAG-3 were significantly higher. This difference suggests defective endometrial immune regulation and overactivation of immune response in women with a history of RPL, at least in relation to controls with dysfunctional uterine bleeding and previous normal reproductive history.

Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women. Despite advances in diagnosis and treatment, EOC remains a challenging disease to manage, and the 5-year survival rate is still poor. The role of hormone receptors (HRs) in EOC carcinogenesis and prognosis has been actively explored; however, the role of hormone therapy (HT) in the treatment of these tumors is not well established. Most available data on HT mainly come from retrospective series and small early clinical trials. Several of these studies suggest that HT may have a role in adjuvant, maintenance therapy, or in the case of recurrent disease, especially for some subtypes of EOC (e.g., low-grade serous EOC). Furthermore, HT has recently been combined with targeted therapies, but most studies evaluating these combinations are still ongoing. The main aim of this review is to provide an overview of the progress made in the last decade to characterize the biological and prognostic role of HRs for EOC and the developments in their therapeutic targeting through HT.

Parvimonas micra isolations are usually part of polymicrobial infections and the pathogenic role of this microrganism is still debated. We describe here a large series of hospitalized patients diagnosed with Parvimonas micra infections and discuss the clinical and therapeutic management and the outcome of these infections., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The proportion of frozen embryo transfer cycles has consistently grown in recent decades. Some adverse obstetric outcomes after frozen embryo transfer could possibly be explained by different approaches in endometrial preparation. The aim of the present study was to investigate reproductive and obstetric outcomes after frozen embryo transfer, comparing different endometrial preparation strategies. Methods: This retrospective study included 317 frozen embryo transfer cycles, of which 239 had a natural or modified natural cycle and 78 underwent artificial endometrial preparation. After excluding late abortion and twin pregnancies, the outcomes of 103 pregnancies were analyzed, 75 of which were achieved after a natural cycle/modified natural cycle, and 28 were achieved after an artificial cycle. Results: The overall clinical pregnancy rate/embryo transfer was 39.7%, the miscarriage rate was 10.1%, and the live birth rate/embryo transfer was 32.8%, without significant differences in reproductive outcomes between natural/modified cycle and artificial cycle groups. The risks of pregnancy-induced hypertension and abnormal placental insertion were significantly increased in pregnancies achieved after the artificial preparation of the endometrium ( p = 0.0327 and =0.0191, respectively). Conclusions: Our study encourages the use of a natural cycle or modified natural cycle for endometrial preparation for frozen embryo transfer in order to ensure the presence of a corpus luteum able to orchestrate maternal adaptation to pregnancy.

Background: This study aimed to investigate the feasibility and accuracy of tattooing suspicious axillary lymph nodes with carbon suspension at the time of breast cancer (BC) diagnosis and the intraoperative correspondence between tattooed lymph node (TLN) and sentinel lymph node (SLN) in patients who underwent neoadjuvant chemotherapy (NACT)., Methods: In this retrospective study, we analyzed consecutive BC patients who underwent NACT, between April 2019 and May 2021, at the Breast Unit of Sant'Anna Hospital in Turin, Italy. Before NACT, all suspicious biopsied lymph nodes were marked with carbon suspension. All SLNs, TLNs, and axillary nodal dissection specimens were sent for histopathological examination., Results: The study group included a total of 49 patients with BC. The overall identification rate of TLNs was 83.7% (41/49; 95%, confidence interval - CI 0.70-0.92). In patients who underwent target axillary dissection (TAD) the carbon tattooing had an intraoperative identification rate of 84.4% (27/32; 95% CI 0.67-0.95) while, in the case of axillary lymph node dissection, TLNs were detected in 82.3% (14/17; 95% CI 0.56-0.96) of patients. The correlation between TLN and SLN was 71.8% (23/32)., Conclusions: These results confirmed that tattooing axillary lymph nodes has an acceptable identification rate. We also confirmed that this procedure, in addition to SLN biopsy, improves the accuracy of surgical axillary staging.

