Delia Savone

Beyond circulating microRNA biomarkers: Urinary microRNAs in ovarian and breast cancer.

Breast cancer is the most common malignancy in women worldwide, and ovarian cancer is the most lethal gynecological malignancy. Women carrying a BRCA1/2 mutation have a very high lifetime risk of developing breast and ovarian cancer. The only effective risk-reducing strategy in BRCA-mutated women is a prophylactic surgery with bilateral mastectomy and bilateral salpingo-oophorectomy. However, many women are reluctant to undergo these prophylactic surgeries due to a consequent mutilated body perception, unfulfilled family planning, and precocious menopause. In these patients, an effective screening strategy is available only for breast cancer, but it only consists in close radiological exams with a significant burden for the health system and a significant distress to the patients. No biomarkers have been shown to effectively detect breast and ovarian cancer at an early stage. MicroRNAs (miRNAs) are key regulatory molecules operating in a post-transcriptional regulation of gene expression. Aberrant expression of miRNAs has been documented in several pathological conditions, including solid tumors, suggesting their involvement in tumorigenesis. miRNAs can be detected in blood and urine and could be used as biomarkers in solid tumors. Encouraging results are emerging in gynecological malignancy as well, and suggest a different pattern of expression of miRNAs in biological fluids of breast and ovarian cancer patients as compared to healthy control. Aim of this study is to highlight the role of the urinary miRNAs which are specifically associated with cancer and to investigate their role in early diagnosis and in determining the prognosis in breast and ovarian cancer.

Circulating tumor cells as trigger to hematogenous spreads and potential biomarkers to predict the prognosis in ovarian cancer.

Despite several improvements in the surgical field and in the systemic treatment, ovarian cancer (OC) is still characterized by high recurrence rates and consequently poor survival. In OC, there is still a great lack of knowledge with regard to cancer behavior and mechanisms of recurrence, progression, and drug resistance. The OC metastatization process mostly occurs via intracoelomatic spread. Recent evidences show that tumor cells generate a favorable microenvironment consisting in T regulatory cells, T infiltrating lymphocytes, and cytokines which are able to establish an “immuno-tolerance mileau” in which a tumor cell can become a resistant clone. When the disease responds to treatment, immunoediting processes and cancer progression have been stopped. A similar inhibition of the immunosuppressive microenvironment has been observed after optimal cytoreductive surgery as well. In this scenario, the early identification of circulating tumor cells could represent a precocious signal of loss of the immune balance that precedes cancer immunoediting and relapse. Supporting this hypothesis, circulating tumor cells have been demonstrated to be a prognostic factor in several solid tumors such as colorectal, pancreatic, gastric, breast, and genitourinary cancer. In OC, the role of circulating tumor cells is still to be defined. However, as opposed to healthy women, circulating tumor cells have been demonstrated in peripheral blood of OC patients, opening a new research field in OC diagnosis, treatment monitoring, and follow-up.

An update of laparoscopy in cervical cancer staging: is it a useful procedure?

Objective: It was the aim of this study to report on the role of laparoscopic staging in a large series of locally advanced cervical cancer (LACC) patients and its impact on prognosis. Methods: Consecutive patients with LACC were considered for surgical staging: gynecological examination, cystoscopy and laparoscopy with peritoneal biopsies and peritoneal fluid cytology. Results: Between February 2000 and September 2010, a total of 167 women were evaluated. In 5 patients, laparoscopy could not be performed. One hundred and sixty-two patients had correct laparoscopic staging: 49 International Federation of Gynecology and Obstetrics (FIGO) stage IB-IIA (>4 cm), 67 IIB, 39 III, and 7 IVA. Abdominal spread was found in 33 cases (20%). There was a minor laparoscopy complication rate of 1%. We found a significant difference in the distribution of peritoneal spread for tumor grade and FIGO stage (p = 0.01 and p < 0.0001, respectively), whereas no statistically significant difference for the histological type was found [p = not significant (NS)]. The median follow-up was 80 months (range 4-144). The median overall survival was 65 months. The patients without abdominal spread did not benefit from a significantly longer survival (median overall survival of 59 vs. 70 months; p = NS). Conclusions: Laparoscopic staging in cervical cancer is a safe and feasible technique but it does not modify the prognosis of LACC patients.

