9-oxo-ODAs suppresses the proliferation of human cervical cancer cells through the inhibition of CDKs and HPV oncoproteins.

Mucosal human papillomavirus (HPV) subtypes 16 and 18 are causative agents of cervical cancer, a leading cause of cancer-related deaths among women worldwide. In Japan, eggplant calyx is a folk remedy used to treat common warts. 9-oxo-(10E,12E)-octadecadienoic acid, isolated from eggplant calyx, may have antitumor effects. This study investigated the antitumor effects of 9-oxo-(10E, 12Z)-octadecadienoic acid and 9-oxo-(10E,12E)-octadecadienoic acid (9-oxo-ODAs) on human cervical cancer cells. 9-oxo-ODAs suppressed the proliferation of human cervical cancer cell lines (HeLa, and SiHa) in a concentration-dependent manner (IC50 = 25-50 µM). FCM analysis revealed that 9-oxo-ODAs induced apoptosis. Transcriptome, proteomics, and enrichment analyses revealed that treatment with 9-oxo-ODAs significantly altered the cell cycle and p53 pathways and decreased cyclin-dependent kinase 1 (CDK1) protein expression. Real-time PCR analysis demonstrated that 9-oxo-ODAs reduced CDK1 mRNA expression in a concentration-dependent manner. In vitro, 9-oxo-ODAs reduced the HPV oncoprotein expression. In ex vivo human cervical cancer tissues, 9-oxo-ODAs decreased CDK1 expression and increased cleaved caspase 3, an apoptosis marker. Further, 9-oxo-ODAs showed the potential to suppressed metastatic formation and growth of cervical cancer in vivo. These findings suggest that 9-oxo-ODAs induce cell cycle arrest and apoptosis in HPV-positive human cervical cancer cells, and this process involves CDK1. Consequently, 9-oxo-ODAs may be potential therapeutic agents for cervical cancer.

The balance between fetal oxytocin and placental leucine aminopeptidase (P-LAP) controls human uterine contraction around labor onset.

A fetal pituitary hormone, oxytocin which causes uterine contractions, increases throughout gestation, and its increase reaches 10-fold from week 32 afterward. Oxytocin is, on the other hand, degraded by placental leucine aminopeptidase (P-LAP) which exists in both terminal villi and maternal blood. Maternal blood P-LAP increases with advancing gestation under the control of non-genomic effects of progesterone, which is also produced from the placenta. Progesterone is converted to estrogen by CYP17A1 localized in the fetal adrenal gland and placenta at term. The higher oxytocin concentrations in the fetus than in the mother demonstrate not only fetal oxytocin production but also its degradation and/or inhibition of leakage from fetus to mother by P-LAP. Until labor onset, the pregnant uterus is quiescent possibly due to the balance between increasing fetal oxytocin and P-LAP under control of progesterone. A close correlation exists between the feto-placental and maternal units in the placental circulation, although the blood in the two circulations does not necessarily mix. Fetal maturation results in progesterone withdrawal via the CYP17A1 activation accompanied with fetal oxytocin increase. Contribution of fetal oxytocin to labor onset has been acknowledged through the recognition that the effect of fetal oxytocin in the maternal blood is strictly regulated by its degradation by P-LAP under the control of non-genomic effects of progesterone. In all senses, the fetus necessarily takes the initiative in labor onset.

Crosstalk between foetal vasoactive peptide hormones and placental aminopeptidases regulates placental blood flow: Its significance in preeclampsia.

