Human endogenous retroviruses (HERVs) in breast cancer: altered expression pattern implicates divergent roles in carcinogenesis.

Introduction Breast cancer is the most common cancer and the leading cause of cancer death in women. Recent research indicates that human endogenous retroviruses (HERVs) may be linked to carcinogenesis, but the data remain controversial. Methods HERVs´ expression was evaluated to show the differences between breast cancer and control samples, and their associations with clinicopathological parameters. Gene expression of 12 HERVs, i.e. ERVE-4, ERVW-1, ERVFRD-1, ERVV-1, ERV3-1, ERVH48-1, ERVMER34-1, ERVK7, ERVK13-1, ERVK11-1, ERVK3-1 and HCP5 was analyzed by qPCR and/or TCGA datasets for breast cancer. Results ERV3-1, ERVFRD-1, ERVH48-1 and ERVW-1 provided data to support their tumor suppressor roles in breast cancer. ERV3-1 evinced the best performing diagnostic data based on qPCR, i.e. AUC: 0.819 (p <0.0001), sensitivity of 72.41%, and specificity of 89.66%. Lower levels of ERV3-1 were noted in advanced stage and higher grades, and significant negative association was found in relation to Ki-67 levels. Oncogenic roles may be inferred for ERVK13-1, ERVV-1, and ERVMER34-1. Data for ERVK-7, ERVE-4, ERVK11-1 and HCP5 remain inconclusive. Conclusion Differential HERVs expression may be applicable to evaluate novel biomarkers for breast cancer. However, more research is needed to reveal their real clinical impact, the biological roles and regulatory mechanisms in breast carcinogenesis.

Conservative management of complete fetal expulsion into the abdominal cavity after silent uterine rupture - case report.

BACKGROUND: Clinically silent uterine rupture with complete fetal expulsion into the abdominal cavity is an extremely rare complication. Diagnosis can be difficult and the risk to the mother and fetus is high. Conservative management has been described only in a few cases of partial expulsion of the fetus so far. CASE PRESENTATION: We present a case of 43-year-old tercigravida with a history of previous laparotomic myomectomy and subsequent cesarean section. The subsequent pregnancy was complicated by uterine wall loosening and rupture at the site of the previous uterine scar after myomectomy and complete fetal expulsion into the abdominal cavity. The diagnosis was made at 24 + 6 weeks of gestation. Considering the absence of clinical symptomatology and the good condition of the fetus, a conservative approach was chosen with intensive monitoring of the maternal and fetal conditions. The pregnancy ended by elective cesarean section and hysterectomy at 28 + 0 weeks of gestation. The postpartum course was uneventful and the newborn was discharged to home care 63 days after delivery. CONCLUSIONS: Fetal expulsion into the abdominal cavity after silent uterine rupture of the scarred uterus may be accompanied by minimal symptomatology making early diagnosis difficult. This rare complication must be considered in the differential diagnosis in women after major uterine surgery. In selected cases and under conditions of intensive maternal and fetal monitoring, conservative management may be chosen to reduce the risks associated with prematurity.

Small non-coding RNA profiling in breast cancer: plasma U6 snRNA, miR-451a and miR-548b-5p as novel diagnostic and prognostic biomarkers.

