Chi Heum Cho

Nuclear factor (erythroid-derived 2)-like 2 regulates drug resistance in pancreatic cancer cells.

Objective: To investigate the molecular basis of drug resistance in pancreatic cancer. Methods: The expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) levels in pancreatic cancer tissues and cell lines was analyzed. Clinical relevance between Nrf2 activation and drug resistance was demonstrated by measuring cell viability after Nrf2 and adenosine 5&vprime;-triphosphate-binding cassette, subfamily G member 2 (ABCG2) regulation by overexpression or knock-down of these genes. Activity of ABCG2 was measured by Hoechst 33342 staining. Results: Abnormally elevated Nrf2 protein levels were observed in pancreatic cancer tissues and cell lines relative to normal pancreatic tissues. Increasing Nrf2 protein levels either by overexpression of exogenous Nrf2 or by activating endogenous Nrf2 resulted in increased drug resistance. Conversely, a reduction in endogenous Nrf2 protein levels or inactivation of endogenous Nrf2 resulted in decreased drug resistance. These changes in drug resistance or sensitivity were also positively correlated to the expression levels of Nrf2 downstream genes. Similarly, the expression of ABCG2 was correlated with drug resistance. Conclusions: Because the intrinsic drug resistance of pancreatic cancers is, in part, due to abnormally elevated Nrf2 protein levels, further research on regulating Nrf2 activity may result in the development of novel pancreatic cancer therapies.Abbreviations: Nrf2 - nuclear factor (erythroid-derived 2)-like 2, ABCG2 - adenosine 5&vprime;-triphosphate-binding cassette, subfamily G member 2, MRP - multidrug resistance protein

Attitudes of cancer patients, family caregivers, oncologists and members of the general public toward critical interventions at the end of life of terminally ill patients

Background: Whereas most studies have focused on euthanasia and physician-assisted suicide, few have dealt comprehensively with other critical interventions administered at the end of life. We surveyed cancer patients, family caregivers, oncologists and members of the general public to determine their attitudes toward such interventions. Methods: We administered a questionnaire to four groups about their attitudes toward five end-of-life interventions — withdrawal of futile life-sustaining treatment, active pain control, withholding of life-sustaining measures, active euthanasia and physician-assisted suicide. We performed multivariable analyses to compare attitudes and to identify sociodemographic characteristics associated with the attitudes. Results: A total of 3840 individuals — 1242 cancer patients, 1289 family caregivers and 303 oncologists from 17 hospitals, as well as 1006 members of the general Korean population — participated in the survey. A large majority in each of the groups supported withdrawal of futile life-sustaining treatment (87.1%–94.0%) and use of active pain control (89.0%–98.4%). A smaller majority (60.8%–76.0%) supported withholding of life-sustaining treatment. About 50% of those in the patient and general population groups supported active euthanasia or physician-assisted suicide, as compared with less than 40% of the family caregivers and less than 10% of the oncologists. Higher income was significantly associated with approval of the withdrawal of futile life-sustaining treatment and the practice of active pain control. Older age, male sex and having no religion were significantly associated with approval of withholding of life-sustaining measures. Older age, male sex, having no religion and lower education level were significantly associated with approval of active euthanasia and physician-assisted suicide. Interpretation: Although the various participant groups shared the same attitude toward futile and ameliorative end-of-life care (the withdrawal of futile life-sustaining treatment and the use of active pain control), oncologists had a more negative attitude than those in the other groups toward the active ending of life (euthanasia and physician-assisted suicide).

Ovarian preservation during the surgical treatment of early stage endometrial cancer: A nation-wide study conducted by the Korean Gynecologic Oncology Group

