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Expression of CD24, phospho-Met, MDR-1 and MRP in cisplatin-treated EC xenogrft tumors

CD24 knocked down EC cells are more cisplatin-resistant

Figure legends of supplemental figure 1 - 5.

Endometrial cancer is the most prevalent gynecologic cancer in the Western world, and the number of advanced chemotherapy-resistant cancers is increasing with the absolute increase in patients. The development of resistance to chemotherapeutic drugs by cancer cells represents a major challenge in the clinical cure of advanced and metastatic cancers. CD24 has been reported to be a marker for a poor prognosis in several tumors, and we herein examined the functions of CD24 in human endometrioid adenocarcinoma cell lines and evaluated how it contributes to cancer drug resistance. We demonstrated that CD24 was responsible for the recruitment of phosphorylated Met to the lipid raft domain of the cell membrane, resulting in amplification of the Met signaling cascade, ultimately leading endometrial cancer cells to express higher levels of ATP-binding cassette (ABC) transporters. Our findings suggest that CD24-mediated amplification of the Met cascade may contribute to the drug resistance of endometrial cancer. Mol Cancer Ther; 14(10); 2353–63. ©2015 AACR.

Confirmation of CD24 overexpression in CD24 DNA construct transfected cells

To evaluate the impact on urodynamic results between the laparoscopic nerve-sparing radical hysterectomy (LRH) following a step-by-step procedure and abdominal nerve-sparing radical hysterectomy (ARH) for patients with uterine cervical cancer.This retrospective study enrolled 76 patients with cervical cancer: 35 in the LRH group and 41 in the ARH group. We analyzed their postoperative bladder function in a urodynamics study and examined the volume of resected pelvic nerves contained in parametrial sections using S-100 antibody staining.Estimated blood loss and hospital stay after operation for the LRH group were significantly better than those in the ARH group (p 0.0001). As well, the number of harvested lymph nodes was significantly higher in the LRH group (p = 0.044). There was no difference in perioperative complications between the two groups in this study. The 5-year disease-free survival rates and overall survival rates were 91.2% and 94.0% in the LRH group and 87.8% and 95.1% in the ARH group, both respectively. Although the median residual urine volume were no statistical differences between the LRH group and the ARH group, the recovery of postoperative bladder function (uroflowmetry) in the LRH group rapidly reached presurgery levels at 1 month, and the LRH group had a smaller number of s-100 antibody stained nerves contained the parametrial sections.We demonstrated that LRH following a step-by-step procedure could achieve a higher level of prevention of damage to the bladder branch of the pelvic splanchnic nerve plexus and thus restore bladder function more rapidly.

Background There is uncertainty surrounding the prognostic value of peritoneal cytology in low-risk endometrial cancer, especially in laparoscopic surgery. The objective of this retrospective study is to determine the prognostic significance of positive peritoneal cytology among patients with low-risk endometrial cancer and to compare it between laparoscopic surgery and conventional laparotomy. Methods From August 2008 to December 2019, all cases of pathologically confirmed stage IA grade 1 or 2 endometrial cancer were reviewed at Osaka Medical College. Statistical analyses used the Chi-square test and the Kaplan–Meier log rank. Results A total of 478 patients were identified: 438 with negative peritoneal cytology (232 who underwent laparotomy and 206 who undertook laparoscopic surgery) and 40 with positive peritoneal cytology (20 who underwent laparotomy and 20 who received laparoscopic surgery). Survival was significantly worse among patients with positive peritoneal cytology compared to patients with negative peritoneal cytology. However, there was no significant difference among patients with negative or positive peritoneal cytology between laparoscopic surgery and laparotomy. Conclusion This retrospective study suggests that, while peritoneal cytology is an independent risk factor in patients with low-risk endometrial cancer, laparoscopic surgery does not influence the survival outcome when compared to laparotomy.

Sentinel node biopsy (SNB) may be a decision-making tool for function preservation surgery, including radical trachelectomy and ovary preservation in the treatment of cervical and endometrial cancer. The intraoperative diagnosis is important for guiding treatment decisions for patients with these conditions. Three hundred seventy-one patients with cervical and endometrial cancer received SNB with an intraoperative frozen section analysis and imprint cytology. The sentinel node was cut in half, parallel to the longest axis, to obtain the maximum section area. After performing imprint cytology, one half was used to create a frozen section. The specimen was cut at 2-mm intervals into 5-μm-thick sections, which were subjected to hematoxylin and eosin staining. The diagnostic accuracy of intraoperative frozen section analyses and imprint cytology was compared to the final pathological diagnosis. Among 951 detected sentinel nodes, 51 nodes were found to be positive in the final pathological diagnosis. The sensitivity of a frozen section analysis, imprint cytology and the combination of the two modalities was 76.5%, 72.6%, and 92.2%, respectively. The specificity of a frozen section analysis and imprint cytology was 100%. The negative predictive value of a frozen section analysis and imprint cytology was 98.7% and 98.5%, respectively. In these settings, the accuracy of the frozen section analysis and imprint cytology in the evaluation of SNB specimens was considered acceptable; however, the sensitivity of the combined approach was higher in comparison to when a frozen section analysis or imprint cytology was performed alone.

