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Objective: Women treated for Cervical Intraepithelial Neoplasia (CIN) grade 2 or 3 are at increased risk of CIN and cervical cancer. Human Papillomavirus (HPV) vaccination is effective in preventing CIN in women who are not infected by HPV. Some studies suggested that vaccination may reduce the risk of CIN2 or 3 in women treated for CIN. A working group including all Italian scientific societies involved in tackling cervical cancer developed a recommendation on vaccination against HPV for women treated for CIN2 or CIN3. Data sources, methodsofstudyselection: The group conducted a systematic review of the literature published from January 2006 to May 2019. Evidence on safety outcomes was retrieved by a recent Cochrane Review on vaccination in the general population. To develop the final recommendation, evidences were appraised and integrated by a Panel of Experts using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence to Decision framework. Tabulation, integrationandresults: Six eligible studies were included. Four were RCTs and two were cohort studies, with different timing of vaccination. An additional study, published in October 2019, was taken into consideration after external review. A reduction of 70% CIN2+ in the treatment group was estimated; the vaccine was considered safe. Conclusion: The working group recommends the use of HPV vaccination in women treated for CIN2 or 3. The strong recommendation is based on large estimated desirable effects and trivial anticipated undesirable effects (moderate certainty of evidence), negligible costs and savings (no studies included), and a positive judgment in terms of feasibility, acceptability, and impact on equity.

The risk of infection associated with immunomodulatory or immunosuppressive disease-modifying drugs (DMDs) in patients with multiple sclerosis (MS) has been increasingly addressed in recent scientific literature. A modified Delphi consensus process was conducted to develop clinically relevant, evidence-based recommendations to assist physicians with decision-making in relation to the risks of a wide range of infections associated with different DMDs in patients with MS. The current consensus statements, developed by a panel of experts (neurologists, infectious disease specialists, a gynaecologist and a neuroradiologist), address the risk of iatrogenic infections (opportunistic infections, including herpes and cryptococcal infections, candidiasis and listeria; progressive multifocal leukoencephalopathy; human papillomavirus and urinary tract infections; respiratory tract infections and tuberculosis; hepatitis and gastrointestinal infections) in patients with MS treated with different DMDs, as well as prevention strategies and surveillance strategies for the early identification of infections. In the discussion, more recent data emerged in the literature were taken into consideration. Recommended risk reduction and management strategies for infections include screening at diagnosis and before starting a new DMD, prophylaxis where appropriate, monitoring and early diagnosis.

Objective: Cervical cancer prevention shows a variability across Italian Regions unjustified by available evidence, increasing the health, economic and organizational burden. Evidence-based recommendations on topics not covered by international guidelines are needed to tackle existing inequalities. This article describes the rationale, methods, and process for development of the Multisociety Italian Guidelines for cervical cancer prevention. Methods: The Italian legislative framework requires guidelines to be consistent with methodological standards set by the National System for Guidelines (SNLG) of the National Institute of Health. Results: The nine scientific societies involved in cervical cancer prevention participated to the project, including clinicians, policy makers, methodologists, and researchers. Patients were involved as full voting panel members. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach was adopted to assess the certainty of evidence collected by systematic reviews. The GRADE Evidenceto- Decision framework (EtD) was used to structure the appraisal of evidence and to formulate final recommendations. The EtD and a conflict-of-interests management policy were adopted to minimize the influence of competing interests. Discussion: Full transparency guided the reporting of each step of the process, to support the implementation of recommendations in each context and the future updating process. Considerations for subgroups, monitoring and evaluation of the implementation of recommendations and research priorities were also provided. A two-step review process by external experts and SNLG reviewers, prior to online publication, ensured the methodological robustness underlying final recommendations. Finally, to increase publication timeliness, guidelines are organised in chapters that group sets of related recommendations to be published independently.

Objective To investigate the effects of fractional microablative CO2 laser on sexual function and overall satisfaction with sexual life in postmenopausal women with vulvovaginal atrophy (VVA).Method This prospective study included 77 postmenopausal women (mean age 60.6 ± 6.2 years) treated for VVA symptoms with the fractional microablative CO2 laser system (SmartXide2 V2LR, Monalisa Touch, DEKA, Florence, Italy). Sexual function and quality of life were evaluated with the Female Sexual Function Index (FSFI) and the Short Form 12 (SF-12), respectively, both at baseline and at 12-week follow-up. A 10-mm visual analog scale was used to measure the overall satisfaction with sexual life and the intensity of VVA symptoms (vaginal burning, vaginal itching, vaginal dryness, dyspareunia and dysuria) before and after the study period.Results We observed a significant improvement in the total score and the scores in each specific domain of the FSFI at 12-week follow-up compared to baseline (p < 0.001). After...

