Differentiated vulvar intraepithelial neoplasia long-term follow up and prognostic factors: An analysis of a large historical cohort.

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.

The International Society for the Study of Vulvovaginal Disease (ISSVD) Vulvar Awareness Day Campaign: Knowledge of Vulvovaginal Diseases Among Italian Obstetrics and Gynecology Residents.

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.

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 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.

Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71.

Different viruses belonging to distinct viral families, such as enterovirus 71, rely on the host methyltransferase METTL3 for the completion of fundamental cytoplasmic stages of their life cycle. Modulation of the activity of this enzyme could therefore provide a broad-spectrum approach to interfere with viral infections caused by viruses that depend on its activity for the completion of their viral cycle. With the aim to identify antiviral therapeutics with this effect, a series of new nucleoside analogues was rationally designed to act as inhibitors of human METTL3, as a novel approach to interfere with a range of viral infections. Guided by molecular docking studies on the SAM binding pocket of the enzyme, 24 compounds were prepared following multiple-step synthetic protocols, and evaluated for their ability to interfere with the replication of different viruses in cell-based systems, and to directly inhibit the activity of METTL3. While different molecules displayed moderate inhibition of the human methyltransferase in vitro, multiple novel, potent and selective inhibitors of enterovirus 71 were identified.

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).

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).

Obstetric and neonatal outcomes after SARS-CoV-2 infection in the first trimester of pregnancy: A prospective comparative study.

OBJECTIVE(S): This prospective observational cohort study aimed to evaluate whether women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the first trimester of pregnancy are at higher risk of adverse obstetric and neonatal outcomes compared to negative patients. STUDY DESIGN: Seromolecular testing for SARS-CoV-2 was performed at 12, 16, 21 weeks, and at delivery; the cohort was then subdivided into a first-trimester SARS-CoV-2-positive (case) group and a SARS-CoV-2-negative (control) group. The primary outcome was a composite adverse obstetric outcome, defined as the presence of either abortion, preterm delivery, preterm prelabor rupture of membranes, preeclampsia, intrauterine growth restriction, stillbirth; and a composite measure of adverse neonatal events, including either 1- and 5-min Apgar score ≤ 7, neonatal intensive care unit admission and congenital birth defects. Maternal symptoms and antibody titer were secondarily assessed. RESULTS: A total of 17 of 164 women tested positive for SARS-CoV-2 (10.3%) in the first trimester. One SARS-CoV-2-positive patient who gave birth at another hospital was excluded. Composite adverse obstetric outcome was observed in 6.2% (1/16) SARS-CoV-2-positive and 10.5% (11/105) SARS-CoV-2-negative women; composite adverse neonatal outcome in 12.5% (2/16) and 7.6% (8/105), respectively. In the newborns of women who had developed IgG antibodies, the same antibodies were detected in arterial cord blood and the nasopharyngeal swab tested negative for SARS-CoV-2. No maternal pneumonia or hospital admission due to coronavirus disease-19 were recorded. CONCLUSION: Asymptomatic or mildly symptomatic women during the first trimester of pregnancy did not experience significantly more adverse events than SARS-CoV-2-negative women.

Structure-Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections.

Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines are currently available to treat or prevent this infection. An antiviral therapy that can be used as treatment and as a prophylactic measure in the case of outbreaks is urgently needed. We previously described the computer-aided design and synthesis of novel small-molecule agents able to inhibit the replication of human norovirus in cell-based systems. These compounds are non-nucleoside inhibitors of the viral polymerase and are characterized by a terminal para-substituted phenyl group connected to a central phenyl ring by an amide-thioamide linker, and a terminal thiophene ring. Here we describe new modifications of these scaffolds focused on exploring the role of the substituent at the para position of the terminal phenyl ring and on removing the thioamide portion of the amide-thioamide linker, to further explore structure-activity relationships (SARs) and improve antiviral properties. According to three to four-step synthetic routes, we prepared thirty novel compounds, which were then evaluated against the replication of both murine (MNV) and human (HuNoV) norovirus in cells. Derivatives in which the terminal phenyl group has been replaced by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thioamide linker has been removed, showed promising results in inhibiting HuNoV replication at low micromolar concentrations. Particularly, compound 28 was found to have an EC50 against HuNoV of 0.9 µM. Although the most active novel derivatives were also associated with an increased cytotoxicity in the human cell line, these compounds represent a very promising starting point for the development of new analogues with reduced cytotoxicity and improved selectivity indexes. In addition, the experimental biological data have been used to create an initial 3D quantitative structure-activity relationship model, which could be used to guide the future design of novel potential anti-norovirus agents.