OBJECTIVES The objective of this study was to determine whether ovarian preservation is feasible in younger endometrial cancer patients. METHODS Endometrial cancer patients who underwent ovary-saving surgery were recruited from the tumor registries of 14 tertiary hospitals under the influence of the Korean Gynecologic Oncology Group (KGOG). Information regarding patient age, preoperative and intraoperative evaluations, pathologic reports, and follow-up results was abstracted from medical records. RESULTS One hundred and seventy five patients were eligible for this study. Mean patient age at the time of surgery was 38.5+/-8.3 years (range 25-57). Ovary-preserving surgery was performed in 101 (57.7%) patients who desired to preserve their ovaries, incidentally in 69 (39.4%) patients with preoperative diagnoses other than endometrial carcinoma, and in 5 patients (2.9%) with unknown reasons. Median duration of follow-up was 55.0 months (range 6.2-180.0 months). Recurrence free survival and overall survival rates were 94.3 and 93.3%, respectively. Seven of the 175 (4.0%) patients had documented recurrence, and no recurrences were observed in stage I patients with endometrioid histology. All 7 recurrences had risk factors that could have reasonably explained recurrence, namely, non-endometrioid histology (4/7), deep myometrial invasion (5/7), cervical stromal invasion (4/7), and inadequate adjuvant treatment (4/7). No metachronous ovarian malignancy occurred during follow-up. Ten (5.8%) deaths occurred during follow-up; five resulted from disease recurrence, and 5 from non-disease related causes. CONCLUSION Our findings suggest that ovarian preservation does not adversely impact the recurrence of early stage endometrial cancer.

Outcomes of ovarian preservation in a cohort of premenopausal women with early-stage endometrial cancer: A Korean Gynecologic Oncology Group study

OBJECTIVE The aim of this study was to evaluate the impact of ovarian preservation on the recurrence and survival rates of premenopausal women with early-stage endometrial cancer. METHODS Using medical records of premenopausal women who received primary surgical treatment for stage I-II endometrial cancer, the demographics and survival rates were compared retrospectively for patients who had ovarian preservation and those who underwent bilateral salpingo-oophorectomy. Cox proportional hazards models with inverse probability of treatment weighting (IPTW) based on propensity score were performed to adjust for selection bias between the two groups. RESULTS A total of 495 women were identified, including 176 patients who had ovarian preservation. The ovarian preservation group was younger (P<0.001) and had an earlier year of diagnosis (P=0.014), a lower prevalence of lymphadenectomy (P<0.001), and a marginally significant association with lower tumor grade (P=0.052). The Kaplan-Meier curve and the log rank test showed no difference in either recurrence-free survival (P=0.742) or overall survival (P=0.462) between the two groups. In a multivariate Cox model adjusted by IPTW and covariates, ovarian preservation had no effect on either recurrence (hazard ratio [HR], 0.73; 95% CI, 0.29-1.81) or overall survival (HR, 1.33; 95% CI, 0.43-4.09). CONCLUSIONS Ovarian preservation does not appear to be associated with an adverse impact on the outcomes of premenopausal women with early-stage endometrial cancer. The present study has useful implications for physicians counseling young women who want to preserve their ovaries.

Clinicopathologic characteristics of malignant germ cell tumors in the ovaries of Korean women: a Korean Gynecologic Oncology Group Study.

From January 1995 to December 2000, medical records of 196 patients were collected from 14 hospitals nationwide and were reviewed retrospectively. We evaluated the clinicopathologic characteristics of malignant germ cell tumors in the ovaries of South Korean women and determined the prognostic factors affecting recurrence. The mean patient age was 23.8 years (range, 4-63 years), and the median follow-up period was 67 months (range, 1-128 months). The distribution of the International Federation of Gynecology and Obstetrics stage was as follows: 128 cases (65.3%) in stage I, 27 cases (13.8%) in stage II, 39 cases (19.9%) in stage III, and 2 cases (1.0%) in stage IV. Histologically, immature teratoma was the most common tumor type (n = 68), followed by dysgerminoma (n = 54), endodermal sinus tumor (n = 38), mixed form (n = 24), and choriocarcinoma (n = 12). A fertility-sparing operation was performed in 134 patients, staging operation in 43 patients, and hysterectomy and bilateral salpingo-oophorectomy in 19 patients. Postoperative chemotherapy was administered in 166 patients, and the most common regimen was bleomycin, etoposide, and cisplatin (n = 120). Recurrence was observed in 13 patients (6.8%) and was influenced by the stage of the tumor and patient age (>40 years). The 5-year survival rate was 96.7%. During the follow-up period, 20 patients had 22 pregnancies that resulted in 17 normal deliveries at term and 5 abortions. The results of this study demonstrate that most malignant germ cell tumors of the ovary in Korean women are detected in the early stage and have excellent survival outcomes with conservative operation and platinum-based chemotherapy.

