Yoo Young Lee

The expression of the miRNA-200 family in endometrial endometrioid carcinoma

OBJECTIVE Recent reports suggest that targeting the unique miRNAs highly expressed in several cancers may be a promising approach in the development of new cancer therapeutic tools. The purpose of this study was to evaluate the roles of miRNAs as therapeutic targets in human endometrial endometrioid carcinomas (EECs). METHODS We evaluated the differential expressions of miRNAs in EECs and normal endometrial tissues using microarrays and cluster analysis. After validation of differentially expressed miRNAs in another set of EECs and normal endometrial tissues, we performed the in vitro experiment using endometrial cancer cells with anti-miRNA (anti-miR) to evaluate the roles of miRNAs that are highly expressed in EECs for cell proliferation and chemosensitivity. RESULTS A miRNA microarray showed that the miR-200 family, including hsa-miR-141, hsa-miR-200a, hsa-miR-200b, hsa-miR-200c, and hsa-miR-429, was up-regulated in EECs as compared with that in normal endometrial tissues. When we treated endometrial cancer cells with specific anti-miRs, including anti-miR-141, -200a, -200b, -200c, or -429, we found that anti-miR-200a, -200b, -200c, and -429 significantly inhibited the growth of HEC-1A cells and anti-miR-141, -200c, and -429 significantly inhibited the growth of Ishikawa cells. Moreover, transfection with anti-miR-429 enhanced the cytotoxic effect of cisplatin in HEC-1A cells. CONCLUSIONS These results indicate that the miR-200 family is highly expressed in EECs compared with that of normal endometrial tissues and could play an important role in cancer growth. Specifically, anti-miR-429 could enhance the cytotoxic activity with cisplatin in EECs. Therefore, the miR-200 family may offer new candidate targets to be exploited in therapeutic strategies for patients with these carcinomas.

Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma

OBJECTIVE The renin-angiotensin system (RAS) influences cardiovascular homeostasis, and Angiotensin II type 1 receptor (AGTR1) is the main effector of RAS, and AGTR2 antagonizes AGTR1. Accumulating evidence supports the role of RAS in the paracrine regulation of tumorigenesis in several cancer types. Although treatment with AGTR1 antagonist (losartan) or AGTR2 agonist (CGP42112A) inhibits tumor progression in several cancer cells, their combined treatment has not been reported. METHODS In this study, we estimated the expression of AGTR1 and AGTR2 in epithelial ovarian cancer cells and tissues. Then, we evaluated the anti-cancer effects of combined treatment with losartan and/or CGP42112A in ovarian cancer cells and human umbilical vein endothelial cells (HUVEC). RESULTS AGTR1 protein was detected in 86% of ovarian cancer tissues, while AGTR2 was not detected in immunohistochemistry. The mRNA expression of AGTR1 obtained from the cancer genome atlas (TCGA) dataset showed that AGTR1 overexpression was correlated with poor survival. Treatment with either losartan or CGP42112A reduced the angiotensin II (Ang II)-mediated cell survival in both ovarian cancer cells and HUVEC. Combined treatment with losartan and CGP42112A synergistically decreased cell survival. As a downstream pathway, phosphorylation of phospholipase C β3 (PLC β3) and expression of vascular endothelial growth factor (VEGF) decreased synergistically in combined treatment. CONCLUSION The results suggest that dual regulation of AGTR1 and AGTR2 may be a novel therapeutic strategy for epithelial ovarian carcinoma through inhibition of cancer cell survival as well as anti-angiogenesis. TRANSLATIONAL RELEVANCE This study investigated the expressions of AGTR1 and AGTR2 in epithelial ovarian carcinoma and the therapeutic potential of AGTR modulation with specific antagonist and/or agonist in epithelial ovarian cancer cells. Treatment of AGTR1 antagonist, losartan and/or AGTR2 agonist, CGP42112A synergistically mediated anti-cancer effects including the decrease of cell survival and down-regulation of VEGF.

Outcomes of laparoscopic fertility-sparing surgery in clinically early-stage epithelial ovarian cancer

Objective Fertility-sparing surgery (FSS) is becoming an important technique in the surgical management of young women with early-stage epithelial ovarian cancer (EOC). We retrospectively evaluated the outcome of laparoscopic FSS in presumed clinically early-stage EOC. Methods We retrospectively searched databases of patients who received laparoscopic FSS for EOC between January 1999 and December 2012 at Samsung Medical Center. Women aged ≤40 years were included. The perioperative, oncological, and obstetric outcomes of these patients were evaluated. Results A total of 18 patients was evaluated. The median age of the patients was 33.5 years (range, 14 to 40 years). The number of patients with clinically stage IA and IC was 6 (33.3%) and 12 (66.7%), respectively. There were 7 (38.9%), 5 (27.8%), 3 (16.7%), and 3 patients (16.7%) with mucinous, endometrioid, clear cell, and serous tumor types, respectively. Complete surgical staging to preserve the uterus and one ovary with adnexa was performed in 4 patients (22.2%). Two out of them were upstaged to The International Federation of Gynecology and Obstetrics stage IIIA1. During the median follow-up of 47.3 months (range, 11.5 to 195.3 months), there were no perioperative or long term surgical complications. Four women (22.2%) conceived after their respective ovarian cancer treatments. Three (16.7%) of them completed full-term delivery and one is expecting a baby. One patient had disease recurrence. No patient died of the disease. Conclusion FSS in young patients with presumed clinically early-stage EOC is a challenging and cautious procedure. Further studies are urgent to determine the safety and feasibility of laparoscopic FSS in young patients with presumed clinically early-stage EOC.

