HPV E6 inhibits E6AP to regulate epithelial homeostasis by modulating keratinocyte differentiation commitment and YAP1 activation.

Human papillomaviruses (HPV) cause persistent infections by modulating epithelial homeostasis in cells of the infected basal layer. Using FUCCI and cell-cell competition assays, we have identifed regulatory roles for E6AP and NHERF1, which are the primary HPV11 E6 cellular targets, as well as being targets of the high-risk E6 proteins, in processes governing epithelial homeostasis (i.e. cell density, cell cycle entry, commitment to differentiation and basal layer delamination). Depletion of E6AP, or expression of HPV11 or 16E6 increased keratinocyte cell density and cell cycle activity, and delayed the onset of differentiation; phenotypes which were conspicuously present in HPV11 and 16 infected patient tissue. In line with proposed E6 functions, in HPV11 condyloma tissue, E6AP and NHERF1 were significantly reduced when compared to uninfected epithelium. In experimental systems, loss of HPV11 E6/E6AP binding abolished 11E6's homeostasis regulatory functions, while loss of E6/NHERF1 binding reduced the cell density threshold at which differentiation was triggered. By contrast, a NHERF1-binding mutant of 16E6 was not compromised in its homeostasis functions, while E6AP appeared essential. RNA sequencing revealed similar transcriptional profiles in both 11 and 16E6-expressing cells and E6AP-/- cells, with YAP target genes induced, and keratinocyte differentiation genes being downregulated. HPV11 E6-mediated Yap activation was observed in 2D and 3D (organotypic raft) cell culture systems and HPV-infected lesions, with both NHERF1, which is a regulator of the Hippo and Wnt pathways, and E6AP, playing an important role. As the conserved binding partner of Alpha group HPV E6 proteins, the precise role of E6AP in modulating keratinocyte phenotype and associated signalling pathways has not previously been defined. Our study suggests a model in which the preserved functions of the low and high-risk Alpha E6 proteins modulate epithelial homeostasis via E6AP activity, and lead to alteration of multiple downstream pathways, including those involving NHERF1 and YAP.

Inflammation-induced mast cell-derived nerve growth factor: a key player in chronic vulvar pain?

Provoked vulvodynia (PV) is characterized by localized chronic vulvar pain. It is associated with a history of recurrent inflammation, mast cell (MC) accumulation, and neuronal sprouting in the vulva. However, the mechanism of how vulvar-inflammation promotes neuronal sprouting and gene-expression adaptation in the spinal cord, leading to hypersensitivity and painful sensations, is unknown. Here, we found that vulvar tissue from women with PV (n=8) is characterized by MC accumulation and neuronal sprouting compared to women without PV (n=4). In addition, we observed these changes in an animal study of PV. Thus, we found that repeated vulvar zymosan-inflammation challenges lead to long-lasting mechanical and thermal vulvar hypersensitivity, which was mediated by MC accumulation, neuronal sprouting, overexpression of the pain channels (TRPV1 and TRPA1) in vulvar neurons, as well as a long-term increase of gene expression related to neuroplasticity, neuroinflammation, and nerve growth factor (NGF) in the spinal cord/DRG(L6-S3). However, regulation of the NGF pathway by stabilization of MC activity with ketotifen fumarate (KF) during vulvar inflammation attenuated the local increase of NGF and histamine, as well as the elevated transcription of pro-inflammatory cytokines, and NGF pathway in the spinal cord. Additionally, KF treatment during inflammation modulates MC accumulation, neuronal hyperinnervation, and overexpression of the TRPV1 and TRPA1 channels in the vulvar neurons, consequently preventing the development of vulvar pain. A thorough examination of the NGF pathway during inflammation revealed that blocking NGF activity by using an NGF-non-peptide-inhibitor (Ro08-2750) regulates the upregulation of genes related to neuroplasticity, and NGF pathway in the spinal cord, as well as modulates neuronal sprouting and overexpression of the pain channels, resulting in a reduced level of vulvar hypersensitivity. On the other hand, stimulation of the NGF pathway in the vulvar promotes neuronal sprouting, overexpression of pain channels, and increase of gene expression related to neuroplasticity, neuroinflammation, and NGF in the spinal cord, resulting in long-lasting vulvar hypersensitivity. In conclusion, our findings suggest that vulvar allodynia induced by inflammation is mediated by MC accumulation, neuronal sprouting, and neuromodulation in the vulvar. Additionally, chronic vulvar pain may involve a long-term adaptation in gene expression in the spinal cord, which probably plays a critical role in central sensitization and pain maintenance. Strikingly, regulating the NGF pathway during the critical period of inflammation prevents vulvar pain development via modulating the neuronal changes in the vestibule and spinal cord, suggesting a fundamental role for the NGF pathway in PV development.

