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Introduction Breast cancer is the most frequently diagnosed tumor in women; globally, it accounts 23% of all cancer deaths. Breast reconstruction after oncologic surgery has become crucial to enhance patients’ quality of life and alleviate the psychological distress related to the disease. The aim of this study was to assess quality of life and esthetic satisfaction of breast cancer patients undergoing muscle-sparing skin-reducing breast reconstruction (MS-SR) with pre-pectoral implants. Methods Sixty-three patients who met definite oncological and reconstructive criteria were enrolled in the study. Specific questionnaires (EORTC QLQ-C30, QLQ-BR23) were administered preoperatively, 1, and 12 months after MS-SR breast reconstruction to evaluate patients’ QoL. Satisfaction with procedure and related Quality of Life were assessed through BREAST-Q questionnaire preoperatively and 12 months after surgery. Results Sixty-three breast cancer patients underwent MS-SR. Seventy-eight procedures were carried out; in 15 patients a bilateral reconstruction was performed. One month after surgery, both EORTC QLQ-C30 and QLQ-BR23 average scores demonstrated a slight drop since preoperative values, but a significant improvement in QoL was documented 12 months after BR (p

The aim of this study is to define the role of preoperative positron emission tomography/computed tomography (PET/CT) scan and sentinel lymph node (SLN) biopsy for nodal metastasis detection in Endometrial Cancer (EC) patients. From January 2014 to August 2016 patients affected by EC scheduled for surgery underwent PET/CT scan and SLN mapping with indocyanine-green. Patients with suspicious lymph nodes at FDG-PET/CT underwent selective pelvic lymphadenectomy. In case of undetectable SLN, no further lymphadenectomy was performed if PET/CT scan was negative. Basic descriptive statistics were used to describe outcomes. A total of 83 patients were enrolled in the study. PET/CT scan was suggestive of nodal involvement in 15 patients. SLN were detected bilaterally in 78% of patients. Detection rate was influenced by patients’ BMI and surgical learning curve. Five patients were node-positive: all of these had hypermetabolic nodes on PET/CT scan; in one patient SLN was not detected. Ten out of 15 patients with suspicious nodes on PET/CT scan were node-negative. After a median follow up of 24 months all patients are alive. Four patients experienced recurrent disease. No nodal relapse was recorded. Lymphatic mapping with sentinel node biopsy is able to reduce morbidity associated with pelvic lymphadenectomy. Sentinel node assessment is a feasible and appealing procedure and should be performed in a specialized center. Detection rate strongly improves with learning curve, while is reduced in morbidly obese patients. PET/CT scan shows high sensitivity but moderate specificity for nodal metastasis and may help to avoid nodal dissection in patients with sentinel node mapping failure.

The objective of this work is to assess the 5-year outcomes of patients undergoing conization for high-grade cervical lesions that simultaneously present as risk factors in the persistence of HPV infection and the positivity of surgical resection margins. This is a retrospective study evaluating patients undergoing conization for high-grade cervical lesions. All patients included had both positive surgical margins and experienced HPV persistence at 6 months. Associations were evaluated with Cox proportional hazard regression and summarized using hazard ratio (HR). The charts of 2966 patients undergoing conization were reviewed. Among the whole population, 163 (5.5%) patients met the inclusion criteria, being at high risk due to the presence of positive surgical margins and experiencing HPV persistence. Of 163 patients included, 17 (10.4%) patients developed a CIN2+ recurrence during the 5-year follow-up. Via univariate analyses, diagnosis of CIN3 instead of CIN2 (HR: 4.88 (95%CI: 1.10, 12.41); p = 0.035) and positive endocervical instead of ectocervical margins (HR: 6.44 (95%CI: 2.80, 9.65); p < 0.001) were associated with increased risk of persistence/recurrence. Via multivariate analyses, only positive endocervical instead of ectocervical margins (HR: 4.56 (95%CI: 1.23, 7.95); p = 0.021) were associated with worse outcomes. In this high-risk group, positive endocervical margins is the main risk factor predicting 5-year recurrence.