CD24, which is upregulated in several human malignancies, is related to Epithelial‑mesenchymal‑transition (EMT) and has characteristics of cancer stem‑like cells, especially in cisplatin‑resistant ovarian carcinoma cells. Drug delivery systems represent a promising therapeutic approach for diseases with treatment resistance, and the present study investigated a novel CD24‑targeted drug delivery system for advanced ovarian carcinoma. We produced liposomal cisplatin with a red fluorescent substance ‑ cyanine 5.5 (GL‑CDDP‑Cy5.5). In order to target CD24‑positive cells, an anti‑CD24 monoclonal antibody was modified to the above drug (CD24‑GL‑CDDP‑Cy5.5). Specific uptake of CD24‑GL‑CDDP‑Cy5.5 was confirmed using a therapeutically resistant ovarian cancer cell line, Caov‑3 cells. Antitumor effects of CD24‑GL‑CDDP‑Cy5.5 were then evaluated in Caov‑3 xenograft mice. CD24‑GL‑CDDP‑Cy5.5 showed more specific uptake by flow cytometry than GL‑CDDP‑Cy5.5. In xenograft mice, GL‑CDDP‑Cy5.5 and CD24‑GL‑CDDP‑Cy5.5 treatment had significantly higher platinum concentration in disseminated tumor cells than cisplatin (P

Human papillomavirus (HPV) vaccine has been used to prevent chronic HPV infection, which accounts for cervical cancer. Japanese Ministry of Health, Labor and Welfare (MHLW) conducted an HPV vaccination campaign in 2010 and the Obstetrical Gynecological Society of Osaka initiated a multicenter, prospective cohort study in Osaka, Japan - OCEAN (Osaka Clinical resEArch of HPV vacciNe) study - to investigate the oncogenic HPV prevalence and the long-term protection rate of HPV vaccine. A total of 2814 participants were enrolled on their visit for HPV vaccination between 12 and 18 years old. Among them, 102 participants received HPV/Pap co-test as primary cancer screening at the age of 20-21. We compared the prevalence in two groups (the vaccinated and the unvaccinated group). HPV infection ratio was significantly lower in the vaccinated group compared to the unvaccinated (12.9% vs. 19.7%

OBJECTIVE: Our purposes of this study were to characterize a group of bulky cervical cancer patients who underwent a nerve sparing radical hysterectomy (NSRH) with or without neoadjuvant chemotherapy (NAC), to compare surgical outcomes and the preservation of bladder function, and to compare prognoses. RESULTS: Fifty-three patients had NSRH without NAC (Group A), and 33 patients had NSRH after NAC (Group B). With regard to prognostic factors, there was only a significant difference between both groups with regard to lymph node metastasis (15% vs 42%, P = 0.01). Moreover, bladder function in Group B patients improved to the same extent as the preoperative rate three months postoperatively. These data were similar to the results in Group A. With regard to overall survival, the 5-year survival rate was 98.1% (95% confidence interval (CI) 87.8-99.7) in Group A and 86.7% (95% CI 71.7-96.7) in Group B (P > 0.1). METHODS: We retrospectively identified 86 patients with cervical cancer who underwent NSRH at Osaka Medical College from May 2009 to November 2016. NAC was performed via balloon occluded arterial infusion. We extracted data on the patient's stage of progress, tumor volume, histological subtype, bleeding volume, urodynamic study results, and postoperative complications. The data were divided into two groups - those patients who received NAC and those who did not - and then compared. CONCLUSIONS: According to our analysis, NSRH surgery after NAC via balloon occluded arterial infusion brings beneficial results to patients with bulky IB2 to IIB cervical cancers.

// Tomohito Tanaka 1 , Yoshito Terai 1 , Satoe Fujiwara 1 , Yoshimichi Tanaka 1 , Hiroshi Sasaki 1 , Satoshi Tsunetoh 1 , Kazuhiro Yamamoto 2 , Takashi Yamada 3 and Masahide Ohmichi 1 1 Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Japan 2 Department of Radiology, Osaka Medical College, Takatsuki, Japan 3 Department of Pathology, Osaka Medical College, Takatsuki, Japan Correspondence to: Yoshito Terai, email: y-terai@osaka-med.ac.jp Keywords: uterine cervical cancer; locally advanced uterine cervical cancer; neoadjuvant chemotherapy; radical hysterectomy Received: June 05, 2018 Accepted: December 13, 2018 Published: December 28, 2018 ABSTRACT OBJECTIVE: We report a balloon-occluded arterial infusion therapy with an original four-lumen double-balloon catheter (4L-DB) which allows for the efficient injection of an anticancer agent at a high concentration to the target spot for patients with locally advanced uterine cervical cancer. METHODS: One hundred and forty-three patients with locally advanced cervical cancer treated with neoadjuvant intra-arterial chemotherapy (NAIAC) or a primary radical hysterectomy (PRH) were retrospectively assessed. The patients in the NAIAC group received irinotecan 70 mg/m2 intravenously on day 1 and 8 and cisplatin 70 mg/m2 intra-arterially using the 4L-DB on day 2 of a 21-day course, and two courses were performed in principle. The radical hysterectomy was performed within 6 weeks after NAIAC. RESULTS: Ninety-four patients were treated with NAIAC, and 49 patients undertook a PRH. The response rate of NAIAC on MRI was 92.6%. Fourteen patients (14.6%) had no evidence of cancer cells on pathologic diagnoses. The NAIAC group had a longer disease-free survival than the PRH group (p=0.02); however, the overall survival was not significantly different. The relative risk (RR) for recurrence was higher in patients with lymph node metastasis (RR, 4.31; 95% CI, 2.23-8.43) and lower in those who underwent NAIAC (RR, 0.30; 95% CI, 0.14-0.68). CONCLUSION: Our results with NAIAC using the 4L-DB catheter in locally advanced cervical cancer indicates beneficial effects on primary lesions and improves disease-free survival.

