Estradiol-mediated hepatocyte growth factor is involved in the implantation of endometriotic cells via the mesothelial-to-mesenchymal transition in the peritoneum.

The pathogenesis of endometriosis, a chronic painful gynecological disease characterized by the presence of endometrial tissue located outside of the uterus and often adhering to the peritoneum, is known to be estrogen dependent. However, the precise pathophysiology of endometriosis remains elusive. Recent studies indicate that the epithelial-to-mesenchymal transition (EMT) of human endometrial cells is important for the progression of endometriosis, and another previous study has implicated hepatocyte growth factor (HGF) in endometriosis progression. The aim of the present study was to examine the role of estradiol in the regulation of HGF production and progression of peritoneal endometriosis, focusing on the interactions between the peritoneum and endometriotic cells. Consequently, estradiol was found to promote the proliferation, invasion, and migration of immortalized human endometrial epithelial cells (hEECs) via HGF upregulation, and the estradiol-induced direct binding of estrogen receptor-α to the HGF promoter was confirmed on a chromatin immunoprecipitation (ChIP) assay. Estradiol also induced the EMT in hEECs by promoting HGF production. Furthermore, human mesothelial cells underwent the mesothelial-to-mesenchymal transition (MMT) during culture with estradiol-stimulated hEEC conditioned medium. Importantly, estradiol itself did not induce the MMT, and the estradiol-stimulated hEEC-conditioned medium in the presence of HGF antibodies reversed the MMT process. These results, which were obtained using immortalized hEECs, indicate that estradiol-induced HGF production may play a crucial role in the peritoneal implantation of human endometriotic cells by exerting proliferative and invasive effects via the EMT in hEECs and promoting the MMT in mesothelial cells.

Hepatocyte growth factor secreted by ovarian cancer cells stimulates peritoneal implantation via the mesothelial-mesenchymal transition of the peritoneum.

OBJECTIVE: A current working model for the metastatic process of ovarian carcinoma suggests that cancer cells are shed from the ovarian tumor into the peritoneal cavity and attach to the layer of mesothelial cells that line the inner surface of the peritoneum, and several studies suggest that hepatocyte growth factor (HGF) plays an important role in the dissemination of ovarian cancer. Our objectives were to evaluate the HGF expression of ovarian cancer using clinical data and assess the effect of HGF secreted from human ovarian cancer cells to human mesothelial cells. METHODS: HGF expression was immunohistochemically evaluated in 165 epithelial ovarian cancer patients arranged as tissue microarrays. HGF expression in four ovarian cancer cell lines was evaluated by using semi-quantitative polymerase chain reaction, Western blotting and enzyme-linked immunosorbent assay. The effect of ovarian cancer cell derived HGF to the human mesothelial cells was assessed by using morphologic analysis, Western blotting and cell invasion assay. The effect of HGF on ovarian cancer metastasis was assessed by using in vivo experimental model. RESULTS: The clinical data showed a significantly high correlation between the HGF expression and the cancer stage. The in vivo and in vitro experimental models revealed that HGF secreted by ovarian cancer cells induces the mesothelial-to-mesenchymal transition and stimulates the invasion of mesothelial cells. Furthermore, manipulating the HGF activity affected the degree of dissemination and ascite formation. CONCLUSIONS: We demonstrated that HGF secreted by ovarian cancer cells plays an important role in cancer peritoneal implantation.

Genitofemoral neuropathy after pelvic lymphadenectomy in patients with uterine corpus cancer.

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.

Preoperative MRI and intraoperative frozen section diagnosis of myometrial invasion in patients with endometrial cancer.

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.

Total laparoscopic modified radical hysterectomy with lymphadenectomy for endometrial cancer compared with laparotomy.