Superficially Invasive Vulvar Squamous Cell Carcinoma: A 37-Year-Long Experience of a Tertiary Referral Center.

Superficially, invasive vulvar squamous cell carcinoma (SISCCA) (FIGO stage IA) is a rare subset of vulvar cancer defined as a single lesion measuring ≤2 cm with a depth of invasion of ≤1.0 mm. This is a retrospective study performed on 48 patients with SISCCA, surgically treated between 1981 and 2018 at the S. Anna Hospital, University of Turin, to evaluate pathological characteristics and prognosis of these tumors. Ten patients (21%) recurred: seven (14%) as SISCCA and three (7%) as deeply invasive carcinoma. One case with perineural invasion and groin node metastasis at recurrence. No patient had groin lymph node metastases at initial diagnosis. Site of SISCCA, type of surgery, status of surgical margins, and histopathological features did not differ between recurrent and non-recurrent patients. We observed a non-significant trend towards an increase of recurrences in younger women (median age: 63 years vs. 70 years, p = 0.09), while, surprisingly, smaller tumors (<12 mm) were significantly related to tumor relapse (p = 0.03). Overall, SISCCA has a good long-term prognosis, regardless of the pathological characteristics and the type of surgical treatment. We recommend close follow-up, especially for younger patients and for small tumors, due to the possibility of recurrence or re-occurrence even after years.

Vulvar Paget's disease and stromal invasion: Clinico-pathological features and survival outcomes.

PURPOSE: To evaluate clinico-pathological features, treatments and survival outcomes of vulvar Paget's disease (VPD). METHODS: We retrospectively reviewed VPD diagnosed between 1983 and 2018 at the Department of Surgical Sciences, Sant'Anna Hospital, Turin. Clinico-pathological characteristics and surgical treatment outcomes were investigated according to the depth of invasion. RESULTS: A total of 122 patients were identified. Eighty-seven patients were diagnosed with intraepithelial VPD, 22 with microinvasive (<=1 mm) VPD and 16 with invasive VPD. The median follow-up was 94.6 months (interquartile range 25th-75th, 26-120). Most of patients 95/122 (77%) were treated by surgery. Local recurrence was observed in 69/95 (73%) patients without significant difference between the 3 groups (p = 0.33), however, total vulvectomy showed better local control in microinvasive and invasive VPD than in intraepithelial tumors. At 120 months the cancer-specific survival was 100% for intraepithelial and microinvasive VPD versus 31% for invasive VPD (log-rank p = <0.0001) Age ≥65 years (OR: 4.17 CI 1.12-15.5, p = 0.03) and VPD's area ≥15 cm2 (OR: 5.83 CI 1.75-19.3, p = 0.004) were associated with risk of invasiveness. CONCLUSION: Microinvasive VPD has an identical prognosis to intraepithelial VPD, suggesting the omission of lymphadenectomy or adjuvant treatments are safe in this subset of patients. We recommend caution to propose medical treatment in patients who are ≥65 years old and with wide tumor area, as they are at the greatest risk of invasiveness.

Four-decade trends in lymph node status of patients with vulvar squamous cell carcinoma in northern Italy.