Abstract Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare disease, characterised by the aplasia of vagina and uterus in women with a 46,XX karyotype. Most cases are sporadic, but familial recurrence has also been described. Herein, we investigated an Italian cohort of 36 unrelated MRKH patients to explore the presence of pathogenic copy number variations (CNVs) by array-CGH and MLPA assays. On the whole, aberrations were found in 9/36 (25%) patients. Interestingly, one patient showed a novel heterozygous microduplication at Xp22.33, not yet described in MRKH patients, containing the PRKX gene. Moreover, a novel duplication of a specific SHOX enhancer was highlighted by MLPA. To predict the potential significance of CNVs in MRKH pathogenesis, we provided a network analysis for protein-coding genes found in the altered genomic regions. Although not all of these genes taken individually showed a clear clinical significance, their combination in a computational network highlighted that the most relevant biological connections are related to the anatomical structure development. In conclusion, the results described in the present study identified novel genetic alterations and interactions that may be likely involved in MRKH phenotype determination, so adding new insights into the complex puzzle of MRKH disease.

Although ovarian cancer often presents as a widespread disease, metastases to the breast and/or axillary lymph nodes are a very rare event, accounting for only 0.03–0.6% of all breast cancers. Its early recognition and accurate distinction from primary breast cancer are of crucial importance to choose an adequate systemic therapy over unnecessary surgeries. We presented the case of a 53-year-old woman who was diagnosed with breast metastases 2 years after the diagnosis of advanced primary serous ovarian cancer. The patient underwent primary cytoreductive surgery and platinum-based chemotherapy in combination with bevacizumab, followed by bevacizumab maintenance for 18 months. After 2 years of negative follow-ups, the disease unexpectedly spread to the left breast and axillary lymph nodes. No axillary lymph node dissection or breast surgery was performed. The patient received axillary radiotherapy and multiple chemotherapy lines: gemcitabine/cisplatin, liposomal doxorubicin, topotecan, olaparib/cediranib, paclitaxel, and cisplatin. Unfortunately, none of these treatments improved her prognosis and she died 3 years after the disease recurrence. Ovarian cancer metastasis to the breast reveals a disseminated disease with a poor prognosis. Currently, no valid treatment options are available as the disease shows multidrug chemoresistance. In the era of precision medicine, the characterization of genetic and molecular markers may play a role in offering new promising targeted therapies.

Abstract Background Mantle cell lymphoma is one of several subtypes of non-Hodgkin lymphoma. Cervical relapse of non-Hodgkin lymphoma is a very rare condition that has a variable and nonspecific presentation and may resemble other neoplastic or inflammatory conditions. Case presentation Our patient was a 58-year-old Caucasian woman who experienced relapse of mantle cell lymphoma with cervical localization. She complained of postmenopausal vaginal bleeding, bladder pressure, and rapid growth of a cervical lesion. An irregular tumor mass of the cervix was visualized during gynecological examination, with findings highly suggestive of locally advanced cervical cancer. Surprisingly, the biopsies showed an extra nodal relapse of mantle cell lymphoma in the cervix. The rarity of this presentation and the scarcity of clinical studies make this type of recurrence very aggressive and difficult to treat. Conclusions Obtaining a definitive histological diagnosis by biopsy or surgical resection and starting appropriate therapy are essential for recovery and treatment of these patients, even if the prognosis is poor.

Lucia Musacchio,1 Giuseppe Caruso,1 Carmela Pisano,2 Sabrina Chiara Cecere,2 Marilena Di Napoli,2 Laura Attademo,2 Rosa Tambaro,2 Daniela Russo,3 Daniela Califano,3 Innocenza Palaia,1 Ludovico Muzii,1 Pierluigi Benedetti Panici,1 Sandro Pignata2 1Department of Maternal and Child Health and Urological Sciences, University “Sapienza”, Policlinico Umberto I, Rome, Italy; 2Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, Italy; 3Functional Genomic Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyCorrespondence: Sandro PignataDepartment of Urology and Gynecology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Semmola, Naples 80131, ItalyTel +39 0815903409Fax +39 0815903861Email s.pignata@istitutotumori.na.itAbstract: Advanced, recurrent and metastatic endometrial cancer (EC) has a dismal prognosis due to poor response rates to conventional treatments. In the era of precision medicine, the improved understanding of cancer genetics and molecular biology has led to the development of targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors. This class of drugs that inhibit PARP enzymes has been investigated in many different types of tumors and its use in the treatment of gynecological malignancies has rapidly increased over the past few years. Data from several clinical trials showed that PARP inhibitors have a beneficial role in cancers with a defect in the homologous DNA recombination system, regardless of the BRCA mutational status. Since EC frequently shows mutations in PTEN and TP53 genes, indirectly involved in the homologous DNA recombination pathway, several in vivo and in vitro studies investigated the efficacy of PARP inhibitors in EC, showing promising results. This review will discuss the use of PARP inhibitors in endometrial cancer, summarizing data from preclinical studies and providing an overview of the ongoing trials, with a special focus on the development of combined treatment strategies with PARP inhibitors and immune checkpoint inhibitors.Keywords: endometrial cancer, PARP inhibitors, PTEN mutation, P53 mutation, homologous recombination deficiency, immune checkpoint inhibitors