Background Ovarian cancer (OC) is a leading cause of cancer-related death in women, and thus an accurate diagnosis of the predisposition and its early detection is necessary. The aims of this study were to determine whether serum exosomal microRNA-34a (miR-34a) in ovarian cancer could be used as a potential biomarker. Methods Exosomes from OC patients’ serum were collected, and exosomal miRNAs were extracted. The relative expression of miR-34a was calculated from 58 OC samples by quantitative real-time polymerase chain reaction. Results Serum exosomal miR-34a levels were significantly increased in early-stage OC patients compared with advanced-stage patients. Its levels were significantly lower in patients with lymph node metastasis than in those with no lymph node metastasis. Furthermore, its levels in the recurrence group were significantly lower than those in the recurrence-free group. Conclusions Serum exosomal miR-34a could be a potential biomarker for improving the diagnostic efficiency of OC.

Introduction: In June of 2013, Japan’s Ministry of Health, Labor and Welfare (MHLW) suspended its position of strong recommendation for the routine immunization of young girls against the Human Papilloma Virus (HPV) because of reports of adverse reactions after the vaccination. For the next four years, the MHLW’s website warned about the significance of these adverse events. In January of 2018, MHLW’s website was modified to reflect a less negative stance. We have studied public awareness of MHLW’s revised leaflet in Japanese women whose daughters were of the targeted age for receiving the HPV vaccine and how this awareness influenced their intentions to get their daughters vaccinated. Materials and Methods: From June to December of 2018, a survey was conducted through the Departments of Obstetrics and Gynecology at 14 different medical facilities. The questionnaire was distributed to women whose daughters were of the HPV–vaccine-targeted age. The survey measured their responses before and after being presented with the 2018-revised MHLW leaflet. Responses from 384 mothers were analyzed. Results: Before being presented with the leaflet, the survey found that the percentage of responder’s daughters already vaccinated was 6.5% (24/372). After reading the MHLW leaflet, an additional 6.9% (24/346) responded “I want to get my daughter vaccinated immediately”, and 37.6% (130/346) responded “I have positive feelings about HPV vaccination”. Discussion: By presenting the new MHLW leaflet at obstetrics and gynecology facilities, we expect to be able to effectively increase the HPV vaccination rate in Japan.

Objective The histological tumor grade is a strong predictor of nodal metastasis in endometrial cancer; as such, an accurate pre- or intraoperative diagnosis is important for performing lymphadenectomy. Methods Ninety-one patients with endometrioid endometrial cancer were imaged on DW-MRI with the apparent diffusion coefficient (ADC) calculated and a frozen section (FS) diagnosis made before and at hysterectomy. The diagnostic accuracy for predicting the tumor grade for diffusion weighted magnetic resonance inaging (DW-MRI) and the FS diagnosis compared to the ultimate histologic status was analyzed. Results Among 91 patients with endometrioid endometrial cancer, high-grade (endometrioid G3) tumors had lower ADC values than low-grade (endometrioid G1/2) tumors. The cut-off of the mean ADCmean values for predicting high-grade tumors resulted in 743×10-6 mm2/sec according to the receiver operating characteristic curve. The true positive rates of ADC values and FSs for the prediction of high-grade tumors did not differ to a statistically significant extent (73.3% vs. 66.7%, p=0.7), however, the true negative rate of ADC values for the prediction of low-grade tumors was significantly lower than that of the FSs (64.5% vs. 98.7%, p=0.01). The kappa statistics of ADC values and FSs were 0.23 and 0.73, respectively. Of note, all five patients with high-grade tumors for whom intraoperative FSs indicated low-grade tumors were predicted to have high-grade tumors on preoperative DW-MRI. Conclusion A FS diagnosis is more suitable for predicting high-grade tumors than DW-MRI; however, physicians should pay close attention to tumors with low ADC values on preoperative DW-MRI.

Background It is well known that ovarian mature cystic teratomas (MCTs) occasionally go through malignant transformations. Among these, approximately 75% of histological types are squamous cell carcinoma, with the other types being exceptionally rare. We report an extremely rare case of ovarian clear cell carcinoma arising from ovarian mature cystic teratoma. Case presentation The case was a 71-year-old woman with abdominal distention. Ultrasonography and magnetic resonance imaging showed a huge mass in her abdominal cavity. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed FDG uptake not only in the pelvic tumor but also in the hepatic nodule, thus suggesting metastases. We performed a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and an omentectomy. The pathological diagnosis showed clear cell carcinoma of the right ovary which arose from the MCT with malignant transformation pT2aNXM1. Although the patient underwent chemotherapy, she died after 17 months. Conclusion This case is histologically characteristic of the proof of transition from simple squamous epithelium via simple glandular epithelium to papillary change with atypia. This is the first case report of unaccompanied clear cell carcinoma arising from MCT reported in English literatures.