The 4-decade (1980-2017) trends in lymph node status of patients with vulvar squamous cell carcinoma (VSCC) in a province of northern Italy were investigated. Information was collected on lymph node dissection, number of lymph nodes dissected, lymph node involvement, and number of positive lymph nodes from a series of 760 patients admitted to a tertiary referral centre for vulvar disease. The adjusted odds ratios (ORs) for lymph node involvement, for ≥ 2 positive nodes, and for a lymph node ratio ≥ 20% were estimated from multiple logistic regression models. The adjusted OR for lymph node dissection was greater in the 2000s and 2010s versus the 1980s. The adjusted OR for lymph node involvement was 1.36 (95% confidence interval (CI), 0.72-2.60) in the 1990s, 1.31 (95% CI, 0.72-2.38) in the 2000s and 1.32 (95% CI, 0.73-2.41) in the 2010s versus the 1980s. The adjusted OR for ≥ 2 positive nodes was 1.36 (95% CI, 0.68-2.72), 0.86 (95% CI, 0.44-1.65) and 0.67 (95% CI, 0.34-1.31), respectively. The adjusted OR for lymph node ratio ≥ 20% was 1.45 (95% CI, 0.62-3.43), 1.21 (95% CI, 0.54-2.72) and 0.81 (95% CI, 0.35-1.89), respectively. This stagnation indicates the need for a serious rethink of the local model for the care of VSCC.

Prenatal Biochemical and Ultrasound Markers in COVID-19 Pregnant Patients: A Prospective Case-Control Study.

This prospective observational study aimed to evaluate whether women with SARS-CoV-2 infection during the first trimester of pregnancy are at higher risk of noninvasive prenatal screening test alterations and/or of congenital fetal anomalies at the second-trimester fetal anatomy scan. Maternal symptoms were secondly investigated. The study was carried out on 12-week pregnant women admitted for noninvasive prenatal testing (16 April and 22 June 2020). The cohort had seromolecular tests for SARS-CoV-2, after which they were divided into a positive case group and a negative control group. Both groups had 20-week ultrasound screening. Seventeen out of the 164 women tested positive for SARS-CoV-2 (10.3%). There were no significant differences in mean nuchal translucency thickness or biochemical markers (pregnancy-associated plasma protein A, alpha-fetoprotein, human chorionic gonadotropin, unconjugated estriol) between cases and controls (p = 0.77, 0.63, 0.30, 0.40, 0.28) or in the fetal incidence of structural anomalies at the second-trimester fetal anatomy scan (p = 0.21). No pneumonia or hospital admission due to COVID-19-related symptoms were observed. Asymptomatic or mildly symptomatic SARS-CoV-2 infection during the first trimester of pregnancy did not predispose affected women to more fetal anomalies than unaffected women. COVID-19 had a favorable maternal course at the beginning of pregnancy in our healthy cohort.

Knowledge of Vulvar Anatomy and Self-examination in a Sample of Italian Women.

OBJECTIVE: The aim of the study was to investigate the knowledge of vulvar anatomy and vulvar self-examination (VSE) in a sample of Italian women attending a gynecology clinic. METHODS: For this original research from May to July 2019, 512 women attending the Lower Genital Tract Clinic at the Department of Surgical Sciences of the University of Torino were invited to participate in a 29-question survey about vulvar anatomy, VSE, and sociodemographic details. Data were analyzed using descriptive statistics. RESULTS: Of 512 patients, 500 completed the questionnaire (98% response rate). The mean age of respondents was 41 years (range = 17-77 years). Education level was evenly distributed between elementary, high school, and university graduates. Only 15% of interviewed women were able correctly sketching vulvar anatomy. Seventy-six percent of the women had not heard about VSE, and 61% of the women approach their genitalia with feelings of shame and embarrassment. Only 23% of the women would seek medical advice after identification of possible abnormalities during VSE. A majority (69%) of the women would like to have more information about VSE and vulvar health through educational videos and social media. CONCLUSIONS: Education about VSE may lead to earlier diagnosis of vulvar cancers and other pathologies. Further efforts are needed to disperse information about normal external female genital anatomy and VSE to achieve self-confidence among women.

The Impact of Vulvar Cancer on Psychosocial and Sexual Functioning: A Literature Review.

