Postoperative chemotherapy for node-positive cervical cancer: Results of a multicenter phase II trial (JGOG1067).

OBJECTIVE: This multicenter phase II Japanese Gynecologic Oncology Group study (JGOG1067) was designed to evaluate the efficacy and safety of postoperative chemotherapy in patients with node-positive cervical cancer. METHODS: Patients with stage IB-IIA squamous cervical cancer who underwent radical hysterectomy and were confirmed to have pelvic lymph node metastasis were eligible for this study. The patients postoperatively received irinotecan (CPT-11; 60mg/m2 intravenously on days 1 and 8) and nedaplatin (NDP; 80mg/m2 intravenously on day 1). Chemotherapy administration commenced within 6weeks after surgery and was repeated every 28days for up to 5cycles. The primary endpoint of this study was the 2-year recurrence-free survival (RFS) rate. The secondary endpoints were the 5-year overall survival (OS) rate, 5-year RFS rate, and adverse events such as complications of chemotherapy and lower-limb edema. RESULTS: Sixty-two patients were analyzed according to our protocol, among whom 55 (88.7%) completed 5cycles of scheduled treatment. The median follow-up period was 66.1months (range, 16.8-96.6months). The 2-year and 5-year RFS rates were 87.1% (95% confidence interval [CI]: 75.9-99.3) and 77.2% (95% CI: 64.5-85.8), respectively. Fourteen patients (22.5%) experienced recurrence during the follow-up period, 8 of whom died of the disease. The 5-year OS rate in this study was 86.5% (95% CI: 74.8-93.0). Only 9.7% of the patients experienced lymphedema in their legs. CONCLUSION: Postoperative chemotherapy without radiotherapy was found to be very effective in high-risk patients with node-positive cervical cancer.

Comparison of methods using paraffin-embedded tissues and exfoliated cervical cells to evaluate human papillomavirus genotype attribution.

Monitoring the attribution of human papillomavirus (HPV) genotypes to cervical precancerous lesions is essential in assessing the efficacy of HPV vaccines. To resolve the lack of studies comparing the HPV genotyping procedures used to estimate HPV genotype attribution, we undertook a retrospective cross-sectional study to determine the appropriate genotyping procedures for evaluating the potential efficacy of HPV vaccines. Three procedures, including two different genotyping methods, Clinichip HPV test (C-Chip) and modified GP5+/6+ PCR coupled to fluorescent bead sorter detection (MGP), using exfoliated cervical cells (C-Chip and C-MGP, respectively) or formalin-fixed paraffin-embedded tissues (F-MGP), were compared. The overall agreement in detecting high-risk HPV was 88.5-92.1% among the three procedures, and genotype-specific agreement was 83.9-100% for all pairwise comparisons. In cervical intraepithelial neoplasia grade 2/3 specimens, HPV16/18 attribution estimated with the hierarchical attribution method was consistent among the procedures: 52.3% (45/86) for C-Chip, 54.7% (47/86) for C-MGP, and 52.3% (45/86) for F-MGP (P = 0.81). HPV16/18/31/33/45/52/58 hierarchical attribution was 88.4% (76/86) with C-Chip, 86.0% (74/86) with C-MGP, and 83.7% (72/86) with F-MGP (P = 0.49). In cervical intraepithelial neoplasia grade 3 specimens, the corresponding hierarchical attribution was 96.4% (53/55) with C-Chip, 89.1% (49/55) with C-MGP, and 94.5% (52/55) with F-MGP (P = 0.27). Although F-MGP is theoretically a reliable method for determining HPV genotype attribution, it is acceptable to use C-Chip or C-MGP, coupled to the hierarchical attribution formula to correct the bias of multiple infections. These approaches using exfoliated cervical cells are practical for monitoring the efficacy of HPV vaccines.

Cytological scoring and prognosis of poorly differentiated endometrioid adenocarcinoma.