Background: The examination of a sentinel lymph node (SLN), where lymph node metastasis first occurs, may be advocated as an alternative staging technique. The aim of this study was to evaluate the feasibility and detection rates of an SLN biopsy in patients with endometrial cancer. Study design: Two hundred and eleven patients with endometrial cancer underwent an SLN biopsy at hysterectomy using three kinds of tracers including 99m-technetium-labeled tin colloid (99mTc), indigo carmine and indocyanine green. Factors related to the side-specific detection rate, sensitivity and false negative rate were analyzed. Results: The detection rates of the SLN biopsy using 99mTc, indigo carmine and indocyanine green were 77.9, 17.0 and 73.4%, respectively. The detection rate was lower in elderly patients (≥60 years) (67.9 vs 89.2%, p < 0.01), patients with >50% myometrial invasion (68.3 vs 85.2%, p < 0.01), patients with high-grade tumors (69.5 vs 84.9%, p < 0.01) and patients who underwent laparotomy (71.2 vs 84.9%, p < 0.01). There were no significant differences in body mass index. The sensitivity was not significantly different in any factor. However, the false negative rate was higher in patients with > 50% myometrial invasion (11.5 vs 1.2%, p < 0.01), high-grade tumors (13.3 vs 0.8%, p < 0.01) and who underwent laparotomy (12.2 vs 0.4%, p < 0.01). Conclusion: Patients who underwent laparoscopy with < 50% myometrial invasion and low-grade tumors not only have higher detection rates, but also have lower false negative rates. These patients may avoid systemic lymphadenectomy according to the status of the SLN biopsy.

The degree of peritoneal dissemination and chemotherapy-resistant tumors is related to the prognosis in patients with advanced-stage ovarian cancer. The epithelial-mesenchymal-transition (EMT) is a multifaceted pathological program that endows cancer cells with the ability to invade and disseminate. CD24 is frequently overexpressed in various human cancers and is correlated with a poor prognosis. We herein examined the functions of CD24 in human ovarian cancer cell lines and evaluated how it contributes to the molecular mechanism underlying the regeneration of cancer stem-like cells (CSCs) through the EMT mechanism in ovarian carcinoma. We demonstrated that CD24 was expressed in 70.1% of primary ovarian carcinoma tissues, which were obtained from 174 patients, and that the expression of CD24 was an independent predictor of survival in patients with ovarian cancer. The expression of CD24 has been found to be correlated with the FIGO stage, presence of peritoneal and lymph node metastasis. CD24 induces the EMT phenomenon, which is involved in cell invasion, the highly proliferative phenotype, colony formation and which is associated with cisplatin resistance and the properties of CSCs, via the activation of PI3K/Akt, NF-κB and ERK in Caov-3 cisplatin-resistant cell lines. CD24-positive ovarian carcinomas have been shown to have a greater potential for intra-abdominal tumor cell dissemination in in vivo models. Our findings suggest that CD24 induced the EMT phenomenon in ovarian cancer, and that CD24 amplified cell growth-related intracellular signaling via the PI3K/Akt and MAPK pathways by affecting the EMT signal pathways. We believe that CD24 is a key molecule of metastatic progression in the EMT phenomenon and a promising therapeutic target for advanced ovarian cancer.

Background Ovarian carcinosarcoma, which contains sarcomatous and carcinomatous components, is a very rare tumor. The carcinomatous component is often adenocarcinoma, and squamous cell carcinoma is extremely rare. We herein report a case of ovarian carcinosarcoma in which the carcinomatous component was squamous cell carcinoma. Case presentation A 68-year-old woman presented with a huge ovarian tumor with a clinical diagnosis of malignant tumor of the ovary. She underwent hysterectomy, bilateral adnexectomy, omentectomy and lymphadenectomy. Histologically, the tumor cells showed undifferentiated pleomorphic sarcoma as the sarcomatous component and squamous cell carcinoma as the carcinomatous component. The final diagnosis was ovarian carcinosarcoma with squamous cell carcinoma in the carcinomatous component, stage IIIA1. Postoperatively, the patient was treated with six cycles of combination chemotherapy with paclitaxel and carboplatin as adjuvant therapy. The patient was free of disease at 45 months’ follow-up consultation. Conclusion This is a rare report of ovarian carcinosarcoma with an epithelial component composed of squamous cell carcinoma. Combination chemotherapy with paclitaxel and carboplatin may be an effective choice as adjuvant chemotherapy in cases of ovarian carcinosarcoma including squamous cell carcinoma.

Introduction Uterine fibroids, which are common benign tumors, rarely cause acute complications. We herein report a case of hemoperitoneum associated with uterine fibroid that could be diagnosed preoperatively with contrast-enhanced computerized tomography (CT). Patient concerns A 48-year-old woman with uterine fibroid developed extremely severe lower abdominal pain on the first day of her menstrual period. Diagnosis Ultrasonography and contrast-enhanced CT revealed a uterine fibroid and extravasation from the dilated vessels of the uterine fibroid. Intervention Emergent abdominal hysterectomy was performed. Outcomes The total amount of bleeding was 4,600 mL. Intraoperative blood salvage (1,357 mL), 6 units of red blood cells, 4 units of fresh frozen plasma, and 20 units of platelet concentrates were transfused. The postoperative course was uneventful. Pathological examination confirmed a benign uterine fibroid. Conclusion CT could be useful to determine a diagnosis for bleeding from ruptured subserosal uterine fibroid.

