Measurement of endometrial thickness in premenopausal women in office gynecology.

Purpose: To define the median endometrial thickness (ET) in office gynecology is thought to be important for clinical practice. However, there are few reports about ET that have included the general female population on a large scale. The median ET was determined prospectively in premenopausal women who attended office gynecology for cervical cancer screening. Methods: In total, 849 women were enrolled. The median ET was determined by using transvaginal ultrasound and the relationships between the ET and various clinical factors were analyzed. Results: The participants' median age was 38.5 years. The median ET was 8.6 mm (90% and 95% quantiles: 13.8 and 15.8 mm). The ET was not related to their age, symptoms, obstetric history, geographical location, or risk factors for endometrial cancer. In the women with a menstrual cycle length of 28-30 days, the ET was 7 mm on days 1-6, but it increased from 5.4 mm immediately after menstruation (day 7 or 8) to 9.2 mm on days 13-14. Subsequently, the ET increased further to 11.1 mm on day 18. Conclusion: In all the women, the upper limit of the ET was 13.8 mm and 15.8 mm in the 90% and 95% quantile, respectively, in office gynecology.

Leptomycin B enhances CDDP-sensitivity via nuclear accumulation of p53 protein in HPV-positive cells.

Cervical cancer, which commonly contains a wild-type p53 gene, is highly correlated with human papilloma virus (HPV) infection. Because the oncoprotein E6, derived from HPV, inhibits the function of p53 protein, the inhibition of apoptosis via the p53 pathway by HPV may be related to cisplatin (CDDP)-sensitivity in cervical cancer. We conducted the present study to determine whether and how HPV is related to CDDP-sensitivity in HPV-positive cervical cancer cells. We used cervical carcinoma cell lines HeLa with integrated HPV 18 and SiHa with integrated HPV 16. An HPV-negative cell line, Yumoto, with wild-type p53 gene was used as a control. Leptomycin B (LMB) enhanced sensitivity to CDDP and CDDP-induced apoptosis in HeLa and SiHa cells, but not in Yumoto cells. After exposure to LMB or CDDP alone, we observed weak p53 staining in HeLa, SiHa and Yumoto cells. Nuclear p53 staining was significantly increased by combined treatment with CDDP and LMB in HeLa and SiHa cells, but not in Yumoto cells. The expression of p53 and Bax protein increased with exposure to CDDP and was enhanced by LMB in HeLa and SiHa cells. The present study demonstrated that LMB enhanced CDDP-sensitivity via nuclear accumulation of p53 protein in HPV-positive cells.

Activity of docetaxel in paclitaxel-resistant ovarian cancer cells.

PURPOSE: The aim of this study was to determine the behavior of docetaxel (DTX) in ovarian cancer cells resistant to paclitaxel (PTX). METHODS: We used human ovarian adenocarcinoma cell lines KF, KFTx (PTX-resistant KF), SK-OV-3, and HAC-2. The sensitivity of the cells to PTX or DTX was determined by the MTT assay. Cellular accumulation of PTX and DTX was measured by high-performance liquid chromatography. mRNA of MDR-1 was detected by RT-PCR. Cell cycle distribution was determined by flow cytometry after exposure to the IC(50) of each drug. Bcl-2 phosphorylation was determined by Western blot analysis. Activity for tubulin polymerization of each drug was examined by a beta-tubulin polymerization assay. RESULTS: KFTx cells had a 5.5-fold greater resistance to PTX and a 7.3-fold greater resistance to DTX than KF cells, indicating that KFTx cells had acquired cross-resistance to DTX. SK-OV-3 cells were sensitive and HAC-2 cells were resistant to both PTX and DTX. The gene expression of MDR-1 increased after exposure to DTX in KF and KFTx cells. Residual cellular accumulation of PTX and DTX was significantly lower in KFTx cells than in KF cells. In contrast, MDR-1 expression was not detected in SK-OV-3 and HAC-2 cells. Flow cytometric analysis indicated no differences in alterations of cell cycle distribution following exposure to the two drugs. Bcl-2 phosphorylation occurred after exposure to DTX at a concentration equivalent to the clinical dose, but did not occur after exposure to PTX in KFTx cells. In HAC-2 cells, Bcl-2 phosphorylation was not detected after exposure to DTX or PTX at concentrations equivalent to the clinical doses. DTX showed greater tubulin polymerization activity than PTX in KFTx cells. beta-tubulin polymerization did not correlate with the concentration of PTX or DTX, suggesting that alteration in the tubulin reaction might contribute to the resistance in HAC-2 cells. CONCLUSIONS: The present study suggests that the mechanisms involved in cytotoxicity of and resistance to PTX and DTX do not differ, but DTX has a greater cytotoxic potential in PTX-resistant cells with an efflux system.

Modeling interaction of fluid and salt in an aquifer/lagoon system.