Federica Tomao,1 Serena Maria Boccia,2 Carolina Maria Sassu,2 Martina Chirra,3 Innocenza Palaia,2 Maria Cristina Petrella,4 Violante Di Donato,2 Nicoletta Colombo,1,5 Pierluigi Benedetti Panici2 1Department of Gynecologic Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy; 2Department of Maternal and Child Health and Urological Sciences, “Sapienza” University of Rome,Polyclinic Umberto I, Rome, Italy; 3Medical Oncology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; 4Medical Oncology, AOUC University Hospital Careggi, Florence, Italy; 5Department of Medicine and Surgery, University of Milan-Bicocca, Milan, ItalyCorrespondence: Carolina Maria SassuDepartment of Maternal and Child Health and Urological Sciences, “Sapienza” University of Rome, Polyclinic Umberto I, Viale Del Policlinico 155, Rome 00161, ItalyTel +393935691077Fax +390649972564Email carolinamaria.sassu@uniroma1.itAbstract: Olaparib is currently approved in maintenance treatment of advanced ovarian cancer after response to first-line chemotherapy for breast related cancer antigens (BRCA) mutated patients. The use of this agent is based on data from SOLO1 study that observed a decreased risk of disease progression or death and a median progression-free survival about 36 months longer in case of therapy with olaparib. However, this trial recruited only patients with advanced stage ovarian cancer. The aim of this review is to retrace the available data in order to clarify the potential efficacy and feasibility of olaparib administration in newly diagnosed epithelial ovarian cancer also in early stages.Keywords: newly diagnosed ovarian cancer, early stage ovarian cancer, olaparib, PARPinhibitors, BRCA mutation

Abstract Background Ovarian cancer (OC) is the most lethal gynecological malignancy and the second leading cause of cancer-related death in women. Treatment with PARP inhibitors (PARPi), such as Olaparib, has been recently introduced for OC patients, but resistance may occur and underlying mechanisms are still poorly understood. The aim of this study is to identify target genes within the tumor cells that might cause resistance to Olaparib. We focused on Neuropilin 1 (NRP1), a transmembrane receptor expressed in OC and correlated with poor survival, which has been also proposed as a key molecule in OC multidrug resistance. Methods Using three OC cell lines (UWB, UWB-BRCA and SKOV3) as model systems, we evaluated the biological and molecular effects of Olaparib on OC cell growth, cell cycle, DNA damage and apoptosis/autophagy induction, through MTT and colony forming assays, flow cytometry, immunofluorescence and Western blot analyses. We evaluated NRP1 expression in OC specimens and cell lines by Western blot and qRT-PCR, and used RNA interference to selectively inhibit NRP1. To identify miR-200c as a regulator of NRP1, we used miRNA target prediction algorithms and Pearsons’ correlation analysis in biopsies from OC patients. Then, we used a stable transfection approach to overexpress miR-200c in Olaparib-resistant cells. Results We observed that NRP1 is expressed at high levels in resistant cells (SKOV3) and is upmodulated in partially sensitive cells (UWB-BRCA) upon prolonged Olaparib treatment, leading to poor drug response. Our results show that the selective inhibition of NRP1 is able to overcome Olaparib resistance in SKOV3 cells. Moreover, we demonstrated that miR-200c can target NRP1 in OC cells, causing its downmodulation, and that miR-200c overexpression is a valid approach to restore Olaparib sensitivity in OC resistant cells. Conclusions These data demonstrate that miR-200c significantly enhanced the anti-cancer efficacy of Olaparib in drug-resistant OC cells. Thus, the combination of Olaparib with miRNA-based therapy may represent a promising treatment for drug resistant OC, and our data may help in designing novel precision medicine trials for optimizing the clinical use of PARPi.

