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Supplementary Figure S2 - PDF file 2513K, A and B: Analysis of the correlation between IL-18 and IL-18BP protein levels in EOC sera (n. 47) (A) and ascites (n. 17) (B). No significant correlation (P=ns) was found by Pearson's test. C: Analysis of the correlation between IL18 and IL-18BP protein levels and IFN-? in the ascites of 15 EOC patients. IFN-? levels are low to undetectable and show no correlation with IL-18 or IL-18BP levels (P=ns). Pearson's correlation coefficients are shown (r). Lines represent the best-fit linear regression analysis with the 95% Confidence Interval

Purpose: Interleukin (IL)-18 is an immune-enhancing cytokine, which induces IFN-γ production, T-helper 1 responses, and antitumor effects. In turn, IFN-γ stimulates IL-18–binding protein production, which blocks IL-18 activity. In view of the potential use of IL-18 in epithelial ovarian cancer (EOC) immunotherapy, here, we studied IL-18BP expression and its regulation by cytokines in EOC cells in vitro and in vivo.Experimental Design: Expression and production of IL-18BP in EOC cell lines, primary ovarian carcinomas, and the corresponding normal tissues, patients' serum, and ascites were investigated by immunochemistry, ELISA, screening of gene expression profiles, and reverse-transcription PCR.Results: Analysis of gene expression profiles revealed that IL18BP mRNA is increased in EOC tumors compared with normal ovary cells. Release of IL-18BP was detectable in EOC sera and to a greater extent in the ascites, indicating production at the tumor site. Indeed, immunochemical analyses on cells isolated from the ascites and on tumor sections indicated that IL-18BP is expressed in both tumor cells and tumor-associated leukocytes, which displayed a CD3−CD20−NKp46−CD13+CD14low phenotype. EOC cell lines do not constitutively express IL-18BP. However, its release is inducible both by IFN-γ stimulation in vitro and by xenotransplantation of EOC cells in immune-deficient mice, suggesting a role for the microenvironment. In vitro experiments and immunochemistry indicated that IL-27 is also involved in IL-18BP upregulation in EOC cell lines and primary cells through STAT1 activation. Together, these data indicate that IL-18BP, which is produced in EOC in response to microenvironmental factors, may inhibit endogenous or exogenous IL-18 activity. Clin Cancer Res; 19(17); 4611–20. ©2013 AACR.

Due to the high number of cesarean sections over the last two decades, there has been a growing awareness of the post-surgical obstetric long-term sequelae (i.e., uterine scar defects and abnormal placentation) following this surgical procedure. Knotless barbed suture is an absorbable bidirectional and unidirectional monofilament, characterized by the presence of "barbs" along its length. After being introduced in gynecology, the favorable features of the knotless barbed suture, such as the uniform distribution of tensile force, provide the rationale for studying its benefits in obstetric surgery. Recently, our research group has investigated a double-layer barbed suture ("fishbone" suture) for closing the uterine wall during cesarean section by a case-control study, reporting a low incidence of uterine scar defects and a reduced size of defects in women who had developed them (NCT04825821). In the near future, large prospective studies are strongly awaited to investigate reproductive outcomes and long-term sequelae after cesarean section performed with knotless barbed suture.

Introduction: Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 8–13% of reproductive-age women. Irregular periods, hirsutism, or infertility are the most common clinical presentations of patients affected by PCOS. This syndrome is also linked to metabolic abnormalities such as type 2 diabetes, insulin resistance and obesity. The optimal therapeutic approach is still unknown. Areas covered: This narrative review offers an overview of the literature on current and experimental pharmacological options for treating PCOS and highlights ongoing clinical trials. Several electronic databases were searched and current research registers were analyzed to the present year. The papers selected for this review were critically analyzed, and all data available were summarized, organized, and explored to derive key information. Expert opinion: The main goal of PCOS treatment is to obtain a metabolic and hormonal balance. Optimal PCOS therapy should be direct to the reproductive abnormalities and the entire spectrum of endocrine and metabolic complications that appear to have a long-term negative impact on PCOS patient health, as in post-menopausal period. The discovery of new mechanisms in PCOS pathogenesis will offer the possibility of testing new drug classes.