BACKGROUND: Breast cancer is a leading cause of cancer-related death in women. Most cases are invasive ductal carcinomas of no special type (NST breast carcinomas). METHODS AND RESULTS: In this prospective, multicentric biomarker discovery study, we analyzed the expression of small non-coding RNAs (mainly microRNAs) in plasma by qPCR and evaluated their association with NST breast cancer. Large-scale expression profiling and subsequent validations have been performed in patient and control groups and compared with clinicopathological data. Small nuclear U6 snRNA, miR-548b-5p and miR-451a have been identified as candidate biomarkers. U6 snRNA was remarkably overexpressed in all the validations, miR-548b-5p levels were generally elevated and miR-451a expression was mostly downregulated in breast cancer groups. Combined U6 snRNA/miR-548b-5p signature demonstrated the best diagnostic performance based on the ROC curve analysis with AUC of 0.813, sensitivity 73.1% and specificity 82.6%. There was a trend towards increased expression of both miR-548b-5p and U6 snRNA in more advanced stages. Further, increased miR-548b-5p levels have been partially associated with higher grades, multifocality, Ki-67 positivity, and luminal B rather than luminal A samples. On the other hand, an association has been observed between high miR-451a expression and progesterone receptor positivity, lower grade, unifocal samples, Ki-67-negativity, luminal A rather than luminal B samples as well as improved progression-free survival and overall survival. CONCLUSIONS: Our results indicated that U6 snRNA and miR-548b-5p may have pro-oncogenic functions, while miR-451a may act as tumor suppressor in breast cancer.

Prospective evaluation of contrast-enhanced ultrasound of breast BI-RADS 3-5 lesions.

BACKGROUND: To determine the benefit of contrast-enhanced ultrasound (CEUS) in the assessment of breast lesions. METHODS: A standardized contrast-enhanced ultrasound was performed in 230 breast lesions classified as BI-RADS category 3 to 5. All lesions were subjected to qualitative and quantitative analysis. MVI (MicroVascular Imaging) technique was used to derive qualitative analysis parameters; blood perfusion of the lesions was assessed (perfusion homogeneity, type of vascularization, enhancement degree). Quantitative analysis was conducted to estimate perfusion changes in the lesions within drawn regions of interest (ROI); parameters TTP (time to peak), PI (peak intensity), WIS (wash in slope), AUC (area under curve) were obtained from time intensity (TI) curves. Acquired data were statistically analyzed to assess the ability of each parameter to differentiate between malignant and benign lesions. The combination of parameters was also evaluated for the possibility of increasing the overall diagnostic accuracy. Biological nature of the lesions was verified by a pathologist. Benign lesions without histopathological verification (BI-RADS 3) were followed up for at least 24 months. RESULTS: Out of 230 lesions, 146 (64%) were benign, 67 (29%) were malignant, 17 (7%) lesions were eliminated. Malignant tumors showed statistically significantly lower TTP parameters (sensitivity 77.6%, specificity 52.7%) and higher WIS values (sensitivity 74.6%, specificity 66.4%) than benign tumors. Enhancement degree also proved to be statistically well discriminating as 55.2% of malignant lesions had a rich vascularity (sensitivity 89.6% and specificity 48.6%). The combination of quantitative analysis parameters (TTP, WIS) with enhancement degree did not result in higher accuracy in distinguishing between malignant and benign breast lesions. CONCLUSIONS: We have demonstrated that contrast-enhanced breast ultrasound has the potential to distinguish between malignant and benign lesions. In particular, this method could help to differentiate lesions BI-RADS category 3 and 4 and thus reduce the number of core-cut biopsies performed in benign lesions. Qualitative analysis, despite its subjective element, appeared to be more beneficial. A combination of quantitative and qualitative analysis did not increase the predictive capability of CEUS.

Poor outcome in hypoxic endometrial carcinoma is related to vascular density.

BACKGROUND: Identification of endometrial carcinoma (EC) patients at high risk of recurrence is lacking. In this study, the prognostic role of hypoxia and angiogenesis was investigated in EC patients. METHODS: Tumour slides from EC patients were stained by immunofluorescence for carbonic anhydrase IX (CAIX) as hypoxic marker and CD34 for assessment of microvessel density (MVD). CAIX expression was determined in epithelial tumour cells, with a cut-off of 1%. MVD was assessed according to the Weidner method. Correlations with disease-specific survival (DSS), disease-free survival (DFS) and distant disease-free survival (DDFS) were calculated using Kaplan-Meier curves and Cox regression analysis. RESULTS: Sixty-three (16.4%) of 385 ECs showed positive CAIX expression with high vascular density. These ECs had a reduced DSS compared to tumours with either hypoxia or high vascular density (log-rank p = 0.002). Multivariable analysis showed that hypoxic tumours with high vascular density had a reduced DSS (hazard ratio [HR] 3.71, p = 0.002), DDFS (HR 2.68, p = 0.009) and a trend for reduced DFS (HR 1.87, p = 0.054). CONCLUSIONS: This study has shown that adverse outcome in hypoxic ECs is seen in the presence of high vascular density, suggesting an important role of angiogenesis in the metastatic process of hypoxic EC. Differential adjuvant treatment might be indicated for these patients.