Background: Genitourinary syndrome of menopause (GSM) majorly caused by the physiological decline in estrogen, affects up to 90% of menopausal women. Hormonal therapy seems to be an effective treatment, often not executable for contraindication or patient’s low compliance to local or systemic medical therapy. Fractional CO2 laser therapy is an emerging and effective choice for women affected by vulvo-vaginal atrophy (VVA), promoting collagen regeneration and improving blood flow of the vaginal mucosa and elasticity of tissues. Methods: Ninety-two menopausal Patients affected by vulvo-vaginal atrophy (VVA) were considered for the present prospective observational study. All women were treated with Fractional CO2 laser Lumenis AcuPulse in a fractionated sequential mode laser pulse. Patients were requested to complete questionnaires regarding the Female Sexual Functional Index (FSFI), Female Sexual Distress Scale (FSDS) and severity of Most Bothersome Symptoms (MBS) at baseline (T0) and at three-month following three-treatment-sessions (T1). Results: Data indicated a significant improvement of MBS (vaginal itching (p < 0.0001), post-coital vaginal bleeding (p < 0.002), vaginal dryness (p < 0.0001), dyspareunia (p < 0.0001) and dysuria (p < 0.0001), higher Vaginal Health Index Score (VHIS) (4.1 ± 1.21; 95% CI = 3.84–4.35) and reduces pH (–0.53 ± 0.24; 95% CI = 0.48–0.58) after CO2 laser treatment. A significantly improvement of FSFI Total score (p < 0.0001) and FSDS (p < 0.0001) have been demonstrated. Conclusions: Fractional CO2 laser improves vaginal health as well as signs and symptoms associated with GSM, while significantly elevating quality of life and sexual functionality among postmenopausal symptomatic women.

Introduction: Peripartum cardiomyopathy (PPCM) is a rare and idiopathic form of dilated cardiomyopathy presenting late in pregnancy or early postpartum. Since the 16-kDa fragment of prolactin has been identified as a key factor in the pathophysiology of PPCM, prolactin inhibitors have been used as an adjuvant to standard heart failure treatment. Although bromocriptine is the current first choice, promising results have been reported with cabergoline, albeit scant. Case Presentation: We presented the case of a 41-year-old woman who received a diagnosis of PPCM one week after delivery and was successfully treated with cabergoline, finally experiencing a complete recovery. Conclusion: The case adds to the scant evidence supporting the use of cabergoline in PPCM patients. We argue that the favorable pharmacokinetic and metabolic profiles of this drug should prompt its consideration as a valid alternative prolactin inhibitor in these critical patients.

Background: Cervical dysplasia persistence/recurrence has a great impact on women’s health and quality of life. In this study, we investigated whether a prognostic nomogram may improve risk assessment after primary conization. Methods: This is a retrospective multi-institutional study based on charts of consecutive patients undergoing conization between 1 January 2010 and 31 December 2014. A nomogram assessing the importance of different variables was built. A cohort of patients treated between 1 January 2015 and 30 June 2016 was used to validate the nomogram. Results: A total of 2966 patients undergoing primary conization were analyzed. The median (range) patient age was 40 (18–89) years. At 5-year of follow-up, 6% of patients (175/2966) had developed a persistent/recurrent cervical dysplasia. Median (range) recurrence-free survival was 18 (5–52) months. Diagnosis of CIN3, presence of HR-HPV types, positive endocervical margins, HPV persistence, and the omission of HPV vaccination after conization increased significantly and independently of the risk of developing cervical dysplasia persistence/recurrence. A nomogram weighting the impact of all variables was built with a C-Index of 0.809. A dataset of 549 patients was used to validate the nomogram, with a C-index of 0.809. Conclusions: The present nomogram represents a useful tool for counseling women about their risk of persistence/recurrence after primary conization. HPV vaccination after conization is associated with a reduced risk of CIN2+.

