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Introduction Vulva squamous cell carcinoma (VSCC) develops through two separate molecular pathways—one involving high‐risk human papilloma virus infection (HPV‐associated), and the other without HPV infection (HPV‐independent) often involving TP53 mutation. HPV‐associated VSCC generally has a better progression‐free survival than HPV‐independent VSCC. The aim of this study was to determine TP53 mutation status using immunohistochemistry, compare different methods of HPV detection and correlate both with survival in a retrospective cohort of 123 patients with VSCC. Material and methods Immunohistochemistry for p53, Ki67 and p16INK4A (a surrogate marker for HPV infection) was performed on formalin‐fixed paraffin‐embedded tissues from a cohort of surgically treated VSCC patients to identify molecular subtypes of VSCC. Presence of HPV infection was detected by HPV DNA PCR and HPV mRNA in situ hybridization (ISH). The Pearson chi‐square test and multivariable Cox regression model were used to investigate the association of different parameters with progression‐free survival and disease‐specific survival (DSS), and Kaplan–Meier curves were used to show the association of different parameters with survival. Results The results of p53 and p16INK4A immunohistochemistry confirmed three VSCC subtypes associated with different prognosis. The TP53 mutation status was identified as an independent prognostic factor of worse progression‐free survival (p = 0.024) after adjustment for FIGO stage. p16INK4A immunohistochemistry, mRNA ISH, and DNA PCR had excellent concordance in terms of HPV detection. According to the multivariable Cox regression model, the presence of hrHPV mRNA correlated significantly with increased progression‐free survival (p = 0.040) and DSS (p = 0.045), after adjustment for other confounders. Conclusions p53 and p16INK4A immunohistochemistry stratify VSCC cohort into three subtypes with TP53mutated patients having the worst prognosis. The detection of hrHPV mRNA by ISH was an independent predictor of increased survival. Thus, the combined detection of p53 and HPV mRNA might improve risk stratification in VSCC. Better tools are required for personalized treatment guidance of women with vulva squamous cell carcinoma. Our results demonstrate that patients with p53‐mutations have the highest risk for recurrence and death, and those positive for HPV mRNA, have better prognosis.

Genitourinary Syndrome of Menopause (GSM) defines a set of symptoms associated with an estrogen deficit involving alterations in organs genitourinary and that results in several urinary, genital, and sexual alterations. Brazilian women live about a third of their life after menopause, where hormonal changes occur along with clinical manifestations, characterized by vaginal and vulvar dryness, burning sensation, discomfort, vulvovaginal irritation, lack of lubrication, dyspareunia and urinary incontinence. Fractionated photothermolysis and radiofrequency systems, alone or in combination were tested to improve GSM. The goal of this study is to elaborate a protocol to evaluate the clinical response of patients with symptoms of GSM after the application of photobiomodulation in the vulvar region. In this randomized, double-blind, placebo-controlled study protocol, women over 50 years of age who are in the postmenopausal period (amenorrhea for at least 12 months, with no pathology involved) with one or more symptoms of GSM will be randomly divided into two groups. The treatment group (n = 30) will receive four consecutive applications, weekly, using DMC laser diode (λ = 808 nm), 4J per point, 100mW of power, 1,016W/cm2, 8 sites in the vulvar region, The Placebo Group (n = 30) will be handled as treated, but with the laser turned off. The quality of life will be assessed using female sexual functioning index (FSFI-6), urinary incontinence questionnaire (ICIQ-SF), Quality of life will be analyzed using the female sexual functioning index (FSFI-6). The intensity of menopausal symptoms will be evaluated using a visual analogue scale (VAS), the vulvo vaginal atrophy will be measured by the Vaginal Health Index (VHI). Also, the vaginal temperature will be measured using a thermal camera, the pressure of the pelvic floor force (vaginal dynamometer) and a 1-hour Pad Test will be performed to quantify the urinary loss. With this procedure, we intend to obtain an overall better life quality and diminished symptoms in women with GSM. All assessments will be performed prior to the first irradiation and after the last one. This protocol is registered at ClinicalTrials.gov under the number NCT05557799.

