Changes in serum D-dimer level and effect of enoxaparin sodium after a cesarean section: a retrospective study.

BACKGROUND: Pregnancy increases the risk of venous thromboembolism (VTE). During pregnancy and a post-cesarean section, an increase in D-dimer levels can be observed. However, to date, the usefulness of the D-dimer level measurement for thrombosis in pregnant women has not been determined. OBJECTS: We aimed to evaluate the changes in D-dimer levels after a cesarean section, the risk factors of high D-dimer levels, and enoxaparin sodium's preventive effects on VTE. METHODS: This retrospective study enrolled 160 pregnant women who underwent a cesarean section. D-dimer levels were measured on postoperative day (POD)1 and POD6. If on POD1, the D-dimer levels were ≥10 µg/mL, enoxaparin sodium was administered until POD7. Regardless of enoxaparin administration, when the D-dimer levels on POD6 were ≥10 µg/mL, lower-limb venous ultrasonography was performed. After a cesarean section, patients were screened for the following: factors causing high D-dimer levels, incidence of deep vein thrombosis (DVT), and need for enoxaparin. RESULTS: The median D-dimer levels on POD1 and POD6 were 7.5 µg/mL (1.1-34.1) and 4.2 µg/mL (0.02-31.4), respectively. Enoxaparin sodium was administered to 56 patients (35%). The D-dimer levels on POD6 decreased more significantly than on POD1. The median D-dimer levels in the enoxaparin administration group significantly dropped from 14.3 (POD1) to 3.9 (POD6) (p<.001). The D-dimer levels on POD1 were higher in patients aged ≥35 years and with a hospitalization history of threatened preterm labor. In addition, on POD6, patients aged ≥35 years and with a high body mass index had high D-levels. Following a multivariate analysis, the elderly represent an independent factor for high D-levels. DVT was not observed. CONCLUSION: When the D-dimer levels on POD1 after a cesarean section are ≥10 µg/mL, enoxaparin reduces D-dimer levels six days after cesarean section. Moreover, patients aged ≥35 years represent an independent factor for high D-levels. These findings should be validated by further studies.

Comparison of Total Laparoscopic Hysterectomy with Abdominal Total Hysterectomy in Patients with Benign Disease: A Retrospective Cohort Study.

BACKGROUND: The present study aimed to determine whether total laparoscopic hysterectomy (TLH) is being implemented safely and appropriately compared with abdominal total hysterectomy (ATH) in our hospital. METHODS: We retrospectively reviewed clinical records of 102 patients who underwent total hysterectomy for benign gynecological disease at Japanese Red Cross Yamaguchi Hospital from January 2017 to August 2018. We examined periods of hospital stay, operation time, blood loss, weight of the uterus, frequency of perioperative complications, and the duration from the first visit to the date of surgery. P < 0.05 was considered to be statistically significant indicated statistical significance. RESULTS: TLH and ATH were performed in 55 (53%) and 47 (46%) cases, respectively. The TLH group had significantly longer total operation time [133 (82-205) min vs. 87 (57-155) min, P < 0.0001], lesser blood loss [5 (5-35) g vs. 100 (10-820) g, P < 0.0001], shorter hospital stay [7 (5-14) days vs. 10 (9-26) days, P < 0.0001], and lighter uterine weight [206 (27-658) g vs. 554 (79-2284) g, P < 0.0001] than the ATH group. The frequency of perioperative complications did not differ between the two groups (3.5% vs. 8.0%, P = 0.4103). CONCLUSION: TLH had a longer operation time and a lesser excised uterine weight, but it had less intraoperative blood loss, shorter hospital stay, and no difference in perioperative complication frequency when compared with ATH.

Clinical Features of Recurrence in Patients Without Residual Tumour in Endometrial Cancer.

BACKGROUND/AIM: Initial treatment of endometrial cancer with surgery and platinum and taxane-based chemotherapy is often successful, but it remains unclear as to whether certain types of the disease relapse. The aim of this study was to identify the clinical features of recurrence in patients without residual tumour in endometrial cancer. PATIENTS AND METHODS: Clinical features, histological type, and time to recurrence were analyzed in 640 endometrial cancer patients without residual tumours. RESULTS: Of 640 patients, 517 were type I and 123 were type II. For type I, early recurrent (ER) disease and late recurrent (LR) disease were noted in 80 and 8 patients, respectively, and 97.5% of ER occurred within 2 years. After recurrence, 76.2% of ER and 50% of LR patients died. In type II, ER and LR were noted in 41 and 1 patients, respectively, and 97.6% of ER occurred within 2 years, of which 75.6% died after recurrence. One LR case died of disease. CONCLUSION: Most patients recurred within 2 years irrespective of clinical stage or type.