A Hypothesis for Anatomical Pathways of Chronic Pelvic Pain of "Unknown Origin".

BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disabling bladder condition. ESSIC, the IC/BPS society defines two types of IC/BPS: with Hunner's lesion (HL) and without. Pathogenesis is stated as unknown, with no cure possible. Scheffler in 2021 reported cystoscopically validated cure of HL IC/BPS by repair of uterosacral ligaments (USLs) and in 2022, Goeschen reported non-HL IC/BPS cure in 198 women following USL repair. Both Scheffler and Goeschen hypothesized IC/BPS may be a phenotype of the Integral Theory's Posterior Fornix Syndrome "PFS" (chronic pelvic pain, OAB, and emptying dysfunctions) and therefore potentially curable. SUMMARY: The hypothesis explores whether visceral plexuses (VPs), due to weakened USLs support, serve as a primary source of pelvic pain impulses, leading to development of an inflammatory condition - for example, IC/BPS, a chronic inflammatory condition, which shares similarities with vulvodynia and complex regional pain syndrome (CRPS). According to our hypothesis, such conditions involve axon reflexes. Stimuli such as gravity applied to unsupported nerve branches within the visceral pelvic plexus, trigger centrally propagating impulses, which then progress antidromally to influence innervated tissues through cytokine release and nociceptor stimulation, perpetuating inflammatory processes at the end organs, and pain perception. KEY MESSAGES: The hypothesis raises the question, "are IC/BPS, vulvodynia, other pain sites, even nonbacterial "chronic prostatitis" in the male, different phenotypes of the chronic pelvic pain syndrome which includes PFS. If so, the hypothesis opens several new research directions and would predict inflammatory findings in tender end organ pain sites.

Is Vulvodynia Associated With an Altered Vaginal Microbiota?: A Systematic Review.

INTRODUCTION: Vulvodynia is defined as vulvar pain of at least 3 months' duration, without clear identifiable cause, which may have potential associated factors. It can have a significant impact on women's quality of life due to a combination of physical pain, emotional distress, and limited treatment options. Despite affecting a considerable number of women worldwide, the causes and underlying mechanisms of vulvodynia remain poorly understood. Given the recognized association of the vaginal microbiota with various gynecologic disorders, there has been growing interest in exploring the potential role of the vaginal microbiota in the etiology of vulvodynia. This systematic review aims to evaluate the current literature on the association between the vaginal microbiota and vulvodynia. MATERIAL AND METHODS: A systematic search of multiple databases, including PubMed, Scopus, Web of Science, Cochrane Library, and Ovid MEDLINE, was conducted to identify relevant peer-reviewed studies up to May 12, 2023. The following search terms were used across these databases: "vulvodynia," "vestibulodynia," "vulvar vestibulitis," "microbiome," "microbiota," and "flora." RESULTS: A total of 8 case-control studies were included, the quality of which was assessed using the Newcastle-Ottawa Scale. Data extraction and synthesis were performed using a standardized protocol. In most studies, no major differences were found between the vaginal bacterial composition of women with vulvodynia and that of controls. No specific bacterial taxa were consistently associated with vulvodynia. The relationship between vaginal microbiota diversity and vulvodynia remains to be fully understood. CONCLUSIONS: The role of vaginal microbiota in vulvodynia, if any, remains unclear. Because of the cross-sectional nature of the included studies, it is not possible to make any causal inferences. Further research, using larger and more diverse study populations and advanced sequencing techniques, is necessary to gain a better understanding of the potential relationship between the vaginal microbiota and vulvodynia.

Exploring Localized Provoked Vulvodynia: Insights from Animal Model Research.