In pregnancy, placental circulation occurs through two independent circulation systems: foetoplacental and uterine (spiral artery)-placental lake. Crosstalk between the foetal peptide hormones, angiotensin II (A-II) and vasopressin (AVP), and their degrading placental aminopeptidases (APs), aminopeptidase A for A-II and placental leucine aminopeptidase for both AVP and oxytocin, primarily regulate placental circulation. On the other hand, placental circulation represents an arteriovenous shunt. In normal pregnancy, the blood pressure decreases, despite increased cardiac output and plasma volume, probably due to the arteriovenous shunt in the growing placenta. Actually, the foetal vasoactive hormones in the foetoplacental circulation are much higher than those in the maternal circulation throughout pregnancy. In normal pregnancy, AP activity derived from the placenta in maternal blood increases with gestation and placental growth. Foetal hypoxia increases the secretion of foetal both AVP and A-II. Although there is an increase in both AP activities in the maternal blood in normal pregnancy, their activities increase more than those in normal pregnancy during mild preeclampsia. However, both AP activities decline significantly compared than those in severe preeclampsia. This suggests that AP prevents leakage of increased foetal vasoactive hormones into the maternal blood in mild preeclampsia, and its protective role breaks down in severe preeclampsia, leading to a massive leak of the hormones into maternal circulation and consequent marked contraction of both the maternal vessels and the uterus. Consequently, AP activity in both placenta and maternal blood acts as the foeto-maternal barrier for foetal vasoactive hormones and thus contributes to the onset of preeclampsia.

A case of ovarian serous cystadenofibroma with scattered lesions in pelvic cavity, like malignant disseminations.

Ovarian serous cystadenofibroma is a relatively rare subtype of serous cystadenoma classified as ovarian benign epithelial tumor. We report a rare case of ovarian serous cystadenofibroma with scattered lesions in pelvic cavity, like malignant disseminations. The patient was 22 years old, gravida 0, para 0. In the laparoscopic surgery, numerous hard yellowish-white solid masses of various sizes were present in the bilateral ovaries. Grossly similar masses were scattered in the fimbria of the fallopian tubes, peritoneum, and great omentum. Because the intraoperative rapid histological diagnosis was benign tumor, surgery was completed for only tumor excision. Postoperative histopathological diagnosis is serous cystadenofibroma. Similar pathological findings were noted in the scattered lesions in the peritoneum and great omentum. No malignant or borderline malignant finding was observed. Because of a benign disease, careful treatment taking fertility preservation into consideration is necessary, especially for young patients.

Extracellular miRNAs as Predictive Biomarkers for Glypican-3-Derived Peptide Vaccine Therapy Response in Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC) has been treated with surgery and chemotherapy; however, the prognosis remains poor because of chemoresistance. Therefore, immunotherapies are attracting attention, including the GPC3 peptide vaccine, which improves overall survival. However, the response rate is limited and there are no sufficient predictive biomarkers that can identify responders before treatment. Our purpose was to identify circulating serum miRNAs as predictive biomarkers for response to GPC3 peptide vaccine. Eighty-four patients in a phase II trial of a GPC3 peptide vaccine were enrolled and miRNA sequencing was performed on their serum samples. Candidate miRNAs were selected from a group of 14 patients for whom treatment was responsive and validated in an independent group of 10 patients for whom treatment was responsive. Three markedly upregulated miRNAs, miR-375-3p, miR-193a-5p, and miR-1228-5p, were identified, and the combination of those miRNAs demonstrated high value in the prediction of the response. The origin of these miRNAs was assessed by referring to OCCC tissue miRNA profiles, and they were not identified as cancer tissue-related miRNAs. Functional annotation analysis suggested that they were associated with interferon-related pathways. The miRNAs identified herein have great potential to allow the realization of liquid biopsy for predicting the immunotherapy response and precision medicine.

[Cooperative Surgery with Gastroenterological Surgeons in Gynecologic Malignant Tumors].

Secondary debulking surgery(SDF)for gynecologic malignancies may improve prognosis. However, recurrent lesions may be invasions of the intestinal tract and observed peritoneal dissemination. SDF can be safely carried out by performing cooperative surgery with a gastroenterological surgeon and gynecologists. Precise cooperation is indispensable for the operation, especially when it comes to aspects such as the contact method and perioperative management at that time. In our hospital, if the gynecologist suspects other organs invasion during a preoperative examination, they contact the gastroenterological surgeon in an elective manner. If other organs invasion is not clear during a preoperative examination or bowel injury occurs during surgery, the gastroenterological surgeon would be contacted urgently. To ensure smooth cooperation, it is necessary to run regular joint conferences. By sharing in planned and combining the expertise of all the department of interest, it is possible to perform highly curative and safe surgery.