Objective This pilot study aimed to assess the efficacy in treating sexually active menopausal patients who had dyspareunia related to vulvovaginal atrophy (VVA). Materials and Methods The intensity of VVA symptoms was recorded for each patient. Patients were administered the Short Form 12 (SF-12) and the female sexual function index (FSFI) to assess quality of life and sexual function, respectively. An objective evaluation of female urogenital health was performed using the Gloria Bachman Vaginal Health Index (VHI). Results At 12-week follow-up, the laser treatment was efficacious in improving dyspareunia in 100% of patients included in the study (n = 15). The intensity of dyspareunia significantly decreased from baseline (8.7 ± 1.0) to 12-week follow-up (2.2 ± 1.0; pConclusions This pilot study demonstrated that treatment with the microablative fractional CO2 laser of patients with dyspareunia related to VVA was efficacious at 12-week follow-up.

Background Human Papillomavirus (HPV) is the leading cause of cervical cancer among women. Immunosuppression is recognized as one of the major risk factors for HPV infection and persistence. Objectives Aim of this study was to determine if solid organs (24 kidney and 24 kidney/pancreas) transplanted Italian women undergoing immunosuppressive therapies were at higher risk of HPV genital infection and cervical precancerous lesions in a ten-year follow-up. Study design Forty-eight women that underwent transplant from 1990 to 2000, receiving multi-drug immunosuppressive therapy, were enrolled prospectively in a long-term follow-up protocol. Patients were cytologically (Pap smear) and virologically (HPV-DNA test) tested each year for 10 years. Incidence of HPV-DNA positivity and of cervical cytological/histological abnormalities was collected. Results were statistically analyzed and compared to a matching control group of 200 healthy women. Results HPV-DNA positivity and cytological High-Grade (HG-SIL) cervical lesions did not show statistically significant differences in cases compared to controls, while statistical significance was observed in Low-Grade (LG-SIL) cytological diagnoses. No statistically significant difference was observed in histology-proven cervical lesions. Conclusions Women receiving immunosuppression therapy following transplant do not seem to require intensive follow-up, and should not be considered a high-risk subgroup, as they do not show a statistically significant higher incidence of HPV infections or high-grade cervical dysplasia compared to healthy immunocompetent matching controls.

Persistent positivity of HPV-DNA testing is considered a prognostic index of recurrent disease in patients treated for CIN2+. HPV detection, and particularly genotyping, has an adequate high rate of sensitivity and specificity (along with an optimal reproducibility), for accurately predicting treatment failure, allowing for an intensified monitoring activity. Conversely, women with a negative HPV-test 6 months after therapy have a very low risk for residual/recurrent disease, which leads to a more individualized follow-up schedule, allowing for a gradual return to the normal screening scheme. HPV testing should be routinely included (with or without cytology) in post-treatment follow-up of CIN2+ patients for early detection of recurrence and cancer progression. HPV genotyping methods, as a biological indicator of persistent disease, could be more suitable for a predictive role and risk stratification (particularly in the case of HPV 16/18 persistence) than pooled HPV-based testing. However, it is necessary to be aware of the performance of the system, adhering to strict standardization of the process and quality assurance criteria.

Background Over the last two decades it has become clear that distinct types of human papillomavirus (HPV), the so-called high-risk types (hrHPV), are the major cause of cervical cancer. The hrHPV-DNA testing has shown excellent performance in several clinical applications from screening to the follow-up of conservatively treated patients. Methods We conducted a systematic review of the recent literature on the performance of HPV DNA testing in follow-up after treatment of high-grade cervical lesions, adenocarcinoma in situ, and microinvasive carcinoma compared to Pap smear cytology. Results Observational studies have demonstrated that the high risk hrHPV-DNA test is significantly more sensitive (95%) compared to follow-up cytology(70%) in detecting post-treatment squamous intraepithelial high-grade lesions. Moreover, in patients treated conservatively for cervical adenocarcinoma in situ, the hrHPV-DNA test is the most significant independent predictor of recurrent disease or progression to invasive cancer, and the combination of viral DNA testing and cytology reaches 90% sensitivity in detecting persistent lesions at the first follow-up visit and 100% at the second follow-up visit. The cause of microinvasive squamous cervical carcinoma is increasingly treated with conservative therapies in order to preserve fertility, and an effective strategy allowing early detection of residual or progressive disease has become more and more important in post-treatment follow-up. Primary results seem to indicate that the median time for viral clearance is relatively longer compared with patients treated for CIN and suggest a prolonged surveillance for these patients. However, the potential clinical value of HPV-DNA testing in this clinical setting needs to be confirmed by further observations. Conclusions The excellent sensitivity, negative predictive value, and optimal reproducibility of the hrHPV DNA testing, currently is considered a powerful tool in the clinicians' hands to better manage post-treatment follow-up either in cervical squamous lesion or in situ adenocarcinoma.