Ovarian Cancer: Differentially Expressed microRNAs in Tumor Tissue and Cell-Free Ascitic Fluid as Potential Novel Biomarkers.

Ovarian cancer is the deadliest gynecologic cancer. The large-scale microRNA (miRNA) expression profiling and individual miRNA validation was performed to find potential novel biomarkers for ovarian cancer. The most consistent overexpression of miRs-200b-3p, 135 b-5p and 182-5p was found in both ascitic fluid and tumors and suggests their potential as oncogenes. miR-451a was consistently underexpressed so may be a tumor suppressor. Results were inconsistent for miR-204-5p, which was overexpressed in ascitic fluid but underexpressed in tumor tissue. miR-203a-3p was generally overexpressed but this failed to be proved in independent sample set in tissue validation.

Added Value of Estrogen Receptor, Progesterone Receptor, and L1 Cell Adhesion Molecule Expression to Histology-Based Endometrial Carcinoma Recurrence Prediction Models: An ENITEC Collaboration Study.

OBJECTIVES: Endometrial carcinoma mortality is mainly caused by recurrent disease, and various immunohistochemical markers to predict recurrences have been studied. Loss of the estrogen receptor (ER) and progesterone receptor (PR) and the presence of the L1 cell adhesion molecule (L1CAM) are promising markers, but their combined value has not been studied. MATERIALS AND METHODS: Expression of ER, PR, and L1CAM was immunohistochemically determined in 293 endometrial carcinomas from 11 collaborating European Network for Individualized Treatment of Endometrial Cancer centers. Estrogen receptor, PR, or L1CAM staining was considered positive or negative when expressed by greater than or equal to 10% or less than 10% of the tumor cells, respectively. The association between these markers and clinicopathological markers, and their combined value in predicting survival were calculated, both in the entire cohort and in a selected groups of stage I endometrioid and low-risk stage I endometrioid carcinomas. RESULTS: Estrogen receptor and PR were negative in 19% and 28% of the cases, respectively, and L1CAM was positive in 18%. All 3 were associated with advanced stage, high-grade, nonendometrioid histology, lymphovascular space invasion (LVSI), and reduced disease-free survival. Only advanced stage, loss of PR, and LVSI were associated with reduced disease-free survival in multivariate analysis. A prognostic model including these 3 markers was superior to 1 including only the 3 immunohistochemical markers, which was superior to the traditional model. In both the stage I endometrioid and the low-risk stage I endometrioid groups, only loss of PR was associated with reduced disease-free survival. CONCLUSIONS: Loss of ER and PR, and the presence of L1CAM are associated with high risk characteristics, and loss of PR is the strongest predictor of recurrent disease. Although a combination of these 3 markers is slightly superior to the traditional histological markers, a prognostic model including stage, PR expression, and LVSI is the most promising model in the identification of high risk carcinomas. In the stage I endometrioid carcinomas, PR immunohistochemistry appears to be of additional value in predicting recurrences.

Brenner tumor of the ovary - ultrasound features and clinical management of a rare ovarian tumor mimicking ovarian cancer.