Provoked vulvodynia represents a challenging chronic pain condition, characterized by its multifactorial origins. The inherent complexities of human-based studies have necessitated the use of animal models to enrich our understanding of vulvodynia's pathophysiology. This review aims to provide an exhaustive examination of the various animal models employed in this research domain. A comprehensive search was conducted on PubMed, utilizing keywords such as "vulvodynia", "chronic vulvar pain", "vulvodynia induction", and "animal models of vulvodynia" to identify pertinent studies. The search yielded three primary animal models for vulvodynia: inflammation-induced, allergy-induced, and hormone-induced. Additionally, six agents capable of triggering the condition through diverse pathways were identified, including factors contributing to hyperinnervation, mast cell proliferation, involvement of other immune cells, inflammatory cytokines, and neurotransmitters. This review systematically outlines the various animal models developed to study the pathogenesis of provoked vulvodynia. Understanding these models is crucial for the exploration of preventative measures, the development of novel treatments, and the overall advancement of research within the field.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) consensus statement on the management of vaginal intraepithelial neoplasia.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vaginal intraepithelial neoplasia (VaIN). The management of VaIN varies according to the grade of the lesion: VaIN 1 (low grade vaginal squamous intraepithelial lesions (SIL)) can be subjected to follow-up, while VaIN 2-3 (high-grade vaginal SIL) should be treated. Treatment needs individualization according to the patient's characteristics, disease extension and previous therapeutic procedures. Surgical excision is the mainstay of treatment and should be performed if invasion cannot be excluded. Total vaginectomy is used only in highly selected cases of extensive and persistent disease. Carbon dioxide (CO2) laser may be used as both an ablation method and an excisional one. Reported cure rates after laser excision and laser ablation are similar. Topical agents are useful for persistent, multifocal lesions or for patients who cannot undergo surgical treatment. Imiquimod was associated with the lowest recurrence rate, highest human papillomavirus (HPV) clearance, and can be considered the best topical approach. Trichloroacetic acid and 5-fluorouracil are historical options and should be discouraged. For VaIN after hysterectomy for cervical intraepithelial neoplasia (CIN) 3, laser vaporization and topical agents are not the best options, since they cannot reach epithelium buried in the vaginal scar. In these cases surgical options are preferable. Brachytherapy has a high overall success rate but due to late side effects should be reserved for poor surgical candidates, having multifocal disease, and with failed prior treatments. VaIN tends to recur and ensuring patient adherence to close follow-up visits is of the utmost importance. The first evaluation should be performed at 6 months with cytology and an HPV test during 2 years and annually thereafter. The implementation of vaccination against HPV infection is expected to contribute to the prevention of VaIN and thus cancer of the vagina. The effects of treatment can have an impact on quality of life and result in psychological and psychosexual issues which should be addressed. Patients with VaIN need clear and up-to-date information on a range of treatment options including risks and benefits, as well as the need for follow-up and the risk of recurrence.

High-risk HPV testing vs liquid-based cytology for cervical cancer screening among 25- to 30-year-old women: A historical cohort study.

INTRODUCTION: High-risk human papilloma virus (hrHPV) DNA testing is more sensitive than cytology screening, achieving greater protection against cervical cancer. Controversy exists regarding the preferred screening method for women 25-30 years of age. At this age, infection with HPV is common and usually transient. Consequently, hrHPV screening in this age group is fraught with high false-positive screening results, leading to more colposcopies and unnecessary treatments with the potential for harm. In the present study, we aimed to compare the results of two screening methods in relation to high-grade cervical intraepithelial lesion detection rate in the young age group of 25-30 years. MATERIAL AND METHODS: Retrospective information on cervical cytology, hrHPV testing, colposcopy referrals and histologic results, from one screening round, were retrieved from the Maccabi HealthCare Health Maintenance Organization centralized database during the study period from March 1, 2017 to April 1, 2019 for 25- to 30-year-old women. Screening with hrHPV testing for types 16, 18 and 12 other hrHPV types was compared with the conventional PAP liquid-based cytology (LBC) test. Odds ratio (OR) of detection with 95% confidence interval (CI) was calculated for cervical intraepithelial neoplasia (CIN) grade 3 or higher (CIN 3+). RESULTS: During the study period, 42 244 women 25-30 years old underwent cervical cancer screening; of them, 20 997 were screened with LBC between March 1, 2017 and March 1, 2018 and compared with 21 247 who were screened with hrHPV between April 1, 2018 and April 1, 2019. Testing for hrHPV resulted in a higher colposcopy referral rate compared with primary LBC screening: 9.8% vs 7.8%, respectively; (OR 1.28; 95% CI 1.2-1.37; p < 0.001). Screening with hrHPV led to significantly higher detection of CIN 3+ lesions (OR 1.4; 95% CI 1.2-1.6; p < 0.001) compared with LBC. HPV infections with non-16/18 hrHPV (other hrHPV) were the most prevalent (84.8%). CONCLUSIONS: In women 25-30 years old, primary hrHPV screening was associated with a higher detection rate of CIN 3+ compared with cytology screening and should be considered for primary screening in this age group.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) Consensus Statement on the Management of Vaginal Intraepithelial Neoplasia.