Purpose The study aimed to evaluate and compare the efficacy and safety of treating atrophied labia majora with hyaluronic acid (HA) and calcium hydroxyapatite (CaHA). Methods Ten participants complaining of sagging or loss of volume in the labia majora were evaluated and randomly assigned to two groups—treated with CaHA or AH. Photographic documentation was taken and appreciated by the participants and by blind observers. Results The study showed an improvement in labia majora regarding volumization and flaccidity that was more significant after 90 days of treatment in both treatments. Besides flaccidity, volume replacement resulted in better balance and proportion between the labia majora and labia minora. The evaluators, independent and blind, judged that in 80% of the cases of the HA group and in 50% of cases of the CaHA group, there was an excellent improvement. Conclusion CaHA and HA are both effective and safe for treating the intimate region, and this study cannot prove the superiority of one over the other. An appropriate assessment involving the analysis of sagging and/or volume loss and the creation of a sequential treatment protocol, involving CaHA and HA, seems to be the best solution. Level of Evidence I Evidence obtained from at least one properly designed randomized controlled trial. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Female sexual dysfunction is highly prevalent among postmenopausal females approaching 50%, with vulvovaginal atrophy (VVA) being a cardinal sign. For decades, hormone replacement therapy was the only solution to relieve symptoms associated with this atrophy. However, it was limited by its serious side effects, raising the need for new treatment strategies. This study aims to compare the efficacy and safety of injection of hyaluronic acid (HA) versus platelet rich plasma (PRP) in post-menopausal females presented with VVA to improve female sexual dysfunction. Twenty post-menopausal females presented with VVA were randomly divided into two groups, 10 patients in each group. Both groups received three sessions of injections into the vulva and vagina, one month apart. Group I was injected with non cross linked HA while Group II received PRP injection. Subjective assessment was carried out through female sexual function index questionnaire and global aesthetic improvement scale.While objective assessment was carried out by measuring the labia majora length and reviewing the histopathological changes occurring in the vulva through skin biopsies before and after treatment. The change in vaginal thickness was estimated by transvaginal ultrasound. Results showed that both HA as well as PRP were effective in the treatment of post-menopausal vulvovaginal atrophy. However, HA showed more significant improvement in female sexual dysfunction. There were also higher values in vaginal wall thickness as measured by transvaginal ultrasound in favor of HA injected group. Histopathological assessment showed more collagen deposition in papillary dermis in HA treated group. No complications were reported in both groups.

Vulvar squamous cell carcinomas and their precursors are currently classified by the World Health Organization based on their association with high-risk human papillomavirus (HPV). HPV independent lesions often harbor driver alterations in TP53, usually seen in the setting of chronic vulvar inflammation. However, a group of pre-invasive vulvar squamous lesions is independent from both HPV and mutant TP53. The lesions described within this category feature marked acanthosis, verruciform growth and altered squamous maturation, and over the last two decades several studies have added to their characterization. They have a documented association with verrucous carcinoma and conventional squamous cell carcinoma of the vulva, suggesting a precursor role. They also harbor recurrent genomic alterations in several oncogenes, mainly PIK3CA and HRAS, indicating a neoplastic nature. In this review, we provide a historical perspective and a comprehensive description of these lesions. We also offer an appraisal of the terminology used over the years, going from Vulvar Acanthosis with Altered Differentiation and Verruciform Lichen Simplex Chronicus to Differentiated Exophytic Vulvar Intraepithelial Lesion and Vulvar Aberrant Maturation, the latter term having been recently proposed by the International Society for the Study of Vulvovaginal Diseases. In line with the recognition of these lesions by the 2020 World Health Organization Classification of Tumours as a neoplastic precursor, we herein propose the term HPV-independent, p53-wild-type verruciform acanthotic Vulvar Intraepithelial Neoplasia (HPVi(p53wt) vaVIN), which better conveys not only the pathology but also the neoplastic nature and the biologic risk inherent to these uncommon and challenging lesions. We outline strict morphologic and immunohistochemical criteria for its diagnosis and distinction from mimickers. Immunohistochemistry for p16 and p53 should be performed routinely in the diagnostic work-up of these lesions, and the morphologic alternative term vaVIN should be reserved for instances in which p16/HPV/p53 status is unknown. We also discuss management considerations and the need to further explore precursors within and beyond the spectrum of verruciform acanthotic vulvar intraepithelial neoplasia.

Ras genes are important oncogenes that are frequently mutated in cancer. Human oncogenic variants exhibit functional distinctions in terms of their representation in different cancer types, impact on cellular targets and sensitivity to pharmacological treatments. However, how these distinct variants influence and respond to the cellular networks in which they are embedded is poorly understood. To identify novel participants in the complex interplay between Ras genotype and cell interaction networks in vivo, we have developed and tested an experimental framework using a simple vulva-development assay in the nematode C. elegans. Using this system, we evaluated a set of Ras oncogenic substitution changes at G12, G13 and Q61. We found that these variants fall into distinct groups based on phenotypic differences, sensitivity to gene dosage and inhibition of the downstream kinase MEK and their response to genetic modulators that influence Ras activity in a non-autonomous manner. Together, our results demonstrated that oncogenic C. elegans Ras variants exhibit clear distinctions in how they interface with the vulva-development network and showed that extracellular modulators yield variant-restricted effects in vivo.

