Search

Objective: The quantitative and qualitative analysis of circulating tumor cells (CTCs) aids in diagnosis of disease, prognosis, disease recurrence, and therapeutic response in several cancers. However, detection and isolation of CTCs from the blood circulation is a difficult task because of their scarcity and the lack of reliable markers to identify these cells. Especially, in epithelial ovarian cancer, there is a little reported data for CTCs and their CTCs has been defined to the EpCAM+ cells, even though EpCAM+ cells are just a few in ovarian cancer. The aim of this study is to investigate the effective principles and methods to detect and isolate CTCs through novel markers in ovarian cancer. Methods: CTC analysis was performed in the spiking test to find cancer cells in the human serum mixed with WBCs. Four cell lines including OVCAR3, SKOV3, SNU8 and SNU251 were used and primary cancer cells from 4 patients were analyzed. Cancer cells were isolated on the basis of cell size by filtration through CytoGen capture device, followed by identification according to validated immunocytochemistry based on the expression of DAPI, CD45, EpCAM, CK, CA-125 and HE4. Results: We obtained cancer cells more than 90% based on the cell size by filtration. Immunocytochemistry confirmed the epithelial origin through the expression of CK and EpCAM in cancer cell lines. The rate of expression was 35-99 % for CK and 1-99 % for EpCAM. A small number of cancer cell lines expressed CD45 that is the marker of WBC. The expression of CA-125 and HE4 showed their ovarian origin. The rate of expression was 7-98 % for CA-125 and 40-99 % for HE4 in cancer cell lines. Primary cancer cells were detected most effectively as the method of combination with 4 markers, including DAPI, CD45, EpCAM and HE4. Conclusion: Our findings provide the first evidence for effective methods to detect and isolate CTCs in ovarian cancer. Combination of DAPI, CD45, EpCAM and HE4 could be a useful marker to support CTCs research in epithelial ovarian cancer. Citation Format: Shin-Wha Lee, Ha-Young Lee, Jin-Young Mo, Byung Chul Kim, Eun Hye Kim, Yong-Man Kim. Detection and isolation of circulating tumor cells in ovarian cancer: Principles and methods. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3073. doi:10.1158/1538-7445.AM2014-3073

Conclusions: Sensitivity for CIN3+ of p16/Ki-67 from SurePath medium in women with HPV positive LSIL is sufficient that immediate colposcopy is not required for women who are p16/Ki67 negative. Compared to current guidelines for LSIL cytology, p16/ Ki-67 triage could reduce immediate referral to colposcopy by 35%. Unlike p16 alone, which requires morphologic assessment of p16positive cells, p16/Ki-67 evaluation is based on staining alone and may be fully automated. Further studies are required to evaluate p16/Ki-67 for triage of HPV-positive women with NILM and ASC-US. If a negative predictive value of similar magnitude is observed for these women, a substantial and welcome decrement in the total number of colposcopies required will be possible without significant loss of sensitivity for the screening program.

The aim of this study was to assess the distribution of HPV genotypes in high-grade cervical intraepithelial neoplasia (CIN) in Korea. This prospective study included consecutive 1009 patients who referred for cervical biopsy due to abnormal cytology. HPV genotyping was performed on the cervical smear using PCR-based DNA chip test for 21 high-risk HPV types. Histologic diagnosis was chronic cervicitis (CC), CIN 1, CIN 2, CIN3, and invasive carcinoma (IC) in 332 (32.9 %), 143 (14.1 %), 104 (10.3 %), 351 (34.7 %), and 79 (7.8 %) patients, respectively. High-risk HPV DNA was detected in 591 (58.7 %) patients and multiple HPV types were identified in 181 (17.9 %) patients. High-risk HPV DNA was detected in 41.5 %, 50.3 %, 63.4 %, 72.3 %, and 77.2% of patients with CC, CIN 1, CIN 2, CIN 3, and IC, respectively. The leading HPV types were HPV 16 (31.0 %), HPV 58 (12.9 %), HPV 18 (8.9 %), HPV 52 (7.4 %), HPV 31 (5.6 %), and HPV 33 (5.2%) for patients with high-grade lesions (CIN 2/3 and IC). The overall positivity rate of HPV 16 (odds ratio [OR], 6.83; 95 % confidence interval [CI], 4.54-10.29; p

Conclusions: Sensitivity for CIN3+ of p16/Ki-67 from SurePath medium in women with HPV positive LSIL is sufficient that immediate colposcopy is not required for women who are p16/Ki67 negative. Compared to current guidelines for LSIL cytology, p16/ Ki-67 triage could reduce immediate referral to colposcopy by 35%. Unlike p16 alone, which requires morphologic assessment of p16positive cells, p16/Ki-67 evaluation is based on staining alone and may be fully automated. Further studies are required to evaluate p16/Ki-67 for triage of HPV-positive women with NILM and ASC-US. If a negative predictive value of similar magnitude is observed for these women, a substantial and welcome decrement in the total number of colposcopies required will be possible without significant loss of sensitivity for the screening program.

