Cytotoxic effect of zinc-citrate compound on choriocarcinoma cell lines.

This study investigated the cytotoxic effect of zinc-citrate compound (CIZAR) on choriocarcinoma cell lines. Primary cultured normal trophoblast cells (NPT), human tumorigenic poorly differentiated trophoblast cell line (HT), and choriocarcinoma cell line (BeWo) were exposed to different concentrations of CIZAR and cultured at different times. Cell viability was determined by CCK-8 assay. The effects on cell cycle progression, population distribution and apoptotic incidence were determined by flow cytometry. The appearance of apoptosis was confirmed by DNA laddering and DAPI staining. The quantitative analysis of telomerase was measured by TRAPeze telomerase detection kit. The molecular mechanism of CIZAR-induced apoptosis was examined with Western blot analysis and colorimetric caspase-3 activity assay. In in vitro condition, CIZAR had a selective cytotoxic effect on choriocarcinoma cell line in dose- and time-dependent patterns. Flow cytometric analysis, DNA laddering, and DAPI staining indicated that BeWo cells only have been induced apoptosis by CIZAR. Shortening of telomere was also observed only in BeWo cells. Results also displayed that CIZAR-induced apoptosis involves the up-regulation of p21(WAF1) and Bax protein and down-regulation of Bcl-2 which were accompanied by the activation of caspase-3. Taken together, our results suggest that CIZAR is an apoptotic inducer in malignant trophoblast cells (BeWo).

Epidemiology and time trends of gestational trophoblastic disease in Korea.

OBJECTIVES: For the purpose of determining the annual incidence and time trends of gestational trophoblastic disease (GTD), the medical records from 24 university hospitals, 13 private general hospitals and the Korean Research Institute of Gestational Trophoblastic Disease (KRI-TRD) were analyzed from 1971 to 1995. MATERIALS & RESULTS: From a total of 7198 GTD cases (H-mole=3831, Invasive mole=2163, Choriocarcinoma=1177, PSTr=27) among 838659 deliveries between 1971 and 1995, the hospital-based incidence of H-mole per 1000 deliveries declined from 40.2 during 1971-975, to 2.3 during 1991-995. The population-based incidence of H-mole, however, revealed an average of 2.05 per 1000 deliveries during 1991-995. Old age and gravidities as factors in GTD patients both decreased significantly during the study period. Time trends for the incidence of GTD in Korea revealed significant changes, not only a decrease in the incidence of GTD, but also an improvement in the annual remission rate. Korea's socio-eonomic improvement in recent decades also contributed to the decreased incidence of GTD and the increased survival rates.

Effects of multiagent chemotherapy and independent risk factors in the treatment of high-risk GTT--25 years experiences of KRI-TRD.

UNLABELLED: A retrospective and comparative study of high-risk gestational trophoblastic tumor (GTT) treated with different chemoregimen from 1971 to 1995 was performed and to find most effective chemotherapy regimen and independent risk factors. Three hundred seven patients in scoring over 8 points in WHO classification were categorized into high-risk group among 802 GTT cases received chemotherapy in the 2,418 GTD patients registered at KRI-TRD (Korean Research Institute for Gestational Trophoblastic Disease), Catholic University Medical College in Korea. Study groups of multiagent combination chemotherapy in 227 patients of the high-risk GTT were divided such as 49 cases of combination chemotherapy with MTX + folinic acid and Act-D, 40 cases of MAC regimen, 42 cases of CHAMOCA regimen, and 96 cases of EMA/CO. Initial tumor response according to hCG titer decrease was found in good response (log fall) 69.8%, of EMA /CO regimen group. On the other hand, good response was shown in only 24.5% of MTX + ACT-D, 32.5% of MAC regimen, and 52.4%, of CHAMOCA regimen respectively. Remission rate of EMA/CO regimen was 90.6% (87/96) and courses of chemotherapy until remission was 8.5+/-2.2. However, remission rate of other regimens of MTX + Act-D, MAC, and CHAMOCA were 63.3%, (31/49) 67.5% (27/40) and 76.2% (32/45) respectively, with 10.0+/-4.0, 10.7+/-4.3, 9.1+/-3.9 chemotherapy courses respectively until remission. Therefore, EMA/CO regimen groups were found to have low drug toxicity, early remission and a low failure rate. In the study of independent risk factors in the 165 cases of high-risk gestational trophoblastic tumor patients received EMA/CO regimen, stepwise Coxs proportional hazard's regression of prognostic factors using multivariate analysis revealed tumor age, number of metastatic organs, metastatic site and inadequate previous chemotherapy. According to the performance of fitted logistic regression model, the prediction rate of death and survival was 80.5%. CONCLUSIONS: The most effective chemotherapy to high-risk GTT was EMA/CO regimen than other regimens. The following factors showed poor prognosis; 1) Tumor age is over 12 month, 2) more than 2 organs had metastatic lesion, 3) inadequate previous therapy that includes unplanned operation and inadequate previous chemotherapy.