ABSTRACT: The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vaginal intraepithelial neoplasia (VaIN). The management of VaIN varies according to the grade of the lesion: VaIN 1 (low grade vaginal squamous intraepithelial lesions (SIL)) can be subjected to follow-up, while VaIN 2-3 (high-grade vaginal SIL) should be treated. Treatment needs individualization according to the patient's characteristics, disease extension and previous therapeutic procedures. Surgical excision is the mainstay of treatment and should be performed if invasion cannot be excluded. Total vaginectomy is used only in highly selected cases of extensive and persistent disease. Carbon dioxide (CO2) laser may be used as both an ablation method and an excisional one. Reported cure rates after laser excision and laser ablation are similar. Topical agents are useful for persistent, multifocal lesions or for patients who cannot undergo surgical treatment. Imiquimod was associated with the lowest recurrence rate, highest human papillomavirus (HPV) clearance, and can be considered the best topical approach. Trichloroacetic acid and 5-fluorouracil are historical options and should be discouraged. For VaIN after hysterectomy for cervical intraepithelial neoplasia (CIN) 3, laser vaporization and topical agents are not the best options, since they cannot reach epithelium buried in the vaginal scar. In these cases surgical options are preferable. Brachytherapy has a high overall success rate but due to late side effects should be reserved for poor surgical candidates, having multifocal disease, and with failed prior treatments. VaIN tends to recur and ensuring patient adherence to close follow-up visits is of the utmost importance. The first evaluation should be performed at 6 months with cytology and an HPV test during 2 years and annually thereafter. The implementation of vaccination against HPV infection is expected to contribute to the prevention of VaIN and thus cancer of the vagina. The effects of treatment can have an impact on quality of life and result in psychological and psychosexual issues which should be addressed. Patients with VaIN need clear and up-to-date information on a range of treatment options including risks and benefits, as well as the need for follow-up and the risk of recurrence.

The Light-weight Mid-urethral Sling Implant for Female Stress Urinary Incontinence Treatment: A One-Year Postoperative Follow-up Study.

BACKGROUND: Serasis® (Serag-Wiessner KG, Naila, Germany) is a light-weight mid-urethral sling for treating stress urinary incontinence (SUI). Its insertion is considered less traumatic than other mid-urethral slings. OBJECTIVES: To define postoperative outcomes following Serasis implantation. To compare the efficacy and complication rates of the implant to those of other common techniques. METHODS: Our retrospective study evaluated patients who underwent Serasis mid-urethral sling surgery for SUI. Data were collected from medical records prior to and at the time of surgery and by telephonic interview for postoperative pain and complications. Follow-up of patients was performed for up to one year postoperatively. Patients rated pain or discomfort according to the Visual Analogue Scale (VAS). The primary outcome was the development of early postoperative pain during the first month after surgery. Secondary outcomes were relief of SUI symptoms, groin pain or discomfort, and other postoperative complications up to 12 months after surgery. RESULTS: The study cohort included 50 consecutive patients aged 31 to 68 years. All patients underwent Serasis implantation procedures by a single surgeon and completed interviews. In total, 35 patients underwent concomitant anterior colporrhaphy. In the immediate postoperative period and at one month after the procedure, complaints were mild. No complaints were recorded during the 12-month follow-up period. Overall, 90% and 92% of the patients were free of SUI symptoms at one month and 12 months after surgery, respectively. CONCLUSIONS: Serasis mid-urethral sling is safe, effective, and associated with mild postoperative pain and a low incidence of complications.