Research Question: Does reproductive outcome differ among the various subgroups of poor ovarian responders according to the Bologna criteria?Design: This was a retrospective, cohort study including poor ovarian responders according to Bologna criteria, undergoing an ICSI cycle from January 2011 until December 2017. Patients were divided into four groups: (1) age ≥ 40 years and abnormal ovarian response test, (2) age ≥ 40 years, abnormal ovarian reserve test and one previous poor response to stimulation, (3) age ≥ 40 years and one previous poor response, (4) abnormal ovarian reserve test and one previous poor response.Result(s): Overall, 846 cycles in 706 Bologna poor ovarian responders were included: 310 cycles in group 1, 169 in group 2, 52 in group 3, and 315 in group 4. There were significant differences in age, antral follicle count, antimüllerian hormone, cycle cancellation rates, and number of retrieved oocytes between the four groups. Live birth and cumulative live birth rate differed significantly between groups and were highest in Group 4 [Live birth rate: 7.4% (1) vs. 4.1% (2) vs. 5.8% (3) vs. 13.4% (4), p = 0.001 and Cumulative live birth rate: 8.3% (1) vs. 4.1 % (2) vs. 9.6% (3) vs. 16.8% (4) p < 0.001]. The multivariate GEE analysis revealed that the number of MIIs and the Bologna criteria pattern were the variables which were significantly associated with cumulative live birth rate.Conclusion(s): Poor ovarian responders represent a heterogeneous population. The young subpopulation has a better clinical prognosis in terms of fresh and cumulative live birth rate.

Abstract Background Over recent years, a growing interest has developed in microbiota and in the concept of maintaining a special balance between Lactobacillus and other bacteria species in order to promote women’s well-being. The aim of our study was to confirm that vaginal Lactobacilli long-lasting implementation in women with HPV-infections and concomitant bacterial vaginosis or vaginitis might be able to help in solving the viral infection, by re-establishing the original eubiosis. Methods A total of 117 women affected by bacterial vaginosis or vaginitis with concomitant HPV-infections were enrolled at Department of Gynecological Obstetrics and Urological Sciences, La Sapienza University, Rome, Italy between February 2015 and March 2016. Women were randomized in two groups, standard treatment (metronidazole 500 mg twice a day for 7 days or fluconazole 150 mg orally once a day for 2 consecutive days) plus short-term (3 months) vaginal Lactobacillus implementation (group 1, short probiotics treatment protocol group, n = 60) versus the same standard treatment plus long-lasting (6 months) vaginal Lactobacillus rhamnosus BMX 54 administration (group 2, treatment group, n = 57). Results After a median follow up of 14 months (range 9–30 months) the chance to solve HPV-related cytological anomalies was twice higher in probiotic long-term users (group 2) versus short probiotics implementation group (group 1) (79.4% vs 37.5%, p = 0.041). Moreover, a total HPV-clearance was shown in 11.6% of short schedule probiotics implementation patients compared to a percentage of 31.2% in vaginal Lactobacilli long term users (p = 0.044), assessed as negative HPV-DNA test documented at the end of the study period. Conclusions The consistent percentage of clearance of PAP-smear abnormalities and HPV-clearance obtained in long-term treatment group has been interestingly high and encouraging. Obviously, larger and randomized studies are warranted to confirm these encouraging results, but we believe that eubiosis re-establishment is the key to tackle effectively even HPV-infection. Trial registration Retrospectively registered on PRS NCT03372395 (12/12/2017).

Abstract Human biliary tree stem/progenitor cells (hBTSCs) are being used for cell therapies of patients with liver cirrhosis. A cryopreservation method was established to optimize sourcing of hBTSCs for these clinical programs and that comprises serum-free Kubota’s Medium (KM) supplemented with 10% dimethyl sulfoxide (DMSO), 15% human serum albumin (HSA) and 0.1% hyaluronans. Cryopreserved versus freshly isolated hBTSCs were similar in vitro with respect to self-replication, stemness traits, and multipotency. They were able to differentiate to functional hepatocytes,cholangiocytes or pancreatic islets, yielding similar levels of secretion of albumin or of glucose-inducible levels of insulin. Cryopreserved versus freshly isolated hBTSCs were equally able to engraft into immunocompromised mice yielding cells with human-specific gene expression and human albumin levels in murine serum that were higher for cryopreserved than for freshly isolated hBTSCs. The successful cryopreservation of hBTSCs facilitates establishment of hBTSCs cell banking offering logistical advantages for clinical programs for treatment of liver diseases.

