Haruo Kuroboshi

Neoadjuvant weekly carboplatin and paclitaxel followed by radical hysterectomy for locally advanced cervical cancer: long-term results.

Introduction: To determine the long-term effect of neoadjuvant chemotherapy with paclitaxel and carboplatin on a weekly schedule followed by radical surgery for patients with locally advanced cervical cancer. Materials and Methods: Thirty patients with stage IB2 to IIIB uterine cervical cancer were treated with paclitaxel (60 mg/m2) and carboplatin (area under the curve, 2-an area under the time-concentration curve of 2 mg × min/mL based on creatinine clearance) every week for 6 cycles. A radical hysterectomy was performed 6 days after the final administration of neoadjuvant chemotherapy. The patients were followed up, and 5-year progression-free survival (PFS) and overall survival (OS) were evaluated. Results: Of 30 patients, 28 were followed up. The median follow-up period was 55.6 months (range, 26-83 months). An objective response (complete response + partial response) to the treatment was observed in 26 patients (87%; 95% confidence interval, 70%-95%). Two had complete response, 4 had stable disease, and the remaining patients had partial response; progressive disease was not seen in this study. A radical hysterectomy was performed in 28 patients without delay. Thirteen patients with high-risk factors received radiotherapy after surgery. The 5-year PFS and OS rates were 78.6% and 81.8%, respectively. The 5-year PFS and OS for patients with stage IB2 to IIB cervical cancer were 79.2% and 83.1%, respectively, which were comparable with those in the concurrent chemoradiation therapy study previously reported. There was no significant correlation in survival between preoperative staging and cell type, whereas larger initial tumor size and lymph node metastasis tended to be negatively correlated with survival. Conclusions: Neoadjuvant chemotherapy with paclitaxel and carboplatin on a weekly schedule followed by radical surgery for patients with locally advanced cervical cancer is a promising mode of therapy that may improve the prognosis. It would be worthwhile to conduct larger-scale trials for comparison with the results of the chemoradiation therapy study.

Estrogen-related receptor α expression and function are associated with vascular endothelial growth factor in human cervical cancer.

Introduction: Estrogen-related receptor &agr; (ERR&agr;), one of orphan nuclear receptors with an unknown ligand, is expressed in various types of cancer. Increased ERR&agr; levels are associated with a higher risk of recurrence and poor clinical outcome in breast cancer, suggesting that ERR&agr; could be a negative prognostic factor. Recently, it has been suggested that vascular endothelial growth factor (VEGF) could be one of the transcriptional targets of ERR&agr; in breast cancer. Here, we examined the expression of ERR&agr; and the association of ERR&agr; with VEGF in uterine cervical cancer cells and tissues. Methods: We evaluated the expression of ERR&agr; and VEGF by immunohistologic analysis using specimens from 40 patients with invasive cervical cancer. We also evaluated the VEGF promoter activity of ERR&agr; in cervical cancer cell lines by transfection and luciferase assay. We overexpressed or knocked down ERR&agr; and examined VEGF expression by real-time polymerase chain reaction. Finally, cell proliferation assay was performed to examine whether ERR&agr; affects tumor growth in cervical cancer. Results: Immunohistologic analysis demonstrated that ERR&agr; expression in cervical cancer tissues was higher than that in noncancerous tissues and that there was a positive association between ERR&agr; and VEGF expression in cancer tissues (P < 0.05). We showed that ERR&agr; stimulated the VEGF promoter activity in cervical cancer cell lines. We further showed the overexpression and knockdown of ERR&agr;-regulated VEGF expression level by real-time polymerase chain reaction. Moreover, we showed that ERR&agr; and VEGF knockdown by small interfering RNA or an inverse agonist of ERR&agr;, XCT 790, could suppress cell growth compared with control cells in cervical cancer. Conclusions: We have provided compelling evidence that ERR&agr; affects VEGF expression and tumor growth in cervical cancer. These results justify further investigation into the use of ERR&agr; as a therapeutic target for patients with uterine cervical cancer.

A pilot study of docetaxel-carboplatin versus paclitaxel-carboplatin in Japanese patients with epithelial ovarian cancer

