The problems of cervical conization for postmenopausal patients.

PURPOSE: Cervical conization is the definitive treatment for women of any age who have cervical intraepithelial neoplasia (CIN). However, complications of the procedure have not been fully investigated in postmenopausal patients. The aim of this retrospective study was to evaluate the results and complications of cervical conization performed on premenopausal and postmenopausal patients. MATERIALS AND METHODS: This study recruited 405 patients who had undergone cervical laser conization. The median age was 36 years (range 20 to 75), and there were 361 (89.1%) premenopausal and 44 (10.9%) postmenopausal women. RESULTS: The length of the cone removed from the postmenopausal patients was significantly longer than the length from the premenopausal patients (17.9 ± 3.9 mm vs. 15.7 ± 3.6 mm, respectively; p = 0.02). The rate of positive endocervical cone margins from the premenopausal patients was significantly higher than the rate from the postmenopausal patients (9.1% vs. 0%, respectively; p = 0.037). The rate of cervical stenosis was significantly higher in postmenopausal patients than in premenopausal patients (59.1% vs. 8.3%; respectively; p < 0.0001). There was no difference in the rates of frequency of intraoperative complications. CONCLUSIONS: Although deep incision is mandatory for complete excision of CIN in postmenopausal patients, it increases the incidence of cervical stenosis. Cervical conization may be a less invasive surgical procedure for older women with CIN than hysterectomy; however, the risk of postoperative complications remains, causing a dilemma for physicians treating postmenopausal women with CIN.

Complications of laser conization versus loop electrosurgical excision procedure in pre- and postmenopausal patients.

Purpose ofinvestigation: The aim of this retrospective study was to compare the results and complications of laser conization and loop electrosurgical excision procedure (LEEP), performed for cervical intraepithelial neoplasia (CIN) or microinvasive carcinoma, between postmenopausal and premenopausal patients. MATERIAL AND METHODS: This study recruited a total of 551 patients. In the laser group (n = 405), there were 361 (89.1%) premenopausal and 44 (10.9%) postmenopausal women. In the LEEP group (n = 146), there were 129 (88.4%) premenopausal and 17 (11.6%) postmenopausal women. The factors investigated in both groups were the length of the tissue cone removed and the presence of positive endocervical cone margins, residual disease, and cervical stenosis. RESULTS: In the laser group, the length of the tissue cone was significantly longer in postmenopausal patients (17.9 ±3.9 mm vs. 15.7 ± 3.6mm; p = 0.002). The rate of positive endocervical margins was significantly higher in premenopausal patients (9.1% vs. 0%; p = 0.037). The rate of cervical stenosis was significantly higher in postmenopausal patients (59.1% vs. 8.3%; p < 0.0001). In the LEEP group, there were no differences in the length of the tissue cone (premenopausal, 11.7 ± 1.9 mm vs. postmenopausal, 11.4 ± 2.7 mm; p = 0.12), the rate of positive endocervical margins (24.0% vs. 17.6%), or the rate of residual disease (13.2% vs. 17.6%). The rate of cervical stenosis was significantly higher in postmenopausal patients (23.5% vs. 4.1%; p = 0.002); however this rate was significantly lower than that seen in the laser group. CONCLUSION: In postmenopausal patients, the rates of positive endocervical cone margins and of residual disease were higher in the LEEP group; however, the rate of cervical stenosis was higher in the laser group. Physicians should be aware of the characteristics of the devices used for cervical conization in postmenopausal women with CIN.

Female pseudohermaphroditism associated with maternal steroid cell tumor, not otherwise specified of the ovary: a case report and literature review.

Maternal virilization in pregnancy with or without fetal female pseudohermaphroditism has several etiologies. Of these, pregnancy luteoma is the most common cause of maternal virilization during pregnancy, and approximately 20 cases have been reported in recent years. Moreover, four cases of pregnancy luteomas with female pseudohermaphroditism have been reported. However, the extremely rare steroid cell tumor, not otherwise specified (NOS), has been reported only once as a cause for maternal virilization. Herein, the authors report the first case of maternal virilization with female pseudohermaphroditism associated with steroid cell tumor-NOS along with the clinical course, pathological features, and a review of the literature.