While the number of refugees fleeing persecution and communal conflict approaches 50 million, people have also been forced to leave their homelands because of economic misery and environmental disruption. The number of environmentally displaced people is estimated to rival, if not exceed, that of treaty-defined political refugees. This chapter examines the political implications of humanitarian concern for environmentally displaced persons who are currently denied refugee status and therefore have little international protection. It is argued that the prevailing definitions of refugees found in UN documents are inadequate. The term environmental refugees’ is still controversial. Uncritical use of the term undermines the validity of refugee status claims and thus misrepresents the complexity of the problems. Efforts to clarify differences between environmental migrants and refugees, political and environmental refugees, and environmental victims and refugees may reduce the controversy. Sudan is discussed as an example of the connections between environmental degradation and forced population movements.

Myomectomy is common gynecologic procedure performed for the conservative management of leiomyomas. The surgical removal of myomas can be associated with a considerable amount of intra-operative blood loss, which represents an important morbidity that may be associated with the procedure. The purpose of this video presentation is to demonstrate various preoperative and intraoperative measures that may decrease blood loss during a myomectomy. A particular emphasis was placed on demonstrating the evidence-based strategies that have been shown to decrease blood loss in minimally-invasive abdominal myomectomies. The strategies that are covered in this video presentation include the preoperative use of medications, temporary and permanent uterine artery occlusion, injection of vasopressin and use of barbed suture for closure of the uterine defect.

Objectives: The objective of this study was to analyze the concentration of serum multivariate markers and find the optimized combination to diagnose ovarian cancer in patients with ovarian tumor. Methods: We collected serum samples prospectively from patients treated with ovarian tumors. Total 398 samples including malignant and benign ovarian tumor and normal controls, in testing set, were analyzed for their ovarian cancer-related 21 proteins, including CA125, HE4, CA19-9, CA15-3, CEA, Leptin, MIF, OPN, Prolactin, Cyfra21-1, IL-6, IL-8, MIP-1-alpha, Eotaxin, sEGFR, Apo AI, Apo CIII, Prealbumin(TTR), C-reactive protein(CRP), sNCAM, and sVCAM-1 by Luminex methods, which is a multiplexed immunoassay. In validation set, 6 protein markers were analyzed. Results: More than half of the biomarkers tested were found to differ significantly between benign and malignant cases. Among them, as individual markers, 6 markers including CA-125 and HE4 provided the discrimination between benign and malignant cases. The diverse combination of these 6 biomarkers provided a higher level of discriminatory power than either marker considered alone. We identified that these multimarker panels could discriminate ovarian cancers from benign cases with more than 95% of sensitivity, 95% of negative predictive value and 85% of accuracy in 75% of specificity. These multimarkers showed the improved differentiation diagnosis in early stage cancer and pre-menopausal women comparing to the CA-125 alone. Conclusions: We describe a blood-based assay using multimarkers that can distinguish women with ovarian cancer from those with benign conditions. Preliminary evaluation of the multimarker panels suggests it has the potential to improve the accuracy to diagnose ovarian cancers. While promising, the performance needs to be assessed in a blinded clinical validation study. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A32. Citation Format: Shin-Wha Lee, So-Jin Shin, Min-Sun Kyung, Young-Man Kim, Young-Tak Kim. Novel biomarker algorithm to improve the differential diagnosis of ovarian cancer with in patients with ovarian tumor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A32.

5568 Background: Cremorphor EL, used to enhance drug solubility, may add to paclitaxel’s toxicities such as hypersensitivity reactions or peripheral neuropathy. This multi-institutional phase II trial is to evaluate the efficacy and safety of Cremophor-Free, Polymeric Micelle Formulation of Paclitaxel (Genexol-PM) compared to Paclitaxel (Genexol) as a combined chemotherapy with carboplatin in patients with advanced epithelial ovarian cancer. Methods: In this phase II, randomized, parallel study, patients with FIGO stage IC-IV epithelial ovarian cancer after debulking surgery received intravenously Genexol-PM 260 mg/m2 or Genexol 175 mg/m2 combined with carboplatin iv (AUC 5) on day 1 of every 3-week cycle for a maximum of six cycles. The primary endpoint was composite response by GCIG CA-125 Response and Response Evaluation Criteria In Solid Tumors (RECIST). Secondary and exploratory endpoints included overall survival, progression-free survival, time to tumor progression, and safety and tolerability. Results: A total of 102 patients were randomized to Genexol-PM plus carboplatin (n = 51) or Genexol plus carboplatin (n = 51). Composite response rate in patients with or without measurable disease was 88.0% in the Genexol-PM plus carboplatin group and 77.1% in the Genexol plus carboplatin group. Noninferiority of Genexol-PM plus carboplatin compared with Genexol plus carboplatin was confirmed for composite response rate by CA-125/RECIST criteria. There were no differences in progression-free survival and overall tumor progression between the groups. Although there was a higher rate of grade 3 neutropenia in the Genexol-PM plus carboplatin group, the overall rate of hemodynamic adverse events was comparable between the 2 groups. There was no difference in peripheral neuropathy and hypersensitivity. No unexpected safety concerns were identified in this study. Conclusions: High-dose of Genexol-PM in combination with carboplatin was well tolerated, and its response rate was noninferior to that of Genexol plus carboplatin in patients with advanced epithelial ovarian cancer. Clinical trial information: NCT01276548.