Multidisciplinary approach in the management of gestational trophoblastic tumor (GTT).

In summary of our 15 years experiences it is obvious that at least about 15% of GTT patients still do not get complete remission in spite of development of multiagent chemotherapy. To obtain better therapeutical result in unceasing problems should be solved and the improvement in newer methods of management as listed below is mandatory: (1) Prediction on risk factors and early diagnosis of the persistent GTT before and after molar evacuation (2) "Clinico-biochemical classification" based on more collective tumor markers (3) New chemotherapeutic agents (4) Regimen for prevention and/or modulation of drug resistance (5) Multimodality treatment including initial and adjuvant surgery, irradiation and immune response modifiers. (6) Remission consolidation

Telomerase activity in complete hydatidiform mole.

OBJECTIVE: The purpose of this study was to evaluate the association of telomerase activity in complete hydatidiform moles with subsequent development of persistent gestational trophoblastic tumor. STUDY DESIGN: By means of the standard telomerase repeat assay, we examined telomerase activity in 4 normal placentas, 31 complete hydatidiform moles (16 cases of uneventful regression, according to serum levels of beta-human chorionic gonadotropin, after evacuation and 15 cases in which persistent gestational trophoblastic disease developed after evacuation), 7 invasive moles, and 5 choriocarcinoma tissue samples. RESULTS: Telomerase activity was detected in 13 of 15 (86.7%) complete hydatidiform moles in patients who eventually underwent chemotherapy for the treatment of persistent gestational trophoblastic tumors. All 9 patients with metastatic disease (International Federation of Gynecology and Obstetrics stage III) had telomerase activity in the initial molar tissue sample. In contrast, telomerase activity was evident in only 3 of 16 (12.5%) complete hydatidiform moles from patients with spontaneous remission after evacuation (P <.05). Telomerase activity was detected in all 7 invasive moles and all 5 choriocarcinoma tissue samples but was not detected in normal placentas. CONCLUSION: The presence of telomerase activity in complete hydatidiform moles is associated with the development of persistent gestational trophoblastic tumors, such as invasive moles and choriocarcinoma.

Risk factors for the prediction of treatment failure in gestational trophoblastic tumors treated with EMA/CO regimen.