Placental Leucine Aminopeptidase as a Potential Specific Urine Biomarker for Invasive Ovarian Cancer.

BACKGROUND: A non-invasive and sensitive biomarker for the detection of ovarian cancer (OvCa) is lacking. We aim to investigate if urinary placental leucine aminopeptidase (P-LAP) can serve as a reliable biomarker for OvCa. METHODS: P-LAP activity was measured using a LAP assay kit (Serotech Co., Ltd., Sapporo, Japan) in the urine of 22 patients with benign or borderline malignant ovarian tumors and 18 patients with OvCa. In this assay, L-methionine was added at 20 mM because P-LAP is functional, but other aminopeptidases are inhibited at this dose of L-methionine. RESULTS: The mean urinary P-LAP activity was significantly higher in the OvCa group than in the benign or borderline malignant tumor group. When the cut-off value of P-LAP was determined as 11.00 U/L, its sensitivity and specificity for differentiating invasive cancer were 77.8% and 95.5%, respectively. CONCLUSION: Although the usefulness of this test should be confirmed in a larger cohort of cases and controls, our study is the first to highlight the importance of urinary P-LAP as a biomarker for OvCa.

The management of hydatidiform mole using prophylactic chemotherapy and hysterectomy for high-risk patients decreased the incidence of gestational trophoblastic neoplasia in Vietnam: a retrospective observational study.

The management of hydatidiform mole (HM) and the incidence of post-molar gestational trophoblastic neoplasia (GTN) in Vietnam has not been reported to date. This study aimed to study the incidence of HM and post-molar GTN and identify factors associated with post-molar GTN at a tertiary hospital in Vietnam. Five hundred and eighty-four patients who were treated for HM at Tu Du Hospital between January and December 2010 were included in this study. The mean age and gestational age at the first evacuation were 28.8 years old and 11.0 weeks, respectively. After the initial evacuation and pathological examination, 87 patients who were older than 40 or did not wish to have children underwent a hysterectomy, while the others underwent second curettage. All 472 patients who had human chorionic gonadotropin (hCG) ≥ 100,000 IU/L before treatment received one cycle of methotrexate with folinic acid as prophylactic chemotherapy. The incidence of HM was 11.1 per 1,000 deliveries; 47 patients (8.0%) developed post-molar GTN. Gestational week, hCG level at one week after the first evacuation, and pathological remnants were significantly associated with the development of post-molar GTN. The results of this study suggest that prophylactic chemotherapy and hysterectomy may be useful for high-risk HM patients to reduce post-molar GTN in settings in which the risk of post-molar GTN and loss to follow-up after HM are greater and hCG measurements and appropriate GTN treatments are unavailable. However, future studies on the long-term outcomes and side effects of prophylactic therapies on HM are required.

Pegylated Liposomal Doxorubicin/Oxaliplatin Chemotherapy Can Overcome Cisplatin Resistance in Spectrin αII-Overexpressing Ovarian Carcinoma.

BACKGROUND: Spectrin αII contributes to cisplatin and carboplatin resistance in ovarian serous carcinoma cells, and its expression in surgical specimens is a valid predictor of prognosis. We sought to identify effective drugs for spectrin αII-mediated cisplatin-resistant cells. MATERIALS AND METHODS: We employed SKOV3 cells with small interfering RNA-mediated spectrin αII downregulation, serous carcinoma cells (NOS2), cisplatin-resistant cells (NOS2CR2), and oxaliplatin-resistant cells (NOS2OXR). RESULTS: In the drug-sensitivity test, oxaliplatin was not affected by the inhibition of spectrin αII expression and was effective for cisplatin-resistant NOS2CR2 cells. NOS2OXR cells did not express higher levels of spectrin αII compared to NOS2 in western blot analysis. Six non-platinum anticancer drugs were not affected by the inhibition and was effective for resistant NOS2CR2 and NOS2OXR cells. Doxorubicin exhibited potent cytotoxicity at 2 µM against both resistant cell lines. CONCLUSION: Pegylated liposomal doxorubicin/oxaliplatin regimen may be effective for cisplatin-resistant ovarian carcinoma with spectrin αII-overexpression.