Predicting nedaplatin sensitivity of cervical cancer using the histoculture drug response assay.

PURPOSE: There are currently no clinically available chemosensitivity assays for cervical cancer. In this study we evaluated whether the histoculture drug response assay (HDRA) could be used to predict chemosensitivity to nedaplatin (NDP) in cervical cancer. METHODS: Fifty-four surgical specimens and biopsies from patients with squamous cell carcinoma of the cervix were tested with the HDRA. The results were used to calculate the concentration resulting in 50% inhibition of tumor growth (IC50). We then determined the cut-off concentration for NDP, and investigated the chemosensitivity of NDP for each patient. Moreover, the correlations between chemosensitivity and the clinical response of NDP-containing chemotherapy, and the clinical outcomes of the patients with Stage I and II disease were also investigated. RESULTS: Fifty-one of 54 specimens (94.0%) were evaluable with this assay. The optimal cutoff concentration of NDP was determined to be 48 microg/ml. In 18 patients with measurable lesions, all nine patients in the high sensitive group by HDRA were judged as partial response (PR) to NDP containing chemotherapy. In contrast five of nine patients in the low sensitive group were classified as stable disease, and four were PR. The true positive rate was 100%, the true negative rate was 55.6%, and the accurate prediction rate was 77.8%. Furthermore, the disease-free survival of the high sensitive group tended to be better than that of the low sensitive group in the patients who received postoperative adjuvant chemotherapy with NDP. CONCLUSIONS: In the current study, the sensitivity of cervical tumors to nedaplatin was predicted by the HDRA.

Biological significance of plasminogen activator inhibitor-1 expression in ovarian clear cell adenocarcinoma.

PURPOSE: Ovarian clear cell adenocarcinoma (OCCA) has been reported to display different characteristics from other histological types of epithelial ovarian cancer, and especially differs from serous adenocarcinoma. We investigated plasminogen activator inhibitor-1 (PAI-1) expression in patients with OCCA and attempted to assess its biological significance. METHODS: Fifty-seven patients with OCCA were enrolled. We used formalin-fixed, paraffin-embedded sections of the primary tumor obtained at the first operation to investigate the immunohistochemical expression of PAI-1 and the association of PAI-1 expression with various clinicopathologic factors. RESULTS: The 57 patients were classified into a high PAI-1 expression group and a low expression group. Comparison between the two groups revealed that the percentage of patients with concomitant endometriosis was significantly larger in the high expression group, while the percentage of Stage I patients with positive peritoneal cytology was significantly larger in the low expression group. Comparison of cumulative 5-year survival rates showed that the high expression group had a better prognosis than the low expression group. CONCLUSION: These data suggest an association between concomitant endometriosis and increased expression of PAI-1 in OCCA. The data also suggest that PAI-1 expression influences both peritoneal dissemination of early OCCA and the prognosis.

Molecular epidemiological and mutational analysis of DNA mismatch repair (MMR) genes in endometrial cancer patients with HNPCC-associated familial predisposition to cancer.

Recently, a high rate of endometrial cancer has been reported in women with hereditary non-polyposis colorectal cancer (HNPCC), suggesting a relationship between familial endometrial cancers and HNPCC. Familial endometrial cancers constitute only about 0.5% of all endometrial carcinomas and it is essential to examine family histories in detail. A mutational analysis of three DNA mismatch repair (MMR) genes (hMLH1, hMSH2 and hMSH6) in patients with endometrial cancer who meet our criteria for familial predisposition to HNPCC-associated endometrial cancers was performed. Mutations were detected in 18 of the 120 patients (15.0%). Most HNPCC-related endometrial cancers do not meet the New Amsterdam Criteria for HNPCC. These clinical criteria may identify only some HNPCC-associated endometrial cancers. Establishing the correct family history for endometrial cancer patients is important for diagnosing familial endometrial carcinomas. An analysis of MMR genes may be useful for patients with endometrial cancer showing familial aggregation. In addition, gynecologists must be accurately informed, and it is important to perform large-scale, multicenter studies both nationwide and internationally.

Sensitivity to cisplatin determined by the histoculture drug response assay and clinical response of endometrial cancer.