Posterior reversible encephalopathy syndrome is a rare complication generally associated with headache and acute changes in blood pressure. Delay in the diagnosis and treatment may result in death or in irreversible neurological sequelae. We present three cases of PRES occurring in young women during puerperium. We report a literature review ranged from January 1990 to June 2015 describing clinical features, diagnostic and medical approach, and maternal outcome.

Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a rare and complex disease defined by congenital aplasia of the vagina and uterus in 46,XX women, often associated with kidney and urinary tract anomalies. The aetiopathogenesis of MRKH syndrome is still largely unknown. Herein, we investigated the role of selected candidate genes in the aetiopathogenesis of MRKH syndrome, with a focus on PRKX, which encodes for protein kinase X. Through RT-qPCR analyses performed on vaginal dimple samples from patients, and principal component analysis (PCA), we highlighted a phenotype-related expression pattern of PRKX, MUC1, HOXC8 and GREB1L in MRKH patients. By using an in vitro approach, we proved that PRKX ectopic overexpression in a cell model of vaginal keratinocytes promotes cell motility through epithelial-to-mesenchymal transition (EMT) activation, a fundamental process in urogenital tract morphogenesis. Moreover, our findings showed that PRKX upregulation in vaginal keratinocytes is able to affect transcriptional levels of HOX genes, implicated in urinary and genital tract development. Our study identified the dysregulation of PRKX expression as a possible molecular cause for MRKH syndrome. Moreover, we propose the specific role of PRKX in vaginal keratinocyte biology as one of the possible mechanisms underlying this complex disease.

Objective: The aim of this meta-analysis was to discuss evidence supporting the efficacy of adjuvant human papillomavirus (HPV) vaccination in reducing the risk of recurrent cervical intraepithelial neoplasia (CIN) 2 or greater after surgical treatment. Methods: A systematic literature search was performed for studies reporting the impact of HPV vaccination on reducing the risk of recurrence of CIN 2+ after surgical excision. Results were reported as mean differences or pooled odds ratios (OR) with 95% confidence intervals (95% CI). Results: Eleven studies met the inclusion criteria and were selected for analysis. In total, 21,310 patients were included: 4039 (19%) received peri-operational adjuvant HPV vaccination while 17,271 (81%) received surgery alone. The recurrence of CIN 2+ after treatment was significantly lower in the vaccinated compared with the unvaccinated group (OR 0.35; 95% CI 0.21–0.56; p < 0.0001). The recurrence of CIN 1+ after treatment was significantly lower in the vaccinated compared with the unvaccinated group (OR 0.51; 95% CI 0.31–0.83; p = 0.006). A non-significant trend of reduction rate of HPV persistence was observed in the vaccinated compared with the unvaccinated cohorts (OR was 0.84; 95% CI 0.61–1.15; p = 0.28). Conclusions: HPV vaccination, in adjuvant setting, is associated with a reduced risk of recurrent CIN 1+ and CIN 2+ after surgical treatment.

Conventional/targeted chemotherapies and ionizing radiation (IR) are being used both as monotherapies and in combination for the treatment of epithelial ovarian cancer (EOC). Several studies show that these therapies might favor oncogenic signaling and impede anti-tumor responses. MiR-200c is considered a master regulator of EOC-related oncogenes. In this study, we sought to investigate if chemotherapy and IR could influence the expression of miR-200c-3p and its target genes, like the immune checkpoint PD-L1 and other oncogenes in a cohort of EOC patients’ biopsies. Indeed, PD-L1 expression was induced, while miR-200c-3p was significantly reduced in these biopsies post-therapy. The effect of miR-200c-3p target genes was assessed in miR-200c transfected SKOV3 cells untreated and treated with olaparib and IR alone. Under all experimental conditions, miR-200c-3p concomitantly reduced PD-L1, c-Myc and β-catenin expression and sensitized ovarian cancer cells to olaparib and irradiation. In silico analyses further confirmed the anti-correlation between miR-200c-3p with c-Myc and β-catenin in 46 OC cell lines and showed that a higher miR-200c-3p expression associates with a less tumorigenic microenvironment. These findings provide new insights into how miR-200c-3p could be used to hold in check the adverse effects of conventional chemotherapy, targeted therapy and radiation therapy, and offer a novel therapeutic strategy for EOC.