Women who are diagnosed and treated for vulvar cancer are at higher risk of psychological distress, sexual dysfunction and dissatisfaction with partner relationships. The aim of this article is to provide a review of the psychological, relational and sexual issues experienced by women with vulvar cancer in order to highlight the importance of this issue and improve the quality of care offered to these patients. A review of the literature was performed using PubMed, CINAHL, PsycINFO, and the Cochrane Library. The results are presented as a narrative synthesis and highlight the massive impact of vulvar cancer: depressive and anxiety symptoms were more frequent in these women, and vulvar cancer may have a negative effect on sexuality from a physical, psychological and behavioural point of view. Factors that may negatively affect these women's lives are shame, insecurity or difficulties in self-care and daily activities. This review highlights the psychosocial and psychosexual issues faced by women diagnosed and treated for vulvar cancer, although more studies are needed to better investigate this field of interest and to identify strategies to relieve their psychological distress. Care providers should implement an integrated care model to help women with vulvar cancer recognise and address their unmet needs.

Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review.

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.

Psychosocial factors associated with postpartum psychological distress during the Covid-19 pandemic: a cross-sectional study.

BACKGROUND: Trauma, natural and man-made catastrophic events can be predictors of postpartum psychological distress. In a public health response due to coronavirus disease 2019 outbreak, the Italian government imposed a lockdown from March 9 to May 3. This extraordinary situation may have been challenging for maternal psychological health. The aim of this study was to investigate the prevalence of depressive and post-traumatic stress symptoms in women giving birth during the Covid-19 pandemic and its associations with quarantine measures, obstetrical factors, and relational attachment style. METHODS: Women who gave birth in a high-volume obstetric/gynaecological medical centre located in an epidemic area during the Covid-19 pandemic (March 8 to June 15) were asked to complete an online survey about their childbirth experience and the perceived effect of the pandemic. The Edinburgh Postnatal Depression Scale (EPDS), the Impact of Event Scale-Revised (IES-R), and the Relationship Questionnaire (RQ) were administered to assess levels of postpartum depressive and post-traumatic stress symptoms (PTSS) and relational style of attachment, respectively. Multivariate analysis was applied to identify associations between quarantine measures, childbirth experience, attachment style, and EPDS and IES-R scores. RESULTS: The survey was completed by 163 women (response rate 60.8%). The prevalence of depressive symptoms was 44.2% (EPDS cut-off score ≥ 11) and the PTSS rate was 42.9% (IES-R cut-off score ≥ 24). Dismissive and fearful avoidant attachment styles were significantly associated with the risk of depression and PTSS, respectively. Perceived pain during birth was a risk factor for postpartum depression. Perceived support provided by healthcare staff was a protective factor against depression and PTSS. Another protective factor against PTSS was quiet on the ward due to the absence of hospital visitors. CONCLUSION: This study reports a high prevalence of postpartum depressive and PTSS in women who gave birth during the Covid-19 pandemic. Postnatal psychological distress seemed to be associated more with the prenatal experience and other individual factors than with the pandemic hospital restrictions. Early detection during pregnancy of an insecure attachment style is fundamental to provide targeted preventive and therapeutic psychological interventions.

Rational design of highly potent broad-spectrum enterovirus inhibitors targeting the nonstructural protein 2C.

There is a great need for antiviral drugs to treat enterovirus (EV) and rhinovirus (RV) infections, which can be severe and occasionally life-threatening. The conserved nonstructural protein 2C, which is an AAA+ ATPase, is a promising target for drug development. Here, we present a structure-activity relationship study of a previously identified compound that targets the 2C protein of EV-A71 and several EV-B species members, but not poliovirus (PV) (EV-C species). This compound is structurally related to the Food and Drug Administration (FDA)-approved drug fluoxetine-which also targets 2C-but has favorable chemical properties. We identified several compounds with increased antiviral potency and broadened activity. Four compounds showed broad-spectrum EV and RV activity and inhibited contemporary strains of emerging EVs of public health concern, including EV-A71, coxsackievirus (CV)-A24v, and EV-D68. Importantly, unlike (S)-fluoxetine, these compounds are no longer neuroactive. By raising resistant EV-A71, CV-B3, and EV-D68 variants against one of these inhibitors, we identified novel 2C resistance mutations. Reverse engineering of these mutations revealed a conserved mechanism of resistance development. Resistant viruses first acquired a mutation in, or adjacent to, the α2 helix of 2C. This mutation disrupted compound binding and provided drug resistance, but this was at the cost of viral fitness. Additional mutations at distantly localized 2C residues were then acquired to increase resistance and/or to compensate for the loss of fitness. Using computational methods to identify solvent accessible tunnels near the α2 helix in the EV-A71 and PV 2C crystal structures, a conserved binding pocket of the inhibitors is proposed.