Terminology for cone dimensions after local conservative treatment for cervical intraepithelial neoplasia and early invasive cervical cancer: 2022 consensus recommendations from ESGO, EFC, IFCPC, and ESP.

Local cervical treatment for squamous intraepithelial lesion (SIL) or cervical intraepithelial neoplasia (CIN) removes or ablates a cone-shaped or dome-shaped part of the cervix that contains abnormal cells. This Series paper introduces the 2022 terminology for cone dimensions after local conservative treatment for SIL, CIN, or early invasive cervical cancer. The terminology was prepared by the Nomenclature Committee of the European Society of Gynaecologic Oncology, the European Federation for Colposcopy, the International Federation of Cervical Pathology and Colposcopy, and the European Society of Pathology. Cone length should be tailored to the type of transformation zone. Treatment of SIL or CIN is associated with an increased risk of preterm birth, which escalates with increasing cone length. There is a lack of agreement regarding terms used to report excised specimen dimensions both intraoperatively and in the pathology laboratory. Consensus is needed to make studies addressing effectiveness and safety of SIL or CIN treatment comparable, and to facilitate their use to improve accuracy of antenatal surveillance and management. This Series paper summarises the current terminology through a review of existing literature, describes new terminology as agreed by a group of experts from international societies in the field of cervical cancer prevention and treatment, and recommends use of the new terminology that will facilitate communication between clinicians and foster more specific treatment guidelines that balance obstetrical harm against therapeutic effectiveness.

Liver stiffness and steatosis in preeclampsia as shown by transient elastography-a prospective cohort study.

BACKGROUND: Preeclampsia is a multisystem disorder and the leading cause of severe morbidity and death in pregnancy. Liver involvement in preeclampsia ranges from elevated liver enzyme levels to hepatic infarction or rupture. Endothelial dysfunction leads to changes in blood flow and congestion and may be involved in the pathophysiology of preeclampsia. Changes in splanchnic blood flow and portal congestion can lead to altered liver stiffness. Transient elastography is a noninvasive, ultrasound-based technique that measures organ stiffness and steatosis and is therefore widely used in clinical hepatology. Previous studies reported elevated liver stiffness and liver steatosis, as measured by transient elastography, in women with preeclampsia. OBJECTIVE: This study followed changes in liver stiffness and steatosis, as measured by transient elastography, from the antepartum period to 1-week postpartum among women with preeclampsia compared with healthy controls and evaluated the association between preeclampsia severity and transient elastography results. STUDY DESIGN: This prospective cohort study was conducted from 2017 through 2021. The study group comprised women with preeclampsia, and the control group comprised healthy pregnant women hospitalized for other reasons. All the participants underwent transient elastography either on diagnosis of preeclampsia (study group) or on hospital admission (control group) and again in the postpartum period. Liver stiffness measurements are expressed in kilopascals (kPa) in the range of 2.5 to 75 kPa, and liver steatosis is expressed by controlled attenuation parameter in the range of 100 to 400 dB/m. RESULTS: The study group comprised 36 women and the control group 37. Liver stiffness scores were significantly elevated in the study when compared with the control group, both in the antepartum period (P<.001) and the postpartum period (P=.025). Liver stiffness scores decreased significantly after delivery in the study and control groups (P<.001 and P=.002, respectively). Liver steatosis scores were higher in the study group than in the control group both in the antepartum and postpartum periods (P<.001 and P<.02, respectively). In the multivariable analysis, the diagnosis of preeclampsia correlated with higher antepartum liver stiffness scores (P=.005). For the study group, postpartum liver stiffness and liver steatosis scores were increased among those with vs those without severe features of preeclampsia (P=.03 and P=.04, respectively) CONCLUSION: Reductions in liver stiffness and steatosis from the antepartum to the postpartum period were documented in both the preeclampsia and control groups. However, both these measures were higher in the preeclampsia group and correlated with preeclampsia severity. Larger studies may be able to determine whether transient elastography can predict the severity of preeclampsia or other related metabolic conditions that correlate with chronic hypertension.