Endometrial cancer is the most prevalent gynecologic cancer in the Western world, and the number of advanced chemotherapy-resistant cancers is increasing with the absolute increase in patients. The development of resistance to chemotherapeutic drugs by cancer cells represents a major challenge in the clinical cure of advanced and metastatic cancers. CD24 has been reported to be a marker for a poor prognosis in several tumors, and we herein examined the functions of CD24 in human endometrioid adenocarcinoma cell lines and evaluated how it contributes to cancer drug resistance. We demonstrated that CD24 was responsible for the recruitment of phosphorylated Met to the lipid raft domain of the cell membrane, resulting in amplification of the Met signaling cascade, ultimately leading endometrial cancer cells to express higher levels of ATP-binding cassette (ABC) transporters. Our findings suggest that CD24-mediated amplification of the Met cascade may contribute to the drug resistance of endometrial cancer. Mol Cancer Ther; 14(10); 2353–63. ©2015 AACR.

CD24, a small heavily glycosylated mucin-like glycosylphosphatidylinositol-anchored cell surface protein, plays an important role in the carcinogenesis of various human malignancies. However, its function in cervical cancer remains unclear. The aim of the present study was to evaluate the expression of CD24 clinicopathologically and to analyze its functional behavior biologically in cervical cancer. A total of 117 uterine cervical cancer tumors were immunohistochemically analyzed using a CD24 monoclonal antibody on paraffin blocks. We also examined whether CD24 enhanced the invasive activity or the Akt, ERK, NF-κB and MMP activity in a uterine cervical cancer cell line (CaSki) by a western blot analysis. The patients with enhanced CD24 expression had a higher rate of advanced clinical stage (50 vs. 16.5%, p

Background PD-0332991, the selective cyclin-dependent kinase 4/6 inhibitor palbociclib, causes cell cycle arrest by inhibiting phosphorylation of retinoblastoma (Rb) protein. The aim of this study was to evaluate the therapeutic potential of PD-0332991 in endometrial cancer. Methods and findings Four human endometrial cancer cell lines, ECC, HEC1A, HEC108 and TEN, were treated with PD-0332991 and their function was evaluated. In vivo, the therapeutic efficacy was evaluated in a model of subcutaneous endometrial cancer. An immunohistochemical analysis was performed in 337 endometrial cancer specimens. A proliferation assay revealed that 2 of the 4 cell lines that expressed Rb were sensitive to PD-0332991 with an IC50 of 0.65 μM (HEC1A) and 0.58 μM (HEC108), respectively. Both cell lines had G0/G1 cell cycle arrest after treatment with PD-0332991 according to flow cytometry. In vivo, PD-0332991 had antitumoral efficacy with a reduction in the activity of Ki67 and phosphorylation of Rb. Immunohistochemical analyses revealed that the positive rate of Rb was 67.7%, however, there was no significant relationship between the expression levels of Rb and the tumor grade. Conclusions PD-0332991 had therapeutic potential against endometrial cancer cell lines expressing Rb protein. Our immunohistochemical analysis revealed that approximately 70% of patients with endometrial cancer might have therapeutic indications for PD-0332991. Of note, the tumor grade had no impact on the indications for treatment.

e17041 Background: G protein-coupled receptor 30 (GPR30) is a 7-transmembrane estrogen receptor that functions alongside traditional estrogen receptors to regulate the cellular responses to estrogen. Recent studies suggest that the high expression of GPR30 is associated with a poor prognosis in breast cancer or endometrial cancer. Although the role of GPR30 in ovarian cancer was unclear, we revealed that GPR30 is associated with poor prognosis in ovarian cancer. On the other hand, Epithelial-to-Mesenchymal Transition (EMT) is involved in cancer metastasis. The purpose of this study is to reveal how GPR30 was associated with poor prognosis and whether associated with EMT in ovarian cancer. Methods: We examined whether GPR30 signaling activates the EGFR-Akt pathway in an ovarian cancer cell line (Caov-3) by a Western blotting analysis. We also examined the effect of GPR30 on EMT were evaluated in Caov-3, which were cultured both in two-dimensional (2D) culture and three-dimensional (3D) culture model. GPR30 agonist, G1, was used to confirm the regulatory effects of GPR30 on the change of phenotypic modulation and EMT markers expression. Results: The phosphorylation of the EGFR and Akt could be significantly enhanced by G1 (p < 0.05) and inhibited by a Src family kinase inhibitor. In 3D culture, the stimulation of GPR30 leads the floating and sphere formation in Caov-3. G1-induced EMT was observed with related regulation of EMT markers expression at both mRNA and protein level. G1 induced the decrease of E-cadherin level and the increase of Snail and Vimentin in RT-PCR and Western blotting. Knockdown of GPR30, using siRNA, blocked G1-induced EMT. Conclusions: GPR30 increases the phosphorylation of Akt via the EGFR in ovarian cancer cells and changes ovarian cancer cells to the EMT state.GPR30 might be an important molecule related to metastasis process in ovarian cancer.