OBJECTIVE: The purpose of this study was to determine the independent risk factors for resistance to EMA/CO chemotherapy in gestational trophoblastic tumor (GTT), to develop a more accurate scoring system for the evaluation of high-risk GTT patients. METHODS: We performed a retrospective study and reviewed 165 GTT patients who received the EMA/CO regimen. Among these patients, 27 showed resistance to EMA/CO. RESULTS: According to the univariate analysis of risk factors, tumor age, initial human chorionic gonadotropin level, metastatic site, number of metastatic organs, unplanned operation, gravidity, and inadequate previous chemotherapy all showed statistical significance. However, the results of the stepwise-Cox proportional hazards regression of prognostic factors using multivariate analysis showed statistical significance for tumor age, number of metastatic organs, metastatic site, and previously inadequate chemotherapy. The results of the stepwise logistic regression of prognostic factors showed tumor age and number of metastatic organs as significant. According to the performance of the fitted logistic regression model, the accuracy of predicted death and survival was 80.5%. CONCLUSIONS: We determined that the following factors indicate a poor prognosis: (1) tumor age greater than 12 months, (2) number of metastatic organs greater 2, (3) incomplete previous treatment, including unplanned operation and inadequate chemotherapy. In patients with two and three of these factors, the death rates were 17.7 and 56.6%, respectively.

Molecular and cellular analysis of basement membrane invasion by human breast cancer cells in Matrigel-based in vitro assays.

In vitro analyses of basement membrane invasiveness employing Matrigel (a murine tumor extract rich in basement membrane components) have been performed on human breast cancer model systems. Constitutive invasiveness of different human breast cancer (HBC) cell lines has been examined as well as regulation by steroid hormones, growth factors, and oncogenes. Carcinoma cells exhibiting a mesenchymal-like phenotype (vimentin expression, lack of cell border associated uvomorulin) show dramatically increased motility, invasiveness, and metastatic potential in nude mice. These findings support the hypothesis that epithelial to mesenchymal transition (EMT)-like events may be instrumental in the metastatic progression of human breast cancer. The MCF-7 subline MCF-7ADR appears to have undergone such a transition. The importance of such a transition may be reflected in the emergence of vimentin expression as an indicator of poor prognosis in HBC. Matrix degradation and laminin recognition are highlighted as potential targets for antimetastatic therapy, and analyses of laminin attachment and the matrix metalloproteinase (MMP) family in HBC cell lines are summarized. Matrigel-based assays have proved useful in the study of the molecular mechanisms of basement membrane invasiveness, their regulation in HBC cells, and their potential as targets for antimetastatic therapy.

Subsequent reproductive experience after treatment for gestational trophoblastic disease.

PURPOSE: The purpose of this study was to evaluate reproductive performance of patients with gestational trophoblastic disease (GTD) after completion of treatment and follow-up periods. PATIENTS AND METHODS: Subjects comprised 115 patients who became pregnant after having been judged completely cured after a follow-up period of at least 1 year. There were 77 hydatidiform-mole patients who had a natural cure and 38 gestational trophoblastic tumor patients who were cured after chemotherapy. We studied these patients with respect to parameters concerning pregnancy outcome. RESULTS: Average age at first pregnancy was 28.0 and average number of past deliveries was 1.3. After a 1-year contraception period, the average time to the next pregnancy was 0.8 year, with 59 of 115 (51.3%) women becoming pregnant within 1 year after pregnancy was permitted and 98 women (85.2%) conceiving within 3 years. Results of the pregnancies after cure of GTD did not deviate from normal ranges in separated analyses of complete mole (CM), partial mole (PM), and gestational trophoblastic tumor. Rate of repeat mole was found to be high, occurring in 5 of 115 (4.3%) cases. Rates of antepartum and postpartum complications did not deviate from normal ranges, and there was nothing peculiar about the neonatal sex and weight. CONCLUSION: GTD and chemotherapy rarely affect later pregnancies; however, the rate of repeat mole is relatively high.

Prognostic significance of pretreatment squamous cell carcinoma antigen and carcinoembryonic antigen in squamous cell carcinoma of the uterine cervix.