Since the introduction of biomolecular testing for the identification of high-risk human papillomavirus DNA (hrHPV-DNA) in cervical cancer preventive strategies, many interesting aspects have emerged in this field; firstly, HPV-DNA testing has been demonstrated to have better sensitivity than conventional cytology in several settings: screening, triage of ASC-US and in follow-up after treatment. Despite this, some limitations of these new technologies have also been underlined: the major issue is the low specificity of the tests, which cannot discriminate between regressive and progressive infections. Thus, recent research has moved the attention towards novel markers of progression that could more precisely detect cases at real risk of cancer development. In view of the fact that progression to cancer is dependable of the E6/E7 proteins integration and transforming action, the overexpression of E6/E7 transcripts has been seen as a valuable marker of this risk. This review aims to summarise the literature data on this topic and to provide a clear view of the emerging perspectives.

Microablative fractional CO2 laser has been proven to determine tissue remodeling with neoformation of collagen and elastic fibers on atrophic skin. The aim of our study is to evaluate the effects of microablative fractional CO2 laser on postmenopausal women with vulvovaginal atrophy using an ex vivo model.This is a prospective ex vivo cohort trial. Consecutive postmenopausal women with vulvovaginal atrophy managed with pelvic organ prolapse surgical operation were enrolled. After fascial plication, the redundant vaginal edge on one side was treated with CO2 laser (SmartXide2; DEKA Laser, Florence, Italy). Five different CO2 laser setup protocols were tested. The contralateral part of the vaginal wall was always used as control. Excessive vagina was trimmed and sent for histological evaluation to compare treated and nontreated tissues. Microscopic and ultrastructural aspects of the collagenic and elastic components of the matrix were studied, and a specific image analysis with computerized morphometry was performed. We also considered the fine cytological aspects of connective tissue proper cells, particularly fibroblasts.During the study period, five women were enrolled, and 10 vaginal specimens were finally retrieved. Four different settings of CO2 laser were compared. Protocols were tested twice each to confirm histological findings. Treatment protocols were compared according to histological findings, particularly in maximal depth and connective changes achieved. All procedures were uneventful for participants.This study shows that microablative fractional CO2 laser can produce a remodeling of vaginal connective tissue without causing damage to surrounding tissue.

This pilot study aimed to assess the efficacy and feasibility of fractional CO2 laser in the treatment of vulvovaginal atrophy (VVA) in postmenopausal women.VVA symptoms were assessed before and after three applications of laser over 12 weeks in 50 women (age 59.6 ± 5.8 years) dissatisfied with previous local estrogen therapies. Subjective (visual analog scale) and objective (Vaginal Health Index Score, VHIS) measures were used during the study period to assess VVA. Quality of life was measured by using the SF-12. A subjective scale to evaluate the degree of pain related to the laser application and the degree of difficulty to perform the laser procedure was used.Fractional CO2 laser treatment was effective to improve VVA symptoms (vaginal dryness, vaginal burning, vaginal itching, dyspareunia, dysuria; p0.001) at 12-week follow-up, as well as the VHIS (13.1 ± 2.5 at baseline vs. 23.1 ± 1.9; p0.001). Both physical and mental scores of quality of life were significantly improved in comparison with baseline (p0.001). Satisfaction with the laser procedure was reported by 42 women (84%) and a minimal discomfort was experienced at the first laser application, mainly because of the insertion and the movements of the probe. Finally, the technique was very easy to perform in all women starting from the second application at week 4 and no adverse events were recorded during the study period.A 12-week treatment with the fractional CO2 laser was feasible and induced a significant improvement of VVA symptoms by ameliorating vaginal health in postmenopausal women. Further controlled studies should be performed to confirm the present data and to assess the long-term effects of the laser procedure on vaginal tissues.