Clinical Presentation of Endometrioid Epithelial Ovarian Cancer with Concurrent Endometriosis: A Multicenter Retrospective Study

Background: Endometrioid epithelial ovarian cancer (EEOC) is frequently diagnosed in conjunction with endometriosis and is suggested to arise during the process of endometriosis. This study evaluates the clinical manifestations, including endometriosis-related symptoms and their relationships according to the coexistence of endometriosis. Methods: Using medical records, a retrospective analysis was conducted on 221 patients treated for EEOC at four tertiary educational hospitals between 2000 and 2008. The initial presenting symptoms, particularly those related to endometriosis, were examined in relation to the coexistence of endometriosis or other clinical variables. Results: Endometriosis was identified in 82 (37.1%) of the 221 patients with EEOC. The most common symptoms were pelvic pain followed by gastrointestinal symptoms, palpable mass, abdominal distension, vaginal bleeding, and newly developed or exacerbated dysmenorrhea (18.1%) and dyspareunia (13.6%). Notably, dysmenorrhea and dyspareunia were frequently observed in patients with endometriosis. Among 210 patients identified with pretreatment serum CA-125, 54 (25.7%) displayed normal CA-125 levels (<35 units/mL) and 23.3% and 29.9% of patients without and with endometriosis had normal CA-125 levels, respectively (P = 0.381). Additionally, 32.6% of the patients with early-stage EEOC displayed normal CA-125 levels. Conclusions: In this large series of patients with EEOC, the main presenting symptoms were pelvic pain followed by gastrointestinal symptoms, palpable mass, abdominal distension, vaginal bleeding, and newly developed or exacerbated dysmenorrhea and dyspareunia. Dyspareunia and dysmenorrhea were more frequently detected in patients with endometriosis. Normal CA-125 levels cannot be applied as a marker to exclude EEOC, particularly at the early stages. Cancer Epidemiol Biomarkers Prev; 19(2); 398–404

A randomized, multi-center, clinical trial to assess the efficacy and safety of alginate carboxymethylcellulose hyaluronic acid compared to carboxymethylcellulose hyaluronic acid to prevent postoperative intrauterine adhesion.

STUDY OBJECTIVE To estimate the efficacy of alginate carboxymethylcellulose hyaluronic acid (ACH) gel to prevent intrauterine adhesions after hysteroscopic surgery in comparison with carboxymethylcellulose hyaluronic acid (CH) gel, which is known as an effective adhesion inhibitor. DESIGN Randomized, multicenter, single-blind, clinical trial (Canadian Task Force classification I). SETTING Tertiary university hospital. PATIENTS One hundred eighty-seven patients with a surgically treatable intrauterine lesion (myomas, polyps, septa, intrauterine adhesion, dysfunctional uterine bleeding). INTERVENTIONS Patients were randomized to 2 groups: hysteroscopic surgery plus intrauterine application of ACH or CH. MEASUREMENTS AND RESULTS The rate of adhesion formation and the adhesion severity score with type and extent were calculated 4 weeks after surgery. The ACH group had results that were comparable to the CH group in terms of the development of intrauterine adhesions at 4 weeks follow-up. The adhesion severities were not different between the 2 groups. In a subgroup without baseline intrauterine adhesion, the ACH group showed a lower intrauterine adhesion rate than the CH group (p = .016). CONCLUSIONS ACH had a comparable efficacy to CH in terms of the adhesion rate and severity. In the case of no baseline intrauterine adhesion, intrauterine application of ACH after hysteroscopic surgery had a lower rate of intrauterine adhesion than application of CH.