To simulate the dynamic interaction between a saline lagoon and a ground water system, a numerical model for two-dimensional, variable-density, saturated-unsaturated, and coupled flow and solute transport (saltwater intrusion by finite elements and characteristics [SIFEC]) was modified to allow the volume of water and mass of salt in the lagoon to vary with each time step. The modified SIFEC allows the stage of a lagoon to vary in accordance with a functional relation between the stage and water volume of the lagoon, and also allows the salt concentration of the lagoon to vary in accordance with the salt budget of the lagoon including chemical precipitation and dissolution of salt. The updated stage and salt concentration of the lagoon are in turn used as transient boundary conditions for the coupled flow and solute transport model. The utility of the modified model was demonstrated by applying it to the eastern Mediterranean coastal region of Turkey for assessing impacts of climate change on the subsurface environment under scenarios of sea level rise, increased evaporation, and decreased precipitation.

The benefit of chemotherapy in a patient with multiple brain metastases and meningitis carcinomatosa from ovarian cancer.

We report on a 45-year-old patient with stage IIIc ovarian cancer, multiple brain metastases, and meningitis carcinomatosa. After three courses of initial chemotherapy, consisting of docetaxel and carboplatin, the patient underwent interval cytoreductive surgery, consisting of hyster-ectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, and retroperitoneal lymphadenectomy. Then five courses of the same chemotherapy were given as adjuvant treatment. At the completion of the primary therapy, she achieved a complete remission. Ten months after the completion of the initial treatment, multiple brain metastases with meningitis carcinomatosa were detected. After four courses of the same chemotherapy, she again had a complete response, confirmed by cranial enhanced magnetic resonance imaging (MRI), and she felt well, with relief from the debilitating neurologic symptoms for 4 months. After this 4 months, her disease recurred, with meningitis carcinomatosa, and she requested supportive care only. She died 4 months after this recurrence. Chemotherapy can help to prolong life for some patients with multiple brain metastases and meningitis carcinomatosa from ovarian cancer.

Ovarian endometrioid adenocarcinoma arising from endometriosis in a young woman.

BACKGROUND: The risk of ovarian cancer increases in women with a long history of ovarian endometriosis, particularly in postmenopausal women. We present here a case of malignant transformation of endometriosis occurring over a short time in a young woman. CASE: The 27-year-old woman underwent laparoscopic cystectomy and was diagnosed with left ovarian endometrioma with an accompanying high level of serum CA125 (734.6 U/mL). Fourteen months later, she underwent cytoreductive surgery for her ovarian cancer. Histological examination revealed endometrioid adenocarcinoma with transitions between endometriosis and adenocarcinoma. She was diagnosed as having stage IIIc of ovarian cancer with paraaortic lymphnode involvement. CONCLUSION: We suggest that endometrial cyst of the ovary associated with high levels of serum CA125 should be managed with special care even in a young woman.

Multidrug resistance gene-1 is a useful predictor of Paclitaxel-based chemotherapy for patients with ovarian cancer.

OBJECTIVE: The objective of this study was to determine the relationship between multidrug resistance and sensitivity to paclitaxel (PTX) in ovarian cancer. METHODS: We used human ovarian adenocarcinoma cell lines, KF, a PTX-resistant cell line (KFTx), SK-OV-3, and KOC7c. Additionally, 27 patients with ovarian cancer who had residual disease were examined. All patients underwent postoperative chemotherapy consisting of 175 mg/m(2) PTX and area under curve (AUC) 5 carboplatin. The sensitivity of the cells to PTX or cisplatin (CDDP) was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. mRNA expression of multidrug resistance gene-1 (MDR-1) and multidrug resistance-associated protein-1 (MRP-1) and MRP-2 was determined by reverse transcription-polymerase chain reaction. beta-Tubulin polymerization and Bcl-2 phosphorylation were examined by Western blot analysis. RESULTS: Compared with KF, the IC(50) to PTX was 5.5-fold higher for KFTx, 0.3-fold for SK-OV-3, and 52.1-fold for KOC7c. The IC(50) to CDDP was 0.7-, 4.2-, and 5.8-fold, respectively. Expression of the MDR-1 gene was clearly observed in KFTx and KOC7c. Expression of MRP-1 was observed in SK-OV-3 and KOC7c. Expression of MRP-2 was detected only in KOC7c. CDDP enhanced beta-tubulin polymerization induced by PTX in CDDP-sensitive cells. Bcl-2 phosphorylation appeared after exposure to IC(50) PTX in all cells. Twenty-one patients responded to chemotherapy and six did not. Expression of the MDR-1 gene for nonresponders was significantly higher than that for responders (260.0 +/- 191.6 vs 9.3 +/- 21.8). With the cutoff value of MDR-1 expression at 100, the predictive value for chemoresponse was 96%. Expression of the MRP-1 and MRP-2 genes did not differ between nonresponders and responders. CONCLUSION: MDR-1 gene expression may be a useful predictor for PTX-based chemotherapy.

Expression of the c-myc gene as a predictor of chemotherapy response and a prognostic factor in patients with ovarian cancer.