OBJECTIVES: To describe the ultrasound features of benign Brenner tumor in the background of complex clinical and histopathological pictures. MATERIAL AND METHODS: We retrospectively identified patients with histologically confirmed benign Brenner tumor of the ovary who were treated in our institution in 2003-2016, and for whom complete imaging, clinical, perioperative and histopathological data were available in the database. Ultrasound findings were drawn from images and reports using terms and definitions of the International Ovarian Tumor Analysis group and pattern recognition description was applied. RESULTS: Twenty-three patients were identified, most postmenopausal and asymptomatic. On ultrasound, 19/23 tumors were found unilaterally, 4/23 bilaterally, and 82% of tumors were detected in the left ovary. Most Brenner tumors (16/23) contained solid components and revealed no or minimal blood flow by subjective color score upon Doppler examination (19/23, 83%). Calcifications with shadowing were observed in 57% of all Brenner tumors and in 81% of tumors containing solid components. The complex appearance of the tumor misled the sonographers to describe the mass as malignant in 9 cases (39%), and frozen section was performed perioperatively. Surgery was performed via laparoscopy in 11 (48%) and via laparotomy in 12 (52%) cases. CONCLUSIONS: The complexity of the ultrasound picture, consisting of features like calcifications with acoustic shadowing, a poorly vascularized solid mass, and a left-sided localization could be signs of a benign Brenner tumor and could preop-eratively help to differentiate between benign and malignant tumor.

Modified posterior pelvic exenteration for advanced ovarian malignancies: a single-institution study of 35 cases.

INTRODUCTION: This study aimed to investigate the possible benefits of a complete cytoreduction in patients with advanced ovarian cancer and concomitant rectal invasion. Furthermore, we evaluated the morbidity associated with radical surgery. MATERIAL AND METHODS: A retrospective analysis examined 35 women who underwent radical surgery in the form of modified posterior pelvic exenteration. Descriptive statistics, Kaplan-Meier survival curves and log-rank test were used for statistical estimations. Surgical complications were analyzed using the Clavien-Dindo classification. RESULTS: The analysis of survival in relation to residual disease assessed according to Sugarbaker confirmed an optimistic prognosis in patients with optimal debulking with a mean disease-free survival period of 33.6 months in R0 patients, 19.6 months in R1 patients, and 14.3 months in R2 patients. A statistically significant difference in disease-free survival (p = 0.023) was observed between the R0 (without residual disease) and R1+2 (with residual disease) groups. Surgical complications occurred in 83% of patients, with early postoperative complications being most frequent (65.7%). While grade III-IV complications occurred in 37.7% of all patients, no cases of surgery-associated mortality occurred. CONCLUSIONS: Modified posterior pelvic exenteration is a highly effective method for achieving optimal debulking in cases of advanced ovarian cancer with the direct invasion of the rectum. Modified posterior pelvic exenteration does not delay the beginning of complementary chemotherapy. However, it is necessary to take into account surgery-related morbidity. As modified posterior pelvic exenteration represents an extremely invasive technique, the surgical plan and perioperative care should be personalized to address the individual medical and surgical conditions of each patient.

L1CAM expression in endometrial carcinomas: an ENITEC collaboration study.

BACKGROUND: Identification of aggressive endometrioid endometrial carcinomas (EECs) and non-endometrioid carcinomas (NEECs) is essential to improve outcome. L1 cell adhesion molecule (L1CAM) expression is a strong prognostic marker in stage I EECs, but less is known about L1CAM expression in advanced-stage EECs and NEECs. This study analyses L1CAM expression in a clinically representative cohort of endometrial carcinomas. METHODS: The expression of L1CAM was immunohistochemically determined in 1199 endometrial carcinomas, treated at one of the European Network for Individualized Treatment of Endometrial Cancer (ENITEC) centres. Staining was considered positive when >10% of the tumour cells expressed L1CAM. The association between L1CAM expression and several clincopathological characteristics and disease outcome was calculated. RESULTS: In all, L1CAM was expressed in 10% of the 935 stage I EECs, 18% of the 160 advanced stage EECs, and 75% of the 104 NEECs. The expression of L1CAM was associated with advanced stage, nodal involvement, high tumour grade, non-endometrioid histology, lymphovascular space invasion, and distant recurrences in all cases, and with reduced survival in the EECs, but not in the NEECs. CONCLUSIONS: The expression of L1CAM is a strong predictor of poor outcome in EECs, but not NEECs. It is strongly associated with non-endometrioid histology and distant spread, and could improve the postoperative selection of high-risk endometrial carcinomas. The value of L1CAM expression in the preoperative selection of high-risk endometrial carcinomas should be studied.