Coexisting Epithelioid Trophoblastic Tumor and Placental Site Trophoblastic Tumor During Asymptomatic Relapse: A Case Report and Literature Review.

Gestational trophoblastic neoplasms are a group of trophoblastic tumors that include choriocarcinoma (CC), epithelioid trophoblastic tumors (ETTs), and placental site trophoblastic tumors (PSTTs). Mixed gestational trophoblastic neoplasms include combinations of CCs with ETTs and/or PSTTs; combinations of ETTs and PSTTs have also been described. This report describes the case of a 49-yr-old female with mixed ETT and PSTT discovered due to menstrual delay and a positive beta-human chorionic gonadotropin in serum 11 yr after normal pregnancy; it is an asymptomatic recurrence of the neoplasm after 2 yr. Moreover, only the ETT recurred without evidence of PSTT by biopsy and without any increase in human chorionic gonadotropin levels, even though human chorionic gonadotropin was positive in the first onset of the disease. We also reviewed published English literature, which revealed that there are only 36 cases of mixed trophoblastic tumors to date, of which pure mixed ETT and PSTT were reported only in four cases including our case. The most common combination is CC admixed with an ETT (52%), followed by CC with PSTT in 30.5%. CC admixed with an ETT and/or PSTT account for 83% of the cases, of which pure mixed ETT and PSTT were reported only in 4 cases (11%). The rarity of this condition entails reporting of all cases to facilitate future research and clinical management.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy (EFC) consensus statements on pre-invasive vulvar lesions.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vulvar squamous intraepithelial neoplasia, vulvar Paget disease in situ, and melanoma in situ. For differentiated vulvar intraepithelial neoplasia (dVIN), an excisional procedure must always be adopted. For vulvar high-grade squamous intraepithelial lesion (VHSIL), both excisional procedures and ablative ones can be used. The latter can be considered for anatomy and function preservation and must be preceded by several representative biopsies to exclude malignancy. Medical treatment (imiquimod or cidofovir) can be considered for VHSIL. Recent studies favor an approach of using imiquimod in vulvar Paget's disease. Surgery must take into consideration that the extension of the disease is usually wider than what is evident in the skin. A 2 cm margin is usually considered necessary. A wide local excision with 1 cm free surgical margins is recommended for melanoma in situ. Following treatment of pre-invasive vulvar lesions, women should be seen on a regular basis for careful clinical assessment, including biopsy of any suspicious area. Follow-up should be modulated according to the risk of recurrence (type of lesion, patient age and immunological conditions, other associated lower genital tract lesions).

Vulvodynia: a neuroinflammatory pain syndrome originating in pelvic visceral nerve plexuses due to mechanical factors.

This short opinion aimed to present the evidence to support our hypothesis that vulvodynia is a neuroinflammatory pain syndrome originating in the pelvic visceral nerve plexuses caused by the failure of weakened uterosacral ligaments (USLs) to support the pelvic visceral nerve plexuses, i.e., T11-L2 sympathetic and S2-4 parasympathetic plexuses. These are supported by the USLs, 2 cm from their insertion to the cervix. They innervate the pelvic organs, glands, and muscles. If the USLs are weak or lax, gravitational force or even the muscles may distort and stimulate the unsupported plexuses. Inappropriate afferent signals could then be interpreted as originating from an end-organ site. Activation of sensory visceral nerves causes a neuro-inflammatory response in the affected tissues, leading to neuroproliferation of small peripheral sensory nerve fibers, which may cause hyperalgesia and allodynia in the territory of the damaged innervation. Repair of the primary abnormality of USL laxity, responsible for mechanical stimulation of the pelvic sensory plexus, may lead to resolution of the pain syndrome.

Changes in the Vaginal Microbiota of Women With Secondary Localized Provoked Vulvodynia.