OBJECTIVE: Histopathological variation has been demonstrated in grade 3 endometrioid adenocarcinomas. We attempted to evaluate the clinicopathological features of grade 3 tumors by endometrial cytological features using a scoring system. STUDY DESIGN: Twenty-one endometrial cytological samples were evaluated using 5 cytological features: rates of cluster formation in tumor cells; nuclear pleomorphism; nuclear dimension; size of nucleoli, and chromatin structure and distribution. The relationships between cytological scores and clinicopathological factors or prognosis were investigated. RESULTS: The median cytological score was 6 (range 4-14); therefore, samples with scores of 4-5 were defined as having low scores, while those with scores of 6-14 were defined as high scores. The accuracy of the cytological diagnosis for grade 3 tumors in the high score group (8/10 patients, 80.0%) was significantly higher than that of the low score group (2/11 patients, 18.2%; p=0.009). Significant relationships between cytological scores and lymph node metastases or positive peritoneal cytology were observed (p=0.03 and 0.035, respectively). The overall survival rate was significantly worse in the high score group (30.0%) than the low score group (88.9%; p=0.02). CONCLUSIONS: Grade 3 endometrioid adenocarcinomas varied in cytological features; according to the scoring system used, high scores were associated with worse clinicopathological factors and poorer prognosis than low scores.

Retrospective comparative study of irinotecan and pegylated liposomal doxorubicin for platinum-resistant or -refractory epithelial ovarian and primary peritoneal carcinoma.

PURPOSE: This study was conducted to retrospectively compare the efficacy and safety of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or -refractory recurrent epithelial ovarian and primary peritoneal carcinoma. METHODS: Nineteen patients who received CPT-11 and eleven patients who received PLD were enrolled. CPT-11 was intravenously administered at a starting dose of 60-100 mg/m(2) on day 1, 8, and 15 every 28 days, and PLD was administered at a starting dose of 40-50 mg/m(2) on day 1 every 28 days. Primary outcomes were overall response rate (complete response [CR] + partial response [PR]), disease control rate (CR + PR + stable disease), and progression-free survival (PFS) in each group. Clinical response was evaluated every two or three cycles using the Response Evaluation Criteria in Solid Tumors criteria; CA125 analysis was not performed. RESULTS: The overall response rate was 21.1 % (PR, four cases) and 0 % (p = 0.10) in the CPT-11 and PLD groups, respectively, and the disease control rate was 73.7 and 45.5 % (p = 0.12), respectively. Median PFS was 25.3 (range 5.4-69.9) weeks and 12.7 (range 4.0-43.1) weeks in the CPT-11 and PLD groups, respectively; however, this difference was not statistically significant (p = 0.064). Major adverse events in the CPT-11 group were neutropenia, nausea, and diarrhea, whereas those in the PLD group included thrombocytopenia, anemia, stomatitis, and hand-foot syndrome. CONCLUSIONS: This retrospective study demonstrated comparable efficacy outcomes for CPT-11 and PLD. The overall response rate, disease control rate, and median PFS were more favorable in the CPT-11 group compared to the PLD group, although the difference was not significant. The adverse event profiles were different between groups. These results suggest that CPT-11 might be a feasible choice as single-agent salvage chemotherapy for platinum-resistant or -refractory recurrent epithelial ovarian and primary peritoneal carcinoma beside established regimen like PLD.

Comparing Injection Site Reactions of Aprepitant and Fosaprepitant in Gynecologic Cancer Chemotherapy.

BACKGROUND/AIM: The frequency rate of injection site reactions (ISR) due to fosaprepitant meglumine (Fos APR) has been shown to vary depending on the types of combined anticancer drug. This study aimed to elucidate the impact of Fos APR on ISR in patients receiving paclitaxel and carboplatin, with and without bevacizumab therapy (TC±Bev). PATIENTS AND METHODS: This study focused on patients with gynecologic cancer (n=93) who received TC±Bev administration at Fujita Health University Hospital from March 2016 to February 2020, and monitored up to six cycles. The patients were randomly assigned to the Fos APR group (n=47) and the Aprepitant (APR) group (n=46). Using Visual Infusion Phlebitis (VIP) scores, ISR was evaluated by comparing the VIP scores of all cycles using a linear mixed model. The risk factors that contribute to the occurrence of vascular pain throughout all cycles were also examined. RESULTS: The VIP scores of all cycles showed a near significant intergroup difference (p=0.071). Factors that affected the development of vascular pain included Fos APR and age (p=0.027 and 0.049, respectively). Regarding age, patients aged <65 years had a higher risk. Four patients underwent a switch from the originally assigned neurokinin-1 receptor antagonist; in all of these cases, Fos APR was changed to APR for vascular pain. CONCLUSION: Fos APR may increase the risk for ISR associated with TC±Bev therapy for gynecological cancer.