The Therapeutic Effects of Goreisan, a Traditional Japanese Herbal Medicine, on Lower-Limb Lymphedema after Lymphadenectomy in Gynecologic Malignancies: A Case Series Study.

BACKGROUND: Lower-limb lymphedema (LLL) is a chronic and progressive complication of gynecologic cancer treatment, including pelvic lymphadenectomy. This study aims to investigate the therapeutic effect of goreisan, a traditional Japanese medicine, which has been used for hydrostatic modulation on patients with LLL. METHODS: Patients diagnosed with LLL in our hospital in 2018 were included and principally treated with complex decongestive therapy (CDT), including elastic clothing and lymph drainage. The patients who received a combination therapy of CDT and goreisan (CDT-G group) were prescribed goreisan extract granules, with a dose of 7.5 g per os daily in three doses. Patients who were not prescribed goreisan received CDT alone (CDT group). The severity of lymphedema was evaluated by the estimated limb volume calculated by limb circumferences and the ratio of extracellular water (ECW) to total body water (TBW). RESULTS: Nineteen women with LLL after pelvic lymphadenectomy were included in the study. The number of patients in the CDT and CDT-G groups was 8 and 11, respectively. There were no statistically significant differences between the CDT and CDT-G groups in terms of patient characteristics and severity of LLL before treatment. Reduction in ECW/TBW in the CDT-G group (in the whole body and the affected lower limb) after the intervention was significantly more remarkable than that in the CDT group. CONCLUSIONS: Goreisan-based Japanese herbal therapy may be effective in patients with LLL after retroperitoneal lymphadenectomy.

The impact of systematic retroperitoneal lymphadenectomy on long-term oncologic outcome of women with advanced ovarian clear-cell carcinoma.

OBJECTIVE: The impact of systematic retroperitoneal lymphadenectomy (SRL) remains controversial in patients with advanced ovarian clear-cell carcinoma (CCC) who are optimally debulked. METHODS: Between 1986 and 2017, a total of 3,227 women with epithelial ovarian carcinoma were analyzed in a multi-institutional study. Among them, 166 optimally debulked women with stage IIB-IV CCC were collected (residual tumor of <1 cm). All patients were divided into 2 groups: 1) Group I (n=112): underwent standard radical surgery with SRL, 2) Group II (n=54): underwent non-staging limited surgery. The pathological slides were assessed based on central pathological review. Oncologic outcomes were compared between the two groups using a propensity score (PS)-matching technique to adjust for various clinicopathologic factors. RESULTS: The median follow-up duration of all surviving women was 52.8 (1.6-184.2) months. Overall, 88 patients (53.0%) experienced recurrence and 68 patients (41.0%) died of the disease. In the original cohort, the 5-year overall survival (OS) rates of groups I and II were 57.9 and 64.9%, respectively (log-rank p=0.415). In the PS-adjusted cohort, the 5-year OS rates were 64.9 and 58.8% in women in groups I and II, respectively (p=0.453). Furthermore, in the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in OS between the 2 groups (group I vs. group II; hazard ratio=1.170; 95% confidence interval=0.633-2.187; p=0.615). CONCLUSIONS: This study suggests that the performance of SRL including radical surgery may not lead to a significant improvement in the oncologic outcome of advanced CCC patients with optimal cytoreduction.

Ovarian cancer-associated mesothelial cells induce acquired platinum-resistance in peritoneal metastasis via the FN1/Akt signaling pathway.

Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell-to-cell crosstalk or phenotypic alterations including the acquisition of platinum-resistance in OvCa cells. Herein, we report how OvCa-associated mesothelial cells (OCAMs) induce platinum-resistance in OvCa cells through direct cell-to-cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro coculturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF-ß1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum-sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell-to-cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that are supposed to originate from MCs. Further, we also confirmed the activation of Akt signaling in OvCa cells in contact with TGF-ß1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell-to-cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum-resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.