Inhibition of checkpoint kinase 2 (CHK2) enhances sensitivity of pancreatic adenocarcinoma cells to gemcitabine

Checkpoint kinase 2 (CHK2) plays pivotal function as an effector of cell cycle checkpoint arrest following DNA damage. Recently, we found that co‐treatment of NSC109555 (a potent and selective CHK2 inhibitor) potentiated the cytotoxic effect of gemcitabine (GEM) in pancreatic cancer MIA PaCa‐2 cells. Here, we further examined whether NSC109555 could enhance the antitumour effect of GEM in pancreatic adenocarcinoma cell lines. In this study, the combination treatment of NSC109555 plus GEM demonstrated strong synergistic antitumour effect in four pancreatic cancer cells (MIA PaCa‐2, CFPAC‐1, Panc‐1 and BxPC‐3). In addition, the GEM/NSC109555 combination significantly increased the level of intracellular reactive oxygen species (ROS), accompanied by induction of apoptotic cell death. Inhibition of ROS generation by N‐acetyl cysteine (NAC) significantly reversed the effect of GEM/NSC109555 in apoptosis and cytotoxicity. Furthermore, genetic knockdown of CHK2 by siRNA enhanced GEM‐induced apoptotic cell death. These findings suggest that inhibition of CHK2 would be a beneficial therapeutic approach for pancreatic cancer therapy in clinical treatment.

Augmentation of Sodium Butyrate-induced Apoptosis by Phosphatidylinositol 3-kinase Inhibition in the Human Cervical Cancer Cell-line

PURPOSE Sodium butyrate (NaBT) is principally a histone deacetylase (HDAC) inhibitor, and it has the potential to arrest HPV-positive carcinoma cells at the G1 to S phase transition of the cell cycle. The aim of study was to determine whether phosphatidylinositol 3-kinase (PI3K) inhibition can enhance the inhibitory effect of NaBT on a human cervical cancer cell line (HeLa). MATERIALS AND METHODS Cervical cancer cells (HeLa) were treated with NaBT alone or in combination with the PI3K inhibitors wortmannin or LY294002. Cell viability analysis and FACS analysis were carried out. The expressions of the cell cycle related proteins were evaluated by Western-blot analysis. RESULTS Inhibition of PI3K enhanced NaBT-mediated apoptosis and this decreased the HeLa cell viability. Either wortmannin or LY294002, combined with NaBT, enhanced the activation of caspase 3 and caspase 9, and this enhanced the subsequent cleavage of poly (ADP-ribose) polymerase (PARP). Cervical cancer cells were arrested in the subG1 and G2/M phase, as was detected by FACS analysis. NaBT treatment in combination with PI3K inhibitors showed the increased expression of the CDK inhibitors p21(Cip1/Waf1) and p27(Kip1), in a p53 dependent manner, and also the increased dephosphorylation of Rb whereas there was a reduction in the expression levels of cyclin A, cyclin D1 and cyclin B1. CONCLUSION The results demonstrate that inhibition of PI3K enhances NaBT-mediated cervical cancer cell apoptosis through the activation of the caspase pathway. Moreover, these findings will support future investigation using the PI3K inhibitors in combination with adjuvant treatment for treating carcinoma of the cervix.

BRCA1 transcriptional activity is enhanced by interactions between its AD1 domain and AhR.

PurposeWe previously reported that BRCA1 interacts with aryl hydrocarbon receptor nuclear translocator (ARNT) and that this interaction affects TCDD-induced CYP1A1 gene expression (Kang et al., J Biol Chem 281:14654–14662, 2006). In this study we continue this investigation and begin to define the significance of this interaction for the regulation of stress-induced transcription.MethodsImmunoprecipitations (IPs), western blot (WB) analysis, GST pull-down assays and promoter reporter assays were used to investigate whether the aryl hydrocarbon receptor (AhR) can regulate transcription that is dependent on the activation domain 1 (AD1) domain of BRCA1.ResultsWe show that AhR, a transcription factor, can bind specifically to AD1 in the C-terminal region of BRCA1 and affect BRCA1’s ability to regulate transcription activity. We found that xenobiotics that positively and negatively affect AhR’s activity as a transcription factor (e.g., dioxin and α-naphthoflavone, respectively), have similar effects on AhR’s ability to affect AD1-domain-dependent transcription. These physical and functional AhR–AD1 interactions may require the coiled-coil motif in AD1 because point-mutations in this motif reduce these interactions.ConclusionXenobiotic-activated AhR can function in two ways, as a component of the AhR/ARNT transcription factor and a regulator of AD1-dependent transcription. Consequently, BRCA1 has two distinct mechanisms for sensing xenobiotics and regulating AhR-dependent stress responses to these xenobiotics. We speculate that the normal functioning of this interaction could play a role in BRCA1’s tumor suppressing ability.