The relationship between ERCC1 expression and clinical outcome in patients with FIGO stage I to stage II uterine cervical adenocarcinoma.

OBJECTIVE: Several studies have suggested that excision repair cross-complementation group 1 (ERCC1), a protein involved in nucleotide excision repair, is associated with resistance to platinum agent-based chemotherapy or chemoradiotherapy with platinum agents in various types of cancer. Herein we evaluated ERCC1 protein expression in uterine cervical adenocarcinoma and the relationship between this expression, clinicopathological factors, and clinical outcome, particularly in patients receiving adjuvant cisplatin-based chemotherapy or chemoradiotherapy with cisplatin. METHODS: Thirty-six patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB to stage IIB cervical adenocarcinoma who underwent radical hysterectomy were evaluated. Excision repair cross-complementation group 1 protein expression was examined by immunohistochemistry in tumor tissues. The relationship between ERCC1 expression levels and clinicopathological factors (age, FIGO stage, histological grade, tumor size, vascular invasion, cervical stromal invasion, and lymph node metastases) and prognosis was evaluated. RESULTS: No significant differences between ERCC1 expression levels and clinicopathological factors were observed. The patients in the ERCC1 high-expression group (n = 7) experienced significantly worse disease-free survival than the patients in the ERCC1 low-expression group (n = 29; P = 0.005). Among the 25 patients who received cisplatin-based chemotherapy or chemoradiotherapy with cisplatin, those with high ERCC1 expression (n = 5) also experienced significantly worse disease-free survival than those with low ERCC1 expression (n = 20; P = 0.002). Moreover, univariate and multivariate analyses revealed that high ERCC1 expression was an independent prognostic factor in patients receiving cisplatin-based chemotherapy or chemoradiotherapy with cisplatin. CONCLUSIONS: This is the first analysis of the association between ERCC1 expression and clinical outcomes in patients with uterine cervical adenocarcinoma. High ERCC1 protein expression was revealed to be associated with worse disease-free survival in the patients who received adjuvant cisplatin-based chemotherapy or chemoradiotherapy with cisplatin and was shown to be an independent prognostic factor. Further evaluation with a larger number of patients is required to confirm these preliminary observations.

A case of primary uterine cervical neuroendocrine tumor with meningeal carcinomatosis confirmed by diagnostic imaging and autopsy.

Primary uterine cervical neuroendocrine tumors are rare, but affect relatively young women and the prognosis is poor despite multidisciplinary treatment. The incidence of meningeal carcinomatosis arising from malignant tumors of the uterine cervix is extremely low, only two patients with meningeal carcinomatosis arising from a uterine cervical neuroendocrine tumor have been reported in the English literature. Moreover, there have been no reports in which this was confirmed at autopsy. We encountered a pregnant woman aged 33 years who was diagnosed as having atypical carcinoid of the uterine cervix after radical surgery. Despite multidrug chemotherapy (paclitaxel + etoposide + cisplatin and irinotecan + carboplatin), the patient developed multiple organ metastases. Although there was no metastasis to the brain parenchyma or the spinal cord parenchyma, the patient also developed meningeal carcinomatosis. Whole-brain radiation therapy was performed, but was ineffective. The patient died at 19 months after her initial operation and 10 days after diagnosis of meningeal carcinomatosis. The presence of meningeal carcinomatosis was confirmed at autopsy.

Effects of a selective COX-2 inhibitor in patients with uterine endometrial cancers.