This study investigated the value of the in vitro histoculture drug response assay (HDRA) for predicting the efficacy of chemotherapy in patients with endometrial cancer. Specimens were obtained from 115 patients with endometrial cancer treated at Keio University Hospital between 1994 and 2002. Tumor fragments were cultured on collagen sponge gel with cisplatin for 7 days, and cell viability was assessed. The cutoff value of the 50% inhibitory concentration of cisplatin was set at 23 microg/mL. Sensitivity of stage III or IV disease to chemotherapy was investigated, and differences of 5-year progression-free survival between patients with sensitive and resistant tumors were evaluated by the Kaplan-Meier method. Tumors were evaluable in 93.0% of patients (107/115). Among 38 patients in stages III or IV, 23 received chemotherapy containing cisplatin. Seven sensitive tumors did not recur, while recurrence/progression occurred within 6 months in 8/16 patients with tumors showing low sensitivity. Among stages III and IV patients, there was a significant difference of 5-year progression-free survival (P < 0.05) between those with tumors showing high or low sensitivity. Accordingly, the HDRA may predict the efficacy of chemotherapy for endometrial cancer.

Chemosensitivity testing of ovarian cancer using the histoculture drug response assay: sensitivity to cisplatin and clinical response.

Despite cytoreductive surgery and chemotherapy, the prognosis of advanced ovarian cancer is still poor. Predicting the chemosensitivity of tumors might improve the outcome. Therefore, we investigated the clinical value of the histoculture drug response assay for ovarian cancer. Tumor specimens were cultured for 7 days on collagen gel sponge in medium containing cisplatin, and the 50% inhibitory concentration was determined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay. Then the in vitro sensitivity to cisplatin was compared with the clinical response and survival. Apoptosis of tumor cells was also investigated. Among 173 ovarian cancer patients, 164 were evaluable by the assay, and 29 patients had measurable lesions for which the clinical response could be determined. The 5-year survival rate was significantly higher in patients with chemosensitive tumors than in those with chemoresistant tumors when the cutoff value was set at a 50% inhibitory concentration of 25 microg/mL and the accuracy of the assay was 82.8% (24/29). As chemosensitivity to cisplatin became greater, the number of apoptotic cells also increased. This chemosensitivity assay may help predict the clinical response to cisplatin-based chemotherapy, thus improving the survival of ovarian cancer patients.

Efficient screening for ovarian cancers using a combination of tumor markers CA602 and CA546.

A new efficient screening for ovarian cancer based on a combination of two tumor markers, CA602 and CA546, is reported. These two tumor markers can be detected by a combination immunoenzymometric assay of these two antigens. This combination assay was initially performed in 1189 patients with clinically detected ovarian tumors (final pathological diagnosis: 645 cases of benign disease and 544 cases of malignant disease), and benign disease included 122 patients with endometriosis and 523 normal healthy women. The combination of CA602 and CA546 increased the detection rate of ovarian cancer from 77.8 to 85.8% compared with CA602 alone, demonstrating that the combination assay was effective at detecting ovarian cancers. The combination assay of CA602 and CA546 was then applied to 21,374 random subjects to screen for asymptomatic ovarian cancer. Ovarian cancer was detected in nine patients (detection rate: 0.04%), of which four cases were stage I disease. A retrospective analysis of these four patients revealed that a screening based on only a single assay would have been negative and further reiterates the effectiveness of this combination assay in detecting potential disease.

Relationship between the classification of vascular invasion severity and the prognosis of uterine endometrial cancer.

The objective of this research is whether the classification of vascular invasion severity can be used as a prognostic factor in cases of uterine endometrial cancer. Sixty-five patients with stage I to III uterine endometrial cancer were included in the study. All patients were seen between 1987 and 1997, and the types of their cancers were histologically confirmed. The degree of vascular invasion was classified according to three different systems: (1). positive or negative; (2). negative, mild, or severe; and (3). negative, mild, moderate, or severe. For each classification, the disease-free survival rate was calculated according to various pathologic factors using the Wilcoxon test; multivariate analyses were performed using the Cox proportional hazard model. Patients with severe vascular invasion showed a significantly lower disease-free survival rate than did patients with moderate or less severe invasion. In the multivariate analysis, severe vascular invasion was shown to be an independent prognostic factor indicating a high relative risk. We conclude that the severity of vascular invasion is an important histopathologic factor in determining the prognosis of uterine endometrial cancer. Vascular invasion classification systems employing three subjective or four objective categories may be more appropriate than a positive/negative classification system for judging the prognosis in cases of uterine endometrial cancer.