Pelvic pain is a common condition which significantly deteriorates health-related quality of life. The most commonly identified causes of pain in the pelvic region are gynaecologic, urologic, gastrointestinal, neurological, and musculoskeletal. However, in up to 33% of patients the source of this symptom is not identified, frustrating both patients and health-care professionals. Pelvic pain may involve both the somatic and visceral systems, making the differential diagnosing challenging. This paper aimed to review the mechanisms involved in pelvic pain perception by analyzing the neural plasticity and molecules which are involved in these complex circuits.

Aneuploidy, defined as an abnormal quantity of DNA in cells nuclei, is the most frequently observed genetic abnormality in cancer cells. Alterations in cell cycle control and chromosomal missegregation very often result in the accumulation of excess genetic material. These genetic reassortments simultaneously imbalance lots of structural and regulatory proteins. This chromosomal instability may be associated with mutations in tumor suppressor genes or loss of function of mismatch repair genes. These are common pathways of cancerogenesis in endometrial cancer. Endometrial cancer represents the most common female genital tract malignancy and is generally associated with favourable outcomes for affected patients. Despite this, recurrence rates and diseaserelated deaths are consistently reported in published series, also in so-defined low-risk groups of patients. Hence, is reasonable to believe that traditional prognostic factors–surgical stage, histologic type, tumor grading, myometrial deep of invasion, involvement of vascular spaces–do not definitely respond to the clinical needs of a comprehensive management. The determination of DNA ploidy in endometrial cancer has been widely investigated in the last decades and clear evidence is available of its direct correlation with prognosis. Despite this, poor acceptance and skepticism are common believes in the scientific community. Aim of the paper has been the attempt to underline, upon scientific strength, the importance and clinical potential usefulness of this determination in gynecological oncological practice.

1Summary Human papillomavirus (HPV) is definitely recognized as the necessary cause for the development of cancer of the uterine cervix and the detection of HPV-DNA in cervical samples is demonstrated to own a significantly higher sensitivity towards preneoplastic lesions than conventional cytology (Pap test). Screening, management of atypical Pap tests and follow up of treated patients, represent the optimal settings where HPV-DNA testing has been demonstrated of clinical value. Atypical Pap tests account for cases in which the cytological alterations cannot clearly be attributed neither to negative nor to positive cytology; in these cases HPV-DNA testing has been demonstrated to have a sensitivity very close to 100% in identifying patients with an histologically proven intraepithelial preneoplastic lesion of high grade (CIN2-CIN3). Despite this, specificity of HPV-DNA positive testing lacks of significance and the referral rate to second-level colposcopy is too high. Different options have been tested to improve the specificity and the overall performance of HPV-DNA testing in cases of equivocal cervical cytology; the present paper aims to collect and present data from the recent literature, in order to better clarify the present state of the art in this particular aspect of cervical cancer prevention.

Antimuscarinics (AMs) are the mainstay of pharmacological treatment of overactive bladder (OAB), a symptom complex defined by the presence of urinary urgency, usually associated with frequency and nocturia, with or without urgency urinary incontinence. The AMs used to treat OAB differ in their pharmacological profiles, which may affect their potential for causing adverse effects (AEs).The present article aims to review the literature about pharmacokinetics (PK) of the different AMs used in the treatment of OAB. Furthermore, the AEs related to the use of these drugs and their incidence are presented. This systematic review is based on material searched and obtained via Medline, Pubmed and EMBASE up to March 2012 using the search terms "adverse events, pharmacokinetics, tolerability" in combination with "darifenacin, fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium."Antimuscarinics are the first-line pharmacological treatment for OAB. Despite the development of new molecules that improve their efficacy/safety profile, there are some drugs that are pharmacokinetically more appropriate to be prescribed in specific populations such as patients with neurological disease or the elderly. Moreover, research should be encouraged in evaluating antimuscarinics in conjunction with other drugs such as estrogens or beta-agonists. The identification of prognostic criteria for pharmacological therapy would be helpful.

The Papanicolaou vaginal smear – the Pap test – for the early detection of cervical cancer in women, represents one of the milestones of the modern medicine and the turning point towards the applicative concepts of preventive oncology. During the 20th century, cytological screening for cervical cancer has been the gold standard and is now widely recognized to have represented one of the major public health advances.