Aim This is the first report to determine the feasibility and safety of total laparoscopic modified radical hysterectomy (TLMRH) in the treatment of presumed stage I endometrial cancer. Methods This was a retrospective study of 132 consecutive patients who underwent surgery for early endometrial cancer. Thirty-nine patients underwent TLMRH and bilateral salpingo-oophorectomy (BSO), and 93 had a total abdominal extrafascial hysterectomy and BSO. Lymphadenectomy was performed in 87 patients. The groups were compared for epidemiological and clinical characteristics, surgical outcomes, hospital stay, lymph nodes harvested, and intraoperative and postoperative complications. Results The patients in the TLMRH group had less blood loss (42.9 ± 76.3 vs 236.8 ± 186.6 mL, P

GPR30 is a seven-transmembrane G protein-coupled estrogen receptor that regulates endometrial cellular responses to estrogen. GPR30 is often highly expressed in cancer cells from aggressive tumors. The aim of this study was to evaluate the expression patterns of GPR30 in endometriosis during medical treatment.A total of 38 females, 28 patients with endometriosis and 10 patients with leiomyoma who underwent laparoscopic surgery were included this study.Eutopic endometrial tissue sampling from women without endometriosis and ectopic endometrial tissue sampling from women with endometriosis.A quantitative real-time polymerase chain reaction analysis of the mRNA expression in eutopic and ectopic endometrial tissues with or without GnRH agonist treatment. The expression of GPR30 was confirmed by immunohistochemistry.There was an increased level of GPR30 mRNA in eutopic endometrium during the proliferative phase, whereas higher expression was observed in the ectopic endometrium during the secretory phase. Increased GPR30 mRNA was observed in ectopic endometrium in comparison to eutopic endometrium. GnRH agonist treatment before laparoscopic surgery decreased GPR30 mRNA in ectopic endometrium. The immunohistochemical analysis also revealed that GPR30 was strongly expressed in epithelial cells in ectopic endometrium, whereas GnRH agonist treatment decreased the GPR30 expression.High levels of GPR30 expression can play an important role in the progression of endometriosis.

Aim The purpose of this study was to compare the intraoperative and postoperative parameters among the three approaches used to treat large uterine myomas: laparoscopic assisted vaginal hysterectomy (LAVH), total laparoscopic hysterectomy (TLH) and abdominal hysterectomy, and to evaluate the selection criteria for laparoscopic hysterectomy as determined by magnetic resonance imaging. Material and Methods The medical records of 155 patients who underwent a hysterectomy between January 2007 and April 2010 were examined. We also compared the indications and outcomes of LAVH and TLH for myomas larger than 7 cm. Results Patients who underwent LAVH or TLH had a lower average intraoperative blood loss, less intense postoperative pain, and shorter hospital stays than patients in the TAH group, although the length of the operations in the laparoscopic groups were significantly longer. To evaluate the selection criteria for the large sized myomas, we compared the LAVH and TLH groups for the myomas larger than 7 cm. The greatest uterine transverse diameters and the weight of the uteri were not significantly different between the LAVH and TLH groups (94.7 ± 20.8 and 83.1 ± 17.6 mm, 371.6 ± 160.3 and 286.7 ± 158.0 g, respectively). The average intraoperative blood loss in the TLH group was significantly lower than that in the LAVH (121.3 ± 111.2 vs 379.3 ± 222.4 g, P

Objectives: The epithelial-mesenchymal-transition (EMT) is an important step in the invasion and metastasis of cancer. A critical molecular feature of this process is the downregulation of E-cadherin expression, which is mainly controlled by Snail-related zinc-finger transcription factors (Snail and Slug). The aim of this study was to evaluate the prognostic impact of EMT-related protein (E-cadherin, Snail and Slug) expression in endometrial cancer. Methods: An immunohistochemical analysis was conducted using tissue microarray samples of 354 primary tumors and 30 metastases of endometrial carcinomas, and the relationship between protein expression, clinicopathological features and outcomes were investigated. Results: Reduced E-cadherin was seen in 39.8% of primary tumors. Reduced E-cadherin was seen in 19.5%, 40.8% and 72.7% of G1, G2 and G3 endometrioid adenocarcinomas, respectively. The nuclear expression of Snail and Slug were positive in 16.9% and 3.7% of primary tumors, respectively. EMT status, which was represented by both reduced E-cadherin and nuclear expression of Snail, was significantly associated with histological type, FIGO stage, myometrial invasion, positive peritoneal cytology and patient survival (p < 0.01). There was no difference in the rates of EMT status between the primary tumors and metastases. A multivariate analysis showed that EMT-positive status was a significant predictor for both the progression-free survival and overall survival (p < 0.01). Conclusions: These data indicate that EMT status has a prognostic impact in endometrial cancer. Therefore, the clarification and control of EMT signaling is a promising molecular targeting therapy in endometrial cancer.