PURPOSE: COX-2 is highly expressed in endometrial cancers, suggesting that a selective COX-2 inhibitor could be valuable for treating endometrial cancers that overexpress COX-2. In this study, we investigated the anti-tumor effects of the selective COX-2 inhibitor etodolac on endometrial cancer patients. METHODS: Etodolac (400 mg, bid, for 2 weeks) was administered preoperatively to 21 endometrial cancer patients who had provided informed consent. Using pre-treatment biopsies and post-treatment surgical specimens, the expression levels of COX-2, Ki-67, p53, p21, p27, and cyclin D1 were evaluated by immunohistochemistry and the apoptotic index (AI) was determined by TUNEL staining. Preoperative biopsies and surgical specimens from 32 patients with endometrial cancer not treated with etodolac served as controls. RESULTS: Surgical specimens from COX-2 positive endometrial cancer patients treated with etodolac had significantly reduced expression levels of COX-2, Ki-67, p53, p21, p27, and cyclin D1 as determined by immunohistochemistry, while AI was not affected. These markers were unchanged for COX-2 negative endometrial cancer patients treated with etodolac and the control group. CONCLUSIONS: The selective COX-2 inhibitor etodolac showed anti-proliferative effects by suppressing COX-2 and cell-cycle regulator protein expression in patients with endometrial cancer positive for COX-2 expression. This study demonstrates that a selective COX-2 inhibitor is a potentially beneficial treatment for COX-2 positive endometrial cancers.

[Treatment outcomes for advanced ovarian cancers with peritoneal dissemination].

PURPOSE: The prognosis of advanced ovarian cancer primarily depends on maximal surgical debulking and chemosensitivity of the tumor. Neo-adjuvant chemotherapy(NAC), maintenance chemotherapy, and interval debulking surgery(IDS)are sometimes used to improve the prognosis of advanced ovarian cancer patients. In this study, we evaluated the outcomes of these therapeutic options in the treatment of FIGO stage III and IV ovarian cancers with intraperitoneal dissemination. METHODS: Fifty patients with FIGO stage IIIc and IV ovarian cancer were evaluated. Progression-free survival(PFS)and overall survival(OS)were compared between different patient groups, including patients who underwent optimal surgery versus suboptimal surgery, patients who received NAC versus those who did not, patients who received 6 cycles of postoperative adjuvant chemotherapy versus those who received more than 7 cycles, and patients who underwent IDS versus those who did not. RESULTS: 1 ) The 5- and 10-year OS rates were 52% and 21%, respectively. 2 ) Patients in the optimal surgery group experienced significantly longer PFS than patients in the suboptimal surgery group(p=0. 04). 3) Although NAC increased the possible rate of optimal surgery from 31. 2% to 66. 7%, no significant differences in PFS or OS were observed between patients who did and did not receive NAC. 4 ) Patients who underwent more than 7 cycles of adjuvant chemotherapy after suboptimal surgery experienced significantly longer OS(p=0. 001)and a tendency toward longer PFS(p=0. 07)compared to patients who received 6 cycles of adjuvant chemotherapy. 5 ) Patients who achieved a complete response(CR)following adjuvant chemotherapy after suboptimal surgery experienced significantly longer PFS(p=0. 001)and OS(p=0. 001) compared to patients who did not obtain CR. Moreover, patients who underwent IDS and who did not obtain a CR after adjuvant chemotherapy tended to experience longer PFS than patients who did not undergo IDS(p=0. 07). CONCLUSIONS: The results of this study are essentially compatible with those of recent randomized controlled trials(RCTs) evaluating NAC, maintenance chemotherapy, and IDS in advanced ovarian cancer. We hope to obtain additional RCT results that will allow improvement of the prognosis of advanced ovarian cancer patients.

Expression of podoplanin in epithelial ovarian carcinomas and its potential as a marker for clear cell adenocarcinoma.