Management of HPV-related cervical disease: role of p16INK4a immunochemistry. Review of the literature.

This systematic review of 43 studies aims to evaluate the absolute and relative sensitivity and specificity of p16INK4a with regard to uterine cervix lesions, describing innovations and techniques for the detection of high-grade cervical dysplasia and allowing correct treatment. Studies were identified in the PubMed database up to March 2015. The keywords hrHPV, p16INK4a gene, and uterine cervical disease (MeSH terms) were used. Only English-language articles were included. We considered retrospective and prospective studies that assessed p16INK4a or p16INK4a/Ki67 staining, with or without HPV-DNA testing (HC2/PCR) as a comparator test, in cytological/histological specimens for which the diagnosis of ASCUS, LSIL or HSIL was verified with a reference standard. The primary outcome for cervical lesions was evaluation of the absolute p16INK4a immunoreactivity; the secondary outcome was evaluation of the relative p16INK4a immunoreactivity versus HPV testing in those studies where comparator tests were available. p16INK4a was more specific than HPV-DNA test (median values of 56.1% vs. 52.25% in CIN grade ≥2 lesions; 82.5% vs. 53% in negative and CIN grade ≥1 lesions). The main limitation of this study is linked to both qualitative and quantitative p16INK4a levels of expression, while the second limitation is the lack of standardized scales. p16INK4a and HPV-DNA used together increased the sensitivity and negative predictive value for CIN detection. p16INK4a can be considered a biomarker of CIN2 or CIN3, indicating a high risk of relapse or evolution to invasive carcinoma. Also p16INK4a-negative CIN should be considered and further research should be performed.

Overactive bladder syndrome treatment with ospemifene in menopausal patients with vulvovaginal atrophy: improvement of sexuality?

Abstract The aim of this study was to assess the effectiveness of ospemifene in the improvement of sexual function in postmenopausal women with vulvovaginal atrophy (VVA) affected by overactive bladder syndrome (OAB) or urge urinary incontinence (UUI). One hundred five postmenopausal patients with VVA affected by OAB and/or UUI were enrolled for the study. All patients received ospemifene 60 mg for 12 weeks. Clinical examination, 3-d voiding diary and the vaginal health index (VHI) were performed at baseline and at 12 weeks. Patients completed the OAB-Q SF, FSFI, FSDS, and SF-36 questionnaires. The patient’s satisfaction was also calculated. After 12 weeks, the reduction of urinary symptoms was observed. The OAB-Q symptoms, OAB-Q (HRQL) score were (55.34 ± 13.54 vs. 23.22 ± 9.76; p < .0001) and (22.45 ± 9.78 vs. 70.56 ± 15.49; p < .0001), before and after treatment. SF-36 questionnaire showed a significant improvement (p < .0001). VHI score increased and the women who regularly practice sexual activity increased after treatment. The total FSFI score increased significantly and the FSDS score changed after 12 weeks (p < .0001). The PGI-I after 12 weeks showed a total success rate of 90.5%. Ospemifene is an effective potential therapy for postmenopausal women with VVA affected by OAB or UUI improving sexual function and quality of life.

Long-term experience of vaginal vault prolapse prevention at hysterectomy time by modified McCall culdoplasty or Shull suspension: Clinical, sexual and quality of life assessment after surgical intervention