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 < 0.0001), a similar number of lymph nodes removed (32.3 ± 13.1 vs 28.0 ± 11.9, P = 0.15), less need for analgesia and a shorter hospital stay (9.3 ± 2.5 vs 14.6 ± 12.6 days, P = 0.009) but longer operations (321.1 ± 65.9 vs 262.6 ± 75.0 min, P < 0.0001) than those treated by laparotomy. In our study, we had no conversions from laparoscopy to laparotomy. No major complications occurred in the TLMRH group. The patients who underwent TLMRH had less intense postoperative pain than patients treated by laparotomy. The median length of vaginal cuff removed was 12.0 ± 4.1 mm in the TLMRH group, and was 5.6 ± 6.6 mm in the laparotomy group (P < 0.0001). No patients demonstrated recurrence in either of the groups after a median follow-up of 48.5 months (range, 1-84). CONCLUSION: TLMRH is a safe and reliable alternative to open surgery in the management of early endometrial carcinoma, with a significantly reduced hospital stay and complications.

Novel para-aortic lymphadenectomy technique for gynecological malignancies prevents postoperative bowel obstruction.

AIM: The aim of this study was to evaluate the effect of our novel technique on the prevention of postoperative ileus in patients undergoing systematic para-aortic lymphadenectomy (PALN). MATERIAL AND METHODS: PALN was performed in 135 gynecological cancer patients (67 with ovarian cancer, 58 with endometrial cancer, 8 with serous surface papillary adenocarcinoma (SSPC) and 2 with fallopian tube cancer) between 2006 and 2011. To prevent postoperative ileus, we performed our novel technique wherein the small bowel and colon are released from pressure and soaked in 2 L of physiological saline for 1 min every 20 min during the lymphadenectomy. We indicated our novel PALN technique and retrospectively analyzed the outcomes of the surgical procedure in terms of the surgical data, and postoperative incidence of gastrointestinal dysfunction in patients with gynecological malignancies. RESULTS: The mean blood loss was 641.2 ± 800.3 mL in the PALN group and 313.9 ± 278.9 mL in the pelvic lymphadenectomy (PLN) without PALN group (P < 0.0001). There was no difference in the first passage of flatus between the PALN group and the PLN group (1.8 ± 0.7 days vs 1.6 ± 0.7 days). The mean time to tolerance of a regular diet was significantly longer in the PALN group than in the PLN group (P < 0.0001), whereas the incidence of vomiting was similar in both groups. Surprisingly, there were no cases of postoperative ileus in either group. CONCLUSION: Our novel technique is a safe and effective way to prevent the incidence and decrease the severity of postoperative ileus after PALN for gynecological malignancies.

A case of pyometra with a colouterine fistula due to rectal cancer presenting as acute abdomen.

Pyometra usually develops in elderly women, and it can be caused by various etiologies. We describe a rare case of pyometra with a colouterine fistula due to rectal cancer presenting as acute abdomen. A 67-year-old woman with purulent vaginal discharge and abdominal distension was referred to our hospital for suspected pyometra. Because the vaginal echogram showed pyometra at her initial medical examination, drainage was performed. Her symptoms subsequently disappeared temporarily, but 4 months later, she developed acute abdomen. The computed tomography scan showed a pelvic mass with expansion of the intestine. The patient underwent en bloc resection of the mass. Histopathologic analysis of the tumor showed rectal cancer with invasion of the uterus and ileum, and a colouterine fistula. Although pyometra due to a colouterine fistula is a very rare condition, the incidence of associated malignancy is considerable. Physicians should be aware of this potential presentation of colorectal cancer.

Endometrial carcinoma with choriocarcinomatous differentiation: a case report and review of the literature.

BACKGROUND: Choriocarcinomas unrelated to pregnancy, teratomas, or germ cell tumors have been found in the stomach, lungs, colon, esophagus, bladder, breast, renal pelvis and other sites. CASE: We present a case of a 58-year-old woman with endometrial carcinoma with choriocarcinomatous differentiation. She received surgery and chemotherapy for endometrial adenocarcinoma. However, a metastatic tumor of choriocarcinomatous element appeared at the vaginal cuff 9 months after surgery. Additional chemotherapy for choriocarcinoma resulted in a decrease in the serum hCG and the tumor regressed. Fifty months following surgery, she is alive without disease. CONCLUSION: Treatment and follow-up must be performed not only for the adenocarcinoma element but also for the choriocarcinoma element in patients presenting with endometrial carcinoma with choriocarcinomatous differentiation.