Sixty-seven patients with squamous cell carcinoma of the uterine cervix (FIGO Stages IB2, IIA, and IIB) were reviewed to evaluate the pretreatment level of squamous cell carcinoma antigen (SCC) and carcinoembryonic antigen (CEA) which may be used to predict a subset of patients with poor prognosis. The rate of pathologic pretreatment serum level of SCC increased significantly in cases with Stage IIB compared to that of Stages IB2 and IIA (50% versus 16.3%). The rate of pathologic pretreatment serum level of CEA did not show any difference between these two groups (29.2% versus 30.2%). The 48-month disease-free survival for patients with pathologic pretreatment serum levels for one or both tumor-associated antigens (TAAs) was 40.0% versus 91.7% for patients with normal levels (log-rank test, P < 0.005) in Stages IB2 and IIA. Patients who had a pathologic pretreatment serum level for one or both TAAs showed higher incidence of lymph node metastasis than patients with normal levels (36.7% versus 10.8%). The patients who had pathologic pretreatment serum levels for both TAAs and lymph node metastasis have the poorest prognosis. The pretreatment serum levels for one or both TAAs make it possible to predict the clinical response to neoadjuvant chemotherapy consisting of cis-platinum (DDP) and 5-fluorouracil (5-FU). Our findings suggest that pretreatment of SCC in conjunction with CEA is a valuable tumor marker to predict the prognosis of squamous cell carcinoma of the uterine cervix and to foresee a clinical response to subsequent neoadjuvant chemotherapy.

Comparative study of the patients with locally advanced stages I and II cervical cancer treated by radical surgery with and without preoperative adjuvant chemotherapy.

Ninety-two patients with locally advanced stages IB, IIA, and IIB cervical cancers, who had completed 4 years of follow-up after treatment with preoperative adjuvant chemotherapy prior to radical surgery, were compared with 138 patients in same disease status who were treated with radical surgery without preoperative adjuvant chemotherapy. In the patients treated with preoperative adjuvant chemotherapy (VBP scheme), the chemotherapeutic response was more favorable in squamous cell carcinomas (87%) than that in adenocarcinomas (38%). The detection rate of pelvic lymph node metastasis from the surgical specimens of radical operation was higher in the patients of radical surgery without preoperative chemotherapy (34%; 47/138) than that in the preoperative adjuvant chemotherapeutic patients (17%; 16/92, P = 0.005). Recurrence occurred in 50 of 138 patients (35.5%) who were treated by radical surgery without preoperative chemotherapy and in 17 of 92 patients (18.5%) who were treated with preoperative adjuvant chemotherapy followed by radical surgery. The difference of recurrence rate between two groups was statistically significant (P = 0.004). The tumor-free survival of preoperative adjuvant chemotherapeutic patients was significantly longer than those in the patients without preoperative chemotherapy (P = 0.0067). Tumor response to chemotherapy was a valuable prognostic factor in management of patients and preoperative adjuvant chemotherapy was beneficial in reducing pelvic lymph node metastases, reducing recurrences, and prolonging the survival of the patients with locally advanced cervical cancers, especially in stage IIA.

Cervical cancer control in Korea: colposcopy / cervicograph / cytology.

PIP: Cervical cancer is the second leading cause of cancer-related death in women of South Korea. The annual incidence rate of cervical cancer is 24.2/100,000 population. Possible risk factors of cervical cancer among South Korean women are low educational level, marriage at early age, high parity, coital frequency, and number of partners. A method for screening the mass population for cervical cancer should be simple, accurate, and cost effective. Cytologic screening methods yield high false negative rates, while colposcopy and cervicography yield high positive rates. The accuracy rates of colposcopy in South Korea are 92.8% for cervicitis, 89.3% for cervical dysplasia, 90.9% for CIS, and 91.5% for invasive carcinoma. Special training and an expensive device are needed for colposcopic examination. Catholic University Medical College (CUMC) gynecologists have developed a Korean type of cervicography for mass screening. It consists of a 100 mm macroles, 35 mm camera body, 50 mm extension ring, and a ring strobe light. It has high accuracy, sensitivity, and specificity. A study to compare the effectiveness of the three screening methods showed that cervicography is best for mass screening. CUMC gynecologists recommend: biannual screening tests for women at high risk of developing cervical cancer; first cervical screening at age 18 years; and screening for all age groups above 18. Women with cervical infection with human papilloma virus (HPV) are more likely to develop cervical cancer than non-HPV infected women. A typing strategy can separate women into high risk and low risk groups. This would allow physicians to individually manage preinvasive cervical lesions. The effectiveness of mass screening in high incidence countries depends on quality control of the screening method, acceptability, reliability, and national organization on a private and public basis.^ieng

Effects of multiagent chemotherapy and independent risk factors in the treatment of high-risk GTT -25 years experiences of KRI-TRD.