Training in the Departments of Urology and Surgery for Gynecologists in Japan.

BACKGROUND: The authors wanted to understand the current situation concerning Japanese obstetricians' and gynecologists' ideas for and against training in other departments. METHODS: We sent questionnaires to obstetrics and gynecology (Ob-Gyn) specialists via a social networking service (SNS) in Japan. They answered anonymously using Google Forms over the internet. RESULTS: The respondents comprised 120 Ob-Gyn specialists, and their age ranges of 28-29, 30-39, 40-49, and 50 or more, were 5.8%, 73.3%, 15.8%, and 5.0%, respectively. Only five Ob-Gyn specialists (4.2%) had experience in other departments, specifically gastrointestinal and urology. Ninety percent of them responded that they thought training in other departments was useful for developing clinical and surgical skills. In addition, 91.0% of respondents thought that surgical knowledge and skills were necessary in the clinical practice of gynecology, while 94% stated training in urology was also necessary. However, 49.2% of respondents answered that they may feel stress training in other departments where there were many issues, including a lack of personnel and difficulties securing cases. CONCLUSION: Many Ob-Gyn specialists think training in other departments is necessary, but potential problems include proper training implementation and stress management for residents. If additional training is enforced, greater flexibility in each facility will be required.

Re-evaluation of Urinary Trypsin Inhibitor on Pregnancy Course in Patients with Threatened Preterm Delivery: A Single-Center Retrospective Study.

BACKGROUND: We evaluated the necessity of urinary trypsin inhibitor for patients with threatened premature labor. METHODS: We enrolled 146 women with singleton pregnancies who were treated for threatened premature labor as inpatients. The uterine cervical length of each patient was ≤ 25 mm at 22-35 weeks of gestation on transvaginal ultrasonography. The patients were divided into two groups: the urinary trypsin inhibitor group (91 patients treated with urinary trypsin inhibitor daily) or non-urinary trypsin inhibitor group (55 patients not treated with urinary trypsin inhibitor). The childbirth outcomes were retrospectively assessed. RESULTS: The median cervical length measured on the day of admission was almost similar between the urinary trypsin inhibitor and non-urinary trypsin inhibitor groups. Depending on the symptoms of uterine contractions, we determined whether ritodrine hydrochloride and/or magnesium sulfate would be appropriate for treatment. The median gestational week at birth was 38 weeks in the urinary trypsin inhibitor group, and no obvious differences were observed when compared with the non-urinary trypsin inhibitor group. With regard to birth weight, no significant difference was found between the two groups (urinary trypsin inhibitor group, 2776 g; non-urinary trypsin inhibitor group, 2800 g). CONCLUSION: Our data showed no significant beneficial effects of urinary trypsin inhibitor in the maternal course and delivery outcomes.

Clinical impact of systematic pelvic and para-aortic lymphadenectomy for pT1 and pT2 ovarian cancer: a retrospective survey by the Sankai Gynecology Study Group.

BACKGROUND: The therapeutic value of systematic lymphadenectomy for early-stage epithelial ovarian cancer (EOC) is controversial. This study evaluates the survival impact and adverse events of systematic pelvic and para-aortic lymphadenectomy in patients with pT1 and pT2 EOC. METHODS: A retrospective investigation was performed using data from patients with pT1 and pT2 EOC at multi-institutions belonging to the Sankai Gynecologic Study Group (SGSG). We selected patients who had undergone systematic pelvic and para-aortic lymphadenectomy (Group LA) (n = 284) and patients who had not undergone lymph node resection (Group no-LA) (n = 138). Outcomes for patients and peri-operative adverse events were compared between the two groups. RESULTS: The median operation time was significantly longer in Group LA (288 min) than in Group no-LA (128 min) (P < 0.0001). Total blood loss was significantly higher in Group LA, 43.7 % of patients receiving blood transfusions. There were no significant differences between the treatment groups for progression-free survival (PFS) or overall survival (OS). However, for patients with pT2, PFS was significantly longer in Group LA than in Group no-LA (P = 0.0150). Lymph node metastases were detected in 23 cases (8.1 %) and these patients had significantly shorter PFS than those without metastasis (P = 0.0409). The outcome for patients who underwent chemotherapy after surgery was significantly improved in the Group no-LA, but no improvement was observed in Group LA. CONCLUSIONS: Systematic lymphadenectomy may improve outcomes only in pT2 EOC patients with acceptable peri-operative events. Furthermore, accurate surgical staging may avoid unnecessary adjuvant chemotherapy in selected early-stage cases.