Podoplanin is a 43-kd mucin-type transmembrane glycoprotein that is a candidate marker for the pathologic diagnosis of mesothelioma and lymphatic endothelial cells and lymphangiogenesis. The aim of this study was to investigate podoplanin expression in epithelial ovarian carcinomas. Immunohistochemistry was performed on the paraffin-embedded tissues from 78 patients with epithelial ovarian carcinomas consisting of serous adenocarcinoma (SA), endometrioid adenocarcinoma (EM), mucinous adenocarcinoma (MA), and clear cell adenocarcinoma (CCC) cases. Only 36.8% (7/19) of SA, 33.3% (6/18) of EM, and 15.8% (3/19) of MA cases were positive for podoplanin expression, whereas 54.5% (12/22) of CCC samples were positive. Immunohistochemical scores (mean+/-SD) were 1.2+/-1.5, 1.9+/-2.6, 0.8+/-1.6 and, 3.6+/-4.0 in SA, EM, MA, and CCC, respectively. Podoplanin expression was significantly stronger in CCC than in other histologic types. However, no significant correlation was observed between its expression and FIGO stage, the presence of endometriosis, lymph node metastasis, or recurrence. There was also no correlation between podoplanin expression and overall survival. We confirmed the expression of podoplanin in epithelial ovarian carcinomas, particularly in CCC. Podoplanin might have utility as a marker for CCC in pathologic diagnosis. Further investigation is needed to clarify the relationship between podoplanin expression and the biologic characteristics of CCC.

A case of primary signet-ring cell carcinoma of the cervix containing full genome of human papillomavirus 16.

We herein present a case of primary signet-ring cell carcinoma of the cervix. Pelvic magnetic resonance imaging revealed a 38-mm cervical tumor, and computed tomography revealed no findings suggestive of distal metastasis or other tumor origins. Gastrointestinal endoscopy showed no abnormal findings. Histopathology revealed signet-ring cell-type mucinous adenocarcinoma. By immunohistochemistry, tumor cells were negative for the mammary neoplasm marker, gross cystic disease fluid protein 15 and gastrointestinal neoplasm markers, MUC2, MUC6, and CDX2, but positive for p16. These findings suggested human papillomavirus (HPV)-related adenocarcinoma of the cervix. HPV genotyping assays with exfoliated cervical cells and formalin-fixed paraffin-embedded tissues demonstrated HPV16 positivity, suggesting that the primary origin of the tumor was the cervix. The full HPV16 genome was amplified by polymerase chain reaction from exfoliated cervical cells, and the full-genome sequence was determined by next-generation sequencing. This is the first report of primary signet-ring cell carcinoma of the cervix containing the full HPV16 genome.

Preliminary therapeutic outcomes of using direct oral anticoagulants to treat venous thromboembolism in gynecological cancer patients.

OBJECTIVES: Venous thromboembolism (VTE) is often a problematic complication in patients with gynecological cancer. Despite increasing opportunities to use direct oral anticoagulants (DOACs) to treat VTE, there are no reports on the therapeutic outcomes of DOACs in patients with gynecological cancer; however, there are some studies on cancer patients in general. We retrospectively examined the efficacy and safety of using DOACs to treat VTE in such patients. METHODS: The study cohort comprised 43 patients with gynecological cancer and VTE who received treatment between May 2005 and April 2016. They were divided into two groups: DOACs used (DOAC group, n=21) and only unfractionated heparin (UFH) and warfarin used (standard group, n=22). The rates of improvement and recurrence of VTE and incidence of adverse events were compared between these groups. RESULTS: At 6 months, the VTE of 85% of patients in the DOAC group and of 75% in the standard group had improved (p=0.59). No recurrences of VTE occurred in the DOAC group; where VTE recurred in 12.5% of patients in the standard group. Adverse events occurred in three patients in the DOAC group (15.3%) and one in the standard group (7.7%). Chemotherapy significantly impacted improvement in VTE (p=0.01). CONCLUSIONS: Rates of VTE improvement and of recurrence of VTE and adverse events did not differ significantly between the study groups.

Identification of miRNAs in cervical mucus as a novel diagnostic marker for cervical neoplasia.

microRNAs (miRNAs) play important roles in regulation of gene expression during cervical carcinogenesis. We investigated expression profiles of miRNAs in cervical cancer and its precursor lesions by utilizing cervical mucus. Cervical mucus was collected from 230 patients with a normal cervix, cervical intraepithelial neoplasia (CIN), squamous cell carcinoma (SCC), or adenocarcinoma (AD). The levels of miRNA in the mucus were quantified by miRNA array and real-time reverse-transcriptase polymerase chain reaction (RT-PCR). The performance for detecting diseases was statistically analysed. The expression of miRNAs was further validated in the surgical tissues of enrolled patients. Four miRNAs (miR-126-3p, -20b-5p, -451a, and -144-3p) were significantly up-regulated in SCC and AD compared with normal, and their expression levels correlated with disease severity and high-risk human papillomavirus infection. Receiver operating characteristic curve analyses revealed that the area under the curve values for miR-126-3p, -20b-5p, -451a, and -144-3p were 0.89, 0.90, 0.94, and 0.93, respectively, for SCC plus AD compared with normal, showing high accuracy of cancer detection. Real-time RT-PCR analyses confirmed the expression of these four miRNAs in frozen tissues from cervical cancer. miR-126-3p, -20b-5p, -451a, and -144-3p in cervical mucus are promising biomarkers for cervical cancer and high-grade CINs.