OBJECTIVE: The etiology of localized provoked vulvodynia (LPV) remains unknown, but observations suggest the involvement of the vaginal microbiota. We examined the vaginal microbiota of women with LPV and healthy controls, upon after a low-oxalate diet (LOD). MATERIALS AND METHODS: A total of 9 women diagnosed with secondary LPV and 21 healthy controls were recruited from the Galilee Medical Center in Israel and subjected to prospective evaluations of their vaginal microbiota. Total DNA was extracted from vaginal discharge samples provided before and after following LOD for 3 weeks and was then subjected to 16S sequencing. Data obtained were then used to evaluate α and ß diversity, identify differentially abundant bacterial taxa in LPV, and determine their impact on the metabolism. RESULTS: These evaluations revealed decreased diversity in the vaginal microbiota of women with LPV and identified the Ochrobactrum genus and Pseudomonadaceae family as indicators for LPV. In addition, we identified 23 differentially expressed bacterial metabolic pathways between the LPV and control samples and revealed that LOD could induce changes in the ß diversity of LPV vaginal microbiomes, which was further supported by some degree of pain reduction in patients. CONCLUSIONS: Localized provoked vulvodynia and LOD were associated with shifts in the vaginal microbiota. However, the impact of these changes on the development of LPV requires additional studies with a larger cohort.

Risk of Development of Vulvar Cancer in Women With Lichen Sclerosus or Lichen Planus: A Systematic Review.

OBJECTIVE: Vulvar lichen sclerosus (VLS) and possibly vulvar lichen planus (VLP) are associated with an increased vulvar cancer (VC) risk. We analyzed the risk of VC and its precursors after a diagnosis of VLS or VLP. MATERIALS AND METHODS: A search was performed to identify articles describing the development of vulvar neoplasia in women with VLS or VLP. This systematic review was registered with the PROSPERO database. RESULTS: Fourteen studies on VLS included 14,030 women without a history of vulvar neoplasia. Vulvar cancer, differentiated vulvar intraepithelial neoplasia (dVIN), and vulvar high-grade squamous intraepithelial lesion occurred in 2.2% (314/14,030), 1.2% (50/4,175), and 0.4% (2/460), respectively. Considering women with previous or current VC, the rate was 4.0% (580/14,372). In one study, dVIN preceded VC in 52.0% of the cases. Progression of dVIN to VC was 18.1% (2/11).The risk was significantly higher in the first 1-3 years after a biopsy of VLS and with advancing age; it significantly decreased with ultrapotent topical steroid use.For the 14,268 women with VLP (8 studies), the rates of VC, dVIN, and vulvar high-grade squamous intraepithelial lesion were 0.3% (38/14,268), 2.5% (17/689), and 1.4% (10/711), respectively. CONCLUSIONS: Vulvar lichen sclerosus is associated with an increased risk of VC, especially in the presence of dVIN and with advancing age. Ultrapotent topical steroids seem to reduce this risk. An increased risk of developing VC has been suggested for VLP. Hence, treatment and regular life-long follow-up should be offered to women with VLS or VLP.

Vulvar High-Grade Squamous Intraepithelial Lesions and Cancer as a Risk Factor for Anal Cancer: A Review.

OBJECTIVES: Anal squamous cell carcinoma (ASCC) has a higher incidence described in certain groups, namely, in women with vulvar high-grade squamous intraepithelial lesions (vHSILs) and/or human papillomavirus squamous cell carcinoma (VSCC). This review describes terminology, vHSIL, and VSCC in their association with ASCC and the published recommendations for early detection of this cancer in these women. MATERIALS AND METHODS: A narrative review was conducted by the authors on vHSIL and VSCC as risk factors for ASCC. RESULTS: The ASCC and VSCC incidence are increasing. Women with vHSIL and/or VSCC can present with ASCC at diagnosis, being one of the highest-risk groups. Suspicious symptoms include rectal bleeding, pain, and a sensation of an anal mass. Digital anorectal examination can help detect early ASCC. Sensitivity of anal cytology in women with vHSIL and VSCC seems low, with the exception of immunosuppressed women with genital neoplasia (cervix, vagina, and vulva). There are still insufficient data on high-resolution anoscopy in women with vHSIL and/or VSCC as a screening method. CONCLUSIONS: Clinicians need be aware that women with vHSIL and VSCC comprise one of the highest-risk groups for ASCC. Inquiring suggestive symptoms of ASCC and a digital anorectal examination can help in the early detection of this type of cancer.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy (EFC) Consensus Statements on Pre-invasive Vulvar Lesions.