OBJECTIVES The aim of this study was to evaluate the effectiveness of modified McCall culdoplasty or Shull suspension in preventing vaginal vault prolapse after vaginal hysterectomy and the long-term impact on quality of life and sexual function. STUDY DESIGN Retrospective analysis in 414 patients underwent vaginal hysterectomy for pelvic organ prolapse (POP) and vaginal suspension through modified McCall culdoplasty (group A) or Shull suspension (group B) was evaluated. Clinical features and concomitant surgical procedures were assessed. Surgical data and perioperative and postoperative complications have also been analyzed. Clinical characteristics, urinary symptoms, POP-Q score classification, Quality of Life and Sexual Function were evaluated at baseline and at median follow up with P-QoL, ICIQ-UI-SF, PISQ-12, FSFI, FSDS questionnaires. RESULTS The median follow up was 8.9 year (5.1-14.2 years). 200 women in group A and 214 in group B were evaluated. Vaginal vault prolapse occurred in 2 patients in group A and in 2 patients in group B. POP-Q score for all compartments showed a significant (p < 0.001) decrease for both groups without significant differences between the 2 groups. The total vaginal length (TVL) was reduced in greater proportion in McCall group (p < 0.001). P-QoL and ICIQ-UI-SF questionnaires documented an improvement for both groups (p < 0.001). The number of patients who regularly practice sexual activity increased in both groups, but patients in group B experienced a better quality of sexual life evaluated with PISQ-12 and FSFI. CONCLUSIONS Both surgical techniques showed effectiveness and safety in preventing vaginal vault prolapse in women who underwent vaginal hysterectomy, with a significant improvement in quality of life and sexuality. Shull technique demonstrated greater improvement in sexual function.

HPV-related Vulvar Diseases and Perspectives of p16INK4a Immunochemistry: A Review of the Literature

Introduction Two different types of vulvar intraepithelial neoplasia (VIN), HPV-related and HPV-unrelated, should be considered as two separate entities with different management options. The incidence of HPV-related VIN is increasing worldwide and is implicated in carcinogenesis. Our objective is to investigate the use of p16INK4a immunostaining or p16INK4a/p53 double staining for the detection of HPV-related disease to overcome the problem that histological criteria often have significant overlap. Methods A systematic literature search was carried out in the online databases PubMed, EMBASE, Cochrane Library, Clincaltrials.gov and Scopus. The key search terms were HPV, VIN, p16INK4a immunochemistry and p53. Results We found that nuclear and cytoplasmic immunostaining for p16INK4a was intense and diffuse in HPV-associated lesions and weak and focal in normal vulvar epithelium, nondysplastic lesions, lichen sclerosus and keratinizing vulvar squamous cell carcinoma. p53 nuclear immunostaining was always negative in HPV-related disease. Conclusions Our findings indicated that p16INK4a or p16INK4a/p53 immunoreactivity, along with histological diagnosis, could be a convenient means to adequately classify VIN and its connection to HPV infection. Therefore, the clear recognition of HPV-associated VIN would lead to an appropriate strategy of treatment and follow-up.

OP29.03: Identification of parametria by 2D-3D ultrasound in patients with cervical cancer: new perspectives and future applications

Objectives: The aim of this study was to evaluate the feasibility of distinguishing the ventral parametrium (vesico-uterine ligament), the lateral parametrium (paracervix), and the dorsal parametrium (recto-uterine ligament) by 2D and 3D ultrasound (US) scan in patients affected by cervical cancer (CC), using anatomy during surgery as probative evidence. Methods: From November 2009 to February 2011, we prospectively analysed 38 consecutive patients, affected by early and locally advanced CC. All patients underwent pelvic US with both transabdominal and transvaginal approaches. Each exam was performed by 2 different operators with 2D and 3D-US scan. Anatomical observations of parametria revealed during the ultrasound evaluations were confirmed by intraoperative live scan. Results: We identified ultrasonographically the ventral and dorsal parametrium in a longitudinal scan, the lateral parametrium in a transversal scan. At the US, the ventral parametrium appears as a hiperechoic ligament with vessels, that starts from the cervix and ends at the lateral side of the bladder. The lateral parametrium is a hiperechoic ligament that starts from the lateral cervix and ends laterally under the iliac vessel. The dorsal parametrium starts from the sacro-uterine and ends at the rectum. We always identified the uterine artery. Proof of the correct identification of the different parts of the parametria was conducted during surgery. The surgeon applied one clip in every parametrium and it was identified by intraoperative live scan procedures. We could identify ventral and lateral parametria in every patient. We could not recognize the dorsal parametria in 8 patients (23.5%). Conclusions: The evaluation of the different cervical parametria can be considered feasible. The identification of dorsal parametria is more difficult than ventral and lateral parametria. We concluded that this method could be used in most cases as an aid in the assessment of parametrial involvement.