Uterine Fibroid Morphology and Histology with Respect to Reproductive Age.

OBJECTIVE: To evaluate histological uterine fibroid incidence among reproductive age women and to deter- mine correlations between fibroid histological type, patient age, and number and size offibroids. STUDY DESIGN: The study cohort consisted of 103 women desiring preg- nancy who underwent myo- mectomy for symptomatic uterine fibroids. The primary endpoints were histological type of fibroid, myomectomy incidence among 2 age groups (18-34 vs. 35-40), solitary or multiple fibroids, and <5 cm vs. >5 cm fibroid diameter. Secondary anal- ysis endpoints evaluated correlations between uterine fibroid histological type, 2 age groups of women,.and uterine fibroid number and size. RESULTS: Following myomectomy, 84.5% exhibited benign histology, and myomatosis malignancy was not detected. Of the 103 women, 50.5% were aged <34 and 49.5% were aged 35-40; 71.8% had a solitary fibroid and 28.2% had α 2 fibroids; 58.3% had a fibroid of <5 cm. and 41.7% had a fibroid >5 cm in diameter. Cellular fibroid incidence was higher (10.3%) in cases of multiple myomatosis in comparison to the solitary fibroid group (n=0) (p=0.021). Among women with multiple myomatosis (n=29), almost all (n=28, 96.6%) had only 1 histological type. CONCLUSION: Among women of. child-bearing age having myomectomy, most have benign histology with no significant differences in histological type with regard to patient age and fibroid size. A higher incidence of cellular fibroids was observed only in multiple myomatosis cases.

Prognostic value of human epididymis protein 4 in endometrial cancer and its utility for surgical staging.

AIM: An optimal surgical staging in the group of patients with the high-risk type of endometrial cancer is often limited by age and serious internal comorbidities. Therefore, in this study we focused on human epididymis protein 4 and its contribution to the preoperative differentiation of prognostically distinct groups of patients and to individualized surgical treatment as compared with cancer antigen (CA) 125 and imaging methods. MATERIAL AND METHODS: The study included 115 patients with endometrioid adenocarcinoma diagnosed through endometrial biopsy. Before the final operation, blood sampling was performed for the determination of human epididymis protein 4 (HE4) and CA125 levels. Serum levels of both biomarkers were analyzed in relation to individual prognostic factors (stage of disease, depth of myometrial invasion, tumor grade, risk type of disease). RESULTS: In the case of HE4, we demonstrated a statistically significant difference (P < 0.001) between patients with low and high risk of the disease. In our model, achieving the maximum sum of sensitivity and specificity, HE4 shows a sensitivity of 72.4% and a specificity of 75.4% for the cut-off 76.5 pmol/L and is a better predictor in distinguishing the high-risk patients than CA125 (area under the curve 0.77 for HE vs 0.71 for CA125). CONCLUSION: HE4 is a marker that could complement the findings of imaging techniques and that may be useful in decision-making on how to individualize surgical staging. The possibility of its introduction as an independent marker in routine practice remains, at the moment however, limited. The optimal cut-off for HE4 has not been established yet and further studies are needed.

Laparoscopic Treatment of Cesarean Scar Ectopic Pregnancy.