New Biomarkers Improving Cervical Cancer Screening Efficacy Carcinoma of the uterine cervix is the third most commonly diagnosed malignant neoplasm in women and the second cancerrelated cause of deaths in many low-resources geographical areas. Cervical cancer cytological screening programs, since the introduction in clinical practice of the Papanicolaou vaginal smear– the Pap test – have represented one of the major public health advantages and improvements of the last century; where cervical cancer screening is realized, incidence and mortality due to this disease have demonstrated a dramatic reduction. Despite this observation, invasive cervical cancer still accounts for almost 500,000 new cases per year worldwide, with approximately 11,000 and 4,000 new cases and deaths respectively in the USA per year.

Risk factors for vulvar cancer have been evaluated in a case-control study conducted between 1987 and 1990 in northern Italy on 73 women with histologically confirmed invasive vulvar cancer and 572 control subjects in hospital for acute nongynecological, nonneoplastic non-hormone-related conditions. The risk of vulvar cancer was inversely related to education level: with reference to women reporting less than 7 years of schooling, the relative risk estimates were 0.6 and 0.4, respectively, in those reporting 7 to 11 and 12 or more years of schooling (chi 2(1) trend = 4.91 P = 0.03). No relationship emerged between number of births and spontaneous or induced abortions. Parous women reporting late first birth tended to be at lower risk (relative risk = 0.5, 95% confidence interval 0.3 to 1.1 for25 vsor = 25 years at first birth), but there was no evidence of the risk to decrease with increasing age at first birth. The risk of vulvar cancer increased with body mass index, but the trend in risk was not significant after taking into account potential confounders in the multivariate analysis. No association emerged with indicators of sexual habits, menstrual history, and smoking. The risk of the disease was lower in women reporting Pap smears during their life and diminished with increasing number of cervical smears and decreasing recency of last Pap: compared to women reporting no Pap screening, it was 0.5 in those who reported one smear and 0.3 in those with two or more.

Objectives: Comparison between 2% testosterone propionate and petrolatum ointment in the treatment of vulvar lichen sclerosus in a randomized, double-blind, controlled clinical study. Methods: Fifty-eight consecutive patients with histologically confirmed vulvar lichen sclerosus were enrolled. They underwent a 1-year period of topical treatment with either medication, with clinical evaluations of symptoms and gross appearance at 2-month intervals, followed by histological evaluation at the end of the treatment period. Statistical analysis was performed according to the chisquared test and the Student-Newman-Keuls test. Results: A substantial improvement in symptoms was achieved in 20 (66.6%) patients in the testosterone group and in 21 (75%) patients in the placebo group. No statistical differences were observed between the two groups. Gross changes were observed in a few cases and no case demonstrated histologic modifications. Conclusions: Petrolatum ointment is as effective as 2% testosterone in the treatment of vulvar lichen sclerosus.

Cervical neoplastic lesions are associated with infection by high-risk human papilloma viruses (HPVs). HPV-16 and HPV-18 are the most common genotypes. It has been proposed that development of HPV-16-positive cervical lesions is associated with impaired CD4+ T cell immunity against early Ags. The aim of the study was to evaluate whether this impairment also applies to HPV-18. We investigated the presence and the quality of anti-HPV-18 E6 CD4+ T cell responses in the blood of 37 consecutive patients with high-grade cervical lesions, 25 normal donors, and 20 cord bloods. The immune infiltrate in the cervical lesions was also evaluated. The characteristics of the responses were correlated to the clinical outcome. We found that one or more HPV-18 E6 peptides, containing naturally processed epitopes, were able to induce a response in 40–50% of the patients, depending on the effector function tested. Importantly, these percentages rose to 80–100% when HPV-18-positive patients were considered. HPV-18 E6-specific CD4+ T cells produced mixed Th1/Th2 responses and statistical analysis of the cytokines produced revealed that the amount of IFN-γ released could predict infection persistence and/or disease relapse after surgery. Finally, we found that a higher number of infiltrating CD4+ and T-bet+ T cells in the lesions correlated with a favorable clinical outcome. Our results strongly suggest a relevant role for CD4+ T cells in the control of the HPV-18 compared with HPV-16 infections in patients with high-grade cervical lesions and identify an immunologic parameter potentially useful for patients’ stratification.