Even though 80% of patients with High-Grade Serous Ovarian Cancer respond to standard first-line chemotherapy, a majority of them could relapse in the following five years due to a resistance to platinum. Human Epididymis protein 4 (HE4) is one of the most promising markers in predicting platinum therapy response. This pilot study aims to evaluate the potential role of HE4 value in predicting chemotherapy response in BRCA mutated patients and in BRCA wild-type (non-mutated) ones. We selected 69 patients, affected by High-Grade Serous Ovarian Cancer, and optimally debulked and submitted to standard chemotherapy protocols. HE4 was dosed during every chemotherapy course. Patients were classified as platinum-resistant and platinum-sensitive. According to BRCA mutation test, patients were further divided into BRCA wild-type (53 patients), and BRCA mutated (16 patients). 35 patients out of 69 (52%) were platinum-sensitive (recurrence > 12 months), while 33 patients (48%) were platinum-resistant (recurrence < 12 months). Thus, in the total population, HE4 performed as a marker of chemosensitivity with a sensibility of 79% and a specificity of 97%. In the BRCA WT group, 23 patients out of 53 (43%) were platinum-sensitive, while 30 patients out of 53 (57%) were platinum-resistant. In the BRCA WT group, HE4 performed as a predictive marker of chemosensitivity with a sensibility of 80% and a specificity of 100%. In the BRCA mutated group, 13 patients out of 16 (82%) were platinum-sensitive, while 3 patients (18%) were platinum-resistant. In the BRCA mutated group, HE4 performed as a predictive marker of chemosensitivity in all patients. The ability to detect platinum-resistant patients before tumor relapse probably could open new therapeutic scenarios.

Background: Primary prevention through vaccination is a prophylactic approach aiming to reduce the risk of developing human papillomavirus (HPV)-related lesions. No mature and long-term data supported the adoption of vaccination in women undergoing conization. Methods: This is a retrospective multi-institutional study. Charts of consecutive patients undergoing conization between 2010 and 2014 were collected. All patients included had at least 5 years of follow-up. We compared outcomes of patients undergoing conization plus vaccination and conization alone. A propensity-score matching algorithm was applied in order to reduce allocation biases. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models. Results: Overall, charts of 1914 women were analyzed. The study group included 116 (6.1%) and 1798 (93.9%) women undergoing conization plus vaccination and conization alone, respectively. Five-year recurrence rate was 1.7% (n = 2) and 5.7% (n = 102) after conization plus vaccination and conization alone, respectively (p = 0.068). After the application of a propensity-score matching, we selected 100 patients undergoing conization plus vaccination and 200 patients undergoing conization alone. The crude number of recurrences was 2 (2%) and 11 (5.5%) for patients undergoing conization plus vaccination and conization alone, respectively (p = 0.231). Vaccination had no impact on persistent lesions (no negative examination between conization and new cervical dysplasia; p = 0.603), but reduced the risk of recurrent disease (patients who had at least one negative examination between conization and the diagnosis of recurrent cervical dysplasia; p = 0.031). Conclusions: Patients having vaccination experience a slightly lower risk of recurrence than women who had not, although not statistically significantly different. Further evidence is needed to assess the cost effectiveness of adopting vaccination in this setting.

Background: Endometriosis is a widespread multifactorial disease in which environmental, genetic, and epigenetic factors contribute to the phenotype. Single Nucleotide Polymorphisms (SNPs) in genes implicated in pivotal molecular mechanisms have been investigated as susceptible risk factors in distinct populations. Among these, Toll-like receptor 4 (TLR4) represents a good candidate due to its role in the immune/inflammatory response and endometriosis pathogenesis. Methods: The TRL4 gene T399I SNP (C/T transition, rs4986791) was investigated in 236 Italian endometriosis patients and 150 controls by using the PCR-RFLP method. One-tailed Fisher’s exact test was used to compare differences between categorical variables. T399I genotype distribution was evaluated for Hardy–Weinberg equilibrium in both groups using the Chi-squared test for given probabilities. Results: Fisher’s exact test comparing C and T allele frequencies showed a difference in the frequency of T alleles between patients and controls (OR = 1.96, 95% confidence interval 0.91–4.23; p-value = 0.0552). Genotype frequencies did not show any significant difference between patients and controls. The homozygous TT genotype was observed in 2% of endometriosis women and not in controls. Conclusions: Our results show that the TLR4 rs4986791 T variant may be considered a genetic risk factor for endometriosis in Italian women. More extensive studies in other populations are needed to confirm this result.