Introduction: Comparable indicators on complete cancer prevalence are increasingly needed in Europe to support survivorship care planning. Direct measures can be biased by limited registration time and estimates are needed to recover long term survivors. The completeness index method, based on incidence and survival modelling, is the standard most validated approach., Methods: Within this framework, we consider two alternative approaches that do not require any direct modelling activity: i) empirical indices derived from long established European registries; ii) pre-calculated indices derived from US-SEER cancer registries. Relying on the EUROCARE-6 study dataset we compare standard vs alternative complete prevalence estimates using data from 62 registries in 27 countries by sex, cancer type and registration time., Results: For tumours mostly diagnosed in the elderly the empirical estimates differ little from standard estimates (on average less than 5% after 10-15 years of registration), especially for low prognosis cancers. For early-onset cancers (bone, brain, cervix uteri, testis, Hodgkin disease, soft tissues) the empirical method may produce substantial underestimations of complete prevalence (up to 20%) even when based on 35-year observations. SEER estimates are comparable to the standard ones for most cancers, including many early-onset tumours, even when derived from short time series (10-15 years). Longer observations are however needed when cancer-specific incidence and prognosis differ remarkably between US and European populations (endometrium, thyroid or stomach)., Discussion: These results may facilitate the dissemination of complete prevalence estimates across Europe and help bridge the current information gaps., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Demuru, Rossi, Ventura, Dal Maso, Guzzinati, Katalinic, Lamy, Jooste, Di Benedetto, De Angelis and the EUROCARE-6 Working Group.)

Backgroud: Several studies showed that human papillomavirus (HPV) affects male fertility, but its impact on female fertility and in vitro fertilization (IVF) outcome is not yet clear., Methods: Objective of this observational, prospective, cohort study was to evaluate the prevalence of HPV infection in women candidate to IVF, and the effects of HPV infection on the kinetic of embryonic development and on IVF outcome. A total number of 457 women candidate to IVF were submitted to HR-HPV test; among them, 326 underwent their first IVF cycle and were included in the analysis on IVF results., Results: 8.9% of women candidate to IVF were HPV-positive, HPV16 being the most prevalent genotype. Among the infertility causes, endometriosis was significantly more frequent in HPV-positive than in negative women (31.6% vs. 10.1%; p < 0.01). Granulosa and endometrial cells resulted HPV-positive in 61% and 48% of the women having HPV-positive cervical swab, respectively. Comparing HPV-positive and negative women at their first IVF cycle, no significant difference was observed in the responsiveness to controlled ovarian stimulation (COS) in terms of number and maturity of retrieved oocytes, and of fertilization rate. The mean morphological embryo score was comparable in the two groups; embryos of HPV-positive women showed a quicker development in the early stages, with a significantly shorter interval between the appearance of pronuclei and their fusion. In the following days, embryo kinetic was comparable in the two groups until the early blastocyst stage, when embryos of HPV-positive women became significantly slower than those of HPV-negative women. Overall, these differences did not affect live birth rate/started cycle, that was comparable in HPV-positive and negative women (22.2 and 28.1%, respectively)., Conclusions: (a) the prevalence of HPV infection in women candidate to IVF is similar to that observed in the general female population of the same age range; (b) HPV infection migrates along the female genital apparatus, involving also the endometrium and the ovary, and perhaps participates in the genesis of pelvic endometriosis; (c) HPV slightly affects the developmental kinetic of in vitro-produced embryos, but does not exert an effect on live birth rate., (© 2023. The Author(s).)

Accumulating evidence highlights the pathogenetic role of human endogenous retroviruses (HERVs) in eliciting and maintaining multiple sclerosis (MS). Epigenetic mechanisms, such as those regulated by TRIM 28 and SETDB1, are implicated in HERV activation and in neuroinflammatory disorders, including MS. Pregnancy markedly improves the course of MS, but no study explored the expressions of HERVs and of TRIM28 and SETDB1 during gestation. Using a polymerase chain reaction real-time Taqman amplification assay, we assessed and compared the transcriptional levels of pol genes of HERV-H, HERV-K, HERV-W; of env genes of Syncytin (SYN)1, SYN2, and multiple sclerosis associated retrovirus (MSRV); and of TRIM28 and SETDB1 in peripheral blood and placenta from 20 mothers affected by MS; from 27 healthy mothers, in cord blood from their neonates; and in blood from healthy women of child-bearing age. The HERV mRNA levels were significantly lower in pregnant than in nonpregnant women. Expressions of all HERVs were downregulated in the chorion and in the decidua basalis of MS mothers compared to healthy mothers. The former also showed lower mRNA levels of HERV-K- pol and of SYN1, SYN2, and MSRV in peripheral blood. Significantly lower expressions of TRIM28 and SETDB1 also emerged in pregnant vs. nonpregnant women and in blood, chorion, and decidua of mothers with MS vs. healthy mothers. In contrast, HERV and TRIM28/SETDB1 expressions were comparable between their neonates. These results show that gestation is characterized by impaired expressions of HERVs and TRIM28/SETDB1, particularly in mothers with MS. Given the beneficial effects of pregnancy on MS and the wealth of data suggesting the putative contribution of HERVs and epigenetic processes in the pathogenesis of the disease, our findings may further support innovative therapeutic interventions to block HERV activation and to control aberrant epigenetic pathways in MS-affected patients.