BackgroundIt has been reported that a docetaxel-carboplatin combination as first-line chemotherapy for ovarian cancer showed a level of progression-free survival similar to that of paclitaxel-carboplatin while reducing neurotoxicity and improving quality of life. We investigated the recommended doses of docetaxel-carboplatin in Japanese patients with ovarian cancer and conducted a comparative study of docetaxel-carboplatin versus paclitaxel-carboplatin.MethodsThirty-nine patients with ovarian cancer were enrolled in this study and 38 patients were evaluated. We conducted a dose-escalation study using a docetaxel dose of 70 mg/m2 and carboplatin AUC 5 and 6. In the comparative study, patients received either docetaxel 70 mg/m2 and carboplatin AUC 5 or paclitaxel 175 mg/m2 and carboplatin AUC 5. Progression-free survival, survival rate at 2 years, response rate, toxicity, and quality of life were investigated.ResultsIn the dose-finding study, we determined the recommended doses as docetaxel 70 mg/m2 and carboplatin AUC 5. In the comparative study, the two arms showed similar progression-free survival. Grade 4 neutropenia occurred more frequently in the docetaxel-carboplatin group (84.6%) than in the paclitaxel-carboplatin group (43.8%), while sensory neurotoxicity was less frequent in the docetaxel-carboplatin group (53.8%) than in the paclitaxel-carboplatin (68.8%) group. There were significant differences in the quality-of-life data in favor of docetaxel-carboplatin.ConclusionWe determined the recommended doses of docetaxel-carboplatin for Japanese patients with ovarian cancer to be docetaxel 70 mg/m2 and carboplatin AUC 5. In the comparative study, we suggest that the docetaxel-carboplatin combination is effective and well tolerated as first-line chemotherapy for Japanese patients with ovarian cancer.

Interferon regulatory factor-1 expression in human uterine endometrial carcinoma

OBJECTIVES The objective was to investigate the expression of interferon regulatory factors 1 (IRF-1) in human uterine endometrial carcinoma. METHODS Formalin-fixed, paraffin-embedded, archival tissue specimens from 76 human endometrial carcinomas and stained with polyclonal anti-IRF-1 antibody, using immunohistochemistry, localization, and immunostaining, were evaluated quantitatively using the H score together with 30 normal endometrium and 16 postmenopausal endometrium. RESULTS The expression of IRF-1 was highest in normal endometrium, and decreased with the grade of endometrioid adenocarcinoma from grade 1 to grade 3. Postmenopausal endometrium was virtually unstained. CONCLUSIONS Expression of IRF-1 is altered in human endometrioid adenocarcinoma compared with normal endometrium and postmenopausal endometrium. The loss of IRF-1 expression does not contradict with the tumor-suppressor function. The intensity of IRF-1 expression in each grade of endometrioid adenocarcinoma could be useful prognostic and therapeutic indicators.

Estrogen-related receptor-γ regulates estrogen receptor-α responsiveness in uterine endometrial cancer.

Objective Estrogen-related receptors (ERRs) are orphan nuclear receptors that modulate the estrogen receptor (ER)-mediated pathway and play roles in the regulation of breast and prostate cancer cell growth. However, the significance of the localization and the function of ERRs in uterine endometrial cancer remain unclear. We aimed to measure the expression of ERR&ggr; and determine its association with the ER-mediated pathway in human endometrial cancer. Methods Proliferation, luciferase, and quantitative polymerase chain reaction assays were performed in ER&agr;-positive (Ishikawa) and ER&agr;-negative (HEC1A) endometrial cancer cell lines. The association between ERR&ggr; and ER&agr; expressions was determined by immunohistochemical analysis in uterine endometrial cancer tissues. Results Estrogen-induced estrogen response element transcriptional activity was repressed by ERR&ggr; in ER&agr;-positive cells but was stimulated by ERR&ggr; in ER&agr;-negative cells. The stable overexpression of ERR&ggr; regulated the in vitro cell growth in the ER&agr;-positive and ER&agr;-negative endometrial cancer cell lines. A selective ERR&ggr; agonist, DY131, inhibited the growth of the ER&agr;-positive endometrial cancer cells but promoted that of the ER&agr;-negative cancer cells. Furthermore, we found that ERR&ggr; is expressed in the nuclei of human uterine endometrial cancer tissues. Estrogen-related receptor &ggr; was not associated with pathological parameters such as the International Federation of Gynecology and Obstetrics stage and histological type. The uterine endometrial cancer tissues with ERR&ggr;-positive/ER&agr;-negative status may have a significantly poor prognosis. Conclusions The relationship between ERR&ggr; and ER&agr; status could be a predictive marker for the treatment of uterine endometrial cancer, which provides an impetus for the identification of ligands for nuclear orphan receptor ERR&ggr;.

(18)F-fluorodeoxyglucose positron emission tomography/computed tomography-positive lymph node endometriosis masquerading as lymph node metastasis of a malignant tumor.

Endometriosis is defined as the presence of endometrium-like tissues at extrauterine sites, most commonly in the abdominal cavity. Lymph node endometriosis is a rare but clinically important type of endometriosis that can mimic lymph node metastasis of a malignant tumor. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is a useful tool for diagnosing malignant tumors, although it occasionally shows false positive results in tissues with high metabolic activity caused by severe inflammation. In the present report, we describe a case of lymph node endometriosis that mimicked lymph node metastasis of a malignant tumor and showed a positive result on 18F-FDG PET/CT. The findings of the present case suggest that lymph node endometriosis could present as swollen lymph nodes with 18F-FDG PET/CT-positive results and provide important information for determining an appropriate treatment strategy.