Lack of AKT activation in lung cancer cells with EGFR mutation is a novel marker of cetuximab sensitivity.

Epidermal growth factor receptor (EGFR) mutation is the best marker of sensitivity to the EGFR tyrosine kinase inhibitor gefitinib, but a marker for the anti-EGFR antibody cetuximab has not been identified in lung cancer. The present study investigated markers for sensitivity to cetuximab. Sensitivity to cetuximab and gefitinib was compared with EGFR expression, EGFR and KRAS mutation, and EGFR gene copy numbers in lung cancer cell lines. We also studied the effect of these agents on the activation of EGFR, ERK, AKT, and STAT3 in cetuximab-sensitive and -resistant cell lines. We found one cetuximab-sensitive cell line with EGFR mutation among 19 lung cancer cell lines. Analysis of molecules downstream from EGFR revealed that AKT phosphorylation was suppressed in this cell line. Augmentation of AKT phosphorylation by transfection of a plasmid induced resistance to cetuximab. Acquisition of cetuximab resistance was associated with AKT activation in this cell line, while pharmacological inhibition of AKT markedly enhanced the growth inhibitory effect of cetuximab. Dephosphorylation of AKT in association with EGFR mutation is a candidate marker for sensitivity to cetuximab, and combined use of an AKT pathway inhibitor with cetuximab could be a novel therapeutic strategy for lung cancer.

Chemotherapy consisting of paclitaxel and carboplatin benefits a patient with malignant mixed müllerian tumor of the fallopian tube.

Malignant mixed müllerian tumors (MMMT) of the fallopian tube are extremely rare, and optimal therapy for them is unknown. A 71-year-old woman presented to us with symptoms of abdominal distension and nausea. A right salpingo-oophorectomy was performed. Pathological examination determined International Federation of Gynecology and Obstetrics (FIGO) stage IIIc MMMT of the right fallopian tube. Of note, multiple tumoral nodules were attached to the sigmoid colon. The patient received three courses of chemotherapy, consisting of 175 mg/m(2) paclitaxel and AUC=5 carboplatin (TC therapy), administered at 3-week intervals. A second, debulking, surgery was then performed, consisting of total abdominal hysterectomy, left salpingo-oophorectomy, and pelvic and paraaortic lymphadenectomy. The tumor attached to the sigmoid colon had shrunk by 60% after chemotherapy. The patient received an additional five courses of adjuvant TC therapy. The patient is alive and free of disease 28 months after the debulking surgery. TC therapy may be effective for MMMT of the fallopian tube.

Detection of peritoneal dissemination in gynecological malignancy: evaluation by diffusion-weighted MR imaging.

The aim of this study is to evaluate the usefulness of diffusion-weighted (DW) magnetic resonance (MR) imaging in detecting peritoneal dissemination in cases of gynecological malignancy. We retrospectively analyzed MR images obtained from 26 consecutive patients with gynecological malignancy. Peritoneal dissemination was histologically diagnosed in 15 of the 26 patients after surgery. We obtained DW images and half-Fourier single-shot turbo-spin-echo images in the abdomen and pelvis, and then generated fusion images. Coronal maximum-intensity-projection images were reconstructed from the axial source images. Reader interpretations were compared with the laparotomy findings in the surgical records. Receiver-operating characteristic (ROC) curves were used to represent the presence of peritoneal dissemination. In addition, the sensitivity and specificity were calculated. DW imaging depicted the tumors in 14 of 15 patients with peritoneal dissemination as abnormal signal intensity. ROC analysis yielded Az values of 0.974 and 0.932 for the two reviewers. The mean sensitivity and specificity were 90 and 95.5%. DW imaging plays an important role in the diagnosis and therapeutic management of patients with gynecological malignancy.

Simultaneous inhibition of the mitogen-activated protein kinase kinase and phosphatidylinositol 3'-kinase pathways enhances sensitivity to paclitaxel in ovarian carcinoma.