Paclitaxel and SN-38 overcome cisplatin resistance of ovarian cancer cell lines by down-regulating the influx and efflux system of cisplatin.

Cisplatin (DDP) is one of the key drugs used to treat patients with ovarian cancer, although resistance to DDP can occur. Paclitaxel and SN-38 (an active metabolite of irinotecan (CPT-11)) are two drugs that are effective in patients with DDP-resistant ovarian cancer. To study how these drugs may overcome the intrinsic and / or acquired resistance of cancer cells to DDP, we investigated the effect of a combination of DDP with paclitaxel and a combination of DDP with SN-38 on three ovarian cancer cell lines, RTSG (intrinsically resistant cell line), KF (DDP-sensitive cell line), and KFra (acquired resistant cell line obtained from KF). We found that these combinations showed additive to synergistic antitumor activity. A time-dependent platinum (Pt) accumulation was observed in the DDP-sensitive KF cell line, while a decrease occurred in the KFra cell line. Little accumulation was observed in RTSG. Intracellular Pt accumulation was increased in all three cell lines by exposure to paclitaxel or SN-38. Ouabain, a Na(+),K(+)-ATPase inhibitor, decreased Pt accumulation in KF and KFra cell lines and inhibited the paclitaxel- and SN-38-induced increases in Pt accumulation in these cell lines. When we assessed the mRNA levels of the multidrug resistance-associated protein (MRP), which may be an efflux pump for DDP, the combination of paclitaxel or SN-38 with DDP down-regulated these levels, which are up-regulated by DDP alone. These results suggest that paclitaxel and SN-38 overcome DDP resistance of ovarian cell lines by controlling intracellular accumulation of DDP via both the influx and efflux systems.

[Dose finding study of paclitaxel and carboplatin for ovarian cancer (JKTB)].

We conducted a dose-finding study for combination therapy of paclitaxel (Taxol; TXL) and carboplatin (Paraplatin; CBDCA). TXL is a novel plant-derived anticancer agent that is a diterpene derivative possessing the taxane ring. The subjects were patients with ovarian carcinoma, who were evaluated by a modified Fibonacci method. The dosage of TXL was 150 to 180 mg/m2. CBDCA was administered by dose escalation from AUC = 4 to 7. The administration schedule was as follows. Pre-medication was administered before TXL was given. TXL was then administered by intravenous infusion over 3 hours, followed by CBDCA. The dose of CBDCA was determined using the Calvert formula: [AUCX (GFR + 25)]. GFR was calculated with the Jelliffe equation. The non-hematological toxicities observed in 15 eligible cases were mainly grade 1, with no grade 3 or above, and no increase in severity was observed with stepping up. The hematological toxicities were grade 3 leukopenia in 5 of 15 cases, neutropenia in 5 cases and thrombocytopenia in 0 cases. No grade 4 toxicity was observed. The lowest counts of leukocytes and neutrophils were reached after 10.8 and 11.7 days, respectively. The toxicities were reversible in most cases with subsequent recovery. The above findings indicate that the recommended dosages for TJ therapy for Japanese ovarian cancer patients should be TXL 180 mg/m2 and CBDCA at a target of AUC = 6.

Effects of coffee cherry, the residue left after removal of the beans from the coffee fruit, on mammary glands, automatic behavior and related parameters in mice.

To clarify the mechanisms of the anti-mammary tumor activity of coffee cherry (CC), the residue left after the removal of beans from the fruit, the effects in SHN mice of CC on plasma and urine component levels, mammary gland growth, spontaneous motor activity and several related parameters were examined. Hot water extract of CC was given to 2-month-old mice in drinking water (0.5%) for 60 days. The treatment prevented the elevation of plasma and urine levels of alanin amino-transferase and asparate aminotransferase, indicating that CC can protect against metabolic abnormality, which is a cause of the high mammary tumor susceptibility of SHN mice. It also resulted in an inhibition of the formation of precancerous mammary hyperplastic alveolar nodules. Neither food and water intake nor spontaneous motor activity was affected by CC. The findings provide novel information on the mechanism of the protective effect of CC on mammary tumorigenesis and confirm the usefulness of CC as a safe chemopreventive agent of mammary and other types of tumors.