5600 Background: The aim of this study was to develop a preoperative risk prediction model for lymph node metastasis in patients with early cervical cancer. Methods: The medical records of 504 patients with early cervical cancer who underwent hysterectomy and pelvic/paraaortic lymphadenectomy between 2007and 2012 in our center were retrospectively reviewed. According to the order of surgery performed, data between 2007 and 2010 were allocated to a model development cohort (n=314), and data between 2011 and 2012 were allocated to an external validation cohort (n=190). By using preoperative clinicopathologic data, magnetic resonance imaging (MRI) data, and positron emission/computed tomography (PET/CT) data, a multivariate logistic model was created. Based on this model, predictive nomogram was developed and externally validated. Results: Age, tumor size measured by MRI, and lymph node metastasis on PET/CT were found to be independent risk factors for nodal metastasis. Developed nomogram incorporating these three predictors showed good discrimination and calibration, with a bootstrap-adjusted concordance index of 0.772. Also, the validation set showed good discrimination with a bootstrap-adjusted concordance index of 0.783. Conclusions: We have developed a robust model to predict lymph node metastasis in patients with early cervical cancer. This new tool may be useful to clinicians and patients when deciding lymphadenectomy and maybe useful in designing clinical trials. [Table: see text]

The responsibility to protect (R2P) is a new norm or set of principles that redefines sovereignty as a responsibility rather than as a privilege or a means of control, which offers a policy guideline on when and how the international community should intervene for the sake of human protection in the face of mass atrocity crimes. Just as in humanitarian intervention, however, the R2P faces several dilemmas: How serious should humanitarian emergencies be to warrant international intervention? Why did we need intervention in Libya while not in Syria where the situation seems to have been more serious than Libya in terms of the necessity of civilian protection? How can the narrowly defined R2P crimes accommodate those suffering in complex humanitarian crises? Is it feasible for the international community to opt for military intervention in North Korea based on the principles of the R2P if a crisis occurs as it did in Libya? Along the line of these inquiries, the paper reviews the concept and debates of the R2P, discusses the possibility of the R2P applied to the real world through examining cases such as Libya, Syria, Sudan Darfur, and Myanmar. Also, the feasibility and validity of expanding the R2P scope, only limited to the "four R2P crimes(i.e. genocide, ethnic cleansing, war crimes, and crimes against humanity), will be assessed, with particular emphasis on the practical implications for the case of North Korea

Objectives : Ovarian cancer is the 7th most common malignancy and the 5th most common cause of death from cancers in women. While many patients initially respond to surgery and chemotherapy, the long-term prognosis is generally unfavorable, with recurrence and development of drug-resistant disease. Therefore, new strategies of treatment, for examples, immunotherapy or targeted therapy, are necessary. This study evaluated the efficacy and safety of activated human natural killer (NK) cells against ovarian cancer. Methods:Four Korean patients were selected from the Asan Medical Center. These patients were diagnosed with endometrioid adenocarcinoma (n = 2), papillary serous adenocarcinoma (n = 2). And two established human ovarian epithelial carcinoma cell lines (SKOV3 and OVCAR3) were used for all experiments. First of all, for the morphological analysis to detect ovarian cancer, cytokeratin (CK-7) was used on primary cells by fluorescence microscopy and nuclei were stained with DAPI. MTT assay to evaluate cell viability, the modified lactate dehydrogenase (LDH) release assay to determine the cytotoxic activity, and ELISA to detect the secretion levels of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and IL-12p70 were measured for the capacity of activated NK cells on the ovarian cancer cells. Results: Primary cells were confirmed using CK-7 as a tool of distinction of ovarian cancers by fluorescence microscopy. Secondly, an MTT assay was performed to determine the effect of NK cells on the proliferation of cancer cells after 4, 12, 24, and 48 h of induction in cell ratios of 0.3:1, 1:1, and 3:1. NK cells caused the loss of cancer cell viability and proliferation, although the time courses and cell ratios differed by cancer cell type. Thirdly, to investigate whether NK cells could have a cytotoxic effect on cancer cells, an LDH assay was performed in NK cells and target cells. SKOV3 showed higher cytotoxicity than OVCAR3 in cancer cell lines and cytotoxicity of papillary serous adenocarcinoma cells was much more pronounced that all other cell types. Finally, IFN-γ and TNF-α were significantly released at all ratios in SKOV3 and OVCAR3 cell lines and patient-derived cells, but IL-12 secretion was not detected in all ovarian cancer cells. Although NK cells were activated independently from IL-12, these results suggest that various cytokines play a pivotal role in NK-cell-induced immune responses and could be evidence for activated NK cells. Conclusion: Taken together, NK cells affect ovarian cancer cells upon treatment of direct killing malignant cells and producing cytokines that enhances both the innate and the antigen-specific anti-tumor response. Therefore, the results suggest that NK cell-based treatment could be an alternative immunotherapy for ovarian cancer patients. Citation Format: Mo Jin Young, Shin-Wha Lee, Yong-Man Kim. The effective activation of highly purified NK cells expanded ex vivo on identified epithelial ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2845. doi:10.1158/1538-7445.AM2013-2845