To evaluate the actual perceptions about combined hormonal contraceptives (CHCs) use in BRCA mutation carriers in comparison to women from the general population. This was a cross-sectional, observational study involving two Italian referral centres for hereditary cancers. An identical questionnaire investigating how CHC use could affect the risk of developing some types of cancer, specific diseases, and symptoms was administered to 85 BRCA mutation carriers and 85 healthy women without this genetic mutation (control group). Women’s perceptions were evaluated using specific questions and Likert scales (−5 to +5). Perceptions about the effects of CHC use on developing specific diseases and symptoms did not differ between BRCA mutation carriers and controls. Conversely, the protective effects of CHC use on colorectal (p = .02), uterine body (p = .01) and ovarian (p = .01) cancers were unknown by BRCA mutation carriers. Moreover, BRCA mutation carriers recognised the association between CHC use and a higher risk of breast (p = .0008) and uterine cervix cancer (p = .007). Investing time and effort in transmitting the correct key messages about oncological risk related to CHC use could potentially increase their use in BRCA mutation carriers.

An interesting original research entitled “Serum albumin as a predictor of survival after interval debulking surgery for advanced ovarian cancer: a retrospective study” has been recently published ...

Paraganglioma is one of the rarest neoplasms involving the ovary, with only 10 previous reports. We present a case of peritoneal carcinomatosis from primary ovarian paraganglioma and a systematic review of the literature. Clinical information was retrieved from medical records, and a systematic review of the literature was performed according to meta-analysis of observational studies in epidemiology guidelines. A 33-year-old woman presented with a 12-month history of hypertension and weight loss. She was diagnosed with ovarian paraganglioma and was treated with extensive debulking surgery to no residual disease after three cycles of neoadjuvant chemotherapy. She recurred after 6 months and was started on somatostatin-analogue. Following further disease progression with bone metastasis (treated with palliative radiotherapy), a trial with Sunitinib was started. The patient died 30 months after initial diagnosis. Of the cases reported to date, only one had peritoneal metastasis at presentation but none of them had such an ominous prognosis. Ovarian paraganglioma is an extremely rare condition. We report the first case of primary malignant ovarian paraganglioma with an exceptionally aggressive behavior. Clinicopathological correlation with immunohistochemistry is essential to avoid misdiagnosis. A standard treatment is not recommended yet but cytoreductive surgery seems to be a favorable approach to prolong survival.

Paraganglioma is one of the rarest neoplasms involving the ovary, with only 10 previous reports. We present a case of peritoneal carcinomatosis from primary ovarian paraganglioma and a systematic review of the literature. Clinical information was retrieved from medical records, and a systematic review of the literature was performed according to meta-analysis of observational studies in epidemiology guidelines. A 33-year-old woman presented with a 12-month history of hypertension and weight loss. She was diagnosed with ovarian paraganglioma and was treated with extensive debulking surgery to no residual disease after three cycles of neoadjuvant chemotherapy. She recurred after 6 months and was started on somatostatin-analogue. Following further disease progression with bone metastasis (treated with palliative radiotherapy), a trial with Sunitinib was started. The patient died 30 months after initial diagnosis. Of the cases reported to date, only one had peritoneal metastasis at presentation but none of them had such an ominous prognosis. Ovarian paraganglioma is an extremely rare condition. We report the first case of primary malignant ovarian paraganglioma with an exceptionally aggressive behavior. Clinicopathological correlation with immunohistochemistry is essential to avoid misdiagnosis. A standard treatment is not recommended yet but cytoreductive surgery seems to be a favorable approach to prolong survival.

In recent years sentinel lymph node (SLN) mapping has emerged as an attractive investigational approach for the treatment of gynecological cancers, and in particular, endometrial cancer (EC). In fact, radical lymphadenectomy may have no therapeutic benefit in patients with early-stage EC who have low probability of lymph nodes involvement; subsequently, SLN mapping may decrease unnecessary lymph node dissections. In recent years, the number of minimally invasive procedures for gynecologic oncology has increased, with robotic procedures rising remarkably. Robotic SLN evaluation by intraoperative near infrared fluorescence (INIF) imaging system (Firefly™, Intuitive Surgical Inc., Sunnyvale, CA, USA) is an innovative surgical tool, which allows for a rapid conversion from the normal robotic view to that for detecting fluorescent indocyanine green (ICG). The aim of this video is to describe the use of this tool and technical outcomes of SLN dissection during our single-center experience in the robotic surgical approach of patients with early endometrial cancer.