Tumor cells release extracellular microvesicles (MVs) in the microenvironment to deliver biological signals to neighboring cells as well as to cells in distant tissues. Tumor-derived MVs appear to play contradictory role promoting both immunosuppression and tumor growth and both evoking tumor specific immune response. Recent evidences indicate that tumor-derived MVs can positively impact Dendritic Cells (DCs) immunogenicity by reprogramming DC antigen processing machinery and intracellular signaling pathways, thus promoting anti-tumor response. DCs are considered pivot cells of the immune system due to their exclusive ability to coordinate the innate and acquired immune responses, cross-present exogenous antigens, and prime naïve T cells. DCs are required for the induction and maintenance of long-lasting anti-tumor immunity and their exploitation has been extensively investigated for the design of anti-tumor vaccines. However, the clinical grade culture conditions that are required to generate DCs for therapeutic use can strongly affect their functions. Here, we investigated the immunomodulatory impact of MVs carrying the MUC1 tumor glycoantigen (MVsMUC1) as immunogen formulation on clinical grade DCs grown in X-VIVO 15 (X-DCs). Results indicated that X-DCs displayed reduced performance of the antigen processing machinery in term of diminished phagocytosis and acidification of the phagosomal compartment suggesting an altered immunogenicity of clinical grade DCs. Pulsing DCs with MVsMUC1 restored phagosomal alkalinization, triggering ROS increase. This was not observed when a soluble MUC1 protein was employed (rMUC1). Concurrently, MVsMUC1 internalization by X-DCs allowed MUC1 cross-processing. Most importantly, MVsMUC1 pulsed DCs activated IFNγ response mediated by MUC1 specific CD8+ T cells. These results strongly support the employment of tumor-derived MVs as immunogen platforms for the implementation of DC-based vaccines.

The incidence of adnexal masses increases exponentially with age and the most frequent causes in young women are physiologic cysts and pelvic abscesses with pelvic inflammatory disease (PID). Clinical examination can direct physicians to an appropriate management of adnexal mass, but the role of transvaginal ultrasound is crucial for diagnosis and treatment decision, even if it sometimes can be misleading, especially in young women. Ca 125, blood count, and CRP are useful to clarify suspected etiology of a pelvic mass, but specificity and positive predictive value are low because elevation of laboratory tests may occur in several benign conditions. In our work we present four cases of suspected pelvic masses. Despite guidelines for management of PID, the right timing to switch to surgical therapy is not clear. Therefore, the treatment decision should be based on a careful evaluation of various parameters such as signs symptoms and above all age. Moreover, we believe that, for a correct diagnosis and for the best fertility sparing treatment, it is also extremely important to refer to a gynecological oncology unit with an expert surgeon.

Dendritic cells (DCs) are the only antigen-presenting cells able to prime naïve T cells and cross-prime antigen-specific CD8+ T cells. Their functionality is a requirement for the induction and maintenance of long-lasting cancer immunity. Albeit intensively investigated, the in vivo mechanisms underlying efficient antigen cross-processing and presentation are not fully understood. Several pieces of evidence indicate that antigen transfer to DCs mediated by microvesicles (MVs) enhances antigen immunogenicity. This mechanism is also relevant for cross-presentation of those tumor-associated glycoproteins such as MUC1 that are blocked in HLA class II compartment when internalized by DCs as soluble molecules. Here, we present pieces of evidence that the internalization of tumor-derived MVs modulates antigen-processing machinery of DCs. Employing MVs derived from ovarian cancer ascites fluid and established tumor cell lines, we show that MV uptake modifies DC phagosomal microenvironment, triggering reactive oxygen species (ROS) accumulation and early alkalinization. Indeed, tumor MVs carry radical species and the MV uptake by DCs counteracts the chemically mediated acidification of the phagosomal compartment. Further pieces of evidence suggest that efficacious antigen cross-priming of the MUC1 antigen carried by the tumor MVs results from the early signaling induced by MV internalization and the function of the antigen-processing machinery of DCs. These results strongly support the hypothesis that tumor-derived MVs impact antigen immunogenicity by tuning the antigen-processing machinery of DCs, besides being carrier of tumor antigens. Furthermore, these findings have important implications for the exploitation of MVs as antigenic cell-free immunogen for DC-based therapeutic strategies.

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2 , two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA -mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA -mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened.

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.