We do appreciate Dr. Seong's comments about our recently published article on the proliferation of regulatory T (Treg) cells in ex vivo expanded ascitic fluid from ovarian cancer, and we would like to address two points that Dr. Seong has made.

Objective Regulatory T lymphocytes evoke the immune tolerance by suppressing and inactivating cytotoxic T lymphocytes. The objective of this study was to compare the proportion of regulatory T lymphocytes, precisely defined as CD4(+)CD25(high+)Foxp3(+) T lymphocytes, in primary and recurrent ovarian carcinoma before and after ex vivo expansion of ascites with interleukin-2 (IL-2). Methods Ascitic fluid samples were obtained from 26 patients with ovarian carcinoma. Lymphocytes were isolated from ascites and cell markers were analyzed by flow cytometry using anti-CD3/CD4/CD8/CD16/CD56/CD25 and anti-Foxp3 antibodies. Lymphocytes were incubated for 2 to 3 weeks and expanded ex vivo by IL-2 stimulation and their phenotypes were analyzed by flow cytometry. Results Following ex vivo expansion, ascitic fluid lymphocytes increased by a greater extent in the recurrent group than in the primary group. The proportion of ex vivo-expanded lymphocytes changed as follows; CD4(+) T lymphocytes increased, CD8(+) T lymphocytes decreased, and the proportion of CD3(-)CD16(+)56(+) NK cells was unchanged. The proportion of CD4(+)CD25(high+)Foxp3(+) regulatory T lymphocytes in CD4(+) T lymphocytes increased after ex vivo expansion in both groups, but to a greater degree in the recurrent group. Conclusion This study showed that regulatory T lymphocytes, neither cytotoxic T lymphocytes nor NK cells, were extensively increased after ex vivo expansion, especially in recurrent ovarian carcinoma. These results may provide information that helps to guide the future development of adoptive immunotherapy against ovarian carcinoma.

Objective : To determine the efficacy and safety of capecitabine in patients with gynecologic cancers as adjuvant chemotherapy or maintenance treatment. Methods : In this study, patients who were treated with capecitabine between January 2000 and June 2007 at Asan Medical Center, Seoul, Korea were reviewed. Thirty-one patients with gynecologic cancers were included 16 patients with recurrent ovarian cancer, 9 patients with cervical cancer after initial treatment, and 6 patients with recurrent cervical cancer. These patients` data were analyzed by review of medical records and pathologic and laboratory reports retrospectively. Response was assessed by both RECIST criteria for patients with measurable disease and CA 125 criteria in patients with ovarian cancer and National Cancer Institute criteria for progression, response, and toxicity were utilized in cervical cancer. Results : Capcitabine was given at a dosage of 2,000-2,500 mg/m2/day orally in a divided dose daily for 14 days followed by a 7-day rest period in all patients. Nine patients with ovarian cancer were treated with more than 2 cycles and their median age was 49 years (43-67). Two patients showed a partial response and the median progression free survival was 3 months. Nine patients with cervical cancer after initial treatment were in the complete response state and their median progression free survival was 24.5 months. No partial or complete responses were seen in 6 patients with recurrent cervical cancer. There was no severe toxicity. Conclusion : Although capecitabine is a well-tolerated regimen, as a single agent, it produces minimal benefit in recurrent ovarian and cervical cancer population.

Meeting abstracts This study is to investigate which Toll Like Receptors (TLRs) are expressed on human ovarian cancer cell lines and to evaluate the effect of TLR expression on the growth of ovarian cancer cells. Four human ovarian epithelial carcinoma cell lines SKOV3 (clear), OVCAR3 (serous