Purpose: Interleukin (IL)-18 is an immune-enhancing cytokine, which induces IFN-γ production, T-helper 1 responses, and antitumor effects. In turn, IFN-γ stimulates IL-18–binding protein production, which blocks IL-18 activity. In view of the potential use of IL-18 in epithelial ovarian cancer (EOC) immunotherapy, here, we studied IL-18BP expression and its regulation by cytokines in EOC cells in vitro and in vivo. Experimental Design: Expression and production of IL-18BP in EOC cell lines, primary ovarian carcinomas, and the corresponding normal tissues, patients' serum, and ascites were investigated by immunochemistry, ELISA, screening of gene expression profiles, and reverse-transcription PCR. Results: Analysis of gene expression profiles revealed that IL18BP mRNA is increased in EOC tumors compared with normal ovary cells. Release of IL-18BP was detectable in EOC sera and to a greater extent in the ascites, indicating production at the tumor site. Indeed, immunochemical analyses on cells isolated from the ascites and on tumor sections indicated that IL-18BP is expressed in both tumor cells and tumor-associated leukocytes, which displayed a CD3−CD20−NKp46−CD13+CD14low phenotype. EOC cell lines do not constitutively express IL-18BP. However, its release is inducible both by IFN-γ stimulation in vitro and by xenotransplantation of EOC cells in immune-deficient mice, suggesting a role for the microenvironment. In vitro experiments and immunochemistry indicated that IL-27 is also involved in IL-18BP upregulation in EOC cell lines and primary cells through STAT1 activation. Together, these data indicate that IL-18BP, which is produced in EOC in response to microenvironmental factors, may inhibit endogenous or exogenous IL-18 activity. Clin Cancer Res; 19(17); 4611–20. ©2013 AACR.

Interleukin (IL)-18 is a proinflammatory and immune-enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)γ. We previously reported that IL-18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro-IL-18) in vitro. In addition, IL-18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL-18 is increased in EOC patients' sera at diagnosis as compared with age-matched healthy women. IL-18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL-18 expression in cytokeratine-positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL-18. The detection of human IL-18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL-18 is tumor-derived. However, IL-18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL-18 present in the ascitic fluid as pro-IL-18, which is biologically inactive. Accordingly, IFNγ was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL-18 levels. Altogether these data indicate that IL-18 in EOC fluids is predominantly tumor-derived and that its lack of biological activity may represent a mechanism of tumor-escape.

5529Background: concurrent CT-RT is the standard treatment for LACC. Currently weekly low dose Cisplatin based CT is the radio-sensitizing treatment suggested. Our single-center, prospective, singl...

A 26-year-old nulliparous woman underwent a laparoscopy to remove a 10-cm endometrial cyst on the left ovary (type II Nezhat). The cyst was extracted from the 10-mm umbilical incision; the other 2 trocars were inserted through 5-mm incisions. One year later, in correspondence to the previous 5-mm incision site, a hernia occurred that contained omentum and was reduced easily with a local anesthetic. After 2 years of good health, an aching nodule occurred on the same trocar site; vaginal ultrasound examination showed another left ovarian cyst. A second laparoscopy was performed; the cyst was very adherent and was removed in fragments. The wall nodule was removed, and the histologic examination classified it as endometriosis.

Activated leukocyte cell adhesion molecule (ALCAM) is involved in cell-cell interactions in cancer. Shedding of its ectodomain by the metalloprotease ADAM17/TACE generates a soluble form (sALCAM). Here, we show that serum sALCAM levels were significantly higher in epithelial ovarian cancer (EOC) (p < 0.005) than in controls. The performance of sALCAM as classifier, tested by receiver operating characteristic curve, resulted in an area under the curve (AUC) of 0.8067. Serum sALCAM levels showed direct correlation with Carbohydrate Antigen-125 (CA125/MUC16). Moreover, significantly higher levels were found in type II tumors, even in stage I/II, suggesting that elevated sALCAM is an early feature of aggressive EOC. In addition, sALCAM levels were higher in ascites than in sera, suggesting local processing of ALCAM in the peritoneal cavity. In immunodeficient mice, intraperitoneally implanted with a human EOC cell line, human sALCAM progressively increased in serum and was even higher in the ascites. The biochemical characterization of the sALCAM in EOC sera and ascites, showed two predominant forms of approximately 95 and 65 kDa but no EOC-specific isoform. In addition, full-length transmembrane ALCAM but no soluble form was detected in tumor-derived exosomes found in ascites. Finally, in vitro invasion assays showed that inhibition of ADAM17/TACE activity decreased EOC invasive properties, while opposite effects were mediated by a sALCAM-Fc chimera and by an antibody interfering with ALCAM/ALCAM interactions. Altogether these data suggest that sALCAM is a marker of EOC, which correlates with more aggressive type II tumors, and that ADAM17/TACE activity and sALCAM itself mediate enhanced invasiveness.