This review includes state-of-the-art prognostic and predictive factors of mucinous ovarian cancer (MOC), a rare tumor. Clinical, pathological, and molecular features and treatment options according to prognosis are comprehensively discussed. Different clinical implications of MOC are described according to the The International Federation of Gynecology and Obstetrics (FIGO) stage: early MOC (stage I-II) and advanced MOC (stage III-IV). Early MOC is characterized by a good prognosis. Surgery is the mainstay of treatment. Fertility-sparing surgery could be performed in patients who wish to become pregnant and that present low recurrence risk of disease. Adjuvant chemotherapy is not recommended, except in patients with high-risk clinical and pathological features. Regarding the histological features, an infiltrative growth pattern is the major prognostic factor of MOC. Furthermore, novel molecular biomarkers are emerging for tailored management of early-stage MOC. In contrast, advanced MOC is characterized by poor survival. Radical surgery is the cornerstone of treatment and adjuvant chemotherapy is recommended, although the efficacy is limited by the intrinsic chemoresistance of these tumors. Several molecular hallmarks of advanced MOC have been described in recent years (e.g., HER2 amplification, distinct methylation profiles, peculiar immunological microenvironment), but target therapy for these rare tumors is not available yet.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine produced and secreted by immune cells in response to an infection, often in response to interferon (IFN) stimulation. In cancer, it has also been shown that IFN stimulates the production of TRAIL, and it has been proposed that this TRAIL can induce apoptosis in an autocrine or paracrine manner in different cancer cells. Yet, the mechanism mediating TRAIL upregulation and the implications of TRAIL as an apoptotic molecule in cancer cells are still poorly understood. We show here that in certain cancer cells, TRAIL is upregulated by enhancer clusters, potent genomic regulatory regions containing densely packed enhancers that have combinatorial and additive activity and that are usually found to be associated with cancer-promoting genes. Moreover, we found that TRAIL upregulation by IFNα is mediated by these enhancer clusters in breast and lung cancer cells. Surprisingly, IFNα stimulation leads to the intracellular accumulation of TRAIL protein in these cancer cells. Consequently, this TRAIL is not capable of inducing apoptosis. Our study provides novel insights into the mechanism behind the interferon-mediated upregulation of TRAIL and its protein accumulation in cancer cells. Further investigation is required to understand the role of intracellular TRAIL or depict the mechanisms mediating its apoptosis impairment in cancer cells.