New insights into human endometrial aminopeptidases in both implantation and menstruation.

The endometrium cycle involves proliferation of endometrial epithelial cells in preparation for implantation of fertilized ovum. With ovulation, the endometrium secretes nutrients such as peptides and amino acids into the endometrial cavity. The histological evidence of ovulation in normal menstrual cycle includes subnuclear glycogen vacuoles surrounded by placental leucine aminopeptidase (P-LAP) in endometrial epithelial cells. P-LAP is an essentially involved in intracellular trafficking of glucose transporter (GLUT) 4 which is primarily important for glucose uptake in skeletal muscles and fat tissues. On the other hand, glucose influx from blood into endometrial epithelial cells is not mainly mediated by GLUTs, but by coincident appearing progesterone just after ovulation. Progesterone increases permeability of not only plasma membranes, but also lysosomal membranes, and this may be primarily involved in glucose influx. Progesterone also expands the exocytosis in the endometrium after ovulation, and endometrial secretion after ovulation is possibly apocrine and holocrine, which is augmented and exaggerated exocytosis of the lysosomal contents. The endometrial spiral arteries/arterioles are surrounded by endometrial stromal cells which are differentiated into decidual/pre-decidual cells. Decidual cells are devoid of aminopeptidase A (APA), possibly leading to enhancement of Angiotensin-II action in decidual cell area due to loss of its degradation by APA. Angiotensin-II is thought to exert growth-factor-like effects in post-implantation embryos in decidual cells, thereby contributing to implantation. Without implantation, angiotensin-II constricts the endometrial spiral arteries/arterioles to promote menstruation. Thus, P-LAP and APA may be involved in homeostasis in uterus via regulating glucose transport and vasoconstrictive peptides.

Is standard radical surgery necessary for elderly patients with early-stage epithelial ovarian carcinoma? ~Propensity score matched analysis~.

OBJECTIVE: The impact of 'standard full-staged radical surgery (SRS)' on overall survival (OS) in elderly patients with early-stage epithelial ovarian cancer (EOC) remains unclear. In the current study, we investigated the impact of SRS on OS in elderly patients with early-stage EOC in a multicentric analysis using a propensity score (PS)-matching technique. METHODS: Between 1986 and 2017, 3227 patients with EOC were registered and accumulated by the Tokai Ovarian Tumor Study Group, consisting of 14 collaborating institutions, after a central pathological review. Among them, 204 elderly patients aged older than or equal to 65 years who had a stage I EOC were analyzed, including 72 patients who had received SRS (Group I) and 132 who had undergone non-SRS limited surgery (Group II). Oncologic outcomes were compared between the two groups using a PS-matching technique to adjust for various clinicopathologic risk factors. RESULTS: The median follow-up duration of all surviving patients was 55.9 months. Consequently, 54 patients (26.5%) developed recurrence. In addition, 33 patients (16.2%) died of the disease. In the original cohort, the 5-year OS rates of Groups I and II were 95.8 and 82.3%, respectively. We identified a marginally significant difference between the two groups (Log-rank: P = 0.086). In the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in OS between the two groups [OS (Group I vs. II), HR: 0.766 (95% CI: 0.271-2.165), P = 0.615]. CONCLUSIONS: After adjustment for clinicopathologic factors, non-SRS limited surgery may not worsen the oncologic outcome in elderly women with early-stage EOC. A large-scale clinical study is necessary to validate the findings.

Clinical Significance of Ubiquitin-associated Protein 2-like in Patients With Uterine Cervical Cancer.