Purpose: Vascular endothelial growth factor (VEGF) plays a central role in tumor angiogenesis and is regarded as a promising therapeutic target. We hypothesized that treatment with bevacizumab, a humanized recombinant anti-VEGF monoclonal antibody, could enhance antitumor response to cisplatin and prolong survival in a murine ovarian cancer model.Experimental Design: We conducted an MTS assay to examine the effect of bevacizumab on proliferation of the VEGF producing human ovarian cancer cell lines in vitro. Next, the antiangiogenic activity of bevacizumab was investigated by in vivo angiogenesis and wound healing assays. We then determined the toxicity and antitumor response of bevacizumab and cisplatin as single agents or in combination in xenograft models of ovarian cancer. Finally, using the same xenograft model, we examined the effect of these regimens, as well as bevacizumab maintenance therapy, on survival.Results: Bevacizumab had no effect on the proliferation of ovarian cancer cells in vitro but significantly inhibited angiogenesis and delayed wound healing in vivo. Bevacizumab inhibited i.p. tumor growth and ascites production in the nu/nu mouse xenograft model and enhanced the therapeutic efficacy of cisplatin. Combination therapy with bevacizumab and cisplatin for 3 weeks was associated with complete disappearance of all macroscopic evidence of disease. Moreover, maintenance treatment with bevacizumab after 3 weeks of induction combination therapy inhibited recurrence and significantly prolonged survival.Conclusions: Bevacizumab has significant antitumor activity not only as a single agent or in combination with cisplatin but may also prolong survival when used as maintenance therapy after a complete response to cisplatin-based chemotherapy.

Objective The rate of lymph node metastasis is extremely low in patients with low-risk endometrial cancer; lymphadenectomy may be unnecessary for these patients under an accurate preoperative diagnosis. The aim of this study was to evaluate the diagnostic accuracy of myometrial invasion (MI) on preoperative magnetic resonance imaging (MRI) and intraoperative frozen sections (FSs). Materials and Methods Endometrial cancer was diagnosed in a total of 378 patients by preoperative endometrial curettage, preoperative magnetic resonance imaging MRI, and intraoperative FSs; the 378 patients underwent hysterectomy. The depth of MI was evaluated between the preoperative MRI, intraoperative FSs, and final paraffin sections (PSs). The histologic grade was also evaluated between preoperative endometrial curettage, intraoperative FSs, and final PSs. Results The sensitivity, specificity, positive predictive value, and negative predictive value for deep MI (≥50%) on MRI were 57.8%, 92.0%, 69.3%, and 87.5%, respectively, with a kappa value of 0.53. These figures on FSs were 66.7%, 97.9%, 90.9%, and 90.4%, with a kappa value of 0.71. When grade 3 endometrioid adenocarcinoma, serous carcinoma, clear cell carcinoma, and carcinosarcoma were considered high-grade tumors, the grade evaluation at the time of FSs was 70.2%, 99.0%, 96.1%, and 89.7%, with a kappa value of 0.75. In the patients with low-grade tumors, including grade 1 or 2 endometrioid adenocarcinoma on preoperative endometrial curettage, the rate of unexpected lymph node metastasis did not differ significantly between the patients who had a diagnosis of MI and lymph node metastasis by MRI and those with diagnosis of MI and histological grade by FSs (4.0% vs 2.6%; P > 0.05). Conclusions Frozen sections had a higher agreement rate for MI than MRI; however, MRI is still considered an acceptable modality to guide preoperative decisions regarding lymphadenectomy especially in grade 1 or 2 endometrioid adenocarcinoma.

Numerous studies-some of them randomized-have failed to find major differences in cure rates of cervical intraepithelial neoplasia (CIN) among cryotherapy, laser treatment, and loop electrosurgical excision. The investigators have, in the past 2 decades, treated CIN in 2107 women by gadolinium (Nd-YAG) laser conization that vaporized the base. The procedure took only 12 minutes on average. Just over 10% of women lost more than 20 mL of blood during the procedure. Approximately 7% of patients, 98% of them postmenopausal, had cervical obstruction during follow up. Either no CIN or grade 1-3 CIN was found in 92.8% of cone specimens, whereas 7.2% exhibited invasive disease. Women lacking invasive disease were followed between 16 months and 21 years. The rate of incomplete excision was 12.3% in patients having CIN in the cone specimen, but the rate of persistent or recurrent disease was only 1.2%. Of 230 patients with postoperative CIN and positive surgical margins, 83.5% had no abnormal cytologic or colposcopic abnormalities during follow up. In contrast, preoperative underdiagnosis of the biopsy results did increase the risk of incomplete excision and failure. The odds ratio for incomplete excision was 1.51 (95% confidence interval [CI], 1.13-2.02) and that for failure was 3.20 (95% CI, 1.44-7.13). Combining laser conization with vaporizing the base is an effective means of treating CIN because it detects otherwise unexpected invasive disease.

