AKR1C3 Is Associated with Better Survival of Patients with Endometrial Carcinomas.

The aldo-keto reductase (AKR) superfamily is gaining attention in cancer research. AKRs are involved in important biochemical processes and have crucial roles in carcinogenesis and chemoresistance. The enzyme AKR1C3 has many functions, which include production of prostaglandins, androgens and estrogens, and metabolism of different chemotherapeutics; AKR1C3 is thus implicated in the pathophysiology of different cancers. Endometrial and ovarian cancers represent the majority of gynecological malignancies in developed countries. Personalized treatments for these cancers depend on identification of prognostic and predictive biomarkers that allow stratification of patients. In this study, we evaluated the immunohistochemical (IHC) staining of AKR1C3 in 123 paraffin-embedded samples of endometrial cancer and 99 samples of ovarian cancer, and examined possible correlations between expression of AKR1C3 and other clinicopathological data. The IHC expression of AKR1C3 was higher in endometrial cancer compared to ovarian cancer. In endometrioid endometrial carcinoma, high AKR1C3 IHC expression correlated with better overall survival (hazard ratio, 0.19; 95% confidence interval, 0.06-0.65, p = 0.008) and with disease-free survival (hazard ratio, 0.328; 95% confidence interval, 0.12-0.88, p = 0.027). In patients with ovarian cancer, there was no correlation between AKR1C3 IHC expression and overall and disease-free survival or response to chemotherapy. These results demonstrate that AKR1C3 is a potential prognostic biomarker for endometrioid endometrial cancer.

Office hysteroscopy in removing retained products of conception - a highly successful approach with minimal complications.

Data of 101 patients with retained products of conception (RPOC), treated with office hysteroscopy (OH) from 2012 to 2015 at the University Medical Centre Ljubljana were analysed. Patients with >30 mm RPOC thickness or strong vascularisation on ultrasound (US) were excluded. Procedures were successfully completed in 94/101 (93%). Mean duration was 18 min (4-60), patient pain estimation with VAS was 2.3 (0-8). No intraoperative complications > Grade II according to Clavien-Dindo classification occurred. Uncompleted cases were safely referred to procedures in general anaesthesia. Follow-up after one month was performed in 78/101 (77%) patients with OH (69) or US (9). Only three patients reported endometritis, three cases of intrauterine adhesions were related to curettage or pre-existing adhesions. We compared preoperative findings of completed and uncompleted cases. Larger size of RPOC and the presence of irregular tissue-myometrial border on US was statistically significantly higher in uncompleted OH (p<.05); mild vascularisation and ß-hCG levels up to 80 U/L did not affect the outcome.Impact statementWhat is already known on this subject? In the last three decades research has focussed on comparing hysteroscopic resection (HR) to traditional dilation and curettage in removing retained products of conception (RPOC). Office hysteroscopy (OH) without hospitalisation or general anaesthesia enables women to return to their daily routine immediately (especially desired by breastfeeding mothers) and is used where available, yet there is little published data to evaluate its role in the management of RPOC.What do the results of this study add? To the best of our knowledge, this article is unique in addressing success, safety and possible limiting factors of OH in removing placental polyps. According to our findings, OH is highly successful (93%), safe, and well tolerated in removing RPOC up to 30 mm in thickness and with no or minimal vascularisation on ultrasound. Thorough follow-up (68% with OH, 9% with US after 1 month) adds to strength of data.What are the implications of these findings for clinical practice and/or further research? Removing large and vascularised RPOC can be a very demanding procedure, yet a majority of patients might benefit from an outpatient approach. Prospective studies on limiting factors and more data on long term reproductive outcomes are needed to fully compare OH to other methods of removal.

Presence and role of stem cells in ovarian cancer.

Ovarian cancer is the deadliest gynecological malignancy. It is typically diagnosed at advanced stages of the disease, with metastatic sites disseminated widely within the abdominal cavity. Ovarian cancer treatment is challenging due to high disease recurrence and further complicated pursuant to acquired chemoresistance. Cancer stem cell (CSC) theory proposes that both tumor development and progression are driven by undifferentiated stem cells capable of self-renewal and tumor-initiation. The most recent evidence revealed that CSCs in terms of ovarian cancer are not only responsible for primary tumor growth, metastasis and relapse of disease, but also for the development of chemoresistance. As the elimination of this cell population is critical for increasing treatment success, a deeper understanding of ovarian CSCs pathobiology, including epithelial-mesenchymal transition, signaling pathways and tumor microenvironment, is needed. Finally, before introducing new therapeutic agents for ovarian cancer, targeting CSCs, accurate identification of different ovarian stem cell subpopulations, including the very small embryonic-like stem cells suggested as progenitors, is necessary. To these ends, reliable markers of ovarian CSCs should be identified. In this review, we present the current knowledge and a critical discussion concerning ovarian CSCs and their clinical role.

Cancer Stem Cell-Related Marker NANOG Expression in Ovarian Serous Tumors: A Clinicopathological Study of 159 Cases.