Factors affecting platinum sensitivity in cervical cancer.

The present study aimed to investigate the association between nedaplatin (NDP) sensitivity and the expression of biological factors in cervical cancer. A total of 45 cervical cancer specimens, including 18 pretreatment biopsies and 27 surgical specimens, were used in histoculture drug response assays to determine the chemosensitivity of cervical cancer specimens to NDP. Each specimen was assessed for immunohistochemical expression of Ki-67, p53, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), cleaved caspase-3, cyclooxygenase-2 (COX-2), and excision repair cross-complementation group 1 (ERCC1). The results revealed that low or negative expression of p53, Bcl-2 and COX-2, and high or positive expression of cleaved caspase-3 were significantly correlated with high sensitivity to NDP. However, there were no significant differences in Ki-67, Bax or ERCC1 expression between the low and high sensitivity groups. These findings indicate that sensitivity to platinum may be easily predicted by immunostaining for the detection of these specific factors in pretreatment biopsies or surgical specimens. The expression profiles of these targets may therefore provide additional information for planning individualized chemotherapy in the treatment of cervical cancer.

ERCC1 expression and chemosensitivity in uterine cervical adenocarcinoma cells.

UNLABELLED: BACKGROUD/AIM: We previously demonstrated that high protein expression of excision repair cross-complementation group-1 (ERCC1) was associated with poor disease-free survival in patients who received adjuvant cisplatin-based chemotherapy or chemoradiotherapy with cisplatin, and was shown to be an independent prognostic factor. In the present study, we evaluated ERCC1 expression levels in uterine cervical adenocarcinoma cell lines to assess whether they are affected by treatment with cisplatin with and without 5-fluorouracil (5-FU). MATERIALS AND METHODS: Firstly, half-maximal (50%) inhibitory concentration (IC50) values for cisplatin or 5-FU were calculated in cervical adenocarcinoma, HCA-1, and TCO-2 cell lines by 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, yellow tetrazole (MTT) assay. ERCC1 mRNA and protein levels were investigated by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. Secondly, cisplatin-resistant HCA-1 cells, designated HCA-1R cells were established, and IC50 values for cisplatin and 5-FU were calculated by the MTT assay. ERCC1 mRNA expression levels were investigated using quantitative RT-PCR following treatment with cisplatin with and without 5-FU. RESULTS: HCA-1 and TCO-2 cells exhibited similar sensitivity to cisplatin, and 5-FU, and comparable expression of ERCC1 mRNA and protein levels. HCA-1R cells exhibited two-fold higher resistance to cisplatin and a significantly higher level of ERCC1 mRNA expression compared to native HCA-1 cells. ERCC1 expression was significantly elevated by cisplatin treatment, which was reduced by co-administration of 5-FU in HCA-1, TCO-2 and HCA-1R cells. CONCLUSION: The current study demonstrated an association between ERCC1 expression and sensitivity to cisplatin in cervical adenocarcinoma cells. Co-administration of cisplatin and 5-FU revealed synergistic or additive effects through inhibition of ERCC1 expression in cervical adenocarcinoma cells. Therefore, it is possible that a combination therapy of cisplatin and 5-FU or 5-FU derivatives constitutes an ideal treatment regimen, from the ERCC1 inhibition point of view in cervical adenocarcinoma.

Human epidermal growth factor receptor-2 overexpression and amplification in metastatic and recurrent high grade or type 2 endometrial carcinomas.