Paclitaxel (PTX), one of the key drugs used to treat ovarian cancer, activates the Raf-mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3'-kinase (PI3K) pathways, both considered to be proliferation and cell-survival pathways. The present study aimed to clarify whether and how MEK and PI3K inhibitors affect sensitivity to PTX in ovarian cancer cells. We treated five ovarian cancer cell lines using PTX combined with MEK inhibitor (PD98059 [PD]) and PI3K inhibitor (LY294002 [LY]), then assessed cell viability, apoptosis, and expression of phosphorylated (p) MEK and pAkt. We also investigated the effect of combined treatment on survival in a xenograft model. The protein expression levels of MEK, pMEK, Akt, and pAkt were confirmed in all cell lines. pMEK levels increased after PTX treatment in all five ovarian cancer cell lines. Combining PTX with either PD or LY had an additive effect on cell-growth inhibition. In contrast, we observed a synergistic effect when PTX was combined with both PD and LY. The number of apoptotic cells was significantly higher after treatment with PTX combined with PD and LY, compared with PTX alone or PTX with either PD or LY (P < 0.05). PD with PTX downregulated the protein expression level of pMEK and upregulated pAkt in all five cell lines. Treating nude mice with PTX and PD and LY prolonged survival in an ovarian cancer xenograft model (P < 0.005). These results indicate that further study is warranted for PTX combined with MEK inhibitor and PI3K inhibitor to treat ovarian carcinoma.

A diagnostic evaluation of serum human telomerase reverse transcriptase mRNA as a novel tumor marker for gynecologic malignancies.

Human telomerase reverse transcriptase (hTERT) and epidermal growth factor receptor (EGFR) play an important role in many cancers including gynecological cancers. We previously reported the usefulness of a quantitative highly sensitive detection method for hTERT mRNA in the serum of cancer patients. By this method, we attempted to elucidate the diagnostic evaluation of serum hTERT mRNA for gynecologic malignancies. In 174 female patients with gynecological lesions (47 with ovarian lesions, 63 with uterine lesions, 2 with malignancies in other gynecological lesions, and 62 benign lesions) and 20 healthy individuals, we measured serum hTERT mRNA and EGFR mRNA by using the newly developed real-time quantitative RT-PCR. We examined their sensitivity and specificity in cancer diagnosis, clinical significance in comparison with conventional tumor markers, and their correlations with the clinical parameters by using multivariate analyses. Serum hTERT mRNA showed higher values in patients with gynecologic cancers than in those with benign diseases and healthy individuals. The hTERT mRNA level independently correlated with the presence of cancers (P=0.004 for both ovarian and uterine cancer) and clinical stage (P<0.001). The sensitivity and specificity of hTERT mRNA in cancer diagnosis was 74.4% and 74.1%, respectively. The hTERT mRNA level showed a significant correlation with CA125 by Pearson's relative test (P=0.035) and with histological findings in ovarian cancer by the Friedman test (P<0.004). EGFR mRNA did not display any differences between the diseases. hTERT mRNA is useful for diagnosing gynecologic cancer and is superior to conventional tumor markers. Therefore, serum hTERT mRNA is a novel and available biomarker for gynecologic malignancies.

Adenovirus type 5 E1A gene therapy for ovarian clear cell carcinoma: a potential treatment strategy.

Resistance of ovarian clear cell carcinoma (CCC) to platinum-based chemotherapy is associated with poor prognosis, and an effective treatment for advanced disease is urgently needed. HER2/neu is up-regulated more often in CCC than in other histologic types of epithelial ovarian cancer. The purpose of this study was to assess possible treatment for ovarian CCC with the anti-HER2 antibody trastuzumab or human adenovirus type 5 E1A. We treated 10 CCC cell lines with trastuzumab or E1A and assessed cell viability, proliferation, and colony formation and the expression of HER2 and wild-type p53 proteins and molecules downstream of those signaling pathways. HER2 protein was detected at various levels in all 10 cell lines by Western blotting and in 5 CCC cell lines by immunohistochemical staining; HER2 gene amplification was detected (by fluorescence in situ hybridization) in only one cell line (RMG-I). Trastuzumab did not inhibit proliferation in any of the four CCC cell lines tested (RMG-I, SKOV-2, OVTOKO, and OVSAYO). However, transfection with E1A (as compared with control vectors) reduced colony formation in all 10 CCC cell lines regardless of HER2 expression level. Infection of RMG-I and SMOV-2 cells with an adenoviral vector encoding E1A led to significant (P < 0.05) suppression of proliferation and enhancement of cell death; this effect required stabilization of p53 (but not p73) protein and was associated with the up-regulation of Bax and the cleavage of caspase-9. Other mechanisms, such as p53-independent apoptosis, may also be involved in E1A-mediated cell death in CCC. Finally, treatment with E1A prolonged survival in a CCC xenograft model (P < 0.001). E1A gene therapy, because of its ability to stabilize wild-type p53, is worth exploring as a treatment modality for women with ovarian CCC, which typically expresses wild-type p53.