Background: An ectopic pregnancy within a Cesarean scar represents a rare type of extrauterine pregnancy in which the fertilized egg nidates in the myometrium of the uterine wall within a scar left from a previous Cesarean delivery. An unrecognized growing Cesarian scar pregnancy may result in uterine rupture, uncontrollable metrorrhagia, and bleeding into the abdominal cavity; therefore, early diagnosis and therapy are necessary to prevent the development of severe complications. Case: A 34-year-old woman after a previous Cesarean delivery presented with amenorrhoa of 7 weeks' duration. Transvaginal ultrasonography revealed an ectopic pregnancy in the Cesarean scar, and a laparoscopic removal of the gestational sac was performed with no complications. Results: Three months later, another laparoscopy with chromopertubation showed no signs of penetration in the suture, both the Fallopian tubes being bilaterally passable. The patient was advised that she could try to achieve pregnancy through spontaneous conception, after which monitoring of the gestational development and a careful assessment of the nidation site would be needed. Conclusions: Laparoscopic surgical management of a viable ectopic pregnancy is technically simple, and is followed by a good recovery. (J GYNECOL SURG 30:309).

Long non-coding RNAs PTENP1, GNG12-AS1, MAGI2-AS3 and MEG3 as tumor suppressors in breast cancer and their associations with clinicopathological parameters.

BACKGROUND: Breast cancer is the most commonly occurring cancer worldwide and is the main cause of death from cancer in women. Novel biomarkers are highly warranted for this disease. OBJECTIVE: Evaluation of novel long non-coding RNAs biomarkers for breast cancer. METHODS: The study comprised the analysis of the expression of 71 candidate lncRNAs via screening, six of which (four underexpressed, two overexpressed) were validated and analyzed by qPCR in tumor tissues associated with NST breast carcinomas, compared with the benign samples and with respect to their clinicopathological characteristics. RESULTS: The results indicated the tumor suppressor roles of PTENP1, GNG12-AS1, MEG3 and MAGI2-AS3. Low levels of both PTENP1 and GNG12-AS1 were associated with worsened progression-free and overall survival rates. The reduced expression of GNG12-AS1 was linked to the advanced stage. A higher grade was associated with the lower expression of PTENP1, GNG12-AS1 and MAGI2-AS3. Reduced levels of both MEG3 and PTENP1 were linked to Ki-67 positivity. The NRSN2-AS1 and UCA1 lncRNAs were overexpressed; higher levels of UCA1 were associated with multifocality. CONCLUSIONS: The results suggest that the investigated lncRNAs may play important roles in breast cancer and comprise a potential factor that should be further evaluated in clinical studies.

Ascites in ovarian cancer: MicroRNA deregulations and their potential roles in ovarian carcinogenesis.

Ovarian cancer comprises the most lethal gynecologic malignancy and is accompanied by the high potential for the incidence of metastasis, recurrence and chemotherapy resistance, often associated with a formation of ascitic fluid. The differentially expressed ascites-derived microRNAs may be linked to ovarian carcinogenesis. The article focuses on a number of miRNAs that share a common expression pattern as determined by independent studies using ascites samples and with regard to their functions and outcomes in experimental and clinical investigations.Let-7b and miR-143 have featured as tumor suppressors in ovarian cancer, which is in line with data on other types of cancer. Although two miRNAs, i.e. miR-26a-5p and miR-145-5p, act principally as tumor suppressor miRNAs, they occasionally exhibit oncogenic roles. The performance of miR-95-3p, upregulated in ascites, is open to debate given the current lack of supportive data on ovarian cancer; however, data on other cancers indicates its probable oncogenic role. Different findings have been reported for miR-182-5p and miR-200c-3p; in addition to their presumed oncogenic roles, contrasting findings have indicated their ambivalent functions. Further research is required for the identification and evaluation of the potential of specific miRNAs in the diagnosis, prediction, treatment and outcomes of ovarian cancer patients.

WNT signaling inducing activity in ascites predicts poor outcome in ovarian cancer.