Comparison of survival outcomes after recurrence detected by cancer antigen 125 elevation versus imaging study in epithelial ovarian cancer.

Objective The aim of this study was to compare survival outcomes in two groups of patients with recurrent epithelial ovarian cancer (EOC) with initial recurrence detection by cancer antigen 125 (CA-125) elevation or imaging, and underwent secondary cytoreductive surgery (SCS). Methods A retrospective review of the medical records was performed on 99 recurrent EOC patients who underwent SCS at the Samsung Medical Center between January 2002 and December 2013. For follow-up after primary treatment, patients were routinely assessed by CA-125 levels every 3 months and computed tomography (CT) scan (or magnetic resonance imaging [MRI]) every 6 months for first 3 years, and by CA-125 every 6 months and CT scan (or MRI) every 12 months thereafter. Results The first recurrence was initially identified by either CA-125 elevation (n=41, 41.4%) or by imaging study (n=58, 58.6%). None of the patients showed the symptoms as initial sign of recurrence. There were higher percentages of extra-pelvic recurrence (87.8%) and multiple recurrences (78.0%) in the group diagnosed by CA-125 elevation. The proportion of no residual disease after SCS was comparably lower in the CA-125 group (22.0% vs. 72.4%). There were 19 cancer-associated deaths (19.2%) within a median follow-up period of 67 months. The group diagnosed by imaging had better overall survival from initial diagnosis (OS1), overall survival after SCS (OS2), progression-free survival after the initial treatment (PFS1) and progression-free survival after SCS compared to those of the CA-125 group (PFS2). Conclusion EOC patients with recurrence initially detected by imaging study showed better survival outcomes than patients diagnosed by CA-125 elevation.

Time-lapse imaging of sentinel lymph node using indocyanine green with near-infrared fluorescence imaging in early endometrial cancer

Objective Indocyanine green with near-infrared fluorescence imaging (NIR-ICG) is a new tracer modality in the limelight used for lymphatic mapping. The advantage of this method is to provide real-time image during surgery. To use ICG for image guided lymph node dissection, a surgeon needs to know initial appearing time and duration. Methods A 52-year-old woman undertook surgery diagnosed with endometrial cancer. She had no past medical history and her body mass index was 25.3 kg/m2. Preoperative magnetic resonance imaging examination revealed 2.7 cm sized cancerous mass in the endometrial cavity with superficial myometrial invasion without lymph node enlargement. Four mL (1.25 mg/mL) of ICG solution was prepared for injection. For each site, 1 mL of solution was injected superficially, 2–3 mm into the cervical submucosa and another 1 mL was injected deep, 1–2 cm into the stroma of the cervix [12]. We recorded video with 30° 10 mm scope equipped with a specific lens and light source emitting both visible and NIR light (KARL STORZ GmbH & Co. KG, Tuttlingen, Germany). Results Pelvic lymph node was visualized from around 5 minutes. ICG was dispersed into organs after hysterectomy (53 minutes after ICG injection), yet we could clearly identify sentinel lymph node (SLN). Pathology revealed endometriod adenocarcinoma grade I, myometrial invasion with less than half of myometrium and no lymph node metastasis. Conclusion Cervical injection of ICG provides good visualization of SLN from 5 minutes to over an hour. Our film gives an idea about time management to make a plan for surgery and not to miss SNLs.

Feasibility of laparoscopic cytoreduction in patients with localized recurrent epithelial ovarian cancer

Objective To assess the feasibility of laparoscopic cytoreduction in patients with localized recurrent epithelial ovarian cancer (EOC) by comparing its outcomes to those of laparotomy. Methods We performed retrospective analysis in 79 EOC patients who had a localized single recurrent site, as demonstrated by computed tomography (CT) scan, magnetic resonance imaging, or positron emission tomography/CT scan; had no ascites; were disease-free for 12 or more months prior; and who had undergone secondary cytoreduction (laparoscopy in 31 patients, laparotomy in 48 patients) at Samsung Medical Center between 2002 and 2013. By reviewing the electronic medical records, we investigated the patients’ baseline characteristics, surgical characteristics, and surgical outcomes. Results There were no statistically significant differences between laparoscopy and laparotomy patients in terms of age, body mass index, cancer antigen 125 level, tumor type, initial stage, grade, recurrence site, type of procedures used in the secondary cytoreduction, adjuvant chemotherapy, and disease-free interval from the previous treatment. With regards to surgical outcomes, reduced operating time, shorter hospital stay, and less estimated blood loss were achieved in the laparoscopy group. Complete debulking was achieved in all cases in the laparoscopy group. Conclusion The laparoscopic approach is feasible without compromising morbidity and survival in selected groups of patients with recurrent EOC. The laparoscopic approach can be a possible treatment option for recurrent EOC.