Purpose Vulvovaginal atrophy (VVA) is a commonly reported issue among breast cancer patients, and its aetiology is multifactorial. Treatment is difficult in these women, particularly because the use of oestrogens has traditionally been discouraged. Vaginal laser treatment has been reported to improve symptoms. We aimed to assess the impact on symptoms and sexual function of vaginal laser in women with early breast cancer (EBC). Methods We performed a single-arm investigator initiated pilot study of female EBC patients with symptomatic VVA. A total of 3 vaginal laser treatments were administered 4 weeks apart. Questionnaires were completed at baseline, 4, 8 and 12 weeks. Our primary endpoint was symptomatic improvement of VVA at 12 weeks on 10 cm visual analogue scales. Our secondary endpoints were improvement in sexual function using the Female Sexual Function Index (FSFI) and patient-reported improvements in symptoms, sexual function and quality of life. Statistical analysis was performed with a Wilcoxon Signed Rank test. Results 26 patients were enrolled between February 2016 and August 2017. All patients were post-menopausal, 25 of whom had received anti-oestrogen therapy for their breast cancer. Questionnaire compliance was high (98%) and all patients received the three pre-planned treatments. There was significant improvement in each of the VVA symptoms: dryness ( p  < 0.001), itch ( p  < 0.001), burning ( p  = 0.003), dysuria ( p  < 0.001) and dyspareunia ( p  < 0.001). Patients also reported improvement in sexual function on the FSFI ( p  ≤ 0.001). Conclusions Patients receiving vaginal laser had improvement in VVA symptoms and sexual function. Further randomised sham-controlled trials are needed to further assess this treatment.

The expression of the cyclin-dependent kinase inhibitor p16 correlates with the presence of human papillomavirus. The purpose of this investigation was to assess the prognostic relevance of p16 expression in patients with vulvar squamous cell carcinoma (VSCC) treated with radical surgery followed by adjuvant (chemo) radiation in selected cases. Seventy-eight patients were analyzed retrospectively. Positive p16 immunostaining was detected in 19 (24.4%) patients. Five-year disease-free survival (DFS) and 5-year overall survival (OS) were better in p16-positive compared to p16-negative patients (83.9% versus 37.3% p=0.002 and 91.7% versus 57.6%, p=0.003, respectively). p16 expression retained prognostic relevance at multivariate analysis for both DFS and OS. p16 expression was detected in 24.4% of patients with VSCC and was found to be an independent prognostic variable for both DFS and OS.

Developmental signaling networks are composed of dozens of components whose interactions are very difficult to quantify in an embryo. Geometric reasoning enumerates a discrete hierarchy of phenotypic models with a few composite variables whose parameters may be defined by in vivo data. Vulval development in the nematode Caenorhabditis elegans is a classic model for the integration of two signaling pathways; induction by EGF and lateral signaling through Notch. Existing data for the relative probabilities of the three possible terminal cell types in diverse genetic backgrounds as well as timed ablation of the inductive signal favor one geometric model and suffice to fit most of its parameters. The model is fully dynamic and encompasses both signaling and commitment. It then predicts the correlated cell fate probabilities for a cross between any two backgrounds/conditions. The two signaling pathways are combined additively, without interactions, and epistasis only arises from the nonlinear dynamical flow in the landscape defined by the geometric model. In this way, the model quantitatively fits genetic experiments purporting to show mutual pathway repression. The model quantifies the contributions of extrinsic vs. intrinsic sources of noise in the penetrance of mutant phenotypes in signaling hypomorphs and explains available experiments with no additional parameters. Data for anchor cell ablation fix the parameters needed to define Notch autocrine signaling.

Background There is currently a lack of information on full anogenital evaluation of women with a previous history of anogenital neoplasia. Methods Retrospective analysis of the Homerton Anogenital Neoplasia Service records from January 2012 to March 2017, to identify all new referrals of women with previous anogenital neoplasia, who had had at least one complete examination of all anogenital sites. Multizonal anogenital disease (MZD) was defined as the presence of high-grade squamous intraepithelial lesions (HSIL)/carcinoma concurrently at two or more of the following sites/zones: perianus, anal canal, vulva, vagina or cervix. Results 253 women were included, mean age was 47 (SD=15) years and median duration of follow-up was 12 (IQR=21) months. Fifty-six women (22%) were diagnosed with MZD at first assessment and/or during follow-up. Current smokers (RR=1.84, 95% CI 1.21–2.79, p=0.004) and women on immunodulators/immunosuppressive drugs (RR=2.57, 95% CI 1.72-3.86, p<0.001) had an increased risk for MZD. The risk was lower for women without a previous history of anogenital high-grade lesions/cancer compared to those with this history (RR=0.06, 95% CI 0.01-0.45, p =0.006). Conclusions Multizonal assessment was important to diagnose occult areas of disease and should be especially considered in current smokers, pharmacologically immunocompromised and those with a previous history of anogenital HSIL/cancer.