High grade serous carcinoma of the ovary, fallopian tube, and peritoneum (HGSC) is the deadliest gynecological disease which results in a five-year survival rate of 30% or less. HGSC is characterized by the early and rapid development of metastases accompanied by a high frequency of ascites i.e. the pathological accumulation of fluid in peritoneum. Ascites constitute a complex tumor microenvironment and contribute to disease progression by largely unknown mechanisms. Methods: Malignant ascites obtained from HGSC patients who had undergone cytoreductive surgery were tested for their ability to induce WNT signaling in the Kuramochi cell line, a novel and clinically relevant in vitro model of HGSC. Next, cancer spheroids (the main form of metastatic cancer cells in ascites) were evaluated with respect to WNT signaling. Kuramochi cells were used to determine the role of individual WNT signaling branches in the adoption of metastatic stem cell-like behavior by HGSC cells. Furthermore, we analyzed genomic and transcriptomic data on WNT/Planar Cell Polarity (PCP) components retrieved from public cancer databases and corroborated with primary patient samples and validated antibodies on the protein level. Results: We have shown that ascites are capable of inducing WNT signaling in primary HGSC cells and HGSC cell line, Kuramochi. Importantly, patients whose ascites cannot activate WNT pathway present with less aggressive disease and a considerably better outcome including overall survival (OS). Functionally, the activation of non-canonical WNT/PCP signaling by WNT5A (and not canonical WNT/ß-catenin signaling by WNT3A) promoted the metastatic stem-cell (metSC) like behavior (i.e. self-renewal, migration, and invasion) of HGSC cells. The pharmacological inhibition of casein kinase 1 (CK1) as well as genetic ablation (dishevelled 3 knock out) of the pathway blocked the WNT5A-induced effect. Additionally, WNT/PCP pathway components were differentially expressed between healthy and tumor tissue as well as between the primary tumor and metastases. Additionally, ascites which activated WNT/PCP signaling contained the typical WNT/PCP ligand WNT5A and interestingly, patients with high levels of WNT5A protein in their ascites exhibited poor progression-free survival (PFS) and OS in comparison to patients with low or undetectable ascitic WNT5A. Together, our results suggest the existence of a positive feedback loop between tumor cells producing WNT ligands and ascites that distribute WNT activity to cancer cells in the peritoneum, in order to promote their pro-metastatic features and drive HGSC progression. Conclusions: Our results highlight the role of WNT/PCP signaling in ovarian cancerogenesis, indicate a possible therapeutic potential of CK1 inhibitors for HGSC, and strongly suggest that the detection of WNT pathway inducing activity ascites (or WNT5A levels in ascites as a surrogate marker) could be a novel prognostic tool for HGSC patients.

Ascites-Derived Extracellular microRNAs as Potential Biomarkers for Ovarian Cancer.

Ovarian cancer as the most fatal gynecological malignancy is often manifested by excessive fluid accumulation known as ascites or effusion. Ascites-derived microRNAs (miRNAs) may be closely associated with ovarian cancer progression. However, our knowledge of their roles, altered expression, and clinical outcomes remained limited. In this study, large-scale expression profiling of 754 human miRNAs was performed using real-time quantitative polymerase chain reaction and 384-well TaqMan array human miRNA A and B cards to identify differentially expressed miRNAs between extracellular fraction of the ascitic fluid associated with high-grade serous ovarian carcinomas and control plasma. Of the 754 miRNAs, 153 were significantly differentially expressed relative to the controls. Expression of 7 individual miRNAs (miR-200a, miR-200b, miR-200c, miR-141, miR-429, miR-1290, and miR-30a-5p) was further validated in extended sample sets, including serous, endometrioid, and mucinous subtypes. All miR-200 family members and miR-1290 were conspicuously overexpressed, while miR-30a-5p was only weakly overexpressed. The ability of miRNAs expression to discriminate the pathological samples from the controls was strong. Receiver operating characteristic curve analyses found area under the curve (AUC) values of 1.000 for miR-200a, miR-200c, miR-141, miR-429, and miR-1290 and of AUC 0.996 and 0.885 for miR-200b and miR-30a-5p, respectively. Preliminary survival analyses indicated low expression level of miR-200b as significantly related to longer overall survival (hazard ratio [HR]: 0.25, mean survival 44 months), while high expression level was related to poor overall survival (HR: 4.04, mean survival 24 months). Our findings suggested that ascites-derived miRNAs should be further explored and evaluated as potential diagnostic and prognostic biomarkers for ovarian cancer.