BACKGROUND: Ubiquitin-associated protein 2-like (UBAP2L) has been demonstrated to be associated with the progression of multiple types of cancer. However, the function of UBAP2L in uterine cervical cancer remains unclear. MATERIALS AND METHODS: Between 2005 and 2015, 84 patients who underwent surgery were included in this study. The patients were stratified into two groups on the basis of immunohistochemical staining for UBAP2L, and survival analysis was performed. Moreover, loss-of-function analysis was performed using the cervical cancer cell lines CaSki and SiHa. RESULTS: Based on immunohistochemistry, the overall survival in patients with low UBAP2L expression was significantly longer than that of those with high UBAP2L expression (p=0.045). The in vitro experiment revealed that knockdown of UBAP2L remarkably inhibited cell proliferation in both live cell imaging and the MTS assay. CONCLUSION: Patients with high UBAP2L expression had unfavorable prognosis and UBAP2L appears to play an important role in proliferation.

Fertility-sparing surgery and oncologic outcome among patients with early-stage ovarian cancer ~propensity score- matched analysis~.

BACKGROUND: The aim of this study was to investigate how much the risks of recurrence and death are increased as a consequence of selecting fertility-sparing surgery (FSS) in young women with epithelial ovarian cancer (EOC). METHODS: After a central pathological review and search of the medical records from 14 collaborating hospitals, a non-randomized, observational cohort study was conducted between 1987 and 2015, including 1183 women with stage I EOC. Finally, a total of 285 patients with stage I EOC at reproductive age were recruited. Oncologic outcomes were compared between the FSS (N = 101) and radical surgery (RS) group (N = 184) using a propensity score (PS)-matching technique to adjust for relevant risk factors: the age, substage, histological type, grade, CA125 values, ascites cytology, ascites volume, and chemotherapy. RESULTS: During 66.0 months (median) of follow-up, 42 patients (14.7%) developed recurrence, and 31 patients (10.9%) died. In the original cohort, there was no significant difference in overall survival (OS) or recurrence-free survival (RFS) between the FSS and RS groups {Log-rank: OS (P = 0.838), RFS (P = 0.377)}. In the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in RFS or OS between the FSS and RS groups {RFS (FSS vs. RS), HR: 1.262 (95% CI: 0.559-2.852), P = 0. 575; OS (FSS vs. RS), HR: 1.206 (95% CI: 0.460-3.163), P = 0.704}. CONCLUSIONS: After adjustment for clinicopathologic factors, FSS in itself may not worsen the oncologic outcome in young women with early-stage EOC. A large-scale clinical study is necessary to validate the findings.

Unique miRNA profiling of squamous cell carcinoma arising from ovarian mature teratoma: comprehensive miRNA sequence analysis of its molecular background.

Owing to its rarity, the carcinogenesis and molecular biological characteristics of squamous cell carcinoma arising from mature teratoma remain unclear. This study aims to elucidate the molecular background of malignant transformation from the aspects of microRNA (miRNA) profiling. We examined 7 patients with squamous cell carcinoma and 20 patients with mature teratoma and extracted their total RNA from formalin-fixed paraffin-embedded tissues. Then we prepared small RNA libraries and performed comprehensive miRNA sequencing. Heatmap and principal component analysis revealed markedly different miRNA profiling in cancer, normal ovarian and mature teratoma tissues. Then we narrowed down cancer-related miRNAs, comparing paired-cancer and normal ovaries. Comparisons of cancer and mature teratoma identified two markedly upregulated miRNAs (miR-151a-3p and miR-378a-3p) and two markedly downregulated miRNAs (miR-26a-5p and miR-99a-5p). In addition, these findings were validated in fresh cancer tissues of patient-derived xenograft (PDX) models. Moreover, several miRNAs, including miR-151a-3p and miR-378a-3p, were elevated in the murine plasma when tumor tissues were enlarged although miR-26a-5p and miR-99a-5p were not elucidated in the murine plasma. Finally, we performed target prediction and functional annotation analysis in silico and indicated that targets genes of these miRNAs markedly correlated with cancer-related pathways, including 'pathway in cancer' and 'cell cycle'. In conclusion, this is the first study on miRNA sequencing for squamous cell carcinoma arising from mature teratoma. The study identified four cancer-related miRNAs that were considered to be related to the feature of malignant transformation. Moreover, miRNAs circulating in the murine plasma of the PDX model could be novel diagnostic biomarkers.