Feasibility study comparing docetaxel-cisplatin versus docetaxel-carboplatin as first-line chemotherapy for ovarian cancer.

OBJECTIVE: To determine the feasibility of docetaxel-cisplatin combination therapy compared with docetaxel-carboplatin combination therapy as first-line chemotherapy for patients with ovarian cancer. METHODS: Fifty patients with International Federation of Gynecology and Obstetrics stage Ic-IV ovarian cancer who underwent primary surgery were randomly assigned to receive treatment with docetaxel-cisplatin (n = 23) or docetaxel-carboplatin (n = 27). Docetaxel 70 mg/m2 and cisplatin 60 mg/m2 or carboplatin to an area under the curve of 5 were administered consecutively on Day 1 of a 3-week cycle, for 3 cycles in patients with stage Ic-II cancer and for over 5 cycles in patients with stage III-IV cancer. Patients were evaluated for treatment-related toxicity in each cycle using the National Cancer Institute Common Toxicity Criteria version 2.0. RESULTS: Five patients (2 in the docetaxel-cisplatin arm and 3 in the docetaxel-carboplatin arm) discontinued the treatment at the end of the second course of chemotherapy because of apparent disease progression; however, no patients came off the protocol therapy because of treatment-related toxicity. Overall, 103 cycles of docetaxel-cisplatin treatment and 130 cycles of docetaxel-carboplatin treatment were delivered. The major toxicity was neutropenia in both regimens. The total incidence of grades 3 and 4 neutropenia was 83% (19/23) in the docetaxel-cisplatin arm and 96% (26/27) in the docetaxel-carboplatin arm. The incidence of grade 4 neutropenia was significantly lower in the docetaxel-cisplatin arm [39% (9/23) versus 74% (20/27)]. CONCLUSION: Docetaxel-cisplatin combination therapy may be feasible as first-line chemotherapy for patients with ovarian cancer.

PTEN is involved in the signal transduction pathway of contact inhibition in endometrial cells.

PTEN is involved in the regulation of normal cellular functions in addition to its well-known role as a tumor suppressor. In the present study, we have shown that stable transfection of the PTEN gene into PTEN-mutated endometrial carcinoma cells leads to contact inhibition accompanied by a decreased level of phosphorylated-Akt (p-Akt) expression, an increase in p27(Kip1), and a decrease in beta-catenin. PTEN-induced cells with contact inhibition exhibit G0-G1 cell-cycle arrest, and the Ki-67 labeling index is reduced. These changes are canceled by transfection of a double-stranded short-interfering RNA against the PTEN gene. Normal endometrial stromal cells increase their PTEN expression when reaching confluence; this is followed by changes in the expression of Akt-related proteins in the same way as in tumor cells. These results indicate that PTEN, p-Akt, p27, and beta-catenin are involved in the signal transduction of contact inhibition and suggest that PTEN may, in part, control the proliferation of endometrial carcinoma cells through the induction of contact inhibition.

PTEN-positive and phosphorylated-Akt-negative expression is a predictor of survival for patients with advanced endometrial carcinoma.

PTEN and the PI3K/Akt pathway are involved in the development and/or progression of endometrial carcinoma. To clarify the impact of the pathway-related molecules on prognosis, we analyzed PTEN, phosphorylated-Akt (p-Akt), and Ki-67 expression by immunohistochemistry in 99 patients with advanced endometrial carcinoma. PTEN-negative or PTEN-mixed staining was found in 66% of tumors. Positive staining of p-Akt was found in 40% of tumors. Loss of PTEN expression (negative or mixed) was significantly associated with positive p-Akt expression. The patients with PTEN-positive and p-Akt-negative expression clearly showed a higher survival rate than patients in the other groups. Subsequent multivariate analysis revealed that the combination of PTEN/Akt expression was an independent prognostic factor. Examining the relationship between p-Akt expression and Ki-67 labeling index (LI), we found that negative p-Akt was related to a decrease in Ki-67 LI. Additionally, the patients with low Ki-67 LI, as determined by p-Akt-expression status, had a better prognosis. In the present study, we demonstrated that PTEN-positive and p-Akt-negative expression was a predictor of survival for patients with advanced endometrial carcinoma. This study suggests the clinical significance of PTEN and p-Akt expression analysis in treatment decisions for patients with advanced endometrial carcinoma.

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.

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.

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.

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.