Histopathological and Immunohistochemical Prognostic Factors in High-Grade Non-Endometrioid Carcinomas of the Endometrium (HG-NECs): Is It Possible to Identify Subgroups at Increased Risk?

Endometrial cancer is an emerging disease with an increase in prevalence of aggressive histotypes in recent years. BACKGROUND: In the present study, potential histopathological and immunohistochemical prognostic markers were investigated. Consecutive cases of high-grade non-endometrioid carcinoma (HG-NEC) of the endometrium were considered. METHODS: Each surgical specimen was routinely processed; the most significant block was selected for immunohistochemistry and tested for ER, PR, ki67, p53, E-cadherin, ß-catenin, Bcl-2 and cyclin D1. For each immunomarker, the percentage of positive tumor cells was evaluated (%) and dichotomized as low and high according to the distribution in the study population. Follow-up was collected for disease-free survival (DFS) and overall survival (OS). Thirty-three cases were eligible: 19 resulted in FIGO I-II; 14 resulted in FIGO III-IV. Twelve patients suffered a recurrent disease (mean follow-up 24.6 months); 8 patients died of the disease (mean follow-up 26.6 months). RESULTS: Women with recurrent disease demonstrated a significantly higher Bcl2% (35.84 ± 30.96% vs. 8.09 ± 11.56%; p = 0.0032) while DOD patients had higher ki67% (75 ± 13.09% vs. 58.6 ± 19.97%; p = 0.033) and Bcl2% of border significance (34.37 ± 34.99% vs. 13 ± 17.97%; p = 0.078). As expected, FIGO III-IV had a worse DFS (HR = 3.34; 95% CI: 1.1-10.99; p = 0.034) and OS (HR = 5.19; 95% CI: 1.27-21.14; p = 0.0217). Bcl-2-high patients (Bcl2 > 10%) demonstrated a significantly worse DFS (HR = 9.11; 95% CI: 2.6-32.4; p = 0.0006) and OS (HR = 7.63; 95% CI: 1.7-34; p = 0.0084); moreover, PR low patients (PR ≤ 10%) had significantly worse DFS (HR = 3.74; 95% CI: 1.2-11.9; p = 0.02). CONCLUSIONS: HG-NEC represents a heterogeneous group of endometrial aggressive neoplasms with a worrisome prognosis, often at an advanced stage at presentation. Bcl-2 and PR may represent promising markers to identify a subgroup of patients having an even worse prognosis requiring a careful and close follow-up.

Incidence and ultrasonographic characteristics of cesarean scar niches after uterine closure by double-layer barbed suture: A prospective comparative study.

OBJECTIVE: To compare the ultrasonographic features of uterine scars and clinical symptoms after cesarean delivery (CD) using barbed and conventional smooth sutures. METHODS: This case-control study enrolled women who underwent primary CD at 37 weeks of pregnancy or later. The uterus was closed using either double-layer unidirectional barbed suture or conventional double-layer smooth suture. Ultrasound scans of the uterine scar and evaluations of menstrual patterns were performed at 6, 12, and 24 months after surgery. RESULTS: In all, 102 patients underwent uterine closure with barbed suture, while 135 patients underwent smooth suture. At 6 months, patients in the barbed group had a lower incidence of uterine niches (20.2% vs 32.6%) that were also shallower in depth (P < 0.001). Lower incidence of niches was also observed in the barbed group at 12 and 24 months (P = 0.043 and 0.048, respectively). At these two follow-up times, the smooth group had a higher number of patients reporting postmenstrual spotting (P < 0.05) and more postmenstrual spotting days per month (P < 0.050). CONCLUSION: The use of double-layer barbed suture during CD was associated with a lower incidence of scar niches and a more favorable menstrual pattern compared with the use of smooth suture.

BRCA mutation carriers' perception about benefits and risks associated with combined hormonal contraceptives use.

OBJECTIVE: To evaluate the actual perceptions about combined hormonal contraceptives (CHCs) use in BRCA mutation carriers in comparison to women from the general population. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Fishbone double-layer barbed suture in cesarean section: a help in preventing long-term obstetric sequelae?

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.

Current and experimental drug therapy for the treatment of polycystic ovarian syndrome.

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.

Peritoneal carcinomatosis from ovarian paraganglioma: Report of a rare case and systematic review of the literature.

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.

The IL-18 antagonist IL-18-binding protein is produced in the human ovarian cancer microenvironment.

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.

Activated leukocyte cell adhesion molecule soluble form: a potential biomarker of epithelial ovarian cancer is increased in type II tumors.

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.

Interleukin (IL)-18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor.

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.

Incisional hernia on the 5-mm trocar port site and subsequent wall endometriosis on the same site: a case report.

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.