INTRODUCTION: Human epidermal growth factor receptor (HER)-2 overexpression or gene amplification is more common in high-grade or type 2 endometrial carcinomas. We assessed the discordance of HER-2 expression between primary and metastatic or recurrent endometrial carcinomas. MATERIALS AND METHODS: Thirty-six primary, along with 14 metastatic and five recurrent tumors (matched to primaries), pathologically confirmed as high-grade or type 2 endometrial carcinomas, were submitted for immunohistochemistry (IHC) for HER-2. Fluorescence in situ hybridization was performed when the tumors showed HER-2 overexpression (≥2+ IHC score). The results of the IHC and fluorescence in situ hybridization assays were compared between the primary and metastatic or recurrent tumors. The relationships between HER-2 expression and clinicopathological factors or prognosis were investigated. RESULTS: HER-2 overexpression and HER-2 amplification (a ratio of HER-2 copies to chromosome 17 [CEP17] copies ≥2.2) were detected in 33.3% (twelve of 36 patients) and 5.6% (two of 36 patients) of primary tumors, respectively. HER-2 overexpression was not associated with clinicopathological factors or prognosis. In 19 tumor specimens obtained from metastatic or recurrent tumors, HER-2 overexpression and HER-2 amplification were detected in 57.9% (eleven patients) and 15.8% (three patients), respectively. HER-2 overexpression tended to predict a worse prognosis. CONCLUSION: HER-2 expression in metastatic or recurrent tumors was more frequent than in matched primary high-grade or type 2 endometrial carcinomas. Trastuzumab in combination with cytotoxic chemotherapy may represent an alternative therapeutic option for these tumors.

Overcoming paclitaxel resistance in uterine endometrial cancer using a COX-2 inhibitor.

Cyclooxygenase (COX)-2 inhibitors have been reported to potentially modulate the resistance of cancer cells to chemotherapeutic drugs by affecting multidrug resistance 1 (MDR1) expression. In the present study, we investigated the association between COX-2 and MDR1 expression in endometrial cancers and evaluated the effects of the COX-2 inhibitor, etodolac, in combination with paclitaxel on paclitaxel-resistant endometrial cancer cells. The relationship between COX-2 and MDR1 mRNA expression was examined by quantitative PCR in 36 endometrial cancer specimens. The paclitaxel-resistant cell line OMC-2P was established from OMC-2 cells. Paclitaxel (1 µg/ml) with or without etodolac (10 µg/ml) was added to OMC-2 and OMC-2P cells, and COX-2 and MDR1 mRNA expression levels were examined. The concentration of prostaglandin E2 (PGE2) in the supernatant of each cell line was examined by enzyme-linked immunosorbent assay. The function of MDR1 was determined by intracellular accumulation of rhodamine 123 using flow cytometry, and the concentration of intracellular paclitaxel was determined by high-performance liquid chromatography. We found a positive relationship between COX-2 and MDR1 mRNA expression in endometrial cancer. Both COX-2 mRNA expression and PGE2 production were elevated in resistant OMC-2P cells when compared to non-resistant OMC-2 cells. Additionally, MDR1 mRNA expression was markedly upregulated in OMC-2P cells. In OMC-2 cells, COX-2 and MDR1 mRNA levels were significantly upregulated by paclitaxel treatment and downregulated by co-administration with etodolac. In OMC-2P cells, COX-2 mRNA expression was also significantly upregulated by paclitaxel treatment and tended to be downregulated by co-administration with etodolac. Moreover, co-administration of paclitaxel and etodolac suppressed the induction of MDR1 mRNA. Rhodamine 123 efflux was increased in OMC-2P cells when compared to the efflux in the OMC-2 cells and was increased in response to paclitaxel treatment. Co-administration of paclitaxel and etodolac in both cell lines resulted in decreased rhodamine 123 efflux. The actual concentration of intracellular paclitaxel in OMC-2P cells was significantly lower than that in OMC-2 cells treated with paclitaxel alone and was significantly increased after co-administration of paclitaxel and etodolac. These findings suggest that paclitaxel resistance may be associated with COX-2 and MDR1 expression in cancer cells. Co-administration of COX-2 inhibitors and paclitaxel may have a key role in modulating or overcoming paclitaxel resistance in endometrial cancers.