The role of miR-409-3p in regulation of HPV16/18-E6 mRNA in human cervical high-grade squamous intraepithelial lesions.

Cervical cancer is one of the most common malignancies in women. MicroRNAs (miRNAs) are involved in a variety of fundamental cellular processes, including carcinogenesis. The potential utilization of aberrantly expressed miRNAs as novel biomarkers in cervical cancer diagnostics is growing. We investigated miRNA expression profiles during the progression of dysplasia in cervical epithelium to identify aberrantly expressed miRNAs. High-throughput miRNA profiling of high-grade precancerous lesions identified 79 miRNAs showing significant difference in expression values compared to normal cervical epithelium. Ten selected miRNAs were subsequently measured in an independent group of samples to validate them as promising biomarkers of cervical carcinogenesis. MicroRNAs miR-10b-5p, miR-34c-5p, miR-409-3p and miR-411-5p were confirmed as downregulated, while miR-10a-5p, miR-132-3p, miR-141-5p were significantly upregulated in dysplastic cervical tissues. Further investigation revealed an inverse correlation of miR-409-3p with E6 mRNA levels in precancerous cervical lesions. Subsequent in vitro analyses showed a direct involvement of this miRNA in the regulation of E6 oncogene levels, thus confirming a potential tumor suppressor function of miR-409-3p in cervical malignancies. Hence, miR-409-3p may represent a useful early marker and a potential therapeutic target for cervical cancer.

A Novel Approach to Preoperative Risk Stratification in Endometrial Cancer: The Added Value of Immunohistochemical Markers.

Background: The current model used to preoperatively stratify endometrial cancer (EC) patients into low- and high-risk groups is based on histotype, grade, and imaging method and is not optimal. Our study aims to prove whether a new model incorporating immunohistochemical markers, L1CAM, ER, PR, p53, obtained from preoperative biopsy could help refine stratification and thus the choice of adequate surgical extent and appropriate adjuvant treatment. Materials and Methods: The following data were prospectively collected from patients operated for EC from January 2016 through August 2018: age, pre- and post-operative histology, grade, lymphovascular space invasion, L1CAM, ER, PR, p53, imaging parameters obtained from ultrasound, CT chest/abdomen, final FIGO stage, and current decision model (based on histology, grade, imaging method). Results: In total, 132 patients were enrolled. The current model revealed 48% sensitivity and 89% specificity for high-risk group determination. In myometrial invasion >50%, lower levels of ER (p = 0.024), PR (0.048), and higher levels of L1CAM (p = 0.001) were observed; in cervical involvement a higher expression of L1CAM (p = 0.001), lower PR (p = 0.014); in tumors with positive LVSI, higher L1CAM (p = 0.014); in cases with positive LN, lower expression of ER/PR (p < 0.001), higher L1CAM (p = 0.002) and frequent mutation of p53 (p = 0.008). Cut-offs for determination of high-risk tumors were established: ER <78% (p = 0.001), PR <88% (p = 0.008), and L1CAM ≥4% (p < 0.001). The positive predictive values (PPV) for ER, PR, and L1CAM were 87% (60.8-96.5%), 63% (52.1-72.8%), 83% (70.5-90.8%); the negative predictive values (NPV) for each marker were as follows: 59% (54.5-63.4%), 65% (55.6-74.0%), and 77% (67.3-84.2%). Mutation of p53 revealed PPV 94% (67.4-99.1%) and NPV 61% (56.1-66.3%). When immunohistochemical markers were included into the current diagnostic model, sensitivity improved (48.4 vs. 75.8%, p < 0.001). PPV was similar for both methods, while NPV (i.e., the probability of extremely low risk in negative test cases) was improved (66 vs. 78.9%, p < 0.001). Conclusion: We proved superiority of new proposed model using immunohistochemical markers over standard clinical practice and that new proposed model increases accuracy of prognosis prediction. We propose wider implementation and validation of the proposed model.