Cross-linked hyaluronate hydrogel prevents adhesion formation and reformation in mouse uterine horn model.

The aim of this study was to evaluate the efficacy of cross-linked hyaluronate hydrogel (HA gel) as an adjuvant for postoperative adhesion prevention, in a mouse uterine horn model. In experiment 1 uterine horns were abrased with iodine. HA gel was applied to the injured surface before closure in the treatment group. In experiment 2, after injuring the uterine horns, three stitches were placed at equal distances around the uterine horns to appose the injured medial surfaces of the two horns during healing. HA gel was inserted between the uterine horns in the treatment group. In experiment 3 prevention of adhesion reformation was assessed. After lysis of adhesions that were induced as in experiment 2, HA gel was introduced between the serosal surfaces of apposing uterine horns. Untreated animals served as controls in each experiment. Statistical analysis was carried out using Student's t-test. The adhesion score was significantly lower in the HA gel group on the 14th day compared with controls in all the experiments: in experiment 1, 0.3 +/- 0.4 versus 1.7 +/- 1.2; in experiment 2, 0.9 +/- 1.0 versus 2.6 +/- 0.5; and in experiment 3, 1.5 +/- 0.9 versus 2.2 +/- 0.6 respectively. Cross-linked HA gel significantly reduced de-novo adhesions (P< 0.03) and adhesion reformation (P < 0.03).

Imbalanced expression of TAN-1 and human Notch4 in endometrial cancers.

The development of cancer is a cellular process that reflects and is partly driven by alterations in cell determination. Mutations in various genes responsible for cell determination have been identified as being oncogenic; however, little is known about the involvement of normal cell fate-determining mechanisms in the oncogenic process. The Notch pathway is an evolutionarily conserved, general cell-interaction mechanism that controls fundamental aspects of cell determination during the development of vertebrates and invertebrates. We have explored the roles of the recently cloned human Notch4 gene, which is a homologue of Drosophila Notch, in endometrial tissue, a cellular environment where cell fate changes take place and neoplastic conditions have been characterized. Northern blot analysis, dot blot analysis, and in situ hybridization were performed on samples of normal endometria at different phases of the menstrual cycle and endometrial cancers. Our results showed that: a) Both human Notch4 and translocation-associated Notch homologue-1 (TAN-1), another human homologue of Drosophila Notch, are expressed in the normal endometrium, mainly in the endometrial glandular cells. b) The level of expression of human Notch4, but not TAN-1, changes during the normal menstrual cycle; i.e., the level of Notch4 expression was significantly lower during the secretory phase than during the proliferative phase. c) Endometrial cancers express a significantly lower level of human Notch4 and a significantly higher level of TAN-1 than normal endometria. These results suggest that human Notch4 and/or TAN-1 are involved in the changes of the endometrium during the menstrual cycle, and also in the development of endometrial cancer.

Cisplatin sensitivity of ovarian cancer in the histoculture drug response assay correlates to clinical response to combination chemotherapy with cisplatin, doxorubicin and cyclophosphamide.

The histoculture drug sensitivity assay (HDRA) has been demonstrated to have high predictability for resistance, sensitivity, and survival for gastrointestinal cancer (Clin Cancer Res 1: 305-311, 1995; Clin Cancer Res 1: 1537-1543, 1995). In this report, we evaluated the clinical usefulness of the HDRA in ovarian cancer. HDRA was performed on tumors from patients with ovarian cancer. Eighty-five cases (97%) were evaluable. Tumor fragments were cultured on collagen-sponge gels. The cultures were incubated with cisplatin (CDDP) for seven days. Cell viability were assessed with the MTT end point. The optimal cut off concentration of CDDP was determined to be 25 micrograms/ml by correlation with the historical clinical response rate to CDDP. HDRA results were correlated to clinical response of 15 patients who received CDDP-based therapy that included doxorubicin and cyclophosphamide (CAP therapy). The true positive rate was 88%, the true negative rate was 86%, the sensitivity was 88%, the specificity was 86%, and the accurate prediction rate was 87% when HDRA results were compared to the response of the treated patients. The data suggest that the HDRA is capable of predicting the response to antitumor chemotherapy in patients with ovarian cancer and that measuring response to CDDP can be useful for optimization of CAP chemotherapy for patients with this disease.