ABSTRACT: The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vulvar squamous intraepithelial neoplasia, vulvar Paget disease in situ, and melanoma in situ. For differentiated vulvar intraepithelial neoplasia (dVIN), an excisional procedure must always be adopted. For vulvar high-grade squamous intraepithelial lesion (VHSIL), both excisional procedures and ablative ones can be used. The latter can be considered for anatomy and function preservation and must be preceded by several representative biopsies to exclude malignancy. Medical treatment (imiquimod or cidofovir) can be considered for VHSIL. Recent studies favor an approach of using imiquimod in vulvar Paget's disease. Surgery must take into consideration that the extension of the disease is usually wider than what is evident in the skin. A 2 cm margin is usually considered necessary. A wide local excision with 1 cm free surgical margins is recommended for melanoma in situ. Following treatment of pre-invasive vulvar lesions, women should be seen on a regular basis for careful clinical assessment, including biopsy of any suspicious area. Follow-up should be modulated according to the risk of recurrence (type of lesion, patient age and immunological conditions, other associated lower genital tract lesions).

Outcomes of a fixed skeletonised mini mesh implant for pelvic organ prolapse repair with uterine preservation.

Mesh repair of pelvic organ prolapse (POP) is complicated, causing erosions, postoperative pain and surgical failure. We hypothesised that reducing the mesh size and fixating it would result in significant cure rates and reduce complication rates. Here, we present the effectiveness of mini mesh implants in POP reconstruction. Sixty women who underwent repair of stage III and IV apical prolapse with cystocele or rectocele using skeletonised mesh implant Seratom PA MR MN® were evaluated. Anatomical outcomes were assessed using modified POP-quantification (POP-Q) staging and functional outcomes were self-reported by patients - one and three months post-operatively. Apical support with anterior and/or posterior colporrhaphy was performed, resulting in 96.6% success rate. Follow-up conducted one and three months post-operatively revealed significant improvement on the modified POP-Q (p < .001) and no complaints of dyspareunia. Para-vesicular fixation using a skeletonised mini mesh implant is feasible and effective in POP repair and has low surgical complication risk.Impact StatementWhat is already known on this subject? Mesh repair for pelvic organ prolapse (POP) is currently under scrutiny as it may result in erosions, postoperative pain, and surgical failure.What do the results of this study add? The use of an apical support with mini-mesh implants resulted in a 96.6% (58/60) success rate and excellent outcomes at 1- and 3-month follow-up.What are the implications of these findings for clinical practice and/or further research? Reconstruction using skeletonised and fixated mini-mesh implants may be safe and effective for POP treatment.

The association between acute lower abdominal pain over a previous caesarean scar and uterine rupture.

Pregnant women with previous caesarean delivery might suffer from acute lower abdominal pain located at the site of previous caesarean scar (CS). The association between this complaint and uterine rupture (UR) is not fully understood. Therefore, we aimed to examine the risk of UR in women with acute persistent abdominal pain (APAP) over a previous CS and to investigate all the women with UR, with or without APAP and with or without previous CS, in order to determine risk factors, clinical presentation and management. We performed a retrospective analysis on two study groups: women who had APAP over previous CS and women who had UR. We found an incidence of UR in patients with APAP over the previous CS was 0.7%; which doubled the total UR rate among women with previous caesarean in our medical centre (0.35%). Forty percent of the women with APAP over a previous CS had preterm delivery. Twenty percent of the cases of UR occurred in preterm weeks. To conclude, APAP over a previous CS is associated with a doubled risk of UR. Considering this symptom as a preliminary sign of UR might lead to elevated rate of iatrogenic preterm deliveries.Impact statementWhat is already known on this subject? Women with UR may present with abdominal pain which may vary from non-specific mild discomfort to severe acute abdominal pain. Additionally, these women may suffer from acute persistent abdominal pain (APAP) located over the previous caesarean scar. The clinical significance of APAP in these women has not been fully investigated.What do the results of this study add? Lower abdominal pain located at the site of previous CS is associated with a doubled risk of UR. Considering this complaint as a major sign of UR might lead to an elevated rate of iatrogenic preterm deliveries.What are the implications of these findings for clinical practice and/or further research? Further studies are needed to explore whether women with a single complaint of APAP over CS could be managed expectantly and even offered a trial of labour after caesarean delivery (CD).