OBJECTIVE: The objectives of this study were to assess cancer stem cell-related marker NANOG expression in ovarian serous tumors and to evaluate its prognostic significance in relation to ovarian serous carcinoma. METHODS: NANOG protein expression was immunohistochemically evaluated in the ovarian tissue microarrays of 20 patients with benign ovarian serous tumors, 30 patients with borderline ovarian serous tumors, and 109 patients with ovarian serous carcinomas, from which 106 were of high-grade and 3 of low-grade morphology Immunohistochemical reaction was scored according to signal intensity and the percentage of positive cells in tumor samples. Pursuant to our summation of signal intensity and positive cell occurrence, we divided our samples into 4 groups: NANOG-negative, NANOG-slightly positive, NANOG-moderately positive, and NANOG-strongly positive group. Complete clinical data were obtained for the ovarian serous carcinoma group, and correlation between clinical data and NANOG expression was analyzed. RESULTS: A specific brown nuclear, or cytoplasmic reaction, was considered a positive NANOG staining. In terms of the ovarian serous carcinoma group, 69.7% were NANOG positive, 22.9% slightly positive, 22.9% moderately positive, and 23.9% strongly positive. All NANOG-positive cases were of high-grade morphology. Benign and borderline tumors and low-grade serous carcinomas were NANOG negative. There was no significant correlation between NANOG expression and clinical parameters in terms of the ovarian serous carcinoma group. CONCLUSIONS: Positive NANOG expression is significantly associated with high-grade ovarian serous carcinoma and is absent in benign, borderline, and low-grade serous lesions. In our study, there was no correlation between NANOG expression and clinical parameters, including its use in the prognosis of ovarian serous carcinoma.

Putative stem cells and epithelial-mesenchymal transition revealed in sections of ovarian tumor in patients with serous ovarian carcinoma using immunohistochemistry for vimentin and pluripotency-related markers.

BACKGROUND: The mechanism of aggressive character of ovarian cancer and unsuccessful treatment of women with this deadly disease has been recently explained by the theory of cancer stem cells (CSCs). It has been reported that ovarian carcinogenesis and progression of disease is associated with epithelial-mesenchymal transition (EMT). EMT, a physiological cell process during embryonic development and later in life during regeneration, could, when induced in pathological condition, generate CSCs-like cells. Until now EMT in the ovarian tissue has been mainly studied in cell cultures in vitro. The aim of this study was to focus on in situ morphological changes in the ovarian surface epithelium of tumor tissue in women with epithelial ovarian cancer after we applied the antibodies for markers of EMT vimentin and pluripotency-related markers NANOG, SOX2 and SSEA-4. METHODS: We analyzed ovarian tissue sections of 20 women with high grade serous ovarian carcinoma. After eosin and hematoxylin staining, used in standard practice, immunohistochemistry was performed for vimentin and markers of pluripotency: NANOG, SSEA-4 and SOX2. We focused on the ovarian surface epithelium in order to observe morphological changes in tumor tissue. RESULTS: Among epithelial cells of the ovarian surface epithelium in women with serous ovarian carcinoma we observed a population of small NANOG-positive cells with diameters of up to 5 µm and nuclei, which filled almost the entire cell volumes. These small NANOG-positive cells were in some cases concentrated in the regions with morphologically changed epithelial cells. In these regions, a population of bigger round cells with diameters of 10-15 µm with large nuclei, and positively stained for vimentin, NANOG and other markers of pluripotnecy, were released from the surface epithelium. These cells are proposed as CSCs, and possibly originate from small stem cells among epithelial cells. They formed typical cell clusters, invaded the tissue by changing their round shape into a mesenchymal-like phenotype, and contributed to the manifestation of ovarian cancer. CONCLUSIONS: Our findings show morphological changes in the ovarian surface epithelium in tumor slides of high grade serous ovarian carcinoma and provide a new population of putative CSCs.

Small putative NANOG, SOX2, and SSEA-4-positive stem cells resembling very small embryonic-like stem cells in sections of ovarian tissue in patients with ovarian cancer.

BACKGROUND: In previous studies it has been found that in cell cultures of human adult ovaries there is a population of small stem cells with diameters of 2-4 µm, which are present mainly in the ovarian surface epithelium and are comparable to very small embryonic-like stem cells (VSELs) from bone marrow. These cells are not observed by histopathologists in the ovarian tissue due to their small size and unknown clinical significance. Because these cells express a degree of pluripotency, they might be involved in the manifestation of ovarian cancer. Therefore we studied the ovarian tissue sections in women with borderline ovarian cancer and serous ovarian carcinoma to perhaps identify the small putative stem cells in situ. METHODS: In 27 women with borderline ovarian cancer and 20 women with high-grade serous ovarian carcinoma the ovarian tissue sections were stained, per standard practice, with eosin and hematoxylin staining and on NANOG, SSEA-4 and SOX2 markers, related to pluripotency, using immunohistochemistry. We focused on the presence and localization of small putative stem cells with diameters of up to 5 µm and with the nuclei spread over nearly the full cell volume. RESULTS: In ovarian sections of both borderline ovarian cancer and serous ovarian carcinoma patients we were able to identify the presence of small round cells complying with the above criteria. Some of these small cells were NANOG-positive, were located among epithelial cells in the ovarian surface epithelium and as a single cell or groups of cells/clusters in typical "chambers", were found only in the presence of ovarian cancer and not in healthy ovaries and are comparable to those in fetal ovaries. We envision that these small cells could be related to NANOG-positive tumor-like structures and oocyte-like cells in similar "chambers" found in sections of cancerous ovaries, which could support their stemness and pluripotency. Further immunohistochemistry revealed a similar population of SSEA-4 and SOX2-positive cells. CONCLUSIONS: We may conclude that putative small stem cells expressing markers, related to pluripotency, are present in the ovarian tissue sections of women with borderline ovarian cancer and high-grade serous ovarian carcinoma thus indicating their potential involvement in ovarian cancer.