A retrospective and comparative study of high-risk gestational trophoblastic tumor (GTT) treated with different chemoregimen from 1971 to 1995 was performed and to find most effective chemotherapy regimen and independent risk factors. Three hundred seven patients in scoring over 8 points in WHO classification were categorized into high-risk group among 802 GTT cases received chemotherapy in the 2,418 GTD patients registered at KRI-TRD (Korean Research Institute for Gestational Trophoblastic Disease), Catholic University Medical College in Korea. Study groups of multiagent combination chemotherapy in 227 patients of the high-risk GTT were divided such as 49 cases of combination chemotherapy with MTX + folinic acid and Act-D, 40 cases of MAC regimen, 42 cases of CHAMOCA regimen, and 96 cases of EMA/CO. Initial tumor response according to hCG titer decrease was found in good response (log fall) 69.8%, of EMA /CO regimen group. On the other hand, good response was shown in only 24.5% of MTX + ACT-D, 32.5% of MAC regimen, and 52.4%, of CHAMOCA regimen respectively. Remission rate of EMA/CO regimen was 90.6% (87/96) and courses of chemotherapy until remission was 8.5 ± 2.2. However, remission rate of other regimens of MTX + Act-D, MAC, and CHAMOCA were 63.3%, (31/49) 67.5% (27/40) and 76.2% (32/45) respectively, with 10.0 ± 4.0, 10.7 ± 4.3, 9.1 ± 3.9 chemotherapy courses respectively until remission. Therefore, EMA/CO regimen groups were found to have low drug toxicity, early remission and a low failure rate. In the study of independent risk factors in the 165 cases of high-risk gestational trophoblastic tumor patients received EMA/CO regimen, stepwise Coxs proportional hazard's regression of prognostic factors using multivariate analysis revealed tumor age, number of metastatic organs, metastatic site and inadequate previous chemotherapy. According to the performance of fitted logistic regression model, the prediction rate of death and survival was 80.5%. CONCLUSIONS: The most effective chemotherapy to high-risk GTT was EMA/CO regimen than other regimens. The following factors showed poor prognosis; 1) Tumor age is over 12 month, 2) more than 2 organs had metastatic lesion, 3) inadequate previous therapy that includes unplanned operation and inadequate previous chemotherapy.

Epidemiology and time trends of gestational trophoblastic disease in Korea.

OBJECTIVES: For the purpose of determining the annual incidence and time trends of gestational trophoblastic disease (GTD), the medical records from 24 university hospitals, 13 private general hospitals and the Korean Research Institute of Gestational Trophoblastic Disease (KRI-TRD) were analyzed from 1971 to 1995. MATERIALS & RESULTS: From a total of 7198 GTD cases (H-mole = 3831, Invasive mole = 2163, Choriocarcinoma = 1177, PSTT = 27) among 838659 deliveries between 1971 and 1995, the hospital-based incidence of H-mole per 1000 deliveries declined from 40.2 during 1971-975, to 2.3 during 1991-995. The population-based incidence of H-mole, hwoever, revealed an average of 2.05 per 1000 deliveries during 1991-995. Old age and gravidities as factors in GTD patients both decreased significantly during the study period. Time trends for the incidence of GTD in Korea revealed significant changes, not only a decrease in the incidence of GTD, but also an improvement in the annual remission rate. Korea's socio-eonomic improvement in recent decades also contributed to the decreased incidence of GTD and the increased survival rates.