Effects of combined treatment with coffee cherry and whole-body hyperthermia on the growth of spontaneous mammary tumours in SHN mice.

Based on findings that free access in drinking water of the extract of coffee cherry (CC), the residue left after the removal of coffee beans, and whole-body hyperthermia (WBH) induced by far-infrared ray (FIR) can markedly inhibit the growth of spontaneous mammary tumours of SHN mice, the effects of the combined treatment with these agents were examined in this study. The significant inhibition of tumour growth by single treatment with either CC or WBH was not enhanced by their combination. Meanwhile, the body weight loss during WBH was significantly decreased by CC. Normal and preneoplastic growth of mammary glands and plasma component levels were affected little by either treatment. The findings confirmed the "normalization effects" of CC usually obtained with natural products and stress the need for prudence in the choice of any agent, natural or synthetic, to be applied simultaneously to increase the efficacy of WBH.

Effects of far-infrared ray on reproduction, growth, behaviour and some physiological parameters in mice.

The effects of chronic exposure to far-infrared ray (FIR) on reproduction, growth, behaviour, survival time and some related parameters were examined in SHN mice. The reproductive parameters differed slightly between the females on the normal racks and those on the FIR racks, which emitted FIR from the ceiling. The age and body weight on the day of vaginal opening was lower in the experimental mice born and maintained on the FIR rack than in the control on the normal rack. In both sexes, the levels of urinary components in the experimental group was significantly higher than the control at 6-7 months of age. Spontaneous motor activity of females during the light and dark phases were higher and lower, respectively, in the experimental group than the control. The survival rate was significantly higher in the experimental group than the control. These findings suggest that FIR has 'normalization effects' on the organisms.

Cervical adenocarcinoma, a novel combination chemotherapy with mitomycin C, etoposide, and cisplatin for advanced or recurrent disease.

We review the cases of 31 patients with stage IVb or recurrent cervical adenocarcinoma who were treated with combination chemotherapy utilizing mitomycin C, etoposide, and cisplatin (MEP). The total response rate was 16.1% (95% confidence intervals (CIs), 5. 5 to 33.7%) with 4 patients having a complete response (CR) and 1 having a partial response. In patients with no prior chemotherapy, the response rate was 26.7% (95% CIs, 7.8 to 55.1%) with 2 of these CR patients surviving over 3 years, 1 a disease-free survival. A marked response was found in distant recurrent lesions. The major toxicity was myelosuppression. Forty-five percent of patients had leukocytopenia above grade 3; thrombocytopenia and anemia were not common. In patients with cervical adenocarcinoma and no prior chemotherapy, there was a moderate response to MEP therapy.

Differences in apoptosis induced by anticancer drugs in sublines (SKG-3a, SKG-3b) from a human uterine cervical epidermoid carcinoma.

SKG-3a and SKG-3b are two distinct human uterine cervical epidermoid carcinoma cell lines derived from a single donor. We studied these two closely related cell lines from the standpoint of drug susceptibility. The growth inhibitory effects of cisplatin (CDDP), doxorubicin (ADM), etoposide (VP-16), and paclitaxel (taxol) on SKG-3a and SKG-3b cells assessed by crystalviolet dye uptake assay were almost the same. SKG-3b cells treated with CDDP, ADM, VP-16, and taxol showed the apoptotic cell death, whereas apoptosis in SKG-3a cells was not induced by these anticancer drugs. Caspase-3 activity was increased only in the SKG-3b cell lysate after treatment with CDDP, ADM, and VP-16 but was not found in the SKG-3a cell lysate. These results indicate that despite growth inhibitory effects of anticancer drugs being almost the same, there may be differences in the common signaling pathways involved in the apoptotic process between SKG-3a and SKG-3b obtained from the same tumor.