Purpose: An impact of different gonadotrophins selection for ovarian stimulation (OS) on oocyte competence has yet to be defined. In this study, we asked whether an association exists between OS protocol and euploid blastocyst rate (EBR) per metaphase-II (MII) oocytes., Methods: Cycles of first preimplantation genetic testing for aneuploidies conducted by women ≥ 35 years old with their own metaphase-II oocytes inseminated in the absence of severe male factor (years 2014-2018) were clustered based on whether recombinant FSH (rec-FSH) or human menopausal gonadotrophin (HMG) was used for OS, then matched for the number of fresh inseminated eggs. Four groups were outlined: rec-FSH (N = 57), rec-FSH plus rec-LH (N = 55), rec-FSH plus HMG (N = 112), and HMG-only (N = 127). Intracytoplasmic sperm injection, continuous blastocyst culture, comprehensive chromosome testing to assess full-chromosome non-mosaic aneuploidies and vitrified-warmed euploid single embryo transfers (SETs) were performed. The primary outcome was the EBR per cohort of MII oocytes. The secondary outcome was the live birth rate (LBR) per first SETs., Results: Rec-FSH protocol was shorter and characterized by lower total gonadotrophin (Gn) dose. The linear regression model adjusted for maternal age showed no association between the Gn adopted for OS and EBR per cohort of MII oocytes. Similarly, no association was reported with the LBR per first SETs, even when adjusting for blastocyst quality and day of full blastulation., Conclusion: In view of enhanced personalization in OS, clinicians shall focus on different endpoints or quantitative effects related to Gn action towards follicle recruitment, development, and atresia. Here, LH and/or hCG was administered exclusively to women with expected sub/poor response; therefore, we cannot exclude that specific Gn formulations may impact patient prognosis in other populations., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Interest in point-of-care ultrasound (POCUS) and lung ultrasound (LUS) is growing in the nephrology and dialysis field, and the number of nephrologists skilled in what is proving to be the "5th pillar of bedside physical examination" is increasing. Patients on hemodialysis (HD) are at high risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) and developing coronavirus disease 2019 (COVID-19) serious complications. Despite this, to our knowledge there are no studies to date that show the role of LUS in this setting, while there are many in the emergency room, where LUS proved to be an important tool, providing risk stratification and guiding management strategies and resource allocation. Therefore, it is not clear whether the usefulness and cut-offs of LUS highlighted in studies in the general population are reliable in dialysis, or whether variations, precautions and adjustments to this specific situation are necessary., Methods: This was a 1-year monocentric prospective observational cohort study of 56 HD patients with COVID-19. Patients underwent a monitoring protocol that included at first evaluation bedside LUS, using a 12-scan scoring system, by the same nephrologist. All data were prospectively and systematically collected. Outcomes. hospitalization rate, combined outcome [non-invasive ventilation (NIV + death)], mortality. Descriptive variables are presented as medians (interquartile range), or percentage. Univariate and multivariate analysis, as well as Kaplan-Meier (K-M) survival curves, were carried out. P was fixed at .05., Results: Median age was 78 years, 90% had at least one comorbidity (46% diabetics), 55% were hospitalized and 23% deaths. Median duration of disease was 23 days (14-34). A LUS score ≥11 represented a 13-fold risk of hospitalization, a 16.5-fold risk of combined outcome (NIV + death) vs risk factors such as age [odds ratio (OR) 1.6], diabetes (OR 1.2), male sex (OR 1.3) and obesity (OR 1.25), and a 7.7-fold risk of mortality. In the logistic regression, LUS score ≥11 is associated with the combined outcome with a hazard ratio (HR) of 6.1 vs inflammations indices such as CRP ≥9 mg/dL (HR 5.5) and interleukin-6 (IL-6) ≥62 pg/mL (HR 5.4). In K-M curves, survival drops significantly with LUS score above 11., Conclusions: In our experience of COVID-19 HD patients, LUS appeared to be an effective and easy tool, predicting the need for NIV and mortality better than "classic" known COVID-19 risk factors such as age, diabetes, male sex and obesity, and even better than inflammations indices such as CRP and IL-6. These results are consistent with those of the studies in the emergency room setting, but with a lower LUS score cut-off (11 vs 16-18). This is probably due to the higher global frailty and peculiarity of HD population, and emphasizes how nephrologists should themselves use LUS and POCUS as a part of their everyday clinical practice, adapting it to the peculiarity of the HD ward., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Our aim was to investigate the inclusion of sexual and reproductive health and rights (SRHR) topics in medical curricula and the perceived need for, feasibility of, and barriers to teaching SRHR. We distributed a survey with questions on SRHR content, and factors regulating SRHR content, to medical universities worldwide using chain referral. Associations between high SRHR content and independent variables were analyzed using unconditional linear regression or χ 2 test. Text data were analyzed by thematic analysis. We collected data from 219 respondents, 143 universities and 54 countries. Clinical SRHR topics such as safe pregnancy and childbirth (95.7%) and contraceptive methods (97.2%) were more frequently reported as taught compared with complex SRHR topics such as sexual violence (63.8%), unsafe abortion (65.7%), and the vulnerability of LGBTQIA persons (23.2%). High SRHR content was associated with high-income level (P = 0.003) and low abortion restriction (P = 0.042) but varied within settings. Most respondents described teaching SRHR as essential to the health of society. Complexity was cited as a barrier, as were cultural taboos, lack of stakeholder recognition, and dependency on fees and ranking., (© 2022 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)