Objective: The outcome of advanced ovarian cancer patients has not significantly improved since the introduction of platinum. One of the major reasons for this failure is the lack of an effective second-line treatment. In this phase II trial we tested the combination of gemcitabine and etoposide in 2 different groups of patients. Group 1 consisted of patients showing disease progression or relapse within 6 months of first-line platinum-based chemotherapy. Group 2 comprised heavily pretreated patients showing progression during the last chemotherapy attempt. Methods: Thirty-four patients were enrolled. Gemcitabine was administered at a dose of 1,000 mg/m2 on days 1 and 8 and etoposide was administered orally at 100 mg/day on days 8–12 for 6 courses. Results: Eighteen patients (52.9%) had an objective response and the median duration of the response was 10.3 months. Our chemotherapy regimen showed a low toxicity and good patient compliance. In 5 patients the treatment had to be delayed and in only 2 patients it was discontinued. Conclusions: The combination of gemcitabine and oral etoposide seems to be a safe and effective second-line treatment for platinum-resistant ovarian cancer patients. Additional data on larger series are warranted to better define the activity of this combination regimen.

We report a case of vesicovaginal fistula associated to a vaginal foreign body. A 72-year-old woman consulted our clinic complaining of severe urinary incontinence. The leakage was continuous and significant and she was feeling a "vaginal mass". Pelvic examination was suspicious for an advanced vaginal cancer, but further investigations showed the presence of a retained vaginal foreign body complicated by perforation of the bladder.

Background: Five randomized studies have demonstrated a beneficial effect of adding cisplatin-based chemotherapy to radiation therapy in the treatment of cervical carcinoma. In the present phase II study, we evaluated the response and toxicity of ciplatin-Taxol chemotherapy combined with concomitant radiotherapy in patients with locally advanced cervical carcinoma (LACC) and locally recurrent cervical carcinoma (LRCC). Patients and Methods: In 2000, this phase II study was initiated with a chemotherapy regimen of cisplatin (75 mg/m2) and Taxol (175 mg/m2) every 21 days, for four cycles, concomitant with external radiotherapy and high-dose-rate brachytherapy. Pelvic radiotherapy was started 2 weeks after the first chemotherapy cycle, while the first brachytherapy insertion was carried out during the fourth chemotherapy cycle. SCC marker was determined before treatment and after every chemotherapy cycle. Results: All of the 27 patients treated achieved a complete clinical response. Two patients with LACC experienced distant recurrence 22 and 24 months after complete response, respectively, and 1 patient with LRCC had local progression 6 months after the end of radiotherapy. Although generally tolerable, neutropenia grade 3–4 in 4 patients and anemia grade 3 in 2 patients were observed, and 1 patient experienced grade 2 neurotoxicity; toxicity due to radiotherapy was moderate. Conclusions: Concomitant cisplatin-Taxol chemoradiotherapy seems to be well tolerated, and results, even in this small series, are encouraging.

Background In the last decade many studies have definitely shown that human papillomaviruses (HPVs) are the major cause of cervical carcinogenesis and, in the last few years, HPV testing has been proposed as a new and more powerful tool for cervical cancer screening. This issue is now receiving considerable attention in scientific and non scientific press and HPV testing could be considered the most important change in this field since the introduction of cervical cytology. This paper reports our prevalence data of HPV infection collected in the '90s, while a follow up of these patients is ongoing. Methods For this study we used polymerase chain reaction (PCR) to search HPV DNA sequences in cervical cell scrapings obtained from 503 asymptomatic women attending regular cervical cancer screening program in the city of Genova, Italy. All patients were also submitted to a self-administered, standardized, questionnaire regarding their life style and sexual activity. On the basis of the presence of HPV DNA sequences women were separated into two groups: "infected" and "non infected" and a statistical analysis of the factors potentially associated with the infection group membership was carried out. Results The infection rate was 15.9% and the most frequent viral type was HPV 16. Conclusion Our HPV positivity rate (15.9%) was consistent to that reported by other studies on European populations.