Maintenance treatment with bevacizumab prolongs survival in an in vivo ovarian cancer model.

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.

Vascular endothelial growth factor-C expression and invasive phenotype in ovarian carcinomas.

PURPOSE: To investigate the biological correlation between vascular endothelial growth factor (VEGF)-C expression and invasive phenotype in ovarian carcinomas. EXPERIMENTAL DESIGN: Gene and protein expression levels of VEGF-C in 10 ovarian carcinoma cell lines were correlated with invasive activity of the cells. The correlation between immunohistochemical expression of VEGF-C and tumor aggressiveness in 73 ovarian carcinomas was also examined with respect to clinicopathologic features and patient outcome. RESULTS: VEGF-C gene and protein expression differed remarkably among the cell lines, and there was a statistical correlation among VEGF-C expression, in vitro invasive activity, and matrix metalloproteinase-2 (MMP-2) gene expression and its activity. Anti-VEGF-C and anti-MMP-2 antibodies inhibited the invasive activity of tumor cells. VEGF-C expression in clinical tissue samples was well correlated with clinical stages, retroperitoneal lymph node metastasis, MMP-2 expression, angiogenesis, lymphangiogenesis, and low apoptotic index (AI). The patients whose tumors had strong VEGF-C expression and low AI underwent a poorer prognosis than did those with weak VEGF-C expression and high AI. CONCLUSION: VEGF-C expression is closely related to invasive phenotype and affects the patient's survival in ovarian carcinomas.

Vascular endothelial zinc finger 1 is involved in the regulation of angiogenesis: possible contribution of stathmin/OP18 as a downstream target gene.

OBJECTIVE: Vascular endothelial zinc finger 1 (Vezf1) is a recently identified zinc finger transcription factor that is expressed in endothelial cells (ECs) during vascular development in mouse embryo. Here, we present that Vezf1 was expressed in ECs at the site of postnatal angiogenesis. We therefore examined whether Vezf1 was involved in the regulation of angiogenesis. METHODS AND RESULTS: The specific downregulation of Vezf1 by antisense oligodeoxynucleotide (AS-ODN) significantly inhibited the proliferation, migration, and network formation of cultured ECs as well as angiogenesis in vivo. Vezf1 AS-ODN downregulated the expression of stathmin/oncoprotein18 (OP18), a microtubule-destabilizing protein, in ECs, whereas transient transfection of Vezf1 cDNA increased the expression of stathmin/OP18 in ECs. To explore the relationship between Vezf1 and stathmin/OP18, we specifically downregulated stathmin/OP18. We found that stathmin/OP18 AS-ODN inhibited the proliferation, migration, and network formation of ECs as Vezf1 AS-ODN did. Moreover, Vezf1 AS-ODN decreased G2/M population of ECs and increased apoptosis, which reproduced the characteristic feature of stathmin/OP18 inhibition. CONCLUSIONS: These results suggest that Vezf1 is involved in the regulation of angiogenesis, at least in part, through the expression of stathmin/OP18 in ECs.

Tumor angiogenesis and molecular target therapy in ovarian carcinomas.

Growth of solid tumors depends on angiogenesis, the process by which new blood vessels develop from the endothelium of a pre-existing vasculature. Tumors promote angiogenesis by secreting various angiogeneic factors, and newly formed blood vessels induce tumor cell proliferation and invasiveness. Ovarian carcinomas have a poor prognosis, often associated with multifocal intraperitoneal dissemination accompanied by intense neovascularization. The degree of angiogenesis of ovarian carcinomas may directly influence the clinical course of the disease. Although a growing body of evidence indicates that angiogenic intensity may play a prognostic role in gynecological malignancies including ovarian carcinomas, the related biological mechanisms remain to be further elucidated. In this review, we describe current knowledge pertaining to mechanisms and regulation of angiogenesis in ovarian carcinomas with special reference to our recent research results.

Palonosetron versus granisetron in combination with aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with gynecologic cancer.