Objective The aim of this study was to estimate the incidence, etiology, and outcomes of genitofemoral neuropathy after pelvic lymphadenectomy (PLD) for uterine corpus cancer. Materials and Methods The medical records of women who underwent PLD for uterine corpus cancer between June 2001 and June 2013 were reviewed. Information regarding neuropathy was directly reported by each subject. Results Thirty-two of 300 patients undergoing PLD during the defined period experienced postoperative neuropathy due to genitofemoral nerve injury, for an incidence of 10.7%. The patients treated with PLD with para-aortic lymphadenectomy (PALD) exhibited a lower rate of genitofemoral neuropathy than those treated without PALD (4.3% vs 13.5%, P = 0.01). The laparoscopy group displayed a higher rate of genitofemoral neuropathy than the laparotomy group (19.1% vs 9.1%, P = 0.04). A total of 81.3% of the patients experienced a full recovery, with a medium time to resolution of 6 months (3–12 months). The administration of adjuvant chemotherapy, including paclitaxel, did not extend the time to recovery. Conclusions Neuropathy resulting from genitofemoral nerve injury is not infrequent; however, most of the patients recover completely. In this study, the use of laparoscopic procedures increased the incidence of genitofemoral neuropathy, whereas that of PALD did not.

Objectives The epithelial-mesenchymal-transition (EMT) is an important step in the invasion and metastasis of cancer. A critical molecular feature of this process is the downregulation of the E-cadherin expression, which is primarily controlled by Snail-related zinc-finger transcription factors. The aim of this study was to evaluate the prognostic impact of the expression of EMT-related proteins (E-cadherin and Snail) in patients with ovarian cancer. Methods An immunohistochemical analysis was conducted using tissue microarray samples of 174 primary tumors and 34 metastases of ovarian carcinoma, and the relationships between the protein expression, clinicopathological features and outcomes were investigated. Results A reduced E-cadherin expression was observed in 36.8% of the primary tumors and 30.4%, 35.7%, 37.7% and 52.7% of the stage I, II, III and IV tumors, respectively. The nuclear expression of Snail was positive in 33.9% of the primary tumors. The rate of an EMT-positive status, as represented by both a reduced E-cadherin expression and a nuclear expression of Snail, was significantly higher in the patients with peritoneal dissemination than in those without (p

Primary carcinoma of the vermiform appendix is a rare disease with few clinical symptoms. Accordingly, preoperative diagnosis of appendiceal cancer is challenging because of the lack of specific symptoms. We herein report a case of appendicular adenocarcinoma found unexpectedly during laparoscopic surgery in a 69-year-old Japanese female patient diagnosed with serous papillary adenocarcinoma, in order to determine whether optimal cytoreduction could successfully be achieved at the time of primary surgery. We performed diagnostic laparoscopic surgery in order to make a correct diagnosis based on the histological tissue. The vermiform appendix was found to contain a tumor measuring 1.5 cm wide and 4.5 cm long. Laparoscopic appendectomy, partial omentectomy, and partial resection of the lesion in the peritoneum were performed. The histological diagnosis was mucinous adenocarcinoma of the vermiform appendix, and the stage was T4NxM1. The patient received adjuvant chemotherapy with mFOLFOX 6 (5FU, leucovorin, and oxaliplatin). She achieved stable disease and was alive with disease eleven months after surgery. We therefore recommend that gynecologists should not rule out the possibility of appendiceal cancer, even in cases with preoperative findings similar to those of serous papillary adenocarcinoma of the peritoneum with peritoneal disseminated tumors.

To avoid the environmental deterioration due to installation/construction of coastal structures, the assessment procedure for marine environment should be investigated. To attract fishes and the other marine organisms on artificial fish reef or the other type of coastal structures, the biological investigation of sesentary organisms and benthos is generally required. It is effective to investigate the attached organisms on silt curtains, for overview the habitat of attached marine organisms on coastal structures. Because silt curtains develop in various marine environments, that is in various water depth under wave and current actions. This paper discussed the relationship between the marine environment and the attached organisms on silt curtains.

Objectives To introduce a safe and reliable method for the management of peripheral vessels around the uterine artery during abdominal radical hysterectomy or abdominal radical trachelectomy. Study design From 2007 to 2011, 102 patients with invasive cervical cancer underwent an abdominal radical hysterectomy. In 48 operations in 2007–2009, we performed the conventional radical hysterectomy, in which we ligated and cut the uterine arteries at their origin, and we divided the anterior leaf of the vesico-uterine ligament by blindly inserting scissors into the ureteral tunnel, pushing the ureter laterally from the cervix. In 54 operations in 2009–2011, we pulled up the origin and the bifurcation of the uterine artery using vessel tape, skeletonized the uterine artery and directly divided the superficial uterine vein, superior vesical vein and ureteric branch of the uterine artery. We also performed four radical trachelectomies using the two point pull-up method. We investigated whether this method was useful for the management of peripheral vessels around the uterine artery. Results The mean total blood loss in the two point pull-up method group (485 ± 270 ml) was significantly lower than that in the conventional surgery group (686 ± 554 ml) (p

Background Mature cystic teratomas (MCTs) are the most common germ cell tumors of the ovary. Malignant tranformation occurs in 1-2% of these neoplasms. Although most of the malignancies arising from MCTs are squamous cell carcinomas, adenocarcinoma of the gastrointestinal type is extremery rare. We herein present a case of adenocarcinoma of the intestinal type arising from a MCT. Case A 49-year-old female underwent surgery for a left ovarian tumor. The histology of the cyst walls revealed a MCT with a few hair shafts and a squamous layer, while another part of the tumor showed adenocarcinoma of the intestinal type. Five years after surgery, she is alive without disease.