Long-term outcomes of magnetic resonance imaging-invisible endometrial cancer

Objective Magnetic resonance imaging (MRI) is useful for staging endometrial cancer. The treatment and prognosis of MRI-invisible endometrial cancer remain unclear. The purpose of this study was to retrospectively evaluate the long-term outcomes of patients with MRI-invisible endometrial cancer. Methods Between February 1995 and December 2011, we reviewed the medical records of 433 patients with endometrial cancer, which was staged IA on MRI. Of these patients, 89 had MRI-invisible cancer and 344 had MRI-visible cancer. Both cancers were treated with simple hysterectomy with or without lymph node dissection according to the surgeons decision. Both cancers were compared regarding pathologic findings, recurrence rates, and survival rates. Results The median sizes of MRI-invisible and MRI-visible cancers were 4 mm (0 to 40 mm) and 20 mm (0 to 89 mm), respectively (p<0.001). Myometrial invasion of these groups were detected in 20.2% (18/89) and 56.7% (195/344), respectively (p<0.001). Lymphadenectomy and follow-up imaging revealed no lymph node metastasis in patients with MRI-invisible cancers, while those revealed in 4.7% (16/344) of patients with MRI-visible cancers (p=0.052). The recurrence rates of MRI-invisible and MRI-visible cancers were 1.1% (1/89) and 7.8% (27/344), respectively (p=0.026). The recurrence-free survival rates of these groups were 98.9% (88/89) and 91.6% (315/344), respectively (p=0.022). Conclusion MRI-invisible endometrial cancer can be treated with less invasive surgery because of its lower tumor burden and better prognosis. This cancer may not require lymphadenectomy because of no metastasis or recurrence in lymph nodes.

Long-term Outcomes of MRI Stage IIB Cervical Cancer.

Objective Magnetic resonance imaging (MRI) can be used to assess parametrial invasion (PMI) in cervical cancer. Discordance between MRI findings and International Federation of Gynecology and Obstetrics (FIGO) staging is not uncommon because FIGO staging depends on physical examination. The purpose of this study was to retrospectively evaluate the long-term outcomes of MRI stage IIB cervical cancer. Methods A total of 312 patients with MRI stage IIB cervical cancer were retrospectively found between 2002 and 2011. Of these patients, 171 (group 1) were FIGO stage IIB cervical cancers and 141 (group 2) were MRI stage IIB cervical cancers that were negative PMI on physical examination. Group 1 was treated with chemotherapy and/or radiation therapy, and group 2 was treated with radical hysterectomy and lymph node dissection. The FIGO stages and pathologic findings of group 2 were recorded. Groups 1 and 2 were compared regarding 5-year overall survival rate. Results The FIGO stages of group 2 were IB1 in 51 (36.2%), IB2 in 28 (19.9%), and IIA in 62 (44%), whereas those of group 1 were all IIB. Group 2 showed lymphovascular space invasion in 71 (50.4%), lymph node metastasis in 48 (34.0%), PMI in 46 (32.6%), and vagina invasion in 9 (6.4%). Five-year overall survival rates of groups 1 and 2 were 73.7% and 84.5%, respectively (P = 0.013). Conclusions Magnetic resonance imaging stage IIB cervical cancers with negative PMI on physical examination should be surgically treated because of better survival rate than FIGO stage IIB cervical cancers.

Abstract 697: c-MET as a potential target in ovarian clear-cell carcinoma

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Purpose: Recent reports revealed that c-MET activation is associated with epithelial ovarian carcinoma (EOC) and is association with poor prognosis. In this study, we investigated the effects of therapeutic targeting for c-MET in ovarian clear cell carcinoma (OCCC). Experimental Design: Expression levels of c-MET in the epithelial ovarian carcinomas and normal ovarian tissues were evaluated using real-time PCR. To test c-MET inhibitors in CCC cell lines, we performed in vitro experiments including MTT and apoptosis assay. We performed Western blots to evaluate the c-MET expression and down-stream pathway. In addition, we performed in vivo therapy experiments in orthotopic ovarian cancer mice model (RMG1) and patient-derived tumor xenograft (PDX) models of CCC to confirm these effects. Results: The c-MET expression was significantly increased in CCCs compared with serous carcinomas and normal ovarian tissues (P < 0.05). CCC cells treated with c-MET inhibitors (SU11274 or crizotinib) demonstrated significantly decreased cell viability and increased apoptosis. Western blot assay showed that the protein expressions for c-MET signaling pathway were decreased by c-MET inhibitor. Moreover, tumor weight was significant decreased in both in vivo RMG1 and PDX models receiving SU11274 treatment compared with control (P < 0.05). Conclusion: These results show that c-MET inhibitor has the significant anti-tumor effects in ovarian CCC, and suggested that c-MET could have the potential agent in the therapy for this cancer. Citation Format: Jeong-Won Lee, Byoung-Gie Kim, Duk-Soo Bae, Yoo Young Lee. c-MET as a potential target in ovarian clear-cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 697. doi:10.1158/1538-7445.AM2015-697