OBJECTIVE: There is no research regarding the appropriate antiemetic agents for female patients, especially those receiving moderately emetogenic chemotherapy (MEC). We evaluated the antiemetic efficacy of a combination of 5-HT3 receptor with/without aprepitant in patients with gynecological cancer treated with the TC (paclitaxel and carboplatin) regimen of MEC. METHODS: We enrolled 38 patients diagnosed with gynecologic cancer and scheduled to receive the TC regimen. The patients were randomly assigned to receive a 5-HT3 receptor antagonist, either palonosetron in the first cycle followed by granisetron in the second cycle or vice versa. In the third cycle, all patients received a combination of the 5-HT3 receptor and dexamethasone with/without aprepitant. RESULTS: When three drugs were administered, palonosetron consistently produced an equivalent complete response (CR) rate to granisetron in the acute phase (89.5% vs. 86.8%, p=0.87) and delayed phase (60.5% vs. 65.8%, p=0.79). With regard to the change in dietary intake, palonosetron exhibited similar efficacy to granisetron in the acute phase (92.1% vs. 89.4%, p=0.19) and delayed phase (65.7% vs. 68.4%, p=0.14). However, in the delayed phase, the addition of aprepitant therapy with a 5-HT3 receptor antagonist and dexamethasone produced a higher CR rate than a 5-HT3 receptor antagonist with dexamethasone (93.3% vs. 47.8%, p<0.001) and allowed the patients to maintain a higher level of dietary intake (93.3% vs. 56.5%, p<0.001). CONCLUSION: The addition of aprepitant therapy was more effective than the control therapy of a 5-HT3 receptor antagonist, and dexamethasone in gynecological cancer patients treated with the TC regimen.

CD24 expression as a marker for predicting clinical outcome and invasive activity in uterine cervical cancer.

CD24, a small heavily glycosylated mucin-like glycosyl-phosphatidylinositol-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<0.01), lymph node metastasis (34.6 vs. 14.3%) and lymphovascular involvement (65.4 vs. 20.4%, p=0.01), and a poor overall and disease-free survival (5-year survival rate: 62 vs. 86%, p=0.03). CD24 overexpression in CaSki cells resulted in activation of Cell Signaling proteins, including Akt, ERK, NF-κB and MMP-9. An invasion assay showed that CD24 overexpression in CaSki cells led to increased invasion ability. The CD24 overexpression also increased mRNA expression of Slug but not Snail. Moreover, the CD24 overexpression also decreased expression of E-cadherin and increased N-cadherin protein levels. Increased expression of CD24 may be associated with tumor progression and prognosis in patients with uterine cervical cancer. CD24 expression may therefore be used not only as a prognostic marker in uterine cervical cancer, but also as a target for the development of new therapeutic approaches.

MS-818 accelerates mobilization of endothelial progenitor cells and differentiation to endothelial cells.

MS-818 that is a synthetic pyrimidine compound and shown to have neurotrophic actions, enhanced basic fibroblast growth factor (bFGF)-induced angiogenesis in vivo. However, the mechanism and whether MS-818 affects endothelial cells (ECs) directly is not known. Here, the authors investigated whether MS-818 alone could induce angiogenesis and tried to clarify the mechanism of neovascularization by MS-818 in terms of angiogenesis and vasculogenesis. The authors show that MS-818 affects ECs directly and induces migration of and tube formation by ECs in vitro (angiogenesis). Furthermore, the authors demonstrate that MS-818 mobilizes endothelial progenitor cells (EPCs) from the bone marrow and potentiates their differentiation to ECs (vasculogenesis). The effect of MS-818 on the endothelial differentiation was further confirmed with an in vitro differentiation system using mouse embryonic stem cells. MS-818 activates the mitogen-activated protein kinase (MAPK) pathway but not the phosphoinositol 3-kinase (PI3K)-Akt pathway in ECs. These results indicate that MS-818, a synthetic compound, promotes both angiogenesis and vasculogenesis.

The EMT (epithelial-mesenchymal-transition)-related protein expression indicates the metastatic status and prognosis in patients with ovarian cancer.