The present study was conducted to determine whether and how expression of the c-myc gene is related to the response to chemotherapy in patients with epithelial ovarian cancer. This study includes 101 consecutive patients with stage Ic to IV epithelial ovarian cancer who underwent primary surgery followed by platinum-based chemotherapy. Immunohistochemical studies were performed to detect Ki-67 and ARF proteins. Apoptotic cells were identified by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick-end labeling method. Mutation of the p53 gene was screened by polymerase chain reaction (PCR)-single strand conformation polymorphism analysis and confirmed by direct sequencing. mRNA expression of c-myc was determined by means of reverse transcription-PCR. Apoptotic index (AI) and ARF labeling index (LI) were significantly increased and Ki-67 LI was decreased after chemotherapy in patients from whom specimens could be obtained before and after chemotherapy. AI, ARF LI, and Ki-67 LI were not related to p53 gene status. A significant correlation between expression of c-myc and ARF LI was observed. Of 38 patients with measurable lesion, 23 (60.5%) responded to chemotherapy and 15 (39.5%) did not. Tumors with the wild-type p53 gene responded significantly better to chemotherapy than did tumors with the mutation. Responders showed a higher expression of c-myc than nonresponders (468 +/- 76 vs. 187 +/- 68). The receiver operating characteristic (ROC) curve according to chemoresponse demonstrated that the cut-off value of c-myc expression was 200. Patients with c-myc expression of more than 200 had a better 5-year survival rate (69.8% vs. 43.5%; 101 patients). Multivariate analysis revealed that c-myc expression was an independent prognostic factor. Our results suggest that the expression of c-myc gene is related to chemoresponse and might be a useful prognostic factor in patients with epithelial ovarian cancer.

Sensitivity to anticancer agents and resistance mechanisms in clear cell carcinoma of the ovary.

We conducted the present study to determine the chemoresistance mechanisms in clear cell carcinoma of the ovary (CCC). Five human CCC cell lines (HAC-2, RMG-I, RMG-II, KK, and KOC-7c) were used in this study. The sensitivity of the cells to the anticancer agents was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and we assessed drug sensitivity by calculating assay area under the curve (AUC) for each agent. The expression of multi-drug resistance genes (MDR-1, MRP-1, MRP-2) was detected by reverse transcription-polymerase chain reaction (RT-PCR). Glutathione (GSH) concentration was measured by an enzymatic assay. Topoisomerase (topo) I activity was assayed in terms of relaxation of supercoiled plasmid substrate DNA. The IC(50) to anticancer agents ranged widely. The assay AUC indicated that 3 of 5 cell lines (RMG-I, RMG-II, and KK) were sensitive to paclitaxel (PTX), 3 (HAC-2, RMG-I, and RMG-II) were sensitive to 7-ethyl-10-hydroxycamptothecin (SN-38), which is an active metabolite of camptothecin (CPT-11), and only one (HAC-2) was sensitive to cisplatin (CDDP). All cell lines were resistant to mitomycin-C (MMC) and etoposide (VP-16). The MRP-1 gene was detected in all cell lines. Only one cell line showed both MRP-2 and MDR-1 gene expression. Except for HAC-2 cells, expression of MRP genes was related to CDDP resistance, and MDR-1 gene expression was associated with PTX resistance. GSH concentrations increased after exposure to CDDP or MMC in all cell lines. There was a significant correlation between topo-I enzymatic activity and the response to SN-38. The present study revealed several resistance mechanisms in CCC and the results suggested that PTX and CPT-11 might be effective agents to treat CCC.

Stromal invasion of the cervix can be excluded from the criteria for using adjuvant radiotherapy following radical surgery for patients with cervical cancer.

BACKGROUND: Regarding complications of radiotherapy, the indications for adjuvant radiotherapy should be restricted. We conducted the present study to determine whether deep stromal invasion of the cervix could be excluded from the criteria used to identify patients for this treatment surgery. METHODS: This study included 115 patients with FIGO stage Ib to IIb cervical cancer who underwent radical hysterectomy and pelvic lymph node dissection. Patients had the following tumors: 61 nonkeratinizing squamous cell carcinoma, 21 keratinizing squamous cell carcinoma, 26 adenocarcinoma, and 7 adenosquamous cell carcinoma. Our study criteria for using adjuvant radiotherapy included positive lymph node involvement, a compromised surgical margin, or parametrial extension. Deep stromal invasion of the cervix was excluded from the criteria in this study. RESULTS: Seventy-two of the 115 patients (62.6%) underwent radical surgery only and all were alive. The remaining 43 patients received a complete course of external irradiation following radical surgery. The estimated 5-year survival rate is 100% for patients with stage Ib, 93.3% for stage IIa, and 52.7% for stage IIb. Fifty-five patients (47.8%) had deep stromal invasion. The prognosis for patients with deep stromal invasion was significantly worse than that for patients without deep stromal invasion (5-year survival rate, 69.8% vs. 98.0%). However, 21 patients (18.3%) with deep stromal invasion, but without positive lymph node involvement, compromised surgical margin, or parametrial extension, were alive without recurrence. Multivariate analysis showed that lymph node involvement and parametrial extension were independent prognostic factors, but that deep stromal invasion was not. CONCLUSION: Deep stromal invasion of the cervix can be excluded from the list of criteria for selecting patients with cervical cancer who would benefit from adjuvant radiotherapy following radical surgery.