Does hysteroscopic metroplasty for septate uterus represent a risk factor for adverse outcome during pregnancy and labor?

The aim of the study was to evaluate whether hysteroscopic metroplasty for septate uterus represents a risk factor of adverse outcome in pregnancy, during labor, and after delivery. This is a retrospective comparative study of obstetric complications of 99 patients who underwent hysteroscopic metroplasty in a 5-year period (study group) and 4155 women, who gave birth in the same hospital in the same period (control group). No difference in obstetric outcome (preterm labor, hemorrhage before and after delivery, mean weeks of gestation at delivery, mean birth weight, breech presentation, and cesarean section rate) between the two groups has been found. The results of this study suggest that patients who underwent hysteroscopic metroplasty for septate uterus are at no higher risk of adverse obstetric outcome at term and during labor, comparing to the general population. Though vaginal delivery seems to be safe, rare but serious complication, reported by several studies, like uterine rupture during pregnancy or labor, should always be taken into consideration.

No clinical relevance of the height of fundal indentation in subseptate or arcuate uterus: a prospective study.

The American Fertility Society has classified the arcuate uterus as a minor malformation with a benign clinical behaviour. The aim of this prospective study was to verify whether there is any scientific basis for this differentiation. Patients with at least one early miscarriage and a subseptate or arcuate uterus were admitted for hysteroscopic metroplasty. Patients were allocated to a subseptate uterus group, with an indentation of 1.5 cm or more, or an arcuate uterus group, with a smaller indentation. The miscarriage rates after metroplasty were similar between the two groups (14.0% in the subseptate uterus group versus 11.1% in the arcuate uterus group). Before metroplasty, the miscarriage rates were significantly higher in subseptate uterus group, as well as in the arcuate uterus group (both P<0.001). According to these results, there is no evidence to support that the arcuate uterus has a different effect on the reproductive outcome in comparison to the subseptate uterus, neither before nor after surgical correction of the anomaly. Since there is no scientific basis for a separate classification of the arcuate uterus, a review of the classifications of uterine congenital anomalies should be considered as necessary. Congenital uterine malformations have been classified by the American Fertility Society (AFS) since 1988. Although the AFS classification received wide acceptance and is still the most broadly used system, it is associated with various limitations in effective categorization of the anomalies. It is interesting that, until now, none of the other available options have been able to effectively replace the AFS system. Numerous papers indicate septate or subseptate (partial septate) uterus (AFS class V) is a possible cause of an unfavourable pregnancy outcome. Arcuate uterus (AFS class VI), a slight malformation similar to septate uterus, should differ from septate or subseptate uterus, because this 'minor' malformation should behave benignly with respect to the septate uterus. The aim of this study was to scientifically validate the difference between the arcuate and subseptate uterus in their effect on reproductive outcome through the results of a metroplasty in both groups of patients. A group of 96 patients, who underwent metroplasty after at least one early miscarriage, was divided into two groups according to the severity of the congenital uterine malformation. Our results indicate that there are no differences in pregnancy outcome after metroplasty either in patients with septate or arcuate utera. The poor pregnancy outcome in women with septate uterus seems not to be correlated to the dimension of the septum itself. There are no scientific bases for a separate classification of the arcuate uterus and it is proposed that a review of the classification of uterine congenital anomalies is necessary.

Possible role of endometriosis in the aetiology of spontaneous miscarriage in patients with septate uterus.

A recent study found a significant correlation between endometriosis and non-obstructive forms of Müllerian anomalies. Other studies described an increased miscarriage rate in patients with endometriosis. This study assessed the effect of endometriosis on pregnancy outcome in a group of patients with endometriosis and septate uterus. Spontaneously achieved pregnancies were taken into consideration. The outcome of 179 infertile women who underwent surgery for septate uterus was analysed in a retrospective study. Stage I or II endometriosis was found by laparoscopy in 36 patients. The pregnancy outcomes, before and after metroplasty, of the group of 36 patients with septum and endometriosis were compared with the pregnancy outcomes of 143 patients with septate uterus with no endometriosis. Before metroplasty the incidence of pregnancy loss was 67% in patients without endometriosis and 75% in patients with endometriosis and the difference was not significant. After metroplasty, no significant differences have been found between the two groups, suggesting that endometriosis could be an occasional finding not influencing pregnancy outcome.