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 < 0.05). The EMT status was significantly associated with both the progression-free survival and overall survival (p <0.01). A multivariate analysis showed an EMT-positive status to be a significant predictor of both the progression-free survival (p < 0.05) and overall survival (P < 0.01). CONCLUSIONS: These data indicate that the EMT status is significantly associated with peritoneal metastasis and both the progression-free survival and overall survival in patients with ovarian cancer. Therefore, clarifying and controlling EMT signaling is a promising approach to molecular targeted therapy for ovarian cancer.

Gemcitabine as a molecular targeting agent that blocks the Akt cascade in platinum-resistant ovarian cancer.

BACKGROUND: Gemcitabine (2', 2' -difluorodeoxycytidine) is one of many nonplatinum drugs that exhibit activity in recurrent, platinum-resistant ovarian cancer. However, the molecular mechanisms by which Gemcitabine treatment inhibits the proliferation of platinum-resistant ovarian cancer cells still remain unclear. We investigated whether Gemcitabine increases the efficacy of Cisplatin in platinum-resistant ovarian cancer models in vitro and in vivo. METHODS: We used Cisplatin-resistant Caov-3 cells, A2780CP cells and Cisplatin-sensitive A2780 cells to examine the sensitivity of the cell viability of Cisplatin and Gemcitabine using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and the sensitivity of the invasive activity of Cisplatin and Gemcitabine using an invasion assay with Matrigel. We examined the Akt kinase activity and matrix metalloproteinase 9 (MMP9) expression following Cisplatin and Gemcitabine treatment using a Western blot analysis and the mRNA expression of vascular endothelial growth factor (VEGF) using semi-quantitative RT-PCR. Moreover, we evaluated the effects of Cisplatin and Gemcitabine on the intra-abdominal dissemination of ovarian cancer in vivo. RESULTS: Gemcitabine significantly inhibited Cisplatin-induced Akt activation in the Caov-3 and A2780CP cells, but not in the A2780 cells. In the presence of Gemcitabine, Cisplatin-induced growth inhibition and apoptosis were significantly enhanced in the Caov-3 and A2780CP cells. Co-treatment with Cisplatin and Gemcitabine almost completely inhibited invasion of both types of cells through the Matrigel; however, neither Cisplatin nor Gemcitabine alone inhibited the invasion of both types of cells. Gemcitabine inhibited not only the Cisplatin-induced activation of Akt, but also the MMP9 and mRNA expression of VEGF. Moreover, treatment with Gemcitabine increased the efficacy of Cisplatin-induced growth inhibition of the intra-abdominal dissemination and production of ascites in the athymic nude mice inoculated with Caov-3 cells. CONCLUSIONS: We herein demonstrated that Gemcitabine inhibits the Akt kinase activity and angiogenetic activity following treatment with Cisplatin in platinum-resistant ovarian cancer cells. These results provide a rationale for using Gemcitabine in clinical regimens containing molecular targeting agents against platinum-resistant ovarian cancers.

Role of the two-point pull-up technique for treating the uterine arteries during radical hysterectomy and trachelectomy.

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<0.05). The mean length of the operation in the two point pull-up method group (481 ± 53 min) was not significantly different from the conventional surgery group (497 ± 74 min) (p=0.111). The mean number of dissected lymph nodes in the two point pull-up method group (37.2 ± 11.6) was not significantly different from that in the conventional method group (34.4 ± 10.2) (p=0.096). The overall survival and progression-free survival were also not substantially different between the two groups. In the radical trachelectomy, the mean blood loss was 377.5 ± 185.6 ml and the mean duration of surgery was 520.0 ± 48.5 min using the two point pull-up method. We were able to preserve both uterine arteries without accidental injury or disruptive bleeding. All four patients were menstruating normally as of the last examination. CONCLUSIONS: The two point pull-up method enabled us to reduce intraoperative blood loss without increasing other complications during abdominal radical hysterectomy or abdominal radical trachelectomy.

Prognostic impact of EMT (epithelial-mesenchymal-transition)-related protein expression in endometrial cancer.

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.

Mucinous adenocarcinoma of the intestinal type arising from mature cystic teratoma of the ovary: a rare case report and review of the literature.

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.