Epidemiological overview of metastatic ovarian carcinoma: long-term experience of TOTSG database.

Malignant ovarian neoplasm is one of the most lethal malignancies among cancers of the female reproductive system. Occasionally, these tumors originate from non-ovarian organs as metastatic lesions since the ovary is a frequent metastatic target of many cancers. However, there limited clinical information on metastatic ovarian carcinoma (MOC) and its hallmarks are unknown. During the period of 1986-2015, 4,284 patients with malignant ovarian neoplasm were identified using the Tokai Ovarian Tumor Study Group (TOTSG) database. Of these, excluding borderline malignant tumor, 3,478 patients with malignant ovarian cancer were extracted. The pathological slides were evaluated under central pathological review. Among them, a total of 143 (4.1%) patients with MOC were identified. The median age of patients with MOC was 54 (29-82) years. The most and second most frequent original tumors were colorectal (43%, N=62) and gastric (29%, N=42) carcinoma, respectively. The rates of carcinoma of the appendix, breast, and pancreas were 8, 6, and 4%, respectively. This is the one of the largest studies clarifying the rates of MOC among malignant ovarian neoplasms. Although the rate is low, we should keep in mind that MOC, particularly from colorectal and gastric cancer should be considered when encountering clinical practice of ovarian cancer.

Long-term oncologic outcome and its prognostic indicators in reproductive-age women with ovarian clear-cell carcinoma.

BACKGROUND: Clear-cell carcinoma (CCC) in reproductive-age women is likely to become an increasingly critical issue regarding possibilities of infertility, hormonal dysfunction, and mortality. The aim of this study was to examine the long-term oncologic outcome and its prognostic indicators based on a multicentric cohort of young patients with CCC. PATIENTS AND METHODS: During the period of 1990-2015, a total of 164 patients aged 45-year-old or younger were enrolled in the study. Clinicopathologic data of these young patients with CCC collected under a centralized pathological review system were subjected to uni- and multivariable analyses to evaluate overall survival (OS). RESULTS: The median follow-up was 73.8 months (range 5.2-244.2) in the surviving patients. Among these patients, 104 (63.4%) had FIGO I disease, and 22 (13.4%), 31 (18.9%), and 7 (4.3%) had II, III, and IV disease, respectively. The 5-year OS rate was 74.5%. On stratification by the FIGO stage, the 5-year OS rates were as follows: stage I (90.2%), stage II (57.9%), and stage III/IV (39.3%), respectively (P < 0.0001). Confining analysis to stage I patients, there was no difference in OS between those who underwent fertility-sparing surgery and those who received radical surgery (P = 0.1593). In relapsed patients, the median survival after recurrence was 11.6 months. In multivariable analysis of stage I patients, the capsule status was an independent prognostic indicator of OS {IC2/IC3 vs. IA/IC1: HR 4.293 (95% CI 1.140-16.422), P = 0.0318}. CONCLUSION: CCC patients staged greater than IC2/IC3 show a markedly increased risk of mortality. Thus, it is important to diagnose patients staged under IC2/IC3.

Estrogen producing ovarian fibrosarcoma: A case report.

Fibrosarcoma is an extremely rare malignant sex-cord stromal tumor. Fibrosarcoma is generally unknown as an estrogen producing tumor. This report presents, for the first time, a case of estrogen producing ovarian fibrosarcoma in an 83-year-old female. We performed total hysterectomy, bilateral salpingo-oophorectomy and omentectomy. Histopathologically, the tumor of the left ovary had high cellularity, cellular atypia and 10-15 mitotic counts per 10 high power fields. The tumor contained small components composed of cells that were similar to Sertoli cells. In an effort to examine which component was producing estrogen, we checked aromatase expression; but both components were positive. We could not explain which component was producing estrogen. Postoperative clinical stage was IA. As she was geriatric patient, we did not recommend adjuvant chemotherapy. There were no signs of recurrence or increase in serum estradiol level at two years after the operation.