Risk of HPV-related extra-cervical cancers in women treated for cervical intraepithelial neoplasia.

BACKGROUND: The aim was to estimate the risk of subsequent extra-cervical Human Papillomavirus (HPV) related cancer in patients surgically treated for high grade cervical intraepithelial neoplasia (CIN 2-3). This is the first study in Italy investigating the occurrence of extra-cervical tumors in this cohort of patients. METHODS: 3184 patients surgically treated for CIN2-3 since 1992 at the Department of Surgical Sciences of University of Torino were considered. The risk of HPV-related cancer was calculated as Standardized Incidence Ratio (SIR), using as expected values tumour age specific incidence of resident population. RESULTS: 173 second primary cancer (SCPs) were identified. SIR to develop cancer after treatment for CIN2-3 was 2.2 (CI 95% 1.89-2.50). Among these occurrences, 10 are in HPV related sites: 1 anus (SIR = 1.8; 0.04-10.0), 3 vagina (SIR = 12.4; 2.56-36.3), 1 vulva (SIR = 1.7; 0.04-9.59), 5 oropharynx (SIR = 8.5; 2.76-19.8). Significant risk has been also recorded for pulmonary (SIR = 3.1; 0.70-5.27) and bladder (SIR = 4.05; 1.10-10.56), with smoking as possible cofactor. We also found increased risk for breast (SIR = 2.4; 2.07-2.84) and ovarian cancers (SIR = 2.1; 1.13-3.49), probably due to an higher adherence to spontaneous and programmed screening programs. CONCLUSIONS: Our study supports the hypothesis of an increased risk of HPV-related tumours for CIN treated patients, mostly for CIN3. It is conceivable the need of early diagnosis for these cancers in this higher-risk populations.

Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis.

BACKGROUND: Systemic sclerosis (scleroderma) is characterized by immunologic abnormalities, injury of endothelial cells, and tissue fibrosis. Abnormal oxidative stress has been documented in scleroderma and linked to fibroblast activation. Since platelet-derived growth factor (PDGF) stimulates the production of reactive oxygen species (ROS) and since IgG from patients with scleroderma reacts with human fibroblasts, we tested the hypothesis that patients with scleroderma have serum autoantibodies that stimulate the PDGF receptor (PDGFR), activating collagen-gene expression. METHODS: We analyzed serum from 46 patients with scleroderma and 75 controls, including patients with other autoimmune diseases, for stimulatory autoantibodies to PDGFR by measuring the production of ROS produced by the incubation of purified IgG with mouse-embryo fibroblasts carrying inactive copies of PDGFR alpha or beta chains or the same cells expressing PDGFR alpha or beta. Generation of ROS was assayed with and without specific PDGFR inhibitors. Antibodies were characterized by immunoprecipitation, immunoblotting, and absorption experiments. RESULTS: Stimulatory antibodies to the PDGFR were found in all the patients with scleroderma. The antibodies recognized native PDGFR, inducing tyrosine phosphorylation and ROS accumulation. Autoantibody activity was abolished by preincubation with cells expressing the PDGFR alpha chain or with recombinant PDGFR or by PDGFR tyrosine kinase inhibitors. Stimulatory PDGFR antibodies selectively induced the Ha-Ras-ERK1/2 and ROS cascades and stimulated type I collagen-gene expression and myofibroblast phenotype conversion in normal human primary fibroblasts. CONCLUSIONS: Stimulatory autoantibodies against PDGFR appear to be a specific hallmark of scleroderma. Their biologic activity on fibroblasts strongly suggests that they have a causal role in the pathogenesis of the disease.